Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:44])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:43])([C:14](=O)[NH:15][CH2:16][C:17](=O)[C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=2)[CH2:4][O:3]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:54])=CC=1>C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:44])[N:6]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@@:5]([CH3:43])([C:14]2[S:54][C:17]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[C:20]([C:37]([F:40])([F:39])[F:38])[CH:19]=3)=[CH:16][N:15]=2)[CH2:4][O:3]1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)C(=O)NCC(=O)c1ccc(OCCCCCCc2ccccc2)c(C(F)(F)F)c1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1C(C)(C)OC[C@]1(C)c1ncc(-c2ccc(OCCCCCCc3ccccc3)c(C(F)(F)F)c2)s1
Temperature: 80 °C

Procedure:
To a solution of (R)-tert-butyl 2,2,4-trimethyl-4-(2-oxo-2-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)ethylcarbamoyl)oxazolidine-3-carboxylate (49 mg, 0.079 mmol, 1.0 equiv) in toluene (1 mL) was added Lawesson's reagent (32 mg, 0.087 mmol, 1.1 equiv). The reaction mixture was heated at 80° C. for 3 h. The crude product was purified directly by SiO2 column chromatograph (EtOAc/hexanes, 3:7) to give (R)-tert-butyl 2,2,4-trimethyl-4-(5-(4-(6-phenylhexyloxy)-3-(trifluoromethyl)phenyl)thiazol-2-yl)oxazolidine-3-carboxylate. HPLC retention time on a C8(2) column (30×50 mm, 3μ) is 3.29 min with gradient 70-98% acetonitrile-H2O (0.1% TFA) in 3.5 min as mobile phase. MS (ESI, M+H+)=619.0.
Reaction SMILES: [NH4+:1].[Cl-].[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:20])[NH:15][C:14](=S)[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:7]=[CH:8][CH:9]=1>CCO>[Br:3][C:4]1[CH:5]=[C:6]([C:10]2([CH3:20])[N:15]=[C:14]([NH2:1])[CH2:13][N:12]3[N:17]=[CH:18][CH:19]=[C:11]23)[CH:7]=[CH:8][CH:9]=1
Reactant: CC1(c2cccc(Br)c2)NC(=S)Cn2nccc21
Reactant: [NH4+]
Agent: [Cl-]
Solvent: CCO
Product: CC1(c2cccc(Br)c2)N=C(N)Cn2nccc21
Temperature: 80 °C
Yield: 98.3 %

Procedure:
NH4Cl (0.15 g, 2.79 mmol) was added to a stirred solution of rac-4-(3-bromo-phenyl)-4-methyl-4,5-dihydro-pyrazolo[1,5-a]pyrazine-6-thione (0.45 g, 1.40 mmol) in EtOH (50 mL) and the mixture was heated at 80° C. for 28 hours. The solvent was removed in vacuo and the residue was dissolved in DCM and washed with water. The organic layer was separated, dried (MgSO4), filtered and the solvents evaporated in vacuo. The crude product was purified by flash column chromatography (silica gel; 7 M solution of ammonia in methanol in AcOEt 0/100 to 20/80). The desired fractions were collected and concentrated in vacuo to yield rac-4-(3-bromo-phenyl)-4-methyl-4,7-dihydro-pyrazolo[1,5-a]pyrazin-6-ylamine (0.42 g, 99% yield) as a yellow solid.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[CH2:24]([S:31][C:2]1[N:3]=[C:4]2[C:9](=[N:10][C:11]=1[N:12]([CH3:14])[CH3:13])[N:8]=[C:7]([N:15]1[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1)[N:6]=[C:5]2[N:21]([CH3:23])[CH3:22])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1Cl
Reactant: SCc1ccccc1
Product: CN(C)c1nc2nc(N3CCNCC3)nc(N(C)C)c2nc1SCc1ccccc1

Procedure:
This compound was prepared analogous to Example 2 from 6-chloro-4,7-bis-(dimethylamino)-2-piperazino-pteridine and benzylmercaptan.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH:7]=[CH:6][N:5]=[CH:4]1.[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13]Cl>CN(C)C=O>[CH3:8][Si:9]([CH3:16])([CH3:15])[CH2:10][CH2:11][O:12][CH2:13][N:3]1[CH:7]=[CH:6][N:5]=[CH:4]1
Reactant: C[Si](C)(C)CCOCCl
Reactant: c1c[nH]cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C[Si](C)(C)CCOCn1ccnc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 134.7 %

