Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].C([N+](CCCC)(CCCC)CCCC)CCC.[CH:21]([C@@H:24]1[CH2:28][C@@H:27]([C@H:29](Br)[CH2:30][C@H:31]([C:35]([N:37]2[C@@H:41]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][O:39][C:38]2=[O:49])=[O:36])[CH:32]([CH3:34])[CH3:33])[O:26][C:25]1=[O:51])([CH3:23])[CH3:22].[N-]=[N+]=[N-]>C1(C)C=CC=CC=1>[CH:21]([C@@H:24]1[CH2:28][C@@H:27]([C@@H:29]([N:1]=[N+:2]=[N-:3])[CH2:30][C@H:31]([C:35]([N:37]2[C@@H:41]([CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[CH2:40][O:39][C:38]2=[O:49])=[O:36])[CH:32]([CH3:34])[CH3:33])[O:26][C:25]1=[O:51])([CH3:22])[CH3:23]
Reactant: CC(C)[C@@H]1C[C@@H]([C@H](Br)C[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C(C)C)OC1=O
Reactant: [N-]=[N+]=[N-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: CC(C)[C@@H]1C[C@@H]([C@H](C[C@H](C(=O)N2C(=O)OC[C@@H]2Cc2ccccc2)C(C)C)N=[N+]=[N-])OC1=O
Temperature: 25 °C

Procedure:
13.6 g of freshly dried tetrabutylammonium azide are added to a solution, stirred at room temperature, of 17.8 g of 3(S)-isopropyl-5(S)-{1(R)-bromo-4-methyl-3(S)-[(4(S)-benzyloxazolidin-2-on-3-yl)-carbonyl]-pentyl}-tetrahydrofuran-2-one in 180 ml of toluene, and a further 10 g of the azide are added in the course of 160 hours' stirring at room temperature. The reaction mixture is then partitioned between ethyl acetate and water (2×) and saturated sodium chloride solution (1×). The organic phases are combined, dried over sodium sulfate and concentrated. The title compound is obtained from the evaporation residue by means of FC (hexane/ethyl acetate=8:2) and crystallisation from diethyl ether/hexane: m.p.=102°-103° C.; Rf (hexane/ethyl acetate=8:2)=0.2; HPLC Rt =18.55 minutes; FAB-MS (M+H)+ =457.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]#[N:15])=[C:12]([C:16]([O:18]CC)=[O:17])[CH:11]=[N:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH-:21].[K+].Cl>C(O)C>[C:16]([C:12]1[CH:11]=[N:10][N:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[C:13]=1[C:14]([NH2:15])=[O:21])([OH:18])=[O:17]
Reactant: CCOC(=O)c1cnn(-c2ccc(Cl)c(Cl)c2)c1C#N
Reactant: [OH-]
Agent: Cl
Agent: [K+]
Solvent: CCO
Product: NC(=O)c1c(C(=O)O)cnn1-c1ccc(Cl)c(Cl)c1

Procedure:
Fifteen g. of ethyl 1-(3,4-dichlorophenyl)-5-cyano-4-pyrazolecarboxylate was dissolved in 200 ml. of ethanol, and 5.6 g. of potassium hydroxide was added. The reaction mixture was stirred under reflux for 1 hour, and was then poured over a large amount of ice and made acid with concentrated hydrochloric acid. The mixture was filtered, and the solids were found by nuclear magnetic resonance analysis to consist of the partially hydrolyzed 4-carboxy-5-cyanopyrazole. A 2 g. portion of that intermediate was held out for further examination, and the rest of the solids were redissolved in 200 ml. of ethanol and stirred under reflux for 18 hours with 5.6 g. of potassium hydroxide. The mixture was then poured over ice, made acid, and filtered. The solids were recrystallized from ethanol, and the mother liquor was chromatographed over a silica gel column with methanol as the eluent. The product-containing fractions were evaporated to dryness and the residues were recrystallized from methanol to obtain the desired product, m.p. 249°-250°. The elemental analysis was as follows.
Reaction SMILES: [CH:1]([C:4]1[C:5](=[O:20])[NH:6][C:7](=[O:19])[NH:8][C:9]=1[O:10][C:11]1[CH:16]=[C:15]([CH3:17])[CH:14]=[C:13]([CH3:18])[CH:12]=1)([CH3:3])[CH3:2].Cl[CH2:22][C:23](=[O:25])[CH3:24]>>[CH2:22]([N:8]1[C:9]([O:10][C:11]2[CH:12]=[C:13]([CH3:18])[CH:14]=[C:15]([CH3:17])[CH:16]=2)=[C:4]([CH:1]([CH3:3])[CH3:2])[C:5](=[O:20])[NH:6][C:7]1=[O:19])[C:23]([CH3:24])=[O:25]
Reactant: Cc1cc(C)cc(Oc2[nH]c(=O)[nH]c(=O)c2C(C)C)c1
Reactant: CC(=O)CCl
Product: CC(=O)Cn1c(Oc2cc(C)cc(C)c2)c(C(C)C)c(=O)[nH]c1=O
Yield: 45 %

