Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7](OC)[CH:6]=[CH:5]2.C[N:18](C)C=O.N.O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N+:12]([O-:14])=[O:13])=[C:7]([NH2:18])[CH:6]=[CH:5]2
Reactant: COc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Reactant: CN(C)C=O
Agent: N
Solvent: CO
Solvent: O
Product: Nc1ccc2cc(Br)ccc2c1[N+](=O)[O-]
Temperature: 130 °C
Reaction time: 48 h
Yield: 95 %

Procedure:
6-bromo-2-methoxy-1-nitronaphthalene (12.6 g, 44.7 mmol), dimethylformamide (25.6 mL) and 7N NH3 solution in MeOH (128 mL, purchased from Sigma Aldrich) were combined in a Parr bomb. The bomb was heated in a lab oven at 130° C. After 48 hours, the reactor was removed from the oven and cooled to room temperature. The contents of the bomb were transferred to a glass round bottom flask. The bomb was thoroughly rinsed with dichloromethane and methanol, and the rinsings added to the flask. The contents of the flask were thoroughly concentrated on a rotary evaporator, leaving a brown solid. Water (200 mL) was added to the flask and the resulting suspension was agitated with a stir bar for 30 minutes. The resulting light brown powder was isolated by filtration, rinsing a few times with water. The filter cake was air dried over night to yield 6-bromo-1-nitronaphthalen-2-amine (11.6 g, >95% yield).
Reaction SMILES: [CH3:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([CH2:12][N:13]2[CH2:33][CH2:32][C:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([O:28]C)=[O:27])=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15][CH2:14]2)=[C:4](Br)[CH:3]=1.[F:35][C:36]1[C:41]([F:42])=[C:40]([F:43])[CH:39]=[CH:38][C:37]=1B(O)O.O.[OH-].[Li+]>O1CCOCC1.O.C(#N)C>[CH3:1][C:2]1[CH:3]=[C:4]([C:39]2[CH:38]=[CH:37][C:36]([F:35])=[C:41]([F:42])[C:40]=2[F:43])[C:5]([CH2:12][N:13]2[CH2:33][CH2:32][C:16]3([O:20][C:19](=[O:21])[N:18]([C:22]4[CH:31]=[CH:30][C:25]([C:26]([OH:28])=[O:27])=[CH:24][CH:23]=4)[CH2:17]3)[CH2:15][CH2:14]2)=[CH:6][C:7]=1[C:8]([F:11])([F:9])[F:10]
Reactant: COC(=O)c1ccc(N2CC3(CCN(Cc4cc(C(F)(F)F)c(C)cc4Br)CC3)OC2=O)cc1
Reactant: OB(O)c1ccc(F)c(F)c1F
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CC#N
Solvent: C1COCCO1
Product: Cc1cc(-c2ccc(F)c(F)c2F)c(CN2CCC3(CC2)CN(c2ccc(C(=O)O)cc2)C(=O)O3)cc1C(F)(F)F
Temperature: 120 °C
Yield: 42.1 %

Procedure:
To a solution of methyl 4-{8-[(4-methyl-5-trifluoromethyl-2-bromophenyl)methyl]-2-oxo-1-oxa-3,8-diazaspiro[4.5]dec-3-yl}benzoate (30 mg, 0.055 mmol) in dioxane (1.5 mL) and water (0.5 mL) in a 5 mL microwave reaction vial were added 2,3,4-trifluorophenylboronic acid (20 mg, 0.111 mmol), 1,1′-bis(diphenylphosphino)ferrocene palladium (II) dichloride dichloromethane complex (9 mg, 0.011 mmol) and lithium hydroxide mono-hydrate (5 mg, 0.111 mmol). The reaction was heated in a microwave at 120° C. for 15-30 minutes. The crude reaction was diluted with acetonitrile and water, filtered and purified by reverse phase chromatography using a gradient of acetonitrile and water with 0.1% ammonium hydroxide. Lypholization of the desired fractions afforded the title compound (13.4 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](O)=[O:25])=[CH:12][N:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:27][NH:28][CH2:29][C:30]1[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=1>>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[C:19]2[C:14](=[CH:15][C:16]([O:22][CH3:23])=[CH:17][C:18]=2[O:20][CH3:21])[C:13]([C:24](=[O:25])[N:28]([CH3:27])[CH2:29][C:30]2[CH:31]=[N:32][CH:33]=[CH:34][CH:35]=2)=[CH:12][N:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CNCc1cccnc1
Reactant: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)O)c2c1
Product: COc1cc(OC)c2c(CNC(=O)OC(C)(C)C)ncc(C(=O)N(C)Cc3cccnc3)c2c1

