Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[CH2:2]([C:5]1[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=1)[C:3]#[CH:4].[N:11]([CH2:14][C:15]([CH3:23])=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[N+:12]=[N-:13]>>[ClH:1].[CH3:23][C:15](=[CH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH2:14][N:11]1[CH:4]=[C:3]([CH2:2][C:5]2[N:6]=[C:7]([NH2:10])[NH:8][CH:9]=2)[N:13]=[N:12]1
Reactant: CC(=Cc1ccccc1)CN=[N+]=[N-]
Reactant: C#CCc1c[nH]c(N)n1
Agent: Cl
Product: CC(=Cc1ccccc1)Cn1cc(Cc2c[nH]c(N)n2)nn1
Yield: 91.2 %

Procedure:
4-Prop-2-ynyl-1H-imidazol-2-ylamine hydrochloride (0.127 g, 0.809 mmol) was reacted with (3-Azido-2-methyl-propenyl)-benzene (0.168 g, 0.971 mmol) following the general procedure for click reactions outlined above to produce 4-[1-(2-Methyl-3-phenyl-allyl)-1H[1,2,3]triazol-4-ylmethyl]-1H-imidazol-2-ylamine hydrochloride (0.244 g, 91%) of a pale yellow solid. 1H NMR (300 MHz, D2O) δ 7.94 (s, 1H), δ 7.40-7.35 (m, 5H), δ 6.56 (s, 1H), δ 5.10 (s, 2H), δ 3.99 (s, 2H), δ 1.76 (s, 3H) ppm; 13C δ 145.8, 138.1, 136.9, 136.5, 136.4, 132.8, 128.3, 128.0, 127.6, 125.3, 123.4, 49.3, 23.8, 23.4; HRMS (ESI) calcd for C16H18N6 (M+) 295.1665, found 295.1665.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45](OC(C)(C)C)([CH3:50])[CH2:46]C(O)=O)/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:38]([OH:40])=[O:39])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([Cl:33])[C:26]=5[CH2:34][C:35]([OH:37])=[O:36])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.FC(F)(F)[C:58]([OH:60])=[O:59]>>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:43]/[O:44][C:45]([C:58]([OH:60])=[O:59])([CH3:50])[CH3:46])/[C:8]([NH:10][CH:11]2[C:41](=[O:42])[N:13]3[C:14]([C:38]([OH:40])=[O:39])=[C:15]([CH2:18][S:19][C:20]4[N:24]([C:25]5[CH:30]=[C:29]([OH:31])[C:28]([OH:32])=[C:27]([Cl:33])[C:26]=5[CH2:34][C:35]([OH:37])=[O:36])[N:23]=[N:22][N:21]=4)[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)(C)OC(C)(CC(=O)O)O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3cc(O)c(O)c(Cl)c3CC(=O)O)CS[C@H]12)c1csc(N)n1
Product: CC(C)(O/N=C(\C(=O)NC1C(=O)N2C(C(=O)O)=C(CSc3nnnn3-c3cc(O)c(O)c(Cl)c3CC(=O)O)CS[C@H]12)c1csc(N)n1)C(=O)O

Procedure:
7-[2-(2-Aminothiazol-4-yl)-2-((Z)-1-t-butoxycarboxy-1-methyl ethoxyimino)acetamido]-3-[(1-(2-carboxymethyl-3-chloro-4,5-dihydroxyphenyl)-tetrazol-5-yl)thiomethyl]ceph-3-em-4-carboxylic acid (0.875 g) was treated with trifluoroacetic acid (10 ml) at room temperature for 1 hour. The mixture was evaporated and the residue triturated with ether to give a solid which was collected by filtration and purified by HPLC (AMICON C18 15 μm), eluting with methanol/water/acetic acid (35:65:1 to 40:60:1) [Dimethylformamide was necessary for dissolution of the crude product.] Thus was obtained the title product (0.38 g); NMR (DMSO-d6 /CD3CO2D/CF3CO2D) 1.55(s,6H, --C(CH3)2 --); 3.35(s,2H,--CH2COOH); 3.60 and 3.85(2d, J=18 Hz, --SCH2 --); 4.30 and 4.65 (2d,J=11.5 Hz, 2H, --CH2 --S--tetrazole); 5.20 and 5.85(2d, J=4.5 Hz, 2H, H6 and H7); 6.85 (s,1H, aromatic); 7.05(s,1H, thiazole).
