Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]1[N:9]=[N:8][C:7]([C:10]([OH:12])=O)=[CH:6][CH:5]=1)[CH3:2].C1N=CN(C(N2C=NC=C2)=O)C=1.CS(O)(=O)=O.[NH2:30][CH2:31][C:32]1[CH:33]=[C:34]2[C:38](=[CH:39][CH:40]=1)[C:37](=[O:41])[N:36]([CH:42]1[CH2:47][CH2:46][C:45](=[O:48])[NH:44][C:43]1=[O:49])[CH2:35]2.O>CN(C)C=O>[O:49]=[C:43]1[CH:42]([N:36]2[CH2:35][C:34]3[C:38](=[CH:39][CH:40]=[C:32]([CH2:31][NH:30][C:10]([C:7]4[N:8]=[N:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][CH:6]=4)=[O:12])[CH:33]=3)[C:37]2=[O:41])[CH2:47][CH2:46][C:45](=[O:48])[NH:44]1
Reactant: NCc1ccc2c(c1)CN(C1CCC(=O)NC1=O)C2=O
Reactant: CCOc1ccc(C(=O)O)nn1
Agent: CS(=O)(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(C(=O)NCc2ccc3c(c2)CN(C2CCC(=O)NC2=O)C3=O)nn1
Temperature: 40 °C
Reaction time: 1 h
Yield: 81 %

Procedure:
A stirred mixture of 6-ethoxy-pyridazine-3-carboxylic acid (0.23 g, 1.40 mmol) and CDI (0.24 g, 1.50 mmol) in N,N-dimethylformamide (10 mL) was heated to 40° C. under nitrogen. After 1 h, 3-(5-aminomethyl-1-oxo-1,3-dihydro-isoindol-2-yl)-piperidine-2,6-dione methane sulfonate (0.5 g, 1.40 mmol) was added and the mixture was heated at 50° C. for 1.5 h. Water (20 mL) was added and the solids were isolated by filtration. The product was triturated in EtOAc (20 mL) for 18 h, then filtered and dried in vacuo to give 6-ethoxy-pyridazine-3-carboxylic acid [2-(2,6-dioxo-piperidin-3-yl)-1-oxo-2,3-dihydro-1H-isoindol-5-ylmethyl]-amide as a white solid (0.48 g, 84% yield): HPLC: Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 to 90/10 CH3CN/0.1% H3PO4 gradient over 15 mins, 7.15 min (97.48%); mp: 243-245° C.; 1H NMR (DMSO-d6) δ 1.41 (t, J=7.0 Hz, 3H, CH3), 1.86-2.11 (m, 1H, CHH), 2.24-2.47 (m, 1H, CHH), 2.59 (d, J=16.8 Hz, 1H, CHH), 2.79-3.04 (m, 1H, CHH), 4.30 (d, J=17.4 Hz, 1H, CHH), 4.44 (d, J=17.4 Hz, 1H, CHH), 4.51-4.76 (m, 4H, CH2, CH2), 5.10 (dd, J=4.9, 13.2 Hz, 1H, CH), 7.35 (d, J=9.3 Hz, 1H, Ar), 7.49 (d, J=7.9 Hz, 1H, Ar), 7.56 (s, 1H, Ar), 7.69 (d, J=7.7 Hz, 1H, Ar), 8.09 (d, J=9.1 Hz, 1H, Ar), 9.73 (t, J=6.2 Hz, 1H, NH), 10.98 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.28, 22.49, 31.18, 42.52, 47.10, 51.56, 63.44, 117.87, 122.14, 122.91, 127.15, 128.80, 130.38, 142.33, 143.63, 149.23, 162.74, 165.80, 167.90, 170.98, 172.85; LCMS: MH=424; Anal Calcd for C21H21N5O5: C, 59.57; H, 5.00; N, 16.54. Found: C, 59.26; H, 4.95; N, 16.53.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([Cl:11])[N:3]=1.[NH2:12][C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1>>[Cl:11][C:4]1[N:3]=[C:2]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(Cl)nc1Cl
Reactant: Cc1ccccc1N
Product: Cc1ccccc1Nc1nc(Cl)ccc1[N+](=O)[O-]

