Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:22][CH2:21][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:19][CH2:18]4)[C:6]=3[C:5]1=2)#[N:2].[OH:32][Li].O.OO>CO>[C:1]([CH2:3][C@H:4]1[CH2:15][CH2:14][C:13]2[S:12][C:11]3[N:10]=[CH:9][N:8]=[C:7]([O:16][CH:17]4[CH2:18][CH2:19][C:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:23])[CH2:21][CH2:22]4)[C:6]=3[C:5]1=2)(=[O:32])[NH2:2]
Reactant: [Li]O
Reactant: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC#N)CC4)CC1
Agent: OO
Solvent: O
Solvent: CO
Product: CC1(NC(=O)OC(C)(C)C)CCC(Oc2ncnc3sc4c(c23)[C@@H](CC(N)=O)CC4)CC1
Reaction time: 8 h
Yield: 71.8 %

Procedure:
A 50-mL round-bottom flask purged and maintained with an inert atmosphere of nitrogen was charged with tert-butyl N-(4-[[(3R)-3-(cyanomethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (600 mg, 1.36 mmol, 1.00 equiv) in methanol (8.0 mL). Then LiOH.H2O (171 mg, 4.08 mmol, 3.00 equiv) and H2O2 (30%, 1.0 mL) were added at 0° C. and the resulting solution was stirred overnight at this temperature. The reaction was then quenched by the addition of 40 mL of NaHSO3 (aq.) and extracted with 3×60 mL of ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate and concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1/1) to afford tert-butyl N-(4-[[(3R)-3-(carbamoylmethyl)-7-thia-9,11-diazatricyclo[6.4.0.0[2,6]]dodeca-1(8),2(6),9,11-tetraen-12-yl]oxy]-1-methylcyclohexyl)carbamate (450 mg, 72%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([CH3:17])([CH3:16])[C:12]([O:14]C)=O)=[CH:6][C:5]=1[F:18])(=[O:3])[NH2:2].[F:19][C:20]([F:33])([F:32])[C:21]1[CH:28]=[C:27]([N:29]=[C:30]=[S:31])[CH:26]=[CH:25][C:22]=1[C:23]#[N:24]>CS(C)=O.O>[C:23]([C:22]1[CH:25]=[CH:26][C:27]([N:29]2[C:12](=[O:14])[C:11]([CH3:17])([CH3:16])[N:10]([C:7]3[CH:8]=[CH:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([F:18])[CH:6]=3)[C:30]2=[S:31])=[CH:28][C:21]=1[C:20]([F:19])([F:32])[F:33])#[N:24]
Reactant: N#Cc1ccc(N=C=S)cc1C(F)(F)F
Reactant: COC(=O)C(C)(C)Nc1ccc(C(N)=O)c(F)c1
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=S)N1c1ccc(C(N)=O)c(F)c1
Reaction time: 0.03 h

