Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([NH:5]C(=O)OC(C)(C)C)[CH2:2]1.Cl[C:14]1[CH:23]=[CH:22][C:21]2[C:20]([C:24]([NH:26][CH2:27][CH:28]3[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]3)=[O:25])=[C:19]([Cl:34])[CH:18]=[CH:17][C:16]=2[N:15]=1.C(N(CC)CC)C>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(#N)C>[NH3:1].[NH2:5][CH:3]1[CH2:2][N:1]([C:14]2[CH:23]=[CH:22][C:21]3[C:20]([C:24]([NH:26][CH2:27][CH:28]4[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]4)=[O:25])=[C:19]([Cl:34])[CH:18]=[CH:17][C:16]=3[N:15]=2)[CH2:4]1
Reactant: O=C(NCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: CC(C)(C)OC(=O)NC1CNC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N
Product: NC1CN(c2ccc3c(C(=O)NCC4CCCCC4)c(Cl)ccc3n2)C1
Temperature: 120 °C
Reaction time: 1 h
Yield: 32.3 %
Yield: 10 %

Procedure:
3-Azetidinyl-carbamic acid, 1,1-dimethylethyl ester (0.5 g) was added to 2,6-dichloro-N-(cyclohexylmethyl)quinoline-5-carboxamide (Example 43(a)) (0.28 g), tetra-butylammonium bromide (0.28 g) and triethylamine (0.5 mL) in acetonitrile (4 mL). The reaction mixture was heated at 120° C. in a microwave for 1 hour, concentrated under reduced pressure and purified (SiO2, methanol:dichloromethane 4:96 as eluant). The residue (0.24 g) was dissolved in dichloromethane and trifluoroacetic acid (1 mL) added. The reaction mixture was stirred at room temperature for 1 hour, concentrated and then treated with 7M ammonia in methanol. Purification (Varian SCX cartridge using methanol and then 10% ammonia in methanol) gave the sub-titled compound as a solid (0.1 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=1.[C:11]([O:15][C:16]([N:18]1[CH2:23][C@@H:22]([CH3:24])[NH:21][CH2:20][C@@H:19]1[CH3:25])=[O:17])([CH3:14])([CH3:13])[CH3:12].C(=O)([O-])[O-].[K+].[K+].CS(C)=O>>[C:11]([O:15][C:16]([N:18]1[CH2:23][C@@H:22]([CH3:24])[N:21]([C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][N:3]=2)[CH2:20][C@@H:19]1[CH3:25])=[O:17])([CH3:14])([CH3:12])[CH3:13]
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)[C@@H](C)CN1c1ccc([N+](=O)[O-])cn1
Yield: 81.4 %

Procedure:
A mixture of 2-chloro-5-nitropyridine (1.0 g, 6.3 mmol), (2S,5R)-2,5-dimethyl-piperazine-1-carboxylic acid tert-butyl ester (1.4 g, 6.3 mmol), and potassium carbonate (1.7 g, 13 mmol) was stirred in DMSO (5.0 mL, 70 mmol) at 100° C. overnight. The reaction mixture was filtered thru a silica gel pad, which was washed with EtOAc (200 mL). The filtrate was washed with water (2×10 mL), concentrated, and purified by silica gel chromatography (eluted with ethyl acetate/hexane=0 to 80%) to give the title intermediate (1.724 g, 81% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].Cl[CH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:11][CH2:12][C:13]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:16][C:17]=2[CH3:18])=[N:9][CH:10]=1.[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][NH:30][N:29]=1)[CH3:26].O>CN(C)C=O>[CH2:25]([O:27][C:28]1[C:32]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:31][N:30]([CH2:4][C:5]2[CH:10]=[N:9][C:8]([O:11][CH2:12][C:13]3[N:14]=[C:15]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)[O:16][C:17]=3[CH3:18])=[CH:7][CH:6]=2)[N:29]=1)[CH3:26]
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cn1
Reactant: CCOC(=O)Cc1c[nH]nc1OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1cn(Cc2ccc(OCc3nc(-c4ccccc4)oc3C)nc2)nc1OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.9 %

