Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[CH:4]([C:6]1[C:7]([F:17])=[C:8]2[C:13](=[CH:14][C:15]=1[F:16])[N:12]=[CH:11][CH:10]=[CH:9]2)[CH3:5].O.[NH2:20][NH2:21]>C(O)C>[F:17][C:7]1[C:6]([CH:4]([CH3:5])[C:3]([NH:20][NH2:21])=[O:2])=[C:15]([F:16])[CH:14]=[C:13]2[C:8]=1[CH:9]=[CH:10][CH:11]=[N:12]2
Reactant: NN
Reactant: COC(=O)C(C)c1c(F)cc2ncccc2c1F
Solvent: CCO
Solvent: O
Product: CC(C(=O)NN)c1c(F)cc2ncccc2c1F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(5,7-Difluoro-quinolin-6-yl)-propionic acid methyl ester (2.270 g, 9.57 mmol) in ethanol (25 mL) was added hydrazine monohydrate (3 mL, 96 mmol), and the reaction mixture was stirred at 25° C. overnight. Solvent was removed under reduced pressure, and the residue was used without further purification. 1H-NMR (400 MHz, DMSO-d6) δ ppm 9.06 (s, 1H), 8.97 (dd, 1H), 8.45 (d, 1H), 7.58-7.67 (m, 2H), 4.23 (br s, 2H), 4.08 (q, 1H), 1.51 (d, 3H). LCMS (method A): [MH]+=252, tR=3.82 min.
Reaction SMILES: ClC[CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1.BrCCCC[Cl:21]>>[Cl:21][CH2:3][CH2:4][CH2:5][CH2:6][C:7]1[N:12]2[CH:13]=[N:14][CH:15]=[C:11]2[CH:10]=[CH:9][CH:8]=1
Reactant: ClCCCCBr
Reactant: ClCCCCCc1cccc2cncn12
Product: ClCCCCc1cccc2cncn12

Procedure:
5-(4-Chlorobutyl)-imidazo[1,5-a]pyridine is prepared by the procedure described for the preparation of 5-(5-chloropentyl)imidazo[1,5-a]pyridine of Example 4 using 1-bromo-3-chloropropane as reagent instead of 1-bromo-4-chlorobutane therein.
Reaction SMILES: Br[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4].[CH3:26][NH:27][CH3:28].C1COCC1>C(OCC)C>[CH3:26][N:27]([CH3:28])[CH:2]([CH2:24][CH3:25])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([O:11][C:12]2[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([OH:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=2)=[CH:7][CH:6]=1)=[O:4]
Reactant: CNC
Reactant: CCC(Br)C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(C(=O)c1ccc(Oc2ccc(C(=O)C(C)(C)O)cc2)cc1)N(C)C

Procedure:
A solution of 7.9 g (0.0195 mol) of 2-bromo-1-{4-[4-(2-hydroxy-2-methyl-propionyl)-phenoxy]-phenyl}-butan-1-one in diethyl ether was added drop wise to a solution of 58.5 ml of dimethylamine 2M in THF (0.117 mol), maintaining the temperature between 0° C. and 5° C. After one night the reaction was diluted with ether, washed three times with water, dried with sodium sulphate and evaporated obtaining 7.47 g of an oil used without purification in the following step.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[CH:10][C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2].[N+:26]([O-])([OH:28])=[O:27].O>C(OC(=O)C)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[C:7](=[O:25])[NH:8][C:9]([C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)=[C:10]([N+:26]([O-:28])=[O:27])[C:11]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)[nH]c(=O)c1C(=O)OCC
Reactant: O=[N+]([O-])O
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CCOC(=O)c1c([N+](=O)[O-])c(-c2ccc(OC)cc2)[nH]c(=O)c1C(=O)OCC
Temperature: -30 °C
Reaction time: 0.75 h