Procedure:
As described in example 1E, 100 mg of 1-(tert-butoxycarbonylamino-methyl)-6,8-dimethoxy-isoquinoline-4-carboxylic acid was coupled with methyl-pyridin-3-ylmethyl-amine to give 98 mg of [6,8-dimethoxy-4-(methyl-pyridin-3-ylmethyl-carbamoyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester. MS: APCI (M+H) calc'd for C20H22N4O3+H 367.2; found 367.2.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:12]=[C:13]([CH:15]([OH:19])[CH:16]([F:18])[F:17])[CH:14]=1)[C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6].[F:20][C:21]1[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=1B(O)O.C1C=C(S([O-])(=O)=O)C=C(P(C2C=CC=C(S([O-])(=O)=O)C=2)C2C=CC=C(S([O-])(=O)=O)C=2)C=1.[Na+].[Na+].[Na+].C(NC(C)C)(C)C>CN(C)C=O.O.[Cl-].[Na+].O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:17][CH:16]([F:18])[CH:15]([C:13]1[CH:12]=[C:4]([C:5]([O:7][C:8]([CH3:11])([CH3:10])[CH3:9])=[O:6])[CH:3]=[C:2]([C:24]2[CH:23]=[CH:22][C:21]([F:20])=[CH:26][C:25]=2[F:27])[CH:14]=1)[OH:19]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CC(C)(C)OC(=O)c1cc(Br)cc(C(O)C(F)F)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=S(=O)([O-])c1cccc(P(c2cccc(S(=O)(=O)[O-])c2)c2cccc(S(=O)(=O)[O-])c2)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(C)NC(C)C
Product: CC(C)(C)OC(=O)c1cc(-c2ccc(F)cc2F)cc(C(O)C(F)F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 93.6 %

Procedure:
To a solution of tert-butyl 3-bromo-5-(2,2-difluoro-1-hydroxyethyl)benzoate (1.0 g, 2.97 mmol) in N,N-dimethylformamide (11.9 mL) and water (2.97 mL) was added (2,4-difluorophenyl)boronic acid (0.61 g, 3.86 mmol), palladium(II) acetate (67 mg, 0.3 mmol), 3,3′3″-phosphinidynetris(benzenesulfonic acid)trisodium salt (0.51 g, 0.89 mmol) and diisopropylamine (1.27 mL, 8.9 mmol). The mixture was stirred at ambient temperature. After 1 h, brine was added and mixture was extracted with ethyl acetate (3×). The combined organic extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% hexanes→60% hexanes/ethyl acetate) gave the title compound (1.03 g). MS 315.0 (M-t-butyl group).
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[CH:10][C:9]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[C:26]#[N:27])=[N:8]1)[CH3:6].B(F)(F)F.CCOCC.[OH-].[Na+]>O1CCCC1.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[CH2:5]([N:7]1[C:11]([O:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:17][CH:18]=2)=[CH:10][C:9]([C:23]2[CH:24]=[C:25]([C:26]3([NH2:27])[CH2:2][CH2:1]3)[CH:28]=[CH:29][CH:30]=2)=[N:8]1)[CH3:6]
Reactant: CC[Mg]Br
Reactant: CCn1nc(-c2cccc(C#N)c2)cc1Oc1ccc(C(F)(F)F)cc1
Agent: [Ti+4]
Agent: CC(C)[O-]
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCn1nc(-c2cccc(C3(N)CC3)c2)cc1Oc1ccc(C(F)(F)F)cc1
Temperature: -78 °C
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
Ethylmagnesium bromide (3.0 M in diethyl ether, 4.3 mL, 13 mmol 2.0 equiv) was added to a solution of titanium (IV) isopropoxide (2.1 mL, 7.1 mmol, 1.1 equiv) and 3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}benzonitrile (2.3 g, 6.4 mmol, 1 equiv) in tetrahydrofuran (26 mL) at −78° C. The reaction mixture was stirred at −78° C. for 5 min, then the cooling bath was removed. After stirring for an additional 60 minutes, boron trifluoride diethyl etherate (1.6 mL, 13 mmol, 2.0 equiv) was added stirred for 45 minutes, then cooled to 0° C. and treated with aqueous sodium hydroxide solution (3.0 N, 40 mL). The biphasic mixture was stirred for 15 minutes, then filtered through celite with the aid of ethyl acetate. The filtrate was partitioned between ethyl acetate and saturated aqueous sodium chloride solution. The organic layer was dried over sodium sulfate. The dried solution was filtered, and the filtrate was concentrated. The residue was purified by flash-column chromatography (50% ethyl acetate-hexanes, followed by 10% methanol-dichloromethane) to afford 1-(3-{1-ethyl-5-[4-(trifluoromethyl)phenoxy]-1H-pyrazol-3-yl}phenyl)cyclopropanamine (1.35 g, 51%). Calcd (M+1)+: 388.2. Found: 388.1.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:5]2[N:6]=[C:7]([NH2:9])[S:8][C:4]=2[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15](B2OC(C)(C)C(C)(C)O2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]>>[F:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:11]=[CH:10][C:5]3[N:6]=[C:7]([NH2:9])[S:8][C:4]=3[CH:3]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH3:20]
Reactant: COc1ccc(B2OC(C)(C)C(C)(C)O2)cc1F
Reactant: Nc1nc2ccc(Br)cc2s1
Product: COc1ccc(-c2ccc3nc(N)sc3c2)cc1F

