Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH:7]([CH3:15])[O:6]1)(=O)C.[C:16]([OH:21])(=[O:20])[C:17]([CH3:19])=[CH2:18].C(C1C(O)=C(C(C)(C)C)C=C(C)C=1)C1C(O)=C(C(C)(C)C)C=C(C)C=1>>[C:16]([O:21][CH:5]1[C:9]2([CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[CH2:8][CH:7]([CH3:15])[O:6]1)(=[O:20])[C:17]([CH3:19])=[CH2:18]
Reactant: CC(=O)OC1OC(C)CC12CCCCC2
Reactant: C=C(C)C(=O)O
Agent: Cc1cc(Cc2cc(C)cc(C(C)(C)C)c2O)c(O)c(C(C)(C)C)c1
Product: C=C(C)C(=O)OC1OC(C)CC12CCCCC2
Temperature: 50 °C

Procedure:
A mixture of 13 g of 3-methyl-2-oxaspiro[4.5]decan-1-yl acetate, 24 g of methacrylic acid, and 13 mg of 2,2′-methylenebis(6-t-butyl-p-cresol) was heated at 50° C. under atmospheric pressure for 30 minutes, after which under a reduced pressure of 0.20 kPa, the reaction mixture was heated for 18 hours for distilling off the acetic acid formed. The reaction mixture was purified by distillation, obtaining 11 g (yield 800) of the target compound, 3-methyl-2-oxaspiro[4.5]decan-1-yl methacrylate.
Reaction SMILES: [ClH:1].CCOC(C)=O.[C:8]([C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[CH:16]([CH:20]1[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1)[N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)#[N:9]>CCOC(C)=O.C(OCC)C>[ClH:1].[CH:20]1([CH:16]2[C:17]3[C:12](=[CH:11][C:10]([C:8]#[N:9])=[CH:19][CH:18]=3)[CH2:13][CH2:14][NH:15]2)[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]1
Reactant: CC(C)(C)OC(=O)N1CCc2cc(C#N)ccc2C1C1CCCCC1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: N#Cc1ccc2c(c1)CCNC2C1CCCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4 M HCl/EtOAc (2 mL) was added to a solution of tert-butyl 6-cyano-1-cyclohexyl-3,4-dihydroisoquinoline-2(1H)-carboxylate (361 mg) in EtOAc (1 mL). The mixture was stirred at room temperature for 1 hour. The reaction mixture together with the precipitated crystal was diluted with diethyl ether (5 mL). The crystal was collected by filtration, washed with diethyl ether, and dried in air to obtain 1-cyclohexyl-1,2,3,4-tetrahydroisoquinoline-6-carbonitrile hydrochloride (259 mg).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[C:10]([NH:12][CH2:13][C:14]([F:20])([F:19])[C:15]([F:18])([F:17])[F:16])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4].[CH2:21](I)[CH3:22].[H-].[Na+]>CN(C)C=O>[CH2:1]([O:5][C:6]1[CH:11]=[C:10]([N:12]([CH2:21][CH3:22])[CH2:13][C:14]([F:19])([F:20])[C:15]([F:16])([F:17])[F:18])[N:9]=[CH:8][N:7]=1)[C:2]#[C:3][CH3:4]
Reactant: CCI
Reactant: CC#CCOc1cc(NCC(F)(F)C(F)(F)F)ncn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC#CCOc1cc(N(CC)CC(F)(F)C(F)(F)F)ncn1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 53.8 %

