Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[C:6](=[O:7])[CH2:5][C:4]([CH3:9])([CH3:8])[O:3]1.C[O-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=O)[CH:23]=1>COCCOC.C(OCC)C>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[CH:17][C:16]=1[C:22]1[CH:27]=[CH:26][C:25]([CH:28]2[CH2:30][CH2:29]2)=[C:24]([CH:31]=[C:5]2[C:4]([CH3:9])([CH3:8])[O:3][C:2]([CH3:10])([CH3:1])[C:6]2=[O:7])[CH:23]=1
Reactant: CC1(C)CC(=O)C(C)(C)O1
Reactant: O=Cc1cc(-c2ccc(Cl)cc2Cl)ccc1C1CC1
Agent: C[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: CC1(C)OC(C)(C)C(=Cc2cc(-c3ccc(Cl)cc3Cl)ccc2C2CC2)C1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 102450.9 %

Procedure:
To an ice-cold solution of dihydro-2,2,5,5-tetramethylfuran-3-one (15.70 g, 0.11 mol) in anhydrous 1,2-dimethoxyethane (285 ml) is added sodium methoxide (6.50 g, 0.12 mol) in one portion, and the mixture is stirred at this temperature for 30 minutes. A solution of 2′,4′-dichloro-4-cyclopropylbiphenyl-3-carbaldehyde (13.70 g, 0.047 mmol) is then added dropwise over 20 minutes, maintaining temperature below 10° C. The reaction mixture is stirred at this temperature for 2 hours, then allowed to warm to room temperature before diluting with diethyl ether and distilled water. The two phases are separated, and the aqueous phase is extracted again with diethyl ether (×2). Organic fractions are combined, washed with brine, then dried over magnesium sulphate. The suspension is filtered and filtrate concentrated in vacuo. The aqueous phase is further acidified with 2M hydrochloric acid then extracted again with diethyl ether (×2), dried over magnesium sulfate and concentrated in vacuo. All organics are combined, then diluted with toluene and azeotroped (×4) to afford 4-[1-(2′,4′-dichloro-4-cyclopropylbiphenyl-3-yl)-methylidene]-2,2,5,5-tetramethyldihydrofuran-3-one (20.0 g) which is of sufficient purity to use directly in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([NH:8][NH2:9])=[O:7])=[CH:4][CH:3]=1.[Cl:12][CH2:13][C:14](Cl)=[O:15]>O1CCOCC1>[Cl:12][CH2:13][C:14]([NH:9][NH:8][C:6](=[O:7])[C:5]1[CH:10]=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=1)=[O:15]
Reactant: O=C(Cl)CCl
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: C1COCCO1
Product: O=C(CCl)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C

Procedure:
To a solution of p-chlorobenzoic hydrazide (11.2 g) in dioxane (100 ml) was added chloroacetyl chloride (6 ml). The resulting mixture was refluxed for three hours cooled to room temperature and filtered. The resulting solid was washed with ethyl ether and dried to yield N'-chloroacetyl-4-chlorobenzoic hydrazide as white solid.
Reaction SMILES: [OH:1][CH:2]([O:20][C:21]1[CH:22]=[C:23]([N+:65]([O-:67])=[O:66])[CH:24]=[C:25]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[C:68](Cl)([CH:70]=[CH2:71])=[O:69]>N1C=CC=CC=1>[C:68]([O:1][CH:2]([O:20][C:21]1[CH:22]=[C:23]([N+:65]([O-:67])=[O:66])[CH:24]=[C:25]([O:46][CH2:47][CH2:48][CH2:49][CH2:50][CH2:51][CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH3:64])[C:26]=1[O:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH3:45])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])(=[O:69])[CH:70]=[CH2:71]
Reactant: C=CC(=O)Cl
Reactant: CCCCCCCCCCCCCCCCCCOc1cc([N+](=O)[O-])cc(OC(O)CCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Solvent: c1ccncc1
Product: C=CC(=O)OC(CCCCCCCCCCCCCCCCC)Oc1cc([N+](=O)[O-])cc(OCCCCCCCCCCCCCCCCCC)c1OCCCCCCCCCCCCCCCCCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 92.2 %

