Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1.[OH-].[Na+].C1C=C(C(C2C=CC(O)=CC=2)C2C=CC([OH:29])=CC=2)C(C(O)=O)=CC=1>O>[OH:29][CH2:2][C:3]1[CH:13]=[CH:12][C:6]([CH2:7][CH2:8][C:9]([OH:11])=[O:10])=[CH:5][CH:4]=1
Reactant: O=C(O)c1ccccc1C(c1ccc(O)cc1)c1ccc(O)cc1
Reactant: O=C(O)CCc1ccc(CCl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)CCc1ccc(CO)cc1

Procedure:
30 g (0.15 mol) of 4-chloromethyl-hydrocinnamic acid (J. Org, Chem. 26, 148 (1961) in 200 ml of water were neutralized with a 10% sodium hydroxide solution against phenol phthaline. 10% of NaOH (on the whole about 60 ml) were added dropwise, while stirring at reflux temperature, to the solution obtained in the same measure as it was consumed. When the reaction was finished, the mixture was saturated with sodium chloride, acidified with concentrated hydrochloric acid, the product precipitated was suction-filtered and washed with water. Melting point: 124°-126° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([NH:9][S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1.Br[CH2:21][C:22]([O:24]C)=[O:23]>>[CH3:1][O:2][C:3]1[N:8]=[CH:7][C:6]([N:9]([CH2:21][C:22]([OH:24])=[O:23])[S:10]([C:13]2[C:18]([CH3:19])=[CH:17][CH:16]=[CH:15][N:14]=2)(=[O:12])=[O:11])=[CH:5][CH:4]=1
Reactant: COC(=O)CBr
Reactant: COc1ccc(NS(=O)(=O)c2ncccc2C)cn1
Product: COc1ccc(N(CC(=O)O)S(=O)(=O)c2ncccc2C)cn1

Procedure:
prepared by reaction of 3-methyl-pyridine-2-sulfonic acid (6-methoxy-pyridin-3-yl)-amide with methyl bromoacetate
Reaction SMILES: [CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][N:5]2[N:9]=[C:10]([N+:12]([O-])=O)[CH:11]=[C:4]2[CH2:3]1.[H][H]>CO.[Ni]>[CH3:1][N:2]1[CH:7]([CH3:8])[CH2:6][N:5]2[N:9]=[C:10]([NH2:12])[CH:11]=[C:4]2[CH2:3]1
Reactant: CC1Cn2nc([N+](=O)[O-])cc2CN1C
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: CC1Cn2nc(N)cc2CN1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.9 %

Procedure:
A solution of 250d (550 mg, 2.8 mmol) in methanol (20 mL) was added Raney Ni (about 600 mg). The reaction was charged with hydrogen gas (via balloon) and stirred for 2 h at room temperature. It was then filtered through a plug of CELITE® and the filtrate was concentrated under reduced pressure to afford 250e as a yellow solid (400 mg, 86%), which was used directly in the next step without further purification. MS-ESI: [M+H]+ 167.3
Reaction SMILES: Br[C:2]1[C:11]([F:12])=[C:10]([F:13])[C:9]([F:14])=[C:8]2[C:3]=1[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.[CH2:24]([Sn](CCCC)(CCCC)C=C)[CH2:25]CC>C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH:15]1([N:7]2[C:8]3[C:3](=[C:2]([CH:24]=[CH2:25])[C:11]([F:12])=[C:10]([F:13])[C:9]=3[F:14])[C:4](=[O:23])[C:5]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:6]2)[CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)c(Br)c2c1=O
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=Cc1c(F)c(F)c(F)c2c1c(=O)c(C(=O)OCC)cn2C1CC1
Temperature: -18 °C
Yield: 87.4 %

