Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([N:8]([C:16]1[S:17][C@H:18]2[O:24][C@H:23]([CH2:25][OH:26])[C@@H:22]([O:27][CH2:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)[C@H:21]([O:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][CH:40]=3)[C@H:19]2[N:20]=1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH3:7]>N1C=CC=CC=1.C(Cl)Cl>[CH3:1][S:2]([O:26][CH2:25][C@H:23]1[O:24][C@H:18]2[C@H:19]([N:20]=[C:16]([N:8]([C:9]([O:10][C:11]([CH3:13])([CH3:14])[CH3:12])=[O:15])[CH2:6][CH3:7])[S:17]2)[C@@H:21]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([O:45][CH3:46])=[CH:43][CH:44]=2)[C@@H:22]1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=1)(=[O:4])=[O:3]
Reactant: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](CO)O[C@@H]2S1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCN(C(=O)OC(C)(C)C)C1=N[C@@H]2[C@@H](OCc3ccc(OC)cc3)[C@H](OCc3ccc(OC)cc3)[C@@H](COS(C)(=O)=O)O[C@@H]2S1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
Methanesulfonyl chloride (0.038 mL, 0.495 mmol) was added in portions to a stirred solution of tert-butyl ethyl(-(3aR,5R,6S,7R,7aR)-5-(hydroxymethyl)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-2-yl)carbamate (0.190 g, 0.323 mmol) in dry pyridine (5 mL) at −20° C. After 3 h, the reaction mixture was diluted with DCM (20 mL) and the DCM extract was washed with satd. NaHCO3, brine, dried over Na2SO4 and concentrated. Residual pyridine was removed by co-evaporation with hexanes. The crude product was purified by silica gel column chromatography (3:7 EtOAc/hexanes) to give (-(3aR,5R,6S,7R,7aR)-2-((tert-butoxycarbonyl)(ethyl)amino)-6,7-bis((4-methoxybenzyl)oxy)-5,6,7,7a-tetrahydro-3aH-pyrano[3,2-d]thiazol-5-yl)methyl methanesulfonate (0.215 g, 99.6%) as a white solid. 1H NMR (400 MHz, CDCl3) δ 7.32 (d, J=8.5 Hz, 2H), 7.17 (d, J=8.5 Hz, 2H), 6.91-6.83 (m, 4H), 6.01 (d, J=6.88 Hz, 1H), 4.66 (d, J=11.6 Hz, 1H), 4.60 (d, J=11.6 Hz, 1H), 4.52 (d, J=11.1 Hz, 1H), 4.42-4.36 (m, 2H), 4.27-4.23 (m, 3H), 3.96-3.84 (m, 2H), 3.8 (s, 3H), 3.79 (s, 3H), 3.55 (m, 2H), 2.98 (s, 3H), 1.52 (s, 9H), 1.20 (t, J=6.9 Hz, 3H).
Reaction SMILES: [C:1]1([N:11]2[C:15]([OH:16])=[CH:14][CH:13]=[N:12]2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.Br[C:18]([CH3:25])([CH3:24])[C:19]([O:21][CH2:22][CH3:23])=[O:20].C(=O)([O-])[O-].[K+].[K+].O>CN(C=O)C>[CH3:24][C:18]([O:16][C:15]1[N:11]([C:1]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[CH:4]=[CH:3][CH:2]=2)[N:12]=[CH:13][CH:14]=1)([CH3:25])[C:19]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: Oc1ccnn1-c1cccc2ccccc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)(C)Oc1ccnn1-c1cccc2ccccc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of 1-(naphthalen-1-yl)-1H-pyrazol-5-ol (250 mg, 1.2 mmol), ethyl bromoisobutyrate (0.2 mL, 1.3 mmol) and potassium carbonate (318 mg, 1.3 mmol) in DMF (3 mL) was stirred at room temperature for 16 hours. Water was then added to the reaction mixture, extracted with ethyl acetate, dried over sodium sulfate and concentrated. Purification by preparative thin layer chromatography (95% dichloromethane/5% methanol) afforded ethyl 2-methyl-2-(1-(naphthalen-1-yl)-1H-pyrazol-5-yloxy)propanoate as a solid.
Reaction SMILES: [CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1[CH2:23]/[CH:24]=[CH:25]/[OH:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2]>[O-2].[O-2].[Mn+4].C(OCC)C>[CH:1]([C:4]1[N:8]2[CH:9]=[CH:10][C:11]3[C:16]([C:7]2=[C:6]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]=1/[CH:23]=[CH:24]/[CH:25]=[O:26])=[CH:15][CH:14]=[CH:13][CH:12]=3)([CH3:3])[CH3:2]
Reactant: CC(C)c1c(C/C=C/O)c(-c2ccccc2)c2c3ccccc3ccn12
Agent: [Mn+4]
Agent: [O-2]
Solvent: CCOCC
Product: CC(C)c1c(/C=C/C=O)c(-c2ccccc2)c2c3ccccc3ccn12
Temperature: 20 °C
Reaction time: 17 h
Yield: 84.6 %

