Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[C@@H:3]([NH:9][C:10](=[O:27])[O:11][CH:12]([C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[CH2:2]2.[Br:28][CH2:29][CH2:30][C:31]1[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=1>C(OCC)(=O)C>[Br-:28].[F:26][C:22]1[CH:21]=[C:20]([CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=2)[O:11][C:10]([NH:9][C@@H:3]2[CH:4]3[CH2:7][CH2:8][N+:1]([CH2:29][CH2:30][C:31]4[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=4)([CH2:6][CH2:5]3)[CH2:2]2)=[O:27])[CH:25]=[CH:24][CH:23]=1
Reactant: Fc1ccc(CCBr)cc1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CCc3ccc(F)cc3)CCC1CC2)OC(c1cccc(F)c1)c1cccc(F)c1
Product: [Br-]
Temperature: 25 °C
Reaction time: 24 h
Yield: 55.9 %

Procedure:
(R)-bis(3-Fluorophenyl)methyl quinuclidin-3-ylcarbamate (55 mg, 0.14 mmol, prepared as in example 1) was dissolved in ethyl acetate (2 ml), and 1-(2-bromoethyl)-4-fluorobenzene (21 μl, 0.15 mmol) was added. The reaction was stirred at room temperature for 24 hours, then 1-(2-bromoethyl)-4-fluorobenzene (6.21 μl, 0.04 mmol) was added again. After being stirred at room temperature for 2 days, the reaction was concentrated under vacuum, and the crude was first purified by flash chromatography (DCM/MeOH=9/1) and then triturated with DCM/Et2O (1/1) to obtain (R)-3-((bis(3-fluorophenyl)-methoxy)carbonylamino)-1-(4-fluorophenethyl)-1-azoniabicyclo[2.2.2]octane bromide (45 mg).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]([O:13][CH3:14])=[O:12])[CH:10]=1)[C:5]([OH:7])=O.C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:35]2[N:36]=[CH:37]C=[CH:39][C:34]=2N=N1.CNCCC>CN(C=O)C.C(OCC)(=O)C>[I:1][C:2]1[CH:10]=[C:9]([CH:8]=[C:4]([C:5]([N:36]([CH3:37])[CH2:35][CH2:34][CH3:39])=[O:7])[CH:3]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COC(=O)c1cc(I)cc(C(=O)O)c1
Agent: CCCNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCCN(C)C(=O)c1cc(I)cc(C(=O)OC)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 3-iodo-5-(methoxycarbonyl)benzoic acid (1.0 g, 3.3 mmol), prepared as in EXAMPLE SP-281, step 1, and diisopropylethylamine (1.7 mL, 9.8 mmol) in DMF (10 mL) is added O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (HATU, 1.5 g, 3.9 mmol) then N-methylpropylamine (503 μL, 4.9 mmol). The solution is stirred at room temperature 2 h. The solution is diluted in ethyl acetate and washed with water, saturated sodium bicarbonate, and brine. The organic layer is dried over sodium sulfate, filtered and concentrated under reduced pressure to give the title compound in crude form. This material is purified by flash chromatography (40% ethyl acetate/hexane) to give the purified title compound. MS (ESI) [M+H+]=362.4.
Reaction SMILES: C([SiH:3]([CH3:5])[CH3:4])C.[N:6]1([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[N:20]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[C:21]4[C:26]([CH:27]=3)=[CH:25][C:24](I)=[CH:23][CH:22]=4)=[O:18])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].CN1CC[CH2:58][C:57]1=O>O.CCOCC.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[N:6]1([C:10]2[N:15]=[CH:14][C:13]([NH:16][C:17]([C:19]3[N:20]([CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[C:32]([F:36])[CH:31]=4)[C:21]4[C:26]([C:27]=3[SiH:3]([CH3:5])[CH3:4])=[CH:25][C:24]([CH2:57][CH3:58])=[CH:23][CH:22]=4)=[O:18])=[CH:12][CH:11]=2)[CH2:9][CH2:8][CH2:7]1
Reactant: CC[SiH](C)C
Reactant: CN1CCCC1=O
Reactant: O=C(Nc1ccc(N2CCC2)nc1)c1cc2cc(I)ccc2n1Cc1cccc(F)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=P([O-])([O-])OP(=O)([O-])OP(=O)([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Product: CCc1ccc2c(c1)c([SiH](C)C)c(C(=O)Nc1ccc(N3CCC3)nc1)n2Cc1cccc(F)c1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
27 mg (0.31 mmol) of (ethyl)dimethylsilane and 15 mg (0.03 mmol) of bis(tri-tert-butylphosphine)palladium are added to a suspension of 0.15 g (0.28 mmol) of N-[6-(azetidin-1-yl)pyridin-3-yl]-5-iodo-1-[(3-fluorophenyl)methyl]-1H-indole-2-carboxamide, prepared according to the protocol described in stage 8.3, and of 0.18 g (0.85 mmol) of potassium triphosphate in 2 ml of dry 1-methyl-2-pyrrolidinone (NMP), maintained under an inert atmosphere. The reaction mixture is then stirred at ambient temperature under an inert atmosphere for 6 h and then diluted with 40 ml of a mixture of water and ethyl acetate (1/1). The resulting mixture is separated by settling out and the aqueous phase is extracted with 2×10 ml of ethyl acetate. The combined organic phases are dried over sodium sulphate, filtered and concentrated under reduced pressure. The resulting oil is purified by silica gel column chromatography, elution being carried out with a mixture of heptane and ethyl acetate. 108 mg of the expected product are isolated.
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([C:12]([O:14][CH3:15])=[O:13])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].[N+:16]([O-])([OH:18])=[O:17]>S(=O)(=O)(O)O>[CH3:7][O:6][C:4](=[O:5])[C:3]1[CH:8]=[C:9]([N+:16]([O-:18])=[O:17])[C:10]([C:12]([O:14][CH3:15])=[O:13])=[CH:11][C:2]=1[F:1]
Reactant: COC(=O)c1ccc(C(=O)OC)c(F)c1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc([N+](=O)[O-])c(C(=O)OC)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 95 %

