Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.[Al](Cl)(C)C.[F:13][CH:14]([F:40])[C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24](OCC)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:35]=[CH:34][C:33]([S:36]([CH3:39])(=[O:38])=[O:37])=[CH:32][CH:31]=3)[C:18]=2[CH:19]=1>ClCCCl>[F:40][CH:14]([F:13])[C:15]1[O:16][C:17]2[CH:23]=[C:22]([C:24]([NH:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=3)=[O:25])[CH:21]=[C:20]([O:29][C:30]3[CH:31]=[CH:32][C:33]([S:36]([CH3:39])(=[O:37])=[O:38])=[CH:34][CH:35]=3)[C:18]=2[CH:19]=1
Reactant: Cc1ccc(N)nc1
Reactant: CCOC(=O)c1cc(Oc2ccc(S(C)(=O)=O)cc2)c2cc(C(F)F)oc2c1
Agent: C[Al](C)Cl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)c2cc(Oc3ccc(S(C)(=O)=O)cc3)c3cc(C(F)F)oc3c2)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.8 %

Procedure:
2-Amino-5-methylpyridine (264 mg, 2.44 mmol) was dissolved in DCE (10 mL) at 0° C., then Al(CH3)2Cl (2.44 mL, 1M in hexanes) was added drop wise. After the addition, the ice-bath was removed, and the mixture was stirred for 30 minutes at room temperature. Ethyl 2-(difluoromethyl)-4-[4-(methylsulfonyl)phenoxy]-1-benzofuran-6-carboxylate (100 mg, 0.244 mmol) was added, and the stirring was continued for 14 h. The reaction was quenched with potassium sodium tartrate tetrahydrate (20% w/w) cautiously. The product was extracted with CHCl3, washed with brine and dried over MgSO4. The product was purified by reverse phase HPLC to give the title compound (92 mg, 80%) as a white solid. 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 2.31 (s, 3 H) 3.08 (s, 3 H) 6.75 (t, J=53.94 Hz, 1 H) 6.98 (s, 1 H) 7.12-7.20 (m, 2 H) 7.51 (d, J=1.01 Hz, 1 H) 7.58 (dd, J=8.46, 2.15 Hz, 1 H) 7.91-7.96 (m, 2 H) 7.97 (s, 1 H) 8.11 (d, J=2.15 Hz, 1 H) 8.23 (d, J=8.46 Hz, 1 H) 8.54 (s, 1 H). LCMS m/z 473.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[CH2:7][C@H:8]([C:18]1[O:22][N:21]=[C:20]([C:23](OCC)=[O:24])[N:19]=1)[CH2:9][CH2:10][CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[N:31]1[C:40]2[CH2:39][CH2:38][NH:37][CH2:36][C:35]=2[CH:34]=[CH:33][CH:32]=1.C(N(CC)CC)C>C(O)C>[CH:12]1([CH2:11][CH2:10][CH2:9][C@@H:8]([C:18]2[O:22][N:21]=[C:20]([C:23]([N:37]3[CH2:38][CH2:39][C:40]4[N:31]=[CH:32][CH:33]=[CH:34][C:35]=4[CH2:36]3)=[O:24])[N:19]=2)[CH2:7][C:6]([O:5][C:1]([CH3:3])([CH3:4])[CH3:2])=[O:28])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: CCOC(=O)c1noc([C@H](CCCC2CCCCC2)CC(=O)OC(C)(C)C)n1
Reactant: c1cnc2c(c1)CNCC2
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(C(=O)N2CCc3ncccc3C2)no1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
A solution of ethyl 5-{(1R)-1-[2-(tert-butoxy)-2-oxoethyl]-4-cyclohexylbutyl}-1,2,4-oxadiazole-3-carboxylate (Preparation 3) (300 mg, 0.76 mmol) in ethanol (4 ml) was treated with 5,6,7,8-tetrahydro[1,6]naphthyridine dihydrochloride (Chem.Pharm.Bull.; 32; 7; 1984; 2522-2529) (0.79 g, 3.80 mmol) and triethylamine (1.27 ml, 9.13 mmol) and the resulting mixture was heated at 60° C. under a nitrogen atmosphere for 16 hours. The mixture was cooled and the solvent removed under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a gradient system of dichloromethane:ethyl acetate (90:10) gradually changing to dichloromethane:ethyl acetate (50:50) to afford the title compound (281 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].Cl.Cl.[NH2:19][CH:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)CC)C.CCN=C=NCCCN(C)C.Cl>ClCCl>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:10][CH2:11][CH2:12][CH2:13][C:14]([NH:19][CH:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=3)[CH2:22][CH2:21]2)=[O:16])=[CH:8][CH:9]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc(CCCCC(=O)O)cc1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(CCCCC(=O)NC2CCN(Cc3ccc(Cl)c(Cl)c3)CC2)cc1
Reaction time: 12 h
Yield: 55.7 %

