Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.[CH3:11][NH2:12]>O1CCCC1.O>[Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:12][CH3:11])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 4-bromobenzoyl chloride (5.6 g) in 50 mL of tetrahydrofuran was cooled to 0° C. and treated with aqueous methylamine (5 mL of 40%). After the addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 16 hours. At the end of this period, the reaction mixture was diluted with water, extracted with ethyl acetate and the organic layer was washed with 10% HCl followed by sodium carbonate. Upon drying over magnesium sulfate and evaporation, a white solid was obtained (4.64 g); MS: 214; NMR: 3.0 (d, J=5, 3), 6.2 (br, 1), 7.5-7.6 (m, 2), 7.6-7.7 (m, 2).
Reaction SMILES: C([O:8][C:9]1[C:21](=[O:22])[N:13]2[CH2:14][CH:15]3[CH2:20][CH2:19][N:18]([C:12]2=[N:11][C:10]=1[C:23]([NH:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[N:34]1[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([CH3:41])[S:35]1(=[O:43])=[O:42])=[O:24])[CH2:17][CH2:16]3)C1C=CC=CC=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]>C(Cl)Cl>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][NH:25][C:23]([C:10]2[N:11]=[C:12]3[N:18]4[CH2:17][CH2:16][CH:15]([CH2:20][CH2:19]4)[CH2:14][N:13]3[C:21](=[O:22])[C:9]=2[OH:8])=[O:24])=[C:28]([N:34]2[CH2:38][C:37]([CH3:40])([CH3:39])[N:36]([CH3:41])[S:35]2(=[O:43])=[O:42])[CH:29]=1.[F:44][C:45]([F:50])([F:49])[C:46]([OH:48])=[O:47]
Reactant: CN1C(C)(C)CN(c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2OCc2ccccc2)CC2CCN3CC2)S1(=O)=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN1C(C)(C)CN(c2cc(F)ccc2CNC(=O)c2nc3n(c(=O)c2O)CC2CCN3CC2)S1(=O)=O

Procedure:
A solution of 3-(benzyloxy)-N-(4-fluoro-2-(4,4,5-trimethyl-1,1-dioxido-1,2,5-thiadiazolidin-2-yl)benzyl)-4-oxo-6,7,8,9-tetrahydro-4H-7,10-ethanopyrimido[1,2-a][1,3]diazepine-2-carboxamide (0.054 g, 0.088 mmol) in CH2Cl2 (5 mL) and trifluoroacetic acid (0.7 mL, 9.09 mmol) was stirred at room temperature for 18 h. The solution was concentrated to give a yellow oil that was purified by preparative HPLC (Solvent A=10% methanol/90% H2O/0.1% trifluoroacetic acid; Solvent B=90% methanol/10% H2O/0-1% trifluoroacetic acid; Start % B=20; Final % B=100; Gradient time=20 min; Stop time=25 min; Column=Sunfire 19×100 mm, C18, 5 μm) to give the title compound (as a trifluoroacetic acid salt) as a pale yellow solid (0.0075 g, 13% yield). LCMS (M+H) calcd for C23H30FN6O5S: 521.19; found: 521.25. 1H NMR (500 MHz, CDCl3) δ: 8.64 (1H, t, J=5.6 Hz), 7.60 (1H, dd, J=8.2, 6.4 Hz), 7.22 (1H, dd, J=9.2, 2.4 Hz), 7.11 (1H, td, J=8.1, 2.2 Hz), 4.64 (2H, d, J=5.8 Hz), 4.00-3.94 (2H, m), 3.79-3.76 (2H, m), 3.72 (2H, s), 3.58 (2H, s), 3.03 (1H, brs), 2.73 (3H, s), 2.32-2.28 (2H, m), 1.91-1.87 (2H, m), 1.46 (6H, s).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:8](=[C:9]([F:14])[CH:10]=[CH:11][CH:12]=2)[CH:7]=[CH:6]1)[CH:2]1[O:4][CH2:3]1.[NH:15]1[CH:20]=[CH:19][CH:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:17][CH2:16]1>>[F:14][C:9]1[CH:10]=[CH:11][CH:12]=[C:13]2[C:8]=1[CH:7]=[CH:6][N:5]2[CH2:1][CH:2]([OH:4])[CH2:3][N:15]1[CH2:16][CH:17]=[C:18]([C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)[CH2:19][CH2:20]1
Reactant: C1=CC(c2c[nH]c3ccccc23)CCN1
Reactant: Fc1cccc2c1ccn2CC1CO1
Product: OC(CN1CC=C(c2c[nH]c3ccccc23)CC1)Cn1ccc2c(F)cccc21
Yield: 52.2 %

