Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:12]3[N:13]=[CH:14][C:15]([C:16]([NH2:18])=[O:17])=[C:11]3[NH:10][CH2:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:21](N1C=CN=C1)(N1C=CN=C1)=[S:22]>O1CCCC1>[C:1]1([C:7]2[N:12]3[C:11]4[N:10]([C:21](=[S:22])[NH:18][C:16](=[O:17])[C:15]=4[CH:14]=[N:13]3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: NC(=O)c1cnn2c1NCC=C2c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=c1[nH]c(=S)n2c3c1cnn3C(c1ccccc1)=CC2
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 41.7 %

Procedure:
A mixture of 7.6 g of 4,5-dihydro-7-phenyl-pyrazolo(1,5-a)pyrimidine-3-carboxamide (prepared as described in Example 25 of commonly assigned U.S. Pat. No. 4,847,256) in 304 ml of dry tetrahydrofuran is stirred and cooled at -78° C., under nitrogen and 2.17 g of sodium hydride (60 percent dispersion in mineral oil) is added. The mixture is stirred at -78° C. for 30 minutes, then 4.84 g of 1,1'-thiocarbonyldiimidazole is added in one portion and the temperature is kept at -78° C. for 2 hours and then is allowed to rise slowly to room temperature. Stirring is continued for 48 hours, and then the reaction mixture is quenched with 500 ml of water and neutralized with 5 percent aqueous hydrochloric acid. A crystalline solid forms which is collected by filtration, triturated with ether, filtered and dried to give 3.2 g of the desired product as white crystals, mp 289-291° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:8](O)=[O:9]>>[C:2]1([NH:1][CH:8]=[O:9])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ccccc1
Reactant: O=CO
Product: O=CNc1ccccc1

Procedure:
Was prepared according to Example 2 from aniline and formic acid.
Reaction SMILES: [C:1]1([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:8]2[CH:9]=[CH:10][C:11](=O)[NH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C=CC(OP(Cl)([Cl:30])=O)=CC=1.[OH-].[NH4+]>>[Cl:30][C:11]1[CH:10]=[CH:9][C:8]([CH:7]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:13][N:12]=1
Reactant: O=c1ccc(C(c2ccccc2)c2ccccc2)c[nH]1
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Agent: [NH4+]
Agent: [OH-]
Product: Clc1ccc(C(c2ccccc2)c2ccccc2)cn1

Procedure:
Heat 55 g. of the crude 5-(diphenylmethyl)-2-pyridone and 110 ml. of phenylphosphoric dichloride at 200°-210° with stirring for 6 hours. Pour the cooled reaction mixture onto ice, basify with ammonium hydroxide, extract with ethyl ether, dry the ether extracts, and concentrate to a residue. Distill the residue at 160°-175°/0.15 mm. and crystallize the distillate from hexane to obtain 2-chloro-5-(diphenylmethyl)-pyridine, m.p. 69.5°-71°.
Reaction SMILES: [N+:1]([C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[O:13][CH2:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:37])[N:26]([C:30]3[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=3)[CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:17][CH:16]=1)([O-])=O.CCO.[NH4+].[Cl-]>[Fe].ClCCCl>[NH2:1][C:4]1[N:9]=[CH:8][C:7]2[CH:10]=[CH:11][O:12][C:6]=2[C:5]=1[O:13][CH2:14][C:15]1[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]2[C:25](=[O:37])[N:26]([C:30]3[CH:31]=[CH:32][C:33]([F:36])=[CH:34][CH:35]=3)[CH:27]=[CH:28][CH:29]=2)=[O:23])=[CH:19][CH:20]=1
Reactant: O=C(Nc1ccc(COc2c([N+](=O)[O-])ncc3ccoc23)cc1)c1cccn(-c2ccc(F)cc2)c1=O
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: ClCCCl
Product: Nc1ncc2ccoc2c1OCc1ccc(NC(=O)c2cccn(-c3ccc(F)cc3)c2=O)cc1
Temperature: 75 °C

