Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)[C:5]2[S:10][C:9]([CH:11]=O)=[CH:8][C:6]=2[N:7]=1.[OH:19][CH:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1.[N:26]1[CH:31]=[CH:30][CH:29]=[C:28](B(O)O)[CH:27]=1>>[O:16]1[CH2:17][CH2:18][N:13]([C:4]2[C:5]3[S:10][C:9]([CH2:11][N:23]4[CH2:24][CH2:25][CH:20]([OH:19])[CH2:21][CH2:22]4)=[CH:8][C:6]=3[N:7]=[C:2]([C:28]3[CH:27]=[N:26][CH:31]=[CH:30][CH:29]=3)[N:3]=2)[CH2:14][CH2:15]1
Reactant: OC1CCNCC1
Reactant: OB(O)c1cccnc1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Product: OC1CCN(Cc2cc3nc(-c4cccnc4)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholinothieno[3,2-d]pyrimidine-6-carbaldehyde 10 from Example 3 (100 mg) was reacted with 4-hydroxypiperidine following the protocol in General Procedure C. One half of the crude material was then used with pyridine-3-boronic acid in General Procedure A to give 24 mg of 142 following reversed phase HPLC purification. MS (Q1) 412 (M)+.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1)(=[O:3])[CH3:2].[F:10][C:11]1[CH:16]=[CH:15][C:14]([N:17]=[C:18]=[O:19])=[CH:13][CH:12]=1>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][N:7]([C:18](=[O:19])[NH:17][C:14]2[CH:15]=[CH:16][C:11]([F:10])=[CH:12][CH:13]=2)[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CC(=O)N1CCNCC1
Reactant: O=C=Nc1ccc(F)cc1
Solvent: C1CCOC1
Product: CC(=O)N1CCN(C(=O)Nc2ccc(F)cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.6 %

Procedure:
To a stirred solution of 1-acetylpiperazine (0.648 g) in tetrahydrofuran (10 ml) was added 4-fluorophenyl isocyanate (0.574 g) at ambient temperature. After stirring at ambient temperature for 1 hour, the solvent was removed by evaporation under reduced pressure, and the residue was triturated with diisopropyl ether to give 1-acetyl-4-(4-fluorophenylcarbamoyl)piperazine (1.25 g).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[CH3:9][C:10]1[N:11]=[CH:12][NH:13][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[Cl:8][C:6]1[CH:7]=[C:2]([N:13]2[CH:14]=[C:10]([CH3:9])[N:11]=[CH:12]2)[N:3]=[CH:4][N:5]=1
Reactant: Cc1c[nH]cn1
Reactant: Clc1cc(Cl)ncn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cn(-c2cc(Cl)ncn2)cn1
Yield: 36.6 %

