Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH2:10][CH:11]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)[C:12]1=[O:22])[C:5]#N.[C:23]1([Mg]Br)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C1C[O:34]CC1>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH2:10][CH:11]2[CH2:15][CH2:14][N:13]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:12]2=[O:22])=[C:2]([Cl:1])[CH:3]=1)(=[O:34])[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: C1CCOC1
Reactant: N#Cc1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reactant: Br[Mg]c1ccccc1
Product: O=C(c1ccccc1)c1ccc(CC2CCN(C3CCCCC3)C2=O)c(Cl)c1
Reaction time: 24 h
Yield: 9 %

Procedure:
Dissolve 3-chloro-4-((1-cyclohexyl-2-oxopyrrolidin-3-yl)methyl)benzonitrile (0.20 g, 0.63 mmol) in THF (20 mL) under N2 and add phenylmagnesium bromide (0.63 mL, 0.63 mmol, 1.0 M in THF). Stir the reaction mixture for 24 hours until LC-MS shows the starting material has gone. Add saturated NH4Cl (20 mL) and extract the aqueous with EtOAc (3×50 mL). Combine the organic layers and dry with Na2SO4, filter, concentrate and purify by flash column chromatography (silica gel, 20-50% of EtOAc-Hexane) to give 0.023 g (9%) of the title compound as white solid: MS (APCI-pos mode) m/z (rel intensity) 396.3 (100), 398.2 (30).
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[N:13][CH:14]=[C:15]([C:18]=2[NH:19][C:20]2[C:21]([CH3:30])=[C:22]3[C:26](=[C:27]([Cl:29])[CH:28]=2)[NH:25][CH:24]=[CH:23]3)[C:16]#[N:17])=[CH:7][CH:6]=1.[CH3:31][N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>COCCOC>[Cl:29][C:27]1[CH:28]=[C:20]([NH:19][C:18]2[C:15]([C:16]#[N:17])=[CH:14][N:13]=[CH:12][C:11]=2[C:8]2[CH:7]=[CH:6][C:5]([O:4][CH2:3][CH2:2][N:35]3[CH2:36][CH2:37][N:32]([CH3:31])[CH2:33][CH2:34]3)=[CH:10][CH:9]=2)[C:21]([CH3:30])=[C:22]2[C:26]=1[NH:25][CH:24]=[CH:23]2
Reactant: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCCl)cc2)cc(Cl)c2[nH]ccc12
Reactant: CN1CCNCC1
Solvent: COCCOC
Product: Cc1c(Nc2c(C#N)cncc2-c2ccc(OCCN3CCN(C)CC3)cc2)cc(Cl)c2[nH]ccc12
Yield: 93.1 %

Procedure:
A solution of 5-[4-(2-chloroethoxy)phenyl]-4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]nicotinonitrile (144 mg, 0.3 mmol) and 1-methylpiperazine (330 mg, 3.3 mmol) in DME (3 mL) was stirred at 110° C. for 48 h. After the solution was concentrated, 1 N HCl was added and the aqueous phase was extracted with ethyl acetate, adjusted to pH of 10 by adding sodium carbonate, and extracted with ethyl acetate. The combined organic phases were washed with water and brine, dried over magnesium sulfate, and concentrated to give 4-[(7-chloro-4-methyl-1H-indol-5-yl)amino]-5-{4-[2-(4-methylpiperazin-1-yl)ethoxy]phenyl}nicotinonitrile as a yellow solid (140 mg, 84% yield). HPLC retention time: 5.1 min.(g); MS: 501.3 (M+H); and HRMS: 501.2159.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([NH2:12])=[S:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:14][C:15]([C:17]1[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=1)=O.O>CN(C=O)C>[CH2:1]([O:8][CH2:9][C:10]1[S:11][CH:14]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC(=S)COCc1ccccc1
Reactant: O=C(CBr)c1ccc(Cl)cc1
Solvent: CN(C)C=O
Solvent: O
Product: Clc1ccc(-c2csc(COCc3ccccc3)n2)cc1
Temperature: 130 °C
Yield: 49.2 %

