Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32](Br)[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2].[C:43]1(B(O)O)[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1.C(=O)(O)[O-].[Na+]>O1CCOCC1>[C:1]([N:4]1[C@@H:10]([CH3:11])[C@H:9]([NH:12][C:13](=[O:25])[C@@H:14]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH3:15])[C:8](=[O:26])[N:7]([CH2:27][C:28]2[CH:33]=[C:32]([C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH:31]=[CH:30][C:29]=2[O:35][CH3:36])[C:6]2[CH:37]=[CH:38][C:39]([C:41]#[N:42])=[CH:40][C:5]1=2)(=[O:3])[CH3:2]
Reactant: OB(O)c1ccccc1
Reactant: COc1ccc(Br)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(C)=O)c2cc(C#N)ccc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 75.2 %

Procedure:
A rt suspension of tert-butyl(S)-1-((3S,4S)-5-acetyl-1-(5-bromo-2-methoxybenzyl)-7-cyano-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (24 mg, 37.4 μmol), phenylboronic acid (6.83 mg, 56.0 μmol), and sodium bicarbonate (7.84 mg, 93.4 μmol) in 1,4-dioxane (280 μl) was sparged with Ar for 5 min, then [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (3.05 mg, 3.74 μmol) was added. The reaction was sparged with Ar for an additional minute, then sealed and stirred at 80° C. for 2 h, then cooled to rt, diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography to provide tert-butyl(S)-1-((3S,4S)-5-acetyl-7-cyano-1-((4-methoxybiphenyl-3-yl)methyl)-4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (18 mg, 75%) as a white solid. MS m/z 662 (MNa)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:9]=[N:10][NH:11][N:12]=2)[CH:5]=[CH:6][CH:7]=1.[C:13](C1C=CC=C(C#N)C=1)#[N:14]>>[N:12]1[NH:11][N:10]=[N:9][C:8]=1[C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:13]#[N:14]
Reactant: Brc1cccc(-c2nn[nH]n2)c1
Reactant: N#Cc1cccc(C#N)c1
Product: N#Cc1cccc(-c2nn[nH]n2)c1

Procedure:
Following the procedure in COMPOUND 3 for the synthesis of 5-(3-bromophenyl)-2H-tetrazole, 1,3-dicyanobenzene (2.0 g, 15.63 mmol) was employed to obtain 3-(2H-tetrazol-5-yl)benzonitrile.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][S:5]([C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([Br:17])[CH:15]=2)[NH:10][C:9]=1[C:18]([NH2:20])=[O:19])(=[O:7])=[O:6].C(N(CC)CC)C.[CH2:28]([S:30](Cl)(=[O:32])=[O:31])[CH3:29]>CCOC(C)=O>[Br:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:18]([NH2:20])=[O:19])=[C:8]2[S:5]([NH:4][CH2:3][CH2:2][NH:1][S:30]([CH2:28][CH3:29])(=[O:32])=[O:31])(=[O:6])=[O:7]
Reactant: CCS(=O)(=O)Cl
Reactant: NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCS(=O)(=O)NCCNS(=O)(=O)c1c(C(N)=O)[nH]c2ccc(Br)cc12
Temperature: 65 °C
Reaction time: 60 h

