Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][CH3:6])=[O:3].[N:7]1([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:21][CH:20]=2)[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]1.C(=O)(O)[O-].[Na+].O>O1CCCC1>[OH2:3].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6].[CH2:5]([O:4][C:2]([N:10]1[CH2:9][CH2:8][N:7]([CH2:13][CH2:14][NH:15][C:16](=[O:32])[CH2:17][O:18][C:19]2[CH:20]=[CH:21][C:22]([C:25]3[CH2:26][NH:27][C:28](=[O:31])[NH:29][N:30]=3)=[CH:23][CH:24]=2)[CH2:12][CH2:11]1)=[O:3])[CH3:6]
Reactant: O=C(COc1ccc(C2=NNC(=O)NC2)cc1)NCCN1CCNCC1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)N1CCN(CCNC(=O)COc2ccc(C3=NNC(=O)NC3)cc2)CC1
Reaction time: 0.5 h

Procedure:
0.15 ml of ethyl chloroformate were added, whilst ice-cooling, to a mixture of 0.360 g of N-[2-(1-piperazinyl)ethyl]-α-[4-(2,3,4,5-tetrahydro-3-oxo-1,2,4-triazin-6-yl)phenoxy]acetamide [prepared as described in step (a) above], 0.13 g of sodium bicarbonate, 10 ml of water and 50 ml of tetrahydrofuran, and the mixture was stirred for 30 minutes. The reaction mixture was then concentrated by evaporation under reduced pressure, and the residue was purified by column chromatography through silica gel (eluent: a 1:1 by volume mixture of ethanol and methylene chloride), followed by recrystallization from ethanol, to give 0.264 g of the title compound as colorless fine crystals melting at 200°-240° C. (with decomposition).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:11]([NH:22][C@H:23]2[C@@H:27]3[O:28][C:29]([CH3:32])([CH3:31])[O:30][C@@H:26]3[C@@H:25]([CH2:33][OH:34])[CH2:24]2)=[N:12][C:13](S(C)(=O)=O)=[N:14][C:15]=1[O:16]C.[CH:35]1([NH2:39])[CH2:38][CH2:37][CH2:36]1>CC#N>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[C:15](=[O:16])[NH:14][C:13]([NH:39][CH:35]2[CH2:38][CH2:37][CH2:36]2)=[N:12][C:11]=1[NH:22][C@H:23]1[C@H:27]2[C@H:26]([O:30][C:29]([CH3:31])([CH3:32])[O:28]2)[C@@H:25]([CH2:33][OH:34])[CH2:24]1
Reactant: NC1CCC1
Reactant: COc1nc(S(C)(=O)=O)nc(N[C@@H]2C[C@H](CO)[C@H]3OC(C)(C)O[C@H]32)c1-c1nc2ccccc2s1
Solvent: CC#N
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](Nc3nc(NC4CCC4)[nH]c(=O)c3-c3nc4ccccc4s3)[C@@H]2O1
Temperature: 80 °C

Procedure:
Compound 8 (100 mg, 0.197 mmol) was dissolved in MeCN (2 mL) and cyclobutylamine (168 μL, 1.97 mmol) was added. The reaction was heated to 80° C. for 1 h. The solvent was evaporated and the residue was purified by column chromatography on silica gel, eluting with EtOAc/hexane to give the title compound as a yellow solid. MS 498 (M+H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[CH:9]1[CH2:18][C:17](=O)[C:12]2[C:13]([CH3:16])=[CH:14][O:15][C:11]=2[CH2:10]1.[C:20]([NH:23][NH2:24])([NH2:22])=[NH:21].[ClH:25].Cl>C(O)C>[ClH:25].[NH:23](/[N:24]=[C:17]1\[CH2:18][CH:9]([C:3]2[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=2[CH3:1])[CH2:10][C:11]2[O:15][CH:14]=[C:13]([CH3:16])[C:12]\1=2)[C:20]([NH2:22])=[NH:21]
Reactant: Cc1ccc(C)c(C2CC(=O)c3c(C)coc3C2)c1
Reactant: N=C(N)NN
Agent: Cl
Solvent: CCO
Product: Cc1ccc(C)c(C2C/C(=N\NC(=N)N)c3c(C)coc3C2)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 42.8 %

