Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[H-].[Na+].[S:14](Cl)([C:17]1[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=1)(=[O:16])=[O:15].C(OCC)(=O)C>CN(C=O)C.CCCCCC>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]([I:11])=[CH:9][N:8]([S:14]([C:17]3[CH:23]=[CH:22][C:20]([CH3:21])=[CH:19][CH:18]=3)(=[O:16])=[O:15])[C:5]2=[N:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1cnc2[nH]cc(I)c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(S(=O)(=O)n2cc(I)c3cc(Br)cnc32)cc1
Reaction time: 0.5 h
Yield: 96.3 %

Procedure:
5-Bromo-3-iodo-1H-pyrrolo[2,3-b]pyridine (7 g, 21.6 mmol) dissolved in dry DMF (50 ml) was added drop wise to a stirred slurry of sodium hydride (1.73 g, 43.2 mmol) in dry DMF (20 ml) at 0° C. and stirred for 30 min. Tosyl chloride (6.15 g, 32.4 mmol) dissolved in dry DMF (14 ml) and added slowly to the above reaction mixture and the reaction temperature was brought to RT and stirred for 30 min. The reaction was monitored by TLC (15% Ethyl acetate in hexane). The reaction mixture was quenched with ice water (500 ml) at 0° C. and filtered the solid precipitated and dried under vacuum to afford 9.92 g (96.3% yield) of 5-bromo-3-iodo-1-tosyl-1H-pyrrolo[2,3-b]pyridine MS: m/z=476.8 (M+1).
Reaction SMILES: [NH2:1][C:2]1[N:16]=[CH:15][C:14](Br)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5].CC1(C)C(C)(C)OB([C:26]2[CH:27]=[C:28]([S:32]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)(=[O:34])=[O:33])[CH:29]=[CH:30][CH:31]=2)O1>>[NH2:1][C:2]1[N:16]=[CH:15][C:14]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([S:32]([N:35]3[CH2:40][CH2:39][CH:38]([OH:41])[CH2:37][CH2:36]3)(=[O:34])=[O:33])[CH:27]=2)=[CH:13][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1)=[O:5]
Reactant: CC1(C)OB(c2cccc(S(=O)(=O)N3CCC(O)CC3)c2)OC1(C)C
Reactant: Nc1ncc(Br)cc1C(=O)Nc1ccncc1
Product: Nc1ncc(-c2cccc(S(=O)(=O)N3CCC(O)CC3)c2)cc1C(=O)Nc1ccncc1

Procedure:
Reaction of 2-amino-5-bromo-N-pyridin-4-yl-nicotinamide with 1-[3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzenesulfonyl]-piperidin-4-ol gives “A79”; method 1: HPLC/MS: 1.29 min, [M+H]=454;
Reaction SMILES: I.[NH2:2][CH2:3][CH:4]1[CH2:9][CH2:8][CH2:7][CH:6]([N:10]2[C:19]3[C:14](=[CH:15][CH:16]=[N:17][CH:18]=3)[C:13]3=[N:20][O:21][C:22]([CH3:23])=[C:12]3[C:11]2=[O:24])[CH2:5]1.[C:25](O)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:23][C:22]1[O:21][N:20]=[C:13]2[C:14]3[C:19](=[CH:18][N:17]=[CH:16][CH:15]=3)[N:10]([CH:6]3[CH2:7][CH2:8][CH2:9][CH:4]([CH2:3][NH:2][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH2:5]3)[C:11](=[O:24])[C:12]=12
Reactant: O=C(O)c1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCC(CN)C1)c1cnccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: I
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1onc2c1c(=O)n(C1CCCC(CNC(=O)c3ccccc3)C1)c1cnccc21
Yield: 74.4 %

Procedure:
Combine 5-(3-aminomethyl-cyclohexyl)-3-methyl-5H-2-oxa-1,5,7-triaza-cyclopenta[a]naphthalen-4-one hydroiodide (136 mg, 0.31 mmol) with benzoic acid (42 mg, 0.34 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (65 mg, 0.34 mmol), 1-hydroxy-7-azabenzo-triazole (46 mg, 0.34 mmol), and N,N-diisopropylethyl amine (0.20 mL, 1.15 mmol), in N,N-dimethylformamide (4 mL) and stir over a weekend at ambient temperature. Concentrate in vacuo and take up in water and extract with dichloromethane. Dry over sodium sulfate and concentrate in vacuo. Elute over silica gel using methanol/dichloromethane to give 96 mg (74%) of the desired product as an off white solid. MS(ES): (M+1)+ 417.2, 418.2 m/z.