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][N:6]=[C:5]([SH:9])[N:4]=1.[OH-].[Na+].CI.[CH2:16](Cl)Cl>C1COCC1>[CH3:16][S:9][C:5]1[N:4]=[C:3]([C:2]([F:10])([F:1])[F:11])[CH:8]=[CH:7][N:6]=1
Reactant: ClCCl
Reactant: FC(F)(F)c1ccnc(S)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CI
Solvent: C1CCOC1
Product: CSc1nccc(C(F)(F)F)n1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-(trifluoromethyl)pyrimidine-2-thiol (1.08 g, 6.0 mmol) in THF (40 mL) was added 1N NaOH (10 mL), followed by the addition of MeI (0.8 mL). The reaction mixture was stirred at room temperature overnight, followed by addition of CH2Cl2. The organic layer was washed with saturated NaHCO3, H2O, and saturated NaCl, dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography (silica gel, hexanes: EtOAc=1:10) to give 2-(methylthio)-4-(trifluoromethyl)pyrimidine as colorless oil (0.6 g). This colorless oil was dissolved in CH2Cl2, and to the solution mCPBA (1.8 g) was added. The resulting mixture was stirred at room temperature for 3 h. To the reaction mixture saturated Na2SO4 (10 mL) was added, followed by the addition of saturated Na2CO3. The aqueous portion was extracted with CH2Cl2 twice and the organic portions were dried over Na2SO4, filtered, and concentrated to give 2-(methylsulfonyl)-4-(trifluoromethyl)pyrimidine as white solids (0.64 g, 46% yield for two steps,). LC-MS RT=1.19 min, [M+Na] 249.06 (LCMS Method 1).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29].C(Cl)Cl>O>[C:28]([NH:2][C:3]1[CH:4]=[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[C:19]4[CH:20]=[CH:21][C:22]([C:24]([F:27])([F:26])[F:25])=[CH:23][C:18]=4[N:17]=[CH:16]3)[CH:10]=2)[CH:6]=[CH:7][CH:8]=1)(=[O:30])[CH3:29]
Reactant: Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(=O)Nc1cccc(-c2cccc(-n3cnc4cc(C(F)(F)F)ccc43)c2)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Compound 8a (0.7 g, 1.79 mmol) was converted to the corresponding free base by partitioning between 0.1M aqueous NaOH (200 ml) and diethyl ether (200 ml). The phases were separated and the aqueous phase was extracted twice with ether. The combined ethereal phases were dried and evaporated. The residue was dissolved in dry methylene chloride (20 ml). Acetic anhydride (0.22 g, 2.15 mmol) was slowly added with ice cooling. After completed addition the mixture was stirred for one hour at room temperature. Methylene chloride (50 ml) and water (50 ml) was added and the aqueous phase was separated. The organic phase was dried and evaporated and the crude product purified by column chromatography, first with methylene chloride, then with methylene chloride/methanol (19:1 ), as eluent. Yield 400 mg, mp 118°-120° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[NH:18][C:17]1=[O:22])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7].[CH3:24][O:25][C:26]1[CH:33]=[C:32]([O:34][CH3:35])[CH:31]=[CH:30][C:27]=1[CH2:28]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:23])[CH:4]([CH:16]1[CH2:20][C:19](=[O:21])[N:18]([CH2:28][C:27]2[CH:30]=[CH:31][C:32]([O:34][CH3:35])=[CH:33][C:26]=2[O:25][CH3:24])[C:17]1=[O:22])[NH:5][C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7]
