Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13](Br)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18].[N+:19]([C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][CH:27]=1)([O-:21])=[O:20].C(=O)([O-])[O-].[Na+].[Na+].C1(C)C=CC=CC=1>ClCCl.[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.CO>[CH3:1][N:2]1[C@H:11]2[C@@:6]([CH3:17])([C:7]3[CH:15]=[CH:14][C:13]([C:26]4[CH:25]=[CH:24][CH:23]=[C:22]([N+:19]([O-:21])=[O:20])[CH:27]=4)=[CH:12][C:8]=3[CH2:9][CH2:10]2)[CH2:5][CH2:4][C:3]1=[O:18]
Reactant: CN1C(=O)CC[C@]2(C)c3ccc(Br)cc3CC[C@@H]12
Reactant: O=[N+]([O-])c1cccc(B(O)O)c1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: CO
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cccc([N+](=O)[O-])c4)cc3CC[C@@H]12
Yield: 69.8 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-4-methyl-8-bromo-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (200 mg, 0.65 mmol), tetrakis (triphenylphosphine) palladium (0) (23 mg, 0.02 mmol), 3-nitrophenylboronic acid (130 mg, 0.78 mmol), 0.65 mL of 2M sodium carbonate solution, 1.5 mL of toluene, and 1 mL of methanol, fitted with a reflux condenser, and the stirred mixture was heated at 80°, under nitrogen, for 24 h. The mixture was cooled, diluted with dichloromethane (75 mL) and washed with brine (2×25 mL). The combined organic extracts were dried over sodium sulfate, concentrated, and purified by silica gel chromatography (ethyl acetate eluent), to give 159 mg (70%) of the title compound as a tan solid. mp 181°-183° FDMS: m/e=350. α[D]589 =+80.70 (c=1.04, chloroform).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:10]([N+:11]([O-])=O)=[C:9]([Cl:14])[C:8]([N+:15]([O-])=O)=[CH:7][C:4]=1[C:5]#[N:6].[OH-].[Na+]>>[Cl:2][C:3]1[C:10]([NH2:11])=[C:9]([Cl:14])[C:8]([NH2:15])=[CH:7][C:4]=1[C:5]#[N:6]
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1Cl
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: N#Cc1cc(N)c(Cl)c(N)c1Cl
Temperature: 25 °C

Procedure:
A solution of 330 g. (1.46 mole) of stannous chloride dihydrate in 807 ml. of concentrated hydrochloric acid is stirred and there is added 53.5 gm. (0.204 mole) of 2,4-dichloro-3,5-dinitrobenzonitrile. The temperature rises to 85° and is then allowed to cool to room temperature over a period of two hours. The mixture is cooled to 5° in an ice-bath and there is added, slowly, 50% sodium hydroxide until the mixture is strongly basic. The precipitate is removed by filtration. The filtrate is placed in a separatory funnel. The precipitate is extracted with three volumes of ethyl acetate. The combined ethyl acetate extracts are added to the aqueous filtrate and the resulting mixture shaken thoroughly for ten minutes. The phases are separated and the organic phase dried over magnesium sulfate. The drying agent is removed by filtration. The filtrate is evaporated to dryness in vacuo. The yellow solid is recrystallized from absolute ethanol to yield 33.7 g. (82%) of yellow needles melting at 189°-191°.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:18](=[O:31])[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)[N:16]=2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C>CN(C=O)C.[Pd]>[C:5]1([S:8]([CH2:11][C:12]2[S:13][CH:14]=[C:15]([C:17]3[C:18](=[O:31])[NH:19][C:20]4[C:25]([CH:26]=3)=[CH:24][CH:23]=[C:22]([C:27]([F:30])([F:29])[F:28])[CH:21]=4)[N:16]=2)(=[O:10])=[O:9])[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=1
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2cc1-c1csc(CS(=O)(=O)c2ccc(Cl)cc2)n1
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2cc1-c1csc(CS(=O)(=O)c2ccccc2)n1
Reaction time: 8 h