Procedure:
5-Isopropyl-6-(3,5-dimethylphenoxy)-2,4-pyrimidinedione and chloroacetone were reacted by the same way with the example 1 to obtain the titled compound (155 mg, yield: 45%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH:15]=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[CH3:19][NH:20][CH3:21]>>[CH3:19][N:20]([CH3:21])[CH2:15][C:9]1([C:6]2[CH:7]=[CH:8][C:3]([C:2]([F:18])([F:17])[F:1])=[CH:4][CH:5]=2)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: O=CC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Reactant: CNC
Product: CN(C)CC1(c2ccc(C(F)(F)F)cc2)CCCCC1
Yield: 32.9 %

Procedure:
The title compound was prepared from 1-(4-(trifluoromethyl)phenyl)cyclohexane-carbaldehyde (128 mg, 0.50 mmol) and dimethylamine (2.0 M in THF, 0.5 ml, 1.0 mmol) according to General Procedure H2.The crude product was purified by silica gel column chromatography (MeOH/CH2Cl2, MeOH from 0% to 15%) to give N,N-dimethyl-1-(1-(4-(trifluoromethyl)phenyl)-cyclohexyl)methanamine (47 mg, 33%). 1H NMR (CDCl3): δ 1.29-1.38 (m 3H), 1.48-1.57 (m, 3H), 1.62-1.68 (m, 2H), 1.97 (s, 6H), 2.13-2.18 (m, 2H), 2.35 (s, 2H), 7.49 (d, J=8.4 Hz, 2H), 7.55 (d, J=8.4 Hz, 2H). 13C NMR (CDCl3) δ 22.4, 26.7, 34.4, 37.5, 43.9, 48.6, 72.8, 123.3, 125.0, 125.1, 126.0, 127.6, 127.9, 128.3, 150.8.ESI MS m/z 286.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH2:8].[NH:9]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]([C:18](O)=O)=[N:10]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[NH:1]1[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[N:8]=[C:18]1[C:11]1[C:12]2[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=2)[NH:9][N:10]=1
Reactant: Nc1ccccc1N
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: c1ccc2[nH]c(-c3n[nH]c4ccccc34)nc2c1
Temperature: 155 °C
Yield: 45.8 %

Procedure:
A mixture of 1,2-diaminobenzene (108 mg), indazole-3-carboxylic acid (118 mg) and polyphosphoric acid (1 mL) was heated at 150-160° C. for 24 hours. The mixture was cooled, then diluted with ice water (10 mL) and then treated with ethyl acetate (10 mL). The aqueous layer was basified by addition of solid potassium carbonate. The layers were separated and the aqueous layer was extracted with ethyl acetate (10 mL). The combined organic phases were dried and then evaporated. The residue was subjected to chromatography on silica eluting with a mixture of heptane and ethyl acetate to give 3-(1H-benzoimidazol-2-yl)-1H-indazole (78 mg). LC-MS (METHOD A): RT=1.28 minutes; 235 (M+H)+. (b) 3-(5-Methoxy-1H-benzoimidazol-2-yl)-1H-indazole
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([S:7][CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[NH:4][N:3]=1.[Cl:15][CH:16]([C:20](=O)[CH3:21])[C:17](=O)[CH3:18]>C(O)(=O)C>[CH2:8]([S:7][C:5]1[N:6]=[C:2]2[N:1]=[C:17]([CH3:18])[C:16]([Cl:15])=[C:20]([CH3:21])[N:3]2[N:4]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: Nc1n[nH]c(SCc2ccccc2)n1
Solvent: CC(=O)O
Product: Cc1nc2nc(SCc3ccccc3)nn2c(C)c1Cl
Temperature: 25 °C
Yield: 51.4 %

