Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]([C:13]2[C:17]([CH2:18][CH2:19][O:20][CH3:21])=[N:16][O:15][N:14]=2)=[N:11][OH:12])[CH:5]=[CH:6][C:7]=1[F:8].C1N=CN([C:27](N2C=NC=C2)=[O:28])C=1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:27](=[O:28])[O:12][N:11]=[C:10]2[C:13]2[C:17]([CH2:18][CH2:19][O:20][CH3:21])=[N:16][O:15][N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: COCCc1nonc1C(=NO)Nc1ccc(F)c(Cl)c1
Solvent: C1CCOC1
Product: COCCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 70 °C
Yield: 100.3 %

Procedure:
N-(3-Chloro-4-fluorophenyl)-N′-hydroxy-4-(2-methoxyethyl)-1,2,5-oxadiazole-3-carboximidamide (2.5 g, 7.9 mmol) was dissolved in THF (44 mL) followed by addition of N,N-carbonyldiimidazole (1.5 g, 9.5 mmol). The reaction was heated to 70° C. for 1.5 h. The reaction solution was concentrated and purified by silica gel chromatography (20% ethyl acetate/hexane) to give the desired product (2.7 g, 99%). MF═C13H10ClFN4O4; LCMS calculated for C13H11ClFN4O4 (M+H)+: m/z=341.0.
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1.[C:17]([NH2:21])([CH3:20])([CH3:19])[CH3:18].[ClH:22]>C1C=CC=CC=1>[ClH:22].[C:17]([NH:21][CH2:16][CH:2]([OH:1])[CH2:3][O:4][C:5]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:8]=[N:7][N:6]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)N
Reactant: c1ccc(-n2nnnc2OCC2CO2)cc1
Agent: Cl
Solvent: c1ccccc1
Product: CC(C)(C)NCC(O)COc1nnnn1-c1ccccc1

Procedure:
2,3-Epoxy-1-[(1-phenyl-5-tetrazolyl)-oxy]propane (43.7 g., 0.20 mole) was heated at the reflux temperature in 150 ml. of tert.-butylamine and 300 ml. of benzene for 9 hours. The solvents were evaporated in vacuo and the residual oil was dissolved in 100 ml. of EtOH and acidified with ethanolic HCl. Dilution with diethyl ether gave 44.8 g. of the hydrochloride of the product, m.p. 73°-82°. Recrystallization from i-PrOH-IPE gave 30.8 g., m.p. 152.5°-154.5° (corr.).
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:16]([OH:18])=O)=[N:8][C:9]=2[O:10][CH2:11][C:12]([F:15])([F:14])[F:13])[CH2:3][CH2:2]1.[NH2:19][C@H:20]([CH2:25][OH:26])[CH2:21][CH:22]([CH3:24])[CH3:23]>>[OH:26][CH2:25][C@@H:20]([NH:19][C:16]([C:7]1[CH:6]=[CH:5][C:4]([CH:1]2[CH2:2][CH2:3]2)=[C:9]([O:10][CH2:11][C:12]([F:13])([F:14])[F:15])[N:8]=1)=[O:18])[CH2:21][CH:22]([CH3:24])[CH3:23]
Reactant: O=C(O)c1ccc(C2CC2)c(OCC(F)(F)F)n1
Reactant: CC(C)C[C@H](N)CO
Product: CC(C)C[C@@H](CO)NC(=O)c1ccc(C2CC2)c(OCC(F)(F)F)n1

Procedure:
The title compound was synthesized in analogy to Example 280c, using 5-cyclopropyl-6-(2,2,2-trifluoro-ethoxy)-pyridine-2-carboxylic acid (Example 301a) and L-leucinol (CAN 17016-87-4) as starting materials, MS (EI): m/e=361.3 [M+H]+.
Reaction SMILES: C([C:3]1[CH:12]=[CH:11][C:10]2[CH:9]([N:13]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31]C)[CH2:14][CH2:15][CH2:16]CC(OCC)=O)[CH2:8][CH2:7][CH2:6][C:5]=2[N:4]=1)#N.[C:33]([O:36][CH2:37][CH3:38])(=[O:35])[CH3:34]>Br>[CH2:37]([O:36][C:33](=[O:35])[CH2:34][CH2:16][CH2:15][CH2:14][N:13]([CH2:23][CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[OH:31])[CH:9]1[CH2:8][CH2:7][CH2:6][C:5]2[N:4]=[C:3]([C:33]([O:36][CH2:37][CH3:38])=[O:35])[CH:12]=[CH:11][C:10]1=2)[CH3:38]
Reactant: CCOC(=O)CCCCN(CCc1ccccc1OC)C1CCCc2nc(C#N)ccc21
Reactant: CCOC(C)=O
Agent: Br
Product: CCOC(=O)CCCCN(CCc1ccccc1O)C1CCCc2nc(C(=O)OCC)ccc21
Temperature: 120 °C
Reaction time: 5 h