Procedure:
5-(4-Acetylphenyl)valeric acid (996 mg) and 4-amino-1-(3,4-dichlorobenzyl)piperidine dihydrochloride (1.50 g) were suspended in dichloromethane (40 mL), and triethylamine (1.26 mL) and EDC hydrochloride (953 mg) were added to the suspension. The suspension was stirred for 12 hrs. The reaction mixture was washed with water and then saturated brine and dried, and the solvent was evaporated under reduced pressure. Diethyl ether was added to the residue to crystallize to give the title compound (1.16 g) as a white solid.
Reaction SMILES: [Na].[CH2:2]([SH:5])[CH:3]=[CH2:4].[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11](Cl)=[C:12]([CH3:15])[C:13]=1[CH3:14]>CO>[CH3:6][O:7][C:8]1[N:9]=[N:10][C:11]([S:5][CH2:2][CH:3]=[CH2:4])=[C:12]([CH3:15])[C:13]=1[CH3:14]
Reactant: COc1nnc(Cl)c(C)c1C
Reactant: C=CCS
Agent: [Na]
Solvent: CO
Product: C=CCSc1nnc(OC)c(C)c1C

Procedure:
0.23 g(0.01 mol) of metallic sodium was dissolved in 30 ml of absolute methanol and then mixed with 0.93 ml(0.01 mol) of allylmercaptan. To this mixture was added 1.73 g(0.01 mol) of 3-methoxy-4,5-dimethyl-6-chloropyridazine obtained from Preparation 5. The reaction solution was refluxed for one hour and then treated according to the same manner as Example 1 to obtain the title compound as a freezing pale white crystal.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1.[CH2:23]([O:25][C:26](=[O:31])[CH:27]=[C:28]([CH3:30])[CH3:29])[CH3:24].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:29][C:28]([N:1]1[CH:5]=[C:4]([C:6]2[CH:11]=[CH:10][N:9]=[C:8]3[N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][C:7]=23)[CH:3]=[N:2]1)([CH3:30])[CH2:27][C:26]([O:25][CH2:23][CH3:24])=[O:31]
Reactant: CCOC(=O)C=C(C)C
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ccnc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CC(C)(C)n1cc(-c2ccnc3c2ccn3COCC[Si](C)(C)C)cn1
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.8 %

Procedure:
4-(1H-Pyrazol-4-yl)-1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridine (220 mg, 0.0006996 mol) and 3-methyl-2-butenoic acid ethyl ester (292 μL, 0.00210 mol) were dissolved in DMF (10 mL). Cesium carbonate (912 mg, 0.00280 mol) was added and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with water, and the product was extracted with MTBE several times. The combined extracts were dried over sodium sulfate and concentrated. The crude residue was purified by flash column chromatography (0-60% EtOAc/Hexanes) to afford ethyl 3-methyl-3-[4-(1-[2-(trimethylsilyl)ethoxy]methyl-1H-pyrrolo[2,3-b]pyridin-4-yl)-1H-pyrazol-1-yl]butanoate (244 mg, 79%). 1H NMR (300 MHz, CDCl3): δ 8.37 (d, 1H), 8.11 (s, 1H), 8.09 (s, 1H), 7.45 (d, 1H), 7.24 (d, 1H), 6.79 (d, 1H), 5.77 (s, 2H), 4.10 (q, 2H), 3.62 (dd, 2H), 3.04 (s, 2H), 1.88 (s, 6H), 1.20 (t, 3H), 0.98 (dd, 2H), 0.00 (s, 9H); MS(ES): 443 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH:5]=[CH:6][C:7]1[S:15][C:10]2[NH:11][C:12](=[O:14])[CH2:13][C:9]=2[CH:8]=1)[CH3:2].[NH:17]1[CH:21]=[CH:20][CH:19]=[C:18]1[CH:22]=O>N1CCCCC1.CC(O)C>[CH2:1]([O:3][C:4](=[O:16])/[CH:5]=[CH:6]\[C:7]1[S:15][C:10]2[NH:11][C:12](=[O:14])[C:13](=[CH:22][C:18]3[NH:17][CH:21]=[CH:20][CH:19]=3)[C:9]=2[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C=Cc1cc2c(s1)NC(=O)C2
Reactant: O=Cc1ccc[nH]1
Solvent: CC(C)O
Solvent: C1CCNCC1
Product: CCOC(=O)/C=C\c1cc2c(s1)NC(=O)C2=Cc1ccc[nH]1
Temperature: 75 °C
Yield: 24.5 %

