Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.CN(C)[CH:41]=[O:42]>CCCCCC.O1CCCC1>[CH:41]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:12]([C:28]3[CH:36]=[C:35]([O:37][CH3:38])[C:31]4[O:32][CH2:33][O:34][C:30]=4[CH:29]=3)[C:13]([NH:15][S:16]([C:19]3[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][C:20]=3[O:26][CH3:27])(=[O:18])=[O:17])=[O:14])=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)=[O:42]
Reactant: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(Br)ccc12
Reactant: CN(C)C=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COc1cc(C)ccc1S(=O)(=O)NC(=O)C(c1cc(OC)c2c(c1)OCO2)c1cn(C)c2cc(C=O)ccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Butylithium (0.8 ml of 2.5M solution in hexane) was added to a stirred solution of 6-bromo-3-{1-(7-methoxy-1,3-benzodioxol-5-yl)-2-[(2-methoxy-4-methylphenyl)sulfonamido]-2-oxoethyl}-1-methyl-1H-indole (from Example 92, 400 mg, 0.67 mmol) in anhydrous tetrahydrofuran at -75° C. under a nitrogen atmosphere. After 30 minutes dimethylformamide (0.15 ml) was added to the orange solution, and after a further 30 minutes the mixture was allowed to warm at 0° C. before quenching with excess 1N hydrochloric acid. Ethyl acetate was added and the organic layer was separated and washed with water. The organic layer was dried (magnesium sulphate), and the solvents removed in vacuo. The residue was flash chromatographed using 1% methanol in dichloromethane as eluant, and the product was crystallised from dichloromethane and diethyl ether mixture to give the title compound (187 mg).
Reaction SMILES: C(O)C.[CH2:4]([NH2:6])[CH3:5].[C:7](OC)(=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1>O>[CH2:4]([NH:6][C:7](=[O:14])[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1)[CH3:5]
Reactant: CCN
Reactant: COC(=O)c1ccncc1
Solvent: O
Solvent: CCO
Product: CCNC(=O)c1ccncc1
Reaction time: 8 h

Procedure:
A mixture of 200 ml of ethanol and 20 ml water was cooled in an ice bath and saturated with ethylamine for 0.5 hr. then 80 g of crude methyl isonicotinate was added with cooling. Ethylamine was again bubbled onto the reaction mixture for 10 min and then it was allowed to stand overnight at room temperature. It was then concentrated in vacuo to leave 82.82 g of a pale oil which became semisolid on cooling.
Reaction SMILES: [C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3Cl)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:33]1([NH2:36])[CH2:35][CH2:34]1.O>C(O)C>[C:1]([O:9][CH2:10][C@@H:11]1[C@@:15]([O:17][C:18](=[O:20])[CH3:19])([CH3:16])[C@:14]([F:22])([CH3:21])[CH:13]([N:23]2[CH:31]=[N:30][C:29]3[C:24]2=[N:25][CH:26]=[N:27][C:28]=3[NH:36][CH:33]2[CH2:35][CH2:34]2)[O:12]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NC1CC1
Reactant: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(Cl)ncnc32)[C@]1(C)F
Solvent: CCO
Solvent: O
Product: CC(=O)O[C@@]1(C)[C@@H](COC(=O)c2ccccc2)OC(n2cnc3c(NC4CC4)ncnc32)[C@]1(C)F
Yield: 62 %

