Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][NH:18][CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2].[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:43]=[CH:42][C:39]([CH2:40]Br)=[CH:38][CH:37]=1.C(N(C(C)C)CC)(C)C>CC#N.CCOC(C)=O>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:10]1[CH:11]=[C:12]([C:22]2[CH:23]=[CH:24][C:25]([C:28]([F:29])([F:30])[F:31])=[CH:26][CH:27]=2)[CH:13]=[C:14]([CH:16]2[CH2:21][CH2:20][CH2:19][N:18]([CH2:40][C:39]3[CH:42]=[CH:43][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=3)[CH2:17]2)[CH:15]=1)[CH2:6][CH:7]([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCNC2)c1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)C(CC(C)C)c1cc(-c2ccc(C(F)(F)F)cc2)cc(C2CCCN(Cc3ccc(OC(F)(F)F)cc3)C2)c1
Yield: 83 %

Procedure:
To a solution of compound 33b 4-Methyl-2-(5-piperidin-3-yl-4′-trifluoromethyl-biphenyl-3-yl)-pentanoic acid ethyl ester (60.8 mg, 0.136 mmol) in CH3CN (5 ml) was added 4-Trifluoromethoxybenzylbromide) (33 μl, 0.20 mmol) and diisopropylethylamine (47 μl, 0.27 mmol). The reaction was microwaved at 130° C. for 10 minutes, then diluted with EtOAc and washed with brine, sat. NaHCO3, and brine, dried and filtered. Purification by silica gel chromatography (Isco) gave the desired product as a clear oil, (69.7 mg, 83%). Calcd for C34H37F6NO3 (M+H) 621.65, Found 622.3
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:13])=O.[CH3:14][N:15]1[C:23]2[C:18](=[CH:19][C:20]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:21][CH:22]=2)[C:17]([CH3:30])([CH3:29])[C:16]1=[CH2:31]>C(O)C>[CH3:14][N:15]1[C:16]2([O:13][C:4]3[CH:5]=[CH:6][C:7]4[C:12]([C:3]=3[N:1]=[CH:31]2)=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:17]([CH3:30])([CH3:29])[C:18]2[C:23]1=[CH:22][CH:21]=[C:20]([O:24][C:25]([F:26])([F:27])[F:28])[CH:19]=2
Reactant: O=Nc1c(O)ccc2ccccc12
Reactant: C=C1N(C)c2ccc(OC(F)(F)F)cc2C1(C)C
Solvent: CCO
Product: CN1c2ccc(OC(F)(F)F)cc2C(C)(C)C12C=Nc1c(ccc3ccccc13)O2

Procedure:
A solution of 1-nitroso-2-naphthol (0.50 g, 2.89 mmol) and 1,3,3-trimethyl-5-trifluoromethoxy-2-methylene-indoline (0.71 g, 2.77 mmol) in ethanol (30 ml) was heated under nitrogen and refluxed for 20 hrs. The solvent was then evaporated and the residue was chromatographed over silica (ethyl acetate/petroleum ether 1:10). After crystallization in ethanol, the yield of the pure product (colorless crystals) was 0.2 g (18%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[N:8](CC2C=CC(OC)=CC=2OC)[CH2:9][CH2:10][CH:11]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:24])[CH2:4][CH2:5][C:6]1[C:7](=[O:23])[NH:8][CH2:9][CH2:10][CH:11]=1
Reactant: COC(=O)CCC1=CCCN(Cc2ccc(OC)cc2OC)C1=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)CCC1=CCCNC1=O
Temperature: 80 °C
Yield: 74 %

Procedure:
310 mg of 3-[1-(2,4-dimethoxybenzyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-propionic acid methyl ester (d) (0.93 mmol) was dissolved in 3 ml of trifluoroacetic acid solution. Then 0.22 ml of triethyl silane (1.395 mmol) was added thereto and the mixture was heated for 20 min at 80° C. The solvent was removed in vacuo and the remaining residue was diluted in 20 ml of chloroform. The organic layer was washed with 5 ml of sat. NaHCO3 solution and 5 ml of sat. NaCl solution. Then the organic layer was dried over anhydrous MgSO4, filtered and concentrated in vacuo. The resulting compound was purified by column chromatography on Silica gel with EtOAc solvent as an eluant to give 126 mg (yield: 55%) of the title compound (f).
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=[CH:16][C:5]2=[C:6]2[C:15]=1[O:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7]2>C(O)(=O)C.CO.[Zn]>[CH:16]1[C:5]2=[C:6]3[C:15](=[CH:2][N:3]=[C:4]2[CH:19]=[CH:18][CH:17]=1)[O:14][C:13]1[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=1)[O:7]3
Reactant: Clc1nc2ccccc2c2c1Oc1ccccc1O2
Agent: [Zn]
Solvent: CO
Solvent: CC(=O)O
Product: c1ccc2c(c1)Oc1cnc3ccccc3c1O2

