Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN(C(C)C)C(C)C.C(OC([N:15]1[C:19]2[C:20]([CH3:24])([CH3:23])[NH:21][CH2:22][C:18]=2[C:17]([NH:25][C:26](=[O:35])[C:27]2[CH:32]=[CH:31][C:30]([Cl:33])=[C:29]([Cl:34])[CH:28]=2)=[N:16]1)=O)C.[F:36][C:37]1([C:44](Cl)=[O:45])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]1>C(Cl)Cl>[Cl:34][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][C:30]=1[Cl:33])[C:26]([NH:25][C:17]1[C:18]2[CH2:22][N:21]([C:44]([C:37]3([F:36])[CH2:42][CH2:41][N:40]([CH3:43])[CH2:39][CH2:38]3)=[O:45])[C:20]([CH3:24])([CH3:23])[C:19]=2[NH:15][N:16]=1)=[O:35]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(Cl)c(Cl)c2)c2c1C(C)(C)NC2
Reactant: CN1CCC(F)(C(=O)Cl)CC1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN1CCC(F)(C(=O)N2Cc3c(NC(=O)c4ccc(Cl)c(Cl)c4)n[nH]c3C2(C)C)CC1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
DIEA (0.220 mL, 1.66 mmol) and 3-(3,4-Dichloro-benzoylamino)-6,6-dimethyl-5,6-dihydro-4H-pyrrolo[3,4-c]pyrazole-1-carboxylic acid ethyl ester (221 mg, 0.51 mmol) were added to a solution of 4-Fluoro-1-methyl-piperidine-4-carbonyl chloride (0.51 mmol) in CH2Cl2 (10 mL). The reaction was stirred at RT for 4 h. The mixture was quenched with H2O (30 mL), extracted with CHCl3 (2×30 mL). The organic layers were dried over MgSO4 and concentrated to give the title compound as brown color oil which was used without further purification. ESI (MNa+): 564.10.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[CH3:30][O:31][NH:32][CH3:33]>S(Cl)(Cl)=O>[CH3:30][O:31][N:32]([CH3:33])[C:17](=[O:19])[C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[N:1]=2)=[CH:21][CH:20]=1
Reactant: O=C(O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reactant: CNOC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CON(C)C(=O)c1ccc(OCc2ccc3ccccc3n2)cc1
Reaction time: 3 h

Procedure:
To a solution of 4-(Quinolin-2-ylmethoxy)-benzoic acid (25.98 g, 93 mmole) was added 250 ml of thionyl chloride under N2. The reaction mixture stirred 3 h and the excess thionyl chloride was removed under vacuum. The acid chloride was dissolved in tetrahydrofuran (450 ml) and triethylamine (50 ml, 4 eq.) was slowly added. O,N-dimethyl hydroxylamine hydrochloride (27 g, 3 eq.) was added and the reaction stirred 18 h. The reaction mixture was placed on a rotovap to remove the solvent, partitioned between 1N NaOH and methylene chloride, separated, dried magnesium sulfate, filtered and concentrated. The crude product was filtered through silica gel eluting with 30-70% ethyl acetate/hexane to proved the title compound as a brown oil (26.26 g, 87%); 1H NMR (400 MHz, CDCl3) δ 8.17 (d, J=8.7 Hz, 1H), 8.06 (d, J=8.3 Hz, 1H), 7.81 (d, J=8.3 Hz, 1H), 7.67 (m, 3H), 7.63 (d, J=8.3 Hz, 1H), 7.52 (m, 1H), 7.01 (M, 2H), 5.39 (s, 2H), 3.52 (s, 3H) 3.31 (s, 2H); MS: (M+H m/z=323.2).
Reaction SMILES: [N:1]1([C:10]2[N:18]=[C:17](Cl)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH2:20][CH2:21][CH:22]1[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]1>CS(C)=O>[N:1]1([C:10]2[N:18]=[C:17]([NH:20][CH2:21][CH:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)[N:16]=[C:15]3[C:11]=2[N:12]=[CH:13][NH:14]3)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Reactant: Clc1nc(-n2cnc3ccccc32)c2nc[nH]c2n1
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CNc2nc(-n3cnc4ccccc43)c3nc[nH]c3n2)CC1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
200 mg of product obtained in stage 1 above are mixed with 5 ml of DMSO and 790 mg (5 equivalents) of 4-aminomethyl-N-Boc-piperidine, and the mixture is then heated at 100° C. for approximately 3 days. The mixture is allowed to return to ambient temperature. The DMSO is concentrated to dryness and the dry product is taken up in CH2Cl2. Purification is carried out by chromatography on silica with a CH2Cl2-MeOH—NH4OH: 95-5-0.33 mixture for eluent. 56 mg of expected product are thus obtained.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10](O)[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2].P(Cl)(Cl)([Cl:18])=O.O>C(OCC)(=O)C>[C:1]([C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][CH:14]=1)[N:11]=[C:10]([Cl:18])[CH:9]=[N:8]2)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)(C)c1ccc2nc(O)cnc2c1
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)c1ccc2nc(Cl)cnc2c1
Temperature: 25 °C
Yield: 80.3 %

