Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C)[CH:3]=[CH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][C:6]=1[N+:15]([O-:17])=O.O1CCCC1.[H][H]>[Pd].C(OCC)(=O)C.CCCCCC>[OH:17][N:15]1[C:6]2[C:5](=[CH:10][CH:9]=[C:8]([S:11]([CH3:14])(=[O:13])=[O:12])[CH:7]=2)[CH:4]=[CH:3]1
Reactant: CN(C)C=Cc1ccc(S(C)(=O)=O)cc1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CS(=O)(=O)c1ccc2ccn(O)c2c1
Temperature: 50 °C
Yield: 25.3 %

Procedure:
A 1-L pressure reactor was charged with 1-dimethylamino-2-(4-methylsulphonyl-2-nitrophenyl)ethene (54.0 g, 0.2 mol), 5.0% palladium on carbon hydrogenation catalyst (0.3 g) and tetrahydrofuran (500 mL). The reactor then was sealed, pressurized to approximately 30 bars absolute with hydrogen and heated with stirring to 50° C., at which point an exotherm caused the temperature to rise to approximately 85° C. The reaction mixture then was stirred at 60°-70° C. for 1 hour, after which time the reactor was cooled and vented. The reaction mixture was filtered to remove the catalyst and the filtrate was concentrated under reduced pressure to give a brown solid which was dissolved in ethyl acetate (500 mL) and washed with 1M aqueous hydrochloric acid (3×200 mL) and then water (2×200 mL). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure to give a pale brown solid which was slurried in 53% weight:weight ethyl acetate in hexane (about 60 mL). The solid was collected by suction filtration and dried to give crude 1-hydroxy-6-methylsulphonylindole as a pale brown solid (33.1 g, 78% of theory). This crude product was recrystallized from acetonitrile to give a white crystalline product (17.8 g, 42% of theory). The filtrate from the recrystallization was concentrated in vacuo to a heavy slush which was cooled, filtered and washed with ice-cold acetonitrile to give a second crop of 1-hydroxy-6-methylsulphonylindole (10.7 g, 25% of theory) which was recrystallized twice from acetonitrile to give the product as a white, crystalline solid (3.8 g, 9% of theory). Thus, the total yield of 1-hydroxy-6-methylsulphonylindole was 21.6 g (51% of theory). Melting point 174°-176° C.; Rf (66% weight:weight ethyl acetate in hexane) 0.36. Calculated: C, 51.17; H, 4,29; N, 6.63. Found: C, 51.10; H, 4,16; N, 6.67.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=1)[NH:5][C:6](=[O:24])[C@H:7]([CH:16](C(C)(C)C)[C:17](=[O:19])[OH:18])[NH:8]C(OC(C)(C)C)=O>FC(F)(F)C(O)=O>[CH3:1][O:2][C:3](=[O:32])[C@H:4]([CH2:25][C:26]1[CH2:27][CH:28]=[CH:29][CH2:30][CH:31]=1)[NH:5][C:6](=[O:24])[C@H:7]([CH2:16][C:17](=[O:18])[OH:19])[NH2:8]
Reactant: COC(=O)[C@H](CC1=CCC=CC1)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C(=O)O)C(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC1=CCC=CC1)NC(=O)[C@@H](N)CC(=O)O
Reaction time: 1 h

