Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1.S(Cl)([Cl:22])=O>ClCCl>[Cl:22][CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][O:6][C:7]1[C:8]([N+:13]([O-:15])=[O:14])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: O=S(Cl)Cl
Reactant: O=[N+]([O-])c1ncccc1OCc1ccccc1CO
Solvent: ClCCl
Product: O=[N+]([O-])c1ncccc1OCc1ccccc1CCl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-(2-hydroxymethylbenzyloxy)-2-nitropyridine (4.09 g) in dichloromethane (40 ml) was added thionyl chloride (0.24 ml) and the mixture was stirred at room temperature for 2 hours. The solvent was evaporated under reduced pressure to give 3-(2-chloromethylbenzyloxy)-2-nitropyridine (4.10 g).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]([OH:10])=[O:9])=[CH:4][N:3]=1.[CH3:11][Si](C=[N+]=[N-])(C)C>CO.C1C=CC=CC=1>[CH3:11][O:9][C:8]([C:5]1[CH:4]=[N:3][C:2]([Cl:1])=[N:7][CH:6]=1)=[O:10]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)c1cnc(Cl)nc1
Solvent: c1ccccc1
Solvent: CO
Product: COC(=O)c1cnc(Cl)nc1
Reaction time: 0.5 h

Procedure:
To a solution 2-chloropyrimidine-5-carboxylic acid (1.63 g, 10.28 mmol) in a mixture of methanol (20 ml) and benzene (50 ml) was added a solution of (trimethylsilyl)diazomethane in hexanes (2.0 M, 10 ml) at room temperature. The mixture was stirred for 30 min, and then was concentrated to give the title compound (1.77 g) as a yellow solid. Mass spectrum (ESI) 173.2 (M+1). 1H NMR (500 MHz, CDCl3) δ 9.18 (s, 2H), 4.02 (s, 3H).
Reaction SMILES: S(C1C=CC=CC=1C(NC1[N:11]([C@H:15]([CH2:19][CH2:20][CH2:21]CCC)[C:16]([OH:18])=[O:17])C=CN=1)=O)(O)(=O)=O.O[C:30]1C2N=NNC=2C=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C>[CH3:30][O:18][C:16](=[O:17])[C@@H:15]1[CH2:19][CH2:20][CH2:21][NH:11]1
Reactant: CCCCCC[C@H](C(=O)O)n1ccnc1NC(=O)c1ccccc1S(=O)(=O)O
Reactant: Oc1cccc2[nH]nnc12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: COC(=O)[C@@H]1CCCN1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
To a solution of the above amine in 10 mL of anhydrous DMF was added (R)-[(2-sulfobenzoyl)amino-1H-imidazol-1-yl]-octanoic acid (1.00 g, 2.45 mmol) and hydroxybenzotriazole (0.37 g, 2.77 mmol). This mixture was cooled to 0° C., and then treated with dicyclohexylcarbodiimide (0.56 g, 2.70 mmol). The resulting solution was warmed to room temperature and stirred for 48 hours. After removal of dicyclohexylurea by filtration, the filtrate was diluted with 100 mL of ethyl acetate and washed several times with H2O. The organic was then dried (Na2SO4) and concentrated in vacuo to an oil. Chromatography (SiO2, 5% methanol/CHCl3) provided 0.84 g (34%) of (R)-1-[1-oxo-2-[4-(2-sulfobenzoyl)amino-1H-imidazol-1-yl]octyl]-4-(cis)-methanesulfonamido))-phenoxy]-L-proline methyl ester as a white solid. M.Pt. 150° C. (dec).
Reaction SMILES: [CH3:1][N:2]1[C:6](OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:5][C:4]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[N:3]1.[C:24]1([C:30]#[CH:31])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>CCCCCCC.C(Cl)Cl>[CH3:1][N:2]1[C:6]([C:31]#[C:30][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[CH:5][C:4]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)=[N:3]1
Reactant: Cc1ccc(S(=O)(=O)Oc2cc(-c3ccccc3)nn2C)cc1
Reactant: C#Cc1ccccc1
Solvent: CCCCCCC
Solvent: ClCCl
Product: Cn1nc(-c2ccccc2)cc1C#Cc1ccccc1