Procedure:
A solution of 250 mg (1.236 mmol) of 6-tert-Butyl-quinoxalin-2-ol in 1.07 mL (11.43 mmol) phosphorus oxychloride under nitrogen was heated at 110° C. for 3 h. The solution was cooled to room temperature and added drop wise to water (10-15° C.). Ethyl acetate was added. The aqueous layer was extracted with ethylacetate. The combined organic phases were washed with water, dried over Na2SO4 and concentrated. The crude compound was purified with flash column chromatography on silica eluting with a gradient formed from n-heptane and ethyl acetate to provide 219 mg (80.3%) of the title compound as a green solid. MS(m/e): 220 (M+H+).
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[S:9][C:10]([C:14]2[CH2:18][C:17]([C:23]3[CH:28]=[C:27]([Cl:29])[CH:26]=[C:25]([Cl:30])[CH:24]=3)([C:19]([F:22])([F:21])[F:20])[O:16][N:15]=2)=[CH:11][C:12]=1[CH3:13])=[O:7])C.Cl>C1COCC1.O>[Cl:30][C:25]1[CH:24]=[C:23]([C:17]2([C:19]([F:20])([F:22])[F:21])[O:16][N:15]=[C:14]([C:10]3[S:9][C:8]([C:6]([OH:7])=[O:5])=[C:12]([CH3:13])[CH:11]=3)[CH2:18]2)[CH:28]=[C:27]([Cl:29])[CH:26]=1
Reactant: CCOC(=O)c1sc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)cc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)sc1C(=O)O
Temperature: 50 °C
Reaction time: 16 h
Yield: 100.4 %

Procedure:
LiOH (3.2 g) is added to a solution of 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid ethyl ester (9.88 g) in a mixture of THF and water (240 ml, 9:1). After 16 hours at room temperature, LiOH (1.05 g) and THF (150 ml) was added. The reaction mixture was heated at 50° C. for 10 hours. HCl (2N) was added to the reaction mixture until pH 1-2 was obtained. The mixture was then extracted three times with ethyl acetate. The organic phases were combined, washed with water and a saturated aqueous solution of NaCl, dried over Na2SO4 and concentrated in vacuo to yield 5-[5-(3,5-dichloro-phenyl)-5-trifluoromethyl-4,5-dihydro-isoxazol-3-yl]-3-methyl-thiophene-2-carboxylic acid (9.3 g) as brown resin. The crude product is used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([CH3:12])([CH3:11])[CH:3]1[CH3:13].C(O)(=O)C.[N+:19]([O-])([OH:21])=[O:20].S(=O)(=O)(O)O>O>[N+:19]([C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[C:4]([CH3:12])([CH3:11])[CH:3]([CH3:13])[C:2]2([CH3:14])[CH3:1])([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: CC1C(C)(C)c2ccccc2C1(C)C
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC1C(C)(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Temperature: 25 °C
Reaction time: 0.1 h

