Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C@:1]12([CH3:30])[C:7]([CH3:9])([CH3:8])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][CH:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:17])([CH3:16])[CH3:15])=[O:11]>C(O)C>[C@:1]12([CH3:30])[C:7]([CH3:8])([CH3:9])[CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[C:10]([O:12][C@@H:13]([C:18]1[CH:23]=[C:22]([O:24][CH3:25])[C:21]([I:26])=[CH:20][C:19]=1[N+:27]([O-:29])=[O:28])[C:14]([CH3:15])([CH3:16])[CH3:17])=[O:11]
Reactant: COc1cc(C(OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Solvent: CCO
Product: COc1cc([C@H](OC(=O)C2CC3CC[C@]2(C)C3(C)C)C(C)(C)C)c([N+](=O)[O-])cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
(R/S)-1-(4-Iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (3.4 g) was dissolved in boiling ethanol (150 ml), the solution was kept in a warm oil bath and slowly cooled to room temperature and stood overnight. Needle crystals were formed gradually and collected by filtration to yield pure single diastereomer (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate (870 mg, 51%). The remaining mother liquor was concentrated in vacuo, and the residue was dissolved again in boiling ethanol (150 ml), and the solution was quickly cooled to room temperature and needle crystals were formed within two hours. The crystals were collected by filtration to yield pure single diastereomer (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (15)-camphanate. The crystallization process was repeated twice to yield additional pure (S)-diastereomer (total 1.07 g, 63%). 1H NMR (400 MHz, CDCl3) for (R)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1-propyl (1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.94 (s, 1H, Ph-H), 6.84 (s, 1H, Ph-CH), 3.93 (s, 3H, OCH3), 2.42 (m, 1H, CH), 2.11 (m, 1H, CH), 1.92 (m, 1H, CH2), 1.75 (m, 1H, CH2), 1.11 (s, 3H, CH3), 1.05 (s, 3H, CH3), 0.97 (s, 9H, C(CH3)3), 0.86 (s, 3H, CH3). 1H NMR (400 MHz, CDCl3) for (S)-1-(4-iodo-5-methoxy-2-nitrophenyl)-2,2-dimethyl-1 propyl(1S)-camphanate: δ 8.48 (s, 1H, Ph-H), 6.95 (s, 1H, Ph-H), 6.80 (s, 1H, Ph-CH), 3.96 (s, 3H, OCH3), 2.37 (m, 1H, CH), 1.92 (m, 2H, CH2), 1.66 (m, 1H, CH), 1.14 (s, 3H, CH3), 1.07 (s, 3H, CH3), 1.06 (s, 3H, CH3), 0.98 (s, 9H, C(CH3)3).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](F)(=[O:18])=[O:17])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1.[CH3:22][NH:23][CH3:24]>O1CCOCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH2:11][CH2:10][C:9]3[CH:12]=[CH:13][C:14]([S:16](=[O:18])(=[O:17])[N:23]([CH3:24])[CH3:22])=[CH:15][C:8]=3[C:7](=[O:20])[C:6]=2[CH:21]=1
Reactant: O=C1c2cc(Br)ccc2CCc2ccc(S(=O)(=O)F)cc21
Reactant: CNC
Solvent: C1COCCO1
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(=O)c1cc(Br)ccc1CC2

