Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[NH:10][CH2:11][CH:12]([NH:14][C:15]1[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:22])[CH3:13].ClC(C)[CH2:25][NH:26]C1C(C)=CC(C)=CC=1C.CC1C=CC=C(C)C=1N.Cl>>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[C:4]([CH3:9])[C:3]=1[N:10]1[CH2:11][CH:12]([CH3:13])[N:14]([C:15]2[C:20]([CH3:21])=[CH:19][CH:18]=[CH:17][C:16]=2[CH3:22])[C:25]1=[NH:26]
Reactant: Cc1cc(C)c(NCC(C)Cl)c(C)c1
Reactant: Cc1cc(C)c(NCC(C)Nc2c(C)cccc2C)c(C)c1
Agent: Cc1cccc(C)c1N
Agent: Cl
Product: Cc1cc(C)c(N2CC(C)N(c3c(C)cccc3C)C2=N)c(C)c1
Yield: 65.6 %

Procedure:
1-(2',4',6'-Trimethylphenyl-amino)-2-(2',6'-dimethylphenyl-amino)-propane, applied as starting substance, is obtained with a yield of 65.6% by reacting N-(β-chloropropyl)-2,4,6-trimethyl-aniline, a compound prepared according to Example 16, point (b), with 2,6-dimethylaniline under the conditions given in Example 16, point (c). The hydrochloride of the product melts at 174°-177° C.
Reaction SMILES: C([O:5][C:6]([C:8]1[O:9][C:10]2[CH:17]=[CH:16][CH:15]=[C:14]([C:18]3[CH:22]=[CH:21][O:20][CH:19]=3)[C:11]=2[C:12]=1[CH3:13])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O.ClCCl>>[O:20]1[CH:21]=[CH:22][C:18]([C:14]2[C:11]3[C:12]([CH3:13])=[C:8]([C:6]([OH:7])=[O:5])[O:9][C:10]=3[CH:17]=[CH:16][CH:15]=2)=[CH:19]1
Reactant: Cc1c(C(=O)OC(C)(C)C)oc2cccc(-c3ccoc3)c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1c(C(=O)O)oc2cccc(-c3ccoc3)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 174 mg of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid tert-butyl ester was added 4 mL of TFA/dichloromethane (1:1). The solution was stirred at room temperature for 2 h. The solvents were removed under vacuum and the residue was triturated with ether. Filtration gave 124 mg of of 4-furan-3-yl-3-methyl-benzofuran-2-carboxylic acid as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH:16]=[CH:17][CH2:18][N:19]([C:26]1[C:31](Br)=[CH:30][C:29]([CH2:33][S:34]([NH:37][CH3:38])(=[O:36])=[O:35])=[CH:28][C:27]=1[Br:39])C(=O)C(F)(F)F)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C)C=O>C(N(CC)CC)C.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[CH2:16][C:17]1[C:31]2[C:26](=[C:27]([Br:39])[CH:28]=[C:29]([CH2:33][S:34]([NH:37][CH3:38])(=[O:35])=[O:36])[CH:30]=2)[NH:19][CH:18]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNS(=O)(=O)Cc1cc(Br)c(N(CC=C[C@H]2CCCN2C(=O)OCc2ccccc2)C(=O)C(F)(F)F)c(Br)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CNS(=O)(=O)Cc1cc(Br)c2[nH]cc(C[C@H]3CCCN3C(=O)OCc3ccccc3)c2c1
Temperature: 80 °C

