Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4].[CH:33]1([C:39](Cl)=[O:40])[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]1>>[CH3:1][N:2]([CH3:32])[C:3]([C:5]1[N:26]([CH:27]2[CH2:31][CH2:30][CH2:29][CH2:28]2)[C:8]2[N:9]=[C:10]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:21][CH2:22][N:23]([C:39]([CH:33]5[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]5)=[O:40])[CH2:24][CH2:25]4)=[CH:16][N:15]=3)[N:11]=[CH:12][C:7]=2[CH:6]=1)=[O:4]
Reactant: O=C(Cl)C1CCCCC1
Reactant: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCNCC4)cn3)nc2n1C1CCCC1
Product: CN(C)C(=O)c1cc2cnc(Nc3ccc(N4CCN(C(=O)C5CCCCC5)CC4)cn3)nc2n1C1CCCC1
Yield: 50.3 %

Procedure:
Following General Procedure G, 7-cyclopentyl-2-(5-piperazin-1-yl-pyridin-2-ylamino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (100 mg, 0.230 mmol) and cyclohexane carbonyl chloride (37 mg, 0.690 mmol) gave 2-[5-(4-cyclohexanecarbonyl-piperazin-1-yl)-pyridin-2-ylamino]-7-cyclopentyl-7H-pyrrolo[2,3-d]pyrimidine-6-carboxylic acid dimethylamide (63 mg, 49%). MS(ESI) m/z 545.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH2:6].C1(CN)CCCCC1.[O:18]=[C:19]1[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:39][C:40]1[CH:48]=[CH:47][CH:46]=[CH:45][C:41]=1[C:42](O)=[O:43].O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][NH:6][C:42](=[O:43])[C:41]1[CH:45]=[CH:46][CH:47]=[CH:48][C:40]=1[CH2:39][N:20]1[C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:27]2([CH2:31][O:30][C:29]3[CH:32]=[C:33]4[C:37](=[CH:38][C:28]2=3)[CH2:36][CH2:35][O:34]4)[C:19]1=[O:18]
Reactant: NCc1cccc(Cl)c1
Reactant: O=C(O)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(NCc1cccc(Cl)c1)c1ccccc1CN1C(=O)C2(COc3cc4c(cc32)CCO4)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 3-chlorobenzylamine to replace cyclohexanemethylamine, and 2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid to replace 3-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzoic acid, N-(3-chlorobenzyl)-2-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (84%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ 7.52-7.47 (m, 1H), 7.39-7.15 (m, 9H), 7.09-7.00 (m, 3H), 6.44 (s, 1H), 6.40 (s, 1H), 5.21-5.06 (m, 2H), 4.93 (d, J=9.0 Hz, 1H), 4.69 (d, J=9.0 Hz, 1H), 4.62 (d, J=5.9 Hz, 2H), 4.52 (t, J=8.6 Hz, 2H), 2.95 (t, J=8.6 Hz, 2H); MS (ES+) m/z 559.1 (M+23).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:23][C:22]3[C:17](=[C:18]([O:30][CH3:31])[C:19]([O:28][CH3:29])=[C:20]([O:26][CH3:27])[C:21]=3[O:24][CH3:25])[CH:16]2O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>FC(F)(F)C(O)=O>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2([C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:16][C:17]3[C:22](=[C:21]([O:24][CH3:25])[C:20]([O:26][CH3:27])=[C:19]([O:28][CH3:29])[C:18]=3[O:30][CH3:31])[CH2:23]2)=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(OC)c(OC)c(OC)c(OC)c2C1O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(c2ccc(OCc3ccccc3)cc2)Cc2c(c(OC)c(OC)c(OC)c2OC)C1
Reaction time: 0.5 h
Yield: 59.1 %

