Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[CH2:7]/[N:8]=[CH:9]/[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:18][C:19]1[CH:20]=[C:21](/[CH:25]=[C:26](/[C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=2)\[C:27]#[N:28])[CH:22]=[CH:23][CH:24]=1.C(N(CC)CC)C>ClCCl>[C:1]([O:5][C:6]([CH:7]1[CH:25]([C:21]2[CH:22]=[CH:23][CH:24]=[C:19]([Cl:18])[CH:20]=2)[C:26]([C:29]2[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=2)([C:27]#[N:28])[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[NH:8]1)=[O:17])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C/N=C/c1cccc(Cl)c1
Reactant: N#C/C(=C\c1cccc(Cl)c1)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)C1NC(c2cccc(Cl)c2)C(C#N)(c2ccc(Cl)cc2)C1c1cccc(Cl)c1
Yield: 42.6 %

Procedure:
In a manner similar to the method described in Example 1c, {[1-(3-Chloro-phenyl)-meth-(E)-ylidene]-amino}-acetic acid tert-butyl ester prepared in Example 32a (2 g, 7.6 mmol) was reacted with (Z)-3-(3-chloro-phenyl)-2-(4-chloro-phenyl)-acrylonitrile (0.55 g, 2 mmol) prepared in Example 1b, AgF (1.3 g, 10 mmol), and triethylamine (1.9 g, 19 mmol) in dichloromethane (30 mL) at 50° C. for 20 h to give rac-(2R,3R,4R,5S)-3,5-bis-(3-chloro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester as a white foam (0.45 g, 44%).
Reaction SMILES: Br[C:2]1[CH:21]=[CH:20][C:5]([C:6]([C@@H:8]2[CH2:12][CH2:11][CH2:10][C@H:9]2[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([NH:29][C:30]2[S:31][C:32]3[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=3[N:34]=2)=[C:25]([F:40])[CH:24]=1.[F:41][C:42]1[CH:43]=[C:44]([C:63]2[CH:68]=[CH:67][C:66]([C:69]([C@@H:71]3[CH2:75][CH2:74][CH2:73][C@H:72]3[C:76]([O:78]C)=[O:77])=[O:70])=[CH:65][CH:64]=2)[CH:45]=[CH:46][C:47]=1[NH:48][C:49]1[S:50][C:51]2[CH:57]=[C:56](OC(F)(F)F)[CH:55]=[CH:54][C:52]=2[N:53]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[F:40][C:25]1[CH:24]=[C:23]([C:2]2[CH:21]=[CH:20][C:5]([C:6]([C@@H:8]3[CH2:12][CH2:11][CH2:10][C@H:9]3[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:7])=[CH:4][CH:3]=2)[CH:28]=[CH:27][C:26]=1[NH:29][C:30]1[S:31][C:32]2[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:33]=2[N:34]=1.[F:41][C:42]1[CH:43]=[C:44]([C:63]2[CH:64]=[CH:65][C:66]([C:69]([C@@H:71]3[CH2:75][CH2:74][CH2:73][C@H:72]3[C:76]([OH:78])=[O:77])=[O:70])=[CH:67][CH:68]=2)[CH:45]=[CH:46][C:47]=1[NH:48][C:49]1[S:50][C:51]2[CH:57]=[C:56]([F:39])[CH:55]=[CH:54][C:52]=2[N:53]=1
Reactant: Fc1ccc2nc(Nc3ccc(Br)cc3F)sc2c1
Reactant: CC(C)(C)OC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(Br)cc1
Reactant: COC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(OC(F)(F)F)cc4s3)c(F)c2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)OC(=O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Product: O=C(O)[C@@H]1CCC[C@H]1C(=O)c1ccc(-c2ccc(Nc3nc4ccc(F)cc4s3)c(F)c2)cc1
Yield: 77 %