Procedure:
A mixture of 4,6-dichloropyrimidine (11.92 g, 80 mmol), 4-methyl-1H-imidazole (6.57 g, 80 mmol), and cesium carbonate (26.1 g, 80 mmol) was stirred in DMF (50 mL) at room temperature for 18 h. The reaction was diluted into 200 mL water and extracted three times with 200 mL EtOAc. The combined organic layers were concentrated and purified by flash chromatography on a 300 g silica gel cartridge with 25 to 75% ethyl acetate in hexane to yield a mixture of the two regioisomeric products. The pooled fractions were concentrated to about 200 mL volume and cooled to yield 4-chloro-6-(4-methyl-1H-imidazol-1-yl)pyrimidine (5.70 g, 37% yield). The positive identification of the 4-methylimidazole regioisomer was accomplished by its NMR NOE properties. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.80 (1H, d, J=0.50 Hz), 8.36 (1H, d, J=1.26 Hz), 7.29-7.31 (1H, m), 7.25 (1H, d, J=1.01 Hz), 2.27 (3H, d, J=1.01 Hz). LCMS: RT=0.50 min, MH+=195.1.
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:36])[C:6]1[CH:35]=[CH:34][CH:33]=[C:8]([C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][O:19][C:20]3[CH:25]=[CH:24][C:23]([C:26](=[O:28])[CH3:27])=[C:22]([OH:29])[C:21]=3[CH2:30][CH2:31][CH3:32])[CH:13]=2)=[O:10])[CH:7]=1.Cl>O1CCCC1.C(O)C.O>[C:26]([C:23]1[CH:24]=[CH:25][C:20]([O:19][CH2:18][C:14]2[CH:13]=[C:12]([NH:11][C:9](=[O:10])[C:8]3[CH:7]=[C:6]([CH:35]=[CH:34][CH:33]=3)[C:5]([OH:36])=[O:4])[CH:17]=[CH:16][CH:15]=2)=[C:21]([CH2:30][CH2:31][CH3:32])[C:22]=1[OH:29])(=[O:28])[CH3:27]
Reactant: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)OC)c3)c2)ccc(C(C)=O)c1O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: C1CCOC1
Product: CCCc1c(OCc2cccc(NC(=O)c3cccc(C(=O)O)c3)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Add 1N lithium hydroxide (20 mL) to a solution of N-[3-(4-acetyl-3-hydroxy-2-propyl-phenoxymethyl)-phenyl]-isophthalamic acid methyl ester (1.75 g, 3.79 mmol) in tetrahydrofuran (15 mL) and ethanol (10 mL). Stir overnight at room temperature. Dilute with water. Acidify with 1N hydrochloric acid. Concentrate to remove organic solvents; filter and wash with water several times, then with hexanes. Dry to afford the title compound as an off-white powder (1.54 g, 91%): 1H NMR (DMSO-d6) δ 0.89 (t, 3H), 1.51 (sextet, 2H), 2.58 (s, 3H), 2.63 (t, 2H), 5.27 (s, 2H), 6.74 (d, 1H), 7.20 (d, 1H), 7.40 (t, 1H), 7.65-7.71 (m, 2H), 7.81 (d, 1H), 7.97 (s, 1H), 8.14 (d, 1H), 8.18 (d, 1H), 8.52 (s, 1H), 10.51 (s, 1H), 12.85 (s, 1H), 13.43 (bs, 1H); MS (APCI-neg mode) m/z (rel intensity) 446 (100).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH2:12][C@@H:11]2[CH3:29])=[O:9])=[CH:4][CH:3]=1.[NH:30]1[CH2:33][CH2:32][CH2:31]1>C(O)(C)C>[ClH:1].[N:30]1([C:2]2[N:7]=[CH:6][C:5]([C:8]([N:10]3[CH2:15][CH2:14][N:13]([S:16]([C:19]4[CH:24]=[CH:23][C:22]([C:25]([F:28])([F:27])[F:26])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH2:12][C@@H:11]3[CH3:29])=[O:9])=[CH:4][CH:3]=2)[CH2:33][CH2:32][CH2:31]1
Reactant: C1CNC1
Reactant: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(Cl)nc1
Solvent: CC(C)O
Product: C[C@H]1CN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CCN1C(=O)c1ccc(N2CCC2)nc1
Product: Cl
Temperature: 120 °C
Yield: 83.6 %

Procedure:
(2S)-1-[(6-Chloro-3-pyridinyl)carbonyl]-2-methyl-4-{[4-(trifluoromethyl)phenyl]sulfonyl}piperazine (may be prepared as described in Example 26) (69 mg, 0.154 mmol) was transferred into a microwave vial as a solution in isopropanol (1.5 ml). Azetidine (0.208 ml, 3.08 mmol) was added and the clear solution was heated in the microwave to 120° C. for 12 h with stirring. LCMS analysis showed complete conversion. The reaction mixture was concentrated to give the crude material as a colourless gum (206 mg). This was purified by MDAP (High pH system) to give the free base of the title compound as a colourless gum (65 mg).
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12](Cl)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1.[NH:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1>C(#N)C>[CH:1]1([CH2:4][CH2:5][NH:6][C:7]([C:9]2[N:10]=[N:11][C:12]([N:16]3[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]3)=[CH:13][CH:14]=2)=[O:8])[CH2:3][CH2:2]1
Reactant: O=C(NCCC1CC1)c1ccc(Cl)nn1
Reactant: C1CNCCN1
Solvent: CC#N
Product: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Yield: 87.6 %

