Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:40])([Cl:39])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:24])([CH3:23])[C@@H:4]([OH:22])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7].N1C=CN=C1.[CH2:47]([Si:49](Cl)([CH2:52][CH3:53])[CH2:50][CH3:51])[CH3:48].O>CN(C)C=O>[O:1]=[C:2]([C@H:25]([CH3:41])[C@@H:26]([O:32][C:33]([O:35][CH2:36][C:37]([Cl:39])([Cl:40])[Cl:38])=[O:34])[C@@H:27]([CH3:31])[CH2:28][CH:29]=[CH2:30])[C:3]([CH3:23])([CH3:24])[C@@H:4]([O:22][Si:49]([CH2:52][CH3:53])([CH2:50][CH3:51])[CH2:47][CH3:48])[C@H:5]([CH3:21])[C:6]([N:8]1[C@@H:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:11][O:10][C:9]1=[O:20])=[O:7]
Reactant: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1
Reactant: CC[Si](Cl)(CC)CC
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: C=CC[C@H](C)[C@H](OC(=O)OCC(Cl)(Cl)Cl)[C@@H](C)C(=O)C(C)(C)[C@@H](O[Si](CC)(CC)CC)[C@H](C)C(=O)N1C(=O)OC[C@@H]1Cc1ccccc1

Procedure:
A solution of (4S)-3-[(2S,3S,6R,7S,8S)-5-oxo-3-hydroxy-2,4,4,6,8-pentamethyl-7-(2,2,2-trichloroethoxycarbonyloxy)-10-undecenoyl]-4-benzyloxazolidinone (2.6 g), imidazole (0.48 g), and triethylsilyl chloride (0.68 g) in 5 mL of dimethylformamide is stirred for 2 hours at ambient temperature, then poured into water and extracted with ether. The extract is washed with sat. aq. NaCl, dried over MgSO4, filtered, and evaporated. The product is purified by chromatography on SiO2.
Reaction SMILES: S[C:2]1[N:3]([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][N:13]=2)[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=1.N([O-])=O.[Na+].[N+]([O-])(O)=O.[OH-].[Na+]>O>[C:18]1([CH:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]2[C:4]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][N:6]=[CH:2]2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: COC(=O)c1cnc(S)n1C(c1ccccc1)c1ccccn1
Agent: O=N[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: O=[N+]([O-])O
Solvent: O
Product: COC(=O)c1cncn1C(c1ccccc1)c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
A mixture of 123.6 parts of methyl 2-mercapto-1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate, 0.2 parts of sodium nitrite, 219 parts of nitric acid and 440 parts of water was stirred for 2 hours at room temperature. The reaction mixture was poured into water and the whole was treated with a sodium hydroxide solution (on an ice bath). The product was extracted with dichloromethane. The extract was dried, filtered and evaporated. The residue was crystallized twice: first from 2-propanone and then from 4-methyl-2-pentanone. The product was filtered off (the filtrates were set aside) and dried in vacuo at 70° C., yielding a first fraction of 37.2 parts (33.3%) of methyl 1-[phenyl(2-pyridinyl)methyl]-1H-imidazole-5-carboxylate; mp. 96.3° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]([CH3:19])=[CH:18][C:13]=3[O:12][CH2:11]2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].CCCCCC.[C:30](OCC)(=[O:32])C>>[CH:30]([C:18]1[C:13]2[O:12][CH2:11][CH:10]([C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[CH:9][CH:8]=3)[C:14]=2[C:15]([CH3:23])=[C:16]([NH:20][CH:21]=[O:22])[C:17]=1[CH3:19])=[O:32]
Reactant: CCOC(C)=O
Reactant: Cc1cc2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Solvent: CCCCCC
Product: Cc1c(C=O)c2c(c(C)c1NC=O)C(c1ccc(C(C)C)cc1)CO2
Yield: 92 %

