Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(OCCCCC)=O.N[C:10]1[N:14]([C:15]2[C:20]([Cl:21])=[CH:19][C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][C:16]=2[Cl:26])[N:13]=[C:12]([CH3:27])[C:11]=1[S:28][C:29]([F:32])([F:31])[F:30].[CH:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>>[Cl:26][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:20]([Cl:21])[C:15]=1[N:14]1[C:10]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[C:11]([S:28][C:29]([F:32])([F:31])[F:30])[C:12]([CH3:27])=[N:13]1
Reactant: c1ccccc1
Reactant: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(N)c1SC(F)(F)F
Agent: CCCCCON=O
Product: Cc1nn(-c2c(Cl)cc(C(F)(F)F)cc2Cl)c(-c2ccccc2)c1SC(F)(F)F
Yield: 49 %

Procedure:
2 ml (0.015 mol) of n-pentyl nitrite are added to 4.1 g (0.01 mol) of 5-amino-1-(2,6-dichloro-4-trifluoromethyl-phenyl)-3-methyl-4-trifluoromethylthio-pyrazole in 30 ml benzene at room temperature with stirring, and the mixture is stirred for a further 15 hours at room temperature. The mixture is worked up by concentrating in vacuo and the residue is purified by chromatography (silica gel; eluant: petroleum ether/ethyl acetate 9:1). 2.3 g (49% of theory) of 1-(2,6-dichloro-4-trifluoromethylphenyl)-3-methyl-5-phenyl-4-trifluoromethylthio-pyrazole are obtained as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C([O:11][CH:12]=[C:13]([C:19](OCC)=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])C.C1(OC2C=CC=CC=2)C=CC=CC=1>C(O)C>[OH:11][C:12]1[C:7]2[C:2](=[CH:3][CH:4]=[C:5]([OH:8])[CH:6]=2)[N:1]=[CH:19][C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15]
Reactant: Nc1ccc(O)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCO
Product: CCOC(=O)c1cnc2ccc(O)cc2c1O
Temperature: 25 °C
Yield: 5.5 %

Procedure:
A mixture of 4-aminophenol (5.457 g) and diethyl ethoxymethylenemalonate (10.81 g) is heated to 130° C. for 2 h with removal of ethanol by a Dean-Stark trap. The reaction is cooled to room temperature. Diphenyl ether (50 mL) is added and the mixture is heated to 250° C. for 45 min with removal of ethanol by a Dean-Stark trap. The solution is cooled to 80° C. and the resulting solid is collected and washed with hexanes. The solid is suspended in 250 mL MeOH and brought to a boil. The insoluble material is filtered and the filtrate is adsorbed onto silica and chromatographed, eluting with 5% MeOH/CH2Cl2 then with 10% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo to yield 0.644 g of ethyl 4,6-dihydroxyquinoline-3-carboxylate. A mixture of this ester (0.500 g) and 4-chlorobenzylamine (1.518 g) are heated to 180° C. for 1 h. The solution is cooled to room temperature and diluted with CH2Cl2. The resulting solid is collected and chromatographed on silica, eluting with 3% MeOH/CH2Cl2. Fractions homogeneous by TLC are combined and concentrated in vacuo. The residue is sonicated with CH2Cl2 /hexanes. The resulting solid is collected and dried to afford 0.372 g of the desired product as a white solid.
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])(=O)[CH3:2].[BH4-].[Na+].[C:16](O)(=O)C.O>O1CCCC1>[CH2:1]([NH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12][CH2:13][CH3:16])=[O:11])[CH3:2]
Reactant: COC(=O)CCCCCNC(C)=O
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCNCCCCCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Crude methyl 6-acetylamino-hexanoate (5.19 g) is dissolved in tetrahydrofuran (50 ml) and thereto is added sodium borohydride (5.03 g). The reaction solution is heated under reflux and thereto is added dropwise acetic acid (7.6 ml) and the mixture is heated under reflux for 1 hour and 30 minutes. To the reaction solution is added water under ice-cooling and the mixture is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in ethanol (30 ml) and thereto is added a 4N-hydrochloric acid in ethyl acetate (7.6 ml) and the mixture is stirred at room temperature overnight. To the reaction solution are added a 2N-aqueous sodium hydroxide solution and ethyl acetate, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give ethyl 6-ethylamino-hexanoate (1.74 g) as a crude product. MS (m/z): 188 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][N:5]2[C:9]([CH:10]=1)=[C:8]([C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12])[C:7]([CH3:21])=[C:6]2[C:22](=[O:34])[C:23]1[CH:28]=[CH:27][C:26]([N+:29]([O-:31])=[O:30])=[C:25]([O:32][CH3:33])[CH:24]=1.F[C:36](F)(F)C(O)=O>>[CH3:33][O:32][C:25]1[CH:24]=[C:23]([CH:28]=[CH:27][C:26]=1[N+:29]([O-:31])=[O:30])[C:22]([C:6]1[N:5]2[C:9]([CH:10]=[C:2]([NH:1][CH3:36])[CH:3]=[CH:4]2)=[C:8]([C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[C:7]=1[CH3:21])=[O:34]
Reactant: COc1cc(C(=O)c2c(C)c(C(=O)OCc3ccccc3)c3cc(N)ccn23)ccc1[N+](=O)[O-]
Reactant: O=C(O)C(F)(F)F
Product: CNc1ccn2c(C(=O)c3ccc([N+](=O)[O-])c(OC)c3)c(C)c(C(=O)OCc3ccccc3)c2c1
Yield: 78 %