Procedure:
Into a 500 ml reaction vessel equipped with stirrer, thermometer, reflux condenser, addition funnel and cooling bath is placed 50 grams of 1,1,2,3,3-pentamethyl indane having the structure: ##STR36## in admixture with 100 grams of acetic acid. While maintaining the reaction mass at 25° C., 40 grams of fuming nitric acid is added over a period of 0.5 hour. The reaction mass is then stirred for a period of 6 minutes. Over a period of 10 minutes while maintaining the reaction mass at 20°-22° C., 10 grams of concentrated sulfuric acid is added to the reaction mass. The reaction mass is then heated to a temperature in the range of 26°-30° C. with stirring and maintained at that temperature for a period of four hours. At the end of the four hour period, the reaction mass is added to water and a solid is formed which precipitates out. The resulting crystals are washed with two 500 ml portions of water. The crystals melt at 99.5° C.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1.[CH2:24]([O:31][NH:32][C:33]([C@H:35]1[CH2:40][N:39]([S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH2:38][CH2:37][N:36]1[S:47]([N:50]1[CH2:55][CH2:54][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]#[N:66])[CH:63]=3)[N:58](S(CC[Si](C)(C)C)(=O)=O)[CH:57]=2)[CH2:52][CH2:51]1)(=[O:49])=[O:48])=[O:34])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>Cl>[CH2:24]([O:31][NH:32][C:33]([C@H:35]1[CH2:40][N:39]([S:41]([N:44]([CH3:46])[CH3:45])(=[O:43])=[O:42])[CH2:38][CH2:37][N:36]1[S:47]([N:50]1[CH2:51][CH2:52][CH:53]([C:56]2[C:64]3[C:59](=[CH:60][CH:61]=[C:62]([C:65]#[N:66])[CH:63]=3)[NH:58][CH:57]=2)[CH2:54][CH2:55]1)(=[O:49])=[O:48])=[O:34])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)N2CCC(c3cn(S(=O)(=O)CC[Si](C)(C)C)c4ccc(C#N)cc34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [F-]
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)N1CCN(S(=O)(=O)N2CCC(c3c[nH]c4ccc(C#N)cc34)CC2)[C@@H](C(=O)NOCc2ccccc2)C1
Yield: 99 %

Procedure:
A solution of tetrabutylammonium fluoride in tetrahydrofuran (1.54 ml, 1.54 mmol) was added to a solution of N-benzyloxy-1-{4-[5-cyano-1-(2-trimethylsilylethanesulfonyl)indole-3-yl]piperidine-1-sulfonyl}-4-(N,N-dimethylaminosulfonyl)piperazine-2-(R)-carboxamide (0.49 g, 0.62 mmol) and the reaction was placed in a 55° C. oil bath for 30 min. The reaction was diluted with 1 M HCl and concentrated in vacuo. The residue was extracted with ethyl acetate and the organic layer was washed with brine, dried over MgSO4 and concentrated in vacuo to give N-benzyloxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide (99%) as a tan solid. This material was converted to N-hydroxy-1-[4-(5-cyanoindol-3-yl)piperidine-1-sulfonyl]-4-(N,N-dimethylamino-sulfonyl)piperazine-2-(R)-carboxamide by following Example 16, Step 5.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]1.[F:19][C:20]([F:33])([F:32])[O:21][C:22]1[CH:23]=[C:24]([S:28](Cl)(=[O:30])=[O:29])[CH:25]=[CH:26][CH:27]=1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][S:28]([C:24]2[CH:25]=[CH:26][CH:27]=[C:22]([O:21][C:20]([F:19])([F:32])[F:33])[CH:23]=2)(=[O:30])=[O:29])=[CH:5][C:4]=1[CH:10]1[CH2:14][CH2:13][N:12]([C:15](=[O:18])[CH2:16][CH3:17])[CH2:11]1
Reactant: O=S(=O)(Cl)c1cccc(OC(F)(F)F)c1
Reactant: CCC(=O)N1CCC(c2cc(N)ccc2OC)C1
Product: CCC(=O)N1CCC(c2cc(NS(=O)(=O)c3cccc(OC(F)(F)F)c3)ccc2OC)C1

