Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][C:6]=1[C:7]([O:9]C)=[O:8].[OH-].[Na+]>C(O)C.O>[Br:1][C:2]1[S:3][C:4]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[CH:5][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: COC(=O)c1cc(-c2ccccc2)sc1Br
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)c1cc(-c2ccccc2)sc1Br
Yield: 94.8 %

Procedure:
A solution of methyl 2-bromo-5-phenylthiophene-3-carboxylate (11c) (290 mg, 0.97 mmol) and sodium hydroxide (156 mg, 3.90 mmol) in a mixture of ethanol (6 mL) and water (2 mL) was refluxed for 30 minutes. The mixture was concentrated in vacuo. The remained aqueous layer was washed with diethyl ether (5 mL), acidified with 1N hydrochloric acid until pH 3 and was extracted with dichloromethane (2×10 mL). The organic layer was dried over sodium sulfate and concentrated in vacuo to provide the desired acid (11d) (260 mg, 0.92 mmol, 95%), which was used without further purification.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([CH3:8])[N:5]=[C:4]([N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[CH2:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[N:3]=1.[C:28]([O:32][C:33]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]2[CH:43]=[C:44](B(O)O)[C:45]([F:48])=[N:46][CH:47]=2)[CH2:37][CH2:36]1)=[O:34])([CH3:31])([CH3:30])[CH3:29].C([O-])(=O)C.[K+].O1CCOCC1>O>[CH3:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([CH2:10][N:9]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=2)[C:4]2[N:5]=[C:6]([CH3:8])[N:7]=[C:2]([C:44]3[CH:43]=[C:42]([CH2:41][N:38]4[CH2:39][CH2:40][N:35]([C:33]([O:32][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:34])[CH2:36][CH2:37]4)[CH:47]=[N:46][C:45]=3[F:48])[N:3]=2)=[CH:12][CH:13]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(Cl)n2)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc(F)c(B(O)O)c2)CC1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(CN4CCN(C(=O)OC(C)(C)C)CC4)cnc3F)n2)cc1
Temperature: 120 °C
Yield: 79 %