Procedure:
β-tert.-butyl-Nα-tert.-butyloxycarbonyl-L-aspartyl-2,5-dihydro-L-phenylalanine methyl ester (13 g.) is dissolved in trifluoroacetic acid (80 ml.) and the solution kept under nitrogen for one hour. The solvent is concentrated in vacuo and the residue is triturated with ether-hexane until it becomes solid. This material is dissolved in water (ca 30 ml.) neutralized with DEAE sephadex (OH cycle), filtered and the filtrate concentrated in vacuo to a small, volume (ca 5 ml.). The dipeptide ester is crystallized on standing in the refrigerator.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:40])([F:39])[F:38])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1.FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:42]#[N:43])=[C:6]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][N:11]([CH:16]([CH2:33][C:34]3([C:37]([F:39])([F:40])[F:38])[CH2:36][CH2:35]3)[C:17]([NH:19][C:20]3[CH:32]=[CH:31][C:23]([C:24]([OH:26])=[O:25])=[CH:22][CH:21]=3)=[O:18])[C:10](=[O:41])[CH:9]=2)[CH:7]=1
Reactant: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)OC(C)(C)C)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: COc1cn(C(CC2(C(F)(F)F)CC2)C(=O)Nc2ccc(C(=O)O)cc2)c(=O)cc1-c1cc(Cl)ccc1C#N

Procedure:
157 mg (255 μmol) of tert-butyl 4-({2-[4-(5-chloro-2-cyanophenyl)-5-methoxy-2-oxopyridin-1(2H)-yl]-3-[1-(trifluoromethyl)cyclopropyl]propanoyl}amino)benzoate (racemate) were hydrolysed with 393 μl (5.10 mmol) of trifluoroacetic acid according to General Method 2, and after preparative HPLC [column: Chromatorex C18, 10 μm, 125 mm×30 mm, mobile phase: acetonitrile/0.1% formic acid gradient (0 to 3 min 10% acetonitrile, to 35 min 90% acetonitrile and a further 3 min 90% acetonitrile)], the title compound was obtained. Yield: 94 mg (65% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[N+:14]([O-])([OH:16])=[O:15].C1C=CC=CC=1>CCCCCC>[Cl:1][C:2]1[CH:3]=[C:4]([F:8])[CH:5]=[CH:6][C:7]=1[N+:14]([O-:16])=[O:15]
Reactant: O=[N+]([O-])O
Reactant: Fc1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: CCCCCC
Solvent: c1ccccc1
Product: O=[N+]([O-])c1ccc(F)cc1Cl
Reaction time: 13 h
Yield: 15.7 %

Procedure:
m-Chlorofluorobenzene (240 g. 1.85 moles) is added to a mixture of sulfuric acid (185 g. 1.85 moles) and nitric acid (166 g., 1.85 moles) at -5° C. in 3.5 hours, stirred 13 hours, then benzene (200 ml.) and hexane (200 ml.) are added. The extract is washed with water (1×300 ml.), sodium carbonate solution (1×300 ml.), and water (1×300 ml.), dried and the solvents removed. The residue is distilled to give 138 g. of mixed isomers. The 4-nitro isomer crystallizes and is filtered off to give 3-chloro-4-nitrofluorobenzene (51 g. 16.7%) m.p. 36°-38° C.
Reaction SMILES: [NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6](O)[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17].S(Cl)([Cl:20])=O>>[NH2:1][C:2]1[C:15]([Cl:16])=[CH:14][C:5]([CH:6]([Cl:20])[CH2:7][NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[CH:4][C:3]=1[Cl:17]
Reactant: O=S(Cl)Cl
Reactant: CC(C)(C)NCC(O)c1cc(Cl)c(N)c(Cl)c1
Product: CC(C)(C)NCC(Cl)c1cc(Cl)c(N)c(Cl)c1

