Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][S:19][CH2:18][CH2:17]1)[N:9]=[CH:8][NH:7][C:6]2=O.S(Cl)([Cl:25])=O>CN(C=O)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][N:16]3[CH2:21][CH2:20][S:19][CH2:18][CH2:17]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: O=S(Cl)Cl
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCN1CCSCC1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCN1CCSCC1
Yield: 25 %

Procedure:
A mixture of 6-methoxy-7-(2-thiomorpholinoethoxy)-3,4-dihydroquinazolin-4-one (1.5 g, 4.6 mmol), thionyl chloride (25 ml) and DMF (0.2 ml) was heated at reflux for 2 hours. Excess thionyl chloride was removed by evaporation and the residue azeotroped with toluene. The resulting gum was partitioned between aqueous sodium hydrogen carbonate solution and methylene chloride. The organic layer was separated and the aqueous layer extracted with methylene chloride (4×40 ml). The combined extracts were passed through phase separating paper, the solvent removed by evaporation and the residue purified by column chromatography eluting with methylene chloride/methanol (95/5). The purified product was triturated with acetone to give 4-chloro-6-methoxy-7-(2-thiomorpholinoethoxy)quinazoline (400 mg, 25%) as an orange/brown solid.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH2:7]([N:14]1[CH2:25][CH2:24][C:17]2([O:22][CH2:21][C:20](=O)[NH:19][CH2:18]2)[CH2:16][CH2:15]1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O1CCCC1>[CH2:7]([N:14]1[CH2:15][CH2:16][C:17]2([O:22][CH2:21][CH2:20][NH:19][CH2:18]2)[CH2:24][CH2:25]1)[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: O=C1COC2(CCN(Cc3ccccc3)CC2)CN1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: c1ccc(CN2CCC3(CC2)CNCCO3)cc1
Temperature: 25 °C
Reaction time: 0.05 h
Yield: 82.7 %

Procedure:
To a stirring mixture of lithium aluminum hydride (2.22 g, 58.5 mmol) in tetrahydrofuran (70 mL) was added compound 399 (3.60 g, 13.8 mmol), portionwise over three minutes. After 1.25 hours of reflux the reaction was cooled to room temperature and quenched with water (2.22 mL), then 1N NaOH (2.22 mL), then water (2×2.22 mL). The remaining solids were filtered off, and the filtrate was concentrated to give compound 402 (2.81 g, 82%). LCMS-ESI (POS), M/Z, M+1: Found 247.1, Calculated 247.2.
Reaction SMILES: Cl[C:2]1[C:3]([CH3:9])=[N:4][CH:5]=[C:6]([CH3:8])[N:7]=1.[CH2:10]([N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])O.[Na+]>>[CH3:9][C:3]1[C:2]([N:20]2[CH2:21][CH2:22][N:17]([CH2:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=3)[CH2:18][CH2:19]2)=[N:7][C:6]([CH3:8])=[CH:5][N:4]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: Cc1cnc(C)c(Cl)n1
Agent: O=C([O-])O
Agent: [Na+]
Product: Cc1cnc(C)c(N2CCN(Cc3ccccc3)CC2)n1
Temperature: 125 °C
Yield: 57.7 %

