Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8](I)=[CH:7][CH:6]=1)([F:4])[CH3:3].C([Mg]Cl)(C)C.[F:17][C:18]1[CH:19]=[C:20]([CH:23]=[CH:24][C:25]=1[C@@H:26]1[N:30]2[CH:31]=[N:32][CH:33]=[C:29]2[C:28](=[O:34])[CH2:27]1)[C:21]#[N:22]>C1COCC1>[F:1][C:2]([C:5]1[CH:10]=[CH:9][C:8]([C@:28]2([OH:34])[C:29]3[N:30]([CH:31]=[N:32][CH:33]=3)[C@@H:26]([C:25]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][C:18]=3[F:17])[CH2:27]2)=[CH:7][CH:6]=1)([F:4])[CH3:3]
Reactant: N#Cc1ccc([C@H]2CC(=O)c3cncn32)c(F)c1
Reactant: CC(F)(F)c1ccc(I)cc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: CC(F)(F)c1ccc([C@@]2(O)C[C@H](c3ccc(C#N)cc3F)n3cncc32)cc1
Temperature: -40 °C
Reaction time: 1 h
Yield: 18.6 %

Procedure:
To a solution of 1-(1,1-difluoro-ethyl)-4-iodo-benzene, (167 mg, 0.62 mmol) in THF (2 mL) cooled to −40° C. was added a 2 M solution of i-PrMgCl in THF (0.42 mL, 0.83 mmol) dropwise. The crude was stirred at −40° C. for 1 hr. 3-fluoro-4-((R)-7-oxo-6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)-benzonitrile (125 mg, 0.52 mmol) in THF (2 mL) was added. The crude was allowed to slowly warm to room temperature over 3 hrs. The crude was quenched with NH4Cl aq. The crude diluted in EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, and concentrated. The crude was purified via preparation plate two times using 2M NH3 in MeOH/CH2Cl2 to give 37 mgs of the entitled product. MS 384.3 (M+H); LCMS condition A, retention time 1.31 min. 1H NMR (400 MHz, CDCl3) δ ppm 1.83 (t, 3H), 2.94 (dd, 1H), 3.24 (dd, 1H), 5.70 (d, 1H), 6.47 (s, 1H), 7.11 (t, 1H), 7.19 (s, 1H), 7.33 (d, 2H), 7.38 (m, 2H), 7.46 (m, 2H).
Reaction SMILES: [CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][Mg][Cl:7].Cl[CH:10]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[CH:14]=[CH:13][C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]1=2.O1CCCC1.Cl>CCOCC>[ClH:7].[CH3:1][N:2]([CH3:8])[CH2:3][CH2:4][CH2:5][CH:10]1[C:11]2[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=2[CH:13]=[CH:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]1=2
Reactant: ClC1c2ccccc2C=Cc2ccccc21
Reactant: CN(C)CCC[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCOCC
Product: CN(C)CCCC1c2ccccc2C=Cc2ccccc21
Temperature: 25 °C

