Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:3](=[O:27])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25]Cl)=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17].[CH3:28][NH:29][CH3:30]>C1COCC1>[Br:1][C:2]1[C:3](=[O:27])[N:4]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][N:29]([CH3:30])[CH3:28])=[CH:21][CH:20]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[CH:12][C:11]=1[F:17]
Reactant: O=c1c(Br)c(OCc2ccc(F)cc2F)ccn1Cc1ccc(CCl)cc1
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)Cc1ccc(Cn2ccc(OCc3ccc(F)cc3F)c(Br)c2=O)cc1
Reaction time: 15 h
Yield: 46 %

Procedure:
To a sealed tube containing 3-bromo-1-(4-chloromethylbenzyl)-4-(2,4-difluoro-benzyloxy)-1H-pyridin-2-one (0.49 g, 1.1 mmol) was added a solution of dimethylamine (5.5 mL of a 2.0 M solution in THF, 11 mmol), and the reaction mixture was stirred for 15 h. The solvent was removed under reduced pressure. Purification by flash column chromatography (silica, eluent methylene chloride to 92:7.2:0.8 methylene chloride/methanol/ammonia) provided 3-bromo-4-(2,4-difluorobenzyloxy)-1-(4-dimethylaminomethylbenzyl)-1H-pyridin-2-one as a light yellow solid (0.23 g, 46%): mp 111-113° C.; 1H NMR (500 MHz, CDCl3) δ 7.50-7.49 (m, 1H), 7.26-7.22 (m, 5H), 6.90-6.88 (m, 1H), 6.82-6.78 (m, 1H), 6.04 (d, J=6 Hz, 1H), 5.16 (s, 2H), 5.11 (s, 2H), 3.37 (s, 2H), 2.19 (s, 6H). ES HRMS m/z 463.0782 (M+H C22H22BrF2N2O2 requires 463.0827).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C@@H:8]([C:17](=[O:22])N(OC)C)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])([CH3:4])([CH3:3])[CH3:2].[C:24]([NH:28][C:29](=[O:38])[C:30]1[C:35]([CH3:36])=[CH:34][CH:33]=[CH:32][C:31]=1[CH3:37])([CH3:27])([CH3:26])[CH3:25]>>[C:1]([O:5][C:6](=[O:23])[NH:7][C@H:8]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])[C:17](=[O:22])[CH2:36][C:35]1[CH:34]=[CH:33][CH:32]=[C:31]([CH3:37])[C:30]=1[C:29](=[O:38])[NH:28][C:24]([CH3:26])([CH3:25])[CH3:27])([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cccc(C)c1C(=O)NC(C)(C)C
Reactant: CON(C)C(=O)[C@@H](Cc1ccccc1F)NC(=O)OC(C)(C)C
Product: Cc1cccc(CC(=O)[C@@H](Cc2ccccc2F)NC(=O)OC(C)(C)C)c1C(=O)NC(C)(C)C

Procedure:
Using general procedure 2 with [(R)-2-(2-fluoro-phenyl)-1-(methoxy-methyl-carbamoyl)-ethyl]-carbamic acid tert-butyl ester (2.65 g, 8.1 mmol) and N-tert-butyl-2,6-dimethyl-benzamide (5.0 g, 24 mmol), followed by purification by silica gel flash column chromatography gives the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[NH2:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13].CCN(C(C)C)C(C)C>C1(C)C=CC=CC=1>[Br:8][C:4]1[N:3]=[C:2]([NH:9][CH2:10][CH:11]([OH:14])[CH2:12][OH:13])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(Br)n1
Reactant: NCC(O)CO
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: OCC(O)CNc1cccc(Br)n1
Yield: 30.2 %