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)NC1=O
Reactant: COc1ccc(CO)c(OC)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(NC(=O)OCc1ccccc1)C1CC(=O)N(Cc2ccc(OC)cc2OC)C1=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
In 100 ml of tetrahydrofuran were dissolved 3.2 g of benzyloxycarbonyl-2-(2,5-dioxopyrrolidin-3-yl)glycine methyl ester, 1.8 g of 2,4-dimethoxybenzyl alcohol and 3.9 g of triphenylphosphine and under ice-cooling 2 ml of diethyl azodicarboxylate was added. The mixture was stirred at room temperature for one hour and concentrated under reduced pressure. The residue was dissolved in ethyl acetate, and the solution was washed with 5% sodium hydrogen carbonate and 10% phosphoric acid in that order and dried over sodium sulfate. The solution was concentrated under reduced pressure and the concentrate was chromatographed on a silica gel column, elution being carried out with toluene-ethyl acetate (7:3). The eluate was concentrated under reduced pressure and to the residue was added petroleum ether. The precipitate was collected by filtration and dried. Yield 1.2 g
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([NH:28][C:29]3[CH:30]=[C:31]4[C:35](=[CH:36][CH:37]=3)[N:34](C(OC(C)(C)C)=O)[N:33]=[CH:32]4)=[N:8][C:9]([C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([NH:19][C:20](=[O:27])[C:21]4[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=4)[CH:14]=3)=[N:10]2)=[CH:5][C:4]=1[O:45][CH2:46][CH2:47][O:48][CH3:49].[C:50]([OH:56])([C:52]([F:55])([F:54])[F:53])=[O:51]>C(Cl)Cl>[F:53][C:52]([F:55])([F:54])[C:50]([OH:56])=[O:51].[NH:34]1[C:35]2[C:31](=[CH:30][C:29]([NH:28][C:7]3[C:6]4[C:11](=[CH:12][C:3]([O:2][CH3:1])=[C:4]([O:45][CH2:46][CH2:47][O:48][CH3:49])[CH:5]=4)[N:10]=[C:9]([C:13]4[CH:14]=[C:15]([NH:19][C:20](=[O:27])[C:21]5[CH:26]=[CH:25][CH:24]=[N:23][CH:22]=5)[CH:16]=[CH:17][CH:18]=4)[N:8]=3)=[CH:37][CH:36]=2)[CH:32]=[N:33]1
Reactant: COCCOc1cc2c(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COCCOc1cc2c(Nc3ccc4[nH]ncc4c3)nc(-c3cccc(NC(=O)c4cccnc4)c3)nc2cc1OC
Yield: 71 %

Procedure:
A solution of tert-butyl 5-(7-methoxy-6-(2-methoxyethoxy)-2-(3-(nicotinamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate in CH2Cl2 (15 mL) and TFA (2.2 mL) was stirred at RT for 1 h. The volatiles were removed in vacuo and the residue was washed with Et2O to give N-(3-(4-(1H-indazol-5-ylamino)-7-methoxy-6-(2-methoxyethoxy)quinazolin-2-yl)phenyl)nicotinamide trifluroacetate salt (0.086 g, 0.127 mmol, 71% over two steps). MS 562.4 (M+1). HPLC retention time 4.92 mins.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:22]3[N:27]=[C:26]4[N:28](C5CCCCO5)[N:29]=[CH:30][C:25]4=[C:24]([C:37]4[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=4)[N:23]=3)=[CH:17][CH:16]=2)[CH2:11][CH2:10]1>C(Cl)Cl>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:16]=[CH:17][C:18]([NH:21][C:22]3[N:27]=[C:26]4[NH:28][N:29]=[CH:30][C:25]4=[C:24]([C:37]4[CH:38]=[C:39]([NH:43][C:44](=[O:47])[CH:45]=[CH2:46])[CH:40]=[CH:41][CH:42]=4)[N:23]=3)=[CH:19][CH:20]=2)[CH2:13][CH2:14]1