Procedure:
1-[3-(2-Methoxy-5-amino-phenyl)-pyrrolidin-1-yl]-propan-1-one (0.44 g, 1.77 mmol) and commercially available 3-trifluoromethoxy-benzene sulfonylchloride (0.23 g, 0.89 mmol) were reacted as described above, to yield, after purification via silica gel chromatography using a ISCO Companion instrument, 0.198 g of the desired compound.
Reaction SMILES: [C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16]O)[CH2:6]1)(=[O:3])[CH3:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:37]([O:40][C:41]([NH:43][S:44]([NH2:47])(=[O:46])=[O:45])=[O:42])[CH:38]=[CH2:39].C(OC(N=NC(OCC)=O)=O)C>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:1]([S:4][C@@H:5]1[CH2:9][N:8]([C:10]([O:12][CH2:13][CH:14]=[CH2:15])=[O:11])[C@H:7]([CH2:16][N:43]([S:44](=[O:45])(=[O:46])[NH2:47])[C:41]([O:40][CH2:37][CH:38]=[CH2:39])=[O:42])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CO
Reactant: C=CCOC(=O)NS(N)(=O)=O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: C=CCOC(=O)N1C[C@@H](SC(C)=O)C[C@H]1CN(C(=O)OCC=C)S(N)(=O)=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 100.6 %

Procedure:
To a solution of (2S,4S)-4-acetylthio-1-allyloxycarbonylpyrrolidine-2-methanol (8.02 g: ca. 30 mmole) in ethyl acetate (83 ml) under ice cooling, triphenylphosphine (9.44 g: 13.6 mmole), N-allyloxycarbonylsulfamide (3.12 g: 15.9 mmole), and azodicarboxylic acid diethylester (5.67 ml: 36 mmole) are successively added. The mixture is stirred under ice cooling for 55 minutes and at room temperature for 4 hours. The reaction mixture is dissolved in toluene (60 ml), concentrated, diluted with toluene (60 ml), filtered to remove separating crystals, and the filtrate is concentrated. The residue is purified by silica gel chromatography to give (2S,4S)-4-acetylthio-1-allyloxycarbonyl-2-(N-sulfamoyl-N-allyloxycarbonylamino)methylpyrrolidine (6.74 g). Yield: 55%. Colorless oil. NMR δ(CDCl3) ppm: 1.5 to 1.7(m, 1H), 2.35(s, 3H), 2.5 to 2.7(m, 1H), 3.19 (dd, J=6.3 Hz, J=11.5 Hz, 1H), 3.68 (dd, J=3.8 Hz, J=14.5 Hz, 1H), 3.9 to 4.3(m, 3H), 4.3 to 4.7(m, 5H), 5.2 to 5.4(m, 4H), 5.8 to 6.1(m, 4H).
Reaction SMILES: [O:1]=[C:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1.CO.[BH4-].[Na+]>C1COCC1>[OH:1][CH:2]1[C:11]2[CH:10]=[C:9]([NH:12][C:13](=[O:19])[O:14][C:15]([CH3:17])([CH3:16])[CH3:18])[CH:8]=[CH:7][C:6]=2[CH2:5][CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(=O)CCC2
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)Nc1ccc2c(c1)C(O)CCC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of the compound of Formula 39-1 (740 mg, 2.83 mmol) in THF (5 mL)/MeOH (5 mL) was added sodium borohydride (107 mg, 2.83 mmol) while cooled at 0° C. The solution was stirred for 1 hour and concentrated to volume in vacuo. The residue was diluted with EtOAc (40 mL) and washed with sat'd sodium bicarbonate (2×10 mL) and brine (10 mL). Organics were dried over sodium sulfate, filtered, and concentrated in vacuo to yield the compound of Formula 39-2 as a solid.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32](Cl)=[O:33])=[CH:30][CH:29]=1>C(Cl)Cl>[Br:25][CH2:26][CH2:27][C:28]1[CH:36]=[CH:35][C:31]([C:32]([O:17][C:14]2[CH:13]=[CH:12][C:11]([S:8](=[O:9])(=[O:10])[NH:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:16][CH:15]=2)=[O:33])=[CH:30][CH:29]=1
Reactant: O=C(Cl)c1ccc(CCBr)cc1
Reactant: O=S(=O)(Nc1ccccc1)c1ccc(O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Oc1ccc(S(=O)(=O)Nc2ccccc2)cc1)c1ccc(CCBr)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86.2 %

