Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([NH:4][C:5]2(N)[N:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]3[C:6]2=[N:7][CH:8]=[N:9]3)[CH2:3][CH2:2]1.[CH3:19][O:20][C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][C:26]=1[O:27][CH3:28].C(N(CC)CC)C.C(#N)C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.C(OCC)(=O)C>[CH:1]1([NH:4][C:5]2[N:13]=[C:12]([C:14]([F:17])([F:15])[F:16])[N:11]=[C:10]3[C:6]=2[N:7]=[CH:8][N:9]3[C:24]2[CH:23]=[CH:22][C:21]([O:20][CH3:19])=[C:26]([O:27][CH3:28])[CH:25]=2)[CH2:3][CH2:2]1
Reactant: NC1(NC2CC2)N=C(C(F)(F)F)N=C2N=CN=C21
Reactant: COc1ccc(B(O)O)cc1OC
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ccc(-n2cnc3c(NC4CC4)nc(C(F)(F)F)nc32)cc1OC
Temperature: 52.5 °C
Reaction time: 18 h
Yield: 10.4 %

Procedure:
A mixture of 6-cyclopropylamino-2-trifluoromethyladenine (46 mg, 0.2 mmol), 3,4-dimethoxyphenyl boronic acid (44 mg, 0.24 mmol), copper(II) acetate (36 mg, 0.2 mmol), triethylamine (1.0 mmol, 101 mg), anhydrous acetonitrile (4 ml) and molecular seives (˜10 pellets) was stirred at 50-55° C. for 18 hours. Ethyl acetate (20 ml) was added and the solid was removed by filtration. The filtrate was washed with 20 ml of 5% sodium bicarbonate aqueous solution. Evaporation and chromatography over SiO2 using hexane/ethylacetate/methanol (50:50:1) as elunt gave 7.9 mg of the title compound (yield 10%). 1H NMR (300 MHz, CDCl3) δ 8.10 (s, 1H), 7.39 (s, 1H), 7.13 (d, J=8.7 Hz, 2H), 6.98 (d, J=8.7 Hz, 2H), 6.35(b, 1H), 3.93 (s, 3H), 3.90 (s, 3H), 3.18 (b, 1H), 0.91 (m, 2H), 0.69 (m, 2H)
Reaction SMILES: Cl[C:2]1[C:7]([Cl:8])=[CH:6][CH:5]=[CH:4][N:3]=1.O.C([O-])([O-])=O.[Na+].[Na+].B(O)(O)[C:17]1[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=1>COCCOC.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>[Cl:8][C:7]1[C:2]([C:17]2[CH:22]=[CH:21][C:20]([C:23]([OH:25])=[O:24])=[CH:19][CH:18]=2)=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Clc1cccnc1Cl
Reactant: O=C(O)c1ccc(B(O)O)cc1
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: COCCOC
Solvent: O
Product: O=C(O)c1ccc(-c2ncccc2Cl)cc1
Temperature: 25 °C
Yield: 75.4 %

Procedure:
To a solution of 5.3 g (36.1 mmol) 2,3-dichloropyridine in 200 mL 1,2-dimethoxyethane and 200 mL distilled water were added 22.3 g (0.21 mol) Na2CO3, 5.0 g (30.1 mmol) 4-carboxylphenylboronic acid and 0.5 g Pd(PPh3)4, followed by mixing for 18 hours under a heat flux condition by stirring. After being cooled to room temperature, the solution was 50% concentrated in a vacuum. The aqueous layer was washed with ethyl acetate and adjusted into pH 1 with conc. HCl. Thereafter, extraction with ethyl acetate was conducted three times and the organic layer was dried over magnesium sulfate and concentrated in a vacuum. The concentrate was separated using column chromatography (developing solvent: chloroform/methanol=10/1) to afford 5.3 g of 4-(3-chloropyridin-2-yl)benzoic acid as a white precipitate (yield: 75%).
Reaction SMILES: [CH3:1][O:2][CH:3]1[O:7][C:6](=[O:8])[CH:5]=[CH:4]1.[C:9]1(S(C2C=CC=CC=2)=C(C)C)[CH:14]=CC=C[CH:10]=1>CO>[CH3:10][C:9]1([CH3:14])[CH:5]2[CH:4]1[CH:3]([O:2][CH3:1])[O:7][C:6]2=[O:8]
Reactant: CC(C)=S(c1ccccc1)c1ccccc1
Reactant: COC1C=CC(=O)O1
Solvent: CO
Product: COC1OC(=O)C2C1C2(C)C