Procedure:
Under nitrogen, 23.23 g (0.05 mol) of ethyl 5-{(2-cyano-5,6,7,8-tetrahydroquinolin-5-yl)[2-(2-methoxyphenyl)ethyl]amino}pentanoate were taken up in 175 ml of hydrobromic acid (48% in water). The syrup-like solution was then heated to 120° C. and stirred at this temperature for 5 hours. The clear yellow reaction solution was then cooled to room temperature and concentrated to dryness. Subsequently, 350 ml of anhydrous ethanol and 25 ml of a 4 N solution of hydrogen chloride in dioxane were added to the residue obtained, and the mixture was stirred at 65° C. overnight. The reaction mixture was then concentrated on a rotary evaporator to about 50 ml, 550 ml of saturated aqueous sodium bicarbonate solution were carefully added and the mixture was extracted three times with in each case 150 ml of ethyl acetate. The combined organic phases were dried over sodium sulphate, filtered and concentrated to dryness. The residue obtained (brown oil) was dissolved in 100 ml of ethyl acetate, 65 g of silica gel were added and the mixture was once more concentrated to dryness. The residue was then purified by column chromatography on silica gel (metal column 58×8 cm, 1600 ml of silica gel; mobile phase: ethyl acetate/petroleum ether 1:5, after about 3 liters 1:4, after about 3.5 liters 1:3). This gave 9.43 g (0.02 mol, 38% of theory) of the target compound as a colourless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=O)=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[S:30]1[CH2:34][C:33](=[O:35])[NH:32][C:31]1=[O:36].N1CCCCC1.C(O)(=O)C1C=CC=CC=1>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:24][CH:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH:22]=[C:34]3[S:30][C:31](=[O:36])[NH:32][C:33]3=[O:35])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=O)cn2)cc1Cl
Reactant: O=C1CSC(=O)N1
Agent: O=C(O)c1ccccc1
Solvent: C1CCNCC1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2cnc(C=C3SC(=O)NC3=O)cn2)cc1Cl
Temperature: 25 °C
Yield: 74.8 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-formyl-pyrazin-2-yl)-propionamide (prepared as in Example 18, 44 mg, 0.1 mmol), 2,4-thiazolidinedione (18 mg, 0.15 mmol), piperidine (2 μL, 0.02 mmol), and benzoic acid (1.2 mg, 0.01 mmol) in anhydrous ethanol (5 mL) was heated under reflux overnight. The reaction mixture was allowed to cool to 25° C. and then was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 0%–60% ethyl acetate/hexanes) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(2,4-dioxo-thiazolidin-5-ylidenemethyl)-pyrazin-2-yl]-propionamide (40 mg, 75%) as a white solid: LC-MS m/e 535 (MH+).
Reaction SMILES: [CH2:1]([N:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)[CH2:2][CH2:3][C:4]#[CH:5].[CH2:12]([N:14]=[C:15]=[O:16])[CH3:13]>C(Cl)Cl>[CH2:12]([NH:14][C:15]([N:9]1[CH2:8][CH2:7][N:6]([CH2:1][CH2:2][CH2:3][C:4]#[CH:5])[CH2:11][CH2:10]1)=[O:16])[CH3:13]
Reactant: CCN=C=O
Reactant: C#CCCCN1CCNCC1
Solvent: ClCCl
Product: C#CCCCN1CCN(C(=O)NCC)CC1

