Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br.[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12]C)[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1.C(O)CO.O.[NH2:19]N>O>[CH3:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][NH2:19])[S:11][C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: CNc1nc2c(C)cccc2s1
Reactant: NN
Agent: Br
Solvent: O
Solvent: OCCO
Product: Cc1cccc2sc(NN)nc12
Yield: 90 %

Procedure:
4-Methyl-2-methylaminobenzothiazole hydrobromide (443 g.; 1.71 mole) was added with stirring to 1.7 liter of ethylene glycol. 85% Hydrazine hydrate (400 grams; 6.75 mole) was added in several portions. The reaction mixture was heated to 130°-135°C. under N2 atmosphere and maintained for about four hours, then cooled slowly with stirring. The product was isolated by addition of water and separated by filtration. It was then dried overnight in a vacuum oven, yielding 275.5 g. (90% yield) of 4-methyl-2-hydrazinobenzothiazole. The nmr spectrum agreed with a reference spectrum and showed no evidence of starting material or other impurity. Non-aqueous titration showed the product to be 97.5% pure.
Reaction SMILES: [CH2:1]([N:8]1[C:17]([C:18]([OH:20])=[O:19])=[C:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:27][CH3:28])[CH:14]=2)[C:9]1=[O:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CI.[C:32](=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:32][O:19][C:18]([C:17]1[N:8]([CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C:9](=[O:29])[C:10]2[C:15]([C:16]=1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[CH:14][C:13]([O:27][CH3:28])=[CH:12][CH:11]=2)=[O:20]
Reactant: O=C([O-])[O-]
Reactant: COc1ccc2c(=O)n(Cc3ccccc3)c(C(=O)O)c(-c3ccccc3)c2c1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)c1c(-c2ccccc2)c2cc(OC)ccc2c(=O)n1Cc1ccccc1
Reaction time: 12 h
Yield: 72.4 %

Procedure:
2-Benzyl-6-methoxy-1-oxo-4-phenyl-1,2-dihydroisoquinoline-3-carboxylic acid (160 mg) was dissolved in DMF (3 ml), and methyl iodide (0.06 ml) and potassium carbonate (120 mg) were added at room temperature. The mixture was stirred for 12 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine. The solvent was dried over anhydrous sodium sulfate and evaporated under reduced pressure, and the obtained residue was crystallized from ethyl acetate-hexane to give the title compound (120 mg).
Reaction SMILES: [CH3:1][C:2]1[C:7]([OH:8])=[C:6]([CH2:9][OH:10])[C:5]([CH2:11][Cl:12])=[CH:4][N:3]=1.C(Cl)(Cl)Cl.N1C=CC=CC=1.[C:23](Cl)(Cl)=[O:24]>C1C=CC=CC=1>[Cl:12][CH2:11][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[C:7]2[O:8][C:23](=[O:24])[O:10][CH2:9][C:6]=12
Reactant: Cc1ncc(CCl)c(CO)c1O
Reactant: O=C(Cl)Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Solvent: c1ccccc1
Product: Cc1ncc(CCl)c2c1OC(=O)OC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 0.01 mole of 2-methyl-3-hydroxy-4-hydroxymethyl-5-chloromethylpyridine in 50 ml. chloroform and 50 ml. pyridine is added at 0°-5° C. a solution of 0.011 moles of phosgene in benzene. The reaction mixture is allowed to warm to room temperature and is stirred overnight. The reaction mixture is then concentrated in vacuo and excess saturated sodium bicarbonate solution is added. The resulting solid is collected by filtration. Chromatography on silica gel and elution with methanol in chloroform (1-5%) gives 5-chloromethyl-8-methyl-2-oxo-4H-m-dioxino[4,5-c]pyridine.
Reaction SMILES: [C:1]1([P:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:20][CH:21](/[CH:23]=[CH:24]/[CH2:25][CH3:26])[CH3:22]>C(#N)C>[Br-:20].[CH3:22][CH:21]([P+:7]([C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)/[CH:23]=[CH:24]/[CH2:25][CH3:26]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CC/C=C/C(C)Br
Solvent: CC#N
Product: CC/C=C/C(C)[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Product: [Br-]
Reaction time: 6 h