Procedure:
Subsequently, into pyridine controlled at 0° C., dissolved was 4.0 g of 3-(1′-hydroxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene and added 0.50 g of acryl chloride for 30 minutes, followed by stirring 1 hour at room temperature. After finishing the reaction, resulting solution was purified via silica gel chromatography (mix solvent of hexane and ethyl acetate) to obtain 3.9 g of 3-(1′-acryloyloxyoctadecyloxy)-4,5-dioctadecyloxy nitrobenzene (yield: 92%).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([OH:12])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.Br[CH2:14][CH2:15][O:16][CH3:17].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[I:1][C:2]1[CH:7]=[C:6]([C:8]([F:10])([F:11])[F:9])[CH:5]=[C:4]([O:12][CH2:14][CH2:15][O:16][CH3:17])[CH:3]=1
Reactant: Oc1cc(I)cc(C(F)(F)F)c1
Reactant: COCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COCCOc1cc(I)cc(C(F)(F)F)c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 84.9 %

Procedure:
A mixture of 3-iodo-5-(trifluoromethyl)phenol (5 g, 17.36 mmol, 1.00 equiv), 1-bromo-2-methoxyethane (3.6 g, 25.90 mmol, 1.49 equiv) and potassium carbonate (7.2 g, 52.09 mmol, 3.00 equiv) in N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 h. The resulting mixture was cooled to room temperature and diluted with water (50 mL). The mixture was extracted with 3×50 mL of ethyl acetate. The combined organic layers were washed with 2×50 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 0-20% of ethyl acetate in petroleum ether to give 5.1 g (85%) of 1-iodo-3-(2-methoxyethoxy)-5-(trifluoromethyl)benzene as a yellow oil. 1H-NMR (300 MHz, DMSO-d6): δ 7.63-7.60 (m, 2H), 7.28 (s, 1H), 4.21-4.18 (m, 2H), 3.66-3.64 (m, 3H), 3.33 (s, 3H) ppm. LCMS (method D, ESI): RT=1.67 min.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[CH:15])[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH:17]1[CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1Br.C(N(CC)CC)C.N>CN(C)C=O.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>[CH2:1]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]#[C:15][C:29]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[O:23][CH2:22][CH:17]2[CH2:16][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C#CC1CCN(Cc2ccccc2)CC1
Reactant: Brc1ccccc1OCC1CCCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: C(#CC1CCN(Cc2ccccc2)CC1)c1ccccc1OCC1CCCCC1
Temperature: 100 °C
Reaction time: 3.5 h
Yield: 13.7 %

Procedure:
1.19 g of 1-benzyl-4-ethynylpiperidine was dissolved in 20 ml of N,N-dimethylformamide, 1.774 g of (2-cyclohexylmethyloxy)bromobenzene, 114 mg of cuprous iodide, 0.92 ml of triethylamine and 347 mg of tetrakis(triphenylphosphine)palladium were added thereto, and the mixture was stirred at 100° C. for 3.5 hours under anitrogen atmosphere. Ice-water and a diluted ammonia were added to the reaction solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and then dried over anhydrous magnesium sulfate. After filtering through alumina and silica gel, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 316 mg of the title compound as a slight yellow oil.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[CH:5]=[CH:4][C:3]=1[N:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([Sn](CCCC)(CCCC)C=C)[CH2:19]CC>O1CCOCC1.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>[CH3:17][N:14]1[CH2:15][CH2:16][N:11]([C:3]2[CH:4]=[CH:5][C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=2[CH:18]=[CH2:19])[CH2:12][CH2:13]1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Reactant: CN1CCN(c2ccc([N+](=O)[O-])cc2Br)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: C=Cc1cc([N+](=O)[O-])ccc1N1CCN(C)CC1
Temperature: 105 °C

