Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:32]=[CH:31][C:25]([C:26]([O:28]CC)=[O:27])=[CH:24][CH:23]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2.[OH-].[Na+]>CCO.C1COCC1>[CH3:1][C:2]1([CH3:33])[CH2:11][CH:10]=[C:9]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[C:8]2[CH:7]=[C:6]([C:19]([NH:21][C:22]3[CH:23]=[CH:24][C:25]([C:26]([OH:28])=[O:27])=[CH:31][CH:32]=3)=[O:20])[CH:5]=[CH:4][C:3]1=2
Reactant: CCOC(=O)c1ccc(NC(=O)c2ccc3c(c2)C(c2ccc(C)cc2)=CCC3(C)C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: Cc1ccc(C2=CCC(C)(C)c3ccc(C(=O)Nc4ccc(C(=O)O)cc4)cc32)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of 26.5 mg (0.06 mmol) ethyl 4[[(5,6-dihydro-5,5-dimethyl-8-(4-methylphenyl)-2-naphthalenyl)carbonyl]amino]-benzoate (Compound 35) in 3.0 ml EtOH and 4.0 ml of THF was added 240.1 mg NaOH (6.00 mmol, 3.0 ml of a 2M aqueous solution). After stirring at room temperature for 72 hours, the reaction was quenched by the addition of 10% HCl. Extraction with EtOAc, and drying of the organic layers over MgSO4, provided a solid after removal of the solvent under reduced pressure. Crystallization from CH3CN afforded the title compound as a colorless solid. 1H NMR (d6-DMSO): δ 10.4 (1H, s), 7.91-7.81 (5H, m), 7.54 (1H, d, J=8.1 Hz), 7.45 (1H, d, J=1.7 Hz), 7.23 (4H, s), 6.04 (1H, t, J=4.7 Hz), 2.35 (5H, s), 1.33 (6H, s).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]2.Cl[CH2:14][C:15]([N:17]1[CH2:22][CH2:21][CH:20]([CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:19][CH2:18]1)=[O:16]>C(O)C>[CH2:23]([CH:20]1[CH2:19][CH2:18][N:17]([C:15](=[O:16])[CH2:14][NH:1][C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[NH:8][C:7](=[O:12])[CH2:6][CH2:5]3)[CH2:22][CH2:21]1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(CCl)N1CCC(Cc2ccccc2)CC1
Reactant: Nc1ccc2c(c1)CCC(=O)N2
Solvent: CCO
Product: O=C1CCc2cc(NCC(=O)N3CCC(Cc4ccccc4)CC3)ccc2N1

Procedure:
The title compound is prepared from 6-amino-3,4-dihydro-1H-quinoline-2-one and 2-chloro-1-(4-benzyl-piperidin-1-yl)-ethanone (Example 200a) according to the method described in Example 206. Melting Point: 184-187° C. (ethanol)
Reaction SMILES: CCCCCC.[S:7]1[CH:11]=[CH:10][C:9]2[CH:12]=[CH:13][CH:14]=[CH:15][C:8]1=2.[Br:16][C:17]1[CH:18]=[CH:19][C:20]([Cl:25])=[C:21]([CH:24]=1)[CH:22]=[O:23].[Cl-].[NH4+]>O1CCCC1>[S:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=2[CH:10]=[C:11]1[CH:22]([C:21]1[CH:24]=[C:17]([Br:16])[CH:18]=[CH:19][C:20]=1[Cl:25])[OH:23]
Reactant: c1ccc2sccc2c1
Reactant: O=Cc1cc(Br)ccc1Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: OC(c1cc2ccccc2s1)c1cc(Br)ccc1Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
1.6 M n-butylithium hexane solution (26.9 mL) was added to a mixture of benzo[b]thiophene (5.8 g, 0.043 mol) and tetrahydrofuran (58 mL) at −78° C. over 20 minutes. After stirred for 0.5 hours, the mixture was added with a tetrahydrofuran (50 mL) solution of 5-bromo-2-chlorobenzaldehyde (9.0 g, 0.041 mol) and stirred for further five minutes. The reaction mixture was warmed to room temperature. After the reaction mixture was added with a saturated ammonium chloride aqueous solution and extracted with ethyl acetate, the organic phase was washed with brine and then dried with anhydrous magnesium sulfate. After the desiccant was filtered off, the residue obtained by evaporating the solvent under reduced pressure was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to obtain pale yellow oily (1-benzothien-2-yl)(5-bromo-2-chlorophenyl)methanol (10.3 g, 71%).
