Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:12]=[CH:11][C:5]2[NH:6][C:7](=O)[N:8]=[CH:9][C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[Br:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[Cl:25])[NH2:21]>CN(C=O)C.CC(N(C)C)=O>[Br:17][C:18]1[CH:19]=[C:20]([NH:21][C:9]2[C:4]3[CH:3]=[C:2]([F:1])[N:12]=[CH:11][C:5]=3[N:6]=[CH:7][N:8]=2)[CH:22]=[CH:23][C:24]=1[Cl:25]
Reactant: O=c1ncc2cc(F)ncc2[nH]1
Reactant: Nc1ccc(Cl)c(Br)c1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Solvent: O=S(Cl)Cl
Product: Fc1cc2c(Nc3ccc(Cl)c(Br)c3)ncnc2cn1
Temperature: 25 °C
Reaction time: 19 h
Yield: 99.6 %

Procedure:
A heterogeneous mixture of 6-fluoropyrido[3,4-d]pyrimidin-4(3H)-one (200) (1.50 g, 9.09 mmol), thionyl chloride (20 mL) and a catalytic amount of DMF (2 drops) was stirred under reflux for 3 h to give a homogeneous mixture. It was evaporated under reduced pressure at 40° C. (bath temperature) to give a light brown solid. To this solid was added a solution of 3-bromo-4-chloroaniline (2.07 g, 10.0 mmol) in dry DMA (15 mL). The residue of 3-bromo-4-chloroaniline was washed down with more DMA (2×2 mL). The reaction mixture was stirred at room temperature for 19 h. It was poured into water (200 mL). The pH was adjusted to ca. 8 using an aqueous solution of Na2CO3 at room temperature. Petroleum ether (300 mL) was added and stirred at room temperature for 30 min. The petroleum ether layer was decanted. It was repeated once more with petroleum ether. The solid was collected by filtration and washed with water (4×20 mL). It was dried in vacuum over silica gel/KOH overnight to give N-(3-bromo-4-chlorophenyl)-6-fluoropyrido[3,4-d]pyrimidin-4-amine (205) (3.20 g, 99%) as a yellow/orange solid, mp 271-275° C.; 1H NMR δ [(CD3)2SO] 10.15 (s, 1H), 8.99 (s, 1H), 8.79 (s, 1H), 8.45 (d, J=2.5 Hz, 1H), 8.26 (br s, 1H), 7.98 (dd, J=8.8, 2.5 Hz, 1H), 7.69 (d, J=8.8 Hz, 11-1). Anal. Calcd for C13N7BrClFN4: C, 44.16; H, 2.00; N, 15.85. Found C, 44.21; H, 1.87; N, 15.98.
Reaction SMILES: C([O:3][C:4](=[O:24])[CH2:5][O:6][C:7]1[C:22]([Br:23])=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])=[N:12][O:13][C:9]=2[CH:8]=1)C.Cl>C(O)C.O.[OH-].[Na+]>[Br:23][C:22]1[C:7]([O:6][CH2:5][C:4]([OH:24])=[O:3])=[CH:8][C:9]2[O:13][N:12]=[C:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:10]=2[CH:21]=1
Reactant: CCOC(=O)COc1cc2onc(-c3ccccc3F)c2cc1Br
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)COc1cc2onc(-c3ccccc3F)c2cc1Br

Procedure:
A suspension of 4 g of ethyl{[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetate in 125 ml of ethanol, 50 ml of water and 4 ml of 50% sodium hydroxide solution is refluxed for several hours, acidified with dilute hydrochloric acid and extracted with ethyl acetate. The extract is dried, the solvent is removed and the residue is recrystallized from acetonitrile to give {[5-bromo-3-(2-fluorophenyl)-1,2-benzisoxazol-6-yl]oxy}acetic acid, mp 223°-224° C.
Reaction SMILES: [OH:1]OS([O-])=O.[K+].[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28][CH2:29][CH3:30])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1>O.CO>[Br:7][C:8]1[CH:32]=[CH:31][C:11]([NH:12][C:13]2[C:22]3[C:17](=[CH:18][C:19]([O:25][CH2:26][CH2:27][S:28]([CH2:29][CH3:30])=[O:1])=[C:20]([O:23][CH3:24])[CH:21]=3)[N:16]=[CH:15][N:14]=2)=[C:10]([F:33])[CH:9]=1
Reactant: CCSCCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCS(=O)CCOc1cc2ncnc(Nc3ccc(Br)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 24.4 %