Procedure:
3-(5-Oxo-5,6-dihydro-4H-thieno[2,3-b]pyrrol-2-yl)-acrylic acid ethyl ester (30 mg, 0.13 mmol) was dissolved in a solution of 1% piperidine in 2-propanol (1 ml). Pyrrole-2-carboxaldehyde (0.15 mmol, 14 mg) was added in one portion and the mixture heated at 75° C. for 30 minutes. The reaction mixture was poured into an ice/water mixture (4 ml) and the precipitated solid was collected by filtration and washed with water to give 10 mg of (Z)-3-[5-Oxo-4-(1H-pyrrol-2-ylmethylene)-5,6-dihydro-4H-thieno[2,3-b]pyrrol-2-yl]-acrylic acid ethyl ester as a red solid. MS(ES): mle 315 [M+H].
Reaction SMILES: [Br:1][CH2:2][CH2:3]Br.C(=O)([O-])[O-].[K+].[K+].[Cl:11][C:12]1[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[CH:15]=[CH:14][C:13]=1[OH:21]>CN(C=O)C.C(OCC)(=O)C>[Br:1][CH2:2][CH2:3][O:21][C:13]1[CH:14]=[CH:15][C:16]([N+:18]([O-:20])=[O:19])=[CH:17][C:12]=1[Cl:11]
Reactant: O=[N+]([O-])c1ccc(O)c(Cl)c1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1ccc(OCCBr)c(Cl)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
36.6 mL (416 mmol) of 1,2-dibromoethane is dissolved in 200 mL of DMF and 11.5 g (83.3 mmol) of potassium carbonate is added. 7.20 g (41.6 mmol) of 2-chloro-4-nitrophenol in 40 mL of DMF is slowly added dropwise to this mixture. The mixture is stirred for 3 hours at ambient temperature. The solvent is eliminated, the residue is taken up in ethyl acetate and washed with saturated saline solution. The organic phase is dried over sodium sulfate. The solvent is eliminated and the residue is purified through a silica gel column with a gradient of petroleum ether/ethyl acetate (4:1 to 9:1). Yield: 7.9 g (68% of theory); Rf value: 0.55 (silica gel, petroleum ether/ethyl acetate=3:1); C8H7BrClNO3.
Reaction SMILES: [O:1]=[C:2]1[N:13]2[C:14]3[C:10]([CH:11]=[CH:12]2)=[C:9]([CH:15]=O)[CH:8]=[CH:7][C:6]=3[CH2:5][NH:4][CH2:3]1.[CH3:17][O:18][NH2:19].Cl>CCO.N1C=CC=CC=1>[CH3:17][O:18][N:19]=[CH:15][C:9]1[CH:8]=[CH:7][C:6]2[CH2:5][NH:4][CH2:3][C:2](=[O:1])[N:13]3[C:14]=2[C:10]=1[CH:11]=[CH:12]3
Reactant: O=Cc1ccc2c3c1ccn3C(=O)CNC2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Solvent: CCO
Product: CON=Cc1ccc2c3c1ccn3C(=O)CNC2
Yield: 23 %

