Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[O:34][CH:35]=[CH:36][CH:37]=1)CCC>>[O:34]1[CH:35]=[CH:36][CH:37]=[C:33]1[C:2]1[N:7]=[C:6]([C:8]2[N:12]3[CH:13]=[CH:14][C:15]([C:17]([CH3:27])([O:19][Si:20]([CH2:25][CH3:26])([CH2:23][CH3:24])[CH2:21][CH3:22])[CH3:18])=[N:16][C:11]3=[N:10][CH:9]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(Cl)n3)cnc2n1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(-c4ccco4)n3)cnc2n1
Yield: 59 %

Procedure:
3-(2-Chloropyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)-imidazo[1,2-α]pyrimidine (from Example 34) (58 mg, 0.14 mmol) and 2-tributylstannylfuran (102 mg, 0.29 mmol) were heated at reflux overnight as described in Example 40. Purification by column chromatography on silica using 70% EtOAc/isohexanes as the eluent gave 3-[2-(furan-2-yl)pyrimidin-4-yl]-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (36 mg, 57%): m/z (ES+) 435 (M+H+).
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]([NH:8][C:9](=[O:28])[C@@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[CH2:11][CH:12]2[CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:6][CH:7]=1.C(N(CC)C(C)C)(C)C.[C:38]([C:40]1([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]1)#[CH:39]>C1(C)C=CC=CC=1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH:12]1([CH2:11][C@H:10]([C:17]2[CH:22]=[CH:21][C:20]([S:23]([CH3:26])(=[O:25])=[O:24])=[C:19]([CH3:27])[CH:18]=2)[C:9]([NH:8][C:5]2[CH:4]=[N:3][C:2]([C:39]#[C:38][C:40]3([OH:46])[CH2:45][CH2:44][O:43][CH2:42][CH2:41]3)=[CH:7][N:6]=2)=[O:28])[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(Br)cn2)ccc1S(C)(=O)=O
Reactant: C#CC1(O)CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C#CC3(O)CCOCC3)cn2)ccc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 17 h
Yield: 55.1 %

Procedure:
A mixture of N-(5-bromo-pyrazin-2-yl)-3-cyclopentyl-2(R)-(4-methanesulfonyl-3-methyl-pheny)-propionamide (prepared as in Example 57, 154 mg, 0.33 mmol), N,N-diisopropylethylamine (0.6 mL, 3.44 mmol), and 4-ethynyl-tetrahydropyran-4-ol (prepared as in Example 46, 85 mg, 0.67 mmol) in toluene (2 mL) was treated with dichlorobis(triphenylphosphine)palladium(II) (14 mg, 0.02 mmol) and copper(I) iodide (7 mg, 0.0367 mmol). The mixture was stirred at 25° C. for 17 h. The reaction mixture was then concentrated in vacuo, and the residue was partitioned with methylene chloride (50 mL) and a 0.2M aqueous hydrochloric acid solution (25 mL) and the layers were separated. The aqueous phase was back-extracted with methylene chloride (25 mL). Each organic layer was washed with a saturated aqueous sodium chloride solution (1 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, gradient elution with mixtures of ethyl acetate/hexanes) afforded 3-cyclopentyl-N-[5-(4-hydroxy-tetrahydro-pyran-4-ylethynyl)-pyrazin-2-yl]-2(R)-(4-methanesulfonyl-3-methyl-phenyl)-propionamide (93 mg, 55%) as a yellow foam: (ES)+-HRMS m/e calcd for C27H33N3O5S (M+H)+ 512.2214, found 512.2219.
Reaction SMILES: Cl.[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:18][NH:17][C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.[Cl:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>>[ClH:29].[CH:2]1([N:12]2[CH2:28][CH2:27][C:15]3([N:19]([C:20]4[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=4)[CH2:18][N:17]([CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]4)[C:16]3=[O:26])[CH2:14][CH2:13]2)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: ClCCN1CCCCC1
Reactant: O=C1NCN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2
Agent: Cl
Product: O=C1N(CCN2CCCCC2)CN(c2ccccc2)C12CCN(C1CCCCCCCCC1)CC2

