Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:21]=[CH:20][N:19]=[CH:18][CH:17]=2)=[C:11]([CH:15]=1)[C:12]([OH:14])=O.[F:32][C:33]([F:42])([F:41])[C:34]1[CH:40]=[CH:39][C:37]([NH2:38])=[CH:36][CH:35]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C>C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[CH:18][N:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([NH:38][C:37]1[CH:39]=[CH:40][C:34]([C:33]([F:32])([F:41])[F:42])=[CH:35][CH:36]=1)=[O:14]
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1c(C)c(Cc2ccc(-c3ccncc3)c(C(=O)Nc3ccc(C(F)(F)F)cc3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 62.2 %

Procedure:
To a solution of 5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(4-pyridyl)benzoic acid (200 mg, 0.4716 mmol) in methylene chloride (10 ml) were added 4-trifluoromethylaniline (114 mg, 0.7080 mmol), triethylamine (95 mg, 0.9405 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (239 mg, 1.4142 mmol) followed by stirring at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (166 mg, 0.2932 mmol, 62%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([Br:11])[C:8](Br)=[N:7][CH:6]=1)[CH3:2].[CH2:14](B(O)O)[CH3:15].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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>[Br:11][C:9]1[C:8]([CH2:14][CH3:15])=[N:7][CH:6]=[C:5]([CH:10]=1)[C:4]([O:3][CH2:1][CH3:2])=[O:13]
Reactant: CCOC(=O)c1cnc(Br)c(Br)c1
Reactant: CCB(O)O
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: [K+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc(CC)c(Br)c1
Temperature: 110 °C
Yield: 38 %

Procedure:
Method-2: A solution of ethyl-5,6-dibromonicotinate (6.0 g, 19.4 mmol, 1.0 eq; prepared by following the procedure described in WO2011024004), ethylboronic acid (1.72 g, 23.3 mmol, 1.2 eq) and potassium carbonate (8.0 g, 58.3 mmol, 3.0 eq) in 1,4-dioxane (10 mL) in a oven dried sealed tube was subjected to three cycles of evacuation-backfilling with argon, and then tetrakis(triphenylphosphine)palladium(0) (2.24 g, 1.94 mmol, 0.1 eq) was added. The sealed tube was sealed and the mixture was stirred and heated in an oil bath to 110° C. After three days of stirring at the same temperature, the reaction was cooled to RT and filtered through Celite®. The filtrate was evaporated and the resultant residue was purified by flash column chromatography (silica gel, ethyl acetate-hexane system as eluent) to afford 1.90 g (38%) of the desired product as a white solid. 1HNMR (400 MHz, CDCl3) δ 9.06 (d, J=1.5 Hz, 1H), 8.40 (d, J=1.5 Hz, 1H), 4.42 (q, J=7.0 Hz, 2H), 3.05 (q, J=7.0 Hz, 2H), 1.43 (t, J=7.0 Hz, 3H), 1.28 (t, J=7.0 Hz, 3H); GC-MS (m/z) 257, 259 [M+, Br79,81].
Reaction SMILES: Br[CH:2]([CH3:6])[CH2:3][CH:4]=[CH2:5].[Mg].Cl[SiH:9]1[CH2:14][CH2:13][CH:12]([C@H:15]2[CH2:20][CH2:19][C@H:18]([CH2:21][CH2:22][C:23]3[CH:28]=[CH:27][C:26]([F:29])=[C:25]([F:30])[CH:24]=3)[CH2:17][CH2:16]2)[CH2:11][CH2:10]1>C1COCC1>[F:30][C:25]1[CH:24]=[C:23]([CH2:22][CH2:21][C@H:18]2[CH2:19][CH2:20][C@H:15]([C@H:12]3[CH2:13][CH2:14][Si@H:9]([CH2:5][CH2:4][CH2:3][CH:2]=[CH2:6])[CH2:10][CH2:11]3)[CH2:16][CH2:17]2)[CH:28]=[CH:27][C:26]=1[F:29]
Reactant: C=CCC(C)Br
Reactant: Fc1ccc(CC[C@H]2CC[C@H](C3CC[SiH](Cl)CC3)CC2)cc1F
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CCCC[Si@H]1CC[C@H]([C@H]2CC[C@H](CCc3ccc(F)c(F)c3)CC2)CC1

