Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1OS(C(F)(F)F)(=O)=O.[CH2:27]([NH:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34])[CH2:28][CH2:29][C:30]#[CH:31]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.[Cu](I)I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(N(CC)CC)C>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]2[CH2:6][CH2:7][N:8]([C:11](=[O:16])[C:12]([F:15])([F:14])[F:13])[CH2:9][CH2:10][C:4]=2[C:3]=1[C:31]#[C:30][CH2:29][CH2:28][CH2:27][NH:32][C:33]([CH:35]1[CH2:39][CH2:38][CH2:37][CH2:36]1)=[O:34]
Reactant: O=C(N1CCc2ccc(Cl)c(OS(=O)(=O)C(F)(F)F)c2CC1)C(F)(F)F
Reactant: C#CCCCNC(=O)C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCN(CC)CC
Product: O=C(NCCCC#Cc1c(Cl)ccc2c1CCN(C(=O)C(F)(F)F)CC2)C1CCCC1
Reaction time: 8 h
Yield: 67.9 %

Procedure:
In an oven dried flask degas DMF (20 mL) by gently bubbling nitrogen gas for 2 h. Add then 7-chloro-3-(2,2,2-trifluoroacetyl)-6-trifluoromethanesulfonyloxy-2,3,4,5-tetrahydro-1H-benzo[d]azepine (1.0 g, 2.35 mmoles), N-pent-4-ynyl-cyclopentylcarboxamide (842 mg, 4.7 mmoles), copper iodide (134 mg, 0.705 mmoles), triethylamine (4.7 mL), tetra-n-butylammonium iodide (2.6 g, 7.05 mmoles) and bis(triphenylphosphine)palladium(II) chloride (165 mg, 0.235 mmoles) and heat the resulting mixture at 80° C. under nitrogen atmosphere while stirring overnight. Concentrate the mixture in vacuo, and then filter through a short pad of Celite® eluting with EtOAc. Purify the residue by chromatography on silica gel eluting with dichloromethane/EtOAc/cyclohexane (3:5:1) to obtain the desired intermediate as an oil (726 mg, 68%). MS (ES+) m/z=455.1 (M+H)+.
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([CH:28]([CH3:30])[CH3:29])/[CH:4]=[CH:5]/[C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@H:23]([OH:25])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7].S([C:35]1C=CC(C)=CC=1)([O-])(=O)=O.C([O-])(=O)C.[K+]>CO>[CH3:1][CH2:2][C@H:3]([CH:28]([CH3:29])[CH3:30])/[CH:4]=[CH:5]/[C@H:6]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][CH:23]([O:25][CH3:35])[CH2:24][C:19]4=[CH:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH3:7]
Reactant: Cc1ccc(S(=O)(=O)[O-])cc1
Reactant: CC[C@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](O)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CO
Product: CC[C@@H](/C=C/[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4CC(OC)CC[C@]4(C)[C@H]3CC[C@]12C)C(C)C
Yield: 97.6 %

Procedure:
A suspension of stigmasterol tosylate (2) (64 g, 112.9 mmol) and potassium acetate (70 g, 713.19 mmol) in anhydrous methanol (1500 mL) was refluxed for 4.5 h under argon atmosphere. The methanol was evaporated in vacuo, and then ether (2 L) was added, washed with water (500 mL), 5% NaHCO3 (2×400 mL) and brine (400 mL) and dried (MgSO4). The solvent was evaporated in vacuo to afford 47 g (92%) of stigmasterol methyl ether (3) as a pale yellow viscous liquid.
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.[C:30]1([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]([NH2:36])=[CH:32][CH:33]=[CH:34][CH:35]=1.[CH:43]1([C:49]2[C:54]3[O:55][C:56]4[C:61](I)=[CH:60][CH:59]=[CH:58][C:57]=4[C:53]=3[CH:52]=[CH:51][CH:50]=2)[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]1.CC(C)([O-])C.[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:30]1([C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=1[NH:36][C:61]1[C:56]2[O:55][C:54]3[C:49]([CH:43]4[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]4)=[CH:50][CH:51]=[CH:52][C:53]=3[C:57]=2[CH:58]=[CH:59][CH:60]=1
Reactant: Ic1cccc2c1oc1c(C3CCCCC3)cccc12
Reactant: Nc1ccccc1-c1ccccc1
Agent: [Pd]
Agent: CC(C)(C)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Product: c1ccc(-c2ccccc2Nc2cccc3c2oc2c(C4CCCCC4)cccc23)cc1
Yield: 99.4 %

