Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[C:7]([O:11][C:12]([N:14]([C:28]1[CH:33]=[CH:32][N:31]=[CH:30][CH:29]=1)[CH2:15][CH2:16][O:17][C:18]1[CH:19]=[C:20]([CH:24]=[C:25]([Cl:27])[CH:26]=1)[C:21]([OH:23])=O)=[O:13])([CH3:10])([CH3:9])[CH3:8].[CH3:34][O:35][C:36](=[O:46])[CH2:37][CH2:38][NH:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1.CCN(C(C)C)C(C)C>ClCCl.CN(C1C=CN=CC=1)C.CN(C=O)C>[CH3:34][O:35][C:36](=[O:46])[CH2:37][CH2:38][N:39]([C:21](=[O:23])[C:20]1[CH:24]=[C:25]([Cl:27])[CH:26]=[C:18]([O:17][CH2:16][CH2:15][N:14]([C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])[C:28]2[CH:29]=[CH:30][N:31]=[CH:32][CH:33]=2)[CH:19]=1)[C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1
Reactant: COC(=O)CCNc1ccccc1
Reactant: CC(C)(C)OC(=O)N(CCOc1cc(Cl)cc(C(=O)O)c1)c1ccncc1
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 73.3 %

Procedure:
2M Oxalyl chloride solution in dichloromethane (1.8 ml), and DMF (0.05 ml) were added to a suspension of 3-[2-(tert-butoxycarbonyl-pyridin-4-yl-amino)-ethoxy]-5-chloro-benzoic acid (1.18 g) in anhydrous dichloromethane (30 ml). The reaction was stirred at room temperature for 1 h then 3-phenylamino-propionic acid methyl ester (0.644 g), DMAP (0.036 g) and DIPEA (1.04 ml) were added. The reaction mixture was stirred at room temperature for 20 h and partitioned between ethyl acetate and 1M aqueous hydrochloric acid. The aqueous layer was removed and the organic phase washed with saturated aqueous sodium bicarbonate, water and dried with brine and over sodium sulphate and concentrated under reduced pressure. The residue was purified by flash column chromatography, eluting with ethyl acetate:petroleum ether (4:1 v/v) and neat ethyl acetate, to give the title compound as a colourless gum (1.22 g).
Reaction SMILES: [CH3:1][NH:2][CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5].C(=O)([O-])O.[Na+].Cl[C:20]([O:22][CH2:23][CH:24]([CH2:29][CH3:30])[CH2:25][CH2:26][CH2:27][CH3:28])=[O:21]>O.O1CCCC1.CC(C)=O>[CH2:29]([CH:24]([CH2:25][CH2:26][CH2:27][CH3:28])[CH2:23][O:22][C:20]([N:2]([CH3:1])[CH2:3][C@@H:4]([C@H:6]([C@@H:8]([C@@H:10]([CH2:12][OH:13])[OH:11])[OH:9])[OH:7])[OH:5])=[O:21])[CH3:30]
Reactant: CNC[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CCCCC(CC)COC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: CCCCC(CC)COC(=O)N(C)C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 5 °C
Reaction time: 8 h
Yield: 49.8 %