Reaction SMILES: [CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-])=O)=[CH:20][CH:19]=2)=[N:4]1)[CH3:2].[Sn].Cl>C(O)C>[CH2:1]([N:3]1[CH:7]=[C:6]([C:8]2[C:13]([F:14])=[CH:12][N:11]=[C:10]3[NH:15][CH:16]=[CH:17][C:9]=23)[C:5]([C:18]2[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=2)=[N:4]1)[CH3:2]
Reactant: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc([N+](=O)[O-])cc2)n1
Agent: Cl
Agent: [Sn]
Solvent: CCO
Product: CCn1cc(-c2c(F)cnc3[nH]ccc23)c(-c2ccc(N)cc2)n1
Temperature: 70 °C

Procedure:
To a suspension of 4-[1-ethyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-5-fluoro-1H-pyrrolo[2,3-b]pyridine (0.655 mmol) in ethanol (3.5 mL) was added tin(0) powder (3.28 mmol) and 6N aqueous hydrochloric acid (3.5 mL) and the mixture was heated to 70° C. for 1 h. The reaction mixture was allowed to cool to room temperature, filtered through a pad of celite. The filtrate was diluted with ethyl acetate (10 mL) and washed with 1N sodium hydroxide (5 mL). The aqueous layer was extracted with ethyl acetate (3×10 mL) and the combined extracts were dried over sodium sulfate, filtered through a pad of celite and concentrated under reduced pressure to give the title compound as a yellow solid which was used without further purification. ESMS [M+H]+: 322
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)[CH:8]=2)[CH:3]=[N:2]1.[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1C1C2C(=CC(C=O)=CC=2)NN=1>>[S:21]1[CH:25]=[CH:24][N:23]=[C:22]1[C:3]1[C:4]2[C:9](=[CH:8][C:7](/[CH:10]=[C:11]3/[C:12](=[O:20])[NH:13][C:14]4[C:19]/3=[CH:18][CH:17]=[CH:16][CH:15]=4)=[CH:6][CH:5]=2)[NH:1][N:2]=1
Reactant: O=Cc1ccc2c(-c3nccs3)n[nH]c2c1
Reactant: O=C1Nc2ccccc2/C1=C\c1ccc2cn[nH]c2c1
Product: O=C1Nc2ccccc2/C1=C\c1ccc2c(-c3nccs3)n[nH]c2c1

Procedure:
According to the procedure for the synthesis of (E)-3-((1H-indazol-6-yl)methylene)indolin-2-one, except substituting 3-(thiazol-2-yl)-1H-indazole-6-carbaldehyde (4.6 mg, 0.02 mmol), the title compound was prepared as a yellow solid (2.3 mg, 36%). 1H NMR (400 MHz, d6-DMSO) δ 13.75 (br. s, 1H), 10.64 (br. s, 1H), 8.44 (d, J=8.5 Hz, 1H), 8.03 (d, J=3.3 Hz, 1H), 7.96 (s, 1H), 7.80-7.78 (m, 2H), 7.60 (d, 7.3 Hz, 1H), 7.58 (d, J=7.5 Hz, 1H), 7.25 (td, J=7.5, 1.0 Hz, 1H), 6.88 (d, J=7.8 Hz, 1H), 6.85 (td, J=7.5, 1.0 Hz, 1H); MS ESI 345.1 [M+H]+, calcd for [C19H12N4OS+H]+ 345.07.
