Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:16](=[O:21])[CH2:17]C(=O)C)=[C:11]([N+:22]([O-])=O)[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([N:25]2[CH:29]=[CH:28][N:27]=[CH:26]2)[C:9]2[CH:10]=[C:11]3[C:12](=[CH:13][CH:14]=2)[NH:15][C:16](=[O:21])[CH:17]=[N:22]3)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)CC(=O)Nc1ccc(C(c2cccc(Cl)c2)n2ccnc2)cc1[N+](=O)[O-]
Agent: [Na+]
Agent: [OH-]
Product: O=c1cnc2cc(C(c3cccc(Cl)c3)n3ccnc3)ccc2[nH]1
Temperature: 80 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
A mixture of 12 parts of N-[4-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2-nitrophenyl]-3-oxobutanamide and 120 parts of a sodium hydroxide solution 6.5% was stirred for 15 minutes at 80° C. After cooling, the product was obtained, yielding 10.25 parts (100%) of 6-[(3-chlorophenyl)(1H-imidazol-1-yl)methyl]-2(1H)-quinoxalinone, N4 -oxide (comp. 175).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH:10]2[O:22][CH2:23][C:24]2[CH:33]=[CH:32][C:31]3[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=3)[CH:25]=2)=[CH:5][CH:4]=1.[CH3:34][Si:35]([CH3:51])([CH3:50])[CH2:36][CH2:37][O:38][CH2:39][O:40][C:41]1[CH:49]=[CH:48][C:44]([C:45](O)=[O:46])=[CH:43][CH:42]=1.Cl.C(N=C=NCCCN(C)C)C>>[CH:25]1[C:26]2[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=2)[CH:32]=[CH:33][C:24]=1[CH2:23][O:22][CH:10]1[CH:9]([C:6]2[CH:7]=[CH:8][C:3]([CH2:2][O:1][C:45](=[O:46])[C:44]3[CH:48]=[CH:49][C:41]([O:40][CH2:39][O:38][CH2:37][CH2:36][Si:35]([CH3:50])([CH3:34])[CH3:51])=[CH:42][CH:43]=3)=[CH:4][CH:5]=2)[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:19])[CH3:20])=[O:16])[CH2:11]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(CO)cc2)C(OCc2ccc3ccccc3c2)C1
Reactant: C[Si](C)(C)CCOCOc1ccc(C(=O)O)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(COC(=O)c3ccc(OCOCC[Si](C)(C)C)cc3)cc2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described under (g) by condensing tert-butyl (3RS,4RS)-4-(4-hydroxymethyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate and 4-(2-trimethylsilanyl-ethoxymethoxy)-benzoic acid using N-ethyl-N'-(3-dimethylaminopropyl)-carbodiimide hydrochloride (EDC) as the condensation agent there was obtained tert-butyl (3RS,4RS)-3-(naphthalen-2-ylmethoxy)-4-{4-[4-(2-trimethylsilanyl-ethoxymethoxy)-benzoyloxymethyl]-phenyl}-piperidine-1-carboxylate; MS: 715 (M+NH4)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][CH:3]=1.[Br:12]Br.Br>[Fe]>[Br:12][C:3]1[CH:4]=[C:5]([C:8]([F:9])([F:10])[F:11])[CH:6]=[CH:7][C:2]=1[NH2:1]
Reactant: BrBr
Reactant: Nc1ccc(C(F)(F)F)cc1
Agent: [Fe]
Agent: Br
Product: Nc1ccc(C(F)(F)F)cc1Br
Reaction time: 2 h

Procedure:
To 161.0 g of p-aminobenzotrifluoride and 10.0 g of iron filings is added, dropwise, with agitation at 35°-40°, 160.0 g of bromine, using a slow stream of nitrogen to sweep out the evolved hydrogen bromide. Subsequently, the mixture is agitated for an additional 2 hours and then distilled in vacuo to give 3-bromo-4-aminobenzotrifluoride.
Reaction SMILES: [CH3:1][Si:2]([C:5]#[CH:6])([CH3:4])[CH3:3].Cl[C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[Cu]I.C(NCC)C>[CH3:1][Si:2]([CH3:4])([CH3:3])[C:5]#[C:6][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][N:9]=1
Reactant: Clc1ccc(Cl)nc1
Reactant: C#C[Si](C)(C)C
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Product: C[Si](C)(C)C#Cc1ccc(Cl)cn1
Yield: 28.6 %