Procedure:
In a reactor, 117 g (0.6 mol) of N-methyl-D-glucamine were dissolved in a mixture of 800 ml of water and 400 ml of tetrahydrofuran, and 201.6 g (2.4 mol) of sodium hydrogen carbonate were then dispersed. While the temperature of the reaction mixture was maintained at 5° C., 115.6 g (0.6 mol) of 2-ethylhexyl chloroformate were added dropwise, and the mixture was then allowed to react for 3 hours with stirring at 5° C. and left standing overnight at room temperature. The reaction mixture was then filtered and concentrated; the pasty residue obtained was dissolved in 2 liters of acetone and then filtered after cooling to 5° C. The crystallized product collected was dried. 105 g (50% yield) of N-(2-ethylhexyloxycarbonyl)-N-methyl-D-glucamine, the melting point of which is 74° C., were obtained.
Reaction SMILES: I[CH2:2][C:3]1[CH2:4][S:5][C@@H:6]2[CH:26]([NH:27][C:28](=[O:58])/[C:29](=[N:55]\[O:56][CH3:57])/[C:30]3[N:31]=[C:32]([NH:35]C(C4C=CC=CC=4)(C4C=CC=CC=4)C4C=CC=CC=4)[S:33][CH:34]=3)[C:25](=[O:59])[N:7]2[C:8]=1[C:9]([O:11]C(C1C=CC=CC=1)C1C=CC=CC=1)=[O:10].[CH3:60][NH:61][C:62]1[S:63][C:64]2[CH:69]=[CH:68][N:67]=[CH:66][C:65]=2[N:70]=1.Cl>C1COCC1.C(O)=O.O>[NH2:35][C:32]1[S:33][CH:34]=[C:30](/[C:29](=[N:55]/[O:56][CH3:57])/[C:28]([NH:27][CH:26]2[C:25](=[O:59])[N:7]3[C:8]([C:9]([O-:11])=[O:10])=[C:3]([CH2:2][N+:67]4[CH:68]=[CH:69][C:64]5[S:63][C:62]([NH:61][CH3:60])=[N:70][C:65]=5[CH:66]=4)[CH2:4][S:5][C@H:6]23)=[O:58])[N:31]=1
Reactant: CNc1nc2cnccc2s1
Reactant: CO/N=C(\C(=O)NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(CI)CS[C@H]12)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Solvent: O=CO
Product: CNc1nc2c[n+](CC3=C(C(=O)[O-])N4C(=O)C(NC(=O)/C(=N\OC)c5csc(N)n5)[C@H]4SC3)ccc2s1
Yield: 27.5 %

Procedure:
A solution of AgClO4 (207 mg, 1.0 mmole) in THF (1 ml) was added in approximately four equal portions, during one hour, to a stirred solution at 25° C. of benzhydryl 3-iodomethyl-7-[(Z)-2-methoxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-cephem-4-carboxylate [VIIa] (913 mg, 1.0 mmole) and 2-methylaminothiazolo[4,5-c]pyridine (165 mg, 1.0 mmole) in THF (8 ml). Stirring was continued for an additional hour. The mixture was filtered through diatomaceous earth and the filtrate concentrated. A solution of the residue in CH2Cl2 was washed with dilute aqueous HCl and then with brine. The CH2Cl2 layer was dried over Na2SO4 and concentrated to leave the crude protected quaternized cephalosporin as a brown froth. Concentrated HCl (0.5 ml) was added to a stirred solution of the froth in 95-97% formic acid (15 ml) at 25° C. The solution was stirred for 50 minutes and then was diluted with H2O (20 ml). The resulting mixture was filtered and the filtrate concentrated on a rotary evaporator. The residue was suspended in H2O (20 ml), and the pH of the stirred mixture was adjusted to 5.1 with dilute NaOH. The mixture was filtered and the product isolated from the filtrate by high performance low pressure liquid chromatography (HPLPLC). The filtrate was applied to a glass column (300×22 mm) which was packed with Waters PrepPAK-500/C18. The column was eluted first with H2O and then with H2O-10% acetonitrile to elute the title compound. The appropriate fractions were combined and partially concentrated to remove the CH3CN. The aqueous solution was lyophilized to afford 154 mg of the title compound (Iy).
Reaction SMILES: OC1C(=O)NN=C(CCC2C=CC=CC=2)C=1.C([O:24][C:25]1[N:26]=[N:27][C:28]([C:39]#[C:40][C:41]2[CH:46]=[CH:45][C:44]([CH3:47])=[C:43]([F:48])[CH:42]=2)=[CH:29][C:30]=1[O:31]CC1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>CO>[F:48][C:43]1[CH:42]=[C:41]([CH2:40][CH2:39][C:28]2[CH:29]=[C:30]([OH:31])[C:25](=[O:24])[NH:26][N:27]=2)[CH:46]=[CH:45][C:44]=1[CH3:47]
Reactant: Cc1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)cc1F
Agent: O=c1[nH]nc(CCc2ccccc2)cc1O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(CCc2cc(O)c(=O)[nH]n2)cc1F