Procedure:
The Grignard solution prepared in Step A. is cooled to room temperature and stirred while a solution of 5.05 g. (0.0221 mole) of 5-chloro-5H-dibenzo[a,d]cycloheptene in 25 ml. of dry tetrahydrofuran is added dropwise, external cooling being applied as required to maintain the temperature close to room temperature. When the addition is complete, the mixture is heated to refluxing for 15 minutes. The bulk of the tetrahydrofuran then is distilled under reduced pressure, keeping the water-bath temperature at 50°-60° C. The syrupy mixture is dissolved in 75 ml. of benzene and water, 15 ml., is added dropwise with stirring. The benzene layer is decanted from the gelatinous precipitate which then is re-extracted with three 20 ml. portions of boiling benzene. The combined benzene extracts are washed with water and extracted with three 15 ml. portions of 3N hydrochloric acid. The acid extract is made basic with sodium hydroxide and the yellow oily base that separates is extracted into hexane. After washing the combined extracts with water, the hexane is evaporated and the product obtained as a yellow oil in a yield of 4.61 g. The base is converted to the hydrochloride by dissolving it in a mixture of 15 ml. of absolute alcohol and 15 ml. of absolute ether and adding 1.8 ml. of a 10.28 N solution of dry hydrogen chloride in absolute alcohol. The solution then is diluted to incipient crystallization by the addition of 25 ml. of absolute ether. The yield of 5-(3-dimethylaminopropyl)-5-dibenzo[a,d]cycloheptene hydrochloride, m.p. 186°-190° C. is 4.17 g. Recrystallization from mixtures of absolute alcohol and absolute ether gives the product, m.p. 191°-193° C.
Reaction SMILES: [NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH:19]=O)[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3].[CH3:21][S-:22].[Na+]>FC(F)(F)C(O)=O.ClCCl>[NH2:1][C:2]([NH:4][C:5]1[NH:6][C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([CH2:19][S:22][CH3:21])[CH:14]=2)=[CH:8][C:9]=1[C:10]([NH2:12])=[O:11])=[O:3]
Reactant: NC(=O)Nc1[nH]c(-c2cccc(C=O)c2)cc1C(N)=O
Reactant: C[S-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CSCc1cccc(-c2cc(C(N)=O)c(NC(N)=O)[nH]2)c1
Reaction time: 0.17 h
Yield: 40.2 %

Procedure:
Under a solution of 2-aminocarbonylamino-5-(3-formylphenyl)pyrrole-3-carboxamide (Compound No. 14-2, 50 mg, 0.18 mmol) in trifluoroacetic acid (4 mL) was added to a solution of sodium methanethiolate (14 mg, 0.20 mmol) in dichloromethane (2 mL) and the mixture was stirred for 10 minutes. Moreover, borane-pyridine complex (41 μL, 0.41 mmol) was added thereto and the whole was stirred for 10 minutes. The reaction solution was concentrated in vacuo. Saturated aqueous sodium hydrogencarbonate (3 mL) and water (2 mL) were added to the residue, extracted with ethyl acetate (10 mL). After the organic layer was dried over anhydrous magnesium sulfate, the solvent was removed under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the target compound (22 mg) as a colorless solid (Yield 39%).
Reaction SMILES: [CH3:1][N:2]([As:4](N(C)C)N(C)C)[CH3:3].[CH2:11]([O:14][CH2:15][CH:16]([OH:19])[CH2:17][OH:18])[CH:12]=[CH2:13]>CCCCCC>[CH2:11]([O:14][CH2:15][CH:16]1[CH2:17][O:18][As:4]([N:2]([CH3:3])[CH3:1])[O:19]1)[CH:12]=[CH2:13]
Reactant: C=CCOCC(O)CO
Reactant: CN(C)[As](N(C)C)N(C)C
Solvent: CCCCCC
Product: C=CCOCC1CO[As](N(C)C)O1
Temperature: 25 °C

Procedure:
is formed when at room temperature, about 0.5 g (0.445 mL, 2.414 mmol, 1.1 equivalents) of tris(dimethylamino)arsine (TDMA), is added to about 10 mL dry hexane in a 25 mL round-bottom flask, and then about 0.29 g (0.27 mL, 2.19 mmol, 1.0 equivalents) of 3-(allyloxy)propane-1,2-diol is added dropwise into the system. The mixture is heated to reflux under nitrogen for about one hour, and then cooled to room temperature. Removal of the solvent in vacuum gives crude 4-((allyloxy)methyl)-N,N-dimethyl-1,3,2-dioxarsolan-2-amine as an oil.
Reaction SMILES: C[N:2]([CH:4]=[C:5]1[CH2:10][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:8][CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:6]1=O)C.Cl.[NH2:25]N>CCO>[N:25]1[NH:2][CH:4]=[C:5]2[C:6]=1[CH:7]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:8][N:9]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:10]2
Reactant: NN
Reactant: CCOC(=O)C1CN(C(=O)OC(C)(C)C)CC(=CN(C)C)C1=O
Agent: Cl
Solvent: CCO
Product: CCOC(=O)C1CN(C(=O)OC(C)(C)C)Cc2c[nH]nc21
Reaction time: 18 h