Procedure:
A mixture of activated manganese dioxide (17.4 g), (E)-3-(3-isopropyl1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propen-1-ol (2.14 g) and anhydrous diethyl ether (50 ml) was stirred at 20° C. under an atmosphere of argon for 17 hours. The suspension was then filtered and the filtrate was evaporated to give an orange-red oil. The oil was triturated with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (1:1 v/v). The resulting crystalline solid was collected, washed with a mixture of petroleum ether (b.p. 40°-60° C.) and diethyl ether (1:1 v/v) and dried to give (E)-3-(3-isopropyl-1-phenylpyrrolo[2,1-a]isoquinolin-2-yl)propenal (1.8 g), in the form of a yellow solid, m.p. indistinct, approximately 170° C. [N.M.R. (in CDCl3): 1.6 (6H, d, J=7 Hz), 3.76 (1H, septet, J=7 Hz), 5.72 (1H, dd, J=8 Hz and 16 Hz), 6.75 (1H, d, J=8 Hz), 7.0-7.6 (9H, m), 7.15 (1H, d, J=16 Hz), 7.82 (1H, d, J=8 Hz), 9.43 (1H, d, J=8 Hz); Mass spectrum, m/e=340 (M+H+)]
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12.C(=O)([O-])[O-].[K+].[K+].[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[OH:27].O>CN(C)C=O>[Cl:19][C:20]1[CH:25]=[C:24]([Cl:26])[CH:23]=[CH:22][C:21]=1[O:27][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[C:4]2[CH:10]=[CH:11][S:12][C:3]=12
Reactant: Oc1ccc(Cl)cc1Cl
Reactant: N#Cc1cnc2ccsc2c1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cnc2ccsc2c1Oc1ccc(Cl)cc1Cl
Temperature: 110 °C
Reaction time: 4 h
Yield: 73.8 %

Procedure:
A mixture of 7-chlorothieno[3,2-b]pyridine-6-carbonitrile (200 mg, 1.03 mmol), potassium carbonate (194.9 mg, 1.41 mmol) and 2,4-dichlorophenol (218.3 mg, 1.34 mmol) in 3 mL of N,N-dimethylformamide is stirred at 110° C. for 4 hours and allowed to cool to ambient temperature. The reaction mixture is treated with water and stirred at ambient temperature for 10 minutes. The crude solid is collected by filtration washing with water, dried in vacuo, then purified by flash column chromatography eluting with a gradient of 5% ethyl acetate in hexane to 20% ethyl acetate in hexane to provide 244 mg of 7-[(2,4-dichlorophenoxy)]thieno[3,2-b]pyridine-6-carbonitrile as a white solid, mp 158-160° C.; 1H NMR (DMSO-d6) δ 7.63 (dd, J=6, 2 Hz, 1H), 7.68 (d, J=4 Hz, 1H), 7.74 (d, J=6 Hz, 1H), 7.80 (d, J=2 Hz, 1H), 8.33 (d, J=4 Hz, 1H), 9.03 (s, 1H); MS 320.9, 322.9 (M+H)+.
Reaction SMILES: [CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16](Cl)[N:17]=[C:18]([N:19]3[CH2:24][CH:23]([CH3:25])[O:22][CH:21]([CH3:26])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH2:1]([S:8][C:9]1[C:14]2[N:15]=[C:16]([N:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[N:17]=[C:18]([N:19]3[CH2:24][CH:23]([CH3:25])[O:22][CH:21]([CH3:26])[CH2:20]3)[C:13]=2[N:12]=[CH:11][N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC1CN(c2nc(Cl)nc3c(SCc4ccccc4)ncnc23)CC(C)O1
Reactant: C1CNCCN1
Product: CC1CN(c2nc(N3CCNCC3)nc3c(SCc4ccccc4)ncnc23)CC(C)O1

