Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].[C:2]([NH:12][C@H:13]([C:21]([OH:23])=O)[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)=[O:3].[NH2:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1.C1(N=C=NC2CCCCC2)CCCCC1.CO>CN(C)C=O>[ClH:1].[C:2]([NH:12][C@H:13]([C:21]([NH:24][C:25]1[CH:34]=[C:33]2[C:28]([C:29]([CH3:36])=[CH:30][C:31](=[O:35])[O:32]2)=[CH:27][CH:26]=1)=[O:23])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:20])[NH2:19])([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:3]
Reactant: Cc1cc(=O)oc2cc(N)ccc12
Reactant: N=C(N)NCCC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1cc(=O)oc2cc(NC(=O)[C@H](CCCNC(=N)N)NC(=O)OCc3ccccc3)ccc12
Temperature: 25 °C
Yield: 28.9 %

Procedure:
Nα -carbobenzoxy-L-arginine hydrochloric acid salt (69.0 g, 0.2 M) and 7-amino-4-methylcoumarin (17.5 g, 0.1 M) were dissolved in dimethylformamide (DMF) (300 ml). Dicyclohexylcarbodiimide (DCCD) (21 g, 0.1 M) was added to the mixture with stirring at room temperature. This mixture was stirred overnight at room temperature, and the produced dicyclohexyl urea was removed by filtration. The obtained filtrate was concentrated under reduced pressure and to the thus obtained residue methyl alcohol (50 ml) and ethyl acetate (500 ml) were added. The precipitated material was separated by filtration to give crude crystals (19 g). These crystals were dissolved in a mixture of heated DMF (30 ml) and heated methyl alcohol (100 ml) and insoluble material was removed by filtration. To the filtrate ethyl acetate (400 ml) was added and the thereby precipitated white crystals were separated by filtration and dried to give 7-(Nα -carbobenzoxy-L-arginyl)amino-4-methylcoumarin hydrochloric acid salt (14.5 g, yield: 29%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH:8][C:9](=O)[CH2:10][CH2:11][CH3:12])=[CH:6][C:5]([C:14]2[CH:15]=[CH:16][C:17]3[O:23][CH2:22][CH2:21][N:20]([C:24]4[C:33]5[CH2:32][C:31]([CH3:35])([CH3:34])[CH2:30][CH2:29][C:28]=5[N:27]=[CH:26][N:25]=4)[CH2:19][C:18]=3[CH:36]=2)=[CH:4][N:3]=1>C(O)(=O)C>[CH3:35][C:31]1([CH3:34])[CH2:30][CH2:29][C:28]2[N:27]=[CH:26][N:25]=[C:24]([N:20]3[CH2:19][C:18]4[CH:36]=[C:14]([C:5]5[CH:6]=[C:7]6[N:8]=[C:9]([CH2:10][CH2:11][CH3:12])[NH:1][C:2]6=[N:3][CH:4]=5)[CH:15]=[CH:16][C:17]=4[O:23][CH2:22][CH2:21]3)[C:33]=2[CH2:32]1
Reactant: CCCC(=O)Nc1cc(-c2ccc3c(c2)CN(c2ncnc4c2CC(C)(C)CC4)CCO3)cnc1N
Solvent: CC(=O)O
Product: CCCc1nc2cc(-c3ccc4c(c3)CN(c3ncnc5c3CC(C)(C)CC5)CCO4)cnc2[nH]1
Temperature: 120 °C
Yield: 24.9 %