Procedure:
To a mixture of 24.93 g (0.10 mol) of N-phenyl-4-hydroxybenzenesulfonamide, 10.12 g (0.10 mol) of triethylamine and 150 ml of methylene chloride was added, dropwise, a solution of 24.75 g (0.10 mol) of 4-(2-bromoethyl)benzoyl chloride in 150 ml of methylene chloride over a period of 12 minutes. The reaction mixture was stirred at room temperature for 3 hours, after which 500 ml of methylene chloride were added. The solution was washed once with 2% HCl and twice with water, dried over magnesium sulfate and concentrated to a white solid. Recrystallization from ethanol gave 39.7 g (86.1% of theory) of 4-(N-phenylsulfamoyl)phenyl 4-(2-bromoethyl)benzoate, mp=156°-7° C.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:11]([CH2:20][CH2:21][CH3:22])[C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[C:14]([OH:19])[CH:13]=3)=[CH:6][CH:5]=1)([O-:3])=[O:2].[CH2:23]([O:25][C:26](=[O:31])[C:27](Br)([CH3:29])[CH3:28])[CH3:24]>>[CH2:23]([O:25][C:26](=[O:31])[C:27]([CH3:29])([O:19][C:14]1[CH:13]=[C:12]2[C:17]([CH:18]=[C:10]([C:7]3[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=3)[N:11]2[CH2:20][CH2:21][CH3:22])=[CH:16][CH:15]=1)[CH3:28])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: CCCn1c(-c2ccc([N+](=O)[O-])cc2)cc2ccc(O)cc21
Product: CCCn1c(-c2ccc([N+](=O)[O-])cc2)cc2ccc(OC(C)(C)C(=O)OCC)cc21

Procedure:
The above compound was prepared from 2-(4-nitro-phenyl)-1-propyl-1H-indole-6-ol and 2-bromo-2-methyl-propanoic acid ethylester using a procedure analogous to that of Example 10.
Reaction SMILES: Cl[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1.[C:17]1(=[O:27])[NH:21][C:20](=[O:22])[C:19]2=[CH:23][CH:24]=[CH:25][CH:26]=[C:18]12.[K]>CN(C)C=O>[O:22]=[C:20]1[C:19]2[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](=[O:27])[N:21]1[CH2:2][CH2:3][CH:4]1[CH2:10][N:9]([CH3:11])[C:8](=[O:12])[C:7]2[CH:13]=[CH:14][CH:15]=[N:16][C:6]=2[O:5]1
Reactant: CN1CC(CCCl)Oc2ncccc2C1=O
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Product: CN1CC(CCN2C(=O)c3ccccc3C2=O)Oc2ncccc2C1=O
Temperature: 100 °C
Reaction time: 5 h
Yield: 37 %

Procedure:
To a solution of 4.92 g (0.02 mole) of 2-(2-chloroethyl)-2,3-dihydro-4-methylpyrido[3,2-f]-1,4-oxazepin-5-(4H)one in 35 ml of dimethylformamide was added 7.55 g (0.041 mole) of potassium phthalimide. The mixture was stirred for 5 hr at 100° C. and left standing at room temperature overnight. Dimethylformamide was removed by rotary evaporation (80° C. vacuum pump). The residue was taken up in 100 ml of chloroform and washed with water (2×30 ml) and 2M potassium hydroxide (2×3 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated by rotary evaporation (70° C., water aspirator). The 6.26 g of crude product was recrystallized from isopropyl alcohol to give 2.60 g (36%) white crystalline powder, m.p. 146°-47° C.
Reaction SMILES: [C:1]1([CH2:7]N2C3C=CC=CC=3N=N2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:17]1([CH:27]=NC2C=CC=CC=2)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1>CO>[C:1]1([C:7]#[C:27][C:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH:20]=[CH:19][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(Cn2nnc3ccccc32)cc1
Reactant: C(=Nc1ccccc1)c1cccc2ccccc12
Solvent: CO
Product: C(#Cc1cccc2ccccc12)c1ccccc1
Yield: 88 %

