Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][N:17]3C(OC(C)(C)C)=O)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8].CO.Cl>O1CCOCC1>[F:1][C:2]1[C:3]([NH:29][C:30]2[CH:35]=[CH:34][C:33]([I:36])=[CH:32][C:31]=2[F:37])=[C:4]([C:9]([N:11]2[CH2:14][C:13]([C@H:16]3[CH2:21][CH2:20][CH2:19][CH2:18][NH:17]3)([OH:15])[CH2:12]2)=[O:10])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1C1(O)CN(C(=O)c2ccc(F)c(F)c2Nc2ccc(I)cc2F)C1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: O=C(c1ccc(F)c(F)c1Nc1ccc(I)cc1F)N1CC(O)([C@H]2CCCCN2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.9 %

Procedure:
1,1-dimethylethyl(2R)-2-[1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-hydroxyazetidin-3-yl]piperidine-1-carboxylate (74.9 mg, 0.12 mmol) was taken into methanol (1 mL) followed by addition of 4 N HCl in dioxane (1 mL) and the solution was stirred at room temperature for one hour. The solution was then concentrated and the residue partitioned with chloroform and saturated aqueous sodium bicarbonate. The organic layer was washed with brine, dried over anhydrous sodium sulfate then filtered and concentrated. Purification of the residue by silica gel flash chromatography using ethyl acetate then concentrated aqueous ammonia in chloroform and methanol (0.1:10:1) as eluents afforded 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol (57.3 mg) as a colorless amorphous solid. The free base was taken into methanol (1 mL) then brought to about pH 1 by addition of 4 N HCl in dioxane and the solution concentrated. The residue was triturated with ethyl ether to afford a suspension. The solid was collected by filtration to afford 1-({3,4-difluoro-2-[(2-fluoro-4-iodophenyl)amino]phenyl}carbonyl)-3-[(2R)-piperidin-2-yl]azetidin-3-ol hydrochloride salt (49 mg, 72% yield) as a colorless solid. 1H NMR (400 MHz, CDCl3): 8.43-8.39 (d, 1H), 7.41-7.38 (dd, 1H), 7.33-7.31 (dt, 1H), 7.14-7.10 (m, 1H), 6.84-6.80 (m, 1H), 6.63-6.57 (m, 1H), 4.12-3.99 (m, 4H), 3.10-3.08 (d, 1H), 2.72-2.69 (d, 1H), 2.64-2.62 (m, 1H), 1.61-1.58 (m, 2H), 1.36-1.16 (m, 4H); MS (EI) for C21H21F3IN3O2: 532 (MH+).
Reaction SMILES: C(OC([NH:8][CH:9]([CH3:22])[CH2:10][C:11]1[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=[C:13]([O:20]C)[CH:12]=1)=O)(C)(C)C.[ClH:23].N1C=CC=CC=1>ClCCl.[OH-].[NH4+]>[ClH:23].[OH:20][C:13]1[CH:12]=[C:11]([CH2:10][CH:9]([NH2:8])[CH3:22])[C:19]2[O:18][CH:17]=[CH:16][C:15]=2[CH:14]=1
Reactant: COc1cc(CC(C)NC(=O)OC(C)(C)C)c2occc2c1
Agent: Cl
Agent: [NH4+]
Agent: [OH-]
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(N)Cc1cc(O)cc2ccoc12
Temperature: 170 °C