Procedure:
To a suspension of 153 g (0.74 mol) 3-amino-5-benzylthio-1,2,4-triazole in 250 ml of glacial acetic acid was added 100 g (0.74 mol) of 3-chloro-2,4-pentanedione in a dropwise manner. The reaction mixture was heated at reflux for 18 hours and cooled to room temperature. The reaction mixture was poured over ice and the oil which separated solidified upon stirring. The solid was collected by filtration and recrystallized from methanol to yield 116 g (79%) of the desired product as an off white solid, m.p. 164°-166° C. IR and 1H NMR spectra were in agreement with the assigned structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=3)([CH2:16][CH2:17]O)[O:12][C:11]2=[O:26])[CH3:9])=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][NH:30][CH2:29][C:28]1=[O:33]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:19]3[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=3)([CH2:16][CH2:17][N:30]3[CH2:31][CH2:32][NH:27][C:28](=[O:33])[CH2:29]3)[O:12][C:11]2=[O:26])[CH3:9])=[CH:6][CH:7]=1
Reactant: O=C1CNCCN1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCO)(c2ccc(F)cc2)OC1=O
Product: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CCN2CCNC(=O)C2)(c2ccc(F)cc2)OC1=O

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxyethyl)-1,3-oxazinan-2-one and piperazin-2-one following procedures analogous to those described in Example 178. LC-MS Method 2 tR=1.117 min, m/z=506; 1H NMR (CDCl3) 1.42 (d, 3H), 2.16-2.35 (m, 5H), 2.75-2.88 (m, 2H), 3.17-3.40 (m, 3H), 3.56-3.80 (m, 4H), 5.45 (m, 1H), 5.61-6.52 (s, 2H), 6.78 (d, 2H), 7.01-7.24 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][CH:20](SCCC)[NH:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:32])([F:31])[F:30])[CH:3]=1.[CH3:33][NH:34][CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>>[Cl:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:34]([CH3:33])[CH2:35][C:36]5[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=5)=[N:19][C:18]4=[O:26])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:29]([F:30])([F:32])[F:31])[CH:3]=1
Reactant: CCCSC1NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: CNCc1cccnc1
Product: CN(Cc1cccnc1)C1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1

Procedure:
5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-(methyl-pyridin-3-ylmethyl-amino)-thiazol-4-one was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-propylsulfanyl-thiazolidin-4-one and Methyl-pyridin-3-ylmethyl-amine following General Procedure B.
Reaction SMILES: [Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[F:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([C:22]2[CH:23]=[N:24][C:25]([C:28]([F:31])([F:30])[F:29])=[N:26][CH:27]=2)[CH2:20][NH2:21])=[CH:15][CH:14]=1>>[Cl:1][C:2]1[C:10]([F:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:21][CH2:20][CH:19]([C:16]1[CH:17]=[CH:18][C:13]([F:12])=[CH:14][CH:15]=1)[C:22]1[CH:23]=[N:24][C:25]([C:28]([F:30])([F:31])[F:29])=[N:26][CH:27]=1)=[O:6]
Reactant: NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1
Reactant: O=C(O)c1cccc(F)c1Cl
Product: O=C(NCC(c1ccc(F)cc1)c1cnc(C(F)(F)F)nc1)c1cccc(F)c1Cl

