Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[N:7]([CH2:10][C:11]1[C:20](Br)=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[N:12]=1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30](B2OC(C)(C)C(C)(C)O2)[CH:29]=1)[CH3:24]>>[CH2:23]([O:25][C:26](=[O:45])[CH2:27][C:28]1[CH:33]=[CH:32][C:31]([O:34][CH3:35])=[C:30]([C:20]2[C:11]([CH2:10][N:7]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:22])[CH2:8][CH3:9])=[N:12][C:13]3[C:18]([CH:19]=2)=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:29]=1)[CH3:24]
Reactant: CCN(Cc1nc2ccccc2cc1Br)C(=O)OC(C)(C)C
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Product: CCOC(=O)Cc1ccc(OC)c(-c2cc3ccccc3nc2CN(CC)C(=O)OC(C)(C)C)c1

Procedure:
Prepared according to the procedure described in Example 5, Step 3, using the following starting materials: (3-bromo-quinolin-2-ylmethyl)-ethyl-carbamic acid tert-butyl ester and [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester.
Reaction SMILES: [Br:1][C:2]1[C:3]([Cl:10])=[C:4]([CH3:9])[C:5]([F:8])=[CH:6][CH:7]=1.[Br:11]N1C(=O)CCC1=O.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[C:4]([CH2:9][Br:11])[C:3]=1[Cl:10]
Reactant: Cc1c(F)ccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(Br)c(Cl)c1CBr
Temperature: 25 °C

Procedure:
A mixture of 3-bromo-2-chloro-6-fluoro-toluene (commercially available) (8.0 g), N-bromosuccinimide (“NBS”) (6.42 g) and benzoyl peroxide (catalytic amount) in carbon tetrachloride (40 ml) was heated to reflux. A 500 watt tungsten halogen lamp was used to initiate the reaction. The reaction mixture was heated to reflux and irradiated for 30 minutes. The reaction mixture was allowed to cool to ambient temperature and then filtered. The filtrate was concentrated to give a colorless oil which solidified on standing to give 1-bromo-3-bromomethyl-2-chloro-4-fluoro-benzene as an off-white solid (10.7 g). 1H-NMR (400 MHz, CDCl3): 7.58 (dd, 1H), 6.94 (t, 1H), 4.64 (d, 21-1) ppm.
Reaction SMILES: [NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4](O)=[O:5])[CH3:3].[F-:17].N1C=CC=CC=1>C(Cl)Cl>[NH:1]([C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[C@H:2]([C:4]([F:17])=[O:5])[CH3:3]
Reactant: [F-]
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)O
Solvent: c1ccncc1
Solvent: ClCCl
Product: C[C@H](NC(=O)OCc1ccccc1)C(=O)F

Procedure:
CBZ-Ala (1 mmole) in dry CH2Cl2 is kept under nitrogen and treated with cyannuric fluoride (8 mmol) and pyridine (1 mmole) to form the corresponding CBZ-Ala-F.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1O)([O-:3])=[O:2].[C:11]([O-:14])([O-])=O.[K+].[K+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>O>[CH2:17]([C:5]1[C:4]([N+:1]([O-:3])=[O:2])=[C:9]([O:14][C:11]2[CH:8]=[CH:7][CH:6]=[C:5]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[C:4]=2[N+:1]([O-:3])=[O:2])[CH:8]=[CH:7][CH:6]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1O
Reactant: ClCc1ccccc1
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1c(Cc2ccccc2)cccc1Oc1cccc(Cc2ccccc2)c1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
A mixture of 2-nitrophenol (27.82 g˜0.18 mol, Lancaster, contains ca 10% H2O), K2CO3 (33.15 g, 0.24 mol), and benzyl chloride (30.38 g, 27.6 ml, 0.24 mol) was heated at 100° C. for 1.5 h. The resulting mixture was poured in 1.3 L of water and extracted with CHCl3 tree times, washed twice with 50% brine, dried with Na2SO4, filtered and concentrated. Distillation in vacuum gave 39.23 g (96%), bp 161-162° C. (˜0.1 mm Hg).
Reaction SMILES: [NH:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3].[H-].[Na+].Br[CH2:13][C@@H:14]1O[C@@H](P(OCC)=O)CC1>CN(C=O)C>[CH2:13]([N:1]1[CH:9]=[C:7]([CH3:8])[C:5](=[O:6])[NH:4][C:2]1=[O:3])[CH3:14]
Reactant: CCO[PH](=O)[C@H]1CC[C@H](CBr)O1
Reactant: Cc1c[nH]c(=O)[nH]c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1cc(C)c(=O)[nH]c1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 25.8 %

