Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH:19]=[C:18]([C:20]([O:22]CC)=[O:21])[N:17]=[N:16]1)[CH3:2].[OH-].[Na+].O>C(O)C>[CH2:1]([O:3][C:4]1[CH:9]=[C:8]([C:10]([NH:12][CH2:13][CH3:14])=[O:11])[CH:7]=[CH:6][C:5]=1[N:15]1[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[N:17]=[N:16]1)[CH3:2]
Reactant: CCNC(=O)c1ccc(-n2cc(C(=O)OCC)nn2)c(OCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccc(-n2cc(C(=O)O)nn2)c(OCC)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 77.1 %

Procedure:
To a solution of ethyl 1-{2-ethoxy-4-[(ethylamino)carbonyl]phenyl}-1H-1,2,3-triazole-4-carboxylate (0.51 g) obtained in Example 131e) in ethanol (8 ml) was added 8N aqueous sodium hydroxide solution (0.39 ml), and the mixture was stirred at room temperature for 5 hr. Water was added to the reaction mixture, and ethanol was evaporated under reduced pressure. Water was added to the obtained aqueous solution and the mixture was washed with ethyl acetate. 1N Hydrochloric acid was added to acidify the aqueous solution. The deposited precipitate was collected by filtration, washed with water and air-dried to give the title compound as a white powder (0.36 g, 76%).
Reaction SMILES: [CH2:1]([C:3]1[CH:27]=[CH:26][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[C:19]4=[N:20][S:21](=[O:25])(=[O:24])[CH2:22][CH2:23][N:18]4[CH:17]=[CH:16][CH:15]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)[CH3:2]>C1COCC1.CO.[Pt](=O)=O>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:9]=[CH:10][C:11]([CH:14]3[C:19]4=[N:20][S:21](=[O:24])(=[O:25])[CH2:22][CH2:23][N:18]4[CH2:17][CH2:16][CH2:15]3)=[CH:12][CH:13]=2)=[CH:26][CH:27]=1)[CH3:2]
Reactant: CCc1ccc(Oc2ccc(C3=CC=CN4CCS(=O)(=O)N=C34)cc2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CO
Product: CCc1ccc(Oc2ccc(C3CCCN4CCS(=O)(=O)N=C34)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 30.2 %

Procedure:
To a suspension of NaH (60%, 81 mg) in THF (dry) (10 mL) was added 2-chloroethanesulfonyl chloride (0.085 mL) at 0° C. and the mixture was stirred for 10 min at the same temperature. A solution of 3-(4-(4-ethylphenoxy)phenyl)pyridin-2-amine (117 mg) in THF (dry) (10 mL) was added at 0° C. and the mixture was stirred at room temperature under nitrogen for 4 hr. The mixture was quenched with water at 0° C. Water, EtOAc and THF were added and the mixture was extracted. Silica-gel was added to the organic phase and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (silica gel, eluted with MeOH in EtOAc) and concentrated in vacuo to give 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide as a white solid. Platinum(IV) oxide (20 mg) was added to a solution of 9-[4-(4-ethylphenoxy)phenyl]-3,4-dihydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (153 mg) in THF (dry) (20 mL) and MeOH (20 mL). The mixture was stirred at room temperature under hydrogen for 3 hr. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Platinum(IV) oxide (20 mg) was added and the mixture was stirred at room temperature under hydrogen overnight. Activated carbon was added and the insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc) and the filtrate was concentrated in vacuo. The residue was crystallized from THF/IPE to give the title compound (46.7 mg) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][NH:5][C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10].[C:12](=O)([O-])[O-].[K+].[K+].CI.Cl>CN(C)C(=O)C.C(OCC)(=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]([CH3:12])[C:4](=[O:8])[C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: O=c1[nH]ccc(Cl)c1[N+](=O)[O-]
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CI
Solvent: O
Product: Cn1ccc(Cl)c([N+](=O)[O-])c1=O
Temperature: 45 °C
Yield: 66.1 %