Procedure:
3.0 g (20 mmol) of 4-bromopentene was dripped into a mixture of 0.5 g (21 mmol) of magnesium and 50 ml of THF to obtain a Grignard's reagent. This solution was then dripped into a 50 ml THF solution of 7.1 g of 1-chloro-4-(trans-4-(2 -(3,4-difluorophenyl) ethyl) cyclohexyl)-1-silacyclohexane. The silacyclohexane rings of the reacted mixture thus obtained were a mixture of trans isomers and cis isomers. After a conventional after treatment, they were separated by means of chromatography to obtain 6.5 g (yield 83%) of trans-4-(trans-4-(2-(3,4-difluorophenyl) ethyl) cyclohexyl)-1-(4-pentenyl)-1-silacyclohexane.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([OH:14])=O)=[N:10][CH:11]=1.CN.C1COCC1.C1C=CC2N(O)N=[N:32][C:30]=2C=1.Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.C(OCC)(=O)C>[NH2:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[F:18])[O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]([NH:32][CH3:30])=[O:14])=[N:10][CH:11]=1
Reactant: On1nnc2ccccc21
Reactant: Nc1cc(Oc2ccc(C(=O)O)nc2)ccc1F
Agent: CCN=C=NCCCN(C)C
Agent: CN
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Oc2ccc(F)c(N)c2)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101 %

Procedure:
In DMF (5 mL) was placed 5-(3-amino-4-fluorophenoxy)picolinic acid from Example A12 (500 mg, 2.01 mmol), 2.0 M methylamine solution/THF (10 mL, 20.1 mmol) and HOBt (324 mg, 2.12 mmol). To this was added N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (772 mg, 4.03 mmol) and the solution stirred overnight at RT. The solution was treated with an additional equiv of N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (775 mg) and warmed to 40° C., then cooled to RT and stirred overnight. The solution was diluted with ethyl acetate (30 mL) and washed with water (30 mL), brine (30 mL), dried (Na2SO4) and concentrated in vacuo to yield 5-(3-amino-4-fluorophenoxy)-N-methylpicolinamide (530 mg, 101% yield) as a thick oil, which was used without further purification. MS (ESI) m/z: 262.0 (M+H+).
Reaction SMILES: [C:1](OC=C)(=O)[CH3:2].[CH3:7][C:8]1([CH3:20])[C@@H:10](/[CH:11]=[C:12](/[F:16])\[C:13](=[O:15])[OH:14])[C@H:9]1[C:17]([OH:19])=[O:18]>>[CH3:7][C:8]1([CH3:20])[C@@H:10](/[CH:11]=[C:12](/[F:16])\[C:13](=[O:14])[O:15][CH:1]=[CH2:2])[C@H:9]1[C:17]([OH:19])=[O:18]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C(/F)C(=O)O
Reactant: C=COC(C)=O
Product: C=COC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C

