Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:3](=O)[C:4]([C:12]#N)=[C:5]([C:10]#N)[C:6](=[O:9])[C:7]=1Cl>C(Cl)Cl>[CH:6]1([CH:7]2[CH2:2][CH2:3][CH2:4][CH2:12][CH2:12][CH2:4][CH2:5]2)[CH2:5][CH2:10][CH2:6][CH2:7][CH2:2][CH2:3][O:9]1
Reactant: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: ClCCl
Product: C1CCCC(C2CCCCCCO2)CCC1
Temperature: 22 °C
Reaction time: 20 h

Procedure:
123 mg of 9-deoxypodophyllol was dissolved in 18 mL of dry methylene chloride, and a solution of 82 mg of 2,3-dichloro-5,6-dicyanobenzoquinone in 2.7 mL of dry methylene chloride was added. The mixture was stirred at 22° C. in an atmosphere of dry nitrogen for 20 hours. Thereafter, the reaction mixture was processed in the manner described in Example 5 using volumes of extraction solvents, reagents, water, and brine in proportion to the amounts of starting diol and oxidizing agent used in this example. The resulting residue after processing was chromatographed on a silica gel plate (GF, 20×20 cm, 500μ), whereby distilled acetone was used as the developing solvent. Removal of the major band from the plate followed by separation of the major product from the silica gel by extraction of the latter with distilled acetone gave the pure oxabicylooctane derivative having a melting point of 148-149° C. and an optical rotation of [α]25D =+44.2 (acetone, c 1.19). HRMS Calcd. For C22H24O7: 400.1522, Found: 400.1526.
Reaction SMILES: I[C:2]1[S:6][C:5]([C:7]2([O:11][CH2:12][C:13]([O:15][CH2:16]C)=[O:14])[CH2:10][CH2:9][CH2:8]2)=[N:4][CH:3]=1.[F-].[Cs+].CC1(C)C(C)(C)OB([C:28]2[CH:34]=[CH:33][C:31]([NH2:32])=[CH:30][CH:29]=2)O1.C(COC)OC>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CO>[NH2:32][C:31]1[CH:33]=[CH:34][C:28]([C:2]2[S:6][C:5]([C:7]3([O:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])[CH2:8][CH2:9][CH2:10]3)=[N:4][CH:3]=2)=[CH:29][CH:30]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: CCOC(=O)COC1(c2ncc(I)s2)CCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: CO
Solvent: COCCOC
Product: COC(=O)COC1(c2ncc(-c3ccc(N)cc3)s2)CCC1
Temperature: 90 °C

Procedure:
A solution of Example 24A (0.750 g, 2/04 mmol), CsF (0.930 g, 6.12 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (0.447 g, 2.04 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.231 g, 0.200 mmol) in a solvent mixture of dimethoxyethane (5 mL) and methanol (5 mL) was heated to 90° C. for 16 h. The reaction was cooled to room temperature and partitioned between H2O (10 mL) and ethyl acetate (10 mL). The layers were separated, and the aqueous was extracted with additional ethyl acetate (2×10 mL). The combined organics were dried with anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography on SiO2 gel, eluting with a gradient of 10% ethyl acetate in hexane to 50% ethyl acetate in hexane, to give the title compound. MS (ESI) m/z 319 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[CH2:46]([NH:49][C:50]([CH:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)=[O:51])[C:47]#[CH:48]>C(N(CC)CC)C.CN(C=O)C.CCOC(C)=O.CCCCCC.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].[Cu]I>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:48]#[C:47][CH2:46][NH:49][C:50]([CH:52]1[CH2:56][CH2:55][CH2:54][CH2:53]1)=[O:51]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCNC(=O)C1CCCC1
Agent: [Cu]I
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CCCCCC
Product: O=C(NCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 49844.5 %