Procedure:
3-Chloro-2,5-dimethylpyrazine (1.0 g, 7.0 mmol) and N-benzylpiperazine (3.7 ml, 21.0 mmol) were mixed under nitrogen and heated to 125° C. for 18 h. Saturated aqueous sodium hydrogen carbonate was added and the product was extracted with chloroform. The combined organic extracts were dried (Na2SO4) and concentrated in vacuo to give a yellow oil. The crude product was purified by flash chromatography using silica gel eluting with methanol:chloroform (2.5:97.5) to give the pure product as a yellow oil (1.14 g, 58%).
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4]([CH3:11])[CH:3]=1.[S:12]1[CH:16]=[CH:15][CH:14]=[C:13]1/[CH:17]=[CH:18]/[S:19]([NH2:22])(=[O:21])=[O:20].BrC1SC=CC=1.C(N=C=NCCCN(C)C)C>ClCCl.CN(C)C1C=CN=CC=1.CN(C)C=O>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:22][S:19](/[CH:18]=[CH:17]/[C:13]2[S:12][CH:16]=[CH:15][CH:14]=2)(=[O:21])=[O:20])=[O:8])=[C:4]([CH3:11])[CH:3]=1
Reactant: Cc1cc(F)ccc1C(=O)O
Reactant: NS(=O)(=O)/C=C/c1cccs1
Agent: Brc1cccs1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: Cc1cc(F)ccc1C(=O)NS(=O)(=O)/C=C/c1cccs1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 4-fluoro-2-methyl-benzoic acid (197 mg, 1.27 mmol) and (E)-2-thiophen-2-yl-ethenesulfonic acid amide (155 mg, 0.82 mmol) (which was prepared analogously to example 1-1 steps i) to ii) starting from 2-bromo-thiophene) in dichloromethane (5 mL) and N,N-dimethylformamide (DMF) (2 mL) is added 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide (EDCI) (277 mg, 1.45 mmol) and 4-(dimethylamino)-pyridine (DMAP) (172 mg, 1.41 mmol) at room temperature (RT). The mixture was stirred at RT for 24 h, and solvent removed under reduced pressure. The crude reaction mixture is partitioned between aq. 1M HCl (25 mL) and ethyl acetate (25 mL). The organic phase is separated and washed with aq. 1M HCl (2×25 mL), and then with sat. aq. K2CO3 solution (3×25 mL) and dried (sodium sulfate) and concentrated in vacuo. After flash chromatography (heptane/ethyl acetate 3:1 to 1:1) ((E)-2-Thiophen-2-yl-ethenesulfonic acid 4-fluoro-2-methyl-benzoylamide can be isolated as a white solid. Yield 65 mg (15%)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH:11]2[CH2:15][CH2:14][NH:13][CH:12]2[CH3:16])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].Cl[C:18]1[N:23]=[CH:22][CH:21]=[CH:20][N:19]=1.C(N(C(C)C)CC)(C)C>C(O)CCCC>[N:19]1[CH:20]=[CH:21][CH:22]=[N:23][C:18]=1[N:13]1[CH2:14][CH2:15][C@@H:11]([C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)[C@@H:12]1[CH3:16]
Reactant: Clc1ncccn1
Reactant: CC1NCCC1c1ccc(C(C)(C)C)cc1
Solvent: CCCCCO
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1[C@H](c2ccc(C(C)(C)C)cc2)CCN1c1ncccn1

Procedure:
1.4 g (0.0065 mol) of the substituted pyrrolidine prepared in (d), 0.74 (0.0065 mol) g of chloropyrimidine and 0.83 g (0.0065 mol) of diisopropylethylamine were mixed together in 40 mL pentanol and refluxed under nitrogen for six hours. The pentanol was distilled off under reduced pressure. The residue was taken up in dichloromethane and washed three times with water. The solution was dried over MgSO4 and filtered. The solvent was evaporated off under reduced pressure. Column chromatography using a toluene/ethylacetate mixture as the eluent afforded both the cis and trans isomers stereochemically pure in a 2:1 ratio in a yield of 1.36 g (70 percent of theoretical). Elemental analysis indicated the following:
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[Br:7][C:8]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:9]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.O1CCCC1>[Br:7][C:8]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:9]=1[O:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[CH2:1]
Reactant: O=C1CCCC1Oc1ccc(Cl)cc1Br
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: C1CCOC1
Product: C=C1CCCC1Oc1ccc(Cl)cc1Br
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 57.8 %

Procedure:
To the mixture of methyl triphenylphosphonium bromide (16.0 g, 44.8 mmol) in anhydrous tetrahydrofuran (125 mL) at 0° C. under nitrogen was added portion wise the potassium tert-butoxide (5.0 g, 44.8 mmol). After stirring at 0° C. for 30 minutes, the mixture of 2-(2-bromo-4-chlorophenoxy)cyclopentanone (516B) (10.8 g, 37.3 mmol) in tetrahydrofuran (40 mL) was added slowly. The resulting mixture was stirred at room temperature under nitrogen for 3 hours. The reaction mixture was quenched with water and extracted with ethyl acetate. The organic phase was washed with water, brine, dried with sodium sulfate and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (5-10% EtOAc in hexanes) to provide 2-bromo-4-chloro-1-(2-methylenecyclopentyloxy)benzene (517) (6.2 g, 58.2%) as a colorless oil.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15](=[CH:16][CH:17]=1)[CH2:14][NH:13][C:12]2=[O:18])(C)(C)C>Cl>[NH2:7][CH2:8][C:9]1[CH:10]=[C:11]2[C:15]([CH2:14][NH:13][C:12]2=[O:18])=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc2c(c1)C(=O)NC2
Agent: Cl
Product: NCc1ccc2c(c1)C(=O)NC2
Reaction time: 8 h
Yield: 92.5 %

