Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([OH:37])=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1.C(P(CCCC)CCCC)CCC.O[CH2:55][CH2:56][N:57]1[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]1>C(Cl)Cl.CCOCC>[Cl:19][C:20]1[CH:39]=[CH:38][C:23]([NH:24][C:25]2[C:34]3[C:29](=[CH:30][C:31]([O:37][CH2:55][CH2:56][N:57]4[CH2:62][CH2:61][S:60](=[O:64])(=[O:63])[CH2:59][CH2:58]4)=[C:32]([O:35][CH3:36])[CH:33]=3)[N:28]=[CH:27][N:26]=2)=[C:22]([F:40])[CH:21]=1
Reactant: O=S1(=O)CCN(CCO)CC1
Reactant: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1O
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: ClCCl
Solvent: CCOCC
Product: COc1cc2c(Nc3ccc(Cl)cc3F)ncnc2cc1OCCN1CCS(=O)(=O)CC1
Reaction time: 18 h
Yield: 3.6 %

Procedure:
1,1′-(Azodicarbonyl)dipiperidine (525 mg, 2.1 mmol) was added in portions to a mixture of 4-(4-chloro-2-fluoroanilino)-7-hydroxy-6-methoxyquinazoline (225 mg, 7.0 mmol), (prepared as described for the starting material in Example 2), tributylphosphine (420 mg, 2.1 mmol) and 4-(2-hydroxyethyl)-1,1-dioxothiomorpholine (140 mg, 7.8 mmol) in methylene chloride (10 ml). The mixture was stirred for 18 hours, diluted with ether and the resulting precipitate, was removed by filtration. The volatiles were removed from the filtrate by evaporation, and the residue was dissolved in acetone and ethereal hydrogen chloride (14 ml of a 1M solution, 14 mmol) and the precipitate was collected by filtration. The residue was purified by column chromatography eluting with methylene chloride/methanol/aqueous ammonia (150/8/1). The purified product was triturated with ether/methylene chloride collected by filtration and dried to give 4-(4-chloro-2-fluoroanilino)-7-(2-(1,1-dioxothiomorpholino)ethoxy)-6-methoxyquinazoline (120 mg, 36%).
Reaction SMILES: [O:1]=[C:2]1[CH2:9][CH:8]2[CH:4]([CH2:5][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:7]2)[CH2:3]1.FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C[Si](C)([O:30][CH2:31][CH2:32]O[Si](C)(C)C)C>C(Cl)Cl>[CH2:3]1[CH:4]2[CH:8]([CH2:7][CH:6]([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:5]2)[CH2:9][C:2]21[O:30][CH2:31][CH2:32][O:1]2
Reactant: CCOC(=O)C1CC2CC(=O)CC2C1
Reactant: C[Si](C)(C)OCCO[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: CCOC(=O)C1CC2CC3(CC2C1)OCCO3
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of ethyl 5-oxooctahydropentalene-2-carboxylate (210 mg) in DCM (5 mL) cooled to −78° C. were added slowly trimethylsilyl trifluoromethanesulfonate (11.89 mg, 0.054 mmol) and 2,2,7,7-tetramethyl-3,6-dioxa-2,7-disilaoctane (287 mg, 1.391 mmol) under nitrogen. After stirring at −78° C. for 30 min, the reaction mixture was warmed to rt and stirred at rt for 16 h. The reaction was quenched with anhydrous pyridine at −78° C. followed by sat. NaHCO3, and then extracted with EtOAc. The combined organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified by flash chromatography to afford ethyl hexahydro-1′H-spiro[[1,3]dioxolane-2,2′-pentalene]-5′-carboxylate (a mixture of endo/exo isomers) as a clear oil.
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15]CC)=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].C(O)C.[OH-].[Na+]>C1COCC1>[CH3:3][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=3)[CH:11]=[C:12]([C:13]([OH:15])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:1]
Reactant: CCOC(=O)c1cc(-c2ccc(OC)cc2)nc2c1cnn2C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(-c2cc(C(=O)O)c3cnn(C(C)C)c3n2)cc1

