Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:8][NH:7][C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3]1.[CH2:13]([N:15]=[C:16]=[O:17])[CH3:14]>>[CH2:13]([NH:15][C:16]([N:7]1[C:6](=[O:9])[CH2:5][C:4]([CH3:11])([CH3:10])[NH:3][C:2]([CH3:12])([CH3:1])[CH2:8]1)=[O:17])[CH3:14]
Reactant: CC1(C)CNC(=O)CC(C)(C)N1
Reactant: CCN=C=O
Product: CCNC(=O)N1CC(C)(C)NC(C)(C)CC1=O

Procedure:
Using the same conditions as in Example 4, 17 parts of 2,2,7,7 -tetramethyl-1,4-diazacycloheptan-5-one and 8 parts of ethylisocyanate afforded an almost colourless oil which was distilled in vacuo to yield 20 parts of 4-ethylcarbamoyl-2,2,7,7-tetramethyl-1,4diazacycloheptan-5-one of boiling point 103° - 107°C at 1mm pressure. This material gave the following elemental analysis by weight:
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:28][Si:29]([CH3:37])([CH3:36])[C:30]#[C:31]/[CH:32]=[CH:33]/[CH2:34]O>ClCCl>[Br:1][CH2:34][CH:33]=[CH:32][C:31]#[C:30][Si:29]([CH3:37])([CH3:36])[CH3:28]
Reactant: O=C1CCC(=O)N1Br
Reactant: C[Si](C)(C)C#C/C=C/CO
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: C[Si](C)(C)C#CC=CCBr
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.1 %

Procedure:
N-Bromosuccinimide (85.3 g, 0.48 mol) was added in portions to a nearly homogeneous solution of triphenylphosphine (128.2 g, 0.49 mol) and 2E-5-trimethylsilylpent-2-en-4-yn-1-ol (72.5 g, 0.47 mol) in dichloromethane (600 mL) under nitrogen and cooled in a dry ice/2-propanol bath to an initial temperature of below −20° C. The internal temperature of the reaction mixture was maintained at −10° C. to 0° C. throughout the addition by adjusting the rate of addition. The bath was allowed to warm to ambient temperature. After 2 hours, the reaction was complete. The reaction mixture was concentrated under vacuum to a thick paste and the residue was triturated with hexane (250 mL). The suspension was filtered and the solids and silica gel were rinsed with hexane (10×150 mL). The filtrate was concentrated under vacuum (30° C./60 mtorr) to obtain 44 g (89% yield) of 1-bromo-5-trimethylsilylpent-2-en-4-yne, a compound of formula (P), as a pale yellow oil: 1H-NMR (300 mHz, CDCl3) δ 0.19 (s, 9H), 3.95 (d, 2H), 5.75 (d, 1H), 6.31 (dt, 1H) ppm.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=[C:12](SC)[N:13]=1.[NH2:26][CH2:27][CH2:28][NH2:29]>>[NH2:26][CH2:27][CH2:28][NH:29][C:12]1[N:13]=[C:8]([C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[Cl:1])[C:9]2[CH:19]=[CH:18][C:17](=[O:20])[N:16]([CH:21]([CH2:24][CH3:25])[CH2:22][CH3:23])[C:10]=2[N:11]=1
Reactant: NCCN
Reactant: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(SC)nc21
Product: CCC(CC)n1c(=O)ccc2c(-c3ccccc3Cl)nc(NCCN)nc21

Procedure:
The product of Example 44, and 1,2-diaminoethane were reacted by the procedure of Example 60 to afford 2-(2-amino-ethylamino)-4-(2-chloro-phenyl)-8-(1-ethyl-propyl)-8H-pyrido[2,3-d]pyrimidin-7-one. LC MS (m/e)=386 (MH+). Rt=1.54 min
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([C:18]3[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=3)([CH3:17])[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:31][CH2:30][CH2:29][CH2:28]1.O>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([NH:10][C:11]2[S:12][C:13]([CH3:17])([C:18]3[CH:26]=[CH:25][C:21]([C:22]([N:27]4[CH2:31][CH2:30][CH2:29][CH2:28]4)=[O:23])=[CH:20][CH:19]=3)[C:14](=[O:16])[N:15]=2)[CH3:9])=[CH:4][CH:3]=1
Reactant: C1CCNC1
Reactant: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)Cl)cc2)S1)c1ccc(F)cc1
Solvent: O
Solvent: ClCCl
Product: C[C@H](NC1=NC(=O)C(C)(c2ccc(C(=O)N3CCCC3)cc2)S1)c1ccc(F)cc1
Reaction time: 0.67 h