Procedure:
Under an argon atmosphere, a dimethylformamide (500 mL) suspension of sodium hydride (60%, 18.9 g) was ice-cooled and then imidazole (30.9 g) was added so as to prevent an inner temperature from rising to 5° C. or higher. The reaction solution was stirred at 0° C. for 45 minutes. To the reaction solution, 2-(trimethylsilyl)ethoxymethyl chloride (72.4 g) was added dropwise. The reaction solution was stirred at room temperature for 14 hours. To the reaction solution, ice water (200 mL) was added. The aqueous layer was extracted twice with a solution (n-hexane:ethyl acetate=1:1 (200 mL)). The combined organic layer was washed with saturated sodium chloride solution and then dried over anhydrous magnesium sulfate. After removing anhydrous magnesium sulfate by filtration, the filtrate was concentrated to obtain the title compound (116 g) having the following physical properties.
Reaction SMILES: [F:1][CH:2]([F:34])[C:3]([N:5]1[C@H:9]([CH2:10][F:11])[C@@H:8]([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:19]=[N:20][C:21]([CH:24]([N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH3:25])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)[O:7]C1(C)C)=[O:4].FC(F)(F)C(O)=O>C(Cl)Cl>[F:34][CH:2]([F:1])[C:3]([NH:5][C@H:9]([CH2:10][F:11])[C@H:8]([OH:7])[C:12]1[CH:13]=[CH:14][C:15]([C:18]2[CH:19]=[N:20][C:21]([CH:24]([N:26]3[CH2:27][CH2:28][O:29][CH2:30][CH2:31]3)[CH3:25])=[CH:22][CH:23]=2)=[CH:16][CH:17]=1)=[O:4]
Reactant: CC(c1ccc(-c2ccc([C@H]3OC(C)(C)N(C(=O)C(F)F)[C@@H]3CF)cc2)cn1)N1CCOCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccc(-c2ccc([C@@H](O)[C@@H](CF)NC(=O)C(F)F)cc2)cn1)N1CCOCC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 56.2 %

Procedure:
To a stirred solution of 2,2-Difluoro-1-((4S,5R)-4-fluoromethyl-2,2-dimethyl-5-{4-[6-(1-morpholin-4-yl-ethyl)-pyridin-3-yl]-phenyl}-oxazolidin-3-yl)-ethanone (0.101 g, 0.309 mmol) in CH2Cl2 (5 mL) is added trifluoroacetic acid (1 mL) at 0° C. Reaction mixture is allowed to stir at room temperature for 4 hours. The solvent evaporated in vacuo and the crude material is diluted with saturated bicarbonate solution and extract with 10% MeOH:DCM. Combined organic layer dried over sodium sulphate, concentrated and purified by combiflash using 5% methanol:CH2Cl2 as eluent to afford desired compound (0.076 g): 1H NMR (400 MHz, CDCl3) δ: 1.33 (d, J=2.52 Hz, 3H), 2.32-2.35 (m, 2H), 2.49-2.50 (m, 2H), 3.55-3.57 (m, 4H), 3.59-3.60 (m, 1H), 4.29-4.30 (m, 1H), 4.32 (m, 0.5H), 4.40-4.44 (m, 0.5H), 4.54-4.55 (m, 0.5H), 4.64-4.66 (m, 0.5H), 4.88 (bs, 1H), 5.92 (d, J=3.96 Hz, 1H), 6.20 (t, J=53.72 Hz, 1H), 7.45 (d, J=8.24 Hz, 2H), 7.49 (d, J=8.24, 1H), 7.69 (d, J=8.28 Hz, 2H), 8.03-8.06 (dd, J1=8.2 Hz, J2=2.4 Hz, 1H), 8.80 (d, J=2.04 Hz, 1H), 8.86 (d, J=8.56 Hz, 1H). LC-Ms (m/z): 438.1[M+H].
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=[O:15])=[CH:9][CH:8]=1)=[O:6].[C:19](=O)([O-])[O-].[K+].[K+].S(OC)(OC)(=O)=O>C(#N)C>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:18])([CH3:17])[C:14]([O:16][CH3:19])=[O:15])=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(C)(C(=O)O)c1ccc(C(=O)CCCCl)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC#N
Product: COC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Yield: 89.5 %

