Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C=O.[BH-](OC(C)=O)(OC(C)=O)O[C:24](C)=O.[Na+]>ClC(Cl)C>[CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH2:4][CH2:5][N:6]2[CH2:11][CH2:12][CH2:13][CH:14]1[CH2:15][CH2:16][N:17]([CH3:24])[CH2:18][CH2:19]1
Reactant: Cc1cccc2c1CCN2CCCC1CCNCC1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: C=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cc1cccc2c1CCN2CCCC1CCN(C)CC1
Reaction time: 1 h

Procedure:
To a mixture of 4-methyl-1-(3-piperidin-4-yl-propyl)-2,3-dihydro-1H-indole (1.50 g, 5.81 mmol) in dichloroethane (20 mL) was added formaldehyde (37% in water; 4.0 mL) and Na(OAc)3BH (6.39 g, 30.1 mmol). After 1 h, the mixture was quenched with satd. aq. NaHCO3 and extracted with CHCl3. The organic layer was dried (Na2SO4) and concentrated to obtain the crude residue, which was purified by FCC to give 1.03 g (66%). MS: mass calcd. for C18H28FN5, 272.23; m/z found, 273.4 [M+H]+. 1H NMR (CDCl3): 6.97 (t, J=7.7, 1H), 6.47 (d, J=7.6, 1H), 6.29 (d, J=7.8, 1H), 3.33 (t, J=8.4, 2H), 3.01 (m, 2H), 2.91-2.81 (m, 4H), 2.26 (s, 3H), 2.19 (s, 3H), 1.95-1.86 (m, 2H), 1.74-1.53 (m, 4H), 1.37-1.16 (m, 5H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][CH:9]([CH2:15][C:16](OC)=[O:17])[CH2:10][C:11](OC)=[O:12].[OH-].[Na+]>C1COCC1>[CH3:7][O:8][CH:9]([CH2:15][CH2:16][OH:17])[CH2:10][CH2:11][OH:12]
Reactant: COC(=O)CC(CC(=O)OC)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(CCO)CCO
Temperature: 0 °C
Reaction time: 8 h
Yield: 38.2 %

Procedure:
To a stirred suspension of LAH (1.77 g, 46.6 mmol) in THF (40 mL) under N2 was cooled to 0° C. and was added dimethyl 3-methoxypentanedioate (3.7 g, 19.5 mmol). The mixture was stirred overnight. Aqueous NaOH (1 N, 12 mL) was added at 0° C. The mixture was filtered and the cake was washed with EtOAc 3 times. The filtrate was dried and concentrated to give 3-methoxypentane-1,5-diol (1 g, 38%). 1H-NMR (CDCl3): 1.75 (m, 4H), 2.62 (s, 2H), 3.37 (m, 3H), 3.6 (m, 2H), 3.7 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([F:12])([F:11])[F:10])=[CH:5][C:4]=1[NH:13][C:14](Cl)=[O:15].[NH2:17][C:18]1[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1.C(N(CC)CC)C.C(Cl)(Cl)Cl>O>[C:18]1([NH:17][C:14]([NH:13][C:4]2[CH:5]=[C:6]([C:9]([F:12])([F:11])[F:10])[CH:7]=[CH:8][C:3]=2[O:2][CH3:1])=[O:15])[C:27]2[CH2:26][CH2:25][CH2:24][CH2:23][C:22]=2[CH:21]=[CH:20][CH:19]=1
Reactant: COc1ccc(C(F)(F)F)cc1NC(=O)Cl
Reactant: Nc1cccc2c1CCCC2
Solvent: ClC(Cl)Cl
Solvent: O
Solvent: CCN(CC)CC
Product: COc1ccc(C(F)(F)F)cc1NC(=O)Nc1cccc2c1CCCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 38.6 %

