Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[CH:9]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[CH2:10][OH:11].[CH3:19][S:20](Cl)(=[O:22])=[O:21].O(C(C)C)C(C)C>N1C=CC=CC=1>[CH3:19][S:20]([O:11][CH2:10][CH:9]([C:3]1[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=1[Cl:1])[CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:22])=[O:21]
Reactant: OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: CC(C)OC(C)C
Product: CS(=O)(=O)OCC(Cc1ccccc1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 15.8 parts of β-(2,4-dichlorophenyl)benzene-propanol, 12.15 parts of methanesulfonyl chloride, 50 parts of pyridine and 70 parts of 2,2'-oxybispropane is stirred overnight at room temperature. The reaction mixture is poured onto water and the product is extracted twice with 2,2'-oxybispropane. The combined extracts are washed twice with a diluted hydrochloric acid solution and once with water, dried, filtered and evaporated. The residue is triturated in methanol. The product is filtered off and crystallized from ethanol, yielding 7.28 parts of β-(2,4-dichlorophenyl)benzenepropanol methanesulfonate; mp. 87.3° C.
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2.CN1CCCC1=O.O.Cl.[NH2:29][C@H:30]([CH2:32][OH:33])[CH3:31]>>[OH:33][CH2:32][C@H:30]([NH:29][C:2]1[N:10]=[C:9]([S:11][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[N:8]=[C:7]2[C:3]=1[NH:4][C:5](=[O:19])[NH:6]2)[CH3:31]
Reactant: O=c1[nH]c2nc(SCc3ccccc3)nc(Cl)c2[nH]1
Reactant: C[C@H](N)CO
Agent: Cl
Solvent: CN1CCCC1=O
Solvent: O
Product: C[C@H](CO)Nc1nc(SCc2ccccc2)nc2[nH]c(=O)[nH]c12
Temperature: 100 °C
Reaction time: 48 h
Yield: 19.4 %

Procedure:
A solution of the product from example 2, step (f) (0.1 g) in a mixture of alaninol (0.128 g), disopropylethylamine (0.35 ml) and N-methylpyrrolidinone (3 ml) was stirred at 100° C. for 48 h before pouring into H2O (75 ml). 2M HCl solution was then added to pH=2 and the light brown solid formed filtered and recrystallised from EtOH to afford the subtitle compound (22 mg, 19%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)[NH:26]C(OCC2C=CC=CC=2)=O)=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8].[BrH:45].C(OCC)C>C(O)(=O)C>[BrH:45].[BrH:45].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:16]2[C:20]([CH3:21])=[N:19][N:18]=[C:17]2[CH2:22][NH:23][C:24](=[O:44])[C@H:25]([CH2:37][C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[NH2:26])=[C:6]([CH:15]=1)[C:7]([C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)=[O:8]
Reactant: Cc1nnc(CNC(=O)[C@H](Cc2ccccc2)NC(=O)OCc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: Cc1nnc(CNC(=O)[C@@H](N)Cc2ccccc2)n1-c1ccc(Cl)cc1C(=O)c1ccccc1
Yield: 79 %