Procedure:
To a stirring suspension of thymine (536 mg, 4.18 mmol) in dry DMF (5 mL) was added sodium hydride (60% oil dispersion, 167 mg, 4.18 mmol). After stirring the mixture for 30 min at room temperature, a solution of trans-5-bromomethyl-2-ethoxyphosphinoyl-tetrahydrofuran (example 66) (630 mg, 2.09 mmol) in DMF (3 mL) was added via cannula. The mixture was then stirred at 90° C. for 18 h after which the mixture was cooled and quenched with saturated ammonium chloride (5 mL). The volatiles were removed under vacuo and the residue was dissolved in a mixture of dichloromethane (20 mL) and water (10 mL). The mixture was filtered and the aqueous layer was collected and extracted with dichloromethane (2×20 mL). The combined extracts were then washed with brine (20 mL), dried (MgSO4) and concentrated to dryness. Purification by chromatography eluting with EtAc, 5% MeOH in EtAc then 10% MeOH in EtAc yielded first N1 -ethyl thymine (83 mg, 26%) and then the title compound as an oil (186 mg, 26%).
Reaction SMILES: CS(C)=O.[C:5](Cl)(=[O:9])[C:6](Cl)=O.CC1[N:13]([CH:18]([CH3:22])[CH:19]([OH:21])[CH3:20])C(C)=CC=1>C(Cl)Cl.C(O)(=O)C>[NH2:13][CH:18]([CH3:22])[CH:19]([OH:21])[CH3:20].[CH2:18]([CH2:22][C:5](=[O:9])[CH3:6])[C:19]([CH3:20])=[O:21]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cc1ccc(C)n1C(C)C(C)O
Solvent: CS(C)=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: CC(=O)CCC(C)=O
Product: CC(N)C(C)O

Procedure:
To a solution of dimethylsulfoxide (1.56 g, 20.0 mmoles) and oxalyl chloride (1.9 g, 15.0 mmoles) in 20 ml of methylene chloride cooled to -78° C. was added 1.67 g (10.0 mmoles) of 3-(2,5-dimethylpyrrol-1-yl)-2-butanol obtained by dehydration cyclization of 3-amino-2-butanol and acetonylacetone in acetic acid. One hour later, 3 ml of triethylamine was added, and the mixture stirred at room temperature for 5 hours. The mixture was extracted with chloroform. The chloroform layer was dried over anhydrous magnesium sulfate, and concentrated, and chromatographed on a column of silica gel using cyclohexane/ethyl acetate (4/1) as an eluent to afford 3-(2,5-dimethylpyrrol-1-yl)-2-butanone (990 mg, 6.0 mmoles, 60%).
Reaction SMILES: [CH3:1][I:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]>CC(C)=O>[I-:2].[CH2:3]([O:9][C:10]1[C:11]([C:15]2[CH:16]=[N+:17]([CH3:1])[CH:18]=[CH:19][CH:20]=2)=[N:12][S:13][N:14]=1)[CH2:4][CH2:5][CH:6]=[CH:7][CH3:8]
Reactant: CC=CCCCOc1nsnc1-c1cccnc1
Reactant: CI
Solvent: CC(C)=O
Product: CC=CCCCOc1nsnc1-c1ccc[n+](C)c1
Product: [I-]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of methyl iodide (1 ml, 15 mmol) and 3-(4-(4-hexenyloxy)-1,2,5-thiadiazol-3-yl)pyridine (3 mmol) in acetone (5 ml) was stirred at room temperature for 18 h. The title compound precipitated from the solution and was collected by filtration to yield 0.54 g (45%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=1.[F:12][C:13]1([F:23])[O:17][C:16]2[CH:18]=[CH:19][C:20]([NH2:22])=[CH:21][C:15]=2[O:14]1>>[F:23][C:13]1([F:12])[O:17][C:16]2[CH:18]=[CH:19][C:20]([NH:22][C:2]3[N:7]=[C:6]([NH:22][C:20]4[CH:19]=[CH:18][C:16]5[O:17][C:13]([F:23])([F:12])[O:14][C:15]=5[CH:21]=4)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][N:3]=3)=[CH:21][C:15]=2[O:14]1
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: Nc1ccc2c(c1)OC(F)(F)O2
Product: O=[N+]([O-])c1cnc(Nc2ccc3c(c2)OC(F)(F)O3)nc1Nc1ccc2c(c1)OC(F)(F)O2