Procedure:
In 8 ml of acetic anhydride was suspended 1.2 g of 3,4-diethoxycarbonyl-6-(4-methoxyphenyl)-2(1H)pyridone. After the mixture was cooled to -30° C. 0 36 ml of fuming nitric acid was added dropwise, followed by stirring for 45 minutes. After water was added, stirring was continued for further 1 hour. The viscous product was collected by filtration, crystallized with diethyl ether and washed.
Reaction SMILES: [CH:1]([CH:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=2)[O:6][CH2:5][CH2:4]1)=O.[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCN(C(C)C)C(C)C>C(Cl)Cl>[CH3:15][C:16]1[C:24]2[CH2:23][O:22][C:21](=[O:25])[C:20]=2[CH:19]=[CH:18][C:17]=1[CH2:26][CH2:27][N:28]1[CH2:33][CH2:32][N:31]([CH2:1][CH:3]2[C:12]3[C:7](=[CH:8][C:9]([C:13]#[N:14])=[CH:10][CH:11]=3)[O:6][CH2:5][CH2:4]2)[CH2:30][CH2:29]1
Reactant: N#Cc1ccc2c(c1)OCCC2C=O
Reactant: Cc1c(CCN2CCNCC2)ccc2c1COC2=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1c(CCN2CCN(CC3CCOc4cc(C#N)ccc43)CC2)ccc2c1COC2=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-formyl-3,4-dihydro-2H-chromene-7-carbonitrile (50 mg, 0.27 mmol) in DCM (3 mL) was added 4-methyl-5-[2-(piperazine-1-yl)ethyl]-2-benzofuran-1(3H)-one (57 mg, 0.27 mmol), sodium triacetoxyborohydride (27.0 mg, 0.267 mmol) and DIPEA (57 mg, 0.27 mmol). The reaction was stirred under nitrogen at room temperature for 16 hours when LC-MS indicated product formation. The mixture was diluted with DCM and the product was isolated by flash chromatography. LC-MS (IE, m/z): 432 [M+1]+. (0.18 μM)
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][NH2:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S(O[CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])(=O)=O)=CC=1.C(=O)([O-])[O-].[K+].[K+]>[N+](C)([O-])=O>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][N:11]([CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])[CH2:22][CH2:23][N:24]=[N+:25]=[N-:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCN=[N+]=[N-])cc1
Reactant: CC(C)(C)OC(=O)NCCN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C[N+](=O)[O-]
Product: CC(C)(C)OC(=O)NCCN(CCN=[N+]=[N-])CCN=[N+]=[N-]

Procedure:
A mixture of 2-(tert-butoxycarbonylamino)ethylamine (10 mg; 0.6 mmol), 2-azidoethyl p-toluenesulphonate (370 mg; 1.5 mmol; 1.25 equiv) and potassium carbonate (2.4 mmol, 2 equiv) is taken to reflux in nitromethane for 16 hours. The solution is then concentrated and the residual product dissolved in dichloromethane (10 ml), washed with water (5 ml) and purified by column chromatography (EtOAc-hexane 1:3) leading to the title product (130 mg, 70%).
Reaction SMILES: [Br:1][CH2:2][C:3](=[O:40])[CH2:4][C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6].[N:41]([O-])=[O:42].[Na+].NC(N)=O>C(Cl)Cl.C(O)(=O)C>[Br:1][CH2:2][C:3](=[O:40])[C:4](=[N:41][OH:42])[C:5]([NH:7][CH:8]1[C:38](=[O:39])[N:10]2[C:11]([C:22]([O:24][CH:25]([C:32]3[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=3)[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)=[O:23])=[C:12](/[CH:15]=[CH:16]\[C:17]3[N:18]=[N:19][S:20][CH:21]=3)[CH2:13][S:14][C@H:9]12)=[O:6]
Reactant: O=C(CBr)CC(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Reactant: O=N[O-]
Agent: NC(N)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(CBr)C(=NO)C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(/C=C\c3csnn3)CS[C@H]12
Reaction time: 0.5 h
Yield: 81.4 %

