Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]([F:6])([F:5])[F:4].C(N(CC)CC)C.[Br:14][C:15]1[CH:26]=[CH:25][C:18]([CH2:19][NH:20][CH2:21][CH2:22][O:23][CH3:24])=[CH:17][CH:16]=1>CN(C=O)C>[Br:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][N:20]([CH2:21][CH2:22][O:23][CH3:24])[CH2:2][C:3]([F:6])([F:5])[F:4])=[CH:25][CH:26]=1
Reactant: COCCNCc1ccc(Br)cc1
Reactant: FC(F)(F)CBr
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COCCN(Cc1ccc(Br)cc1)CC(F)(F)F
Reaction time: 18 h

Procedure:
To a solution of 2-bromo-1,1,1-trifluoroethane (0.74 ml) and triethylamine (1.13 ml) in DMF (30 ml) was added (4-bromobenzyl)-(2-methoxyethyl)amine (2.05 g). The resulting mixture was stirred for 18 h. The mixture was partitioned between ethyl acetate and water, the organic layer was dried and evaporated to an oil, which was purified by column chromatography eluting with a gradient of ethyl acetate (60 to 100%) in isohexane to give (4-bromobenzyl)-(2-methoxyethyl)-(2,2,2-trifluoroethyl) amine (1.84 g). 1H NMR (DMSO-D6) δ 2.1 (bs, 2H), 2.6 (t, 2H), 3.2 (s, 3H), 3.4 (t, 2H), 3.65 (d, 2H), 7.25 (d, 2H), 7.45 (d, 2H). c) (4-Bromobenzyl)-(2-methoxyethyl)amine 2-Methoxyethylamine (16 ml) was added to a solution of 4-bromobenzaldehyde (17.2 g) in THF (150 ml). Glacial acetic acid (5.32 ml) and MgSO4 (0.5 g) were added and the mixture was stirred for 45 min. Sodium triacetoxyborohydride (29.7 g) was added and the resulting mixture was stirred for 4 h. The mixture was partitioned between ethyl acetate and saturated sodium bicarbonate. The organic layer was dried and concentrated to an oil, which was purified by column chromatography, eluting with a gradient of ethyl acetate (10 to 100%) in isohexane, then eluting with methanol/DCM (10:90) to give (4-bromobenzyl)-(2-methoxyethyl)amine (13.0 g) as a yellow oil. MS (ES) 244 (M+H)+. 1H NMR (DMSO-D6) δ 2.05 (bs, 1H), 2.6 (t, 2H), 3.38 (t, 2H), 3.2 (s, 3H), 3.62 (s, 2H), 7.25 (d, 2H), 7.45 (d, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13]O)=[C:7]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[C:6]=2[CH:22]=1.P(Br)(Br)[Br:24].O.C(OCC)(=O)C>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][C:9]([CH3:12])([CH3:11])[C:8]([CH2:13][Br:24])=[C:7]([N:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]3=[O:21])[C:6]=2[CH:22]=1
Reactant: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CO
Reactant: BrP(Br)Br
Solvent: O
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CC1(C)Oc2ccc(Br)cc2C(n2ccccc2=O)=C1CBr
Yield: 236.2 %

Procedure:
6-bromo-2,2-dimethyl-3-hydroxymethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran (9.0 g, 0.0248 mol) was suspended in toluene (150 ml). Phosphorus tribromide (0.94 ml, 2.69 g, 0.0099 mol) was added and the mixture heated at reflux for two hours. The cooled solution was treated with water and ethyl acetate, the organic phase separated and washed three times with aqueous sodium chloride solution, and then dried and evaporated under reduced pressure. The residue was triturated with pentane and dried to afford 9.94 g of 6-bromo-2,2-dimethyl-3-bromomethyl-4-(2-oxo-1,2-dihydropyridin-1-yl)-2H-1-benzopyran, m.p. 175° C.
Reaction SMILES: [OH2:1].[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]>>[CH3:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[CH2:6]([OH:1])[CH3:7]
Reactant: O
Solvent: CCCCCC
Product: CCO

