Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[NH:11][C:5]2[N:6]=[CH:7][CH:8]=[C:9]([OH:10])[C:4]=2[CH:3]=1.[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O>[F:12][C:13]1[CH:14]=[C:15]([N+:20]([O-:22])=[O:21])[CH:16]=[CH:17][C:18]=1[O:10][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[NH:11][C:2]([CH3:1])=[CH:3][C:4]=12
Reactant: Cc1cc2c(O)ccnc2[nH]1
Reactant: O=[N+]([O-])c1ccc(F)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(Oc3ccc([N+](=O)[O-])cc3F)ccnc2[nH]1
Temperature: 50 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
A mixture of 2-methyl-1H-pyrrolo[2,3-b]pyridin-4-ol (90 mg, TFA salt, 0.34 mmol), 3,4-difluoronitrobenzene (0.05 mL) and potassium carbonate (100 mg, 0.72 mmol) in DMF (1 mL) was stirred at 50° C. for 2 h. The mixture was diluted with water and extracted with ethyl acetate (3×5 mL). The combined extracts were washed with water, dried (MgSO4) and concentrated in vacuo to afford the crude product, which was purified by preparative HPLC to give the title compound (45 mg, 46%). 1H NMR (CD3OD) δ 8.25 (dd, 2H, J=10.4, 2.6 Hz), 8.12 (m, 1H), 8.04 (d, 1H, J=5.5 Hz), 7.30 (t, 1H, J=8.3 Hz), 6.67 (d, 1H, J=5.5 Hz), 5.95 (s, 1H), 2.41 (s, 3H); MS(ESI+) m/z 288 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15]Cl>>[CH3:10][O:11][CH2:12][CH2:13][O:14][CH2:15][O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: COCCOCCl
Product: COCCOCOc1ccc(C=O)cc1
Yield: 81.4 %

Procedure:
The hydroxyl group of 4-hydroxybenzaldehyde (24.9 g) was protected by use of 2-methoxyethoxymethyl chloride (24.4 g) in accordance with (production process 1), to thereby produce 4-methoxyethoxymethoxybenzaldehyde (33.5 g, yield: 80%). The thus-produced 4-methoxyethoxymethoxybenzaldehyde (21.0 g) and 3,4-dimethoxybenzyl cyanide (17.7 g) were subjected to condensation in accordance with process A of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxyphenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (29.1 g, yield: 86%). Separately, 2-methoxyethoxymethyl chloride (4.1 g), which had been prepared in a manner similar to that described above, and 3,4-dimethoxybenzyl cyanide (3.4 g) were subjected to condensation in accordance with process B of (production process 2), to thereby produce (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]acrylonitrile (5.2 g, yield: 73%). The thus-produced (Z)-2-(3,4-dimethoxy-phenyl)-3-[4-(2-methoxy-ethoxymethoxy)-phenyl]-acrylonitrile (10.2 g) was subjected to deprotection in accordance with (production process 3), to thereby produce the target product (6.22 g, yield: 74%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])O.[Na+].[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23](Cl)=[O:24])([CH3:19])[CH3:18])#[N:16]>O1CCCC1.O>[C:15]([C:17]([C:20]1[CH:21]=[C:22]([CH:26]=[CH:27][CH:28]=1)[C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:9])=[C:6]([OH:8])[CH:7]=1)=[O:24])([CH3:19])[CH3:18])#[N:16]
Reactant: CC(C)(C#N)c1cccc(C(=O)Cl)c1
Reactant: Cc1ccc(N)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2cccc(C(C)(C)C#N)c2)cc1O
Temperature: 25 °C
Yield: 94 %

