Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][CH2:5][C:6]([Cl:9])([Cl:8])[Cl:7])=[O:3].[NH2:10][C:11]1[N:15]([C:16]2[CH:17]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:19]=[CH:20][CH:21]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1.CCN(C(C)C)C(C)C>C1COCC1.O>[Cl:7][C:6]([Cl:9])([Cl:8])[CH2:5][O:4][C:2](=[O:3])[NH:10][C:11]1[N:15]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22][CH2:23][CH2:24][OH:25])[CH:17]=2)[N:14]=[C:13]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:12]=1
Reactant: CC(C)(C)c1cc(N)n(-c2cccc(SCCO)c2)n1
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)c1cc(NC(=O)OCC(Cl)(Cl)Cl)n(-c2cccc(SCCO)c2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100 %

Procedure:
2,2,2-Trichloroethyl chloroformate (0.10 mL, 0.78 mmol) was added to a solution of Intermediate 35b (176 mg, 0.60 mmol) and DIPEA (0.31 mL, 1.81 mmol) in THF (10 mL) and the mixture stirred at RT for 3 h. The mixture was diluted with water (15 mL), extracted with EtOAc (3×20 mL), then the combined organic extracts dried (Na2SO4) and concentrated in vacuo. The residue was suspended in cyclohexane, and filtered to give the title compound as a yellow solid (280 mg, 100%). LCMS (Method 1): Rt 3.93 min, m/z 466, 468 [MH+]
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])=[CH:2]1.Br[CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25].CC(C)([O-])C.[K+]>CN(C)C=O>[CH2:13]([O:12][C:10]([C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[N:1]([CH2:21][CH2:22][CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:2]=1)=[O:11])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: O=C(OCc1ccccc1)c1c[nH]c2ccccc12
Reactant: CCOC(=O)CCCBr
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)CCCn1cc(C(=O)OCc2ccccc2)c2ccccc21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
A mixture of benzyl indole-3-carboxylate, ethyl 4-bromobutyrate and potassium t-butoxide in N,N-dimethylformamide was stirred at 50° C. for 4 hours. After insoluble materials were filtered off, the filtrate was diluted with ethyl acetate, and washed with diluted hydrochloric acid and water, dried over magnesium sulfate and concentrated. The concentrate was chromatographed on a silica gel column to give the object compound.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([N:7]2[CH:11]=[CH:10][C:9]([C:12]([OH:14])=O)=[N:8]2)[CH:4]=[N:3]1.[NH2:15][C@@H:16]([CH3:33])[CH2:17][N:18]1[CH:22]=[CH:21][C:20]([C:23]2[CH:30]=[C:29]([F:31])[C:26]([C:27]#[N:28])=[C:25]([Cl:32])[CH:24]=2)=[N:19]1.CN(C=O)C>C(Cl)Cl>[Cl:32][C:25]1[CH:24]=[C:23]([C:20]2[CH:21]=[CH:22][N:18]([CH2:17][C@@H:16]([NH:15][C:12]([C:9]3[CH:10]=[CH:11][N:7]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[CH:6]=4)[N:8]=3)=[O:14])[CH3:33])[N:19]=2)[CH:30]=[C:29]([F:31])[C:26]=1[C:27]#[N:28]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: Cn1cc(-n2ccc(C(=O)O)n2)cn1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1ccn(-c2cnn(C)c2)n1
Yield: 41.2 %