Procedure:
2-methoxy-5-(trifluoromethyl)phenyl carbamoylchloride (0.81 g, 3.2 mmol), 1-amino-5,6,7,8-tetrahydronaphtalene (445 μl, 3.2 mmol) and triethylamine (446 μl, 3.2 mmol) were added to chloroform (20 ml) and the resulting mixture was stirred at RT overnight. The reaction mixture was poured into water and extracted with ethyl acetate. The solvent was evaporated in vacuuo and the residue recrystallized from toluene (20 ml). 0.45 g of the title compound was isolated.
Reaction SMILES: COCCN[S](F)(F)([F:12])NCCOC.[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH2:39]O)[N:36]=[N:35]3)[O:30][C:29]2=[O:41])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1>ClCCl>[F:15][C:16]1[CH:17]=[C:18]([N:28]2[CH2:32][C@H:31]([CH2:33][N:34]3[CH:38]=[C:37]([CH2:39][F:12])[N:36]=[N:35]3)[O:30][C:29]2=[O:41])[CH:19]=[CH:20][C:21]=1[N:22]1[CH:26]=[C:25]([CH3:27])[N:24]=[CH:23]1
Reactant: COCCN[S](F)(F)(F)NCCOC
Reactant: Cc1cn(-c2ccc(N3C[C@H](Cn4cc(CO)nn4)OC3=O)cc2F)cn1
Solvent: ClCCl
Product: Cc1cn(-c2ccc(N3C[C@H](Cn4cc(CF)nn4)OC3=O)cc2F)cn1
Temperature: 25 °C
Reaction time: 20 h
Yield: 16 %

Procedure:
Bis[(2-methoxyethyl)amino]sulfur trifluoride (150 μl, 0.81 mmol) was added to a solution of (5R)-3-[3-fluoro-4-(4-methyl-1H-imidazol-1-yl)phenyl]-5-[4-(hydroxymethyl)-1H-1,2,3-triazol-1-ylmethyl]-1,3-oxazolidin-2-one (Example 48) (222 mg, 0.60 mmol) in dichloromethane (2 ml) at −78° C. The reaction mixture was allowed to gradually warm to room temperature. After 20 hours, the reaction mixture was heated to 40° C. for 3 hours before cooling to room temperature and quenching with methanol. Chromatography on silica gel with 7.5% methanol in dichloromethane gave 36 mg of product.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]3[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=3[N:10]=[CH:9]2)=[CH:4][CH:3]=1.CC([O-])(C)C.[K+].[Na+].[I-].[F:29][C:30]([F:41])([F:40])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36]Br)=[CH:34][CH:33]=1>CN(C=O)C>[F:29][C:30]([F:40])([F:41])[O:31][C:32]1[CH:39]=[CH:38][C:35]([CH2:36][O:1][C:2]2[CH:3]=[CH:4][C:5]([N:8]3[C:12]4[CH:13]=[CH:14][C:15]([C:17]([O:19][CH3:20])=[O:18])=[CH:16][C:11]=4[N:10]=[CH:9]3)=[CH:6][CH:7]=2)=[CH:34][CH:33]=1
Reactant: FC(F)(F)Oc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc2c(c1)ncn2-c1ccc(O)cc1
Agent: CC(C)(C)[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2c(c1)ncn2-c1ccc(OCc2ccc(OC(F)(F)F)cc2)cc1
Temperature: 60 °C

