Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([C:4]1[CH:5]=[C:6]([N:10]2[CH2:15][CH2:14][O:13][C@H:12]([CH2:16][OH:17])[CH2:11]2)[CH:7]=[CH:8][CH:9]=1)[CH3:3].[C:18](O)(=[O:27])[CH:19]=[CH:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(Cl)CCl.C(N(CC)CC)C>CN(C1C=CN=CC=1)C.ClCCl>[OH:17][CH2:16][CH:12]1[O:13][CH2:14][CH2:15][N:10]([C:6]2[CH:5]=[C:4]([C@@H:2]([NH:1][C:18](=[O:27])[CH:19]=[CH:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[CH3:3])[CH:9]=[CH:8][CH:7]=2)[CH2:11]1
Reactant: O=C(O)C=Cc1ccccc1
Reactant: CC(N)c1cccc(N2CCO[C@H](CO)C2)c1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCCl
Solvent: ClCCl
Product: C[C@H](NC(=O)C=Cc1ccccc1)c1cccc(N2CCOC(CO)C2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Mixture of (S)-{4-[3-(1-amino-ethyl)-phenyl]-morpholin-2-yl}-methanol (27 mg, 0.09 mmol), cinnamic acid, Preparation 27 (12.8 mg, 0.09 mmol), EDC (34 mg, 0.18 mmol), DMAP (11 mg, 0.09 mmol), triethylamine (0.05 ml, 0.36 mmol) in dichloromethane (0.6 ml) was stirred at room temperature overnight. The reaction mixture was purified by filtering through 2 g silica-gel syringe with 60:40:1 acetone:hexanes:methanol. The filtrate was concentrated under vacuum to provide the title compound as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].S([O-])([O-])(=O)=O.[Mg+2].[OH:15][C:16]1[C:21]([CH3:22])=[CH:20][C:19]([C:23]2[N:28]=[N:27][C:26]([O:29][CH3:30])=[C:25]([C:31](=O)[CH3:32])[CH:24]=2)=[CH:18][C:17]=1[CH3:34].C(O)(=O)C>CC(N(C)C)=O>[NH:4]1[C:3]2[C:2](=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH:32]=[C:31]1[C:25]1[CH:24]=[C:23]([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([OH:15])=[C:17]([CH3:34])[CH:18]=2)[N:28]=[N:27][C:26]=1[O:29][CH3:30]
Reactant: Nc1ccccc1Br
Reactant: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1C(C)=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC(=O)O
Solvent: CC(=O)N(C)C
Product: COc1nnc(-c2cc(C)c(O)c(C)c2)cc1-c1cc2ccccc2[nH]1
Temperature: 140 °C

Procedure:
205 mg of 2-bromoaniline and 72 mg of anhydrous magnesium sulfate are suspended in 7 ml dimethylacetamide. 325 mg of 1-[6-(4-Hydroxy-3,5-dimethyl-phenyl)-3-methoxy-pyridazin-4-yl]-ethanone and 86.6 μl acetic acid are added and the reaction is degassed with argon. 330 mg of tripotassium phosphate and 61 mg of bis(tri-tert-butylphosphine) palladium (0) are added and the reaction is degassed with argon. The reaction is heated to 140° C. for 5 h. The solution is poured into water and extracted with ethyl acetate. The solvent is removed under reduced pressure. The product is purified by silica gel chromatography, eluting with a gradient of ethyl acetate in heptane. Yield 105 mg. LC-MS (ES+) 346 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14](Br)[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:24])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.[CH:31](OC)=[O:32].O>O1CCCC1.CCCCCC>[CH2:1]([O:8][C:9]1[C:18]2[C:13](=[C:14]([CH:31]=[O:32])[CH:15]=[C:16]([CH:19]([CH2:21][CH3:22])[CH3:20])[CH:17]=2)[N:12]=[C:11]([CH3:24])[C:10]=1[CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC=O
Reactant: CCC(C)c1cc(Br)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC(C)c1cc(C=O)c2nc(C)c(C)c(OCc3ccccc3)c2c1
Reaction time: 0.17 h