Procedure:
To a mixture of dimethyl 2-fluoroterephthalate (42.0 g, 0.198 mol) in concentrated sulfuric acid (200 mL) at 0° C. was added 36 mL of a 1:1 mixture of nitric acid and sulfuric acid dropwise. The mixture was stirred at 0° C. for 15 min., the ice-bath was removed, and the reaction mixture was stirred for an additional 45 min. HPLC indicated that the starting material had been consumed. The reaction mixture was poured over ice and extracted with EtOAc. The organic layer was collected, washed with brine, and dried over anhydrous sodium sulfate. Concentration under reduced pressure followed by recrystallization from MeOH afforded 48.5 g (95%) of 174A as a white solid. HPLC retention time=2.69 min. (Condition B). 1H-NMR (500 MHz, CDCl3) δ 3.95 (s, 3H), 3.98 (s, 3H), 7.44 (d, 1H), and 8.59 (d, 1H).
Reaction SMILES: [Na].Cl.[C:3]([NH2:9])(=[NH:8])[CH2:4][CH2:5][CH2:6][CH3:7].[CH:10]1([N:16]=[C:17]=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>CC(C)=O>[CH:10]1([NH:16][C:17]([NH:8][C:3](=[NH:9])[CH2:4][CH2:5][CH2:6][CH3:7])=[O:18])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1
Reactant: O=C=NC1CCCCC1
Reactant: CCCCC(=N)N
Agent: Cl
Agent: [Na]
Solvent: CC(C)=O
Product: CCCCC(=N)NC(=O)NC1CCCCC1

