Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=1.C([Mg]Cl)(C)C.[CH2:26]([O:28][C:29]1[C:36]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)=[CH:35][CH:34]=[CH:33][C:30]=1[CH:31]=[O:32])[CH3:27].O>O1CCCC1>[CH2:38]([O:37][C:36]1[C:29]([O:28][CH2:26][CH3:27])=[C:30]([CH:31]([C:2]2[C:10]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[N:4]([Si:11]([CH:18]([CH3:20])[CH3:19])([CH:15]([CH3:17])[CH3:16])[CH:12]([CH3:14])[CH3:13])[CH:3]=2)[OH:32])[CH:33]=[CH:34][CH:35]=1)[C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cccnc21
Reactant: CCOc1c(C=O)cccc1OCc1ccccc1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: O
Product: CCOc1c(OCc2ccccc2)cccc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncccc12
Temperature: -20 °C
Reaction time: 1.5 h
Yield: 13.9 %

Procedure:
To a solution of 3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (635, 1.306 g, 3.26 mmol) in tetrahydrofuran (42 mL) at −20° C. under nitrogen was added isopropylmagnesium chloride (1.70 mL, 2.0 M solution in tetrahydrofuran, 3.40 mmol). The reaction mixture was stirred at −20° C. for 1.5 hours. It was allowed to warm to 5° C. and then kept at 5° C. for 1 hour. The reaction mixture was then cooled down to −20° C. To this solution was slowly added a solution of 2-ethoxy-3-benzyloxybenzaldehyde (663, 0.698 g, 2.72 mmol, prepared by protocol of Example 43, Steps 1-3 of Scheme 71, using benzyl bromide in place of 4-chloro-benzyl bromide in Step 1) in tetrahydrofuran (42 mL). The reaction mixture was stirred at −20° C. for 2.5 hrs, and was allowed to warm to 5° C. for 2.5 hours. The reaction mixture was poured into iced water, extracted with ethyl acetate, washed with saturated ammonium chloride and brine, and dried over magnesium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography eluting with ethyl acetate in hexane to provide the compound as light-yellow oil (664, 200 mg, 13.9%).
Reaction SMILES: [C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9](B2OC(C)(C)C(C)(C)O2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[N:30]=[C:29]([O:31][CH3:32])[C:28](Br)=[CH:27][N:26]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([C:28]2[C:29]([O:31][CH3:32])=[N:30][C:25]([NH2:24])=[N:26][CH:27]=2)=[CH:8][C:7]=1[N+:21]([O-:23])=[O:22])([CH3:2])([CH3:3])[CH3:4]
Reactant: COc1nc(N)ncc1Br
Reactant: CC(C)(C)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cc1[N+](=O)[O-]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1nc(N)ncc1-c1ccc(NC(C)(C)C)c([N+](=O)[O-])c1
Temperature: 110 °C
Reaction time: 18 h
Yield: 86.1 %