Procedure:
A solution of methyl 2-(4-carbamoyl-3-fluorophenylamino)-2-methylpropanoate and 2-(trifluoromethyl)-4-isothiocyanatobenzonitrile (1.5 equivalents) in dry DMSO (5 mL per mmol) was heated to 80-82° C. for 12 h. The reaction mixture was diluted with water and extracted with ethyl acetate. The combined organic layer was concentrated under reduced pressure and the residue was purified by silica gel chromatography eluting with 40% Acetone-Hexanes. MS (m/z): 451 (M+1). HPLC: Column, YMC ODS A, 4.6×150 mm, 5 μm, Mobile Phase A: 10 mM Ammonium acetate, Mobile Phase B: Acetonitrile, Gradient, 10% B up to 2 min, 10% to 90% B in 3 min, hold for 3 min, 90% to 10% B in 5 min, Retention time, 2.782 min, HPLC Purity, 99.4%, Flow Rate, 1 mL/min. 1H NMR (CDCl3, Freebase): δ (ppm) 8.3 (t, 1H), 8.0 (d, 1H) 7.98 (s, 1H), 7.8 (d, 1H), 7.27 (d, 1H), 7.2 (d, 1H), 6.65 (d, 1H), 6.0 (s, 1H), 1.62 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[CH2:16][C:17]([O:19]C)=[O:18].O.O[Li].O.Cl>C1COCC1>[F:22][C:2]([F:1])([F:21])[CH2:3][O:4][C:5]1[CH:10]=[C:9]([N:11]2[CH:15]=[CH:14][N:13]=[N:12]2)[CH:8]=[CH:7][C:6]=1[CH2:16][C:17]([OH:19])=[O:18]
Reactant: COC(=O)Cc1ccc(-n2ccnn2)cc1OCC(F)(F)F
Agent: Cl
Agent: [Li]O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1ccc(-n2ccnn2)cc1OCC(F)(F)F
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a stirred solution of methyl 2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetate (0.54 g, 1.7 mmol) from Step 2 above in THF (10 mL) and water (2.5 mL) was added LiOH·H2O (0.11 g, 2.6 mmol). The mixture was stirred at ambient temperature for 14 h. The solution was adjusted to pH 2 by the addition of 5 N aqueous HCl and the solvents were removed under reduced pressure to give 2-(2,2,2-trifluoroethoxy)-4-(1-triazolyl)phenylacetic acid was obtained as a gum (HPLC retention time=6.0 min (method A)).
Reaction SMILES: [N+:1]([C:4]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][CH:7]=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:21][CH2:22][O:23][CH3:24]>CC(C)=O>[CH3:24][O:23][CH2:22][CH2:21][O:13][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]([N+:10]([O-:12])=[O:11])[C:4]=1[N+:1]([O-:3])=[O:2]
Reactant: COCCBr
Reactant: O=[N+]([O-])c1cccc(O)c1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COCCOc1cccc([N+](=O)[O-])c1[N+](=O)[O-]

Procedure:
1.50 g (8.15 mmol) 2,3-Dinitro-phenol were dissolved in 75 mL acetone. Subsequently 1.69 g (12.22 mol) K2CO3, 135.3 mg KI (0.81 mmol) and 0.93 mL (9.77 mmol) 1-bromo-2-methoxy-ethane were added. The reaction mixture was refluxed for 8 h. After that time further 1.69 g (12.22 mol) K2CO3, 400 mg KI and 0.93 mL (9.77 mmol) 1-bromo-2-methoxy-ethane were added. The resulting mixture was refluxed for 16 h and then concentrated under reduced pressure. The residue was dissolved in warm ethyl acetate and purified by flash-chromatography on silica gel using an ethyl acetate/heptane-mixture as eluent to afford 1-(2-Methoxy-ethoxy)-2,3-dinitro-benzene as an orange crystalline material. Yield: 1.35 g MS (ES+): m/e=243.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([OH:14])=O.C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl>[O:2]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[CH:5][C:4]=1[CH2:11][C:12]([Cl:18])=[O:14])[CH3:1]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(OC)c(CC(=O)O)c1
Solvent: ClCCl
Product: COc1ccc(OC)c(CC(=O)Cl)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 196 mg (1.00 mmol) of (2,5-dimethoxyphenyl)acetic acid in 3 mL of CH2Cl2 was added 100 μL of oxalyl chloride. The mixture was stirred at ambient temperature for 1 hour then concentrated under reduced pressure to a thick liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:24]=[CH:23][C:6]([CH2:7][O:8][C:9]2[C:14]([N:15]3[CH2:20][CH2:19][C:18](=[O:21])[CH2:17][CH2:16]3)=[C:13]([CH3:22])[CH:12]=[CH:11][N:10]=2)=[CH:5][CH:4]=1.CO[CH:27](OC)[N:28]([CH3:30])[CH3:29]>>[CH3:27][N:28]([CH:30]=[C:17]1[C:18](=[O:21])[CH2:19][CH2:20][N:15]([C:14]2[C:9]([O:8][CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:24][CH:23]=3)=[N:10][CH:11]=[CH:12][C:13]=2[CH3:22])[CH2:16]1)[CH3:29]
Reactant: COC(OC)N(C)C
Reactant: COc1ccc(COc2nccc(C)c2N2CCC(=O)CC2)cc1
Product: COc1ccc(COc2nccc(C)c2N2CCC(=O)C(=CN(C)C)C2)cc1
Temperature: 100 °C

