Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:33])[F:32])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23](O)=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[CH3:37][N:38]([CH3:43])[S:39]([NH2:42])(=[O:41])=[O:40]>>[F:1][C:2]([F:36])([F:35])[C:3]1[CH:30]=[C:29]([C:31]([F:34])([F:32])[F:33])[CH:28]=[CH:27][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11](/[CH:15]=[C:16]3/[C:17](=[O:26])[N:18]([CH2:22][C:23]([NH:42][S:39](=[O:41])(=[O:40])[N:38]([CH3:43])[CH3:37])=[O:24])[C:19](=[O:21])[S:20]/3)=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: O=C(O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O
Reactant: CN(C)S(N)(=O)=O
Product: CN(C)S(=O)(=O)NC(=O)CN1C(=O)S/C(=C\c2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)C1=O

Procedure:
2-[(5Z)-5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidin-3-yl]-N-(dimethylsulfamoyl)acetamide was prepared from {5-[1-(2,4-bis-trifluoromethylbenzyl)-1H-indazol-5-ylmethylene]-2,4-dioxo-1,3-thiazolidin-3-yl}acetic acid (Example 59) and N,N-dimethylsulfamide following General Procedure L.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C@@H:14](O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl>[C:1]([O:5][C:6]([NH:8][C@H:9]([C@@H:14]([S:30]([CH3:29])(=[O:32])=[O:31])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:10]([O:12][CH3:13])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](O)c1ccccc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](NC(=O)OC(C)(C)C)[C@H](c1ccccc1)S(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of alcohol 15 (1.94 g, 6.81 mmol) and triethylamine (1.25 g, 12.4 mmol) at 0° C. in Cl2CH2 (15 mL), methanesulfonyl chloride (0.96 g, 8.4 mmol) was added. The reaction mixture was allowed to stir at 0° C. for 20 min. It was quenched with cold dilute HCl, diluted with Cl2CH2 and the organic layer was washed with an aqueous solution of NaHCO3 followed by brine and dried over Na2SO4. The solvent was removed in vacuo and the crude mesylate 16 was obtained as a foamy white solid, which was used in the next step without further purification. 1H NMR (CDCl3).δ1.394 (s, 9H), 2.916 (s, 3H), 3.718 (s, 3H), 4.878 (dd, J=8.7, 5.0 Hz, 1H, H-2), 5.231 (bd, J=8.7 Hz, 1H, H--N), 5.917 (d, J =5.0 Hz, 1H, H-3), 7.379-7.425 (m, 5H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[C:4]([Cl:18])[N:3]=1.[NH:19]1[CH:23]=[CH:22][N:21]=[CH:20]1.N1C=CC=CC=1.C1C=CC=CC=1>O>[Cl:18][C:4]1[N:3]=[C:2]([N:19]2[CH:23]=[CH:22][N:21]=[CH:20]2)[C:11]2[C:6]([C:5]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Clc1nc(Cl)c2ccccc2c1-c1ccccc1
Reactant: c1c[nH]cn1
Solvent: O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: Clc1nc(-n2ccnc2)c2ccccc2c1-c1ccccc1

Procedure:
2.74 g (10 mmoles) of 1,3-dichloro-4-phenylisoquinoline, 1.02 g (15 mmoles) of imidazole and 5 ml of pyridine were heated for 8 hours under reflux and, after cooling, distributed between benzene and water. The residue which remained behind after evaporation of the organic phase was chromagtographed on silica-gel. As solvent, a mixture of chloroform and methanol 95:5 was found to be suitable.
Reaction SMILES: [Cl-].[Ce+3].[Cl-].[Cl-].[CH:5](/[Mg]Br)=[CH:6]\[CH3:7].CON(C)[C:13](=[O:45])[CH2:14][N:15]([C@@H:23]([C:33](=[CH2:44])[CH2:34][CH2:35][O:36][Si:37]([CH3:43])([CH3:42])[C:38]([CH3:41])([CH3:40])[CH3:39])[CH2:24][O:25][Si:26]([CH3:32])([CH3:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19]>C1COCC1>[CH3:28][C:27]([CH3:30])([Si:26]([CH3:31])([CH3:32])[O:25][CH2:24][C@@H:23]([N:15]([CH2:14][C:13](=[O:45])[CH:5]=[CH:6][CH3:7])[C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:33](=[CH2:44])[CH2:34][CH2:35][O:36][Si:37]([CH3:42])([CH3:43])[C:38]([CH3:39])([CH3:40])[CH3:41])[CH3:29]
Reactant: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)N(C)OC)C(=O)OC(C)(C)C
Reactant: C/C=C/[Mg]Br
Agent: [Ce+3]
Agent: [Cl-]
Solvent: C1CCOC1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N(CC(=O)C=CC)C(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 2 h
Yield: 76.4 %