Procedure:
From 2,6-dichloro-3-nitropyridine and o-toluidine, prepared in a similar manner as the one described in Example 1.127, Step A, the title compound was obtained. LCMS m/z=264.30 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:11]=[C:10]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:9]([OH:16])=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[CH:7]=1.[CH2:23](O)[CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]C.C([Sn](=O)CCCC)CCC>>[CH2:1]([O:2][C:3](=[O:22])[CH:4]([CH3:21])[CH2:5][C:6]1[CH:7]=[C:8]([C:17]([CH3:20])([CH3:19])[CH3:18])[C:9]([OH:16])=[C:10]([C:12]([CH3:14])([CH3:13])[CH3:15])[CH:11]=1)[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH3:30]
Reactant: CCCCCCCCCO
Reactant: COC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Agent: CCCC[Sn](=O)CCCC
Product: CCCCCCCCCOC(=O)C(C)Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 100 °C

Procedure:
30.6 g of methyl-2-methyl-3-(3',5'-di-tert.-butyl-4'-hydroxyphenyl)-propionate and 14.4 g of n-nonyl alcohol are placed in a 100 ml sulfonating flask and heated to 100° C. 0.2 g of dibutyltin oxide is added and the temperature is increased to 150° C. Methyl alcohol is split off from a temperature of 125° C. The reaction is maintained at 150° C. for 6 hours.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH2:8][CH:9](OS(C(F)(F)F)(=O)=O)[C:4]=2[CH:3]=[CH:2]1.C([O-])([O-])=O.[Na+].[Na+].CO[CH2:26][CH2:27][O:28][CH3:29]>CCOC(C)=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>[CH3:29][O:28][C:27]1[CH:5]=[CH:4][C:3]([C:9]2[C:4]3[CH:3]=[CH:2][S:1][C:5]=3[CH:6]=[CH:7][CH:8]=2)=[CH:2][CH:26]=1
Reactant: O=S(=O)(OC1CC=Cc2sccc21)C(F)(F)F
Reactant: COCCOC
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: [Na+]
Solvent: CCOC(C)=O
Product: COc1ccc(-c2cccc3sccc23)cc1

Procedure:
A mixture of trifluoromethanesulfonic acid 4,5-dihydro-1-benzothiophene-4-yl ester (9.0 g, 31.7 mmol), Na2CO3 (39.6 ml 2 N aqueous, 79.2 mmol), Pd(PPh3)4 (1.83 g, 1.6 mmol), 4-methoxyboronic acid (5.78 mg, 38.03 mmol), and ethylene glycol dimethyl ether (350 ml) was heated to reflux for 6 h. The reaction was cooled, diluted with EtOAc and the layers separated. The organic layer was dried over anhydrous Na2SO4, passed through a silica plug and concentrated to 5.0 g solid (1.44:1 ratio of desired to [6,7,6′,7′-tetrahydro-[4,4′]bi[benzo[b]thiophenyl]). This material was dissolved in toluene (50 ml) and activated MnO2 (4.5 g) was added. The mixture was refluxed overnight, cooled, filtered, and concentrated to afford a 5 g solid (1.4:1 ratio of [4,4′]bi[benzo[b]thiophenyl] to desired). Column chromatography (3:97 EtOAc/hexanes) managed to isolate 880 mg of pure product: 1H NMR (300 MHz, DMSO-d6): δ 3.83 (3H, s), 7.09 (2H, d, J=8.6 Hz), 7.33 (1H, d, J=7.2 Hz), 7.40–7.45 (2H, m), 7.51 (2H, d, J=8.7 Hz), 7.79 (1H, d, J=5.5 Hz), 7.99 (1H, d, J=8.0 Hz).
Reaction SMILES: [C:1]([N:5]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])=[C:16]([CH3:29])[CH:15]=1)[O:6][Si](C(C)(C)C)(C)C)([CH3:4])([CH3:3])[CH3:2].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O.[NH4+].[Cl-]>C1COCC1.C(OCC)(=O)C>[C:1]([N:5]([C:14]1[CH:28]=[CH:27][C:17]([C:18]([NH:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)=[O:19])=[C:16]([CH3:29])[CH:15]=1)[OH:6])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(N(O[Si](C)(C)C(C)(C)C)C(C)(C)C)ccc1C(=O)Nc1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: Cc1cc(N(O)C(C)(C)C)ccc1C(=O)Nc1ccccn1
Reaction time: 24 h
Yield: 59.9 %