Procedure:
The title compound was prepared in the same manner as described for intermediate 58 using ethyl 1-(1-methylethyl)-6-[4-(methyloxy)phenyl]-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (200 mg, 0.589 mmol), Ethanol (4 mL) and THF (1 mL), and sodium hydroxide (0.982 mL, 2.95 mmol). The final product was collected as 181 mg (98%). LCMS E-S (M+H)=312.3. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.51-1.63 (m, 6H), 3.85 (s, 3H), 5.35 (m, 1H), 7.11 (d, J=9.1 Hz, 2H), 8.15 (s, 1H), 8.18-8.25 (m, 2H), 8.33 (s, 1H), 13.95 (br. s., 1H).
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][S:9]([CH2:12][CH2:13][OH:14])(=[O:11])=[O:10])=[N+:2]=[N-:3].N1C=CC=CC=1.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C(Cl)Cl>[C:22](=[O:23])([O:24][C:25]1[CH:26]=[CH:27][C:28]([N+:31]([O-:33])=[O:32])=[CH:29][CH:30]=1)[O:14][CH2:13][CH2:12][S:9]([CH2:8][CH2:7][O:6][CH2:5][CH2:4][N:1]=[N+:2]=[N-:3])(=[O:11])=[O:10]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: [N-]=[N+]=NCCOCCS(=O)(=O)CCO
Solvent: ClCCl
Solvent: c1ccncc1
Product: [N-]=[N+]=NCCOCCS(=O)(=O)CCOC(=O)Oc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 90.6 %

Procedure:
A solution of alcohol 5 (4.0 g, 17.9 mmol) and pyridine (10 ml, 6.9 equiv.) in CH2Cl2 (100 ml) was cooled in an ice bath and p-nitrophenyl chloroformate (5.42 g, 1.5 equiv.) was added. The resulting solution was stirred at RT for 16 h then washed with a 1 M HCl aqueous solution (3×50 ml), dried over MgSO4, filtrated then concentrated under reduced pressure. Purification by flash column chromatography (eluent: pet. ether/AcOEt 7:3 then 1:1) afforded carbonate 6 as a white amorphous solid (6.3 g, 91%).
Reaction SMILES: [O:1]1[CH:3]2[CH2:4][CH2:5][CH:6]=[CH:7][CH2:8][CH2:9][CH:10]=[CH:11][CH2:12][CH2:13][CH:2]12.[I-].[Li+]>>[C:2]1(=[O:1])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: C1=CCCC2OC2CCC=CCC1
Agent: [I-]
Agent: [Li+]
Product: O=C1CCCCCCCCCCC1

Procedure:
Cyclododecanone was prepared by the same reaction procedures and reactor as in Example 4, except that the fed liquid reaction mixture comprised 98.8% by weight of 1,2-epoxy-5,9-cyclododecadiene, 0.70% by weight of lithium iodide (corresponding to 0.95 molar % based on the molar amount of 1,2-epoxy-5,9-cyclododecadiene) and the balance consisting of impurities.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=O)=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:8]=[C:9]([C:12]([CH3:15])([CH3:14])[CH3:13])[C:10]=1[OH:11])([CH3:4])([CH3:3])[CH3:2].[S:37]1[CH2:41][C:40](=[O:42])[NH:39][C:38]1=[O:43].N1CCCCC1>C(O)C>[C:12]([C:9]1[CH:8]=[C:7]([S:16][C:17]2[CH:18]=[CH:19][C:20]3[N:24]=[C:23]([CH2:25][O:26][C:27]4[CH:34]=[CH:33][C:30]([CH:31]=[C:41]5[S:37][C:38](=[O:43])[NH:39][C:40]5=[O:42])=[CH:29][CH:28]=4)[N:22]([CH3:35])[C:21]=3[CH:36]=2)[CH:6]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[C:10]=1[OH:11])([CH3:15])([CH3:13])[CH3:14]
Reactant: O=C1CSC(=O)N1
Reactant: Cn1c(COc2ccc(C=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Solvent: C1CCNCC1
Solvent: CCO
Product: Cn1c(COc2ccc(C=C3SC(=O)NC3=O)cc2)nc2ccc(Sc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)cc21
Yield: 86 %