Procedure:
In a preferred embodiment of the invention, the alcohol ZOH is methanol and the 5(RS)-methoxy-2,5-dihydrofuran-2-one is reacted with diphenyl isopropylidene sulfurane to obtain (1RS, 5SR) 6,6-dimethyl-4(RS)-methoxy-3-oxabicyclo (3,1,0) hexan-2-one which is then subjected to acid hydrolysis to obtain (1RS, 5SR) 6,6-dimethyl-4(RS)-hydroxy-3-oxabicyclo (3,1,0) hexan-2-one.
Reaction SMILES: Cl[C:2]1[N:3]=[C:4]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[C:5]2[S:10][C:9]([CH2:11][N:12]3[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]3)=[CH:8][C:6]=2[N:7]=1.Br[C:29]1[C:38]2[C:33](=[CH:34][CH:35]=[CH:36][CH:37]=2)[C:32]([NH:39][CH2:40][CH3:41])=[N:31][CH:30]=1>>[CH2:40]([NH:39][C:32]1[C:33]2[C:38](=[CH:37][CH:36]=[CH:35][CH:34]=2)[C:29]([C:2]2[N:3]=[C:4]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:5]3[S:10][C:9]([CH2:11][N:12]4[CH2:17][CH2:16][CH:15]([C:18]([OH:21])([CH3:20])[CH3:19])[CH2:14][CH2:13]4)=[CH:8][C:6]=3[N:7]=2)=[CH:30][N:31]=1)[CH3:41]
Reactant: CC(C)(O)C1CCN(Cc2cc3nc(Cl)nc(N4CCOCC4)c3s2)CC1
Reactant: CCNc1ncc(Br)c2ccccc12
Product: CCNc1ncc(-c2nc(N3CCOCC3)c3sc(CN4CCC(C(C)(C)O)CC4)cc3n2)c2ccccc12

Procedure:
Following the procedures for 108, 2-(1-((2-chloro-4-morpholinothieno[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol and 4-bromo-N-ethylisoquinolin-1-amine were converted to 137. LCMS: M+H+=547. 1H NMR (400 MHz, DMSO) δ 9.03 (d, J=8.5, 1H), 8.67 (s, 1H), 8.28 (d, J=8.3, 1H), 7.68 (dd, J=16.9, 6.5, 2H), 7.51 (t, J=7.5, 1H), 7.37 (s, 1H), 4.04 (s, 1H), 3.93 (d, J=4.8, 4H), 3.80 (d, J=6.3, 6H), 3.65-3.54 (m, 2H), 2.99 (d, J=10.9, 2H), 2.07 (s, 1H), 1.97 (t, J=11.5, 2H), 1.67 (d, J=10.9, 2H), 1.36-1.12 (m, 6H), 1.04 (s, 6H)
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH:11]=[CH:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)[OH:14].O.C1C=C(Cl)C=C(C(OO)=O)C=1>CC(C)=O>[CH2:1]([N:8]1[CH2:12][CH:11]2[O:14][CH:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1=CCN(Cc2ccccc2)C1
Reactant: O=S(=O)(O)O
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: CC(C)=O
Solvent: O
Product: c1ccc(CN2CC3OC3C2)cc1
Yield: 97 %