Procedure:
Under an inert atmosphere, 1 mmol of 6-chloro-5-aza-7,12-dioxabenz[a]anthracene and 8 mmol of powdered zinc are brought to 50° C. in 5 ml of acetic acid for 8 hours. After cooling, the reaction mixture is diluted in methanol and then filtered through Celite. The residue is concentrated under vacuum, then washed with saturated sodium hydrogen carbonate solution and then extracted with chloroform. The organic phase is dried over magnesium sulfate and concentrated under vacuum. The crude mixture is chromatographed by flash chromatography on silica gel (eluent: ethyl acetate/petroleum ether).
Reaction SMILES: [N:1]#[C:2]Cl.[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5].C(N(CC)CC)C>C(O)(C)C>[O-:5][C:2]#[N:1].[C:4]1([CH:11]=[CH:10][CH:9]=[C:7]([OH:8])[CH:6]=1)[OH:5]
Reactant: N#CCl
Agent: Oc1cccc(O)c1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N#C[O-]

Procedure:
271 g (4.4 mols) of cyanogen chloride in 1.1 liter of isopropanol are introduced at -5° C. into a 3 liter glass vessel equipped with a stirrer, a thermometer and an inlet pipe. By means of a metering pump, a solution of 220 g (2 mols) of resorcinol and 430 g (4.04 mols) of triethyl amine in 750 ml of isopropanol is pumped in below the surface with stirring. The reaction temperature is best kept at -5° C. to +3° C. On completion of the reaction, the crystalline sludge formed is filtered off under suction from the isopropanol and the filter residue is washed with 100 ml of isopropanol. The residue is thoroughly stirred with 1.1 liter of water and filtered off under suction again. The filter residue is then taken up in 800 ml of methylene chloride and washed with water until free from chloride. Following the addition of 600 ml of perchloroethylene, the methylene chloride distils off initially at 45° to 50° C. and subsequently at 60° C. and at about 160 Torr. The residue is left to cool with stirring to 5°-10° C. and the resorcinol dicyanate which has crystallised out is filtered off under suction, washed twice with 50 ml of perchloroethylene and dried in a stream of air. 270 g (84% of the theoretical) of resorcinol cyanate are obtained. Mp: 81° C., nD90 :1.4980
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[N:12]=[CH:13][CH:14]=[CH:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1.[BH4-].[Na+]>C(O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]3[NH:12][CH2:13][CH2:14][CH2:15][N:10]3[N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nn3cccnc3c2-c2ccncc2)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Fc1ccc(-c2nn3c(c2-c2ccncc2)NCCC3)cc1
Temperature: 0 °C
Yield: 77.5 %

Procedure:
A mixture of 2-(4-fluorophenyl)-3-(pyridin-4-yl)pyrazolo[1,5-a]pyrimidine (56 mg) and sodium borohydride (16 mg) in ethanol (2 ml) was refluxed for 2 hours, cooled, and poured into ice water. The separated oil was extracted with dichloromethane. The extract was washed with brine, dried and concentrated in vacuo. The residue was crystallized from a mixture of ethyl acetate and ethyl ether to yield 2-(4-fluorophenyl)-3-(pyridin-4-yl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine (44 mg).
Reaction SMILES: [Li]CCCC.[CH3:6][C@@H:7]([CH2:16][C:17]#[CH:18])[CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1.[CH:19](=[O:21])[CH3:20].[NH4+].[Cl-]>CCCCCC.C1COCC1.COC(C)(C)C>[CH3:6][C@H:7]([CH2:8][O:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][O:11]1)[CH2:16][C:17]#[C:18][CH:19]([OH:21])[CH3:20]
Reactant: CC=O
Reactant: C#CC[C@H](C)COC1CCCCO1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: COC(C)(C)C
Solvent: CCCCCC
Product: CC(O)C#CC[C@H](C)COC1CCCCO1
Reaction time: 0.5 h
Yield: 100 %