Reaction SMILES: [F:1][C:2]([C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:14][C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=[CH:9][CH:8]=2)([F:4])[F:3].[OH:19]O>C(O)(=O)C>[F:3][C:2]([F:1])([F:4])[C:5]1[NH:6][C:7]2[C:12]([C:13]=1[S:14]([C:15]([F:16])([F:17])[F:18])=[O:19])=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: FC(F)(F)Sc1c(C(F)(F)F)[nH]c2ccccc12
Reactant: OO
Solvent: CC(=O)O
Product: O=S(c1c(C(F)(F)F)[nH]c2ccccc12)C(F)(F)F
Temperature: 50 °C
Yield: 50 %

Procedure:
A mixture of 2-(trifluoromethyl -3-[(trifluoromethyl)thio]indole (0.96 g, 3.36 mmole) and 30% hydrogen peroxide (1.15 mL, 10.1 mmole) in acetic acid is heated at 50° C. for 16 hours, cooled to room temperature, poured onto water and filtered. The filter cake is air-dried to give the title product as a colorless solid, 0.535 g (50% yield), mp 183°-185° C., identified by IR, 1HNMR, 13CNMR, 19FNMR and mass spectral analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH:8]([C:15]([OH:17])=[O:16])[CH2:7][CH2:6][C:5]2=1.Cl.[CH2:19](O)[CH3:20]>>[CH2:19]([O:16][C:15]([CH:8]1[CH2:7][CH2:6][C:5]2[C:4]3[C:12](=[CH:13][CH:14]=[C:2]([CH3:1])[CH:3]=3)[NH:11][C:10]=2[CH2:9]1)=[O:17])[CH3:20]
Reactant: Cc1ccc2[nH]c3c(c2c1)CCC(C(=O)O)C3
Reactant: CCO
Agent: Cl
Product: CCOC(=O)C1CCc2c([nH]c3ccc(C)cc23)C1
Reaction time: 48 h

Procedure:
6-Methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid (10 g.) was dissolved in 300 ml. of warm ethanol and 5 ml. of 7N alcoholic hydrogen chloride was added. The solution was thoroughly mixed and allowed to remain at room temperature for 2 days. After cooling in an ice bath for 5 hours, the mixture was filtered and washed with several volumes of ethanol. Upon drying, a yield of 7.3 g. of 6-methyl-1,2,3,4-tetrahydrocarbazole-2-carboxylic acid ethyl ester, m.p. 117°-118° , was obtained.
Reaction SMILES: [CH2:1]1[CH:10]2[N:5]([C:6](=[O:15])[C:7]3[CH:14]=[CH:13][CH:12]=[CH:11][C:8]=3[CH2:9]2)[CH2:4][CH2:3][CH2:2]1.[N+:16]([O-])([O-:18])=[O:17].[K+].[OH-].[NH4+]>S(=O)(=O)(O)O>[N+:16]([C:13]1[CH:12]=[CH:11][C:8]2[CH2:9][CH:10]3[N:5]([C:6](=[O:15])[C:7]=2[CH:14]=1)[CH2:4][CH2:3][CH2:2][CH2:1]3)([O-:18])=[O:17]
Reactant: O=C1c2ccccc2CC2CCCCN12
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Agent: [NH4+]
Product: O=C1c2cc([N+](=O)[O-])ccc2CC2CCCCN12
Reaction time: 8 h
Yield: 91.6 %

Procedure:
1,3,4,6,11,11a-Hexahydro-2H-benzo[b]quinolizin-6-one (3.78 g, 18.7 mmol) was dissolved in concentrated sulfuric acid (50 ml) at 0° C., potassium nitrate (2.02 g, 20 mmol) was added and the reaction mixture was stirred overnight. The reaction mixture was poured onto ice (200 g) and was partially neutralized with concentrated ammonium hydroxide. The precipitate was collected and air-dried to give the title compound as a yellow solid (4.22 g, 92%), m.p. 137-42° C.