Procedure:
This product was prepared from toluene-4-sulfonic acid 2-methyl-5-phenyl-2H-pyrazol-3-yl ester and phenylacetylene. Chromatography eluent: heptane/DCM 1:1; yield (64 mg, 50%); 1H NMR δ (CDCl3): 7.78 (d, J=8.22 Hz, 2H), 7.65-7.57 (m 5H), 7.43-7.34 (m, 3H), 6.63 (s, 1H), 3.98 (s, 3H); LCMS m/z: 258.
Reaction SMILES: [S-:1][C:2]#[N:3].[NH4+].Cl.[CH3:6][O:7][C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9].C1COCC1>CCOC(C)=O>[NH2:3][C:2]([N:15]1[CH2:14][CH2:13][C:12]2[C:17](=[CH:18][CH:19]=[C:10]([C:8]([O:7][CH3:6])=[O:9])[CH:11]=2)[CH2:16]1)=[S:1]
Reactant: N#C[S-]
Reactant: COC(=O)c1ccc2c(c1)CCNC2
Agent: Cl
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(c1)CCN(C(N)=S)C2
Temperature: 100 °C
Yield: 100.1 %

Procedure:
A mixture of ammonium thiocyanate (0.105 g, 1.384 mmol), 6-methoxycarbonyl-1,2,3,4-tetrahydroisoquinoline hydrochloride (0.3 g, 1.3176 mmol) and THF (2 mL) was heated in a CEM microwave reactor for 1 h at 100° C. Upon cooling to room temperature, the reaction mixture was diluted with EtOAc, and washed with H2O, 1 N HCl, saturated aqueous NaHCO3 and brine respectively, dried over anhydrous MgSO4, and concentrated under reduced pressure to afford methyl 2-(aminocarbonothioyl)-1,2,3,4-tetrahydroisoquinoline-6-carboxylate (0.33 g, 47%) as a white solid. LCMS: (FA) ES+251.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][C:5]2[CH:10]=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:16][CH2:15][CH2:14][CH2:13]3)[C:6]=2[N:7]=1.[Cl:17]N1C(=O)CCC1=O>ClCCl>[Cl:1][C:2]1[N:3]=[CH:4][C:5]2[C:10]([Cl:17])=[C:9]([CH3:11])[N:8]([CH:12]3[CH2:13][CH2:14][CH2:15][CH2:16]3)[C:6]=2[N:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: Cc1cc2cnc(Cl)nc2n1C1CCCC1
Solvent: ClCCl
Product: Cc1c(Cl)c2cnc(Cl)nc2n1C1CCCC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 84 %

Procedure:
To a solution of 2-Chloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (164 mg, 0.70 mmol) in dichloromethane (3 mL) is added N-chlorosuccinimide (0.4M in DCM, 1.1 eq) over 1 h. The reaction mixture is allowed to stir for 3 days at room temperature. The reaction mixture is diluted with dichloromethane and washed with saturated aqueous sodium bicarbonate followed by brine. The organic phase is concentrated and the crude product is purified by normal phase chromatography (SiO2, EtOAc/heptane) to obtain 2,5-Dichloro-7-cyclopentyl-6-methyl-7H-pyrrolo[2,3-d]pyrimidine (158 mg, 84%).
Reaction SMILES: [N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=O)[CH:5]=[N:4][N:3]=[N:2]1.S(Cl)([Cl:15])=O>C1C=CC=CC=1.CN(C=O)C>[N:1]1([CH2:6][CH2:7][CH2:8][CH2:9][C:10]([Cl:15])=[O:12])[CH:5]=[N:4][N:3]=[N:2]1
Reactant: O=C(O)CCCCn1cnnn1
Reactant: O=S(Cl)Cl
Solvent: CN(C)C=O
Solvent: c1ccccc1
Product: O=C(Cl)CCCCn1cnnn1

