Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2OC3C=CC(OC)=CC=3N=2)=[CH:4][CH:3]=1.[CH3:19][C:20]1[CH:25]=[CH:24][C:23](C2OC3C=C(OC)C=CC=3N=2)=[CH:22][CH:21]=1>>[C:8]1([C:5]2[CH:4]=[CH:3][C:2]([CH:1]=[CH:19][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)=[CH:7][CH:6]=2)[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=1
Reactant: COc1ccc2oc(-c3ccc(C)cc3)nc2c1
Reactant: COc1ccc2nc(-c3ccc(C)cc3)oc2c1
Product: C(=Cc1ccc(-c2ccccc2)cc1)c1ccccc1

Procedure:
In place of the 2-(4'-methylphenyl)-5-methoxybenzoxazol of formula (17), the 2-(4'-methylphenyl)-6-methoxybenzoxazol of formula ##STR19## can be employed to yield the 4-(6"-methoxybenzoxazolyl-2")-4'-phenylstilbene of formula (11), which is obtained in comparably good yield and can be purified as given in the foregoing.
Reaction SMILES: [OH:1][CH:2]([CH:26]1[CH2:30][O:29]C(C)(C)[O:27]1)[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:24])(=[O:23])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH:7]=1.Cl>C(O)C.O>[OH:1][CH:2]([CH:26]([OH:27])[CH2:30][OH:29])[CH2:3][NH:4][C:5](=[O:25])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([S:12](=[O:23])(=[O:24])[NH:13][C:14]2[C:19]([F:20])=[CH:18][C:17]([F:21])=[CH:16][C:15]=2[F:22])[CH:7]=1
Reactant: CC1(C)OCC(C(O)CNC(=O)c2cccc(S(=O)(=O)Nc3c(F)cc(F)cc3F)c2)O1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(NCC(O)C(O)CO)c1cccc(S(=O)(=O)Nc2c(F)cc(F)cc2F)c1
Temperature: 60 °C
Reaction time: 4 h

Procedure:
4.74 g (10 mmol) of 3-[N-(2,4,6-trifluorophenyl)sulfamoyl]-benzoic acid-[2-hydroxy-2-(2,2-dimethyl-1,3-dioxolan-4-yl)-ethylamide] is dissolved in a mixture of 50 ml of ethanol and 20 ml of water and the solution is acidified to pH 1 with dilute hydrochloric acid. At this pH, it is stirred for 4 hours at 60° C. The solution is then adjusted to pH 6.6 with anion exchanger Amberlite IRA 67, filtered and evaporated to dryness in a vacuum. The solid amorphous residue is dried in a vacuum at 50° C. 3.61 g (8.32 mmol)=83.2% of the theoretical yield is obtained as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([Cl:9])=[CH:4][N:3]=1.[NH2:10][C:11]1[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=1[O:13][CH2:14][C:15]#[N:16].C(O)(C)C>>[Cl:1][C:2]1[N:7]=[C:6]([NH:10][C:11]2[CH:20]=[CH:19][CH:18]=[CH:17][C:12]=2[O:13][CH2:14][C:15]#[N:16])[C:5]([Cl:9])=[CH:4][N:3]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: N#CCOc1ccccc1N
Solvent: CC(C)O
Product: N#CCOc1ccccc1Nc1nc(Cl)ncc1Cl
Yield: 53.9 %

