Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH3:25][C:26]1[N:31]=[C:30]([C:32]([OH:34])=O)[CH:29]=[CH:28][CH:27]=1.FC(F)(F)C(O)=O.[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH2:60])[CH2:59][CH2:58]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:68])([F:67])[F:66])[CH:45]=1>CN(C=O)C>[CH3:42][O:43][C:44]1[CH:64]=[CH:63][C:47]([O:48][C:49]2[CH:62]=[CH:61][C:52]([CH2:53][NH:54][C:55]([C:57]3([NH:60][C:32]([C:30]4[CH:29]=[CH:28][CH:27]=[C:26]([CH3:25])[N:31]=4)=[O:34])[CH2:58][CH2:59]3)=[O:56])=[CH:51][CH:50]=2)=[C:46]([C:65]([F:66])([F:67])[F:68])[CH:45]=1
Reactant: COc1ccc(Oc2ccc(CNC(=O)C3(N)CC3)cc2)c(C(F)(F)F)c1
Reactant: Cc1cccc(C(=O)O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: COc1ccc(Oc2ccc(CNC(=O)C3(NC(=O)c4cccc(C)n4)CC3)cc2)c(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
28 μL (0.20 mmol) of TEA and 118.8 mg (0.30 mmol) of HATU were added to a solution of 27.7 mg (0.20 mmol) of 6-methylpicolinic acid in 5 mL DMF and the mixture was stirred for 5 min at RT. Then 112 μL (0.81 mmol) of TEA and 100 mg (0.20 mmol) of 1-amino-cyclopropanecarboxylic acid 4-(4-methoxy-2-trifluoromethyl-phenoxy)-benzylamide-trifluoroacetic acid salt (from 85a) were added and the mixture was stirred overnight at RT. The reaction mixture was purified by chromatography (reversed phase).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9](Cl)=[N:10][C:11]=2[NH2:15].[CH2:20]([NH2:24])[CH2:21][CH2:22][CH3:23]>C(O)CCC>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][N:6]1[CH:14]=[N:13][C:12]2[C:7]1=[N:8][C:9]([NH:24][CH2:20][CH2:21][CH2:22][CH3:23])=[N:10][C:11]=2[NH2:15]
Reactant: CCCCN
Reactant: Nc1nc(Cl)nc2c1ncn2Cc1cccc(Br)c1
Solvent: CCCCO
Product: CCCCNc1nc(N)c2ncn(Cc3cccc(Br)c3)c2n1
Temperature: 170 °C

Procedure:
9-(3-bromobenzyl)-2-chloro-9H-purin-6-amine (2.3 g) (100 mg, 0.295 mmol), n-butylamine (0.5 mL) and n-butanol (1 mL) were combined and heated in the microwave at 170° C. for 15 minutes. The solvent was evaporated under vacuum and the residue was partitioned between water and ethylacetate. The organic layer was washed with brine, dried with Na2SO4 and evaporated under vacuum. The crude product was triturated with diethylether and filtered giving 9-(3-bromobenzyl)-N2-butyl-9H-purine-2,6-diamine (Compound 54) (60.9 mg) as off-white solid.
Reaction SMILES: [CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[NH:8][C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4].N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[CH3:59][C:60]1[S:61][C:62]([CH2:66]O)=[C:63]([CH3:65])[N:64]=1>C(OCC)(=O)C.O1CCCC1>[CH2:1]([C:5]1[N:6]=[C:7]([CH3:27])[N:8]([CH2:66][C:62]2[S:61][C:60]([CH3:59])=[N:64][C:63]=2[CH3:65])[C:9](=[O:26])[C:10]=1[CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18]2[C:19]([C:24]#[N:25])=[CH:20][CH:21]=[CH:22][CH:23]=2)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nc(C)[nH]c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: Cc1nc(C)c(CO)s1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCCc1nc(C)n(Cc2sc(C)nc2C)c(=O)c1Cc1ccc(-c2ccccc2C#N)cc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.5 %