Procedure:
Following a procedure similar to that described in Example 23 but using 8.4 g. sodium in 1100 ml. dry acetone, 50 g. valeramidine hydrochloride, and 46.4 g. cyclohexyl isocyanate in 300 ml. dry acetone there was obtained, after recrystallization from isopropyl alcohol 58.4 g. 1-cyclohexyl-3-(pentanimidoyl)urea hydrochloride; m.p. 146°-148°C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]=[N+]=[N-])=[O:8])=[CH:5][CH:4]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16])=[O:8])=[CH:19][CH:20]=1
Reactant: COc1ccc(C(=O)OCCCCCCN=[N+]=[N-])cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C(=O)OCCCCCCN)cc1
Temperature: 25 °C
Reaction time: 144 h
Yield: 7.8 %

Procedure:
A mixture of 4-methoxybenzoic acid, 6-azidohexyl ester (1.119 g, 4.035 mmol), triphenylphosphine (1.164 g, 4.439 mmol), and water (0.08 ml) in THF was stirred under nitrogen at room temperature. After ˜144 h, the reaction mixture was diluted with EtOAc (50 ml), dried over Na2SO4, filtered and the filtrate concentrated in vac and dried. The residue was purified by flash chromatography (2×)(alumina, chloroform to 10% MeOH/CHCl3 gradient) to give the desired product as a light yellow oil (0.0796 g, 78%); 1H NMR (400 MHz, DMSO-d6) δ 1.18–1.40 (m, 6H), 1.63–1.71 (m, 2H), 2.50 (t, J=6.4 Hz, 2H), 3.82 (s, 3H), 4.21 (t, J=6.6 Hz, 2H), 7.01–7.06 (m, 2H), 7.87–7.92 (m, 2H); IR (KBr) 3410 (broad), 2940, 1710, 1605, 1510, 1260 cm−1; mass spectrum [(+)ESI], m/z 252 (M+H)+.
Reaction SMILES: C(O[BH-](O[C:11](=[O:13])[CH3:12])OC(=O)C)(=O)C.[Na+].[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32](S(CC5C=CC=CC=5)(=O)=O)[CH2:31][CH2:30]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1.O1C=C[CH:53]=[C:52]1[CH:56]=O>ClCCl>[O:15]1[C:19]2[CH:20]=[CH:21][C:22]([C:24]3[N:28]=[C:27]([CH:29]4[CH2:34][CH2:33][N:32]([C:31]5[O:13][CH:11]=[CH:12][CH:30]=5)[CH:52]([CH3:56])[CH2:53]4)[NH:26][C:25]=3[C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][N:46]=3)=[CH:23][C:18]=2[O:17][CH2:16]1
Reactant: O=S(=O)(Cc1ccccc1)N1CCC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: O=Cc1ccco1
Agent: [Na+]
Solvent: ClCCl
Product: CC1CC(c2nc(-c3ccc4c(c3)OCO4)c(-c3ccccn3)[nH]2)CCN1c1ccco1
Temperature: 25 °C
Reaction time: 18 h
Yield: 23.3 %

Procedure:
Sodium triacetoxyborohydride (0.030 g, 0.14 mmol) was added to a solution of 2-(5-benzo[1,3]dioxol-5-yl-2-piperidin-4-yl-3H-imidazol-4-yl)-pyridine (0.035 g, 0.10 mmol; prepared as described in Example 11) and furan-2-carbaldehyde (0.0083 mL, 0.10 mmol) in dichloromethane (5 mL). The mixture was stirred at room temperature for 18 hours and was filtered and concentrated. HPLC purification eluting with acetonitrile:water gave 0.010 g (23%) of the title compound as a yellow solid. MS (ESP+) m/z 429.1. 1H NMR (400 MHz, DMSO-d6) δ 8.67 (m, 1H), 7.87 (m, 2H), 7.44 (m, 2H), 7.09 (m, 3H), 6.73 (d, 1H, J=3.2 Hz), 6.60 (m, 1H), 6.12 (s, 2H), 4.45 (s, 2H), 3.54 (m, 2H), 3.26 (m, 1H), 3.11 (m, 2H), 2.33 (m, 2H), 2.06 (m, 2H).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:13]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH2:16][C:15](=[O:20])[CH2:14]1)([O:10][CH2:11][CH3:12])=[O:9].[CH:26]1([C:29](Cl)=[O:30])[CH2:28][CH2:27]1>O1CCCC1>[CH:26]1([C:29]([O:20][C:15]2[CH2:14][C:13]([C:8]([O:10][CH2:11][CH3:12])=[O:9])([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:18][C:17](=[O:19])[CH:16]=2)=[O:30])[CH2:28][CH2:27]1
Reactant: CCOC(=O)C1(C(=O)OCC)CC(=O)CC(=O)C1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1(C(=O)OCC)CC(=O)C=C(OC(=O)C2CC2)C1
Reaction time: 1 h

