Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][CH:5]1[C:9]2=[N:10][CH:11]=[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:43]([F:44])=[CH:42][CH:41]=[CH:40][C:39]=4[F:45])[N:32]=3)=[O:30])[C:13]([N:14]3[CH2:19][CH2:18][CH2:17][C@H:16]([NH:20]C(OC(C)(C)C)=O)[CH2:15]3)=[C:8]2[CH2:7][CH2:6]1)(=O)C.CO.[OH-].[Na+].C(O)(C(F)(F)F)=O>C(Cl)Cl.C1COCC1>[NH2:20][C@H:16]1[CH2:17][CH2:18][CH2:19][N:14]([C:13]2[C:12]([NH:28][C:29]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[C:33]([C:38]4[C:39]([F:45])=[CH:40][CH:41]=[CH:42][C:43]=4[F:44])[N:32]=3)=[O:30])=[CH:11][N:10]=[C:9]3[CH:5]([OH:4])[CH2:6][CH2:7][C:8]=23)[CH2:15]1
Reactant: CC(=O)OC1CCc2c1ncc(NC(=O)c1ccc(F)c(-c3c(F)cccc3F)n1)c2N1CCC[C@H](NC(=O)OC(C)(C)C)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@H]1CCCN(c2c(NC(=O)c3ccc(F)c(-c4c(F)cccc4F)n3)cnc3c2CCC3O)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-{(3S)-3-[(tert-Butoxycarbonyl)amino]piperidin-1-yl}-3-({[6-(2,6-difluorophenyl)-5-fluoropyridin-2-yl]carbonyl}amino)-6,7-dihydro-5H-cyclopenta[b]pyridin-7-yl acetate (4.0 mg, 0.0064 mmol) was mixed with MeOH (76 μL), THF (38 μL) and 1.0 M NaOH (42 μL, 0.042 mmol). The reaction mixture was stirred at room temperature for 30 min. The organic solvents were removed under reduced pressure. The aqueous layer was diluted with aq. NH4Cl then extracted with EtOAc twice. The combined organic layers were dried, filtered and concentrated under reduced pressure to give an intermediate, which was treated with DCM (0.065 mL) and TFA (0.065 mL, 0.84 mmol). The mixture was stirred at room temperature for 30 min., then concentrated under reduced pressure. The residue was diluted with MeOH and neutralized with small amount of NH4OH. The resulting mixture was filtered and purified by preparative LC-MS (XBridge™ preparative C18 5 μm 30×10 mm OBD™ column, flow rate 60 mL/min., eluting with a gradient of MeCN and water with 0.15% NH4OH) to give two diastereoisomers of the title compound as white powders.
Reaction SMILES: [CH3:1][N:2]1[C:6]([NH2:7])=[CH:5][C:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[N:3]1.[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24](Cl)(=[O:26])=[O:25])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]>N1C=CC=CC=1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]([S:24]([NH:7][C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH:5]=2)(=[O:25])=[O:26])[CH:19]=[CH:20][C:21]=1[O:22][CH3:23]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Reactant: Cn1nc(-c2ccccc2)cc1N
Solvent: c1ccncc1
Product: COc1ccc(S(=O)(=O)Nc2cc(-c3ccccc3)nn2C)cc1OC
Temperature: 25 °C
Reaction time: 22 h
Yield: 93.7 %

Procedure:
To a solution of 1-methyl-3-phenyl-pyrazol-5-amine (346 mg, 2 mmol) in 10 mL of dry pyridine was added 529 mg (2.23 mmol) of 3,4-dimethoxybenzenesulfonyl chloride. The solution was stirred at room temperature under Argon. After 22 h, the pyridine was removed in vacuo and flashed off with toluene. The crude base soluble material (1M NaOH) weighed 1.1 g. The crude product was taken up in EtOAc and extracted with 1M NaOH and H2O alternately. The basic aqueous phase was made acidic with 1M HCl, extracted with EtOAc, washed with water, dried and evaporated in vacuo to give a cream colored solid (0.70 g) which was taken up in 5 mL of hot EtOH, diluted with 5 mL of H2O and seeded to give 473 mg of a solid with mp 163-165° C. after drying in vacuo.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([OH:30])=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[CH:31]1(O)[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:18]([CH:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)[CH:17]3[C:12]([C:13]4[CH:27]=[CH:26][C:25]([C:28]([O:30][CH:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[O:29])=[CH:24][C:14]=4[CH2:15][CH2:16]3)=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4CCC3C2C2CCCC2)cc1Cl
Reactant: OC1CCCCC1
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)OC5CCCCC5)cc4CCC3C2C2CCCC2)cc1Cl