Procedure:
A mixture of 4-[6-(3,5-di-t-butyl-4-hydroxyphenylthio)-1-methyl-1H-benzimidazole-2-ylmethoxy]benzaldehyde (502 mg), thiazolidine-2,4-dione (234 mg), piperidine (170 mg ) and ethanol (60 ml) was heated at reflux for 19 hours. The reaction mixture was evaporated to dryness and to the residue was added water and insoluble product was isolated by filtration and washed with water and diisopropyl ether to give the title compound (517 mg).
Reaction SMILES: CNC=O.N([C:8]1[CH:9]=[C:10]([CH:14]=[CH:15][CH:16]=1)[C:11]([OH:13])=[O:12])=C=S.IC>CO>[C:11]([OH:13])(=[O:12])[C:10]1[CH:14]=[CH:15][CH:16]=[CH:8][CH:9]=1
Reactant: O=C(O)c1cccc(N=C=S)c1
Solvent: CO
Solvent: CI
Solvent: CNC=O
Product: O=C(O)c1ccccc1
Temperature: 60 °C
Reaction time: 3 h

Procedure:
To 4-[3-amino-4-(methylamino)phenoxy](2-pyridyl)}-N-methylcarboxamide (1 eq) in methanol was added 3-isothiocyanatobenzoic acid (1 eq) and stirred at 60° C. for 3 h. To it was then added iodomethane (1 eq) and heated to 60° C. for 3 h and concentrated the solvent and purified on silica gel to yield 3-({1-methyl-5-[2-(N-methylcarbamoyl)(4-pyridyloxy))]benzimidazol-2-yl}amino)benzoic acid. MS: MH+=417.
Reaction SMILES: C[O:2]CCN.[CH3:6][O:7][CH2:8][CH2:9][NH:10][C:11]([C@H:13]1[NH:32][C:31](=[O:33])[C:30]2=[CH:34][C:26](=[C:27]([CH3:36])[CH:28]=[C:29]2[CH3:35])[C:25]2=[CH:37][C:21](=[N:22][C:23]([NH2:38])=[N:24]2)[S:20][CH2:19][CH2:18][C:17](=[O:39])[NH:16][CH2:15][CH2:14]1)=[O:12]>>[CH3:6][O:7][CH2:8][CH2:9][NH:10][C:11]([C@H:13]1[NH:32][C:31](=[O:33])[C:30]2=[CH:34][C:26](=[C:27]([CH3:36])[CH:28]=[C:29]2[CH3:35])[C:25]2=[CH:37][C:21](=[N:22][C:23]([NH2:38])=[N:24]2)[S:20][CH2:19][CH2:18][C:17](=[O:39])[NH:16][CH2:15][CH2:14]1)=[O:12].[NH2:38][C:23]1[N:22]=[C:21]2[CH:37]=[C:25]([C:26]3[CH:34]=[C:30]([C:31](=[O:33])[NH:32][C@H:13]([C:11]([OH:12])=[O:2])[CH2:14][CH2:15][NH:16][C:17](=[O:39])[CH2:18][CH2:19][S:20]2)[C:29]([CH3:35])=[CH:28][C:27]=3[CH3:36])[N:24]=1
Reactant: COCCN
Agent: COCCNC(=O)[C@@H]1CCNC(=O)CCSc2cc(nc(N)n2)-c2cc(c(C)cc2C)C(=O)N1
Product: Cc1cc(C)c2cc1C(=O)N[C@H](C(=O)O)CCNC(=O)CCSc1cc-2nc(N)n1