Procedure:
This compound was prepared analogous to Example 1 from 8-benzylthio-2-chloro-(2,6-dimethyl-morpholino)-pyrimido-[5,4-d]-pyrimidine (m.p.: 85°-90° C.) and piperazine.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([O:9]C)=[O:8])=[C:5]([CH3:11])[CH:4]=[N:3]1.Cl>O1CCOCC1.Cl>[CH3:1][N:2]1[C:6]([C:7]([OH:9])=[O:8])=[C:5]([CH3:11])[CH:4]=[N:3]1
Reactant: COC(=O)c1c(C)cnn1C
Agent: Cl
Solvent: C1COCCO1
Product: Cc1cnn(C)c1C(=O)O
Yield: 84.9 %

Procedure:
Methyl 1,4-dimethyl-1H-pyrazole-5-carboxylate (171 mg) was dissolved in 1,4-dioxane (2 ml). Hydrochloric acid (2 ml) was added and the mixture was heated at reflux for 70 h. One drop of concentrated hydrochloric acid was added and the mixture heated at reflux for 45 h. The solution was left to cool and then the solvent was removed in vacuo. To the residue toluene (15 ml) was added and the solvent was removed in vacuo. The solid was dried in a vacuum oven overnight to give the title compound (132 mg) as a white solid.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[NH:5][C:6]2[CH:7]=[CH:8][NH:9][C:10](=[O:24])[C:11]=2[CH:12]([C:19]2[S:20][CH:21]=[CH:22][CH:23]=2)[C:13]=1[C:14]([O:16][CH2:17][CH3:18])=[O:15].[CH:25](I)([CH3:27])[CH3:26]>CN(C)C=O>[CH:25]([O:24][C:10]1[N:9]=[CH:8][CH:7]=[C:6]2[C:11]=1[CH:12]([C:19]1[S:20][CH:21]=[CH:22][CH:23]=1)[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:4]([CH3:3])[NH:5]2)([CH3:27])[CH3:26]
Reactant: CCOC(=O)C1=C(C)Nc2cc[nH]c(=O)c2C1c1cccs1
Reactant: CC(C)I
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1=C(C)Nc2ccnc(OC(C)C)c2C1c1cccs1
Temperature: 25 °C

Procedure:
2.1 g (70 mMole) sodium hydride (80% in oil) are suspended in 100 ml dry dimethylformamide and, while stirring at ambient temperature, 20 g (63 mMole) ethy (±)-1,4,5,6-tetrahydro-2-methyl-5-oxo-4-(2-thienyl)-1,6-naphthyridine-3-carboxylate are added thereto portionwise. After cessation of the gas evolution, the reaction mixture is further stirred for 30 minutes at ambient temperature. 16 g (94 mMole) isopropyl iodide in 30 ml diemthylformamide are then added thereto. The reaction mixture is stirred for two days at ambient temperature, the solvent is removed in a vacuum and the residue is taken up with water and ethyl acetate. After shaking up, the ethyl acetate phase is separated off and dried over anhydrous magnesium sulphate. After distilling off the solvent, the residue obtained is separated chromatographically on silica gel with toluene/ethyl acetate (3:1 v/v). The fraction with the Rf of 0.3 is isolated and recrystallized from n-hexane. There is obtained ethyl (±)-1,4-dihydro-5-isopropoxy-2-methyl-4-(2-thienyl)-1,6-naphthyridine-3 -carboxylate in the form of colorless crystals; mp 110°-111° C.
Reaction SMILES: C([O:3][C:4]([C:6]1([NH:15][C:16]([C:18]2[CH:23]=[CH:22][N:21]=[CH:20][C:19]=2[N:24]([CH:26]([CH3:28])[CH3:27])[CH3:25])=[O:17])[CH2:14][C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[CH2:7]1)=[O:5])C.O1CCOCC1.CO>O>[CH:26]([N:24]([CH3:25])[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][C:18]=1[C:16]([NH:15][C:6]1([C:4]([OH:5])=[O:3])[CH2:7][C:8]2[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH2:14]1)=[O:17])([CH3:28])[CH3:27]
Reactant: CCOC(=O)C1(NC(=O)c2ccncc2N(C)C(C)C)Cc2ccccc2C1
Solvent: O
Solvent: C1COCCO1
Solvent: CO
Product: CC(C)N(C)c1cnccc1C(=O)NC1(C(=O)O)Cc2ccccc2C1
Reaction time: 96 h
Yield: 88 %