Procedure:
Mix 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid (10.0 g, 37.3 mmol) and anhydrous potassium carbonate (3.5 g, 25.3 mmol). Heat to 40° C. in acetonitrile (100 mL) and stir under a nitrogen atmosphere. Add dimethyl sulfate (13.3 g, 105 mmol) and reflux for 45 minutes. Evaporate the solvent in vacuo, dissolve the residue in ethyl acetate (50 mL) and wash with water (4×50 mL). Dry (MgSO4), filter through silica gel and evaporate the solvent in vacuo to give the title compound (6.4 g, 89%).
Reaction SMILES: [Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].C(Cl)(=O)C([Cl:16])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]([Cl:12])=[CH:3][C@H:4]1[C@H:6]([C:7]([Cl:16])=[O:8])[C:5]1([CH3:11])[CH3:10]
Reactant: O=C(Cl)C(=O)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)O
Solvent: Cc1ccccc1
Product: CC1(C)[C@@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Yield: 94.5 %

Procedure:
In a manner similar to Example 13A, the reaction of 25.0 g (0.12 mole) of (+)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarboxylic acid, 180 ml of toluene, and 30.4 g (0.24 mole) of oxalyl chloride gave 25.8 g of (+)-trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride. The nmr spectrum was consistent with the proposed structure.
Reaction SMILES: [Se](=O)=[O:2].[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([CH2:18][C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]>O1CCOCC1.O>[C:4]([O:9][C:10]([NH:12][C:13]1[S:14][CH:15]=[C:16]([C:18](=[O:2])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[N:17]=1)=[O:11])([CH2:7][CH3:8])([CH3:6])[CH3:5]
Reactant: O=[Se]=O
Reactant: CCOC(=O)Cc1csc(NC(=O)OC(C)(C)CC)n1
Solvent: C1COCCO1
Solvent: O
Product: CCOC(=O)C(=O)c1csc(NC(=O)OC(C)(C)CC)n1
Yield: 70.6 %

Procedure:
To a solution of selenium dioxide (0.11 g.) in a mixture of dioxane (2.5 ml.) and water (0.1 ml.) was added a mixture of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)acetate (0.3 g.) and dioxane (2.5 ml.) at 110° C. with stirring. The mixture was stirred for 30 minutes at the same temperature, and selenium dioxide (0.055 g.) was further added thereto and then the mixture was stirred for 1.5 hours at the same temperature. After the reaction, the reaction liquid is separated by decantation, and the residue was washed with a small amount of dioxane. The reaction liquid and washing were combined together, and then the solvents were distilled off. The residue was dissolved in ethyl acetate. The solution was washed with water and dried and then the solvent was distilled off to give brown oil of ethyl 2-(2-tert-pentyloxycarbonylamino-1,3-thiazol-4-yl)glyoxylate (0.22 g.).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([N:8]2[C:12]([CH3:13])=[CH:11][CH:10]=[C:9]2[CH3:14])[CH:3]=1.[B:15](OC(C)C)([O:20]C(C)C)[O:16]C(C)C.[Li]CCCC>C1COCC1>[CH3:14][C:9]1[N:8]([C:4]2[CH:3]=[C:2]([B:15]([OH:20])[OH:16])[CH:7]=[CH:6][N:5]=2)[C:12]([CH3:13])=[CH:11][CH:10]=1
Reactant: Cc1ccc(C)n1-c1cc(Br)ccn1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccc(C)n1-c1cc(B(O)O)ccn1
Temperature: 20 °C
Reaction time: 1 h