Procedure:
To a solution of 4-(2-((S)-1-(4-fluorophenyl)ethylamino)-5-methyl-4-oxo-4,5-dihydrothiazol-5-yl)benzoyl chloride (0.100 g, 0.26 mmol) in CH2Cl2 (1 mL) in a 0° C. bath was added pyrrolidine (Aldrich, 0.063 ml, 0.77 mmol). The mixture was gradually warmed to ambient temp. and stirred for 40 min. The reaction mixture was then added to water (5 mL), and the aqueous layer was extracted with CH2Cl2 three times. The combined organic phases were dried over Na2SO4, and concentrated in vacuo. The crude product was purified by silica gel chromatography. MS: 426 (M+1).
Reaction SMILES: [C:1](Cl)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[C:21]1([C:27]2[S:28][C:29]3[NH:30][CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[N:36]=2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(N(CC)CC)C>C1COCC1>[C:21]1([C:27]2[S:28][C:29]3[N:30]([C:1](=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]=3[N:36]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCCCCCCCCCCCCCCCCC(=O)Cl
Reactant: c1ccc(-c2nc3c(s2)NCCCC3)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCC(=O)N1CCCCc2nc(-c3ccccc3)sc21
Yield: 76 %

Procedure:
Stearoyl chloride (4.65 ml) was added dropwise to a mixture of 2-phenyl-5,6,7,8-tetrahydro-4H-thiazolo[5,4-b]-azepine (2.65 g), triethylamine (2.26 ml) and THF (30 ml) under ice-cooling and stirring. After completing addtion dropwise, the mixture was stirred for 1.5 hrs. at room temperature and distilled under reduced pressure to remove the solvent. The residue was extracted with chloroform, and the extract was washed with water, dried and distilled to remove the solvent. The residue was purified by a column chromatography on silica gel to give the title compound (4.31 g, 76%).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[P:17](Cl)([Cl:20])([Cl:19])=[O:18]>CCOCC>[P:17]([Cl:20])([Cl:19])(=[O:18])[O:16][C:13]1[CH:14]=[CH:15][C:10]([O:9][CH3:8])=[CH:11][CH:12]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COc1ccc(O)cc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: COc1ccc(OP(=O)(Cl)Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.3 %

Procedure:
Dry triethylamine (4.2 ml, 30 mmol) and p-methoxyphenol (3.72 g, 30 mmol) in 100 ml dry ether were added dropwise to a stirred solution of dry ether (50 ml) containing phosphorus oxychloride (2.80 ml, 30 mmol), at −78° C. under nitrogen. Following the addition, the reaction mixture was slowly allowed to warm at room temperature and stirred for one hour. The solvent was removed under reduced pressure to give the crude product (6.6 g, 92%) as an oil, which was used in the following step without any further purification.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH2:31])=[CH:28][CH:27]=2)[CH2:21][CH2:20]1.[OH-].[Na+]>CS(C)=O.O>[CH3:18][N:19]1[CH2:25][CH2:24][CH2:23][N:22]([C:26]2[CH:33]=[CH:32][C:29]([CH2:30][NH:31][C:2]3[C:7]([C:8]([NH:10][C:11]4[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][N:12]=4)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=3)=[CH:28][CH:27]=2)[CH2:21][CH2:20]1
Reactant: CN1CCCN(c2ccc(CN)cc2)CC1
Reactant: O=C(Nc1ccc(Cl)cn1)c1cccnc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CN1CCCN(c2ccc(CNc3ncccc3C(=O)Nc3ccc(Cl)cn3)cc2)CC1
Yield: 8.4 %

Procedure:
A mixture of 2-chloro-N-(5-chloropyridin-2-yl)pyridine-3-carboxamide (1.00 g, 3.7 mmol) and 4-(4-methylhexahydro-1,4-diazepin-1-yl)benzylamine (0.63 g, 2.9 mmol), in 5 mL of DMSO, was heated in a sealed tube at 70–75° C. for 35 h. This reaction mixture was diluted with 250 mL of water, basified with 2 N NaOH, and extracted with ethyl acetate and evaporated to give 0.83 g crude product. Flash chromatography purification with 10% MeOH—CHCl3, 1% NH4OH gave the title product (0.11 g, 8.5%).
Reaction SMILES: [CH3:1][C:2]1[N:9]2[C:5]([S:6][CH:7]=[CH:8]2)=[CH:4][N:3]=1.[I:10]N1C(=O)CCC1=O>ClCCl.IN1C(=O)CCC1=O>[I:10][C:4]1[N:3]=[C:2]([CH3:1])[N:9]2[CH:8]=[CH:7][S:6][C:5]=12
Reactant: O=C1CCC(=O)N1I
Reactant: Cc1ncc2sccn12
Solvent: ClCCl
Product: Cc1nc(I)c2sccn12
Temperature: 25 °C
Reaction time: 24 h
Yield: 105.1 %