Procedure:
The compound was prepared from triphenylphosphine and 2-bromo-(E)-3-hexene, a compound which was reported previously (Bianchini and Guillemonat, 1968). Triphenylphosphine (1.6 g, 0.0061 mole) and 2-bromo-(E)-3-hexene (1.0 g, 0.0061 mole) were added to 10 ml dry acetonitrile and refluxed for 6 hr. The solvent was removed by rotary evaporation. The thick, sticky liquid product was stirred with dry ether 4 times, with the ether being decanted. After removing further traces of ether by rotary evaporation, the product was placed in a vacuum desiccator for 6 hr, where the product became a friable white solid (1.6 g, 61%).
Reaction SMILES: OO.O[Li].O.C([C@@H]1COC(=O)N1[C:19](=[O:42])[C@H:20]([C@H:28]1[N:32]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[C:31]([CH3:41])([CH3:40])[CH2:30][CH2:29]1)[C:21]1[CH:26]=[CH:25][C:24]([Br:27])=[CH:23][CH:22]=1)C1C=CC=CC=1.[O-:43]S([O-])=O.[Na+].[Na+]>C1COCC1.O.C1COCC1>[Br:27][C:24]1[CH:25]=[CH:26][C:21]([C@@H:20]([C@@H:28]2[CH2:29][CH2:30][C:31]([CH3:40])([CH3:41])[N:32]2[C:33]([O:35][C:36]([CH3:38])([CH3:39])[CH3:37])=[O:34])[C:19]([OH:43])=[O:42])=[CH:22][CH:23]=1
Reactant: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)N2C(=O)OC[C@H]2Cc2ccccc2)c2ccc(Br)cc2)CCC1(C)C
Reactant: O=S([O-])[O-]
Agent: OO
Agent: [Li]O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@H]([C@@H](C(=O)O)c2ccc(Br)cc2)CCC1(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87 %

Procedure:
30% H2O2 (0.67 mL, 7.0 mmol) was added to a solution of LiOH—H2O (0.24 g, 5.60 mmol) in THF/water (2:1, 93 mL), and the solution was stirred at room temperature for 10 minutes. The solution was then cooled to 0° C. and treated with a solution of (S)-tert-butyl 5-((S)-2-((R)-4-benzyl-2-oxooxazolidin-3-yl)-1-(4-bromophenyl)-2-oxo ethyl)-2,2-dimethylpyrrolidine-1-carboxylate (1.60 g, 2.80 mmol) in THF (10 mL). The reaction was stirred at 0° C. for 2 hours and allowed to warm to room temperature and stirred overnight. The reaction was then cooled to 0° C. and treated with 1M Na2SO3 (10 mL) and stirred for 10 minutes. The reaction was then warmed to room temperature and stirred for 10 minutes. The reaction was next concentrated and extracted with EtOAc (2×20 mL). The aqueous layer was then acidified with 1N HCl to a pH of about 1 to about 2 and extracted with DCM (2×20 mL). The combined DCM fractions were dried over sodium sulfate, filtered, and concentrated to give (S)-2-(4-bromophenyl)-2-((S)-1-(tert-butoxycarbonyl)-5,5-dimethylpyrrolidin-2-yl)acetic acid (1.01 g, 87% yield) as a solid. MS ESI (+) m/z 412 detected.
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH2:9][N:8]([C:11](=[O:19])[CH2:12][N:13]3[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]3)[CH2:7][CH2:6]2)[CH2:4][CH2:3][CH2:2]1.[Cl:20][C:21]1[N:22]=[N:23][C:24](Cl)=[CH:25][CH:26]=1.C([O-])([O-])=O.[K+].[K+]>CS(C)=O>[Cl:20][C:21]1[N:22]=[N:23][C:24]([N:16]2[CH2:15][CH2:14][N:13]([CH2:12][C:11]([N:8]3[CH2:9][CH2:10][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:6][CH2:7]3)=[O:19])[CH2:18][CH2:17]2)=[CH:25][CH:26]=1
Reactant: O=C(CN1CCNCC1)N1CCN(C2CCC2)CC1
Reactant: Clc1ccc(Cl)nn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: O=C(CN1CCN(c2ccc(Cl)nn2)CC1)N1CCN(C2CCC2)CC1