Procedure:
As a result, when a mixing ratio of hexane was 20% or less in the test, water remained in the removal of the solvent from the extract oil by a vacuum concentration whereby an emulsion was formed and, therefore, no yield was determined. However, when the mixing ratio of hexane was from 40 to 80%, the lipids were able to be recovered in a yield of 90% or higher. On the other hand, it was confirmed that purity of the phospholipid in the extract oil was almost constant in any mixing ratio of the solvents other than the case where 100% of hexane was used.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:24][C:18]3=[CH:19][N:20]=[C:21](Cl)[CH:22]=[C:17]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:25][S:26]([N:29]1[CH2:34][CH:33]=[C:32](B2OC(C)(C)C(C)(C)O2)[CH2:31][CH2:30]1)(=[O:28])=[O:27]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:15]2[O:24][C:18]3=[CH:19][N:20]=[C:21]([C:32]4[CH2:33][CH2:34][N:29]([S:26]([CH3:25])(=[O:28])=[O:27])[CH2:30][CH:31]=4)[CH:22]=[C:17]3[CH:16]=2)([CH3:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCN(S(C)(=O)=O)CC2)OC1(C)C
Reactant: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(Cl)ncc3o2)CC1
Product: CC(C)(C)OC(=O)N1CCC(C)(c2cc3cc(C4=CCN(S(C)(=O)=O)CC4)ncc3o2)CC1

Procedure:
The title compound is prepared from 4-(5-chloro-furo[2,3-c]pyridin-2-yl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester and 1-methanesulfonyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,2,3,6-tetrahydro-pyridine following a procedure analogous to that described for Example 1; the reaction is conducted at 150° C. LC (method 4): tR=1.58 min; Mass spectrum (ESI+): m/z=476 [M+H]+.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]([CH3:14])[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH3:20]O>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]([CH3:14])[C:11]([O:13][CH3:20])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CO
Reactant: CC(C(=O)O)c1ccc([N+](=O)[O-])cc1
Agent: O=S(=O)(O)O
Product: COC(=O)C(C)c1ccc([N+](=O)[O-])cc1

Procedure:
2-(4-Nitrophenyl)propionic acid is refluxed in methanol in the presence of sulfuric acid, to give methyl 2-(4-nitrophenyl)propanoate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]#[N:24])=[N:9]2)=[CH:4][CH:3]=1.[Cl-].[NH4+].[N-:27]=[N+:28]=[N-:29].[Na+]>CN(C)C=O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]3[NH:29][N:28]=[N:27][N:24]=3)=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C#N)nn2-c2ccc(F)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cc(-c3nnn[nH]3)nn2-c2ccc(F)cc2)cc1
Temperature: 105 °C
Reaction time: 10 h
Yield: 63.1 %

Procedure:
A mixture of 1-(4-fluoropheny)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonitrile (1 g), ammonium chloride (0.25 g) and sodium azide (0.24 g) in N,N-dimethylformamide (10 ml) was stirred at 105° C. for 10 hours. The mixture was poured into ice-water, and the precipitates were collected, washed with water, and recrystallized from a mixture of ethanol and tetrahydrofuran to give crystals of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]-3-(5-tetrazolyl)pyrazole (0.71 g).
Reaction SMILES: Cl.[NH2:2][C@@H:3]([CH2:17][CH2:18][CH2:19][CH3:20])[C@@H:4]([OH:16])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8].Cl.N[C@@H](CCCC)[C@H](O)CNS(C1C=CC=CN=1)(=O)=O.[C:41](=O)([O:60]C1C=CC([N+]([O-])=O)=CC=1)[O:42][C@H:43]([CH2:48][N:49]1[C:53]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:52]=2[N:51]=[CH:50]1)[C:44]([CH3:47])([CH3:46])[CH3:45].C(N(C(C)C)CC)(C)C>CN(C)C=O>[OH:16][C@@H:4]([C@@H:3]([NH:2][C:41](=[O:60])[O:42][C@H:43]([CH2:48][N:49]1[C:53]2[CH:54]=[C:55]([Cl:59])[C:56]([Cl:58])=[CH:57][C:52]=2[N:51]=[CH:50]1)[C:44]([CH3:47])([CH3:46])[CH3:45])[CH2:17][CH2:18][CH2:19][CH3:20])[CH2:5][NH:6][S:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1)(=[O:9])=[O:8]
Reactant: CC(C)(C)[C@@H](Cn1cnc2cc(Cl)c(Cl)cc21)OC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCCC[C@H](N)[C@@H](O)CNS(=O)(=O)c1ccccn1
Agent: CCCC[C@H](N)[C@H](O)CNS(=O)(=O)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCCC[C@H](NC(=O)O[C@H](Cn1cnc2cc(Cl)c(Cl)cc21)C(C)(C)C)[C@H](O)CNS(=O)(=O)c1ccccn1
Reaction time: 72 h
Yield: 50 %