Procedure:
A suspension of cerium (III) chloride (47.6 g, 193.26 mmol) in THF (200 mL) 3 at room temperature was stirred vigorously for 2 hours. The suspension was cooled to −78° C. and (E)-prop-1-enylmagnesium bromide (0.5 M in THF) (387 mL, 193.26 mmol) was added dropwise. The mixture was stirred at −78° C. for 1.5 hours. (5)-tert-butyl (2-(methoxy(methyl)amino)-2-oxoethyl)(2,2,3,3,11,11,12,12-octamethyl-7-methylene-4,10-dioxa-3,11-disilatridecan-6-yl)carbamate (Intermediate 278, 13.55 g, 24.16 mmol) in THF (50 mL) was then added dropwise at −78° C. The reaction was stirred at −78° C. for 1 hour and then warmed to 0° C. for 30 minutes. The reaction was quenched with 10% citric acid, diluted further with water and extracted twice with ether. The organics were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-20% ethyl acetate/hexanes) afforded the title compound (10 g, 76%) as a yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH3:17])(=[O:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].Cl[Si](C)(C)C.[N:33]1[CH:38]=[CH:37][CH:36]=[N:35][C:34]=1[CH2:39][CH2:40][CH2:41][CH:42]=O>C1COCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][N:11]([S:14]([CH:17]=[CH:42][CH2:41][CH2:40][CH2:39][C:34]3[N:35]=[CH:36][CH:37]=[CH:38][N:33]=3)(=[O:15])=[O:16])[CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=CCCCc1ncccn1
Reactant: CS(=O)(=O)N1CCN(c2ccc(Br)cc2)CC1
Agent: C[Si](C)(C)Cl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=S(=O)(C=CCCCc1ncccn1)N1CCN(c2ccc(Br)cc2)CC1
Temperature: -20 °C
Reaction time: 1 h

Procedure:
To the 1-(4-bromophenyl)-4-(methanesulfonyl)piperazine (902 mg, 2.0 mmol) suspended in anhydrous THF (15 ml), under Nitrogen, cooled to between −20 and −30° C. was added sequentially Lithium bis(trimethylsilyl)amide (1.0 M in THF, 4.0 ml), Chlorotrimethylsilane (217 mg, 2.0 mmol, 253 μl) and 4-pyrimidin-2-ylbutanal (300 mg, 2.0 mmol). The mixture was stirred at −20° C. for 1 hour, quenched with saturated ammonium chloride solution and allowed to stand at ambient temperature overnight. The solvents were removed in vacuo and the residue partitioned between dichloromethane (15 ml) and water (5 ml), the organics separated and chromatogrammed (50 g Silica Bond Elute, eluted with 0→100% Ethyl Acetate/Hexane gradient) to give the 2-(5-[4-(4-bromophenyl)piperazino]sulfonylpent-4-enyl)pyrimidine as a white crystalline material (759 mg, 84% Yield)
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][C:10]([OH:12])=O.[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1>>[CH:15]1([CH2:18][CH2:19][NH:20][C:21]([C:23]2[N:24]=[N:25][C:26]([N:29]3[CH2:34][CH2:33][N:32]([C:10](=[O:12])[CH2:9][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=4[C:2]([F:1])([F:14])[F:13])[CH2:31][CH2:30]3)=[CH:27][CH:28]=2)=[O:22])[CH2:17][CH2:16]1
Reactant: O=C(O)Cc1ccccc1C(F)(F)F
Reactant: O=C(NCCC1CC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CC1)c1ccc(N2CCN(C(=O)Cc3ccccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 9, making variations only as required to use (2-trifluoromethylphenyl)acetic acid in place of 2,5-dichlorobenzoic acid to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclopropylethyl)-amide, the title compound was obtained as a white solid (78.7% yield). 1H NMR (300 MHz, CDCl3) δ 8.03, 7.97, 7.67-7.64, 7.53-7.48, 7.39-7.35, 6.96, 3.91, 3.87-3.67, 3.66-3.6, 3.58-3.51, 1.53-1.46, 0.78-0.64, 0.48-0.42, 0.10-0.06. 13C NMR (75 MHz, CDCl3) δ 168.8, 162.9, 159.9, 145.3, 133.2, 132.0, 131.5, 128.5, 128.2, 127.2, 127.0, 126.3, 126.2, 125.5, 112.3, 45.0, 44.7, 44.2, 41.2, 39.6, 37.13, 37.11, 34.4, 8.6, 4.2. MS (ES+) m/z 462.2 (M+1).
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([C:16]([N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)=O)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.CO>C(Cl)(Cl)Cl>[CH:11]1[C:12]2[C:13]3([CH2:16][N:18]4[CH2:23][CH2:22][CH:21]([OH:24])[CH2:20][CH2:19]4)[CH2:15][CH:6]([C:5]4[C:14]3=[CH:1][CH:2]=[CH:3][CH:4]=4)[C:7]=2[CH:8]=[CH:9][CH:10]=1
Reactant: O=C(N1CCC(O)CC1)C12CC(c3ccccc31)c1ccccc12
Solvent: ClC(Cl)Cl
Solvent: CO
Product: OC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 88 %