Procedure:
The title compound was prepared using the procedure described in Example 3(h) starting from 1′-methyl-1′H-[1,4′-bipyrazole]-3-carboxylic acid (0.861 mmol, 165 mg) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzo-nitrile (0.718 mmol, 200 mg) and using DMF (2 ml) as the solvent. DCM was added and the reaction mixture was evaporated. The residue was purified by flash chromatography. The purified product was dissolved in DCM and washed three times with 1 M NaHCO3. The combined organics were evaporated. 134 mg of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 1.15 (d, 3H), 3.88 (s, 3H), 4.28-4.42 (m, 2H), 4.42-4.52 (m, 1H), 6.75 (d, 1H), 7.01 (d, 1H), 7.81-7.88 (m, 3H), 7.94 (s, 1H), 8.13-8.17 (m, 2H), 8.18 (s, 1H).
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:23]#[N:24])=[C:6]1[S:25][CH2:26][CH3:27].[CH2:28]([NH2:30])[CH3:29].[ClH:31]>O1CCOCC1>[ClH:31].[CH2:28]([NH:30][CH2:2][CH2:3][CH2:4][N:5]1[C:9](=[O:10])[C:8]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:7]([C:23]#[N:24])=[C:6]1[S:25][CH2:26][CH3:27])[CH3:29]
Reactant: CCSC1=C(C#N)C(c2ccccc2)(c2ccccc2)C(=O)N1CCCBr
Reactant: CCN
Agent: Cl
Solvent: C1COCCO1
Product: CCNCCCN1C(=O)C(c2ccccc2)(c2ccccc2)C(C#N)=C1SCC

Procedure:
8.8 g 1-(3-bromopropyl)-2-ethylthio-5-oxo-4,4-diphenyl-2-pyrroline-3-carbonitrile and 3.0 g ethylamine are stirred for two days at room temperature in 300 ml dioxan. The solvent is removed on a Rotavapor and the residue partitioned between chloroform and dil. sodium bicarbonate solution. The organic phase is evaporated and the residue chromatographed on silica gel with toluene/ethanol 10+1 as elution agent. The base so obtained is converted in ethanolic solution into the corresponding hydrochloride by mixing with ethereal hydrochloric acid solution. One obtains 1.0 g of colorless crystals of mp 173°-174° C., decomp.
Reaction SMILES: [C:1]1([C:7]#[C:8][CH2:9][O:10][C:11]2[CH:12]=[C:13]([C:17]([OH:21])([CH3:20])[CH2:18][OH:19])[CH:14]=[N:15][CH:16]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:22][C:23]([CH3:25])=O>>[CH3:22][C:23]1([CH3:25])[O:21][C:17]([CH3:20])([C:13]2[CH:14]=[N:15][CH:16]=[C:11]([O:10][CH2:9][C:8]#[C:7][C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:12]=2)[CH2:18][O:19]1
Reactant: CC(C)=O
Reactant: CC(O)(CO)c1cncc(OCC#Cc2ccccc2)c1
Product: CC1(C)OCC(C)(c2cncc(OCC#Cc3ccccc3)c2)O1
Yield: 76 %

Procedure:
Using the procedure described in Example 1, 2-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]propane-1,2-diol was reacted with acetone to give 2,2,4-trimethyl-4-[5-(3-phenylprop-2-ynyloxy)pyrid-3-yl]-1,3-dioxolane in 76% yield, as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)=[CH:4][C:3]=1[C:22]([F:25])([F:24])[F:23].FC(F)(F)C(O)=O.[OH-].[Na+]>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:21])[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]2)=[CH:4][C:3]=1[C:22]([F:25])([F:23])[F:24]
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2ccc(F)c(C(F)(F)F)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: OC1(c2ccc(F)c(C(F)(F)F)c2)CCNCC1
Temperature: 25 °C
Reaction time: 20 h
Yield: 41.6 %

Procedure:
To a solution of tert-butyl 4-[4-fluoro-3-(trifluoro-methyl)phenyl]-4-hydroxypiperidine-1-carboxylate (4.25 g, 11.7 mmol) in methylen chloride (30 ml) was added trifluoroacetic acid (4 ml) and the solution was stirred at ambient temperature for 20 h. 1 M aqueous sodium hydroxide (50 ml) was added and the aqueous phase was extracted with methylen chloride (3×50 ml). The combined organic phases was dried (MgSO4), filtered and evaporated to dryness. The residue was purified by flash column chromatography (ethylacetate/methanol, 1:1) to give the title compound (1.28 g). MS m/z (rel. intensity, 70 eV) 263 (M+, 9), 245 (59), 244 (29), 163 (20), 56 (bp).
Reaction SMILES: Br[C:2]1[O:3][C:4]2[C:16]([CH2:17][CH2:18][OH:19])=[CH:15][CH:14]=[CH:13][C:5]=2[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C(O)=O)CC=CCC1.C(Cl)(Cl)Cl.[N+:33]([O-:38])([N+]([O-])=O)=[O:34]>O>[OH:19][CH2:18][CH2:17][C:16]1[C:4]2[O:3][C:2]([N+:33]([O-:38])=[O:34])=[C:6]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)[C:5]=2[CH:13]=[CH:14][CH:15]=1
Reactant: O=[N+]([O-])[N+](=O)[O-]
Reactant: OCCc1cccc2c(-c3ccccc3)c(Br)oc12
Agent: O=C(O)C1CC=CCC1
Solvent: O
Solvent: ClC(Cl)Cl
Product: O=[N+]([O-])c1oc2c(CCO)cccc2c1-c1ccccc1
Temperature: 45 °C
Reaction time: 16 h