Procedure:
A solution of 1-(pent-4-ynyl)piperazine (1.08) in DCM (5 mL) was treated with ethyl isocyanate (0.56 mL) at rt for 2 h, and evaporated to yield N-ethyl-4-(pent-4-ynyl)piperazine-1-carboxamide.
Reaction SMILES: [CH3:1][CH:2]([CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)[CH:3]=[O:4].[O:15]=[CH:16][C:17](=C)C.C(OC(=O)C)(=O)C>>[C:16]([O:4][CH:3]=[C:2]([CH3:1])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]2[O:12][CH2:13][O:14][C:8]=2[CH:7]=1)(=[O:15])[CH3:17]
Reactant: C=C(C)C=O
Reactant: CC(C=O)Cc1ccc2c(c1)OCO2
Solvent: CC(=O)OC(C)=O
Product: CC(=O)OC=C(C)Cc1ccc2c(c1)OCO2

Procedure:
The production process (B) comprises the step (3) of reacting 1,2-methylenedioxybenzene [formula (1)], methacrolein and acetic anhydride with each other to produce 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene [formula (3)]; and the step (2) of subjecting the obtained 1-acetoxy-2-methyl-3-(3,4-methylenedioxyphenyl)-1-propene [formula (3)] to hydrolysis reaction or to transesterification reaction with an alcohol, followed by subjecting the resulting reaction mixture to distillative purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:23]=[CH:22][C:21]([NH2:24])=[CH:20][CH:19]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1.C1([O:31][C:32](=O)[NH:33][C:34]2[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:43])([F:42])[F:41])[N:35]=2)C=CC=CC=1.C(N(CC)CC)C>CN(C=O)C>[NH2:1][C:2]1[C:7]2=[C:8]([C:18]3[CH:19]=[CH:20][C:21]([NH:24][C:32]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([F:42])([F:41])[F:43])[N:35]=4)=[O:31])=[CH:22][CH:23]=3)[CH:9]=[C:10]([C:11]([O:13][CH2:14][CH2:15][CH2:16][CH3:17])=[O:12])[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CCCCOC(=O)c1cc(-c2ccc(N)cc2)c2c(N)ncnn12
Reactant: O=C(Nc1cccc(C(F)(F)F)n1)Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCCCOC(=O)c1cc(-c2ccc(NC(=O)Nc3cccc(C(F)(F)F)n3)cc2)c2c(N)ncnn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
To a solution of butyl 4-amino-5-(4-aminophenyl)pyrrolo[2,1-f][1,2,4]triazine-7-carboxylate (118.0 mg, 0.36 mmol) in DMF (3.5 mL) was added phenyl[6-(trifluoromethyl)pyridin-2-yl]carbamate (153.5 mg, 0.54 mmol), followed by triethylamine (0.10 mL, 0.73 mmol). The solution was stirred at rt overnight and then purified directly by HPLC using a gradient of 50-80% MeCN in water to yield 107.7 mg (58%) of the title compound as a white solid. 1H-NMR (DMSO-d6) δ 9.88 (s, 1 H), 9.73 (s, 1 H), 8.08 (s, 1 H), 8.04 to 7.97 (m, 2 H), 7.58 (d, J=8.6 Hz, 2 H), 7.51 to 7.49 (m, 1 H), 7.44 (d, J=8.5 Hz, 2 H), 7.22 (s, 1 H), 4.26 (t, J=6.6 Hz, 2 H), 1.71-1.64 (m, 2 H), 1.47-1.38 (m, 2 H), 0.93 (t, J=7.3, 3 H); MS [M+H]+=514.2; LCMS RT=3.49 min.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6](F)[CH:5]=1.[N:15]1([CH2:20][CH2:21][NH2:22])[CH2:19][CH2:18][CH2:17][CH2:16]1>CO.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[C:6]([NH:22][CH2:21][CH2:20][N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)[CH:5]=1
Reactant: COC(=O)c1ccc([N+](=O)[O-])c(F)c1
Reactant: NCCN1CCCC1
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc([N+](=O)[O-])c(NCCN2CCCC2)c1