Procedure:
To a mixture of 6-(2,5-dimethylphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran-4-one (0.36 g) and aminoguanidine hydrochloride (157 mg) were added ethanol (28 ml) and 6N hydrochloric acid (0.12 ml), and the mixture was stirred at 90° C. for 2 hours and cooled. The reaction solution was concentrated under reduced pressure, and the residue was washed with ethanol, ethyl acetate and isopropylether, and dried to give (E)-4-guanidinoimino-6-(2,5-dimethylphenyl)-3-methyl-4,5,6,7-tetrahydrobenzofuran hydrochloride (Compound 38) (0.21 g).
Reaction SMILES: [Br-].[O:2]1[CH2:6][CH2:5][O:4][CH:3]1[CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1.C(OCC)C>O1CCCC1>[O:4]1[CH2:5][CH2:6][O:2][CH:3]1[CH2:7][CH:8]=[C:29]1[CH2:34][CH2:33][CH:32]([C:35]2[CH:43]=[CH:42][C:38]([C:39]([NH2:41])=[O:40])=[CH:37][CH:36]=2)[CH2:31][CH2:30]1
Reactant: NC(=O)c1ccc(C2CCC(=O)CC2)cc1
Reactant: c1ccc([P+](CCC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Solvent: CCOCC
Solvent: C1CCOC1
Product: NC(=O)c1ccc(C2CCC(=CCC3OCCO3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.3 %

Procedure:
140.9 g of 2-(1,3-dioxolan-2-yl)ethyl-triphenylphosphonium bromide were suspended in 4.5 l of tetrahydrofuran while gassing with nitrogen and the suspension was treated at 0° C. within 5 minutes with 36.8 g of potassium tert.butylate. The orange suspension was stirred at room temperature for a further 1 hour and treated within 5 minutes with 46.1 g of 4-(4oxocyclohexyl)benzamide. The reaction mixture was stirred at room temperature for a further 4.5 hours and then concentrated in a vacuum. The yellowish crystals obtained (212.5 g) were treated with 1.2 l of diethyl ether. The mixture was stirred at room temperature for 30 minutes and then suction filtered. The residue was washed with diethyl ether and then suspended in 700 ml of water. The mixture was stirred for 15 minutes and then suction filtered. The residue was washed with water and dissolved while heating in 600 ml of dioxan. The solution was left to cool to room temperature. The separated crystals were removed by filtration under suction, washed with a small amount of dioxan and hexane and fried at 60° C. in a vacuum, whereby there were obtained 39.2 g of crystalline 4-[4-[2(-1,3-dioxolan-2-yl)ethylidene]cyclo-hexyl]benzamide with m.p. 209°-212° C. Working-up of the mother liquor (72.6 g) gave a further 7.7 g of produce and 64.2 g of a second mother liquor.
Reaction SMILES: [OH:1][CH:2]([C:7](=[O:20])[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)S(O)(=O)=O.[Na].Cl.CC(C)=[O:25]>>[OH:1][CH:2]([OH:25])[C:7]([C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH:17]([CH3:19])[CH3:18])=[CH:10][CH:9]=1)=[O:20]
Reactant: CC(C)CCOc1ccc(C(=O)C(O)S(=O)(=O)O)cc1
Reactant: CC(C)=O
Agent: Cl
Agent: [Na]
Product: CC(C)CCOc1ccc(C(=O)C(O)O)cc1

