Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6](S(C)=O)[C:5]([C:11]#[N:12])=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[N:3]=1.[OH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1.C1CCN2C(=NCCC2)CC1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([C:13]2[O:14][C:15]([CH3:18])=[CH:16][CH:17]=2)[C:5]([C:11]#[N:12])=[C:6]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:7]=1
Reactant: OCc1ccccn1
Reactant: Cc1ccc(-c2nc(N)nc(S(C)=O)c2C#N)o1
Solvent: COCCOC
Solvent: C1CCC2=NCCCN2CC1
Product: Cc1ccc(-c2nc(N)nc(OCc3ccccn3)c2C#N)o1

Procedure:
From 2-amino-4-methanesulfinyl-6-(5-methyl-furan-2-yl)-pyrimidine-5-carbonitrile, 2-(hydroxymethyl)pyridine and DBU in DME. ES-MS m/e (%): 308 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][C:3]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[O-]S([O-])(=O)=O.[Mg+2]>O1CCCC1>[CH3:1][C:2]1([CH3:22])[C:10]2[C:5](=[N:6][CH:7]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:18])[F:19])=[CH:13][CH:12]=3)[CH:9]=2)[NH:4][CH2:3]1
Reactant: CC1(C)C(=O)Nc2ncc(-c3ccc(C(F)(F)F)cc3)cc21
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)CNc2ncc(-c3ccc(C(F)(F)F)cc3)cc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.6 %

Procedure:
1.33 g 3,3-Dimethyl-5-(4-trifluoromethyl-phenyl)-1,3-dihydro-pyrrolo[2,3-b]pyridin-2-one were dissolved in 50 ml tetrahydrofuran. 330 mg lithium aluminiumhydride were added and the reaction mixture stirred for one hour at room temperature. Then 330 mg lithium aluminiumhydride were added and the reaction mixture stirred for two hours at room temperature. Then 330 mg lithium aluminiumhydride were added and the reaction mixture stirred for four hours at 50° C. Then 1 ml water was added to the cooled reaction mixture. Then 1 g MgSO4 were added followed by 3 g isolute. The solvent was removed in vacuo and the residue purified by chromatography on silica gel to obtain 490 mg 3,3-Dimethyl-5-(4-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: CN1CCCC1.[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29](=O)[O:30]C(C)=C.Cl.[F:36][C:37]([F:45])([F:44])[C:38]([CH3:43])([CH3:42])[CH2:39][CH2:40][NH2:41]>C1COCC1.CCOC(C)=O>[F:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]2[C:26]([CH3:27])=[N:25][C:18]3[N:19]=[C:20]([S:23][CH3:24])[N:21]=[CH:22][C:17]=3[CH:16]=2)=[CH:10][C:9]=1[NH:28][C:29]([NH:41][CH2:40][CH2:39][C:38]([CH3:43])([CH3:42])[C:37]([F:45])([F:44])[F:36])=[O:30]
Reactant: C=C(C)OC(=O)Nc1cc(-c2cc3cnc(SC)nc3nc2C)c(C)cc1F
Reactant: CC(C)(CCN)C(F)(F)F
Agent: CN1CCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CSc1ncc2cc(-c3cc(NC(=O)NCCC(C)(C)C(F)(F)F)c(F)cc3C)c(C)nc2n1
Temperature: 65 °C
Yield: 75.1 %