Procedure:
5 Grams of 4-hydroxy-6-s-butyl-8-bromo-2,3-dimethylquinoline synthesized in the same way as that described in Example 1 was suspended in 20 ml of dimethylformamide, to which 700 mg of 60% sodium hydride was added under cooling with ice and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added dropwise 3 g of benzyl bromide under cooling with ice and the mixture was allowed to react at room temperature overnight. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated brine and dried over anhydrous sodium sulfate overnight. After the solvent was evaporated under reduced pressure, the resultant crude product was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane to obtain 2.5 g of 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline. 2.5 Grams of the thus-obtained 4-benzyloxy-6-s-butyl-8-bromo-2,3-dimethylquinoline was dissolved in 25 ml of anhydrous tetrahydrofuran and cooled to −78° C., to which 2.8 ml of a 2.5 M solution of n-butyl lithium in n-hexane was added dropwise and the mixture was stirred for 10 minutes. One ml of methyl formate dissolved in 2 ml of anhydrous tetrahydrofuran was added dropwise to the reaction mixture and the mixture was stirred at 0° C. for 30 minutes. After the addition of 50 ml of water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with an aqueous saturated ammonium chloride solution and a saturated brine and then dried over anhydrous sodium sulfate. After the solvent was evaporated under reduced pressure, the residue was purified by column chromatography on silica gel (WAKOGEL® C-200) eluting with n-hexane/ethyl acetate (20:1) to obtain 800 mg of 4-benzyloxy-6-s-butyl-8-formyl-2,3-dimethylquinoline.
Reaction SMILES: [Si](O[CH2:9][CH:10]1[CH2:12][CH:11]1[CH:13]([CH2:16][CH2:17][O:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][O:20]1)CC)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.[O:43]1CC[CH2:45][CH2:44]1>>[O:20]1[CH2:21][CH2:22][CH2:23][CH2:24][CH:19]1[O:18][CH2:17][C:16]#[C:13][CH2:11][CH2:12][CH:10]1[CH2:9][CH:45]1[CH2:44][OH:43]
Reactant: C1CCOC1
Reactant: CCC(CCOC1CCCCO1)C1CC1CO[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Product: OCC1CC1CCC#CCOC1CCCCO1
Reaction time: 0.5 h

Procedure:
The 2-(5-tetrahydropyranyloxy-3-pentyl)cyclopropylmethyl t-butyldimethylsilyl ether (3 g, 10 mmol) was dissolved in tetrahydrofuran (10 ml), and tetrabutyl ammonium fluoride (factor=1.0, 12 ml, 12 mmol) was added at 0° C. The mixture was stirred for 30 minutes. The solvent was distilled off, and the product was purified by silica gel column chromatography to obtain 2-(5-tetrahydropyranyloxy-3-pentynyl)cyclopropanemethanol (1.2 g)
Reaction SMILES: [H-].[K+].COCCOCCOCCOC.[OH:15][CH:16]1[CH2:19][N:18]([CH:20]2[CH2:44][CH2:43][C@@:42]3([CH3:45])[C@@H:22]([CH2:23][CH2:24][C@@H:25]4[C@@H:41]3[CH2:40][CH2:39][C@@:38]3([CH3:46])[C@H:26]4[CH2:27][CH2:28][C@@H:29]3[C@H:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]2)[CH2:17]1.[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53](Cl)(=[O:55])=[O:54])=[CH:49][CH:48]=1>O1CCCC1>[C:47]1([CH3:57])[CH:52]=[CH:51][C:50]([S:53]([O:15][CH:16]2[CH2:17][N:18]([CH:20]3[CH2:44][CH2:43][C@@:42]4([CH3:45])[C@@H:22]([CH2:23][CH2:24][C@@H:25]5[C@@H:41]4[CH2:40][CH2:39][C@@:38]4([CH3:46])[C@H:26]5[CH2:27][CH2:28][C@@H:29]4[C@H:30]([CH3:37])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:21]3)[CH2:19]2)(=[O:55])=[O:54])=[CH:49][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)CCC[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4CC(N5CC(O)C5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: [H-]
Agent: [K+]
Solvent: COCCOCCOCCOC
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)OC2CN(C3CC[C@@]4(C)[C@@H](CC[C@@H]5[C@@H]4CC[C@]4(C)[C@@H]([C@H](C)CCCC(C)C)CC[C@@H]54)C3)C2)cc1