Procedure:
The title compound, white solid, m. p. 245° C. and MS: m/e=481.5 (M+H+) was prepared in accordance with the general method of example 24 from 8-cyclodecyl-1-phenyl-1,3,8-triaza-spiro[4,5]decan-4-one hydrochloride and 1-(2-chloroethyl)piperidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:52])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:35])[O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[O:31][CH:32]=[CH:33][N:34]=5)=[CH:24][N:23]=4)=[O:21])=[CH:15][C:14]=3[C@@:5]2([CH3:36])[N:4]=[C:3]1[N:37](C(OC(C)(C)C)=O)C(=O)OC(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[NH2:37][C:3]1[C:2]([CH3:1])([CH3:52])[S:7](=[O:9])(=[O:8])[C@@H:6]2[CH2:10][C@H:11]([CH3:35])[O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:21])[C:22]4[CH:27]=[CH:26][C:25]([O:28][CH2:29][C:30]5[O:31][CH:32]=[CH:33][N:34]=5)=[CH:24][N:23]=4)=[CH:15][C:14]=3[C@@:5]2([CH3:36])[N:4]=1
Reactant: C[C@H]1C[C@@H]2[C@](C)(N=C(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@H]1C[C@@H]2[C@](C)(N=C(N)C(C)(C)S2(=O)=O)c2cc(NC(=O)c3ccc(OCc4ncco4)cn3)ccc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 84.6 %

Procedure:
To a solution tert-butyl N-[(4aR,6S,11bR)-3,3,6,11b-tetramethyl-10-[[5-(oxazol-2-ylmethoxy)pyridine-2-carbonyl]amino]-4,4-dioxo-5,6-dihydro-4aH-[1]benzoxepino[4,5-b][1,4]thiazin-2-yl]-N-tert-butoxycarbonyl-carbamate (19 mg, 0.026 mmol) in DCM (2 mL) was added TFA (0.049 mL, 0.642 mmol). The reaction was stirred at ambient temperature for 2 h. The reaction mixture was diluted with DCM and neutralized with saturated aqueous sodium bicarbonate. The crude product was purified by column chromatography, eluting with 20-100% (3:1 ethyl acetate/ethanol) in heptane, to provide N-((4aR,6S,11bR)-2-amino-3,3,6,11b-tetramethyl-4,4-dioxido-4a,5,6,11b-tetrahydro-3H-benzo[6,7]oxepino[4,5-b][1,4]thiazin-10-yl)-5-(oxazol-2-ylmethoxy)picolinamide (12 mg, 0.022 mmol, 87% yield) as a white powder. MS m/z=540.0 (M+H).
Reaction SMILES: COC1C=CC(C[O:8][C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]#[N:17])[CH:10]=2)=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[OH:8][C:9]1[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([C:16]#[N:17])[CH:10]=1
Reactant: COc1ccc(COc2cc(C#N)nc(C)n2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1nc(O)cc(C#N)n1
Reaction time: 0.17 h

Procedure:
The 6-[(4-methoxybenzyl)oxy]-2-methylpyrimidine-4-carbonitrile from step 2 of this example (2.8 g, 11 mmol) was dissolved in DCM (9.1 mL) and TFA (1.8 mL) was added via syringe drop-wise. The reaction was allowed to proceed 10 min. at room temperature and was concentrated to near dryness, without heating, under vacuum. The residue was dissolved in DCM (10 mL), and saturated NaHCO3 solution (aq, 5 mL) was added to adjust pH to ˜7. Acetic acid (1 mL) was then added to the solution to adjust pH to ˜4 and the mixture was concentrated to dryness i. vac. The residue was purified by chromatography on silica gel using gradient elution: starting at 30% ethyl acetate/hexane, then switching to 5% methanol/DCM to yield the titled compound as a white solid. LC-MS (M+1): 136.16.
Reaction SMILES: [CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[OH:13])(=[O:6])[O:4][CH3:5].I[CH3:22].[OH-].[Na+]>CN(C=O)C>[CH3:1][O:2][P:3]([C:7]1[CH:8]=[C:9]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:22])(=[O:6])[O:4][CH3:5]
Reactant: COP(=O)(OC)c1cc(-c2ccc(C)cc2)ccc1O
Reactant: CI
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(C)cc2)cc1P(=O)(OC)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.4 %

