Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([OH:9])=O)[CH:5]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.Cl.[NH2:37][CH2:38][C:39]([C:41]1[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=1)=[O:40].C(N(C(C)C)CC)(C)C>CN(C)C=O.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:12]=[CH:11][CH:10]=[C:6]([C:7]([NH:37][CH2:38][C:39]([C:41]2[CH:46]=[CH:45][C:44]([O:47][CH3:48])=[CH:43][CH:42]=2)=[O:40])=[O:9])[CH:5]=1
Reactant: COC(=O)c1cccc(C(=O)O)c1
Reactant: COc1ccc(C(=O)CN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C(=O)NCC(=O)c2ccc(OC)cc2)c1
Reaction time: 8 h
Yield: 194.4 %

Procedure:
1.8 g (5.5 mmol) of isophthalic acid monomethyl ester from Preparation 1, 3.5 g (18.5 mmol) of EDAC.HCl, 2.5 g (18.5 mmol) of HOBt, and 3.1 g (15.4 mmol) of 2-amino-1-(4-methoxy-phenyl)-ethanone hydrochloride were dissolved in 20 mL of dimethylformamide. 1.9 g (15.4 mmol) of di-isopropyl ethylamine was then added. Stirring was continued overnight at room temperature. Water (60 ml) was added, and the product was filtered, washed with water. The resulting solid was triturated in hot methanol, filtered and dried in a vacuum oven overnight at 70° C. to provide 3.5 g (69%) desired product. MS: m/z (APCI, AP+) 328 [M−]+ NMR: DMSO 1H δ (ppm) 3.84 (3H, s); 3.88 (3H, s); 4.73 (2H, d, J=5.6 Hz); 7.04–7.08 (2H m); 7.63–7.66 (1H, t, J=7.8 Hz); 7.99–8.027 (2H, m); 8.097–8.16 (2H, m); 8.47–8.48 (1H, m); 9.00–9.03 (1H, t, J=5.8 Hz).
Reaction SMILES: [CH3:1][C:2]([C:5]1[CH:6]=[C:7]([CH:16]=[CH:17][C:18]=1[OH:19])[C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:9])([CH3:4])[CH3:3].Cl.[CH3:21][NH:22][CH3:23].[OH-].[Na+].[CH2:26]=O>C(O)C>[CH3:21][N:22]([CH2:26][C:17]1[CH:16]=[C:7]([CH:6]=[C:5]([C:2]([CH3:1])([CH3:3])[CH3:4])[C:18]=1[OH:19])[C:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)=[O:9])[CH3:23]
Reactant: CC(C)(C)c1cc(C(=O)c2ccccc2)ccc1O
Reactant: CNC
Reactant: C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CN(C)Cc1cc(C(=O)c2ccccc2)cc(C(C)(C)C)c1O
Yield: 68.6 %

Procedure:
3-(1,1-Dimethylethyl)-4-hydroxybenzophenone (2.5 g), 1.71 g of dimethylamine hydrochloride, 0.78 g of sodium hydroxide, and 0.68 g of paraformaldehyde were dissolved in 30 ml of ethanol and the mixture was heated to reflux for 16 hours. The ethanol was then evaporate. Water was added to the residue and the crystals which separated out were filtered and recrystallized from 90% ethanol to give 2.1 g of the desire product, m.p. 129° C.
Reaction SMILES: [C:1]1([S:7]([O-:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Na+].[Br:11]Br>>[C:1]1([S:7]([Br:11])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrBr
Reactant: O=S([O-])c1ccccc1
Agent: [Na+]
Product: O=S(=O)(Br)c1ccccc1