Procedure:
Toluene (250 mL) was bubbled with nitrogen for 15 min, followed by addition of 2-dicyclohexylphosphino-2′,6′-dimethoxybiphenyl (1.0 g, 2.4 mmol) and Pd2(dba)3 (0.5 g, 0.6 mmol). The mixture was bubbled with nitrogen for 15 min, then [1,1′-biphenyl]-2-amine (3.4 g, 20.0 mmol), 4-cyclohexyl-6-iododibenzo[b,d]furan (7.5 g, 20.0 mmol), and sodium tert-butoxide (3.8 g, 40.0 mmol) were added. The mixture was bubbled with nitrogen for 15 min and refluxed for 24 h. After cooling, the reaction mixture was filtered through a silica pad and washed with 50% DCM/hexane. After cooling, the solvent was removed in vacuo and the residue was purified by flash chromatography using 15% DCM/hexane to yield N-([1,1′-biphenyl]-2-yl)-6-cyclohexyldibenzo[b,d]furan-4-amine (8.3 g, 100% yield) as a colorless oil.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.Br[C:21]1[CH:26]=[C:25]([C@@H:27]([NH:30][S:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:28][CH3:29])[CH:24]=[CH:23][N:22]=1.[CH3:37][N:38](C)C=O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.[C-]#N.[Zn+2].[C-]#N>[C:37]([C:21]1[CH:26]=[C:25]([C@@H:27]([NH:30][S:31]([C:33]([CH3:36])([CH3:35])[CH3:34])=[O:32])[CH2:28][CH3:29])[CH:24]=[CH:23][N:22]=1)#[N:38]
Reactant: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(Br)c1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [C-]#N
Product: CC[C@H](NS(=O)C(C)(C)C)c1ccnc(C#N)c1
Temperature: 140 °C
Reaction time: 1 h
Yield: 55 %

Procedure:
Triphenylphosphine (PS-resin bound, 287 mg) and palladium acetate (70 mg, 0.31 mmol) were combined in a pressure vial. Dimethylformamide (3 mL) was added. The vial was flushed with nitrogen and a septa was affixed. The mixture was stirred at room temp. for 1 h, then the septa was removed and zinc cyanide (367 mg, 3.13 mmol) was added, followed by 2-methylpropane 2-sulfinic acid [(S)-1-(2-bromo-pyridin-4-yl)-propyl]-amide (1.00 g, 3.13 mmol) in dimethylformamide (7 mL). The vial was again flushed with nitrogen and sealed. The reaction was allowed to heat at 140° C. in an oil bath for 1 h. The solids are filtered of using a glass frit and rinsed with diethylether. The filtrate was diluted with diethylether and extracted with water (2×40 mL) and with brine (40 mL). The organic phase was dried with sodium sulfate and concentrated. The residue was purified by prepHPLC (eluted with 15-85% acetonitrile in water, with 0.1% TFA). Fractions were concentrated to remove acetonitrile, basified by sat. sodium bicarbonate solution, extracted with ethyl acetate, washed with brine, dried over sodium sulfate, filtered, and concentrated to yield 2-methyl-propane-2-sulfinic acid [(S)-1-(2-cyano-pyridin-4-yl)-propyl]-amide as a colorless oil (460 mg, 55%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH:5](C(OCC)=O)[CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=1)[CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:2].[OH-].[Na+]>CCO>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH:6]([C:14]1[CH:15]=[N:16][C:17]([CH3:20])=[N:18][CH:19]=1)[CH2:7][C:8](=[O:13])[CH2:9][CH2:10][CH:11]=[CH2:12])[CH3:2]
Reactant: C=CCCC(=O)CC(c1cnc(C)nc1)C(C(=O)OCC)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C=CCCC(=O)CC(CC(=O)OCC)c1cnc(C)nc1
Temperature: 40 °C
Reaction time: 2 h