Procedure:
In 2 ml of N,N-dimethylformamide were dissolved 73 mg of 4-(2-butynyloxy)-6-(2,2,3,3,3-pentafluoropropylamino)pyrimidine and 47 mg of ethyl iodide, to which 12 mg of sodium hydride (60% in oil) was added, followed by stirring at room temperature for 3.5 hours. Then, ice water was added to the reaction mixture, which was extracted with ethyl acetate. The organic layer was washed twice with an aqueous sodium chloride solution, dried over anhydrous magnesium sulfate, and then concentrated. The residue was subjected to preparative silica gel thin layer chromatography to give 43 mg of 4-(2-butynyloxy)-6-(N-ethyl-N-(2,2,3,3,3-pentafluoropropyl)amino)pyrimidine (the present compound (112)).
Reaction SMILES: [Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:33]2[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]2)([CH2:29][S:30]([CH3:32])=[O:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:4])[CH3:3].[OH:39]OS([O-])=O.[K+].Cl>C(O)C.O.CCOCC>[Cl-:1].[C:2]([NH+:6]1[CH2:10][C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[C@@H:8]([C:19]([N:21]2[CH:26]3[CH2:27][CH2:28][CH:22]2[CH2:23][C:24]([CH:33]2[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]2)([CH2:29][S:30]([CH3:32])(=[O:39])=[O:31])[CH2:25]3)=[O:20])[CH2:7]1)([CH3:5])([CH3:3])[CH3:4]
Reactant: O=S([O-])OO
Reactant: CS(=O)CC1(C2CCCCC2)CC2CCC(C1)N2C(=O)[C@H]1C[NH+](C(C)(C)C)C[C@H]1c1ccc(F)cc1F
Agent: Cl
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: CCOCC
Solvent: CCO
Product: CC(C)(C)[NH+]1C[C@H](C(=O)N2C3CCC2CC(CS(C)(=O)=O)(C2CCCCC2)C3)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
To a solution of (3R,4R)-1-tert-butyl-3-({3-cyclohexyl-3-[(methylsulfinyl)methyl]-8-azabicyclo[3.2.1]oct-8-yl}carbonyl)-4-(2,4-difluorophenyl)pyrrolidinium chloride (3-8) (50 mg, 0.090 mmol) in ethanol (2.0 mL) was added a solution of the oxone® (276 mg, 0.451 mmol) in 2.0 mL of water. The mixture was stirred at room temperature for 40 min. The solid was filtered and filtrate was concentrated, diluted with methylene chloride dried over anhydrous Na2SO4, filtered, and concentrated, followed by the addition of one equivalent HCl in ether to afford (3-9) as white solid (in/z (ES) 551 (MH+)).
Reaction SMILES: Cl.[O:2]=[C:3]1[CH2:8][CH2:7][NH:6][CH2:5][CH:4]1[C:9]([O:11][CH3:12])=[O:10].C(N(CC)CC)C.[C:20](OC(=O)C)(=[O:22])[CH3:21]>ClCCl>[C:20]([N:6]1[CH2:7][CH2:8][C:3](=[O:2])[CH:4]([C:9]([O:11][CH3:12])=[O:10])[CH2:5]1)(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)C1CNCCC1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)C1CN(C(C)=O)CCC1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 59.3 %

Procedure:
Methyl 4-oxo-3-piperidinecarboxylate hydrochloride (10 g, 51.65 mmol) was dissolved in dichloromethane (130 mL). Triethylamine (7.20 mL, 51.65 mmol) was added followed by acetic anhydride (4.87 mL, 51.65 mmol). The reaction mixture was stirred at room temperature for 2 h. The organic phase was washed with water, dried over MgSO4, filtered and concentrated to give methyl 1-acetyl-4-oxopiperidine-3-carboxylate (6.10 g, 59.3%), which was used in the next step as such.
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][N:5]([C:8]2[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]1[O:18][CH2:19][CH2:20][CH3:21].[Cl:22][C:23]1[N:24]=[C:25]([C:30](O)=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>>[Cl:22][C:23]1[N:24]=[C:25]([C:30]([NH:1][C@H:2]2[CH2:7][CH2:6][N:5]([C:8]3[CH:9]=[C:10]([CH:15]=[CH:16][CH:17]=3)[C:11]([O:13][CH3:14])=[O:12])[CH2:4][C@H:3]2[O:18][CH2:19][CH2:20][CH3:21])=[O:31])[NH:26][C:27]=1[CH2:28][CH3:29]
Reactant: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1N
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Product: CCCO[C@@H]1CN(c2cccc(C(=O)OC)c2)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1