Procedure:
A microwave vial (80 mL) was charged with 4-chloro-N,N-bis(4-methoxybenzyl)-6-methyl-1,3,5-triazin-2-amine (2.496 g, 6.49 mmol), 5-((4-(tert-butoxycarbonyl)piperazin-1-yl)methyl)-2-fluoropyridin-3-ylboronic acid (2.000 g, 5.90 mmol), potassium acetate (1.777 g, 18.10 mmol), Am-Phos (0.403 g, 0.649 mmol), dioxane (20 mL) and water (3.00 mL, 167 mmol). The vial was heated in a CEM Voyager Microwave (Large-Scale Unit) for 25 minutes at 120° C. while 100 Watts of energy was supplied via Powermax (Simultaneous heating while cooling technology). The reaction mixture was diluted with water (15 mL) and extracted with Chloroform (3×50 mL). The organic extracts were combined and dried over Na2SO4. The solution was filtered and concentrated in vacuo to give the crude product as a yellow oil. The crude product was adsorbed onto a plug of silica gel and purified by chromatography through a SiliCycle SiliaSep pre-packed silica gel column (220 g) with a gradient of 10% to 100% ethyl acetate/hexanes over 45 min to give tert-butyl 4-((5-(4-(bis(4-methoxybenzyl)amino)-6-methyl-1,3,5-triazin-2-yl)-6-fluoropyridin-3-yl)methyl)piperazine-1-carboxylate (3.000 g, 4.66 mmol, 79% yield) as a yellow oil. 1H NMR (400 MHz, d6-DMSO) δ 8.50 (dd, J=9.39, 2.35 Hz, 1H); 8.28 (d, J=1.37 Hz, 1H); 7.25 (d, J=8.61 Hz, 4H); 6.89 (dd, J=11.15, 8.61 Hz, 4H); 6.70-6.81 (m, 1H); 4.77 (d, J=4.69 Hz, 4H); 3.65-3.82 (m, 6H); 3.58 (s, 2H); 3.24-3.37 (m, 4H); 2.47 (s, 3H); 2.28-2.38 (m, 4H); 1.33-1.50 (m, 9H). m/z (ESI, +ve ion) 644.2 (M+H)+.
Reaction SMILES: Br/[C:2](/[F:16])=[C:3](/[F:15])\[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1.[CH3:17][O:18][C:19]1[CH:20]=[C:21](B(O)O)[CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26].C([O-])([O-])=O.[Na+].[Na+].CC(C)=O>C1(C)C=CC=CC=1.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>[F:16]/[C:2](/[C:21]1[CH:22]=[C:23]([O:27][CH3:28])[C:24]([O:25][CH3:26])=[C:19]([O:18][CH3:17])[CH:20]=1)=[C:3](\[F:15])/[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([N+:12]([O-:14])=[O:13])[CH:5]=1
Reactant: COc1ccc(/C(F)=C(/F)Br)cc1[N+](=O)[O-]
Reactant: COc1cc(B(O)O)cc(OC)c1OC
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: Cc1ccccc1
Solvent: CC(C)=O
Product: COc1ccc(/C(F)=C(/F)c2cc(OC)c(OC)c(OC)c2)cc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
A mixture of 90 mg (0.31 mmol; 1 eq.) of (9), 198 mg (0.93 mmol; 3 eq.) of 3,4,5-trimethoxyphenyl-boronic acid, 0.6 mL of Na2CO3 2M aqueous solution and 19 mg (0.0016 mmol; 0.05 eq.) of Pd(Ph3P)4 in 4 mL toluene was refluxed for 2.5 h. The solution was then cooled down to room temperature, dried over anhydrous sodium sulfate and the crude mixture was passed through a short silica gel column to remove catalyst. The crude product was purified by chromatography on silica gel with Hexane/Acetone 8:2 to give 57 mg (0.15 mmol; 48%) of a yellow oil. Rf=0.17 in Hex./Acetone 8:2.
Reaction SMILES: O([BH-](OC(C)=O)OC(C)=O)C(C)=O.[Na+].[Cl:15][C:16]1[N:21]=[C:20]([NH2:22])[CH:19]=[N:18][CH:17]=1.[CH:23]1([O:28][C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[CH:32]=O)[CH2:27][CH2:26][CH2:25][CH2:24]1>ClCCCl.CC(O)=O>[Cl:15][C:16]1[N:21]=[C:20]([NH:22][CH2:32][C:31]2[CH:34]=[CH:35][C:36]([O:37][CH3:38])=[C:29]([O:28][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:30]=2)[CH:19]=[N:18][CH:17]=1
Reactant: COc1ccc(C=O)cc1OC1CCCC1
Reactant: Nc1cncc(Cl)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: COc1ccc(CNc2cncc(Cl)n2)cc1OC1CCCC1
Temperature: 50 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
Sodium triacetoxyl-borohydride (1315 mg, 6.2 mmol) was added to a solution of 6-chloro-pyrazin-2-yl-amine (400 mg, 3.10 mmol) and 3-cyclopentyloxy-4-methoxy-benzaldehyde (818 mg, 3.7 mmol) in 50 ml of DCE, 1 ml of HOAc was added and the mixture was stirred overnight at 50° C., followed by addition of another 50 ml of DCE. The organic phase was washed with water, and the product was purified with column (silica gel, hexane:EtOAc 6:1) to give 50 mg of (6-chloro-pyrazin-2-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine, yield 10%.
Reaction SMILES: [C:1]([OH:4])(=[O:3])[CH3:2].C([N:12]1[CH2:28][C:27]([CH3:30])([CH3:29])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])[CH2:16][CH2:15]2)[CH2:13]1)C1C=CC=CC=1.Cl.[H][H]>[OH-].[OH-].[Pd+2].C(O)C>[C:1]([OH:4])(=[O:3])[CH3:2].[CH3:29][C:27]1([CH3:30])[O:26][C:14]2([CH2:19][CH2:18][N:17]([C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])[CH2:16][CH2:15]2)[CH2:13][NH:12][CH2:28]1
Reactant: [H][H]
Reactant: CC1(C)CN(Cc2ccccc2)CC2(CCN(C(=O)C(F)(F)F)CC2)O1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: CC1(C)CNCC2(CCN(C(=O)C(F)(F)F)CC2)O1

