Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]1)=[O:5])[CH3:2].C(N(C(C)C)C(C)C)C.C1(C)C=CC(S(O[CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)(=O)=O)=CC=1>CN(C)C=O>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([CH2:31][CH2:32][CH:33]2[O:38][C:37]3[CH:39]=[CH:40][CH:41]=[CH:42][C:36]=3[O:35][CH2:34]2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: Cc1ccc(S(=O)(=O)OCCC2COc3ccccc3O2)cc1
Reactant: CCOC(=O)C1CCNCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1CCN(CCC2COc3ccccc3O2)CC1
Reaction time: 16 h
Yield: 115.8 %

Procedure:
First 1.96 g (12.5 mmol) of piperidine-4-carboxylic acid ethyl ester and then 2.58 g (20 mmol) of N-ethyl-N,N-diisopropylamine are added to a solution of 3.34 g (10 mmol) of 2-[2-(p-toluenesulphonyloxy)ethyl]-benzo-1,4-dioxan in 50 ml of absolute dimethylformamide. The mixture is stirred for 16 hours at 60° and, after cooling, is concentrated by evaporation under a high vacuum. Water is added to the oily residue and extraction is carried out with diethyl ether. The combined organic phases are washed with water and extracted with 2N hydrochloric acid. The combined hydrochloric acid extracts are rendered alkaline, while cold, with sodium hydroxide solution (30% strength) and extracted with dichloromethane. The combined dichloromethane phases are dried over sodium sulphate and concentrated by evaporation in vacuo. 3.80 g (99.2%) of crude product are obtained which are filtered over 190 g of silica gel (0.040-0.063 mm) using ethyl acetate as the eluant. 3.7 g (96.6%) of 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester are then obtained in the form of a yellow oil. The 1-[2-(benzo-1,4-dioxan-2-yl)ethyl]-piperidine-4-carboxylic acid ethyl ester hydrochloride produced therefrom using hydrochloric acid in diethyl ether crystallises from ethanol/diethyl ether and melts at 165°-168°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]([F:14])([F:13])[F:12])[O:8][N:7]=1)=O)C.[H-].[Na+].Cl>C(O)C>[F:14][C:11]([F:12])([F:13])[C:9]1[O:8][N:7]=[C:6]([CH2:4][OH:3])[CH:10]=1
Reactant: CCOC(=O)c1cc(C(F)(F)F)on1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Product: OCc1cc(C(F)(F)F)on1
Temperature: 25 °C
Reaction time: 16 h
Yield: 96.8 %

Procedure:
To a solution of 7.5 g 5-trifluoromethyl-isoxazole-3-carboxylic acid ethyl ester in 85 mL ethanol was added 3.66 g sodium hydride portion wise at RT. The reaction mixture was stirred at RT for 16 h. 100 mL 1M HCl were added drop by drop under ice-bath cooling. The reaction mixture was extracted with 250 mL diethyl ether and 200 mL sat. NaCl solution/water mixture 1:1. The aqueous layer was back-extracted with diethyl ether (2×100 mL). The org. layers were washed with sat. NaCl solution/water mixture 1:1 (2×200 mL). The combined org. layer was dried over Na2SO4, filtered off and concentrated in vacuo to yield 5.8 g of the title compound as brown oil. MS (EI): 167 (M+H)+.
Reaction SMILES: [C:1]1([C:7]2[N:12]=[C:11]([C:13]([OH:15])=O)[CH:10]=[CH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(N1C=CN=C1)(N1[CH:22]=[CH:21]N=C1)=O.C(O)(=O)[CH2:29][C:30]([OH:32])=[O:31].C([K])C.[Cl-].[Mg+2].[Cl-]>O1CCCC1>[CH2:21]([O:32][C:30](=[O:31])[CH2:29][C:13](=[O:15])[C:11]1[CH:10]=[CH:9][N:8]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:12]=1)[CH3:22]
Reactant: O=C(O)CC(=O)O
Reactant: O=C(O)c1ccnc(-c2ccccc2)n1
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: CC[K]
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Product: CCOC(=O)CC(=O)c1ccnc(-c2ccccc2)n1
Temperature: 25 °C
Reaction time: 7 h
Yield: 58.3 %

