Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.I[C:7]1[CH:12]=[C:11]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:9][C:8]=1[O:17][CH3:18].[B:19](OC(C)C)([O:24]C(C)C)[O:20]C(C)C>C1COCC1>[CH3:18][O:17][C:8]1[CH:9]=[CH:10][C:11]([C:13]([F:16])([F:15])[F:14])=[CH:12][C:7]=1[B:19]([OH:24])[OH:20]
Reactant: COc1ccc(C(F)(F)F)cc1I
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COc1ccc(C(F)(F)F)cc1B(O)O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (1.6M in hexanes, 456 μL, 0.729 mmol) was added dropwise to a stirred solution of 2-iodo-1-methoxy-4-(trifluoromethyl)benzene (Step A, 200 mg, 0.662 mmol) in THF (1.5 mL) at −78° C. under an atmosphere of nitrogen. The reaction stirred at −78° C. for 30 min prior to the addition of triisopropyl borate (458 μL, 1.986 mmol). The reaction stirred an additional 2 h at −78° C. and was quenched with sat. NH4Cl. The mixture was extracted with CH2Cl2 and the organic phase was washed with NaHCO3 (15 mL) and brine (15 mL), dried (Na2SO4), filtered, conc. in vacuo to afford [2-methoxy-5-(trifluoromethyl)phenyl] boronic acid which was carried on without purification.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.[C:24](O)(=[O:27])[CH2:25][OH:26]>>[Cl:1][C:2]1[N:3]=[C:4]([N:18]2[CH2:19][CH2:20][O:21][CH2:22][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][N:15]([C:25](=[O:26])[CH2:24][OH:27])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1
Reactant: O=C(O)CO
Reactant: Clc1nc(N2CCOCC2)c2sc(CN3CCNCC3)cc2n1
Product: O=C(CO)N1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1

Procedure:
2-Chloro-4-morpholino-6-((piperazin-1-yl)methyl)thieno[3,2-d]pyrimidine (630 mg) was reacted with glycolic acid via General Procedure B to give 1-(4-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperazin-1-yl)-2-hydroxyethanone.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH:31]([C:33]1[CH:38]=[CH:37][C:36](B(O)O)=[CH:35][CH:34]=1)=[O:32].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:17][C:16]1[CH:15]=[C:14]([CH3:18])[NH:13][C:12](=[O:19])[C:11]=1[CH2:10][NH:9][C:7]([C:6]1[CH:20]=[C:2]([C:36]2[CH:37]=[CH:38][C:33]([CH:31]=[O:32])=[CH:34][CH:35]=2)[CH:3]=[C:4]([N:22]([CH2:29][CH3:30])[CH:23]2[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[C:5]=1[CH3:21])=[O:8]
Reactant: CCN(c1cc(Br)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Reactant: O=Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CCN(c1cc(-c2ccc(C=O)cc2)cc(C(=O)NCc2c(C)cc(C)[nH]c2=O)c1C)C1CCOCC1
Temperature: 25 °C
Yield: 69.8 %

Procedure:
To a stirred solution of 5-bromo-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-2-methylbenzamide (5.0 g, 10 mmol) and (4-formylphenyl) boronic acid (2.35 g, 15.8 mmol) in dioxane/water (30 mL/10 mL) was added Na2CO3 (4.01 g, 37.9 mmol). The solution was purged with argon for 15 min., Pd(PPh3)4 (1.21 g, 1.05 mmol) and the mixture was heated at 100° C. for 2 h. The mixture was allowed to cool to room temperature, diluted with water and extracted with 10% MeOH/CH2Cl2. The combined organic layers were dried over sodium sulphate and the solvent removed under reduced pressure. The resulting crude material was purified by column chromatography over silica gel to afford N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-5-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-4′-formyl-4-methyl-[1,1′-biphenyl]-3-carboxamide (3.5 g, 66%).
