Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:37])[C:5]([CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:27][CH:26]=1)([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:14][CH:13]=1)C(OCC)=O)[CH3:2].[Cl-].[Na+].CS(C)=O>O>[CH2:1]([O:3][C:4](=[O:37])[CH:5]([CH2:11][C:12]1[CH:13]=[CH:14][C:15]([C:18](=[O:23])[C:19]([CH3:22])([CH3:21])[CH3:20])=[CH:16][CH:17]=1)[CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:31](=[O:36])[C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:29][CH:30]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)(Cc1ccc(C(=O)C(C)(C)C)cc1)C(=O)OCC
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOC(=O)C(Cc1ccc(C(=O)C(C)(C)C)cc1)Cc1ccc(C(=O)C(C)(C)C)cc1

Procedure:
A mixture of 50.0 g. (0.100 mole) bis(p-pivaloylbenzyl)malonic acid diethylester, 6.0 g. (0.103 mole) sodium chloride, 200 ml. dimethylsulfoxide and 3.5 ml. water is heated at 180° for 22 hours. The resulting mixture is then cooled and poured into water. The water mixture is extracted twice with methylene chloride and the methylene chloride washed with water and dried over anhydrous magnesium sulfate, filtered and evaporated in vacuo. The resulting oil is crystallized from pentane to give bis(p-pivaloylbenzyl) acetic acid ethyl ester; m.p. 60°-63° C.
Reaction SMILES: CI.[OH:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8].[C:17](=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[CH3:17][O:3][C:4]1[CH:5]=[C:6]([CH:11]=[C:12]([N+:14]([O-:16])=[O:15])[CH:13]=1)[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=C([O-])[O-]
Reactant: COC(=O)c1cc(O)cc([N+](=O)[O-])c1
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OC)cc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 62.8 %

Procedure:
A mixture of methyl iodide (0.200 mL, 3.2 mmol), 93A (328 mg, 1.66 mmol), and potassium carbonate (250 mg, 1.80 mmol) in DMF (2 mL) was stirred overnight at rt. The reaction mixture was diluted with water and extracted with ethyl acetate (3×). The combined organic layers were washed with water and concentrated in vacuo. The residue was purified by silica gel chromatography (gradient of 0 to 50% ethyl acetate in hexanes) to give 93B (0.22 g, 63%) as a white solid. 1H NMR (400 MHz, CDCl3) δ ppm 3.95 (s, 3H) 3.98 (s, 3H) 7.87-7.90 (m, 1H) 7.90-7.93 (m, 1H) 8.44-8.48 (m, 1H); LC/MS 212 (M+H).
Reaction SMILES: Br[C:2]1[S:3][C:4]([Cl:7])=[CH:5][CH:6]=1.[CH:8]([C:10]1[S:14][C:13](B(O)O)=[CH:12][CH:11]=1)=[O:9].C([O-])([O-])=O.[Na+].[Na+]>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.CCO>[Cl:7][C:4]1[S:3][C:2]([C:13]2[S:14][C:10]([CH:8]=[O:9])=[CH:11][CH:12]=2)=[CH:6][CH:5]=1
Reactant: O=Cc1ccc(B(O)O)s1
Reactant: Clc1ccc(Br)s1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: O=Cc1ccc(-c2ccc(Cl)s2)s1
Temperature: 85 °C
Reaction time: 0.17 h
Yield: 23.6 %

