Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([O:7]C)=O.[NH2:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]1[S:18][CH2:17][CH2:16][NH:15][C:14]2[N:19]([CH3:28])[N:20]=[C:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[C:13]1=2)[C:5]([NH:29][C:30]1[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=1)=[O:7]
Reactant: COC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Reactant: Cc1ncccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ncccc1NC(=O)c1ccc(C2SCCNc3c2c(-c2ccccn2)nn3C)c(Cl)c1
Temperature: -40 °C
Reaction time: 0.5 h
Yield: 8.8 %

Procedure:
To a mixture of methyl 3-chloro-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydropyrazolo[3,4-e][1,4]thiazepin-4-yl]benzoate (0.14 g, 0.34 mmol, Example #E.1) and 3-amino-2-methylpyridine (0.04 g, 0.37 mmol) in anhydrous THF (10 mL), was added lithium bis(trimethylsilyl)amide solution (1.3 mL, 1 M in THF, 1.3 mmol), at about −40° C. The resulting mixture was stirred for about 30 min, at about −40° C., and then quenched by the addition of water (10 mL) and ethyl acetate (130 mL). The layers were separated and the organic layer was washed with water (25 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, ethyl acetate/methanol 100:0 to 0:100) and preparative HPLC (Table 2, Method a) to afford 3-chloro-N-(2-methyl-3-pyridyl)-4-[1-methyl-3-(2-pyridyl)-4,6,7,8-tetrahydro-pyrazolo[3,4-e][1,4]thiazepin-4-yl]benzamide (0.0162 g, 0.03 mmol, 9%): LC-MS (Table 1, Method b) Rt=3.70 min, m/z 491 (M+H)+; 1H-NMR (CDCl3, Bruker 400 MHz) 2.56 (3H, s), 2.70-2.90 (2H, m), 3.26-3.35 (1H, m), 3.63-3.71 (1H, m) 3.60-4.00 (1H, br s) 3.84 (3H, s) 6.91 (1H, s) 7.09 (1H, ddd, J=1.2, 4.8, 7.9 Hz) 7.21 (1H, dd, J=4.8, 8.2 Hz) 7.44 (1H, d, J=8.0 Hz) 7.58-7.64 (3H, m) 7.80 (1H, d, J=8.0 Hz) 7.92 (1H, d, J=2.0 Hz) 8.28-8.34 (2H, m) 8.48-8.51 (1H, m).
Reaction SMILES: [C:1]1([PH:7][C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH:14]([Si:16]([O:23][CH2:24][CH3:25])([O:20][CH2:21][CH3:22])[O:17][CH2:18][CH3:19])=[CH2:15].C([O:30]OC(C)(C)C)(C)(C)C>>[C:8]1([P:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([CH2:15][CH2:14][Si:16]([O:17][CH2:18][CH3:19])([O:23][CH2:24][CH3:25])[O:20][CH2:21][CH3:22])=[O:30])[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: C=C[Si](OCC)(OCC)OCC
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: c1ccc(Pc2ccccc2)cc1
Product: CCO[Si](CCP(=O)(c1ccccc1)c1ccccc1)(OCC)OCC
Yield: 65.7 %

Procedure:
To diphenylphosphine (18.6 g, 1.0 mol) heated to 140° C. under nitrogen, a mixture of vinyl triethoxysilane (19.0 g, 1.0 mol) and di-t-butyl peroxide (1.92 g) is added with stirring during 3/4 hour. The solution is held at 140°-160° C for an additional hour. Distillation in vacuum gives the product (24.7 g, 65.7 percent yield, b.p. 162° C/0.3 mm, nD27 1.5370. The efficiency on the basis of the vinyl silane consumed is 93 percent. The H'NMR, delta (C6H6): 0.8 (m, 2H). 1.12 (t, 9H); 2.24 (m, 2H); 3.76 (q, 6H); and 7.0-7.7 (m, 10H) is consistent with the expected structure.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.NC1C=CC=CC=1O.[CH3:18][C:19]1[CH:20]=[CH:21][C:22](C(O)=O)=[CH:23][CH:24]=1>>[C:19]1([CH3:18])[CH:20]=[CH:21][C:22]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[N:3]=2)=[CH:23][CH:24]=1
Reactant: c1ccc2ocnc2c1
Reactant: Cc1ccc(C(=O)O)cc1
Agent: Nc1ccccc1O
Product: Cc1ccc(-c2nc3ccccc3o2)cc1