Procedure:
0.94 g (9.4 mmol) of triethylamine was added to a solution of 2.4 g (9.4 mmol) of 5,5-biscarbethoxy-cyclohexane-1,3-dione in 25 ml of anhydrous tetrahydrofuran. A solution of 0.98 g (9.4 mmol) of cyclopropanecarboxylic chloride in 5 ml of tetrahydrofuran was added dropwise to this mixture at 0° to 10° C. After the mixture had been stirred at 0° to 10° C. for about 1 hour, no more starting material could be detected by thin-layer chromatography. Subsequently, the solvent was removed and the residue was taken up in ethyl acetate. The organic phase was washed twice with 1% strength acetic acid and twice with water, dried and evaporated down. The tube [sic] product was purified chromatographically (developer: cyclohexane/ethyl acetate 8:2). Yield: 1.2 g.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH2:6][CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1.C([Mg]Br)(C)C.C[Si]([N:21]=[C:22]=[S:23])(C)C>C1(C)C=CC=CC=1.O>[CH3:1][C:2]1[CH:3]=[N:4][C:5]2[CH:6]([C:22](=[S:23])[NH2:21])[CH2:7][CH2:8][CH2:9][C:10]=2[CH:11]=1
Reactant: C[Si](C)(C)N=C=S
Reactant: Cc1cnc2c(c1)CCCC2
Agent: CC(C)[Mg]Br
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cnc2c(c1)CCCC2C(N)=S
Temperature: 25 °C
Reaction time: 12 h

Procedure:
3-Methyl-5,6,7,8-tetrahydroquinoline (7.3 g, 0.05 mol.) was added to a solution of isopropylmagnesium bromide [prepared from isopropylbromide (6.15 g, 0.05 mol), magnesium (1.44 g, 0.06 mol) in ether (10 ml.)] and the solution heated at 60° to remove the ether by distillation. Toluene (5 ml.) was added and the reaction mixture was heated at 120° for 2 hours, cooled, diluted with toluene (30 ml) and this solution was added to a solution of trimethylsilyl isothiocyanate (7.85 g, 0.06 mol) in toluene (50 ml.) at 0° C. The reaction mixture was stirred at room temperature for 12 hours. The solution of 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-bromomagnesio-N-trimethylsilyl)thiocarboxamide was diluted with water (15 ml.) causing hydrolysis to 3-methyl-5,6,7,8-tetrahydroquinoline-8-(N-trimethylsilyl) thiocarboxamide and subsequent hydrolysis to the title compound and the pH adjusted to 2.0 with Conc. HCl. The aqueous solution was extracted with ether and the extracts discarded. The aqueous solution was adjusted to pH 9.0 with Na2CO3 and extracted with chloroform (3 × 50 ml.). The combined extracts were washed with brine, dried and the solvent removed to give a mixture of 3-methyl-5,6,7,8-tetrahydroquinoline and the title compound (5%) which was isolated by chromatography and identified by comparison with authentic material.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][NH:27][CH2:28][CH:29]=3)[S:21][C:20]=2[CH:30]=1>C(O)C>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]2[CH:23]=[C:22]([C:24]3[CH2:25][CH2:26][N:27]([CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]4[CH:14]=[CH:13][CH:12]=[C:11]5[C:7]=4[CH:8]=[CH:9][NH:10]5)[CH2:28][CH:29]=3)[S:21][C:20]=2[CH:30]=1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Clc1ccc2cc(C3=CCNCC3)sc2c1
Solvent: CCO
Product: O[C@H](COc1cccc2[nH]ccc12)CN1CC=C(c2cc3ccc(Cl)cc3s2)CC1