Procedure:
Sodium hydride (60%, oily, 70.0 mg) was added to a solution of 5-chloromethyl-2-(5-methyl-2-phenyl-4-oxazolylmethoxy)pyridine (551 mg), ethyl 3-ethoxy-1H-pyrazol-4-ylacetate (347 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water, and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), and concentrated. The residue was subjected to silica gel column chromatography to obtain ethyl 3-ethoxy-1-[6-(5-methyl-2-phenyl-4-oxazolylmethoxy)-3-pyridylmethyl]-1H-pyrazol-4-ylacetate (608 mg, yield: 73%) as a colorless oily substance from the fraction eluted with ethyl acetate-hexane (1:1, volume ratio).
Reaction SMILES: [CH:1]1([N:4]([CH:12]([C:14]2[CH:23]=[C:22]([OH:24])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:13])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH2:3][CH2:2]1.[C:25](=O)([O-])[O-].[K+].[K+].CN(C)C=O.CI>O>[CH:1]1([N:4]([CH:12]([C:14]2[CH:23]=[C:22]([O:24][CH3:25])[C:21]3[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:15]=2)[CH3:13])[C:5](=[O:11])[O:6][C:7]([CH3:9])([CH3:10])[CH3:8])[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CC(c1cc(O)c2ccccc2c1)N(C(=O)OC(C)(C)C)C1CC1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COc1cc(C(C)N(C(=O)OC(C)(C)C)C2CC2)cc2ccccc12
Yield: 73.6 %

Procedure:
To a mixture of tert-butyl cyclopropyl[1-(4-hydroxy2-naphthyl)ethyl]carbamate (43 mg) and potassium carbonate (27 mg) was added N,N-dimethylformamide (2.0 mL), and then thereto added methyl iodide (0.016 mL), and the mixture was stirred at room temperature for 4 hours. After cooling, to the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was sequentially washed with water twice and saturated saline, dried over sodium sulfate, and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: n-hexane/ethyl acetate=10/1→4/1) to give tert-butyl cyclopropyl[1-(4-methoxy-2-naphthyl)ethyl]carbamate [REx(4-1)] (33 mg) as a colorless oil.
Reaction SMILES: [OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-])=O)=[CH:7][CH:6]=1.[H][H]>C(OCC)(=O)C.[Pd]>[OH:1][CH:2]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[CH:7][CH:6]=1
Reactant: [H][H]
Reactant: CCCCCCCCC(O)COc1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CCCCCCCCC(O)COc1ccc(N)cc1

Procedure:
4-(2-hydroxy-1-decyloxy)nitrobenzene (20 g, 0.68 mol) was dissolved in ethyl acetate (200 mL) and 10% palladium on carbon (2.5 g) was added to a Parr pressure bottle. The contents were then hydrogenated at 50 psi until hydrogen uptake ceased. The catalyst was removed by suction filtration through a pad of Celite. Removal of solvent afforded 4-(2-hydroxy-1-decyloxy)aniline in quantitative yield (18.0 g, 0.68 mol, 100% yield) as a tan solid.
Reaction SMILES: Cl[C:2]1[C:7]([F:8])=[C:6]([Cl:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>C1COCC1.CCOC(C)=O>[Cl:9][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)[C:7]=1[F:8]
Reactant: Cc1nc(Cl)c(F)c(Cl)n1
Reactant: CNCCc1ccncc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1nc(Cl)c(F)c(N(C)CCc2ccncc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
4,6-Dichloro-5-fluoro-2-methylpyrimidine (280 mg, 1.54 mmol) was dissolved in 5 mL of THF and stirred at room temperature. Methyl[2-(4-pyridinyl)ethyl]amine (210 mg, 1.54 mmol) was added, followed by triethylamine (240 μL, 1.69 mmol). The resulting reaction mixture was stirred overnight. The reaction was diluted with EtOAc, washed with brine, was dried (sodium sulfate) and was evaporated to provide 6-chloro-5-fluoro-N,2-dimethyl-N-[2-(4-pyridinyl)ethyl]-4-pyrimidinamine (350 mg, 81%) that was used without further purification. LCMS: (M+H)+: 281.1.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH2:20]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].FC(F)(F)C(O)=O>ClCCl.CO>[NH2:1][C:2]([NH:4][C:5]1[S:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[N:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2-c2cc(C(N)=O)c(NC(N)=O)s2)CC1
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NC(=O)Nc1sc(-c2ccccc2N2CCNCC2)cc1C(N)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 40.3 %

