Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[C:11]=1B(O)O.O=O>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:11]2[C:10]([F:9])=[CH:15][CH:14]=[CH:13][C:12]=2[F:16])=[CH:4][CH:3]=1
Reactant: Oc1ccc(Br)cc1
Reactant: OB(O)c1c(F)cccc1F
Agent: O=O
Solvent: ClCCl
Product: Fc1cccc(F)c1Oc1ccc(Br)cc1

Procedure:
Into a 100 mL round bottom flask was added 4-bromophenol (2.19 g, 12.7 mmol), 2,6-difluorophenylboronic acid (1.00 g, 6.33 mmol), cupric acetate (1.4 g, 7.70 mmol) and DCM (50 mL). TEA (4.0 mL, 29.0 mmol) was then added followed by 4 A° molecular sieves and the reaction mixture was stirred at rt for 48 h with an air balloon to supply oxygen. Purification by flash column chromatography using 5% EtOAc in hexanes afforded the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH:26](=O)[C:27]1[CH:32]=[CH:31][CH:30]=[N:29][CH:28]=1.C([BH3-])#N.[Na+].C(=O)(O)[O-].[Na+]>CO.C(O)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][N:15]([CH2:26][C:27]3[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=3)[C@H:14](/[CH:17]=[CH:18]\[CH2:19][CH2:20][CH2:21][C:22]([O:24][CH3:25])=[O:23])[CH2:13]2)(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Reactant: O=Cc1cccnc1
Agent: O=C([O-])O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)CCC/C=C\[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1Cc1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.3 %

Procedure:
To a mixture of (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]pyrrolidine (356 mg) and nicotinaldehyde (98.6 mg) in methanol (5 ml) were added acetic acid (0.1 ml) and sodium cyanoborohydride (58 mg) and the mixture was stirred at room temperature for 3 hours. Saturated aqueous sodium bicarbonate (20 ml) was added to the solution and the aqueous solution was extracted with chloroform (50 ml). The organic layer was washed with brine and dried over magnesium sulfate. The solvent was evaporated in vacuo and the residue was chromatographed on a silica gel (10 g) column with a mixture of chloroform and methanol (99:1) to give (2S,4R)-4-(4-chlorophenylsulfonylamino)-2-[(Z)-5-methoxycarbonyl-1-pentenyl]-1-(3-pyridylmethyl)pyrrolidine (340 mg).
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][N:11]2C(OC(C)(C)C)=O)=[C:6]([C:22]([O:24][CH3:25])=[O:23])[C:5]([N:26](C(OC(C)(C)C)=O)C(OC(C)(C)C)=O)=[CH:4][CH:3]=1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[NH2:26][C:5]1[C:6]([C:22]([O:24][CH3:25])=[O:23])=[C:7]([O:8][CH2:9][C@H:10]2[CH2:14][CH2:13][CH2:12][NH:11]2)[C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc(Br)c1OC[C@H]1CCCN1C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc(Br)c1OC[C@H]1CCCN1
Yield: 100.2 %

Procedure:
A solution of tert-butyl (R)-2-[6-bromo-3-bis-(tert-butoxycarbonyl)amino-2-methoxycarbonylphenoxymethyl]pyrrolidine-1-carboxylate (Intermediate 8, 3.15 g) in TFA (20 mL) and DCM (20 mL) was stirred at room temperature for 1 hour. The mixture was concentrated in vacuo and the residue was dissolved in ethyl acetate and washed with aqueous potassium carbonate solution. The aqueous layer was extracted with ethyl acetate, dried (Na2SO4) and filtered. The filtrate was concentrated in vacuo to give methyl 6-amino-3-bromo-2-((R)-1-pyrrolidin-2-ylmethoxy)benzoate (1.65 g) as a colourless gum.
Reaction SMILES: CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.[NH2:43][C:44]1[N:49]=[C:48]([NH:50][C@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:62])[CH3:61])[C:47]([Cl:65])=[CH:46][C:45]=1[C:66]([NH:68][C:69]([C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1)([CH3:71])[CH3:70])=[O:67].C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:85]1[CH:86]=[N:87][CH:88]=[C:89]([CH3:91])[CH:90]=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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C(OCC)(=O)C.O.O1CCOCC1>[Cl:65][C:47]1[C:48]([NH:50][C@H:51]2[CH2:56][CH2:55][CH2:54][CH2:53][C@H:52]2[NH:57][C:58](=[O:64])[O:59][C:60]([CH3:63])([CH3:61])[CH3:62])=[N:49][C:44]([NH:43][C:85]2[CH:86]=[N:87][CH:88]=[C:89]([CH3:91])[CH:90]=2)=[C:45]([C:66]([NH:68][C:69]([C:72]2[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=2)([CH3:70])[CH3:71])=[O:67])[CH:46]=1
Reactant: Cc1cncc(Br)c1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCC[C@@H]1Nc1nc(N)c(C(=O)NC(C)(C)c2ccccc2)cc1Cl
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cncc(Nc2nc(N[C@H]3CCCC[C@H]3NC(=O)OC(C)(C)C)c(Cl)cc2C(=O)NC(C)(C)c2ccccc2)c1
Temperature: 25 °C
Yield: 55 %