Procedure:
A mixture of 0.73 gm (2.38 mMol) N-tert-butoxycarbonyl 1-(5-methoxybenzofur-7-yl)-2-aminopropane and 3.30 gm (28.52 mMol) pyridine hydrochloride were heated at 170° C. in a sealed tube for 15 hours. The mixture was cooled and the residue was dissolved in dichloromethane containing 10% methanol and 1% ammonium hydroxide. The solution was concentrated under reduced pressure and the pyridine remaining in the residue was removed azeotropically by diluting the residue with water and concentrating three times. The residue was crystallized from ethanol:diethyl ether. The 1-(5-hydroxybenzofur-7-yl)-2-aminopropane was recovered in the second crop and the filtrate. 0.045 gm (0.24 mMol) was treated with hydrochloric acid in diethyl ether to provide the title compound.
Reaction SMILES: [Br-:1].[Br-].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.C([N+](CCCC)(CCCC)CCCC)CCC.[Cl:55][C:56]1[CH:61]=[C:60]([Cl:62])[CH:59]=[CH:58][C:57]=1[C:63](=[O:66])[CH2:64][CH3:65]>C(Cl)Cl.CO>[Br:1][CH:64]([CH3:65])[C:63]([C:57]1[CH:58]=[CH:59][C:60]([Cl:62])=[CH:61][C:56]=1[Cl:55])=[O:66]
Reactant: CCC(=O)c1ccc(Cl)cc1Cl
Reactant: [Br-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CO
Solvent: ClCCl
Product: CC(Br)C(=O)c1ccc(Cl)cc1Cl
Reaction time: 24 h

Procedure:
17.4 g of tetra-butylammonium tribromide are added, at room temperature, to 7 g of 1-(2,4-dichlorophenyl)-1-propanone dissolved in a mixture of 420 ml of methylene chloride and 140 mi of methanol. After 24 hours, the reaction medium is evaporated to dryness under vacuum. The residue is taken up in water and extracted with ethyl acetate, and the organic phase is dried over sodium sulphate. The solvent is evaporated off under vacuum and the product is then purified on a column of silica, using a mixture of cyclohexane and ethyl acetate (20:1 v/v) as eluent.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][N:18]=[C:19]([O:20]C)[C:14]4=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1.Br.C(O)(=O)C>CCOCC>[CH:1]1([NH:4][C:5]2[N:10]=[C:9]([C:11]3[N:15]4[CH:16]=[CH:17][NH:18][C:19](=[O:20])[C:14]4=[N:13][C:12]=3[C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[CH:8]=[CH:7][N:6]=2)[CH2:3][CH2:2]1
Reactant: COc1nccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: O=c1[nH]ccn2c(-c3ccnc(NC4CC4)n3)c(-c3ccc(F)cc3)nc12
Yield: 76.7 %

Procedure:
Cyclopropyl-{4-[2-(4-fluorophenyl)-8-methoxyimidazo[1,2-a]pyrazin-3-yl]-pyrimidin-2-yl}-amine (Example #A.10.1, 0.156 g, 0.414 mmol) was treated with a 4 M solution of hydrogen bromide in acetic acid (3 mL, 12 mmol) at ambient temperature. After about 45 min the mixture was treated with Et2O and filtered, washing the solid successively with Et2O, saturated aqueous NaHCO3 and Et2O. The solid was then dried in the oven for about 16 h to yield the product as white solid (0.115 g, 77%): LC/MS (Table 1, Method b) Rt=1.7 min; MS m/z: 361.4 (M−H)−.
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][OH:5].[CH2:6](Br)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+]>C1COCC1>[Cl:1][CH2:2][CH2:3][CH2:4][O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: BrCc1ccccc1
Reactant: OCCCCl
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: ClCCCOCc1ccccc1
Temperature: 0 °C
Yield: 97.9 %

