Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[C:6]([SH:7])=[N:5][N:4]=[N:3]1.C(=O)([O-])[O-].[K+].[K+].[CH3:14][C:15]([CH2:17]Cl)=[O:16]>CC(C)=O>[CH3:1][N:2]1[C:6]([S:7][CH2:14][C:15](=[O:16])[CH3:17])=[N:5][N:4]=[N:3]1
Reactant: CC(=O)CCl
Reactant: Cn1nnnc1S
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC(=O)CSc1nnnn1C
Reaction time: 2 h
Yield: 48 %

Procedure:
1-Methyl-5-mercapto-1,2,3,4-tetrazole (0.01 mol), potassium carbonate (0.015 mol) and α-chloroacetone (0.015 mol) are added to acetone (50 ml) and the mixture is refluxed with stirring for 2 hours. The reaction mixture is concentrated to dryness under reduced pressure and the residue is dissolved in chloroform. Insolubles are filtered off. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel column chromatography [Kieselgel 60, eluant: benzene-ether (10:1)] and the product is recrystallized from methanol-ether to obtain 1-methyl-5-acetylmethylthio-1,2,3,4-tetrazole (yield 48%) as colorless needles, m.p. 31° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.C([Li])CCC.[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](OC)=[O:20]>C1COCC1>[Cl:13][C:14]1[CH:18]=[CH:17][S:16][C:15]=1[C:19](=[O:20])[CH2:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1sccc1Cl
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(Cc1ccncc1)c1sccc1Cl
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 22.4 %

Procedure:
To a solution of 4-methylpyridine (1 eq, 75 mmol) in anhydrous THF (50 mL) was added n-butyl lithium 2.5 M solution (1.3 eq, 98 mmol) at −50° C. under nitrogen. The reaction mixture was stirred for 30 min at −50° C. To the mixture was slowly added a solution of methyl 3-chloro-2-thiophenecarboxylate (1 eq, 75 mmol, synthesis described in Heterocycles, 2007, 71(1), 87) in anhydrous THF (50 mL) at −50° C. The reaction mixture was stirred at −50° C. for 30 min, then allowed to warm to room temperature and stirred for 2 h. The mixture was quenched with aqueous saturated ammonium chloride solution (150 mL). The organic layer was separated and the aqueous phase was extracted with ethyl acetate (3×100 mL). The combined extracts were washed with water, brine, dried over Na2SO4 and concentrated. The obtained dark brown residue was purified by column chromatography on silica gel (DCM:MeOH, 100:1 to 80:1) to afford 4 g of 1-(3-chloro-2-thienyl)-2-(pyridin-4-yl)ethanone (22% yield).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.Cl[C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]3[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=3)[NH:17][N:16]=2)=[CH:11][CH:10]=1.CC([O-])(C)C.[Na+]>C1(C)C=CC=CC=1.CO>[CH3:1][N:2]1[CH2:7][CH2:6][N:5]([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:19]=[C:18](/[CH:20]=[CH:21]/[C:22]4[CH:23]=[CH:24][C:25]([OH:28])=[CH:26][CH:27]=4)[NH:17][N:16]=3)=[CH:13][CH:14]=2)[CH2:4][CH2:3]1
Reactant: CN1CCNCC1
Reactant: Oc1ccc(/C=C/c2cc(-c3ccc(Cl)cc3)n[nH]2)cc1
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc(-c3cc(/C=C/c4ccc(O)cc4)[nH]n3)cc2)CC1
Temperature: 80 °C
Reaction time: 24 h
Yield: 8.4 %