Procedure:
A suspension of 4-chloro-3-nitro-2-pyridone (1.00 g, 5.7 mmol), potassium carbonate (1.58 g, 11.5 mmol) and methyl iodide (4.07 g, 28.7 mmol) in N,N-dimethylacetamide (5 ml) were heated at 45° C. for 18 h. The mixture was allowed to cool to ambient temperature, poured into water (100 ml), layered with ethyl acetate (50 ml) and pH adjusted to 5 by the addition of 5N hydrochloric acid. The aqueous phase was extracted into ethyl acetate (2×100 ml), the combined organics were washed with water (2×100 ml) and brine (50 ml), dried over anhydrous sodium sulfate, filtered and evaporated to give a pale yellow solid. The solid was triturated with diethyl ether (20 ml), filtered and washed with diethyl ether (5 ml) and isohexane (10 ml) and left to air dry, to give 4-chloro-1-methyl-3-nitro-1H-pyridin-2-one (0.71 g, 66%) as a pale yellow solid: δH (360 MHz, DMSO) 3.36 (1H, dd, J 5 and 3), 3.54 (6H, s), 6.69 (2H, d, J 7), 8.09 (2H, d, J 7).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]([NH:15][CH2:16][CH2:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:19])[CH3:14])=[CH:9][CH:8]=1.C([O-])([O-])=O.[Na+].[Na+].O(C(C)C)C(C)C>ClCCl.O>[CH3:5][O:4][C:2](=[O:3])[N:15]([C@H:13]([C:10]1[CH:11]=[CH:12][C:7]([Cl:6])=[CH:8][CH:9]=1)[CH3:14])[CH2:16][CH2:17][C:18](=[O:19])[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: COC(=O)Cl
Reactant: C[C@H](NCCC(=O)c1ccccc1)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: CC(C)OC(C)C
Product: COC(=O)N(CCC(=O)c1ccccc1)[C@@H](C)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Methyl chloroformate (15.5 mL) dissolved in dichloromethane (100 mL) was added to a mixture of 3-[(S)-1-(4-chloro-phenyl)-ethylamino]-1-phenyl-propan-1-one (38.0 g) and Na2CO3 (23.5 g) in a mixture of dichloromethane (100 mL) and water (100 mL) at such a rate that the solution temperature maintains between 20 and 26° C. After complete addition, the solution was stirred at ambient temperature for an additional 30 min. Then, the organic phase was separated and the aqueous phase was extracted once with dichloromethane. The combined organic phases were washed with brine and dried (MgSO4). Then, silica gel (20 g) was added and the resulting mixture was stirred vigorously for 30 min. The silica gel was separated by filtration, washed with dichloromethane (200 mL), and the combined filtrate was concentrated under reduced pressure to give an oil. The oil was treated with iPr2O (150 mL) to precipitate the title compound that was separated by filtration, washed with petroleum ether (30 mL), and dried. The filtrate was concentrated and the residue was taken up in petroleum ether (60 mL). The precipitate formed after a while of stirring was separated by filtration, washed with petroleum ether (20 mL), dried, and combined with the precipitate obtained before.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:28]([SH:30])[CH3:29]>CN(C=O)C.O>[CH2:28]([S:30][C:2]1[C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[C:10]([CH3:17])[C:9]2[C:4](=[CH:5][C:6]([C:18]([F:21])([F:20])[F:19])=[CH:7][N:8]=2)[N:3]=1)[CH3:29]
Reactant: CCS
Reactant: CCOC(=O)c1c(Cl)nc2cc(C(F)(F)F)cnc2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(SCC)nc2cc(C(F)(F)F)cnc2c1C
Temperature: 60 °C
Reaction time: 16 h
Yield: 71.5 %