Procedure:
A mixture of 4′-[(4-butyl-2-methyl-6-oxo-1,6-dihydropyrimidin-5-yl)methyl]biphenyl-2-carbonitrile (1 g), 1,1′-(azodicarbonyl)dipiperidine (1.41 g), tributylphosphine (1.56 mL), (2,4-dimethyl-1,3-thiazol-5-yl)methanol (0.6 g) and tetrahydrofuran (50 mL) was stirred at room temperature for 4 hr. The reaction mixture was diluted with ethyl acetate, washed with water and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (1.33 g, 99%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=1.[C:22]1([CH2:28][C:29](Cl)=[O:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>ClC1C=CC=CC=1>[NH2:8][C:6]1[C:5]([CH2:9][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[C:12]([O:20][CH3:21])[CH:11]=2)=[CH:4][N:3]=[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:7]=1
Reactant: COc1cc(Cc2cnc(N)nc2N)cc(OC)c1OC
Reactant: O=C(Cl)Cc1ccccc1
Solvent: Clc1ccccc1
Product: COc1cc(Cc2cnc(NC(=O)Cc3ccccc3)nc2N)cc(OC)c1OC

Procedure:
5.8 g of 2,4-diamino-5-(3,4,5-trimethoxybenzyl)-pyrimidine (trimethoprim) are suspended in 58 ml of chlorobenzene. At 125° C., 1.55 g of phenylacetyl chloride are dripped in, and the whole is maintained at this temperature for five hours. The difficultly soluble trimethoprim hydrochloride is filtered off and the filtrate is concentrated in vacuo. Upon recrystallization from ethanol there is obtained 4-amino-2-phenylacetamido-5-(3,4,5-trimethoxybenzyl)-pyrimidine of melting point 181° to 183° C.
Reaction SMILES: [I:1][C:2]1[CH:13]=[CH:12][C:5]([CH2:6][CH:7]([C:9]([OH:11])=[O:10])[NH2:8])=[CH:4][CH:3]=1.[Si](Cl)(C)(C)C.C(N(CC)CC)C.[C:26](OC(=O)C)(=[O:28])[CH3:27]>ClCCl>[C:26]([NH:8][C@H:7]([C:9]([OH:11])=[O:10])[CH2:6][C:5]1[CH:4]=[CH:3][C:2]([I:1])=[CH:13][CH:12]=1)(=[O:28])[CH3:27]
Reactant: CC(=O)OC(C)=O
Reactant: NC(Cc1ccc(I)cc1)C(=O)O
Agent: C[Si](C)(C)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H](Cc1ccc(I)cc1)C(=O)O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 94.2 %

Procedure:
A solution of 15 g (51 mmol) of 4-iodo-D,L-phenylalanine and 16.2 ml (127.5 mmol) of Me3SiCl in 150 mL of dichloromethane was heated at reflux for 1 h under N2. The reaction mixture was cooled to 0° C. with an ice bath and 17.7 mL (127 mmol) of triethyl amine was added, followed by 5.83 mL (61.2 mmol) of acetic anhydride. The mixture was stirred at 0° C. for 30 min, then warmed up to room temperature and stirred for another 30 min. The reaction was quenched by adding 1M aqueous sodium hydroxide and then the mixture was acidified with 2M aqueous hydrogen chloride to pH 1. The precipitate was collected by filtration and dried under vacuum to afford 16 g (95%) of N-acetyl-4-iodophenylalanine as a white solid: 1H NMR (DMSO-d6) 8.19 (d, 1H), 7.61 (d, 2H), 7.02 (d, 2H), 4.39-4.31 (m, 1H), 3.01-2.92 (dd, 1H), 3.80-2.69 (dd, 1H), 2.67 (s, 3H).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:16]=[CH:15][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:9][C:8]=1[C:17]([O:19][CH3:20])=[O:18])(=O)=O.CN(C=O)C.[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C(=O)([O-])[O-].[K+].[K+]>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[F:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[C:7]1[C:8]([C:17]([O:19][CH3:20])=[O:18])=[CH:9][C:10]([C:11]([O:13][CH3:14])=[O:12])=[CH:15][CH:16]=1
Reactant: COC(=O)c1ccc(OS(=O)(=O)C(F)(F)F)c(C(=O)OC)c1
Reactant: OB(O)c1ccccc1F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1ccc(-c2ccccc2F)c(C(=O)OC)c1
Temperature: 90 °C
Reaction time: 22 h
Yield: 82 %