Procedure:
Prepared by the same method as for 4-hydroxy-6-(2-phenylethyl)pyridazin-3(2H)-one (Example 1) from 3,4-bis(benzyloxy)-6-[2-(3-fluoro-4-methylphenyl)ethynyl]pyridazine (Intermediate 28) except that the solvent mixture used for the hydrogenation was ethyl acetate and methanol (1:1) and the final product was recrystallised from ethyl acetate.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:10])[C:5]([Cl:9])=[C:6]([Cl:8])[CH:7]=1.[CH3:11][C:12]1(C)[C:16](C)(C)OB(C(C)=C)O1.C([O-])([O-])=O.[K+].[K+].CC(=O)OCC>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:10][C:4]1[CH:3]=[C:2]([C:12]([CH3:16])=[CH2:11])[CH:7]=[C:6]([Cl:8])[C:5]=1[Cl:9]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(Br)cc(Cl)c1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1CCOC1
Product: C=C(C)c1cc(Cl)c(Cl)c(Cl)c1
Yield: 80.6 %

Procedure:
To a mixture of 5-bromo-1,2,3-trichlorobenzene (3.64 g, 14 mmol), 4,4,5,5-tetramethyl-2-(prop-1-en-2-yl)-1,3,2-dioxaborolane (2.5 g, 15 mmol) and Pd(PPh3)2Cl2 (983 mg, 1.4 mmol) in THF (50 ml) and H2O (5 ml) at rt was added K2CO3 (5.8 g, 42 mmol). The mixture was refluxed overnight and then concentrated under reduced pressure. The residue was purified by column chromatography over silica gel eluted with PE:EA (5:1 to 2:1) to give the desired intermediate (2.5 g, yield 81%) as a yellow oil: 1H NMR (300 MHz, CDCl3): δ 7.44 (s, 2H), 5.39 (s, 1H), 5.19-5.18 (t, 1H), 2.10 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH:37]([O:39][CH3:40])[CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH2:41].C[Si]([N-][Si](C)(C)C)(C)C.[Na+]>CN(C=O)C>[Cl:24][C:25]1[CH:33]=[C:32]([C:34]#[C:35][CH2:36][CH:37]([O:39][CH3:40])[CH3:38])[C:28]2[O:29][CH2:30][O:31][C:27]=2[C:26]=1[NH:41][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: COC(C)CC#Cc1cc(Cl)c(N)c2c1OCO2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Nc3c(Cl)cc(C#CCC(C)OC)c4c3OCO4)ncnc2cc1OCCCN1CCOCC1
Yield: 64.3 %

Procedure:
This was prepared by the method described in example 4 but using 4-chloro-6-methoxy-7-(3-morpholin-4-ylpropoxy)quinazoline (200 mg, 0.59 mmol), 5-chloro-7-(4-methoxypent-1-yn-1-yl)-1,3-benzodioxole-4-amine (174 mg, 0.65 mmol) and sodium bis(trimethylsilyl)amide (1.0M in THF, 1.24 ml) in DMF (3 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (216 mg, 64%) as an off-white solid; NMR Spectrum:(CDCl3) 1.33 (d, 3H), 2.12 (quintet, 2H), 2.47 (m, 4H), 2.55 (m, 3H), 2.74 (dd, 1H), 3.40 (s, 3H), 3.58 (m, 1H), 3.71 (m, 4H), 3.98 (s, 3H), 4.25 (t, 2H), 6.07 (s, 2H), 6.90 (s, 1H), 7.03 (s, 1H), 7.09 (s, 1H), 7.30 (s, 1H ), 8.62 (s, 1H); Mass Spectrum: M+H+ 569/571.
Reaction SMILES: [CH:1]([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4]=1[C:12]([O:14][CH2:15][CH3:16])=[O:13])=O.[Br-].[CH:18]1([CH2:24][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1>>[C:18]1([CH:24]=[CH:1][C:3]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CCOC(=O)c1[nH]c2ccccc2c1C=O
Reactant: c1ccc([P+](CC2CCCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: [Br-]
Agent: c1ccc(C[P+](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: CCOC(=O)c1[nH]c2ccccc2c1C=Cc1ccccc1
Yield: 73 %

