Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=1.[CH3:11][C:12](Cl)([O:14][CH2:15][C:16]#[CH:17])[CH3:13].[I:19]I.[I-].[K+].[OH-].[K+]>CN(C=O)C>[I:19][C:17]#[C:16][CH2:15][O:14][C:12]([CH3:13])([CH3:11])[O:1][C:2]1[C:6]([C:7]#[N:8])=[C:5]([S:9][CH3:10])[S:4][N:3]=1
Reactant: C#CCOC(C)(C)Cl
Reactant: CSc1snc(O)c1C#N
Reactant: II
Agent: [I-]
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: CSc1snc(OC(C)(C)OCC#CI)c1C#N
Temperature: 50 °C
Reaction time: 1 h
Yield: 60 %

Procedure:
1.7 Grams of 3-hydroxy-4-cyano-5-methylthioisothiazole was dissolved in 30 ml of DMF, 1.4 g of 1,1-dimethyl-2-propynyloxymethyl chloride was added thereto, and then the reaction solution was stirred at 50° C. for 1 hour. Thereafter, the reaction solution was ice-cooled to 5° to 10° C., 5.1 g of iodine and 3.5 g of potassium iodide were added thereto, and then 6.6 g of 10% KOH was added dropwise. The temperature of the reaction solution was returned to room temperature, and after stirring for 1 hour, the reaction solution was extracted with ethyl acetate. The extract was washed with water, dried and concentrated under reduced pressure to obtain crude crystals. The crystals were recrystallized from ether to obtain 2.4 g of crystals having a melting point of 96° to 97° C. (yield 60%).
Reaction SMILES: [S:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[C:2]1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=[O:13])=[O:12].[Cl:20]N1C(=O)CCC1=O.C(OCC)(=O)C>CN(C=O)C>[Cl:20][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:1][C:2]=1[NH:10][S:11]([C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)(=[O:12])=[O:13]
Reactant: O=S(=O)(Nc1cc2cccnc2s1)c1ccccc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S(=O)(Nc1sc2ncccc2c1Cl)c1ccccc1
Reaction time: 16 h
Yield: 34.5 %

Procedure:
To compound 147-F (0.26 g, 0.643 mmol) in DMF (1 mL) under argon at ambient temperature was added N-chlorosuccinimide (94.4 mg, 0.707 mmol) and the reaction mixture was stirred for 16 h. Ethyl acetate was added, the mixture washed with H2O (2×), brine, evaporated under reduced pressure and purified by reverse phase pHPLC (C18) to afford 0.072 g of compound 813-A as a tan solid. 1H-NMR (DMSO-d6): δ 7.50 (dd, 1H), 7.56-7.65 (m, 2H), 7.65-7.74 (m, 1H), 7.81-7.89 (m, 2H), 8.00 (dd, 1H), 8.58 (dd, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]#[C:6][C:7]([O:9][CH3:10])=[O:8])=[O:4].[Cl:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[CH2:14][N:15]=[N+:16]=[N-:17]>C1C=CC=CC=1.C1CCCCC1>[CH3:1][O:2][C:3]([C:5]1[N:17]=[N:16][N:15]([CH2:14][C:13]2[CH:18]=[CH:19][CH:20]=[CH:21][C:12]=2[Cl:11])[C:6]=1[C:7]([O:9][CH3:10])=[O:8])=[O:4]
Reactant: [N-]=[N+]=NCc1ccccc1Cl
Reactant: COC(=O)C#CC(=O)OC
Solvent: C1CCCCC1
Solvent: c1ccccc1
Product: COC(=O)c1nnn(Cc2ccccc2Cl)c1C(=O)OC