Procedure:
3-Bromo-7-fluorosulfonyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one (2.5 g., 0.00677 mole) together with 30 ml. of 25% aqueous dimethylamine and 30 ml. of p-dioxane is heated to refluxing for 3 hours. The brown solution is evaporated to dryness under reduced pressure and the residue partitioned between benzene and water. After washing with water, the benzene layer is evaporated to dryness under reduced pressure, leaving 3-bromo-7-dimethylsulfamoyl-10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-one as a tan solid, m.p. 142°-145°C., in a yield of 2.1 g. (80%). An analytical sample melts at 146°-148°C. after crystallizations from mixtures of benzene and hexane and from methanol.
Reaction SMILES: [Cl:1][CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[N:11]12[CH2:18][CH2:17][CH:14]([CH2:15][CH2:16]1)[C@@H:13]([NH:19][C:20](=[O:35])[O:21][CH:22]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[CH2:12]2>C(OCC)(=O)C>[Cl-:1].[CH:22]([O:21][C:20]([NH:19][C@@H:13]1[CH:14]2[CH2:15][CH2:16][N+:11]([CH2:2][C:3](=[O:4])[C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)([CH2:18][CH2:17]2)[CH2:12]1)=[O:35])([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(N[C@H]1CN2CCC1CC2)OC(c1ccccc1)c1ccccc1
Reactant: O=C(CCl)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(N[C@H]1C[N+]2(CC(=O)c3ccccc3)CCC1CC2)OC(c1ccccc1)c1ccccc1
Product: [Cl-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 74.7 %

Procedure:
2-Chloro-1-phenylethanone (55.0 mg, 0.36 mmol) was added to a solution of (R)-benzhydryl quinuclidin-3-ylcarbamate (100 mg, 0.30 mmol, prepared as in example 2) in ethyl acetate (4 ml). The reaction was stirred at room temperature overnight. The suspension was decanted, solvent was removed, and the product was evaporated to dryness. Et2O was added, and the suspension was sonicated. The precipitate was collected by suction filtration and dried under vacuum at 40° C. to obtain (R)-3-(benzhydryloxycarbonylamino)-1-(2-oxo-2-phenylethyl)-1-azoniabicyclo-[2.2.2]octane chloride (110 mg)
Reaction SMILES: [C:1](N)(=O)[CH:2]([CH:4]([C:6](N)=O)[OH:5])O.[CH:11]1[CH:12]=[CH:13][C:14]2[C:15](=CC=CC=2O)[CH:16]=1>CO>[CH:2]1[C:1]2[C:12](=[CH:11][CH:16]=[CH:15][CH:14]=2)[CH:13]=[CH:6][C:4]=1[OH:5]
Reactant: Oc1cccc2ccccc12
Reactant: NC(=O)C(O)C(O)C(N)=O
Solvent: CO
Product: Oc1ccc2ccccc2c1
Yield: 36.8 %

Procedure:
4.80 g of (+)-tartaric acid diamide (VI) and 1.44 g of naphthol (α:β=1 : 1) were dissolved in 10 ml of methanol by heating, and the thus-obtained solution was allowed to stand for 12 hours at room temperature, with 2.3 g of a clathrate compound (colorless needle-like crystal, mp. 199-204° C.) containing tartaric acid diamide (VI) and 8 -naphthol in a ratio of 1 : 1 being crystallized. When the tartaric acid diamide (VI) was separated from the clathrate compound by column chromatography, 0.53 g of β-naphthol was obtained. (Function and Effect of the Invention)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:25])[C@H:4]([CH2:20][CH2:21][CH2:22][CH2:23][NH2:24])[N:5]([CH2:16][CH:17]([CH3:19])[CH3:18])[S:6]([C:9]1[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=1)(=[O:8])=[O:7].[CH2:26]1[CH2:30]O[CH2:28][CH2:27]1.[C:31]([O-:34])([O-])=O.[K+].[K+]>Cl>[CH3:28][C:27]1[CH:11]=[CH:10][C:9]([S:6]([NH:5][C@H:30]([C:31]([NH:24][CH2:23][CH2:22][CH2:21][CH2:20][C@H:4]([N:5]([S:6]([C:9]2[CH:14]=[CH:13][C:12]([CH3:15])=[CH:11][CH:10]=2)(=[O:8])=[O:7])[CH2:16][CH:17]([CH3:18])[CH3:19])[C:3]([O:2][CH3:1])=[O:25])=[O:34])[CH2:26][C:27]2[CH:21]=[CH:20][CH:4]=[CH:3][CH:28]=2)(=[O:7])=[O:8])=[CH:30][CH:26]=1
Reactant: COC(=O)[C@H](CCCCN)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reactant: C1CCOC1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1ccc(C)cc1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Reaction time: 8 h
Yield: 77 %