Procedure:
The mixture of 1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxylic acid [4-(6-nitrofuro[3,2-c]pyridin-7-yloxymethyl)phenyl]amide (13.8 mg, 0.0248 mmol), iron powder (62 mg, 1.1 mmol), EtOH (1.5 ml), 1,2-Dichloroethane (1.5 ml), and saturated NH4Cl (0.3 ml) was heated at 75° C. for 30 min. After that time, the solvent was removed, and it was then dissolved in DMSO for Gilson HPLC purification. It gave the title compound as a light-yellow solid. 1H NMR (400 MHz, CDCl3): δ=4.55 (brs, 2H), 5.35 (s, 2H), 6.60 (dd, J=6.8 & 7.2 Hz, 1H), 6.68 (d, J=2.4 Hz, 1H), 7.24-7.29 (m, 2H), 7.38-7.43 (m, 4H), 7.43 (d, J=2.4 Hz, 1H), 7.60 (dd, J=2.0 & 6.8 Hz, 1H), 7.73 (dd, J=2.0 & 6.4 Hz, 2H), 8.07 (s, 1H), 8.75 (dd, J=2.0 & 6.8 Hz, 1H), 11.85 (brs, 1H). MS (ES+): m/z 471.05 [MH+]. HPLC: tR=2.60 min (polar—5 min, ZQ3).
Reaction SMILES: [Na].[N:2](OCCC(C)C)=[O:3].O.[CH3:11][C@:12]12[C:20](=[O:21])[CH2:19][C@H:15]([C:16]1([CH3:18])[CH3:17])[CH2:14][CH2:13]2>C(OCC)C>[OH:3][N:2]=[C:19]1[CH:15]2[C:16]([CH3:17])([CH3:18])[C:12]([CH3:11])([CH2:13][CH2:14]2)[C:20]1=[O:21]
Reactant: CC1(C)[C@@H]2CC[C@@]1(C)C(=O)C2
Reactant: CC(C)CCON=O
Agent: [Na]
Solvent: O
Solvent: CCOCC
Product: CC12CCC(C(=NO)C1=O)C2(C)C

Procedure:
In 600 ml of dried diethyl ether was dissolved 130 g (0.854 mol) of commercially available D-camphor, and 20.4 g of metallic sodium was added thereto. The solution was kept at 0° C. with stirring, and 123 ml (0.916 mol) of isoamyl nitrite was added thereto to conduct a reaction for 14 hours. After completion of the reaction, 200 ml of water was added to the reaction mixture, and the aqueous layer was separated. To the aqueous layer was added 400 ml of 10% hydrochloric acid, and the solid thus formed was extracted with diethyl ether. The ether layer was dried and concentrated to obtain 51 g of 3-hydroxyiminocamphor.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[OH:14])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.Br[C:16]([CH3:25])([CH3:24])[C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5](/[C:7](=[N:13]/[O:14][C:16]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])([CH3:25])[CH3:24])/[C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1
Reactant: CCOC(=O)/C(=N\O)c1csc(N)n1
Reactant: CC(C)(C)OC(=O)C(C)(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)/C(=N\OC(C)(C)C(=O)OC(C)(C)C)c1csc(N)n1
Temperature: 42.5 °C

