Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][S:11](Cl)(=[O:13])=[O:12].[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:46])[NH:20]2>C(Cl)Cl>[F:15][C:16]1[C:24]([O:25][C:26]2[C:35]3[C:30](=[CH:31][C:32]([O:38][CH2:39][CH:40]4[CH2:45][CH2:44][N:43]([S:11]([CH3:10])(=[O:13])=[O:12])[CH2:42][CH2:41]4)=[C:33]([O:36][CH3:37])[CH:34]=3)[N:29]=[CH:28][N:27]=2)=[CH:23][CH:22]=[C:21]2[C:17]=1[CH:18]=[C:19]([CH3:46])[NH:20]2
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCNCC1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3F)ncnc2cc1OCC1CCN(S(C)(=O)=O)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 47.4 %

Procedure:
Diisopropylethylamine (72 μl, 0.41 mmol) and methanesulphonyl chloride (32 μl, 0.41 mmol) were added to a suspension of 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-(piperidin-4-ylmethoxy)quinazoline (150 mg, 0.34 mmol), (prepared as described for the starting material in Example 11), in methylene chloride (4 ml). After a few minutes all the material had gone into solution. The mixture was stirred for 3 hours at ambient temperature, washed with saturated sodium hydrogen carbonate solution, dried (MgSO4) and concentrated under reduced pressure. The solid was suspended in methanol and filtered to give 4-[(4-fluoro-2-methyl-1H-indol-5-yl)oxy]-6-methoxy-7-{[1-(methylsulfonyl)piperidin-4-yl]methoxy}quinazoline (83 mg, 47%).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8]C)=O)=[C:4]([OH:12])[CH:3]=1.[CH:13]1([NH2:16])[CH2:15][CH2:14]1.[N+](C1C=C(C=CC=1)O[CH2:24][C@@H:25]1[CH2:27][O:26]1)([O-])=O.C(=O)([O-])[O-].[Cs+].[Cs+]>>[CH:13]1([NH:16][C:6](=[O:8])[C:5]2[CH:10]=[CH:11][C:2]([F:1])=[CH:3][C:4]=2[O:12][CH2:24][C@@H:25]2[CH2:27][O:26]2)[CH2:15][CH2:14]1
Reactant: COC(=O)c1ccc(F)cc1O
Reactant: O=[N+]([O-])c1cccc(OC[C@@H]2CO2)c1
Reactant: NC1CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(NC1CC1)c1ccc(F)cc1OC[C@@H]1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41 %