Procedure:
In a 2 l flask, a mixture of 3-chloropropanol (56.7 g), benzyl bromide (102.6 g) and dry THF (600 ml) is stirred and cooled with ice/salt mixture. Potassium tert-butoxide (70 g) is added in portions (5-10 g), maintaining the internal temperature at about 0° C. After the mixture is stirred for 3 more hours at room temperature, the solvent is evaporated. Addition of 1N HCl (1 l), extraction with ether (1 l), and evaporation of solvent gives crude material (113.6 g), which is distilled under vacuum to give 1-chloro-3-benzyloxypropane (108.4 g) b.p.0.01 60°-80° C.
Reaction SMILES: [ClH:1].C([NH:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1)(OC(C)(C)C)=O>O1CCOCC1.C(Cl)Cl>[ClH:1].[ClH:1].[NH2:9][CH2:10][CH2:11][NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1
Reactant: CC(C)(C)OC(=O)NCCNc1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: NCCNc1ccccn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
4 N HCl in dioxane (3.2 mL) was added in a stream to a solution of 2-[[2-(Boc-amino)ethyl]amino]pyridine (148.4 mg, 0.63 mmole) in anhydrous CH2Cl2 (3.2 mL) at 0° C., then the reaction was warmed to RT. After 2 hr, the mixture was suction filtered to collect the precipitated solid, which was washed with anhydrous Et2O and dried to afford the title compound (132.8 mg, quantitative) as a yellow solid: 1H NMR (400, CD3OD) δ 7.99-8.07 (m, 1 H), 7.92-7.98 (m, 1 H), 7.19 (d, J=9.1 Hz, 1 H), 6.98-7.04 (m, 1 H), 3.76 (t, J=6.2 Hz, 2 H), 3.27 (t, J=6.2 Hz, 2 H, partially obscured by residual solvent signal); MS (ES) m/e 138 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:19]O>CN(C=O)C>[F:1][C:2]1[CH:9]=[C:8]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:19]
Reactant: COc1ccc(Oc2ccc(C=O)c(F)c2)cc1
Reactant: NO
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CN)c(F)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
180 mg (0.73 mmol) of 2-fluoro-4-(4-methoxy-phenoxy)-benzaldehyde were stirred with 180 μl (3 mmol) of hydroxylamine solution (50% in water) in 5 ml DMF at 100° C. for 1 h and then stirred overnight at ambient temperature. The mixture was evaporated down, dissolved in 10 ml of 7M methanolic ammonia and combined with 50 mg Raney nickel. It was then shaken for 4 h at ambient temperature and 3 bar hydrogen pressure. The catalyst was removed by suction filtering, the residue was evaporated down and purified by reversed-phase chromatography.
Reaction SMILES: Cl.C[O:3][C:4]1[C:5]([S:15](=[O:18])(=[O:17])[NH2:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1.[BrH:19]>>[BrH:19].[OH:3][C:4]1[C:5]([S:15](=[O:17])(=[O:18])[NH2:16])=[CH:6][C:7]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9][C:8]=2[CH:14]=1
Reactant: COc1cc2c(cc1S(N)(=O)=O)CCNCC2
Agent: Br
Agent: Cl
Product: NS(=O)(=O)c1cc2c(cc1O)CCNCC2

Procedure:
8-Methoxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrochloride (1.5 g, 0.005 m) was dissolved in 48% hydrobromic acid (15 ml), refluxed for 2 hours and concentrated in vacuo. The residue was triturated with acetone and then recrystallized from methanol to give 8-hydroxy-7-sulfamoyl-2,3,4,5-tetrahydro-1H-3-benzazepine hydrobromide, m.p. 315°-320° (decomp.).
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:8]2[NH:7][C:6]3[C:11]4[C:16]([CH2:17][C:5]=3[C:4]=2[CH:3]=1)=[CH:15][CH:14]=[CH:13][CH:12]=4.C([Li])CCC.[CH3:23][Si:24]([CH3:27])([CH3:26])Cl>>[CH3:23][Si:24]([CH3:27])([CH3:26])[N:7]1[C:8]2[CH:9]=[CH:10][C:2]([CH3:1])=[CH:3][C:4]=2[C:5]2[CH2:17][C:16]3[C:11]([C:6]1=2)=[CH:12][CH:13]=[CH:14][CH:15]=3
Reactant: C[Si](C)(C)Cl
Reactant: Cc1ccc2[nH]c3c(c2c1)Cc1ccccc1-3
Agent: [Li]CCCC
Product: Cc1ccc2c(c1)c1c(n2[Si](C)(C)C)-c2ccccc2C1

Procedure:
The general procedure of Example A is followed. 8-Methyl-5, 10-dihydroindeno[1,2-b]indole reacts with n-butyllithium and the product then reacts with trimethylchlorosilane to form 5-trimethylsilyl-8-methyl-5, 10-dihydroindeno[1,2-b]indole. The later reacts with n-butyllithium to form a lithium salt, which reacts with zirconium tetrachloride to give Catalyst IV.
Reaction SMILES: [CH2:1](I)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH2:12].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.C(OCC)(=O)C>[CH3:8][O:9][CH:10]([O:13][CH3:14])[CH2:11][NH:12][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: COC(CN)OC
Reactant: CCCCCCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCCCCCNCC(OC)OC
Yield: 78.1 %