Procedure:
In a flask are placed 2-bromo-5-chlorothiophene (0.55 mL, 5.0 mmol) and Pd(PPh3)4 (0.17 g, 0.15 mmol), and the flask is vacuum purged and nitrogen filled (3×). THF (10 mL) is added by syringe and stirred 10 min. In a separate flask is placed 5-formyl-2-thiopheneboronic acid (0.94 g, 6.0 mmol) and EtOH (2 mL) and stirred until dissolved. This mixture is added by syringe to the first flask followed by vacuum purge and nitrogen fill (3×). A solution of Na2CO3 (2M, 5.0 mL, 10.0 mmol) is added by syringe followed by vacuum purge and nitrogen fill (3×). The reaction mixture is heated at 85° C. for 20 h. The reaction is cooled to rt and diluted with water. The aqueous solution is extracted with ether (3×). The combined ether layers are washed with water (3×) then brine (2×). The ether is dried over MgSO4, filtered, and concentrated. The crude product is purified over silica gel (5% EtOAc-heptane) to provide the product as an orange solid (0.27 g, 24%). 1H NMR (400 MHz, CDCl3) δ 9.89, 7.69, 7.20, 7.16, 6.93.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:15]=[C:14]2[C:6]([C:7]3[C:8]([Br:19])=[CH:9][CH:10]=[C:11]([C:16]([NH2:18])=[O:17])[C:12]=3[NH:13]2)=[CH:5][CH:4]=1.[CH3:20][S:21](Cl)(=[O:23])=[O:22]>CN(C=O)C.C1COCC1.C(Cl)Cl>[Br:19][C:8]1[C:7]2[C:6]3[C:14](=[CH:15][C:3]([CH2:2][NH:1][S:21]([CH3:20])(=[O:23])=[O:22])=[CH:4][CH:5]=3)[NH:13][C:12]=2[C:11]([C:16]([NH2:18])=[O:17])=[CH:10][CH:9]=1
Reactant: CS(=O)(=O)Cl
Reactant: NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CS(=O)(=O)NCc1ccc2c(c1)[nH]c1c(C(N)=O)ccc(Br)c12
Temperature: 25 °C
Reaction time: 3 h
Yield: 104.5 %

Procedure:
A suspension of 7-(aminomethyl)-4-bromo-9H-carbazole-1-carboxamide (Step 2 of Example 33-1, 100 mg, 0.314 mmol) and TEA (0.110 mL, 0.786 mmol) in DMF-THF-DCM (25:25:50, 6 mL) was treated dropwise with methanesulfonyl chloride (37 μL, 0.471 mmol) and the resulting mixture was stirred at rt for 3 h. The mixture was partitioned between NaHCO3 (aq) and EtOAc, and the organic phase was washed with brine, dried and concentrated to provide crude 4-bromo-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide as a yellow solid (130 mg, 88%). Without purification, using the procedure of Example 3-2, this material (25 mg, 0.063 mmol) and 6-fluoro-2-(2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)isoindolin-1-one (Intermediate 50-5, 27.8 mg, 0.076 mmol) were converted into 4-(3-(6-fluoro-1-oxoisoindolin-2-yl)-2-methylphenyl)-7-(methylsulfonamidomethyl)-9H-carbazole-1-carboxamide (22 mg, 58%). 1H NMR (400 MHz, DMSO-d6) δ 11.58 (1H, s), 8.20 (1H, br. s.), 8.03 (1H, d, J=7.9 Hz), 7.70-7.78 (2H, m), 7.45-7.67 (6H, m), 7.36 (1H, dd, J=7.7, 1.1 Hz), 7.00-7.07 (2H, m), 6.93-7.00 (1H, m), 4.86-5.04 (2H, m), 4.26 (2H, d, J=6.2 Hz), 2.87 (3H, s), 1.84 (3H, s). Mass spectrum m/z 557.1 (M+H)+.
Reaction SMILES: Br[C:2](Br)=[CH:3][C@H:4]1[CH2:9][CH2:8][C@H:7]2[C@H:10]3[C@H:20]([CH2:21][CH2:22][C@:5]12[CH3:6])[C@:18]1([CH3:19])[C@H:13]([CH2:14][C@H:15]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:16][CH2:17]1)[CH2:12][CH2:11]3.[Li]CCCC.[CH:47](=[O:49])[CH3:48].Cl>C1COCC1>[Si:24]([O:23][C@@H:15]1[CH2:16][CH2:17][C@@:18]2([CH3:19])[C@@H:13]([CH2:12][CH2:11][C@@H:10]3[C@@H:20]2[CH2:21][CH2:22][C@@:5]2([CH3:6])[C@H:7]3[CH2:8][CH2:9][C@@H:4]2[C:3]#[C:2][CH:47]([OH:49])[CH3:48])[CH2:14]1)([C:37]([CH3:38])([CH3:40])[CH3:39])([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@]2(C)[C@@H](CC[C@@H]3[C@@H]2CC[C@]2(C)[C@@H](C=C(Br)Br)CC[C@@H]32)C1)(c1ccccc1)c1ccccc1
Reactant: CC=O
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(O)C#C[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O[Si](c5ccccc5)(c5ccccc5)C(C)(C)C)CC[C@]4(C)[C@H]3CC[C@]12C
Reaction time: 2 h