Procedure:
5-Methylimidazo[5,1-b]thiazole (6.90 g) was dissolved in 500 ml of dichloromethane. N-Iodosuccinimide (10.6 g) was added to the solution. The mixture was stirred at room temperature for 24 hr. N-Iodosuccinimide (1.06 g) was added thereto, followed by stirring for additional one hr. The reaction solution was washed with an aqueous sodium thiosulfate solution and brine in that order, dried over anhydrous magnesium sulfate, and then filtered. The solvent was removed by distillation under the reduced pressure. The residue was dissolved in 200 ml of dichloromethane and 100 ml of ethyl acetate. Silica gel (30 g) was added to the solution. The mixture was stirred. The silica gel was removed by filtration. The filtrate was washed with 200 ml of a mixed solution of dichloromethane:ethyl acetate=2:1. The filtrate was concentrated under the reduced pressure to give 13.08 g of 7-iodo-5-methylimidazo[5,1-b]thiazole.
Reaction SMILES: O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.P([O-])([O-])([O-])=O.[Na+].[Na+].[Na+].Cl.[CH3:22][NH:23][CH:24]([CH3:33])[C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)=[O:26]>>[CH3:33][C@H:24]([NH:23][CH3:22])[C@@H:25]([OH:26])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CNC(C)C(=O)c1ccccc1
Agent: Cl
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Product: CN[C@@H](C)[C@@H](O)c1ccccc1
Temperature: 30 °C
Reaction time: 48 h

Procedure:
Microbacterium arborescens IFO 3750 was inoculated to a medium (5 ml) containing 1% glucose, 0.5% peptone, and 0.3% yeast extract, and shake-culturing was carried out at 30° C. for 48 hours. After the cultured solution was centrifuged to give bacterial cells, the cells were placed into a test tube. To this was added 0.1 M sodium phosphate buffer (pH 7.0, 1 ml) and suspended. To this was added dl-2-methylamino-1-phenyl-1-propanone hydrochloride (1 mg) and reaction was allowed to take place under shaking at 30° C. for 24 hours. After the reaction, the reaction solution was centrifuged to remove the bacterial cells and the supernatant was subjected to HPLC to give optically active pseudoephedrine: μ Bondapakphenyl manufactured by Waters Inc.; diameter of 4 mm; length of 300 mm; eluent-0.05 M sodium phosphate buffer (containing 7% acetonitrile); pH 5.0; flow rate of 0.8 ml/min; and detection light wavelength at 220 nm.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]([NH:11][C:12]2[N:17]=[C:16]([C:18]3[C:26]4[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=4)[N:20]([CH3:27])[CH:19]=3)[CH:15]=[CH:14][N:13]=2)=[C:4]([O:28][CH3:29])[CH:3]=1.Cl.Cl.[CH3:32][N:33]1[CH2:40][CH2:39][CH2:38][C:34]21[CH2:37][NH:36][CH2:35]2.CCN(C(C)C)C(C)C>CC(N(C)C)=O>[CH3:29][O:28][C:4]1[CH:3]=[C:2]([N:36]2[CH2:37][C:34]3([N:33]([CH3:32])[CH2:40][CH2:39][CH2:38]3)[CH2:35]2)[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][C:5]=1[NH:11][C:12]1[N:17]=[C:16]([C:18]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]([CH3:27])[CH:19]=2)[CH:15]=[CH:14][N:13]=1
Reactant: CN1CCCC12CNC2
Reactant: COc1cc(F)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Agent: Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(N2CC3(CCCN3C)C2)c([N+](=O)[O-])cc1Nc1nccc(-c2cn(C)c3ccccc23)n1
Temperature: 100 °C
Yield: 55 %