Procedure:
Preparation of the above benzoxazole reactant is as follows: o-aminophenol is reacted with p-toluic acid to yield 2-(p-tolyl)benzoxazole; this intermediate is then brominated with N-bromosuccinimide to obtain 2-4-bromomethylphenyl)-benzoxazole.
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1.[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH2:21]>CCOC(C)=O>[CH3:10][O:11][C:12]1[CH:17]=[C:16]([O:18][CH3:19])[CH:15]=[CH:14][C:13]=1[CH2:20][NH:21][C:2]1[CH:7]=[C:6]([I:8])[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COc1ccc(CN)c(OC)c1
Reactant: Cc1cnc(F)cc1I
Solvent: CCOC(C)=O
Product: COc1ccc(CNc2cc(I)c(C)cn2)c(OC)c1
Temperature: 110 °C
Reaction time: 8 h
Yield: 56.6 %

Procedure:
A mixture of 2-fluoro-4-iodo-5-methylpyridine (60 g, 253 mmol) and 1-(2,4-dimethoxyphenyl)methanamine (190.6 mL, 1270 mmol) was allowed to stir at 110° C. overnight. The mixture was allowed to cool to rt and was then diluted with EtOAc (190 mL). The resulting solid was filtered and washed with EtOAc and then purified by column chromatography to give N-(2,4-dimethoxybenzyl)-4-iodo-5-methylpyridin-2-amine (55.0 g, 57%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].C([N-]C(C)C)(C)C.[Li+].O1CCCC1.[S:26](Cl)([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([S:26]([C:29]1[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=1)(=[O:28])=[O:27])[CH:6]=[C:5]2[CH:11]=[O:12]
Reactant: O=Cc1c[nH]c2ccc(Br)cc12
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(Br)ccc32)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 248.8 %

Procedure:
To a solution of 5-bromoindole-3-carboxaldehyde (10 g) in dry tetrahydrofuran (75 ml), cooled to -78° C., was added with 2M lithium diisopropylamide/tetrahydrofuran (22.5 ml). After 30 min., the mixture was treated with a solution of tosyl chloride (9.5 g) in dry tetrahydrofuran (75 ml). The mixture was allowed to warm to room temperature overnight and evaporated. The residue was dissolved in dimethylformamide, filtered, and the filtrate was diluted with water. The precipitate was collected and recrystallized from ethanol to give 42 g (25%) of product.
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[CH2:12][C:11]2[C:6](=[CH:7][C:8]([Cl:13])=[CH:9][CH:10]=2)[C:5]1=O.O.[NH2:16][CH2:17][CH:18]([OH:20])[CH3:19]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[Cl:13][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:12]1[N:16]([CH2:17][CH:18]([OH:20])[CH3:19])[CH:2]=[CH:3][C:4]=1[CH2:5]2
Reactant: CC(O)CN
Reactant: O=CCC1Cc2ccc(Cl)cc2C1=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: CC(O)Cn1ccc2c1-c1ccc(Cl)cc1C2
Reaction time: 0.58 h
Yield: 80 %

Procedure:
A solution of 2 g of (RS)-2-(2-oxoethyl)-6-chlor-1-indanone and 100 mg of p-toluenesulfonic acid in 90 ml of anhydrous toluene was heated on a water separator. A solution of 2.88 g of (RS)-1-amino-2-propanol in 20 ml of anhydrous toluene was added dropwise to the boiling solution over a period of 5 minutes. Subsequently, the mixture was boiled for an additional 35 minutes, during which the solvent was reduced to a volume of 30 ml. The cooled reaction mixture was purified by column chromatography on silica gel (ethyl acetate/toluene 1:1). There were obtained 1.9 g (80%) of (RS)-1-(6-chloro-1,4-dihydro-indeno[1,2-b]pyrrol-1-yl)-propan-2-ol as a brown oil which was used directly in the next reaction.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[CH2:3].N12CCCN=C1CCCCC2.Br[CH:22]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[C:23]([O:25][CH2:26][CH3:27])=[O:24]>C1(C)C=CC=CC=1.[Cu](Br)Br>[CH2:26]([O:25][C:23]([C:22]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:1][C:2]1([CH3:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:24])[CH3:27]
Reactant: C=C(C)c1ccccc1
Reactant: CCOC(=O)C(Br)C(=O)OCC
Agent: Br[Cu]Br
Solvent: C1CCC2=NCCCN2CC1
Solvent: Cc1ccccc1
Product: CCOC(=O)C1(C(=O)OCC)CC1(C)c1ccccc1
Temperature: 25 °C
Reaction time: 22 h
Yield: 45.2 %

