Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])[CH:5]=[CH:6][C:7]=1[F:8].[N+:17]([O-])([OH:19])=[O:18]>OS(O)(=O)=O>[Cl:1][C:2]1[C:3]([F:16])=[C:4]([NH:9][C:10](=[O:15])[C:11]([F:12])([F:13])[F:14])[C:5]([N+:17]([O-:19])=[O:18])=[CH:6][C:7]=1[F:8]
Reactant: O=C(Nc1ccc(F)c(Cl)c1F)C(F)(F)F
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: O=C(Nc1c([N+](=O)[O-])cc(F)c(Cl)c1F)C(F)(F)F
Temperature: 0 °C
Reaction time: 4 h
Yield: 95 %

Procedure:
To a solution of 15.1 g (58.1 mmol) of 3-chloro-2,4-difluoro-(trifluoroacetamido)benzene in 80 mL of H2SO4 kept in an ice-bath was added dropwise 10 mL of HNO3. Solid precipitate was observed during addition of HNO3. The mixture was stirred in an ice-bath for 4 h, then added to 600 mL of ice-water. The precipitate was filtered, washed with water, and dried to leave an almost colorless solid (16.8 g, 95%); mp 124°-125° C.; 1H NMR (CDCl3), 7.69 (dd, 1), 8.936 (mb, 1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([NH:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[O:9])([CH3:6])([CH3:5])[CH3:4].[N+:18]([C:21]1[CH:22]=[CH:23][C:24]([N:29]2[CH:33]=[CH:32][CH:31]=[CH:30]2)=[C:25]([CH:28]=1)[CH2:26]Br)([O-:20])=[O:19]>CN(C)C=O>[C:14]([O:13][C:11]([N:10]([C:8]([O:7][C:3]([CH3:6])([CH3:5])[CH3:4])=[O:9])[CH2:26][C:25]1[CH:28]=[C:21]([N+:18]([O-:20])=[O:19])[CH:22]=[CH:23][C:24]=1[N:29]1[CH:33]=[CH:32][CH:31]=[CH:30]1)=[O:12])([CH3:17])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccc(-n2cccc2)c(CBr)c1
Reactant: CC(C)(C)OC(=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N(Cc1cc([N+](=O)[O-])ccc1-n1cccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 74 %

Procedure:
To a mixture of sodium hydride (60% content, 21 mg), iminodicarboxylic acid di-tert-butyl ester (117 mg) and dimethylformamide (5 ml), a solution in dimethylformamide (3 ml) of the compound (137 mg) obtained in Example 1c was added dropwise under cooling with ice. The reaction mixture was stirred for 2 hours at room temperature and then concentrated at reduced pressure. Brine was added to the resulting residue and the mixture was extracted with ethyl acetate. The organic layer was dried with anhydrous sodium sulfate and then concentrated at reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent; ethyl acetate:n-hexane=1:9) to give the titled compound (yield, 74%).
Reaction SMILES: [NH2:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Cl[C:14](Cl)([O:16]C(=O)OC(Cl)(Cl)Cl)Cl.C(OCC)C>O1CCCC1>[CH3:12][O:11][C:10]1[C:2]2[NH:1][C:14](=[O:16])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cccc(C(=O)O)c1N
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Yield: 226.5 %

Procedure:
To 2-amino-3-methoxybenzoic acid (5 g, 30 mmol) in anhydrous tetrahydrofuran (50 mL) was added triphosgene (3.55 g, 12 mmol). This mixture was heated to reflux under a nitrogen atmosphere for 3 hours. It was cooled to ambient temperature, and diethyl ether (50 mL) was added. The mixture was filtered to yield 8-methoxy-1H-benzo[d][1,3]oxazine-2,4-dione (5.25 g, 91%) as a solid.
Reaction SMILES: [C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18](Br)=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2].[C:39]([N:42](CC1C=C(C(F)(F)F)C=C(C(F)(F)F)C=1)[CH:43]1CCCN(C(OC(C)C)=O)C2C=C(Cl)C(N(C)C)=CC1=2)(=O)C>>[C:1]([N:4]([CH2:24][C:25]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[C:27]([C:35]([F:38])([F:37])[F:36])[CH:26]=1)[CH:5]1[CH2:11][CH2:10][CH2:9][N:8]([C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[O:13])[C:7]2[C:18]([N:42]([CH3:43])[CH3:39])=[CH:19][C:20]([CH3:22])=[CH:21][C:6]1=2)(=[O:3])[CH3:2]
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c(Br)cc(C)cc21
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2cc(Cl)c(N(C)C)cc21
Product: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2c1cc(C)cc2N(C)C

