Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.[N+:12]([O-])([O-:14])=[O:13].[K+].CCCCCC.N>S(=O)(=O)(O)O.C(OCC)(=O)C>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[N+:12]([O-:14])=[O:13])[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc2ccccc12
Reactant: O=[N+]([O-])[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: O=[N+]([O-])c1cccc2cncc(Br)c12
Yield: 48.5 %

Procedure:
With vigorous stirring, concentrated sulfuric acid (36 ml) was added with 4-bromoisoquinoline (10.0 g, Tokyo Kasei Kogyo) to such an extent that the temperature should not exceed 10° C. and stirred for a while to attain complete dissolution. Potassium nitrate (4.9 g, Kanto Chemicals) was dissolved in concentrated sulfuric acid (20 ml), added dropwise to the aforementioned solution at a temperature below −5° C. and further stirred for 2 hours while maintaining that temperature. Disappearance of 4-bromoisoquinoline was confirmed by thin layer chromatography (n-hexane:ethyl acetate=1:1), and then the reaction mixture was slowly poured into cold aqueous ammonia (200 ml, Wako Pure Chemical Industries) with vigorous stirring. The reaction mixture was stirred for 15 minutes and then extracted three times with ethyl acetate (150 ml for each time), and the combined organic layer was washed successively with water (250 ml) and saturated brine (250 ml) and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was recrystallized with ethyl acetate to obtain the title compound (5.9 g) as thick yellow needle-like crystals.
Reaction SMILES: [CH2:1]([N:3]([CH2:13][CH3:14])[C:4](=[O:12])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:2].[Cl:15][CH2:16][Si:17](Cl)([CH3:19])[CH3:18]>>[CH2:13]([N:3]([CH2:1][CH3:2])[C:4](=[O:12])[C:5]1[C:10]([Si:17]([CH2:16][Cl:15])([CH3:19])[CH3:18])=[CH:9][CH:8]=[CH:7][C:6]=1[Cl:11])[CH3:14]
Reactant: C[Si](C)(Cl)CCl
Reactant: CCN(CC)C(=O)c1ccccc1Cl
Product: CCN(CC)C(=O)c1c(Cl)cccc1[Si](C)(C)CCl

Procedure:
The title compound was prepared according to General Method A from the compound of Example e and 1.5 eq (chloromethyl)dimethylsilyl chloride. Purification by HPLC using 1:9 ethyl acetate/hexanes gave 5.4 g of the desired compound as a yellow oil, an 85% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([OH:11])[CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH3:32][C:33]1[CH:34]=[C:35]([CH2:39][CH2:40]O)[CH:36]=[CH:37][CH:38]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[C:6]([O:11][CH2:40][CH2:39][C:35]2[CH:34]=[C:33]([CH3:32])[CH:38]=[CH:37][CH:36]=2)[CH:5]=1
Reactant: Cc1cccc(CCO)c1
Reactant: COC(=O)c1ccc(Br)c(O)c1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)c1ccc(Br)c(OCCc2cccc(C)c2)c1
Yield: 102.7 %

Procedure:
4-Bromo-3-hydroxy-benzoic acid methyl ester (1.00 g, 4.32 mmol) and triphenylphosphine (1.36 g, 5.19 mmol) were dissolved in THF. 2-(3-Methylphenyl)-ethanol (2-m-tolyl-ethanol) (0.707 g, 5.19 mmol) was added, the mixture was cooled in an ice bath, and DIAD (1.05 g, 5.19 mmol) was added slowly with stirring. The ice bath was removed and stirring continued overnight at room temperature. The volatiles were evaporated in vacuo, and the residue was purified by silica gel chromatography (HEP/EA gradient) to give 1.55 g of the title compound.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N+:10]([O-])=[CH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].[CH3:15][C:16]([O:18]C(C)=O)=[O:17]>>[N+:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([O:18][C:16](=[O:17])[CH3:15])[CH:8]=[CH:7]2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2c(ccc[n+]2[O-])c1
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Oc1ccc2cc([N+](=O)[O-])ccc2n1
Temperature: 25 °C
Yield: 33 %