Procedure:
(R)-1-(N-Benzyloxycarbonylpyrrolidin-2-yl)-3-[N-(4-methylaminosulfonylmethyl-2,6-dibromophenyl)-N-trifluoroacetylamino]propene (9.00 g) in triethylamine (70 mL) containing N,N-dimethylformamide (20 mL), tetra-n-butylammonium chloride (3.61 g) and palladium acetate (1.01 g) was heated at 80° C. until conversion was complete. The cooled reaction mixture was filtered through CELITE and washed with methylene chloride. The combined filtrate and washings were then evaporated in vacuo onto silica gel (15 g) then purified by column chromatography (SiO2-1.6 kg) eluted with 4% acetone in chloroform. The product-rich fractions were combined and evaporated then re-purified by crystallisation from a mixture of diethyl ether (50 mL) and methylene chloride (10 mL). The title compound was recovered by filtration (washing with hexanes) as a colorless solid (2.40 g). TLC (methylene chloride/acetone 10:1) Rf=0.35; Anal calcd. for C23H26BrN3O4S: C, 53.1; H, 5.0; N, 8.1. Found C, 53.13; H, 5.0; N, 7.8.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([OH:17])=O)=[CH:4][CH:3]=1.[CH2:19]([NH2:27])[CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:18])[C:15]([NH:27][CH2:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:17])=[CH:6][CH:7]=1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)O
Reactant: NCCc1ccccc1
Product: Cc1noc(-c2ccc(Br)cc2)c1C(O)C(=O)NCCc1ccccc1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-hydroxy-acetic acid and phenethylamine.
Reaction SMILES: Cl[S:2]([C:5]1[CH:13]=[CH:12][CH:11]=[CH:10][C:6]=1[C:7](Cl)=[O:8])(=[O:4])=[O:3].O.[NH3:15]>CO>[CH:11]1[CH:10]=[C:6]2[C:7]([NH:15][S:2](=[O:4])(=[O:3])[C:5]2=[CH:13][CH:12]=1)=[O:8]
Reactant: O=C(Cl)c1ccccc1S(=O)(=O)Cl
Reactant: N
Solvent: O
Solvent: CO
Product: O=C1NS(=O)(=O)c2ccccc21
Yield: 93 %

Procedure:
A 20 g amount of the mixture of o-chlorosulfonylbenzoylchloride and dichlorotolylsultone was added dropwise to 40 ml of methanol with stirring at 15°-20° C. and the mixture was stirred and reacted for 1 hour. After the reaction, the reaction mixture was added dropwise to 35 g of 8% ammonia water with stirring at 20°-25° C., and the reaction mixture was kept for one night. Then, methanol was removed by distillation from the reaction mixture under a reduced pressure, and hydrochloric acid was added to the residual product to adjust pH to 1-2. The precipitated crystals were filtered and washed with water and dried, to obtain 14.3 g of white crystals of o-sulfobenzimide having a melting point of 227°-228° C. (yield of 93%).
Reaction SMILES: [OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[NH:4][N:3]=1.Cl[C:16]([O:18][CH2:19][CH3:20])=[O:17].O>N1C=CC=CC=1>[OH:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[CH:9]=2)[N:4]([C:16]([O:18][CH2:19][CH3:20])=[O:17])[N:3]=1
Reactant: COC(=O)c1ccc2[nH]nc(O)c2c1
Reactant: CCOC(=O)Cl
Solvent: O
Solvent: c1ccncc1
Product: CCOC(=O)n1nc(O)c2cc(C(=O)OC)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 79.5 %

Procedure:
Methyl 3-hydroxy-1H-indazole-5-carboxylate (1.60 g, 8.33 mmol) was suspended in pyridine (10 mL). Ethyl chloroformate (0.90 mL, 9.3 mmol) was added slowly and the reaction was stirred at room temperature for 1 hour. Additional ethyl chloroformate (0.30 mL, 3.1 mmol) was added and the reaction was stirred for another 30 minutes. The reaction was poured into water (65 mL) and cooled in a refrigerator for 3 hours. The brown solid was collected by filtration, rinsed with water, and dried under vacuum to give the title compound (1.75 g, 80%). +ESI (M+H) 265.1; 1H NMR (400 MHz, CDCl3, δ): 8.56 (s, 1H), 8.29 (d, J=7.8 Hz, 1H), 8.13 (br. s., 1H), 4.59 (q, J=7.0 Hz, 2H), 3.97 (s, 3H), 1.56 (t, J=7.0 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[NH:4][C:3]1=[O:15].Cl[CH2:17][CH2:18][CH2:19][CH2:20][P:21]([O:26][CH2:27][CH3:28])(=[O:25])[O:22][CH2:23][CH3:24]>>[CH3:1][N:2]1[C:10]2[N:9]=[CH:8][N:7]([CH2:11][CH2:12][CH3:13])[C:6]=2[C:5](=[O:14])[N:4]([CH2:17][CH2:18][CH2:19][CH2:20][P:21](=[O:25])([O:26][CH2:27][CH3:28])[O:22][CH2:23][CH3:24])[C:3]1=[O:15]
Reactant: CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CCOP(=O)(CCCCCl)OCC
Product: CCCn1cnc2c1c(=O)n(CCCCP(=O)(OCC)OCC)c(=O)n2C