Procedure:
To a solution of ethyl 2-chloro-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.97 g, 3.05 mmol, 1 eq.) in DMF (10 ml) were added K2CO3 (1.26 g, 9.15 mmol, 3 eq.) and ethanethiol (0.66 ml, 9.15 mmol, 3 eq.) at RT. The mixture was stirred at 60° C. for 16 h. Afterwards the mixture was diluted with water (80 ml) and was extracted with EtOAc (3×80 ml). The combined organic layers were washed with water (100 ml), brine (100 ml), dried over anhydrous Na2SO4 and evaporated to provide the crude product, which is purified by CC (EtOAc/hexane 1:9) to yield ethyl 2-(ethylthio)-4-methyl-7-(trifluoromethyl)-1,5-naphthyridine-3-carboxylate (0.75 g, 2.18 mmol, 71%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:10]=[N:11][N:12]([CH3:17])[C:13]=1[C:14]([OH:16])=O.[Cl:18][C:19]1[C:24]([N:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[CH:23][C:22]([NH:31][C:32](=[O:43])[C:33]2[CH:38]=[CH:37][C:36]([CH2:39][N:40]([CH3:42])[CH3:41])=[CH:35][CH:34]=2)=[C:21]([N+:44]([O-:46])=[O:45])[CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C1C=CN=CC=1)C.CN1C(=O)CCC1>[Cl:18][C:19]1[C:24]([N:25]2[CH2:26][CH2:27][N:28]([C:14]([C:13]3[N:12]([CH3:17])[N:11]=[N:10][C:9]=3[C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=3[O:2][CH3:1])=[O:16])[CH2:29][CH2:30]2)=[CH:23][C:22]([NH:31][C:32](=[O:43])[C:33]2[CH:34]=[CH:35][C:36]([CH2:39][N:40]([CH3:42])[CH3:41])=[CH:37][CH:38]=2)=[C:21]([N+:44]([O-:46])=[O:45])[CH:20]=1
Reactant: COc1ccccc1-c1nnn(C)c1C(=O)O
Reactant: CN(C)Cc1ccc(C(=O)Nc2cc(N3CCNCC3)c(Cl)cc2[N+](=O)[O-])cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: CN(C)c1ccncc1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Product: COc1ccccc1-c1nnn(C)c1C(=O)N1CCN(c2cc(NC(=O)c3ccc(CN(C)C)cc3)c([N+](=O)[O-])cc2Cl)CC1
Reaction time: 3 h
Yield: 25.6 %

Procedure:
A mixture of 4-(2-methoxyphenyl)-1-methyl-1H-1,2,3-triazole-5-carboxylic acid (44.7 mg, 0.192 mmol), N-(4-chloro-2-nitro-5-(piperazin-1-yl)phenyl)-4-((dimethylamino)methyl)benzamide (85 mg, 0.160 mmol), HATU (79 mg, 0.208 mmol), and DMAP (78 mg, 0.639 mmol) in NMP (2 mL) was stirred for 3 h. HPLC purification, then silica column purification afforded the title compound (28 mg, 0.041 mmol). 1H-NMR (CDCl3, 500 MHz): δ11.62 (1H, s), 8.57 (1H, s), 8.31 (1H, s), 8.06 (2H, d, J=8.24 Hz), 7.81 (1H, d, J=7.24 Hz), 7.69 (2H, d, J=7.93 Hz), 7.43 (1H, t, J=8.24 Hz), 7.13 (1H, t, J=7.32 Hz), 7.01 (1H, d, J=7.24 Hz), 4.28 (2H, s), 4.20 (2H, s), 3.94 (2H, m), 3.83 (3H, s), 3.25 (4H, s), 2.83 (6H, s), 2.68 (2H, m). HPLC/MS (Method J): (ES+) m/z (M+H)+=633; Rt=1.52 min.
Reaction SMILES: [C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[C:15]([F:16])=[CH:14][C:13]([C:17](=[O:29])[C:18](=[CH:24][NH:25][CH:26]3[CH2:28][CH2:27]3)[C:19]([O:21][CH2:22][CH3:23])=[O:20])=[C:12](F)[CH:11]=2)[CH2:6]1)(=[O:3])[CH3:2].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[C:1]([NH:4][CH:5]1[CH2:9][CH2:8][CH:7]([C:10]2[CH:11]=[C:12]3[C:13]([C:17](=[O:29])[C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:24][N:25]3[CH:26]3[CH2:28][CH2:27]3)=[CH:14][C:15]=2[F:16])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(=CNC1CC1)C(=O)c1cc(F)c(C2CCC(NC(C)=O)C2)cc1F
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C2CC2)c2cc(C3CCC(NC(C)=O)C3)c(F)cc2c1=O
Yield: 82.4 %