Procedure:
1.2 ml (10 mmol) of trimethylsilylacetylene, 40 ml of diethylamine and 1.5 g (10 mmol) of 2,5-dichloropyridine are stirred at 20° under argon. To the colourless solution obtained there are added 0.1 g (0.4 mmol) of triphenylphosphine, 0.01 g (0.05 mmol) of copper-(I) iodide as well as 0.06 g (0.25 mmol) of palladium-dichloro-bis(acetonitrile). The reaction solution is subsequently heated to reflux for 5 hours while stirring. After cooling to 25° the reaction solution is evaporated at 40° under reduced pressure. 50 ml of ethanol are subsequently added to the residue and the mixture is again evaporated. The crude product is filtered over 30 g of silica gel with ethyl acetate and the eluate is evaporated, whereby 1.6 g of brown liquid remain behind. 1.0 g thereof is distilled in a bulb tube at 70°/0.1 Pa, whereby there are obtained as the main fraction 0.6 g of 2-trimethylsilylethynyl-5-chloropyridine which solidifies upon standing.
Reaction SMILES: Cl[CH:2]([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4].[N-:9]=[N+:10]=[N-:11].[Na+]>C(COC)OC>[N:9]([CH:2]([O:7][CH3:8])[C:3]([O:5][CH3:6])=[O:4])=[N+:10]=[N-:11]
Reactant: COC(=O)C(Cl)OC
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)C(N=[N+]=[N-])OC
Temperature: 25 °C
Yield: 72.4 %

Procedure:
A mixture of methyl 2-chloro-2-methoxyacetate (13.86 g., 0.1 mole), powdered sodium azide (8.46 g., 0.13 mole) and dry dimethoxyethane (80ml.) is stirred and heated at reflux for 39 hours. After cooling to room temperature, the mixture is filtered to remove salts which are washed with dry ether. Evaporation of the solvents at aspirator pressure leaves a yellow liquid which is distilled to give methyl 2-azido-2-methoxyacetate (10.5 g.) as a water-white liquid (b.p. 75°-77°C./17 mm.).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:24])=[O:23])[CH:15]=[CH:14][C:13]=1[C:25]([N:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])[CH2:29][CH2:28]1)=[O:26])(C)(C)C.FC(F)(F)C(O)=O.C(=O)([O-])O.[Na+]>ClCCl>[NH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:17]=[C:16]([N:18]2[CH2:22][CH2:21][CH2:20][S:19]2(=[O:23])=[O:24])[CH:15]=[CH:14][C:13]=1[C:25]([N:27]1[CH2:28][CH2:29][N:30]([C:33]2[CH:38]=[CH:37][C:36]([CH3:39])=[CH:35][C:34]=2[CH3:40])[CH2:31][CH2:32]1)=[O:26]
Reactant: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCNC(=O)OC(C)(C)C)CC2)c(C)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3OCCCN)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.4 %