Procedure:
0.50 g of 5-chloro-2-{[(N-benzyloxycarbonyl-L-phenylalanyl)aminomethyl]-5-methyl-4H-1,2,4-triazol-4-yl}benzophenone was treated with a 35% solution of hydrogen bromide in glacial acetic acid for 1 hour. Dry diethyl ether was then added and the separated solid was filtered off, washed with ether and dried in vacuo. The crude product was purified by precipitation from methanol/ethyl acetate. There was obtained 0.36 g (79%) of 5-chloro-2-[3-(L-phenylalanylaminomethyl)-5-methyl-4H-1,2,4-triazol-4-yl]benzophenone dihydrobromide of melting point 164°-171° C (slow decomposition).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[Cl-].[NH4+:22]>CN(C)C=O>[C:5]([NH:6][C:2](=[N:1][C:2]1[S:3][C:4]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)=[C:5]([CH3:7])[N:6]=1)[S:3][CH3:4])#[N:22]
Reactant: [NH4+]
Reactant: Cc1ccnc(-c2sc(N)nc2C)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CSC(=Nc1nc(C)c(-c2cc(C)ccn2)s1)NC#N
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a suspension of 2-amino-4-methyl-5-(4-methylpyridin-2-yl)-thiazole (410 mg) and potassium carbonate (415 mg) in N,N-dimethylformamide (10 ml) was added dimethyl N-cyanodithioimino-carbonate (292 mg), and the mixture was stirred at 100° C. for 1 hour. The mixture was poured into a saturated aqueous solution of ammonium chloride. Then the precipitate was collected by filtration, purified by column chromatography (silica gel 30 g, 0 to 3% methanol in dichloromethane) and recrystallized from 2-propanol to give N-cyano-N′-(4-methyl-5-(4-methylpyridin-2-yl) thiazol-2-yl)-S-methylisothiourea (0.08 g).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:10]=[C:11]3[C:16](=[C:17]4[CH:22]=[CH:21][N:20]=[CH:19][C:18]=24)[N:15]=[CH:14][N:13]([C@H:23]2[CH2:28][CH2:27][CH2:26][CH2:25][C@@H:24]2[OH:29])[C:12]3=[O:30])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:36]1[CH:41]=[N:40][CH:39]=[CH:38][N:37]=1)CCC>O1CCOCC1.C(OCC)(=O)C.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>[OH:29][C@H:24]1[CH2:25][CH2:26][CH2:27][CH2:28][C@@H:23]1[N:13]1[C:12](=[O:30])[C:11]2[C:16](=[C:17]3[CH:22]=[CH:21][N:20]=[CH:19][C:18]3=[C:9]([CH2:8][C:5]3[CH:6]=[N:7][C:2]([C:36]4[CH:41]=[N:40][CH:39]=[CH:38][N:37]=4)=[CH:3][CH:4]=3)[CH:10]=2)[N:15]=[CH:14]1
Reactant: O=c1c2cc(Cc3ccc(Cl)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: O=c1c2cc(Cc3ccc(-c4cnccn4)nc3)c3cnccc3c2ncn1[C@H]1CCCC[C@@H]1O
Temperature: 25 °C

Procedure:
To a solution of 6-[(6-chloropyridin-3-yl)methyl]-3-[(1S,2S)-2-hydroxycyclohexyl]pyrido[3,4-h]quinazolin-4(3H)-one (Example 1, 0.050 g, 0.12 mmol) in 1 mL of dioxane under an atmosphere of nitrogen was added 2-(tributylstannyl)-pyrazine (0.175 g, 0.475 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.014 g, 0.012 mmol). The mixture was irradiated in a microwave reactor at 160° C. for 1 h, cooled to rt, and diluted with ethyl acetate. The organic solution was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via preparative reverse phase HPLC to provide the title compound that gave a proton NMR spectra consistent with theory and a mass ion (ES+) of 464.9 for [M+H]: 1H NMR (400 MHz, CD3OD) δ 9.84 (s, 1H), 9.51 (s, 1H), 9.32 (d, J=6.2 Hz, 1H), 8.84 (d, J=6.2 Hz), 8.75-8.64 (m, 4H), 8.41 (d, J=8.2 Hz, 1H), 8.34 (s, 1H), 7.96-7.94 (m, 1H), 4.86 (s, 2H), 4.16 (br s, 1H), 2.19 (br s, 1H), 2.03 (br s, 1H), 1.96-1.86 (m, 3H), 1.56-1.42 (m, 4H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.F[C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cccc(F)n1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Product: Cc1cccc(-n2cc(C#Cc3cccc(Cl)c3)nc2C)n1

