Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:10]=[C:11]([O:15][CH3:16])[C:12]=1[O:13][CH3:14])[CH:6]=[CH:7][CH2:8]Cl.[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][NH:23][CH2:24][CH2:25][C:26]=2[N:27]=1>C(Cl)(Cl)Cl>[OH2:2].[NH2:17][C:18]1[S:19][C:20]2[CH2:21][CH2:22][N:23]([CH2:8][CH:7]=[CH:6][C:5]3[CH:4]=[C:3]([O:2][CH3:1])[C:12]([O:13][CH3:14])=[C:11]([O:15][CH3:16])[CH:10]=3)[CH2:24][CH2:25][C:26]=2[N:27]=1
Reactant: COc1cc(C=CCCl)cc(OC)c1OC
Reactant: Nc1nc2c(s1)CCNCC2
Solvent: ClC(Cl)Cl
Product: COc1cc(C=CCN2CCc3nc(N)sc3CC2)cc(OC)c1OC
Product: O
Yield: 17 %

Procedure:
Prepared from 3,4,5-trimethoxy-cinnamyl chloride and 2 equivalents of 2-amino-4,5,7,8-tetrahydro-6H-thiazolo[5,4-d]azepine in chloroform. Yield: 17% of theory, Melting point: 70°-73° C. (decomp.)
Reaction SMILES: [C:1](#[N:3])[CH3:2].C([Li])CCC.C([O:11][C:12](=O)[C:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=1[CH3:20])C.[OH-].[Na+]>C1COCC1>[CH3:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[C:12](=[O:11])[CH2:2][C:1]#[N:3]
Reactant: CCOC(=O)c1ccc(C)cc1C
Reactant: CC#N
Agent: [Li]CCCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cc1ccc(C(=O)CC#N)c(C)c1
Temperature: -78 °C
Reaction time: 8 h

Procedure:
Under Ar(g), a solution of anhydrous acetonitrile (1.6 mL) in 35 mL anhydrous THF is cooled to −78° C. in a dry ice-acetone bath and then slowly treated with 12 mL of a 2.5 M n-butyl lithium in hexanes. The reaction mixture is maintained at −78° C. for an additional 45 min. and then slowly treated with a solution of 5 gms. of 2,4-dimethyl-benzoic acid ethyl ester in 5 mL of anhydrous THF. The resulting solution is then stirred overnight at room temperature. Subsequently, the reaction mixture is treated with 10% NaOH(aq) to dissolve solids and then extracted with ethyl acetate. The aqueous layer is acidified (pH 6) with HCl(aq) affording a white precipitate which subsequently is filtered. The organic layer is concentrated in vacuo and the residue is triturated with isopropanol resulting in the formation of additional white precipitate. The combined precipitates provide the desired 3-(2,4-dimethyl-phenyl)-3-oxo-propionitrile in the amount of2.0011 gms.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9](I)[CH:8]=[N:7]1)[CH3:2].[CH3:13][O:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][SH:20])=[CH:17][CH:16]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C>O1CCOCC1.CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:1]([O:3][C:4](=[O:12])[CH2:5][N:6]1[CH:10]=[C:9]([S:20][CH2:19][C:18]2[CH:21]=[CH:22][C:15]([O:14][CH3:13])=[CH:16][CH:17]=2)[CH:8]=[N:7]1)[CH3:2]
Reactant: CCOC(=O)Cn1cc(I)cn1
Reactant: COc1ccc(CS)cc1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CCOC(=O)Cn1cc(SCc2ccc(OC)cc2)cn1
Temperature: 90 °C

