Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:30]=[CH:29][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17]([OH:20])=[C:16]([C:21]([NH:23][CH2:24][C:25]([OH:27])=[O:26])=[O:22])[C:15]3=[O:28])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+:32]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[N:12]=[CH:11][C:10]([CH2:13][N:14]3[CH2:19][CH2:18][C:17]([OH:20])=[C:16]([C:21]([NH:23][CH2:24][C:25]([O-:27])=[O:26])=[O:22])[C:15]3=[O:28])=[CH:9][CH:8]=2)=[CH:29][CH:30]=1.[Na+:32]
Reactant: O=C(O)CNC(=O)C1=C(O)CCN(Cc2ccc(Oc3ccc(Cl)cc3)nc2)C1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: O=C([O-])CNC(=O)C1=C(O)CCN(Cc2ccc(Oc3ccc(Cl)cc3)nc2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution in acetone of the compound (645 mg) obtained in step (2) above, 1 mol/L sodium hydroxide in aqueous solution (1.50 mL) was added and the mixture was stirred at room temperature for 30 minutes. The resulting precipitate was recovered by filtration to give the titled compound as a colorless solid (543 mg).
Reaction SMILES: [CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8](O)=[O:9])[CH:2]([CH3:4])[CH3:3].CCN(C(C)C)C(C)C.CN(C(O[N:32]1[N:40]=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.NN.C1COCC1>CN(C=O)C.CCOCC>[CH2:1]([C:5]1[CH:6]=[C:7]([CH:11]=[C:12]([CH3:14])[N:13]=1)[C:8]([NH:32][NH2:40])=[O:9])[CH:2]([CH3:4])[CH3:3]
Reactant: Cc1cc(C(=O)O)cc(CC(C)C)n1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: NN
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NN)cc(CC(C)C)n1
Reaction time: 2 h
Yield: 49.7 %

Procedure:
To a solution of 2-isobutyl-6-methyl-isonicotinic acid (83 mg, 0.359 mmol) and DIPEA (186 mg, 1.44 mmol) in DMF (6 mL) is added TBTU (127 mg, 0.395 mmol) at rt. The mixture is stirred for 45 min before 1 M hydrazine in THF (1.44 mL, 1.44 mmol) is added and stirring is continued for 2 h. The mixture is diluted with ether (200 mL) and washed with 1M aq. HCl (3×5 mL), 1M aq. NaOH (3×5 mL) and brine (5 mL). The org. phase is separated, dried over MgSO4, filtered and evaporated. The crude product is purified on prep. TLC plates with DCM containing 4% of methanol to give 2-isobutyl-6-methyl-isonicotinic acid hydrazide (37 mg) as a yellow oil; LC-MS: tR=0.44 min, [M+1]+=208.10.
Reaction SMILES: O1CCCC1.[Cl-].[F:7][C:8]1[CH:9]=[C:10]([Zn+])[CH:11]=[C:12]([F:15])[C:13]=1[F:14].[Cl-].[Li+].[Cl-].[NH4+].FC(F)(F)S(O[C:27]1[CH:32]=[CH:31][C:30]([CH:33]2[CH2:38][CH2:37][Si:36]([CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])([C:39]3[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=3)[CH2:35][CH2:34]2)=[CH:29][C:28]=1[F:50])(=O)=O>[Cl-].[Zn+2].[Cl-].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.CN(C)C=O>[CH2:45]([Si:36]1([C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:37][CH2:38][CH:33]([C:30]2[CH:31]=[CH:32][C:27]([C:10]3[CH:9]=[C:8]([F:7])[C:13]([F:14])=[C:12]([F:15])[CH:11]=3)=[C:28]([F:50])[CH:29]=2)[CH2:34][CH2:35]1)[CH2:46][CH2:47][CH2:48][CH3:49]
Reactant: Fc1cc([Zn+])cc(F)c1F
Reactant: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(OS(=O)(=O)C(F)(F)F)c(F)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CCCCC[Si]1(c2ccccc2)CCC(c2ccc(-c3cc(F)c(F)c(F)c3)c(F)c2)CC1
Reaction time: 8 h
Yield: 85.1 %