Procedure:
The title compound was prepared from (±)-(3SR,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentyl-3,3a,4,5-tetrahydro-2H-benzo[g]indazole-7-carboxylic acid, Example 15 and cyclohexanol according to Method E. 1H NMR (400 MHz, CDCl3) δ ppm 1.19-1.68 (m, 13H), 1.70-1.86 (m, 3H), 1.87-2.03 (m, 3H), 2.06-2.20 (m, 1H), 2.23-2.39 (m, 1H), 2.85-2.98 (m, 1H), 3.13 (ddd, J=16.18, 3.36, 3.02 Hz, 1H), 3.49 (ddd, J=13.76, 9.33, 4.83 Hz, 1H), 4.63 (dd, J=9.53, 5.50 Hz, 1H), 5.04 (ddd, J=12.82, 8.93, 3.76 Hz, 1H), 7.02 (dd, J=8.86, 1.88 Hz, 1H), 7.30 (d, J=2.15 Hz, 1H), 7.46 (d, J=8.86 Hz, 1H), 7.87-7.97 (m, 2H), 8.14 (d, J=8.32 Hz, 1H).
Reaction SMILES: CN1[C@@]2(CO)SS[C@]3(N(C2=O)[C@H]2NC4C([C@@]2(N2[C:32]5[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=5)[C:26]([CH2:33][C:34]56SS[C@@](CO)(C(N5C)=O)N(C)[C:35]6=[O:36])=C2)C3)=CC=CC=4)C1=O.[OH2:48]>>[C:35]([OH:36])(=[O:48])[CH2:34][CH2:33][CH2:26][CH2:27][CH2:32][CH2:31][CH2:30]/[CH:29]=[CH:28]\[CH2:34][CH2:33][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31]
Reactant: CN1C(=O)[C@]2(CO)SSC1(Cc1cn([C@]34C[C@@]56SS[C@@](CO)(C(=O)N5[C@H]3Nc3ccccc34)N(C)C6=O)c3ccccc13)C(=O)N2C
Reactant: O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)O

Procedure:
Four hundred grams of oleic acid (SO-90L, produced by Kao Corporation), 16 g of activated clay (CS-1, mean inter-layer distance of 4 Å, produced by Mizusawa Kagaku) and 8 g of water were placed in an autoclave. After the inside atmosphere of the autoclave was replaced with nitrogen, the mixture was stirred. The inside of the autoclave was heated to 240° C. and kept in a steam atmosphere of 14 kgf/cm2 for 6 hours. After cooling, the reaction mixture obtained was taken out from the autoclave, and the semisynthetic clay was filtered off. The filtrate was distilled under a reduced pressure to yield 167.6 g of monomeric acids.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[C:12]2[C:7]([CH:8]=[CH:9][CH:10]=[C:11]2[NH2:14])=[CH:6][CH:5]=1)[CH3:2].[Li].CO.N>O1CCCC1.O>[CH2:1]([O:3][C:4]1[CH2:13][C:12]2[C:11]([NH2:14])=[CH:10][CH:9]=[CH:8][C:7]=2[CH2:6][CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2cccc(N)c2c1
Agent: N
Agent: [Li]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCOC1=CCc2cccc(N)c2C1
Temperature: -78 °C
Reaction time: 1 h
Yield: 75.3 %