Procedure:
To a solution of 15.9 g (0.1 mol) of 1-benzyl-3-pyrroline, 12.0 g (0.12 mol) of 98% sulfuric acid, 15.0 g of water, and 60.0 g of acetone in a round flask reactor, 31.1 g (0.13 mol) of 70% m-CPBA (m-chloroperbenzoic acid produced by Tokyo Chemical Industry Co., Ltd.) was added with stirring and allowed to react for 10 hours at room temperature without irradiation by lamps. After completion, acetone was evaporated under reduced pressure, neutralized by NaOH (aq), and extracted with toluene and water. After the solvent was evaporated under reduced pressure, 17.0 g of 1-benzyl-3,4-epoxypyrrolidine (yield 97.0%) was obtained.
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH:15]2[CH2:17][O:16]2)=[CH:9][CH:8]=1)(C)(C)C.[S:20]1[CH:24]=[CH:23][CH:22]=[C:21]1[C:25]1[C:33]2[C:32]([N:34]3[CH2:39][CH2:38][CH:37]([NH2:40])[CH2:36][CH2:35]3)=[N:31][CH:30]=[N:29][C:28]=2[S:27][CH:26]=1>>[OH:16][CH:15]([CH2:17][NH:40][CH:37]1[CH2:36][CH2:35][N:34]([C:32]2[C:33]3[C:25]([C:21]4[S:20][CH:24]=[CH:23][CH:22]=4)=[CH:26][S:27][C:28]=3[N:29]=[CH:30][N:31]=2)[CH2:39][CH2:38]1)[CH2:14][O:13][C:10]1[CH:9]=[CH:8][C:7]([OH:6])=[CH:12][CH:11]=1
Reactant: NC1CCN(c2ncnc3scc(-c4cccs4)c23)CC1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc(OCC2CO2)cc1
Product: Oc1ccc(OCC(O)CNC2CCN(c3ncnc4scc(-c5cccs5)c34)CC2)cc1
Yield: 27 %

Procedure:
Synthesis followed SP6 (5 h), using 150 μmol tert-butyldimethyl(4-(oxiran-2-ylmethoxy)phenoxy)silane and 1-(5-(2-thienyl)thieno[2,3-d]pyrimidin-4-yl)piperidin-4-amine to give O-silylated intermediate upon purification by prep. HPLC (reversed phase) and prep. TLC (1 mm silica gel, CH2Cl2MeOH 95:5) with 27% yield. Product was obtained by deprotection according to SP7 and purification by prep. HPLC (reversed phase) with 27% yield.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][C:13]([F:16])=[C:12]([O:17][CH3:18])[CH:11]=1)(C)(C)C.[ClH:20].C(OCC)(=O)C>C(OCC)(=O)C.C(OCC)C>[ClH:20].[F:16][C:13]1[CH:14]=[CH:15][C:10]([CH2:9][CH2:8][NH2:7])=[CH:11][C:12]=1[O:17][CH3:18]
Reactant: COc1cc(CCNC(=O)OC(C)(C)C)ccc1F
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: COc1cc(CCN)ccc1F
Reaction time: 2.5 h