Procedure:
A solution of 6-chloropyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (7.8 g, 34 mmol) and piperazine (8.93 g, 103 mmol) in acetonitrile (100 mL) was heated to refluxed for 2 hours. The solvent was removed by evaporation and the residue was dissolved in water (100 mL). The aqueous solution was extracted with dichloromethane (5×100 mL) and the organic extract was dried over anhydrous Na2SO4, filtered through a pad of silica gel and concentrated to give 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)amide (8.2 g, 88%). 1H NMR (300 MHz, CDCl3) δ 7.90-7.87, 6.89, 3.78-3.50, 3.12-2.90, 1.77-1.49, 0.83-0.60, 0.51-0.36, 0.15-0.01.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][C:3]=1[C:4]([O:6][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25](=[O:38])[C:26]1[CH:31]=[C:30]([N+:32]([O-:34])=[O:33])[CH:29]=[C:28]([N+:35]([O-:37])=[O:36])[CH:27]=1)=[O:5]
Reactant: O=C(OCCCCCCCCCCCBr)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: O=C(O)c1cc(O)ccc1O
Solvent: CN(C)C=O
Product: O=C(OCCCCCCCCCCCOC(=O)c1cc(O)ccc1O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Temperature: 80 °C
Yield: 56.6 %

Procedure:
2.78 g (18.0 mmol) 2,5-dihydroxybenzoic acid was dissolved in 36 ml dimethylformamide. 2.96 ml (19.8 mmol) 1,8-diazabicyclo[5.4.0]undec-7-ene(1,5-5) (DBU) was added dropwise in the course of 15 minutes. The reaction temperature rose to 30° C. and 8.83 g (19.8 mmol) 3,5-dinitrobenzoic acid 11-bromoundecyl ester was subsequently added in one portion. The mixture was then heated at 80° C. for 2 hours. The reaction mixture was cooled and then partitioned between dichloromethane and 1N hydrochloric acid; the organic phase was washed twice with water, dried over sodium sulfate, filtered and concentrated by rotary evaporation. Chromatography of the residue on 200 g silica gel using Toluene yielded 5.28 g (57%) 3,5-dinitrobenzoic acid 11-[2,5-dihydroxybenzoyloxy]undecyl ester as yellow powder.
Reaction SMILES: [Br:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14].[N+:15]([O-])([OH:17])=[O:16].C(OCC)C.CCCCCC>S(=O)(=O)(O)O>[Br:1][C:2]1[C:10]([F:11])=[C:9]([N+:15]([O-:17])=[O:16])[C:5]([C:6]([OH:8])=[O:7])=[C:4]([F:12])[C:3]=1[O:13][CH3:14]
Reactant: O=[N+]([O-])O
Reactant: COc1c(F)c(C(=O)O)cc(F)c1Br
Agent: O=S(=O)(O)O
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1c(F)c(C(=O)O)c([N+](=O)[O-])c(F)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 8 ml of sulfuric acid was dissolved 2.0 g of 4-bromo-2,5-difluoro-3-methoxybenzoic acid, and 4 ml of nitric acid was dropwise added to the solution with ice-cooling, after which the resulting mixture was stirred at room temperature for one hour. The reaction mixture was added to a mixed solvent of 50 ml of diethyl ether and 50 ml of ice water, and the organic layer formed was separated, washed with a saturated saline solution and then dried over anhydrous magnesium sulfate. The solvent was then removed by distillation under reduced pressure. To the residue thus obtained was added n-hexane, and the resulting crystals were collected by filtration to obtain 1.9 g of pale yellow, crystalline 4-bromo-2,5-difluoro-3-methoxy-6-nitrobenzoic acid.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=O)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:20]([F:23])([F:22])[F:21])[CH:3]=1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][CH2:39][C:40](=[O:42])[N:41]=2)[CH2:33][C@@H:32]1[CH2:43][OH:44])=[O:30])([CH3:27])([CH3:26])[CH3:25]>>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][N:34]([C:37]2[S:38][C:39](=[CH:16][C:12]3[CH:11]=[C:10]4[C:15](=[CH:14][CH:13]=3)[N:7]([CH2:6][C:5]3[CH:18]=[CH:19][C:2]([F:1])=[CH:3][C:4]=3[C:20]([F:23])([F:22])[F:21])[N:8]=[CH:9]4)[C:40](=[O:42])[N:41]=2)[CH2:33][C@@H:32]1[CH2:43][OH:44])=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)CS2)C[C@@H]1CO
Reactant: O=Cc1ccc2c(cnn2Cc2ccc(F)cc2C(F)(F)F)c1
Product: CC(C)(C)OC(=O)N1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(F)cc4C(F)(F)F)c3)S2)C[C@@H]1CO