Procedure:
From 2-chloro-3-fluorobenzoic acid and 2-(4-fluorophenyl)-2-(2-(trifluoromethyl)pyrimidin-5-yl)ethanamine. LCMS (MH+): m/z=442.1, tR (minutes, Method F)=3.24
Reaction SMILES: C([C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]([S:14]([C:17]2[CH:22]=[CH:21][C:20]([CH3:23])=[CH:19][CH:18]=2)(=[O:16])=[O:15])[CH:4]=1)=O.[C:24]1([CH:29]2CNCC2)[CH2:28][CH2:27][CH2:26][CH:25]=1.[OH2:34]>C1C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:34]=[C:25]1[CH2:26][CH2:27][CH2:28][C:24]1=[CH:29][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:12]#[N:13])[CH:10]=2)[N:5]([S:14]([C:17]2[CH:18]=[CH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)(=[O:15])=[O:16])[CH:4]=1
Reactant: C1=C(C2CCNC2)CCC1
Reactant: Cc1ccc(S(=O)(=O)n2cc(C=O)c3cc(C#N)ccc32)cc1
Reactant: O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Product: Cc1ccc(S(=O)(=O)n2cc(C=C3CCCC3=O)c3cc(C#N)ccc32)cc1
Reaction time: 0.25 h
Yield: 42 %

Procedure:
A solution of 3-formyl-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (6.0 g, 18.5 mMol) and 4-(1−cyclopentenyl)pyrrolidine (3.05 g, 22.2 mMol) in benzene (200 mL) containing p-toluenesufonic acid (100 mg) were heated to reflux with azeotropic removal of water for 2 h. The solution was cooled and concentrated to dryness. The residue was then dissolved in THF (100 mL) and methanol (50 mL) and 6 N HCl (100 mL) was added dropwise with stirring over 15 min. The solution was stirred for 48 h and concentrated in vacuo. The residue was dissolved in chloroform/methanol (9:1), extracted with brine (3×250 mL), and dried over Na2SO4. The solution was concentrated and the residue was purified by silica gel column chromatography (20% ethyl acetate/hexanes-90% ethyl acetate/hexanes) to give 3-(2-oxo-cyclopent-ylidenemethyl)-1-(toluene-4-sulfonyl)-1H-indole-5-carbonitrile (3.0 g, 42%). 1H NMR (400 MHz, CDCl3) δ 8.07 (2H, d, J=6.4 Hz), 7.85 (1H, s), 7.80 (2H, d, J=6.8 Hz), 7.61 (1H, dd, J=8.8 Hz, 1.2 Hz), 7.46 (1H, t, J=2.8 Hz), 7.29 (2H, d, J=8.0 Hz), 2.91 (2H, m), 2.47 (2H, m), 2.37 (3H, s), 2.12 (2H, m); MS m/e 391 (M+H)+.
Reaction SMILES: O1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1.[C:8]([NH2:12])([CH3:11])([CH3:10])[CH3:9]>>[C:8]([N:12]1[CH:6]=[CH:5][C:4](=[O:7])[CH:3]=[CH:2]1)([CH3:11])([CH3:10])[CH3:9]
Reactant: O=c1ccocc1
Reactant: CC(C)(C)N
Product: CC(C)(C)n1ccc(=O)cc1

Procedure:
The starting material may be prepared as follows: A solution of 4-pyrone (730 mg.) in t-butylamine (3.0 ml.) was set aside for 3 days. The excess t-butylamine was evaporated under reduced pressure and the residue was purified by chromatography on Kieselgel 60 (20 g.) eluting with methylene chloride/MeOH 100:0 to 90:10 v/v to give 1-t-butyl-4-pyridone (530 mg.) N.m.r. in solvent A: 1.55(s, 9H); 6.4(d, 2H); 7.6(d, 2H). This material was chlorinated as described in the second part of Example 56 to give 4-chloro-1-t-butylpyridiniumtoluene-p-sulphonate.
Reaction SMILES: [CH3:1][N:2](C1CCCCO1)[C:3]1[S:4][C:5]([CH:8]=O)=[CH:6][N:7]=1.[Cl:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[C:25]([NH2:28])[S:26][CH:27]=2)=[CH:19][CH:18]=1>>[ClH:16].[ClH:16].[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[N:24]=[C:25]([NH:28][CH2:8][C:5]3[S:4][C:3]([NH:2][CH3:1])=[N:7][CH:6]=3)[S:26][CH:27]=2)=[CH:21][CH:22]=1
Reactant: Nc1nc(-c2ccc(Cl)cc2)cs1
Reactant: CN(c1ncc(C=O)s1)C1CCCCO1
Product: CNc1ncc(CNc2nc(-c3ccc(Cl)cc3)cs2)s1
Product: Cl