Reaction SMILES: COC1C=CC([NH:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:35])[F:34])[CH:26]=3)[CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:21])[F:20])[CH:13]=[CH:14][CH:15]=2)=CC=1.CI.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54]NC2C=C(CC(NCC3C=CC=C(OC(F)(F)C(F)F)C=3)(O)C(F)(F)F)C=CC=2)=[CH:50][CH:49]=1>O1CCCC1>[CH3:46][O:47][C:48]1[CH:53]=[CH:52][C:51]([CH2:54][NH:9][C:10]2[CH:11]=[C:12]([N:16]([CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]([F:37])([F:36])[CH:33]([F:34])[F:35])[CH:26]=3)[CH2:17][CH:18]([OH:23])[C:19]([F:22])([F:20])[F:21])[CH:13]=[CH:14][CH:15]=2)=[CH:50][CH:49]=1
Reactant: COc1ccc(Nc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Reactant: COc1ccc(CNc2cccc(CC(O)(NCc3cccc(OC(F)(F)C(F)F)c3)C(F)(F)F)c2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(CNc2cccc(N(Cc3cccc(OC(F)(F)C(F)F)c3)CC(O)C(F)(F)F)c2)cc1
Temperature: 23 °C
Reaction time: 2 h

Procedure:
To a solution of 3-[[3-[(4methoxyphenyl)amino]phenyl]-[[3-(1,1,2,2-tetrafluoro-ethoxy)phenyl]methyl]amino]-1,1,1-trifluoro-2-propanol (44.3 mg, 0.083 mmol) in tetrahydrofuran (1.0 mL), methyl iodide (6.21 μL, 0.099 mmol) and cesium carbonate (36.6 mg, 0.112 mmol) were added. The dark solution was stirred at 23° C. for 2 h, then heated to 55° C. for 12 h. The reaction mixture was filtered through celite, and the residue was purified by silica gel chromatography eluting with 20% ethyl acetate in hexane to give 25.2 mg (55%) of the desired 3-[[3-[(4methoxyphenyl)methylamino]-phenyl][[3-(1,1,2,2-tetrafluoroethoxy)phenyl]methylamino]-1,1,1-trifluoro-2-propanol product as an orange oil. HRMS calcd for C26H25F7N2O3: 546.1753, found: 546.1750 [M]+. 1H NMR (CDCl3), δ 3.54 (m, 1H), 3.38 (s, 3H), 3.65-3.80 (m, 4H), 4.59 (s, 2H), 5.90 (tt, 1H), 6.20 (d, 1H), 6.37 (d, 1H), 6.68 (s, 1H), 6.76 (d, 2H), 6.90-7.15 (m, 6H), 7.31 (t, 1H). 19F NMR (CDCl3), δ −137.21 (d, 2F), −88.52 (s, 2F), −78.79 (s, 3F).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:7]=[C:6]([Cl:8])[S:5][C:4]=1[S:9]([NH2:12])(=[O:11])=[O:10].[CH2:13]([N:27]=[C:28]=S)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>>[Cl:8][C:6]1[S:5][C:4]2[S:9](=[O:10])(=[O:11])[N:12]=[C:28]([NH:27][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])[NH:2][C:3]=2[CH:7]=1
Reactant: CCCCCCCCCCCCCCN=C=S
Reactant: Nc1cc(Cl)sc1S(N)(=O)=O
Agent: Cl
Product: CCCCCCCCCCCCCCNC1=NS(=O)(=O)c2sc(Cl)cc2N1

Procedure:
The title compound was prepared from 3-amino-5-chlorothiophene-2-sulfonamide hydrochloride and n-tetradecyl isothiocyanate by a procedure analogous to the procedure described in example 3Bc-d; mp 157°-158° C.; 1H-NMR (DMSO-d6): δ 0.85 (distorted t, 3H), 1.25 (m, 22H), 1.50 (m, 2H), 3.19 (q, 2H), 7.05 (s, 1H), 7.26 (br. s, 1H), 10.95 (br. s, 1H).
