Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:10]=1)=[O:4].[OH-].[Na+].Cl>C1COCC1>[CH3:14][S:11]([C:9]1[CH:10]=[C:5]([C:3]([OH:4])=[O:2])[C:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[CH:7][CH:8]=1)(=[O:12])=[O:13]
Reactant: COC(=O)c1cc(S(C)(=O)=O)ccc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(-c2ccccc2)c(C(=O)O)c1
Temperature: 60 °C
Yield: 95 %

Procedure:
To 4-Methanesulfonyl-biphenyl-2-carboxylic acid methyl ester (1.00 g, 3.44 mmol) in 5 ml THF was added 5 M aq NaOH solution (7.58 ml, 37.9 mmol) and the mixture was heated at 60° C. for 16 h. The mixture was then cooled to RT, acidified to pH 1 with conc hydrochloric acid, and extracted 3 times with ethyl acetate. The combined organic phases were dried with Na2SO4. Evaporation in vacuo afforded the title compound (903 mg, 95%) as an off-white crystalline solid. MS (ISN): 275.1 M−H−.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7](Cl)[CH:6]=[N:5]2.CC1(C)C(C)(C)OB([C:21]2[CH:22]=[CH:23][C:24]3[N:28]=[C:27]([C@@H:29]4[CH2:34][C@@H:33]5[C@@H:31]([CH2:32]5)[N:30]4[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[NH:26][C:25]=3[CH:42]=2)O1.C(=O)(O)[O-].[Na+]>O1CCOCC1.O.CO.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>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:22]1[CH:21]=[CH:42][C:25]3[N:26]=[C:27]([C@@H:29]4[CH2:34][C@@H:33]5[C@@H:31]([CH2:32]5)[N:30]4[C:35]([O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[O:36])[NH:28][C:24]=3[CH:23]=1)[CH:6]=[N:5]2
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2[nH]1
Reactant: Clc1cnc2cc(Br)ccc2n1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1c1nc2ccc(-c3cnc4cc(Br)ccc4n3)cc2[nH]1
Temperature: 110 °C
Reaction time: 2 h
Yield: 82.1 %

Procedure:
Pd(Ph3P)4 (28.5 mg, 0.025 mmol) was added to a degassed solution of 6-bromo-2-chloroquinoxaline (60 mg, 0.246 mmol), (1R,3S,5R)-tert-butyl 3-(6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (115 mg, 0.271 mmol) and sodium bicarbonate (62.1 mg, 0.739 mmol) in dioxane (1 mL) and H2O (0.2 mL) and the mixture was stirred at 110° C. for 2 h and then at 120° C. for 2 h. The reaction was diluted with MeOH, filtered and purified by prep HPLC (H2O-MeOH with 10 mM NH4OAc buffer) to yield (1R,3S,5R)-tert-butyl 3-(6-(6-bromoquinoxalin-2-yl)-1H-benzo[d]imidazol-2-yl)-2-azabicyclo[3.1.0]hexane-2-carboxylate (102.2 mg, 0.202 mmol, 82% yield) as bright yellow solid. LC-MS retention time 2.31 min; m/z 506 [M+H]+. (Column PHENOMENEX® Luna 3.0×50 mm S10. Solvent A=90% water:10% methanol:0.1% TFA. Solvent B=10% water:90% methanol:0.1% TFA. Flow Rate=4 mL/min. Start % B=0. Final % B=100. Gradient Time=3 min. Wavelength=220).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:28]=[CH:27][C:14]([CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)=[CH:13][CH:12]=1)([O:3][CH3:4])=[O:2].O.NN>C(O)C>[C:1]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][NH2:16])=[CH:27][CH:28]=1)([O:3][CH3:4])=[O:2]
Reactant: COC(=O)c1ccccc1-c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Agent: NN
Solvent: CCO
Solvent: O
Product: COC(=O)c1ccccc1-c1ccc(CN)cc1
Temperature: 25 °C
Yield: 66.3 %