Procedure:
Compound 6-(3-fluoro-4-methoxyphenyl)benzo[d]thiazol-2-amine (W143) was prepared using the general procedure for Suzuki coupling reaction between 6-bromobenzo[d]thiazol-2-amine (75 mg, 0.3 mmol) and 2-(3-fluoro-4-methoxyphenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (69 mg, 0.3 mmol), as a white solid (30 mg, 36%). 1H NMR (400 MHz, acetone-d6) δ 7.92 (d, J=2.0 Hz, 1 H), 7.52 (dd, J=8.4, 2.0 Hz, 1 H), 7.47-7.24 (m, 3 H), 7.20 (t, J=8.4 Hz, 1 H), 6.86 (brs, 2 H), 3.92 (s, 3 H); MS (ESI) m/z 275 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([C:10](=[O:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14].[BH4-].[Na+].O>CO>[CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:12])[CH3:11])=[CH:6][C:5]=1[N+:13]([O-:15])=[O:14]
Reactant: COC(=O)c1ccc(C(C)=O)cc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)c1ccc(C(C)O)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 73.5 %

Procedure:
To a solution of 4-acetyl-2-nitro-benzoic acid methyl ester (1 g, 4.48 mmol) in MeOH (5 mL) was added NaBH4. The reaction mixture was stirred at r.t. for 24 h (TLC control). To the reaction mixture was added water until the appearance of a white turbid solution and the reaction was stirred for 15 min at r.t. MeOH was removed under reduced pressure. The aqueous phase was extracted with EtOAc three times. The combined organic phases were dried (Na2SO4) and concentrated in vacuo to afford 4-(1-hydroxy-ethyl)-2-nitro-benzoic acid methyl ester (0.742 g, 73%) as a brown oil which was used in the next step without further purification. rt 4.74 min.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[N+:22]([O-])=O>CO.[Pd].[H][H]>[CH3:1][NH:2][C:3]1[CH:21]=[CH:20][C:6]([C:7]([C:9]2([CH2:15][C:16]([O:18][CH3:19])=[O:17])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:8])=[CH:5][C:4]=1[NH2:22]
Reactant: [H][H]
Reactant: CNc1ccc(C(=O)C2(CC(=O)OC)CCCCC2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CO
Product: CNc1ccc(C(=O)C2(CC(=O)OC)CCCCC2)cc1N

Procedure:
Prepared analogously to Example 1c from methyl [1-(4-methylamino-3-nitro-benzoyl)-cyclohexyl]-acetate and palladium on activated charcoal/hydrogen in methanol.
Reaction SMILES: [CH2:1]([N:4]([CH2:22][CH2:23][CH3:24])[C:5]([N:7]1[CH2:13][CH2:12][C:11]2[CH:14]=[CH:15][C:16]([S:18]([NH2:21])(=[O:20])=[O:19])=[CH:17][C:10]=2[CH2:9][CH2:8]1)=[O:6])[CH2:2][CH3:3].[CH:25]1([N:31]=[C:32]=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([NH:31][C:32]([NH:21][S:18]([C:16]2[CH:15]=[CH:14][C:11]3[CH2:12][CH2:13][N:7]([C:5](=[O:6])[N:4]([CH2:1][CH2:2][CH3:3])[CH2:22][CH2:23][CH3:24])[CH2:8][CH2:9][C:10]=3[CH:17]=2)(=[O:20])=[O:19])=[O:33])[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCN(CCC)C(=O)N1CCc2ccc(S(N)(=O)=O)cc2CC1
Product: CCCN(CCC)C(=O)N1CCc2ccc(S(=O)(=O)NC(=O)NC3CCCCC3)cc2CC1