Procedure:
(4-Iodo-pyrazol-1-yl)-acetic acid ethyl ester (1.8 g, 10.3 mmol), 4-methoxybenzyl mercaptan (1.43 mL, 10.3 mmol), Xantphos (0.298 g, 0.515 mmol) and then Hünig's base (3.7 mL, 21.2 mmol) were dissolved in dioxane (100 mL). The reaction was purged with N2 (g) for 10 minutes and then tris(dibenzylideneacetone)dipalladium(0) (0.235 g, 0.258 mmol) was added. The reaction was heated to 90° C. for 2 hours then cooled and diluted with EtOAc. The organic portion was washed with H2O and brine, with back-extraction, then dried and concentrated. The crude material was purified on silica gel (0-20% EtOAc in hexanes) to afford the title compound.
Reaction SMILES: C([Li])CCC.[F:6][C:7]1[CH:16]=[CH:15][C:10]2[CH2:11][CH2:12][CH2:13][O:14][C:9]=2[CH:8]=1.[C:17](=[O:19])=[O:18].C(OCC)C>O1CCCC1>[F:6][C:7]1[CH:16]=[CH:15][C:10]2[CH2:11][CH2:12][CH2:13][O:14][C:9]=2[C:8]=1[C:17]([OH:19])=[O:18]
Reactant: Fc1ccc2c(c1)OCCC2
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1c(F)ccc2c1OCCC2
Temperature: -78 °C

Procedure:
A stirred solution of 30.4 mL (0.076 mole) of n-butyllithium (2.5M in hexanes) in 200 mL of tetrahydrofuran was cooled to -78 °C., and 10.5 grams (0.069 mole) of 3,4-dihydro-7-fluoro-2H-1-benzopyran was added portionwise. Upon completion of the addition, the reaction mixture was maintained at -78° C. for 30 minutes. The reaction mixture was then exposed to a carbon dioxide atmosphere for 18 hours. The reaction mixture was then stirred with diethyl ether and extracted with an aqueous 5% sodium hydroxide solution. The basic layer was washed with diethyl ether, made acidic with concentrated hydrochloric acid, and then extracted with diethyl ether. The extract was dried with magnesium sulfate and filtered. The filtrate was concentrated under reduced pressure, yielding 10.2 grams of 3,4-dihydro-7-fluoro-2H-1-benzopyran-8-ylcarboxylic acid. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][CH:14]=[CH:13][C:9]=1[C:10]([OH:12])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1.N[C@H]1C2CCN(CC2)C1>>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[C@H:18]([NH:17][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][CH:15]=[CH:16][C:8]=1[CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH2:19]2
Reactant: NC1CN2CCC1CC2
Reactant: O=C(O)c1ccccc1Cc1ccccc1
Agent: N[C@@H]1CN2CCC1CC2
Product: O=C(N[C@@H]1CN2CCC1CC2)c1ccccc1Cc1ccccc1

Procedure:
Proceeding as in Example 1, Method A, but replacing 2,3-dimethyl benzoic acid with 2-benzylbenzoic acid and (RS)-3-amino-1-azabicyclo[2.2.2]octane with (S)-3-amino-1-azabicyclo[2.2.2]octane gave (S)-N-(1-azabicyclo[2.2.2]oct-3-yl)-2-benzylbenzamide.
Reaction SMILES: Cl[C:2]1[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=[C:6]([CH2:8][Cl:9])[N:7]=1.O.[NH2:14][NH2:15]>O1CCCC1>[Cl:9][CH2:8][C:6]1[N:7]=[C:2]([NH:14][NH2:15])[C:3]2[S:12][CH:11]=[CH:10][C:4]=2[N:5]=1
Reactant: ClCc1nc(Cl)c2sccc2n1
Reactant: NN
Solvent: O
Solvent: C1CCOC1
Product: NNc1nc(CCl)nc2ccsc12
Temperature: 5 °C
Reaction time: 15 h