Procedure:
N-{2-amino-5-[4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepin-7-yl]pyridin-3-yl}butanamide (50 mg) was dissolved in acetic acid (0.2 mL) and heated in a microwave oven at 150 watts, 120° C. for 30 minutes. The reaction mixture was concentrated, dissolved in methanol (2 mL) and purified by preparative reverse phase HPLC (0.1% aqueous ammonium acetate-acetonitrile) to give 4-(6,6-dimethyl-5,6,7,8-tetrahydroquinazolin-4-yl)-7-(2-propyl-3H-imidazo[4,5-b]pyridin-6-yl)-2,3,4,5-tetrahydro-1,4-benzoxazepine (12 mg, 32% yield), 1H NMR (400 MHz, Methanol-d4): 8.51 (br, 1H), 8.37 (s, 1H), 8.06 (s, 1H), 7.61 (s, 1H), 7.51 (d, 1H), 7.10 (d, 1H), 4.74 (s, 2H), 4.36 (m, 2H), 3.96 (m, 2H), 2.94 (t, 2H), 2.77 (t, 2H), 2.48 (s, 2H), 1.89 (m, 2H), 1.66 (t, 2H), 1.01 (t, 3H), 0.81 (s, 6H); MS (EI) for C28H32N6O: 469 (MH+).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([CH:22]=2)[NH2:21])[CH:5]=[CH:4][N:3]=1.[F:24][C:25]1[CH:26]=[C:27]([S:31](Cl)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:12][C:11]([CH:13]([CH3:15])[CH3:14])=[N:10][C:9]=2[C:16]2[CH:17]=[CH:18][C:19]([F:23])=[C:20]([NH:21][S:31]([C:27]3[CH:28]=[CH:29][CH:30]=[C:25]([F:24])[CH:26]=3)(=[O:33])=[O:32])[CH:22]=2)[CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(Cl)c1cccc(F)c1
Reactant: CC(C)c1nc(-c2ccc(F)c(N)c2)c(-c2ccnc(Cl)n2)s1
Product: CC(C)c1nc(-c2ccc(F)c(NS(=O)(=O)c3cccc(F)c3)c2)c(-c2ccnc(Cl)n2)s1

Procedure:
Following a procedure analogous to the procedure described in Intermediate 14 using 5-[5-(2-chloro-4-pyrimidinyl)-2-(1-methylethyl)-1,3-thiazol-4-yl]-2-fluoroaniline (12 g, 34.5 mmol) and 3-fluorobenzenesulfonyl chloride (8.72 g, 44.8 mmol) the title compound of Step A was obtained (9.3 g, 53.4%). 1H NMR (400 MHz, CDCl3) δ ppm 8.35 (d, J=5.3 Hz, 1H), 7.65-7.73 (m, 1H), 7.52-7.60 (m, 1H), 7.41-7.50 (m, 2H), 7.20-7.37 (m, 1H), 7.04-7.12 (m, 1H), 6.83-7.00 (m, 2H), 3.30-3.40 (m, 1H), 1.46 (d, J=6.8 Hz, 6H). MS (ES+): 507 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1([C:18]([OH:20])=O)[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(CC)CC.P([N:44]=[N+:45]=[N-:46])(OC1C=CC=CC=1)(OC1C=CC=CC=1)=O>C1COCC1>[C:1]([O:5][C:6]([C:8]1([C:18]([N:44]=[N+:45]=[N-:46])=[O:20])[CH2:17][CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)C1(C(=O)O)CCc2ccccc2C1
Reactant: [N-]=[N+]=NP(=O)(Oc1ccccc1)Oc1ccccc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C1(C(=O)N=[N+]=[N-])CCc2ccccc2C1
Yield: 58 %

Procedure:
3,4-Dihydro-1H-naphthalene-2,2-dicarboxylic acid tert-butyl ester from Example 43A was dissolved in THF (50 mL) followed by addition of Et3N (5.05 g, 50 mmol) and (PhO)2PON3 (11 g, 40 mmol) at 0° C. After 3 hours the volatiles were removed under reduced pressure and the residue purified by column chromatography to provide the titled compound (13.1 g, 58% over three steps).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[CH:19][C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:12]=1.[C:21]1([NH:27][C:28](=[N:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)SC)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[C:32]1([NH:31][C:28]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH:12]=2)=[N:27][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1
Reactant: NCCCCCCCCOc1ccc2ccccc2c1
Reactant: CSC(=Nc1ccccc1)Nc1ccccc1
Product: c1ccc(N=C(NCCCCCCCCOc2ccc3ccccc3c2)Nc2ccccc2)cc1