Procedure:
To a solution of 5-amino-2-methylphenol (3.00 g, 24.3 mmol) in tetrahydrofuran (20 mL) was added a suspension of sodium hydrogencarbonate (3.00 g, 36.5 mmol) in water (30 mL), and the mixture was vigorously stirred at room temperature. To this mixture was added dropwise a solution of 3-(1-cyano-1-methylethyl)benzoyl chloride produced above in tetrahydrofuran (30 mL) under ice-cooling, and the mixture was stirred at room temperature for 5 hr. The aqueous layer was separated from the reaction mixture, and the organic layer was diluted with ethyl acetate and washed with saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was passed through a pad filled with two layers of silica gel and celite for filtration. The solvent was evaporated under reduced pressure, and the obtained solid was washed with ethyl acetate-hexane mixture to give the title compound (6.75 g, 94%) as a white powder.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[Cl-].ClC1N(C)CC[NH+]1C.[CH3:26][O:27][C:28]1[C:29](=[O:52])[C:30]([CH3:51])=[C:31]([CH2:37][C:38]2[CH:39]=[CH:40][C:41]([O:47][C:48](=[O:50])[CH3:49])=[C:42]([CH:46]=2)[C:43](O)=[O:44])[C:32](=[O:36])[C:33]=1[O:34][CH3:35]>C(Cl)Cl>[CH3:9][O:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:1][C:43](=[O:44])[C:42]2[CH:46]=[C:38]([CH2:37][C:31]3[C:32](=[O:36])[C:33]([O:34][CH3:35])=[C:28]([O:27][CH3:26])[C:29](=[O:52])[C:30]=3[CH3:51])[CH:39]=[CH:40][C:41]=2[O:47][C:48](=[O:50])[CH3:49])[CH:7]=1
Reactant: COc1cc(N)ncn1
Reactant: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)O)c2)=C(C)C1=O
Agent: CN1CC[NH+](C)C1Cl
Agent: [Cl-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC1=C(OC)C(=O)C(Cc2ccc(OC(C)=O)c(C(=O)Nc3cc(OC)ncn3)c2)=C(C)C1=O
Temperature: 25 °C
Reaction time: 10 h
Yield: 46.5 %

Procedure:
4-Amino-6-methoxypyrimidine (0.134 g, 1.070 mmol), triethylamine (0.141 g, 1.390 mmol) and 2-chloro-1,3-dimethylimidazolinium chloride (0.118 g, 0.695 mmol) were added to a methylene chloride solution (100 ml) of 5-(5,6-dimethoxy-3-methyl-1,4-benzoquinon-2-yl)methyl-2-acetoxybenzoic acid (0.200 g, 0.535 mmol) and the resulting solution was stirred at room temperature for 10 hours. The reaction solution was poured into ice water and then extracted with methylene chloride. The extract was washed with water and then dried, and the solvent was removed by distillation. The obtained residue was purified by preparative thin-layer chromatography (chloroform:methanol=10:1) to obtain the titled compound (0.120 g, 0.249 mmol, 47%).
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@:26]2([CH3:27])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([OH:21])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:29][C:30](=[O:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2].[CH3:33]OC(O[C@@H]1[C@@]2(C)C(=CC=C3[C@@H]2CC[C@@]2(C)[C@H]3CC[C@@H]2C(C(O)=O)C)C[C@@H](OC(OC)=O)C1)=O>>[C:1]([O:4][C@@H:5]1[C@@:26]2([CH3:27])[C:9](=[CH:10][CH:11]=[C:12]3[C@@H:25]2[CH2:24][CH2:23][C@@:22]2([CH3:28])[C@H:13]3[CH2:14][CH2:15][C@@H:16]2[CH:17]([C:19]([O:21][CH3:33])=[O:20])[CH3:18])[CH2:8][C@@H:7]([O:29][C:30](=[O:32])[CH3:31])[CH2:6]1)(=[O:3])[CH3:2]
Reactant: CC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(C)=O)C1
Reactant: COC(=O)O[C@@H]1CC2=CC=C3[C@@H]4CC[C@H](C(C)C(=O)O)[C@@]4(C)CC[C@@H]3[C@@]2(C)[C@@H](OC(=O)OC)C1
Product: COC(=O)C(C)[C@H]1CC[C@H]2C3=CC=C4C[C@@H](OC(C)=O)C[C@H](OC(C)=O)[C@]4(C)[C@H]3CC[C@]12C
Yield: 100.3 %