Procedure:
To a nitrogen blanketed, ice-cooled, stirred suspension of 1.08 g of 35% potassium hydride in mineral oil in 58 ml dry tetrahydrofuran and 2-3 ml triglyme add 3.49 g 3-(3-hydroxy-1-azetidinyl)-5α-cholestane (a mixture of the 3α- and 3β-epimers). Continue stirring the mixture for 5 days at room temperature, adding an additional 80 ml dry tetrahydrofuran after the first 24 hours. After 5 days add a solution of 1.52 g of p-toluenesulfonyl chloride in 10 ml tetrahydrofuran and stir one hour. Destroy the excess potassium hydride by the cautious addition of approximately 70 ml of water-saturated ethyl ether; then, add 350 ml water and saturate with sodium chloride. Extract once with 300 ml ethyl ether and then twice with 150 ml portions of ethyl ether. Combine the etheral extracts, dry over anhydrous sodium sulfate, and acidify the solution with a solution of 0.93 g maleic acid in 50 ml ethyl ether. Filter the crude maleate salt and triturate with 150 ml hexane. Dissolve the triturated material in 20 ml methylene chloride and treat the solution with decolourizing carbon. Filter the carbon and dilute the filtrate with 250 ml isopropyl ether. Concentrate the solution in vacuo until a precipitate begins to form. Filter the precipitate to obtain the maleate salt of the title compound, m.p. 105°-109° C. dec. (a mixtuer of 3α- and 3β- epimers).
Reaction SMILES: [CH2:1]([O:3][C:4](=O)[CH2:5][N:6]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:2].[C:22]1([Li])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:7]([N:6]([CH2:5][CH:4]1[CH:11]=[C:12]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:13]2[C:1](=[CH:2][CH:10]=[CH:9][CH:8]=2)[O:3]1)[CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: [Li]c1ccccc1
Reactant: CCOC(=O)CN(Cc1ccccc1)Cc1ccccc1
Product: C1=C(c2ccccc2)c2ccccc2OC1CN(Cc1ccccc1)Cc1ccccc1

Procedure:
The process of Example 4 was repeated using N,N-dibenzylglycine ethyl ester in place of N,N-dimethylalanine ethyl ester in part (a), then following the precedure in part (b) and in part (c) using phenyl lithium in place of the 4-bromochlorobenzene/butyl lithium, to yield the title compound as an oil, after dehydration in dilute HCl as in part (d).
Reaction SMILES: [I:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH3:9].[Br:10]N1C(=O)CCC1=O>ClC(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[F:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:9][Br:10])=[C:2]([I:1])[CH:7]=1
Reactant: Cc1ccc(F)cc1I
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: Fc1ccc(CBr)c(I)c1
Yield: 78.8 %

Procedure:
A solution of 23.6 g of 2-iodo-4-fluorotoluene in 50 ml of tetrachloromethane was treated with 0.2 g of dibenzoyl peroxide and 19.6 g of N-bromosuccinimide. The mixture was then refluxed for 6 hours and illuminated by a 200 W bulb. After cooling, the spearated succinimide was filtered off and washed with 15 ml tetrachloromethane. The filtrate was evaporated and the residue distilled. There was obtained 24.8 g of 4-fluoro-2-iodobenzyl bromide with a b.p. of 130°-140° C./20 Torr. The product crystallized on standing and a sample recrystallized from petroleum ether; m.p. 71°-73° C.
Reaction SMILES: [OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12](O)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N1C=CN=C1)(N1C=CN=C1)=O.[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].C(O)(=O)C(O)=O.[NH2:39][CH:40]1[CH2:45][CH2:44][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]2[C:59]3[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=3)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=2)=[O:50])[CH2:42][CH2:41]1>CN(C)C=O>[C:27]([OH:32])(=[O:31])[C:28]([OH:30])=[O:29].[OH:1][C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([NH:39][CH:40]4[CH2:41][CH2:42][N:43]([CH2:46][CH2:47][NH:48][C:49]([C:51]5[C:59]6[C:54](=[CH:55][CH:56]=[CH:57][CH:58]=6)[N:53]([CH:60]([CH3:62])[CH3:61])[N:52]=5)=[O:50])[CH2:44][CH2:45]4)=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2
Reactant: CC(C)n1nc(C(=O)NCCN2CCC(N)CC2)c2ccccc21
Reactant: O=C(O)C12CC3CC(CC(O)(C3)C1)C2
Agent: O=C(O)C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CC(C)n1nc(C(=O)NCCN2CCC(NC(=O)C34CC5CC(CC(O)(C5)C3)C4)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 39.9 %

