Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1.[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1B(O)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>[Cl:23][C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[C:2]1[C:3]([C:19]([O:21][CH3:22])=[O:20])=[N:4][C:5]([NH:8][C@@H:9]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:11][C@@H:10]2[OH:18])=[CH:6][N:7]=1
Reactant: OB(O)c1ccc(Cl)cc1Cl
Reactant: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1Br
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Product: COC(=O)c1nc(N[C@@H]2c3ccccc3C[C@@H]2O)cnc1-c1ccc(Cl)cc1Cl
Temperature: 85 °C
Yield: 59.1 %

Procedure:
Charge a Kimble vial with methyl 3-bromo-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate (0.45 g, 1.14 mmol), Pd(PPh3)4 (198 mg, 0.17 mmol), and 2,4-dichlorophenylboronic acid (325 mg, 1.71 mmol). Flush with N2 and add DMF (4 mL) and 2 M Na2CO3 (1.1 mL). The resulting mixture was heated at 85° C. overnight. The mixture was diluted with sat. aq. NaHCO3. Extract with Et2O. The organic extract was dried over MgSO4, filtered and concentrated. Purify by biotage MPLC (90 g column, 30% ethyl acetate/hexanes) to afford 290 mg (59%) of methyl 3-(2,4-dichlorophenyl)-6-{[(1R,2S)-2-hydroxy-2,3-dihydro-1H-inden-1-yl]amino}pyrazine-2-carboxylate as a solid: 1H NMR (CDCl3) δ 3.06–3.09, 3.27–3.32, 3.80, 4.09–4.15, 4.84, 5.58, 7.28–7.49, 8.25; MS (ESI+) for C21H17Cl2N3O3 m/z 430 (M+H)+.
Reaction SMILES: [C:1]([CH:3]([CH:7]1[C:11]([Cl:12])=[C:10](Cl)C(=O)O1)[C:4]([NH2:6])=[O:5])#[N:2].Cl.[NH2:16][CH2:17][C:18]1[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=1[S:25]([NH:28][CH3:29])(=[O:27])=[O:26].C(N(CC)CC)C>CO>[ClH:12].[Cl:12][C:11]1[CH:7]=[C:3]([C:4]([NH2:6])=[O:5])[C:1](=[NH:2])[N:16]([CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[CH:20][C:19]=2[S:25](=[O:27])(=[O:26])[NH:28][CH3:29])[CH:10]=1
Reactant: CNS(=O)(=O)c1ccc(F)cc1CN
Reactant: N#CC(C(N)=O)C1OC(=O)C(Cl)=C1Cl
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: CNS(=O)(=O)c1ccc(F)cc1Cn1cc(Cl)cc(C(N)=O)c1=N
Temperature: 50 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(Step 2) To a suspension of 2-cyano-2-(3,4-dichloro-5-oxo-2,5-dihydrofuran-2-yl)acetamide (0.90 g) in methanol (10 ml) was added a solution of 2-(aminomethyl)-4-fluoro-N-methylbenzenesulfonamide hydrochloride obtained in Step 1 (1.17 g) and triethylamine (1.6 ml) in methanol (5 ml) at room temperature, and the mixture was stirred overnight at 50° C. The reaction solvent was evaporated under reduced pressure, acetic acid (5 ml) was added, and the mixture was stirred at 50° C. for 2 hr. The solvent was evaporated under reduced pressure, the residue was extracted with 1N hydrochloric acid, and the extract was washed with ethyl acetate. The aqueous layer was basified with 1N aqueous sodium hydroxide solution, the mixture was partitioned with ethyl acetate, and the organic layer was dried over sodium sulfate. The solvent was evaporated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate:hexane=7:3→1:0). The obtained residue was dissolved in methanol, and 4N hydrogen chloride-ethyl acetate solution (1 ml) was added. The mixture was crystallized from methanol-ethyl acetate. The precipitated crystals were collected by filtration, and recrystallized from methanol-ethyl acetate to give the title compound (0.74 g).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][Cl:16])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[O:7].[CH3:36][NH:37][CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>O1CCCC1>[ClH:16].[F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:17])[CH2:15][N:37]([CH2:38][C:39]2[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=2)[CH3:36])[CH2:10][C@H:9]1[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[C:21]([CH3:26])[CH:20]=1)=[O:7]
Reactant: Cc1ccc(C[C@@H]2CN(C(=O)CCl)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Reactant: CNCc1ccccc1
Solvent: C1CCOC1
Product: Cc1ccc(C[C@@H]2CN(C(=O)CN(C)Cc3ccccc3)CCN2C(=O)c2cc(C(F)(F)F)cc(C(F)(F)F)c2)cc1C
Product: Cl
Temperature: 45 °C
Reaction time: 2 h
Yield: 94.6 %