Procedure:
To a vial is added tert-butyl-[2-nitro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl]-amine (300 mg, 0.937 mmol), 2-amino-5-bromo-4-methoxypyrimidine (215 mg, 1.054 mmol) and 2M Na2CO3 (2 mL, 4 mmol) in DMF (10 mL), followed by the addition of tetrakis(triphenylphosphine)palladium(0) (108 mg, 0.093 mmol). The vial is sealed under Argon gas. The reaction mixture is stirred at 110° C. for 18 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is separated, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-5% MeOH/CH2Cl2. The product fractions are collected and concentrated to afford 5-(4-tert-butylamino-3-nitro-phenyl)-4-methoxy-pyrimidin-2-ylamine (256 mg, 86%) as a red solid. LCMS (ESMS): m/z 318.72 (M++1)
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7](O)[CH:6]=[CH:5]2.C([O-])([O-])=[O:14].[K+].[K+].S1C=CC(C(Cl)=O)=C1>C(Cl)Cl>[C:3]1([OH:14])[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:10]=[CH:11][CH:2]=1
Reactant: Nc1ccc2cc(O)ccc2c1
Reactant: O=C([O-])[O-]
Agent: O=C(Cl)c1ccsc1
Agent: [K+]
Solvent: ClCCl
Product: Oc1cccc2ccccc12
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
The hydrochloride salt of 6-aminonaphthalen-2-ol (3.93 g, 20.1 mmol) and K2CO3 (9.45 g, 68.5 mmol) were suspended in CH2Cl2 (38 ml) and 3-thiophenecarbonyl chloride (4.3 g, 29.3 mmol) was added. The reaction was stirred at room temperature for 17.5 hours and then quenched with water (50 ml) and filtered. The solid was washed with CH2Cl2 and then the solvent was removed in vacuo to provide the intermediate napthyl alcohol.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18](Br)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2].[Cl:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29]>>[N+:1]([C:4]1[CH:5]=[C:6]([C:12]2[O:13][C:14]3[CH:20]=[CH:19][C:18]([C:25]4[CH:26]=[CH:27][C:28]([F:29])=[C:23]([Cl:22])[CH:24]=4)=[CH:17][C:15]=3[N:16]=2)[C:7]([O:10][CH3:11])=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OB(O)c1ccc(F)c(Cl)c1
Reactant: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(Br)ccc2o1
Product: COc1ccc([N+](=O)[O-])cc1-c1nc2cc(-c3ccc(F)c(Cl)c3)ccc2o1

Procedure:
Prepared by the method of Example 15d), from 2-(3-nitro-6-methoxyphenyl)-5-bromobenzoxazole (400 mg, 1.14 mmol) and 3-chloro-4-fluorophenylboronic acid (299 mg, 1.71 mmol) the subtitle compound was obtained (277 mg, 47%). The product was used directly in the next step without purification
Reaction SMILES: Cl[CH:2]1[C:8]2[CH:9]=[C:10]([F:13])[CH:11]=[CH:12][C:7]=2[S:6][C:5]2[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=2[CH2:3]1.[N:19]1([CH2:25][CH2:26][N:27]2[CH2:31][CH2:30][O:29][C:28]2=[O:32])[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>C(Cl)(Cl)Cl>[F:13][C:10]1[CH:11]=[CH:12][C:7]2[S:6][C:5]3[CH:14]=[C:15]([CH3:18])[CH:16]=[CH:17][C:4]=3[CH2:3][CH:2]([N:22]3[CH2:23][CH2:24][N:19]([CH2:25][CH2:26][N:27]4[CH2:31][CH2:30][O:29][C:28]4=[O:32])[CH2:20][CH2:21]3)[C:8]=2[CH:9]=1
Reactant: Cc1ccc2c(c1)Sc1ccc(F)cc1C(Cl)C2
Reactant: O=C1OCCN1CCN1CCNCC1
Solvent: ClC(Cl)Cl
Product: Cc1ccc2c(c1)Sc1ccc(F)cc1C(N1CCN(CCN3CCOC3=O)CC1)C2

Procedure:
10.6 g. of 10-chloro-8-fluoro-10,11-dihydro-3-methyldibenzo[b,f]thiepin are heated at reflux together with 200 ml. of chloroform and 22.8 g. of 3-[2-(1-piperazinyl)-ethyl]-2-oxazolidinone for 30 hours. Thereafter, the mixture is evaporated under reduced pressure, and the residue is worked up as described in Example 5. The insoluble base is recrystallized from ethanol, whereby there is obtained 3-{2-[4-(8-fluoro-10,11-dihydro-3-methyl-dibenzo[b,f]thiepin-10-yl)-1-piperazinyl]-ethyl}-2-oxazolidinone which melts at 173°-175°C. The maleate crystallizes from acetone/ether and has a melting point of 147°-149°C.
Reaction SMILES: [CH3:1][C:2]([CH3:16])=[CH:3][CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][OH:13])=[CH:8][CH:7]=1.[H-].[Na+].[CH2:19]([N:21]=[C:22]=[S:23])[CH3:20]>>[CH2:19]([NH:21][C:22](=[S:23])[O:13][CH2:12][CH2:11][O:10][C:9]1[CH:14]=[CH:15][C:6]([O:5][CH2:4][CH:3]=[C:2]([CH3:16])[CH3:1])=[CH:7][CH:8]=1)[CH3:20]
Reactant: CC(C)=CCOc1ccc(OCCO)cc1
Reactant: CCN=C=S
Agent: [H-]
Agent: [Na+]
Product: CCNC(=S)OCCOc1ccc(OCC=C(C)C)cc1