Procedure:
To a solution of 0.06 g (0.145 mmol) of compound 7 in THF (1 mL) was added 0.73 mL (0.73 mmol) of 1 M solution of tetrabutylammonium fluoride in THF at room temperature, and the solution was stirred for 24 hours. After completion of the reaction, 2 mL of water was added to quench the reaction. Ethyl acetate and sat'd NH4Cl solution were added to the mixture. The organic layer was separated, dried over anhydrous MgSO4, filtered and concentrated under reduced pressure. The residue was purified by flash column chromatography (silica, Hex:EtOAc=1:2) to give 0.026 g of compound 8 in 60% yield.
Reaction SMILES: [C:1]([C:3]1[S:4][C:5]2[C:11]([C:12]#[N:13])=[C:10](/[N:14]=[CH:15]/[N:16](C)C)[CH:9]=[CH:8][C:6]=2[N:7]=1)#[N:2].[N+:19]([C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])N)([O-:21])=[O:20].[K+].[Br-]>C(Cl)Cl.CCOC(C)=O>[CH3:30][O:29][C:28]1[CH:27]=[CH:26][C:24]([NH:13][C:12]2[C:11]3[C:10](=[CH:9][CH:8]=[C:6]4[N:7]=[C:3]([C:1]#[N:2])[S:4][C:5]4=3)[N:14]=[CH:15][N:16]=2)=[CH:23][C:22]=1[N+:19]([O-:21])=[O:20]
Reactant: COc1ccc(N)cc1[N+](=O)[O-]
Reactant: CN(C)/C=N/c1ccc2nc(C#N)sc2c1C#N
Agent: [Br-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: COc1ccc(Nc2ncnc3ccc4nc(C#N)sc4c23)cc1[N+](=O)[O-]
Yield: 61 %

Procedure:
Prepared from VII and 3-nitro-4-methoxyaniline. Flash chromatography eluent (DCM-EtOAc, 7:3). Yield: 61%; yellow solid; mp 200-260° C.; IR (KBr) νmax/cm−1 2226, 1644, 1523, 1459, 1346, 1267, 1191, 1155, 1075, 1015, 970, 928, 890, 822; 1H NMR (300 MHz, DMSO-d6) δ 8.47 (d, 1H, J=9.0 Hz), 8.26 (s, 1H), 7.97 (d, 1H, J=9.0 Hz), 7.70 (s, 2H), 7.32 (d, 1H, J=9.0 Hz), 3.93 (s, 3H); HRMS calcd for C17H11N6O3S (M+H+): 379.0613, found 379.0614.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][O:9][C:10]2[CH:15]=[CH:14][C:13]([NH2:16])=[CH:12][CH:11]=2)[CH2:3]1.[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28]O)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1>>[F:17][C:18]1[CH:26]=[C:25]2[C:21]([C:22](=[CH:28][NH:16][C:13]3[CH:12]=[CH:11][C:10]([O:9][CH2:8][CH:4]4[CH2:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]4)=[CH:15][CH:14]=3)[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1
Reactant: CN1CCCC(COc2ccc(N)cc2)C1
Reactant: O=C1Nc2cc(F)ccc2C1=CO
Product: CN1CCCC(COc2ccc(NC=C3C(=O)Nc4cc(F)ccc43)cc2)C1
Yield: 54.8 %

Procedure:
In a manner similar to that described in Example 231, 4-(1-methyl-piperidin-3-ylmethoxy)-phenylamine (590 mg, 1.2 equiv.) and 6-fluoro-3-hydroxymethylene-1,3-dihydro-indol-2-one (400 mg, 2.23 mmol, 1 equiv.) are reacted to give the named compound as a yellow solid (466 mg, 55%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)=[CH:15][C:10]=1[C:11](OC)=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl-].[Ca+2].[Cl-].[BH4-].[Na+]>>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([CH:19]([OH:32])[CH2:20][NH:21][C:22]([CH3:31])([CH3:30])[CH2:23][CH2:24][N:25]2[CH:29]=[N:28][CH:27]=[N:26]2)=[CH:15][C:10]=1[CH2:11][OH:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COC(=O)c1cc(C(O)CNC(C)(C)CCn2cncn2)ccc1OCc1ccccc1
Agent: [BH4-]
Agent: [Ca+2]
Agent: [Cl-]
Product: CC(C)(CCn1cncn1)NCC(O)c1ccc(OCc2ccccc2)c(CO)c1