Procedure:
To a solution of 1,1-dibromo-2-[3α-(t-butyidiphenylsilyloxy)-5α-androstan-17β-yl]-ethylene (308 mg, 0.44 mmol) in THF (11 mL) was added at −78° C. a solution of n-BuLi 1.6 M in hexanes (2.76 mL, 4.4 mmol) and the mixture was stirred for 2 h. Acetaldehyde (0.032 mL, 0.57 mmol) was added at −78° C. and the temperature was let to rise to 25° C. Addition of HCl solution 2N at 0° C. was followed by extraction with ethyl acetate. The organic layer was washed with NaHCO3 brine and dried with (Na2SO4) and the solvent was evaporated in vacuo. Subsequent purification of the residue with flash column chromatography using petroleum etherlethyl acetate 90/10 as eluent afforded the desired compound named above.
Reaction SMILES: C([N:3](CC)CC)C.Cl.N=[C:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:12]=[CH:11]1.[CH3:22][N:23]=[C:24]=[O:25]>CC(C)=O>[CH3:22][NH:23][C:24]([CH:10]1[CH:15]=[CH:14][N:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[NH:12][C:11]1=[NH:3])=[O:25]
Reactant: N=c1ccn(-c2ccccc2)nc1
Reactant: CN=C=O
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CC(C)=O
Product: CNC(=O)C1C=CN(c2ccccc2)NC1=N
Yield: 27 %

Procedure:
5.3 g (52.4 millimoles) of triethylamine were added dropwise to 10.0 g (48.2 millimoles) of 1,4-dihydro-4-imino-1-phenylpyridazine hydrochloride in 25 ml (24.2 g 424 millimoles) of methyl isocyanate at room temperature, while stirring. After the addition was complete, the reaction mixture was diluted with 50 ml of acetone, and stirred for a further 2 hours at room temperature. The product was filtered off under suction, washed with water and acetone, and recrystallized from methanol. 3.0 g (27% of theory) of 1,4-dihydro-4-(methylcarbamyl)-imino-1-phenylpyridazine were isolated as slightly greenish crystals of melting point 205°-206° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.[O:10]([C:12]1[CH:18]=[CH:17][CH:16]=[CH:15][C:13]=1[NH2:14])[CH3:11].O1CCOCC1>C(#N)C.O>[Cl:1][C:2]1[N:7]=[C:6]([NH:14][C:13]2[CH:15]=[CH:16][CH:17]=[CH:18][C:12]=2[O:10][CH3:11])[C:5]([F:9])=[CH:4][N:3]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: COc1ccccc1N
Solvent: C1COCCO1
Solvent: CC#N
Solvent: O
Product: COc1ccccc1Nc1nc(Cl)ncc1F
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
A round-bottomed flask was charged with 2,4-dichloro-5-fluoropyrimidine (0.84 g, 5 mmol), 2-methoxylaniline (0.61 g, 5 mmol) and dioxane (5 mL). The reaction mixture was heated at 85° C. overnight. The reaction was cooled down and diluted with acetonitrile/water, stirred for 30 min. and filtered. The collected solid was re-suspended in acetonitrile/water, stirred and filtered to give a 2-chloro-5-fluoro-N-(2-methoxyphenyl)pyrimidin-4-amine (0.9 g, 70% yield). To a seal tube was added 2-chloro-5-fluoro-N-(2-methoxyphenyl)pyrimidin-4-amine (254 mg), 3-methoxyaniline (500 mg, 4 eq.) and dioxane (5 mL). The mixture was heated to 130° C. overnight. The reaction mixture was cooled and partitioned between EtOAc and water. The organic layer was concentrated; the residue was triturated with a 1:1 mixture of dichloromethane and acetonitrile, then filtered to give the title product as a white solid (150 mg).
Reaction SMILES: [CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[NH:5][S@@](C(C)(C)C)=O)[CH2:3][CH2:2]1.C(O)C.Cl.O1CCOCC1>>[CH:1]1([C@H:4]([C:12]2[CH:13]=[N:14][C:15]([C:18]([F:21])([F:19])[F:20])=[CH:16][CH:17]=2)[NH2:5])[CH2:3][CH2:2]1
Reactant: CC(C)(C)[S@@](=O)N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CCO
Product: N[C@@H](c1ccc(C(F)(F)F)nc1)C1CC1
Reaction time: 8 h