Procedure:
To a solution of α-methylstyrene (570 mL, 4.4 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (240 mL, 1.6 mol) and copper (II) bromide (9.8 g, 44 mmol) in toluene (700 mL) was added diethyl bromomalonate (210 g, 0.88 mol) at 0° C., and the mixture was stirred for 22 hours at room temperature. The obtained solution was washed with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, and dried over sodium sulfate. Then, the solution was filtrated and the solvent was evaporated. The obtained residue was separated and purified by silica gel chromatography (hexane:ethyl acetate=20:1) to give the title compound (110 g, yield 45%) as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14](SC)[N:15]=[CH:16][C:11]=2[CH:10]=1.[CH2:23]([N:25]([CH2:36][CH3:37])[CH2:26][CH2:27][O:28][C:29]1[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=1)[CH3:24].COCCOCCOC>O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[C:9]1[C:20](=[O:21])[N:19]([CH3:22])[C:12]2[N:13]=[C:14]([NH:33][C:32]3[CH:31]=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:25]([CH2:36][CH3:37])[CH2:23][CH3:24])=[CH:35][CH:34]=3)[N:15]=[CH:16][C:11]=2[CH:10]=1
Reactant: CSc1ncc2cc(-c3c(Cl)cccc3Cl)c(=O)n(C)c2n1
Reactant: CCN(CC)CCOc1ccc(N)cc1
Solvent: COCCOCCOC
Solvent: O
Product: CCN(CC)CCOc1ccc(Nc2ncc3cc(-c4c(Cl)cccc4Cl)c(=O)n(C)c3n2)cc1
Temperature: 150 °C

Procedure:
A mixture of 0.155 g (0.40 mmol) of 6-(2,6-dichlorophenyl)-8-methyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one of Example 37, 0.167 g (0.80 mmol) of 4-(2-diethylaminoethoxy)aniline and 1 mL of (2-methoxyethyl)ether (bp 162° C.) was heated with stirring in a 150° C. oil bath. All solid gradually dissolved over a period of 10 minutes. The solution was heated another 10 minutes and cooled to 100° C. Water was added dropwise until slight turbidity. The crystals that separated on inducement were filtered, washed with 0.5 mL of ether and 2 mL of water, and dried; wt 0.105 g. Purification was effected by chromatography eluting with chloroform, then ethyl acetate and finally 10% methanol/chloroform to obtain fraction with pure product. The eluent was evaporated to dryness. The remaining amorphous solid was dissolved in 1 mL of warm ethyl acetate. The crystals that separated on inducement were filtered and washed sparingly with ethyl acetate and ether; wt 0.042 g; mp 141°-143° C.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([Cl:18])[CH:13]=2)=[N:8][O:9][C:10]=1[CH3:11])=[O:5])C.[OH-].[Na+].Cl.O>C(O)C>[Cl:18][C:14]1[CH:13]=[C:12]([C:7]2[C:6]([C:4]([OH:5])=[O:3])=[C:10]([CH3:11])[O:9][N:8]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: CCOC(=O)c1c(-c2cccc(Cl)c2)noc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1onc(-c2cccc(Cl)c2)c1C(=O)O
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of 3-(3-chloro-phenyl)-5-methyl-isoxazole-4-carboxylic acid ethyl ester (9.1 g, 36 mmol) in ethanol (50 mL) was added aqueous sodium hydroxide (4 N, 10 mL). After heating at reflux for 1 h the mixture was cooled to room temperature and acidified with HCl (4 N, 10 mL) and water (10 mL) at 0° C. Purification by filtration and drying afforded the title compound (8.3 g, 97%) which was obtained as a white solid. Mp: 171-173° C.
Reaction SMILES: [C:1]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:17]([O:21][CH2:22][CH:23]1[C:35]2[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=2[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)(=[O:20])[NH:18][NH2:19].C1(N=C=NC2CCCCC2)CCCCC1>CN(C)C=O>[C:17]([NH:18][NH:19][C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][NH:8][C:1]([O:3][C:4]([CH3:5])([CH3:6])[CH3:7])=[O:2])([O:21][CH2:22][CH:23]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]2[C:24]1=[CH:25][CH:26]=[CH:27][CH:28]=2)=[O:20]
Reactant: CC(C)(C)OC(=O)NCCCCCC(=O)O
Reactant: NNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCCCC(=O)NNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 0 °C
Reaction time: 2 h
Yield: 60.8 %