Procedure:
Trifluoroacetic acid (30 ml) was added to ethyl 2-(4-benzyloxyphenyl)-1-hydroxy-4,5,6,7-tetramethoxy-2-indancarboxylate (3.02 g, 5.94 mmols) with cooling with ice, and then triethylsilane (3.80 ml, 23.8 mmols) was added thereto at room temperature. The reaction mixture was stirred for 30 minutes, and then concentrated in vacuo. The residue was diluted with ethyl acetate, and the organic layer was washed with a saturated aqueous sodium bicarbonate solution, water and a saturated aqueous sodium chloride solution, and then dried. The solvent was evaporated out, and the resulting crude product was purified by silica gel column chromatography (hexane:ethyl acetate=10:1 to 8:1) to obtain the entitled compound (1.73 g) as an oil.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:14][OH:15])[C@H:3]([C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)[OH:4].Br[CH2:17][CH2:18][CH2:19][CH2:20][N:21]1C(=O)C2=CC=CC=C2C1=O>>[NH2:21][CH2:20][CH2:19][CH2:18][CH2:17][NH:1][C@H:2]([CH2:14][OH:15])[C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]([N+:11]([O-:13])=[O:12])=[CH:9][CH:10]=1)[OH:4]
Reactant: N[C@@H](CO)[C@@H](O)c1ccc([N+](=O)[O-])cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCCBr
Product: NCCCCN[C@H](CO)[C@H](O)c1ccc([N+](=O)[O-])cc1
Yield: 68.9 %

Procedure:
By using (1S,2S)-(+)-2-amino-1-(4-nitrophenyl)-1,3-propanediol (3.0 g) and N-(4-bromobutyl)phthalimide (4.77 g) as starting materials, the title compound (2.76 g) was obtained in the same manner as that of Reference Example 139.
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[C:4]([CH:5]=O)[C:3]=1[OH:11].Cl[CH:13](C(OC)=O)[C:14]([O:16][CH3:17])=[O:15].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C>[Cl:10][C:9]1[CH:8]=[CH:7][C:4]2[CH:5]=[C:13]([C:14]([O:16][CH3:17])=[O:15])[O:11][C:3]=2[C:2]=1[Cl:1]
Reactant: COC(=O)C(Cl)C(=O)OC
Reactant: O=Cc1ccc(Cl)c(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: COC(=O)c1cc2ccc(Cl)c(Cl)c2o1
Yield: 75.5 %

Procedure:
A suspension of 3,4-dichlorosalicylaldehyde (191 mg, 1.0 mmol), dimethyl chloromalonate (330 mg, 2.0 mmol), and powdery anhydrous potassium carbonate (414 mg, 3.0 mmol) in 4 ml of methyl ethyl ketone is refluxed under heating for 3 hours and evaporated under reduced pressure. The remaining residue is dissolved in ethyl acetate, washed with 10% hydrochloric acid, then water, dried over anhydrous sodium sulfate, and evaporated under reduced pressure to give a residue, which is chromatographed on a silca gel with methylene chloride as an eluent. The eluates are recrystallized from an ethyl acetate-diethyl ether solution to give 185 mg (Yield 75.2%) of methyl 6,7-dichloro-2-benzofurancarboxylate (D-1), m.p. 161.5°-162° C.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[N:11])=[C:4](Cl)[N:3]=1.[CH3:13][NH:14][CH3:15]>O1CCCC1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[N:6][C:5]([C:10]#[N:11])=[C:4]([N:14]([CH3:15])[CH3:13])[N:3]=1
Reactant: N#Cc1nc(C#N)c(Cl)nc1N
Reactant: CNC
Solvent: C1CCOC1
Product: CN(C)c1nc(N)c(C#N)nc1C#N
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The starting material, 2-amino-6-chloro-3,5-dicyanopyrazine (100 mg; 0.557 mM), is prepared in accordance with the method described by Perchais and Fleury in Tetrahedron, 30:999-1009 (1974), and stirring in 1 ml of dry tetrahydrofuran. There was then added dropwise 0 54 ml of a chilled solution of dimethylamine gas in tetrahydrofuran (93 mg/ml) over 10 minutes. The reaction mixture was then stirred at room temperature for 0.5 hours; the product was removed by centrifuging, and then recrystallized from 1:1 ethanol/i-propanol (50 mg); m.p. 201°-202° C.
Reaction SMILES: C1(O)C=CC=CC=1.[NH:8]([C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([O:25]C)[CH:21]=2)[N:16]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[Na].C(S)C>CN(C=O)C>[NH:8]([C:15]1[CH:24]=[N:23][C:22]2[C:17](=[CH:18][CH:19]=[C:20]([OH:25])[CH:21]=2)[N:16]=1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1ccc2nc(Nc3ccccc3)cnc2c1
Agent: [Na]
Solvent: Oc1ccccc1
Solvent: CN(C)C=O
Solvent: CCS
Product: Oc1ccc2nc(Nc3ccccc3)cnc2c1
Temperature: 110 °C