Procedure:
A mixture of 2′-(4-Methoxybenzyloxy)-4′-methyl-2,3,5,6-tetrahydro[1,3′]bipyridinyl-4-one (6.40 g, 19.61 mmol) in N,N-dimethylformamide-dimethylacetal (44.63 ml, 333.37 mmol) from a freshly opened bottle was heated at 100° C. for 48 hours. The solvent was removed in vacuo and the residue was eluted through a flash column (silica gel 60, 230-400 mesh, EtOAc to 8% methanol in EtOAc) to give title compound as an orange, viscous oil which slowly solidified on standing (5.21 g, 70%).
Reaction SMILES: [OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:16][C:17]([O:19]CC)=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1.[Li+].[OH-].O>C1COCC1>[OH:1][CH:2]1[N:11]([CH2:12][C:13]([N:15]([CH2:22][CH:23]([NH2:31])[C:24]([O:26][C:27]([CH3:29])([CH3:30])[CH3:28])=[O:25])[CH2:16][C:17]([OH:19])=[O:18])=[O:14])[C:10]2[NH:9][C:8]3[CH:32]=[CH:33][CH:34]=[CH:35][C:7]=3[S:6][C:5]=2[CH:4]=[N:3]1
Reactant: CCOC(=O)CN(CC(N)C(=O)OC(C)(C)C)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C(N)CN(CC(=O)O)C(=O)CN1C2=C(C=NC1O)Sc1ccccc1N2
Yield: 90.6 %

Procedure:
Ethyl N-[(2-hydroxy-10-H-pyrimido[5,4-b][1,4]-benzothiazin-1-yl)acetyl]-N-(2-Boc-aminoethyl)glycinate (201 mg, 0.4 mmol) was dissolved in THF (10 mL) and LiOH (2M, aqueous, 1.0 mL) was added. After 15 minutes at room temperature water (10 mL) was added, the THF was evaporated in vacuo and HCl (2M, aqueous, 1.0 mL) was added with vigorous stirring. The solid yellow material was filtered off and dried in vacuo to give 173 mg (91%) of the title compound.
Reaction SMILES: [CH:1]([C:3]1[CH:11]=[CH:10][C:6]2=[N:7][O:8][N:9]=[C:5]2[C:4]=1[CH3:12])=[CH2:2].C1C=C(Cl)C=C(C(OO)=[O:21])C=1>C(Cl)Cl>[CH3:12][C:4]1[C:5]2[C:6](=[N:7][O:8][N:9]=2)[CH:10]=[CH:11][C:3]=1[CH:1]1[CH2:2][O:21]1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C=Cc1ccc2nonc2c1C
Solvent: ClCCl
Product: Cc1c(C2CO2)ccc2nonc12
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A mixture of 5-ethenyl-4-methyl-2,1,3-benzoxadiazole (1.4 g, 8.4 mmol) and mCPBA (85%, 2.57 g, 12.6 mmol) in 200 mL of DCM was stirred at room temperature for 96 hours. The reaction mixture was cooled to 0° C. and was washed subsequently with saturated NaHCO3 (50 mL), saturated Na2SO3 (50 mL), 5% NaOH (50 mL×2) and brine (50 mL), dried over anhydrous Na2SO4 and concentrated. The residue was purified by silica column chromatography (PE:EtOAc=5:1) to afford the title compound.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([CH:9]=O)=[CH:7][C:6]=1[CH3:14].[NH2:15][C:16]1[CH:31]=[CH:30][CH:29]=[CH:28][C:17]=1[C:18]([NH:20][C:21]1[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=1)=[O:19].S([O-])(O)=O.[Na+].C1(C)C=CC(S(O)(=O)=O)=CC=1>CN(C)C(=O)C.O>[OH:1][CH2:2][CH2:3][O:4][C:5]1[C:12]([CH3:13])=[CH:11][C:8]([C:9]2[N:20]([C:21]3[CH:26]=[CH:25][C:24]([I:27])=[CH:23][CH:22]=3)[C:18](=[O:19])[C:17]3[C:16](=[CH:31][CH:30]=[CH:29][CH:28]=3)[N:15]=2)=[CH:7][C:6]=1[CH3:14]
Reactant: Nc1ccccc1C(=O)Nc1ccc(I)cc1
Reactant: Cc1cc(C=O)cc(C)c1OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1cc(-c2nc3ccccc3c(=O)n2-c2ccc(I)cc2)cc(C)c1OCCO
Temperature: 155 °C