Procedure:
A 250 ml round bottom flask was charged with 4,190 g (0.0181 mol) of N-BOC-6-aminocaproic acid, 4.60 g of 9-fluorenylmethyl carbazate (FMOC), (prepared by the method of Carpino et. al., 1972, J. Org. Chem., 37:3404) and 35 ml of N,N-dimethylformamide. The reaction solution was cooled to 0° C. and then 3.75 g (0.0182 mol) of 1,3-dicyclohexylcarbodiimide (Aldrich) was added. The reaction mixture was allowed to stir for 2 h at 0° C. The white precipitate which formed during this time was filtered off and the solvents evaporated under reduced pressure. The distillation residue was applied to a 225 cc pad of silica gel (Merck), which was then washed with 1L of chloroform. The product was then eluted from the column using 1L of 50% methanol in chloroform. The solvents were evaporated from the desired eluent fractions to give 4.98 g (0.011 mol, 59% yield) of N-BOC-6-aminocaproic acid (N'-FMOC-hydrazide) as a yellow oil. 1H NMR (DMSO-d6) showed the peaks observed in the starting material and new protons in the aromatic region between 7-8 ppm (FMOC group).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]2[CH:13]=[C:12]([O:14][C:15]3[CH:23]=[CH:22][CH:21]=[CH:20][C:16]=3[C:17]([OH:19])=O)[CH:11]=[CH:10][N:9]=2)[S:5][CH:6]=1.C(N(CC)CC)C.C([Cl:36])(=O)OCC.[CH2:37]([N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1)[CH3:38]>C1COCC1>[ClH:36].[ClH:36].[CH2:37]([N:39]1[CH2:44][CH2:43][N:42]([C:17]([C:16]2[CH:20]=[CH:21][CH:22]=[CH:23][C:15]=2[O:14][C:12]2[CH:11]=[CH:10][N:9]=[C:8]([NH:7][C:4]3[S:5][CH:6]=[C:2]([CH3:1])[N:3]=3)[CH:13]=2)=[O:19])[CH2:41][CH2:40]1)[CH3:38]
Reactant: Cc1csc(Nc2cc(Oc3ccccc3C(=O)O)ccn2)n1
Reactant: CCN1CCNCC1
Reactant: CCOC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCN1CCN(C(=O)c2ccccc2Oc2ccnc(Nc3nc(C)cs3)c2)CC1
Product: Cl
Yield: 59.9 %

Procedure:
Using the method of Example 32, 2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)-benzoic acid (0.1 g, 0.3055 mmol), triethylamine (0.2129 mL, 1.527 mmol), ethyl carbonochloridate (0.03213 mL, 0.3360 mmol), 1-ethylpiperazine (0.1164 mL, 0.9164 mmol) in THF (2 mL) were reacted to provide (4-ethylpiperazin-1-yl)(2-(2-(4-methylthiazol-2-ylamino)pyridin-4-yloxy)phenyl)methanone dihydrochloride (0.05 g, 32.64% yield). 1H NMR (DMSO) δ 8.18 (d, 1H), 7.6859 (dt, 1H), 7.54 (d, 1H), 7.42 (t, 1H), 7.29 (d, 1H), 6.59 (m, 2H), 6.56 (m, 1H), 3.35-3.63 (m, 4H), 3.12 (m, 2H), 2.50 (m, 4H, under DMSO), 2.22 (d, 3H), 1.22 (t, 2H); Mass spectrum (esi) m/z=424(100) (M+H).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[C:6]([F:9])[C:5]([F:10])=[C:4]([F:11])[C:3]=1[F:12].C(Cl)C[Cl:15].Cl.[N:18]12[CH2:25][CH2:24][CH:21]([CH2:22][CH2:23]1)[CH:20]([CH2:26][C:27](O)=[O:28])[CH2:19]2>C(N(CC)C(C)C)(C)C.ClCCl>[ClH:15].[N:18]12[CH2:23][CH2:22][CH:21]([CH2:24][CH2:25]1)[CH:20]([CH2:26][C:27]([O:8][C:7]1[C:2]([F:1])=[C:3]([F:12])[C:4]([F:11])=[C:5]([F:10])[C:6]=1[F:9])=[O:28])[CH2:19]2
Reactant: Oc1c(F)c(F)c(F)c(F)c1F
Reactant: O=C(O)CC1CN2CCC1CC2
Reactant: ClCCCl
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CC1CN2CCC1CC2)Oc1c(F)c(F)c(F)c(F)c1F
Temperature: 25 °C
Reaction time: 18 h