Procedure:
A methylene chloride-acetic acid (20 ml-10 ml) solution of diphenylmethyl 7-(4-bromoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (2.22 g, 3.4 mmol) was cooled from -7° C. to -5° C. and an aqueous solution (2 ml) of sodium nitrite (0.32 g, 4.6 mmol) was added in portions. After its dropwise addition the mixture was stirred for 30 minutes, then urea (0.3 g) was added and the temperature of the reaction solution was returned to toom temperature. The reaction mixture was extracted with methylene chloride, then washed with water (40 ml×2) and then dried over magnesium sulfate. When the solvent was distilled off, diphenylmethyl 7-(4-bromo-2-hydroxyiminoacetoacetamido)-3-[(Z)-2-(1,2,3-thiadiazol-4-yl)vinyl]-3-cephem-4-carboxylate (1.85 g) was obtained as a light yellow powder compound.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][NH:19][C:20]([C:22]3([NH2:25])[CH2:24][CH2:23]3)=[O:21])=[CH:16][CH:15]=2)=[C:11]([C:30]([F:33])([F:32])[F:31])[CH:10]=1>>[CH3:7][O:8][C:9]1[CH:29]=[CH:28][C:12]([O:13][C:14]2[CH:27]=[CH:26][C:17]([CH2:18][NH:19][C:20]([C:22]3([NH:25][C:4](=[O:6])[CH2:3][C:1]#[N:2])[CH2:23][CH2:24]3)=[O:21])=[CH:16][CH:15]=2)=[C:11]([C:30]([F:31])([F:32])[F:33])[CH:10]=1
Reactant: N#CCC(=O)O
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)CC#N)CC3)cc2)c(C(F)(F)F)c1

Procedure:
Prepared analogously to Example 85b) starting from cyanoacetic acid and 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide (from 85a). In addition, the residue was finally purified by chromatography (reversed phase).
Reaction SMILES: [C:1]1([CH3:20])[CH:6]=[CH:5][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]#[N:19])=[O:8])=[CH:3][CH:2]=1.[OH2:21]>>[C:1]1([CH3:20])[CH:2]=[CH:3][C:4]([C:7]([C:9]2[CH:17]=[CH:16][CH:15]=[C:14]3[C:10]=2[CH2:11][CH2:12][CH:13]3[C:18]([NH2:19])=[O:21])=[O:8])=[CH:5][CH:6]=1
Reactant: O
Reactant: Cc1ccc(C(=O)c2cccc3c2CCC3C#N)cc1
Product: Cc1ccc(C(=O)c2cccc3c2CCC3C(N)=O)cc1
Temperature: 90 °C
Reaction time: 0.5 h

Procedure:
To 2.3 g. of 4-(p-toluoyl)indan-1-carbonitrile is added 75 g. of polyphosphoric acid and the mixture is worked into a homogeneous solution by heating on a water bath at 90°C for 30 minutes and, then, on an oil bath at 120°-130°C for 30 minutes. Following the addition of water to decompose the polyphosphoric acid, the reaction mixture is extracted with ethyl acetate. The extract is washed with water, 5 % aqueous sodium hydrogen carbonate and water in the order mentioned and, then, dried. It is, then, treated with activated carbon and concentrated under reduced pressure. The resultant crystalline residue is recrystallized from a mixture of ethanol and ethyl acetate. The described procedure gives 4-(p-toluoyl)indan-1-carboxamide as crystals melting at 188°-191°C.
Reaction SMILES: [CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[OH:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C(C)=CC=CC=1C.[Si:43](OS(C(F)(F)F)(=O)=O)([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44]>C(Cl)Cl>[CH2:1]([O:8][C@H:9]1[C@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@@H:13]([CH2:23][O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[O:12][C@H:11]([CH2:32][I:33])[C@@H:10]1[O:34][Si:43]([C:46]([CH3:49])([CH3:48])[CH3:47])([CH3:45])[CH3:44])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)O[C@@H]1[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@@H](COCc2ccccc2)O[C@@H]1CI
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 87.6 %