Procedure:
Vinyl acetate and (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-hydroxy-1-propenyl]-cyclopropane carboxylic acid were reacted in the presence of mercuric acetate as a catalyst to obtain (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-ethenyloxy-1-propenyl]-cyclopropane carboxylic acid which was reacted with benzyl alcohol to obtain benzyl (1R,cis,E) 2,2-dimethyl-3-[2-fluoro-3-oxo-3-ethenyloxy-1-propenyl]-cyclopropanecarboxylate with a specific rotation of [α]D20 =+26° (c=1.2% in chloroform).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([I:9])=[C:5]([O:10][CH3:11])[CH:4]=1)#[CH:2].[N:12]([CH:15]1[CH2:21][CH2:20][C:19]2[C:22]([F:26])=[CH:23][CH:24]=[CH:25][C:18]=2[NH:17][C:16]1=[O:27])=[N+:13]=[N-:14].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+].CCO>ClCCl.O.CN(C=O)C>[F:26][C:22]1[C:19]2[CH2:20][CH2:21][CH:15]([N:12]3[CH:2]=[C:1]([C:3]4[CH:8]=[CH:7][C:6]([I:9])=[C:5]([O:10][CH3:11])[CH:4]=4)[N:14]=[N:13]3)[C:16](=[O:27])[NH:17][C:18]=2[CH:25]=[CH:24][CH:23]=1
Reactant: [N-]=[N+]=NC1CCc2c(F)cccc2NC1=O
Reactant: C#Cc1ccc(I)c(OC)c1
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(-c2cn(C3CCc4c(F)cccc4NC3=O)nn2)ccc1I
Temperature: 25 °C
Reaction time: 17 h
Yield: 95.1 %

Procedure:
4-Ethynyl-1-iodo-2-methoxy-benzene (22.23 g, 86 mmol), 3-azido-6-fluoro-1,3,4,5-tetrahydro-1-benzazepin-2-one (20.87 g, 95 mmol), and sodium ascorbate (15.69 g, 86 mmol) were added to EtOH (155 mL) and DMF (155 mL). CuSO4.5H2O (10.75 g, 43.1 mmol) was added to 20 mL water and added dropwise to the stirring reaction mixture. The reaction stirred for 17 hrs at room temp. Dichloromethane was added and the organic layer was washed with 2N NaOH, dried with sodium sulfate and concentrated. Purification on silica gel (dichloromethane:methanol, 1-15%). 6-Fluoro-3-[4-(4-iodo-3-methoxy-phenyl)-1,2,3-triazol-1-yl]-1,3,4,5-tetrahydro-1-benzazepin-2-one (39.1 g) was obtained as a colorless solid and carried on the next step.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][CH2:3]1.[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:7]1[CH:6]=[C:5]2[C:10]([CH2:11][C:2]([CH3:12])([CH3:1])[CH2:3][NH:4]2)=[CH:9][CH:8]=1)([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CC1(C)CNc2ccccc2C1
Product: CC1(C)CNc2cc([N+](=O)[O-])ccc2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.1 %

Procedure:
1,2,3,4-Tetrahydro-3,3-dimethylquinoline (51 mg, 0.32 mmol) was dissolved in sulfuric (0.5 mL) and the temperature lowered to 0° C. To this solution 90% fuming nitric acid (14 mL, 0.32 mmol) was added slowly and the mixture stirred at 0° C. for 1 h, then warmed to rt. The reaction mixture was then poured onto 1 g of ice and extracted with dichloromethane (2×5 mL). The organic phase was washed with saturated aqueous NaHCO3 (3 mL) and concentrated in vacuo to a reddish residue that was subjected to chromatography (silica gel, hexanes/ethyl acetate, 85:15) which afforded 39 mg (58%) of 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline. Data for 7-nitro-1,2,3,4-tetrahydro-3,3-dimethylquinoline: 1H NMR (400 MHz, CDCl3) 7.40 (dd, J=8.3, 2.1, 1H), 7.29 (d, J=1.8, 1H), 7.01 (d, J=8.3H, 1H), 4.25 (s, 1H), 2.98 (s, 2H), 2.54 (s, 2H), 1.01 (s, 6H).
Reaction SMILES: [C:1]1(=O)[O:6][C:4](=[O:5])[CH:3]2[CH2:7][CH:8]=[CH:9][CH2:10][CH:2]12.[H-].[Al+3].[Li+].[H-].[H-].[H-].[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>O1CCCC1>[CH:2]1([CH2:1][OH:6])[CH2:10][CH:9]=[CH:8][CH2:7][CH:3]1[CH2:4][OH:5]
Reactant: O=C1OC(=O)C2CC=CCC12
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1CC=CCC1CO
Yield: 82 %