Procedure:
Into an 80 ml microwave vessel was added 2,4,5-Trichloro-pyrimidine (1.86 g, 0.01 mol), (2-Amino-phenoxy)-acetonitrile (1.500 g, 0.01 mol), and N,N-DIEA (1.96 g, 0.015 mol), Isopropyl alcohol (20 mL, 0.3 mol). The reaction was microwaved at 120° C. for 60 minutes. The resulting orange suspension was filtered and the solid was washed with Isopropyl alcohol to afford a light pink solid (1.59 g, 53%). HPLC purity 95%.
Reaction SMILES: [CH:1]1[C:6]([CH2:7][C@H:8]([NH2:12])[C:9]([OH:11])=[O:10])=[CH:5][C:4]([OH:13])=[C:3]([OH:14])[CH:2]=1.Cl.O.[CH2:17]=O.[OH-].[Na+]>O>[OH:13][C:4]1[CH:5]=[C:6]2[C:1](=[CH:2][C:3]=1[OH:14])[CH2:17][NH:12][C@H:8]([C:9]([OH:11])=[O:10])[CH2:7]2
Reactant: C=O
Reactant: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)[C@@H]1Cc2cc(O)c(O)cc2CN1
Temperature: 2.5 °C
Reaction time: 10 h
Yield: 95.4 %

Procedure:
To a cold (0-5° C.) suspension of Levodopa (197.2 g, 1.0 mol) in water (1.18 L) was added 32% aqueous HCl (159.5 g, 1.4 mol). The resulting solution was cooled to 0-5° C., and 37% formaldehyde water solution (243.24 g, 3.0 mol) was added. The resulting solution was allowed to warm to 20-25° C., and stirred at 20-25° C. for 10 h. The reaction solution was cooled to 0-5° C., and 2 N aqueous NaOH (700 mL, 1.4 mol) was slowly added to adjust pH to 5-5.5. White or light yellow solids precipitated during the addition. The resulting suspension was stirred at 0-5° C. for 2-3 h. The mixture was filtered, and rinsed with water (2×500 mL). The solids were dried under vacuum to give 199.52 g of a light yellow solid. Yield=95.3%.
Reaction SMILES: C(=O)(O)O.[NH2:5][NH:6][C:7]([NH2:9])=[NH:8].Cl.[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=O>O.C(O)C.C(OCC)C>[ClH:11].[Cl:11][C:12]1[CH:19]=[C:18]([N+:20]([O-:22])=[O:21])[CH:17]=[C:16]([Cl:23])[C:13]=1[CH:14]=[N:5][NH:6][C:7]([NH2:9])=[NH:8]
Reactant: O=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl
Reactant: N=C(N)NN
Agent: Cl
Agent: O=C(O)O
Solvent: O
Solvent: CCO
Solvent: CCOCC
Product: N=C(N)NN=Cc1c(Cl)cc([N+](=O)[O-])cc1Cl

Procedure:
Aminoguanidine hydrogen carbonate (0.96 g, 7.0 mmol) was added to a solution of concentrated hydrochloric acid (0.6 cm3) in water (2 cm3). After diluting the resulting solution with ethanol (20 cm3), 2,6-dichloro-4-nitrobenzaldehyde (1.53 g, 7.0 mmol) was added and the suspension heated under reflux for 2.5 h. The reaction mixture was cooled and diluted with diethyl ether to yield (2,6-dichloro-4-nitrobenzylidene amino)-guanidine hydrochloride as a yellow solid, mp 190° C. (dec).
Reaction SMILES: [N+:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[C-].[CH:8]([C:10]1[CH:19]=[CH:18][CH:17]=[CH:16][C:11]=1[C:12]([O:14]C)=O)=O.[H-].[Na+].C(O)(=O)C>CN(C)C=O.O>[O:14]=[C:12]1[C:11]2[C:10](=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH:8]=[C:3]([C:4]([O:6][CH3:7])=[O:5])[NH:1]1
Reactant: [C-]#[N+]CC(=O)OC
Reactant: COC(=O)c1ccccc1C=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Solvent: CC(=O)O
Product: COC(=O)c1cc2ccccc2c(=O)[nH]1
Reaction time: 5 h