Procedure:
A mixture of acetic acid (100 μL, 1.76 mmol), Pd(OH)2 (11 mg, 0.02 mmol), 1-(8-benzyl-10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone (80 mg, 0.22 mmol), HCl (108 μL of 4 M in dioxane, 0.43 mmol) and ethanol (2 mL) was treated to an atmosphere of hydrogen at 85 psi for 3 days. The reaction mixture was filtered and the catalyst was washed with methanol, then concentrated in vacuo to give 1-(10,10-dimethyl-11-oxa-3,8-diazaspiro[5.5]undecan-3-yl)-2,2,2-trifluoro-ethanone acetic acid salt as a yellow solid. ESI-MS m/z calc. 280.1. found 281.5 (M+1)+; Retention time: 0.91 minutes (3 min run).
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[CH:22]2)=[CH:17][CH:16]=1.CI>O1CCCC1>[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([N:21]2[C:25]([C:26]3[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=3)=[CH:24][N:23]=[C:22]2[CH3:1])=[CH:19][CH:20]=1
Reactant: COc1ccc(-n2cncc2-c2ccncc2)cc1
Reactant: CC(C)NC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CI
Product: COc1ccc(-n2c(-c3ccncc3)cnc2C)cc1
Temperature: -20 °C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
A solution of diisopropyl amine (0.51 mL, 3.6 mmol) in tetrahydrofuran (12 mL) at −20° C., was treated with n-butyl lithium (2.5 M in hexanes, 1.45 mL, 3.6 mmol) and the solution was stirred for 10 minutes. A solution of Preparation 80 (4-(1-(4-methoxyphenyl)-1H-imidazol-5-yl)pyridine, 730 mg, 2.9 mmol) in tetrahydrofuran was added and the solution became dark orange. The solution was stirred for 30 minutes as the temperature was allowed to rise to 0° C. After cooling to −20° C., methyl iodide (0.54 mL, 8.7 mmol) in tetrahydrofuran (12 mL) was added and the solution was stirred for 30 min at −20° C. and for 2 hr at 23° C. The solvent was removed in vacuo, the residue was diluted with brine and was extracted with ethyl acetate. The organic layer was then dried (MgSO4), was filtered, and was concentrated in vacuo. The residue was purified by silica gel chromatography using ethyl acetate-hexanes-methanol (63:32:5 to 72:18:10) to afford 555 mg (72% yield) of the title compound; diagnostic 13C NMR signals (100 MHz, CDCl3) δ 160.144, 150.034, 149.197, 137.749, 131.265, 129.463, 128.985, 128.828, 120.849, 115.233, 55.78, 14.203; MS (AP/CI) 266.4 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[NH:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH2:13][O:14][CH3:15])[C:10]([N:17]1[CH2:20][CH:19]([C:21]#[N:22])[CH2:18]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#CC1CNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.8 %