Procedure:
In a manner analogous to that described in Example 1, from 3-dipropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide and cyclohexylisocyanate, there is obtained 1-cyclohexyl-3-[(3-dipropylcarbamoyl-2,3,4,5-tetrahydro-1H-3-benzazepin-7-yl)sulfonyl]urea, m.p. 179°-180° C. The starting material can be prepared by the reaction of 2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonamide hydrochloride with dipropylcarbamoyl chloride in a manner analogous to that described in Example 1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19]S[CH2:17]1.C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O.O[O:42][S:43]([O-:45])=O.[K+].C(=O)(O)[O-].[Na+]>COCCOC.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:16]1[CH2:20][CH2:19][S:43](=[O:45])(=[O:42])[CH2:17]1
Reactant: O=S([O-])OO
Reactant: CCOC(=O)c1cc(Br)cc2c(C3CCSC3)c[nH]c12
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1cc(Br)cc2c(C3CCS(=O)(=O)C3)c[nH]c12
Temperature: 25 °C
Reaction time: 18 h
Yield: 84.8 %

Procedure:
Ethyl 5-bromo-3-(tetrahydro-3-thienyl)-1H-indole-7-carboxylate (0.670 g, 1.82 mmol) was dissolved in 1,2-dimethoxyethane (50 mL). A solution of 0.0004 M EDTA (10 mL) was added followed by the portion-wise addition of a suspension of Oxone (3.49 g, 5.67 mmol) and Sodium bicarbonate (1.59 g, 18.9 mmol), in water (15 mL). The reaction was stirred for 18 hours at room temperature. Afterwards, the reaction was diluted with water (50 mL) and extracted with dichloromethane (2×50 mL). The combined organics were washed with water (2×100 mL). The combined aqueous layers were backwashed with dichloromethane (100 mL). The combined organics were washed with brine, dried with MgSO4, concentrated. The crude compound was purified by Combiflash silica column chromatography using 10% ethyl acetate/dichloromethane on silica to give 0.596 g (82%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:1][C:2]4[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=4[S:9][C:10]4[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
The product from Example 6c was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.22 (m, J=1.84 Hz, 4H), 2.24-2.39 (m, 1H), 2.29 (s, 3H), 6.73 (d, J=8.82 Hz, 2H), 6.91 (d, J=8.09 Hz, 1H), 7.04 (dd, J=8.09, 1.47 Hz, 1H), 7.17 (d, J=8.82 Hz, 2H), 7.25 (s, 1H), 7.57 (d, J=8.82 Hz, 1H), 8.49 (s, 1H), 8.71 (d, J=8.46 Hz, 1H), 9.74 (s, 1H), 9.92 (s, 1H); MS (ESI)+ m/z 401 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:13](O)([C:25]([F:28])([F:27])[F:26])[CH2:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.C1(C)C=CC=CC=1.S(Cl)(Cl)=O>N1C=CC=CC=1>[F:30][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([C:13]([C:25]([F:28])([F:27])[F:26])=[CH:14][C:15]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([Cl:24])[CH:18]=2)=[O:16])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: Cc1ccc(C(=O)CC(O)(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: Cc1ccc(C(=O)C=C(c2cc(C(F)(F)F)cc(C(F)(F)F)c2)C(F)(F)F)cc1Cl
Temperature: 70 °C
Reaction time: 6 h
Yield: 99.6 %

