Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH2:9])=[N:7][CH:8]=1)[CH3:2].[Li][CH2:11]CCC.CI.O>C1COCC1>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([NH:9][CH3:11])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(N)nc1
Reactant: [Li]CCCC
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCc1ccc(NC)nc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 9.5 %

Procedure:
A solution of 5-ethylpyridin-2-amine (330 mg, 2.70 mmol) in THF (10 mL) was cooled to −78° C. and n-BuLi (1.2 mL, 3.0 mmol) was added. The reaction stirred at −78° C. for 30 min, and then MeI (423 mg, 2.97 mmol) was added. The reaction was stirred for 2 h while warming to r.t. Water (10 mL) was added, and the solution was extracted with EtOAc (20 mL). The organic layer was dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (PE:EtOAc=5:1) to give 35 mg (9%) of the title compound as a yellow oil. [M+H] Calc'd for C8H12N2, 137. Found, 137.
Reaction SMILES: [C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([O:33]C)=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[C:1]([O:5][C:6]([CH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:9]1[C:19](=[O:36])[CH2:20][NH:21][C:22](=[O:35])[NH:23][C:24]1[CH:25]=[C:26]([CH2:30][C:31]([OH:33])=[O:32])[CH:27]=[CH:28][CH:29]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)Cc1cccc(NC(=O)NCC(=O)N2C(C(=O)OC(C)(C)C)CCC2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)C1CCC(c2ccccc2)N1C(=O)CNC(=O)Nc1cccc(CC(=O)O)c1
Yield: 21 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4.9 g of methyl (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetate in solution in 80 cm3 of methanol and 0.56 g of potassium hydroxide dissolved in 40 cm3 of water and after treatment, 1 g of (2RS,5SR)-3-{3-[2-(2-tert-butoxycarbonyl-5-phenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenylacetic acid is obtained [proton NMR (200 MHz, DMSO D6, δ in ppm), 2 rotamers at room temperature, peak coalescence at 120° C.: 1.5 (bs, 9H, (CH3)3); 3.5 (s, 2H, CH2CO); 6.8 to 7.7 (m, 9H, aromatic). Infrared spectrum (KBr), characteristic bands in cm-1 : 3380, 3700 to 2250 with a maximum at 2625, 3155, 3110, 3090, 3060, 3030, 2975, 2930, 2880, 1735, 1635, 1610, 1595, 1560, 1495, 1450, 1395, 1365, 1310, 1225, 1155, 905, 890, 860, 840, 780, 760, 705].
Reaction SMILES: FC(F)(F)C([N:5]1[CH2:11][CH2:10][C:9]2[CH:12]=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=2[CH2:7][CH2:6]1)=O.[Si:22]([O:29][C:30]1[CH:31]=[C:32](Br)[CH:33]=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]>>[Si:22]([O:29][C:30]1[CH:31]=[C:32]([S:16]([C:14]2[CH:13]=[CH:12][C:9]3[CH2:10][CH2:11][NH:5][CH2:6][CH2:7][C:8]=3[CH:15]=2)(=[O:17])=[O:18])[CH:33]=[CH:34][CH:35]=1)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23]
Reactant: O=C(N1CCc2ccc(S(=O)(=O)F)cc2CC1)C(F)(F)F
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(Br)c1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(S(=O)(=O)c2ccc3c(c2)CCNCC3)c1
Yield: 80 %

Procedure:
Prepared from 3-trifluoroacetyl-2,3,4,5-tetrahydro-1H-3-benzazepine-7-sulfonyl fluoride and 3-t-butyldimethylsilyloxybromobenzene using the method of Example 1, yield 80%.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH:11]([NH2:13])=O>>[N:1]1[C:2]2[N:10]=[CH:9][CH:8]=[CH:7][C:3]=2[C:4](=[O:6])[NH:13][CH:11]=1
Reactant: Nc1ncccc1C(=O)O
Reactant: NC=O
Product: O=c1[nH]cnc2ncccc12