Procedure:
2-[(Aminocarbonyl)amino]-5-[2-(4-t-butyloxycarbonylpiperazin-1-yl)phenyl]thiophene-3-carboxamide (64 mg) was stirred in dichloromethane (4 ml). Trifluoroacetic acid (1 ml) was added and the solution was stirred at room temperature for 1 h. The volatile materials were removed in vacuo; the residue was diluted with water (2 ml) and basified with a few drops of aqueous ammonia. The precipitated product was collected by filtration and washed with water. The gummy solid obtained was dissolved in methanol, the solvent was evaporated and the residue triturated with a mixture of methanol and ether and then filtered to give the product as an off-white solid (20 mg).
Reaction SMILES: [NH:1]([C:3]1[N:8]([CH2:9][CH:10]([CH3:12])[CH3:11])[C:7](=[O:13])[N:6]([CH3:14])[C:5](=[O:15])[CH:4]=1)[NH2:2].[CH3:16][C:17]1[CH:18]=[C:19]2[C:23](=[CH:24][CH:25]=1)[NH:22][CH:21]=[C:20]2[CH:26]=O.[CH:28]([C:30]1[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=1)=O>>[CH2:9]([N:8]1[C:3]2=[N:1][N:2]([CH2:26][C:20]3[C:19]4[C:23](=[CH:24][CH:25]=[C:17]([CH3:16])[CH:18]=4)[NH:22][CH:21]=3)[C:28]([C:30]3[N:34]([CH3:35])[CH:33]=[C:32]([C:36]([O:38][CH3:39])=[O:37])[CH:31]=3)=[C:4]2[C:5](=[O:15])[N:6]([CH3:14])[C:7]1=[O:13])[CH:10]([CH3:11])[CH3:12]
Reactant: CC(C)Cn1c(NN)cc(=O)n(C)c1=O
Reactant: Cc1ccc2[nH]cc(C=O)c2c1
Reactant: COC(=O)c1cc(C=O)n(C)c1
Product: COC(=O)c1cc(-c2c3c(=O)n(C)c(=O)n(CC(C)C)c3nn2Cc2c[nH]c3ccc(C)cc23)n(C)c1

Procedure:
This compound was made following the procedure described above, starting with 6-hydrazino-1-isobutyl-3-methylpyrimidine-2,4(1H,3H)-dione, and condensing first with 5-methyl-1H-indole-3-carbaldehyde, followed by methyl 5-formyl-1-methyl-1H-pyrrole-3-carboxylate. Mass: 503.20 (M+H).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([C:15]#N)[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2].O.[PH2]([O-])=[O:20].[Na+]>O.N1C=CC=CC=1.C(O)(=O)C.[Ni]>[CH2:1]([O:3][C:4](=[O:17])[CH2:5][C:6]1[N:10]2[CH:11]=[C:12]([CH:15]=[O:20])[CH:13]=[CH:14][C:9]2=[N:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1cnc2ccc(C#N)cn12
Reactant: O=[PH2][O-]
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Solvent: c1ccncc1
Product: CCOC(=O)Cc1cnc2ccc(C=O)cn12
Temperature: 75 °C
Yield: 44.4 %