Reaction SMILES: OS(O)(=O)=O.[CH3:6][O:7][C:8]1[C:9](=[O:20])[C:10]2[C:15]([C:16](=[O:18])[CH:17]=1)=[C:14]([CH3:19])[CH:13]=[CH:12][CH:11]=2.[N-:21]=[N+]=[N-].[Na+].CO>O>[CH3:6][O:7][C:8]1[C:9](=[O:20])[NH:21][C:10]2[CH:11]=[CH:12][CH:13]=[C:14]([CH3:19])[C:15]=2[C:16](=[O:18])[CH:17]=1
Reactant: COC1=CC(=O)c2c(C)cccc2C1=O
Reactant: [N-]=[N+]=[N-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: COc1cc(=O)c2c(C)cccc2[nH]c1=O
Yield: 93 %

Procedure:
To stirred, ice bath cold, concd H2SO4 (12 mL, Baker), there was added 2-methoxy-5-methylnaphthalene-1,4-dione (800 mg, 3.96 mmol) in portions. A deep red solution resulted. To this cold solution, NaN3 (515 mg, 7.92 mmol, Aldrich) was added in portions over one min. The ice bath was removed and the reaction was allowed to stir at rt for 18 h under N2. Nitrogen evolution was noted. The reaction was added to crushed ice (50 mL) to give a thick green suspension. This was diluted with H2O (30 mL) and vigorously stirred with 30% MeOH/70% CHCl3 (60 mL) until all the solid had dissolved. The layers were separated and the aqueous portion was extracted with 30% MeOH/70% CHCl3 (2×30 mL). The combined red organic portion was washed with water (1×30 mL), saturated NaHCO3 (1×30 mL) and brine (1×30 mL), filtered through cotton and the solvent removed in vacuo to give a red solid (800 mg). Crystallization from 95% EtOH (dissolved in 30 mL, hot filtered, concd to 20 mL, allowed to cool to rt then in an ice bath) a gave colorless fluffy needles (564 mg, 66%, pure by 1H NMR); mp 215.5° -217° C.; 1H NMR (DMSO-d6) δ2.32 (s, 3H), 3.71 (s, 3H), 6.32 (s, 1H), 7.08 (d, J=7.5 Hz, 1H), 7.15 (d, J=8.1 Hz, 1H), 7.36 (t, J=7.8 Hz, 1H), 11.00 (s, 1H); IR (KBr) 3195 (m), 3134 (m), δ3061 (m), 2999 (m), 2967 (m), 2939 (m), 1691 (s), 1649 (s), 1616 (s), 1212 (m), 834 (m), 783 (m); MS (m/z) 217 (M+, 100).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[NH:13][N:14]=[C:15](Cl)[CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17].[CH2:23]([NH:25][C:26]#[N:27])[CH3:24].C(N(CC)CC)C>O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:26]([NH:25][CH2:23][CH3:24])=[N:27][C:15]([CH:16]([C:18]([F:21])([F:20])[F:19])[CH3:17])=[N:14]1
Reactant: CC(C(Cl)=NNc1c(Cl)cc(C(F)(F)F)cc1Cl)C(F)(F)F
Reactant: CCNC#N
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCNc1nc(C(C)C(F)(F)F)nn1-c1c(Cl)cc(C(F)(F)F)cc1Cl
Reaction time: 3 h
Yield: 68.9 %

Procedure:
7.8 g (0.02 mol) of 2-trifluoromethylpropionyl chloride 2,6-dichloro-4-trifluoromethylphenylhydrazone and 1.5 g (0.022 mol) of ethyl cyanamide were dissolved in 50 ml of tetrahydrofuran, and 2.5 g (0.025 mol) of triethylamine was dropwise added thereto under stirring and cooling with ice. After completion of the dropwise addition, the stirring was continued at room temperature for 3 hours. The solvent was distilled off under reduced pressure. The residue was dissolved in hexane, and the organic layer was washed with water and dried over anhydrous magnesium sulfate. Then, hexane was distilled off under reduced pressure. Further, the residue was subjected to distillation under reduced pressure. The fraction having a boiling point of 110°-120° C./0.1-0.2 mmHg was subjected to recrystallization from hexane to obtain 5.8 g (yield: 69%) of the desired compound having a melting point of from 82° to 83° C. as slightly yellow prismatic crystals.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10](C=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1.[N:51]1([C:57](OC(C)(C)C)=O)[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C>CS(C)=O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:57][N:51]3[CH2:52][CH2:53][NH:54][CH2:55][CH2:56]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[C:24]([CH3:26])[CH:23]=[C:22]([C:27]([NH:29][CH2:30][C:31]3[C:32]([NH:44][CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)=[C:33]4[CH:41]=[N:40][N:39]([CH2:42][CH3:43])[C:34]4=[N:35][C:36]=3[CH2:37][CH3:38])=[O:28])[CH:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CS(C)=O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cc(C)cc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCNCC4)c3)c2)c1
Temperature: 60 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
N-[(6-Chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-5-methyl-1,3-benzenedicarboxamide (30.36 mg, 0.044 mmol), 1,1-dimethylethyl 1-piperazinecarboxylate (82 mg, 0.44 mmol, 10 eq) and acetic acid (2.51 μL, 0.044 mmol, 1 eq) were dissolved in DMSO (1.5 mL). The mixture was stirred in VX-2500 Multi-Tube Vortexer for overnight at room temperature. MP-triacetoxyborohydride (133 mg, 0.310 mmol, 7 eq) was then added and the mixture was stirred again in VX-2500 Multi-Tube Vortexer for overnight at room temperature. The reaction mixture was filtered through a polypropylene cartridge (10 mL tube) on Bohdan Miniblock in a reaction tube and concentrated in a Glas-Col evaporator. Methanol (2 mL) then hydrochloric acid (5 μL) were added for the deprotection of 1,1-dimethylethyl 4-[(2′-chloro-5′-{[({3-[({[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}amino)carbonyl]-5-methylphenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate. The vial containing the reaction mixture was closed and stirred in a Glas-Col evaporator for overnight at 60° C. The reaction mixture was then concentrated and purified using a Gilson HPLC with a water-acetonitrile with 0.1% TFA buffer. The desired product fractions were combined, filtered through amine cartouche (500 mg) on Bohdan Miniblock and concentrated in a Glas-Col evaporator, giving 23.82 mg (64.1%) of the title compound. LC-MS m/z 763 (M+H)+, 1.32 min (ret time).