Procedure:
A mixture of 3-[2-(4-chloro-benzenesulfonylmethyl)-thiazol-4-yl]-7-trifluoromethyl-1H-quinolin-2-one (Example 103, 67 mg, 0.14 mmol), 0.5 mL of IPEA, and 0.1 g of Pd-C (10%) in anhydrous DMF (10 mL) was stirred under H2 overnight. The catalysts were filtered through Celite and the filtrate was concentrated. CH2Cl2 was added and precipitates were filtered, washed with MeOH, CH2Cl2 to afford the title compound as a tan solid. MS m/z: 451.2 (M+1).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[OH:11].Br[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].C(OCC)(=O)C>CN(C=O)C>[Cl:3][C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[CH:6][C:5]=1[O:11][CH:19]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:13]=1)[C:20]([O:22][CH3:23])=[O:21]
Reactant: COC(=O)Cc1ccccc1Br
Reactant: Cc1ccc(O)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)C(Oc1ccc(C)cc1Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 83.1 %

Procedure:
To a suspension of 0.282 g (7.04 mmol) of a 60% oil dispersion of sodium hydride in DMF was added 1.00 g (7.04 mmol) of 2-chloro-4-methylphenol and the mixture was stirred under an N2 atmosphere at room temperature. After 10 minutes, a solution of 1.94 g (8.45 mmol) of methyl 2-bromophenylacetate dissolved in 10 mL of DMF was added and the reaction was stirred an additional 1.5 hours. The reaction was then diluted into ethyl acetate, washed with water, dried (MgSO4), filtered and evaporated. The residue was purified on a silica gel flash chromatography column eluted with 4% ethyl acetate/hexane to afford 1.70 g (83%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1([CH2:11][CH2:12][NH:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][C:15]=2[CH3:21])[CH2:10][CH2:9][O:8][CH2:7][CH2:6]1)=O.CC(C)([O-])C.[K+].O.[Sn]>C1COCC1.C(Cl)Cl.CO>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([N:13]2[CH2:12][CH2:11][C:5]3([CH2:10][CH2:9][O:8][CH2:7][CH2:6]3)[C:3]2=[O:2])=[C:15]([CH3:21])[CH:16]=1
Reactant: COC(=O)C1(CCNc2ccc(Br)cc2C)CCOCC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Agent: [Sn]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(Br)ccc1N1CCC2(CCOCC2)C1=O
Reaction time: 0.5 h
Yield: 98.6 %

Procedure:
To a clear solution of 4-[2-(4-Bromo-2-methyl-phenylamino)-ethyl]-tetrahydro-pyran-4-carboxylic acid methyl ester (2 g, 5.6 mmol) in THF (80 mL) was added a solution of potassium t-butoxide (1M in THF) 2.5 mL (2.5 mmol, 0.45 equiv.) at r.t. (water bath at rt). The clear solution turned a little bit cloudy. After 30 min, TLC (5% MeOH in DCM) showed the reaction is complete (spot to spot), LC/MS detected the product peak of 324/326 (t 3.267 min). The reaction was cooled tin an ice-water bath, diluted with 100 mL of DCM, quenched with 20 mL of water. The two layers were separated. The aqueous layer was extracted with DCM (2×20 mL). The combined DCM extracts were washed with brine, and concentrated on rotavap to yield 1.79 g (98% yield) of the title product as a white solid.
Reaction SMILES: [CH:1]1([C:4]2[C:5](OS(C(F)(F)F)(=O)=O)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1.C([Sn](CCCC)(CCCC)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)CCC.CN(C=O)C>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.O>[CH:1]1([C:4]2[C:5]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=3)=[CH:6][C:7]([O:14][CH2:15][CH3:16])=[C:8]([CH:13]=2)[C:9]([O:11][CH3:12])=[O:10])[CH2:3][CH2:2]1
Reactant: CCOc1cc(OS(=O)(=O)C(F)(F)F)c(C2CC2)cc1C(=O)OC
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2ccccn2)c(C2CC2)cc1C(=O)OC
Temperature: 100 °C
Reaction time: 8 h
Yield: 23.8 %

Procedure:
A mixture of methyl 5-cyclopropyl-2-ethoxy-4-(((trifluoromethyl)sulfonyl)oxy)benzoate (2.5 g), 2-(tributylstannyl)pyridine (3.75 g), tetrakis(triphenylphosphine)palladium (0.784 g), and DMF (20 mL) was stirred overnight at 100° C. The reaction mixture was poured to water, followed by extraction with ethyl acetate. The obtained organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain the title compound (480 mg).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11](=[O:29])[N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)[C:7](O)=[O:8].[CH3:34][N:35]1[CH2:40][CH2:39][N:38]([CH:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH2:37][CH2:36]1>>[CH3:1][C:2]1[CH:3]=[C:4]([CH:30]=[CH:31][C:32]=1[CH3:33])[CH2:5][CH:6]([CH2:10][C:11]([N:12]1[CH2:17][CH2:16][CH:15]([N:18]2[CH2:27][C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[NH:20][C:19]2=[O:28])[CH2:14][CH2:13]1)=[O:29])[C:7]([N:44]1[CH2:45][CH2:46][CH:41]([N:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH2:37]2)[CH2:42][CH2:43]1)=[O:8]
Reactant: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)O)cc1C
Reactant: CN1CCN(C2CCNCC2)CC1
Product: Cc1ccc(CC(CC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)C(=O)N2CCC(N3CCN(C)CC3)CC2)cc1C