Procedure:
(6-Cyano-imidazo[1,2-a]pyridin-3-yl)-acetic acid ethyl ester (1.80 g, 7.46 mmol) is dissolved in a mixture of water (5.0 ml), pyridine (10 ml) and glacial acetic acid (5.0 ml). Sodium hypophosphite monohydrate (6.03 g, 56.4 mmol, 8 equiv) and Raney nickel (approx. 1.2 g) are added at room temperature. The reaction mixture is heated to 75° C. for 1 h, cooled to room temperature and filtered through Celite. The filtrate is extracted three times with EtOAc. The combined organic layers are washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification of the residue via flash chromatography (cylcohexane/EtOAc 1:1, +0.1% NEt3) affords the title compound (770 mg, 42%). 1H NMR (400 MHz, CDCl3): δ=10.01 (s, 1H), 8.69 (s, 1H), 7.73 (s, 1H), 7.72 (s, 1H), 7.69 (s, 1H), 4.23 (q, J=7.1 Hz, 2H), 4.04 (s, 2H), 1.30 (t, J=7.4 Hz, 3H). MS (ES+): 233 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:27])=[C:4]([CH2:8][N:9]2[C:14]3[N:15]=[C:16]([N:18]4[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)[S:17][C:13]=3[C:12](=[O:24])[N:11]=[C:10]2SC)[CH:5]=[CH:6][CH:7]=1.C([NH2:30])=O>O>[NH2:30][C:10]1[N:9]([CH2:8][C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[C:3]=2[CH3:27])[C:14]2[N:15]=[C:16]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:17][C:13]=2[C:12](=[O:24])[N:11]=1
Reactant: NC=O
Reactant: CSc1nc(=O)c2sc(N3CCOCC3)nc2n1Cc1cccc(Cl)c1C
Solvent: O
Product: Cc1c(Cl)cccc1Cn1c(N)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 198 °C
Reaction time: 1 h
Yield: 32.1 %

Procedure:
4-[(3-chloro-2-methylphenyl)methyl]-5-(methylthio)-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (500 mg, 1.182 mmol) in formamide (8 ml, 201 mmol) was heated at 192° C. and stirred for 1 h. The temperature was increased to 198° C. and stirring was continued for additional 3 h. After cooling, water was added in and the precipitate was collected, washed with water, then Et2O and dried to give 437 mg of crude. The material was purified by prep HPLC on a Kromasil Silica 5u 60 A 21×250 mm column, eluting with 95:5—CHCl3:CH3OH (2M NH3) at 20 mL/min and collecting fraction at about 7.2 min. 5-amino-4-[(3-chloro-2-methylphenyl)methyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one (151 mg, 0.380 mmol, 32.1% yield) was obtained from the crude as an off white powder. LC/MS (ES) m/z=392.1 (M+H); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.36 (d, J=7.83 Hz, 1H), 7.16 (t, J=7.96 Hz, 1H), 6.97 (s, 2H), 6.51 (d, J=7.58 Hz, 1H), 5.31 (s, 2H), 3.61-3.70 (m, 4H), 3.42 (t, J—=4.80 Hz, 4H), 2.38 (s, 3H)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[C:5]([O:9][CH3:10])=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][CH:14]([C:17]([O:19]CC)=O)[CH2:13][CH2:12]1.[Cl:22][CH2:23]I.C[Li]>C1COCC1>[Cl:22][CH2:23][C:17]([CH:14]1[CH2:13][CH2:12][N:11]([C:3]2[CH:4]=[C:5]([O:9][CH3:10])[C:6]([Cl:8])=[CH:7][C:2]=2[Cl:1])[CH2:16][CH2:15]1)=[O:19]
Reactant: CCOC(=O)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Reactant: ClCI
Agent: [Li]C
Solvent: C1CCOC1
Product: COc1cc(N2CCC(C(=O)CCl)CC2)c(Cl)cc1Cl
Temperature: -70 °C
Reaction time: 1.5 h
Yield: 102.5 %