Procedure:
Hexyl iodide (50 mmol, 7.38 ml) was added to a mixture of 2-amino acetaldehyde dimethyl acetal (100 mmol, 11 ml) and potassium carbonate (50 mmol, 6.9 g) in DMF (10 ml) at 0° C. Stirring was continued for 16h before diluting with ethyl acetate (200 ml), and ffitering the solution through a plug of celite. Concentration in vacuo was follwed by column chromatography (eluant ethyl acetate) to give N-hexyl 2-amino acetaldehyde dimethyl acetal (7.39 g, 78%) as a colourless oil.
Reaction SMILES: [CH:1]1[N:5]=[C:4]2[C:6]([N:8]=[CH:9][NH:10][N:3]2[CH:2]=1)=O.O=P(Cl)(Cl)[Cl:13]>>[CH:1]1[N:5]=[C:4]2[C:6]([Cl:13])=[N:8][CH:9]=[N:10][N:3]2[CH:2]=1
Reactant: O=c1nc[nH]n2ccnc12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1ncnn2ccnc12

Procedure:
Imidazo[1,2-f][1,2,4]triazin-4-ol (C-5) (400 mg, 2.94 mmol, 1.0 eq) is dissolved in POCl3 (10 mL, 109.2 mmol, 37.1 eq) and the resulting mixture is stirred at reflux for 2 h. The mixture is concentrated in vacuo to remove POCl3. The residue is poured into ice water (30 mL) and neutralized with saturated aqueous NaHCO3 solution to adjust the pH to 6-7 while keeping the temperature below 5° C. The mixture is extracted with ethyl acetate (30 mL×4). The combined organic layers are washed with brine, dried over Na2SO4 and filtered. The filtrate is concentrated in vacuo and the residue is purified by flash column chromatography on silica gel (16% ethyl acetate in petro ether) to afford the product, 4-chloroimidazo[1,2-f][1,2,4]triazine (C-6).
Reaction SMILES: [ClH:1].Cl.Cl.C1([NH:7][C:8]([C:10]2[C:18]3[CH:17]=[C:16]([C:19]4[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]5[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]5)[N:20]=4)[S:15][C:14]=3[CH:13]=[CH:12][CH:11]=2)=[O:9])CC1.[Cl:37]C1N=C(C2SC3C=CC=C([C:53](O)=[O:54])C=3C=2)C(Cl)=CN=1>>[ClH:25].[ClH:37].[ClH:1].[CH3:53][O:54][NH:7][C:8]([C:10]1[C:18]2[CH:17]=[C:16]([C:19]3[C:24]([Cl:25])=[CH:23][N:22]=[C:21]([NH:26][CH2:27][CH2:28][CH2:29][N:30]4[CH2:35][CH2:34][N:33]([CH3:36])[CH2:32][CH2:31]4)[N:20]=3)[S:15][C:14]=2[CH:13]=[CH:12][CH:11]=1)=[O:9]
Reactant: O=C(O)c1cccc2sc(-c3nc(Cl)ncc3Cl)cc12
Reactant: CN1CCN(CCCNc2ncc(Cl)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CC1
Agent: Cl
Product: CONC(=O)c1cccc2sc(-c3nc(NCCCN4CCN(C)CC4)ncc3Cl)cc12

Procedure:
Using the method of 2-{5-chloro-2-[3-(4-methylpiperazin-1-yl)-propylamino]-pyrimidin-4-yl}-benzo[b]thiophene-4-carboxylic acid cyclopropylamide tri-hydrochloride, the title compound is synthesized from 2-(2,5-dichloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid and isolated as a yellow solid. ES+(m/z) 475 (35Cl) and 477 (37Cl) [M(free base)+H].
Reaction SMILES: Cl[C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]2[C:4](=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[SH-:17].[Na+]>CN(C=O)C>[Cl:16][C:6]1[CH:5]=[C:4]2[C:9](=[CH:8][C:7]=1[Cl:15])[N:10]=[C:11]([CH:12]([CH3:14])[CH3:13])[C:2]([S:17][C:2]1[C:11]([CH:12]([CH3:14])[CH3:13])=[N:10][C:9]3[C:4]([N:3]=1)=[CH:5][C:6]([Cl:16])=[C:7]([Cl:15])[CH:8]=3)=[N:3]2
Reactant: [SH-]
Reactant: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)c1nc2cc(Cl)c(Cl)cc2nc1Sc1nc2cc(Cl)c(Cl)cc2nc1C(C)C
Temperature: 57.5 °C
Reaction time: 8 h
Yield: 20 %

