Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([CH2:5][O:6][C:7]2[CH:12]=[C:11]([O:13][CH3:14])[C:10]([F:15])=[CH:9][C:8]=2[C:16]2[C:17]3[NH:24][C:23]([CH3:25])=[C:22]([C:26]([NH:28][C@@H:29]4[CH2:34][CH2:33][NH:32][CH2:31][C@H:30]4[OH:35])=[O:27])[C:18]=3[N:19]=[CH:20][N:21]=2)[CH2:4][CH2:3]1.[C:36](Cl)(=[O:38])[CH3:37]>>[C:36]([N:32]1[CH2:33][CH2:34][C@@H:29]([NH:28][C:26]([C:22]2[C:18]3[N:19]=[CH:20][N:21]=[C:16]([C:8]4[CH:9]=[C:10]([F:15])[C:11]([O:13][CH3:14])=[CH:12][C:7]=4[O:6][CH2:5][CH:2]4[CH2:4][CH2:3]4)[C:17]=3[NH:24][C:23]=2[CH3:25])=[O:27])[C@H:30]([OH:35])[CH2:31]1)(=[O:38])[CH3:37]
Reactant: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCNC[C@H]4O)c(C)[nH]c23)cc1F
Reactant: CC(=O)Cl
Agent: Cl
Product: COc1cc(OCC2CC2)c(-c2ncnc3c(C(=O)N[C@@H]4CCN(C(C)=O)C[C@H]4O)c(C)[nH]c23)cc1F

Procedure:
Starting from 4-[2-(cyclopropylmethoxy)-5-fluoro-4-methoxyphenyl]-N-[(3R*,4R*)-3-hydroxypiperidin-4-yl]-6-methyl-5H-pyrrolo[3,2-d]pyrimidine-7-carboxamide hydrochloride (example D.f47) and commercially available acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([OH:12])=O)=[N:4][CH:5]=[CH:6][CH:7]=1.[CH3:13][C:14]1[CH:15]=[CH:16][CH:17]=[C:18]2[C:23]=1[NH:22][CH2:21][CH2:20][CH2:19]2.CCN=C=NCCCN(C)C>C1COCC1.CN(C1C=CN=CC=1)C.C(Cl)Cl>[Cl:1][C:2]1[C:3]([S:8][CH2:9][C:10]([N:22]2[C:23]3[C:18](=[CH:17][CH:16]=[CH:15][C:14]=3[CH3:13])[CH2:19][CH2:20][CH2:21]2)=[O:12])=[N:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)CSc1ncccc1Cl
Reactant: Cc1cccc2c1NCCC2
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc2c1N(C(=O)CSc1ncccc1Cl)CCC2
Temperature: 25 °C
Reaction time: 20 h
Yield: 33 %

Procedure:
To a solution of (3-chloro-pyridin-2-ylsulfanyl)-acetic acid (19, 0.27 g, 1.3 mmol) in 12 mL of dry THF at 0° C. was added neat 8-methyl-1,2,3,4-tetrahydroquinolin (0.20 g, 1.3 mmol) followed by addition of DMAP (0.19 g, 1.6 mmol) and EDCI (0.31 g, 1.6 mmol). The reaction was stirred for 20 h at room temperature under N2. The reaction mixture was diluted with 50 mL of CH2Cl2, washed with H2O, 10% citric acid, NaHCO3 (saturated), brine, dried over Na2SO4 and concentrated. The crude was purified by column chromatography (hexanes/EtOAc) to give 0.15 g (33% yield) of the target 20 as an off-white solid. MS (APCI) m/z: 333.1 (100%, [M+H]+, 186.0 (35%, [M−147+H]+; HPLC purity: 100%; Anal. Calcd. for C17H17ClN2OS: C, 61.34; H, 5.15; N, 8.42; Cl, 10.65; S, 9.63. Found: C, 61.04; H, 5.28; N, 8.36; Cl, 10.78; S, 9.68.
Reaction SMILES: FC(F)(F)C(O)=O.C(OC([N:15]([CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])[C:16]1[CH:21]=[CH:20][C:19]([C:22](=[O:25])[NH:23][CH3:24])=[CH:18][CH:17]=1)=O)(C)(C)C>>[CH3:24][NH:23][C:22]([C:19]1[CH:18]=[CH:17][C:16]([NH:15][CH2:26][C:27]([OH:29])=[O:28])=[CH:21][CH:20]=1)=[O:25]
Reactant: CNC(=O)c1ccc(N(CC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)c1ccc(NCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 87.5 %