Procedure:
A solution of 8 g (0.054 mol) of acetylene-dicarboxylic acid dimethyl ester in 25 ml of benzene is added dropwise to a solution of 8.4 g (0.05 mol) of o-chlorobenzyl azide in 50 ml of benzene that is boiling under reflux. After a further hour under reflux, the whole is diluted with 75 ml of cyclohexane and, after cooling, the substance that has crystallised out is filtered off with suction. After washing with a mixture of diethyl ether and hexane (1:1), there is obtained 1-(o-chlorobenzyl)-1H-1,2,3-triazole-4,5-dicarboxylic acid dimethyl ester having a melting point of 88°-91°.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([O:35][CH3:36])[C:5]2[N:6]([C:8]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18]4)=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[NH3:37].[CH3:38][OH:39]>>[C:38]([C:2]1[CH:3]=[C:4]([O:35][CH3:36])[C:5]2[N:6]([C:8]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)=[C:9]([C:11]3[CH:12]=[CH:13][C:14]([C:17]4([NH:21][C:22](=[O:28])[O:23][C:24]([CH3:26])([CH3:27])[CH3:25])[CH2:18][CH2:19][CH2:20]4)=[CH:15][CH:16]=3)[N:10]=2)[N:7]=1)(=[O:39])[NH2:37]
Reactant: CO
Reactant: COc1cc(Cl)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Reactant: N
Product: COc1cc(C(N)=O)nn2c(-c3ccccc3)c(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)nc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 57 %

Procedure:
To a solution of tert-butyl {1-[4-(6-chloro-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate that was prepared in a manner analgous to that described for Intermediate Example Int-7.3 (0.54 g, 1.00 mmol) in a solution of ammonia in MeOH (7 N; 5.7 mL, 40 mmol, 40 equiv.) in an autoclave was added 1,1′-bis(diphenylphosphino)ferrocenepalladium(II) dichloride DCM complex (0.16 g, 0.20 mmol, 0.20 equiv). The autoclave was flushed with CO (approximately 5 bar) three times, then was pressurized with CO (5.2 bar), stirred at room temperature 30 min., and briefly placed under reduced atmosphere (0.06 bar). The autoclave was then pressurized with CO (5.9 bar at 20° C.), heated to 100° C., and stirred at this temperature for 18 h. The resulting material was filtered and concentrated under reduced pressure to give tert-butyl {1-[4-(6-carbamoyl-8-methoxy-3-phenylimidazo[1,2-b]pyridazin-2-yl)phenyl]cyclobutyl}carbamate (0.29 g, 57%):
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:7](=[O:17])[CH:8]=[C:9]1[C:13](=[O:14])OC(C)(C)[O:10]1.[CH2:32]=O.[NH2:34][CH2:35][CH2:36][N:37]1[CH2:42][CH2:41][O:40][CH2:39][CH2:38]1>CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:5][N:6]([O:18][CH2:19][CH2:20][CH2:21][N:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1)[C:7]([C:8]1[CH2:32][N:34]([CH2:35][CH2:36][N:37]2[CH2:42][CH2:41][O:40][CH2:39][CH2:38]2)[C:13](=[O:14])[C:9]=1[OH:10])=[O:17]
Reactant: CC1(C)OC(=O)C(=CC(=O)N(Cc2ccc(Cl)c(Cl)c2)OCCCN2CCOCC2)O1
Reactant: NCCN1CCOCC1
Reactant: C=O
Solvent: CO
Product: O=C1C(O)=C(C(=O)N(Cc2ccc(Cl)c(Cl)c2)OCCCN2CCOCC2)CN1CCN1CCOCC1
Yield: 68 %

Procedure:
Reaction of N-(3,4-dichloro-benzyl)-2-(2,2-dimethyl-5-oxo-[1,3]dioxolan-4-ylidene)-N-(3-morpholin-4-yl-propoxy)-acetamide (0.200 g, 0.42 mmol) with the paraformaldehyde-N-(2-aminoethyl)morpholine adduct in methanol using a procedure similar to the one described in the preparation of compound 13 gave 0.160 g (68% yield) of the title compound as a solid after chromatography on reversed phase silica gel. 1HNMR 400 MHz (CDCl3) δ (ppm); 1.56 (2H, m, CH2), 2.18 (2H, t, J=7.1 Hz, NCH2), 2.25 (4H, broad, 2×NCH2), 2.39 (4H, broad, 2×NCH2), 2.46 (2H, t, J=6.1 Hz, CH2), 3.50 (2H, t, J=6.1 Hz, NCH2), 3.54 (8H, broad, 4×OCH2), 3.71 (2H, broad t, OCH2), 3.99 (2H, s, NCH2), 4.87 (2H, s, NCH2), 7.40 (1H, broad d, aromatic), 7.58 (1H, d, J=8.1 Hz, aromatic), 7.73 (1H, broad s, aromatic). HRMS (FAB+) calculated for C25H35Cl2N4O6: [M+H]+: 557.193366. found: 557.192134.
Reaction SMILES: Cl[CH:2]1[C:7](=[O:8])[CH2:6][C:5]([CH2:14][CH2:15][C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([Cl:24])[CH:17]=2)([CH:9]2[CH2:13][CH2:12][CH2:11][CH2:10]2)[O:4][C:3]1=[O:25].[CH3:26][N:27]([CH2:29][C:30]1[N:31]([CH3:36])[C:32]([SH:35])=[N:33][N:34]=1)[CH3:28].O.OC1N=CN=C2C=1NC(S)=N2>O>[Cl:24][C:18]1[CH:17]=[C:16]([CH2:15][CH2:14][C:5]2([CH:9]3[CH2:13][CH2:12][CH2:11][CH2:10]3)[O:4][C:3](=[O:25])[C:2]([S:35][C:32]3[N:31]([CH3:36])[C:30]([CH2:29][N:27]([CH3:28])[CH3:26])=[N:34][N:33]=3)=[C:7]([OH:8])[CH2:6]2)[CH:21]=[CH:20][C:19]=1[O:22][CH3:23]
Reactant: CN(C)Cc1nnc(S)n1C
Reactant: COc1ccc(CCC2(C3CCCC3)CC(=O)C(Cl)C(=O)O2)cc1Cl
Agent: Oc1ncnc2nc(S)[nH]c12
Solvent: O
Product: COc1ccc(CCC2(C3CCCC3)CC(O)=C(Sc3nnc(CN(C)C)n3C)C(=O)O2)cc1Cl

Procedure:
The title compound was prepared as described in Example C(70), where 3-chloro-6-[2-(3-chloro-4-methoxyphenyl)ethyl]-6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione was used in place of 3-chloro-6-[2-(5-chloro-2,4-dimethoxyphenyl)ethyl]6-cyclopentyldihydro-2H-pyran-2,4(3H)-dione and 5-[(dimethylamino)methyl]-4-methyl-4H-1,2,4-triazole-3-thiol, as described in Step 1 of Example C(83), was used in place of 6-hydroxy-8-mercaptopurine monohydrate. 1H NMR (500 MHz, DMSO-d6, WET suppression of DMSO-h6 (2.5 ppm) and H2O (3.35 ppm) peak areas) δ 1.50-1.69 (m, 8H) 2.02 (m, 2H) 2.35 (m, 1H) 2.50 (m, 1H, overlap with dmso) 2.63 (m, 1H) 2.72 (d, J=18.1 Hz, 1H) 2.87 (s, 6H) 2.92 (d, J=15.0 Hz, 1H) 3.63 (s, 3H) 3.80 (s, 3H) 4.53 (s, 2H) 7.01 (d, J=8.5 Hz, 1H) 7.18 (dd, J=8.4, 2.1 Hz, 1H) 7.31 (d, J=1.9 Hz, 1H). MS (APCI) calcd for C25H33ClN4O4S: 521.08; found M=521.2.
Reaction SMILES: [NH2:1][C:2]1[C:10]([C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:19](N)=[NH:20].C(N)=O.[OH-].[Na+]>C(O)C>[C:11]([C:10]1[CH:9]=[CH:8][CH:7]=[C:3]2[C:2]=1[N:1]=[CH:19][NH:20][C:4]2=[O:5])([CH3:14])([CH3:13])[CH3:12]
Reactant: N=CN
Reactant: CC(C)(C)c1cccc(C(=O)O)c1N
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Solvent: NC=O
Product: CC(C)(C)c1cccc2c(=O)[nH]cnc12
Temperature: 160 °C
Reaction time: 12 h