Procedure:
A stirred solution of 2,6-dibromopyridine (0.76 g, 3.20 mmol), 1-amino-2,3-dihydroxypropane (0.29 g, 3.20 mmol) and DIPEA (0.56 mL, 3.24 mmol) in toluene (3.2 mL) was heated to 160° C. under microwave irradiation in a sealed tube for 2 h, and then concentrated in vacuo. Water (5 mL) was added, the mixture sonicated for 10 minutes, and then filtered through Celite®. The filtrate was concentrated in vacuo to yield the title compound (0.239 g, 30%) as a white solid that was used without further purification. δH (DMSO-d6) 7.29-7.18 (1H, m), 6.92-6.79 (1H, m), 6.61 (1H, d, J 7.3 Hz), 6.51 (1H, d, J 8.3 Hz), 4.79 (1H, d, J 4.9 Hz), 4.58 (1H, t, J 5.8 Hz), 3.65-3.54 (1H, m), 3.15-3.04 (1H, m). Exchangeable protons were not observed. LCMS (ES+) 247.0 and 249.0 (1:1 ratio) (M+H)+, RT 2.07 minutes (Method 1).
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[NH:24][CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[CH:30](=O)[C:31]1[O:35][CH:34]=[CH:33][CH:32]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].O>ClCCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:30][C:31]4[O:35][CH:34]=[CH:33][CH:32]=4)[CH2:23][CH2:22][C:21]([C:25]([O:27][CH3:28])=[O:26])=[CH:20][C:19]=3[CH:29]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3)cc1
Reactant: O=Cc1ccco1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: O
Solvent: ClCCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3Cc2ccco2)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 66.3 %

Procedure:
To a solution of methyl 7-(4-butoxyethoxyphenyl)-2,3-dihydro-1-benzazepine-4-carboxylate (400 mg) and furfural (485 mg) in 1,2-dichloroethane (15 ml) was added sodium triacetoxyborohydride (536 mg), and the mixture was stirred under nitrogen atmosphere at room temperature for 1 day. Then, water was added to the mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried with magnesium sulfate. The solvent was evaporated under reduced pressure, and the resulting residue was purified with silica gel column chromatography (hexane:ethyl acetate=3:1) to give methyl 7-(4-butoxyethoxyphenyl)-1-(2-furylmethyl)-2,3-dihydro-1-benzazepine-4-carboxylate (319 mg) as yellow oil.
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C(N(CC)CC)C.[N+:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([O-:19])=[O:18]>C1COCC1.C(OCC)(=O)C>[CH2:3]([N:2]([CH3:1])[C:23](=[O:24])[C:22]1[CH:26]=[CH:27][CH:28]=[C:20]([N+:17]([O-:19])=[O:18])[CH:21]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CNCc1ccccc1
Reactant: O=C(Cl)c1cccc([N+](=O)[O-])c1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CN(Cc1ccccc1)C(=O)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.9 %

Procedure:
To a solution of N-methyl benzylamine (600 mg, 5 mmol) and triethylamine (1.5 ml, 10 mmol) in anhydrous THF (15 ml), was slowly added 3-nitro benzoyl chloride (1 g, 5.4 mmol) and stirred overnight at room temperature. The solvent was evaporated to give a residue which was dissolved in ethyl acetate and washed thoroughly with water. The organic layer was dried and evaporated to give N-benzyl-N-methyl-3-nitro-benzamide (350 mg, 27%) as solid.
Reaction SMILES: CS(Cl)(=O)=O.[Br:6][C:7]1[CH:11]=[C:10]([C:12]([OH:14])=O)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:8]=1.C(N(CC)CC)C.[NH2:30][C:31]1[C:39]([Cl:40])=[CH:38][C:37]([Cl:41])=[CH:36][C:32]=1[C:33](O)=[O:34]>C(#N)C.O>[Br:6][C:7]1[CH:11]=[C:10]([C:12]2[O:14][C:33](=[O:34])[C:32]3[CH:36]=[C:37]([Cl:41])[CH:38]=[C:39]([Cl:40])[C:31]=3[N:30]=2)[N:9]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([Cl:22])=[CH:17][N:16]=2)[N:8]=1
Reactant: Nc1c(Cl)cc(Cl)cc1C(=O)O
Reactant: O=C(O)c1cc(Br)nn1-c1ncc(Cl)cc1Cl
Agent: CS(=O)(=O)Cl
Solvent: CC#N
Solvent: O
Solvent: CCN(CC)CC
Product: O=c1oc(-c2cc(Br)nn2-c2ncc(Cl)cc2Cl)nc2c(Cl)cc(Cl)cc12
Reaction time: 1 h
Yield: 45 %