Procedure:
A methanolic solution of 1-N-glycidyl-4-fluoroindole (0.52 g, 3.0 mmole) from example 3 and 3-(4-tetrahydropyridinyl)indole (0.59 g, 3.0 mmole) was refluxed under nitrogen for 15 hours. The reaction mixture was concentrated in vacuo and the product purified by flash silica gel chromatography (ethyl acetate) to afford the titled compound as a pale yellow colored solid (0.61 g, 53% yield). Treatment with a 0.25M ethanolic solution of fumaric acid (0.5 equivalents) gave the required product as a yellow colored solid. The product was recrystallized from ethanol.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20]([NH2:22])=[S:21])[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:24]I>>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[NH:22])[S:21][CH3:24])[CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CC(C)(C)OC(=O)NC1(c2cccc(NC(N)=S)c2)CCCC1
Product: CSC(=N)Nc1cccc(C2(NC(=O)OC(C)(C)C)CCCC2)c1
Yield: 94 %

Procedure:
Using the compound obtained in Example 149 as a starting material and also using methyl iodide as a reagent, reaction was performed as in Example 29 to give 82 mg of the titled compound (yield, 94%).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=2)=[N:2]1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(O)C>[CH2:12]([N:9]1[CH2:10][CH:11]=[C:6]([C:3]2[CH:4]=[CH:5][NH:1][N:2]=2)[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1cc(-c2cc[nH]n2)ccn1
Reactant: BrCc1ccccc1
Solvent: CC(C)O
Product: C1=C(c2cc[nH]n2)CCN(Cc2ccccc2)C1
Reaction time: 0.5 h

Procedure:
To a hot (80° C.) solution of 4-(1H-pyrazol-3-yl)pyridine (9.6 g) in 2-propanol (60 mL) was added benzyl bromide (20 mL, 2.5 equiv.) and the resulting mixture heated at reflux for 10 minutes. After cooling in an ice bath, the precipitate was filtered and washed with more 2-propanol and air dried. The solid was suspended in ethanol at 0° C. and sodium borohydride (13 g) was added in several portions over 30 minutes, and the mixture was stirred for an additional 30 minutes. The reaction was quenched by carefully addition of water, and the ethanol was removed by evaporation, and the residue was partitioned between dichloromethane and water. The organic layer was dried over MgSO4, and filtrated and evaporation gives 1-benzyl-4-(1H-pyrazol-3-yl)-1,2,3,6-tetrahydropyridine (16 g)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[CH:8]=[N:9][CH:10]=[CH:11][C:5]2=[N:4][C:3]=1[N:12]1[CH2:17][CH2:16][N:15]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[CH2:14][CH2:13]1.[F-].[K+].CC[N:31](C(C)C)[CH:32]([CH3:34])[CH3:33].CC(N)C>CS(C)=O.O>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][N:15]1[CH2:16][CH2:17][N:12]([C:3]2[N:4]=[C:5]3[CH:11]=[CH:10][N:9]=[CH:8][C:6]3=[N:7][C:2]=2[NH:31][CH:32]([CH3:34])[CH3:33])[CH2:13][CH2:14]1
Reactant: Fc1ccc(CN2CCN(c3nc4ccncc4nc3Cl)CC2)c(F)c1
Reactant: CCN(C(C)C)C(C)C
Agent: [F-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Solvent: CC(C)N
Product: CC(C)Nc1nc2cnccc2nc1N1CCN(Cc2ccc(F)cc2F)CC1
Temperature: 23 °C
Reaction time: 22 h
Yield: 60 %