Procedure:
A mixture of 4-hydroxy-4′-methylbiphenyl-3-yl-phosphonic acid dimethyl ester (500 mg, 1.7 mmol), iodomethane (342 mg, 2.4 mmol) and 10 M aqueous NaOH (190 μL, 1.9 mmol) in DMF (10 mL) was stirred at r.t. overnight. After dilution with H2O, the mixture was extracted with EtOAc. Chromatography over silica gel and elution with EtOAc with 5% of MeOH gave 330 mg (63%) of title compound as a white solid.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([O:23]CC)=[O:22])[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)=[O:10]>CCO.[OH-].[Na+]>[F:26][C:2]([F:1])([F:27])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]([NH:11][C:12]1[CH:13]=[C:14]([C:21]([OH:23])=[O:22])[C:15]2[O:19][CH2:18][CH2:17][C:16]=2[CH:20]=1)=[O:10]
Reactant: CCOC(=O)c1cc(NC(=O)c2ccccc2C(F)(F)F)cc2c1OCC2
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(Nc1cc2c(c(C(=O)O)c1)OCC2)c1ccccc1C(F)(F)F
Temperature: 80 °C
Reaction time: 4 h
Yield: 95.7 %

Procedure:
To a suspension of ethyl 5-({[2-(trifluoromethyl)phenyl]carbonyl}amino)-2,3-dihydro-1-benzofuran-7-carboxylate (220 mg) obtained in Step 2 in EtOH (5 mL), 1N aqueous sodium hydroxide solution (1 mL) was added and the mixture was stirred at 80° C. for 4 hours. The reaction mixture was cooled to room temperature, and EtOH was removed under reduced pressure. To the residue was added water, and the solution was acidified to pH 3 with 1N hydrochloric acid under ice-cooling and extracted with ethyl acetate. The organic layer was washed sequentially with water and brine, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure to obtain the titled compound (195 mg) as slightly yellow powder.
Reaction SMILES: [NH2:1][C:2](=[O:34])[CH:3]([CH2:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18]2[C:19]3[CH2:33][CH2:32][CH2:31][C:20]=3[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[CH:25]=3)[N:23]=2)=[CH:13][CH:12]=1)[C:4](OC(C)C)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[Cl:30][C:26]1[CH:25]=[C:24]([C:22]2[N:23]=[C:18]([NH:17][C:14]3[CH:13]=[CH:12][C:11]([CH2:10][CH:3]([CH2:4][OH:5])[C:2]([NH2:1])=[O:34])=[CH:16][CH:15]=3)[C:19]3[CH2:33][CH2:32][CH2:31][C:20]=3[N:21]=2)[CH:29]=[CH:28][CH:27]=1
Reactant: CC(C)OC(=O)C(Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1)C(N)=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC(=O)C(CO)Cc1ccc(Nc2nc(-c3cccc(Cl)c3)nc3c2CCC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 24.9 %