Procedure:
In like manner to the preparation of N2,N4-bis(3-hydroxyphenyl)-5-fluoro-2,4-pyrimidinediamine, the reaction of 2,4-dichloro-5-nitropyrimidine with 2,2-difluoro-5-amino-1,3-benzodioxole gave N2,N4-bis-(2,2-difluoro-1,3-benzodioxol-5-yl)-5-nitro-2,4-pyrimidinediamine. LCMS: ret. time: 38.15 min.; purity: 96%; MS (m/e): 467 (M+); 1H NMR (CDCl3): δ 10.76 (1H, s), 10.49 (1H, s), 9.20 (1H, s), 7.74 (2H, s), 7.56 (1H, d, J=11.4 Hz), 7.33 (2H, m), 7.20 (1H, m).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]1=[O:13].[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]2)[CH:21]=[C:20]([C:30]([F:33])([F:32])[F:31])[N:19]=1)([CH3:17])([CH3:16])[CH3:15].C(N(CC)CC)C.O>CS(C)=O>[C:14]([C:18]1[N:23]=[C:22]([N:24]2[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]3[CH:11]=[CH:10][C:9]([CH3:12])=[CH:8][C:7]3=[O:13])[CH2:28][CH2:29]2)[CH:21]=[C:20]([C:30]([F:31])([F:32])[F:33])[N:19]=1)([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)c1nc(N2CCNCC2)cc(C(F)(F)F)n1
Reactant: Cc1ccn(CCCCCl)c(=O)c1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: Cc1ccn(CCCCN2CCN(c3cc(C(F)(F)F)nc(C(C)(C)C)n3)CC2)c(=O)c1
Yield: 60.7 %