Procedure:
4.0 g of 1-amino-8(2-naphthyloxy)octane and 3.6 g of 1,3-diphenyl-S-methylisothiourea were heated to 110° C. under a nitrogen atmosphere for 3 hours. The crude product was chromatographically separated from the reaction mixture on a silica gel column with the mobile phase being methylene chloride:methanol:ammonium hydroxide 100:12:1.2 thereby isolating the 1,2-diphenyl-3-[8-(2-naphthyloxy)octyl]guanidine which was converted to the hydrochloride (mp 124°-126°) using the procedure of Example IV.
Reaction SMILES: ClS(O)(=O)=O.[Sb](F)(F)(F)(F)F.Cl[CH2:13][C:14](O)=O.[C:17]1([S:23](Cl)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>C1C=CC=CC=1>[C:17]1([S:23]([C:14]2[CH:13]=[CH:19][CH:18]=[CH:17][CH:22]=2)(=[O:25])=[O:24])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: O=C(O)CCl
Agent: F[Sb](F)(F)(F)F
Agent: O=S(=O)(O)Cl
Solvent: c1ccccc1
Product: O=S(=O)(c1ccccc1)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h

Procedure:
Into a mixture of 6.6 ml of chlorosulfonic acid, 6 ml of antimony pentafluoride and 10 ml of monochloroacetic acid, was added 8.9 ml of benzene at 25° C., and the mixture was stirred for 3 hours. The reaction mixture was transferred into ice water and the precipitated product was extracted with benzene. From the results of analysis, it was confirmed that benzene-sulfonyl chloride and diphenylsulfone were formed in yields of 50% and 20%, respectively, based on benzene.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[S:24][C:23]([C:25]([O:27][CH3:28])=[O:26])=[C:22]([CH3:29])[C:9]=3[N:10](COC)[C:11]=2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[OH:18])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl.CC1(C)[N:36]([C:37]([O:39][CH2:40][C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)=[O:38])[C@@H:35]([CH2:47]OS(C2C=CC([N+]([O-])=O)=CC=2)(=O)=O)[CH2:34][O:33]1>O1CCOCC1.CN(C=O)C.CO>[CH2:40]([O:39][C:37]([NH:36][C@H:35]([CH2:34][OH:33])[CH2:47][O:18][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[C:11]1[NH:10][C:9]2[C:22]([CH3:29])=[C:23]([C:25]([O:27][CH3:28])=[O:26])[S:24][C:8]=2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)=[O:38])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: COCn1c(-c2ccccc2O)c(C2CCCCC2)c2sc(C(=O)OC)c(C)c21
Reactant: CC1(C)OC[C@H](COS(=O)(=O)c2ccc([N+](=O)[O-])cc2)N1C(=O)OCc1ccccc1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Solvent: CN(C)C=O
Product: COC(=O)c1sc2c(C3CCCCC3)c(-c3ccccc3OC[C@@H](CO)NC(=O)OCc3ccccc3)[nH]c2c1C
Temperature: 50 °C
Yield: 31 %

Procedure:
Methyl 6-cyclohexyl-5-(2-hydroxyphenyl)-4-(methoxymethyl)-3-methyl-4H-thieno[3,2-b]pyrrole-2-carboxylate was dissolved in dioxane (0.036M) and the same volume of 6N HCl was added. The mixture was subjected to microwave irradiation (10 min @ 130° C.). All volatiles were evaporated and the product was enriched by prep. RP-HPLC. The product-containing fractions were lyophilised to give a green glassy solid. This material was dissolved in DMF (0.16M) and benzyl (4R)-2,2-dimethyl-4-({[(4-nitrophenyl)sulfonyl]oxy}methyl)-1,3-oxazolidine-3-carboxylate (excess, prepared according to Synthesis 1996, 189 in analogy to benzyl (4R)-2,2-dimethyl-4-({[(4-methylphenyl)sulfonyl]oxy}methyl)-1,3-oxazolidine-3-carboxylate from benzyl (4S)-4-(hydroxymethyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate and substituting tosyl chloride with 4-nitrobenzenesulfonyl chloride) was added. The suspension was heated to 50° C. overnight. All volatiles were evaporated i. vac. and the residual material was purified by prep. RP-HPLC. The product fractions were evaporated and the residual material lyophilised from MeCN/water. A beige solid was obtained, which was dissolved dry MeOH (0.2M) and 1.25M HCl in MeOH (excess) was added. The solution was left stirring at RT. After 3 h all volatiles were evaporated and the residual material was subjected to purification by chromatography (PE:EtOAc, 6:4). After evaporation of the product fractions the product was obtained as a yellow powder (31%). MS (ES+) m/z 577 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][OH:10])=[CH:4][CH:3]=1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].CN(C)C=O>O>[Br:1][C:2]1[CH:12]=[CH:11][C:5]([O:6][CH2:7][CH2:8][CH2:9][O:10][Si:13]([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14])=[CH:4][CH:3]=1
Reactant: OCCCOc1ccc(Br)cc1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCCCOc1ccc(Br)cc1
Temperature: 25 °C