Procedure:
To a solution of (2S,3R,4R,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-ol (1.0 g, 1.74 mmol, 1.0 equiv) in dry DCM (10 mL) under nitrogen atmosphere, was added 2,6-lutidine (0.41 mL, 3.5 mmol, 2.0 equiv) at room temperature. The resulting mixture was stirred for 5 minutes. The reaction was cooled to 0° C. and TBSOTf (0.6 mL, 2.6 mmol, 1.5 equiv) was added dropwise. The mixture was then slowly allowed to warm to room temperature. After 1 hour, the mixture was diluted with DCM (20 mL) and washed with water (2×20 mL). The organic layer was dried over Na2SO4 and over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give an oil. The oil was then purified by silica gel chromatography, eluting with 5% EtOAc in petroleum ether to give (((2S,3R,4S,5R,6R)-4,5-bis(benzyloxy)-6-((benzyloxy)methyl)-2-(iodomethyl)tetrahydro-2H-pyran-3-yl)oxy)(tert-butyl)dimethylsilane as a colorless oil (1.05 g, 94%). 1H NMR (400 MHz, CDCl3) δ 7.40-7.22 (m, 13H), 7.09-7.04 (m, 2H), 4.90-4.77 (m, 2H), 4.77-4.68 (m, 2H), 4.53 (d, J=12.1 Hz, 1H), 4.47 (d, J=10.7 Hz, 1H), 4.09 (ddd, J=12.2, 5.9, 3.4 Hz, 1H), 3.91 (dd, J=9.2, 5.9 Hz, 1H), 3.81 (dd, J=10.7, 3.2 Hz, 1H), 3.75 (dd, J=10.7, 2.1 Hz, 1H), 3.69 (dd, J=9.9, 8.7 Hz, 1H), 3.63-3.56 (m, 2H), 3.51 (dt, J=9.9, 2.6 Hz, 1H), 3.41 (t, J=11.8 Hz, 1H), 0.91 (s, 9H), 0.09 (s, 3H), 0.07 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[O:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][NH:10][C:11]([C:13]2[N:14]=[C:15]([CH2:18][NH2:19])[O:16][CH:17]=2)=[O:12])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(NCCc1cccc(Cl)c1)c1coc(CN2C(=O)c3ccccc3C2=O)n1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1nc(C(=O)NCCc2cccc(Cl)c2)co1
Reaction time: 12 h

Procedure:
2-(1,3-Dioxo-1,3-dihydro-isoindol-2-ylmethyl)-oxazole-4-carboxylic acid [2-(3-chloro-phenyl)-ethyl]-amide (0.75 g, 1.8 mmol) was dissolved in ethanol (5 mL). Hydrazine monohydrate (0.44 mL, 9.2 mmol) was added. The mixture was stirred for 12 hours. A white precipitate formed during the course of the reaction. The mixture was filtered and the solid was washed with methanol. The filtrate was reduced in vacuo to afford the title compound: 1H NMR (400 MHz, d6-DMSO): 8.46 (s, 1H), 8.27 (t, 1H), 7.27 (m, 3H), 7.16 (m, 1H), 3.78 (s, 2H), 3.45 (m, 2H), 2.82 (t, 2H); MS (ESI-LCMS) for C13H14ClN3O2: 280 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([N+:9]([O-])=O)[C:3]=1[OH:12].[H][H]>C(OCC)(=O)C.[Ni]>[NH2:9][C:4]1[C:3]([OH:12])=[C:2]([Br:1])[CH:7]=[C:6]([Cl:8])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(Cl)cc(Br)c1O
Reactant: [H][H]
Agent: [Ni]
Solvent: CCOC(C)=O
Product: Nc1cc(Cl)cc(Br)c1O
Yield: 99 %

