Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[CH2:7][CH2:6][CH2:5]2.[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=1.Cl.CO>O>[OH:13][C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[C:7]2[CH2:6][CH2:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([OH:1])[CH:3]=3)[C:8]2=[O:12])=[CH:16][CH:15]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CCCc2cc(O)ccc21
Agent: Cl
Solvent: CO
Solvent: O
Product: O=C1C(=Cc2ccc(O)cc2)CCc2cc(O)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 57.3 %

Procedure:
After 6-hydroxy-1-tetralone 1.0 g and 4-hydroxybenzaldehyde 0.903 g were added to a mixture of concentrated hydrochloric acid 50 ml and methanol 75 ml, the mixture was refluxed for one hour and cooled to room temperature, and water 200 ml was added and allowed to stand for one hour. The precipitated crystals were filtered. The crystals were dried over phosphorous pentoxide for four hours under reduced pressure to obtain the desired compound 0.941 g.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(=O)([O-])[O-].[K+].[K+].[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22]Br)[CH3:20].Cl>CN(C)C=O>[CH2:19]([CH:21]([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:22][O:12][C:10]1[CH:9]=[CH:8][C:3]([C:4]([O:6][CH3:7])=[O:5])=[C:2]([OH:1])[CH:11]=1)[CH3:20]
Reactant: CCCCC(CC)CBr
Reactant: COC(=O)c1ccc(O)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C(=O)OC)c(O)c1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 70.3 %

Procedure:
To 30 ml of dimethylformamide (DMF) were added 5.00 g (29.9 mmol) of methyl 2,4-dihydroxybenzoate and 4.52 g (32.7 mmol) of potassium carbonate, and 6.32 g (32.7 mmol) of 2-ethylhexyl bromide was added thereto dropwise at room temperature. After the dropwise addition, the mixture was stirred at 80° C. for 5.5 hours. The reaction mixture was added to 200 ml of dilute hydrochloric acid and extracted with a 150 ml portion and two 50 ml portions of ethyl acetate. The resulting extract was washed successively with water and a saturated sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated to obtain a crude product. The resultant crude product was purified by column chromatography to obtain 5.89 g (yield: 78%) of methyl 4-(2-ethylhexyloxy)-2-hydroxybenzoate represented by the following chemical formula (hereinafter referred to as compound 1) as a colorless, clear and oily substance. The analytical results of the product are shown below. ##STR22##
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([Cl:16])[CH:9]=2)[CH:5]=[N:6][CH:7]=1.[Cl:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24][S:25](Cl)(=[O:27])=[O:26]>N1C=CC=CC=1>[Cl:16][C:10]1[CH:9]=[C:8]([C:4]2[CH:3]=[C:2]([NH:1][S:25]([CH2:24][C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=3[Cl:17])(=[O:26])=[O:27])[CH:7]=[N:6][CH:5]=2)[CH:15]=[CH:14][C:11]=1[C:12]#[N:13]
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Reactant: N#Cc1ccc(-c2cncc(N)c2)cc1Cl
Solvent: c1ccncc1
Product: N#Cc1ccc(-c2cncc(NS(=O)(=O)Cc3ccccc3Cl)c2)cc1Cl
Yield: 41.5 %

Procedure:
According to General Sulfonylation Procedure 2 in Example 1, to a solution of 4-(5-amino-pyridin-3-yl)-2-chloro-benzonitrile (20 mg, 87 μmol, 1 eq) in anhydrous pyridine (500 μl) was added (2-chloro-phenyl)-methanesulfonyl chloride (21.6 mg, 96 μmol, 1.1 eq). The crude product was purified by Isco Cornbiflash® Companion™ flash chromatography system on normal phase (4 g SiO2, flow rate 18 mL/min), eluting with mixtures of dichloromethane/methanol, to give N-[5-(3-chloro-4-cyano-phenyl)-pyridin-3-yl]-1-(2-chloro-phenyl)-methanesulfonamide (15.1 mg, >95% purity, yield: 41.5%). The isolated product was lyophilized and identified by LC-MS (system 1) and NMR (system 2): ESI-MS m/z: 418 [M+H]+, retention time=2.34 min, 1H NMR (400 MHz, DMSO-d6) δ ppm 4.80 (s, 2H) 7.30-7.32 (m, 2H) 7.37-7.39 (m, 1H) 7.47-7.49 (m, 1H) 7.69 (t, J=2.27 Hz, 1H) 7.75 (dd, J=8.08, 1.77 Hz, 1H) 7.98 (d, J=1.77 Hz, 1H) 8.09 (d, J=8.08 Hz, 1H) 8.37 (d, J=2.53 Hz, 1H) 8.61 (d, J=1.89 Hz, 1H) 10.50 (br. s., 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([Br:8])=[N:4][CH:5]=[CH:6][CH:7]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>ClCCl.N1C=CC=CC=1>[Br:8][C:3]1[C:2]([NH:1][S:16]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[CH:11][CH:12]=2)(=[O:18])=[O:17])=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: Nc1cccnc1Br
Reactant: O=S(=O)(Cl)c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=S(=O)(Nc1cccnc1Br)c1ccc(F)cc1
Reaction time: 8 h

