Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5]([NH:7][C:8]([NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:20])([F:19])[F:18])[C:12]=1[F:21])=[S:9])=[O:6].[CH3:23]C([O-])(C)C.[Na+].IC.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3](=[O:22])[CH2:4][C:5](/[N:7]=[C:8](/[NH:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([C:17]([F:18])([F:20])[F:19])[C:12]=1[F:21])\[S:9][CH3:23])=[O:6]
Reactant: CC(C)(C)[O-]
Reactant: COC(=O)CC(=O)NC(=S)Nc1cccc(C(F)(F)F)c1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CI
Product: COC(=O)CC(=O)/N=C(/Nc1cccc(C(F)(F)F)c1F)SC
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
An ice-cooled solution of intermediate D19 (17.1 g) in THF (450 ml) was stirred under an atmosphere of N2. NaOtBu (1 eq) was added and after 30 minutes a solution of iodomethane (3.15 ml) in THF was added dropwise. After another 30 minutes an additional NaOtBu (1 eq) was added and the contents stirred at ˜0° C. When the reaction was completed after 45 minutes, a saturated solution of NH4Cl was added and the reaction was diluted with EtOAc. The phases were separated and the aqueous phase extracted with EtOAc (×2). The combined organic extracts were washed with brine, then dried (Na2SO4). Filtration and concentration under reduced pressure gave the crude material as an amber oil. Yield: 17.2 g of intermediate D20 (59%).
Reaction SMILES: [F:1][C:2]1([F:11])[CH2:5][C:4]([CH2:9][F:10])(C(O)=O)[CH2:3]1.C1C=CC(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)=CC=1.[Cl:29][C:30]1[CH:31]=[C:32]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][NH:41][CH2:42][CH2:43][N:38]3[N:37]=2)[CH:33]=[CH:34][CH:35]=1.C[N:49]([CH:51]=[O:52])C>C1(C)C=CC=CC=1>[Cl:29][C:30]1[CH:31]=[C:32]([C:36]2[C:44]([C:45]([NH2:47])=[O:46])=[C:39]3[CH2:40][N:41]([C:51]([NH:49][C:4]4([CH2:9][F:10])[CH2:3][C:2]([F:1])([F:11])[CH2:5]4)=[O:52])[CH2:42][CH2:43][N:38]3[N:37]=2)[CH:33]=[CH:34][CH:35]=1
Reactant: NC(=O)c1c(-c2cccc(Cl)c2)nn2c1CNCC2
Reactant: CN(C)C=O
Reactant: O=C(O)C1(CF)CC(F)(F)C1
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: Cc1ccccc1
Product: NC(=O)c1c(-c2cccc(Cl)c2)nn2c1CN(C(=O)NC1(CF)CC(F)(F)C1)CC2
Temperature: 85 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
To a stirred solution of Intermediate 302E (26.7 mg, 0.159 mmol) in toluene (3 mL) was added TEA (0.101 mL, 0.723 mmol), DPPA (0.066 mL, 0.289 mmol) and the solution was heated to 85° C. for 1 hr. The reaction mass was cooled to RT and to it was added a solution of Intermediate 156E (40 mg, 0.145 mmol) in DMF (1 mL) and the reaction mixture was stirred at RT for 8 h. It was then concentrated and extracted with ethyl acetate (3×10 mL) The combined organic layer was dried over Na2SO4, filtered and the filtrate concentrated. The crude product was further purified by preparative HPLC to afford Compound 302 as an off-white solid (32 mg, 50%). HPLC retention times 1.41 min. and 1.41 min. (Methods E and L respectively). MS(ES): m/z=441 [M+H]+; 1H NMR (400 MHz, DMSO-d6) δ ppm 7.71 (t, J=1.76 Hz, 1H), 7.64 (dt, J=6.65, 1.95 Hz, 1H), 7.41-7.47 (m, 2H), 7.37 (s, 2H), 7.19 (br. s., 1H), 4.75 (s, 2H), 4.44-4.61 (m, 2H), 4.15 (t, J=5.52 Hz, 2H), 3.86 (t, J=5.52 Hz, 2H), 2.81 (t, J=12.30 Hz, 4H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=O)=[CH:4][CH:3]=1.[CH:13]([NH:16][NH:17][C:18](=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)([CH3:15])[CH3:14].C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][C:10]([N:16]([CH:13]([CH3:15])[CH3:14])[NH:17][C:18](=[O:25])[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[O:12])=[CH:6][CH:7]=1
Reactant: O=C(O)CCc1ccc(Br)cc1
Reactant: CC(C)NNC(=O)c1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccc(Br)cc1
Yield: 72.8 %