Procedure:
A solution of 21.0 g (50 mmol) of 4-[3-(acetylamino) cyclopentyl]-α-[(cyclopropylamino)methylene]-2,5-difluoro-β-oxobenzenepropanoic acid, ethyl ester in 250 ml of dry t-butanol was treated with a slurry of 6.2 g (55 mmol) of potassium t-butoxide in 50 ml of dry t-butanol. The resulting suspension was stirred and heated at 65° for 3 hours and then at room temperature overnight. The solvent was removed in vacuo and the residue was dissolved in methylene chloride and washed with 1.0 M hydrochloric acid. After drying (MgSO4) and evaporating the solvent in vacuo, the residue was recrystallized from ethyl acetate/hexane to give 16.5 g of the title compound.
Reaction SMILES: C[C:2]1[NH:6][C:5]([C:7]2[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH:14]=[N:15][NH:16][C:17]([O:19]C)=O.Cl[C:22]1C=CC=CC=1Cl>>[CH3:22][C:14]1[C:3]2[N:4]([C:5]([C:7]3[CH:8]=[C:9]([CH3:13])[CH:10]=[CH:11][CH:12]=3)=[N:6][CH:2]=2)[C:17](=[O:19])[NH:16][N:15]=1
Reactant: Clc1ccccc1Cl
Reactant: COC(=O)NN=Cc1nc(-c2cccc(C)c2)[nH]c1C
Product: Cc1cccc(-c2ncc3c(C)n[nH]c(=O)n23)c1
Temperature: 25 °C
Reaction time: 15.5 h

Procedure:
A mixture of 3-[(5-methyl-2-m-tolyl-4-imidazolyl)-methylene]carbazic acid, methyl ester (5.1 g, 0.019 mole) and o-dichlorobezene (75 ml) is heated slowly (45 minutes) to reflux, refluxed for 1.5 hours, then stirred at room temperature over night (appr. 15-16 hours). The reaction mixture is filtered to afford 3.9 g (0.016 mole) title product. Recrystallization from o-dichlorobenzene yields partially solvated product, m.p. 188°-198° C.
Reaction SMILES: C(OC(=O)[NH:7][C:8](=[NH:43])[C:9]1[S:10][C:11]([S:41][CH3:42])=[C:12]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]3[C:31]4[N:30]=[CH:29][N:28](COCC[Si](C)(C)C)[C:27]=4[CH:26]=[CH:25][C:24]=3[CH3:40])[CH:18]=2)(=[O:16])=[O:15])[CH:13]=1)(C)(C)C>C(O)(C(F)(F)F)=O>[CH3:40][C:24]1[CH:25]=[CH:26][C:27]2[NH:28][CH:29]=[N:30][C:31]=2[C:23]=1[C:19]1[CH:18]=[C:17]([S:14]([C:12]2[CH:13]=[C:9]([C:8]([NH2:43])=[NH:7])[S:10][C:11]=2[S:41][CH3:42])(=[O:15])=[O:16])[CH:22]=[CH:21][CH:20]=1
Reactant: CSc1sc(C(=N)NC(=O)OC(C)(C)C)cc1S(=O)(=O)c1cccc(-c2c(C)ccc3c2ncn3COCC[Si](C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: CSc1sc(C(=N)N)cc1S(=O)(=O)c1cccc(-c2c(C)ccc3[nH]cnc23)c1
Temperature: 25 °C
Yield: 150.6 %