Procedure:
Xantphos (5 mg) and Pd2(dba)3 (4 mg) were added to a mixture of tert-butyl cis-2-(6-amino-3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)pyridin-2-ylamino)cyclohexylcarbamate (20 mg), cesium carbonate (20 mg), 3-bromo-5-methylpyridine (9 mg), and 1,4-dioxane (2 ml) in a nitrogen atmosphere, followed by reflux for 3 hours in a nitrogen atmosphere. The reaction mixture was cooled to room temperature, and water and ethyl acetate were added. The organic layer was collected, washed with saturated saline, and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel chromatography (silica gel: Kanto Chemical Co., Inc., silica gel 60 (spherical shape), hexane•ethyl acetate=2:1 to 3:1), and a white solid of tert-butyl cis-2-(3-chloro-5-(2-phenylpropan-2-ylaminocarbonyl)-6-(5-methylpyridin-3-ylamino)pyridin-2-ylamino)cyclohexylcarbamate (13 mg) was thus obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5](O)=[O:6].[CH3:21][S:22]([NH2:25])(=[O:24])=[O:23]>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([Br:20])[C:10]=1[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([Br:19])[CH:14]=1)[C:5]([NH:25][S:22]([CH3:21])(=[O:24])=[O:23])=[O:6]
Reactant: CS(N)(=O)=O
Reactant: O=C(O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Product: CS(=O)(=O)NC(=O)c1cc(Br)c(OCc2cccc(Br)c2)c(Br)c1
Yield: 67.6 %

Procedure:
3,5-Dibromo-4-(3-bromobenzyloxy)benzoic acid (0.15 mmol) was coupled with methanesulphonamide (0.77 mmol) using the procedure described in Example 31. Purification on column (silica gel, chloroform/methanol 9:1) gave 55 mg (67%) of N-[3,5-dibromo-4-(3-bromobenzyloxy)benzoyl]methanesulphonamide.
Reaction SMILES: Cl[C:2](=[O:13])[CH2:3][C:4]1([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.[Br:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Cl-].[Cl-].[Al+3].Cl>C(OCC)(=O)C.O.ClCCl>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([C:2](=[O:13])[CH2:3][C:4]2([C:9]([O:11][CH3:12])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[CH:17][CH:16]=1
Reactant: Brc1ccccc1
Reactant: COC(=O)C1(CC(=O)Cl)CCCC1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)C1(CC(=O)c2ccc(Br)cc2)CCCC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a 150 mL flask was added dichloromethane (70 mL), methyl 1-(2-chloro-2-oxoethyl)cyclopentanecarboxylate] (3.50 g, 16.8 mmol) [prepared as described by Bajaj, et al., J. Indian Chem. Soc. 52:1076-78, 1975] and bromobenzene (2.77 g, 17.6 mmol), and the reaction mixture cooled to 0° C. before aluminum trichloride (4.77 g, 35.7 mmol) was slowly added. The mixture was stirred for 1 h at 0° C., then for 12 h at rt. The reaction mixture was slowly poured into 50 mL chilled (0° C.) 1 N aqueous hydrochloric acid solution. Water (50 mL) was added, followed by ethyl acetate (100 mL), and the mixture stirred for 30 minutes. The layers were separated and the aqueous layer extracted with additional ethyl acetate (100 mL). The combined organic layer was washed with saturated aqueous sodium chloride (100 mL), dried over anhydrous sodium sulfate, and concentrated under reduced pressure to yield a brown oil which was purified by flash chromatography (10:1/hexane:ethyl acetate) to afford methyl 1-[2-(4-bromophenyl)-2-oxoethyl]cyclopentane carboxylate as a yellow, crystalline solid (1.62 g, 30%). LC-MS ret. time 3.45 min, m/z 324.8 (MH+); 1H NMR (300 MHz, CDCl3) δ 1.50-1.83 (overlapping signals, 6H), 2.22-2.33 (m, 2H), 3.37 (s, 2H), 3.66 (s, 3H), 7.59 (d, 2H), 7.80 (d, 2H).
Reaction SMILES: [Se](=O)=O.[OH2:4].[CH3:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[CH:9][C:10]([O:20][CH3:21])=[C:11]([O:18][CH3:19])[C:12]=2[O:16][CH3:17])[N:7]=1>O1CCOCC1>[CH3:17][O:16][C:12]1[C:11]([O:18][CH3:19])=[C:10]([O:20][CH3:21])[CH:9]=[C:8]2[C:13]=1[CH:14]=[CH:15][C:6]([CH:5]=[O:4])=[N:7]2
Reactant: COc1cc2nc(C)ccc2c(OC)c1OC
Reactant: O
Agent: O=[Se]=O
Solvent: C1COCCO1
Product: COc1cc2nc(C=O)ccc2c(OC)c1OC
Temperature: 45 °C
Reaction time: 1.5 h