Reaction SMILES: Br[CH2:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[N:16]=[C:15]([C:17]3[CH:21]=[C:20]([CH3:22])[N:19]([CH2:23][C:24]4[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=4)[N:18]=3)[O:14][N:13]=2)=[CH:8][CH:7]=1)=[O:4].[CH2:31]1N2CN3CN(C2)C[N:32]1C3.C(OCC)(=O)C.C(=O)(O)[O-].[Na+]>C(O)C>[CH3:22][C:20]1[N:19]([CH2:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=2)[N:18]=[C:17]([C:15]2[O:14][N:13]=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([N:5]4[C:3](=[O:4])[CH2:2][NH:32][CH2:31]4)=[CH:7][CH:8]=3)[N:16]=2)[CH:21]=1
Reactant: Cc1ccc(Cn2nc(-c3nc(-c4ccc(NC(=O)CBr)cc4)no3)cc2C)cc1
Reactant: C1N2CN3CN1CN(C2)C3
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1ccc(Cn2nc(-c3nc(-c4ccc(N5CNCC5=O)cc4)no3)cc2C)cc1
Temperature: 25 °C

Procedure:
To a solution of 2-bromo-N-(4-{5-[5-methyl-1-(4-methylbenzyl)-1H-pyrazol-3-yl]-1,2,4-oxadiazol-3-yl}phenyl)acetamide (Step 2, 190 mg, 0.407 mmol) in ethanol (4 mL) was added hexamethylenetetramine (286 mg, 2.04 mmol). The reaction mixture was stirred and heated at reflux for 2.5 h. After being cooled to rt, the solvent was evaporated, and the residue was subjected to preparative HPLC. The crude product thus obtained was treated with a mixture of ethyl acetate and saturated aqueous sodium bicarbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over anhydrous sodium sulfate. Subsequent filtration and evaporation of the solvent yielded the title compound which was obtained in pure form after stirring with cyclohexane (84 mg, 50%): 1H NMR (400 MHz, CDCl3) δ 8.23 (d, 2H), 7.70 (d, 2H), 7.13 (d, 2H), 7.07 (d, 2H), 6.79 (s, 1H), 5.40 (s, 2H), 4.92 (s, 2H), 3.69 (s, 2H), 2.32 (s, 3H), 2.25 (s, 3H); ES-MS m/z 415, HPLC RT (Method E) 1.62 min.
Reaction SMILES: [OH-:1].[Na+].[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]#[N:29])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]>C(O)C>[C:3]([O:7][C:8]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:23]2[C:27]([C:28]([NH2:29])=[O:1])=[C:26]([C:30]([OH:33])([CH3:32])[CH3:31])[N:25]=[C:24]2[CH2:34][CH2:35][CH2:36][CH3:37])=[CH:18][CH:17]=1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CCCCc1nc(C(C)(C)O)c(C#N)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Reactant: [OH-]
Agent: [Na+]
Solvent: CCO
Product: CCCCc1nc(C(C)(C)O)c(C(N)=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1

Procedure:
10 ml of a 1N aqueous solution of sodium hydroxide were added to a solution of 232 mg of 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-(1-hydroxy-1-methylethyl)imidazole-5-carbonitrile [prepared as described in Example 10(a)]in 10 ml of ethanol, and the resulting mixture was heated under reflux for 3 hours. At the end of this time, the reaction mixture was worked up in a similar manner to that described in Example 45(c), to afford 185 mg of the title compound as an amorphous solid.
