Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B2OC(C)(C)C(C)(C)O2)[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][C:9]([F:12])([F:11])[F:10].Br[C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:13][C:6]1[CH:5]=[C:4]([C:24]([C:26]([F:29])([F:28])[F:27])=[CH2:25])[CH:3]=[C:2]([Cl:1])[C:7]=1[O:8][C:9]([F:10])([F:11])[F:12]
Reactant: CC1(C)OB(c2cc(Cl)c(OC(F)(F)F)c(Cl)c2)OC1(C)C
Reactant: C=C(Br)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: C=C(c1cc(Cl)c(OC(F)(F)F)c(Cl)c1)C(F)(F)F
Temperature: 80 °C
Yield: 71.4 %

Procedure:
A mixture of 2-(3,5-dichloro-4-(trifluoromethoxy)phenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (1.2 g, 3.36 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (647 mg, 3.70 mmol), K2CO3 (927 mg, 6.72 mmol) and Pd(PPh3)2Cl2 (47.2 mg, 0.067 mmol) in THF (10 mL) and H2O (6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (780 mg; 72% yield) as colorless oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:10])=[O:9].C(N(CC)CC)C.[C:19](Cl)([CH3:21])=[O:20]>C1COCC1>[C:19]([NH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[S:8]([NH2:11])(=[O:9])=[O:10])(=[O:20])[CH3:21]
Reactant: CC(=O)Cl
Reactant: Nc1ccccc1S(N)(=O)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1ccccc1S(N)(=O)=O
Temperature: 25 °C
Yield: 79.3 %

Procedure:
A stirred solution of 2-aminobenzenesulfonamide (1.72 g; 10 mmol) and triethylamine (1.53 ml; 11 mmol) in THF (25 ml) at 0° C. was added AcCl (0.85 ml; 12 mmol) and left with stirring at rt. over night. The reaction mixture was filtered and adsorbed onto silica. Column chromatography gave 1.7 g (79%) product. M.p. 153.5-155.5° C.
Reaction SMILES: [Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([CH3:9])[CH:3]=1.F[C:11]1[CH:12]=[N:13][CH:14]=[CH:15][C:16]=1[C:17]([OH:19])=[O:18].[Li+].C[Si]([N-][Si](C)(C)C)(C)C>C1COCC1>[Br:1][C:2]1[CH:8]=[CH:7][C:5]([NH:6][C:15]2[CH:14]=[N:13][CH:12]=[CH:11][C:16]=2[C:17]([OH:19])=[O:18])=[C:4]([CH3:9])[CH:3]=1
Reactant: O=C(O)c1ccncc1F
Reactant: Cc1cc(Br)ccc1N
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: Cc1cc(Br)ccc1Nc1cnccc1C(=O)O
Temperature: -78 °C
Yield: 70 %

Procedure:
4-Bromo-2-methylaniline (186 mg, 1.00 mmol) and 3-fluoropyridine-4-carboxylic acid (141 mg, 1.00 mmol) were dissolved in dry THF (6.0 ml) under argon and the mixture was cooled to −78° C. A solution of LiHMDS (1.0M in THF, 3.5 ml) was added and the reaction mixture was allowed to warm to ambient temperature. After 24 h the reaction was quenched by adding a solution of HCl in dioxane (4.0M, 2.0 ml). The volatiles were removed in vacuo and the crude material was purified by flash chromatography using silica gel and a gradient of 0-10% methanol in DCM as eluent to give 215 mg (701 μmol; 70% yield) of pure desired product.
Reaction SMILES: [I-:1].[Na+].F[B-](F)(F)F.[F:8][S:9]([F:21])([F:20])([F:19])([F:18])[C:10]1[CH:15]=[CH:14][C:13]([N+]#N)=[CH:12][CH:11]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][CH:28]=1>CC#N>[I:1][C:13]1[CH:14]=[CH:15][C:10]([S:9]([F:21])([F:20])([F:19])([F:18])[F:8])=[CH:11][CH:12]=1.[CH3:22][C:23]1[CH:24]=[CH:25][C:26]([CH3:29])=[CH:27][C:28]=1[C:13]1[CH:14]=[CH:15][C:10]([S:9]([F:21])([F:20])([F:19])([F:18])[F:8])=[CH:11][CH:12]=1
Reactant: [I-]
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Reactant: Cc1ccc(C)cc1
Agent: F[B-](F)(F)F
Agent: [Na+]
Solvent: CC#N
Product: Cc1ccc(C)c(-c2ccc(S(F)(F)(F)(F)F)cc2)c1
Product: FS(F)(F)(F)(F)c1ccc(I)cc1
Yield: 14 %
Yield: 14 %