Procedure:
This compound is obtained according to the same method as the compound of Example 49 by deprotection of the amino functional group of 849 mg (1.48 mmol) of benzyl [7-[(N-tert-butoxycarbonyl)(N-methyl)amino]-3-(3-methoxy-4-nitrobenzoyl)-2-methylindolizin-1-yl]carboxylate with trifluoroacetic acid. 549 mg of an orange-coloured powder are obtained.
Reaction SMILES: [F:1][C:2]([F:25])([C:21]([F:24])([F:23])[F:22])[C:3](=O)[CH:4]=[CH:5][C:6]1[CH:7]=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=2)[CH:9]=[CH:10][CH:11]=1.Cl.[Cl:27][C:28]1[CH:29]=[C:30]([NH:34][NH2:35])[CH:31]=[CH:32][CH:33]=1>>[Cl:27][C:28]1[CH:29]=[C:30]([N:34]2[CH:5]([C:6]3[CH:7]=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([S:18][CH3:19])=[CH:14][CH:13]=4)[CH:9]=[CH:10][CH:11]=3)[CH2:4][C:3]([C:2]([F:25])([F:1])[C:21]([F:24])([F:23])[F:22])=[N:35]2)[CH:31]=[CH:32][CH:33]=1
Reactant: CSc1ccc(-c2cccc(C=CC(=O)C(F)(F)C(F)(F)F)c2)cc1
Reactant: NNc1cccc(Cl)c1
Agent: Cl
Product: CSc1ccc(-c2cccc(C3CC(C(F)(F)C(F)(F)F)=NN3c3cccc(Cl)c3)c2)cc1

Procedure:
The titled compound was prepared in accordance with the same procedures as in Example 23, except for using 4,4,5,5,5-pentafluoro-1-(4′-methylsulfanyl-biphenyl-3-yl)-pent-1-en-3-one prepared in Step 3 of Preparation 4; and using 3-chlorophenylhydrazine hydrochloride instead of 4-chlorophenylhydrazine hydrochloride.
Reaction SMILES: C(N(CC)CC)C.[O:8]=[C:9]1[O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]([OH:13])=[C:10]1[OH:11].[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O>C(#N)C>[CH3:20][C:21]([CH2:37][CH2:38][CH2:39][CH:40]([CH3:52])[CH2:41][CH2:42][CH2:43][CH:44]([CH3:51])[CH2:45][CH2:46][CH2:47][CH:48]([CH3:50])[CH3:49])=[CH:22][CH2:23][CH2:24][CH2:25][O:11][C:10]1[C:9]([O:15][C@H:14]([C@H:16]([CH2:18][OH:19])[OH:17])[C:12]=1[OH:13])=[O:8]
Reactant: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reactant: CC(=CCCCOS(=O)(=O)c1ccc(C)cc1)CCCC(C)CCCC(C)CCCC(C)C
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=CCCCOC1=C(O)[C@@H]([C@@H](O)CO)OC1=O)CCCC(C)CCCC(C)CCCC(C)C
Temperature: 90 °C

