Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1.[Br:17][CH:18]=[CH:19][CH2:20]Br.C(=O)([O-])[O-].[K+].[K+].CCOC(C)=O.CCCC(C)C>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]([CH2:20][CH:19]=[CH:18][Br:17])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[Cl:16])[N:5]=[CH:4][N:3]=1
Reactant: BrC=CCBr
Reactant: Cc1ccc(Cl)c(Nc2cc(Cl)ncn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCC(C)C
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: Cc1ccc(Cl)c(N(CC=CBr)c2cc(Cl)ncn2)c1
Temperature: 25 °C

Procedure:
4-Chloro-6-(2-chloro-5-methylanilino)pyrimidine (Reference Example 12) (0.5 g, 1.97 mmol) and 1,3-dibromopropene [cis/trans mixture] (0.6 g, 3.0 mmol) were dissolved in NMP (2 ml). Anhydrous potassium carbonate (0.54 g, 4 mmol) was added and the mixture stirred at room temperature for seventeen hours. After aqueous work-up the product was obtained by column chromatography on silica gel using EtOAc/isohexane mixtures (0.68 g, 93%). M/z 372 (MH)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][OH:20])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[N:10]2.[H-].[Na+].I[CH3:34]>O1CCCC1>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@:9]12[CH2:18][O:17][C@@H:16]([CH2:19][O:20][CH3:34])[CH2:15][C@H:14]1[C@@H:13]([CH3:21])[S:12][C:11]([NH:22][C:23](=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[N:10]2
Reactant: CI
Reactant: C[C@H]1SC(NC(=O)c2ccccc2)=N[C@@]2(c3ccc(F)cc3F)CO[C@@H](CO)C[C@@H]12
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COC[C@H]1C[C@H]2[C@@H](C)SC(NC(=O)c3ccccc3)=N[C@@]2(c2ccc(F)cc2F)CO1
Temperature: 25 °C
Reaction time: 0.42 h

Procedure:
A solution of N-[(4R,4aR,6R,8aS)-8a-(2,4-difluorophenyl)-6-(hydroxymethyl)-4-methyl-4,4a,5,6,8,8a-hexahydropyrano[3,4-d][1,3]thiazin-2-yl]benzamide (P2) (140 mg, 0.324 mmol) in tetrahydrofuran (2.5 mL) was added to a mixture of sodium hydride (60% in mineral oil, 31 mg, 0.78 mmol) in tetrahydrofuran (5 mL), and the reaction mixture was stirred at room temperature for 25 minutes. To this was added iodomethane (24.3 μL, 0.389 mmol), and the reaction mixture was heated at 41° C. for 6 hours, cooled back to room temperature, and quenched with saturated aqueous ammonium chloride solution (15 mL). After extraction with ethyl acetate (3×20 mL), the combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (Gradient: 0% to 100% ethyl acetate in heptane) provided the product as a white solid. Yield: 110 mg, 0.246 mmol, 76%. 1H NMR (400 MHz, CD3OD) δ 8.12 (br d, J=7 Hz, 2H), 7.51-7.57 (m, 1H), 7.40-7.50 (m, 3H), 7.02-7.11 (m, 2H), 4.14 (br d, J=11.7 Hz, 1H), 3.90 (d, J=11.9 Hz, 1H), 3.83-3.9 (m, 1H), 3.44-3.54 (m, 2H), 3.37-3.38 (s, 3H), 3.18-3.28 (br m, 1H), 2.96-3.05 (br m, 1H), 1.73-1.81 (m, 1H), 1.51-1.63 (m, 1H), 1.25 (d, J=6.8 Hz, 3H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]#[N:15].[CH2:20](N)[CH2:21][NH2:22]>>[F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[NH:11][C:12]1[CH:19]=[CH:18][CH:17]=[CH:16][C:13]=1[C:14]1[NH:22][CH2:21][CH2:20][N:15]=1
Reactant: NCCN
Reactant: N#Cc1ccccc1Nc1ccc([N+](=O)[O-])cc1F
Product: O=[N+]([O-])c1ccc(Nc2ccccc2C2=NCCN2)c(F)c1
Yield: 60 %