Procedure:
A solution of OXONE, (trade mark of E.I. du Pont de Nemours & Co.,Inc), (150 mg) in water (2 ml) was added to a solution of 4-(4-bromo-2-fluoroanilino)-7-(2-ethylthioethoxy)-6-methoxyquinazoline (125 mg, 0.28 mmol), (prepared as described in Example 24), in methanol (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature, the methanol was removed by evaporation, the aqueous residue was basified with sodium hydrogen carbonate solution and then extracted with ethyl acetate (3×30 ml). The extracts were combined, washed with water (×2), and then brine, and dried (MgSO4). The solvent was removed by evaporation and the residue was purified by column chromatography eluting with ethyl acetate and then with methylene chloride/methanol (9/1) to give 4-(4-bromo-2-fluoroanilino)-7-(2ethylsulphinylethoxy)-6methoxyquinazoline (32 mg, 31%).
Reaction SMILES: [CH3:1][O:2][N:3]([CH3:19])[C:4](=[O:18])[C:5]1[CH:10]=[CH:9][C:8]([NH2:11])=[C:7]([NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)[CH:6]=1.C[O-].[Li+].[N:23]#[C:24]Br>ClCCl>[CH3:19][N:3]([O:2][CH3:1])[C:4]([C:5]1[CH:10]=[CH:9][C:8]2[N:11]=[C:24]([NH2:23])[N:12]([CH:13]3[CH2:14][CH2:15][CH2:16][CH2:17]3)[C:7]=2[CH:6]=1)=[O:18]
Reactant: N#CBr
Reactant: CON(C)C(=O)c1ccc(N)c(NC2CCCC2)c1
Agent: C[O-]
Agent: [Li+]
Solvent: ClCCl
Product: CON(C)C(=O)c1ccc2nc(N)n(C3CCCC3)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.4 %

Procedure:
Combine N-[methoxy]-N-[methyl]3-cyclopentylamino-4-aminobenzamide (1.79 g, 6.82 mmol) and lithium methoxide (0.27 g, 7.16 mmol) in anhydrous dichloromethane (25 mL) and stir for 20 minutes. Add a solution of cyanogen bromide (0.83 g, 7.84 mmol) anhydrous dichloromethane (8 mL) and stir overnight at room temperature under nitrogen. Concentrate under reduced pressure and partition the residue between ethyl acetate and water. Wash the organic layer sequentially saturated aqueous sodium bicarbonate (2×20 mL), saturated aqueous sodium chloride (2×20 mL), and water (2×20 mL). Dry over magnesium sulfate and concentrate under reduced pressure to provide the desired compound as a dark solid (1.62 g, 82%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH2:22])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1.C(N(CC)CC)C.CN(C)C=O.[CH:35]1([C:38](Cl)=[O:39])[CH2:37][CH2:36]1>C(Cl)Cl>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]2[CH2:15][CH2:14][N:13]([CH2:16][C:17]3[N:18]=[C:19]([NH:22][C:38]([CH:35]4[CH2:37][CH2:36]4)=[O:39])[S:20][CH:21]=3)[CH2:12][CH2:11]2)=[CH:2]1
Reactant: Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Nc1nc(CN2CCC(c3c[nH]c4ccccc34)CC2)cs1)C1CC1