Procedure:
2450 ml n-BuLi solution, 1.6 M, in hexane is added dropwise to a 650 g solution (3.566 mol) of (RS)-2-{[(S)-2-methylpent-4-in-1-yl]oxy}-3,4,5,6-tetrahydro-2H-pyrane (prepared in accordance with Ireland, Robert E. et al., Tetrahedron, 1997, 53, 39, 13221-13256.) in 325 ml of THF at −10° C. A solution of 310 g acetaldehyde in 1200 ml THF is then added dropwise. After 30 min., 3250 ml MTBE (methyl-tert.butylether) is added and 3250 ml 10% aq NH4Cl is added and further stirred for 10 min. The organic phase is washed twice with 1300 ml H2O each and concentrated in vacuo to dryness. 930 g of product is obtained. The obtained product is directly used in the subsequent step.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][CH:5]([C@H:8]([NH:10]C(=O)OC(C)(C)C)[CH3:9])[CH2:4][CH2:3]1.CCOCC>ClCCl>[NH2:10][C@@H:8]([CH:5]1[CH2:6][CH2:7][CH:2]([OH:1])[CH2:3][CH2:4]1)[CH3:9]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C1CCC(O)CC1
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@@H](N)C1CCC(O)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Tert-butyl (R)-1-(4-hydroxycyclohexyl)ethylcarbamate (4.49 g, 18.45 mmol) was dissolved in dichloromethane (25 mL) and cooled to 0° C. under nitrogen. HCl 2M in Ether (27.68 mL of 2 M, 55.35 mmol) was added and the reaction allowed to warm slowly to ambient temperature for 18 hours. The reaction mixture was concentrated in vacuo. The crude mixture was dissolved in MeOH (25 mL). MP-Carbonate was added (11.75 g, 36.90 mmol) and the reaction mixture was stirred for 3 hours. The resin was filtered and the mother liquors were concentrated to dryness to afford the title compound as an off white solid (2.39 g, 90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:22]=[C:21]([S:23][CH3:24])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18].ClC1C=CC=C(C(OO)=[O:33])C=1>ClCCl.C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:22]=[C:21]([S:23]([CH3:24])=[O:33])[CH:20]=[CH:19][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][C:11]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:13]=[C:8]2[N:7]=[C:6]1[CH3:18]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COC(=O)c1ccc2nc(C)n(Cc3ccc(SC)cc3Cl)c2n1
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COC(=O)c1ccc2nc(C)n(Cc3ccc(S(C)=O)cc3Cl)c2n1
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(2-chloro-4-(methylthio)benzyl)-2-methyl-3H-imidazo[4,5-b]pyridine-5-carboxylate (148 mg) in dichloromethane (2.8 ml) was added m-chloroperbenzoic acid (81 mg) under ice-cooling, and the mixture was stirred for 1 hr. The reaction mixture was diluted with chloroform, washed successively with a saturated aqueous sodium hydrogencarbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and acetonitrile was added to the residue for crystallization, whereby the objective compound (118 mg) was obtained as a white powder.
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[CH3:38]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:27][C:26]=3[CH3:38])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCN
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Product: Cc1cc(C2=NNC(=O)CC2)ccc1OCCCNCC(O)COc1ccc(CCOCC2CCC2)cc1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxyethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-methyl-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[O:32][CH3:33])=[CH:16][CH:15]=2)[C@@H:10]([O:34][CH2:35][C:36]2[CH:45]=[C:44]3[C:39]([CH2:40][CH2:41][CH2:42][N:43]3[CH2:46][CH2:47][N:48]3[CH:52]=[CH:51][N:50]=[CH:49]3)=[CH:38][CH:37]=2)[CH2:9]1)=O)(C)(C)C.Cl.CO>>[N:48]1([CH2:47][CH2:46][N:43]2[C:44]3[C:39](=[CH:38][CH:37]=[C:36]([CH2:35][O:34][C@@H:10]4[C@@H:11]([C:14]5[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][O:24][CH2:25][C:26]6[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=6[O:32][CH3:33])=[CH:16][CH:15]=5)[CH2:12][CH2:13][NH:8][CH2:9]4)[CH:45]=3)[CH2:40][CH2:41][CH2:42]2)[CH:52]=[CH:51][N:50]=[CH:49]1
Reactant: COc1ccccc1COCCCOc1ccc([C@H]2CCN(C(=O)OC(C)(C)C)C[C@@H]2OCc2ccc3c(c2)N(CCn2ccnc2)CCC3)cc1
Agent: Cl
Solvent: CO
Product: COc1ccccc1COCCCOc1ccc([C@H]2CCNC[C@@H]2OCc2ccc3c(c2)N(CCn2ccnc2)CCC3)cc1