Procedure:
Dissolve 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1 g, 2.35 mmol), tris(dibenzylideneacetone)-dipalladium(0) (0.03 equiv.), copper(I) iodide (0.06 equiv.) and triphenylphosphine (0.25 equiv.) in triethylamine/DMF (3:1, 4 mL). Stir the mixture for 5 min at ambient temperature, add N-prop-2-ynyl-cyclopentylcarboxamide (430 mg, 2.82 mmol) and heat at 70° C. for 18 h in a sealed tube. Cool the reaction mixture to ambient temperature, dilute with EtOAc/hexane (1:1) and wash with water. Dry the organic fraction over MgSO4, filter and concentrate in vacuo. Purify by chromatography on silica gel eluting with hexane/EtOAc (10:1 to 7:3) to obtain 7-chloro-6-[3-(cyclopentanecarbonyl-amino)-prop-1-ynyl]-3-(2,2,2-trifluoroacetyl)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (500 g, 50%).
Reaction SMILES: B.C1COCC1.[OH:7][CH2:8][CH:9]([C:14]([F:21])([N+:18]([O-:20])=[O:19])[N+:15]([O-:17])=[O:16])[CH2:10][C:11](O)=[O:12]>O>[F:21][C:14]([N+:18]([O-:20])=[O:19])([N+:15]([O-:17])=[O:16])[CH:9]([CH2:10][CH2:11][OH:12])[CH2:8][OH:7]
Reactant: O=C(O)CC(CO)C(F)([N+](=O)[O-])[N+](=O)[O-]
Agent: B
Solvent: C1CCOC1
Solvent: O
Product: O=[N+]([O-])C(F)(C(CO)CCO)[N+](=O)[O-]
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To a 1M solution of borane-THF (5 ml, 5 mmole) stirred under a nitrogen atmosphere in an ice bath was added 1.0 g (4.8 mmole) of 4-hydroxy-3-(fluorodinitromethyl)butyric acid, gamma-lactone. The solution was then held in a water bath at 25°-28° C. for 24 hr. before 1 ml of water was slowly added dropwise. The solution was poured into 15 ml of water and extracted with ether to give 1.02 g (100%) of an oil which was essentially pure by TLC. Chromatography on silica gel 60 using methylene chloride-acetone (80/20) as eluent gave an analytical sample. 1H NMR (CDCl3) 1.70-1.93 (m, 2H), 2.36(OH), 3.34-3.97 (m, 5H); IR (film) 3700-3050 (OH), 1605 (NO2) cm-1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[CH:21])=[CH:16][CH:15]=2)[N:13]=1.[Cl:23][C:24]1[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][C:25]=1I.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CS(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:10][C:11](=[O:22])[N:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]#[C:21][C:28]3[CH:29]=[C:24]([Cl:23])[CH:25]=[CH:26][C:27]=3[Cl:30])=[CH:16][CH:15]=2)[N:13]=1
Reactant: Clc1ccc(Cl)c(I)c1
Reactant: C#Cc1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CS(C)=O
Product: O=c1[nH]c(-c2c(F)cccc2Cl)nn1-c1ccc(C#Cc2cc(Cl)ccc2Cl)cc1
Yield: 27.3 %

Procedure:
The title compound was prepared according to the procedure described in Example-3 using 5-(2-chloro-6-fluorophenyl)-2-(4-ethynylphenyl)-2,4-dihydro-3H-1,2,4-triazol-3-one (Intermediate-2, 0.100 g, 0.319 mmol), 1,4-dichloro-2-iodobenzene (0.130 g, 0.470 mmol), TBAF (0.201 g, 0.638 mmol), bis(triphenylphosphine)palladium(II) chloride (0.020 g, 0.028 mmol) and DMSO (3.0 mL). The obtained product was purified with column chromatography on silica gel eluting with 1.0% MeOH:DCM to afford 0.040 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50-7.72 (m, 7H), 7.82 (s, 1H), 8.05 (d, J=8.7 Hz, 2H), 12.75 (br s, 1H). MS (m/z): 458.31 (M+).
Reaction SMILES: Cl.CC(O)=O.[NH:6]([S:45]([C:48]1[CH:54]=[CH:53][C:51]([CH3:52])=[CH:50][CH:49]=1)(=[O:47])=[O:46])[C@@H:7]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:41])[NH2:40])=[O:32])[CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][NH:12]C(OC(C)(C)C)=O.Cl>>[NH:6]([S:45]([C:48]1[CH:49]=[CH:50][C:51]([CH3:52])=[CH:53][CH:54]=1)(=[O:47])=[O:46])[C@@H:7]([C:20]([NH:22][C@H:23]([C:31]([NH:33][C@H:34]([C:42]([OH:44])=[O:43])[CH2:35][CH2:36][CH2:37][NH:38][C:39](=[NH:40])[NH2:41])=[O:32])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:21])[CH2:8][CH2:9][CH2:10][CH2:11][NH2:12]
Reactant: Cc1ccc(S(=O)(=O)N[C@H](CCCCNC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Product: Cc1ccc(S(=O)(=O)N[C@H](CCCCN)C(=O)N[C@@H](Cc2ccccc2)C(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cc1
Yield: 131.8 %