Procedure:
In a procedure similar to that of Example 16 using [phenylmethyl]-1H-benzotriazole (10 mmol) and N-([1-naphthalenyl]methylene)benzenamine (10 mmol): 88% yield: mp 51°-53° C. (MeOH) (lit1 oil); 1H NMR (300 MHz, CDCl3) δ 7.39-7.69 (m, 8H), 7.77-7.90 (m, 3H), 8.46 (br d, 2.7H, 1H); IR (CDCl3) 3060 (s), 2245 (eyne), 1596, 1581, 1508, 1491 (s), 1442, 1398, 1333, 1215, 1070, 1017 cm-1. MS (EI) m/e 228 (M+, 100).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[CH:6][CH:7]=1.[S:8]1[CH:12]=[CH:11][N:10]=[C:9]1[C:13]1[N:18]=[C:17]([C:19]2[N:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N:4]1[CH:5]=[CH:6][CH:7]=[C:2]([C:12]2[S:8][C:9]([C:13]3[N:18]=[C:17]([C:19]4[N:20]=[CH:21][CH:22]=[CH:23][N:24]=4)[CH:16]=[CH:15][CH:14]=3)=[N:10][CH:11]=2)[CH:3]=1
Reactant: Brc1cccnc1
Reactant: c1cnc(-c2cccc(-c3nccs3)n2)nc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: c1cnc(-c2cccc(-c3ncc(-c4cccnc4)s3)n2)nc1

Procedure:
Under argon, 79 mg (0.50 mmol) of 3-bromopyridine, 120 mg (0.50 mmol) of 2-[6-(1,3-thiazol-2-yl)pyridin-2-yl]pyrimidine (cf. step 1), 326 mg (1.0 mmol) of cesium carbonate and 8 mg (0.01 mmol) of [(t-Bu)2P(OH)]2PdCl2 (“POPd”) in 10 ml of N,N-dimethylformamide were stirred at 120° C. for 16 hours. For work-up, the solvent was removed under reduced pressure, the residue was partitioned between ethyl acetate and water and the organic phase was dried, concentrated under reduced pressure and purified by column chromatography on silica gel RP-18 (mobile phase: water/acetonitrile/formic acid). This gave 28 mg (18% of theory) of 2-{6-[5-(pyridin-3-yl)-1,3-thiazol-2-yl]pyridin-2-yl}pyrimidine.
Reaction SMILES: C([O-])(=O)C.[NH4+:5].[CH3:6][C:7]([CH3:45])([CH2:43][CH3:44])[CH2:8][C:9](=O)[CH2:10][NH:11][C:12]([C:14]1([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]3[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=3)=[CH:31][CH:30]=2)[CH2:18][C:17]([F:20])([F:19])[CH2:16][N:15]1C(OC(C)(C)C)=O)=O>C(OCC)(=O)C.O>[CH3:45][C:7]([CH3:6])([CH2:43][CH3:44])[CH2:8][C:9]1[N:5]=[C:12]([C:14]2([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]4[CH:40]=[CH:39][C:38]([F:41])=[CH:37][N:36]=4)=[CH:31][CH:30]=3)[CH2:18][C:17]([F:20])([F:19])[CH2:16][NH:15]2)[NH:11][CH:10]=1
Reactant: CCC(C)(C)CC(=O)CNC(=O)C1(Cc2ccc(-c3ccc(F)cn3)cc2)CC(F)(F)CN1C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CCC(C)(C)Cc1c[nH]c(C2(Cc3ccc(-c4ccc(F)cn4)cc3)CC(F)(F)CN2)n1
Temperature: 160 °C
Reaction time: 1 h