Procedure:
Dissolve 1-cyclobutyl-4-(piperazin-1-ylacetyl)piperazine (2.05 g, 5.46 mmol) and 3,6-dichloropyridazine (810 mg, 5.46 mmol) in dry DMSO (25 mL). Add K2CO3 (3.77 g, 27.3 mmol) and heat the mixture at 120° C. overnight. Cool and partition between CH2Cl2 (100 mL) and 1 N NaOH (150 mL). Extract the aqueous phase with CH2Cl2 (2×100 mL). Combine, dry and evaporate the organic extracts. Triturate the resulting residue with ether and filter off the solid (product). Evaporate the filtrate and chromatograph the resulting residue with EtOAc followed by EtOAc/MeOH (95:5) and EtOAc/MeOH/TEA(95:5:5) to yield additional product. 1H NMR (CDCl3) δ 7.21 (d, 1H), 6.89 (d, 1H), 3.68-3.59 (m, 8H), 3.22 (s, 2H), 2.78-2.62 (m, 5H), 2.38-2.28 (m, 4H), 2.13-2.03 (m, 2H), 1.93-1.8 (m, 2H), 1.73-1.69 (m, 2H); LC-MS (M+1) 378.98.
Reaction SMILES: [C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35]Cl)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[N:37]1([CH2:43][CH2:44][OH:45])[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1.C(N(C(C)C)CC)(C)C>[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:1]([C:5]1[O:9][N:8]=[C:7]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([S:20][C:21]3[C:30]4[C:25](=[CH:26][C:27]([O:33][CH2:34][CH2:35][N:40]5[CH2:41][CH2:42][N:37]([CH2:43][CH2:44][OH:45])[CH2:38][CH2:39]5)=[C:28]([O:31][CH3:32])[CH:29]=4)[N:24]=[CH:23][N:22]=3)[CH:15]=2)=[O:12])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCCl
Reactant: OCCN1CCNCC1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2c(Sc3cccc(NC(=O)Nc4cc(C(C)(C)C)on4)c3)ncnc2cc1OCCN1CCN(CCO)CC1
Temperature: 60 °C
Yield: 12.8 %

Procedure:
To the intermediate 1-(5-tert-butyl-isoxazol-3-yl)-3-{3-[7-(2-chloro-ethoxy)-6-methoxy-quinazolin-4-ylsulfanyl]-phenyl}-urea (225 mg, 0.426 mmol) from Example 79A was added 2-piperazin-1-yl-ethanol (0.157 mL, 1.278 mmol) followed by diisopropyl ethylamine (1.3 mmol) and tetrabutyl ammonium iodide (0.43 mmol). The reaction mixture was heated at 60° C. for 3 days. Formation of product was determined by LCMS. The crude reaction mixture was purified by preparative HPLC (using phenylhexyl reverse phase column eluted with gradient of solvent A=0.05% HOAc/H2O and solvent B=0.05% HOAc/CH3CN) to afford 1-(5-tert-butylisoxazol-3-yl)-3-(3-(7-(2-(4-(2-hydroxyethyl)piperazin-1-yl)ethoxy)-6-methoxyquinazolin-4-ylthio)phenyl)urea (34 mg, 13%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 9.05 (s, 1H), 8.65 (s, 1H), 7.85 (s, 1H), 7.60-7.20 (m, 5H), 6.45 (s, 1H), 4.45-4.25 (m, 3H), 4.00 (s, 3H), 3.45 (m, 2H), 2.80-2.30 (m, 12H), 1.25 (s, 9H); LC-MS (ESI)m/z 622 (M+H)+.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8](F)=[CH:7][CH:6]=1)[CH3:2].[NH:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>>[CH2:1]([NH:3][C:4](=[O:12])[C:5]1[CH:10]=[CH:9][C:8]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:7][CH:6]=1)[CH3:2]
Reactant: C1CNCCN1
Reactant: CCNC(=O)c1ccc(F)cc1
Product: CCNC(=O)c1ccc(N2CCNCC2)cc1
Yield: 77 %