Procedure:
A 0.2M DMF solution of methyl 1-(4-hydroxyphenyl)-1H-benzimidazole-5-carboxylate (3.0 g, 9.8 mmol) with KOtBu (2.2 g, 19.6 mmol) was stirred at rt for 20 min. prior to treatment with NaI (9.8 mmol, 1.47 g) and p-(trifluoromethoxy) benzylbromide (1.88 mL, 11.2 mmol). The mixture was heated at 60° C. for 24 h. after which the mixture was concentrated in vacuo, and the residue purified by chromatography over silica gel eluting with 1:1 EtOAc:Hexane to afford methyl 1-(4-{[4-(trifluoromethoxy)benzyl]oxy}phenyl)-1H-benzimidazole-5-carboxylate. 1H NMR (DMSO-d6, 400 MHz) δ 3.89 (s, 3H), 5.26 (s, 2H), 7.26-7.29 (m, 2H), 7.43 (d, 2H, J=7.6 Hz), 7.61-7.65 (m, 5H), 7.86 (dd, 1H, J=8.8 Hz, 1.6 Hz), 8.35 (d, 1H, J=1.2 Hz), 8.65 (s, 1H); MS (ES+): m/z 443 (MH+).
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([OH:12])=[O:11])[C:4]=2[CH:3]=[CH:2]1.[N+](=[CH2:15])=[N-].S([O-])([O-])(=O)=O.[Mg+2]>CO.C(OCC)C>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([C:10]([O:12][CH3:15])=[O:11])[C:4]=2[CH:3]=[CH:2]1
Reactant: C=[N+]=[N-]
Reactant: O=C(O)c1cccc2[nH]ccc12
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CO
Solvent: CCOCC
Product: COC(=O)c1cccc2[nH]ccc12
Yield: 98 %

Procedure:
To a solution of indole-4-carboxylic acid (506 mg, 3.14 mmol) dissolved in a mixture of methanol (5 mL) and diethyl ether (10 mL) was added ethereal diazomethane until disappearance of the starting acid was indicated by TLC. Magnesium sulfate was then added and the solution filtered and concentrated in vacuo. Flash chromatography on Merck silica gel (10 g) eluted with 2:1, chloroform:hexanes, followed by 10:1, chloroform: ether afforded the title compound (540 mg, 98%).
Reaction SMILES: B1([O-])OO1.[OH2:5].[OH2:6].O.O.[Na+].[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[NH2:18]>C(O)(=O)C>[Br:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([F:17])[C:12]=1[N+:18]([O-:6])=[O:5]
Reactant: O
Reactant: Nc1c(F)cccc1Br
Agent: [Na+]
Agent: [O-]B1OO1
Solvent: CC(=O)O
Product: O=[N+]([O-])c1c(F)cccc1Br
Temperature: 55 °C
Reaction time: 3 h
Yield: 29.5 %

Procedure:
To a suspension of sodium perborate tetrahydrate (135.374 g., 886.4 mmol) in 500 mL acetic acid at 55° C. was added dropwise a solution of 2-bromo-6-fluoro-phenylamine (33.685 g., 177.271 mmol) in 70 mL acetic acid over 1 hour. The reaction mixture was stirred at 55° C. for an additional 3 hours, then cooled to 0° C. in an ice bath. Insoluble materials were removed by filtration through a plug of celite, which was rinsed with 100 mL acetic acid. The combined acetic acid fractions were added to 3 L ice water with stirring to give a waxy solid which was removed by filtration. The crude solid was dissolved in 250 mL ethyl acetate, washed three times with 200 mL of 10% aqueous hydrogen chloride, 200 mL saturated sodium bicarbonate and 100 mL brine. The solution was concentrated in vacuo to give 11.51 g of 1-bromo-3-fluoro-2-nitro-benzene as a red oil,
Reaction SMILES: [C:1]1([N:11]=[C:12]=[O:13])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.[C:14]1([CH:20]([OH:25])[CH2:21][CH2:22][CH2:23][OH:24])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[OH:25][CH:20]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH2:21][CH2:22][CH2:23][O:24][C:12](=[O:13])[NH:11][C:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: OCCCC(O)c1ccccc1
Reactant: O=C=Nc1cccc2ccccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1cccc2ccccc12)OCCCC(O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 76.8 %