Procedure:
This compound prepared utilizing the same methodology described in Example 51 wherein replacement of isopropyl-5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-7-bromo-8-chloro-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate with isopropyl 5-[acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-9-bromo-7-methyl-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylate following the procedure of Example 51 for the synthesis of isopropyl 5-[acetyl-(3,5-bistrifluoromethylbenzyl)amino]-8-chloro-7-dimethylamino-2,3,4,5-tetrahydrobenzo[b]azepine-1-carboxylate. CI MS 574 (M+H).
Reaction SMILES: [SH:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=2)[C:16]#[N:17])=[C:11]2[C:6]([N:7]([CH3:24])[C:8](=[O:23])[N:9]([CH3:22])[C:10]2=[O:21])=[CH:5]1.[Cl:25][C:26]1[O:30][C:29]([CH:31]=O)=[CH:28][CH:27]=1.[O-]S(C(F)(F)F)(=O)=O.[Bi+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O.C(OCC)C>C1(C)C=CC=CC=1.CCOC(C)=O>[Cl:25][C:26]1[O:30][C:29]([CH:31]2[C:5]3=[C:6]4[N:7]([CH3:24])[C:8](=[O:23])[N:9]([CH3:22])[C:10](=[O:21])[C:11]4=[C:12]([C:13]4[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=4)[C:16]#[N:17])[N:4]3[CH2:3][CH2:2][S:1]2)=[CH:28][CH:27]=1
Reactant: O=Cc1ccc(Cl)o1
Reactant: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCS)cc2n(C)c1=O
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Bi+3]
Solvent: CCOCC
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)SCC3
Temperature: 100 °C

Procedure:
A suspension comprising 3-(6-(2-mercaptoethyl)-1,3-dimethyl-2,4-dioxo-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-5-yl)benzonitrile (Intermediate G) (150 mg, 0.441 mmol), 5-chlorofuran-2-carbaldehyde (57.5 mg, 0.441 mmol) and bismuth triflate (28.9 mg, 0.044 mmol) in toluene (5 ml) was heated to 100° C. for 10 min using microwave radiation. After cooling to RT, the reaction mixture was diluted with EtOAc (25 ml) and washed with water. The layers were separated and the aqueous extracted with EtOAc (3×20 ml). The combined organics were dried over MgSO4, filtered and concentrated to yield a brown oil. Purification was carried out by chromatography on silica eluting with 0-45% EtOAc in iso-hexane. The relevant fraction were combined and concentrated in vacuo to yield a pale yellow oil. Diethyl ether (5 ml) was added to the oil to give a white solid. The solid was isolated by suction filtration to afford the title compound.
Reaction SMILES: C(OC([NH:11][CH:12]([C:14]1[NH:18][C:17]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:16]=2[N:15]=1)[CH3:13])=O)C1C=CC=CC=1.[H][H]>CO.C(Cl)Cl.[Pd]>[Cl:23][C:21]1[CH:20]=[CH:19][C:17]2[N:18]=[C:14]([CH:12]([NH2:11])[CH3:13])[NH:15][C:16]=2[CH:22]=1
Reactant: CC(NC(=O)OCc1ccccc1)c1nc2cc(Cl)ccc2[nH]1
Reactant: [H][H]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: CC(N)c1nc2ccc(Cl)cc2[nH]1

Procedure:
5.00 g (contaminated) of rac.-N-benzyloxycarbonyl-1-(5-chloro-1H-benzimidazol-2-yl)ethylamine is dissolved in a mixture of 100 mL of methanol and 40 mL methylene chloride, combined with 1.0 g palladium on charcoal, and hydrogenated for 1 hour at 3.4 bar hydrogen pressure. The solvents are distilled off and the crude product is purified by chromatography with silica gel (eluent: methylene chloride/ethanol=95:5+0.2% ammonia). Yield: 1.08 g (25% over 3 steps); Rf value: 0.37 (silica gel; dichloromethane/ethanol=4:1+2% ammonia); C9H10ClN3 (195.65); mass spectrum: (M+H)+=196/198 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]#[N:33])=[CH:4][N:3]=1.C(=O)([O-])[O-:35].[K+].[K+].OO>CS(C)=O>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]([NH2:33])=[O:35])=[CH:4][N:3]=1
Reactant: O=C([O-])[O-]
Reactant: COc1cc(-c2csc3c(C#N)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: OO
Agent: [K+]
Solvent: CS(C)=O
Product: COc1cc(-c2csc3c(C(N)=O)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Yield: 3.9 %