Procedure:
Into 1.7 ml (3.5 mmoles) of 2N HCl/AcOH was dissolved 0.77 g (0.88 mmoles) of Tos-D-Lys(BOC)-Phe-Arg-CHA.HCl. After reacting it at room temperature for 2 hours, the reaction mixture was reprecipitated in dry ether and the deposited crystalline product was collected by filtration and dried. Thus, 0.70 g of crude Tos-D-Lys-Phe-Arg-CHA.2HCl was obtained. It was purified by means of Toyopearl HW40F column with 30% AcOH as a developing solvent. Thus, 0.48 g (67.6%) of Tos-D-Lys-Phe-Arg-CHA.2HCl was obtained.
Reaction SMILES: [F:1][C:2]([F:50])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH3:36])[C:8]1[N:13]=[CH:12][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([O:20]CC)=[O:19])=[CH:10][N:9]=1.[OH-].[Na+]>C(O)C>[F:50][C:2]([F:1])([F:49])[C:3]1[CH:4]=[C:5]([CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[CH:44]=1)[CH2:6][N:7]([CH2:23][C:24]1[CH:29]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:27]=[CH:26][C:25]=1[N:34]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[CH2:35][CH3:36])[C:8]1[N:9]=[CH:10][C:11]([O:14][CH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:12][N:13]=1
Reactant: CCOC(=O)CCCOc1cnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2N(CC)C(=O)OCC)nc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCOC(=O)N(CC)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(OCCCC(=O)O)cn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
Ethyl 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyrate (170 mg) is dissolved in ethanol (2 ml), and thereto is added 2N-aqueous sodium hydroxide solution (352 μl) and the mixture is stirred at room temperature for 1.5 hours and concentrated under reduced pressure. To the residue are added ethyl acetate and a 1N-hydrochloric acid, and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate and concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid (147 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml) and thereto is added 2N-aqueous sodium hydroxide solution (106 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2-{(3,5-bis-trifluoromethyl-benzyl)-[2-(ethoxycarbonyl-ethyl-amino)-5-trifluoromethyl-benzyl]-amino}-pyrimidin-5-yloxy)-butyric acid sodium salt (151 mg). MS (m/z): 695 [M−Na]−
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[C@H:7]([OH:8])[C:5](=[O:6])[O:4][CH2:3]1.[BH4-].[Na+]>CO>[CH3:1][C:2]([CH3:9])([CH2:3][OH:4])[C@H:7]([OH:8])[CH2:5][OH:6]
Reactant: CC1(C)COC(=O)[C@H]1O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(CO)[C@H](O)CO
Temperature: 0 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a 0° C. solution of 5.01 g (38.5 mmol) of (S)-(+)-pantolactone in 150 mL of methanol was added 3.72 g (98.5 mmol) of sodium borohydride carefully. After gas evolution had subsided, the ice-bath was removed and the reaction mixture was closely monitored, cooling again to 0° C. with an ice-water bath as needed when gas evolution became vigorous. The ice-water bath was removed and the reaction mixture was stirred at room temperature for 4 h. Dowex 50Wx4-400 (H+) resin was added to the solution until the reaction mixture was neutral. The resin was filtered off and the filtrate was concentrated under reduced pressure. The oil was diluted and concentrated with portions of methanol and then toluene. The remaining clear oil was dried under high vacuum to afford 5.16 g (>99%) of (2S)-3,3-dimethyl-1,2,4-butanetriol. 1H-NMR (300 MHz, CDCl3): δ 3.82–3.49 (m, 5H), 3.11 (d, J=4 Hz, 1H), 2.62 (m, 1H), 2.42 (m, 1H), 0.98 (d, J=6 Hz, 6H).
Reaction SMILES: [ClH:1].[CH2:2]([NH:4][C:5](=[O:40])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:39])[C@H:12]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:38])[NH2:37])[NH:13][C:14](=[O:31])[C@H:15]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:16]C(OCC1C=CC=CC=1)=O)[CH3:3]>[Pd].CO>[ClH:1].[CH2:2]([NH:4][C:5](=[O:40])[C@@H:6]1[CH2:10][CH2:9][CH2:8][N:7]1[C:11](=[O:39])[C@H:12]([CH2:32][CH2:33][CH2:34][NH:35][C:36](=[NH:37])[NH2:38])[NH:13][C:14](=[O:31])[C@H:15]([CH2:27][CH:28]([CH3:29])[CH3:30])[NH2:16])[CH3:3]
Reactant: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@H](CC(C)C)NC(=O)OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: CCNC(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)N)NC(=O)[C@@H](N)CC(C)C