Procedure:
A solution of methyl isocyanoacetate (4.20 mL, 46.2 mmol) and methyl 2-formylbenzoate (6.90 g, 42.0 mmol) in 30 mL of N,N-dimethylformamide was added dropwise to a suspension of sodium hydride (1.21 g, 50.4 mmol) in 20 mL of N,N-dimethylformamide. After 5 hr, the mixture was treated with 10% aqueous acetic acid and water and extracted 2× with ethyl acetate. The combined organic extracts were washed 3× with water and brine, dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was crystallized from 1:10 ethyl acetate:hexanes to provide methyl 1-oxo-1,2-dihydroisoquinoline-3-carboxylate.
Reaction SMILES: [CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7].[F:21][C:22]([F:32])([F:31])[C:23]1[CH:30]=[CH:29][CH:28]=[CH:27][C:24]=1[CH2:25]Cl.N12CCCN=C1CCCCC2>CCOC(C)=O>[CH3:1][CH:2]([CH3:20])[CH2:3][CH2:4][NH:5][C:6]([C:8]1[N:9]=[N:10][C:11]([N:14]2[CH2:19][CH2:18][N:17]([CH2:25][C:24]3[CH:27]=[CH:28][CH:29]=[CH:30][C:23]=3[C:22]([F:21])([F:31])[F:32])[CH2:16][CH2:15]2)=[CH:12][CH:13]=1)=[O:7]
Reactant: CC(C)CCNC(=O)c1ccc(N2CCNCC2)nn1
Reactant: FC(F)(F)c1ccccc1CCl
Solvent: CCOC(C)=O
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)CCNC(=O)c1ccc(N2CCN(Cc3ccccc3C(F)(F)F)CC2)nn1
Temperature: 60 °C
Yield: 72 %

Procedure:
A mixture of 6-piperazin-1-yl-pyridazine-3-carboxylic acid (3-methylbutyl)amide (0.255 mmol), 2-trifluoromethylbenzyl chloride (0.255 mmol), and 1,8-diazabicylco[5.4.0]undec-7-ene (0.77 mmol) was stirred and heated at 60° C. overnight. The reaction mixture was ten diluted with EtOAc (100 mL) and washed with aqueous saturated NaHCO3 (2×20 mL) and brine (2×20 mL). The organic layer was dried over anhydrous Na2SO4, concentrated, and purified by flash chromatography to give the title compound as a white solid (80 mg, 72% yield). 1H NMR (500 MHz, CDCl3) δ 8.00, 7.86, 7.82, 7.65, 7.55, 7.37, 6.95, 3.74-3.79, 3.73, 3.46-3.52, 2.62, 1.65-1.76, 1.52, 0.94. MS (ES+) m/z 436 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=2[N:11]=1.[Cl:15][C:16]1[N:21]=[C:20](Cl)[C:19]([F:23])=[CH:18][N:17]=1>CO.O.ClCCl>[Cl:15][C:16]1[N:21]=[C:20]([NH:1][C:2]2[CH:3]=[CH:4][C:5]3[O:6][C:7]([CH3:14])([CH3:13])[C:8](=[O:12])[NH:9][C:10]=3[N:11]=2)[C:19]([F:23])=[CH:18][N:17]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CC1(C)Oc2ccc(N)nc2NC1=O
Solvent: O
Solvent: ClCCl
Solvent: CO
Product: CC1(C)Oc2ccc(Nc3nc(Cl)ncc3F)nc2NC1=O
Temperature: 65 °C
Reaction time: 4 h
Yield: 77 %