Procedure:
Benzenesulfonyl bromide was synthesized with 1316.0 g of the mother liquid containing sodium benzenesulfinate by procedures similar to those of the fourth step and the fifth step of Example 1 except that bromine was used instead of chlorine in the fifth step. Thus, 36.0 g of benzenesulfonyl bromide was yielded. Gas chromatographic analysis revealed that the concentration of benzenesulfonyl bromide in the organic layer was 81.3% (weight; 29.27 g, 0.133 mole), and the yield was 94.4%.
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([OH:11])=[O:10].S(=O)(=O)(O)O.[CH3:17]O>>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][C:9]([O:11][CH3:17])=[O:10]
Reactant: O=C(O)CCCCCCCBr
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)CCCCCCCBr
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Methanol (4.7 L), 8-bromooctanoic acid (0.912 kg) and sulfuric acid (0.912 L) were charged into a suitable reactor and the mixture was heated at reflux temperature for 5 hours and was then stirred at ambient temperature overnight. The solvent was removed at reduced (3 mm Hg) pressure and the oily residue was dissolved in ether (4 L). The solution was washed with water (3×2 L), saturated NaHCO3 solution (1 L) and brine (1 L). The ether portion was dried (MgSO4) and filtered to remove dessicant. Evaporation of solvent followed by distillation of the crude oil gave methyl 8-bromooctanoate, b.p. 73°-76°/0.05 mm Hg, nD23 1.4614.
Reaction SMILES: [CH3:1][CH:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=2)=[CH:7][CH:6]=1)[CH3:3].[H-].[Na+].Cl[CH2:21][CH2:22][S:23](Cl)(=[O:25])=[O:24].O>C1COCC1.CCCCCC>[CH3:3][CH:2]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[C:12]3=[N:17][S:23](=[O:25])(=[O:24])[CH2:22][CH2:21][N:13]3[CH:14]=[CH:15][CH:16]=2)=[CH:9][CH:10]=1)[CH3:1]
Reactant: O=S(=O)(Cl)CCCl
Reactant: CC(C)Oc1ccc(-c2cccnc2N)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: O
Product: CC(C)Oc1ccc(C2=CC=CN3CCS(=O)(=O)N=C23)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 73.7 %

Procedure:
A mixture of 3-[4-(1-methylethoxy)phenyl]pyridin-2-amine (350 mg) in dehydrated THF (5 mL) was added to a mixture of sodium hydride (60%, 307 mg) and 2-chloroethanesulfonyl chloride (750 mg) in dehydrated THF (5 mL) under ice-cooling. The reaction mixture was stirred at room temperature overnight, and water and hexane were added. The resulting precipitate was collected by filtration, and washed with water and diisopropyl ether to give the title compound (360 mg) as a white solid. The obtained solid was crystallized from THF, acetonitrile and diisopropyl ether to give a white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH2:12])[CH3:8])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.FC1C([O:30][C:31](=O)[C:32]2[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=2[NH:40][C:41]2[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=2[CH3:48])=C(F)C(F)=C(F)C=1F>CN(C)C=O>[C:1]([O:5][C:6](=[O:13])[N:7]([CH2:9][CH2:10][O:11][NH:12][C:31]([C:32]1[CH:37]=[CH:36][C:35]([F:38])=[C:34]([F:39])[C:33]=1[NH:40][C:41]1[CH:46]=[CH:45][C:44]([I:47])=[CH:43][C:42]=1[CH3:48])=[O:30])[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(I)ccc1Nc1c(C(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc(F)c1F
Reactant: CN(CCON)C(=O)OC(C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(I)ccc1Nc1c(C(=O)NOCCN(C)C(=O)OC(C)(C)C)ccc(F)c1F
Temperature: 25 °C
Reaction time: 5 h
Yield: 62.6 %