Procedure:
Sodium iodide (5.5 mg, 0.037 mmol) was added portion-wise to a solution of 1 (9.9 mg, 0.031 mmol) and p-xylene (60.1 mg, 0.566 mmol) in CH3CN (0.11 g). The reaction mixture was filtered through Celite 545 using CH2Cl2. The solvent was evaporated to give a brown oil, which was purified by SiO2 column chromatography with hexane to afford 25b (1.4 mg, 14%) and 28b as a colorless oil (1.3 mg, 14%): MS (GC, EI): m/z=308 [M+], 181 [M+-SF5]. IR (ATR): {tilde over (v)}=2924, 1599, 1493, 1456, 1395, 1099, 833 cm−1. 1H NMR (500 MHz, CDCl3): δ=7.79 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.18 (d, J=8.3 Hz, 1H), 7.12 (d, J=8.3 Hz, 1H), 7.02 (s, 1H), 2.36 (s, 3H), 2.22 (s, 3H) ppm. 13C NMR (125 MHz, CDCl3): δ=155.0 (C), 145.6 (C), 139.5 (C), 132.0 (C), 130.5 (CH), 130.2 (CH), 129.4 (2CH), 128.8 (CH), 125.7 (2CH), 20.9 (CH3), 19.8 (CH3) ppm. 19F NMR (470 MHz, CDCl3): δ=84.9 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[NH:10][CH2:11][C:12]1[CH:13]=[N:14][CH:15]=[CH:16][CH:17]=1)([O-])=O.[H][H]>[Ni].CO>[N:14]1[CH:15]=[CH:16][CH:17]=[C:12]([CH2:11][NH:10][C:5]2[C:4]([NH2:1])=[CH:9][CH:8]=[CH:7][CH:6]=2)[CH:13]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1ccccc1NCc1cccnc1
Agent: [Ni]
Solvent: CO
Product: Nc1ccccc1NCc1cccnc1

Procedure:
A mixture of 33 parts of N-(2-nitrophenyl)-3-pyridine-methanamine and 480 parts of methanol is hydrogenated at normal pressure and at room temperature with 5 parts of Raney-nickel catalyst. After the calculated amount of hydrogen is taken up, the catalyst is filtered off and the filtrate is evaporated, yielding 33 parts of N-(3-pyridinylmethyl)-1,2-benzenediamine as a residue.
Reaction SMILES: [CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16][CH3:17])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(S(N2C(C3C=CC=CC=3)O2)(=O)=[O:27])C=CC=CC=1>ClCCl>[CH:1]1([N:6]2[C:11]3[N:12]=[C:13]([S:16]([CH3:17])=[O:27])[N:14]=[CH:15][C:10]=3[CH:9]=[C:8]([F:18])[C:7]2=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: CSc1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Solvent: ClCCl
Product: CS(=O)c1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.3 %

Procedure:
8-Cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one (10.5 g, 37.9 mmol) and 2-benzenesulfonyl-3-phenyl-oxaziridine (11.8 g, 45.4 mmol) were combined in dichloromethane (120 ml) and stirred at room temperature for 18 hours. The mixture was evaporated to an oil, crystallized from ethyl acetate/diethyl ether, filtered and dried in vacuo to provide 8-cyclopentyl-6-fluoro-2-methanesulfinyl-8H-pyrido[2,3-d]pyrimidin-7-one as a white solid (8.88 g, 79.6%).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Cl:11][S:12](O)(=[O:14])=[O:13]>C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([S:12]([Cl:11])(=[O:14])=[O:13])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: c1ccc2c(c1)OCCO2
Reactant: O=S(=O)(O)Cl
Solvent: ClC(Cl)Cl
Product: O=S(=O)(Cl)c1ccc2c(c1)OCCO2
Temperature: 0 °C