Procedure:
7.6 g of methyl 2-benzyloxy-5-[2-[1,1-dimethyl-3-[1,2,4]triazol-1-yl-propylamino]-1-hydroxy-ethyl]-benzoate are reduced in an ethanolic calcium chloride solution with sodium borohydride as described for Example 1c. The product is obtained as a colourless oil after purification by column chromatography (CHCl3/MeOH/NH3=90/10/0.5). Yield: 6 g (84%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([C:13]([CH3:16])([CH3:15])[CH3:14])=[N:10][C:9]=2[C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[CH:5]=[CH:4][N:3]=1.[Cl-].[CH3:37][Zn+]>C1COCC1>[CH3:14][C:13]([C:11]1[S:12][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([CH3:37])[N:7]=2)=[C:9]([C:17]2[C:18]([F:35])=[C:19]([NH:23][S:24]([C:27]3[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=3[F:34])(=[O:26])=[O:25])[CH:20]=[CH:21][CH:22]=2)[N:10]=1)([CH3:16])[CH3:15]
Reactant: CC(C)(C)c1nc(-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)c(-c2ccnc(Cl)n2)s1
Reactant: C[Zn+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1nccc(-c2sc(C(C)(C)C)nc2-c2cccc(NS(=O)(=O)c3cc(F)ccc3F)c2F)n1
Temperature: 60 °C
Reaction time: 16 h
Yield: 46.8 %

Procedure:
To a suspension of N-{3-[5-(2-chloro-4-pyrimidinyl)-2-(1,1-dimethylethyl)-1,3-thiazol-4-yl]-2-fluorophenyl}-2,5-difluorobenzenesulfonamide (200 mg, 0.371 mmol) and tetrakis(triphenylphoshine)palladium (8.6 mg, 7.4 μmol) in THF (5 mL) was added a 2 M solution of methylzinc chloride in THF (0.371 mL, 0.742 mmol). The suspension was stirred for 16 h at 60° C. The reaction mixture was partitioned between water and EtOAc, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over anhydrous Na2SO4, filtered, concentrated, and purified via column chromatography, eluting with 0-100% EtOAc/DCM. The desired fractions were combined and concentrated to generate 90 mg (0.174 mmol, 46.8% yield) of the title compound as a white powder. 1H NMR (400 MHz, DMSO-d6): δ 10.75 (s, 1H), 8.47 (d, J=5.3 Hz, 1H), 7.52-7.58 (m, 1H), 7.40-7.50 (m, 4H), 7.29 (t, J=7.8 Hz, 1H), 6.64 (d, J=5.3 Hz, 1H), 2.58 (s, 3H), 1.42 (s, 9H). MS (ESI): 520.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:9]2[CH:13]=[C:12]([CH:14]=[O:15])[C:11]([CH:16]([CH3:18])[CH3:17])=[N:10]2)[CH:6]=[CH:7][CH:8]=1.[CH:19]1([Mg]Br)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1>O1CCCC1>[CH:19]1([CH:14]([C:12]2[C:11]([CH:16]([CH3:18])[CH3:17])=[N:10][N:9]([C:5]3[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:13]=2)[OH:15])[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1
Reactant: COc1cccc(-n2cc(C=O)c(C(C)C)n2)c1
Reactant: Br[Mg]C1CCCCC1
Solvent: C1CCOC1
Product: COc1cccc(-n2cc(C(O)C3CCCCC3)c(C(C)C)n2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 75 %