Procedure:
Using N-ethyl-4-fluorobenzamide in the general procedure for nucleophilic aromatic substitution reactions with piperazine, the title compound was obtained (77% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.10 (t, J=7.07 Hz, 3H) 2.25 (br. s., 1H) 2.76-2.86 (m, 4H) 3.09-3.18 (m, 4H) 3.21-3.28 (m, 2H) 6.90 (m, J=8.84 Hz, 2H) 7.67-7.75 (m, 2H) 8.11 (t, J=5.31 Hz, 1H). ESI-MS: m/z 234.2 (M+H)+. mp=131.3-134.4° C.
Reaction SMILES: [C:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[N:14]1[CH:19]=[CH:18][CH:17]=[C:16]([CH2:20][C:21](O)=[O:22])[CH:15]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[C:1]([N:8]1[CH2:9][CH2:10][N:11]([C:21](=[O:22])[CH2:20][C:16]2[CH:15]=[N:14][CH:19]=[CH:18][CH:17]=2)[CH2:12][CH2:13]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(O)Cc1cccnc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)Cc2cccnc2)CC1
Reaction time: 3 h
Yield: 69.1 %

Procedure:
1-Boc-piperazine (12 g, 64 mmol), 3-pyridylacetic acid (8.85 g, 64 mmol), and HOBt (8.64 g, 64 mmol) were dissolved in DMF. To this solution, EDCI (14.7 g, 76.8 mmol) was added in portions. The mixture became homogenous and was stirred for 3 h. The mixture was diluted with water and ethyl acetate. The layers were separated, and the aqueous layer extracted with ethyl acetate. The organic layers were washed with water and brine, dried (Na2SO4), filtered, and concentrated to provide a yellow solid. The crude product was purified by recrystallization from hexanes:dichloromethane to provide 1-Boc-4-[(3-pyridinyl)acetyl]piperazine (13.5 g, 69%) as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)CC=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:21](OC)([O:24][CH3:25])[O:22][CH3:23].[CH3:28]O>CCCCCC.C(OCC)(=O)C.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>[CH2:1]([O:8][C:9]([NH:11][CH:15]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:28]=1)[CH:21]([O:24][CH3:25])[O:22][CH3:23])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(OC)OC
Reactant: O=CCN(C(=O)OCc1ccccc1)c1ccccc1
Reactant: CO
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: COC(OC)C(NC(=O)OCc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
N-Benzyloxycarbonylphenylglycinal (1.38 g, 5.12 mmol) was dissolved in methanol (2.6 ml), and trimethyl orthoformate (1.12 ml, 10.24 mmol) and camphor sulfonic acid (59.5 mg, 0.256 mmol) were added to it and stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure, and the resulting residue was purified by column chromatography on alumina (50 g alumina, hexane/ethyl acetate=2/1) whereby the title compound (1.21 g, 77% yield) was obtained.
Reaction SMILES: [C:1](N1C=CN=C1)(N1C=CN=C1)=[O:2].[NH2:13][CH2:14][CH2:15][CH2:16][C@H:17]([NH:46][C:47](=[O:53])[O:48][C:49]([CH3:52])([CH3:51])[CH3:50])[C:18](=[O:45])[NH:19][C@@H:20]([C:32](=[O:44])[NH:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][CH:23]=1.[C:54]([O:58][C:59]([NH:61][CH2:62][CH2:63][NH:64][CH2:65][CH2:66][NH:67][C:68](=[O:74])[O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:60])([CH3:57])([CH3:56])[CH3:55]>C(Cl)Cl>[C:49]([O:48][C:47]([NH:46][C@H:17]([C:18](=[O:45])[NH:19][C@@H:20]([C:32](=[O:44])[NH:33][C:34]1[CH:35]=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][CH:40]=[CH:39][CH:38]=2)[CH2:21][C:22]1[CH:23]=[CH:24][C:25]([C:28]([F:30])([F:29])[F:31])=[CH:26][CH:27]=1)[CH2:16][CH2:15][CH2:14][NH:13][C:1]([N:64]([CH2:65][CH2:66][NH:67][C:68]([O:69][C:70]([CH3:73])([CH3:72])[CH3:71])=[O:74])[CH2:63][CH2:62][NH:61][C:59](=[O:60])[O:58][C:54]([CH3:57])([CH3:56])[CH3:55])=[O:2])=[O:53])([CH3:50])([CH3:52])[CH3:51]
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCN)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCN(CCNC(=O)OC(C)(C)C)C(=O)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)N[C@H](Cc1ccc(C(F)(F)F)cc1)C(=O)Nc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 44 %