Procedure:
3-Fluoro-4-nitro-benzoic acid methyl ester (xiv) (1.08 g, 5.41 mmol) and 2-pyrrolidin-1-yl-ethylamine (1.36 g, 11.9 mmol) in MeOH (19 mL) were stirred under microwave irradiation at 100° C. for 10 min. The RM was diluted with EtOAc and washed with aqueous saturated NaHCO3 and brine, dried over Na2SO4, filtered and evaporated to dryness. The residue was dry loaded on silica gel and purified by chromatography with DCM and MeOH to yield the title product as an orange solid (tR 2.45 min (conditions 8), MH+=294).
Reaction SMILES: Cl[C:2]1[CH:13]=[CH:12][CH:11]=[C:10](Cl)[C:3]=1[O:4][CH2:5][CH2:6][C@H:7]([NH2:9])[CH3:8].[F:15][C:16]([F:25])([F:24])C1C=CC=CC=1O>>[F:15][C:16]([F:25])([F:24])[C:2]1[CH:13]=[CH:12][CH:11]=[CH:10][C:3]=1[O:4][CH2:5][CH2:6][C@H:7]([NH2:9])[CH3:8]
Reactant: Oc1ccccc1C(F)(F)F
Reactant: C[C@@H](N)CCOc1c(Cl)cccc1Cl
Product: C[C@@H](N)CCOc1ccccc1C(F)(F)F
Yield: 88 %

Procedure:
Intermediate 14 (55 mg, 0.250 mmol, 88% yield) was prepared as a white powder following the procedure described for Intermediate 13 by replacing 2,6-dichlorophenol with 2-trifluoromethylphenol. LC-MS (ESI) 221 (M+H), RT=1.48 min (Method B).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][N:5]=1.[CH3:13][C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>C1COCC1>[Br:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[N:6]([S:20]([C:17]2[CH:18]=[CH:19][C:14]([CH3:13])=[CH:15][CH:16]=2)(=[O:22])=[O:21])[N:5]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: Brc1n[nH]c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2nc(Br)c3cccnc32)cc1
Reaction time: 0.17 h
Yield: 69.8 %

Procedure:
NaH (1.8 g, 44.9 mmol, 60% suspension in mineral oil) was added portionwise to a cold (0° C.) solution of 3-bromo-1H-pyrazolo[3,4-b]pyridine (3.7 g, 18.7 mmol) in dry THF (50 mL). After 10 minutes, 4-methylbenzene-1-sulfonyl chloride (5.3 g, 28.0 mmol) was added. The cold bath was removed, and the reaction mixture was left at room temperature overnight. The reaction mixture was placed in an ice bath, diluted with ethyl acetate (200 mL) and carefully quenched with water (20 mL). The aqueous layer was extracted with ethyl acetate (3×50 mL). The combined organic layers were dried, filtered and concentrated. The crude product was purified by column chromatography, eluting with hexanes/ethyl acetate (7:3) to give 3-bromo-1-tosyl-1H-pyrazolo[3,4-b]pyridine (4.6 g, 70%) as a solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:12])[CH:11]=1)[CH2:8][CH:7]([NH:13][CH:14]([CH2:18][CH2:19][CH3:20])[C:15]([OH:17])=O)[CH2:6][CH2:5]2.[CH3:21][C:22]([N:30]1[CH:34]=[C:33]([N+:35]([O-])=O)[N:32]=[CH:31]1)([CH3:29])[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:29][C:22]([N:30]1[CH:34]=[C:33]([NH:35][C:15](=[O:17])[CH:14]([NH:13][CH:7]2[CH2:6][CH2:5][C:4]3[C:9](=[C:10]([F:12])[CH:11]=[C:2]([F:1])[CH:3]=3)[CH2:8]2)[CH2:18][CH2:19][CH3:20])[N:32]=[CH:31]1)([CH3:21])[CH2:23][N:24]1[CH2:25][CH2:26][CH2:27][CH2:28]1
Reactant: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1
Reactant: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)O
Product: CCCC(NC1CCc2cc(F)cc(F)c2C1)C(=O)Nc1cn(C(C)(C)CN2CCCC2)cn1