Procedure:
Next, to a flask containing a mixture of 7-ethoxy-naphthalen-1-ylamine (1.80 g, 9.61mmol) and t-buthanol (2.13 g, 28.8 mmol) in tetrahydrofuran (20mL) was collected liquid ammonia (300 mL) at −78° C. To the mixture was added lithium (0.200 g, 28.8 mmol) over 30 minutes and stirred at −78° C. for 1 hour. Methanol and water was added, and the mixture was stirred at room temperature for 16 hours to allow ammonia to evaporate. To the obtained residue was added ethylacetate. The organic layer was washed with water, dried over Na2SO4, filtered, and concentrated under reduced pressure to afford 7-ethoxy-5,8-dihydronaphtalen-1-ylamine (1.37 g, 76% yield).
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[CH:11][C:12]([F:38])=[C:13]([CH:15]2[C:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[CH:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][CH:16]2[C:35]([OH:37])=O)[CH:14]=1.[NH2:39][C:40]1[CH:49]=[CH:48][C:43]([C:44]([O:46][CH3:47])=[O:45])=[CH:42][CH:41]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:47][O:46][C:44](=[O:45])[C:43]1[CH:48]=[CH:49][C:40]([NH:39][C:35]([C@H:16]2[C@H:15]([C:13]3[CH:14]=[C:9]([Cl:8])[CH:10]=[CH:11][C:12]=3[F:38])[C@:19]([C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=3[F:29])([C:20]#[N:21])[C@H:18]([CH2:30][C:31]([CH3:33])([CH3:34])[CH3:32])[NH:17]2)=[O:37])=[CH:41][CH:42]=1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cc(Cl)ccc2F)C1(C#N)c1ccc(Cl)cc1F
Reactant: COC(=O)c1ccc(N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc(NC(=O)[C@@H]2N[C@@H](CC(C)(C)C)[C@](C#N)(c3ccc(Cl)cc3F)[C@H]2c2cc(Cl)ccc2F)cc1
Yield: 26.2 %

Procedure:
In a manner similar to the method described in Examples 1e, rac-(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid trifluoroacetic acid prepared in Example 98c (0.5 g, 0.89 mmol) was reacted with methyl 4-aminobenzoate (0.24 g, 1.6 mmol), HATU (0.61 g, 1.6 mmol) and iPr2NEt (0.39 mL, 2.2 mmol) in CH2Cl2 at room temperature to give rac-4-{[(2R,3S,4R,5S)-3-(5-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-benzoic acid methyl ester as a white solid (0.14 g, 27%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:40]=[CH:39][C:6]([CH2:7][N:8]([CH2:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=2)[C:9]2[N:14]=[CH:13][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][NH:27][C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:11][N:10]=2)=[CH:5][CH:4]=1.Br[C:42]1[CH:43]=[C:44]([S:48]([N:51]2[CH2:56][CH2:55][O:54][CH2:53][CH2:52]2)(=[O:50])=[O:49])[CH:45]=[CH:46][CH:47]=1>>[CH3:38][O:37][C:34]1[CH:33]=[CH:32][C:31]([CH2:30][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:40][CH:39]=2)[C:9]2[N:10]=[CH:11][C:12]([C:15]3[C:16]4[CH2:29][CH2:28][N:27]([C:46]5[CH:47]=[CH:42][CH:43]=[C:44]([S:48]([N:51]6[CH2:56][CH2:55][O:54][CH2:53][CH2:52]6)(=[O:50])=[O:49])[CH:45]=5)[C:17]=4[N:18]=[C:19]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)[N:20]=3)=[CH:13][N:14]=2)=[CH:36][CH:35]=1
Reactant: O=S(=O)(c1cccc(Br)c1)N1CCOCC1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4)cn2)cc1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2ncc(-c3nc(N4CCOCC4)nc4c3CCN4c3cccc(S(=O)(=O)N4CCOCC4)c3)cn2)cc1