Procedure:
A mixture of methyl 4-fluoro-2-hydroxybenzoate (0.17 g, 1 mmol) and cyclopropylamine (1 ml) was stirred at room temperature overnight. Cyclopropylamine was removed in vacuo, and the residue dissolved in dry DMF (5 ml). (2S)-2-[(3-nitrophenoxy)-methyl]oxirane (0.195 g, 1.0 mmol) and cesium carbonate (0.478 g, 1.5 mmol) were added, and the mixture was stirred at room temperature for 2 days. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml). The aqueous layer was extracted with ethyl acetate (25 ml) and the combined organic layers were dried with sodium sulphate and concentrated. The residue was purified by flash chromatography (silica gel, n-heptane/ethyl acetate, 1:1) to afford the subtitle compound (0.104 g, 0.41 mmol, 41%) as a colourless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH:8]([CH2:10]C(O)=O)[CH2:9][C:5]=2[CH:4]=1.C[N:17](C=O)C.S(Cl)(Cl)=O>ClCCl>[CH3:1][O:2][C:3]1[CH:15]=[CH:14][C:6]2[O:7][CH:8]([CH2:10][NH2:17])[CH2:9][C:5]=2[CH:4]=1
Reactant: CN(C)C=O
Reactant: COc1ccc2c(c1)CC(CC(=O)O)O2
Solvent: ClCCl
Solvent: O=S(Cl)Cl
Product: COc1ccc2c(c1)CC(CN)O2
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
To 81 g of 5-methoxy-2,3-dihydro-3-benzofuranacetic acid in 250 ml of dichloromethane were added 0.5 ml of DMF and 48 ml of thionyl chloride. The mixture was stirred for 10 minutes and then heated at reflux for 1 hour. Dichloromethane and thionyl chloride were evaporated, and remaining traces of thionyl chloride were removed by evaporation with n-heptane. The resulting acid chloride was dissolved in 240 ml of acetone and added dropwise to a stirred solution of 25.5 g of NaN3 in 120 ml of water at 10°-15° C. Cold toluene (1500 ml) was added, and the organic phase was separated, washed with brine, dried (MgSO4) and finally placed in a 5 l beaker and heated slowly to 80° C. When the N2 evolution had ceased 600 ml of conc. hydrochloric acid and 900 ml of water were added. The resulting mixture was stirred overnight at room temperature. The water phase was separated and made alkaline (pH 10-11) by addition of ammonium hydroxide and finally extracted with dichloromethane. The organic phase was evaporated and the remaining oil was dissolved in 1000 ml of dil. hydrochloric acid. This solution was left for 16 hours and then added to 600 ml of ammonium hydroxide at 0° C. Dichloromethane was added, the organic phase was separated, dried (Na2SO4) and evaporated yielding 61 g of product as an oil.
Reaction SMILES: P([O-])(O)(O)=O.SCC(C(CS)O)O.Cl[C:15]1[N:19]2[N:20]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=3)[CH:22]=[CH:23][C:18]2=[N:17][N:16]=1.CC([C:35]1[C:40]2[N:41]=[C:42]([N:44]([CH2:48][CH2:49][N:50]3[CH2:55][CH2:54][O:53][CH2:52][CH2:51]3)C(=O)[O-])[S:43][C:39]=2[CH:38]=[C:37]([S:56]C#N)[CH:36]=1)(C)C>O.C(O)C>[F:30][C:27]1[CH:28]=[CH:29][C:24]([C:21]2[CH:22]=[CH:23][C:18]3[N:19]([C:15]([S:56][C:37]4[CH:36]=[CH:35][C:40]5[N:41]=[C:42]([NH:44][CH2:48][CH2:49][N:50]6[CH2:55][CH2:54][O:53][CH2:52][CH2:51]6)[S:43][C:39]=5[CH:38]=4)=[N:16][N:17]=3)[N:20]=2)=[CH:25][CH:26]=1
Reactant: Fc1ccc(-c2ccc3nnc(Cl)n3n2)cc1
Reactant: CC(C)(C)c1cc(SC#N)cc2sc(N(CCN3CCOCC3)C(=O)[O-])nc12
Agent: O=P([O-])(O)O
Agent: OC(CS)C(O)CS
Solvent: CCO
Solvent: O
Product: Fc1ccc(-c2ccc3nnc(Sc4ccc5nc(NCCN6CCOCC6)sc5c4)n3n2)cc1
Yield: 32.4 %

Procedure:
8 mg of dihydrogen phosphate in 1 cm3 of water, 680 mg of DL-dithiothreitol and 336 mg of 3-chloro-6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazine are added, at 20° C., to a solution of 636 mg of 1,1-dimethylethyl[2-(morpholin-4-yl)ethyl](6-thiocyanato-1,3-benzothiazol-2-yl)carbamate in 10 cm3 of ethanol degassed with argon for 5 min. The suspension is stirred at reflux for 18 h. The reaction is placed in a refrigerator overnight and then the greyish-white solid is spin-filter-dried. This solid is washed with diethyl ether and then made into a paste in dichloromethane and spin-filter-dried. 222 mg of 6-{[6-(4-fluorophenyl)[1,2,4]triazolo[4,3-b]pyridazin-3-yl]sulphanyl}-N-[2-(morpholin-4-yl)ethyl]-1,3-benzothiazol-2-amine are thus obtained in the form of a greyish-white powder, the characteristics of which are as follows:
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1.[NH3:17]>>[NH2:17][C:2]1[C:3]2[C:10]([Cl:11])=[CH:9][N:8]([CH2:12][O:13][CH2:14][CH2:15][OH:16])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: N
Reactant: OCCOCn1cc(Cl)c2c(Cl)ncnc21
Product: Nc1ncnc2c1c(Cl)cn2COCCO
Temperature: 135 °C