Procedure:
6-amino-2,2-dimethyl-4H-pyrido[3,2-b][1,4]oxazin-3-one (450 kg, 1.00 mol eq) is stirred in a mixture of methanol (1971 kg) and water (1610 kg) under a nitrogen atmosphere with heating to about 65° C. To this is added a solution of 2,4-dichloro-5-fluoro-pyrimidine in dichloromethane (545 kg 2,4-dichloro-5-fluoro-pyrimidine, 1.40 mol eq, about 50% w/w solution) over a period of about 4 hours, during which dichloromethane is distilled off. The mixture is then stirred at about 70° C. until distillation is complete and then at reflux for about 15 hours. This is then cooled to about 45° C. and filtered. The filtered solid is washed twice with methanol (2×675 kg) and then dried under vacuum at about 55° C. Once dry, the solid is slurried in 85% w/w aqueous formic acid (3150 kg) at about 50° C. for about 6 hours and then filtered. This slurry may be repeated. The resulting damp solid is cooled to about 20° C., washed twice with methanol (2×1800 kg) and dried under vacuum at about 80° C. to give the title compound (577 kg, 77%) as a colored solid.
Reaction SMILES: [NH2:1][CH:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([O:9][CH3:10])[N:3]1[CH:11]([F:13])[F:12].[N+:14]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[S:23]([N:26]=[C:27]=[O:28])(=[O:25])=[O:24])([O-:16])=[O:15]>C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]([O:9][CH3:10])[N:3]([CH:11]([F:12])[F:13])[CH:2]([NH:1][C:27]([NH:26][S:23]([C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[N+:14]([O-:16])=[O:15])(=[O:24])=[O:25])=[O:28])[N:7]=1
Reactant: O=C=NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Reactant: COC1=NC(Cl)=NC(N)N1C(F)F
Solvent: ClCCl
Product: COC1=NC(Cl)=NC(NC(=O)NS(=O)(=O)c2ccccc2[N+](=O)[O-])N1C(F)F
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.2 %

Procedure:
A solution of 4.2 g of 2-amino-4-chlorodifluoromethyl-6-methoxy-1,3,5-triazine (20 mmol) in 20 ml of methylene chloride was treated at 25° C. with a solution of 4.6 g of 2-nitrobenzenesulfonyl isocyanate (20 mmol) in 5 ml of methylene chloride. The mixture was subsequently stirred at 25° C. for 16 h, and the deposited product was filtered off with suction, washed with a little ether and dried at 40° C. in a water-jet vacuum. 3.1 g of the title compound (35% of theory) of m.p. 181° C. were thus obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([OH:10])=[O:9])[C:4](=[O:11])[O:3]1.C(N(CC)CC)C.[C:20]([Si:24](Cl)([C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)([CH3:23])([CH3:22])[CH3:21]>ClCCl.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH2:7][C:8]([O:10][Si:24]([C:20]([CH3:23])([CH3:22])[CH3:21])([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:9])[C:4](=[O:11])[O:3]1
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Reactant: CC1(C)OC(=O)[C@H](CC(=O)O)O1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)OC(=O)[C@H](CC(=O)O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)O1
Reaction time: 3 h
Yield: 99.8 %

Procedure:
A solution of (S)-(+)-2,2-dimethyl-5-oxo-1,3-dioxolane-4-acetic acid (2.08 g, 11.9 mmol) in dry dichloromethane (20 ml) was treated with triethylamine (1.83 ml, 13.1 mmol) followed by a solution of t-butylchlorodiphenylsilane (3.44 g, 12.5 mmol) in dichloromethane (5 ml) added dropwise over 5 minutes. After 3 hours at 22° C., the reaction mixture was diluted with toluene (250 ml) washed with water, saturated sodium bicarbonate, brine and dried over magnesium sulfate. Evaporation of the solvent under reduced pressure and chromatography of the residue on silica gel (4×12 cm) using a mixture of toluene and ethyl acetate (0–2%) as eluent gave 4.90 g (99% yield) of the title material as a clear oil. 1H NMR (400 MHz, CDCl3) δ: 1.13 (s, 9), 1.58 (s, 3), 3.05 (m, 2), 4.79 (dd, 1, J=4, 7), 7.4–7.8 (m, 10).
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[NH2:14][C:15]1[C:24]2[C:19](=[C:20](Br)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]>>[NH2:14][C:15]1[C:24]2[C:19](=[C:20]([C:2]3[CH:10]=[C:9]4[C:5]([C:6]([CH:11]5[CH2:13][CH2:12]5)=[N:7][NH:8]4)=[CH:4][CH:3]=3)[C:21]([CH3:25])=[CH:22][CH:23]=2)[N:18]=[N:17][C:16]=1[C:27]([NH2:29])=[O:28]
Reactant: Brc1ccc2c(C3CC3)n[nH]c2c1
Reactant: Cc1ccc2c(N)c(C(N)=O)nnc2c1Br
Product: Cc1ccc2c(N)c(C(N)=O)nnc2c1-c1ccc2c(C3CC3)n[nH]c2c1