Procedure:
A 6.0 g. portion of hydroxy [p-(isopentyloxy)benzoyl]methanesulfonic acid, sodium salt was dissolved in a mixture of 100 ml. of 0.5N hydrochloric acid and 15 ml. of acetone. The solid was collected, giving the desired product, m.p. 80°-85° C.
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.Cl.[N:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)=[CH:16][CH:15]=1>>[N:14]1[CH:19]=[CH:18][C:17]([O:20][C:21]2[CH:22]=[CH:23][C:24]([S:27]([N:2]3[CH:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH:4]4[CH2:7][CH:1]3[CH2:6][CH2:5]4)(=[O:29])=[O:28])=[CH:25][CH:26]=2)=[CH:16][CH:15]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccncc2)cc1
Reactant: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Agent: Cl
Product: CCOC(=O)C1C2CCC(C2)N1S(=O)(=O)c1ccc(Oc2ccncc2)cc1

Procedure:
Ethyl 2-azabicyclo[2.2.1]heptane-3-carboxylate obtained in Example 1 (b) is subjected to a reaction similar to the reaction (c) of Example 1 using [4-(4-pyridyloxy)phenyl]sulfonyl chloride hydrochloride in place of 4-methoxybenzenesulfonyl chloride, to give ethyl 2-{[4-(4-pyridyloxy)phenyl]sulfonyl}-2-azabicyclo[2.2.1]heptane-3-carboxylate.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5]2[CH:6]=[CH:7][N:8]=[CH:9][C:10]=2[CH:11]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:24]=[CH:23][C:18]([CH2:19][N:20]=[C:21]=[O:22])=[CH:17][CH:16]=1>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[CH:9]2)=[C:4]([NH:12][C:21]([NH:20][CH2:19][C:18]2[CH:17]=[CH:16][C:15]([C:14]([F:13])([F:26])[F:25])=[CH:24][CH:23]=2)=[O:22])[CH:3]=1
Reactant: Nc1cc(Cl)cc2cnccc12
Reactant: O=C=NCc1ccc(C(F)(F)F)cc1
Product: O=C(NCc1ccc(C(F)(F)F)cc1)Nc1cc(Cl)cc2cnccc12