Procedure:
A solution of 2-phenyl-pyrimidine-4-carboxylic acid (3.49 g, 17.4 mmol) and 1,1′-carbonyldiimidazole (2.86 g, 17.7 mmol) in tetrahydrofuran (100 ml) was stirred at 60° C. for 20 min. After cooling to room temperature, ethyl potassium malonate (3.28 g, 19.2 mmol) and magnesium chloride (2.48 g, 26.1 mmol) were added and the solution was stirred at 60° C. for 7 hours. After removal of the solvent, hydrochloric acid was added to adjust pH to 4 to 2, and the resulting solution was partitioned between water and ethyl acetate. The organic layer was washed with brine and dried over sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified with silica gel column chromatography (eluent; hexane/ethyl acetate=2/1) to afford 3-oxo-3-(2-phenyl-pyrimidin-4-yl)-propionic acid ethyl ester (2.74 g, 58%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:18])[C:4]1[CH:9]=[C:8]([N+:10]([O-:12])=[O:11])[C:7](OC)=[C:6]([N+:15]([O-:17])=[O:16])[CH:5]=1.[F:19]C1C([N+]([O-])=O)=CC([N+]([O-])=O)=CC=1C(O)=O>>[F:19][C:5]1[C:6]([N+:15]([O-:17])=[O:16])=[CH:7][C:8]([N+:10]([O-:12])=[O:11])=[CH:9][C:4]=1[C:3]([O:2][CH3:1])=[O:18]
Reactant: O=C(O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F
Reactant: COC(=O)c1cc([N+](=O)[O-])c(OC)c([N+](=O)[O-])c1
Product: COC(=O)c1cc([N+](=O)[O-])cc([N+](=O)[O-])c1F

Procedure:
Methyl 2-fluoro-3,5-dinitrobenzoate (D137) was prepared in an analogous manner to Description 25 (D25) from 2-fluoro-3,5-dinitrobenzoic acid (D136).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=2)=[C:11]2[C:6]([N:7]([CH3:23])[C:8](=[O:22])[N:9]([CH3:21])[C:10]2=[O:20])=[CH:5]1.[Cl:24][C:25]1[O:29][C:28]([CH:30]=O)=[CH:27][CH:26]=1>C(O)C.C(O)(C(F)(F)F)=O>[Cl:24][C:25]1[O:29][C:28]([CH:30]2[C:5]3=[C:6]4[C:11](=[C:12]([C:13]5[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=5)[N:4]3[CH2:3][CH2:2][NH:1]2)[C:10](=[O:20])[N:9]([CH3:21])[C:8](=[O:22])[N:7]4[CH3:23])=[CH:27][CH:26]=1
Reactant: Cn1c(=O)c2c(-c3cccc(Cl)c3)n(CCN)cc2n(C)c1=O
Reactant: O=Cc1ccc(Cl)o1
Solvent: CCO
Solvent: O=C(O)C(F)(F)F
Product: Cn1c(=O)c2c(-c3cccc(Cl)c3)n3c(c2n(C)c1=O)C(c1ccc(Cl)o1)NCC3
Temperature: 50 °C