Procedure:
73 mg (0.18 mmol) of N-[(2S,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride & N-[(2R,3S)-3-amino-2-hydroxyheptyl]-2-pyridinesulfonamide hydrochloride was slurried in 3.5 mL of anhydrous dimethylformamide. Addition of 80 mg (0.18 mmol) of (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl 4-nitrophenyl carbonate followed by 0.14 mL (0.72 mmol) of diisopropylethylamine resulted in a light yellow solution, which was stirred for 3 d. It was then concentrated under reduced pressure. The resulting residue was dissolved in ethyl acetate, and the solution was washed with a saturated aqueous sodium bicarbonate solution., dried over anhydrous magnesium sulfate, filtered, and concentrated. The residue was purified by silica gel chromatography eluting with a methanol:chloroform solution (1:9) to afford 54 mg (50%) of (1 S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1R)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate & (1S)-1-[(5,6-dichloro-1H-benzimidazol-1-yl)methyl]-2,2-dimethylpropyl (1S)-1-{(1S)-1-hydroxy-2-[(2-pyridinylsulfonyl)amino]ethyl}pentylcarbamate. ES-LCMS n/z 622 (M+Na) retention time=3.96 min.
Reaction SMILES: [C:1](Cl)(=O)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH2:21]([N:39]([C@@H:53]1[O:61][C@H:60]([CH2:62][OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@H:54]1[OH:55])[C:40](=[O:52])[CH2:41][C:42](=[O:51])[CH2:43][CH2:44][C:45](=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38].C(N(CC)CC)C.C1(C)C=CC=CC=1.C(O)(C)C>O1CCCC1>[CH2:21]([N:39]([C@@H:53]1[O:61][C@H:60]([CH:62]([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH3:1])[OH:63])[C@@H:58]([OH:59])[C@H:56]([OH:57])[C@H:54]1[OH:55])[C:40](=[O:52])[CH2:41][C:42](=[O:51])[CH2:43][CH2:44][C:45](=[O:50])[CH2:46][CH2:47][CH2:48][CH3:49])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH3:38]
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCN(C(=O)CC(=O)CCC(=O)CCCC)[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCCCCC(O)[C@H]1O[C@@H](N(CCCCCCCCCCCCCCCCCC)C(=O)CC(=O)CCC(=O)CCCC)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 20 °C
Reaction time: 24 h

Procedure:
1.2 g (0.004 mol) of octadecanoyl chloride and 2.0 g (0.0034 mol) of N-octadecyl-N-3,6-dioxodecanoyl-β-D-glucopyranosylamine in 50 ml of tetrahydrofuran are initially taken, and 0.4 g of triethylamine (0.004 mol) is added at 0° C. The mixture is stirred for 1 day at 20° C., the solid is filtered off with suction and the solvent is removed in a water-pump vacuum. The residue is chromatographed on a column containing 250 g of silica gel, using as mobile phase 10:1 toluene/isopropanol, and 1.9 g (65% of theory) of N-octadecyl-N-3,6-dioxodecoyl-(6-stearyl-β-D-glucopyranosyl)-amine are obtained, having an Rf value of 0.296 (6:1 toluene/isopropanol).
Reaction SMILES: C[O:2][C:3](=[O:22])[CH2:4][CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[C:15](Br)[CH:14]=2)=[CH:8][C:7]=1[CH3:21].[CH2:23]([C:30]1[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[CH:32][C:31]=1[OH:38])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([C:30]1[CH:35]=[C:34]([CH2:36][CH3:37])[CH:33]=[CH:32][C:31]=1[O:38][C:15]1[CH:14]=[C:13]([CH:18]=[C:17]([F:19])[CH:16]=1)[O:12][C:9]1[CH:10]=[CH:11][C:6]([CH2:5][CH2:4][C:3]([OH:2])=[O:22])=[C:7]([CH3:21])[CH:8]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)CCc1ccc(Oc2cc(F)cc(Br)c2)cc1C
Reactant: CCc1ccc(O)c(Cc2ccccc2)c1
Product: CCc1ccc(Oc2cc(F)cc(Oc3ccc(CCC(=O)O)c(C)c3)c2)c(Cc2ccccc2)c1