Procedure:
A solution of compound 45A (564 mg, 2.96 mmol) in Ac2O (20 mL) was heated to 145° C. for 5 h. After cooling to rt, the reaction was concentrated and the residue purified by silica gel flash chromatography eluting with CH2Cl2 to give the title compound (227 mg, 33%) as a beige solid. LC/MS m/z 233 [M+H]+.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH2:7][OH:8].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18].C(=O)([O-])O.[Na+]>O1CCCC1>[CH3:16][S:17]([O:8][CH2:7][CH2:6][C:2]1[S:1][CH:5]=[CH:4][CH:3]=1)(=[O:19])=[O:18]
Reactant: OCCc1cccs1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1cccs1
Reaction time: 0.33 h

Procedure:
2-(Thiophen-2-yl)ethanol (1.05 g) was dissolved in tetrahydrofuran (25 ml), triethylamine (1.63 ml) and methanesulfonyl chloride (725 μl) were added and the mixture was stirred for 20 min. Saturated aqueous sodium hydrogen carbonate (50 ml) was added to the reaction mixture, and the mixture was extracted with diisopropyl ether. The extract was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure to give the object product (1.62 g).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]([C:12]1[CH:17]=[C:16]([SH:18])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:11])[CH3:10].[CH:24]12[CH2:33][CH:28]3[CH2:29][CH:30]([CH2:32][CH:26]([CH2:27]3)[CH:25]1[NH:34][C:35](=[O:38])[CH:36]=[CH2:37])[CH2:31]2>CO>[CH3:11][C:9]([C:12]1[CH:17]=[C:16]([S:18][CH2:37][CH2:36][C:35]([NH:34][CH:25]2[CH:26]3[CH2:32][CH:30]4[CH2:29][CH:28]([CH2:33][CH:24]2[CH2:31]4)[CH2:27]3)=[O:38])[CH:15]=[C:14]([C:19]([CH3:22])([CH3:21])[CH3:20])[C:13]=1[OH:23])([CH3:8])[CH3:10]
Reactant: C=CC(=O)NC1C2CC3CC(C2)CC1C3
Reactant: CC(C)(C)c1cc(S)cc(C(C)(C)C)c1O
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)c1cc(SCCC(=O)NC2C3CC4CC(C3)CC2C4)cc(C(C)(C)C)c1O

Procedure:
Following the procedure of Example 4, triethylamine (0.5 ml) was added to a solution of 2,6-bis(1,1-dimethylethyl)-4-mercaptophenol (1.19 g, 0.005 mole) and the N-tricyclo[3.3.1.13,7 ]dec-2-yl-2-propenamide (1.02 g, 0.005 mole) in methanol (100 ml) and the solution stirred at room temperature for 12 hours. The solvent and triethylamine were removed on a rotary evaporator and the product purified by chromatography on silica, recrystallized from ethyl acetate/ethyl ether/hexane and dried, m.p. ca. 155.5°-156° C.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][C@@H:6]([CH3:8])[CH2:5][N:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([N+:17]([O-])=O)[CH:10]=2)[CH2:3]1>C(O)C.[Pd]>[CH3:8][C@H:6]1[NH:7][C@@H:2]([CH3:1])[CH2:3][N:4]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]([CH:10]=2)[NH2:17])[CH2:5]1
Reactant: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1ccc(N2C[C@@H](C)N[C@@H](C)C2)cc1N
Reaction time: 8 h

Procedure:
A mixture of cis-3,5-dimethyl-1-[4-(methyloxy)-3-nitrophenyl]piperazine (D3) (2.65 g, 10 mmol) in ethanol (60 ml) containing palladium on charcoal (300 mg, 10% paste) was stirred under aone atmosphere of hydrogen gas overnight. The mixture was filtered through celite, the pad washed in ethanol and the combined ethanol solutions evaporated. The residue was purified by column chromatography (Biotage (SiO2) 100 g, dichloromethane to 1:10 2M ammonia in methanol:dichloromethane) to afford the title product (D4). MS (ES+) m/e 236 [M+H]+.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]([Cl:22])([Cl:21])[CH2:5][O:6][C:7]([NH:9][C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:8].S(OC)(O[CH3:27])(=O)=O.O>O1CCCC1>[CH3:27][N:9]([C:10]1[CH:11]=[C:12]([CH:18]=[CH:19][CH:20]=1)[C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]([O:6][CH2:5][C:4]([Cl:21])([Cl:22])[Cl:3])=[O:8]
Reactant: CCOC(=O)c1cccc(NC(=O)OCC(Cl)(Cl)Cl)c1
Reactant: COS(=O)(=O)OC
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(=O)c1cccc(N(C)C(=O)OCC(Cl)(Cl)Cl)c1
Yield: 80.7 %