Procedure:
4,5-Dichloro-7-(2-hydroxyethoxymethyl)pyrrolo[2,3-d]-pyrimidine (7b, 0.07 g) was covered with methanolic-ammonia (20 mL) and heated in a sealed reaction vessel at 135° C. for 10 hours. The solvent was evaporated in vacuo to give a thick syrup. This syrup was subjected to column chromatography and elution of the silica gel column (20×3 cm) with 5% MeOH in CHCl3, which, after evaporation of the appropriate UV absorbing fractions, furnished colorless needles of 10, 0.04 g. (66.6%), mp 149°-150° C. 1H-NMR (DMSO-d6): δ8.14 (s, 1, C2--H), 7.56 (s, 1, C6--H), 6.92 (bs, 2, exchangeable with D2O, NH2), 5.49 (s, 1, N7--CH2), 4.64 (bs, 1, exchangeable with D2O, OH), 3.43 (m, 4, CH2): UVεmax nm (ε33 104): (pH 7) 214 (2.5), 278 (1.3); (pH 1) 233 (2.8), 280 (1.3); (pH 11) 227 (1.4), 278 (1.3). Anal. Calcd. for C9H11N4O2Cl.1/4H2O: C, 43.73; H, 4.66; N, 22.67. Found: C, 43.87; H, 4.36; N. 22.23.
Reaction SMILES: C(O[C:6](=O)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]2)=[O:16])=[CH:11][CH:10]=1)(C)(C)C.[H-].[Na+].CI.C(O)(C(F)(F)F)=O>CN(C=O)C>[CH3:6][NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[CH2:18][CH2:19][N:20]([CH3:23])[CH2:21][CH2:22]2)=[O:16])=[CH:11][CH:10]=1
Reactant: CN1CCN(C(=O)c2ccc(CNC(=O)OC(C)(C)C)cc2)CC1
Agent: [H-]
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Solvent: CI
Product: CNCc1ccc(C(=O)N2CCN(C)CC2)cc1

Procedure:
A crude product of [4-(4-methyl-piperazine-1-carbonyl)-benzyl]-carbamic acid tert-butyl ester obtained in Example 1-D-293, sodium hydride and methyl iodide were treated in DMF, and further treated with TFA, to obtain (4-methylaminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone. Using bis-(4-methoxy-benzyl)-[5-(2-morpholin-4-yl-6,7-dihydro-5H-pyrrolo[2,3-d]pyrimidin-4-yl)-pyrimidin-2-yl]-amine (100 mg) and (4-methylaminomethyl-phenyl)-(4-methyl-piperazin-1-yl)-methanone (126 mg) instead of 4-(4-ethyl-piperazin-1-yl)-2,6-difluoro-phenylamine used in Step D in Example 1-D-18, in the same manner as Step D in Example 1-D-18, a crude product of 4-{2-[bis-(4-methoxy-benzyl)-amino]-pyrimidin-5-yl}-2-morpholin-4-yl-5,6-dihydro-pyrrolo[2,3-d]pyrimidine-7-carboxylic acid methyl-[4-(4-methyl-piperazine-1-carbonyl)-benzyl]-amide was obtained, and then the PMB groups were removed according to the above Deprotection method 3, to obtain the desired compound (D-297) as a colorless powder (6 mg, 6%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH:7]=[C:6]2[CH2:13][NH2:14]>CO.CC(O)=O.[Ni]>[F:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][CH:6]2[CH2:13][NH2:14]
Reactant: NCC1=CCOc2ccc(F)cc21
Agent: [Ni]
Agent: Cl
Solvent: CO
Solvent: CC(=O)O
Product: NCC1CCOc2ccc(F)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
To a solution of 1-(6-fluoro-2H-chromen-4-yl)methanamine hydrochloride (1.36 g, 7.6 mmol) in MeOH (20 mL) and AcOH (10 mL) was added Raney Nickel (760 mg) at room temperature. The suspension was stirred at rt overnight under 50 psi of H2. The reaction mixture was filtered and concentrated. The residue was dissolved in DCM and washed with sat. NaHCO3, dried (Na2SO4), and concentrated to give 490 mg (36%) of the title compound as a green oil. [M+H] calc'd for C10H12FNO, 182; found 182.
Reaction SMILES: CS(O[CH2:6][C@H:7]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)(=O)=O.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>C1COCC1>[C:18]([O:17][C:15]([NH:14][C@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:22]1[CH2:27][CH2:26][CH:25]([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:24][CH2:23]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)OC(=O)N[C@@H](COS(C)(=O)=O)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C[C@H](NC(=O)OC(C)(C)C)c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 14 h