Procedure:
To a stirred solution of ((2R,3S,4R)-3-acetoxy-5-(6-chloro-9H-purin-9-yl)-4-fluoro-3,4-dimethyl-tetrahydrofuran-2-yl)methyl benzoate (about 0.2 g, 0.43 mmol) in ethanol (about 5 ml) was added cyclopropylamine (about 0.296 ml, 5.19 mmol) and refluxed for about 30 minutes. Completion of the reaction monitored by thin-layer chromatography, water added to the reaction mixture and the aqueous layer was extracted with ethyl acetate and the combined organic layers were washed with brine and dried over sodium sulphate. Concentration under reduced pressure and purification by silica gel column chromatography using 40% ethyl acetate in hexane as eluent furnished title compounds Isomer A and B (0.13 g) as a colorless gummy mass. Yield: 62%;
Reaction SMILES: C[O:2][C:3](=[O:25])[C:4]1[CH:9]=[C:8]([N:10]2[C:15](=[O:16])[N:14]([CH2:17][CH:18]([OH:22])[CH2:19][O:20][CH3:21])[C:13](=[O:23])[CH:12]=[N:11]2)[CH:7]=[CH:6][C:5]=1[Cl:24].C(N(CC)CC)C.[Si:33](Cl)([C:36]([CH3:39])([CH3:38])[CH3:37])([CH3:35])[CH3:34].[OH-].[Na+]>C1COCC1>[C:36]([Si:33]([CH3:35])([CH3:34])[O:22][CH:18]([CH2:19][O:20][CH3:21])[CH2:17][N:14]1[C:13](=[O:23])[CH:12]=[N:11][N:10]([C:8]2[CH:7]=[CH:6][C:5]([Cl:24])=[C:4]([CH:9]=2)[C:3]([OH:2])=[O:25])[C:15]1=[O:16])([CH3:39])([CH3:38])[CH3:37]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COCC(O)Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)OC)c2)c1=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COCC(Cn1c(=O)cnn(-c2ccc(Cl)c(C(=O)O)c2)c1=O)O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To Intermediate 2 (14.8 g, 40 mmol) in THF (200 ml) and triethylamine (44 mmol, 4.45) at 0° C., is added t-butyldimethylsilylchloride (TBDMS-Cl) (44 mmol, 6.63 g). The reaction is allowed to warm to room temperature and stirred overnight. 1 N NaOH solution (100 ml) is added, and the reaction is stirred at 40° C. for 4 h. THF is evaporated under reduced pressure, and the resulting mixture is acidified with 1 N HCl to pH<2. The mixture is extracted with ethyl acetate (2×100 ml). The organic phase is washed with brine solution, dried over MgSO4, and concentrated in vacuo to give 5-{4-[2-(tert-Butyl-dimethyl-silanyloxy)-3-methoxy-propyl]-3,5-dioxo-4,5-dihydro-3H-[1,2,4]triazin-2-yl}-2-chloro-benzoic acid.
Reaction SMILES: [CH2:1]([O:3][CH:4]1[NH:8][C:7](=[O:9])[CH2:6][CH2:5]1)[CH3:2].[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16]Br)=[CH:14][CH:13]=1>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH3:10][O:11][C:12]1[CH:19]=[CH:18][C:15]([CH2:16][N:8]2[CH:4]([O:3][CH2:1][CH3:2])[CH2:5][CH2:6][C:7]2=[O:9])=[CH:14][CH:13]=1
Reactant: CCOC1CCC(=O)N1
Reactant: COc1ccc(CBr)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: C1CCOC1
Product: CCOC1CCC(=O)N1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.4 %

Procedure:
To a mixture of 2.25 g of 5-ethoxy-pyrrolidin-2-one, 1.23 g of hydrated potassium hydroxide and 0.2 g of tetra-n-butylammonium bromide in 45 cm3 of tetrahydrofuran, there is added, without exceeding 30° C., a solution of 3.5 g of 4-methoxybenzyl bromide in 15 cm3 of tetrahydrofuran. After agitating for 1 hour at ambient temperature, filtering and evaporating the solvent under reduced pressure, the residue is taken up with water and extracted with ethyl acetate. The extracts are dried and the solvent is evaporated under reduced pressure. The residue is distilled at 245° C. under 0.2 mbar. 3.10 g of the expected product is obtained.
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1.[CH:26]([C:29]1[S:30][C:31]([C:35](O)=[O:36])=[C:32]([CH3:34])[N:33]=1)([CH3:28])[CH3:27].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1>ClCCl>[CH3:1][N:2]([CH:3]1[CH2:16][C:15]2[C:6]([CH3:25])([CH:7]3[CH:12]([CH2:13][CH:14]=2)[CH:11]2[CH2:17][CH2:18][CH:19]4[CH:20]([CH3:24])[N:21]([CH3:23])[CH2:22][C:10]24[CH2:9][CH2:8]3)[CH2:5][CH2:4]1)[C:35]([C:31]1[S:30][C:29]([CH:26]([CH3:27])[CH3:28])=[N:33][C:32]=1[CH3:34])=[O:36]
Reactant: Cc1nc(C(C)C)sc1C(=O)O
Reactant: CNC1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: Cc1nc(C(C)C)sc1C(=O)N(C)C1CCC2(C)C(=CCC3C2CCC24CN(C)C(C)C2CCC34)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 58 %