Procedure:
To a 150 mL flask, methanesulfonyl chloride (1.1 g, 9.8 mmol), acetonitrile (20 mL) was added. Then the mixture of 3-bromo-1-(3,5-dichloropyridin-2-yl)-1H-pyrazole-5-carboxylic acid (3.0 g, 8.9 mmol, the product of step (3), example 4) and triethylamine (0.89 g, 8.9 mmol) in acetonitrile (30 mL) were added dropwise in 10 minutes at room temperature. The mixture was stirred for 1 hour. 2-Amino-3,5-dichlorobenzoic acid (1.6 g, 17 mmol) was added, and the reaction mixture turned into reddish brown. After being stirred for 30 minutes, the solution of triethylamine (1.8 g, 17 mmol) in acetonitrile (10 mL) was added dropwise and yellow solid precipitated. The mixture was stirred for 1 hour, another solution of methanesulfonyl chloride (1.1 g, 9.8 mmol) in acetonitrile (10 mL) was added. The reaction mixture turned into yellow and solid was precipitated. After being stirred for 1 hour, another solution of triethylamine (0.89 g, 8.9 mmol) in acetonitrile (4 mL) was added. Then the reaction mixture was stirred for overnight at room temperature. The reaction mixture was poured into water (100 mL), extracted with ethyl acetate (2×100 mL), washed with saturated sodium carbonate solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography (Fluent: ethyl acetate/petroleum ether=1/2) to give the product (2.0 g) as a yellow solid in 45% yield.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[C:8]([CH2:15][C:16]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=O)C.[CH3:27][NH2:28]>>[CH3:27][NH:28][C:4]([C:6]1[N:7]=[C:8]([CH2:15][C:16]2([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH2:20][CH2:19][CH2:18][CH2:17]2)[N:9]([CH3:14])[C:10](=[O:13])[C:11]=1[OH:12])=[O:3]
Reactant: CN
Reactant: CCOC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O
Product: CNC(=O)c1nc(CC2(c3ccccc3)CCCC2)n(C)c(=O)c1O
Temperature: 60 °C
Yield: 23.9 %

Procedure:
To a mixture of 5-hydroxy-1-methyl-6-oxo-2-(1-phenyl-cyclopentylmethyl)-1,6-dihydro-pyrimidine-4-carboxylic acid ethyl ester (175 mg, 0.491 mmol) and methyl amine (0.98 ml, 1.96 mmol, 2M in THF) was added a catalytic amount of Me3AI under argon atmosphere in a sealed tube and it was heated at 60° C. for 16 h. After completion of the reaction, it was quenched with ice slowly and then extracted with EtOAc. The combined organic layer was then washed with water and brine. It was then dried over Na2SO4 and concentrated under vacuum. Purification by preparative HPLC provided the title compound as an off-white solid (40 mg, 24%). LCMS: m/z=342.0 (MH+).
Reaction SMILES: [CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([N:13]=O)[C:8](=[O:9])[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3].[OH-].[NH4+].S(S([O-])=O)([O-])=O.[Na+].[Na+]>O>[CH2:1]([N:4]1[C:11]([NH2:12])=[C:10]([NH2:13])[C:8](=[O:9])[N:7]([CH2:15][CH2:16][CH3:17])[C:5]1=[O:6])[CH2:2][CH3:3]
Reactant: CCCn1c(N)c(N=O)c(=O)n(CCC)c1=O
Agent: O=S([O-])S(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: O
Product: CCCn1c(N)c(N)c(=O)n(CCC)c1=O
Yield: 64.3 %