Procedure:
A mixture of 1-(2-bromo-4-nitrophenyl)-4-methylpiperazine (0.900 g, 3.00 mmol), tetrakis(triphenylphosphine)palladium(0) (0.104 g, 0.090 mmol), and tributyl(vinyl)tin (0.964 mL, 3.30 mmol) in 1,4-dioxane (30 mL) was degassed and heated at 105° C. overnight. After cooling, the suspension was filtered, concentrated, and purified on a 40 g column using the ISCO Companion flash system eluting with methanol/ethyl acetate (5:95 to 10:90) to provide the title compound.
Reaction SMILES: Cl.[NH:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1.C([O-])([O-])=O.[K+].[K+].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15]>O.C1COCC1>[CH2:17]([O:16][C:14]([N:2]1[CH2:5][CH:4]([OH:6])[CH2:3]1)=[O:15])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC1CNC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N1CC(O)C1
Temperature: 22.5 °C
Reaction time: 0.5 h
Yield: 99.2 %

Procedure:
To a solution of azetidin-3-ol hydrochloride 7 (25 g, 0.23 mol) in water (150 mL) and THF (300 mL) was added K2CO3 (63.1 g, 0.46 mol). The mixture was stirred for 30 min. at 20-25° C. Then benzyl chloroformate (40.9 g, 0.24 mol) was added within 30 min. at 0-5° C. followed by stirring the mixture overnight at 20-25° C. THF was removed on a rotavap at 30° C./vacuum and the mixture was extracted with ethyl acetate (2×150 mL). The combined organic layer was washed with water (1×50 mL), dried over Na2SO4 and concentrated. The residue was purified by flash column chromatography on silica gel, eluting with ethyl acetate-heptanes 1:1 and 4:1 to yield 8 as a clear oil (47.3 g, 100%). 1H NMR (300 MHz, CDCl3): δ 3.72 (1H, d, J=6.2 Hz), 3.85 (2H, dd, J=9.5, 4.4 Hz), 4.17 (2H, dd, J=9.5, 6.7 Hz), 4.49-4.57 (1H, m), 5.06 (2H, s), 7.31-7.38 (5H, m); 13C NMR (75 MHz, CDCl3): δ 59.2, 61.6, 66.9, 127.9, 128.1, 128.5, 136.5, 156.6; IR: (film) 3406, 1686, 1438 cm−1; ES-HRMS m/z: (M++1H) calcd. for C11H14NO3 208.0968. found 208.0967.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+].C(COC)OC>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.O>[CH3:8][C:6]1[CH:5]=[CH:4][N:3]=[C:2]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:7]=1
Reactant: Cc1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1
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: [K+]
Solvent: COCCOC
Solvent: O
Product: Cc1ccnc(-c2ccccc2)c1
Yield: 84.4 %

Procedure:
A 1 L round bottom flask was charged with 2-chloro-4-methylpyridine (25 g, 196 mmol), phenylboronic acid (23.9 g, 196 mmol), potassium carbonate (81 g, 588 mmol), Pd(PPh3)4 (2.3 g, 1.9 mmol), dimethoxyethane (500 mL) and water (150 mL). The reaction mixture was degassed with nitrogen and heated to reflux for 22 h. After cooling, the aqueous layer was extracted with EtOAc; the organic portion was combined and subjected to column chromatography (SiO2, 5% EtOAc in hexane to 10% EtOAc in hexane) to give 28 g (78%) of 4-methyl-2-phenylpyridine. The product was confirmed by NMR and GC/MS.
Reaction SMILES: [CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[C:4]1=[CH:11][N+:12]([O-])=O)[CH3:2]>[Ni].CO>[CH2:1]([N:3]1[CH2:10][CH:9]2[CH:5]([CH2:6][CH2:7][CH2:8]2)[CH:4]1[CH2:11][NH2:12])[CH3:2]
Reactant: CCN1CC2CCCC2C1=C[N+](=O)[O-]
Agent: [Ni]
Solvent: CO
Product: CCN1CC2CCCC2C1CN