Procedure:
A mixture of compound 7B (15 mg, 0.044 mmol), 2-isopropyl-4-methyl-thiazole-5-carboxylic acid (9.0 mg, 0.048 mmol), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (13 mg, 0.066 mmol), 1-hydroxybenzotriazole (9.0 mg, 0.066 mmol) and dichloromethane (1 mL) was stirred at room temperature overnight. The solvent was evaporated under reduced pressure and the residue was dissolved in minimum amount of dichloromethane and purified on silica gel column, which was eluted with 0.5% ammonium hydroxide and 5% methanol in dichloromethane to give the desired product (13 mg, 59% yield). 1H NMR (CDCl3): δ 0.96 (s, 3 H) 1.00-1.35 (m, 6 H) 1.38 (d, J=6.78 Hz, 6 H) 1.55-2.35 (m, 21 H) 2.39 (s, 3 H) 2.59 (m, 2 H) 2.95 (s, 3 H) 3.26 (m, 2 H) 5.37 (m, 1 H); MS: (M+H)+=510.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9](Cl)[O:8][N:7]=1)=[O:5])[CH3:2].[C:12]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[C:16]([F:23])[CH:15]=1)#[N:13].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][C:16]=2[F:23])[O:8][N:7]=1)=[O:5])[CH3:2]
Reactant: N#Cc1ccc(B(O)O)c(F)c1
Reactant: CCOC(=O)c1cc(Cl)on1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(-c2ccc(C#N)cc2F)on1
Temperature: 140 °C

Procedure:
A mixture of 5-chloro-isoxazole-3-carboxylic acid ethyl ester (600 mg), 4-cyano-2-fluorophenylboronic acid (665 mg), and aqueous Na2CO3 solution (2 M; 4.41 mL) in 1,4-dioxane (15 mL) is purged with argon for 15 min prior to the addition of Pd(PPh3)4 (276 mg). The reaction mixture is heated under an argon atmosphere to 140° C. for 20 min in a microwave oven. The solvent is evaporated in vacuo and the residue is mixed with water and ethyl acetate. The aqueous phase is extracted with ethyl acetate and the combined extracts are washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product is purified by silica gel chromatography (cyclohexane/ethyl acetate 80:20→50:50). LC (method 19): tR=1.50 min; Mass spectrum (ESI+): m/z=261 [M+H]+.
Reaction SMILES: C[Si](C)(C)N[Si](C)(C)C.[NH2:10][CH:11]([C:17]([OH:19])=O)[CH2:12][CH2:13][CH2:14][CH2:15][NH2:16].C(O)C>Cl[Si](C)(C)C.C1(C)C(C)=CC=CC=1>[NH2:10][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][NH:16][C:17]1=[O:19]
Reactant: NCCCCC(N)C(=O)O
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)N[Si](C)(C)C
Solvent: Cc1ccccc1C
Solvent: CCO
Product: NC1CCCCNC1=O
Reaction time: 48 h
Yield: 60.5 %