Procedure:
An oven-dried, 50-mL 2-neck round bottom flask containing a stir bar was fitted with an inert gas inlet and a rubber septum and placed under argon. The flask was charged with ethyl 1-(2,4-dichloro-5-methoxyphenyl)piperidine-4-carboxylate (233 mg, 0.701 mmol) and anhydrous THF (5 mL) and chloroiodomethane (0.102 mL, 1.403 mmol). The mixture was cooled to −70° C. (internal temperature). Once at the prescribed temperature, a solution of methyllithium (0.877 mL of 1.6 M in Et2O, 1.403 mmol) was added dropwise to the mixture via syringe over 5 min. At the conclusion of this period, the mixture was stirred at −70° C. (internal temperature) for 1.5 h and then quenched by adding saturated NH4Cl (2 mL). The pH of the mixture was adjusted to pH 7.5 by careful addition of 2 M HCl. Once at the prescribed pH, the mixture was extracted with EtOAc (25 mL). The aqueous phase was back-extracted with EtOAc and the combined extracts washed with brine, dried (MgSO4) and concentrated on a rotary evaporator to give 2-chloro-1-(1-(2,4-dichloro-5-methoxyphenyl)piperidin-4-yl)ethanone (242 mg). LC-MS: 336.24, [M+H]+; tR=3.84 min (b).
Reaction SMILES: [H-].[Na+].[C:3]1([CH2:13][NH:14][C:15]2[O:19][N:18]=[C:17]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH:16]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.[Br:26][CH2:27][CH2:28][CH2:29][CH2:30]Br.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Br:26][CH2:27][CH2:28][CH2:29][CH2:30][N:14]([CH2:13][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[C:15]1[O:19][N:18]=[C:17]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:16]=1
Reactant: BrCCCCBr
Reactant: c1ccc(-c2cc(NCc3cccc4ccccc34)on2)cc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: BrCCCCN(Cc1cccc2ccccc12)c1cc(-c2ccccc2)no1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 26.2 %

Procedure:
Charged flask with a 60% sodium hydride in oil dispersion (64.0 mg, 1.6 mmol) and suspended in DMF (1 ml). A DMF (1 ml) solution of naphthalen-1-ylmethyl-(3-phenyl-isoxazol-5-yl)-amine (300 mg, 1.0 mmol) was added and the mixture stirred under argon at rt for 30 min resulting in a light yellow solution. After adding 1,4-dibromobutane (358 μl, 3.0 mmol), the reaction was stirred at rt for 1 hr, poured into 10% sodium bicarbonate (aq) and extracted with ethyl acetate (3×). The extracts were combined, washed with brine, dried over magnesium sulfate, filtered and concentrated in vacuo to give a crude oil (181 mg). Flash chromatography on silica gel (10% ethyl acetate in hexane) gave the product as a colorless oil (114 mg, 26.2%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH2:17])=[CH:11][N:10]=2)=[CH:4][CH:3]=1.[CH:18](O)=[O:19]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9]2[N:14]=[C:13]([NH:15][CH3:16])[C:12]([NH:17][CH:18]=[O:19])=[CH:11][N:10]=2)=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: CNc1nc(Nc2ccc(Cl)cc2)ncc1N
Product: CNc1nc(Nc2ccc(Cl)cc2)ncc1NC=O

Procedure:
200 mg of 2-(4-chlorophenylamino)-4-methylamino-5-amino-pyrimidine are refluxed in 5 ml of formic acid for 5 hours. The reaction mixture is evaporated to dryness and then the residue is stirred with 15 ml of water. The solid is suction filtered, washed with water, briefly boiled with 15 ml ethanol, cooled, suction filtered again, then washed with hot ethanol and dried.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([C:8]1[CH:28]=[CH:27][C:11]([O:12][C:13]([CH3:26])([CH3:25])[CH:14]([OH:24])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N+:17]=2[O-:23])=[CH:10][CH:9]=1)#[N:7]>C(N(CC)CC)C.ClCCl>[C:6]([C:8]1[CH:9]=[CH:10][C:11]([O:12][C:13]([CH3:26])([CH3:25])[CH:14]([O:24][S:2]([CH3:1])(=[O:4])=[O:3])[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[N+:17]=2[O-:23])=[CH:27][CH:28]=1)#[N:7]
Reactant: CS(=O)(=O)Cl
Reactant: Cc1cccc(CC(O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cccc(CC(OS(C)(=O)=O)C(C)(C)Oc2ccc(C#N)cc2)[n+]1[O-]
Yield: 92.3 %