Procedure:
2-Amino nicotinic acid (15 g, 108.6 mmol) in formamide (35 mL) is heated to 165 −170° C. for 3.5 h. Upon cooling a solid precipitates. The solid is filtered and washed with H2O and dried in a vacuum oven to give 3H-pyrido[2,3-d]pyrimidin-4-one (7.87 g, 49.4). 1H NMR (DMSO) δ 12.50 (1H, s), 8.97 (1H, dd, J=1.9, 4.5 Hz), 8.53 (1H, dd, J=2.1, 7.9 Hz), 8.34 (1H, s), 7.57 (1H, dd, J=4.6, 8.0 Hz).
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]1.C(NC(C)C)(C)C.[Li]>O1CCCC1>[N:4]12[CH2:5][C:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])([CH2:2][CH2:3]1)[CH2:7][CH2:8][CH2:9]2
Reactant: CCOC(=O)C1CCCN(CCCl)C1
Agent: [Li]
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C12CCCN(CC1)C2
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
Ethyl 1-(2-chloroethyl)piperidine-3-carboxylate (3.73 g, 17 mmol) in tetrahydrofuran (30 mL) was cooled to −65° C. under nitrogen; lithium diisopropylamine (17 mL, 2 M in tetrahydrofuran) was added slowly to the solution at −65° C. in 25 min. The mixture was allowed to warm up to room temperature and stirred overnight. The reaction was quenched with potassium carbonate and extracted with ether. The combined organic layer were dried over anhydrous magnesium sulfate, filtered and concentrated. The resulting orange oil was co-evaporated with dichloromethane three times. The extracts were combined and concentrated to give the ethyl 1-azabicyclo[3.2.1]octane-5-carboxylate (1.9 g, yield 61%). 1H-NMR (400 MHz, CD3OD) δ: 1.33 (t, 3H), 1.90-2.25 (m, 5H), 2.32-2.47 (m, 1H), 3.20-3.38 (m, 3H), 3.40-3.53 (m, 1H), 3.57-3.80 (m, 2H), 4.20 (q, 2H). LC-MS (ESI) (m/z): 184 (M+1)+.
Reaction SMILES: Cl.C([O:6][C:7](=[O:36])[CH2:8][N:9]([S:18]([C:21]1[CH:30]=[C:29]2[C:24]([C:25]([Cl:35])=[CH:26][N:27]=[C:28]2[NH:31][C:32]([NH2:34])=[NH:33])=[CH:23][CH:22]=1)(=[O:20])=[O:19])[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=1)(C)(C)C.[C:37]([C:41]([OH:43])=[O:42])([F:40])([F:39])[F:38]>C1(C)C=CC=CC=1>[F:38][C:37]([F:40])([F:39])[C:41]([OH:43])=[O:42].[Cl:35][C:25]1[C:24]2[C:29](=[CH:30][C:21]([S:18]([N:9]([CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[C:13]([Cl:17])[CH:12]=3)[CH2:8][C:7]([OH:36])=[O:6])(=[O:20])=[O:19])=[CH:22][CH:23]=2)[C:28]([NH:31][C:32]([NH2:34])=[NH:33])=[N:27][CH:26]=1
Reactant: CC(C)(C)OC(=O)CN(Cc1cccc(Cl)c1)S(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N(CC(=O)O)Cc3cccc(Cl)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine t-butyl ester hydrochloride (60 mg, 0.104 mmol) was dissolved in CF3CO2H (0.5 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was dissolved in Et2O and stirred at room temperature for 1 h. The resulting precipitate was collected by filtration, washed with Et2O and dried to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-N-(3-chlorobenzyl)glycine trifluoroacetate (31 mg, 0.052 mmol) as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[CH:25]([CH2:29]Br)[C:26]([NH2:28])=[O:27]>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=3)[CH:25]([C:26]([NH2:28])=[O:27])[CH2:29]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1ccc(CNCCNc2cc(Cl)cc(Cl)c2)cc1OC
Reactant: NC(=O)C(Br)CBr
Product: COc1ccc(CN2CCN(c3cc(Cl)cc(Cl)c3)CC2C(N)=O)cc1OC

