Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][CH2:27][N:28](C(OC(C)(C)C)=O)[CH2:29][CH2:30][C:3]1=2.[ClH:38]>ClCCl>[ClH:38].[CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([N:11]3[CH:16]=[CH:15][C:14]([CH2:17][CH2:18][C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:13][C:12]3=[O:25])[CH:7]=[CH:6][C:5]=2[C:4]2[CH2:26][CH2:27][NH:28][CH2:29][CH2:30][C:3]1=2
Reactant: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)nc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Agent: Cl
Solvent: ClCCl
Product: Cn1c2c(c3ccc(-n4ccc(CCc5ccccc5)nc4=O)cc31)CCNCC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 52 %

Procedure:
To a solution of tert-butyl 6-methyl-8-(2-oxo-4-phenethylpyrimidin-1(2H)-yl)-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H) carboxylate (44 mg, 0.088 mmol) in dichloromethane (4.0 mL) was added HCl (2M in diethyl ether, 4.0 mL). The resulting slurry was stirred at room temperature for 2 days and then concentrated under reduced pressure. The residue was purified by semi-preparative HPLC (Phenomenex Luna C18 (2), 250.0×21.20 mm, 10 micron, H2O with 0.05% TFA and CH3CN with 0.05% TFA). The clean fractions were combined and concentrated under reduced pressure. The resulting trifluoroacetate salt was treated with aqueous sodium carbonate and extracted with EtOAc (2×). The combined organic extract was washed with brine, dried over Na2SO4 and concentrated under reduced pressure. The free base was converted to the HCl salt using HCl in methanol and lypholized to provide the title compound (19.8 mg, 52%) as a light yellow solid: 1H NMR (500 MHz, CD3OD) δ 8.03 (d, J=7.0 Hz, 1H), 7.58 (d, J=8.5 Hz, 1H), 7.45 (d, J=2.0 Hz, 1H), 7.30-7.28 (m, 4H), 7.22-7.17 (m, 1H), 7.05 (dd, J=8.5, 2.0 Hz, 1H), 6.56 (d, J=6.5 Hz, 1H), 3.73 (s, 3H), 3.42-3.34 (m, 4H), 3.27-3.25 (m, 2H), 3.17-3.15 (m, 2H), 3.10-3.08 (m, 2H), 3.04-3.02 (m, 2H); ESI MS m/z 399 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1.[NH2:29][C@H:30]1[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C(=O)C>O>[F:1][CH:2]([F:28])[C:3]1[N:7]([C:8]2[CH:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:29][C@H:30]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31]3)[N:9]=2)[C:6]2[CH:24]=[CH:25][CH:26]=[CH:27][C:5]=2[N:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: CS(=O)(=O)c1nc(N2CCOCC2)cc(-n2c(C(F)F)nc3ccccc32)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)(C)OC(=O)N1CC[C@H](Nc2nc(N3CCOCC3)cc(-n3c(C(F)F)nc4ccccc43)n2)C1
Temperature: 100 °C
Reaction time: 1 h
Yield: 32 %

Procedure:
A mixture of 2-difluoromethyl-1-[2-(methylsulfonyl)-6-morpholin-4-ylpyrimidin-4-yl]-1H-benzimidazole (770 mg), tert-butyl (3S)-3-aminopyrrolidine-1-carboxylate (525 mg), potassium carbonate (390 mg), and N,N-dimethylacetamide (19 mL) was stirred in a microwave reactor at 100° C. for 1 hour. The reaction mixture was cooled to room temperature and then poured into water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and then the residue was purified by amino silica gel column chromatography (hexane:ethyl acetate=80:20-50:50) to obtain tert-butyl (3S)-3-({4-[2-(difluoromethyl)-1H-benzimidazol-1-yl]-6-morpholin-4-ylpyrimidin-2-yl}amino)pyrrolidine-1-carboxylate (310 mg) as a pale yellow amorphous substance.
Reaction SMILES: Cl.[C:2]([O:6][C:7](=[O:29])[C@H:8]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH2:18])=[CH:13][CH:12]=1)([CH3:5])([CH3:4])[CH3:3].C(N(CC)CC)C.Cl[CH2:38][CH2:39][S:40](Cl)(=[O:42])=[O:41].C(Cl)(Cl)Cl>ClCCl>[C:2]([O:6][C:7](=[O:29])[C@H:8]([CH2:20][CH2:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[NH:9][C:10](=[O:19])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][S:40]([CH:39]=[CH2:38])(=[O:42])=[O:41])=[CH:13][CH:12]=1)([CH3:4])([CH3:5])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC[C@H](NC(=O)c1ccc(CN)cc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)CCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: C=CS(=O)(=O)NCc1ccc(C(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58.3 %