Procedure:
A solution of 2-bromo-4-chloro-6-nitro-phenol (16.27 g, 64.4 mmol) in ethyl acetate (160 ml) was hydrogenated, at room temperature, with Raney-nickel (6 g). After hydrogen uptake (approx. 4.8 l) was complete, the nickel was removed by filtration and the filtrate evaporated in-vacuo to give 14.19 g (99.0%) of the title compound which was suitable for the next step.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15](Cl)(=[O:17])=[O:16])=[CH:11][CH:10]=1.Cl.Cl.[Cl:21][C:22]1[CH:27]=[C:26]([Cl:28])[CH:25]=[CH:24][C:23]=1[C:29]1[NH:33][C:32](=[O:34])[C:31]2([CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[N:30]=1>ClCCl>[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([N:37]2[CH2:36][CH2:35][C:31]3([N:30]=[C:29]([C:23]4[CH:24]=[CH:25][C:26]([Cl:28])=[CH:27][C:22]=4[Cl:21])[NH:33][C:32]3=[O:34])[CH2:39][CH2:38]2)(=[O:17])=[O:16])=[CH:11][CH:10]=1
Reactant: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCNCC2
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C1NC(c2ccc(Cl)cc2Cl)=NC12CCN(S(=O)(=O)c1ccc(Cl)cc1)CC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.1 %

Procedure:
Triethylamine (88 μl, 0.632 mmol) and 4-chlorobenzenesulfonyl chloride (70 mg, 0.332 mmol) were added to a mixed solution of 2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one dihydrochloride (100 mg, 0.299 mmol) in dichloromethane (3 ml). The reaction solution was stirred at room temperature for 16 hours and then diluted with dichloromethane, and the organic layer was washed with water. The organic layer was dried over sodium sulfate and then concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (ethyl acetate:hexane) to give 8-(4-chloro-benzenesulfonyl)-2-(2,4-dichloro-phenyl)-1,3,8-triaza-spiro[4.5]dec-1-en-4-one (70.8 mg, 96%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13](I)[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2].[F:21][C:22]([F:33])([F:32])[C:23]([F:31])([F:30])[C:24]([F:29])([F:28])C([O-])=O.[K+].C1(C)C=CC=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[C:11]2[CH:12]=[C:13]([C:24]([F:29])([F:28])[C:23]([F:31])([F:30])[C:22]([F:33])([F:32])[F:21])[CH:14]=[CH:15][C:10]=2[O:9][C:8]([CH2:19][F:20])([CH2:17][F:18])[CH:7]=1)=[O:5])[CH3:2]
Reactant: O=C([O-])C(F)(F)C(F)(F)C(F)(F)F
Reactant: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(I)cc21
Agent: [K+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1=CC(CF)(CF)Oc2ccc(C(F)(F)C(F)(F)C(F)(F)F)cc21