Procedure:
To a dry 100 mL round bottom flask under nitrogen was added 3-(4-bromophenoxy)propan-1-ol (9.0 g, 39.0 mmol), tert-butyldimethylsilyl chloride (7.0 g, 47.0 mmol), imidizole (3.2 g, 47.0 mmol), and 20 mL of N,N-dimethylformamide. The reaction was allowed to stir at room temperature while being monitored by thin layer chromatography. Upon disappearance of the starting material the reaction mixture was poured into a separatory funnel containing 50 mL of cold water. The product was extracted using 3×25 mL ether. The organic layers were combined and washed with 3×25 mL cold water and 3×25 mL saturated sodium chloride solution. The resulting organic layer was dried over magnesium sulfate, filtered from drying agent, and the solvent was removed under reduced pressure. The material was purified by filtering through a plug of silica gel eluting with 4:6 dichloromethane:hexane. The solvent was removed under reduced pressure (12.1 g, 89.4%). 1H NMR (300 MHz, CDCl3) δ 7.34 (d, J=9.0 Hz, 2H), 6.76 (d, J=9.0 Hz, 2H), 4.00 (t, J=6.0 Hz, 2H), 3.76 (t, J=6.0 Hz, 2H), 1.95 (q, J=6.0 Hz, 2H), 0.87 (s, 9H), 0.03 (s, 6H).
Reaction SMILES: S(S([O-])=O)([O-])=O.[Na+].[Na+].[F:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]3[CH:24]=[CH:25][C:26]([N+:38]([O-])=O)=[C:27]([CH:37]=3)[NH:28][C:29]3[CH:34]=[CH:33][C:32]([O:35][CH3:36])=[CH:31][CH:30]=3)=[N:20][N:19]=2)[CH:13]=[CH:14][CH:15]=1.O1CCCC1.C(=O)([O-])O.[Na+]>C(O)C>[F:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]2[O:22][C:21]([C:23]3[CH:37]=[C:27]([NH:28][C:29]4[CH:30]=[CH:31][C:32]([O:35][CH3:36])=[CH:33][CH:34]=4)[C:26]([NH2:38])=[CH:25][CH:24]=3)=[N:20][N:19]=2)[CH:13]=[CH:14][CH:15]=1
Reactant: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2[N+](=O)[O-])cc1
Agent: O=C([O-])O
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(Nc2cc(-c3nnc(CCc4cccc(F)c4)o3)ccc2N)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 72.4 %

Procedure:
To an aqueous solution (5.1 mL) of sodium hydrosulfite (1.15 g, 6.61 mmol) was added a mixed solution of 5-[5-[2-(3-fluorophenyl)ethyl]-1,3,4-oxadiazol-2-yl]-N-(4-methoxyphenyl)-2-nitroaniline (0.20 g, 0.41 mmol), tetrahydrofuran (4.1 mL) and ethanol (2.1 mL) at 0° C., and the resulting mixture was stirred at room temperature for 30 min. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=1/2) to give the title compound (0.12 g, yield 71%) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([CH3:9])=[CH:4][N:3]=1.Br[C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].C1(P(C2C=CC=CC=2)C2C3OC4C(=CC=CC=4P(C4C=CC=CC=4)C4C=CC=CC=4)C(C)(C)C=3C=CC=2)C=CC=CC=1>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:1][C:2]1[N:7]=[C:6]([NH:8][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][CH3:18])[CH:12]=2)[C:5]([CH3:9])=[CH:4][N:3]=1
Reactant: COc1cccc(Br)c1
Reactant: Cc1cnc(Cl)nc1N
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: COc1cccc(Nc2nc(Cl)ncc2C)c1