Procedure:
In a manner similar to Preparation 1, react N-(3,5-dichlorophenyl)-N'-[(3,4-dimethoxyphenyl)methyl]-1,2-ethanediamine with 2,3-dibromopropanamide to obtain the title compound.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]2[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[O:19][CH:20]=2)=[CH:10][CH:9]=1)(=O)=O.[NH:29]1[CH:33]=[CH:32][N:31]=[CH:30]1>>[N:29]1([CH2:6][CH2:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][CH2:15][C:16]3[N:17]=[C:18](/[CH:21]=[CH:22]/[C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[O:19][CH:20]=3)=[CH:10][CH:9]=2)[CH:33]=[CH:32][N:31]=[CH:30]1
Reactant: c1c[nH]cn1
Reactant: CS(=O)(=O)OCCc1ccc(OCc2coc(/C=C/c3ccccc3)n2)cc1
Product: C(=C/c1nc(COc2ccc(CCn3ccnc3)cc2)co1)\c1ccccc1
Yield: 38 %

Procedure:
In substantially the same manner as in Working Example 25, 2-[4-[2-[(E)-2-phenylethenyl]-4-oxazolylmethoxy]phenyl]ethyl methanesulfonate was allowed to react with imidazole to give 4-[4-[2-(1-imidazolyl)ethyl]phenoxymethyl]-2-[(E)-2-phenylethenyl]oxazole. The yield was 38%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 165-166° C.
Reaction SMILES: CON(C)[C:4](=[O:30])[CH:5]=[C:6]1[CH2:11][CH2:10][CH:9]([CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][N:17]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=3)[CH2:16][CH2:15]2)[CH2:8][CH2:7]1.[CH3:32][Mg]Cl.O>O1CCCC1>[F:29][C:26]([F:28])([F:27])[C:22]1[CH:21]=[C:20]([N:17]2[CH2:16][CH2:15][N:14]([CH2:13][CH2:12][CH:9]3[CH2:10][CH2:11][C:6](=[CH:5][C:4](=[O:30])[CH3:32])[CH2:7][CH2:8]3)[CH2:19][CH2:18]2)[CH:25]=[CH:24][CH:23]=1
Reactant: CON(C)C(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Reactant: C[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CC(=O)C=C1CCC(CCN2CCN(c3cccc(C(F)(F)F)c3)CC2)CC1
Temperature: 5 °C
Reaction time: 1.5 h
Yield: 44 %

Procedure:
To a solution of 114 mg (0.25 mmol) of N-methoxy-N-methyl-2-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}-cyclohexylidene)acetamide in 5 mL of dry tetrahydrofuran cooled to 0° C. is added 0.2 mL (0.50 mmol) of a 22% methylmagnesium chloride solution in tetrahydrofuran. The mixture is warmed up to 5° C. and stirred for 90 minutes. Hydrolysis is performed by slow addition of 3 mL of water. The product is extracted 3 times with ethyl acetate. The organic phases are combined, dried over magnesium sulfate, filtered and concentrated under reduced pressure. The obtained residue is purified over 5 g of silica gel (eluant dichloromethane/methanol 95/5) to give 43 mg (44%) of 1-(4-{2-[4-(3-trifluoromethylphenyl)piperazin-1-yl]ethyl}cyclohexylidene)propan-2-one as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH2:13][CH2:12][CH:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[CH2:10][CH:9]=2)=[CH:4][CH:3]=1>C1(C)C=CC=CC=1.[Ni]>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C@H:8]2[CH2:9][CH2:10][C@H:11]([C@H:14]3[CH2:19][CH2:18][C@H:17]([C@H:20]4[CH2:25][CH2:24][C@H:23]([CH2:26][CH3:27])[CH2:22][CH2:21]4)[CH2:16][CH2:15]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: CC[C@H]1CC[C@H]([C@H]2CC[C@H](C3CC=C(c4ccc(C)cc4)CC3)CC2)CC1
Agent: [Ni]
Solvent: Cc1ccccc1
Product: CC[C@H]1CC[C@H]([C@H]2CC[C@H]([C@H]3CC[C@H](c4ccc(C)cc4)CC3)CC2)CC1

