Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][NH:4][C:5]([CH:7]([O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:24]=[CH:23][C:22]([N:25]3[CH2:30][CH2:29][N:28](C(O[Si](C(C)C)(C(C)C)C(C)C)=O)[CH2:27][CH2:26]3)=[CH:21][CH:20]=2)[CH:16]=[CH:17][CH:18]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])=[O:6])#[N:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)C.C(OCC)(=O)C.O.C(=O)(O)[O-].[Na+]>[C:1]([CH2:3][NH:4][C:5](=[O:6])[CH:7]([O:12][C:13]1[CH:14]=[C:15]([C:19]2[CH:20]=[CH:21][C:22]([N:25]3[CH2:26][CH2:27][NH:28][CH2:29][CH2:30]3)=[CH:23][CH:24]=2)[CH:16]=[CH:17][CH:18]=1)[CH2:8][CH:9]([CH3:11])[CH3:10])#[N:2]
Reactant: CC(C)CC(Oc1cccc(-c2ccc(N3CCN(C(=O)O[Si](C(C)C)(C(C)C)C(C)C)CC3)cc2)c1)C(=O)NCC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)CC(Oc1cccc(-c2ccc(N3CCNCC3)cc2)c1)C(=O)NCC#N

Procedure:
Triisopropylsilyl 4-[3′-(1-{[(cyanomethyl)amino]carbonyl}-3-methylbutoxy)[1,1′-biphenyl]-4-yl]-1-piperazinecarboxylate (365 mg, 0.6 mmoles) in 8 mL of tetrahydrofuran was treated with tetrabutylammonium fluoride (0.75 mL, 1 M in THF, 0.75 mmoles) at 0° C. until the disappearance of the starting material was observed by TLC. The reaction was diluted with diethyl ether, ethyl acetate, water and sat. aq. sodium bicarbonate. The phases were separated, the organic phase washed with brine and dried over sodium sulfate. After concentration under reduced pressure, the residue was purified by flash chromatography (1% sat. aqueous ammonium hydroxide, 9% methanol, 90% dichloromethane) to afford N-(cyanomethyl)-4-methyl-2-{[4′-(1-piperazinyl)[1,1′-biphenyl]-3-yl]oxy}pentanamide. MS (−ESI): 405.3 [M−1]−.
Reaction SMILES: [Mg].[F:2][C:3]1[C:8]([F:9])=[CH:7][CH:6]=[CH:5][C:4]=1Br.[CH2:11]([C@H:14]1[CH2:19][CH2:18][C@H:17]([C@H:20]2[CH2:25][CH2:24][C@H:23]([CH2:26][CH2:27][CH2:28][CH:29]=O)[CH2:22][CH2:21]2)[CH2:16][CH2:15]1)[CH2:12][CH3:13].[Cl-].[NH4+]>C1COCC1>[F:9][C:8]1[C:3]([F:2])=[C:4]([CH:29]=[CH:28][CH2:27][CH2:26][C@H:23]2[CH2:24][CH2:25][C@H:20]([C@H:17]3[CH2:16][CH2:15][C@H:14]([CH2:11][CH2:12][CH3:13])[CH2:19][CH2:18]3)[CH2:21][CH2:22]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCCC=O)CC2)CC1
Reactant: Fc1cccc(Br)c1F
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](CCC=Cc3cccc(F)c3F)CC2)CC1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
Under nitrogen gas stream, 8.05 g (331 mmol) of magnesium was added to 20.0 ml of THF, and a solution of 58.1 g (301 mmol) of 2,3-difluoro-1-bromobenzene in 600 ml of THF was added by drops thereto so that the reaction temperature was maintained at about 50° C. and then stirred at room temperature for 1 hour. To the reaction solution was added by drops a solution of 70.0 g (251 mmol) of the crude 4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)butanal obtained by the same manner as in the fifth step of Example 1 in 700 ml of THF, stirred at 50 to 60° C. for 2 hours, and then 200 ml of saturated aqueous ammonium chloride solution was added thereto to terminate the reaction. The reaction mixture was filtered with Celite, the solvent was distilled off under a reduced pressure, and then the residue was extracted with 700 ml of toluene. The organic layer was washed with 400 ml of water thrice and then dried over anhydrous magnesium sulfate. After the anhydrous magnesium sulfate was filtered off, 3.56 g of p-toluenesulfonic acid monohydrate was added to the filtrate, and heated to reflux for 4 hours. The organic layer was washed with 300 ml of water thrice and dried over anhydrous magnesium sulfate. The solvent was distilled off under a reduced pressure, and the residue was subjected to silica gel column chromatography (eluent: heptane) to obtain 63.5 g of a crude 2,3-difluoro-4-(4-(trans-4-(trans-4-propylcyclohexyl)cyclohexyl)-1-butenyl)benzene.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:18][CH3:19])(=[O:17])[CH:14]([CH3:16])[CH3:15].[C:20]1([CH2:26][CH2:27][CH2:28][CH2:29][CH:30]=[O:31])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[NH4+].[Cl-]>C1COCC1.C(O)(=O)C>[OH:31][CH:30]([CH2:29][CH2:28][CH2:27][CH2:26][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]([CH3:16])([CH3:15])[C:13]([O:18][CH3:19])=[O:17]
Reactant: O=CCCCCc1ccccc1
Reactant: COC(=O)C(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CC(=O)O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C(C)(C)C(O)CCCCc1ccccc1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 99 %