Procedure:
A solution of enaminoketone 3b (327 mg, 1.00 mmol) in abs. EtOH (10 mL) was cooled to 0° C. and hydrazine monohydrogen chloride was added in one portion. The mixture was stirred for 18 h during which time the temperature reached rt after 2 h. The mixture was concentrated and the residue partitioned with deionized H2O and EtOAc. The organic layer was removed and the aqueous portion extracted with EtOAc (2×). The combined EtOAc portions were washed with brine, dried over MgSO4 and filtered through a SiO2 plug capped with a MgSO4 layer (EtOAc for elution). The solution was concentrated give the title compound 4b as a brittle white foam crushed to a white solid; 253 mg, 87%, MS m/z 240.0, 194.0 (ESI+, M−tBu, M−Boc).
Reaction SMILES: [CH2:1]([O:3][CH2:4][C:5]1[N:6]([CH2:38][C:39]([CH3:52])([O:41][CH2:42][CH2:43][NH:44]C(=O)OC(C)(C)C)[CH3:40])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH:17]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[C:8]=2[N:37]=1)[CH3:2].C(O)(C(F)(F)F)=O.[OH-].[Na+]>ClCCl>[NH2:44][CH2:43][CH2:42][O:41][C:39]([CH3:40])([CH3:52])[CH2:38][N:6]1[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:17])[C:8]=2[N:37]=[C:5]1[CH2:4][O:3][CH2:1][CH3:2]
Reactant: CCOCc1nc2c(NC(c3ccccc3)(c3ccccc3)c3ccccc3)nc3ccccc3c2n1CC(C)(C)OCCNC(=O)OC(C)(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)OCCN
Temperature: 25 °C
Reaction time: 3 h
Yield: 83.8 %

Procedure:
tert-Butyl 2-(1-(2-(ethoxymethyl)-4-(tritylamino)-1H-imidazo[4,5-c]quinolin-1-yl)-2-methylpropan-2-yloxy)ethylcarbamate (1.45 g, 2.07 mmol) was combined with dichloromethane (DCM, 12 mL) to give a colorless solution. TFA (6.0 mL, 77.9 mmol) was added and the mixture was stirred for 3 hours at room temperature. The reaction mixture was cooled to 0° C., 2N sodium hydroxide solution (40 mL) was added, and the basic solution was extracted with dichloromethane. Organic layers were combined, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash chromatography (silica gel, 0 to 10% methanol in DCM) to give the title compound (0.62 g, 83%) as white solid; LC-MS (UV peak area, ESI) 97.5%, 358.2238 (MH+).
Reaction SMILES: [CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=4)[CH2:20][CH2:19][C:18]4(OCC[O:21]4)[CH2:17][CH2:16]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CC(C)=O.O>[CH:1]1([O:6][C:7]2[CH:8]=[C:9]([C:15]3([C:25]#[C:26][C:27]4[CH:28]=[CH:29][N:30]=[CH:31][CH:32]=4)[CH2:16][CH2:17][C:18](=[O:21])[CH2:19][CH2:20]3)[CH:10]=[CH:11][C:12]=2[O:13][CH3:14])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc(C2(C#Cc3ccncc3)CCC3(CC2)OCCO3)cc1OC1CCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CC(C)=O
Solvent: O
Product: COc1ccc(C2(C#Cc3ccncc3)CCC(=O)CC2)cc1OC1CCCC1
Yield: 85.6 %