Procedure:
5.9 g of ethyl 5-bromo-1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylate, 6.7 g of tributyl-vinylstannane and 0.69 g of tetrakis(triphenylphosphine)-palladium(0) are refluxed for 10 hours in 60 ml of absolute toluene under a nitrogen atmosphere. The reaction mixture is cooled to -18° C., and the solid which has precipitated is filtered off with suction, washed with toluene and dried. 4.46 g of the title compound are obtained (88% of theory).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1N)[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])=[O:3].N([O-])=O.[Na+].[ClH:22]>O.[Cu]Cl>[CH3:1][C:2]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[Cl:22])[C:9]([CH3:15])([CH3:14])[CH2:8][C:7]2([CH3:17])[CH3:16])=[O:3]
Reactant: CC(=O)c1cc2c(cc1N)C(C)(C)CC2(C)C
Reactant: Cl
Agent: Cl[Cu]
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: CC(=O)c1cc2c(cc1Cl)C(C)(C)CC2(C)C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
113.1 g of (6-amino-1,1,3,3-tetramethyl-5-indanyl) methyl ketone are suspended in 2260 ml of 20% hydrochloric acid and the suspension is cooled down to 0°-5° C. The cold mixture is treated dropwise within 10 minutes with a solution of 33.9 g of sodium nitrite in 115 ml of water and the resulting solution is stirred for 30 minutes. The cold solution is subsequently introduced dropwise over a period of 2 hours while stirring into a solution of 243.2 g of copper (I) chloride in 250 ml of water and 250 ml of concentrated hydrochloric acid, which is warmed to 40°-45° C. The mixture is then cooled down, introduced into ice-water and extracted three times with methylene chloride. The organic extract is washed with a sodium chloride solution, dried over sodium sulphate and freed from solvent under reduced pressure. The residue is purified by adsorption on silica gel using hexane/acetone (19:1) for the elution. The (6-chloro-1,1,3,3-tetramethyl-5-indanyl) methyl ketone obtained from the eluate melts at 69°-71° C. after recrystallisation from hexane/ether.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:38]=[CH:37][C:36]([CH2:39][C:40]#[N:41])=[CH:35][CH:34]=3)=[N:8]2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: CC1(C)OB(c2ccc(CC#N)cc2)OC1(C)C
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1ccc(CC#N)cc1)nn2C1CCCC1
Yield: 62.5 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (160 mg) obtained in Step C of Example 12, (4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)acetonitrile (160 mg), tetrakis(triphenylphosphine)palladium(0) (50.6 mg) and 2M aqueous sodium carbonate solution (1.10 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (91.0 mg).
Reaction SMILES: [NH2:1][C@H:2]([C:7]([NH:9][C@@H:10]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C@H:11]([OH:30])[CH2:12][N:13]1[C@H:22]([C:23]([NH:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14]1)=[O:8])[CH2:3][C:4](=[O:6])[NH2:5].[C:38](O)(=[O:49])[C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1.OC1C2N=NNC=2C=CC=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1.C(OCC)(=O)C>[C:26]([NH:25][C:23]([C@@H:22]1[CH2:21][C@H:20]2[C@H:15]([CH2:16][CH2:17][CH2:18][CH2:19]2)[CH2:14][N:13]1[CH2:12][C@@H:11]([OH:30])[C@@H:10]([NH:9][C:7](=[O:8])[C@H:2]([CH2:3][C:4](=[O:6])[NH2:5])[NH:1][C:38]([C:39]1[CH:48]=[CH:47][C:46]2[C:41](=[CH:42][CH:43]=[CH:44][CH:45]=2)[N:40]=1)=[O:49])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: O=C(O)c1ccc2ccccc2n1
Reactant: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@@H](N)CC(N)=O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)NC(=O)[C@@H]1C[C@@H]2CCCC[C@@H]2CN1C[C@@H](O)[C@H](Cc1ccccc1)NC(=O)[C@H](CC(N)=O)NC(=O)c1ccc2ccccc2n1
Temperature: 0 °C
Reaction time: 64 h
Yield: 25 %