Procedure:
Under N2 atmosphere, 27.72 g of 4-amino-α-[(tert-butylamino)methyl]-3,5-dichlorobenzyl alcohol is added to 200 ml of thionyl chloride stirred at 0-5%C. After addition is completed, the reaction mixture is stirred at ambient temperature for 3 hours. Subsequently, the mixture is evaporated to dryness in vacuo to afford 37.34 g of yellow solid, which is used as is.
Reaction SMILES: [Cl:1][C:2]1C=C[C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:37][CH2:36][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:34][CH2:33]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10].ClC1C=CC(Cl)=CC=1[S:51](Cl)(=O)=O>>[Cl:1][C:2]1[S:51][C:5]([Cl:8])=[CH:4][C:3]=1[S:9]([NH:12][CH2:13][C:14]1[CH:15]=[C:16]([C:20]2[CH:21]=[C:22]3[C:26](=[C:27]([C:29]([NH2:31])=[O:30])[CH:28]=2)[NH:25][CH:24]=[C:23]3[CH:32]2[CH2:33][CH2:34][N:35]([S:38]([CH2:41][CH3:42])(=[O:40])=[O:39])[CH2:36][CH2:37]2)[CH:17]=[CH:18][CH:19]=1)(=[O:11])=[O:10]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)ccc5Cl)c4)cc23)CC1
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cccc(CNS(=O)(=O)c5cc(Cl)sc5Cl)c4)cc23)CC1
Yield: 27 %

Procedure:
The title compound was prepared according to the general procedure of 5-[3-({[(2,5-dichlorophenyl)sulfonyl]amino}methyl)phenyl]-3-[1-(ethylsulfonyl)-4-piperidinyl]-1H-indole-7-carboxamide substituting 2,5-dichloro-3-thiophenesulfonyl chloride (86 mg, 0.352 mmol) for 2,5-dichlorobenzenesulfonyl chloride. Reaction mixture was then concentrated and purified by Gilson Preparatory HPLC to give 16.7 mg the title compound (27%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[C:12]1([C:2]2[CH:3]=[C:4]([S:8]([NH2:11])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: OB(O)c1ccccc1
Reactant: NS(=O)(=O)c1cccc(Br)c1
Product: NS(=O)(=O)c1cccc(-c2ccccc2)c1
Yield: 66.4 %

Procedure:
Using preparation method 2, 3-bromobenzenesulfonamide (236 mg, 1 mmol) was reacted with phenylboronic acid (134 mg, 1.1 mmol). Purification by flash chromatography on SiO2 with CH2Cl2 gave 3-phenylbenzenesulfonamide as an off-white crystalline solid (155 mg, 66%). NMR 1H (ppm, d6-DMSO): 8.11 (s, 1H), 7.84 (d, J3=7.8 Hz, 1H), 7.70 (d, J3=7.8 Hz, 1H), 7.56-7.53 (m, 2H), 7.48 (t, J3=7.8 Hz, 1H), 7.43-7.34 (m, 3H), 5.10 (br. s, 2H).
Reaction SMILES: [CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]#[N:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2].Cl.[NH2:18][OH:19].[OH-].[K+]>C(O)C>[CH2:1]([C:3]1[C:4]([O:15][CH3:16])=[N:5][C:6]2[N:7]([CH:10]=[C:11]([C:13]([NH:18][OH:19])=[NH:14])[N:12]=2)[C:8]=1[CH3:9])[CH3:2]
Reactant: NO
Reactant: CCc1c(OC)nc2nc(C#N)cn2c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CCc1c(OC)nc2nc(C(=N)NO)cn2c1C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
A suspension of 8.0 g of 6-ethyl-7-methoxy-5-methylimidazo [1,2-a]pyrimidine-2-carbonitrile, 2.82 g of hydroxylamine hydrochloride and 2.28 g of potassium hydroxide in 100 ml of ethanol was refluxed with stirring for 2 hours and the mixture was cooled. The precipitated product was filtered, suspended in water with stirring for 15 minutes, filtered, then washed with water and ether and dried under vacuum to give 7.96 g of 6-ethyl-N-hydroxy-7-methoxy-5-methylimidazo[1,2-a]pyrimidine-2-carboxamidine (86% yield) melting at 249°-250° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:17]>C1COCC1>[C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([O:12][CH3:17])[CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CO[C@H]1C[C@H](NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl(trans-3-hydroxycyclobutyl)carbamate (1.18 g, 6.3 mmol) was dissolved in dry THF (25 mL) under a nitrogen atmosphere, and the solution cooled to 0° C. To this clear solution was added, sodium hydride (60% dispersion in oil, 0.25 g, 6.3 mmol) portion wise (evolution of H2 observed). The reaction mixture was stirred at RT for 30 min. then iodomethane (0.40 mL, 1.5 mmol) added dropwise and the resulting yellow suspension stirred at RT for 16 h. The reaction mixture was quenched with saturated aqueous solution of NH4Cl (20 mL) and partitioned between saturated aqueous solution of NaHCO3 (40 mL) and DCM (60 mL). The combined organic fractions were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. The resulting residue was purified by column chromatography (gradient 0-70% EtOAc in cyclohexane) to afford the title compound as a yellow oil (1.05 g, 82%). 1H NMR (CDCl3, 300 MHz): δ 4.65 (1H, br s), 4.22-4.10 (1H, m), 4.00-3.92 (1H, m), 2.40-2.28 (2H, m), 2.18-2.12 (2H, m), 1.43 (9H, s).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:14])[CH3:13])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[OH:19])[CH3:3].[OH-].[Na+:21]>O>[CH3:3][N:2]([CH2:4][C:5]1[CH:10]=[C:9]([CH2:11][N:12]([CH3:13])[CH3:14])[CH:8]=[C:7]([CH2:15][N:16]([CH3:18])[CH3:17])[C:6]=1[O-:19])[CH3:1].[Na+:21]
Reactant: CN(C)Cc1cc(CN(C)C)c(O)c(CN(C)C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CN(C)Cc1cc(CN(C)C)c([O-])c(CN(C)C)c1