Procedure:
Add 1-methylpyrrolidine (1.214 mL, 11.54 mmol) in a mixture of prop-1-en-2-yl (2-fluoro-4-methyl-5-(7-methyl-2-(methylthio)pyrido[2,3-d]pyrimidin-6-yl)phenyl)carbamate (0.92 g, 2.31 mmol) and 4,4,4-trifluoro-3,3-dimethylbutan-1-amine hydrochloride (0.487 g, 2.54 mmol) in THF (23 mL) and heat at 65° C. for 4 h. Cool the mixture to RT, dilute with EtOAc, wash with brine (2×), dry over MgSO4, concentrate to dryness and purify via silica gel chromatography (0-50% EtOAc/Hexanes) to afford the title compound (860 mg, 75% yield). MS (m/z): 496.2 (M+1).
Reaction SMILES: [H-].[Na+].[CH3:3]CCCCC.CI.[OH:11][C@@H:12]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C@@H:13]([CH3:16])[CH:14]=[CH2:15]>CN(C)C=O>[CH3:3][O:11][C@@H:12]([C@@H:17]1[CH2:21][CH2:20][CH2:19][N:18]1[C:22]([O:24][C:25]([CH3:27])([CH3:26])[CH3:28])=[O:23])[C@@H:13]([CH3:16])[CH:14]=[CH2:15]
Reactant: CCCCCC
Reactant: C=C[C@H](C)[C@@H](O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CI
Product: C=C[C@H](C)[C@@H](OC)[C@@H]1CCCN1C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 73 %

Procedure:
Sodium hydride (60% in mineral oil, 3.38 g, 84.4 mmol, 1.1 eq.) was combined with hexane (40 mL), and the mixture was subjected to rapid mechanical stirring for 5 minutes. The solids were allowed to settle and the hexane was removed. This procedure was repeated twice to remove mineral oil. N,N-Dimethylformamide (59 mL, 1.3 M) was added and the mixture was cooled to 0° C.; methyl iodide (5 mL; 81 mmol, 1.05 eq.) was then added drop-wise, followed by drop-wise addition of a solution of #9 (19.6 g, 76.8 mmol, 1 eq.) in N,N-dimethylformamide (59 mL) over 5 minutes, while keeping the temperature between 0° C. and 5° C. The reaction was stirred at 0° C. for 2 hours. The reaction was quenched with saturated aqueous ammonium chloride solution (150 mL), poured into aqueous sodium chloride solution (5% wt, 300 mL), and the mixture was extracted with ethyl acetate (3×50 mL). The combined organic layers were washed with 10% aqueous sodium chloride solution (2×300 mL), washed with water (200 mL), and concentrated in vacuo. The resulting water-wet oil was reconcentrated from ethyl acetate (150 mL) and purified by silica gel chromatography (Gradient: 2% to 10% ethyl acetate in heptane) to afford #10 (15.0 g, 73%) as a colorless oil. 1H NMR (400 MHz, CDCl3), presumed to be a mixture of rotamers: δ 5.60-5.83 (m, 1H), 4.91-5.06 (m, 2H), 3.81-3.95 (br m, 1H), 3.43 (s, 3H), 3.36-3.61 (m, 2H), 3.19-3.31 (m, 1H), 2.09-2.21 (m, 1H), 1.86-2.02 (br m, 2H), 1.62-1.85 (br m, 2H), 1.47 and 1.49 (2 s, total 9H), 1.09 (d, J=6.6 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]([CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:12]=1)C(=O)OC(C)(C)C.C(OCC)(=O)C.[ClH:36]>CO>[ClH:36].[CH3:1][NH:2][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[CH:20]=[CH:19][S:18][CH:17]=2)[N:13]([S:21]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH:12]=1
Reactant: CN(Cc1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CO
Product: CNCc1cc(-c2ccsc2)n(S(=O)(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 71 %

Procedure:
To a solution of tert-butyl methyl{[1-(phenylsulfonyl)-5-(3-thienyl)-1H-pyrrol-3-yl]methyl}carbamate (0.62 g) in methanol (10 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 3 hr. Activated carbon was added to the reaction mixture, the mixture was filtrated, and the filtrate was concentrated under reduced pressure. The residue was recrystallized from ethanol to give the title compound as a colorless solid (yield 0.38 g, 71%).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([Cl:8])[C:5]([OH:9])=[C:4]([Cl:10])[N:3]=1.[CH2:11]([O:13][C:14](=[O:18])[C@H:15](O)[CH3:16])[CH3:12].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCOCC1>[CH2:11]([O:13][C:14](=[O:18])[C@H:15]([O:9][C:5]1[C:4]([Cl:10])=[N:3][C:2]([Cl:1])=[N:7][C:6]=1[Cl:8])[CH3:16])[CH3:12]
Reactant: CCOC(=O)[C@@H](C)O
Reactant: Oc1c(Cl)nc(Cl)nc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CCOC(=O)[C@@H](C)Oc1c(Cl)nc(Cl)nc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 57.9 %