Procedure:
In analogy to the procedure described in example 4(b), the (3R,4R)-3-[1-(2-imidazol-1-yl-ethyl)-1,2,3,4-tetrahydro-quinolin-7-ylmethoxy]-4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidine-1-carboxylic acid tert-butyl ester was deprotected with HCl/methanol to yield the (3R,4R)-1-(2-imidazol-1-yl-ethyl)-7-(4-[4-[3-(2-methoxy-benzyloxy)-propoxy]-phenyl]-piperidin-3-yloxymethyl)-1,2,3,4-tetrahydro-quinoline as a yellow oil; MS: 611 (M+H)+.
Reaction SMILES: [F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:28])([C@@H:10]([OH:27])[CH2:11][C@@:12]3([CH3:26])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:25])[CH2:20][O:21]C(=O)C)[C@:8]2([CH3:29])[C:3]1=[CH:4][C:5](=[O:30])[CH:6]=[CH:7]2>C(O)C>[F:1][C@H:2]1[CH2:18][C@@H:17]2[C@:9]([F:28])([C@@H:10]([OH:27])[CH2:11][C@@:12]3([CH3:26])[C@H:16]2[CH2:15][CH:14]=[C:13]3[C:19](=[O:25])[CH2:20][OH:21])[C@:8]2([CH3:29])[C:3]1=[CH:4][C:5](=[O:30])[CH:6]=[CH:7]2
Reactant: CC(=O)OCC(=O)C1=CC[C@H]2[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@]12C
Solvent: CCO
Product: C[C@]12C=CC(=O)C=C1[C@@H](F)C[C@H]1[C@@H]3CC=C(C(=O)CO)[C@@]3(C)C[C@H](O)[C@@]12F
Temperature: 37 °C
Reaction time: 8 h
Yield: 70.6 %

Procedure:
To a solution of intermediate 2 (2.55 g, 6.06 mmol) in ethanol (100 ml), Candida antarctica Lipase (2 U/mg) (510 mg, 6.06 mmol) was added, and the reaction mixture was stirred at 37° C. overnight. The reaction mixture was filtered, washing with methanol, and the residue was purified by flash chromatography on silica gel, in gradient elution from DCM/AcOEt 90:10 to DCM/AcOEt 50:50, to afford the title compound (1.62 g, 70.6% yield).
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.CCCCCC.[Cl:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH2:25][C:24]=2[N:23]=[CH:22][CH:21]=1.[C:30]1([Se:36]Cl)[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>O1CCCC1>[Cl:19][C:20]1[C:29]2[CH2:28][CH2:27][CH2:26][CH:25]([Se:36][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]=2[N:23]=[CH:22][CH:21]=1
Reactant: Cl[Se]c1ccccc1
Reactant: Clc1ccnc2c1CCCC2
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: Clc1ccnc2c1CCCC2[Se]c1ccccc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 63.4 %