Procedure:
Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (44 mg) and 4-(3-bromo-benzenesulfonyl)-morpholine (prepared from 3-bromobenzenesulfonyl chloride, morpholine and pyridine in acetonitrile, 51 mg) instead of 4-bromobenzoic acid methyl ester in Example 1-D-08, in the same manner as Example 1-D-08, a crude product of bis-(4-methoxy-benzyl)-(5-{7-[3-(morpholine-4-sulfonyl)-phenyl]-2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl}-pyrimidin-2-yl)-amine was obtained, and then the PMB groups were removed according to the above Deprotection method 1, to obtain the desired compound (D-86) as a yellow powder (59 mg, 73%).
Reaction SMILES: C([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]1[CH2:31][C@@:29]2([CH3:30])[C@@H:25]([CH2:26][CH2:27][C@@H:28]2[O:32][Si:33]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34])[C@@:24]2([CH:40]=[O:41])[C:15]=1[C:16]1[CH:17]=[CH:18][C:19]([O:42][CH3:43])=[CH:20][C:21]=1[CH2:22][CH2:23]2)C1C=CC=CC=1>O1CCCC1.CO.[Pd]>[Si:33]([O:32][C@H:28]1[CH2:27][CH2:26][C@H:25]2[C@@:24]3([CH:40]=[O:41])[C@H:15]([C@@H:14]([CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][OH:8])[CH2:31][C@:29]12[CH3:30])[C:16]1[CH:17]=[CH:18][C:19]([O:42][CH3:43])=[CH:20][C:21]=1[CH2:22][CH2:23]3)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34]
Reactant: COc1ccc2c(c1)CC[C@]1(C=O)C2=C(CCCCCOCc2ccccc2)C[C@]2(C)[C@@H](O[Si](C)(C)C(C)(C)C)CC[C@H]21
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CC[C@@]1(C=O)[C@@H]3CC[C@H](O[Si](C)(C)C(C)(C)C)[C@@]3(C)C[C@H](CCCCCO)[C@H]21
Temperature: 25 °C
Reaction time: 48 h
Yield: 67.3 %

Procedure:
A solution of 14.36 g of tetraene 6 in 400 ml of tetrahydrofuran/methanol (3:1) is mixed with 2.8 g of palladium (10% on carbon) and stirred under a hydrogen atmosphere (100 bar) for two days at room temperature. This reaction is repeated twice. For working-up, it is filtered on Celite and concentrated by evaporation in a vacuum. The residue is purified by column chromatography (cyclohexane/ethyl acetate) and yields 8.25 g of 7 as a colorless foam (GC-MS: m/z theor.: 514, pract.: 514).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:32]([N:39]1[CH2:42][CH2:41][C@H:40]1[CH2:43][OH:44])([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33].[Cl:45][C:46]1[C:51](O)=[CH:50][CH:49]=[CH:48][N:47]=1>C1COCC1>[Cl:45][C:46]1[C:51]([O:44][CH2:43][C@@H:40]2[CH2:41][CH2:42][N:39]2[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[CH:50][CH:49]=[CH:48][N:47]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1CO
Reactant: Oc1cccnc1Cl
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC[C@H]1COc1cccnc1Cl
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 37.2 %

Procedure:
To a solution of triphenylphosphine (1.73 g, 6.6 mmol) in THF (26 mL) was added diethyl azodicarboxylate (1.04 mL, 6.6 mmol) at 0° C., and the reaction mixture was stirred for 15 minutes. 1-BOC-2-(S)-azetidinemethanol (1.03 g, 5.5 mmol) and 2-chloro-3-pyridinol (785 mg, 6.0 mmol, Aldrich Chemical Co.) were then added. The reaction mixture was allowed to warm slowly to room temperature and stir overnight. Solvent was removed, and the residue was dissolved in ethyl acetate. The solution was washed with saturated aqueous K2CO3 and brine, dried over MgSO4 and concentrated. The residue was chromatographed on a silica gel column, eluting with ethyl acetate:hexane (1:4 to 1:1) to afford the title compound (611 mg). MS (DCI/NH3) m/z 299 (M+H)+.
Reaction SMILES: [BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2(O)[CH2:13][S:12][C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[CH3:22])[N:10]2[CH3:23])=[CH:5][C:4]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27]>C(O)(=O)C>[BrH:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]([CH3:23])[C:11](=[N:14][C:15]3[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=3[CH3:22])[S:12][CH:13]=2)=[CH:5][C:4]=1[S:25](=[O:30])(=[O:29])[N:26]([CH3:28])[CH3:27]
Reactant: Cc1ccc(N=C2SCC(O)(c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)N2C)c(C)c1
Agent: Br
Solvent: CC(=O)O
Product: Cc1ccc(N=c2scc(-c3ccc(Cl)c(S(=O)(=O)N(C)C)c3)n2C)c(C)c1