Procedure:
A mixture of 2,4,6-trichloro-pyrimidin-5-ol (600 mg, 3.01 mmol), (R)-2-hydroxy-propionic acid ethyl ester (411 μL, 3.60 mmol), triphenylphosphine (906 mg, 3.45 mmol) and DIAD (678 μL, 3.45 mmol) in dioxane (5 mL) was stirred at RT for 18 hours before being concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, gradient 0-25% ethyl acetate in cyclohexane) affording (R)-2-(2,4,6-Trichloro-pyrimidin-5-yloxy)-propionic acid ethyl ester (522 mg, 52%). 1H NMR (400 MHz, CDCl3): δ 4.30-4.16 (2H, m), 4.12 (1H, q, J=7.14 Hz), 1.70 (3H, d, J=6.78 Hz), 1.29 (3H, t, J=7.19 Hz).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([O:18]CC)=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:28])([F:27])[F:26])[N:3]=1.[Li+].[OH-]>>[NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:22][CH2:21][C:11]3([CH2:15][NH:14][C@H:13]([C:16]([OH:18])=[O:17])[CH2:12]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([O:23][C@H:24]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][C:30]=2[N:36]2[CH:40]=[CH:39][C:38]([CH3:41])=[N:37]2)[C:25]([F:26])([F:28])[F:27])[N:3]=1
Reactant: CCOC(=O)[C@@H]1CC2(CCN(c3cc(O[C@H](c4ccc(Cl)cc4-n4ccc(C)n4)C(F)(F)F)nc(N)n3)CC2)CN1
Agent: [Li+]
Agent: [OH-]
Product: Cc1ccn(-c2cc(Cl)ccc2[C@@H](Oc2cc(N3CCC4(CC3)CN[C@H](C(=O)O)C4)nc(N)n2)C(F)(F)F)n1