Procedure:
1 g of 5-(tetrazol-1-yl)-valeric acid is heated for 20 minutes at reflux temperature in 12 ml of absolute benzene with 0.6 ml of thionyl chloride and 2 drops of DMF. After concentration by evaporation under reduced pressure, the title compound is obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:11][CH:10]=2)[C:5]([NH2:8])=[N:6][CH:7]=1.[H-].[Na+].Cl[CH2:26][CH2:27][S:28](Cl)(=[O:30])=[O:29].O>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[CH:11][C:12]([O:15][C:16]3[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=3)=[CH:13][CH:14]=2)[C:5]2[N:6]([CH:7]=1)[CH2:26][CH2:27][S:28](=[O:30])(=[O:29])[N:8]=2
Reactant: Nc1ncc(Cl)cc1-c1ccc(Oc2ccc(Cl)cn2)cc1
Reactant: O=S(=O)(Cl)CCCl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: O=S1(=O)CCN2C=C(Cl)C=C(c3ccc(Oc4ccc(Cl)cn4)cc3)C2=N1
Temperature: 80 °C
Reaction time: 3 h
Yield: 93 %

Procedure:
A mixture of 5-chloro-3-{4-[(5-chloropyridin-2-yl)oxy]phenyl}pyridin-2-amine (440 mg) in THF (dry) (10 mL) was added to a mixture of NaH (60%, 265 mg) and 2-chloroethanesulfonyl chloride (648 mg) in THF (dry) (10 mL) at room temperature. The mixture was stirred at room temperature overnight and 80° C. for 3 hr. Water was added and the mixture was concentrated in vacuo. The residue was washed with water and Et2O to give an off-white solid. The solid was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (520 mg) as an off-white solid. The solid was crystallized from CH3CN—IPE to give a white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]([CH:12]1[CH2:21][NH:20][CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11].[C:22]([O:30][C:31](Cl)=[O:32])(=O)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[CH3:8][O:9][C:10]([CH:12]1[CH2:21][N:20]([C:31]([O:30][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:32])[CH2:19][CH2:18][C:13]21[O:17][CH2:16][CH2:15][O:14]2)=[O:11]
Reactant: COC(=O)C1CNCCC12OCCO2
Reactant: O=C(Cl)OC(=O)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(=O)OCc2ccccc2)CCC12OCCO2
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 84.7 %

