Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([Li])CCC.CC1(C)CCCC(C)(C)N1.[F:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[C:23]1[C:24]([C:29]#[N:30])=[CH:25][CH:26]=[CH:27][CH:28]=1.[B:31](OC)([O:34]C)[O:32]C.Cl>C1COCC1>[C:29]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[C:18]1[CH:19]=[CH:20][CH:21]=[C:22]([B:31]([OH:34])[OH:32])[C:17]=1[F:16])#[N:30]
Reactant: COB(OC)OC
Reactant: N#Cc1ccccc1-c1ccccc1F
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccccc1-c1cccc(B(O)O)c1F
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 67 %

Procedure:
A cooled (−78° C.) solution of n-butyllithium (11.7 ml of a 2.5 M solution in hexanes, 29.1 mmol) in THF (100 ml) was treated with 2,2,6,6-tetramethylpiperidine (5.16 ml) and stirring at −78° C. was continued for 15 min. The reaction was then treated with a cooled (0° C.) solution of 2′-fluorobiphenyl-2-carbonitrile (5.50 g) in THF (15 ml) added dropwise over 10 min. This mixture was stirred at −78° C. for 2 h and then treated with trimethyl borate (6.30 ml) added dropwise over 5 min. The reaction was stirred at −78° C. for 10 min then allowed to warm to ambient temperature. 2 N Hydrochloric acid (5 ml) was added and the mixture evaporated to dryness. The residue was stirred with 2 N hydrochloric acid (95 ml) for 30 min and then extracted with diethyl ether (2×100 ml). The organics were combined, extracted with 2 N sodium hydroxide (100 ml) and the organics discarded. The aqueous was cooled to 0° C. and made just acidic (pH 6) with 36% hydrochloric acid. After stirring at 0° C. for 1 h the resulting solid was collected by filtration and dried. Crystallisation from diethyl ether/isohexane afforded 4.50 g (67%) of the title compound as a yellow solid: 1H NMR (360 MHz, CDCl3) δ 5.23 (1H, s), 5.25 (1H, s), 7.33 (1H, m), 7.42-7.56 (3H, m), 7.65 (1H, m), 7.77 (1H, m), 7.93 (1H, m).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[CH:21]=2)[CH2:3][CH2:2]1.[I:26]N1C(=O)CCC1=O>C(#N)C.O>[CH:1]1([CH2:4][O:5][C:6]2[C:11]([CH2:12][CH3:13])=[CH:10][CH:9]=[CH:8][C:7]=2/[CH:14]=[CH:15]/[C:16]2[N:17]=[C:18]3[S:25][CH:24]=[CH:23][N:19]3[C:20](=[O:22])[C:21]=2[I:26])[CH2:2][CH2:3]1
Reactant: O=C1CCC(=O)N1I
Reactant: CCc1cccc(/C=C/c2cc(=O)n3ccsc3n2)c1OCC1CC1
Solvent: CC#N
Solvent: O
Product: CCc1cccc(/C=C/c2nc3sccn3c(=O)c2I)c1OCC1CC1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
To a solution of Step 3 intermediate (3.89 g, 10.72 mmol) was added N-iodosuccinimide (2.69 g, 11.79 mmol) in acetonitrile at room temperature. The reaction temperature was then raised to 60° C. and stirred for 4 h. The reaction mixture was then cooled to room temperature, diluted with water and stirred for 20 min. The filtered solid was washed with water and dried to afford 5.19 g of the desired compound; 1H NMR (300 MHz, CDCl3) δ 0.32-0.33 (m, 2H), 0.54-0.56 (d, J=7.2 Hz, 2H), 1.22 (br s, 1H), 3.77-3.81 (m, 5H), 7.06-7.14 (m, 2H), 7.27-7.29 (d, J=7.2 Hz, 1H), 7.49-7.52 (m, 1H), 7.57 (s, 1H), 7.96 (d, J=3.9 Hz, 1H), 8.18 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 481.45 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][NH:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:22][CH:21]=3)[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[CH3:35][S:36]([CH2:39][C:40](O)=[O:41])(=[O:38])=[O:37].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:31][CH2:32][CH2:33][CH3:34])[N:14]([CH2:15][CH2:16][CH2:17][N:18]([CH2:19][C:20]3[CH:21]=[CH:22][C:23]([CH2:26][C:27]([O:29][CH3:30])=[O:28])=[CH:24][CH:25]=3)[C:40](=[O:41])[CH2:39][S:36]([CH3:35])(=[O:38])=[O:37])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCCCc1nc2c(N)nc3ccccc3c2n1CCCNCc1ccc(CC(=O)OC)cc1
Reactant: CS(=O)(=O)CC(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CCCCc1nc2c(N)nc3ccccc3c2n1CCCN(Cc1ccc(CC(=O)OC)cc1)C(=O)CS(C)(=O)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.1 %