Procedure:
6-(2-Amino-ethyl)-5-(3-chloro-phenyl)-1,3-dimethyl-1,6-dihydro-pyrrolo[3,4-d]pyrimidine-2,4-dione (Intermediate B) (150 mg, 0.451 mmol) and 5-chlorofuran-2-carbaldehyde (commercially available, 58.8 mg, 0.451 mmol) were suspended in ethanol (1.2 ml). The mixture was heated at 50° C. under microwave irradiation for 1 hour. TFA (4 drops) was added to the reaction mixture and heating continued at 60° C. for a further 30 mins under microwave irradiation. The reaction mixture was diluted with ethanol (0.5 mL) and purified using mass directed HPLC. The product containing fractions were combined and evaporated under reduced pressure to afford a white solid which was dried under vacuum at 50° C. for 16 h to afford the title compound as a pale tan solid;
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]=[CH:12][C:11]2=[O:16])=[CH:6][CH:5]=1.[O:17]=[C:18]([NH:33][C@@H:34]1[CH2:38][CH2:37][NH:36][CH2:35]1)[CH2:19][NH:20][C:21](=[O:32])[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=1.[NH4+].[OH-]>CCOC(C)=O.CO>[CH3:2][O:3][C:4]1[CH:5]=[CH:6][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:36]3[CH2:37][CH2:38][C@@H:34]([NH:33][C:18](=[O:17])[CH2:19][NH:20][C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:29])([F:31])[F:30])[CH:23]=4)[CH2:35]3)[CH2:12][C:11]2=[O:16])=[CH:8][CH:9]=1
Reactant: COc1ccc(N2CCC=CC2=O)cc1
Reactant: O=C(CNC(=O)c1cccc(C(F)(F)F)c1)N[C@@H]1CCNC1
Agent: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: CCOC(C)=O
Product: COc1ccc(N2CCC(N3CC[C@@H](NC(=O)CNC(=O)c4cccc(C(F)(F)F)c4)C3)CC2=O)cc1
Yield: 53.1 %

Procedure:
A slurry of water (19 μL, 0.10 mmol), 1-(4-methoxyphenyl)-5,6-dihydropyridin-2(1H)-one (42 mg, 0.207 mmol) and N-{2-oxo-2-[(3R)-pyrrolidin-3-ylamino]ethyl}-3-(trifluoromethyl)benzamide (130 mg, 0.41 mmol) was heated to 90° C. overnight. The crude mixture was subjected to flash chromatography (1% NH4OH, 15% MeOH, EtOAc) to yield the title compound as a white solid (57 mg, 53%). 1H-NMR (CD3OD) δ: 1.70-1.82 (m, 1H), 1.83-2.00 (m, 1H), 2.15-2.37 (m, 2H); 2.40-2.58 (m, 1H), 2.56-2.81 (m, 4H), 2.83-3.00 (m, 2H), 3.29-3.33 (m, 2H), 3.60-3.71 (m, 2H), 3.79 (s, 3H), 4.04 (s, 2H), 4.38-4.47 (m, 1H), 6.94 (d, J=8.7 Hz, 2H), 7.16 (d, J=8.7 Hz, 2H), 7.69 (t, J=7.8 Hz, 1H), 7.86 (d, J=7.8 Hz, 1H), 8.14 (d, J=7.8 Hz, 1H), 8.22 (s, 1H). MS m/z: 519 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9][NH:10][CH2:11][C:5]=2[CH:4]=1.[CH2:19](Br)[CH3:20].C(N(CC)C(C)C)(C)C.CN(C)C=O>[I-].[Na+]>[CH2:19]([N:10]1[CH2:11][C:5]2[CH:4]=[C:3]([O:2][CH3:1])[C:15]([N+:16]([O-:18])=[O:17])=[CH:14][C:6]=2[N:7]([CH3:13])[C:8](=[O:12])[CH2:9]1)[CH3:20]
Reactant: CCBr
Reactant: COc1cc2c(cc1[N+](=O)[O-])N(C)C(=O)CNC2
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN1CC(=O)N(C)c2cc([N+](=O)[O-])c(OC)cc2C1
Yield: 71.6 %