Procedure:
3. 8.2 g of 4-chloro-2-(chloromethyl)thieno[3,2-d]pyrimidine are dissolved in 500 ml of absolute tetrahydrofuran. The solution is cooled to 5° C. 7 ml of hydrazine hydrate are added dropwise within 5 min., whereby a solution results and the temperature rises to 15° to 20° C. The reaction mixture is stirred at room temperature for 15 h. and then evaporated in a vacuum. The residue is stirred with 100 ml of saturated aqueous sodium hydrogen carbonate solution for 30 min. and then filtered off. The crystals are washed neutral with water and dried in a vacuum. 14.7 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]-pyrimidine are obtained. A further 1.0 g of 2-(chloromethyl)-4-hydrazinothieno[3,2-d]pyrimidine are obtained by extracting the filtrate with chloroform.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]#N)[C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[OH-:19].[Na+].C(O)CO.Cl.[OH2:26]>>[CH3:1][C:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[C:10]([C:11]([OH:26])=[O:19])[C:5]=2[O:4][C:3]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: Cc1c(-c2ccccc2)oc2c(C#N)cccc12
Reactant: [OH-]
Reactant: O
Agent: Cl
Agent: [Na+]
Solvent: OCCO
Product: Cc1c(-c2ccccc2)oc2c(C(=O)O)cccc12

Procedure:
A mixture of 364 mg of 3-methyl-2-phenylbenzofuran-7-nitrile, 3 g of an aqueous 30% sodium hydroxide solution and 8 ml of ethylene glycol is refluxed for 2 hours. After cooling, the reaction mixture is poured into water, acidified with 10% hydrochloric acid and then extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is recrystallized from tetrahydrofuran-n-hexane to give 257 mg of 3-methyl-2-phenylbenzofuran-7-carboxylic acid as colorless prisms.
Reaction SMILES: Br[CH2:2][C:3]([CH3:7])([CH3:6])[CH2:4][OH:5].[S-:8][C:9]#[N:10].[K+].CN(C)C=O.C(OCC)C>O>[OH:5][CH2:4][C:3]([CH3:7])([CH3:6])[CH2:2][S:8][C:9]#[N:10]
Reactant: N#C[S-]
Reactant: CC(C)(CO)CBr
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(CO)CSC#N
Temperature: 25 °C
Reaction time: 4 h
Yield: 85.4 %

Procedure:
A mixture of 16.7 g of 3-bromo-2,2-dimethyl-1-propanol, 14.6 g of potassium thiocyanate and 60 ml of dimethylformamide was stirred for 4 hours at 130°- 140° C. The reaction solution was cooled to room temperature (hereinafter means "5°-20° C."), to which a mixture of 200 ml of diethyl ether and 200 ml of water was added. The ethereal layer was collected. The aqueous layer was extracted with 150 ml of diethyl ether. The combined ethereal layers were washed with a saturated saline, dried over anhydrous magnesium sulfate and distilled to remove the solvent. The residue was distilled under reduced pressure to obtain 12.4 g of 3-hydroxy-2,2-dimethyl-1-propylthiocyanate.
Reaction SMILES: [C:1]([NH2:10])(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].N1C=CC=CC=1.C(#N)C.Cl[C:21](OCC)=[O:22]>O>[O:4]1[C:3]2[CH:5]=[CH:6][CH:7]=[CH:8][C:2]=2[C:1](=[O:9])[NH:10][C:21]1=[O:22]
Reactant: CCOC(=O)Cl
Reactant: NC(=O)c1ccccc1O
Solvent: O
Solvent: c1ccncc1
Solvent: CC#N
Product: O=c1[nH]c(=O)c2ccccc2o1
Temperature: 5 °C
Reaction time: 0.5 h