Procedure:
0.96 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-3-hydroxybutan-1-one, 1.92 g of toluene, 0.48 g of thionyl chloride and 0.32 g of pyridine were fed, and stirred for 6 hours at 70° C. The mixture was cooled to room temperature, and separated by adding 10 ml of toluene and iced water. The organic phase was washed with water, and the solvent was distilled off under reduced pressure. The obtained residue was roughly purified by using a small amount of silica gel to obtain 0.92 g of 3-(3,5-bis(trifluoromethyl)phenyl)-1-(3-chloro-4-methylphenyl)-4,4,4-trifluoro-2-buten-1-one as yellow liquid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([OH:10])=[CH:9][C:4]=2[N:3]=[CH:2]1.F[C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][C:13]=1[CH3:21].C(=O)([O-])[O-].[Cs+].[Cs+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:21][C:13]1[CH:14]=[C:15]([N+:18]([O-:20])=[O:19])[CH:16]=[CH:17][C:12]=1[O:10][C:8]1[CH:7]=[CH:6][C:5]2[O:1][CH:2]=[N:3][C:4]=2[CH:9]=1
Reactant: Cc1cc([N+](=O)[O-])ccc1F
Reactant: Oc1ccc2ocnc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])ccc1Oc1ccc2ocnc2c1
Temperature: 50 °C
Yield: 56.3 %

Procedure:
To a solution of benzo[d]oxazol-5-ol (1.50 g, 11.10 mmol) and 1-fluoro-2-methyl-4-nitrobenzene (1.89 g, 12.21 mmol) in DMF was added cesium carbonate (1.81 g, 5.55 mmol) and potassium carbonate (2.30 g, 16.65 mmol). After heating to 50° C. for 16 hours, the mixture was poured into ice water and extracted with ethyl acetate (3×). The combined organics were washed with brine, dried, and concentrated under reduced pressure. The residue was chromatographed (30% ethyl acetate in hexanes) to provide the product (1.69 g, 56%) as white solid.
Reaction SMILES: C[Sn](C)(C)C.[CH3:6]N1CCCC1=O.I[C:14]1[C:15](=[O:22])[C@@H:16]2[O:21][CH2:20][C@H:18]([CH:19]=1)[O:17]2.C1([As](C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl.C(OCC)(=O)C>[CH3:6][C:14]1[C:15](=[O:22])[C@@H:16]2[O:21][CH2:20][C@H:18]([CH:19]=1)[O:17]2
Reactant: CN1CCCC1=O
Reactant: O=C1C(I)=C[C@H]2CO[C@@H]1O2
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: C[Sn](C)(C)C
Solvent: N#Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1=C[C@H]2CO[C@H](O2)C1=O
Temperature: 80 °C
Reaction time: 4 h

Procedure:
5.3 g of tetramethyltin was added to 20 ml of a dry N-methylpyrrolidinone solution containing a mixture comprising 5 g of 1,6-anhydro-3,4-dideoxy-3-iodo-β-D-glycero-hex-3-enopyranos-2-ulose, 0.4 g of copper(I) iodide, 0.6 g of triphenylarsine and 0.4 g of dichlorobis(benzonitrile)palladium(II) under an inert atmosphere of nitrogen gas. The mixture was stirred at 80° C. for 4 hours. Then, 200 ml of ethyl acetate was added thereto, and the mixture was washed three times with 100 ml of a 10% potassium fluoride aqueous solution. The organic layer was dried over anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained syrup product was purified by silica gel column chromatography (ethyl acetate: hexane=1:3) and then distilled under reduced pressure to obtain 1.61 g of the desired product (Intermediate No. 2) as a colorless transparent liquid. The NMR analytical data of this product are as follows.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])(=O)=O)=CC=1.[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:42]=[CH:41][C:40]([OH:43])=[CH:39][CH:38]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.C(OCC)C>[Cl:18][C:19]1[CH:24]=[CH:23][C:22]([C@H:25]2[C@H:30]([OH:31])[C@@H:29]([OH:32])[C@H:28]([OH:33])[C@@H:27]([CH2:34][OH:35])[O:26]2)=[CH:21][C:20]=1[CH2:36][C:37]1[CH:38]=[CH:39][C:40]([O:43][CH2:12][CH2:13][O:14][CH2:15][CH2:16][F:17])=[CH:41][CH:42]=1
Reactant: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(O)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Reactant: Cc1ccc(S(=O)(=O)OCCOCCF)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCOCCF)cc3)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 48 h
Yield: 6.4 %