Procedure:
Obtained by a procedure analogous to that indicated in Example 1 (b), from 4-(4-chloro-3-dimethylsulfamoylphenyl)-3-methyl-2-(2,4-dimethylphenyl-imino)thiazolidin-4-ol hydrobromide. Colorless crystals; melting point 264° C. (from glacial acetic acid).
Reaction SMILES: O[Li].O.[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([O:19]CC2C=CC=CC=2)=[O:18])=[CH:13][CH:12]=1)[CH3:8])[CH3:5].C1COCC1.CO.O>O>[CH2:4]([O:6][C:7](=[N:9][O:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]([OH:19])=[O:18])=[CH:13][CH:12]=1)[CH3:8])[CH3:5]
Reactant: CCOC(C)=NOc1ccc(C(=O)OCc2ccccc2)cc1
Agent: [Li]O
Solvent: C1CCOC1
Solvent: CO
Solvent: O
Product: CCOC(C)=NOc1ccc(C(=O)O)cc1
Temperature: 25 °C
Yield: 94.2 %

Procedure:
LiOH.H2O (550 mg, 13.1 mmol) was added to a solution of ethyl-N-(4-benzyloxycarbonylphenoxy)acetimidate 19 (1.04 g, 3.32 mmol) in a 9/3/3 mL mixture of THF/MeOH/H2O and the reaction was stirred at room temperature. After 24 h the reaction was diluted with H2O (100 mL), washed with CH2Cl2 (4×30 mL), acidified to pH˜5.0-5.5 with 0.5 N HCl, and extracted with EtOAc (3×30 mL). The combined organics were washed with H2O (30 mL) and brine (30 mL), dried over Na2SO4, filtered, and concentrated to afford 21 as a white crystalline solid (698 mg, 94%). 1H-NMR (500 MHz, CDCl3) δ 1.37 (t, J=6.9 Hz, 3H), 2.14 (s, 3H), 4.22 (q, J=6.9 Hz, 2H), 7.18-7.22 (m, 2H), 8.04-8.08 (m, 2H); 13C-NMR (125 MHz, CDCl3) δ 14.5, 14.6, 63.3, 113.7, 122.1, 132.3, 164.2, 166.7, 172.0; ESI-MS 224 m/z [MH]+, C11H14NO4 requires 224.
Reaction SMILES: [OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5].C(=O)(O)[O-].[Na+].Cl[C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25]>ClCCl>[OH:1][C:2]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:3]=1[C:4]([CH:6]1[CH2:7][CH2:8][N:9]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])[CH2:10][CH2:11]1)=[O:5]
Reactant: COc1ccc(C(=O)C2CCNCC2)c(O)c1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(C(=O)C2CCN(C(=O)OCc3ccccc3)CC2)c(O)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 76.5 %

Procedure:
To a stirred, ice-cooled mixture of 36.1 g of 4-(2-hydroxy-4-methoxybenzoyl)piperidine, 16.3 g of sodium bicarbonate and 350 ml of dichloromethane, was added dropwise 22.9 ml of benzyl chloroformate in dichloromethane. After the addition was complete, the mixture was stirred at ambient temperature for 1.5 hrs, filtered and the filtrate concentrated to an oil. The oil crystallized. The crystals were collected, washed with hexane and dried to yield 42.4 g (76.5%) of product. Recrystallization from isopropanol gave the analytical sample, mp, 89°-91°.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]([OH:17])=[CH:4][CH:3]=1.[CH3:18][O-:19].[Na+]>C1(C)C(C)=CC=CC=1>[CH2:5]([C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:18]=1[OH:19])[C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:17]
Reactant: Cc1ccc(O)c(-c2cccc3[nH]nnc23)c1
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cc(Cc2cc(C)cc(-c3cccc4[nH]nnc34)c2O)c(O)c(-c2cccc3[nH]nnc23)c1
Yield: 95 %