Procedure:
The title compound was prepared in a fashion similar to that described in Example 1 using (S)-(+)-4-(oxiranylmethoxy)-1H-indole (0.166 g, 0.088 mmol) and 6-chloro-2-(1,2,3,6-tetrahydropyridin-4-yl)benzo[b]thiophene (0.200 g, 0.080 mmol) using ethanol as reaction solvent. Yield 0.122 g (35%) of a tan powder. FDMS m/e=438 (M+ of free base).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[CH:7][C:8]([OH:14])=[C:9]([CH:13]=1)[C:10]([OH:12])=[O:11])(=[O:4])=[O:3].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.Cl>O1CCCC1>[OH:14][C:8]1[CH:7]=[CH:6][C:5]([S:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)(=[O:4])=[O:3])=[CH:13][C:9]=1[C:10]([OH:12])=[O:11]
Reactant: C1CCNC1
Reactant: O=C(O)c1cc(S(=O)(=O)Cl)ccc1O
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)c1cc(S(=O)(=O)N2CCCC2)ccc1O

Procedure:
A solution of 5-chlorosulfonyl-2-hydroxybenzoic acid (0.52 g, 2.0 mmol, Matrix Scientific) in tetrahydrofuran (10 mL) was treated with pyrrolidine (1.5 g, 21 mmol) and refluxed for 2 h. This was cooled and poured into dilute aqueous hydrochloric acid and extracted into dichloromethane (2×50 mL). The combined extracts were washed with brine, dried over magnesium sulfate, filtered, and concentrated to give a solid. This was triturated with ether to give 2-hydroxy-5-(pyrrolidine-1-sulfonyl)benzoic acid as a solid. It was then converted to 2-ethoxy-5-(pyrrolidine-1-sulfonyl)benzoic acid ethyl ester In a manner analogous to the method described in example 33.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[S:9][CH:8]=[CH:7][C:5]=2[CH:6]=1.[Br:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[F:19])[CH:14]=O>>[S:9]1[C:8]([CH2:14][C:13]2[CH:16]=[CH:17][C:18]([F:19])=[C:11]([Br:10])[CH:12]=2)=[CH:7][C:5]2[CH:6]=[CH:1][CH:2]=[CH:3][C:4]1=2
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1ccc(F)c(Br)c1
Product: Fc1ccc(Cc2cc3ccccc3s2)cc1Br