Procedure:
A solution of (3-(4-bromophenyl)propionic acid (387 mg, 1.68 mmoles) and benzoic acid N′-isopropyl-hydrazide (300 mg, 1.68 mmoles) in DMF (10 mL) was treated with triethylamine (0.70 mL, 5.05 mmol), HOBT (273 mg, 2.02 mmoles) and EDCI (387 mg, 2.02 mmoles) at room temperature for 72 h. The reaction mixture was partitioned between 1N HCl and ethyl acetate. The organic layer was successively washed with water, 1N NaOH and brine, then dried over sodium sulfate, filtered and concentrated to afford the product as a solid (476 mg, 73%). The product was not further purified.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=C1.S(Cl)(Cl)=O.[CH3:10][C:11]1[S:12][C:13]([C:17]([OH:19])=O)=[C:14]([CH3:16])[N:15]=1.[S:20]1[CH:24]=[CH:23][C:22](NCC#N)=[CH:21]1>O1CCCC1>[CH3:10][C:11]1[S:12][C:13]([C:17]([NH:3][CH:4]([C:22]2[CH:23]=[CH:24][S:20][CH:21]=2)[C:5]#[N:1])=[O:19])=[C:14]([CH3:16])[N:15]=1
Reactant: c1c[nH]cn1
Reactant: N#CCNc1ccsc1
Reactant: Cc1nc(C)c(C(=O)O)s1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1nc(C)c(C(=O)NC(C#N)c2ccsc2)s1
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
To a solution of imidazole (2.72 g; 40 mmol) in dry tetrahydrofuran (60 ml) was added dropwise thionyl chloride (1.20 g; 10 mmol) under ice-cooling while stirring. After the resultant mixture was turned to room temperature, 2,4-dimethyl-5-thiazolecarboxylic acid (1.57 g; 10 mmol) was added thereto at once, and stirring was continued for 30 minutes. To the mixture was added dropwise a solution of 2-(3-thienyl)aminoacetonitrile (1.65 g; 12 mmol) in dry tetrahydrofuran under ice-cooling, and the resultant mixture was stirred at room temperature for 1 hour. After completion of the reaction, tetrahydrofuran was removed under reduced pressure to separate the residue. Water was added to the residue, which was extracted with ethyl acetate. The ethyl acetate layer was washed with water twice, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give crude oil. The oil was purified by silica-gel column chromatography (eluent:n-hexane:ethyl acetate=2:1 volume) to give crude crystals. Recrystallization from n-hexane/ethyl acetate gave 1.95 g of 2-(2,4-dimethylthiazole-5-carboxamido)-2-(3-thienyl)acetonitrile as colorless crystals. m.p., 94°-95° C. Yield, 70%.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[CH2:2]1.Cl.[NH2:15][OH:16]>>[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH2:2]1.[O:1]1[CH2:5][CH2:4][CH:3]([CH2:6][N:7]2[CH2:12][CH2:11][C:10](=[N:15][OH:16])[CH2:9][CH2:8]2)[CH2:2]1
Reactant: O=C1CCN(CC2CCOC2)CC1
Reactant: NO
Agent: Cl
Product: ON=C1CCN(CC2CCOC2)CC1

Procedure:
1-(3-Tetrahydrofuranylmethyl)-4-piperidone Oxime 1-(3-Tetrahydrofuranylmethyl)-4-piperidone oxime is prepared from 1-(3-tetrahydrofuranylmethyl)-4-piperidone and hydroxylamine hydrochloride essentially as described above in Example 38, Scheme C, step b.
Reaction SMILES: [N+:1]([C:4]12[CH:11]3[CH:6]4[C:7]5([N+:12]([O-:14])=[O:13])[CH:10]3[CH:9]1[CH:8]5[CH:5]24)([O-:3])=[O:2].[C:15]([Cl:20])(=O)[C:16]([Cl:18])=O>>[Cl:18][C:8]12[CH:5]3[CH:6]4[CH:11]5[C:4]3([N+:1]([O-:3])=[O:2])[CH:9]1[CH:10]5[C:7]24[N+:12]([O-:14])=[O:13].[Cl:18][C:16]12[CH:11]3[CH:6]4[CH:5]5[C:4]3([N+:1]([O-:3])=[O:2])[C:15]1([Cl:20])[CH:8]5[C:7]24[N+:12]([O-:14])=[O:13]
Reactant: O=[N+]([O-])C12C3C4C1C1C2C3C41[N+](=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Product: O=[N+]([O-])C12C3C4C1C1(Cl)C2C3C41[N+](=O)[O-]
Product: O=[N+]([O-])C12C3C4C1C1(Cl)C4([N+](=O)[O-])C3C21Cl