Procedure:
A solution of 154 mg of 2-[3(S)-[(L-asparaginyl)amino]-2(R)-hydroxy-4-phenylbutyl]-N-tert.butyl-decahydro(4aS,8aS)-isoquinoline-3(S)-carboxamide and 52 mg of quinaldic acid in 6 ml of dry tetrahydrofuran was cooled in an ice/salt mixture. 41 mg of hydroxybenzotriazole, 35 mg of N-ethylmorpholine and 68 mg of dicyclohexylcarbodiimide were added and the mixture was stirred for 64 hours. The mixture was diluted with ethyl acetate and filtered. The filtrate was washed with aqueous sodium bicarbonate solution and with sodium chloride solution and then evaporated. The residue was chromatographed on silica gel using dichloromethane/methanol (9:1) for the elution to give 50 mg of N-tert.butyl-decahydro-2-[2(R)-hydroxy-4-phenyl-3(S)-[[N-(2-quinolylcarbonyl)-L-asparaginyl]amino]butyl]-(4aS,8aS)-isoquinoline-3(S)-carboxamide as a white solid; MS: m/e 671 [M+H]+, NMR: δ (d4CH3OH, 400 MHz):
Reaction SMILES: [NH2:1][S:2][O:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:19]3[C:18]4[CH:20]=[C:21]([N+:24]([O-])=O)[CH:22]=[CH:23][C:17]=4[CH2:16][CH2:15][C:14]=3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12]2)=[CH:7][CH:6]=1.[H][H]>CN(C=O)C.[Pd]>[NH2:24][C:21]1[CH:22]=[CH:23][C:17]2[CH2:16][CH2:15][C:14]3[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[N:12][N:11]([C:8]4[CH:7]=[CH:6][C:5]([O:4][O:3][S:2][NH2:1])=[CH:10][CH:9]=4)[C:19]=3[C:18]=2[CH:20]=1
Reactant: [H][H]
Reactant: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc([N+](=O)[O-])cc1-2
Agent: [Pd]
Solvent: CN(C)C=O
Product: CCOC(=O)c1nn(-c2ccc(OOSN)cc2)c2c1CCc1ccc(N)cc1-2
Yield: 85.8 %

Procedure:
The product of Example 2 (2.0 g) and 10% Pd/C (350 mg) in DMF (20 mL) were shaken at 55 psi hydrogen for 3 hours. The catalyst was removed by filtration and the filtrate was concentrated under vacuum to yield a yellow wax. The wax was triturated with methanol and the resulting amber solid was collected by filtration to afford the title compound (1.6 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:22]=[CH:21][C:7]([CH2:8][N:9]2[C@@H:14]([CH3:15])[CH2:13][N:12]([C:16](=[O:19])[CH2:17][OH:18])[C@H:11]([CH3:20])[CH2:10]2)=[CH:6][CH:5]=1.Cl[C:24]1[C:29]([CH:30]=[O:31])=[CH:28][C:27]([Cl:32])=[CH:26][N:25]=1>C1(C)C=CC=CC=1>[Cl:32][C:27]1[CH:28]=[C:29]([CH:30]=[O:31])[C:24]([O:18][CH2:17][C:16]([N:12]2[CH2:13][C@H:14]([CH3:15])[N:9]([CH2:8][C:7]3[CH:6]=[CH:5][C:4]([F:3])=[CH:22][CH:21]=3)[CH2:10][C@H:11]2[CH3:20])=[O:19])=[N:25][CH:26]=1
Reactant: O=Cc1cc(Cl)cnc1Cl
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ncc(Cl)cc1C=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 67.1 %