Procedure:
Ethyl (Z)-2-(2-aminothiazol-4-yl)-2-hydroxyiminoacetate (32.25 g) of Formula (I) is dissolved in N,N-dimethylformamide (258 ml) at room temperature. Tert.-butyl 2-bromoisobutyrate (38.47 g) and anhydrous potassium carbonate (47.61 g) are added and the resulting suspension is heated to 40-45° C. for 20-25 hrs. The reaction mass is cooled to 30-32° C. and it is added slowly to water. The resulting slurry is stirred at 25-30° C. for about one and a half hours. The product is filtered, washed with water and dried under reduced pressure. Yield: 50 g (93.37%), water content <1.0% w/w; Chromatographic purity (HPLC) >98%.
Reaction SMILES: [F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][N:22](S(C3C=CC(C)=CC=3)(=O)=O)[C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1.[OH-].[Na+].O>C(O)C>[F:1][C:2]1[CH:38]=[C:37]([F:39])[CH:36]=[CH:35][C:3]=1[O:4][C:5]1[C:13]2[N:12]=[N:11][NH:10][C:9]=2[CH:8]=[CH:7][C:6]=1[C:14]1[C:15]2[CH:24]=[CH:23][NH:22][C:16]=2[C:17](=[O:21])[N:18]([CH3:20])[CH:19]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4ccc5[nH]nnc5c4Oc4ccc(F)cc4F)cn(C)c(=O)c32)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cn1cc(-c2ccc3[nH]nnc3c2Oc2ccc(F)cc2F)c2cc[nH]c2c1=O
Temperature: 20 °C
Reaction time: 15 h
Yield: 57 %

Procedure:
A solution of 4-[4-(2,4-difluorophenoxy)-1H-1,2,3-benzotriazol-5-yl]-6-methyl-1-[(4-methylphenyl)sulfonyl]-1,6-dihydro-7H-pyrrolo[2,3-c]pyridin-7-one (32 mg, 0.058 mmol) in ethanol (3.4 mL) was treated with 3.0 M sodium hydroxide in water (195 μL, 0.584 mmol) and stirred at 20° C. for 15 h. The reaction mixture was purified via preparative LCMS (XBridge C18 column, eluting with a gradient of acetonitrile/water 0.1% ammonium hydroxide, at flow rate of 60 mL/min) to give the desired product (13 mg, 56%). 1H NMR (400 MHz, DMSO-d6) δ 12.05 (s, 1H), 7.77 (br s, 1H), 7.53 (d, J=8.5 Hz, 1H), 7.37-7.19 (m, 3H), 6.77 (br s, 2H), 6.23-6.07 (m, 1H), 3.50 (s, 3H); LCMS calculated for C20H14F2N5O2 (M+H)+: m/z=394.1. found: 394.0.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[O:5][N:4]=1.C1C(=O)[N:30](OC(ON2C(=O)CCC2=O)=O)[C:28](=[O:29])C1.N>CC#N>[NH2:30][C:28]([NH:1][CH2:2][C:3]1[N:7]=[C:6]([C@H:8]([CH2:17][CH2:18][CH2:19][CH:20]2[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:16])[CH3:14])=[O:11])[O:5][N:4]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CN)no1
Reactant: O=C(ON1C(=O)CCC1=O)ON1C(=O)CCC1=O
Agent: N
Solvent: CC#N
Product: CC(C)(C)OC(=O)C[C@@H](CCCC1CCCCC1)c1nc(CNC(N)=O)no1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 72.9 %

Procedure:
A solution of tert-butyl (3R)-3-[3-(aminomethyl)-1,2,4-oxadiazol-5-yl]-6-cyclohexylhexanoate (preparation 18) (310 mg, 0.88 mmol) in MeCN (10 ml) was treated with N,N-disuccinimidyl carbonate (271 mg, 1.06 mmol) and stirred at room temperature, under a nitrogen atmosphere for 4.5 hours. NH3 (0.5M in dioxan) was added forming a white precipitate. The reaction mixture was stirred at room temperature for 18 hours. The reaction mixture was filtered and the solvent removed under reduced pressure. The residue was purified on a silica column eluting with a solvent gradient of DCM:MeOH (100:0) gradually changing to (95:5) to afford the title compound as a colourless oil (253 mg, 73%).
Reaction SMILES: [C:1]([O:7]CC)(=O)[CH2:2][C:3]([CH3:5])=O.N.C(OC(C1[CH:21]([C:22]2C=CC=C[N+:23]=2[O-:28])C(C(OCC)=O)=C(C)NC=1C)=O)C>C(O)C>[N+:23]1([O-:28])[C:2]([CH:1]=[O:7])=[CH:3][CH:5]=[CH:21][CH:22]=1
Reactant: CCOC(=O)C1=C(C)NC(C)=C(C(=O)OCC)C1c1cccc[n+]1[O-]
Reactant: CCOC(=O)CC(C)=O
Agent: N
Solvent: CCO
Product: O=Cc1cccc[n+]1[O-]