Procedure:
To a solution of carbonyldiimidazole (204 mg, 1.25 mmol) in DCM (20 mL) was added tert-butyl N-[(1S)-4-amino-1-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamate CXV (687 mg, 1.20 mmol) and stirred at r.t. for 1 h. To this mixture was added tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate X (436 mg, 1.44 mmol) and the reaction was stirred overnight at r.t. The mixture was diluted DCM and washed with 1 M HCl, brine, dried over MgSO4 and purified on a silica gel column (100:1→70:1→50:1 CHCl3/MeOH) to give product tert-butyl N-[2-({[(4S)-4-{[(tert-butoxy)carbonyl]amino}-4-{[(1R)-1-[(quinolin-3-yl)carbamoyl]-2-[4-(trifluoromethyl)phenyl]ethyl]carbamoyl}butyl]carbamoyl} (2-{[(tert-butoxy)carbonyl]amino}ethyl)amino)ethyl]carbamate CXVI (500 mg, 0.55 mmol, 44% yield). ESIMS found for C44H61F3N8O9 m/z 904 (M+H).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23]Br)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]([N:32]1[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1)([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26].C(N(CC)CC)C>C(#N)C>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([O:21][CH2:22][CH2:23][N:35]3[CH2:34][CH2:33][N:32]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:37][CH2:36]3)[C:15]=2[C:14]2[C:9]1=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: BrCCOc1cccc2c1c1ccccc1n2Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)N1CCN(CCOc2cccc3c2c2ccccc2n3Cc2ccccc2)CC1
Yield: 78.7 %

Procedure:
A mixture of 9-benzyl-4-(2-bromoethoxy)-9H-carbazole (0.0647 g, 0.170 mmol), Boc-piperazine (0.0380 g, 0.204 mmol), triethylamine (0.0206 g, 0.204 mmol), and acetonitrile (2 mL) is heated at reflux for 24 h. After cooling, the mixture is partitioned between CH2Cl2 and aq. sodium bicarbonate. The organic layers are dried over sodium sulfate; chromatography on silica gel eluting with CH3OH—CH2Cl2 (2/98) gave poor separation of product and impurities. Re-chromatography (silica gel, 20 mL) using acetone-hexane (10/90 to 20/80) gave 0.0650 g (83%) of the title compound; IR (drift) 1693, 1457, 1420, 1365, 1341, 1332, 1291, 1266, 1243, 1174, 1154, 1145, 1129, 1112, 752 cm−1; 1H NMR (CDCl3) δ1.46, 2.65, 3.06, 3.48, 4.41, 5.51, 6.69, 6.99, 7.12, 7.2-7.4, 8.37. Anal. Calcd for C30H35N3O3: C, 74.20; H, 7.26; N, 8.65. Found: C, 73.82; H, 7.41; N, 8.52.
Reaction SMILES: [F:1][C:2]([F:30])([F:29])[C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13]([NH:15][C:16]1[CH:24]=[CH:23][CH:22]=[C:21]3[C:17]=1[CH:18]=[N:19][N:20]3C(OC)=O)=[O:14])[CH2:7][CH2:6]2.Cl>>[NH:20]1[C:21]2[C:17](=[C:16]([NH:15][C:13]([NH:12][CH:8]3[C:9]4[C:5](=[CH:4][C:3]([C:2]([F:1])([F:29])[F:30])=[CH:11][CH:10]=4)[CH2:6][CH2:7]3)=[O:14])[CH:24]=[CH:23][CH:22]=2)[CH:18]=[N:19]1
Reactant: COC(=O)n1ncc2c(NC(=O)NC3CCc4cc(C(F)(F)F)ccc43)cccc21
Agent: Cl
Product: O=C(Nc1cccc2[nH]ncc12)NC1CCc2cc(C(F)(F)F)ccc21