Procedure:
To a stirred solution of (2R)-1-[3,5-bis(trifluoromethyl)benzoyl]-2-(3,4-dimethylbenzyl)-4-(2-chloroacetyl)piperazine (300 mg) in tetrahydrofuran (5 ml) was added N-methylbenzylamine (140 mg) at room temperature. After stirring for 2 hours, additional N-methylbenzylamine (70 mg) was added, and then the whole was heated at 45° C. for 6 hours. The mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate (20 ml) and aqueous sodium bicarbonate solution (10 ml). The organic layer was separated and dried over magnesium sulfate. After evaporation of the solvent in vacuo, the residue was purified by column chromatography on a silica gel eluting with a mixture of dichloromethane and methanol (50:1) and treated with 4N hydrogen chloride in ethyl acetate solution to afford (2R)-1-[3,5-bis(trifluoromethyl)-benzoyl]-4-[2-(N-benzyl-N-methylamino)acetyl]-2-(3,4-dimethylbenzyl)piperazine hydrochloride (0.35 g).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:27]=[C:26]([NH2:28])[CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11])(=[O:3])[CH3:2].[CH3:29][S:30]([Cl:33])(=[O:32])=[O:31]>N1C=CC=CC=1>[ClH:33].[C:1]([NH:4][C:5]1[CH:27]=[C:26]([NH:28][S:30]([CH3:29])(=[O:32])=[O:31])[CH:25]=[CH:24][C:6]=1[O:7][CH2:8][CH2:9][N:10]([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH3:23])[CH:15]=1)[CH3:11])(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(CCN(C)CCOc2ccc(N)cc2NC(C)=O)cc1OC
Solvent: c1ccncc1
Product: COc1ccc(CCN(C)CCOc2ccc(NS(C)(=O)=O)cc2NC(C)=O)cc1OC
Product: Cl
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A portion (510 mg, 1.32 mmol) of the 1-(2-acetamido-4-aminophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane produced in (4) above was dissolved in pyridine (5 ml) and, thereafter, the solution was cooled to 0° C. and methanesulfonyl chloride (0.21 ml, 2.63 mmol) was added, followed by stirring at room temperature for 2 h. Thereafter, the solvent was evaporated from the reaction mixture and the resulting residue was diluted with an aqueous solution of sodium bicarbonate, followed by extraction with chloroform. The organic layer was dried with sodium sulfate and the solvent was evaporated, with the resulting residue being purified by being subjected to column chromatography on silica gel using, as an eluent, chloroform containing methanol (6%). The resulting product was dissolved in methanol (10 ml) and the HCl as generated by adding conc. sulfuric acid to ammonium chloride was passed through the resulting solution. Thereafter, the solvent was evaporated for drying to yield the titled compound 1-(2-acetamido-4-methanesulfonamidophenoxy)-2-[N-(3,4-dimethoxyphenethyl)-N-methylamino]ethane hydrochloride (420 mg) as a foamy substance of ivory color.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25](O)=[O:26])=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.ClC(OCC)=O.[NH2:43][OH:44]>[Cl-].[Na+].O.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[CH:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([NH:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]([NH:43][OH:44])=[O:26])=[O:18])=[CH:15][CH:14]=1
Reactant: NO
Reactant: O=C(O)CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1
Agent: CCOC(=O)Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(CCCCCNC(=O)c1ccc(C=C2C(=O)Nc3ccc(F)cc32)cc1)NO
Temperature: 0 °C
Reaction time: 2 h
Yield: 45.9 %