Procedure:
A solution of one hundred (100) parts by weight of a 1,2,3,6-tetrahydrophthalic anhydride in 500 parts of dry tetrahydrofuran is slowly added to a stirring mixture of 28.75 parts of lithium aluminum hydride and 162 parts of tetrahydrofuran. After the addition is complete, the mixture is refluxed for 24 hours. It is then hydrolyzed by a slow addition of a saturated Rochelle salt solution until it turns white. The mixture is refluxed for an additional 10 hours, allowed to room temperature, and suction filtered. The solvent is removed by a distillation and the viscous liquid crude product is purified by a fractional distillation under vacuum (yield 82%. b.p.: 165-170° C. at 12 mm).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[CH:18]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:21][OH:22].N1C=CC=CC=1>CCO>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][CH:10]1[CH2:11][CH2:12][CH:13]2/[CH:18]=[N:21]/[OH:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NO
Reactant: O=C[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: O=C1N2CC(CCC2/C=N/O)N1OCc1ccccc1
Yield: 42.3 %

Procedure:
A solution of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde (510 mg, 1.96 mmol), hydroxylamine hydrochloride (158 mg, 2.27 mmol) and pyridine (621 mg, 7.85 mmol) in EtOH (15 mL) was stiffed at rt for 2 hrs. Then, the reaction mixture was concentrated and the residue was diluted with DCM (25 mL), washed with water (3×), and saturated sodium chloride, dried over Na2SO4 and concentrated. The residue was purified by silica gel column chromatography (3:1 to 3:2 petroleum ether/EtOAc) to afford (E)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carbaldehyde oxime (228 mg, 42%) as a white solid. ESI-MS (EI+, m/z): 276 [M+H]+.
Reaction SMILES: O[C:2]1[CH2:7][CH2:6][C:5]([CH3:9])([CH3:8])[CH2:4][C:3]=1[C:10]([O:12]C)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:22]=[CH:23][C:24]=1[Br:25])[C:18]([O:20][CH3:21])=[O:19].O1CCOCC1>O>[Br:25][C:24]1[C:15]2[NH:14][C:2]3[CH2:7][CH2:6][C:5]([CH3:8])([CH3:9])[CH2:4][C:3]=3[C:10](=[O:12])[C:16]=2[C:17]([C:18]([O:20][CH3:21])=[O:19])=[CH:22][CH:23]=1
Reactant: COC(=O)C1=C(O)CCC(C)(C)C1
Reactant: COC(=O)c1ccc(Br)c(N)c1
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(Br)c2[nH]c3c(c(=O)c12)CC(C)(C)CC3
Temperature: 130 °C
Yield: 26.7 %

Procedure:
A mixture of methyl 2-hydroxy-5,5-dimethylcyclohex-1-enecarboxylate (26 g, 0.141 mol), methyl 3-amino-4-bromobenzoate (25 g, 0.109 mol), polyphosphoric acid (220 g) and dioxane (220 mL) was heated at 130° C. for 5 hours. After cooling, the mixture was diluted with water. The resulting precipitate was collected by filtration and dried. The solid was suspended in methanol (400 mL), and TMSCl (90 mL) was added. The mixture was stirred at reflux for 5 hours, concentrated and treated with water (80 mL), extracted with ethyl acetate (250 mL). The organic layer was separated, concentrated and recrystallized with methanol to afford desired compound (10.6 g, 27%). 1H NMR (DMSO-d6) δ 10.32 (s, 1H), 7.98 (d, 1H, J=7.2 Hz), 7.10 (d, 1H, J=7.2 Hz), 3.80 (s, 3H), 2.90 (t, 2H, J=6.6 Hz), 2.22 (s, 2H), 1.56 (t, 2H, J=6.6 Hz), and 0.97 (s, 6H). MS (ESI) m/e [M+1]+364.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:18]([O:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19].CCCCC>C(Cl)Cl.C(OCC)C>[C:6]([C:5]1[CH:9]=[CH:10][C:2]([NH:1][C:18](=[O:19])[O:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:3][CH:4]=1)(=[O:7])[NH2:8]
Reactant: NC(=O)c1ccc(N)cc1
Reactant: O=C(Cl)Oc1ccccc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: c1ccncc1
Product: NC(=O)c1ccc(NC(=O)Oc2ccccc2)cc1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 76.6 %