Procedure:
To a stirred solution of Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-L-lysine methyl ester (369 mg, 1 mmol, example 65, step C) in THF/K2CO3(1M) (3 mL/3 mL) was added Nα-(4-methylbenzenesulfonyl)-L-phenylalanine N-hydroxysuccinimide ester (500 mg, 1.2 mmol). The reaction mixture was stirred overnight, then diluted with 1N HCl and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated. The crude was purified by flash chromatography using hexane/EtOAc as eluent to afford the desired product (77% yield).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][C:5]([Cl:12])=[C:4]([O:13][CH2:14][C:15]#[CH:16])[N:3]=1.C1OCCOCCOCCOCCOCCOC1.[F-:35].[K+].S1(CCCC1)(=O)=O>C(OC)(C)(C)C>[Cl:12][C:5]1[C:4]([O:13][CH2:14][C:15]#[CH:16])=[N:3][C:2]([F:35])=[C:7]([C:8]([F:11])([F:10])[F:9])[CH:6]=1
Reactant: [F-]
Reactant: C#CCOc1nc(Cl)c(C(F)(F)F)cc1Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: COC(C)(C)C
Solvent: O=S1(=O)CCCC1
Product: C#CCOc1nc(F)c(C(F)(F)F)cc1Cl
Reaction time: 5 h

Procedure:
47.3 g (0.175 mol) of 2,5-dichloro-6-propargyloxy-3-trifluoromethylpyridine, 0.5 g (1.89 mmol) of 18-crown-6 and 15.2 g (0.263 mol) of potassium fluoride were added to 150 ml of sulfolane and the mixture was stirred for 5 hours at 150°-155° C. After cooling, the reaction mixture was stirred with methyl tert-butyl ether and separated from the inorganic precipitate. The filtrate was extracted four times using water, dried and concentrated. The residue together with methylene chloride was filtered with suction through a silica gel frit and concentrated, giving 31.4 g (71% of theory) of the title compound of ηD24 1.4732 (Table III, No. 3.036).
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH:12]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C@H:21]([NH:27][C:28]([C:30]2[CH:34]=[C:33]([CH3:35])[O:32][N:31]=2)=[O:29])[C:20](=[O:36])[N:19]2[CH2:37][C@H:38]([O:40][C:41]3[N:42]=[C:43]4[C:48](=[C:49]5[C:54]=3[CH:53]=[CH:52][CH:51]=[CH:50]5)[CH:47]=[CH:46][CH:45]=[CH:44]4)[CH2:39][C@H:18]2[C:17](=[O:55])[NH:16][C@:15]2([C:57]([O:59][C:60]([CH3:63])([CH3:62])[CH3:61])=[O:58])[CH2:56][C@H:14]2[CH2:13]1.C(N(CC)CC)C>ClCCl>[CH3:35][C:33]1[O:32][N:31]=[C:30]([C:28]([NH:27][C@@H:21]2[C:20](=[O:36])[N:19]3[CH2:37][C@H:38]([O:40][C:41]4[N:42]=[C:43]5[C:48](=[C:49]6[C:54]=4[CH:53]=[CH:52][CH:51]=[CH:50]6)[CH:47]=[CH:46][CH:45]=[CH:44]5)[CH2:39][C@H:18]3[C:17](=[O:55])[NH:16][C@:15]3([C:57]([O:59][C:60]([CH3:62])([CH3:61])[CH3:63])=[O:58])[CH2:56][C@H:14]3[CH2:13][C:12](=[O:11])[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[O:29])[CH:34]=1
Reactant: Cc1cc(C(=O)N[C@H]2CCCCCC(O)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CS(C)=O
Product: Cc1cc(C(=O)N[C@H]2CCCCCC(=O)C[C@@H]3C[C@@]3(C(=O)OC(C)(C)C)NC(=O)[C@@H]3C[C@@H](Oc4nc5ccccc5c5ccccc45)CN3C2=O)no1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 59 %