Procedure:
tert-Butyl (1R,2R)-2-({3′-fluoro-4′-[(6-fluoro-1,3-benzothiazol-2-yl)amino]-1,1′-biphenyl-4-yl}carbonyl)cyclopentanecarboxylate was prepared from tert-butyl (1R,2R)-2-(4-bromobenzoyl)-cyclopentanecarboxylate and N-(4-bromo-2-fluorophenyl)-N-(6-fluoro-1,3-benzothiazol-2-yl)amine in a similar manner to that described above for methyl (1R,2R)-2-[(3′-fluoro-4′-{[6-(trifluoromethoxy)-1,3-benzothiazol-2-yl]amino}-1,1′-biphenyl-4-yl)carbonyl]cyclopentanecarboxylate. A solution of the tert-butyl ester (1.5 g, 2.81 mmol) in 2.0 mL TFA and 10 mL CH2Cl2 was stirred at rt overnight. After the solvent was removed by rotary evaporation, 50 mL EtOAc and 50 mL water were added. The organic layer was separated, washed with 50 mL water, and then dried over Na2SO4. After the solvent was removed by rotary evaporation, 5 mL EtOAc was added to the residue, followed by 5 mL hexanes. The precipitate that formed was collected by filtration to afford the desired product as a light yellow solid (1.0 g, 77%, 95.2% ee). 1H NMR (400 MHz, DMSO-d6) δ 12.20 (br s, 1 H), 10.50 (bs, 1 H), 8.70 (t, 1 H), 7.60-8.10 (m, 8 H), 7.20 (t, 1 H), 4.10 (m, 1 H), 3.20 (m, 1 H), 2.20 (m, 1 H), 2.00 (m, 1 H), 1.50-1.90 (m, 4 H); LC-MS m/z 479.3 (MH+), ret. time 3.64 min.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.O.[F:13][C:14]([F:27])([F:26])[C:15]([C:22]([F:25])([F:24])[F:23])([C:18]([F:21])([F:20])[F:19])[CH:16]=[CH2:17].C(=O)(O)[O-].[Na+]>C(OCC)C>[F:13][C:14]([F:26])([F:27])[C:15]([C:18]([F:21])([F:20])[F:19])([C:22]([F:23])([F:24])[F:25])[CH:16]1[O:9][CH2:17]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=CC(C(F)(F)F)(C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Product: FC(F)(F)C(C1CO1)(C(F)(F)F)C(F)(F)F

Procedure:
32.9 g (105 mmol) of 3-chloroperbenzoic acid with a peracid content of 55% is added in portions with stirring and cooling with water to a solution of 24.6 g (100 mmol) of 4,4,4-trifluoro-3,3-bis(trifluoromethyl)-but-1-ene in 150 ml of absolute diethyl ether. After addition is completed, it is refluxed for 3 hours. It is allowed to cool, and the solution is stirred in cold, saturated sodium bicarbonate solution. The ethereal solution is separated, washed with sodium chloride solution, dried on sodium sulfate and concentrated by evaporation on a column. The residue is purified by bulb tube distillation (vacuum 30 mbar, 130° C. bath).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([C:26]([F:29])([F:28])[F:27])=[CH:10][C:11]([C:13]2[CH:14]=[CH:15][C:16]([N:21]3[CH:25]=[N:24][CH:23]=[N:22]3)=[C:17]([CH:20]=2)[C:18]#[N:19])=O)[CH:5]=[C:6]([Cl:8])[CH:7]=1.[OH-:30].[Na+].Cl.[NH2:33]O.Cl>C1(C)C=CC=CC=1.O.CN1CCCC1=O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:26]([F:29])([F:28])[F:27])[O:30][N:33]=[C:11]([C:13]3[CH:14]=[CH:15][C:16]([N:21]4[CH:25]=[N:24][CH:23]=[N:22]4)=[C:17]([CH:20]=3)[C:18]#[N:19])[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: NO
Reactant: N#Cc1cc(C(=O)C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)ccc1-n1cncn1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
1.52 g of toluene and 0.91 g of N-methyl-2-pyrrolidone were added to 0.30 g (0.96 mmol) of 5-(3-(3,5-dichlorophenyl)-4,4,4-trifluoro-2-butenoyl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile, and the mixture was cooled to 0° C. After adding in dropwise to this mixture the aqueous solution which was prepared by adding 0.28 g of water to 0.11 g (2.77 mmol) of sodium hydroxide, and then adding the solution in which 0.053 g (0.76 mmol) of hydroxylamine hydrochloride was dissolved into 0.11 g of water in dropwise, the mixture was stirred for 2 hours at 0° C. The aqueous solution which was prepared from 0.43 g (4.16 mmol) of 35% hydrochloric acid and 1.30 g of water was added in dropwise to the reaction solution, and the mixture was stirred for 1 hour. 5 ml of toluene was added and separation operation was performed. The toluene phase was washed twice with 3 ml of water. The solvent was distilled off under reduced pressure to obtain 0.30 g of 5-(5-(3,5-dichlorophenyl)-5-trifluoromethyl-4,5-dihydroisoxazol-3-yl)-2-(1H-1,2,4-triazol-1-yl)benzonitrile (yield 94.5%).
Reaction SMILES: [C:1]([NH:11][C@@H:12]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@H:13]([OH:29])[CH2:14][N:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:21])[CH2:17][C:18](=[O:20])[CH3:19])([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].S([N:47]=[N+:48]=[N-])(C1C=CC(C)=CC=1)(=O)=O.C1CCN2C(=NCCC2)CC1.ClCCl>C(#N)C>[C:1]([NH:11][C@@H:12]([CH2:30][C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C@H:13]([OH:29])[CH2:14][N:15]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16](=[O:21])[C:17](=[N+:47]=[N-:48])[C:18](=[O:20])[CH3:19])([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: Cc1ccc(S(=O)(=O)N=[N+]=[N-])cc1
Reactant: CC(=O)CC(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Solvent: ClCCl
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)C(=[N+]=[N-])C(=O)N(Cc1ccccc1)C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 78 %