Procedure:
The procedure of Example 7 was repeated except that 89 mg of 1α,3β-diacetoxypregna-5,7-diene-20-carboxylic acid obtained in Example 22 was used in lieu of 85 mg of 1α,3β-bis(methoxycarbonyloxy)pregna-5,7-diene-20-carboxylic acid to give 82 mg of methyl 1α,3β-di-acetoxypregna-5,7-diene-20-carboxylate.
Reaction SMILES: C1(N=C=O)C=CC(N=C=O)=CC=1.[C:13]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[O:21][CH3:22])#[CH:14].[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][N+:30]([O-])=[O:31].C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25](=[O:33])[CH2:26][CH2:27][CH2:28][C:29]1[CH:14]=[C:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])[O:31][N:30]=1
Reactant: COC(=O)CCCC[N+](=O)[O-]
Reactant: C#Cc1ccccc1OC
Agent: O=C=Nc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COC(=O)CCCc1cc(-c2ccccc2OC)on1
Yield: 112.6 %

Procedure:
Add 1,4-phenylenediisocyanate (19.22 g, 120.0 mmol) to a stirred solution of 1-ethynyl-2-methoxy-benzene (2204901, 5.29 g, 40.0 mmol) and 5-nitro-pentanoic acid methyl ester (7.91 g, 49.1 mmol) in toluene (300 mL, anhydrous) and stir under N2. Add triethylamine (16.7 mL, 120.0 mmol) and heat to reflux under N2 overnight. Filter mixture through a pad of Celite® and rinse with toluene. Concentrate to get 12.4 g yellow oil. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-30% EtOAc/hexanes to afford the title compound (14.0 g, 74%). MS (IS) 276 (M+1)+.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([C:15]3[O:19][C:18]([NH:20][CH2:21][C:22]4[CH:27]=[CH:26]N=[CH:24][CH:23]=4)=[N:17][CH:16]=3)[CH:12]=[CH:11][CH:10]=2)[CH:3]=1.Cl[C:29]1[O:30][CH:31]=CN=1.COC1C=CC(CN)=CC=1>CC(O)C>[CH3:29][O:30][C:31]1[CH:26]=[CH:27][C:22]([CH2:21][NH:20][C:18]2[O:19][C:15]([C:13]3[CH:12]=[CH:11][CH:10]=[C:9]([NH:8][C:4]4[CH:3]=[C:2]([CH3:1])[CH:7]=[CH:6][N:5]=4)[N:14]=3)=[CH:16][N:17]=2)=[CH:23][CH:24]=1
Reactant: Clc1ncco1
Reactant: Cc1ccnc(Nc2cccc(-c3cnc(NCc4ccncc4)o3)n2)c1
Agent: COc1ccc(CN)cc1
Solvent: CC(C)O
Product: COc1ccc(CNc2ncc(-c3cccc(Nc4cc(C)ccn4)n3)o2)cc1

Procedure:
Prepared as for 5-[6-(4-methylpyridin-2-ylamino)pyridin-2-yl]-N-(pyridin-4-ylmethyl)oxazol-2-amine above from the chlorooxazole and 4-methoxybenzylamine in iPrOH. 1H NMR (300 MHz, DMSO-d6) δ 9.60 (s, 1H), 8.18-8.00 (m, 2H), 7.75 (s, 1H), 7.63 (t, J=7.9 Hz, 1H), 7.45 (d, J=8.3 Hz, 1H), 7.38-7.24 (m, 3H), 6.95-6.86 (m, 3H), 6.73 (d, J=5.0 Hz, 1H), 4.37 (d, J=5.9 Hz, 2H), 3.72 (s, 3H), 2.30 (s, 3H). (ESI+) m/z 388 (M+H)+.
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[C:8]([OH:15])(=O)/[CH:9]=[CH:10]\[C:11]([OH:13])=O.[H][H]>>[C:4]1(=[O:5])[O:6][C:1](=[O:7])[CH2:2][CH2:3]1.[C:11]1(=[O:13])[O:15][CH2:8][CH2:9][CH2:10]1
Reactant: O=C1C=CC(=O)O1
Reactant: O=C(O)/C=C\C(=O)O
Reactant: [H][H]
Product: O=C1CCC(=O)O1
Product: O=C1CCCO1