Procedure:
Diisopropylamine (7.2 mL, 52 mmol) is dissolved in THF (85 mL), cooled to -78° C. and n-butyl lithium in hexanes (23 mL, 52 mmol) is added slowly. The reaction is allowed to warm to -30° C. over 15 minutes and is then recooled to -78° C. A solution of methyl isobutyrate (6 mL, 52 mmol) in THF (15 mL) is added dropwise over 20 minutes and then stirred an additional 40 minutes. Next solution of 5-phenylpentanal (7 g, 43 mmol) in THF (10 mL) is added dropwise over 10 minutes and the reaction is stirred 1 hour. Acetic acid (3 mL) is added slowly followed by a solution of NH4Cl (20 mL) and the reaction is allowed to warm to room temperature. The reaction is partitioned between ether (200 mL) and water (150 mL). The organic phase is washed with 1 N HCl (2×50 mL), NaHCO3 (50 mL) and brine (50 mL). The solution is dried over MgSO4 and concentrated in vacuo to provide methyl 3-hydroxy-2,2-dimethyl-7-phenylheptanoate (11.2, 99%): 1H NMR (300 MHz, CDCl3) δ 7.30-7.24 (m, 2H), 7.18-7.16 (m, 3H), 3.68 (s, 3H), 3.60 (dd, J=9.7, 1.9 Hz, 1H), 2.61 (t, J=7.5 Hz, 2H), 2.37 (s, 1H), 1.73-1.20 (m, 6H), 1.17 (s, 3H), 1.15 (s, 3H); MS (EI) m/e 264 (M+).
Reaction SMILES: [N+]([O-])([O-])=O.[Nd+3:5].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[O:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(N(CC)CC)C>CO>[Nd:5].[O:14]([CH2:21][C:22]([OH:24])=[O:23])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [Nd+3]
Agent: O=C(O)COc1ccccc1
Agent: O=[N+]([O-])[O-]
Solvent: CO
Solvent: CCN(CC)CC
Product: [Nd]
Temperature: 25 °C

Procedure:
The compound was synthesized by the same method as that for Synthesis Example 1-2 above, that is, after forming a triethylamine salt of phenoxyacetic acid in anhydrous methanol, a methanol solution of neodymium nitrate was added while stirring. Specifically, a reactor similar to that of 1-1 was used to stir a solution obtained by adding 100 ml of an anhydrous methanol to 45.65 g (0.3 mol) of phenoxyacetic acid, while dripping 30.4 g (0.3 mol) of triethylamine while maintaining at 25° C. by cooling in an ice water bath. After dripping, the solution was heated for 30 minutes at 40° C. to prepare a transparent synthesis solution of phenoxyacetic acid-triethylamine salts. Next, this synthesis solution was maintained at about 30° C., and a solution obtained by dissolving 43.8 g of neodymium nitrate into 100 ml of methanol was dripped in while stirring. Upon completion of the dripping of the neodymium nitrate solution, it began to cloud, and the clouding increased with time. 30 minutes after completion of dripping, the solution was heated to 40° C. for 30 minutes, to produce a slurry solution of a neodymium salt of phenoxyacetic acid. Crystals obtained by filtering this slurry solution were added to 200 ml of methanol, stirred and washed, then refiltered, and 200 ml of methanol were once again added to the crystals, stirred and washed, then filtered. The resulting crystals were dried under reduced pressure at 50° C., to obtain 38.8 g of a neodymium salt of phenoxyacetic acid (yield 65%).
Reaction SMILES: C([O-])(O)=O.[Na+].[CH2:6]([N:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2=[N:19][C:20]([C:22]([O:24]CC)=[O:23])=[N:21][N:11]2[C:10]1=[O:27])[CH2:7][CH3:8]>O>[CH2:6]([N:9]1[C:18]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:12]2=[N:19][C:20]([C:22]([OH:24])=[O:23])=[N:21][N:11]2[C:10]1=[O:27])[CH2:7][CH3:8]
Reactant: CCCn1c(=O)n2nc(C(=O)OCC)nc2c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CCCn1c(=O)n2nc(C(=O)O)nc2c2ccccc21