Procedure:
4-(aminomethyl)benzoyl-glutamic acid di-t-butyl ester hydrochloride as obtained in Reference Example 37 (255 mg) and triethylamine (0.27 ml) were dissolved in dichloromethane (4 ml). To this solution, a solution of chloroethylsulfonyl chloride (161 mg) in dichloromethane (4 ml) was added drop by drop under ice cooling conditions over a period of about 15 minutes, followed by stirring at the same ternperature for 30 minutes. To the mixture, ice water (12 ml). and chloroform (10 ml) were added, followed by vigorous stirring, after which the organic layer was separated, and concentrated to dryness under reduced pressure. The resulting residue was purified by silica gel column chromatography (methanol:chloroform=1:99) to yield the title compound (172 mg, yield 58.3%) as a colorless solid.
Reaction SMILES: Cl.Cl.[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH2:12])[CH:6]=1.[C:13](O)(=[O:17])[C:14](O)=[O:15].Cl>>[CH3:3][O:4][C:5]1[CH:6]=[C:7]2[C:8](=[CH:9][CH:10]=1)[N:11]=[C:14]([OH:15])[C:13]([OH:17])=[N:12]2
Reactant: O=C(O)C(=O)O
Reactant: COc1ccc(N)c(N)c1
Agent: Cl
Product: COc1ccc2nc(O)c(O)nc2c1
Temperature: 90 °C
Yield: 97.5 %

Procedure:
In a 50 L round bottomed flask equipped with a mechanical stirrer, thermocouple and condenser was added 4-methoxy-1,2-phenylenediamine dihydrochloride salt (Compound 9) (2.65 kg @ 98 wt %, 12.30 mol), oxalic acid (1.582 kg @ 98 wt. %, 17.22 mol) and 3N HCl(aq) (17.8 L) under nitrogen. The grey heterogeneous slurry was heated to 90° C. with steam for 7.25 hours. The reaction was monitored by HPLC. The resulting grey slurry was then cooled to an internal temperature of 20° C. overnight The slurry was filtered, water (1.0-1.5 L/Kg) was used to help with the transfer. The light grey solids were washed with 2 cake volumes water (5.0-5.5 L/Kg). The solids were dried under vacuum/N2 sweep for 24 hours, at which time the solids were still very wet. The product was then slurry washed with methanol, and dried over 48 hours at 40-45° C. in a vacuum oven to give 2.304 kg of Compound 10 as an off-white product (97% yield) of 99.95% purity by HPLC assay. There was no methanol by NMR and the KF=0.05 wt. % water.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9](F)[CH:10]=1)[C:5]([OH:7])=[O:6].[CH3:12][O-:13].[Na+].Cl>CN(C=O)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([O:13][CH3:12])[CH:10]=1)[C:5]([OH:7])=[O:6]
Reactant: O=C(O)c1cc(F)cc(F)c1
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(F)cc(C(=O)O)c1
Temperature: 120 °C
Reaction time: 12 h
Yield: 74.4 %