Procedure:
A mixture of 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)-1,1-(ethylenedioxy)cyclohexane (0.10 g, 0.24 mmol) and pyridinium p-toluenesulfonate (0.06 g, 0.24 mmol) in acetone (4 mL) and water (1 mL) was refluxed for 20 h., then was evaporated. Water was added, the mixture was extracted three times with dichloromethane, was dried (magnesium sulfate) and was evaporated. Purification by flash chromatography, eluting with 35:65 ethyl acetate:hexanes, provided 4-(3-cyclopentyloxy-4-methoxyphenyl)-4-(4-pyridylethynyl)cyclohexan-1-one (0.08 g, 91%) as a white solid, mp 148°-149° C. Anal. (C25H27NO3.0.5 H2O) calcd: C, 75.29; H, 7.08; N, 3.51; found: C, 75.51; H, 6.95; N, 3.42.
Reaction SMILES: I[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[F:10][C:11]([F:19])([F:18])[C:12]([F:17])([F:16])C([O-])=O.[Na+].CN(C=O)C>[Cu]I.C1(C)C=CC=CC=1>[F:16][C:12]([F:17])([C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1)[C:11]([F:19])([F:18])[F:10]
Reactant: N#Cc1ccc(I)cc1
Reactant: O=C([O-])C(F)(F)C(F)(F)F
Agent: [Cu]I
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1ccc(C(F)(F)C(F)(F)F)cc1
Temperature: 160 °C
Yield: 52.3 %

Procedure:
A mixture of 4-iodobenzonitrile (10.0 g, 43.7 mmol), sodium pentafluoroproprionate (15.4 g, 82.9 mmol), and copper(I) iodide (16.6 g, 87.3 mmol), DMF (160 mL), and toluene (60 mL) was heated at 160° C. for 16 h, allowing most of the toluene to distil off. After cooling, ethyl acetate (200 mL) was added, and the mixture was filtered through diatomaceous earth, and the filtrate was partitioned between ethyl acetate/heptane and water. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2, heptane-ethyl acetate gradient) afforded the title compound (5.05 g 52%). Yellow oil, MS (EI) 221.1 (M+).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[CH3:24][C:25]1[N:26]=[C:27]2[C:32]([CH3:33])=[CH:31][CH:30]=[CH:29][N:28]2[C:34]=1[C:35](O)=[O:36]>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:35]([C:34]2[N:28]3[CH:29]=[CH:30][CH:31]=[C:32]([CH3:33])[C:27]3=[N:26][C:25]=2[CH3:24])=[O:36])=[O:8])[N:6]=1
Reactant: Cc1nc2c(C)cccn2c1C(=O)O
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Product: Cc1nc2c(C)cccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,8-Dimethyl-imidazo[1,2-a]pyridine-3-carboxylic acid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9](O)=[O:10])[CH:5]=[CH:6][CH:7]=1.S(Cl)([Cl:16])=O>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:13])([CH3:12])[C:9]([Cl:16])=[O:10])[CH:5]=[CH:6][CH:7]=1
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C(=O)O)c1cccc(Cl)c1
Product: CC(C)(C(=O)Cl)c1cccc(Cl)c1

Procedure:
2-(3-Chlorophenyl)-2-methylpropanoic acid (5.7 g, 28.7 mmol) was stirred in thionyl chloride (100 mL) for 2 hours at reflux. The thionyl chloride was removed under vacuum to give the product (5.69 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].C(Cl)(=O)C([Cl:20])=O>CN(C)C=O.ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:13][C:14]([Cl:20])=[O:16])[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10]
Reactant: COc1cc(CC(=O)O)cc(OC)c1OC
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cc(CC(=O)Cl)cc(OC)c1OC
Temperature: -5 °C
Reaction time: 1 h

Procedure:
Combine 3,4,5-trimethoxy-phenyl-acetic acid (2.26 g, 10 mmol) and dichloromethane (50 mL). Cool to -5° C. using a ice-salt bath. Add 2 drops of dimethylformamide followed by dropwise addition of oxalyl chloride (1.74 mL, 20 mmol). after 1 hour, warm the reaction mixture to ambient temperature. After 2 hours, evaporate the reaction mixture in vacuo to give the title compound as a liquid.
Reaction SMILES: [C:1]([NH2:4])(=O)[CH3:2].[P:5]([OH:8])([OH:7])[OH:6].Cl>>[NH2:4][C:1]([P:5]([OH:8])(=[O:6])[OH:7])([P:5]([OH:8])(=[O:7])[OH:6])[CH3:2]
Reactant: OP(O)O
Reactant: CC(N)=O
Agent: Cl
Product: CC(N)(P(=O)(O)O)P(=O)(O)O
Reaction time: 3 h