Procedure:
A mixture of 8.5 g (33 mmol) of 2-(2-fluoro-4-nitrophenylamino)-benzonitrile and 16.7 ml (249 mmol) of ethylenediamine was heated in an autoclave to 180° for 1 hour, and the reaction mixture was then worked up as described in Example (1a). After crystallisation from dichloromethane and ether/petroleum ether, the reaction product was obtained in a 60% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8](Cl)=[CH:7][C:6]=1[Cl:12].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH2:51]([C:53]([C:72]1[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([C:86]([F:89])([F:88])[F:87])([OH:85])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=1)([C:56]1[CH:61]=[CH:60][C:59](B2OC(C)(C)C(C)(C)O2)=[C:58]([CH3:71])[CH:57]=1)[CH2:54][CH3:55])[CH3:52]>C1(C)C=CC=CC=1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O>[CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:59]2[CH:60]=[CH:61][C:56]([C:53]([CH2:54][CH3:55])([C:72]3[CH:77]=[CH:76][C:75](/[CH:78]=[CH:79]/[C:80]([OH:85])([C:86]([F:88])([F:89])[F:87])[C:81]([F:84])([F:83])[F:82])=[C:74]([CH3:90])[CH:73]=3)[CH2:51][CH3:52])=[CH:57][C:58]=2[CH3:71])=[CH:7][C:6]=1[Cl:12]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(B2OC(C)(C)C(C)(C)O2)c(C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCC(CC)(c1ccc(/C=C/C(O)(C(F)(F)F)C(F)(F)F)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)c(Cl)c2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h
Yield: 7.1 %

Procedure:
(2,4-Dichloro-phenyl)acetic acid methyl ester (Example 41; 28.7 mg, 0.131 mmol), palladium acetate (2.0 mg, 0.009 mmol), 2-dicyclohexylphosphino-2′,6′-dimethoxy-1,1′-biphenyl (7.2 mg, 0.018 mmol), potassium phosphate (56 mg, 0.263 mmol) and water (0.1 mL) were added to a solution of (E)-4-(4-{1-ethyl-1-[3-methyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-propyl}-2-methyl-phenyl)-1,1,1-trifluoro-2-trifluoromethyl-3-buten-2-ol (Example 26-(5); 50 mg, 0.088 mmol) in toluene (1 mL). After replacement with nitrogen, the mixture was stirred at 100° C. overnight. Then, the reaction mixture was filtered through amino silica gel, and the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (hexane:ethyl acetate=2:1) to give the target compound as a colorless oil (3.9 mg, 7%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=1.[N+:23]([C:26]1[CH:33]=[CH:32][CH:31]=[CH:30][C:27]=1[CH:28]=O)([O-:25])=[O:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>O1CCCC1.O.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][CH:7]=[C:6]2[O:15][C:16]1[CH:17]=[CH:18][C:19](=[N:22][CH2:28][C:27]2[CH:30]=[CH:31][CH:32]=[CH:33][C:26]=2[N+:23]([O-:25])=[O:24])[CH2:20][CH:21]=1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3)c2cc1OC
Reactant: O=Cc1ccccc1[N+](=O)[O-]
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Solvent: O
Product: COc1cc2nccc(OC3=CCC(=NCc4ccccc4[N+](=O)[O-])C=C3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 62.2 %

