Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH2:6][CH2:5][CH2:4]1)#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:27][C:28]1[C:29]([F:51])=[CH:30][C:31]([Cl:50])=[C:32]([CH:49]=1)[O:33][C:34]1[CH:35]=[CH:36][C:37]2[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]3[CH2:48][CH2:47]3)=[O:45])[N:42]=2)[N:39]=1>CN(C)C=O.CN1CCCC1=O>[Cl:50][C:31]1[C:32]([O:33][C:34]2[CH:35]=[CH:36][C:37]3[N:38]([CH:40]=[C:41]([NH:43][C:44]([CH:46]4[CH2:47][CH2:48]4)=[O:45])[N:42]=3)[N:39]=2)=[CH:49][C:28]([NH:27][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][CH:15]=[C:7]([C:3]3([C:1]#[N:2])[CH2:4][CH2:5][CH2:6]3)[CH:8]=2)=[C:29]([F:51])[CH:30]=1
Reactant: N#CC1(c2cccc(C(=O)O)c2)CCC1
Reactant: Nc1cc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)c(Cl)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: N#CC1(c2cccc(C(=O)Nc3cc(Oc4ccc5nc(NC(=O)C6CC6)cn5n4)c(Cl)cc3F)c2)CCC1
Yield: 67.8 %

Procedure:
Using 3-(1-cyanocyclobutyl)benzoic acid (110 mg, 0.56 mmol), oxalyl chloride (60 μL, 0.70 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-chloro-4-fluorophenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (170 mg, 0.46 mmol) and N-methylpyrrolidone (3.0 mL) as starting materials and in the same manner as in Example 335, the title compound (170 mg, 68%) was obtained as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[C:9]([CH3:10])=[CH:8][CH:7]=[CH:6][C:5]=1[I:11].[Br:13]NC(=O)CCC(N)=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C:4]1[C:5]([I:11])=[CH:6][CH:7]=[CH:8][C:9]=1[CH2:10][Br:13]
Reactant: NC(=O)CCC(=O)NBr
Reactant: COC(=O)c1c(C)cccc1I
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)c1c(I)cccc1CBr

Procedure:
A mixture of 2-iodo-6-methyl-benzoic acid methyl ester (3.59 g, 13 mmol), N-bromosuccinamide (2.3 g, 13 mmol), and benzoyl peroxide (0.056 g, 0.21 mmol) in carbon tetrachloride (20 mL) was heated at reflux until the starting materials were mostly consumed. Workup afforded 2-bromomethyl-6-iodo-benzoic acid methyl ester. The material was used without further purification.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[CH2:3][N:4]=[C:5]=[S:6].[CH3:9][S:10]([NH2:13])(=[O:12])=[O:11].[OH-].[Na+]>CC(C)=O.O>[CH3:9][S:10]([NH:13][C:5]([NH:4][CH2:3][C:2]([F:8])([F:7])[F:1])=[S:6])(=[O:12])=[O:11]
Reactant: CS(N)(=O)=O
Reactant: FC(F)(F)CN=C=S
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CS(=O)(=O)NC(=S)NCC(F)(F)F
Yield: 19.2 %

Procedure:
A solution of 2,2,2-trifluoroethylisothiocyanate (1.4 g.) in acetone (20 ml.) was added to a solution of methanesulphonamide (0.95 g.) and sodium hydroxide (0.44 g.) in water (10 ml.) and the mixture stirred and heated under reflux for 18 hours, and then evaporated to dryness. The residue was dissolved in water and the solution washed with ethyl acetate and then acidified with concentrated hydrochloric acid. The mixture was extracted three times with ethyl acetate and the combined extracts dried and evaporated to dryness. The residue was triturated with acetonitrile and filtered and the filtrate evaporated to dryness. The residue was dissolved in ether, and the solution extracted with aqueous sodium bicarbonate solution. The extract was neutralised with N hydrochloric acid and the mixture extracted with ethyl acetate. The ethyl acetate extract was dried and evaporated to dryness to give 1-methanesulphonyl-3-(2,2,2-trifluoroethyl)thiourea (0.45 g.) which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[C:7]([CH3:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[Li]CCCC.[CH3:19][C:20]1([CH3:31])[C:24]([CH3:26])([CH3:25])[O:23][B:22](OC(C)C)[O:21]1>O1CCCC1>[CH3:11][C:7]1[NH:8][C:9]2[C:5]([CH:6]=1)=[CH:4][CH:3]=[C:2]([B:22]1[O:23][C:24]([CH3:26])([CH3:25])[C:20]([CH3:31])([CH3:19])[O:21]1)[CH:10]=2
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: Cc1cc2ccc(Br)cc2[nH]1
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1cc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 49 %