Procedure:
Trifluoroacetic acid (3.3 ml) was added to a solution of N-(tert-butoxycarbonyl)-N-(tert-butoxycarbonylmethyl)-4-methylcarbamoylaniline (250 mg) in ice water bath and stirred for 20 hours at ambient temperature. The solvent was evaporated under reduced pressure. The residue was pulverized with diethyl ether to give N-(4-methylcarbamoylphenyl) glycine (125 mg).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[Cl:12])[CH:5]=[C:4]([NH:13]C(=O)C)[N:3]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)CCC.O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cl:12][C:10]1[CH:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:2]=[N:3][C:4]([NH2:13])=[CH:5]2
Reactant: CC(=O)Nc1cc2cccc(Cl)c2c(Br)n1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCCCO
Solvent: O
Product: Nc1cc2cccc(Cl)c2cn1
Temperature: 100 °C
Yield: 45.3 %

Procedure:
N-(1-Bromo-8-chloroisoquinolin-3-yl)acetamide (1.00 g, 3.33 mmol), potassium carbonate (0.508 mg, 3.67 mmol), triphenylphosphine (35 mg, 0.134 mmol) and palladium acetate (7.49 mg, 0.033 mmol) were stirred in 1-butanol (10 mL) with nitrogen bubbling through it for 10 minutes. Butanol (5 mL) was added to the reaction mixture, which was then heated overnight at 100° C. in a sealed vial. The reaction mixture was cooled, diluted with water and extracted twice with ethyl acetate. The combined organic layers were washed with brine, dried (Na2SO4) and concentrated to give an orange solid. Flash chromatography on silica (20 g), eluting with 15-60% ethyl acetate-hexane, gave the title compound as a yellow solid (333 mg, 1.51 mmol, 45%). LC-MS (1) Rt=1.68 min; m/z (ES+) 221/223.
Reaction SMILES: [C:1](=[S:3])=[S:2].C[O-].[Na+].Cl[C:8]1[CH:14]=[C:13]([Cl:15])[C:12]([Cl:16])=[CH:11][C:9]=1[NH2:10].Cl>CN(C=O)C.O>[Cl:16][C:12]1[C:13]([Cl:15])=[CH:14][C:8]2[S:2][C:1]([SH:3])=[N:10][C:9]=2[CH:11]=1
Reactant: S=C=S
Reactant: Nc1cc(Cl)c(Cl)cc1Cl
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Sc1nc2cc(Cl)c(Cl)cc2s1
Temperature: 115 °C
Yield: 88.2 %