Procedure:
To a stirred solution of 12 g of 1,4-benzodioxane in 40 mL of chloroform cooled to -10° C. under calcium sulfate drying tube was added dropwise over 15 min, 6 mL of chlorosulfonic acid. The mixture was allowed to warm to 20C over 15 min, poured onto 400 mL of ice and extracted into 1 L of chloroform. Drying over MgSO4 and concentration under reduced pressure gave 21.5 g of 1,4-benzodioxane-6-sulfonylchloride as a white crystalline solid.
Reaction SMILES: [F:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([C:12]([OH:14])=O)=[CH:4][CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.[NH2:38][CH:39]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:59])[CH3:58])=[CH:52][CH:51]=1)[CH:40]([C:42]1[CH:47]=[CH:46][CH:45]=[C:44]([Cl:48])[CH:43]=1)[OH:41]>CN(C)C=O.C(OCC)(=O)C>[Cl:48][C:44]1[CH:43]=[C:42]([CH:40]([OH:41])[CH:39]([NH:38][C:12]([C:5]2[C:6]3[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=3)[C:2]([F:1])=[CH:3][CH:4]=2)=[O:14])[CH2:49][C:50]2[CH:55]=[CH:54][C:53]([C:56]([F:62])([F:61])[C:57]([CH3:60])([CH3:58])[CH3:59])=[CH:52][CH:51]=2)[CH:47]=[CH:46][CH:45]=1
Reactant: O=C(O)c1ccc(F)c2ccccc12
Reactant: CC(C)(C)C(F)(F)c1ccc(CC(N)C(O)c2cccc(Cl)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)C(F)(F)c1ccc(CC(NC(=O)c2ccc(F)c3ccccc23)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.1 %

Procedure:
To a solution of 4-fluoronaphthalene-1-carboxylic acid (216 mg, 1.15 mmol) in N,N-dimethylformamide (5 ml) were added 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (220 mg, 1.15 mmol) and 1-hydroxybenzotriazole monohydrate (176 mg, 1.15 mmol), and (1RS,2SR)-2-amino-1-(3-chlorophenyl)-3-[4-(1,1-difluoro-2,2-dimethylpropyl)phenyl]-1-propanol (0.40 g, 1.09 mmol) was finally added. The mixture was stirred overnight at room temperature. The mixture was diluted with ethyl acetate, washed with saturated aqueous sodium hydrogen carbonate solution, water and saturated brine, dried over anhydrous magnesium sulfate, and filtered using a glass filter filled with silica gel. The filtrate was washed with ethyl acetate and concentrated under reduced pressure. The residue was purified by recrystallization (hexane-ethyl acetate) to give N-{(1RS,2SR)-2-(3-chlorophenyl)-1-[4-(1,1-difluoro-2,2-dimethylpropyl)benzyl]-2-hydroxyethyl}-4-fluoro-1-naphthamide (289 mg, 49%) as colorless crystals.
Reaction SMILES: [Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[C:3]1[O:7][CH:6]=[CH:5][CH:4]=1.[CH3:27][C:28](C)([O-])C.[K+].[CH2:33]([O:40][C:41]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[C:58]([CH3:59])=[CH:57][C:56]([N+:60]([O-:62])=[O:61])=[C:55]3[C:51]=2[CH2:52][CH2:53][CH2:54]3)=[CH:45][C:42]=1C=O)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.Cl>O1CCCC1>[CH2:33]([O:40][C:41]1[CH:48]=[CH:47][C:46]([O:49][C:50]2[C:58]([CH3:59])=[CH:57][C:56]([N+:60]([O-:62])=[O:61])=[C:55]3[C:51]=2[CH2:52][CH2:53][CH2:54]3)=[CH:45][C:42]=1[CH:27]=[CH:28][C:5]1[CH:4]=[CH:3][O:7][CH:6]=1)[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: c1ccc([P+](Cc2ccco2)(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=O)c1)CCC2
Reactant: CC(C)(C)[O-]
Agent: Cl
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc([N+](=O)[O-])c2c(c1Oc1ccc(OCc3ccccc3)c(C=Cc3ccoc3)c1)CCC2
Reaction time: 0.25 h
Yield: 73.5 %