Procedure:
The title compound was prepared using the procedure in Example 9, except using methyl 4-[({[5-(trifluoromethyl)-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate instead of methyl 4-[({[5-tert-butyl-2,3-dihydro-1H-inden-1-yl]amino}carbonyl)amino]-1H-indazole-1-carboxylate. 1H NMR (DMSO-d6) δ 1.06 (t, 2.4H, EtOH), 1.82–1.94 (m, 1H), 2.52–2.60 (m, 1H), 2.85–2.97 (m, 1H), 2.98–3.10 (m, 1H), 3.44 (q, 1.6H, EtOH), 5.28 (m, 1H), 7.08 (m, 2H), 7.21 (m, 1H), 7.56 (m, 2H), 7.63 (s, 1H), 7.69 (d, 1H), 8.17 (s, 1H), 8.91 (s, 1H); MS (ESI+) 361 (M+H)+; Elemental: Calculated for C18H15N4OF3.HCl.0.8EtOH.0.1H2O: C, 54.06; H, 4.86; N, 12.87. Found: C, 54.02; H, 4.58; N, 12.62.
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:20])[CH2:4][CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([NH:16][C:17](=[O:19])[CH3:18])[CH:10]=[CH:9][C:8]=2[CH:7]=1.CCN=C=NCCCN(C)C.[C:32]1([C:41]2[CH:46]=[CH:45]C=[CH:43][CH:42]=2)[CH:37]=[CH:36][C:35](C(O)=O)=[CH:34][CH:33]=1>CN(C1C=CN=CC=1)C.C(OCC)(=O)C.CN(C)C=O>[CH3:20][N:3]([CH3:2])[CH2:4][CH2:5][C:6]1[CH2:15][CH2:14][C:13]2[CH:12]=[C:11]([NH:16][C:17]([C:18]3[CH:43]=[CH:42][C:41]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)=[CH:46][CH:45]=3)=[O:19])[CH:10]=[CH:9][C:8]=2[CH:7]=1
Reactant: CC(=O)Nc1ccc2c(c1)CCC(CCN(C)C)=C2
Reactant: O=C(O)c1ccc(-c2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)CCC1=Cc2ccc(NC(=O)c3ccc(-c4ccccc4)cc3)cc2CC1
Temperature: 100 °C
Reaction time: 1 h
Yield: 22.5 %