Procedure:
Thianaphthene and 3-bromo-4-fluorobenzaldehyde were treated in a manner similar to Reference Example 7 to give the target compound.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([F:22])[F:21])(=[O:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)=[O:4].C(O)(=O)C.[BH4-].[Na+].Cl>O.O1CCCC1>[Cl:1][CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]([F:22])[F:21])(=[O:18])=[O:19])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1)[OH:4]
Reactant: O=C(CCl)c1ccc(-c2ccc(S(=O)(=O)C(F)F)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: O=S(=O)(c1ccc(-c2ccc(C(O)CCl)cc2)cc1)C(F)F
Temperature: 5 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a 500-mL sidearm flask equipped with a thermometer and nitrogen inlet was charged 47.0 g (0.130 mol) of ca. 95%-pure 2-chloro-1-[4'-[(difluoromethyl) -sulfonyl][1,1'-biphenyl]-4-yl]ethanone, 200 mL of tetrahydrofuran, 1.40 mL (23 mmol) of glacial acetic acid, and 10 mL of water. The orange solution was cooled to 5° C. and 2.4 g (31 mmol) of sodium borohydride was added in three portions over about 15 minutes. The mixture was held for 15 minutes at 10° C., diluted with 200 mL of water, and acidified to pH 2 with about 40 mL of aqueous 1N HCl. Most of the THF was removed in vacuo and the oil was extracted with 400 mL of ethyl acetate. The ethyl acetate layer was washed in succession with water, aqueous NaHCO3, and aqueous NaCl, then dried with MgSO4, filtered, and concentrated to dryness. Then residue was crystallized from 200 mL of 1:1 toluene/hexanes, filtered, and washed with 50 mL of 1:1 toluene/hexanes to afford 35.3 g (78% yield) of product as a pale orange solid, m.p. 104-107° C.; a sample purified by chromatography and crystallization from EtOAc/hexanes had m.p. 111-112° C. 1H-NMR (CDCl3) δ3.3 (br s, 1H), 3.7 (dd, 1H), 3.8 (dd, 1H), 5.0 (dd, 1H), 6.23 (t, 1H, J=60 Hz), 7.55 (d, 2H), 7.65 (d, 2H), 7.82 (d, 2H), 8.05 (d, 2H). 13C-NMR (CDCl3) δ50.5, 73.5, 114.7 (t, JCF =286 Hz), 126.9, 127.7, 128.1, 130.1, 131.1, 138.6, 141.0, 148.1 ppm. 19F-NMR(CDCl3) δ-121.8 ppm (d, JHF =53 Hz). Mass spectrum m/z=346 (M+), 297 (M+ --CH2Cl, base peak), 182 amu.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)#[N:2].P([O-])([O-])([O-])=[O:10].[K+].[K+].[K+]>CO>[C:1]([NH2:2])(=[O:10])[C:3]1[CH:8]=[CH:7][CH:6]=[N:5][CH:4]=1
Reactant: O=P([O-])([O-])[O-]
Reactant: N#Cc1cccnc1
Agent: [K+]
Solvent: CO
Product: NC(=O)c1cccnc1
Reaction time: 0.17 h

Procedure:
3-Cyanopyridine was added at different concentrations (3.1-800 mM; 0.500 ml) to a solution comprising nitrile hydratase solution (0.0697 μmol/min; 0.025 ml) and 15 potassium phosphate buffer (0.1 M; pH 7.0; 0.475 ml). The reaction mixture was incubated at 20° C. for 10 min. The reaction was stopped by adding methanol and the amount of nicotinamide produced was determined by means of HPLC according to Example 1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][N:11]=[C:10]([NH:14][CH:15]3[CH2:17][CH2:16]3)[C:9]=2[NH2:18])=[CH:4][CH:3]=1.[CH2:19]([C:21]1[N:29]=[CH:28][CH:27]=[CH:26][C:22]=1[C:23](Cl)=[O:24])[CH3:20].C([O-])(O)=O.[Na+]>C(Cl)Cl.N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:9]([NH:18][C:23](=[O:24])[C:22]3[CH:26]=[CH:27][CH:28]=[N:29][C:21]=3[CH2:19][CH3:20])=[C:10]([NH:14][CH:15]3[CH2:16][CH2:17]3)[N:11]=[CH:12][N:13]=2)=[CH:6][CH:7]=1
Reactant: Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Reactant: CCc1ncccc1C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCc1ncccc1C(=O)Nc1c(NC2CC2)ncnc1-c1ccc(Cl)cc1
Temperature: 0 °C

Procedure:
6-(4-Chlorophenyl)-N-cyclopropylpyrimidine-4,5-diamine (1.00 g, 3.83 mmol) was initially charged in a mixture of DCM (3.20 ml) and pyridine (0.93 ml) and cooled to 0° C. Solid 2-ethylnicotinoyl chloride (780 mg, 4.60 mmol) was added, and the reaction mixture was warmed to room temperature and stirred for another hour. After addition of semisaturated NaHCO3 solution, the organic phase was separated off and concentrated under reduced pressure.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:22][N:23]=1)=[CH:15]2)(=[O:8])=[O:7].C[N:29](C)C=O.Cl.CN(C)CCCN=C=NCC>C(OCC)(=O)C>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[S:6]([NH:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:18]=1[NH:17][C:16]([C:19]1[S:20][CH:21]([CH2:24][C:25]([NH2:29])=[O:27])[CH2:22][N:23]=1)=[CH:15]2)(=[O:7])=[O:8]
Reactant: CN(C)C=O
Reactant: O=C(O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Product: NC(=O)CC1CN=C(c2cc3cccc(NS(=O)(=O)c4cccs4)c3[nH]2)S1
Temperature: 25 °C
Yield: 77 %