Procedure:
To a solution of isopropyl 3-amino-2-(4-((2-(3-chlorophenyl)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)amino)benzyl)-3-oxopropanoate (0.090 g, 0.19 mmol) in THF (5 mL) was added lithium aluminum hydride (1.0 M, 0.38 mL, 0.38 mmol). The mixture stirred at 0° C. for 2 h. The mixture was quenched with water and sodium hydroxide (2M) and then extracted with ethyl acetate. The organic layer were dried over anhydrous sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography (silica, dichloromethane/methanol) to afford the title compound (0.020 g, 25%) as a white solid. MW=422.91. 1H NMR (DMSO-d6, 500 MHz) δ 8.77 (s, 1H), 8.30-8.21 (m, 2H), 7.70 (d, J=8.5 Hz, 2H), 7.55-7.49 (m, 2H), 7.23 (s, 1H), 7.18 (d, J=8.0 Hz, 2H), 6.73 (s, 1H), 4.67 (t, J=5.5 Hz, 1H), 3.59-3.52 (m, 1H), 3.43-3.36 (m, 1H), 2.94-2.84 (m, 4H), 2.79-2.56 (m, 3H), 2.10 (quin, J=7.5 Hz, 2H); APCI MS m/z 423 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]3[C:29]4[C:24](=[CH:25][CH:26]=[C:27]([N+:30]([O-])=O)[CH:28]=4)[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:22]=3)[CH:18]=[N:17][CH:16]=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].O.NN>CO.[Ni]>[NH2:30][C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[N:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH:22]=[C:21]2[C:19]1[CH:18]=[N:17][CH:16]=[C:15]([N:12]2[CH2:13][CH2:14][CH:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:10][CH2:11]2)[N:20]=1
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc([N+](=O)[O-])cc34)n2)CC1
Agent: [Ni]
Agent: NN
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NC1CCN(c2cncc(-c3cn(C(=O)OC(C)(C)C)c4ccc(N)cc34)n2)CC1
Temperature: 50 °C
Reaction time: 0.17 h
Yield: 85 %

Procedure:
To a solution of tert-butyl 3-(6-(4-(tert-butoxycarbonylamino)piperidin-1-yl)pyrazin-2-yl)-5-nitro-1H-indole-1-carboxylate (200 mg, 0.37 mmol) in MeOH (2 mL) was added Raney Ni (30 mg) and then heated at 50° C. for 5 min. Hydrazine hydrate (0.2 mL) was added and the resulting mixture was stirred at the same temperature for another 10 min. The reaction mixture was cooled to RT and filtered off the Raney Ni through Celite. The filtrate was concentrated to obtain the title compound as a pale brown solid (160 mg, 85%). MS (ESI, pos. ion) m/z: 509.3 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][CH2:11][NH:12][CH2:13][C:14]2([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]2)[CH:5]=[CH:6][C:7]=1[F:8].Cl[C:29](Cl)([O:31]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.CCOC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([N:9]2[CH2:10][CH2:11][N:12]([CH2:13][C:14]3([C:21]4[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=4)[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]3)[C:29]2=[O:31])[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: CN1CCC(CNCCNc2ccc(F)c(F)c2)(c2ccc(I)cc2)CC1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CN1CCC(CN2CCN(c3ccc(F)c(F)c3)C2=O)(c2ccc(I)cc2)CC1
Temperature: 25 °C
Reaction time: 4 h
Yield: 6.9 %

Procedure:
To a stirred solution of N-(3,4-difluoro-phenyl)-N′-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-ethane-1,2-diamine (0.36 g, 1.0 mmol) in THF (10 mL) at 0° C. was added TEA (0.91 mL, 6.5 mmol, 6.5 eq.) and triphosgene (0.195 g, 0.65 mmol, 0.65 eq.). The mixture was stirred at room temperature for 4 h, diluted with EtOAc (25 mL) and washed with saturated brine (2×25 mL). The organic extracts were dried over sodium sulfate, filtered and concentrated by rotary evaporation to give a yellow oil. The crude product was purified by flash column chromatography by eluting with 2% MeOH/CH2Cl2 to give 1-(3,4-difluoro-phenyl)-3-[4-(4-iodo-phenyl)-1-methyl-piperidin-4-ylmethyl]-imidazolid in-2-one (0.023 g, 0.045 mmol, 5%) as a pale foam. MS (ESI): 512.1/513.1 (M+H), impurity peak 690.9/692.0.
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][CH3:10])[N:5]=[CH:4][N:3]=1.[CH2:11]([N:14]1[CH2:18][CH:17]([NH2:19])[CH2:16][CH:15]1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH:12]=[CH2:13].C(N1CC(O)CC1C1C=CC=CC=1)C=C.C(N(CC)CC)C>O>[Cl:8][C:7]1[CH:2]=[N:3][C:4]([NH:19][CH:17]2[CH2:18][N:14]([CH2:11][CH:12]=[CH2:13])[CH:15]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:16]2)=[N:5][C:6]=1[CH2:9][CH3:10]
Reactant: C=CCN1CC(N)CC1c1ccccc1
Reactant: CCc1ncnc(Cl)c1Cl
Agent: C=CCN1CC(O)CC1c1ccccc1
Solvent: O
Solvent: CCN(CC)CC
Product: C=CCN1CC(Nc2ncc(Cl)c(CC)n2)CC1c1ccccc1
Temperature: 85 °C