Procedure:
4-Methyl-{4-[trans-4-(trans-4-ethylcyclohexyl)-cyclohexyl]cyclohexen-1-yl}benzene (3.2 g) was dissolved in toluene (300 ml) and Raney Ni catalyst (1.5 g) was added, followed by catalytic reduction under ordinary pressure at ordinary temperature. When the raw material disappeared through gas chromatography, the reaction finished. The solvent was distilled off and recrystallization from toluene was repeated to obtain 4-methyl-{trans-4-[trans-4-(trans-4-ethylcyclohexyl)cyclohexyl]cyclohexyl}benzene (yield: 0.8 g) having a C-Sm point of 71.0° C., a Sm-N point of 254° C. and a N-I point of 293° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:16]#[N:17].[Br:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][C:25]=1[CH3:26])[NH2:22].Cl.N1C=CC=CC=1.C(OC(O)C)C.C(=O)([O-])[O-].[Na+].[Na+].Cl>O>[Br:18][C:19]1[CH:20]=[C:21]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:16]#[N:17])[CH:23]=[CH:24][C:25]=1[CH3:26]
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1OC
Reactant: Cc1ccc(N)cc1Br
Agent: CCOC(C)O
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: c1ccncc1
Solvent: O
Product: COc1cc2ncc(C#N)c(Nc3ccc(C)c(Br)c3)c2cc1OC
Yield: 71.8 %

Procedure:
A mixture of 0.249 g of 4-chloro-6,7-dimethoxy-3-quinolinecarbonitrile, 0.186 g of 3-bromo-4-methylaniline, 20 mg of pyridine hydrochloride, and 10 ml of ethoxyethanol was stirred under nitrogen, at reflux temperature for 30 minutes. The mixture was cooled and added to 40 ml of water. To this mixture was added sodium carbonate and concentrated hydrogen chloride to adjust pH to 7. The product was collected, washed with water, and dried to give 0.286 g of 4-(3-bromo-4-methyl-phenylamino)-6,7-dimethoxy-quinoline-3-carbonitrile as a solid, mp 292-294° C.; mass spectrum (EI, m/e): M 397.0446.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([N:14]([CH2:24][C:25](O)=[O:26])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21](=[O:23])[NH2:22])(=[O:13])=[O:12])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:28]([NH:35][CH2:36][CH3:37])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]([CH2:36][CH3:37])[C:25]([CH2:24][N:14]([S:11]([C:8]1[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=1)(=[O:13])=[O:12])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[C:21]([NH2:22])=[O:23])=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: CCNCc1ccccc1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)N(CC(=O)O)c2ccccc2C(N)=O)cc1
Product: CCN(Cc1ccccc1)C(=O)CN(c1ccccc1C(N)=O)S(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
prepared by reaction of [(4-tert-butyl-benzenesulfonyl)-(2-carbamoyl-phenyl)-amino]-acetic acid with benzyl-ethyl-amine
Reaction SMILES: [NH2:1]C(N)=O.[F-].[Ce+3].[F-].[F-].[CH3:9][O:10][CH2:11][C@H:12]1[CH2:16][O:15][C:14](=O)[O:13]1>CS(C)=O>[CH3:9][O:10][CH2:11][C@@H:12]1[O:13][C:14](=[O:15])[NH:1][CH2:16]1
Reactant: NC(N)=O
Reactant: COC[C@H]1COC(=O)O1
Agent: [Ce+3]
Agent: [F-]
Solvent: CS(C)=O
Product: COC[C@H]1CNC(=O)O1
Temperature: 140 °C
Reaction time: 36 h
Yield: 82972.7 %