Procedure:
Compound 2aa was prepared as described for 2w starting from 2-(methyl-(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carbaldehyde and 4-(4-chloro phenyl)thiazol-2-amine: (30 mg, 77%). Mp. 122-123° C.
Reaction SMILES: [CH2:1]([SH:3])[CH3:2].[H-].[Na+].[O:6]=[C:7]1[C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=2[S:10][C:9]([C:17]2[N:22]=[C:21]([CH2:23]S([O-])(=O)=O)[CH:20]=[CH:19][CH:18]=2)=[N:8]1.C(OCC)(=O)C>CN(C=O)C.O>[CH2:1]([S:3][CH2:23][C:21]1[N:22]=[C:17]([C:9]2[S:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:7](=[O:6])[N:8]=2)[CH:18]=[CH:19][CH:20]=1)[CH3:2]
Reactant: CCS
Reactant: O=c1nc(-c2cccc(CS(=O)(=O)[O-])n2)sc2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCSCc1cccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 24.4 %

Procedure:
Ethyl mercaptan (0.25 g, 3.30 mmol) and sodium hydride (60% in oil, 0.15 g, 3.60 mmol) were dissolved in DMF (30 ml), and 6-(4-oxo-4H-1,3-benzothiazin-2-yl)-2-pyridylmethanesulfonate (1.05 g, 3.00 mmol) was added thereto. The reaction mixture was stirred at room temperature for 18 hrs and combined with ethyl acetate and water. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was recrystallized from n-hexane-ethyl acetate to give the titled compound (0.23 g, 24%) as pale yellow crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15]Cl)[N:14]=1)=[O:8].[Na+].[I-:22]>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:5][NH:6][C:7]([NH:9][C:10]1[S:11][CH:12]=[C:13]([CH2:15][I:22])[N:14]=1)=[O:8]
Reactant: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CCl)cs1
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: O=C(NCc1ccc(Cl)c(Cl)c1)Nc1nc(CI)cs1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 1-(3,4-dichlorobenzyl)-3-(4-(chloromethyl)thiazol-2-yl)urea (1 eq) in acetone was added NaI (10 eq) at once. The mixture was stirred at room temperature for 2 h. The volatiles were removed in vacuo and the mixture was taken up in water and EtOAc. The layers were separated and the organic phase was partitioned with water and then brine, dried over Na2SO4, filtered, and concentrated in vacuo to afford 1-(3,4-dichlorobenzyl)-3-(4-(iodomethyl)thiazol-2-yl)urea as a tan-colored solid in near quantitative yield.
Reaction SMILES: [C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-])=O)[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1.C([O-])=O.[NH4+].C(OCC)(=O)C>CO.[Pd]>[C:1](=[O:22])([O:20][CH3:21])[O:2][C:3]1[CH:8]=[C:7]([NH2:9])[C:6]([F:12])=[CH:5][C:4]=1[C:13]1([CH3:19])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(F)cc1C1(C)CCCCC1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)Oc1cc(N)c(F)cc1C1(C)CCCCC1
Yield: 82.1 %