Procedure:
40 ml of a tetrahydrofuran solution of 0.8 moles of 3,4,5-trifluorophenylzinc chloride prepared by reaction between a corresponding Grignard reagent and zinc chloride was dropped in a mixture of 10.0 g of (2-fluoro-4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)phenyl) trifluoromethanesulfonate, 100 mg of tetrakis(triphenylphosphine)palladium (0), 500 mg of lithium chloride and 50 ml of N,N-dimethylformamide. After agitation at 50° C. for 8 hours, the mixture was charged into an ammonium chloride aqueous solution, followed by extraction with ethyl acetate. The ethyl acetate solution was washed with brine, dried, and concentrated, followed by purification of the resultant residue through silica gel chromatography to obtain 8.20 g (yield: 75%) of 4-(4-n-pentyl-4-phenyl-4-silacyclohexyl)-2,3',4',5'-tetrafluorobiphenyl. The results of IR and 1H-NMR analyses of the product are shown below.
Reaction SMILES: S(Cl)([Cl:4])(=O)=O.[C:6]([C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:10]=1[N:11]([CH3:14])[CH:12]=[O:13])(=[O:8])[CH3:7].O>ClCCl>[Cl:19][C:16]1[CH:17]=[CH:18][C:9]([C:6](=[O:8])[CH2:7][Cl:4])=[C:10]([CH:15]=1)[N:11]([CH3:14])[CH:12]=[O:13]
Reactant: O=S(=O)(Cl)Cl
Reactant: CC(=O)c1ccc(Cl)cc1N(C)C=O
Solvent: O
Solvent: ClCCl
Product: CN(C=O)c1cc(Cl)ccc1C(=O)CCl
Reaction time: 0.08 h

Procedure:
A solution of sulphuryl chloride (9 ml) in dichloromethane (15 ml) was added dropwise to the solution of 2'-acetyl-5'-chloro-N-methylformanilide under nitrogen whilst maintaining the temperature at 0 to Water (40 ml) was then added dropwise whilst maintaining the temperature at 0 to 10°. The mixture was stirred for a further 5 minutes and then the dichloromethane layer was separated and dried over magnesium sulphate to give a solution of 5'-chloro-2'-(2-chloroacetyl)-N-methylformanilide.
Reaction SMILES: [ClH:1].[CH:2]1([C:5](=[O:35])[CH:6]([N:14]2[CH2:19][CH2:18][CH:17]([SH:20])/[C:16](=[CH:21]/[C:22]3[N:26]([CH2:27][CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:25]=[N:24][N:23]=3)/[CH2:15]2)[C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=2[F:13])[CH2:4][CH2:3]1.C(#N)C>Cl>[ClH:1].[C:30]([CH2:29][CH2:28][CH2:27][N:26]1[C:22](/[CH:21]=[C:16]2\[CH2:15][N:14]([CH:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[F:13])[C:5]([CH:2]3[CH2:4][CH2:3]3)=[O:35])[CH2:19][CH2:18][CH:17]\2[SH:20])=[N:23][N:24]=[N:25]1)([OH:32])=[O:31]
Reactant: CCOC(=O)CCCn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Agent: Cl
Solvent: CC#N
Product: O=C(O)CCCn1nnnc1/C=C1\CN(C(C(=O)C2CC2)c2ccccc2F)CCC1S
Yield: 71.8 %

Procedure:
A solution of (E)-1-[2-cyclopropyl-1-(2-fluorophenyl)-2-oxoethyl]-3-({1-[3-(ethoxycarbonyl)propyl]-1H-tetrazol-5-yl}methylidene)-4-sulfanylpiperidine hydrochloride (134 mg) in 3 N HCl (4 ml) was stirred at 50° C. for 2 hours. The solvent and excess HCl were removed in vacuo, and the residue was purified by preparative HPLC (YMC-Pack ODS-A; YMC, eluent: acetonitrile/0.024 N aqueous HCl, 30/70, v/v) to afford the title compound as a colourless amorphous solid (91 mg, yield: 72%).
Reaction SMILES: [C:1]([NH2:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:10][O:11][CH:12](OC)[CH2:13][Cl:14].S(=O)(=O)(O)O>O>[CH3:10][O:11][CH:12]([NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][Cl:14]
Reactant: COC(CCl)OC
Reactant: NC(=O)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: O
Product: COC(CCl)NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 70.3 %