Procedure:
To a suspension of CS2 (0.64 mL, 10.6 mmol) and sodium methylate (0.55 g, 10.2 mmol) in DMF (10 mL) was added 2,4,5-trichloroaniline (7, 1.00 g, 5.09 mmol) in DMF (5 mL) under N2. The reaction mixture was heated at 110-120° C. for 16 h. After cooling, the reaction mixture was diluted with water (30 mL) and acidified with 1N HCl. The precipitate was collected by filtration, washed with water, and dried over P2O5 under vacuum to give yield compound 8 (1.06 g). This crude material was used in subsequent reactions without further purification.
Reaction SMILES: [OH-].[Na+].[N+:3]([C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([O:19]C)=[O:18])=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1)([O-:5])=[O:4]>CO>[N+:3]([C:6]1[CH:24]=[CH:23][C:9]2[NH:10][C:11]([C:13]3[CH:22]=[CH:21][C:16]([C:17]([OH:19])=[O:18])=[CH:15][CH:14]=3)=[N:12][C:8]=2[CH:7]=1)([O-:5])=[O:4]
Reactant: COC(=O)c1ccc(-c2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(-c2nc3cc([N+](=O)[O-])ccc3[nH]2)cc1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
2M NaOH (75 ml) is added, at 0° C., to methyl 4-(5-nitro-1H-benzimidazol-2-yl)benzoate (15 g, 0.050 mol) (Example 26) in methanol (250 ml). The mixture is stirred at room temperature for 20 hours and evaporated, and the residue is taken up in water and acidified with HCl (pH=6). The resulting mixture is stirred for 16 hours at 0° C., and the product is filtered off, washed with water and recrystallized from 9/1 methanol/isopropyl ether. Yield: 10 g (70%); IR (KBr): 3357, 1675, 1602, 1537, 1377, 1320 cm−1; 1H-NMR (d6-DMSO) 7.5-8.6 (m, 7H).
Reaction SMILES: [C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19](S(C)=O)[CH3:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:3])[CH3:2].C1(C=CC(O)=CC=1)O.O>COCCOCCOC>[C:1]([C@@H:5]1[CH2:10][CH2:9][C@H:8]([NH:11][C:12]2[C:17]([Cl:18])=[C:16]([CH:19]=[CH2:20])[N:15]=[CH:14][N:13]=2)[CH2:7][CH2:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(c1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl)S(C)=O
Agent: Oc1ccc(O)cc1
Solvent: COCCOCCOC
Solvent: O
Product: C=Cc1ncnc(N[C@H]2CC[C@@H](C(C)(C)C)CC2)c1Cl
Temperature: 150 °C

Procedure:
A solution of 7.6 g (21 mmol) of 4-(cis-4-tert-butylcyclohexylamino)-5-chloro-6-(1-methylsulfinylethyl)pyrimidine (Example 26) in 100 ml of diethylene glycol dimethyl ether to which a little hydroquinone had been added was heated at 150° C. for 30 minutes. After cooling to room temperature the mixture was poured into water and extracted by stirring with dichloromethane. This left a brown oil which was extracted twice by stirring with petroleum ether. The petroleum ether phase was concentrated and the residue was purified with chromatography on silica gel, to give 1.1 g (17.8% of theory) of colorless solid.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([O:16]CC)=[O:15].[OH-].[Na+]>CCO>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:14]([OH:16])=[O:15]
Reactant: CCOC(=O)c1cnc2ccc(OC)cc2c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc2ncc(C(=O)O)c(N)c2c1
Temperature: 0 °C
Yield: 92.6 %

Procedure:
To a stirred solution of ethyl 4-amino-6-methoxyquinoline-3-carboxylate (Example 1a, 1.23 g, 5.0 mmol) in EtOH (20.0 mL) was added aqueous NaOH (2.0 N, 5.0 mL) at room temperature. The reaction mixture was then refluxed for 3 hr. The solution was then filtered and washed with water. The filtrate was cooled to 0° C. and neutralized carefully with 1 N HCl to pH 7. Most of the EtOH was removed under reduced pressure, and the precipitate was collected by filtration, washed with cold water, and dried under vacuum to give the title compound as an off-white solid (1.01 g, 93%). 1H NMR (400 MHz, DMSO-d6) δ 3.89 (s, 3H), 7.40 (dd, J=2.8, 9.4 Hz, 1H), 7.73 (d, J=9.4 Hz, 1H), 7.77 (d, J=2.8 Hz, 1H), 8.77 (s, 1H). MS 219 (MH+).
Reaction SMILES: Cl[C:2]1[C:7](=[O:8])[C:6]([O:9][CH3:10])=[CH:5][N:4]([CH2:11][CH:12]2[CH2:14][CH2:13]2)[N:3]=1.[C:15]1([N:21]2[C:25](B3OC(C)(C)C(C)(C)O3)=[CH:24][CH:23]=[N:22]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.O.C(=O)([O-])O.[Na+].[Cl-].[Na+].O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:12]1([CH2:11][N:4]2[CH:5]=[C:6]([O:9][CH3:10])[C:7](=[O:8])[C:2]([C:25]3[N:21]([C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:22]=[CH:23][CH:24]=3)=[N:3]2)[CH2:14][CH2:13]1
Reactant: CC1(C)OB(c2ccnn2-c2ccccc2)OC1(C)C
Reactant: COc1cn(CC2CC2)nc(Cl)c1=O
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])O
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cn(CC2CC2)nc(-c2ccnn2-c2ccccc2)c1=O
Temperature: 25 °C
Yield: 59.6 %