Procedure:
N2-[4-(4-amino-7-cyanothieno[3,2-c]pyridin-3-yl)-2-methoxyphenyl]-1-methyl-1H-2-indolecarboxamide (A-825289.0, 50 mg, 0.11 mmol), potassium carbonate (61 mg, 0.44 mmol), and hydrogen peroxide (0.150 mL, 30% aqueous) were heated in dimethylsulfoxide (1 mL) for 25 minutes at 150° C. in a microwave. The mixture was evaporated, diluted in dimethylformamide, filtered, and the filtrate was purified by RP-HPLC to yield the title compound (2 mg, 4% yield): 1H NMR (DMSO-d6, 400 MHz) δ 9.50 (s, 1H), 8.57 (s, 1H), 8.00 (d, 1H), 7.71 (d, 1H), 7.58-7.62 (m, H), 7.06-7.35 (m, 5H), 4.04 (s, 3H), 3.91 (s, 3H); RP-HPLC (Conditions i) Rt 11.7 min. MS: 470.0 MH−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[C:15](C)[CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1.COC(OC)(C)CC=O.Cl.CCCCCC.C(OCC)(=O)C>C(O)C.C(OCC)(=O)C>[Br:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[N:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH3:20])[N:18]=2)[C:13]([C:22]#[N:23])=[CH:12]1
Reactant: Cc1cc(C)c2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Agent: COC(C)(CC=O)OC
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: Cc1ccc2c(C#N)cn(-c3ccc(C(C)C)cc3Br)c2n1
Yield: 9.8 %

Procedure:
To a solution of 1.085 g (5.07 mmole) of the product from Example 64 (part B) and 0.80 mL (0.797 g; 6.03 mmole) of acetoacetaldehyde dimethyl acetal in 20 mL of ethanol was added 0.10 mL of conc. hydrochloric acid. The mixture was refluxed for 16 hours, then cooled and evaporated to give a dark, thick oil. TLC on silica gel with 70:30 hexane-ethyl acetate showed two major spots at Rf 0.47 and 0.41. The oil was dissolved in ethyl acetate, 20 mL silica gel powder was added, and the mixture was evaporated to dryness. The powdery residue was loaded on top of a column of 60 mL of silica gel in hexane. The column was eluted in step gradients of 0, 5, 10, 15, 20, and 25% ethyl acetate in hexane. The first fraction to elute was 0.32 g of the desired 1-(2-bromo-4-isopropyl-phenyl)-3-cyano-6-methyl-7-azaindole, Rf 0.47. The material can be crystallized from hexane to give 176 mg of crystals; mp 176.0° C. Mass spec. (m+H)+=354.0595; calcd., 354.0606.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.C(N(CC)CC)C.ClC(Cl)(O[C:34](=[O:40])OC(Cl)(Cl)Cl)Cl.Cl.[Br:43][C:44]1[CH:45]=[C:46]([C@@H:50]([NH2:52])[CH3:51])[CH:47]=[CH:48][CH:49]=1>C(Cl)(Cl)Cl>[Br:43][C:44]1[CH:45]=[C:46]([C@@H:50]([NH:52][C:34]([NH:20][C:19]2[CH:21]=[CH:22][C:16]([O:15][C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][CH:7]=3)=[CH:17][CH:18]=2)=[O:40])[CH3:51])[CH:47]=[CH:48][CH:49]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: C[C@H](N)c1cccc(Br)c1
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc2nccc(Oc3ccc(NC(=O)N[C@@H](C)c4cccc(Br)c4)cc3)c2cc1OC
Temperature: 25 °C
Reaction time: 1.25 h
Yield: 130.8 %