Reactant: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3c2cnn3C2CCCCO2)c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C=CC(=O)Nc1cccc(-c2nc(Nc3ccc(N4CCN(C)CC4)cc3)nc3[nH]ncc23)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2,2,2-Trifluoroacetic acid (0.15 mL, 1.86 mmol) was added to a solution of N-(3-(6-((4-(4-methylpiperazin-1-yl)phenyl)amino)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazolo[3,4-d]pyrimidin-4-yl)phenyl)acrylamide (10 mg, 0.018 mmol) in CH2Cl2 (4 mL) and the reaction mixture was stirred for 16 h at room temperature, after which the solvent was removed in vacuo. The residue was purified by flash chromatography (6% CH3OH/CH2Cl2) to yield the title compound as an off white solid. 1H NMR (400 MHz, CD3OD): δ 8.67 (s, 1H), 8.31 (s, 1H), 7.99 (d, 1H, J=7.6 Hz), 7.75 (m, 3H), 7.54 (m, 1H), 6.99 (m, 2H), 6.46 (m, 2H), 5.81 (dd, 1H, J=2.4 Hz and 9.6 Hz), 3.17 (m, 4H), 2.64 (m, 4H), 2.35 (s, 3H); ESI-MS: 455.27 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([NH:11][C:12](=[N:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([O:28][CH3:29])(=[O:27])=[O:26])(=[O:18])=[O:17])SC)[N:4]=1.[CH3:30][O:31][NH2:32].Cl>O1CCOCC1>[CH3:10][O:9][C:7]1[N:8]=[C:3]([O:2][CH3:1])[N:4]=[C:5]([NH:11][C:12]([NH:15][S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[S:25]([O:28][CH3:29])(=[O:26])=[O:27])(=[O:18])=[O:17])=[N:32][O:31][CH3:30])[N:6]=1
Reactant: CON
Reactant: COc1nc(NC(=NS(=O)(=O)c2ccccc2S(=O)(=O)OC)SC)nc(OC)n1
Agent: Cl
Solvent: C1COCCO1
Product: CON=C(Nc1nc(OC)nc(OC)n1)NS(=O)(=O)c1ccccc1S(=O)(=O)OC
Temperature: 0 °C
Reaction time: 96 h
Yield: 32.5 %

Procedure:
N-(4,6-Dimethoxy-1,3,5-triazin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) S-methylisothiourea (4.63 g) was dissolved in dioxane (100 ml), and O-methylhydroxylamine (2.35 g) was added to the solution. The mixture was stirred at room temp. for 4 days. The reaction mixture was poured into ice water, and adjusted to pH 3 with hydrochloric acid. The precipitated crude crystals were collected by filtration, and recrystallized from acetonitrile to give 1.5 g of the desired N-(4,6-dimethoxy-1,3,5-triazin-2-yl) N'-(2-methoxysulfonylbenzenesulfonyl) N"-(methoxy)guanidine represented by the following formula. mp. 148°-150° C. ##STR22## By the same method as in Example 1 or 2, the compounds of the invention shown in Table 1 below were synthesized.
Reaction SMILES: [NH2:1][OH:2].[OH-].[Na+].[C:5](#[N:14])[C:6]1[CH:13]=[CH:12][CH:11]=[C:8]([C:9]#[N:10])[CH:7]=1>C(O)C>[C:9]([C:8]1[CH:7]=[C:6]([CH:13]=[CH:12][CH:11]=1)[C:5](=[N:1][OH:2])[NH2:14])#[N:10]
Reactant: N#Cc1cccc(C#N)c1
Reactant: NO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: N#Cc1cccc(C(N)=NO)c1
Temperature: 25 °C

Procedure:
Hydroxylamine (Aldrich, 7.65 g, 100 mmol) in ethanol (100 mL) was treated with 10 N sodium hydroxide (10 mL, 100 mmol). To this solution, isophthalonitrile (Aldrich, 12.8 g, 100 mmol) in 100 mL ethanol was added. The reaction mixture was heated to reflux for 3 hours and then cooled to room temperature. The solvent was removed under vacuum and the residue was purified with flash column chromatography (5% methanol/dichloromethane) to provide the titled compound. 1H NMR (300 MHz, DMSO-d6) δ 5.98 (bs, 2H), 7.59 (t, J=7.4 Hz, 1H), 8.06-8.0 (m, 2H), 9.89 (s, 1H) ppm; MS (DCI/NH3) m/z 162 (M+H)+.