Reaction SMILES: F[B-](F)(F)F.[CH2:6]([O+](CC)CC)[CH3:7].[CH3:13][C:14]1([CH3:21])[NH:17][C:16](=[O:18])[C:15]1([CH3:20])[CH3:19].C([O-])([O-])=O.[K+].[K+]>ClCCl>[CH2:6]([O:18][C:16]1[C:15]([CH3:20])([CH3:19])[C:14]([CH3:21])([CH3:13])[N:17]=1)[CH3:7]
Reactant: CC1(C)NC(=O)C1(C)C
Reactant: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC1=NC(C)(C)C1(C)C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 60 ml (1M) of triethyloxonium tetraflouroborate in dichloromethane was added 5 g (0.039 mol) of tetramethylazetidinone in 10 ml of dry CH2Cl2 under an inert atmosphere. The reaction mixture was stirred for 1 hour at room temperature and then was refluxed for 1 hour. After cooling, the reaction mixture was added dropwise to 20 ml of a 50% K2CO3 solution at -10° C. and the mixture was diluted with 20 ml of CH2Cl2 and then filtered. The organic phase was separated out and immediately dried over MgSO4. After filtration, the solvent was stripped off under vacuum and the residue was distilled at 78° to 80° C./50 mmHg to obtain the product as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:12])[C:9](O)=O)[CH:5]=[CH:6][CH:7]=1.[C:13]1([NH2:20])[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[NH2:19]>>[NH:19]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:20]=[C:9]1[CH:8]([C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Br:1])[CH:3]=1)[OH:12]
Reactant: Nc1ccccc1N
Reactant: O=C(O)C(O)c1cccc(Br)c1
Product: OC(c1cccc(Br)c1)c1nc2ccccc2[nH]1
Temperature: 25 °C

Procedure:
A mixture of (3-bromophenyl)hydroxyacetic acid (20 g) and ortho-phenylenediamine (9.36 g) in 5N aqueous hydrochloric solution (100 mL) is heated under reflux for 4 h and cooled back to room temperature. The precipitate is separated by filtration, rinsed with acetonitrile and dried under vacuum with phosphorus pentoxyde et give 1H-benzimidazol-2-yl(3-bromophenyl)methanol as a white crystalline solid used without further purification.
Reaction SMILES: [C:1](Cl)(=O)C.[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([OH:12])=[O:11])=[C:8]([CH3:16])[CH:7]=1>CO>[OH:5][C:6]1[C:14]([CH3:15])=[CH:13][C:9]([C:10]([O:12][CH3:1])=[O:11])=[C:8]([CH3:16])[CH:7]=1
Reactant: Cc1cc(C(=O)O)c(C)cc1O
Reactant: CC(=O)Cl
Solvent: CO
Product: COC(=O)c1cc(C)c(O)cc1C
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Acetyl chloride (0.107 mL) was added dropwise to a solution of 4-hydroxy-2,5-dimethylbenzoic acid (example 18, step a) (0.249 g) in methanol (15 mL) and the resulting mixture stirred at room temperature for 72 h. Acetyl chloride (0.107 mL) was then added and the reaction heated to 50° C. and stirred at this temperature overnight. The reaction was concentrated and the residue purified by silica gel chromatography eluting with 1:1 isohexane:ethyl acetate to 100% ethyl acetate gradient. The fractions containing product were combined and evaporated in vacuo to give the subtitled compound as a white solid. Yield 0.25 g.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:5]([C:14]([O:16]CC)=[O:15])[S:6][C:7]=1[N:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)#[N:2].[OH-].[Na+].Cl>CO.O>[C:1]([C:3]1[C:4]([CH:19]([C:25]2[CH:30]=[CH:29][C:28]([Cl:31])=[C:27]([Cl:32])[CH:26]=2)[CH2:20][CH2:21][N:22]([CH3:24])[CH3:23])=[C:5]([C:14]([OH:16])=[O:15])[S:6][C:7]=1[N:8]1[CH2:9][CH2:10][O:11][CH2:12][CH2:13]1)#[N:2]