Procedure:
The diester 15-4 (11.2 g, 31.1 mmol) was dissolved in EtOH (100 mL) at room temperature. To this was added 1N NaOH (31.1 mL, 31.1 mmol), the mixture stirred at 40° C. for 2 hours then overnight at room temperature. The mixture was concentrated in vacuo, dissolved in toluene (100 mL) and heated at reflux for 5 hours. After removal of the solvent, the residue was partitioned between water and CHCl3 washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (eluting with EtOAc) to give the ester 15-5 as an oil.
Reaction SMILES: Cl.[N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][C:3]=1[NH2:8].C(=O)([O-])[O-].[K+].[K+].[N:15]1[CH:20]=[CH:19][C:18]([C:21](=O)[CH2:22][C:23](OCC)=[O:24])=[N:17][CH:16]=1>C(O)C>[N:15]1[CH:20]=[CH:19][C:18]([C:21]2[N:8]=[C:3]3[CH2:4][CH2:5][CH2:6][CH2:7][N:2]3[C:23](=[O:24])[CH:22]=2)=[N:17][CH:16]=1
Reactant: NC1=NCCCC1
Reactant: CCOC(=O)CC(=O)c1ccncn1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: O=c1cc(-c2ccncn2)nc2n1CCCC2
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 21.8 %

Procedure:
To a suspension of 25.0 g (185.72 mmol) of 3,4,5,6-tetrahydro-pyridin-2-ylamine monohydrochloride in 138 mL of ethanol was added 25.67 g (185.72 mmol) of potassium carbonate. The reaction mixture was stirred at room temperature for 10 min, 36.06 g (185.72 mmol) of ethyl 3-(4-pyrimidinyl)-3-oxopropionate was added and the resulting mixture was stirred under reflux for 16 h. The cooled solution was evaporated to remove solvent. The mixture was dissolved in ethylacetate, washed with a saturated aqueous solution of sodium chloride, dried over sodium sulfate and evaporated to dryness. The resulting solid was triturated in diethyl ether, filtrated to afford 9.23 g (22%) of the desired compound as a white-brown powder.
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH2:13]1[O:24][CH:16]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([NH2:23])[CH:18]=2)[O:15][CH2:14]1.[CH3:25][C:26]1[CH:27]=[N:28][CH:29]=[C:30]([CH:34]=1)[C:31](O)=[O:32].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[O:24]1[CH2:13][CH2:14][O:15][CH:16]1[C:17]1[CH:18]=[C:19]([NH:23][C:31](=[O:32])[C:30]2[CH:34]=[C:26]([CH3:25])[CH:27]=[N:28][CH:29]=2)[CH:20]=[CH:21][CH:22]=1
Reactant: Cc1cncc(C(=O)O)c1
Reactant: Nc1cccc(C2OCCO2)c1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cncc(C(=O)Nc2cccc(C3OCCO3)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.6 %