Procedure:
To a 0° C. suspension of sodium hydride (60% dispersion in mineral oil, 0.031 g, 0.78 mmol) in toluene (3 mL) was added 1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-2-hydroxy-ethanone (0.20 g, 0.71 mmol) in toluene (2 mL). The reaction mixture was stirred at 0° C. for 30 minutes, and then treated with 2,5-dichloro-pyridine-3-carbaldehyde (0.14 g, 0.78 mmol). The resulting mixture was refluxed for 4 hours, cooled to ambient temperature and washed with saturated aqueous sodium hydrogen carbonate and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Silica gel chromatography provided the title compound (0.20 g).
Reaction SMILES: C([O:4][CH2:5][C:6]([CH3:19])([CH3:18])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH2:15])[C:10]=1[C:16]#[N:17])(=O)C.O=[C:21]([CH3:28])[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24]>>[NH2:17][C:16]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][C:9]=2[O:8][CH2:7][C:6]([CH3:18])([CH3:19])[CH2:5][OH:4])[N:15]=[C:21]([CH3:28])[C:22]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CC(=O)OCC(C)(C)COc1cccc(N)c1C#N
Reactant: CCOC(=O)CC(C)=O
Product: CCOC(=O)c1c(C)nc2cccc(OCC(C)(C)CO)c2c1N

Procedure:
Prepared as in Example 2a from 3-(3-amino-2-cyanophenoxy)-2,2-dimethylpropyl acetate (Tachdjian, C. et al. PCT Int. App. 2008, WO 2008154221) and ethyl 3-oxobutanoate as a pale yellow solid (26%). MS 333 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C:9]1[N:13]=[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])[NH:11][N:10]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C>[CH2:33]([N:11]1[C:12]([C@H:14]([NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23])[C:15]([CH3:18])([CH3:17])[CH3:16])=[N:13][C:9]([C:3]2[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=2[F:1])=[N:10]1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)n[nH]1)C(C)(C)C
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](c1nc(-c2cc(F)ccc2F)nn1Cc1ccccc1)C(C)(C)C

Procedure:
To a stirred suspension of (R)-tert-butyl 1-(3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropylcarbamate (5.89 g, 16.1 mmol) and Cs2CO3 (10.5 g, 32.2 mmol) in DMF (46 mL, 0.35 M) was added benzyl bromide (2.11 mL, 17.7 mmol). Once the organic layer was separated and washed with H2O, brine, then dried over Na2SO4, filtered, and evaporated in vacuo to give (R)-tert-butyl 1-(1-benzyl-3-(2,5-difluorophenyl)-1H-1,2,4-triazol-5-yl)-2,2-dimethylpropyl-carbamate. The desired regioisomer was obtained on silica gel column (0% to 100% EtOAc in Hexanes, 3.25 g, 44.3%). The structure was verified by 1H NMR nOe experiments.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([OH:16])=O)=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18].[NH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[S:8][C:9]1[S:13][C:12]([C:14]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:16])=[CH:11][C:10]=1[N+:17]([O-:19])=[O:18]
Reactant: Nc1ccccc1
Reactant: O=C(O)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1
Product: O=C(Nc1ccccc1)c1cc([N+](=O)[O-])c(Sc2c(Cl)cncc2Cl)s1

Procedure:
Prepared according to the procedure described for example 44 from 5-[(3,5-dichloro-4-pyridyl)sulfanyl]-4-nitro-thiophene-2-carboxylic acid (35 mg, 0.1 mmol) and aniline (11.0 mg, 0.12 mmol). The title compound was obtained as a yellow solid (5.0 mg, 11% yield). MS m/z: 425.96, 427.95 [M+H]+.
Reaction SMILES: [CH2:1]([N:8]([CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C@H:9]([CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])/[CH:10]=[CH:11]/[C:12]1[N:20]=[CH:19][CH:18]=[CH:17][C:13]=1[C:14](O)=[O:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:36]([NH2:40])([CH3:39])([CH3:38])[CH3:37]>>[C:36]([NH:40][C:14](=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[N:20][C:12]=1/[CH:11]=[CH:10]/[C@H:9]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[F:28])([CH3:39])([CH3:38])[CH3:37]
Reactant: O=C(O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1
Reactant: CC(C)(C)N
Product: CC(C)(C)NC(=O)c1cccnc1/C=C/[C@@H](Cc1ccccc1F)N(Cc1ccccc1)Cc1ccccc1