Procedure:
To a stirred mixture of 28.6 g. (0.0904 mole) of 2-bromo-7-(2-hydroxyethyl)-3-phenylbenzofuran (the product of step A, Example 5) and 15.1 g. of 4-cyclohexenecarboxylic acid in 250 ml. of chloroform is added dropwise 10.8 g. (0.118 mole) of dinitrogen tetraoxide in 30 ml. of chloroform. After 16 hours, 7 g. of dinitrogen tetraoxide and 5 g. of 4-cyclohexenecarboxylic acid in 30 ml. of chloroform are added, and the mixture is heated at 45° C. for four hours. Water is added to the mixture, the chloroform layer is separated and washed with water, then thrice with sodium bicarbonate solution, thrice with water, once with saturated sodium chloride solution and dried. Evaporation provides a yellow residue. Thin layer chromatographic analysis shows two main products. This residue is recrystallized from 50/50 ethanol/water, then again from carbon tetrachloride to yield 7-(2-hydroxyethyl)-2-nitro-3-phenylbenzofuran as a yellow solid, m.p. 133.5°-136° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[OH:12])([CH3:3])[CH3:2].[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH:1]([C:4]1[CH:9]=[C:8]([O:10][CH3:11])[CH:7]=[CH:6][C:5]=1[O:12][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])([CH3:3])[CH3:2]
Reactant: COc1ccc(O)c(C(C)C)c1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc(OS(=O)(=O)c2ccc(C)cc2)c(C(C)C)c1
Temperature: 10 °C
Reaction time: 3 h
Yield: 95.6 %

Procedure:
To a solution of 180 g of 2-Isopropyl-4-methoxy-phenol (1.084 moles) in 2.5 L toluene was added 206.7 g p-toluene sulfonylchloride (1.084 moles), and the reaction mixture was stirred vigorously The resultant mixture was cooled to 10° C., and triethylamine (3 mol) was gradually added, keeping the temperature below 50 degrees C. The reaction mixture was aged for 3 hours at approximately 50° C. and then allowed to cool to RT. An HPLC sample obtained at this point showed completion of the reaction. The resultant suspension was filtered and the filter-cake was washed with 300 mL toluene. The collected filtrate was distilled under vacuum until the pot-temperature reached 65° C., and 1 L of methanol was added to the mixture. The methanolic solution was stirred for 30 minutes at reflux; then the mixture was permitted to cool overnight. The white crystalline solid which separated was collected by filtration and dried at 50° C. under vacuum to yield a total of 332 grams of toluene-4-sulfonic acid 2-isopropyl-4-methoxy-phenyl ester, representing an yield of 95.7%:m.p. 85.1 degrees C.
Reaction SMILES: [O:1]1[CH2:13][CH:2]1[CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12].[F:14][C:15]1[CH:32]=[CH:31][C:18]([C:19]([NH:21][C:22]([NH:24][CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)=[O:23])=[O:20])=[CH:17][CH:16]=1>C(O)(C)C>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:19]([NH:21][C:22](=[O:23])[NH:24][CH:25]2[CH2:26][CH2:27][N:28]([CH2:13][CH:2]([OH:1])[CH2:3][O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[O:11][CH3:12])[CH2:29][CH2:30]2)=[O:20])=[CH:31][CH:32]=1
Reactant: COc1ccccc1OCC1CO1
Reactant: O=C(NC(=O)c1ccc(F)cc1)NC1CCNCC1
Solvent: CC(C)O
Product: COc1ccccc1OCC(O)CN1CCC(NC(=O)NC(=O)c2ccc(F)cc2)CC1