Procedure:
6,7-Dimethoxy-4-(4-aminophenyloxy)quinoline (500 mg, 1.6873 mmol) was dissolved in tetrahydrofuran (64 ml), and after adding 2-nitrobenzaldehyde (320 mg, 2.1091 mmol) and acetic acid (0.58 ml), sodium triacetoxyborohydride (720 mg, 3.3746 mmol) was further added and the mixture was stirred at room temperature for 11 hours and 30 minutes. Water and saturated sodium bicarbonate were added, the mixture was extracted with ethyl acetate, washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained crystals were washed with hexane-diethyl ether, filtered out, washed with hexane and dried by aspiration at room temperature to obtain the title compound (453 mg) as light yellow crystals.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH:14]([N:16]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:17]([CH:19]1[CH:23]([C:24]([O:26]C(C)(C)C)=[O:25])[CH2:22][C:21](=[O:31])[O:20]1)=[O:18])[CH3:15].C(OC(C1CC(=O)OC1C(O)=O)=O)(C)(C)C.C(C([O-])=O)(C([O-])=O)(C([O-])=O)CC>C(O)=O>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1/[CH:10]=[CH:11]/[CH2:12][CH:13]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH:14]([N:16]([CH2:32][C:33]1[CH:42]=[CH:41][C:40]2[C:35](=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH:34]=1)[C:17]([CH:19]1[CH:23]([C:24]([OH:26])=[O:25])[CH2:22][C:21](=[O:31])[O:20]1)=[O:18])[CH3:15]
Reactant: CC(C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)C1OC(=O)CC1C(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)C1CC(=O)OC1C(=O)O
Agent: CCC(C(=O)[O-])(C(=O)[O-])C(=O)[O-]
Solvent: O=CO
Product: CC(C(C/C=C/c1nc2ccccc2o1)c1ccc2c(c1)OCO2)N(Cc1ccc2ccccc2c1)C(=O)C1OC(=O)CC1C(=O)O
Reaction time: 8 h
Yield: 46.3 %

Procedure:
47 mg of tert-butyl (2RS,3RS)-2-[N-{(1RS,2RS,4E)-5-(2-benzoxazolyl)-1-methyl-2-(3,4-methylenedioxyphenyl)-4-pentenyl}-N-(2-naphthylmethyl)carbamoyl]-5-oxotetrahydrofuran-3-carboxylate prepared in a manner similar to Example 27 except that (2RS,3RS)-3-tert-butoxycarbonyl-5-oxotetrahydrofuran-2-carboxylic acid obtained in Reference Example 4 was used, instead of the 1,2-di-tert-butyl (R*)-1,2,3,-propanetricarboxylate in Example 27, was dissolved in 1 ml of formic acid, and the solution was left to stand at room temperature overnight. The reaction solution was distilled under reduced pressure. Then, toluene was added to the residue, followed by distillation again. The product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1)→chloroform/methanol=50/1) to obtain 20 mg (yield: 46%) of the above-identified compound as white solid.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2.[C-]#N.[Na+]>CS(C)=O.O>[OH:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[C:8](=[O:14])[CH2:7][CH2:6]2
Reactant: COc1cc2c(cc1OC)C(=O)CC2
Agent: [C-]#N
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cc2c(cc1O)CCC2=O
Temperature: 100 °C
Reaction time: 48 h
Yield: 54 %

Procedure:
5,6-Dimethoxy-1-indanone (1 g, 5.20 mmol) and NaCN (2.55 g, 52 mmol) were combined in DMSO (10 mL). The reaction was stirred at 100° C. for two days, cooled, diluted with water and extracted with dichloromethane. The aqueous solution was acidified with concentrated HCl, and extracted with dichloromethane. The organic layer was dried over MgSO4 and evaporated to give the title compound (500 mg). MS (DCI/NH3) m/z: 178.99 (M+H)+. 1H NMR (500 MHz, CD2Cl2) δ ppm 2.59 (t, J=5.62 Hz, 2H) 3.01 (t, J=5.62 Hz, 2H) 3.93 (s, 3H) 6.33 (s, 1H) 6.95 (s, 1H) 7.17 (s, 1H).
Reaction SMILES: [CH2:1]([CH2:3][NH2:4])[OH:2].C(N(CC)CC)C.C(O)C.Cl[CH2:16][C:17]([NH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:39])[F:38])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1)=[O:18]>O>[OH:2][CH2:1][CH2:3][NH:4][CH2:16][C:17]([NH:19][C:20]1[CH:29]=[C:28]2[C:23]([CH:24]=[C:25]([C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=3[C:37]([F:40])([F:38])[F:39])[NH:26][C:27]2=[O:30])=[CH:22][CH:21]=1)=[O:18]
Reactant: O=C(CCl)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: NCCO
Solvent: O
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=C(CNCCO)Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Temperature: 70 °C
Reaction time: 18 h
Yield: 25.5 %