Procedure:
According to the method of Example 2-14 except that 2-methoxyethylamine (15 μl, 0.175 mmol) was used instead of methylamine, (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (2-methoxyethyl)amide (Compound 66) (16 mg) was obtained as a white solid material from (S)-4-amino-18,20-dimethyl-10,16-dioxo-7-thia-3,5,11,15-tetraazatricyclo[15.3.1.12,6]docosa-1(20),2(22),3,5,17(21),18-hexaene-14-carboxylic acid (25 mg, 0.058 mmol) obtained in Example 2-13.
Reaction SMILES: C(P(C[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][CH3:16])[CH:9]=1)(=O)[O-])C.[CH2:17]([O:19][P:20]([O:24]CC)[O:21][CH2:22][CH3:23])[CH3:18]>>[CH2:17]([O:19][P:20]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[C:10]([O:15][CH3:16])[CH:9]=1)(=[O:24])[O:21][CH2:22][CH3:23])[CH3:18]
Reactant: CCP(=O)([O-])CCc1ccc(N)c(OC)c1
Reactant: CCOP(OCC)OCC
Product: CCOP(=O)(Cc1ccc(N)c(OC)c1)OCC

Procedure:
This material was prepared according to the procedure described above for ethyl(4-amino-3-methoxybenzyl)methylphosphinate using triethylphosphite in the first step. MS (ES+): m/z 274.01 [MH+] (ZQ3, polar 5 min).
Reaction SMILES: [CH2:1]([N:4]([CH2:19][CH2:20][CH3:21])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH2:18])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:2][CH3:3].[O-:22][C:23]#[N:24].[K+]>O.Cl>[CH2:19]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:14][CH2:13][C:12]2[C:7](=[C:8]([O:15][CH2:16][CH2:17][NH:18][C:23]([NH2:24])=[O:22])[CH:9]=[CH:10][CH:11]=2)[CH2:6]1)[CH2:20][CH3:21]
Reactant: CCCN(CCC)C1CCc2cccc(OCCN)c2C1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: O
Product: CCCN(CCC)C1CCc2cccc(OCCNC(N)=O)c2C1
Reaction time: 3 h

Procedure:
1.45 g (5 mmol) of 2-dipropylamino-8-(2-aminoethoxy)-1,2,3,4-tetrahydronaphthalene were dissolved in 10 ml of water and 10 ml of 1 N hydrochloric acid. A solution of 4.1 g (50 mmol) of potassium cyanate and 20 ml of water was then added dropwise at a temperature of +60° C. The mixture was stirred for 3 h at +60° C., the reaction product precipitating. This was filtered off under suction, and the residue was stirred with hot petroleum ether. After cooling, the product was filtered off under suction.
Reaction SMILES: [CH3:1][Si]([N-][Si](C)(C)C)(C)C.[Li+].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[C:19]([C:21](=O)[CH3:22])[CH:20]=1)[NH:17][CH:16]=[CH:15]2>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1COCC1>[C:21]([C:19]1[CH:20]=[C:12]([NH2:11])[CH:13]=[C:14]2[C:18]=1[NH:17][CH:16]=[CH:15]2)([CH3:22])=[CH2:1]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(=O)c1cc(N)cc2cc[nH]c12
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=C(C)c1cc(N)cc2cc[nH]c12
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.9 %