Procedure:
To a suspension of furfuryltriphenylphosphonium bromide (377 mg) in tetrahydrofuran (30 mL) was added potassium tert-butoxide (136 mg) at room temperature, and the mixture was stirred for 15 min. After adding 2-benzyloxy-5-(5-methyl-7-nitroindan-4-yloxy)benzaldehyde (377 mg), the mixture was stirred at room temperature for 6 hours. After adding dropwise diluted hydrochloric acid to make the mixture acidify fully, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate) to give the title compound (306 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4](Cl)=[O:5].Cl.[CH:16]([NH:19][OH:20])([CH3:18])[CH3:17].C(N(CC)CC)C>O1CCOCC1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Si:11]([CH3:14])([CH3:13])[CH3:12])[C:3]=1[C:4]([N:19]([OH:20])[CH:16]([CH3:18])[CH3:17])=[O:5]
Reactant: CC(C)NO
Reactant: C[Si](C)(C)c1cccc(Cl)c1C(=O)Cl
Agent: Cl
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)N(O)C(=O)c1c(Cl)cccc1[Si](C)(C)C

Procedure:
The title compound was prepared by reaction of the compound of Example b and the i-propylhydroxylamine hydrochloride in dioxane in the presence of two equivalents of triethylamine using the amination methods described above. m.p. 175-179° C.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17]([NH:19][CH:20]([CH3:22])[CH3:21])=[O:18].C(N(CC)CC)C.[Br:33][C:34]1[C:42]2[C:41]([N:43]3[CH2:48][CH2:47][NH:46][C@@H:45]([CH3:49])[CH2:44]3)=[N:40][CH:39]=[N:38][C:37]=2[N:36]([S:50]([C:53]2[CH:58]=[CH:57][CH:56]=[CH:55][CH:54]=2)(=[O:52])=[O:51])[CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.CO>[Br:33][C:34]1[C:42]2[C:41]([N:43]3[CH2:48][CH2:47][N:46]([C:5]([NH:13][C:14]4[CH:25]=[CH:24][CH:23]=[C:16]([C:17](=[O:18])[NH:19][CH:20]([CH3:22])[CH3:21])[CH:15]=4)=[O:11])[C@@H:45]([CH3:49])[CH2:44]3)=[N:40][CH:39]=[N:38][C:37]=2[N:36]([S:50]([C:53]2[CH:54]=[CH:55][CH:56]=[CH:57][CH:58]=2)(=[O:51])=[O:52])[CH:35]=1
Reactant: C[C@H]1CN(c2ncnc3c2c(Br)cn3S(=O)(=O)c2ccccc2)CCN1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)NC(=O)c1cccc(N)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)c1cccc(NC(=O)N2CCN(c3ncnc4c3c(Br)cn4S(=O)(=O)c3ccccc3)C[C@@H]2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 220 %

Procedure:
To a solution of triphosgene (15 mg, 0.05 mmol) in THF (1 ml) at 0° C. under N2 was added dropwise a solution of 3-amino-N-isopropylbenzamide (25 mg, 0.14 mmol) and triethylamine (43 μL, 0.3 mmol) in THF (1 ml). The mixture was stirred for 15 min at 0° C. and another 15 min at room temperature. The piperazine from step C (65 mg, 0.14 mmol) in THF (1 ml) was added, and the resulting mixture was stirred at room temperature overnight, then quenched with MeOH and K2CO3 (97 mg, 0.70 mmol) and filtered. The solution was concentrated under vacuum and purified by Prep-HPLC to give (S)-4-(5-bromo-7-(phenylsulfonyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)-N-(3-(isopropylcarbamoyl)phenyl)-2-methylpiperazine-1-carboxamide (70 mg, 0.11 mmol, 77%). MS (ES+) [M+H]+=641.
Reaction SMILES: [CH2:1](Cl)CCCCC.[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28]CCCCC(C)C)=[CH:20][O:19][N:18]=1>CN(C)C=O>[CH3:8][N:9]1[C:13]([N+:14]([O-:16])=[O:15])=[CH:12][N:11]=[C:10]1[C:17]1[C:21]([CH2:22][CH2:23][CH2:24][CH2:25][CH:26]([CH2:27][NH2:28])[CH3:1])=[CH:20][O:19][N:18]=1
Reactant: CC(C)CCCCNCCCCCCc1conc1-c1ncc([N+](=O)[O-])n1C
Reactant: CCCCCCCl
Solvent: CN(C)C=O
Product: CC(CN)CCCCc1conc1-c1ncc([N+](=O)[O-])n1C