Procedure:
To the solution of 2-Benzyloxy-thioacetamide (3.0 g, 16.57 mmol) in 3 ml of DMF was added 2-Bromo-1-(4-chloro-phenyl)-ethanone (3.0 g, 12.87 mmol). The reaction mixture was heated at 130° C. for 24 h under nitrogen atmosphere. After the completion of the reaction mixture (TLC monitoring), water (25 mL) was added and extracted with ethyl acetate (3×50 mL). The combined organics was washed with water, brine, dried (Na2SO4), filtered and concentrated. The crude residue was purified over silica gel (230-400 M, 2% EtOAc-Hexane) to get the desired product (2.0 g, 49%). The corresponding cyano derivative was also prepared by the same general method.
Reaction SMILES: [NH2:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1.CCN(CC)CC.[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28](Cl)=[O:29]>>[Br:23][CH2:24][CH2:25][CH2:26][CH2:27][C:28]([NH:1][CH:2]1[CH2:8][O:7][CH2:6][CH2:5][N:4]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:3]1)=[O:29]
Reactant: O=C(Cl)CCCCBr
Reactant: CC(C)(C)OC(=O)N1CCOCC(N)C1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N1CCOCC(NC(=O)CCCCBr)C1
Reaction time: 1 h

Procedure:
To an ice bath stirring solution of tert-butyl 6-amino-1,4-oxazepane-4-carboxylate 38.4 (1.01 g, 4.67 mmol) and Et3N (1.95 mL, 14.0 mmol) was added 5-bromo-pentanoyl chloride (0.62 mL, 4.7 mmol). The ice bath was removed and the solution was stirring for 1 h and then diluted with water and extracted with DCM. The organic phase was washed with diluted citric acid, water, sat. NaHCO3, dried (MgSO4), filtered and concentrated in vacuo to afford an oil which was purification by flash column chromatography (gradient EtOAc/hexanes). LCMS m/z 324.1 & 325.1 [M−tBu]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[C:4]([Cl:9])[N:3]=1.C(N(CC)CC)C.[CH3:17][C:18]([CH3:23])([CH3:22])[C:19](Cl)=[O:20]>ClCCl>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:19](=[O:20])[C:18]([CH3:23])([CH3:22])[CH3:17])[CH:5]=[C:4]([Cl:9])[N:3]=1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Nc1cc(Cl)nc(Cl)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)C(=O)Nc1cc(Cl)nc(Cl)c1
Yield: 76.5 %