Procedure:
To a solution of 2,6,7-trichloro-3-isopropylquinoxaline (105 mg, 0.38 mmol) in DMF (3 ml) was added sodium hydrosulfide (21 mg, 0.23 mmol). The reaction mixture was stirred at 55-60° C. in an oil bath overnight. The product was purified by a plug filtration through silica gel using ethyl acetate:hexanes 1:20 followed by preparative thin layer chromatography using ethyl acetate:hexanes 1:60. Extraction of the product band using chloroform afforded the title compound as a white solid in 20% yield.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][NH:28]3)=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[CH3:33][O:34][CH2:35]/[CH:36]=[CH:37]/[C:38](O)=[O:39]>>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:27]3[CH2:32][CH2:31][CH2:30][CH2:29][N:28]3[C:38](=[O:39])/[CH:37]=[CH:36]/[CH2:35][O:34][CH3:33])=[N:9][C:10]=2[C:11]2[CH:26]=[CH:25][C:14]([C:15]([NH:17][C:18]3[S:19][C:20]([CH2:23][CH3:24])=[CH:21][N:22]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1
Reactant: COC/C=C/C(=O)O
Reactant: CCc1cnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4)n4ccnc(N)c34)cc2)s1
Product: CCc1cnc(NC(=O)c2ccc(-c3nc([C@@H]4CCCCN4C(=O)/C=C/COC)n4ccnc(N)c34)cc2)s1
Yield: 47.6 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 2, from (S)-4-(8-amino-3-(piperidin-2-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(5-ethylthiazol-2-yl)benzamide (intermediate 37) and (E)-4-methoxybut-2-enoic acid (Intermediate 3), to afford the title compound (11.7 mg, 47.6%). Data: UPLC(C) Rt: 2.59 min; m/z 546.3 (M+H)+.
Reaction SMILES: [C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH2:9][C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li+].CC([N-]C(C)C)C.[C:29]1([S:35]([O:38][C:39]2[CH:40]=[CH:41][C:42]([CH2:45]Br)=[N:43][CH:44]=2)(=[O:37])=[O:36])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[C:1]1([C:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[N:8][CH:9]([CH2:45][C:42]2[CH:41]=[CH:40][C:39]([O:38][S:35]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)(=[O:37])=[O:36])=[CH:44][N:43]=2)[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=S(=O)(Oc1ccc(CBr)nc1)c1ccccc1
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CCOC(=O)C(Cc1ccc(OS(=O)(=O)c2ccccc2)cn1)N=C(c1ccccc1)c1ccccc1
Reaction time: 0.75 h
Yield: 72.8 %