Procedure:
The product prepared above is treated in a similar fashion with hexyl chloride in dimethylformamide for two hours. The recrystallized product is identified as 1-methyl-2-(5-methylhexylaminohexylisoxazol-3-yl)-5-nitroimidazole.
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([C:32](OC)=[O:33])[C:19]=2[C:36](OC)=[O:37])[CH:15]=[CH:14][N:13]=1.[BH4-].[Na+].CO.Cl>O1CCCC1.C(Cl)Cl>[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[C:12]1[CH:17]=[C:16]([C:18]2[C:27]3[C:22](=[CH:23][C:24]([O:30][CH3:31])=[C:25]([O:28][CH3:29])[CH:26]=3)[CH:21]=[C:20]([CH2:32][OH:33])[C:19]=2[CH2:36][OH:37])[CH:15]=[CH:14][N:13]=1
Reactant: COC(=O)c1cc2cc(OC)c(OC)cc2c(-c2ccnc(-n3c(=O)ccc4ccccc43)c2)c1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: C1CCOC1
Product: COc1cc2cc(CO)c(CO)c(-c3ccnc(-n4c(=O)ccc5ccccc54)c3)c2cc1OC
Temperature: 25 °C
Yield: 50.4 %

Procedure:
To a suspension of 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(methoxycarbonyl)-6,7-dimethoxynaphthalene (200 mg) in tetrahydrofuran is added sodium borohydride (36 mg), and the mixture is refluxed. To the mixture is added methanol (0.3 ml) under reflux over a period of one hour. The mixture is cooled to room temperature, and thereto is added sodium borohydride (36 mg). To the mixture is added methanol (0.3 ml) under reflux over a period of one hour. After the reaction is complete, methylene chloride and diluted hydrochloric acid are added to the mixture. The methylene chloride layer is separated, washed, dried and concentrated under reduced pressure to remove the solvent. The residue is purified by silica gel column chromatography (solvent; chloroform:methanol=20:1) to give 1-[2-(2-oxo-1,2-dihydroquinolin-1-yl)-4-pyridyl]-2,3-bis(hydroxymethyl)-6,7-dimethoxynaphthalene (90 mg), which is listed in Table 6.
Reaction SMILES: C(N)[C@@H]1OCCC1.[N+:8]([C:11]1[CH:24]=[CH:23][C:14]([CH2:15][NH:16][CH2:17][C@H:18]2[CH2:22][CH2:21][CH2:20][O:19]2)=[CH:13][CH:12]=1)([O-])=O>C(OCC)(=O)C.[Rh]>[O:19]1[CH2:20][CH2:21][CH2:22][C@@H:18]1[CH2:17][NH:16][CH2:15][C:14]1[CH:13]=[CH:12][C:11]([NH2:8])=[CH:24][CH:23]=1
Reactant: O=[N+]([O-])c1ccc(CNC[C@H]2CCCO2)cc1
Agent: [Rh]
Agent: NC[C@H]1CCCO1
Solvent: CCOC(C)=O
Product: Nc1ccc(CNC[C@H]2CCCO2)cc1
Reaction time: 2 h