Procedure:
N-Methylpiperazine (50 μL, 0.49 mmol) was added to a suspension of 4-{(E)-2-[3-(4-chlorophenyl)-1H-pyrazol-5-yl]ethenyl}phenol (0.097 g, 0.33 mmol), NaOtBu (0.110 g, 1.14 mmol) and acetato(2′-di-tert-butylphosphino-1,1′-biphenyl-2-yl)palladium (0.015 g, 33 μmol, 10 mol %) in anhydrous toluene (1.5 mL) and heated to 80° C. After 24 hours, the reaction was cooled to room temperature, diluted with methanol and filtered though a celite pad. The filtrate was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the title compound (10 mg, 9% yield) as an off-white solid: 1H NMR (400 MHz, CD3OD): δ 7.71 (m, 2H), 7.40 (m, 2H), 7.20 (d, J=16.4 Hz, 1H), 7.10 (m, 2H), 6.87 (d, J=16.4 Hz, 1H), 6.84 (s, 1H), 6.79 (m, 2H), 3.95 (bd, J=14.4 Hz, 2H), 3.63 (bd, J=11.2 Hz, 2H), 2.28 (m, 2H), 3.10 (bt, J=13.2 Hz, 2H), 2.99 (s, 3H); MS (EI) for C22H24N4O: 361.2 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH2:8]([O:12][C:13]1[NH:14][C:15]([NH2:24])=[C:16]2[C:20]([N:21]=1)=[N:19][C:18]([O:22][CH3:23])=[N:17]2)[CH2:9][CH2:10][CH3:11].C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH2:33][CH:34]1[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]1>CN(C=O)C>[CH2:8]([O:12][C:13]1[N:21]=[C:20]2[C:16]([N:17]=[C:18]([O:22][CH3:23])[N:19]2[CH2:32][CH2:33][CH:34]2[CH2:39][CH2:38][O:37][C:36]([CH3:41])([CH3:40])[CH2:35]2)=[C:15]([NH2:24])[N:14]=1)[CH2:9][CH2:10][CH3:11]
Reactant: CC1(C)CC(CCBr)CCO1
Reactant: CCCCOc1nc2nc(OC)nc-2c(N)[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=C(O)C(F)(F)F
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2nc(OC)n(CCC3CCOC(C)(C)C3)c2n1
Temperature: 60 °C
Yield: 13.5 %

Procedure:
A mixture of 2-(butyloxy)-8-(methyloxy)-1H-purin-6-amine trifluoroacetate (0.2 g, 0.569 mmol) and anhydrous potassium carbonate (0.315 g, 2.277 mmol) in DMF was heated at 60° C. for 1 hour. The mixture was cooled to room temperature and 4-(2-bromoethyl)-2,2-dimethyltetrahydro-2H-pyran (0.151 g, 0.683 mmol) was added and the mixture heated at 50° C. for 18 hours. The mixture was quenched with water (2 ml) and extracted with DCM (2×5 ml). The DCM was separated through a hydrophobic frit and evaporated by blowing down under a stream of nitrogen. Addition of DMSO:MeOH (1:1) gave a precipitate which was collected by filtration, washed with methanol and dried in vacuo to give the title compound (29 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][NH:9][C:10]([C:12]2[O:13][CH:14]=[CH:15][CH:16]=2)=[O:11])=[C:4]([CH3:17])[CH:3]=1.C(N(CC)CC)C.[C:25](N1C=CN=C1)(N1C=CN=C1)=[O:26]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:9]=[C:10]([C:12]3[O:13][CH:14]=[CH:15][CH:16]=3)[O:11][C:25]2=[O:26])=[C:4]([CH3:17])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NNC(=O)c1ccco1
Reactant: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1cc(Cl)ccc1-n1nc(-c2ccco2)oc1=O
Yield: 60 %

Procedure:
A mixture of N′-(4-chloro-2-methylphenyl)furan-2-carbohydrazide (0.5 mmol), triethylamine (0.1 mL, 0.75 mmol), and carbonyldiimidazole (0.24 g, 1.5 mmol) was stirred at 80° C. in 2 mL of THF overnight. The crude product obtained after removal of the solvent was then subject to chromatography (silica gel, 1:9 ethyl acetate-hexanes), followed by crystallization from hexanes to provide 83 mg (0.3 mmol, yield 60%) of 3-(4-Chloro-2-methyl-phenyl)-5-furan-2-yl-3H-[1,3,4]oxadiazol-2-one as a white solid with an HPLC purity of 98.9%. LC-MS [M+H] 277.9 (C13H9ClN2O3+H, expected 277.68). The 1H-NMR spectrum was in accordance with the chemical structure.
Reaction SMILES: [NH:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1)N.[C:12]1(=O)[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.Cl>C(O)(=O)C.O>[CH2:14]1[C:13]2[NH:1][C:3]3[C:11](=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=3)[C:12]=2[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: NNc1ccc(C(=O)O)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)c1ccc2[nH]c3c(c2c1)CCCC3
Yield: 50.8 %