Procedure:
Procedure analogous to M. Berg et al., Chem. Med. Chem. 2009, 4, 2, 249: a mixture of 19.3 g (100 mmol) of 2-amino-3-tert-butylbenzoic acid [917874-35-2], 31.4 g (300 mmol) of formamidine acetate [3473-63-0] and 4.4 ml (110 mmol) of formamide is stirred at 160° C. for 12 h. After cooling to 60° C., a mixture of 200 ml of ethanol and 200 ml of 2 N sodium hydroxide solution is added dropwise, the mixture is filtered through a P4 frit covered with sea sand in order to remove polymeric material and then rendered neutral by addition of 2 N hydrochloric acid. After stirring for 12 h, the crystals formed are filtered off with suction and washed three times with 100 ml of water each time. Yield: 13.9 g (68 mmol), 68%. Purity: >95% according to 1H-NMR.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:11][CH2:12][N:13]([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:11][CH2:12][N:13]([CH3:15])[CH3:14]
Reactant: CN(C)CCCl
Reactant: Oc1cccc(Br)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C)CCOc1cccc(Br)c1

Procedure:
3-Bromophenol (0.870 g, 5.00 mmol), (2-chloro-ethyl)-dimethylamine hydrochloride (0.792 g, 5.50 mmol) and Cs2CO3 (8 g, 25 mmol) were combined in DMF (20 mL) and the mixture was heated at reflux over night. H2O (20 mL) was added and the mixture was extracted with EtOAc, then washed with 2N NaOH and brine. The organic layers were combined, dried over Na2SO and concentrated to a brown oil which was then purified by flash chromatography (eluent: 20% EtOAc in hexanes).
Reaction SMILES: [F:1][C:2]1[C:7](F)=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]1([OH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>CN(C=O)C>[F:1][C:2]1[C:7]([O:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:6][C:5]([CH2:9][OH:10])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(F)c(F)cc1CO
Reactant: Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(F)c(Oc2ccccc2)cc1CO
Temperature: 50 °C
Reaction time: 8 h

Procedure:
To a solution of (4,5-difluoro-2-nitrophenyl)methanol (950 mg, 5 mmol) in DMF (15 mL) were added potassium carbonate (1.23 g, 10 mmol) and phenol (520 mg, 5.5 mmol). The resulting mixture was stirred at 50° C. overnight, cooled to room temperature, filtered, washed with ethyl acetate (2×20 mL), and concentrated. The resulting crude mixture was purified by chromatography (silica gel, 30-70% ethyl acetate in heptane) to yield a slightly yellow solid.
Reaction SMILES: [C:1]1([C:7]2[C:12]([NH:13][C:14]([C:16]3[N:17](COCC[Si](C)(C)C)[CH:18]=[C:19]([C:21]#[N:22])[N:20]=3)=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1.CO.[C:33]([OH:39])([C:35]([F:38])([F:37])[F:36])=[O:34]>C(Cl)Cl>[F:36][C:35]([F:38])([F:37])[C:33]([OH:39])=[O:34].[C:1]1([C:7]2[C:12]([NH:13][C:14]([C:16]3[NH:17][CH:18]=[C:19]([C:21]#[N:22])[N:20]=3)=[O:15])=[CH:11][CH:10]=[CH:9][N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]=1
Reactant: C[Si](C)(C)CCOCn1cc(C#N)nc1C(=O)Nc1cccnc1C1=CCCCC1
Solvent: ClCCl
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1c[nH]c(C(=O)Nc2cccnc2C2=CCCCC2)n1
Yield: 30 %

Procedure:
A solution of 615 mg (1.45 mmol) of 4-cyano-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazole-2-carboxylic acid (2-cyclohex-1-enyl-pyridin-3-yl)-amide (as prepared in the previous step) in CH2Cl2 (12 mL) was treated with MeOH (100 μL) and TFA (3 mL) at RT for 3.5 h. MeOH (5 mL) was added to the mixture before concentrating in vacuo. RP-HPLC (C18) of the residue with 10-80% CH3CN in 0.1% TFA/H2O over 30 min afforded 177 mg (30%) of the title compound as a white solid: 1H-NMR (CD3OD; 400 MHz): δ 9.03 (dd, 1H, J=8.4, 1.6 Hz), 8.45 (dd, 1H, J=5.2, 1.6 Hz), 8.07 (s, 1H), 7.81-7.74 (m, 1H), 6.36-6.29 (m, 1H), 2.49-2.34 (m, 4H), 1.97-1.79 (m, 4H). Mass spectrum (ESI, m/z): Calcd. for C16H15N5O, 294.1 (M+H), found 294.1.
Reaction SMILES: Br[CH:2]([C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([O-:23])=[O:22].[Na+]>C(O)C.CCOC(C)=O.O>[F:18][C:19]1[CH:27]=[CH:26][CH:25]=[C:24]([F:28])[C:20]=1[C:21]([O:23][CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:8]([C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=1)=[O:9])=[O:22]
Reactant: O=C([O-])c1c(F)cccc1F
Reactant: CCOC(=O)C(Br)C(=O)c1ccc(OC)cc1
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(OC(=O)c1c(F)cccc1F)C(=O)c1ccc(OC)cc1
Yield: 96.7 %