Procedure:
2,6-Dichloro-4-pyridinamine (10 g, 61.3 mmol) (Aldrich) and triethylamine (10.69 ml, 77 mmol) were combined in dichloromethane (DCM) (75 ml) and cooled in an ice-bath. 2,2-dimethylpropanoyl chloride (8.30 ml, 67.5 mmol) (Aldrich) in DCM (15 ml) was added drop wise and the mixture stirred whilst allowing to warm up overnight producing a clear dark orange solution. LCMS showed good conversion to product. The solution was washed with water and sat. NaHCO3 (100 ml each), dried with Na2SO4, filtered and concentrated to yield a dark orange solid. The crude product was taken up in the minimum of DCM and applied to a 320 g Companion XL silica column and eluted with 0% EtOAc in cyclohexane for 2 CVs then 0-15% EtOAc in cyclohexane over 12 CVs then held at 15% for 2 CV. Appropriate fractions were combined and evaporated to give the title compound as a yellow solid (11.59 g).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6](=[O:37])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])=[CH:14][CH:15]=2)[C:10]([CH2:35][CH3:36])=[CH:9]1)C.C(OCC)C>C1COCC1>[CH2:35]([C:10]1[C:11]2[C:16](=[CH:15][CH:14]=[C:13]([O:17][CH2:18][C:19]3[S:23][C:22]([C:24]4[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][CH:25]=4)=[N:21][C:20]=3[CH3:34])[CH:12]=2)[N:8]([CH2:7][C:6]([OH:37])=[O:5])[CH:9]=1)[CH3:36]
Reactant: CCOC(=O)Cn1cc(CC)c2cc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)ccc21
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCc1cn(CC(=O)O)c2ccc(OCc3sc(-c4ccc(C(F)(F)F)cc4)nc3C)cc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
A 1 M aqueous solution of LiOH (2.3 ml, 2.3 mmol) was added to a solution of {3-ethyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid ethyl ester (577 mg, 1.15 mmol) in THF (6 ml). After stirring for 1 h at ambient temperature, additional 0.58 ml of the 1N LiOH solution were added and the reaction mixture was stirred for further 2.5 h. Diethyl ether (10 ml) was added, the resulting precipitate was filtered off and redissolved in ethyl acetate and 25% aqueous HCl solution (2 ml). The organic layer was washed with water and dried over sodium sulfate. Removal of the solvent under reduced pressure gave 365 mg (0.77 mmol, 67%) {3-ethyl-5-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[NH:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:39])([F:38])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:7]=[N:8][C:9]=1[O:10]CC1C=CC(OC)=CC=1)[CH3:2].C(Cl)[Cl:44].O.C(#N)C>C(O)(C(F)(F)F)=O>[ClH:44].[CH2:1]([O:3][C:4]1[C:9](=[O:10])[NH:8][CH:7]=[C:6]([C:20]2[CH:25]=[CH:24][C:23]([CH2:26][C:27]([NH:29][C:30]3[NH:34][N:33]=[C:32]([C:35]([CH3:41])([CH3:40])[C:36]([F:38])([F:39])[F:37])[CH:31]=3)=[O:28])=[C:22]([F:42])[CH:21]=2)[CH:5]=1)[CH3:2]
Reactant: ClCCl
Reactant: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)n[nH]3)c(F)c2)cnc1OCc1ccc(OC)cc1
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCOc1cc(-c2ccc(CC(=O)Nc3cc(C(C)(C)C(F)(F)F)n[nH]3)c(F)c2)c[nH]c1=O
Product: Cl
Yield: 49.2 %

Procedure:
A mixture of 2-(4-(5-ethoxy-6-((4-methoxybenzyl)oxy)pyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide (100 mg, 0.170 mmol) in TFA.DCM (solvate) (10 mL, 10%) was stirred for 0.5 h at 25° C. Then the mixture was concentrated to give a residue which purified by preparative HPLC (column: ASB C18 150*25 mm/Mobile phase A: Water(Water+0.1% HCl)/Mobile phaseB: Acetonitrile/Gradient: 33-63 (B %)/Flowrate: 25 mL/min/Run time: 15 min) to yield a white solid of 2-(4-(5-ethoxy-6-oxo-1,6-dihydropyridin-3-yl)-2-fluorophenyl)-N-(3-(1,1,1-trifluoro-2-methylpropan-2-yl)-1H-pyrazol-5-yl)acetamide hydrochloride (43.33 mg, 0.084 mmol, 49.2% yield): 1H NMR (400 MHz, DMSO-d6) δ 11.81 (s, 1H), 10.68 (s, 1H), 7.46-7.28 (m, 5H), 7.11 (d, J=2.0 Hz, 1H), 6.41 (s, 1H), 4.03 (q, J=6.8 Hz, 2H), 3.66 (s, 2H), 1.45 (s, 6H), 1.32 (t, J=6.9 Hz, 3H). ES-LCMS m/z 467 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)=[CH:9][C:3]=1[C:4]([O:6]CC)=[O:5].O.[OH-].[Li+].C(O)C.O.O1CCCC1>O>[Cl:1][C:2]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:17][CH2:16][CH:15]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:14]2)=[CH:9][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCOC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)C2)ccc1Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NC1CCN(c2ccc(Cl)c(C(=O)O)c2)C1
Yield: 99.6 %