Procedure:
To a flask charged with 3-chloro-2-(4-(2,4-difluorobenzyl)piperazin-1-yl)pyrido[3,4-b]pyrazine (2.34 g, 6.23 mmol) and potassium fluoride (0.470 g, 8.09 mmol) in DMSO (12 mL) was added DIPEA (2.169 mL, 12.45 mmol) and propan-2-amine (1.605 mL, 18.68 mmol) at 23° C. The reaction was stirred at 23° C. for 22 hr and diluted with water (48 mL) to furnish an orange, oily sludge. The crude product was extracted with EtOAc (25 mL) to furnish a suspension. The resulting solid was filtered, rinsed with EtOAc, and the filtrate was allowed to separate into two layers. The organic phase was washed with brine, dried over Na2SO4, filtered, rinsed with EtOAc, and dried in vacuo. The crude material was dissolved in toluene (5 mL) and purified via medium pressure chromatography using a 20% to 100% gradient eluant of EtOAc in heptane on an NH 60 μM, size 400 column (Shoko Scientific Purif-Pack™) to give the title compound (1.489 g, 60.0%) as a yellow solid. 1H NMR (500 MHz, DMSO-d6) δ ppm 1.24 (d, J=6.4 Hz, 6H), 2.62 (t, J=4.9 Hz, 4H), 3.34-3.41 (m, 4H), 3.59 (s, 2H), 4.22-4.42 (m, 1H), 6.46 (d, J=7.8 Hz, 1H), 7.04-7.17 (m, 1H), 7.22 (td, J=10.0, 2.4 Hz, 1H), 7.40-7.44 (m, 1H), 7.49 (td, J=8.5, 6.8 Hz, 1H), 8.27 (d, J=5.9 Hz, 1H), 8.76 (s, 1H); ESI-MS m/z [M+H]+ 399.0.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([OH:12])=O.Cl.[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH2:23])[CH2:19][CH2:18]1)([CH3:16])[CH3:15].C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.C([O-])(O)=O.[Na+]>CN(C=O)C.CCN(CC)CC>[CH:14]([N:17]1[CH2:22][CH2:21][CH:20]([NH:23][C:10]([C:2]2[NH:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[O:12])[CH2:19][CH2:18]1)([CH3:16])[CH3:15]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1nc2ccccc2[nH]1
Agent: Cl
Agent: O=C([O-])O
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N1CCC(NC(=O)c2nc3ccccc3[nH]2)CC1
Reaction time: 3 h

Procedure:
To a solution of 300 mg 1H-Benzoimidazole-2-carboxylic acid in 3 mL DMF and 1 mL NEt3, 398 mg 1-Isopropyl-piperidin-4-ylamine hydrochloride and 470 mg BOP-Cl were added and the mixture was stirred for 3 h. Finally, 3 mL saturated NaHCO3 solution were added and the mixture was filtered through a chem elut® cartridge by elution with ethyl acetate. After removal of the solvent under reduced pressure the crude product was subjected to the next reaction step without further purification.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH2:17][C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16].[H-].[Na+].[C:22](OCC)(=[O:24])[CH3:23]>O1CCCC1>[CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([CH:17]([C:22](=[O:24])[CH3:23])[C:18]#[N:19])[CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][O:15][CH3:16]
Reactant: CCOC(C)=O
Reactant: COCCOc1ccc(CC#N)cc1OCCOC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCOc1ccc(C(C#N)C(C)=O)cc1OCCOC
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 86.4 %

Procedure:
To a suspension of (3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)acetonitrile (0.59 g, 2.2 mmol), and sodium hydride (40% oil dispersion, 270 mg, 6.7 mmol) in tetrahydrofuran (10 mL), was added ethyl acetate (1.1 mL, 11.1 mmol), and the resulting mixture was stirred at 60° C. for 1.5 hours. Then it was cooled to room temperature, and poured into a mixture of ice-water (50 mL). This aqueous mixture was washed with dichloromethane (3×20 mL) then acidified to pH of 2. The acidified mixture was extracted with ethyl acetate (3×30 mL). The combined extract was washed with saturated sodium bicarbonate solution, brine, dried over sodium sulfate, filtered and concentrated to give 2-(3,4-bis{[2-(methyloxy)ethyl]oxy}phenyl)-3-oxobutanenitrile (0.57 g, 1.9 mmol, 86% yield), MS (EI) for C16H21NO5: 308 (MH+).
Reaction SMILES: [N:1]([CH2:4][C@@H:5]([NH2:15])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3].[OH:16][C@H:17]1[C:21]2[N:22]=[CH:23][N:24]=[C:25]([C:26]3[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=3)[C:20]=2[C@H:19]([CH3:34])[CH2:18]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl.CN(C=O)C>[N:1]([CH2:4][C@@H:5]([NH:15][C:31]([C:29]1[S:30][C:26]([C:25]2[C:20]3[C@H:19]([CH3:34])[CH2:18][C@@H:17]([OH:16])[C:21]=3[N:22]=[CH:23][N:24]=2)=[CH:27][CH:28]=1)=[O:32])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Cl:13])=[CH:9][C:8]=1[Cl:14])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NC[C@@H](N)Cc1ccc(Cl)cc1Cl
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)O)s3)c21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: C[C@@H]1C[C@@H](O)c2ncnc(-c3ccc(C(=O)N[C@H](CN=[N+]=[N-])Cc4ccc(Cl)cc4Cl)s3)c21
Temperature: 25 °C
Reaction time: 1 h
Yield: 11 %