Reaction SMILES: [OH:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1.[H-].[Na+].[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C=O)C>[CH2:25]([O:1][C@H:2]([CH3:22])[CH2:3][CH2:4][CH2:5][CH2:6][O:7][C:8]1([CH3:21])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: C[C@@H](O)CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](CCCCOC1(C)CCN(C(=O)OC(C)(C)C)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
To a solution of (R)-tert-butyl 4-((5-hydroxyhexyl)oxy)-4-methylpiperidine-1-carboxylate (4.5 g, 14.27 mmol) in DMF (50 mL) at 0° C. was added 60% NaH (0.685 g, 17.12 mmol) and the resulting mixture was stirred at room temp for 1 h. Benzyl bromide (2.55 mL, 21.40 mmol) was then added and the mixture was stirred for 16 h. Water (20 mL) was then added and the mixture was extracted with ether (100 mL), washed with brine (25 ml), dried (Na2SO4), filtered and concentrated. The residue was then purified by Biotage (0-20% EtOAc/hexane) to afford (R)-tert-butyl 4-((5-(benzyloxy)hexyl)oxy)-4-methylpiperidine-1-carboxylate (3.5 g, 8.63 mmol, 60.5% yield) as light yellow oil. 1H NMR (500 MHz, CDCl3) δ 7.38-7.35 (m, 4H), 7.31-7.25 (m, 1H), 4.60 (d, J=11.8 Hz, 1H), 4.48 (d, J=11.8 Hz, 1H), 3.86-3.62 (m, 3H), 3.58-3.50 (m, 1H), 3.31 (t, J=6.3 Hz, 2H), 3.14 (br. s., 2H), 1.74 (d, J=12.9 Hz, 2H), 1.59-1.51 (m, 3H), 1.47 (s, 9H), 1.46-1.37 (m, 4H), 1.22 (d, J=6.1 Hz, 3H), 1.17 (s, 3H). LCMS (M+H)=406.3.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11](Cl)=[O:12].[CH2:15]([OH:17])[CH3:16]>C1C=CC=CC=1.C(Cl)(Cl)Cl>[CH3:1][C:2]1([CH3:14])[C@@H:4](/[CH:5]=[CH:6]/[C:7]([O:9][CH3:10])=[O:8])[C@H:3]1[C:11]([O:17][CH2:15][CH3:16])=[O:12]
Reactant: CCO
Reactant: COC(=O)/C=C/[C@H]1[C@@H](C(=O)Cl)C1(C)C
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@@H]1[C@H](/C=C/C(=O)OC)C1(C)C

Procedure:
Using the procedure of Example 3, 1.51 g of (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylic acid chloride in 10 ml of benzene and 0.465 ml of ethanol were reacted to obtain 0.837 g of ethyl (1R,cis) 2,2-dimethyl-3-[(E)-3-methoxy-3-oxo-1-propenyl]-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =-21°±1.5° (c=1% in chloroform).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:25]([C:26]([NH2:28])=[O:27])=[C:17]3[NH:18][C:19]4[CH2:24][CH2:23][NH:22][CH2:21][C:20]=4[N:16]3[N:15]=2)=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:36][CH:37]=[CH:38][C:39]#[N:40]>CC(C)=O>[C:39](/[CH:38]=[CH:37]/[CH2:36][N:22]1[CH2:23][CH2:24][C:19]2[NH:18][C:17]3[N:16]([N:15]=[C:14]([C:11]4[CH:10]=[CH:9][C:8]([O:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)=[CH:13][CH:12]=4)[C:25]=3[C:26]([NH2:28])=[O:27])[C:20]=2[CH2:21]1)#[N:40]
Reactant: N#CC=CCBr
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c3c([nH]c12)CCNC3
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: N#C/C=C/CN1CCc2[nH]c3c(C(N)=O)c(-c4ccc(Oc5ccccc5)cc4)nn3c2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 6 %

Procedure:
To a solution of 2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide (100 mg, 0.268 mmol) in 10 mL of acetone at RT was added K2CO3 (140 mg, 1.07 mmol). After stirring at RT for 2 hr, 4-bromobut-2-enenitrile (40 mg, 0.268 mmol) in 2 mL of acetone was added and stirred at RT overnight. The mixture was then partitioned between EA (50 mL) and water (100 mL). The aqueous phase was further extracted with 50 mL of EA. The combined organic layers were washed with brine, dried over Na2SO4, concentrated to get crude product which was further purified by pre-TLC (DCM/MeOH=15/1) to afford 7 mg (6%) of (E)-7-(3-cyanoallyl)-2-(4-phenoxyphenyl)-5,6,7,8-tetrahydro-4H-pyrazolo[5′,1′:2,3]imidazo[4,5-c]pyridine-3-carboxamide as a light yellow solid. 1H NMR (400 MHz, CDCl3) δ 10.45 (s, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.42-7.30 (m, 2H), 7.16 (t, J=7.6 Hz, 1H), 7.10 (d, J=8.4 Hz, 2H), 7.06 (d, J=7.6 Hz, 2H), 6.76 (dt, J=16.3, 4.6 Hz, 1H), 5.67 (d, J=16.3 Hz, 1H), 5.62 (s, 2H), 3.82 (s, 2H), 3.41 (d, J=4.6 Hz, 2H), 2.95-2.75 (m, 4H). MS (ESI) m/e [M+1]+ 439.9.