Procedure:
Hydrolysis of (S)-ethyl 8-(2-amino-6-((R)-1-(4-chloro-2-(3-methyl-1H-pyrazol-1-yl)phenyl)-2,2,2-trifluoroethoxy)pyrimidin-4-yl)-2,8-diazaspiro[4.5]decane-3-carboxylate using the LiOH general method provided the title compound as an off-white solid.
Reaction SMILES: [CH3:1][Li].[C:3]1([CH2:9][O:10][NH:11][C:12]2([CH3:30])[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:15]=[CH:14][C:13]2=3)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1>O1CCCC1>[C:3]1([CH2:9][O:10][N:11]([CH3:1])[C:12]2([CH3:30])[CH2:21][CH2:20][CH2:19][C:18]3[N:17]=[C:16]([O:22][CH2:23][C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[CH:15]=[CH:14][C:13]2=3)[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: [Li]C
Reactant: CC1(NOCc2ccccc2)CCCc2nc(OCc3ccccc3)ccc21
Solvent: C1CCOC1
Product: CN(OCc1ccccc1)C1(C)CCCc2nc(OCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Methyllithium (1.4M in diethyl ether, 37.7 ml) was added dropwise over 20 min to a solution of N,2-bis(phenylmethoxy)-5,6,7,8-tetrahydro-5-methyl-5-quinolinamine (18.1 g) and tetrahydrofuran (20 ml) at -78° C. The mixture was allowed to warm to room temperature over 2 hrs and was stirred at room temperature for an additional 1 hr. The solution was quenched with saturated ammonium chloride solution and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over anhydrous potassium carbonate, filtered, and the filtrate was concentrated. The residue was purified by high performance liquid chromatography (silica gel, elution with ethyl acetate-hexanes) to provide 12.3 g (65%) of product.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[NH:16][C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]2[S:45][CH:46]=[CH:47][CH:48]=2)=[CH:34][CH:33]=1>CN(C)C=O.C(OCC)(=O)C>[C:1]([O:5][C:6]([NH:8][C:9]([CH3:27])([CH3:26])[CH2:10][C:11]([NH:13][C@@H:14]1[CH2:20][CH2:19][C:18]2[CH:21]=[CH:22][CH:23]=[CH:24][C:17]=2[N:16]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[S:45][CH:46]=[CH:47][CH:48]=3)=[CH:36][CH:37]=2)[C:15]1=[O:25])=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccc(-c2ccccc2-c2cccs2)cc1
Reactant: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2NC1=O)NC(=O)OC(C)(C)C
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(CC(=O)N[C@@H]1CCc2ccccc2N(Cc2ccc(-c3ccccc3-c3cccs3)cc2)C1=O)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 174 mg (0.465 mmol) of 3-t-butoxycarbonylamino-3-methyl-N-[2,3,4,5-tetrahydro-2oxo-1H-1-benzazepin-3(R)-yl]-butanamide (Example 1, Step I) in 3.0 mL of dry dimethylformamide was treated with 22.2 mg of 60% sodium hydride oil dispersion (13.3 mg NaH, 0.558 mmol, 1.2 eq). The reaction mixture was stirred at room temperature for 30 minutes. To the solution was added 153 mg (0.465 mmol) of a solution of 4-bromomethyl-2'-(2-thienyl)-1,1'-biphenyl dissolved in 3 mL of dry dimethylformamide. After stirring at room temperature for 3 hours, the reaction mixture was diluted with ethyl acetate. The organic layer was washed with water (4×), dried over magnesium sulfate, filtered and evaporated under vacuum. The residue was purified by chromatography on silica gel, eluting with hexane/ethyl acetate (1:1) to give 160 mg of the product.
Reaction SMILES: Cl.[F:2][C:3]([F:22])([F:21])[O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][CH:14]3[CH2:17][NH:18][CH2:19][CH:13]3[C:12]2=[O:20])=[CH:7][CH:6]=1.Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=1.CCN(CC)CC.ClCCl>CO>[F:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:18]2[CH2:17][CH:14]3[CH:13]([C:12](=[O:20])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][C:3]([F:2])([F:21])[F:22])=[CH:6][CH:7]=4)[CH2:16][CH2:15]3)[CH2:19]2)=[CH:26][CH:27]=1
Reactant: O=C1C2CNCC2CCN1c1ccc(OC(F)(F)F)cc1
Reactant: Fc1ccc(CBr)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: O=C1C2CN(Cc3ccc(F)cc3)CC2CCN1c1ccc(OC(F)(F)F)cc1
Reaction time: 12 h
Yield: 30.6 %

Procedure:
5-(4-Trifluoromethoxy-phenyl)-octahydro-pyrrolo[3,4-c]pyridin-4-one, hydrochloride (80 mg, 0.24 mmol), 1-(bromomethyl)-4-fluorobenzene (90 mg, 0.48 mmol) and Et3N (0.12 g, 1.2 mmol) were added to dichloromethane (2 mL), and the mixture was stirred for 12 h. The product (30 mg, 31%) was obtained by prep-TLC (eluting with dichloromethane: MeOH=25:1). 1H NMR (300 MHz, CDCl3): δ 7.48-7.44 (m, 2H), 7.29-7.09 (m, 6H), 4.23-4.19 (m, 2H), 3.85-3.25 (m, 7H), 2.50-2.48 (m, 1H), 2.28-2.24 (m, 1H), 1.25-1.23 (m, 1H); LC-MS: [M+1]+ 409.1.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH3:8])[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>C(O)C>[CH3:8][C:6]1[N:7]=[C:2]([NH:15][CH2:14][CH2:12][OH:13])[CH:3]=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10]
Reactant: Cc1nc(Br)ccc1[N+](=O)[O-]
Reactant: NCCO
Solvent: CCO
Product: Cc1nc(NCCO)ccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.4 %