Procedure:
To a mixture of 4-(2-hydroxy-ethoxy)-3,5-dimethyl-benzaldehyde (0.570 g, 2.96 mmol) and 2-amino-N-(4-iodo-phenyl)-benzamide (1.00 g, 2.96 mmol) in N,N-dimethylacetamide (10 mL) was added sodium hydrogen sulfite (0.470 g, 4.44 mmol) and p-toluenesulfonic acid (0.280 g, 1.48 mmol). The reaction mixture was heated at 155° C. for 14 hours. The reaction mixture was cooled to room temperature and diluted with cold water (20 mL) to produce the precipitate. The yellow solid was filtered, washed with cold water (2×20 mL), methanol and dried under vacuum to provide crude product, which was purified by column chromatography (silica gel 230-400 mesh; 10% EtOAc/hexane as eluent) to give the title compound as white solid. Yield: 0.20 g (13%). MP 101-103° C. 1H-NMR (400 MHz, CDCl3): δ 8.38 (d, 1H), 7.81-7.78 (m, 2H), 7.75 (d, 2H), 7.59-7.48 (m, 1H), 7.01-6.85 (m, 4H), 3.98-3.81 (m, 4H), 2.40 (s, 6H), 2.01 (t, 1H). MS (ES+) m/z: 513.09 (M+1).
Reaction SMILES: [CH2:1]([C:3]1[NH:7][C:6]([CH:8]=[O:9])=[N:5][C:4]=1[C:10]([F:13])([F:12])[F:11])[CH3:2].Cl([O-])=[O:15].[Na+].P([O-])(O)(O)=O.[Na+].CC(=CC)C>>[CH2:1]([C:3]1[NH:7][C:6]([C:8]([OH:15])=[O:9])=[N:5][C:4]=1[C:10]([F:12])([F:13])[F:11])[CH3:2]
Reactant: CCc1[nH]c(C=O)nc1C(F)(F)F
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [Na+]
Product: CCc1[nH]c(C(=O)O)nc1C(F)(F)F
Yield: 99 %

Procedure:
The same operation as in Example (33c) was performed using 5-ethyl-4-(trifluoromethyl)-1H-imidazole-2-carbaldehyde obtained in Example (39d) (110 mg, 0.57 mmol), sodium chlorite (108 mg, 1.19 mmol), sodium dihydrogenphosphate (178 mg, 1.14 mmol) and 2-methyl-2-butene (0.3 mL, 2.84 mmol), to obtain 117.5 mg of the title compound as a white solid (99%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH2:9])=[CH:4][N:3]=1.[N+:10]([CH2:13][C:14](=O)[CH2:15][CH3:16])([O-:12])=[O:11]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:14]([CH2:15][CH3:16])=[CH:13][N+:10]([O-:12])=[O:11])=[CH:4][N:3]=1
Reactant: NCc1ccc(Cl)nc1
Reactant: CCC(=O)C[N+](=O)[O-]
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CCC(=C[N+](=O)[O-])NCc1ccc(Cl)nc1
Yield: 57.6 %