Procedure:
By the method of Feutrill, G. I., Mirrington, R. N. Tet. Lett. 1970, 1327; the aryl methyl ether is converted to the phenol derivative. To 2-anilino-6-methoxy-quinoxaline (0.27 g, 1.07 mmol) under argon in DMF is added the sodium salt of ethanethiol (0.19 g, 2 mmol). The reaction mixture is heated to 110° C. overnight. The mixture is concentrated and partitioned between EtOAc and H2O/5% tartaric acid such that the pH of the aqueous layer is approximately 4. The organic layer is washed with H2O (4×), then with 2.5% NaOH (4×). The basic layers combined, washed with EtOAc (2×), re-acidified with 5% tartaric acid, and washed with multiple portions of EtOAc. The organic layers are combined, washed with brine, dried (Na2SO4), and concentrated. The resulting solid is chromatographed (50% EtOAc/hexanes). An analytical sample is obtained by triturating the product with Et2O to provide a yellow powder (m.p. 211-213° C.). Anal. Calcd. for C14H11N3O: C, 70.88; H, 4.67; N, 17.71; Found: C, 70.64; H, 4.85; N, 17.58.
Reaction SMILES: [C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:73]=[CH:72][C:15]([O:16][CH2:17][C:18]3([O:42][C:43](=[O:71])[CH:44]([NH:60]C(OCC4C=CC=CC=4)=O)[CH2:45][CH2:46][CH2:47][CH2:48][NH:49]C(OCC4C=CC=CC=4)=O)[CH2:23][CH2:22][N:21]([C:24]4[N:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:20][CH2:19]3)=[C:14]([F:74])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]>[OH-].[Pd+2].[OH-]>[C:1]([NH:4][CH2:5][C@@H:6]1[O:10][C:9](=[O:11])[N:8]([C:12]2[CH:73]=[CH:72][C:15]([O:16][CH2:17][C:18]3([O:42][C:43](=[O:71])[CH:44]([NH2:60])[CH2:45][CH2:46][CH2:47][CH2:48][NH2:49])[CH2:19][CH2:20][N:21]([C:24]4[N:33]=[C:32]5[C:27]([C:28](=[O:40])[C:29]([C:37]([OH:39])=[O:38])=[CH:30][N:31]5[CH:34]5[CH2:36][CH2:35]5)=[CH:26][C:25]=4[F:41])[CH2:22][CH2:23]3)=[C:14]([F:74])[CH:13]=2)[CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(CCCCNC(=O)OCc4ccccc4)NC(=O)OCc4ccccc4)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Agent: [Pd+2]
Agent: [OH-]
Product: CC(=O)NC[C@H]1CN(c2ccc(OCC3(OC(=O)C(N)CCCCN)CCN(c4nc5c(cc4F)c(=O)c(C(=O)O)cn5C4CC4)CC3)c(F)c2)C(=O)O1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A suspension of 94 mg 7-[4-{4-[(5S)-5-(acetylamino-methyl)-2-oxo-oxazolidin-3-yl]-2-fluoro-phenoxymethyl}-4-(2,6-bis-benzyloxycarbonylamino-hexanoyloxy)-piperidin-1-yl]-1-cyclopropyl-6-fluoro-4-oxo-1,4-dihydro-[1,8]naphthyridine-3-carboxylic acid (MW: 1024.05, 0.091 mmol) and 20 mg of palladium hydroxide 20% on activated carbon in 20 ml of a 6/3/1 dichloromethane/methanol/water mixture was stirred at room temperature under hydrogen for four hours. The catalyst was filtered off using a glass fibre filter paper. The solvents were evaporated under reduced pressure and the residue dissolved in 10 ml methanol. The solution was diluted with 20 ml water while a white solid precipitated. The solid was collected and dried. Yield: 29 mg, 43%. MS: 757.0 (M+H)+, 755.2 Method ESI+, ESI−.
Reaction SMILES: O[CH:2]1[CH:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1.COCCN(CCOC)S(F)(F)[F:34]>C(Cl)Cl>[F:34][CH:2]1[CH:7]([NH:8][C:9]2[C:14]([N+:15]([O-:17])=[O:16])=[CH:13][N:12]=[C:11]3[CH:18]=[CH:19][S:20][C:10]=23)[CH2:6][CH2:5][N:4]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:3]1
Reactant: COCCN(CCOC)S(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(O)C1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC(Nc2c([N+](=O)[O-])cnc3ccsc23)C(F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
To a solution of tert-butyl 3-hydroxy-4-[(6-nitrothieno[3,2-b]pyridin-7-yl)amino]piperidine-1-carboxylate (716 mg, 1.82 mmol) in methylene chloride (4 mL) cooled at 0° C. was added slowly 2-methoxy-N-(2-methoxyethyl)-N-(trifluoro-λ(4)-sulfanyl)ethanamine (0.50 mL, 2.7 mmol). The reaction was stirred at room temperature for 4 h. The mixture was diluted with dichloromethane, washed with water, and concentrated. The residue was purified on silica gel (eluting with 0 to 30% EtOAc in dichloromethane) to give the desired product (0.32 g, 44%) as a mixture of cis- and trans-isomers mixture. LCMS calculated for C17H22FN4O4S (M+H)+: m/z=397.1. Found: 397.1.
Reaction SMILES: C(OC([NH:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][CH:24]([C:31]2[NH:35][C:34]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=3[N:32]=2)[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:22])=[CH:19][C:18]=1[Cl:43])=[O:16])=O)(C)(C)C.FC(F)(F)C(O)=O.ClCl>ClCCl.CO>[NH2:8][CH2:9][CH:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15]([C:17]1[CH:42]=[CH:41][C:20]([C:21]([NH:23][CH:24]([C:31]2[NH:35][C:34]3[CH:36]=[CH:37][C:38]([Cl:40])=[CH:39][C:33]=3[N:32]=2)[CH2:25][C:26]2[N:27]=[CH:28][NH:29][CH:30]=2)=[O:22])=[CH:19][C:18]=1[Cl:43])=[O:16]
Reactant: CC(C)(C)OC(=O)NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Agent: ClCl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: NCC1CCCN1C(=O)c1ccc(C(=O)NC(Cc2c[nH]cn2)c2nc3cc(Cl)ccc3[nH]2)cc1Cl
Yield: 98 %