Procedure:
Using (3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)formamide obtained in Example 58, the title compound was synthesized in the same manner as in Example 20. Yield: 92%. Melting point: 123-124° C. (hexane-ethyl acetate).
Reaction SMILES: [C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:9](=[O:24])[C:10]3[N:11]=[C:12]([CH2:22]Br)[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1.[CH3:38][S-:39].[Na+].Cl>CN(C=O)C>[C:1]1([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH:6]=[CH:5][C:4]([C:7]2[N:8]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:9](=[O:24])[C:10]3[N:11]=[C:12]([CH2:22][S:39][CH3:38])[N:13]([C:16]4[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:14]=3[N:15]=2)=[CH:3][CH:2]=1
Reactant: C[S-]
Reactant: O=c1c2nc(CBr)n(-c3ccccc3)c2nc(-c2ccc(-c3ccccc3)cc2)n1-c1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSCc1nc2c(=O)n(-c3ccc(Cl)cc3)c(-c3ccc(-c4ccccc4)cc3)nc2n1-c1ccccc1
Reaction time: 0 h
Yield: 87.2 %

Procedure:
A solution of 2-biphenyl-4-yl-8-bromomethyl-1-(4-chloro-phenyl)-9-phenyl-1,9-dihydro-purin-6-one (17 mg, 0.030 mmol) in anhydrous DMF (0.2 mL) was treated with sodium thiomethoxide (3 mg, 0.042 mmol). The reaction mixture was stirred for (0 min and acidified with 1N aqueous HCl. The resulting precipitate was collected by filtration to give 2-biphenyl-4-yl-1-(4-chloro-phenyl)-8-methylsulfanylmethyl-9-phenyl-1,9-dihydro-purin-6-one (14 mg, 86%) as a white solid. HPLC-MS calculated for C31H23ClN4OS (M+H+): 535.1. Found 535.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:11]=[C:10]([C@H:12]2[CH2:14][C@H:13]2[C:15]([OH:17])=O)[O:9][N:8]=1.Cl.[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([NH2:30])[CH2:26][CH2:25]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>ClCCl>[Cl:19][C:20]1[CH:21]=[C:22]([CH:31]=[CH:32][C:33]=1[Cl:34])[CH2:23][N:24]1[CH2:25][CH2:26][CH:27]([NH:30][C:15]([C@@H:13]2[CH2:14][C@@H:12]2[C:10]2[O:9][N:8]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:11]=2)=[O:17])[CH2:28][CH2:29]1
Reactant: O=C(O)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Reactant: NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(NC1CCN(Cc2ccc(Cl)c(Cl)c2)CC1)[C@@H]1C[C@@H]1c1nc(-c2ccccn2)no1
Reaction time: 24 h
Yield: 19 %

Procedure:
Cis-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxylic acid (0.139 g) and N,N′-carbonyldiimidazole (0.110 g) in dichloromethane was stirred under nitrogen for 1 hour. 1-(3,4-dichlorobenzyl)-4-piperidinamine hydrochloride (0.198 g), and triethylamine (0.121 g) was then added and allowed to stir for 24 hours under nitrogen. Saturated sodium hydrogen carbonate was added to the reaction with the resulting solution being extracted three times with dichloromethane. The pooled organic phases were washed once with water, once with brine, dried over magnesium sulfate, filtered and the solvent removed under reduced pressure to leave an oil. This oil was purified by RPHPLC (75%-5%, 0.1% ammonium acetate/acetonitrile). The solvent was removed under reduced pressure to leave Cis-N-[1-(3,4-dichlorobenzyl)-4-piperidinyl]-2-[3-(2-pyridinyl)-1,2,4-oxadiazol-5-yl]cyclopropanecarboxamide (0.054 g) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH3:41])[C@@H:9]([CH3:40])[C:10]([NH:12][C@@H:13]([CH:37]([CH3:39])[CH3:38])[C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25]OS(C1C=CC(C)=CC=1)(=O)=O)=[O:15])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])([O-])=O.[K+].[K+].[NH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>O1CCOCC1.C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[N:8]([CH3:41])[C@H:9]([C:10](=[O:11])[NH:12][C@H:13]([C:14]([N:16]1[C:20]2=[N:21][CH:22]=[CH:23][CH:24]=[C:19]2[CH2:18][C@H:17]1[CH2:25][NH:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)=[O:15])[CH:37]([CH3:39])[CH3:38])[CH3:40])([CH3:3])([CH3:2])[CH3:4]
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2Cc3cccnc3N2C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(C)C)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: C1COCCO1
Product: CC(C)[C@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)C(=O)N1c2ncccc2C[C@H]1CNc1ccccc1
Yield: 69.3 %