Procedure:
Using the procedure of Example 121 but replacing the resultant compound of Example 98 with the resultant compound of Example 97 and replacing the resultant compound of Example 120 with benzyltriphenylphosphonium bromide gave the desired compound in 73% yield after silica gel chromatography using 4:1 hexane/ethyl acetate. 1H NMR (CDCl3) δ 1.49 (t,J=7 Hz,3H), 4.48 (q,J=7 Hz,2H), 7.2-7.3 (m,2H), 7.35-7.45 (m,5H), 7.60 (br d,J=8 Hz,1H), 8.07 (d,J=16 Hz,1H), 8.16 (d,J=8 Hz,1H), 8.88 (br,1H). Mass spectrum: (M+H)+ =292.
Reaction SMILES: [CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([O:8]CC)=[O:7].S(=O)(=O)(O)O.C(O)(=O)C>O>[CH3:1][CH:2]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:3][CH2:4][CH2:5][C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)CCCC(C)c1ccccc1
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Solvent: O
Product: CC(CCCC(=O)O)c1ccccc1
Yield: 0.1 %

Procedure:
A mixture of ethyl 5-methyl-5-phenylpentanoate (16.0 g, 72.6 mmol), a 30% aqueous sulfuric acid solution and acetic acid (250 ml) was stirred at 75-80° C. for 6 hours. The reaction mixture was poured into cold water and extracted twice with toluene, and the extract solution was washed twice with a 5% aqueous sodium chloride solution and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 13.4 mg of 5-methyl-5-phenylpentanoic acid.
Reaction SMILES: [C:1]([N:8]1[CH:12]=[CH:11][N:10]=[CH:9]1)([N:3]1[CH:7]=[CH:6]N=[CH:4]1)=[O:2].N[C:14]1[CH:19]=CC=CN=1.CCN(C(C)C)C(C)C.[CH3:29][C:30]1[C:31]([CH2:36][N:37]([CH2:44][C:45]2[C:50]([CH3:51])=[CH:49][CH:48]=[CH:47][N:46]=2)[CH:38]2CCNC[CH2:39]2)=[N:32][CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:10]1[CH:11]=[CH:12][CH:19]=[CH:14][C:9]=1[NH:8][C:1]([N:3]1[CH2:4][CH2:39][CH:38]([N:37]([CH2:36][C:31]2[C:30]([CH3:29])=[CH:35][CH:34]=[CH:33][N:32]=2)[CH2:44][C:45]2[C:50]([CH3:51])=[CH:49][CH:48]=[CH:47][N:46]=2)[CH2:6][CH2:7]1)=[O:2]
Reactant: Cc1cccnc1CN(Cc1ncccc1C)C1CCNCC1
Reactant: Nc1ccccn1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cccnc1CN(Cc1ncccc1C)C1CCN(C(=O)Nc2ccccn2)CC1
Temperature: 60 °C
Reaction time: 20 h
Yield: 51.3 %