Procedure:
To a solution of the product from example 1 (221 mg) in DCM (10 mL) was added 2-(methylsulfonyl)acetic acid (66.4 mg) followed by TEA (0.201 mL) and HATU (201 mg). The reaction mixture was stirred at rt for 16 h then the solvents were evaporated. The crude product was purified by RPHPLC to afford the title compound (120 mg) as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH:10]C(=O)OC(C)(C)C)=[CH:7][C:6]=1[C:20]([F:23])([F:22])[F:21])(=[O:4])=[O:3].[ClH:24]>C(Cl)Cl.CCOCC>[ClH:24].[CH3:1][S:2]([C:5]1[CH:19]=[CH:18][C:8]([CH2:9][NH2:10])=[CH:7][C:6]=1[C:20]([F:21])([F:22])[F:23])(=[O:4])=[O:3]
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(C)(=O)=O)c(C(F)(F)F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCOCC
Product: CS(=O)(=O)c1ccc(CN)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
tert-Butyl 4-(methylsulfonyl)-3-(trifluoromethyl)benzylcarbamate (420 mg, 1.18 mmol) was dissolved in CH2Cl2 (12 ml) and HCl in Et2O (3 ml, 2M) were added. Resulting mixture was stirred at room temperature overnight followed by evaporation to give 4-(methylsulfonyl)-3-(trifluoromethyl)benzylamine hydrochloride as white solids. This material was used in subsequent reactions without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([NH2:7])=[CH:3][N:2]=1.C(N(CC)CC)C.[Cl:15][CH2:16][C:17](Cl)=[O:18]>ClCCl>[Cl:15][CH2:16][C:17]([NH:7][C:4]1[CH:5]=[CH:6][N:1]=[N:2][CH:3]=1)=[O:18]
Reactant: O=C(Cl)CCl
Reactant: Nc1ccnnc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(CCl)Nc1ccnnc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 48 %

Procedure:
A solution of pyridazin-4-ylamine (1.0 g) in dry dichloromethane (10 mL) under nitrogen was cooled to 0° C. in an ice bath. Triethylamine (1.6 mL) was added, followed by slow addition of chloroacetyl chloride (0.92 mL). On completion of the addition the ice bath was removed and the reaction mixture was allowed to reach room temperature and stirred for 2 hours. The reaction mixture was diluted with water (25 mL) and dichloromethane (30 mL) A solid was filtered off and washed with pentane, water and more pentane to give the sub-titled compound (0.87 g, 48%) as a brown solid.
Reaction SMILES: [Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11](=O)[NH:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12.ClC1SC=C2C(Cl)=NC3C=CC=CC=3OC=12.[CH3:33][N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1.[C:40]([O-:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([O-:45])=[O:44]>>[C:40]([OH:47])(=[O:46])/[CH:41]=[CH:42]/[C:43]([OH:45])=[O:44].[Cl:1][C:2]1[S:3][CH:4]=[C:5]2[C:11]([N:37]3[CH2:38][CH2:39][N:34]([CH3:33])[CH2:35][CH2:36]3)=[N:10][C:9]3[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=3[O:7][C:6]=12
Reactant: O=C1Nc2ccccc2Oc2c1csc2Cl
Reactant: O=C([O-])/C=C/C(=O)[O-]
Reactant: CN1CCNCC1
Agent: ClC1=Nc2ccccc2Oc2c1csc2Cl
Product: CN1CCN(C2=Nc3ccccc3Oc3c2csc3Cl)CC1
Product: O=C(O)/C=C/C(=O)O