Procedure:
A mixture of N-(4-fluoro-2-methoxy-5-nitrophenyl)-4-(1-methylindol-3-yl)pyrimidin-2-amine (Intermediate 129, 300 mg, 0.76 mmol), 8-methyl-2,8-diazaspiro[3.4]octane (Intermediate 47, 115 mg, 0.92 mmol), DIPEA (0.158 mL, 0.92 mmol) and DMA (4 mL) was heated at 100° C. for 1 h. The mixture was then absorbed onto an SCX column, and the column was washed with CH3OH. The column was then eluted with 1:1 methanoic ammonia in CH2Cl2 and fractions containing the desired product were combined and concentrated in vacuo. Purification by FCC, eluting with 1.5% CH3OH in CH2Cl2 gave the title compound (209 mg, 55%) as an orange solid; 1H NMR: 1.71 (2H, dt), 2.00-2.10 (2H, m), 2.40 (3H, s), 2.67 (2H, t), 3.74 (2H, d), 3.88 (3H, s), 3.96 (3H, s), 4.11 (2H, d), 6.31 (1H, s), 7.12 (1H, t), 7.20 (1H, d), 7.25 (1H, dd), 7.52 (1H, d), 8.02 (1H, s), 8.28-8.34 (2H, m), 8.36 (1H, d), 8.63 (1H, s); m/z: ES+ MH+ 500.6.
Reaction SMILES: [BH3-]C#N.[Na+].[C:5]([O:9][C:10]([NH:12][N:13]=[C:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:18][CH:17]=1)[CH3:15])=[O:11])([CH3:8])([CH3:7])[CH3:6].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>C1COCC1.CCOC(C)=O.C(Cl)Cl>[CH2:25]([O:24][C:22]([C:19]1[CH:20]=[CH:21][C:16]([CH:14]([NH:13][NH:12][C:10]([O:9][C:5]([CH3:7])([CH3:6])[CH3:8])=[O:11])[CH3:15])=[CH:17][CH:18]=1)=[O:23])[CH3:26]
Reactant: CCOC(=O)c1ccc(C(C)=NNC(=O)OC(C)(C)C)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1ccc(C(C)NNC(=O)OC(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In a N2 filled round-bottomed flask equipped with serum caps and magnetic stirrer, NaBH3CN (6.0 g, 0.095 mol) and tert-butyl-2-{1-[4-(ethoxycarbonyl)phenyl]ethylidene}hydrazinecarboxylate (25.6 g, 0.084 mol) were dissolved in THF (200 mL). A solution of p-toluenesulfonic acid monohydrate (17.3 g, 0.091 mol) in THF (50 mL) was slowly added via syringe pump. Completion of addition required about 10 h. The mixture was diluted with EtOAc (200 mL) and the suspension extracted with brine (150 mL). The organic phase was separated, dried (Na2SO4) and concentrated on a rotovap to give white solid. The white solid was taken in CH2Cl2 (100 mL) and 1 N NaOH (100 mL) was added. The suspension was stirred vigorously at r.t. for 1 h and then diluted with CH2Cl2 (100 mL). The organic phase was separated and extracted with 1N HCl (2×150 mL), brine (2×150 mL), dried (Na2SO4) and concentrated to approximately 50 mL. Product precipitated as white solid and was collected by filtration and washed with hexane to yield tert-butyl 2-{1-[4-(ethoxycarbonyl)phenyl]ethyl}hydrazinecarboxylate. HPLC/MS: m/z=331.3 (M+Na)+, Rt=3.24 min. 1H NMR (500 MHz, CDCl3): δ 8.03 (2H, d, J=8.0 Hz), 7.44 (2H, d, J=8.0 Hz), 5.99 (1H, br s), 4.40 (2H, q, J=7.0 Hz), 4.29 (1H, m), 1.45 (9H, s), 1.41 (3H, t, J=7.0 Hz), 1.35 (3H, d, J=6.5 Hz).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8][CH2:7]2)([O-:3])=[O:2].Cl.Cl[CH2:17][CH2:18][N:19]([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:20][N:19]([CH3:21])[CH2:18][CH2:17][N:10]1[C:11]2[C:6](=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][CH:12]=2)[CH2:7][CH2:8][C:9]1=[O:14]
Reactant: CN(C)CCCl
Reactant: O=C1CCc2cc([N+](=O)[O-])ccc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CCN1C(=O)CCc2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 72 h
Yield: 73 %