Procedure:
6-bromo-2-methyl-3-nitropyridine (2 g, 9.22 mmol) was dissolved in ethanol (20 mL) and to this solution was added ethanolamine (1.115 mL, 18.43 mmol). The reaction was left to stir overnight under nitrogen, at room temperature. The reaction was concentrated in vacuo, then diluted with ethyl acetate and saturated sodium bicarbonate solution. The organic phase was separated and washed with saturated sodium bicarbonate and brine, then dried using a hydrophobic frit and concentrated in vacuo to give the title compound as a yellow solid (1.68 g). Crude material used directly in next step, without further purification. LCMS (2 min, formic) Rt 0.60 min, m/z (ES+) 198 (M+H).
Reaction SMILES: CC(C)([O-])C.[K+].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:15]=[CH:16]/[CH:17]=O)=[CH:11][CH:10]=1.[C:19]([CH2:21][C:22]([NH2:24])=[O:23])#[N:20].O=O>CS(C)=O>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][NH:24][C:22](=[O:23])[C:21]=2[C:19]#[N:20])=[CH:11][CH:10]=1
Reactant: COc1ccc(/C=C/C=O)cc1
Reactant: N#CCC(N)=O
Agent: CC(C)(C)[O-]
Agent: O=O
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(-c2cc[nH]c(=O)c2C#N)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 35.8 %

Procedure:
A mixture of potassium tert-butoxide (5.54 g, 49.3 mmol) in DMSO (20 mL) was added to a mixture of (E)-3-(4-methoxyphenyl)acrylaldehyde (2.0 g, 12.33 mmol) and 2-cyanoacetamide (1.140 g, 13.56 mmol) in DMSO (30 mL) dropwise under an oxygen balloon with a water bath cooling outside. After completion of addition, the mixture was stirred under oxygen for 1 h at room temperature, quenched with water (100 mL) and adjusted to pH 5-6 with careful addition of 1 N HCl. A brown precipitate was formed, collected by filtration, washed with water (2×50 mL), dried under vacuum to give 4-(4-methoxyphenyl)-2-oxo-1,2-dihydropyridine-3-carbonitrile (1.0 g, 36% yield). 1H NMR (500 MHz, DMSO-d6) δ ppm 7.69 (1H, δ, J=6.60 Hz), 7.62 (2H, δ, J=8.80 Hz), 7.11 (2H, δ, J=8.80 Hz), 639 (1H, δ, J=6.60 Hz), 3.87 (3H, s); MS (ES+) m/z: 227 (M+H); LC retention time: 2.532 min (analytical HPLC Method A).
Reaction SMILES: [CH3:1][C:2]([N:10]1[CH:14]=[C:13]([N+:15]([O-])=O)[N:12]=[CH:11]1)([CH3:9])[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][CH2:5]1.[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:29][C@@H:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31](O)=[O:32])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1>>[F:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27]([NH:29][C@@H:30]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[C:31]([NH:15][C:13]2[N:12]=[CH:11][N:10]([C:2]([CH3:9])([CH3:1])[CH2:3][N:4]3[CH2:8][CH2:7][CH2:6][CH2:5]3)[CH:14]=2)=[O:32])=[O:28])[CH:22]=[C:23]([F:25])[CH:24]=1
Reactant: O=C(Cc1cc(F)cc(F)c1)N[C@H](C(=O)O)c1ccccc1
Reactant: CC(C)(CN1CCCC1)n1cnc([N+](=O)[O-])c1
Product: CC(C)(CN1CCCC1)n1cnc(NC(=O)[C@@H](NC(=O)Cc2cc(F)cc(F)c2)c2ccccc2)c1