Procedure:
To a stirred solution of dimethyl 4-(trifluoromethylsulfonyloxy)isophthalate T9.2 (1.60 g, 4.7 mmol) in DMF (9.4 mL, 4.7 mmol) at 23° C. was added 2-fluorophenylboronic acid (0.98 g, 7.0 mmol, commercially available from Aldrich), potassium carbonate (1.9 g, 14 mmol), and then tetrakis(triphenylphosphine)palladium (0.54 g, 0.47 mmol). The reaction mixture was heated to 90° C. and the reaction was stirred for 22 hours. The reaction was then cooled to room temperature, diluted with water, and extracted three times with EtOAc. After drying over anhydrous magnesium sulfate and filtering, the organic solvent was removed under reduced pressure and the product was then purified on silica gel (0-10% EtOAc in hexanes) to yield T19.1 as a colorless oil (1.10 g, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([CH2:16][NH2:17])[CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH2:16][CH:13]2[CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Reactant: NCC1CC1
Solvent: ClCCl
Product: O=S(=O)(NCC1CC1)c1ccc(Br)cc1F
Yield: 40 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclopropylmethylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-(cyclopropylmethyl)-2-fluorobenzenesulfonamide (0.18 g, 40%) was provided after purification. MS (ESI) m/z 308. HPLC purity 97.7% at 210-370 nm, 10.7 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (Ammonium Bicarb Buff. pH=9.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([O:24]CC4C=CC([N+]([O-])=O)=CC=4)=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.[H][H]>[Pd].O1CCCC1.CO>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:37][O:38][CH3:39])[C:8]([NH:10][CH:11]2[C:35](=[O:36])[N:13]3[C:14]([C:18]([O:20][CH2:21][C:22]([OH:24])=[O:23])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12)c1csc(N)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)OCC(=O)O)=CCS[C@H]12)c1csc(N)n1
Yield: 34.1 %

Procedure:
A suspension of 4-nitrobenzyloxycarbonylmethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer, 1.34 g) and 10% palladium on carbon (0.7 g) in tetrahydrofuran (50 ml) and methanol (15 ml) was subjected to catalytic reduction under hydrogen atmosphere at 1 atm., until the uptake of hydrogen ceased. After removing the insoluble substance by filtration, the filtrate was concentrated in vacuo. The residue was triturated with ethyl acetate to give powder (0.35 g) of carboxymethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn isomer), mp>250° C.
Reaction SMILES: C(OC(N1CC2C([CH2:11][N:12]([CH2:16][C:17]3[S:18][C:19]4[C:24]([N:25]5[CH2:30][CH2:29][O:28][CH2:27][CH2:26]5)=[N:23][C:22]([Cl:31])=[N:21][C:20]=4[N:32]=3)[CH2:13]2)C1)=O)(C)(C)C.[CH:33]1([CH2:36][N:37]2[CH2:42]CNC[CH2:38]2)[CH2:35][CH2:34]1>>[Cl:31][C:22]1[N:23]=[C:24]([N:25]2[CH2:30][CH2:29][O:28][CH2:27][CH2:26]2)[C:19]2[S:18][C:17]([CH2:16][N:12]3[CH2:11][CH2:42][N:37]([CH2:36][CH:33]4[CH2:35][CH2:34]4)[CH2:38][CH2:13]3)=[N:32][C:20]=2[N:21]=1
Reactant: C1CN(CC2CC2)CCN1
Reactant: CC(C)(C)OC(=O)N1CC2CN(Cc3nc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Product: Clc1nc(N2CCOCC2)c2sc(CN3CCN(CC4CC4)CC3)nc2n1