Reaction SMILES: [CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([CH:24]=[O:25])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:26][CH3:27])[CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[BH4-].[Li+].Cl>O1CCCC1>[CH2:1]([N:8]1[C:21]2[CH:20]=[CH:19][C:18]([O:22][CH3:23])=[C:17]([CH2:24][OH:25])[C:16]=2[S:15][C:14]2[C:9]1=[CH:10][CH:11]=[C:12]([O:26][CH3:27])[CH:13]=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc2c(c1)Sc1c(ccc(OC)c1C=O)N2Cc1ccccc1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)Sc1c(ccc(OC)c1CO)N2Cc1ccccc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
The crude 10-benzyl-3,7-dimethoxy-phenothiazine-4-carbaldehyde obtained was dissolved in 150 ml of absolute tetrahydrofuran, whereupon the solution was treated at 0° with 31.5 ml of lithium borohydride solution (1M in tetrahydrofuran). The reaction mixture was brought slowly to room temperature, stirred for 1 hour and then poured into ice-water, and the pH was adjusted to 3-4 with 0.5N hydrochloric acid solution. The mixture was extracted with ethyl acetate. The combined organic phases were washed with saturated sodium chloride solution, dried over magnesium sulphate and evaporated. After chromatography on silica gel with ethyl acetate/hexane (1:2) 8.0 g (73.7%) of (10-benzyl-3,7-dimethoxy-phenothiazin-4-yl)-methanol were obtained as a white amorphous solid.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[S:19][C:18]([CH3:20])=[C:17]3[C:13]=2[CH2:14][C@H:15]2[C:21]([CH3:23])([CH3:22])[C@H:16]23)=[O:11])=[C:4]([O:24][CH3:25])[CH:3]=1.[CH2:26]([CH:28]1[O:30][CH2:29]1)Cl>C(O)(C)C.[OH-].[Na+].C(OCC)C>[CH3:25][O:24][C:4]1[CH:3]=[C:2]([O:1][CH2:26][CH:28]2[CH2:29][O:30]2)[CH:7]=[CH:6][C:5]=1[CH2:8][CH2:9][C:10]([C:12]1[S:19][C:18]([CH3:20])=[C:17]2[C:13]=1[CH2:14][C@H:15]1[C:21]([CH3:22])([CH3:23])[C@H:16]12)=[O:11]
Reactant: COc1cc(O)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Reactant: ClCC1CO1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: CC(C)O
Product: COc1cc(OCC2CO2)ccc1CCC(=O)c1sc(C)c2c1C[C@@H]1[C@H]2C1(C)C
Temperature: 25 °C
Reaction time: 9 h
Yield: 66.2 %

Procedure:
A solution of 3-(4-hydroxy-2-methoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (600 mg, 1.68 mmol, Intermediate 20) in isopropanol (10 mL) and 3 N aq. NaOH (6 mL) is treated with epichlorohydrine (631 mg, 5.05 mmol). The reaction mixture is stirred at rt for 9 h before it is diluted with diethyl ether (150 mL) and washed with sat. aq. NaHCO3 followed by water. The organic layer is dried over MgSO4 and evaporated. The crude product is purified by CC on silica gel eluting with heptane:EA 4:1 to give 3-(2-methoxy-4-oxiranylmethoxy-phenyl)-1-((1aS,5aR)-1,1,2-trimethyl-1,1a,5,5a-tetrahydro-3-thia-cyclopropa[a]pentalen-4-yl)-propan-1-one (459 mg) as an almost colourless oil; LC-MS: tR=1.13 min, [M+1]+=413.28.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:12][Mg]Br.O>O1CCCC1>[C:1]([C:5]1[O:9][N:8]=[C:7]([CH:10]([OH:11])[CH3:12])[CH:6]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)c1cc(C=O)no1
Reactant: C[Mg]Br
Solvent: O
Solvent: C1CCOC1
Product: CC(O)c1cc(C(C)(C)C)on1
Reaction time: 1 h

Procedure:
1.29 g of 5-t-butyl-isoxazole-3-carbaldehyde was dissolved in 10 ml of tetrahydrofuran, and 10 ml of a 0.93 M solution of methylmagnesium bromide in tetrahydrofuran was then added. The mixture was stirred for 1 hour under ice-cooling. After water was added, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 1.18 g of 1-(5-t-butyl-isoxazol-3-yl)ethanol.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([Mg]Br)=[CH:4][CH:3]=1.[C:10]([N:15]1[C@@H:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][O:17][C:16]1=[O:26])(=[O:14])/[CH:11]=[CH:12]/[CH3:13]>C1COCC1.CSC>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:12]([CH3:13])[CH2:11][C:10]([N:15]2[C@@H:19]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:18][O:17][C:16]2=[O:26])=[O:14])=[CH:4][CH:3]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: C/C=C/C(=O)N1C(=O)OC[C@@H]1c1ccccc1
Solvent: CSC
Solvent: C1CCOC1
Product: C[C@H](CC(=O)N1C(=O)OC[C@@H]1c1ccccc1)c1ccc(F)cc1
Temperature: -10 °C
Reaction time: 12 h

Procedure:
To a stirred solution of copper(II)bromide dimethylsulfide complex (6.85 g, 33.3 mmol) in anhydrous THF (60 mL) and dimethylsulfide (30 mL) was added 4-fluorophenylmagnesium bromide (30.0 mL, 1.0 M in THF, 30.0 mmol) at −40° C. The resultant mixture was stirred at −40° C. for 30 min, then warmed to −10° C. The product from Step A (1.18 g, 5.10 mmol) in THF (30 mL) was added to the above reaction mixture over 1 h at −10° C. The resultant mixture was stirred at −10° C. for 2 h, then slowly warmed to room temperature and stirred at room temperature for 12 h. The reaction was quenched by slow addition of saturated aqueous ammonium chloride solution. The organic phase was separated and the aqueous phase was extracted with two portions of ethyl acetate. The combined organic layers were washed with brine and concentrated in vacuo. Purification by flash chromatography (silica gel, 80:20 hexanes/ethyl acetate) afforded the desired product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([C:16]([OH:18])=O)[CH2:12][CH2:11]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)(=O)OCC.Cl.[NH2:33][C@H:34]([C:42]([NH2:44])=[O:43])[CH2:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>O1CCCC1>[C:1]([O:5][C:6]([NH:8][CH2:9][C@H:10]1[CH2:11][CH2:12][C@H:13]([C:16]([NH:44][C:42](=[O:43])[C@H:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[NH2:33])=[O:18])[CH2:14][CH2:15]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC(=O)[C@@H](N)Cc1ccccc1
Reactant: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NC[C@H]1CC[C@H](C(=O)NC(=O)[C@@H](N)Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of trans-4-(t-butoxycarbonylaminomethyl)cyclohexyl carboxylic acid (3.86 g) dissolved in dry tetrahydrofuran (150.00 ml), triethylamine (2.25 ml) was added under ice-cooling and the mixture was stirred for 5 minutes. A solution of ethyl chlorocarbonate (1.63 g) in dry tetrahydrofuran (10.00 ml) was added to the mixture under ice-cooling, and the mixture was stirred at the same temperature for 20 minutes. L-phenylalanine amide hydrochloride and triethylamine (2.25 ml) were added to the mixture, and the mixture was stirred under ice-cooling for 2 hours and under room temperature for one hour, followed by concentration under a reduced pressure. Water was added to the residue, and the insolubles therein were filtered, thoroughly washed with water, and further washed with 50% aqueous ethyl alcohol and 50% ethyl alcohol-ethyl ether, followed by drying, to give N-[trans-4-(t-butoxycarbonylaminomethyl)cyclohexylcarbonyl]-L-phenylalanine amide (I) (4.82 g) as a white powder. This structure was confirmed by NMR spectrum.