Procedure:
Hexamethyldisilazane (30 ml) and chloro-trimethylsilane (several drops) were added to a suspension of DL-lysine (3.0 g, 20.5 mmol) in xylene (270 ml) at room temperature, and the reaction was carried out at 140° C. for 48 hours. The reaction mixture was cooled and then poured into ethanol (600 ml), and the resulting mixture was concentrated. The resulting residue was suspended in chloroform, followed by filtration and concentration, whereby 3-amino-2-azepanone (1.59 g, 60%) was obtained.
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:15])[C@H:6]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[NH2:7])[CH3:3].CN1CCOCC1.[C:23]1(=[O:42])[N:27]([C@@H:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29](O)=[O:30])[C:26](=[O:37])[C:25]2=[CH:38][CH:39]=[CH:40][CH:41]=[C:24]12.OC1C2N=NNC=2C=CC=1.C(N=C=NCCCN(C)C)C>CN(C)C=O>[C:26]1(=[O:37])[N:27]([CH:28]([CH2:32][CH2:33][CH2:34][CH2:35][OH:36])[C:29]([NH:7][C@@H:6]([C:5]([O:4][CH2:2][CH3:3])=[O:15])[CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:30])[C:23](=[O:42])[C:24]2=[CH:41][CH:40]=[CH:39][CH:38]=[C:25]12
Reactant: CCOC(=O)[C@@H](N)Cc1ccccc1
Reactant: O=C(O)[C@H](CCCCO)N1C(=O)c2ccccc2C1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)[C@@H](Cc1ccccc1)NC(=O)C(CCCCO)N1C(=O)c2ccccc2C1=O
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of L-phenylalanine ethyl ester hydrochloride salt (998 mg., 4.3 mmol) in dimethylformamide (10 mL.) was added with 4-methylmorpholine (575 μl, 529 mg., 5.2 mmol.). After stirring at room temperature for 5 minutes, the solution was cooled to 0° C. and treated successively with (S)-2-phthalimido-6-hydroxyhexanoic acid (1.002 g., 3.6 mmol.), hydroxybenzotriazole (582 mg., 4.3 mmol.) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide (770 mg., 4.0 mmol.). The resulting mixture was stirred at 0° C. for 0.5 hour and at room temperature for 1.5 hours. The solution was partitioned between ethyl acetate and water and the organic extract was washed successively with 0.5N hydrochloric acid, water, 50% saturated sodium bicarbonate, and brine, then dried (sodium sulfate), filtered and stripped to give 1.63 g. of essentially pure title product as an oil/foam. TLC (1:1--acetone:hexanes) Rf =0.30.
Reaction SMILES: O[CH:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH:9]1([NH2:12])[CH2:11][CH2:10]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH:9]1([NH:12][CH:2]2[CH2:7][CH2:6][CH:5]([OH:8])[CH2:4][CH2:3]2)[CH2:11][CH2:10]1
Reactant: NC1CC1
Reactant: O=C1CCC(O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: OC1CCC(NC2CC2)CC1
Temperature: 25 °C
Reaction time: 13 h
Yield: 96.3 %

Procedure:
4-hydroxycyclohexanone (443 mg, 3.88 mmol) was dissolved in 1,2-dichloroethane (20 ml), followed by sequential addition of cyclopropylamine (0.295 ml, 4.27 mmol), NaBH(OAc)3 (1.3 g, 6.21 mmol), and acetic acid (0.2 ml, 3.88 mmol), and then the resulting mixture was stirred at room temperature under nitrogen stream for 13 hours. The resulting reaction liquid was neutralized by addition of 10% aqueous NaOH solution, and extracted with 10% MeOH/MC (15 ml×4). The organic layer was dried over anhydrous sodium sulfate, followed by filtration, concentration, and vacuum drying, to obtain 580 mg of yellow solid (96%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH2:4][CH2:3]1.[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=O)=[CH:14][CH:13]=1)[CH3:10].[OH-].[K+]>CO>[CH2:9]([N:11]([CH2:20][CH3:21])[C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[C:4]2[C:5](=[O:8])[C:6](=[CH:16][C:15]3[CH:18]=[CH:19][C:12]([N:11]([CH2:9][CH3:10])[CH2:20][CH3:21])=[CH:13][CH:14]=3)[CH2:7][N:2]([CH3:1])[CH2:3]2)=[CH:14][CH:13]=1)[CH3:10]
Reactant: CN1CCC(=O)CC1
Reactant: CCN(CC)c1ccc(C=O)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CCN(CC)c1ccc(C=C2CN(C)CC(=Cc3ccc(N(CC)CC)cc3)C2=O)cc1
Reaction time: 8 h