Procedure:
Prepared as described in Example 5b) using (+/−)-2-chloro-5-[3-[[(1,1-dimethylethoxy)carbonyl]amino]-1-pyrrolidinyl]-benzoic acid, ethyl ester (Example 7a, 0.25 g), lithium hydroxide monohydrate (1.36 ml of a 3M solution in water), 1:1 ethanol/water (7 ml) and tetrahydrofuran (1 ml) to give the subtitle compound as a solid (0.23 g).
Reaction SMILES: [C:1]([NH2:9])(=[S:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:10][CH2:11][C:12]([CH2:14]Cl)=O>CO>[Cl:10][CH2:11][C:12]1[N:9]=[C:1]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[S:8][CH:14]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=S)c1ccccc1
Solvent: CO
Product: ClCc1csc(-c2ccccc2)n1
Temperature: 25 °C
Yield: 57 %

Procedure:
2.33 g of thiobenzamide was dissolved in 20 ml of dry methanol, and 2.16 g of 1,3-dichloroacetone was added thereto at room temperature and then heated under reflux for 1 hour. The solvent was distilled off under reduced pressure, and ice water was added to the remaining product, which was then neutralized with an aqueous solution of sodium hydrogen carbonate. The resulting product was extracted with ethyl acetate, washed with saturated saline, and dried over sodium sulfate, and the solvent was distilled off under reduced pressure. The residual product was purified through silica gel column chromatography to obtain 2.03 g of 4-chloromethyl-2-phenylthiazole, was obtained from the fraction eluted with chloroform/n-hexane=1/2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9].[CH:19]1(B(O)O)[CH2:21][CH2:20]1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1>[CH:19]1([C:4]2[CH:5]=[CH:6][C:7]([N+:8]([O-:10])=[O:9])=[C:2]([F:1])[CH:3]=2)[CH2:21][CH2:20]1
Reactant: OB(O)C1CC1
Reactant: O=[N+]([O-])c1ccc(OS(=O)(=O)C(F)(F)F)cc1F
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: Cc1ccccc1
Product: O=[N+]([O-])c1ccc(C2CC2)cc1F
Temperature: 90 °C
Yield: 81.1 %

Procedure:
A stirred suspension of trifluoro-methanesulfonic acid 3-fluoro-4-nitro-phenyl ester (5.6 g, 19 mmol), cyclopropyl boronic acid (2.09 g, 23.3 mmol) Pd(dppf)Cl2 (1.24 g, 1.5 mmol) and 2M aqueous cesium carbonate (30 mL, 60 mmol) in toluene (20 mL) was degassed before being heated at 90° C. under an argon atmosphere for 2.5 hours. The reaction mixture was allowed to cool to room temperature before filtering through a pad of Celite®, washing with ethyl acetate. The filtrate was washed (water, brine), and then dried (MgSO4), filtered and concentrated in vacuo. The resultant residue was subjected to flash chromatography (Si-PPC, gradient 0-30% ethyl acetate in pentane) to give the title compound as a yellow solid (2.79 g, 81%). 1H NMR (DMSO-d6, 400 MHz) 8.03 (1 H, t, J=8.39 Hz), 7.28 (1 H, dd, J=13.19, 1.91 Hz), 7.16 (1 H, dd, J=8.61, 1.90 Hz), 2.14-2.05 (1 H, m), 1.21-1.05 (2 H, m), 0.92-0.82 (2 H, m).
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][C:7](=O)[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C1(C)C=CC=CC=1.[NH:18]1[CH2:22][CH2:21][CH2:20][CH2:19]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O.C1C=CC=CC=1>[N:18]1([C:7]2[CH2:6][CH2:5][N:4]([C:1](=[O:3])[CH3:2])[CH2:9][CH:8]=2)[CH2:22][CH2:21][CH2:20][CH2:19]1
Reactant: C1CCNC1
Reactant: CC(=O)N1CCC(=O)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CC(=O)N1CC=C(N2CCCC2)CC1