Procedure:
In the same manner, 2-[4-(3-methyl-2-butenoxy)phenoxy]ethanol is reacted with sodium hydride and ethyl isothiocyanate to yield O-2-[4-(3-methyl-2-butenoxy)phenoxy]ethyl N-ethylthiocarbamate (compound 37, Table A).
Reaction SMILES: C([O:5][C:6](=[O:19])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][NH2:18])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.Cl[C:21]1[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=1.[C:29]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH:34]=[CH:33][C:32]([CH2:35]Cl)=[CH:31][CH:30]=1.FC(F)(F)C(O)=O>ClCCl>[C:29]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:30]=[CH:31][C:32]([CH2:35][N:18]([C:21]2[CH:26]=[CH:25][C:24]([C:27]#[N:28])=[CH:23][N:22]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:19])[S:12][CH:13]=2)=[CH:33][CH:34]=1
Reactant: N#Cc1ccc(Cl)nc1
Reactant: CC(C)(C)OC(=O)C(C)(C)Sc1nc(CCN)cs1
Reactant: ClCc1ccc(-c2ccccc2)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(Sc1nc(CCN(Cc2ccc(-c3ccccc3)cc2)c2ccc(C#N)cn2)cs1)C(=O)O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A compound obtained by an operation similar to that of Example 265-1 and using 2-{[4-(2-aminoethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester synthesized in Example 7 and 2-chloro-5-cyanopyridine as starting materials, followed by an operation similar to that of Example 265-2 and using biphenyl-4-ylmethyl chloride as starting material was treated with dichloromethane and trifluoroacetic acid, and the mixture was stirred at room temperature for 12 hr. The reaction solution was concentrated under reduced pressure, and the residue was purified by high performance liquid chromatography (elution solvent; 0.05% trifluoroacetic acid-water:0.05% trifluoroacetic acid-acetonitrile) to give the title compound.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[S:7])=[CH:4][CH:3]=1.C(Cl)CCl.[C:15]([C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:20]=1[OH:29])([CH3:18])([CH3:17])[CH3:16].Cl>[Ti](Cl)(Cl)(Cl)Cl.CCCCCC>[CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([C:23]2[CH:22]=[C:21]([C:25]([CH3:26])([CH3:27])[CH3:28])[C:20]([OH:29])=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:24]=2)=[S:7])=[CH:4][CH:3]=1
Reactant: Cc1ccc(C(=S)Cl)cc1
Reactant: CC(C)(C)c1cccc(C(C)(C)C)c1O
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCCl
Product: Cc1ccc(C(=S)c2cc(C(C)(C)C)c(O)c(C(C)(C)C)c2)cc1

Procedure:
A solution of 54.4 g. (0.29 mole) of 4-methylthiobenzoyl chloride in 200 ml. of dichloroethylene is added gradually to 55 g. (0.29 mole) of titanium tetrachloride. After cooling this mixture, a solution of 60 g. of 2,6-di(t-butyl)phenol in 200 ml. of dichloroethylene is added. The resulting mixture is stirred for several hours, then hydrolyzed with 10 percent hydrochloric acid. The organic layer is separated, washed with water, dried and evaporated to provide a yellow oil. This product is mixed with hexane to provide a white solid which is recrystallized from hexane to provide 4-(4-methylthiobenzoyl)-2,6-di(t-butyl)phenol, m.p. 135°-136 C.
Reaction SMILES: [NH3:1].[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[NH:11][CH:12]([C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[CH2:13][C:14]([O:16]C)=O)[CH:6]=[CH:7][CH:8]=1>CO>[CH3:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:35])[NH:11][CH:12]([CH2:13][C:14]([NH2:1])=[O:16])[C:18]([N:20]([CH2:27][C:28]([O:30][C:31]([CH3:32])([CH3:33])[CH3:34])=[O:29])[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:19])[CH:6]=[CH:7][CH:8]=1
Reactant: N
Reactant: COC(=O)CC(NC(=O)Nc1cccc(C)c1)C(=O)N(CC(=O)OC(C)(C)C)c1ccccc1
Solvent: CO
Product: Cc1cccc(NC(=O)NC(CC(N)=O)C(=O)N(CC(=O)OC(C)(C)C)c2ccccc2)c1