Procedure:
Using a procedure similar to that described in Example 82b except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylcarbonyl)piperidin-4-ol (described in Example 83b), the title compound was formed in 88% yield as a white solid TLC analysis (Rf 0.59, 10% methanol in chloroform). MS (CI, CH4) m/z 306 (M+1,100), 334 (M+29,14), 288 (62), 114(8)
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[NH2:14][OH:15]>C(O)C>[F:1][C:2]1[CH:9]=[C:8]([S:10]([CH3:13])(=[O:12])=[O:11])[CH:7]=[CH:6][C:3]=1[C:4](=[N:14][OH:15])[NH2:5]
Reactant: NO
Reactant: CS(=O)(=O)c1ccc(C#N)c(F)c1
Solvent: CCO
Product: CS(=O)(=O)c1ccc(C(N)=NO)c(F)c1
Temperature: 90 °C

Procedure:
To a stirred solution of the product from Step E (0.29 g, 0.144 mmol) in ethanol (15 mL) was added hydroxylamine (50% in water, 3.0 mL). The reaction was heated at 90° C. for 3 h. The reaction was then concentrated to give the desired product.
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6]C=[CH:4][CH:3]=1.C(O[C:12](=[N:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[C:22]([OH:24])=[O:23])[CH3:13])C>>[C:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[O:15][N:14]=[CH:12][C:13]1[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1)([OH:24])=[O:23]
Reactant: CCOC(C)=NOc1ccccc1C(=O)O
Reactant: O=Cc1ccccc1
Product: O=C(O)c1ccccc1ON=Cc1ccccc1
Yield: 61.8 %