Procedure:
A 25 mL round-bottomed flask was charged with (R)-2-tert-butoxycarbonylamino-3-methoxy-propionic acid (0.475 g, 2.17 mmol), azetidine-3-carbonitrile hydrochloride (314 mg, 2.65 mmol) and HATU (832 mg, 2.19 mmol). Then added DMF (3.6 mL) followed by N,N-diisopropylethylamine (1.5 mL, 8.67 mmol). The reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers were dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/heptane (gradient: 0-100% EtOAc) to afford 288 mg (47%) of [(R)-2-(3-cyano-azetidin-1-yl)-1-methoxymethyl-2-oxo-ethyl]-carbamic acid tert-butyl ester as a viscous colorless oil.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]2[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=2)[CH:4]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1>>[CH3:22][O:21][C:13]1[CH:12]=[C:11]([C:10]#[C:9][C:5]2[CH:4]=[C:3]([CH2:2][N:23]3[CH2:28][CH2:27][N:26]([CH2:2][C:3]4[CH:8]=[CH:7][N:6]=[C:5]([C:9]#[C:10][C:11]5[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[C:13]([O:21][CH3:22])[CH:12]=5)[CH:4]=4)[CH2:25][CH2:24]3)[CH:8]=[CH:7][N:6]=2)[CH:16]=[C:15]([O:17][CH3:18])[C:14]=1[O:19][CH3:20]
Reactant: C1CNCCN1
Reactant: COc1cc(C#Cc2cc(CCl)ccn2)cc(OC)c1OC
Product: COc1cc(C#Cc2cc(CN3CCN(Cc4ccnc(C#Cc5cc(OC)c(OC)c(OC)c5)c4)CC3)ccn2)cc(OC)c1OC

Procedure:
4-Chloromethyl-2-(3,4,5-Trimethoxyphenylethynyl)-pyridine (254 mg) and piperazine (31 mg) were reacted in the same manner in Example 1 to obtain the title compound as a free base.
Reaction SMILES: CCN(CC)CC.[C:8]([NH:11][CH:12](Br)[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9].[CH3:24][SH:25]>C1COCC1>[C:8]([NH:11][CH:12]([S:25][CH3:24])[C:13]([NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14])(=[O:10])[CH3:9]
Reactant: CC(=O)NC(Br)C(=O)NCc1ccccc1
Reactant: CS
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CSC(NC(C)=O)C(=O)NCc1ccccc1
Reaction time: 0.5 h
Yield: 27 %

Procedure:
A cooled (-78° C.) solution or Et3N (4.85 g, 48.0 mmol) in THF (20 mL) was added to a cooled (-78° C.) solution of 2-acetamido-N-benzyl-2-bromoacetamide (prepared from 2-acetamido-N-benzyl-2-ethoxyacetamide (4.00 g, 16.0 mmol) and BBr3 (1M in CH2Cl2, 20.0 mL, 20.0 mmol)) in THF (275 mL). A cooled (-78° C.) solution of excess MeSH (5-6 equiv) in THF (55 mL) was then added. The reaction mixture was stirred at this temperature (30 min) and then at room temperature (1 h). The insoluble materials were filtered and the filtrate was evaporated to dryness in vacuo. The oily residue obtained was purified by flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 1.10 g (27%) of the desired product as a yellow orange oil. The product was purified by a second flash column chromatography on SiO2 gel (2% MeOH/CHCl3) to give 0.72 g of the pure product as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[C:5]2=[O:19].C(=O)([O-])[O-].[K+].[K+].[CH2:26](Br)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.O>CN(C=O)C>[CH2:26]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:11])[N:6]([C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:5][C:4]3[CH:8]=[CH:9][CH:10]=[CH:2][CH:3]=3)=[CH:14][CH:13]=1)[C:5]2=[O:19])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: BrCc1ccccc1
Reactant: O=C1c2ccc(O)cc2C(=O)N1c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccc(OCc3ccccc3)cc2C(=O)N1c1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 186 %