Procedure:
The title substance was prepared from 0.072 mol of 3-methyl-7-propyl-xanthine and 0.072 mol of diethyl 4-chlorobutanephosphonate analogously to Example 23, chromatographed on silica gel (eluent: dichloromethane/methanol 20:1) and crystallized from diisopropyl ether.
Reaction SMILES: C([O:4][C:5]1[C:9]([CH3:10])=[N:8][N:7]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)[N:6]=1)(=O)C.[OH-].[Na+]>CO.O>[F:17][C:14]1[CH:13]=[CH:12][C:11]([N:7]2[NH:6][C:5](=[O:4])[C:9]([CH3:10])=[N:8]2)=[CH:16][CH:15]=1
Reactant: CC(=O)Oc1nn(-c2ccc(F)cc2)nc1C
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1nn(-c2ccc(F)cc2)[nH]c1=O

Procedure:
2-(4-Fluorophenyl)-5-methyl-2H-1,2,3-triazol-4-yl acetate (i.e. the product of Step B, 7.8 g, 33 mmol) was suspended in methanol (150 mL). A solution of sodium hydroxide (7 M, 22 mL, 140 mmol) was added over several minutes with stirring during which time the mixture became homogeneous and then stirred at 23° C. for 18 h. The reaction was concentrated under reduced pressure to remove excess methanol. The remaining residue was diluted with water (200 mL) and washed with hexanes. The aqueous layer was acidified with concentrated hydrochloric acid during which time a thick creamy precipitate formed. The mixture was diluted with water and stirred for 30 min. The precipitate was filtered and washed well with water. The moist solid was dissolved in ethyl acetate, dried (MgSO4) and concentrated under reduced pressure to afford the title compound (6.1 g) as a beige solid. The title compound was used directly in the next step without further purification.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH:10]=O)=[CH:8][CH:7]=1.[CH3:18][CH:19]([CH3:35])[C:20]([NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)[N:24]=1)=[O:21]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]=1[F:17])[O:5][C:6]1[CH:13]=[CH:12][C:9]([CH2:10][N:32]2[CH2:33][CH2:34][CH:29]([C:25]3[N:24]=[C:23]([NH:22][C:20](=[O:21])[CH:19]([CH3:18])[CH3:35])[CH:28]=[CH:27][CH:26]=3)[CH2:30][CH2:31]2)=[CH:8][CH:7]=1
Reactant: O=Cc1ccc(Oc2ccc(F)c(F)c2)cc1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)n1
Product: CC(C)C(=O)Nc1cccc(C2CCN(Cc3ccc(Oc4ccc(F)c(F)c4)cc3)CC2)n1

Procedure:
Prepared by Procedure AA and Scheme AJ using 4-(3,4-difluorophenoxy)benzaldehyde and 2-methyl-N-[6-(4-piperidinyl)-2-pyridinyl]propanamide: ESMS m/e: 466.0 (M+H)+.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=1.[CH2:14]([O:16][C:17](=[O:28])[CH:18]([CH3:27])[CH2:19][C:20]1[CH:25]=[CH:24][C:23]([OH:26])=[CH:22][CH:21]=1)[CH3:15]>>[CH2:14]([O:16][C:17](=[O:28])[CH:18]([CH3:27])[CH2:19][C:20]1[CH:21]=[CH:22][C:23]([O:26][CH2:2][C:3]2[C:4]([S:10][CH:11]([CH3:13])[CH3:12])=[N:5][CH:6]=[C:7]([CH3:9])[CH:8]=2)=[CH:24][CH:25]=1)[CH3:15]
Reactant: CCOC(=O)C(C)Cc1ccc(O)cc1
Reactant: Cc1cnc(SC(C)C)c(CCl)c1
Product: CCOC(=O)C(C)Cc1ccc(OCc2cc(C)cnc2SC(C)C)cc1
Yield: 33 %