Procedure:
358 mg (1.94 mmol) of pentafluorophenol, 120.5 mg (0.63 mmol) of EDC and 1 drop of N,N-diisopropylethylamine are added to a solution of 100 mg (0.49 mmol) of 1-azabicyclo[2.2.2]oct-3-ylacetic acid hydrochloride in 4 ml of dichloromethane at 0° C. The mixture is stirred at room temperature for 18 h. The contents of the flask are concentrated in vacuo and dried under high vacuum. The resulting crude product is employed without further purification in the following stages.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH2:8][CH3:9])=[CH:6][C:5]([Br:10])=[CH:4][C:3]=1[NH2:11].O.O.[C:14](O)(=[O:18])[C:15](O)=[O:16]>Cl.[OH-].[Na+]>[Br:10][C:5]1[CH:4]=[C:3]2[C:2]([NH:1][C:14](=[O:18])[C:15](=[O:16])[NH:11]2)=[C:7]([CH2:8][CH3:9])[CH:6]=1
Reactant: O=C(O)C(=O)O
Reactant: CCc1cc(Br)cc(N)c1N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CCc1cc(Br)cc2[nH]c(=O)c(=O)[nH]c12
Temperature: 25 °C
Yield: 31.9 %

Procedure:
A mixture of 1,2-diamino-4-bromo-6-ethylbenzene (40 mg, 0.14 mmol) and oxalic acid dihydrate (25 mg, 0.20 mmol, used as received) in 4N HCl (1.5 mL) was refluxed at 120°-5° C. for 3 h, then cooled to room temperature. The mixture was centrifuged and the liquid layer was removed. The yellow solid was washed with cold water (2×1 mL), collected by filtration, and dried at 60° C. under reduced pressure for 2 h, affording 40 mg of crude product (80%) as a yellow powder. The crude product was dissolved in 1N NaOH (2 mL) and filtered. The filtrate was acidified to pH=5, affording 12 mg of pure title compound; mp: >350° C. (dec. from 300° C.); IR (KBr, cm-1): 3410, 3164, 2919, 1740, 1705, 1600. 1H NMR (DMSO-d6): δ1.099 (t, 3H, J=6 Hz), 2.741 (q, 2H, J=7.2 Hz), 7.117 (d, 1H, J=1.8 Hz), 7,138 (d, 1H, J=1.8 Hz); 11.343 (s, 1H); 11.958 (s, 1H). HRMS: calcd for C10H9BrN2O2 (M+) m/z: 267.9846; found 267.9853.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([C:9]2[N:13]3[CH:14]=[CH:15][C:16]([C:19]([OH:22])([CH3:21])[CH3:20])=[C:17]([F:18])[C:12]3=[N:11][CH:10]=2)[CH:5]=[CH:6][C:7]=1[F:8].[CH:23]([C:26]1[CH:27]=[CH:28][C:29]([O:35][CH3:36])=[C:30](B(O)O)[CH:31]=1)([CH3:25])[CH3:24]>>[F:18][C:17]1[C:12]2[N:13]([C:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([C:30]4[CH:31]=[C:26]([CH:23]([CH3:25])[CH3:24])[CH:27]=[CH:28][C:29]=4[O:35][CH3:36])[CH:3]=3)=[CH:10][N:11]=2)[CH:14]=[CH:15][C:16]=1[C:19]([OH:22])([CH3:21])[CH3:20]
Reactant: CC(C)(O)c1ccn2c(-c3ccc(F)c(Cl)c3)cnc2c1F
Reactant: COc1ccc(C(C)C)cc1B(O)O
Product: COc1ccc(C(C)C)cc1-c1cc(-c2cnc3c(F)c(C(C)(C)O)ccn23)ccc1F
Yield: 6 %