Procedure:
Triethylamine (29.0 mL, 208 mmol) was added to a solution of 1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (91) (16.6, 82.5 mmol) in CH2Cl2 (159 mL, 0.5 M). The solution was cooled to 0° C. in an ice bath, then benzoylchloroformate (12.8 mL, 89.9 mmol) was added dropwise, with stirring, over 40 minutes. When the reaction was judged complete by TLC (0.75 h), the solution was concentrated in vacuo and purified by silica gel chromatography (10:3 Hexanes:EtOAc) to provide pure 8-benzyloxycarbonyl-1,4-dioxa-8-aza-spiro[4.5]-decane-6-carboxylic acid methyl ester (92) (23.43 g, 85%). 1H NMR (CDCl3): 7.41-7.25 (5H, m), 5.10 (2H, broad s), 4.02-3.50 (11H, m), 2.80-2.62 (1H, broad s), 2.20-2.00 (1H, broad s), 1.70-1.50 (1H, broad s) ppm. 13C NMR (CDCl3): 170.26, 154.88, 136.47, 128.32, 127.86, 127.74, 106.78, 67.09, 64.90, 64.59, 51.71, 48.63, 43.94, 41.76, 33.15 ppm.
Reaction SMILES: C([O:5][C:6]1[C:7]([CH:12](F)[N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH2:15][CH2:14]2)=[N:8][CH:9]=[CH:10][N:11]=1)(C)(C)C.[F:30]C(F)(F)C(O)=O>>[F:30][C:10]1[NH:11][C:6](=[O:5])[C:7]([CH2:12][N:13]2[CH2:18][CH2:17][CH:16]([C:19](=[O:28])[CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[F:27])[CH2:15][CH2:14]2)=[N:8][CH:9]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)Oc1nccnc1C(F)N1CCC(C(=O)Cc2ccccc2F)CC1
Product: O=C(Cc1ccccc1F)C1CCN(Cc2ncc(F)[nH]c2=O)CC1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
After dissolving 122 mg of 1-[1-(3-tert-butoxy-fluoro-2-pyrazinylmethyl)piperidin-4-yl]-2-(2-fluorophenyl)ethanone in 3 ml of trifluoroacetic acid, the mixture was stirred for 1.5 hours at room temperature. The reaction solution was cooled on ice, the pH was adjusted to 7 with a 5% sodium hydroxide solution, and extraction was performed with dichloromethane. The extract was dried over anhydrous magnesium sulfate, and then the solvent was distilled off under reduced pressure. Diethyl ether was added to the residue and the mixture was filtered to obtain the title compound (97 mg, 93% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][C:15]=1[F:16])[CH:12]1[CH2:17][CH:10]([CH2:11]1)[N:9]1[C:5]2=[N:6][C:7]([C:18]([NH2:20])=[O:19])=[CH:8]1.[I:21]N1C(=O)CCC1=O>CN(C=O)C>[F:16][C:15]1[C:2]([Br:1])=[CH:3][C:4]2[C:5]3[N:9]([CH:10]4[CH2:11][CH:12]([C:13]=2[CH:14]=1)[CH2:17]4)[C:8]([I:21])=[C:7]([C:18]([NH2:20])=[O:19])[N:6]=3
Reactant: O=C1CCC(=O)N1I
Reactant: NC(=O)c1cn2c(n1)-c1cc(Br)c(F)cc1C1CC2C1
Solvent: CN(C)C=O
Product: NC(=O)c1nc2n(c1I)C1CC(C1)c1cc(F)c(Br)cc1-2
Temperature: 70 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
9-bromo-10-fluoro-2,5-diazatetracyclo[11.1.1.0[2,6].0[7,12]]pentadeca-3,5,7,9,11-pentaene-4-carboxamide (20.00 g, 59.5 mmol) and N-iodosuccinimide (2.00 equiv., 27.60 g, 119 mmol) were dissolved in DMF (300 mL, 5 mL/mmol) and stirred at 70° C. overnight. After 24 hours, the solution was concentrated in vacuo and diluted with water, then triturated for 1 hour and filtered. The solid was redissolved in ethyl acetate, triturated for 1 hour, and filtered to afford 23.93 g (87% yield) of the titled compound as a light orange solid, 1H NMR (400 MHz, DMSO) δ 8.92 (d, J=7.4 Hz, 1H), 7.74 (br s, 1H), 7.37 (d, J=9.5 Hz, 1H), 7.16 (br s, 1H), 5.12 (td, J=6.7, 4.1 Hz, 1H), 3.68 (td, J=7.6, 4.1 Hz, 1H), 3.25-3.11 (m, 2H), 1.78-1.64 (m, 2H).
Reaction SMILES: O.[C:2]([OH:6])(=O)[CH:3]=O.Br.[NH2:8][C:9]1[S:10][CH2:11][C:12]([C:15]2[CH:20]=[C:19]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:18]([OH:25])=[C:17]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:16]=2)=[N:13][N:14]=1>O.C(O)(=O)C.Cl>[C:26]([C:17]1[CH:16]=[C:15]([C:12]2[N:14]3[N:13]=[CH:3][C:2](=[O:6])[N:8]=[C:9]3[S:10][CH:11]=2)[CH:20]=[C:19]([C:21]([CH3:24])([CH3:22])[CH3:23])[C:18]=1[OH:25])([CH3:29])([CH3:27])[CH3:28]
Reactant: CC(C)(C)c1cc(C2=NN=C(N)SC2)cc(C(C)(C)C)c1O
Reactant: O=CC(=O)O
Agent: Br
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(C)c1cc(-c2csc3nc(=O)cnn23)cc(C(C)(C)C)c1O
Temperature: 80 °C
Reaction time: 20 h