Procedure:
(R)—N—((R)-Cyclopropyl(6-(trifluoromethyl)pyridin-3-yl)methyl)-2-methylpropane-2-sulfinamide (0.245 g, 0.000765 mol), ethanol (2.7 g, 0.059 mol), and 4.0 M of hydrogen chloride in dioxane (2.7 mL, 0.011 mol) were combined and stirred overnight. Reaction was concentrated to down to oil and then redissolved and washed with ethanol for 3 times, and concentrated. The residue was dried on the high vacuum overnight to obtain the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)=[CH2+:4][CH:3]1[O-].[CH:16]([S@:18]([C:20]1[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=1)=[O:19])=[CH2:17].[O:27]1CCOCC1>>[CH3:1][N:2]1[C@@H:3]2[C@H:16]([S:18]([C:20]3[CH:25]=[CH:24][C:23]([CH3:26])=[CH:22][CH:21]=3)=[O:19])[CH2:17][C@H:7]1[C:6](=[O:27])[C:5]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=[CH:4]2
Reactant: C=C[S@@](=O)c1ccc(C)cc1
Reactant: C1COCCO1
Reactant: CN1C=CC(c2ccc(F)cc2)=[CH2+]C1[O-]
Product: Cc1ccc(S(=O)[C@@H]2C[C@H]3C(=O)C(c4ccc(F)cc4)=C[C@@H]2N3C)cc1

Procedure:
A solution of 1-methyl-4-(p-fluorophenyl)-3-pyridiniumolate 27 (2.45 g, 12.04 mmol) and (+)-(R)-p-tolyl vinyl sulphoxide (2.00 g, 12.04 mmol).in dioxane (25 mL) was allowed to reflux for 20 hours. The resulting reaction mixture was concentrated under reduced pressure, purified by silica gel flash chromatography, and recrystallized from EtOAc to give the compound 30 as a white solid; [α]25D −77° (c 1.25, CHCl3); Rf0.2 (EtOAc/hexane, 7/3); mp 186° C. (EtOAc); 1H NMR (CDCl3) δ1.64 (dd, H7α, J=8.7 and 14.7 Hz), 2.14 (ddd, H7β, J=3.6, 7.8 and 14.7 Hz), 2.42 (s, 3H), 2.62 (s, 3H), 3.33 (dd, H6, J=3.6 and 8.7 Hz), 3.73 (d, H1, J=7.5 Hz), 4.51 (d, H5, J=5.4 Hz), 7.01 (d, H4, J=5.4 Hz), 7.041 (t, 2H, J=8.7 Hz), 7.30-7.40 (m, 4H), 7.66 (d, 2H, J=8.1 Hz).
Reaction SMILES: [CH:1]([B-](F)(F)F)=[CH2:2].[K+].C(N(CC)CC)C.Br[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([F:22])[N:17]=1.C(=O)([O-])O.[Na+]>C(O)CC>[F:22][C:18]1[CH:19]=[CH:20][CH:21]=[C:16]([CH:1]=[CH2:2])[N:17]=1
Reactant: C=C[B-](F)(F)F
Reactant: Fc1cccc(Br)n1
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCCO
Solvent: CCN(CC)CC
Product: C=Cc1cccc(F)n1
Temperature: 100 °C
Reaction time: 11 h
Yield: 35.7 %