Procedure:
4-{5-[1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-2-(R)-hydroxymethyl-piperazine-1-carboxylic acid tert-butyl ester was prepared from 1-(4-Fluoro-2-trifluoromethyl-benzyl)-1H-indazole-5-carbaldehyde and 2(R)—Hydroxymethyl-4-(4-oxo-4,5-dihydro-thiazol-2-yl)piperazine-1-carboxylic acid tert-butyl ester following general procedure D.
Reaction SMILES: [CH3:1][C:2]([NH:10]O)=[C:3]1[CH:9]=CC(=O)C=C1.[C:12]([OH:15])(=O)[CH3:13].S([O-])([O-])(=O)=O.[Mg+2].[CH2:22]([OH:24])[CH3:23]>>[C:22]([NH:10][C:2]1[CH:1]=[CH:13][C:12]([OH:15])=[CH:9][CH:3]=1)(=[O:24])[CH3:23]
Reactant: CCO
Reactant: CC(=O)O
Reactant: CC(NO)=C1C=CC(=O)C=C1
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Product: CC(=O)Nc1ccc(O)cc1
Yield: 66.7 %

Procedure:
A mixture of 3.0 g of Amberlyst 15, (a sulfonic acid ion-exchange resin made by Rohm & Haas), 3.0 g (22.0 mmol) of 4-hydroxyacetophenone oxime, and 50 mL of acetic acid was heated at reflux under nitrogen for 2 h. The ion exchange resin was then removed and the acetic acid was distilled in vacuo to afford an orange residue. The residue was dissolved in ethanol and treated with activated carbon and anhydrous magnesium sulfate. Removal of the ethanol using a rotary evaporator produced 2.9 of a yellow oil, which upon drying afforded 2.0 g (66.7%) of N-acetyl-para-aminophenol.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]2)=[CH:5][C:4]=1[O:20][CH3:21].CC(O)=O.[Cl:26]N1C(=O)CCC1=O>O.CCOCC>[Cl:26][C:7]1[CH:8]=[C:3]([Cl:2])[C:4]([O:20][CH3:21])=[CH:5][C:6]=1[N:9]1[CH2:14][CH2:13][CH:12]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:11][CH2:10]1
Reactant: CCOC(=O)C1CCN(c2ccc(Cl)c(OC)c2)CC1
Reactant: O=C1CCC(=O)N1Cl
Agent: Cl
Solvent: CC(=O)O
Solvent: CCOCC
Solvent: O
Product: CCOC(=O)C1CCN(c2cc(OC)c(Cl)cc2Cl)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.6 %