Procedure:
To a solution of 1.8 g. of Nα -benzyloxycarbonyl-L-leucyl-L-arginyl-L-proline-N-ethylamide hydrochloride in 100 ml. of methanol is added 400 mg. of 20% palladium on carbon and the mixture is stirred under a hydrogen atmosphere for four hours. Disappearance of the starting material is determined by thin layer chromatography of samples of the solution. The catalyst is removed by filtration and the filtrate is evaporated to dryness. The product is used without further purification.
Reaction SMILES: [CH:1]1([N:7]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH3:22])[C:12](=[O:23])[CH2:11][N:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].[N:30](OCCC(C)C)=[O:31]>C1(C)C=CC=CC=1>[CH:1]1([N:7]([C:9]2[C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=3[N:13]([CH2:20][CH2:21][CH3:22])[C:12](=[O:23])[C:11](=[N:30][OH:31])[N:10]=2)[CH3:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCCN1C(=O)CN=C(N(C)C2CCCCC2)c2ccccc21
Reactant: CC(C)CCON=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCCn1c(=O)c(=NO)nc(N(C)C2CCCCC2)c2ccccc21
Temperature: -20 °C
Reaction time: 18 h

Procedure:
The product from step (A) (5 g, 0.016 mol) was dissolved in dry toluene (500 ml) and cooled to -20° C. under an atmosphere of nitrogen. Potassium t-butoxide (8.59 g, 0.080 mol) was added followed after 30 minutes by the dropwise addition of isoamyl nitrite (2.36 ml, 0.0176 mol). The reaction mixture was stirred at -20° C. for 18 hours. The reaction was quenched by the addition of water (50 ml) and the mixture was neutralized to pH 7.4 by the addition of 1M hydrochloric acid. The solvents were removed in vacuo, the resulting solid was resuspended in dichloromethane and absorbed onto silica. The product was purified using flash silica chromatography, eluting with 0.5% 0.88 ammonium solution/2% methanol/dichloromethane followed by chromatography on an alumina column, eluting with 2% methanol/dichloromethane followed by 5% methanol/dichloromethane. Yield--2.31 g (42%) as a pale yellow foam. 1H NMR (DMSO)δ0.52-2.06 (16 H, m), 2.60-2.92 (3H, m), 3.60 (1H, m), 4.26 (1H, m), 7.22-7.66 (14H, m), 9.84 and 10.02 (1H, 2×s).
Reaction SMILES: O=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5][CH2:4][CH:3]1[CH2:12][C:13]([OH:15])=O.Cl.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([NH:24][NH2:25])=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+]>C(O)C>[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]2[C:13](=[O:15])[CH2:12][CH:3]3[CH2:4][S:5][C:6]4[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=4[C:2]3=[N:25]2)=[CH:20][CH:19]=1
Reactant: NNc1ccc(Cl)cc1
Reactant: O=C(O)CC1CSc2ccccc2C1=O
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C1CC2CSc3ccccc3C2=NN1c1ccc(Cl)cc1
Yield: 77.7 %