Procedure:
To a mixture of 4-[4-(3-indolyl)piperidinomethyl]-2-aminothiazole (3.0 g), triethylamine (5.4 ml) and N,N-dimethylformamide (30 ml) was added dropwise a solution of cyclopropylcarbonyl chloride (2.18 ml) in methylene chloride (2.5 ml) over a period of 30 minutes at 0° C. in a stream of nitrogen gas with stirring. After the reaction was finished, the reaction mixture was filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (20:1 V/V) to give 4-[4-(3-indolyl)piperidinomethyl]-2-cyclopropylcarbonylaminothiazole (2.9 g).
Reaction SMILES: [CH2:1]([C:4]1([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([O:16][Si](C(C)(C)C)(C)C)([CH3:15])[CH3:14])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]>C(O)(C(F)(F)F)=O.C(Cl)Cl>[CH2:1]([C:4]1([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]([OH:16])([CH3:14])[CH3:15])[CH3:12])[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O[Si](C)(C)C(C)(C)C)C(=O)O1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CCC1(c2ccccc2)CCN([C@@H](C)C(C)(C)O)C(=O)O1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
A mixture of 6-allyl-3-((S)-3-(tert-butyldimethylsilyloxy)-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one isomer 1 (80 mg, 0.19 mmol) in 20% TFA/DCM (2 mL) was stirred for 30 min at 0° C. The mixture was concentrated to give crude 6-allyl-3-((S)-3-hydroxy-3-methylbutan-2-yl)-6-phenyl-1,3-oxazinan-2-one isomer 1 (50 mg, 86%). LC-MS Method 2 tR=1.85 min, m/z=326, 304; 1H NMR (CDCl3) 1.07 (m, 6H), 1.18 (s, 3H), 2.15 (m, 1H), 2.25 (m, 1H), 2.58 (m, 2H), 2.90 (m, 1H), 3.08 (m, 1H), 3.20 (m, 1H), 5.02 (m, 2H), 5.68 (m, 1H), 7.22 (3H), 7.31 (2H).
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2.[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>O1CCCC1>[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26]([NH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4](=[O:21])[N:5]([CH:13]1[CH2:18][CH2:17][C:16](=[O:19])[NH:15][C:14]1=[O:20])[C:6]([CH3:12])=[N:7]2)=[O:27]
Reactant: Cc1nc2cccc(N)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: C1CCOC1
Product: Cc1nc2cccc(NC(=O)c3cccc(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Temperature: 80 °C
Yield: 47.1 %

Procedure:
To a stirred mixture of 3-(5-amino-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione (0.46 g, 1.5 mmol) in tetrahydrofuran (10 mL), was added 3-chlorobenzoyl chloride (0.68 mL, 5.3 mmol) and heated at 80° C. for three hours. The mixture was quenched with a few drops of methanol. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 3-chloro-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-yl]-benzamide as a white solid (300 mg, 46% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, gradient to 95/5 in 5 min, kept for 5 min, 7.04 min (98.2%); mp, 326-328° C.; 1HNMR (DMSO-d6) 2.18-2.28 (m, 1H, CHH), 2.61-2.92 (m, 6H, CHCH2, CH3), 5.36 (dd, J=6, 11 Hz, 1H, CH), 7.37-8.70 (m, 7H, Ar), 11.12 (s, 1H, NH), 12.72 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.74, 23.39, 30.66, 40.41, 56.90, 115.69, 121.28, 125.21, 127.12, 131.13, 132.14, 135.78, 163.46, 169.30, 172.59, 172.62. LCMS MH=425, 427; Anal Calcd For C21H17N4O4Cl+0.3H2O: C, 58.62; H, 4.12; N, 13.02; Cl, 8.24. Found: C, 58.46; H, 3.74; N, 12.70; Cl, 7.98.
Reaction SMILES: [H-].[Na+].[C:3]1([C:13]2[NH:14][CH:15]=[CH:16][N:17]=2)[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1.I[CH2:19][CH3:20]>CN(C=O)C>[CH2:19]([N:17]1[CH:16]=[CH:15][N:14]=[C:13]1[C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=1)[CH3:20]
Reactant: c1ccc2c(-c3ncc[nH]3)cccc2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccnc1-c1cccc2ccccc12
Temperature: 50 °C
Reaction time: 1 h