Procedure:
1-(4-Chlorobutyl)-4-methylpyridin-2(1H)-one (0.99 g, 4.96 mmol) from Example 1.1, 2-tert-butyl-4-piperazin-1-yl-6-(trifluoromethyl)pyrimidine (1.36 g, 4.71 mmol; prepared as described in DE 19735410) and triethylamine (1.51 g, 14.87 mmol) in 25 ml of dimethyl sulfoxide were stirred at 100° C. for 5 hours. Water was then added to the reaction mixture, and the aqueous mixture was extracted twice with tert-butyl methyl ether. The organic phase was extracted three times with a saturated aqueous sodium chloride solution and three times with a 5% aqueous citric acid solution. The aqueous phase was then made alkaline and extracted three times with tert-butyl methyl ether. The combined organic phases were dried over Na2SO4 and, after removal of the desiccant by filtration, concentrated. The resulting oily residue (1.99 g) was purified by chromatography on silica gel (eluent: CH2Cl2/CH3OH: 96.5:3.5), resulting in 1.29 g of the title compound.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15].N1C=CC=CC=1.[C:22](Cl)([Cl:24])=[O:23]>O1CCCC1.C1C=CC=CC=1>[Cl:24][C:22]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12][CH3:13])=[CH:4][C:3]=1[O:14][CH3:15])=[O:23]
Reactant: O=C(Cl)Cl
Reactant: COc1cc(OC)c2ccccc2c1O
Solvent: C1CCOC1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COc1cc(OC)c2ccccc2c1OC(=O)Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1.27 g of 1-hydroxy-2,4-dimethoxynaphthalene, prepared as shown in Preparations 7 and 8, in 50 ml of tetrahydrofuran and 1 ml of pyridine is added 10 ml of a solution of 12.5% phosgene in benzene. The mixture is stirred overnight at 25° C., filtered and the filtrate evaporated under vacuum to afford crude 1-chlorocarbonyloxy-2,4-dimethoxynaphthalene. This chloroformate is dissolved in 50 ml of dry tetrahydrofuran and a solution of 1.14 g of diethylamine in 10 ml of tetrahydrofuran added. After 4 hours at room temperature the reaction mixture is diluted with ethyl acetate and washed with dilute hydrochloric acid. The organic phase is dried over sodium sulfate and solvent removed under reduced pressure to yield 1-diethylcarbamoyloxy-2,4-dimethoxynaphthalene.
Reaction SMILES: [OH-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12].Cl>C1COCC1.O>[Cl:3][C:4]1[CH:5]=[C:6]([C:14]2[O:18][N:17]=[C:16]([C:19]3[CH:20]=[CH:21][C:22]([F:35])=[C:23]4[C:27]=3[NH:26][CH:25]=[C:24]4[CH2:28][CH2:29][C:30]([OH:32])=[O:31])[N:15]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12]
Reactant: CCOC(=O)CCc1c[nH]c2c(-c3noc(-c4ccc(OC(C)C)c(Cl)c4)n3)ccc(F)c12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)Oc1ccc(-c2nc(-c3ccc(F)c4c(CCC(=O)O)c[nH]c34)no2)cc1Cl
Temperature: 90 °C
Reaction time: 1 h
Yield: 66.2 %

Procedure:
Sodium hydroxide (25 mg) was added to a solution of ethyl 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoate (D46) (204 mg) in THF (3 mL) and water (3 mL). The reaction mixture was stirred at 90° C. for 1 hour. Then 0.5 M HCl was added until pH was about 6. The solvent was concentrated, and the residue was dissolved in water. The precipitated solid was purified by Mass Directed Auto Prep to afford 3-[7-(5-{3-chloro-4-[(1-methylethyl)oxy]phenyl}-1,2,4-oxadiazol-3-yl)-4-fluoro-1H-indol-3-yl]propanoic acid (E19) (127 mg) as a white needle crystal. δH (DMSO-d6, 400 MHz): 1.36 (6H, d), 2.62 (2H, t), 3.06 (2H, t), 4.89 (1H, m), 6.98 (1H, dd), 7.25 (1H, d), 7.45 (1H, d), 7.91 (1H, dd), 8.19 (1H, dd), 8.35 (1H, d), 11.10 (1H, s), 12.14 (1H, br s). δF (DMSO-d6, 376 MHz): −118.9. MS (ES): C22H19ClFN3O4 requires 443; found 444.1 (M+H+).
Reaction SMILES: [C:1]([C:4]1[S:5][CH:6]=[CH:7][CH:8]=1)(=O)[CH3:2].[CH2:9]([N:11]([CH2:32][CH3:33])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2C=C(C3C=CSC=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:10]>C(Cl)Cl.CO>[CH2:32]([N:11]([CH2:9][CH3:10])[CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]2[CH:2]=[C:1]([C:4]3[S:5][CH:6]=[CH:7][CH:8]=3)[NH:24][N:23]=2)=[CH:17][CH:16]=1)[CH3:33]
Reactant: CCN(CC)CCOc1ccc(Nc2cc(-c3ccsc3)[nH]n2)cc1
Reactant: CC(=O)c1cccs1
Solvent: CO
Solvent: ClCCl
Product: CCN(CC)CCOc1ccc(Nc2cc(-c3cccs3)[nH]n2)cc1