Procedure:
573 mg of methanesulphonyl chloride were added to a stirred solution of 1.56 g of 2-[3-(4-cyanophenoxy)-2-hydroxy-3-methylbutyl]-6-methylpyridine N-oxide in 3 ml of triethylamine and 25 ml of dichloromethane at room temperature. After 1 hour a further 573 mg of methanesulphonyl chloride were added and the mixture was stirred until thin-layer chromatography indicated that the reaction was complete. The mixture was washed with dilute hydrochloric acid and 2M sodium hydroxide solution, dried over sodium sulphate and evaporated to give 1.8 g of 2-[3-(4-cyanophenoxy)-2-methanesulphonyloxy-3-methylbutyl]-6methylpyridine N-oxide.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[O:12][CH3:13].[C:14](Cl)(=[O:16])[CH3:15].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C1C=CC=CC=1)([O-])=O>[C:14]([C:8]1[CH:9]=[CH:10][C:11]2[C:6](=[CH:5][CH:4]=[C:3]([O:12][CH3:13])[C:2]=2[Cl:1])[CH:7]=1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: COc1ccc2ccccc2c1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: COc1ccc2cc(C(C)=O)ccc2c1Cl

Procedure:
A mixture of 1925 g. of 1-chloro-2-methoxynaphthalene, 80 g. of acetyl chloride, 400 g. of aluminum chloride and 2.5 liters of nitrobenzene are stirred for 60 hours at room temperature. The resulting mixture is then washed with dilute hydrochloric acid, dried over sodium sulfate and evaporated to yield 2-acetyl-5-chloro-6-methoxynaphthalene. The resulting acetyl product is added to a mixture of 39 g. of sulfur and 105 g. of morpholine and heated to about 150°C for 3 hours. The mixture is then added to 1 liter of concentrated hydrochloric acid and refluxed for 3 hours. The mixture is then cooled, diluted with 6 liters of ice-water and extracted with methylene chloride. The extracts are combined, washed with water to neutrality, dried over sodium sulfate and evaporated to yield 2-(5'-chloro-6'-methoxy-2'-naphthyl) acetic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]([F:19])[CH:18]=2)[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12]3)[N:5]=[C:4]([NH:21][C:22]2[NH:26][N:25]=[C:24]([CH3:27])[CH:23]=2)[CH:3]=1.[CH3:28][N:29]1[CH2:34][CH2:33][CH:32]([N:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:31][CH2:30]1.C(N(C(C)C)CC)(C)C>C(O)CCC>[F:19][C:17]1[CH:18]=[C:9]([S:8][C:6]2[N:5]=[C:4]([NH:21][C:22]3[NH:26][N:25]=[C:24]([CH3:27])[CH:23]=3)[CH:3]=[C:2]([N:38]3[CH2:37][CH2:36][N:35]([CH:32]4[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]4)[CH2:40][CH2:39]3)[N:7]=2)[CH:10]=[C:11]2[C:16]=1[N:15]=[C:14]([CH3:20])[CH:13]=[CH:12]2
Reactant: Cc1cc(Nc2cc(Cl)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Reactant: CN1CCC(N2CCNCC2)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: Cc1cc(Nc2cc(N3CCN(C4CCN(C)CC4)CC3)nc(Sc3cc(F)c4nc(C)ccc4c3)n2)[nH]n1
Temperature: 90 °C
Yield: 30.3 %