Procedure:
12.1 g of benzamide and 14.3 g of chloroacetaldehyde dimethyl acetal were agitated while being cooled in an ice bath, and into this, 7 ml of concentrated sulfuric acid was dripped over a period of 1 hour. After agitating this for 2 hours at room temperature, 200 ml of water was added to the reaction fluid, and this was extracted in 300 ml of chloroform. The extracted layer was washed twice with 100 ml of water, and the chloroform and excess chloroacetaldehyde dimethyl acetal were removed by distillation under reduced pressure, and 15.0 g of compound (1) was obtained.
Reaction SMILES: Br[C:2]1[O:6][C:5]([C:7]2[O:8][C:9]([C:12]3[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=3)=[CH:10][CH:11]=2)=[CH:4][CH:3]=1.[CH3:20][N:21](C=O)C>>[C:16]([C:15]1[CH:18]=[CH:19][C:12]([C:9]2[O:8][C:7]([C:5]3[O:6][C:2]([C:20]#[N:21])=[CH:3][CH:4]=3)=[CH:11][CH:10]=2)=[CH:13][CH:14]=1)#[N:17]
Reactant: CN(C)C=O
Reactant: N#Cc1ccc(-c2ccc(-c3ccc(Br)o3)o2)cc1
Product: N#Cc1ccc(-c2ccc(-c3ccc(C#N)o3)o2)cc1
Yield: 40 %

Procedure:
A mixture of 4 (740 mg, 2.35 mmol) and Cu(I)CN (423 mg, 4.7 mmol) in dry DMF (25 mL) was refluxed for 48 h. The reaction mixture was poured onto water/ammonia and extracted with methylene chloride. The extract was washed with water and brine, dried over Na2SO4, then passed on silica gel to give analytically pure product 5 in 40% yield, mp 194-195° C. 1H NMR (DMSO-d6); δ 7.17 (d, J=3.6 Hz, 1H), 7.21 (d, J=3.6 Hz, 1H), 7.43 (d, J=3.6 Hz, 1H), 7.76 (d, J=3.6 Hz, 1H), 7.91 (d, J=8.4 Hz, 2H), 7.99 (d, J=8.4 Hz, 2H). 13C NMR (DMSO-d6); δ 152.3, 149.3, 144.3, 133.0, 132.9, 125.6, 124.3, 124.1, 118.7, 112.0, 111.8, 111.5, 110.0, 107.9. EIMS (m/z, rel.int.); 260 (M+, 100), 231 (15), 203 (25), 177 (25), 140 (10), 130 (55). Calcd for C16H8N2O2: C, 73.84; H, 3.09; N, 10.76. Found. C, 73.62; H, 3.18; N, 10.92.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@@H:13]3[C:20](=O)[NH:19][C@@H:18]([CH3:22])[C:17](=O)[N:14]3[C:15]=2[CH:16]=1.[OH-].[Na+].S([O-])([O-])(=O)=O.[Mg+2].Cl>CCOCC.O>[ClH:7].[Cl:7][C:8]1[CH:9]=[CH:10][C:11]2[CH2:12][C@@H:13]3[CH2:20][NH:19][C@@H:18]([CH3:22])[CH2:17][N:14]3[C:15]=2[CH:16]=1
Reactant: C[C@@H]1NC(=O)[C@H]2Cc3ccc(Cl)cc3N2C1=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Solvent: CCOCC
Solvent: O
Product: C[C@H]1CN2c3cc(Cl)ccc3C[C@@H]2CN1
Temperature: 25 °C
Yield: 145 %