Procedure:
In stage 1, the compound 1-acetyl-4-piperidinone is reacted in a reaction medium, preferably selected from the group consisting of toluene and benzene, with pyrrolidine in the presence of a catalytic quantity of an acid, preferably in the presence of p-toluenesulfonic acid, with refluxing on a water separator to yield the compound 1-(4-pyrrolidin-1-yl-3,6-dihydro-2H-pyridin-1-yl)-ethanone (A).
Reaction SMILES: [H-].[Na+].Cl[CH2:4][CH2:5][S:6](Cl)(=[O:8])=[O:7].[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]([NH2:28])=[N:24][CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2>C1COCC1>[CH3:10][O:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][CH:21]=1)[CH:18]=[C:17]([C:22]1[C:23]3=[N:28][S:6](=[O:8])(=[O:7])[CH2:5][CH2:4][N:24]3[CH:25]=[CH:26][CH:27]=1)[CH:16]=[CH:15]2
Reactant: COc1ccc2cc(-c3cccnc3N)ccc2c1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2cc(C3=CC=CN4CCS(=O)(=O)N=C34)ccc2c1
Reaction time: 0.08 h

Procedure:
To a suspension of NaH (60%, 951 mg) in THF (dry) (40 ml) was added 2-chloroethanesulfonyl chloride (1.50 ml) at 0° C. and the mixture was stirred for 5 min at the same temperature. A solution of 3-(6-methoxynaphthalen-2-yl)pyridin-2-amine (1190 mg) in THF (dry) (25 mL) was added at 0° C. and the mixture was stirred at room temperature overnight. The mixture was quenched with water. Water and EtOAc were added and the precipitates were collected, washed with water/EtOAc, dried in vacuo to give the title compound (835.3 mg). A part of this was recrystallized from MeCN-THF/IPE.
Reaction SMILES: CS(O[CH2:6][CH:7]([N:9]1[C:17]2[C:12](=[C:13]([C:20]([F:23])([F:22])[F:21])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2)[CH:11]=[C:10]1[CH3:24])[CH3:8])(=O)=O.[CH3:25][S-:26].[Na+]>CN(C=O)C.O>[CH3:24][C:10]1[N:9]([CH:7]([CH3:8])[CH2:6][S:26][CH3:25])[C:17]2[C:12]([CH:11]=1)=[C:13]([C:20]([F:21])([F:23])[F:22])[C:14]([C:18]#[N:19])=[CH:15][CH:16]=2
Reactant: C[S-]
Reactant: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)COS(C)(=O)=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CSCC(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Reaction time: 1.5 h
Yield: 74.9 %

Procedure:
To a solution of 2-(5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl)propyl methanesulfonate (0.145 g, 0.402 mmol) in DMF (3 mL) was added sodium thiomethoxide (0.056 g, 0.805 mmol) in one portion. After 90 min, additional sodium thiomethoxide (2 eq) was added, and the mixture stirred for another 1 h. The reaction mixture was diluted with water (25 mL) and extracted with EtOAc (30 mL). The organic phase was washed with 0.1N HCl (1×20 mL) and brine, dried over Na2SO4, filtered and concentrated. The residue was chromatographed over silica gel using a 0-30% EtOAc-hexane gradient to give 2-methyl-1-(1-(methylthio)propan-2-yl)-4-(trifluoromethyl)-1H-indole-5-carbonitrile (0.094 g, 71% yield) as a colorless oil: MS (ESI): m/z 313 (MH+).
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:7]1[N:8]=[C:9]([N:15]2[CH2:18][CH:17]([NH:19][C:20]([C:22]3[NH:23][C:24]([CH2:28][CH3:29])=[C:25]([Cl:27])[N:26]=3)=[O:21])[CH2:16]2)[S:10][C:11]=1[C:12]([OH:14])=[O:13])[CH2:4][CH2:5]C.O>CO.C1COCC1>[Cl:27][C:25]1[N:26]=[C:22]([C:20]([NH:19][CH:17]2[CH2:16][N:15]([C:9]3[S:10][C:11]([C:12]([OH:14])=[O:13])=[C:7]([CH2:3][CH2:4][CH3:5])[N:8]=3)[CH2:18]2)=[O:21])[NH:23][C:24]=1[CH2:28][CH3:29]
Reactant: CCCCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCCc1nc(N2CC(NC(=O)c3nc(Cl)c(CC)[nH]3)C2)sc1C(=O)O
Reaction time: 18 h
Yield: 36.2 %