Procedure:
To a solution of 6-bromo-2-methyl-1H-indole (2.0 g, 9.52 mmol) in dry tetrahydrofuran (100 mL) was added sodium hydride (381 mg, 9.53 mmol) with ice-cooling. After stirring for about 30 min, a solution of n-BuLi (15 mL, 2.5 M solution in hexane) was added dropwise with stirring at −78° C. under nitrogen. It was warmed slowly to −40° C. during 45 min and stirred at this temperature for another 30 min. The mixture was cooled again below −78° C. followed by dropwise addition of 4,4,5,5-tetramethyl-2-(propan-2-yloxy)-1,3,2-dioxaborolane (3.54 g, 19.03 mmol). After warming to room temperature, the mixture was quenched with NH4Cl (aq) and extracted with ethyl acetate (3×80 mL). The combined organic layers were dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give the residue, which was purified by silica gel column chromatography (2% ethyl acetate in petroleum ether) to afford 2-methyl-6-(tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indole (1.2 g, 49%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:20]2[C:19]3[C:14](=[CH:15][C:16]([CH2:21][OH:22])=[CH:17][CH:18]=3)[NH:13][C:12]=2[C:11]([C:23]([NH2:25])=[O:24])=[CH:10][CH:9]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1COCC1.CCOC(C)=O>[CH3:26][S:27]([O:22][CH2:21][C:16]1[CH:17]=[CH:18][C:19]2[C:20]3[C:12](=[C:11]([C:23](=[O:24])[NH2:25])[CH:10]=[CH:9][C:8]=3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[F:1])[NH:13][C:14]=2[CH:15]=1)(=[O:29])=[O:28]
Reactant: CS(=O)(=O)Cl
Reactant: NC(=O)c1ccc(-c2ccccc2F)c2c1[nH]c1cc(CO)ccc12
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)OCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(-c3ccccc3F)c12
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 4-(2-fluorophenyl)-7-(hydroxymethyl)-9H-carbazole-1-carboxamide (Example 30-1, 223 mg, 0.667 mmol) and TEA (0.279 mL, 2.001 mmol) in THF (8 mL) was treated with methanesulfonyl chloride (0.104 mL, 1.334 mmol). The resulting suspension was stirred at rt for 15 min. The mixture was diluted with EtOAc, washed with water and brine, and dried and concentrated to provide crude (8-carbamoyl-5-(2-fluorophenyl)-9H-carbazol-2-yl)methyl methanesulfonate as a yellow glassy foam (300 mg, ca. 50% purity). A portion of this material (80 mg, 0.097 mmol) was dissolved in DMF (1 mL), treated with morpholine (84 mg, 0.970 mmol) and heated at 45° C. for 3 days. The mixture was purified by preparative HPLC to provide 4-(2-fluorophenyl)-7-(morpholinomethyl)-9H-carbazole-1-carboxamide (9.6 mg, 23%). 1H NMR (400 MHz, methanol-d4) δ 7.94 (1 H, d, J=7.8 Hz), 7.59 (1 H, s), 7.52-7.58 (1 H, m), 7.48-7.52 (1 H, m), 7.33-7.39 (1 H, m), 7.30 (1 H, t, J=9.0 Hz), 7.21 (1 H, d, J=8.3 Hz), 7.14 (1 H, d, J=7.8 Hz), 6.99 (1 H, dd, J=8.3, 1.5 Hz), 3.81 (2H, s), 3.71-3.77 (4 H, m), 2.66 (4 H, br. s.). Mass spectrum m/z 404.2 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](I)[CH:5]=[C:6]2[C:11]=1[N:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]=[C:8]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:27].[Cl-].[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][Zn+].[Cl-].[NH4+].C(OCC)(=O)C>C1COCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1.C(Cl)(Cl)Cl>[Cl:30][C:31]1[C:38]([Cl:39])=[CH:37][CH:36]=[CH:35][C:32]=1[CH2:33][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([F:1])[CH:3]=1)[N:10]([CH2:12][CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH:9]=[C:8]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:7]2=[O:27]
Reactant: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(I)cc2c1=O
Reactant: Clc1cccc(C[Zn+])c1Cl
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [Cl-]
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(CCO[Si](C)(C)C(C)(C)C)c2c(F)cc(Cc3cccc(Cl)c3Cl)cc2c1=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 101.7 %