Procedure:
A solution of ethyl N-(diphenylmethylene)glycinate (1.71 g, 6.40 mmol) in dry THF (10 ml) was added to a stirred solution of LDA (2M in heptane/THF/ethylbenzene, 3.20 ml, 6.40 mmol) in dry THF (10 ml) at −70° under nitrogen. After stirring at this temperature for 0.75 h, a solution of 5-benzenesulphonyloxy-2-bromomethyl-pyridine [2.00 g, 6.01 mmol; prepared as described by Myers et al, J.Org.Chem. (1996), 61, 813] in dry THF (10 ml) was added. The reaction mixture was stirred at −70° for 1 h then at room temperature for 18 h. The reaction was quenched with water (10 ml) then partitioned between EtOAc (70 ml) and brine (30 ml). The phases were separated and the aqueous phase re-extracted with EtOAc (2×40 ml). The combined organic extracts were washed with brine (10 ml), dried (Na2SO4) and evaporated in vacuo to afford the crude product as a dark oil. Purification by flash chromatography (silica, 60% to 75% Et2O/hexane; applied as DCM solution) afforded the title compound as a tan-coloured solid (2.25 g, 72%). δH (CDCl3) 8.02 (1H, d, J 2.8 Hz, pyr-H(6), 7.72 (2H, d, J˜8 Hz, ortho-Ar—H), 7.59 (1H, t, J˜8 Hz, para-Ar—H), 7.50 (2H, dd, J 8.4, 1.4 Hz, phenyl-H), 7.40-7.27 (8H, ms, Ar and phenyl-H), 7.19 (1H, dd, J 8.5, 2.8 Hz, pyr-H(4), 7.11 (1H, d, J 8.5 Hz, pyr-H(3), 6.67 (2H, br d, J˜8 Hz, phenyl-H), 4.50 (1H, dd, J 9, 4.6 Hz, CH-α), 4.24-4.10 (2H, sym.m. CH2CH3), 3.50-3.33 (2H, m, pyr-CH2), 1.24 (3H, t, J 7.2 Hz, CH2CH3); m/z (ESI) 515 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[CH:15])=[N:12][CH:13]=2)=[CH:4][CH:3]=1.I[C:17]1[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]([C:14]#[C:15][C:17]3[CH:22]=[CH:21][C:20]([CH2:23][CH2:24][OH:25])=[CH:19][CH:18]=3)=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: OCCc1ccc(I)cc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: OCCc1ccc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)cc1

Procedure:
The product was prepared analogously to Example 48.1c from 1.74 g (8.06 mmol) of 5-(4-chlorophenyl)-2-ethynylpyridine and 2.00 g (8.06 mmol) of 2-(4-iodophenyl)ethanol (24 at RT, triethylamine as base and acetonitrile as solvent). Yield: 1.80 g (67% of theoretical); C21H16ClNO (M=333.811); calc.: molpeak (M+H)+:334/336 (Cl); found: molpeak (M+H)+:334/336 (Cl).
Reaction SMILES: [C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23](I)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:26]([C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1)#[N:27]>>[C:1]1([C@@H:7]([NH:9][C:10]2[N:15]=[C:14]([N:16]3[C:20]4[CH:21]=[CH:22][C:23]([C:31]5[CH:32]=[CH:33][C:28]([C:26]#[N:27])=[CH:29][CH:30]=5)=[CH:24][C:19]=4[N:18]=[CH:17]3)[CH:13]=[CH:12][N:11]=2)[CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: N#Cc1ccc(B(O)O)cc1
Reactant: C[C@H](Nc1nccc(-n2cnc3cc(I)ccc32)n1)c1ccccc1
Product: C[C@H](Nc1nccc(-n2cnc3cc(-c4ccc(C#N)cc4)ccc32)n1)c1ccccc1