Procedure:
Prepared according to the method used in the preparation of 5-(5-chloro-7-morpholin-4-ylthiazolo[4,5-d]pyrimidin-2-ylmethyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester using 1-cyclopropylmethylpiperazine in place of hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester. The title compound was obtained as a yellow solid (170 mg, 58%).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH2:16][CH3:17])[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=1.C([O-])([O-])=O.[K+].[K+].[NH:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1>CN(C=O)C>[CH2:16]([N:4]1[C:5]2[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[N:8]=[CH:7][C:6]=2[N:15]=[C:3]1[CH2:2][N:24]1[CH:28]=[CH:27][N:26]=[C:25]1[C:29]1[S:30][CH:31]=[CH:32][N:33]=1)[CH3:17]
Reactant: c1c[nH]c(-c2nccs2)n1
Reactant: CCn1c(CCl)nc2cnc(C(F)(F)F)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCn1c(Cn2ccnc2-c2nccs2)nc2cnc(C(F)(F)F)cc21
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 2-Chloromethyl-1-ethyl-6-trifluoromethyl-1H-imidazo[4,5-c]pyridine (1 g, 3.8 mmol) in anhydrous DMF (15 mL) were added K2CO3 (2.68 g, 19 mmol), and 2-(1H-imidazol-2-yl)-thiazole (555 mg, 3.8 mmol) and stirred at room temperature for 48 h. The crude residue after usual work up was purified eluting with 5% MeOH-CH2Cl2 containing few drops of NH4OH to afford1-ethyl-2-{[2-(1,3-thiazol-2-yl)-1H-imidazol-1-yl]methyl}-6-(trifluoromethyl)-1H-imidazo[4,5-c]pyridine (800 mg, 80 %); 1H NMR (CD3OD): δ 8.83 (s, 1H), 8.14 (s, 1H), 7.71 (d, J=2.7 Hz, 1H), 7.53 (d, J=2.7 Hz, 1H), 7.45 (d, J=0.9 Hz, 1H), 7.19 (d, J=0.9 Hz, 1H), 6.30 (s, 2H), 4.54 (q, J=5.4 Hz, 2H), 1.46 (t, J=5.4 Hz, 3H); m/z 379 [M+1]
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1Br.[C:33]1(B(O)O)[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:32])[CH2:4][O:5][C:6]1[CH:14]=[C:13]2[CH2:15][CH2:16][CH2:17][C:12]2=[C:11]2[C:7]=1[C:8]([C:27](=[O:31])[C:28]([NH2:30])=[O:29])=[C:9]([CH3:26])[N:10]2[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1
Reactant: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1Br)CCC2
Reactant: OB(O)c1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: COC(=O)COc1cc2c(c3c1c(C(=O)C(N)=O)c(C)n3Cc1ccccc1-c1ccccc1)CCC2
Temperature: 100 °C
Yield: 30.7 %