Procedure:
53.1 g (0.2 mol) of 2,4,6-tris(dimethylaminomethyl)phenol and 100 ml of H2O are placed in a 500 ml round-bottomed flask having a magnetic stirrer and dropping funnel and, with stirring, 16.0 g (0.2 mol) of a 50% aqueous NaOH solution are added dropwise thereto. The clear, slightly yellow solution is concentrated by evaporation in a rotary evaporator at 70° C., and the residue is dried at 100° C./125 T (16.6×103Pa), yielding 55.1 g of sodium 2,4,6-tris(dimethylaminomethyl)phenolate in the form of a brownish solid of which the elemental analysis is as follows:
Reaction SMILES: [C:1]([CH2:4][CH2:5][C:6]1[CH:51]=[CH:50][CH:49]=[CH:48][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)=[O:39])[CH2:13]1)(O)=[O:2].C[N:53](C)[CH:54]=[O:55].C(Cl)(=O)C(Cl)=O>ClCCl>[OH:55][CH2:54][NH:53][C:1]([CH2:4][CH2:5][C:6]1[CH:51]=[CH:50][CH:49]=[CH:48][C:7]=1[O:8][CH2:9][CH2:10][O:11][CH:12]1[CH:17]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][C:31]=3[O:36][CH3:37])=[CH:20][CH:19]=2)[CH2:16][CH2:15][N:14]([C:38]([O:40][CH2:41][C:42]2[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=2)=[O:39])[CH2:13]1)=[O:2]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCCOc2ccccc2CCC(=O)O)cc1
Reactant: CN(C)C=O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OCc3ccccc3)CC2OCCOc2ccccc2CCC(=O)NCO)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 0.136 g of benzyl 3-{2-[2-(2-carboxyethyl)phenoxy]ethoxy}-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate in 3 ml of dichloromethane is admixed with 0.01 ml of N,N-dimethylformamide and 0.034 ml of oxalyl chloride and stirred at room temperature over 2 hours. The reaction mixture is concentrated by evaporation, and the residue is dissolved in 3 ml of tetrahydrofuran, cooled to 0° C. and added dropwise to the suspension of 0.033 g of N-methylhydroxylamine hydrochloride and 0.11 ml of triethylamine in a 4:1 tetrahydrofuran/water mixture (2 ml). The reaction mixture is stirred at room temperature over 14 hours, diluted with ethyl acetate, washed successively with 1N HCl, 1M aqueous sodium hydrogencarbonate solution and brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a colourless oil from the residue by means of flash chromatography (SiO2 60F). Rf=0.40 (200:20:1 dichloromethane-methanol-25% conc. ammonia); Rt=5.53.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1.[NH2:18][C:19]1[C:24]([CH3:25])=[CH:23][C:22]([OH:26])=[C:21]([CH3:27])[CH:20]=1>>[CH3:25][C:24]1[CH:23]=[C:22]([OH:26])[C:21]([CH3:27])=[CH:20][C:19]=1[NH:18][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)[N:3]=1
Reactant: Cc1cc(O)c(C)cc1N
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccncc2)n1
Product: Cc1cc(Nc2cc(C(F)(F)F)nc(-c3ccncc3)n2)c(C)cc1O