Procedure:
To a suspension of sodium hydride (2.40 g, 60% mineral oil suspension, 60 mmol) in anhydrous DMF (30 ml) is added a solution of 2-naphthalen-1-yl-1H-imidazole (9.70 g, 50 mmol) in DMF (70 ml) at rt. The resulting mixture is stirred at 50° C. for 1 hr, and then cooled to 0° C., after which iodoethane (8.19 g, 52.5 mmol, 1.05 eq.) is added dropwise. The mixture is stirred at rt for 1 hr, and then heated to 50° C. and stirred for an additional 8 hr. The reaction mixture is cooled to rt, and poured into ice-water (500 ml). The mixture is extracted with EtOAc (100 ml×3). The combined organic layers are washed with water and brine, dried over anhydrous sodium sulfate, and solvent is evaporated at reduced pressure. The crude product is purified by flash chromatography on silica gel to give the title compound. LCMS 223 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH2:11][CH:12]([OH:21])[CH:13]=[CH:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:5].[C:22]1(C)[CH:27]=CC(S(O)(=O)=O)=C[CH:23]=1>CC(C)=O>[CH3:23][C:22]1([CH3:27])[O:1][CH:2]([CH2:3][C:4]([O:6][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:5])[CH2:11][CH:12]([CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[O:21]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CC(C)(C)OC(=O)CC(O)CC(O)C=Cc1ccccc1
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)CC1CC(C=Cc2ccccc2)OC(C)(C)O1
Reaction time: 2 h

Procedure:
To a solution of 1,1-dimethylethyl 3,5-dihydroxy-7-phenyl-6-heptenoate (5.5 g, 19 mmol) in acetone (2.2 g, 40 mmol) was added a catalyic amount of p-toluenesulfonic acid. After stirring for 2 hours, the mixture had solidified and was dissolved in excess acetone and filtered through a pad of sodium carbonate. The excess acetone was removed in vacuo and the residue crystallized from isopropyl ether to give 3.4 g of the title compound; m.p.=91-93° C.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]([O:9]C)=[O:8])=[N:3]1.CO.[OH-].[K+]>O>[CH3:1][N:2]1[CH:6]=[N:5][C:4]([C:7]([OH:9])=[O:8])=[N:3]1
Reactant: COC(=O)c1ncn(C)n1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cn1cnc(C(=O)O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71.4 %

Procedure:
Methyl 1-methyl-1H-1,2,4-triazole-3-carboxylate (280 mg) and methanol (1 ml) were added to potassium hydroxide (145 mg) in water (1 ml). The reaction was stirred for 3 h at RT. The solvent was evaporated and the residue was loaded onto an aminopropyl SPE cartridge (5 g) in DMF. The cartridge was washed with 10% methanol in DCM (3×15 ml), followed by 30% acetic acid in methanol. The appropriate fractions were combined, the solvent was evaporated and the residue dried at 50° C. under vacuum to give title compound (180 mg).
Reaction SMILES: [OH:1][C:2]([CH3:12])([CH3:11])[CH2:3][C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:13]([O:15][C:16](=[O:20])[C:17]#[C:18][CH3:19])[CH3:14].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[C:18](/[O:10][C:7]1[CH:8]=[CH:9][C:4]([CH2:3][C:2]([OH:1])([CH3:12])[CH3:11])=[CH:5][CH:6]=1)\[CH3:19])[CH3:14]
Reactant: CC#CC(=O)OCC
Reactant: CC(C)(O)Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccc(CC(C)(C)O)cc1
Temperature: 80 °C
Yield: 81.6 %