Procedure:
Ammonium acetate (947 mg, 12.3 mmol) was added to an ambient temperature solution of tert-butyl 2-{[(4,4-dimethyl-2-oxohexyl)amino]carbonyl}-4,4-difluoro-2-[4-(5-fluoropyridin-2-yl)benzyl]pyrrolidine-1-carboxylate (138 mg, 0.25 mmol) in xylenes (10 mL). After stirring in a sealed tube at 160° C. for 1 h, the reaction mixture was diluted with ethyl acetate and water. The organic phase was dried (magnesium sulfate), filtered, and concentrated in vacuo. The residue was purified by chromatography over silica eluting with 0-100% ethyl acetate/hexane followed by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was dissolved in trifluoroacetic acid (1 mL). After stirring at ambient temperature for 2 h, the reaction mixture was concentrated to afford the title compound. (M+H) found: 443.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH2:23][CH3:24])[C:3]=1[OH:25].Cl[S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]>>[Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:20]3[C:19]([CH3:21])=[C:18]([CH3:22])[O:17][C:16]=3[CH:15]=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([CH2:23][CH3:24])[C:3]=1[O:25][S:27]([C:30]1[CH:38]=[CH:37][C:33]([C:34]([OH:36])=[O:35])=[C:32]([OH:39])[CH:31]=1)(=[O:29])=[O:28]
Reactant: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1O
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Product: CCc1cc(-c2c3ccccc3cc3oc(C)c(C)c23)cc(Br)c1OS(=O)(=O)c1ccc(C(=O)O)c(O)c1
Yield: 23.9 %

Procedure:
The title compound was prepared according to the procedure in Example 1, step 9, using 2-bromo-4-(2,3-dimethyl-naphtho[2,3-b]furan-4-yl)-6-ethyl-phenol (0.458 g, 1.16 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.994 g, 4.19 mmol). Purification on 2% H3PO4 /MeOH treated silica gel eluting with a 0 & 10% EtOAc/hexane step gradient gave 0.165 g of the title compound as a white solid, mp 238-243° C. 1H NMR (DMSO-d6) δ 1.13 (t, 3 H), 1.56 (s, 3 H), 2.39 (s, 3 H), 2.65-2.70 (m, 2 H), 7.37-7.60 (m, 7 H), 8.01-8.08 (m, 3 H). mass spectrum (-ESI) m/z 593 (M-H). Anal. Calcd. for C29H23BrO7S: C, 58.50; H, 3.89; N, 0.00. Found: C, 58.91; H, 4.02; N, 0.05.
Reaction SMILES: C([O:4][CH:5]1[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8][CH:7]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:6]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO.C(Cl)Cl>[CH2:19]([O:18][C:16]([NH:15][CH:7]1[CH2:6][CH:5]([OH:4])[C:14]2[N:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH2:8]1)=[O:17])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)OC1CC(NC(=O)OCc2ccccc2)Cc2cccnc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CO
Product: O=C(NC1Cc2cccnc2C(O)C1)OCc1ccccc1
Reaction time: 24 h
Yield: 97 %

Procedure:
To a stirred solution of 8-acetoxy-6-benzyloxycarbonylamino-5,6,7,8-tetrahydroquinoline, cis-trans mixture (1.73 g, 5.07 mmol) in methanol (16 mL) at room temperature under nitrogen was added 10% aqueous potassium carbonate solution (8 mL, 5.79 mmol). After 24 h, the reaction mixture was diluted with methylene chloride. The organic layer was washed sequentially with saturated aqueous ammonium chloride solution and brine, dried over anhydrous magnesium sulfate, and evaporated under vacuum to obtain the title compound (1.47 g, 97%). Silica gel chromatography (eluted with 5% methanol in chloroform) provided inefficient separation of the cis and trans isomers. The cis isomer eluted first. Stereochemical assignment was made based on NOE experiments. Cis isomer: 13C NMR (400 MHz, CDCl3) δ 156.3, 155.8, 147.5, 138.0, 136.5, 128.5, 128.1, 123.1, 77.4, 67.5, 66.5, 44.4, 35.0. HPLC/MS [M+H]+, 299.