Procedure:
4-[(6,7-Dimethoxy-4-quinolyl)oxy]aniline (70 mg) was dissolved in chloroform (1 ml) and triethylamine (0.14 ml) to prepare a solution. A solution of triphosgene (33 mg) in chloroform (0.2 ml) was then added to the solution, and the mixture was stirred at room temperature for 75 min. Next, a solution of (1S)-1-(3-bromophenyl)ethylamine hydrochloride (54 mg) in chloroform (0.2 ml) was added thereto, and the mixture was stirred at room temperature for 10 hr. The stirred mixture was purified by chromatography on silica gel using chloroform/methanol for development to give the title compound (76 mg, yield 62%).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([N:14]3[C:18]([CH3:19])=[N:17][N:16]=[N:15]3)[CH:11]=[C:10]([C:20]([OH:22])=O)[CH:9]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.[CH3:33][O:34][CH2:35][CH:36]([NH2:38])[CH3:37].CN1C(=O)CCC1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C=O)C>[CH3:33][O:34][CH2:35][CH:36]([NH:38][C:20]([C:10]1[CH:9]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([CH3:1])=[CH:3][CH:4]=2)[CH:13]=[C:12]([N:14]2[C:18]([CH3:19])=[N:17][N:16]=[N:15]2)[CH:11]=1)=[O:22])[CH3:37]
Reactant: Cc1ccc(-c2cc(C(=O)O)cc(-n3nnnc3C)c2)cc1
Reactant: COCC(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CN1CCCC1=O
Product: COCC(C)NC(=O)c1cc(-c2ccc(C)cc2)cc(-n2nnnc2C)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 90 %