Procedure:
To a solution (20 mL) of 1-(3-methoxyphenyl)-3-(propan-2-yl)-1H-pyrazole-4-carbaldehyde (2.6 g) synthesized in the above-mentioned (2) in tetrahydrofuran was added dropwise cyclohexylmagnesium bromide (15.0 mL, 1M tetrahydrofuran solution) under ice-cooling. After the completion of the dropwise addition, the ice bath was removed, and the mixture was stirred at room temperature for 15 min. To the reaction mixture was added aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The extract was concentrated under reduced pressure to give a crude product (2.6 g, 75%) of the title object compound as a pale-yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[C@H:16]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH:17]C(OC(C)(C)C)=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:31]>O1CCOCC1.C(OCC)C>[ClH:31].[CH2:1]([O:8][C:9](=[O:30])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:29])[C@H:16]([C@H:25]([CH2:27][CH3:28])[CH3:26])[NH2:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCOCC
Product: CC[C@H](C)[C@H](N)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
N-t-butyloxycarbonyl-L-isoleucyl-L-proline benzylester (39.76 g, 95 mmole) was dissolved in 4N hydrochloric acid in dioxane (360 ml), and stirred for 30 minutes at room temperature. The solvent was distilled and the residue thus obtained was powdered in diethyl ether to obtain L-isoleucyl-L-proline benzylester hydrochloride(yield: 31.31 g, 92.9%).
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][CH:13]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:14][N:15]1C(=O)C2C(=CC=CC=2)C1=O.O.NN>C(O)C>[NH2:3][CH2:12][CH:13]([O:26][CH2:27][CH2:28][NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:33])[CH3:35])[CH2:14][NH2:15]
Reactant: CC(C)(C)OC(=O)NCCOC(CN1C(=O)c2ccccc2C1=O)CN1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)NCCOC(CN)CN
Temperature: 42.5 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
A 20 L 4-neck round-bottom flask was flushed with N2. Then charged a solution of tert-butyl 2-(1,3-bis(1,3-dioxoisoindolin-2-yl)propan-2-yloxy)ethylcarbamate (919 g, 1.9 mol, 1.0 eq) in ethanol (12000 mL, 13.0 v), followed by dropwise addition of hydrazine hydrate (602 g, 12.0 mol, 6.3 eq) with stirring at 40-45° C. over 30 min. The resulting mixture was stirred for 7 hours at 40-45° C. in an oil bath. The reaction progress was monitored with LCMS. The reaction mixture was cooled to 20˜30° C. and filtered. The filtrate was concentrated under vacuum to give 424.0 g (97.5%) of tert-butyl 2-(1,3-diaminopropan-2-yloxy)ethylcarbamate as a brown oil.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.[C:23]([CH2:25][C:26]([O:28][CH2:29][CH3:30])=[O:27])#[N:24].[H-].[Na+].Cl>O.O1CCOCC1>[C:23]([CH:25]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[C:11]1[C:12]([F:14])=[C:13]2[C:8]([C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5][N:4]2[CH:1]2[CH2:2][CH2:3]2)=[CH:9][C:10]=1[F:16])#[N:24]
Reactant: CCOC(=O)CC#N
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(C(C#N)C(=O)OCC)c(F)cc2c1=O

Procedure:
86.2 g of ethyl 1-cyclopropyl-6,7,8-trifluoro-1,4-dihydro-4-oxo-3-quinoline-carboxylate and 63.3 g of ethyl cyanoacetate are initially introduced into 1,000 ml of dioxane. 15.8 g of NaH are added in portions. The mixture is then heated to reflux for 4 hours. The completeness of the reaction is checked using thin-layer chromatography. After completion of the reaction, water is added dropwise. The mixture is then rendered acidic using dilute HCl and extracted using methylene chloride. The organic phase is dried and evaporated. The residue is recrystallized from isopropanol.
Reaction SMILES: Cl.Cl.[C:3]([O:6][CH:7]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[S:9][CH:8]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)(=[O:5])[CH3:4]>>[CH3:4][C:3]([O:6][C@H:7]1[C:13](=[O:14])[N:12]([CH2:15][CH2:16][N:17]([CH3:19])[CH3:18])[C:11]2[CH:20]=[CH:21][CH:22]=[CH:23][C:10]=2[S:9][C@H:8]1[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1)=[O:5]
Reactant: COc1ccc(C2Sc3ccccc3N(CCN(C)C)C(=O)C2OC(C)=O)cc1
Agent: Cl
Product: COc1ccc([C@@H]2Sc3ccccc3N(CCN(C)C)C(=O)[C@@H]2OC(C)=O)cc1