Procedure:
The same operation as in Example (1g) was performed using methyl cis(±)-3-(4-amino-3-propoxypiperidin-1-yl)benzoate obtained in Example (178b) (42.4 mg, 0.14 mmol), 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid obtained by the method described in Example (1d) (24.1 mg, 0.14 mmol), WSC hydrochloride (79.4 mg, 0.41 mmol) and HOBt (18.7 mg, 0.14 mmol), to obtain 35.5 mg of the title compound as a yellow oily substance (67%).
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH2:16][O:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21]C=1)(C)(C)C.[C:26]1(C2C=CC=CC=2)[CH:31]=[CH:30][C:29]([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38]OS(C3C=CC(C)=CC=3)(=O)=O)[N:36]=2)=[CH:28][CH:27]=1.CN(C=O)C.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOCC>[CH:29]1([C:32]2[O:33][C:34]([CH3:50])=[C:35]([CH2:37][CH2:38][O:15][C:12]3[CH:13]=[CH:14][C:9]([CH2:8][CH2:7][C:6]([OH:5])=[O:25])=[C:10]([CH2:16][O:17][C:18]4[CH:19]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH:11]=3)[N:36]=2)[CH2:28][CH2:27][CH2:26][CH2:31][CH2:30]1
Reactant: CC(C)(C)OC(=O)CCc1ccc(O)cc1COCc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CCC(=O)O)c(COc2ccccc2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 78.3 %

Procedure:
General procedure for the parallel synthesis of analogs using the DynaVac Carousel apparatus: A 50 mL glass tube with screw cap and nitrogen inlet was charged with 3-(2-benzyloxymethyl-4-hydroxy-phenyl)-propionic acid tert-butyl ester (0.050 g, 0.146 mmol), toluene-4-sulfonic acid 2-(2-biphenyl-4-yl-5-methyloxazol-4-yl)ethyl ester (0.078 g, 0.18 mmol), anhydrous DMF (0.5 mL), and then cesium carbonate (0.072 g, 0.22 mmol). The mixture was stirred at ambient temperature for 16 h. MS analysis of the reaction indicated that the intermediate ester was formed, MS (ES) m/e 534 (M+1). The crude reaction was poured into ether (30 mL), and washed with brine (2×), dried (Na2SO4), and concentrated in vacuo. The crude residue was dissolved in CH2Cl2 (2 mL) and trifluoroacetic acid was added (1.0 mL). The reaction mixture was stirred at ambient temperature for 2 h and was concentrated under a stream of N2. The crude product was purified by mass-directed reverse phase HPLC to provide 0.053 g (71%) of 3-{4-[2-(2-Cyclohexyl-5-methyloxazol-4-yl)ethoxy]-2-phenoxymethylphenyl}propionic acid. MS (ES) m/e 478 (M+1).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH2:2][CH3:3].Cl[C:12]([CH3:20])([CH2:14][CH2:15][C:16](Cl)([CH3:18])[CH3:17])[CH3:13]>>[CH2:1]([C:4]1[C:5]([OH:10])=[CH:6][C:7]2[C:12]([CH3:20])([CH3:13])[CH2:14][CH2:15][C:16]([CH3:18])([CH3:17])[C:8]=2[CH:9]=1)[CH2:2][CH3:3]
Reactant: CC(C)(Cl)CCC(C)(C)Cl
Reactant: CCCc1ccccc1O
Product: CCCc1cc2c(cc1O)C(C)(C)CCC2(C)C

Procedure:
In a manner similar to Example 7(a), by the reaction of 13.6 g (0.1 mol) of 2-n-propylphenol with 18.3 g (0.1 mol) of 2,5-dichloro-2,5-dimethylhexane, 11.6 g (65%) of the expected phenolic derivative of melting point 96-7° C. were obtained after chromatography on a silica column eluted with dichloromethane.
Reaction SMILES: [CH3:1][CH:2]([OH:7])[CH2:3][CH2:4][CH2:5][CH3:6].[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14](O)=[O:15]>>[ClH:8].[NH2:9][CH2:10][C:11](=[O:17])[CH2:12][CH2:13][C:14]([O:7][CH:2]([CH3:1])[CH2:3][CH2:4][CH2:5][CH3:6])=[O:15]
Reactant: CCCCC(C)O
Reactant: NCC(=O)CCC(=O)O
Agent: Cl
Product: CCCCC(C)OC(=O)CCC(=O)CN
Reaction time: 4 h