Procedure:
To a solution of 1 g of (2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl methanesulfonate in 5 mL of THF were added 0.4 mL of ethyl piperidine-4-carboxylate and 1 mL of diisopropylethylamine, followed by stirring at 70° C. for 14 hours, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to obtain 160 mg of ethyl 1-{(2R)-2-[(tert-butoxycarbonyl)amino]-2-phenylethyl}piperidine-4-carboxylate.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=2)[CH:5]=[CH:6][C:7]=1[C:8](=[O:16])[CH:9]=[CH:10][C:11]1[CH:15]=[CH:14][S:13][CH:12]=1.S(=O)(=O)(O)O.[OH-].[Na+]>>[CH3:20][C:18]1[N:19]=[C:3]2[C:2]3[NH:1][CH:10]([C:11]4[CH:15]=[CH:14][S:13][CH:12]=4)[CH2:9][C:8](=[O:16])[C:7]=3[CH:6]=[CH:5][N:4]2[C:17]=1[CH3:21]
Reactant: Cc1nc2c(N)c(C(=O)C=Cc3ccsc3)ccn2c1C
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Product: Cc1nc2c3c(ccn2c1C)C(=O)CC(c1ccsc1)N3
Yield: 69.2 %

Procedure:
2.6 g of 8-amino-2,3-dimethyl-7-[3-(3-thienyl)-1-oxo-2-propenyl]imidazo[1,2-a]pyridine are treated at room temperature with 20 ml of aqueous 70% strength sulfuric acid, poured onto ice water (100 ml) after 90 minutes, neutralized with aqueous 6 N sodium hydroxide solution and extracted three times with 50 ml of methylene chloride each time. The combined organic phases are washed with water, dried over sodium sulfate, the solvent is stripped off in vacuo and the remaining yellow oil is stirred with 15 ml of diethyl ether. The yellowish solid obtained here is filtered off and dried in vacuo. 1.8 g of the title compound of m.p. 176–77° C. (diethyl ether) are obtained.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[CH2:12][S:13]([CH3:15])=[O:14].[OH-].[K+].S(OC)(O[CH3:22])(=O)=O.Cl>O>[CH3:22][N:5]1[C:6]2[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=2)[C:2](=[O:1])[C:3]([CH2:12][S:13]([CH3:15])=[O:14])=[CH:4]1
Reactant: CS(=O)Cc1cnc2ccccc2c1O
Reactant: COS(=O)(=O)OC
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cc(CS(C)=O)c(=O)c2ccccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a stirred solution of 4-hydroxy-3-methylsulphinylmethylquinoline (4.4 g.) and potassium hydroxide (1.68 g.) in water (20 ml.) at 0°-5° was added dimethyl sulphate (2.52 g.). The solution was stirred at room temperature for 30 minutes, then neutralised with 5 N aqueous hydrochloric acid. The resultant sticky solid was triturated with industrial methylated spirit to give a solid product. The product was purified by high pressure liquid chromatography over silica gel, eluting with isopropanol:dichloromethane 95:5 at a flow rate of 200 ml. per minute. This procedure gave the novel 1-methyl-3-methylsulphinylmethyl-4-quinolone, m.p. 94°-96°.
Reaction SMILES: [F:1][CH:2]([F:22])[C:3]1[N:8]2[CH:9]=[N:10][CH:11]=[C:7]2[N:6]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:14][CH:13]=2)[CH:4]=1.C([O-])(=O)C.[Na+].[I:28]Cl>C(O)(=O)C.O>[F:22][CH:2]([F:1])[C:3]1[N:8]2[CH:9]=[N:10][C:11]([I:28])=[C:7]2[N:6]=[C:5]([C:12]2[CH:13]=[CH:14][C:15]([C:18]([F:21])([F:20])[F:19])=[CH:16][CH:17]=2)[CH:4]=1
Reactant: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2cncn12
Reactant: ClI
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: FC(F)c1cc(-c2ccc(C(F)(F)F)cc2)nc2c(I)ncn12
Temperature: 25 °C
Reaction time: 17 h
Yield: 112 %

Procedure:
To a stirred solution of 4-difluoromethyl-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (1.56 g, 4.98 mmol) in acetic acid (9 ml) was added at room temperature sodium acetate (0.46 g, 5.63 mmol) and drop wise a solution of iodine monochloride (0.91 g, 5.63 mmol) in acetic acid (4 ml). The reaction mixture was stirred at room temperature for 17 h, diluted slowly with water (150 ml), stirred at room temperature for 30 min, the precipitate was filtered off, washed with water and dried to give 4-difluoromethyl-8-iodo-2-(4-trifluoromethyl-phenyl)-imidazo[1,5-a]pyrimidine (2.45 g, 100%) as a yellow solid. MS (EI) 439.0 [(M)+]; mp 159° C.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19]#[C:20][CH3:21]>CC(C)=O>[CH2:18]([O:1][C:2]1[CH:10]=[CH:9][C:5]2[O:6][CH2:7][O:8][C:4]=2[CH:3]=1)[C:19]#[C:20][CH3:21]
Reactant: CC#CCBr
Reactant: Oc1ccc2c(c1)OCO2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC#CCOc1ccc2c(c1)OCO2
Temperature: 25 °C

Procedure:
A mixture of 7.0 g (0.05 moles) of 5-hydroxy-benzo[1.3]dioxole, 6.91 g (0.05 moles) of anhydrous potassium carbonate in ml 25 of acetone was added with 6.65 g (0.05 moles) of 1-bromo-2-butyne. The mixture was heated to reflux for 6 hrs. The mixture was then cooled to room temperature, filtered and the filtrate evaporated u.v (20° C./21 mbar). The residue was then purified on silica gel column (eluant n-hexane: ethyl acetate 3:1 v/v). A liquid product (6.1 g, 95% purity) was obtained whose NMR and MS analyses correspond to those of the aforementioned compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH2:11][CH3:12])[CH:5]=1)[CH3:2].[C:13]1(=[O:19])[O:18][C:16](=[O:17])[CH2:15][CH2:14]1.[Cl-].[Al+3].[Cl-].[Cl-].O>ClCCCl>[CH2:11]([O:10][C:6]1[CH:5]=[C:4]([O:3][CH2:1][CH3:2])[CH:9]=[CH:8][C:7]=1[C:13]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[O:19])[CH3:12]
Reactant: CCOc1cccc(OCC)c1
Reactant: O=C1CCC(=O)O1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Solvent: O
Product: CCOc1ccc(C(=O)CCC(=O)O)c(OCC)c1
Reaction time: 1 h

Procedure:
A mixture of m-diethoxybenzene (22 g.) and succinic anhydride (15 g.) was dissolved in 1,2-dichloroethane and the resultant solution was stirred and treated with powdered aluminium chloride (30 g.), added gradually during 1 hour with external cooling to keep the reaction temperature at 10° C. The reaction mixture was stirred for 1 hour further, poured into water and the solvent was boiled off. The remaining oily suspension crystallised on stirring and cooling and the solid was collected and dried (Yield 15.5 g.). It had m.p. 139°-141° C after crystallisation from toluene.
Reaction SMILES: [CH:1]([O-:5])([O-])[O:2][CH3:3].[CH3:6]N1CCN(C)C1=O.S(=O)(=O)(O)O.[N+:19]([N:22]=[C:23]1[NH:27][CH2:26][CH2:25][NH:24]1)([O-:21])=[O:20]>>[CH3:6][O:5][CH:1]([O:2][CH3:3])[N:24]1[CH2:25][CH2:26][NH:27][C:23]1=[N:22][N+:19]([O-:21])=[O:20]
Reactant: O=[N+]([O-])N=C1NCCN1
Reactant: COC([O-])[O-]
Reactant: CN1CCN(C)C1=O
Agent: O=S(=O)(O)O
Product: COC(OC)N1CCNC1=N[N+](=O)[O-]
Temperature: 25 °C

Procedure:
22.0 g of methyl orthoformate was dropped in about 2 hours in a mixture of 10 g of 2-nitroiminoimidazolidine, 20 ml of 1,3-dimethyl-2-imidazolidinone and 0.05 g of sulfuric acid at 150° C., followed by heating under reflux for further 1 hour while removing the resultant distillate by means of the Dean-Stark trap. After cooling to room temperature, the mixture was poured into water, and extracted with ethyl acetate. After washing with water, the extract was dried with anhydrous magnesium sulfate, after which the solvent was distilled off under reduced pressure. The resultant crude crystals were sludged with ether to give 1.9 g of 1-dimethoxymethyl-2-nitroiminoimidazolidine.
Reaction SMILES: [CH3:1]/[C:2](=[CH:6]\[CH2:7][CH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)/[C:3]([OH:5])=[O:4].[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([SH:25])=[CH:21][CH:20]=1.N1CCCCC1>>[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25][CH:6]([CH2:7][CH2:8][CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH:2]([CH3:1])[C:3]([OH:5])=[O:4])=[CH:21][CH:20]=1
Reactant: C/C(=C\CCCCc1ccccc1)C(=O)O
Reactant: COc1ccc(S)cc1
Solvent: C1CCNCC1
Product: COc1ccc(SC(CCCCc2ccccc2)C(C)C(=O)O)cc1
Temperature: 85 °C
Yield: 25.1 %

Procedure:
(E)-2-Methyl-7-phenyl-hept-2-enoic acid (2.2 g, 10 mmol), 4-methoxybenzenethiol (2.8 g, 20 mmol) and piperidine (0.1 mL, 1 mmol) are combined and heated at 85° C. for 12 hours. The reaction is cooled and purified by gradient elution chromatography (silica, 35 to 100% ether in petroleum ether) to yield (±)-3-(4-Methoxyphenylsulfanyl)-2-methyl-7-phenylheptanoic acid (0.9 g, 25%) as a 50/50 mixture of diastereomers: 1H NMR (300 MHz, CDCl3) δ 7.39-7.34 (m, 2H), 7.29-7.25 (m, 2H), 7.20-7.11 (m, 3H), 6.81 (m, 2H), 3.79 (s, 1.5H), 3.78 (s, 1.5H), 3.30-3.16 (m, 1H), 2.70-2.54 (m, 3H), 1.72-1.40 (m, 6H), 1.28 (d, J=7.0 Hz, 1.5H), 1.22 (d, J=7.0 Hz, 1.5H); MS (FAB) m/e 359 (M+H)+.
Reaction SMILES: [C:1]([C:3]1[C:11]2[CH2:10][CH2:9][NH:8][CH2:7][C:6]=2[S:5][C:4]=1[NH:12][C:13](=[O:22])[CH:14]=[CH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)#[N:2].C(C1C2CCNCC=2SC=1N[C:35](=[O:44])[CH:36]=CC1C=NC=CC=1)#N.ClC(OCC)=S>>[C:35]([N:8]1[CH2:9][CH2:10][C:11]2[C:3]([C:1]#[N:2])=[C:4]([NH:12][C:13](=[O:22])/[CH:14]=[CH:15]/[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[S:5][C:6]=2[CH2:7]1)(=[O:44])[CH3:36]
Reactant: N#Cc1c(NC(=O)C=Cc2ccccc2)sc2c1CCNC2
Reactant: N#Cc1c(NC(=O)C=Cc2cccnc2)sc2c1CCNC2
Agent: CCOC(=S)Cl
Product: CC(=O)N1CCc2c(sc(NC(=O)/C=C/c3ccccc3)c2C#N)C1

Procedure:
The following compounds 35 and 36 can be prepared according to the general procedure F described below starting from N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-phenyl-acrylamide (compound B1) or N-(3-cyano-4,5,6,7-tetrahydro-thieno[2,3-c]pyridin-2-yl)-3-(pyridin-3-yl)-acrylamide (compound B2) and ethyl chlorothioformate.
Reaction SMILES: Cl.C([N:9]1[CH:14]([CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH:13]2[CH2:22][CH:23]([C:24](OCC)=[O:25])[CH:10]1[CH:11]=[C:12]2[CH3:29])C1C=CC=CC=1.C(C1C2CC(C(OCC)=O)C(C=C2C)N1)C1C=CC=CC=1>>[CH2:15]([CH:14]1[NH:9][C:24](=[O:25])[CH:23]2[CH2:22][CH:13]1[C:12](=[CH2:29])[CH:11]=[CH:10]2)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CCOC(=O)C1CC2C(C)=CC1N(Cc1ccccc1)C2Cc1ccccc1
Agent: CCOC(=O)C1CC2C(C)=CC1NC2Cc1ccccc1
Agent: Cl
Product: C=C1C=CC2CC1C(Cc1ccccc1)NC2=O