Procedure:
To a mixture of [4-(2,4-dimethylphenyl)piperazin-1-yl][4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-hydroxyphenyl]methanone (241 mg) described in Example 124, (3-bromopropyl)carbamic acid tert-butyl ester (200 mg) and cesium carbonate (548 mg) was added 2-butanone (4 mL), and the mixture was stirred with heating under reflux for 4 hr. Water was added to the reaction mixture, the mixture was extracted with ethyl acetate, and the solvent was evaporated. The obtained residue was purified by column chromatography (ethyl acetate:hexane) to give (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg). The obtained (3-{2-[4-(2,4-dimethylphenyl)piperazine-1-carbonyl]-5-(1,1-dioxo-1λ6-isothiazolidin-2-yl)phenoxy}propyl)carbamic acid tert-butyl ester (221 mg) was dissolved in dichloromethane (2 mL), trifluoroacetic acid (0.46 mL) was added, and the mixture was stirred at room temperature overnight. The reaction mixture was poured into ice water, the mixture was neutralized with sodium hydrogen carbonate and extracted with chloroform, and the solvent was evaporated. The obtained residue was purified by NH-coated silica gel column chromatography (ethyl acetate:methanol) to give the title compound (74 mg).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22].N1C2C(=CC=CC=2)C2(C3=CC4OCOC=4C=C3OC2)C1=O.CC1C=CC(S(O[CH2:55][C@@H:56]2[CH2:61][O:60][CH2:59][CH2:58][O:57]2)(=O)=O)=CC=1.CC1C=CC(S(OC[C@H]2COCCO2)(=O)=O)=CC=1>>[O:57]1[CH2:58][CH2:59][O:60][CH2:61][C@H:56]1[CH2:55][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C@@:3]2([C:21]3[C:12](=[CH:13][C:14]4[O:19][CH2:18][CH2:17][O:16][C:15]=4[CH:20]=3)[O:11][CH2:10]2)[C:2]1=[O:22]
Reactant: O=C1Nc2ccccc2[C@]12COc1cc3c(cc12)OCCO3
Reactant: Cc1ccc(S(=O)(=O)OC[C@@H]2COCCO2)cc1
Agent: Cc1ccc(S(=O)(=O)OC[C@H]2COCCO2)cc1
Agent: O=C1Nc2ccccc2C12COc1cc3c(cc12)OCO3
Product: O=C1N(C[C@@H]2COCCO2)c2ccccc2[C@]12COc1cc3c(cc12)OCCO3

Procedure:
Following the procedure as described in EXAMPLE 8 and making non-critical variations using (S)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace spiro[furo[2,3-f][1,3]benzodioxole-7,3′-indol]-2′(1′H)-one, and (S)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate to replace (R)-(1,4-dioxan-2-yl)methyl 4-methylbenzenesulfonate, (8S)-1′-[(2R)-1,4-dioxan-2-ylmethyl]-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one was obtained (84%) as a colorless solid: mp 207-210° C. (diethyl ether/hexanes); 1H NMR (300 MHz, CDCl3) δ7.30 (ddd, J=7.7, 7.7, 1.2 Hz, 1H), 7.15 (dd, J=7.5 Hz, 0.9 Hz, 1H), 7.08-7.02 (m, 2H), 6.49 (s, 1H), 6.21 (s, 1H), 4.87 (d, J=9.0 Hz, 1H), 4.63 (d, J=9.0 Hz, 1H), 4.21-4.16 (m, 2H), 4.13-4.09 (m, 2H), 3.98-3.77 (m, 4H), 3.75-3.56 (m, 4H), 3.41 (dd, J=11.7, 9.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ177.8, 155.3, 144.7, 142.7, 138.4, 132.3, 128.9, 123.9, 123.5, 121.1, 111.6, 109.4, 99.5, 80.2, 73.3, 69.4, 66.8, 66.5, 64.6, 64.0, 58.0, 41.9; MS (ES+) m/z 396.0 (M+1).
Reaction SMILES: [Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[OH:29])=[C:11](I)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[O:41]1[CH2:46][CH:45]=[C:44](B2OC(C)(C)C(C)(C)O2)[CH2:43][CH2:42]1.C(=O)([O-])[O-].[Cs+].[Cs+].[F-].[Cs+]>O.O1CCCC1.C1(C)C=CC=CC=1>[Si:1]([O:8][C@H:9]1[CH2:18][C:17]2([CH2:21][CH2:20][CH2:19]2)[CH2:16][C:15]2[N:14]=[C:13]([CH:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)[C:12]([C@@H:28]([C:30]3[CH:35]=[CH:34][C:33]([C:36]([F:39])([F:38])[F:37])=[CH:32][CH:31]=3)[OH:29])=[C:11]([C:44]3[CH2:45][CH2:46][O:41][CH2:42][CH:43]=3)[C:10]1=2)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(F)(F)F)cc3)c(I)c21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [F-]
Solvent: Cc1ccccc1
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC2(CCC2)Cc2nc(C3CCOCC3)c([C@H](O)c3ccc(C(F)(F)F)cc3)c(C3=CCOCC3)c21