Procedure:
Analogously to the process described in Example 1 there is obtained from 22.5 g of pyridine-2-carboxaldehyde-1-oxide, 37 ml of ethyl acetoacetate and 14.5 ml of 30% aqueous ammonia in 29 ml of absolute ethanol, 2,6-dimethyl-4-(1-oxido-2-pyridyl)-1,4-dihydropyridine-3,5-dicarboxylic acid dietyl ester which, after recrystallisation from 250 ml of acetonitrile, melts at 198°-200°.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:22]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:20]=[CH:19][C:16]=1[C:17]#[N:18])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.[CH2:36]([Mg]Br)[CH3:37].[BH4-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1(C)C=CC=CC=1.CCOCC>[NH2:18][CH:17]([C:16]1[CH:19]=[CH:20][C:21]([C:23]([F:26])([F:25])[F:24])=[CH:22][C:15]=1[CH2:14][N:7]([CH2:6][C:5]1[CH:4]=[C:3]([C:2]([F:1])([F:34])[F:35])[CH:29]=[C:28]([C:30]([F:31])([F:32])[F:33])[CH:27]=1)[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1)[CH2:36][CH3:37]
Reactant: CC[Mg]Br
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C#N)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CCC(N)c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1nnn(C)n1
Reaction time: 2.5 h
Yield: 87 %

Procedure:
To a solution of 2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-benzonitrile (Preparation 7) (300.0 mg, 0.590 mmoles) in toluene (1.2 mL) was added ethyl magnesium bromide (0.59 mL, 1.77 mmoles of a 3M solution in ether) dropwise at room temperature and the reaction mixture was stirred for 2.5 hours. The reaction was quenched by adding methanol (0.98 mL) dropwise with stirring until methanol and toluene were thoroughly mixed. To this mixture sodium borohydride (22.3 mg, 0.590 mmoles) was added in one portion and the reaction stirred for 1.5 hours. A 10% aqueous citric acid (1.5 mL) solution was added drop wise at room temperature until bubbling stopped. The reaction mixture was made basic to pH 10 with 1 N NaOH solution. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified using cation exchange resin (Waters Oasis MCX 6CC 500 mg LP Extraction Cartridge, Waters, Milford, Mass., USA) to yield the title compound (278.4 mg, 87% yield) as yellow gum. MS (ES+) Calc: 608.5, Found: 609.1 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=2)[O:16][CH2:17][C:18]([O:20]C)=[O:19])=[CH:11][C:10]([C:25]([F:28])([F:27])[F:26])=[N:9]1.O.[OH-].[Li+]>CO>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:14]=[C:15]([CH:22]=[CH:23][CH:24]=2)[O:16][CH2:17][C:18]([OH:20])=[O:19])=[CH:11][C:10]([C:25]([F:28])([F:26])[F:27])=[N:9]1
Reactant: COC(=O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)COc1cccc(-c2cc(C(F)(F)F)nn2-c2ccccc2Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 51.2 %