Procedure:
2-[3-(3-Chloro-4-fluorophenyl)-8-fluoroimidazo[1,2-α]pyridin-7-yl]-propan-2-ol and 5-isopropyl-2-methoxybenzeneboronic acid were coupled in the same way as in Example 30 to give 2-[8-fluoro-3-(2-fluoro-5′-isopropyl-2′-methoxybiphenyl-5-yl)imidazo[1,2-α]pyridin-7-yl]propan-2-ol as an off-white solid (8 mg, 6%): m/z (ES+) 437 [MH+].
Reaction SMILES: CC1(C)CO[CH:5]([CH:8]([C@@H:10]2[C@:27]3([CH3:28])[C@H:13]([C@H:14]4[C@H:24]([CH2:25][CH2:26]3)[C@:22]3([CH3:23])[C:17]([CH2:18][C@@H:19]([OH:30])[C@@H:20]5[O:29][C@@H:21]53)=[CH:16][C@H:15]4[OH:31])[CH2:12][CH2:11]2)[CH3:9])[O:4]C1.C1(C)C=CC(S(O)(=O)=O)=CC=1.C(OCC)(=O)C.CCCCCC>CC(C)=O>[O:29]1[C@H:20]2[C@H:19]([OH:30])[CH2:18][C:17]3[C@:22]([CH3:23])([C@@H:21]12)[C@@H:24]1[C@H:14]([C@H:13]2[C@:27]([CH3:28])([CH2:26][CH2:25]1)[C@@H:10]([CH:8]([CH:5]=[O:4])[CH3:9])[CH2:11][CH2:12]2)[C@H:15]([OH:31])[CH:16]=3
Reactant: CC(C1OCC(C)(C)CO1)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(C)=O
Product: CC(C=O)[C@H]1CC[C@H]2[C@@H]3[C@H](O)C=C4C[C@@H](O)[C@@H]5O[C@@H]5[C@]4(C)[C@H]3CC[C@]12C
Temperature: 25 °C
Reaction time: 12 h
Yield: 66.6 %

Procedure:
In 2.5 ml of acetone was dissolved 2.2 mg (0.005 mmole) of 20-(5,5-dimethyl-1,3-dioxan-2-yl)-1α,2α-epoxypregn-5-ene-3β,7α-diol, followed by addition of 0.5 ml of a 1 mmol/1 solution of p-toluenesulfonic acid in acetone (containing 0.0005 mmole of p-toluenesulfonic acid). The mixture was stirred at room temperature for 12 hours. From the reaction mixture thus obtained, the solvent was distilled off under reduced pressure and methylene chloride was added to the residue. This methylene chloride solution was washed successively with saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride solution and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure and the residue was purified by silica gel chromatography (eluent:ethyl acetate-hexane=1:5, v/v) to recover 1.2 mg of 1α,2α-epoxy- 3β,7α-dihydroxypregna-5-ene-20-carbaldehyde (yield: 67%).
Reaction SMILES: S(C1C=CC(C)=CC=1)([O-])(=O)=O.[CH2:12]([O:17][C:18](=[O:24])[C@@H:19]([NH2:23])[CH:20]([CH3:22])[CH3:21])[C:13]([CH3:16])([CH3:15])[CH3:14].[P:25](Cl)(Cl)(=[O:37])[O:26][C:27]1[CH:28]=[C:29]2[C:34](=[CH:35][CH:36]=1)[N:33]=[CH:32][CH:31]=[CH:30]2.C(Cl)[Cl:41]>>[Cl:41][C:32]1[CH:31]=[CH:30][C:29]2[C:34](=[CH:35][CH:36]=[C:27]([O:26][P:25](=[N:23][C@@H:19]([CH:20]([CH3:21])[CH3:22])[C:18]([O:17][CH2:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:24])=[O:37])[CH:28]=2)[N:33]=1
Reactant: O=P(Cl)(Cl)Oc1ccc2ncccc2c1
Reactant: ClCCl
Reactant: CC(C)[C@H](N)C(=O)OCC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CC(C)[C@H](N=[P+]([O-])Oc1ccc2nc(Cl)ccc2c1)C(=O)OCC(C)(C)C