Procedure:
A 25-mL round bottom flask containing a magnetic stir bar and fitted with an inert gas inlet was charged with ethyl 1-(4-chloro-3-methoxyphenyl)piperidine-4-carboxylate, hydrochloride salt (367 mg, 1.23 mmol), AcOH (6 mL) and water (3.0 mL). The mixture was treated with N-chlorosuccinimide (206 mg, 1.54 mmol) in one portion. The mixture was stirred under argon at RT overnight and then diluted with water (20 mL) and Et2O (60 mL). The pH of the mixture was adjusted to a pH=10. The phases were separated and the aqueous phase was extracted with Et2O. The combined Et2O extracts were washed with brine, dried (MgSO4) and concentrated on a rotary evaporator. The resultant residue was purified by flash chromatography using a 12 g silica gel cartridge and gradient elution from 50:1 Hex/EtOAc to 20:1 Hex/EtOAc to elute the product. The fractions containing the product were pooled and concentrated on a rotary evaporator to give ethyl 1-(2,4-dichloro-5-methoxyphenyl)piperidine-4-carboxylate (255 mg, 0.77 mmol, 70% yield) as a clear oil, which solidified on standing at room temperature. 1H-NMR (400 MHz, CDCl3) δ ppm 7.33 (1 H, s), 6.58 (1 H, s), 4.15 (2 H, qd, J=7.04, 6.87 Hz), 3.87 (3 H, s), 3.33 (2 H, d, J=11.70 Hz), 2.70 (2 H, t, J=9.66 Hz), 2.43 (1 H, dq, J=10.17, 5.09 Hz), 1.94-2.05 (4 H, m), 1.22-1.30 (3 H, m).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18](Cl)=[O:19])[S:17][C:10]=12.CCN(CC)CC>C(Cl)Cl.O>[Cl:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]([N:5]3[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]3)=[O:19])[S:17][C:10]=12
Reactant: CN1CCNCC1
Reactant: O=C(Cl)c1cc2nccc(Cl)c2s1
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CN1CCN(C(=O)c2cc3nccc(Cl)c3s2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.2 %

Procedure:
1-Methylpiperazine (0.574 mL, 5.17 mmol) was added to a suspension of 7-chlorothieno[3,2-b]pyridine-2-carbonyl chloride (435, 1 g, 4.31 mmol) and Et3N (1.80 mL, 12.93 mmol) in DCM (50 mL). The reaction mixture was stirred for 1 h at room temperature, diluted with water and a saturated aqueous solution of ammonium chloride and extracted with DCM. The organic layer was successively washed with a saturated aqueous solution of ammonium chloride and brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by biotage (SNAP 25 g cartridge; MeOH/DCM: 0/100 to 10/90 over 20CV), to afford the title compound 436 (1.16 g, 3.93 mmol, 91% yield) as a yellow solid. MS (m/z): 296.2 (M+H).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=1.[NH:10]1[CH2:15][CH2:14][CH:13]([C@H:16]2[CH2:18][C@H:17]2[CH2:19][CH2:20][OH:21])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C=O)C>[OH:21][CH2:20][CH2:19][C@@H:17]1[CH2:18][C@@H:16]1[CH:13]1[CH2:12][CH2:11][N:10]([C:2]2[N:7]=[CH:6][C:5]([CH:8]=[O:9])=[CH:4][CH:3]=2)[CH2:15][CH2:14]1
Reactant: O=Cc1ccc(Cl)nc1
Reactant: OCC[C@@H]1C[C@@H]1C1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: O=Cc1ccc(N2CCC([C@H]3C[C@H]3CCO)CC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
In a 250 ml RBF the 6-chloropyridine-3-carbaldehyde (1.907 g, 13.47 mmol) and 2-[(1S,2R)-2-(piperidin-4-yl)cyclopropyl]ethanol (2.28 g, 13.47 mmol) were dissolved in DMF (13.47 ml). Cesium carbonate (13.17 g, 40.4 mmol) was added and the mixture stirred at RT overnight. The mixture was poured into 4:1 water:brine (200 ml), extracted with EtOAc (3×100 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuo. The residue was purified by column chromatography on silica gel, Biotage 100M, using a gradient eluant of 0-100% EtOAc/hexanes to afford the title compound. LC/MS (m/z): 275 (M+H)+.
Reaction SMILES: [C:1]1([S:11]([O-:14])(=O)=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[Na+].P(Cl)(Cl)([Cl:18])=O.O>C(#N)C.CC(N(C)C)=O>[C:1]1([S:11]([Cl:18])(=[O:14])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: O=S(=O)([O-])c1cccc2ccccc12
Reactant: O=P(Cl)(Cl)Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=S(=O)(Cl)c1cccc2ccccc12
Temperature: 30 °C