Procedure:
70% HClO4 (14.0 μL, 0.163 mmol), benzaldehyde (18.0 mL, 0.177 mmol), and 20 (39.0 mg, 0.175 mmol) were subjected to the representative coupling procedure as outlined above (method 3), yielding 2a as a white solid (26.1 mg, 62%). 1H-NMR (500 MHz, d6-Acetone) δ 7.15 (dt, J=0.9, 7.8 Hz, 1H), 7.48-7.55 (m, 3H), 7.59 (dt, J=1.8, 7.8 Hz, 1H), 7.71 (d, J=8.2 Hz, 1H), 7.83-7.89 (m, 3H), 8.66 (s, 1H), 10.8-11.5 (broad s, 1H); 13C-NMR (125 MHz, d6-DMSO) δ 115.7, 119.7, 122.1, 127.8, 129.0, 130.8, 130.9, 131.1, 133.1, 153.4, 157.7, 166.8; MALDI-FTMS (DHB) 242.0811 m/z [MH]+, C14H12NO3 requires 242.0812. RP-HPLC: >99% pure.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:7][CH2:6]1.[C:24]([Cl:32])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[ClH:33]>N1C=CC=CC=1.C(Cl)(Cl)Cl>[ClH:32].[ClH:33].[C:24]([NH:1][CH2:2][CH2:3][CH2:4][N:5]1[CH2:6][CH2:7][N:8]([CH:11]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH2:9][CH2:10]1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1
Reactant: O=C(Cl)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: O=C(NCCCN1CCN(C(c2ccccc2)c2ccccc2)CC1)c1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 1-(3-aminopropyl)-4-benzhydrylpiperazine (1.2 g) in a mixture of pyridine (2 ml) and chloroform (15 ml) was dropwise added a solution of benzoyl chloride (0.55 ml) in chloroform (3 ml) at ambient temperature with stirring, which was continued for 1.5 hours. The reaction mixture was washed successively with aqueous sodium bicarbonate and water. The chloroform layer was separated, dried and evaporated in vacuo to give an oil. According to a conventional manner, the oil was converted to hydrochloric acid salt, which was recrystallized from a mixture of methanol and diethyl ether to afford 1-(3-benzoylaminopropyl)-4-benzhydrylpiperazine dihydrochloride (1.0 g) as white crystals. mp: 235°-237° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=O)=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:48])=CC=1.C(Cl)Cl.C1COCC1>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:36]=[C:35]([O:37][CH3:38])[CH:34]=[CH:33][C:4]=1[CH2:5][NH:6][C:7]1[C:8]2[N:9]([C:13]([C@@H:26]3[CH2:31][CH2:30][CH2:29][NH:28][C:27]3=[S:48])=[N:14][C:15]=2[C:16]2[CH:25]=[CH:24][C:19]([C:20]([O:22][CH3:23])=[O:21])=[CH:18][CH:17]=2)[CH:10]=[CH:11][N:12]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=O)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2nc([C@@H]3CCCNC3=S)n3ccnc(NCc4ccc(OC)cc4OC)c23)cc1
Yield: 62 %

Procedure:
To a solution of (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-oxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (940 mg, 1.82 mmol) in toluene (25 mL) was added Lawesson's reagent (1.5 g, 3.65 mmol). The mixture was heated to reflux overnight. The solvent was evaporated and the residue was purified by column chromatography on silica gel eluted with EA:DCM:THF=1:2:1 to give (S)-methyl 4-(8-((2,4-dimethoxybenzyl)amino)-3-(2-thioxopiperidin-3-yl)imidazo[1,5-a]pyrazin-1-yl)benzoate (600 mg, yield 62%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[O:20])[O:18][CH:17]3[OH:22])[N:4]=1.Cl[CH2:24][C:25]#[N:26].C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].C1OCCOCCOCCOCCOCCOC1>CC(CC)=O.COC(C)(C)C>[C:25]([CH2:24][O:22][CH:17]1[C:16]2[C:21](=[C:12]([O:11][C:5]3[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([O:9][CH3:10])[N:6]=3)[CH:13]=[CH:14][CH:15]=2)[C:19](=[O:20])[O:18]1)#[N:26]
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3O)n1
Reactant: N#CCCl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: COC(C)(C)C
Solvent: CCC(C)=O
Product: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3OCC#N)n1

Procedure:
A mixture of 1.5 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-hydroxy-phthalide (see Example 84) and 0.8 ml of chloroacetonitrile is maintained at 60° C. for 1 hour in ethyl methyl ketone in the presence of 2.1 g of dry potassium carbonate and a spatula tip each of sodium iodide and 18-crown-6. When the reaction material has cooled, it is taken up in tert-butyl methyl ether and the solution is washed with dilute hydrochloric acid and water, concentrated by evaporation and purified by chromatography on silica gel (eluant: ethyl acetate/n-hexane 1:1) to yield 3-cyanomethoxy-7-[(4,6-dimethoxypyrimidin-2-yl)oxy]-phthalide, m.p. 99°-102° C.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[N:16]1[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]1)C1C=CC=CC=1.B(Br)(Br)Br>C(Cl)Cl>[Cl:15][C:13]1[CH:12]=[CH:11][C:10]([N:16]2[S:20](=[O:22])(=[O:21])[NH:19][C:18](=[O:23])[CH2:17]2)=[C:9]([OH:8])[CH:14]=1
Reactant: O=C1CN(c2ccc(Cl)cc2OCc2ccccc2)S(=O)(=O)N1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=C1CN(c2ccc(Cl)cc2O)S(=O)(=O)N1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-(2-benzyloxy-4-chlorophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (388 mg, 1.1 mmol) in methylene chloride (10 mL) at 0° C. is added dropwise BBr3 (1.65 mL of 1.0M in methylene chloride, 1.65 mmol) and the mixture is stirred at 0° C. for 30 min. Ice is added and the organic phase is washed with 1N HCl. The aqueous phase is washed with methylene chloride and the combined organic layers are dried over sodium sulfate. The solvent is removed under reduced pressure and the residue is purified by preparative HPLC to give the title compound as a white solid: (M−1)−=261.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14])([O-])=O.O.O.[Sn](Cl)(Cl)(Cl)Cl>C(O)C.Cl.[OH-].[Na+].CCOCC>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10][C:11]1[CH:21]=[CH:20][CH:19]=[CH:18][C:12]=1[C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: CCOC(=O)c1ccccc1Sc1ccccc1[N+](=O)[O-]
Agent: Cl
Agent: Cl[Sn](Cl)(Cl)Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CCOCC
Product: CCOC(=O)c1ccccc1Sc1ccccc1N
Temperature: 25 °C
Reaction time: 3 h
Yield: 101.1 %