Procedure:
2-{[3-(Isopropyl-methyl-amino)-pyridine-4′-carbonyl]-amino}-indan-2-carboxylic acid ethyl ester 357, 270 mg, 0.71 mmol) is charged with 1,4-dioxane (3 mL) and MeOH (3 mL). A stirring bar is added and stirring is initiated. After dissolution, water (1.5 mL) is added followed by the LiOH monohydrate (75 mg, 1.94 mmol). After 4 days, tlc analysis (silica, 50% EtOAc/heptanes) indicates that the starting material is completely consumed. Amberlyst highly acidic exchange resin (0.5 g) is added to the reaction vial. The reaction is capped and allowed to stir at ambient temperature. After 3 h, the contents of the flask are filtered through a pad of Celite. The solvent is removed from the filtrate. The residue is reconstituted with iPrOH/toluene (20+20 mL) and the solvent is removed. This process is repeated 1 time. Pumping to constant weight provides white solid (0.22 g, 88%).
Reaction SMILES: Br[C:2]1[NH:3][C:4]2[C:9]([C:10]=1C1CCCCC1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=2.O[Li].O.Cl.C1COCC1>CO.C1COCC1.O.O>[NH:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2)[CH:10]=[CH:2]1
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1ccc2cc[nH]c2c1
Temperature: 25 °C

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (117 g, 349 mmol) and LiOH.H2O (26.4 g, 629 mmol) in MeOH/THF/H2O (1:1:1, 1.8 L) was heated at reflux for 3 h. The reaction mixture was cooled in an ice/H20 bath to ˜2° C., neutralized with 1M HCl (˜650 mL) (added at such a rate that temperature did not exceed 5° C.), diluted with H2O (1 L) and stirred while warming to ambient temperature. The precipitates were collected by filtration rinsed with H2O and dried to yield the mono THF solvate of 1H-indole-6-carboxylic acid, 2-bromo-3-cyclohexyl- (135.5 g, 345 mmol, 99%) as a yellow solid, which was used without further purification. 1HNMR (300 MHz, CDCl3) δ 11.01 (br s, 1H), 8.77 (s, 1H), 8.07 (d, J=1.5 Hz, 1H), 7.82 (dd, J=1.5, 8.8 Hz, 1H), 7.72 (d, J=8.8 Hz, 1H), 3.84-3.74 (m, 4H), 2.89 (m, 1H), 1.98-1.72 (m, 11H), 1.50-1.24 (m, 3H). 13CNMR (75 MHz, CDCl3) δ 172.7, 135.5, 130.7, 122.3, 120.9(2), 118.8, 113.3, 111.1, 67.9(2), 37.0, 32.2(2), 27.0(2), 26.1, 25.5(2). LCMS: m/e 320 (M−H)−, ret time 2.21 min, column A, 4 minute gradient.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:10][O:11][C:12](=[O:19])[CH:13]=[C:14]([NH2:18])[O:15][CH2:16][CH3:17]>C(O)(C)C>[CH3:10][O:11][C:12]([C:13]1[CH:4]([C:3]2[CH:6]=[CH:7][CH:8]=[CH:9][C:2]=2[F:1])[CH:13]([C:12]([O:11][CH3:10])=[O:19])[C:14]([O:15][CH2:16][CH3:17])=[N:18][C:14]=1[NH2:18])=[O:19]
Reactant: CCOC(N)=CC(=O)OC
Reactant: O=Cc1ccccc1F
Solvent: CC(C)O
Product: CCOC1=NC(N)=C(C(=O)OC)C(c2ccccc2F)C1C(=O)OC

Procedure:
Heating a solution of 6.3 g of 2-fluorobenzaldehyde and 14.5 g of 3-amino-3-ethoxyacrylic acid methyl ester in 50 ml isopropanol for 8 hours yields 2-amino-4-(2-fluorophenyl)-6-ethoxy-4,5-dihydropyridine-3,5-dicarboxylic acid dimethyl ester of melting point 180°C (isopropanol).
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:19]=[CH:18][C:7]([CH2:8][O:9][CH2:10][C:11]2([NH2:17])[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]2)=[CH:6][CH:5]=1.Cl[C:21]1[C:22]2[CH:29]=[CH:28][NH:27][C:23]=2[N:24]=[CH:25][N:26]=1.C(N(CC)CC)C>C(O)CCC>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([CH2:8][O:9][CH2:10][C:11]2([NH2:17])[CH2:16][CH2:15][N:14]([C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:13][CH2:12]2)=[CH:18][CH:19]=1
Reactant: NC1(COCc2ccc(Cl)cc2)CCNCC1
Reactant: Clc1ncnc2[nH]ccc12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCCCO
Product: NC1(COCc2ccc(Cl)cc2)CCN(c2ncnc3[nH]ccc23)CC1
Temperature: 100 °C
Reaction time: 17 h
Yield: 78.6 %