Procedure:
A 2 N aqueous lithium hydroxide solution (1.53 mL, 3.07 mmol) was added to a mixed solution of ethyl 4-n-butyl-2-(3-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl)]amino}azetidin-1-yl-1,3-thiazole-5-carboxylate obtained in Example (220d) (214 mg, 0.50 mmol) in methanol/THF (3 mL/0.5 mL) at room temperature, followed by stirring for 18 hours. Water was added to the reaction solution, and then the mixture was washed with ethyl acetate. A 1 N aqueous hydrochloric acid solution (2.5 mL) was added to the aqueous layer. The precipitated solid was collected by filtration to obtain 72 mg of the title compound as a white solid (57%).
Reaction SMILES: [C:1]12([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH2:2]1)[CH2:8]2.[C:18]([O:22][CH3:23])(=[O:21])[C:19]#[CH:20].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>C1(C)C=CC=CC=1>[CH3:23][O:22][C:18](=[O:21])/[CH:19]=[CH:20]/[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:1]23[CH2:8][CH:7]4[CH2:9][CH:3]([CH2:4][CH:5]([CH2:6]4)[CH2:10]2)[CH2:2]3)=[CH:16][CH:15]=1
Reactant: Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Reactant: C#CC(=O)OC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)/C=C/Oc1ccc(C23CC4CC(CC(C4)C2)C3)cc1
Temperature: 115 °C
Yield: 90.6 %

Procedure:
4-(Adamantan-1-yl)-phenol (1.0 mg, 4.38 mmol) and methyl propiolate (737 mg, 0.74 ml, 8.76 mmol) were dissolved in 25 ml of toluene, to which Ph3P (1.15 g, 4.38 mmol) was added, followed by reflux at 115° C. for 3 hours. The reaction solution was concentrated and extracted with EtoAC and NaCl solution. The organic layer was dried over anhydrous MgSO4, and concentrated. The residue was purified by silica gel column chromatography (n-Hexane:EtOAc=50:1) to give the target compound as a white solid (1.24 g, yield: 90.6%).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH:9]2[CH2:10][CH2:11][N:6]([CH2:7][CH2:8]2)[CH2:5]1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1[C:17]([NH:19][C:20](N)=[O:21])=[O:18].C(N(C(C)C)CC)(C)C.C([O-])(=O)/C=C\C([O-])=O>N1C=CC=CC=1>[N:6]12[CH2:11][CH2:10][CH:9]([CH2:8][CH2:7]1)[CH:4]([NH:3][C:20]([NH:19][C:17]([C:13]1[S:12][CH:16]=[CH:15][CH:14]=1)=[O:18])=[O:21])[CH2:5]2
Reactant: NC1CN2CCC1CC2
Reactant: NC(=O)NC(=O)c1cccs1
Agent: Cl
Agent: O=C([O-])/C=C\C(=O)[O-]
Solvent: CCN(C(C)C)C(C)C
Solvent: c1ccncc1
Product: O=C(NC(=O)c1cccs1)NC1CN2CCC1CC2