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH2:31][C:32]2[CH:33]=[C:34]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:35]#[N:36])[CH2:9][C:10]2[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=2[C:20]2[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=2[O:29][CH3:30])=[N:6][CH:7]=1.[H-].[Na+].Br[CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51].O>CN(C)C=O>[C:35]([C:34]1[CH:33]=[C:32]([CH:39]=[C:38]([C:40]([F:43])([F:41])[F:42])[CH:37]=1)[CH2:31][N:8]([CH2:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:19])[F:17])[CH:13]=[CH:12][C:11]=1[C:20]1[CH:25]=[C:24]([CH:26]([CH3:28])[CH3:27])[CH:23]=[CH:22][C:21]=1[O:29][CH3:30])[C:5]1[N:6]=[CH:7][C:2]([O:1][CH2:47][CH2:48][CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])=[CH:3][CH:4]=1)#[N:36]
Reactant: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(O)cn1
Reactant: CC(C)(C)OC(=O)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C#N)cc(C(F)(F)F)c1)c1ccc(OCCCC(=O)OC(C)(C)C)cn1
Reaction time: 0.5 h
Yield: 91.1 %

Procedure:
3-{[(5-Hydroxy-pyridin-2-yl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-methyl}-5-trifluoromethyl-benzonitrile (150 mg) is dissolved in N,N-dimethylformamide (2.5 ml), and thereto is added 60% sodium hydride (12 mg) under ice-cooling and the mixture is stirred for 30 minutes and thereto is added tert-butyl 4-bromobutyrate (85 mg), and the mixture is stirred at room temperature for 6 hours. To the reaction solution is added water under ice-cooling, and the mixture is extracted with methylene chloride, and the organic layer is washed with a saturated brine, and the mixture is dried over magnesium sulfate and is concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (hexane:ethyl acetate=9:1→3:1) to give tert-butyl 4-{6-[(3-cyano-5-trifluoromethyl-benzyl)-(5′-isopropyl-2′-methoxy-4-trifluoromethyl-biphenyl-2-ylmethyl)-amino]-pyridin-3-yloxy}-butyrate (169 mg). MS (m/z): 742 [M+H]+
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24](=[S:26])[NH2:25])[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.Cl[CH2:28][C:29](=O)[CH3:30]>>[CH:1]1([N:5]2[CH2:10][CH2:9][CH:8]([O:11][C:12]3[CH:17]=[CH:16][C:15]([C:18]4([C:24]5[S:26][CH:28]=[C:29]([CH3:30])[N:25]=5)[CH2:23][CH2:22][O:21][CH2:20][CH2:19]4)=[CH:14][CH:13]=3)[CH2:7][CH2:6]2)[CH2:2][CH2:3][CH2:4]1
Reactant: NC(=S)C1(c2ccc(OC3CCN(C4CCC4)CC3)cc2)CCOCC1
Reactant: CC(=O)CCl
Product: Cc1csc(C2(c3ccc(OC4CCN(C5CCC5)CC4)cc3)CCOCC2)n1
Yield: 83 %

Procedure:
The title compound (155 mg, 83%) was prepared from 4-{4-[(1-cyclobutylpiperidin-4-yl)oxy]phenyl}tetrahydro-2H-pyran-4-carbothioamide and chloroacetone similarly to the procedure used for example 136. 1H NMR (400 MHz, CDCl3) δ 1.64-1.71 (m, 2H), 1.78-1.81 (m, 2H), 1.88-2.04 (m, 6H), 2.10-2.20 (m, 2H), 2.31-2.38 (m, 2H), 2.42 (s, 3H), 2.61-2.64 (m, 4H), 2.74 (m, 1H), 3.71 (t, 2H), 3.81-3.85 (m, 2H), 4.28 (m, 1H), 6.75 (s, 1H), 6.83 (d, 2H), 7.23 (d, 2H). HRMS ESI+ m/z 413.2257 [MH]+.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]3[C:17]4[N:16]=[CH:15][N:14]=[CH:13][C:12]=4[CH:11]=[CH:10][C:9]=3[C:4]=2[N:3]=[CH:2]1.[C:18]([Si:20]([CH3:23])([CH3:22])[CH3:21])#[CH:19]>C(N(CC)CC)C.C1(C)C=CC=CC=1>[CH3:21][Si:20]([C:18]#[C:19][C:4]1[CH:5]=[C:6]([C:13]2[C:12]3[CH:11]=[CH:10][C:9]4[C:4]5[N:3]=[CH:2][NH:1][C:5]=5[CH:6]=[CH:7][C:8]=4[C:17]=3[N:16]=[CH:15][N:14]=2)[CH:7]=[CH:8][CH:9]=1)([CH3:23])[CH3:22]