Procedure:
To the stirred solution of toluene-4-sulfonic acid (S)-1-{(S)-2-[(S)-2-(tert-butoxycarbonyl-methyl-amino)-propionylamino]-3-methyl-butyryl}-2,3-dihydro-1H-pyrrolo[2,3-b]pyridin-2-ylmethyl ester (Intermediate 2) (50 mg, 0.085 mmol) in 1,4-dioxane (0.5 mL), K2CO3 (29.3 mg, 0.127 mmol), was added aniline (0.012 mL, 0.127 mmol) and the reaction mixture irradiated in a microwave at 125° C. for 1 h. The reaction mixture was diluted with DCM (10 mL), washed with water and brine and the separated organic layer was concentrated in vacuo. The crude product was purified by preparative HPLC (X Bridge Prep C18 (250×19.0 mm) 5μ, acetonitrile and 0.05% formic acid) to give methyl-{(S)-1-[(S)-2-methyl-1-((S)-2-phenylaminomethyl-2,3-dihydro-pyrrolo[2,3-b]pyridine-1-carbonyl)-propylcarbamoyl]-ethyl}-carbamic acid tert-butyl ester (30 mg), m/z=510.6 (M+H).
Reaction SMILES: [C:1]([NH:5][C:6](=[O:8])[OH:7])([CH3:4])([CH3:3])[CH3:2].[CH:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1.C([Li])CCC.[CH3:21][O:22][CH2:23]Cl.Cl>C1COCC1>[C:1]([NH:5][C:6](=[O:7])[OH:8])([CH3:4])([CH3:3])[CH3:2].[CH3:21][O:22][CH2:23][C:9]1([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:11][CH2:10]1
Reactant: COCCl
Reactant: NS(=O)(=O)C1CC1
Agent: CC(C)(C)NC(=O)O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COCC1(S(N)(=O)=O)CC1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of cyclopropylsulfonylamine tert-butyl carbamate (1.0 g, 4.5 mmol) dissolved in THF (30 mL) cooled to −78° C. was added n-butyllithium (6.4 mL, 10.2 mmol, 1.6M in hexane) and the reaction mixture was stirred for 1 hour. To this solution was added a neat solution of chloromethyl methyl ether (0.40 mL, 5.24 mmol), and the mixture was slowly warmed to room temperature overnight. The solution pH was adjusted to 3 using 1N aqueous HCl and was then extracted with ethyl acetate (4×50 mL portions). The combined extracts were dried (MgSO4), filtered, and concentrated to provide the desired product as a waxy solid (1.20 g, 100%) which was taken directly into the next reaction without further purification: 1H NMR (CDCl3) δ 1.03 (m, 2H), 1.52 (s, 9H), 1.66 (m, 2H), 3.38 (s, 3H), 3.68 (s, 2H), 7.54 (s, 1H); 13C NMR (CDCl3) δ 11.37, 28.29, 40.38, 58.94, 73.43, 83.61, 149.57.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1.CCN(CC)CC.[C:26](Cl)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(Cl)Cl>[C:26]([NH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:18]=[CH:17][C:11]([C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:10][CH:9]=2)[CH2:4][CH2:3]1)(=[O:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)c1ccc(N2CCC(N)CC2)cc1
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOC(=O)c1ccc(N2CCC(NC(=O)c3ccccc3)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 98.5 %