Procedure:
To a solution of (2-aminooxy-ethyl)-methyl-carbamic acid tert-butyl ester (0.63 g, 3.31 mmol) and diisopropylethylamine (0.6 mL, 3.44 mmol) in dimethylformamide (10 mL) was added 3,4-Difluoro-2-(4-iodo-2-methyl-phenylamino)-benzoic acid pentafluorophenyl ester (1.66 g, 2.99 mmol). The resultant reaction mixture was stirred 5 h at ambient temperature and concentrated under reduced pressure. The residue was diluted with ether (100 mL), washed with water (2×25 mL) and brine (2×25 mL), dried over magnesium sulfate and concentrated in vacuo. The residue was purified by silica gel chromatography. Elution with dichloromethane afforded [2-({1-[3,4-difluoro-2-(4-iodo-2-methyl-phenylamino)-phenyl]-methanoyl}-aminooxy)-ethyl]-methyl-carbamic acid tert-butyl ester (1.05 g, 62%) as a white foam: 1 H NMR (400 MHz, DMSO-d6) δ 11.85 and 11.80 (br s, 1 H), 8.49 (br s, 1 H), 7.50 (s, 1 H), 7.39 (m, 1H), 7.35 (d, J=8.3 Hz, 1 H), 7.14 (m, 1 H), 6.46 (dd, J=7.8, 5.9 Hz, 1 H), 3.85 (br s, 2 H), 3.35 (br s, 2 H), 2.79 (br s, 3 H), 2.21 (s, 3 H), 1.36 and 1.33 (s, 9 H); 19F NMR (376 MHz, DMSO-d6) δ −132.9, −143.3 (d, J=17.7 Hz); MS (APCI+)=562.1.
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]([C:28]([O:30]CC)=O)[C:23]([O:25]CC)=O)=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].[NH2:34][NH2:35]>C(O)C>[CH:1]([N:4]1[C:8]([C:9]2[N:10]=[C:11]3[C:17]4[CH:18]=[CH:19][C:20]([CH:22]5[C:28](=[O:30])[NH:35][NH:34][C:23]5=[O:25])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13][N:12]3[CH:33]=2)=[N:7][CH:6]=[N:5]1)([CH3:2])[CH3:3]
Reactant: NN
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2c(c1)OCCn1cc(-c3ncnn3C(C)C)nc1-2
Solvent: CCO
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1ccc(C3C(=O)NNC3=O)cc1OCC2
Temperature: 75 °C

Procedure:
A mixture of 181 mg (0.40 mmol) of diethyl 2-(2-(1-isopropyl-1H-1,2,4-triazol-5-yl)-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepin-9-yl)malonate and 0.314 mL (10.0 mmol) of hydrazine in 4.0 ml of Ethanol was heated at 75° C. for 18 hours. The mixture was concentrated, the residue triturated with acetic acid. A precipitate was filtered off, washed with acetic acid, ethyl ether and recrystallized from ethyl ether/ethanol mixture to give 360. Yield 59 mg (37.5%). M/z 394.1, calc. 393.15. 1H NMR (400 MHz, DMSO) δ 10.20 (s, 2H), 8.29 (d, J=8.6, 1H), 7.89 (d, J=12.9, 2H), 7.70 (d, J=8.5, 1H), 7.63 (s, 1H), 5.93 (dt, J=13.1, 6.7, 1H), 4.48 (d, J=7.2, 4H), 1.49 (d, J=6.6, 6H)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][CH3:16])[CH:13]=2)[NH:8][CH:7]=1.[NH:17]1[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=2)[C:19]([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:18]1.C(N1CCC(=O)CC1)(OC(C)(C)C)=O>>[ClH:1].[CH3:16][O:15][C:12]1[CH:13]=[C:14]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:5][CH2:4][CH2:3][CH2:2][N:29]1[CH2:30][CH2:31][CH:26]([C:19]2[C:20]3[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=3)[NH:17][CH:18]=2)[CH2:27][CH2:28]1
Reactant: COc1ccc2[nH]cc(CCCCCl)c2c1
Reactant: c1ccc2c(C3CCNCC3)c[nH]c2c1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Product: COc1ccc2[nH]cc(CCCCN3CCC(c4c[nH]c5ccccc45)CC3)c2c1
Product: Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.2 g of 3-(4-chlorobutyl)-5-methoxyindole [obtainable by reaction of 5-methoxyindole with 4-chlorobutyryl chloride to give 3-(4-chlorobutyryl)-5-methoxyindole and subsequent reduction with diborane] and 1.0 g of 4-(indol-3-yl)piperidine [obtainable by reaction of N-BOC-4-piperidone with indole, subsequent dehydration and hydrogenation of the resulting double bond, and removal of the protective group] are dissolved in 200 ml of acetonitrile and the mixture is stirred at room temperature for 8 hours. Working-up in a conventional manner gives 3-[1-(4-(5-methoxyindol-3-yl)-butyl)-4-piperidyl]indole, hydrochloride, m.p. 138°-141° (dec.).
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[N:9]([O-])=O.[Na+].[CH3:13][C:14]1([CH3:23])[CH2:19][CH:18]([OH:20])[CH2:17][C:16]([CH3:22])([CH3:21])[NH:15]1.[OH-].[Na+]>C1COCC1.Cl.O>[Br:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[N:4]=[N:9][N:15]1[C:16]([CH3:22])([CH3:21])[CH2:17][CH:18]([OH:20])[CH2:19][C:14]1([CH3:23])[CH3:13]
Reactant: O=N[O-]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: Nc1ccccc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CC(O)CC(C)(C)N1N=Nc1ccccc1Br
Reaction time: 3 h