Procedure:
(S)-1-Azido-3-(2,4-dichlorophenyl)propan-2-amine (20 mg, 0.0724 mmol) was added to a solution of 5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxylic acid (35 mg, 0.145 mmol) in DCM (0.5 mL). DMF (125 μL) was added to solubilize the starting material completely. DIPEA (126 μL, 0.724 mmol) was added, followed by the addition of HBTU (30 mg, 0.079 mmol). The reaction mixture was stirred at room temperature for 1 hour. LC-MS of the reaction mixture showed no more starting material. The solvent was removed, and the resulting residue was purified by reversed phase HPLC to yield N-((S)-1-azido-3-(2,4-dichlorophenyl)propan-2-yl)-5-((5R,7R)-7-hydroxy-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)thiophene-2-carboxamide product as a solid (4 mg, 10%). m/z 504 (MH+).
Reaction SMILES: [C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:35])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][C@@H:31]([OH:34])[CH:32]=[CH2:33])/[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([C:5]1[N:9]([CH3:10])[N:8]([CH2:11][C@H:12]2[CH2:16][CH2:15][CH2:14][O:13]2)/[C:7](=[N:17]/[C:18](=[O:35])[C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:20]=2[O:29][CH2:30][C@@H:31]([OH:34])[CH2:32][CH3:33])/[CH:6]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: C=C[C@H](O)COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Agent: [Pd]
Product: CC[C@H](O)COc1ccc(C(F)(F)F)cc1C(=O)/N=c1\cc(C(C)(C)C)n(C)n1C[C@H]1CCCO1
Yield: 67 %

Procedure:
A suspension of Example 107 (40 mg, 0.081 mmol) and 10% Pd/C (20 mg) was stirred under an atmosphere of hydrogen (balloon) at room temperature for 2 hours. The mixture was filtered through Celite, and the filtrate was concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 50% hexanes/EtOAc to 100% EtOAc to 9:1:0.1 EtOAc:MeOH:Et3N) to afford 27 mg (67%) of the title compound. 1H NMR (500 MHz, chloroform-d) δ ppm 1.00 (t, J=7.32 Hz, 3H) 1.42 (s, 9H) 1.60 (s, 3H) 1.65-1.80 (m, 2H) 1.81-1.91 (m, 1H) 1.97-2.08 (m, 1H) 3.66-3.81 (m, 2H) 3.85-3.92 (m, 3H) 3.87-3.97 (m, 1H) 4.17 (s, 1H) 4.31 (d, J=5.49 Hz, 1H) 4.39 (d, J=7.93 Hz, 1H) 4.55 (d, J=14.34 Hz, 1H) 6.62 (s, 1H) 6.95-7.16 (m, 2H) 7.51 (s, 1H) 8.09 (s, 1H); MS (DCI/NH3) m/z 498 (M+H)+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][CH:13]=2)=[CH:10][CH:11]=1)[CH3:2].[CH:30]([NH:32][NH:33][CH:34]=O)=O.Cl[Si](C)(C)C.C(N(CC)CC)C>N1C=CC=CC=1.O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][C:7]1[N:8]([C:19]2[CH:24]=[CH:23][C:22]([C:25](=[O:27])[NH2:26])=[CH:21][C:20]=2[CH3:28])[C:9]([C:12]2[CH:13]=[CH:14][C:15]([N:18]3[CH:34]=[N:33][N:32]=[CH:30]3)=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=CNNC=O
Reactant: CCOC(=O)CCc1ccc(-c2ccc(N)cc2)n1-c1ccc(C(N)=O)cc1C
Agent: C[Si](C)(C)Cl
Solvent: O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCOC(=O)CCc1ccc(-c2ccc(-n3cnnc3)cc2)n1-c1ccc(C(N)=O)cc1C
Temperature: 100 °C
Yield: 82 %