Procedure:
To a solution of methyl 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetate (140 mg, 0.34 mmol) in MeOH (5 mL), was added lithium hydroxide monohydrate (60 mg, 1.42 mmol). The resulting mixture was stirred at ambient temperature for 18 hours. The reaction mixture was then concentrated under reduced pressure and the residue was taken up in CH2Cl2 and H2O. The aqueous was made acidic by the addition of 1 N HCl. The layers were separated and the acidic aqueous was further extracted with CH2Cl2 (3×). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. This white solid was taken up in warm CH2Cl2 and hexane and the resulting solution was cooled in an ice bath. Filtration, washing with hexane and drying of the precipitated solids afforded 2-(3-(1-(2-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-5-yl)phenoxy)acetic acid (69 mg, 51% yield) as a white solid. MS(ES): 397 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[CH:10]1[N:14]2[CH:15]=[N:16][CH:17]=[C:13]2[CH2:12][CH2:11]1)[C:5]#[N:6].[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>CN(C=O)C>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([CH:10]2[N:14]3[CH:15]=[N:16][CH:17]=[C:13]3[CH2:12][CH2:11]2)=[C:2]([NH:1][C:21]([NH:20][CH2:18][CH3:19])=[O:22])[CH:3]=1)#[N:6]
Reactant: N#Cc1ccc(C2CCc3cncn32)c(N)c1
Reactant: CCN=C=O
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1cc(C#N)ccc1C1CCc2cncn21
Temperature: 70 °C

Procedure:
To a solution of 3-Amino-4-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)benzonitrile (0.090 g, 0.420 mmol), given as example 6B, and DMF (5 mL) is added ethylisocyanate (0.040 mL, 0.510 mmol). The solution is heated to 70° C. in a microwave reactor for 1.5 h followed by heating at 70° C. in an oil bath overnight. The solution is then concentrated and the residue purified via flash chromatography (1-10% MeOH/CH2Cl2) to give 1-[5-Cyano-2-(6,7-dihydro-5H-pyrrolo[1,2-c]imidazol-5-yl)phenyl]-3-ethylurea. MS (ESI) m/z 296.1 (M+H); 1H NMR (400 MHz, CDCl3) δ ppm 1.16 (t, J=7.2 Hz, 3 H), 2.47-2.62 (m, 1 H), 2.82-3.04 (m, 2 H), 3.05-3.17 (m, 1 H), 3.21-3.33 (m, 2 H), 5.63 (app t, J=6.8 Hz, 1 H), 5.80 (br s, 1 H), 6.82 (s, 1 H), 6.91 (d, J=8.1 Hz, 1 H), 7.30 (dd, J=8.1, 1.5 Hz, 1 H), 7.39 (s, 1 H), 7.53 (br s, 1 H), 7.97 (d, J=1.3 Hz, 1 H).
Reaction SMILES: C([O:5][C:6](=[O:38])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:30]2[N:35]=[CH:34][C:33]([CH2:36][CH3:37])=[CH:32][N:31]=2)[CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=2)[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[ClH:39].C(OCC)(=O)C>C(O)=O>[ClH:39].[CH2:36]([C:33]1[CH:34]=[N:35][C:30]([N:18]([CH2:19][C:20]2[CH:25]=[CH:24][C:23]([NH:26][CH2:27][CH2:28][CH3:29])=[CH:22][CH:21]=2)[CH2:17][CH2:16][C:14]2[N:15]=[C:11]([S:10][C:7]([CH3:9])([CH3:8])[C:6]([OH:38])=[O:5])[S:12][CH:13]=2)=[N:31][CH:32]=1)[CH3:37]
Reactant: CCCNc1ccc(CN(CCc2csc(SC(C)(C)C(=O)OC(C)(C)C)n2)c2ncc(CC)cn2)cc1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: O=CO
Product: CCCNc1ccc(CN(CCc2csc(SC(C)(C)C(=O)O)n2)c2ncc(CC)cn2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-{[4-(2-{(5-Ethylpyrimidin-2-yl)[4-(propylamino)benzyl]amino}ethyl)-1,3-thiazol-2-yl]thio}-2-methylpropionic acid tert-butyl ester (68 mg) synthesized in Example 441-1 was dissolved in formic acid (2.5 mL), 4 mol/L hydrochloric acid-ethyl acetate (0.5 mL) was added thereto, and the mixture was stirred at room temperature overnight. The reaction solution was evaporated under reduced pressure, and the residue was dried by heating at 60° C. to give the title compound (77 mg) as a white amorphous solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([NH:17][NH:18]C(OC(C)(C)C)=O)=[O:16])[CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1.[ClH:26]>CO>[ClH:26].[ClH:26].[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:6]=[CH:7][C:8]=1[N:9]1[CH:13]=[N:12][C:11]([CH3:14])=[N:10]1)[C:15]([NH:17][NH2:18])=[O:16]
Reactant: COc1cc(C(=O)NNC(=O)OC(C)(C)C)ccc1-n1cnc(C)n1
Agent: Cl
Solvent: CO
Product: COc1cc(C(=O)NN)ccc1-n1cnc(C)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a mixture of tert-butyl 2-{[3-methoxy-4-(3-methyl-1H-1,2,4-triazol-1-yl)phenyl]carbonyl}hydrazinecarboxylate (0.22 g) in methanol (2 mL) was added hydrochloric acid (4-Methyl acetate solution, 1 mL) at room temperature, and the mixture was stirred at room temperature for 4 hr. The precipitated solid was collected by filtration, and washed with ethyl acetate to give the title compound (0.15 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[C:4]([F:17])[CH:3]=1.C([Li])CCC.C([O:26][B:27](OC(C)C)[O:28]C(C)C)(C)C>>[F:17][C:4]1[CH:3]=[C:2]([B:27]([OH:28])[OH:26])[CH:7]=[CH:6][C:5]=1[O:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16]
Reactant: CCCCCCCCOc1ccc(Br)cc1F
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Product: CCCCCCCCOc1ccc(B(O)O)cc1F