Procedure:
A solution of 1,4-dinitrocubane (Eaton, P. E.; et al; J. Org. Chem.; 1984, 49, 185; Eaton, P. E.; Wicks, G. E.; J. Org. Chem.; 1988, 53, 5353) in oxalyl chloride was irradiated under a sunlamp for 12 h at room temperature. After removing oxalyl chloride under reduced pressure, the reaction mixture was hydrolyzed and partioned between ethyl acetate and 5% aqueous NaOH. From the organic phase was isolated 2-chloro-1,4-dinitrocubane, 3, and 2,5-dichloro-1,4-dinitrocubane, 4. After acidification of the alkaline layer with HCl and extraction with ethyl acetate, 2-carboxy-1,4-dinitrocubane, 5, was obtained in 68% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:13]2[CH2:17][S:16][C:15](=S)[S:14]2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[I:19][C:20]1[C:21]([OH:30])=[C:22]([O:28][CH3:29])[CH:23]=[C:24]([CH:27]=1)C=O.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.C1C=CC=CC=1>C1C=CC=CC=1.O>[OH:30][C:21]1[C:20]([I:19])=[CH:27][C:24]([C@H:15]2[S:14][C@H:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:17][S:16]2)=[CH:23][C:22]=1[O:28][CH3:29]
Reactant: COc1cc(C=O)cc(I)c1O
Reactant: COc1cc(C2CSC(=S)S2)cc(OC)c1OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: c1ccccc1
Product: COc1cc([C@@H]2SC[C@@H](c3cc(OC)c(OC)c(OC)c3)S2)cc(I)c1O

Procedure:
1-(3,4,5-trimethoxyphenyl)-1,2-ethanedithiol (32) (FIG. 26) (0.500 g, 1.92 mmole), 5-iodovanillin (0.411 g, 1.48 mmole), pyridinium para-toluenesulfonate (0.193 g, 0.769 mmole) and 50 ml dry benzene were refluxed under an argon atmosphere with Dean-Stark removal of the benzene-water azeotrope for 12 hours. The benzene was removed in vacuo, and the remaining oil redissolved in dichloromethane. The organic layer was washed with 3×30 ml H2O and was dried over MgSO4, and evaporated in vacuo to an oil which was purified by flash column chromatography with 2:1 hex/ethyl acetate as eluent. The product mixture contains a 1.0/1.3 cis/trans ratio (0.578 g, 75%) after one crystallization from methanol. The trans isomer (50 mg) was isolated after one additional crytallization from ethanol.
Reaction SMILES: Cl[C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5].[F-:11].[Cs+]>CS(C)=O.O>[F:11][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[C:4]#[N:5]
Reactant: [F-]
Reactant: Cc1cccc(Cl)c1C#N
Agent: [Cs+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cccc(F)c1C#N
Temperature: 140 °C
Yield: 65.7 %