Procedure:
A mixture of 2-[[3-(2-amino-1,2-dioxoethyl)-2-methyl-1-(2-bromobenzyl)-1,6,7,8-tetrahydrocyclopent[g]indol-4-yl]oxy]acetic acid methyl ester (200 mg, 0.400 mmol), phenylboronic acid (49 mg, 0.40 mmol), cesium carbonate (260 mg, 0.800 mmol), and tetrakis(triphenylphosphine)palladium(0) (14 mg, 0.0012 mmol) in dioxane (20 mL) was sparged with nitrogen for 5 min then heated at 100° C. for 6 h. The mixture was allowed to cool to room temperature and filtered through a pad of silica gel that was subsequently washed with acetone. The filtrate was concentrated in vacuo. Reverse-phase chromatography (C18, water/acetonitrile) of the residue provided 61 mg (31%) of the title compound. 1H NMR (CDCl3) δ 7.49 (t, J=7.0 Hz, 2H), 7.42 (t, J=7.3 Hz, 1H), 7.37 (d, J=7.0 Hz, 2H), 7.29 (m, 2H), 7.17 (m, 1H), 6.56 (bs, 1H), 6.48 (d, J=8.0 Hz, 1H), 6.44 (s, 1H), 5.42 (bs, 1H), 5.26 (s, 2H), 4.68 (s, 2H), 3.76 (s, 3H), 2.86 (t, J=7.3 Hz, 4H), 2.34 (s, 3H), 2.01 (quintet, J=7.0 Hz, 2H); MS FD+ m/e 496 (p); IR (KBr, cm−1) 3461, 1757, 1699, 1642.
Reaction SMILES: [CH:1](NC(C)C)(C)C.C([Li])CCC.[CH:13]([S:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14].CI.Cl>O1CCCC1>[CH:13]([S:16][CH:17]([CH3:1])[C:18]([O:20][CH2:21][CH3:22])=[O:19])([CH3:15])[CH3:14]
Reactant: CC(C)NC(C)C
Reactant: CCOC(=O)CSC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CI
Solvent: C1CCOC1
Product: CCOC(=O)C(C)SC(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 56.7 %

Procedure:
A solution of diisopropylamine (15.4 mL, 0.11 mol) in tetrahydrofuran is cooled to 0° C., treated dropwise with a 2.04 M solution of n-butyllithium in tetrahydro-furan (51.4 mL, 0.105 mol), stirred at 0° C. for 30 minutes, treated dropwise with ethyl (isopropylthio)acetate (16.3 g, 0.1 mol), stirred at 0° C. for 1 hour, treated with methyl iodide (15.6 g, 0.11 mol), stirred at room temperature for 20 hours, and poured into an ice-water mixture (100 g) containing 15 mL of 6 N hydrochloric acid. The resulting aqueous mixture is extracted with ether. The combined organic extracts are washed sequentially with water, saturated sodium thiosulfate solution, water and brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo to obtain a brown solution. Vacuum distillation of the brown solution gives the title product as a liquid (10.0 g) which is identified by NMR spectral analysis.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[C:10]([NH:13][CH:14]1[CH2:19][CH2:18][CH2:17][NH:16][CH2:15]1)(=[O:12])[CH3:11]>>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([N:16]2[CH2:17][CH2:18][CH2:19][CH:14]([NH:13][C:10](=[O:12])[CH3:11])[CH2:15]2)=[N:3][CH:4]=1)#[N:7]
Reactant: CC(=O)NC1CCCNC1
Reactant: N#Cc1ccc(Cl)nc1
Product: CC(=O)NC1CCCN(c2ccc(C#N)cn2)C1
Yield: 96 %

Procedure:
This compound was synthesized from 6-chloronicotinonitrile and 3-acetamidopiperidine as described for example 51 step 1 (850 mg, yield 96%) as white solid. 1H NMR (300 MHz, DMSO-d6) δ 8.44 (d, J=2.2 Hz, 1H), 7.88 (d, J=7.5 Hz, 1H), 7.82-7.79 (dd, J=9.0 Hz, 2.4 Hz, 1H), 6.86 (d, J=9.2 Hz, 1H), 4.20-4.14 (dd, J=12.7 Hz, 3.1 Hz, 1H), 4.08-4.02 (dd, J=13.2 Hz, 3.9 Hz, 1H), 3.62 (m, 1H), 3.22-3.14 (m, 1H), 3.01-2.93 (dd, J=12.9 Hz, 9.2 Hz, 1H), 1.87-1.71 (m, 2H), 1.78 (s, 3H), 1.53-1.41 (m, 2H). MS (ESI) m/z: Calculated for C13H16N4O: 244.13. found: 245.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1.[H-].[Na+].[CH3:32][N:33]1[CH:37]=[C:36]([S:38](Cl)(=[O:40])=[O:39])[CH:35]=[N:34]1>>[Br:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][C:7]2[S:8][C:9]([CH3:27])=[C:10]([CH3:26])[C:11]=2[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][S:38]([C:36]3[CH:35]=[N:34][N:33]([CH3:32])[CH:37]=3)(=[O:40])=[O:39])=[C:16]([CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)[CH:15]=2)=[O:13])=[CH:4][CH:3]=1
Reactant: Cn1cc(S(=O)(=O)Cl)cn1
Reactant: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(O)c(C3CCCC3)c2)c1C
Agent: [H-]
Agent: [Na+]
Product: Cc1sc(Cc2ccc(Br)cc2)c(C(=O)c2ccc(OS(=O)(=O)c3cnn(C)c3)c(C3CCCC3)c2)c1C
Reaction time: 0.5 h
Yield: 54.6 %