Reactant: CCOC(=O)c1sc(N2CCOCC2)c(C#N)c1C(CCN(C)C)c1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)CCC(c1ccc(Cl)c(Cl)c1)c1c(C(=O)O)sc(N2CCOCC2)c1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
To a solution of ethyl 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylate (29.0 mg, 0.0584 mmol) in methanol (0.500 mL) was added 1.030 M of sodium hydroxide in water (284 uL, 0.284 mmol). The reaction was stirred at rt over 2 days. The mixture was neutralized with 1.00 M of hydrochloric acid in water (0.292 mL), diluted with 5 mL of water and extracted with 10% MeOH/CHCl3 (×5). The combined organic layer was dried and concentrated, and the resulting white syrup/solid was lyophilized to provide 4-cyano-3-[1-(3,4-dichlorophenyl)-3-(dimethylamino)propyl]-5-(morpholin-4-yl)thiophene-2-carboxylic acid as a white solid (26 mg, 95% yield). LCMS: (AA) ES+ 468, 470, 472; 1H NMR (400 MHz, DMSO) δ 7.63-7.52 (d, J=8.4 Hz, 1H), 7.44-7.37 (s, 1H), 7.15-7.02 (d, J=8.1 Hz, 1H), 5.49-5.34 (d, J=9.4 Hz, 1H), 3.73-3.63 (t, J=4.8 Hz, 4H), 3.38-3.31 (dd, J=6.2, 4.0 Hz, 4H), 3.13-2.97 (s, 1H), 2.85-2.73 (s, 1H), 2.72-2.60 (s, 6H), 2.56-2.52 (m, 1H).
Reaction SMILES: [CH2:1]([C:3]1([CH2:23][C:24]([O:26]C)=[O:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=3[O:17][CH2:18][C:19]([F:22])([F:21])[F:20])[CH3:2].O>CO>[CH2:1]([C:3]1([CH2:23][C:24]([OH:26])=[O:25])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[C:14]([CH3:16])[CH:13]=[CH:12][C:11]=3[O:17][CH2:18][C:19]([F:21])([F:20])[F:22])[CH3:2]
Reactant: CCC1(CC(=O)OC)OCCc2c1[nH]c1c(OCC(F)(F)F)ccc(C)c21
Solvent: CO
Solvent: O
Product: CCC1(CC(=O)O)OCCc2c1[nH]c1c(OCC(F)(F)F)ccc(C)c21

Procedure:
A mixture consisting of 4-methyl-7-(2,2,2-trifluoroethoxy)tryptophol (9.8 g, 0.036 mol), methyl 3-methoxy-2-pentenoate (5.0 g, 0.035 mol), CH2Cl2 (400 mL) and BF3.Et2O (1 mL) was stirred at room temperature for 3 hours, washed with 5% NaHCO3, water, dried (MgSO4) and concentrated to afford 12 g of crude 1-ethyl-1,3,4,9-tetrahydro-5-methyl-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetic acid, methyl ester. Flash chromatography using 13% EtOAc-hexane gave 7.2 g of solid ester, mp 138°-140° C. The above ester was hydrolyzed in 400 mL MeOH containing 7.0 g KOH and 10 mL water by refluxing for 4 hours. The reaction solution was concentrated, diluted with water and extracted with ether (2×200 mL). The aqueous phase was acidified with 6N HCl and extracted with chloroform (2×200 mL). The combined chloroform extracts were washed with water, dried (MgSO4) and concentrated to afford 6.4 g of solid 1-ethyl-1,3,4,9-tetrahydro-5-methyl-8-(2,2,2-trifluoroethoxy)-pyrano[3,4-b]indole-1-acetic acid. Recrystallization from toluene-petroleum ether afforded 5.0 g (37%) of pure product, m.p. 149°-151° C.