Procedure:
A mixture of 2-chloro-6-methylbenzonitrile (5 g, 33.0 mmol) and CsF (14 g, 92.2 mmol) in DMSO (30 ml) was heated at 140° C. for 15 hr and then allowed to cool to room temperature. It was diluted with water, extracted with dichloromethane, washed with brine, dried (Na2SO4) and concentrated to give 2-fluoro-6-methylbenzonitrile (2.93 g, 66%). A mixture of the above nitrile (250 mg), 1-(4-aminophenyl)-3-(3-pyridyl)-5-ethylpyrazole (200 mg, 0.76 mmol) and Raney Ni (50% in water, 100 mg) in glacial acetic acid (15 ml) was shaken in a Parr apparatus under H2 (40 psi) for 7 hr. The catalyst was removed by filtration and the solvent was evaporated. Chromatography on silica gel (hexane/ethyl acetate=2:1) afforded the title compound (146 mg). 1H-NMR (CDCl3): 1.30 (t, J=7.5 Hz, 3H), 2.46 (s, 3H), 2.67 (q, J=7.5 Hz, 2H), 3.92 (bs, 1H), 4.38 (s, 2H), 6.58 (s, 1H), 6.78 (d, J=8.6 Hz, 2H), 6.99 (t, J=6.8Hz, 1H), 7.05 (d, J=7.8 Hz, 1H), 7.19-7.38 (m, 4 H), 8.20 (d, J=7.8 Hz, 1H), 8.56 (d, J=3.7Hz, 1H), 9.10 (s, 1H).
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5](Br)=[CH:4][C:3]=2[O:2]1.[Mg].[B:12]([O:23]CCCC)([O:18]CCCC)[O:13]CCCC>C1COCC1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([O:13][B:12]([OH:23])[OH:18])=[CH:4][C:3]=2[O:2]1
Reactant: Brc1ccc2c(c1)OCO2
Reactant: CCCCOB(OCCCC)OCCCC
Agent: [Mg]
Solvent: C1CCOC1
Product: OB(O)Oc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
A solution of 3,4-methylenedioxybromobenzene (2.00 g, 9.95 mmol) in anhydrous THF (20 ml) was added dropwise to magnesium turnings(254 mg, 10.45 mmol) and stirred for 1 h. After the reaction completed, the reaction mixture was cooled to −78° C., and a solution of tributyl borate (3.22 ml, 11.94 mmol) in anhydrous THF (30 ml) was added dropwise and stirred for 15 min at the same temperature. Cooling bath was removed and the reaction mixture was allowed to warm to ambient temperature and stirred for another 15 min. Ice water was added and the mixture was acidified with hydrochloric acid and extracted twice with ether. A combined organic layers were washed with brine and dried over magnesium sulfate and the solvent was removed under reduced pressure. The residue was air-dried to give 3,4-methylenedioxyphenyl boric acid (986 mg, 60%) as white crystals.
Reaction SMILES: C(OC(=O)[NH:7][C@H:8]([C:29]([N:31]1[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]1)=[O:30])[C@H:9]([CH:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:22]=2[F:28])=[O:19])[CH2:13][CH2:12]1)[CH3:10])(C)(C)C.[F:38][C:39]([F:44])([F:43])[C:40]([OH:42])=[O:41]>ClCCl>[F:38][C:39]([F:44])([F:43])[C:40]([O-:42])=[O:41].[F:28][C:22]1[CH:23]=[C:24]([F:27])[CH:25]=[CH:26][C:21]=1[NH:20][C:18]([NH:17][CH:14]1[CH2:15][CH2:16][CH:11]([C@H:9]([CH3:10])[C@H:8]([NH3+:7])[C:29]([N:31]2[CH2:35][CH2:34][C@H:33]([F:36])[CH2:32]2)=[O:30])[CH2:12][CH2:13]1)=[O:19]
Reactant: C[C@@H](C1CCC(NC(=O)Nc2ccc(F)cc2F)CC1)[C@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@H](F)C1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H](C1CCC(NC(=O)Nc2ccc(F)cc2F)CC1)[C@H]([NH3+])C(=O)N1CC[C@H](F)C1
Product: O=C([O-])C(F)(F)F

Procedure:
To a solution of the material prepared in Step C (0.23 g, 0.48 mmol) in dichloromethane (3 mL) was added trifluoroacetic acid (1 mL). After 3 h at ambient temperature the reaction was concentrated in vacuo. Purification by reverse phase HPLC (20%-50% acetonitrile in water) afforded the title compound as a white solid. LC/MS 427.2 (M+H).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][OH:8].[O:9]1[CH:14]=[CH:13][CH2:12][CH2:11][CH2:10]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][O:8][CH:10]1[CH2:11][CH2:12][CH2:13][CH2:14][O:9]1
Reactant: OCCCCCCBr
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: BrCCCCCCOC1CCCCO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 17.1 %