Procedure:
A mixture of the product of Step 2 (100 g, 0.38 mol) and HCl (dissolved in MeOH, 3 M, 500 ml) was stirred overnight. Removal of the solvent gave a solid which was washed with Et2O and dried to afford 6-(aminomethyl)-2,3-dihydro-1H-isoindol-1-one (57 g, 76% yield). 1H-NMR (300 MHz, D2O) δ: 7.69-7.67 (m, 1H), 7.52 (s, 1H), 7.45-7.43 (m, 1H), 4.39 (s, 2H), 4.17 (s, 2H).
Reaction SMILES: CC1(C)[O:21][CH:5]2[CH:6]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:7][C:8]3[CH:9]([CH2:10][O:11][N:12]=3)[CH:4]2[O:3]1.Cl.C(=O)([O-])O.[Na+]>O1CCCC1.C(OCC)C>[OH:3][CH:4]1[CH:9]2[CH2:10][O:11][N:12]=[C:8]2[CH2:7][CH:6]([O:13][Si:14]([C:17]([CH3:19])([CH3:18])[CH3:20])([CH3:15])[CH3:16])[CH:5]1[OH:21]
Reactant: CC1(C)OC2C(O[Si](C)(C)C(C)(C)C)CC3=NOCC3C2O1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)(C)[Si](C)(C)OC1CC2=NOCC2C(O)C1O
Temperature: 25 °C
Reaction time: 4 h
Yield: 68.3 %

Procedure:
4,5-(Dimethylmethylenedioxy)-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole (327 mg) was dissolved in 10 ml of tetrahydrofuran, and 1 ml of 1N hydrochloric acid was added, followed by stirring the mixture at room temperature for 4 hours. The reaction mixture was diluted with diethyl ether, and neutralized with a sodium hydrogen carbonate aqueous solution. The organic layer was washed with a sodium chloride aqueous solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give 196 mg of 4,5-dihydroxy-6-(tert-butyldimethylsilyloxy)-3,3a,4,5,6,7-hexahydro-2,1-benzoisooxazole having the following property (yield 68%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13](=[O:14])[O:12][N:11]=[C:10]2[C:15]2[C:19]([CH2:20][OH:21])=[N:18][O:17][N:16]=2)[CH:5]=[CH:6][C:7]=1[F:8].C(N(CC)CC)C.[CH3:29][S:30](Cl)(=[O:32])=[O:31]>C(Cl)Cl.O>[CH3:29][S:30]([O:21][CH2:20][C:19]1[C:15]([C:10]2[N:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([Cl:1])[CH:3]=3)[C:13](=[O:14])[O:12][N:11]=2)=[N:16][O:17][N:18]=1)(=[O:32])=[O:31]
Reactant: O=c1onc(-c2nonc2CO)n1-c1ccc(F)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)OCc1nonc1-c1noc(=O)n1-c1ccc(F)c(Cl)c1
Temperature: 0 °C
Yield: 82.9 %