Procedure:
A solution of 1,1′-carbonyldiimidazole (0.0924 g, 0.57 mmol), 2-aminopyridine (0.0489 g, 0.52 mmol), and DIPEA (0.18 mL, 1.04 mmol) in CH2Cl2 (6 mL) was stirred at room temperature for 4.5 hours. The mixture was concentrated, then dissolved in DMF (6 mL), and DIPEA (0.18 mL, 1.04 mmol) and COMPOUND 249 (0.1614 g, 0.52 mmol) were added. The mixture stirred at 60° C. for 20 hours, then concentrated. Saturated NaHCO3 (10 mL) was added and extracted with CH2Cl2 (3×40 mL). The combined organic extracts were dried (Na2SO4), filtered and concentrated. Purification of the crude material by column chromatography on silica gel (50:1:1 CH2Cl2-MeOH—NH4OH) provided 0.1148 g (46%) COMPOUND 344 as a white solid. 1H NMR (CDCl3) δ 1.61-1.74 (m, 2H), 1.95 (d, 2H, J=12.0 Hz), 2.07 (s, 6H), 2.68-2.77 (m, 3H), 3.80 (s, 4H), 4.17 (d, 2H, J=13.2 Hz), 6.88-6.92 (m, 1H), 7.05-7.09 (m, 2H), 7.35-7.37 (m, 2H), 7.58-7.65 (m, 2H), 7.98 (d, 1H, J=8.4 Hz), 8.17 (d, 1H, J=4.8 Hz), 8.32 (d, 2H, J=6.0 Hz). 13C NMR (CDCl3) 18.37, 27.49, 44.78, 54.96, 57.77, 113.67, 118.68, 122.36, 122.88, 133.82, 135.55, 138.51, 146.26, 147.82, 153.23, 154.14, 157.41. ES-MS m/z 431.3 (M+H). Anal. Calcd. for C25H30N6O.0.5H2O.0.6C3H4N2: C, 67.00; H, 7.01; N, 20.99. Found: C, 67.11; H, 6.94; N, 21.04.
Reaction SMILES: C[S:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[C:5]#[N:6].O.S(Cl)(Cl)(=O)=[O:13]>ClC1C=CC=CC=1>[S:2]1[C:3]2[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=2[C:5](=[O:13])[NH:6]1
Reactant: CSc1ccccc1C#N
Reactant: O=S(=O)(Cl)Cl
Solvent: O
Solvent: Clc1ccccc1
Product: O=c1[nH]sc2ccccc12
Temperature: 25 °C
Yield: 95.9 %

Procedure:
To a 500 ml four-necked flask equipped with a stirrer, a thermometer, and a condenser, 29.8 g (0.2 mol) of 2-(methylthio)benzonitrile, 100 g of monochlorobenzene, and 4.32 g (0.24 mol) of water were added. To the flask, 29.7 g (0.22 mol) of sulfuryl chloride was added with stirring at a temperature of from 5° to 15° C., heated to a temperature of from 70° to 80° C., and allowed to react for 1 hour. After the completion of the reaction, the reaction mixture was cooled to room temperature to precipitate white crystals. The white crystals were washed with monochlorobenzene, and dried to give 29.0 g of 1,2-benzisothiazol-3-one (melting point: 157° to 158° C.). The yield of the product was 96% against the starting 2-(methylthio)benzonitrile.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[NH:12][C:11](=[O:19])[C:10]=2[NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:32])[CH3:31])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+].Br[CH2:45][CH:46]([CH3:48])[CH3:47]>CN(C=O)C.O>[CH2:45]([N:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][N:14]=2)[C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)=[C:10]([NH:20][C:21]([NH:23][C:24]2[C:29]([CH:30]([CH3:31])[CH3:32])=[CH:28][CH:27]=[CH:26][C:25]=2[CH:33]([CH3:35])[CH3:34])=[O:22])[C:11]1=[O:19])[CH:46]([CH3:48])[CH3:47]
Reactant: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)[nH]c3ncccc23)c1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cccc(-c2c(NC(=O)Nc3c(C(C)C)cccc3C(C)C)c(=O)n(CC(C)C)c3ncccc23)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 61.9 %