Procedure:
A mixture of 4-hydrazinobenzoic acid (5.0 g, 32.9 mmol) and cyclohexanone (3.3 g, 33 mmol) in 30 mL of acetic acid was heated under reflux for 4 hours, then cooled, diluted with water and acidified with HCl. The resultant solid was collected by filtration, washed with water and dried to give 3.6 g of the title compound as a crystalline solid.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:22](O)=[O:23])=[CH:20][N:21]=3)[CH2:13][C@H:12]2[O:25][CH3:26])=[O:9])[NH:5][C:6]=1[CH3:7].[CH3:27][O:28][NH2:29].CCN=C=NCCCN(C)C.Cl>CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[N:3]=[C:4]([C:8]([NH:10][C@H:11]2[CH2:16][CH2:15][N:14]([C:17]3[S:18][C:19]([C:22]([NH:29][O:28][CH3:27])=[O:23])=[CH:20][N:21]=3)[CH2:13][C@H:12]2[O:25][CH3:26])=[O:9])[NH:5][C:6]=1[CH3:7]
Reactant: CO[C@@H]1CN(c2ncc(C(=O)O)s2)CC[C@@H]1NC(=O)c1nc(Cl)c(C)[nH]1
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Product: CONC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(C)[nH]3)[C@H](OC)C2)s1
Yield: 18 %

Procedure:
The same operation as in Example (1g) was performed using cis(±)-2-(4-{[(4-chloro-5-methyl-1H-imidazol-2-yl)carbonyl]amino}-3-methoxypiperidin-1-yl)-1,3-thiazole-5-carboxylic acid obtained by the method described in Example (5f) (17 mg, 0.045 mmol), O-methylhydroxylamine (15 mg, 0.18 mmol), WSC hydrochloride (0.46 g, 0.24 mmol) and DMAP (5 mg, 0.042 mmol), to obtain 3.5 mg of the title compound as a white solid (18%).
Reaction SMILES: C(O)(C(F)(F)F)=O.C(OC([N:15](C(OC(C)(C)C)=O)[C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH:20]=[CH:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30])=O)(C)(C)C.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[NH2:15][C:16]1[CH:25]=[CH:24][C:23]2[C:22]3=[CH:26][CH:27]=[N:28][N:21]3[CH:20]=[CH:19][C:18]=2[C:17]=1[C:29]([O:31][CH3:32])=[O:30]
Reactant: COC(=O)c1c(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)ccc2c1ccn1nccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1c(N)ccc2c1ccn1nccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.5 %