Procedure:
The above compound was prepared, following the procedure of Example 14b, from 3-aminoquinuclidine dihydrochloride (1.0 g, 5 mmol), 2-thienoylurea (0.85 g, 5 mmol) and diisopropylethylamine (1.3 g, 10 mmol) in pyridine (20 ml). The product (0.79 g) was converted to hydrochloride half hydrate, mp 232°-233° C.
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3]C.[CH:6]([C@H:8]1[CH2:24][N:12]2[CH2:13][CH2:14][N:15]([C:17]3[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=3)[CH2:16][C@@H:11]2[CH2:10][CH2:9]1)=O.[CH2:25]1[CH2:29]O[CH2:27][CH2:26]1>[Cl-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>[C:25]1([CH:29]=[CH:6][CH:8]2[CH2:24][N:12]3[CH2:13][CH2:14][N:15]([C:17]4[N:22]=[CH:21][C:20]([F:23])=[CH:19][N:18]=4)[CH2:16][CH:11]3[CH2:10][CH2:9]2)[CH:3]=[CH:2][CH:1]=[CH:27][CH:26]=1
Reactant: [Li]CCCC
Reactant: O=C[C@@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Reactant: C1CCOC1
Agent: [Cl-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: Fc1cnc(N2CCN3CC(C=Cc4ccccc4)CCC3C2)nc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of 1.70 g (4.38 mmol) of benzyl triphenyl phosphonium chloride in 20 mL of dry THF was chilled to −78° C. and treated with 1.75 mL (4.38 mmol) of n-butyllithium (2.5 M in hexane). After 15 min, 1.05 g (3.98 mmol) of (7R,9aS)-7-formyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine in 20 mL of dry THF was added dropwise over 30 min, the cooling bath was removed and the solution allowed to warm slowly to ambient temperature overnight (16 h). The solution was concentrated in vacuo and the residue was partitioned between ethyl ether and water. The organic layer was dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with petroleum ether:ethyl ether in ratios from 4:1 to 3:1 gave the following isomers of 7-(2-phenyl)ethenyl-2-(5-fluoropyrimidin-2-yl)-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine: E-(7S,9aS), 0.19 g (Rf=0.75 with 3:1 hexane:ethyl acetate); Z-(7R,9aS), 0.16 g (Rf=0.47 with 3:1 hexane:ethyl acetate); E-(7R,9aS), 0.46 g (Rf=23 with 3:1 hexane:ethyl acetate).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13]([OH:15])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.[CH2:40]([O:47][CH2:48][C@@H:49]([NH:66][CH3:67])[C:50]([N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)=[O:51])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]([CH3:17])([CH3:16])[CH2:10]/[CH:11]=[CH:12]/[C:13](=[O:15])[N:66]([C@@H:49]([C:50](=[O:51])[N:52]([CH3:65])[C@@H:53]([C:61](=[O:64])[NH:62][CH3:63])[CH2:54][C:55]1[CH:60]=[CH:59][CH:58]=[CH:57][CH:56]=1)[CH2:48][O:47][CH2:40][C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)[CH3:67])([CH3:2])([CH3:3])[CH3:4]
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Reactant: CC(C)(C/C=C/C(=O)O)NC(=O)OC(C)(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 102.7 %

Procedure:
(2E)-5-(tert-Butyloxycarbonylamino)-5-methylhex-2-enoic acid (0.12 g; 0.49 mmol) was dissolved in methylene chloride (10 mL). 1-Hydroxy-7-azabenzotriazole (0.07 g; 0.49 mmol) and N-(3-dimethylaminopropyl)-N'-ethylcarbodiimide hydrochloride (0.1 g; 0.51 mmol) were added and the reaction mixture was stirred for 15 min at room temperature. (2R)-3-Benzyloxy-N-methyl-2-(methyl-amino)-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)-propionamide (0.17 g; 0.44 mmol) and diisopropylethylamine (0.084 mL; 0.49 mmol) were added and the reaction mixture was stirred for 12 hours at room temperature. The reaction mixture was extracted with an aqueous solution of sodium hydrogen carbonate (saturated; 30 mL) and an aqueous solution of sodium hydrogen sulfate (10%; 30 mL) and dried (magnesium sulfate). The solvent was removed in vacuo and the residue was chromatographed on silica (2.5×30 cm) using methylene chloride/ethyl acetate (1:1) as eluent to afford 0.275 g of ((3E)-4-(N-((1R)-2-benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester.