Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH:2]1([C:5](=[NH:7])[NH2:6])[CH2:4][CH2:3]1.[OH-:8].[Na+]>CC#N.O>[CH:2]1([C:5]2[N:6]=[CH:4][C:2]([CH:5]=[O:8])=[CH:3][N:7]=2)[CH2:4][CH2:3]1
Reactant: [OH-]
Reactant: N=C(N)C1CC1
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: O=Cc1cnc(C2CC2)nc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 97.7 %

Procedure:
To a mixture of a1 (ca. 0.095 mol) in CH3CN (300 mL) was added cyclopropanecarboximidamide hydrochloride (12.5 g, 0.105 mol), then sodium hydroxide (7.6 g, 0.19 mol) in water (7.6 mL) was added drop-wise at 0° C. After addition was complete, the resulting mixture was stirred at room temperature overnight. After filtration, the filtrate was concentrated to remove CH3CN under reduced pressure and the residue water phase was extracted with DCM (3×300 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuum to give a red oil, which was purified by column chromatography on silica gel (petroleum ether:EtOAc=2:1) to afford 2-cyclopropylpyrimidine-5-carbaldehyde (7.6 g, yield: 53.5%). 1H NMR (CDCl3 400 MHz): δ 10.06 (s, 1H), 8.99 (s, 2H), 2.41-2.35 (m, 1H), 1.32-1.21 (m, 4H).
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[Cl:34][C:35]1[C:39]([Cl:40])=[C:38]([CH2:41][OH:42])[S:37][N:36]=1.[C:43](O)(=[S:45])[CH3:44]>C(OCC)(=O)C.C1COCC1>[C:43]([O:42][CH2:41][C:38]1[S:37][N:36]=[C:35]([Cl:34])[C:39]=1[Cl:40])(=[S:45])[CH3:44]
Reactant: OCc1snc(Cl)c1Cl
Reactant: CC(O)=S
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(=S)OCc1snc(Cl)c1Cl
Reaction time: 0.5 h
Yield: 31.9 %

Procedure:
To a THF (50 ml) solution of 2.85 g (10.9 mmol) of triphenylphosphine was added, under ice-cooling, 2.2 g (10.9 mmol) of diisopropyl azodicarboxylate, followed by stirring for 30 minutes. To the solution was added a THF (5 ml) solution of 1.0 g (5.43 mmol) of (3,4-dichloroisothiazol-5-yl)methanol and 0.83 g (10.9 mmol) of thioacetic acid, followed by stirring at room temperature for 5 hours, to give rise to a reaction. After the completion of the reaction, ethyl acetate was added to the reaction mixture. The resulting mixture was washed with water, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by silica gel column chromatography to obtain 0.42 g (yield: 32%) of (3,4-dichloroisothiazol-5-yl)methyl thioacetate as a light red oily substance (refractive index: 1.5855).
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:11]B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.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>[CH3:11][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CB(O)O
Reactant: O=[N+]([O-])c1cccnc1Cl
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: [K+]
Solvent: C1COCCO1
Product: Cc1ncccc1[N+](=O)[O-]
Temperature: 25 °C

Procedure:
Heat a mixture of 2-chloro-3-nitro-pyridine (1a-1, 7.9 g, 49.8 mmol), methylboronic acid (1.10 equiv. 54.8 mmol, 3.30 g), K2CO3 (3.0 equiv, 150 mmol, 20.7 g) and Pd(PPh3)4 (1.2 g, 1.2 mmol) to 110° C. in dioxane (250 mL) for 16 h. Allow the reaction to cool to rt, concentrate to a dark oil and flash chromatograph on SiO2 (heptane/Et2O 3:1, dilute the oil with limited quantities of CH2Cl2 to apply to the column) to give compound 2a-1 (Niu, C.; Li, J.; Doyle, T. W.; Chen, S-H. Tetrahedron, 1998, 6311-6318).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[NH:16][CH:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[CH:13][CH:12]=[CH:11][C:10]=2[O:22][CH3:23])=O)C.[Cl:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([N:31]=[C:32]=[O:33])[CH:26]=1>>[Cl:24][C:25]1[CH:26]=[C:27]([N:31]2[C:4](=[O:3])[C:6]3[CH:7]=[N:8][C:9]4[C:10]([O:22][CH3:23])=[CH:11][CH:12]=[CH:13][C:14]=4[C:15]=3[N:16]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21]3)[C:32]2=[O:33])[CH:28]=[CH:29][CH:30]=1
Reactant: CCOC(=O)c1cnc2c(OC)cccc2c1NC1CCCC1
Reactant: O=C=Nc1cccc(Cl)c1
Product: COc1cccc2c1ncc1c(=O)n(-c3cccc(Cl)c3)c(=O)n(C3CCCC3)c12
Yield: 27.2 %

Procedure:
3-(3-Chloro-phenyl)-1-cyclopentyl-7-methoxy-1H-pyrimido[5,4-c]quinoline-2,4-dione (55 mg) was prepared from 4-cyclopentylamino-8-methoxy-quinoline-3-carboxylic acid ethyl ester (0.48 mmol) and 1-chloro-3-isocyanato-benzene (0.72 mmol) following general procedure C. LCMS: m/z 422 [M+1]+.
Reaction SMILES: C([NH:5][S:6]([C:9]1[S:10][C:11]([Si:22]([CH3:25])([CH3:24])[CH3:23])=[CH:12][C:13]=1[C:14]([F:21])=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17])(=[O:8])=[O:7])(C)(C)C.FC(F)(F)C(O)=O>O>[F:21][C:14]([C:13]1[CH:12]=[C:11]([Si:22]([CH3:24])([CH3:25])[CH3:23])[S:10][C:9]=1[S:6]([NH2:5])(=[O:8])=[O:7])=[C:15]([F:20])[C:16]([F:19])([F:18])[F:17]
Reactant: CC(C)(C)NS(=O)(=O)c1sc([Si](C)(C)C)cc1C(F)=C(F)C(F)(F)F
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: C[Si](C)(C)c1cc(C(F)=C(F)C(F)(F)F)c(S(N)(=O)=O)s1
Temperature: 25 °C
Reaction time: 13 h
Yield: 71.5 %

Procedure:
A portion (1.5 g) of the N-tert-butyl-3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide prepared in (2) was reacted with 4 ml of trifluoroacetic acid under stirring at room temperature for 13 hours. After completion of the reaction, the resulting product was poured into water and extracted with methylene chloride. The extracted layer was washed with water and dried. After distilling off methylene chloride under vacuum, the residue was purified by column chromatography on silica gel (eluent: methylene chloride) to provide 0.93 g of 3-(1,2,3,3,3-pentafluoropropen-1-yl)-5-trimethylsilyl-2-thiophenesulfonamide having a melting point of 129° to 140° C.
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH:11]=[CH2:12])=[CH:5][CH:4]=1)=[CH2:2].[CH3:13][O:14][SiH:15]([O:18][CH3:19])[O:16][CH3:17]>C(O)(C)C>[CH:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:10][CH2:11][CH2:12][Si:15]([O:18][CH3:19])([O:16][CH3:17])[O:14][CH3:13])=[CH:5][CH:4]=1)=[CH2:2]
Reactant: CO[SiH](OC)OC
Reactant: C=CCOc1ccc(C=C)cc1
Solvent: CC(C)O
Product: C=Cc1ccc(OCCC[Si](OC)(OC)OC)cc1
Reaction time: 0.5 h
Yield: 78 %

Procedure:
To a 500 ml glass flask equipped with a stirring machine, a reflux condenser, a thermometer and a dropping funnel, there were added 48.0 g (0.3 mole) of 3-(4-vinylphenyloxy)propene, 0.1 g of a 4% isopropyl alcohol solution of H2PtCl6 and 0.2 g of BHT. To the mixture, there was dropwise added 36.6 g (0.3 mole) of trimethoxysilane through the dropping funnel at 60° to 70° C. over one hour, followed by ripening at 70° C. for 30 minutes. The reaction solution was distilled to give 66.1 g of a compound having a boiling point of 147°-151° C./3 mmHg. The yield thereof was found to be 78.0%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]#[C:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1.[H][H]>C(O)C.[Pd]>[OH:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1[CH:7]=[C:8]([C:11]([O:13][CH3:14])=[O:12])[S:9][CH:10]=1
Reactant: COC(=O)c1cc(C#CCCO)cs1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1cc(CCCCO)cs1
Yield: 81.9 %

Procedure:
A Parr flask was charged with 4.00 g of methyl 4-(4-hydroxybut-1-yn-1-yl)thien-2-ylcarboxylate in 100 mL of ethanol. Then 2.00 g (50% wt eq) of 5% palladium on charcoal was added. Parr hydrogenation was carried out at 50 psi of hydrogen for 6 hours. The reaction mixture was filtered through a Celite pad which was washed with ethanol. The filtrate was concentrated under reduced pressure to give 3.34 g (81.9%) of methyl 4-(4-hydroxybutyl)thien-2-ylcarboxylate as a clear oil; IR (KBr, cm-1): 1710, 1444, 1293, 1260, 1225; UV (Ethanol) :λmax =281 nm (epsilon=6450), 248 nm (epsilon=10,100); 1H NMR (CDCl3, 300 MHz) delta 7.59 (s, 1H), 7.12, (s, 1H), 3.81 (s, 3H), 3.60 (t, J=6.3 Hz, 2H), 2.59 (t, J=7.4 Hz, 2H), 2.10 (bs, 1H), 1.60-1.68 (m, 2H), 1.51-1.58 (m, 2H); MASS: M+ =2148 (EICEC).
Reaction SMILES: [CH3:1][C@H:2]([NH2:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Br[C:11]1[CH:12]=[C:13]2[C:17]3=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]3[C@H:15]3[CH2:24][CH2:25][N:26](C(OC(C)(C)C)=O)[CH2:27][C@@H:14]23)[CH:19]=1>>[C:3]1([C@@H:2]([NH:9][C:11]2[CH:12]=[C:13]3[C:17]4=[C:18]([CH2:20][S:21][CH2:22][CH2:23][N:16]4[C@H:15]4[CH2:24][CH2:25][NH:26][CH2:27][C@@H:14]34)[CH:19]=2)[CH3:1])[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]2[C@@H](C1)c1cc(Br)cc3c1N2CCSC3
Reactant: C[C@H](N)c1ccccc1
Product: C[C@H](Nc1cc2c3c(c1)[C@@H]1CNCC[C@@H]1N3CCSC2)c1ccccc1

Procedure:
Using (S)-(−)-α-methylbenzylamine and following the procedures described in EXAMPLE 168, tert-butyl (7bR,11aS)-6-bromo-1,2,7b,10,11,11a-hexahydro-4H-pyrido[4,3-b][1,4]thiazepino[6,5,4-hi]indole-9(8H)-carboxylate from EXAMPLE 7, Part A was converted into the title compound of EXAMPLE 169. 1H NMR(CDCl3) δ 7.40-7.20 (m, 5H), 6.22 (d, 1H, J=2.2 Hz), 6.14 (d, 1H, J=2.2 Hz), 4.39 (q, 1H, J=6.6 Hz), 3.62 (ABq, 2H, JAB=15.5 Hz), 3.55-3.43 (m, 1H), 3.32-3.20 (m, 2H), 3.05-2.81 (m, 4H), 2.77-2.60 (m, 1H), 2.50 (dd, 1H, J=12.8, 9.7 Hz), 2.00-1.85 (m, 2H), 1.49 (d, 3H, J=6.6 Hz). LRMS (ES)+: 366.4 (M+H)+.
Reaction SMILES: [CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10](N)=[N:11][C:12]=2[Cl:16])=[O:4].[CH3:20][S:21]SC.N(OC(C)(C)C)=O>C(#N)C>[CH3:1][C:2]([CH3:19])([CH3:18])[C:3]([O:5][CH2:6][N:7]1[CH:15]=[N:14][C:13]2[C:8]1=[N:9][C:10]([S:21][CH3:20])=[N:11][C:12]=2[Cl:16])=[O:4]
Reactant: CSSC
Reactant: CC(C)(C)C(=O)OCn1cnc2c(Cl)nc(N)nc21
Agent: CC(C)(C)ON=O
Solvent: CC#N
Product: CSc1nc(Cl)c2ncn(COC(=O)C(C)(C)C)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.8 %

Procedure:
To a stirred solution of 2-amino-6-chloropurin-9-yl-methyl 2,2-dimethylpropionate 81 (0.566 g, 2 mmol) in acetonitrile (2 mL) was added methyl disulfide (0.94 g, 10 mmol), and tert-butyl nitrite (90%, 1.14 g, 10 mmol) and the resulting reaction mixture was stirred at room temperature for 8 h. The reaction mixture was concentrated in vacuo, and the resulting crude product was subjected to silica gel column chromatography (AcOEt/petroleum ether=1/10), which furnished 82 (0.364 g, 55%): 1H NMR (CDCl3, 300 MHz) δ 8.19 (s, 1H), 6.12 (s, 2H), 2.65 (s, 3H), 1.17 (s, 9H). MS (m/e) (positive-FAB) 315 (M+1)+.
Reaction SMILES: [CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4](O)=[O:5].C(Cl)(=O)C([Cl:16])=O>C1C=CC=CC=1>[CH3:1][C@H:2]([CH2:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])[CH2:3][C:4]([Cl:16])=[O:5]
Reactant: CC(C)CCC[C@@H](C)CC(=O)O
Reactant: O=C(Cl)C(=O)Cl
Solvent: c1ccccc1
Product: CC(C)CCC[C@@H](C)CC(=O)Cl
Yield: 95.4 %

Procedure:
A solution of 11.37 g (66.1 mmoles) of (R)-(+)-3,7-dimethyloctanoic acid in 50 ml of benzene was stirred while 10 ml (114.6 mmoles) of oxalyl chloride was added. The solution was stirred and refluxed overnight then concentrated in vacuo giving 12.03 g (95.6%) of (R)-(+)-3,7-dimethyloctanoyl chloride as an oil. An 8.2 g (43.0 mmoles) sample of this material in 10 ml of dichloromethane was added to a stirred solution of 6.2 (43.0 mmoles) of Meldrum's Acid and 8.68 ml of pyridine in 40 ml of dichloromethane, at 0° C. The resulting solution was stirred overnight then treated with cold 3N aqueous HCl. The organic phase was separated and the aqueous phase was extracted with dichloromethane. The dichloromethane extracts were combined, dried (Na2SO4), and concentrated in vacuo giving 12.1 g of crude product. This material was dissolved in 100 ml of methanol and the solution was refluxed for 4 hr then cooled and concentrated in vacuo. The residue was chromatographed on silica gel giving (R)-5,9-dimethyl-3-oxodecanoic acid methyl ester as an oil, eluted with pet. ether-ether mixtures.
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C@@H:9]([O:13][C:14]1[NH:15][C:16]([NH2:25])=[C:17]2[C:21]([N:22]=1)=[N:20][C:19]([O:23][CH3:24])=[N:18]2)[CH2:10][CH2:11][CH3:12].Br[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]1[CH2:36][CH2:35][O:34][CH2:33][CH2:32]1>>[CH3:8][C@@H:9]([O:13][C:14]1[N:22]=[C:21]2[C:17]([N:18]=[C:19]([O:23][CH3:24])[N:20]2[CH2:27][CH2:28][CH2:29][CH2:30][CH:31]2[CH2:36][CH2:35][O:34][CH2:33][CH2:32]2)=[C:16]([NH2:25])[N:15]=1)[CH2:10][CH2:11][CH3:12]
Reactant: BrCCCCC1CCOCC1
Reactant: CCC[C@@H](C)Oc1nc2nc(OC)nc-2c(N)[nH]1
Solvent: O=C(O)C(F)(F)F
Product: CCC[C@@H](C)Oc1nc(N)c2nc(OC)n(CCCCC3CCOCC3)c2n1

Procedure:
Prepared similarly to Intermediate 216 from 2-{[(1R)-1-methylbutyl]oxy}-8-(methyloxy)-1H-purin-6-amine trifluoroacetate and 4-(4-bromobutyl)tetrahydro-2H-pyran.
Reaction SMILES: [Si]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[C:11](=[C:12]([NH2:23])[N:13]=[C:14]3[CH:22]=[CH:21][CH:20]=[CH:19][C:15]3=2)[N:10]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(O)(=O)C>O1CCCC1>[NH2:23][C:12]1[C:11]2[NH:10][C:9](=[O:8])[CH:18]=[CH:17][C:16]=2[C:15]2[CH:19]=[CH:20][CH:21]=[CH:22][C:14]=2[N:13]=1
Reactant: CC(C)(C)[Si](C)(C)Oc1ccc2c(n1)c(N)nc1ccccc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: Nc1nc2ccccc2c2ccc(=O)[nH]c12
Reaction time: 0.25 h

Procedure:
To a solution of 3-(tert-butyldimethylsilyloxy)benzo[f][1,7]naphthyridin-5-amine (from step 4) (1.0 eq.) in tetrahydrofuran (0.05 M) was added tetra-n-butylammonium fluoride (TBAF) (1.0 eq.) and acetic acid (1.0 eq.). The reaction was stirred for 15 minutes, and then concentrated en vacuo. The crude residue was suspended in water and neutralized by addition of saturated aqueous NaHCO3 solution to pH 7. The solids were filtered, washed with acetone, and dried to give 5-aminobenzo[f][1,7]naphthyridin-3(4H)-one. 1H NMR (DMSO d-6): δ 8.59 (d, 1H), 8.20 (d, 1H), 7.49 (d, 1H), 7.37-7.41 (dd, 1H), 7.23-7.27 (dd, 1H), 6.88 (br, 2H), 6.79 (d, 1H). LRMS [M+H]=212.1
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:13][CH2:12][N:11]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[NH3:22]>>[C:15]1([CH2:14][N:11]2[CH2:12][CH:13]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH2:22])=[CH:3][CH:4]=3)[CH2:9][CH2:10]2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N
Reactant: OC1(c2ccc(Br)cc2)CCN(Cc2ccccc2)CC1
Product: Nc1ccc(C2=CCN(Cc3ccccc3)CC2)cc1
Temperature: 180 °C

Procedure:
A mixture of 4-(4-bromophenyl)-1-(phenylmethyl)-4-piperidinol (0.23 mole) and Cu2O (2 g) in aqueous ammonia (500 ml) was stirred at 180° C. for twelve hours. The mixture was cooled, extracted with DCM and washed with water. The organic layer was dried, filtered off and evaporated, yielding 60 g of 4-[1,2,3,6-tetrahydro-1-(phenylmethyl)-4-pyridinyl]benzenamine.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:8])[CH3:7].C(Cl)Cl>C(Cl)(Cl)Cl>[C:6]([N:9]1[CH2:18][CH2:17][C:16]2[C:11](=[C:12]([Cl:19])[CH:13]=[CH:14][C:15]=2[S:2]([Cl:1])(=[O:5])=[O:3])[CH2:10]1)(=[O:8])[CH3:7]
Reactant: O=S(=O)(O)Cl
Reactant: CC(=O)N1CCc2cccc(Cl)c2C1
Solvent: ClCCl
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CCc2c(S(=O)(=O)Cl)ccc(Cl)c2C1
Temperature: 0 °C

Procedure:
51.75 ml. (0.78 mole) of chlorosulfonic acid was added dropwise with stirring to a solution of 20.7 g. (0.099 mole) 2-acetyl-8-chloro-1,2,3,4-tetrahydroisoquinoline in 25 ml. of methylene chloride at -70° C. To effectuate a solution of the reactants 10 ml. of dry chloroform was added and the reaction mixture stirred for one hour at -70° C. The reaction mixture was then refluxed at 40°-45° C. for 2 hours and then stirred at ambient temperature for about 16 hours. The reaction mixture was then cautiously poured onto one liter of ice. The crude reaction product was then extracted into methylene chloride (3×100 ml.), washed with saturated sodium chloride solution, dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated to dryness at reduced pressure to afford 2-acetyl-8-chloro-5-chlorosulfonyl-1,2,3,4-tetrahydroisoquinoline as whitish yellow solid with a melting point of 105°-115° C.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][OH:19])[CH2:16][OH:17])[C:6]=2[N:5]=[C:3]1[NH2:4].[C:20](Cl)(=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27].C(Cl)Cl>CN(C=O)C>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[N:9]=[CH:8][N:7]([CH2:13][O:14][CH:15]([CH2:18][O:19][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[CH2:16][O:17][C:20](=[O:28])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:6]=2[N:5]=[C:3]1[NH2:4]
Reactant: CCCCCCCC(=O)Cl
Reactant: Cn1c(N)nc2c(ncn2COC(CO)CO)c1=O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: CCCCCCCC(=O)OCC(COC(=O)CCCCCCC)OCn1cnc2c(=O)n(C)c(N)nc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 80.5 %

Procedure:
1-Methyl-9-(1,3-dihydroxy-2-propoxymethyl) guanine (340 mg, 1.26 mmol) was suspended in dry DMF and dry pyridine (approximately 20 ml total) and evaporated to dryness. This process was repeated twice, the final time concentrating the suspension down to 10 ml. This suspension was cooled to 0°, under N2, and a solution of octanoyl chloride (822 mg, 5.05 mmol) in dry DMF (1 ml) was added. This reaction was stirred overnight at room temperature. Methylene chloride was then added and the mixture was extracted with saturated aqueous NaHCO3 solution. The organic phase was then washed three times with H2O, dried over MgSO4, filtered and evaporated to dryness. The residual oil was dissolved in CH2Cl2 and applied to a column of silica gel, packed in CH2Cl2. Elution was first performed with CH2Cl2 followed by 1% MeOH in CH2Cl2 (200 ml), 2% MeOH in CH2Cl2 (200 ml), 3% MeOH in CH2Cl2 (100 ml) and finally 5% MeOH in CH2Cl2 (100 ml). Fractions containing the required product were pooled and evaporated to dryness to give 529 mg of product. It was recrystallized from ether/petroleum ether. The PMR spectrum was in accord with the structure.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]([NH2:11])=[S:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[C:13]([CH3:20])([CH3:19])[C:14](OCC)=[O:15]>>[CH:1]1([CH2:7][NH:8][C:9]2[S:10][C:13]([CH3:20])([CH3:19])[C:14](=[O:15])[N:11]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NC(=S)NCC1CCCCC1
Reactant: CCOC(=O)C(C)(C)Br
Product: CC1(C)SC(NCC2CCCCC2)=NC1=O

Procedure:
Synthesis was performed from N-(cyclohexylmethyl)thiourea and ethyl 2-bromoisobutyrate according to Method C.
Reaction SMILES: C1CO[C:3]2([C:9]3[CH:10]=[CH:11][C:12]([CH:14]([CH3:18])[C:15]([NH2:17])=[O:16])=[CH:13][C:8]=3[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]2=3)[O:2]1.CO>O>[CH:13]1[C:8]2[CH:7]=[CH:6][C:5]3[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=3[C:3](=[O:2])[C:9]=2[CH:10]=[CH:11][C:12]=1[CH:14]([CH3:18])[C:15]([NH2:17])=[O:16]
Reactant: CC(C(N)=O)c1ccc2c(c1)C=Cc1ccccc1C21OCCO1
Solvent: CO
Solvent: O
Product: CC(C(N)=O)c1ccc2c(=O)c3ccccc3ccc2c1
Temperature: 50 °C
Yield: 80 %

Procedure:
2.0 Gm. of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)propionamide is dissolved in 50 ml. of methanol and 5 ml. of N-hydrochloric acid is added. The mixture is heated to 50°C. for 30 minutes then cooled and added to water. The solution is extracted with ethyl acetate and the extract washed, dried and evaporated to yield 80% of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)propionamide which is recrystallized from methanol, m.p. 158°-159°C. Use of 2-(5,5-ethylenedioxy-5H-dibenzo[a,d]cyclohepten-2-yl)acetamide gives a similar yield of 2-(5H-dibenzo[a,d]cyclohepten-5-on-2-yl)acetamide.
Reaction SMILES: [CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12]O[CH2:14][C:15]4[C:16]=3[C:17]=2[CH:18]=[CH:19][CH:20]=4)[CH2:3]1.BrC1C=CC2C[S:27]CC3C=2C=1C=CC=3>>[CH3:1][C@H:2]1[NH:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]3[CH2:12][S:27][CH2:14][C:15]4[C:16]=3[C:17]=2[CH:18]=[CH:19][CH:20]=4)[CH2:3]1
Reactant: Brc1ccc2c3c(cccc13)CSC2
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)COC3)CCN1
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)CSC3)CCN1