Procedure:
A mixture of 10 g of α-(2,3-dihydro-4-oxo-4H-1-benzothiopyran-3-yl)acetic acid, 12 g of 4-chlorophenyhydrazine hydrochloride and 5.5 g of sodium acetate in 200 ml of ethanol is refluxed under heating for 10 hours. The ethanol is distilled off under reduced pressure and to the residue is added 200 ml of acetic acid and the mixture is refluxed under heating for 10 hours. After the acetic acid is distilled off, the residue is extracted with chloroform. The extract is washed with water, dried over magnesium sulfate anhydride and the chloroform is distilled off under reduced pressure. To the precipitated crystals is added diisopropyl ether. The crystals are collected by filtration and recrystallized from acetic acid to give 11.5 g of 2-(4-chlorophenyl)-2,3,4,4a-tetrahydro-5H-(1)benzothiopyrano[4,3-c]pyridazin-3-one, melting at 146°-147° C., as colorless prisms.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[C:8]([N:15]([CH2:17][C:18]1([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1)[CH3:16])[N:7]=[C:6]2[NH2:30].[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([N:37]=[C:38]=[O:39])[CH:32]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl.C1(C)C=CC=CC=1>[N:31]1[CH:36]=[CH:35][CH:34]=[C:33]([NH:37][C:38]([N:21]2[CH2:20][CH2:19][C:18]([CH2:17][N:15]([C:8]3[N:7]=[C:6]([NH2:30])[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=3)[CH3:16])([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:23][CH2:22]2)=[O:39])[CH:32]=1
Reactant: COc1cc2nc(N(C)CC3(c4ccccc4)CCNCC3)nc(N)c2cc1OC
Reactant: O=C=Nc1cccnc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: ClCCl
Product: COc1cc2nc(N(C)CC3(c4ccccc4)CCN(C(=O)Nc4cccnc4)CC3)nc(N)c2cc1OC

Procedure:
To a solution of 6,7-dimethoxy-N2-(4-phenyl-piperidin-4-ylmethyl)-N2-methyl-quinazoline-2,4-diamine 11 (340 mg) in dichloromethane (5 mL) was slowly added dropwise with stirring a dilute solution of 3-pyridylisocyanate in toluene. The progress of the reaction was monitored by TLC. After completion of the reaction, aq. sodium carbonate was added and the mixture was extracted with dichloromethane. The extract was washed with water, dried over magnesium sulfate, and evaporated. The residue was chromatographed on silica gel to yield 4-{[(4-Amino-6,7-dimethoxy-quinazolin-2-yl)-methyl-amino]-methyl}-4-phenyl-piperidine-1-carboxylic acid pyridin-3-ylamide 15, MS: 528 ([M+H]+). Treatment of the product with HCl in methanol/ethyl acetate gave 242 mg of the hydrochloride salt.
Reaction SMILES: CC1(C)C(C)(C)OB(C2C=CC([N:15]([C:23]3[CH:28]=[CH:27][C:26](C)=[CH:25][CH:24]=3)[C:16]3[CH:21]=[CH:20][C:19]([CH3:22])=[CH:18][CH:17]=3)=CC=2)O1.Br[C:32]1[CH:33]=[CH:34][C:35]2[C:39](C3C=CC(C)=CC=3)=[C:38](C3C=CC(C)=CC=3)[S:37][C:36]=2[CH:54]=1>>[C:19]1([CH3:22])[CH:20]=[CH:21][C:16]([NH:15][C:24]2[C:23]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:28][CH:27]=[CH:26][C:25]=2[C:38]2[S:37][C:36]3[CH:54]=[CH:32][CH:33]=[CH:34][C:35]=3[CH:39]=2)=[CH:17][CH:18]=1
Reactant: Cc1ccc(N(c2ccc(C)cc2)c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)cc1
Reactant: Cc1ccc(-c2sc3cc(Br)ccc3c2-c2ccc(C)cc2)cc1
Product: Cc1ccc(Nc2cccc(-c3cc4ccccc4s3)c2Nc2ccc(C)cc2)cc1

Procedure:
2,3-di-p-tolylaminophenyl-benzo[b]thiophene was synthesized in the same manner as in Synthesis Example 1, except that [4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolane-2-yl)-phenyl]-di-p-tolylamine was used instead of p-tolylboronic acid used to synthesize Intermediate B in Synthesis Example 1.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][NH:16][CH:15]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2].[CH2:29]=O>C(O)=O>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:24])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH3:29])[CH:15]([CH2:19][O:20][CH:21]([CH3:23])[CH3:22])[CH2:14]3)[CH:11]=2)[C:6](=[O:25])[C:5]([C:26]([OH:28])=[O:27])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCNC(COC(C)C)C3)cc21
Reactant: C=O
Solvent: O=CO
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C)C(COC(C)C)C3)cc21