Procedure:
From 2-hexanol (6.0 ml) and 5-amino-4-oxopentanoic acid hydrochloride (1.0 g; 6.0 mmol) at 70° C. The reaction was complete after ca. 4 h. The yield was 1.0 g (66%).
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([C:16](OC)=[O:17])=[N:8]1.O>O1CCCC1.[OH-].[Na+]>[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9]([CH2:16][OH:17])=[N:8]1
Reactant: COC(=O)c1n[nH]c2ccccc12
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: OCc1n[nH]c2ccccc12
Temperature: 0 °C
Reaction time: 2 h
Yield: 52.9 %

Procedure:
3.2 g of lithium aluminium hydride are added portionwise to a solution of 7.08 g of methyl 3-indazolecarboxylate in 80 ml of tetrahydrofuran, cooled to a temperature in the region of 0° C. by an ice bath. After 4 hours at a temperature in the region of 0° C., 1.6 g of lithium aluminium hydride are added. After 2 hours at a temperature in the region of 0° C., the reaction medium is treated successively with 6 ml of water and then 6 ml of aqueous IN sodium hydroxide solution and finally 18 ml of water. The reaction mixture is filtered through paper and the aqueous filtrate is then extracted with dichloromethane. The collected organic fractions are combined, dried over magnesium sulphate and concentrated under reduced pressure at a temperature in the region of 40° C. 3.15 g of (1H-indazol-3-yl)methanol are obtained in the form of an off-white powder, the characteristics of which are as follows:
Reaction SMILES: [C:1]1([CH3:21])[CH:6]=[CH:5][CH:4]=[C:3]([S:7]([N:10]2[CH2:15][CH2:14][O:13][C:12]3[CH:16]=[CH:17][C:18]([NH2:20])=[N:19][C:11]2=3)(=[O:9])=[O:8])[CH:2]=1.[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25](Cl)=[O:26].C([O-])(O)=O.[Na+]>O1CCOCC1.O>[Cl:22][C:23]1[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[C:24]=1[C:25]([NH:20][C:18]1[CH:17]=[CH:16][C:12]2[O:13][CH2:14][CH2:15][N:10]([S:7]([C:3]3[CH:2]=[C:1]([CH3:21])[CH:6]=[CH:5][CH:4]=3)(=[O:9])=[O:8])[C:11]=2[N:19]=1)=[O:26]
Reactant: Cc1cccc(S(=O)(=O)N2CCOc3ccc(N)nc32)c1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cc1cccc(S(=O)(=O)N2CCOc3ccc(NC(=O)c4c(Cl)cccc4Cl)nc32)c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
4-(Toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-ylamine (20 mg, 0.065 mmol) was dissolved in p-dioxane (0.400 mL) and water (0.100 mL), followed by 2,6-dichlorobenzoyl chloride (21 μL, 0.098 mmol) and NaHCO3 (11 mg, 0.13 mmol). The resulting mixture was stirred at room temperature for 15 hours, concentrated under vacuum, and purified by HPLC to give 2,6-dichloro-N-[4-(toluene-3-sulfonyl)-3,4-dihydro-2H-pyrido[3,2-b][1,4]oxazin-6-yl]-benzamide. LCMS (ESI): calc. C21H17Cl2N3O4S=477; obs. M+H=478.
Reaction SMILES: [F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9]([CH2:10][C:11]3([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]3)[C:12]2=O)=[CH:8][CH:7]=1.[CH3:22][C:23]([S:26]([NH2:28])=[O:27])([CH3:25])[CH3:24].CCOC(C)=O>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.O>[F:1][CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:14]=[C:13]2[C:9](=[CH:8][CH:7]=1)[CH2:10][C:11]1([CH2:20][CH2:19][CH:18]([OH:21])[CH2:17][CH2:16]1)[C:12]2=[N:28][S:26]([C:23]([CH3:25])([CH3:24])[CH3:22])=[O:27]
Reactant: O=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)S(=O)N=C1c2cc(OCCCF)ccc2CC12CCC(O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 22.6 %