Procedure:
6.2 g of the Mannich base obtained in Example 1 and 4-methyl-6benzotriazolyl-phenol 4.5 g were dissolved in 200 ml of xylene, and sodium methylate (28% methanol solution) 0.2 g was added. The solution was heated with stirring under reflux at 140°-150° C. for 10 hours with a stream of nitrogen. After distilling of the solvent, and recrystallizing the residue from xylene, the desired product 2,2'-methylene-bis-(4methyl-6-benzotriazolyl-phenol) was obtained in 95% yield.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[C:3]([N:10]2[CH2:15][CH2:14][N:13]([C:16](=O)[CH2:17][C:18]3[CH:23]=[C:22]([O:24][CH3:25])[C:21]([O:26][CH3:27])=[CH:20][C:19]=3[N+:28]([O-:30])=[O:29])[CH2:12][CH2:11]2)=[N:2]1.C(=O)(O)[O-].[Na+]>>[CH3:27][O:26][C:21]1[C:22]([O:24][CH3:25])=[CH:23][C:18]([CH2:17][CH2:16][N:13]2[CH2:14][CH2:15][N:10]([C:3]3[C:4]4[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=4[S:1][N:2]=3)[CH2:11][CH2:12]2)=[C:19]([N+:28]([O-:30])=[O:29])[CH:20]=1
Reactant: COc1cc(CC(=O)N2CCN(c3nsc4ccccc34)CC2)c([N+](=O)[O-])cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Product: COc1cc(CCN2CCN(c3nsc4ccccc34)CC2)c([N+](=O)[O-])cc1OC
Temperature: 110 °C
Yield: 74.4 %

Procedure:
1-(4-1,2-Benzisothiazol-3-yl-piperazin-1-yl)-2-(4,5-dimethoxy-2-nitro-phenyl)-ethanone (6.08 g, 13.8 mmol) was diluted in 50 mL of toulene. Borane methyl sulfide complex (2.0 M in tolulene, 7.22 mL) was slowly added to the stirring mixture. The reaction mixture was heated to 110° C. in an oil bath overnight. Upon cooling, excess sodium bicarbonate was added dropwise and the mixture was heated to 85° C. until gas evolution subsided. The water layer was removed and extracted in methylene chloride. The organic layers were combined, dried over Na2SO4 then concentrated and purified by column chromatography to afford 4.40 g of a brown solid. Yield 74%; 100% purity at 254 nm; LCMS (APCI): 428 [M+H]+; mp 135° C.
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][CH:10]=[C:9]([F:13])[C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Li+].CC([N-]C(C)C)C.CN([CH:25]=[O:26])C>C1COCC1>[Cl:1][C:2]1[C:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])=[C:9]([F:13])[C:10]([CH:25]=[O:26])=[CH:11][CH:12]=1
Reactant: CCOC(=O)c1c(F)cccc1Cl
Reactant: CN(C)C=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(Cl)ccc(C=O)c1F
Reaction time: 2 h
Yield: 35.1 %

Procedure:
To a cold solution of ethyl 2-chloro-6-fluorobenzoate (0.500 g, 24.7 mmol) in THF (35 mL) was added LDA (6.6 g, 61.8 mmol) at −78° C. The reaction mixture was stirred for 2 h at same temperature, followed by addition of DMF (2.7 g, 37 mmol). The reaction mixture was further stirred for 2 h at same temperature. The reaction mass was quenched in dilute HCl, extracted with ethyl acetate and concentrated to afford crude product which was further purified by column chromatography eluting with EtOAC: pet. ether to afford 2.00 g of pure product. 1H NMR (300 MHz, DMSO d6): δ 1.31 (t, 3H), 4.42 (q, 2H), 7.94-7.99 (m, 2H), 10.14 (s, 1H).
Reaction SMILES: CC(C)CC(O)C.[F:8][C:9]([F:24])([F:23])[C:10]1[CH:11]=[C:12]([C:20](=[O:22])[CH3:21])[CH:13]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:15]=1.C1N=C(N)C2N=CN([C@@H]3O[C@H](COP(OP(OC[C@H]4O[C@@H](N5C=C(C(N)=O)CC=C5)[C@H](O)[C@@H]4O)(O)=O)(O)=O)[C@@H](O)[C@H]3O)C=2N=1>[Cl-].[Cl-].[Zn+2].OCC(CO)O>[F:8][C:9]([F:23])([F:24])[C:10]1[CH:11]=[C:12]([C@@H:20]([OH:22])[CH3:21])[CH:13]=[C:14]([C:16]([F:17])([F:18])[F:19])[CH:15]=1
Reactant: CC(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: NC(=O)C1=CN([C@@H]2O[C@H](COP(=O)(O)OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)C=CC1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: OCC(O)CO
Solvent: CC(C)CC(C)O
Product: C[C@H](O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reaction time: 24 h