Procedure:
4.8 g (0.05 mol) of glyoxylic acid monohydrate in 75 ml of water were added dropwise to a solution of 10.0 g (0.025 mol) of 2-amino-5-(3,5-di-tert.butyl-4-hydroxyphenyl)-6H-1,3,4-thiadiazine hydrobromide from step (c1) in 250 ml of glacial acetic acid and 25 ml of 4N hydrochloric acid at 80° C. After the mixture had been stirred at 80° C. for 20 hours, it was evaporated under reduced pressure. It was advantageously possible to purify the solid residue by column chromatography on silica gel using methylene chloride/methanol (25:1) as the eluent and subsequent recrystallization from ethanol, and, from analytical and spectroscopic investigations, the product proved to be identical to that prepared by procedures (a) and (b).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:14]([OH:16])=O)[CH2:10][CH2:11][S:12][CH3:13])=[O:7])([CH3:4])([CH3:3])[CH3:2].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.Cl.[NH2:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:69])([CH3:68])[CH3:67])([CH3:65])[CH3:64])[CH:60]=2)[C:55]([Br:70])=[CH:54][CH:53]=1.C(N(CC)C(C)C)(C)C>>[C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:10][CH2:11][S:12][CH3:13])[C:14]([NH:51][C:52]1[C:61]2[C:56](=[CH:57][CH:58]=[C:59]([O:62][Si:63]([C:66]([CH3:68])([CH3:67])[CH3:69])([CH3:64])[CH3:65])[CH:60]=2)[C:55]([Br:70])=[CH:54][CH:53]=1)=[O:16])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(Br)ccc(N)c2c1
Reactant: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Product: CSCC[C@@H](NC(=O)OC(C)(C)C)C(=O)Nc1ccc(Br)c2ccc(O[Si](C)(C)C(C)(C)C)cc12
Reaction time: 3 h

Procedure:
To (R)-N-(tert-butoxycarbonyl)methionine (1.33 g, 5.48 mmol) in dry H2Cl2 (5 mL) under argon were added PYBOP (2.85 g, 5.48 mmol), 1-amino-4-bromo-7-(tert-butyldimethylsilyloxy)naphthalene hydrochloride, as described above Step E, (800 mg, 2.19 mmol), and N,N-diisopropylethylamine (1.7 mL, 9.9 mmol). The reaction mixture was stirred for 3 hours, then partitioned between 10% aqueous citric acid (100 mL) and CH2Cl2 (100 mL). The organic extract was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by flash column chromatography on silica, eluting with a gradient of hexane—5% EtOAc to hexane—20% EtOAc to yield the product as a pale foam.
Reaction SMILES: C(OC(=O)NC(C)(C)C/C=C/[C:12](=O)[N:13]([C@@H:15]([C:25](=[O:40])[N:26]([CH3:39])[C@@H:27]([C:35](=[O:38])[NH:36][CH3:37])[CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)C)(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+].C(=O)([O-])[O-].[Na+].[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl>[CH2:18]([O:17][CH2:16][C@@H:15]([NH:13][CH3:12])[C:25]([N:26]([CH3:39])[C@@H:27]([C:35](=[O:38])[NH:36][CH3:37])[CH2:28][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)=[O:40])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)N(C)C(=O)/C=C/CC(C)(C)NC(=O)OC(C)(C)C
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNC(=O)[C@@H](Cc1ccccc1)N(C)C(=O)[C@@H](COCc1ccccc1)NC
Temperature: 25 °C
Reaction time: 0.12 h
Yield: 75 %

Procedure:
((3E)-4-(N-((1R)-2-Benzyloxy-1-(N-methyl-N-((1R)-1-(methylcarbamoyl)-2-phenylethyl)carbamoyl)ethyl)-N-methylcarbamoyl)-1,1-dimethylbut-3-enyl)carbamic acid tert-butyl ester (0.275 g; 0.452 mmol) was dissolved in methylene chloride (3 mL) and trifluoroacetic acid (3 mL) was added and the reaction mixture was stirred for 7 min at room temperature. Methylene chloride (30 mL), an aqueous solution of sodium hydrogen carbonate/sodium carbonate (pH 9; 30 mL) and sodium hydrogen carbonate (solid) were added to the reaction mixture until pH 8. The organic phase was dried (magnesium sulfate) and evaporated in vacuo to afford 0.13 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([N+:15]([O-])=O)[CH:10]=1)=[O:4].[C:20]1([CH2:26][CH2:27][CH:28]=O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CCOC(C)=O>[F:1][C:2]([F:19])([F:18])[C:3]([NH:5][CH2:6][CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][CH2:28][CH2:27][CH2:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH:10]=1)=[O:4]
Reactant: O=C(NCC=Cc1cccc([N+](=O)[O-])c1)C(F)(F)F
Reactant: O=CCCc1ccccc1
Solvent: CCOC(C)=O
Product: O=C(NCCCc1cccc(NCCCc2ccccc2)c1)C(F)(F)F
Reaction time: 16 h