Reactant: c1ncc2ccc3c(ccc4[nH]cnc43)c2n1
Reactant: C#C[Si](C)(C)C
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: C[Si](C)(C)C#Cc1cccc(-c2ncnc3c2ccc2c3ccc3[nH]cnc32)c1
Reaction time: 3.5 h
Yield: 70.5 %

Procedure:
A slurry of 3.00 g (9.02 mmoles) of 6-bromophenyl)benzimidazoquinazoline, 100 mg of diacetatobis(triphenylphosphine)palladium[II] in 150 ml of 2:1 triethylamine-toluene was heated to 100° C. under argon and then treated with dropwise addition of 1.57 g (16.0 mmoles) of ethynyltrimethylsilane. After 3.5 hours, the mixture was cooled and filtered. The filtrate was diluted with 100 ml of ether, washed with 200 ml each of 5% hydrochloric acid and water, and then dried over magnesium sulfate. Concentrating the clear solution yielded a solid mass which upon trituration with hexane gave 2.21 g (56.5 mmoles, 70.5%) of 6-(m-trimethylsilylethynylphenyl)benzimidazoquinazoline: ir (KBr): 3077 (medium, sharp, C-H), 2960 (medium, sharp, SiCH), 2155 (strong, sharp, C≡C), 1621, 1587 (v. strong, sharp, C=N), 1524, 1456, 1441, 1355, 1325 (strong, sharp, C=C), 1247 (v. strong, sharp, Si--C) and 844 cm-1 (v. strong, broad, Si--C bending); mass spectrum (70 ev) m/e 391.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([CH2:12][N:13]3[CH:17]=[C:16]([C:18]([NH:20][CH2:21][C:22]4[C:23]([CH3:37])=[CH:24][C:25]([NH:29]C(=O)OC(C)(C)C)=[N:26][C:27]=4[CH3:28])=[O:19])[CH:15]=[N:14]3)=[N:9]2)=[CH:4][CH:3]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:29][C:25]1[N:26]=[C:27]([CH3:28])[C:22]([CH2:21][NH:20][C:18]([C:16]2[CH:15]=[N:14][N:13]([CH2:12][C:8]3[CH:7]=[CH:6][C:5]4[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:9]=3)[CH:17]=2)=[O:19])=[C:23]([CH3:37])[CH:24]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(N)nc(C)c1CNC(=O)c1cnn(Cc2ccc3ccc(Cl)cc3n2)c1
Temperature: 23 °C
Reaction time: 7.5 h

Procedure:
To a solution of tert-butyl (5-((1-((7-chloroquinolin-2-yl)methyl)-1H-pyrazole-4-carboxamido)methyl)-4,6-dimethylpyridin-2-yl)carbamate (151 mg, 0.29 mmol) in DCM (2 ml) was added TFA (0.447 ml, 5.80 mmol). Reaction mixture was stirred for 7.5 h at 23° C. After evaporation of solvents, the crude material was purified by preparative HPLC (SunFire C18-ODB, 5 μm, 100×30 mm, elution with A=water+0.1% TFA and B=ACN+0.1% TFA, gradient from 5% to 100% B in 25 min, flow: 40 mL/min). Fractions were combined, and the solvents were evaporated to afford the title cpd as a TFA salt, which was dissolved in hot methanol/ACN and eluted through a PL-HCO3 MP-resin column (Stratosphere SPE) in order to remove salt. The eluted solution was evaporated, and the residue was dried over a weekend under high vacuum (dessicator, 50° C.) to afford the title compound as a free base. 1H-NMR (DMSO-d6, 400 MHz) δ 8.40 (d, 1H), 8.38 (s, 1H), 8.03 (s, 1H), 8.02 (d, 1H), 7.94 (broad s, 2H), 7.65 (d, 1H), 7.24 (d, 1H), 6.11 (s, 1H), 5.63 (s, 2H), 5.61 (broad s, 2H), 4.28 (d, 2H), 2.29 (s, 3H), 2.16 (s, 3H); HPLC (Method G) Rt=1.476 min, MS (Method V) [M+H]+=422.3.