Procedure:
To a solution of 6-bromo hexan-ol (F) (2 g, 11 mmol) in CH2Cl2 (50 ml) was added dropwise dihyrdopyran (1.6 ml, 16.5 mmol) followed by para-toluenesulphonic acid (commercially available) (0.075 g). The reaction mixture was stirred at room temperature for 16 h. The dark blue solution was then washed with water (2×25 ml) then saturated hydrogen carbonate solution (25 ml) and finally with a saturated sodium chloride solution (25 ml). The organic phase was then dried (MgSO4) and the solvent was evaporated under reduced pressure. The crude material was then purified through flash silica gel chromatography (hexane/EtOAc, 10:1) to afford compound 2-(6-Bromo-hexyloxy)-tetrahydropyran (G) as an oil (0.5 g, 70%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([OH:8])=O.[NH2:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11]>>[O:1]1[CH2:5][CH2:4][CH2:3][CH:2]1[C:6]([NH:9][C@H:10]([C:12]([N:14]1[C:20](=[O:21])[CH:19]([CH3:22])[C:18]2[CH:23]=[CH:24][CH:25]=[CH:26][C:17]=2[C:16]2[C:27]([NH2:31])=[CH:28][CH:29]=[CH:30][C:15]1=2)=[O:13])[CH3:11])=[O:8]
Reactant: O=C(O)C1CCCO1
Reactant: CC1C(=O)N(C(=O)[C@H](C)N)c2cccc(N)c2-c2ccccc21
Product: CC1C(=O)N(C(=O)[C@H](C)NC(=O)C2CCCO2)c2cccc(N)c2-c2ccccc21

Procedure:
Following General Procedure C-P above using tetrahydro-2-furoic acid and 5-(L-alaninyl)-amino-7-methyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one, as described in Example 7-B, the title compound was prepared. The molecular weight as determined by mass spectrometry (FD) was: 408 (M+H).
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[C:2]#[C:3][CH2:4][CH3:5].I[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][O:19][CH3:20])=[CH:13][CH:12]=1.[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC(C#N)=CC=1.C1C=CC(C#N)=CC=1.Cl[Pd]Cl>[CH3:20][O:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11](/[C:2](=[C:3](\[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)/[CH2:4][CH3:5])/[C:1]([O:7][CH2:8][CH3:9])=[O:6])=[CH:12][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: CCC#CC(=O)OCC
Reactant: COCOc1ccc(I)cc1
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: N#Cc1ccccc1
Product: CCOC(=O)/C(=C(\CC)c1ccccc1)c1ccc(OCOC)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 29 %

Procedure:
To a mixture of Ethyl 2-pentynoate (5.5 g, 43.6 mmol), 1-iodo-4-(methoxymethoxy)benzene (23.0 g, 87.1 mmol), Phenylboronic acid (10.6 g, 86.9 mmol) in DMF (132 ml) was added a solution of K2CO3 (12.1 g, 87.5 mmol) in H2O (33 ml) under ice cooling, then the mixture was stirred at room temperature for 10 min. PdCl2(PhCN)2 (167 mg, 0.435 mmol) was added under Ar atmosphere, and the mixture was stirred at room temperature for 24 h. The reaction was quenched with H2O under ice cooling, and the whole was extracted with Et2O. The organic layer was washed with H2O, brine, dried over Na2SO4, then concentrated. Purification by silica gel flash column chromatography (eluent: hexane/AcOEt, 30:1 to 10:1) gave 2 (29%) and the regioisomer (24%). 2: colorless oil; 1H-NMR (CDCl3) δ 1.00 (3H, t, J=7.4), 1.31 (3H, t, J=7.1 Hz), 2.63 (2H, q, J=7.4 Hz), 3.42 (3H, s), 4.28 (2H, q, J=7.1 Hz), 5.07 (2H, s), 6.75 (2H, d, J=8.8 Hz), 6.90 (2H, d, J=8.8 Hz), 7.04 (2H, m), 7.12-7.21 (3H, m); regioisomer: H1-NMR (CDCl3) δ 1.02 (3H, t, J=7.4 Hz), 1.29 (3H, t, J=7.1 Hz), 2.64 (2H, q, J=7.4 Hz), 3.45 (3H, s), 4.27 (2H, q, J=7.1 Hz), 5.10 (2H, s), 6.81 (2H, d, J=8.8 Hz), 6.95 (2H, d, J=8.8 Hz), 7.00 (2H, m), 7.06-7.14 (3H, m).
Reaction SMILES: Cl[C:2]1[C:11]2[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=2[C:5]2=[N:12][CH:13]=[CH:14][N:4]2[N:3]=1.[NH:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.CC(C)=O>C(Cl)Cl>[N:15]1([C:2]2[C:11]3[CH2:10][CH2:9][CH2:8][CH2:7][C:6]=3[C:5]3=[N:12][CH:13]=[CH:14][N:4]3[N:3]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Clc1nn2ccnc2c2c1CCCC2
Reactant: C1CCNCC1
Solvent: CC(C)=O
Solvent: ClCCl
Product: c1cn2nc(N3CCCCC3)c3c(c2n1)CCCC3