Procedure:
The 1,3-di-n-propyl-5-nitroso-6-aminouracil (61.6 g) was suspended in 1 L of water, and the suspension was made alkaline to pH 11 with 50% ammonium hydroxide and treated with 100 g of sodium dithionite, in portions, until the purple color faded. The aqueous mixture was extracted with chloroform (8×200 ml), dried over magnesium sulfate, filtered and concentrated. The residue was purified by flash chromatography (5/10% methanol/chloroform) and recrystallized from 10% isopropanol in hexane and recrystallized from 10% isopropanol to yield 37.29 g of 1,3-di-n-propyl-5,6-diaminouracil, m.p., 127°-128° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:14](Cl)(=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl>[Cu].C1(C)C=CC=CC=1>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([S:10]([NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:11])=[O:12])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: NS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Cu]
Agent: Cl
Solvent: Cc1ccccc1
Product: O=C(NS(=O)(=O)c1ccc([N+](=O)[O-])cc1)c1ccccc1
Temperature: 25 °C
Yield: 80.8 %

Procedure:
In a reaction flask with a thermometer and a stirrer, 25 g of p-nitrobenzenesulfonamide, 18 g of benzoylchloride, 1 g of copper powder, and 100 g of toluene were charged and refluxed until evolution of hydrogen chloride gas was completely ended. The reaction mixture was then cooled to room temperature to precipitate a crystal, which was filtered. The crystal was dissolved in an aqueous sodium carbonate solution and filtered. The filtrate was neutralized with hydrochloric acid to precipitate a crystal. The crystal was filtered to obtain 30.6 g of N-(4-nitrobenzenesulfonyl)benzamide.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7](=[O:19])[N:8]([CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[CH2:9][CH2:10][C:5]=2[NH:4][C:3]=1[CH:20]=O.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][C:31]=1[NH2:32])[NH:28][C:27](=[O:33])[CH2:26]2>>[NH2:32][C:31]1[CH:30]=[C:29]2[C:25]([C:26](=[CH:20][C:3]3[NH:4][C:5]4[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)[C:7](=[O:19])[C:6]=4[C:2]=3[CH3:1])[C:27](=[O:33])[NH:28]2)=[CH:24][C:23]=1[F:22]
Reactant: Nc1cc2c(cc1F)CC(=O)N2
Reactant: Cc1c(C=O)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Product: Cc1c(C=C2C(=O)Nc3cc(N)c(F)cc32)[nH]c2c1C(=O)N(CCN1CCOCC1)CC2
Yield: 50 %

Procedure:
The title compound was prepared under the same conditions as described in Example 15 with 3-methyl-5-(2-morpholin-4-yl-ethyl)-4-oxo-4,5,6,7-tetrahydro-1H-pyrrolo[3,2-c]pyridine-2-carbaldehyde and 5-fluoro-6-amino-1,3-dihydro-indol-2-one as starting materials to give 2-(6-amino-5-fluoro-2-oxo-1,2-dihydro-indol-3-ylidenemethyl)-3-methyl-5-(2-morpholin-4-yl-ethyl)-1,5,6,7-tetrahydro-pyrrolo[3,2-c]pyridin-4-one (40 mg, 50%) as a red solid.
Reaction SMILES: C[O:2][C:3](=[O:32])[CH:4]([O:6][C:7]1[CH:16]=[CH:15][C:14]([F:17])=[C:13]2[C:8]=1[C:9]([CH3:31])=[C:10]([CH2:22][C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=1[Cl:30])[C:11]([O:18][CH:19]([F:21])[F:20])=[N:12]2)[CH3:5].CO.[OH-].[Li+]>O>[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][C:10]1[C:11]([O:18][CH:19]([F:20])[F:21])=[N:12][C:13]2[C:8]([C:9]=1[CH3:31])=[C:7]([O:6][CH:4]([CH3:5])[C:3]([OH:32])=[O:2])[CH:16]=[CH:15][C:14]=2[F:17]
Reactant: COC(=O)C(C)Oc1ccc(F)c2nc(OC(F)F)c(Cc3ccc(Cl)cc3Cl)c(C)c12
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(Cc2ccc(Cl)cc2Cl)c(OC(F)F)nc2c(F)ccc(OC(C)C(=O)O)c12
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-[3-(2,4-dichlorobenzyl)-2-difluoromethoxy-8-fluoro-4-methylquinolin-5-yloxy]propionic acid methyl ester (0.15 g), methanol (5.0 mL), water (0.2 mL) and 5.0 M aqueous lithium hydroxide solution (0.090 mL) was stirred at room temperature for 24 hours. The mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was acidified by the addition of glacial acetic acid and the resulting precipitate collected by filtration, washed with water and a mixture of water and methanol (1:1 by volume) and then dried to afford title compound as a white solid, 0.13 g.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH:26]=[CH2:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([O:15][C:16]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:17]=2[C:18]([CH2:26][CH3:27])=[CH:19][N:20]=[CH:21]3)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C=Cc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Agent: O=[Pt]
Solvent: CO
Product: CCc1cncc2cccc(O[C@H]3CC[C@H](NC(=O)OC(C)(C)C)CC3)c12
Reaction time: 15 h