Procedure:
To a solution of N-[4-(3-methoxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl]-N'-(2,6-diisopropylphenyl)urea (100 mg, 0.21 mmol) in DMF (5 ml) were added potassium carbonate (1.39 g, 10.1 mmol), potassium iodide (10 mg, 0.07 mmol) and 1-bromo-2-methylpropane (58 mg, 0.43 mmol), and the mixture was stirred at room temperature for five hours. The mixture was poured into water, and the mixture was extracted with ethyl acetate. The extract was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (1-3% methanol in chloroform) to give the title compound (71 mg, 0.13 mmol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:16][C:17]([NH:19][C:20]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][CH:21]=1)=[NH:18])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1.[C:27]([N:34]1[CH:38]=[CH:37]N=C1)(N1C=CN=C1)=[O:28].[Cl:39][C:40]1[CH:45]=[CH:44]C(CN)=[CH:42][CH:41]=1.Cl>C1COCC1.CCOCC>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([NH:16][C:17]([NH:19][C:20]1[CH:21]=[CH:22][C:23]([Cl:26])=[CH:24][CH:25]=1)=[N:18][C:27]([NH:34][CH2:38][C:37]1[CH:44]=[CH:45][C:40]([Cl:39])=[CH:41][CH:42]=1)=[O:28])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[CH:12]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: NCc1ccc(Cl)cc1
Reactant: N=C(Nc1ccc(Cl)cc1)NC(Cn1ccnc1)c1ccc(Cl)cc1Cl
Agent: Cl
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(N=C(Nc1ccc(Cl)cc1)NC(Cn1ccnc1)c1ccc(Cl)cc1Cl)NCc1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a stirred solution of N-[1-(2,4-dichlorophenyl)-2-(imidazol-1-yl)-ethyl]-N′-(4-chlorophenyl)guanidine of Example 231 (step B) in THF was added carbonyldimidazole. The reaction mixture was allowed to stir at rt for 2 h, then 4-chlorophenylmethylamine was added. This was allowed to stir at rt for 18 h. The solvent was removed and the residue partitioned between EtOAc and ammonium chloride solution. The organic layer was separated, dried, concentrated, and purified by silica gel column chromatography (EtOAc, MeOH, NH4OH; 90:10:0.1) to give an oil. The oil was dissolved in MEOH, and to this was added HCl solution in ether. The solvent was removed to give the title compound as a solid. MS (ES): r/z 576 [M+H]+.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:6]=1[C:5]2=[O:22].[B-][C:24]#[N:25].[Na+].[CH2:27]=O>C(O)(=O)C>[CH3:27][N:25]([CH3:24])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7]1[N:12]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][N:17]=3)[N:13]=[C:14]([CH3:15])[C:6]=1[C:5]2=[O:22]
Reactant: Cc1nn(-c2ccccn2)c2[nH]c3ccc(N)cc3c(=O)c12
Reactant: C=O
Reactant: [B-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Product: Cc1nn(-c2ccccn2)c2[nH]c3ccc(N(C)C)cc3c(=O)c12
Yield: 51.1 %