Procedure:
To a solution of 3-amino-2-bromo-pyridine (0.4 g, 2.3 mmol) in dichloromethane (4 ml) and pyridine (4 ml) was added 4-fluoro-benzenesulfonylchloride (0.45 g, 2.3 mmol) in one portion. The mixture was stirred overnight. The mixture was diluted with dichloromethane and washed with saturated NaCl solution. The organic layer was dried over sodium sulfate and concentrated. The crude product was purified through chromatography (2-5% EtOAc in dichloromethane). MS 331.8 (M+H)+
Reaction SMILES: C(OC([N:8]1[CH:12]=[C:11]([CH2:13][CH2:14][O:15][C:16]2[CH:25]=[CH:24][C:23]3[C:22](=[O:26])[CH2:21][CH2:20][CH2:19][C:18]=3[CH:17]=2)[N:10]=[CH:9]1)=O)(C)(C)C.[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=O)=[CH:30][CH:29]=1>[OH-].[K+].CCO>[Br:27][C:28]1[CH:35]=[CH:34][C:31]([CH:32]=[C:21]2[CH2:20][CH2:19][C:18]3[C:23](=[CH:24][CH:25]=[C:16]([O:15][CH2:14][CH2:13][C:11]4[N:10]=[CH:9][NH:8][CH:12]=4)[CH:17]=3)[C:22]2=[O:26])=[CH:30][CH:29]=1
Reactant: CC(C)(C)OC(=O)n1cnc(CCOc2ccc3c(c2)CCCC3=O)c1
Reactant: O=Cc1ccc(Br)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2ccc(Br)cc2)CCc2cc(OCCc3c[nH]cn3)ccc21
Yield: 52.4 %

Procedure:
According to the method of Example 32, 4-[2-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-ethyl]-imidazole-1-carboxylic acid tert-butyl ester (0.278 g, 0.78 mmol) was reacted with p-bromobenzaldehyde (0.217 g, 1.17 mmol) in 5 mL of 4% KOH in EtOH overnight to afford 0.173 g (51%) of the title compound as a dark cream-colored powder, mp 176-178° C.: CI-MS m/e 423, 425 (M+ +1).
Reaction SMILES: [C@@H:1]12[CH2:7][C@@H:4]([CH2:5][CH2:6]1)[C@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[NH:2]2.C(N(CC)CC)C.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([S:28](Cl)(=[O:30])=[O:29])=[CH:24][CH:23]=1>C(Cl)(Cl)Cl>[CH3:20][O:21][C:22]1[CH:23]=[CH:24][C:25]([S:28]([N:2]2[C@@H:3]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C@H:4]3[CH2:7][C@@H:1]2[CH2:6][CH2:5]3)(=[O:30])=[O:29])=[CH:26][CH:27]=1
Reactant: CCOC(=O)[C@@H]1N[C@H]2CC[C@@H]1C2
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CCOC(=O)[C@H]1[C@@H]2CC[C@@H](C2)N1S(=O)(=O)c1ccc(OC)cc1
Yield: 59.6 %