Procedure:
Following a procedure similar to that described in Example 15A, catalytic debenzylation of the ethyl 2,3-dibenzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate hydrochloride described in Example 1F and base catalyzed rearrangement of the resulting ethyl 3-benzyl-5-methyl-2-azabicyclo[2.2.2]oct-5-ene-7-carboxylate affords 2-benzyl-8-methylene-3-azabicyclo[3.3.1]non-6-en-4-one.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH:11]=O)[CH:5]=[CH:6][C:7]=1[Cl:8].[CH3:26][S:27]([C:29]1[C:34]([CH:35]2[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)=[CH:33][CH:32]=[CH:31][N:30]=1)=[O:28]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]([CH:13]2[C:21]3[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=3)[C:15](=[O:24])[N:14]2[CH3:25])[CH2:10][CH2:11][N:38]2[CH2:39][CH2:40][CH:35]([C:34]3[C:29]([S:27]([CH3:26])=[O:28])=[N:30][CH:31]=[CH:32][CH:33]=3)[CH2:36][CH2:37]2)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: COc1ccc2c(c1)C(=O)N(C)C2C(CC=O)c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)c1ncccc1C1CCNCC1
Product: COc1ccc2c(c1)C(=O)N(C)C2C(CCN1CCC(c2cccnc2S(C)=O)CC1)c1ccc(Cl)c(Cl)c1
Product: Cl
Yield: 95.7 %

Procedure:
3-(3,4-Dichlorophenyl)-3-(5-methoxy-2-methyl-3-oxo-2,3-dihydro-1H-isoindol-1-yl)propionaldehyde (0.33 g) was coupled to 4-(2-methylsulfinyl-3-pyridyl)piperidine(0.423 g) by a method similar to that described in Example 8. The reaction product was purified by chromatography and converted to the corresponding hydrochloride salt as described in the Example 8 to afford the title compound (0.26 g); mp 120-182° C. (d); MS: m/z=586(M+1); NMR(CD3OD): 2.0-2.3 (m,4), 2.6 (m,2), 2.9 (m,5), 3.2-3.3 (m,4), 3.6-3.9 (m,8), 4.8 (m,1), 6.7-7.3 (m,5), 7.5-8.1 (m,3), 8.7 (broad,1). Analysis for C30H33Cl2N3O3S.2.0 HCl.1.0 H2O: Calculated: C, 53.18; H, 5.50, N, 6.20; Found: C, 53.39; H, 4.49; N, 6.53.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([CH3:9])=[CH:4][C:3]=1[N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.[Cl:16][CH2:17][CH2:18][C:19](Cl)=[O:20]>>[Cl:16][CH2:17][CH2:18][C:19]([N:13]1[CH2:12][CH2:11][N:10]([C:3]2[CH:4]=[C:5]([CH3:9])[C:6]([CH3:8])=[CH:7][C:2]=2[CH3:1])[CH2:15][CH2:14]1)=[O:20]
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Reactant: O=C(Cl)CCCl
Product: Cc1cc(C)c(N2CCN(C(=O)CCCl)CC2)cc1C

Procedure:
A target compound (925 mg, 3.137 mmol, 62.5%) was yielded as liquid in the same manner as Reference Example 13 by reacting 1-(2,4,5-trimethylphenyl)piperazine (1.03 g, 5.041 mmol) with 3-chloropropionyl chloride (484.9 mg, 5.041 mmol) and purifying by separation through column chromatography (EtOAc/hexane, 1:2).
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH2:19][CH2:18][CH2:17][CH:16]([C:21]([NH2:23])=[O:22])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:26][CH3:27])=[CH:12][C:13]=2[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[Pd].CCOCCOCCO>[CH2:1]([N:8]1[C:20]2[CH:19]=[CH:18][CH:17]=[C:16]([C:21](=[O:22])[NH2:23])[C:15]=2[C:14]2[C:9]1=[CH:10][C:11]([O:26][CH3:27])=[CH:12][C:13]=2[O:24][CH3:25])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(OC)c2c3c(n(Cc4ccccc4)c2c1)CCCC3C(N)=O
Agent: [Pd]
Solvent: CCOCCOCCO
Product: COc1cc(OC)c2c3c(C(N)=O)cccc3n(Cc3ccccc3)c2c1

Procedure:
A mixture of 2.0 gm. of the product from Example 2, 2 gm. of 5% Pd/C, and 100 mL of carbitol was refluxed for 17 hours, filtered while still hot, and the solid washed well with ethyl acetate. The combined filtrates were washed with water, washed with brine, dried over sodium sulfate, and evaporated in vacuo to give subtitled product, 1.4 gm., 70%, mp 240-243° C.