Procedure:
Prepared from 7-chloroisoquinolin-5-amine (Description 87) and [4-(trifluoromethyl)benzyl]isocyanate (Description 58) according to Description 61. m/z (ES+) 380 (M+H)+.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH3:8][N:9]([CH3:44])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([O:34]C(C)(C)C)=[O:33])[CH:25]=2)[CH:21]=1)=[O:14]>C(Cl)Cl>[CH3:44][N:9]([CH3:8])[C:10]1[CH:11]=[C:12]([CH:41]=[CH:42][CH:43]=1)[C:13]([NH:15][C:16]1[CH:17]=[CH:18][C:19]([CH3:40])=[C:20]([NH:22][C:23](=[O:39])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([O:30][CH2:31][C:32]([OH:34])=[O:33])[CH:25]=2)[CH:21]=1)=[O:14].[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4]
Reactant: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)OC(C)(C)C)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(NC(=O)c2cccc(N(C)C)c2)cc1NC(=O)c1cccc(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (10 ml) was added to a stirred solution of N-[5-(3-dimethylaminobenzamido)-2-methylphenyl]-3-tert-butoxycarbonylmethoxybenzamide (0.5 g) in methylene chloride (10 ml) and the mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was azeotroped with toluene. The resultant gum was triturated under diethyl ether. The solid so obtained was isolated and dried under vacuum at 60° C. There was thus obtained the title compound as its trifluoroacetic acid salt (0.39 g); NMR Spectrum: (DMSOd6) 2.17 (s, 3H), 2.93 (s, 6H), 4.76 (s, 2H), 6.93 (m, 1H), 7.13 (m, 1H), 7.23 (m, 3H), 7.3 (t, 1H), 7.43 (t, 1H), 7.51 (d, 1H), 7.59 (d, 2H), 7.78 (d, 1H), 9.88 (br s, 1H), 10.1 (br s, 1H); Mass Spectrum: M−H− 446.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH3:7][C:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:14][CH:15]=2)[NH:10][CH:9]=1.Cl[C:22]1[N:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[F:34])=[CH:24][N:23]=1.O>CN(C1C=CN=CC=1)C.CS(C)=O>[F:34][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=1[C:25]1[CH:26]=[N:27][C:22]([N:10]2[C:11]3[C:16](=[CH:15][CH:14]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:12]=3)[C:8]([CH3:7])=[CH:9]2)=[N:23][CH:24]=1
Reactant: COC(=O)c1ccc2c(C)c[nH]c2c1
Reactant: Fc1ccccc1-c1cnc(Cl)nc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1ccc2c(C)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (1.61 g, 11.6 mmol) and DMAP (0.18 g, 1.45 mmol) were added to a solution of methyl 3-methyl-1H-indole-6-carboxylate (1.1 g, 5.81 mmol) and 2-chloro-5-(2-fluorophenyl)-pyrimidine (1.21 g, 5.81 mmol) in dry DMSO (10 mL). The solution was stirred at 100° C. for 1 h, then cooled to room temperature and slowly poured into vigorously stirred water (100 mL). The precipitating solid was filtered off, washed with water and dried in vacuum. Light-brown solid. Yield: 1.89 g (80% chemical purity). HPLC-MS: m/z [M+H]+=362.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([C:42](O)=[O:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C(N(CC)C(C)C)(C)C.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([C:42]([CH:39]3[CH2:40][CH2:41][N:36]([C:34]([O:33][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:35])[CH2:37][CH2:38]3)=[O:43])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCC(C(=O)N2CCC(C(=O)NC(CCCc3ccccc3)CCCc3ccccc3)CC2)CC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Piperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (4) (1.00 g; 2.64 mmol) is dissolved in methylene chloride (25 mL) at ambient temperature. 1-tert-Butoxycarbonyl-piperidine-4-carboxylic acid (0.73 g; 3.17 mmol), N,N-diisopropylethylamine (0.75 g; 5.81 mmol) and PyBOP (1.65 g; 3.17 mmol) are added sequentially. The reaction is stirred for 16 hours at room temperature, then concentrated under reduced pressure. The residue is purified via silica gel chromatography (70%→90% ethyl acetate in hexanes) affording the desired product (70) as a solid. ESMS: MH+ 590.6
Reaction SMILES: [OH-].[Na+].[I-].[CH3:4][S+](C)(C)=O.[CH:9]1([C:12](=[O:22])[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)[CH2:11][CH2:10]1>CS(C)=O>[CH:9]1([C:12]([CH:13]2[CH2:4][CH:14]2[C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[O:22])[CH2:11][CH2:10]1
Reactant: C[S+](C)(C)=O
Reactant: O=C(C=Cc1cccc(O)c1)C1CC1
Agent: [I-]
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(C1CC1)C1CC1c1cccc(O)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a 500 ml round bottom flask equipped with magnetic stirrer, nitrogen inlet, thermometer and addition funnel was charged 20 g (0.5 moles) of powdered sodium hydroxide, 110 (0.5 moles) of trimethyl sulfoxonium iodide, and 200 mls of anhydrous DMSO. The mixture was then stirred at ambient temperature for 30 minutes. The mixture was then cooled to 15° C., and a solution of 1-cyclopropyl-3-(3-hydroxyphenyl)-2-propene-1-one (47 g, 0.25 moles) was added dropwise in 50 mls of DMSO. The reaction was stirred for 2 hours at 10-15° C., then allowed to warm to ambient temperature, and stirred for an additional 16 hours. The reaction mixture was the quenched with 200 mls of 0.1 N HCl, and extracted with 3×100 mls of ethyl ether. The combined ether extracts were washed successively with 2×100 mls of water, and 100 mls of saturated aqueous sodium chloride solution. The ether extract was then dried over anhydrous magnesium sulfate, filtered and concentrated to dryness under reduced pressure with a rotary evaporator at 45° C. to afford 32 g of the title compound, 2-(3-hydroxyphenyl)cyclopropyl cyclopropyl ketone, as a thick amber oil that crystallized upon standing in a 64% isolated yield.
Reaction SMILES: [OH:1][C:2]1[C:3]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[C:3]([S:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:4][CH:5]=[CH:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Reactant: COC(=O)CSc1ncccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)CSc1ncccc1Oc1cc(-n2c(=O)cc(C(F)(F)F)n(C)c2=O)c(F)cc1[N+](=O)[O-]
Temperature: 70 °C
Reaction time: 2 h
Yield: 85.4 %