Procedure:
A stream of ammonia is passed for 11 hours at a temperature in the region of 25° C. into a solution of methyl (RS)-3-[3-(3-methylphenyl)ureido]-N-(tertbutoxycarbonylmethyl)-N-phenylsuccinamate (4.7 g) in methanol (150 cc). The solution is then outgassed with a stream of nitrogen and concentrated under vacuum (2.7 kPa) at 60° C. The residue is crystallised in diethyl ether and the solid extracted with dichloromethane (40 cc). The solution thereby obtained is purified by chromatography on silica (0.063-0.200 mm) (25 g) contained in a column 1.6 cm in diameter [eluent: methylene chloride (1100 cc), then methylene chloride/methanol (98.5:1.5 by volume)], collecting 15-cc fractions. Fractions 80 to 127 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 60° C. After crystallisation in petroleum ether, (RS)-2-[3-(3-methylphenyl)ureido]-N-(tert-butoxycarbonylmethyl)-N-phenylsuccinamide (1.1 g), m.p. 192° C., is obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH2:22])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:25]=[C:26]([NH:40][C:41](OC2C=CC=CC=2)=[O:42])[C:27](=[CH:38][CH:39]=1)[C:28]([O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:29]>>[CH2:1]([O:8][C:9]([NH:11][C:12]1[CH:13]=[C:14]([S:19]([NH:22][C:41]([NH:40][C:26]2[CH:25]=[C:24]([Cl:23])[CH:39]=[CH:38][C:27]=2[C:28]([O:30][CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)=[O:29])=[O:42])(=[O:21])=[O:20])[CH:15]=[CH:16][C:17]=1[CH3:18])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(N)(=O)=O)cc1NC(=O)OCc1ccccc1
Reactant: O=C(Nc1cc(Cl)ccc1C(=O)OCc1ccccc1)Oc1ccccc1
Product: Cc1ccc(S(=O)(=O)NC(=O)Nc2cc(Cl)ccc2C(=O)OCc2ccccc2)cc1NC(=O)OCc1ccccc1
Yield: 62 %

Procedure:
960 mg (3.00 mmol) of 3-benzyloxycarbonylamino-4-methylbenzenesulfonamide and 1.14 g (3.00 mmol) of benzyl 4-chloro-2-N-phenoxycarbonylanthranilate were treated in the same way as in Example 8 to obtain 1.14 g (yield 62% of benzyl 2-{[(3-benzyloxycarbonylamino-4-methylbenzenesulfonylamino)carbonyl]amino}-4-chlorobenzoate. Properties: colorless amorphous, PMR (δ ppm, DMSO-d6): 2.30 (3H, s), 5.17 (2H, s), 5.36 (2H, s), 7.20 (1H, dd), 7.33–7.48 (l1H, m), 7.63 (1H, d), 7.97 (1H, d), 8.11 (1H, s), 8.25 (1H, s), 9.27 (1H, s), 10.30 (1H, s), 12.20 (1H, br).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[N:7]1([C:13]2[N:18]=[CH:17][C:16]([C:19]([OH:21])=O)=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[NH2:22][C:23]1[CH:35]=[C:34]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:33]=[CH:32][C:24]=1[C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(=O)([O-])O.[Na+]>C(N(CC)CC)C.C(Cl)Cl.CN(C)C=O>[C:36]1([C:34]2[CH:33]=[CH:32][C:24]([C:25]([O:27][C:28]([CH3:31])([CH3:29])[CH3:30])=[O:26])=[C:23]([NH:22][C:19]([C:16]3[CH:17]=[N:18][C:13]([N:7]4[CH2:8][CH2:9][CH2:10][CH2:11][CH2:12]4)=[CH:14][CH:15]=3)=[O:21])[CH:35]=2)[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1N
Reactant: O=C(O)c1ccc(N2CCCCC2)nc1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccc(N2CCCCC2)nc1
Reaction time: 1 h