Procedure:
A solution of 1-oxo-1,2,3,4-tetrahydro-[1,4]diazepino[6,7,1-hi]indole-7-carbaldehyde (Example 45, 0.050 g, 0.234 mmol) and MeONH2. HCl (0.020 g, 0.242 mmol) in EtOH (5 mL) and pyridine (5 mL) was refluxed for 20 h. The reaction mixture was then evaporated to dryness and the residue was taken up in H2O and extracted with EtOAc several times. The combined organic layers were dried over anhydrous MgSO4, filtered and concentrated. The residue was purified by flash silica gel chromatography eluting with a gradient of 0-1% MeOH in CHCl3 to give 0.036 g (63%) of the (E) and 0.013 g (23%) of the (Z) isomers. (Z) isomer: 1H NMR (DMSO-d6) δ 3.54-3.58 (m, 2H), 3.96 (s, 3H), 4.43 (bs, 2H), 7.27 (t, 1H, J=9.0 Hz), 7.89-7.92 (m, 2H), 8.14 (d, 1H, J=9.0 Hz), 8.21 (s, 1H), 8.35-8.39 (m, 1H). HRMS calcd for C13H13N3O2 (M+) 243.1008, found 243.1020. Anal. (C13H13N3O2.0.1 H2O.0.1 EtOAc) C, H, N. (E) isomer: 1H NMR (DMSO-d6) δ 3.55 (bs, 2H), 3.87 (s, 3H), 4.37 (bs, 2H), 7.27 (t, 1H, J=7.5 Hz), 7.75 (s, 1H), 7.91 (d, 1H, J=7.5 Hz), 8.24 (d, 1H, J=7.5 Hz), 8.34-8.38 (m, 2H). HRMS calcd. for C13H13N3O2 (M+) 243.1008, found 243.1016. Anal. (C13H13N3O2.0.25 H2O) C, H, N.
Reaction SMILES: [CH3:1][NH:2][S:3]([CH3:6])(=[O:5])=[O:4].C(#N)C.Cl[C:11]1[N:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=2)[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=1>O>[F:23][C:20]1[CH:21]=[CH:22][C:17]([C:15]2[C:14]([C:24]([O:26][CH3:27])=[O:25])=[C:13]([CH:28]([CH3:30])[CH3:29])[N:12]=[C:11]([N:2]([CH3:1])[S:3]([CH3:6])(=[O:5])=[O:4])[N:16]=2)=[CH:18][CH:19]=1
Reactant: COC(=O)c1c(-c2ccc(F)cc2)nc(Cl)nc1C(C)C
Reactant: CNS(C)(=O)=O
Solvent: O
Solvent: CC#N
Product: COC(=O)c1c(-c2ccc(F)cc2)nc(N(C)S(C)(=O)=O)nc1C(C)C
Temperature: 81.5 °C
Yield: 88.9 %

Procedure:
In a 25 mL-volume glass flask equipped with a stirrer, a thermometer and a reflux condenser were placed 546 mg (5 mmol.) of N-methylmethanesulfonamide, 551 mg (5 mmol.) of sodium t-pentoxide, 10 mL of acetonitrile, and 309 mg (1 mmol.) of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine. The mixture was heated to 81-82° C. for 3 hours under refluxing, to carry out reaction. After the reaction was complete, the reaction mixture was cooled to room temperature. To the cooled mixture was added 10 mL of water, and the aqueous mixture was extracted with ethyl acetate. The ethyl acetate portion was separated, and dried over anhydrous magnesium sulfate. The dried ethyl acetate portion was filtered and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (column: Wako Gel C-200, eluent: hexane/ethyl acetate (2:1, volume ratio)). There was obtained 339 mg of 4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonyl-2-(N-methyl-N-methanesul-fonylamino)pyrimidine. The yield was 89% (based on the amount of 2-chloro-4-(4-fluorophenyl)-6-isopropyl-5-methoxycarbonylpyrimidine).
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH2:9][S:10][CH3:11])([O-])=O.[H][H].C(=O)([O-])[O-].[Na+].[Na+]>[Ni]>[NH2:1][C:4]1[CH:18]=[CH:17][CH:16]=[CH:15][C:5]=1[CH2:6][NH:7][C@H:8]([C:12]([OH:14])=[O:13])[CH2:9][S:10][CH3:11]
Reactant: CSC[C@H](NCc1ccccc1[N+](=O)[O-])C(=O)O
Reactant: [H][H]
Agent: [Ni]
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: CSC[C@H](NCc1ccccc1N)C(=O)O