Procedure:
3-Chloromethyl-2-isopropylsulfanyl-5-methyl-pyridine (0.02 g, 0.09 mmol) obtained in Step D of Preparation Example 30 and 3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester obtained in Step B of Preparation Example 3 were reacted in the same manner as in Step A of Example 1 to obtain the title compound (0.012 g, 33%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:24])=[O:23])=[CH:8][C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].C1(S(C(N)C2N(C)C(C(O)=O)=C(O)C(=O)C=2)(=O)=O)C=CC=CC=1>>[CH3:1][NH:2][C:3]([C:5]1[N:6]([CH3:32])[C:7]([CH2:20][NH:21][S:22]([C:25]2[C:26]([CH3:31])=[CH:27][CH:28]=[CH:29][CH:30]=2)(=[O:23])=[O:24])=[CH:8][C:9](=[O:19])[C:10]=1[OH:11])=[O:4]
Reactant: CNC(=O)c1c(OCc2ccccc2)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Agent: Cn1c(C(N)S(=O)(=O)c2ccccc2)cc(=O)c(O)c1C(=O)O
Product: CNC(=O)c1c(O)c(=O)cc(CNS(=O)(=O)c2ccccc2C)n1C
Yield: 35.5 %

Procedure:
3-Hydroxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (16-02) (40.0 mg, 35.50%, purified by Prep-HPLC) was synthesized as an off white solid from 3-benzyloxy-1-methyl-4-oxo-6-[(toluene-2-sulfonylamino)-methyl]-1,4-dihydro-pyridine-2-carboxylic acid methylamide (15-02) (140.0 mg, 0.308 mmol) following the procedure described for 6-(benzene sulfonyl amino-methyl)-3-hydroxy-1-methyl-4-oxo-1,4-dihydro-pyridine-2-carboxylic acid (14-01).
Reaction SMILES: ClC1C=C(CC[CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)C=CC=1.[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44]C(O)=O)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41].C(OC(=O)CSC1SC(N)=NC=1)C>>[CH3:32][O:33][C:34]1[CH:35]=[C:36]([CH2:42][CH2:43][CH2:44][CH2:10][N:11]([C@H:25]2[CH2:30][CH2:29][C@H:28]([CH3:31])[CH2:27][CH2:26]2)[C:12](=[O:24])[NH:13][C:14]2[S:15][C:16]([S:19][CH2:20][C:21]([OH:23])=[O:22])=[CH:17][N:18]=2)[CH:37]=[CH:38][C:39]=1[O:40][CH3:41]
Reactant: COc1ccc(CCCC(=O)O)cc1OC
Reactant: C[C@H]1CC[C@H](N(CCCc2cccc(Cl)c2)C(=O)Nc2ncc(SCC(=O)O)s2)CC1
Agent: CCOC(=O)CSc1cnc(N)s1
Product: COc1ccc(CCCCN(C(=O)Nc2ncc(SCC(=O)O)s2)[C@H]2CC[C@H](C)CC2)cc1OC

Procedure:
The compound was prepared following an analogous procedure to the one described for the synthesis of {2-[-3-[3-(3-chloro-phenyl)-propyl]-3-(trans-4-methyl -cyclohexyl)-ureido]-thiazol-5-ylsulfanyl}-acetic acid using 4-(3,4-dimethoxy-phenyl)-butyric acid and (2-aminothiazol-5-ylsulfanyl) acetic acid ethyl ester.
Reaction SMILES: [C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:13][CH:12]([NH:29][C:30]([NH:32][C:33]3[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([O:41]CC)=[O:40])[CH:34]=3)=[O:31])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1.O.[OH-].[Li+].O1CCCC1>CO>[C:1]1([CH3:45])[C:2]([C:7]([CH2:9][N:10]2[C:16]3[CH:17]=[C:18]([CH3:21])[CH:19]=[CH:20][C:15]=3[N:14]([C:22]([C:24]3[O:25][CH:26]=[CH:27][CH:28]=3)=[O:23])[CH2:13][CH:12]([NH:29][C:30](=[O:31])[NH:32][C:33]3[CH:34]=[C:35]([CH:36]=[CH:37][CH:38]=3)[C:39]([OH:41])=[O:40])[C:11]2=[O:44])=[O:8])=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCOC(=O)c1cccc(NC(=O)NC2CN(C(=O)c3ccco3)c3ccc(C)cc3N(CC(=O)c3ccccc3C)C2=O)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2c(c1)N(CC(=O)c1ccccc1C)C(=O)C(NC(=O)Nc1cccc(C(=O)O)c1)CN2C(=O)c1ccco1
Yield: 57.9 %