Procedure:
1.3 mL of methylene chloride, 1.3 μL of N,N-dimethylformamide and 3.031 mL of oxalyl chloride were sequentially added to 69 mg of 6-(piperidin-1-yl)pyridine-3-carboxylic acid at room temperature, and stirred at the same temperature for 1 hour. The reaction mixture was added to a mixed solution of 54 mg of tert-butyl 2-amino-4-phenylbenzoate, 3.7 mL of methylene chloride and 6.22 mL of triethylamine and stirred at room temperature for 2 hours. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1] to obtain tert-butyl 4-phenyl-2-(6-(piperidin-1-yl)pyridine-3-carboxamido)benzoate.
Reaction SMILES: IC.[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([C:18]2[CH:19]=[C:20]3[C:25](=[CH:26][CH:27]=2)[N:24]2[N:28]=[N:29][N:30]=[C:23]2[CH:22]=[C:21]3[C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([Cl:37])[CH:32]=2)[C:11]2[N:12]([CH3:17])[C:13]([SH:16])=[N:14][N:15]=2)=[CH:6][CH:5]=1.[CH3:38]O[Na].CO.O>CO>[Cl:37][C:33]1[CH:32]=[C:31]([C:21]2[C:20]3[C:25](=[CH:26][CH:27]=[C:18]([CH:10]([C:7]4[CH:8]=[CH:9][C:4]([Cl:3])=[CH:5][CH:6]=4)[C:11]4[N:12]([CH3:17])[C:13]([S:16][CH3:38])=[N:14][N:15]=4)[CH:19]=3)[N:24]3[N:28]=[N:29][N:30]=[C:23]3[CH:22]=2)[CH:36]=[CH:35][CH:34]=1
Reactant: CO[Na]
Reactant: Cn1c(S)nnc1C(c1ccc(Cl)cc1)c1ccc2c(c1)c(-c1cccc(Cl)c1)cc1nnnn12
Solvent: CI
Solvent: CO
Solvent: O
Product: CSc1nnc(C(c2ccc(Cl)cc2)c2ccc3c(c2)c(-c2cccc(Cl)c2)cc2nnnn23)n1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 98 %

Procedure:
Iodomethane (0.0092 mol) was added to a mixture of intermediate (62) (0.0092 mol) and MeONa/MeOH (0.0092 mol) in methanol (50 ml). The mixture was stirred at room temperature overnight and poured out into water. The precipitate was filtered washed with diethyl ether and dried, yielding 4.8 g (98%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)[4-methyl-5-(methylthio)-4H-1,2,4triazol-3-yl]methyl]-tetrazolo[1,5-a]quinoline, MS (ESI) m/z:532, 534, 536 (MH+) (intermediate 63).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-:2].C(N(CC)CC)C.[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20](Cl)=[O:21]>O1CCCC1>[S:15]1[CH:19]=[CH:18][CH:17]=[C:16]1[C:20]1[O:21][CH:2]=[N:1][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: [C-]#[N+]CC(=O)OC
Reactant: O=C(Cl)c1cccs1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1ncoc1-c1cccs1
Yield: 86 %