Procedure:
1.1 g of NaHCO3 were added to 3.5 g (0.012 mole) of ethyl 6-propyl-1,2,4-triazolo[1,5-c]quinazolin-5-one-2-carboxylate in 50 ml of water, and the mixture was refluxed for 8 hours. It was then filtered, and acidified with dilute HCl, and the precipitate was filtered off under suction and dried. Yield: 1.0 g (32%), mp. 233°-235° C.
Reaction SMILES: [CH2:1]([NH2:5])[CH2:2][CH2:3][CH3:4].Cl[CH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1>C(#N)C.CN(C)C=O>[CH2:1]([NH:5][CH2:7][C:8]1[NH:9][C:10]2[CH:16]=[CH:15][CH:14]=[CH:13][C:11]=2[N:12]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN
Reactant: ClCc1nc2ccccc2[nH]1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCCCNCc1nc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 3 h
Yield: 42.6 %

Procedure:
Butylamine (30 mL, 300 mmol) was dissolved in 150 mL of acetonitrile at room temperature. 2-Chloromethylbenzimidazole (5 g, 30 mmol) dissolved in 50 mL dimethylformamide was added dropwise. After stirring 3 hours at room temperature, the solvent was removed in vacuo. The residue was dissolved in 100 mL ethyl acetate and washed 2×100 mL H2O followed by 1×100 mL brine. The organic layer was dried over MgSO4, filtered, and then concentrated. The residue was purified by silica gel chromatography eluting first with ethyl acetate then with 10/2/1 ethyl acetate/methanol/triethylamine to yield 2.6 g 2-butylaminomethylbenzimidazole.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:10]=[C:9]([C:11]([Cl:14])([CH3:13])[CH3:12])[CH:8]=[C:7]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:6]=1)=[N+]=[N-]>CO.[Pd]>[CH2:16]([O:15][C:7]1[CH:6]=[C:5]([CH2:4][NH2:1])[CH:10]=[C:9]([C:11]([Cl:14])([CH3:13])[CH3:12])[CH:8]=1)[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)(Cl)c1cc(CN=[N+]=[N-])cc(OCc2ccccc2)c1
Agent: [Pd]
Solvent: CO
Product: CC(C)(Cl)c1cc(CN)cc(OCc2ccccc2)c1
Temperature: 25 °C
Reaction time: 4.5 h

Procedure:
A mixture of 103 mg of 1-(azidomethyl)-3-(benzyloxy)-5-(2-chloropropan-2-yl)benzene and 10.4 mg of 10% Pd/C in 5 mL of MeOH was stirred at r.t. under H2 balloon for 4.5 h. The mixture was filtered through Celite and concentrated. (3-(benzyloxy)-5-(2-chloropropan-2-yl)phenyl)methanamine was used in the next reaction without further purification.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH:4]1[CH2:6][CH2:5]1.[OH-].[K+].C([O-])([O-])=O.[K+].[K+].Cl[C:16]1[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([OH:23])[C:17]=1[CH3:24]>O.C1COCC1>[CH:4]1([CH2:3][NH:2][C:16]2[N:21]=[C:20]([CH3:22])[N:19]=[C:18]([OH:23])[C:17]=2[CH3:24])[CH2:6][CH2:5]1
Reactant: NCC1CC1
Reactant: Cc1nc(O)c(C)c(Cl)n1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(O)c(C)c(NCC2CC2)n1
Temperature: 80 °C
Yield: 81.1 %