Procedure:
6-(4-((5-fluoro-2-oxoindolin-3-ylidene)methyl)benzamido)hexanoic acid (396 mg, 1 mmol), triethylamine (151 mg, 1.5 mmol) and 20 ml of DMF were stirred at 0° C. while ethyl chloroformate (163 mg, 1.5 mmol) was added. The mixture was stirred at 0° C. for 2 hours, and then 50% aqueous solution of hydroxylamine (1.32 g, 20 mmol) was added. The mixture was stirred for 3 hours at room temperature, and then diluted with 1000 mL of brine. The solids were collected by vacuum filtration, washed with water and dried under vacuum to give the title compound (189 mg, 46%) as a brown solid. LC-MS (m/z) 412 (M+1).
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=2[O:5][C:4]=1/[N:17]=[CH:18]/[N:19](C)C)#[N:2].[C:22]([C:24]1[CH:25]=[C:26]([CH:28]=[CH:29][CH:30]=1)N)#[CH:23]>>[C:22]([C:24]1[CH:30]=[C:29]([NH:2][C:1]2[C:3]3[C:11]4[CH2:10][CH2:9][N:8]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:7][C:6]=4[O:5][C:4]=3[N:17]=[CH:18][N:19]=2)[CH:28]=[CH:26][CH:25]=1)#[CH:23]
Reactant: C#Cc1cccc(N)c1
Reactant: CCOC(=O)N1CCc2c(oc(/N=C/N(C)C)c2C#N)C1
Product: C#Cc1cccc(Nc2ncnc3oc4c(c23)CCN(C(=O)OCC)C4)c1

Procedure:
In analogy to Example 38A, the title compound was prepared from ethyl 3-cyano-2-{[(1E)(dimethylamino)methylidene]amino}-4,7-dihydrofuro[2,3-c]pyridine-6(5H)-carboxylate from Example 37A (1.20 g, 4.14 mmol) and 3-ethynylaniline (968 mg, 8.27 mmol) to yield 443 mg (28%).
Reaction SMILES: ClS(O)(=O)=O.[F:6][C:7]([F:19])([F:18])[C:8]1[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=1.II.[Cl:22]Cl>>[Cl:22][C:12]1[CH:11]=[C:10]([C:14]([F:15])([F:16])[F:17])[CH:9]=[C:8]([C:7]([F:18])([F:19])[F:6])[CH:13]=1
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Reactant: ClCl
Agent: II
Agent: O=S(=O)(O)Cl
Product: FC(F)(F)c1cc(Cl)cc(C(F)(F)F)c1

Procedure:
130 parts of chlorosulfonic acid are introduced, at room temperature, into a reaction vessel, and 42.8 parts of 1,3-bis-(trifluoromethyl)-benzene and 2 parts of iodine are added. The suspension is cooled to 0° and 30 parts of chlorine are introduced in the course of 5 hours at 0° to 5°. The suspension is then poured out onto ice and the organic phase is separated from the aqueous phase. The organic phase is washed neutral with ice-cold water and is dried over calcined sodium sulfate. 38 parts of 5-chloro-1,3-bis-(trifluoromethyl)-benzene, of boiling point 111° to 112°, are obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[CH2:7][CH2:6][CH2:5]2.C1(CN)CCCCC1.[O:19]=[C:20]1[C:28]2([CH2:32][O:31][C:30]3[CH:33]=[C:34]4[C:38](=[CH:39][C:29]2=3)[CH2:37][CH2:36][O:35]4)[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]1[CH2:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1C=C(C=CC=1)C(O)=O>>[CH2:7]1[C:8]2[C:4](=[CH:3][C:2]([NH:1][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([CH2:40][N:21]4[C:22]5[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=5)[C:28]5([CH2:32][O:31][C:30]6[CH:33]=[C:34]7[C:38](=[CH:39][C:29]5=6)[CH2:37][CH2:36][O:35]7)[C:20]4=[O:19])=[CH:42][CH:43]=3)=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: Nc1ccc2c(c1)CCC2
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1
Agent: NCC1CCCCC1
Agent: O=C(O)c1cccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)c1
Product: O=C(Nc1ccc2c(c1)CCC2)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)cc1