Procedure:
A mixture of 1.07 g (5.45 mmol) of 3-hydroxy-1-adamantylcarboxylic acid and 0.88 g (5.45 mmol) of 1,1'-carbonyldiimidazole in 10 mL of dimethylformamide was stirred for 2 hours at ambient temperature. To this solution was dropwise added 1.80 g (5.45 mmol) of the product of Example 23 in 7 mL of dimethylformamide. The reaction was stirred for 18 hours and then concentrated in vacuo, diluted with dichloromethane and solids removed by filtration. The crude product was purified by chromatography (silica, 9:1 dichloromethane-methanol) to provide 1.30 g (47%) of the desired product as a foam. Further treatment of the product with 0.23 g (2.62 mmol) of oxalic acid in 20 mL of ethanol provided, upon concentration of the solution, 1.51 g of the oxalate salt (LSN343031). 1H NMR (500 MHz, DMSO-d6) d 8.51 (t, 1H), 8.19 (d, 1H), 7.9 (br s, 3H), 7.78 (d, 1H), 7.44 (t, 1H), 7.40 (d, 1H), 7.27 (t, 1H), 5.06 (m, 1H), 3.84 (m, 1H), 3.72 (m, 2H), 3.52 (m, 2H), 3.24 (br t, 2H), 3.07 (br t, 2H), 2.11 (br s, 2H), 1.82 (m, 4H), 1.64 (m, 6H), 1.55 (m, 10H), 1.48 (br s, 2H).
Reaction SMILES: [CH:1]1([C:4]2[CH:8]=[C:7]([CH:9]3[CH2:11][CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.C1C(=O)N([Br:19])C(=O)C1>C(Cl)Cl>[Br:19][C:8]1[C:4]([CH:1]2[CH2:3][CH2:2]2)=[N:5][O:6][C:7]=1[CH:9]1[CH2:11][CH2:10]1
Reactant: O=C1CCC(=O)N1Br
Reactant: c1c(C2CC2)noc1C1CC1
Solvent: ClCCl
Product: Brc1c(C2CC2)noc1C1CC1

Procedure:
3,5-Dicyclopropylisoxazole (70.0 mg, 0.469 mmol) was treated with NBS (167.0 mg, 0.938 mmol, equiv) in CH2Cl2 at room temperature for 12 h. The solvent was removed under a reduced pressure and the residue was directly loaded onto a silica gel column chromatography (hexane EtOAc 87:13) to give 4-bromo-3,5-dicyclopropylisoxazole.
Reaction SMILES: C[I:2].[C:3]([C:5]1[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][N:20]([CH3:22])[CH3:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)#[N:4].[CH3:27]C(C)=O>ClC(Cl)Cl>[I-:2].[C:3]([C:5]1[CH:26]=[CH:25][CH:24]=[CH:23][C:6]=1[CH2:7][O:8][C:9]1[C:10]2[N:11]([C:15]([CH2:19][N+:20]([CH3:27])([CH3:22])[CH3:21])=[C:16]([CH3:18])[N:17]=2)[CH:12]=[CH:13][CH:14]=1)#[N:4]
Reactant: Cc1nc2c(OCc3ccccc3C#N)cccn2c1CN(C)C
Reactant: CC(C)=O
Reactant: CI
Solvent: ClC(Cl)Cl
Product: Cc1nc2c(OCc3ccccc3C#N)cccn2c1C[N+](C)(C)C
Product: [I-]
Reaction time: 24 h