Procedure:
3-Chloro-1-(cyclopropylmethyl)-5-methoxypyridazin-4(1H)-one (0.133 g), 1-phenyl-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (0.200 g), potassium carbonate (0.171 g) and bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (0.0219 g) were suspended in toluene (3.09 mL) and water (0.309 mL), and the suspension was heated under reflux for 20 hr under an argon atmosphere. The reaction mixture was cooled to room temperature, diluted with water, saturated aqueous sodium hydrogen carbonate solution and saturated brine, extracted with ethyl acetate, dried over anhydrous sodium sulfate, filtered, concentrated, purified by NH silica gel column chromatography (ethyl acetate/hexane→methanol/ethyl acetate) and recrystallized from ethyl acetate/hexane to give the title compound (0.119 g).
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:16]=2[Cl:22])=[CH:13][S:12][C:11]=1[N:23]1[C:31](=[O:32])[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]1=[O:33])=[O:9])C.Cl>O>[Cl:22][C:16]1[C:17]([Cl:21])=[CH:18][CH:19]=[CH:20][C:15]=1[C:14]1[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:23]2[C:24](=[O:33])[C:25]3[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:31]2=[O:32])[S:12][CH:13]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)c1c(-c2cccc(Cl)c2Cl)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(2,3-dichlorophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 25, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21](O)=[O:22])[CH:9]=2)=[CH:4][CH:3]=1.Cl.Cl.[CH3:26][C:27]1[N:32]=[CH:31][C:30]([C@H:33]([NH2:35])[CH3:34])=[CH:29][CH:28]=1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C)C=O>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[C:12]([O:14][CH2:15][CH:16]3[CH2:20][CH2:19][CH2:18][O:17]3)[CH:11]=[C:10]([C:21]([NH:35][C@@H:33]([C:30]3[CH:31]=[N:32][C:27]([CH3:26])=[CH:28][CH:29]=3)[CH3:34])=[O:22])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)O)c2)cc1
Reactant: Cc1ccc([C@@H](C)N)cn1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2cc(OCC3CCCO3)cc(C(=O)N[C@H](C)c3ccc(C)nc3)c2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a stirred solution of 4′-methyl-5-((tetrahydrofuran-2-yl)methoxy)biphenyl-3-carboxylic acid (40 mg, 0.13 mmol) in N,N-dimethylformamide (1 mL) were added (R)-1-(6-methylpyridin-3-yl)ethanamine dihydrochloride (60 mg, 0.29 mmol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (120 mg, 0.32 mmol), and N,N-diisopropylethylamine (400 μL, 2.3 mmol). The reaction mixture was stirred for 16 hours at 25° C., and then purified by preparative HPLC to afford the final product as a light brown solid.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.Cl[C:16]([O:18][CH:19]([CH3:21])[CH3:20])=[O:17]>C(Cl)Cl.C1(C)C=CC=CC=1>[CH:19]([O:18][C:16]([N:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)=[O:17])([CH3:21])[CH3:20]
Reactant: CC(C)OC(=O)Cl
Reactant: OC1CCNCC1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: CC(C)OC(=O)N1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 4-hydroxyl-piperidine (8.1 g, 80 mmol) and triethylamine (11.2 mL, 1 eq) in 200 mL of DCM, was added isopropyl chloroformate (80 mL of a 1 M solution in toluene, 1 eq). The reaction mixture was stirred at room temperature for 3 h, quenched with a saturated solution of bicarbonate and extracted with DCM twice. The combined extracts were washed with a saturated solution of bicarbonate, dried over magnesium sulfate and evaporated to give 2a.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[OH:17][CH2:18][CH2:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[CH:24][CH:25]=1>CCOC(C)=O>[OH:17][CH2:18][CH2:19][C:20]1[CH:25]=[C:24]([C:2]2[N:3]=[C:4]3[C:10]([C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13])=[CH:9][NH:8][C:5]3=[N:6][CH:7]=2)[CH:23]=[CH:22][CH:21]=1
Reactant: OCCc1cccc(B(O)O)c1
Reactant: CC(C)(C)C(=O)c1c[nH]c2ncc(Br)nc12
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)c1c[nH]c2ncc(-c3cccc(CCO)c3)nc12