Procedure:
Prepared analogously to Example 17 from 4-[2-(N-tert-butoxycarbonylaminomethyl)pyrrolidin-1-ylcarbonyl]-3-chloro-N-[1-(5-chloro-1H-benzimidazol-2-yl)-2-(1H-imidazol-4-yl)ethyl]benzamide and trifluoroacetic acid. Yield: 98% of theory; Rf value: 0.47 (silica gel; dichloromethane/methanol=7:3); C25H25C12N7O2 (526.43); mass spectrum: (M+H)+=526/528/530 (chlorine isotope).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1.[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24]Cl)=[O:20])([CH3:17])([CH3:16])[CH3:15].[I-].[Na+].C(=O)([O-])[O-].[Na+].[Na+]>CC(C)=O>[C:14]([O:18][C:19]([NH:21][C:22]1[CH:29]=[CH:28][CH:27]=[C:26]([CH3:30])[C:23]=1[CH2:24][NH:1][C:2]1[C:3]2[N:4]([C:8]([CH:12]=[O:13])=[C:9]([CH3:11])[N:10]=2)[CH:5]=[CH:6][CH:7]=1)=[O:20])([CH3:17])([CH3:16])[CH3:15]
Reactant: Cc1nc2c(N)cccn2c1C=O
Reactant: Cc1cccc(NC(=O)OC(C)(C)C)c1CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: Cc1cccc(NC(=O)OC(C)(C)C)c1CNc1cccn2c(C=O)c(C)nc12

