Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(C)C=CC=CC=1.N1CCCCC1.[S:14]1[CH2:18][C:17](=[O:19])[NH:16][C:15]1=[O:20].[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=O)=[CH:24][C:23]=1[C:30]1[C:39]([CH3:40])=[CH:38][C:37]2[C:36]([CH3:42])([CH3:41])[CH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[C:32]=2[CH:31]=1>O.C(O)(=O)C>[Cl:21][C:22]1[CH:29]=[CH:28][C:25]([CH:26]=[C:18]2[S:14][C:15](=[O:20])[NH:16][C:17]2=[O:19])=[CH:24][C:23]=1[C:30]1[C:39]([CH3:40])=[CH:38][C:37]2[C:36]([CH3:42])([CH3:41])[CH2:35][CH2:34][C:33]([CH3:44])([CH3:43])[C:32]=2[CH:31]=1
Reactant: Cc1cc2c(cc1-c1cc(C=O)ccc1Cl)C(C)(C)CCC2(C)C
Reactant: O=C1CSC(=O)N1
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCNCC1
Product: Cc1cc2c(cc1-c1cc(C=C3SC(=O)NC3=O)ccc1Cl)C(C)(C)CCC2(C)C
Temperature: 25 °C
Yield: 69.7 %

Procedure:
To a solution of toluene (30 mL) containing piperidine (0.26 mL, 2.64 mmol) and acetic acid (0.26 mL) were added 2,4-thiazolidinedione (1.03 g, 8.81 mmol) and 4-chloro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzaldehyde (3.0 g, 8.81 mmol). The reaction mixture was heated at reflux for 12 hours with continuous removal of water using a Dean-Stark water separator. After cooling to room temperature, a yellow solid formed that was collected and washed with ethanol, dried under vacuum to give 2.7 g of 5-[4-chloro-3-(3,5,5,8,8-pentamethyl-5,6,7,8-tetrahydronaphtalen-2-yl)benzylidene] thiazolidine-2,4-dione (70% yield). 1H NMR (300 MHz; DMSO-d6): 1.19 (s, 3H); 1.20 (s, 3H); 1.25 (s, 3H); 1.26 (s, 3H); 1.63 (s, 4H); 2.01 (s, 3H); 7.07 (s, 1H); 7.26 (s, 1H); 7.52 (d, J=2.1 Hz, 1H); 7.59 (dd, J1 =2.1 Hz, J2=8.1 Hz, 1H); 7.71 (d, J=8.1Hz, 1H); 7.83 (s, 1H); 12.68 (s, 1H).
Reaction SMILES: [P:1]([F:5])([F:4])(=[O:3])[OH:2].F[P-](F)(F)(F)(F)F.[Li+:13].[Cl-].[K+:15].C(=O)(OC)OC>>[P:1]([F:5])([F:4])([O-:3])=[O:2].[K+:15].[P:1]([F:5])([F:4])([O-:3])=[O:2].[Li+:13]
Reactant: O=P(O)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [K+]
Solvent: COC(=O)OC
Product: O=P([O-])(F)F
Temperature: 130 °C
Reaction time: 1 h

Procedure:
Difluorophosphoric acid (reagent, produced by Fluorochem Ltd.) (18.6 g) was weighed into a 250 ml-volume PFA vessel, and 4.1 g of lithium hexafluorophosphate (reagent, produced by Stella Chemifa Corporation) was added. Furthermore, 13.5 g of potassium chloride (reagent, produced by Wako Pure Chemical Industries, Ltd.) and 20.0 g of dimethyl carbonate were added, and the mixture was stirred for 1 hour under nitrogen flow and after heating at 130° C. for 17 hours, cooled to room temperature to obtain a mixed crystal of potassium difluorophosphate and lithium difluorophosphate. Anion analysis was performed in the same manner as in Example 2-6, as a result, the obtained difluorophosphate ion was 91% in terms of the relative area.