Procedure:
To a stirred suspension of lithium aluminium hydride (95%; 55 mg, 1.4 mmol) in anhydrous ether (15 mL) under Ar was added (3S,10aR) 7-chloro-1,2,3,4,10,10a-hexahydro-3-methylpyrazino[1,2-a]indole-1,4-dione (83 mg, 0.33 mmol). The mixture was heated at reflux for 18 h, then allowed to cool to ambient temperature. Water (0.06 mL) was added, followed by aqueous NaOH (15% w/v; 0.06 mL) then water (0.18 mL) and magnesium sulfate (2 g) was added. The mixture was filtered and the filter-cake washed with ethyl acetate. The filtrate was concentrated in vacuo and purification by flash column chromatography [SiO2; ethyl acetate-methanol-ammonium hydroxide (9:1:0)→(90:8:2)] gave a colourless oil which crystallised on standing (68 mg, 92%). The oil was dissolved in acetone (0.5 mL) and treated with ethereal HCl (1M; 0.81 mL, 0.81 mmol) followed by ether (5 mL). The resultant precipitate was filtered, washed with ether and dried to afford the title compound (62 mg, 78%) as a white solid: mp 265° C. (dec); Found C, 55.66; H, 6.28; N, 10.72%. C12H16Cl2N2 requires: C, 55.61; H, 6.22; N, 10.80%.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[N:36]1[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][NH2:43])[CH:37]=1>>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([S:17]([CH2:20][C:21]2[N:22]=[C:23]([C:27]3[CH:35]=[CH:34][C:30]([C:31]([NH:43][CH2:42][C:38]4[CH:37]=[N:36][CH:41]=[CH:40][CH:39]=4)=[O:32])=[CH:29][CH:28]=3)[O:24][C:25]=2[CH3:26])(=[O:19])=[O:18])=[CH:15][CH:16]=1)([CH3:9])([CH3:10])[CH3:8]
Reactant: Cc1oc(-c2ccc(C(=O)O)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: NCc1cccnc1
Agent: O=C(Cl)C(=O)Cl
Product: Cc1oc(-c2ccc(C(=O)NCc3cccnc3)cc2)nc1CS(=O)(=O)c1ccc(C(C)(C)C)cc1
Yield: 46.3 %

Procedure:
Method E. Reaction of oxalyl chloride (27 λL, 0.31 mmol) and benzoic acid 23 (85 mg, 0.21 mmol) with subsequent coupling to 3-pyridinylmethylamine (23 λL, 0.23 mmol) gave benzamide 24 (49 mg, 46%) as a white powder: mp (EtOAc) 177-180° C.; 1H NMR δ 9.20 (t, J=5.8Hz, 1 H, CONH), 8.57 (d, J=1.8Hz, 1 H, H-2′), 8.46 (dd, J=4.7, 1.5Hz, 1 H, H-6′), 7.98 (br d, J=8.5Hz, 2 H, H-2, H-6), 7.86 (br d, J=8.5Hz, 2 H, H-3, H-5), 7.73 (br dt, J=7.9, 1.9Hz, 1 H, H-4′), 7.70 (br dd, J=8.6, 1.9Hz, 2 H, H-2″, H-6″), 7.63 (br dd, J=8.6, 1.9Hz, 2 H, H-3″, H-5″), 7.36 (ddd, J=7.89, 4.7, 0.6Hz, 1 H, H-5′), 4.60 (s, 2 H, CH2SO2), 4.51 (d, J=5.8Hz, 2 H, CH2N), 2.14 (s, 3 H, CH3), 1.30 us, 9 H, C(CH3)31; 13C NMR δ 165.4, 157.8, 157.0, 149.8, 148.7, 148.0, 135.4, 135.3, 135.0, 134.8, 128.7, 128.1 (2), 127.9 (2), 125.9 (2), 125.3 (2), 123.3, 52.9, 40.4, 34.8, 30.6 (3), 9.5, one resonance not observed; MS m/z 504.5 (MH+, 100%). Anal. calcd for C28H29N3O4SCH3OH: C, 65.03; H, 6.21; N, 7.84. Found: C, 65.03; H, 5.94; N, 7.99%.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([O:11][CH:12]2[C:17](=O)[CH2:16][CH2:15][O:14][CH2:13]2)[NH:8][N:7]=1)=[O:5])[CH3:2].CS(O)(=O)=O>C(O)(=O)C.C1(C)C=CC=CC=1>[N:7]1[N:8]2[C:9]([O:11][C:12]3[CH2:13][O:14][CH2:15][CH2:16][C:17]=32)=[CH:10][C:6]=1[C:4]([O:3][CH2:1][CH3:2])=[O:5]
Reactant: CCOC(=O)c1cc(OC2COCCC2=O)[nH]n1
Agent: CS(=O)(=O)O
Solvent: CC(=O)O
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2oc3c(n2n1)CCOC3
Temperature: 25 °C
Yield: 50.8 %