Procedure:
In 130 ml of ethanol was suspended 22.5 g of ethyl 2-(2-nitrophenylthio)benzoate and, then, a solution of 58.7 g of tin(IV) chloride dihydrate in a mixture of 70 ml of concentrated hydrochloric acid and 45 ml of ethanol was added en bloc. The mixture was stirred at room temperature for 3 hours, after which it was poured in a mixture of 600 ml of 10% aqueous sodium hydroxide solution and 500 ml of ether with cooling and stirring. The ether layer was separated, washed with water and saturated aqueous sodium chloride solution in that order and dried. Finally, the ether was distilled off to give 20.5 g of the title compound as a light yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][NH:14][C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1.Br[C:19]1[CH:20]=[CH:21][C:22]2[C:23]3[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=3[N:25]([CH3:28])[C:26]=2[CH:27]=1>>[F:1][C:2]1[C:3]([CH2:9][O:10][C:11]2[CH:16]=[CH:15][N:14]([C:19]3[CH:20]=[CH:21][C:22]4[C:23]5[CH2:33][CH2:32][N:31]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])[CH2:30][CH2:29][C:24]=5[N:25]([CH3:28])[C:26]=4[CH:27]=3)[C:13](=[O:17])[CH:12]=2)=[N:4][CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Cn1c2c(c3ccc(Br)cc31)CCN(C(=O)OC(C)(C)C)CC2
Reactant: O=c1cc(OCc2ncc(F)cc2F)cc[nH]1
Product: Cn1c2c(c3ccc(-n4ccc(OCc5ncc(F)cc5F)cc4=O)cc31)CCN(C(=O)OC(C)(C)C)CC2
Yield: 31.2 %

Procedure:
4((3,5-Difluoropyridin-2-yl)methoxy)pyridin-2(1H)-one (100 mg, 0.418 mmol) and tert-butyl 8-bromo-6-methyl-1,2,4,5-tetrahydroazepino[4,5-b]indole-3(6H)-carboxylate (206 mg, 0.544 mmol) were reacted following the procedure for Example 2 (step d) to provide the title compound (70 mg, 30%) as a brown oil; ESI MS m/z 537 [M+H]+.
Reaction SMILES: [F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13](Cl)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][C:24]1[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=1>>[F:1][C:2]([F:22])([F:21])[C:3]1[C:12]([C:13]([NH:23][C:24]2[N:25]([CH3:29])[CH:26]=[CH:27][N:28]=2)=[O:14])=[C:11]([OH:16])[C:10]2[C:5](=[C:6]([C:17]([F:20])([F:19])[F:18])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cn1ccnc1N
Reactant: O=C(Cl)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Product: Cn1ccnc1NC(=O)c1c(C(F)(F)F)nc2c(C(F)(F)F)cccc2c1O
Yield: 33.9 %

Procedure:
Using the procedure of Example 1, 2,8-bis-(trifluoromethyl)-4-hydroxy-3-quinoline-carboxylic acid chloride and 2-amino-N-methyl-imidazole were reacted to obtain a 33.9% yield of 2,8-bis-(trifluoromethyl)-4-hydroxy-N-(1-methyl-1H-imidazol-2-yl-)-3-quinolinecarboxamide melting at 259° C.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.CCOC(OC(OCC)=O)=O.[NH2:26][C:27]1[C:35]2[O:34][C:33](=[O:36])[NH:32][C:31]=2[CH:30]=[CH:29][CH:28]=1>C1COCC1>[F:13][C:2]([F:1])([F:14])[C:3]1[CH:4]=[CH:5][C:6]([CH2:9][C:10]([NH:26][C:27]2[C:35]3[O:34][C:33](=[O:36])[NH:32][C:31]=3[CH:30]=[CH:29][CH:28]=2)=[O:12])=[CH:7][CH:8]=1
Reactant: Nc1cccc2[nH]c(=O)oc12
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CCOC(=O)OC(=O)OCC
Solvent: C1CCOC1
Product: O=C(Cc1ccc(C(F)(F)F)cc1)Nc1cccc2[nH]c(=O)oc12
Temperature: 80 °C
Yield: 46 %