Procedure:
To a solution of 3,5-difluoro-benzoic acid (6.38 g, 40.3 mmol) in DMF (10 mL), NaOMe (6.48 g, 121 mmol) was added at room temperature. The mixture was stirred at 120° C. for 12 h, cooled to room temperature and filtered. The solid obtained was dissolved in H2O and pH was adjusted to 3˜4 with 4M aqueous HCl solution. The mixture was filtered again and the white solid was washed with water (3×10 mL) to give 5.1 g of 3-fluoro-5-methoxybenzoic acid. 1H NMR (CDCl3): δ 7.37-7.43 (m, 2H), 6.83-6.88 (m, 1H), 3.86 (s, 3H).
Reaction SMILES: [N:1]1[C:6]([OH:7])=[CH:5][CH:4]=[CH:3][C:2]=1[OH:8].C([O:11][C:12](=O)[CH:13]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=1)[C:14](=O)[CH3:15])C.O>CO.C(S([O-])(=O)=O)(F)(F)F.C(S([O-])(=O)=O)(F)(F)F.[Zn+2]>[OH:7][C:6]1[N:1]=[C:2]2[O:8][C:12](=[O:11])[C:13]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[C:20]([N+:24]([O-:26])=[O:25])[CH:19]=3)=[C:14]([CH3:15])[C:3]2=[CH:4][CH:5]=1
Reactant: Oc1cccc(O)n1
Reactant: CCOC(=O)C(Cc1cccc([N+](=O)[O-])c1)C(C)=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Zn+2]
Solvent: O
Solvent: CO
Product: Cc1c(Cc2cccc([N+](=O)[O-])c2)c(=O)oc2nc(O)ccc12
Temperature: 75 °C
Reaction time: 30 h
Yield: 57.4 %

Procedure:
Zn(OTf)2 (669 mg, 1.84 mmol) was added to a suspension of pyridine-2,6-diol (204 mg, 1.84 mmol) and 2-(3-nitrobenzyl)-3-oxobutyric acid ethyl ester (488 mg, 1.84 mmol) in methanol (10 mL), and the mixture was stirred at 75° C. for 30 hours. The reaction mixture was then poured into water and extracted with ethyl acetate. The organic extract was washed with saturated saline and dried over magnesium sulfate. It was then concentrated under reduced pressure to yield a crude product, which was then purified by column chromatography to yield the title compound (330 mg, 57%).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH:14]=[CH:13][C:12]2[N:8]3[C:9]([C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=5)=[CH:24][CH:23]=4)=[CH:21][C:7]=13)=[C:10]1[C:18](=[O:19])[O:17][C:15](=[O:16])[C:11]1=2)(=[O:3])[CH3:2].[CH3:36][NH:37][CH3:38]>>[C:1]([O:4][CH2:5][C:6]1[C:7]2[N:8]3[C:12](=[CH:13][CH:14]=1)[C:11]([C:15]([OH:17])=[O:16])=[C:10]([C:18](=[O:19])[N:37]([CH3:38])[CH3:36])[C:9]3=[C:20]([C:22]1[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:24][CH:23]=1)[CH:21]=2)(=[O:3])[CH3:2]
Reactant: CNC
Reactant: CC(=O)OCc1ccc2c3c(c4c(-c5ccc(OCc6ccccc6)cc5)cc1n24)C(=O)OC3=O
Product: CC(=O)OCc1ccc2c(C(=O)O)c(C(=O)N(C)C)c3c(-c4ccc(OCc5ccccc5)cc4)cc1n23
Yield: 68 %