Procedure:
A solution of 6-amino-3-methyl-1-(2-pyridinyl)-1,9-dihydro-4H-pyrazolo[3,4-b]quinolin-4-one (1.00 g, 3.43 mmol), sodium cyanotrihydroborate (1.08 g, 17.2 mmol) and paraformaldehyde (1.00 g) in acetic acid (20 mL) was stirred at room temperature for 18 hours under an argon atmosphere. The reaction solvent was evaporated under reduced pressure, and the residue was poured into iced water. After the solution was made basic by the addition of a sodium hydroxide solution, the organic matter was extracted with chloroform. The extract was washed with saturated brine and water and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue thus obtained was purified by silica gel column chromatography (chloroform to chloroform:methanol=99:1) to give the title compound (0.56 g, 51% yield).
Reaction SMILES: CS(O[CH2:6][C:7]1([NH:10][C:11]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:12])[CH2:9][CH2:8]1)(=O)=O.[N-:21]=[N+:22]=[N-:23].[Na+].O>CN(C=O)C>[N:21]([CH2:6][C:7]1([NH:10][C:11](=[O:12])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:9][CH2:8]1)=[N+:22]=[N-:23]
Reactant: [N-]=[N+]=[N-]
Reactant: CS(=O)(=O)OCC1(NC(=O)OCc2ccccc2)CC1
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCC1(NC(=O)OCc2ccccc2)CC1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a stirred solution of (1-(benzyloxycarbonylamino)cyclopropyl)methyl methanesulfonate (5 g, 16.7 mmol) in 100 mL of DMF was added NaN3 (3 g, 46.15 mmol) in one portion at room temperature. Then the reaction mixture was stirred at 70° C. for 16 hours. The mixture was poured into 400 mL of water, extracted with ethyl acetate (600 mL). The organic phase was washed with brine (50 mL) and dried over anhydrous sodium sulfate. The drying agent was removed by filtration and the filtrate was evaporated at 40° C. under reduced pressure to give a crude product as colorless oil, which was used in the next step without further purification MS: (M+H)+=247.2.
Reaction SMILES: [CH3:1][C@H:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[C:8](=O)[NH:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([C:17]([O:19][CH3:20])=[O:18])=[CH:12][CH:11]=2.P(Cl)(Cl)([Cl:24])=O>>[Cl:24][C:8]1[C:7]([N:3]2[CH2:4][CH2:5][CH2:6][C@@H:2]2[CH3:1])=[N:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]([O:19][CH3:20])=[O:18])[CH:14]=2)[N:9]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COC(=O)c1ccc2[nH]c(=O)c(N3CCC[C@@H]3C)nc2c1
Product: COC(=O)c1ccc2nc(Cl)c(N3CCC[C@@H]3C)nc2c1
Yield: 80 %

Procedure:
The solution of methyl 3-[(2S)-2-methylpyrrolidin-1-yl]-2-oxo-1,2-dihydroquinoxaline-6-carboxylate (5.9 g, 20.54 mmol,) in phosphorus oxychloride (100 mL) was stirred overnight at 120° C. in an oil bath. The reaction mixture was concentrated in vacuo and diluted with dichloromethane (500 mL) and ice-water (500 mL), adjusted to pH 7 with NaHCO3 solution. The solution was extracted with dichloromethane (3×200 mL) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated in vacuo to give a residue, which was purified by silica gel column chromatography eluting with 2% ethyl acetate in petroleum ether to afford methyl 2-chloro-3-[(2S)-2-methylpyrrolidin-1-yl]quinoxaline-6-carboxylate as a yellow solid (5 g, 80%).
Reaction SMILES: [Br:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)=[C:4]([C:15]#[N:16])[CH:3]=1.[Cl:17]OC(C)(C)C.O.BrC1NC(C2C=CC(Cl)=C(Cl)C=2)=C([N+]([O-])=O)C=1>O1CCCC1>[Br:1][C:2]1[NH:6][C:5]([C:7]2[CH:12]=[CH:11][C:10]([Cl:13])=[C:9]([Cl:14])[CH:8]=2)=[C:4]([C:15]#[N:16])[C:3]=1[Cl:17]
Reactant: N#Cc1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Reactant: CC(C)(C)OCl
Agent: O=[N+]([O-])c1cc(Br)[nH]c1-c1ccc(Cl)c(Cl)c1
Solvent: C1CCOC1
Solvent: O
Product: N#Cc1c(-c2ccc(Cl)c(Cl)c2)[nH]c(Br)c1Cl
Reaction time: 8 h

Procedure:
A sample of 5-bromo-2-(3,4-dichlorophenyl)pyrrole-3-carbonitrile (0.158 g, 0.005 mole) is dissolved in tetrahydrofuran (5 mL). An equivalent amount of t-butyl hypochlorite is added and the solution stirred overnight. The solution is poured into water and the precipitate (0.052 g, 30%) is collected. The mp is >275° C. In a similiar fashion one can prepare 2-bromo-3-chloro-5-(3,4-dichlorophenyl)-4-nitropyrrole by starting with 2-bromo-5-(3,4-dichlorophenyl)-4-nitropyrrole.