Procedure:
Using general procedure 5 with 2-[(E)-(R)-3-dibenzylamino-4-(2-fluoro-phenyl)-but-1-enyl]-nicotinic acid (0.64 g, 1.4 mmol) and tert-butylamine (0.73 mL, 1.5 mmol) gives the title compound.
Reaction SMILES: [CH3:1][NH:2][C:3]([CH:5]([NH:7][C:8](=O)[C:9]1[CH:14]=[CH:13][CH:12]=[N:11][CH:10]=1)[CH3:6])=O.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:25])=CC=1>ClCCCl>[CH3:1][NH:2][C:3]1[S:25][C:8]([C:9]2[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=2)=[N:7][C:5]=1[CH3:6]
Reactant: CNC(=O)C(C)NC(=O)c1cccnc1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: ClCCCl
Product: CNc1sc(-c2cccnc2)nc1C
Temperature: 130 °C
Yield: 68.7 %

Procedure:
To a 10 mL microwave vessel containing DCE (5 mL) was added N-(1-methylcarbamoyl-ethyl)nicotinamide (207 mg, 1.0 mmol) followed by Lawesson's reagent (2,4-bis-(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane 2,4-disulfide, 404 mg, 1.0 mmol) in one portion. The heterogeneous mixture was heated in a microwave for 5 min at 130° C. The reaction mixture was partitioned between CH2Cl2 and saturated aqueous sodium bicarbonate (NaHCO3). The layers were separated and the organic layer was washed once with brine. The solution was dried over MgSO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column chromatography (ethyl acetate) to give the desired product as an orange solid (141 mg, 68%): mp 84-87° C.; 1H NMR (300 MHz, CDCl3) δ 8.98 (d, J=1.7 Hz, 1H), 8.51 (dd, J=4.9, 1.7 Hz, 1H), 8.08 (dt, J=8.0, 1.7 Hz, 1H), 7.29 (m, 1H), 3.00 (s, 3H), 2.30 (s, 3H); ESIMS m/z 206.4 (M+1), m/z 204.2 (M−1).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH2:13])=[CH:7][C:6]=2[Br:14].[F:17][C:18]([F:29])([F:28])[C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][N:20]=1.CCN(CC)CC>C(Cl)Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[NH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][C:8]([CH2:12][NH:13][C:23]([C:22]1[CH:21]=[N:20][C:19]([C:18]([F:29])([F:17])[F:28])=[CH:27][CH:26]=1)=[O:24])=[CH:7][C:6]=2[Br:14]
Reactant: O=C(Cl)c1ccc(C(F)(F)F)nc1
Reactant: NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NCc1cc(Br)c2[nH]c(C(F)(F)F)cc2c1)c1ccc(C(F)(F)F)nc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.7 %

Procedure:
[(2-Trifluoromethyl-7-bromo-1H-indol-5-yl)methyl]amine (Intermediate 9, 230 mg, 0.785 mmol) was dissolved in DCM (10 mL) and 6-(trifluoromethyl)nicotinoyl chloride (ABCR; 181 mg, 0.863 mmol) was added. Et3N (0.219 mL, 1.570 mmol) was added and the reaction mixture was then left to stir at room temperature for 30 min. The reaction mixture was quenched with water then the organic layer was collected, dried (MgSO4), filtered and evaporated to dryness. The resulting residues were purified by MDAP to give the title compound, (200 mg);
Reaction SMILES: O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C[O:14][CH:15](OC)[C:16]1[C:40]([O:41]COC)=[C:39]([C:45]([F:48])([F:47])[F:46])[CH:38]=[CH:37][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=2)=[CH:22][CH:21]=1.O>CC(C)=O>[CH:15]([C:16]1[C:40]([OH:41])=[C:39]([C:45]([F:46])([F:48])[F:47])[CH:38]=[CH:37][C:17]=1[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:27]=2)=[CH:22][CH:21]=1)=[O:14]
Reactant: COCOc1c(C(F)(F)F)ccc(COc2ccc(-c3cccc(CC(=O)OC)c3)cc2)c1C(OC)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)Cc1cccc(-c2ccc(OCc3ccc(C(F)(F)F)c(O)c3C=O)cc2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 82.7 %