Procedure:
Compound (f) of Example 6 (3.85 g, 0.01 mole) is dissolved in 100 mL of absolute ethanol with warming. Hydrazine hydrate (7.5 mL) is added at once. The solution is heated to reflux for 10 minutes and the reaction mixture sets up. The mixture is cooled to room temperature and filtered. The precipitate is washed with excess hot ethanol. The ethanol fraction is rotovapped to a pale yellow oil. Chromatography on silica gel using methylene chloride/25% methanol as the mobile phase yields 1.6 g (66%) of a pale yellow oil. 1H NMR (CDCl3) 7.83 (1H, d, J=7 Hz); 7.6-7.2 (7H, m); 3.92 (2H, s); 3.66 (3H, s); 2.16 (2H, bs). Mass Spec. (DCI) m/z 242 (M+H). Analysis-calc'd for C15H15NO2.H2O: C, 71.97; H, 6.44; N, 5.60; found: C, 71.60; H, 6.27; N, 5.70.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH2:14])[CH:9]=1.[O-:15][C:16]#[N:17].[Na+].FC(F)(F)C(O)=O.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[CH:5][CH:4]=[C:3]1[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([NH:14][C:16]([NH2:17])=[O:15])[CH:9]=1
Reactant: N#C[O-]
Reactant: Cn1cccc1Cc1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: Cn1cccc1Cc1cccc(NC(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.7 %

Procedure:
To a stirred solution of 4.4 g (23 mmol) of 1-methyl-2-(3'-aminobenzyl)pyrrole in 400 ml of benzene there were added 3.08 g (47 mmol) of sodium cyanate followed by the dropwise addition of a solution of 3.65 ml (47 mmol) of trifluoroacetic acid in 300 ml of benzene. When the addition was completed, the reaction mixture was stirred at room temperature for 1 hour further and then poured into 500 ml of saturated sodium carbonate solution. The organic phase was separated and the aqueous layer extracted with ethyl acetate (3×500 ml). The combined extracts were washed with water (1×500 ml), dried and evaporated under reduced pressure. The residue was purified by column chromatography on 500 g of silica gel, using methylene chloride-acetone (80:20) as eluant, thus obtaining 5.1 g (90%) of the title compound, 1-methyl-2-(3'-ureidobenzyl)pyrrole, which was recrystallized from acetone-hexane.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C@H:8]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C@@H:9]([OH:12])[CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:21]1(=O)[O:26][C:24](=[O:25])[C:23]2=[CH:27][CH:28]=[CH:29][CH:30]=[C:22]12.CCN(CC)CC>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[NH:7][C@@H:8]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C@H:9]([OH:12])[CH2:10][N:11]1[C:24](=[O:25])[C:23]2[C:22](=[CH:30][CH:29]=[CH:28][CH:27]=2)[C:21]1=[O:26])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1ccccc1)[C@@H](O)CN
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](O)CN1C(=O)c2ccccc2C1=O
Temperature: 80 °C
Reaction time: 24 h
Yield: 57.5 %

Procedure:
(1R,2S)-(3-amino-1-benzyl-2-hydroxy-propyl)-carbamic acid t-butyl ester (1.4 g, 5 mmol) prepared in Preparation 103 was dissolved in DMF (20 mL), to which was added phthalic anhydride (735 mg, 5 mmol). Et3N (1.4 mL, 10 mmol) was added thereto, and the mixture was stirred for 24 h at 80° C. The reaction was quenched by water, and the reaction mixture was extracted with EtOAc, and dried over MgSO4. The solvent was removed under reduced pressure, and the residue was dissolved in DCM. TFA was added thereto, and the mixture was stirred for 2 h at room temperature. After completion of the reaction, the solvent was removed under reduced pressure. The residue was recrystallized from DCM/Hex to give the title compound (1.18 g, Yield 71%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:23])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[Cl:26][CH:27]=[CH:28][CH2:29]Cl.CC(O)=O>CN(C=O)C.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]([CH2:29][CH:28]=[CH:27][Cl:26])[C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:19]([O:21][CH3:22])=[O:20])[CH:15]=2)[C:10]=1[Br:23])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClC=CCCl
Reactant: COC(=O)c1ccc2c(Br)c(NC(=O)OC(C)(C)C)ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(Br)c(N(CC=CCl)C(=O)OC(C)(C)C)ccc2c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 94.8 %