Procedure:
A suspension of 6-nitro-3,4-dihydroquinolin-2(1H)-one (1.5 g, 7.80 mmol), 2-chloro-N,N-dimethylethanamine hydrochloride (2.25 g, 15.60 mmol) and potassium carbonate (6.47 g, 46.80 mmol) in 25 mL DMF was stirred at room temperature for 3 days. After this time, the mixture was poured into 20 mL H2O then extracted with 3×150 mL EtOAc. The combined organic fractions were washed with brine, dried over Na2SO4, filtered and concentrated. The residue was subjected to flash chromatography on silica gel using 5% 2M NH3 in MeOH/CH2Cl2 to give a yellow viscous oil (1.5 g, 73.2%). 1H-NMR (CDCl3) δ: 8.14 (dd, J=2.4, 9.0 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.15 (d, J=9.0 Hz, 1H), 4.09 (t, J=7.5 Hz, 2H), 3.03-2.98 (m, 2H), 2.73-2.68 (m, 2H), 2.51 (t, J=7.5 Hz, 2H), 2.31 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]([N:5]([CH2:15][CH:16]1[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18][CH2:17]1)[C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:4].FC(F)(F)C(O)=O>C(Cl)(Cl)Cl>[F:30][C:2]([F:1])([F:29])[C:3]([N:5]([C@@H:6]1[CH2:8][C@H:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:15][CH:16]1[CH2:17][CH2:18][NH:19][CH2:20][CH2:21]1)=[O:4]
Reactant: CC(C)(C)OC(=O)N1CCC(CN(C(=O)C(F)(F)F)[C@@H]2C[C@H]2c2ccccc2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: O=C(N(CC1CCNCC1)[C@@H]1C[C@H]1c1ccccc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.8 %

Procedure:
To the solution of tert-butyl 4-((2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)acetamido)methyl)piperidine-1-carboxylate (700 mg, 1.641 mmol) in chloroform (2 mL) was added trifluoroacetic acid (2 ml, 26.0 mmol). The reaction mixture was stirred at the room temperature for 1 hr. The reaction was evaporated, and then 2 ml of 1 M Na2CO3 (2 mL) were added followed by 10 mL of ethyl acetate. The organic layer was separated, washer with brine, dried over MgSO4, filtered and evaporated. 2,2,2-trifluoro-N-(trans-2-phenylcyclopropyl)-N-(piperidin-4-ylmethyl)acetamide (450 mg, 1.310 mmol, 80% yield) was isolated as yellow oil. 1H NMR (400 MHz, CHLOROFORM-d) δ 7.30-7.38 (m, 2H), 7.27 (d, J=7.33 Hz, 1.5H), 7.08 (d, J=7.33 Hz, 1.5H), 3.35-3.49 (m, 1.7H), 3.10-3.22 (m, 2H), 2.97-3.09 (m, 0.8H), 2.52-2.67 (m, 2H), 2.30-2.44 (m, 0.8H), 1.75-2.10 (m, 2.3H), 1.59-1.75 (m, 2.4H), 1.39-1.58 (m, 2H), 1.13-1.38 (m, 2.5H); LC-MS Rt=0.70 min; MS (ESI): 327.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27]C(OC(C)(C)C)=O)=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4NC(=O)OC(C)(C)C)cc3)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reaction time: 1 h

Procedure:
1-[4′-(4-tert-Butoxycarbonylamino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester (1.5 g, 3.2 mmol) in CH2Cl2 (10 mL) was treated with trifluoroacetic acid (4 mL), and the reaction was stirred for 1 hour. The mixture was neutralized and worked up to give the title compound.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[C@H:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C@:11]([C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)([C:21]#[N:22])[C@H:10]([C:30]([CH3:33])([CH3:32])[CH3:31])[NH:9]1)=[O:7])(C)(C)C.[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37]>ClCCl>[F:34][C:35]([F:40])([F:39])[C:36]([OH:38])=[O:37].[C:30]([CH:10]1[NH:9][CH:8]([C:6]([OH:7])=[O:5])[CH:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[F:20])[C:11]1([C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[C:21]#[N:22])([CH3:33])([CH3:31])[CH3:32]
Reactant: CC(C)(C)OC(=O)[C@@H]1N[C@@H](C(C)(C)C)[C@](C#N)(c2ccc(Cl)cc2)[C@H]1c1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)C1NC(C(=O)O)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1