Procedure:
The keto amide (XI) (0.040 g, 0.08 mmol) was dissolved in 0.5 ml of acetonitrile and cooled to 0° C. To this tosyl azide (0.024 g, 0.12 mmol) was added followed by the addition of DBU (18 μL, 0.12 mmol) dropwise. The reaction mixture was stirred for 1 hr at 0° C. and then 3 hrs at room temperature. It was then concentrated under reduced pressure to give dark red oil. The residue was taken up in a minimum volume of dichloromethane and placed on a silica gel column. The compound was eluted with 2:1 hexane/ethyl acetate to give the diazo keto-amide (XII) as yellow oil. 0.033 g (78% yield). 1H NMR (500 MHz, CDCl3) δ 7.13-7.49 (m, 15H), 5.02-5.37 (m, 3H), 4.46-4.87 (m, 2H), 3.75-4.06 (m, 2H), 3.28-3.51 (m, 1H), 2.75-2.94 (m, 2H), 2.05 (s, 3H). 13CNMR (125 MHz, CDCl3) 171, 165.4, 155.85, 140.91, 140.36, 139.22, 129.14, 128.68, 128.26, 128.17, 128.10, 127.72, 127.41, 127.64, 126.75, 79.23, 60.38, 53.14, 50.15, 47.99, 45.6, 37.43, 26.6.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:48])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[N:30](C(OC(C)(C)C)=O)[CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]>ClCCl>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[C:8]([C:10]1[CH:11]=[C:12]([C:20]2[O:24][N:23]=[C:22]([C:25]3[C:26]([CH3:48])=[C:27]4[C:32](=[CH:33][CH:34]=3)[CH:31]([CH2:35][CH2:36][CH2:37][C:38]([OH:40])=[O:39])[NH:30][CH2:29][CH2:28]4)[N:21]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH:17]([CH3:19])[CH3:18])#[N:9]
Reactant: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCN(C(=O)OC(C)(C)C)C2CCCC(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1c(-c2noc(-c3ccc(OC(C)C)c(C#N)c3)n2)ccc2c1CCNC2CCCC(=O)O
Temperature: 25 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Trifluoroacetic acid (1.0 ml, 13.0 mmol) was added dropwise at 25° C. under nitrogen to a solution of 4-(6-(5-{3-cyano-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-2-{[(1,1-dimethylethyl)oxy]carbonyl}-5-methyl-1,2,3,4-tetrahydro-1-isoquinolinyl)butanoic acid (Preparation 32; 102 mg, 0.182 mmol) in dichloromethane (4.0 ml) and the resulting mixture was stirred at 25° C. for 1 h. The solvent was removed, and the residue co-evaporated with toluene followed by trituration with diethyl ether to give the title compound (76 mg) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[CH2:19][C:20]([NH2:22])=[O:21].[C:23](OCC)(=[O:29])[C:24](OCC)=[O:25].CC(C)([O-])C.[K+].Cl>CN(C)C=O.O>[Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[C:19]1[C:20](=[O:21])[NH:22][C:24](=[O:25])[C:23]=1[OH:29]
Reactant: CC1(C2CCCC2)Cc2cc(CC(N)=O)c(Cl)c(Cl)c2C1=O
Reactant: CCOC(=O)C(=O)OCC
Agent: CC(C)(C)[O-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(C3=C(O)C(=O)NC3=O)c(Cl)c(Cl)c2C1=O