Procedure:
6′-(3-Fluoropropoxy)-4-hydroxyspiro[cyclohexane-1,2′-inden]-1′(3′H)-one (Intermediate 21, 0.91 g, 3.11 mmol), 2-methylpropane-2-sulfinamide (0.566 g, 4.67 mmol) and titanium(IV) ethoxide (1.283 mL, 6.23 mmol) were dissolved in 2-Me THF (8 mL) and heated to reflux over a weekend. More 2-methyl-2-propanesulfinamide (0.189 g, 1.56 mmol) and titanium(IV) ethoxide (0.325 mL, 1.56 mmol) were added, and the mixture was refluxed overnight. The reaction was cooled to r.t. EtOAc (50 mL) and water (10 mL) were added under stirring. The mixture were let to stand still for 1 h. The organic phase was collected by filtration, dried, and concentrated. The residue was purified by flash column chromatography using a gradient of 0-40% EtOAc in heptane, to give 0.278 g (23% yield) of the title compound. 1H NMR (500 MHz, CDCl3) δ ppm 1.33 (s, 9 H) 1.45-1.54 (m, 4 H) 1.87 (br. s., 1 H) 2.03 (dd, 2 H) 2.14-2.19 (m, 1 H) 2.20-2.25 (m, 1 H) 2.93-3.01 (m, 2 H) 3.71-3.80 (m, 1 H) 4.13-4.18 (m, 2 H) 4.59-4.66 (m, 1 H) 4.69-4.75 (m, 1 H) 7.11 (dd, 1 H) 7.29 (s, 1 H); MS (ES+) m/z 396.11 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([OH:21])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:24])[F:23])=[N:3]1.C(N(CC)CC)C.[C:33](Cl)(=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35]>C1COCC1>[CH3:1][N:2]1[C:6]([Cl:7])=[C:5]([C:8]([O:21][C:33](=[O:38])[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:9]([C:12]2[S:13][CH:14]=[C:15]([C:17]([CH3:20])([CH3:19])[CH3:18])[N:16]=2)[C:10]#[N:11])[C:4]([C:22]([F:25])([F:23])[F:24])=[N:3]1
Reactant: CC(C)(C)C(=O)Cl
Reactant: Cn1nc(C(F)(F)F)c(C(O)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(C(F)(F)F)c(C(OC(=O)C(C)(C)C)=C(C#N)c2nc(C(C)(C)C)cs2)c1Cl
Temperature: 0 °C
Yield: 26.3 %

Procedure:
0.5 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-hydroxyacrylonitrile and 0.14 g of triethylamine were added to 15 ml of THF at room temperature and stirred to give a uniform solution. 0.16 g of pivaloyl chloride was dropwise added to the solution with cooling with ice, then gradually heated, and stirred at room temperature for 8 hours. The reaction mixture was poured into ice water, extracted with ethyl acetate, and washed thrice with saturated saline. After having been dried over sodium sulfate, the resulting product was passed through a short column filled with silica gel. The solvent was distilled off under reduced pressure, and the residual product was applied to silica gel thin-layer chromatography (developer solvent: chloroform) to obtain 0.16 g of 3-(1-methyl-3-trifluoromethyl-5-chloropyrazol-4-yl)-2-(4-tert-butylthiazol-2-yl)-3-pivaloyloxyacrylonitrile (III-6) and 0.35 g of its geometric isomer (III-15).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5][C:4]=1[OH:16])#[N:2].S(C1C=CC([N+]([O-])=O)=CC=1)(O[CH2:21][C@@H:22]1[O:24][CH2:23]1)(=O)=O>>[CH2:21]([O:16][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2])[C@@H:22]1[O:24][CH2:23]1
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Reactant: CCOC(=O)CCc1ccc(C#N)c(O)c1
Product: CCOC(=O)CCc1ccc(C#N)c(OC[C@H]2CO2)c1
Yield: 85.9 %