Procedure:
A solution of [Imino-(5-methylsulfanyl-4-{3-[5-methyl-1-(2-trimethylsilanyl-ethoxymethyl)-1H-benzoimidazol-4-yl]-benzenesulfonyl}-thiophen-2-yl)-methyl]-carbamic acid tert-butyl ester (14 mg, 0.021 mmol, Example 287: step c) in 1 mL of TFA was heated at 50° C. for 2 h under Ar, cooled to RT. Removal of the solvent under reduced pressure followed by flash chromatography of the residue on silica gel (10–15% MeOH/CH2Cl2) gave 14 mg (100%) of product as colorless oil: 1H-NMR (CD3OD; 400 MHz) δ 9.28 (s, 1H). 8.35 (s, 1H), 8.20 (d, 1H, J=7.6 Hz). 8.11 (s, 1H), 7.86 (dd, 1H, J=7.7, 7.7), 7.80 (m, 2H), 7.63 (d, 1H, J=8.6 Hz), 2.72 (s, 3H), 2.30 (s, 3H). Mass spectrum (ESI, m/z): Calcd. for C20H18N4O2S3, 443.1.00 (M+H), found 443.1.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[CH2:22]2)=[O:20])[CH2:13][CH2:12]1)=O)C1C=CC=CC=1.[ClH:35]>[Pd].O1CCCC1>[ClH:35].[NH:11]1[CH2:16][CH2:15][CH:14]([O:17][CH2:18][C:19]([N:21]2[CH2:26][CH2:25][CH2:24][CH:23]([C:27]([NH:29][CH2:30][CH2:31][C:32]([OH:34])=[O:33])=[O:28])[CH2:22]2)=[O:20])[CH2:13][CH2:12]1
Reactant: O=C(O)CCNC(=O)C1CCCN(C(=O)COC2CCN(C(=O)OCc3ccccc3)CC2)C1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: O=C(O)CCNC(=O)C1CCCN(C(=O)COC2CCNCC2)C1
Reaction time: 2 h

Procedure:
A mixture of N-[1-{2-(1-benzyloxycarbonyl-4-piperidyloxy)acetyl}-3-piperidylcarbonyl]-β-alanine (1.16 g) and 10% Pd—C (0.23 g, 50% wet) in a solution of 1N HCl (2.44 ml) and tetrahydrofuran (20 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo and freeze-dried to give N-[1-{2-(4-piperidyloxy)acetyl}-3-piperidylcarbonyl]-β-alanine hydrochloride (0.69 g).
Reaction SMILES: C[O:2][C:3](=[O:39])[C:4]1[CH:9]=[CH:8][C:7]([NH:10][CH2:11][CH2:12][C:13]2[C:21]3[C:16](=[CH:17][CH:18]=[C:19]([Cl:22])[CH:20]=3)[N:15]([CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:14]=2[CH2:36][CH2:37][NH2:38])=[CH:6][CH:5]=1.[Cl:40][C:41]1[CH:46]=[CH:45][CH:44]=[C:43]([CH3:47])[C:42]=1[S:48](Cl)(=[O:50])=[O:49]>>[CH:23]([N:15]1[C:16]2[C:21](=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=2)[C:13]([CH2:12][CH2:11][NH:10][C:7]2[CH:8]=[CH:9][C:4]([C:3]([OH:39])=[O:2])=[CH:5][CH:6]=2)=[C:14]1[CH2:36][CH2:37][NH:38][S:48]([C:42]1[C:43]([CH3:47])=[CH:44][CH:45]=[CH:46][C:41]=1[Cl:40])(=[O:50])=[O:49])([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: COC(=O)c1ccc(NCCc2c(CCN)n(C(c3ccccc3)c3ccccc3)c3ccc(Cl)cc23)cc1
Reactant: Cc1cccc(Cl)c1S(=O)(=O)Cl
Product: Cc1cccc(Cl)c1S(=O)(=O)NCCc1c(CCNc2ccc(C(=O)O)cc2)c2cc(Cl)ccc2n1C(c1ccccc1)c1ccccc1
Yield: 85 %