Procedure:
Following the method of Shapiro et al., JACS, 79:2811 (1957), salicylamide (59.0 g, 0.43 mol, 1.0 eq), pyridine (150 mL) and acetonitrile (125 mL) were placed in a 500 mL three-neck flask equipped with a magnetic stir bar, a thermometer, and an addition funnel. After cooling to about 5° C. in a salt ice bath, ethyl chloroformate (45.2 mL, 0.47 mol, 1.1 eq) was added dropwise over 25 minutes so that the reaction temperature did not exceed 10° C. during the addition. The reaction mixture was stirred for 30 minutes at 10° C. The addition funnel was replaced with a Dean-Stark trap and a water-cooled condenser. The mixture was heated to a distillation temperature of about 90° C. Distillation was continued until the internal temperature reached about 124° C. (200 ml. of distillate removed). The temperature was reduced so that the reaction mixture refluxed but did not distill. After one hour at reflux, the reaction mixture was cooled to about 25° C. and poured into water (400 mL). Concentrated aqueous hydrochloric acid (24 mL) was added. A white solid formed, which was collected by filtration, washed with water (200 mL), and dried under vacuum. The 2H-1,3-benzoxazine-2,4(3H)-dione was isolated as a white solid (59.3 g, 85% yield).
Reaction SMILES: [C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][OH:13])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.[Si:20](Cl)([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21]>CN(C=O)C>[C:1]([N:5]1[C:10](=[O:11])[C:9]([CH2:12][O:13][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])=[C:8]([Cl:14])[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(Cl)c(CO)c1=O
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)n1ncc(Cl)c(CO[Si](C)(C)C(C)(C)C)c1=O
Reaction time: 10 h

Procedure:
2-tert-butyl-4-hydroxymethyl-5-chloro 3(2H)-pyridazinone (1 g, 4.62 mmol) is dissolved in DMF in a 25 ml round bottom flask and to this were added imidazole (0.377 g, 5.0 mmol) and tert-butyldimethylsilyl chloride (0.762 g, 3.09 mmol). The mixture is stirred for 10 hours after which it is extracted in dichloromethane and the organic layer washed with water and dried. Purification by flash chromatography (silica gel; ethyl acetate/hexanes) affords the above mentioned product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](C=O)[CH:5]=[C:6]2[C:10]=1[C:9](=[O:11])[N:8]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][C:20]([F:23])([F:22])[F:21])=[CH:15][CH:14]=1)[CH2:7]2.C(O)=O.[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH2:43])[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30].C([BH3-])#N.[Na+]>CO.O>[C:29]([O:33][C:34]([N:36]1[CH2:41][CH2:40][CH:39]([CH2:42][NH:43][C:4]2[CH:5]=[C:6]3[C:10](=[C:2]([Cl:1])[CH:3]=2)[C:9](=[O:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([O:19][C:20]([F:21])([F:23])[F:22])=[CH:15][CH:14]=2)[CH2:7]3)[CH2:38][CH2:37]1)=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: O=Cc1cc(Cl)c2c(c1)CN(Cc1ccc(OC(F)(F)F)cc1)C2=O
Reactant: CC(C)(C)OC(=O)N1CCC(CN)CC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: O=CO
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(CNc2cc(Cl)c3c(c2)CN(Cc2ccc(OC(F)(F)F)cc2)C3=O)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.4 %

Procedure:
To a solution of 7-chloro-1-oxo-2-(4-trifluoromethoxy-benzyl)-2,3-dihydro-1H-isoindole-5-carbaldehyde (60 mg, 0.162 mmol) in methanol (1.6 mL) was added formic acid (0.02 ml), 4-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (35 mg, 0.162 mmol), and Sodium cyanoborohydride (0.2 mL, 1M in THF) respectively. The mixture stirred at room temperature for 1 hour and was then diluted with water and extracted with ethyl acetate. The organic were washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated. Column chromatography (56-60% ethyl acetate in hexanes) provided the title compound (47 mg, 52%). 1H NMR (300 MHz, CDCl3): δ (7.35 (d, 4H), 7.18 (d, 2H), 4.77 (s, 2H), 4.25 (s, 2H), 4.13 (br s, 1H), 3.86 (s, 2H), 2.65 (t, 4H), 2.54 (d, 2H), 1.70 (t, 4H), 1.45 (s, 9H)
Reaction SMILES: [NH2:1][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1.ClC[C:11]([N:13](CCCCCC)CCCCCC)=[O:12].C(N(C(C)C)CC)(C)C.C(COC)[O:36]C>CCCCCCC>[N:4]1[CH:5]=[CH:6][CH:7]=[C:8]([C:11]([NH2:13])=[O:12])[C:3]=1[C:2]([NH2:1])=[O:36]
Reactant: COCCOC
Reactant: CCCCCCN(CCCCCC)C(=O)CCl
Reactant: NCc1ccccn1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCCCC
Product: NC(=O)c1cccnc1C(N)=O