Procedure:
TFA (3 mL) was added to a solution of methyl 8-[bis-(tert-butoxycarbonyl)amino]-pyrazolo[5,1-a]isoquinoline-7-carboxylate (Intermediate 7, 0.280 g) in DCM (3 mL) and the reaction mixture was stirred at room temperature for 2 hours. The mixture was stirred with saturated aqueous sodium bicarbonate solution for 30 minutes and then the organic layer was separated, dried (MgSO4) and filtered. The filtrate was concentrated in vacuo and the residue was purified by chromatography on silica, eluting with a mixture of ethyl acetate and cyclohexane with a gradient of 0-100% to give methyl 8-aminopyrazolo[5,1-a]isoquinoline-7-carboxylate (0.140 g) as a glass.
Reaction SMILES: [N+](C1C=CC(O[C:9]([O:11][C:12]2[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=2)[C:17]([O:19][CH3:20])=[O:18])=[O:10])=CC=1)([O-])=O.C(#N)C.Cl.[NH:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH2:35][C:36]2[CH:37]=[C:38]([NH:42][C:43]([NH2:45])=[O:44])[CH:39]=[CH:40][CH:41]=2)[CH2:30][CH2:29]1>CCOC(C)=O>[NH2:45][C:43]([NH:42][C:38]1[CH:37]=[C:36]([CH2:35][CH2:34][CH:31]2[CH2:32][CH2:33][N:28]([C:9]([O:11][C:12]3[CH:13]=[N:14][CH:15]=[C:16]([CH:21]=3)[C:17]([O:19][CH3:20])=[O:18])=[O:10])[CH2:29][CH2:30]2)[CH:41]=[CH:40][CH:39]=1)=[O:44]
Reactant: COC(=O)c1cncc(OC(=O)Oc2ccc([N+](=O)[O-])cc2)c1
Reactant: NC(=O)Nc1cccc(CCC2CCNCC2)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COC(=O)c1cncc(OC(=O)N2CCC(CCc3cccc(NC(N)=O)c3)CC2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.8 %

Procedure:
Methyl 5-{[(4-nitrophenoxy)carbonyl]oxy}nicotinate (228 mg) was added to an acetonitrile (5 ml) solution of 1-{3-[2-(4-piperidinyl)ethyl]phenyl}urea hydrochloride (185 mg) and TEA (0.2 ml), followed by stirring overnight at room temperature. The reaction liquid was diluted with EtOAc, washed with aqueous saturated sodium hydrogencarbonate solution and saturated brine in that order, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the resulting residue was purified by silica gel column chromatography (eluent: chloroform:methanol=10:1 (v/v)) to obtain methyl 5-({[4-(2-{3-[(aminocarbonyl)amino]phenyl}ethyl)-1-piperidyl]carbonyl}oxy)nicotinate (183 mg).
Reaction SMILES: [C-:1]#[N:2].[Na+].[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]=[O:17])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11].ClC1C=CC(C2(C=O)CCC2)=CC=1.S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+]>O.CO>[Cl:4][C:5]1[CH:6]=[C:7]([C:12]2([CH:16]([OH:17])[C:1]#[N:2])[CH2:15][CH2:14][CH2:13]2)[CH:8]=[CH:9][C:10]=1[Cl:11]
Reactant: O=CC1(c2ccc(Cl)c(Cl)c2)CCC1
Reactant: [C-]#N
Agent: O=CC1(c2ccc(Cl)cc2)CCC1
Agent: O=S([O-])S(=O)(=O)[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: N#CC(O)C1(c2ccc(Cl)c(Cl)c2)CCC1
Temperature: 20 °C
Reaction time: 16 h

Procedure:
A solution of sodium cyanide (19.5 g) in water (50 ml) was added dropwise over a period of 30 minutes to a solution of 1-(3,4-dichlorophenyl)cyclobutanecarbaldehyde [(62.16 g) prepared in a similar manner to that described in Example A for 1-(4-chlorophenyl)cyclobutanecarbaldehyde] in methanol (70 ml) whilst the temperature was maintained at 20° C. by cooling. A saturated aqueous solution of sodium metabisulphite (81 ml) was added over a period of 20 minutes at 20° C. and the mixture was stirred for 16 hours and then poured into a mixture of ice and water. The resulting mixture was extracted with ether and the extracts were washed and dried. Evaporation of the solvent gave 2-[1-(3,4-dichlorophenyl)cyclobutyl]-2-hydroxyacetonitrile as a yellow oil which was used without further purification.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(O)C>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[C:12]1([C:2]2[CH:3]=[C:4]([CH:9]=[CH:10][CH:11]=2)[C:5]([O:7][CH3:8])=[O:6])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1cccc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCO
Product: COC(=O)c1cccc(-c2ccccc2)c1
Yield: 9853.7 %