Procedure:
Into a mixture of 59 gm of acetamide and 82 gm of phosphorous acid, hydrogen chloride gas was introduced therein for a period of 3 hours. During this time the mixture was stirred and the temperature was maintained at 145° - 155° C. By further processing of the reaction mixture, analogously to Example 1, the 1-aminoethane-1,1 -diphosphonic acid was isolated and purified. The yield was 19.2 gm.
Reaction SMILES: [CH:1]([C:3]1[CH:18]=[CH:17][C:6]([O:7][C:8]2[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=2)=[C:5]([CH3:19])[CH:4]=1)=O.[O:20]1[CH2:25][CH2:24][CH:23]([CH2:26][CH2:27][NH2:28])[CH2:22][CH2:21]1.[BH4-].[Na+]>CO>[CH3:19][C:5]1[CH:4]=[C:3]([CH2:1][NH:28][CH2:27][CH2:26][CH:23]2[CH2:24][CH2:25][O:20][CH2:21][CH2:22]2)[CH:18]=[CH:17][C:6]=1[O:7][C:8]1[N:9]=[CH:10][C:11]([C:14]([NH2:16])=[O:15])=[N:12][CH:13]=1
Reactant: NCCC1CCOCC1
Reactant: Cc1cc(C=O)ccc1Oc1cnc(C(N)=O)cn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1cc(CNCCC2CCOCC2)ccc1Oc1cnc(C(N)=O)cn1
Reaction time: 8 h
Yield: 42 %