Procedure:
Under an argon stream, 1M solution (2.9 ml, 2.9 mmol) of 2,3-dichlorobenzylzinc chloride in THF obtained in the same manner as in Reference Example 1 was added to THF (20 ml), and then bis(dibenzylideneacetone)palladium(0) (22 mg, 0.039 mmol), tri(2-furyl)phosphine (18 mg, 0.077 mmol) and ethyl 1,4-dihydro-8-fluoro-6-iodo-1-[2-(tert-butyldimethylsilyloxy)ethyl]-4-oxo-3-quinolinecarboxylate (1.0 g, 1.9 mmol) obtained in Step 4 were added. The mixture was stirred at room temperature for 17 hrs, and then a solution (1.0 ml, 1.0 mmol) of 2,3-dichlorobenzylzinc chloride in THF was added. The mixture was heated under reflux for 1 hr. After allowing the mixture to cool, saturated aqueous ammonium chloride solution was added to the reaction solution and insoluble materials were filtered off with Celite. The filtrate was extracted with ethyl acetate, and the organic layer was washed with water and saturated brine, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the obtained residue was purified by silica gel chromatography (ethyl acetate:hexane=1:1), and then by PTLC (ethyl acetate:chloroform=1:2) to give an object product (562 mg, yield 53%) as a pale-yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:30])[CH:7]([CH:11]([C:16](=[O:29])[NH:17][CH:18]([C:23](=[O:28])[NH:24][CH:25]1[CH2:27][CH2:26]1)[C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH:13]([CH3:15])[CH3:14])[CH2:8][CH:9]=[CH2:10])(C)(C)C>ClCCl.C(O)(C(F)(F)F)=O>[CH:25]1([NH:24][C:23]([CH:18]([NH:17][C:16]([CH:11]([CH:7]([CH2:8][CH:9]=[CH2:10])[C:6]([OH:30])=[O:5])[CH2:12][CH:13]([CH3:15])[CH3:14])=[O:29])[C:19]([CH3:21])([CH3:22])[CH3:20])=[O:28])[CH2:27][CH2:26]1
Reactant: C=CCC(C(=O)OC(C)(C)C)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCC(C(=O)O)C(CC(C)C)C(=O)NC(C(=O)NC1CC1)C(C)(C)C
Reaction time: 8 h

Procedure:
2-[1-(1-Cyclopropylcarbamoyl-2,2-dimethyl-propylcarbamoyl)-3-methyl-butyl]-pent-4-enoic acid-tert-butyl ester (2.05 g, 4.83 mmol) was dissolved in dichloromethane (7 ml) and TFA (7 ml). The mixture was allowed to stand at 0°-5° C. overnight then solvent was evaporated under reduced pressure, azeotroping with three times toluene to provide the title compound as a white solid which was recrystallised from ethyl acetate. Yield: 1.81 g (74%). 1H-NMR; δ (CD3OD), 8.19 (1H, br s), 7.95 (1H, d, J=9.2 Hz), 5.72 (1H, m), 4.98 (2H, m), 4.19 (1H, d, J=9.3 Hz), 2.76 (1H,m), 2.56 (2H, m) 2.23 (1H, m), 1.59 (1H, m), 1.37 (1H, m), 0.96 (9H, s), 0.87 (3H, d,J=6.5 Hz), 0.81 (3H, d, J=6.6 Hz), 0.68 (2H, m) and 0.43 (2H, m).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:16]=O)[C:9]1=[O:18].Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+]>CO.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:13]([CH3:14])=[CH:12][C:11]([OH:15])=[C:10]([CH:16]=[N:20][OH:21])[C:9]1=[O:18]
Reactant: Cc1cc(O)c(C=O)c(=O)n1-c1ccccc1Cl
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CO
Product: Cc1cc(O)c(C=NO)c(=O)n1-c1ccccc1Cl
Temperature: 70 °C
Yield: 92.9 %