Procedure:
The intermediate from Example 143 step 12 was treated with 2-chloro-6-methyl-benzenesulfonyl chloride according to the procedure in Example 87 step 2 to generate the desired product in 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[CH:12][NH:11][N:10]=2)=[C:5]2[NH:14][CH:15]=[C:16]([C:17](=[O:37])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[N:29]=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:4]=12.[H-].[Na+].[CH3:40]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:8]=[N:7][C:6]([C:9]2[CH:13]=[CH:12][N:11]([CH3:40])[N:10]=2)=[C:5]2[NH:14][CH:15]=[C:16]([C:17](=[O:37])[C:18]([N:20]3[CH2:25][CH2:24][N:23]([C:26]4[N:30]([C:31]5[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=5)[N:29]=[N:28][N:27]=4)[CH2:22][CH2:21]3)=[O:19])[C:4]=12
Reactant: CI
Reactant: COc1cnc(-c2cc[nH]n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cnc(-c2ccn(C)n2)c2[nH]cc(C(=O)C(=O)N3CCN(c4nnnn4-c4ccccn4)CC3)c12
Yield: 23.9 %

Procedure:
To a solution of 1-(4-methoxy-7-(1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione (0.069 g, 0.138 mmol) in DMF (3 mL) was added NaH (0.055 g, 1.381 mmol). The mixture was stirred for ten minutes and MeI (0.017 mL, 0.276 mmol) was added. After being stirred for 45 minutes, the mixture was quenched with water. The mixture was concentrated under reduced pressure. The resulting residue was diluted with DMF and was passed through a plug of cotton to remove solids. The DMF solution was purified by prep HPLC to give 1-(4-methoxy-7-(1-methyl-1H-pyrazol-3-yl)-1H-pyrrolo[2,3-c]pyridin-3-yl)-2-(4-(1-(pyridin-2-yl)-1H-tetrazol-5-yl)piperazin-1-yl)ethane-1,2-dione as a light-yellow solid (0.017 g, 0.033 mmol, 33.1% yield). 1H NMR (500 MHz, DMSO-D6) δ ppm 12.37 (s, 1H) 8.67 (dd, J=4.88, 1.22 Hz, 1H) 8.33 (s, 1H) 8.13-8.18 (m, 1H) 8.05 (s, 1H) 7.93 (d, J=2.14 Hz, 1H) 7.85 (d, J=7.93 Hz, 1H) 7.64 (dd, J=7.48, 4.73 Hz, 1H) 6.99 (s, 1H) 4.05 (s, 3H) 4.00 (s, 3H) 3.70-3.74 (m, 2H) 3.40-3.48 (m, 4H) 3.24-3.29 (m, 2H). LCMS: m/e 514.38 (M+H)+, ret time 1.820 min (method 1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[N+:23]([O-])([OH:25])=[O:24].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].[OH-].[Na+]>O>[Cl:1][C:2]1[C:7]([N+:23]([O-:25])=[O:24])=[C:6]([CH3:8])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cc(Cl)nc(Cl)c1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: Cc1cc(Cl)nc(Cl)c1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 18 h
Yield: 92.9 %

Procedure:
To a suspension of 2,6-dichloro-4-methylpyridine (1 g, 6.17 mmol) in trifluoroacetic acid anhydride (5 mL, 35.4 mmol) cooled down to 0° C. was added dropwise nitric acid (0.579 mL, 12.96 mmol) into it. The resulting solution was stirred at RT for 18 hr. The reaction mixture was added slowly to a chilled solution of sodium metabisulfite (1.183 g, 6.17 mmol) in water (8 mL) and stirred at RT for 2 hr. The reaction mixture was neutralized to pH 7 using 8N NaOH solution and extracted twice with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure to afford the title product (1.187 g, 5.73 mmol, 93% yield) as white solid. tR: 1.07 min (LC-MS 2); ESI-MS: 208 [M+H]+ (LC-MS 2); 1H NMR (400 MHz, DMSO-d6) δ ppm 2.39 (s, 3H) 7.90 (s, 1H).
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[C@H:35]([CH2:36][OH:37])[CH2:34][C@H:33]2[C@@H:31]1[CH2:32]2)=[O:29])([CH3:26])([CH3:25])[CH3:24].C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+]>C(Cl)Cl>[C:23]([O:27][C:28]([N:30]1[C@H:35]([CH:36]=[O:37])[CH2:34][C@H:33]2[C@@H:31]1[CH2:32]2)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)C[C@@H]2C[C@@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2C[C@@H]21