Procedure:
Place 5-(4-formyl-2-methylphenoxy)pyrazine-2-carboxamide (Example 404, Part D) (0.200 g, 0.777 mmol), 2-(tetrahydropyran-4-yl)ethylamine (0.100 g, 0.777 mmol) and 3 Å molecular sieves in a vial. Add methanol (3.8 mL) cap and stir overnight. Add NaBH4 (in excess over two portions) and stir until the gasses stop evolving. Load the reaction mixture directly onto a 5 g ISCO® pre-load column. Dry the pre-loaded column in a vacuum oven at room temperature. Purify by eluting through a 10 g ISCO® column with (2.0 M NH3 in methanol), ethyl acetate and hexanes. After concentrating, take the product up in CH2Cl2 (25 mL) and wash with 1.0 N NaOH solution (2× 10 mL). Dry the organic layer over Na2SO4, filter and concentrate to give the title compound (0.121 g, 42.0%): MS ES+ 371.1 (M+H)+, base peak 242.0 (M-C7H14NO)+; HPLC [YMC-Pack Pro C-18 (150×4.6 mm, S-5 microm), 0.1% TFA/acetonitrile in 0.1% TFA/water at 1.0 mL/in, 5-95% over 19 min], tR=7.9 min, 100% purity.
Reaction SMILES: C([Li])CCC.CCCCCC.[CH2:12]([O:14][C:15](=[O:25])[CH2:16]P(OCC)(OCC)=O)[CH3:13].[Cl:26][C:27]1[N:31]=[C:30]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[N:29]([CH3:38])[C:28]=1[CH:39]=O>C1COCC1>[CH2:12]([O:14][C:15](=[O:25])[CH:16]=[CH:39][C:28]1[N:29]([CH3:38])[C:30]([C:32]2[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=2)=[N:31][C:27]=1[Cl:26])[CH3:13]
Reactant: Cn1c(-c2ccccc2)nc(Cl)c1C=O
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCOC(=O)C=Cc1c(Cl)nc(-c2ccccc2)n1C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
2.72 ml of a 1.6 M solution of n-butyllithium in n-hexane (4.4 mmol) were added at 0° C. to a solution of 1.219 g (5.4 mmol) of diethylphosphonoacetic acid ethyl ester in 30 ml of dry THF. After stirring at 0° C. for 30 min, 0.8 g (3.8 mmol) of 5-chloro-3-methyl-2-phenyl-3H-imidazole-4-carbaldehyde in 10 ml of THF were added. The reaction mixture was allowed to stand overnight and then concentrated. The residue was taken up in 100 ml of ethyl acetate, and the solution washed three times with 30 ml each of a sodium hydrogencarbonate solution, dried with magnesium sulfate and evaporated. The obtained crude 3-(5-chloro-3-methyl-2-phenyl-3H-imidazol-4-yl)-acrylic acid ethyl ester was stirred in 5.4 ml of 1 N sodium hydroxide solution and 20 ml of tert-butanol at room temperature for 24 h. After concentration, 10 ml of water were added, and the mixture was acidified to pH=5 with hydrochloric acid. The mixture was stirred for 1 h, and the precipitated product was filtered off with suction and dried.
Reaction SMILES: [CH3:1][CH:2]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH2:15][N:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[CH3:3].CN1CCOCC1.I[Si](C)(C)C>ClCCl>[CH3:3][CH:2]([C:4]1[CH:9]=[C:8]([N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:7]=[CH:6][C:5]=1[CH2:15][N:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)[CH3:1]
Reactant: CC(C)c1cc(N2CCCC2)ccc1CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: C[Si](C)(C)I
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)c1cc(N2CCCC2)ccc1CN1CCNCC1
Temperature: 0 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
A 100 mL round-bottom flask was charged with tert-butyl 4-[[2-(propan-2-yl)-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine-1-carboxylate (200 mg, 0.52 mmol, 1.00 equiv), dichloromethane (10 mL) with an inert atmosphere of nitrogen. 4-Methylmorpholine (265 mg, 2.62 mmol, 5.00 equiv) and iodotrimethylsilane (412 mg, 2.08 mmol, 4.00 equiv) were added at 0° C. The resulting solution was stirred for 1 h at 0° C. The resulting mixture was concentrated under reduced pressure to provide 150 mg (crude) of 1-[[2-(propan-2-yl)-4-(pyrrolidin-1-yl)phenyl]methyl]piperazine as light yellow oil. LCMS (ESI, m/z): 238 [M+H]+.
Reaction SMILES: [C:1]1([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Br:31])C(=O)C1.O>CN(C=O)C>[Br:31][C:3]1[CH:2]=[C:1]([C:14]2[CH:23]=[CH:22][CH:21]=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[C:13]2[NH:12][C:11]3[C:6]([C:5]=2[CH:4]=1)=[CH:7][CH:8]=[CH:9][CH:10]=3
Reactant: COC(=O)c1ccccc1-c1cccc2c1[nH]c1ccccc12
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1-c1cc(Br)cc2c1[nH]c1ccccc12
Reaction time: 6 h

Procedure:
62 g (207 mmol) of methyl 2-(9H-carbazolyl)benzoate are cooled to −10° C. in 2 l of DMF, and 37.3 g (207 mmol) of NBS are added in portions. The solution is then brought to room temperature and stirred at this temperature for 6 h. 500 ml of water are subsequently added to the mixture, which is then extracted with CH2Cl2. The organic phase is dried over MgSO4, and the solvents are removed in vacuo. The product is washed by stirring with hot toluene, and the solid is isolated.
Reaction SMILES: [Na].[CH:2](=[O:10])[C:3]1[C:4](=[CH:6][CH:7]=[CH:8][CH:9]=1)[OH:5].Cl[CH2:12][CH2:13][O:14][CH2:15][CH2:16][O:17][CH2:18][CH2:19][OH:20]>CN(C)C=O>[OH:20][CH2:19][CH2:18][O:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][O:5][C:4]1[CH:6]=[CH:7][CH:8]=[CH:9][C:3]=1[CH:2]=[O:10]
Reactant: OCCOCCOCCCl
Reactant: O=Cc1ccccc1O
Agent: [Na]
Solvent: CN(C)C=O
Product: O=Cc1ccccc1OCCOCCOCCO