Procedure:
The title compound is prepared as described in Example 33 but using 2-acetylthiophene and diethyl-[2-(4-isothiocyanato-phenoxy)-ethyl]-amine (Example 37). Title compound: ES-MS: 357.1 [M+H]+; single peak at tR=2.98 min (System 2); Rf=0.11 (CH2Cl2/MeOH, 80/20).
Reaction SMILES: [CH2:1]1[C@@H:10]2[C@H:4]([CH2:5][CH2:6][NH:7][C:8]3[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=32)[CH2:3][N:2]1[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16].[Cl:22]N1C(=O)CCC1=O>CN(C)C=O>[Cl:22][C:14]1[C:8]2[NH:7][CH2:6][CH2:5][C@@H:4]3[CH2:3][N:2]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:1][C@H:10]3[C:9]=2[CH:11]=[CH:12][CH:13]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H]2CCNc3ccccc3[C@@H]2C1
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1C[C@H]2CCNc3c(Cl)cccc3[C@@H]2C1
Temperature: 50 °C

Procedure:
To a solution of Example 389B (172 mg, 0.60 mmol) in N,N-dimethylformamide (1 mL) was added N-chlorosuccinimide (80 mg, 0.60 mmol). The mixture was heated at 50° C. for 2 hours and purified by reversed phase HPLC (0.1% trifluoroacetic acid(aq):acetonitrile) to afford the title compound with a longer retention time than that of Example 391A.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=2)[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2].N1C=CC=CC=1.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>ClCCl.C(Cl)(Cl)Cl>[C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([O:14][C:15]2[CH:16]=[CH:17][C:18]([NH:21][S:30]([CH3:29])(=[O:32])=[O:31])=[CH:19][CH:20]=2)[CH2:6][C@@H:5]1[CH3:22])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1c2ccccc2[C@H](Oc2ccc(N)cc2)C[C@@H]1C
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N1c2ccccc2[C@H](Oc2ccc(NS(C)(=O)=O)cc2)C[C@@H]1C
Temperature: 0 °C
Reaction time: 2 h

Procedure:
[Step 3] (2S,4R)-1-acetyl-4-(4-aminophenoxy)-2-methyl-1,2,3,4-tetrahydroquinoline was dissolved in 2 mL of dichloromethane, and 28.4 μL of pyridine and 19.1 μL of methanesulfonyl chloride were added to the solution at 0° C. The mixture was stirred for 2 hours at 0° C. After completion of the reaction, the reaction mixture was diluted with chloroform, and then was washed with 1 N hydrochloric acid, a saturated aqueous solution of sodium hydrogen carbonate, and saturated brine. Subsequently, the resultant was dehydrated over anhydrous sodium sulfate, and then was concentrated under reduced pressure. The resulting residue was purified by using silica gel chromatography (hexane:acetone=2:1), and then was recrystallized from chloroform-hexane. Thus, 28.2 mg (32.0%, cis-form only) of the title compound was obtained as a pale peach-colored amorphous compound.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](Br)=[CH:4][CH:3]=1.C([Li])CCC.[CH3:14][Si:15]([CH3:18])([CH3:17])Cl>CCOCC.CCCCCC>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([Si:15]([CH3:18])([CH3:17])[CH3:14])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)Cl
Reactant: Brc1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: C[Si](C)(C)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Under argon, 94.4 g of p-dibromobenzene is cooled to -20° C. in 400 ml of absolute ether. To the solution is added dropwise 255 ml of 15% butyllithium in hexane so that the temperature does not rise above -10° C. Then the mixture is agitated for one hour at room temperature. After a negative Gilman test (H. Gilman, J. Swiss, J. Amer. Chem. Soc. 62: 1847 [1940]), the mixture is again cooled to -20° C. and 46 ml of trimethylchlorosilane in 200 ml of absolute ether is added dropwise thereto so that the temperature does not exceed -10° C. After the addition step is finished, the mixture is stirred for 16 hours at room temperature and another hour under reflux. The thus-formed precipitate is suctioned off and thoroughly washed with ether. The resultant filtrate is concentrated and then distilled with a water-jet aspirator, thus producing 65.52 g of p-bromotrimethylsilylbenzene, bp (16 torr) 103°-110° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6].CO.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:10]([CH:13]2[CH:17]=[N:16][N:15]=[N:14]2)=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1cc(C2C=NN=N2)ccc1OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: COc1ccc(C2C=NN=N2)cc1C(=O)O
Reaction time: 8 h