Procedure:
To a mixture of 0.26 g of 3-hydroxy-2-(methoxycarbonyl)methylthiopyridine, 0.38 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyri midin-1-yl]nitrobenzene, and 2 ml of N,N-dimethylformamide was added 0.17 g of potassium carbonate, and the mixture was stirred at 70° C. for 2 hours. The reaction mixture was cooled to room temperature and then poured into ice water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to silica gel column chromatography to give 0.49 g of 3-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methylthiopyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][NH:11]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].F[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1.O>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][N:11]2[C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=[N+]([O-])c1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CC1CN2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CC1CN2c1ccc([N+](=O)[O-])cc1
Reaction time: 2 h

Procedure:
A suspension of 2,5-diazabicyclo[2.2.1]heptane-2-carboxylic acid tert-butyl ester (400 mg) and potassium carbonate (300 mg) in DMF (5 ml) was mixed with 4-fluoronitrobenzene (290 mg). After 2 hours, the reaction mixture was poured into water, and the resulting precipitate was filtered off with suction. Alternatively, the product can also be extracted with ethyl acetate and purified after concentration by chromatography. The product with the molecular weight of 319.36 (C16H21N3O4); MS (ESI): 320 (M+H+) was obtained in this way.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[CH:12][CH:13]=2)=[O:5])[CH3:2].[Br:20]Br>C(O)(=O)C.O>[CH2:1]([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2[C:9]3=[C:10]([CH2:17][CH2:18][CH2:19][N:8]3[CH:7]=1)[CH:11]=[C:12]([Br:20])[CH:13]=2)=[O:5])[CH3:2]
Reactant: BrBr
Reactant: CCOC(=O)c1cn2c3c(cccc3c1=O)CCC2
Solvent: CC(=O)O
Solvent: O
Product: CCOC(=O)c1cn2c3c(cc(Br)cc3c1=O)CCC2
Temperature: 25 °C
Reaction time: 24 h
Yield: 134.1 %

Procedure:
To the solution of 1-Oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylic acid ethyl ester (7.5 g, 29 mmol) in glacial acetic acid (120 mL) was added bromine (1.6 ml, 32 mmol). The mixture was stirred over night at room temperature, and new portion of bromine (1.6 mL, 32 mmol) was added. After 24 h, reaction mixture was diluted with 100 mL of H2O and pH was adjusted to 2.9. Precipitate was filtered and dried. The crude product was precipitated from CH2Cl2/Diisoprophylether and dried in vacuum drier yielding 13.07 g of the crude title product.
Reaction SMILES: [F:1][C:2]1[C:3]([C:32]([F:35])([F:34])[F:33])=[C:4]([CH:8]2[CH2:13][CH2:12][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[ClH:36]>C(Cl)Cl.CCOCC>[ClH:36].[F:1][C:2]1[C:3]([C:32]([F:35])([F:33])[F:34])=[C:4]([CH:8]2[CH2:9][CH2:10][N:11]([C:14]([C:16]3[C:24]4[CH2:23][CH2:22][NH:21][CH2:20][C:19]=4[NH:18][N:17]=3)=[O:15])[CH2:12][CH2:13]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(C(=O)N3CCC(c4cccc(F)c4C(F)(F)F)CC3)n[nH]c2C1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(c1n[nH]c2c1CCNC2)N1CCC(c2cccc(F)c2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 47 %