Procedure:
In a nitrogen atmosphere, (+)-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)acetamide (19.8 g., 0.0582 mole) and diethyl oxalate (9.14 g., 0.0626 mole) are dissolved in dimethylformamide (100 ml.) and stirred in an ice bath. Potassium tert. butoxide (15.2 g, 0.136 mole) is added in two portions at a 10 minute interval. The reaction mixture is stirred at 25° C. for 18 hours, poured into water (600 ml) acidified with hydrochloric acid, extracted with ether, washed with water and brine and dried over MgSO4. Evaporation of the ether at reduced pressure gives (+)3-(6,7-dichloro-2-cyclopentyl-2,3-dihydro-2-methyl-1-oxo-1H-inden-5-yl)-4-hydroxy-1H-pyrrole-2,5-dione as the hemietherate in the form of a foam. Upon drying at reduced pressure, the analysis of the hemietherate is as follows:
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[C:8]([NH2:13])[C:9]([NH2:12])=[CH:10][CH:11]=1.[C:14]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15].CCOC(C)=O>C(#N)C.N1C=CC=CC=1>[C:14]([NH:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:13][C:8]2[CH:7]=[C:6]([C:2]3[S:1][CH:5]=[CH:4][N:3]=3)[CH:11]=[CH:10][C:9]=2[NH2:12])=[O:23])=[CH:20][CH:19]=1)(=[O:16])[CH3:15]
Reactant: Nc1ccc(-c2nccs2)cc1N
Reactant: CC(=O)Nc1ccc(C(=O)Cl)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: CC#N
Product: CC(=O)Nc1ccc(C(=O)Nc2cc(-c3nccs3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 5.7 %

Procedure:
To a stirred suspension of 222a (47 mg, 0.25 mmol) in acetonitrile (10 mL) and pyridine (20 uL) was added 4-acetamidobenzoyl chloride (49 mg, 0.25 mmol) in acetonitrile (1 mL) at 0° C. for 15 min. The reaction mixture was warmed up to room temperature and stirred for 4 hours, concentrated under reduced pressure. The crude was diluted in DCM and washed with NaHCO3 and brine. The organic layer was dried with Na2SO4 and evaporated. The residue was purified by flash chromatography on silica gel, eluents hexane-EtOAc (1:3), then EtOAc (100%) to afford the title compounds 223 (3 mg, 4% yield) and 224a (5 mg, 5% yield).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:20])=[O:19])[CH:10]=2)O1.[Cl:29][C:30]1[CH:35]=[C:34](Cl)[N:33]=[CH:32][N:31]=1.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O>CN(C=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:29][C:30]1[N:31]=[CH:32][N:33]=[C:34]([C:9]2[C:17]3[C:12](=[N:13][CH:14]=[CH:15][CH:16]=3)[N:11]([S:18]([C:21]3[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=3)(=[O:19])=[O:20])[CH:10]=2)[CH:35]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(B3OC(C)(C)C(C)(C)O3)c3cccnc32)cc1
Reactant: Clc1cc(Cl)ncn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(S(=O)(=O)n2cc(-c3cc(Cl)ncn3)c3cccnc32)cc1
Yield: 33 %

Procedure:
A solution of boronate 4 (0.11 g, 0.276 mmol), 4,6-dichloropyrimidine (0.049 g, 0.331 mmol), catalytic Pd(PPh3)4 and excess potassium carbonate in DMF was heated in the microwave at 160° C. for 5 minutes resulting in conversion to product by TLC (20% EtOAc:hexanes). The reaction was partitioned between EtOAc/H2O, extracted, stripped down in vacuo and purified by silica column (eluent:5% EtOAc:hexanes) giving 8 (0.035 g) as a white solid in 33% yield.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11](=[O:23])[C:12]([CH3:22])([S:14][CH2:15][CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH3:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)C(C)C)(C)C.[C:33](OC(=O)C)(=[O:35])[CH3:34]>>[C:33]([SH:14]([CH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]1)[C:12]([CH3:13])([CH3:22])[C:11]([NH:10][C:7]1[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[O:9][N:8]=1)=[O:23])(=[O:35])[CH3:34]
Reactant: CC(C)(SCC1CCCNC1)C(=O)Nc1cc(C(C)(C)C)on1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)[SH](CC1CCCNC1)C(C)(C)C(=O)Nc1cc(C(C)(C)C)on1