Reaction SMILES: C([Li])CCC.[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.CON(C)[C:18](=[O:20])[CH3:19]>C1COCC1>[CH3:6][O:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][N:12]=[C:11]1[C:18](=[O:20])[CH3:19]
Reactant: CON(C)C(C)=O
Reactant: COCCn1ccnc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCCn1ccnc1C(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 82.4 %

Procedure:
A solution of 30 ml (75 mmol) of 2.5 M n-butyllithium in hexanes was added slowly to a solution of 8.48 g (61.3 mmol) 1-(2-Methoxyethyl)-1H-imidazole (WO 2003055876 A1 in 200 ml THF cooled in a dry ice-acetone bath. After stirring 1 hour, 8 ml (75 mmol) of N-methoxy-N-methylacetamide was added quickly, and the solution was allowed to warm to room temperature over 30 min. After quenching with aqueous NH4Cl, the mixture was diluted with water and extracted twice with EtOAc, which was washed with brine, dried (MgSO4) and concentrated to give an oil that was chromatographed on silica gel (100% DCM followed by gradient elution to 50% EtOAc in DCM). Product (8.5 g) was obtained as a mobile oil. MS (ES) (M+H)+: 169 for C8H12CN2O2
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[S:15][CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][Si](C(C)(C)C)(C)C)=[CH:19][CH:18]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:31])[S:15][CH2:16][C:17]2[CH:18]=[CH:19][C:20]([OH:23])=[CH:21][CH:22]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(O[Si](C)(C)C(C)(C)C)cc2)CC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)SCc2ccc(O)cc2)CC1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 47.7 %

Procedure:
to a stirred solution of S-4-(tert-butyl-dimethylsilyloxy)benzyl 4-tert-butoxycarbonylpiperazine-1-thiocarboxylate (10 g, 22 mmol) in THF (100 mL) was added a solution of TBAF in THF (1 N, 24 mL, 24 mmol). The mixture was stirred at room temperature for 40 min then diluted with water (200 mL) and extracted with EtOAc (2×250 mL). The combined organic extracts were washed successively with water (250 mL) and brine (500 mL) then dried (MgSO4), filtered and concentrated to reveal a brown oil. Trituration with EtOAc/hexane afforded the product as a white solid (3.7 g, 47%): 1H-NMR (400 MHz, d6-DMSO) 9.32 (1H, m), 7.11 dt (2H, t, J 8.5, 2.5 Hz), 6.67 (2H, t, J 8.5, 2.5 Hz), 4.02 (2H, s), 3.43 (4H, m), 3.33 (4H, m) and 1.40 (9H, s).