Procedure:
To a solution of 4-fluoro-2-(1-methylcyclohexyl)-5-nitrophenyl methyl carbonate 24.1 g, 77.5 mmol) in 220 mL of CH3OH was added Pd/C 10%, 9.6 g, then ammonium formate (26.7 g, 445 mmol) was portion-wise added to the above reaction mixture at room temperature until starting material is consumed. The mixture was filtrated and the filtrate was evaporated under vacuum. The residue was purified by column chromatography on silica gel diluted with hexane:ethyl acetate=50:1 to give 5-amino-4-fluoro-2-(1-methylcyclohexyl)phenyl methyl carbonate as a red brown oil (17.9 g, 82% yield). 1H NMR (400 MHz, CDCl3) δ 6.99 (d, J=13.6 Hz, 1H), 6.51 (d, J=8.4 Hz, 1H), 3.89 (s, 3H), 3.43 (brs, 2H), 1.96-1.91 (m, 2H), 1.58-1.38 (m, 8H), 1.18 (s, 3H): MS m/z: 281.9 [M+H]+
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2[CH:8]=[CH:9][C:10]([CH:12]=O)=[CH:11][C:6]=2[O:5][CH2:4]1.[CH2:14]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](=[O:27])[CH3:26])[CH:15]([CH3:17])[CH3:16].Cl>O.CCO>[O:3]1[C:7]2[CH:8]=[CH:9][C:10](/[CH:12]=[CH:26]/[C:25]([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=3[O:18][CH2:14][CH:15]([CH3:17])[CH3:16])=[O:27])=[CH:11][C:6]=2[O:5][CH2:4]1
Reactant: CC(=O)c1ccccc1OCC(C)C
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(C)COc1ccccc1C(=O)/C=C/c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a round bottomed flask was added EtOH (20 mL) and potassium hydroxide (320.0 mg, 8 mmol). The mixture was stirred until homogeneous before benzo[d][1,3]dioxole-5-carbaldehyde (0.83 mL, 4.0 mmol) and 1-(2-isobutoxyphenyl)ethanone (770 mg, 4 mmol) were added. The reaction was stirred at room temperature for 16 h, and 5 mL of water was added. The reaction mixture was acidified with 1N HCl until pH=6. The resulting orange precipitate was filtered and submitted to the next step without further purification. MS (EI) for C20H20O4: 325 (MH+).
Reaction SMILES: [C:1]1([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][N:21]3C(=O)C4C(=CC=CC=4)C3=O)[CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NN.CO.C(Cl)[Cl:37]>O1CCOCC1>[ClH:37].[ClH:37].[C:1]1([S:7]([C:10]2[C:18]3[C:13](=[N:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][CH2:20][NH2:21])[CH:11]=2)(=[O:9])=[O:8])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: ClCCl
Reactant: O=C1c2ccccc2C(=O)N1CCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Agent: NN
Solvent: C1COCCO1
Solvent: CO
Product: Cl
Product: NCCn1cc(S(=O)(=O)c2ccccc2)c2cccnc21
Temperature: 50 °C

Procedure:
A solution of 2-{2-[3-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridin-1-yl]ethyl}-1H-isoindole-1,3(2H)-dione (4.54 g, 10.5 mmol) in dioxane is treated with anhydrous hydrazine (8.3 mL, 265 mmol), heated at 50° C. for 3 h, concentrated in vacuo, diluted with water and extracted with CH2Cl2. The combined extracts are dried over MgSO4 and concentrated in vacuo to give a clear gum residue. Chromatography (1:9 methanol:CH2Cl2) of the residue affords the free amine of the title compound as a clear gum. The free amine is dissolved in ethanol, acidified with 2N aqueous HCl and concentration in vacuo. Crystallization of the resultant residue from ethanol/ether affords the title compound as a white solid, 3.20 g, mp 195-197° C., characterized by mass spectral and HNMR analyses.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](F)[C:5]([N+:9]([O-:11])=[O:10])=[CH:4][C:3]=1[CH3:12].C(N(CC)CC)C.CN(C=O)C.Cl.[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH2:31])[CH3:27]>C1COCC1>[CH2:26]([O:28][C:29](=[O:32])[CH2:30][NH:31][C:6]1[CH:7]=[C:2]([F:1])[C:3]([CH3:12])=[CH:4][C:5]=1[N+:9]([O-:11])=[O:10])[CH3:27]
Reactant: CCOC(=O)CN
Reactant: Cc1cc([N+](=O)[O-])c(F)cc1F
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCOC(=O)CNc1cc(F)c(C)cc1[N+](=O)[O-]
Yield: 60.8 %