Procedure:
To a solution of 4-aminobenzamide (5.0 g, 36.7 mmol) and pyridine (2.9 g, 36.7 mmol)) in dry CH2Cl2 (100 mL) at −10° C., phenyl chloroformate (6.9 g, 44.1 mmol) was added dropwise, stirred at −10° C. for 30 min and then at room temperature for 30 minutes The reaction mixture was diluted with CH2Cl2 (100 mL) and washed with water (2×70 mL). The organic layer was dried over anhydrous Na2SO4 and concentrated to get the crude product. The crude product was dissolved in diethyl ether (15 mL) and sonicated for 10 minutes and then pentane (30 mL) was added, the resulting solid was filtered and washed with pentane to give phenyl 4-carbamoylphenylcarbamate (7.2 g, 77% yield).
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:15]=[CH:16][C:17]([N+:21]([O-])=O)=[C:18]([NH2:20])[CH:19]=2)[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]>C(O)C.[Pd]>[NH2:20][C:18]1[CH:19]=[C:14]([C:10]2([CH3:13])[CH:9]3[CH:11]2[CH2:12][N:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH2:8]3)[CH:15]=[CH:16][C:17]=1[NH2:21]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccc([N+](=O)[O-])c(N)c1
Agent: [Pd]
Solvent: CCO
Product: CCCCCCN1CC2C(C1)C2(C)c1ccc(N)c(N)c1
Temperature: 50 °C
Yield: 100.1 %

Procedure:
To a solution of 5-(3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)-2-nitrophenylarnine (Preparation 47, 360 mg, 1.14 mmol) in ethanol (15 ml) was added 10% palladium on carbon (50 mg). The mixture was placed under an atmosphere of hydrogen (50 psi, 345 kPa) and heated at 50° C. for 16 hours. The mixture was then cooled and filtered through Celite™, washing with ethanol. The filtrate was concentrated in vacuo to give the crude title compound (328 mg, 100%) as a yellow oil which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([O:15]CC)=[O:14])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].P(=O)(O)(O)O>O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:12][CH2:11][S:10][CH:9]2[C:13]([OH:15])=[O:14])=[O:7])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C1SCCN1C(=O)c1ccc(F)cc1
Agent: O=P(O)(O)O
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: O=C(O)C1SCCN1C(=O)c1ccc(F)cc1
Temperature: 50 °C