Procedure:
A solution of ethyl 2-bromo-3-(4-methoxyphenyl)-3-oxopropanoate (0.090 g, 0.3 mmol) and sodium 2,6-difluorobenzoate (0.054 g, 0.30 mmol) in ethanol (2 mL) was heated at 120° C. in the microwave for 10 minutes. The reaction mixture was diluted with EtOAc (25 mL) and water (25 mL). The organic phase was washed with water and brine, dried over MgSO4 and the solvent evaporated in vacuo. The residue was purified by silica gel column chromatography using a gradient of 0-40% EtOAc in hexanes to afford 3-ethoxy-1-(4-methoxyphenyl)-1,3-dioxopropan-2-yl 2,6-difluorobenzoate (0.108 g, 0.29 mmol, 96%) as a clear film. 1H NMR (CDCl3) δ 1.27 (3H, t), 3.89 (3H, s), 4.30 (2H, m), 6.47 (1H, s), 6.97 (4H, m), 7.46 (1H, m), 8.06 (2H, d). LCMS (1) Rt: 2.26 min; m/z (ES+) 379.
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]([NH:8][N:9]([CH3:14])[C:10]([NH:12][CH3:13])=[S:11])=O)=[CH:4][CH:3]=1.Cl.N1C=CC=CC=1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[CH:16]=[CH:15][C:5]([C:6]2[N:12]([CH3:13])[C:10](=[S:11])[N:9]([CH3:14])[N:8]=2)=[CH:4][CH:3]=1
Reactant: CNC(=S)N(C)NC(=O)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Product: Cn1nc(-c2ccc(Cl)cc2)n(C)c1=S

Procedure:
The 1:1 mixture of 1-(4-chlorobenzoyl)-2,4-dimethylthiosemicarbazide and pyridine hydrochloride (3.61 g of mixture) from Example 2 and 1 molar aqueous NaHCO3 (100 ml, 1.00×100-1 mole) were stirred and warmed to reflux. After refluxing for 5 hours the reaction was allowed to cool. It was then placed in a refrigerator for several hours before the precipitate was collected by filtration. The collected material was dried partially by suction before being transferred to a desiccator where it was dried at high vacuum. This affords the desired product as a beige powder: 2.01 g (84%). This was purified by flash chromatography and subsequent crystallization from isopropanol yielding small, slightly yellowish plates: 1.74 g (73%), mp 113°-115° C. In a similar manner, by substituting a variety of substituted benzoyl chlorides and a variety of 4-substituted thiosemicarbazides for the reactants of examples 1-3 and by substantially following the techniques therein, the following compounds are readily prepared.
Reaction SMILES: C(=O)(O[CH2:6][CH3:7])OCC.C[O-].[Na+].[CH:12]([O:14][CH:15]1[CH2:22][CH2:21][CH2:20][CH:19]=[CH:18][CH2:17][CH2:16]1)=[O:13]>O>[CH:12]([O:14][C:15]1([CH:7]2[CH2:6][CH2:18][CH2:17][CH2:16][CH2:15][CH2:22][CH2:21]2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:13]
Reactant: O=COC1CCC=CCCC1
Reactant: CCOC(=O)OCC
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: O=COC1(C2CCCCCCC2)CCCCCCC1
Temperature: 85 °C