Procedure:
A mixture of 1-(2-chlorophenyl)-4-hydroxy-6-methyl-2-oxo-1,2-dihydropyridine-3-carbaldehyde obtained in Step B (3.95 g), hydroxylamine hydrochloride (2.08 g) and sodium acetate (2.46 g) in methanol/water (4:1, 75.0 mL) was heated at 70° C. for 2 hr, cooled to room temperature, and poured into ice water. The resulting solid was collected by filtration, washed with water, and dried under reduced pressure to give the title compound (3.88 g).
Reaction SMILES: [CH3:1][S:2]([NH2:5])(=[O:4])=[O:3].[Br:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11](Cl)=[O:12]>C(OCC)(=O)C>[CH3:1][S:2]([NH:5][C:11](=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7][Br:6])(=[O:4])=[O:3]
Reactant: O=C(Cl)CCCCBr
Reactant: CS(N)(=O)=O
Solvent: CCOC(C)=O
Product: CS(=O)(=O)NC(=O)CCCCBr
Yield: 74.7 %

Procedure:
A mixture of 23.5 g. (0.25 mole) of methanesulfonamide and 49.8 g. (0.25 mole) of 5-bromovaleric acid chloride was heated at 80-85° (oil bath) for 45 minutes. The brown reaction mixture was allowed to cool and was dissolved in ethyl acetate. The organic solution was washed with water and saturated brine, was dried (anhydrous magnesium sulfate), was Darcoed, concentrated, and cooled to afford the white, crystalline N-methanesulfonyl-5-bromovaleramide weighing 48.2 g. (74.8% yield) which melted at 97°-98°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15]Br)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[N-:26]=[N+:27]=[N-:28].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[F:25])[C@H:12]([CH3:17])[CH2:13][CH2:14][CH2:15][N:26]=[N+:27]=[N-:28])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: C[C@H](CCCBr)N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](CCCN=[N+]=[N-])N(c1cc(Cl)ccc1F)S(=O)(=O)c1ccc(Cl)cc1
Temperature: 22 °C
Reaction time: 240 h
Yield: 72.1 %

Procedure:
To a solution of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-4-bromobutyl]-benzenesulfonamide (0.343 g, 0.730 mmol) in THF/H2O (8/2 mL) was added sodium azide (0.237 g, 7.30 mmol) at 22° C. The resulting mixture was allowed to stir at 22° C. for 10 days. The mixture was extracted with ether (3×20 mL). The combined organic extracts were washed with sat. NaHCO3, dried over MgSO4, filtered, and concentrated under reduced pressure. Silica gel chromatography (1:9 ethyl acetate:hexanes) of the concentrate afforded 0.227 g of 4-chloro-N-(5-chloro-2-fluorophenyl)-N-[(R)-1-methyl-4-azidobutyl]benzenesulfonamide as a colorless oil in 72% yield.
Reaction SMILES: CC([O-])(C)C.[K+].[C:7]([CH2:9][C:10]([NH2:12])=[O:11])#[N:8].[CH3:13][C:14](=O)/[CH:15]=[CH:16]/[CH2:17][CH2:18][CH3:19]>CS(C)=O>[CH3:13][C:14]1[NH:12][C:10](=[O:11])[C:9]([C:7]#[N:8])=[C:16]([CH2:17][CH2:18][CH3:19])[CH:15]=1
Reactant: CCC/C=C/C(C)=O
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCCc1cc(C)[nH]c(=O)c1C#N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a solution of DMSO (300 mL) containing t-BuOK (20 g, 178 mmol) and cyanoacetamide (16.5 g, 196 mmol) was added (3E)-3-hepten-2-one (20 g, 178 mmol), and the contents were stirred at room temperature for 30 min. Additional t-BuOK (60 g, 534 mmol) was added and the reaction mixture was placed under an atmosphere of oxygen for an additional 1 h. The reaction mixture was purged with argon, diluted with 4 volumes of H2O, and then 5 volumes of 4 N HCl, which were added slowly. The reaction mixture was filtered, washed with water, and dried to give 6-methyl-2-oxo-4-propyl-1,2-dihydro-3-pyridinecarbonitrile (10 g, 32%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.25-12.40 (br s, 1H), 6.18 (s, 1H), 2.53 (t, 2H), 2.22 (s, 3H), 1.57-1.64 (m, 2H), 0.84 (t, 3H).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH:6]=O.[CH3:13][C:14]([S@@:17]([NH2:19])=[O:18])([CH3:16])[CH3:15].O>C(Cl)Cl>[CH3:13][C:14]([S@@:17]([N:19]=[CH:6][C:5]1[CH:8]=[CH:9][CH:10]=[C:3]([C:2]([F:12])([F:11])[F:1])[CH:4]=1)=[O:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)[S@](=O)N=Cc1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 88 %