Procedure:
A solution of diisopropylamine (18.5 ml, 132 mmol) in tetrahydrofuran (100 ml) at 0° was treated with 1.5M butyllithium solution in hexane (88 ml, 132 mmol) under an atmosphere of nitrogen, stirred for 10 min, cooled to -78°, treated dropwise with the product of Step 2 (7.35 g, 44 mmol) in tetrahydrofuran (50 ml) at <-65°, stirred at -78° for 20 min, treated with phenylselenyl chloride (8.5 g, 44 mmol) in tetrahydrofuran (50 ml), warmed to room temperature, and quenched with saturated aqueous ammonium chloride (250 ml). The reaction was worked-up in a similar way to that described in Example 25, Step 1 and the product (9 g) isolated by chromatography [silica; hexane-ether (2:1)] as an oil.
Reaction SMILES: [CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[NH:13][CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2].I[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:24]=1[CH3:25].[O-]P([O-])([O-])=O.[K+].[K+].[K+].CN[C@@H]1CCCC[C@H]1NC>[Cu]I.O1CCOCC1>[CH2:1]([N:3]1[C:15]2[C:14](=[O:16])[N:13]([C:19]3[CH:20]=[N:21][CH:22]=[CH:23][C:24]=3[CH3:25])[CH:12]([CH3:17])[CH2:11][C:10]=2[C:9]2[C:4]1=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH3:2]
Reactant: Cc1ccncc1I
Reactant: CCn1c2c(c3ccccc31)CC(C)NC2=O
Agent: [Cu]I
Agent: CN[C@@H]1CCCC[C@H]1NC
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Product: CCn1c2c(c3ccccc31)CC(C)N(c1cnccc1C)C2=O
Temperature: 120 °C
Yield: 4.3 %

Procedure:
9-Ethyl-3-methyl-2,3,4,9-tetrahydro-b-carbolin-1-one (I-42d: 0.150 g, 0.657 mmol) was reacted with 3-iodo-4-methyl-pyridine (0.144 g, 0.657 mmol), K3PO4 (0.348 g, 1.644 mmol), CuI (0.012 g, 0.065 mmol), trans-N,N′-dimethyl-cyclohexane-1,2-diamine (0.028 g, 0.197 mmol) and 1,4-dioxane (15 mL). The resulting mixture was heated at 120° C. for 23 hours to afford the crude product. Purification by column chromatography on silica gel (30% ethyl acetate in hexane) followed by preparative HPLC afforded 9 mg of the product (4.3% yield).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[N:4]=[C:3]1S(C)(=O)=O.[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:29])([F:28])[F:27])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([OH:36])=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16].[H-].[Na+]>O>[CH2:15]([N:17]1[C:25]2[C:20](=[N:21][CH:22]=[CH:23][C:24]=2[C:26]([F:27])([F:29])[F:28])[N:19]([C:30]2[CH:35]=[CH:34][C:33]([O:36][C:3]3[N:2]([CH3:1])[C:6]4=[N:7][CH:8]=[CH:9][CH:10]=[C:5]4[N:4]=3)=[CH:32][CH:31]=2)[C:18]1=[O:37])[CH3:16]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCn1c(=O)n(-c2ccc(O)cc2)c2nccc(C(F)(F)F)c21
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCn1c(=O)n(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2nccc(C(F)(F)F)c21
Temperature: 100 °C
Reaction time: 1 h
Yield: 43 %

Procedure:
To a mixture of 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (81 mg) and 1-ethyl-3-(4-hydroxyphenyl)-7-(trifluoromethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (103 mg) in DMF(dry) (1.5 ml) was added NaH (19.12 mg), and the mixture was stirred at 100° C. for 1 h. The mixture was heated at 180° C. for 30 min under microwave irradiation. The mixture was poured into water, and the mixture was extracted with EtOAc. The organic layer was separated, washed with brine, dried over Na2SO4 and concentrated in vacuo. The residue was purified by column chromatography (silica gel, EtOAc/hexane) to give the title compound as white crystals (62.2 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([O:12]C)=[O:11])=[CH:4][CH:3]=1.[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]O)[CH:26]=1)[CH:15]([CH3:17])[CH3:16]>>[CH2:14]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[C:19]=1[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:6][CH:7]=2)[CH:26]=1)[CH:15]([CH3:17])[CH3:16]
Reactant: COC(=O)CCc1ccc(O)cc1
Reactant: Cc1cccc(CC(C)C)c1-c1cccc(CO)c1
Product: Cc1cccc(CC(C)C)c1-c1cccc(COc2ccc(CCC(=O)O)cc2)c1