Procedure:
2-(2,3-Epoxypropoxy)anisole (0.99 g, 0.0055 m) and 1-(4-fluorobenzoyl)-3-(piperid-4-yl)urea (1.32 g, 0.005 m) in isopropyl alcohol (50 cm3) were refluxed for 24 hours. The solution was cooled and the product which crystallised was filtered off. This was dissolved in ethanol and acidified with ethanolic hydrogen chloride. The solution was heated on a water bath and ethyl acetate was added to replace the lost solvent. The product crystallised out and was recrystallised twice from ethanol giving the title compound as the hydrochloride, hemihydrate (0.44 g) m.p. 194°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([N:15]=[C:16]=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:9])[CH3:8])=[O:5].[NH2:18]/[C:19](/[CH3:26])=[CH:20]\[C:21]([O:23][CH2:24][CH3:25])=[O:22]>>[Cl:1][C:2]1[CH:13]=[C:12]([F:14])[C:11]([NH:15][C:16]([NH:18][C:19]([CH3:26])=[CH:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[O:17])=[CH:10][C:3]=1[C:4]([O:6][CH:7]([CH3:8])[CH3:9])=[O:5]
Reactant: CC(C)OC(=O)c1cc(N=C=O)c(F)cc1Cl
Reactant: CCOC(=O)/C=C(/C)N
Product: CCOC(=O)C=C(C)NC(=O)Nc1cc(C(=O)OC(C)C)c(Cl)cc1F

Procedure:
using isopropyl 2-chloro-4-fluoro-5-isocyanatobenzoate and ethyl 3-aminocrotonate there is obtained isopropyl 2-chloro-4-fluoro-5-{3-[2-(ethoxycarbonyl)-1-methylvinyl]ureido}benzoate, m.p. 147°-150° C.,
Reaction SMILES: O.[OH-].[Li+].C([O:6][C:7]([C:9]1([CH2:22][OH:23])[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]1)=[O:8])C>CO.O>[C:18]([O:17][C:15]([N:12]1[CH2:13][CH2:14][C:9]([CH2:22][OH:23])([C:7]([OH:8])=[O:6])[CH2:10][CH2:11]1)=[O:16])([CH3:21])([CH3:20])[CH3:19]
Reactant: CCOC(=O)C1(CO)CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(CO)(C(=O)O)CC1
Temperature: 0 °C
Yield: 100.1 %

Procedure:
Lithium hydroxide monohydrate (6.95 g, 165.6 mmol) was added to solution of N-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid ethyl ester (9.52 g, 33.1 mmol) in 2:1 methanol/water (100 mL). The mixture was heated to reflux for 30 minutes, the methanol removed in vacuo by concentration using a bath temperature no higher than 45° C. The aqueous layer was cooled to 0° C., acidified to pH 3.0 using 6M aqueous hydrochloric acid, and extracted with ethyl acetate (4×75 mL). The combined organic layers were dried over magnesium sultate, and concentrated in vacuo, and recrystallized from dichloromethane/hexanes to afford N-(tert-butoxycarbonyl)-4-(hydroxymethyl)piperidine-4-carboxylic acid (8.59 g, 100%).
Reaction SMILES: [OH:1][C:2]([CH3:35])([CH3:34])[CH2:3][C@@:4]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[O:9][C:8](=[O:10])[N:7]([C@H:11]([C:13]2[CH:18]=[CH:17][C:16](B3OC(C)(C)C(C)(C)O3)=[CH:15][CH:14]=2)[CH3:12])[CH2:6][CH2:5]1.Cl[C:37]1[CH:42]=[C:41]([Cl:43])[N:40]=[N:39][C:38]=1[CH3:44]>>[Cl:43][C:41]1[N:40]=[N:39][C:38]([CH3:44])=[C:37]([C:16]2[CH:15]=[CH:14][C:13]([C@@H:11]([N:7]3[CH2:6][CH2:5][C@:4]([CH2:3][C:2]([OH:1])([CH3:35])[CH3:34])([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[O:9][C:8]3=[O:10])[CH3:12])=[CH:18][CH:17]=2)[CH:42]=1
Reactant: Cc1nnc(Cl)cc1Cl
Reactant: C[C@@H](c1ccc(B2OC(C)(C)C(C)(C)O2)cc1)N1CC[C@](CC(C)(C)O)(c2ccccc2)OC1=O
Product: Cc1nnc(Cl)cc1-c1ccc([C@H](C)N2CC[C@](CC(C)(C)O)(c3ccccc3)OC2=O)cc1