Procedure:
A 150 mg portion of 1-ethyl-6-fluoro-1,4-dihydro-7-[3-[(1-methylethoxy)methyl]-1-piperazinyl]-4-oxo-3-quinolinecarboxylic acid was dissolved in 0.6 ml of 37% formaldehyde and 0.75 ml of 90% formic acid, heated on a steam bath for one hour and then evaporated. A 5 ml portion of water was added, the solution neutralized with 5N sodium hydroxide and the solid collected, giving 76 mg of the desired product, mp 184°-186° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:8]=[C:9]2[C:13]([CH3:15])([CH3:14])[O:12][C:11]([CH3:17])([CH3:16])[C:10]2=[O:18])[CH:7]=1.[OH-:22].[Li+].OO>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH:19]2[CH2:21][CH2:20]2)=[C:6]([CH:8]2[C:9]3([C:10](=[O:18])[C:11]([CH3:17])([CH3:16])[O:12][C:13]3([CH3:14])[CH3:15])[O:22]2)[CH:7]=1
Reactant: [OH-]
Reactant: CC1(C)OC(C)(C)C(=Cc2cc(Br)ccc2C2CC2)C1=O
Agent: OO
Agent: [Li+]
Solvent: CO
Product: CC1(C)OC(C)(C)C2(OC2c2cc(Br)ccc2C2CC2)C1=O
Temperature: 45 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-[1-(5-bromo-2-cyclopropylphenyl)methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (189 g, 541 mmol) in methanol (2650 ml) at 53° C. is added and 2M aqueous lithium hydroxide (27.1 ml, 54.2 mmol) then 50% aqueous hydrogen peroxide (46.1 ml, 812 mmol). After stirring for 30 minutes at this temperature the solution is cooled to 45° C. and quenched with saturated aqueous sodium thiosulfate. Distilled water (1000 ml) is added and the organic solvents are removed in vacuo. The aqueous phase is then extracted into ethyl acetate (×2) and the combined organic extracts are washed with saturated aqueous sodium hydrogen carbonate (×2), brine (500 mL), then dried over anhydrous magnesium sulfate. Volatile solvents are removed under vacuum to afford 2-(5-bromo-2-cyclopropylphenyl)-4,4,6,6-tetramethyl-1,5-dioxaspiro[2.4]heptan-7-one.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([C:14](N(C)OC)=[O:15])[O:7][CH2:6][CH2:5]2.CC(C[AlH]CC(C)C)C>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][CH3:13])[CH:8]([CH:14]=[O:15])[O:7][CH2:6][CH2:5]2
Reactant: COc1cc2c(cc1Br)CCOC2C(=O)N(C)OC
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Product: COc1cc2c(cc1Br)CCOC2C=O
Temperature: -78 °C
Reaction time: 1 h

Procedure:
A solution of 6-bromo-N-methyl-N,7-bis(methyloxy)-3,4-dihydro-1H-isochromene-1-carboxamide (800 mg, 2.4 mmol) in 20 mL of anhydrous THF was cooled to −78° C. and then DIBAL-H (4.8 mL, 4.8 mmol, 1M) was added. The mixture was stirred at −78° C. for 1 h. The reaction was quenched with water and extracted with DCM. The orgainc layer was washed with brine, dried over anhydrous sodium sulfate and concentrated. The resulting 6-bromo-7-(methyloxy)-3,4-dihydro-1H-isochromene-1-carbaldehyde was used without further purification.
Reaction SMILES: [C:1]([CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=O)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:16]([O:21]CC)(=[O:20])[C:17]([CH3:19])=O.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[C:1]([C:9]1[CH:14]=[C:13]([CH:12]=[CH:11][CH:10]=1)[CH:17]([CH3:19])[C:16]([OH:21])=[O:20])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)=O
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CC(C(=O)O)c1cccc(C(=O)c2ccccc2)c1

Procedure:
A mixture of 20 g of 2-benzoyl-cyclohexanone, 21.6 g of ethyl pyruvate and 0.2 g of p-toluenesulfonic acid is heated at 150° for 15 hours. There is removed that fraction which distills at 1 mm (Hg up to 150°) and the residue is heated for 10 hours at 230° with 5 parts by weight of pyridine hydrochloride. After cooling the raw reaction products are poured in water and extracted with ether. The residue which is obtained after evaporation of the solvent is steam distilled. The part which does not distil is extracted with ether, the ether solution is dried well over sodium sulfate and to the dried solution there is added diethylamine until a clearly alkaline pH is reached. There thus precipitates a mixture of diethylamine salts from which, through fractional crystallization with hexane-ethyl acetate there is obtained the diathylamine salt of m-benzoyl-hydratropic acid m.p. 102°-104°. The free acid is obtained therefrom with the usual techniques.