Procedure:
Under a nitrogen atmosphere, 3-[5-(4-aminophenyl)-1-(4-carbamoyl-2-methylphenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11A, synthesis described in Scheme 4 where R1=4-carbamoyl-2-methylphenyl) (102 mg, 0.26 mmol) was dissolved in 4 mL pyridine. 1,2-diformylhydrazine (69 mg, 0.78 mmol) was added. Chlorotrimethylsilane (0.5 mL, 3.9 mmol) was added dropwise. Triethylamine (0.25 mL, 1.82 mmol) was added dropwise. The reaction was heated to 100° C. for 24 hrs. After cooling, the reaction was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by preparative tlc plate (1500 microns, 10% IPA/CH2Cl2). The desired band (rf=0.3) was isolated and dried under high vacuum to yield 3-[1-(4-carbamoyl-2-methylphenyl)-5-(4-[1,2,4]triazol-4-yl-phenyl)-1H-pyrrol-2-yl]-propionic acid ethyl ester (11B) (95 mg, 82%, light tan powder).
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.[CH2:15]([Sn](CCCC)(CCCC)C#CC)[CH2:16][CH2:17]C>C1(C)C=CC=CC=1.CCOC(C)=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>[Cl:8][C:5]1[N:4]=[C:3]([NH:9][CH:10]([CH2:13][CH3:14])[CH2:11][CH3:12])[C:2]([C:15]#[C:16][CH3:17])=[CH:7][N:6]=1
Reactant: CCC(CC)Nc1nc(Cl)ncc1Br
Reactant: CC#C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC#Cc1cnc(Cl)nc1NC(CC)CC
Temperature: 120 °C
Yield: 74.8 %

Procedure:
To a microwave vial is added a solution of (5-Bromo-2-chloro-pyrimidin-4-yl)-(1-ethyl-propyl)-amine (0.5 g, 1.80 mmol) in anhydrous toluene (10 ml), tributyl(1-propynyl)-tin (1.1 ml, 3.6 mmol) and 2 mol % of Pd(PPh3)4 (41.5 mg, 0.036 mmol). The reaction is heated at 120° C. for 1 hr by employing microwave. The reaction mixture is diluted with EtOAc, washed with sat. NaHCO3 aqueous solution and water, dried over Na2SO4, and concentrated in vacuo. Purification with column chromatography (SiO2, 1:5 EtOAC/Hexane) gives 0.32 g of the desired product.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8](OC)=[O:9])[CH2:4][O:3]1.[BH4-].[Na+].O>CO>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][CH2:8][OH:9])[CH2:4][O:3]1
Reactant: COC(=O)C[C@H]1COC(C)(C)O1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CC1(C)OC[C@H](CCO)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 96.4 %

Procedure:
To an ice cooled solution of methyl (4S)-2,2-dimethyl-1,3-dioxolane-4-acetate (1.0 g, 5.74 mmol) in methanol (10 ml) was added portionwise NaBH4 (1.3 g, 34.4 mmol). After the addition was completed, the reaction mixture was stirred at room temperature for 3 hours. Water (40 ml) was added, and the resulting mixture was stirred for several minutes and concentrated in vacuo. The residue was extracted with ethyl acetate. The organic layer was washed with brine, dried (magnesium sulfate), and concentrated in vacuo to give 2-[(4S)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (808.9 mg, 96.4%) as a colorless oil.
Reaction SMILES: [NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][CH:16]=4)[NH:7][C:8]=3[C:9]([Cl:14])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1.S(=O)(=O)(O)[OH:24].[OH-].[Na+]>C(O)(=O)C>[NH2:1][CH:2]1[C:12]2[C:13]3[C:5](=[C:6]([C:15]4[CH:20]=[CH:19][C:18]([C:21](=[O:24])[NH2:22])=[CH:17][CH:16]=4)[NH:7][C:8]=3[C:9]([Cl:14])=[CH:10][CH:11]=2)[CH2:4][CH2:3]1
Reactant: N#Cc1ccc(-c2[nH]c3c(Cl)ccc4c3c2CCC4N)cc1
Reactant: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: NC(=O)c1ccc(-c2[nH]c3c(Cl)ccc4c3c2CCC4N)cc1
Temperature: 120 °C
Reaction time: 2 h
Yield: 17 %