Procedure:
Methyl iodide (1.33 g) was added dropwise to a solution of 8-(2-cyanobenzyloxy)-3-dimethylaminomethyl-2-methylimidazo[1,2-a]pyridine (3 g) in the mixture of acetone (30 ml) and trichloromethane (30 ml) at room temperature and the mixture was stirred for 24 hours. The resulting precipitate was collected by filtration, washed with acetone, and dried in a desiccator to give 8-(2-cyanobenzyloxy)-2-methyl-3-trimethylammoniomethylimidazo[1,2-a]pyridine iodide.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:15]3C=CC=[CH:19][C:14]=3[N:13](C)[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[CH2:22]([O:26][C:27]1[CH:32]=[CH:31][C:30](Cl)=[CH:29][CH:28]=1)[CH:23]1[O:25][CH2:24]1>>[NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][NH:8][C:9]([N:11]2[C:32]3[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=3[N:13]([CH:14]([CH3:15])[CH3:19])[C:12]2=[O:21])=[O:10])[CH2:3][CH2:2]1.[O:25]1[CH:23]([CH2:22][O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH2:24]1
Reactant: Clc1ccc(OCC2CO2)cc1
Reactant: Cn1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: CC(C)n1c(=O)n(C(=O)NCC2CCNCC2)c2ccccc21
Product: c1ccc(OCC2CO2)cc1

Procedure:
The procedure given in Example 104 was followed using 3-methyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 4-chlorophenyl glycidyl ether as a reactant, instead of 3-isopropyl-2-oxo-2,3-dihydro-benzimidazole-1-carboxylic acid (piperidin-4-ylmethyl)-amide and 1,2-epoxy-3-phenoxypropane, to give the title compound.
Reaction SMILES: ClS(C1C=CC(C(O)=O)=CC=1)(=O)=O.[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1.[F:28][C:29]([F:45])([F:44])[CH2:30][NH:31][S:32]([C:35]1[CH:43]=[CH:42][C:38]([C:39](O)=[O:40])=[CH:37][CH:36]=1)(=[O:34])=[O:33]>FC(F)(F)CN>[Cl:14][C:15]1[CH:21]=[CH:20][C:18]([NH:19][C:39](=[O:40])[C:38]2[CH:42]=[CH:43][C:35]([S:32](=[O:33])(=[O:34])[NH:31][CH2:30][C:29]([F:28])([F:44])[F:45])=[CH:36][CH:37]=2)=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
Reactant: O=C(O)c1ccc(S(=O)(=O)NCC(F)(F)F)cc1
Agent: NCC(F)(F)F
Agent: O=C(O)c1ccc(S(=O)(=O)Cl)cc1
Product: O=C(Nc1ccc(Cl)c(-c2ccccn2)c1)c1ccc(S(=O)(=O)NCC(F)(F)F)cc1

Procedure:
1 g of 4-(chlorosulfonyl)benzoic acid was reacted with 500 mL of 2,2,2-trifluoroethanamine via Procedure H. 60 mg of 4-chloro-3-(pyridin-2-yl)aniline was coupled to 92 mg of 4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzoic acid by Procedure G and purified by reverse phase HPLC to yield N-(4-chloro-3-(pyridin-2-yl)phenyl)-4-(N-(2,2,2-trifluoroethyl)sulfamoyl)benzamide. MS (Q1) 470 (M)+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH2:17])[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11].[CH3:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([CH3:27])[C:25]=1[F:26].C(N(CC)CC)C>ClCCl.CC([O-])=O.CC([O-])=O.[Cu+2]>[CH3:1][O:2][C:3](=[O:18])[C@H:4]([NH:17][C:22]1[CH:23]=[C:24]([CH3:27])[C:25]([F:26])=[C:20]([CH3:19])[CH:21]=1)[CH2:5][CH2:6][CH2:7][CH2:8][NH:9][C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11]
Reactant: COC(=O)[C@H](N)CCCCNC(=O)OC(C)(C)C
Reactant: Cc1cc(B(O)O)cc(C)c1F
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](CCCCNC(=O)OC(C)(C)C)Nc1cc(C)c(F)c(C)c1
Temperature: 25 °C
Reaction time: 87 h
Yield: 79.8 %