Procedure:
Selenium dioxide (980 mg) was suspended in a mixed solvent of dioxane (12 mL) and water (0.5 mL), and the suspension was heated to 45° C. A solution of 2-methyl-5,6,7-trimethoxyquinoline (1.97 g) in dioxane (3 mL) was slowly added dropwise thereto, and the mixture was heated to 105° C. and stirred for 1.5 hours. After allowing the reaction mixture to room temperature, selenium dioxide was filtered, and the filtrate was concentrated and purified by column chromatography on silica gel (ethyl acetate:hexane=1:4) to obtain the title compound.
Reaction SMILES: [C:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])=[CH2:2]>[Pd]>[CH:1]([C:4]1[C:13]2[C:8](=[CH:9][C:10]([OH:14])=[CH:11][CH:12]=2)[CH:7]=[C:6]([NH:15][C:16]2[CH:20]=[C:19]([CH3:21])[NH:18][N:17]=2)[N:5]=1)([CH3:3])[CH3:2]
Reactant: C=C(C)c1nc(Nc2cc(C)[nH]n2)cc2cc(O)ccc12
Agent: [Pd]
Product: Cc1cc(Nc2cc3cc(O)ccc3c(C(C)C)n2)n[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.4 %

Procedure:
The mixture of 1-Isopropenyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (100 mg) and 10% Pd/C (15 mg) was sealed in high-pressure bottle under 40 psi H2 pressure and stirred overnight at room temperature. Then the mixture was filtered, and the filtrate was evaporated to give 1-Isopropyl-3-(5-methyl-1H-pyrazol-3-ylamino)-isoquinolin-6-ol (80 mg) as oil. LC-MS: m/e 283 (MH+).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[S:13][C:12]2[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=2[CH:5]=1.Cl.[CH3:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][CH:22]=[C:23]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)[C:19]=2[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>O.C1(C)C=CC=CC=1.CN(C)C=O>[CH3:16][C:17]1[CH:31]=[CH:30][C:20]2[O:21][CH:22]=[C:23]([CH:24]3[CH2:25][CH2:26][N:27]([CH2:2][CH2:3][C:4]4[S:13][C:12]5[CH2:11][CH2:10][CH2:9][C:8](=[O:14])[NH:7][C:6]=5[CH:5]=4)[CH2:28][CH2:29]3)[C:19]=2[CH:18]=1
Reactant: Cc1ccc2occ(C3CCNCC3)c2c1
Reactant: O=C1CCCc2sc(CCCl)cc2N1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1ccc2occ(C3CCN(CCc4cc5c(s4)CCCC(=O)N5)CC3)c2c1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
A mixture of 2.0 g of 2-(2-chloroethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, 2.1 g of 4-(5-methylbenzo(b)furan-3-yl)piperidine hydrochloride, 2.6 g of potassium carbonate, 1.5 g of potassium iodide, 20 ml of dimethylformamide and 20 ml of toluene was stirred at 80° C. for 8 hours and then poured into water. The toluene layer was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was recrystallized from ethyl acetate to give 2-(2-(4-(5-methylbenzo(b)furan-3-yl)piperidin-1-yl)ethyl)-4,6,7,8-tetrahydro-5H-thieno[3,2-b]azepin-5-one, m.p. 156°-158° C.
Reaction SMILES: [C:1]1(=[O:9])[C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[CH2:2]1.[S:10]([Cl:14])(=O)(=[O:12])[OH:11]>C(Cl)(Cl)Cl>[Cl:14][S:10]([C:6]1[CH:7]=[CH:8][C:3]2[CH2:2][C:1](=[O:9])[C:4]=2[CH:5]=1)(=[O:12])=[O:11]
Reactant: O=C1Cc2ccccc21
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=C1Cc2ccc(S(=O)(=O)Cl)cc21
Reaction time: 5 h