Procedure:
To a solution of methyltriphenylphosponium bromide (3.8 g, 10 mmol) in 40 mL of THF was added 15 mL of a solution of lithium bis(trimethylsilyl)amide (15 mmol) and the resulting reaction mixture was stirred for 1 h at −78° C. A solution of 5-amino-7-acetylindole (0.55 g, 3.1 mmol) in 10 mL of THF was added into the solution slowly for 0.5 h period. The reaction mixture was slowly warmed to 25° C. and stirred for 12 h at the temperature. Column chromatographic separation of reaction mixture (50% EtOAc/n-Hexane) provided 0.45 g (2.6 mmol, 82%) of the desired product.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:4][CH2:3]1.Cl[C:20]1[CH:33]=[CH:32][C:23]([C:24]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:25])=[CH:22][C:21]=1[N+:34]([O-:36])=[O:35]>>[N+:34]([C:21]1[CH:22]=[C:23]([C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:25])[CH:32]=[CH:33][C:20]=1[N:2]1[CH2:3][CH2:4][CH:5]([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[CH2:11][O:10][C:9]2=[O:18])[CH2:6][CH2:7]1)([O-:36])=[O:35]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: O=C1OCc2ccccc2N1C1CCNCC1
Agent: Cl
Product: O=C(c1ccccc1)c1ccc(N2CCC(N3C(=O)OCc4ccccc43)CC2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 1-piperidin-4-yl-1,4-dihydro-2H-3,1-benzoxazin-2-one hydrochloride (0.3 g) and 4-chloro-3-nitrobenzophenone (0.29 g) using the method of example 1. Yield 0.25 g as a solid.
Reaction SMILES: CN(C=O)C.[C:6]([NH:23][CH2:24][C:25](O)=[O:26])([O:8][CH2:9][CH:10]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][CH:15]=2)=[O:7].C(N=C=NC(C)C)(C)C>C(Cl)Cl.CN(C)C1C=CN=CC=1>[CH:13]1[CH:12]=[C:11]2[CH:10]([CH2:9][O:8][C:6]([NH:23][CH2:24][CH:25]=[O:26])=[O:7])[C:22]3[C:17]([C:16]2=[CH:15][CH:14]=1)=[CH:18][CH:19]=[CH:20][CH:21]=3
Reactant: O=C(O)CNC(=O)OCC1c2ccccc2-c2ccccc21
Agent: CC(C)N=C=NC(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=CCNC(=O)OCC1c2ccccc2-c2ccccc21
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
Wang resin (70 g, 119 mmol, PL-Wang, Polymer Labs, 1.7 mmol/g.) was swollen in 550 mL of methylene chloride and 100 mL of DMF and stirred for 30 min with an overhead stirrer. 71 g (238 mmol) of FMOC-glycine were added, followed by 60 g (476 mmol) of diisopropylcarbodiimide and 2.4 g (19.7 mmol) of 4-dimethylaminopyridine. The reaction was stirred for 3.5 h at room temperature, the resin was filtered, washed with alternating methanol and methylene chloride and dried in a vacuum oven.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[NH2:14][NH2:15]>N1C=CC=CC=1>[NH:14]([C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:6][CH:5]=[CH:4][N:3]=1)[NH2:15]
Reactant: Clc1ncccc1-c1ccccn1
Reactant: NN
Solvent: c1ccncc1
Product: NNc1ncccc1-c1ccccn1

Procedure:
A mixture of 2.5 g of 2'-chloro-2,3'-bipyridine, 12.6 ml of anhydrous hydrazine and 50 ml of pyridine was refluxed for 36 hours and concentrated under vacuum to a gum. The gum was dissolved in methylene chloride, treated with activated carbon, dried over sodium sulfate and the solvent removed. The residue was crystallized from etherhexane to give 2.1 g of 2'-hydrazino-2,3'-bipyridine as yellow crystals, mp 64°-65° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1.[NH:16](C1C=CC(C2C(C)CC(=O)NN=2)=CC=1)N>>[NH:1]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[CH:10][C:11](=[O:15])[N:12]([CH3:14])[N:13]=2)=[CH:4][CH:3]=1)[NH2:16]
Reactant: CC1CC(=O)NN=C1c1ccc(NN)cc1
Reactant: Cn1nc(-c2ccc(N)cc2)ccc1=O
Product: Cn1nc(-c2ccc(NN)cc2)ccc1=O

Procedure:
The title compound was prepared from 6-(4-aminophenyl)-2-methyl-2H-pyridazin-3-one similarly as 6-(4-hydrazinophenyl)-5-methyl-4,5-dihydro-2H-pyridazin-3-one.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([CH2:15][OH:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:10]([CH:15]=[O:16])=[N:11][CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1ncccc1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)Cl
Product: O=Cc1ncccc1OCc1ccccc1
Yield: 60.6 %

Procedure:
A solution of 3-benzyloxy-2-hydroxymethylpyridine (0.25 g, 1.16 mmol) in chloroform (15 ml) was treated with manganese dioxide (0.45 g, 6.34 mmol). The reaction mixture was heated to reflux and held at reflux for 18 hours. The reaction mixture was then filtered through Celite and evaporated to give a yellow gum. This gum was purified by chromatography (EtOAc/CH2Cl2) to give 3-benzyloxy-2-pyridinecarbaldehyde as a colourless gum (0.15 g, 62%).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].Cl.[NH2:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1.C(N(CC)CC)C>O1CCCC1>[Cl:1][CH2:2][C:3]([NH:7][CH:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[O:10][CH2:9]1)=[O:4]
Reactant: O=C(Cl)CCl
Reactant: NC1COc2ccccc2C1=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NC1COc2ccccc2C1=O
Reaction time: 1 h
Yield: 28.1 %