Procedure:
To a stirred mixture of 4-(2-hydroxy-2-methyl-propyl)-phenol (0.850 g, 5.11 mmol) and ethyl-2-butynoate (3.45 g, 30.66 mmol) in tetrahydrofuran (20 mL) was added potassium carbonate (0.710 g, 5.11 mmol). The mixture was heated in a sealed tube at 80° C. for 5.5 h. The reaction mixture was then cooled to room temperature. The solids were isolated by filtration and washed with a small amount of tetrahydrofuran. The filtrate was concentrated in vacuo and the residue was purified by flash chromatography (silica gel, 0% to 30% ethyl acetate/hexanes) which afforded (E)-3-[4-(2-hydroxy-2-methyl-propyl)-phenoxy]-but-2-enoic acid ethyl ester (1.16 g, 81%) as a viscous colorless oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:7]([NH:10][C:11]1[CH:16]=[CH:15][C:14]([S:17](Cl)(=[O:19])=[O:18])=[CH:13][CH:12]=1)(=[O:9])[CH3:8]>O1CCOCC1>[C:7]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([S:17]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:19])=[O:18])=[CH:15][CH:16]=1)(=[O:9])[CH3:8]
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Reactant: C1CCNCC1
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)N2CCCCC2)cc1
Temperature: 80 °C
Yield: 52.14 %

Procedure:
Piperidine (0.0114 Mol) is added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a white solid (52.14% yield) and used without further purification. m.p. 137° C.-139° C. 1H NMR (acetone-d6): δ 1.35-1.43 (m, 2H); 1.52-1.63 (m, 4H); 2.17 (s, 3H); 2.89-2.95 (m, 4H); 7.68-7.70 (d, 2H, J=7); 7.90-7.92 (d, 2H, J=7); 9.55 (bs, 1H). In a similar fashion, the following sulfonamides were prepared:
Reaction SMILES: [NH2-].[Na+].[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([CH:17]=O)=[C:12]3[CH2:11][N:10]([CH3:19])[C:9](=[O:20])[C:8]=2[CH:21]=1>[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)CCC.O1CCCC1>[F:3][C:4]1[CH:5]=[CH:6][C:7]2[N:13]3[CH:14]=[N:15][C:16]([CH:17]=[CH:5][CH2:4][CH2:21][CH3:8])=[C:12]3[CH2:11][N:10]([CH3:19])[C:9](=[O:20])[C:8]=2[CH:21]=1
Reactant: CN1Cc2c(C=O)ncn2-c2ccc(F)cc2C1=O
Agent: CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [NH2-]
Solvent: C1CCOC1
Product: CCCC=Cc1ncn2c1CN(C)C(=O)c1cc(F)ccc1-2
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
40.70 g of an equimolar mixture of butyltriphenylphosphonium bromide and sodium amide was stirred at room temperature for 15 minutes in 150 ml of tetrahydrofuran. 20.73 g (80 mmol) of 8-fluoro-5,6-dihydro-5-methyl-6-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxaldehyde was then added thereto, the mixture was stirred at room temperature for a further 1.5 hours, filtered and the filtrate was evaporated. After chromatography of the residue on silica gel while eluting with cyclohexane/ether/isopropanol (3:3:1) and recrystallization from ethyl acetate and n-hexane there was obtained 8-fluoro-4,5-dihydro-5-methyl-3-(1-pentenyl)-6H-imidazo[1,5-a][1,4]-benzodiazepin-6-one of melting point 150°-151°.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.[CH2:16]([O:18][C:19]([N:21]1[CH2:26][CH2:25][N:24]([C:27](=[O:36])[C@@H:28]([NH2:35])[CH2:29][CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[CH2:23][CH2:22]1)=[O:20])[CH3:17].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[CH2:16]([O:18][C:19]([N:21]1[CH2:22][CH2:23][N:24]([C:27](=[O:36])[C@@H:28]([NH:35][C:13]([C:4]2[CH:3]=[C:2]([OH:1])[N:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[N:5]=2)=[O:15])[CH2:29][CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[CH2:25][CH2:26]1)=[O:20])[CH3:17]
Reactant: CCOC(=O)N1CCN(C(=O)[C@@H](N)CCS(C)(=O)=O)CC1
Reactant: O=C(O)c1cc(O)n(-c2ccccc2)n1
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CCOC(=O)N1CCN(C(=O)[C@H](CCS(C)(=O)=O)NC(=O)c2cc(O)n(-c3ccccc3)n2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 190 mg of 5-Hydroxy-1-phenyl-1H-pyrazole-3-carboxylic acid and 299 mg of 4-((S)-2-Amino-4-methanesulfonyl-butyryl)-piperazine-1-carboxylic acid ethyl ester in 3 ml of DMF, 142 mg of HOBT, 178 mg of EDC and 0.2 ml DIPEA was added and the reaction mixture was stirred for 16 h at RT. Then, the solvents were removed under reduced pressure and the crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 327 mg.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1S(C)(=O)=O)[CH3:2].C1(C)C=CC=CC=1.[OH-:32].[Na+]>[Cl-].C([N+](C)(C)C)C1C=CC=CC=1.O>[CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12]1[C:13](=[O:24])[N:14]([CH3:23])[N:15]=[C:16]([CH3:22])[C:17]=1[OH:32])[CH3:2]
Reactant: CCc1cc(C)cc(CC)c1-c1c(S(C)(=O)=O)c(C)nn(C)c1=O
Reactant: [OH-]
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: CCc1cc(C)cc(CC)c1-c1c(O)c(C)nn(C)c1=O
Temperature: 120 °C
Reaction time: 38 h
Yield: 88.9 %