Procedure:
To a mixture of (2-{7-[(2-thienylsulfonyl)amino]-1H-indol-2-yl}-4,5-dihydro-1,3-thiazol-5-yl)acetic acid (153 mg), 1H-1,2,3-benzotriazol-1-ol-ammonia complex (72 mg) and N,N-dimethylformamide (8 mL) was added N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (91 mg) under ice-cooling, and the mixture was stirred from under ice-cooling to room temperature for 15 hr. The reaction solution was diluted with ethyl acetate, washed with water, aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate-ethyl acetate:methanol=95:5), and the obtained pale-yellow oil was crystallized from ethyl acetate-hexane to give the title compound (118 mg, yield: 77%) as pale-yellow crystals.
Reaction SMILES: [CH2:1]([O:8][CH:9]([CH3:18])[CH2:10][CH2:11][C:12]1[C:13](=[O:17])[CH2:14][CH2:15][CH:16]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CCCCC>C(OCC)C>[CH2:1]([O:8][CH:9]([CH3:18])[CH2:10][CH2:11][CH:12]1[CH2:16][CH2:15][CH2:14][C:13]1=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(CCC1=CCCC1=O)OCc1ccccc1
Solvent: CCCCC
Solvent: CCOCC
Product: CC(CCC1CCCC1=O)OCc1ccccc1
Yield: 94 %

Procedure:
General procedure B using (S)-p-tol-BfNAP and 3-benzyloxybutyl-cyclopent-2-enone (0.146 g, 0.6 mmol) gave, after 30 h at 0° C. and flash chromatography (1:2 pentane:diethyl ether), the title compound as a clear oil (0.139 g, 94% yield). 1H NMR (300 MHz, CDCl3): δ7.37-7.23 (m, 5 H), 4.50 (s, 2 H), 3.47 (t, J=6.3 Hz, 2 H), 2.43-2.04 (m, 5 H), 1.78 (ddd, J=18.0, 9.6, 1.2 Hz, 1 H), 1.70-1.56 (m, 2 H), 1.56-1.34 (m, 5 H). 13C NMR (75 MHz, CDCl3): δ219.8, 138.6, 128.4, 127.7, 127.6, 73.1, 70.3, 45.4, 38.7, 37.4, 35.7, 30.0, 29.7, 24.8. IR (neat): 2934, 2860, 1741, 1455, 1405, 1363, 1158, 1100, 737, 699 cm−1. HRMS m/z calcd for C16H22O2 246.1620, obsd 246.1615. [α]D25° C.−89° (c 1.4, CHCl3). Chiral HPLC analysis (Chiracel OD column) indicated that the title compound was obtained in 94% ee.
Reaction SMILES: [CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[NH:9]2)[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Cl:15][C:16]1[C:23]([Cl:24])=[CH:22][CH:21]=[CH:20][C:17]=1[CH2:18]Br>>[CH:1]1([N:8]2[C:11](=[O:12])[C:10]([CH3:14])([CH3:13])[N:9]2[CH2:18][C:17]2[CH:20]=[CH:21][CH:22]=[C:23]([Cl:24])[C:16]=2[Cl:15])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: CC1(C)NN(C2CCCCCC2)C1=O
Reactant: Clc1cccc(CBr)c1Cl
Product: CC1(C)C(=O)N(C2CCCCCC2)N1Cc1cccc(Cl)c1Cl

Procedure:
2-Cycloheptyl-4,4-dimethyl-1,2-diazetidin-3-one prepared in Process 4 of Example 83 and 2,3-dichlorobenzyl bromide were used for a similar reaction and treatment as Process 6 of Example 1, and the title compound was obtained as a colorless oil.