Procedure:
A solution of the product from Example 63 (15 mg, 0.038 mmol), triethylamine (0.017 mL, 0.11 mmol) and ethanesulfonyl chloride (0.004 mL, 0.04 mmols) were combined in a sealed tube and heated to 65° C. overnight. The solvent was removed under a stream of N2 and replaced with DMF. After adding an additional 3 equivalents of ethanesulfonyl chloride and triethylamine, the reaction was heated to 65° C. for 8 hours and stirred at room temperature for 60 hours. The mixture was diluted with EtOAc and washed with 10% Na2CO3 and brine, dried over Na2SO4, filtered and concentrated in vac o. Purification by reversed-phase preparative HPLC gave the titled compound. ESI+ MS: 453 [M+H]+.
Reaction SMILES: [CH3:1][S-:2].[Na+].FC(F)(F)CO[C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1>CS(C)=O.Cl>[CH3:1][S:2][C:8]1[CH:13]=[CH:12][N:11]2[N:14]=[C:15]([S:17]([NH:20][C:21]3[C:26]([Cl:27])=[CH:25][CH:24]=[CH:23][C:22]=3[Cl:28])(=[O:19])=[O:18])[N:16]=[C:10]2[N:9]=1
Reactant: O=S(=O)(Nc1c(Cl)cccc1Cl)c1nc2nc(OCC(F)(F)F)ccn2n1
Reactant: C[S-]
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Product: CSc1ccn2nc(S(=O)(=O)Nc3c(Cl)cccc3Cl)nc2n1
Temperature: 25 °C
Reaction time: 25 h
Yield: 66 %

Procedure:
To 25 ml (13 mmol) of a 0.52M solution of sodium methyl mercaptide in DMSO prepared by bubbling methyl mercaptan into a suspension of sodium hydride in DMSO, was added 2.6 g (5.9 mmol) of 5-(2,2,2-trifluoroethoxy)N-(2,6-dichlorophenyl)-1,2,4-triazolo[1,5-a]pyrimidine-2-sulfonamide. The solution was stirred at room temperature for 25 hours, diluted with 100 ml of ice water and neutralized with 3N aqueous HCl. The gummy solid which separated was collected and taken up in 0.5N aqueous NaOH. The mixture was filtered to remove insoluble material, and the filtrate was acidified with 6N aqueous HCl. The solid which separated was collected by filtration and dried to yield 1.5 g (66%) of the desired product as a pale yellow solid, mp 239°-243° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [SH:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1.IC.[C:18](=O)([O-])[O-].[K+].[K+]>O>[CH3:18][S:1][C:2]1[NH:6][C:5]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:4]=2[N:3]=1
Reactant: CCOC(=O)c1cccc2[nH]c(S)nc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Product: CCOC(=O)c1cccc2[nH]c(SC)nc12
Reaction time: 20 h
Yield: 58.3 %

Procedure:
To a solution of ethyl 2-mercapto-1H-benzimidazole-4-carboxylate (500 mg) were added iodomethane (351 mg) and potassium carbonate (622 mg) at ambient temperature and the mixture was stirred for 20 hours at same temperature. The reaction mixture was poured into water and extracted with chloroform. The organic layer was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was washed with diisopropyl ether to give ethyl 2-methylthio-1H-benzimidazole-4-carboxylate (310 mg).
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)=[CH2:2].[CH2:12](O)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C1(C)C=CC(S(O)(=O)=O)=CC=1.C1(C)C=CC=CC=1>O>[CH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([O:9][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])=[O:8])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: C=Cc1ccc(C(=O)O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: O
Product: C=Cc1ccc(C(=O)OCCCCCCCCCCCCCCCCCC)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 51 %

Procedure:
A stirred mixture of 2.91 g (20 mmol) of 4-vinylbenzoic acid, 5.84 g (22 mmol) of 1-octadecanol, 0.17 g (1 mmol) of 4-toluenesulfonic acid, and 75 ml of toluene was heated at reflux with water separated azeotropically using a Dean-Stark trap. After 16 hours, the mixture was cooled to ambient temperature and filtered through a short column of basic alumina, eluting with tetrahydrofuran. The filtrate was concentrated to deposit a solid product, which was purified by chromatography on silica gel (a heptane/dichloromethane eluate), followed by recrystallization from acetonitrile. A white solid was obtained, mass 3.98 g (51% yield).
Reaction SMILES: Cl[C:2]1[C:3]([F:11])=[N:4][C:5]([F:10])=[C:6]([F:9])[C:7]=1[NH2:8].CCN(CC)CC.[H][H]>CO.[Pd]>[F:10][C:5]1[C:6]([F:9])=[C:7]([NH2:8])[CH:2]=[C:3]([F:11])[N:4]=1
Reactant: [H][H]
Reactant: Nc1c(F)c(F)nc(F)c1Cl
Agent: [Pd]
Solvent: CO
Solvent: CCN(CC)CC
Product: Nc1cc(F)nc(F)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 89.8 %