Procedure:
The title compound, MS: m/e=308.2 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 2-fluoro-6-methyl-pyridine.
Reaction SMILES: C(O)[C@H]1O[C@H](O[C@]2(CO)O[C@H](CO)[C@@H](O)[C@@H]2O)[C@H](O)[C@@H](O)[C@@H]1O.[O:24]=[CH:25][C@@H:26]([C@H:28]([C@@H:30]([C@@H:32]([CH2:34][OH:35])[OH:33])[OH:31])[OH:29])[OH:27]>>[O:24]=[C:25]1[O:31][C@H:30]([C@H:32]([CH2:34][OH:35])[OH:33])[C:28]([OH:29])=[C:26]1[OH:27]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: OC[C@H]1O[C@@](CO)(O[C@H]2O[C@H](CO)[C@@H](O)[C@H](O)[C@H]2O)[C@@H](O)[C@@H]1O
Product: O=C1O[C@H]([C@@H](O)CO)C(O)=C1O
Reaction time: 0.29 h

Procedure:
Isolation and Culture of Growth Plate Chondrocytes: Six-to eight-week old broiler chickens were obtained commercially, sacrificed by cervical displacement, and the tibiae harvested. Epiphyseal growth plate chondrocytes were obtained from the tibiae as described (Ali et al., 1970, Proc. Natl. Acad. Sci. USA 67: 1513-1520). Briefly, cartilage slices were digested in 1% trypsin solution prepared in synthetic cartilage lymph (SCL). SCL contains 2 mM Ca2+ and 1.42 mM Pi, in addition to 104.5 mM Na+, 133.5 mM Cl−, 63.5 mM sucrose, 16.5 mM N-tris methyl-2-aminoethane sulfonic acid (TES), 12.7 mM K+, 5.55 mM D-glucose, 1.83 mM HCO3−, 0.57 mM Mg2+, and 0.57 mM SO4−. Cartilage slices were digested for 15 to 20 minutes at 37° C. After digestion, part of the trypsin solution was removed and 10 ml of SCL and 0.5 ml of 0.78% collagenase solution added to the tissue slices. After 30 min of collagenase/trypsin digestion at 34° C., the liquid was removed from the slices and replaced with 0.5 ml of 0.78% collagenase solution plus 15 ml DMEM, with 10% FBS. The collagenase-DMEM solution was removed from the cartilage digestate after 15 hours (overnight) of digestion. The chondrocytes were released from the residual tissues by vortexing for a total of 3 min. mm (1 min. mm each time) in fresh medium. Isolated cells were demineralized in iso-osmotic citrate buffer (8.0 mM citric acid in 80.5 mM sodium citrate, pH 6.0) for 15 min. mm at 34° C. After demineralization cells were washed with fresh medium, resuspended in 10 ml of DMEM with 10% FBS, and counted using a hemocytometer. Cell viability was determined by trypan blue exclusion. Cells were plated at 3-4×105 cells per 35 mm dish in 2 ml of medium. The cells were initially cultured in DMEM with 10% FBS and 1% penicillin/streptomycin solution. The culture medium was changed twice a week for the duration of the experiments. On day 7, the cell cultures were changed into a 1:1 (v/v) mixture of DMEM with 10% FBS and serum-free HL-1 medium. Ascorbic acid was provided at 50 μg/ml medium after day 3. For treatment of endothelial cell cultures, the concentrated fusarochromanone solution was diluted in methanol to final concentrations of 0.6, 3, and 15 mM. On day 7, 2 μl samples of the FC solutions or pure methanol for the control were added to the cultures in 2 ml of media. FIGS. 5A to 5D show there is no appreciable change in the morphology of chondrocytes treated with FC101 for seven days. Note that there is little difference between the control cells (5A) and those treated with FC101 (B: 0.6 μM; C: 3 μM; D: 15 μM FC101).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12].[CH2:14](Br)[CH3:15].C(=O)([O-])[O-].[Li+].[Li+]>CN(C=O)C>[CH2:14]([O:12][C:11](=[O:13])[CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][OH:1])[CH3:15]
Reactant: O=C(O)CCCCCCCCCO
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCCCCCCCO
Reaction time: 6 h
Yield: 27.8 %