Procedure:
4-(3-Chloro-4-fluorophenyl)-3-[4-(hydroxymethyl)-1,2,5-oxadiazol-3-yl]-1,2,4-oxadiazol-5(4H)-one (250 mg, 0.7996 mmol) was dissolved in anhydrous DCM (8 mL) followed by addition of triethylamine (TEA) (134 μL, 0.96 mmol). Reaction was cooled to 0° C. and methanesulfonyl chloride (68 μL, 0.88 mmol) was added dropwise. The reaction was diluted with water and extracted with ethyl acetate three times, dried with sodium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by flash column chromatography eluting with 25%-70% EtOAc to yield the desired product (259 mg, 83%). MF═C12H8ClFN4O6S; LCMS calculated for C12H9ClFN4O6S (M+H)+: m/z=390.992.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:7]=[C:8]([CH:27]=[C:28]([O:30][CH3:31])[N:29]=1)[C:9]([NH:11][CH:12]([CH:20]1[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[O:21]1)[CH2:13][CH:14]([CH3:19])[CH2:15][CH2:16][CH:17]=[CH2:18])=[O:10])[CH2:2]C=C>C(Cl)Cl.CC1C=C(C)C=C(C)C=1N1CCN(C2C(C)=CC(C)=CC=2C)C1=[Ru-2](Cl)(Cl)=CC1C=CC=CC=1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1>[CH3:31][O:30][C:28]1[N:29]=[C:6]2[CH:7]=[C:8]([C:9](=[O:10])[NH:11][CH:12]([CH:20]3[CH2:24][CH:23]([CH3:25])[C:22](=[O:26])[O:21]3)[CH2:13][CH:14]([CH3:19])[CH2:15][CH2:16][CH:17]=[CH:18][CH2:2][CH2:1][NH:5]2)[CH:27]=1
Reactant: C=CCCNc1cc(C(=O)NC(CC(C)CCC=C)C2CC(C)C(=O)O2)cc(OC)n1
Agent: Cc1cc(C)c(N2CCN(c3c(C)cc(C)cc3C)C2=[Ru-2](Cl)(Cl)=Cc2ccccc2)c(C)c1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Solvent: ClCCl
Product: COc1cc2cc(n1)NCCC=CCCC(C)CC(C1CC(C)C(=O)O1)NC2=O
Reaction time: 1 h

Procedure:
A solution of 90 mg (0.21 mmol) 2-but-3-enylamino-6-methoxy-N-[3-methyl-1-(4-methyl-5-oxo-tetrahydro-furan-2-yl)-hept-6-enyl]-isonicotinamide in 6 ml DCM is added dropwise over 30 min to a refluxing solution of 3.5 mg tricyclohexylphosphine [1,3-bis(2,4,6-trimethyl-phenyl)-4,5-dihydroimidazol-2-ylidene][benzylidene]ruthenium(IV)dichloride(‘Grubbs second generation catalyst’) in 6 ml DCM and then stirred for 1 h at reflux. LC/MS shows that only little product has been formed, therefore, 7 mg catalyst are added and the mixture stirred for 18 h at reflux. Again, 11 mg catalyst are added and heating continued for 4 h. The reaction mixture is directly chromatographed on silica gel and eluted with DCM/MeOH 98:2 to yield the title compound (mixture of diastereomers) as a greenish foam.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18](Cl)[N:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:9][CH:8]=1)[CH3:2].[CH2:38]([N:45]1[CH2:50][CH2:49][NH:48][CH2:47][CH2:46]1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C)C=O>[CH2:1]([O:3][C:4](=[O:37])[C:5]([CH3:36])([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:48]3[CH2:49][CH2:50][N:45]([CH2:38][C:39]4[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=4)[CH2:46][CH2:47]3)[N:17]=[C:16]([NH:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:15]=2)=[CH:9][CH:8]=1)[CH3:2]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)C(C)(Cc1ccc(Oc2cc(Cl)nc(NCc3ccccc3)n2)cc1)Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(NCc3ccccc3)n2)cc1)Oc1ccccc1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
3-[4-(2-Benzylamino-6-chloro-pyrimidin-4-yloxy)-phenyl]-2-methyl-2-phenoxy-propionic acid ethyl ester (60 mg, 0.1 mmol), 1-Benzyl-piperazine (25 mg, 0.25 ml, 0.15 mmol) and Cs2CO3 (35 mg, 0.11 mmol) were combined in anhydrous N,N-dimethylformamide (DMF) (5 mL) and stirred at 90° C. in dry atmosphere overnight. The DMF was removed in vacuo, the residue was purified in silica to provide a white oil.
Reaction SMILES: [C:1]([C:5]([F:20])([C:16]([F:19])([F:18])[F:17])[O:6][C:7]([F:15])([C:11]([F:14])([F:13])[F:12])[C:8](F)=[O:9])([O:3]C)=[O:2].C[Si](C)(C)[O-:23].[K+:26]>CCOCC>[F:15][C:7]([C:11]([F:14])([F:13])[F:12])([O:6][C:5]([F:20])([C:16]([F:17])([F:18])[F:19])[C:1]([O-:3])=[O:2])[C:8]([O-:9])=[O:23].[K+:26].[K+:26]
Reactant: C[Si](C)(C)[O-]
Reactant: COC(=O)C(F)(OC(F)(C(=O)F)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: CCOCC
Product: O=C([O-])C(F)(OC(F)(C(=O)[O-])C(F)(F)F)C(F)(F)F
Yield: 97.9 %