Procedure:
A mixture was prepared by adding 15 g of 6-chloro-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine to 30.5 g of piperidine and the mixture was heated at reflux for 72 hours. The mixture was subjected to preparative liquid chromatography using 15% acetone in methylene chloride to separate the desired product from the impurities. The appropriate fractions from the chromatography were combined and the solvent was evaporated under reduced pressure. The resulting solid was collected by filtration and dried to give 6-(1-piperidinyl)-7,8,9,10-tetrahydroimidazo[2,1-a]phthalazine melting at about 95° C. This compound has the following structural formula ##STR2##
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4]CC1.C1(C=[CH:13][C:11]([OH:12])=CC=1)O.[CH2:15]=[O:16]>C(O)(=O)C>[C:6]([CH:5]([CH3:4])[C:15]([O:12][CH2:11][CH3:13])=[O:16])#[N:1]
Reactant: C=O
Reactant: Oc1ccc(O)cc1
Reactant: C1CCNCC1
Solvent: CC(=O)O
Product: CCOC(=O)C(C)C#N

Procedure:
Following the procedure of Example 5 omitting the 0.25 parts of piperidine and 0.025 parts of hydroquinone and adding 9.6 parts of the formalin, piperidine and acetic acid solution in place of the 8.6 parts of Example 5 over 151/4 hours gave 6.8 parts of ethyl 2-cyanopropionate of boiling point 82-90°C/8 mm. of mercury.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9]([C:11]1[N:18]2[C:14]([S:15][CH:16]=[CH:17]2)=[N:13][C:12]=1[CH3:19])=[O:10].[C:20]1([C:26]2[C:27]([C:32](O)=[O:33])=[N:28][CH:29]=[CH:30][N:31]=2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>>[C:20]1([C:26]2[C:27]([C:32]([N:3]3[CH2:4][C@H:5]4[C@H:1]([CH2:6]4)[C@H:2]3[CH2:7][NH:8][C:9]([C:11]3[N:18]4[C:14]([S:15][CH:16]=[CH:17]4)=[N:13][C:12]=3[CH3:19])=[O:10])=[O:33])=[N:28][CH:29]=[CH:30][N:31]=2)[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1nc2sccn2c1C(=O)NC[C@H]1NC[C@@H]2C[C@@H]21
Reactant: O=C(O)c1nccnc1-c1ccccc1
Product: Cc1nc2sccn2c1C(=O)NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nccnc1-c1ccccc1

Procedure:
prepared by reaction of 6-Methyl-imidazo[2,1-b]thiazole-5-carboxylic acid[(1S,2S,5R)-1-(3-aza-bicyclo[3.1.0]hex-2-yl)methyl]-amide with 3-Phenyl-pyrazine-2-carboxylic acid. LC-MS (basic): tR=1.18 min; [M+H]+=458.9.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:11]1[O:21][C:14]2([CH2:19][CH2:18][C:17](=[O:20])[CH2:16][CH2:15]2)[O:13][CH2:12]1.[S:22]1[C:26]2[CH:27]=[C:28]([C:31](Cl)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1.O>C1COCC1>[S:22]1[C:26]2[CH:27]=[C:28]([C:31]([CH:18]3[C:17](=[O:20])[CH2:16][CH2:15][C:14]4([O:13][CH2:12][CH2:11][O:21]4)[CH2:19]3)=[O:32])[CH:29]=[CH:30][C:25]=2[N:24]=[CH:23]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: O=C(Cl)c1ccc2ncsc2c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CCC2(CC1C(=O)c1ccc3ncsc3c1)OCCO2
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 35.6 %