Procedure:
In a manner similar to the method described in Example 25a, rac-(2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid tert-butyl ester prepared in Example 51b (0.3 g, 0.6 mmol) was reacted with trifluoroacetic acid in dichloromethane at room temperature to give rac-(2R,3S,4R,5S)-5-tert-Butyl-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-phenyl)-4-cyano-pyrrolidine-2-carboxylic acid trifluoroacetic acid as a off white solid (0.4 g, 100%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9](=[O:13])[CH2:10][CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[Cl:8].C(N(CC)CC)C.[C:21]([Si:25]([CH3:28])([CH3:27])Cl)([CH3:24])([CH3:23])[CH3:22].O>CN(C)C=O>[Si:25]([O:12][CH2:11][CH2:10][C:9]([C:4]1[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=1)=[O:13])([C:21]([CH3:24])([CH3:23])[CH3:22])([CH3:28])[CH3:27]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=C(CCO)c1ccc(Cl)c(Cl)c1
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(CC)CC
Product: CC(C)(C)[Si](C)(C)OCCC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.4 %

Procedure:
In 460 ml of dimethylformamide, 46.0 g (0.21 mole) of the 3-(3,4-dichlorophenyl)-3-oxo-1-propanol obtained in Referential Example 4(a) were dissolved, followed by the addition of 35 ml (0.25 mole) of triethylamine and 38.0 g (0.25 mole) of tert-butyldimethylchlorosilane under ice-cooling. The resulting mixture was stirred at 0° C. for 2 hours. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure to give a residue, which was purified by chromatography on a silica gel column (eluting solvent: n-hexane: ethyl acetate=96:4), whereby 66.1 g of the title compound were obtained as white crystals.
Reaction SMILES: [ClH:1].Cl.[NH2:3][CH:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][CH2:5]1.C(N(CC)CC)C.[O:32]1[C:37]2=[CH:38][N:39]=[C:40]([CH:42]=O)[CH:41]=[C:36]2[CH2:35][CH2:34][CH2:33]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C([O-])(O)=O.[Na+]>C(Cl)(Cl)Cl.CO>[ClH:1].[O:32]1[C:37]2=[CH:38][N:39]=[C:40]([CH2:42][NH:3][CH:4]3[CH2:5][CH2:6][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:24])[CH2:8][CH2:9]3)[CH:41]=[C:36]2[CH2:35][CH2:34][CH2:33]1
Reactant: O=Cc1cc2c(cn1)OCCC2
Reactant: COc1cnc2ccc(=O)n(CCN3CCC(N)CC3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: CO
Product: COc1cnc2ccc(=O)n(CCN3CCC(NCc4cc5c(cn4)OCCC5)CC3)c2c1
Yield: 75 %

Procedure:
A mixture of 1-[2-(4-amino-1-piperidinyl)ethyl]-7-(methyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (174 mg, 0.466 mmol) in chloroform (5 ml) and MeOH (0.1 ml) was treated with triethylamine (205 μl, 1.484 mmol) and stirred for 0.25 h before addition of 3,4-dihydro-2H-pyrano[2,3-c]pyridine-6-carbaldehyde (for a synthesis see WO2004058144, Example 126(e)) (69 mg, 0.424 mmol). The reaction was stirred for 0.5 h before addition of NaBH(OAc)3 (270 mg, 1.272 mmol). The reaction was stirred for 0.5 h before addition of sat. aq NaHCO3 (50 ml). The reaction was then extracted with 20% MeOH in DCM (3×200 ml). The combined organic phases were dried, evaporated and the crude residue purified by chromatography on silica gel using a 0-20% MeOH/DCM gradient to provide the free base of the title compound (157 mg, 75%).
Reaction SMILES: C(O[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([F:27])([F:26])[F:25])[CH2:10][CH2:9]1)=O)(C)(C)C.C=O.C(=O)([O-])O.[Na+]>C(O)=O>[CH3:6][N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[C:24]([F:25])([F:26])[F:27])[CH2:10][CH2:9]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=CO
Product: CN1CCC(Oc2ccc([N+](=O)[O-])cc2C(F)(F)F)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 95.3 %

Procedure:
To a suspension of 4-(1-t-butoxycarbonylpiperidin-4-yloxy)-3-trifluoromethylnitrobenzene (2.45 g) obtained in reference example 100 in 90% formic acid (8.80 g) was added 37% formaldehyde (5.50 g), and the resulting mixture was stirred at 100° C. for 6 hours. After cooling to room temperature, the reaction mixture was neutralized with an aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of dichloromethane and methanol (10:1) as the eluent to afford the title compound (1.82 g, yield: 95%) as a yellow oil.