Procedure:
A 4.0 g. portion of 3-chloro-thieno[3,4-b][1,5]benzoxazepin-10(9H)-one is converted to 3,10-dichloro-thieno[3,4-b][1,5]benzoxazepine as described in Example 12. This compound is then reacted with N-methylpiperazine giving the base compound as a foam which is further converted to the fumarate, m.p. 150°-151° C.
Reaction SMILES: [H-].[Na+].[NH:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[CH:14]=[CH:13][C:12]3[CH:21]=[CH:22][CH:23]=[CH:24][C:11]2=3)[CH2:4]1.[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28]Br.O>CN(C)C=O>[CH3:25][C:26]([CH3:30])=[CH:27][CH2:28][N:3]1[CH2:8][CH2:7][O:6][CH:5]([CH2:9][N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[CH:13]=[CH:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=3)[CH2:4]1
Reactant: CC(C)=CCBr
Reactant: C1=Cc2ccccc2N(CC2CNCCO2)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)=CCN1CCOC(CN2c3ccccc3C=Cc3ccccc32)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (0.05 g) in dimethylformamide was added a solution of 5-(2-morpholinylmethyl)-5H-dibenz[b,f]azepine (0.2 g) in dimethylformamide under ice cooling, and the resulting mixture was stirred at room temperature for 30 minutes. To the mixture was added a solution of 3,3-dimethylallyl bromide (0.12 g) in dimethylformamide, and the reaction mixture was stirred at room temperature for 3 hours, cooled, admixed with water and extracted with benzene. The benzene extract was washed with water, dried over anhydrous sodium sulfate and evaporated to afford 5-{4-(3,3-dimethylallyl)-2-morpholinylmethyl}-5H-dibenz[b,f]azepine. M.P. 99°-100° C.
Reaction SMILES: CS(O[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[S:16][C:17]3[C:18]([N:23]=2)=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:10][CH:9]=1)(=O)=O.[C:24]([N:27]1[CH2:32][C@@H:31]2[CH2:33][C@H:28]1[CH2:29][NH:30]2)(=[O:26])C.C([O-])([O-])=O.[K+].[K+].CC#[N:42]>>[S:16]1[C:17]2[C:18](=[N:19][CH:20]=[CH:21][CH:22]=2)[N:23]=[C:15]1[O:14][C:11]1[CH:12]=[CH:13][C:8]([CH2:7][CH2:6][N:30]2[CH2:29][C@@H:28]3[CH2:33][C@H:31]2[CH2:32][N:27]3[C:24]([NH2:42])=[O:26])=[CH:9][CH:10]=1
Reactant: CC#N
Reactant: CC(=O)N1C[C@@H]2C[C@H]1CN2
Reactant: CS(=O)(=O)OCCc1ccc(Oc2nc3ncccc3s2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: NC(=O)N1C[C@@H]2C[C@H]1CN2CCc1ccc(Oc2nc3ncccc3s2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 16 %

Procedure:
To a solution of 2-[4-([1,3]thiazolo[4,5-b]pyridin-2-yloxy)phenyl]ethyl methanesulfonate (100 mg, 0.29 mmol, 1.0 equiv.) and (1 S,4S)-2-acetyl-2,5-diazabicyclo[2.2.1]heptane (48 mg, 0.34 mmol, 1.2 equiv.) in CH3CN (3 mL) was added K2CO3 (39 mg, 0.29 mmol, 1.0 equiv.). The solution was stirred at 80° C. for 16 h and then cooled to rt. Purification by preparative reverse phase HPLC produced a white solid (16%). 1H NMR (500 MHz, CDCl3): 8.57 (dd, J=4.8, 1.7, 1H), 8.03 (dd, J=7.9, 1.7, 1H), 7.36-7.28 (m, 4H), 7.22 (dd, J=7.9, 4.8, 1H), 4.32 (s, 2H), 3.61 (s, 1H), 3.23 (dd, J=8.8, 2.1, 1H), 3.02 (dd, J=9.5, 2.0, 1H), 3.53-3.46 (m, 1H), 2.90-2.77 (m, 4H), 2.73 (d, J=9.4, 1H), 1.92 (d, J=9.6, 1H), 1.77 (d, J=9.3, 1H), 1.62 (s, 1H). MS (ESI): mass calcd. for C20H21N6O2S, 395.14; m/z found, 396.1 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[CH:6][CH:7]=1.[CH:9]12[CH2:14][CH:13]1[C:12](=[O:15])[O:11][C:10]2=O.C(N1C=CN=C1)(N1C=CN=C1)=O>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([N:8]2[C:10](=[O:11])[CH:9]3[CH:13]([CH2:14]3)[C:12]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: Nc1cccc(Br)c1
Reactant: O=C1OC(=O)C2CC12
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Product: O=C1C2CC2C(=O)N1c1cccc(Br)c1
Temperature: 50 °C
Reaction time: 3 h
Yield: 98.6 %