Procedure:
To 3.92 g (36.3 mmol, 4 equiv.) of (aminomethyl)cyclopropane hydrochloride was added 2.5 g (44.6 mmol) of potassium hydroxide dissolved in 10 mL of water. The resulting slurry was thoroughly mixed and then dried with 1.0 g of KOH. The free amine was filtered through anhydrous K2CO3 with dry THF rinses (3×2 mL) into 1.44 g (9.08 mmol) of 6-chloro-2,5-dimethyl-4-pyrimidinol. The stirred clear solution was heated at 80° C. for 31/2 days in a sealed 40 mL tube. The cooled, 23° C., mixture was purified by flash chromatography (silica gel, 41 mm column, 5% MeOH in EtoAc as eluant) to afford 1.42 g (7.36 mmol, 81%) of pure product m.p. 227°-228° C.
Reaction SMILES: S(Cl)([Cl:3])=O.[CH2:5]([CH:10]1[CH2:13][CH:12]([C:14]([OH:16])=O)[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]>C1C=CC=CC=1>[CH2:5]([CH:10]1[CH2:13][CH:12]([C:14]([Cl:3])=[O:16])[CH2:11]1)[CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: O=S(Cl)Cl
Reactant: CCCCCC1CC(C(=O)O)C1
Solvent: c1ccccc1
Product: CCCCCC1CC(C(=O)Cl)C1
Yield: 91.1 %

Procedure:
A reaction vessel was charged with 140 g of thionyl chloride and 100 ml of benzene, and 100 g of 3-pentylcyclobutanecarboxylic acid was added dropwise under reflux with stirring. The resultant mixture was refluxed with stirring for 8 hours and the excess thionyl chloride was azeotropically distilled off with benzene and the residue was distilled under reduced pressure to obtain 101 g (yield 91%) of 3-pentylcyclobutanecarboxylic acid chloride.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=3)=[CH:16][C:11]=2[C:12]([O:14]C)=[O:13])=[CH:4][CH:3]=1.[OH-].[Li+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][O:9][C:10]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[N:22][N:23]([CH2:25][CH2:26][N:27]4[CH2:32][CH2:31][O:30][CH2:29][CH2:28]4)[CH:24]=3)=[CH:16][C:11]=2[C:12]([OH:14])=[O:13])=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc(-c2cnn(CCN3CCOCC3)c2)ccc1OCc1ccc(F)cc1

Procedure:
To a solution of methyl 2-{[(4-fluorophenyl)methyl]oxy}-5-{1-[2-(4-morpholinyl)ethyl]-1H-pyrazol-4-yl}benzoate (may be prepared as described in Description 113; 372 mg, 0.85 mmol) in tetrahydrofuran (25 ml) was added lithium hydroxide (60.8 mg, 2.54 mmol), water (5 ml) and the mixture was refluxed for 4 hours. The mixture was evaporated under reduced pressure on a buchi. The residue was taken up into water (10 ml) and acidified using 2M aqueous HCl to pH 1. The solid formed was filtered, washed with water and dried in air under vacuum to yield the title compound as a light brown solid. 170 mg.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetic acid (156 mg, 0.501 mmol, described in Intermediate 22), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (145 mg, 0.577 mmol, described in Intermediate 9), HOBT (95 mg, 0.620 mmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between H2O (60 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH-100:0 to 90:10, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2025; calculated m/z=545.1995 for C30H27F2N4O4.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:13](=[CH:14][CH:15]=1)[N:12]([CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=1)[C:11]1[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:28])[CH3:27])[CH2:7][C:6]2=1)#[N:2].N[NH:31][C:32]([NH2:34])=[S:33].[NH4+].[OH-]>FC(F)(F)C(O)=O>[NH2:34][C:32]1[S:33][C:1]([C:3]2[CH:4]=[C:5]3[C:13](=[CH:14][CH:15]=2)[N:12]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)[C:11]2[CH2:10][CH2:9][CH:8]([NH:24][C:25](=[O:29])[CH:26]([CH3:27])[CH3:28])[CH2:7][C:6]3=2)=[N:2][N:31]=1
Reactant: NNC(N)=S
Reactant: CC(C)C(=O)NC1CCc2c(c3cc(C#N)ccc3n2Cc2cccc(F)c2)C1
Agent: [NH4+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C(=O)NC1CCc2c(c3cc(-c4nnc(N)s4)ccc3n2Cc2cccc(F)c2)C1
Yield: 16.9 %