Procedure:
To a solution of ethyl (1S, 3R, 4R)-2-azabicyclo[2.2.1]heptane-3-carboxylate (807 mg, 4.77 mmol) in chloroform (8 ml) were added triethylamine (0.67 ml, 4.77 mmol) and 4-methoxybenzenesulfonyl chloride (1.08 g, 5.25 mmol) while being cooled with ice. After a reaction at room temperature for 4 hours, the reaction mixture was washed with 1N hydrochloric acid, saturated sodium bicarbonate water and saturated brine successively, and dried over magnesium sulfate. The solvent was evaporated and the residue was recrystallized (hexane/ethyl acetate), to give ethyl (1S, 3R, 4R)-2-[(4-methoxyphenyl) sulfonyl]-2-azabicyclo[2.2.1]heptane-3-carboxylate (0.965 g, 60%).
Reaction SMILES: [CH3:1][C:2]1([CH2:7][CH:8]=O)OCCO1.[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[NH:17][NH2:18]>C(O)C>[Br:10][C:11]1[CH:12]=[N:13][CH:14]=[C:15]([N+:19]([O-:21])=[O:20])[C:16]=1[N:17]1[C:2]([CH3:1])=[CH:7][CH:8]=[N:18]1
Reactant: CC1(CC=O)OCCO1
Reactant: NNc1c(Br)cncc1[N+](=O)[O-]
Solvent: CCO
Product: Cc1ccnn1-c1c(Br)cncc1[N+](=O)[O-]

Procedure:
2-(2-methyl-1,3-dioxolan-2-yl)acetaldehyde (320 mg, 2.459 mmol) and (3-bromo-5-nitro-4-pyridyl)hydrazine (286.4 mg, 1.229 mmol) were heated under reflux in ethanol (2.864 mL) overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between DCM and a saturated aqueous sodium hydrogen carbonate solution. Combined organic extract was dried over MgSO4 and concentrated in vacuo to leave 3-bromo-4-(5-methyl-1H-pyrazol-1-yl)-5-nitropyridine as a yellow oil. (200 mg, 85%). MS (ES+) 284.9.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:8][CH:7]=1)=[O:5])C.[OH-].[Na+]>C(O)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:9]2[S:10][C:6]([C:4]([OH:5])=[O:3])=[CH:7][N:8]=2)=[O:28])[CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)s1
Temperature: 25 °C
Yield: 22.4 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (prepared as in Example 1 (B)(g), 1.0 g, 2.27 mmol) in absolute ethanol (10 mL) was treated with a 1N aqueous sodium hydroxide solution (4.77 mL, 4.77 mmol). The reaction mixture was heated under reflux for 15 h. The reaction mixture was allowed to cool to 25° C. and then concentrated in vacuo to remove absolute ethanol. The resulting yellow residue was acidified to pH=2 with concentrated hydrochloric acid and extracted with ethyl acetate (2×75 mL). The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo. Recrystallization from ethyl acetate afforded 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid (210 mg, 22%) as a white solid: mp 269-270° C.; FAB-HRMS m/e calcd for C18H18Cl2N2O3S (M+H)+ 413.0493, found 413.0483.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[O:4][CH:5]=[C:6]([OH:10])[C:7](=[O:9])[CH:8]=1.CO[CH:13]=[C:14]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH:28]=[CH:27][CH:26]=[CH:25]3)[CH:22]=2)[C:17](=[O:29])[NH:16][C:15]1=[O:30]>CN(C)C=O>[OH:10][C:6]1[C:7](=[O:9])[CH:8]=[C:3]([CH2:2][NH:1][CH:13]=[C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([N:24]4[CH:28]=[CH:27][CH:26]=[CH:25]4)[CH:22]=3)[C:17](=[O:29])[NH:16][C:15]2=[O:30])[O:4][CH:5]=1
Reactant: NCc1cc(=O)c(O)co1
Reactant: COC=C1C(=O)NC(=O)c2ccc(-n3cccc3)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(-n3cccc3)cc2C1=CNCc1cc(=O)c(O)co1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 2-aminomethyl-5-hydroxy-pyran-4-one (106 mg, 0.75 mmole), 4 mL of N,N-dimethylformamide and 4-methoxymethylene-6-pyrrol-1-yl-4H-isoquinoline-1,3-dione (201 mg, 0.80 mmole) is stirred for one hour at ambient temperature. The reaction mixture is evaporated to dryness, dissolved in 7.5% methanol in chloroform passed through Florisil eluting with 7.5% methanol in chloroform. The eluate is evaporated, treated with acetonitrile, the resulting solid filtered and dried to give a beige solid, 157 mg, (55%), mp 310-2° C. dec; MS (ES+): m/z 378.1 (M+H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1.N1C=CC=CC=1.CS([Cl:21])(=O)=O>CN(C)C=O>[Cl:21][CH2:2][CH2:3][CH2:4][CH2:5][CH:6]1[CH2:10][CH2:9][CH:8]=[CH:7]1
Reactant: OCCCCC1C=CCC1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: ClCCCCC1C=CCC1