Procedure:
1-Naphthyl isocyanate (4.3 ml, 30 mmol) in 50 ml of methylene chloride was added under nitrogen dropwise over 1 hour to a solution of 4-phenyl-4-hydroxybutanol (5.00 g, 30 mmol), prepared in step (a) of Example 6, and triethylamine (4.2 ml, 30 mmol) in 200 ml of methylene chloride at room temperature. After the addition the reaction was stirred at room temperature for 18 hours. The solid present in the reaction was removed by filtration. The filtrate was extracted with 1 N HCl, dried (MgSO4) and the solvent removed under reduced pressure to give 10.08 g of a clear oil Purification of the oil by chromatography on 1 kg of silica gel (230-400 mesh) using 3%-20% ethyl acetate-methylene chloride as the eluent gave naphthalen-1-yl-carbamic acid 4-hydroxy-4-phenyl-butyl ester (7.73 g, 77%) as a white solid, mp 92-92° C.
Reaction SMILES: [Si:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][C:10]=1[O:17][CH2:18][CH3:19])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].P(Br)(Br)[Br:21].C([O-])(O)=O.[Na+]>>[Br:21][CH2:15][C:12]1[CH:13]=[CH:14][C:9]([O:8][Si:1]([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2])=[C:10]([O:17][CH2:18][CH3:19])[CH:11]=1
Reactant: CCOc1cc(CO)ccc1O[Si](C)(C)C(C)(C)C
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Product: CCOc1cc(CBr)ccc1O[Si](C)(C)C(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.6 %

Procedure:
To a solution of (4-(tert-butyldimethylsilyloxy)-3-ethoxyphenyl)methanol (12.5 g, 44.4 mmol, 1.0 equiv.) in CH2CI2 (45 mL), PBr3 (5.0 mL, 53.2 mmol, 1.2 equiv.) was added at 0° C., and the mixture was stirred at 0° C. for 30 min. After slow addition of sat. aq. NaHCO3-solution, the aqueous layer was extracted with CH2Cl2 (2×). The combined organic phases were washed with brine, dried (MgSO4), filtered and the filtrate was concentrated to yield 14.5 g (94%) of (4-(bromomethyl)-2-ethoxyphenoxy)(tert-butyl)dimethylsilane as a light yellow oil.
Reaction SMILES: [O:1]1[CH2:3][CH:2]1[CH2:4][O:5][CH:6]1[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1.[CH3:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([CH3:22])[C:17]=1[NH:23][C:24](=[O:32])[CH2:25][N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1>C(O)C>[CH3:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH3:15])[C:17]=1[NH:23][C:24](=[O:32])[CH2:25][N:26]1[CH2:27][CH2:28][N:29]([CH2:3][CH:2]([OH:1])[CH2:4][O:5][CH:6]2[CH2:14][C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7]2)[CH2:30][CH2:31]1
Reactant: Cc1cccc(C)c1NC(=O)CN1CCNCC1
Reactant: c1ccc2c(c1)CC(OCC1CO1)C2
Solvent: CCO
Product: Cc1cccc(C)c1NC(=O)CN1CCN(CC(O)COC2Cc3ccccc3C2)CC1
Reaction time: 24 h

Procedure:
To a solution of 6 (0.43 g, 2.3 mmol) in ethanol(4 ml) was added 5 (0.405 g, 1.64 mmol). The solution was heated to reflux and stirred for 24 h. Upon completion the solution was concentrated in vacuo and purified using Prep TLC (10:1, DCM:MeOH) to yield 7. Mass Spectrum (M+1)=438.36.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][CH:3]=1.[OH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][N:11]=1>>[I:8][C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH:12]=[CH:13][CH:14]=[CH:15][C:10]2=[O:9])=[CH:3][CH:4]=1
Reactant: Oc1ccccn1
Reactant: Ic1ccc(I)cc1
Product: O=c1ccccn1-c1ccc(I)cc1