Procedure:
A mixture of 3-chloro-2,5,6-trifluoro-pyridin-4-ylamine (1.82 g, 10 mmol), 5% Pd/C (0.5 g), and Et3N (3.04 g, 30 mmol) in 50 mL of MeOH was equipped with a balloon of hydrogen gas and stirred at room temperature overnight. The solution was filtered through diatomaceous earth (Celite®). The filtrate was concentrated under vacuum and the residue was partitioned between ethyl acetate and H2O. The aqueous layer was extracted with additional ethyl acetate, and the combined organic layers were washed with brine, dried (MgSO4), filtered and concentrated under vacuum. The residue was purified by flash column chromatography on silica gel with 7:3 hexanes/ethyl acetate to provide 1.33 g (90%) of the desired product. MS (DCI) m/e 149 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:25]=[CH:24][C:6]([C:7]([NH:9][C:10](=S)[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[O:8])=[CH:5][CH:4]=1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([NH2:35])[N:30]=1>CN(C=O)C.C(OCC)(=O)C>[NH2:28][C:29]1[N:30]=[C:31]([NH:35]/[C:10](/[NH:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])=[N:9]\[C:7](=[O:8])[C:6]2[CH:24]=[CH:25][C:3]([C:2]([F:27])([F:26])[F:1])=[CH:4][CH:5]=2)[CH:32]=[CH:33][CH:34]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(NC(=S)NCc1ccccc1C(F)(F)F)c1ccc(C(F)(F)F)cc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Nc1cccc(N/C(=N\C(=O)c2ccc(C(F)(F)F)cc2)NCc2ccccc2C(F)(F)F)n1
Temperature: 25 °C
Yield: 55.3 %

Procedure:
A solution of 4-(trifluoromethyl)-N-((2-(trifluoromethyl)benzyl)carbamothioyl) benzamide (2.0 g, 4.92 mmol), 2,6-diaminopyridine (591 mg, 5.41 mmol), and 1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (EDC hydrochloride) (1.13 g, 5.91 mmol) in DMF (49 mL) was heated to 65° C. for 30 minutes, then allowed to cool to room temperature. The mixture was then diluted with ethyl acetate, washed with aqueous sodium bicarbonate solution, washed with brine, dried over sodium sulfate, and concentrated to provide the crude product. The crude product was purified by chromatography (gradient: 9:1 hexanes:EtOAc to 6:4 hexanes:EtOAc) to provide (Z)-N-(((6-aminopyridin-2-yl)amino)((2-(trifluoromethyl) benzyl)amino)methylene)-4-(trifluoromethyl)benzamide as a yellow solid (1.31 g, 55% yield).
Reaction SMILES: [Br:1]Br.[Cl:3][C:4]1[CH:5]=[C:6]([C:11]2([C:15](=[O:17])[CH3:16])[CH2:14][CH2:13][CH2:12]2)[CH:7]=[CH:8][C:9]=1[Cl:10]>C(Cl)(Cl)Cl.CO>[Br:1][CH2:16][C:15]([C:11]1([C:6]2[CH:7]=[CH:8][C:9]([Cl:10])=[C:4]([Cl:3])[CH:5]=2)[CH2:14][CH2:13][CH2:12]1)=[O:17]
Reactant: CC(=O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=C(CBr)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of bromine (96 ml) in chloroform (427 ml) was added dropwise at 10°-15° C. over 1.5 hours to a stirred solution of 1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone (477.2 g; prepared in a similar manner to that described above) in a mixture of methanol (643 ml) and chloroform (107 ml). After the addition was complete, the mixture was stirred at ambient temperature for 3 hours, then poured into ice-water (21). The aqueous layer was separated and washed with dichloromethane (3×500 ml), then the combined organic solutions were washed with saturated aqueous sodium hydrogencarbonate solution (2×400 ml) and water (500 ml), dried over calcium chloride, and the, solvents were removed in vacuo to leave 2-bromo-1-[1-(3,4-dichlorophenyl)cyclobutyl]ethanone as an orange oil (593.5 g) which was used without purification.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14](Br)[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3].[NH3:23]>CN(C)C=O.[Cu-]=O>[CH3:1][CH:2]([O:4][C:5](=[O:22])[NH:6][C@H:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([NH2:23])[CH:15]=2)[N:10]([C:18](=[O:20])[CH3:19])[C@@H:9]([CH3:21])[CH2:8]1)[CH3:3]
Reactant: N
Reactant: CC(=O)N1c2ccc(Br)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Agent: O=[Cu-]
Solvent: CN(C)C=O
Product: CC(=O)N1c2ccc(N)cc2[C@H](NC(=O)OC(C)C)C[C@@H]1C
Temperature: 110 °C
Reaction time: 5 h
Yield: 85 %