Procedure:
In 50 ml of toluene, 4.2 g of 2-chloro-5-pyridylmethylamine, 3.5 g of 1-nitro-2-butanone and 0.1 g of p-toluene sulfonic acid were mixed and the mixture was refluxed for 2 hours. The solvent was then distilled off and the residue was purified by column chromatography on silica gel to afford 4.1 g of compound No. 368. m.p. 95°-98° C.
Reaction SMILES: [OH:1][C@@H:2]([C:7]1[C:36]([CH3:37])=[N:35][C:34]2=[CH:38][C:31]3=[N:32][N:33]2[C:8]=1[N:9]1[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]2[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=2[C:26]2[CH:39]=[C:30]3[CH:29]=[CH:28][CH:27]=2)[CH2:11][CH2:10]1)[C:3]([O:5]C)=[O:4].C(O[C:49]1([CH3:53])[CH2:52][CH2:51][CH2:50]1)(=O)C.Cl(O)(=O)(=O)=O.[OH-].[Na+]>C(Cl)Cl.CO>[CH3:53][C:49]1([O:1][C@@H:2]([C:7]2[C:36]([CH3:37])=[N:35][C:34]3=[CH:38][C:31]4=[N:32][N:33]3[C:8]=2[N:9]2[CH2:43][CH2:42][C:12]([CH3:44])([O:13][CH2:14][CH2:15][CH2:16][CH2:17][C@H:18]([CH3:41])[O:19][C:20]3[CH:21]=[CH:22][C:23]([CH3:40])=[CH:24][C:25]=3[C:26]3[CH:39]=[C:30]4[CH:29]=[CH:28][CH:27]=3)[CH2:11][CH2:10]2)[C:3]([OH:5])=[O:4])[CH2:52][CH2:51][CH2:50]1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc3nn2c1N1CCC(C)(CC1)OCCCC[C@H](C)Oc1ccc(C)cc1-c1cccc-3c1
Reactant: CC(=O)OC1(C)CCC1
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: Cc1ccc2c(c1)-c1cccc(c1)-c1cc3nc(C)c([C@H](OC4(C)CCC4)C(=O)O)c(n3n1)N1CCC(C)(CC1)OCCCC[C@H](C)O2
Reaction time: 3 h
Yield: 35.8 %

Procedure:
To a stirred solution of methyl (2S)-2-hydroxy-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetate (40 mg, 0.067 mmol) in DCM (2 mL) and 1-methylcyclobutyl acetate (599 mg, 4.68 mmol) at rt was added 70 wt % perchloric acid (0.017 mL, 0.200 mmol). After 3 h, the reaction mixture was diluted with DCM (25 mL), carefully quenched with sat. NaHCO3 (5 mL), organic layer separated and washed with brine (10 mL), dried (Na2SO4), filtered and concentrated to give yellow paste. The crude was then tretated with 1N NaOH (0.334 mL, 0.334 mmol) in MeOH (1 mL) at 75° C. for 3 h. Mixture was then cooled and purified by prep HPLC to afford (2S)-2-(1-methylcyclobutoxy)-2-[(22S)-4,17,22,28-tetramethyl-21,27-dioxa-1,5,7,8-tetraazahexacyclo[26.2.2.16,9.110,14.02,7.015,20]tetratriaconta-2,4,6(34),8,10(33),11,13,15(20),16,18-decaen-3-yl]acetic acid (15.8 mg, 0.024 mmol, 36.2% yield). 1H NMR (500 MHz, DMSO-d6) δ 8.52 (s, 1H), 7.91 (d, J=7.9 Hz, 1H), 7.51 (t, J=7.6 Hz, 1H), 7.33 (d, J=7.6 Hz, 1H), 7.17-7.11 (m, 2H), 7.08 (s, 1H), 7.05 (d, J=8.2 Hz, 1H), 5.49 (s, 1H), 4.62 (d, J=5.5 Hz, 1H), 4.45 (t, J=12.2 Hz, 1H), 3.61-3.53 (m, 1H), 3.40-3.20 (m, 7H), 2.83 (d, J=10.4 Hz, 1H), 2.29 (s, 3H), 2.22 (q, J=10.0 Hz, 1H), 2.01-1.86 (m, 4H), 1.82 (br. s., 1H), 1.70-1.62 (m, 5H), 1.58-1.41 (m, 4H), 1.28 (s, 3H), 1.17 (s, 3H), 1.07 (d, J=5.8 Hz, 3H). LCMS (M+H)=653.6.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[F:13][C:14]([F:26])([F:25])[C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>>[F:26][C:14]([F:13])([F:25])[C:15]1[CH:16]=[CH:17][C:18]([S:21]([NH:1][C:2]2[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=2)(=[O:23])=[O:22])=[CH:19][CH:20]=1
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccc(C(F)(F)F)cc2)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 4-trifluoromethylbenzenesulfonyl chloride according to METHOD A, giving 0.14 g (33%) of an off-white solid after recrystallization from acetone/ether/petroleum ether: mp 174° C.; MS (Ionspray, [M+H]+) m/z 395; Anal. Calcd (found) for C14H13F3N2O4S2: C, 42.6 (42.4)%, H, 3.3 (2.8)%, N, 7.1 (6.8)%
Reaction SMILES: CO[C:3](=[O:31])[C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[C:13]([C:15]3[C:16]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)=[N:17][O:18][C:19]=3[C:20]([F:23])([F:22])[F:21])[N:12]=[CH:11]2)=[CH:6][CH:5]=1.[F:32][C:33]([F:37])([F:36])[CH2:34][NH2:35]>>[F:30][C:27]1[CH:26]=[CH:25][C:24]([C:16]2[C:15]([C:13]3[N:12]=[CH:11][N:10]([C:7]4[CH:8]=[CH:9][C:4]([C:3]([NH:35][CH2:34][C:33]([F:37])([F:36])[F:32])=[O:31])=[CH:5][CH:6]=4)[CH:14]=3)=[C:19]([C:20]([F:23])([F:21])[F:22])[O:18][N:17]=2)=[CH:29][CH:28]=1
Reactant: NCC(F)(F)F
Reactant: COC(=O)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Product: O=C(NCC(F)(F)F)c1ccc(-n2cnc(-c3c(-c4ccc(F)cc4)noc3C(F)(F)F)c2)cc1
Yield: 87 %