Procedure:
Heat a mixture of N-[6-cyano-9-(3-fluorobenzyl)-2,3,4,9-tetrahydro-1H-carbazol-3-yl]isobutyramide (example 51) (0.500 g, 1.28 mmol) and thiosemicarbazide (0.129 g, 1.41 mmol) in trifluoroacetic acid (5 ml) at 70° C. under nitrogen for 18 h. Pour the mixture onto dilute NH4OH solution and collect 0.510 g of the resultant precipitate by filtration. Azetrope the precipitate with absolute EtOH and purify by silica chromatography eluting with 0.05% NH4OH in EtOAc to give 0.10 g of a white solid. MS (ES): m/z 464 (M+1); HPLC: Rt=1.89 min, (100%); m.p.=251-254° C.
Reaction SMILES: [CH2:1]([N:8]([CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[F:16])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.CN(C)[CH:31]=[O:32].O>O1CCCC1>[CH2:17]([N:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]1[C:10]([F:16])=[C:11]([C:12]([F:15])=[CH:13][CH:14]=1)[CH:31]=[O:32])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: Fc1ccc(N(Cc2ccccc2)Cc2ccccc2)c(F)c1
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: O=Cc1c(F)ccc(N(Cc2ccccc2)Cc2ccccc2)c1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To dibenzyl-(2,4-difluoro-phenyl)-amine (52, 4.30 g, 13.9 mmol) in tetrahydrofuran (60 mL), under an atmosphere of nitrogen, cooled in a −78° C. acetone/dry ice bath, was added n-butyllithium (2.50 M in hexane, 6.1 mL, 15.3 mmol) slowly. The reaction was stirred for 1 hour, N,N-dimethylformamide (1.2 mL, 15.3 mmol) was added and the reaction was allowed to warm to room temperature for 1 hour. The reaction was poured into water and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 10% ethyl acetate in hexane to provide the compound (53, 4.0 g, 85%). MS (ESI) [M+H+]+=337.2.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]4[CH2:32][O:31]4)=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8].FC(F)(F)C(O)=[O:36].[OH-].[Na+].O>C(Cl)Cl>[CH3:1][C:2]1[CH:3]=[C:4]([O:15][C:16]2[C:25]3[C:20](=[CH:21][C:22]([O:28][CH2:29][CH:30]([OH:31])[CH2:32][OH:36])=[C:23]([O:26][CH3:27])[CH:24]=3)[N:19]=[CH:18][CH:17]=2)[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:6][C:7]=1[CH3:8]
Reactant: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC1CO1
Reactant: O=C(O)C(F)(F)F
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O
Product: COc1cc2c(Oc3cc(C)c(C)nc3-c3ccccc3)ccnc2cc1OCC(O)CO
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66 %

Procedure:
4-(5,6-Dimethyl-2-phenyl-pyridin-3-yloxy)-6-methoxy-7-oxiranylmethoxy-quinoline (compound 334) (130 mg) was dissolved in methylene chloride (2 ml) to prepare a solution which was then brought to 0° C. Trifluoroacetic acid (1 ml) was added to the solution, and the mixture was stirred at 0° C. for 30 min and was then stirred at room temperature for 3 hr. The reaction solution was brought to 0° C., was stirred, and was made alkaline by the addition of a 10% aqueous sodium hydroxide solution. Water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was then washed with saturated brine and was dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (89 mg, yield 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.[NH2:17][CH2:18][C:19]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C)C=O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]=[C:13]([CH3:16])[S:14][CH:15]=2)=[CH:7][C:3]=1[C:4]([NH:17][CH2:18][C:19]1([OH:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)=[O:6]
Reactant: Cc1nc(-c2ccc(Cl)c(C(=O)O)c2)cs1
Reactant: NCC1(O)CCCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: Cc1nc(-c2ccc(Cl)c(C(=O)NCC3(O)CCCCCC3)c2)cs1
Temperature: 25 °C
Reaction time: 16 h
Yield: 33.2 %