Procedure:
4-trifluoromethylphenylacetic acid (453 mg, 2.2 mmol) was dissolved in 20 ml of THF and at 0° C. DEPC (0.43 ml, 1.3 equiv) and amine 1c (400 mg, 2.66 mmol) were added to the solution. The mixture was warmed at 80° C. overnight, then evaporated and the crude was dissolved in AcOEt (30 ml) and washed with water (1×20 ml) and brine. The organic phase was dried over sodium sulfate and concentrated under vacuum. The purification of the crude residue by chromatographic column using AcOEt 3/petroleum ether 7 as eluant gave 340 mg of a white solid. Yield=46% 1HNMR (DMSO, 200 MHz) δ 3.86 (2H, s), 6.86 (1H, d), 7.06 (1H, t), 7.58 (3H, m), 7.70 (2H, d, J=8.4 Hz), 10.32 (1H, bs), 8.73 (1H, bs), 11.80 (1H, bs); [M+1] 337.2 (C16H11F3N2O3 requires 336.3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19]Cl)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[I-].[K+].C(=O)([O-])[O-].[K+].[K+].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1>CC#N.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([S:14]([CH2:17][CH2:18][CH2:19][N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)(=[O:16])=[O:15])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCCl)CC1
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)CCCN2CCOCC2)CC1
Reaction time: 16 h

Procedure:
Amine preparation: A mixture of 1-BOC-piperazine (3.26 g), 3-chloropropanesulfonyl chloride (2.63 g) and triethylamine (2.68 mL) was stirred at room temperature in DCM (25 mL). After 2 h the reaction mixture was diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g). A mixture of 4-(3-chloro-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.65 g), potassium iodide (1.1 g),potassium carbonate and morpholine (1.6 mL) was heated to reflux in MeCN (100 ml). After 16 h, the reaction mixture was cooled, diluted with DCM, washed with brine, dried (MgSO4) and the solvent removed in vacuo to yield 4-(3-morpholin-4-yl-propane-1-sulfonyl)-piperazine-1-carboxylic acid tert-butyl ester (4.8 g). Treatment of this compound with HCl in DCM/MeOH yielded the desired compound, which was isolated as the hydrochloride salt.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][N:3]=1.[NH2:19][C@@H:20]([CH3:23])[CH2:21][OH:22].O(C(C)(C)C)[Na]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[OH:22][CH2:21][C@@H:20]([NH:19][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:9]2)=[CH:4][N:3]=1)[CH3:23]
Reactant: CC(C)(C)OC(=O)N1CCc2cnc(Cl)cc2C1
Reactant: C[C@H](N)CO
Agent: [Pd]
Agent: CC(C)(C)O[Na]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: C[C@@H](CO)Nc1cc2c(cn1)CCN(C(=O)OC(C)(C)C)C2
Temperature: 90 °C
Yield: 28 %

Procedure:
A vial was charged with tert-butyl 7-chloro-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (175 mg, 0.651 mmol, CASRN 1060816-50-3), Pd2(dba)3 (29.8 mg, 0.0326 mmol), Binap-rac (40.5 mg, 0.0651 mmol), (S)-2-aminopropan-1-ol (97.8 mg, 1.30 mmol), and NaO-tert-Bu (125 mg, 1.30 mmol) and toluene (3 mL), sealed, degassed with nitrogen for 5 min then heated to 90° C. for 4 h. The reaction was cooled and filtered through a plug of CELITE. The filtrate was concentrated and the resulting residue was purified by reverse phase chromatography (SP4) eluting with a MeCN/H2O gradient (5-95% ACN) to afford 56 mg (28%) of (S)-tert-butyl 7-(1-hydroxypropan-2-ylamino)-3,4-dihydro-2,6-naphthyridine-2(1H)-carboxylate (326).