Procedure:
Chloroacetyl chloride (41.6 g, 368 mmol) was added to a solution of 3-amino-chroman-4-one hydrochloride (67 g, 335 mmol) and triethylamine (102 g, 1.01 mol) in tetrahydrofuran (700 ml) and the mixture was stirred for one hour. The solution was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluent; 5-10% methanol in chloroform) to afford 2-chloro-N-(4-oxo-chroman-3-yl)-acetamide (22.6 g, 94.3 mmol, 28%) as white crystals.
Reaction SMILES: I[C:2]1[CH:29]=[CH:28][C:5]2[N:6]([CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH2:17][C:18]4[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=4)=[C:12]([O:26][CH3:27])[CH:11]=3)[CH:7]=[N:8][C:4]=2[CH:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.C(=O)([O-])[O-].[Na+].[Na+].N1CCC[C@H]1C(O)=O>CS(C)=O.[Cu]I>[CH3:27][O:26][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][C:13]=1[O:16][CH2:17][C:18]1[CH:19]=[N:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1)[CH2:9][N:6]1[C:5]2[CH:28]=[CH:29][C:2]([N:34]3[CH2:35][CH2:36][N:31]([CH3:30])[CH2:32][CH2:33]3)=[CH:3][C:4]=2[N:8]=[CH:7]1
Reactant: COc1ccc(COc2ccc(Cn3cnc4cc(I)ccc43)cc2OC)cn1
Reactant: CN1CCNCC1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1ccc(COc2ccc(Cn3cnc4cc(N5CCN(C)CC5)ccc43)cc2OC)cn1
Temperature: 90 °C
Reaction time: 1 h
Yield: 19 %

Procedure:
To a stirred suspension of 5-iodo-1-(3-methoxy-4-((6-methoxypyridin-3-yl)methoxy)benzyl)-1H-benzo[d]imidazole (0.25 g, 0.50 mmol) in dimethyl sulfoxide (5 mL) was added 1-methylpiperazine (0.28 g, 1.50 mmol), copper(I) iodide (0.029 g, 0.15 mmol), sodium carbonate (0.32 g, 2.60 mmol), and L-proline (0.035 g, 0.30 mmol). The mixture was heated to 90° C. in a microwave reactor. After 1 h, the reaction mixture was allowed to cool to room temperature and was filtered through Celite. The filtrate was concentrated, and the residue purified via prep-HPLC to afford 0.045 g (19%) of the product as a white solid: 1H NMR (500 MHz, CDCl3) δ 8.20 (d, J=2.5 Hz, 1H), 7.87 (s, 1H), 7.68 (dd, J=8.5, 2.0 Hz, 1H), 7.36 (d, J=1.0 Hz, 1H), 7.18 (d, J=9.0 Hz, 1H), 7.02 (dd, J=9.0, 2.0 Hz, 1H), 6.88 (d, J=8.5 Hz, 1H), 6.77 (d, J=8.5 Hz, 1H), 6.73-6.72 (m, 2H), 5.25 (s, 2H), 5.04 (s, 2H), 3.95 (s, 3H), 3.78 (s, 3H), 3.24-3.18 (m, 4H), 2.67-2.62 (m, 4H), 2.39 (s, 3H) ppm; (M+1)=474.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][C:14]([C:15]([O:17]C)=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1.[CH3:21]I.Cl>C1COCC1.O>[F:3][C:4]1[CH:5]=[C:6]([N:10]([CH3:21])[C:11]2[CH:20]=[CH:19][C:14]([C:15]([OH:17])=[O:16])=[CH:13][CH:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CI
Reactant: COC(=O)c1ccc(Nc2cccc(F)c2)cc1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN(c1ccc(C(=O)O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
NaH 60% dispersed in mineral oil (0.024 g; 0.611 mmol) was added to a solution of methyl 4-(3-fluorophenylamino)benzoate in THF (3 mL). After stirring the resulting solution for 10 minutes methyl iodide (0.062 mL; 0.994 mmol) was added and the resulting mixture was stirred overnight at room temperature. The mixture was diluted with water, acidified with a 6N solution of hydrochloride acid and extracted with ethyl acetate. The organic layer was dried to yield 0.119 g (quantitative) of the title compound as a brown solid. The compound was used without further purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([O:16]CC2C=CC=CC=2)=[O:15])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+].O1CCCC1.Cl>C(O)C>[CH2:1]([O:8][C:9]1[CH:13]=[C:12]([C:14]([OH:16])=[O:15])[N:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[N:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OCc1ccccc1)c1cc(OCc2ccccc2)nn1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc(OCc2ccccc2)nn1-c1ccccc1
Temperature: 25 °C
Yield: 94.8 %