Procedure:
To a solution of oxalyl chloride (0.017 ml, 0.198 mmol) in dichloromethane (0.6 ml) cooled to −60° C. was added DMSO (0.030 ml, 0.419 mmol) dropwise. The mixture was stirred for 15 min and added dropwise a solution of compound (2R,6S,13aS,14aR,16aS)-tert-butyl 12-hydroxy-6-(5-methylisoxazole-3-carboxamido)-5,16-dioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclo propa[e]pyrrolo[1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (Example 18h, 80 mg, 0.11 mmol) in dichloromethane (0.4 ml). The reaction mixture was stirred for 20 min at −60° C., and triethylamine (0.123 ml, 0.882 mmol) was added dropwise. The mixture was stirred at −60° C. for 5 min, and allowed to warm to room temperature with stirring for 10 min. The reaction mixture was quenched with water, stirred for 15 min, and diluted with dichloromethane. The organic layer was separated, dried over anhydrous sodium sulfate, filtered, and evaporated under reduced pressure to give a foamy material. The crude product was purified by flash chromatography on silica gel (5% methanol/dichloromethane) to provide the title compound (2R,6S,13aS,14aR,16aS)-tert-butyl 6-(5-methylisoxazole-3-carboxamido)-5, 12, 16-trioxo-2-(phenanthridin-6-yloxy)octadecahydrocyclopropa[e]pyrrolo [1,2-a][1,4]diazacyclopentadecine-14a-carboxylate (47 mg, 59% yield) .
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:21])[F:20])=[CH:12][CH:11]=2)[C:5]([NH2:24])=[C:4]([NH2:25])[N:3]=1.[O:26]=[C:27]1O[C@H]([C@H](CO)O)[C:30]([O-])=[C:28]1O.[Na+].C1OC(O)(CO)COC1(O)CO>CC(N(C)C)=O.O>[NH2:1][C:2]1[N:7]=[C:6]([O:8][CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][NH:17][C:18](=[O:23])[C:19]([F:22])([F:20])[F:21])=[CH:14][CH:15]=2)[C:5]2[C:4](=[N:25][CH:30]=[C:28]([CH2:27][OH:26])[N:24]=2)[N:3]=1
Reactant: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Reactant: Nc1nc(N)c(N)c(OCc2ccc(CNC(=O)C(F)(F)F)cc2)n1
Agent: OCC1(O)COC(O)(CO)CO1
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Nc1nc(OCc2ccc(CNC(=O)C(F)(F)F)cc2)c2nc(CO)cnc2n1
Temperature: 40 °C

Procedure:
Pyrimidine 61 (Example 43, 5.0 g, 14.1 mmol) is dissolved in dimethylacetamide/water (1:1) with sodium ascorbate (2.85 g, 14.4 mmol). Dihydroxyacetone dimer (2.57 g, 14.3 mmol) is added and the reaction mixture is heated to 40° C. while air is bubbled into the reaction mixture. After 4 h the reaction mixture is poured into 250 mL of H2O, and the formed solid collected by filtration. This solid is redissolved in CH2Cl2/MeOH (3:1, 500 mL), and dried over MgSO4. The crude product is adsorbed on SiO2 and purified by flash column chromatography using CH2Cl2/MeOH (20:1).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[O:4][CH2:3][CH:2]1[C:11]([OH:13])=O.[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:23](=[CH:24][C:25]=1[O:26][CH3:27])[N:22]=[C:21]([N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[N:20]=[C:19]2[NH2:34].C1(N=C=NC2CCCCC2)CCCCC1.C>CC(C)=O.O1CCCC1>[CH3:14][O:15][C:16]1[CH:17]=[C:18]2[C:19]([NH2:34])=[N:20][C:21]([N:28]3[CH2:29][CH2:30][N:31]([C:11]([CH:2]4[O:1][C:6]5[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=5[O:4][CH2:3]4)=[O:13])[CH2:32][CH2:33]3)=[N:22][C:23]2=[CH:24][C:25]=1[O:26][CH3:27]
Reactant: O=C(O)C1COc2ccccc2O1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: COc1cc2nc(N3CCN(C(=O)C4COc5ccccc5O4)CC3)nc(N)c2cc1OC
Temperature: 22.5 °C
Reaction time: 0.12 h
Yield: 93.6 %