Procedure:
A stirred solution of bromide 148 (1.05 g, 2.76 mmol) in dry DMF (8 mL) was treated at 0° C. with NaH (132 mg, 60% in oil, 3.30 mmol). The resulting suspension was warmed to room temperature for 30 min, then cooled to 0° C. and treated with 1,3-dichloropropene (0.80 mL, 8.7 mmol, mixed isomers). The mixture was stirred at room temperature for a further 4 h then poured into dilute aqueous AcOH and exacted with EtOAc (×2). The combined organic layers were washed with dilute aqueous NaHCO3 and water (×2), dried, and concentrated to dryness under reduced pressure at 100° C. The residue was chromatographed on silica gel, eluting with CH2Cl2/EtOAc (19:1) to give methyl 2-[(tert-butoxycarbonyl)(3-chloro-2-propen-1-yl)amino]-1-bromo-6-naphthoate (149) (1.19 g, 95%) as a gum; 1H NMR [(CD3)2SO] (mixture of rotamers and E and Z forms) δ 8.73 (s, 1H), 8.34 (d, J=8.9 z, 1H), 8.16 (d, J=8.9 Hz, 1H), 7.63, 7.58 (2 d, J=8.7 Hz, 1H), 8.25, 8.24 (2 d, J=8.6 Hz, 1H), 6.45-6.31 (m, 1H), 6.20-6.00 (m, 1H), 4.58-4.48, 4.43-4.21, 4.16-4.00 (3 m, 2H), 3.95 (s, 3H), 1.50, 1.27 (2 s, 9H). HRMS (FAB) calcd. for C20H2279Br35ClNO4 (MH+) m/z 454.0421, found 454.0410.
Reaction SMILES: Br[C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=O.[CH2:15]([NH2:18])[CH2:16][NH2:17]>C(O)CCC>[N+:12]([C:11]1[C:2]2[NH:18][CH2:15][CH2:16][NH:17][C:4](=[O:6])[C:3]=2[CH:8]=[CH:9][CH:10]=1)([O-:14])=[O:13]
Reactant: COC(=O)c1cccc([N+](=O)[O-])c1Br
Reactant: NCCN
Solvent: CCCCO
Product: O=C1NCCNc2c1cccc2[N+](=O)[O-]
Reaction time: 0.5 h

Procedure:
A mixture of 11.7 parts of methyl 2-bromo-3-nitrobenzoate, 8.1 parts of 1,2-ethanediamine mononohydrate and 40 parts of 1-butanol was stirred for ½ hour at reflux temperature. The reaction mixture was evaporated and the residue was diluted with 50 parts of water. The precipitate was filtered off and washed with water and 2-propanol. It was then recrystallized from 2-methoxyethanol, yielding 6.5 parts of 2,3,4,5-tetrahydro-9-nitro-1H-1,4-benzodiazepin-5-one; m.p. 191-195° C. (interm. 1).
Reaction SMILES: [CH2:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][C:2]1=O.Cl.[C:12]1([NH:18]N)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.CC(O)C.C([O-])(O)=O.[Na+]>O>[CH:14]1[CH:15]=[CH:16][CH:17]=[C:12]2[C:13]=1[C:1]1[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[CH2:3][C:2]=1[NH:18]2
Reactant: O=C1Cc2ccccc2C1
Reactant: NNc1ccccc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Solvent: O
Product: c1ccc2c(c1)Cc1[nH]c3ccccc3c1-2
Temperature: 80 °C