Procedure:
The procedure of Example 1 was followed using ~95% pure 4-carbomethoxyperfluoro-2-methyl-3-oxapentanoyl fluoride (12.5 g, 39 mmol), potassium trimethylsilanolate (10 g, 78 mmol), and dry ether (300 mL). Dipotassium perfluoro-2,4-dimethyl-3-oxa-1,5-pentanedioate (14.6 g, 98% yield) was isolated as a white solid: 19F NMR (D2O) δ -78.8 (m, CF3, 6F), -124.1 (m, CF, 1F), -130.3 ppm (m, CF, 1F). Anal. Calcd. for C6F8K2O5 : C, 18.85; F, 39.76; K, 20.46. Found: C, 17.45; F, 37.65, 37.53; K, 21.50, 21.30.
Reaction SMILES: S(Cl)(Cl)=O.C1(C2C=CC(C(O)=O)=CC=2)CCCCC1.C1(C2C=CC(C(Cl)=O)=CC=2)CCCCC1.[Cl:35][C:36]1[CH:37]=[C:38]([CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1)[NH2:39].[CH:58]1([C:64]2[CH:69]=[CH:68][C:67]([C:70]([N:72]=[C:73]=[S:74])=[O:71])=[CH:66][CH:65]=2)[CH2:63][CH2:62][CH2:61][CH2:60][CH2:59]1>C1(C)C=CC=CC=1.C(O)C>[Cl:35][C:36]1[CH:37]=[C:38]([NH:39][C:73]([NH:72][C:70](=[O:71])[C:67]2[CH:68]=[CH:69][C:64]([CH:58]3[CH2:59][CH2:60][CH2:61][CH2:62][CH2:63]3)=[CH:65][CH:66]=2)=[S:74])[CH:40]=[CH:41][C:42]=1[O:43][C:44]1[C:53]2[C:48](=[CH:49][C:50]([O:56][CH3:57])=[C:51]([O:54][CH3:55])[CH:52]=2)[N:47]=[CH:46][CH:45]=1
Reactant: O=C(N=C=S)c1ccc(C2CCCCC2)cc1
Reactant: COc1cc2nccc(Oc3ccc(N)cc3Cl)c2cc1OC
Agent: O=C(Cl)c1ccc(C2CCCCC2)cc1
Agent: O=C(O)c1ccc(C2CCCCC2)cc1
Solvent: CCO
Solvent: O=S(Cl)Cl
Solvent: Cc1ccccc1
Product: COc1cc2nccc(Oc3ccc(NC(=S)NC(=O)c4ccc(C5CCCCC5)cc4)cc3Cl)c2cc1OC
Temperature: 100 °C
Reaction time: 2 h
Yield: 54 %

Procedure:
Toluene (20 ml) and thionyl chloride (1 ml) were added to commercially available 4-cyclohexylbenzoic acid (80 mg), and the mixture was heated at 100° C. for one hr. The solvent was removed by distillation, and 4-cyclohexyl-1-benzenecarbonyl isothiocyanate was prepared using the resultant 4-cyclohexyl-1-benzenecarbonyl chloride as a starting compound according to the description of the literature. 3-Chloro-4-[(6,7-dimethoxy-4-quinolyl)oxy]aniline (50 mg) was dissolved in toluene (5 ml) and ethanol (1 ml) to prepare a solution. A solution of 4-cyclohexyl-1-benzenecarbonyl isothiocyanate in ethanol (1 ml) was then added to the solution, and the mixture was stirred at room temperature for 2 hr. The reaction solution was concentrated, and the residue was purified by chromatography on silica gel using chloroform/acetone for development to give the title compound (47 mg, yield 54%).
Reaction SMILES: C([O:5][N:6]=[C:7]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:18][CH2:19][Cl:20])[CH:15]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]3[CH:27]=[CH:28][CH:29]=[C:23]3[CH:22]=2)=[CH:8]1)(C)(C)C.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[ClH:20].[ClH:20].[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([CH2:19][CH2:18][O:17][C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[O:10][C:9]([C:21]2[N:26]=[CH:25][N:24]4[CH:27]=[CH:28][CH:29]=[C:23]4[CH:22]=2)=[CH:8][C:7]3=[N:6][OH:5])[CH2:33][CH2:32]1
Reactant: CC(C)(C)ON=c1cc(-c2cc3cccn3cn2)oc2ccc(OCCCl)cc12
Reactant: CN1CCNCC1
Product: CN1CCN(CCOc2ccc3oc(-c4cc5cccn5cn4)cc(=NO)c3c2)CC1
Product: Cl