Procedure:
A mixture of 10-hydroxydecanoic acid (0.25 g, 1.33 mmol; 11-hydroxyundecanoic acid for compound 881 and 12-hydroxydodecanoic acid for compound 882), ethyl bromide (0.16 g, 1.46 mmol), and lithium carbonate (0.11 g, 1.46 mmol) in DMF (25 mL) was stirred at 70 C for 6 h. Then the product was extracted with ether (30 mL), and the ether solution was washed with 1 N NaOH aqueous solution (20 mL) and water (30 mL), dried over Na2SO4, and concentrated. The residue was purified by column chromatography on silica gel eluting with hexane and ethyl acetate (3:1) to give 10-hydroxydecanoic acid ethyl ester (80 mg, 28%). This alcohol was coupled with 4-(3-adamantan-1-yl-ureido)butyric acid 822 by using EDCI/DMAP coupling reagent to give 880 (0.11 g, 60%) as a solid: 1H NMR (CDCl3) 1.24-1.32 (13H, m), 1.62-1.68 (10H, m), 1.80 (2H, quint, J=6.9 Hz), 1.94-1.97 (6H, m), 2.05-2.07 (3H, m), 2.28 (2H, t, J=6.9 Hz), 2.36 (2H, t, J=6.9 Hz), 3.16 (2H, q, J=6.9 Hz), 4.05-4.14 (5H, m), 4.25 (1H, s); LC-MS (ESI) m/z calcd for C27H46N2O5 [M+H]+ 479.34, found [M+H]+ 479.29; mp 60-61 C. Anal. Calcd for C27H46N2O5: C, 67.75; H, 9.69; N, 5.85. Found: C, 68.33; H, 9.92; N, 5.97.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9](=[O:16])[N:10]([CH2:12][C:13](O)=[O:14])[CH:11]=2)=[CH:4][CH:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[F:47][C:48]([F:60])([F:59])[C:49]1[CH:50]=[C:51]([C:55]([NH2:58])([CH3:57])[CH3:56])[CH:52]=[CH:53][CH:54]=1>CN(C=O)C.O>[Cl:1][C:2]1[S:6][C:5]([C:7]2[N:8]([CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[C:9](=[O:16])[N:10]([CH2:12][C:13]([NH:58][C:55]([CH3:57])([C:51]3[CH:52]=[CH:53][CH:54]=[C:49]([C:48]([F:59])([F:60])[F:47])[CH:50]=3)[CH3:56])=[O:14])[CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O
Reactant: CC(C)(N)c1cccc(C(F)(F)F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(NC(=O)Cn1cc(-c2ccc(Cl)s2)n(Cc2ccccc2F)c1=O)c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h

Procedure:
45 mg (0.123 mmol) of [4-(5-chloro-2-thienyl)-3-(2-fluorobenzyl)-2-oxo-2,3-dihydro-1H-imidazol-1-yl]-acetic acid from Example 238A, 20 mg (0.147 mmol) of HOBt and 31 mg (0.159 mmol) of EDC hydrochloride are placed in 1.5 ml of DMF and stirred for 10 mins. Next, 30 mg (0.147 mmol) of 1-methyl-1-[(3-trifluoromethyl)phenyl]ethylamine from Example 1A are added and the mixture is stirred overnight at RT. For the workup, the reaction mixture is stirred with 2 ml of water and extracted twice with 5 ml of ethyl acetate each time. The combined organic phases are dried over sodium sulphate, filtered and concentrated in vacuo. The crude product is purified by preparative HPLC [Method 10]. 50 mg (74% of theory) of the target compound are thus obtained.
Reaction SMILES: [NH2:1][C:2]1[C:11]([C:12]([NH2:14])=[O:13])=[C:10]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[C:21](OCC)(=O)[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(O)(=O)C>CCOCC>[C:15]1([C:10]2[C:9]3[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=3)[N:3]=[C:2]3[N:1]=[C:21]([C:22]([O:24][CH2:25][CH3:26])=[O:23])[NH:14][C:12](=[O:13])[C:11]=23)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: NC(=O)c1c(N)nc2ccccc2c1-c1ccccc1
Solvent: CCOCC
Solvent: CC(=O)O
Product: CCOC(=O)c1nc2nc3ccccc3c(-c3ccccc3)c2c(=O)[nH]1