Procedure:
A solution of EDC hydrochloride (6.3 g, 32.81 mmol) in DCM (20 mL) is added over 5 min. to a solution of 3-aminobenzaldehyde ethylene acetal (3,614 g, 21.9 mmol), 5-methylnicotinic acid (3 g, 21.9 mmol), HOBt (6.7 g, 43.75 mmol), DMAP (534.5 mg, 4.38 mmol) and DIPEA (11.2 mL, 65.63 mmol) in DCM (30 mL) at RT under argon. The mixture is stirred at RT for 18 h. The mixture is diluted with DCM (50 mL) and washed twice with aq. sat. NaHCO3 (50 mL). The organic phase is separated and the aq. phase extracted twice with DCM (100 mL). The combined organic phases are washed with brine (200 mL), dried over MgSO4 and evaporated. The crude product is purified by flash chromatography on silica gel using a gradient of heptane and EtOAc 1:1 to heptane/EtOAc 1:4. After concentration of the product-containing fractions, the title compound (6.14 g, 99%) is obtained as a colorless solid LC-MS A: tR=0.58 min; [M+H]+=285.22.
Reaction SMILES: Cl.[CH3:2][C:3]([CH3:44])([CH3:43])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:42])([CH3:41])[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C:26]4[CH:30]=[N:31][N:32](COCC[Si](C)(C)C)[C:25]3=4)=[CH:20][CH:19]=2)[N:8](S(N(C)C)(=O)=O)[CH:9]=1>CO>[CH3:2][C:3]([CH3:44])([CH3:43])[CH2:4][C:5]1[N:6]=[C:7]([C:16]([OH:42])([CH3:41])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]3[CH2:29][CH2:28][CH2:27][C:26]4[CH:30]=[N:31][NH:32][C:25]3=4)=[CH:22][CH:23]=2)[NH:8][CH:9]=1
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(N2CCCc3cnn(COCC[Si](C)(C)C)c32)cc1
Agent: Cl
Solvent: CO
Product: CC(C)(C)Cc1c[nH]c(C(C)(O)Cc2ccc(N3CCCc4cn[nH]c43)cc2)n1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
Hydrogen chloride (4 M in 1,4-dioxane) (1 mL, 4 mmol) was added to an ambient temperature solution of 4-(2,2-dimethylpropyl)-2-{1-hydroxy-1-methyl-2-[4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1,4,5,6-tetrahydro-7H-pyrazolo[3,4-b]pyridin-7-yl)phenyl]ethyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (1 eq) in methanol (3 mL). After stirring at 70° C. for 1 h, volatiles were removed in vacuo. The residue was purified by high pressure liquid chromatography (KR100-5C18 100×21.2 mm column) eluting with 10-100% acetonitrile/water containing 0.05% trifluoroacetic acid. The residue was partitioned between methanol/ethyl acetate and 10% aqueous sodium hydroxide. The aqueous phase was extracted with ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford the title compound. (M+H) found: 394.
Reaction SMILES: [CH2:1]([C:5]1[N:10]2[N:11]=[CH:12][CH:13]=[C:9]2[N:8]=[C:7]([CH3:14])[CH:6]=1)[CH:2]([CH3:4])[CH3:3].[Br:15]N1C(=O)CCC1=O.[OH-].[Na+]>C(Cl)(Cl)Cl>[Br:15][C:13]1[CH:12]=[N:11][N:10]2[C:5]([CH2:1][CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]([CH3:14])=[N:8][C:9]=12
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(CC(C)C)n2nccc2n1
Agent: [Na+]
Agent: [OH-]
Solvent: ClC(Cl)Cl
Product: Cc1cc(CC(C)C)n2ncc(Br)c2n1
Temperature: 25 °C

Procedure:
A solution of 7.5 g (0.026 mol) of 7-isobutyl-5-methylpyrazolo-[1,5-a]pyrimidine in 60 ml chloroform was treated with 4.6 gm (0.026 mol) of N-bromosuccinimide. The mixture was stirred at ambient temperature and then allowed to cool overnight in the refrigerator. The mixture was then poured over ice (100 gm), rendered alkaline with 6N NaOH, and extracted with chloroform. The chloroform solution was separated, dried (Na2SO4), and distilled to yield 5.5 gm, (47%) of a light yellow, viscous oil, b.p. 127°-129° /1.5 mm.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]Br)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2].[I:30][C:31]1[CH:32]=[C:33]([OH:41])[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O.CC(C)=O>[CH2:1]([O:3][C:4](=[O:29])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:41][C:33]2[CH:34]=[C:35]([S:37]([CH3:40])(=[O:39])=[O:38])[CH:36]=[C:31]([I:30])[CH:32]=2)[C:10]=1[CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH3:2]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCBr)c1CCC(=O)OCC
Reactant: CS(=O)(=O)c1cc(O)cc(I)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(I)cc(S(C)(=O)=O)c2)c1CCC(=O)OCC
Temperature: 25 °C
Yield: 90.8 %