Procedure:
3-Bromophenylamine (2.78 g, 16.2 mmol) and 3-oxabicyclo[3.1.0]hexane-2,4-dione (2.0 g, 17.8 mmol) were suspended in 90 mL dichloromethane. The reaction was stirred at 50° C. for 3 h. The reaction was cooled to room temperature and 1,1′-carbonyldiimidazole (3.14 g, 19.4 mmol) was added in portions. The reaction was heated again to 50° C. and stirred overnight then cooled to room temperature and the solvent was evaporated. The residue was redissolved in 90 mL 1,2-dichloroethane and additional 1,1′-carbonyldiimidazole (1.13 g, 7.0 mmol) was added. The reaction mixture was heated at reflux for 2.5 h then cooled to room temperature. The solvent was evaporated and the product was crystallized from isopropyl alcohol to give 4.25 g (99%) of 3-(3-bromo-phenyl)-3-aza-bicyclo[3.1.0]hexane-2,4-dione as a white solid.
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10]3[S:11][CH:12]=[C:13]([C:14]([OH:16])=[O:15])[C:9]=3[C:8](=[O:17])[N:7]([CH3:18])[C:6]2=[O:19])[CH2:3][CH2:2]1.C([N-]C(C)C)(C)C.[Li+].[F:28][C:29]([F:39])([F:38])[C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH:32]=O.Cl>O1CCCC1>[CH3:36][CH2:37][CH2:30][CH:31]([CH3:34])[CH3:32].[CH:1]1([CH2:4][N:5]2[C:10]3[S:11][C:12]([CH2:32][C:31]4[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=4[C:29]([F:28])([F:38])[F:39])=[C:13]([C:14]([OH:16])=[O:15])[C:9]=3[C:8](=[O:17])[N:7]([CH3:18])[C:6]2=[O:19])[CH2:3][CH2:2]1
Reactant: O=Cc1ccccc1C(F)(F)F
Reactant: Cn1c(=O)c2c(C(=O)O)csc2n(CC2CC2)c1=O
Agent: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC(C)C
Product: Cn1c(=O)c2c(C(=O)O)c(Cc3ccccc3C(F)(F)F)sc2n(CC2CC2)c1=O
Temperature: 25 °C
Reaction time: 72 h

Procedure:
1-(Cyclopropylmethyl)-1,2,3,4-tetrahydro-3-methyl-2,4-dioxo-thieno[2,3-d]pyrimidine-5-carboxylic acid (6.8 g) was suspended in tetrahydrofuran (100 ml) and cooled to −78° C. to which lithium diisopropylamide (63 ml, 1M) was added. After complete addition the solution was left for 30 min before 2-(trifluoromethyl)-benzaldehyde, (7.4 mls) was added neat. After 1 h HCl(2M in water) was added and the reaction allowed to warm to room temperature. The reaction was concentrated in vacuo and partitioned between ethyl acetate and HCl (2M in water). The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo and redissolved in diethyl ether, then washed with half saturated sodium hydrogen bicarbonate. The aqueous phase was collected and the diethyl ethyl was washed a seconded time with half saturated sodium hydrogen bicarbonate. The aqueous extracts were combined, acidified with HCl (conc.) and extracted with ethyl acetate. The organic phase was collected, dried over magnesium sulfate, filtered and concentrated in vacuo to brown gum. The gum was redissolved in trifluoroacetic acid (10 mls) and triethyl silane(5 mls) and stirred at room temperature for 72 hrs. The reaction was then concentrated in vacuo, and partioned between dichloromethane and water. The organics were collected, dried over magnesium sulfate, filtered and concentrated in vacuo before being purified by chromatography eluting with 20:1 dichloromethane:acetic acid and recrstallisation from ethyl acetate and isohexane, to yield 3.63 g of the subtitle compound.
Reaction SMILES: CO[CH2:3][CH2:4]OC.C(O)C.[ClH:10].[C:11]([O:15][CH2:16][CH3:17])(=[O:14])[CH:12]=[O:13]>O>[Cl:10][CH:12]([O:13][CH2:3][CH3:4])[C:11]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: COCCOC
Reactant: CCOC(=O)C=O
Reactant: Cl
Solvent: O
Solvent: CCO
Product: CCOC(=O)C(Cl)OCC