Procedure:
3-(4-Hydroxybut-1-yl)cyclopentene {2-cyclopentene-1-butanol} (51 g, 0.37 moles) is diluted in dimethylformamide (100 ml) and added to pyridine (38 g, 0.40 moles). The solution is stirred and methanesulfonyl chloride (46 g, 0.40 moles) is added dropwise over 10 minutes. The reaction is partitioned between hexane (500 ml) and the organic phase separated. The aqueous layer is extracted with hexane (2×500 ml) and the organic extracts combined. The solvent volume is reduced under vacuum and the residue dried over anhydrous magnesium sulfate. The solid is filtered off and the remaining solvent removed leaving a clear yellow oil. The crude product is fractionally distilled under reduced pressure leaving a clear, colorless oil (43 g, 0.27 moles), BP 40°0/0.2 mm.
Reaction SMILES: [F:1][C:2]1([F:31])[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[C:11]([N:15](C(OC(C)(C)C)=O)[NH:16]C(OC(C)(C)C)=O)[CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.[C:32]([CH2:38][C:39]#[N:40])(=O)[C:33]([CH3:36])([CH3:35])[CH3:34].Cl.C([O-])(O)=O.[Na+]>C(O)C>[C:33]([C:32]1[CH:38]=[C:39]([NH2:40])[N:15]([C:11]2[CH:12]=[CH:13][CH:14]=[C:9]([CH2:8][N:5]3[CH2:4][CH2:3][C:2]([F:31])([F:1])[CH2:7][CH2:6]3)[CH:10]=2)[N:16]=1)([CH3:36])([CH3:35])[CH3:34]
Reactant: CC(C)(C)OC(=O)NN(C(=O)OC(C)(C)C)c1cccc(CN2CCC(F)(F)CC2)c1
Reactant: CC(C)(C)C(=O)CC#N
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2cccc(CN3CCC(F)(F)CC3)c2)n1
Yield: 43.9 %

Procedure:
A mixture of Intermediate 12b (1.30 g, 2.94 mmol), pivaloyl acetonitrile (0.37 g, 2.94 mmol), and concentrated HCl (1.5 mL) in ethanol (10 mL) was heated under reflux for 3 h. The cooled mixture was taken to ca. pH 7 with aqueous saturated NaHCO3, and the mixture partitioned between water (15 mL) and EtOAc (3×15 mL). The combined organic extracts were washed with brine (20 mL) and dried (Na2SO4). The solvent was evaporated, and the residue purified by FCC, eluting with 0-100% EtOAc in pentane, to give the title compound as a pale yellow solid (450 mg, 43%). LCMS (Method 1): Rt 1.93 min, m/z 349 [MH+].
Reaction SMILES: [CH2:1]([N:4]([CH2:8][CH:9]=[CH2:10])[C:5](Cl)=[O:6])[CH:2]=[CH2:3].[CH2:11]([S:13][C:14]1[N:18]=[CH:17][NH:16][N:15]=1)[CH3:12].C(N(CC)CC)C>O1CCCC1>[CH2:1]([N:4]([CH2:8][CH:9]=[CH2:10])[C:5]([N:16]1[CH:17]=[N:18][C:14]([S:13][CH2:11][CH3:12])=[N:15]1)=[O:6])[CH:2]=[CH2:3]
Reactant: C=CCN(CC=C)C(=O)Cl
Reactant: CCSc1nc[nH]n1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C=CCN(CC=C)C(=O)n1cnc(SCC)n1