Procedure:
Benzocyclobutenone (2.36 g, 0.02mol) was added slowly to a strongly stirred chlorosulfuric acid (3 mL) in chloroform (10 mL) solution. After the addition was done, the reaction mixture was stirred for 5 hours. Then the chloroform was evaporated, and the residue was precipitated in water yielding fine pink crystals. m.p. 80° C.; IR (KBr, cm−1): 1762; UV (λmax, methanol) 272 nm.
Reaction SMILES: [C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]5=[N:24][CH:23]=4)[N:20]=3)[N:15](COCC[Si](C)(C)C)[CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2].C(O)(C(F)(F)F)=O>>[C:1]([CH:3]1[CH2:6][N:5]([C:7](=[O:39])[C@H:8]([NH:10][C:11]([C:13]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([C:22]4[N:26]5[CH:27]=[CH:28][CH:29]=[CH:30][C:25]5=[N:24][CH:23]=4)[N:20]=3)[NH:15][CH:14]=2)=[O:12])[CH3:9])[CH2:4]1)#[N:2]
Reactant: C[C@@H](NC(=O)c1cn(COCC[Si](C)(C)C)c2ncc(-c3cnc4ccccn34)nc12)C(=O)N1CC(C#N)C1
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](NC(=O)c1c[nH]c2ncc(-c3cnc4ccccn34)nc12)C(=O)N1CC(C#N)C1

Procedure:
2-Imidazo[1,2-a]pyridin-3-yl-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide was deprotected using the described two step procedure (TFA followed by aqueous base) followed by chromatography to give 2-imidazo[1,2-a]pyridin-3-yl-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid [(R)-2-(3-cyano-azetidin-1-yl)-1-methyl-2-oxo-ethyl]-amide. (ES+): 414. 1H NMR (300 MHz, DMSO-d6) δ: 12.9 (m, 1H, 9.86 (m, 1H) 9.11 (s, 1H) 8.57 (s, 1H) 8.42 (d, 1H) 8.34 (d, 1H) 7.78 (d, 1H) 7.47 (t, 1H) 7.19 (m, 1H) 4.65 (m, 1H) 4.13 (m, 2H) 3.89 (m, 2H) 3.78 (m, 1H) 1.39 (d, 3H)
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][CH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1.[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br>>[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36][N:11]([CH2:12][C:13]1[CH:32]=[CH:31][C:16]([O:17][C:18]2[CH:19]=[C:20]([CH:28]=[CH:29][CH:30]=2)[O:21][CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:15][CH:14]=1)[C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([N+:8]([O-:10])=[O:9])[C:2]=1[CH3:1]
Reactant: CCOC(=O)COc1cccc(Oc2ccc(CNc3cccc([N+](=O)[O-])c3C)cc2)c1
Reactant: Fc1ccc(CBr)c(F)c1
Product: CCOC(=O)COc1cccc(Oc2ccc(CN(Cc3ccc(F)cc3F)c3cccc([N+](=O)[O-])c3C)cc2)c1

Procedure:
The product from Example 83B and 2,4 difluorobenzyl bromide were processed as described in Example 6B to provide the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([OH:22])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:23][C:24]1[CH:25]=[CH:26][C:27]([CH:30]([CH3:32])[CH3:31])=[N:28][CH:29]=1>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH3:19])=[C:15]2[C:10]=1[CH2:11][CH2:12][CH2:13][CH:14]2[C:20]([NH:23][C:24]1[CH:29]=[N:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=1)=[O:22])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)O)CCC2
Reactant: CC(C)c1ccc(N)cn1
Product: Cc1ccc(OCc2ccccc2)c2c1C(C(=O)Nc1ccc(C(C)C)nc1)CCC2
Yield: 93.4 %