Procedure:
1.5 g (8.5 mmol) of 4,5-dichloro-6-ethylpyrimidine, 1.7 g (8.5 mmol) of 1-allyl-4-amino-2-phenylpyrrolidine (prepared from 1-allyl-2-phenylpyrrolidin--4-ol analogously to the route described in Example A) and 2 ml (4 mmol) of triethylamine were heated for 12 hours at 85° C. After cooling, the mixture was diluted with water and extracted with ether, and the organic phase was washed with saturated NaCl solution. After drying and concentrating, the residue was purified by column chromatography using petroleum ether/ethyl acetate (9:1, 8:2). This gave 0.95 g (33% of theory) of a colorless syrup (diastereomers 1:1)
Reaction SMILES: [C:1]([NH:8][CH2:9][C:10]1[S:11][C:12]([C:19](=S)[NH2:20])=[C:13]([C:15]([F:18])([F:17])[F:16])[N:14]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].IC.C([O-])(=O)C.[NH4+:28].C([O-])(=O)C>ClCCl>[C:19]([C:12]1[S:11][C:10]([CH2:9][NH:8][C:1]([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2])=[N:14][C:13]=1[C:15]([F:18])([F:17])[F:16])(=[NH:20])[NH2:28]
Reactant: [NH4+]
Reactant: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(N)=S)s1
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CI
Product: CC(C)(C)OC(=O)NCc1nc(C(F)(F)F)c(C(=N)N)s1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
2-(N-BOC-Aminomethyl)-4-trifluoromethylthiazole-5-thioamide [sic] (2.5 g, 7.32 mmol) was dissolved in dichloromethane (10 ml), and iodomethane (10.4 g, 73.24 mmol) was added. Then, the mixture was stirred for 48 hours at room temperature. After the solvent had been removed on a rotary evaporator, the residue was taken up in methanol (5 ml), and 10% strength methanolic ammonium acetate solution (8.5 ml, 10.98 mmol) was added. After the mixture had been stirred for 4 days at room temperature, the solution of the crude product was passed over an acetate-loaded ion exchanger and the solvent was removed on a rotary evaporator. The crude product was purified by flash chromatography. Yield: 0.8 g (2.08 mmol, 28%).
Reaction SMILES: [O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[CH2:11][C:12]([O:14]C)=[O:13]>Cl.O>[O:1]=[C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[S:4][N:3]1[CH2:11][C:12]([OH:14])=[O:13]
Reactant: COC(=O)Cn1sc2ccccc2c1=O
Agent: Cl
Solvent: O
Product: O=C(O)Cn1sc2ccccc2c1=O
Temperature: 100 °C
Reaction time: 6 h
Yield: 98.2 %