Procedure:
A mixture of 2-amino-4-phenylquinoline-3-carboxamide (263 mg., 1.0 millimole), diethyl oxalate (5 ml.) acetic acid (5 ml.) is heated to reflux overnight. It is then cooled, diluted with ether (50 ml.) and the brown solid which forms filtered off. The filtrate is evaporated in vacuo and the oily residue triturated with saturated aqueous sodium bicarbonate solution. The resulting solid (110 mg.) is recovered by filtration and recrystallized from hot ethyl acetate (8 ml.). A small amount of insoluble material is filtered off from the hot solution. Upon cooling, the title product separates as crystals (25 mg.). M.P. = 255° C. (dec.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C:15]([CH:16]=1)=[C:14]1[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]1)=[N:8][C:7]=2[CH3:17].[BH4-].[Na+].FC(F)(F)C(O)=O.C1C=CC2C3C=CC=CC=3NCC=2C=1.C(N(CC)CC)C.[CH3:48][O:49][C:50]1[CH:55]=[CH:54][C:53]([S:56](Cl)(=[O:58])=[O:57])=[CH:52][CH:51]=1>O1CCCC1.ClCCl>[CH:4]1[CH:3]=[CH:16][C:15]2[C:14]3[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=3[NH:8][CH2:7][C:6]=2[CH:5]=1.[CH3:1][O:2][C:3]1[CH:16]=[C:15]2[C:6]([CH:7]([CH3:17])[N:8]([S:56]([C:53]3[CH:52]=[CH:51][C:50]([O:49][CH3:48])=[CH:55][CH:54]=3)(=[O:58])=[O:57])[C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:14]=32)=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(C)nc3ccccc3c2c1
Agent: [BH4-]
Agent: [Na+]
Agent: c1ccc2c(c1)CNc1ccccc1-2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2c3ccccc3-c3cc(OC)ccc3C2C)cc1

Procedure:
The intermediate dihydrophenanthridine was prepared from 9-methoxy-6-methylphenanthridine (0.7 g, 3.1 mmol) by treatment with sodium borohydride (0.48 g, 12.6 mmol) and trifluoroacetic acid (0.5 mL, 6.3 mmol) in tetrahydrofuran (35 mL). In a separate, second step, the dihydrophenanthridine was treated with triethylamine (1.0 mL, 7.5 mmol) and 4-methoxybenzenesulfonyl chloride (0.77 g, 3.7 mmol, 2 equivalents) in dichloromethane (10 mL) according to the procedure and in the same manner as described in Example 32, Method A, Step d. The crude product was purified by flash column chromatography on silica gel, eluting with a mixture of ethyl acetate-hexane (1:9 to 1:4 gradient), to yield 9-methoxy-5-[(4-methoxyphenyl)sulfonyl]-6-methyl-5,6-dihydrophenanthridine as a homogeneous, white solid (0.45 g, 61% from the dihydrophenanthridine), m.p. 129-130° C.;
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][C:8](=O)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH2:12]([O:19][C:20]([NH:22][CH:23](P(OC)(OC)=O)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)C(N(C)C)=N>CCOC(C)=O>[CH2:12]([O:19][C:20]([NH:22][C:23](=[C:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)[C:24]([O:26][CH3:27])=[O:25])=[O:21])[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: CCOC(C)=O
Product: COC(=O)C(NC(=O)OCc1ccccc1)=C1CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 72 h
Yield: 26.8 %