Procedure:
Using the method of example 30(b), supra, ethyl 3-(4-cyano-3-hydroxyphenyl)propionate (1.32 g, 6 mmol) and (R)-glycidyl nosylate (1.48 g, 5.71 mmol) were used to prepare 1.35 g (86%) of the title compound as a white solid.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[C:2]#[CH:3].[Li]N([Si](C)(C)C)[Si](C)(C)C.[CH2:17]1[CH2:21][O:20][CH2:19][CH2:18]1.[Cl-].[NH4+].[CH2:24]1[CH2:28]OC[CH2:25]1>>[CH:17]1([CH:21]([OH:20])[C:3]#[C:2][C:1]([O:5][CH3:6])=[O:4])[CH2:18][CH2:19][CH2:28][CH2:24][CH2:25]1
Reactant: C#CC(=O)OC
Reactant: C1CCOC1
Agent: [Cl-]
Agent: [Li]N([Si](C)(C)C)[Si](C)(C)C
Agent: [NH4+]
Product: COC(=O)C#CC(O)C1CCCCC1
Reaction time: 1 h

Procedure:
Under nitrogen flow, a solution of methyl propiolate (compound 6) (1.68 g; 20.0 mmoles) in 4 ml of dry THF was added dropwise to a solution of 20.0 ml (20.0 mmoles) of 1M LiN(TMS)2 -THF in 40 ml of dry THF at -78° C. After completion of the addition, the reaction solution was stirred for 1 hour, and a solution of 2.24 g (20.0 mmoles) of cyclohexanecarboxyaldehyde (compound 9k) in 5 ml of dry THF was added dropwise thereto. The mixture was stirred for additional 1 hour, a saturated aqueous ammonium chloride was added to the reaction solution and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried over anhydrous magnesium sulfate and concentrated in vacuo to give a crude product of the desired alcohol 10k as an oil. This was used in the next reaction without further purification.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH2:8][CH2:9]O)[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=1)[CH3:2].S(Cl)([Cl:17])=O>ClC(Cl)Cl>[Cl:17][CH2:9][CH2:8][N:7]1[C:6]2[CH:11]=[CH:12][CH:13]=[CH:14][C:5]=2[N:4]=[C:3]1[CH2:1][CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCc1nc2ccccc2n1CCO
Solvent: ClC(Cl)Cl
Product: CCc1nc2ccccc2n1CCCl
Reaction time: 2 h

Procedure:
To a stirred and refluxing mixture of 7 parts of 2-ethyl-1H-benzimidazole-1-ethanol and 150 parts of trichloromethane are added dropwise 16 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 2 hours at reflux temperature. The reaction mixture is cooled and evaporated. Water is added to the residue and the whole is stirred with activated charcoal. The latter is filtered off and the filtrate is alkalized. The product is extracted with trichloromethane. The extract is dried, filtered and evaporated. The residue is crystallized from 2,2'-oxybispropane. The product is filtered off and dried, yielding 1-(2-chloroethyl)-2-ethyl-1H-benzimidazole.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[Cl:6][C:7]1[C:8]([C:18]([NH:20][CH2:21][CH2:22][CH:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:19])=[C:9]2[C:14](=[CH:15][CH:16]=1)[N+:13](O)=[CH:12][CH:11]=[CH:10]2>>[Cl:3][C:12]1[CH:11]=[CH:10][C:9]2[C:8]([C:18]([NH:20][CH2:21][CH2:22][CH:23]3[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:19])=[C:7]([Cl:6])[CH:16]=[CH:15][C:14]=2[N:13]=1
Reactant: O=C(NCCC1CCCCC1)c1c(Cl)ccc2c1ccc[n+]2O
Reactant: O=P(Cl)(Cl)Cl
Product: O=C(NCCC1CCCCC1)c1c(Cl)ccc2nc(Cl)ccc12
Temperature: 60 °C