Procedure:
Potassium vinyltrifluoroborate (2.28 g), triethylamine (2.38 mL) and [1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane complex (928 mg) were added in that order to an n-propanol solution (12 mL) of 2-bromo-6-fluoropyridine (2.0 g), and stirred at 100° C. for 11 hours, and then at room temperature for 2 days. Saturated sodium hydrogencarbonate solution was added to the reaction liquid, and extracted with ethyl acetate. The organic layer was washed with saturated saline water, dried, concentrated under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=9/1) to obtain the entitled compound (500 mg).
Reaction SMILES: [Li+].[BH4-].[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[C:20](OCC)=[O:21])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>CO>[CH2:3]([O:10][N:11]1[C:17](=[O:18])[N:16]2[CH2:19][C@H:12]1[CH2:13][CH2:14][C@H:15]2[CH2:20][OH:21])[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: O=C1N2C[C@@H](CC[C@H]2CO)N1OCc1ccccc1
Temperature: -5 °C
Reaction time: 0.25 h
Yield: 88.1 %

Procedure:
LiBH4 (0.54 g, 24.67 mmol) was added to a solution of (2S,5R)-ethyl 6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylate (5 g, 16.44 mmol) in MeOH (50 mL) at −10° C. After 15 min, another portion of LiBH4 (0.54 g, 24.67 mmol) was added and the mixture was stirred at −10 to 0° C. for 4-5 h. The reaction mixture was carefully quenched by addition of sat. NaH2PO4 (50 mL) at 0° C. The mixture was diluted with water (20 mL) and extracted with DCM three times. The combined organic layer was concentrated and purified by silica gel column chromatography (gradient elution 0-100% petroleum ether/EtOAc, then 0-2% MeOH/EtOAc) to give (2S,5R)-6-(benzyloxy)-2-(hydroxymethyl)-1,6-diazabicyclo[3.2.1]octan-7-one (3.8 g, 88%) as a white solid. ESI-MS (EI+, m/z): 263.1. 1H-NMR (500M, CDCl3): 7.44-7.35 (m, 5H), 5.05 (d, J=11.5 Hz, 1H), 4.90 (d, J=11.5 Hz, 1H), 3.73-3.69 (m, 1H), 3.61-3.58 (m, 2H), 3.33 (m, 1H), 3.01 (br d, J=12.0 Hz, 1H), 2.91 (m, 1H), 2.03-1.95 (m, 2H), 1.58-1.54 (m, 1H), 1.39-1.24 (m, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([CH2:14]O)=[C:12]([CH:16]([CH3:18])[CH3:17])[N:11]=[C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])[N:9]=2)=[CH:4][CH:3]=1.Cl[P:26]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.[OH-:39].[K+].O>C1(C)C=CC=CC=1.[Cl-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:27]1([P:26]([CH2:14][C:13]2[C:8]([C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[N:9][C:10]([N:19]([CH3:24])[S:20]([CH3:23])(=[O:22])=[O:21])=[N:11][C:12]=2[CH:16]([CH3:18])[CH3:17])([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)=[O:39])[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: [OH-]
Reactant: ClP(c1ccccc1)c1ccccc1
Reactant: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CO
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: Cc1ccccc1
Product: CC(C)c1nc(N(C)S(C)(=O)=O)nc(-c2ccc(F)cc2)c1CP(=O)(c1ccccc1)c1ccccc1
Temperature: 111 °C
Reaction time: 2 h