Procedure:
At ambient temperature, to a stirred solution of [2-(4-bromobenzyl)-4,5-dimethyl-thiophen-3-yl]-(3-cyclopentyl-4-hydroxy-phenyl)-methanone (0.283 g, 0.603 mmol) in N,N-DMF (3.0 mL) was added 60% sodium hydride/mineral oil (24.1 mg, 0.603 mmol). After 0.5 h, to the reaction was added a solution of 1-methyl-1H-pyrazole-4-sulfonyl chloride (0.120 g, 0.664 mmol) in N,N-DMF (1.3 mL). After 3 h, the reaction was quenched with 1N NaOH (40 mL), extracted with CH2Cl2, dried (Na2SO4) and concentrated. Purification on Biotage KP-Sil eluting with 20% acetone/hexane gave 0.202 g (55%) of the title compound as a yellow solid, mp 55-60 C. (DMSO-d6) δ 1.29-1.34 (m, 2H), 1.59-1.79 (m, 6H), 1.81 (s, 3H), 2.28 (s, 3H), 3.08 (quintet, 1H), 3.87 (s, 2H), 3.89 (s, 3H), 6.98 (d, 2H), 7.32 (d, 1H), 7.39 (d, 2H), 7.53-7.57 (m, 2H), 7.97 (s, 1H), 8.62 (s, 1H). IR (KBr) 3450, 2950, 1650, 1490, 1400, 1370 and 1170 cm−1. mass spectrum (+ESI) m/z 613/615 (M +H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1.[N+:15]([O-])([OH:17])=[O:16]>>[CH3:1][C:2]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[C:4]([CH:3]=1)[NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1cccc(Nc2ccccn2)c1
Product: Cc1ccc([N+](=O)[O-])c(Nc2ccccn2)c1
Temperature: 25 °C
Reaction time: 40 h
Yield: 18 %