Procedure:
1-(2-methyl-1-(pyrrolidin-1-yl)propan-2-yl)-4-nitro-1H-imidazole (U.S. Ser. No. 11/078,898 filed Mar. 11, 2005) was reduced and coupled with (S)-2-(2-(3,5-difluorophenyl)acetamido)-2-phenylacetic acid to afford the title compound: MS 496 m/z (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.Br[CH2:19][C:20]([C:22]1[CH:23]=[C+:24][CH:25]=[CH:26][CH:27]=1)=O>C(O)CCC.[Cl-].[Na+].O>[C:7]1([C:5]2[N:6]3[CH:19]=[C:20]([C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=4)[N:1]=[C:2]3[S:3][C:4]=2[C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(CBr)C1=CC=C[C+]=C1
Reactant: CCOC(=O)c1sc(N)nc1-c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCCCO
Solvent: O
Product: CCOC(=O)c1sc2nc(-c3ccccc3)cn2c1-c1ccccc1
Temperature: 25 °C
Yield: 18.3 %

Procedure:
A solution of ethyl 2-amino-4-phenylthiazole-5-carboxylate 93 (0.7 g, 2.82 mmol) and 3-(2-bromoacetyl)benzene-1-ylium 68 (0.34 mL, 2.82 mmol) was stirred at 120° C. in butanol (9 mL) for 3 d. The solution was cooled to room temperature, diluted with brine and extracted with ethyl acetate. The combined organics were dried over Na2SO4, filtered and concentrated under reduced pressure to afford ethyl 3,6-diphenylimidazo[2,1-b]thiazole-2-carboxylate 94 (0.18 g, 18% yield) as a tan solid after purification by flash chromatography (0 to 30% MeOH in ethyl acetate) followed by trituration in hexane. LRMS (ESI): (calc) 348.42 (found) 349.2 (MH)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([OH:8])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1.I[CH:29]([CH3:31])[CH3:30].C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([O:8][CH:29]([CH3:31])[CH3:30])[C:3]=1[CH:9]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([O:21][C:22]([F:23])([F:24])[F:25])=[CH:17][CH:16]=2)[C:12](=[O:26])[CH:11]([CH3:27])[CH2:10]1
Reactant: CC(C)I
Reactant: CC1CC(c2c(O)cccc2F)N(Cc2ccc(OC(F)(F)F)cc2)C1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Oc1cccc(F)c1C1CC(C)C(=O)N1Cc1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A mixture of 5-(2-fluoro-6-hydroxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one (50 mg; 0.13 mmol), 2-iodopropane (66 mg; 0.39 mmol), potassium carbonate (36 mg; 0.26 mmol), and cesium carbonate (8.5 mg; 0.026 mmol) in anh. DMF (0.7 ml) was stirred at rt, under nitrogen, for 17 h. Subsequent filtration and purification by preparative HPLC afforded the target compound 5-(2-fluoro-6-isopropoxyphenyl)-3-methyl-1-(4-(trifluoromethoxy)benzyl)pyrrolidin-2-one. LC-MS (conditions A): tR=1.00 min.; [M+H]+: 426.01 g/mol.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][CH:30]=1)[C:5]([NH:7][C:8]1[C:9]([N:18]2[CH2:23][CH2:22][CH:21]([CH2:24][C:25]([OH:27])=O)[CH2:20][CH2:19]2)=[N:10][C:11]([S:14]([CH3:17])(=[O:16])=[O:15])=[CH:12][CH:13]=1)=[O:6].[C:31]([NH2:35])([CH3:34])([CH3:33])[CH3:32].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C=O.O>[C:31]([NH:35][C:25]([CH2:24][CH:21]1[CH2:22][CH2:23][N:18]([C:9]2[C:8]([NH:7][C:5](=[O:6])[C:4]3[CH:28]=[CH:29][CH:30]=[C:2]([Cl:1])[CH:3]=3)=[CH:13][CH:12]=[C:11]([S:14]([CH3:17])(=[O:16])=[O:15])[N:10]=2)[CH2:19][CH2:20]1)=[O:27])([CH3:34])([CH3:33])[CH3:32]
Reactant: CC(C)(C)N
Reactant: CS(=O)(=O)c1ccc(NC(=O)c2cccc(Cl)c2)c(N2CCC(CC(=O)O)CC2)n1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)NC(=O)CC1CCN(c2nc(S(C)(=O)=O)ccc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 21 %