Procedure:
Using the procedure of Example 1, (R)-(−)-tetrahydrofurfurylamine Compound 40a was used in place of piperidine to prepare (4-nitro-benzyl)-[(2R)-tetrahydro-furan-2-ylmethyl]-amine Compound 40b. 5% Rh/C (1.5 g) was added to a solution of Compound 40b (5.95 g, 25.2 mmol) in ethyl acetate (40 mL). The mixture was hydrogenated at 40 psi for a period of 2 hrs, then filtered through Celite. The filtrate was evaporated in vacuo to provide 4-({[(2R)-tetrahydro-furan-2-ylmethyl]-amino}-methyl)-phenylamine Compound 40c. MS 207 (MH+). Using the procedure of Example 1, Compound 40c was used in place of 4-piperidin-1-ylmethyl-phenylamine Compound 1k to provide Compound 17. MS 553, 555 (MH+).
Reaction SMILES: C([N:8]([CH3:40])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:28][C:29]2[CH:30]=[C:31](B(O)O)[CH:32]=[CH:33][C:34]=2[O:35][CH3:36])[C:16]([C:18]2[S:22][C:21]3[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=3[C:19]=2[Cl:27])=[O:17])[CH2:11][CH2:10]1)(OC(C)(C)C)=O.Br[C:42]1[CH:43]=[CH:44][C:45]([NH:48][CH3:49])=[N:46][CH:47]=1>>[ClH:27].[ClH:27].[CH3:36][O:35][C:34]1[CH:33]=[CH:32][C:31]([C:42]2[CH:47]=[N:46][C:45]([NH:48][CH3:49])=[CH:44][CH:43]=2)=[CH:30][C:29]=1[CH2:28][N:15]([CH:12]1[CH2:13][CH2:14][CH:9]([NH:8][CH3:40])[CH2:10][CH2:11]1)[C:16]([C:18]1[S:22][C:21]2[CH:23]=[CH:24][CH:25]=[CH:26][C:20]=2[C:19]=1[Cl:27])=[O:17]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2ccccc2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CNc1ccc(Br)cn1
Product: CNc1ccc(-c2ccc(OC)c(CN(C(=O)c3sc4ccccc4c3Cl)C3CCC(NC)CC3)c2)cn1
Product: Cl

Procedure:
The title compound was prepared from boronic acid (5) (25 mg, 43 μmol) and 5-bromo-2-methylaminopyridine (6.6 mg, 41 μmol) in accordance with Method L2.
Reaction SMILES: [F:1][C:2]1[CH:43]=[CH:42][CH:41]=[C:40]([F:44])[C:3]=1[C:4]([N:6]1[CH2:11][CH2:10][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[N:23]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[N:24]=[C:25]([C:27]([CH3:31])([CH3:30])[CH2:28][F:29])[CH:26]=3)=[O:20])=[CH:14][C:13]=2[CH3:39])[CH2:8][CH2:7]1)=[O:5].F[C:46](F)(F)[S:47]([OH:50])(=[O:49])=[O:48]>C(Cl)Cl>[CH3:46][S:47]([OH:50])(=[O:49])=[O:48].[F:44][C:40]1[CH:41]=[CH:42][CH:43]=[C:2]([F:1])[C:3]=1[C:4]([N:6]1[CH2:7][CH2:8][N:9]([C:12]2[N:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]3[N:23]([C:32]4[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=4)[N:24]=[C:25]([C:27]([CH3:30])([CH3:31])[CH2:28][F:29])[CH:26]=3)=[O:20])=[CH:14][C:13]=2[CH3:39])[CH2:10][CH2:11]1)=[O:5]
Reactant: O=S(=O)(O)C(F)(F)F
Agent: Cc1ccc(-n2nc(C(C)(C)CF)cc2NC(=O)Nc2cnc(N3CCN(C(=O)c4c(F)cccc4F)CC3)c(C)c2)cc1
Solvent: ClCCl
Product: CS(=O)(=O)O
Reaction time: 0.5 h