Procedure:
A mixture of ethyl-5-[(4-oxotetrahydro-2H-pyran-3-yl)oxy]-1H-pyrazole-3-carboxylate (254 mg, 1 mmol) and methane sulfonic acid (192 mg) in 7 ml of acetic acid and toluene (50 ml) was refluxed for 18 hours using a Dean-Stark trap to remove water. The reaction mixture was allowed to cool to room temperature. The reaction mixture was filtered. The filtrate was concentrated to an oil. The residue was dissolved in ethyl acetate aqueous bicarbonate solution. The organic layer was washed with water and dried over MgSO4. After removal of the ethyl acetate, the residue was purified by silica gel chromatography eluting with ethyl acetate/hexane to give 120 mg (51%) of the desired product as white solid. Mp; 116-118° C.; Electrospray-MS m/z 237.0 (M+H)+
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([C:19](OCC)=[O:20])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12.O.O.O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Na+].[Na+]>O1CCCC1>[C:7]1([CH2:19][OH:20])[CH:8]=[N:9][N:10]2[CH:15]=[CH:14][C:13]3[O:16][CH2:17][CH2:18][C:12]=3[C:11]=12
Reactant: CCOC(=O)c1cnn2ccc3c(c12)CCO3
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: O
Solvent: C1CCOC1
Product: OCc1cnn2ccc3c(c12)CCO3
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 83.6 %

Procedure:
To a suspension of 80% lithium aluminum hydride (760 mg, 16.4 mmol) in tetrahydrofuran (40 mL) was added a solution of ethyl 8,9-dihydrofuro[3,2-c]pyrazolo[1,5-a]pyridine-1-carboxylate (950 mg, 4.09 mmol) in tetrahydrofuran (40 mL) under ice-cooling, and the mixture was stirred at room temperature for 30 min. Sodium sulfate decahydrate (10 g) was added under ice-cooling, and the insoluble material was filtered off. The filtrate was concentrated under reduced pressure, and the residue was washed with diisopropyl ether to give the title compound (650 mg, yield 83%).
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[NH2:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33]([NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[O:34])=[CH:31][C:30]=1[F:45]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:13])[F:14])[CH2:9][CH2:10][C:4]=2[C:3]=1[NH:27][CH2:28][C:29]1[CH:44]=[CH:43][C:32]([C:33](=[O:34])[NH:35][CH:36]2[CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]2)=[CH:31][C:30]=1[F:45]
Reactant: NCc1ccc(C(=O)NC2CCCCCC2)cc1F
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Solvent: Cc1ccccc1
Product: O=C(NC1CCCCCC1)c1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)C(F)(F)F)CC3)c(F)c1
Yield: 70.1 %

Procedure:
Use a method similar to the General Procedure 5-2 to couple 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (640 mg, 1.5 mmol) with 4-aminomethyl-N-cycloheptyl-3-fluoro-benzamide (795 mg, 3 mmol) in anhydrous toluene (20 mL). Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (19:1 to 3:2 gradient) to obtain 7-chloro-6-(4-cycloheptylcarbamoyl-2-fluoro-benzylamino)-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (568 mg, 70%). MS (ES+) m/z: 540.2 (M+H)+.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8](Cl)=[O:9]>CC(C)=O>[Cl:5][C:6]1[N:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([N:3]=[C:2]=[S:1])=[O:9]
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: N#C[S-]
Agent: [NH4+]
Solvent: CC(C)=O
Product: O=C(N=C=S)c1cccnc1Cl
Reaction time: 0.08 h