Procedure:
Maleic anhydride is hydrogenated to produce 1,4-butanediol in a two-stage process. In the first stage maleic anhydride and/or maleic acid contacted with hydrogen at a temperature of about 100° C. to about 350° C. in the presence of a suitable hydrogenation catalyst to produce succinic anhydride and/or gamma-butyrolactone. In the second stage, the succinic anhydride and/or gamma-butyrolactone and hydrogen are contacted at a temperature of about 180° C. to about 350° C. in the presence of a ruthenium-containing hydrogenation catalyst to produce 1,4-butanediol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1.[Na].[CH:24](OCC)=[O:25].C(OC(CC1CCCCC(C=O)C1=O)=O)C>CCOCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]([CH:24]=[O:25])[C:10]2=[O:16])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC=O
Reactant: CCOC(=O)CC1(c2cccc(OC)c2)CCCCCC1=O
Agent: CCOC(=O)CC1CCCCC(C=O)C1=O
Agent: [Na]
Solvent: CCOCC
Product: CCOC(=O)CC1(c2cccc(OC)c2)CCCCC(C=O)C1=O
Temperature: 25 °C
Reaction time: 120 h

Procedure:
A mixture was prepared containing 313 g. of 2-(m-methoxyphenyl)-2-ethoxycarbonylmethyl-cycloheptanone, 2 liters of ether, 332.9 g. of sodium and 115.7 g. of ethyl formate. The reaction mixture was stirred at ambient temperature for 5 days and then poured onto an ice-water mixture. The ether layer was separated and saved for recovery of starting material. The aqueous layer was acidified with cold 10 percent aqueous hydrochloric acid and the resulting acidic layer extracted with an equal volume of ether. The ether extract was separated, washed three times with a saturated aqueous sodium chloride solution and then dried. Evaporation of the solvent yielded 243 g. of 2-m-methoxyphenyl)-2-ethoxycarbonylmethyl-7-formylcycloheptanone. Molecular ion by mass spectrograph 332.
Reaction SMILES: [C:1]([CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:13])([CH3:12])[CH3:11])[CH2:5][OH:6])#[N:2].[H-].[Na+].[CH3:17]I.O>O1CCCC1>[C:1]([CH2:3][C@H:4]([NH:7][C:8](=[O:14])[O:9][C:10]([CH3:11])([CH3:13])[CH3:12])[CH2:5][O:6][CH3:17])#[N:2]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@H](CO)CC#N
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COC[C@H](CC#N)NC(=O)OC(C)(C)C
Reaction time: 0.17 h

Procedure:
To a solution in tetrahydrofuran (10 mL) of the compound (650 mg) obtained in step (1) above, sodium hydride (60% dispersion in mineral oil, 143 mg) was added under cooling with ice. After stirring the mixture at the same temperature for 10 minutes, methyl iodide (603 μL) was added. After stirring the mixture at the same temperature for 30 minutes and then at room temperature for an hour, water was added and extraction was conducted with ethyl acetate. The combined organic layers were passed through a phase separator and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=90:10-60:40) to give tert-butyl [(2S)-1-cyano-3-methoxypropan-2-yl]carbamate as a colorless oil (247 mg).
Reaction SMILES: Br.Br[CH:3]1[C:8](=[O:9])[CH:7](Br)[C:6]([CH3:12])([CH3:11])[NH:5][C:4]1([CH3:14])[CH3:13].CC([O-])(C)C.[K+].[NH2:21][CH:22]1[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24][CH:23]1[OH:31]>C(O)(C)C>[OH:31][CH:23]1[CH:22]([NH:21][C:8]([C:7]2[C:6]([CH3:11])([CH3:12])[NH:5][C:4]([CH3:3])([CH3:13])[CH:14]=2)=[O:9])[CH2:28][O:27][C:26]([CH3:30])([CH3:29])[O:25][CH2:24]1
Reactant: CC1(C)OCC(N)C(O)CO1
Reactant: CC1(C)NC(C)(C)C(Br)C(=O)C1Br
Agent: Br
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)O
Product: CC1(C)C=C(C(=O)NC2COC(C)(C)OCC2O)C(C)(C)N1