Procedure:
To a mixture of 3-(trifluoromethyl)benzaldehyde (5 g, 28.7 mmol) and (S)-2-methylpropane-2-sulfinamide (4.17 g, 34.4 mmol) in DCM (50 ml) at 0° C., was drop wise added Ti(O-iPr)4 (12 g, 43 mmol) under N2 atmosphere. After stirring for 20 h at room temperature, the reaction mixture was poured into water (100 mL) with vigorous stirring. The precipitate was filtered off and the filtrate was extracted with DCM (2×150 mL). The combined organic layers were washed with brine (100 mL), dried over anhydrous MgSO4, and then concentrated. The residue was purified by silica gel chromatography (PE/EtOAc=5/1 to 2/1) to give the title compound (7 g, yield: 88%); m/z (ES+): 278 [M+H]+.
Reaction SMILES: FC1C=C(C2CCC3C(=CC=C(O)C=3)O2)C=CC=1.[CH3:19][CH:20]1[CH:29](O)[C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=2)[O:22][CH:21]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>>[CH3:19][CH:20]1[CH2:29][C:28]2[C:23](=[CH:24][CH:25]=[C:26]([OH:31])[CH:27]=2)[O:22][CH:21]1[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CC1C(O)c2cc(O)ccc2OC1c1ccccc1
Agent: Oc1ccc2c(c1)CCC(c1cccc(F)c1)O2
Product: CC1Cc2cc(O)ccc2OC1c1ccccc1

Procedure:
3-Methyl-2-phenylchroman-6-ol was prepared as described for 2-(3-fluorophenyl)chroman-6-ol in Example 9(c) starting from 605 mg of 3-methyl-2-phenylchroman-4,6-diol. 1H NMR (400 MHz, CD3OD) δ: 8.77 (s, 1H), 7.41-7.33 (m, 5H), 6.59-6.48 (m, 3H), 4.56 (d, 1H, J 9.2 Hz), 2.73 (dd, 1H, J −16.5, 5.0 Hz), 2.54 (dd, 1H, J −116.5, 5.8 Hz), 2.11 (m, 1H), 0.72 (d, 3H, J 6.6 Hz).
Reaction SMILES: [NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([O:15][CH3:16])[CH2:13][CH3:14])(=[O:11])=[O:10])[C:5](Cl)=[CH:6][CH:7]=1.[H][H]>CCO.[Pd]>[NH2:1][C:2]1[C:3]([OH:17])=[C:4]([S:9]([N:12]([CH2:13][CH3:14])[O:15][CH3:16])(=[O:10])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCN(OC)S(=O)(=O)c1c(Cl)ccc(N)c1O
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCN(OC)S(=O)(=O)c1cccc(N)c1O
Reaction time: 5 h