Procedure:
A solution of 175 mg (0.52 mmol) of N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-2-(piperidin-3-ylmethylsulfanyl)-propionamide 0.18 mL (1.04 mmol) of N,N-diisopropylethylamine and acetic anhydride (1.5 mL) were heated for 0.5 h to 100° C. within a microwave (CEM discover). The solvent was removed under reduced pressure. The residue was dissolved in DCM (5 mL) and washed with saturated aqueous NaHCO3 solution (5 mL). The organic phase was dried over Na2SO4, filtered and the filtrate concentrated under reduced pressure to afford 183 mg of 2-(1-acetyl-piperidin-3-ylmethylsulfanyl)-N-(5-tert-butyl-isoxazol-3-yl)-2-methyl-propionamide, which was used in the next step without further purification.
Reaction SMILES: Cl[C:2]1[C:3]2[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:4]=2[N:5]([CH2:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=2)[C:6](=[O:20])[CH:7]([CH2:9][C:10]2[CH:19]=[CH:18][C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH:11]=2)[N:8]=1.[NH2:35][C:36]1[CH:41]=[CH:40][C:39](B2OC(C)(C)C(C)(C)O2)=[CH:38][N:37]=1>>[NH2:35][C:36]1[N:37]=[CH:38][C:39]([C:2]2[C:3]3[CH:33]=[C:32]([Cl:34])[CH:31]=[CH:30][C:4]=3[N:5]([CH2:21][C:22]3[CH:27]=[CH:26][C:25]([O:28][CH3:29])=[CH:24][CH:23]=3)[C:6](=[O:20])[CH:7]([CH2:9][C:10]3[CH:11]=[CH:12][C:17]4[C:18](=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:19]=3)[N:8]=2)=[CH:40][CH:41]=1
Reactant: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(Cl)c3cc(Cl)ccc32)cc1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: COc1ccc(CN2C(=O)C(Cc3ccc4ccccc4c3)N=C(c3ccc(N)nc3)c3cc(Cl)ccc32)cc1

Procedure:
5,7-Dichloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (0.10 g, 0.20 mmol) and 2-aminopyridine-5-boronic acid pinacol ester were reacted according to the corresponding procedure described in Example 12 to yield intermediate 5-(6-aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one. (77 mg, 69%). 5-(6-Aminopyridin-3-yl)-7-chloro-1-(4-methoxybenzyl)-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (77 mg, 0.14 mmol) was dissolved in anhydrous anisole (2 mL) under a nitrogen atmosphere, and aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The mixture was heated to 80° C. for 1 hour then cooled to ambient temperature and an additional amount of aluminum bromide (1M in dichloromethane, 0.70 mL, 0.70 mmol) was added. The solution was heated to 80° C. for 1 hour, cooled, poured into ice, diluted with ethyl acetate and saturated sodium bicarbonate. The layers were separated and the organic layer dried with sodium sulfate, decanted and concentrated in the presence of silica gel. Column chromatography eluting with a gradient of 70-100% ethyl acetate in hexanes provided 5-(6-aminopyridin-3-yl)-7-chloro-3-(naphthalen-2-ylmethyl)-1H-benzo[e][1,4]diazepin-2(3H)-one (25 mg, 42% yield). 1H NMR (300 MHz, d6-DMSO) δ 3.47 (m, 2H) 3.71 (m, 1H), 6.40-6.46 (m, 2H), 7.20-7.26 (m, 2H), 7.42-7.62 (m, 5H), 7.78-7.87 (m, 4H), 10.64 (s, 1H); ESI m/z measured 427.1324 [M+H]+. calculated 427.1326.
Reaction SMILES: CON(C)[C:4]([C@H:6]1[CH2:11][CH2:10][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:8][CH2:7]1)=[O:5].[CH3:24][Mg]Br>C1COCC1>[C:4]([C@H:6]1[CH2:7][CH2:8][C@H:9]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH2:10][CH2:11]1)(=[O:5])[CH3:24]
Reactant: CON(C)C(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Reactant: C[Mg]Br
Solvent: C1CCOC1
Product: CC(=O)[C@H]1CC[C@H](NC(=O)OCc2ccccc2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of benzyl {trans-4-[methoxy(methyl)carbamoyl]cyclohexyl}carbamate (3.43 g, 10.71 mmol) in THF (107 mL) at 0° C. was added methylmagnesium bromide (3.0 M in diethyl ether, 5.35 mL, 16.06 mmol) and the reaction was stirred for one hour at 0° C. An additional portion of methylmagnesium bromide (3.0 M in diethyl ether, 5.35 mL, 16.06 mmol) was then added and the reaction was allowed to warm to room temperature and then stirred for one hour. The reaction was slowly quenched with aqueous saturated ammonium chloride. Water and ethyl acetate were added and the organic layer was separated, dried over magnesium sulfate, filtered and concentrated to afford benzyl (trans-4-acetylcyclohexyl)carbamate that was used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[N:6][CH:7]=1.[NH:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1>N1C=CC=CC=1.C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C1CCNCC1
Reactant: Fc1ccc(Br)cn1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCOC(=O)C1CCN(c2ccc(Br)cn2)CC1
Temperature: 190 °C
Yield: 99 %