Procedure:
In a 1-L flask were charged 36.55 g of 2-indanone (Aldrich, Mw=−132.16, 276.6 mmol), 40.00 g of phenyl-hydrazine hydrochloride (Aldrich, 99%, Mw=144.61, 276.6 mmol) and 0.3 L of i-PrOH. The suspension was warmed to 80° C. in about 30 minutes and the slurry changed color from yellow to dark brown under stirring. The reaction mixture was stirred at 80° C. for 1.5 hours and then was cooled to room temperature in about 30 minutes. The slurry was siphoned into 1.0 L of water containing 34.85 g of NaHCO3, thus obtaining a fine dispersion of a green product (no heat evolution was observed). The slurry was then filtered on a G4 frit, washed with water, dried in air under moderate vacuum for 24 h until to achieve constant weight.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:31][C@H:30]([NH2:32])[CH2:29][C@H:28]2[C:33]([O:35][CH3:36])=[O:34])[CH:21]=1.Cl.C(N(CC)CC)C.[Cl:45][C:46]1[CH:51]=[CH:50][C:49]([S:52](Cl)(=[O:54])=[O:53])=[CH:48][CH:47]=1>C(OCC)(=O)C.O>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:27]2[CH2:31][C@H:30]([NH:32][S:52]([C:49]3[CH:50]=[CH:51][C:46]([Cl:45])=[CH:47][CH:48]=3)(=[O:54])=[O:53])[CH2:29][C@H:28]2[C:33]([O:35][CH3:36])=[O:34])[CH:21]=1
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1Cc1cccnc1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: O
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
In an atmosphere of nitrogen,(2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-azidopyrrolidine (49.4 g) was dissolved in ethyl acetate (500 ml) followed by addition of triphenylphosphine (60.75 g, 0.232 mol) at 20°-30° C. (foaming took place). After completion of addition, the mixture was warmed to 40°-45° C. and stirred for 30 minutes. The mixture was diluted with water (16.5 ml) and warmed and stirred at 60°-65° C. for 1.5 hours to provide a reaction mixture containing (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-aminopyrrolidine. This reaction mixture was cooled to 5°-10° C. and adjusted to pH 3.5 with 1N hydrochloric acid (ca. 350 ml). After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with triethylamine (ca. 20 ml) (pH prior to adjustment: 1.5). This aqueous solution was cooled to 5° C. and ethyl acetate (475 ml) and triethylamine (70.5 g, 0.696 mol) were added thereto in that order. Then, at 5°-10° C., 4-chlorobenzenesulfonyl chloride (49 g, 0.232 mol) was added in 3 successive portions and the mixture was stirred at 5° C. for 1 hour. The reaction mixture was adjusted to pH 2.0 with 6N-hydrochloric acid. After phase separation, the organic layer was washed with 1% hydrochloric acid (125 ml). The aqueous layer was combined and adjusted to pH 7.0 with 24% aqueous sodium hydroxide solution. The aqueous solution was extracted with ethyl acetate (500 ml) and the extract was washed with a saturated aqueous sodium chloride solution (125 ml). The ethyl acetate layer was concentrated to 187.5 ml under reduced pressure and the concentrate was stirred at 20°-25° C. for 1.5 hours for crystallization and ripening. To this solution was added diisopropyl ether (562.5 ml) dropwise and the mixture was stirred for 1 hour. The resulting crystal was collected by filtration and washed with diisopropyl ether (100 ml). The washed crystal was dried in vacuo overnight to provide (2S,4R)-1-(3-pyridylmethyl)-2-methoxycarbonyl-4-(4-chlorophenyl-sulfonylamino)pyrrolidine (51.51 g) as a crystal.
Reaction SMILES: [C:1]1([C:7](=O)[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH:23]=O)[CH3:18].[NH2:32][C:33]([NH2:35])=[O:34].Cl>C(O)C>[CH2:17]([O:19][C:20]1[CH:21]=[C:22]([CH:23]2[C:8]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH3:15])=[C:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[NH:35][C:33](=[O:34])[NH:32]2)[CH:25]=[C:26]([N+:29]([O-:31])=[O:30])[C:27]=1[OH:28])[CH3:18]
Reactant: CCOc1cc(C=O)cc([N+](=O)[O-])c1O
Reactant: Cc1ccccc1CC(=O)c1ccccc1
Reactant: NC(N)=O
Agent: Cl
Solvent: CCO
Product: CCOc1cc(C2NC(=O)NC(c3ccccc3)=C2c2ccccc2C)cc([N+](=O)[O-])c1O
Yield: 10.5 %

Procedure:
To a solution of 1-phenyl-2-o-tolylethanone (Intermediate 9) (100 mg, 0.47 mmol), 3-ethoxy-4-hydroxy-5-nitrobenzaldehyde (93.8 mg, 0.47 mmol), and urea (84.7 mg, 1.41 mmol) in 20 mL of ethanol was added 0.2 ml con HCl solution. The mixture was stirred at reflux for 2 days. After the solvent was removed under reduced pressure, the residue was purified by reverse-phase preparatory HPLC (26-53% acetonitrile+0.1% trifluoroacetic acid in water+0.1% trifluoroacetic acid, over 15 min.) to give Compound 26 (22 mg, yield 10.4%). 1H NMR (DMSO-d6 400 MHz): δ 8.60 (m, 1H), 7.47-6.36 (m, 11H), 4.87 (m, 1H), 4.03-3.70 (m, 2H), 2.24 (m, 3H), 1.41-1.20 (m, 3H); MS (ESI): m/z 446.0 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>ClCCl>[CH3:14][O:13][C:10]1[C:11]2[N:12]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(OC)c2nc(-c3cccnc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g, Reference Example 8(a)] and triethylamine (0.94 g) in dry dichloromethane (20 ml), at 0° C., was treated with nicotinyl chloride (0.53 g). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in acetic acid (8 ml) and the solution heated at 80° C. for 2 hours. After cooling to room temperature the reaction mixture was treated with water. The insoluble material was subjected to flash chromatography on silica to give the title compound (0.46 g). NMR (CDCl3): δ 4.00(s, 3H), 4.15(s, 3H), 6.70(d, 1H), 7.40(m, 1H), 7.90(d, 1H), 8.45(m, 1H), 8.75(d, 1H), 9.30(d, 1H), 10.80(s, 1H)].
Reaction SMILES: [C:1]([O:4]C(=O)C)(=[O:3])[CH3:2].[CH:8]1([CH:11]([OH:36])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:19]([NH:22][C:23]([NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[O:24])(=[O:21])=[O:20])[CH2:10][CH2:9]1.C(OCC)(=O)C>N1C=CC=CC=1.O>[C:1]([OH:4])(=[O:3])[CH3:2].[CH:8]1([CH:11]([OH:36])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[NH:18][S:19]([NH:22][C:23]([NH:25][C:26]2[N:31]=[C:30]([O:32][CH3:33])[CH:29]=[C:28]([O:34][CH3:35])[N:27]=2)=[O:24])(=[O:21])=[O:20])[CH2:10][CH2:9]1
Reactant: CC(=O)OC(C)=O
Agent: COc1cc(OC)nc(NC(=O)NS(=O)(=O)Nc2ccccc2C(O)C2CC2)n1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)O
Temperature: 25 °C
Reaction time: 18 h