Procedure:
By the reaction and treatment in the same manner as in Preparation Example 18 using 5-benzyloxy-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxylic acid (1.34 g) and 5-amino-2-isopropylpyridine (0.62 g) as starting materials, 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-8-methyl-1,2,3,4-tetrahydronaphthalene-1-carboxamide (1.75 g) was obtained.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(N(CC)CC)C.[CH3:35][N:36]1[CH:40]=[C:39]([S:41](Cl)(=[O:43])=[O:42])[N:38]=[CH:37]1>CN(C=O)C>[CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]2[C:17]([N+:18]([O-:20])=[O:19])=[C:16]([O:21][CH:22]3[CH2:27][CH2:26][N:25]([S:41]([C:39]4[N:38]=[CH:37][N:36]([CH3:35])[CH:40]=4)(=[O:43])=[O:42])[CH2:24][CH2:23]3)[N:15]=[CH:14][N:13]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)c1ccc(Nc2ncnc(OC3CCNCC3)c2[N+](=O)[O-])cc1
Reactant: Cn1cnc(S(=O)(=O)Cl)c1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1cnc(S(=O)(=O)N2CCC(Oc3ncnc(Nc4ccc(S(C)(=O)=O)cc4)c3[N+](=O)[O-])CC2)c1

Procedure:
Compound A31 was prepared in a similar manner as described above using (4-methanesulfonyl-phenyl)-[5-nitro-6-(piperidin-4-yloxy)-pyrimidin-4-yl]-amine (i.e., Compound A2) (15 mg, 0.035 mmol), triethylamine (20 μL), 1-methyl-1H-imidazole-4-sulfonyl chloride (9 mg, 0.050 mmol), DMF (0.6 mL), 1H NMR (CDCl3, 400 MHz) δ 2.07 (m,4H), 3.08 (s, 3H), 3.32 (m, 2H), 3.53 (m, 2H), 3.79 (s,3H), 5.55 (m, 1H), 7.46 (s, 1H), 7.53 (s, 1H), 7.85 (d, 2H), 7.97 (d, 2H), 8.38 (s, 1H), 10.16 (s, 1H). Exact mass calculated for C20H23N7O7S2 537.11, found 538.4 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([S:5][C:6]1[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[CH:8][CH:7]=1)=[O:4].B.CSC.CO.[H][H]>C1COCC1>[CH3:1][N:2]([CH3:14])[C:3]([S:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][NH2:11])=[CH:8][CH:7]=1)=[O:4]
Reactant: [H][H]
Reactant: CN(C)C(=O)Sc1ccc(C#N)cc1
Agent: B
Solvent: CSC
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)C(=O)Sc1ccc(CN)cc1

Procedure:
Dissolve 4-dimethylcarbamoylthio-benzonitrile (3.07 g, 14.9 mmol) in anhydrous THF (30 mL). Add borane-dimethylsulfide complex (4.24 mL, 44.7 mmol, 1M solution in diethyl ether) and stir the mixture at room temperature for 3 h. Add methanol dropwise until hydrogen evolution ceases. Concentrate the mixture in vacuo and purify the crude mixture by SCX chromatography eluting with methanol and 2M ammonia in methanol to obtain the title compound as a slightly impure oil (2.9 g). Dissolve the oil (2.9 g) in DCM and add 2M hydrogen chloride in ether. Stir the mixture for 1 h and concentrate in vacuo to obtain a solid. Suspend the solid in DCM and add diethyl ether to precipitate the salt. Filter and dry the solid in vacuo to obtain the hydrochloride salt of the title compound as a white solid (2.33 g, 64%). Elute the compound through a SCX column to obtain the desired intermediate as an oil. MS (ES+) m/z: 211 (M+H)+.
Reaction SMILES: [Mg].[CH2:2](Br)[CH3:3].[Cl:5][C:6]1[CH:7]=[C:8]([CH:25]=[CH:26][CH:27]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:13][CH:12]=1)=[O:10].[Cl-].[NH4+]>O1CCCC1.CCOCC>[Cl:5][C:6]1[CH:7]=[C:8]([C:9]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[CH:15][CH:16]=2)([OH:10])[CH2:2][CH3:3])[CH:25]=[CH:26][CH:27]=1
Reactant: CCBr
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Agent: [Cl-]
Agent: [Mg]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CCC(O)(c1ccc(OCc2ccccc2)cc1)c1cccc(Cl)c1
Reaction time: 0.5 h