Procedure:
Following the procedure for Example 86, 2-(6,8-Difluoro-1,2,3,4-tetrahydro-naphthalen-2-ylamino)-pentanoic acid (diastereomer 1) was reacted with 1-(1,1-Dimethyl-2-pyrrolidin-1-yl-ethyl)-4-nitro-1H-imidazole to afford the title compound: C13 NMR (100 MHz, CDCl3) 14.2, 19.6, 24.3, 26.6, 28.2, 28.6, 29.6, 36.6, 51.9, 56.0, 59.3, 60.3, 67.2, 100.8, 101.0, 101.3, 104.9, 110.7, 112.5, 130.8, 172.6; MS m/z 474.3 (M+1).
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][N:7]([C:10]2[N:15]=[CH:14][C:13]([N+:16]([O-])=O)=[CH:12][N:11]=2)[CH2:6][CH2:5]1)([CH3:3])[CH3:2]>C(Cl)Cl.CO>[CH:1]([N:4]1[CH2:5][CH2:6][N:7]([C:10]2[N:15]=[CH:14][C:13]([NH2:16])=[CH:12][N:11]=2)[CH2:8][CH2:9]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCN(c2ncc([N+](=O)[O-])cn2)CC1
Solvent: ClCCl
Solvent: CO
Product: CC(C)N1CCN(c2ncc(N)cn2)CC1
Reaction time: 1.5 h

Procedure:
The title compound was prepared in analogy to the procedure described in Step 33.1 but using 2-(4-isopropyl-piperazin-1-yl)-5-nitro-pyrimidine (Step 35.2) and stirring the reaction mixture for 1.5 h. The title compound: ESI-MS: 222.1 [M+H]+; TLC: Rf=0.13 (DCM/MeOH/NH3aq, 94:5:1).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]3[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=3)=[O:13])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[Br:31]C1C=C2C(=CC=1)NC=C2CC(O)=O>>[Br:31][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:2]=1)[NH:8][CH:7]=[C:6]2[CH2:11][C:12]([N:14]=[C:15]([NH2:30])[NH:16][CH2:17][C:18]1[CH:23]=[C:22]([Cl:24])[C:21]([NH:25][C:26](=[O:28])[CH3:27])=[C:20]([Cl:29])[CH:19]=1)=[O:13]
Reactant: O=C(O)Cc1c[nH]c2ccc(Br)cc12
Reactant: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3cc(Br)ccc23)cc1Cl
Product: CC(=O)Nc1c(Cl)cc(CNC(N)=NC(=O)Cc2c[nH]c3ccc(Br)cc23)cc1Cl

Procedure:
In a manner similar to that used in the preparation of the compound of example 1, but using 2-(5-bromo-1H-indol-3-yl)acetic acid in step 20 (A), the title compound was prepared. MS (ESI) (M+H)+=509.84/511.92/513.90 1H-NMR (500 MHz, CD3OD) δ 7.73 (d, J=1.53 Hz, 1 H), 7.46 (s, 2 H), 7.29-7.40 (m, 2 H), 7.26 (d, J=1.83 Hz, 1 H), 4.54 (s, 2 H), 3.96 (s, 2 H), 2.19 (s, 3 H).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=1)=[O:6].[C:21]1([C:27]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[OH:28])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.Cl>C1(C)C(C)=CC=CC=1>[ClH:1].[OH:28][C:27]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)([C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH:29]1[CH2:34][CH2:33][N:32]([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:12]=[CH:11][C:10]([C:13]([CH3:20])([CH3:19])[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:9][CH:8]=2)=[O:6])[CH2:31][CH2:30]1
Reactant: OC(c1ccccc1)(c1ccccc1)C1CCNCC1
Reactant: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCCl)cc1
Agent: Cl
Solvent: Cc1ccccc1C
Product: CCOC(=O)C(C)(C)c1ccc(C(=O)CCCN2CCC(C(O)(c3ccccc3)c3ccccc3)CC2)cc1
Reaction time: 2 h
Yield: 70.5 %

Procedure:
Dissolve 2-[4-(4-chloro-butyryl)-phenyl]-2-methyl-propionic acid, ethyl ester (15.0 g, 49.53 mmol) and α,α-diphenyl-4-piperidinemethanol (29.66 g, 106.4 mmol) in xylene (60 mL). Reflux for 5.5 hours, cool in an ice bath, filter and wash with cold xylenes (25 mL). Filter the filtrate though silica gel (20 g) and wash the gel with xylenes (40 mL). Add xylene (60 mL) and concentrated hydrochloric acid (6.45 g, 65.6 mmol) with stirring. Add additional xylenes (40 mL) and stir for 2 hour. Filter, wash with xylene (50 mL), vacuum dry and slurry with a mixture of ethanol (60 mL) and hexane (120 mL) at 70-72° C. for 30 minutes. Filter, wash with 3:1 v/v solution of n-heptane/ethanol (30 mL) and dry to give the title compound as a light white solid (19.7 g, 70%); mp 206-208° C.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[CH:7][N:8]([CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])[CH:9]=1)=O.[NH3:18]>CO>[F:17][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=1[CH2:10][N:8]1[CH:9]=[C:5]([C:3]([NH2:18])=[O:2])[N:6]=[CH:7]1
Reactant: N
Reactant: COC(=O)c1cn(Cc2ccccc2F)cn1
Solvent: CO
Product: NC(=O)c1cn(Cc2ccccc2F)cn1