Procedure:
Dissolve 50 mg (0.083 mmol) of the free base 1-{6-[4-(2,6-difluoro-benzoyl)-piperazin-1-yl]-5-methyl-pyridin-3-yl}-3-[5-(2-fluoro-1,1-dimethyl-ethyl)-2-p-tolyl-2H-pyrazol-3-yl]-urea in DCM (0.5 mL). Add 1 equiv of trifluoromethanesulfonic acid in DCM (1 N). After 30 min, remove solvent to afford a white solid. After several washings with ether/DCM, dry the solid under reduced pressure to obtain 55 mg of the title compound (95% yield). ES+(m/z):606 [M+1].
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1.[C:27]1([O:33][C:34](Cl)=[O:35])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>ClCCl.CCOCC>[O:33]([C:34]([N:8]1[CH2:13][CH2:12][C:11]([C:25]#[CH:26])([O:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[N+:22]([O-:24])=[O:23])[CH2:10][CH2:9]1)=[O:35])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C)CC1
Reactant: O=C(Cl)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOCC
Product: C#CC1(Oc2ccc(F)cc2[N+](=O)[O-])CCN(C(=O)Oc2ccccc2)CC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.1 %

Procedure:
To a stirred suspension of 5.01 g of potassium carbonate, 50 ml of dichloromethane (dried over anhydrous magnesium sulfate) and 10.1 g of 1-N-methyl-4-ethynyl-4-(4-fluoro-2-nitrophenoxy)piperidine was added dropwise a solution of 5.66 g of phenylchloroformate in 50 ml of dichloromethane (dried over anhydrous magnesium sulfate). The mixture was stirred 12 hr at ambient temperature and 6 hr at reflux under nitrogen. The suspension was poured into ice, extracted with dichloromethane, washed with 15% sodium hydroxide solution, 1N hydrochloric acid and saturated sodium chloride solution. The dichloromethane solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dissolved in ether, washed with water, 1N hydrochloric acid and saturated sodium chloride solution. The solution was dried over anhydrous sodium sulfate, filtered and the solvent evaporated to provide an oil. The oil was dried overnight at room temperature (1 mm) during which time it crystallized to provide 10.3 g (73.8%) of product. Recrystallization from cyclohexane/ethyl acetate provided the analytical sample, mp 82°-83°.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:26](O)=[O:27])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@H:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1.[NH:29]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]([NH2:36])[CH2:30]1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>>[NH2:1][C:2]1[C:3]([C:26]([NH:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][NH:29][CH2:30]2)=[O:27])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([NH:16][C@@H:17]3[C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH2:19][CH2:18]3)=[O:15])[CH:9]=2)=[CH:6][N:7]=1
Reactant: Nc1ncc(-c2cccc(C(=O)N[C@@H]3CCc4ccccc43)c2)nc1C(=O)O
Reactant: NC1CCCCNC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Product: Nc1ncc(-c2cccc(C(=O)N[C@H]3CCc4ccccc43)c2)nc1C(=O)NC1CCCCNC1
Reaction time: 2 h
Yield: 4.3 %

Procedure:
To a solution of 3-amino-6-(3-{[(1R)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}phenyl)pyrazine-2-carboxylic acid (409 mg, 1.09 mmol) were added azepan-3-amine (125 mg, 1.09 mmol), EDCI (252 mg, 1.31 mmol), HOBt (178 mg, 1.31 mmol) at ambient temperature. After being stirred for 2 h, the reaction mixture was quenched by addition of aqueous sodium bicarbonate followed by extraction with ethyl acetate (20 mL×3). The aqueous phase was extracted once with additional ethyl acetate. The combined organic layers were washed with saturated aqueous sodium chloride then dried over anhydrous magnesium sulfate. Filtration and concentration in vacuo gave a crude oil, which was purified by preparative HPLC to yield the 3-amino-N-azepan-3-yl-6-(3-{[(1S)-2,3-dihydro-1H-inden-1-ylamino]carbonyl}phenyl)pyrazine-2-carboxamide (22 mg, 4.2% yield): 1H NMR (400 MHz, CD3OD): δ 8.70 (m, 1H), 8.67 (m, 1H), 8.27 (m, 1H) 7.97 (m, 1H), 7.62 (t, 1H), 7.25 (m, 4H), 5.70 (m, 1H), 4.99 (m, 1H), 4.43 (m, 1H), 3.46 (m, 2H), 3.38 (m, 1H), 3.15 (m, 2H), 2.94 (m, 1H), 2.61 (m, 1H), 2.17 (m, 2H), 1.95 (m, 4H), 1.62 (m, 1H); MS (EI) for C27H30N6O2: 471.32 (MH+).