Procedure:
A solution of 10 g of sodium salt of salicylaldehyde and 10 g of 2-[2-(2-chloroethoxy)ethoxy]ethanol in dimethylformamide was refluxed for 50 hours. After evaporation, the residue was dissolved in ethyl acetate and the solution washed with water, dried over magnesium sulfate and evaporated. The compound was purified by chromatography (silica; ethyl acetate).
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH2:18][CH:19]3[CH2:23][CH2:22][N:21]([CH:24]4[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]4)[C:20]3=[O:30])=[C:14]([Cl:31])[CH:13]=2)=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:5])C.[OH-].[K+].O>C(O)C>[Cl:31][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:17]=[CH:16][C:15]=1[CH2:18][CH:19]1[CH2:23][CH2:22][N:21]([CH:24]2[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29]2)[C:20]1=[O:30]
Reactant: CCOC(=O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccccc1-c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Temperature: 25 °C
Reaction time: 72 h
Yield: 82.2 %

Procedure:
Dissolve 3′-chloro-4′-(1-cyclohexyl-2-oxo-pyrrolidin-3-ylmethyl)-biphenyl-2-carboxylic acid ethyl ester (Preparation 81) (287 mg, 0.65 mmol) in ethanol (10 mL) and add KOH (370 mg, 6.5 mmol). Stir at room temperature for 3 days. Pour into water and extract with ether. Acidify the aqueous layer to pH 1. Extract with ether. Dry over sodium sulfate, filter and concentrate to yield 220 mg (82%) of the title compound as a pale yellow solid: Mass spectrum (apci) m/z=410.3 (M−H).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].C(NC(C)C)(C)C.[Li].Cl[C:22]([O:24][CH3:25])=[O:23]>C1COCC1>[CH3:1][O:2][C:3]([C:5]1([C:22]([O:24][CH3:25])=[O:23])[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: COC(=O)Cl
Reactant: CCCCC1CC(C(=O)OC)C1
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCCCC1CC(C(=O)OC)(C(=O)OC)C1
Temperature: 25 °C
Yield: 80.4 %

Procedure:
A solution of 3-butyl-cyclobutanecarboxylic acid methyl ester (7.75 g, 45.6 mmol) in THF (30 mL) was added dropwise to a solution of lithium diisopropylamine (7.26 g, 68.4 mmol) in THF (70 mL) at −78° C. After stirring for 1.5 h at the same temperature, methyl chloroformate (6.46 g, 68.4 mmol) was added slowly and the mixture was allowed to warm to room temperature. After 18 h the reaction mixture was quenched with saturated aqueous NH4Cl solution (200 mL) and the aqueous residue was extracted with EtOAc (75 mL×5). The combined organic layers were dried (MgSO4). After removal of the solvent under reduced pressure, purification by flash column chromatography using an eluting system of hexane/EtOAc (95:5) yielded the title compound as a clear yellow oil (8.37 g, 81%). MH+229.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13]Br.C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH3:10][C:11]1[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=1[CH2:13][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: Cc1ccccc1CBr
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1ccccc1COc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 103 %

Procedure:
4-Hydroxybenzaldehyde (10.0 g, 81.9 mmol) and 2-methyl benzyl bromide (40.0 g, 98.3 mmol) were dissolved in dimethylformamide (100 mL), and cesium carbonate (18.2 g, 123 mmol) was added thereto, and then, the resulting mixture was stirred under a nitrogen atmosphere at room temperature for 1 hour. Water was added to the reaction solution, and the organic matter was extracted with diethyl ether. The organic layer was washed with water and a saturated sodium chloride solution, then dried over anhydrous magnesium sulfate and filtered. Then, the solvent was distilled off under reduced pressure, whereby a crude product was obtained. This crude product was purified by silica gel column chromatography (hexane:ethyl acetate=100:0 to 60:40 (v/v)), whereby the objective title compound was obtained as a colorless oily substance (19.2 g, yield: 103%).