Procedure:
N-(2-amino-benzyl)-S-methyl-cysteine of the formula ##STR11## was prepared in analogy to Example 1 (b) by reducing N-(2-nitro-benzyl)-S-methyl-cysteine with hydrogen under pressure in the presence of sodium carbonate and Raney nickel. Melting point: 193° C.
Reaction SMILES: O[CH:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CCN(S(F)(F)[F:34])CC.C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:34][CH:2]([C:9]1[CH:10]=[C:11]([N:15]([CH2:21][C:22]2[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=2)[S:16]([CH2:19][CH3:20])(=[O:18])=[O:17])[CH:12]=[CH:13][CH:14]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CCN(CC)S(F)(F)F
Reactant: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(O)c2ccccc2)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CCS(=O)(=O)N(Cc1cccnc1)c1cccc(C(F)c2ccccc2)c1
Reaction time: 8 h

Procedure:
To a solution of N-(3-(α-hydroxybenzyl)phenyl)-N-(ethylsulfonyl)pyrid-3-ylmethylamine (0.106 g, 2.77 mmol) in DCM was added DAST (0.040 mL, 3.05 mmol). The reaction was stirred overnight and poured into saturated NaHCO3 solution and extracted with EtOAc, dried over MgSO4, filtered, and concentrated. The residue was chromatographed on silica gel with 2:1 DCM/EtOAc to give the title compound as a clear oil. 1H NMR: 8.47 (dd,J=4.9, 1.5 Hz, 1H), 8.33 (d,J=2.0 Hz, 1H), 7.63 (dt,J=7.8, 2.0 Hz, 1H), 7.38-7.28 (m,4H), 7.24-7.16 (m,6H), 4.89 (AofAB,d,J=14.8 Hz, 1H), 4.83 (BofABd,J=14.8 Hz, 1H), 3.07 (q,J=7.3 Hz, 2H), 1.40 (t,J=7.3 Hz, 3H). MS calcd. 384.1; MS (M+1) 385.1.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1.[O:11]1[CH:16]=[CH:15][CH2:14][CH2:13][CH2:12]1>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[O:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH:12]1[O:1][CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Cl:8])=[CH:5][CH:4]=1
Reactant: C1=COCCC1
Reactant: OCc1ccc(CCl)cc1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: ClCc1ccc(COC2CCCCO2)cc1
Temperature: 5 °C
Reaction time: 24 h
Yield: 947.1 %

Procedure:
p-Hydroxymethylbenzyl chloride (1.33 kg, 1 mole) in dichloromethane (6 liters) was charged to a 10 liter Morton flask. Addition of 3,4-dihydro-2H-pyran (925 g, 1.1 moles) to the flask was followed by cooling to 5° C. Pyridinium p-toluenesulfonate (1.25 g, 5 mmoles) was added as a catalyst. The contents were allowed to warm up to 20°-25° C. and stirred for 24 hours. The contents were washed with water followed by a sodium bicarbonate solution and then dried over anhydrous magnesium sulfate. The residue, after removal of solvent, was kept under high vacuum (1-2 mm Hg) for 24 hours and provided 2.28 kg (95% yield) of the desired product. 1H NMR spectral data were as follows: (CDCl3, 300 MHz): δ7.4 (s, 4H), 4.75 (t, 1H), 4.65 (AB quartet, 2H, J=13 Hz), 4.6 (s, 2H), 3.85 (m, 1H), 3.55 (m, 1H), 1.5-1.95 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][CH:3]=1.[C:11]1(=[O:17])[O:16][C:14](=[O:15])[CH2:13][CH2:12]1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH2:9][C:11](=[O:17])[CH2:12][CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(=O)c1ccc(Cl)cc1
Reactant: O=C1CCC(=O)O1
Product: O=C(O)CCC(=O)CC(=O)c1ccc(Cl)cc1

