Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16](=[O:29])[C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:18]=2[CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.[OH-].[K+].O>CCO>[CH3:23][C:19]1[C:18]([CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])=[C:17]([CH:22]=[CH:21][CH:20]=1)[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:29]
Reactant: CCCCCc1c(C)cccc1C(=O)NC1(C(=O)OCC)Cc2ccccc2C1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCCCCc1c(C)cccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 101.4 %

Procedure:
The mixture of 2-(3-methyl-2-pentyl-benzoylamino)-indan-2-carboxylic acid ethyl ester (126) (68 mg, 0.17 mmol) and KOH (500 mg, 8.9 mmol) is dissolved in EtOH (8 mL) and water (0.5 mL) under a water bath. The water bath is removed when KOH is completely dissolved and the resulting reaction solution is stirred at RT for 8 h. After concentration in vacuo, the residue is dissolved in water (20 mL) and acidified with conc. HCl until no more white precipitate came out of the water. The precipitate is filtered to give a pure product (127) as a pale brown solid (63 mg, 100%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[CH3:17][S:18](Cl)(=[O:20])=[O:19]>N1C=CC=CC=1>[CH3:17][S:18]([NH:1][C:2]1[CH:3]=[C:4]([O:15][CH3:16])[CH:5]=[CH:6][C:7]=1[NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:20])=[O:19]
Reactant: COc1ccc(Nc2ccccc2)c(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc(Nc2ccccc2)c(NS(C)(=O)=O)c1
Reaction time: 2 h
Yield: 81.9 %

Procedure:
21.4 g of 3-amino-4-phenylaminoanisole was dissolved in 210 ml of pyridine. The solution was then ice-cooled. Thereto was dropwise added 12 g of methanesulfonyl chloride in 30 minutes. Stirring was conducted for 2 hours at 5°-10° C. The mixture was subjected to distillation under reduced pressure to remove the solvent. To the residue were added 500 ml of water and 300 ml of ethyl acetate. The resulting mixture was adjusted to pH 4 with 4N hydrochloric acid. The organic layer was separated, washed with water and a saturated aqueous sodium chloride solution in this order, and dried with anhydrous magnesium sulfate. The organic layer was then subjected to distillation under reduced pressure to remove the solvent. Toluene was added to the residue, and the resulting crystal was filtered to obtain 23.9 g (yield: 81.8%) of 3-methylsulfonylamino-4-phenylaminoanisole having a melting point of 109°-111° C.
Reaction SMILES: N#N.O[CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1.CCN(CC)CC.S([Cl:24])(C)(=O)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:24][CH2:4][C:5]1[O:9][C:8]([C:10](=[O:12])[CH3:11])=[CH:7][CH:6]=1
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(CO)o1
Agent: CN(C)c1ccncc1
Agent: N#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)c1ccc(CCl)o1
Temperature: 25 °C
Reaction time: 3 h
Yield: 173.7 %

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of 1-(5-hydroxymethyl-furan-2-yl)-ethanone (2.00 g, 14.27 mmol) in dry CH2Cl2 (29 mL) was treated at 0° C. with Et3N (2.58 mL, 18.55 mmol) followed by DMAP (178 mg, 1.43 mmol) and Ms-Cl (1.33 mL, 17.13 mmol). After stirring at rt for 3 h, the reaction was quenched with water. The layers were separated and the aq. layer extracted with CH2Cl2 (3×) The org. layer was dried over MgSO4, filtered, and the solvents were removed under reduced pressure to give 3.93 g (quant.) of crude 1-(5-chloromethyl-furan-2-yl)-ethanone as a brown oil. Part of this crude material (1.718 g, 10.83 mmol) in DMF (10.3 mL) was added to a solution of 4-nitro-2H-[1,2,3]triazole (10.30 g of a 10% solution in acetone, 9.03 mmol) in DMF (10.3 mL) pre-treated for 30 min with DIPEA (3.09 mL, 18.06 mmol) and the reaction mixture was stirred overnight at 50° C. Water (32 mL), followed by EA (65 mL) were added. The aq. layer was extracted with EA (65 mL) and the combined org. extracts were dried over Na2SO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (2:1 hept-EA) gave the title compound as a yellow solid: TLC:rf (2:1 hept-EA)=0.20. LC-MS-conditions 02: tR=0.85 min, [M+H]+=237.46.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]1[C:12]2[C:17]([CH:18]=[C:19]3[C:24]=1[CH:23]=[CH:22][CH:21]=[CH:20]3)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Br:25]N1C(=O)CCC1=O.O>CN(C)C=O>[Br:25][C:18]1[C:19]2[C:24]([C:11]([C:2]3[CH:3]=[CH:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[CH:1]=3)=[C:12]3[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]3)=[CH:23][CH:22]=[CH:21][CH:20]=2
Reactant: c1ccc2cc(-c3c4ccccc4cc4ccccc34)ccc2c1
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: Brc1c2ccccc2c(-c2ccc3ccccc3c2)c2ccccc12
Temperature: 25 °C
Reaction time: 7 h
Yield: 99 %