Procedure:
To a solution of ethyl 4-(4-aminopiperidin-1-yl)benzoate (3.0 g, 12.1 mmol) in CH2Cl2 under nitrogen was added Et3N (2.45 g, 24.2 mmol), followed by benzoyl chloride (1.70 g, 12.1 mmol). The mixture was stirred at room temperature overnight, washed with brine (200 mL), dried over anhydrous MgSO4, filtered, and concentrated. The resulting solids were triturated with hexanes to afford ethyl 4-(4-benzamidopiperidin-1-yl)benzoate as a yellow solid (4.2 g, 100%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH2:9])[CH3:2].Br.[C:21]([O:24][C:25]1[CH:33]=[CH:32][C:28]([C:29](O)=[O:30])=[CH:27][CH:26]=1)(=[O:23])[CH3:22].C(N(CC)CC)C.C(N=C=NCCCN(C)C)C.Cl>ClCCl>[CH2:1]([O:3][C:4](=[O:19])[C@H:5]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=1)[NH:6][C:7](=[O:10])[CH2:8][NH:9][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([O:24][C:21](=[O:23])[CH3:22])=[CH:33][CH:32]=1)[CH3:2]
Reactant: CC(=O)Oc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CN
Agent: Br
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)[C@H](Cc1ccc(O)cc1)NC(=O)CNC(=O)c1ccc(OC(C)=O)cc1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
17.4 g (0.05 mol) of glycyl-L-tyrosine ethyl ester·HBr, 9 g (0.05 mol) of p-acetoxybenzoic acid and 5.1 g (0.05 mol) of triethylamine were dissolved in 250 ml of dichloromethane, and after the solution was cooled to 0° C., 9.6 g (0.05 mol) of 1-ethyl-3(3-dimethylaminopropyl)carbodiimide·HCl was added to the solution, and the solution was stirred overnight. The reaction mixture was washed with a 0.1% aqueous solution of Na2CO3 and with a 0.1 N HCl solution, and was dried over anhydrous sodium sulfate. Dichloromethane was removed from the mixture under reduced pressure to obtain p-acetoxybenzoylglycyl-L-tyrosine ethyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][SH:11])=[N:5][N:4]=[N:3]1.[CH:12]1(Br)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>[OH-].[Na+].CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:8][CH2:9][CH2:10][S:11][CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[N:5][N:4]=[N:3]1
Reactant: Cn1nnnc1SCCCS
Reactant: BrC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Product: Cn1nnnc1SCCCSC1CCCCC1
Yield: 55.1 %

Procedure:
1-Methyl-5-(3-mercaptopropyl)thio-1,2,3,4-tetrazole (1.9 g) is dissolved in 1 N aqueous sodium hydroxide (30 ml), and thereto is added dropwise a solution of cyclohexyl bromide (2.0 g) in acetone (20 ml) with stirring under ice-cooling. After the addition, the mixture is stirred at room temperature for 3 hours. Acetone is distilled off and water is added to the residue, and the mixture is extracted with ether. The ether solution is washed with diluted aqueous sodium hydroxide and saturated aqueous sodium chloride, and dried over sodium sulfate. After ether is distilled off, the residue is purified by column chromatography (Kieselgel 60), followed by eluting with n-hexane-ether (4:1) to give 1-methyl-5-(3-cyclohexylthiopropyl)thio-1,2,3,4-tetrazole (1.5 g), colorless liquid, nD18 =1.5433.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:42][CH2:43][CH2:44][CH2:45][C:46]([O:48]CC)=[O:47]>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:40]=[CH:39][C:25]([O:26][C:27]2[CH:32]=[CH:31][C:30]([CH2:33][CH2:34][CH2:35][C:36]([NH:42][CH2:43][CH2:44][CH2:45][C:46]([OH:48])=[O:47])=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CCCN
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)O)cc2)cc1
Agent: Cl
Product: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(CCCC(=O)NCCCC(=O)O)cc2)cc1

Procedure:
The product from Example 100 and ethyl 4-aminobutyrate hydrochloride were processed as described in Example 104B to provide the title compound. 1H NMR (300 MHz, DMSO-d6) δ8.97 (s, 1 H), 7.80 (br.s, 1 H), 7.13-7.33 (m, 8 H), 7.01 (m, 4 H), 6.88 (m, 4 H), 3.94-4.16 (m, 4 H), 3.06 (m, 4 H), 2.91 (s, 3 H), 2.39 (s, 2 H), 2.20 (m, 2 H), 2.07 (m, 2 H), 1.79 (m, 2 H), 1.61 (m, 2 H); MS (APCI) m/z 644 (M+H+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:16][CH:15]=1)[CH2:6][CH2:5]2.[C:28]1(C)[CH:33]=CC=C[CH:29]=1.C([Sn](CCCC)(CCCC)CCCC)C=C>C(OCC)(=O)C.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:33]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH2:8][C@@H:7]([NH:12][C:13](=[O:27])[C:14]1[CH:15]=[CH:16][C:17]([O:20][CH2:21][C@@H:22]3[CH2:26][CH2:25][CH2:24][O:23]3)=[CH:18][CH:19]=1)[CH2:6][CH2:5]2)[CH:28]=[CH2:29]
Reactant: O=C(N[C@H]1CCc2cc(Br)ccc2C1)c1ccc(OC[C@@H]2CCCO2)cc1
Reactant: Cc1ccccc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: C=CC[Sn](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Product: C=CCc1ccc2c(c1)CC[C@H](NC(=O)c1ccc(OC[C@@H]3CCCO3)cc1)C2