Procedure:
Obtained by starting from (R)—((S)-5′-(tert-butyldimethylsilyloxy)-4′-iodo-2′-(tetrahydro-2H-pyran-4-yl)-6′,8′-dihydro-5′H-spiro[cyclobutane-1,7′-quinoline]-3′-yl)(4-(trifluoromethyl)phenyl)methanol and 2-(3,6-dihydro-2H-pyran-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane. A 2 M solution of caesium carbonate in water is used instead caesium fluoride. The reaction is run in tetrahydrofurane/toluene 4:1.
Reaction SMILES: [OH:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:3]1.[CH3:40]I>CN(C=O)C>[CH3:40][O:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([NH:8][C:9](=[O:18])[O:10][CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C@H:4]([CH2:19][O:20][C:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[CH2:3]1
Reactant: CI
Reactant: O=C(N[C@H]1CC[C@@H](O)C[C@H]1COC(c1ccccc1)(c1ccccc1)c1ccccc1)OCc1ccccc1
Solvent: CN(C)C=O
Product: CO[C@@H]1CC[C@H](NC(=O)OCc2ccccc2)[C@H](COC(c2ccccc2)(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Yield: 49.1 %

Procedure:
A sample of benzyl (1S,2R,4R)-4-hydroxy-2-(trityloxymethyl)cyclohexylcarbamate (6.9 g, 13.24 mMol) was dissolved in a mixture of MeI (12.4 mL, 198.6 mMol) and anhydrous DMF (15 mL) prior to the addition of Ag2O (6.1 g, 26.48 mMol) in one portion under an argon flush. The reaction was set to stir at rt in the dark. After stirring for 30 hr (the reaction was incomplete), it was diluted with CH2Cl2 and filtered. through Celite. Filtered and concentrated to a yellow oil and flash chromatographed to get benzyl (1S,2R,4R)-4-methoxy-2-(trityloxymethyl)cyclohexylcarbamate (3.48 g) as a white foamy solid and recover the starting materiel.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[N:9]3[C:10]=1[NH:11][C:12](=[O:13])[C:8]3=[CH:7][CH:6]=[CH:5]2.[H-].[Na+].Br[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][N:22]1[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]2[C:23]1=[O:32].O>CN(C=O)C>[C:23]1(=[O:32])[N:22]([CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][N:11]2[C:10]3=[C:2]([CH3:1])[N:3]=[C:4]4[CH:5]=[CH:6][CH:7]=[C:8]([N:9]34)[C:12]2=[O:13])[C:26](=[O:27])[C:25]2=[CH:28][CH:29]=[CH:30][CH:31]=[C:24]12
Reactant: O=C1c2ccccc2C(=O)N1CCCCCBr
Reactant: Cc1nc2cccc3c(=O)[nH]c1n23
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1nc2cccc3c(=O)n(CCCCCN4C(=O)c5ccccc5C4=O)c1n23
Yield: 66 %