Procedure:
A mixture of 7-Methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one (0.50 g, 0.0020 mol), Ethyl bromide (0.297 mL, 0.00401 mol), Sodium iodide (0.0029 g, 0.000019 mol) and N,N-Diisopropylethylamine (0.87 mL, 0.0050 mol;) in N,N-Dimethylformamide (4 mL, 0.05 mol;) was reacted in an analogous manner to example 743-C to give 4-Ethyl-7-methoxy-1-methyl-8-nitro-1,3,4,5-tetrahydro-benzo[e][1,4]diazepin-2-one as a tan solid (0.40 g, 72%). Mp129-131° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([NH:8][CH:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH3:17])[CH2:13][CH2:12]2)[CH3:10])=[C:6]([NH:18]C(=O)OC(C)(C)C)[CH:5]=[C:4]([Cl:26])[N:3]=1>Cl.O1CCOCC1>[Cl:1][C:2]1[C:7]([NH:8][CH:9]([C@H:11]2[CH2:16][CH2:15][C@H:14]([CH3:17])[CH2:13][CH2:12]2)[CH3:10])=[C:6]([NH2:18])[CH:5]=[C:4]([Cl:26])[N:3]=1
Reactant: CC(Nc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1
Agent: Cl
Solvent: C1COCCO1
Product: CC(Nc1c(N)cc(Cl)nc1Cl)[C@H]1CC[C@H](C)CC1
Temperature: 50 °C

Procedure:
Crude tert-butyl (2,6-dichloro-3-((1-(trans-4-methylcyclohexyl)ethyl)amino)pyridin-4-yl)carbamate (70 g, 0.17 mol) was dissolved in a solution of HCl in dioxane (550 mL, 4 mol/L). The mixture was heated to 50° C. for 12 h. TLC (petroleum ether/ethyl acetate=5:1) showed the reaction was complete. White solid appeared. The solvent was removed under reduced pressure. The residue was washed with methyl tertiary butyl ether to give crude 2,6-dichloro-N3-(1-(trans-4-methylcyclohexyl)ethyl)pyridine-3,4-diamine, which was used for the next step without further purification. 1H NMR (400 MHz, DMSO-d6) δ: 6.63 (s, 1H), 3.16-3.13 (m, 1H), 1.84-1.76 (m, 2H), 1.67 (bs, 2H), 1.39 (bs, 1H), 1.25 (bs, 1H), 1.10-0.96 (m, 5H), 0.89-0.81 (m, 5H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:8]([NH:11][C:12]2[CH:13]=[C:14]([CH:29]=[CH:30][CH:31]=2)[C:15]([NH:17][C:18]2[CH:26]=[CH:25][C:21]([C:22]([OH:24])=[O:23])=[C:20]([O:27][CH3:28])[CH:19]=2)=[O:16])(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.Cl[C:33]1C=C(S(Cl)(=O)=O)C=C[CH:38]=1>>[CH2:33]([O:23][C:22](=[O:24])[C:21]1[CH:25]=[CH:26][C:18]([NH:17][C:15](=[O:16])[C:14]2[CH:29]=[CH:30][CH:31]=[C:12]([NH:11][S:8]([C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=3)(=[O:9])=[O:10])[CH:13]=2)=[CH:19][C:20]=1[O:27][CH3:28])[CH3:38]
Reactant: O=S(=O)(Cl)c1cccc(Cl)c1
Reactant: COc1cc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)ccc1C(=O)O
Product: CCOC(=O)c1ccc(NC(=O)c2cccc(NS(=O)(=O)c3cccc(Cl)c3)c2)cc1OC

Procedure:
4-[3-(3-Chloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid, MS (ISP): m/e=459.3 (M+H+), was prepared in analogy to example 17, steps A to D. Step C was performed using 3-chloro-benzenesulfonyl chloride and yielded 4-[3-(3-chloro-benzenesulfonylamino)-benzoylamino]-2-methoxy-benzoic acid ethyl ester, which was hydrolyzed in step D.
Reaction SMILES: [N:1]#[N:2].[S:3]([NH:19][C@H:20]([C:28]([OH:30])=[O:29])[CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:27])[NH2:26])([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:14])[CH3:13])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:5])=[O:4].O.[C:32]1([CH3:42])[CH:37]=[CH:36][C:35]([S:38]([OH:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1.[CH:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C(C(CCCC)CO)C>[N:1]#[N:2].[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[C:32]1([CH3:42])[CH:33]=[CH:34][C:35]([S:38]([OH:41])(=[O:39])=[O:40])=[CH:36][CH:37]=1.[CH2:32]([CH:48]([CH2:47][CH2:46][CH2:45][CH3:44])[CH2:43][O:29][C:28](=[O:30])[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24][C:25](=[NH:26])[NH2:27])[NH:19][S:3]([C:6]1[C:18]2[CH:17]=[CH:16][CH:15]=[C:11]([N:12]([CH3:13])[CH3:14])[C:10]=2[CH:9]=[CH:8][CH:7]=1)(=[O:4])=[O:5])[CH3:33]
Reactant: CN(C)c1cccc2c(S(=O)(=O)N[C@@H](CCCNC(=N)N)C(=O)O)cccc12
Reactant: c1ccccc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: O
Solvent: CCCCC(CC)CO
Product: CCCCC(CC)COC(=O)[C@H](CCCNC(=N)N)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: 100 °C
Yield: 91 %