Procedure:
A dispersion of 10% Pd/C (200 mg) in a solution of 3-amino-6-chloro-2-hydroxy-N-methoxy-N-ethyl-benzenesulfonamide (Int. FA step 2) (400 mg, 1.425 mmol) in EtOH (50 ml) was placed under a positive pressure of hydrogen at 0.5 bar above atmospheric pressure. After 5 hours, the catalyst was removed by filtration through Celite® (filter material), and the filtrate was reduced in vacuo. The resulting solid was used in the next step, without further purification.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16](O)[O:15][C:14](=O)[CH:13]=2)=[CH:8][CH:7]=1.O.[NH2:20][NH2:21]>CCO>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:16]=[N:21][NH:20][C:14](=[O:15])[CH:13]=2)=[CH:8][CH:7]=1
Reactant: NN
Reactant: O=C1C=C(c2ccc(OCCCCl)cc2)C(O)O1
Solvent: CCO
Solvent: O
Product: O=c1cc(-c2ccc(OCCCCl)cc2)cn[nH]1
Yield: 60.8 %

Procedure:
A solution of the product from example 94 step 3 (2.0 g, 7.45 mmol) and hydrazine hydrate (0.59 g, 1.5 eq.) in 20 mL of EtOH was stirred at 85° C. for 2 h. The solvent was reduced and the solid was collected and washed with cold EtOH to give 1.2 g (61%) of 5-[4-(3-chloropropoxy)phenyl)-2H-pyridazin-3-one: Mp 197-9° C.; MS m/z 265 (M+H).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:15])[C:10](=O)[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:17].ClCCl.C(OCC)C>C1C=CC=CC=1>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][N:9]([CH3:15])[C:10](=[S:17])[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1
Reactant: CC(C)C(=O)N(C)Cc1ccc(Cl)nc1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: CCOCC
Solvent: c1ccccc1
Solvent: ClCCl
Product: CC(C)C(=S)N(C)Cc1ccc(Cl)nc1
Temperature: 25 °C

Procedure:
In a 250 ml two-necked flask, N-(6-chloro-3-pyridylmethyl)-N-methyl-2-methylpropanamide (6.80 g, 30.0 mmol) is dissolved in 120 ml of benzene, 1.47 g (3.3 mmol) of phosphorus pentasulfide are added and the mixture is heated at reflux for 1.5 hours. After this period of time, the mixture is cooled to room temperature and filtered, and the filtrate is concentrated under reduced pressure using a rotary evaporator. To increase the yield on the same day, the product should be subjected to silica gel column chromatography using the mobile phase dichloromethane/diethyl ether 10/3; Rf=0.8.
Reaction SMILES: [CH2:1]=[CH:2][CH:3]1[CH2:8][CH:7]2[O:9][CH:6]2[CH2:5][CH2:4]1.O.S(=O)(=O)(O)[OH:12]>CC(C)=O>[OH:9][CH:6]1[CH2:5][CH2:4][CH:3]([CH:2]=[CH2:1])[CH2:8][CH:7]1[OH:12]
Reactant: C=CC1CCC2OC2C1
Reactant: O=S(=O)(O)O
Solvent: O
Solvent: CC(C)=O
Product: C=CC1CCC(O)C(O)C1

Procedure:
Into a two-neck flask (100 ml) were fed 15.9 g (128 mmol) of 4-vinylcyclohexene-1,2-epoxide, 40 ml of water, 20 ml of acetone, and 40 μl of sulfuric acid, and the reaction mixture was refluxed at 75° C. for 4 hours. After complete reaction, an object compound was extracted with each 60 ml of diethylether four times, and was washed with saturated salt solution, and then was dried with sodium sulfate. The solvent was evaporated to obtain 1,2-dihydroxy-4-vinylcyclohexane.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:52])([F:51])[C:17]1[CH:18]=[C:19]([CH:44]=[C:45]([C:47]([F:50])([F:49])[F:48])[CH:46]=1)[CH2:20][N:21]([C:38]1[N:39]=[N:40][N:41]([CH3:43])[N:42]=1)[C@H:22]1[CH2:28][CH2:27][CH2:26][NH:25][C:24]2[CH:29]=[C:30]([C:34]([F:37])([F:36])[F:35])[C:31]([CH3:33])=[CH:32][C:23]1=2.[CH2:53]([N:60]1[CH2:65][CH2:64][C:63](=O)[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.C(O)(=O)C>C(#N)C.ClCCl>[CH2:53]([N:60]1[CH2:65][CH2:64][CH:63]([N:25]2[CH2:26][CH2:27][CH2:28][C@H:22]([N:21]([CH2:20][C:19]3[CH:44]=[C:45]([C:47]([F:50])([F:48])[F:49])[CH:46]=[C:17]([C:16]([F:51])([F:15])[F:52])[CH:18]=3)[C:38]3[N:39]=[N:40][N:41]([CH3:43])[N:42]=3)[C:23]3[CH:32]=[C:31]([CH3:33])[C:30]([C:34]([F:35])([F:36])[F:37])=[CH:29][C:24]2=3)[CH2:62][CH2:61]1)[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Reactant: Cc1cc2c(cc1C(F)(F)F)NCCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Solvent: CC#N
Product: Cc1cc2c(cc1C(F)(F)F)N(C1CCN(Cc3ccccc3)CC1)CCC[C@@H]2N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 24 h
Yield: 26.6 %