Procedure:
The title compound is prepared by reacting the compound of 3-[4-(3-bromo-5-fluoro-phenoxy)-2-methyl-phenyl]-propionic acid methyl ester with 2-benzyl-4-ethyl-phenol as in Example 18 to afford 0.040 g (13%). 1H NMR (400 MHz, CDCl3); MS (ES+) m/z mass calculated for C31H29O4F 484, found 485 (M+1, 100%).
Reaction SMILES: [Br:1][CH2:2][C:3]([CH:5]1[O:10][C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6]1)=[O:4].[BH4-].[Na+].Br>CO>[O:10]1[C:9]2[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=2[O:7][CH2:6][CH:5]1[CH:3]([OH:4])[CH2:2][Br:1]
Reactant: O=C(CBr)C1COc2ccccc2O1
Agent: Br
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: OC(CBr)C1COc2ccccc2O1
Temperature: -70 °C
Reaction time: 12 h
Yield: 25.8 %

Procedure:
2-Bromoacetyl-1,4-benzodioxan(53.8 g) in methanol (500 mls) was cooled to -70° C. Sodium borohydride (10.3 g) was added and the solution stirred at -70° C. for 12 hours. The solution was treated with hydrobromic acid until acidic and the solvent evaporated. The residue was dissolved in ether and the ether extracts were washed with sodium bicarbonate solution; then water and dried (MgSO4) and evaporated to give a white solid. This was recrystallised eight times from petroleum spirit 60-80 to give 14 grams of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[NH:14][C:13](=[O:15])[CH2:12][S:11][CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[H-].[Na+].[C:18]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)(=[O:20])[CH3:19]>C1COCC1>[F:8][C:6]1[CH:5]=[C:4]([C@@H:9]2[CH2:10][S:11][CH2:12][C:13](=[O:15])[N:14]2[CH2:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:20])[CH:3]=[C:2]([F:1])[CH:7]=1
Reactant: O=C1CSC[C@@H](c2cc(F)cc(F)c2)N1
Reactant: CC(=O)OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CN1C(=O)CSC[C@H]1c1cc(F)cc(F)c1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a 0° C. solution of (5R)-5-(3,5-difluorophenyl)thiomorpholin-3-one (247 mg, 1.08 mmol, prepared by analogy to Intermediate 2) in THF (8.0 mL) was added sodium hydride (38 mg, 1.5 mmol, 95% by weight). After 5 minutes, the ice bath was removed and the reaction was allowed to warm to ambient temperature. Once hydrogen gas evolution had ceased, as judged by an oil bubbler, the reaction mixture was cooled to 0° C., prior to the introduction of benzyl acetate (272 mg, 1.19 mmol). After 5 minutes, the ice bath was removed and the reaction was stirred for 15 hours. The bulk of the THF was removed under reduced pressure. The residue was then diluted with water and ether. The aqueous layer was extracted once with ether and the combined organics were washed with saturated brine. The organics were then dried over sodium sulfate, filtered, and concentrated in vacuo to give a residue that was purified by silica gel chromatography, eluting with a gradient of MeOH:DCM-0.5:99.5 to 5:95, to give the title compound. MS: m/z=378 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[H-].[Na+].[CH:13]([Si:16](Cl)([CH:20]([CH3:22])[CH3:21])[CH:17]([CH3:19])[CH3:18])([CH3:15])[CH3:14].[Cl-].[NH4+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[N:8]([Si:16]([CH:20]([CH3:22])[CH3:21])([CH:17]([CH3:19])[CH3:18])[CH:13]([CH3:15])[CH3:14])[CH:9]=[CH:10][C:3]=12
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Reactant: Clc1ccnc2[nH]ccc12
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)[Si](C(C)C)(C(C)C)n1ccc2c(Cl)ccnc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 98.7 %