Procedure:
Diallylcarbamoyl chloride (8 g.) was added to a solution of 7.1 g. 3-ethylthio-1,2,4-triazole and 8 ml. dry triethylamine in 50 ml. dry tetrahydrofuran and the mixture refluxed for 4 hours under anhydrous conditions. The cooled reaction mixture was diluted with 100 ml. toluene and washed, firstly with 1N aqueous sodium hydroxide and then with water. The resulting solution was dried over anhydrous sodium sulphate and distilled under reduced pressure to remove the solvent and give 1-diallylcarbamoyl-3-ethylthio-1,2,4-triazole, b.p. 120° - 122° C./0.1 mm. (97.1% 1-isomer by GLC assay).
Reaction SMILES: [CH2:1]([O:5][CH:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])[P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:2][CH2:3][CH3:4].CC(C)([O-])C.[K+].[CH2:29](Br)[CH2:30][CH2:31][CH3:32]>C(O)(C)(C)C.C(OCC)(=O)C>[CH2:1]([O:5][C:6]([P:15](=[O:22])([O:19][CH2:20][CH3:21])[O:16][CH2:17][CH3:18])([P:7](=[O:14])([O:11][CH2:12][CH3:13])[O:8][CH2:9][CH3:10])[CH2:29][CH2:30][CH2:31][CH3:32])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reactant: CCCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Solvent: CCOC(C)=O
Product: CCCCOC(CCCC)(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Reaction time: 0.5 h

Procedure:
Tetraethyl (n-butoxymethylene)-bisphosphonate (1.2 g) was added to a stirred solution of potassium tert-butoxide (0.37 g) in tert-butanol (5 ml). After 30 minutes at room temperature, butyl bromide (0.36 ml) was added, and the mixture was refluxed for 8 hours. After cooling, the mixture was diluted with ethyl acetate and washed with water. The organic phase was dried and evaporated to give an oil which was purified by chromatography to yield the title compound.
Reaction SMILES: F[P-](F)(F)(F)(F)F.[N:8]1([O:17][P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:28][N:29]1[C@H:36]([C:37]([NH:39][C:40]2[CH:45]=[CH:44][C:43]([O:46][CH2:47][C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=4)[N:51]=[C:50]([CH3:58])[CH:49]=3)=[CH:42][CH:41]=2)=[O:38])[C@@H:35]([C:59](O)=[O:60])[CH2:34][C:31]2([CH2:33][CH2:32]2)[CH2:30]1.Cl.NO.CN1CCOCC1>CN(C=O)C>[OH:17][NH:8][C:59]([C@H:35]1[CH2:34][C:31]2([CH2:32][CH2:33]2)[CH2:30][N:29]([CH3:28])[C@@H:36]1[C:37]([NH:39][C:40]1[CH:41]=[CH:42][C:43]([O:46][CH2:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[CH:55][CH:56]=3)[N:51]=[C:50]([CH3:58])[CH:49]=2)=[CH:44][CH:45]=1)=[O:38])=[O:60]
Reactant: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Reactant: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)O)CC4(CC4)CN3C)cc2)c2ccccc2n1
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: NO
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: Cc1cc(COc2ccc(NC(=O)[C@@H]3[C@@H](C(=O)NO)CC4(CC4)CN3C)cc2)c2ccccc2n1
Reaction time: 2 h

Procedure:
To BOP (120.0 mg, 0.24 mmol) was added to a solution of (6S,7S)-5-methyl-6-[({4-[(2-methylquinolin-4-yl)methoxy]phenyl}amino)carbonyl]-5-azaspiro[2.5]octane-7-carboxylic acid (140 mg, 0.20 mmol) in DMF (1.0 mL) at 0° C. followed by hydroxylamine hydrochloride (28.0 mg, 0.40 mmol). 4-methylmorpholine (0.07 mL, 0.70 mmol) was then added to the above mixture at 0° C. and stirred at this temperature for 2 h. The product (70 mg) was purified by preparative HPLC. ESI (M+H)+475.4.
Reaction SMILES: Br[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[CH:26])=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]>C(N(CC)CC)C.N1C=CC=CC=1.[Cu]I.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[CH2:13]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[C:26][C:2]2[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=2)=[CH:21][CH:20]=1)[CH2:14][CH2:15][CH2:16][CH3:17]
Reactant: CCOC(=O)c1ccc(Br)cc1
Reactant: C#Cc1ccc(OCCCCC)cc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CCCCCOc1ccc(C#Cc2ccc(C(=O)OCC)cc2)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 35.2 %