Procedure:
Using the general procedure for synthesizing naphthyl (amino acid ester) phosphorochloridates the tosylate salt of (S)-neopentyl-2-amino-3-methylbutanoate (1.9 g), quinolin-6-yl phosphorodichloridate (1.4 g), TEA (1.49 mL) and DCM (20 mL) were combined to give 600 mg of desired (2S)-neopentyl 2-(chloro(quinolin-6-yloxy)phosphorylamino)-3-methylbutanoate as thick oil.
Reaction SMILES: [CH2:1]([C:4]1[N:9]=[C:8]([NH:10][C:11](=[O:32])[NH:12][C:13]2[N:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([NH:24]C(=O)OC(C)(C)C)=[CH:20][CH:19]=3)[S:16][CH:17]=2)[CH:7]=[CH:6][CH:5]=1)[CH2:2][CH3:3].C1(SC)C=CC=CC=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:15]2[S:16][CH:17]=[C:13]([NH:12][C:11]([NH:10][C:8]3[CH:7]=[CH:6][CH:5]=[C:4]([CH2:1][CH2:2][CH3:3])[N:9]=3)=[O:32])[N:14]=2)=[CH:19][CH:20]=1
Reactant: CCCc1cccc(NC(=O)Nc2csc(-c3ccc(NC(=O)OC(C)(C)C)cc3)n2)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Solvent: CSc1ccccc1
Product: CCCc1cccc(NC(=O)Nc2csc(-c3ccc(N)cc3)n2)n1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
In an oven-dried, 25-mL, round-bottomed flask were placed N-[6-propylpyridine]-N′-[4-[N-Bocamino]pheny]-4-thiazolyl]urea (55 mg, 0.12 mmol, Example 187), thioanisole (0.35 mL) in CH2Cl2 (10 mL). TFA (0.35 mL) was added, the mixture was stirred at RT for 6 h then concentrated in vacuo. Purification by flash chromatography on silica gel [EtOAc/hexane (extracted with aq. NH4OH), 40:60] afforded the title compound. MS m/z: 354.0 (M+H). Calc'd for C18H19N50S: 353.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[N+:3]=1[O-:9].[C:10]1([SH:16])[CH:15]=[CH:14][CH:13]=CC=1.[OH-].[Na+]>CS(C)=O>[Cl:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:13]2[S:16][CH:10]=[CH:15][CH:14]=2)[N+:3]=1[O-:9]
Reactant: [O-][n+]1c(Cl)cccc1Cl
Reactant: Sc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: [O-][n+]1c(Cl)cccc1-c1cccs1

Procedure:
The 1.64 g (0.010 moles) of 2,6-dichloropyridine N-oxide and 1.11 g (99%) (0.010 moles) of thiophenol was reacted with 0.400 g (0.010 moles) of ground sodium hydroxide of 16.4 ml of DMSO at 80° C. for 5 hours to give 2-chloro-6-thiophenylpyridine N-oxide. It was reacted with 1.20 g (0.030 moles) of ground sodium hydroxide at 80° C. for 2.5 hours to give 1-hydroxy-6-thiophenylpyridine-2-(1H)-one. After cooling, it was added 148 ml of water and was adjusted with 6N HCl to pH 3. The precipitate was filtered, washed with water and washed with hexanes to give 1.64 g (75%). It was recrystallized from ethanol: mp 180°-181° C.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([C:13]3[C:14]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=4)=[N:15][O:16][C:17]=3[CH3:18])=[N:11][N:12]=2)=[C:4]([O:25][CH3:26])[CH:3]=1.[NH2:27][CH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C(N(CC)C(C)C)(C)C>>[CH3:26][O:25][C:4]1[CH:3]=[C:2]([NH:27][CH:28]2[CH2:33][CH2:32][O:31][CH2:30][CH2:29]2)[CH:7]=[CH:6][C:5]=1[C:8]1[O:9][C:10]([C:13]2[C:14]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:15][O:16][C:17]=2[CH3:18])=[N:11][N:12]=1
Reactant: NC1CCOCC1
Reactant: COc1cc(F)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc(NC2CCOCC2)ccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 29.6 %

Procedure:
As described for example 26, 2-(4-fluoro-2-methoxy-phenyl)-5-(5-methyl-3-phenyl-isoxazol-4-yl)-[1,3,4]oxadiazole (200 mg, 0.57 mmol) was converted using 4-aminotetrahydropyran (173 mg, 1.71 mmol) and N,N-diisopropylethylamine (147 mg, 1.14 mmol) instead of thiomorpholine to the title compound (SiO2, heptane:ethyl acetate:dichloromethane:methanol=40:40:20:0 to 0:75:20:5, 73 mg, 30%) which was obtained as a white solid. MS: m/e=433.3 [M+H]+.