Procedure:
As described for Example 32, 4-{4-[3-(4-fluoro-phenyl)-5-trifluoromethyl-isoxazol-4-yl]-imidazol-1-yl}-benzoic acid methyl ester (100 mg, 0.23 mmol) was converted, using 2,2,2-trifluoroethylamine instead of cyclopropanemethylamine, to the title compound (100 mg, 87%) which was obtained as a white solid. MS: m/e=498.9 [M+H]+.
Reaction SMILES: C([O:3][C:4](=O)[CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:9])=[O:8])C.[BH4-].[Li+].Cl>O1CCCC1.CO>[OH:3][CH2:4][CH2:5][N:6]([C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[NH:22][C:21]([C:24]1[S:25][CH:26]([CH2:29][N:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[CH2:27][N:28]=1)=[CH:20]2)[S:7]([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:9]
Reactant: CCOC(=O)CN(c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12)S(=O)(=O)c1cccs1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CO
Product: O=S(=O)(c1cccs1)N(CCO)c1cccc2cc(C3=NCC(CN4CCOCC4)S3)[nH]c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 75.8 %

Procedure:
To a solution of N-{2-[5-(morpholinomethyl)-4,5-dihydro-1,3-thiazol-2-yl]-1H-indol-7-yl}-N-(2-thienylsulfonyl)glycine ethyl ester (100 mg) in tetrahydrofuran (10 mL) and methanol (2 mL) was added lithium borohydride (18.0 mg), and the mixture was stirred at room temperature for 4 hr. 1M Hydrochloric acid was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4), and concentrated. The residue was recrystallized from a mixed solvent of ethyl acetate-hexane to give the title compound (70 mg, yield 76%) as white crystals. MS:507(MH+).
Reaction SMILES: C([Li])CCC.[O:6]1[CH:10]=[CH:9][N:8]=[CH:7]1.[CH2:11]([Sn:13](Br)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]>CCOCC>[CH2:11]([Sn:13]([CH2:16][CH3:17])([CH2:14][CH3:15])[C:7]1[O:6][CH:10]=[CH:9][N:8]=1)[CH3:12]
Reactant: CC[Sn](Br)(CC)CC
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: CCOCC
Product: CC[Sn](CC)(CC)c1ncco1
Temperature: -78 °C
Reaction time: 0.08 h