Procedure:
To a suspension of 277 mg (1.60 mmol) of 3,4-dihydro-2-methyl-1,3,7b-triazacyclopent[cd]inden-4-one in 3 ml of DMF was added, while stirring under ice-cooling, 77 mg (1.93 mmol) of 60% sodium hydride (dispersion in oil). The mixture was stirred for 15 minutes at the same temperature. To the reaction mixture was added 521 mg (1.76 mmol) of N-(5-bromopentyl)phthalimide. The mixture was stirred for one hour at 110° C. After cooling, the reaction mixture was poured into water, and extracted with ethyl acetate. The extract solution was washed with an aqueous saline solution, and dried over anhydrous magnesium sulfate. The solvent was distilled off, and the residue was purified by column chromatography (eluent: ethyl acetate/ethanol=10:1) to afford 410 mg of the desired compound (66.0%, a pale brown solid).
Reaction SMILES: CC1C=CC(S([NH:11][NH2:12])(=O)=O)=CC=1.[F:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([C:22]2[N:27]=[CH:26][C:25]3[C@:28]4([CH2:41][C:42]5[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=5)[CH2:40][CH2:39][C:34]5([O:38][CH2:37][CH2:36][O:35]5)[CH2:33][C@H:29]4[CH2:30][CH2:31][CH2:32][C:24]=3[CH:23]=2)=O)=[CH:16][CH:15]=1>CO>[F:13][C:14]1[CH:15]=[CH:16][C:17]([C:20]2[N:11]=[N:12][N:27]3[CH:26]=[C:25]4[C@:28]5([CH2:41][C:42]6[CH:47]=[CH:46][CH:45]=[CH:44][N:43]=6)[CH2:40][CH2:39][C:34]6([O:35][CH2:36][CH2:37][O:38]6)[CH2:33][C@H:29]5[CH2:30][CH2:31][CH2:32][C:24]4=[CH:23][C:22]=23)=[CH:18][CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)NN)cc1
Reactant: O=C(c1ccc(F)cc1)c1cc2c(cn1)[C@]1(Cc3ccccn3)CCC3(C[C@H]1CCC2)OCCO3
Solvent: CO
Product: Fc1ccc(-c2nnn3cc4c(cc23)CCC[C@@H]2CC3(CC[C@@]42Cc2ccccn2)OCCO3)cc1
Temperature: 50 °C
Reaction time: 48 h
Yield: 100.1 %