Procedure:
Analogously to Example 7, 78.79 g (200 mmol) of 3,5-dibromo-2,2,6,6-tetramethylpiperidin-4-one hydrobromide, 69.34 g of potassium tert-butylate, and 35.47 g (220 mmol) of 6-amino-2,2-dimethyl-1,3-dioxepan-5-ol are reacted in 800 ml of isopropanol and then extracted with dichloromethane. Yield: 37.66 g (60.3% of theory) of 2,2,5,5-tetramethyl-3-pyrroline-3-carboxylic acid (5-hydroxy-2,2-dimethyl-1,3-dioxepan-6-yl)amide which, crystallized from diethyl ether/hexane, shows a melting point of 125°-127° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][Cl:15])[N:13]=2)=[N:6][CH:7]=1.[C:23]1([SH:29])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>>[ClH:15].[Br:1][C:2]1[CH:3]=[C:4]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH2:14][S:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)[N:13]=2)=[N:6][CH:7]=1
Reactant: ClCc1csc(Nc2ncc(Br)cc2Oc2ccccc2)n1
Reactant: Sc1ccccc1
Product: Brc1cnc(Nc2nc(CSc3ccccc3)cs2)c(Oc2ccccc2)c1
Product: Cl

Procedure:
Prepared according to the method of Example 345 using 5-bromo-N-(4-(chloromethyl)thiazol-2-yl)-3-phenoxypyridin-2-amine and benzenethiol. 1H NMR (CDCl3) δ 4.13 (s, 2H), 6.48 (s, 1H), 7.19 (d, J=8.0 Hz, 2H), 7.26-7.32 (m, 5H), 7.38 (d, J=7.0 Hz, 2H), 7.44 (t, J=7.6 Hz, 2H), 8.12 (d, J=1.6 Hz, 1H), 12.71 (s, 1H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10]NC=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.ClC(Cl)(OC(=O)OC(Cl)(Cl)Cl)Cl.[Se].[CH2:34]([N:41]=[C:42]=[Se:43])[C:35]1C=CC=CC=1>C(Cl)Cl>[C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:35][CH2:34][N:41]=[C:42]=[Se:43])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: [Se]=C=NCc1ccccc1
Reactant: O=CNCCCCc1ccccc1
Agent: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Agent: [Se]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: [Se]=C=NCCCCCCc1ccccc1
Yield: 95 %

Procedure:
A mixture of phenylbutyl formamide (g, 1.5 mmol), triethylamine (6.4 mmol), 4 Å molecular sieves (g), triphosgene (0.8 mmol), and selenium powder (3.0 mmol) in CH2Cl2 was refluxed and worked up as mentioned for 2a. The crude residue thus obtained was purified by silica gel column chromatography (EtOAc/hexanes 2:98) to give 0.96 g (95%) of 2d as an oil. 1H NMR (CDCl3) δ 1.37-1.43 (m, 2H), 1.45-1.51 (m, 2H), 1.67 (dt, 2H, J=15.2 and 7.6 Hz), 1.75 (dt, 2H, J=14.9 and 6.7 Hz), 2.64 (t, 2H, J=7.6 Hz), 3.60 (t, 21-1, J=6.7 Hz), 7.19-7.25 (m, 3H), 7.32-7.40 (m, 2H); HRMS (EI) calcd for C13H17NSe, 267.0521. found, 267.0529.
Reaction SMILES: [C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH2:26])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N(CC)CC)C.Cl[C:35]([O:37][CH3:38])=[O:36]>ClCCl>[C:1]1([C@@H:7]2[C:12]3=[CH:13][C:14]([NH:26][C:35](=[O:36])[O:37][CH3:38])=[N:15][C:16]4[C@@H:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)[CH2:18][CH2:19][N:10]([C:11]=43)[CH2:9][CH2:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cl
Reactant: Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)Nc1cc2c3c(n1)[C@@H](c1ccccc1)CCN3CC[C@@H]2c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 15.5 %