Procedure:
To a solution of [2-(4-fluoro-3-methoxyphenyl)ethyl]carbamic acid t-butyl ester (90 mg) in ethyl acetate (3 mL) was added a solution of 4N hydrochloric acid-ethyl acetate (3 mL) at room temperature and allowed to stand for 2.5 hours. The resulting solid was diluted with diethyl ether, then filtered, and washed with diethyl ether. After drying by aeration, and the title compound (416 mg) was obtained as a colorless solid.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[C:9]([Cl:14])[CH:8]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].O.Br[CH2:26][CH2:27][CH2:28][O:29][C:30]1[CH:35]=[CH:34][C:33]([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:31]=1>CC#N>[CH2:1]([O:3][C:4](=[O:17])[CH:5]([O:15][CH3:16])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:26][CH2:27][CH2:28][O:29][C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[C:9]([Cl:14])[CH:8]=1)[CH3:2]
Reactant: CCOC(=O)C(Cc1ccc(O)c(Cl)c1)OC
Reactant: BrCCCOc1ccc(-c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: CCOC(=O)C(Cc1ccc(OCCCOc2ccc(-c3ccccc3)cc2)c(Cl)c1)OC
Temperature: 85 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
3-(3 Chloro-4-hydroxy-phenyl)-2-methoxy-propionic acid ethyl ester (0.020 g, 0.077 mmol) was dissolved in CH3CN (3 mL) and 4-(3-bromo-propoxy)-biphenyl (Example 132, Step D), (0.025 g 0.085 mmol) and K2CO3 (0.032 g, 0.23 mmol) were added. The mixture was heated to 85° C. and stirred for 5 hours. After cooling, water (2 mL) was added. The mixture was extracted in EtOAc (3×10 mL), washed with H2O (2×5 mL) and brine (2×5 mL). The organic layer was dried (MgSO4), filtered, and concentrated in vacuo. The crude product was purified by silica gel column chromatography (silica gel, hexanes/ethyl acetate 9:1) to produce 3-{4-[3-(Biphenyl-4-yloxy)-propoxy]-3-chloro-phenyl}-2-methoxy-propionic acid ethyl ester (0.017 mg, 48%). 1H-NMR (200.15 MHz, CDCl3): δ 7.57–7.24 (m, 9H), 7.02–6.89 (m, 3H), 4.28–4.12 (m, 5H), 3.89 (dd, 1H, J=7.24, 5.62), 3.62 (t, 1H, J=6.44), 3.36 (s, 3H), 2.93 (dd, 2H, J=6.31, 2.42), 2.32 (qn, 2H, J=5.10), 1.25 (t, 3H, J=7.2).
Reaction SMILES: [C:1]([C:3]1[CH:52]=[CH:51][CH:50]=[CH:49][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[N:20](C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[N:19]=[C:18]3[C:43]2[CH:48]=[CH:47][N:46]=[CH:45][CH:44]=2)=[O:14])[CH2:7]1)#[N:2].[C:53]([OH:59])([C:55]([F:58])([F:57])[F:56])=[O:54]>>[F:56][C:55]([F:58])([F:57])[C:53]([O-:59])=[O:54].[C:1]([C:3]1[CH:52]=[CH:51][CH:50]=[CH:49][C:4]=1[CH2:5][N:6]1[CH2:11][CH2:10][CH2:9][C@@H:8]([NH:12][C:13]([C:15]2[CH:16]=[C:17]3[C:21](=[CH:22][CH:23]=2)[NH:20][N:19]=[C:18]3[C:43]2[CH:44]=[CH:45][NH+:46]=[CH:47][CH:48]=2)=[O:14])[CH2:7]1)#[N:2]
Reactant: N#Cc1ccccc1CN1CCC[C@@H](NC(=O)c2ccc3c(c2)c(-c2ccncc2)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Reactant: O=C(O)C(F)(F)F
Product: N#Cc1ccccc1CN1CCC[C@@H](NC(=O)c2ccc3[nH]nc(-c4cc[nH+]cc4)c3c2)C1
Product: O=C([O-])C(F)(F)F
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
To a microwave vial equipped with a stir bar was added N-[(3R)-1-(2-cyanobenzyl)piperidin-3-yl]-3-pyridin-4-yl-1-trityl-1H-indazole-5-carboxamide (41.7 mg, 0.061 mmol) and TFA (1000 μl, 12.98 mmol). The reaction was stirred at room temperature for 20 minutes. After 20 minutes the LCMS indicates formation of the desired product. Triethylsilane (19.62 μl, 0.123 mmol) was addes, and the crude reaction was concentrated in vacuo. The crude was dissolved in 1 ml DMSO, filtered, and purified by reverse phase chromatography. The material was concentrated, and was then dissolved in acetonitrile and water. The compound was dried on the lyophilizer over 2 days to provide fluffy white solid. LCMS calc'd for C26H25N6O [M+H]+=437; found 437 1H NMR (600 MHz, CD3OD) δ 8.9 (d, 2H), 8.9 (s, 1H), 8.7 (d, 2H), 8.0 (d, 1H), 7.9 (d, 1H), 7.8 (s, 2H), 7.8 (d, 1H), 7.7 (m, 1H), 4.6 (s, 2H), 4.4 (m, 1H), 3.7 (m, 1H), 3.6 (m, 1H), 3.2 (m, 2H), 2.2 (m, 2H), 2.0 (m, 1H), 1.8 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[CH2:10][CH2:9][CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:7][C:6]1=O.[CH2:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[NH:29]N)[CH3:22].O.B(F)(F)F.CCOCC>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3](=[O:20])[CH2:4][C:5]1([CH2:18][CH3:19])[C:6]2[NH:29][C:24]3[C:25](=[CH:26][CH:27]=[CH:28][C:23]=3[CH2:21][CH3:22])[C:7]=2[CH:8]([CH2:11][CH2:12][CH2:13][CH2:14][CH:15]=[CH2:16])[CH2:9][CH2:10]1
Reactant: CCc1ccccc1NN
Reactant: C=CCCCCC1CCC(CC)(CC(=O)OC)C(=O)C1
Agent: FB(F)F
Solvent: Cc1ccccc1
Solvent: O
Solvent: CCOCC
Product: C=CCCCCC1CCC(CC)(CC(=O)OC)c2[nH]c3c(CC)cccc3c21
Yield: 64 %