Procedure:
By using 3.00 g of 2,4-difluoro-5-nitrotoluene, 8.77 g of triethylamine, 40 ml of DMF, 40 ml of THF and 2.42 g of glycine ethyl ester hydrochloride, 2.70 g (61%) of N-(5-fluoro-4-methyl-2-nitrophenyl)glycine ethyl ester was obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][O:10][CH3:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH3:14].Br[CH2:16][C:17]([O:19][CH3:20])=[O:18].CN(C)C=O.[H-].[Na+]>O>[CH3:11][O:10][CH2:9][O:8][C:6]1[CH:5]=[CH:4][C:3]([CH2:12][CH2:13][CH3:14])=[C:2]([CH:7]=1)[O:1][CH2:16][C:17]([O:19][CH3:20])=[O:18]
Reactant: CCCc1ccc(OCOC)cc1O
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCc1ccc(OCOC)cc1OCC(=O)OC
Temperature: 25 °C
Reaction time: 13 h
Yield: 78 %

Procedure:
To a mixture of 2-hydroxy-4-methoxymethoxy-1-propylbenzene (1.50 g), methyl bromoacetate (1.39 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60%, oil, 1.50 g) under ice-cooling. The reaction mixture was stirred at room temperature for 13 hrs. Water was added to the reaction mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated. The obtained residue was subjected to silica gel column chromatography to give methyl 2-(5-methoxymethoxy-2-propylphenoxy)acetate as a colorless oil (1.60 g, 78%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=2)[N:5]=[C:4]([CH3:13])[CH:3]=1.[CH3:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1>>[ClH:1].[CH3:14][O:15][C:16]1[CH:17]=[C:18]([NH:22][C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:12])[CH:10]=3)[N:5]=[C:4]([CH3:13])[CH:3]=2)[CH:19]=[CH:20][CH:21]=1
Reactant: Cc1cc(Cl)c2cc(O)ccc2n1
Reactant: COc1cccc(N)c1
Product: COc1cccc(Nc2cc(C)nc3ccc(O)cc23)c1
Product: Cl

Procedure:
In a manner similar to that described in Example 39, Part B, 4-chloro-2-methylquinolin-6-ol and m-anisidine were converted into the title compound: m.p. 309°-311° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:34]=[CH:33][N:32]=[CH:31][CH:30]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[NH:19]2)=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37].CN1CCOCC1.C(=O)([O-])[O-].[K+].[K+]>O.CN(C=O)C>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]([NH:12][C:13]1[N:21]=[C:20]2[C:16]([C:17]([C:29]3[CH:30]=[CH:31][N:32]=[CH:33][CH:34]=3)=[C:18]([C:22]3[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=3)[N:19]2[C:36]([O:38][CH2:39][CH:40]([CH3:42])[CH3:41])=[O:37])=[CH:15][CH:14]=1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc2c(-c3ccncc3)c(-c3ccc(F)cc3)[nH]c2n1
Reactant: CC(C)COC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CC(C)COC(=O)n1c(-c2ccc(F)cc2)c(-c2ccncc2)c2ccc(NC(=O)CNC(=O)OC(C)(C)C)nc21

Procedure:
6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-7-aza-indole (29) (50 mg, 0.108 mmol), isobutyl chloroformate (42 ml, 0.325 mmol), N-methylmorpholine (119 ml, 1.08 mmol), potassium carbonate (74.9 mg, 0.542 mmol), and DMF (4 mL) were warmed at 80° C. for 16 h. After cooling to 23 C., the reaction was diluted with water (20 mL), extracted with ethyl acetate (2×20 mL), and dried (Na2SO4). After concentration in vacuo, the residue was purified by preparative plate chromatography to afford 6-(2′-t-butoxycarbonylamino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (142). Compound (104) was converted to 6-(2′-amino-1′-oxo-ethylamino)-3-(4-pyridyl)-2-(4-fluorophenyl)-1-isobutoxycarbonyl-7-aza-indole (143) in the manner of example 6: Mass Spectrum (CI) 462 (MH+).