Procedure:
To a stirred solution of 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (0.3402 mmol, 100 mg), HOBt (0.6804 mmol, 91.9 mg), 2-methoxy-1-methyl-ethylamine (0.4083 mmol, 43 μL) and NMP (1.0206 mmol, 112 μL) in CH2Cl2(1 mL) and DMF (0.5 mL) was added EDCI (0.6804 mmol, 130.4 mg) at room temperature, and the mixture was stirred at room temperature for 18 hours. The mixture was extracted with ethyl acetate and the organic layer was washed with 2N aqueous NaOH, 1 N aqueous HCl, brine, dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was purified by Flash column chromatography, eluting with n-hexane:ethyl acetate (4:1) to give 4′-methyl-5-(5-methyl-tetrazol-1-yl)-biphenyl-3-carboxylic acid (2-methoxy-1-methyl-ethyl)-amide (white powder, 90% yield). MS (M+H)=366.
Reaction SMILES: BrC1C(C)=CC(C)=CC=1C.[Li]C(C)(C)C.[CH3:16][O:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=1.CON(C)[C:27]([CH:29]1[CH2:33][CH:32]=[CH:31][CH2:30]1)=[O:28]>C1COCC1.CCCCC>[CH2:32]1[CH2:31][CH:30]=[C:29]([C:27]([C:23]2[C:18]([O:17][CH3:16])=[N:19][CH:20]=[CH:21][CH:22]=2)=[O:28])[CH2:33]1
Reactant: COc1ccccn1
Reactant: CON(C)C(=O)C1CC=CC1
Agent: Cc1cc(C)c(Br)c(C)c1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCCCC
Product: COc1ncccc1C(=O)C1=CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Bromo-2,4,6-trimethylbenzene (16.9 g, 85 mmol) was stirred in anhydrous THF (340 mL) at −78° C. under nitrogen and treated with t-BuLi (100 mL of 1.7 M soln. in pentane, 170 mmol) dropwise via an addition funnel over 30 min. A yellow slurry forms and is stirred 1 h. To this was added 2-methoxypyridine (8.45 g, 77.3 mmol) in anhydrous THF (10 mL) over 5 min. The mixture was allowed to warm to 0° C. and stirred for 1 h, then at ambient temperature for 1 h, then recooled to −78° C. and treated with cyclopent-3-enecarboxylic acid methoxy-methyl-amide (12.4 g, 80 mmol) in anhydrous THF (20 mL) over 5 min. The resulting mixture was stirred 18 h (the bath evaporated and the mixture achieved ambient temperatures). The mixture was poured into saturated aqueous NaHCO3 solution (250 mL) and stirred 20 min. The mixture was extracted with Et2O (3×100 mL). The organic layer was washed with H2O (2×100 mL) and saturated aqueous NaCl solution then dried over Na2SO4, filtered and concentrated to an oil (26 g). Purification by chromatography on silica gel eluting first with hexane to remove mesitylene followed by 10% then 20% Et2O/hexanes elutes product, which was concentrated to a clear oil (12.2 g, 75% crude). (TLC 10% Et2O/hexanes Rf 0.36); 1H NMR (400 MHz, CDCl3) δ 8.28 (dd, J=4.9, 2.0 Hz, 1H), 8.02 (m, 1H), 6.97 (m, 1H), 5.65 (s, 2H), 4.03 (s, 3H), 4.17, (m, 1H), 2.67 (m, 4H); GCMS m/z 203 (M)+.
Reaction SMILES: [Br:1][C:2]1[N:7]=[C:6]([C@:8]2([CH3:20])[CH2:13][O:12][C@@:11]([CH3:18])([C:14]([F:17])([F:16])[F:15])[C:10]([NH2:19])=[N:9]2)[C:5]([F:21])=[CH:4][CH:3]=1.[C:22](Cl)([C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)([C:31]1[CH:38]=[CH:37][C:34]([O:35][CH3:36])=[CH:33][CH:32]=1)[C:23]1[CH:30]=[CH:29][C:26]([O:27][CH3:28])=[CH:25][CH:24]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:22]([NH:19][C:10]2[C@:11]([CH3:18])([C:14]([F:15])([F:17])[F:16])[O:12][CH2:13][C@:8]([C:6]3[C:5]([F:21])=[CH:4][CH:3]=[C:2]([Br:1])[N:7]=3)([CH3:20])[N:9]=2)([C:23]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[CH:29][CH:30]=2)[C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:38][CH:37]=1
Reactant: C[C@@]1(c2nc(Br)ccc2F)CO[C@@](C)(C(F)(F)F)C(N)=N1
Reactant: COc1ccc(C(Cl)(c2ccccc2)c2ccc(OC)cc2)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(NC2=N[C@](C)(c3nc(Br)ccc3F)CO[C@@]2(C)C(F)(F)F)(c2ccccc2)c2ccc(OC)cc2)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of (2R,5R)-5-(6-bromo-3-fluoro-pyridin-2-yl)-2,5-dimethyl-2-trifluoromethyl-5,6-dihydro-2H-[1,4]oxazin-3-ylamine (500 mg, 1.35 mmol, CAS registry 1387561-18-3, WO 2012/095469) in DCM (13.5 ml) was added DMTr-Cl (0.481 g, 1.418 mmol) and triethylamine (0.374 ml, 2.70 mmol), the reaction mixture was stirred under argon at rt for 18 h. The reaction mixture was washed with NaHCO3 saturated aqueous solution and brine. The organic layers were backextracted with DCM. The combined organic layer were dried with Na2SO4. The residue was purified by chromatography (eluent: CyHex/EtOAc gradient) to afford the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H: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])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][C@H:38]2[CH2:43][CH2:42][C@H](N)[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1.[S:46]([NH2:50])([NH2:49])(=[O:48])=[O:47]>C1COCC1>[Cl:8][C:9]1[C:10]([F:45])=[C:11]([C@@H: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])[C@H:18]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[NH:17][C@H:16]2[C:35]([NH:37][CH:38]2[CH2:43][CH2:42][N:49]([S:46]([NH2:50])(=[O:48])=[O:47])[CH2:40][CH2:39]2)=[O:36])[CH:12]=[CH:13][CH:14]=1
Reactant: NS(N)(=O)=O
Reactant: CC(C)(C)C[C@@H]1N[C@@H](C(=O)N[C@H]2CC[C@H](N)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)C[C@@H]1N[C@@H](C(=O)NC2CCN(S(N)(=O)=O)CC2)[C@H](c2cccc(Cl)c2F)[C@@]1(C#N)c1ccc(Cl)cc1F
Temperature: 110 °C
Reaction time: 0.42 h

Procedure:
To a stirred solution of rac-4-{[(2R,3S,4R,5S)-3-(3-Chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carbonyl]-amino}-trans-cyclohexylamine trifluoroacetic acid salt (50 mg, 0.091 mmol) in THF (3 mL), sulfamide (Aldrich, 40 mg, 0.416 mmol) was added and the mixture was stirred at 110° C. for 25 min. on microwave oven. The reaction was quenched with addition of water. The mixture was extracted with EtOAc (2×10 mL) and the extracts were dried with magnesium sulfate. The solvent was removed and the residue was purified on a reverse phase HPLC (25-90, acetonitrile/water) to give a white solid. 49 mg.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.Cl.[C:13]1([C:19]2([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:27]3[CH:23]([CH2:24][NH:25][CH2:26]3)[C:22](=[O:28])[CH2:21][CH2:20]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([N:25]1[CH2:24][CH:23]2[CH:27]([C:19]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH2:20][CH2:21][C:22]2=[O:28])[CH2:26]1)=[O:11]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: O=C1CCC(c2ccccc2)(c2ccccc2)C2CNCC12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1CCC(c2ccccc2)(c2ccccc2)C2CN(C(=O)Cc3ccccc3Br)CC12
Reaction time: 0.75 h
Yield: 59.9 %