Procedure:
A mixture of 1.512 g (9.5 mmol) of 2-chloronicotinic acid, 15 ml of thionyl chloride and two droplets of DMF was heated under reflux for 2 hours. The reaction mixture was allowed to cool, and then concentrated under reduced pressure. The resulting residue was then dissolved in 10 ml of acetone to obtain an acetone solution of 2-chloronicotinoyl chloride. 804 mg of ammonium thiocyanate was then dissolved in 15 ml of acetone. To the solution thus obtained was then added dropwise the acetone solution of 2-chloronicotinoyl chloride with stirring in 5 minutes. The reaction mixture was then stirred over a 40° C. oil bath for 5 minutes. The resulting insoluble matters were then removed by filtration to obtain an acetone solution of 2-chloronicotinoyl isothiocyanate. To the solution thus obtained was then added dropwise a mixture of 1.685 g of 5-(N-ethylamino)-1-methyl-1H-benzimidazole and 10 ml of acetone with stirring in 5 minutes. The reaction mixture was further stirred for 6 hours, and then poured into about 1,000 ml of ice-water. The resulting crystal was collected by filtration, washed with water, and then dried under reduced pressure. The compound thus obtained was suspended in 30 ml of toluene, and then heated under reflux for 2 hours. After allowed to cool, the reaction mixture was collected by filtration, and then recrystallized from a mixture of ethanol and ether to obtain 1.171 g of 2-[N-ethyl-N-(1H-1-methylbenzimidazol-5-yl)amino]-4H-pyrido[3,2-e]-1,3-thiazin-4-one hydrochloride.
Reaction SMILES: Cl.[F:2][C:3]([F:25])([F:24])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:15]=[N:14][C:13]([C:16]3[CH:21]=[CH:20][C:19]([CH2:22][NH2:23])=[CH:18][CH:17]=3)=[N:12]2)=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[N:42]=[C:43]=[S:44])([CH3:35])[CH3:34]>ClCCl>[CH:33]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[NH:42][C:43]([NH:23][CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:13]2[N:14]=[CH:15][N:11]([C:8]3[CH:7]=[CH:6][C:5]([O:4][C:3]([F:2])([F:24])[F:25])=[CH:10][CH:9]=3)[N:12]=2)=[CH:17][CH:18]=1)=[S:44])([CH3:35])[CH3:34]
Reactant: CC(C)c1ccccc1N=C=S
Reactant: NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)c1ccccc1NC(=S)NCc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
In a 100 mL flask, to a solution of (4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenyl) methanamine hydrochloride (0.200 g, 0.598 mmol) in dichloromethane (5 mL) was added triethylamine (0.0720 g, 0.718 mmol) and 1-isopropyl-2-isothiocyanatobenzene (0.106 g, 0.598 mmol) in dichloromethane (5 mL) and the reaction mixture was stirred overnight at room temperature. The reaction mixture was concentrated and the residue purified by flash column chromatography eluting with 10-100% ethyl acetate/B, where B=1:1 dichloromethane/hexanes as eluent to give the title compound as a white solid (0.145 g, 48%).
Reaction SMILES: [OH-].[Na+].[O:3]=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.O[C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][C:17]=1[N:23]1[N+:27]([O-])=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1.S(=O)(=O)(O)O>C1C2C(=O)C3C(=CC=CC=3)C=2C=CC=1.O.CO>[OH:3][C:18]1[C:19]([CH3:22])=[CH:20][CH:21]=[CH:16][C:17]=1[N:23]1[N:27]=[C:26]2[CH:29]=[CH:30][CH:31]=[CH:32][C:25]2=[N:24]1
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: Cc1ccc(O)c(-n2nc3ccccc3[n+]2[O-])c1
Agent: O=C1c2ccccc2-c2ccccc21
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1cccc(-n2nc3ccccc3n2)c1O
Yield: 92.8 %