Procedure:
A solution of 1,4-dioxaspiro[4.5]decan-8-one (15 g, 96 mmol) in EtOAc (150 mL) was added to a solution of methyl 2-(benzyloxycarbonylamino)-2-(dimethoxyphosphoryl)acetate (21.21 g, 64.0 mmol) in 1,1,3,3-tetramethylguanidine (10.45 mL, 83 mmol) and EtOAc (150 mL). The resulting solution was the stirred at ambient temperature for 72 h and then it was diluted with EtOAc (25 mL). The organic layer was washed with 1N HCl (75 mL), H2O (100 mL) and brine (100 mL), dried (MgSO4), filtered and concentrated. The residue was purified via BIOTAGE® (5% to 25% EtOAc/Hexanes; 300 g column). The combined fractions containing the product were then concentrated under vacuum and the residue was re-crystallized from hexanes/EtOAc to give white crystals that corresponded to methyl 2-(benzyloxycarbonylamino)-2-(1,4-dioxaspiro[4.5]decan-8-ylidene)acetate (6.2 g) 1H NMR (400 MHz, CDCl3-d) δ ppm 7.30-7.44 (5 H, m), 6.02 (1 H, br. s.), 5.15 (2 H, s), 3.97 (4 H, s), 3.76 (3 H, br. s.), 2.84-2.92 (2 H, m), 2.47 (2 H, t, J=6.40 Hz), 1.74-1.83 (4 H, m). LC (Cond. OL1): Rt=2.89 min. LC/MS: Anal. Calcd. for [M+Na]+ C19H23NNaO6: 745.21; found: 745.47.
Reaction SMILES: [CH:1]1([B-](F)(F)F)[CH2:3][CH2:2]1.[K+].Cl[C:10]1[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=1.C([O-])([O-])=O.[Cs+].[Cs+].C(P(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2)CCC>C(Cl)Cl.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH:1]1([C:10]2[CH:15]=[C:14]([CH3:16])[C:13]([N+:17]([O-:19])=[O:18])=[CH:12][N:11]=2)[CH2:3][CH2:2]1
Reactant: F[B-](F)(F)C1CC1
Reactant: Cc1cc(Cl)ncc1[N+](=O)[O-]
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CCCCP(C12CC3CC(CC(C3)C1)C2)C12CC3CC(CC(C3)C1)C2
Solvent: ClCCl
Product: Cc1cc(C2CC2)ncc1[N+](=O)[O-]
Temperature: 100 °C

Procedure:
Potassium cyclopropyltrifluoroborate (857 mg, 5.79 mmol), 2-chloro-4-methyl-5-nitropyridine (500 mg, 2.90 mmol), Pd(OAc)2 (26 mg, 0.12 mmol), Cs2CO3 (2.83 g, 8.69 mmol), and n-butyl-di-adamantylphosphine (62 mg, 0.17 mmol) were charged into a capped vial. The vial was purged with argon and then sealed with a septum cap. Toluene/H2O 10:1 (11 mL) was added by syringe and the mixture was heated at 100° C. for 16 h. More potassium cyclopropyltrifluoroborate (857 mg, 5.79 mmol) was added to the mixture which was further heated at 100° C. for 72 h. The mixture was diluted with CH2Cl2 and filtered through a pad of Celite. The filtrate was dried (Phase separator) and concentrated under reduced pressure. The residue was purified by preparative HPLC (Waters Sunfire, C18-ODB, 5 μm, 30×100 mm, flow: 40 mL/min, eluent: 5-100% CH3CN/H2O/30 min, 100% CH3CN/3 min, CH3CN and H2O containing 0.1% TFA). MS (LC-MS): 179 [M+H]+, tR (HPLC conditions c): 4.26 min.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:6][N:7]1[C:16](=[O:17])[C:15]2[C:10](=[CH:11][CH:12]=[C:13](I)[CH:14]=2)[N:9]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)[C:8]1=[O:25].C([Sn](CCCC)(CCCC)[C:36]([O:38]CC)=[CH2:37])CCC>C1(C)C=CC=CC=1.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>[C:36]([C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH:19]1[CH2:20][CH2:21][O:22][CH2:23][CH2:24]1)[C:8](=[O:25])[N:7]([CH2:6][C:5]1[CH:26]=[CH:27][C:28]([O:29][CH3:30])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:16]2=[O:17])(=[O:38])[CH3:37]
Reactant: COc1ccc(Cn2c(=O)c3cc(I)ccc3n(C3CCOCC3)c2=O)cc1OC
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(Cn2c(=O)c3cc(C(C)=O)ccc3n(C3CCOCC3)c2=O)cc1OC
Temperature: 130 °C
Reaction time: 48 h