Procedure:
Prepared analogously to Example 76e) from 2-(3,4-dimethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,4-dihydro-2H-quinazolin-3-yl)-piperidin-1-yl]-butanoic acid and 1-methyl-4-piperidin-4-yl-piperazine
Reaction SMILES: [N+](=[CH2:3])=[N-].[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]=[CH2:20])[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(OCC)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:4]([O:11][C:12]([N:14]1[CH2:18][C@H:17]([CH:19]2[CH2:3][CH2:20]2)[C@H:16]([NH:21][C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:15]1)=[O:13])[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: C=[N+]=[N-]
Reactant: C=C[C@H]1CN(C(=O)OCc2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N[C@@H]1CN(C(=O)OCc2ccccc2)C[C@@H]1C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
An excessive amount of a solution of diazomethane in diethyl ether (30 mL) was added to (3S,4S)-1-benzyloxycarbonyl-3-(tert-butoxycarbonyl)amino-4-vinylpyrrolidine (270 mg, 779 mmol). Under cooling with ice, palladium acetate (10 mg) was added thereto, followed by stirring at room temperature for 2 hours. After completion of reaction, insoluble matter was removed through filtration. The filtrate was concentrated under reduced pressure, and the obtained residue was purified though silica gel column chromatography (ethyl acetate:n-hexane=1:9 to 1:4), to thereby yield the title compound as a colorless oily substance (269 mg, 96%).
Reaction SMILES: Cl.N(OCCC(C)C)=O.[CH3:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]([NH:20][C@H:21]([C:28]([N:30]=[N+]=[N-])=[O:29])[CH2:22][C:23]2[N:27]=[CH:26][NH:25][CH:24]=2)=[O:19])=[CH:14][CH:13]=1.[N-]=[N+]=[N-].Cl.N[C@@H:40]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH:41]([OH:48])[C:42]([O:44][CH:45]([CH3:47])[CH3:46])=[O:43]>CN(C)C=O.C(N(CC)CC)C>[CH3:10][O:11][C:12]1[CH:34]=[CH:33][C:15]([CH2:16][O:17][C:18]([NH:20][C@H:21]([C:28]([NH:30][C@@H:40]([CH2:49][CH:50]([CH3:52])[CH3:51])[CH:41]([OH:48])[C:42]([O:44][CH:45]([CH3:46])[CH3:47])=[O:43])=[O:29])[CH2:22][C:23]2[N:27]=[CH:26][NH:25][CH:24]=2)=[O:19])=[CH:14][CH:13]=1
Reactant: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N=[N+]=[N-])cc1
Reactant: CC(C)C[C@H](N)C(O)C(=O)OC(C)C
Agent: CC(C)CCON=O
Agent: Cl
Agent: [N-]=[N+]=[N-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc(COC(=O)N[C@@H](Cc2c[nH]cn2)C(=O)N[C@@H](CC(C)C)C(O)C(=O)OC(C)C)cc1
Reaction time: 16 h