Procedure:
29.7 g of methyl α-isocyanoacetate, 120 g of triethylamine, 450 ml of tetrahydrofuran and 48.4 g of 2-thienylcarbonyl chloride are treated in the same manner as described in Preparation 1-(1). 53.9 g of 5-(2-thienyl)-4-methoxycarbonyloxazole are thereby obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:22])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N:23]1[N:27]2[CH:28]=[CH:29][CH:30]=[N:31][C:26]2=[C:25]([C:32]2[CH:40]=[CH:39][C:35]([C:36](O)=[O:37])=[CH:34][CH:33]=2)[CH:24]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>CN(C=O)C.O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][N+:16]=2[O-:22])[C:36](=[O:37])[C:35]2[CH:34]=[CH:33][C:32]([C:25]3[CH:24]=[N:23][N:27]4[CH:28]=[CH:29][CH:30]=[N:31][C:26]=34)=[CH:40][CH:39]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1ccc[n+]([O-])c1N[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Reactant: O=C(O)c1ccc(-c2cnn3cccnc23)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc[n+]([O-])c1N(C(=O)c1ccc(-c2cnn3cccnc23)cc1)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Preparation 14 (R)-2-(1-(tert-butoxycarbonyl)piperidin-3-ylamino)-3-methylpyridine 1-oxide (540 mg, 1.76 mmol) and Preparation 19 4-(pyrazolo[1,5-a]pyrimidin-3-yl)benzoic acid (420 mg, 1.76 mmol) in DMF (10 mL) was added HATU (803 mg, 2.11 mmol) at 30° C. The reaction was stirred at room temperature for 30 min. Diisopropylethyl amine (682 mg, 5.28 mmol) was then added at 0° C. dropwise. The reaction was stirred at 30° C. for 2 h. The resulting mixture poured into water then extracted with EtOAc (3×30 mL). The combined organic layers were washed with brine, dried over Na2SO4, filtered and the filtrate was concentrated under reduced pressure. The crude product was purified by silica gel chromatography to deliver the title compound (760 mg, 82%) as a brown oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][N:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=O)=[CH:17][N:16]=1.[CH2:24]([CH2:26][NH2:27])[OH:25]>>[OH:25][CH2:24][CH2:26][NH:27][C:19](=[O:21])[C:18]1[CH:22]=[CH:23][C:15]([O:14][CH2:13][C:3]2[C:4]([C:7]3[CH:12]=[CH:11][N:10]=[CH:9][N:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:16][CH:17]=1
Reactant: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)O)cn1
Reactant: NCCO
Product: Cc1onc(-c2ccncn2)c1COc1ccc(C(=O)NCCO)cn1
Yield: 73 %

Procedure:
As described for example 313b, 6-(5-methyl-3-pyrimidin-4-yl-isoxazol-4-ylmethoxy)-nicotinic acid (53 mg, 0.17 mmol) was converted, using ethanolamine instead of isopropylamine, to the title compound (44 mg, 73%) which was obtained as a white solid. MS: m/e=356.3 [M+H]+.
Reaction SMILES: [CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH:38]C(C)(C)C)=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:22])([F:21])[F:20])[N:9]=1)[CH2:2][CH2:3][CH3:4].FC(F)(F)C(O)=O.C1(OC)C=CC=CC=1>>[CH2:1]([C:5]1[N:6]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[S:37](=[O:44])(=[O:43])[NH2:38])=[CH:27][C:26]=2[F:45])[C:7](=[O:23])[N:8]([C:10]2[CH:15]=[C:14]([N+:16]([O-:18])=[O:17])[CH:13]=[CH:12][C:11]=2[C:19]([F:20])([F:22])[F:21])[N:9]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(=O)(=O)NC(C)(C)C)cc1F
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Product: CCCCc1nn(-c2cc([N+](=O)[O-])ccc2C(F)(F)F)c(=O)n1Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1F
Yield: 94 %