Procedure:
Nitric acid (100 ml) and 3-methyl-N-(2-pyridyl)aniline (Hirota, M.; Kobayashi, K. Bull Chem. Soc. Jpn. 1981, 54, 1583) (16.8 g, 91.2 mmol) was mixed with ice cooling, the ice bath was removed and the reaction mixture was stirred for 40 h at room temperature. The reaction mixture was poured into saturated aqueous sodium bicarbonate solution (200 ml), the aqueous mixture was basified with the addition of potassium carbonate and the resulting basic solution was extracted with ethyl acetate (500 ml). The organic extracts were washed with water (50 ml) and brine (50 ml), dried (magnesium sulfate) and concentrated to dryness. The residue was purified by column chromatography (silica gel, 350 g; n-hexane/ethyl acetate (9/1)) to give 3.85 g (18%) of the titled compound as yellow solids. 1H-NMR (CDCl3) δ: 10.21 (1H, br.s), 8.54 (1H, s), 8.38-8.32 (1H, m), 8.13 (1H, d J=8.8 Hz), 7.68-7.60 (1H, m), 6.98-6.92 (2H, m), 6.80-6.70 (1H, m), 2,42 (3H, s).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([C@H:10]([CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)[C:11]([OH:13])=O)[CH3:9])=[O:7])([CH3:4])([CH3:3])[CH3:2].ON1C2N=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.[CH3:47][N:48]([CH3:63])[N:49]([CH3:62])[C:50](=[O:61])[C@H:51]([NH:59][CH3:60])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:9])[C@@H:10]([C:11](=[O:13])[N:59]([CH3:60])[C@@H:51]([C:50]([N:49]([CH3:62])[N:48]([CH3:63])[CH3:47])=[O:61])[CH2:52][C:53]1[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=1)[CH2:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)O
Reactant: CN[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)OC(C)(C)C)[C@H](Cc1ccc2ccccc2c1)C(=O)N(C)[C@H](Cc1ccccc1)C(=O)N(C)N(C)C
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
Then (2R)-2-(N-tert-butoxycarbonyl-N-methylamino)-3-(2-naphthyl)propionic acid (0.35 g, 1.07 mmol) was dissolved in methylene chloride (20 ml) and a mixture of 1-hydroxy-7-azabenzotriazole (0.15 g, 1.07 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g, 1.07 mmol) was added and stirred for 30 min. Then a mixture of (2R)-2-methylamino-3-phenylpropionic acid trimethylhydrazide (0.21 g, 0.89 mmol) and diisopropylethylamine (0.20 ml) was added and the mixture was stirred overnight. Methylene chloride (30 ml) was added and the mixture was washed with water (10 ml). The organic layer was washed with aqueous sodium bicarbonate (10 ml) and brine (50 ml), dried (MgSO4), filtered, concentrated to an oil, and chromatographed on silica (40 g) with heptane:ethyl acetate (3:7) to give 0.43 g of N-methyl-N-((1R)-1-(N-methyl-N-[(1R)-2-phenyl-1-(N,N',N'-trimethylhydrazinocarbonyl)ethyl]carbamoyl)-2-(2-naphthyl)ethyl)carbamic acid tert-butyl ester as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH2:24])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=3)[S:17][C:10]=12.[CH2:25]([O:27][CH:28](O)[C:29]([F:32])([F:31])[F:30])[CH3:26].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH2:25]([O:27][CH:28]([NH:24][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]2[CH:14]=[CH:13][N:12]=[C:11]3[CH:15]=[C:16]([C:18]4[N:19]=[CH:20][N:21]([CH3:23])[CH:22]=4)[S:17][C:10]=23)=[C:2]([F:1])[CH:3]=1)[C:29]([F:32])([F:31])[F:30])[CH3:26]
Reactant: Cn1cnc(-c2cc3nccc(Oc4ccc(N)cc4F)c3s2)c1
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Solvent: O
Product: CCOC(Nc1ccc(Oc2ccnc3cc(-c4cn(C)cn4)sc23)c(F)c1)C(F)(F)F
Yield: 68.7 %

Procedure:
A mixture of 12 (Scheme 3) (500 mg, 1.47 mmol), trifluoroacetaldehyde ethyl hemiacetal (0.35 mL, 2.94 mmol) and 4-toluenesulfonic acid monohydrate (280 mg, 1.47 mmol) in ethanol (25 mL) was heated to reflux for 48 h. The reaction mixture was concentrated and the residue was purified by column chromatography on silica gel (eluent methanol-dichloromethane 5:95 to 8:92) to afford title compound 318 (470 mg, 1.01 mmol, 68% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm: 8.42 (d, J=5.5 Hz, 1H), 7.85 (d, J=1.2 Hz, 1H), 7.72 (d, J=0.8 Hz, 1H), 7.67 (s, 1H), 7.29 (t, J=9.2 Hz, 1H), 7.08-7.02 (m, 2H), 3.86 (dd, J=9.2, 2.0 Hz, 1H), 6.52 (d, J=5.5 Hz, 1H), 5.68 (qd, J=10.4, 5.2 Hz, 1H), 3.72 (s, 3H), 3.76-3.59 (m, 2H), 1.15 (t, J=7.0 Hz, 3H). LRMS (M+1) 467.0 (100%).