Procedure:
6-[2-(4-methyl-piperazin-1-yl)-ethoxy]-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one oxime, dihydrochloride was prepared in 26% overall yield using the method described in example 87, starting from 6-(2-chloro-ethoxy)-2-pyrrolo[1,2-c]pyrimidin-3-yl-chromen-4-one O-tert-butyl oxime (example 87B) and 4-methyl-piperazine.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16](/[CH:19]=[CH:20]/[C:21](=[O:34])[CH2:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.C(OC(NC1C=CC(/C=C/C(=O)CC(=O)/C=C/C2C=CC(O)=CC=2)=CC=1)=O)(C)(C)C>C(Cl)(Cl)Cl.CO>[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16](/[CH:19]=[CH:20]/[C:21](=[O:34])[CH2:22][C:23](=[O:33])/[CH:24]=[CH:25]/[C:26]2[CH:31]=[CH:30][C:29]([OH:32])=[CH:28][CH:27]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Agent: CC(C)(C)OC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: NCC(=O)Nc1ccc(/C=C/C(=O)CC(=O)/C=C/c2ccc(O)cc2)cc1

Procedure:
The title compound was synthesized using the same procedure employed for Example 281, but with (1E,6E)-1-{4-[2-(tert-butoxycarbonylamino)acetylamino]phenyl}-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione (18 mg, 39 μmol, synthesized in Example 268) as the starting material instead of (1E,6E)-1-[4-(tert-butoxycarbonylamino)phenyl]-7-(4-hydroxyphenyl)hepta-1,6-diene-3,5-dione, and was purified by silica gel chromatography (chloroform/methanol=95/5 to 80/20). The product was obtained as a solid (1.5 mg, 11%) having the following characteristic.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:7](=[O:18])[C:8]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12](=[O:17])[C:9]=2[NH:10][CH:11]=1)=[O:5])C>Cl>[O:18]=[C:7]1[C:6]([C:4]([OH:5])=[O:3])=[CH:11][NH:10][C:9]2[C:12](=[O:17])[CH:13]=[CH:14][CH:15]=[CH:16][C:8]1=2
Reactant: CCOC(=O)c1c[nH]c2c(=O)ccccc2c1=O
Agent: Cl
Product: O=C(O)c1c[nH]c2c(=O)ccccc2c1=O
Yield: 89.9 %

Procedure:
A mixture of 4,9-dihydro-4,9-dioxo-1H-cyclohepta[b]pyridine-3-carboxylic acid ethyl ester (5.5 g, described in example 2) and 5% aqueous HCl (v/v, 100 ml) was heated at reflux for 2 hr. The reaction mixture was cooled. The precipitate was collected and washed with water and acetone to give 4.38 g of the title compound, nmr (DMSO-d6) δ7.5 (m, 4H), 8.55 (s, 1H), 8.95 (broad, 1H), 10.8 (s, 1H).
Reaction SMILES: C(O)(C1C=CC=CC=1)C1C=CC=CC=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19]([NH:22][C:23](=[O:45])[NH:24][C:25]2[CH:40]=[C:39]([C:41]([F:44])([F:43])[F:42])[CH:38]=[CH:37][C:26]=2[O:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([O-:32])=[O:31])=[CH:18][CH:17]=1>C(OCC)(=O)C.[Pd]>[Br:15][C:16]1[CH:17]=[CH:18][C:19]([NH:22][C:23](=[O:45])[NH:24][C:25]2[CH:40]=[C:39]([C:41]([F:43])([F:44])[F:42])[CH:38]=[CH:37][C:26]=2[O:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=[O:31])=[CH:20][CH:21]=1
Reactant: O=C(Nc1ccc(Br)cc1)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)[O-]
Agent: [Pd]
Agent: OC(c1ccccc1)c1ccccc1
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Br)cc1)Nc1cc(C(F)(F)F)ccc1Oc1ccccc1C(=O)O