Procedure:
This was prepared using a similar method to that described for compound 5. Quantities: 1-bromo-3-fluoro-4-octoxybenzene (15 g, 0.05 mol), n-butyllithium (5 ml, 10M in hexane, 0.05 mol), tri-isopropylborate (18.81 g, 0.1 mol).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)SC)[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[NH2:26][CH:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH3:28]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:11](=[C:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)[NH:26][CH:27]([CH3:28])[C:29]([CH3:32])([CH3:31])[CH3:30])[C:12]#[N:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1
Product: CC(NC(Nc1cccc(C#N)c1)=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)C(C)(C)C
Yield: 25 %

Procedure:
2-(4-Chlorophenylsulfonyl)-3-(3-cyanophenylamino)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.6 mmol) was stirred in 2-amino-3,3-dimethylbutane (1 ml) for 48 h at 100° C. under nitrogen in a sealed flask. The reaction mixture was concentrated and the residue dissolved in dichloromethane, washed twice with 1N aqueous HCl, once with brine, and once with water. The organic phase was dried (sodium sulphate) and concentrated. The residue was trituated with ether to afford a white crystalline substance which was further purified by flash chromatography (SiO2) using heptane/ethyl acetate (1:1) to yield 85 mg(25%) of the title compound. Mp 80-82° C. 1H NMR (200 MHz, CDCl3): δ=0.90 (s, 9H), 1.02 (d, 3H), 3.02 (m, 1H), 7.27 (s, 2H), 7.47 (d, 2H), 7.51 (d,2H), 7.81 (d, 2H);
Reaction SMILES: [ClH:1].[OH:2][C:3]1[C:16]2[C:15](=[O:17])[C:14]3[C:9](=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3)[O:8][C:7]=2[CH:6]=[C:5]([O:20][CH2:21][CH:22]2[CH2:24][O:23]2)[CH:4]=1>C(OCC)(=O)C>[Cl:1][CH2:24][CH:22]([OH:23])[CH2:21][O:20][C:5]1[CH:4]=[C:3]([OH:2])[C:16]2[C:15](=[O:17])[C:14]3[C:9]([O:8][C:7]=2[CH:6]=1)=[C:10]([O:18][CH3:19])[CH:11]=[CH:12][CH:13]=3
Reactant: COc1cccc2c(=O)c3c(O)cc(OCC4CO4)cc3oc12
Reactant: Cl
Solvent: CCOC(C)=O
Product: COc1cccc2c(=O)c3c(O)cc(OCC(O)CCl)cc3oc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92 %