Procedure:
To 5-hydroxy-2-(4-hydroxyphenyl)isoindoline-1,3-dione (2.08 g) in DMF (20 mL) was added potassium carbonate (4.62 g) and a solution of benzyl bromide (3.07 g) in DMF (3.0 mL) dropwise under nitrogen atmosphere. The reaction was stirred at room temperature for 2 h then heated to 80° C. for 3 h. The mixture was cooled to room temperature, poured into water (250 mL) and let sit undisturbed for 2.0 h. The white solid was collected by filtration and washed with water. The solid was dried under high vacuum at 50° C. for 18 h yielding the title compound (3.30 g) as a white solid. 1H NMR (DMSO-d6): 7.87 (d, 1H, J=8.4 Hz), 7.48-7.35 (m, 12H), 7.32 (d, 2H, J=8.7 Hz), 7.13 (d, 2H, J=8.7 Hz), 5.35 (s, 2H), 5.17 (s, 2H); MS: 436 (MH+).
Reaction SMILES: CN(C=O)C.[C:6]([O:10][C:11]([N:13]1[CH2:16][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[OH:25])[CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:32](Br)[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1>O>[C:6]([O:10][C:11]([N:13]1[CH2:14][CH:15]([O:17][C:18]2[CH:23]=[C:22]([Br:24])[CH:21]=[CH:20][C:19]=2[O:25][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:16]1)=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2O)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CC(Oc2cc(Br)ccc2OCc2ccccc2)C1
Reaction time: 48 h
Yield: 99.8 %

Procedure:
To a DMF (10 mL) solution of the title compound of Step C (0.52 g, 1.5 mmol), Cs2CO3 (0.54 g, 1.7 mmol) and KI (0.20 g, 1.20 mmol) was added benzyl bromide (0.20 mL, 0.29 g, 1.7 mmol). After 48 h, H2O was added and the mixture extracted with EtOAc (2×). The combined organics were washed with brine (2×) and dried. Silica gel chromatography (5-20% EtOAc in hexanes) gave 0.65 g (99%) of the title compound as a clear oil. 1H NMR (CDCl3): 7.42-7.36 (m, 3H), 7.34-7.31 (m, 2H), 7.03 (dd, J=8.6, 2.3 Hz, 1H), 6.81 (d, J=8.6 Hz, 1H), 6.70 (d, J=2.3 Hz, 1H), 5.09 (s, 2H), 4.88-4.83 (m, 1H), 4.26 (ddd, J=9.7, 6.5, 0.9 Hz, 2H), 4.05 (dd, J=9.8, 4.0 Hz, 2H), 1.45 (s, 9H).
Reaction SMILES: N#N.[NH2:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:10][CH3:11])[O:8][CH3:9].C[O-].[Na+].[C:17](Cl)(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1.CO>[C:17]([NH:3][CH2:4][CH2:5][CH2:6][Si:7]([O:12][CH3:13])([O:8][CH3:9])[O:10][CH3:11])(=[O:20])[CH:18]=[CH2:19]
Reactant: C=CC(=O)Cl
Reactant: CO[Si](CCCN)(OC)OC
Agent: C[O-]
Agent: N#N
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CO
Product: C=CC(=O)NCCC[Si](OC)(OC)OC
Temperature: 0 °C

Procedure:
A one liter, three-necked flask equipped with a thermometer, stirring paddle, air tight stirring sleeve, N2 inlet and dropping funnel was charged with aminopropyltrimethoxysilane (100.0 g, 0.558 moles), toluene (160.1 g), sodium methoxide (33.16 g, 0.614 moles) and methanol (10.11 g). The mixture was stirred under N , atmosphere and cooled to 0° C using a dry ice/isopropanol bath. To this, 55.37 g (0.614 moles) of acrylyl chloride dissolved in 100 g of toluene was added gradually over a period of 30 minutes. The mixture was agitated for another 30 minutes. By-product sodium chloride was removed by filtration and the solvent was removed under reduced pressure to obtain acrylamidopropyltrimethoxysilane in essentially quantitative yield. Sodium nitrite (0.001 g) was added as an inhibitor.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17]Br)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:19]1([NH2:22])[CH2:21][CH2:20]1>C(#N)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][C@@H:14]([F:16])[C@@H:13]([CH2:17][NH:22][CH:19]2[CH2:21][CH2:20]2)[CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: O=C(OCc1ccccc1)N1C[C@H](CBr)[C@H](F)C1
Solvent: CC#N
Product: O=C(OCc1ccccc1)N1C[C@H](CNC2CC2)[C@H](F)C1
Temperature: 80 °C
Reaction time: 6 h