Procedure:
A solution of 1-ethyl-4-(5-hexenyl)-2-oxocyclohexaneacetic acid methyl ester isomer B (4.24 g, 15.14 mmol) and 2-ethylphenylhydrazine (2.27 g, 16.7 mmol) in 30.3 mL of toluene was refluxed under nitrogen for 22 hours with azeotropic removal of water. The toluene was then removed in vacuo and replaced with 10.8 mL of acetic acid. The solution was treated with borontrifluoride etherate (2.79 g, 19.7 mmol, 2.42 mL) and refluxed for 20 minutes under nitrogen. The reaction mixture was poured into 120 mL of water and extracted with 4×80 mL of ether. The pooled extracts were washed with 2×110 mL of 1M HCl and 2×80 mL of 2.5N NaOH. Drying (MgSO4) and flash chromatography (75 mm diameter column, 8% ethyl acetate in petroleum ether eluent) afforded 3.72 g (9.73 mmol, 64%) of 1,8-diethyl-4-(5-hexenyl)-2,3,4,9-tetrahydro-1H-carbazole-1 -acetic acid methyl ester. Of this, 3.68 g (9.66 mmol) were refluxed in a solution of ethanol (30.9 mL) and 2.5N NaOH (7.7 mL) for 45 minutes under nitrogen. The ethanol was then removed in vacuo and the residue was suspended in 120 mL of 1N HCl. It was extracted with 4×40 mL of ether and the pooled extracts were dried over MgSO4. Flash chromatography (50 mm diameter column, 10% ethyl acetate in petroleum ether eluent, 2% H3PO4 in MeOH treated silica gel) afforded 3.41 g (9.18 mmol, 95%) of a light yellow solid which was recrystallized from 85:15 petroleum ether:benzene. This resulted in 1.98 g of a white powder which were dried at 84° C. for 31 hours followed by recrystallization from 85:15 petroleum ether:benzene once again. Drying at 84° C. for 24 hours resulted in 1.41 g of a white powder, m.p. 96°-97° C.
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([OH:14])[CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29]Br)=[C:23]([Cl:32])[CH:22]=1)(=[O:20])=[O:19]>CN(C=O)C>[NH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28](=[O:31])[CH2:29][O:14][C:10]2[CH:11]=[CH:12][CH:13]=[C:8]([O:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH:9]=2)=[C:23]([Cl:32])[CH:22]=1)(=[O:20])=[O:19]
Reactant: Oc1cccc(Oc2ccccc2)c1
Reactant: NS(=O)(=O)c1ccc(NC(=O)CBr)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: NS(=O)(=O)c1ccc(NC(=O)COc2cccc(Oc3ccccc3)c2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A stirred solution of 37 mg (0.198 mmol) of 3-phenoxyphenol (1-1) in 1 mL anhydrous DMF under nitrogen was treated with 10 mg (0.397 mmol) of 60% NaH dispersion. The resulting mixture was stirred at room temperature for 4 hours and then treated with 65 mg (0.198 mmol) of N-[4-(aminosulfonyl)-2-chlorophenyl]-2-bromoacetamide (A-3). This mixture was then stirred at room temperature for an additional 4 hours. The reaction was concentrated in vacuo, and the residue was purified by reverse phase prep LC on a Gilson unit. Clean product fractions were combined and concentrated in vacuo to give the desired product 1-2 as a white solid. MS: M+1=433.2.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][N:9](C3N=C(N4CCOCC4)C4N=CN=C(N(CC5C=CC=CC=5)C)C=4N=3)[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.ClC1N=C(N2CCOCC2)C2N=CN=C(N(CC3C=CC=CC=3)C)C=2N=1>>[N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(N3CCC(N4CCCC4)CC3)nc12
Agent: CN(Cc1ccccc1)c1ncnc2c(N3CCOCC3)nc(Cl)nc12
Product: C1CCN(C2CCNCC2)C1
Yield: 57 %