Procedure:
The title compound is prepared according to the procedure described for example 7 starting from 8-amino-3-formyl-2-methylimidazo[1,2-a]pyridine (4.0 g), 2-tert-butoxycarbonylamino-6-methylbenzylchloride (7.0 g), sodium iodide (4.1 g) and sodium carbonate (6.1 g) in acetone (250 ml). Purification by chromatography on silica gel (toluene/dioxane 9:1 as eluent) and crystallization from diisopropyl ether yield 7.3 g (81%) of m.p. 210°-212° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([NH:21][CH2:22][C:23]3[C:24]([NH:36][CH:37]4[CH2:42][CH2:41][O:40][CH2:39][CH2:38]4)=[C:25]4[CH:33]=[N:32][N:31]([CH2:34][CH3:35])[C:26]4=[N:27][C:28]=3[CH2:29][CH3:30])=[O:20])[CH:14]=2)=[O:12])[CH:5]=[CH:6][C:7]=1[F:8].CC1(C)C(C)(C)OB([C:51]2[CH:52]=[C:53]([CH2:57][CH:58]3[CH2:63][CH2:62][N:61](C(OC(C)(C)C)=O)[CH2:60][CH2:59]3)[CH:54]=[CH:55][CH:56]=2)O1.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:34]([N:31]1[C:26]2=[N:27][C:28]([CH2:29][CH3:30])=[C:23]([CH2:22][NH:21][C:19]([C:15]3[CH:16]=[CH:17][CH:18]=[C:13]([C:11]([NH:10][CH2:9][C:4]4[CH:3]=[C:2]([C:55]5[CH:56]=[CH:51][CH:52]=[C:53]([CH2:57][CH:58]6[CH2:63][CH2:62][NH:61][CH2:60][CH2:59]6)[CH:54]=5)[C:7]([F:8])=[CH:6][CH:5]=4)=[O:12])[CH:14]=3)=[O:20])[C:24]([NH:36][CH:37]3[CH2:42][CH2:41][O:40][CH2:39][CH2:38]3)=[C:25]2[CH:33]=[N:32]1)[CH3:35]
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(Br)c2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Cc2cccc(B3OC(C)(C)C(C)(C)O3)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(F)c(-c3cccc(CC4CCNCC4)c3)c2)c1
Reaction time: 0.5 h
Yield: 21.9 %

Procedure:
To a solution of N-[(3-bromo-4-fluorophenyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-1,3-benzenedicarboxamide (0.641 g, 0.1 mmol) in 1,4-dioxane (1.5 ml) and water (0.500 ml) was added 1,1-dimethylethyl 4-{[3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]methyl}-1-piperidinecarboxylate (0.048 g, 0.120 mmol), Pd(Ph3P)4 (4.62 mg, 4.00 μmol), and K2CO3 (0.041 g, 0.300 mmol). This mixture was heated using a microwave instrument at 150° C. for 15 min. The organic layer was separated, concentrated using a Glas-Col evaporator, purified using a Gilson HPLC (with TFA), concentrated by GeneVav EZ-2 evaporator. The resulting solid was added to DCM (0.3 mL) then TFA (0.15 mL) and this mixture was left stand for 30 min before it was concentrated using a Glas-Col evaporator. The concentrate was purified using a Gilson HPLC (with TFA), concentrated by GeneVav EZ-2 evaporator, basified by amine cartridge to afford the title compound 0.016 g (21%). LC-MS m/z 732 (M+H)+.
Reaction SMILES: [OH-].[Na+].[O:3]=[C:4]1[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]([O:20]CC)=[O:19])=[CH:16][C:17]=3[N:9]2[CH2:8][C:7]2([CH2:24][CH2:23]2)[CH2:6][NH:5]1.C(O)(=O)C>O.C(O)C>[O:3]=[C:4]1[C:10]2=[CH:11][C:12]3[CH:13]=[CH:14][C:15]([C:18]([OH:20])=[O:19])=[CH:16][C:17]=3[N:9]2[CH2:8][C:7]2([CH2:23][CH2:24]2)[CH2:6][NH:5]1
Reactant: CCOC(=O)c1ccc2cc3n(c2c1)CC1(CC1)CNC3=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: O=C(O)c1ccc2cc3n(c2c1)CC1(CC1)CNC3=O
Temperature: 80 °C
Yield: 66.2 %