Reaction SMILES: Cl.[O:2]=[C:3]([NH:18][CH:19]1[CH:23]([O:24][CH2:25][CH2:26][CH3:27])[CH2:22][NH:21][CH2:20]1)[CH2:4][NH:5][C:6](=[O:17])[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1.[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][N+:39]([O-:42])=[CH:38][CH:37]=2)[CH2:34][CH2:33][C:32](=O)[CH2:31][CH2:30]1>>[OH:28][C:29]1([C:36]2[CH:41]=[CH:40][N+:39]([O-:42])=[CH:38][CH:37]=2)[CH2:30][CH2:31][CH:32]([N:21]2[CH2:22][C@H:23]([O:24][CH2:25][CH2:26][CH3:27])[C@@H:19]([NH:18][C:3](=[O:2])[CH2:4][NH:5][C:6](=[O:17])[C:7]3[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=3)[CH2:20]2)[CH2:33][CH2:34]1
Reactant: O=C1CCC(O)(c2cc[n+]([O-])cc2)CC1
Reactant: CCCOC1CNCC1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1
Agent: Cl
Product: CCCO[C@H]1CN(C2CCC(O)(c3cc[n+]([O-])cc3)CC2)C[C@@H]1NC(=O)CNC(=O)c1cccc(C(F)(F)F)c1

Procedure:
This compound was synthesized from N-(2-oxo-2-{[4-propoxypyrrolidin-3-yl]amino}ethyl)-3-(trifluoromethyl)benzamide hydrochloride and 4-hydroxy-4-(1-oxidopyridin-4-yl)cyclohexanone according to typical reductive animation precedure. MS (m/e): 565 (M+1)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].C(N(CC)CC)C.[Cl:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=2[N:20]([C@H:29]2[CH2:33][CH2:32][NH:31][CH2:30]2)[C:19]1=[O:34].O>ClCCl>[Cl:13][C:14]1[CH:15]=[C:16]([CH:35]=[CH:36][C:37]=1[O:38][CH3:39])[CH2:17][N:18]1[C:22]2[CH:23]=[C:24]([C:27]#[N:28])[CH:25]=[CH:26][C:21]=2[N:20]([C@H:29]2[CH2:33][CH2:32][N:31]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:30]2)[C:19]1=[O:34]
Reactant: COc1ccc(Cn2c(=O)n([C@H]3CCNC3)c3ccc(C#N)cc32)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(Cn2c(=O)n([C@H]3CCN(S(C)(=O)=O)C3)c3ccc(C#N)cc32)cc1Cl
Temperature: 0 °C
Reaction time: 3 h
Yield: 84.2 %

Procedure:
Methanesulfonyl chloride (27 mg) and triethylamine (24 mg) were added to a solution of 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-pyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (75 mg) in dichloromethane (2 mL). The reaction mixture was stirred at 0° C. for 3 hours. The reaction mixture was poured into water and extracted with a mixture of chloroform and methanol (5:1). The organic layer was washed with an aqueous saturated sodium chloride solution, dried over magnesium sulfate, and concentrated in vacuo. The obtained crystals were suspended in hot ethyl acetate and then cooled with stirring. The resulting precipitate was collected by filtration and washed with ethyl acetate to give 3-(3-chloro-4-methoxybenzyl)-5-cyano-1-[(S)-1-methanesulfonylpyrrolidin-3-yl]-2,3-dihydro-1H-benzimidazol-2-one (76 mg) as colorless crystals.