Procedure:
Into a mixture of 10 ml. of 1,2-dimethoxyethane and 5.8 ml. of ethanol is passed 3.65 g. hydrogen chloride gas with cooling. Then 10.2 g. of ethyl glyoxylate is added and after 24 hours at 25° C., 200 ml. of water and ice is added. The mixture is then extracted several times with ether and the extracts dried over anhydrous sodium sulfate. After evaporation of the extracts to an oil, the ethyl α-chloro-α-ethoxy-acetate so formed is added to a stirred mixture of 35.0 g. of sodium 4-(hexadecylamino)benzoate in 125 ml. of hexamethylphosphoramide. After 24 hours at 20° C., the product is obtained as white crystals by careful addition of water.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[S:22][CH:21]=[CH:20][N:5]2[C:6](=[O:19])[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][CH:9]=1.[CH:23]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2[CH:31]=O)[CH2:26][CH2:25][CH2:24]1.[O-]CC.[Na+]>C(O)C>[CH:23]1([CH2:27][O:28][C:29]2[C:36]([O:37][CH3:38])=[CH:35][CH:34]=[CH:33][C:30]=2/[CH:31]=[CH:1]/[C:2]2[N:3]=[C:4]3[S:22][CH:21]=[CH:20][N:5]3[C:6](=[O:19])[C:7]=2[C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]([F:17])([F:18])[F:16])=[CH:10][CH:9]=2)[CH2:24][CH2:25][CH2:26]1
Reactant: COc1cccc(C=O)c1OCC1CCC1
Reactant: Cc1nc2sccn2c(=O)c1-c1ccc(OC(F)(F)F)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc(/C=C/c2nc3sccn3c(=O)c2-c2ccc(OC(F)(F)F)cc2)c1OCC1CCC1
Yield: 54.6 %

Procedure:
The title compound was prepared by condensation of Intermediate 15 (350 mg, 1.012 mmol) with 2-cyclobutylmethoxy-3-methoxybenzaldehyde (330 mg, 1.501 mmol) in the presence of sodium ethoxide (146 mg, 2.147 mmol) in ethanol (15 ml) according to the procedure described in Example 24 to give 292 mg of the desired product as an off-white solid; 1H NMR (300 MHz, DMSO-d6) δ 1.80-1.90 (m, 5H), 2.00-2.08 (m, 2H), 3.77 (s, 3H), 3.83 (d, J=6.9 Hz, 2H), 6.80-6.87 (m, 2H), 6.91-6.99 (m, 2H), 7.40-7.46 (m, 4H), 7.51 (d, J=4.8 Hz, 1H), 7.99 (d, J=3.6 Hz, 1H), 8.12 (d, J=15.6 Hz, 1H); ESI-MS (m/z) 529.13 (M+H)+.
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH3:8][C:9]1[C:15]2C=CC(O)=[CH:19][C:14]=2[O:13][C:11](=[O:12])[CH:10]=1.[CH3:21][SiH:22]([CH3:24])[Cl:23].C1(C)C=CC=CC=1>O1CCCC1>[Cl:23][Si:22]([CH3:24])([CH3:21])[CH2:3][CH2:2][CH2:1][O:4][C:5]1[CH:19]=[C:14]2[C:15]([C:9]([CH3:8])=[CH:10][C:11](=[O:12])[O:13]2)=[CH:7][CH:6]=1
Reactant: Cc1cc(=O)oc2cc(O)ccc12
Reactant: C=CCOCC=C
Reactant: C[SiH](C)Cl
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: Cc1cc(=O)oc2cc(OCCC[Si](C)(C)Cl)ccc12
Temperature: 140 °C
Reaction time: 15 h