Procedure:
54 parts of N-ethyl-2-nitromethylene-3-azabicyclo (3,3,0) octane, in solution in 500 parts of anhydrous methanol were reduced in presence of 20 parts of Raney Nickel at 5 kg/m2 pressure. After filtration and washing of the catalyst by methanol, the filtrate was evaporated under vacuo then distilled. There were obtained 30 parts of N-ethyl-2-aminomethyl-3-azabicyclo (3,3,0) octane, B.P./0.25-0.30 mm Hg : 88°-90° C. This reduction can be easily carried out with lithium aluminium hydride too.
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]([CH2:6][O:7][C:8]([C:15]([F:18])([F:17])[F:16])([C:11]([F:14])([F:13])[F:12])[C:9]#[N:10])=[CH:4][CH:3]=1.[OH-].[K+].C([OH:25])C>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][O:7][C:8]([C:11]([F:12])([F:13])[F:14])([C:15]([F:16])([F:17])[F:18])[C:9]([NH2:10])=[O:25])=[CH:19][CH:20]=1
Reactant: N#CC(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F
Reactant: CCO
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: NC(=O)C(OCc1ccc(Cl)cc1)(C(F)(F)F)C(F)(F)F

Procedure:
A mixture of 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionitrile (20 g.), potassium hydroxide (25 g.), ethanol (250 ml.) and water (250 ml.) is heated under reflux for 15 minutes. Most of the ethanol is evaporated in vacuo, and the residue is cooled until the precipitated oil solidifies. The solid is filtered off, and is recrystallised from a mixture of ether and light petroleum (b.p. 40°-60° C.) (charcoal) to give 2-(4-chlorobenzyloxy)-3,3,3-trifluoro-2-trifluoromethylpropionamide, m.p. 94°-95° C. (13.9 g.).
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[ClH:9]>>[ClH:9].[I:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH3+:5]
Reactant: Nc1cccc(I)c1
Agent: Cl
Product: [NH3+]c1cccc(I)c1

Procedure:
46.00 g (0.21 mol) of 3-iodoaniline were admixed with 100 ml of 15% strength hydrochloric acid. The 3-iodoanilinium hydrochloride formed was filtered off with suction, recrystallized from water and dried under reduced pressure (yield: 52.57 g=98%). The total amount of the anilinium salt was mixed with 14.42 g (0.205 mol) of dimethylcyanamide and heated at 130° C. for 10 minutes on an oil bath. After the reaction had abated, the reaction mixture was cooled, admixed with 100 ml of water and the water-soluble constituents were filtered off. The aqueous solution was extracted twice with 100 ml each time of diethyl ether, adjusted to a pH of 10-12 using KOH and subsequently extracted three times with 100 ml of dichloromethane. The CH2Cl2 extracts were dried over magnesium sulfate and the solvent was then taken off under reduced pressure. This left 48.2 g of N′-(3-iodophenyl)-N,N-dimethylguanidine as a colorless solid (yield: 81%).
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[CH3:23][O:24][C:25]([CH:27]1[CH2:31][C:30](=O)[S:29][CH2:28]1)=[O:26]>C1(C)C=CC=CC=1>[CH3:23][O:24][C:25]([CH:27]1[CH2:31][C:30](=[S:10])[S:29][CH2:28]1)=[O:26]
Reactant: COC(=O)C1CSC(=O)C1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1CSC(=S)C1
Yield: 144.1 %

Procedure:
207 g (0.51 mol) of Lawesson reagent are added at room temperature to a suspension of 149 g (0.93 mol) of tetrahydro-5-oxo-3-thiophenecarboxylic acid methyl ester in 1.23 litres of absolute toluene, and the mixture is boiled at reflux for 16 hours. Then the solvent is removed by distillation in vacuo, the residue is boiled at reflux for 20 minutes four times in one litre of a solvent mixture of petroleum ether and diethyl ether 1:1 each time, and the extract phase is in each case decanted off and concentrated. After distillation of the crude substance at 130°-140° C./0.03 mbar using a bulb tube, 129.5 g of orange oil are obtained.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH2:7])=[N:4][N:3]=1.OP([O-])([O-])=O.[K+].[K+].[C:15]([NH:22][CH2:23][CH2:24][NH2:25])([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16]>CN(C=O)C>[NH2:7][C:5]1[S:6][C:2]([NH:25][CH2:24][CH2:23][NH:22][C:15](=[O:16])[O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[N:3][N:4]=1
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: Nc1nnc(Br)s1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCNc1nnc(N)s1
Temperature: 25 °C
Reaction time: 18 h
Yield: 79.4 %