Procedure:
5-Acetoxymethyl-3-(4-benzyloxyphenyl)pyrrolo[2,1,5-cd]indolizine-1,2-dicarboxylic acid anhydride was reacted with dimethylamine by the general synthetic principles outlined in example 62, step 9, to afford 5-acetoxymethyl-3-(4-benzyloxyphenyl)-2-dimethylcarbamoylpyrrolo[2,1,5-cd]indolizine-1-carboxylic acid as crystals in 68% yield. 1H-NMR (DMSO-d6, 300 MHz) δ: 2.22 (s, 3H); 2.72 (s, 3H); 3.08 (s, 3H); 5.20 (s, 2H); 5.70 (s, 2H); 7.19 (d, 2H); 7.32-7.53 (m, 5H); 7.82 (d, 2H); 7.89 (s, 1H); 8.02 (d, 1H); 8.32 (d, 1H); 12.78 (br s, 1H).
Reaction SMILES: [C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)S[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2].OO.[S:20]([O-:23])(O)=[O:21].[Na+]>C(O)(=O)C>[C:1]([C:4]1[C:5]([Cl:17])=[C:6]2[C:11](=[C:12]([Cl:14])[CH:13]=1)[S:20](=[O:23])(=[O:21])[CH2:9][CH2:8][C:7]2([CH3:16])[CH3:15])(=[O:3])[CH3:2]
Reactant: O=S([O-])O
Reactant: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1cc(Cl)c2c(c1Cl)C(C)(C)CCS2(=O)=O
Temperature: 80 °C
Yield: 71 %

Procedure:
1 ml of acetic acid was added to 1.22 g (4.22 mmol) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman, 1.43 g (12.66 mmol) of a 30% hydrogen peroxide aqueous solution was further added, and the mixture was heated at 80° C. for 2 hours. To the reaction mixture was added 10 ml of a 2% sodium hydrogensulfite, and a precipitated solid was recovered by filtration to give 0.96 g (yield 71%) of 6-acetyl-5,8-dichloro-4,4-dimethylthiochroman-1,1-dioxide.
Reaction SMILES: [Cl:1][C:2]1[N:3]([CH2:18]NC(=O)C)[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)=[C:5]([C:8]#[N:9])[C:6]=1[Cl:7].P(Cl)(Cl)([Cl:25])=O>O>[Cl:7][C:6]1[C:5]([C:8]#[N:9])=[C:4]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[C:12]([Cl:17])[CH:11]=2)[N:3]([CH2:18][Cl:25])[C:2]=1[Cl:1]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(=O)NCn1c(Cl)c(Cl)c(C#N)c1-c1ccc(Cl)c(Cl)c1
Solvent: O
Product: N#Cc1c(Cl)c(Cl)n(CCl)c1-c1ccc(Cl)c(Cl)c1
Yield: 78 %

Procedure:
A mixture of N-{[2,3-dichloro-4-cyano-5-(3,4-dichlorophenyl)pyrrol-1-yl]methyl}acetamide (3.2 g, 0.0085 mol) and phosphorus oxychloride (6.51 g, 4 mL, 0.0424 mol) is heated at reflux temperature for 40 minutes, cooled, diluted with water and extracted with ethyl acetate. The combined organic extracts are washed sequentially with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to obtain a solid. Recrystallization of the solid from an ethyl acetate/heptane solution gives the title product as a pale brown solid (2.35 g, mp 153°-156.0° C.) which is identified by IR and NMR spectral analyses.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][NH:6]2.[I:11]I.[OH-].[K+].OS([O-])=O.[Na+]>CN(C=O)C>[F:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([I:11])=[N:5][NH:6]2
Reactant: Fc1cccc2[nH]ncc12
Reactant: II
Agent: O=S([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Fc1cccc2[nH]nc(I)c12
Reaction time: 2 h

Procedure:
To a solution of 4-fluoroindazole A-1 (5.00 g, 36.7 mmol) in DMF (80 mL) was added I2 (18.6 g, 73.5 mmol) and KOH (7.73 g, 134 mmol) successively at rt. After 2 h, the reaction mixture was poured into aq. 10% NaHSO3 (200 mL) and extracted with EtOAc (200 mL*3). The combined organic layers were washed with H2O and brine, dried over Na2SO4, and concentrated. The crude solid was washed with PE to give the title compound as a yellow solid. LCMS (ESI) calc'd for C7H5FIN2 [M+H]+: 262.9. found: 262.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:23][CH:24]=[CH2:25])[CH2:10][O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[C:15](OC)=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl-].[Cl-].[Ca+2].[BH4-].[Na+]>CCO.C1COCC1>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:23][CH:24]=[CH2:25])[CH2:10][O:11][CH2:12][C:13]1[CH:22]=[CH:21][CH:20]=[CH:19][C:14]=1[CH2:15][OH:16])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=CC[C@H](COCc1ccccc1C(=O)OC)NC(=O)OC(C)(C)C
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: CCO
Product: C=CC[C@H](COCc1ccccc1CO)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.8 %