Procedure:
Reaction of 5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluorobiphenyl-4-yl]methyl]-2,4-dihydro-2-[5-nitro-2-(trifluoromethyl)phenyl]-3H-1,2,4-triazol-3-one (from Step A) with trifluoroacetic acid in the presence of anisole according to the procedure of Example 28, Step G, gave a 94% yield of the title compound as a pale yellow foam, homogeneous by TLC (95:5 CH2Cl2 --MeOH); mass spectrum (FAB) m/e 594 (M+1)+.
Reaction SMILES: [N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][CH:6]=2)[CH2:4][CH2:3][CH2:2]1.[Br:25]N1C(C)(C)C(=O)N(Br)C1=O>C(Cl)(Cl)Cl>[N:1]1([C:5]2[N:14]=[C:13]3[C:8]([C:9](=[O:24])[C:10]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:11][N:12]3[CH2:15][CH2:16][C:17]#[N:18])=[CH:7][C:6]=2[Br:25])[CH2:2][CH2:3][CH2:4]1
Reactant: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)ccc2c1=O
Reactant: CC1(C)C(=O)N(Br)C(=O)N1Br
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cn(CCC#N)c2nc(N3CCC3)c(Br)cc2c1=O

Procedure:
A solution of EXAMPLE 81C (0.50 g) and 1,3-dibromo-5,5-dimethylhydantoin (0.26 g) in chloroform (100 mL) was refluxed for 10 minutes then cooled, diluted with chloroform, washed with 10% sodium bisulfate and brine, dried (MgSO4), filtered, and concentrated; and the concentrate was crystallized from dichloromethane/ethyl acetate/hexanes.
Reaction SMILES: Cl.[CH3:2][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:6])[CH2:4][NH2:5].C(N(CC)CC)C.[F:20][C:21]([F:32])([F:31])[C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)Cl.CCOC(C)=O>[CH3:6][C:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)([CH3:2])[CH2:4][NH:5][C:26](=[O:27])[C:25]1[CH:29]=[CH:30][C:22]([C:21]([F:20])([F:31])[F:32])=[CH:23][CH:24]=1
Reactant: CC(C)(CN)c1ccccc1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(C)(CNC(=O)c1ccc(C(F)(F)F)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
To a suspension of 2-methyl-2-phenylpropan-1-amine hydrochloride (5.32 g, 28.6 mmol) in dry DCM (60 mL) at 0° C. was added triethylamine (8.3 mL, 60.1 mmol) and then slowly 4-(trifluoromethyl)benzoyl chloride (4.48 mL, 30.1 mmol). Then, the mixture was stirred at RT for 45 min, diluted with EtOAc, washed with 10% HCl, sat NaHCO3 and water. After drying over Na2SO4 the solvent was removed under vacuum and the title compound was obtained as a white solid. MS (ESI, positive ion) m/z: 322 (M+H).
Reaction SMILES: Br[C:2]1[C:3]2[C:4]3[CH:18]=[CH:17][S:16][C:5]=3[C:6](=[O:15])[NH:7][C:8]=2[C:9]([CH3:14])=[CH:10][C:11]=1[O:12][CH3:13].CC1(C)C(C)(C)OB([C:27]2[CH:32]=[CH:31][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[CH:29][CH:28]=2)O1>>[CH3:13][O:12][C:11]1[CH:10]=[C:9]([CH3:14])[C:8]2[NH:7][C:6](=[O:15])[C:5]3[S:16][CH:17]=[CH:18][C:4]=3[C:3]=2[C:2]=1[C:27]1[CH:28]=[CH:29][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35][C:36](=[O:42])[O:37][C:38]([CH3:40])([CH3:39])[CH3:41])=[CH:31][CH:32]=1
Reactant: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1Br
Reactant: C[C@@H](CNC(=O)OC(C)(C)C)c1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Product: COc1cc(C)c2[nH]c(=O)c3sccc3c2c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1
Yield: 36.1 %

Procedure:
Following General Procedure B, 9-bromo-8-methoxy-6-methylthieno[2,3-c]quinolin-4(5H)-one (3.0 g, 9.26 mmol) was reacted with (R)-tert-butyl 2-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propylcarbamate (5.2 g, 13.89 mmol) to afford the desired product (1.60 g, 35%) as a brown solid: ESI MS m/z 479 [C27H30N2O4S+H]+.