Procedure:
A mixture of 5-bromo-1,3,4-thiadiazol-2-ylamine (5.40 g), K2HPO4 (7.84 g), and Boc-ethylenediamine (9.6 g) in 20 ml of DMF is stirred at ambient temperature for 18 hours. The solid paste obtained is recrystallized from 100 ml of acetonitrile and 100 ml of water to provide 6.18 g (79%) of the title compound.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22](O)=[O:23])[N:19]([CH3:21])[N:20]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[CH2:37]([N:39]([CH2:45][CH3:46])[CH:40]1[CH2:44][CH2:43][NH:42][CH2:41]1)[CH3:38].CCN(CC)CC>CN(C=O)C>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[C:16]1[CH:17]=[C:18]([C:22]([N:42]2[CH2:43][CH2:44][CH:40]([N:39]([CH2:45][CH3:46])[CH2:37][CH3:38])[CH2:41]2)=[O:23])[N:19]([CH3:21])[N:20]=1
Reactant: CCN(CC)C1CCNC1
Reactant: Cn1nc(-c2ccccc2-c2cc3ccccc3o2)cc1C(=O)O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCN(CC)C1CCN(C(=O)c2cc(-c3ccccc3-c3cc4ccccc4o3)nn2C)C1
Reaction time: 4 h
Yield: 75.3 %

Procedure:
A solution of 0.124 g (0.39 mmol) of 5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazole-3-carboxylic acid in 1.28 ml of DMF was treated with 0.063 g (0.39 mmol) of CDI. After 4 h, 0.055 g (0.39 mmol) of 3-(diethylamino)pyrrolidine and 0.217 ml (1.56 mmol) of Et3N in 1.28 ml of DMF were added and stirring was continued for 2 h. The solution was partitioned between aqueous saturated NaHCO3/Et2O (3×). The organic phases were washed with aqueous saturated NaHCO3 and aqueous 10% NaCl, dried (Na2SO4) and evaporated. The crude product was crystallized with Et2O/pentane to give 0.130 g (75%) of [5-(3-benzofuran-2-yl-phenyl)-2-methyl-2H-pyrazol-3-yl]-(3-diethylamino-pyrrolidin-1-yl)-methanone as light pink powder. MS: 443.2 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[NH:32]1[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:32]5[CH2:37][CH2:36][CH:35]([C:38]([OH:40])=[O:39])[CH2:34][CH2:33]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:29])([F:30])[F:31])[CH:3]=1
Reactant: O=C(O)C1CCNCC1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Product: O=C1N=C(N2CCC(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(Cl)cc2C(F)(F)F)c1

Procedure:
1-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}piperidine-4-carboxylic acid was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and piperidine-4-carboxylic acid following General Procedure C.
Reaction SMILES: O=[CH:2][CH:3]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>CCO>[Br:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]=[CH:2][CH:3]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:18][CH:17]=1
Reactant: Nc1ccc(Br)cc1
Reactant: CCOC(=O)C(C=O)c1ccccc1
Solvent: CCO
Product: CCOC(=O)C(C=Nc1ccc(Br)cc1)c1ccccc1

Procedure:
A solution of ethyl 3-oxo-2-phenylpropanoate (3.50 g, 18.2 mmol) and 4-bromoaniline (2.60 g, 15.1 mmol) in EtOH (25 mL) was stirred at room temperature overnight and concentrated to give the title compound as an oil.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([CH2:6][C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)=[N:2]1.C([N-]C(C)C)(C)C.[Li+].[C:23]1(=[O:30])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1.O>O1CCCC1>[OH:30][C:23]1([CH:6]([C:7]2[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[CH:9][CH:8]=2)[C:3]2[N:4]=[CH:5][NH:1][N:2]=2)[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: N#Cc1ccc(Cc2nc[nH]n2)cc1
Reactant: O=C1CCCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: N#Cc1ccc(C(c2nc[nH]n2)C2(O)CCCCCC2)cc1
Reaction time: 0.5 h
Yield: 98.2 %