Procedure:
To a suspension of the hydrazide compound in 5 ml of N,N-dimethylformamide were added successively 0.90 ml of a dry 5.1N-hydrogen chloride in N,N-dimethylformamide solution and 0.23 ml of isoamyl nitrite at -20° C. with stirring. After disappearance of hydrazide compound, the reaction mixture was cooled to -30° C., and then the reaction mixture was neutralized by adding 0.67 ml of triethylamine to prepare a solution of N-(4-methoxybenzyloxycarbonyl)-L-histidine azide. The cold azide solution was added dropwise to a solution of 350 mg of isopropyl (2RS,3S)-3-amino-2-hydroxy-5-methylhexanoate hydrochloride and 0.46 ml of triethylamine in 8 ml of dry N,N-dimethylformamide under ice-cooling, and the mixture was stirred for 16 hours. The reaction mixture was concentrated under reduced pressure, and to the residue was added a 5% aqueous sodium bicarbonate solution. The mixture was extracted with ethyl acetate, and the ethyl acetate layer was washed with a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified with silica gel flash column chromatography (eluent: chloroform/methanol=20:1 by volume) to obtain 325 mg of isopropyl (2RS,3S)-3-[N-(4-methoxybenzyloxycarbonyl)-L-histidyl]amino-2-hydroxy-5-methylhexanoate as a white powder. To a solution of 320 mg of the isopropyl ester compound in 46 ml of isopropyl alcohol were added 300 mg of p-toluenesulfonic acid (anhydride) and 48 mg of a 10% palladium charcoal. The mixture was hydrogenated under a hydrogen atmosphere at room temperature. After filtration of the reaction mixture, the filtrate was concentrated under reduced pressure to obtain 513 mg of isopropyl (2RS,3S)-3-(L-histidyl)amino-2-hydroxy-5-methylhexanoate.2p-toluene sulfonic acid salt as a white powder.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28](Br)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2].[CH:34]([N:37]1[CH:41]=[C:40](B2OC(C)(C)C(C)(C)O2)[CH:39]=[N:38]1)([CH3:36])[CH3:35]>>[C:1]([O:5][C:6](=[O:33])[CH2:7][O:8][C:9]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]2[C:10]=1[C:11]([CH3:32])=[C:12]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:40]3[CH:39]=[N:38][N:37]([CH:34]([CH3:36])[CH3:35])[CH:41]=3)=[CH:27][CH:26]=1)[C:13]([O:20][CH:21]([F:23])[F:22])=[N:14]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1c(Cc2ccc(Br)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12
Product: Cc1c(Cc2ccc(-c3cnn(C(C)C)c3)cc2)c(OC(F)F)nc2c(Cl)ccc(OCC(=O)OC(C)(C)C)c12

Procedure:
The title compound was prepared by the method of Preparation 22b using [3-(4-bromobenzyl)-8-chloro-2-difluoromethoxy-4-methylquinolin-5-yloxy]acetic acid tert-butyl ester and 1-isopropyl-4-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrazole.
Reaction SMILES: Cl.[CH:2]([C:5]1[CH:6]=[C:7]([C@@H:11]([NH2:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1)([CH3:4])[CH3:3].[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](O)=[O:30])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]>>[Cl:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][N:20]2[C:28]3[C:23](=[CH:24][C:25]([C:29](=[O:30])[NH:13][C@H:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([CH:2]([CH3:4])[CH3:3])[CH:6]=4)[CH3:12])=[CH:26][CH:27]=3)[C:22]([CH3:32])=[C:21]2[CH3:33])=[CH:17][C:16]=1[O:36][C@@H:37]([CH2:42][CH3:43])[C:38]([O:40][CH3:41])=[O:39]
Reactant: CC(C)c1cccc([C@H](C)N)c1
Reactant: CC[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)O)ccc32)ccc1Cl)C(=O)OC
Agent: Cl
Product: CC[C@H](Oc1cc(Cn2c(C)c(C)c3cc(C(=O)N[C@@H](C)c4cccc(C(C)C)c4)ccc32)ccc1Cl)C(=O)OC

Procedure:
The title compound was prepared following the same protocol as described in Step 5, Example 36, using the (S)-1-(3-isopropylphenyl)ethanamine hydrochloride instead of the (S)-1-(3-cyclopropylphenyl)ethanamine hydrochloride and the (S)-1-(4-chloro-3-((1-methoxy-1-oxobutan-2-yl)oxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid instead of the 1-(4-(2-methoxy-2-oxoethoxy)benzyl)-2,3-dimethyl-1H-indole-5-carboxylic acid.
Reaction SMILES: C(OC=C(C(=O)C1C=C(F)C(F)=CC=1F)C(OCC)=O)C.NC1CC1F.FC(F)(F)C([O-])=O.[F:34][C@H:35]1[CH2:37][C@H:36]1[NH:38][CH:39]=[C:40]([C:46](=[O:56])[C:47]1[CH:52]=[C:51]([F:53])[C:50]([F:54])=[CH:49][C:48]=1F)[C:41]([O:43][CH2:44][CH3:45])=[O:42].[H-].[Na+]>O1CCOCC1.C(N(CC)CC)C>[F:34][CH:35]1[CH2:37][CH:36]1[N:38]1[C:48]2[C:47](=[CH:52][C:51]([F:53])=[C:50]([F:54])[CH:49]=2)[C:46](=[O:56])[C:40]([C:41]([O:43][CH2:44][CH3:45])=[O:42])=[CH:39]1
Reactant: CCOC(=O)C(=CN[C@@H]1C[C@@H]1F)C(=O)c1cc(F)c(F)cc1F
Agent: CCOC=C(C(=O)OCC)C(=O)c1cc(F)c(F)cc1F
Agent: NC1CC1F
Agent: O=C([O-])C(F)(F)F
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2F)c2cc(F)c(F)cc2c1=O