Procedure:
Ethyl 3-(4-fluorobenzoyl)thiazolidinecarboxylate (28.33 g, 0.1 mol) is suspended in ethanolic KOH (5% strength, 165 ml, 0.15 mol) and the mixture is subsequently heated at 50° C. (IT) for 2 h. The cooled solution is acidified (pH 2-3) with water (100 ml) and dil. phosphoric acid (8%, 150 ml). Precipitated salts are brought into solution again by addition of water (150 ml). This aqueous solution is extracted with diethyl ether (500 ml), the ethereal extracts are washed with sat. NaCl solution (100 ml), dried over Na2SO4 (sicc.) and concentrated in vacuo. The residue is crystallized from diisopropyl ether (40 ml): 24.87 g.
Reaction SMILES: C([N:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)=[CH:16][C:11]=2[N:10]=[CH:9]1)(OC(C)(C)C)=O.C([O-])([O-])=O.[K+].[K+].[CH2:33](Br)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CN(C=O)C.O>[CH3:26][O:25][C:22]1[CH:21]=[CH:20][C:19]([CH2:18][N:17]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:15]2[CH:14]=[CH:13][C:12]3[N:8]=[CH:9][NH:10][C:11]=3[CH:16]=2)=[CH:24][CH:23]=1
Reactant: COc1ccc(CNc2ccc3c(c2)ncn3C(=O)OC(C)(C)C)cc1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(CN(Cc2ccccc2)c2ccc3nc[nH]c3c2)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
N1-Boc-N-(4-methoxybenzyl)benzimidazol-5-amine (353 mg; 1 mmol; 1 eq.) was dissolved in DMF (5 ml), treated with K2CO3 (166 mg; 1.2 mmol; 1.2 eq.) and benzylbromide (0.143 ml; 1.2 mmol; 1.2 eq.) and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The remains were taken up with THF (5 ml), treated with 5 N NaOCH3 and stirred for 2 h at room temperature. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.049 g (14.3%); MS m/z: 344.1 [M+H]+; 1H-NMR (500 MHz, DMSO d6): δ 3.70 (s, 3H); 4.60 (s, 2H), 4.64 (s, 2H); 6.71 (d, 1H, 4J=2.1 Hz); 6.77 (dd, 1H, 4J=2.1 Hz, 3J=8.9 Hz); 6.85-6.88 (m, 2H); 7.19-7.22 (m, 3H); 7.26-7.32 (m, 4H); 7.34 (d, 1H, 3J=8.9 Hz); 7.99 (s, 1H); HPLC (METHOD [A]): rt 15.26 min (99.8%)
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:4][C:3]=1[N+:16]([O-])=O.[H][H]>CO>[NH2:16][C:3]1[CH:4]=[CH:5][C:6]([S:8]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[O:9])=[CH:7][C:2]=1[NH2:1]
Reactant: [H][H]
Reactant: Nc1cc(S(=O)c2ccccc2)ccc1[N+](=O)[O-]
Solvent: CO
Product: Nc1ccc(S(=O)c2ccccc2)cc1N

Procedure:
5.4 G. of 2-amino-4-phenylsulfinyl-1-nitrobenzene is hydrogenated at 1 atmosphere pressure in 500 ml. methanol in the presence of 5 g. 5% palladized carbon, until the theoretical uptake of hydrogen has occurred. The catalyst is removed by filtration and the filtrate stripped under vacuum. The residue is recrystallized from methanol-benzene, yielding 1,2-diamino-4-phenylsulfinylbenzene.
Reaction SMILES: [C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:3])[NH2:2].[CH2:15]([NH2:18])[CH2:16][NH2:17]>>[C:1]([C:4]1[CH:14]=[CH:13][CH:12]=[CH:11][C:5]=1[O:6][CH2:7][CH:8]([OH:10])[CH2:9][NH:17][CH2:16][CH2:15][NH2:18])(=[O:3])[NH2:2]
Reactant: NCCN
Reactant: NC(=O)c1ccccc1OCC1CO1
Product: NCCNCC(O)COc1ccccc1C(N)=O
Reaction time: 1 h

Procedure:
1-(o-Carbamoylphenoxy)-2,3-epoxypropane (20 g.) is added to ethylenediamine (125 ml.) and the mixture is stirred at laboratory temperature for 1 hour and then evaporated to dryness under reduced pressure. The residue is stirred with water (150 ml.), the mixture is filtered and the filtrate is evaporated to dryness under reduced pressure. The residue is crystallised from acetonitrile and there is thus obtained a residue 1-(o-carbamoylphenoxy)-3-(β-aminoethyl)aminopropan-2-ol, m.p. 91°-93° C.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH:9]2[C:13](=[O:14])[C:12](=[CH:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:4]([CH3:23])[CH:3]=1.[H][H]>CO.[C].[Pt]>[Br:1][C:2]1[CH:3]=[C:4]([CH3:23])[C:5]([CH:9]2[C:13](=[O:14])[CH:12]([CH2:15][CH:16]3[CH2:21][CH2:20][O:19][CH2:18][CH2:17]3)[CH2:11][C:10]2=[O:22])=[C:6]([CH3:8])[CH:7]=1
Reactant: Cc1cc(Br)cc(C)c1C1C(=O)CC(=CC2CCOCC2)C1=O
Reactant: [H][H]
Agent: [Pt]
Solvent: CO
Product: Cc1cc(Br)cc(C)c1C1C(=O)CC(CC2CCOCC2)C1=O
Yield: 91.3 %