Procedure:
A solution of Intermediate 124 (90.5 mg) in methanol (5 ml) was added with platinum oxide (13 mg, Wako Pure Chemical Industries) and stirred for 15 hours under hydrogen atmosphere. The reaction mixture was filtered through a Celite layer, and the solvent was evaporated under reduced pressure. Then, the residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain the title compound (41.1 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=O)[NH:12][CH2:11][CH2:10]2.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[F:1][C:2]1[CH:3]=[C:4]([CH:18]=[CH:19][CH:20]=1)[CH2:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[CH2:13][NH:12][CH2:11][CH2:10]2
Reactant: O=C1NCCc2cc(OCc3cccc(F)c3)ccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Fc1cccc(COc2ccc3c(c2)CCNC3)c1
Temperature: 60 °C

Procedure:
A mixture of 6-(3-fluoro-benzyloxy)-3,4-dihydro-2H-isoquinolin-1-one (1.2 g, 4.423 mmol) and lithium aluminum hydride (0.337 g, 8,84 mmol) in tetrahydrofuran (24 ml) was heated to 60° C. for 8 h. Water was added and an 15% aqueous solution of sodium hydroxide and the mixture was extracted with ethylacetate. After drying of the organic layer with MgSO4, filtration and evaporation, an oil was obtained (1.14 g, 99%). MS: m/e 258.0 (M+H+).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH2:10][C:9](O)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:7]=1)=[O:5])[CH3:2].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][N:12]=2)[N:8]([C:18]2[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=2)[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1=NN(c2ccc(OC)nc2)C(O)(c2ccccn2)C1
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccccn2)n(-c2ccc(OC)nc2)n1
Temperature: 105 °C
Reaction time: 4 h

Procedure:
The above-obtained 5-hydroxy-1-(6-methoxy-3-pyridyl)-5-(2-pyridyl)-4,5-dihydropyrazole-3-carboxylic acid ethyl ester (0.546 g) was dissolved in ethanol (11 mL). Acetic acid (0.456 mL) was added to the resultant mixture, followed by stirring at 105° C. for 4 hours. The mixture was cooled in air. Subsequently, the reaction mixture was partitioned by use of saturated aqueous solution of sodium hydrogencarbonate, water, and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid substance (0.516 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([S:11](F)(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[N:15]1([C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1.C(N(C(C)C)C(C)C)C.N1CCNCC1.S(F)(F)(=O)=O>C(OCC)(=O)C>[CH2:24]([O:23][C:21]([N:15]1[CH2:16][CH2:17][N:18]([S:11]([C:8]2[CH:9]=[CH:10][C:2]([Cl:1])=[C:3]([C:4]([OH:6])=[O:5])[CH:7]=2)(=[O:13])=[O:12])[CH2:19][CH2:20]1)=[O:22])[CH3:25]
Reactant: O=C(O)c1cc(S(=O)(=O)F)ccc1Cl
Reactant: CCOC(=O)N1CCNCC1
Agent: C1CNCCN1
Agent: O=S(=O)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(S(=O)(=O)c2ccc(Cl)c(C(=O)O)c2)CC1
Reaction time: 14 h
Yield: 80.8 %