Procedure:
A portion (1.0 g) of the compound obtained in Example 168 was dissolved in acetic acid (30 ml) and to the solution was added 50% sulfuric acid (60 ml). The mixture was stirred for 2 hours at 120° C. and allowed to cool. The reaction mixture was neutralized with 6N aqueous solution of sodium hydroxide and the insoluble matter was filtered off. The filtrate was extracted three times with ethyl acetate, washed with saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the residue was crystallized from ether to yield 170 mg (17%) of the titled compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[C:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:23]1[CH:28]=[CH:27][C:26]([O:29][CH:30]2[CH2:35][CH2:34][CH2:33][CH2:32][O:31]2)=[CH:25][CH:24]=1.CC(C)([O-])C.[Na+].F[B-](F)(F)F.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:21]=[CH:20][C:12]([CH:13]=[C:14]2[CH2:19][CH2:18][N:17]([C:23]3[CH:28]=[CH:27][C:26]([O:29][CH:30]4[CH2:35][CH2:34][CH2:33][CH2:32][O:31]4)=[CH:25][CH:24]=3)[CH2:16][CH2:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Brc1ccc(OC2CCCCO2)cc1
Reactant: C(=C1CCNCC1)c1ccc(OCc2ccccc2)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Solvent: O
Solvent: Cc1ccccc1
Product: C(=C1CCN(c2ccc(OC3CCCCO3)cc2)CC1)c1ccc(OCc2ccccc2)cc1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
4-[4-(Benzyloxy)benzylidene]piperidine (2.32 g, 8.3 mmol), 1-bromo-4-(tetrahydro-2H-pyran-2-yloxy)benzene (2.35 g, 9.1 mmol), toluene (20 ml), sodium tert-butoxide (1.12 g, 11.6 mmol), palladium acetate (0.075 g, 0.3 mmol) and tri-tert-butylphosphine tetrafluoroborate (0.19 g, 0.7 mmol) were mixed and stirred at 100° C. overnight. Water was poured into the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with water, dried over sodium sulfate, and concentrated. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=80:20→50:50) to afford the title compound as a colorless powder.
Reaction SMILES: S(Cl)([Cl:3])=O.O[CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1>C(Cl)(Cl)Cl>[Cl:3][CH2:6][CH2:7][CH2:8][NH:9][C:10]1[N:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:13]2[CH:21]=[CH:22][CH:23]=[CH:24][C:12]=2[N:11]=1
Reactant: OCCCNc1nc2ccccc2n1-c1ccccc1
Reactant: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: ClCCCNc1nc2ccccc2n1-c1ccccc1

Procedure:
Thionyl chloride (10 ml.) was added dropwise to a stirred solution of 2-(3-hydroxypropylamino)-1-phenylbenzimidazole (11.0 g.) in dry chloroform (100 ml.) and the solution heated under reflux for 2 hours. On dilution with ether the title compound crystallised as its hydrochloride (13.06 g., m.p. 176° to 179° C). Found: C, 59.65, H, 5.3, N, 12.95%. C16H16ClN3.HCl requires: C, 59.65, H, 5.3, N, 13.05%.
Reaction SMILES: Br[C:2]1[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9][C:8]([CH3:13])([CH3:12])[CH2:7][C:6]=12.C([Sn](CCCC)(CCCC)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)CCC>O1CCOCC1>[CH3:12][C:8]1([CH3:13])[CH2:7][C:6]2=[C:2]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:3][C:4]([S:14][CH3:15])=[C:5]2[C:10](=[O:11])[CH2:9]1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccccn1
Reactant: CSc1sc(Br)c2c1C(=O)CC(C)(C)C2
Solvent: C1COCCO1
Product: CSc1sc(-c2ccccn2)c2c1C(=O)CC(C)(C)C2
Yield: 56 %

Procedure:
1-Bromo-6,6-dimethyl-3-methylthio-4,5,6,7-tetrahydrobenzo[c]thiophen-4-one (300 mg, 1 mmol) was dissolved in dioxane (25 mL), and 2-(tri-n-butylstannyl)pyridine (550 mg, 1.35 mmol) was added. The solution was de gassed with nitrogen then tetrakis (tri-phenylphosphine)palladium (30 mg, 0.025 mmol) was added and the solution refluxed for 16 h. The solvent was then removed in vacuo and the residue triturated with a mixture of ethyl acetate and hexane (1:3). After filtration the solid product was washed with a little diethyl ether to give the title compound as a white solid (170 mg, 57%). mp 217-220° C. Found: C, 63.02; H, 5.64; , 4.47%. C16H17NOS2 requires: C, 63.36; H, 5.61; N, 4.62%. 1H NMR (250 MHz, CDCl3)δ1.08 (6H, s), 2.44 (2H, s), 2.65 (3H, s), 2.93 (2H, s), 7.18 (1H, m), 7.47 (1H, d, J=8Hz), 7.71-7.77 (1H, m), 8.61-8.63 (1H, m). MS (ES+) 304 (M+1).