Procedure:
The procedure of Preparation Example 1 (6) was repeated using 2,2-bisfluoromethyl-6-iodo-2H-1-benzopyran-4-carboxylic acid ethyl ester, potassium heptafluorobutyrate, cuprous iodide, toluene and N,N-dimethylformamide to give 2,2-bisfluoromethyl-6-heptafluoropropyl-2H-1-benzopyran-4-carboxylic acid ethyl ester as an oil;
Reaction SMILES: [H-].[Na+].[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:25]=[CH:24][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:22][CH:21]=3)[C:18]3[C:29]([CH3:36])=[C:30]([OH:35])[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH3:37][O:38][C:39]1[CH:46]=[CH:45][C:42]([CH2:43]Cl)=[CH:41][CH:40]=1.O>CN(C)C=O>[CH2:3]([N:10]1[CH2:15][CH2:14][C:13]2([CH:19]([C:20]3[CH:21]=[CH:22][C:23]([CH:26]([CH3:28])[CH3:27])=[CH:24][CH:25]=3)[C:18]3[C:29]([CH3:36])=[C:30]([O:35][CH2:43][C:42]4[CH:45]=[CH:46][C:39]([O:38][CH3:37])=[CH:40][CH:41]=4)[C:31]([CH3:34])=[C:32]([CH3:33])[C:17]=3[O:16]2)[CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COc1ccc(CCl)cc1
Reactant: Cc1c(C)c2c(c(C)c1O)C(c1ccc(C(C)C)cc1)C1(CCN(Cc3ccccc3)CC1)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(COc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C2(CCN(Cc4ccccc4)CC2)O3)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
Sodium hydride (60% liquid paraffin dispersion, 81.4 mg, 1.81 mmol) was added to a solution of 1′-benzyl-3-(4-isopropylphenyl)-4,6,7-trimethylspiro[benzofuran-2(3H),4′-piperidine]-5-ol (824.0 mg. 1.81 mmol) in N,N-dimethylformamide (15 mL) at 0° C., and the mixture was stirred for 30 minutes at the same temperature. To the reaction mixture was added 4-methoxybenzyl chloride (319.9 mg, 2.04 mmol) and the mixture was stirred for further 30 minutes at room temperature. The reaction mixture was poured into water, and extracted twice with ethyl acetate. The organic layers were combined, washed with an aqueous saturated sodium hydrogencarbonate, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain the title compound (539 mg, yield 52%). This was amorphous.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].CS([O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])(=O)=O.O[C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27](=[O:29])[CH3:28])=[CH:22][C:21]=1[C:30]1[N:31]([CH3:35])[N:32]=[CH:33][CH:34]=1>CC(N(C)C)=O>[CH3:35][N:31]1[C:30]([C:21]2[CH:22]=[C:23]([NH:26][C:27](=[O:29])[CH3:28])[CH:24]=[CH:25][C:20]=2[O:11][CH2:12][C:13]([CH3:18])([N+:15]([O-:17])=[O:16])[CH3:14])=[CH:34][CH:33]=[N:32]1
Reactant: CC(=O)Nc1ccc(O)c(-c2ccnn2C)c1
Reactant: CC(C)(COS(C)(=O)=O)[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: CC(=O)Nc1ccc(OCC(C)(C)[N+](=O)[O-])c(-c2ccnn2C)c1
Temperature: 160 °C
Reaction time: 2 h
Yield: 82.8 %

Procedure:
Cesium carbonate (7.04 g, 21.6 mmol) was added to a solution of 2-methyl-2-nitropropyl methanesulfonate (2.39 g, 12.1 mmol) and N-(4-hydroxy-3-(2-methyl-2H-pyrazol-3-yl)phenyl)acetamide (2.00 g, 8.65 mmol) in dimethylacetamide (15 mL) and the mixture was stirred at 160° C. After 2 h, the solvent was evaporated, and the residue was triturated with water. The precipitate was isolated by filtration, washed with water and dried in vacuo to afford the product (2.38 g, 83%) as a tan solid. LCMS m/z (%)=333.4 (M+H 100%). 1H NMR (400 MHz, DMSO-d6) δ ppm 1.47 (s, 6H), 2.02 (s, 3H), 3.53 (s, 3H), 4.32 (s, 2H), 6.15 (d, J=2.02 Hz, 1H), 7.14 (d, J=8.84 Hz, 1H), 7.44 (d, J=1.77 Hz, 1H), 7.49 (d, J=2.78 Hz, 1H), 7.62 (dd, J=8.97, 2.65 Hz, 1H), 9.94 (s, 1H).
Reaction SMILES: FC1C=C([C@@H]2CCCC(=O)N2[C:16]([O:18]C(C)(C)C)=[O:17])C=C(F)C=1.[F:23][C:24]1[CH:25]=[C:26]([C@H:31]2[N:36]([C:37](OC(C)(C)C)=O)[C:35](=[O:44])[C@H:34]([CH3:45])[CH2:33][CH2:32]2)[CH:27]=[C:28]([F:30])[CH:29]=1>>[F:30][C:28]1[CH:27]=[C:26]([C@H:31]2[N:36]([CH2:37][C:16]([OH:18])=[O:17])[C:35](=[O:44])[C@H:34]([CH3:45])[CH2:33][CH2:32]2)[CH:25]=[C:24]([F:23])[CH:29]=1
Reactant: CC(C)(C)OC(=O)N1C(=O)CCC[C@H]1c1cc(F)cc(F)c1
Reactant: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(C(=O)OC(C)(C)C)C1=O
Product: C[C@@H]1CC[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O