Procedure:
To a mixture of 4-[3-(6-bromo-hexyl)-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (1.17 g, 2.49 mmol), 3-iodo-5-methanesulfonyl-phenol (620 mg, 2.08 mmol), and potassium carbonate (575 mg, 4.16 mmol) were added dimethylformamide (13.4 mL) and acetone (26.8 mL) at room temperature. The resulting suspension was heated to reflux for 2 days. Then, the reaction mixture was cooled to room temperature and diluted with water (100 mL). The organic compound was extracted into ethyl acetate (3×50 mL) and the combined organic extracts were washed with water (100 mL) and brine solution (100 mL). The organic layers were dried over anhydrous magnesium sulfate and filtration of the drying agent and concentration of the solvent gave the crude product which was purified by using an ISCO 40 g column, eluting with 2-20% ethyl acetate in hexanes to afford 4-{2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-iodo-5-methanesulfonyl-phenoxy)-hexyl]-phenoxy}-butyric acid ethyl ester (1.3 g, 91%) as a colorless oil: ES(+)-HRMS m/e calcd for C30H41IO8S (M+Na)+ 711.1459, found 711.1460.
Reaction SMILES: [CH2:1]([CH:3]([CH2:18][CH3:19])[CH:4](O)[C:5]([O:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)=[O:6])[CH3:2].FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.N1C(C)=CC=CC=1C.CCN(C(C)C)C(C)C.[Si:52]([O:59][CH2:60][C@@H:61]1[C@@H:65]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:64][NH:63][CH2:62]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]>C(Cl)Cl>[Si:52]([O:59][CH2:60][C@@H:61]1[C@@H:65]([C:66]2[CH:71]=[CH:70][CH:69]=[C:68]([F:72])[CH:67]=2)[CH2:64][N:63]([CH:4]([CH:3]([CH2:18][CH3:19])[CH2:1][CH3:2])[C:5]([O:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)=[O:6])[CH2:62]1)([C:55]([CH3:58])([CH3:57])[CH3:56])([CH3:54])[CH3:53]
Reactant: CCC(CC)C(O)C(=O)OCc1ccc(OC)cc1
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1CNC[C@@H]1c1cccc(F)c1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: Cc1cccc(C)n1
Solvent: CCN(C(C)C)C(C)C
Product: CCC(CC)C(C(=O)OCc1ccc(OC)cc1)N1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@@H](c2cccc(F)c2)C1
Reaction time: 0.08 h
Yield: 67.3 %

Procedure:
A solution of 0.82 g (2.93 mmol) of 3-Ethyl-2-hydroxyvaleric acid, 4-methoxybenzyl ester (step B) in 5 mL of dry CH2Cl2 was cooled in a −78° C. bath and 0.6 mL (3.57 mmol) of trifluoromethanesulfonic anhydride was added. After 5 min, 0.46 mL (4 mmol) of 2,6-lutidine was added and stirred for 15 min. To this solution, 1.3 mL (7.47 mmol) of DIEA was added and after 10 min a solution of 0.907 g (2.93 mmol) of 3-(R)-t-butyldimethylsilyloxymethyl-4-(S)-(3-fluorophenyl)pyrrolidine in 5 mL of CH2Cl2 was added. The cold bath was removed and the reaction was stirred overnight. The reaction was quenched with saturated NaHCO3 and extracted with Et2O. The combined Et2O layer was washed with brine, dried and concentrated. The residue was purified on a flash column using 10% EtOAc-hexane to isolate 1.1 g of the desired product as a mixture of two diastereomers. 1H NMR (CDCl3) 0.06 and 0.16 (6H), 0.87 (m, 15H), 1.2-3.6 (m, 13H), 3.82 (2s, 3H), 5.11 (s, 2H), 6.8-7.4 (m, 8H),
Reaction SMILES: [F:1][C:2]1[S:6][C:5]([C@:7]23[CH2:15][N:14]([C:16]4[N:21]=[CH:20][CH:19]=[CH:18][N:17]=4)[CH2:13][C@H:12]2[CH2:11][S:10][C:9]([NH:22]C(=O)C2C=CC=CC=2)=[N:8]3)=[CH:4][CH:3]=1.[OH-].[Li+]>CO>[F:1][C:2]1[S:6][C:5]([C@:7]23[CH2:15][N:14]([C:16]4[N:17]=[CH:18][CH:19]=[CH:20][N:21]=4)[CH2:13][C@H:12]2[CH2:11][S:10][C:9]([NH2:22])=[N:8]3)=[CH:4][CH:3]=1
Reactant: O=C(NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncccn3)C[C@H]2CS1)c1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Product: NC1=N[C@@]2(c3ccc(F)s3)CN(c3ncccn3)C[C@H]2CS1
Yield: 94.6 %