Procedure:
Using Preparation Method 2, Methyl 3-bromobenzoate (3.86 g, 18.6 mmol) was reacted with phenyl boronic acid (2.4 g, 20.5 mmol) in the presence of 5 mol % Pd(PPh3)4, 18 mL of 2N Na2CO3, 9.4 mL of Ethanol and 37 mL of toluene. The resulting reaction mixture was purified using SiO2 with hexane/diethyl ether 98:2 to give a colourless thick oil (389 g, 96%). NMR 1H (ppm, CDCl3): 8.29 (s, 1H), 8.03 (d, J3=7.8 Hz, 1H), 7.79 (d, J3=7.8 Hz, 1H), 7.63 (d, J3=7.2 Hz, 2H), 7.54-7.26 (m, 4H), 3.96 (s, 3H). MS: M+1 463.2.
Reaction SMILES: O.[N:2](=[CH:4][C:5](=[O:17])[CH2:6][C:7]([O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:8])[OH:3].[CH2:18](O)[CH2:19][OH:20].C1(C)C(S(O)(=O)=O)=CC=CC=1>C1C=CC=CC=1>[CH2:19]1[O:20][C:5]([CH:4]=[N:2][OH:3])([CH2:6][C:7]([O:9][CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)=[O:8])[O:17][CH2:18]1
Reactant: OCCO
Reactant: O=C(C=NO)CC(=O)OCc1ccccc1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: c1ccccc1
Product: O=C(CC1(C=NO)OCCO1)OCc1ccccc1
Yield: 35 %

Procedure:
In a two liter flask fitted with a Dean Stark water separator and a condenser were placed 186.5 g. (0.85 mole) of benzyl oximino-acetoacetate (17), 62 g. (1 mole) of ethylene glycol, 800 ml. of benzene (reagent grade) and 2 g. of toluenesulfonic acid. The reaction mixture was boiled at reflux until 15 ml. of water was removed (3 hours). The benzene solution was washed once with saturated sodium bicarbonate solution and once with brine. After drying over anhydrous sodium sulfate, the benzene solution was evaporated, leaving 212 g. (94%) of 17 as a light yellow oil. Its NMR spectrum was consistent with the assigned structure. Generally the compound was used as used in subsequent reaction but one of the isomers can be crystallized in 35% yield from toluene-petroleum ether, m.p. 52° C. ##STR144##
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[S:8][C:7]1([CH2:16][CH2:15][CH2:14]1)[CH2:6][C:5]2=O.Cl.[CH3:20][O:21][NH2:22]>N1C=CC=CC=1>[CH3:20][O:21][N:22]=[C:5]1[C:4]2[C:9](=[C:10]([CH3:13])[C:11]([CH3:12])=[C:2]([OH:1])[C:3]=2[CH3:18])[S:8][C:7]2([CH2:16][CH2:15][CH2:14]2)[CH2:6]1
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC1(CCC1)S2
Reactant: CON
Agent: Cl
Solvent: c1ccncc1
Product: CON=C1CC2(CCC2)Sc2c(C)c(C)c(O)c(C)c21
Reaction time: 8 h

Procedure:
To a solution of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one prepared as described above (300 mg) in 2 mL of pyridine was added methoxyamine hydrochloride (192 mg, 2.3 mmol). The reaction mixture was allowed to stir overnight. The mixture was washed with water and extracted with ethyl acetate. After concentration in vacuo, the residue was purified by flash chromatography eluted with 20% ethyl acetate in hexane to give 150 mg of 6′-hydroxy-5′,7′,8′-trimethylspiro[cyclobutane-1,2′-thiochromen]-4′(3′H)-one O-methyloxime, as a white solid.
Reaction SMILES: [C:1]([CH2:3][CH:4]1[O:9][C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5]1)#[N:2].[CH2:14]([OH:16])[CH3:15].[ClH:17]>C(OCC)C>[ClH:17].[O:9]1[C:8]2[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=2[O:6][CH2:5][CH:4]1[CH2:3][C:1](=[NH:2])[O:16][CH2:14][CH3:15]
Reactant: CCO
Reactant: N#CCC1COc2ccccc2O1
Agent: Cl
Solvent: CCOCC
Product: CCOC(=N)CC1COc2ccccc2O1
Reaction time: 96 h
Yield: 59 %