Procedure:
2-Chloro-5-fluorosulfonylbenzoic acid (Acros Organics, 105 mg, 440 μmol, 1.0 eq) was placed in a vial and the vial was flushed with nitrogen and a positive pressure was maintained. Anhydrous dichloromethane (1.4 mL) was added, followed by ethyl 1-piperazine carboxylate (80 μL, 528 μmol, 1.2 eq) and ethyldiisopropylamine (redistilled, 80 μL, 440 μmol, 1.0 eq). The mixture was stirred for 1.5 h after which time additional piperazine was added (60 μL, 352 μmol, 0.8 eq). After 14 h the mixture was analyzed by reverse-phase HPLC-MS in negative ionization mode. The sulfonyl fluoride starting material was present, as well as a less polar compound showing (M−1) ion in about 35:65 ratio. An additional 0.35 eq of piperazine and ethyldiisopropylamine each (154 μmol, 30 μl) were added and the mixture was stirred for 4 h. HPLC-MS at this time indicated little progress and an additional 0.25 eq of piperazine (100 mmol, 20 μL) was added. After stirring for 14 h HPLC-MS indicated the reaction was complete. The reaction mixture was diluted with 2 mL of ethyl acetate, washed with 1 M HCl solution (2×1 mL) and dried over anhydrous sodium sulfate. The solution was filtered, the solvents removed on a rotary evaporator and vacuum pump to afford 134 mg of a white solid, 81%. NOTE: Addition of excess nucleophilic amine at the beginning of the reaction results in significant bis addition, giving sulfonamide and carboxamide product. Stepwise addition of nucleophilic amine as needed suppresses formation of this side product.
Reaction SMILES: [CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C@@H:5]2[OH:23])[CH2:2][CH3:3].CC(C)[O-].[Al+3].CC(C)[O-].CC(C)[O-]>C1(C)C=CC=CC=1.C1(=O)CCCCC1>[CH2:1]([C@:4]12[CH2:12][CH2:11][C@@H:10]3[C:13]4[CH2:14][CH:15]=[C:16]([O:21][CH3:22])[CH2:17][C:18]=4[CH2:19][CH2:20][C@H:9]3[C@@H:8]1[CH2:7][CH2:6][C:5]2=[O:23])[CH2:2][CH3:3]
Reactant: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CC[C@@H]2O)CC(OC)=CC4
Agent: CC(C)[O-]
Agent: [Al+3]
Solvent: O=C1CCCCC1
Solvent: Cc1ccccc1
Product: CCC[C@]12CC[C@@H]3C4=C(CC[C@H]3[C@@H]1CCC2=O)CC(OC)=CC4
Yield: 67.1 %

Procedure:
Reflux 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17β-ol (3.0 g.) with aluminium isopropoxide in toluene and cyclohexanone according to the conditions of Oppenauer oxidation. Isolate and recrystallize the product from methanol to give 13β-n-propyl-3-methoxy-gona-2,5(10)-dien-17-one (2.0 g.), m.p. 128°-31° C. with softening at 125°.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[CH:11][CH:10]=[C:9]1B(O)O)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[Na+].[Na+].C(COC)OC.Br[C:29]1[CH:30]=[C:31]([CH:37]=[CH:38][C:39]=1[O:40][CH2:41][O:42][CH3:43])[C:32]([O:34][CH2:35][CH3:36])=[O:33]>O>[CH2:35]([O:34][C:32]([C:31]1[CH:30]=[CH:29][C:39]([O:40][CH2:41][O:42][CH3:43])=[C:38]([C:9]2[N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH:12]=[CH:11][CH:10]=2)[CH:37]=1)=[O:33])[CH3:36]
Reactant: CCOC(=O)c1ccc(OCOC)c(Br)c1
Reactant: CC(C)(C)OC(=O)n1cccc1B(O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CCOC(=O)c1ccc(OCOC)c(-c2cccn2C(=O)OC(C)(C)C)c1