Procedure:
A mixture of 1.0 gram of N2 -dansyl-L-arginine and 1.4 gram of p-toluenesulfonic acid monohydrate in 10 ml of 2-ethylhexanol was heated for 30 minutes at 100° C. To the thus obtained clear solution, 100 ml of benzene was added, and the mixture was refluxed for 10 hours, removing water by azeotropic distillation. After the solvent was removed by distillation, 100 ml of ethyl ether was added to the residue to give a crystalline mass. Crystallization from acetone gave N2 -dansyl-L-arginine 2-ethylhexyl ester di(p-toluenesulfonate) in 91% yield; mp. 170°-174° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[O:24][CH:25]=[C:26]([C:28]([O:30]C)=[O:29])[N:27]=5)[C:14]4=[O:32])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1.O=C1C2(COC3C=C4C(=CC2=3)CCO4)C2C(=CC=CC=2)N1CC1OC(C(OC)=O)=CC=1>>[CH3:1][C:2]1[C:6]2[CH:7]=[C:8]3[C:13]4([C:21]5[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=5)[N:15]([CH2:22][C:23]5[O:24][CH:25]=[C:26]([C:28]([OH:30])=[O:29])[N:27]=5)[C:14]4=[O:32])[CH2:12][O:11][C:9]3=[CH:10][C:5]=2[O:4][N:3]=1
Reactant: COC(=O)c1coc(CN2C(=O)C3(COc4cc5onc(C)c5cc43)c3ccccc32)n1
Agent: COC(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)CCO5)c3ccccc32)o1
Product: Cc1noc2cc3c(cc12)C1(CO3)C(=O)N(Cc2nc(C(=O)O)co2)c2ccccc21

Procedure:
Following the procedure as described in EXAMPLE 13 and making non-critical variations using methyl 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylate to replace methyl 5-[(2′-oxo-5,6-dihydrospiro[benzo[1,2-b:5,4-b′]difuran-3,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylate, 2-[(3-methyl-2′-oxospiro[furo[3,2-f][1,2]benzisoxazole-5,3′-indol]-1′(2′H)-yl)methyl]-1,3-oxazole-4-carboxylic acid was obtained (69%) as a colorless solid: 1H NMR (300 MHz, DMSO-d6) δ 13.13 (s, 1H), 8.70 (s, 1H), 7.74-7.71 (m, 1H), 7.40-7.34 (m, 1H), 7.26-7.23 (m, 2H), 7.07-7.02 (m, 2H), 5.28-5.22 (m, 2H), 5.00-4.90 (m, 2H), 2.39 (s, 3H); MS (ES+) m/z 417.8 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([OH:23])=[O:22])[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.IC.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:1]([O:8][C:9]1[CH:31]=[CH:30][C:12]([CH2:13][N:14]2[CH:18]=[C:17]([CH2:19][CH2:20][C:21]([O:23][CH3:34])=[O:22])[C:16]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[N:15]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=C(O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: O
Product: COC(=O)CCc1cn(Cc2ccc(OCc3ccccc3)cc2)nc1-c1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 89.8 %