Reaction SMILES: [CH3:1][N:2]1[C:6]2=[N:7][C:8]([CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[CH:9][C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3]1.[Br:17]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[Br:17][C:9]1[C:10]([CH3:11])=[C:5]2[CH2:4][CH2:3][N:2]([CH3:1])[C:6]2=[N:7][C:8]=1[CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Reactant: CCCCCc1cc(C)c2c(n1)N(C)CC2
Solvent: ClC(Cl)Cl
Product: CCCCCc1nc2c(c(C)c1Br)CCN2C
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 108 mg (0.50 mmol) of 1,4-dimethyl-6-pentyl-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine in 3 mL of chloroform was added 70.7 mg (0.25 mmol) of 1,3-dibromo-5,5-dimethylhydantoin in portions at 0° C. The reaction mixture was stirred at 0° C. for 30 min. The reaction was quenched by the addition of 5 mL of sat aq. NaHCO3. The mixture was extracted with chloroform and the combined organic layer was washed with brine and dried over MgSO4. The concentrated residue was purified by flash chromatography on a silica gel column (20 1.7 cm). Elution with 100:1 hexanes/ethyl acetate gave the product as a yellow oil: yield 136 mg (92%); silica gel TLC Rf 0.65 (8:1:1 hexanes/ethyl acetate/methanol); 1H NMR (CDCl3) δ 0.89 (t, 3H, J=7.2 Hz), 1.33-1.38 (m, 4H), 1.66 (quint, 2H, J=7.6 Hz), 2.16 (s, 3H), 2.77 (t, 2H, J=8.0 Hz), 2.82-2.87 (m, 5H) and 3.40 (t, 2H, J=8.0 Hz); 13C NMR (CDCl3) δ 14.1, 19.5, 22.6, 25.2, 28.4, 31.8, 33.0, 38.1, 52.4, 110.9, 120.4, 141.1, 156.8 and 161.8; mass spectrum, m/z 297.1 and 299.1 (M+H)+ (theoretical 297.1 and 299.1); mass spectrum (APCI), m/z 297.0968 and 199.0937 (M+H)+ (C14H22N2Br requires 297.0966 and 299.0946).
Reaction SMILES: [C:1](=[S:4])([NH2:3])[CH3:2].Br.Br.Br[CH2:8][C:9](=O)[CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][CH:15]([CH2:18][C:19]2[N:23]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=2)[CH2:14][CH2:13]1>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:23]2[C:22]3[CH:32]=[CH:33][CH:34]=[CH:35][C:21]=3[N:20]=[C:19]2[CH2:18][CH:15]2[CH2:14][CH2:13][N:12]([CH2:11][CH2:10][C:9]3[N:3]=[C:1]([CH3:2])[S:4][CH:8]=3)[CH2:17][CH2:16]2)=[CH:26][CH:27]=1
Reactant: O=C(CBr)CCN1CCC(Cc2nc3ccccc3n2Cc2ccc(F)cc2)CC1
Reactant: CC(N)=S
Agent: Br
Solvent: CO
Product: Cc1nc(CCN2CCC(Cc3nc4ccccc4n3Cc3ccc(F)cc3)CC2)cs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33 %

Procedure:
A mixture of 0.75 parts of ethanethioamide, 7 parts of 1-bromo-4-[4-[[1-[(4-fluorophenyl)methyl]-1H-benzimidazol-2-yl]methyl]-1-piperidinyl]-2-butanone dihydrobromide and 80 parts of methanol was stirred overnight at room temperature. The reaction mixture was evaporated. Water was added. The whole was treated with sodium hydroxide. The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was purified by column chromatography over silica gel using a mixture of trichloromethane and methanol, saturated with ammonia, (97:3 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was further purified by column chromatography (HPLC) over silica gel using a mixture of hexane, trichloromethane and methanol (45:45:10 by volume) as eluent. The pure fractions were collected and the eluent was evaporated. The residue was converted into the ethanedioate salt in ethanol and 2-propanone. The salt was filtered off and dried, yielding 2 parts (33%) of 1-[(4-fluorophenyl)methyl]-2-[[1-[2-(2-methyl-4-thiazolyl)ethyl]-4-piperidinyl]methyl]-1H-benzimidazole ethanediote(2:5); mp. 124.1° C. (459).