Procedure:
1-[1-(2-Toluoylmethyl)-2-oxo-5-(furan-2-ylcarbonyl)-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepin-3-yl]-3-(3-ethoxycarbonylphenyl)urea (429 mg) was dissolved in methanol (22 ml), aqueous lithium hydroxide monohydrate (148 mg) solution (11 ml) and tetrahydrofuran (11 ml) were added, and the mixture was refluxed for one hour. The reaction mixture was concentrated under reduced pressure, the residue was dissolved in water (150 ml), the solution was washed with diethyl ether, acidified with 1N hydrochloric acid, and extracted with methylene chloride. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. Isoproryl ether was added to the residue for trituration,collected by filtration, to thereby obtain 237 mg of the titled compound.
Reaction SMILES: [F:1][C:2]1[C:8]([F:9])=[CH:7][C:5]([NH2:6])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[Cl:13]Cl>C(O)(=O)C>[Cl:13][C:7]1[C:8]([F:9])=[C:2]([F:1])[CH:3]=[C:4]([N+:10]([O-:12])=[O:11])[C:5]=1[NH2:6]
Reactant: Nc1cc(F)c(F)cc1[N+](=O)[O-]
Reactant: ClCl
Solvent: CC(=O)O
Product: Nc1c([N+](=O)[O-])cc(F)c(F)c1Cl
Temperature: 0 °C

Procedure:
Into a solution of 4,5-difluoro-2-nitroaniline (20 g) in acetic acid (200 ml) was boubled chlorine gas at 13° to 15° C. during 45 minutes. The reaction mixture was poured into ice water (500 ml) and extracted with dichloromethane. The organic layer was washed with 6% aqueous sodium carbonate and with water successively, dried over anhydrous sodium sulfate and then concentrated. The residue was purified with silica gel chromatography eluting with dichloromethane-n-hexane (1:4) and further recrystallized from hexane to give the title compound (2.91 g) as yellow needles, mp 86°-88° C.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[N+:8]([C:11]1[CH:16]=[CH:15][C:14]([N:17]2[CH2:20][CH:19]([NH2:21])[CH2:18]2)=[CH:13][CH:12]=1)([O-:10])=[O:9]>N1C=CC=CC=1>[N+:8]([C:11]1[CH:12]=[CH:13][C:14]([N:17]2[CH2:18][CH:19]([NH:21][C:5](=[O:7])[CH3:6])[CH2:20]2)=[CH:15][CH:16]=1)([O-:10])=[O:9]
Reactant: CC(=O)OC(C)=O
Reactant: NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Solvent: c1ccncc1
Product: CC(=O)NC1CN(c2ccc([N+](=O)[O-])cc2)C1
Reaction time: 1 h