Procedure:
(3S,4S)-1-Benzyloxycarbonyl-3-bromomethyl-4-fluoropyrrolidine (415 mg), cyclopropylamine (0.91 mL) and acetonitrile (3 mL) were mixed together. The mixture was stirred at 80° C. for 6 hours and was subsequently concentrated under reduced pressure. To the resulting residue, cyclopropylamine (4.55 mL) was added and the mixture was again stirred at 80° C. for 6 hours and was concentrated under reduced pressure. The residue was dissolved in ethyl acetate (15 mL), washed with saturated brine (2×5 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluant: hexane:ethyl acetate=2:1) to give (3S,4S)-1-benzyloxycarbonyl-3-cyclopropylaminomethyl-4-fluoropyrrolidine as a pale brown oil (239 mg).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([OH:19])=O)[N:8]=2)[CH:2]=1.CC1C=CC(C(O)=O)=CC=1NC1N=C(C2C=NC=CC=2)C=CN=1.[CH3:46][C:47]1[N:48]=[CH:49][N:50]([C:52]2[CH:53]=[C:54]([C:59]([F:62])([F:61])[F:60])[CH:55]=[C:56]([NH2:58])[CH:57]=2)[CH:51]=1.C(N)C1OC=CC=1>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=3)[C:17]([NH:58][C:56]3[CH:57]=[C:52]([N:50]4[CH:51]=[C:47]([CH3:46])[N:48]=[CH:49]4)[CH:53]=[C:54]([C:59]([F:62])([F:61])[F:60])[CH:55]=3)=[O:19])[N:8]=2)[CH:2]=1
Reactant: Cc1cn(-c2cc(N)cc(C(F)(F)F)c2)cn1
Reactant: O=C(O)c1cccc(Nc2nccc(-c3cccnc3)n2)c1
Agent: Cc1ccc(C(=O)O)cc1Nc1nccc(-c2cccnc2)n1
Agent: NCc1ccco1
Product: Cc1cn(-c2cc(NC(=O)c3cccc(Nc4nccc(-c5cccnc5)n4)c3)cc(C(F)(F)F)c2)cn1

Procedure:
Utilising the procedure described in example 1, but employing 3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid in lieu of 4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]-benzoic acid and 5-(4-methyl-1H-imidazol-1-yl)-3-(trifluoromethyl)-benzenamine in lieu of furfurylamine, afforded the title compound as as pale-yellow crystalline solid, m.p. 264–266° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:8]=[CH:9][C:10]2[C:14]([C:15]3[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=3)=[C:13]([CH3:22])[S:12][C:11]=2[CH:23]=1.[CH3:24][NH:25][CH3:26]>>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]3[CH:9]=[CH:8][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:25]([CH3:26])[CH3:24])=[CH:23][C:11]=3[S:12][C:13]=2[CH3:22])=[CH:16][CH:17]=1
Reactant: Cc1sc2cc(OCCCCBr)ccc2c1-c1ccc(Br)cc1
Reactant: CNC
Product: Cc1sc2cc(OCCCCN(C)C)ccc2c1-c1ccc(Br)cc1