Procedure:
74.1 Using the method described in example 73.1, 1,4-diiodobenzene was reacted with 2-hydroxypyridine to give 1-(4-iodo-phenyl)-1H-pyridin-2-one. Pale yellow solid. MS: 298.1 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:20])[CH3:19])[CH2:13][CH2:12]1.CO>[Pd]>[NH2:8][C:6]1[CH:5]=[CH:4][C:3]([N:11]2[CH2:16][CH2:15][N:14]([CH2:17][C@@H:18]([OH:20])[CH3:19])[CH2:13][CH2:12]2)=[C:2]([F:1])[CH:7]=1
Reactant: C[C@H](O)CN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1
Agent: [Pd]
Solvent: CO
Product: C[C@H](O)CN1CCN(c2ccc(N)cc2F)CC1
Yield: 81.4 %

Procedure:
(S)-1-[4-(2-Fluoro-4-nitro-phenyl)-piperazin-1-yl]-propan-2-ol (0.583 g, 0.00206 mol) was combined with Methanol (42 mL, 1.0 mol) in a flask. The solution was passed through a 10% Pd/C CatCart (30×4 mm) in an H-cube hydrogenator at 10 bar, 30° C. for 3 hours. The reaction was concentrated and triturated with ether to yield a brown solid, (S)-1-[4-(4-Amino-2-fluoro-phenyl)-piperazin-1-yl]-propan-2-ol (425 mg, 82%). LCMS: m/z=254.09 (M+H+); 1H NMR (400 MHz, DMSO-d6) δ 6.75 (m, 1H), 6.30 (m, 2H), 4.95 (s, 2H), 4.29 (d, 1H, J=3.4 Hz), 3.77 (m, 1H), 2.81 (m, 4H), 2.22 (m, 2H), 1.04 (d, 3H, J=6.1 Hz).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18](Cl)[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].CC(C)([O-])C.[Na+].[I:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[C:31]([F:36])[CH:30]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1(C2C=CC=CC=2)C=CC=C(P(C(C)(C)C)C(C)(C)C)C=1>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[C:19]([CH3:20])=[C:18]([NH:33][C:32]3[CH:34]=[CH:35][C:29]([I:28])=[CH:30][C:31]=3[F:36])[N:17]=[CH:16][N:15]=2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: Cc1c(Cl)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Reactant: Nc1ccc(I)cc1F
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)P(c1cccc(-c2ccccc2)c1)C(C)(C)C
Solvent: C1COCCO1
Product: Cc1c(Nc2ccc(I)cc2F)ncnc1OC1CCN(C(=O)OC(C)C)CC1
Temperature: 120 °C
Yield: 47.1 %