Procedure:
A solution of compound 18h (4.2 g, 12.0 mmol) in EtOH/THF (30 mL, v/v=1/1) was treated with CaCl2 (5.3 g, 48.0 mmol) and the resulting slurry was cooled under argon in an ice bath. To this mixture was added NaBH4 (3.6 g, 96 mmol) portionwise. After 1 h the ice bath was removed and the reaction mixture was allowed to stir at rt for 16 hr. The mixture was quenched with 10% aq. Na2CO3 and water and the resulting thick, white slurry was extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by CC to give the desired compound 18i (3.0 g, 78% yield) as yellow oil. LCMS (m/z): 322.1 (MH+).
Reaction SMILES: [CH3:1][CH:2]([OH:6])[CH2:3][CH2:4][CH3:5].CC(C)([O-])C.[Na+].Cl[C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1>>[CH3:1][CH:2]([O:6][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[CH:19][N:20]2[CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][O:24]2)=[C:16]([NH2:29])[N:15]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCC(C)O
Reactant: Nc1nc(Cl)nc2c1ncn2C1CCCCO1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Product: CCCC(C)Oc1nc(N)c2ncn(C3CCCCO3)c2n1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To 2-pentanol (3.65 mL) was added sodium tert-butoxide (760 mg) in portions over 5 mins. The mixture was stirred at room temperature until homogeneous. 2-Chloro-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (500 mg) was added and the reaction was heated at 50° C. overnight, then for a further 72 h. The reaction mixture was cooled and quenched with water (10 mL) and was extracted with EtOAc (3×25 mL). The organics were combined, washed with brine (30 mL), dried over MgSO4, filtered and concentrated in vacuo to give crude title compound as a viscous yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C@@H:5]([C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[OH:6].[CH3:12][C:13]([CH3:16])([O-])[CH3:14].[K+]>CS(C)=O>[CH3:1][NH:2][CH2:3][CH2:4][C@H:5]([O:6][C:3]1[C:16]2[C:13](=[CH:14][CH:9]=[CH:10][CH:11]=2)[CH:12]=[CH:5][CH:4]=1)[C:7]1[S:8][CH:9]=[CH:10][CH:11]=1
Reactant: CNCC[C@H](O)c1cccs1
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CNCC[C@H](Oc1cccc2ccccc12)c1cccs1

Procedure:
In the step (iv) of the process of the present invention, the reaction of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol and halonaphthalene is carried out by using a proper base such as potassium tert-butoxide in a suitable amount of DMSO to form (S)-(+)-N-methyl-3-(1-naphthyloxy)-3-(2-thienyl)propylamine (Duloxetine®). The excess amount of halonaphthalene, ranging from about 1.5 to 4 equivalents, can be recovered. The reaction is performed at a temperature ranged from 20° C. to 110° C., preferably from 40° C. to 90° C., for 1 to 24 hours. One embodiment of the present invention is conducted in the presence of excess halonaphthalene and a suitable amount of DMSO to overcome the problems regarding racemization and environmental protection. In one preferred embodiment, DMSO is used in amounts ranging from one to ten times the amount of (S)-(−)-3-methylamino-1-(2-thienyl)propan-1-ol, more preferably from one to five times the amount of (S)-(+3-methylamino-1-(2-thienyl)propan-1-ol.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1.[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:55])([CH3:54])[CH3:53])[CH:48]=3)[C:43]2=[O:57])=[N:35][CH:36]=[CH:37][C:38]=1B(O)O)(=[O:30])[CH3:29].[O-]P([O-])([O-])=O.[K+].[K+].[K+].O.O.O.C([O-])(=O)C.[Na+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C.O>[C:28]([O:31][CH2:32][C:33]1[C:34]([N:42]2[N:51]=[CH:50][C:49]3[C:44](=[C:45]([F:56])[CH:46]=[C:47]([C:52]([CH3:54])([CH3:53])[CH3:55])[CH:48]=3)[C:43]2=[O:57])=[N:35][CH:36]=[CH:37][C:38]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH2:22][CH2:21][N:20]([CH:23]4[CH2:26][O:25][CH2:24]4)[CH2:19][C@@H:18]3[CH3:27])=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[N:7]=1)(=[O:30])[CH3:29]
Reactant: CC(=O)OCc1c(B(O)O)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Reactant: C[C@H]1CN(C2COC2)CCN1c1ccc(Nc2cc(Cl)nn(C)c2=O)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CCN(C5COC5)C[C@@H]4C)cn3)c(=O)n(C)n2)ccnc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Temperature: 100 °C
Yield: 30.4 %