Procedure:
To a suspension of (R)-2-Amino-6-tert-butoxycarbonylamino-hexanoic acid methyl ester (3.000 g, 10.108 mmol), 3,5-dimethyl-4-fluorophenylboronic acid (3.398 g, 20.216 mmol), Cu(OAc)2 (2.019 g, 11.119 mmol), and molecular sieves 4 Å (7.591 g) in 45 mL of dichloromethane, was added triethylamine (2.8 mL, 20.216 mmol). After stirring at room temperature under O2 (1 atm) for 87 h, the reaction mixture was filtered through a pad of Celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was isolated by Flash column chromatography (silica gel column) eluting with 0-30% ethyl acetate/hexanes to give the title compound as colorless oil (3.084 g, 80% yield). LC-MS: tR=9.8 min; m/z 383 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.Cl.[C:12]1([C:18]2[C:19]([N:27]3[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]3)=[C:20]3[CH:26]=[CH:25][NH:24][C:21]3=[N:22][CH:23]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:33]([O:37][C:38]([N:40]1[CH2:44][CH2:43][CH2:42][C@H:41]1[C@H:45]([C:49]1[CH:54]=[CH:53][C:52]([Cl:55])=[CH:51][CH:50]=1)[C:46](O)=[O:47])=[O:39])([CH3:36])([CH3:35])[CH3:34].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>C(Cl)Cl>[Cl:55][C:52]1[CH:51]=[CH:50][C:49]([C@@H:45]([C@@H:41]2[CH2:42][CH2:43][CH2:44][N:40]2[C:38]([O:37][C:33]([CH3:36])([CH3:35])[CH3:34])=[O:39])[C:46](=[O:47])[N:30]2[CH2:29][CH2:28][N:27]([C:19]3[C:18]([C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=4)=[CH:23][N:22]=[C:21]4[NH:24][CH:25]=[CH:26][C:20]=34)[CH2:32][CH2:31]2)=[CH:54][CH:53]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)O)c1ccc(Cl)cc1
Reactant: c1ccc(-c2cnc3[nH]ccc3c2N2CCNCC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1[C@@H](C(=O)N1CCN(c2c(-c3ccccc3)cnc3[nH]ccc23)CC1)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
DIEA (0.103 mL, 0.592 mmol) was added to 5-phenyl-4-(piperazin-1-yl)-1H-pyrrolo[2,3-b]pyridine dihydrochloride (0.052 g, 0.15 mmol, see Example 19), (S)-2-((S)-1-(tert-butoxycarbonyl)pyrrolidin-2-yl)-2-(4-chlorophenyl)acetic acid (0.0503 g, 0.148 mmol, see Example F) and TBTU (0.0570 g, 0.178 mmol) in DCM (1 mL) and stirred at room temperature for 1 hour. The mixture was directly loaded onto a column and purified by chromatography (1:1 hexane:ethyl acetate) to give (S)-tert-butyl 2-((S)-1-(4-chlorophenyl)-2-oxo-2-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyridin-4-yl)piperazin-1-yl)ethyl)pyrrolidine-1-carboxylate as a solid. The solid was then dissolved in DCM (1 mL), and TFA (0.2 mL) was added. The mixture was stirred at room temperature for 1 hour. The solvent was removed. The residue was dissolved in DCM (0.5 mL), and 2M HCl in ether (1 mL) was added. The resulting solid was collected by filtration to give (S)-2-(4-chlorophenyl)-1-(4-(5-phenyl-1H-pyrrolo[2,3-b]pyri din-4-yl)piperazin-1-yl)-2-((S)-pyrrolidin-2-yl)ethanone dihydrochloride (0.062 g, 63%). MS ESI (+) m/z 500 detected.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[Li]CCCC.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]=[O:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1>C1COCC1>[Br:13][C:14]1[CH:19]=[CH:18][C:17]([NH:20][C:21]2[C:22]([CH:32]([C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=3)[OH:33])=[CH:23][C:24]3[N:28]([CH3:29])[CH:27]=[N:26][C:25]=3[C:30]=2[F:31])=[C:16]([Cl:34])[CH:15]=1
Reactant: Brc1ccccn1
Reactant: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C=O)cc21
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cn1cnc2c(F)c(Nc3ccc(Br)cc3Cl)c(C(O)c3ccccn3)cc21
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 60.9 %