Procedure:
A solution of NaOH (3 g, 75 mmol) in water (75 mL) is added to a suspension of ethyl 1′-oxo-2′,3′-dihydro-1′H-spiro[cyclopropane-1,4′-[1,4]diazepino[1,2-a]indole]-8′-carboxylate (9 g, 30.2 mmol) in ethanol (300 mL). The reaction mixture is heated at 80° C. for 2 h. Acetic acid (48 mL) and water (250 mL) are added and the resulting solid is filtered, rinsed with water and dried to afford the title compound (5.4 g, 66%) as a white solid.
Reaction SMILES: C(OC([N:8]([C:26](OC(C)(C)C)=O)[C:9]1[N:25]=[C:12]2[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][N:18]3[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]3)[N:11]2[N:10]=1)=O)(C)(C)C.CS(OS(C)(=O)=O)(=O)=O.C(OC(N(C(OC(C)(C)C)=O)[C:50]1[N:60]=[C:53]2[CH:54]=[CH:55][CH:56]=[C:57](CO)[N:52]2N=1)=O)(C)(C)C.C(N(CC)C(C)C)(C)C.N1CCNCC1=O>ClCCl>[NH:52]1[C:53]2=[N:60][CH:50]=[C:26]([NH:8][C:9]3[N:25]=[C:12]4[CH:13]=[CH:14][CH:15]=[C:16]([CH2:17][N:18]5[CH2:23][CH2:22][NH:21][C:20](=[O:24])[CH2:19]5)[N:11]4[N:10]=3)[CH:54]=[C:55]2[CH:56]=[CH:57]1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2cccc(CO)n2n1
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)c1nc2cccc(CN3CCNC(=O)C3)n2n1
Agent: CS(=O)(=O)OS(C)(=O)=O
Agent: O=C1CNCCN1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C1CN(Cc2cccc3nc(Nc4cnc5[nH]ccc5c4)nn23)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96 %

Procedure:
N,N-Di-tert-butoxycarbonyl-5-((3-oxopiperazinyl)methyl)-[1,2,4]triazolo[1,5-a]pyridin-2-amine. Methanesulfonic anhydride (0.374 g, 2.147 mmol) was added to a stirred solution of N,N-di-tert-butoxycarbonyl-5-hydroxymethyl-[1,2,4]triazolo[1,5-a]pyridin-2-amine (0.652 g, 1.789 mmol) and N,N-diisopropylethylamine (0.935 mL, 5.37 mmol) in dichloromethane (15 mL). The resulting light yellow solution was stirred at room temperature under nitrogen for 30 min and then piperazin-2-one (0.269 g, 2.68 mmol) was added. The resulting mixture was stirred and heated at 50° C. under a reflux condenser under nitrogen for 5.5 h. The resulting mixture was purified using flash chromatography (Biotage) (0-10% methanol in dichloromethane) to give the desired product (0.764 g, 1.711 mmol, 96% yield) as a white foam-solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm) 7.71-7.83 (m, 3H), 7.31 (dd, J=1.37, 6.83 Hz, 1H), 4.08 (s, 2H), 3.17-3.23 (m, 2H), 3.14 (s, 2H), 2.74 (t, J=5.47 Hz, 2H), 1.40 (s, 18H); MS (ESI) m/z 447.3 [M+1]+.
Reaction SMILES: [N+:1]([C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1)([O-])=O.[H][H]>C(O)C.[Ni]>[NH2:1][C:4]1[CH:22]=[CH:21][C:7]2[NH:8][C:9](=[O:20])[CH2:10][C:11](=[O:19])[N:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[C:6]=2[CH:5]=1
Reactant: [H][H]
Reactant: O=C1CC(=O)N(c2ccccc2)c2cc([N+](=O)[O-])ccc2N1
Agent: [Ni]
Solvent: CCO
Product: Nc1ccc2c(c1)N(c1ccccc1)C(=O)CC(=O)N2