Procedure:
1-{2-[3-(2-Hydroxy-ethyl)-phenyl]-5H-pyrrolo[2,3-b]pyrazin-7-yl}-2,2-dimethyl-propan-1-one was prepared starting from 1-(2-bromo-5H-pyrrolo[2,3-b]pyrazin-7-yl)-2,2-dimethyl-propan-1-one and 3-(2-hydroxyethyl)benzeneboronic acid following general procedures as described in these Examples. Silica gel chromatography using 20-100% EtOAc in hexanes as eluant provided 69 mg (41%) of a yellow solid. MP 202-203° C., M+H=324.
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([OH:22])=O)[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1.C(Cl)(=O)C([Cl:26])=O.CN(C=O)C>C(Cl)Cl>[CH3:1][N:2]1[C:6]2=[C:7]3[CH:13]=[C:12]([C:14]4[N:15]([CH2:19][C:20]([Cl:26])=[O:22])[CH:16]=[CH:17][CH:18]=4)[NH:11][C:8]3=[N:9][CH:10]=[C:5]2[CH:4]=[N:3]1
Reactant: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)O)cc3c21
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1ncc2cnc3[nH]c(-c4cccn4CC(=O)Cl)cc3c21
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a flask was added 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetic acid (0.125 g, 0.423 mmol, Example #AN.1.2) and oxalyl chloride (0.275 mL, 0.550 mmol) in DCM (4 mL) followed by a drop of DMF. The mixture was stirred for about 40 min at rt and then concentrated to dryness to afford 2-(2-(1-methyl-1,6-dihydropyrazolo[3,4-d]pyrrolo[2,3-b]pyridin-7-yl)-1H-pyrrol-1-yl)acetyl chloride. The mixture was used immediately in the next step. Analytics were performed by quenching a sample with MeOH and methyl ester is the observed (M+H)+: LC/MS (Table 2, Method c) Rt=1.30 min; MS m/z 310 (M+H)+.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].FC(F)(F)S(O[C@@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])(=O)=O.C(OCC)(=O)C>C(#N)C>[CH:11]([C:10]1[CH:9]=[C:8]([CH:15]=[CH:14][CH:13]=1)[O:7][C@H:22]([CH2:30][CH3:31])[C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])=[O:12]
Reactant: CCCCOC(=O)[C@H](CC)OS(=O)(=O)C(F)(F)F
Reactant: O=Cc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCCCOC(=O)[C@@H](CC)Oc1cccc(C=O)c1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Potassium carbonate (473 mg) was added to a solution of 3-hydroxybenzaldehyde (418 mg) in acetonitrile (10 mL). Subsequently, n-butyl (S)-2-trifluoromethanesulfonyloxybutyrate (1.0 g) was added to the mixture, followed by stirring at room temperature for 12 hours. Ethyl acetate was added to the reaction mixture, and the resultant mixture was washed sequentially with water and saturated brine, followed by drying over sodium sulfate anhydrate. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified through silica gel column chromatography (hexane/ethyl acetate=4/1), to thereby yield 904 mg of a colorless, oily substance (99.9%).
Reaction SMILES: [BH4-].[Na+].[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:25][CH2:24][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:22][CH2:21]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[N+:11]([O-])=O.CO>C1COCC1>[CH3:3][O:4][C:5]1[CH:6]=[C:7]([N:14]2[CH2:19][CH2:18][CH:17]([N:20]3[CH2:21][CH2:22][N:23]([S:26]([CH3:29])(=[O:28])=[O:27])[CH2:24][CH2:25]3)[CH2:16][CH2:15]2)[CH:8]=[CH:9][C:10]=1[NH2:11]
Reactant: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1[N+](=O)[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: COc1cc(N2CCC(N3CCN(S(C)(=O)=O)CC3)CC2)ccc1N
Temperature: 25 °C
Yield: 89.3 %