Reaction SMILES: C[O:2][C:3](=[O:19])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15](I)=[CH:14][CH:13]=2)[CH:5]=1.C(=O)([O-])[O-].[K+].[K+].O1CCOCC1.[CH:32]1[C:41]2[CH:40]=[CH:39][CH:38]=[C:37](B(O)O)[C:36]=2[CH:35]=[CH:34][N:33]=1>O>[CH:32]1[C:41]2[C:36](=[C:37]([C:15]3[CH:16]=[CH:17][C:12]([O:11][CH2:10][C:6]4[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=4)[C:3]([OH:2])=[O:19])=[CH:13][CH:14]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34][N:33]=1
Reactant: COC(=O)c1cccc(COc2ccc(I)cc2)c1
Reactant: OB(O)c1cccc2cnccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)c1cccc(COc2ccc(-c3cccc4cnccc34)cc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.5 mL of a sonicated and degassed solution of 3-(4-iodo-phenoxymethyl)-benzoic acid methyl ester (of Intermediate 1; 740 mg, 2 mmol), potassium carbonate (830 mg, 6 mmol), bis(tri-cyclohexylphosphine)palladium (available from Strem Chemicals, Inc., Newburyport, Mass.; 70 mg, 0.1 mmol), dioxane (41 mL) and water (4.1 mL) was added to a reaction vial containing 5-isoquinolineboronic acid (available from Frontier Scientific, Inc., Logan, Utah; 104 mg, 0.6 mmol). The solution was sonicated and degassed. The mixture was heated in a microwave oven at 170 degrees for 25 min. The reaction mixture was filtered through silica, and washed with dioxane (1 mL) and dimethylacetamide (1 mL). 2 M potassium hydroxide solution (0.4 mL) was added. The mixture was stirred at room temperature overnight, and then 1 M HCl (0.8 mL) was added. The solvents were removed in the Genevac and then 50% aqueous methanol (2 mL) was added. The vial was centrifuged and the solvent removed. This process was repeated and then the same was dried overnight in the oven to give 3-(4-isoquinolin-5-yl-phenoxymethyl)-benzoic acid. Mass spectrum MH+=356.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].[Cl:10][C:11]1[CH:16]=[CH:15][C:14]([NH:17][C:18](=[O:25])[CH2:19][O:20][CH2:21][C:22](O)=[O:23])=[C:13]([C:26]([O:28]C)=[O:27])[CH:12]=1>>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:22](=[O:23])[CH2:21][O:20][CH2:19][C:18]([NH:17][C:14]1[CH:15]=[CH:16][C:11]([Cl:10])=[CH:12][C:13]=1[C:26]([OH:28])=[O:27])=[O:25]
Reactant: COC(=O)c1cc(Cl)ccc1NC(=O)COCC(=O)O
Reactant: NCc1cccc(Br)c1
Product: O=C(COCC(=O)Nc1ccc(Cl)cc1C(=O)O)NCc1cccc(Br)c1

Procedure:
Using the same method as in Example 15-(i), 3-bromobenzylamine was reacted with the (2-([4-chloro-2-(methoxycarbonyl)phenyl]amino)-2-oxoethoxy)acetic acid obtained in Example 1-(i) to give 2-[((2-[(3-bromobenzyl)amino]-2-oxoethoxy)acetyl)amino]-5-chlorobenzoic acid.methyl ester (yield: 78%).