Procedure:
1-methyl-4-piperidone (2.25 g) and 7.1 g of p-diethylamino-benzaldehyde were added to a solution of 4 g potassium hydroxide in 50 ml methanol. The reaction mixture was heated at reflex 31/2 hours and allowed to stand at room temperature overnight. The product was collected and recrystallized from 700 ml acetonitrile. The UV spectra of the isolated product was consistent with the structure of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:59]=[CH:58][N:57]=[CH:56][CH:55]=2)[C:48]([CH3:52])=[CH:49][C:50]=1O>C1COCC1.CN(C=O)C>[Br:44][C:45]1[C:46](=[O:60])[N:47]([CH2:53][C:54]2[CH:55]=[CH:56][N:57]=[CH:58][CH:59]=2)[C:48]([CH3:52])=[CH:49][C:50]=1[O:5][CH2:4][C:3]1[CH:6]=[CH:7][C:8]([F:10])=[CH:9][C:2]=1[F:1]
Reactant: Cc1cc(O)c(Br)c(=O)n1Cc1ccncc1
Reactant: OCc1ccc(F)cc1F
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1cc(OCc2ccc(F)cc2F)c(Br)c(=O)n1Cc1ccncc1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a cold solution of 2,4-difluorobenzylalcohol (0.569 mL, 5.1 mmol) in THF (5 mL) was added PPh3 (resin, 2.55 g, 7.65 mmol) followed by the addition of DIAD (1.48 mL, 7.65 mmol). The reaction mixture stirred at −10° C. for 15 minutes under nitrogen. A solution of 3-bromo-4-hydroxy-6-methyl-1-(pyridin-4-ylmethyl)pyridin-2(1H)-one (1.0 g, 3.4 mmol), in DMF (10 mL) was added to the resin suspension. The reaction mixture stirred at 0° C. for 1.5 hours and then allowed to stir at room temperature overnight. The resin was filtered and rinsed with fresh MeOH and the filtrate was concentrated. The residue was dissolved in ethyl acetate and purified by flash column chromatography (ethyl acetate). The appropriate fractions were concentrated. 1H-NMR (CD3OD, 400 MHz) δ 8.47 (d, 2H, J=5.6 Hz), 7.63 (q, 1H), 7.15 (d, 1H, J=5.6 Hz), 7.05 (m, 2H), 6.55 (s, 1H), 5.45 (s, 2H), 5.31 (s, 2H), 2.35 (s, 3H); ES-HRMS m/z 421.0366/423.0355 (M+H calculated for C19H16N2O2F2Br requires 421.0358/423.0339).
Reaction SMILES: [SH:1][C:2]1O[CH:4]=[CH:5][N:6]=1.[CH:7]([NH2:11])([CH2:9][CH3:10])[CH3:8]>C(O)C>[CH:7]([N:11]1[CH:4]=[CH:5][N:6]=[C:2]1[SH:1])([CH2:9][CH3:10])[CH3:8]
Reactant: CCC(C)N
Reactant: Sc1ncco1
Solvent: CCO
Product: CCC(C)n1ccnc1S
Yield: 53.7 %

Procedure:
1 g (9.89 mmol) of 2-mercaptooxazole and 0.72 g (9.89 mmol) of sec-butylamine were dissolved in 20 ml of ethanol and refluxed for 2 hours. After cooling, the solvent was distilled off under reduced pressure and the residue was treated with column chromatography to obtain 0.83 g of 1-sec-butyl-2-mercaptoimidazole. mp.=108-121° C., yield 54%.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10](F)[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:19]([SH:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(OCC)(=O)C>CS(C)=O>[CH2:19]([S:26][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([Cl:1])[CH:11]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: SCc1ccccc1
Reactant: COC(=O)c1ccc(F)cc1Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COC(=O)c1ccc(SCc2ccccc2)cc1Cl
Temperature: 50 °C
Yield: 94.4 %