Procedure:
The title compound was prepared according to the procedure described in EXAMPLE 397, starting from 2-[(S)-1-Phenylethylamino]-4-[5-iodobenzimidazol-1-yl]pyrimidine and 4-cyanophenyl boronic acid. Mass spectrum (ESI) 417.2 (M+1).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([O:14][CH2:15][C:16]([F:19])([F:18])[F:17])[C:11]([C:20]([F:23])([F:22])[F:21])=[CH:10][C:9]=1[NH:24][C:25](=[O:41])[CH2:26][C:27]([C:29]1[CH:34]=[CH:33][N:32]=[C:31]([C:35]2[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=2)[CH:30]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[N:32]1[CH:33]=[CH:34][C:29]([C:27]2[CH2:26][C:25](=[O:41])[NH:24][C:9]3[CH:10]=[C:11]([C:20]([F:23])([F:22])[F:21])[C:12]([O:14][CH2:15][C:16]([F:17])([F:19])[F:18])=[CH:13][C:8]=3[N:7]=2)=[CH:30][C:31]=1[C:35]1[CH:36]=[N:37][CH:38]=[CH:39][CH:40]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(C(F)(F)F)cc1NC(=O)CC(=O)c1ccnc(-c2cccnc2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2ccnc(-c3cccnc3)c2)=Nc2cc(OCC(F)(F)F)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from [2-(3-[2,3′]bipyridinyl-4-yl-3-oxo-propionylamino)-5-(2,2,2-trifluoro-ethoxy)-4-trifluoromethyl-phenyl]-carbamic acid tert-butyl ester (Example M296) (305 mg, 0.51 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a yellow solid (201 mg, 82%).
Reaction SMILES: [C:1]([C:3]1[C:4](=[O:8])[CH2:5][CH2:6][CH:7]=1)#[N:2].N(C(C)(C)C#N)=NC(C)(C)C#N.C([SnH](CCCC)CCCC)CCC.Br[CH2:35][CH2:36][C:37]1[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])=[CH:39][CH:38]=1>C1C=CC=CC=1>[C:1]([CH:3]1[CH:7]([CH2:35][CH2:36][C:37]2[CH:49]=[CH:48][C:40]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])=[CH:39][CH:38]=2)[CH2:6][CH2:5][C:4]1=[O:8])#[N:2]
Reactant: N#CC1=CCCC1=O
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: CCCC[SnH](CCCC)CCCC
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)c1ccc(CCC2CCC(=O)C2C#N)cc1

Procedure:
A solution of the 2-cyano-2-cyclopenten-1-one (2.41 g, 22.5 mmol) prepared in the Preparative Example 101 in anhydrous benzene and a solution of azobisisobutyronitrile (AIBN) (0.05 g, a catalytic amount) and tri-n-butyltin hydride (3.62 g, 12.4 mmol) in anhydrous benzene were simultaneously gradually dropped into a solution of t-butyl 4-(2-bromoethyl)benzoate (3.21 g, 11.3 mmol) prepared in the Preparative Example 104 in anhydrous benzene under reflux by heating. The obtained mixture was heated under reflux for about 20 minutes and distilled to remove the solvent. The residue was purified by silica gel column chromatography to give the objective compound. yield: 0.43 g
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][NH:10][C@H:11]2[CH2:16][CH2:15][C@H:14]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:25]([O:27][CH3:28])=[O:26]>[OH-].[Na+].C1COCC1.CCOC(C)=O>[CH3:28][O:27][C:25](=[O:26])[N:10]([C@H:11]1[CH2:12][CH2:13][C@H:14]([C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:15][CH2:16]1)[CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Oc1ccc([C@H]2CC[C@H](NCCCc3ccccc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)N(CCCc1ccccc1)[C@H]1CC[C@H](c2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of trans-4-[4-(3-phenylpropylamino) cyclohexyl]-phenol (0.40 g, 1.3 mmol) in a mixture of 2 N NaOH (5 mL) and THF (5 mL) was added methyl chloroformate (0.12 mL, 1.6 mmol). The reaction mixture was stirred at room temperature for 2 hours. Methyl chloroformate (0.05 mL, 0.65 mmol) was added and stirring continued for another 2 hours. The mixture was diluted with EtOAc (50 mL), washed with H2O, dried (Na2SO4), filtered and concentrated under reduced pressure. Purification by flash chromatography (silica, 97:3 MeOH/CH2Cl2) gave trans-N-[4-(4-hydroxyphenyl)cyclohexyl]-N-(3-phenylpropyl)carbamic acid methyl ester, as an off-white solid (0.068 g, 14%): mp 128-133° C.; IR (KBr): 3403, 2923, 1673, 1518 cm−1; 1H NMR(300MHz, CD3OD) δ 7.31-7.15 (m, 5H), 7.01 (d, J=8 Hz, 2H), 6.68 (d, J=8 Hz, 2H), 3.91-3.78 (m, 1H), 3.67 (s, 3H), 3.25-3.13 (m, 2H), 2.61 (t, J=8 Hz, 2H), 2.40-2.29 (m, 1H), 1.95-1.45 (m, 10H); CI-MS (methane) (m/z): 368 [M+I]+; HRMS-API (m/z): [M+1]+ Calcd for C23H29NO3, 368.2225. found: 368.2227; HPLC: method A, 13.78 minutes (85.2%).