Procedure:
A mixture of 2-chloro-5-(2-methyl-thiazol-4-yl)-benzoic acid (7 mg, 0.027 mmol), 1-aminomethyl-cycloheptanol (6 mg, 0.03 mmol), 1-hydroxybenzotriazole (5 mg, 0.03 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (6 mg, 0.03 mmol) and triethylamine (5 μL, 0.03 mmol) in N,N-dimethylformamide (0.5 mL) was stirred at room temperature for 16 h. The mixture was diluted with ethyl acetate and washed with 5% citric acid, water, then brine. The organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography (1:1 ethyl acetate-hexanes) to afford the title compound (3.4 mg).
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[CH2:24]([CH:26]([CH2:30][CH3:31])[C:27](Cl)=[O:28])[CH3:25]>>[CH2:24]([CH:26]([CH2:30][CH3:31])[C:27]([NH:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1)=[O:28])[CH3:25]
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Reactant: CCC(CC)C(=O)Cl
Product: CCC(CC)C(=O)Nc1c[nH]nc1-c1nc2cc3c(cc2[nH]1)C(C)(C)C(=O)N3CC

Procedure:
2-Ethyl-N-[3-(5-ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-butyramide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 2-ethylbutyryl chloride (121 μl, 0.87 mmol). The title compound was obtained as yellow powder (230 mg, 70%).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([C:7]2[NH:11][N:10]=[C:9]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=3)[C:8]=2[C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[CH2:3][CH2:2]1.Cl.[O:26]1CC[O:29][CH2:28][CH2:27]1>CCOCC>[ClH:18].[OH:29][CH2:28][C:27]([N:11]1[C:7]([CH:4]2[CH2:5][CH2:6][NH:1][CH2:2][CH2:3]2)=[C:8]([C:19]2[CH:24]=[CH:23][N:22]=[CH:21][N:20]=2)[C:9]([C:12]2[CH:13]=[CH:14][C:15]([Cl:18])=[CH:16][CH:17]=2)=[N:10]1)=[O:26]
Reactant: C1COCCO1
Reactant: Clc1ccc(-c2n[nH]c(C3CCNCC3)c2-c2ccncn2)cc1
Agent: Cl
Solvent: CCOCC
Product: O=C(CO)n1nc(-c2ccc(Cl)cc2)c(-c2ccncn2)c1C1CCNCC1
Reaction time: 2 h

Procedure:
A 25 mL round bottom flask was charged with 65 mg (0.164 mmol) of N-(2-hydroxyacetyl-(5-(4piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole and 2.5 mL of dioxane. To this suspension was added 0.0.82 mL of 4 N HCl in dioxane. The mixture was stirred for 2 hours. The mixture was diluted with 5 mL of Et2O and filtered. The solid was dried over solid CaSO4 under vacuum for 12 h to afford 68 mg of N-(2-hydroxyacetyl)-5-(4-piperidyl)-4-(4-pyrimidyl)-3-(4-chlorophenyl)pyrazole hydrochloride. 1H NMR (DMSO-d6) 9.18(s, 1H), 8.63(d, J=5.37 Hz, 1H), 7.40(d, J=8.59 Hz, 2H), 7.33(d, J=8.59 Hz, 2H), 7.15(m, 1H), 4.40(m, 1H), 4.06(m, 2H), 3.72(m, 1H), 3.33(m, 1H), 2.97(m, 1H), 2.62(m, 1H), 1.83(m, 2H), 1.64(m, 2H); MS (M+H): 398
Reaction SMILES: C[O:2][CH:3]=[CH:4][CH2:5][CH2:6][C@H:7]1[CH2:12][CH2:11][C@H:10]([C:13]2[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=2)[CH2:9][CH2:8]1.O>O1CCCC1>[C:17]([C:16]1[CH:19]=[CH:20][C:13]([C@H:10]2[CH2:11][CH2:12][C@H:7]([CH2:6][CH2:5][CH2:4][CH:3]=[O:2])[CH2:8][CH2:9]2)=[CH:14][CH:15]=1)#[N:18]
Reactant: COC=CCC[C@H]1CC[C@H](c2ccc(C#N)cc2)CC1
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc([C@H]2CC[C@H](CCCC=O)CC2)cc1

Procedure:
A solution of 2.95 g of p-[trans-4-(4-methoxy-3-butenyl)cyclohexyl]benzonitrile in 100 ml of tetrahydrofuran/2N hydrochloric acid (vol. 4:1 ) was heated to reflux for 15 minutes. The reaction mixture was subsequently poured into 100 ml of water and extracted three times with 100 ml of diethyl ether each time. The organic phases were washed twice with 100 ml of water each time, dried over magnesium sulphate and concentrated, whereby 2.6 g (93%) of 4-[trans-4-(p-cyanophenyl)cyclohexyl]butyraldehyde were obtained as a slightly yellowish oil; Rf-value (toluene/ethyl acetate vol. 95:5) 0.23.