Procedure:
To a suspension of ethyl 4-bromobenzoate (1.37 g), (4-n-pentyloxyphenyl)acetylene (565 mg), triphenylphosphine (16 mg) and copper(I) iodide (6 mg) in triethylamine (10 ml) and pyridine (4 ml) was added palladium(II) chloride bis(triphenylphosphine) (21 mg) and the reaction mixture was stirred for 24 hours at 80° C. After cooling, the precipitate was filtered off, and the filtrate was evaporated under reduced pressure. The residue was taken up to dichloromethane, and the solution was washed successively with 1N HCl, water, brine and dried over magnesium sulfate. The solvents were removed under reduced pressure and the residue was triturated with acetonitrile, collected by filtration and dried under reduced pressure to give ethyl 4-(4-n-pentyloxyphenylethynyl)benzoate (355 mg).
Reaction SMILES: [N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH2:14])[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.Cl[C:17]1[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]2[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=2)=[CH:19][N:18]=1.C(N(CC)CC)C>C(O)C>[N:1]1[C:10]2[CH:9]([CH2:11][CH2:12][CH2:13][NH:14][C:17]3[C:22]([N+:23]([O-:25])=[O:24])=[CH:21][C:20]([CH2:26][C:27]4[CH:28]=[N:29][CH:30]=[CH:31][CH:32]=4)=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1Cl
Reactant: NCCCC1CCCc2cccnc21
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(Cc2cccnc2)cnc1NCCCC1CCCc2cccnc21
Yield: 86.5 %

Procedure:
A mixture of 3-(5,6,7,8-tetrahydroquinol-8-yl)propylamine (4.5 g), 2-chloro-3-nitro-5-(pyrid-3-ylmethyl)pyridine hydrochloride (5 g) and triethylamine (10 ml) was refluxed in ethanol (200 ml) for 7.5 hours. The solvent was removed in vacuo, the residue was dissolved in chloroform and chromatographed on silica in chloroform and later chloroform/methanol 4:1. The fractions containing the product were concentrated to give the title compound as an oil (6.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[C:23]3[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=3)[CH:17]=[C:16]([CH2:25][C:26]([O:28][CH3:29])=[O:27])[C:15]=2[CH3:30])[CH2:10][CH2:9]1)=O)(C)(C)C.[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34]>ClCCl>[F:31][C:32]([F:37])([F:36])[C:33]([OH:35])=[O:34].[CH3:29][O:28][C:26](=[O:27])[CH2:25][C:16]1[C:15]([CH3:30])=[C:14]([CH:11]2[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]2)[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([F:24])[CH:22]=2)[CH:17]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(C2CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)Cc1cc2ccc(F)cc2c(C2CCNCC2)c1C
Temperature: 25 °C
Reaction time: 2 h
Yield: 53.4 %