Procedure:
To a suspension of 0.14 g of 60% sodium hydride in 5 ml of tetrahydrofuran was dropwise added a solution of 1.0 g of ethyl 3-(2,2,2-trichloroethoxycarbonylamino)benzoate in 5 ml of tetrahydrofuran, and the resultant mixture was stirred at room temperature. Then, a solution of 0.45 g of dimethyl sulfate in 5 ml of tetrahydrofuran was dropwise added, and the resultant mixture was stirred at room temperature for 3 hours. After water was added to the mixture, the mixture was subjected to extraction with ethyl acetate, and an organic layer was washed twice with water and dried with anhydrous magnesium sulfate. Then, the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent; hexane:ethyl acetate=4:1) to obtain 0.84 g (yield 79%) of the title compound as an oily material.
Reaction SMILES: N1C=CC=CC=1.[C:7](OC(=O)C)(=[O:9])[CH3:8].[C:14]([N:24]1[CH2:27][CH:26]([C:28]2[CH:33]=[CH:32][C:31]([N:34]3[CH2:38][C@H:37]([CH2:39][NH2:40])[O:36][C:35]3=[O:41])=[CH:30][C:29]=2[F:42])[CH2:25]1)([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>CN(C)C1C=CN=CC=1.C(Cl)Cl>[F:42][C:29]1[CH:30]=[C:31]([N:34]2[CH2:38][C@H:37]([CH2:39][NH:40][C:7](=[O:9])[CH3:8])[O:36][C:35]2=[O:41])[CH:32]=[CH:33][C:28]=1[CH:26]1[CH2:27][N:24]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:25]1
Reactant: CC(=O)OC(C)=O
Reactant: NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CN(C(=O)OCc4ccccc4)C3)c(F)c2)C(=O)O1
Reaction time: 1 h

Procedure:
Pyridine (1.0 mL), acetic anhydride (1.0 mL) and a few crystals of 4-dimethylaminopyridine were added to a stirred solution of (S)-(-)-N-carbobenzyloxy-3-[2-fluoro-4-[5-aminomethyl-2-oxo-3-oxazolidinyl]phenyl]azetidine (Example 81, Step 8, 1.42 g, 3.56 mmol) in methylene chloride (30 mL), then stirred for 1 hr. The solvents were removed at 38°/0.75 mm and the residue chromatographed over silica gel (50 g, 40-60 μm) eluting with 1-2% methanol-chloroform. The title compound was isolated as a white foam. FAB-HRMS: theory 442.1778 (M+1); meas. 442.1777.
Reaction SMILES: N12CCCN=C1CCCCC2.[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[NH:16][C:15](=[O:21])[C:14]=1[CH3:22].Cl[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=1>C(#N)C>[Br:12][C:13]1[N:18]([CH3:19])[C:17](=[O:20])[N:16]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[C:27]([O:33][CH3:34])[CH:26]=2)[C:15](=[O:21])[C:14]=1[CH3:22]
Reactant: COc1ccc(CCl)cc1OC
Reactant: Cc1c(Br)n(C)c(=O)[nH]c1=O
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COc1ccc(Cn2c(=O)c(C)c(Br)n(C)c2=O)cc1OC
Temperature: 60 °C