Procedure:
The isomeric title compounds were prepared by reaction of (S)-6-(2-hydroxy-2-methylpropyl)-6-phenyl-3-((S)-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborol-an-2-yl)phenyl)ethyl)-1,3-oxazinan-2-one and 4,6-dichloro-3-methylpyridazine following a procedure analogous to that described in Example 14.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([NH2:7])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:3]=1.Br[C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH2:20])=[O:19].C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>CN(C=O)C.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][C:2]1[CH:6]=[C:5]([NH:7][C:16]2[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=2[C:18]([NH2:20])=[O:19])[N:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[CH3:14])[N:3]=1
Reactant: Cc1cc(N)n(-c2ccccc2C)n1
Reactant: NC(=O)c1ccccc1Br
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: Cc1cc(Nc2ccccc2C(N)=O)n(-c2ccccc2C)n1
Temperature: 150 °C
Yield: 21.6 %

Procedure:
A mixture of 3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-amine (Intermediate F, 1.00 g, 5.3 mmol), 2-bromobenzamide (1.07 g, 5.3 mmol), potassium carbonate (0.89 g, 6.4 mmol), and copper (II) acetate (39 mg, 0.2 mmol) in DMF (20 mL) was heated (150° C.) in a sealed tube for 18 h. After cooling, the solution was adjusted to pH=4 using glacial acetic acid. The reaction mixture was extracted with dichloromethane (3×20 mL), and then the combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 33-50% ethyl acetate/hexane afforded a yellow solid that was washed with diethyl ether to give 2-{[3-methyl-1-(2-methylphenyl)-1H-pyrazol-5-yl]amino}benzamide (350 mg, 21%) as a white solid. 1H NMR (300 MHz, DMSO-d6) δ 10.48 (s, 1H), 8.01 (s, 1H), 7.67 (dd, 1H), 7.32 (m, 7H), 6.77 (ddd, 1H), 6.08 (s, 1H), 2.19 (s, 3H), 2.00 (s, 3H); ES-MS m/z 307.1 (MH+); HPLC RT (min) 2.41.
Reaction SMILES: [CH3:1]C1C=CC(C(NC2C(C)=CC=CC=2C)=N)=CC=1.[CH2:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]([NH:37][P:38]([C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:20][CH3:21].C([Li])CCC.CI>>[CH2:19]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[N:28]=[C:29]([N:37]([P:38]([C:39]1[CH:40]=[CH:41][CH:42]=[CH:43][CH:44]=1)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1)[CH3:1])[C:30]1[CH:35]=[CH:34][C:33]([CH3:36])=[CH:32][CH:31]=1)[CH2:20][CH3:21]
Reactant: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Reactant: CCCc1ccccc1N=C(NP(c1ccccc1)c1ccccc1)c1ccc(C)cc1
Agent: [Li]CCCC
Solvent: CI
Product: CCCc1ccccc1N=C(c1ccc(C)cc1)N(C)P(c1ccccc1)c1ccccc1

Procedure:
Procedure as described for NSP Amidine III using the following amounts: 1.42 g of N′-(2-n-propylphenyl)-N-(diphenylphosphino)-4-methylbenzamidine (3.0 mmol), 1.50 mL of 2.0 M butyllithium (15.0 mmol), 1.50 mL of 2.0 M methyliodide (3.0 mmol). Following removal of lithium iodide via filtration and removal of solvent in vacuo, a yellow sticky residue was recovered (1.63 g, 67%).
Reaction SMILES: [Li+].CC([N-]C(C)C)C.C(NC(C)C)(C)C.[Li]CCCC.[Br:21][C:22]1[CH:31]=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1.[CH2:32]=[O:33]>C1COCC1>[Br:21][C:22]1[C:31]([CH2:32][OH:33])=[CH:30][C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[N:23]=1
Reactant: C=O
Reactant: Brc1ccc2ccccc2n1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: OCc1cc2ccccc2nc1Br
Reaction time: 1 h