Procedure:
To N-[(4aR,7aR)-7a-(5-fluorothiophen-2-yl)-6-(pyrimidin-2-yl)-4,4a,5,6,7,7a-hexahydropyrrolo[3,4-d][1,3]thiazin-2-yl]benzamide (456 mg, 1.04 mmol) is added methanol (10.4 mL) and lithium hydroxide (218 mg, 5.19 mmol). The solution is heated to reflux for 2.5 hours under an atmosphere of nitrogen. The resulting solution is allowed to cool for a few minutes then concentrated under reduced pressure. The residue is extracted with dichloromethane (30 mL) and water (30 mL). The phases are partitioned and the aqueous phase further extracted with dichloromethane (1×30 mL). The combined dichloromethane extracts are dried over sodium sulfate, filtered, and concentrated under reduced pressure. The residue is purified by silica gel chromatography eluting with dichloromethane/methanol, gradient from 99:1 to 90:10, to give the title compound (330 mg, 95%) as an amorphous white solid. ES/MS (m/e): 335.8 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([CH3:14])(C)[C:10](O)=O)[CH:6]=[CH:7][CH:8]=1.C([N:17](CC)CC)C.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1>CC(O)(C)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([NH2:17])([CH3:14])[CH3:10])[CH:6]=[CH:7][CH:8]=1
Reactant: CCN(CC)CC
Reactant: COc1cccc(C(C)(C)C(=O)O)c1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CC(C)(C)O
Product: COc1cccc(C(C)(C)N)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 2-(3-methoxyphenyl)-2-methylpropanoic acid (330 mg, 1.70 mmol) and triethylamine (191 mg, 1.87 mmol) in t-BuOH (15 ml), DPPA (514 mg, 1.87 mmol) was added and the resultant solution was refluxed for 2 h. Then t-BuOH was removed under vacuum. Crude residue was dissolved in THF (10 ml) and 2N HCl (10 ml) was added and stirred overnight at RT. Then solvent was removed, crude residue dissolved in water and extracted with ether. Aqueous layer was basified with 5N NaOH and extracted with ethyl acetate. Organic layer was dried and evaporated to yield 2-(3-methoxyphenyl)propan-2-amine.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([CH:18]([OH:32])[CH:19]4[CH2:24][CH2:23][N:22]([C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH2:21][CH2:20]4)[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2].C(Cl)Cl.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>>[CH2:1]([C:3]1[N:7]([C:8]2[N:16]=[C:15]3[C:11]([N:12]=[C:13]([C:18]([CH:19]4[CH2:20][CH2:21][N:22]([C:25]([CH3:31])([CH3:30])[C:26]([O:28][CH3:29])=[O:27])[CH2:23][CH2:24]4)=[O:32])[N:14]3[CH3:17])=[C:10]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[N:9]=2)[C:6]2[CH:39]=[CH:40][CH:41]=[CH:42][C:5]=2[N:4]=1)[CH3:2]
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(O)C3CCN(C(C)(C)C(=O)OC)CC3)n(C)c2n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Solvent: ClCCl
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(C(=O)C3CCN(C(C)(C)C(=O)OC)CC3)n(C)c2n1
Reaction time: 1 h
Yield: 64 %