Procedure:
Pyridine diamide 3 was prepared according to the general procedure described in Example 8 using 2-(aminomethyl)pyridine (0.015 mol), 2-chloro-N,N-dihexylacetamide (0.048 mol), diisopropylethylamine (0.033 mol) and dimethoxyethane (25 mL). The product was isolated from a heptane extraction of the acidic aqueous layer. The product was made basic by extraction with aqueous NaOH. The organic solution was concentrated, and the residue was distilled (200° C., 0.05 mm) to afford 6.1 g of pure product.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[N:17]=[C:16]([CH3:18])[NH:15][C:14](=O)[CH:13]=1.N.O=P(Cl)(Cl)[Cl:23]>>[Cl:23][C:14]1[CH:13]=[C:12]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[O:5][CH2:4][CH2:3][O:2][CH3:1])[N:17]=[C:16]([CH3:18])[N:15]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: COCCOc1ccccc1-c1cc(=O)[nH]c(C)n1
Agent: N
Product: COCCOc1ccccc1-c1cc(Cl)nc(C)n1
Temperature: 5 °C
Yield: 87 %

Procedure:
A stirred suspension of 6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-3H-pyrimidin-4-one (0.17 g, 0.66 mmol) in POCl3 (2 mL) was heated at reflux for 1 h. The reaction mixture was cooled to about 5° C. and poured cautiously into 10 ml ice-water, ammonia (10 mL) was added and extracted with ethyl acetate (2×10 mL), organic layers were combined, washed with water (5 mL) then dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (eluent CHCl3-EtOAc, 10:1), yielding 0.16 g (87%) 4-chloro-6-[2-(2-methoxy-ethoxy)-phenyl]-2-methyl-pyrimidine as colorless solid.
Reaction SMILES: [CH2:1]([CH2:4][C:5](=[O:7])[CH3:6])[CH:2]=[CH2:3].[C:8]([OH:11])(=[O:10])C.[H-].[Na+].[CH3:14]COCC>>[CH3:14][O:11][C:8](=[O:10])[CH2:6][C:5](=[O:7])[CH2:4][CH2:1][CH:2]=[CH2:3]
Reactant: CCOCC
Reactant: C=CCCC(C)=O
Reactant: CC(=O)O
Agent: [H-]
Agent: [Na+]
Product: C=CCCC(=O)CC(=O)OC
Reaction time: 8 h

Procedure:
A solution of allylacetone (40 g; 0.42 mol) in 110 ml of ether was added dropwise to the stirred mixture during about 5 hours. The mixture was allowed to stand overnight at room temperature, and was stirred for 1 hour under refluxing, and then 50 ml of acetic acid was added to the mixture to decompose the unreacted sodium hydride. The reaction mixture was treated by the conventional method and the remained oily material was distilled to obtain 50 g of 3-oxo-6-heptenoic acid methyl ester.
Reaction SMILES: [C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][N:17](CC3C=CC=CC=3)[CH2:16][CH2:15]2)=[CH:10][CH:9]=1)([CH3:4])([CH3:3])[CH3:2].CCOC(C)=O>CCO.[Pd]>[C:1]([O:5][C:6](=[O:27])[NH:7][C:8]1[CH:9]=[CH:10][C:11]([N:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[CH:12][CH:13]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(N2CCN(Cc3ccccc3)CC2)cc1
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1ccc(N2CCNCC2)cc1
Reaction time: 72 h
Yield: 53.3 %