Procedure:
A mixture of 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionic acid (7.01 g), iodomethane (2.12 ml), potassium carbonate (4.70 g) and N,N-dimethylformamide (30 ml) was stirred at room temperature for 48 hours. The reaction mixture was poured into water, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The residue was subjected to silica gel column chromatography, and methyl 3-[1-(4-benzyloxybenzyl)-3-phenyl-1H-pyrazol-4-yl]propionate (6.51 g, yield: 90%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [N:1]1(C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4][CH:3]2[CH2:7][NH:8][CH2:9][CH:2]12.CC1C=CC(S(O[C:28]2[C:37]3[CH2:36][CH2:35][CH2:34][C:33]4([CH2:41][CH2:40][CH2:39][CH2:38]4)[C:32]=3[N:31]=[C:30]([NH2:42])[N:29]=2)(=O)=O)=CC=1>>[NH:1]1[CH2:6][CH2:5][CH2:4][C@@H:3]2[CH2:7][N:8]([C:28]3[C:37]4[CH2:36][CH2:35][CH2:34][C:33]5([CH2:41][CH2:40][CH2:39][CH2:38]5)[C:32]=4[N:31]=[C:30]([NH2:42])[N:29]=3)[CH2:9][C@H:2]12
Reactant: Cc1ccc(S(=O)(=O)Oc2nc(N)nc3c2CCCC32CCCC2)cc1
Reactant: CC(C)(C)OC(=O)N1CCCC2CNCC21
Product: Nc1nc(N2C[C@H]3CCCN[C@H]3C2)c2c(n1)C1(CCCC1)CCC2

Procedure:
The title compound was prepared using the procedures outlined in Examples 1G and 1H, substituting tert-butyl octahydro-1H-pyrrolo[3,4-b]pyridine-1-carboxylate (CAS# 159877-36-8) for the product from Example 1D. 1H NMR (300 MHz, CDCl3) δ 4.38-4.47 (m, 2 H), 3.70-3.82 (m, 2 H), 3.38-3.52 (m, 2 H), 3.31 (td, 1 H), 3.00 (dt, 1 H), 2.57-2.69 (m, 3 H), 2.16-2.26 (m, 2 H), 1.96-2.07 (m, 1 H), 1.79-1.92 (m, 2 H), 1.64-1.76 (m, 6 H), 1.42-1.59 (m, 6 H). MS (DCI+) m/z 328 (M+H).
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][CH:3]=1.[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15]Br.[H-].[Na+]>CN(C)C=O>[CH3:12][O:13][CH:14]([O:17][CH3:18])[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:10][CH:11]=1
Reactant: COC(=O)c1ccc(O)cc1
Reactant: COC(CBr)OC
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(OCC(OC)OC)cc1
Yield: 66.6 %