Procedure:
50 g crushed ice are added to a solution of 2-bromoaniline in 4 ml THF and 4 ml aqueous HCl (32% w/w). The yellow suspension is diazotized at −5° C. by treatment with a solution of 1.1 g sodium nitrite in 10 ml water. After 3 h, a solution of 2.76 g 2,2,6,6-tetramethyl-4-hydroxypiperidine in 1.5 ml aqueous HCl (32% w/w) and 1 ml THF are added dropwise to the thick yellow suspension at −3° C. Addition of water (ca. 20 ml) is necessary to keep the mixture well stirrable. The reaction mixture is then neutralized by adding dropwise 8.8 ml of aqueous sodium hydroxide (30% w/w) and 4 ml THF between 0 and 2° C. The brownish mixture is extracted with ethyl acetate. The organic phase is separated, evaporated and chromatographed on silica gel with hexane-ethylacetate (3:1), yielding 1.11 g of 1-(2-bromophenyl-diazenyl)-2,2,6,6-tetramethyl-piperidin-4-ol as a red-brown solid, m.p. 81° C.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[C:11](=O)[CH2:10][CH2:9]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:33].[Na+]>CO>[F:1][C:2]([F:26])([F:25])[CH:3]([C:16]1[CH:21]=[C:20]([Cl:22])[C:19]([Cl:23])=[C:18]([Cl:24])[CH:17]=1)/[CH:4]=[CH:5]/[C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[CH:11]([NH2:33])[CH2:10][CH2:9]2
Reactant: O=C1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: NC1CCc2cc(/C=C/C(c3cc(Cl)c(Cl)c(Cl)c3)C(F)(F)F)ccc21
Yield: 49.7 %

Procedure:
To a stirred solution of (E)-5-(4,4,4-trifluoro-3-(3,4,5-trichlorophenyl)but-1-enyl)-2,3-dihydro-1H-inden-1-one (1 g, 2.39 mmol) in CH3OH (10 mL) were added ammonium acetate (1.84 g, 23.9 mmol) and sodium cyanoborohydride (NaCNBH3; 0.44 g, 7.17 mmol) and the reaction mixture was heated at reflux for 16 h. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with water and extracted with EtOAc. The combined organic extracts were washed with water and saturated aqueous sodium bicarbonate (satd aq NaHCO3) solution, dried over anhydrous Na2SO4, and concentrated under reduced pressure to afford the title compound as a liquid (500 mg, crude): 1H NMR (400 MHz, DMSO-d6) δ 7.85 (s, 2H), 7.40 (s, 1H), 7.30 (s, 2H), 6.71 (s, 2H), 4.78 (m, 1H), 4.2 (m, 1H), 2.80 (m, 1H), 2.73 (m, 1H), 1.60 (m, 2H); ESIMS m/z 419.02 ([M+H]+); IR (thin film) 2924, 1552, 1112, 807 cm−1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[NH:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=1.[H-].[Na+].[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Br>CN(C=O)C.O>[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22][N:11]1[C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[N:8]=[C:7]1[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: Clc1ccc(CBr)cc1Cl
Reactant: c1ccc(-c2nc3ccccc3[nH]2)nc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(Cn2c(-c3ccccn3)nc3ccccc32)cc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 36.7 %