Procedure:
A mixture of N-((S)-6-bromo-1,2,3,4-tetrahydronaphthalen-2-yl)-4-[(S)-1-(tetrahydrofuran-2-yl)methoxy]benzamide (1.00 g), toluene (10 ml), Pd(PPh3)4 (26.7 mg) and allyltributyltin (2.46 g) was boiled at reflux for 5 hours. The cooled reaction mixture was diluted with ethyl acetate and washed with water. The organic phase was washed with sodium chloride solution, dried over sodium sulfate and concentrated. The residue was purified by chromatography on silica gel. The product was thus obtained with the molecular weight of 391.51 (C25H29NO3); MS (ESI): 392 (M+H+).
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:21])([F:20])[F:19])C=1C(O)=O.CN(C)C=O>ClCCl>[CH3:7][O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]([F:19])([F:21])[F:20])[C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cccc(C(F)(F)F)c1C(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1cccc(C(F)(F)F)c1C(=O)Cl
Temperature: 25 °C

Procedure:
Oxalyl chloride (3 mL, 34.27 mmol) was added dropwise to a mixture of 2-methoxy-6-(trifluoromethyl)benzoic acid (1.5 g, 6.81 mmol) (prepared according to known method, see: EP0897904B1), N,N-dimethylformamide (0.3 mL), and dichloromethane (40 mL) with stirring at rt. The reaction mixture was stirred overnight. Evaporation of solvent and excess oxalyl chloride and drying under vacuum afforded 2-methoxy-6-(trifluoromethyl)benzoyl chloride as a solid, which was used without purification.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[C:7](Cl)=[O:8].[K+].[C:11]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:12]C([O-])=O.CCN(CC)CC.[Mg+2].[Cl-].[Cl-]>CC#N>[CH2:18]([O:17][C:11](=[O:16])[CH2:12][C:7]([C:3]1[S:4][CH:5]=[CH:6][C:2]=1[Cl:1])=[O:8])[CH3:19]
Reactant: CCOC(=O)CC(=O)[O-]
Reactant: O=C(Cl)c1sccc1Cl
Agent: [Cl-]
Agent: [K+]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1sccc1Cl

Procedure:
Prepared from 3-chloro-2-thiophenecarbonyl chloride [CAS-No. 86427-02-3] by reaction with ethyl malonate potassium salt with Et3N and MgCl2 in CH3CN according to general procedure H (method a). Obtained as a brown oil (6.84 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=3)[N:8]=2)=[C:4]([F:23])[CH:3]=1.[F:24][C:25]1[CH:30]=[CH:29][C:28]([CH2:31][C:32]([N:34]=[C:35]=[O:36])=[O:33])=[CH:27][CH:26]=1.COC1C=CC(CNC2N=CN=C(OC3C=CC(NC(NC(=O)CC4C=CC(F)=CC=4)=O)=CC=3F)C=2)=CC=1>C1COCC1>[F:23][C:4]1[CH:3]=[C:2]([NH:1][C:35]([NH:34][C:32](=[O:33])[CH2:31][C:28]2[CH:29]=[CH:30][C:25]([F:24])=[CH:26][CH:27]=2)=[O:36])[CH:22]=[CH:21][C:5]=1[O:6][C:7]1[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]2[CH:15]=[CH:16][C:17]([F:20])=[CH:18][CH:19]=2)[N:8]=1
Reactant: O=C=NC(=O)Cc1ccc(F)cc1
Reactant: Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Agent: COc1ccc(CNc2cc(Oc3ccc(NC(=O)NC(=O)Cc4ccc(F)cc4)cc3F)ncn2)cc1
Solvent: C1CCOC1
Product: O=C(Cc1ccc(F)cc1)NC(=O)Nc1ccc(Oc2ccnc(Nc3ccc(F)cc3)n2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 93 %