Procedure:
To a 100 mL volume four-necked flask, 4-(2,6-diethyl-4-methylphenyl)-2,6-dimethyl-5-methylsulfonyl-2,3-dihydropyridazin-3-one ((2-34)-(1)-39) (6.57 g), toluene (16.7 g), benzyltrimethylammonium chloride (0.16 g), and sodium hydroxide (2.86 g) were added under a nitrogen atmosphere, and stirred at 120° C. for 38 hours. Then, water (24.2 g) was added at room temperature. The organic layer was removed, and the aqueous layer was mixed with 3.5 w/w % of hydrochloric acid (20 g) at the same temperature, and filtered. The residue was washed with water (12 g) and dried to give 4.8 g of 4-(2,6-diethyl-4-methylphenyl)-5-hydroxy-2,6-dimethyl-2,3-dihydro-3-pyridazinone ((1-4)-(1)-39).
Reaction SMILES: C(O[C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(C)C.C[S:26]([C:29]1N=CC([C@@H](N)C)=C[CH:30]=1)(=[O:28])=[O:27].CS(C1N=CC(C(=O)C)=CC=1)(=O)=O.BrC1C=CC(S(C)(=O)=O)=NC=1>>[CH2:29]([S:26]([C:5]1[N:10]=[CH:9][C:8]([C@@H:11]([NH:13][C:14]([C@H:16]2[CH2:18][C@@H:17]2[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:15])[CH3:12])=[CH:7][CH:6]=1)(=[O:28])=[O:27])[CH3:30]
Reactant: C[C@H](N)c1ccc(S(C)(=O)=O)nc1
Reactant: CC(C)Oc1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1
Agent: CC(=O)c1ccc(S(C)(=O)=O)nc1
Agent: CS(=O)(=O)c1ccc(Br)cn1
Product: CCS(=O)(=O)c1ccc([C@H](C)NC(=O)[C@H]2C[C@@H]2c2ccccc2)cn1