Procedure:
Acetic anhydride (0.18 mL, 0.19 g, 1.9 mmol) is added to a mixture of 1-[(α-cyclopropyl-α-hydroxy-o-tolyl)sulfamoyl]-3-(4,6-dimethoxy-2-pyrimidinyl)urea (0.40 g, 0.9 mmol) in pyridine. The reaction mixture is stirred at room temperature for 18 hours, treated with additional acetic anhydride (0.27 mL, 2.9 mmol), stirred for 5 hours, diluted with water and extracted with ether. The combined organic extracts are dried over anhydrous sodium sulfate and concentrated in vacuo to obtain a residue. Flash column chromatography of the residue using silica gel and 50% to 75% ethyl acetate in hexanes solutions gives the title product as a white powder (0.10 g, 23%, mp 156°-158° C.) which is identified by 1HNMR and MS spectral analyses.
Reaction SMILES: [CH:1]1([N:6]2[C:10]([C:11]3[C:16]([CH2:17]O)=[CH:15][CH:14]=[CH:13][N:12]=3)=[CH:9][CH:8]=[N:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.O=S(Cl)[Cl:21]>C(Cl)Cl>[ClH:21].[Cl:21][CH2:17][C:16]1[C:11]([C:10]2[N:6]([CH:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)[N:7]=[CH:8][CH:9]=2)=[N:12][CH:13]=[CH:14][CH:15]=1
Reactant: OCc1cccnc1-c1ccnn1C1CCCC1
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cl
Product: ClCc1cccnc1-c1ccnn1C1CCCC1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridin-3-yl)methanol (301 mg, 1.24 mmol) in DCM (3 mL) was added SOCl2 (3 eq) at 0° C. The reaction mixture was stirred at RT for 15 mins (thew reaction was done in 10 mins by LCMS) and concentrated to dryness. The crude solid was suspended in toluene and concentrated to dryness. The process was repeated three times and dried under vacuum to give 3-(chloromethyl)-2-(1-cyclopentyl-1H-pyrazol-5-yl)pyridine hydrochloride (305 mg) as an off-white solid, which was used for next step without further purification. MS (ESI) m/z 262.2 [M+H]+.
Reaction SMILES: [Si:1]([O-])([O-:4])([O-:3])[O-:2].[Na+:6].[Na+].[Na+].[Na+].[Si:10](O)([OH:13])([OH:12])[OH:11].O=[Al-:16]=O.[Na+]>>[O-:3][Si:1]([O-:4])=[O:2].[O-:12][Si:10]([O-:13])=[O:11].[Na+:6].[Al+3:16]
Reactant: O=[Al-]=O
Reactant: [O-][Si]([O-])([O-])[O-]
Reactant: O[Si](O)(O)O
Agent: [Na+]
Product: O=[Si]([O-])[O-]
Product: [Al+3]