Procedure:
To a solution of 2-bromopyridine (0.10 mL, 1.04 mmol) in THF (3 mL) at −78° C. is added n-BuLi (0.39 mL, 0.98 mmol, 2.5 M solution in hexane). After stirring for 10 minutes at −78° C., a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-methyl-3H-benzoimidazole-5-carbaldehyde 10h (25 mg, 0.064 mmol) in THF (1 mL) is added. The resulting reaction mixture is stirred for 1.5 hours at −78° C., quenched with saturated aqueous NH4Cl, and extracted with EtOAc. The organic layer is dried over MgSO4, filtered, concentrated in vacuo, and purified by flash chromatography (2.5% MeOH in CH2Cl2) to afford the desired product (18 mg, 62%): MS APCI (+) m/z 461, 463 (M+, Br pattern) detected; 1H NMR (400 MHz, CD3OD) δ 8.31 (d, 1H), 8.16 (s, 1H), 7.65 (m, 3H), 7.38 (d, 1H), 7.10 (m, 1H), 7.00 (dd, 1H), 6.11 (dd, 1H), 6.05 (s, 1H), 3.94 (s, 3H); 19F NMR (376 MHz, CD3OD) −135.79 (s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([N:8]=[C:9]=[S:10])[CH:7]=1.[CH3:12][N:13]1[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:11])=[C:6]([NH:8][C:9]([NH:18][C:15]2[CH:16]=[CH:17][N:13]([CH3:12])[N:14]=2)=[S:10])[CH:7]=1
Reactant: Cn1ccc(N)n1
Reactant: Cc1ccc(Cl)cc1N=C=S
Product: Cc1ccc(Cl)cc1NC(=S)Nc1ccn(C)n1
Yield: 94.2 %

Procedure:
Prepared using Method A from 4.73 g (27.5 mmol) of 5-chloro-2-methyl-phenyl isothiocyanate and 2.5 g (25.7 mmol) of 1-methyl-3-aminopyrazole to give 6.8 g of title compound as a white solid (95% yield, m.p. 217-218° C.).
Reaction SMILES: Cl[C:2]1[S:6][N:5]=[C:4]([S:7][CH3:8])[N:3]=1.[Br-].[CH:10]1([Zn+])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>O1CCCC1>[CH3:8][S:7][C:4]1[N:3]=[C:2]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)[S:6][N:5]=1
Reactant: [Zn+]C1CCCCC1
Reactant: CSc1nsc(Cl)n1
Agent: [Br-]
Solvent: C1CCOC1
Product: CSc1nsc(C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
500 mg of 5-chloro-3-methylthio-1,2,4-thiadiazole and 122 mg of {1,1′-bis(diphenylphosphino)ferrocene} dichloro palladium(II) dichloromethane complex were dissolved in 6 ml of tetrahydrofuran under nitrogen atmosphere, 6.58 ml of solution of cyclohexyl zinc bromide in tetrahydrofuran (0.5 mol/l) was added thereto under ice-cooling taking for about 5 minutes, and the reaction mixture was stirred for 16 hours at room temperature. Then, the reaction mixture was concentrated, and the residue subjected to silica gel column chromatography to give 370 mg of 3-methylthio-5-cyclohexyl-1,2,4-thiadiazole.