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:14]=[C:13]([Cl:15])[S:12][C:11]=2[CH:16]=O)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH3:32]>>[CH3:18][O:19][C:20](=[O:33])[CH2:21][N:22]1[C:30]2[C:25](=[CH:26][C:27]([F:31])=[CH:28][CH:29]=2)[C:24]([CH2:16][C:11]2[S:12][C:13]([Cl:15])=[CH:14][C:10]=2[S:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)(=[O:8])=[O:9])=[C:23]1[CH3:32]
Reactant: O=Cc1sc(Cl)cc1S(=O)(=O)c1ccccc1
Reactant: COC(=O)Cn1c(C)cc2cc(F)ccc21
Product: COC(=O)Cn1c(C)c(Cc2sc(Cl)cc2S(=O)(=O)c2ccccc2)c2cc(F)ccc21

Procedure:
The title compound was prepared by the method of Preparation 42b using 3-benzenesulfonyl-5-chlorothiophene-2-carbaldehyde and (5-fluoro-2-methylindol-1-yl)acetic acid methyl ester.
Reaction SMILES: S(Cl)(Cl)=O.[Br:5][C:6]1[CH:15]=[C:14]([Br:16])[CH:13]=[C:12]2[C:7]=1[CH:8]=[CH:9][CH:10]=[C:11]2[C:17](Cl)=[O:18].Cl.[CH3:21]OCN>CN(C=O)C>[C:17]([C:11]1[C:12]2[C:7](=[C:6]([Br:5])[CH:15]=[C:14]([Br:16])[CH:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:18])[CH3:21]
Reactant: COCN
Reactant: O=C(Cl)c1cccc2c(Br)cc(Br)cc12
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(=O)c1cccc2c(Br)cc(Br)cc12

Procedure:
The 1-acetyl-5,7-dibromonaphthalene used in the foregoing procedure was prepared by dibromination of benz[cd]indol-2-(1H)-one with bromine in glacial acetic acid to give 41 g of 6,8-dibromobenz[cd]indol-2(1H)-one, m.p. 259°-260° C. The latter (12.8 g) was heated under reflux for one hour in two liters of 5% potassium hydroxide, the reaction mixture was cooled, filtered and then treated with 28 g of a solution of sodium nitrite in 50 ml of water. The resulting solution, cooled to 0° C., was added dropwise to 800 ml of a 40% solution of sulfuric acid while maintaining the temperature at -5° C. The reaction mixture was stirred for one hour, then poured slowly into a solution of 140 g of sodium hypophosphite in 800 ml of water at 0° C. with stirring. The solid which separated was collected by filtration and dissolved in 3 liters of 2% sodium carbonate solution, and the resulting solution was filtered, acidified with concentrated hydrochloric acid and the mixture extracted with ethyl acetate. The combined organic extracts were dried and taken to dryness to give 8 g of 5,7-dibromo-1-naphthalenecarboxylic acid which was heated with thionyl chloride in the presence of a small amount of DMF. The resulting crude 5,7-dibromo-1-naphthalenecarboxylic acid chloride, together with 6.0 g of methoxymethylamine hydrochloride in 750 ml of MDC, was treated dropwise at 0° C. with 60 ml of tirethylamine in 250 ml of MDC. The reaction mixture was filtered, the filtrate was taken to dryness, and the resulting residue (12.0 g) was dissolved in THF and treated at 0° C. with stirring with a solution of 29.5 ml of 3M methyl magnesium bromide. The reaction mixture was stirred for ten minutes, quenched with water, taken to dryness and the residue partitioned between ethyl acetate and water. The mixture was filtered, the organic extracts were separated, dried and taken to dryness to give 9.9 g of 1-acetyl-5,7-dibromonaphthalene.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]1[CH:22]=[N:21][C:8]2[CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][O:13][C:7]=2[N:6]=1)[CH3:3].C[Si](C)(C)[N-][Si](C)(C)C.[K+].I[CH2:34][CH3:35].O>O1CCCC1>[CH2:34]([N:4]([CH:2]([CH3:1])[CH3:3])[C:5]1[CH:22]=[N:21][C:8]2[CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11][CH2:12][O:13][C:7]=2[N:6]=1)[CH3:35]
Reactant: CC(C)Nc1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2
Reactant: CCI