Procedure:
After p-toluenesulfonic acid monohydrate (0.716 g, 3.77 mmol) was added to a solution of methyl (4′-{[2-(dimethoxymethyl)-3-(methoxymethoxy)-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate (1.83 g, 3.43 mmol) obtained in Example (8-2) in acetone (20 ml), the mixture was stirred at room temperature for 6 hours. After the reaction mixture was poured into water and the mixture was extracted with ethyl acetate (twice), the organic layer was successively washed with water and a saturated aqueous NaCl solution and dried with anhydrous sodium sulfate. The solvent was removed under reduced pressure to give a residue. The obtained residue was purified by silica gel column chromatography (eluting solvent: n-hexane/ethyl acetate=80/20-70/30) to give methyl (4′-{[2-formyl-3-hydroxy-4-(trifluoromethyl)benzyl]oxy}-1,1′-biphenyl-3-yl)acetate (1.26 g, yield: 83%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:22][C:23]1[CH:35]=[CH:34][C:26]([O:27][CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:25][CH:24]=1>CN(C)C=O.C(O)C>[F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]([OH:18])[CH2:19][N:31]4[CH2:30][CH2:29][CH:28]([O:27][C:26]5[CH:34]=[CH:35][C:23]([F:22])=[CH:24][CH:25]=5)[CH2:33][CH2:32]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Reactant: Fc1ccc(OC2CCNCC2)cc1
Solvent: CCO
Solvent: CN(C)C=O
Product: O[C@@H](COc1ccc(-c2noc3cc(F)ccc23)cc1)CN1CCC(Oc2ccc(F)cc2)CC1

Procedure:
The title compound is prepared from a mixture of (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole in dimethylformamide and 4-(4-fluoro-phenoxy)-piperidine (Table No.1, SM 5) in ethanol essentially as described above in Example 21. Purity by LC/MS=86%, [M+H]+=481 and 8%, [M+H]+=573.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH:12]=O)=[N:4][CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][NH2:24])([O-:16])=[O:15]>C(O)C>[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[NH:23][N:24]=[CH:12][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:11])([F:10])[F:9])=[CH:5][N:4]=1)([O-:16])=[O:15]
Reactant: O=Cc1ncc(C(F)(F)F)cc1Cl
Reactant: NNc1ccccc1[N+](=O)[O-]
Solvent: CCO
Product: O=[N+]([O-])c1ccccc1NN=Cc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C

Procedure:
A mixture of 3-chloro-5-(trifluoromethyl)pyridine-2-carboxaldehyde (1.05 g) and 2-nitrophenylhydrazine (0.76 g) in ethanol (75 ml) was heated at reflux for 2.5 hours and then allowed to cool to room temperature overnight. The resulting orange solid was isolated by filtration and recrystallised (petrol) to afford the title compound as admixture of isomers, m.p. 127-35° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1.[NH3:19]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[NH:19])[C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][C:10]=2[OH:17])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)c2ccc(Cl)cc2)c(O)c1
Reactant: N
Solvent: CO
Product: COc1ccc(C(=N)c2ccc(Cl)cc2)c(O)c1

Procedure:
A suspension of 132 g. of 4'-chloro-2-hydroxy-4-methoxy-benzophenone in 500 ml. of methanol is cooled to -20° C. in a 2l. shaking autoclave and treated with 120 ml. of liquid ammonia. The mixture is then shaken at 120° C. for 20 hours under a nitrogen atmosphere. After cooling, the yellow crude product is filtered off under suction and washed with a small amount of methanol. There is obtained 4'-chloro-2-hydroxy-4-methoxy-benzophenone imine, having a melting point of 210°-212° C., which can be used in the next step without further purification. An analytical sample is obtained by recrystallization from methanol and has a melting point of 212°-214° C.