Procedure:
Urea (246 g, 4.09 mmol) was dissolved in dimethyl sulfoxide (2.27 L), and thereto were added cerium fluoride (69.0 g, 0.454 mol) and (S)-4-methoxymethyl-1,3-dioxolan-2-one (600 g, 4.54 mol, optical purity 98.9%ee), in order. The mixture was stirred for 36 hours at 140° C. under an atmosphere of argon. After filtering off the insoluble materials, the filtrate was condensed in vacuo, and the residue was purified by distillation to give the subject (R)-5-methoxymethyloxazolidin-2-one (445 g, yield 74.7%, optical purity 98.6%ee).
Reaction SMILES: [OH-].[Na+].Cl.[N:4]1[CH:9]=[CH:8][N:7]=[CH:6][C:5]=1[CH2:10][S:11][C:12](=N)N.BrC[CH2:17][CH2:18][Cl:19]>O>[Cl:19][CH2:18][CH2:17][CH2:12][S:11][CH2:10][C:5]1[CH:6]=[N:7][CH:8]=[CH:9][N:4]=1
Reactant: ClCCCBr
Reactant: N=C(N)SCc1cnccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: ClCCCSCc1cnccn1
Temperature: 70 °C
Reaction time: 15 h
Yield: 76.8 %

Procedure:
A 10 N aqueous solution of sodium hydroxide (39 cc) is added dropwise, in the course of 15 minutes and at a temperature of about 10° C., to a solution of 2-(pyrazinylmethyl)-isothiourea monohydrochloride (77.6 g) in distilled water (250 cc). After heating for 30 minutes at 70° C. and then cooling to 15° C., a 10 N aqueous solution of sodium hydroxide (47 cc) and then 1-bromo-3-chloropropane (66.5 g) are added and stirring is continued for 15 hours at a temperature of about 20° C. The reaction mixture is then extracted three times with methylene chloride (280 cc in total). The organic extracts are combined, washed twice with distilled water (200 cc in total), dried over anhydous sodium sulphate and filtered. The solution obtained is poured onto neutral silica gel (80 g) contained in a column of diameter 2.7 cm; the column is then eluted with methylene chloride (900 cc). The first fraction (300 cc) is discarded; the second fraction (600 cc) is collected and concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 35° C. Pyrazinylmethyl 3-chloropropyl sulphide (59 g) is thus obtained in the form of a yellow-orange oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18](B3OC(C)(C)C(C)(C)O3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11].I[C:31]1[CH:32]=[N:33][N:34]([CH:36]2[CH2:41][CH2:40][C:39](=[O:42])[CH2:38][CH2:37]2)[CH:35]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1>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.O>[Cl:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[C:4]([Cl:9])[C:3]=1[CH:10]([C:12]1[C:20]2[C:15](=[N:16][CH:17]=[C:18]([C:31]3[CH:32]=[N:33][N:34]([CH:36]4[CH2:37][CH2:38][C:39](=[O:42])[CH2:40][CH2:41]4)[CH:35]=3)[CH:19]=2)[NH:14][CH:13]=1)[CH3:11]
Reactant: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(B3OC(C)(C)C(C)(C)O3)cc12
Reactant: O=C1CCC(n2cc(I)cn2)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: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CC(c1c(Cl)ccc(F)c1Cl)c1c[nH]c2ncc(-c3cnn(C4CCC(=O)CC4)c3)cc12
Temperature: 90 °C