Procedure:
Following the procedure as described in EXAMPLE 12 and making non-critical variations using 5-aminoindan to replace cyclohexanemethylamine, and 4-[(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-(2,3-dihydro-1H-inden-5-yl)-4-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]benzamide was obtained (65%) as a colorless solid: 1H NMR (300 MHz, CDCl3) δ7.83 (d, J=8.1 Hz, 2H), 7.79 (s, 1H), 7.56 (s, 1H), 7.42 (d, J=8.1 Hz, 2H), 7.28-7.21 (m, 2H), 7.21-7.14 (m, 2H), 7.08-6.97 (m, 1H), 6.74 (d, J=7.7 Hz, 1H), 6.46 (s, 1H), 6.42 (s, 1H), 4.99 (ABq, 2H), 4.83 (ABq, 2H), 4.53 (t, J=8.6 Hz, 2H), 3.03-2.80 (m, 6H), 2.15-1.97 (m, 2H); MS (ES+) m/z 529.1 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH2:21])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:30][C:31]1[O:35][N:34]=[C:33]([C:36](Cl)=[O:37])[CH:32]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([O:17][C@H:18]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[C@@H:19]([NH:21][C:36]([C:33]4[CH:32]=[C:31]([CH3:30])[O:35][N:34]=4)=[O:37])[CH3:20])=[CH:14][CH:15]=3)[CH:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)N)c1
Reactant: Cc1cc(C(=O)Cl)no1
Product: COc1cccc([C@@H](Oc2ccc3c(cnn3-c3ccc(F)cc3)c2)[C@H](C)NC(=O)c2cc(C)on2)c1

Procedure:
Prepared as described in Example 1 using (1R,2S)-1-{[1-(4-fluorophenyl)-1H-indazol-5-yl]oxy}-1-(3-methoxyphenyl)propan-2-amine (6a, 20 mg, 50 μmol) and 5-methylisoxazole-3-carbonyl chloride (22 mg, 150 μmol). Yield 19 mg (74%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][CH:11]2[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]=3[N:13]([CH2:31][C:32](O)=[O:33])[C:12]2=[O:35])=[CH:2]1.[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([NH:45][CH:46]([CH3:48])[CH3:47])=[CH:41][CH:40]=1)[CH3:37].P(Cl)(Cl)Cl>ClC(Cl)C>[CH2:36]([O:38][C:39]1[N:44]=[CH:43][C:42]([N:45]([CH:46]([CH3:47])[CH3:48])[C:32](=[O:33])[CH2:31][N:13]2[C:12](=[O:35])[CH:11]([CH2:10][C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][CH:2]=3)[C:20]3[N:16]([C:17]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)=[N:18][N:19]=3)[C:15]3[CH:27]=[CH:28][CH:29]=[CH:30][C:14]2=3)=[CH:41][CH:40]=1)[CH3:37]
Reactant: CCOc1ccc(NC(C)C)cn1
Reactant: O=C(O)CN1C(=O)C(Cc2c[nH]c3ccccc23)c2nnc(-c3ccccc3)n2-c2ccccc21
Solvent: CC(Cl)Cl
Solvent: ClP(Cl)Cl
Product: CCOc1ccc(N(C(=O)CN2C(=O)C(Cc3c[nH]c4ccccc34)c3nnc(-c4ccccc4)n3-c3ccccc32)C(C)C)cn1
Yield: 20.9 %

Procedure:
Following the procedure described for Example 2(A), [4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-acetic acid (Preparation 15) (300 mg, 0.65 mmol) was reacted with (6-ethoxy-pyridin-3-yl)-isopropyl-amine (Preparation 2(B)) (117 mg, 0.65 mmol) and PCl3 in dichloroethane at 100° C. Purification by medium pressure chromatography eluting with a solvent gradient (5% of 0.5% NH4OH/MeOH in CH2Cl2 to 10% of 0.5% NH4OH/MeOH in CH2Cl2) provided 85.1 mg of N-(6-ethoxy-pyridin-3-yl)-2-[4-(1H-indol-3-ylmethyl)-5-oxo-1-phenyl-4,5-dihydro-2,3,6,10b-tetraaza-benzo[e]azulen-6-yl]-N-isopropyl-acetamide. 1H NMR (CD3OD) δ 8.05 (d, 1H), 7.62 (m, 3H), 7.38-7.52 (m, 6H), 7.24 (d, 1H), 7.11 (m, 2H), 6.99 (t, 1H), 6.89 (m, 3H), 4.78 (m, 1H), 4.53 (m, 1H), 4.35 (q, 2H), 4.12 (m, 1H), 3.88 (t, 1H), 3.78 (dd, 1H), 3.69 (dd, 1H), 1.38 (t, 3H), 0.99 (m, 6H); MS 626.7 (M+1), 624.6 (M−1).
Reaction SMILES: [CH2:1]([N:3]1[CH2:8][CH2:7][NH:6][CH2:5][C:4]1=[O:9])[CH3:2].C(N(CC)C(C)C)(C)C.[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1F.FC(F)(F)C(O)=O.C(N(CC)C(C)C)(C)C>C(#N)C>[F:19][C:20]1[CH:21]=[C:22]([N+:27]([O-:29])=[O:28])[CH:23]=[CH:24][C:25]=1[N:6]1[CH2:7][CH2:8][N:3]([CH2:1][CH3:2])[C:4](=[O:9])[CH2:5]1
Reactant: CCN1CCNCC1=O
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CCN1CCN(c2ccc([N+](=O)[O-])cc2F)CC1=O