Procedure:
29.7 g of 7-nitro-5-phenyl-1-H-1,5-benzodiazepine-2,4-dione in 200 ml ethanol containing 1.0 g of Raney nickel is hydrogenated at room temperature at an initial hydrogen pressure of 50 p.s.i. The reaction is stopped after 0.3 moles of hydrogen has been absorbed. The reaction mixture is filtered and the filtrate evaporated to give 7-amino-5-phenyl-3H-1,5-benzodiazepine-2,4-dione.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2)(=O)=O.O.[I-:23].[Li+]>CN(C)C=O>[I:23][C:7]1[C:15]([CH3:16])=[CH:14][C:13]([N+:17]([O-:19])=[O:18])=[C:12]2[C:8]=1[CH2:9][CH2:10][CH2:11]2
Reactant: Cc1cc([N+](=O)[O-])c2c(c1OS(=O)(=O)C(F)(F)F)CCC2
Reactant: [I-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc([N+](=O)[O-])c2c(c1I)CCC2
Temperature: 150 °C
Reaction time: 7 h
Yield: 77.8 %

Procedure:
To a solution of 5-methyl-7-nitroindan-4-yl trifluoromethanesulfonate (3.02 g) in N,N-dimethylformamide (10 mL) was added lithium iodide mono hydrate (6.10 g). The mixture was stirred under an argon atmosphere at 150° C. for 7 hours. Adding water, the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a 1 mol/L aqueous solution of sodium hydroxide, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (2.19 g).
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]([NH:13][NH:14]S(C2C=CC(C)=CC=2)(=O)=O)=[CH:10][C:9](=[O:25])[CH2:8]1.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:34][C:35](=O)[CH3:36].[I-].[Na+]>COCCOC.CO>[Cl:1][C:2]1[S:3][C:4]([Cl:26])=[CH:5][C:6]=1[CH:7]1[CH2:12][C:11]2[N:13]=[N:14][CH:34]=[C:35]([CH3:36])[C:10]=2[C:9](=[O:25])[CH2:8]1
Reactant: Cc1ccc(S(=O)(=O)NNC2=CC(=O)CC(c3cc(Cl)sc3Cl)C2)cc1
Reactant: CC(=O)CCl
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CO
Solvent: COCCOC
Product: Cc1cnnc2c1C(=O)CC(c1cc(Cl)sc1Cl)C2
Temperature: 80 °C
Reaction time: 3 h
Yield: 52.8 %

Procedure:
A mixture of 5-(2,5-dichlorothiophen-3-yl)-1-[2-(4-methylphenylsulfonyl)hydrazino]cyclohexen-3-one (1.33 g), anhydrous potassium carbonate (1.14 g), chloroacetone (0.4 g), sodium iodide (0.3 g), methanol (25 ml) and 1,2-dimethoxyethane (10 ml) was stirred at 80° C. for 3 hours. Under reduced pressure, the solvent was evaporated, and the residue was extracted with ethyl acetate. The organic layer was concentrated, and the residue was purified with silica gel column chromatography to give 7-(2,5-dichlorothiophen-3-yl)-4-methyl-5,6,7,8-tetrahydrocinnolin-5-one (0.51 g) as colorless crystals.