Procedure:
As for the method for producing the starting materials, an example for the preparation of the compound (IIa) is described below: ##STR7## That is, ethyl 3-ethoxy-2-(2,4,5-trifluorobenzoyl)acrylate (VIa; R4 =C2H5) is reacted with 1-amino-2-fluorocyclopropane (or an acid addition salt thereof such as trifluoroacetate in the presence of at least a molar equivalent of a proper base such as triethylamine), and the resulting ethyl 3-(cis-2-fluorocyclopropyl)amino-2-(2,4,5-trifluorobenzoyl)acrylate (VIIa; R4 =C2H5) can be reacted with approximately a molar equivalent of sodium hydride in a solvent such as anhydrous dioxane at a temperature of from 20° C. to 50° C. to yield ethyl 1-(2-fluorocyclopropyl)-6,7-difluoro-1,4-dihydro-4-oxoquinoline-3-carboxylate (IIa; R4 =C2H5) in good yield.
Reaction SMILES: [OH-].[Na+].[NH:3]=[C:4]1[CH:9]=[C:8]([CH3:10])[CH:7]=[C:6]([CH3:11])[N:5]1[NH2:12].[C:13](OC)(=O)[CH2:14][OH:15]>C(O)C>[CH3:11][C:6]1[N:5]2[N:12]=[C:13]([CH2:14][OH:15])[N:3]=[C:4]2[CH:9]=[C:8]([CH3:10])[CH:7]=1
Reactant: COC(=O)CO
Reactant: Cc1cc(C)n(N)c(=N)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cc(C)n2nc(CO)nc2c1
Temperature: 55 °C
Reaction time: 1 h
Yield: 10 %

Procedure:
To a solution of 0.79 g of sodium hydroxide in ethanol (20 mL) was added 2-imino-4,6-dimethyl-2H-pyridin-1-ylamine (1.7 g, 0.012 mol; obtained by HPLC purification of intermediate 10). After being stirred at 50-60° C. for 1 hour, methyl glycolate (1.4 g, 0.016 mop was added, and the resulting mixture was stirred at reflux for 6 hours. After removal of the solvent under reduced pressure, the residue was purified by column chromatography on silica gel (ethyl acetate) to afford (5,7-Dimethyl-[1,2,4]triazolo[1,5-a]pyridin-2-yl)-methanol (0.2 g, 10%); 1H NMR (300 MHz, DMSO-d6): δ 7.39 (s, 1H), 6.87 (s, 1H), 5.38 (t, J=6.3 Hz, 1H), 4.59 (d, J=6.3 Hz, 2H), 2.64 (s, 3H), 2.38 (s, 3H). A mixture of this compound (31 mg, 0.175 mmol) and SOCl2 (10 mL) in dry CH2Cl2 (10 mL) was stirred at room temperature for 2 hours. The solvent and excess SOCl2 was evaporated under vacuum to yield the title compound as a crude product, which was used for the preparation of final compounds without purification or characterization.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][OH:10])=[CH:7][CH:6]=1.Cl[C:14]1[C:19]([C:20]([O:22][CH2:23][CH3:24])=[S:21])=[CH:18][N:17]=[C:16]([CH3:25])[N:15]=1>O1CCCC1>[CH3:3][O:4][C:5]1[CH:12]=[CH:11][C:8]([CH2:9][O:10][C:18]2[C:19]([C:20]([O:22][CH2:23][CH3:24])=[S:21])=[CH:14][N:15]=[C:16]([CH3:25])[N:17]=2)=[CH:7][CH:6]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOC(=S)c1cnc(C)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=S)c1cnc(C)nc1OCc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 103.7 %