Procedure:
Into a 2 liter reaction flask equipped with heating mantle, stirrer, Bidwell water trap, reflux condenser, thermometer and nitrogen blanket apparatus is placed 1,000 ml (8.4 moles) of diethyl carbonate, and 25 grams (0.45 moles) of sodium methoxide. The resulting mixture is heated to 85° C. While maintaining the reaction mass at 85°-86° C. over a period of 1 hour, 695 grams (4.5 moles) of a composition containing a major proportion of 4-cyclooctenyl formate having the structure: ##STR77## and a minor proportion of bicyclooctanyl formate having the structure: ##STR78## produced according to Example I, is added while removing ethyl formate reaction product from the reaction mass using the Bidwell trap. At the end of the 1 hour period, the reaction mass is stirred at a temperature of 85°-86° C. for an additional 1 hour.
Reaction SMILES: [ClH:1].[CH3:2][NH:3][CH3:4].C=O.[CH2:7](O)C.[CH2:10]([O:12][C:13]([CH2:15][O:16][C:17]1[CH:29]=[CH:28][CH:27]=[CH:26][C:18]=1/[CH:19]=[C:20]1/[C:21](=[O:25])[CH2:22][CH2:23][CH2:24]/1)=[O:14])[CH3:11]>Cl.O>[ClH:1].[CH3:2][N:3]([CH2:7][CH:22]1[CH2:23][CH2:24]/[C:20](=[CH:19]\[C:18]2[CH:26]=[CH:27][CH:28]=[CH:29][C:17]=2[O:16][CH2:15][C:13]([O:12][CH2:10][CH3:11])=[O:14])/[C:21]1=[O:25])[CH3:4]
Reactant: CCO
Reactant: CCOC(=O)COc1ccccc1/C=C1\CCCC1=O
Reactant: CNC
Agent: C=O
Agent: Cl
Solvent: O
Product: CCOC(=O)COc1ccccc1/C=C1\CCC(CN(C)C)C1=O
Reaction time: 0.17 h

Procedure:
2.0 g of dimethylamine hydrochloride, 1.8 g of paraformaldehyde and 30 ml of ethanol were added with 3 drops of concentrated hydrochloric acid to 6.5 g of 2-(E)-(2-ethoxycarbonylmethoxylbenzylidene) cyclopentanone. After refluxing for about 2 hours, the resulting solution was treated with 0.7 g of paraformaldehyde and then refluxed for about 2 additional hours. After the solvent was removed in vacuo, a syrupy residue was obtained. Then 100 ml of water was added to the residue, stirred for about 10 minutes, and filtered. The filtrate was adjusted to about pH 9 by the addition of 10% sodium carbonate solution and extracted with three 20 ml portions of ether. The aqueous layer was again treated with 10% sodium carbonate solution to about pH 11 and extracted with two additional 20 ml portions of ether. The combined ether was dried over anhydrous magnesium sulfate and treated with ethanolic hydrogen chloride. It was filtered to give 4.7 g of product Recrystallization from absolute ethanol-acetone gave 4.2 g of 2-Dimethylaminomethyl-5-(E)-(2-ethoxycarbonylmethoxyl-benzylidene) cyclopentanone hydrochloride as a white powder product. The melting point of the product was determined to be 124°-126° C.
Reaction SMILES: [C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40]C#N)([O:3]C(C)(C)C)=[O:2].C(CC1C(C2C=CC([O:61]C)=CC=2O)C2C(=CC=C(OCCC)C=2)C1C1C=CC2OCOC=2C=1)#N.[H-].[Na+].C(OC(=O)CBr)CCC.CN([CH:91]=[O:92])C>>[C:1]([CH2:8][O:9][C:10]1[CH:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:11]=1[CH:18]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24]([O:27][CH2:28][CH2:29][CH3:30])[CH:25]=2)[CH:20]([C:31]2[CH:36]=[CH:35][C:34]3[O:37][CH2:38][O:39][C:33]=3[CH:32]=2)[CH:19]1[CH2:40][C:91]([OH:92])=[O:61])([OH:3])=[O:2]
Reactant: CN(C)C=O
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)OC(C)(C)C)C(CC#N)C2c1ccc2c(c1)OCO2
Reactant: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1O)C(CC#N)C2c1ccc2c(c1)OCO2
Agent: CCCCOC(=O)CBr
Agent: [H-]
Agent: [Na+]
Product: CCCOc1ccc2c(c1)C(c1ccc(OC)cc1OCC(=O)O)C(CC(=O)O)C2c1ccc2c(c1)OCO2
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 79 %