Procedure:
4-Chloro-1H-pyrrolo[2,3-b]pyridine (5.0 g, 32.8 mmol) in THF (50 mL) was cooled to 0° C., and NaH (1.64 g, 41.0 mmol, 60% oil dispersion) was added. After 15 minutes, triisopropylsilylchloride (“TIPS-Cl”; 6.94 mL, 32.8 mmol) was added, and the reaction was stirred at room temperature for 1 hour. A saturated ammonium chloride solution (20 mL) was added, and the mixture was extracted with hexanes (40 mL), washed with brine and dried over sodium sulfate. After removal of the solvent, the residue was purified by chromatography (hexanes) to give 4-chloro-1-(triisopropylsilyl)-1H-pyrrolo[2,3-b]pyridine (10.0 g, 99% yield) as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@H:12]2[NH:17][C:18](=O)[C:19]2[CH:24]=[CH:23][C:22]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)(=[O:28])=[O:27])=[CH:21][CH:20]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].P(Cl)(Cl)(Cl)=O.C(=O)([O-])O.[Na+]>C(#N)C>[CH3:10][O:9][C:8]1[CH:7]=[C:6]2[C:5](=[CH:4][C:3]=1[O:2][CH3:1])[C@H:11]1[C@H:12]([CH2:13][CH2:14][CH2:15][CH2:16]1)[N:17]=[C:18]2[C:19]1[CH:20]=[CH:21][C:22]([NH:25][S:26]([C:29]2[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=2)(=[O:27])=[O:28])=[CH:23][CH:24]=1
Reactant: COc1ccc([C@H]2CCCC[C@H]2NC(=O)c2ccc(NS(=O)(=O)c3ccc(C)cc3)cc2)cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc2c(cc1OC)[C@@H]1CCCC[C@@H]1N=C2c1ccc(NS(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
3.5 g of (+/-)-cis-N-[2-(3,4-dimethoxyphenyl)cyclohexyl]-4-p-toluenesulfonamidobenzamide are dissolved in 100 ml of acetonitrile and 1.0 ml of phosphorus oxychloride and the solution is stirred at 50° C. for 8 h. The reaction mixture is added to 100 ml of saturated sodium hydrogencarbonate solution and extracted with ethyl acetate. The organic phase is washed with sodium hydrogencarbonate solution and water, dried using sodium sulfate and concentrated. The residue is recrystallized from ethanol. 1.8 g (53.2% of theory) of the title compound of melting point: 122° C. (decomposition) are obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([Cl:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].CN1CCCC1=O.[Cl:23][C:24]1[C:29](F)=[C:28]([C:31]([F:34])([F:33])[F:32])[CH:27]=[CH:26][N:25]=1>O>[Cl:23][C:24]1[C:29]([O:9][C:4]2[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=2)=[C:28]([C:31]([F:32])([F:33])[F:34])[CH:27]=[CH:26][N:25]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: Fc1c(C(F)(F)F)ccnc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: FC(F)(F)c1ccnc(Cl)c1Oc1cc(Cl)cc(Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a round bottom flask charged with 3,5-dichlorophenol (1.23 g, 7.52 mmol) and potassium carbonate (1.04 g, 7.52 mmol) was added N-methylpyrrolidinone (5 mL). To this suspension under N2 was added 2-chloro-3-fluoro-4-(trifluoromethyl)pyridine (1.50 g, 7.52 mmol) and the reaction mixture was placed in an oil bath at 120° C. After 60 minutes, the reaction mixture was allowed to cool to room temperature, water (20 mL) was added and the mixture was extracted with ethyl acetate (2×25 mL). The combined organic extracts were washed with brine (3×25 mL), dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The resulting residue was purified by column chromatography on a pre-packed silica gel Redi Sep 80 gram column, eluting with 0-75% CH2Cl2 in hexanes to afford the title compound. 1H NMR (DMSO-d6) δ 8.52 (d, J=4.5 Hz, 1H), 7.60 (d, J=4.6 Hz, 1H), 7.14-7.10 (m, 1H), 6.72-6.68 (m, 2H). HRMS (M+1)=341.9465.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]=1[N+:24]([O-])=O.[O-]S(S([O-])=O)=O.[Na+].[Na+]>>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[CH:5]=[CH:4][C:3]=1[C:10]1[CH:15]=[CH:14][N:13]=[C:12]([NH:16][CH:17]([CH2:21][CH2:22][CH3:23])[CH2:18][CH2:19][CH3:20])[C:11]=1[NH2:24]
Reactant: CCCC(CCC)Nc1nccc(-c2ccc(OC)cc2Cl)c1[N+](=O)[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Product: CCCC(CCC)Nc1nccc(-c2ccc(OC)cc2Cl)c1N
Yield: 171.8 %