Procedure:
Acetic anhydride (0.6 ml) was added to a solution of 1-(4-nitrophenyl)-azetidin-3-ylamine (0.5 g ) in pyridine (1.2 ml). After one hour, volatile fractions were removed. This resulted in the product with the molecular weight of 235.24 (C11H13N3O3); MS (ESI): 236 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[S:24][C:5]2[C:6]3[C:22]([CH3:23])=[N:21][O:20][C:7]=3[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[NH:9][C:10](=[O:11])[C:4]=2[C:3]=1[CH3:25].S1C=[CH:29][CH:28]=[CH:27]1.IC(C)C>C1(C)C=CC=CC=1.[Ag]=O>[CH:28]([O:11][C:10]1[C:4]2[C:3]([CH3:25])=[C:2]([CH3:1])[S:24][C:5]=2[C:6]2[C:22]([CH3:23])=[N:21][O:20][C:7]=2[C@H:8]([CH2:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[N:9]=1)([CH3:29])[CH3:27]
Reactant: Cc1noc2c1-c1sc(C)c(C)c1C(=O)N[C@H]2CC(=O)OC(C)(C)C
Reactant: c1ccsc1
Agent: O=[Ag]
Solvent: CC(C)I
Solvent: Cc1ccccc1
Product: Cc1noc2c1-c1sc(C)c(C)c1C(OC(C)C)=N[C@H]2CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A mixture of tert-butyl 2-((6S)-2,3,9-trimethyl-4-oxo-5,6-dihydro-4H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate (17 wherein ring A is thiophene; 100 mg, 0.276 mmol), silver oxide (70 mg, 0.304 mmol) and 2-iodopropane (61 mg, 0.359 mmol) in toluene (5 mL) was heated to 90° C., and stirred overnight. After cooling to room temperature, the reaction mixture was evaporated to dryness and the residue was purified by flash chromatography eluting with petroleum ether/ethyl acetate=5:1 to give tert-butyl 2-((6S)-4-isopropoxy-2,3,9-trimethyl-6H-isoxazolo[5,4-c]thieno[2,3-e]azepin-6-yl)acetate as a yellow solid (80 mg, 72% yield). LC/MS m/z 404 [M+1-1]+; 1H NMR (300 MHz, CDCl3) δ 5.30-5.03 (m, 1H), 4.51 (t, J=6 Hz, 1H), 3.11-3.08 (m, 2H), 2.43 (s, 3H), 2.39 (s, 3H), 2.26 (s, 3H), 1.46 (s, 9H), 1.30 (d, J=6 Hz, 3H), 1.20 (d, J=6 Hz, 3H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=2)[CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])([O-])=O.C(N1C2C(=CC=C(C3C=CC=CN=3)C=2)[C:24](=[O:37])C(C(O)=O)=C1)C.NC1C=C(C2C=CN=CC=2)C=CC=1C(O)=O.C(Cl)(Cl)=O>>[N:16]1[CH:17]=[CH:18][C:13]([C:11]2[CH:12]=[C:4]3[NH:1][C:24](=[O:37])[O:8][C:6](=[O:7])[C:5]3=[CH:9][CH:10]=2)=[CH:14][CH:15]=1
Reactant: CCn1cc(C(=O)O)c(=O)c2ccc(-c3ccccn3)cc21
Reactant: O=C(O)c1ccc(-c2ccncc2)cc1[N+](=O)[O-]
Agent: Nc1cc(-c2ccncc2)ccc1C(=O)O
Agent: O=C(Cl)Cl
Product: O=c1[nH]c2cc(-c3ccncc3)ccc2c(=O)o1

Procedure:
It was found that the 2-nitro-4-(4-pyridinyl)benzoic acid prepared in the preceding examples could be converted to 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylic acid by (a) reducing it to 2-amino-4-(4-pyridinyl)benzoic acid, (b) reacting the 2-amino-4-(4-pyridinyl)benzoic acid with phosgene to form 4-(4-pyridinyl)isatoic anhydride, (c) alkylating the 4-(4-pyridinyl)isatoic anhydride with ethyl bromide to produce N-ethyl-4-(4-pyridinyl)isatoic anhydride, (d) reacting the N-ethyl-4-(4-pyridinyl)isatoic anhydride with the potassium salt of ethyl formyl acetate to form ethyl 1-ethyl-1,4-dihydro-4-oxo-7-pyridinyl-3-quinolinecarboxylate, and (e) hydrolyzing that ester.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:24]=[C:11]3[N:12]=[C:13]([NH:22][NH2:23])[CH:14]=[C:15]([N:16]4[CH2:21][CH2:20][O:19][CH2:18][CH2:17]4)[N:10]3[N:9]=2)=[CH:4][CH:3]=1.C(O)(=O)C.[C:29]1([CH3:37])[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]=O)[CH:30]=1>C(O)C>[CH3:37][C:29]1[CH:30]=[C:31]([CH:32]=[CH:33][CH:34]=1)[CH:35]=[N:23][NH:22][C:13]1[CH:14]=[C:15]([N:16]2[CH2:17][CH2:18][O:19][CH2:20][CH2:21]2)[N:10]2[N:9]=[C:8]([C:5]3[CH:6]=[N:7][C:2]([CH3:1])=[CH:3][CH:4]=3)[CH:24]=[C:11]2[N:12]=1
Reactant: Cc1ccc(-c2cc3nc(NN)cc(N4CCOCC4)n3n2)cn1
Reactant: Cc1cccc(C=O)c1
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1cccc(C=NNc2cc(N3CCOCC3)n3nc(-c4ccc(C)nc4)cc3n2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53 %