Reaction SMILES: [CH3:1][CH:2]([CH3:30])[C:3]([NH:5][CH:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:14][CH:13]=2)=[CH:8][CH2:7]1)=[O:4]>CO>[CH3:1][CH:2]([CH3:30])[C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C:9]([C:12]2[CH:13]=[CH:14][C:15]([NH:18][C:19]([N:21]3[CH2:29][C:28]4[CH:27]=[CH:26][N:25]=[CH:24][C:23]=4[CH2:22]3)=[O:20])=[CH:16][CH:17]=2)=[CH:8][CH2:7]1)=[O:4]
Reactant: CC(C)C(=O)NC1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1
Solvent: CO
Product: CC(C)C(=O)N[C@@H]1CC=C(c2ccc(NC(=O)N3Cc4ccncc4C3)cc2)CC1

Procedure:
A racemic mixture of N-(4-{4-[(2-methylpropanoyl)amino]cyclohex-1-en-1-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide (250 mg) was dissolved in methanol and separated using SCF-LC with a ChiralPak AD-H 21×250 mm column to provide N-(4-{(4S)-4-[(2-methylpropanoyl)amino]cyclohex-1-en-1-yl}phenyl)-1,3-dihydro-2H-pyrrolo[3,4-c]pyridine-2-carboxamide. 1H NMR (300 MHz, DMSO-d6) δ 8.61 (s, 1H), 8.50 (d, J=5.0 Hz, 1H), 8.41 (s, 1H), 7.66 (d, J=7.6 Hz, 1H), 7.56-7.49 (m, 2H), 7.43 (d, J=5.1 Hz, 1H), 7.37-7.29 (m, 2H), 6.05-5.99 (m, 1H), 4.84-4.77 (m, 4H), 3.89-3.73 (m, 1H), 2.47-2.39 (m, 1H), 2.41-2.30 (m, 2H), 2.11-1.97 (m, 1H), 1.93-1.82 (m, 1H), 1.67-1.50 (m, 1H), 1.00 (dd, J=6.8, 2.4 Hz, 6H); MS (ESI(+)) m/e 405 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:13]=[C:12]2[C:8]([C:9]([C:27]#[N:28])=[C:10]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=3)[N:11]2[CH2:14][CH3:15])=[CH:7][CH:6]=1.[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Na+].[I-].C(N(C(C)C)CC)(C)C>CC#N.O>[C:27]([C:9]1[C:8]2[C:12](=[CH:13][C:5]([O:4][CH2:3][CH2:2][N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)=[CH:6][CH:7]=2)[N:11]([CH2:14][CH3:15])[C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([NH:22][S:23]([CH3:26])(=[O:25])=[O:24])=[CH:18][CH:17]=1)#[N:28]
Reactant: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OCCCl)cc21
Reactant: C1COCCN1
Agent: [I-]
Agent: [Na+]
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CCn1c(-c2ccc(NS(C)(=O)=O)cc2)c(C#N)c2ccc(OCCN3CCOCC3)cc21
Temperature: 25 °C
Yield: 41.7 %

Procedure:
A solution of N-{4-[6-(2-chloroethoxy)-3-cyano-1-ethyl-1H-indol-2-yl]-phenyl}methanesulfonamide (90 mg, 0.21 mmol), morpholine (0.06 mL, 0.65 mmol), NaI (32 mg, 0.21 mmol) and diisopropyl ethylamine (0.06 mL, 0.32 mmol) in CH3CN (2 mL) is heated in a sealed tube at 100° C. for 25 h. The reaction mixture is cooled to room temperature, diluted with H2O and extracted with EtOAc (3×). The combined organic phases are washed with saturated NaCl, dried and concentrated. The crude solid is triturated with EtOAc and filtered to give 41 mg (41%) of N-{4-[3-cyano-1-ethyl-6-(2-morpholin-4-yl-ethoxy)-1H-indol-2-yl]-phenyl}methanesulfonamide as a tan solid.