Procedure:
Concentrated hydrochloric acid (1.5 ml) was added to N-[6-[2-(dimethylamino)ethyl]-7,8-dihydro-2-naphthalenyl]acetamide (57.5 mg, 0.223 mmol) obtained in Reference Example 104, which was stirred at 100° C. for 1 hour. The solvent was distilled out under reduced pressure. Ethyl acetate was added to the residue, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. WSC (29.2 mg, 0.139 mmol) was added to a dimethylformamide solution (0.7 ml) of the resulting oily substance (30 mg, 0.139 mmol), [1,1′-biphenyl]-4-carboxylic acid (30.2 mg, 0.139 mmol) and DMAP (16.9 mg, 0.139 mmol) under ice-cooling, which was stirred at room temperature for 16 hours. Ethyl acetate was added to the reaction mixture, which was washed with aqueous potassium carbonate solution and saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, and then the solvent was distilled out under reduced pressure. The resulting residue was purified by aluminum column chromatography (development solvent; ethyl acetate), powdered with ethyl acetate-isopropyl ether (1:5), to give the titled compound (12.4 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:12]3[N:13]=[C:14]4[C:20]([C:21]([OH:23])=O)=[CH:19][N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:30])[CH3:29])[C:15]4=[N:16][CH:17]=3)=[N:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[NH2:32][CH:33]([CH2:36][OH:37])[CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C1C=CC2N(O)N=NC=2C=1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[OH:35][CH2:34][CH:33]([NH:32][C:21]([C:20]1[C:14]2[C:15](=[N:16][CH:17]=[C:12]([C:6]3[C:5]4[C:9](=[CH:10][C:2]([Cl:1])=[CH:3][CH:4]=4)[N:8]([CH3:11])[N:7]=3)[N:13]=2)[N:18]([CH2:24][O:25][CH2:26][CH2:27][Si:28]([CH3:31])([CH3:29])[CH3:30])[CH:19]=1)=[O:23])[CH2:36][OH:37]
Reactant: NC(CO)CO
Reactant: Cn1nc(-c2cnc3c(n2)c(C(=O)O)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cn1nc(-c2cnc3c(n2)c(C(=O)NC(CO)CO)cn3COCC[Si](C)(C)C)c2ccc(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 67.2 %

Procedure:
A 25 mL round-bottomed flask was charged with 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (0.20 g, 0.44 mmol), 2-aminopropane-1,3-diol (119 mg, 1.31 mmol), HBTU (331 mg, 0.87 mmol), and HOBT (134 mg, 0.87 mmol). Then added DMF (1 mL) followed by N,N-diisopropylethylamine (0.31 mL, 1.75 mmol). The yellow reaction mixture was stirred at room temperature overnight then quenched with water and extracted with EtOAc (30 mL). The organic layer was washed once with saturated NaHCO3 and water. The combined aqueous layers were back extracted with EtOAc (25 mL). The combined organic layers was dried over sodium sulfate, filtered and concentrated. The residue was purified by chromatography over SiO2 with EtOAc/hexanes (gradient: 0-100% EtOAc) to afford 157 mg (68%) of 2-(6-chloro-1-methyl-1H-indazol-3-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carboxylic acid (2-hydroxy-1-hydroxymethyl-ethyl)-amide as a white solid. MS: [M+Na]+=552.
Reaction SMILES: [NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([OH:16])=O)[CH:11]([CH3:13])C)=[O:8])[CH2:3][CH:4]([CH3:6])[CH3:5].[CH3:27][NH-:28].[NH:29](C(OCC1C=CC=CC=1)=O)[C@H:30]([C:35]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:36])[CH2:31][CH:32]([CH3:34])[CH3:33].C1C=[CH:57][C:58]2N(O)N=N[C:59]=2C=1.C1CC[CH:68]([N:71]=[C:72]=[N:73]C2CCCCC2)CC1.CN>CN(C=O)C>[NH:1]([C:17]([O:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[C@H:2]([C:7]([NH:9][C@H:10]([C:14]([NH:29][C@H:30]([C:35]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:40])[CH3:41])=[O:36])[CH2:31][CH:32]([CH3:33])[CH3:34])=[O:16])[CH2:11][C:13]1[N:73]=[CH:72][NH:71][CH:68]=1)=[O:8])[CH2:3][C:4]1[CH:5]=[CH:57][CH:58]=[CH:59][CH:6]=1.[CH3:27][NH-:28]
Reactant: CC(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Reactant: On1nnc2ccccc21
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN
Agent: C[NH-]
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1c[nH]cn1)NC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)O)C(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Z-Leu-Val-methyl amide: A mixture of 100 mg of Z-Leu-Val-OH (Example 1e), 2 ml of DMF, 49 mg of HOBt and 66 mg of DCCI is left to stand at 0° for 24 hours. An excess of methylamine is added to the mixture and the whole is stirred for 2 hours at 0° and for 2 hours at room temperature. The title compound is obtained in the form of a colourless oil after flash chromatography with system N3. Rf (N7)=0.55.