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (98%, 5.57 mL, 36.5 mmol) was added to a suspension of C2 (4.00 g, 18.3 mmol) and 4-(chloromethyl)-1,2-dimethoxybenzene (5.16 g, 27.6 mmol) in acetonitrile (80 mL), and the reaction mixture was heated at 60° C. for 18 hours. After removal of solvent in vacuo, the residue was purified via silica gel chromatography (Gradient: 25% to 50% ethyl acetate in heptane) to afford the product as a white solid. Yield: 5.70 g, 15.4 mmol, 84%. 1H NMR (400 MHz, CDCl3) δ 7.08-7.12 (m, 2H), 6.80 (d, J=8.0 Hz, 1H), 5.07 (s, 2H), 3.88 (s, 3H), 3.85 (s, 3H), 3.65 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[CH2:11][NH:12][C:13]1[N:14]=[N:15][CH:16]=[CH:17][CH:18]=1.[F:19][C:20]1[CH:25]=[C:24]([F:26])[C:23]([Cl:27])=[CH:22][C:21]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:27][C:23]1[C:24]([F:26])=[CH:25][C:20]([F:19])=[C:21]([S:28]([N:12]([CH2:11][C:4]2[CH:5]=[CH:6][C:7]([O:9][CH3:10])=[CH:8][C:3]=2[O:2][CH3:1])[C:13]2[N:14]=[N:15][CH:16]=[CH:17][CH:18]=2)(=[O:30])=[O:29])[CH:22]=1
Reactant: O=S(=O)(Cl)c1cc(Cl)c(F)cc1F
Reactant: COc1ccc(CNc2cccnn2)c(OC)c1
Product: COc1ccc(CN(c2cccnn2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1

Procedure:
The title compound was prepared according to the method described for Preparation 14 using N-[(2,4-dimethoxyphenyl)methyl]pyridazin-3-amine (Preparation 19) and 2,4-difluoro-5-chlorobenzenesulfonyl chloride.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=O)[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].Cl.[NH2:22][OH:23].C([O-])(=O)C.[NH4+]>O>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10](=[N:22][OH:23])[C:11]2[CH:16]=[C:15]([O:17][CH3:18])[CH:14]=[CH:13][C:12]=2[OH:19])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: COc1ccc(O)c(C(=O)C2CCN(C(C)=O)CC2)c1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [NH4+]
Solvent: O
Product: COc1ccc(O)c(C(=NO)C2CCN(C(C)=O)CC2)c1
Yield: 17.1 %

Procedure:
A solution of 15.5 g of 1-acetyl-4-(2-hydroxy-5-methoxybenzoyl)piperidine, 7.0 g of hydroxylamine hydrochloride, 9.5 g of ammonium acetate and 75 ml of water was heated under reflux for 20 hrs. The solution was poured into water and extracted with dichloromethane. The dichloromethane extract was washed with water, dried over anhydrous magnesium sulfate and the solvent was removed in vacuo to give an oil. The oil was triturated with hot toluene. The toluene was decanted and the oil was triturated with ether to give a solid. The tolulene triturant, upon standing, yielded a solid. The solids were combined and recrystallized from acetonitrile to yield 2.8 g (17.4%) of product, mp, 191°-193°, as a mixture of E- and Z-isomers. The chromatogram showed 2 spots.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([NH:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=1)=[O:7].[CH3:17][C:18]1[NH:19][CH:20]=[CH:21][N:22]=1>>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][NH:8][C:6](=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2][N:19]2[CH:20]=[CH:21][N:22]=[C:18]2[CH3:17])=[CH:11][CH:12]=1
Reactant: O=C(CCCCCl)NCc1ccc(Cl)cc1
Reactant: Cc1ncc[nH]1
Product: Cc1nccn1CCCCC(=O)NCc1ccc(Cl)cc1
Yield: 53.7 %