Reaction SMILES: [OH:1][C:2]1[C:19]([I:20])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]4)[C@@H:6]([OH:22])[CH2:5][C:4]=2[CH:3]=1.CC([O-])C.CC([O-])C.CC([O-])C.[Al+3]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[OH:1][C:2]1[C:19]([I:20])=[CH:18][C:17]2[C@@H:16]3[C@H:7]([C@H:8]4[C@@:12]([CH2:14][CH2:15]3)([CH3:13])[C:11](=[O:21])[CH2:10][CH2:9]4)[C:6](=[O:22])[CH2:5][C:4]=2[CH:3]=1
Reactant: C[C@]12CC[C@@H]3c4cc(I)c(O)cc4C[C@H](O)[C@H]3[C@@H]1CCC2=O
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: C[C@]12CC[C@@H]3c4cc(I)c(O)cc4CC(=O)[C@H]3[C@@H]1CCC2=O
Reaction time: 0.5 h
Yield: 62.9 %

Procedure:
A solution of 206 mg (0.5 mmol) of 3,7β-dihydroxy-2-iodo-estra-1,3,5(10)-trien-17-one 14 in 15 ml of toluene and 4 ml of cyclohexanone was heated to 140° C. (oil bath temperature), and a solution of 400 mg of aluminum isopropylate in 10 ml of toluene was added drop by drop. In the meantime, a portion of the reaction mixture was distilled off. After complete addition of the aluminum isopropylate, it was refluxed for still another 5 hours. Then, the reaction solution was cooled and diluted with 80 ml of dichloromethane and 30 ml of potassium/sodium tartrate solution, and the resulting mixture was first stirred vigorously for 30 minutes before the organic phase was separated from the aqueous phase. The aqueous phase was finally extracted with dichloromethane (3×30 ml), and the combined organic phases were washed with a saturated NaCl solution, dried on sodium sulfate and concentrated by evaporation in a rotary evaporator. Flash chromatography (cyclohexane/ethyl acetate) yielded 129 mg (63%) of colorless crystals.
Reaction SMILES: [C:1]([C:3]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[C:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1)#[N:2].N>C(O)C.[Ni].O>[NH2:2][CH2:1][CH:3]([CH:4]1[CH2:5][CH2:6][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:8][CH2:9]1)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CCC(=C(C#N)c2ccccc2)CC1
Agent: [Ni]
Agent: N
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(CN)c2ccccc2)CC1
Reaction time: 5.5 h

Procedure:
tert-butyl 4-[cyano(phenyl)methylene]piperidine-1-carboxylate (1.18 g, 3.95 mmol) in ethanol (15 ml) was saturated with NH3 at ambient temperature and Raney nickel (1 ml, 3.95 mmol) in water was added. The reaction was placed on a Parr reactor under H2 pressure (48 psi) for 19 hours. The reaction mixture was then re-saturated with NH3 and additional Raney nickel (1 ml, 3.95 mmol) was added before placing back on the Parr reactor for an additional 5.5 hours. The reaction mixture was filtered through Celite, washing with EtOH, and concentrated in vacuo. The product was carried on without further purification.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[NH2:10][CH2:11][CH2:12][O:13][CH2:14][CH2:15][O:16][CH2:17][CH2:18][O:19][C:20]1[C:25]([Cl:26])=[CH:24][C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[CH:22][C:21]=1[Cl:37].[CH:38]1[C:43]([N:44]=[C:45]=[S:46])=[CH:42][C:41]2[C:47]([O:49][C:50]3([C:60]4[CH:61]=[CH:62][C:63]([OH:65])=[CH:64][C:59]=4[O:58][C:52]4[CH:53]=[C:54]([OH:57])[CH:55]=[CH:56][C:51]3=4)[C:40]=2[CH:39]=1)=[O:48]>CN(C=O)C>[Cl:37][C:21]1[CH:22]=[C:23]([NH:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])[CH:24]=[C:25]([Cl:26])[C:20]=1[O:19][CH2:18][CH2:17][O:16][CH2:15][CH2:14][O:13][CH2:12][CH2:11][NH:10][C:45]([NH:44][C:43]1[CH:42]=[C:41]2[C:40](=[CH:39][CH:38]=1)[C:50]1([C:51]3[CH:56]=[CH:55][C:54]([OH:57])=[CH:53][C:52]=3[O:58][C:59]3[C:60]1=[CH:61][CH:62]=[C:63]([OH:65])[CH:64]=3)[O:49][C:47]2=[O:48])=[S:46]
Reactant: O=C1OC2(c3ccc(O)cc3Oc3cc(O)ccc32)c2ccc(N=C=S)cc21