Procedure:
Ester 6 (500 mg, 2.24 mmol) was suspended in conc. HCl (8 mL) and heated with stirring at 100° C. for 6 h until hydrolysis completed.4 The mixture was cooled to room temperature, diluted with water (500 mL), and the precipitate was collected to give the title compound (460 mg, 98% yield). C9H7NO3S; white solid; mp 241-243° C.; 1H NMR (400 MHz, CDCl3) δ 7.97 (1H, dt, J=8, 0.8 Hz), 7.79 (1H, dt, J=8, 0.8 Hz), 7.70 (1H, td, J=8, 1.2 Hz), 7.46 (1H, td, J=8, 1.2 Hz), 4.64 (2H, s); 13C NMR (100 MHz, CDCl3) δ 169.4, 166.4, 141.8, 132.3, 125.8, 125.5, 123.4, 121.0, 44.4; ESI-HRMS (negative mode) calcd for C9H7NO3S: 208.0068. found: m/z 208.0064 [M−H]−.
Reaction SMILES: O.[OH-].[Li+].OO.C([C@@H]1COC(=O)N1[C:19]([C@H:21]1[C@H:25]([CH3:26])[C:24](=[O:27])[N:23]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][C:30]=2[O:37][CH3:38])[CH2:22]1)=[O:20])C1C=CC=CC=1.S([O-])(O)=[O:40].[Na+]>O.O1CCCC1>[CH3:38][O:37][C:30]1[CH:31]=[C:32]([O:35][CH3:36])[CH:33]=[CH:34][C:29]=1[CH2:28][N:23]1[C:24](=[O:27])[C@@H:25]([CH3:26])[C@H:21]([C:19]([OH:20])=[O:40])[CH2:22]1
Reactant: O=S([O-])O
Reactant: COc1ccc(CN2C[C@@H](C(=O)N3C(=O)OC[C@H]3Cc3ccccc3)[C@H](C)C2=O)c(OC)c1
Agent: OO
Agent: [Li+]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2C[C@@H](C(=O)O)[C@H](C)C2=O)c(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 109.7 %

Procedure:
To a solution of lithium hydroxide monohydrate (1.26 g) in water (30 ml) was added dropwise 30 wt % aqueous solution of hydrogen peroxide (7.0 ml) under ice-cooling, and the mixture was stirred for 10 minutes. To this reaction solution was added tetrahydrofuran 30 ml, and then a solution of the low-polarity component of (R)-4-benzyl-3-[(trans)-1-(2,4-dimethoxybenzyl)-4-methyl-5-oxopyrrolidine-3-carbonyl]-2-oxazolidinone (11.4 g) in tetrahydrofuran (90 ml) was added dropwise thereto, and then the mixture was stirred for additional 1 hour. To this reaction solution was added dropwise a solution of sodium hydrogen sulfite (7.18 g) in water (50 ml), and then the mixture was warmed to room temperature, and stirred for 1 hour. This mixture was extracted with ethyl acetate, and the resulting organic layer was washed with a saturated aqueous solution of sodium chloride, and then dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (eluent: chloroform/ethyl acetate=1/1 to 1/2, chloroform/methanol=5/1) to give a crude product of the titled compound (8.11 g). An analysis of the solid by HPLC analysis condition 1 showed that an isomer with shorter retention time was a main product.
Reaction SMILES: C(O)(C(F)(F)F)=O.[CH3:8][O:9][C:10]([NH:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][N:16](C(OC(C)(C)C)=O)[CH2:15]1)=[O:11]>ClCCl>[CH3:8][O:9][C:10](=[O:11])[NH:12][CH2:13][C@H:14]1[O:19][CH2:18][CH2:17][NH:16][CH2:15]1
Reactant: COC(=O)NC[C@@H]1CN(C(=O)OC(C)(C)C)CCO1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)NC[C@@H]1CNCCO1

Procedure:
To a 4:1 solution of dichloromethane and TFA (0.1 M) was added (R)-tert-butyl 2-(((methoxycarbonyl)amino)methyl)morpholine-4-carboxylate. After 1 h the solution was then concentrated in vaccuo to give crude (S)-methyl(morpholin-2-ylmethyl)carbamate which was used in the next step without further purification. LCMS (m/z) (M+H)=175.0, Rt=0.11 min.
Reaction SMILES: C(O[NH:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:20])[F:19])[CH2:13][CH2:12]1)C1C=CC=CC=1>C(O)C.[Pd]>[NH2:9][CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]([F:21])([F:19])[F:20])[CH2:13][CH2:12]1
Reactant: FC(F)(F)CN1CCC(CNOCc2ccccc2)CC1
Agent: [Pd]
Solvent: CCO
Product: NCC1CCN(CC(F)(F)F)CC1