Procedure:
0.71 mL (5.1 mmol) of triethylamine was added and dissolved in a suspension of 0.82 g (4.63 mmol) of ascorbic acid in acetonitrile (9 mL). The above crude product of (5,9,13,17-tetramethyloctadec-4-enyl)tosylate was added at room temperature, and the reaction mixture was heated for 2 hours at 90° C. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (methanol/methylene chloride mixture) to obtain the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([C:11](O)=[O:12])[CH2:6]1)=[O:4].S(C)C>C1COCC1>[OH:12][CH2:11][CH:7]1[CH2:8][CH2:9][CH2:10][CH:5]([C:3]([O:2][CH3:1])=[O:4])[CH2:6]1
Reactant: COC(=O)C1CCCC(C(=O)O)C1
Solvent: CSC
Solvent: C1CCOC1
Product: COC(=O)C1CCCC(CO)C1
Reaction time: 8 h
Yield: 73.1 %

Procedure:
To a cold (−78° C.) solution of 3-(methoxycarbonyl)cyclohexanecarboxylic acid (1.25 g, 6.71 mmol) in THF (20 mL) was added BH3.Me2S (0.7 mL, 7.38 mmol). The resulting mixture was stirred at −78° C. to room temperature overnight. The reaction mixture was quenched with a saturated aqueous NH4Cl solution and extracted with ethyl acetate. The organic phase was washed with brine, dried over Na2SO4, and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-(hydroxymethyl)cyclohexanecarboxylate as a colorless oil (845 mg, yield; 73%). To a solution of methyl 3-(hydroxymethyl)cyclohexanecarboxylate (840 mg, 4.88 mmol) in Et3N (4.4 mL, 32 mmol) and DMSO (10 mL) was added sulfur trioxide-pyridine complex (2.56 g, 16.1 mmol). The mixture was stirred at room temperature for 1 hr. The reaction mixture was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over Na2SO4, filtered and evaporated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate=2/1) to give methyl 3-formylcyclohexanecarboxylate as a pale yellow oil (795 mg, yield; 96%).
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][C:6]1([CH3:20])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH3:19])[C:10]=2[CH2:9][CH2:8][O:7]1)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.O1CCCC1>O1CCCC1>[CH3:20][C:6]1([CH2:5][CH2:4][OH:3])[C:18]2[C:17]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[N:11]([CH3:19])[C:10]=2[CH2:9][CH2:8][O:7]1
Reactant: CCOC(=O)CC1(C)OCCc2c1c1ccccc1n2C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c2c(c3ccccc31)C(C)(CCO)OCC2

Procedure:
A solution of 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-acetic acid ethyl ester (17.0 g), described in Example 916, in tetrahydrofuran (200 ml) is added dropwise to a suspension of lithium aluminium hydride (5.0 g) in tetrahydrofuran (150 ml). The mixture is heated at reflux for 2.5 hr. and then cooled and treated with a mixture of water-tetrahydrofuran (30 ml - 150 ml). The mixture is filtered through celite and the filtrate is evaporated. The residue is purified by chromatography on silica gel. Elution with chloroform gives 1,5-dimethyl-1,3,4,5-tetrahydropyrano[4,3-b]indole-1-ethanol.
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1.C(N(CC)CC)C.[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38]Cl.[I-].[Na+]>C(O)C>[F:32][C:33]1[CH:43]=[CH:42][CH:41]=[CH:40][C:34]=1[O:35][CH2:36][CH2:37][CH2:38][N:3]1[CH2:8][CH2:7][CH:6]([CH2:9][NH:10][C:11]([C:13]2[S:23][C:22]3[N:24]4[C:15](=[CH:16][N:17]=[C:18]4[CH:19]=[CH:20][CH:21]=3)[CH:14]=2)=[O:12])[CH2:5][CH2:4]1
Reactant: O=C(NCC1CCNCC1)C1=Cc2cnc3cccc(n23)S1
Reactant: Fc1ccccc1OCCCCl
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CCO
Product: O=C(NCC1CCN(CCCOc2ccccc2F)CC1)C1=Cc2cnc3cccc(n23)S1

Procedure:
To a solution of 0.58 g (1.5 mM) of N-(piperidin-4-ylmethyl)-5-thia-1,8b-diazaacenaphthylene-4-carboxamide dihydrochloride and 1.0 ml (7.5 mM) of triethylamine in ethanol were added 0.37 g (2.0 mM) of 3-(2-fluorophenoxy)-propyl chloride and 0.28 g (1.9 mM) of sodium iodide at room temperature and the mixture was refluxed under nitrogen for 20 hours. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with chloroform. The organic layer was washed with saturated aqueous solution of sodium chloride and dried over MgSO4. The resulting crude product was purified by column chromatography (methanol/ethyl acetate 30-50%) to provide the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:7]=[C:8]=[S:9])=[CH:4][S:5][CH:6]=1.[Cl:10][C:11]1[C:16]([Cl:17])=[CH:15][C:14]([NH2:18])=[C:13]([NH2:19])[CH:12]=1>>[NH2:19][C:13]1[CH:12]=[C:11]([Cl:10])[C:16]([Cl:17])=[CH:15][C:14]=1[NH:18][C:8]([NH:7][C:3]1[C:2]([CH3:1])=[CH:6][S:5][CH:4]=1)=[S:9]
Reactant: Nc1cc(Cl)c(Cl)cc1N
Reactant: Cc1cscc1N=C=S
Product: Cc1cscc1NC(=S)Nc1cc(Cl)c(Cl)cc1N