Procedure:
In a similar manner to Example 70, 5-chloro-N-(4-chlorobenzyl)valeramide (10.3 g, prepared from 4-chlorobenzylamine and 5-chlorovaleryl chloride) and 2-methylimidazole (6.5 g) were reacted together to give N-(4-chlorobenzyl)-5-(2-methylimidazol-1-yl) valeramide, (6.5 g) , m.p. 72°-75° C. which was reduced with borane/THF (86 ml, 1M) to give N-(4-chlorobenzyl)-5-(2-methylimidazol-1-yl)pentylamine, b.p. 170°-185° C. (0.1 mmHg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([C:12]([OH:14])=O)[CH2:7][CH2:6]2.[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)[CH:19]=[N:18]1)[CH3:16]>>[CH2:15]([N:17]1[CH:21]=[C:20]([CH2:22][N:23]([C:24]2[CH:25]=[CH:26][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:29]=2)[C:12]([CH:8]2[C:9]3[C:5](=[CH:4][C:3]([O:2][CH3:1])=[CH:11][CH:10]=3)[CH2:6][CH2:7]2)=[O:14])[CH:19]=[N:18]1)[CH3:16]
Reactant: COc1ccc2c(c1)CCC2C(=O)O
Reactant: CCn1cc(CNc2ccc(C(C)C)cc2)cn1
Product: CCn1cc(CN(C(=O)C2CCc3cc(OC)ccc32)c2ccc(C(C)C)cc2)cn1
Yield: 74.6 %

Procedure:
By the reaction and treatment in the same manner as in Example 4 using 5-methoxyindan-1-carboxylic acid (0.29 g) and [(1-ethylpyrazol-4-yl)methyl](4-isopropylphenyl)amine (0.37 g) as starting materials, N-[(1-ethylpyrazol-4-yl)methyl]-N-(4-isopropylphenyl)-5-methoxyindan-1-carboxamide (0.47 g) was obtained. melting point: 115-116° C.
Reaction SMILES: [CH3:1][S:2][C:3](=[NH:8])[NH:4][N+:5]([O-:7])=[O:6].[C:9](OC(=O)C)(=[O:11])[CH3:10]>N1C=CC=CC=1>[C:9]([NH:8][C:3](=[N:4][N+:5]([O-:7])=[O:6])[S:2][CH3:1])(=[O:11])[CH3:10]
Reactant: CSC(=N)N[N+](=O)[O-]
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CSC(=N[N+](=O)[O-])NC(C)=O
Reaction time: 0.17 h
Yield: 77.8 %

Procedure:
To a mixture of 5.0 g of S-methyl-N-nitroisothiourea and 25 ml of pyridine was dropwise added 11.3 g of acetic anhydride at room temperature, taking for 10 minutes, followed by stirring for 5 hours at the same temperature. The reaction mixture was concentrated, and the residue was poured into 50 ml of 2N-hydrochloric acid. The resulting solid was collected by filtration and dried to obtain 5.1 g of N-acetyl-S-methyl-N'-nitroisothiourea. mp. 109°-110° C.
Reaction SMILES: N12CCCN=C1CCCCC2.Cl[C:13]1[C:14]2[CH:26]=[CH:25][C:24]([CH2:27][N:28]3[CH:32]=[CH:31][N:30]=[CH:29]3)=[CH:23][C:15]=2[S:16][C:17]=1[C:18]([O:20][CH2:21][CH3:22])=[O:19].[CH3:33][O:34][C:35]1[CH:36]=[C:37]([SH:41])[CH:38]=[CH:39][CH:40]=1>CN(C)C=O>[N:28]1([CH2:27][C:24]2[CH:25]=[CH:26][C:14]3[C:13]([S:41][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=4)=[C:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:16][C:15]=3[CH:23]=2)[CH:32]=[CH:31][N:30]=[CH:29]1
Reactant: COc1cccc(S)c1
Reactant: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CN(C)C=O
Product: CCOC(=O)c1sc2cc(Cn3ccnc3)ccc2c1Sc1cccc(OC)c1
Temperature: 60 °C
Yield: 90.5 %

Procedure:
1,8-Diazabicyclo[5.4.0]undec-7-ene (DBU--0.26 ml, 1.7 mmol) was added to a mixture of ethyl 3-chloro-6-(1H-1-imidazolylmethyl)benzo[b]thiophene-2-carboxylate (Preparation 11, 500 mg, 1.6 mmol) and 3-methoxybenzenethiol (0.29 ml, 2.3 mmol) in dimethylformamide (2 ml) under a nitrogen atmosphere. The solution was heated to 60° C. for 5 hours and then partitioned between ethyl acetate and water. The organics were separated and washed with water, dried (magnesium sulfate) and evaporated under reduced pressure. The residue was flash chromatographed on silica gel using 5% methanol in dichloromethane as eluant to give the title compound as a gum (615 mg).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[Na].[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[OH:23]>CN(C=O)C>[CH:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1[O:23][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8]
Reactant: CCOC(=O)CCCCCBr
Reactant: Oc1ccc2ccccc2c1
Agent: [Na]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCOc1ccc2ccccc2c1