Procedure:
2-Pyridin-2-yl-lH-benzoimidazole (1.95 g, 0.01 mol) was dissolved in DMF (50 mL) under an atmosphere of nitrogen. Sodium hydride (60% dispersion in oil, 0.48 g, 0.012 mol) was then added. The reaction mixture was stirred at ambient temperature for 0.5 hour. 3,4-Dichlorobenzyl bromide (2.4 g, 0.01 mol) was then added. The mixture was stirred at 80° C. for a period of 4 hours. The mixture was cooled and diluted with water. The mixture was then extracted with ethyl acetate. The organic extract was washed with water twice then evaporated. The residue was triturated with a small amount of ethyl acetate/hexane. The solid was collected and crystallized from ethanolic hydrogen chloride. The solid was collected to give the title compound (1.3 g, 36.7% yield) as a mono-hydrochloride, light brown solid, m.p. 227°-229° C. Anal. Calcd. for Cl9Hl3Cl2N3-HCl: C, 58.41; H, 3.61; N, 10.76.. Found: C, 58.21; H, 3.54; N, 10.80. Mass spectrum (+FAB; [M+H]+) 354/356/358. 1H-NMR (DMSO-d6 ; 400 MHz) 8 8.78 (d, 1H), 8.52 (d, 1H), 8.15 (t, 1H), 7.9 (d, 1H), 7.77 (d, 1H), 7.65 (d, 2H), 7.54 (d, 1H), 7.48-7.52 (m, 2H), 7.23 (d, 1H), and 6.22 ppm (s, 2H).
Reaction SMILES: [Mg].C(Br)Br.Cl[CH:6]1[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]1.[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23](=[O:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1>C1COCC1>[Br:13][C:14]1[CH:15]=[CH:16][C:17]2[C:23]([CH:6]3[CH2:11][CH2:10][N:9]([CH3:12])[CH2:8][CH2:7]3)([OH:24])[C:22]3[CH:25]=[CH:26][CH:27]=[CH:28][C:21]=3[CH2:20][O:19][C:18]=2[CH:29]=1
Reactant: CN1CCC(Cl)CC1
Reactant: O=C1c2ccccc2COc2cc(Br)ccc21
Agent: [Mg]
Solvent: C1CCOC1
Solvent: BrCBr
Product: CN1CCC(C2(O)c3ccccc3COc3cc(Br)ccc32)CC1

Procedure:
Magnesium turnings (3.42 g, 143 mmol) were suspended in 15 mL of dry THF under nitrogen. To this was added CH2Br2 (1.25 mL, 14.5 mmol) and a vigorous reaction was observed. The reaction was heated to reflux, and 4-chloro-1-methyl-piperidine (21 mL, 128 mmol) was added. The reaction was refluxed for 1 h. The reaction was allowed to cool, and the supernatant was transferred via cannula to a stirring solution of compound 2c (8 g, 128 mmol) in THF at room temperature. The slurry was rinsed with 2×20 mL THF and the supernatant was transferred. At that time, all of the starting ketone had been consumed. To the reaction was added saturated sodium bicarbonate, and the mixture was extracted with ethyl acetate. The combined organics were dried over magnesium sulfate, filtered, and concentrated. The crude product Compound 1d was used without further purification. MS m/z (MH+) 388.14.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[N:16]=[C:10]3[CH:11]=[CH:12][C:13]([NH2:15])=[CH:14][N:9]3[N:8]=2)[CH:2]=1.[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](O)=[O:28])=[O:21])[CH3:18].CCCP(=O)=O.C(OCC)(=O)C.C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:17]([O:19][C:20]([C:22]1[CH:23]=[N:24][N:25]([CH3:30])[C:26]=1[C:27](=[O:28])[NH:15][C:13]1[CH:12]=[CH:11][C:10]2[N:9]([N:8]=[C:7]([C:3]3[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=3)[N:16]=2)[CH:14]=1)=[O:21])[CH3:18]
Reactant: Nc1ccc2nc(-c3cccnc3)nn2c1
Reactant: CCOC(=O)c1cnn(C)c1C(=O)O
Agent: CCCP(=O)=O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cnn(C)c1C(=O)Nc1ccc2nc(-c3cccnc3)nn2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
A mixture of 2-(pyridin-3-yl)-[1,2,4]triazolo[1,5-a]pyridin-6-ylamine (480 mg, 2.27 mmol), 4-(ethoxycarbonyl)-1-methyl-1H-pyrazole-5-carboxylic acid (495 mg, 2.5 mmol), propylphosphonic anhydride in ethyl acetate 50% (3.62 g, 3.35 ml, 5.68 mmol) and N,N-diisopropylethylamine (1.17 g, 1.55 ml, 9.09 mmol) in tetrahydrofuran (10 ml) was stirred for 18 hours at 70° C. The solvent was evaporated under reduced pressure, the residue was triturated with saturated aqueous sodium hydrogencarbonate. The precipitated solid was filtered off, washed with water and dried in vacuo, affording 1-methyl-5-(2-pyridin-3-yl-[1,2,4]triazolo[1,5-a]pyridin-6-ylcarbamoyl)-1H-pyrazole-4-carboxylic acid ethyl ester (825 mg, 93%) as light brown solid. Mp.: 217° C. MS: m/z=392.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][S:5][C:6]=1[CH:7]=[O:8].[CH3:9]C(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-].[H-].[Na+]>CC(O)C.C(COC)OC.IC>[CH3:9][O:8][CH2:7][C:6]1[S:5][CH:4]=[N:3][C:2]=1[CH3:1]
Reactant: CC(C)[O-]
Reactant: Cc1ncsc1C=O
Agent: [Al+3]
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CC(C)O
Solvent: COCCOC
Product: COCc1scnc1C

Procedure:
4-Methyl-5-thiazolecarbaldehyde (J. Amer. Chem. Soc., 1982, 104, 4934-4943) was reduced using aluminium isopropoxide in 2-propanol. The resulting alcohol was treated with sodium hydride in dimethoxyethane and iodomethane was added. Distillation gave the title compound.
Reaction SMILES: [Si:1]([O:8]S(C(F)(F)F)(=O)=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH2:23]([C:26]1([CH:30](O)[CH2:31][C:32]#[CH:33])[CH2:29][CH2:28][CH2:27]1)[CH2:24][CH3:25].C([O-])(O)=O.[Na+]>C(Cl)Cl>[C:4]([Si:1]([CH3:3])([CH3:2])[O:8][CH:30]([C:26]1([CH2:23][CH2:24][CH3:25])[CH2:27][CH2:28][CH2:29]1)[CH2:31][C:32]#[CH:33])([CH3:7])([CH3:6])[CH3:5]
Reactant: C#CCC(O)C1(CCC)CCC1
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCC(O[Si](C)(C)C(C)(C)C)C1(CCC)CCC1
Reaction time: 1 h
Yield: 153.8 %

Procedure:
t-Butyldimethylsilyltrifluoromethanesulfonate (1.8 mL, 7.88 mmol) was added to a solution of triethylamine (2.2 mL, 15.8 mmol) and alcohol 4 (650 mg, 3.94 mmol) in CH2Cl2 (5.0 mL) at 0° C. The reaction was stirred for 1 h and then saturated aqueous NaHCO3 was added. The mixture was extracted with CH2Cl2. The organic portion was washed with brine, dried (Na2SO4), filtered and concentrated in vacuo. FCC (silica gel, 100% hexane) gave 1.7 g (100%) of the silyl ether 5 as a clear, colorless oil.
Reaction SMILES: [H-].[Na+].[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][OH:28].Br[CH2:30][C:31]([O:33][CH3:34])=[O:32].[C:35]1(C)C=CC=CC=1>>[CH2:3]1[CH:8]2[C:9]3[CH:21]=[CH:20][CH:19]=[CH:18][C:10]=3[CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[N:7]2[CH2:6][CH2:5][N:4]1[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][O:28][CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: COC(=O)CBr
Reactant: OCCCCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Reactant: Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Product: CCOC(=O)COCCCCCCN1CCN2c3ccccc3Cc3ccccc3C2C1
Temperature: 40 °C
Reaction time: 2 h
Yield: 18 %