Procedure:
Prepared analogously to Compound 1 using IM46 and (S)-1-(6-Methanesulfonyl-pyridin-3-yl)-ethylamine (prepared from 1-(6-Methanesulfonyl-pyridine-3-yl)-ethanone analogously to IM24, which was prepared from commercially available 5-Bromo-2-methanesulfonyl-pyridine CAS 98626-95-0). Yield from IM48=1.54 g (68%). 1H-NMR (500 MHz, DMSO) δ 8.80 (d, 1H), 8.72 (s, 1H), 8.02 (m, 2H), 7.27 (m, 2H), 7.20 (s, 1H), 7.12 (d, 2H), 5.08 (m, 1H), 3.27 (s, 3H), 2.20 (m, 1H), 1.95 (m, 1H), 1.42 (d, 3H), 1.37 (m, 1H), 1.22 (m, 1H), LC-MS (m/z) 345.1 (MH+), tR=1.21 min (method A).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([F:9])=[CH:4][C:3]=1[NH:10][C:11]([C:13]1[C:14](=[O:26])[N:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[N:16]([CH3:19])[C:17]=1[CH3:18])=[O:12].CC([O-])(C)C.[K+].[Cl:33][C:34]1[C:35]([C:41]([NH2:43])=[O:42])=[N:36][CH:37]=[CH:38][C:39]=1Cl>CN(C=O)C>[Cl:33][C:34]1[C:35]([C:41]([NH2:43])=[O:42])=[N:36][CH:37]=[CH:38][C:39]=1[O:8][C:6]1[CH:7]=[C:2]([F:1])[C:3]([NH:10][C:11]([C:13]2[C:14](=[O:26])[N:15]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:16]([CH3:19])[C:17]=2[CH3:18])=[O:12])=[CH:4][C:5]=1[F:9]
Reactant: Cc1c(C(=O)Nc2cc(F)c(O)cc2F)c(=O)n(-c2ccccc2)n1C
Reactant: NC(=O)c1nccc(Cl)c1Cl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1c(C(=O)Nc2cc(F)c(Oc3ccnc(C(N)=O)c3Cl)cc2F)c(=O)n(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 60.3 %

Procedure:
To a solution of N-(2,5-difluoro-4-hydroxyphenyl)-1,5-dimethyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (395 mg, 1.1 mmol) in DMF (5.0 mL) was added t-BuOK (202 mg, 1.8 mmol) and the mixture was stirred at rt for 30 minutes. Then 3,4-dichloropicolinamide (190 mg, 1.0 mmol) was added and the mixture was microwaved at 120° C. for 2 hours, then cooled to rt, quenched with water (30 mL) and extracted with EtOAc (50 mL×3). The combined organic phases were washed with brine (50 mL×3), dried over anhydrous Na2SO4, and concentrated in vacuo. The residue was purified by a silica gel column chromatography (MeOH/DCM (v/v)=1/30) to give the title compound as a pale yellow solid (310 mg, 60%).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:22])=[O:14])[CH:3]=1.[CH:23]([B-](F)(F)F)=[CH2:24].[K+].C(=O)([O-])[O-].[Cs+].[Cs+].ClCCl>C(OCC)(=O)C.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O.C1COCC1>[CH:23]([C:2]1[C:11]2[C:6](=[C:7]([F:12])[CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]([NH:15][C@H:16]2[CH2:21][CH2:20][CH2:19][CH2:18][C@@H:17]2[OH:22])=[O:14])[CH:3]=1)=[CH2:24]
Reactant: O=C(N[C@H]1CCCC[C@@H]1O)c1cc(Br)c2cccc(F)c2n1
Reactant: C=C[B-](F)(F)F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: C=Cc1cc(C(=O)N[C@H]2CCCC[C@@H]2O)nc2c(F)cccc12
Temperature: 100 °C

Procedure:
To a solution of 4-bromo-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (C7) (1.88 g, 5.12 mmol) in 10:1 THF:H2O (22 mL) was added potassium vinyltrifluoroborate (2.06 g, 15.4 mmol) and cesium carbonate (3.34 g, 10.2 mmol). The reaction was placed under N2(g), and [1,1′-bis(diphenylphosphino)-ferrocene]dichloro palladium(II), complex with dichloromethane (0.100 g, 0.122 mmol) was added. The mixture was heated to 100° C. for 3 h, then cooled to RT and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate (1×) and brine (1×), dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was purified via silica gel chromatography eluting with 0-5% methanol in dichloromethane to provide 4-ethenyl-8-fluoro-N-[(1S,2S)-2-hydroxycyclohexyl]quinoline-2-carboxamide (C8) that gave a mass ion (ES+) of 315.1 for M+H+.