Procedure:
A degassed mixture of 4-(4-chloro-benzyloxymethyl)-piperidin-4-ylamine dihydrochloride (9.2 mg, 0.028 mmol), 4-chloro-7H-pyrrolo[2,3-d]pyrimidine (5.9 mg, 0.035 mmol), triethylamine (36 uL, 0.2 mmol) and n-butanol (0.35 mL) was stirred at 100° C. for 17 h. The solvents were removed by evaporation. The crude mixture was purified on an SCX-II acid resin, eluting with methanol then 2M ammonia/methanol, and then by preparative TLC eluting with 10% methanol in dichloromethane, to give 4-(4-chloro-benzyloxymethyl)-1-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)-piperidin-4-ylamine (8.2 mg, 0.022 mmol, 78%). LC-MS (LCT2) m/z 372 [M+H+], Rt 3.19 min.
Reaction SMILES: [Cl:1][CH2:2][C:3](=[O:36])[C@:4]1([OH:35])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][O:28]C1CCCCO1>C(O)(=O)C.O>[Cl:1][CH2:2][C:3](=[O:36])[C@:4]1([OH:35])[C@:21]2([CH3:22])[C@H:7]([C@H:8]3[C@H:18]([C@@H:19]([OH:23])[CH2:20]2)[C@:16]2([CH3:17])[C:11](=[CH:12][C:13](=[O:24])[CH:14]=[CH:15]2)[CH2:10][CH2:9]3)[CH2:6][C@H:5]1[O:25][CH2:26][CH2:27][OH:28]
Reactant: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCOC1CCCCO1)[C@]2(O)C(=O)CCl
Solvent: O
Solvent: CC(=O)O
Product: C[C@]12C=CC(=O)C=C1CC[C@@H]1[C@@H]2[C@@H](O)C[C@@]2(C)[C@H]1C[C@@H](OCCO)[C@]2(O)C(=O)CCl

Procedure:
A solution of 21-chloro-11β,17-dihydroxy-16α-[2-(tetrahydropyran-2-yloxy)ethoxy]pregna-1,4-diene-3,20-dione (8.4 mmoles) in 50 ml of acetic acid and 50 ml of water is stirred at room temperature for 6 hours, diluted with cold water, and the resulting solid filtered and dried in vacuo to yield the title compound.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[OH:7][CH:8]1[CH2:11][N:10]([C:12](=O)[C@@H:13]([NH:18][C:19](=O)OC(C)(C)C)[C@@H:14]([CH3:17])[CH2:15][CH3:16])[CH2:9]1.O.[OH-].[Na+]>C1COCC1>[CH3:17][C@@H:14]([CH2:15][CH3:16])[C@H:13]([NH:18][CH3:19])[CH2:12][N:10]1[CH2:9][CH:8]([OH:7])[CH2:11]1
Reactant: CC[C@H](C)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC(O)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC[C@H](C)[C@@H](CN1CC(O)C1)NC
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.9 %