Procedure:
133 g of sodium α-naphthalenesulfonate was suspended in a mixture of 260 ml of acetonitrile and 7 ml of dimethylacetamide. 80 ml of phosphorus oxychloride was added dropwise to the suspension while being cooled with water at a temperature of lower than 50° C. After the dropwise addition was completed, the reaction system was further reacted at a temperature of 65° C. for 1 hour. After cooled to 30° C., the reaction mixture was poured into 2 l of ice water. The resulting grayish white crystal was filtered off, and air-dried. The yield was 110.8 g (84.6% of theoretical value). The melting point of the product was 66° to 68° C.
Reaction SMILES: [CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[NH:18][CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2].[H-].[Na+].[CH3:30][C:31]1[CH:36]=[CH:35][C:34]([S:37](Cl)(=[O:39])=[O:38])=[CH:33][CH:32]=1>CN(C=O)C.CCOC(C)=O>[CH2:1]([C@H:3]1[C@@H:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[N:18]([S:37]([C:34]4[CH:35]=[CH:36][C:31]([CH3:30])=[CH:32][CH:33]=4)(=[O:39])=[O:38])[CH:19]=[CH:20][C:10]=23)[CH2:6][C@@H:5]([NH:21][S:22]([CH:25]2[CH2:27][CH2:26]2)(=[O:24])=[O:23])[CH2:4]1)[CH3:2]
Reactant: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2[nH]ccc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC[C@@H]1C[C@H](NS(=O)(=O)C2CC2)C[C@@H]1Nc1c([N+](=O)[O-])cnc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Reaction time: 0.08 h
Yield: 126.8 %

Procedure:
To a solution of N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)cyclopropanesulfonamide (0.123 g, 0.314 mmol) in DMF (3.0 mL) at about 0° C. was added NaH (60% in mineral oil, 0.015 g, 0.37 mmol). The reaction mixture was stirred for about 5 min. 4-Methylbenzene-1-sulfonyl chloride (0.060 g, 0.314 mmol) was added and the reaction mixture was stirred for about 30 min. Additional NaH (60% in mineral oil, 0.007 g, 0.18 mmol) was added and the reaction mixture was stirred for about 10 min. Additional NaH (60% in mineral oil, 0.005 g, 0.12 mmol) was added and the reaction mixture was stirred for about 15 min. Additional 4-methylbenzene-1-sulfonyl chloride (0.012 g, 0.063 mmol) was added and the reaction mixture was stirred for about 40 min. The reaction mixture was concd under reduced pressure. The residue was dissolved in EtOAc (25 mL) and washed with water (15 mL). The organic layer was separated, dried over anhydrous MgSO4, filtered and concd under reduced pressure to give N-((1S,3R,4S)-3-ethyl-4-(5-nitro-1-tosyl-1H-pyrrolo[2,3-b]pyridin-4-ylamino)cyclopentyl)-cyclopropanesulfonamide (0.218 g) as a red-orange oil containing 40 mol % DMF and 1 equivalent EtOAc: LC/MS (Table 1, Method n) Rt=0.88 min; MS m/z 548 (M+H)+.
Reaction SMILES: [OH:1][NH2:2].C([O:5][C:6](=O)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1)C>CN(C=O)C.CO>[OH:1][NH:2][C:6](=[O:5])[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][N:13]([C:20]1[CH:25]=[C:24]([O:26][CH:27]([CH3:29])[CH3:28])[CH:23]=[CH:22][N:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CCOC(=O)CCCCCCN(c1ccccn1)c1cc(OC(C)C)ccn1
Reactant: NO
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1ccnc(N(CCCCCCC(=O)NO)c2ccccn2)c1
Reaction time: 26 h
Yield: 65 %