Procedure:
The title compound was prepared in a manner similar to EXAMPLE 96 using 6-bromo-3-cyclopropyl-1H-indazole and 4-amino-8-bromo-7-methylcinnoline-3-carboxamide. 1H NMR (500 MHz, CD3OD) δ ppm 1.09 (d, J=7.32 Hz, 4H), 2.31 (s, 3 H), 2.31-2.41 (m, 1H), 7.03 (d, J=8.30 Hz, 1 H), 7.37 (s, 1 H), 7.71 (d, J=8.79 Hz, 1 H), 7.90 (d, J=7.81 Hz, 1 H), 8.22 (d, J=8.79 Hz, 1 H); ESI-MS m/z [M+H]+ 359.3.
Reaction SMILES: [C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH:19]=[CH:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H][H]>CO.[Pd]>[C:1]1([S:7]([CH2:10][CH2:11][CH2:12][CH2:13][O:14][C:15]2[CH:16]=[C:17]3[C:22](=[CH:23][CH:24]=2)[NH:21][C:20](=[O:25])[CH2:19][CH2:18]3)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [H][H]
Reactant: O=c1ccc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2[nH]1
Agent: [Pd]
Solvent: CO
Product: O=C1CCc2cc(OCCCCS(=O)(=O)c3ccccc3)ccc2N1

Procedure:
107 mgm of 6-(4-phenylsulfonyl-butoxy)-carbostyril were suspended in 15 ml of methanol, the suspension was admixed with 40 mgm of palladium-on-charcoal, and the mixture was hydrogenated at 50° C. and a hydrogen pressure of 2.5 bar for 14 hours. After filtering off the catalyst and evaporating the clear solution, a colorless crystalline residue was obtained.
Reaction SMILES: C1C2C(=CC=CC=2)CC1C(O)=O.[Cl:13][C:14]1[CH:19]=[CH:18][C:17]([N:20]2[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]2)=[CH:16][CH:15]=1.C[O:27][C:28]([CH:30]1[CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][C:36]=2[S:39](Cl)(=[O:41])=[O:40])[CH2:31]1)=[O:29]>>[Cl:13][C:14]1[CH:15]=[CH:16][C:17]([N:20]2[CH2:25][CH2:24][N:23]([S:39]([C:36]3[CH:35]=[CH:34][CH:33]=[C:32]4[C:37]=3[CH2:38][CH:30]([C:28]([OH:29])=[O:27])[CH2:31]4)(=[O:41])=[O:40])[CH2:22][CH2:21]2)=[CH:18][CH:19]=1
Reactant: COC(=O)C1Cc2cccc(S(=O)(=O)Cl)c2C1
Reactant: Clc1ccc(N2CCNCC2)cc1
Agent: O=C(O)C1Cc2ccccc2C1
Product: O=C(O)C1Cc2cccc(S(=O)(=O)N3CCN(c4ccc(Cl)cc4)CC3)c2C1