Procedure:
Ethanolamine (22 μl, 0.368 mmol) and triethylamine (128 μl) were added to an ethanol solution (2 ml) that contained the 2-chloro-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (70 mg, 0.184 mmol) obtained in step A. The obtained mixture was stirred at 70° C. for 18 hours. Thereafter, water was added to the reaction solution, and the mixture was then extracted with ethyl acetate. The extract was washed with water and a saturated saline solution, and was then dried over anhydrous sodium sulfate. Thereafter, the solvent was distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (methylene chloride:methanol=10:1), so as to obtain 2-(2-hydroxyethylamino)-N-[1-oxo-3-(2-trifluoromethylphenyl)-1,2-dihydroisoquinolin-7-yl]acetamide (19 mg, 26%).
Reaction SMILES: [NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10](Cl)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:16][CH:17]([CH2:27][NH:28][CH:29]([CH3:31])[CH3:30])[CH2:18][O:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[CH:22][CH:21]=1.Cl>C(O)CCC.CO>[NH:1]([C:8]1[C:13]([Cl:14])=[CH:12][N:11]=[C:10]([NH:24][C:23]2[CH:25]=[CH:26][C:20]([O:19][CH2:18][CH:17]([OH:16])[CH2:27][NH:28][CH:29]([CH3:30])[CH3:31])=[CH:21][CH:22]=2)[N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)NCC(O)COc1ccc(N)cc1
Reactant: Clc1ncc(Cl)c(Nc2ccccc2)n1
Agent: Cl
Solvent: CCCCO
Solvent: CO
Product: CC(C)NCC(O)COc1ccc(Nc2ncc(Cl)c(Nc3ccccc3)n2)cc1
Temperature: 100 °C
Yield: 41.3 %

Procedure:
4-Anilino-2,5-dichloropyrimidine (Method 7, 241 ma, 1.0 mmol) was dissolved in n-butanol (20 ml) and methanol (4 ml). 4-[2-Hydroxy-3-(isopropylamino)propoxy]aniline (obtained as described in Pharmazie 1980, 35, 278; 202 mg, 0.9 mmol) and ethereal hydrogen chloride (1.0M; 2 ml, 2.0 mmol) were added and the solution was heated at 100° C. for 20 hours, allowed to cool to ambient temperature and then concentrated to a volume of 5 ml. The solution was loaded on a Varian Mega Bond Elut column and the column was eluted with 0-4% 2.0M methanolic ammonia solution in DCM. Concentration of the appropriate fractions and recrystallization of the residue from acetonitrile gave the product as a white solid (159 mg, 41%). NMR: 1.0 (d, 6H), 2.5-2.6 (m, 1H), 2.65-2.75 (m, 2H), 3.8-3.95 (m, 3H), 4.9 (br s, 1H), 6.8 (d, 2H), 7.1 (t, 1H), 7.35 (t, 2H), 7.45 (d, 2H), 7.65 (d, 2H), 8.1 (s, 1H), 8.7 (s, 1H), 9.1 (s, 1H); MS (MH+): 428, 430.
Reaction SMILES: O[Li].O.C[O:5][C:6](=[O:46])[CH2:7][C:8]1[CH:45]=[CH:44][CH:43]=[CH:42][C:9]=1[CH2:10][CH2:11][C:12]1[C:17]([C:18]([F:21])([F:20])[F:19])=[CH:16][N:15]=[C:14]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([CH:29]3[CH2:34][CH2:33][N:32]([C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[CH2:31][CH2:30]3)=[N:27][CH:28]=2)[N:13]=1>O.C1COCC1>[C:38]([O:37][C:35]([N:32]1[CH2:31][CH2:30][CH:29]([C:26]2[N:27]=[CH:28][C:23]([NH:22][C:14]3[N:13]=[C:12]([CH2:11][CH2:10][C:9]4[CH:42]=[CH:43][CH:44]=[CH:45][C:8]=4[CH2:7][C:6]([OH:46])=[O:5])[C:17]([C:18]([F:19])([F:20])[F:21])=[CH:16][N:15]=3)=[CH:24][CH:25]=2)[CH2:34][CH2:33]1)=[O:36])([CH3:41])([CH3:39])[CH3:40]
Reactant: COC(=O)Cc1ccccc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)nc2)ncc1C(F)(F)F
Agent: [Li]O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4ccccc4CC(=O)O)n3)cn2)CC1
Temperature: 40 °C