Procedure:
2-(4-pyrrolidino-piperidin-1-yl)-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido [5,4-d]pyrimidine From 2-chloro-8-(N-benzyl-N-methyl-amino)-4-morpholino-pyrimido[5,4-d]pyrimidine and 4-pyrrolidino-piperidine Yield: 57% of theory, Melting point: 131°-134° C. C27H36N8O (488.64)
Reaction SMILES: C(NCC[C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1)(=O)CC.[H-].[Na+].C(O[CH2:21][CH3:22])(=O)C>O1CCCC1>[C:22]1([O:14][C:11]2[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=2)[CH:21]=[CH:10][CH:9]=[CH:8][CH:13]=1
Reactant: CCC(=O)NCCc1ccc(O)cc1
Reactant: CCOC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: c1ccc(Oc2ccccc2)cc1
Reaction time: 0.17 h
Yield: 32 %

Procedure:
To a stirred solution of N-ethyl, N-propionyl tyramine (2.84 g, 12.83 mmole) in tetrahydrofuran (32.1 ml) was added 60% sodium hydride dispersion (0.56 g, 14.11 mmole). After stirring for 10 minutes, the compound of Example 42(E) (4.70 g, 12.83 mmole) was added. The reaction was allowed to stir at room temperature for 5 hours, poured into ethyl acetate, and extracted with 10% sodium sulfate, then brine. The organic layer was dried over sodium sulfate, evaporated to dryness, and chromatographed on silica gel using a hexane-ethyl acetate gradient. Further chromatography on silica gel using toluene-acetone gradients yielded the intermediate phenyl ether (2.10 g, 32%):
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][O:10][C:3]=12.[NH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1>CO>[N:11]1([C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[CH:8]=[CH:9][O:10][C:3]=23)[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1
Reactant: C1CNCCN1
Reactant: Clc1ccnc2ccoc12
Solvent: CO
Product: c1cc(N2CCNCC2)c2occc2n1
Temperature: 130 °C
Yield: 21.8 %

Procedure:
A mixture of 7-Chloro-furo[3,2-b]pyridine (0.73 g, 4.75 mmol) and piperazine (1.2 g, 14 mmol) in a sealed tube was heated to 130° C. for 4 hours. After cooling, the solid was dissolved in MeOH and DCM, concentrated and subject to column chromatography, eluted by DCM/MeOH (10:1-1:1) to give 7-Piperazin-1-yl-furo[3,2-b]pyridine (0.21 g, 22%). MS (APCI+) [M+H]+204.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][OH:11])[CH:5]=[CH:6][C:7]=1[Cl:8].CC(C)([O-])C.[K+].[Cl:20][C:21]1[N:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH2:34]Cl)[C:23](=[O:27])[N:24]([CH3:26])[N:25]=1>O1CCCC1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]([S:12][CH3:13])=[N:10][O:11][CH2:34][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=2[N:22]2[C:23](=[O:27])[N:24]([CH3:26])[N:25]=[C:21]2[Cl:20])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CSC(=NO)c1ccc(Cl)c(Cl)c1
Reactant: Cn1nc(Cl)n(-c2ccccc2CCl)c1=O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CSC(=NOCc1ccccc1-n1c(Cl)nn(C)c1=O)c1ccc(Cl)c(Cl)c1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
The product from Step C (2.07 g) was dissolved in 10 mL of tetrahydrofuran and 10 mL of 1.0 M potassium t-butoxide in THF was added dropwise. After the addition was complete, the mixture was stirred 15 min, and then the title compound of Step E (2.06 g) was added. The reaction mixture was stirred at room temperature overnight, and then diluted with 20 mL of water and extracted with three 30 mL portions of ethyl acetate. The combined organic extracts were dried (MgSO4), filtered, and concentrated to give 3.53 g of the title compound of Step F as an oil. 1H NMR (CDCl3): δ 7.5 (m,5H), 7.25 (m,2H), 5.34 (d,1H), 5.18 (d,1H), 3.49 (s,3H), 2.08 (s,3H). The crude product contained minor amounts of impurities and solvent, but the material was not further purified before Step G.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N+:11]([O-])=O)=[C:7]([CH:10]=1)[NH:8][CH3:9].[CH3:14]O>[Pd]>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:9][N:8]([CH3:14])[C:7]=2[CH:10]=1
Reactant: CNc1cc(OC)ccc1[N+](=O)[O-]
Reactant: CO
Agent: [Pd]
Product: COc1ccc2ncn(C)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
To a solution (200 mL) of 5-methoxy-N-methyl-2-nitroaniline (6.30 g) synthesized above in methanol was added 10% palladium/carbon (1.00 g) and the mixture was stirred under hydrogen atmosphere overnight at room temperature. Palladium/carbon was filtered off, and the filtrate was concentrated. A solution (150 mL) of the residue in formic acid was stirred overnight with heating under reflux, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (25% ethyl acetate/petroleum ether) to give the title object compound (4.07 g, 60%) as a white solid.
Reaction SMILES: C[O-].[Na+].[C:4]1([CH:10]2[CH2:18][C:17]3[C:12](=[C:13]([Cl:22])[C:14]([Cl:21])=[C:15]([O:19][CH3:20])[CH:16]=3)[C:11]2=[O:23])[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.I[CH2:25][CH3:26].C1C=CC=CC=1>O.CN(C)C=O>[CH2:25]([C:10]1([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:18][C:17]2[C:12](=[C:13]([Cl:22])[C:14]([Cl:21])=[C:15]([O:19][CH3:20])[CH:16]=2)[C:11]1=[O:23])[CH3:26]
Reactant: COc1cc2c(c(Cl)c1Cl)C(=O)C(c1ccccc1)C2
Reactant: CCI
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: c1ccccc1
Product: CCC1(c2ccccc2)Cc2cc(OC)c(Cl)c(Cl)c2C1=O
Reaction time: 1 h