Reactant: NCCOCCOCCOc1c(Cl)cc(Nc2ccccc2C(=O)O)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(O)c1ccccc1Nc1cc(Cl)c(OCCOCCOCCNC(=S)Nc2ccc3c(c2)C(=O)OC32c3ccc(O)cc3Oc3cc(O)ccc32)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61.1 %

Procedure:
N,N-Diisopropylethylamine (10 μL, 0.057 mmol) was added to a solution of the compound 4 (1.9 mg, 0.0035 mmol) and fluorescein isothiocyanate (FITC) (1.2 mg, 0.003 mmol) in DMF (1.0 ml) and the reaction mixture was stirred at room temperature overnight. The solvent was removed under reduced pressure and the residue was subjected to flash column chromatography (silica gel, 1-20% methanol/methylene chloride) to give the desired compound 5 (1.5 mg, 52% yield); 1H NMR (CD3OD, 400 MHz) δ 8.14-8.10 (m, 1H), 7.88 (dd, 1H, J=2.0 Hz, 8.0 Hz), 7.80-7.62 (m, 2H), 7.34-7.30 (m, 1H), 7.24-7.18 (m, 1H), 7.18-7.12 (m, 3H), 6.86-6.78 (m, 1H), 6.72-6.64 (m, 3H), 6.54-6.50 (m, 2H), 4.21-4.04 (m, 4H), 3.92-3.66 (m, 8H); HRMS (ESI+) m/z: calcd for C40H33Cl2N3O10S+H+ 818.1342. found 818.1328 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][N:23](C(OC(C)(C)C)=O)[CH2:22][CH2:21]2)=[CH:14][CH:13]=1.[ClH:33]>O1CCOCC1.CCOCC>[ClH:33].[F:1][C:2]1[CH:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:13]=[CH:14][C:15]([O:18][CH2:19][CH:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC(COc2ccc(-c3ccc(S(C)(=O)=O)cc3F)cc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(-c2ccc(OCC3CCNCC3)cc2)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
1,1-Dimethylethyl 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)-1-piperidinecarboxylate (Example 65, 0.484 g, 1.04 mmol) was dissolved in 1,4-dioxane (20 mL). To this solution was added ether (15 mL), followed by addition of 4.0M HCl in 1,4-dioxane (15 mL) and 2M HCl in ether (15 mL). The reaction mixture was stirred at ambient temperature overnight. The white solid was collected via filtration and washed with ether to yield 0.386 mg (92%) of 4-({[2′-fluoro-4′-(methylsulfonyl)-4-biphenylyl]oxy}methyl)piperidine hydrochloride as a white solid. 1H NMR (400 MHz, CD3OD): δ 7.85-7.50 (m, 3H), 7.56 (d, 2H, J=7.3 Hz), 7.06 (d, 2H, J=8.7 Hz), 3.98 (d, 2H, J=5.9 Hz), 3.50-3.40 (m, 2H), 3.17 (s, 3H), 3.10-3.00 (m, 2H), 2.25-2.05 (m, 3H), 1.70-1.55 (m, 2H); LRMS (ESI), m/z 364 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[C:3]=1[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+].F[C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][C:22]=1[N+:28]([O-:30])=[O:29].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>CS(C)=O.O>[NH2:25][C:24]1[CH:26]=[CH:27][C:21]([O:1][C:2]2[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=[O:10])=[C:4]([CH3:12])[C:3]=2[CH3:13])=[C:22]([N+:28]([O-:30])=[O:29])[CH:23]=1
Reactant: Cc1c(O)ccc(CC(=O)O)c1C
Reactant: Nc1ccc(F)c([N+](=O)[O-])c1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1c(CC(=O)O)ccc(Oc2ccc(N)cc2[N+](=O)[O-])c1C
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
Under an N2 atmosphere, 2-(4-hydroxy-2,3-dimethylphenyl)acetic acid (0.780 g, 4.33 mmol) was dissolved in DMSO (29 mL). Cesium carbonate (3.53 g, 10.8 mmol) was added and the reaction was allowed to stir at room temperature for 5 min. 4-Fluoro-3-nitroaniline (0.678 g, 4.33 mmol) was added and the reaction was heated to 80° C. for 2.25 h. The reaction was allowed to cool to room temperature and diluted with water. Citric acid was added to pH 4 and the reaction was extracted with ethyl acetate. The layers were separated and the aqueous layer was washed with additional ethyl acetate. The organics were combined, dried (Na2SO4), filtered, and concentrated in vacuo. Flash column chromatography of the residue, eluting with 0% to 8% methanol in dichloromethane, afforded the title compound. LC-MS ESI (pos.) m/z: 317.2 (M+H).