Procedure:
n-Butyllithium (1.6M, 11 mL, 17.38 mmol) was added to a solution of oxazole (1.0 g, 14.48 mmol) in anhydrous ether (20 mL) stirred at −78° C. under nitrogen. After 5 min, triethylstannyl bromide (2.07 g, 7.24 mmol) was added, then the reaction mixture was allowed to warm to room temperature, and stirred for another 1 h. The mixture was quenched, and washed with 1N sodium hydroxide, dried through MgSO4, and then the solvent was evaporated to give the sub-title compound as a brown oily residue (1.0 g), which was used without further purification in the next step.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([OH:9])=[O:8])(=[O:3])[CH3:2].[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C1CCN2C(=NCCC2)CC1>C1(C)C=CC=CC=1>[C:1]([S:4][CH2:5][CH:6]([CH2:10][CH:11]([CH3:13])[CH3:12])[C:7]([O:9][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:8])(=[O:3])[CH3:2]
Reactant: BrCc1ccccc1
Reactant: CC(=O)SCC(CC(C)C)C(=O)O
Solvent: Cc1ccccc1
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)SCC(CC(C)C)C(=O)OCc1ccccc1
Yield: 83.2 %

Procedure:
A solution of 3-acetylthio-2-isobutylpropionic acid [obtained by Michael addition of thiolacetic acid onto 2-isobutylacrylic acid] (7 g, 34.3 mmol), benzyl bromide (4.29 ml, 36 mmol) and DBU (5.2 ml, 35 mmol) in toluene (55 ml) was stirred for 18 hours at room temperature. The solvents were evaporated in vacuo. The residue was partitioned between ethyl acetate and 5% sodium bicarbonate. The organic layer was washed with brine and dried over MgSO4. Purification of the residue by chromatography on silica gel (eluant: dichloromethane-ether (9:1)) gave benzyl 3-acetylthio-2-isobutylpropionate (8.4 g).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18](Cl)=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.C([Li])CCC.[CH3:32][C:33]([CH3:35])=[O:34]>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([C:33]([OH:34])([CH3:35])[CH3:32])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(C(C)(C)O)cc1Cl
Reaction time: 0.5 h

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (300.0 mg, 0.659 mmol) in tetrahydrofuran (6.0 mL) was added n-butyllithium (1.60 M solution in n-hexane, 1.03 mL, 1.65 mmol) at −78° C., and the mixture was stirred for 30 min. To the mixture was added acetone (0.24 mL, 3.30 mmol) at −78° C. The mixture was stirred at room temperature for 4.5 hrs. The mixture was quenched with aqueous saturated ammonium chloride and extracted with ethyl acetate (×3). The combined organic layer was washed with brine (×1), dried over anhydrous magnesium sulfate, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography eluting with a 10-70% ethyl acetate/n-hexane gradient mixture to give the title compound as a colorless amorphous (80.0 mg, 0.185 mmol, 28%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CCN(C(C)C)C(C)C>C(Cl)Cl>[CH2:12]([CH:19]1[CH2:24][CH2:23][N:22]([S:8]([C:5]2[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])[CH2:21][CH2:20]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: c1ccc(CC2CCNCC2)cc1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=S(=O)(c1ccc(Br)cc1)N1CCC(Cc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 17 h

Procedure:
4-Bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) at ambient temperature. 4-Benzylpiperidine (89 mg, 0.51 mmol) were diluted in DCM (2.0 mL) and treated with DIPEA (0.205 mL, 1.174 mmol) at ambient temperature. To this mixture a solution of 4-bromobenzene-1-sulfonyl chloride (100 mg, 0.391 mmol) dissolved in DCM (2.0 mL) was added and the reaction stirred at ambient temperature for 17 hours. The reaction was then concentrated in vacuo to afford the title compound, which was used without further purification. LRMS (ESI) calc'd for C18H20BrNO2S [M+H}+: 394. found 394