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5]([C:7]([CH3:49])([CH3:48])[CH2:8][O:9][C:10]([N:12]1[C:25]2[C:17](=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C@@H:16]([N:26]([CH2:33][C:34]2[CH:39]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:37]=[C:36]([C:44]([F:47])([F:46])[F:45])[CH:35]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11])=[O:6].Cl.C(OCC)(=O)C>CO.O>[C:5]([C:7]([CH3:49])([CH3:48])[CH2:8][O:9][C:10]([N:12]1[C:25]2[C:17](=[CH:18][C:19]3[CH2:20][CH2:21][CH2:22][C:23]=3[CH:24]=2)[C@@H:16]([N:26]([CH2:33][C:34]2[CH:35]=[C:36]([C:44]([F:47])([F:45])[F:46])[CH:37]=[C:38]([C:40]([F:42])([F:43])[F:41])[CH:39]=2)[C:27]2[N:28]=[N:29][N:30]([CH3:32])[N:31]=2)[CH2:15][CH2:14][CH2:13]1)=[O:11])([OH:6])=[O:4]
Reactant: COC(=O)C(C)(C)COC(=O)N1CCC[C@H](N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)c2nnn(C)n2)c2cc3c(cc21)CCC3
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@H]2CCCN(C(=O)OCC(C)(C)C(=O)O)c3cc4c(cc32)CCC4)n1
Temperature: 60 °C
Yield: 72.9 %

Procedure:
Add aqueous 5 M NaOH (2.4 mL, 12 mmol) to a solution of (S)-9-[(3,5-Bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-2,3,6,7,8,9-hexahydro-1H-5-aza-cyclohepta[f]indene-5-carboxylic acid 2-methoxycarbonyl-2-methyl-propyl ester (86 mg, 0.13 mmol) in methanol (3.4 mL). Heat the mixture at 60° C. for 1 h. Cool down to room temperature. Dilute with water and neutralize with 2 M HCl. Extract aqueous phase with ethyl acetate. Dry organic layers with anhydrous sodium sulphate and evaporate the solvent. Purify the residue by chromatography (elution with dichloromethane/methanol) to afford the title compound (62 mg, 73%). MS (ES+): 655 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][NH:9][C:10]2[N:11]=[C:12]([N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)[S:13][C:14]=2[C:15]([NH2:17])=[O:16])[CH:5]=[CH:6][CH:7]=1.C([O:28][C@@H:29]([CH3:33])[C:30](Cl)=O)(=O)C.[OH-].[Na+].Cl>O1CCCC1.CO>[Cl:1][C:2]1[C:3]([CH3:24])=[C:4]([CH2:8][N:9]2[C:10]3[N:11]=[C:12]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)[S:13][C:14]=3[C:15](=[O:16])[N:17]=[C:30]2[C@@H:29]([OH:28])[CH3:33])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O[C@@H](C)C(=O)Cl
Reactant: Cc1c(Cl)cccc1CNc1nc(N2CCOCC2)sc1C(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(Cl)cccc1Cn1c([C@H](C)O)nc(=O)c2sc(N3CCOCC3)nc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-{[(3-chloro-2-methylphenyl)methyl]amino}-2-(4-morpholinyl)-1,3-thiazole-5-carboxamide (200 mg, 0.545 mmol) in Tetrahydrofuran (THF) (20001) was added (1S)-2-chloro-1-methyl-2-oxoethyl acetate (164 mg, 1.090 mmol). The mixture was stirred at room temperature overnight, and then stirred at 60° C. for 3 h. To the mixture was added sodium hydroxide (454 μl, 2.73 mmol) and