Procedure:
Step 2) To a solution of the above prepared 4-bromo-2-(2,5-dimethyl-pyrrol-1-yl)-pyridine (1.95 g, 7.77 mmol) and triisopropyl borate (2.68 mL, 11.6 mmol) in THF (40 mL) at −78° C. was added n-BuLi (1.6 M in hexane, 4.85 mL, 7.77 mmol) keeping the internal temperature below −65° C. Stirring was continued at −78° C. for 1 h, then more triisopropyl borate (2.68 mL, 11.6 mmol) and n-BuLi (4.85 mL, 7.77 mmol) was added and stirring was continued at −78° C. for 1 h. The reaction mixture was quenched with 1 M NaH2PO4-sol., allowed to quickly (waterbath) warm to ca. 20° C. and stirred for 10 min. Diluted with EtOAc, layers were separated, washed organic layer with brine and dried over Na2SO4. Removal of the solvent in vacuum left the title compound as a yellow foam (2.1 g, 100%, 80% purity), which was used without further purification. MS (ISN) 215.3 [(M−H)−].
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[CH:3]=1.[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH2:26]>COCCO>[CH3:22][O:23][C:24]1[CH:30]=[C:29]([N:31]2[CH2:36][CH2:35][CH:34]([N:37]3[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)[CH2:33][CH2:32]2)[CH:28]=[CH:27][C:25]=1[NH:26][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[S:16]([CH:19]([CH3:21])[CH3:20])(=[O:18])=[O:17])[N:5]=[C:6]([CH3:8])[N:7]=1
Reactant: Cc1nc(Cl)cc(Nc2ccccc2S(=O)(=O)C(C)C)n1
Reactant: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1N
Solvent: COCCO
Product: COc1cc(N2CCC(N3CCN(C)CC3)CC2)ccc1Nc1cc(Nc2ccccc2S(=O)(=O)C(C)C)nc(C)n1

Procedure:
To the compound 6-chloro-2-methyl-N-[2-(propan-2-ylsulfonyl)phenyl]pyrimidin-4-amine (0.16 mmol) in 1 mL of 2-methoxyethanol is added 2-methoxy-4-[4-(4-methylpiperazin-1-yl)piperidin-1-yl]aniline (0.71 g, 0.16 mmol). The mixture is stirred at 110° C. until formation of the desired compound. The mixture is basified with saturated sodium bicarbonate solution and extracted with limited amount of ethyl acetate. The compound can be purified by chromatography.
Reaction SMILES: [CH2:1]([NH:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3].C1(O)C=CC=CC=1.Cl.Br[C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1.[OH-].[Na+]>>[CH2:1]([N:4]([C:24]1[CH:29]=[CH:28][N:27]=[CH:26][CH:25]=1)[N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7][C:6]1=[O:14])[CH2:2][CH3:3]
Reactant: CCCNN1C(=O)Cc2ccccc21
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Oc1ccccc1
Product: CCCN(c1ccncc1)N1C(=O)Cc2ccccc21
Temperature: 25 °C
Reaction time: 7 h
Yield: 14.4 %

Procedure:
To a stirred solution of 1,3-dihydro-1-(propylamino)-2H-indol-2-one (10.4 g) and phenol (30.8 g), preheated to 150° C. under nitrogen, was added 4-bromopyridine hydrochloride (11.04 g) over 5 min. Heating was continued for 7 hours at which time the reaction mixture was cooled to room temperature and made basic by slow addition of dilute aqueous sodium hydroxide. The product was extracted four times with ethyl acetate and the combined organic layers back-extracted with dilute aqueous sodium hydroxide, washed with brine, and dried (K2CO3). Filtration and concentration gave the crude product. Purification via flash column chromatography (silica gel, EtOAc), preparative high performance liquid chromatography (HPLC) (silica gel, EtOAc-.2% Et3N/0-7% MeOH/EtOAc), and a third column (alumina, EtOAc) followed. Recrystallization from ethyl acetate-pentane afforded 2.10 g (14%) of 1,3-dihydro-1-(propyl-4-pyridinylamino)-2H-indol-2-one, as a solid, m.p. 140°-143° C.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10](Cl)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1.[CH2:18]([NH2:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>O>[NH2:1][C:2]1[C:11]([C:12]#[N:13])=[C:10]([NH:25][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([N:15]([CH3:17])[CH3:16])[CH:8]=2)[N:3]=1
Reactant: CN(C)c1ccc2nc(N)c(C#N)c(Cl)c2c1
Reactant: NCc1ccccc1
Solvent: O
Product: CN(C)c1ccc2nc(N)c(C#N)c(NCc3ccccc3)c2c1