Procedure:
4.0 g of 1-(o-fluorobenzyl)-imidazole-4-carboxylic acid methyl ester are dissolved in 80 ml of methanol and transferred to an autoclave. 20.0 g of ammonia are introduced under pressure and the whole is heated at 100° for 19 hours. When the excess ammonia has been blown off, the resulting product is filtered off and recrystallised from ethanol. 1-(o-fluorobenzyl)-imidazole-4-carboxamide having a melting point of 204°-205° is obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]([C:8]1[S:28][C:11]2[CH2:12][CH2:13][CH:14]3[C:19]([C:10]=2[CH:9]=1)=[N:18][N:17]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)[C:16](=[O:27])[CH2:15]3)=O)(=[O:3])[CH3:2].C([SiH](CC)CC)C.C(=O)([O-])[O-].[K+].[K+]>FC(F)(F)C(O)=O>[C:1]([O:4][CH2:5][CH2:6][C:8]1[S:28][C:11]2[CH2:12][CH2:13][CH:14]3[C:19]([C:10]=2[CH:9]=1)=[N:18][N:17]([C:20]1[CH:21]=[CH:22][C:23]([CH3:26])=[CH:24][CH:25]=1)[C:16](=[O:27])[CH2:15]3)(=[O:3])[CH3:2]
Reactant: CC(=O)OCC(=O)c1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Agent: CC[SiH](CC)CC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)OCCc1cc2c(s1)CCC1CC(=O)N(c3ccc(C)cc3)N=C21
Temperature: 25 °C
Reaction time: 24 h
Yield: 69.1 %

Procedure:
To a solution of 3 g of 8-acetoxyacetyl-4,4a,5,6-tetrahydro-2-(4methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one in 30 ml of trifluoroacetic acid was added 2.7 ml of triethylsilane and the mixture was stirred at room temperature for 24 hours. The mixture was poured into ice-cold water, neutrallized with potassium carbonate and then extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel (SiO2 :100 g) column using chloroform as an eluent. The resulting solid was recrystallized from a mixed solvent of ethyl acetate and hexane to give 2.0 g of 8-(2-acetoxyethyl)-4,4a,5,6-tetrahydro-2-(4-methylphenyl)thieno-[2,3-h]cinnolin-3(2H)-one as a white powder, melting at 73°-75° C.
Reaction SMILES: [H-].[Na+].C([O:5][C:6](=[O:33])[C:7]([CH3:32])([O:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:16][CH2:17][CH:18]2[CH2:22][NH:21][C:20](=[O:23])[N:19]2[CH3:24])=[CH:11][CH:10]=1)C.[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41]Cl)=[CH:39][CH:38]=1)([CH3:36])[CH3:35]>CN(C=O)C>[CH:34]([C:37]1[CH:44]=[CH:43][C:40]([CH2:41][N:21]2[CH2:22][CH:18]([CH2:17][CH2:16][O:15][C:12]3[CH:11]=[CH:10][C:9]([CH2:8][C:7]([CH3:32])([O:25][C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C:6]([OH:33])=[O:5])=[CH:14][CH:13]=3)[N:19]([CH3:24])[C:20]2=[O:23])=[CH:39][CH:38]=1)([CH3:36])[CH3:35]
Reactant: CCOC(=O)C(C)(Cc1ccc(OCCC2CNC(=O)N2C)cc1)Oc1ccccc1
Reactant: CC(C)c1ccc(CCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1ccc(CN2CC(CCOc3ccc(CC(C)(Oc4ccccc4)C(=O)O)cc3)N(C)C2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 69.1 %