Procedure:
HONH2 (50% aqueous, 2 mL) was added to III (23 mg, 0.06 mmol) in DMF (0.5 mL) and MeOH (2 mL) at rt. The reaction mixture was stirred for 26 h, after which the solvents were evaporated under reduced pressure. The resulting residue was dissolved and co-evaporated with toluene (2×2 mL) then was purified by silica gel column chromatography eluting with CH2Cl2/MeOH (100:5 to 100:8) to furnish IV as a colourless oil (14 mg, 65%).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH:11][C:12]1[CH:13]=[C:14]([F:22])[CH:15]=[C:16]2[C:21]=1[N:20]=[CH:19][CH:18]=[CH:17]2)(=[O:10])=[O:9].N(OC(C)(C)C)=O.CC(O)=O>C1COCC1>[F:22][C:14]1[CH:15]=[C:16]2[C:21]([N:20]=[CH:19][CH:18]=[CH:17]2)=[C:12]2[C:13]=1[C:4]1[C:3]([S:8](=[O:10])(=[O:9])[NH:11]2)=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: Nc1ccccc1S(=O)(=O)Nc1cc(F)cc2cccnc12
Agent: CC(C)(C)ON=O
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: O=S1(=O)Nc2c(c(F)cc3cccnc23)-c2ccccc21
Yield: 18.5 %

Procedure:
In a similar fashion using route 16 general procedure 61, 2-amino-N-(6-fluoro-quinolin-8-yl)-benzenesulfonamide (Intermediate 290) (200 mg, 0.63 mmol), t-butyl nitrite (0.11 ml, 0.94 mmol), AcOH (2 ml) and THF (2 ml) gave the title compound (35 mg, 19%) after purification by column chromatography with DCM/MeOH (99:1) as the eluent.
Reaction SMILES: [Cl:1][C:2]([C:12]([F:15])([F:14])[F:13])=[CH:3][C@H:4]1[C@H:6]([C:7](O)=[O:8])[C:5]1([CH3:11])[CH3:10].S(Cl)([Cl:18])=O>>[Cl:18][C:7]([C@H:6]1[C@H:4]([CH:3]=[C:2]([Cl:1])[C:12]([F:15])([F:14])[F:13])[C:5]1([CH3:11])[CH3:10])=[O:8]
Reactant: O=S(Cl)Cl
Reactant: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)O
Product: CC1(C)[C@@H](C=C(Cl)C(F)(F)F)[C@@H]1C(=O)Cl

Procedure:
A mixture of (±)-cis/trans-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane carboxylic acid (0.4 g) and thionyl chloride (5.0 ml) was heated at the reflux temperature for a period of 2 hours, after which the excess thionyl chloride was removed by distillation under reduced pressure, leaving (±)-cis/trans-1-chlorocarbonyl-3-(2-chloro-3,3,3-trifluoroprop-1-en-1-yl)-2,2-dimethylcyclopropane.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:7][S:6][CH2:5][N:4]1[CH3:8].[C:9]1([CH3:20])[CH:14]=[CH:13][C:12]([S:15]([O:18]C)(=[O:17])=[O:16])=[CH:11][CH:10]=1>>[C:9]1([CH3:20])[CH:10]=[CH:11][C:12]([S:15]([O-:18])(=[O:16])=[O:17])=[CH:13][CH:14]=1.[CH3:8][N+:4]1([CH3:9])[C@H:3]([CH2:2][OH:1])[CH2:7][S:6][CH2:5]1
Reactant: COS(=O)(=O)c1ccc(C)cc1
Reactant: CN1CSC[C@H]1CO
Product: C[N+]1(C)CSC[C@H]1CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Yield: 171.8 %

Procedure:
The procedures of Reference Example 10 were repeated using 520 mg of 4(R)-hydroxymethyl-3-methyl-1,3-thiazolidine and 726 mg of methyl p-toluenesulfonate to give 1070 mg of the desired compound as a white crystalline product.