Procedure:
LiOH.H2O (297 mg, 7.1 mmol) was added to a stirred solution of tert-butyl 4-(5-((4-(2-(2-methoxy-2-oxoethyl)phenethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)pyridin-2-yl)piperidine-1-carboxylate (A45) (85 mg, 0.14 mmol) in H2O (2 mL) and THF (20 mL) and the resulting mixture heated at 40° C. for 18 hours. The volatiles were removed in vacuo and the residue was partitioned between EtOAc (100 mL), and aqueous 2 M HCl (50 mL). The layers were separated and the organics washed with water (100 mL), brine (50 mL) and dried over MgSO4. The volatiles were removed in vacuo to give the title compound A46 as an orange foam (74 mg, 89%); 1H NMR (400 MHz, d4-MeOH) δ 9.00 (d, J=1.8 Hz, 1H), 8.66 (s, 1H), 8.36 (dd, J=8.7, 2.6 Hz, 1H), 7.54 (d, J=8.7 Hz, 1H), 7.28-7.10 (m, 4H), 4.25 (d, J=13.4 Hz, 2H), 3.72 (s, 2H), 3.19-3.09 (m, 4H), 3.07-2.83 (m, 3H), 1.94 (d, J=12.7 Hz, 2H), 1.72 (m, 2H), 1.48 (s, 9H). LCMS-A: rt 5.707 min; m/z 586 [M+H]+.
Reaction SMILES: [CH:1]1([N:7]2[C:16]3[C:11](=[CH:12][C:13]([NH:20]C(=O)C(OCC)=O)=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=3)[NH:10][C:9](=[O:28])[C:8]2=[O:29])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>S(=O)(=O)(O)O.C(O)C>[NH2:20][C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][C:14]=1[N+:17]([O-:19])=[O:18])[N:7]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C:8](=[O:29])[C:9](=[O:28])[NH:10]2
Reactant: CCOC(=O)C(=O)Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Agent: O=S(=O)(O)O
Solvent: CCO
Product: Nc1cc2[nH]c(=O)c(=O)n(C3CCCCC3)c2cc1[N+](=O)[O-]
Yield: 111.7 %

Procedure:
42 g (0.1 mol) of ethyl N-(1-cyclohexyl-7-nitro-2,3(1H,4H)-quinoxalinedion-6-yl)oxamate were refluxed in a mixture of 1 l of concentrated sulfuric acid and 500 ml of ethanol for 4 h. The precipitate was filtered off with suction to yield 34 g (100%) of the product. Melting point >250° C. (decomposition).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[N:6][CH:7]=1.[N+:9]([O-])([OH:11])=[O:10]>S(=O)(=O)(O)O>[F:1][C:2]1[CH:3]=[C:4]([OH:8])[C:5]([N+:9]([O-:11])=[O:10])=[N:6][CH:7]=1
Reactant: O=[N+]([O-])O
Reactant: Oc1cncc(F)c1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1ncc(F)cc1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
With ice cooling, 5 g of 5-fluoropyridin-3-ol (44 mmol, 1 equivalent) were dissolved in 43 ml of concentrated sulphuric acid, and 2.8 ml of concentrated nitric acid were added at 0° C. over a period of 5 min. The reaction was warmed to RT and stirred overnight. The mixture was added to 100 g of ice and stirred for 30 min. The solid formed was filtered off and dried under reduced pressure. This gave 5.6 g (81% of theory) of the title compound which was used without further purification for the next reaction.
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:10](=O)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[N+:13]([O-])=O)[N:3]=1.P(Cl)(Cl)(Cl)(Cl)Cl.C([O-])(O)=O.[Na+]>P(Cl)(Cl)(Cl)=O.[Pd]>[NH2:13][C:8]1[CH:7]=[CH:6][CH:5]=[C:4]2[C:9]=1[CH:10]=[N:11][C:2]([CH3:1])=[N:3]2
Reactant: Cc1nc2cccc([N+](=O)[O-])c2c(=O)[nH]1
Agent: [Pd]
Agent: ClP(Cl)(Cl)(Cl)Cl
Agent: O=C([O-])O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ncc2c(N)cccc2n1
Yield: 5.4 %