Procedure:
A mixture of 2,2,2-trifluoro-N-(3-(3-nitrophenyl)allyl)acetamide (1.0 g, 3.6 mmol) and 3-phenylpropanal (0.48 g, 3.6 mmol) in EtOAc was degassed and saturated with argon. 10% Pd/C (500 mg) was added to this solution and the resulting mixture was stirred under H2 at 1 atm for 16 hrs, filtered through Celite, and concentrated under reduced pressure. Purification by flash chromatography (40% to 50% EtOAc—hexanes gradient) gave 2,2,2-trifluoro-N-(3-(3-(3-phenylpropylamino)phenyl)propyl)acetamide as a colorless semi-solid. Yield (0.54 g, 41%). 1H NMR (400 MHz, DMSO-d6) δ 9.41 (br.s, 1H), 7.30-7.17 (m, 5H) 6.95 (t, J=7.6 Hz, 1H), 6.36-6.34 (m, 3H), 5.50 (t, J=5.6 Hz, 1H), 3.18 (q, J=6.4 Hz, 2H), 2.98 (q, J=6.4 Hz, 2H), 2.67 (t, J=8.0 Hz, 2H), 2.43 (t, J=7.6 Hz, 2H), 1.82 (quintet, J=7.6 Hz, 2H), 1.73 (quintet, J=7.6 Hz, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(O)C.[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14]OC1C=CC=C(C)C=1S([O-])(=O)=O>O>[F:10][C:11]([F:31])([C:27]([F:30])([F:29])[F:28])[CH2:12][CH2:13][CH2:14][N:1]1[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1
Reactant: C1CNCCN1
Reactant: Cc1cccc(OCCCC(F)(F)C(F)(F)F)c1S(=O)(=O)[O-]
Solvent: CCO
Solvent: O
Product: FC(F)(F)C(F)(F)CCCN1CCNCC1
Yield: 70.7 %

Procedure:
Piperazine (777 mg, 9.0 mmol) was added to ethanol solution (10 ml) of 4,4,5,5,5-pentafluoropentyloxytoluenesulfonate (600 mg, 1.81 mmol) and then heated under refluxing for 40 hours. After adding water, the reaction solution was extracted with ethyl acetate. The solvent was distilled off under reduced pressure from the extract to obtain 315 mg (yield: 100%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4](Cl)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1.C([O-])([O-])=O.[K+].[K+].[CH3:18][N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CCO>[Cl:1][C:2]1[N:3]=[C:4]([N:22]2[CH2:23][CH2:24][N:19]([CH3:18])[CH2:20][CH2:21]2)[C:5]2[S:10][CH:9]=[CH:8][C:6]=2[N:7]=1
Reactant: CN1CCNCC1
Reactant: Clc1nc(Cl)c2sccc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CN1CCN(c2nc(Cl)nc3ccsc23)CC1
Temperature: 25 °C
Reaction time: 12 h
Yield: 85.6 %

Procedure:
To a solution of 2,4-dichloro-thieno[3,2-d]pyrimidine (0.20 g, 1.0 mmol) in EtOH (3.2 mL) was added K2CO3 (0.31 g, 2.2 mmol) followed by N-methylpiperazine (0.13 mL, 1.2 mmol). After stirring at rt for 12 h, the mixture was filtered to afford 0.23 g of the desired product. MS: 269.0. 1H NMR (400 MHz, CD3OD) δ ppm 8.06 (d, J=5.6 Hz, 1H), 7.27 (d, J=5.6 Hz, 1H), 4.05-4.00 (m, 4H), 2.62-2.56 (m, 4H), 2.36 (s, 3H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]([OH:11])=O)[CH2:8][CH2:7]1)=[O:5])[CH3:2].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>C(Cl)Cl>[C:37]1([NH:36][C:9]([C:6]2([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:7][CH2:8]2)=[O:11])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1
Reactant: CCOC(=O)C1(C(=O)O)CC1
Reactant: Nc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1(C(=O)Nc2ccccc2)CC1
Reaction time: 0.17 h
Yield: 88.8 %