Procedure:
NaBH4 (1.18 g, 31.1 mmol) was added carefully in portions (exothermic) to a suspension of 1-{1-[3-(methyloxy)-4-nitrophenyl]-4-piperidinyl}-4-(methylsulfonyl)piperazine (3.54 g, 8.9mmol), NiCL2.6H2O (1.06 g, 4.4 mmol), MeOH (100 mL) and THF (50 mL) at 0° C. The ice bath was removed and the reaction mixture was warmed to room temperature. The reaction mixture was concentrated onto silica gel and flash chromatography afforded 2-(methyloxy)-4-{4-[4-(methylsulfonyl)-1-piperazinyl]-1-piperidinyl}aniline (2.93 g, 90%) as a colourless solid. 1H NMR (400 MHz, DMSO-d6) δ 6.49-6.46 (m, 2H), 6.27 (dd, J=8.5, 2.6 Hz, 1H), 4.18 (bs, 2H), 3.71 (s, 3H), 3.44-3.38 (m, 2H), 3.11-3.04 (m, 4H), 2.84 (s, 3H), 2.61-2.54 (m, 6H complicated by DMSO peak), 2.35-2.26 (m, 1H), 1.80-1.77 (m, 2H), 1.56-1.46 (m, 2 H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.Cl.Cl.[CH3:20][C:21]1[CH:22]=[CH:23][C:24]([CH2:27][NH2:28])=[N:25][CH:26]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4]([NH:28][CH2:27][C:24]2[CH:23]=[CH:22][C:21]([CH3:20])=[CH:26][N:25]=2)[N:3]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: Cc1ccc(CN)nc1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: COCCOC
Product: Cc1ccc(CNc2nc(N)nc(-c3ccco3)c2C#N)nc1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile, C-(5-methyl-pyridin-2-yl)-methylamine dihydrochloride and DBU in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1/[CH:16]=[CH:17]/[S:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29])(=[O:20])=[O:19].[H][H]>C(OCC)(=O)C.[Pd]>[O:1]1[C:6]2=[CH:7][CH:8]=[CH:9][C:5]2=[CH:4][CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][CH2:17][S:18]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[S:28]([NH2:31])(=[O:30])=[O:29])(=[O:20])=[O:19]
Reactant: NS(=O)(=O)c1ccccc1NS(=O)(=O)/C=C/c1ccccc1-c1ccc2cccc-2o1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: NS(=O)(=O)c1ccccc1NS(=O)(=O)CCc1ccccc1-c1ccc2cccc-2o1
Yield: 27.7 %