Procedure:
To a cooled (0° C.) suspension of NaH (24 mg, 0.60 mmol, 60% w/w in mineral oil) in DMF (1 ml) is added a solution of 2-Methyl-3-{4-[2-(3-methyl-2-oxo-imidazolidin-4-yl)-ethoxy]-phenyl}-2-phenoxy-propionic acid ethyl ester (128 mg, 0.30 mmol) in DMF (1.5 ml). After 5 minutes, the reaction mixture is removed from the cooling bath and stirred while warming to ambient temperature over 45 minutes. After the solution is cooled again to 0° C., 4-isopropylbenzyl chloride (126 mg, 0.75 mmol) is added in a single portion, the cooling bath removed, and the mixture stirred for 50 minutes. The reaction mixture is quenched with 1N HCl and extracted with ethyl acetate (2×). The organic extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil. The crude product is dissolved in ethanol (4 ml), treated with 5N NaOH (1.5 ml), and stirred for 24 hours at ambient temperature. The mixture is poured into 1N HCl, then extracted with ethyl acetate (2×20 ml). The combined ethyl acetate extracts were washed with water, brine, dried (Na2SO4), and concentrated to an oil which is purified by MS/LC to provide a foam (110 mg, 69%).
Reaction SMILES: [Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[C:11]([C:15]1[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:16]=1[OH:25])([CH3:14])([CH3:13])[CH3:12]>ClC(Cl)C>[Cl:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([C:19]1[CH:18]=[C:17]([C:21]([CH3:22])([CH3:23])[CH3:24])[C:16]([OH:25])=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH:20]=1)=[O:5]
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CC(Cl)Cl
Product: CC(C)(C)c1cc(C(=O)c2cccnc2Cl)cc(C(C)(C)C)c1O
Reaction time: 0.83 h
Yield: 79.8 %

Procedure:
To a solution of 282 g of 2-chloronicotinoyl chloride and 400 g of 2,6-di-tertiary butylphenol in 1000 ml of dichloroethane under ice-cooling is added dropwise a solution of 500 g of anhydrous stannic chloride in 250 ml of dichloroethane with stirring over 50 minutes. The reaction temperature is kept below 5° C. during the addition. After completion of the addition, the mixture is stirred at room temperature for 1.5 hours. The resulting reaction mixture is poured into ice-cold water and stirred for a while. The organic layer is separated, washed with water, dried and then concentrated. The obtained residue is recrystallized from an aqueous solution of 80% methanol to give 442 g of 4-(2-chloronicotinoyl)-2,6-di-tertiary butylphenol as pale yellow crystals, melting at 135°-137° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([N:21](CC4C=CC(OC)=CC=4)[C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:20])=[O:19])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][C:14]([S:18]([NH:21][C:22]4[S:23][CH:24]=[CH:25][N:26]=4)(=[O:19])=[O:20])=[CH:15][CH:16]=3)[CH:11]=[CH:10][N:9]=2)=[C:4]([OH:36])[CH:3]=1
Reactant: COc1ccc(CN(c2nccs2)S(=O)(=O)c2ccc3c(-c4ccc(F)cc4O)nccc3c2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1nccs1)c1ccc2c(-c3ccc(F)cc3O)nccc2c1
Yield: 22 %

Procedure:
1-(4-fluoro-2-hydroxyphenyl)-N-(4-methoxybenzyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide was dissolved in DCM (1 ml) and TFA (1 ml) and stirred at ambient temperature for 2 h. The mixture was purified by reverse phase chromatography, eluting with 0.1% NH4OH in ACN and water as mobile phase to obtain 1-(4-fluoro-2-hydroxyphenyl)-N-(thiazol-2-yl)isoquinoline-6-sulfonamide (20 mg, 22%). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.88 (br. s., 1H) 10.19 (s, 1H) 8.65 (d, J=5.67 Hz, 1H) 8.51 (d, J=1.56 Hz, 1H) 8.06 (d, J=5.87 Hz, 1H) 7.78-7.91 (m, 2H) 7.34 (t, J=7.78 Hz, 1H) 7.26 (d, J=4.50 Hz, 1H) 6.76-6.88 (m, 3H). m/z (ESI) 402.0 (M+H)+.