Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:20]N1C(=O)CCC1=O.O[C@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1.CO>C1COCC1>[Cl:20][C@@H:29]1[CH2:46][CH2:45][C@@:44]2([CH3:47])[C@@H:31]([CH2:32][CH2:33][C@@H:34]3[C@@H:43]2[CH2:42][CH2:41][C@@:39]2([CH3:40])[C@H:35]3[CH2:36][CH2:37][C@@H:38]2[O:48][CH3:49])[CH2:30]1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CO
Solvent: C1CCOC1
Product: CO[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](Cl)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
A solution of triphenylphosphine (8.22 g.) in THF (80 ml.) is added dropwise to N-chlorosuccinimide (4.18 g.) with stirring and cooling so that the temperature remains below 30°. A solution of 3β-hydroxy-17β-methoxy-5α-androstane (Example 27, 4.8 g.) in THF (50 ml.) is slowly added to the N-chlorosuccinimide mixture. After 2 hours, methanol is added and the mixture is filtered to obtain the title compound (recrystallized from acetone): m.p. 151°-154°; NMR (CDCl3) 0.74, 0.78, 3.20, 3.33 and 4.47 δ; MS (m/e) 324, 309, 277 and 251.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][S:5][C:6]1[N:7]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][CH:17]=2)[C:8](=[O:15])[C:9]2[C:10](=[CH:12][S:13][CH:14]=2)[N:11]=1.C(N(CC)CC)C.[C:35](OC(=O)C)(=[O:37])[CH3:36]>O1CCCC1.CN(C)C1C=CN=CC=1>[O:15]=[C:8]1[N:7]([C:16]2[CH:17]=[CH:18][C:19]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:20][CH:21]=2)[C:6]([S:5][CH2:4][CH2:3][NH:2][C:35](=[O:37])[CH3:36])=[N:11][C:10]2=[CH:12][S:13][CH:14]=[C:9]12
Reactant: NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCCSc1nc2cscc2c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2-[(2-Aminoethyl)sulfanyl]-3-[4-(2,2,2-trifluoroethoxy)phenyl]thieno[3,4-d]pyrimidin-4(3H)-one hydrochloride (0.33 g) was suspended in tetrahydrofuran (30 ml), triethylamine (0.31 ml), acetic anhydride (0.28 ml) and 4-dimethylaminopyridine (37 mg) were added successively thereto, and the mixture was stirred at room temperature for 18 hr. The reaction mixture was concentrated under reduced pressure, and the residue was diluted with ethyl acetate. The extract was washed successively with saturated aqueous citric acid solution, water and saturated aqueous sodium hydrogen carbonate solution, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained pale-yellow solid was purified by silica gel column chromatography (ethyl acetate/hexane) to give a colorless solid. This solid was recrystallized from ethyl acetate/hexane to give the title compound (0.22 g) as a colorless solid.
Reaction SMILES: [O:1]1CCOC[CH2:2]1.[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20](Br)[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8].C[Zn]C>CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C.CCCCCCC.C(OCC)(=O)C>[C:7]([O:11][C:12](=[O:38])[NH:13][C:14]1[C:15]([O:36][CH3:37])=[N:16][N:17]2[C:21]([C:22]3[C:27]([O:28][CH3:29])=[CH:26][C:25]([CH2:30][O:31][CH3:32])=[CH:24][C:23]=3[O:33][CH3:34])=[C:20]([O:1][CH3:2])[S:19][C:18]=12)([CH3:10])([CH3:9])[CH3:8]
Reactant: C1COCCO1
Reactant: COCc1cc(OC)c(-c2c(Br)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: C[Zn]C
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COCc1cc(OC)c(-c2c(OC)sc3c(NC(=O)OC(C)(C)C)c(OC)nn23)c(OC)c1
Temperature: 60 °C

Procedure:
To a dioxane (15 mL) solution of tert-butyl{2-bromo-3-[2,6-dimethoxy-4-(methoxymethyl)phenyl]-6-methoxypyrazolo[5,1-b][1,3]thiazol-7-yl}carbamate (323 mg, 0.612 mmol) were added 2M dimethyl zinc (0.612 mL, 1.22 mmol) and bis(tri-tert-butylphosphine)palladium(0) (15.6 mg, 0.031 mmol), and the mixture was heated at 60° C. for one hour. After the reaction was completed, the solvent was directly distilled off under reduced pressure. The residue was purified by silica gel column chromatography (a mixed solvent of n-heptane and ethyl acetate: n-heptane/ethyl acetate=1/1) to obtain the title compound (205 mg, 0.442 mmol).
Reaction SMILES: [CH3:1][CH:2]([N:4]([CH:17]([CH3:19])[CH3:18])[CH2:5][CH2:6][CH:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])[C:8]#[N:9])[CH3:3].C[N:21](C)C=O.[C:25]1(C)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>O>[CH3:18][CH:17]([N:4]([CH:2]([CH3:1])[CH3:3])[CH2:5][CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[Cl:16])([CH2:25][C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][N:21]=1)[C:8]#[N:9])[CH3:19]
Reactant: Cc1ccccc1
Reactant: CC(C)N(CCC(C#N)c1ccccc1Cl)C(C)C
Reactant: CN(C)C=O
Solvent: O
Product: CC(C)N(CCC(C#N)(Cc1ccccn1)c1ccccc1Cl)C(C)C

Procedure:
The title compound was prepared by the method of Example 1 using 33 g (118 mmole) of α-[2-[bis(1-methylethyl)amino]ethyl]-2-chlorophenylacetonitrile instead of α-[2-[bis(1-methylethyl)amino]ethyl]phenylacetonitrile and dimethylformamide at 45°-50° instead of toluene at 65°-70°. After water was added to quench the reaction, the aqueous dimethylformamide solution was extracted with diethyl ether. The organic phase was separated, washed with water, and extracted into dilute aqueous hydrochloric acid. As in Example 1, the aqueous layer was made basic and extracted into dichloromethane, which was then dried and concentrated. The resultant oil was used in subsequent reactions without chromatographic purification. nmr (CDCl3): δ(ppm) 3.7 (pair of pseudo-d's, pyridyl-CH2 (isomers, each with non-equivalent H's)); 6.9-7.7 (m's, aromatic CH's); 8.35-8.55 (m, pyridine 6-H).
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29]([C:31]([C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=O)[CH:30]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>C1COCC1.O>[CH2:17]([O:24][C:25]1[CH:26]=[CH:27][C:28]([O:39][CH3:40])=[C:29](/[C:31](/[C:33]2[S:34][C:35]([CH3:38])=[CH:36][N:37]=2)=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:30]=1)[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Reactant: COc1ccc(OCc2ccccc2)cc1C(=O)c1ncc(C)s1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\c1ncc(C)s1)c1cc(OCc2ccccc2)ccc1OC
Temperature: -78 °C
Reaction time: 1 h
Yield: 58 %

Procedure:
To a suspension of NaH (60%, 884 mg, 22.1 mmol) in dry THF (120 mL) was added ethyl 2-(diethoxyphosphoryl)acetate (4.96 g, 22.1 mmol) at −78° C. After being stirred at −78° C. for 1 hour, a solution of (5-(benzyloxy)-2-methoxyphenyl)(5-methylthiazol-2-yl)methanone (2.50 g, 7.37 mmol) in THF (30 mL) was added drop wise over 30 min. The mixture was stirred at −78° C. for 30 min and then warmed to room temperature with stirring overnight. The mixture was cooled to 0° C. and treated with water (50 mL), pH value was adjusted to 6 with HCl (0.5 N). The organic layer was dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel chromatography eluting with petroleum ether/EtOAc (3:1) to afford (Z)-ethyl 3-(5-(benzyloxy)-2-methoxyphenyl)-3-(5-methylthiazol-2-yl)acrylate (1.75 g, 58.0%) as yellow gel.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH2:30])([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1.C(N(C(C)C)C(C)C)C.CN(C1C=CC=CN=1)C.[CH3:49][O:50][C:51]1[CH:52]=[C:53]([CH:57]=[CH:58][C:59]=1[O:60][CH3:61])[C:54](Cl)=[O:55]>C(Cl)Cl.C(OCC)C>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]=[C:4]([O:9][CH:10]([C:14]([O:27][CH2:28][CH2:29][NH:30][C:54](=[O:55])[C:53]2[CH:57]=[CH:58][C:59]([O:60][CH3:61])=[C:51]([O:50][CH3:49])[CH:52]=2)([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:11]([OH:13])=[O:12])[N:3]=1
Reactant: Cc1cc(C)nc(OC(C(=O)O)C(OCCN)(c2ccccc2)c2ccccc2)n1
Reactant: COc1ccc(C(=O)Cl)cc1OC
Agent: CN(C)c1ccccn1
Solvent: ClCCl
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(C(=O)NCCOC(c2ccccc2)(c2ccccc2)C(Oc2nc(C)cc(C)n2)C(=O)O)cc1OC
Temperature: 25 °C
Reaction time: 96 h

Procedure:
A solution of 1.0 g (2.5 mmol) of 2-(4,6-dimethylpyrimidin-2-yloxy)-3-(2-aminoethoxy)-3,3-diphenylpropionic acid in 10 ml of methylene chloride was successively admixed at room temperature with 0.35 g (2.7 mmol) of N-ethyldiisopropylamine, 0.03 g (0.2 mmol) of dimethylaminopyridine and 0.54 g (2.7 mmol) of 3,4-dimethoxybenzoyl chloride. The mixture was stirred at room temperature for 4 days and then diluted with diethyl ether and extracted with 1M hydrochloric acid and 1M aqueous sodium hydroxide solution, and the combined alkaline phases were made acidic and extracted with ether. The organic phase was dried over sodium sulfate, the solvent was distilled off and the residue (0.9 g) was chromatographed over silica gel (methylene chloride/methanol 9:1). Yield: 280 mg of a white foam.
Reaction SMILES: Cl[C:2]1[C:3]2[N:4]([CH:12]=[C:13]([CH2:15][CH:16]([CH3:18])[CH3:17])[N:14]=2)[C:5]2[C:10]([N:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.C(N(CC)C(C)C)(C)C.[CH3:28][O:29][C:30]1[CH:46]=[CH:45][C:33]([CH2:34][NH:35][CH2:36][C:37]2[CH:42]=[CH:41][C:40]([O:43][CH3:44])=[CH:39][CH:38]=2)=[CH:32][CH:31]=1.O>CN1CCCC1=O>[CH2:15]([C:13]1[N:14]=[C:3]2[C:2]([N:35]([CH2:34][C:33]3[CH:32]=[CH:31][C:30]([O:29][CH3:28])=[CH:46][CH:45]=3)[CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH3:44])=[CH:41][CH:42]=3)=[N:11][C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]2[CH:12]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)Cc1cn2c(n1)c(Cl)nc1ccccc12
Reactant: COc1ccc(CNCc2ccc(OC)cc2)cc1
Solvent: O
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc3ccccc3n3cc(CC(C)C)nc23)cc1
Temperature: 120 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a solution of the 4-chloro-2-isobutylimidazo[1,2-a]quinoxaline (130 mg, 0.50 mmol) in 2 mL of 1-methylpyrrolidin-2-one was added N,N-diisopropylethylamine (129 mg, 1.0 mmol) and followed by bis(4-methoxybenzyl)amine (154 mg, 0.60 mmol). The reaction mixture was stirred at 120° C. overnight. And then 10 mL of water was added. The resulting mixture was extracted with ethyl ether (50 mL×3). The combined organic layers were washed with water (20 mL), brine (20 mL), dried over MgSO4, filtered and concentrated. The crude product was purified by flash column chromatography eluted with ethyl acetate and hexanes to give the titled compound (195 mg, 81%). MS: MH+=481 1H NMR (300 MHz, CDCl3): δ 7.72 (s, 1H), 7.65 (m, 2H), 7.21-7.39 (m, 6H), 6.84 (d, 4H), 5.34 (brs, 4H), 3.79 (s, 6H), 2.63 (d, 2H), 2.06 (m, 1H), 0.94 (d, 6H).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([C:11]([O:13]C)=[O:12])[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=1.[SH-:16].[Na+]>O>[C:11]([C:9]1[N:10]=[C:6]2[N:5]=[C:4]([CH3:15])[CH:3]=[C:2]([SH:16])[N:7]2[N:8]=1)([OH:13])=[O:12]
Reactant: [SH-]
Reactant: COC(=O)c1nc2nc(C)cc(Cl)n2n1
Agent: [Na+]
Solvent: O
Product: Cc1cc(S)n2nc(C(=O)O)nc2n1
Temperature: 60 °C
Yield: 63.4 %

Procedure:
The product obtained in Step 1 (17 g) was added at a time, in a nitrogen atmosphere, to a solution of sodium hydrosulfide (16 g) in 280 ml of water at room temperature with stirring, and the mixture was heated to 60° C. with stirring continued. The resultant yellow solution was cooled to room temperature, the insoluble matters were filtered off, the filtrate was acidified with concentrated hydrochloric acid to pH 2.0, and the crystals thus formed were collected by filtration and washed twice with 20 ml of water, affording 10 g of the objective compound as yellow crystals.
Reaction SMILES: C(O[C:6]([N:8]1[CH2:12][C:11](=[N:13][O:14][CH3:15])[CH2:10][C@H:9]1[C:16]([OH:18])=O)=[O:7])(C)(C)C.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]2[CH:33]=[CH:32][C:28](C(O)=O)=[CH:27][CH:26]=2)[CH:20]=1.[NH2:34][CH2:35][C@@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[OH:37]>>[OH:37][C@H:36]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1)[CH2:35][NH:34][C:16]([C@@H:9]1[CH2:10][C:11](=[N:13][O:14][CH3:15])[CH2:12][N:8]1[C:6](=[O:7])[C:28]1[CH:27]=[CH:26][C:25]([C:21]2[CH:20]=[N:19][CH:24]=[CH:23][CH:22]=2)=[CH:33][CH:32]=1)=[O:18]
Reactant: NC[C@H](O)c1ccccc1
Reactant: O=C(O)c1ccc(-c2cccnc2)cc1
Reactant: CON=C1C[C@@H](C(=O)O)N(C(=O)OC(C)(C)C)C1
Product: CON=C1C[C@@H](C(=O)NC[C@H](O)c2ccccc2)N(C(=O)c2ccc(-c3cccnc3)cc2)C1

Procedure:
Following the general method as outlined in Example 22, starting from (2S,4EZ)-1-(tert-butoxycarbonyl)-4-(methoxyimino)-2-pyrrolidinecarboxylic acid, 4-(3-pyridinyl)benzoic acid, and (1R)-2-amino-1-phenylethanol, the title compound was obtained in 76% purity by HPLC. MS(ESI+): m/z=459.
Reaction SMILES: I[CH:2]([CH3:4])[CH3:3].[NH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12]>>[CH:2]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])([CH3:4])[CH3:3]
Reactant: CC(C)I
Reactant: Nc1ccccc1O
Product: CC(C)Nc1ccccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The same procedure as in Example 1 was repeated except that the molar ratio of 2-iodopropane to o-aminophenol was changed to 1.0, the 2-iodopropane was dropped over 3 h, and then the reaction mixture was stirred at room temperature for 2 h.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][CH:14]=[C:13]([C:18](O)=[O:19])[CH:12]=2.[C:21]([C:25]1[CH:31]=[CH:30][C:28]([NH2:29])=[CH:27][CH:26]=1)([CH3:24])([CH3:23])[CH3:22].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(OCC)(=O)C>CN(C=O)C>[C:21]([C:25]1[CH:26]=[CH:27][C:28]([NH:29][C:18]([C:13]2[CH:12]=[C:11]3[C:16]([CH:17]=[C:9]([C:3]4[C:4]([CH3:8])=[CH:5][CH:6]=[CH:7][C:2]=4[CH3:1])[NH:10]3)=[CH:15][CH:14]=2)=[O:19])=[CH:30][CH:31]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: CC(C)(C)c1ccc(N)cc1
Reactant: Cc1cccc(C)c1-c1cc2ccc(C(=O)O)cc2[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1-c1cc2ccc(C(=O)Nc3ccc(C(C)(C)C)cc3)cc2[nH]1
Reaction time: 18 h

Procedure:
A mixture of 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid. (17 mg, 60 μmol), 4-tert.-butylaniline (10 μL, 9.4 mg, 63 μmol) and HATU (33 mg, 87 μmol) in DMF (3 mL) was stirred, initially at ambient temperature, then at 60° C. for 18 h. The mixture was poured into ethyl acetate and extracted once with water and five times with brine. The organic layer was dried, filtered, and solvent was removed under reduced pressure. The residual material was chromatographed using a gradient of 20-60% heptane/ethyl acetate to give 2-(2,6-dimethylphenyl)-1H-indole-6-carboxylic acid (4-tert-butylphenyl)-amide. 1H NMR (CDCl3, 400 MHz) δ 8.54 (s, broad, 1H), 8.12 (s, 1H), 7.89 (s, 1H), 7.70 (d, J=8.3 Hz, 1H), 7.56 (m, 3H), 7.37 (d, J=8.7 Hz, 2H), 7.15 (d, J=7.6 Hz, 2H), 6.46 (s, 1H), 2.18 (s, 6H), 1.33 (s, 9H). MS (m/z) 397.2 (M+1).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].[Cl:5][C:6]1[CH:10]=[C:9](CBr)[O:8][N:7]=1.[C:13](#N)C>>[Cl:5][C:6]1[C:10]([CH2:13][NH:3][CH2:2][CH2:1][NH2:4])=[CH:9][O:8][N:7]=1
Reactant: CC#N
Reactant: Clc1cc(CBr)on1
Reactant: NCCN
Product: NCCNCc1conc1Cl
Reaction time: 1 h

Procedure:
Ethylenediamine (10 g) was dissolved in acetonitrile (30 ml), and a solution of 3-chloro-5-bromomethylisoxazole (11.3 g) in acetonitrile (10 g) was added dropwise at 10° C.-15° C. The reaction mixture was then allowed to reach ambient temperature over 1 hour, decanted from a gummy precipitate and the acetonitrile removed by evaporation to give an orange oil, N-(3-chloroisoxazolylmethyl)ethylene diamine. The orange oil (8.7 g) was dissolved in ethanol (20 ml) and added to a suspension of 1-nitro-2,2-bis(methylthio)ethylene (8 g) in ethanol (50 ml) and the reaction mixture refluxed, with stirring, until evolution of methylmercaptan ceased (about 11/2 hours). Thin layer chromatography indicated two products. The solvent was removed in vacuo, and the residue thin-layer chromatographed to give the title compound as a colorless solid (5.9 g), m.p. after recrystallization was 173° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][N:9]2[C:13](=[O:14])[CH2:12][CH2:11][CH:10]2[C:15]([OH:17])=O)[CH:5]=[CH:6][CH:7]=1.S(Cl)(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]2[C:15](=[O:17])[CH:10]3[CH2:11][CH2:12][C:13](=[O:14])[N:9]3[CH2:8][C:4]=2[CH:3]=1
Reactant: O=C(O)C1CCC(=O)N1Cc1cccc(F)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: O=C1c2ccc(F)cc2CN2C(=O)CCC12
Temperature: 5 °C
Reaction time: 8 h

Procedure:
To a solution of 50.00 g of (±)-1-[(3-fluorophenyl)methyl]-5-oxo-2-pyrrolidine carboxylic acid in sieve dried dichloromethane (450 ml), 27.48 g of thionyl chloride was added, and the resultant solution was stirred and refluxed for 5 hours. An infrared spectrum of the solution indicated the presence of the acid chloride. After standing overnight at ambient temperature, the solution was chilled to 5° C. and 84 g of aluminum chloride was added in portions with vigorous stirring. The reaction was exothermic and there was a slow evolution of gas. The mixture was stirred at ambient temperature for 3 hours. The reaction was quenched by the addition of ice chips and water. The two phases of the mixture was separated and the aqueous phase was extracted with dichloromethane (4×150 ml). The combined organic phase was dried (Na2SO4) and concentrated to a solid (69.73 g).
Reaction SMILES: C(#N)C.[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[N:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]=2[CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:8]=[CH:9][CH:10]=1.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34].C(N(CC)CC)C>C(OCC)(=O)C>[Br:4][C:5]1[CH:6]=[C:7]([C:11]2[C:20]3[C:15](=[N:16][C:17]([CH3:21])=[CH:18][CH:19]=3)[N:14]([CH2:22][CH3:23])[C:13](=[O:24])[C:12]=2[CH:25]2[CH2:30][CH2:29][N:28]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:27][CH2:26]2)[CH:8]=[CH:9][CH:10]=1
Reactant: CCn1c(=O)c(C2CCNCC2)c(-c2cccc(Br)c2)c2ccc(C)nc21
Reactant: CCOC(=O)CBr
Solvent: CCN(CC)CC
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CCOC(=O)CN1CCC(c2c(-c3cccc(Br)c3)c3ccc(C)nc3n(CC)c2=O)CC1
Temperature: 25 °C
Reaction time: 13 h

Procedure:
To a 5 ml acetonitrile solution containing 400 mg of 4-(3-bromophenyl)-1-ethyl-7-methyl-3-(piperidin-4-yl)-1,8-naphthyridin-2(1H)-one were added 0.11 ml of ethyl bromoacetate and 0.13 ml of triethylamine, followed by stirring at room temperature for 13 hours. Ethyl acetate was added to the reaction solution and the solution was washed with saturated sodium bicarbonate aqueous solution and saturated brine and dried over anhydrous magnesium sulfate. After removal of the solvent from the organic layer, the resulting residue was purified by a silica gel column chromatography (hexane-ethyl acetate) and then recrystallized from ethyl acetate-diisopropyl ether to obtain 120 mg of ethyl {4-[4-(3-bromophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-l,8-naphthyridin-3-yl]piperidin-1-yl}acetate as colorless crystals.
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[OH:9][CH2:10][CH:11]([CH2:24][OH:25])[CH2:12][CH2:13][N:14]1[CH:21]=[C:20]([CH:22]=[CH2:23])[C:18](=[O:19])[NH:17][C:15]1=[O:16].[N-:26]=[N+:27]=[N-:28].[Na+]>COCCOC.O>[OH:9][CH2:10][CH:11]([CH2:24][OH:25])[CH2:12][CH2:13][N:14]1[CH:21]=[C:20]([CH:22]([N:26]=[N+:27]=[N-:28])[CH2:23][Cl:1])[C:18](=[O:19])[NH:17][C:15]1=[O:16]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C1CCC(=O)N1Cl
Reactant: C=Cc1cn(CCC(CO)CO)c(=O)[nH]c1=O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: [N-]=[N+]=NC(CCl)c1cn(CCC(CO)CO)c(=O)[nH]c1=O
Temperature: -5 °C
Reaction time: 2 h
Yield: 46.7 %

Procedure:
N-Chlorosuccinimide (50 mg, 0.37 mmol) was added slowly with stirring to a precooled (−5° C.) suspension, prepared by mixing a solution of 20 (75 mg, 0.31 mmol) in 1,2-dimethoxyethane (25 ml) with a solution of sodium azide (81 mg, 1.24 mmol) in water (0.23 ml). The reaction mixture was allowed to proceed for 2 h at 0° C. with stirring and the solvent was removed in vacuo. The resulting residue was purified by silica gel column chromatography using chloroform:methanol (90:10, v/v) as eluent to afford 21b (46 mg, 47%) as a viscous oil.
Reaction SMILES: [C:1]([C:3]1[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)=[CH:7][C:6]([NH:16][C@H:17]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:18]([NH2:20])=[O:19])=[CH:5][C:4]=1[F:25])#[N:2].CC[OH:28]>CS(C)=O.[OH-].[Na+].OO>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[CH:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:28])=[C:4]([F:25])[CH:5]=1)[CH2:21][CH:22]([CH3:23])[CH3:24]
Reactant: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C#N)sn1
Reactant: CCO
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: Cc1cc(Nc2cc(N[C@H](CC(C)C)C(N)=O)cc(F)c2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (R)-2-(4-cyano-3-fluoro-5-(3-methylisothiazol-5-ylamino)phenylamino)-4-methylpentanamide (38 mg, 0.105 mmol) in EtOH (1 mL) and DMSO (0.5 mL), 1N aq. NaOH (0.4 mL) and H2O2 (50% aq., 0.4 mL) were added. After being stirred at room temperature for 1 h, the mixture was concentrated in vacuo. The residue was acidified with HOAc (0.5 mL), and then was purified by HPLC to give the titled compound (18 mg). MS 380.3 (M+H); UV 221.1, 282.9, 297.7 nm
Reaction SMILES: CC([N:5]=[C:6]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH2:7][CH2:8][CH3:9])(C)C.[CH:21]([C:30]([O:32][CH3:33])=[O:31])([C:26](OC)=[O:27])[C:22](OC)=[O:23]>COCCOCCOC>[CH2:8]([C:7]1[C:22]([OH:23])=[C:21]([C:30]([O:32][CH3:33])=[O:31])[C:26](=[O:27])[NH:5][C:6]=1[C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]([CH3:20])[CH2:15][CH2:14][CH2:13]2)[CH3:9]
Reactant: CCCC(=NC(C)(C)C)c1ccc2c(c1)CCCN2C
Reactant: COC(=O)C(C(=O)OC)C(=O)OC
Solvent: COCCOCCOC
Product: CCc1c(-c2ccc3c(c2)CCCN3C)[nH]c(=O)c(C(=O)OC)c1O
Temperature: 160 °C
Reaction time: 4 h
Yield: 6.1 %

Procedure:
To a suspension of 2-methyl-N-(1-(1-methyl-1,2,3,4-tetrahydroquinolin-6-yl)butylidene)propan-2-amine (1.96 g, ca. 7.2 mmol), prepared according to procedure described in Example 1 Step 6, in diglyme (7 mL) was added trimethyl methanetricarboxylate (2.33 g, 12.2 mmol, 1.7 eq). The reaction was stirred at 160° C. for 4 h then cooled to room temperature. The precipitate was collected by filtration then washed with Et2O to afford the title compound as a yellow solid (150 mg, 0.44 mmol, 6.5% over two steps).
Reaction SMILES: C1OCCOCCOCCOCCOCCOC1.CC(C)([O-])C.[K+].[CH3:25][C:26]1[NH:42][C:29]2=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]=[CH2:41])=[CH:36][CH:35]=3)[N:31]=[CH:32][CH:33]=[C:28]2[C:27]=1[CH3:43].[F:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][Cl:49]>O1CCCC1>[ClH:49].[F:44][C:45]1[CH:46]=[C:47]([CH:50]=[CH:51][CH:52]=1)[CH2:48][N:42]1[C:29]2=[C:30]([C:34]3[CH:39]=[CH:38][C:37]([CH:40]=[CH2:41])=[CH:36][CH:35]=3)[N:31]=[CH:32][CH:33]=[C:28]2[C:27]([CH3:43])=[C:26]1[CH3:25]
Reactant: Fc1cccc(CCl)c1
Reactant: C=Cc1ccc(-c2nccc3c(C)c(C)[nH]c23)cc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=Cc1ccc(-c2nccc3c(C)c(C)n(Cc4cccc(F)c4)c23)cc1
Product: Cl
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
18-Crown-6 (2.5 mg, 0.0097 mmol) and potassium tert-butoxide (33 mg, 0.291 mmol) were added to a solution of 2,3-dimethyl-7-(4-vinylphenyl)-1H-pyrrolo[2,3-c]pyridine (24 mg, 0.097 mmol) prepared in Example 242 in anhydrous tetrahydrofuran (0.5 ml). The reaction mixture was stirred for 30 minutes at room temperature and 3-fluorobenzyl chloride (20 μl, 0.16 mmol) was added thereto. The reaction mixture was stirred overnight and then concentrated under reduced pressure. The resulting residue was purified with silica gel column chromatography. The resulting product was dissolved in ethyl acetate, saturated with hydrochloric acid gas, and then filtered to give 3.8 mg of the titled compound as a white solid.