Procedure:
A solution of [4-(4-benzyl-piperazine-1-yl)-phenyl)-carbamic acid tert-butyl ester (43.5 g) in EtOH (1 L) containing Pd/C 10% (4 g) was hydrogenated at room temperature. After 72 hours, the catalyst was removed by filtration and the filtrate was evaporated under reduced pressure. The oily residue was then purified by flash chromatography eluting with AcOEt/isopropylamine (90/10) and the solid obtained was recristallized from AcOEt to give the title compound (17.5 g) as white crystals.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[Br:10][CH2:11][CH2:12]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>CN(C=O)C.O>[Br:10][CH2:11][CH2:12][O:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: BrCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: N#Cc1ccc(OCCBr)cc1
Temperature: 100 °C
Reaction time: 5 h
Yield: 53.1 %

Procedure:
A reaction mixture of 4-hydroxybenzonitrile (1.19 g, 10 mmol), 1,2-dibromoethane (9.39 g, 50 mmol), and K2CO3 (4.14 g, 30 mmol) in DMF (20 mL) was stirred at 100° C. for 5 h and cooled to room temperature. To the reaction mixture was added ethyl acetate and water. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated. The residue was purified by column chromatography to afford the 4-(2-bromoethoxy)benzonitrile (1.2 g, 53%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:24])[CH2:15][CH2:14][C:13]2(OC3C=CC=CC=3[O:16]2)[CH2:12][CH2:11]1.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O>CC(C)=O.ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([S:25]([NH2:28])(=[O:27])=[O:26])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]1([F:24])[CH2:15][CH2:14][C:13](=[O:16])[CH2:12][CH2:11]1
Reactant: NS(=O)(=O)c1cnc(OCC2(F)CCC3(CC2)Oc2ccccc2O3)c(Cl)c1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: O
Solvent: ClCCl
Solvent: CC(C)=O
Product: NS(=O)(=O)c1cnc(OCC2(F)CCC(=O)CC2)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
To a solution of EXAMPLE 350D (1.6 g) and pyridinium p-toluenesulfonate (1.2 g) in acetone (10 mL) was added water (2 mL) and the mixture was stirred under microwave irradiation at 100° C. for 10 minutes. The mixture was diluted with dichloromethane (300 mL) and washed with aqueous NaHCO3, water, brine and dried over Na2SO4. Filtration and evaporation of the solvent gave the title compound.
Reaction SMILES: C([C:8](CC1C=CC=CC=1)([C:12]([O-])=[O:13])[C:9]([O-:11])=[O:10])C1C=CC=CC=1.[H-].[Na+].[C:24]1(=[C:30]([C:34]#[N:35])[C:31]([NH2:33])=[O:32])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1.Cl.[C:37]1([CH3:43])[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1>>[C:34]([CH:30]1[C:24]2([CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH:8]([C:9]([O:11][CH2:43][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)=[O:10])[C:12](=[O:13])[NH:33][C:31]1=[O:32])#[N:35]
Reactant: Cc1ccccc1
Reactant: O=C([O-])C(Cc1ccccc1)(Cc1ccccc1)C(=O)[O-]
Reactant: N#CC(C(N)=O)=C1CCCCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Product: N#CC1C(=O)NC(=O)C(C(=O)OCc2ccccc2)C12CCCCC2
Reaction time: 0.25 h

Procedure:
3.41 g of dibenzylmalonate, 30 ml of toluene and 0.58 g of 60% sodium hydride in mineral oil are placed in a 100 ml flask equipped with a magnetic stirrer, thermometer and condenser, in a nitrogen atmosphere. After 15 minutes, 1.97 g of cyclohexylidenecyanoacetamide are added. The reaction mixture is left under agitation for 6 hours at 25° C. and is then acidified with 36% HCl. The organic phase is separated and the solvent is evaporated under reduced pressure to obtain 3.18 g of benzyl 5-cyano-2,4-dioxo-3-azaspiro[5,5]undecane-1-carboxylate.
Reaction SMILES: [Mg].[CH2:2](Cl)[CH:3]=[C:4]([CH3:6])[CH3:5].[CH3:8][C:9]([CH3:14])=[CH:10][C:11](Cl)=[O:12]>O1CCCC1.CC(C)=CCCl>[CH3:5][C:4]([CH3:6])([C:11](=[O:12])[CH:10]=[C:9]([CH3:14])[CH3:8])[CH:3]=[CH2:2]
Reactant: CC(C)=CC(=O)Cl
Reactant: CC(C)=CCCl
Agent: [Mg]
Solvent: C1CCOC1
Product: C=CC(C)(C)C(=O)C=C(C)C
Reaction time: 3 h