Procedure:
N,N'-Carbonyldimidazole (1.13 g) is added to a solution of 2-(2-bromophenyl)acetic acid (1.5 g) in dry dichloromethane (30 cc), cooled to +5° C. The mixture is stirred for 45 minutes at +5° C. and a solution of (3aRS,7aRS)-7,7-diphenyl-4-perhydroiso-indolone hydrochloride (2.3 g) and triethylamine (0.98 cc) in dichloromethane (40 cc) is then added. The reaction mixture is stirred for 4 hours at 20° C. The reaction mixture is washed with distilled water (3×50 cc), dried over magnesium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (2.7 kPa). The residue is recrystallized from acetonitrile (74 cc). The crystals are drained, washed with isopropyl ether (10 cc) and dried. (3aRS,7aRS)-2-[(2-bromophenyl)acetyl]-7,7-diphenyl-4-perhydroisoindolone (2.04 g) melting at 217° C. is obtained.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5](C[Br:7])=[CH:4][CH:3]=1.[C:10]1([P:16]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(#N)C>[Br-:7].[F:1][C:2]1[CH:3]=[CH:4][C:5]([P+:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:8][CH:9]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Product: Fc1ccc([P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: [Br-]

Procedure:
98.6 g (0.52 mol) of 4-fluorobenzyl bromide (XIV, R1 =4-fluorophenyl, X=Br) and 136.7 g (0.52 mol) of triphenylphosphine in 400 ml of acetonitrile are boiled under reflux for 6 hours. After cooling, the mixture is concentrated to one half the volume in vacuo, cooled in an ice bath, and the crystals which have separated out are filtered off with suction and washed with cold acetonitrile and diethyl ether. The crystals are thoroughly dried in vacuo at 100° C.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]1([C:11]2([C:18]3[CH:27]=[C:26]([O:28][CH2:29][C:30]4[CH:39]=[CH:38][C:37]5[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=5)[N:31]=4)[CH:25]=[CH:24][C:19]=3[C:20]([NH:22][NH2:23])=O)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(N(CC)CC)C.C(=O)(O)[O-].[Na+]>>[CH3:2][C:1]1[O:3][C:20]([C:19]2[CH:24]=[CH:25][C:26]([O:28][CH2:29][C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[N:31]=3)=[CH:27][C:18]=2[C:11]2([C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH2:16][CH:15]3[CH2:17][CH:12]2[CH2:13][CH2:14]3)=[N:22][N:23]=1
Reactant: CC(=O)Cl
Reactant: NNC(=O)c1ccc(OCc2ccc3ccccc3n2)cc1C1(c2ccccc2)CC2CCC1C2
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Product: Cc1nnc(-c2ccc(OCc3ccc4ccccc4n3)cc2C2(c3ccccc3)CC3CCC2C3)o1
Reaction time: 18 h

Procedure:
Acetyl chloride (10.0 μL, 0.14 mmol) was added to a stirred solution of 4d (50.0 mg, 0.11 mmol) and triethylamine (38.0 μL, 0.27 mmol) in THB (900 μL) at room temperature. After approximately 18 h, the reaction mixture was poured into saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude intermediary acylhydrazide was treated with thionyl chloride (˜1 mL, excess), and the resulting mixture was aged for approximately 18 h. The reaction mixture was poured carefully into cold saturated aqueous sodium bicarbonate and extracted three times with methylene chloride. The combined organic extracts were washed with brine, dried (Na2SO4) and concentrated in vacuo. The crude residue was purified by preparative reversed phase HPLC on YMC Pack Pro C18 stationary phase (gradient elution; 20-100% acetonitrile/water as eluent, 0.1% TFA as modifier). Lyophilization of the purified fractions afforded the title compound 5d, m/z (ES) 488 (MH)+.