Procedure:
U.S. Pat. No. 5,117,054 describes a process wherein p-chloroacetophenone is reacted with succinic anhydride to form 4-chloro-γ,ε-dioxo-benzenehexanoic acid which is reacted with acetic anhydride or acetyl chloride to yield 5-[2-(4-chlorophenyl)-2-oxoethylidene]dihydro-2(3H)-furanone. This compound is then added to a mixture of N-methylhydroxylamine hydrochloride and an amine base such as triethylamine, Hunig's base, pyridine or lutidine and a solvent such as methylene chloride or chloroform to form 4-chloro-N-hydroxy-N-methyl-γ,ε-dioxo-benzenehexanamide which is combined with 4-methoxyphenyl hydrazine hydrochloride, an amine base as described above in an alcoholic solvent such as methanol, ethanol or propanol.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH:29]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][N:13](C(OC(C)(C)C)=O)[CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1.Cl>CO.O1CCOCC1>[NH2:1][C:2]1[C:7]2=[C:8]([C:25]3[CH:26]=[CH:27][C:28]4[C:32]([CH:33]=3)=[N:31][N:30]([CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[CH:29]=4)[CH:9]=[C:10]([C:11]3([OH:24])[CH2:16][CH2:15][CH2:14][NH:13][CH2:12]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCC(O)(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: Nc1ncnn2c(C3(O)CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Temperature: 25 °C
Reaction time: 17 h
Yield: 96 %

Procedure:
To a solution of tert-butyl 3-[4-amino-5-(2-benzyl-2H-indazol-6-yl)pyrrolo[2,1-f][1,2,4]triazin-7-yl]-3-hydroxypiperidine-1-carboxylate (270 mg, 0.500 mmol) in MeOH (2.5 mL) was added 4M HCl in dioxane (1.25 mL). The mixture was stirred at rt for 17 h. The mixture was concentrated and the residue was dissolved in 3:1 CHCl3/isopropanol (25 mL). The mixture was washed with saturated, aqueous NaHCO3 (25 mL), brine, dried (Na2SO4) and concentrated to dryness to afford 211 mg (96%) of the desired product, which was approximately 50% pure. ES-MS m/z 440.19 [M+H]+, HPLC RT (min) 1.97. 50 mg of material was purified by preparative HPLC using a gradient elution from 15% to 40% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 28 mg of pure desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.89 (s, 1 H), 7.80 (d, 1 H), 7.58 (s, 1 H), 7.27-7.37 (m, 5 H), 7.13 (dd, 1.36 Hz, 1 H), 6.69 (s, 1 H), 5.64 (s, 2 H), 5.19 (s, 1 H), 2.77-2.93 (m, 2 H), 2.43-2.54 (m, 3 H), 2.12 (br s, 1 H), 1.68-1.88 (m, 2 H), 1.33-1.46 (m, 1 H); ES-MS m/z 439.92 [M+H]+, HPLC RT (min) 2.06.
Reaction SMILES: C(OC([N:8]1[CH2:11][C:10]([O:13][C:14]2[CH:15]=[C:16]3[C:25](=[CH:26][C:27]=2[CH3:28])[O:24][CH2:23][C:22]2[N:17]3[CH:18]([CH3:30])[C:19](=[O:29])[NH:20][N:21]=2)([CH3:12])[CH2:9]1)=O)(C)(C)C.[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(Cl)Cl>[F:34][C:33]([F:36])([F:35])[C:31]([OH:37])=[O:32].[CH3:30][CH:18]1[N:17]2[C:22]([CH2:23][O:24][C:25]3[C:16]2=[CH:15][C:14]([O:13][C:10]2([CH3:12])[CH2:9][NH:8][CH2:11]2)=[C:27]([CH3:28])[CH:26]=3)=[N:21][NH:20][C:19]1=[O:29]
Reactant: Cc1cc2c(cc1OC1(C)CN(C(=O)OC(C)(C)C)C1)N1C(=NNC(=O)C1C)CO2
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1OC1(C)CNC1)N1C(=NNC(=O)C1C)CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 44 %