Procedure:
For the conversion, a mixture of 1 mL of a buffer (100 mM TEA, pH=7, 10% glycerol, 1 mM ZnCl2), 3 ml 4-methyl-2-pentanol, 1 ml 1-[3,5 bis-(trifluoro-methyl)phenyl]ethane-1-one, 2 mg NAD and 0.7 kU recombinant oxidoreductase from Microbacterium spec. DSMZ 20028 was incubated at room temperature for 24 h with constant thorough mixing. After 24 h, more than 90% of the 1-[3,5 bis-(trifluoro-methyl)phenyl]ethane-1-one used had been reduced to (1S)-1[3,5-bis(trifluoromethyephenyl)ethane-1-ol. Subsequently, the 4-methyl2-pentanol phase containing the product was separated from the aqueous phase, filtered, and the product (1S)-1[3,5-bis(trifluoromethyl)phenyl]ethane-1-ol was obtained by distillation. The crude product (1S)-1-[3,5-bis(trifluoromethyl)phenyl]ethane-1-one obtained in this manner exhibited an enantiomeric excess of >99.5%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:14]2[CH2:15][CH2:16][C@@H:9]1[CH2:10][N:11]([C:18]1[CH:19]=[N:20][C:21]([NH2:24])=[CH:22][CH:23]=1)[C:12](=[O:17])[CH2:13]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:26]1[N:27]=[CH:28][C:29]2[CH:34]=[C:33]([C:35]([N:37]([CH3:39])[CH3:38])=[O:36])[N:32]([CH:40]3[CH2:44][CH2:43][CH2:42][CH2:41]3)[C:30]=2[N:31]=1>>[CH:40]1([N:32]2[C:30]3[N:31]=[C:26]([NH:24][C:21]4[N:20]=[CH:19][C:18]([N:11]5[C:12](=[O:17])[CH2:13][C@H:14]6[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[C@H:9]([CH2:16][CH2:15]6)[CH2:10]5)=[CH:23][CH:22]=4)[N:27]=[CH:28][C:29]=3[CH:34]=[C:33]2[C:35](=[O:36])[N:37]([CH3:38])[CH3:39])[CH2:41][CH2:42][CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2CC[C@H]1CC(=O)N(c1ccc(N)nc1)C2
Reactant: CN(C)C(=O)c1cc2cnc(Cl)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4C[C@H]5CC[C@@H](CC4=O)N5C(=O)OC(C)(C)C)cn3)nc2n1C1CCCC1
Yield: 88.3 %

Procedure:
Following general N—C coupling procedure 1, (1R,6S)-3-(6-Amino-pyridin-3-yl)-4-oxo-3,9-diaza-bicyclo[4.2.1]nonane-9-carboxylic acid tert-butyl ester (0.548 gm, 1.65 mmol) was combined with 2-chloro-7-cyclopentyl-N,N-dimethyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide (483 mg, 1.65 mmol) which gave (1R,6S)-tert-butyl 3-(6-(7-cyclopentyl-6-(dimethylcarbamoyl)-7H-pyrrolo[2,3-d]pyrimidin-2-ylamino)pyridin-3-yl)-4-oxo-3,9-diazabicyclo[4.2.1]nonane-9-carboxylate (858 mg) in 88% yield.