Procedure:
12.7 g (62 mmol) of 2-methyl-5-nitro-3H-quinazolin-4-one (M. T. Bogert, V. J. Chambers J. Org Chem. 1905, 649-658) and 37.5 g of phosphorus pentachloride are refluxed in 75 ml of phosphoryl chloride over 20 hours. After cooling, it is poured into saturated NaHCO3 solution and extracted with ethyl acetate. The organic phase is dried, and the solvent is removed. 14 g of 4-chloro-2-methyl-5-nitroquinazoline, of which 4.5 g (20.2 mmol) in 225 ml of ethyl acetate and 22.5 ml of triethylamine are dissolved, is obtained. 2 g of palladium is added to carbon, and it is stirred while being cooled with ice for 4 hours under hydrogen atmosphere at normal pressure. Catalyst is removed from the solution by means of filtration through Celite, whereby it is rewashed with 200 ml of ethanol and concentrated by evaporation. After chromatography on silica gel with ethyl acetate-ethanol (0-10%), 530 mg of the product is obtained.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].[CH3:13][NH2:14].CO>CO>[Si:6]([O:5][CH2:4][CH2:3][CH2:2][NH:14][CH3:13])([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7]
Reactant: CN
Reactant: CC(C)(C)[Si](C)(C)OCCCBr
Solvent: CO
Product: CNCCCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
(3-Bromopropoxy)(tert-butyl)dimethylsilane (1.65 g, 6.52 mmol) was dissolved in methanol (13 mL), and the mixture was added to a 40% methyl amine-methanol solution (13.3 mL, 130.0 mmol) under ice cooling, and the mixture was stirred overnight at room temperature. The solvent was evaporated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (ethyl acetate:methanol=10:1→methylene chloride:methanol=10:1, v/v) to give the title compound (864 mg; yield, 65%) as a yellow oily substance.
Reaction SMILES: [O:1]1[C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=[N:2]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[O:21]=[C:22]1[N:26]([C:27]2[CH:32]=[CH:31][C:30]([CH:33]3[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]3)=[C:29]([F:39])[CH:28]=2)[CH2:25][C@H:24]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:23]1>O1CCCC1>[O:1]1[C:5]([C:6]([N:36]2[CH2:37][CH2:38][CH:33]([C:30]3[CH:31]=[CH:32][C:27]([N:26]4[CH2:25][C@H:24]([CH2:40][NH:41][C:42](=[O:44])[CH3:43])[O:23][C:22]4=[O:21])=[CH:28][C:29]=3[F:39])[CH2:34][CH2:35]2)=[O:8])=[CH:4][CH:3]=[N:2]1
Reactant: O=C(O)c1ccno1
Reactant: CC(=O)NC[C@H]1CN(c2ccc(C3CCNCC3)c(F)c2)C(=O)O1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Product: CC(=O)NC[C@H]1CN(c2ccc(C3CCN(C(=O)c4ccno4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 19 h