Procedure:
The procedure used for the synthesis of (3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]pyran-6-yl)piperazine (Example 5b)) was followed, using 6-bromo-1H,3H-naphtho[1,8-cd]thiopyran as starting material and making non-critical variations, to obtain the title compound (3R)-3-methyl-1-(1H,3H-naphtho[1,8-cd]thiopyran-6-yl)piperazine as brown solid.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:22]=1.[C:23]([C@:25]1([OH:32])[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31])#[CH:24]>>[OH:32][C@@:25]1([C:23]#[C:24][C:2]2[CH:3]=[CH:4][C:5]3[O:11][CH2:10][CH2:9][N:8]4[C:12]([C:18]([NH:20][CH3:21])=[O:19])=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]4[C:6]=3[CH:22]=2)[CH2:29][CH2:28][N:27]([CH3:30])[C:26]1=[O:31]
Reactant: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(Br)cc1-2
Reactant: C#C[C@]1(O)CCN(C)C1=O
Product: CNC(=O)c1c(C(N)=O)nc2n1CCOc1ccc(C#C[C@]3(O)CCN(C)C3=O)cc1-2
Yield: 9 %

Procedure:
10-bromo-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide was reacted with (3R)-3-ethynyl-3-hydroxy-1-methyl-pyrrolidin-2-one similarly to as described in General Procedure F with non-critical modifications to afford 4.4 mg (9%) of 10-[2-[(3R)-3-hydroxy-1-methyl-2-oxo-pyrrolidin-3-yl]ethynyl]-N3-methyl-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2,3-dicarboxamide. M+1=424.0.
Reaction SMILES: [SH:1][C:2]1[S:3][CH:4]=[CH:5][CH:6]=1.C(N(CC)CC)C.[CH3:14][C@H:15]1[O:19][C:17](=[O:18])[CH2:16]1>O1CCCC1>[S:3]1[CH:4]=[CH:5][CH:6]=[C:2]1[S:1][C@@H:15]([CH3:14])[CH2:16][C:17]([OH:19])=[O:18]
Reactant: C[C@@H]1CC(=O)O1
Reactant: Sc1cccs1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: C[C@@H](CC(=O)O)Sc1cccs1
Reaction time: 0.17 h
Yield: 93.5 %

Procedure:
To a magnetically-stirred 25 mL round-bottomed flask blanketed with nitrogen was charged 2-mercaptothiophene (0.73 g, 6.29 mmol) in tetrahydrofuran (7 mL, K.F. <0.1 mg/mL) at 25° C. Triethylamine (0.87 mL, 6.29 mmol) was injected and the reaction mixture was stirred for 10 minutes to complete salt formation. To this mixture was added (R)-(+)-β-methyl-β-propiolactone (0.54 g, 6.29 mmol) in one portion and the reaction mixture was stirred at 25° C. for approximately 3 hours. When complete, the mixture was stripped of solvent on a rotary evaporator at 25° C. and diluted with ethyl acetate (10 mL) and water (10 mL). The pH of the mixture was then adjusted to 2.0 with 5N hydrochloric acid and the layers separated. The upper ethyl acetate product layer was dried over sodium sulfate and concentrated to an oil on a rotary evaporator. Silica gel chromatography (10% ethyl acetate/hexanes) afforded 1.19 g of (S)-3-(2-thienylthio)butyric acid (94%).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11].[C:26]1([C:36](Cl)=[O:37])[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][CH:27]=1>>[CH3:2][O:3][C:4]1[CH:5]=[C:6]([C:12]2[C:13]([CH3:25])([CH3:24])[C:14](=[O:23])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([C:36]([C:26]4[C:35]5[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=5)[CH:29]=[CH:28][CH:27]=4)=[O:37])[CH2:19][CH2:18]3)[N:16]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: O=C(Cl)c1cccc2ccccc12
Reactant: COc1ccc(C2=NN(C3CCNCC3)C(=O)C2(C)C)cc1OC
Agent: Cl
Product: COc1ccc(C2=NN(C3CCN(C(=O)c4cccc5ccccc45)CC3)C(=O)C2(C)C)cc1OC

Procedure:
The title compound is prepared analogously as described for GP1 using 5-(3,4-dimethoxyphenyl)-4,4-dimethyl-2-(piperidin-4-yl)-2,4-dihydro-3H-pyrazol-3-one hydrochloride (compound B1*HCl) and 1-naphthoyl chloride as starting compounds. The crude product is purified by crystallization from EA to yield the title compound.