Reaction SMILES: BrC1C=CC(OC)=CC=1CC[C:12]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:13].[CH2:20](O)[CH2:21][OH:22]>>[C:14]1([CH:12]2[O:13][CH2:20][CH2:21][O:22]2)[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COc1ccc(Br)c(CCC(=O)c2ccccc2)c1
Reactant: OCCO
Product: c1ccc(C2OCCO2)cc1

Procedure:
The product of step 2 is reacted with ethylene glycol to produce 2-[2-(2-bromo-5-methoxyphenyl)-ethyl]-2-phenyl)-ethyl]-2-phenyl-[1,3]dioxolane;
Reaction SMILES: Cl[C:2]1[C:7]([S:8]([N:11]2[CH2:32][CH2:31][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:25]=[CH:24][C:23]([O:26][C:27]([F:30])([F:29])[F:28])=[CH:22][CH:21]=4)[CH2:16][CH2:15]3)[CH2:13][CH2:12]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:33]([CH2:35][NH2:36])[OH:34]>>[OH:34][CH2:33][CH2:35][NH:36][C:2]1[C:7]([S:8]([N:11]2[CH2:12][CH2:13][C:14]3([C:18](=[O:19])[N:17]([C:20]4[CH:21]=[CH:22][C:23]([O:26][C:27]([F:28])([F:30])[F:29])=[CH:24][CH:25]=4)[CH2:16][CH2:15]3)[CH2:31][CH2:32]2)(=[O:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: NCCO
Reactant: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1Cl)CC2
Product: O=C1N(c2ccc(OC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1NCCO)CC2

Procedure:
The title compound was prepared in analogy to example 189 from 8-(2-chloro-pyridine-3-sulfonyl)-2-(4-trifluoromethoxy-phenyl)-2,8-diaza-spiro[4.5]decan-1-one (described in example 188) and ethanolamine. White gum. MS (ESI): 515.3 (MH+).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:5]=[CH:6][C:7]=1[NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([OH:15])[CH2:11][CH2:10]1.[C:20](N1C=CN=C1)(N1C=CN=C1)=[O:21].[OH-].[Na+].Cl>C(#N)C>[OH:15][C@H:12]1[CH2:13][CH2:14][C@H:9]([N:8]2[C:7]3[CH:6]=[CH:5][C:4]([C:16]([F:17])([F:18])[F:19])=[CH:3][C:2]=3[NH:1][C:20]2=[O:21])[CH2:10][CH2:11]1
Reactant: Nc1cc(C(F)(F)F)ccc1N[C@H]1CC[C@H](O)CC1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: O=c1[nH]c2cc(C(F)(F)F)ccc2n1[C@H]1CC[C@H](O)CC1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To a solution of 3-amino-4-(trans-4-hydroxycyclohexylamino)benzotrifluoride (657 mg) in acetonitrile (7 mL) was added 1,1′-carbonyldiimidazole (1.17 g), and the mixture was stirred at 60° C. under nitrogen atmosphere for 3 hours. After adding 1N-sodium hydroxide solution (5 mL), the mixture was stirred at 60° C. for an hour. The mixture was neutralized with concentrated hydrochloric acid at 0° C. The resulting precipitate was collected by filtration and washed successively with water and diethyl ether to give 1-(trans-4-hydroxycyclohexyl)-5-trifluoromethyl-2,3-dihydro-1H-benzimidazol-2-one (549.5 mg) as a colorless solid.