Procedure:
4-Methylbenzenesulfonohydrazide (0.177 g, 0.948 mmol) in MeOH (4 mL) was combined with (4-fluorophenyl)((7aR,11aS)-11a-(pyridin-2-ylmethyl)-5,6,7,7a,8,10,11,11a-octahydrospiro[benzo[6,7]cyclohepta[1,2-c]pyridine-9,2′-[1,3]dioxolan]-3-yl)methanone (0.224 g, 0.474 mmol) and the mixture was stirred at about 50° C. for about 48 h. The reaction mixture was cooled to rt and was washed with sat. aq. NaHCO3 and extracted with DCM (10 mL). The organics were dried over MgSO4 and concentrated in vacuo. The residue was purified on silica gel (12 g) using a gradient of 10-100% EtOAc in heptane to afford (4aR,13bS)-9-(4-fluorophenyl)-13b-(pyridin-2-ylmethyl)-1,2,4,4a,5,6,7,13b-octahydrospiro[benzo[3,4]cyclohepta[1,2-d][1,2,3]triazolo[1,5-a]pyridine-3,2′-[1,3]dioxolane] (156, R1=4-Fluorophenyl, R2=Pyridin-2-ylmethyl) (0.230 g, 56%); LC/MS, method 3, Rt=2.52 min, MS m/z 485 (M+H)+. 1H NMR (400 MHz, DMSO) δ 8.36 (s, 1H), 8.28-8.23 (m, 1H), 8.10-8.02 (m, 3H), 7.80-7.72 (m, 1H), 7.41-7.30 (m, 2H), 7.02-6.97 (m, 1H), 6.57-6.53 (m, 1H), 3.96-3.80 (m, 4H), 3.63-3.54 (m, 1H), 3.52-3.40 (m, 1H), 3.25-3.17 (m, 2H), 2.39-2.34 (m, 1H), 2.21-2.05 (m, 2H), 1.95-1.55 (m, 7H), 1.50-1.37 (m, 1H)
Reaction SMILES: [C:1]([CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9][CH3:10])=[O:8])#[N:2].[H-].[Na+].Cl[CH2:17][CH2:18][O:19][CH2:20][CH2:21]Cl.O>CS(C)=O>[C:1]([C:3]1([C:4]2[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=2)[C:7]([O:9][CH3:10])=[O:8])[CH2:21][CH2:20][O:19][CH2:18][CH2:17]1)#[N:2]
Reactant: ClCCOCCCl
Reactant: COC(=O)c1cccc(CC#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)c1cccc(C2(C#N)CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of methyl 3-(cyanomethyl)benzoate 1 (2 g, 11.4 mmol) in DMSO (20 mL) was added NaH (60%, 959 mg, 24.0 mmol) portion wise over 10 min. The reaction mixture was stirred for 40 min at rt and then bis(2-chloroethyl)ether (1.27 mL, 10.9 mmol) was added slowly and stirring continued for 18 hours. The reaction was poured into water and extracted with EtOAc/toluene (2:1). The combined extracts were washed with 2N HCl solution, water, brine, dried and evaporated the crude methyl 3-(4-cyanotetrahydro-2H-pyran-4-yl)benzoate 80 (1.25 g, 44%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[NH:5][C:4](=[O:10])[CH:3]=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[CH3:30][C:31]1[CH:32]=[CH:33][C:34]([C@H:37]2[CH2:39][C@@H:38]2[CH2:40]O)=[N:35][CH:36]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH3:9])[N:5]=[C:4]([O:10][CH2:40][C@H:38]2[CH2:39][C@@H:37]2[C:34]2[CH:33]=[CH:32][C:31]([CH3:30])=[CH:36][N:35]=2)[CH:3]=1
Reactant: Cc1ccc([C@H]2C[C@@H]2CO)nc1
Reactant: Cn1[nH]c(=O)cc(Br)c1=O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1ccc([C@H]2C[C@@H]2COc2cc(Br)c(=O)n(C)n2)nc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-1-methyl-1,2-dihydropyridazine-3,6-dione (100 mg, 0.49 mmol) in THF (3 mL) at 0° C. was added triphenyl phosphorous (257 mg, 0.98 mmol) and ((1S,2S)-2-(5-methylpyridin-2-yl)cyclopropyl)methanol (4) (80 mg, 0.49 mmol) followed by dropwise addition of DIAD (198 mg, 0.98 mmol). The reaction mixture was warmed to ambient temperature. After stirred for 1 h, the mixture was concentrated. The residue was purified by column chromatography on silica gel, eluting with PE/EA (1/2) to give the title compound as oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:34])=[C:14]([C:29](OCC)=[O:30])[C:15](=[O:28])[N:16]3[CH2:19][C:20]([N:22]3[CH2:27][CH2:26][O:25][CH2:24][CH2:23]3)=[O:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[CH2:35]([O:37][CH2:38][CH2:39][NH2:40])[CH3:36]>>[CH2:35]([O:37][CH2:38][CH2:39][NH:40][C:29]([C:14]1[C:15](=[O:28])[N:16]([CH2:19][C:20]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)=[O:21])[C:17]2[C:12]([C:13]=1[OH:34])=[N:11][CH:10]=[C:9]([CH2:8][C:5]1[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=1)[CH:18]=2)=[O:30])[CH3:36]
Reactant: CCOCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O
Product: CCOCCNC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(=O)N2CCOCC2)c1=O

Procedure:
This compound was prepared from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-1-[2-(4-morpholinyl)-2-oxoethyl]-2-oxo-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-ethoxyethylamine employing methods similar to those those described in Example 9 and was purified by reverse phase preparative HPLC (C-18 stationary phase; 10-100% CH3CN/water/0.1% formic acid mobile phase). The product was obtained as a white solid: 1H NMR (CDCl3) δ 10.14 (1H, m), 8.55 (1H, s), 7.15 (2H, dd, J=8.5, 5.5 Hz), 7.04 (3H, m), 4.94 (2H, s), 4.11 (2H, s), 3.73-3.52 (14H, m), 1.22 (3H, t, J=7 Hz); HRMS calcd for C26H29FN4O6+H+: 513.2149. Found: 513.2134.
Reaction SMILES: CN(CC1N=C(OCCCN)C=CC=1)C.NC1C(OC)=NS(=O)N=1.[NH2:25][C:26]1[C:30]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]3[CH2:48]CCC[CH2:44]3)[N:37]=2)=[N:29][S:28](=O)[N:27]=1>>[NH2:25][C:26]1[C:30]([NH:31][CH2:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH2:42][N:43]([CH3:44])[CH3:48])[N:37]=2)=[N:29][S:28][N:27]=1
Reactant: NC1=NS(=O)N=C1NCCCOc1cccc(CN2CCCCC2)n1
Agent: CN(C)Cc1cccc(OCCCN)n1
Agent: COC1=NS(=O)N=C1N
Product: CN(C)Cc1cccc(OCCCNc2nsnc2N)n1