Procedure:
3 g of 2-amino-3-cyano-4-chloro-6-dimethylaminoquinoline and 6 mL of benzylamine are stirred at 125° C. for 3 hours. The reaction mixture is poured onto 30 mL of water. The precipitated material is filtered off, washed with 20 mL of water. After drying 2.3 g of the title compound is obtained, m.p.: 265° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=2)[N:5]=[C:4]([C:13]2[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=2)[C:3]=1[CH3:20].[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:39][CH2:38][O:37][CH2:36][CH2:35]3)=[CH:30][C:28]=2[NH2:29])[CH2:23][CH2:22]1.Cl.O1CCOCC1>CO>[N:24]1([C:27]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:35][CH2:36][O:37][CH2:38][CH2:39]3)=[CH:30][C:28]=2[NH:29][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([F:12])[CH:10]=3)[N:5]=[C:4]([C:13]3[CH:14]=[N:15][CH:16]=[C:17]([F:19])[CH:18]=3)[C:3]=2[CH3:20])[CH2:25][CH2:26][O:21][CH2:22][CH2:23]1
Reactant: Nc1cc(N2CCOCC2)ccc1N1CCOCC1
Reactant: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1c(-c2cncc(F)c2)nc2ccc(F)cc2c1Nc1cc(N2CCOCC2)ccc1N1CCOCC1

Procedure:
Prepared according to general Procedure K using 4-chloro-6-fluoro-2-(5-fluoropyridin-3-yl)-3-methylquinoline (110 mg, 0.38 mmol), 2,5-dimorpholinoaniline (120 mg, 0.38 mmol) and a 4.0M solution of HCl in dioxane (0.09 mL, 0.38 mmol) in MeOH (1.0 mL) and heating in the microwave for 2 h at 150° C. After purification N-(2,5-di-4-morpholinylphenyl)-6-fluoro-2-(5-fluoro-3-pyridinyl)-3-methyl-4-quinolinamine was obtained. 1H NMR (500 MHz, chloroform-d) δ ppm 8.70 (1H, t, J=1.7 Hz), 8.60 (1H, d, J=2.7 Hz), 8.13-8.22 (1H, m), 7.77 (1H, dt, J=8.8, 2.3 Hz), 7.44-7.55 (2H, m), 7.25 (1H, s), 7.15 (1H, d, J=8.6 Hz), 6.51 (1H, dd, J=8.8, 2.7 Hz), 6.01 (1H, dd, J=2.4, 0.5 Hz), 3.91 (4H, t, J=4.6 Hz), 3.69-3.79 (4H, m), 3.06 (4H, t, J=4.6 Hz), 2.90-2.99 (4H, m), 2.34 (3H, s). Mass Spectrum (ESI) m/e=518.1 (M+1).
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2>S(=O)(=O)(O)O>[CH3:6][C:7]1[NH:8][C:9]2[C:14]([CH:15]=1)=[CH:13][C:12]([N+:1]([O-:4])=[O:2])=[CH:11][CH:10]=2
Reactant: Cc1cc2ccccc2[nH]1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1cc2cc([N+](=O)[O-])ccc2[nH]1
Reaction time: 0.25 h
Yield: 59.2 %

Procedure:
A solution of 17.0 g (0.2 mol) of sodium nitrate in 150 mL of sulfuric acid was added dropwise to 26.9 g (0.205 mol) of 2-methyl-1H-indole in 150 mL of sulfuric acid keeping the temperature at −10 to 0° C. with an ethanol-water bath. After 0.25 hours, the mixture was poured onto ice, extracted with EtOAc, the EtOAc solution washed with water, Na2CO3 solution and dried (Na2SO4). After concentrating at reduced pressure, the residue was crystallized from EtOH to give 20.86 g (59% yield) of 2-methyl-5-nitro-1H-indole, mp, 163-165° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14].C[O-].[Na+].[CH2:19](I)[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]>CO>[CH2:19]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH3:11])=[C:5]2[CH2:12][C:13]([OH:15])=[O:14])[CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: Cc1[nH]c2ccc(O)cc2c1CC(=O)O
Reactant: CCCCCCI
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCCCCCOc1ccc2[nH]c(C)c(CC(=O)O)c2c1
Yield: 61.5 %