Procedure:
Dess-Martin periodinane (39.4 mmol, 2.1 eq) is added to a solution of (1S,3S,5S)-3-hydroxymethyl-2-aza-bicyclo[3.1.0]hexane-2-carboxylic acid tert-butyl ester (18.8 mmol, 1.0 eq) in DCM (300 mL). After 2 h sat. NaHCO3 solution and aqueous Na2S2O3 solution are added, the layers are separated and the aqueous layer is extracted twice with DCM. The combined organic layers are washed twice with NaOH solution (1.0 M), water and brine, dried over Na2SO4 and concentrated in vacuo to give the desired product as an orange oil which is used without further purification.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]Cl)=[C:6]([C:12]([Cl:15])([Cl:14])[Cl:13])[CH:5]=1)([O-:3])=[O:2].[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([SH:23])[N:18]=1>O>[OH:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([S:23][S:10][C:7]2[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=2[C:12]([Cl:15])([Cl:14])[Cl:13])[N:18]=1
Reactant: O=[N+]([O-])c1ccc(SCl)c(C(Cl)(Cl)Cl)c1
Reactant: Oc1ccnc(S)n1
Solvent: O
Product: O=[N+]([O-])c1ccc(SSc2nccc(O)n2)c(C(Cl)(Cl)Cl)c1
Yield: 94.1 %

Procedure:
61.4 g of 4-nitro-2-trichloromethylbenzenesulfenyl chloride are reacted with 26.6 g of 4-hydroxy-2-mercaptopyrimidine by a method similar to that described in Example 7. Water is then added and the product is filtered off. 75 g (94% of theory) of 4-hydroxypyrimidin-2-yl-dithio-(4-nitro-2-trichloromethylbenzene), of melting point 174° C., are obtained.
Reaction SMILES: [H][H].[Si:3]([O:10][CH2:11][CH:12]([NH:14]C(=O)OCC1C=CC=CC=1)[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]>[Pd].C(O)C>[Si:3]([O:10][CH2:11][CH:12]([NH2:14])[CH3:13])([C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:5])[CH3:4]
Reactant: [H][H]
Reactant: CC(CO[Si](C)(C)C(C)(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCO
Product: CC(N)CO[Si](C)(C)C(C)(C)C
Yield: 80.3 %

Procedure:
Hydrogen was introduced into a mixture of 4.0 g of benzyl N-(2-t-butyldimethylsilyloxy-1-methylethyl)carbamate (prepared as described in Preparation 8), 0.80 g of 10% w/w palladium-on-carbon and 40 ml of ethanol for 1 hour. At the end of this time, the atmosphere was replaced by nitrogen, the palladium-on-carbon was removed by filtration from the reaction mixture, and the filtrate was concentrated by evaporation under reduced pressure, to give 1.88 g of the title compound having an Rf value of 0.27 (on silica gel thin layer chromatography, using a 1:3 by volume mixture of ethyl acetate and hexane as the developing solvent).
Reaction SMILES: Cl.Br.N[C:4]1[C:5]([CH:18]([CH3:20])[CH3:19])=[C:6]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[Br:10].[Br:21]C1C(C(C)C)=CC(S(N)(=O)=O)=C(C(C)C)C=1C#N>>[Br:21][C:4]1[C:5]([CH:18]([CH3:20])[CH3:19])=[C:6]([S:14]([NH2:17])(=[O:16])=[O:15])[CH:7]=[C:8]([CH:11]([CH3:13])[CH3:12])[C:9]=1[Br:10]
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(C#N)c1Br
Reactant: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(N)c1Br
Agent: Br
Agent: Cl
Product: CC(C)c1cc(S(N)(=O)=O)c(C(C)C)c(Br)c1Br

Procedure:
If hydrochloric acid is substituted for hydrobromic acid and cuprous cyanide for cuprous bromide, the 3-amino-4-bromo-2,5-diisopropylbenzenesulfonamide may be converted to 4-bromo-3-cyano-2,5-diisopropylbenzenesulfonamide.