Procedure:
is obtained analogously to the reaction described in example 1 b) from 4-methyl-3-thienyl isothiocyanate and 4,5-dichloro-1,2-diaminobenzene. Crystalline solid, m.p. 310-320° C.
Reaction SMILES: [OH:1][C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8]CC)=[O:7])=[CH:4][CH:3]=1.[CH2:13](Br)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]>>[CH2:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:11][CH:12]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20]
Reactant: CCOC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCBr
Product: CCCCCCCCOc1ccc(C(=O)O)cc1

Procedure:
Using ethyl p-hydroxybenzoate (36.7 g, 0.22 mol) and n-octyl bromide (50 g, 0.26 mol), the reaction was carried out in the same manner as described in Example 13, (1), and then recrystallized from ethanol to give the title compound as a white micro-needles; yield: 43.0 g (71.6%); mp 100.2°-101.4° C. (the 1st mp), 107.0°-107.6° C. (the 2nd mp).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@@H:12](O)[CH3:13])[CH2:11][O:10]1.[NH:15]1[C:23]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:17]=[CH:16]1.FC1C=C(F)C=CC=1[C@]1([C@H](N2C3=NC=CC=C3N=C2)C)CO1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]1([C@H:12]([N:15]2[C:23]3[C:18](=[N:19][CH:20]=[CH:21][CH:22]=3)[N:17]=[CH:16]2)[CH3:13])[CH2:11][O:10]1
Reactant: c1cnc2nc[nH]c2c1
Reactant: C[C@H](O)[C@@]1(c2ccc(F)cc2F)CO1
Agent: C[C@@H](n1cnc2cccnc21)[C@@]1(c2ccc(F)cc2F)CO1
Product: C[C@@H](n1cnc2ncccc21)[C@@]1(c2ccc(F)cc2F)CO1
Yield: 22.7 %

Procedure:
Using (1S)-1-[(2R)-2-(2,4-difluorophenyl)-2-oxiranyl]ethanol (981 mg) and 1H-imidazo[4,5-b]pyridine (472 mg), (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(3H-3imidazo [4,5-b]pyridyl)ethyl]oxirane (501 mg) and (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1-imidazo[4,5-b]pyridyl) ethyl]oxirane (271 mg) were obtained by the same way as in Reference Example 2.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][C:6]1=[O:16].[BH4-].[Na+].O>CO>[Cl:1][CH2:2][CH2:3][CH2:4][C:5]1([C:17]([O:19][CH3:20])=[O:18])[O:11][C:10]2[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=2[O:8][CH2:7][CH:6]1[OH:16]
Reactant: COC(=O)C1(CCCCl)Oc2ccccc2OCC1=O
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COC(=O)C1(CCCCl)Oc2ccccc2OCC1O
Yield: 69.5 %

Procedure:
To a mixture of 2.5 g of methyl 2-(3-chloropropyl)-3-oxo-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate obtained in Reference Example 4 in 20 ml of methanol, sodium borohydride is added in small portions with stirring and under ice-cooling. After completion of the reaction, the reaction mixture is treated with water and extracted with ethyl acetate. The organic layer is washed with water, dried, and evaporated under reduced pressure. The residue is purified by column chromatography on silica gel (eluant: hexane:ethyl acetate=3:1→1:1). From the first fraction eluted, 1.75 g of methyl 2-(3-chloropropyl)-3-hydroxy-3,4-dihydro-2H-1,5-benzodioxepin-2-carboxylate (A isomer) is obtained as a colorless oil. Mass spectrum m/e: 300, 302 (M+). IR νmaxneat cm-1 : 3500(OH), 1755, 1735. NMR (CDCl3) δ: 3.21 (4H, multiplet), 3.3 (2H, triplet, ClCH2 --), 3.70 (3H, singlet, OCH3), 4.2 (3H, multiplet).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([NH:13][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:15][NH2:16])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.[C:29](=S)=[S:30].CCN(C(C)C)C(C)C>CCO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([N:13]3[CH:14]([C:17]4[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:24])([F:25])[F:26])[CH:18]=4)[CH2:15][NH:16][C:29]3=[S:30])=[CH:9][CH:8]=2)=[CH:27][CH:28]=1
Reactant: S=C=S
Reactant: NCC(Nc1ccc(Oc2ccc(Cl)cc2)cc1)c1cccc(C(F)(F)F)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: FC(F)(F)c1cccc(C2CNC(=S)N2c2ccc(Oc3ccc(Cl)cc3)cc2)c1
Temperature: 80 °C
Yield: 68.5 %