Procedure:
Methyl 2-chloro-4-fluorobenzoate (1.92 g, 10.2 mmol, 1 eq), cesium carbonate (3.74 g, 11.5 mmol, 0.13 eq) and benzyl mercaptan (1.3 g, 10.5 mmol, 1.03 eq) were combined in dimethyl sulphoxide (20 ml) and the reaction mixture heated at 50° C. for 4 hours. The reaction mixture was poured into ethyl acetate (10 ml) then washed with water (10 ml). The organic phase was dried over sodium sulphate, evaporated to yield the title compound as pink oil (2.82 g, 9.63 mmol, 95%).
Reaction SMILES: Br[CH:2]([C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=2)=[CH:9][CH:8]=1)[C:3]([O:5][CH3:6])=[O:4].[F:24][C:25]([F:34])([F:33])[C:26]1[CH:27]=[C:28]([OH:32])[CH:29]=[CH:30][CH:31]=1>>[F:24][C:25]([F:33])([F:34])[C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH:2]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:16][CH:15]=3)=[CH:9][CH:8]=2)[C:3]([O:5][CH3:6])=[O:4])[CH:27]=1
Reactant: COC(=O)C(Br)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Reactant: Oc1cccc(C(F)(F)F)c1
Product: COC(=O)C(Oc1cccc(C(F)(F)F)c1)c1ccc(Oc2ccc(C(C)(C)C)cc2)cc1
Yield: 88.1 %

Procedure:
In a manner similar to Example 16, 7.54 g of methyl α-bromo-α-[p-(p-tert-butylphenoxy)phenyl]acetate was treated with 4.05 g of m-trifluoromethylphenol to give 8.07 g of product as a pale yellow glass.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[Na+].S(=O)(=O)(O)O.[F:11][C:12]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]>>[F:11][C:12]1[C:20]([F:21])=[CH:19][C:18]([N+:1]([O-:4])=[O:2])=[CH:17][C:13]=1[C:14]([OH:16])=[O:15]
Reactant: O=[N+]([O-])[O-]
Reactant: O=C(O)c1cccc(F)c1F
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(O)c1cc([N+](=O)[O-])cc(F)c1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 79.3 %

Procedure:
Sodium nitrate (1.7 g) was added to a concentrated sulfuric acid (7 ml) solution containing 2,3-difluorobenzoic acid (1.58 g), followed by stirring at room temperature for 0.5 hours. The reaction solution was poured into ice water, followed by extraction with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate. The solvent was distilled away under reduced pressure, the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 4:1). A light yellow solid of 2,3-difluoro-5-nitrobenzoic acid (1.61 g) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18]([C:23]#[C:24][CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:4][CH:3]=1>[Pd].C(Cl)Cl.CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:13]=[N:14][C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][C:18](/[CH:23]=[CH:24]\[CH2:25][S:26][CH3:27])=[CH:17][C:16]=3[F:28])=[O:11])=[CH:6][CH:7]=1
Reactant: CSCC#Cc1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Agent: [Pd]
Solvent: CO
Solvent: ClCCl
Product: CSC/C=C\c1cc(F)c2ncc(C(=O)NCc3ccc(Cl)cc3)c(O)c2c1
Reaction time: 2 h

Procedure:
A mixture of N-[(4-Chlorophenyl)methyl]-8-fluoro-4-hydroxy-6-[3-(methylthio)-1-propynyl]-3-quinolinecarboxamide from Example 126 (0.226 g) and Pd/C (10%, 0.032 g) in 3:1 CH2Cl2 /MeOH (20 mL) are placed on a Parr hydrogenator under 38 psi of H2 and shaken for 2 h. Another 0.060 g of Pd/C is added, and the resulting
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][CH:7]=[CH:8][C:4]=2[CH:3]=1.C([Li])CCC.[CH3:16][Sn:17](Cl)([CH3:19])[CH3:18].[Cl-].[NH4+]>CCOCC.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]2[S:6][C:7]([Sn:17]([CH3:19])([CH3:18])[CH3:16])=[CH:8][C:4]=2[CH:3]=1
Reactant: C[Sn](C)(C)Cl
Reactant: Cc1ccc2sccc2c1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCOCC
Solvent: CCCCCC
Product: Cc1ccc2sc([Sn](C)(C)C)cc2c1
Reaction time: 0.5 h