Procedure:
1-Ethyl-2-oxopiperazine (3TFA salt, 10.5 g) was dissolved in acetonitrile (200 ml), and N,N-diisopropylethylamine (19.5 ml) followed by 3,4-difluoronitrobenzene (2.25 ml) were added. The mixture was heated to reflux for 18 hours. Solvent was evaporated, and the residue chromatographed on silica using as eluant a gradient increasing in polarity from 0 to 4% methanol in dichloromethane. Relevant fractions were combined and evaporated to give a solid containing some N,N-diisopropylethylamine trifluoroacetate. The solid was purified by dissolving in ethyl acetate and washing well with water. Evaporation of the organic layer gave 3-fluoro-4-(4-ethyl-3-oxopiperazin-1-yl)nitrobenzene as a solid (3.44 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[C:9]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)=[CH:10]N(C)C.[C:22]([CH2:24][C:25]([NH2:27])=[O:26])#[N:23].[H-].[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:27][C:25](=[O:26])[C:24]([C:22]#[N:23])=[CH:10][C:9]=1[C:14]1[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=1
Reactant: CN(C)C=C(C(=O)c1ccccc1Cl)c1ccc(Cl)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#Cc1cc(-c2ccc(Cl)cc2)c(-c2ccccc2Cl)[nH]c1=O
Temperature: 95 °C

Procedure:
A solution of the crude product from step A dissolved in 80 mL of DMF containing 4.4 mL methanol and 4.61 g cyanoacetamide was transferred by cannula into a flask containing a suspension of NaH (4.98 g, 60% dispersion in mineral oil, freed of excess oil by washing with hexane just prior to use) in DMF (40 mL). The solution was heated to 95° C. for 2.5 hours then concentrated. The residue was dissolved in ethyl acetate, washed twice with 10% aqueous NaHSO4, and twice with water before concentrating to a solid. The solid was suspended in warm ethanol and then cooled, and the title compound was subsequently isolated by filtration and dried in vacuo.
Reaction SMILES: [O:1]1[CH2:21][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[Cl:22]CC(O)COC1C=C[C:30]([C:33]2[CH2:34]CC(=O)N[N:38]=2)=CC=1[N+]([O-])=O.CO.C(N)(C)C>C(Cl)(Cl)Cl.CO>[OH:1][CH:2]([CH2:21][NH:38][CH:33]([CH3:34])[CH3:30])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH2:12][CH2:13][C:14](=[O:17])[NH:15][N:16]=2)=[CH:7][C:6]=1[N+:18]([O-:20])=[O:19].[ClH:22]
Reactant: O=C1CCC(c2ccc(OCC(O)CCl)c([N+](=O)[O-])c2)=NN1
Reactant: O=C1CCC(c2ccc(OCC3CO3)c([N+](=O)[O-])c2)=NN1
Solvent: CO
Solvent: CC(C)N
Solvent: ClC(Cl)Cl
Product: CC(C)NCC(O)COc1ccc(C2=NNC(=O)CC2)cc1[N+](=O)[O-]
Product: Cl

Procedure:
A mixture of 6-[4-(2,3-epoxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone and 6-[4-(3-chloro-2-hydroxypropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone (0.9g) was stirred with methanol (9 ml) and isopropylamine (1.6 ml) and heated under reflux for 60 minutes. Evaporation under reduced pressure gave a glassy solid, 0.96g, from which 6-[4-(2-hydroxy-3-isopropylaminopropoxy)-3-nitrophenyl]-4,5-dihydro-3(2H)-pyridazinone was isolated as its hydrochloride (m.p. 210°-215° C) by column chromatography (silica, chloroform-methanol mixtures).
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=O)[C:3]1=2.[NH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.Cl.CN(C)CCCN=C=NCC>O1CCOCC1>[C:15]1([NH:14][C:11]([C:4]2[C:3]3[C:2](=[O:1])[CH2:10][CH2:9][CH2:8][C:7]=3[NH:6][CH:5]=2)=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: Nc1ccccc1
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1COCCO1
Product: O=C(Nc1ccccc1)c1c[nH]c2c1C(=O)CCC2
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 64.5 %