Procedure:
A mixture of 4-(6-chloro-5-methyl-pyrimidin-4-yloxy)-piperidine-1-carboxylic acid isopropyl ester (2.58 g, 8.22 mmol), palladium acetate (185 mg, 0.82 mmol), biphenyl-3-yl-di-tert-butyl-phosphane (25 mg, 0.08 mmol), sodium tert-butoxide (2.4 g, 21.2 mmol), and 4-iodo-2-fluoro aniline (2.0 g, 8.4 mmol) in 15 mL dioxane was heated in microwave for 1 hour at 120° C. Solids were filtered off and mixture was purified by column chromatography and precipitating out of hexane/AcOEt to give compound A77 as a tanned solid (1.99 g, 47%). 1H NMR (CDCl3, 400 MHz) δ 1.15-1.16 (d, 6H), 1.61-1.71 (m, 2H), 1.85-1.90 (m, 2H), 1.99 (s, 3H), 3.27-3.33 (m, 2H), 3.63-3.66 (m, 2H), 4.82-4.85 (m, 1H), 5.20-5.23 (m, 1H), 6.35-6.36 (d, 1H), 7.33-7.36 (m, 2H), 8.08-8.13 (m, 1H), 8.22 (s, 1H). Exact mass calculated for C20H24F1N4O3 514.09, found 515.2 (MH+).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][C@H:3]1[O:15][CH2:16][CH3:17].[Cl:18][C:19]1[N:20]=[C:21]([C:26](O)=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:18][C:19]1[N:20]=[C:21]([C:26]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:4][C@H:3]2[O:15][CH2:16][CH3:17])=[O:27])[NH:22][C:23]=1[CH2:24][CH3:25]
Reactant: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCO[C@@H]1CN(C(=O)OC(C)(C)C)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using tert-butyl cis(±)-4-amino-3-ethoxypiperidine-1-carboxylate obtained by the method described in Example (112d) (0.48 g, 1.96 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (0.31 g, 1.51 mmol), WSC hydrochloride (0.88 g, 4.59 mmol) and HOBT (0.21 g, 1.51 mmol), to obtain 0.59 g of the title compound as a white foamy substance (91%).
Reaction SMILES: [Li][CH2:2]CCC.[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:42])([F:41])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:35])([F:34])[F:33])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:9]([CH:43]=O)[CH:8]=1>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[Br:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:41])([F:42])[O:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[C:21]2[N:26]=[C:25]([N:27]3[C:31]([C:32]([F:33])([F:35])[F:34])=[C:30]([C:36]([O:38][CH2:39][CH3:40])=[O:37])[CH:29]=[N:28]3)[CH:24]=[CH:23][CH:22]=2)=[C:9]([CH:43]=[CH2:2])[CH:8]=1
Reactant: [Li]CCCC
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3ccccc3OC(F)(F)c3ccc(Br)cc3C=O)n2)c1C(F)(F)F
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Product: C=Cc1cc(Br)ccc1C(F)(F)Oc1ccccc1-c1cccc(-n2ncc(C(=O)OCC)c2C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a cooled (0° C.) suspension of methyltriphenyl phosphonium bromide (5.33 g, 14.9 mmol) in THF (100 mL) was added dropwise n-BuLi (5.5 mL, 2.5 M in hexanes, 13.8 mmol). After aging for 40 min, the reaction mixture was allowed to warm up to ambient temperature for 25 min, at which point 7.4 mL of the supernatant was taken and added to the title compound from Example 302 Step D (270 mg, 0.442 mmol). After 30 min, the mixture was quenched by addition of water and the aqueous phase was extracted with hexane-EtOAc. The organic phase was separated and concentrated in vacuo. Purification by silica gel flash chromatography (5% to 15% EtOAc in hexanes) provided the title compound: LCMS m/z 590.5 [M−F]+; 1H NMR (500 MHz, CD2Cl2) δ 8.13 (s, 1H), 7.86 (m, 2H), 7.77 (m, 2H), 7.60 (d, J=8.0 Hz, 1H), 7.55-7.48 (m, 2H), 7.45-7.40 (m, 3H), 7.08 (m, 1H), 5.68 (d, J=17.2 Hz, 1H), 5.32 (d, J=11.0 Hz, 1H), 4.38 (q, J=7.2 Hz, 2H), 1.40 (t, J=7.2 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:4]=[C:5]([NH2:9])[CH:6]=[CH:7][CH:8]=1.CC1(C)[O:20][C:19](=O)[C:16]2([CH2:18][CH2:17]2)[C:15](=[O:22])[O:14]1>ClCCl>[O:20]=[C:19]1[CH:16]([C:15]([OH:22])=[O:14])[CH2:17][CH2:18][N:9]1[C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:10])([F:11])[F:1])[CH:4]=1
Reactant: CC1(C)OC(=O)C2(CC2)C(=O)O1
Reactant: Nc1cccc(C(F)(F)F)c1
Solvent: ClCCl
Product: O=C(O)C1CCN(c2cccc(C(F)(F)F)c2)C1=O
Temperature: 22.5 °C
Reaction time: 18 h
Yield: 69.4 %