Procedure:
17.5 g (0.10 mole) 2-cyanomethyl-1,4-benzodioxane, prepared as described by Augstein, et al., J. Med. Chem. 8: 446 (1965), was dissolved in a mixture containing 7 g ethanol and 50 ml diethyl ether. 4.5 g (0.15 moles) of dry HCl was bubbled though the mixture, which was then capped. The mixture was allowed to stand at 5° C. for 4 days, followed by 3 days at room temperature. The crude product imidate hydrochloride (IV) precipitated out and was harvested by filtration, and washed with 100 ml ether, followed by 3×100 ml portions of methylene chloride. The solid was then purified by thin layer chromatography using 10% methanol in chloroform as a developing solvent. The product has an Rf value of 0.7-0.8; starting material moves farther in this solvent system, and none was present in the crude product. The yield of product was 15.3 g, as the hydrochloride, or 59% yield.
Reaction SMILES: C(C1OC(C(C2OC(CC)=CC=2)[C:9]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][C:10]=2[C:11](O)=[O:12])=CC=1)C.C1([N:33]=C=NC2CCCCC2)CCCCC1.N>ClCCl>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][CH:9]=[C:10]([CH:14]=1)[C:11]([NH2:33])=[O:12]
Reactant: CCc1ccc(C(c2ccc(CC)o2)c2ccc(OC)cc2C(=O)O)o1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Agent: N
Solvent: ClCCl
Product: COc1cccc(C(N)=O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 65 %

Procedure:
Under argon, 2-formyl-5-methoxybenzoic acid (10 mmol) and 2-ethylfuran (40 mmol) were dissolved in abs. dioxane (20 ml), and after 10 minutes of stirring at room temperature, conc. perchloric acid (0.3 ml) was added. The resulting reaction mixture was subsequently stirred at 60° C. for 1 h, then poured into water and stirred. Filtration and drying of the resulting precipitate gave 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid in the form of a colourless solid (60% of theory). 2-[Bis(5-ethyl-2-furyl)methyl]-5-methoxybenzoic acid (10 mmol), dicyclohexylcarbodiimide (2.27 g, 11 mmol) were dissolved in abs. dichloromethane (90 ml) and stirred at room temperature for 10 min. Aqueous ammonia (4 ml) was then added, and the resulting reaction mixture was then stirred at room temperature for 1 h. Filtration, concentration under reduced pressure and subsequent purification by column chromatography (gradient ethyl acetate/n-heptane) of the residue that remained gave 2-[bis(5-ethyl-2-fury))methyl]-5-methoxybenzamide (982 mg, 28% of theory) in the form of a colourless solid. Under argon, abs. 1,2-dichloroethane (10 ml) was added to 2-[bis(5-ethyl-2-furyl)methyl]-5-methoxybenzamide (706 mg, 2 mmol) and p-toluenesulphonic acid bound to macroporous polystyrene resin (2 mmol). The resulting reaction mixture was stirred at a temperature of 100° C. for 1 h, after cooling to room temperature filtered off through Celite and concentrated under reduced pressure. Purification of the residue that remained by column chromatography (gradient ethyl acetate/n-heptane) gave 2,4-diethyl-10-methoxy-6,7-dihydro-8H-furo[2′,3′:3,4]cyclohepta[1,2-c]isoquinolin-8-one (51 mg, 8% of theory) in the form of a colourless solid. 1H-NMR (400 MHz, d6-DMSO δ, ppm) 11.66 (br. s, 1H, NH), 8.31 (d, 1H), 7.68 (d, 1H), 7.38 (dd, 1H), 6.47 (s, 1H), 5.35 (t, 1H), 3.87 (s, 3H), 2.79 (q, 2H), 2.68 (m, 2H), 2.33 (q, 2H), 1.30 (t, 3H), 0.96 (t, 3H).
Reaction SMILES: [CH:1]1([C:4]([NH:10][C:11]([C:13]2[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:24])([F:23])[F:22])[C:16]([CH:25]3[CH2:27][CH2:26]3)=[CH:15][N:14]=2)=[O:12])([CH3:9])[CH2:5][C:6]([OH:8])=O)[CH2:3][CH2:2]1.[Cl-].[NH4+:29]>>[NH2:29][C:6](=[O:8])[CH2:5][C:4]([NH:10][C:11]([C:13]1[CH:18]=[C:17]([O:19][CH2:20][C:21]([F:22])([F:23])[F:24])[C:16]([CH:25]2[CH2:26][CH2:27]2)=[CH:15][N:14]=1)=[O:12])([CH:1]1[CH2:2][CH2:3]1)[CH3:9]
Reactant: [NH4+]
Reactant: CC(CC(=O)O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1
Agent: [Cl-]
Product: CC(CC(N)=O)(NC(=O)c1cc(OCC(F)(F)F)c(C2CC2)cn1)C1CC1