Procedure:
To a solution (4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-amine (Intermediate 4), (110 mg, 0.322 mmol) in dichloromethane (10 mL) was added two equivalent of triethyl amine (0.090 mL, 0.644 mmol), followed by methyl chloroformate (0.037 mL, 0.483 mmol) under argon at 0° C. The reaction mixture was then stirred at room temperature for overnight. The mixture was quenched with water (30 mL). The residue was isolated in a typical aqueous workup and purified by MPLC (medium pressure liquid chromatography) using silica gel column with 10 to 15% EtOAc:Hexane to give methyl(4R,10R)-4,10-diphenyl-4,5,6,8,9,10-hexahydropyrido[3,2,1-de][1,5]naphthyridin-2-ylcarbamate, (179), (20 mg). 1H NMR (300 MHz, CDCl3) δ ppm 2.00-2.18 (m, 2H) 2.22-2.39 (m, 2H) 3.03-3.22 (m, 4H) 3.50-3.64 (m, 3H) 3.54-3.65 (m, 3H) 4.05-4.23 (m, 2H) 6.61 (br. s., 2H) 7.08-7.38 (m, 10H)
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:15](=[O:17])[NH:14][C:13](=[O:18])[NH:12][C:11]=2[N:10]=[CH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:25](I)[CH2:26][CH2:27][CH3:28].C(O)(=O)C>CN(C=O)C>[CH2:25]([N:12]1[C:11]2[N:10]=[CH:9][N:8]([CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:16]=2[C:15](=[O:17])[NH:14][C:13]1=[O:18])[CH2:26][CH2:27][CH3:28]
Reactant: CCCCI
Reactant: O=c1[nH]c(=O)c2c(ncn2Cc2ccccc2)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CCCCn1c(=O)[nH]c(=O)c2c1ncn2Cc1ccccc1
Yield: 44.9 %

Procedure:
7-benzyl-3,7-dihydro-1H-purine-2,6-dione (17.14 g, 70.8 mmol) [Synthetic Communications, 20(16), 2459-2467, 1990] and potassium carbonate (11.43 g, 82.8 mmol) were suspended in DMF (400 mL) at 40° C. After stirring for thirty minutes, butyl iodide (8.76 mL, 77.0 mmol) was added, and the mixture was stirred at 40° C. overnight. 50% Aqueous acetic acid (60 mL) was added, and the solution was concentrated under reduced pressure. The residue was suspended in water (500 mL), and the products were extracted into chloroform. The organics were collected, concentrated, and product was isolated using flash chromatography eluting with 1% methanol in dichloromethane to provide the product (9.49 g, 45%); 1H NMR (400 MHz; CDCl3) δ: 0.95 (3H, t), 1.34-1.41 (2H, m), 1.70-1.78 (2H, m), 4.05 (2H, t), 5.46 (2H, s), 7.31-7.40 (5H, m), 7.56 (1H, s), 8.21 (1H, br.s); m/z 299 [MH+].
Reaction SMILES: [F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:18])[F:17].FC(F)(F)C(O)=[O:23]>[O-2].[O-2].[O-2].[Cr+6].C(O)(=O)C>[F:1][C:2]1([F:19])[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[C:6](=[O:23])[C:5]2[CH:13]=[CH:14][CH:15]=[CH:16][C:4]=2[C:3]1([F:17])[F:18]
Reactant: FC1(F)c2ccccc2Cc2ccccc2C1(F)F
Reactant: O=C(O)C(F)(F)F
Agent: [Cr+6]
Agent: [O-2]
Solvent: CC(=O)O
Product: O=C1c2ccccc2C(F)(F)C(F)(F)c2ccccc21