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: CCN(c1cnc2c(n1)OCCN(C(=O)OC(C)(C)C)C2)C(C)C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 7 %

Procedure:
To a solution of tert-butyl 3-[(1-methylethyl)amino]-6,7-dihydropyrazino[2,3-f][1,4]oxazepine-8(9H)-carboxylate (137 mg) in tetrahydrofuran (3 mL) was added dropwise potassium hexamethyl disilazide (1.06 mL, 0.5 M toluene solution) at 0° C. The mixture was stirred at 0° C. for 15 min, and iodoethane (105 μL) was added dropwise thereto. The mixture was stirred at 0° C. for 1.5 hr, and further at room temperature overnight. Water (5 mL) was added, and the mixture was extracted with ethyl acetate. The aqueous layer was extracted again with ethyl acetate. The combined organic layer was washed with water and saturated brine, dried over magnesium sulfate, and concentrated. The residue was purified by silica gel column chromatography (solvent gradient: 10→40% ethyl acetate/hexane) to give the title compound (10 mg, 7%) as a pale-yellow oil.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:2]1.Cl[CH2:15][C:16]1[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=1.C(N(C(C)C)C(C)C)C>CN(C=O)C>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][N:1]2[CH2:5][CH2:4][C@@H:3]([NH:6][C:7](=[O:13])[O:8][C:9]([CH3:10])([CH3:12])[CH3:11])[CH2:2]2)=[CH:18][CH:17]=1
Reactant: Cc1ccc(CCl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCNC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(CN2CC[C@@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Yield: 75.2 %

Procedure:
To a mixture of tert-butyl (3R)-3-pyrrolidinylcarbamate (4.0 g) and 1-(chloromethyl)-4-methylbenzene (3.17 g) in DMF (40 mL) was added N-ethyl-N-isopropyl-2-propanamine (5.55 g) at ambient temperature and the resulting mixture was heated at 70 for four hours. The mixture was allowed to cool to ambient temperature and extracted with ethyl acetate (100 mL). The organic phase was washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated in vacuo. The residue was purified by a flash chromatography etluting with gradient solvent system (ethyl acetate-hexane from 1:4 v/v to 1:1 v/v) to give tert-butyl [(3R)-1-(4-methylbenzyl)-3-pyrrolidinyl]carbamate (4.69 g) as a pale yellow syrup.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=[CH:8][C:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](O)=[O:22])=[CH:15][CH:16]=2)[NH:11][N:10]=1.[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH2:34].C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[O:28]1[CH:32]=[CH:31][CH:30]=[C:29]1[CH2:33][NH:34][C:21](=[O:22])[C:20]1[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=1[NH:18][C:14]1[CH:13]=[C:12]2[C:17]([C:9](/[CH:8]=[CH:7]/[C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:10][NH:11]2)=[CH:16][CH:15]=1
Reactant: NCc1ccco1
Reactant: O=C(O)c1ccccc1Nc1ccc2c(C=Cc3ccccn3)n[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(NCc1ccco1)c1ccccc1Nc1ccc2c(/C=C/c3ccccn3)n[nH]c2c1
Reaction time: 8 h
Yield: 123 %

Procedure:
A solution of 2-[3-(2-Pyridin-2-yl-vinyl)-1H-indazol-6-ylamino]-benzoic acid (50.0 mg, 0.084 mmol), C-furan-2-yl-methylamine (19 μL, 0.17 mmol), triethylamine (58 μl, 0.42 mmol), dissolved in DMF (0.8 mL), was treated with HATU (48 mg, 0.13 mmol). The mixture was stirred overnight, then purified by reverse phase HPLC yielding 45 mg (85%) of the title compound as a TFA salt (1.5 H2O, 1.5 TFA, effective MW=633.52). 1H NMR (DMSO-d6): δ 9.82(1H, s), 9.05 (1H, t, J=2.6), 8.73 (1H, d, J=3.7), 8.13 (4H, m), 7.73 (1H, d, J=6.8), 7.57 (2H, m), 7.26 (1H, s), 7.03 (1H, d, J=7.5), 6.40 (1H, m), 6.28 (1H, m), 4.48 (2H, d, J=6.5). ESIMS (M+H+): 436.1.