Procedure:
A mixture of 1-methylethyl[(2S,4R)-1-acetyl-6-bromo-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (for a preparation see example 4) (2.71 g, 7.34 mmol) and copper(I) oxide (0.247 g, 1.726 mmol) in N,N-dimethylformamide (DMF) (5 mL) was treated with NH3 (35% w/w in water) (5 mL, 258 mmol) and the resulting mixture was stirred at 110° C. for 5 h under microwave irradiation then cooled to room temperature and concentrated in vacuo. The residue was partitioned between water and AcOEt and the layers were separated. The aqueous phase was extracted with AcOEt (2×50 mL) and the combined organic phases were dried over MgSO4 then concentrated in vacuo. Purification of the residue by flash chromatography on silica gel (gradient: 10 to 100% AcOEt in Hexanes) gave 1-methylethyl[(2S,4R)-1-acetyl-6-amino-2-methyl-1,2,3,4-tetrahydro-4-quinolinyl]carbamate (1.91 g, 6.25 mmol, 85%) as an orange foamy solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28](O)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][C:37]=1[N:38]1[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]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>CN(C=O)C>[CH2:1]([O:8][C:9]([NH:11][C:12]1[C:13]([C:28]([NH:31][C:32]2[CH:33]=[N:34][CH:35]=[CH:36][C:37]=2[N:38]2[CH2:43][C@H:42]([CH3:44])[C@H:41]([NH:45][C:46](=[O:49])[O:47][CH3:48])[C@H:40]([NH:50][C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:39]2)=[O:29])=[N:14][C:15]2[C:20]([CH:21]=1)=[CH:19][CH:18]=[C:17]([N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[CH:16]=2)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2N)C[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Nc1cc2ccc(N3CCOCC3)cc2nc1C(=O)O)OCc1ccccc1
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: CN(C)C=O
Product: COC(=O)N[C@H]1[C@@H](C)CN(c2ccncc2NC(=O)c2nc3cc(N4CCOCC4)ccc3cc2NC(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 52 %