Procedure:
An ice-cooled suspension of 2.1 g (53 mmol) of sodium hydride (60% w/w dispersion in mineral oil) in 120 ml of tetrahydrofuran was treated dropwise with a solution of 6.5 g (47 mmol) of 4-methoxybenzyl alcohol in 40 ml of tetrahydrofuran. After 30 minutes, a solution of 10 g (43 mmol) of ethyl 4-chloro-2-methylthiopyrimidine-5-carboxylate was added slowly. After a further 40 minutes the reaction was quenched by the cautious addition of 60 ml of saturated aqueous ammonium chloride. The mixture was separated and the organic phase dried over magnesium sulfate, filtered and evaporated to give 14.2 g (99%) of ethyl 4-(4-methoxy-benzyloxy)-2-methylthiopyrimidine-5-carboxylate as a pale yellow oil. [Mass spectrum (ESI) MH+ =335].
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]([C:31]1[S:35][N:34]=[CH:33][N:32]=1)[S:7]([C:10]1[CH:15]=[C:14]([F:16])[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:12][C:11]=1[F:30])(=[O:9])=[O:8].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>ClCCl>[F:30][C:11]1[CH:12]=[C:13]([O:17][C@H:18]2[CH2:23][CH2:22][CH2:21][CH2:20][C@@H:19]2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:14]([F:16])=[CH:15][C:10]=1[S:7]([NH:6][C:31]1[S:35][N:34]=[CH:33][N:32]=1)(=[O:9])=[O:8]
Reactant: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc(F)c(O[C@H]3CCCC[C@@H]3c3ccccc3)cc2F)c(OC)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(Nc1ncns1)c1cc(F)c(O[C@H]2CCCC[C@@H]2c2ccccc2)cc1F
Yield: 74.1 %

Procedure:
The reaction and aftertreatment were conducted in the same manner as in Example 1b by using the N-(2,4-dimethoxybenzyl)-2,5-difluoro-4-{[(1S,2R)-2-phenylcyclohexyl]oxy}-N-(1,2,4-thiadiazol-5-yl)benzenesulfonamide (55.7 mg, 0.0926 mmol) prepared in Example 2a, triethylsilane (0.10 mL), trifluoroacetic acid (1.0 mL) and dichloromethane (1.0 mL), to yield the title compound (31.0 mg, 74%) as a colorless solid.
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.S(Cl)([Cl:26])=O.O>ClCCl>[Cl:26][CH2:2][C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: O=S(Cl)Cl
Reactant: CCCCCCOc1ccc(/C=C/c2ccc(CO)cc2)cc1
Solvent: ClCCl
Solvent: O
Product: CCCCCCOc1ccc(/C=C/c2ccc(CCl)cc2)cc1
Yield: 60 %

Procedure:
To a solution of 1.7 g (5.5 mmole) of (E)-4-hydroxymethyl-4′-hexyloxystilbene (7) in 12 ml of dichloromethane cooled in an ice bath under N2 atmosphere were added dropwise 0.5 ml of thionylchloride in 3 ml of dichloromerthane. After 1.5 h 16 ml of water were added and the organic layer was separated. It was washed with 12 ml of brine, dried over MgSO4 and the solvent was evaporated. A white solid was obtained which was recrystallized from 80 ml of a 1:1 mixture of hexane and ethanol. 1.1 g of white crystals were obtained (yield: 60%).
Reaction SMILES: C([N:8]1[CH2:12][C@@H:11]([O:13][CH3:14])[C@H:10]([NH:15][CH2:16]CC2C=CC=CC=2)[CH2:9]1)C1C=CC=CC=1.[ClH:24]>CO.[Pd]>[ClH:24].[ClH:24].[CH3:14][O:13][C@@H:11]1[CH2:12][NH:8][CH2:9][C@H:10]1[NH:15][CH3:16]
Reactant: CO[C@@H]1CN(Cc2ccccc2)C[C@H]1NCCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CN[C@@H]1CNC[C@H]1OC

Procedure:
9.3 g (29 mmol) of trans-1-benzyl-3-benzylmethylamino-4-methoxy-pyrrolidine are dissolved in 100 ml of methanol, 4.8 ml of concentrated hydrochloric acid are added and the mixture is hydrogenated on 4 g of 10% strength Pd-on-active charcoal at 90° C. under 100 bar. The catalyst is filtered off with suction, the filtrate is concentrated and the residue is recrystallized from isopropanol/methanol.