Procedure:
A mixture of 1.45 g. (0.00544 mole) of 10,11-dihydro-10,10,11,11-tetrafluoro-5H-dibenzo[a,d]cycloheptene, 0.73 g. (0.0073 mole) of chromium trioxide, 25 ml. of trifluoroacetic acid and 2 ml. of glacial acetic acid is stirred at reflux for 21/4 hours. During this period, almost all of the chromium trioxide dissolves. Solvents are evaporated under reduced pressure and the residue is partitioned between benzene and water. The aqueous layer is separated and re-extracted twice with benzene. The combined benzene extracts are washed thoroughly with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under reduced pressure. The crude product is left as the residual oily solid and is purified by column chromatography on 75 g. of silica gel, eluting the product with 1:1 benzene-carbon tetrachloride. The fractions that show one spot of Rf 0.75 on a silica thin layer plate developed with benzene are combined. Evaporation of the solvent under reduced pressure leaves the white crystalline product, m.p. 70°-75° C.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[CH3:5][C:6]([CH3:18])=[CH:7][C:8]([S:10][C:11]1[CH:16]=[CH:15][C:14]([Br:17])=[CH:13][CH:12]=1)=[O:9]>C(Cl)Cl.[Cl-].[Na+].O>[CH3:5][C:6]1([CH3:18])[C:12]2[C:11](=[CH:16][CH:15]=[C:14]([Br:17])[CH:13]=2)[S:10][C:8](=[O:9])[CH2:7]1
Reactant: CC(C)=CC(=O)Sc1ccc(Br)cc1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC1(C)CC(=O)Sc2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a stirred, ice-cooled suspension of 15.9 g (119 mmol) of aluminum chloride in 140 ml of methylene chloride was added under nitrogen a solution of 21.64 g (79.9 mmol) of S-(4-bromophenyl) 3,3-dimethyl-thioacrylate (Compound 30) in 100 ml of methylene chloride. The mixture was then stirred at room temperature for 72 h and then poured into 250 g of an ice and brine mixture. The mixture was extracted with methylene chloride and the combined organic extracts were washed with saturated NaCl solution and then dried (MgSO4). The solvent was removed in vacuo and the residue recrystallized from hexanes to give the title compound as white crystals. PMR (CDCl3) & 1.40 (6H, s), 2.67 (2H, s), 7.31-7.40 (3H, m). MS exact mass, m/e 269.9714 (calcd. for C11H11SOBr, 269.9714).
Reaction SMILES: C1N=C[N:3]([C:6]([N:8]2[CH:12]=[N:11][CH:10]=[CH:9]2)=[S:7])C=1.C1C2[C:17](=[CH:18][CH:19]=[CH:20]C=2)[CH:16]=[C:15](N)N=1.C([O-])(=O)C.[NH4+]>C(#N)C>[CH:10]1[C:9]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[C:12]([NH:8][C:6]([NH2:3])=[S:7])[N:11]=1
Reactant: Nc1cc2ccccc2cn1
Reactant: S=C(n1ccnc1)n1ccnc1
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: CC#N
Product: NC(=S)Nc1cc2ccccc2cn1
Reaction time: 12 h

Procedure:
0.618 g (3.47 mmol) N,N′-thiocarbonyldiimidazole was dissolved in 20 mL acetonitrile, and 0.500 g (3.47 mmol) isoquinoline-3-amine in the form of a suspension in 15 mL acetonitrile was added dropwise in portions. The clear orange solution which formed was stirred for 12 hr, whereupon a reddish precipitate formed. The intermediate product was directly reacted, without workup, with 0.535 g (6.940 mmol) ammonium acetate for 25 min at 85° C. in a CEM microwave (100 watts). The solvent was removed under vacuum. The residue was stirred in water, and the resulting precipitate was suctioned off and washed with water. For further purification the solid was taken up in 5 mL acetonitrile and combined with 50 mL diisopropyl ether. The precipitate was filtered again and dried in a vacuum drying oven at 40° C., resulting in the isolation of 0.540 g (2.647 mmol, 76%) purified N-isoquinolin-3-yl-thiourea.
Reaction SMILES: [CH:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:20][N:21]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[C:22](Cl)=[O:23]>>[CH:1]1([CH2:7][CH2:8][NH:9][S:10]([C:13]2[CH:18]=[CH:17][C:16]([O:19][C:22](=[O:23])[N:21]([CH3:20])[C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[CH:15][CH:14]=2)(=[O:12])=[O:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=S(=O)(NCCC1CCCCC1)c1ccc(O)cc1
Reactant: CN(C(=O)Cl)c1ccccc1
Product: CN(C(=O)Oc1ccc(S(=O)(=O)NCCC2CCCCC2)cc1)c1ccccc1

Procedure:
The title compound was prepared from N-(2-cyclohexyl-ethyl)-4-hydroxy-benzenesulfonamide and N-methyl-N-phenyl carbamoylchloride, preparative HPLC (Method C) (14%, light yellow oil). HPLC-MS m/z=417.3 (M+1), Rt: 4.89 min.