Procedure:
There was suspended, in ethanol (3 mL), [2-(6-methyl-pyridin-3-yl)-7-morpholin-4-yl-pyrazolo[1,5-a]pyrimidin-5-yl]-hydrazine (70 mg, 0.22 mM) prepared in the preceding step 2, then acetic acid (6.3 μL, 0.11 mM) and metatolualdehyde (28 μL, 0.24 mM) were added to the suspension and the mixture was stirred at room temperature for 16 hours. The precipitated solid was recovered through filtration and then washed with diethyl ether to thus give the title compound (50.2 mg, yield: 53%).
Reaction SMILES: [NH2:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH:38]([F:40])[F:39])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:23][CH2:22][C:21]([CH3:29])([C:24]([O:26]CC)=[O:25])[CH2:20][CH2:19]4)=[N:16][CH:17]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH3:30].[OH-].[Na+:42]>C1COCC1.CO>[NH2:1][CH:2]([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH:38]([F:39])[F:40])[C:3]1[N:7]2[CH:8]=[C:9]([C:12]3[CH:13]=[N:14][C:15]([N:18]4[CH2:19][CH2:20][C:21]([CH3:29])([C:24]([O-:26])=[O:25])[CH2:22][CH2:23]4)=[N:16][CH:17]=3)[CH:10]=[CH:11][C:6]2=[N:5][C:4]=1[CH3:30].[Na+:42]
Reactant: CCOC(=O)C1(C)CCN(c2ncc(-c3ccc4nc(C)c(C(N)c5ccccc5OC(F)F)n4c3)cn2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1nc2ccc(-c3cnc(N4CCC(C)(C(=O)[O-])CC4)nc3)cn2c1C(N)c1ccccc1OC(F)F
Temperature: 60 °C
Yield: 90.5 %

Procedure:
To a suspension of Example 300 (0.155 g, 0.2815 mmol) in THF (1 mL) and methanol (1 mL) was added 1.0M aqueous sodium hydroxide solution (0.27 mL, 0.28 mmol) and the mixture was heated at 60° C. for a total of 18 h. The mixture was concentrated in vacuo and re-dissolved in water (10 mL), then frozen and freeze-dried, to afford the title compound (0.138 g, 90%) as an off white solid. δH (400 MHz, DMSO-d6) 8.62 (d, 1H, J 0.2 Hz), 8.54 (s, 2H), 8.04 (m, 1H), 7.42 (m, 3H), 7.11 (m, 1H), 5.87 (m, 1H), 4.32 (m, 2H), 3.25 (m, 2H), 2.42 (d, 2H, J 5.6 Hz), 2.20 (s, 3H), 2.08 (m, 2H), 1.10 (m, 2H), 0.99 (s, 3H). LCMS (pH 3): MH+ 523.8, RT 1.48 minutes.
Reaction SMILES: [Li]CCCC.[C:6]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[O:16][CH2:17][O:18][CH3:19])([CH3:9])([CH3:8])[CH3:7].CN(C)CCN(C)C.CN(C)[CH:30]=[O:31]>CCOCC.C(OCC)(=O)C.CCCCCC>[C:6]([C:10]1[C:11]([O:16][CH2:17][O:18][CH3:19])=[C:12]([CH:13]=[CH:14][CH:15]=1)[CH:30]=[O:31])([CH3:9])([CH3:7])[CH3:8]
Reactant: CN(C)C=O
Reactant: COCOc1ccccc1C(C)(C)C
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Solvent: CCOC(C)=O
Product: COCOc1c(C=O)cccc1C(C)(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 120.1 %

Procedure:
A 2.6 M hexane solution of n-BuLi was gradually added to a solution of the 1-(tert-butyl)-2-(methoxymethoxy)benzene (1013 g, 4.67 mol) and tetramethylethylenediamine (754 g, 6.5 ml) in dry ether while cooling on ice, and the mixture was stirred at room temperature for 3 hours. After recooling to 0° C., dimethylformamide (1000 ml, 14 mol) was gradually added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was gradually added to ice water, extraction was performed with ethyl acetate, and the organic layer was washed with water and brine and then dried over anhydrous magnesium sulfate. The organic layer was concentrated under reduced pressure to yield a crude product of the title compound (1247 g) as a red oil.