Procedure:
A mixture of benzyl 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylate (50.88 g), 1N aqueous sodium hydroxide solution (200 ml), tetrahydrofuran (200 ml) and ethanol (200 ml) was refluxed at room temperature for 5 hrs. 1N Hydrochloric acid (200 ml) was added and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained colorless crystals were collected by filtration to give 3-benzyloxy-1-phenyl-1H-pyrazole-5-carboxylic acid (36.91 g, yield 95%), which was then recrystallized from acetone-isopropyl ether. melting point: 163–164° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:10][CH:9]=1.[CH3:18][S:19](Cl)(=[O:21])=[O:20].Cl>O>[CH3:18][S:19]([NH:7][C:8]1[CH:9]=[CH:10][C:11]([CH2:14][C:15]([OH:17])=[O:16])=[CH:12][CH:13]=1)(=[O:21])=[O:20]
Reactant: Nc1ccc(CC(=O)O)cc1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CS(=O)(=O)Nc1ccc(CC(=O)O)cc1
Temperature: 85 °C
Yield: 58.9 %

Procedure:
In a solution containing 5.44 g (53 mmol) of sodium carbonate in 36 ml of water, 3.2 g (20 mmol) of 4-aminophenylacetic acid are dissolved, 1.7 ml (2.48 g, 22 mmol) of methanesulfonyl chloride are added in one portion and the mixture is heated at 85° C. for 4 hours. After cooling down and acidifying the reaction mixture to pH 3 with concentrated hydrochloric acid, the mixture is cooled in the refrigerator overnight, filtered, washed with water and dried to obtain 2.7 g of a crude product, which is recrystallized from 6 ml of hot water to give 2.40 g of the title substance as beige laminar crystals; yield: 53%, m.p.: 145-147° C.
Reaction SMILES: [N:1]#N.[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]=[C:11]([C:13]([O:15][CH3:16])=[O:14])[CH:12]=1)[C:7](O)=[O:8].S(Cl)(Cl)=O.N.O1CCOCC1>>[C:7]([C:6]1[CH:10]=[C:11]([CH:12]=[C:4]([Cl:3])[CH:5]=1)[C:13]([O:15][CH3:16])=[O:14])(=[O:8])[NH2:1]
Reactant: COC(=O)c1cc(Cl)cc(C(=O)O)c1
Reactant: N#N
Agent: N
Solvent: C1COCCO1
Solvent: O=S(Cl)Cl
Product: COC(=O)c1cc(Cl)cc(C(N)=O)c1

Procedure:
Steps N2 and N3. A mixture of 3-chloro-5-(methoxycarbonyl)benzoic acid (2 g, 9.3 mmol) and thionyl chloride (8 mL) was refluxed for 2 hours. After the excess thionyl chloride was removed under vacuum, the residue was treated with a 0.5M solution of ammonia in 1,4-dioxane (40 mL, 20 mmol) overnight. The solvent was removed under vacuum and methyl 3-carbamoyl-5-chlorobenzoate was obtained as a white solid.