Procedure:
A 20 ml sealable vial was charged with 3-[1-(2,6-Dichloro-3-fluorophenyl)ethyl]-5-(4,4,5,5-tetramethyl[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (80.0 mg, 0.156 mmol), 4-(4-Iodopyrazol-1-yl)cyclohexanone (52.5 mg, 0.172 mmol), Pd(PPh3)4 (12.0 mg, 0.0103 mmol), potassium carbonate (71.8 mg, 0.514 mmol), and 4:1 dioxane:water (5 mL). The cap was sealed and the vial was evacuated and backfilled with nitrogen (3×). After that, the vial was heated at 90° C. for 2 h. The reaction mixture was partitioned between EtOAc/H2O (15 ml/10 ml). The aqueous phase was extracted with EtOAc (10 ml). The combined organic extracts were washed with water (10 ml) and brine (10 ml), dried over MgSO4, filtered, and concentrated in vacuo to give a brown oil that was purified by prep. TLC eluting with 4% MeOH/DCM to give the title compound. 1H NMR (400 MHz, CDCl3): δ=1.88 (d, J=7.2 Hz, 3H), 2.31-2.68 (m, 8 H), 4.64 (tt, J=11.8, 4.0 Hz, 1 H), 5.28 (q, J=7.2 Hz, 1 H), 7.01 (dd, J=8.0 & 8.8 Hz, 1 H), 7.30 (s, 1 H), 7.32 (brs, 1 H), 7.48 (s, 1 H), 7.60 (d, J=0.8 Hz, 1 H), 7.66 (d, J=0.8 Hz, 1 H), 8.41 (brs, 1 H), 9.77 (brs, 1 H). MS (ES+): m/z=471.16/473.11 (100/68) [MH+]. HPLC: tR=3.39 min (polar—5 min, ZQ3).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]3[CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:17][C:18]=3[N:19]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1B1OC(C)(C)C(C)(C)O1)(=[O:29])[CH3:28].[O-]P([O-])([O-])=O.[K+].[K+].[K+].C([O-])(=O)C.[Na+]>O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(#N)C>[C:27]([O:30][CH2:31][C:32]1[C:33]([N:47]2[CH2:58][CH2:57][N:56]3[C:49](=[CH:50][C:51]4[CH2:52][C:53]([CH3:60])([CH3:59])[CH2:54][C:55]=43)[C:48]2=[O:61])=[N:34][CH:35]=[CH:36][C:37]=1[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[S:12][C:13]3[CH2:14][N:15]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH2:17][C:18]=3[N:19]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1)(=[O:29])[CH3:28]
Reactant: Cn1cc(Br)cc(Nc2nc3c(s2)CN(C(=O)OC(C)(C)C)CC3)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CC#N
Product: CC(=O)OCc1c(-c2cc(Nc3nc4c(s3)CN(C(=O)OC(C)(C)C)CC4)c(=O)n(C)c2)ccnc1N1CCn2c(cc3c2CC(C)(C)C3)C1=O
Temperature: 100 °C