Procedure:
To a solution of 3-(4,7-dimethyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yloxy)-3-methyl-azetidine-1-carboxylic acid tert-butyl ester (0.024 g, 0.058 mmol) in DCM (2 mL) was added TFA (0.35 mL) and the mixture was stirred at ambient temperature for 2 h. The solvent was removed in vacuo. The residue was purified by preparative HPLC (Table 3, Method 6) to give 4,7-dimethyl-6-(3-methyl-azetidin-3-yloxy)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one trifluoroacetic acid as a pale solid (0.008 g, 44%). LC/MS (Table 1, Method 5) Rt=1.913 min.; MS m/z: 317 [M+H]+
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[N:13]=[C:14]=[O:15].[NH2:16][C:17]1[CH:34]=[CH:33][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:19][CH:18]=1.CO>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[CH:19][C:20]([O:21][C:22]2[CH:23]=[C:24]3[C:28](=[CH:29][CH:30]=2)[C:27](=[O:31])[NH:26][C:25]3=[O:32])=[CH:33][CH:34]=1)=[O:15]
Reactant: Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reactant: COc1ccc(C(F)(F)F)cc1N=C=O
Solvent: ClCCl
Solvent: CO
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1ccc(Oc2ccc3c(c2)C(=O)NC3=O)cc1
Reaction time: 12 h
Yield: 90.3 %

Procedure:
To a stirring solution of 2-methoxy-5-(trifluoromethyl)phenyl isocyanate (0.10 g, 0.47 mmol) in CH2Cl2 (1.5 mL) was added 5-(4-aminophenoxy)isoindoline-1,3-dione (Method A3, Step 3; 0.12 g, 0.47 mmol) in one portion. The resulting mixture was stirred for 12 h, then was treated with CH2Cl2 (10 mL) and MeOH (5 mL). The resulting mixture was sequentially washed with a 1N HCl solution (15 mL) and a saturated NaCl solution (15 mL), dried (MgSO4) and concentrated under reduced pressure to afford N-(2-methoxy-5-(trifluoromethyl)phenyl-N′-(4-(1,3-dioxoisoindolin-5-yloxy)phenyl)urea as a white solid (0.2 g, 96%): TLC (70% EtOAc/30% hexane) Rf 0.50; 1H NMR (DMSO-d6) δ 3.95 (s, 3H), 7.31-7.10 (m, 6H), 7.57 (d, J=9.3 Hz, 2H), 7.80 (d, J=8.7 Hz, 1H), 8.53 (br s, 2H), 9.57 (s, 1H), 11.27 (br s, 1H); HPLC ES-MS 472.0 ((M+H)+, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C:9]1=[O:14].[Br:15]Br>C(Cl)(Cl)Cl>[Br:15][CH:10]1[C:9](=[O:14])[CH:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[CH2:13][CH2:12][CH2:11]1
Reactant: O=C1CCCCC1c1ccccc1Cl
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccccc1Cl
Temperature: 25 °C
Yield: 112.7 %

Procedure:
2-(2-Chloro-phenyl)-cyclohexanone (51 mg, 0.25 mmol) was dissolved in chloroform (1 mL). To this solution bromine (42.3 mg, 0.27 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (81 mg) which was used directly in the next step without further purification.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][C:14]#[CH:15])(=O)=O)=CC=1.[N:16]1([C:22]2[N:27]=[CH:26][CH:25]=[CH:24][N:23]=2)[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:12]([N:19]1[CH2:20][CH2:21][N:16]([C:22]2[N:23]=[CH:24][CH:25]=[CH:26][N:27]=2)[CH2:17][CH2:18]1)[CH2:13][C:14]#[CH:15]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1cnc(N2CCNCC2)nc1
Solvent: ClCCCl
Solvent: CCN(C(C)C)C(C)C
Product: C#CCCN1CCN(c2ncccn2)CC1
Yield: 54.6 %

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.14 g), 2-(piperazin-1-yl)pyrimidine (1.06 g) and diisoproylethylamine (1.24 mL) in 1,2-dichloroethane (6 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 1:1→1:0) afforded 2-(4-(but-3-ynyl)piperazin-1-yl)pyrimidine (0.60 g).