Procedure:
HCl: 3-acetoxy-5-(2-dimethylaminoethyl)-2,3-dihydro-2-(4-methoxyphenyl)-1,5-benzothiazepin-4(5H)-one hydrochloride
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].I[CH2:8][C:9]([NH2:11])=[O:10].[N+:12]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[OH:21])([O-:14])=[O:13]>CC(C)=O>[C:9]([CH2:8][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[N+:12]([O-:14])=[O:13])(=[O:10])[NH2:11]
Reactant: NC(=O)CI
Reactant: O=[N+]([O-])c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: NC(=O)COc1ccccc1[N+](=O)[O-]

Procedure:
8.0 g of potassium carbonate and 11.4 g of iodoacetamide are added to a solution of 4.0 g of 2-nitrophenol in 50 ml acetone. The reaction mixture is heated under reflux for 7 h and then concentrated. The residue is dissolved in chloroform and extracted with 0.05N of sodium hydroxide solution. Recyrstallization of the crude product from tetrahydrofuran gives 2-(carbamoylmethoxy)nitrobenzene of mp 190°-1° C.; Rf (O)=0.55.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2)(C)(C)C.[ClH:37]>C(OCC)(=O)C>[ClH:37].[NH2:7][CH2:8][C:9]1[N:10]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:11](=[O:31])[C:12]2[C:17]([C:18]=1[C:19]1[CH:20]=[CH:21][C:22]([F:25])=[CH:23][CH:24]=1)=[CH:16][C:15]([O:26][CH2:27][C:28]([NH2:30])=[O:29])=[CH:14][CH:13]=2
Reactant: CC(C)Cn1c(CNC(=O)OC(C)(C)C)c(-c2ccc(F)cc2)c2cc(OCC(N)=O)ccc2c1=O
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(CN)c(-c2ccc(F)cc2)c2cc(OCC(N)=O)ccc2c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.1 %

Procedure:
To a solution of tert-butyl[6-(2-amino-2-oxoethoxy)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-3-isoquinolinyl]methylcarbamate (0.20 g, 0.4 mmol) in ethyl acetate (5 mL) was added a solution of 4N hydrogen chloride in ethyl acetate (5 mL) and the obtained solution was stirred at room temperature for 2 h. The reaction mixture was concentrated under reduced pressure, and the residue was crystallized from ethyl acetate-diisopropyl, ether to give 2-[[3-(aminomethyl)-4-(4-fluorophenyl)-2-isobutyl-1-oxo-1,2-dihydro-6-isoquinolinyl]oxy]acetamide hydrochloride (0.16 g, 94.1%) as crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13](Cl)=[N:12][CH:11]=1.[CH2:18]([NH2:21])[CH2:19][NH2:20]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][C:9](=[O:17])[C:10]1[CH:15]=[CH:14][C:13]([NH:20][CH2:19][CH2:18][NH2:21])=[N:12][CH:11]=1
Reactant: Nc1ccccc1NC(=O)c1ccc(Cl)nc1
Reactant: NCCN
Product: NCCNc1ccc(C(=O)Nc2ccccc2N)cn1
Yield: 55 %

Procedure:
N-(2-Aminophenyl)-6-chloronicotinamide (248 mg, 1 mmol) and 5 ml of ethylenediamine were heated to 80° C. for 3 hours. The excess ethylenediamine was removed under vacuum. To the residue was added 5 ml of 0.20 M NaOH. The mixture was extracted with 100 ml of ethyl acetate. The ethyl acetate was removed under vacuum to give the title compound (150 mg, 55% yield) as a brown solid. LC-MS (m/z) 272 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:18]([CH3:20])=[CH:17][C:16](=[O:21])[NH:15][C:14]=3[N:13]([CH3:22])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.CCN(C(C)C)C(C)C.Br[CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35].O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:19]3[C:14](=[N:15][C:16]([O:21][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[CH:17][C:18]=3[CH3:20])[N:13]([CH3:22])[N:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1
Reactant: COc1cc(OC)cc(-c2nn(C)c3[nH]c(=O)cc(C)c23)c1
Reactant: CCOC(=O)CBr
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)COc1cc(C)c2c(-c3cc(OC)cc(OC)c3)nn(C)c2n1
Temperature: 90 °C
Reaction time: 1 h
Yield: 70.7 %