Procedure:
A mixture of 1 g of 3-(3,4-dimethoxybenzyl)-6-iodo-1-(tetrahydro-2H-pyran-4-yl)-quinazoline-2,4(1H,3H)-dione, 1.3 ml of tributyl(1-ethoxyvinyl)tin and 0.04 g of Pd(PPh3)4 in 20 ml of toluene is heated for 1 hour at 130° C. and then stirred for 48 hours at room temperature. The solvent is evaporated off under reduced pressure. The residue is taken up in EtOAc and washed four times with 4N HCl and then with water. The organic phase is dried over Na2SO4, filtered and evaporated under reduced pressure. The residue is chromatographed on silica gel, eluting with a DCM/EtOAc mixture from (80/20, v/v) to give 0.84 g of the expected product.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([OH:14])=[CH:13][C:8]=2[S:7][CH:6]=1.[CH3:17][C:18]1[C:23]([CH2:24]O)=[CH:22][CH:21]=[C:20]([C:26]([F:29])([F:28])[F:27])[N:19]=1.C(P(CCCC)CCCC)CCC.C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1COCC1>[CH3:1][O:2][C:3](=[O:16])[CH2:4][C:5]1[C:9]2[C:10]([CH3:15])=[CH:11][C:12]([O:14][CH2:24][C:23]3[C:18]([CH3:17])=[N:19][C:20]([C:26]([F:29])([F:27])[F:28])=[CH:21][CH:22]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: Cc1nc(C(F)(F)F)ccc1CO
Reactant: COC(=O)Cc1csc2cc(O)cc(C)c12
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: COC(=O)Cc1csc2cc(OCc3ccc(C(F)(F)F)nc3C)cc(C)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.6 %

Procedure:
To a mixture of methyl(6-hydroxy-4-methyl-1-benzothiophen-3-yl)acetate (150 mg) and THF (dry) (5 mL) were added (2-methyl-6-(trifluoromethyl)pyridin-3-yl)methanol (133 mg), tri-n-butylphosphine (0.204 mL) and ADDP (192 mg) at room temperature. The mixture was stirred at room temperature for 4 h. The insoluble material was removed by filtration, and the filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (238 mg).
Reaction SMILES: C(N[C:5]1[C:14]2[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=2)[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[C:7]([C:23]#[N:24])[N:6]=1)C=C.[OH:25][C@H:26]1[C@H:30]([OH:31])[CH2:29][NH:28][CH2:27]1>>[OH:25][C@H:26]1[C@H:30]([OH:31])[CH2:29][N:28]([C:5]2[C:14]3[C:9](=[CH:10][C:11]([O:15][CH3:16])=[CH:12][CH:13]=3)[C:8]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[C:7]([C:23]#[N:24])[N:6]=2)[CH2:27]1
Reactant: C=CCNc1nc(C#N)c(-c2ccccc2)c2cc(OC)ccc12
Reactant: O[C@@H]1CNC[C@H]1O
Product: COc1ccc2c(N3C[C@@H](O)[C@H](O)C3)nc(C#N)c(-c3ccccc3)c2c1

Procedure:
Following the procedure for 1-(allylamino)-6-methoxy-4-phenylisoquinoline-3-carbonitrile, using (3R,4R)-3,4-dihydroxypyrrolidine in place of allylamine, the title compound was synthesized.