Procedure:
When a methanolic solution of 3-(6-dimethylaminomethyl-2-pyridyloxy)propylamine [prepared according to published United Kingdom Patent Application No. 2,098,988] is reacted with 3-amino-4-methoxy-1,2,5-thiadiazole 1-oxide according to the general procedure described in United Kingdom Patent Application No. 2,067,987 and the resulting 3-amino-4-[3-(6-piperidinomethyl-2-pyridyloxy)propylamino]-1,2,5-thiadiazole 1-oxide is successively reacted by the general procedure described in Example 1, Step A, and then by either Example 1, Step B, or Example 10, the title compound is thereby produced.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:8][C:9]([C:11]1[CH:12]=[CH:13][C:14]([O:31][CH2:32][CH2:33][CH3:34])=[C:15]([C:17]2[NH:18][C:19](=[O:30])[C:20]3[N:25]([CH3:26])[N:24]=[C:23]([CH2:27][CH2:28][CH3:29])[C:21]=3[N:22]=2)[CH:16]=1)=[O:10]>>[CH3:26][N:25]1[C:20]2[C:19](=[O:30])[NH:18][C:17]([C:15]3[CH:16]=[C:11]([C:9](=[O:10])[CH2:8][N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)[CH:12]=[CH:13][C:14]=3[O:31][CH2:32][CH2:33][CH3:34])=[N:22][C:21]=2[C:23]([CH2:27][CH2:28][CH3:29])=[N:24]1
Reactant: CCCOc1ccc(C(=O)CBr)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: C1COCCN1
Product: CCCOc1ccc(C(=O)CN2CCOCC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Yield: 47 %

Procedure:
This compound was prepared from morpholine and 5-(5-bromoacetyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one (Preparation 11), following the procedure of Example 1, and was obtained as white crystals (47%), m.p. 128°-129° C. Found: C,63.62; H,7.07; N,15.53. C24H31N5O4 requires C,63.56; H,6.89; N,15.44%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]([CH3:18])=[C:9]2[C:19](O)=[O:20])[CH:5]=[CH:6][CH:7]=1.[CH2:22]([NH2:31])[CH:23]=[CH:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>CN(C=O)C>[C:25]1([CH:24]=[CH:23][CH2:22][NH:31][C:19]([C:9]2[CH:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)[C:13]([N+:14]([O-:16])=[O:15])=[C:12]([CH3:17])[NH:11][C:10]=2[CH3:18])=[O:20])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: CC1=C(C(=O)O)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1
Reactant: NCC=Cc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC1=C(C(=O)NCC=Cc2ccccc2)C(c2cccc(Cl)c2)C([N+](=O)[O-])=C(C)N1

Procedure:
93 mg (0.30 mmol) of 4-(3-chlorophenyl)-2,6-dimethyl-5-nitro-1,4-dihydropyridine-3-carboxylic acid, 100 mg (0.75 mmol) of cinnamylamine, 138 mg (0.54 mmol) of 2-chloro-1-methylpyridinium iodide and 0.15 ml (1.08 mmol) of triethylamine were stirred in 5 ml of DMF at room temperature for 2 days. DMF was evaporated under reduced pressure. Ethyl acetate was added to the reaction mixture. After washing with 1 N hydrochloric acid, the organic layer was dried over anhydrous sodium sulfate. After the concentration under reduced pressure, the residue was purified by the silica gel chromatography (hexane/ethyl cetate=4/1) to obtain the title compound.