Procedure:
Aqueous ethyl acetate 1M-HCl (3 mL) was added to 1-hydroxy-5-methoxy-3-(oxiran-2-ylmethoxy)-9H-xanthen-9-one (30 mg, 0.10 mmol) synthesized in Step 2 of Example 1, followed by stirring at room temperature for 30 minutes, and the reaction solvent was removed under reduced pressure. Ether was added to the residue, followed by sonication, and the solvent was removed to obtain the title compound (31 mg, 92%) as a light brown solid.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][NH:12][CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15].S(C1C=CC(C)=CC=1)(O[CH2:22][CH3:23])(=O)=O.C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C@@H:9]1[CH2:13][N:12]([CH2:22][CH3:23])[CH2:11][C@H:10]1[C:14]([O:16][CH3:17])=[O:15]
Reactant: CCOS(=O)(=O)c1ccc(C)cc1
Reactant: COC(=O)[C@@H]1CNC[C@H]1c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1C[C@@H](C(=O)OC)[C@H](c2ccc(F)cc2F)C1
Temperature: 25 °C

Procedure:
A mixture of methyl (3S,4R)-4-(2,4-difluorophenyl)pyrrolidine-3-carboxylate from Preparation 31 (500 mg, 2.07 mmol), ethyl tosylate (519 mg, 2.59 mmol) and potassium carbonate (573 mg, 4.15 mmol) were heated in acetonitrile at 70° C. for 16 hours under nitrogen. The reaction mixture was then cooled to room temperature and concentrated in vacuo. The residue was dissolved in dichloromethane (30 ml) and partitioned with saturated aqueous sodium bicarbonate (30 ml). The organic layer was then washed with brine (20 ml), dried over magnesium sulfate, filtered, and the solvent was removed in vacuo. The above procedure was performed in duplicate. The crude products from the two reactions were then combined and purified by column chromatography on silica eluting with dichloromethane:methanol (99:1) to give the title compound as a pale yellow oil, 968 mg.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:5][C:4]=1[CH2:16][S:17][C:18]([CH3:21])([CH3:20])[CH3:19].[C-:22]#[N:23].[K+]>CS(C)=O>[C:18]([S:17][CH2:16][C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])[CH:7]=[CH:8][C:3]=1[CH2:2][C:22]#[N:23])([CH3:21])([CH3:20])[CH3:19]
Reactant: [C-]#N
Reactant: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CBr
Agent: [K+]
Solvent: CS(C)=O
Product: CC(C)(C)SCc1cc(NC(=O)C(C)(C)C)ccc1CC#N
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-(4-Bromomethyl-3-tert-butylsulfanylmethyl-phenyl)-2,2-dimethyl-propionamide (1.8 g, 4.8 mmol) in DMSO (40 mL) was treated with potassium cyanide (0.325 g, 5.0 mmol), and the reaction was stirred for 1 hour at room temperature. The mixture was worked-up and purified by silica gel chromatography to give the title compound.
Reaction SMILES: [C:1]([C:3]([CH:5]([OH:8])[CH2:6][CH3:7])=[CH2:4])#[N:2].[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>CO>[CH2:9]([NH:16][CH2:4][CH:3]([C:1]#[N:2])[CH:5]([OH:8])[CH2:6][CH3:7])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: NCc1ccccc1
Reactant: C=C(C#N)C(O)CC
Solvent: CO
Product: CCC(O)C(C#N)CNCc1ccccc1
Reaction time: 8 h

Procedure:
To a solution of 2-cyano-3-hydroxy-1-pentene (10 g) in methanol (100 ml) was added benzylamine (10 ml). After stirring for 8 hours under reflux, the solvent was evaporated, and the residue was chromatographed on silica gel with eluting a mixture of n-hexane and ethyl acetate (1:1, V/V) to give 1-benzylamino-2-cyano-3-hydroxypentane (10 g).