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Na+].[Cl-].O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](OP(O)(O)=O)[C@@H]3O)(O)=O)(O)=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.[Cl:71][CH2:72][C:73](=[O:80])[CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76].C([O-])([O-])=O.[Na+].[Na+]>C(OCCCC)(=O)C>[Cl:71][CH2:72][C@@H:73]([OH:80])[CH2:74][C:75]([O:77][CH2:78][CH3:79])=[O:76]
Reactant: CCOC(=O)CC(=O)CCl
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](OP(=O)(O)O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C([O-])[O-]
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Solvent: CCCCOC(C)=O
Product: CCOC(=O)C[C@H](O)CCl
Reaction time: 3 h
Yield: 97 %

Procedure:
To a well-stirred solution of 100 mM potassium phosphate buffer, 500 mM NaCl, pH 7 (1 L) at room temperature was added glucose (160 g, 830 mmoles, 1.1 equiv). To this was added ketoreductase SEQ ID NO: 2 (0.9 g), glucose dehydrogenase S06 SEQ ID. NO: 10 (0.5 g) and NADP (0.5 g) as lyophilized powders. Once dissolved, butyl acetate (500 mL) was added to form an emulsion. To this emulsion was added a solution of ethyl 4-chloroacetoacetate (100 g, 608 mmoles) in butyl acetate (500 mL), dropwise over 3 hours. The pH was maintained between 6.8 and 7 by an automatic titrater that dispensed Na2CO3 (2M in water, about 160 mL total). After 40 hours the automated addition of the base had ceased and there was no residual starting material by gas chromatography. The layers were separated, and the aqueous phase was washed with ethyl acetate (500 mL). The combined organics were dried over anhydrous sodium sulfate, filtered and evaporated on a rotary evaporator, to give essentially pure (˜97%) ethyl (S)-4-chloro-3-hydroxybutyrate.