Procedure:
A round-bottomed flask equipped with a reflux condenser was charged with 117c (200 mg, 0.50 mmol), 3-(acetoxymethyl)-2-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)pyridin-4-yl-boronic acid 116c (300 mg, 0.75 mmol), Pd(dppf)Cl2 (25 mg, 0.025 mmol), K3PO4 (220 mg, 1.0 mmol), sodium acetate trihydrate (150 mg, 1.0 mmol), and acetonitrile/water (20/1 mL). After three cycles of vacuum/argon flush, the mixture was heated at 100° C. for 2 h. It was then cooled to room temperature and filtered. The filtrate was evaporated under reduced pressure and the residue was purified with silica-gel column chromatography eluting with 25:1 dichloromethane/methanol to afford 117d as a yellow solid (110 mg, 42%). MS-ESI: [M+H]+ 724.4
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][NH:5][C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[H-].[Na+].C1OCCOCCOCCOCCOC1.[S:32]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33]1>>[CH3:1][C:2]1[C:3]([CH:13]=[O:14])=[CH:4][N:5]([S:37]([C:34]2[CH:35]=[CH:36][S:32][CH:33]=2)(=[O:39])=[O:38])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=S(=O)(Cl)c1ccsc1
Reactant: Cc1c(C=O)c[nH]c1-c1ccccc1
Agent: C1COCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Product: Cc1c(C=O)cn(S(=O)(=O)c2ccsc2)c1-c1ccccc1
Yield: 87.6 %

Procedure:
Using 4-methyl-5-phenyl-1H-pyrrole-3-carbaldehyde (185 mg), sodium hydride (60% in oil, 60 mg), 15-crown-5 (0.30 mL) and (3-thienyl)sulfonyl chloride (237 mg), a procedure as in Reference Example 219 was performed to give the title compound as a solid (yield 290 mg, 88%).
Reaction SMILES: [CH3:1][C:2]1[S:10][C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]=1[N+:11]([O-])=O.C(N(CC)CC)C.[Cl:21][C:22]([Cl:27])([Cl:26])[C:23](Cl)=[O:24]>CO.C(Cl)Cl.[Ni]>[Cl:21][C:22]([Cl:27])([Cl:26])[C:23]([NH:11][C:3]1[C:4]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[S:10][C:2]=1[CH3:1])=[O:24]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: Cc1sc2cnccc2c1[N+](=O)[O-]
Agent: [Ni]
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: Cc1sc2cnccc2c1NC(=O)C(Cl)(Cl)Cl
Temperature: 0 °C
Reaction time: 16 h
Yield: 49.7 %