Procedure:
The thus obtained polymeric sodium silicate is used as a silicic acid source, to which is added an alkali aluminate, for example, sodium aluminate (a molar ratio of Na2O to Al2O3 1.5 - 3.0 : 1) in a molar ratio of SiO2 to Al2O3 of 1.0 - 2.0 : 1. Thereby, the sodium aluminate is bonded with polymeric sodium silicate by the lattice siloxane structure as a frame to produce sodium aluminosilicate, (1.0 - 2.0) SiO2.Al2O3.(2.0 - 1.0)Na2O. Here, part of sodium hydroxide is isolated according to an amount of aluminate ion bonded. Further, an amount of a water soluble magnesium salt, for example, magnesium chloride corresponding to the alkali amount of the sodium aluminosilicate is added in a molar ratio of MgO to Al2O3 of 1.0 - 2.0 : 1 to effect double decomposition. Thus, the desired magnesium aluminosilicate is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:19]=[CH:18][C:15]([C:16]#[N:17])=[CH:14][CH:13]=1)[C:6]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[C:5]2[CH3:26].[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+].CN(C=[O:37])C>>[NH4+:7].[OH-:37].[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:16]3[N:27]=[N:28][NH:29][N:17]=3)=[CH:18][CH:19]=1)[C:6]([C:20]1[CH:21]=[N:22][CH:23]=[CH:24][CH:25]=1)=[C:5]2[CH3:26]
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1c(-c2cccnc2)n(Cc2ccc(C#N)cc2)c2ccc(Cl)cc12
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1c(-c2cccnc2)n(Cc2ccc(-c3nn[nH]n3)cc2)c2ccc(Cl)cc12
Product: [OH-]
Temperature: 120 °C

Procedure:
To a solution of 4-(5-chloro-3-methyl-2-pyridin-3-yl-indol-1-ylmethyl)-benzonitrile (Example 17, 179 mg, 0.5 mmol) in DMF (5 mL) is added sodium azide (97 mg, 1.5 mmol) and ammonium chloride (80 mg, 1.5 mmol) and the mixture is heated to 120° C. The reaction mixture is cooled to room temperature and filtered. The filtrate is purified by reverse phase HPLC with Xbridge C18 and a gradient of 0.1% NH4OH in acetonitrile to give 5-chloro-3-methyl-2-pyridin-3-yl-1-[4-(2H-tetrazol-5-yl)-benzyl]-1H-indole. 1H NMR (400 MHz, DMSO-d6) δ ppm 2.21 (s, 3H), 5.34 (s, 2H), 6.81 (d, J=8.1 Hz, 2H), 7.11 (br. s, 1H), 7.17 (dd, J=8.7, 2.1 Hz, 1H), 7.48-7.53 (m, 2H), 7.67 (d, J=2.0 Hz, 1H), 7.77 (d, J=8.3 Hz, 2H), 7.80-7.84 (m, 1H), 8.60 (d, J=1.5 Hz, 1H), 8.62 (dd, J=4.8, 1.5 Hz, 1H). HRMS (ESI) m/z 401.1276 [(M+H)+ Calcd for C22H18N6Cl: 401.1281].
Reaction SMILES: [N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7](Cl)=[O:8])([O-:3])=[O:2].[F:16][C:17]([F:23])([F:22])[C:18]([NH:20][NH2:21])=[O:19].N1C=CC=CC=1.Cl>C(OCC)C>[N+:1]([C:4]([N+:13]([O-:15])=[O:14])([N+:10]([O-:12])=[O:11])[CH2:5][CH2:6][C:7]([NH:21][NH:20][C:18](=[O:19])[C:17]([F:23])([F:22])[F:16])=[O:8])([O-:3])=[O:2]
Reactant: O=C(Cl)CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-]
Reactant: NNC(=O)C(F)(F)F
Agent: Cl
Solvent: c1ccncc1
Solvent: CCOCC
Product: O=C(CCC([N+](=O)[O-])([N+](=O)[O-])[N+](=O)[O-])NNC(=O)C(F)(F)F
Reaction time: 0.05 h

Procedure:
To 1.65 g (0.007 mole) of 4,4,4-trinitrobutyryl chloride in 15 mL of anhydrous diethyl ether stirred in a water bath at 15° C. was added 0.9 g (0.007 mole) of N-(trifluoroacetyl)hydrazine. Pyridine (0.6 mL, 0.007 mole) was added dropwise. After 3 minutes, dilute hydrochloric acid was added and the ether layer was separated and dried (Na2SO4). The volatiles were removed and the residue was stirred with water and then with CH2Cl2 to give the product N-(4,4,4-trinitrobutyryl)-N'-(trifluoroacetyl)hydrazine, 1.15 g (50%), mp 154°-156° C. Crystallization from 1,2-dichloroethane raised the melting point to 157°-159° C.; 1H NMR (acetone-d6 +D2O): 2.97 (t, 2H), 3.86 (t, 2H); IR (KBr): 3330, 3220 (NH), 1745, 1690 (C=O); 1610, 1590 (NO2); 1195 (C--F).