Procedure:
Phosphorous oxychloride (2 mL) was added to 6-chloro-5-[[(2-cyclohexylethyl)amino]carbonyl]-1-hydroxy-quinolinium Example 94(c)) (0.089 g) and the mixture heated at 60° C. for 2 hours. The reaction mixture was concentrated under reduced pressure and added to water. The aqueous was extracted with ethyl acetate and the combined organics dried filtered and evaporated give the sub titled compound as a solid (0.079 g).
Reaction SMILES: [CH2:1]([NH2:3])[CH3:2].[CH3:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]2[CH:16]=[CH:15][N:14]=[C:13]([NH:17][C:18]#[N:19])[N:12]=2)[CH:6]=1>C(O)C>[CH2:1]([NH:3][C:18]([NH:17][C:13]1[N:12]=[C:11]([C:7]2[CH:6]=[C:5]([CH3:4])[CH:10]=[CH:9][N:8]=2)[CH:16]=[CH:15][N:14]=1)=[NH:19])[CH3:2]
Reactant: Cc1ccnc(-c2ccnc(NC#N)n2)c1
Reactant: CCN
Solvent: CCO
Product: CCNC(=N)Nc1nccc(-c2cc(C)ccn2)n1

Procedure:
To a solution of ethylamine in ethanol (20 w/w %, 5 ml) was added N-(4-(4-methylpyridin-2-yl)pyrimidin-2-yl)cyanamide (150 mg). The mixture was heated in a steel autoclave at 120° C. for 4.5 hours. After cooling, the solvent was evaporated under reduced pressure. To the residue was added 2-propanol, and the resultant precipitate was collected by filtration and dried under reduced pressure to give N-ethyl-N′-(4-(4-methylpyridin-2-yl)pyrimidin-2-yl)guanidine (50 mg).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12].C(N(CC)CC)C.[CH3:20][S:21](Cl)(=[O:23])=[O:22].O>ClCCl.CCCCCC>[CH3:20][S:21]([O:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:12])(=[O:23])=[O:22]
Reactant: O=C1NCc2c(O)ccc(I)c21
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCCCCC
Product: CS(=O)(=O)Oc1ccc(I)c2c1CNC2=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.9 %

Procedure:
4-Hydroxy-7-iodoisoindolinone (400 mg, 1.45 mmol) was dissolved in dichloromethane (10 mL), and the solution was added with triethylamine (0.808 mL, 5.80 mmol) and added with methanesulfonyl chloride (0.224 mL, 2.89 mmol) at 0° C., followed by stirring at room temperature for 2 hours. The mixture was added with methanesulfonyl chloride (0.112 mL, 1.45 mmol) at 0° C., followed by stirring at room temperature for 2 hours. The reaction mixture was added with water and hexane. The precipitated solid was collected by filtration, washed with hexane and water and then dried under reduced pressure to obtain 4-methanesulfonyloxy-7-iodoisoindolinone (353 mg, yield 69%).
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[N:8][CH:9]=[CH:10][CH:11]=1)=[O:5].[CH3:13]OC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>C1(C)C=CC=CC=1>[N:8]1[CH:9]=[CH:10][CH:11]=[C:6]([CH:4]([OH:5])[CH3:13])[N:7]=1
Reactant: CON(C)C(=O)c1cccnn1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: Cc1ccccc1
Product: CC(O)c1cccnn1
Temperature: 130 °C
Yield: 248.7 %

Procedure:
To a solution of compound 2 (68 mg, 0.149 mmol) in dry toluene (2 mL) was added Lawesson's reagent (91 mg, 0.224 mmol) under N2. The reaction mixture was heated in a CEM microwave reactor at 130° C. for 1 h. The solvent was removed under reduced pressure, and the residue was purified by preparative TLC (petroleum ether:EtOAc=3:1) to give compound 3 (46 mg, 66%) as a white solid.