Procedure:
To a solution of 2-chloro-5-methylpyrimidin-4-amine (320 mg, 2.23 mmol) in 1,4-dioxane (40 mL) was added 1-bromo-3-methoxybenzene (458.5 mg, 2.45 mmol), Cs2CO3 (2.9 g, 8.9 mmol), Pd2(dba)3 (201 mg, 0.22 mmol), and 4,5-bis(diphenylphosphino)-9,9-dimethyxanthene (Xant Phos, 382 mg, 0.66 mmol). The mixture was heated under reflux for 4 h under Ar. The solid was filtered off and the filtrate washed with brine (1×100 mL). The organic solution was separated and dried (Na2SO4). The solvent was removed until 5 mL and hexane (100 mL) was added, the solid was collected by filtration. The crude product, the title intermediate 24 (500 mg, 90%), was used for next reaction without further purification.
Reaction SMILES: [CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:19])=[O:18])=[CH:13][CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[CH:34]=[CH:33][N:32]([CH2:35][C:36]([CH3:39])([OH:38])[CH3:37])[N:31]=1.N1C(C)=CC=CC=1C>C(Cl)Cl.CN(C)C=O>[CH:1]1([CH2:6][C@H:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH:20]3[CH2:22][CH2:21]3)(=[O:18])=[O:19])=[CH:13][CH:12]=2)[C:8]([NH:29][C:30]2[CH:34]=[CH:33][N:32]([CH2:35][C:36]([OH:38])([CH3:37])[CH3:39])[N:31]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: O=C(O)[C@H](CC1CCCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Reactant: CC(C)(O)Cn1ccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Product: CC(C)(O)Cn1ccc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(=O)(=O)C3CC3)cc2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 57.1 %

Procedure:
A solution of (R)-3-cyclopentyl-2-(4-cyclopropanesulfonyl-phenyl)-propionic acid (50 mg, 0.16 mmol) was dissolved in methylene chloride (5 mL) and N,N-dimethylformamide (one drop) and cooled to 0° C. To this solution was added dropwise a solution of oxalyl chloride in methylene chloride (2 M solution, 93 μL, 0.19 mmol) which produced gas evolution and it was stirred at 0° C. for 10 min and it was then allowed to warm to 25° C. and stirred 25 min at 25° C. After this time, the reaction was concentrated in vacuo to ˜1 mL. In a separate flask, a solution of 1-(3-amino-pyrazol-1-yl)-2-methyl-propan-2-ol (prepared as in Example 80, 36 mg, 0.23 mmol), 2,6-lutidine (34 μL, 0.31 mmol) and methylene chloride (5 mL) was cooled to 0° C. in an ice bath. To this solution was added the solution of the prepared acid chloride, diluted with another portion of methylene chloride (1 mL), dropwise. After addition was complete the reaction was then allowed to warm to 25° C. and stirred for 16 hours. After this time the reaction mixture quenched with a saturated aqueous sodium bicarbonate solution (10 mL) and transferred to a separatory funnel where it was extracted with methylene chloride (3×10 mL). The organic layers were then washed with a 1 N aqueous hydrochloric acid solution (10 mL) and then dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (12 g column, 55% ethyl acetate/hexanes to 70% ethyl acetate/hexanes) afforded (R)-3-cyclopentyl-2-(4-cyclopropanesulfonyl-phenyl)-N-[1-(2-hydroxy-2-methyl-propyl)-1H-pyrazol-3-yl]-propionamide (42 mg, 59%) as a white foam: [α]30589=−12.0° (c=0.10, methylene chloride); ES-HRMS m/e calcd for C24H33N3O4S (M+H)+ 460.2265, observed 460.2264; 1H NMR (300 MHz, DMSO-d6) δ ppm 0.96-1.21 (m, 6H, 3×CH2), 1.03 (s, 3H, CH3), 1.04 (s, 3H, CH3), 1.35-1.81 (m, 8H, 4×CH2), 2.10 (m, 1H, CH), 2.81 (m, 1H, SCH), 3.86 (s, 2H, NCH2), 3.93 (m, 1H, ArCHCO), 4.65 (s, 1H, OH), 6.45 (d, J=2.1 Hz, 1H, Ar), 7.50 (d, J=2.1 Hz, 1H, Ar), 7.63 (d, J=8.2 Hz, 2H, Ar), 7.84 (d, J=8.2 Hz, 2H, Ar), 10.78 (s, 1H, NH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([CH:11]1[CH2:16][CH2:15][NH:14][CH2:13][CH2:12]1)=[O:10].[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:29][CH2:28][C@H:27]([CH2:30][CH:31]=O)[CH2:26][CH2:25]1)([CH3:20])([CH3:19])[CH3:18]>>[C:17]([O:21][C:22](=[O:33])[NH:23][C@H:24]1[CH2:25][CH2:26][C@H:27]([CH2:30][CH2:31][N:14]2[CH2:15][CH2:16][CH:11]([C:9](=[O:10])[C:3]3[CH:4]=[CH:5][C:6]([Cl:8])=[CH:7][C:2]=3[Cl:1])[CH2:12][CH2:13]2)[CH2:28][CH2:29]1)([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CC=O)CC1
Reactant: O=C(c1ccc(Cl)cc1Cl)C1CCNCC1
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](CCN2CCC(C(=O)c3ccc(Cl)cc3Cl)CC2)CC1