Procedure:
To a solution of LDA, freshly prepared from diisopropylamine (0.42 mL, 2.97 mmol) and n-BuLi (2.97 mmol), in THF (10 mL) at -78° C. was added 2-bromoquinoline (T. Young and E. Amstutz, J. Am. Chem. Soc. 73, 4773 (1951)) (570 rag, 2.7 mmol) and stirring was continued for 1 h. This mixture was cannulated into a solution of formaldehyde in THF at -78° C., which was prepared by cracking paraformaldehyde (1.24 g, 14.8 mmol) under 140°-180° C. and releasing the gas into THF (25 mL) at -23 ° C. Stirring was continued for 6.5 h at -78° C. The reaction was quenched with water (5 mL) and extracted with EtOAc (3×25 mL). After drying (MgSO4), concentration gave a light yellow solid (660 mg) which was purified by recrystallization and chromatography (silica gel, 15% EtOAc/hexanes) to give 373 mg (58%) of the product as a white solid: mp 173°-4° C. 1H NMR (300 MHz, CDCl3) δ8.24 (s, 1H), 8.05 (d, 1 H, J=8 Hz), 7.84 (d, 1 H, J=8 Hz), 7.75 (m, 1 H), 7.59 (m, 1 H). 4.90 (d, 2 H, J=6 Hz), 2.36 (rt, 1 H, J=6 Hz). Analysis calculated for C10H8BrNO was as follows: C, 50.45; H, 3.39; N, 5.88. Found: C, 50.72; H, 3.35; N, 5.94 .
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4](=[O:25])[CH2:5][S:6][C:7]=1[CH:8]1[CH:13]=[CH:12][N:11](C(OCC(Cl)(Cl)Cl)=O)[CH:10]=[C:9]1[C:22](=[O:24])[CH3:23].[S]>>[CH3:1][C:2]1[NH:3][C:4](=[O:25])[CH2:5][S:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][C:9]=1[C:22](=[O:24])[CH3:23]
Reactant: CC(=O)C1=CN(C(=O)OCC(Cl)(Cl)Cl)C=CC1C1=C(C)NC(=O)CS1
Agent: [S]
Product: CC(=O)c1cnccc1C1=C(C)NC(=O)CS1
Yield: 7.7 %

Procedure:
A mixture of 5-methyl-6-[1-(2,2,2-trichloroethoxycarbonyl)-3-acetyl-1,4-dihydro-4-pyridinyl]-2H-1,4-thiazin-3(4H)-one (1.77 g) and sulfur sublimed (0.8 g) was treated in the same manner as described in Example 3 (ii) to give the titled compound (0.08 g, yield 7.8%) as pale yellow crystals. Ethyl acetate was used as a developing eluant.
Reaction SMILES: O=C(Cl)[O:3][C:4](Cl)(Cl)[Cl:5].[CH2:9]([O:16][NH:17][C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[N:35]=[CH:34][O:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)Cl>[CH2:9]([O:16][N:17]([C:4]([Cl:5])=[O:3])[C@H:18]1[CH2:23][N:22]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[C@H:21]([C:31]2[N:35]=[CH:34][O:33][N:32]=2)[CH2:20][CH2:19]1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1C[C@H](NOCc2ccccc2)CC[C@H]1c1ncon1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@H](N(OCc2ccccc2)C(=O)Cl)CC[C@H]1c1ncon1
Reaction time: 3 h
Yield: 183.1 %