Procedure:
A solution of 7.411 g of 5-methylbenzo[b]thiophene (Maybridge, Chemical Co. Ltd., 11-78) in 35 ml of ether is added dropwise at 0° to a mixture of 40 ml of 1.5N butyllithium in hexane and 40 ml of ether. After 30 minutes, a solution of 9.963 g of trimethyltin chloride in 50 ml of ether is also added dropwise at 0°. After stirring for 1 hour at 0°, 50 ml of 5% ammonium chloride solution are added. The product is obtained by extracting with 100 ml and 150 ml of ether. Distillation at 0.15 mbar and 100°-106° yields 5-methyl-2-trimethylstannylbenzo[b]thiophene.
Reaction SMILES: [Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].ClCC(N[C:17]1[CH:26]=[C:25]([NH:27][C:28](=[O:31])[CH2:29][Cl:30])[C:24]([OH:32])=[C:23]2[C:18]=1[CH:19]=[CH:20][C:21]([CH3:33])=[N:22]2)=O.[OH2:34]>C(O)(=O)C>[Cl:30][CH2:29][C:28]([NH:27][C:25]1[C:24](=[O:32])[C:23]2[N:22]=[C:21]([CH3:33])[CH:20]=[CH:19][C:18]=2[C:17](=[O:34])[CH:26]=1)=[O:31]
Reactant: Cc1ccc2c(NC(=O)CCl)cc(NC(=O)CCl)c(O)c2n1
Reactant: O
Agent: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: [K+]
Solvent: CC(=O)O
Product: Cc1ccc2c(n1)C(=O)C(NC(=O)CCl)=CC2=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 59 %

Procedure:
This compound was prepared by the oxidation of the corresponding acylamido with potassium dichromate in glacial acetic acid. In a 500 ml. round-bottom flask equipped with a magnetic bar, 5,7-bis(chloroacetamido)-8-hydroxy-2-methylquinoline (32) (prepared as described in Example 32) (3.42 g., 0.01 mol) was suspended in 122 ml. of glacial acetic acid. A solution of potassium dichromate (8.8 g., 0.03 mol) in 115 ml. of water was added and the resulting dark solution was stirred at room temperature overnight. The solution was extracted with dichloromethane (12×50 ml.). The organic extracts were washed with 3% sodium bicarbonate solution (200 ml.), dried with magnesium sulfate, and rotoevaporated to yield a bright yellow solid. After vacuum drying, the nearly pure product weighed 1.56 g. (yield of 59%). The product was recrystallized from ethyl acetate: mp 196-200 EC (dec.); 1H NMR (CDCl3)*2.76 (3H, s, C—2CH3), 4.23 (2H, s, C—7NHCOCH2Cl), 7.56 (1H, d, J=8.1 Hz, C—3H), 7.89 (1H, s, C—6H), 8.30 (1H, d, J=8.1 Hz, C—4H), 9.48 (1H, br. s, C—7NH); IR (KBr) vmax 3299, 3078, 2948, 1712, 1683, 1641, 1614, 1588, 1515, 1398, 1384, 1323, 1130 cm−1; EIMS, m/e (relative intensity) 264/266 (M+, 2.9/1, 67) 229 (62), 215 (74), 201 (43), 188 (86), 161 (base), 132 (21); HRMS, m/e for C14H9ClN2O3, calculated 264.030170, found 264.029824; analysis for C14H9ClN2O3 calculated: C, 54.46; H, 3.43; Cl, 13.40; N, 10.58; found: C, 54.19; H, 3.37; Cl, 13.29; N, 10.36.