Procedure:
21 g of 1-(t-butoxycarbonyl)pyrrole-2-boronic acid, 4.2 g of tetrakistriphenylphosphine palladium and 153 ml of aqueous sodium carbonate solution (2 M) were added in order to a dimethoxyethane (350 ml) solution of 21 g of ethyl 3-bromo-4-methoxymethoxybenzoate, and the reaction liquid was heated overnight under reflux in a nitrogen atmosphere. After cooled, the reaction liquid was diluted with water, extracted with chloroform, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting residue was purified through silica gel column chromatography (developing solvent: hexane/ethyl acetate=12/1 to 10/1) to obtain the entitled compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[C:11]([CH:12]([CH3:15])[CH:13]=[CH2:14])=[CH:10][C:9]([CH3:16])=[C:8]2[C:3]=1[CH2:4][C:5]([CH3:19])([CH3:18])[C:6](=[O:17])[NH:7]2.[Br:20]N1C(=O)CCC1=O>C(Cl)(Cl)Cl>[Br:20][CH2:14][CH:13]1[O:1][C:2]2=[C:3]3[C:8](=[C:9]([CH3:16])[CH:10]=[C:11]2[CH:12]1[CH3:15])[NH:7][C:6](=[O:17])[C:5]([CH3:18])([CH3:19])[CH2:4]3
Reactant: C=CC(C)c1cc(C)c2c(c1O)CC(C)(C)C(=O)N2
Reactant: O=C1CCC(=O)N1Br
Solvent: ClC(Cl)Cl
Product: Cc1cc2c(c3c1NC(=O)C(C)(C)C3)OC(CBr)C2C
Reaction time: 1 h
Yield: 90.6 %

Procedure:
A solution of 5-hydroxy-6-(1-methyl-2-propenyl)-3,3,8-trimethyl-3,4-dihydrocarbostyril (1.6 g, 6.2 mmol) and N-bromosuccinimide (1.2 g, 6.5 mmol) in chloroform (20 ml) was refluxed while stirring for 1 hour. Chloroform was added to the reaction mixture, followed by washing with water, and drying. The solvent was evaporated, and the residue was recrystallized from ethyl acetate-hexane. 1.9 g of the title compound was obtained as colorless crystals (90.6%).
Reaction SMILES: CNC(O[N:6]1[C:14]2[C:9](=[N:10][CH:11]=[C:12]([Cl:15])[CH:13]=2)[N:8]=[C:7]1[C:16]([F:19])([F:18])[F:17])=O.[ClH:20].O>CO>[Cl:20][C:11]1[N:10]=[C:9]2[N:8]=[C:7]([C:16]([F:19])([F:18])[F:17])[NH:6][C:14]2=[CH:13][C:12]=1[Cl:15]
Reactant: Cl
Reactant: CNC(=O)On1c(C(F)(F)F)nc2ncc(Cl)cc21
Solvent: O
Solvent: CO
Product: FC(F)(F)c1nc2nc(Cl)c(Cl)cc2[nH]1
Reaction time: 3 h

Procedure:
1-(Methylcarbamoyloxy)-6-chloro-2-(trifluoromethyl) -1H-imidazo [4,5-b] pyridine (250 milligrams) in 2.5milliliters of methanol was saturated with HCl. The reaction mixture was permitted to stand for three hours, then poured into water and filtered to separate the desired 5,6-dichloro-2-(trifluoromethyl)-1H-imidazo[ 4,5-b] pyridine, m.p., 280° -30° C.