Procedure:
Combine methyl 2-methoxy-5-(4H-triazol-4-yl)benzoate (56 mmol) and methanol (200 mL) and water (50 mL). Add 1M aqueous solution of sodium hydroxide (62.5 mL, 62.5 mmol). Heat to reflux. After 8 hour, concentrate in vacuo to remove most of the solvent. Adjust the pH to about 1 to 2 using a 1M aqueous hydrochloric acid solution, extract with dichloromethane. Dry the organic layer over MgSO4, filter, and evaporate in vacuo to give 2-methoxy-5-(4H-triazol-4-yl)benzoic acid.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[C:12]2[C:11]3[O:19][C@H:20]4[CH2:25][CH2:24][CH2:23][C@H:21]4[NH:22][C:10]=3[CH:9]=[CH:8][C:7]=2[N:6]=1)([CH3:3])[CH3:2].[BH4-].[Na+].[C:28](O)(=O)[CH3:29]>>[CH2:28]([N:22]1[C:10]2[CH:9]=[CH:8][C:7]3[N:6]=[C:5]([O:4][CH:1]([CH3:3])[CH3:2])[CH:14]=[C:13]([C:15]([F:17])([F:16])[F:18])[C:12]=3[C:11]=2[O:19][C@H:20]2[CH2:25][CH2:24][CH2:23][C@@H:21]12)[CH3:29]
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(C(F)(F)F)c2c3c(ccc2n1)N[C@@H]1CCC[C@@H]1O3
Agent: [BH4-]
Agent: [Na+]
Product: CCN1c2ccc3nc(OC(C)C)cc(C(F)(F)F)c3c2O[C@H]2CCC[C@H]21

Procedure:
Compound 134 was prepared according to General Method 5 (EXAMPLE 2) from (7aR,10aS)-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline (5 mg, 0.014 mmol) and NaBH4 pellets (>10 equiv) in 5 mL acetic acid to afford 5 mg of (7aR,10aS)-7-ethyl-7,7a,8,9,10,10a-hexahydro-3-isopropoxy-1-(trifluoromethyl)-cyclopenta[5,6][1,4]oxazino[2,3-f]quinoline. This material (5 mg, 0.01 mmol) was carried on according to General Method 4 (EXAMPLE 1) by treatment with 4 mL of 1:1 acetic acid:concentrated HCl (3 mM) and heated at 90° C. for 4 h to afford 4 mg (89%) of Compound 134, a yellow solid, after column chromatography (3:1 hexanes:EtOAc to 1:1 hexanes:EtOAc, gradient elution). 1H NMR (500 MHz, CDCl3)δ11.01 (bs, 1H), 7.10 (s, 1H), 7.01 (d, J=8.8, 1H), 6.90 (d, J=8.8, 1H), 4.00 (m, 1H), 3.59 (ddd, J=10.0, 7.1, 3.4 1H), 3.44 (m, 2H), 2.03 (m, 4H), 1.61 (m, 2H), 1.20 (t, J=7.1, 3H).
Reaction SMILES: [C:1]([O:5][C:6]1[CH:11]=[C:10](I)[CH:9]=[C:8]([Cl:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2].C(COC)OC.C(O)C.[C:23]1([S:29]([N:32]2[C:36]3=[N:37][CH:38]=[CH:39][CH:40]=[C:35]3[C:34](B3OC(C)(C)C(C)(C)O3)=[CH:33]2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]1[CH:11]=[C:10]([C:34]2[C:35]3[C:36](=[N:37][CH:38]=[CH:39][CH:40]=3)[N:32]([S:29]([C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)(=[O:31])=[O:30])[CH:33]=2)[CH:9]=[C:8]([Cl:13])[N:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)Oc1cc(I)cc(Cl)n1
Reactant: CC1(C)OB(c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: COCCOC
Solvent: CCOC(C)=O
Product: CC(C)(C)Oc1cc(-c2cn(S(=O)(=O)c3ccccc3)c3ncccc23)cc(Cl)n1
Temperature: 80 °C