Procedure:
The title compound was synthesized in analogy to Example 112e, using 3-cyclopropyl-3-[[5-cyclopropyl-4-(2,2,2-trifluoroethoxy)pyridine-2-carbonyl]amino]butanoic acid (Example 229d) and ammonium chloride as starting materials and isolated (72 mg, 48%); MS (ESI, m/z): 386.6 (M+H+).
Reaction SMILES: Cl[C:2](=[CH2:5])[C:3]#[N:4].Cl.[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24])(=[NH:9])[NH2:8].N12CCCCC1C=NCCC2>C(#N)C>[NH2:4][C:3]1[CH:2]=[CH:5][N:8]=[C:7]([CH2:10][CH2:11][CH2:12][CH2:13][N:14]2[C:15](=[O:24])[C:16]3=[CH:23][CH:22]=[CH:21][CH:20]=[C:17]3[C:18]2=[O:19])[N:9]=1
Reactant: C=C(Cl)C#N
Reactant: N=C(N)CCCCN1C(=O)c2ccccc2C1=O
Agent: C1=NCCCN2CCCCC12
Agent: Cl
Solvent: CC#N
Product: Nc1ccnc(CCCCN2C(=O)c3ccccc3C2=O)n1
Temperature: 0 °C
Reaction time: 2 h
Yield: 42.2 %

Procedure:
A solution of 2-chloroacrylonitrile (1.75 g.) in acetonitrile (10 ml.) was added over 15 minutes to an ice-cooled mixture of 1-amidino-4-phthalimidobutane hydrochloride (5.64 g.), acetonitrile (50 ml.) and 1,5-diazabicyclo[5,4,0]undec-5-ene (6.08 g.). The mixture was stirred for a further two hours and then evaporated to dryness. The residue was treated with water (50 ml.) and the mixture extracted with ethyl acetate (2×50 ml.). The combined ethyl acetate extracts were extracted with N hydrochloric acid (3×30 ml.) and the combined aqueous extracts neutralised with sodium bicarbonate and extracted with ethyl acetate. The ethyl acetate extracts were evaporated to dryness and the residue recrystallised from acetonitrile to give 4-amino-2-(4-phthalimidobutyl)pyrimidine (2.5 g.), m.p. 139°-140°.
Reaction SMILES: [I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:14])=O.CN(C)C=O>C(Cl)Cl>[I:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:14])=[O:7])=[CH:4][CH:3]=1
Reactant: O=C(O)c1ccc(I)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(I)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A suspension of 4-iodobenzoic acid (20.0 g, 80.6 mL) in CH2Cl2 (350 mL) at 0° C. was treated with oxalyl chloride (42.3 mL of a 2.0 M solution in CH2Cl2, 81.7 mmol). Dimethylformamide was added (0.5 mL) until a homogeneous solution was achieved and then the cooling bath was removed. The reaction mixture was stirred at ambient temperature for 3 hours and then concentrated to provide crude 4iodobenzoyl chloride as a waxy oil that was used without further purification.