Procedure:
To a solution of N1-(4-(4-chlorophenoxy)phenyl)-1-(3-(trifluoromethyl)phenyl)ethane-1,2-diamine (127 mg, 0.312 mmol) in EtOH (2.0 mL) are added CS2 (188 μL, 3.12 mmol) and iPr2NEt (272 μL, 1.56 mmol). The reaction mixture is heated at 80° C. overnight before removal of the solvent. The residue is purified by silica gel chromatography (0˜40% EtOAc/Hexanes) to provide the title compound (95.9 mg, 69% yield) as a white solid product; HPLC-MS calculated for C22H16ClF3N2OS (M+H+) 449.1, found 449.1.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Br[C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25]>C(OCC)(=O)C>[C:9]([CH2:8][C:5]1[CH:6]=[CH:7][C:2]([O:1][C:23]([CH3:32])([CH3:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:3][CH:4]=1)#[N:10]
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Reactant: N#CCc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)C(C)(C)Oc1ccc(CC#N)cc1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
4-Hydroxyphenylacetonitrile (13.3 g, 100 mmol) and potassium carbonate (20.73 g, 150 mmol) were added to dimethylformamide (75 mL). Subsequently, tert-butyl 2-bromoisobutyrate (50.41 mL, 250 mmol) was added thereto, and the mixture was stirred for 24 hours at 80° C. The temperature of the reaction mixture was returned to room temperature, and ethyl acetate was added thereto. Washing was performed sequentially with water and brine, followed by drying over sodium sulfate. The resultant mixture was subjected to concentration under reduced pressure and purification by silica gel column chromatography (n-hexane/ethyl acetate=7/1), whereby the target compound was obtained (18.62 g, 67.62 mmol, 67.6%).
Reaction SMILES: [C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:19]=2)[C:14]([CH3:29])=[CH:13][C:12]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH4-].[Na+].[O:34]1CCOCC1>CCOCC>[C:1]([O:5][C:6]([CH2:8][CH2:9][CH2:10][N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:21][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH:19]=2)[C:14]([CH2:29][OH:34])=[CH:13][C:12]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC1=CC(C)(C)N(CCCC(=O)OC(C)(C)C)c2cc(O[Si](C)(C)C(C)(C)C)ccc21
Reactant: C1COCCO1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Product: CC(C)(C)OC(=O)CCCN1c2cc(O[Si](C)(C)C(C)(C)C)ccc2C(CO)=CC1(C)C
Reaction time: 1 h