Procedure:
The title compound was prepared from a mixture of 4-chloro-2-(4-pyridinyl)-6-(trifluoromethyl)pyrimidine (50 mg, 0.193 mmol) and 4-amino-2,5-dimethylphenol (40 mg, 0.290 mmol) similar to Example 117 and isolated as a white solid (2 mg). 1H NMR (CDCl3): 8.77 (d, J=6.0 Hz, 2H), 8.27 (d, J=6.3 Hz, 2H), 7.05 (s, 1H), 6.86 (s, 1H), 6.77 (s, 1H), 6.47 (s, 1H), 5.25 (bs, 1H), 2.26 (s, 3H), 2.19 (s, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:11]3[N:17]=[C:16]([CH3:18])[C:15]([Cl:19])=[C:12]3[NH:13][N:14]=2)=[CH:4][CH:3]=1.[C:22]([OH:26])(=[O:25])[CH:23]=[CH2:24]>CC(N(C)C)=O>[C:22]([CH2:23][CH2:24][NH:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH2:7][CH2:8][CH2:9][C:10]2[N:11]3[N:17]=[C:16]([CH3:18])[C:15]([Cl:19])=[C:12]3[NH:13][N:14]=2)=[CH:4][CH:3]=1)([OH:26])=[O:25]
Reactant: C=CC(=O)O
Reactant: Cc1nn2c(CCCOc3ccc(N)cc3)n[nH]c2c1Cl
Solvent: CC(=O)N(C)C
Product: Cc1nn2c(CCCOc3ccc(NCCC(=O)O)cc3)n[nH]c2c1Cl
Temperature: 85 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
23 g 3-[3-(4-aminophenoxy)-propyl]-6-methyl-7-chloro-1H-pyrazolo[5,1-c]-1,2,4-triazole and 10.8 g acrylic acid are dissolved in dimethyl acetamide heated to 85° C. and are stirred at that temperature for 1 hour. The reaction mixture is then poured onto 300 g of an ice/water mixture, the deposit precipitated is filtered off under suction and recrystallized from ethyl acetate. 3-[3-(4-carboxyethylaminophenoxy)-propyl]-6-methyl-7-chloro-1H-pyrazolo-[5,1-c]-1,2,4-triazole melting at 151° to 153° C. is obtained in a yield of 61%.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]([NH2:11])=[O:10])[CH:4]=1.Cl[C:15]([S:17]Cl)=[O:16]>C(OCC)(=O)C>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([C:9]2[O:10][C:15](=[O:16])[S:17][N:11]=2)[CH:4]=1
Reactant: NC(=O)c1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)SCl
Solvent: CCOC(C)=O
Product: O=c1oc(-c2cccc(C(F)(F)F)c2)ns1
Yield: 86.3 %