Procedure:
1RS,2RS,3RS)-3-(2-Carbo-t-butoxymethoxy-4-methoxyphenyl)-2-cyanomethyl-1-(3,4methylenedioxyphenyl)-5-(prop-1-yloxy)indane. To a solution of 1RS,2RS,3RS)-2-cyanomethyl-3-(2-hydroxy-4-methoxyphenyl)-1-(3,4-methylenedioxyphenyl)-5-(prop-1-yloxy)indane (250 mg, 0.55 mmol) in DMF (4 ml) stirred at 0° C. under argon added NaH (21 mg of 80% oil dispersion, 0.7 mmol). The mixture stirred at 0° C. for 15 min then t -butylbromoacetate (107 mg, 0.55 mmol) was added. The cooling bath was removed and the mixture was stirred for 3 h at room temperature then partitioned between EtOAc and 3N HCl. The organic extract was washed with H2O, saturated NaHCO3 solution, H2O, then brine, dried (Na2SO4) and solvent removed in vacuo. The residue was purified by flash chromatography on silica gel, (eluent 25-50% Et2O/hexanes) to afford the title compound as an oil (247 mg, 79%).
Reaction SMILES: [CH3:1][CH:2]([CH3:6])[C:3](=O)[CH3:4].[N+:7]([C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)([O-:9])=[O:8].C([BH3-])#N.[Na+].O>CO.C(O)(=O)C>[CH3:4][CH:3]([N:19]1[CH2:20][CH2:21][N:16]([C:13]2[CH:12]=[CH:11][C:10]([N+:7]([O-:9])=[O:8])=[CH:15][CH:14]=2)[CH2:17][CH2:18]1)[CH:2]([CH3:6])[CH3:1]
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: CC(=O)C(C)C
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Solvent: O
Product: CC(C)C(C)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 34.3 %

Procedure:
3-Methyl-2-butanone (0.76 mL, 7.24 mmol) was added to a solution of 1-(4-nitrophenyl)piperazine (1.0 g, 4.83 mmol) in methanol (10 mL) and acetic acid (1 mL) and stirred for 30 min at ambient temperature. Sodium cyanoborohydride (1.81 g, 28.98 mmol) was added and the mixture refluxed for 12 h, cooled and then poured into water and extracted with ethyl acetate. The combined organic layers were washed with water, brine, dried over anhydrous sodium sulfate and concentrated in vacuo to afford the crude product. Purification by column chromatography over silica gel (100-200 mesh) using 5-10% ethyl acetate/petroleum ether as eluent afforded 1-(1,2-Dimethylpropyl)-4-(4-nitrophenyl)piperazine (0.46 g, 34%).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[C:12]3[C:13]([NH2:16])=[N:14][O:15][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[C:4]([F:19])[CH:3]=1.Cl[C:21]1[CH:26]=[C:25]([C:27]2[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=2)[N:24]=[C:23]([NH2:33])[N:22]=1.Cl>O>[NH2:16][C:13]1[C:12]2[C:7]([O:6][C:5]3[CH:17]=[CH:18][C:2]([NH:1][C:21]4[CH:26]=[C:25]([C:27]5[CH:32]=[CH:31][N:30]=[CH:29][CH:28]=5)[N:24]=[C:23]([NH2:33])[N:22]=4)=[CH:3][C:4]=3[F:19])=[CH:8][CH:9]=[CH:10][C:11]=2[O:15][N:14]=1
Reactant: Nc1nc(Cl)cc(-c2ccncc2)n1
Reactant: Nc1ccc(Oc2cccc3onc(N)c23)c(F)c1
Agent: Cl
Solvent: O
Product: Nc1nc(Nc2ccc(Oc3cccc4onc(N)c34)c(F)c2)cc(-c2ccncc2)n1

Procedure:
70 mg (0.27 mmol) of 4-(4-amino-2-fluorophenoxy)-1,2-benzisoxazole-3-amine (from example VII) and 55.8 mg (0.27 mmol) of 4-chloro-6-(4-pyridinyl)-2-pyrimidineamine (from example XXIX) are suspended in 4 ml of water, and 0.02 ml of concentrated hydrochloric acid is added. The reaction mixture is heated at reflux overnight, resulting in the formation of a lightly colored precipitate. This is filtered off, washed repeatedly with water and dried under high vacuum.