Procedure:
To a stirred mixture of 6-chloro-2-(8-fluoro-2-methylquinolin-6-ylthio)-N-(3-methyl-1H-pyrazol-5-yl)pyrimidin-4-amine (200 mg, 0.5 mmol), 1-(1-methylpiperidin-4-yl)piperazine (367 mg, 2 mmol) and diisopropylethylamine (194 mg, 1.5 mmol) in nBuOH (5 ml) was heated to 90° C. for 18 hours. The crude mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic layer was further extracted with water. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The resulting residue was triturated with cold acetonitrile, filtered and dried to afford the title compound as an off-white solid (83 mg, 30% yield).
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:12]([N-]C(C)C)(C)C.[Li+].S(OC)(OC)(=O)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:12][N:11]1[CH:10]=[CH:9][N:8]=[C:7]1[C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(-c2ncc[nH]2)cc1
Reactant: CC(C)[N-]C(C)C
Agent: [Cl-]
Agent: [Li+]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COS(=O)(=O)OC
Product: Cn1ccnc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A solution of 40 mL tetrahydrofuran containing 1.0 g of 2-phenylimidazole was cooled to 0° C. and 4 mL of 2M lithium diisopropylamide was added dropwise which resulted in the formation of a white suspension. The mixture was stirred for 10 min at 0° C. and then 0.7 mL of dimethyl sulfate was added The reaction was allowed to stir at room temperature for an additional 30 min during which time the solution became homogeneous. Aqueous ammonium chloride was added and the tetrahydrofuran was removed by evaporation under reduced pressure. The aqueous phase was extracted with 2×100 mL aliquots of dichloromethane. The combined organic extracts were washed with dilute ammonium hydroxide and brine. The combined organic extracts were dried over anhydrous sodium sulfate and concentrated under reduced pressure to yield 1 g of 1-methyl-2-phenylimidazole which was used in the next step without further purification or characterization.
Reaction SMILES: [C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH3:9][NH:10][CH3:11]>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[CH3:9][N:10]([CH3:11])[C:1]([C:4]1[O:5][CH:6]=[CH:7][CH:8]=1)=[CH2:2]
Reactant: CC(=O)c1ccco1
Reactant: CNC
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: C=C(c1ccco1)N(C)C
Reaction time: 3 h

Procedure:
To a solution of 55 g of 2-acetylfuran and 193 g of dimethylamine in 1 liter of dry benzene, stirred at 3° under nitrogen, is added dropwise a solution of 31 mL of titanium tetrachloride in 100 mL benzene over 45 minutes. The mixture is stirred for a further 3 hours at 3°, then at ambient temperature overnight. The brown reaction mixture is filtered through a medium frit glass funnel under nitrogen, and the filtered solids are washed with dry benzene. The combined filtrates are concentrated in vacuo to give the desired enamine as an oil.
Reaction SMILES: [NH2:1][C:2]1[C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]Cl)=[O:7])=[CH:4][C:3]=1[Br:24].[Cl:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:27]=1[NH:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[CH2:40][C:41]([O-:43])=[O:42].[Na+]>>[NH2:1][C:2]1[C:16]([CH2:17][N:18]2[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]2)=[CH:15][C:5]([C:6]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][O:43][C:41](=[O:42])[CH2:40][C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][C:34]=2[NH:33][C:27]2[C:26]([Cl:25])=[CH:31][CH:30]=[CH:29][C:28]=2[Cl:32])=[O:7])=[CH:4][C:3]=1[Br:24]
Reactant: O=C([O-])Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: Nc1c(Br)cc(C(=O)OCCCCCCl)cc1CN1CCCCC1
Agent: [Na+]
Product: Nc1c(Br)cc(C(=O)OCCCCCOC(=O)Cc2ccccc2Nc2c(Cl)cccc2Cl)cc1CN1CCCCC1

Procedure:
This compound was prepared from 5-(4-amino-3-bromo-5-piperidinomethyl-benzoyloxy)-n-pentyl chloride and sodium 2-[(2,6-dichlorophenyl)-amino]-phenylacetate analogous to Example 8.