Procedure:
In a reaction vessel, 0.25 mol (45.0 g) of 2,3-dihydro-1,4-benzodioxine-2-carboxylic acid, tetrahydrofuran (328 ml) and 6,7-dimethoxy-2-(piperazin-1-yl)quinazolin-4-amine (0.22 mol; 63.58 g) were charged and contents were stirred at 20-25° C. for 5-10 min. To the resulting mixture dicyclohexylcarbodiimide (0.26 mol; 54.0 g) was added and stirring continued at 20-25° C. for 1.5 hr. To the resulting reaction mass charcoal was added and contents were stirred at 26-28° C. for 45 min. The contents were filtered through celite and washed with tetrahydrofuran. The solvent was distilled out at 35° C. under reduced pressure to obtain solid residue. Acetone (1000 ml) was added to the solid and contents were refluxed for 2 hr. On cooling to 25-28° C., the slurry was filtered, washed with acetone and dried at 60° C. under reduced pressure to obtain 93 g of doxazosin base (HPLC purity −99.0%).
Reaction SMILES: CN1C(C(F)(F)F)=C([B:11]2[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]2)C=N1.Br[C:21]1[C:22]([CH3:28])=[N:23][N:24]([CH3:27])[C:25]=1[F:26]>>[F:26][C:25]1[N:24]([CH3:27])[N:23]=[C:22]([CH3:28])[C:21]=1[B:11]1[O:15][C:14]([CH3:17])([CH3:16])[C:13]([CH3:19])([CH3:18])[O:12]1
Reactant: Cc1nn(C)c(F)c1Br
Reactant: Cn1ncc(B2OC(C)(C)C(C)(C)O2)c1C(F)(F)F
Product: Cc1nn(C)c(F)c1B1OC(C)(C)C(C)(C)O1

Procedure:
Following the procedure of Intermediate 149, replacing 4-bromo-1-methyl-5-(trifluoromethyl)pyrazole with 4-bromo-5-fluoro-1,3-dimethyl-1H-pyrazole (commercial) provided the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([C:24](O)=[O:25])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CCN(C(C)C)C(C)C.FC(F)(F)C([O-])=O.[C:67]([CH:69]1[CH2:73][CH2:72][NH2+:71][CH2:70]1)#[CH:68]>CN1C(=O)CCC1>[C:1]([O:5][C:6]([N:8]1[CH2:28][CH2:27][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([C:24]([N:71]4[CH2:72][CH2:73][CH:69]([C:67]#[CH:68])[CH2:70]4)=[O:25])[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(C(=O)O)C3)c2CC1
Reactant: C#CC1CC[NH2+]C1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])C(F)(F)F
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: C#CC1CCN(C(=O)C2CN(c3c4c(nc5ccnn35)CCN(C(=O)OC(C)(C)C)CC4)C2)C1
Reaction time: 1 h