Procedure:
A glass pressure bottle was charged with 21.6 g of the allyl ether of 4-methylumbelliferone, 11 mls of dimethylmonochlorosilane, 25 mls of toluene and 0.1 cc of a 0.1M H2PtCl6 solution in tetrahydrofuran. The mixture was heated to 140 degrees C. at 40 psi for 15 hours. Toluene was removed by rotary evaporation. The title product was recovered in a yield of 27 g at greater than 70% purity as determined by proton NMR. A broad UV absorption spectrum was observed with maxima at 319.5, 281, 248 and 223 nanometers (nm). The extinction coefficient at 319.5 was greater than 20,000. Fluorescence spectra obtained after excitation at 384 nm gave maxima at 390 (v.s.), 421, 521, and 585 nm.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=1.[F:10][C:11]1[CH:16]=[CH:15][C:14](B(O)O)=[CH:13][C:12]=1[C:20]([F:23])([F:22])[F:21].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[F:10][C:11]1[CH:16]=[CH:15][C:14]([C:2]2[N:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][CH:3]=2)=[CH:13][C:12]=1[C:20]([F:21])([F:22])[F:23]
Reactant: O=Cc1cccc(Br)n1
Reactant: OB(O)c1ccc(F)c(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: O=Cc1cccc(-c2ccc(F)c(C(F)(F)F)c2)n1
Temperature: 80 °C
Yield: 90.5 %

Procedure:
To a solution of 6-bromopicolinaldehyde (1.00 g, 5.38 mmol) in dioxane (30 mL) at ambient temperature was added 4-fluoro-3-(trifluoromethyl)phenylboronic acid (1.11 g, 5.38 mmol), 2M cesium carbonate (8.0 mL, 16 mmol) and 1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (0.220 g, 0.269 mmol). The mixture was degassed (3× vacuum/purge N2), then heated at 80° C. overnight. After cooling to room temperature the mixture was concentrated and the residue partitioned between water and CH2Cl2. The organic extract was concentrated and purified by chromatography (10% ethyl acetate:hexanes) to provide 1.31 g (91%) of the title compound. MS (DCI+) m/z 270 (M+H).
Reaction SMILES: [OH-].[NH4+:2].[F:3][C:4]1[CH:9]=[C:8]([Br:10])[C:7]([F:11])=[CH:6][C:5]=1[S:12](Cl)(=[O:14])=[O:13].O>O1CCCC1>[Br:10][C:8]1[C:7]([F:11])=[CH:6][C:5]([S:12]([NH2:2])(=[O:14])=[O:13])=[C:4]([F:3])[CH:9]=1
Reactant: O=S(=O)(Cl)c1cc(F)c(Br)cc1F
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: NS(=O)(=O)c1cc(F)c(Br)cc1F
Reaction time: 0.17 h

Procedure:
Ammonium hydroxide (5 ml) was added to a solution of 2,5-difluoro-4-bromophenylsulfonyl chloride (4.3 g) in tetrahydrofuran (20 ml) at room temperature (CARE:exotherm) and stirred for 10 min. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated and the residue triturated with 20% diethyl ether in isohexane to give the sub-title compound as a solid (4.3 g).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:37])[O:6][C@:7]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@:28]([F:34])([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:35])[CH:24]=[CH:25]2)[CH2:20][CH2:19]3)[CH2:16][C@@H:15]1[CH3:36])[C:8](=[O:14])[CH2:9][O:10]C(=O)C)[CH2:2][CH3:3].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1.CO.CO.O>[CH2:1]([NH:4][C:5](=[O:37])[O:6][C@:7]1([C@:31]2([CH3:32])[C@H:17]([C@H:18]3[C@:28]([F:34])([C@@H:29]([OH:33])[CH2:30]2)[C@:26]2([CH3:27])[C:21](=[CH:22][C:23](=[O:35])[CH:24]=[CH:25]2)[CH2:20][CH2:19]3)[CH2:16][C@@H:15]1[CH3:36])[C:8](=[O:14])[CH2:9][OH:10])[CH2:2][CH3:3]
Reactant: CCCNC(=O)O[C@]1(C(=O)COC(C)=O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CCCNC(=O)O[C@]1(C(=O)CO)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Reaction time: 0.17 h
Yield: 60.2 %

Procedure:
To a solution of (11β,16β)-21-(acetyloxy)-9-fluoro-11-hydroxy-16-methyl-3,20-dioxopregna-1,4-dien-17-yl propylcarbamate (8.5 mg, 0.016 mmol) in 0.3 mL of tetrahydrofuran and 0.1 mL of methanol was added 0.030 mL of a 0.1M solution of potassium carbonate in methanol/water (9:1). After 10 minutes at room temperature, the solution was partitioned between ethyl acetate and water and the organic layer was washed with water (twice) and brine and dried over Na2SO4. The solution was filtered and evaporated in vacuo to give an oil which was purified by preparative thin layer chromatography on silica gel, eluting with ethyl acetate/hexane/dichloromethane/methanol (3:3:3:1), to yield 4.6 mg of the title compound as a semi-solid.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH:4]([C:7]#N)[CH2:3][CH2:2]1.[C:9]1([Mg]Br)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.CC[O:19]CC.Cl>C1COCC1.[Cu]I>[C:9]1([C:7]([CH:4]2[CH2:5][CH2:6][S:1][CH2:2][CH2:3]2)=[O:19])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CCOCC
Reactant: Br[Mg]c1ccccc1
Reactant: N#CC1CCSCC1
Agent: [Cu]I
Agent: Cl
Solvent: C1CCOC1
Product: O=C(c1ccccc1)C1CCSCC1
Temperature: 25 °C