Procedure:
To a solution of 2-(4-bromo-2,6-dimethylphenyl)-4-[1-(tetrahydropyran-4-yl)-methylidene]-cyclopentane-1,3-dione (0.1 g, 0.26 mmol) in methanol (100 ml) is subjected to hydrogenation under H-Cube conditions using 10% platinum carbon under a 20 bar hydrogen atmosphere. The reaction mixture is then concentrated to give a crude product which is purified by flash chromatography (hexane/ethyl acetate) to afford 2-(4-bromo-2,6-dimethylphenyl)-4-(tetrahydropyran-4-ylmethyl)cyclopentane-1,3-dione (0.09 g).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[C:17]([C:25]([F:28])([F:27])[F:26])[CH:16]=2)=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[N:29]1([C:35](Cl)=[O:36])[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>>[O:32]1[CH2:33][CH2:34][N:29]([C:35]([O:1][C:2]2[CH:11]=[CH:10][C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[C:3]=2[C:12]([NH:14][C:15]2[CH:20]=[C:19]([C:21]([F:24])([F:22])[F:23])[CH:18]=[C:17]([C:25]([F:27])([F:26])[F:28])[CH:16]=2)=[O:13])=[O:36])[CH2:30][CH2:31]1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc2ccccc2cc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1c(OC(=O)N2CCOCC2)ccc2ccccc12
Yield: 98 %

Procedure:
Using 3-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]-2-naphthamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([OH:12])=O.S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([Cl:15])=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccccc1Cl
Solvent: Cc1ccccc1
Product: O=C(Cl)CCc1ccccc1Cl

Procedure:
A mixture of 3-(2-chlorophenyl)propanoic acid (5.0 g, 27.1 mmole), thionyl chloride (10.9 ml, 149 mmole) and toluene (75 ml) was refluxed for two hours. Concentration in vacuo gave 3-(2-chlorophenyl)propanoyl chloride which was taken up in methylene chloride and used in the next step without further purification. Step 2:
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC(C)([O-])C.[K+].Cl[C:22]1[C:27]([N+:28]([O-:30])=[O:29])=[CH:26][CH:25]=[CH:24][N:23]=1>O1CCCC1>[N+:28]([C:27]1[C:22]([O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[N:23][CH:24]=[CH:25][CH:26]=1)([O-:30])=[O:29]
Reactant: O=[N+]([O-])c1cccnc1Cl
Reactant: Oc1cccc(Oc2ccccc2)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=[N+]([O-])c1cccnc1Oc1cccc(Oc2ccccc2)c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
3-Phenoxyphenol (3 g, 16.1 mmol) was added to a solution of potassium t-butoxide (1.90 g of 90%, 16.6 mmol) in 50 mL of dry tetrahydrofuran at room temperature after which the reaction was stirred at room temperature for 10 min. Then, 2-chloro-3-nitropyridine (2.56 g, 16.1 mmol) was added. The reaction mixture was stirred at room temperature for 16 h. The reaction mixture was concentrated under reduced pressure. The residue was diluted with water, extracted twice with methylene chloride and dried over magnesium sulfate. The solvent was then removed to yield the title compound of Step A as an oil. 1H NMR (CDCl3 ; 300 MHz): δ 6.85 (m,1H), 6.90 (m,2H), 7.0-7.2 (m,4H), 7.3-7.4 (m,3H), 8.35 (m,2H).