Procedure:
Methyl-3-nitro-thieno[2,3-c]pyridine (2.05 g, 10.6 mmol) was dissolved in MeOH (250 mL) and added to a suspension of Raney-Nickel (20 g) in MeOH (100 mL). The reaction flask was flushed with H2. After 3 hours at room temperature under a balloon of H2 the reaction mixture was filtered and condensed to provide a yellow solid. This was then dissolved in DCM (100 mL) and triethylamine (1.6 mL, 11.5 mmol) was added. The solution was cooled to 0° C. in an ice bath. Trichloroacetyl chloride (1.3 mL, 11.6 mmol) was added dropwise. The solution was allowed to slowly warm to room temperature and stirred overnight (16 hrs), then concentrated to a yellow paste and partitioned between equal volumes of water and EtOAc (150 mL each). After separation the organic phase was washed with water (2×70 mL) and brine (1×70 mL), dried (MgSO4) and condensed to provide the title compound as a tan solid (1.63 g, 42%). Used without purification.
Reaction SMILES: [N:1]1[CH:2]=[C:3]([C:10]([OH:12])=O)[N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.C(Cl)(=O)C(Cl)=O.[NH2:19][C:20]1[CH:21]=[C:22]([CH:25]=[CH:26][C:27]=1[F:28])[C:23]#[N:24]>ClCCl.CN(C=O)C.N1C=CC=CC=1>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([F:28])=[C:20]([NH:19][C:10]([C:3]2[N:4]3[CH:9]=[CH:8][CH:7]=[CH:6][C:5]3=[N:1][CH:2]=2)=[O:12])[CH:21]=1)#[N:24]
Reactant: O=C(O)c1cnc2ccccn12
Reactant: N#Cc1ccc(F)c(N)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)c(NC(=O)c2cnc3ccccn23)c1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirring suspension of imidazo[1,2-a]pyridine-3-carboxylic acid (1) (3.0 g, 18.5 mmol) in anhydrous dichloromethane (50 mL) at 0° C. was added dropwise oxalyl chloride (4.84 mL, 55.5 mmol). Then, three drops of anhydrous DMF was added and the reaction mixture was stirred at room temperature for 15 minutes. The solvent was concentrated and the crude solid was added to a stirring solution of 3-amino-4-fluorobenzonitrile (48) (2.5 g, 18.5 mmol) in anhydrous pyridine (50 mL) at room temperature. The reaction was stirred for 20 minutes and quenched with water (200 mL) with stirring for another 10 minutes. Then the precipitate was filtered and dried in air to yield N-(5-cyano-2-fluorophenyl)imidazo[1,2-a]pyridine-3-carboxamide (49). 1H NMR (400 MHz, d6-DMSO) δ 10.40 (s, 1H), 9.43 (td, J=1.2, 6.8 Hz, 1H), 8.63 (s, 1H), 8.21 (dd, J=2.0, 7.2 Hz, 1H), 7.78-7.84 (m, 2H), 7.54-7.63 (m, 2H), 7.22 (dt, J=1.2, 6.8, 1H). MS m/z 281.1 (M+1)+.
Reaction SMILES: N.[SH2:2].[C:3]([O:7][C:8]([NH:10][CH2:11][C:12]#[N:13])=[O:9])([CH3:6])([CH3:5])[CH3:4].O>CO>[C:3]([O:7][C:8]([NH:10][CH2:11][C:12](=[S:2])[NH2:13])=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: S
Reactant: CC(C)(C)OC(=O)NCC#N
Agent: N
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCC(N)=S
Yield: 75.7 %

Procedure:
25 g of ammonia gas and 50 g of hydrogen sulfide gas were successively dissolved in 230 ml of methanol with ice-cooling and stirring. To this was added 71.45 g of (tert-butoxycarbonylamino)acetonitrile, and the mixture was stirred overnight at room temperature. The reaction solution was cooled with ice. To this was slowly added 500 ml of water, and the mixture was stirred for an additional 2 hours with ice- cooling. The crystals precipitated were collected by filtration, washed with 300 ml of cold water, and then dried under reduced pressure to give 65.88 g of (tert-butoxycarbonyl-amino)acetothioamide as colorless crystals.