Procedure:
To a solution of 1-(ethoxycarbonyl)cyclopropane carboxylic acid (7.4 g, 46.84 mmol) in dry CH2Cl2 (70 mL) was added HATU (35.62 g, 93.67 mmol) at 0° C. After stirring for 10 minutes, a solution of the aniline (8.71 g, 93.67 mmol) and Et3N-(9.48 g, 93.67 mmol) in dry CH2Cl2 (30 mL) was then added and the reaction mixture was continued to stir at 40° C. for 24 hrs. The reaction mixture was quenched with water (30 mL) and extracted with CH2Cl2 (100 mL×3). The combined organic phases were dried over anhydrous Na2SO4, filtered and the filtrate was concentrated in vacuo. The residue was chromatographed with a silica gel column (1:5 (v/v) EtOAc/n-hexane) to afford the title compound as a pale yellow solid (9.7 g, 89%).
Reaction SMILES: [I:1][C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([NH:13][NH2:14])=[O:12])=[CH:10][C:5]2=[N:4][CH:3]=1.C(N(CC)CC)C.[C:22](Cl)(=[O:27])[C:23]([CH3:26])([CH3:25])[CH3:24].S(=O)(=O)(O)O>C1COCC1>[CH3:24][C:23]([CH3:26])([CH3:25])[C:22]([NH:14][NH:13][C:11]([C:9]1[CH:8]=[CH:7][N:6]2[C:2]([I:1])=[CH:3][N:4]=[C:5]2[CH:10]=1)=[O:12])=[O:27]
Reactant: CC(C)(C)C(=O)Cl
Reactant: NNC(=O)c1ccn2c(I)cnc2c1
Agent: O=S(=O)(O)O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)C(=O)NNC(=O)c1ccn2c(I)cnc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 75.5 %

Procedure:
3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid hydrazide (906 mg, 3 mmol) (prepared as described in 2 Step preparation of example 329) was suspended in THF (10 mL). Triethylamine (0.42 mL, 3 mmol) was added followed by pivaloyl chloride (0.37 mL, 3 mmol). The reaction was stirred for 2 h at room temperature. Concentrated sulphuric acid (0.5 mL) was added to the mixture and it was stirred 1 h further. The reaction was filtered, the solid washed with EtOAc and Et2O and dried to give 3-Iodo-imidazo[1,2-a]pyridine-7-carboxylic acid N′-(2,2-dimethylpropionyl) hydrazide (875 mg) as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1.[OH-].[K+].[CH3:18][CH2:19][OH:20]>CS(C)=O>[CH2:19]([O:20][C:2]1[C:3]([C:12]([F:15])([F:14])[F:13])=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([NH2:8])[CH:7]=1)[CH3:18]
Reactant: Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CCOc1cc(N)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from 5-chloro-2-nitro-4-trifluoromethyl-phenylamine [CAS-No. 35375-74-7] (7.06 g, 29.3 mmol) and KOH (4.26 g, 64.6 mmol) in EtOH (30 mL) and DMSO (60 mL) according to the general procedure E. Obtained as a yellow solid (4.20 g).
Reaction SMILES: [CH2:1]([O:8][CH2:9][C:10]([CH3:14])([OH:13])[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>CN(C)C=O>[CH2:1]([O:8][CH2:9][C:10]([O:13][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])[CH2:11][O:12][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(O)(CO)COCc1ccccc1
Reactant: ClCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(COCc1ccccc1)(COCc1ccccc1)OCc1ccccc1
Reaction time: 0.25 h

Procedure:
1 Benzyloxymethyl-1-methylethane-1,2-diol (2g) in dimethyl formamide (25 ml) was treated with a slight excess of sodium hydride (0.6g) at ambient temperature for 1h, then 90° for 15 mins. The product was then treated with benzyl chloride (4g) and 1,2,3-tribenzyloxy-2-methylpropane was isolated by evaporation of the solvent followed by chromatography on silica gel eluted with 9/1 methylene chloride/ether. The desired product was a colourless oil whose structure was confirmed by n.m.r.