Procedure:
To LAH (1 M solution in THF) (69.8 mL, 69.84 mmol) was added a solution of tert-butyl (2S,3S)-1-(3-hydroxyazetidin-1-yl)-3-methyl-1-oxopentan-2-ylcarbamate (Compound F2.1) (5 g, 17.5 mmol) in anhydrous THF (24 mL) dropwise (1 h) under nitrogen. The reaction mixture was stirred at rt for 1 h and then heated at 60° C. over night. The reaction mixture was cooled to 0° C. Water (3.5 ml) was added dropwise, followed by 15% aq. NaOH (3.5 ml), THF (50 ml) and water (7.5 ml). The mixture was allowed to reach rt and stirred for 30 min. The solids were filtered off and washed with THF. The filtrate was dried over Na2SO4 and concentrated under reduced pressure to give the title compound as colorless oil (2.8 g, 86%). The product was used in the next step without further purification. 1H NMR (600 MHz, CDCl3) δ 0.80 (d, 3H), 0.91 (t, 3H), 1.10-1.23 (m, 1H), 1.25-1.38 (m, 1H), 1.53-1.63 (m, 1H), 2.15-2.30 (m, 3H), 2.36 (s, 3H), 2.38-2.47 (m, 2H), 2.77-2.84 (m, 1H), 2.89-2.97 (m, 1H), 3.50-3.64 (m, 2H), 4.33-4.44 (m, 1H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[C:6](B(O)O)[CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][N:2]=1.Br[C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:41])[N:26]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[N:27]([CH2:30][C:31]([OH:34])([CH3:33])[CH3:32])[C:28]=2[CH3:29])=[O:23])=[CH:17][C:16]=1[CH3:42].C([O-])(O)=O.[Na+].N#N>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl.O1CCOCC1>[OH:34][C:31]([CH3:33])([CH3:32])[CH2:30][N:27]1[C:28]([CH3:29])=[C:24]([C:22]([NH:21][C:18]2[CH:19]=[CH:20][C:15]([C:6]3[CH:7]=[CH:8][CH:9]=[C:10]4[C:5]=3[CH:4]=[CH:3][N:2]=[CH:1]4)=[C:16]([CH3:42])[CH:17]=2)=[O:23])[C:25](=[O:41])[N:26]1[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: Cc1cc(NC(=O)c2c(C)n(CC(C)(C)O)n(-c3ccccc3)c2=O)ccc1Br
Reactant: OB(O)c1cccc2cnccc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: N#N
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(NC(=O)c2c(C)n(CC(C)(C)O)n(-c3ccccc3)c2=O)ccc1-c1cccc2cnccc12
Temperature: 25 °C

Procedure:
A sealable tube was charged with PdCl2(dppf)-CH2Cl2 adduct (0.013 g, 0.016 mmol), isoquinolin-5-ylboronic acid (0.057 g, 0.33 mmol), N-(4-bromo-3-methylphenyl)-1-(2-hydroxy-2-methylpropyl)-5-methyl-3-oxo-2-phenyl-2,3-dihydro-1H-pyrazole-4-carboxamide (0.150 g, 0.33 mmol) and 4 mL dioxane. To this mixture, NaHCO3 solution (0.49 ml, 0.98 mmol) was added and the reaction mixture blanket with N2. The vessel was sealed and heated at 80 C for 19 h. The mixture was allowed to cool to rt, filtered through a pad of celite using ethyl acetate as the eluent and the organic layer washed with water, brine, dried over Na2SO4, filtered and evaporated. The mixture was purified via flash chromatography using a mixture of MeOH in EtOAc as the eluent. The title compound was isolated as an off-white solid (80 mg). MS (ESI pos. ion) m/z=507 (MH+). Calc'd mass for C31H30FN4O3: 506.60. 1H NMR (400 MHz, dmso-d6) δ 10.86 (s, 1H), 9.39 (s, 1H), 8.45 (d, J=5.9 Hz, 1H), 8.17 (d, J=8.1 Hz, 1H), 7.74-7.80 (m, 1H), 7.56-7.85 (m, 5H), 7.44-7.50 (m, 1H), 7.37 (d, J=7.7 Hz, 2H), 7.25 (d, J=5.8 Hz, 1H), 7.17 (d, J=8.1 Hz, 1H), 3.31 (s, 2H), 2.82 (s, 3H), 1.95 (s, 3H), 0.98 (s, 6H).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1.[CH3:11][N:12]=[C:13]=[S:14]>C(O)(C)C>[CH3:11][NH:12][C:13]([NH:1][CH2:2][CH2:3][O:4][CH2:5][C:6]1[N:7]=[CH:8][NH:9][CH:10]=1)=[S:14]
Reactant: CN=C=S
Reactant: NCCOCc1c[nH]cn1
Solvent: CC(C)O
Product: CNC(=S)NCCOCc1c[nH]cn1
Yield: 23.5 %