Procedure:
To a mixture of 3-{[(benzyloxy)carbonyl]amino}-7-morpholin-4-ylquinoline-2-carboxylic acid (31 mg, 0.075 mmol), tert-butyl methyl [(3R,4S,5S)-1-(3-aminopyridin-4-yl)-5-methylpiperidine-3,4-diyl]biscarbamate (30 mg, 0.079 mmol) and HATU (92 mg, 0.24 mmol) in DMF (1.0 mL), DIPEA (90 μL, 0.52 mmol) was added. The reaction mixture was stirred at room temperature overnight. The mixture was then purified by preparative LCMS (pH=10 method; XBridge™ preparative C18 5 μm OBD™ column, 30×10 mm, 60 mL/min., eluting with a gradient of MeCN and water with 0.1% NH4OH) to give the sub-title compound as a yellow solid (30 mg, 51%). LCMS calc. for C40H49N8O8 (M+H)+: m/z=769.4. Found: 769.4.
Reaction SMILES: [CH3:1][N:2]([CH3:6])[CH2:3][CH2:4]O.[CH3:7][N:8]([CH3:12])[C:9]([NH2:11])=[S:10]>Br>[CH3:7][N:8]([CH3:12])[C:9](=[NH:11])[S:10][CH2:4][CH2:3][N:2]([CH3:6])[CH3:1]
Reactant: CN(C)C(N)=S
Reactant: CN(C)CCO
Agent: Br
Product: CN(C)CCSC(=N)N(C)C
Yield: 128 %

Procedure:
A mixture of 2-dimethylaminoethanol (2.23 g), N,N1 -dimethylthiourea (2.6 g) and aqueous hydrobromic acid (48%, 20 ml) was boiled under reflux for 50 hours and evaporated to dryness. The residue was recrystallised from a mixture of methanol and ethanol to give the dihydrobromide of the title compound (5.6 g) m.p. 198°-199°.
Reaction SMILES: [CH:1]1([C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+].S(Cl)([Cl:21])(=O)=O>>[Cl:21][C:1]1([C:8]([C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=S(=O)(Cl)Cl
Reactant: O=C(c1ccccc1)C1CCCCCC1
Agent: [Na+]
Agent: [OH-]
Product: O=C(c1ccccc1)C1(Cl)CCCCCC1
Temperature: 0 °C

Procedure:
Sulfuryl chloride (210 mL) was added dropwise to neat cycloheptyl-phenyl-methanone (Example 14a) (86.5 g) at 0° C. over approximately 1 hour. Gas evolution and an exotherm were observed. The internal temperature was kept below 15° C. during the addition and the evolved gas was scrubbed by passing through a 10.2M aqueous solution of NaOH. The reaction mixture was heated to reflux overnight. The reaction mixture was cooled to 0° C and poured slowly onto ice (1 L) with stirring. The layers were separated and the aqueous layer was extracted with ether (2×400 mL). The combined organic layers were washed with water (600 mL), saturated aqueous sodium hydrogen carbonate (600 mL), and brine (600 mL), dried over magnesium sulphate, filtered and evaporate to give the sub-titled compound as a brown oil (100 g).
Reaction SMILES: [F:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[Cl:9][C:10]1[N:19]=[C:18](Cl)[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1.CN(C)C=O.C(=O)([O-])[O-].[K+].[K+]>O>[Cl:9][C:10]1[N:19]=[C:18]([NH:4][C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[F:1])[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[N:11]=1
Reactant: Nc1ccccc1F
Reactant: Clc1nc(Cl)c2ccccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccccc1Nc1nc(Cl)nc2ccccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 40 %