Procedure:
3 g of 3-methyl-but-2-enyl chloride (prenyl chloride) were added, under stirring, to a suspension of magnesium turnings (20 g; 0.83 M) in 100 ml of absolute tetrahydrofurane (THF). After initiation of the reaction, there were still added 900 ml of THF and the whole mixture was then cooled to -5°. A solution of 80 g of prenyl chloride in 400 ml of THF was then added to the above mixture which was finally kept at 10° for 3 hours. After cooling to 0°, a solution of 83 g. (0.7 M) of 3-methyl-but-2-en-1-oyl chloride in 350 ml of THF was added thereto and, after having been kept at room temperature for 3 further hours, the reaction mixture was poured onto ice-water. After evaporation of the volatile parts (THF) under reduced pressure, the concentrated residue was extracted twice with diethyl ether and the combined organic extracts washed with water, then neutralized with sodium hydrogencarbonate, dried and concentrated. The crude material thus obtained was finally distilled through a VIGREUX column to yield 55.0 g of 3,3,6-trimethyl-hepta-1,5-dien-4-one having b.p. 70°-75°/11 Torr.
Reaction SMILES: [O:1]1[CH2:7][CH:6]([N:8]2[C:12]([C:13]3[CH:18]=[CH:17][C:16]([C:19]4[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([O:26][CH3:27])[C:20]=4[CH3:28])=[CH:15][C:14]=3[N+:29]([O-])=O)=[C:11]([C:32]([O:34]CC)=O)[CH:10]=[N:9]2)[CH2:5][O:4][CH2:3][CH2:2]1.O.C(OCC)(=O)C>C(O)(=O)C.[Fe]>[O:4]1[CH2:5][CH:6]([N:8]2[C:12]3[C:13]4[CH:18]=[CH:17][C:16]([C:19]5[C:24]([CH3:25])=[CH:23][N:22]=[C:21]([O:26][CH3:27])[C:20]=5[CH3:28])=[CH:15][C:14]=4[NH:29][C:32](=[O:34])[C:11]=3[CH:10]=[N:9]2)[CH2:7][O:1][CH2:2][CH2:3]1
Reactant: CCOC(=O)c1cnn(C2COCCOC2)c1-c1ccc(-c2c(C)cnc(OC)c2C)cc1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ncc(C)c(-c2ccc3c(c2)[nH]c(=O)c2cnn(C4COCCOC4)c23)c1C
Temperature: 80 °C
Reaction time: 2.5 h
Yield: 53.7 %

Procedure:
Iron powder (28.8 mg) was added to a solution of ethyl 1-(1,4-dioxepan-6-yl)-5-[4-(2-methoxy-3,5-dimethylpyridin-4-yl)-2-nitrophenyl]-1H-pyrazole-4-carboxylate (64 mg) in acetic acid (2 mL)-water (0.1 mL), and the reaction mixture was stirred at 80° C. for 2.5 hours in a nitrogen atmosphere. The reaction mixture was returned to room temperature, and ethyl acetate (10 mL) was added to the reaction mixture. The insoluble matter was removed by filtration through Celite™. The filtrate was concentrated under reduced pressure. A solution of the residue in ethyl acetate was sequentially washed with a saturated aqueous sodium bicarbonate solution and brine, dried over anhydrous magnesium sulfate, filtered. The filtrate was passed through a NH silica gel pad. The resulting solution was concentrated under reduced pressure. Ethyl acetate (0.3 mL) and MTBE (0.3 mL) were added to the residue. The precipitated solid was collected by filtration to give the title compound (29.1 mg).