Procedure:
2.03 g (5.69 mmol) of [4-(4-fluorophenyl)-6-isopropyl-2-(N-methyl-N-methylsulfonylamino)pyrimidin-5-yl]methanol was initially charged in 13 g of toluene and, with ice-bath cooling, admixed with 1.67 g (7.51 mmol) of chlorodiphenylphosphine in 2 g of toluene. The mixture was heated at 111° C. for 2.5 h. After cooling to room temperature, 1.08 g (8.66 mmol) of a 45 percent strength potassium hydroxide solution and 175 mg (0.574 mmol) of tetrabutylammonium chloride was added, and the mixture was stirred vigorously at 60° C. for 2 h. 30 ml of water was added to the warm reaction mixture. The mixture was briefly stirred at 60° C. and slowly cooled to 4° C., and the precipitated solid was filtered off. The product was washed with cold water (10 ml) and cold toluene (10 ml) and dried under reduced pressure at 40° C. 2.66 g (84.1 percent; content: 96.6 percent) of N-[5-(diphenylphosphinoylmethyl)-4-(4-fluorophenyl)-6-isopropylpyrimidin-2-yl]-N-methylmethanesulfonamide was isolated in the form of a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][OH:20])=[CH:15][C:14]=3[C:21]([F:24])([F:23])[F:22])=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:28]N(C1C2C(N(C)C)=CC=CC=2C=CC=1)C.F[B-](F)(F)F.C[O+](C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:27][CH2:26][N:11]2[C:12](=[O:25])[C:13]3[C:18]([C@@H:10]2[CH2:9]1)=[CH:17][C:16]([CH2:19][O:20][CH3:28])=[CH:15][C:14]=3[C:21]([F:22])([F:24])[F:23])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(C)c1cccc2cccc(N(C)C)c12
Reactant: CC(C)(C)OC(=O)N1CCN2C(=O)c3c(cc(CO)cc3C(F)(F)F)[C@@H]2C1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Product: COCc1cc2c(c(C(F)(F)F)c1)C(=O)N1CCN(C(=O)OC(C)(C)C)C[C@@H]21
Reaction time: 16 h
Yield: 40.6 %

Procedure:
To a stirring solution of N-(t-butoxycarbonyl)-(R)-1,3,4,10b-tetrahydro-9-hydroxymethyl-7-trifluoromethyl-pyrazino[2,1-a]isoindol-6(2H)-one (30 mg, 0.08 mmol) and proton sponge (26 mg, 0.12 mmol) in dry CH2Cl2 (1.0 mL) was added trimethyloxonium tetrafluoroborate (11.5 mg, 0.08 mmol). The reaction was stir for 16 hr and then quenched with 1M aq. HCl. The reaction was extracted with EtOAc (3×10 mL). The organic layers were combined, dried over Na2SO4, and conc. in vacuo to a pink oil. The oil was purified by flash chromatography (silica gel, 0-40% EtOAc in hexanes) to yield 13 mg of the desired product as a colorless oil. MS (ESI) 401 (M+H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14]([OH:16])=O)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[Br:19][C:20]1[CH:21]=[C:22]([NH2:31])[CH:23]=[C:24]([C:26]2[NH:30][N:29]=[N:28][N:27]=2)[CH:25]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[C@H:13]([C:14](=[O:16])[NH:31][C:22]2[CH:23]=[C:24]([C:26]3[NH:30][N:29]=[N:28][N:27]=3)[CH:25]=[C:20]([Br:19])[CH:21]=2)[CH2:12][C@@H:11]2[C@H:9]1[CH2:10]2)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cc(Br)cc(-c2nnn[nH]2)c1
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H]2C[C@H]1C(=O)Nc1cc(Br)cc(-c2nnn[nH]2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S,5R)-2-aza-bicyclo[3.1.0]hexane-2,3-dicarboxylic acid 2-tert-butyl ester (250 mg, 1.1 mmol) in CH2Cl2 (6 mL) was added 3-bromo-5-(1H-tetrazol-5-yl)-phenylamine dihydrochloride (prepared as described in Part C, 365 mg, 1.32 mmol), HBTU (626 mg, 1.65 mmol) and DIPEA (0.576 ml, 3.3 mmol). The reaction mixture was stirred at RT overnight. The reaction mixture was diluted with CH2Cl2 and successively washed with 1M aqueous HCl solution (30 mL) and a saturated aqueous NaHCO3 solution. The organic phase was dried (phase separator) and evaporated under vacuum. The crude mixture was purified by preparative HPLC (C18 Nucleosil 100-10, flow: 40 ml/min, eluent: 5-100% CH3CN/H2O/20 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA). After combination of the purified fractions, CH3CN was removed under vacuum and lyophilization gave the desired compound. MS (LC/MS): 447.1 [M−H]−; tR (HPLC conditions k): 4.62 min.
Reaction SMILES: C1C=C([N+]([O-])=O)C2C(=NON=2)C=1N[C@H:14]([C@@H:17]([OH:24])[C@H:18]([OH:23])[C@H:19]([OH:22])[CH2:20][OH:21])[CH:15]=[O:16].[OH2:25]>>[O:21]=[CH:20][C@@H:19]([C@H:18]([C@@H:17]([C@@H:14]([CH2:15][OH:16])[OH:25])[OH:24])[OH:23])[OH:22]
Reactant: O=C[C@H](Nc1ccc([N+](=O)[O-])c2nonc12)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: O
Product: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reaction time: 3 h