Reaction SMILES: [OH-].[Na+].[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:26])[CH3:25])=[N:21][C:20]([CH2:27][O:28]C(=O)C)=[N:19]1)(=[O:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO.O>[C:3]([C:11]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:12]=1[N:18]1[C:22]([CH2:23][N:24]([CH3:25])[CH3:26])=[N:21][C:20]([CH2:27][OH:28])=[N:19]1)(=[O:10])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)OCc1nc(CN(C)C)n(-c2ccc(Cl)cc2C(=O)c2ccccc2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CN(C)Cc1nc(CO)nn1-c1ccc(Cl)cc1C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
60 ml of 1 N sodium hydroxide solution (0.060 mole) is added at room temperature, with stirring, to a solution of 8.26 g (about 0.020 mole) of crude [[1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazol-3-yl]-methyl]-acetate (see Example 20) in 250 ml of methanol and 115 ml of water. The temperature of the reaction solution rises to 33°. The reaction mixture is stirred for one hour at room temperature, and is subsequently concentrated in vacuo. Water is added to the residue, and extraction is performed twice with ethyl acetate. The combined organic phases are extracted three times with 2 N hydrochloric acid. There are added to the aqueous acidified extracts ice and sufficient sodium carbonate to bring the pH-value to 10. The precipitated base is taken up in ethyl acetate. The organic phase is washed twice with water and once with saturated sodium chloride solution; it is dried over sodium sulphate and concentrated in vacuo. There is obtained crude 1-(2-benzoyl-4-chlorophenyl)-5-[(dimethylamino)-methyl]-1H-1,2,4-triazole-3-methanol as solidified foam.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH:29]=O)[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].NC1C=CC=CC=1>ClCCCl.C(Cl)Cl.CO>[CH2:10]([O:12][C:13]([C:15]1([CH2:28][CH2:29][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)=[O:14])[CH3:11]
Reactant: CCOC(=O)C1(CC=O)CCN(C(=O)OC(C)(C)C)CC1
Reactant: Cc1cc(Br)ccc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: Nc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C1(CCNc2ccc(Br)cc2C)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
2-Methyl-4-bromo-aniline (0.637 g, 3.427 mmol) was dissolved in DCE (15 mL); to this solution was transferred a solution of 4-(2-oxo-ethyl)-piperidine-1,4-dicarboxylic acid 1-tert-butyl ester 4-ethyl ester (1.03 g, 3.425 mmol) in DCE (35 mL). The flask was submerged in a water bath at rt. To this clear solution was then added acetic acid (0.647 g, 10.8 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (2.18 g, 10.3 mmol, 3 equiv.) under N2 at r.t. The yellowish milky suspension was stirred at r.t. overnight. LC/MS showed m/z 469/471 at t=4.930 min. along with small amount of aniline sm at 2.103 (186/188). TLC (5% of MeOH in DCM) showed no SM. of aldehyde, but aniline. The reaction was diluted with DCM (20 mL), cooled to ice-water bath, and quenched with 10 mL of 1N NH4OH. The two layers were separated, and the aqueous layer was extracted with DCM (15 mL×3). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 40 g-silica gel column eluted with 0-2% of MeOH in DCM to get 0.65 g (41%) of the title compound as an oil.
Reaction SMILES: [NH2:1]C1N=C(C2CCN(C(=O)CN3C(C)=CC(C(F)(F)F)=N3)CC2)SC=1.C(N(C(C)C)CC)(C)C.[C:35]1([O:41][C:42](Cl)=[O:43])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>ClCCl>[C:35]1([O:41][C:42](=[O:43])[NH2:1])[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Cc1cc(C(F)(F)F)nn1CC(=O)N1CCC(c2nc(N)cs2)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: NC(=O)Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-[4-(4-amino-thiazol-2-yl)-piperidin-1-yl]-2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-ethanone (80 mg, 0.21 mmol) in dichloromethane (5 mL) is added diisopropylethylamine (0.053 mL, 0.25 mmol), and subsequently phenylchloroformate (0.033 mL, 0.21 mmol) at 0° C. After stirring overnight at RT, solvents are evaporated under reduced pressure and the residue is purified by column chromatography on silica gel (ethyl acetate/heptane 7:3) to give 2-{1-[2-(5-methyl-3-trifluoromethyl-pyrazol-1-yl)-acetyl]-piperidin-4-yl}-thiazol-4-yl)-carbamic acid phenyl ester (Compound No. I.g.023, 71 mg, 67%). 1H-NMR (400 MHz, CDCl3): δ=1.57-1.78 (m, 2H), 2.08-2.19 (m, 2H), 2.22 (s, 3H), 2.75-2.81 (m, 1H), 3.05-3.20 (m, 2H), 3.95-3.99 (m, 1H), 4.44-4.52 (m, 1H), 4.83-4.98 (2d, 2H, diastereotopic protons), 6.25 (s, 1H), 7.05-7.20 (m, 3H), 7.29-7.38 (m, 2H), 7.95 (br, 1H). MS: m/z=494 (M+1).