Procedure:
SeO2 (1.50 g, 13.5 mmol) was added in portions to a hot (60° C.) solution of compound 4 (3.24 g, 6.74 mmol) in dioxane (50 mL). Then the reaction mixture was at this temperature for 1 h. After cooling, it was diluted with ether, and the organic layer was washed with sat. aq. NaHCO3 and dried over MgSO4. Solvents were evaporated, and the residue was purified by column chromatography (with hexane/ether/dichloromethane [10/3/1] as an eluent). After evaporation of solvents, the compound 5 (1.3 g) was dissolved in THF/MeOH (20/1), and NaBH4 (100 mg, 2.6 mmol) was added in portions at room temp. After 5 min, the reaction was complete (TLC). The excess of NaBH4 was destroyed by adding acetone (0.5 mL); all volatile materials were evaporated in vacuo, and the alcohol 6a was isolated by column chromatography (with hexane/ether/dichloromethane/MeOH mixture (10/3/4/0.3) as an eluent; Rf=0.42); yield 0.745 g (22%) of light yellow oil.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH:6](P(OCC)(OCC)=O)[CH3:7])=[O:5].[H-].[Na+].[CH3:18][CH:19]([CH:21]=O)[CH3:20].CC(O)=O>C(COC)OC>[CH2:2]([O:3][C:4](=[O:5])[C:6]([CH3:7])=[CH:18][CH:19]([CH3:21])[CH3:20])[CH3:1]
Reactant: CC(C)C=O
Reactant: CCOC(=O)C(C)P(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CC(=O)O
Product: CCOC(=O)C(C)=CC(C)C
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
Within a period of 90 min., a solution of triethyl 2-phosphonopropionate (238 g, 1.00 mol) in dimethoxyethane (DME, 150 ml) was added dropwise with stirring under an atmosphere of N2 to a solution of NaH (43.6 g, 1.00 mol) in DME (600 ml). The mixture was then heated to reflux, and after 15 min. at reflux temp., isobutyric aldehyde (72.1 g, 1.00 mol) was added dropwise. After a further 30 min. stirring at reflux, the mixture was poured into ice/water (1:1, 1 L). AcOH (60 ml) was added, and the product was extracted with Et2O (2×200 ml). The combined organic extracts were washed with water (400 ml) and brine (100 ml), dried (Na2SO4), and concentrated in a rotary evaporator. The resulting residue was distilled to provide at 86-75° C./27 mbar 117 g (75%) of 2,4-dimethylpent-2-enoic acid ethyl ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][NH:20][CH2:19]2)=[O:17])[CH:10]=1.C(N(CC)CC)C.[CH3:31][S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C:16]([CH:18]2[CH2:23][CH2:22][CH2:21][N:20]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:19]2)=[O:17])[CH:10]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccccc1-c1cc(NC(=O)C2CCCNC2)ncn1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1-c1cc(NC(=O)C2CCCN(S(C)(=O)=O)C2)ncn1
Temperature: 0 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
Piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #16A) (110 mg, 0.352 mmol) was dissolved in 5 mL of anhydrous dichloromethane, cooled to 0° C. and triethyl amine (13.0 g, 15.5 mmol) and methane sulfonyl chloride (60 mg, 0.53 mmol) were added simultaneously. The mixture was stirred for two hours at room temperature, treated with crushed ice and partitioned with between water and dichloromethane. The organic layer was separated, dried over sodium sulfate and concentrated to provide 1-methanesulfonyl-piperidine-3-carboxylic acid [6-(2-methoxy-phenyl)-pyrimidin-4-yl]-amide (compound #21A) (90 mg, 80.3%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]#[N:38])[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:23][CH2:22]2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:9]1)=[O:7].[N-:50]=[N+:51]=[N-:52].[Na+].Cl.C([NH+](CC)CC)C>CN1CCCC1=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:43]=[C:44]([O:48][CH3:49])[C:45]=1[O:46][CH3:47])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:19][CH2:20][N:21]2[CH2:22][CH2:23][CH:24]([NH:27][C:28]3[N:32]([CH2:33][CH2:34][CH2:35][CH2:36][C:37]4[NH:52][N:51]=[N:50][N:38]=4)[C:31]4[CH:39]=[CH:40][CH:41]=[CH:42][C:30]=4[N:29]=3)[CH2:25][CH2:26]2)([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCCC#N)CC3)(c3ccccc3)C2)cc(OC)c1OC
Reactant: [N-]=[N+]=[N-]
Agent: CC[NH+](CC)CC
Agent: Cl
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: COc1cc(C(=O)N2CCC(CCN3CCC(Nc4nc5ccccc5n4CCCCc4nnn[nH]4)CC3)(c3ccccc3)C2)cc(OC)c1OC
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Combine 1-(3,4,5-trimethoxybenzoyl)-3-(2-(4-(1-(4-cyanobutyl)-1H-benzimidazol-2-yl-amino)piperidin-1-yl)ethyl)-3-phenylpyrrolidine (0.7 mmol), sodium azide (0.13 g, 2.04 mmol), and triethylammonium hydrochloride (0.14 g, 1.03 mmol) in N-methylpyrrolidinone (6 mL). Heat to 150° C. After 4 hours, cool to ambient temperature and partition the reaction mixture between water and ethyl acetate. Separate the layers and extract the aqueous layer three times with ethyl acetate. Adjust the pH of the aqueous layer to about 1 using a 1 M aqueous hydrochloric acid solution. The aqueous layer is again extracted three times with ethyl acetate, and twice with dichloromethane. The aqueous layer is saturated with sodium chloride and again extracted four times with dichloromethane. Combine the organic layers, dry over MgSO4, filter, and evaporate in vacuo to give residue. Chromatograph the residue on silica to give the title compound.