Procedure:
4-|4-(4-Chloro-phenyl)-piperazine-1-sulfonyl|-indan-2-carboxylic acid. The compound 4-[4-(4-chloro-phenyl)-piperazine-1-sulfonyl]-indan-2-carboxylic acid was prepared from 1-(4-chloro-phenyl)-piperazine and 4-chlorosulfonyl-indan-2-carboxylic acid methyl ester following the procedure outlined in Example 79. 1H NMR (400 MHz, DMSO-d6): δ 7.58 (d, 1H), 7.56 (d, 1H), 7.43 (t, 1H), 7.23 (d, 2H), 6.92 (d, 2H), 3.50-3.41 (m, 2H), 3.40-3.29 (m, 1H), 3.28-3.13 (m, 6H), 3.12-3.04 (m, 4H); MS (ESI): 420.9 (M+H).
Reaction SMILES: [CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[NH:4][C:3]1=[O:14].[H-].[Na+].[C:17]([S:20][CH2:21][C@H:22]([CH3:26])[C:23](Cl)=[O:24])(=[O:19])[CH3:18].C(SC[C@@H](C)C(O)=O)(=O)C.S(Cl)(Cl)=O>O1CCCC1>[CH3:1][N:2]1[CH2:6][C@@H:5]([C:7]([O:9][C:10]([CH3:11])([CH3:13])[CH3:12])=[O:8])[N:4]([C:23](=[O:24])[C@H:22]([CH3:26])[CH2:21][S:20][C:17](=[O:19])[CH3:18])[C:3]1=[O:14]
Reactant: CC(=O)SC[C@H](C)C(=O)Cl
Reactant: CN1C[C@@H](C(=O)OC(C)(C)C)NC1=O
Agent: CC(=O)SC[C@@H](C)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=S(Cl)Cl
Product: CC(=O)SC[C@@H](C)C(=O)N1C(=O)N(C)C[C@H]1C(=O)OC(C)(C)C
Yield: 44.7 %

Procedure:
1.3 g of tert.-butyl (4S)-1-methyl-2-oxo-imidazolidine-4-carboxylate are dissolved in 15 ml of tetrahydro-furan, and 0.35 g of sodium hydride (62% oil dispersion) is added thereto under ice-cooling and stirring. A solution of (2S)-3-acetylthio-2-methylpropionyl chloride (prepared by heating a mixture of 1.5 g of (2S)-3-acetylthio-2-methylpropionic acid and 6 ml of thionyl chloride at 50° C. for 3 hours and then evaporting excess thionyl chloride under reduced pressure) in 5 ml of tetrahydrofuran is added dropwise to the mixture. Then, the mixture is treated in the same manner as described in Example 1-(4). 1.0 g of tert.-butyl (4S)-1-methyl-3-[(2S)-3-acetylthio-2-methylpropionyl]-2-oxoimidazolidine-4-carboxylate is obtained as colorless crystals.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:5][CH2:4]1.C(N(CC)CC)C.[Cl:20][CH2:21][CH2:22][CH2:23][S:24](Cl)(=[O:26])=[O:25].Cl>C(Cl)(Cl)Cl>[Cl:20][CH2:21][CH2:22][CH2:23][S:24]([NH:2][C@H:3]1[CH2:4][CH2:5][C@H:6]([C:9]([O:11][CH3:12])=[O:10])[CH2:7][CH2:8]1)(=[O:26])=[O:25]
Reactant: O=S(=O)(Cl)CCCCl
Reactant: COC(=O)[C@H]1CC[C@H](N)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H]1CC[C@H](NS(=O)(=O)CCCCl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Methyl trans-4-aminocyclohexanecarboxylate hydrochloride (4.08 g) obtained in Reference Example 2(1) is suspended in chloroform (50 ml), and thereto is added triethylamine (8.8 ml) under ice-cooling. Subsequently, a solution of 3-chloropropanesulfonyl chloride (3.35 ml) in chloroform (20 ml) is added dropwise over 20 minutes under the same temperature. After stirring for 2 hours at room temperature, 5% hydrochloric acid is added to the reaction solution and the mixture is extracted with chloroform. The organic layer is washed with saturated brine, dried over sodium sulfate and evaporated to remove the solvent under reduced pressure. The resulting residue is suspended in diisopropylamine, and filtered to collect precipitates to give methyl trans-4-{[(3-chloropropyl)sulfonyl]amino}cyclohexanecarboxylate (6.14 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]([C:17]#[N:18])=[C:11]2[NH:10][CH2:9]1.ClCCC(NC1C=C(C2N3N=C(C4C=CC(OC5C=CC=CC=5)=CC=4)C(C(N)=O)=C3NCC2)C=CC=1)=[O:36]>>[NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]1[CH2:13][N:12]2[N:14]=[C:15]([C:19]3[CH:24]=[CH:23][C:22]([O:25][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)=[CH:21][CH:20]=3)[C:16]([C:17]([NH2:18])=[O:36])=[C:11]2[NH:10][CH2:9]1
Reactant: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCCC2c1cccc(NC(=O)CCCl)c1
Reactant: N#Cc1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)C2
Product: NC(=O)c1c(-c2ccc(Oc3ccccc3)cc2)nn2c1NCC(c1ccccc1N)C2