Procedure:
According to the method in example 31, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-2-methyl-benzo[b]thiophene and dimethylamine were converted to yield {4-[3-(4-Bromo-phenyl)-2-methyl-benzo[b]thiophen-6-yloxy]-butyl}-dimethyl-amine as yellowish oil, MS: 418 (MH+,1Br).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.Br.Br[CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16].C(N(CC)CC)C>ClCCl>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][CH2:12][CH2:13][N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][CH:3]=1
Reactant: CCN(CC)CCBr
Reactant: NCc1ccc(Cl)cc1
Agent: Br
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCN(CC)CCNCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
4-Chlorobenzylamine (1.0 mL, 8.2 mmol) was added to a solution of 2-bromo-N,N-diethylethylamine hydrobromide (2.4 g, 9.0 mmol) and triethylamine (3.4 mL, 25 mmol) in dichloromethane (16 mL). The mixture was stirred at room temperature for 5 hours. The mixture was then concentrated to give N1-(4-chlorobenzyl)-N2,N2-diethylethane-1,2-diamine as an oil which was used immediately without purification.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][C:26]=2[C:28](O)=[O:29])[CH:21]=[CH:20][CH:19]=1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(N(CC)CC)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:28]([C:26]2[CH:25]=[CH:24][CH:23]=[C:22]3[C:27]=2[N:18]=[CH:19][CH:20]=[CH:21]3)=[O:29])[CH2:10][C@@H:9]1[CH2:14][CH2:15][CH2:16][CH3:17])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCCC[C@H]1CNCCN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1cccc2cccnc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCCC[C@H]1CN(C(=O)c2cccc3cccnc23)CCN1C(=O)OC(C)(C)C

Procedure:
The title compound was prepared according to the procedure described in Example 1, Step A, except using 1-tert-butoxycarbonyl-2(S)-n-butyl-piperazine (0.261 g, 1.078 mmol), 8-quinoline carboxylic acid (0.187 g, 1.078 mmol), EDC.HCl (0.217 g, 1.13 mmol), HOBT (0.157g, 1.02 mmol) in DMF at pH 7 (adjusted with triethylamine). The crude product was chromatographed on silica gel with 5% methanol in chloroform. The title compound was obtained as an oil (0.253 g).
Reaction SMILES: [Mg].[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][CH:11]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.CN([CH:20]=[O:21])C>C1COCC1.C(OC1C=C(F)C=CC=1)C1C=CC=CC=1>[CH2:2]([O:9][C:10]1[CH:15]=[C:14]([F:16])[CH:13]=[CH:12][C:11]=1[CH:20]=[O:21])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Fc1cccc(OCc2ccccc2)c1
Reactant: CN(C)C=O
Agent: [Mg]
Solvent: C1CCOC1
Product: O=Cc1ccc(F)cc1OCc1ccccc1
Temperature: 25 °C

Procedure:
To a slurry of magnesium (9.52 g, 0.39 mol) in THF (25 mL) in a 1 L round bottom flask fitted with a condenser was added the intermediate obtained in Step A (1 g). A vigorous reflux commenced at once. To this refluxing mixture was added a solution of the intermediate from Step A (109 g) at a rate which maintained reflux. After completion of addition the reaction was allowed to proceed until it cooled to 25° C. and was then heated at reflux for 1 h. The reaction was allowed to cool to 25° C. and DMF (48 mL) was then added portionwise. The reaction was allowed to cool to 25° C. and was then filtered through a plug of Celite. The THF was removed under reduced pressure and the residue was dissolved in ethyl acetate (500 mL) and washed sequentially with water (100 mL), 10% HCl (100 mL), saturated sodium bicarbonate solution (100 mL), and brine (100 mL). The organic layer was dried (Na2SO4) and concentrated under reduced pressure. The resultant residue was purified by flash chromatography (10% ethyl acetate-hexane) to provide 77.3 g of 2-benzyloxy-4-fluorobenzaldehyde. 1H NMR (300 MHz, CDCl3): δ 5.16 (s, 2 H), 6.70-6.76 (m, 2 H), 7.34-7.44 (m, 5 H), 7.87-7.92 (m, 1 H), 10.43 (s, 1 H). FAB-MS: calcd for (C14H11O2F) 230; found 231 (M+1).