Procedure:
2-[[(E)-2-(4-Benzofuran-2-ylphenyl)ethenyl]sulfonylamino]benzenesulfonamide (Example 3, 43 mg, 95 μmol) was dissolved in ethyl acetate (5 ml) and subjected to the H-cube (1 ml/min, full hydrogen. 10% Pd/C). The material obtained was purified by preparative HPLC (XTerra MS C8 column, acetonitrile/ammonium acetate buffer) to give the title compound (12 mg, 28%) as a white solid. The compound of Example 2 was also obtained.
Reaction SMILES: [C:1]([C:4]1[CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:6]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]Br)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2].[I-].[Na+].Cl.[C:34]1([C:40]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]2)[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[C:1]([C:4]1[CH:5]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:6]([C:12](=[O:21])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][N:43]2[CH2:44][CH2:45][C:40]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:41][CH2:42]2)=[C:7]([CH3:11])[NH:8][C:9]=1[CH3:10])(=[O:3])[CH3:2]
Reactant: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCCCBr)C1c1cccc([N+](=O)[O-])c1
Reactant: c1ccc(C2(c3ccccc3)CCNCC2)cc1
Agent: Cl
Agent: [I-]
Agent: [Na+]
Product: CC(=O)C1=C(C)NC(C)=C(C(=O)CCCCCCCN2CCC(c3ccccc3)(c3ccccc3)CC2)C1c1cccc([N+](=O)[O-])c1

Procedure:
10 g (21 mmol) 5-acetyl-3-(8-bromo-octanoyl)-1,4-dihydro-2,6-dimethyl-4(3-nitrophenyl)-pyridine are reacted first with 6.3 g (42 mmol) sodium iodide and then with 11. 5 g (40 mmol) 4,4-diphenylpiperidine hydrochloride, as described for starting compound B. Working up is carried out as described for starting compound B. The crude product is chromatographed with increasing polarity, first with toluene/acetone=9/1 and finally with toluene/acetone =6/4. The product thus obtained is recrystallized from 70 ml acetonitrile. The title compound is obtained as a yellow solid. Yield: 11 g (82%). M.p. 141°-145° C. (acetonitrile).
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3](C1C2N=NNC=2C=CC=1)=[O:4].[OH:16][CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][CH:26]([C:29]3[CH:34]=[CH:33][C:32]([CH2:35][CH2:36][CH3:37])=[CH:31][CH:30]=3)[CH2:25][CH2:24]2)[CH2:19][CH2:18]1>C1COCC1>[CH2:35]([C:32]1[CH:33]=[CH:34][C:29]([CH:26]2[CH2:25][CH2:24][CH:23]([CH:20]3[CH2:19][CH2:18][CH:17]([O:16][C:3](=[O:4])[C:2]([F:15])([F:14])[F:1])[CH2:22][CH2:21]3)[CH2:28][CH2:27]2)=[CH:30][CH:31]=1)[CH2:36][CH3:37]
Reactant: CCCc1ccc(C2CCC(C3CCC(O)CC3)CC2)cc1
Reactant: O=C(c1cccc2[nH]nnc12)C(F)(F)F
Solvent: C1CCOC1
Product: CCCc1ccc(C2CCC(C3CCC(OC(=O)C(F)(F)F)CC3)CC2)cc1

Procedure:
Trifluoroacetylbenzotriazole described above in an amount of 4.0 g (18.6 mmol) was dissolved in 50 ml of THF, 2.5 g (8.3 mmol) of 4-(4-(4-hydroxycyclohexyl)cyclohexyl)-1-propylbenzene was added thereto, they were refluxed for 1 hour, and then the solvent was distilled off. After the residue was purified by column chromatography on silica gel (eluent: heptane/ethyl acetate=3/1), the solvent was distilled off. The residue was subjected twice to recrystallization by using mixed solvent of heptane/ethyl acetate (1/5) to give 1.2 g (3.0 mmol) of trifluoroacetic acid 4-(4-(4-propylphenyl)cyclohexyl)cyclohexyl ester. Yield of this compound was 36%.