Procedure:
Ethyl 6-bromohexanoate and the sodium salt of 2-naphthol are reacted in DMF at 70° to provide ethyl 6-(2-naphthyloxy)hexanoate, which after the usual workup is reduced with lithium aluminum hydride in THF to provide 6-(2-naphthyloxy)hexanol.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[C:10]2[C:5](=[CH:6][CH:7]=[C:8](OS(C(F)(F)F)(=O)=O)[CH:9]=2)[C:4](=[O:19])[CH2:3]1.[Cl:21][C:22]1[CH:23]=[C:24](B(O)O)[CH:25]=[CH:26][C:27]=1[F:28]>>[Cl:21][C:22]1[CH:23]=[C:24]([C:8]2[CH:9]=[C:10]3[C:5](=[CH:6][CH:7]=2)[C:4](=[O:19])[CH2:3][C:2]3([CH3:1])[CH3:20])[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: CC1(C)CC(=O)c2ccc(OS(=O)(=O)C(F)(F)F)cc21
Reactant: OB(O)c1ccc(F)c(Cl)c1
Product: CC1(C)CC(=O)c2ccc(-c3ccc(F)c(Cl)c3)cc21

Procedure:
The title compound was prepared from trifluoro-methanesulfonic acid 3,3-dimethyl-1-oxo-indan-5-yl ester and 3-chloro-4-fluorophenyl boronic acid according to the procedure described in example 21. MS m/z 289; HRMS: calcd for C17H14ClFO+H+, 289.07900; found (ESI, [M+H]+), 289.0785.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:9])=[C:6]([NH2:8])[CH:7]=1.[C:10]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=O)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1.C(OCC)(=O)C>[C:10](=[N:8][C:6]1[CH:7]=[C:2]([Br:1])[CH:3]=[CH:4][C:5]=1[F:9])([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: Nc1cc(Br)ccc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: Fc1ccc(Br)cc1N=C(c1ccccc1)c1ccccc1
Yield: 42.2 %

Procedure:
While a solution of 2.43 g 5-bromo-2-fluorophenylamine (compound in Production Example 335), 2.6 g benzophenone and 122 mg 4-toluenesulfonic acid in 50 ml toluene was azeotropically dehydrated, the mixture was heated for 6 hours under reflux. The reaction mixture was diluted with ethyl acetate and washed with brine, the organic layer was dried over anhydrous sodium sulfate, the solvent was removed, and the resulting crude product was purified by silica gel column chromatography (ethyl acetate/hexane) to give 1.91 g of the title compound (colorless oil).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:15][OH:16])[CH2:10][C:11]([O:13][CH3:14])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO[C:19](OC)([CH3:21])[CH3:20]>CC(C)=O.B(F)(F)F.CCOCC>[CH3:14][O:13][C:11](=[O:12])[CH2:10][C@H:9]1[CH2:15][O:16][C:19]([CH3:21])([CH3:20])[N:8]1[C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7]
Reactant: COC(=O)C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: COC(C)(C)OC
Agent: FB(F)F
Solvent: CC(C)=O
Solvent: CCOCC
Product: COC(=O)C[C@H]1COC(C)(C)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.6 %