Reaction SMILES: [I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[NH:26][C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28].[CH3:55]I>[OH-].[Na+]>[I:1][C:2]1[C:7]([C:8]([NH:10][CH2:11][CH:12]([OH:15])[CH2:13][OH:14])=[O:9])=[C:6]([I:16])[C:5]([C:17]([NH:19][CH2:20][CH:21]([OH:24])[CH2:22][OH:23])=[O:18])=[C:4]([I:25])[C:3]=1[N:26]([CH3:55])[C:27]([NH:29][C:30]1[C:35]([I:36])=[C:34]([C:37]([NH:39][CH2:40][CH:41]([OH:44])[CH2:42][OH:43])=[O:38])[C:33]([I:45])=[C:32]([C:46]([NH:48][CH2:49][CH:50]([OH:53])[CH2:51][OH:52])=[O:47])[C:31]=1[I:54])=[O:28]
Reactant: O=C(Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Product: CN(C(=O)Nc1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I)c1c(I)c(C(=O)NCC(O)CO)c(I)c(C(=O)NCC(O)CO)c1I
Temperature: 25 °C
Reaction time: 60 h

Procedure:
N,N'-bis[2,4,6-triiodo-3,5-bis(2,3-dihydroxypropylaminocarbonyl)phenyl]-urea (7.32 g, 5.1 mmol) was dissolved in 2 M aqueous NaOH (10 ml) and methyl iodide (0.95 ml) was added. The mixture was stirred at ambient temperature for 60 h, treated with a strongly acidic ion exchange resin (Amberlyst 15) evaporated and purified by preparative HPLC. Yield 4.7 g (63%) of the product as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25](F)=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1.[NH2:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35].CN1CCOCC1>CN(C)C1C=CN=CC=1.O1CCCC1>[Cl:1][C:2]1[CH:7]=[C:6]2[NH:8][C:9](=[O:31])[C:10]3([CH:15]([C:16]4[CH:21]=[CH:20][CH:19]=[C:18]([Cl:22])[CH:17]=4)[CH2:14][C:13](=[O:23])[N:12]([CH2:24][C:25]([NH:32][C:33]([CH3:37])([CH3:36])[CH2:34][OH:35])=[O:26])[CH:11]3[C:28]([CH3:30])=[CH2:29])[C:5]2=[CH:4][CH:3]=1
Reactant: CC(C)(N)CO
Reactant: C=C(C)C1N(CC(=O)F)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: C=C(C)C1N(CC(=O)NC(C)(C)CO)C(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Yield: 35.8 %

Procedure:
In a manner similar to the method described in example 34b, racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-fluorocarbonylmethyl-2′-isopropenylspiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione (0.18 g, 0.39 mmol) prepared in example 116d was reacted with 2-amino-2-methyl-propan-1-ol (69 mg, 0.78 mmol), N-methylmorpholine (81 mg, 0.78 mmol) and 4-dimethylaminopyridine (5 mg) in tetrahydrofuran to give racemic (2′R,3R,4′S)-6-chloro-4′-(3-chlorophenyl)-1′-[(2-hydroxy-1,1-dimethyl-ethyl)aminocarbonyl-methyl]-2′-isopropenyl-spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as an off-white solid (Yield: 74 mg, 35.9%).
Reaction SMILES: [CH2:1]([S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:2]#[CH:3].Cl[C:12]([O:14][CH2:15][CH3:16])=[O:13]>>[CH2:15]([O:14][C:12](=[O:13])[C:3]#[C:2][CH2:1][S:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH3:16]
Reactant: CCOC(=O)Cl
Reactant: C#CCSc1ccccc1
Product: CCOC(=O)C#CCSc1ccccc1

Procedure:
The title compound was prepared from prop-2-ynylsulfanyl-benzene and ethyl chloroformate in accordance with the procedures of G. Cai et al., Tetrahedron, 2006, (5697-5708).