Procedure:
Tetrahydro-2H-thiopyran-4-carbonitrile (2.6 g, 20.5 mmol) and CuI (195 mg, 1 mmol) were diluted in dry THF (200 ml). A 1M solution of phenyl magnesium bromide in THF (41 ml, 41 mmol) was added and the mixture was heated at reflux for 16 hours. After cooling at room temperature, ether was added and the imine was hydrolyzed with a 1 N HCl solution for 10 minutes. The organic phase was separated and treated with a 0.1 N HCl solution for 10 minutes. The organic phase was separated and washed with brine, dried over MgSO4 and evaporated in vacuum. After chromatography on silica gel (CH2Cl2/hexane 30/70), the phenyl(tetrahydro-2H-thiopyran-4-yl)methanone 17 was obtained as a white solid (3 g, 70%).
Reaction SMILES: [OH:1][CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[C:3]([OH:5])=[O:4].Br[CH:11]([CH3:15])[C:12](Br)=[O:13].C(N(CC)CC)C>CC(C)=O>[CH3:15][CH:11]1[O:4][C:3](=[O:5])[CH:2]([CH2:6][CH2:7][CH2:8][CH3:9])[O:1][C:12]1=[O:13]
Reactant: CCCCC(O)C(=O)O
Reactant: CC(Br)C(=O)Br
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Product: CCCCC1OC(=O)C(C)OC1=O
Temperature: 60 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
2.5 g 2-hydroxyhexanoic acid (18.9 mmol) and 2.1 mL 2-bromopropionyl bromide (19.7 mmol) were stirred at 75° C. under nitrogen for 12 h. 150 mL acetone and 5.3 mL anhydrous triethylamine (38 mmol) were added to the mixture and the solution was stirred for 3 h at 60° C. After filtration of the triethylammonium bromide salts, acetone was distilled off and the resulting mixture was dissolved in 300 mL ethyl acetate:hexane mixture (1:2). After filtration over silica gel the solvents were distilled off, and the remaining crude product was recrystallized from hexane. 1H NMR (500 MHz, CDCl3): δ 5.05 (q, 1H), 4.90 (dd, 1H), 1.9-2.15 (br m, 2H), 1.68 (d), 1.65 (d), (3H, of 2 diastereoisomers), 1.3-1.6 (br m, 4H), 0.93 (t, 3H). 13C NMR (500 MHz, CDCl3): δ 167.54, 166.93, 166.25, 165.85, 75.79, 72.50, 72.24, 31.61, 29.70, 26.69, 26.42, 22.19, 21.97, 17.52, 15.81, 13.72, 13.66. ELEM. ANAL. Calcd. for C9H14O4: C, 58.06; H, 7.53. Found: C, 57.62; H, 7.60. Yield: 40%.
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C(O[CH:16]=[C:17]([C:23]([CH3:25])=O)[C:18]([O:20]CC)=[O:19])C>>[F:1][C:2]([F:11])([F:12])[C:3]1[CH:4]=[CH:5][C:6]([N:9]2[C:23]([CH3:25])=[C:17]([C:18]([OH:20])=[O:19])[CH:16]=[N:10]2)=[CH:7][CH:8]=1
Reactant: NNc1ccc(C(F)(F)F)cc1
Reactant: CCOC=C(C(C)=O)C(=O)OCC
Product: Cc1c(C(=O)O)cnn1-c1ccc(C(F)(F)F)cc1
Yield: 68.9 %

Procedure:
By the reaction and treatment in the same manner as in Starting Material Synthesis Example 1 using 4-trifluoromethylphenylhydrazine (12.8 g) and ethyl 2-ethoxymethyleneacetoacetate (12.3 g), the title compound (12.3 g) was obtained, melting point: 181° C.