Procedure:
To 150 mg (0.29 mmol) of 10-(3-Carboxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohept[f]indene-7-carboxylic acid tert-butyl ester (as DIPEA salt) in 1.0 mL NMP was added 105 mg (0.33 mmol) TBTU and 120 μL (0.70 mmol) DIPEA and stirring was continued at room temperature for 1 h. Then 60.7 mg (0.29 mmol) of 3-Ethynyl-pyrrolidinium trifluoro-acetate was added and the reaction mixture was stirred overnight. The reaction mixture was filtered and the purified by HPLC.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](O)=[O:30])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH:32]1([NH2:35])[CH2:34][CH2:33]1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[CH:17][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[CH2:27][CH2:28][C:29](=[O:30])[NH:35][CH:32]4[CH2:34][CH2:33]4)=[CH:19][CH:20]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: NC1CC1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)O)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4CCC(=O)NC4CC4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 33, Step 4, using 1-{4′-[4-(2-carboxy-ethyl)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid ethyl ester and cyclopropylamine.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15](O)=[O:16])=[O:9])[CH2:4][CH2:3]1.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH2:33])[CH:28]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1>CN(C)C=O.O>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([O:19][CH2:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[C:14]([CH:18]=2)[C:15]([NH:33][C:29]2[CH:28]=[N:27][CH:32]=[CH:31][CH:30]=2)=[O:16])=[O:9])[CH2:4][CH2:3]1
Reactant: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Reactant: Nc1cccnc1
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)Nc3cccnc3)c2)CC1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
To a solution of 5-[(4-methyl-1-piperazinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoic acid (may be prepared as described in Description 51; 166 mg, 0.47 mmol), 3-pyridinamine (44.1 mg, 0.47 mmol), and EDC (90 mg, 0.47 mmol) in N,N-dimethylformamide (DMF) (4 mL) stirred under nitrogen at room temperature was added neat HOBT (71.7 mg, 0.47 mmol) in one charge. The reaction mixture was stirred at room temperature for 6 h. The mixture was diluted with water (50 ml), extracted with ethyl acetate (3×50 ml). The organic phase was washed with saturated brine (25 ml), dried over sodium sulfate, and evaporated in vacuo to give the crude product. The crude product was purified by Prep-HPLC (Gilson GX-281; Durashell 10 μm, 21.5*250 nm n; A: 10 mmol/water, B: MeCN, O-7.2 min, 35%-35%; 7.2-7.5 min, 35%-95%; 7.5-11.5 min, 95%; RT: 7.0 min) to yield the title compound as a white solid. 30 mg.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10]([C:15]([O:17]C)=[O:16])[C:11](=[O:14])[NH:12][N:13]=2)=[CH:4][C:3]=1[CH3:19].CS(O[CH2:25][CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[Cl:34])(=O)=O>>[C:15]([C:10]1[C:11](=[O:14])[N:12]([CH2:25][CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[C:3]([CH3:19])[CH:4]=2)[CH:9]=1)([OH:17])=[O:16]
Reactant: CS(=O)(=O)OCCCc1ccccc1Cl
Reactant: COC(=O)c1cc(-c2ccc(F)c(C)c2)n[nH]c1=O
Product: Cc1cc(-c2cc(C(=O)O)c(=O)n(CCCc3ccccc3Cl)n2)ccc1F
Yield: 76.8 %

Procedure:
Following the procedure of Example 1(6), 6-(4-fluoro-3-methylphenyl)-4-methoxycarbonyl-2H-pyridazin-3-one and 3-(2-chlorophenyl)-1-propanol methanesulfonate were reacted to yield a crude product. Without purification, the crude product was reacted further in accordance with the procedure of Example 1(7) to yield the title compound as a yellow crystalline powder (76.8%).
Reaction SMILES: O[C:2]1[C:11](OC)=[CH:10][C:9]([N+]([O-])=O)=[C:8]2[C:3]=1[C:4](C)=[CH:5][CH:6]=[N:7]2.Br[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C1[O:35]C1C.CCN(CC)CC>CN(P(N(C)C)(N(C)C)=O)C>[C:26]1([CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][O:35][C:10]2[CH:9]=[C:8]3[C:3]([CH:4]=[CH:5][CH:6]=[N:7]3)=[CH:2][CH:11]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: COc1cc([N+](=O)[O-])c2nccc(C)c2c1O
Reactant: CC1CO1
Reactant: BrCCCCCCCc1ccccc1
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Solvent: CCN(CC)CC
Product: c1ccc(CCCCCCCOc2ccc3cccnc3c2)cc1
Reaction time: 1 h