Procedure:
TEA (405 mg, 4.0 mmol) and diphosgene (514 mg, 2.6 mmol) were added to a solution of (2S,5R)-tert-butyl 5-(benzyloxyamino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (750 mg, 2.0 mmol) in DCM (70 mL). The mixture was stiffed at 0° C. for 3 hrs. Then, the reaction mixture was washed with saturated sodium chloride (2×), dried over Na2SO4, and concentrated to give (2S,5R)-tert-butyl 5-(benzyloxy(chlorocarbonyl)amino)-2-(1,2,4-oxadiazol-3-yl)piperidine-1-carboxylate (1.6 g), which was used directly in the next step. ESI-MS (EI+, m/z): 437[M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[CH:4]([CH:7]=[O:8])[CH2:5][CH3:6].[Cl:10][CH2:11][CH2:12]O>C1C=CC=CC=1.S(=O)(=O)(O)[O-].[Na+]>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH2:5][CH3:6])=[CH:7][O:8][CH2:12][CH2:11][Cl:10]
Reactant: OCCCl
Reactant: CCC(C=O)C(=O)OC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: CCC(=COCCCl)C(=O)OC
Yield: 82.3 %

Procedure:
35 g 2-Formyl-butyric acid methyl ester (0.27 mole) was dissolved in 250 ml benzene, and the solution was mixed with 26 g 2-chloroethanol (0.324 mole) and 700 mg sodium bisulfate. The mixture was refluxed for 18 hours, and the water formed during the reaction was withdrawn continuously. After removal of the solvent by distillation, the residue was fractionated in a vacuum and 42.8 g (44.2 g) 3-(2-chloroethoxy)-2-ethylacrylic acid methyl ester boiling at 99°-101° C./3 torr was obtained (82.4%-85% yield). nD23 =1.4770.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[SH:10].Br[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[S:10][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: N#Cc1ccc(N)c(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)c(SCc2ccccc2)c1
Yield: 79 %

Procedure:
Following General Procedure A, the title compound (615 mg, 79%) was prepared from 4-amino-3-mercaptobenzonitrile (486 mg, 3.24 mmol), (bromomethyl)benzene (0.38 ml, 3.24 mmol) and K2CO3 (2.2 g, 16.20 mmol) in DMF (10 ml).
Reaction SMILES: [F:1][CH:2]([F:24])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH:11]=O)=[N:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4]1.[CH3:25][NH:26][CH3:27]>>[F:24][CH:2]([F:1])[N:3]1[C:7]([C:8]2[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=2)[CH2:11][N:26]([CH3:27])[CH3:25])=[N:6][C:5]([C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=2)=[N:4]1
Reactant: CNC
Reactant: COc1ccc(-c2nc(-c3cccc(C=O)c3)n(C(F)F)n2)cc1
Product: COc1ccc(-c2nc(-c3cccc(CN(C)C)c3)n(C(F)F)n2)cc1

Procedure:
Using 3-[2-difluoromethyl-5-(4-methoxy-phenyl)-2H-[1,2,4]triazol-3-yl]-benzaldehyde and dimethylamine the title compound was prepared as a white amorphous solid (83.4% yield), MS: m/e=359.168 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[NH:13][C@@H:12]([CH2:14][CH:15]([CH3:17])[CH3:16])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1.[CH2:19](Br)[CH:20]([CH3:22])[CH3:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]=[C:9]2[N:13]([CH2:19][CH:20]([CH3:22])[CH3:21])[C@@H:12]([CH2:14][CH:15]([CH3:16])[CH3:17])[CH2:11][S:10]2)=[C:4]([CH3:18])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1N=C1N[C@@H](CC(C)C)CS1
Reactant: CC(C)CBr
Product: Cc1cc(Cl)ccc1N=C1SC[C@H](CC(C)C)N1CC(C)C

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (1S)-1-(chloromethyl)-3-methylbutanammonium chloride as described in Method B7a. 4-Chloro-2-methylphenyl isothiocyanate was reacted with (1S)-1-(chloromethyl)-3-methylbutanammonium chloride according to Method C1a to give (4S)-2-(4-Chloro-2-methylphenylimino)-4-isobutyl-1,3-thiazolidine. The thiazolidine was reacted with isobutyl bromide according to Method D2a to give (4S)-2-(4-chloro-2-methylphenylimino)-3,4-diisobutyl-1,3-thiazolidine.