Procedure:
To a mixture of 2-fluoroaniline (232 mg), 2,4-dichloroquinazoline (400 mg) and N,N-dimethylformamide (4 mL), potassium carbonate (430 mg) was added and stirred at room temperature for 8 hours. The reaction mixture was diluted with water (40 mL), and the precipitated solid was collected by filtration and purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1-3:1) to give 2-chloro-N-(2-fluorophenyl)quinazoline-4-amine (0.22 g) as a light-yellow solid.
Reaction SMILES: [C:1]([C:9]1[CH:41]=[CH:40][C:12]2[N:13]([CH2:17][CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][CH:27]([NH:32][C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:28]([O:30][CH3:31])=[O:29])=[CH:22][CH:21]=3)[C:14](=[O:16])[S:15][C:11]=2[CH:10]=1)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:42][O:43][NH2:44]>>[C:36]([O:35][C:33]([NH:32][CH:27]([CH2:26][C:23]1[CH:22]=[CH:21][C:20]([O:19][CH2:18][CH2:17][N:13]2[C:12]3[CH:40]=[CH:41][C:9]([C:1](=[N:44][O:43][CH3:42])[C:2]4[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=4)=[CH:10][C:11]=3[S:15][C:14]2=[O:16])=[CH:25][CH:24]=1)[C:28]([O:30][CH3:31])=[O:29])=[O:34])([CH3:37])([CH3:38])[CH3:39]
Reactant: COC(=O)C(Cc1ccc(OCCn2c(=O)sc3cc(C(=O)c4ccccc4)ccc32)cc1)NC(=O)OC(C)(C)C
Reactant: CON
Product: CON=C(c1ccccc1)c1ccc2c(c1)sc(=O)n2CCOc1ccc(CC(NC(=O)OC(C)(C)C)C(=O)OC)cc1

Procedure:
Starting from the compound obtained in Step C, the procedure is as in Step B of Example 2, replacing the hydroxylamine by O-methylhydroxylamine.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:25])=[C:7]([C:9]2[NH:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[N:10]=2)[CH:8]=1.[CH:26]1([S:29](Cl)(=[O:31])=[O:30])[CH2:28][CH2:27]1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:25][C:6]1[CH:5]=[CH:4][C:3]([CH2:2][NH:1][S:29]([CH:26]2[CH2:28][CH2:27]2)(=[O:31])=[O:30])=[CH:8][C:7]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:19][CH:20]=2)[N:10]=1
Reactant: NCc1ccc(Cl)c(-c2nn(-c3ccc(C(F)(F)F)cc3)c(=O)[nH]2)c1
Reactant: O=S(=O)(Cl)C1CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: O=c1[nH]c(-c2cc(CNS(=O)(=O)C3CC3)ccc2Cl)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
The title compound was prepared according to the procedure described in Example-100 by using 3-(5-(aminomethyl)-2-chlorophenyl)-1-(4-(trifluoromethyl)phenyl)-1H-1,2,4-triazol-5(4H)-one (Intermediate-63, 0.070 g, 0.189 mmol), cyclopropanesulfonyl chloride (0.2 mL), DIPEA (3 mL), and dry THF (5 mL) to afford 0.029 g of pure product. 1H NMR (400 MHz, DMSO d6): δ 0.86-0.92 (m, 4H), 1.14-1.24 (m, 1H), 4.26-4.28 (d, J=6.4 Hz, 2H), 7.57-7.60 (d, J=8.4 Hz, 1H), 7.63-7.68 (d, J=8.4 Hz, 1H), 7.58-7.81 (m, 1H), 7.86-7.88 (d, J=8.8 Hz, 2H), 8.19-8.21 (d, J=8.4 Hz, 2H), 12.89 (br s, 1H); MS (m/z): 471.30 (M−H−).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:11]3[CH:12]=[C:13]([O:16]C)[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[B-](Br)(Br)(Br)[S+](C)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:18]([C:19]([NH:21][CH3:22])=[O:20])=[C:11]3[CH:12]=[C:13]([OH:16])[CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:6][CH:7]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(OC)cc12
Agent: C[S+](C)[B-](Br)(Br)Br
Solvent: Cc1ccccc1
Product: CNC(=O)c1c(-c2ccc(F)cc2)nn2ccc(O)cc12
Temperature: 105 °C
Reaction time: 40 h