Procedure:
To a yellow solution of (4-(7-fluoro-3-methoxycarbonylmethyl-2-methyl-naphthalen-1-yl)-piperidine-1-carboxylic acid tert-butyl ester (200 mg, 0.48 mmol) in dichloromethane (10 mL) was added excess trifluoroacetic acid (1.1 g, 742 μL, 9.6 mmol) at room temperature under nitrogen. The resulting dark brown solution was stirred for 2 hours at room temperature under nitrogen. The solvent was removed under vacuum and the residue (˜270 mg) was purified by flash chromatography (40 g ISCO column, 0-100% ethyl acetate/hexanes then 20% MeOH/dichloromethane) to give (6-fluoro-3-methyl-4-piperidin-4-yl-naphthalen-2-yl)-acetic acid methyl ester trifluoroacetate salt as a light yellow solid (110 mg, 53%). MS cald. for C19H23FNO2 [(M+H)+] 316, obsd. 316.1.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:11]([N:12]2[N:21]=[CH:20][C:19]3[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:25])([CH3:24])[CH3:23])[CH:18]=3)[C:13]2=[O:27])=[CH:10][CH:9]=[CH:8][C:7]=1[C:28]1[CH:29]=[C:30]([NH:36][C:37]2[N:42]=[CH:41][C:40]([N:43]3[CH2:56][C:45]4([CH2:48][N:47]([C:49]([O:51][C:52]([CH3:55])([CH3:54])[CH3:53])=[O:50])[CH2:46]4)[CH2:44]3)=[CH:39][CH:38]=2)[C:31](=[O:35])[N:32]([CH3:34])[N:33]=1)(=O)C.[Li+].[OH-]>O1CCOCC1>[C:52]([O:51][C:49]([N:47]1[CH2:46][C:45]2([CH2:56][N:43]([C:40]3[CH:41]=[N:42][C:37]([NH:36][C:30]4[C:31](=[O:35])[N:32]([CH3:34])[N:33]=[C:28]([C:7]5[CH:8]=[CH:9][CH:10]=[C:11]([N:12]6[N:21]=[CH:20][C:19]7[C:14](=[C:15]([F:26])[CH:16]=[C:17]([C:22]([CH3:23])([CH3:24])[CH3:25])[CH:18]=7)[C:13]6=[O:27])[C:6]=5[CH2:5][OH:4])[CH:29]=4)=[CH:38][CH:39]=3)[CH2:44]2)[CH2:48]1)=[O:50])([CH3:53])([CH3:54])[CH3:55]
Reactant: CC(=O)OCc1c(-c2cc(Nc3ccc(N4CC5(CN(C(=O)OC(C)(C)C)C5)C4)cn3)c(=O)n(C)n2)cccc1-n1ncc2cc(C(C)(C)C)cc(F)c2c1=O
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cn1nc(-c2cccc(-n3ncc4cc(C(C)(C)C)cc(F)c4c3=O)c2CO)cc(Nc2ccc(N3CC4(CN(C(=O)OC(C)(C)C)C4)C3)cn2)c1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 33.7 %

Procedure:
In a 250 mL round-bottomed flask, tert-butyl 6-(6-(6-(2-(acetoxymethyl)-3-(6-tert-butyl-8-fluoro-1-oxophthalazin-2(1H)-yl)phenyl)-2-methyl-3-oxo-2,3-dihydropyridazin-4-ylamino)pyridin-3-yl)-2,6-diazaspiro[3.3]heptane-2-carboxylate (530 mg, 693 μmol) was combined with dioxane (15 ml) and 1M LiOH (3 ml) to give a dark brown solution. The reaction mixture was stirred at 25° C. for 4 h. The crude reaction mixture was concentrated in vacuo. The crude material was purified by flash chromatography (silica gel, 220 g, 0% to 4% MeOH in DCM) to afford 0.169 g (34%) of the title compound as a light yellow powder. (M+H)'=723 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ: 8.36 (s, 1H), 8.26 (d, J=2.6 Hz, 1H), 8.19 (s, 1H), 7.37-7.69 (m, 6H), 6.84-6.94 (m, 1H), 6.80 (d, J=3.0 Hz, 1H), 4.39 (d, J=6.8 Hz, 2H), 4.08 (s, 4H), 3.96 (s, 4H), 3.85 (s, 3H), 1.42 (s, 9H), 1.39 (s, 9H).
Reaction SMILES: [NH2:1][C:2]1[CH2:8][N:7]=[C:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[Cl:15])[C:5]2[CH:16]=[C:17]([N+:20]([O-:22])=[O:21])[CH:18]=[CH:19][C:4]=2[N:3]=1.[C:23](OC)(=[O:26])[C:24]#[CH:25]>CO>[N+:20]([C:17]1[CH:18]=[CH:19][C:4]2[N:3]3[CH:25]=[CH:24][C:23](=[O:26])[N:1]=[C:2]3[CH2:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[Cl:15])[C:5]=2[CH:16]=1)([O-:22])=[O:21]
Reactant: C#CC(=O)OC
Reactant: NC1=Nc2ccc([N+](=O)[O-])cc2C(c2ccccc2Cl)=NC1
Solvent: CO
Product: O=c1ccn2c(n1)CN=C(c1ccccc1Cl)c1cc([N+](=O)[O-])ccc1-2

Procedure:
In the manner given in Example 1, 2-amino-7-nitro-5-(o-chlorophenyl)-3H-1,4-benzodiazepine, methyl propiolate and methanol were refluxed. The mixture was chromatographed to give 9-nitro-7-(o-chlorophenyl)pyrimido[1,2-a][1,4]benzodiazepin-3(5H)-one.