Procedure:
23.1 g of 9-(naphthalene-2-yl)anthracene was dispersed into 250 ml of DMF (dimethylformamide), and then 14.9 g of NBS (N-bromosuccinimide) in DMF solution (150 ml) was dropped therein. After stirred at room temperature for 7 hours, it was left over a night. 200 ml of water was added thereto, and then the crystal precipitated was separated by filtration. Subsequently it was washed by ethanol adequately, followed by drying, and 28.8 g of 9-bromo-10-(naphthalene-2-yl)anthracene of beige color crystal was obtained (Yield: 99%).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:39][C:40]1[N:41]=[C:42]([CH3:45])[S:43][CH:44]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([CH2:39][C:40]2[N:41]=[C:42]([CH3:45])[S:43][CH:44]=2)[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: Cc1nc(CCl)cs1
Agent: Cl
Product: Cc1nc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)cccc43)c3ccc(C(C)C)nc3)cn2)cs1
Yield: 76.8 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.83 g) and 4-(chloromethyl)-2-methylthiazole (0.55 g) as starting materials, 5-benzyloxy-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.73 g) was obtained. By the reaction and treatment of this compound in the same manner as in Example 139, 5-hydroxy-N-(6-isopropylpyridin-3-yl)-N-({1-[(2-methylthiazol-4-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.62 g) was obtained.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][CH3:5].[Cl:6][C:7]1[CH:8]=[CH:9][C:10]([F:37])=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([CH2:19][N:20]([CH2:31][C@@H:32]([OH:36])[C:33]([OH:35])=[O:34])[NH:21][C:22]([C:24]3[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=3)=[O:23])=[CH:15][CH:14]=2)[CH:12]=1.CCN(C(C)C)C(C)C.CC(C)=O.[Na+].[I-]>>[CH3:5][O:4][CH2:3][CH2:2][O:35][C:33](=[O:34])[C@H:32]([OH:36])[CH2:31][N:20]([CH2:19][C:16]1[CH:15]=[CH:14][C:13]([C:11]2[CH:12]=[C:7]([Cl:6])[CH:8]=[CH:9][C:10]=2[F:37])=[CH:18][CH:17]=1)[NH:21][C:22]([C:24]1[O:28][N:27]=[C:26]([O:29][CH3:30])[CH:25]=1)=[O:23]
Reactant: COCCBr
Reactant: COc1cc(C(=O)NN(Cc2ccc(-c3cc(Cl)ccc3F)cc2)C[C@@H](O)C(=O)O)on1
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCOC(=O)[C@H](O)CN(Cc1ccc(-c2cc(Cl)ccc2F)cc1)NC(=O)c1cc(OC)no1
Temperature: 60 °C
Reaction time: 2 h
Yield: 11.6 %

Procedure:
1-Bromo-2-methoxyethane (12.2 μL, 129 μmol) was added to a mixture of (R)-3-[N-(5′-chloro-2′-fluorobiphenyl-4-ylmethyl)-N′-(3-methoxyisoxazole-5-carbonyl)hydrazino]-2-hydroxypropionic acid (20.0 mg, 43 μmol) and DIPEA (45.1 μL, 259 μmol) in acetone (1.0 mL, 14 mmol). The resulting mixture was heated at 60° C. for 4 hours. NaI (19.4 mg, 129 μmol) was added and the reaction was monitored for 2 hours. Additional 1-bromo-2-methoxyethane (3 eq.), DIEA (4 eq.), and NaI (3 eq.) were added and the heating continued overnight. Additional 1-bromo-2-methoxyethane (3 eq.), NaI (3 eq.), and DIEA (3 eq.) were added and heating continued overnight. The mixture was then concentrated, and the residue was dissolved in AcOH (1.5 mL), filtered and purified by reverse phase preparative HPLC to yield the title compound (2.6 mg, purity 99%). MS m/z [M+H]+ calc'd for C24H25ClFN3O7, 522.14. found 522.4.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][O:16][CH3:17])[N:9]=[CH:8][N:7]=[C:6]2[O:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37](=O)[O:38]C3C=CC=CC=3)[O:33][N:32]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1.C(N(CC)C(C)C)(C)C>>[CH:26]1([C:31]2[CH:35]=[C:34]([NH:36][C:37]([NH:22][C:21]3[CH:23]=[CH:24][CH:25]=[C:19]([O:18][C:6]4[C:5]5[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][O:16][CH3:17])=[C:3]([O:2][CH3:1])[CH:4]=5)[N:9]=[CH:8][N:7]=4)[CH:20]=3)=[O:38])[O:33][N:32]=2)[CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: COCCOc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: O=C(Nc1cc(C2CCCC2)no1)Oc1ccccc1
Solvent: CCN(C(C)C)C(C)C
Product: COCCOc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C5CCCC5)no4)c3)c2cc1OC
Yield: 28 %

Procedure:
The title compound was prepared as described in Example 113C by using 3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)aniline from Example 117B (104 mg, 0.35 mmol), phenyl 3-cyclopentylisoxazol-5-ylcarbamate described in Example 163A (124 mg, 0.45 mmol) and N,N-diisopropylethylamine (73 μl, 0.42 mmol) to give 1-(3-cyclopentylisoxazol-5-yl)-3-(3-(6-methoxy-7-(2-methoxyethoxy)quinazolin-4-yloxy)phenyl)urea (51.72 mg, 28%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.05 (s, 1H), 8.56 (s, 1H), 7.57 (s, 2H), 7.50-7.35 (m, 2H), 7.30 (d, 1H), 7.00 (d, 1H), 5.95 (s, 1H), 4.34 (bs, 2H), 3.99 (s, 3H), 3.77 (bs, 2H), 3.34 (s, 3H), 3.11-2.99 (m, 1H), 2.10-1.80 (m, 2H), 1.75-1.50 (m, 6H); LC-MS (ESI) m/z 520 (M+H)+.
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1.[OH-].[Na+].Cl>O.O1CCOCC1>[CH2:5]([O:4][C:2]([N:12]1[CH2:17][CH2:16][CH:15]([OH:18])[CH2:14][CH2:13]1)=[O:3])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: OC1CCNCC1
Reactant: O=C(Cl)OCc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(OCc1ccccc1)N1CCC(O)CC1

Procedure:
Benzyl chloroformate (8.55 mL; 60 mmol) was added drop wise over a period of 30 min to a well stirred chilled mixture of piperidin-4-ol (5 g; 49.44 mmol), 1N aqueous NaOH (60 mL; 60 mmol) and dioxane (60 mL). The mixture was stirred for 30 min. at room temperature, treated with water, acidified with conc. HCl to pH 2 and extracted with EtOAc. The EtOAc layer was washed with water, brine, dried (Na2SO4), concentrated and purified using flash chromatography (silica gel, 50% CH2Cl2 in PE 60-80° C., 10% CH3CN+2% MeOH in chloroform). Yield, 12.5 g (99%), oil; MS (CI): 236 (M++1). 218, 192, 174, 91.
Reaction SMILES: NC1C([N+]([O-])=O)=C(N2CCN(CC(NC3SC=CN=3)=O)CC2)C(Cl)=CN=1.[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32](Cl)[C:31]([Cl:38])=[CH:30][N:29]=1.[CH3:39][O:40][C:41]1[CH:46]=[CH:45][C:44]([C:47]([N:49]2[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]2)=[O:48])=[CH:43][CH:42]=1>C(O)(C)C>[NH2:27][C:28]1[C:33]([N+:34]([O-:36])=[O:35])=[C:32]([N:52]2[CH2:51][CH2:50][N:49]([C:47]([C:44]3[CH:45]=[CH:46][C:41]([O:40][CH3:39])=[CH:42][CH:43]=3)=[O:48])[CH2:54][CH2:53]2)[C:31]([Cl:38])=[CH:30][N:29]=1
Reactant: Nc1ncc(Cl)c(Cl)c1[N+](=O)[O-]
Reactant: COc1ccc(C(=O)N2CCNCC2)cc1
Agent: Nc1ncc(Cl)c(N2CCN(CC(=O)Nc3nccs3)CC2)c1[N+](=O)[O-]
Solvent: CC(C)O
Product: COc1ccc(C(=O)N2CCN(c3c(Cl)cnc(N)c3[N+](=O)[O-])CC2)cc1
Yield: 60.6 %

Procedure:
The method followed that used to prepare 2-[4-(2-amino-5-chloro-3-nitro-pyridin-4-yl)-piperazin-1-yl]-N-thiazol-2-yl-acetamide (Example 1, step 5), but using 2-amino-4,5-dichloro-3-nitropyridine (0.034 g, 0.16 mmol), isopropanol (3.0 ml), and (4-methoxyphenyl)(piperazin-1-yl)methanone (0.055 g, 0.25 mmol). Purification of the crude product on an isolute silica column using a gradient of ethyl acetate in dichloromethane as eluant (10 to 30%) afforded the title compound as a yellow solid (0.038 g, 61%). 1H-NMR (500 Mz, DMSO-d6) 3.13 (br s, 4H, piperazine N(CH2)2), 3.65 (br s, 4H, piperazine N(CH2)2), 3.86 (s, 3H, OCH3), 7.06 (d, J=8.27 Hz, 2H) and 7.47 (d, J=8.21 Hz, 2H) (2,6-C6H4—OMe and 3,5-C6H4—OMe), 7.14 (s, 2H, 2-NH2), 8.19 (s, 1H, 6-H);
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.Cl>C1(C)C=CC=CC=1>[C:16]1([NH:15][C:4](=[O:6])[C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1ccccc1Cl
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O=S(Cl)Cl
Product: O=C(Nc1ccccc1)c1ccccc1Cl
Temperature: 25 °C
Yield: 93 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 31.3 g (0.2 mol) of 2-chlorobenzoic acid and 180 g of toluene are placed. To the above mixture in the flask, 25.0 g (0.21 mol) of thionyl chloride is added dropwise over 30 minutes while stirring at a temperature of from 60° to 65° C. to be allowed to react with each other for about 30 minutes. To the above reaction mixture, a solution containing 27.9 g (0.3 mol) of aniline dissolved in 100 g of toluene is dropwise added to be allowed to react with each other at a temperature of from 70° to 75° C. for 30 minutes. After completion of the reaction, the reaction mixture is cooled to room temperature, and 70 g of a 5% by weight hydrochloric acid solution is added to the above mixture. The mixture is vigorously shaken and kept standing for separation of the toluene layer from the aqueous layer. After separation of the toluene layer, it is condensed to precipitate white crystals, followed by recrystallization (in a water/methanol mixture of 3/7), to give 43.1 g of N-phenyl-2-chlorobenzamide (melting point: 116° to 117° C.). The yield of the product against 2-chlorobenzoic acid is 93%.
Reaction SMILES: [CH3:1][O-:2].[Na+].Cl[C:5]1[CH:14]=[C:13]([Cl:15])[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=1.O>C1COCC1>[Cl:15][C:13]1[C:12]2[C:7](=[N:8][C:9]([C:16]3[C:21]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:19]=[CH:18][N:17]=3)=[CH:10][CH:11]=2)[N:6]=[C:5]([O:2][CH3:1])[CH:14]=1
Reactant: FC(F)(F)c1cccnc1-c1ccc2c(Cl)cc(Cl)nc2n1
Reactant: C[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COc1cc(Cl)c2ccc(-c3ncccc3C(F)(F)F)nc2n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Add sodium methoxide (4M, 1.0 mL, 4.0 mmol) to a solution of 2,4-dichloro-7-(3-trifluoromethyl-pyridin-2-yl)-[1,8]naphthyridine (1.2 g, 3.5 mmol) in THF (30 mL). Stir at room temperature overnight, add water (25 mL) and extract with ethyl acetate. Wash the combined organic extracts with brine, dry (MgSO4) and evaporate. Purify the residue by flash chromatography (elute with 1:2 hexane:ether) to give the title compound.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][N:17]2[C:22]3[CH:23]=[C:24]([O:27][CH3:28])[CH:25]=[CH:26][C:21]=3[O:20][CH2:19][C:18]2=[O:29])[CH2:11][CH2:10]1.[O:30]=[C:31]1[CH2:36][S:35][C:34]2[CH:37]=[CH:38][C:39]([CH:41]=O)=[N:40][C:33]=2[NH:32]1.C([BH3-])#N.[Na+]>>[CH3:28][O:27][C:24]1[CH:25]=[CH:26][C:21]2[O:20][CH2:19][C:18](=[O:29])[N:17]([CH2:16][CH2:15][N:12]3[CH2:11][CH2:10][CH:9]([NH:8][CH2:41][C:39]4[CH:38]=[CH:37][C:34]5[S:35][CH2:36][C:31](=[O:30])[NH:32][C:33]=5[N:40]=4)[CH2:14][CH2:13]3)[C:22]=2[CH:23]=1
Reactant: O=Cc1ccc2c(n1)NC(=O)CS2
Reactant: COc1ccc2c(c1)N(CCN1CCC(N)CC1)C(=O)CO2
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc2c(c1)N(CCN1CCC(NCc3ccc4c(n3)NC(=O)CS4)CC1)C(=O)CO2
Yield: 29 %

Procedure:
4-[2-(4-aminopiperidin-1-yl)ethyl]-6-methoxy-2H-1,4-benzoxazin-3(4H)-one (Intermediate 46) (0.2 mmol), 3-oxo-3,4-dihydro-2H-pyrido[3,2-b][1,4]thiazine-6-carbaldehyde (WO 2004/058144) (42 mg, 0.22 mmol) and sodium cyanoborohydride (23 mg, 0.36 mmol) were reacted as described under Example 21 to give 28 mg (32%) of product as a dry film.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([OH:32])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:34][C:35]#[N:36].C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C)=O>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([C:17]2[O:18][C:19]([C:22]3[CH:23]=[C:24]4[C:29](=[CH:30][CH:31]=3)[CH:28]=[C:27]([O:32][CH2:34][C:35]#[N:36])[CH:26]=[CH:25]4)=[CH:20][N:21]=2)=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#CCBr
Reactant: Oc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(C)=O
Product: N#CCOc1ccc2cc(-c3cnc(-c4cn(Cc5ccccc5)c5ccccc45)o3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.8 %

Procedure:
A mixture of 6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthol (137 mg, 0.329 mmol), prepared in step 4 of Example 5, bromoacetonitrile (28 μL, 0.402 mmol) and cesium carbonate (213 mg, 0.402 mmol) in 20 mL of acetone was stirred under nitrogen at room temperature for 20 h (overnight). The acetone was removed under reduced pressure and the residue partitioned between methylene chloride and water. The organic layer was separated and the aqueous layer extracted two times with methylene chloride. The combined extracts were dried (MgSO4), filtered and the solvent removed under reduced pressure to give ({6-[2-(1-benzyl-1H-indol-3-yl)-1,3-oxazol-5-yl]-2-naphthyl}oxy)acetonitrile (142 mg, 95%) as a tan solid, mp 205-208° C. Elemental Analysis for C30H21N3O2+0.38 mole of CH2Cl2 Calc'd: C, 74.86; H, 4.50; N, 8.62. Found: C, 73.58; H, 4.74; N, 8.32.
Reaction SMILES: [C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([O:13]CC)=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2].[OH-].[Na+]>CO.C1COCC1>[C:1]([C:3]1[C:4]([CH3:16])=[CH:5][C:6]([C:11]([OH:13])=[O:12])=[N:7][C:8]=1[O:9][CH3:10])#[N:2]
Reactant: CCOC(=O)c1cc(C)c(C#N)c(OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1nc(C(=O)O)cc(C)c1C#N
Temperature: 60 °C
Reaction time: 2 h
Yield: 87 %

Procedure:
To a stirred solution of ethyl 5-cyano-6-methoxy-4-methylpicolinate (1.0 g, 4.54 mmol) in MeOH (30 mL) and THF (10 mL) was added 6N NaOH (2 mL, 12.00 mmol). The suspension was heated to 60° C. and stirred for 2 hr. (The reaction cleared up right away.) LCMS indicated that the reaction was complete. The reaction was cooled to RT and concentrated to near dryness. The slurry was neutralized with 6N HCl (2 mL) diluted with water, filtered, washed with water and dried under vacuum to give the product 5-cyano-6-methoxy-4-methylpicolinic acid (0.76 g, 3.95 mmol, 87% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ13.65 (br. s., 1H), 7.73 (s, 1H), 4.03 (s, 3H), 2.54 (s, 3H). MS(ES)+ m/e 192.9 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.C(Cl)CCl.[C:16]1([NH2:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([NH:22][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:11])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1ccc(Br)cc1
Reactant: Nc1ccccc1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: O=C(Cc1ccc(Br)cc1)Nc1ccccc1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 69 %

Procedure:
A mixture of 4-Bromophenylacetic acid (1.5 g, 7.0 mmol, 1 eq.), EDC (2.67 g, 14.0 mmol, 2 eq.), DMAP (846 mg, 7.0 mmol, 1 eq.), and phenylamine (0.765 mL, 8.4 mmol, 1.2 eq.) in 15 mL of DMF was stirred under nitrogen at room temperature for 3.5 hrs. After aqueous workup and recrystallization, 2-(4-Bromophenyl)-N-phenyl-acetamide was obtained in 69% yield (1.4 g). 1H NMR (400 MHz, DMSO-D6) δ ppm 3.6 (s, 2 H) 7.0 (m, 1 H) 7.3 (m, 4 H) 7.5 (m, 2 H) 7.6 (dd, J=8.7, 1.1 Hz, 2 H) 10.2 (s, 1 H).
Reaction SMILES: [NH2:1][OH:2].[C:3]([C:5]1[CH:21]=[CH:20][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:7][CH:6]=1)#[N:4]>CCO.O>[NH2:4][C:3](=[N:1][OH:2])[C:5]1[CH:6]=[CH:7][C:8]([CH2:9][N:10]([CH3:19])[CH2:11][C:12]([O:14][C:15]([CH3:16])([CH3:17])[CH3:18])=[O:13])=[CH:20][CH:21]=1
Reactant: NO
Reactant: CN(CC(=O)OC(C)(C)C)Cc1ccc(C#N)cc1
Solvent: O
Solvent: CCO
Product: CN(CC(=O)OC(C)(C)C)Cc1ccc(C(N)=NO)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95 %

Procedure:
A 50% aqueous solution of hydroxylamine (13.25 mL, 225 mmol) was added at once into a solution of tert-butyl N-(4-cyanobenzyl)-N-methylglycinate (11.70 g, 45 mmol) in EtOH (75 mL). The reaction mixture was stirred at RT overnight. The solvents were removed under reduced pressure to give a white solid. The solid was suspended in water (200 mL) and stirred for 20 minutes, then filtered off, washed with water and dried to give the title compound as a white powder (12.54 g, 95%). 1H NMR (DMSO-d6, 300 MHz) δ 9.58 (s, 1H), 7.62 (d, J=8.3 Hz, 2H), 7.28 (d, J=8.3 Hz, 2H), 5.78 (s, 2H), 3.62 (s, 2H), 3.15 (s, 2H), 2.24 (s, 3H), 1.42 (s, 9H). LC/MS (Method B): 294.0 (M+H)+.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:56][CH2:57][NH:58]C(OC(C)(C)C)=O)[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:39][CH2:38][CH2:37][CH2:36]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:52]=[CH:51][C:50]([Cl:53])=[CH:49][CH:48]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:23][CH:22]=1)=[O:16])[CH3:14])=[O:11])=O)(C)(C)C.[ClH:66]>ClCCl.C(OCC)C>[ClH:53].[ClH:66].[NH2:8][C@@H:9]([CH2:56][CH2:57][NH2:58])[C:10]([NH:12][C@H:13]([C:15]([O:17][CH2:18][CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]2[C:32]([C:33]#[N:34])=[C:31]([N:35]3[CH2:36][CH2:37][CH2:38][CH2:39]3)[N:30]=[C:29]([S:40][CH2:41][C:42]3[N:43]=[C:44]([C:47]4[CH:48]=[CH:49][C:50]([Cl:53])=[CH:51][CH:52]=4)[S:45][CH:46]=3)[C:28]=2[C:54]#[N:55])=[CH:25][CH:26]=1)=[O:16])[CH3:14])=[O:11]
Reactant: C[C@H](NC(=O)[C@H](CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Agent: Cl
Solvent: CCOCC
Solvent: ClCCl
Product: C[C@H](NC(=O)[C@@H](N)CCN)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCCC3)c2C#N)cc1
Reaction time: 4 h

Procedure:
420 mg (0.444 mmol) of 2-{4-(2-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-3,5-dicyano-6-(pyrrolidin-1-yl)pyridin-4-yl)phenoxy}ethyl N-{(2S)-2,4-bis((tert-butoxycarbonyl)-amino)butanoyl}-L-alaninate were dissolved in 5 ml dichloromethane, and 4.442 ml of a 1N solution of hydrogen chloride in diethyl ether were added. After 4 hours of stirring, the precipitated solid was filtered off with suction, washed with diethyl ether and dried under reduced pressure. 322 mg (88% of theory) of the target compound were obtained.