Procedure:
A mixture of 4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol), aniline (0.46 mL, 5 mmol), and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (959 mg, 5 mmol) in 50% aqueous dioxane (10 mL) was allowed to stir at ambient temperature for 17.5 hours, then concentrated in vacuo. The residue was cooled in an ice water bath, aqueous 3.6N hydrochloric acid was added, and the precipitate collected, rinsed with aqueous 3.6N hydrochloric acid then water and dried. Recrystallization from ethyl alcohol afforded N-phenyl-4-oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxamide (Compound 35) (164 mg). mp 225-226° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30](F)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:20]=[CH:21][CH:22]=1>>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([N:23]2[C:32]3[C:27](=[CH:28][C:29]([F:34])=[C:30]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)[CH:31]=3)[C:26](=[O:35])[N:25]([O:36][CH2:37][C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=3)[C:24]2=[O:44])[CH:20]=[CH:21][CH:22]=1
Reactant: CN1CCNCC1
Reactant: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(F)cc32)c1
Solvent: CCN(CC)CC
Product: COc1cccc(-n2c(=O)n(OCc3ccccc3)c(=O)c3cc(F)c(N4CCN(C)CC4)cc32)c1
Yield: 81.5 %

Procedure:
Using General Method 4, the reaction of N-methylpiperazine (0.1 mL, 0.9 mmol), triethylamine (0.12 mL, 0.9 mmol), and 1-(3-methoxyphenyl)-3-benzyloxy-6,7-difluoro-1H-quinazoline-2,4-dione (Example E-1, 0.12 g, 0.3 mmol) provided 0.12 g of the title compound as a solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][C:13]([CH2:17][N:18]1[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]1)=[CH:12][N:11]=2.[NH:31]1[C:35]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39](O)=[O:40])=[N:34][N:33]=[N:32]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[NH:34]1[C:35]([C:36]2[CH:37]=[C:38]([CH:42]=[CH:43][CH:44]=2)[C:39]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[C:8]2[S:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([CH2:17][N:18]2[CH2:23][CH2:22][N:21]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:20][CH2:19]2)=[CH:12][N:11]=3)=[O:40])=[N:31][N:32]=[N:33]1
Reactant: O=C(O)c1cccc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4N)nc3c2)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCN(Cc2cnc3sc(-c4ccccc4NC(=O)c4cccc(-c5nnn[nH]5)c4)nc3c2)CC1
Temperature: 50 °C
Reaction time: 18 h

Procedure:
tert-Butyl 4-((2-(2-aminophenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate (85 mg, 0.2 mmol) was taken up in 3 mL of DMF along with 3-(1H-tetrazol-5-yl)benzoic acid (38 mg, 0.2 mmol), HATU (114 mg, 0.3 mmol) and DIEA (35 mL, 0.4 mmol). The reaction mixture was stirred at 50° C. (18 h). It was then diluted with EtOAc (15 mL) and washed with water (3 mL×3). The organic layer was dried (Na2SO4) and concentrated in vacuo to afford crude tert-butyl 4-((2-(2-(3-(1H-tetrazol-5-yl)benzamido)phenyl)thiazolo[5,4-b]pyridin-6-yl)methyl)piperazine-1-carboxylate. This material was taken up in 5 mL of 25% TFA in CH2Cl2 and was allowed to stand at room temperature (18 h). The reaction mixture was concentrated in vacuo and the resulting residue was purified by reverse-phase HPLC to afford 12 mg of N-(2-(6-(piperazin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-3-(1H-tetrazol-5-yl)benzamide as a light yellow solid. 1H NMR (300 MHz, DMSO-d6) δ 9.5 (br s, 2H), 7.5-9.1 (m, 10H), 4.5 (br s, 1H), 3.5-4.0 (m, 10H). MS (ESI) calcd for C25H23N9OS (m/z): 497.17, found: 498.2 (M+1)+.