Procedure:
5 g of 4-[1-(1,2,4-triazolyl)methyl]benzonitrile is dissolved in 100 ml of tetrahydrofuran and combined at -50° with 19.8 ml of 1.5-molar solution of lithium diisopropylamide in tetrahydrofuran, stirred for 0.5 hour, further stirred for 1 hour at -70° with 3.05 g of cycloheptanone, and heated to 25°. Then the mixture is combined with water, extracted twice with ethyl acetate, washed neutral with water, dried over sodium sulfate, and concentrated to dryness under vacuum, thus obtaining 7.9 g of crude 4-[1-hydroxycyclohept-1-yl-1-(1,2,4-triazolyl)methyl]benzonitrile.
Reaction SMILES: CS([C:5]1[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:7][N:6]=1)(=O)=O.[CH3:19][C:20]1([CH2:24][NH2:25])[CH2:23][O:22][CH2:21]1>>[CH3:19][C:20]1([CH2:24][NH:25][C:5]2[N:10]=[CH:9][C:8]([C:11]#[C:12][C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[CH:7][N:6]=2)[CH2:23][O:22][CH2:21]1
Reactant: CC1(CN)COC1
Reactant: CS(=O)(=O)c1ncc(C#Cc2ccccc2)cn1
Product: CC1(CNc2ncc(C#Cc3ccccc3)cn2)COC1

Procedure:
The title compound, white solid, MS: m/e=280.2 (M+H+), can be prepared in accordance with the general method of example 1, step 3 from 2-methanesulfonyl-5-phenylethynyl-pyrimidine (example 1, step 2) and (3-methyloxetan-3-yl)methanamine.
Reaction SMILES: C1(C)C=CC=CC=1.[Cl:8][C:9]1[CH:14]=[CH:13][C:12]([S:15]([CH2:18][C:19]2[CH:24]=[CH:23][N:22]=[CH:21][CH:20]=2)(=[O:17])=[O:16])=[CH:11][CH:10]=1.C(C=P(CCCC)(CCCC)CCCC)#N.[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51](O)[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1>CO>[CH2:41]([N:48]1[CH2:53][CH2:52][CH:51]([CH:18]([S:15]([C:12]2[CH:13]=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=2)(=[O:17])=[O:16])[C:19]2[CH:20]=[CH:21][N:22]=[CH:23][CH:24]=2)[CH2:50][CH2:49]1)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1
Reactant: O=S(=O)(Cc1ccncc1)c1ccc(Cl)cc1
Reactant: OC1CCN(Cc2ccccc2)CC1
Agent: CCCCP(=CC#N)(CCCC)CCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: O=S(=O)(c1ccc(Cl)cc1)C(c1ccncc1)C1CCN(Cc2ccccc2)CC1
Temperature: 25 °C
Yield: 34.8 %

Procedure:
A toluene (5 ml) solution of the 4-(4-chlorophenylsulfonylmethyl)pyridine (70 mg, 0.261 mmol) obtained in Referential Example 2,1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) was heated under reflux for 3 days under an argon atmosphere. After cooling to room temperature, 1-benzylpiperidin-4-ol (103 mg, 0.538 mmol) and cyanomethylenetri-n-butylphosphorane (129 mg, 0.538 mol) were added to the reaction mixture. Under an argon atmosphere, the resulting mixture was heated under reflux for 22 hours. After cooling to room temperature, the reaction mixture was concentrated under reduced pressure. The residue thus obtained was subjected to flash silica gel column chromatography. The fraction obtained from the methanol:methylene chloride (=1:10) eluate was concentrated under reduced pressure. The residue thus obtained was purified by high performance liquid chromatography (by using a mixed solvent system of water/acetonitrile/formic acid) to give the title compound (40 mg, 35%) as an amorphous substance.