Procedure:
The desired product was prepared from 6-(2-aminophenyl)-2-(4-phenoxyphenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidine-3-carbonitrile using the procedure similar to step 2 for compound 2. 1H NMR (400 MHz, DMSO-d6) δ 7.58 (d, J=8.4 Hz, 2H), 7.53-7.44 (m, 2H), 7.24 (t, J=7.6 Hz, 1H), 7.19-7.09 (m, 4H), 7.06-7.99 (m, 2H), 6.84 (d, J=1.6 Hz, 1H), 6.74 (d, J=7.2 Hz, 1H), 6.61 (t, J=7.6 Hz, 1H), 5.20 (s, 2H), 4.24 (dd, J=4.0, 12.0, Hz, 1H), 4.07 (dd, J=12.0, 12.0 Hz, 1H), 3.56-3.41 (m, 3H). MS (ESI, m/e) [M+1]+ 425.9.
Reaction SMILES: [CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][OH:5])[CH3:2].ClCCl.[N+:13]([C:16]1[CH:24]=[CH:23][C:19]([C:20](Cl)=[O:21])=[CH:18][CH:17]=1)([O-:15])=[O:14]>N1C=CC=CC=1>[CH2:1]([CH:3]([CH2:6][CH2:7][CH2:8][CH3:9])[CH2:4][O:5][C:20](=[O:21])[C:19]1[CH:18]=[CH:17][C:16]([N+:13]([O-:15])=[O:14])=[CH:24][CH:23]=1)[CH3:2]
Reactant: CCCCC(CC)CO
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCC(CC)COC(=O)c1ccc([N+](=O)[O-])cc1
Reaction time: 0.17 h
Yield: 65 %

Procedure:
To the 250 ml 3-necked flask was added 10.0 gm 2-ethyl 1-hexanol, 100 ml dichloromethane, and 6.0 gm pyridine and the contents were stirred for 10 minutes. To this mixture, 14.2 gm 4-nitro benzoyl chloride was added slowly and stirred under reflux conditions for 2 hrs. The reaction mixture was then cooled, washed with 20% aqueous ammonium hydroxide. The organic layer was washed with 1N hydrochloric acid and brine, and dried over anhydrous sodium sulfate to give a crude product (˜65% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH:6]1[CH2:12][CH2:11][C:10]2[CH:13]=[C:14]([NH2:17])[CH:15]=[CH:16][C:9]=2[CH2:8][CH2:7]1.Cl[C:19]1[N:24]=[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[C:22]([Cl:37])=[CH:21][N:20]=1.[C:38](O)(C(F)(F)F)=[O:39]>>[Cl:37][C:22]1[C:23]([NH:25][C@@H:26]2[CH2:31][CH2:30][CH2:29][CH2:28][C@H:27]2[NH:32][S:33]([CH3:36])(=[O:35])=[O:34])=[N:24][C:19]([NH:17][C:14]2[C:15]([O:39][CH3:38])=[CH:16][C:9]3[CH2:8][CH2:7][CH:6]([NH:5][CH2:4][CH2:3][O:2][CH3:1])[CH2:12][CH2:11][C:10]=3[CH:13]=2)=[N:20][CH:21]=1
Reactant: CS(=O)(=O)N[C@@H]1CCCC[C@H]1Nc1nc(Cl)ncc1Cl
Reactant: COCCNC1CCc2ccc(N)cc2CC1
Reactant: O=C(O)C(F)(F)F
Product: COCCNC1CCc2cc(Nc3ncc(Cl)c(N[C@@H]4CCCC[C@H]4NS(C)(=O)=O)n3)c(OC)cc2CC1