Procedure:
Benzhydrol 2-[2-[3-(4-bromophenyl)ureido]-4-(trifluoromethyl)-phenoxy]benzoate (3.7 g, 5 mmol) was dissolved in ethyl acetate (125 mL) and was hydrogenated for 0.75 hour at 50 psi over 10% palladium on carbon (0.5 g). The catalyst was filtered off and the solvent evaporated to give the crude product which was purified by flash chromatography (silica gel, ethyl acetate/hexane/formic acid). Recrystallization from ethyl acetate/hexane gave the title compound as a white crystalline solid; mp 229°-231° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[N:3]=1.ClC1C=CC=C(C(OO)=[O:19])C=1>C(Cl)(Cl)Cl>[Cl:1][C:2]1[C:7]([CH3:8])=[C:6]([Cl:9])[CH:5]=[C:4]([CH3:10])[N+:3]=1[O-:19]
Reactant: Cc1cc(Cl)c(C)c(Cl)n1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClC(Cl)Cl
Product: Cc1c(Cl)cc(C)[n+]([O-])c1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 76.8 %

Procedure:
A mixture of 2,4-dichloro-3,6-dimethyl-pyridine (790 mg, 4.49 mmol) and 50% m-chloro-perbenzoic acid (1.544 g, 4.49 mmol) in 10 ml of chloroform was stirred at room temperature for 20 hours. The mixture was quenched with water, washed with saturated sodium thiosulfate and saturated sodium carbonate, brine and extracted with chloroform. The organic layer was dried and concentrated to give 954 mg of crude material. The material was purified through silica gel to give 662 mg of the title compound as a white crystals, mp 131-132° C. 1H NMR (CDCl3) δ 7.22 (s, 1H), 2.51 (s, 3H), 2.47 (s, 3H) ppm.
Reaction SMILES: B.[Cl:2][N:3]1[CH2:9][C:8]2[CH2:10][CH:11]([C:14]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)=O)[CH2:12][CH2:13][C:7]=2[N:6]2[C:22]3[CH:32]=[CH:31][N:30]=[CH:29][C:23]=3[C:24]3[C:25](=O)[CH2:26][CH:27]=[C:4]1[C:5]=32>O1CCCC1>[Cl:2][N:3]1[CH2:9][C:8]2[CH2:10][CH:11]([CH2:14][CH:16]3[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]3)[CH2:12][CH2:13][C:7]=2[N:6]2[C:22]3[CH:32]=[CH:31][N:30]=[CH:29][C:23]=3[C:24]3[CH2:25][CH2:26][CH:27]=[C:4]1[C:5]=32
Reactant: O=C1CC=C2c3c1c1cnccc1n3C1=C(CC(C(=O)C3CCCCC3)CC1)CN2Cl
Agent: B
Solvent: C1CCOC1
Product: ClN1CC2=C(CCC(CC3CCCCC3)C2)n2c3c(c4cnccc42)CCC=C31

Procedure:
A solution of borane in tetrahydrofuran (1 M, 50 ml) was added carefully to a stirred solution-suspension of 6-chloro-3-cyclohexylcarbonyl-1,2,3,4-tetrahydropyrido[4',3':2,3]indolo[1,7-ab][1,4]benzodiazepin-9(8H)-one (3.0 g) in tetrahydrofuran (100 ml) and the resulting mixture refluxed for 2 hours, cooled and the excess of borane destroyed by dropwise addition of water. The mixture was then evaporated to dryness under reduced pressure and the residue refluxed with a mixture of 1-octene (50 ml) and xylene (80 ml) for 1 hour and xylene and the combined filtrates were evaporated under reduced pressure. The residue was triturated with a small quantity of ether, filtered, and recrystallized from a mixture of 2-propanol and ethanol to yield the title compound, m.p. 230°-233° (dec.).