Procedure:
Sodium methoxide (1.24 g., 0.023 mole) is added portionwise to a stirred mixture of 2-phenyl-5-methoxy-6,7-dichloro-1-indanone (4.61 g., 0.015 mole), iodoethane (15.5 ml., 0.15 mole), benzene (60 ml.) and dimethylformamide (60 ml.) under nitrogen in an ice-water bath. The reaction mixture is left to come to ambient temperature over one hour, then poured into water (1 l.), the benzene layer separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give 3.23 g. of 2-ethyl-2-phenyl-5-methoxy-6,7-dichloro-1-indanone which melts at 139°-141° C. on crystallization from benzene:hexane, 1:1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH:9]([S:12]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH2:10]Cl)=[CH:4][CH:3]=1.C(N(CC)CC)C>O1CCCC1.C(OCC)C>[Cl:21][C:18]1[CH:17]=[CH:16][C:15]([S:12]([C:9]([S:8][C:5]2[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=2)=[CH2:10])(=[O:14])=[O:13])=[CH:20][CH:19]=1
Reactant: O=S(=O)(c1ccc(Cl)cc1)C(CCl)Sc1ccc(Br)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=C(Sc1ccc(Br)cc1)S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 0.25 h
Yield: 40.7 %

Procedure:
Thirty-five grams (82 mmoles) of 2-chloro-1-(p-chlorophenylsulfonyl)ethyl p-bromophenyl sulfide was dissolved in 100 ml of tetrahydrofuran and treated with 12 ml (86 mmoles) of triethylamine. The mixture was diluted with 100 ml of diethyl ether and allowed to stand for 15 minutes. The precipitated triethylamine hydrochloride was separated by filtration. Evaporation of solvent from the filtrate gave 35 g of crude solid m.p. 45°-95°. Recrystallization from 100 ml of ethyl acetate-pentane (45:55) gave 13 g of pure product, m.p. 97°-99°.
Reaction SMILES: C(OC([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)=[O:16])[CH2:11][CH2:10]1)=O)(C)(C)C.Cl.O1CCOCC1>C(Cl)Cl>[NH2:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]([O:17][CH2:18][C:19]2[CH:24]=[C:23]([C:25]([F:26])([F:27])[F:28])[CH:22]=[C:21]([C:29]#[N:30])[CH:20]=2)=[O:16])[CH2:13][CH2:14]1
Reactant: CC(C)(C)OC(=O)NC1CCN(C(=O)OCc2cc(C#N)cc(C(F)(F)F)c2)CC1
Agent: Cl
Solvent: ClCCl
Solvent: C1COCCO1
Product: N#Cc1cc(COC(=O)N2CCC(N)CC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
3-Cyano-5-(trifluoromethyl)benzyl 4-((tert-butoxycarbonyl)amino)piperidine-1-carboxylate (119 mg, 0.278 mmol) was dissolved in DCM (5 ml) and 4M HCl in Dioxane (0.696 ml, 2.78 mmol) was added with stirring at RT under nitrogen. After 3 hrs, the mixture was concentrated in vacuo to give the title compound as the hydrochloride salt.