Procedure:
The title compound was prepared from N(7)-(2-methoxyethyl)-6,7,8,9-tetrahydro-5H-benzocycloheptene-2,7-diamine and N[(1R,2R)-2-(2,5-dichloropyrimidin-4-ylamino)-cyclohexyl]methanesulfonamide in an analogous manner to Example 179. Product was prepared as a TFA salt (16.6 mg, 21%). LCMS (m/e) 567 (M+H); 1H NMR (400 MHz, CDCl3) 9.89 (broad s, 1H), 9.03 (broad s, 1H), 8.03 (s, 1H), 7.54 (broad s, 1H), 7.20 (s, 2H), 6.46 (s, 1H), 3.82 (s, 1H), 3.67 (s, 5H), 3.36 (m, 5H), 3.19 (s, 2H), 3.02 (s, 3H), 2.61-2.86 (m, 4H), 2.34 (m, 2H), 2.17 (m, 1H), 2.08 (d, 1H, J=11.37 Hz), 1.85 (d, 1H, J=12.3 Hz), 1.72 (m, 1H), 1.59 (m, 3H), 1.32 (m, 1H), 1.13 (m, 2H).
Reaction SMILES: CO[C:3](=[O:28])[C:4]1[CH:9]=[CH:8][C:7]([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[C:23]([NH:24][CH:25]([CH3:27])[CH3:26])=[CH:22][CH:21]=[CH:20][N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:6][CH:5]=1.[NH2:29][CH2:30][CH2:31][N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.O>C(O)C.C(#N)C>[CH:25]([NH:24][C:23]1[C:18]([N:15]2[CH2:16][CH2:17][N:12]([C:10]([C:7]3[CH:8]=[CH:9][C:4]([C:3](=[O:28])[NH:29][CH2:30][CH2:31][N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[CH:5][CH:6]=3)=[O:11])[CH2:13][CH2:14]2)=[N:19][CH:20]=[CH:21][CH:22]=1)([CH3:27])[CH3:26]
Reactant: NCCN1CCOCC1
Reactant: COC(=O)c1ccc(C(=O)N2CCN(c3ncccc3NC(C)C)CC2)cc1
Solvent: CCO
Solvent: CC#N
Solvent: O
Product: CC(C)Nc1cccnc1N1CCN(C(=O)c2ccc(C(=O)NCCN3CCOCC3)cc2)CC1
Reaction time: 1 h
Yield: 80.9 %

Procedure:
4-[1-[3-(Isopropylamino)-2-pyridyl]piperazin-4-yl-carbonyl]benzoic acid methyl ester (1.2 g) was dissolved in a co-solvent of ethanol (10 ml) and acetonitrile (20 ml), and 4-(2-aminoethyl)morpholine (0.82 g) was added. The reaction mixture was heated to reflux for 15 hours and cooled. After excess of water was added to the solution at 30° C. to precipitate the crystals, the solution was stirred for 1 hour. Then, the solution was again cooled slowly, stirred at 10~15° C. for 2 hours and filtered. The filtered crystal was washed with preheated water(40° C.) and was recrystallized using isopropanol and ether, filtered and dried to give 1.22 g (yield: 81%) of the desired compound.
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: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: C1CCOC1
Solvent: O
Product: CC(CNS(=O)(=O)C(C)C)c1ccc(-c2ccc(C=CC#N)cc2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

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.