Procedure:
To a suspension containing 2-(4-fluorophenyl)-5-methoxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide (0.30 g, 1.0 mmol) and toluene (10 mL), was added boron tribromide-methylsulfide complex (1.3 g, 4.0 mmol) in one portion. The mixture was stirred in a closed vessel at 105° C. for 40 h under a nitrogen atmosphere, cooled to room temperature and extracted with aqueous sodium hydroxide (3×20 mL, 2.0 M). The combined aqueous extracts were neutralized with aqueous HCl (2.0 M, approx. 60 mL) and extracted with ethyl acetate (3×50 mL). The combined organic portions were dried over MgSO4, filtered and concentrated to afford 2-(4-fluorophenyl)-5-hydroxy-N-methylpyrazolo[1,5-a]pyridine-3-carboxamide as a tan solid which was used without further purification. 1H NMR (500 MHz, DMSO-D6) δ ppm 10.69 (s, 1H), 8.55 (d, J=7.32 Hz, 1H), 7.75-7.82 (m, 2H), 7.50 (d, J=4.58 Hz, 1H), 7.28 (t, J=9.00 Hz, 2H), 7.05 (d, J=2.44 Hz, 1H), 6.65 (dd, J=7.48, 2.59 Hz, 1H), 2.72 (d, J=4.58 Hz, 3H). LCMS: retention time: 1.102 min. LC data was recorded on a Shimadzu LC-10AS liquid chromatograph equipped with a Phenomenex-Luna, 10u, C18, 3.0×50 mm column using a SPD-10AV UV-Vis detector at a detector wave length of 220 nM. The elution conditions employed a flow rate of 4 mL/min, a gradient of 100% solvent A/0% solvent B to 0% solvent A/100% solvent B, a gradient time of 4 min, a hold time of 1 min, and an analysis time of 5 min where solvent A was 10% CH3CN/90% H2O/10 mM TFA and solvent B was 10% H2O/90% CH3CN/10 mM TFA. MS data was determined using a Micromass Platform for LC in electrospray mode. m/z 285 (MH+).
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[S:12](=[O:14])(=[O:13])[CH:11]=[CH:10][C:9]=2[CH:15]=1)=[O:4].Cl.[C@@H:17]12[N:24]([CH2:25][C@@H:26]([C:28]3[C:29]([CH3:38])=[C:30]4[C:34](=[CH:35][CH:36]=3)[C:33](=[O:37])[O:32][CH2:31]4)[OH:27])[C@@H:21](CC1)[CH2:20][NH:19][CH2:18]2.C(N(CC)C(C)C)(C)C>C1COCC1>[O:13]=[S:12]1(=[O:14])[C:8]2[CH:7]=[CH:6][C:5]([C:3](=[O:4])[CH2:2][N:19]3[CH2:18][CH2:17][N:24]([CH2:25][C@@H:26]([C:28]4[CH:36]=[CH:35][C:34]5[C:33](=[O:37])[O:32][CH2:31][C:30]=5[C:29]=4[CH3:38])[OH:27])[CH2:21][CH2:20]3)=[CH:15][C:9]=2[CH:10]=[CH:11]1
Reactant: Cc1c([C@@H](O)CN2[C@@H]3CC[C@H]2CNC3)ccc2c1COC2=O
Reactant: O=C(CBr)c1ccc2c(c1)C=CS2(=O)=O
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1c([C@@H](O)CN2CCN(CC(=O)c3ccc4c(c3)C=CS4(=O)=O)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromo-1-(1,1-dioxido-1-benzothiophen-5-yl)ethanone (50 mg, 0.17 mmol) in 1.0 mL THF and 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one hydrochloride (INTERMEDIATE 12) (61 mg, 0.17 mmol) was added N,N-diisopropylethylamine (0.70 mmol, 120 μL) and allowed to stir at ambient temperature for 2 hours. The reaction was quenched by the addition of water and extracted three times with ethyl acetate (10 mL). The combined organic layers were then dried over sodium sulfate, filtered and concentrated in vacuo. The crude residue was purified via MPLC (10% DCM/MeOH) to afford 5-[(1R)-2-{4-[2-(1,1-dioxido-1-benzothiophen-5-yl)-2-oxoethyl]piperazin-1-yl}-1-hydroxyethyl]-4-methyl-2-benzofuran-1 (3H)-one.