Procedure:
5-Bromo-2-fluoropyridine A-5 (0.31 mL, 3.0 mmol) and ethyl piperidine-4-carboxylate (1.39 mL, 9.0 mmol) were dissolved in anhydrous pyridine (2.0 mL) at room temperature under an argon atmosphere, in a 10 mL microwave reactor vial. The reaction mixture was sealed and heated at 190° C. for 60 mins under microwave irradiation, then successively cooled to room temperature, diluted with methylene chloride (60 mL), quenched with a 1 N aqueous solution of hydrogen chloride (40 mL) and decanted. The aqueous layer was extracted with methylene chloride (2×100 mL); the combined extracts were sequentially washed with water (70 mL), brine (70 mL), dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure. The crude residue was purified by flash column chromatography on silica gel (hexanes:ethyl acetate gradient) to give ethyl 1-(5-bromopyridin-2-yl)piperidine-4-carboxylate A-14 (935.0 mg, Yield=99%). MS (ESI), [M+1]+ 313, 315.
Reaction SMILES: [C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:39][CH2:38][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[C:28]([OH:36])[CH:27]=4)[NH:23][C:22]3=[O:37])[CH2:20][CH2:19]2)(=[O:17])=[O:16])=[C:9]([CH3:40])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2].[C:42]([O:46][C:47]([N:49]([CH3:72])[CH2:50][CH2:51][O:52][CH2:53][C:54]([F:71])([F:70])[C:55]([F:69])([F:68])[C:56]([F:67])([F:66])[CH2:57]OS(C(F)(F)F)(=O)=O)=[O:48])([CH3:45])([CH3:44])[CH3:43].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:41])[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][S:15]([N:18]2[CH2:19][CH2:20][C:21]3([N:25]=[C:24]([C:26]4[CH:31]=[C:30]([C:32]([F:34])([F:33])[F:35])[CH:29]=[C:28]([O:36][CH2:57][C:56]([F:66])([F:67])[C:55]([F:68])([F:69])[C:54]([F:70])([F:71])[CH2:53][O:52][CH2:51][CH2:50][N:49]([C:47]([O:46][C:42]([CH3:43])([CH3:44])[CH3:45])=[O:48])[CH3:72])[CH:27]=4)[NH:23][C:22]3=[O:37])[CH2:38][CH2:39]2)(=[O:16])=[O:17])=[C:9]([CH3:40])[CH:8]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(O)cc(C(F)(F)F)c1)NC2=O
Reactant: CN(CCOCC(F)(F)C(F)(F)C(F)(F)COS(=O)(=O)C(F)(F)F)C(=O)OC(C)(C)C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(C(=O)OC(C)(C)C)ccc1CCS(=O)(=O)N1CCC2(CC1)N=C(c1cc(OCC(F)(F)C(F)(F)C(F)(F)COCCN(C)C(=O)OC(C)(C)C)cc(C(F)(F)F)c1)NC2=O
Temperature: 60 °C
Reaction time: 8 h
Yield: 46.3 %

Procedure:
4-{2-[2-(3-Hydroxy-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (77.0 mg, 0.13 mmol) and trifluoro-methanesulfonic acid 5-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-2,2,3,3,4,4-hexafluoro-pentyl ester (58.0 mg, 0.13 mmol) were dissolved in DMF (1 ml). Potassium carbonate (53.8 mg, 0.39 mmol) was added and the mixture was stirred at 60° C. overnight. The reaction mixture was extracted with ethyl acetate, and the organic layer was then washed with saturated brine, dried over MgSO4 and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to give 4-{2-[2-(3-{5-[2-(tert-butoxycarbonyl-methyl-amino)-ethoxy]-2,2,3,3,4,4-hexafluoro-pentyloxy}-5-trifluoromethyl-phenyl)-4-oxo-1,3,8-triaza-spiro[4.5]dec-1-ene-8-sulfonyl]-ethyl}-3-methyl-benzoic acid tert-butyl ester (57 mg, 46%).