Procedure:
Under a nitrogen atmosphere, lithium hexamethyldisilazide (2.4 mL, 2.4 mmol) was mixed with THF (5 mL). The reaction was cooled to −78° C. 1,4-cyclohexane-dione monoethylene acetal (374 mg, 2.4 mmol), dissolved in THF (2 mL) was slowly added via dropping funnel. The reaction was stirred for 20 min at −78° C. It was then cannulated to a flask, cooled at −78° C., containing benzothiazole-6-carbonyl chloride (498 mg, 2.52 mmol) dissolved in THF (5 mL). After the addition, the reaction was stirred at −78° C. for 1 hr, and then allowed to warm to room temperature. After 12 h, water (30 mL) was added and extracted with ethyl acetate (3×20 mL). The combined organic layers were washed with 10% citric acid (20 mL), water (20 mL), bicarb (20 mL), and brine (20 mL). It was then dried over Na2SO4, filtered and concentrated in vacuo. The crude material was purified by silica gel column (1:1 EtOAc/Hexanes) to yield 7-(Benzothiazole-6-carbonyl)-1,4-dioxa-spiro[4.5]decan-8-one (19B) (271 mg, 35%, light yellow solid).
Reaction SMILES: C([O:3][C:4]([C:6]1[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]2[C:15]([C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=3)=[N:16][O:17][C:18]=2[CH3:19])=[CH:10][CH:11]=1)=O)C.[NH2:27][CH2:28][CH:29]1[CH2:31][CH2:30]1>>[CH:29]1([CH2:28][NH:27][C:4]([C:6]2[N:7]=[N:8][C:9]([NH:12][CH2:13][C:14]3[C:15]([C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[CH:21]=4)=[N:16][O:17][C:18]=3[CH3:19])=[CH:10][CH:11]=2)=[O:3])[CH2:31][CH2:30]1
Reactant: CCOC(=O)c1ccc(NCc2c(-c3cccc(F)c3)noc2C)nn1
Reactant: NCC1CC1
Product: Cc1onc(-c2cccc(F)c2)c1CNc1ccc(C(=O)NCC2CC2)nn1
Yield: 63 %

Procedure:
As described for example 116e, 6-{[3-(3-fluoro-phenyl)-5-methyl-isoxazol-4-ylmethyl]-amino}-pyridazine-3-carboxylic acid ethyl ester (107 mg, 0.3 mmol) was converted, using aminomethylcyclopropane instead of cyclopropylamine, to the title compound (72 mg, 63%) which was obtained as a white solid. MS: m/e=382.5 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[OH:11].N12CCCN=C1CCCC[CH2:13]2>CCOC(C)=O.O>[CH3:10][O:9][C:5]1[C:4]([O:11][CH3:13])=[C:3]([O:2][CH3:1])[CH:8]=[CH:7][CH:6]=1
Reactant: COc1cccc(OC)c1O
Reactant: C1CCC2=NCCCN2CC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc(OC)c1OC
Temperature: 90 °C

Procedure:
To a solution of 2,6-dimethoxyphenol (1.0 g, 6.49 mmol) in DMC (10 mL), 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (0.99 g, 6.49 mmol) was added and the resulting solution was heated to reflux (90° C.) for 4.5 hours. The reaction was cooled to ambient temperature and diluted with EtOAc (50 mL) and H2O (40 mL). The organic layer was separated and washed in sequence with H2O (40 mL), 2M HCl (2×40 mL), 2M NaOH (2×40 mL) and H2O. The organic layer was dried over Na2SO4, filtered and concentrated under vacuum to give trimethoxybenzene as a solid. The yield of trimethoxybenzene as determined by HPLC was 99%.
Reaction SMILES: [C-:1]#[N:2].[Na+].[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1.[CH3:12][C:13]([CH3:15])=O.C(OCC)(=O)C>C(O)(=O)C>[CH3:12][C:13]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[CH:7][CH:6]=1)([CH3:15])[C:1]#[N:2]
Reactant: CC(C)=O
Reactant: Cc1ccc(N)cc1
Reactant: [C-]#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1ccc(NC(C)(C)C#N)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 95 %

Procedure:
Sodium cyanide (0.735 g, 15 mmol) was added to a mixture of p-toluidine (1.07 g, 10 mmol) and acetone (1.16 g, 20 mmol) in 90% acetic acid (10 ml). The reaction mixture was stirred at room temperature for 12 h and then ethyl acetate (50 ml) was added. The organic layer was washed with water (4×30 ml), dried over magnesium sulfate and concentrated under vacuum to dryness to yield 2-methyl-2-(4-methylphenyl)aminopropanenitrile, 5a (1.65g, 9.5 mmol, 95%) as a brown solid.