Procedure:
To the wet product 12 g (~ 0.4 mol) thus obtained, is added methanol (60 ml), water (30 ml), 97% sodium hydroxide (13.0 g) and 9-fluorenone (0.5 g), and glucose (5.5 g) (0.3 mol) is further added to the mixture over an hour while stirring at 50° to 55° C. The mixture is reacted while stirring at 75° C. (boiling point) for 5 hours. As a result, the N-oxide disappears. The reaction liquor is neutralized with 62% sulfuric acid (19.8 g) to pH 8 to precipitate a crystal. The precipitated crystal is separated by filtration, and the separated crystal is fully washed with water and further with methanol. The washed crystal is then dried, thus obtaining 9.4 g of 2-(2'-hydroxy-methylphenyl) benzotriazole having a melting point of 128 to 130° C. at the yield of 92.8%. One can see that the reduction with aromatic ketones takes over 9 hours to complete. This reduction also required the use of two catalysts and a greater amount of total catalysts.
Reaction SMILES: [CH:1]1([N:4]([CH2:37][C:38]2[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=2)[C:5](=[O:36])[CH:6]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]3[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=3[Cl:35])=[CH:19][CH:18]=2)[CH2:7][NH:8]C(=O)OC(C)(C)C)[CH2:3][CH2:2]1.Cl>C(Cl)Cl>[NH2:8][CH2:7][CH:6]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([O:23][CH2:24][CH2:25][O:26][C:27]2[C:32]([Cl:33])=[CH:31][C:30]([CH3:34])=[CH:29][C:28]=2[Cl:35])=[CH:21][CH:22]=1)[C:5]([N:4]([CH:1]1[CH2:2][CH2:3]1)[CH2:37][C:38]1[CH:39]=[CH:40][N:41]=[CH:42][CH:43]=1)=[O:36]
Reactant: Cc1cc(Cl)c(OCCOc2ccc(CC(CNC(=O)OC(C)(C)C)C(=O)N(Cc3ccncc3)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc(CC(CN)C(=O)N(Cc3ccncc3)C3CC3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a CH2Cl2 solution (0.09 M) of tert-butyl (3-[cyclopropyl(pyridin-4-ylmethyl)amino]-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxopropyl)carbamate from the previous step (I eq.) was added HCl (4.0 M dioxane solution, 46 eq.). The resulting solution was stirred at RT for 5 h. The reaction was quenched with 2.0 M NH3 in MeOH and concentrated in vacuo. The resulting residue was directly loaded onto a SiO2 column packed with 90:9:1 (v/v) CH2Cl2:MeOH:conc. NH4OH. Elution with the same solvent system furnished the title compound. MS (ESI+): 527.9.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH:10]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:11](OC)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CC(C[AlH]CC(C)C)C>ClCCl>[O:12]=[CH:11][CH:10]([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[CH2:9][NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)C(CNC(=O)OC(C)(C)C)c1ccccc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(C=O)c1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-[(tert-butoxycarbonyl)amino]-2-phenylpropanoate from Step A (2.1 g, 7.52 mmol) in anhydrous dichloromethane (75 mL) was cooled to −78° C. under nitrogen and DIBAL-H (15 mL, 15 mmol, 1.0 M in hexanes) was added to the solution dropwise over 45 minutes. This solution was then stirred at −78° C. for 1 h. The reaction was then quenched by the addition of a saturated aqueous solution of Rochel's salt (75 mL) and the biphasic solution was stirred at ambient temperature for 30 minutes. The layers were separated and the aqueous layer was extracted twice with DCM. The combined organics were dried over sodium sulfate, filtered, and concentrated in vacuo to provide a residue. The residue was applied to a silica gel column for purification, eluting with a gradient of 1-3% methanol in DCM to yield the title compound. MS: m/z=250 (M+1).