Procedure:
4-(2-Aminoethoxymethyl)imidazole (2.24 g.) was caused to react with methyl isothiocyanate (1.21 g.) in isopropyl alcohol (25 ml.) in the usual way. The crude product was purified by chromatography on a column of silica gel with ethyl acetate as eluant and subsequently on a dry column of alumina, using chloroform. The final product was recrystallised from ethyl acetate to give N-methyl-N'-[2-(4-imidazolylmethoxy)ethyl]thiourea (0.80 g.), m.p. 96°-98°. (Found: C, 44.6; H, 6.5; N, 26.0; S, 14.7. C6H14N4OS requires: C, 44.8; H, 6.6; N, 26.2; S, 15.0).
Reaction SMILES: FC1C=C([N:21]2[CH2:25][CH:24]([CH2:26][N:27]=[N+]=[N-])[O:23][C:22]2=[O:30])C=CC=1N1CCN(C(OC(C)(C)C)=O)CC1.FC1C=C(N2CC(CN)OC2=O)C=CC=1N1CCN(C([O:46][C:47](C)(C)[CH3:48])=O)CC1.C(OC(=O)C)(=O)C.C([O-])(O)=O.[Na+]>C(OCC)(=O)C.[Pd].ClCCl.N1C=CC=CC=1>[C:47]([NH:27][CH2:26][CH:24]1[O:23][C:22](=[O:30])[NH:21][CH2:25]1)(=[O:46])[CH3:48]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CN)OC3=O)cc2F)CC1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(N3CC(CN=[N+]=[N-])OC3=O)cc2F)CC1
Agent: [Pd]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)NCC1CNC(=O)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of 1.42 g (3.38 mmol) of the azide 11 in 200 mL ethyl acetate was treated with 400 mg of 10% Palladium on carbon followed by hydrogenation at atmospheric pressure for 48 hours. The resulting ethyl acetate solution of 12 was treated with 1.34 g (1.37 mL, 16.9 mmol) of pyridine and 870 mg (0.80 mL, 8.5 mmol) of acetic anhydride followed by stirring at ambient temperature for 48 hours. The solution was treated with 1.37 mL pyridine and 0.8 mL acetic anhydride followed by stirring at ambient temperature for another 48 hours. The solution was filtered through celite, washing the filter cake with ethyl acetate. The filtrate was washed with water (4×50mL), 1.0M CuSO4 solution (50 mL), and again with water (50 mL). Drying (Na2SO4) and concentration in vacuo afforded a foam which was diluted with dichloromethane and stirred for 1 hour with saturated NaHCO3 solution. The mixture was extracted with dichloromethane and the combined organic layers were dried (Na2SO4) and concentrated in vacuo to afford an amber oil which was chromatographed over 74 g of 230-400 mesh silica gel, eluting with 2% (v/v) methanol in dichloromethane and then with 5% (v/v) methanol in dichloromethane. These procedures afforded 1.19 g (81%) of 3-(3-fluoro-4-tert-butoxycarbonylpiperazin-1-yl)phenyl)-5-acetylaminomethyl-2-oxazolidinone (21) as a rigid off-white foam, mp=162°-164° C.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]([F:23])([F:22])[F:21])=[N:18][N:19]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C(N(C(C)C)CC)(C)C.ClC(OC(Cl)C)=O>ClCCl>[NH:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]2[S:16][C:17]([C:20]([F:23])([F:21])[F:22])=[N:18][N:19]=2)[CH2:10][CH2:9]1
Reactant: FC(F)(F)c1nnc(NC2CCN(Cc3ccccc3)CC2)s1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1nnc(NC2CCNCC2)s1
Temperature: 25 °C
Reaction time: 2 h
Yield: 78.7 %

Procedure:
To a stirred solution of (1-benzyl-piperidin-4-yl)-(5-trifluoromethyl-[1,3,4]thiadiazol-2-yl)-amine (D3) (0.50 g, 1.46 mmol) and diisopropylethylamine (0.76 ml, 4.38 mmol) in dichloromethane (20 ml) at 0° C., was added 1-chloroethyl chloroformate (0.47 ml, 4.38 mmol). The reaction mixture was stirred at room temperature for 2 h. and after this period, the solvent evaporated in vacuo. The crude product was dissolved in methanol (30 ml) and the reaction mixture was stirred at reflux for 1.5 h. After evaporation of the solvent, the crude product was dissolved in water and extracted with diethyl ether (2×25 ml) and dichloromethane (3×25 ml). The aqueous layer was separated and evaporated in vacuo. The crude product was purified by reverse phase HPLC. The desired fractions were collected and evaporated in vacuo to yield D4 (0.29 g, 79%) as a solid. C8H11F3N4S requires 252. Found 253 (MH+).