Procedure:
A mixture of 3-trifluoromethyl-phenylamine (2.8 g, 17.5 mmol) and 6,6-dimethyl-5,7-dioxa-spiro[2.5]octane-4,8-dione (1.0 g, 5.8 mmol) was stirred at 20-25° C. for 18 hrs. The reaction mixture was diluted with dichloromethane and washed with 10% NaOH solution (3×10 ml). The aqueous layer was cooled and acidified with dil HCl. The aqueous layer was extracted with dichloromethane, washed with saturated brine solution. The organic layer was dried over Na2SO4 and evaporated to obtain 2-oxo-1-(3-trifluoromethyl-phenyl)-pyrrolidine-3-carboxylic acid (1.1 g, 69%) as an off white solid.
Reaction SMILES: [CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[CH:14])=[CH:9][C:8]=2[CH:15]([CH3:17])[CH3:16])[CH2:6][CH2:5]1)[CH3:2].C(O)(=O)C1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](I)=[CH:33][CH:32]=1)[CH3:28]>C(N(CC)CC)C.[Cu]I.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>[CH2:1]([O:3][C:4]1([C:7]2[CH:12]=[CH:11][C:10]([C:13]#[C:14][C:34]3[CH:35]=[CH:36][C:31]([C:30]([O:29][CH2:27][CH3:28])=[O:38])=[CH:32][CH:33]=3)=[CH:9][C:8]=2[CH:15]([CH3:16])[CH3:17])[CH2:6][CH2:5]1)[CH3:2]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C#Cc1ccc(C2(OCC)CC2)c(C(C)C)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: O=C(O)c1ccccc1
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(C#Cc2ccc(C3(OCC)CC3)c(C(C)C)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 33.8 %

Procedure:
Using General Procedure F; 1-(1-ethoxycyclopropyl)-4-ethynyl-2-isopropylbenzene (Intermediate 103, 50.0 mg, 0.22 mmol) and ethyl-4-iodo benzoate (Reagent A, 60.0 mg, 0.22 mmol) in triethylamine (5 mL) was treated with copper(I)iodide (14.0 mg, 0.07 mmol) and sparged with argon for 5 minutes. Dichlorobis(triphenylphosphine)-palladium(II) (51 mg, 0.07 mmol) was added and the reaction mixture was stirred overnight at room temperature. Column chromatography (1-2% EtOAc-hexanes) afforded 28.0 mg (34%) of the title compound.
Reaction SMILES: [CH3:1][Si:2]([CH3:12])([CH3:11])[C:3]#[C:4][C:5](=[O:10])[CH2:6][CH2:7][CH2:8][Cl:9].[CH2:13]([Mg]Br)[C:14]#[CH:15]>>[Cl:9][CH2:8][CH2:7][CH2:6][C:5]([OH:10])([C:4]#[C:3][Si:2]([CH3:1])([CH3:11])[CH3:12])[CH2:15][C:14]#[CH:13]
Reactant: C[Si](C)(C)C#CC(=O)CCCCl
Reactant: C#CC[Mg]Br
Product: C#CCC(O)(C#C[Si](C)(C)C)CCCCl

Procedure:
In the manner described hereinabove in Reference Example 11, 1-trimethylsilyl-3-oxo-6-chloro-1-hexyne is reacted with propargyl magnesium bromide to give 7-chloro-4-hydroxy-4-trimethylsilylethynyl-1-heptyne.
Reaction SMILES: [CH3:1][C:2]1([CH:15]2[CH2:19][CH2:18][O:17][C:16]2=[O:20])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3.[CH3:21][NH2:22]>O1CCCC1.[Cl-].[Na+].O>[CH3:21][NH:22][C:16](=[O:20])[CH:15]([CH2:19][CH2:18][OH:17])[C:2]1([CH3:1])[C:7]2[NH:8][C:9]3[C:14]([C:6]=2[CH2:5][CH2:4][O:3]1)=[CH:13][CH:12]=[CH:11][CH:10]=3
Reactant: CN
Reactant: CC1(C2CCOC2=O)OCCc2c1[nH]c1ccccc21
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CNC(=O)C(CCO)C1(C)OCCc2c1[nH]c1ccccc21