Procedure:
A solution of isoxazole-5-carboxylic acid (79 mg) and 1,1'-carbonyldiimidazole (80 mg) in dry tetrahydrofuran (2.0 mL) is stirred at ambient temperature for one hour, and a solution of (S)-(-)-N-[[2-oxo-3-[4-(4-piperidinyl)-3-fluorophenyl]-5-oxazolidinyl]methyl]acetamide (EXAMPLE 20, 150 mg) in dry tetrahydrofuran (6.0 mL) is added. The mixture is then stirred at ambient temperature for 19 hours, concentrated under reduced pressure, diluted with methylene chloride (20 mL), washed with saturated aqueous sodium bicarbonate (10 mL), water (10 mL) and saline (10 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to give the crude product which is chromagraphed on silica gel (70-230 mesh, 10 g), eluting with methanol/methylene chloride (7.5/92.5). Pooling and concentration of those fractions with an Rf =0.67 by TLC (methanol/chloroform, 10/90) and recrystallization from chloroform/diethyl ether gives the title compound, mp 290-292° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12].O=S(Cl)[Cl:16]>ClCCCl>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:16])=[O:7])=[CH:4][C:3]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C(O)c1ccc(F)c([N+](=O)[O-])c1
Reactant: O=S(Cl)Cl
Solvent: ClCCCl
Product: O=C(Cl)c1ccc(F)c([N+](=O)[O-])c1
Temperature: 80 °C

Procedure:
To a solution of 4-Fluoro-3-nitro-benzoic acid (1.00 g, 5.40 mmol) dissolved in 1,2-dichloroethane (30 mL) was added SOCl2 (6.42 g, 54.0 mmol). The reaction mixture was then heated to 80° C. for 16 hrs. At this time the reaction mixture was cooled to room temperature and the solvent removed under vacuum to provide the title product.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].C(N(CC)CC)C.[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26](Cl)=[O:27])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[Cl:21][C:22]1[CH:30]=[CH:29][C:25]([C:26]([NH:2][CH:3]([C:4]([O:6][CH2:7][CH3:8])=[O:5])[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[O:27])=[CH:24][CH:23]=1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(=O)C(N)C(=O)OCC
Agent: Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)C(NC(=O)c1ccc(Cl)cc1)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 90.5 %

Procedure:
5.00 g of diethyl aminomalonate hydrochloride and 4.78 g of triethylamine were added to 100 ml of chloroform, and the resulting solution was stirred at the room temperature for 30 minutes. After cooling down the solution to 10° C., 4.13 g of 4-chlorobenzoylchloride was slowly added to the solution and the resulting solution was stirred at the room temperature for 2 hours. Upon the completion of the reaction, the solution was washed with 20 ml of water and 20 ml of 5% sodium bicarbonate and the organic layer was subjected to dry filtration to yield 6.70 g (90.4%) of diethyl 4-chlorobenzamidomalonate.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:10]OC)[C:5]([NH2:8])=[N:6][CH:7]=1.Cl(O)(=O)(=O)=O.CN>O1CCOCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:10][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COC=C(c1ccccc1)c1cc(Br)cnc1N
Agent: CN
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: C1COCCO1
Product: Brc1cnc2[nH]cc(-c3ccccc3)c2c1
Temperature: 100 °C
Yield: 77.9 %

Procedure:
1.093 g (3.582 mmol) of 5-bromo-3-(2-methoxy-1-phenylvinyl)-2-pyridinylamine was dissolved in 60 ml of anhydrous 1,4-dioxane, 800 μl of 70% aqueous perchloric acid was added and the mixture heated to 100° C. for 13 hours. The mixture was then cooled to room temperature and 3 ml of methylamine was added and the mixture evaporated to dryness. The resulting crude was crystallized from hot ethanol to afford 763 mg (2.79 mmol, 78% yield) of 5-bromo-3-phenylpyrrolo[2,3-b]pyridine as a beige-brown to brown crystalline solid. 1H-NMR (d6-DMSO) δ: 12.19 [1H] s, 8.44 [1H] d, 8.34 [1H] d, 7.97 [1H] d, 7.72 [2H] d(m), 7.45 [2H] t, 7.27 [1H] t(m). MS: m/z [MH+].