Procedure:
The title compound was synthesized in the same manner as in Reference Example 230 from methyl 3-(4-hydroxyphenyl)propanoate and (2′-isobutyl-6′-methylbiphenyl-3-yl)methanol. colorless oil (yield 58%). MS (APCI−): 401 (M−H).
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[SH:21]>>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[S:21][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Sc1ccc(Cl)cc1Cl
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2ccc(Cl)cc2Cl)s1

Procedure:
Prepared according to the procedure described as in Step B for example 1 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.164 g, 0.8 mmol) and 2,4-dichlorobenzenethiol (0.143 g, 0.8 mmol). The title compound was obtained as an orange solid (132 mg, 47.3% yield). 1H NMR (300 MHz, CDCl3) δ: 8.09 (1H, s), 7.68 (2H, m), 7.42 (1H, d), 2.50 (3H, s).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[CH:6]=[CH:5][C:4]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1.C(O)(=O)C>O.[Fe]>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH:6]=[CH:5][C:4]=1[C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[NH2:9]
Reactant: COc1cc([N+](=O)[O-])ccc1-c1cccs1
Agent: [Fe]
Solvent: O
Solvent: CC(=O)O
Product: COc1cc(N)ccc1-c1cccs1
Yield: 86.1 %

Procedure:
In a manner similar to Example 1, Step B, the reaction of 6.6 g (0.03 mole) of 2-(2-methoxy-4-nitrophenyl)thiophene, 13.65 g (0.24 mole) of iron powder and 25.2 g (0.42 mole) of glacial acetic acid in 36 ml of water produced 5.3 g of 3-methoxy-4-(thien-2-yl)aniline.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11]([OH:13])=O)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][CH2:23][NH2:24])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([C:11]([NH:24][CH2:23][CH2:22][C:19]3[CH:20]=[CH:21][C:16]([O:15][CH3:14])=[CH:17][CH:18]=3)=[O:13])[CH2:9][CH2:10]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CC1
Reactant: COc1ccc(CCN)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Product: COc1ccc(CCNC(=O)C2(c3ccc(Cl)cc3)CC2)cc1
Reaction time: 8 h

Procedure:
A solution of 1-(4-chlorophenyl)cyclopropanecarboxylic acid (5.0 g, 25.3 mmol), 2-(4-methoxyphenyl)ethanamine (4.2 g, 28 mmol) and 4-N,N-Dimethylaminopyridin (3.3 g; 28 mmol) in methylenehloride (200 ml) was cooled to −10° C. N-ethyl-N′-(3-Dimethylaminopropyl)-carbodiimid hydrochloride (EDC, 5.3 g, 28 mmol) was added in several portions and the resulting mixture stirred overnight. The reaction mixture was poured into water and consecutively extracted with water, 2N NaOH and 1N HCl. Evaporation of the dried (NaSO4) extract yielded an oily residue that crystallized upon addition of n-heptan, which was used without further purification. Yield 7.0 g (21.2 mmol, 83%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].[Cl:11][C:12]1[CH:17]=[CH:16][C:15](B(O)O)=[CH:14][CH:13]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.C(O)C.[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>[Cl:11][C:12]1[CH:17]=[CH:16][C:15]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N+:8]([O-:10])=[O:9])=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1Br
Reactant: OB(O)c1ccc(Cl)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: O=[N+]([O-])c1ccccc1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 86.5 %

Procedure:
To a solution of 2-bromonitrobenzene (646 mg) in THF (17 ml) under nitrogen was added tetrakis(triphenylphosphine) palladium (0) (900 mg). The resulting mixture was stirred at room temperature for 20 min, then a solution of 4-chlorophenylboronic acid (1.0 g) in ethanol (17 ml) was added and the resulting mixture stirred at room temperature for 1 hr. 2M sodium carbonate (17 ml) was then added and the reaction heated to reflux for 2 hrs. The mixture was then allowed to cool and concentrated under reduced pressure. The residue was dissolved in ethyl acetate (100 ml) and the aqueous layer removed. The organic phase was washed with brine (20 ml), dried (magnesium sulfate), filtered and concentrated. The reside was purified by flash chromatography (0-10% ethyl acetate/hexane)to afford the sub-title compound as a yellow solid (646 mg) 1H NMR (400 MHz, CDCl3) 67 7.24-7.31 (2H, m), 7.41-7.47 (3H, m), 7.52 (1H, m), 7.65 (1H, m), 7.90 (1H, d).