Procedure:
A solution of 4,5-dihydro-3-(1,3,4,9-tetrahydro-1-methylpyrano[3,4-b]indole-1-yl)-2(3H)-furanone (described in Example 1, 20 g, 0.074 mole) in tetrahydrofuran (200 ml) and 40% aqueous methylamine (200 ml) is refluxed for 24 hr. The reaction mixture is diluted with brine and extracted with diethyl ether. The organic extracts are washed with brine, dried over magnesium sulfate and evaporated. The residue is subjected to chromatography on silica gel using acetone-benzene (1:2). The eluates are evaporated and crystallized from diethyl ether-hexane to obtain isomer A (6.9 g) of the title compound, mp 169°-171° C. The eluant for the column is changed to acetone-benzene (1:1) and the eluates are evaporated followed by trituration of the residue to obtain isomer B (7.5 g) of the title compound, mp 194°-196° C.
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[C:11]3[N:15]([C:16]=2[C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]4[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]4)[N:18]=2)[CH:14]=[CH:13][S:12]3)=[CH:5][CH:4]=1.C(N(CC)CC)C.[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH:42]=O)=[CH:40][CH:39]=1.ClCCCl.CN(C=O)C>ClCCCl.CN(C=O)C>[F:37][C:38]1[CH:45]=[CH:44][C:41]([CH2:42][N:26]2[CH2:27][CH2:28][CH2:29][CH:24]([NH:23][C:19]3[N:18]=[C:17]([C:16]4[N:15]5[C:11]([S:12][CH:13]=[CH:14]5)=[N:10][C:9]=4[C:6]4[CH:7]=[CH:8][C:3]([F:2])=[CH:4][CH:5]=4)[CH:22]=[CH:21][N:20]=3)[CH2:25]2)=[CH:40][CH:39]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Fc1ccc(-c2nc3sccn3c2-c2ccnc(NC3CCCNC3)n2)cc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCCl
Product: Fc1ccc(CN2CCCC(Nc3nccc(-c4c(-c5ccc(F)cc5)nc5sccn45)n3)C2)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 56.2 %

Procedure:
The racemic 4-[6-(4-fluorophenyl)imidazo[2,1-b][1,3]thiazol-5-yl]-N-[piperidin-3-yl]pyrimidin-2-amine hydrochloride (70 mg g, 0.15 mmol) was dissolved in a 80/20 mixture of DCE and DMF (1.2 ml) and treated with three equivalent of triethylamine (63 uL). The 4-fluorobenzaldehyde (19 mg, 0.15 mmol) was added, followed by a 0.2 M solution of Me4NBH(OAc)3 in 80/20 DCE/DMF (1.2 ml). The mixture was stirred at room temperature for 18 hours. The mixture was washed with a 1N sodium hydroxide solution (2 ml). Concentration in vacuo followed by purification on reverse phase HPLC provides the title compound as a pale yellow solid (42.4 mg, 56%). M.p.=131-133° C. 400 MHz 1H NMR (DMSO-d6) δ: 8.73 (br. s, 1H), 8.06 (d, J=5.1 Hz, 1H), 7.64-7.58 (m, 2H), 7.44 (d, J=4.7 Hz, 1H), 7.35-7.31 (m, 2H), 7.30-7.23 (m, 2H), 7.07 (t, J=8.8 Hz, 2H), 7.00 (br. s, 1H), 6.29 (d, J=5.1 Hz, 1H), 4.00-3.90 (m, 1H), 3.49 (s, 2H), 2.96-2.90 (m, 1H), 2.69-2.62 (m, 1H), 2.08-1.94 (m, 2H), 1.93-1.85 (m, 1H), 1.76-1.67 (m, 1H), 1.61-1.48 (m, 1H), 1.42-1.30 (m, 1H). LCMS: 503 [M+H].