Procedure:
2-(2-fluoroethoxy)ethyl 4-methylbenzenesulfonate (52 mg, 0.19 mmol) dissolved in anhydrous DMF (3 mL) was added to a flask containing (2S,3R,4R,5S,6R)-2-(4-chloro-3-(4-hydroxybenzyl)phenyl)-6-(hydroxymethyl)tetrahydro-2H-pyran-3,4,5-triol (intermediate D1) (57 mg, 0.15 mmol) in DMF (3 mL) at room temperature. Cesium carbonate (0.12 g, 0.36 mmol) was added to the flask, and the resulting mixture was stirred at room temperature for 48 hr. The reaction mixture was diluted with diethyl ether (50 mL) and the organic layer was washed with aqueous solutions of ammonium chloride (50 mL), sodium bicarbonate (50 mL), and NaCl (50 mL), followed by drying over sodium sulfate. The organic layer was concentrated in vacuo, followed by preparative TLC using 15% methanol in dichloromethane as the mobile phase to yield the title compound (4.5 mg, 5.0%). 1H NMR (CDCl3, 300 MHz): δ 7.30 (d, 1H, J=11.6 Hz), 7.17-7.12 (br m, 2H), 7.04 (d, 2H, J=11.6 Hz), 6.78 (d, 2H, J=11.6 Hz), 4.52 (dt, 2H, J1=5.6 Hz, J2=63.6 Hz), 4.33 (br s, 1H), 4.13 (br s, 1H), 4.04-3.96 (m, 4H), 3.81-3.67 (m, 5H), 3.63-3.49 (m, 2H), 3.38-3.21 (m, 3H), 2.78 (br s, 1H), 1.77 (br s, 2H); LC/MS: theoretical mass=470.15; observed M+1=471.6, M+Na=493.4).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH2:15][CH:16]([NH:27]C(OC(C)(C)C)=O)[C:17]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:18])[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:27][CH:16]([CH2:15][C:11]1[CH:12]=[CH:13][CH:14]=[C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[CH:10]=1)[C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(OCc2ccccc2)c1)C(=O)OCc1ccccc1
Reaction time: 1 h
Yield: 100.5 %

Procedure:
172 (610 mg) was dissolved in 4 ml of DCM and 4 ml of TFA was added then the reaction mixture was let 1 h at room temperature. The reaction mixture is concentrated and 50 ml of AcOEt are added. The organic phase are washed with saturated NaHCO3 and brine then dried over Na2SO4, filtered and concentrated. The crude product was purified by flash chromatography (AcOEt/Hexane 2/8) to afford 173 as white solid (480 mg, 85%). 1H NMR (DMSO): δ 2.90 (m, 2H), 3.73 (t, 1H, J=7.4 Hz), 5.19 (s, 4H), 6.70 (d, 1H, J=7.3 Hz), 6.74 (m, 2H), 6.97 (m, 1H), 7.17 (t, 1H, J=7.9 Hz), 7.41 (d, 2H, J=6.5 Hz), 7.48 (m, 2H), 9.37 (s, 2H).
Reaction SMILES: N1CCC[C@H]1C(O)=O.C(SC[C@@H](C)C(Cl)=O)(=O)C.[OH-].[K+].P([O-])([O-])([O-])=O.[K+].[K+].[K+].C([S:32][CH2:33][C@@H:34]([CH3:45])[C:35]([N:37]1[CH2:44][CH2:43][CH2:42][C@H:38]1[C:39]([OH:41])=[O:40])=[O:36])(=O)C.[OH-].[Na+]>>[CH3:45][C@@H:34]([C:35]([N:37]1[C@H:38]([C:39]([OH:41])=[O:40])[CH2:42][CH2:43][CH2:44]1)=[O:36])[CH2:33][SH:32]
Reactant: CC(=O)SC[C@@H](C)C(=O)N1CCC[C@H]1C(=O)O
Agent: CC(=O)SC[C@@H](C)C(=O)Cl
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=P([O-])([O-])[O-]
Product: C[C@H](CS)C(=O)N1CCC[C@H]1C(=O)O
Yield: 67 %

Procedure:
It has been found that the compound of the formula I can be prepared from L-proline in two reaction steps with a total yield of 67% through the acylation of L-proline, if L-proline is acylated with (R)-3-acetylthio-2-methylpropanoyl chloride of formula III: ##STR3## in the presence of KOH and potassium phosphate buffer at pH 7.5-8.5, and at a temperature of between about 0°-5° C. The resulting compound is 1-[3-acetylthio-2-(S)-methylpropanoyl]-L-proline, ##STR4## Compound IV, which also can be termed "S-acetyl captopril", can be acidified and then deblocked with sodium hydroxide to give captopril in yield of 67% relative to starting material of formula III, without any unwanted byproducts.