Procedure:
To a solution of tert-butyl 3-(4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidine-1-carbonyl)-4,5-dihydro-1H-pyrazolo[3,4-c]pyridine-6(7H)-carboxylate (29, 0.066 g, 0.13 mmol) in CH2Cl2 (2 mL) was added HCl (2 mL, 2.0 N solution in Et2O). The mixture stirred at ambient temperature for 18 h, was diluted with Et2O (30 mL), and the resulting solids were collected by filtration to give (4-(3-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)(4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridin-3-yl)methanone hydrochloride (30) as a white solid (0.027 g, 47%): 1H NMR (300 MHz, DMSO-d6) δ 9.46-9.20 (m, 2H), 7.74-7.61 (m, 1H), 7.46 (d, J=8.1 Hz, 1H), 7.37-7.25 (m, 1H), 4.70-4.44 (m, 2H), 4.34-4.22 (m, 2H), 3.50-3.10 (m, 4H), 2.93-2.76 (m, 3H), 1.86-1.60 (m, 4H); ESI MS m/z 468 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][NH:13]1.C(=O)([O-])[O-].[Na+].[Na+]>CS(C)=O.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:13]2[CH2:14][CH2:15][CH2:16][CH2:17][CH:12]2[CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: CC1CCCCN1
Reactant: O=Cc1cc(Br)ccc1F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1CCCCN1c1ccc(Br)cc1C=O
Temperature: 120 °C
Yield: 88.8 %

Procedure:
To a solution of 5-bromo-2-fluorobenzaldehyde (13.20 g; 65.02 mmol) in DMSO (160 mL) and water (40 mL) were added 2-methylpiperidine (15.35 mL; 130.04 mmol) and anhydrous sodium carbonate (13.78 g; 130.04 mmol). The resulting mixture was heated at 120° C. for 16 h after which it was allowed to cool to RT. Reaction mixture was partitioned between H2O (1 L) and Et2O (2×750 mL) and the combined organic layers were washed with brine (500 mL, pH 5-6 adjusted with HCl), dried over MgSO4, filtered and dried under vacuum to give the title compound as a brown yellow oil (16.3 g, 89%). LC/MS (Method B): 282.1 (M+H)+. HPLC (Method A): Rt 2.20 min (Purity: 93.7%).
Reaction SMILES: CCCCCC.C([Li])CCC.Br[C:13]1[CH:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>O>[N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])[CH:14]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Brc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)c1cccnc1
Reaction time: 0.17 h

Procedure:
1.45 ml of a hexane solution containing 1.54 M normal butyl lithium was added dropwise into 200 ml of diethyl solution containing 10.0 g of 3-bromopyridine at −78° C. in a nitrogen atmosphere over 10 minutes. After the dropwise addition, the mixture was stirred for 10 minutes and then 20 ml of tributyltin chloride was added dropwise thereinto over 10 minutes. Then, after stirring for 30 minutes, water was added to the reaction mixture and then extracted with ethyl acetate. The extract was washed with brine and the solvent was removed. The residue was subjected to silica column chromatography and eluted with hexane and then with hexane/ethyl acetate (7:1), to give 21.9 g of the target compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:17](=[O:18])[C:16]2[C:11](=[N:12][C:13](S(C)=O)=[N:14][CH:15]=2)[N:10]2[CH:22]=[CH:23][N:24]=[C:9]12.[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=1.C([O-])(O)=O.[Na+]>>[Br:25][C:26]1[CH:32]=[CH:31][C:29]([NH:30][C:13]2[N:12]=[C:11]3[C:16]([C:17](=[O:18])[N:8]([C:3]4[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=4[Cl:1])[C:9]4[N:10]3[CH:22]=[CH:23][N:24]=4)=[CH:15][N:14]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CS(=O)c1ncc2c(=O)n(-c3ccccc3Cl)c3nccn3c2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: O=c1c2cnc(Nc3ccc(Br)cc3)nc2n2ccnc2n1-c1ccccc1Cl

Procedure:
A mixture of Example 1E (250.0 mg, 0.695 mmol) and 4-bromoaniline (191 mg, 1.112 mmol) was heated at 90° C. for 1 hour. While warm, the residue was treated with saturated aqueous NaHCO3 solution and extracted with ethyl acetate (twice). The combined organic layers were dried over MgSO4, filtered, and concentrated. The residue was triturated with a small amount of ethyl acetate. The solids were filtered, washed with ethyl acetate/hexane, and oven-dried to provide the title compound.