Procedure:
Add sodium triacetoxyborohydride (0.153 g, 0.724 mmol) portionwise to a solution of (S)-(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-(7-methyl-8-trifluoromethyl-2,3,4,5-tetrahydro-1H-benzo[b]azepin-5-yl)-amine (Example 3, Step 18) (0.200 g, 0.362 mmol), 1-benzyl-piperidin-4-one (0.206 g, 1.09 mmol) and glacial acetic acid (1 mL) in acetonitrile (10 mL) at room temperature under an atmosphere of nitrogen and stir for 24 h. Quench the reaction with saturated sodium bicarbonate (5 mL) and dilute with dichloromethane (15 mL). Separate the layers and wash the organic layer with saturated sodium bicarbonate and brine (20 mL each). Dry the organic layer over sodium sulfate, filter and remove the solvent under reduced pressure. Purify the residue using flash column chromatography on silica gel, eluting with hexanes/ethyl acetate (80:20), to provide the title compound as an off-white solid (0.070 g, 61%). 1H NMR (CDCl3, 300 MHz) δ 1.63-2.13 (m, 8H), 2.34 (s, 3H), 2.82-3.0 (m, 3H), 3.10-3.22 (m, 1H), 3.33-3.41 (m, 1H), 3.50 (s, 2H), 4.09-4.13 (m, 1H), 4.14 (s, 3H), 4.74-4.97 (m, 2H), 5.34-5.49 (m, 1H), 6.89 (s, 1H), 7.32 (s, 1H), 7.41 (s, 5H), 7.60 (s, 2H), 7.71 (s, 1H); ESI MS m/z 726 [C35H36F9N7+H]+.
Reaction SMILES: C(C1C=CC(I)=C(C=1)C(O)=O)#N.[NH2:13][CH2:14][C@@H:15]1[C@H:20]([CH3:21])[CH2:19][CH2:18][CH2:17][N:16]1[C:22]([C:24]1[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=1[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1)[C:27]#[N:28])=[O:23].Cl[C:39]1[N:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=1>>[CH3:21][C@@H:20]1[CH2:19][CH2:18][CH2:17][N:16]([C:22]([C:24]2[CH:25]=[C:26]([CH:29]=[CH:30][C:31]=2[C:32]2[N:33]=[CH:34][CH:35]=[CH:36][N:37]=2)[C:27]#[N:28])=[O:23])[C@@H:15]1[CH2:14][NH:13][C:39]1[N:44]=[CH:43][C:42]([C:45]([F:48])([F:47])[F:46])=[CH:41][N:40]=1
Reactant: C[C@@H]1CCCN(C(=O)c2cc(C#N)ccc2-c2ncccn2)[C@@H]1CN
Reactant: FC(F)(F)c1cnc(Cl)nc1
Agent: N#Cc1ccc(I)c(C(=O)O)c1
Product: C[C@@H]1CCCN(C(=O)c2cc(C#N)ccc2-c2ncccn2)[C@@H]1CNc1ncc(C(F)(F)F)cn1

Procedure:
The title compound was prepared following the same general protocol as described for Example A230 using 5-cyano-2-iodobenzoic acid to make 3-((2S,3R)-2-(aminomethyl)-3-methylpiperidine-1-carbonyl)-4-(pyrimidin-2-yl)benzonitrile and 2-chloro-5-(trifluoromethyl)pyrimidine. ESI-MS (m/z): 482 [M+1]+.