Procedure:
To a solution of EXAMPLE 34A (2.6 g, 8.35 mmol) in 5:1 dimethoxyethane/ethanol (90 mL) was added 1-(phenylsulfonyl)-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (3.53 g, 9.18 mmol), 1M aqueous sodium carbonate (6.68 mL) and dichlorobis(triphenylphosphine)-palladium (II) (0.29 g, 0.42 mmol). The reaction was heated at 80° C. for 3 hours, cooled, and diluted with ethyl acetate. The solution was washed with brine, dried over magnesium sulfate, filtered and concentrated to give the title compound. MS (ESI) m/e 442.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=O)[CH2:10]1.[C:21]([NH:24][NH2:25])([NH2:23])=[NH:22].Cl.Cl>C(O)C>[ClH:1].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH:9]1[CH2:18][C:17]2[N:16]=[CH:15][CH:14]=[C:13]([CH3:19])[C:12]=2[C:11](=[N:25][NH:24][C:21]([NH2:23])=[NH:22])[CH2:10]1
Reactant: N=C(N)NN
Reactant: Cc1ccnc2c1C(=O)CC(c1c(Cl)cccc1Cl)C2
Agent: Cl
Solvent: CCO
Product: Cc1ccnc2c1C(=NNC(=N)N)CC(c1c(Cl)cccc1Cl)C2
Yield: 175.1 %

Procedure:
A mixture of 7-(2,6-dichlorophenyl)-4-methyl-5,6,7,8-tetrahydroquinolin-5-one (171 mg), aminoguanidine hydrochloride (67 mg) and concentrated hydrochloric acid (0.1 ml) in ethanol (3 ml) was refluxed for 2 hours. The reaction solution was concentrated under reduced pressure, and precipitated crystals were recrystallized form ethanol to give 7-(2,6-dichlorophenyl)-5-guanidinoimino-4-methyl-5,6,7,8-tetrahydroquinoline hydrochloride (Compound 63) (195 mg) as colorless crystals.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[Li+].CC([N-]C(C)C)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([F:28])=[CH:24][N:23]=1.[B:29](OC(C)C)([O:34]C(C)C)[O:30]C(C)C>C1COCC1>[F:21][C:22]1[CH:27]=[C:26]([B:29]([OH:34])[OH:30])[C:25]([F:28])=[CH:24][N:23]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(F)nc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: OB(O)c1cc(F)ncc1F
Temperature: -20 °C
Reaction time: 4 h
Yield: 44 %

Procedure:
Diisopropylamine (1.74 ml, 1.24 g, 12.20 mmol) was dissolved in anhydrous THF (22 ml) and placed under argon. The solution was cooled to −20° C. and then treated with n-butyllithium (7.66 ml, 12.25 mmol, 1.6 M in hexanes) by slow addition over 10 min. The newly formed LDA (LDA=lithium diisopropylamide, this acronyl should be listed in the general session) was then cooled to −78° C. and treated with a solution of 2,5-difluoropyridine (1.05 ml, 1.33 g, 11.56 mmol) dissolved in anhydrous THF (3 ml) by slow addition over 30 min. Once the addition was complete the reaction mixture was allowed to stir at −78° C. for 4 hr. At this time the reaction mixture was treated with a solution of triisopropyl borate (5.90 ml, 4.78 g, 25.4 mmol) dissolved in anhydrous THF (8.6 ml) by dropwise addition. Once the addition was complete the reaction mixture was allowed to warm to ambient temperature then stirred at ambient temperature for an additional hour. The reaction mixture was then quenched by adding 4% aq NaOH (34 ml). The layers were separated and the aqueous layer was cooled in an ice bath. It was then acidified to pH=4 with 6N HCl (˜10 ml) not letting the temperature go above 10° C. This was then extracted with EtOAc (3×50 ml). The extracts were then washed with brine (1×50 ml), dried (Na2SO4), filtered, and the solvent removed in vacuo. The resulting residue was triturated with Et2O to give 0.8084 g (44%) of 2,5-difluoropyridin-4-ylboronic acid.