Procedure:
To a solution of (S)-methyl 3-(tert-butoxycarbonylamino)-4-hydroxybutanoate (7.0 g, 30.0 mmol) in acetone (90 mL), there was added 2,2-dimethoxypropane (37 mL, 300 mmol) followed by BF3.Et2O (0.11 mL, 0.9 mmol). The resulting solution was stirred at rt overnight. Solvents were removed under vacuum, and the residue was redissolved in ether (100 mL), washed with sat'd NaHCO3 (20 mL). Upon concentrating under vacuum, the residue was purified by flash column chromatography to give (S)-tert-butyl 4-(2-methoxy-2-oxoethyl)-2,2-dimethyloxazolidine-3-carboxylate (7.51 g, 92%). MS m/z 296 (M+Na+).
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][C:9]([C:11](O)=[O:12])=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][C:31]([N:33]1[CH2:38][CH2:37][N:36]([CH3:39])[CH2:35][CH2:34]1)=[O:32].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>>[CH3:39][N:36]1[CH2:37][CH2:38][N:33]([C:31](=[O:32])[CH2:30][NH:29][C:11]([C:9]2[CH:8]=[CH:7][C:6]3[N:2]([CH3:1])[C:3]([NH:14][C:15]4[S:16][C:17]5[CH:23]=[C:22]([O:24][C:25]([F:26])([F:28])[F:27])[CH:21]=[CH:20][C:18]=5[N:19]=4)=[N:4][C:5]=3[CH:10]=2)=[O:12])[CH2:34][CH2:35]1
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)ccc21
Reactant: CN1CCN(C(=O)CN)CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Product: CN1CCN(C(=O)CNC(=O)c2ccc3c(c2)nc(Nc2nc4ccc(OC(F)(F)F)cc4s2)n3C)CC1

Procedure:
1-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid [2-(4-methyl-piperazin-1-yl)-2-oxo-ethyl]amide (41 mg) was prepared by following General Procedure F using 1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzimidazole-5-carboxylic acid (41 mg), 2-amino-1-(4-methyl-piperazin-1-yl)-ethanone (0.30 ml), HBTU (38 mg), and DIEA (0.1 ml). LC/MS: m/z 549. 1H NMR (DMSO-d6, 400 MHz): δ 8.48 (t, 1H), 8.10 (s, 1H), 7.96 (s, 1H), 7.91 (d, 1H), 7.78 (d, 1H), 7.64 (br, 1H), 7.48 (d, 1H), 7.36 (d, 1H), 4.14 (d, 2H), 3.67 (s, 3H), 3.61 (m, 2H), 3.48 (m, 4H), 2.89 (s, 3H), and 2.32 (m, 2H).
Reaction SMILES: [H-].[Na+].Cl.[NH:4]1[CH2:7][CH:6]([C:8]2[O:12][N:11]=[C:10]([C:13]3[N:18]=[C:17]([N:19]([CH3:26])[C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[N:16]=[C:15]([NH2:27])[N:14]=3)[N:9]=2)[CH2:5]1.[F:28][C:29]([F:40])([F:39])[CH2:30]OS(C(F)(F)F)(=O)=O>CN(C=O)C.CCOC(C)=O>[CH3:26][N:19]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:17]1[N:16]=[C:15]([NH2:27])[N:14]=[C:13]([C:10]2[N:9]=[C:8]([CH:6]3[CH2:5][N:4]([CH2:30][C:29]([F:40])([F:39])[F:28])[CH2:7]3)[O:12][N:11]=2)[N:18]=1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CNC3)n2)n1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(C3CN(CC(F)(F)F)C3)n2)n1
Temperature: 25 °C
Reaction time: 16 h
Yield: 8.9 %

Procedure:
To a solution of sodium hydride (60% dispersion in mineral oil, 16 mg, 0.41 mmol) in anhydrous DMF (20 mL) at 0 C was added 6-[5-(azetidin-3-yl)-1,2,4-oxadiazol-3-yl]-2-N-methyl-2-N-phenyl-1,3,5-triazine-2,4-diamine hydrochloride (Intermediate 129, 50 mg, 0.138 mmol) and trifluoromethanesulfonic acid 2,2,2-trifluoro-ethyl ester (160 mg, 0.69 mmol) under nitrogen. The reaction mixture was stirred at room temperature for 16 h and then was quenched with saturated ammonium chloride aqueous solution (10 mL) and evaporated to dryness. The solid obtained was dissolved in EtOAc (20 mL), washed with water (2×25 mL), dried over magnesium sulfate and evaporated to dryness. The resulting crude product was purified by silica chromatography (2% MeOH in DCM) and then further by preparative HPLC-MS (Method B) to afford the title compound as white solid (5 mg, 9%).