Procedure:
The title compound was prepared as described on example 1 from (2,4-Dichloro-phenyl)-piperidin-4-yl-methanone and Trans-[4-(2-Oxo-ethyl)-cyclohexyl]-carbamic acid tert-butyl ester (m/e): 483.4 (M+H+)
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([O:24]C(=O)C(C)(C)C)[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2].C(O[C:36]([N:38]1[CH2:43][CH2:42][CH:41]([C:44]2[CH:49]=[CH:48][C:47]([C:50](O)=O)=[CH:46][CH:45]=2)[CH2:40][CH2:39]1)=O)(C)(C)C>>[CH2:1]([N:3]([CH2:50][C:47]1[CH:46]=[CH:45][C:44]([CH:41]2[CH2:40][CH2:39][N:38]([CH3:36])[CH2:43][CH2:42]2)=[CH:49][CH:48]=1)[C:4]1[CH:9]=[C:8]([O:10][CH3:11])[C:7]([O:12][CH3:13])=[CH:6][C:5]=1[CH:14]1[CH2:23][CH2:22][C:21]2[CH:20]=[C:19]([OH:24])[CH:18]=[CH:17][C:16]=2[CH2:15]1)[CH3:2]
Reactant: CCNc1cc(OC)c(OC)cc1C1CCc2cc(OC(=O)C(C)(C)C)ccc2C1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(C(=O)O)cc2)CC1
Product: CCN(Cc1ccc(C2CCN(C)CC2)cc1)c1cc(OC)c(OC)cc1C1CCc2cc(O)ccc2C1
Yield: 70.4 %

Procedure:
Synthesized from pivalic acid 6-(2-ethylamino-4,5-dimethoxyphenyl)-5,6,7,8-tetrahydronaphthalen-2-yl ester (50 mg) and 4-(4-carboxyphenyl)piperidine-1-carboxylic acid tert-butyl ester (100 mg) according to an analogous synthetic method to Example 337 described below, the title compound (44 mg) was obtained.
Reaction SMILES: [CH2:1]([OH:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[CH3:20][O:21][C:22]([CH2:24][C:25]#[N:26])=[O:23].[ClH:27]>C(OCC)C>[ClH:27].[CH3:20][O:21][C:22]([CH2:24][C:25](=[NH:26])[O:19][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18])=[O:23]
Reactant: CCCCCCCCCCCCCCCCCCO
Reactant: COC(=O)CC#N
Agent: Cl
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCCCOC(=N)CC(=O)OC
Reaction time: 48 h
Yield: 46.8 %