Procedure:
α,α,α-Trifluoro-m-toluamide (82.7 g, 0.437 mol) and chlorocarbonylsulfenyl chloride (86 g, 0.667 mol, 53% excess) were reacted under the conditions of Example 2 for 0.5 hours. The light yellow residue was dissolved in ethyl acetate and cooled to -78°. The white precipitate was filtered and washed with hexane to yield 93.14 g (0.377 mol, 86.2%) of white solid, m.p. 85°-86.5°.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].C(=O)([O-])[O-].[K+].[K+].[CH2:21](Br)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CN(C=O)C>[CH2:21]([O:1][C:2]1[CH:7]=[C:6]([O:8][CH2:12][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=2)[C:5]([CH:9]([CH3:11])[CH3:10])=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: CC(=O)c1cc(C(C)C)c(O)cc1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1cc(C(C)C)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: 150 °C
Reaction time: 16 h

Procedure:
1-(2,4-Dihydroxy-5-isopropyl-phenyl)-ethanone (1 eq) was dissolved in DMF and potassium carbonate (2.2 eq) then benzyl bromide (2.2 eq) were added. The suspension was heated, with stirring to 150° C., under nitrogen, for 16 hrs. The solution was cooled to room temperature and the mixture was poured into 1MHCl (aq) then extracted in to ethyl acetate. The organic phases were combined and washed again with 1MHCl (aq) then five times with brine solution. The organic phase was dried over MgSO4, filtered and concentrated in vacuo, to give a solid, which was purified by diethyl ether hexane (1:1) trituration to give 1-(2,4-Bis-benzyloxy-5-isopropyl-phenyl)-ethanone.
Reaction SMILES: [CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13](Br)[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][N:36]1C(=O)CCC1.C([Cu])#N.O>CCOC(C)=O>[CH2:1]([O:8][C:9]([C:11]1[C:19]([CH3:20])=[C:18]2[C:14]([C:15]3[CH2:24][CH2:23][O:22][C:21]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])([CH2:25][CH2:26][CH3:27])[C:16]=3[NH:17]2)=[C:13]([C:35]#[N:36])[CH:12]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(Br)c21
Reactant: CN1CCCC1=O
Agent: N#C[Cu]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCC1(CC(=O)OCC)OCCc2c1[nH]c1c(C)c(C(=O)OCc3ccccc3)cc(C#N)c21
Temperature: 190 °C
Reaction time: 0.75 h
Yield: 81.8 %

Procedure:
A 500 mL RBF was charged with 5-bromo-1-ethoxycarbonylmethyl-8-methyl-1-propyl-1,3,4,9-tetrahydro-pyrano[3,4-b]indole-7-carboxylic acid benzyl ester (12.00 g, 23 mmol), NMP (100 mL), and CuCN (20.34 g, 0.227 mol). The reaction was heated to 190° C. with vigorous stirring for 45 minutes. The reaction was then cooled to ambient temperature, diluted with EtOAc followed by water (300 mL). A 1:1 mixture of Celite/silica gel were added to the mixture. This suspension was stirred for several minutes and filtered through a pad of Celite. The Celite pad was washed with EtOAc, and the filtrate was washed with water (5×) and saturated NaCl (1×), dried over MgSO4, and concentrated. Upon trituration with hexanes, 8.82 g (81.8%) of a light tan solid was obtained. 1H NMR (CDCl3) δ 10.11 (br s, 1H), 8.12 (s, 1H), 7.40 (m, 5H), 5.37 (s, 2H), 4.22 (m, 2H), 3.95 (m, 2H), 3.00 (m, 4H), 2.83 (s, 3H), 2.00 (m, 2H), 1.30 (m, 5H), 0.89 (t, J=7.6 Hz, 3H).
Reaction SMILES: [CH3:1][C:2]1[C:3](=[O:14])[C:4]([CH3:13])([CH2:8][CH:9]=C(C)C)[CH2:5][CH2:6][CH:7]=1.C([Al](Cl)Cl)C.[NH4+].[Cl-].[C:22]1(C)[CH:27]=CC=C[CH:23]=1>>[CH:22]([C:6]12[CH2:5][C:4]([CH3:13])([CH2:8][CH2:9]1)[C:3](=[O:14])[C:2]([CH3:1])=[CH:7]2)([CH3:27])[CH3:23]
Reactant: Cc1ccccc1
Reactant: CC(C)=CCC1(C)CCC=C(C)C1=O
Agent: CC[Al](Cl)Cl
Agent: [Cl-]
Agent: [NH4+]
Product: CC1=CC2(C(C)C)CCC(C)(C2)C1=O
Yield: 90 %