Procedure:
4-Benzyloxyaminomethyl-1-(2,2,2-trifluoroethyl)piperidine was dissolved in ethanol (50 mL) and hydrogenated over 10% palladium on carbon (0.5 g) for 10 hours. The mixture was filtered through a pad of celite and washed with methanol. The filtrate was evaporated to give 1.17 g of 4-aminomethyl-1-(2,2,2-trifluoroethyl)piperidine as a semi-solid.
Reaction SMILES: [CH2:1]1[CH2:6][NH:5][CH2:4][C:3]2[C:7](=[O:15])[O:8][C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:2]1=2.C(N(CC)CC)C.Cl.Cl[CH2:25][CH2:26][N:27]1[CH2:33][CH:32]2[CH2:34][CH2:35][CH:29]([CH2:30][CH2:31]2)[CH2:28]1>>[CH:32]12[CH2:34][CH2:35][CH:29]([CH2:30][CH2:31]1)[CH2:28][N:27]([CH2:26][CH2:25][N:5]1[CH2:6][CH2:1][C:2]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[O:8][C:7](=[O:15])[C:3]=3[CH2:4]1)[CH2:33]2
Reactant: ClCCN1CC2CCC(CC2)C1
Reactant: O=c1oc2ccccc2c2c1CNCC2
Agent: Cl
Solvent: CCN(CC)CC
Product: O=c1oc2ccccc2c2c1CN(CCN1CC3CCC(CC3)C1)CC2
Yield: 64.8 %

Procedure:
Prepared by the method described for Example 1 from 1,2,3,4-tetrahydro-5H-[1]benzopyrano[3,4-c]pyridin-5-one (1.5 g, 0.007 moles), triethylamine (2.2 ml, 0.016 moles), and 3-(2-chloroethyl)-3-azabicyclo[3.2.2]nonane hydrochloride (1.7 g, 0.0076 moles). Recrystallization from ethanol gave the product (1.6 g) as the monohydrochloride, 5:1 hydrate, mp 267° C. (dec).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.O[CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27].CCOC(C)=O>C(Cl)Cl.CCCCCC>[Br:20][CH2:23]/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH3:30])=[O:27]
Reactant: CCOC(=O)/C=C/CO
Reactant: BrBr
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: ClCCl
Product: CCOC(=O)/C=C/CBr
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 81.2 %

Procedure:
Triphenyl phosphine (295 g, 1.12 mol) and methylene chloride (665 mL) were introduced into a 3 L one-neck flask and were stirred for 10 minutes at 0° C. And then, bromine (179.3 g) dissolved in methylene chloride (665 mL) was slowly added as droplets therein for 1 hours. At this time, the temperature of the reactor was maintained to be 0° C. The reaction product was further stirred for 30 minutes after all of bromine was added. (E)-ethyl 4-hydroxybut-2-enoate (133 g, 1.02 mol) dissolved in methylene chloride (665 mL) was slowly added as droplets into the reaction mixture for 1 hours. At this time, the temperature of the reactor was also maintained to be 0° C. After all of (E)-ethyl 4-hydroxybut-2-enoate was added, the mixture was further stirred for 30 minutes at 0° C. (the reaction was confirmed with TLC, EtOAc:hexane=1:4). After washing the organic layer of the reaction product with water (900 mL×2), the organic layer was dried with anhydrous MgSO4, and then a large quantity of Ph3P═O was extracted in company with the product by filtering and concentrating the same. The triphenyl phosphine oxide was eliminated by filtering the product, after adding n-hexane (1 L) therein and stirring the same for 30 minutes with a mechanical stirrer. (E)-ethyl 4-bromobut-2-enoate of 160 g was obtained with a yield of 81.2% by concentrating the filtered solution under a decompressed condition and distillating the concentrated solution under vacuum condition.