Procedure:
To a stirred solution of 3-(3,5-dimethoxyphenyl)-1,4-dimethyl-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.0 g, 3.34 mmol) in DMF (5 ml) were added DIPEA (1.17 ml, 6.68 mmol) and ethyl 2-bromoacetate (0.56 ml, 5.01 mmol). After stirring at 90° C. for 1 h the mixture was cooled to rt, water was added and extracted three times with CH2Cl2. The organic phases were dried over Na2SO4, filtered and concentrated under reduced pressure. The resulting crude product was purified by column chromatography (eluent 50% hexane in EtOAc) to yield 910 mg (71%) of the title compound. [1H-NMR (DMSO-d6, 600 MHz): δ 6.71 (d, 2H), 6.61 (s, 1H), 6.57 (br s, 1H), 4.98 (s, 2H), 4.18 (q, 2H), 3.91 (s, 3H), 3.78 (s, 6H), 2.37 (s, 3H), 1.21 (t, 3H); UPLC-MS RtJ=1.21 min; [M+H]+=386.1]
Reaction SMILES: Br[C:2]1[C:10]2[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]3[CH:23]=[CH:22][C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[N:15]=3)[N:7]=[CH:6][C:5]=2[S:4][CH:3]=1.[N:24]1[CH:29]=[CH:28][C:27](B(O)O)=[CH:26][CH:25]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)OCC.CCCCCCC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:24]1[CH:29]=[CH:28][C:27]([C:2]2[C:10]3[C:9](=[O:11])[N:8]([CH2:12][CH2:13][C:14]4[CH:23]=[CH:22][C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]=4)[N:7]=[CH:6][C:5]=3[S:4][CH:3]=2)=[CH:26][CH:25]=1
Reactant: O=c1c2c(Br)csc2cnn1CCc1ccc2ccccc2n1
Reactant: OB(O)c1ccncc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: O=c1c2c(-c3ccncc3)csc2cnn1CCc1ccc2ccccc2n1
Temperature: 120 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
3-Bromo-5-[2-(quinolin-2-yl)ethyl]thieno[2,3-d]pyridazin-4(5H)-one (130 mg, 0.33 mmol), pyridine-4-ylboronic acid (45.7 mg, 0.37 mmol), Pd(dppf)Cl2 (15 mg) and K2CO3 (93 mg, 0.67 mmol) were dissolved in dioxane/H2O (3/1, 2.8 mL). The mixture was stirred in nitrogen atmosphere at 120° C. for 1 h in a microwave tube. The solution was concentrated and purified by TLC (DCM/MeOH=10/1) and recrystallized from MeOH to give the title product (90 mg, 69.4%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH:23]4[CH2:25][CH2:24]4)=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[C:4]([N:26]2[CH2:30][CH2:29][CH2:28][S:27]2(=[O:32])=[O:31])[CH:3]=1.C([N:36]1[CH2:40][CH2:39][NH:38][C:37]1=[O:41])(=O)C>>[CH:23]1([C:19]2[CH:20]=[C:21]([CH3:22])[C:16]([N:13]3[CH2:14][CH2:15][N:10]([C:8]([C:5]4[CH:6]=[CH:7][C:2]([N:36]5[CH2:40][CH2:39][NH:38][C:37]5=[O:41])=[CH:3][C:4]=4[N:26]4[CH2:30][CH2:29][CH2:28][S:27]4(=[O:32])=[O:31])=[O:9])[CH2:11][CH2:12]3)=[N:17][CH:18]=2)[CH2:25][CH2:24]1
Reactant: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(Br)cc2N2CCCS2(=O)=O)CC1
Reactant: CC(=O)N1CCNC1=O
Product: Cc1cc(C2CC2)cnc1N1CCN(C(=O)c2ccc(N3CCNC3=O)cc2N2CCCS2(=O)=O)CC1
Yield: 60.8 %

Procedure:
Using [4-bromo-2-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenyl][4-(5-cyclopropyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (223 mg) described in Preparation Example 240 and 1-acetylimidazolidin-2-one (83 mg) and by the reaction and treatment in the same manner as in Example 638, the title compound (137 mg) was obtained.