Procedure:
A 50-mL round-bottomed flask equipped with a reflux condenser was charged with 233a (300 mg, 0.68 mmol), (3-(acetoxymethyl)-2-(7,7-dimethyl-1-oxo-3,4,7,8-tetrahydro-1H-cyclopenta[4,5]pyrrolo-[1,2-a]pyrazin-2(6H)-yl)pyridin-4-yl)boronic acid 199e (1.8 g, 2.72 mmol), Pd(dppf)Cl2 (27.7 mg, 0.034 mmol), K3PO4 (288.3 mg, 1.36 mmol), sodium acetate (111.5 mg, 1.36 mmol), water (10 drops), and acetonitrile (10 mL). After bubbling nitrogen through the mixture for 30 minutes, it was heated at 100° C. under N2 protection for 1 h. Analysis of reaction mixture by LCMS showed complete conversion to the desired product. The mixture was filtered and the filtrate was concentrated under reduced pressure and the residue was purified by silica-gel column chromatography eluting with 100:1 dichloromethane/methanol to afford 233b (220 mg, 45%) as a yellow solid. MS-ESI: [M+H]+ 714.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.[NH2:56][CH:57]1[CH2:62][CH2:61][O:60][CH2:59][CH2:58]1>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:9]=[N:10][N:11]([CH3:24])[C:12]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([NH:56][CH:57]2[CH2:62][CH2:61][O:60][CH2:59][CH2:58]2)=[O:21])=[CH:17][N:16]=1
Reactant: NC1CCOCC1
Reactant: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)O)cn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1nnc(-c2ccccc2F)c1COc1ccc(C(=O)NC2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of 6-((4-(2-fluorophenyl)-1-methyl-1H-1,2,3-triazol-5-yl)methoxy)nicotinic acid (98 mg, 0.3 mmol) and TBTU (105 mg, 0.33 mmol) in DMF (1 mL) was added DIPEA (261 μL, 1.49 mmol). Then 4-aminotetrahydropyran (34 μL, 0.33 mmol) was added and the mixture was stirred at room temperature under Ar for 1 h. The mixture was then evaporated and purification by chromatography (silica, 50 to 100% ethyl acetate in heptane) afforded the title compound (108 mg, 88%) as a white solid after recrystallisation from ethyl acetate/heptane. MS: m/e=412.3 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[N:9]=[N:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Cl[C:14]1[CH:19]=[CH:18][N:17]=[C:16]([S:20][CH3:21])[N:15]=1>CN(C=O)C>[CH3:21][S:20][C:16]1[N:17]=[C:18]([N:7]2[C:6]3[CH:5]=[CH:4][CH:3]=[C:2]([NH2:1])[C:10]=3[N:9]=[N:8]2)[CH:19]=[CH:14][N:15]=1
Reactant: Nc1cccc2[nH]nnc12
Reactant: CSc1nccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1nccc(-n2nnc3c(N)cccc32)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.5 %

Procedure:
Dry DMF (100 mL) was cooled under N2 in an ice bath. To this was added 4-amino-1H-benzotriazole (9.0 g), and the mixture stirred for 10 min. To this was added NaH (60%, 2.95 g), and the mixture stirred on the ice bath for 15 min. Finally, 4-chloro-2-methylsulfanyl-pyrimidine (11.00 g) was added, the ice bath removed, the mixture allowed to warm to RT, and then heated to 85° C. for 1 h. The reaction mixture was then cooled to RT, and diluted with ice water. The fine yellow precipitate was filtered, washed with cold water, and titurated with EtOAc to provide 1-(2-methylsulfanyl-pyrimidin-4-yl)-1H-benzotriazol-4-ylamine (13.43 g, 78% yield).
Reaction SMILES: [O:1]([C:19]1[CH:26]=[C:25]([O:27][CH3:28])[C:22]([CH2:23][OH:24])=[C:21]([O:29][CH3:30])[CH:20]=1)[Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.N1C=CN=C1.[C:36]([Si:40](Cl)([CH3:42])[CH3:41])([CH3:39])([CH3:38])[CH3:37].O>CN(C)C=O>[O:24]([CH2:23][C:22]1[C:21]([O:29][CH3:30])=[CH:20][C:19]([O:1][Si:2]([C:15]([CH3:18])([CH3:17])[CH3:16])([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[CH:26][C:25]=1[O:27][CH3:28])[Si:40]([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:42])[CH3:41]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc(OC)c1CO[Si](C)(C)C(C)(C)C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the crude 4-t-butyldiphenylsiloxy-2,6-dimethoxybenzyl alcohol (4.01 g) obtained by the above-described procedure in anhydrous dimethylformamide (30 mL) were added imidazole (1.29 g, 18.98 mmol) and t-butylchlorodimethylsilane (1.79 g, 11.86 mmol). After stirring at 50° C. for 4 hours, water was added and the resulting mixture was extracted with ethyl acetate-hexane (1:2). The organic layer was washed with water, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield crude 4-(t-butyldimethylsiloxy)methyl-1-t-butyldiphenylsiloxy-3,5-dimethoxybenzene was obtained as a colorless amorphous powder (5.33 g).