Procedure:
[4-(2-Chloro-4-methoxy-phenyl)-3-nitro-pyridin-2-yl]-(1-propyl-butyl)-amine (0.31 g, 0.82 mmol) and Na2S2O4 (1.15 g, 6.62 mmol) were treated substantially as described in Part E of Example 9 to give 0.49 g (100%) 4-(2-chloro-4-methoxy-phenyl)-N2-(1-propyl-butyl)-pyridine-2,3-diamine: MS (AP) m/z 347.9 [(M+H)+, 100].
Reaction SMILES: [CH2:1]([C:5]1[S:9][C:8]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:7]([C:14]2[CH:19]=[CH:18][C:17]([CH2:20][N:21]3[N:25]=[N:24][CH:23]=[N:22]3)=[CH:16][CH:15]=2)[CH:6]=1)[CH:2]([CH3:4])[CH3:3].N1(C2C=CC=CN=2)CCCC1.Cl[C:38]([O:40][CH2:41][CH2:42][CH2:43][CH3:44])=[O:39].C(C1SC(S(NC(C)(C)C)(=O)=O)=C(C2C=CC(CN3N=NC=N3)=CC=2)C=1)C(C)C>N1C=CC=CC=1>[CH2:41]([O:40][C:38]([NH:13][S:10]([C:8]1[S:9][C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[N:25]=[N:24][CH:23]=[N:22]2)=[CH:16][CH:15]=1)(=[O:12])=[O:11])=[O:39])[CH2:42][CH2:43][CH3:44]
Reactant: CCCCOC(=O)Cl
Reactant: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(N)(=O)=O)s1
Agent: CC(C)Cc1cc(-c2ccc(Cn3ncnn3)cc2)c(S(=O)(=O)NC(C)(C)C)s1
Agent: c1ccc(N2CCCC2)nc1
Solvent: c1ccncc1
Product: CCCCOC(=O)NS(=O)(=O)c1sc(CC(C)C)cc1-c1ccc(Cn2ncnn2)cc1
Temperature: 25 °C
Reaction time: 30 h
Yield: 54 %

Procedure:
The crude product from step (d) above was dissolved in pyridine (1 mL, dried over 4 Å molecular sieve). Pyrrolidinopyridine (14 mg, 0.0095 mmol) and butyl chloroformate (120 μL, 0.97 mmol) were added to the mixture, which was then stirred for 30 hours under N2(g) at room temperature. The solvent was removed in vacuo and then co-evaporated with acetonitrile. Purification using column chromatography with CHCl3:MeOH (35:1) as eluent yielded the title compound (24.9 mg, 0.052 mmol) in 54% yield (from 5-iso-butyl-N-tert-butyl-3-(4-tetrazol-2-ylmethylphenyl)thiophene-2-sulfonamide).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[C:7]([NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][NH2:21])[CH:15]=1)(=[O:13])=[O:12])(=[O:9])[CH3:8].[F:22][C:23]1[CH:24]=[C:25]([C:29]2[N:34]=[CH:33][C:32]([C:35](Cl)=[O:36])=[CH:31][N:30]=2)[CH:26]=[CH:27][CH:28]=1.Cl>CCOC(C)=O.O.C([O-])(=O)C>[C:7]([NH:10][S:11]([C:14]1[CH:15]=[C:16]([CH:17]=[CH:18][CH:19]=1)[CH2:20][NH:21][C:35]([C:32]1[CH:33]=[N:34][C:29]([C:25]2[CH:26]=[CH:27][CH:28]=[C:23]([F:22])[CH:24]=2)=[N:30][CH:31]=1)=[O:36])(=[O:12])=[O:13])(=[O:9])[CH3:8]
Reactant: O=C(Cl)c1cnc(-c2cccc(F)c2)nc1
Reactant: CC(=O)NS(=O)(=O)c1cccc(CN)c1
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(=O)NS(=O)(=O)c1cccc(CNC(=O)c2cnc(-c3cccc(F)c3)nc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of potassium carbonate (1.22 mmol) and N-acetyl-3-aminomethyl-benzenesulfonamide (1.22 mmol) in EtOAc (10 mL) and water (10 mL) is added a solution of 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid chloride (1.22 mmol) in acetate (10 mL) at 0° C., and the mixture is stirred at room temperature overnight. The mixture is acidified with 5% HCl to pH ˜2-3 and extracted with EtOAc. The organic layer is separated, washed with water and brine, dried (MgSO4), filtered and concentrated in vacuo. The residue is purified by silica gel column chromatography eluting with EtOAc to afford 2-(3-fluoro-phenyl)-pyrimidine-5-carboxylic acid 3-acetylsulfamoyl-benzylamide as a solid. MS: 429 (M+H); 1H NMR (300 MHz, CD3OD): δ 3.95-4.00 (d, 3H), 4.85 (s, 3H), 7.22-7.34 (m, H), 7.41-7.62 (m, H), 7.66-7.83 (d, 2H), 7.88-7.95 (d, H), 8.04 (s, H), 8.12-8.23 (m, H), 8.26-8.37 (d, H), 9.26-9.34 (m, 2H).