Procedure:
A mixture of 0.023 g (0.226 mmol) of [3′-(3-chloro-benzoylamino)-6′-methanesulfonyl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid, 0.011 g (0.15 mmol) of tert-butyl amine, 0.021 g (0.066 mmol) of O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate, and 0.021 mL (0.15 mmol) of triethylamine in N,N-dimethylformamide (2 mL) is stirred at room temperature for 2 hours. The mixture is diluted with water and purified using preparative reverse phase HPLC to give 0.016 g (62%) of the title compound (286) as colorless foam. [M+H]+=507.2.
Reaction SMILES: [ClH:1].[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:5][CH2:4]1.N[C@H]1CC[C@H](C(O)=O)CC1>>[ClH:1].[CH2:12]([O:11][C:9]([C@H:6]1[CH2:7][CH2:8][C@@H:3]([NH2:2])[CH2:4][CH2:5]1)=[O:10])[CH3:13]
Reactant: CCOC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Agent: N[C@H]1CC[C@H](C(=O)O)CC1
Product: CCOC(=O)[C@H]1CC[C@@H](N)CC1

Procedure:
19.3 mL of concentrated hydrochloric acid (2.8 eq) was added to a solution of cis-4-aminocyclohexane carboxylic acid (10 g, 69.83 mmol) in anhydrous ethyl alcohol (250 mL). Mixture was stirred overnight at about 60° C. and then cooled to room temperature. Solvent was evaporated in vacuo. Crude material was then redissolved in acetonitrile, sonicated, and concentrated to a solid in vacuo. This acetonitrile wash was repeated three times to obtain 11.5 g of while solid (96% yield). Trans-ethyl 4-aminocyclohexanecarboxylate hydrochloride can be prepared following the same procedure using trans-4-aminocyclohexane carboxylic acid.
Reaction SMILES: C([O:3][C:4](=[O:25])[C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][C:6]=1[O:12][CH2:13][CH:14]([CH3:24])[CH2:15][NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])C.C(OC(=O)C1C=CC(F)=CC=1F)C.CC(CNC(OC(C)(C)C)=O)CO>>[C:20]([O:19][C:17]([NH:16][CH2:15][CH:14]([CH3:24])[CH2:13][O:12][C:6]1[CH:7]=[C:8]([F:11])[CH:9]=[CH:10][C:5]=1[C:4]([OH:25])=[O:3])=[O:18])([CH3:23])([CH3:21])[CH3:22]
Reactant: CCOC(=O)c1ccc(F)cc1OCC(C)CNC(=O)OC(C)(C)C
Agent: CC(CO)CNC(=O)OC(C)(C)C
Agent: CCOC(=O)c1ccc(F)cc1F
Product: CC(CNC(=O)OC(C)(C)C)COc1cc(F)ccc1C(=O)O
Yield: 7 %

Procedure:
Using methods substantially equivalent to those described in Example 21-C, ethyl-2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluorobenzoate was prepared from ethyl-2,4-difluorobenzoate and 2-methyl-3-tert-butoxycarbonylaminopropanol. The impure material was saponified using methods substantially equivalent to those described in Example 21-D to give 2-(3-tert-butoxycarbonylamino-2-methylpropoxy)-4-fluoro-benzoic acid (554 mg, 1.69 mmol, 7% for 2 steps after RPHPLC purification).