Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([C:13]#N)=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCCCC1.[H-].C([NH2+]CC(C)C)C(C)C.C1C[O:41]CC1>>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[O:41])=[C:11]([NH:17][CH2:18][C@@H:19]([OH:21])[CH3:20])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1CCOC1
Reactant: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C#N
Agent: CC(C)C[NH2+]CC(C)C
Agent: [H-]
Solvent: C1CCCCC1
Product: C[C@H](O)CNc1cc(OCc2ccccc2)ccc1C=O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of the product of Step B (19.3 g, 68.3 mmol) in a mixture of anhydrous cyclohexane and THF (200 mL, 40 mL) at 0° C. under nitrogen was added diisobutylammonium hydride (1 M solution in hexane, 239 mL, 239 mmol) over 30 min. This mixture was stirred 18 h at ambient temperature, additional diisobutylammonium hydride (40 mL, 40 mmol) was added, and the mixture was stirred an additional 24 h. The reaction mixture was cooled on an ice bath and the reaction was quenched by the addition of MeOH (exothermic) and 2 N HCl to maintain a pH of 1. The mixture was extracted with EtOAc (3×300 mL) and the extracts were dried and concentrated to a brown oil (18.5 g). The crude oil was triturated with EtOAc/hexane, and filtered to give an oil (16.1 g, 83% crude yield). A small portion of this material was purified by chromatography (silica, 20% to 50% EtOAc/hexane) to afford a solid; mp 68-69° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N+:9]([O-:11])=[O:10].Cl[S:13]([OH:16])(=[O:15])=[O:14].[C:17]1(O)[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(N(CC)CC)C>CC(C)=O.O>[Cl:1][C:2]1[C:3]([N+:9]([O-:11])=[O:10])=[C:4]([Cl:8])[CH:5]=[CH:6][C:7]=1[S:13]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)(=[O:15])=[O:14]
Reactant: Oc1ccccc1
Reactant: O=[N+]([O-])c1c(Cl)cccc1Cl
Reactant: O=S(=O)(O)Cl
Solvent: CC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=[N+]([O-])c1c(Cl)ccc(S(=O)(=O)Oc2ccccc2)c1Cl
Reaction time: 1 h

Procedure:
2,6-Dichloronitrobenzene was stirred for 7 hours at 130° C. with an excess of chlorosulfonic acid. After cooling, the mixture was poured onto ice, the sulfochloride was filtered off with suction, washed to neutrality and dried over sodium hydroxide, melting point 91° C. The resulting sulfochloride (29.05 g, 0.1 mol) and phenol (11.5 g, 0.12 mol) were dissolved in 150 ml of acetone and treated with 14 ml of triethylamine at 10° C. The mixture was stirred for 1 hour with cooling, stirring was then continued for a further 4 hours at room temperature, the mixture was then treated with 200 ml of water, the resulting precipitate was filtered off with suction at 10° C., washed with water and dried in vacuo at 80° C., melting point 102° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:16]4[C:15]([S:17][C:4]=2[CH:3]=1)=[C:14]([CH3:18])[CH:13]=[CH:12][C:11]=4[N:10]([CH2:19][CH2:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[N:9]=3.[OH:26]O>CC(C)=O>[OH2:26].[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:16]4[C:15]([S:17][C:4]=2[CH:3]=1)=[C:14]([CH3:18])[CH:13]=[CH:12][C:11]=4[N:10]([CH2:19][CH2:20][N:21]([CH:23]([CH3:25])[CH3:24])[CH3:22])[N+:9]=3[O-:26]
Reactant: OO
Reactant: Cc1ccc2c3c(nn2CCN(C)C(C)C)-c2ccc(Cl)cc2Sc13
Solvent: CC(C)=O
Product: Cc1ccc2c3c1Sc1cc(Cl)ccc1-c3[n+]([O-])n2CCN(C)C(C)C
Product: O

Procedure:
To a solution of 8-chloro-2-(2-(isopropylmethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole (0.19 g.) in acetone (3 ml.) was added 0.25 ml. of 30% aqueous hydrogen peroxide and the mixture was kept at room temperature for 4 days. The solid obtained on evaporation of the solution under reduced pressure was crystallized from ethanol-ether to give 8-chloro-2-(2 -(isopropylmethylamino)ethyl)-5-methyl-2H(1)benzothiopyrano[4,3,2-cd]indazole N-oxide monohydrate, m.p. 132°-133° (decomp.).
Reaction SMILES: C(NC(C)C)(C)C.[Cl:8][C:9]1[CH:17]=[C:16](I)[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19].[CH3:20][Si:21]([C:24]#[CH:25])([CH3:23])[CH3:22]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:8][C:9]1[CH:17]=[C:16]([C:25]#[C:24][Si:21]([CH3:23])([CH3:22])[CH3:20])[C:12]2[O:13][CH2:14][O:15][C:11]=2[C:10]=1[NH2:19]
Reactant: Nc1c(Cl)cc(I)c2c1OCO2
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(C)NC(C)C
Product: C[Si](C)(C)C#Cc1cc(Cl)c(N)c2c1OCO2
Temperature: -20 °C
Reaction time: 4 h

Procedure:
Bis(triphenylphosphine)palladium(II) chloride (0.283 g), cuprous iodide (0.115 g) and diisopropylamine (0.57 ml) were added to a stirred solution of 5-chloro-7-iodo-1,3-benzodioxol-4-amine (0.600 g) and trimethylsilylacetylene (0.57 ml) in ethyl acetate (10 ml) cooled to −20° C. under a nitrogen atmosphere. The mixture was stirred for 4 hr at ambient temperature. The reaction mixture was filtered through Celite and the crude product in solution was then absorbed onto silica and purified by column chromatography using 20% dichloromethane in isohexane as eluent. There was thus obtained the title compound as an oil (0.560 g). NMR Spectrum: (CDCl3) 0.24 (s 9H), 4.03 (s, 2H), 6.02 (s, 2H), 6.91 (s, 1H); Mass Spectrum: M+H+ 268 and 270.
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[CH:6][C:5]([Br:9])=[CH:4][N:3]=1.[CH3:10][CH2:11][C:12](=O)[CH2:13][CH3:14].CC(O)=O>ClC(Cl)C>[Br:9][C:5]1[CH:6]=[C:7]([NH:8][CH:12]([CH2:13][CH3:14])[CH2:11][CH3:10])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1cc(Br)cnc1N
Reactant: CCC(=O)CC
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: CCC(CC)Nc1cc(Br)cnc1N
Reaction time: 8 h

Procedure:
To a solution of 2,3-diamino-5-bromopyridine (10.0 g, 53.2 mmol, 1.0 equiv) and 3-pentanone (6.18 mL, 58.5 mmol, 1.1 equiv) in dichloroethane (150 mL) was added AcOH (3.0 mL, 53.2 mmol, 1.0 equiv) followed by NaHB(OAc)3 (16.9 g, 79.8 mmol, 1.5 equiv), added as a solid in several portions over ˜5 min. The reaction was allowed to stir overnight. The reaction mixture was then washed with satd. aq. NaHCO3 and brine, and the resulting organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. Purification by silica gel MPLC (10%-40% EtOAc/Hexanes) provided 5-bromo-N3-(pentan-3-yl)pyridine-2,3-diamine as an off white solid (2.0 g, 14%). m/z=240.1 [M+H]+
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)[C:17]3[CH:26]=[CH:27][CH:28]=[CH:29][C:16]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])[C:14]2=[O:37])[CH:5]=1.O=C1N(CC(O)=O)N=C(C2C=CC=CN=2)C2C=CC=CC=2N1CC(=O)C1C=CC=CC=1C.[C:72]([O:76][C:77](=[O:87])[N:78](C1C=CC=C(N)C=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73].C1(C2C3C=CC=CC=3N(CC(=O)C(C)(C)C)C(=O)N(CC(O)=O)N=2)CCCCC1.COC(=O)C1C=CC=C(N)C=1>>[C:72]([O:76][C:77](=[O:87])[N:78]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11](=[O:38])[CH2:12][N:13]2[N:19]=[C:18]([CH:17]3[CH2:16][CH2:29][CH2:28][CH2:27][CH2:26]3)[C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:25]=3[N:15]([CH2:30][C:31](=[O:36])[C:32]([CH3:34])([CH3:35])[CH3:33])[C:14]2=[O:37])[CH:5]=1)[CH3:79])([CH3:75])([CH3:74])[CH3:73]
Reactant: COC(=O)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Agent: CC(C)(C)C(=O)CN1C(=O)N(CC(=O)O)N=C(C2CCCCC2)c2ccccc21
Agent: COC(=O)c1cccc(N)c1
Agent: Cc1ccccc1C(=O)CN1C(=O)N(CC(=O)O)N=C(c2ccccn2)c2ccccc21
Product: CN(C(=O)OC(C)(C)C)c1cccc(NC(=O)CN2N=C(C3CCCCC3)c3ccccc3N(CC(=O)C(C)(C)C)C2=O)c1

Procedure:
The title compound was obtained by the method used in the preparation of 3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-benzoic acid methyl ester (Example 1, step e) except that [2-oxo-1-(2-oxo-2-o-tolyl-ethyl)-5-pyridin-2-yl-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 7, step a) and (3-amino-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step c) were used in place of [5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetic acid (Example 1, step d) and 3-amino-benzoic acid methyl ester respectively, followed by reaction of the product obtained, in place of (3-{2-[5-cyclohexyl-1-(3,3-dimethyl-2-oxo-butyl)-2-oxo-1,2-dihydro-3H-1,3,4-benzotriazepin-3-yl]-acetylamino}-phenyl)-methyl-carbamic acid tert-butyl ester (Example 3, step d), according to the method of Example 3, step e. 1H NMR (CDCl3) 8.64 (1H, d), 8.08 (1H, d), 8.03 (1H, s), 7.79 (1H, dt), 7.59 (2H, m), 7.39-7.26 (5H, m), 7.19 (2H, m), 7.01 (1H, t), 6.90 (1H, s), 6.47 (1H, dd), 6.30 (1H, dd), 4.98 (2H, s), 4.45 (2H, br m), 3.30 (1H, br s), 2.76 (3H, s), 2.47 (3H, s). Found: C, 69.63; H, 5.45; N, 15.59%; C31H28N6O3 requires: C, 69.91; H, 5.30; N, 15.78%.
Reaction SMILES: [Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][NH:23][CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.C(N(C(C)C)CC)(C)C.[CH3:44][S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:3]([F:34])=[C:4]([NH:8][C:9]2[C:18]3[C:13](=[CH:14][C:15]([O:32][CH3:33])=[C:16]([CH2:19][N:20]([CH3:31])[C:21]4([C:27]([NH:29][CH3:30])=[O:28])[CH2:26][CH2:25][CH2:24][N:23]([S:45]([CH3:44])(=[O:47])=[O:46])[CH2:22]4)[CH:17]=3)[N:12]=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCNC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)C1(N(C)Cc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCCN(S(C)(=O)=O)C1
Reaction time: 1 h
Yield: 59 %

Procedure:
3-[({4-[(3-Chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}methyl)(methyl)amino]-N-methylpiperidine-3-carboxamide (Example 89.1, Isomer 1) (100 mg, 0.21 mmol) was dissolved in dichloromethane (2.5 ml) and diisopropylethylamine (54 μl, 0.31 mmol) added. Methanesulfonyl chloride (19 μl, 0.25 mmol) was added and the mixture stirred for 1 hour, absorbed onto an Isolute SCX column, washed with methanol and eluted with ammonia in methanol. The appropriate fractions were concentrated and the residues purified by column chromatography on silica, eluting with methanol/dichloromethane (2/98) to give the title product (Isomer 1) (70 mg, 60%) as a white solid; 1H NMR Spectrum: (DMSO d6) 1.67 (m, 1H); 1.92 (m, 2H); 2.07 (m, 1H); 2.21 (s, 3H); 2.66 (d, 3H); 2.88 (s, 3H); 3.03 (m, 1H); 3.21 (m, 1H); 3.34 (d, 1H); 3.52 (d, 1H); 3.62 (d, 1H); 3.79 (d, 1H); 3.96 (s, 3H); 7.20 (s, 1H); 7.30 (dt, 1H); 7.50 (m, 1H); 7.62 (m, 2H); 8.32 (s, 1H); 8.44 (s, 1H); 9.57 (s, 1H). Mass Spectrum: (M+H)+ 565.5
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:5]([CH3:9])=[N:6][NH:7][CH:8]=1.CS(O[CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1)(=O)=O>CN(C=O)C>[Br:3][C:4]1[CH:8]=[N:7][N:6]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:5]=1[CH3:9].[Br:3][C:4]1[C:5]([CH3:9])=[N:6][N:7]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1n[nH]cc1Br
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1c(Br)cnn1C1CCN(C(=O)OC(C)(C)C)CC1
Product: Cc1nn(C2CCN(C(=O)OC(C)(C)C)CC2)cc1Br
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Sodium hydride (60% dispersion in mineral oil, 11.53 g) was added portionwise to a stirred solution of 4-bromo-3-methyl-1H-pyrazole (42.2 g) dissolved in DMF (600 ml) over a period of 15 minutes at 0° C. under nitrogen. The resulting slurry was stirred at 0° C. for 1 hour. Then tert-butyl 4-methylsulphonyloxypiperidine-1-carboxylate (73.2 g) was added and the mixture was stirred 1 hour at room temperature then heated to 90° C. overnight. The reaction mixture was then allowed to stir at room temperature over a period of 2 days, quenched with water (2 ml), concentrated to dryness, diluted with ethyl acetate (1500 ml), washed with water (2×1000 ml), brine (1000 ml), dried over magnesium sulfate and concentrated to afford the crude product. A purification by flash chromatography on silica gel eluting with 20% ethyl acetate in petroleum ether afforded tert-butyl 4-(4-bromo-5-methyl-pyrazol-1-yl)piperidine-1-carboxylate (22.5 g) (NMR Spectrum: (DMSOd6) 1.42 (s, 9H), 1.72-1.86 (m, 4H), 2.28 (s, 3H), 2.91 (bs, 2H), 3.96-4.13 (m, 2H), 4.34-4.43 (m, 1H), 7.50 (s, 1H); Mass spectrum: M−tBu: 288,290), and tert-butyl 4-(4-bromo-3-methyl-pyrazol-1-yl)piperidine-1-carboxylate (28.7 g) (NMR Spectrum (DMSOd6): 1.44 (s, 9H), 1.70 (dd, 1H), 1.75 (dd, 1H), 1.91-1.99 (m, 2H), 2.11 (s, 3H), 2.87 (bs, 2H), 4.95-4.10 (m, 2H), 4.21-4.30 (m, 1H), 7.95 (s, 1H); Mass spectrum: M−tBu: 288,290).
Reaction SMILES: [CH2:1]([C:3]([CH2:8][OH:9])([CH2:6][OH:7])[CH2:4]C)[OH:2].[CH2:10](C(CO)(C)C)O>CC(C)=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH2-:10][C:8]([CH3:3])=[O:9].[CH2:1]([C:3]([CH2:8][OH:9])([CH3:4])[CH2:6][OH:7])[OH:2]
Reactant: CC(C)(CO)CO
Reactant: CCC(CO)(CO)CO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)=O
Product: CC(CO)(CO)CO
Product: [CH2-]C(C)=O
Yield: 170.9 %

Procedure:
To a stirred solution of trimethylolpropane (TMP) (50.0 g, 373 mmol) in acetone (1000 ml) was added p-toluene sulfonicacid (p-TSA) (1.39 g, 7.46 mmol) and 2,2-dimethylolpropane (58.2 g, 560 mmol). The reaction was stirred over night and quenched with NH4OH/ethanol (50/50 v/v) and the acetone evaporated. The crude product was dissolved in CH2Cl2 (1000 ml), extracted 3 times with water (100 ml), dried with mgSO4, and concentrated to yield a colorless oil (56.5 g, 87%). 1H NMR (CDCl3): δ0.79 (t, CH2CH3, J=7.6 Hz, 3H), 1.30 (q, CH2CH3, J=7.6 Hz, 2H), 1.38 (s, CCH3, 3H), 1.41 (s, CCH3, 3H), 2.70 (t, —OH, J=7.4 Hz, 1H), 3.54 (s, CH2OH, 2H), 3.65 (s, CH2O, 2H), 3.68 (s, CH2O, 2H). 13C NMR (CDCl3): δ7.00 (s, CH2CH3, 1C), 20.17 (s, CH2CH3, 1C), 23.74 (s, CCH3, 1C), 27.30 (s, CCH3, 1C), 36.91 (s, C(CH2)4, 1C), 62.51 (s, CH2OH, 1C), 65.15 (s, CH2O, 2C), 98.16 (s C(CH3)2, 1C).
Reaction SMILES: [N+:1]([C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11])([O-])=O>CO.[Pd]>[NH2:1][C:4]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:11]
Reactant: O=[N+]([O-])c1c(O)cccc1F
Agent: [Pd]
Solvent: CO
Product: Nc1c(O)cccc1F
Yield: 79.9 %

Procedure:
To a solution of 2-nitro-3-fluorophenol(1 g, 6.4 mmol) in methanol(250 mL) was added 10% Pd/C (1 g). The mixture was flushed with argon, then hydrogen was bubbled through the solution for 10 min. and a hydrogen atmosphere was maintained at balloon pressure overnight The mixture was filtered through celite and the celite was washed with methanol. The solvent was evaporated and chromatography of the resulting solid on silica gel (5% MeOH/CH2Cl2) gave the desired product(650 mg, 80.2%). 1H NMR (CD3OD): δ 6.41-6.17 (m, 3H).
Reaction SMILES: [Cl-].[C:2]1([N+:8]#[N:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:10](#[N:14])[CH2:11][C:12]#[N:13].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.Cl.[N:27]1C=CC=CC=1>>[C:2]1([N:8]2[N:27]=[C:11]([C:12]#[N:13])[C:10]([NH2:14])=[N:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccncc1
Reactant: N#[N+]c1ccccc1
Reactant: N#CCC#N
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Cl-]
Product: N#Cc1nn(-c2ccccc2)nc1N
Temperature: 25 °C
Reaction time: 5 h

Procedure:
20 Parts phenylazo-malonic dinitrile prepared by coupling phenyldiazonium chloride with malononitrile and 12.5 parts hydroxylaminochlorohydrate are suspended in 100 parts pyridine. 33.7 parts para-toluenesulfonic acid chloride are added thereto with ice cooling and stirred at room temperature from 5 hours. Then the mixture is adjusted with concentrated hydrochloric acid, extracted with 100 parts methylene chloride and the organic phase dried with the solvent being separated by distillation. The aminotriazole product is recrystallized from a methanol/water mixture.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18](O)[CH3:19])[CH:3]=1.CN(C)C=O.S(Cl)([Cl:28])=O>C(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[C:5]([O:15][CH2:16][CH3:17])=[C:4]([CH:18]([Cl:28])[CH3:19])[CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: CCOc1c(C(C)O)cc(Cl)c(C#N)c1N1CCCC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOc1c(C(C)Cl)cc(Cl)c(C#N)c1N1CCCC1
Reaction time: 2 h
Yield: 102.2 %

Procedure:
The 6-chloro-3-ethoxy-4-(1-hydroxyethyl)-2-pyrrolidin-1-ylbenzonitrile (0.045 g, 0.15 mmol) was taken up in methylene chloride (3.0 mL) and N,N-dimethylformamide (0.002 mL, 0.03 mmol) and cooled in an ice bath. The thionyl chloride (0.017 mL, 0.23 mmol) was added and the reaction was monitored by LC/MS. After stirring for 2 hrs the reaction was complete. The reaction was then taken up in ethyl acetate, washed with sodium bicarbonate, brine, dried over magnesium sulfate and concentrated to give crude 6-chloro-4-(1-chloroethyl)-3-ethoxy-2-pyrrolidin-1-ylbenzonitrile as a yellow oil (0.048 g, 100%). LCMS calculated for C15H19Cl2N2O (M+H)+: m/z=313.1; found 313.1.
Reaction SMILES: Br[C:2]1[O:11][CH2:10][C:9]2[CH:8]([N:12]([CH3:14])[CH3:13])[CH2:7][C:6]3=[CH:15][N:16]([Si:18]([CH:25]([CH3:27])[CH3:26])([CH:22]([CH3:24])[CH3:23])[CH:19]([CH3:21])[CH3:20])[CH:17]=[C:4]([C:5]=23)[CH:3]=1.[Li]CCCC.[CH3:33][S:34]SC>O1CCCC1.[Cl-].[NH4+]>[CH3:14][N:12]([CH3:13])[CH:8]1[C:9]2[CH2:10][O:11][C:2]([S:34][CH3:33])=[CH:3][C:4]3=[CH:17][N:16]([Si:18]([CH:22]([CH3:24])[CH3:23])([CH:25]([CH3:27])[CH3:26])[CH:19]([CH3:20])[CH3:21])[CH:15]=[C:6]([C:5]=23)[CH2:7]1
Reactant: CC(C)[Si](C(C)C)(C(C)C)N1C=C2C=C(Br)OCC3=C2C(=C1)CC3N(C)C
Reactant: CSSC
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: CSC1=CC2=CN([Si](C(C)C)(C(C)C)C(C)C)C=C3CC(N(C)C)C(=C23)CO1
Reaction time: 1 h
Yield: 69 %

Procedure:
A solution of compound (42) 451 mg in dry tetrahydrofuran 5 ml was cooled at −70° C. n-BuLi (1.56 mol/l hexane solution) 1.3 ml was added dropwise to the solution and the mixture was stirred for 1 h. Then, dimethyldisulfide 185 μl was added and the mixture was stirred for 2 h. The reaction mixtures was diluted with an aqueous ammonium chloride solution and extracted with ethyl acetate. The extracts were washed with brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue obtained was chromatographed on aluminum oxide in ethyl acetate:hexane (1:5) to give the titled compound as colorless crystals, 289.8 mg. Yield 69%. This was recrystallized from hexane to give the titled compound as colorless crystals, m.p. 77-79° C.
Reaction SMILES: [N+:1]([C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:6][CH:5]=1)([O-])=O.C(O)C.O.[Cl-].[NH4+]>O1CCOCC1>[NH2:1][C:4]1[CH:18]=[CH:17][C:7]([CH2:8][NH:9][C:10](=[O:16])[O:11][C:12]([CH3:14])([CH3:15])[CH3:13])=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc([N+](=O)[O-])cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCc1ccc(N)cc1
Temperature: 25 °C
Yield: 99 %

Procedure:
C4 (7.0 g, 27.7 mmol) was dissolved in dioxane (325 mL), ethanol (240 mL), and water (160 mL). The resultant solution was then treated with Fe(0) powder (7.12 g, 127.4 mmol) and ammonium chloride (5.33 g, 99.7 mmol), and the resultant mixture was stirred at 70° C. for 4 hours. The reaction mixture was cooled to 25° C., filtered through Celite®, and washed with EtOAc. The organic solvents were evaporated, and the resultant aqueous residue was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated to provide C5 as a yellow solid. Yield: 6.52 g, 99% yield. 1H NMR (400 MHz, d6-DMSO) δ: 7.146 (t, 1H), 6.87 (d, 2H), 6.48 (d, 2H), 4.95 (s, 2H), 3.92 (d, 2H), 1.38 (s, 9H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([OH:24])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2].[C:25](OC(=O)C)(=[O:27])[CH3:26]>C(N(CC)CC)C>[CH2:1]([O:3][C:4]([C:6]1[C:7]([O:24][C:25](=[O:27])[CH3:26])=[C:8]2[CH:16]=[CH:15][N:14]([CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[C:9]2=[C:10]([C:12]#[N:13])[N:11]=1)=[O:5])[CH3:2]
Reactant: CC(=O)OC(C)=O
Reactant: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1O
Solvent: CCN(CC)CC
Product: CCOC(=O)c1nc(C#N)c2c(ccn2Cc2ccccc2)c1OC(C)=O

Procedure:
Prepared in analogy to that of Example 120(a) from 1-benzyl-7-cyano-4-hydroxy-1H-pyrrolo[2,3-c]pyridine-5-carboxylic acid ethyl ester, acetic anhydride, and triethylamine. The title compound, ESI MS (m/z): 364 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14][C@@H:13]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:30]1(C)C=CC(S(O)(=O)=O)=CC=1.[O:41]1CCC[CH2:42]1>CO.COC(OC)(C)C>[CH2:1]([O:8][C:9]([NH:11][C@@H:12]1[CH2:17][CH2:16][C:15]([O:41][CH3:42])([O:18][CH3:30])[CH2:14][C@@H:13]1[NH:19][C:20]([O:22][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:21])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCOC1
Reactant: O=C1CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: COC(C)(C)OC
Product: COC1(OC)CC[C@@H](NC(=O)OCc2ccccc2)[C@@H](NC(=O)OCc2ccccc2)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(±)-cis-N1,N2-Bis(benzyloxycarbonyl)-4-oxo-1,2-cyclohexanediamine (3.89 g) was dissolved in a mixed solvent of methanol (15 ml) and tetrahydrofuran (15 ml), 2,2-dimethoxypropane (10.7 ml) and p-toluenesulfonic acid (187 mg) were added, and the mixture was stirred at room temperature for 3 hours. The solvent was concentrated, and a saturated aqueous solution of sodium hydrogencarbonate was added to conduct extraction with ethyl acetate. After the resultant organic layer was washed with saturated saline and dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (ethyl acetate:hexane=1:2) to obtain the title compound (3.54 g) as a colorless amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][O:6][C:7]([C:9]1[CH:10]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[N+:27]([O-:29])=[O:28])[C:11]([C:17]([O:19]C)=O)=C(C)[NH:13][C:14]=1[CH3:15])=[O:8].[CH2:34]([OH:36])C.[CH2:37]([OH:40])[CH2:38]C>>[CH3:34][O:36][C:37]([CH2:38][C:17](/[CH:11]=[CH:10]/[C:21]1[C:22]([N+:27]([O-:29])=[O:28])=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:19])=[O:40].[Cl:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[Cl:33])[CH2:5][O:6][C:7](=[O:8])/[CH:9]=[C:14](\[NH2:13])/[CH3:15]
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCc2ccc(Cl)c(Cl)c2)C1c1ccccc1[N+](=O)[O-]
Reactant: CCO
Reactant: CCCO
Product: C/C(N)=C/C(=O)OCc1ccc(Cl)c(Cl)c1
Product: COC(=O)CC(=O)/C=C/c1ccccc1[N+](=O)[O-]

Procedure:
Analogously to Example 1 heating a solution of 75 mmols of 2'-nitrobenzylideneacetoacetic acid methyl ester and 75 mmols of β-aminocrotonic acid 3,4-dichlorobenzyl ester in 120 ml of n-propanol gave 2,6-dimethyl-3-methoxycarbonyl-4-(2'-nitrophenyl)-1,4-dihydropyridine-5-carboxylic acid 3,4-dichlorobenzyl ester of melting point 137° C (from ethanol).