Procedure:
To a Grignard reactant prepared from 7.2 g. of magnesium turnings and 32.6 g. of ethyl bromide in 120 ml. of dry ether a solution of 24 g. of 3-chloro-4'-benzyloxy-benzophenone in 120 ml. of tetrahydrofurane is added dropwise, with stirring at 0° to 5° C. The reaction mixture is then slightly boiled for 30 minutes, and the Grignard complex is decomposed with a saturated aqueous solution of ammonium chloride under cooling. The aqueous phase is extracted with ether, the combined organic phases are washed with saturated aqueous sodium chloride solution. After drying over anhydrous sodium sulfate, the solvent is distilled off under reduced pressure. Crystallization of the residue from a mixture of ethyl acetate and n-hexane yields 16.2 g. of the named compound, melting at 52°-53° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]([C:12]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([O:20]C)=[O:19])[CH:13]=2)=[O:11])=[CH:4][C:3]=1[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([CH2:28][N:29]2[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]2)[CH:23]=1.O[Li].O.Cl>CO.O>[CH3:41][C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][N:29]([CH2:28][C:24]2[CH:23]=[C:22]([C:3]3[C:2]([F:1])=[CH:7][CH:6]=[C:5]([CH2:8][NH:9][C:10]([C:12]4[CH:13]=[C:14]([CH:15]=[CH:16][CH:17]=4)[C:18]([OH:20])=[O:19])=[O:11])[CH:4]=3)[CH:27]=[CH:26][CH:25]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:39])[CH3:40]
Reactant: COC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CN4CCN(C(=O)OC(C)(C)C)CC4)c3)c2)c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2cccc(-c3cc(CNC(=O)c4cccc(C(=O)O)c4)ccc3F)c2)CC1
Temperature: 80 °C
Yield: 101 %

Procedure:
To a solution of 1,1-dimethylethyl 4-[(2′-fluoro-5′-{[({3-[(methyloxy)carbonyl]phenyl}carbonyl)amino]methyl}-3-biphenylyl)methyl]-1-piperazinecarboxylate (0.26 g, 0.463 mmol) in MeOH/H2O (2/1 mL) was added LiOH.H2O (0.0971 g, 2.32 mmol). The mixture was heated with a microwave at 80° C. for 30 min. Then HCl was added to adjust the pH to ˜5. Then solvents were removed. The residue was extracted with DCM to afford the title compound 0.256 g (100%). LC-MS m/z 548 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([OH:25])=O)=[N:9]2)=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:27]>C1(C)C=CC=CC=1.O1CCCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=3)=[CH:11][C:10]([C:23]([Cl:27])=[O:25])=[N:9]2)=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)c1ccc(-c2cc(C(=O)O)nn2-c2ccc(F)cc2)cc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CS(=O)(=O)c1ccc(-c2cc(C(=O)Cl)nn2-c2ccc(F)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carboxylic acid (1.1 g) and phosphorus pentachloride (0.67 g) in toluene (16 ml) and tetrahydrofuran 9 ml) was stirred at ambient temperature for 2 hours. The insoluble material was filtered and the filtrate was concentrated to give an oil of 1-(4-fluorophenyl)-5-[4-(methylsulfonyl)phenyl]pyrazole-3-carbonyl chloride (1.37 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[NH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1>>[CH3:14][S:11]([C:8]1[CH:9]=[CH:10][C:2]([N:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5])(=[O:13])=[O:12]
Reactant: CS(=O)(=O)c1ccc(Cl)c(C(=O)O)c1
Reactant: C1CCNC1
Product: CS(=O)(=O)c1ccc(N2CCCC2)c(C(=O)O)c1

Procedure:
A mixture of 163.8 mg (0.7 mmol) 2-Chloro-5-methanesulfonyl-benzoic acid in 2 ml pyrrolidine was heated for 16 h to 100° C. After evaporation of all volatiles the residue was taken up in 2 ml methanol/formic acid 3/1 and subjected to reversed phase HPLC purification eluting with an acetonitrile/water gradient to yield after evaporation of the product fractions 143.4 mg (77%) of the title compound. MS (m/e): 268.1 (MH−, 100%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:10])[CH:9]=1)[CH:5]=[O:6].[C:11]([Si:15](Cl)([CH3:17])[CH3:16])([CH3:14])([CH3:13])[CH3:12]>>[Si:15]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:10][Si:15]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16])[CH:9]=1)[CH:5]=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:17])[CH3:16]
Reactant: O=Cc1cc(O)cc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Product: CC(C)(C)[Si](C)(C)Oc1cc(C=O)cc(O[Si](C)(C)C(C)(C)C)c1
Yield: 100 %

Procedure:
Prepared as in Example 12-1c from 3,5-dihydroxybenzaldehyde and tert-butylchlorodimethylsilane. Yield 100%, yellowish liquid. MS 267 (MH+).