Procedure:
In a mixture of 27.0 parts of stearyl alcohol in 200 volume parts of dry ethyl ether and 9.9 parts of methyl cyano acetate was introduced about 5.3 parts of dry hydrogen chloride gas at room temperature, followed by keeping at room temperature for 2 days. The resulting white precipitates were washed with ethylether and dried to give 19.0 parts of stearyl methoxycarbonylacetimidate hydrochloride melting at 83° to 85°C (decomposition). Yield: 46.8%
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:13])([CH3:12])[C:6]=2[CH:14]=1.C(=O)([O-])[O-].[K+].[K+].[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]Br>CS(C)=O>[Br:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][O:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][C:9](=[O:11])[O:8][C:7]([CH3:12])([CH3:13])[C:6]=2[CH:14]=1
Reactant: CC1(C)OC(=O)Nc2ccc(O)cc21
Reactant: BrCCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: CC1(C)OC(=O)Nc2ccc(OCCCCCBr)cc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 19.3 gm (0.1 mol) of 6-hydroxy-4,4-dimethyl-4H-3,1-benzoxazin-2-one in 200 ml of dimethyl sulfoxide is mixed at ambient temperature with 41.5 gm (0.3 mol) of potassium carbonate and 92 gm (0.4 mol) of 1,5-dibromopentane, whereupon the temperature rises to 45° C. After stirring a further two hours, ice water is added, and the resulting mixture is extracted with chloroform. The chloroform phase is washed with water and dried with sodium sulfate, and the chloroform is distilled off. The residue is recrystallized from ethyl acetate/petroleum ether.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]([CH2:25][CH3:26])([CH3:24])[CH3:23])=[CH:18][CH:17]=2)[C:10]([O:12]CC)=[O:11])[CH:5]=[CH:6][CH:7]=1.[OH-].[Na+].CO.O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:27])[CH:9]([CH2:15][C:16]2[CH:17]=[CH:18][C:19]([C:22]([CH2:25][CH3:26])([CH3:23])[CH3:24])=[CH:20][CH:21]=2)[C:10]([OH:12])=[O:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(Cc1ccc(C(C)(C)CC)cc1)C(O)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCC(C)(C)c1ccc(CC(C(=O)O)C(O)c2cccc(Cl)c2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of ethyl (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionate (6.650 g, 17.10 mmol), sodium hydroxide (1.37 g, 34.2 mmol), methanol (20 ml), water (20 ml) and tetrahydrofuran (20 ml) was stirred overnight at room temperature. The reaction solution was concentrated, diluted with water, acidified with hydrochloric acid, and extracted twice with ethyl acetate. The recovered organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated under reduced pressure to give a crude product of (2RS,3RS)-3-(3-chlorophenyl)-3-hydroxy-2-[4-(tert-pentyl)benzyl]propionic acid as a white solid.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[C:10]([CH3:12])[N:9]=[C:8]([NH:13][CH:14]([CH3:16])[CH3:15])[N:7]=1)=O)C.[NH3:17]>CO>[CH:14]([NH:13][C:8]1[N:7]=[C:6]([C:4]([NH2:17])=[O:3])[CH:11]=[C:10]([CH3:12])[N:9]=1)([CH3:16])[CH3:15]
Reactant: CCOC(=O)c1cc(C)nc(NC(C)C)n1
Reactant: N
Solvent: CO
Product: Cc1cc(C(N)=O)nc(NC(C)C)n1

Procedure:
A solution of 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid ethyl ester (1.46 g, 6.54 mmol) in 3M NH3 in MeOH (50 mL) is stirred at 60° C. for 1 day. Volatiles are evaporated to give the crude 2-isopropylamino-6-methyl-pyrimidine-4-carboxylic acid amide as a pale yellow solid (1.24 g); LC-MS: tR=0.59; [M+H]+=195.0.