Procedure:
Essentially following the procedures described for Intermediate 26, but using tert-butyl (3R,6S)-6-(3,5-difluorophenyl)-3-methylpiperidin-2-one-1-carboxylate in place of tert-butyl (6S)-6-(3,5-difluorophenyl)-3,3-diethylpiperidin-2-one-1-carboxylate, the title compound was prepared. MS: m/z=284 (M+1).
Reaction SMILES: I[C:2]1[N:3]=[C:4]([CH2:7][CH2:8][CH3:9])[NH:5][CH:6]=1.[N:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][CH:11]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O>[CH2:7]([C:4]1[NH:5][CH:6]=[C:2]([C:13]2[CH:14]=[CH:15][N:10]=[CH:11][CH:12]=2)[N:3]=1)[CH2:8][CH3:9]
Reactant: CCCc1nc(I)c[nH]1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCCc1nc(-c2ccncc2)c[nH]1
Yield: 37 %

Procedure:
[step 1] 4-Iodo-2-propylimidazole obtained in Reference Example A16 was dissolved in dioxane/water (2 mL/1 mL), 4-pyridineboronic acid (0.108 g, 0.889 mmol), 1,1-bisdiphenylphosphinoferrocene dichloropalladium (0.052 g, 0.064 mmol) and sodium carbonate (0.202 g, 1.91 mmol) were added, and the mixture was heated under reflux for 3 hr. The reaction mixture was concentrated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=1/2) to give 2-propyl-4-(4-pyridyl)imidazole (0.044 g, 37%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[CH:13][C:14]([S:17][CH3:18])=[N:15][CH:16]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH3:18][S:17][C:14]1[CH:13]=[CH:12][C:11]([NH:10][CH2:6][C:5]2[CH:8]=[CH:9][C:2]([F:1])=[CH:3][CH:4]=2)=[CH:16][N:15]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: CSc1ccc(N)cn1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CSc1ccc(NCc2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 5 h
Yield: 40.3 %

Procedure:
To 344 μL (3.20 mmol) of 4-fluorobenzaldehyde and 449 mg (3.20 mmol) of 5-amino-2-methylthio-pyridine dissolved in 8 mL dichloromethane was added 1.11 g (5.25 mmol) sodium triacetoxyborohydride. The reaction mixture was stirred at room temperature for 5 h, and partitioned between ethyl acetate and water, dried over MgSO4 and concentrated to obtain 320 mg of 5-[(4-fluorobenzyl)amino]-pyridin-2-yl methyl sulfide, pure by 1H NMR.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N+:19]([O-])=O)[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[NH4+].[Cl-].O>CCO.[Fe]>[Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2
Reactant: O=[N+]([O-])c1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(Oc2cnc3ccccc3c2)c(Cl)c1
Yield: 95 %

Procedure:
To a solution of nitrobenzene 198 (2.07 g) and NH4Cl (1.84 g) in EtOH (40 ml)-H2O (10 ml), was added iron powder (1.92 g). The mixture was heated to reflux for 1 hr. After cooling the reaction mixture was filtered through short celite pad. The filtrate was concentrated, diluted with sat. NaHCO3 (30 ml) and extacted with AcOEt (30 ml). The combined organic layers were washed with brine (30 ml) and dried over Na2SO4. Concentration of the solvent afforded the aniline 199 (1.77 g, 95%) as a yellow solid.