Procedure:
To a stirred mixture of 5-hydroxy-6-methoxy-4-methyl-8-nitroquinoline (18 g, 0.077 mol) and 1-bromo-7phenyl heptane [Example 1a] (15 g, 0.059 mol) in HMPA (45 ml) at 130° C., was added, dropwise, during 1 h, a solution of propylene oxide (18 ml) and Et3N (1 ml). After six more hours, second portions of propylene oxide (4 ml) and Et3N (1 ml) were added and heating was continued for 4 h. The cooled mixture was extracted successively with pet ether, Et2O and Me2CO. The residue returned 2.5 g of starting material (i.e., 5-hydroxy-6-methoxy-4methyl-8-nitroquinoline). The combined pet ether and Et2O extracts were washed (H2O, dil NaOH, H2O) dried (Na2SO4) and concentrated to a viscous oil. This material was dissolved in CHCl3, placed on a silica gel column (200 g) and eluted with CHCl3. Concentration of the eluates and crystallization of the residue from pet ether (Darco) gave 12 g, (50%) of 6-methoxy-4-methyl-8-nitro-5-(7-(phenyl heptoxy) quinoline as yellow crystals, mp 53°-54° C.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1C(=O)[NH:5][NH:6][C:7]2=O.P(Cl)(Cl)(Cl)(Cl)[Cl:15].Cl[CH2:21][Cl:22]>>[Cl:15][C:7]1[C:8]2[C:3](=[C:2]([Cl:1])[CH:11]=[CH:10][CH:9]=2)[C:21]([Cl:22])=[N:5][N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: O=c1[nH][nH]c(=O)c2c(Cl)cccc12
Reactant: ClCCl
Product: Clc1nnc(Cl)c2c(Cl)cccc12
Temperature: 150 °C

Procedure:
5-Chloro-2,3-dihydrophthalazin-1,4-dione (5b) (1 g, 5.10 mmol) and phosphorus pentachloride (2.5 g, 12 mmol) were added into a reaction flask successively, and gradually warmed to 150° C. After the solid was melted, the mixture was reflux for two hours at 150° C., and then cooled down to room temperature. 200 mL dried dichloromethane was added, filtrated to remove insoluble substances, and the filtrate was concentrated. Rapid column chromatography was performed with dichloromethane, and the solvent was dried to give 1,4-dichloro-5-chloro-phthalazine (5c), 307 mg white solid (yield 26%).
Reaction SMILES: [N+:1]([C:4]1[CH:8]=[CH:7][NH:6][N:5]=1)([O-:3])=[O:2].[H-].[Na+].Br[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:15][CH:14]=1>CN(C)C=O>[CH3:22][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:6]2[CH:7]=[CH:8][C:4]([N+:1]([O-:3])=[O:2])=[N:5]2)=[CH:14][CH:15]=1)(=[O:20])=[O:21]
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Reactant: O=[N+]([O-])c1cc[nH]n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(Cn2ccc([N+](=O)[O-])n2)cc1
Yield: 55.3 %

Procedure:
To a solution of 3-nitro-1H-pyrazole (prepared in example 3, 150 mg, 1.33 mmol) in anhydrous N,N-dimethylformamide (2 mL), a 60% dispersion of sodium hydride in mineral oil (58 mg, 1.46 mmol) was added while stirring under nitrogen. After the effervescence ceased and the mixture was stirred for additional 30 min, 1-bromomethyl-4-methanesulfonyl-benzene (364 mg, 1.46 mmol) was added. The mixture was continued to stir under nitrogen for an additional 2 h. The solvent was removed in vacuo and purification by ISCO flash column chromatography (Teledyne Isco RediSep Flash Column 40 g; 0% ethyl acetate/hexanes to 50% ethyl acetate/hexanes) afforded 1-(4-methanesulfonyl-benzyl)-3-nitro-1H-pyrazole (207 mg, 55%) as a white solid.