Procedure:
A solution of 4-(4-amino-2-fluorophenoxy)-N-(4-fluorophenyl)pyrimidin-2-amine (10 mg, 0.032 mmol) in THF (1 mL) was cooled in an ice bath and treated with a solution of 2-(4-fluorophenyl)acetyl isocyanate in toluene (Compound D of Example of 11, 228 μL, 0.064 mmol) and stirred at RT for 2 h. The reaction mixture was concentrated in vacuo and the residue triturated with isopropyl ether to give the title compound (15 mg, 93%) as a white solid. 1H NMR (DMSO-d6) δ 11.06 (s, 1H), 10.56 (s, 1H), 9.68 (s, 1H), 8.39 (d, 1H, J=5.7 Hz), 7.76 (dd, 1H, J=13.5, 2.1 Hz), 7.43 (br s, 2H), 7.46-7.35 (m, 6H), 7.18 (dd, 2H, J=8.8, 8.8 Hz), 6.57 (d, 1H, J=5.4 Hz), 3.76 (s, 2H); MS(ESI+) m/z 492.0 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:29]1([CH2:32]Br)[CH2:31][CH2:30]1>>[CH2:1]([O:8][C:9]1[CH:27]=[CH:26][C:25]([Br:28])=[CH:24][C:10]=1[CH2:11][N:12]([C:13]1[CH:18]=[CH:17][C:16]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:15][N:14]=1)[CH2:32][CH:29]1[CH2:31][CH2:30]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: BrCC1CC1
Reactant: CCOC(=O)c1ccc(NCc2cc(Br)ccc2OCc2ccccc2)nc1
Product: CCOC(=O)c1ccc(N(Cc2cc(Br)ccc2OCc2ccccc2)CC2CC2)nc1

Procedure:
Ethyl 2-[N-(2-benzyloxy-5-bromobenzyl)-N-(cyclopropyl-methyl)amino]pyridine-5-carboxylate was prepared from ethyl 2-[N-(2-benzyloxy-5-bromobenzyl)amino]pyridine-5-carboxylate and cyclopropylmethyl bromide by a similar method to that described in Reference example 5, purifying the product by MPLC and eluting with 80% dichloromethane in hexane.
Reaction SMILES: [CH2:1]=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2.[H][H]>CO.CCOC(C)=O.[Pd]>[CH3:1][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[C:7]([OH:12])=[CH:6][CH:5]=[CH:4][C:3]1=2
Reactant: [H][H]
Reactant: C=C1CCCc2c(O)cccc21
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC1CCCc2c(O)cccc21
Yield: 36 %

Procedure:
To a suspension of CH3PPh3I (897 mg, 2.22 mmol) in Et2O (10 mL) was added t-BuOK (249 mg, 2.22 mmol). The mixture was stirred for 15 minutes, to which was added dropwise 5-hydroxy-3,4-dihydro-2H-naphthalen-1-one (300 mg, 1.85 mmol). The mixture was stirred at room temperature overnight, diluted with diethylether, and then filtered through a celite pad. The filtrate was concentrated under reduced pressure. The crude residue was purified by short column chromatography and was concentrated under reduced pressure to give 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol. A mixture of 5-methylene-5,6,7,8-tetrahydro-naphthalen-1-ol and 10% Pd/C (40 mg) in methanol (10 ml) was hydrogenated under 50 psi hydrogen atmosphere for 1 hour. The mixture was dissolved in EtOAc, filtered through a celite pad. The filtrate was concentrated under reduced pressure, and dried to give 5-methyl-5,6,7,8-tetrahydro-naphthalen-1-ol (110 mg, 36%).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH2:28])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[C:29]1([CH2:35][CH2:36][C:37](Cl)=[O:38])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][NH:28][C:37](=[O:38])[CH2:36][CH2:35][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CN)cc3)cc2)CC1
Reactant: O=C(Cl)CCc1ccccc1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CNC(=O)CCc4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 3, Step 7, using 1-[4′-(4-aminomethyl-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 3-phenyl-propionyl chloride.
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: O=C(O)c1ccc(S(=O)(=O)NCC(F)(F)F)cc1
Reactant: Nc1ccc(Cl)c(-c2ccccn2)c1
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 μL 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)+.