Procedure:
At 72 hpf, larvae were placed into a 96-well plate (6 eggs/well in 200 μL E3 water supplemented with 0.2 mM 2-phenylthiourea; Sigma). Drug of interest was added for h. The solution was then replaced with E3 water supplemented with 600 μM 2-NBDG and incubated for 3 h. The larva were washed with E3 water and anesthetized with 0.02% tricaine-supplemented E3 water. One larva was then placed on a chamber slide, containing 3% methylcellulose in E3 water, for fluorescent microscopy (Leica DM2500 microscope equipped with a DFC425 C digital camera). Images were captured at 50× magnification. The remaining 5 larvae where lysed with 120 μL of CelLytic M solution (Sigma-Aldrich) and sonication (4° C., 10″/5″ pulse, 10 min). Lysed larvae were centrifuged at 10000 rpm for 10 min. 100 μL of the supernatant was transferred to a 96-well plate and fluorescence was measured with a fluorescent microplate reader (SpectraMAX Gemini XS, Molecular Devices; λex=466 nm λex=540 nm).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:46])[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[N:20](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[C:19]4=[O:43])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1.C(O)(=O)C>O>[Cl:1][C:2]1[N:7]=[C:6]2[N:8]([CH3:46])[C:9]([CH2:11][O:12][C:13]3[CH:45]=[CH:44][C:16]([CH2:17][CH:18]4[S:22][C:21](=[O:23])[NH:20][C:19]4=[O:43])=[CH:15][CH:14]=3)=[N:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cn1c(COc2ccc(CC3SC(=O)N(C(c4ccccc4)(c4ccccc4)c4ccccc4)C3=O)cc2)nc2ccc(Cl)nc21
Solvent: O
Solvent: CC(=O)O
Product: Cn1c(COc2ccc(CC3SC(=O)NC3=O)cc2)nc2ccc(Cl)nc21

Procedure:
A procedure similar to that described in Example 12 was repeated, except that 1.16 g of 5-{4-(5-chloro-3-methylimidazo[5,4-b]pyridin-2-ylmethoxy)benzyl}-3-triphenylmethylthiazolidine-2,4-dione (prepared as described in Preparation 45) and 16 ml of a 3:1 by volume mixture of acetic acid and water were used, to give the title compound as a crude product. The product was crystallized by trituration with ethyl acetate, to give 0.38 g of the title compound, melting at 222-223° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:28])[C:14]2[C:6]([N:7]=[C:8]3[C:13]=2[CH:12]=[CH:11][CH:10]=[CH:9]3)=[CH:5][C:4]2[CH:15]=[C:16]3[C:21]([C:3]1=2)=[CH:20][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:18]=[CH:17]3.CN(C=O)C.[Br:34]N1C(=O)CCC1=O>O>[Br:34][C:15]1[C:4]2[CH:5]=[C:6]3[C:14]([C:2]([CH3:28])([CH3:1])[C:3]=2[C:21]2[C:16]=1[CH:17]=[CH:18][CH:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH:20]=2)=[C:13]1[C:8]([CH:9]=[CH:10][CH:11]=[CH:12]1)=[N:7]3
Reactant: CC1(C)C2=C(C=C3C=CC(c4ccccc4)C=C32)C=C2N=c3ccccc3=C21
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)C2=C(C=C3N=c4ccccc4=C31)C(Br)=C1C=CC(c3ccccc3)C=C12
Reaction time: 9 h
Yield: 94.8 %

Procedure:
The resulting 12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (7.5 g) and DMF (53 ml) were added to a reaction vessel. N-bromosuccinimide (3.72 g) was added under ice-cooled conditions, and the mixture was stirred for 9 hours and then left for one night. Water (260 ml) was added, and the mixture was subjected to filtration to obtain a brownish white powder of 7-bromo-12,12-dimethyl-10-phenyl-10,12-dihydroindeno[2,1-b]carbazole (8.67 g; yield 94.6%).