methanol (0.5 mL). After 30 min, the mixture was acidified (pH ˜5) with 6N HCl, and then concentrated. The residue was partitioned between dichloromethane and water. The organic layer was dried (sodium sulfate), filtered, and concentrated. The crude was purified by reversed-phase HPLC and subsequently converted to the HCl salt to provide 4-[(3-chloro-2-methylphenyl)methyl]-5-[(S)-1-hydroxyethyl]-2-(4-morpholinyl)[1,3]thiazolo[4,5-d]pyrimidin-7(4H)-one. (14 mg, 6%); LC/MS: MS (ES+) m/e 421 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 1.34 (d, J=6.3 Hz, 3H), 2.44 (s, 3H), 3.53-3.62 (m, 4H), 3.67 (m, 4H), 4.57 (q, J=6.3 Hz, 1H), 5.67 (s, 2H), 6.51 (d, J=7.8 Hz, 1H), 7.14 (m, 1H), 7.37 (d, J=7.8 Hz, 1H).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH2:8][CH2:9][CH3:10])[C:6](=[O:11])[N:5]([CH2:12][CH2:13][CH3:14])[C:4](=[O:15])[C:3]=1[NH:16][C:17](=O)/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1.[OH-].[Na+]>O1CCOCC1>[Cl:26][C:23]1[CH:24]=[CH:25][C:20](/[CH:19]=[CH:18]/[C:17]2[NH:16][C:3]3[C:4](=[O:15])[N:5]([CH2:12][CH2:13][CH3:14])[C:6](=[O:11])[N:7]([CH2:8][CH2:9][CH3:10])[C:2]=3[N:1]=2)=[CH:21][CH:22]=1
Reactant: CCCn1c(N)c(NC(=O)/C=C/c2ccc(Cl)cc2)c(=O)n(CCC)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: CCCn1c(=O)c2[nH]c(/C=C/c3ccc(Cl)cc3)nc2n(CCC)c1=O
Yield: 91.1 %

Procedure:
To Compound c (7.84 g, 20.1 mmol) were added 100 ml of dioxane and 100 ml of 2N aqueous solution of sodium hydroxide, followed by heating under reflux for 10 minutes. After cooling, the mixture was neutralized, and deposited crystals were collected by filtration and recrystallized from dioxane-water to give 6.83 g (yield: 91%) of Compound 5 as white crystals.
Reaction SMILES: [CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([OH:34])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([O:8]CC)=[O:7])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].BrCC(C)(C)C.[H-].[Na+].[Cl-].[NH4+]>CN(C=O)C>[CH:1]1([CH:4]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][O:18][C:19]3[CH:24]=[CH:23][C:22]([C:25]4[CH:30]=[C:29]([O:31][CH3:32])[CH:28]=[CH:27][C:26]=4[F:33])=[C:21]([OH:34])[CH:20]=3)[CH:12]=2)[CH2:5][C:6]([OH:8])=[O:7])[CH2:2][CH2:3]1
Reactant: CCOC(=O)CC(c1cccc(COc2ccc(-c3cc(OC)ccc3F)c(O)c2)c1)C1CC1
Agent: CC(C)(C)CBr
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CN(C)C=O
Product: COc1ccc(F)c(-c2ccc(OCc3cccc(C(CC(=O)O)C4CC4)c3)cc2O)c1
Temperature: 90 °C
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of ethyl 3-cyclopropyl-3-(3-(((2′-fluoro-2-hydroxy-5′-methoxybiphenyl-4-yl)oxy)methyl)phenyl)propanoate (203 mg) and potassium carbonate (179 mg) in DMF (3.0 mL) was added 1-bromo-2,2-dimethylpropane (0.11 mL), and the mixture was stirred at 90° C. for 1 hr. 60% Sodium hydride (35 mg) was added at room temperature, and the mixture was stirred at 50° C. for 3 hr. To the reaction mixture was added saturated aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (128 mg) as a brown oil.