Procedure:
To a solution of 5-hydroxy-2-methyl-1H-indole-3-acetic acid (7.17 g, 35.0 mmol) in methanol (40 mL) is added sodium methoxide (70 mmol). The solution is evaporated, dimethylformamide (40 mL) is added followed by hexyl iodide (35.0 mmol). After 2 days the solvent is removed and the residue is partitioned between ethyl acetate and pH=4 buffer. The organic layer is separated, dried over MgSO4 and evaporated to 8.6 g of a brown solid. Recrystallization from ethanol/water affords 6.23 g (62%) of white crystals, m.p. 65°-67° C.
Reaction SMILES: CC(C)([O-])C.[K+].C(O)(C)(C)C.[CH2:12]([C:15]1[CH:20]=[CH:19][C:18]([C:21](Cl)=[CH2:22])=[CH:17][CH:16]=1)[CH2:13][CH3:14]>O>[CH2:12]([C:15]1[CH:16]=[CH:17][C:18]([C:21]#[CH:22])=[CH:19][CH:20]=1)[CH2:13][CH3:14]
Reactant: C=C(Cl)c1ccc(CCC)cc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: O
Product: C#Cc1ccc(CCC)cc1

Procedure:
Potassium t-butoxide (21.5 g) was added to stirred t-butanol and warmed to gentle reflux. The alkene product from step 2.3 (20 g) was added dropwise and then the mixture was heated under reflux for 3 hrs. Water (100 ml) was added and the product extracted into petroleum spirit (3×100 ml), washed with 10% HCl and water. The crude alkine product was 97% pure by gc. Yield 12 g.
Reaction SMILES: [CH3:1][C:2](N(C)C)=[O:3].[CH:7]([C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12](=[CH:13][CH:14]=[CH:15]2)[CH:11]=1)([CH3:9])[CH3:8].P(Cl)(Cl)(Cl)=O.[OH-].[K+]>O>[C:2]([C:13]1[C:12]2[C:16]([CH:17]=[CH:18][CH:19]=[C:10]([CH:7]([CH3:9])[CH3:8])[CH:11]=2)=[CH:15][CH:14]=1)(=[O:3])[CH3:1]
Reactant: CC(C)c1cccc2cccc-2c1
Reactant: CC(=O)N(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CC(=O)c1ccc2cccc(C(C)C)cc1-2
Temperature: 25 °C
Reaction time: 5 h
Yield: 41 %

Procedure:
To a dimethylacetamide (80 ml) solution of the compound (19) (8.41 g), while stirring and cooling with ice. a dimethylacetamide (76 ml) solution of phosphorus oxychloride (POC13) (92 g) was added dropwise over 40 minutes. After the addition of the POC13 solution, it was further stirred for 5 hours at room temperature, and then poured into water (800 ml). The solution was made basic (pH 10) by the addition of aqueous potassium hydroxide, and was extracted 5 times with benzene. The benzene solutions were mixed, washed with water and dried. From the benzene solution, the solvent was distilled off to obtain an oily substance. It was purified by silica gel column chromatography (650 g), eluting with benzene. The secondeluted part gave 1-acetyl-7-isopropylazulene (20) (4.29 g, 41%) in a red oily state.
Reaction SMILES: [NH2:1][C:2]1[C:3]([N:9]2[CH:13]=[CH:12][N:11]=[C:10]2[CH:14]2[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]2)=[N:4][CH:5]=[C:6]([Cl:8])[CH:7]=1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21]>>[Cl:8][C:6]1[CH:5]=[N:4][C:3]2[N:9]3[C:10]([CH:14]4[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]4)=[N:11][CH:12]=[C:13]3[C:20](=[O:21])[NH:1][C:2]=2[CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Nc1cc(Cl)cnc1-n1ccnc1C1CCCCC1
Product: O=c1[nH]c2cc(Cl)cnc2n2c(C3CCCCC3)ncc12