Procedure:
060 g of a 55% w/w dispersion of sodium hydride in mineral oil was added to a solution of 0.40 g of 6-(1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2 -a]azepin-2-yl)hexanol (prepared as described in Example 18) dissolved in 10 m of toluene, under an atmosphere of nitrogen. The mixture was stirred at 40° C. for 2 hours and then cooled with ice, after which 0.229 g of methyl bromoacetate were added, and the mixture was stirred at 40° C. for a further 4 hours. At the end of this time, the reaction mixture was filtered, and the solvent was removed from the filtrate by evaporation under reduced pressure. The residue was subjected column chromatography through silica gel, using a 1:1 by volume mixture of ethyl acetate and hexane as the eluent, to afford 90 mg (yield 18%) of the title compound as an oil.
Reaction SMILES: ClCCl.C(N(CC)CC)C.[NH2:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]1[CH2:27][CH2:26][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[CH2:24][CH2:23]1)[C:17](=[O:40])[CH2:16][CH2:15]2.[C:41](OC(=O)C)(=[O:43])[CH3:42]>O>[C:41]([NH:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[N:18]([CH:22]1[CH2:23][CH2:24][N:25]([C:28](=[O:39])[C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=3[O:37][CH3:38])[CH2:26][CH2:27]1)[C:17](=[O:40])[CH2:16][CH2:15]2)(=[O:43])[CH3:42]
Reactant: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc(N)ccc43)CC2)c(OC)c1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)N2CCC(N3C(=O)CCc4cc(NC(C)=O)ccc43)CC2)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dichloromethane (10 ml) and triethylamine (0.15 ml) are added to 6-amino-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.3 g). Acetic anhydride (0.2 ml) is added thereto and the mixture is stirred at room temperature for 1 hour. Water is added to the reaction mixture and extracted with dichloromethane. After concentration, the residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) and further recrystallized from ethanol to give 6-acetylamino-1-[1-(2,4-dimethoxybenzoyl)-4-piperidinyl]-3,4-dihydrocarbostyril (0.25 g) as white powder, m.p. 271°-272° C.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[N:5][CH:6]=[CH:7][CH:8]=1)=O.[CH3:9][Si:10]([CH3:18])([CH3:17])[CH2:11][CH2:12][S:13]([NH2:16])(=[O:15])=[O:14].C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.B(F)(F)F.CCOCC>[N:5]1[CH:6]=[CH:7][CH:8]=[C:3]([CH:1]=[N:16][S:13]([CH2:12][CH2:11][Si:10]([CH3:18])([CH3:17])[CH3:9])(=[O:15])=[O:14])[CH:4]=1
Reactant: O=Cc1cccnc1
Reactant: C[Si](C)(C)CCS(N)(=O)=O
Agent: FB(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)CCS(=O)(=O)N=Cc1cccnc1
Yield: 102.2 %

Procedure:
To a solution of 3-formylpyridine (0.228 mL, 2.42 mmol) and 2-(trimethylsilyl)ethanesulfonamide (0.438 g, 2.42 mmol) in toluene (30 mL) was added boron trifluoride etherate (0.02 mL, 0.15 mmol) under Ar. The mixture was heated at reflux for 20 hours using a Dean-Stark trap. After cooling, 10% aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The combined organic extracts were washed with brine, dried (Na2SO4), filtered and concentrated to dryness to under reduced pressure obtain crude 2-trimethylsilyl-ethanesulfonic acid pyridin-3-ylmethyleneamide (669 mg), which was used directly in the next step.