Procedure:
To a solution of racemic methyl 2-(4-((2-(2-ethyl-1H-benzo[d]imidazol-1-yl)-9-methyl-6-morpholino-9H-purin-8-yl)(hydroxy)methyl)piperidin-1-yl)-2-methylpropanoate, from the procedures for 526 and 527, (0.115 g, 0.199 mmol) in methylene chloride (5.0 mL, 78 mmol) was added Dess-Martin periodinane (0.0930 g, 0.219 mmol). The resulting mixture was then stirred at room temp. for 1 hour. The reaction mixture was filtered though paper to remove all solid precipitates and then concentrated. The residue was then purified by RP-HPLC to give 528 (52 mg, 64%). LCMS m/z: 288.3 (2M+H+)
Reaction SMILES: [CH:1]1([N:4]2[CH2:27][CH2:26][C:7]3[N:8]([CH2:16][C:17]([C:20]4[CH:25]=[CH:24][N:23]=[CH:22][CH:21]=4)(O)[CH3:18])[C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:3][CH2:2]1>S(Cl)(Cl)=O>[CH:1]1([N:4]2[CH2:27][CH2:26][C:7]3[N:8](/[CH:16]=[C:17](/[C:20]4[CH:21]=[CH:22][N:23]=[CH:24][CH:25]=4)\[CH3:18])[C:9]4[CH:10]=[CH:11][C:12]([CH3:15])=[CH:13][C:14]=4[C:6]=3[CH2:5]2)[CH2:2][CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(C)(O)c2ccncc2)CCN(C2CC2)C1
Solvent: O=S(Cl)Cl
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C1CC1)CC2)c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1-(2-Cyclopropyl-1,2,3,4-tetrahydro-8-methylpyrido[4,3-b]indol-5-yl)-2-(pyridin-4-yl)propan-2-ol (100 mg, 0.27 mmol) was dissolved in thionyl chloride (1 mL), and stirred for 1-2 h at RT. The reaction mixture was concentrated under reduced pressure; the residue was cooled in ice water and basified with saturated aqueous NaHCO3. The product was extracted with EtOAc and organic layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by HPLC. Yield: 100 mg. 1H NMR (CD3OD, TFA salt) δ (ppm): 8.80 (d, 2H), 8.30 (d, 2H), 7.78 (s, 1H), 7.38 (s, 1H), 7.18 (m, 2H), 4.70 (m, 2H), 3.90 (m, 2H), 3.22 (m, 2H), 3.15 (m, 1H), 2.45 (s, 3H), 2.16 (s, 3H), 1.20 (m, 2H), 1.10 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[OH:13].[C:14]([O-])([O-])=O.[K+].[K+].S(OC)(OC)(=O)=O>CC(C)=O>[Br:1][C:2]1[CH:7]=[C:6]([Br:8])[N:5]=[C:4]([C:9]([O:11][CH3:12])=[O:10])[C:3]=1[O:13][CH3:14]
Reactant: COC(=O)c1nc(Br)cc(Br)c1O
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: COS(=O)(=O)OC
Solvent: CC(C)=O
Product: COC(=O)c1nc(Br)cc(Br)c1OC

Procedure:
To methyl 4,6-dibromo-3-hydroxypyridine-2-carboxylate 3.98 g (3.98 g, 12.81 mmol) in 40 mL of acetone was added K2CO3 (2.0 g, 14.47 mmol) and dimethyl sulfate (1.20 mL, 12.37 mmol). The reaction mixture was refluxed overnight and concentrated to dryness. The residue was dissolved in ethyl acetate and saturated sodium bicarbonate. The phases were separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were dried (MgSO4) and concentrated to dryness. The residue was purified by chromatography (silica gel). Elution with 15% ethyl acetate/hexane gave 0.980 g, of a white solid. 1H NMR(CDCl3): δ 3.95 (s, 3H); 3.90 (s, 3H); 7.80 (s, 1H).