Procedure:
To a solution of 2,6-dimethyl-6-(3-methyl-but-2-enyl)-cyclohex-2-enone (5.00 g, 26.04 mmol) in toluene (40 ml) was added dropwise neat EtAlCl2 (97%, 1.5 eq., 4.96 g, 39.06 mmol). During the addition, the temperature was kept below 10° C. The brown mixture was kept at room temperature over night and was then poured on icecold saturated NH4Cl. The mixture was extracted with MTBE, washed with brine, dried (MgSO4) and concentrated in vacuo. The residue was distilled bulb to bulb to yield 4.50 g (90%) of an colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][CH:10]=1)[C:5](Cl)=[O:6].[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH2:26])=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:19]([C:21]1[S:25][C:24]([NH:26][C:5](=[O:6])[C:4]2[CH:8]=[CH:9][CH:10]=[C:2]([Cl:1])[CH:3]=2)=[N:23][C:22]=1[CH3:27])=[O:20])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1cccc(Cl)c1
Reactant: Cc1nc(N)sc1C(=O)NCc1ccccc1
Product: Cc1nc(NC(=O)c2cccc(Cl)c2)sc1C(=O)NCc1ccccc1
Yield: 32 %

Procedure:
Following the procedure as described in Example 2, making variations only as required to use 3-chlorobenzoyl chloride in place of benzoyl chloride to react with 2-amino-4-methylthiazole-5-carboxylic acid benzylamide, the title compound was obtained as a white solid in 32% yield; m.p. 178-179° C.; 1H NMR (CDCl3, 300 MHz) δ 8.05 (t, J=1.6 Hz, 1H), 7.86 (ddd, J=1.1, 1.6, and 7.8 Hz, 1H), 7.59-7.27 (m, 7H), 5.98 (t, J=5.3 Hz, 1H), 4.59 (d, J=5.6 Hz, 2H), 2.57 (s, 3H); MS (ES+) m/z 386 (M+1).
Reaction SMILES: [H-].[Na+].[C:3]([CH2:5]P(=O)(OCC)OCC)#[N:4].[CH:14]([C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)=O>O1CCCC1.O.C(OCC)C>[C:3]([CH:5]=[CH:14][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][C:25]([CH:28]([CH3:37])[CH2:29][NH:30][S:31]([CH:34]([CH3:36])[CH3:35])(=[O:33])=[O:32])=[CH:24][CH:23]=2)=[CH:18][CH:17]=1)#[N:4]
Reactant: CCOP(=O)(CC#N)OCC
Reactant: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=O)cc2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 78 %

Procedure:
To a suspension of 0.4 g (10.4 mmol) of sodium hydride (washed three times with hexane) in 2 mL of tetrahydrofuran was added 1.6 mL (10.4 mmol) of diethyl cyanomethylphosphonate. The mixture was stirred at ambient temperature for 15 minutes. To the mixture was added a solution of 3.0 g (8.7 mmol) of material from Example 45 in 15 mL of tetrahydrofuran. After stirring for two hours, the mixture was diluted with 25 mL of water and extracted three times with 20 mL each of ethyl ether. The combined organics were dried (MgSO4), filtered and concentrated in vacuo. Chromatography (150 g of silica gel, 35% ethyl acetate/hexane) of the residue gave a white solid which was suspended in ethyl ether, filtered and dried in vacuo to afford 2.5 g (79%) of the title compound.