Procedure:
3-Amino-5-chloro-2-(2-cyclohexyl-1H-imidazol-1-yl)pyridine as synthesized in Production Example 103, 838 mg, 1,1′-carbonyldiimidazole 983 mg and 1,2-chlorobenzene 25 mL were mixed and heated under reflux for 15 hours. Cooling the reaction liquid off, the precipitate was recovered by filtration and washed with methanol. The resulting crystals were dissolved in a liquid mixture of 2N hydrochloric acid and methanol, and the insoluble matter was separated by filtration. The filtrate was made weakly alkaline with saturated aqueous sodium hydrogencarbonate solution, and the precipitate was recovered by filtration. Drying the same in flowing air under heating, 620 mg of the title compound was obtained.
Reaction SMILES: Cl.[CH2:2]([NH:4][O:5][CH3:6])[CH3:3].[C:7]([C:11]1[O:12][C:13]2[C:19]([S:20](Cl)(=[O:22])=[O:21])=[C:18]([Cl:24])[CH:17]=[CH:16][C:14]=2[N:15]=1)([CH3:10])([CH3:9])[CH3:8]>C1COCC1.CCOC(C)=O>[CH2:2]([N:4]([O:5][CH3:6])[S:20]([C:19]1[C:13]2[O:12][C:11]([C:7]([CH3:9])([CH3:8])[CH3:10])=[N:15][C:14]=2[CH:16]=[CH:17][C:18]=1[Cl:24])(=[O:21])=[O:22])[CH3:3]
Reactant: CC(C)(C)c1nc2ccc(Cl)c(S(=O)(=O)Cl)c2o1
Reactant: CCNOC
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCN(OC)S(=O)(=O)c1c(Cl)ccc2nc(C(C)(C)C)oc12
Temperature: 0 °C

Procedure:
N-Ethyl-O-methylhydroxylamine hydrochloride (Intermediate G) (3.39 g, 30.4 mmol) was suspended in dry THF (20 ml) and cooled to 0° C. in an ice bath while stirring. TEA (4.24 ml, 30.4 mmol) was added followed by dropwise addition of 2-tert-butyl-6-chloro-benzooxazole-7-sulfonyl chloride (US 2007/0249672 page 9) (4.68 g, 15.19 mmol) in THF (10 ml) over 2.5 hours. The reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was diluted with EtOAc and washed with H2O, brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by flash chromatography, eluting with 0-10% EtOAc in iso-hexane, to yield a white solid [M+H]+ 347.2
Reaction SMILES: [C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1C=C[C:11](Cl)=[C:10](Cl)[CH:9]=1)(=[O:3])[CH3:2].ClCC(=O)CC1[S:22]C=CC=1.C(O)(=O)C.C(N(CC)CC)C>>[C:1]([O:4][CH2:5][C:6](=[O:16])[CH2:7][C:8]1[S:22][CH:11]=[CH:10][CH:9]=1)(=[O:3])[CH3:2]
Reactant: O=C(CCl)Cc1cccs1
Reactant: CC(=O)OCC(=O)Cc1ccc(Cl)c(Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)O
Product: CC(=O)OCC(=O)Cc1cccs1
Yield: 13 %

Procedure:
The procedure described above for the synthesis of 3-(3,4-dichlorophenyl)-2-oxopropyl acetate was followed, reacting 1-chloro-3-(thiophen-2-yl)propan-2-one (1.00 g, 5.73 mmol) with acetic acid (0.66 mL, 0.69 g, 12 mmol) and triethylamine (1.60 mL, 1.16 g, 11.5 mmol). Purification by flash chromatography over silica gel (1040% ethyl acetate in hexanes) gave an orange oil (0.144 g, 13% yield): 1H NMR (400 MHz, CDCl3) δ 2.17 (s, 3H) 3.95 (s, 2H) 4.74 (s, 2H) 6.92-6.94 (m, 1H) 6.99 (dd, J=5.2, 3.4 Hz, 1H) 7.25 (dd, J=5.1, 1.3 Hz, 1H).