Procedure:
Methyl 4-hydroxybenzoate (15.52 g), bromoacetaldehyde dimethyl acetal (16.90 g) and 60% sodium hydride (5.00 g) were heated in dimethyl formamide (50 ml) at 80° C. for 18 hr. Dimethyl formamide was distilled away from the reaction mixture, and toluene and water were added. The separated toluene layer was dried over magnesium sulfate, and the solvent was distilled away to give the objective compound (16.00 g).
Reaction SMILES: [CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([OH:15])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:3][CH2:2]1.Cl[C:19]([O:21][CH3:22])=[O:20]>N1C=CC=CC=1>[CH:1]1([C:4]2[S:8][C:7]([N:9]3[CH:14]([O:15][C:19]([O:21][CH3:22])=[O:20])[CH2:13][CH2:12][N:11]([CH3:16])[C:10]3=[O:17])=[N:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cl
Reactant: CN1CCC(O)N(c2nnc(C3CC3)s2)C1=O
Solvent: c1ccncc1
Product: COC(=O)OC1CCN(C)C(=O)N1c1nnc(C2CC2)s1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
Tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl)-3-methyl-6-hydroxy-2(1H)-pyrimidinone (0.05 mole) dissolved in pyridine (80 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10° C and methyl chloroformate (0.06 mole) dissolved in pyridine (25 ml) is slowly added with stirring over a period of about 15 minutes. After the addition is completed, the reaction mixture is warmed to room temperature and is stirred for an additional period of about 20 minutes to ensure completion of the reaction. After this time the reaction mixture is filtered. The filtrate is then combined with water (100 ml) resulting in the formation of a precipitate. This precipitate is recovered by filtration and is dissolved in ether. The ether solution is washed with dilute aqueous sodium carbonate, is dried over anhydrous magnesium sulfate and is filtered. The filtrate is then stripped of ether to yield the desired product tetrahydro-1-(5-cyclopropyl-1,3,4-thiadiazol-2-yl) -3-methyl-6-methoxycarbonyloxy-2(1H)-pyrimidinone as the residue.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:7]([N:36]2[CH2:48][CH2:47][N:39]3[C:40]4[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=4[CH:46]=[C:38]3[C:37]2=[O:49])=[N:8][CH:9]=[CH:10][C:11]=1[C:12]1[N:13]=[C:14]([NH:20][C:21]2[CH:26]=[CH:25][C:24]([C@@H:27]3[C:32](=[O:33])[N:31]([CH3:34])[CH2:30][CH2:29][N:28]3[CH3:35])=[CH:23][CH:22]=2)[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=1)(=O)C.O[Li].O>CC(O)C.C1COCC1.O>[CH3:35][N:28]1[CH2:29][CH2:30][N:31]([CH3:34])[C:32](=[O:33])[C@H:27]1[C:24]1[CH:25]=[CH:26][C:21]([NH:20][C:14]2[C:15](=[O:19])[N:16]([CH3:18])[CH:17]=[C:12]([C:11]3[CH:10]=[CH:9][N:8]=[C:7]([N:36]4[CH2:48][CH2:47][N:39]5[C:40]6[CH2:41][CH2:42][CH2:43][CH2:44][C:45]=6[CH:46]=[C:38]5[C:37]4=[O:49])[C:6]=3[CH2:5][OH:4])[N:13]=2)=[CH:22][CH:23]=1
Reactant: CC(=O)OCc1c(-c2cn(C)c(=O)c(Nc3ccc([C@@H]4C(=O)N(C)CCN4C)cc3)n2)ccnc1N1CCn2c(cc3c2CCCC3)C1=O
Agent: [Li]O
Solvent: CC(C)O
Solvent: C1CCOC1
Solvent: O
Product: CN1CCN(C)[C@H](c2ccc(Nc3nc(-c4ccnc(N5CCn6c(cc7c6CCCC7)C5=O)c4CO)cn(C)c3=O)cc2)C1=O
Temperature: 30 °C
Reaction time: 2 h
Yield: 21.4 %

Procedure:
A mixture of 114b (360 mg, 0.54 mmol) and LiOH.H2O (138 mg, 2.76 mmol) in iPrOH/THF (1:1, 3 mL) and H2O (1 mL) was stirred at 30° C. for 2 h. The mixture was evaporated in vacuo and the residue was extracted with EtOAc (10 mL×2). The combined EtOAc extract was concentrated under reduced pressure and the residue was purified with reverse-phase prep-HPLC to afford 114 (72 mg, 21%) as a white solid. LCMS: [M+H] 623. 1H NMR (500 MHz, CDCl3) δ 8.53 (d, J=4.5, 1H), 8.31 (s, 1H), 8.10 (s, 1H), 7.83-7.78 (m, 3H), 7.36 (d, J=8.0, 2H), 6.89 (s, 1H), 5.12-5.14 (m, 1H), 4.68-4.70 (m, 1H), 4.49-4.53 (m, 1H), 4.38-4.43 (m, 1H), 4.15-4.06 (m, 2H), 3.89-3.90 (m, 1H), 3.72-3.73 (m, 2H), 3.65 (s, 3H), 3.21-3.22 (m, 1H), 3.01-3.03 (m, 4H), 2.71-2.56 (m, 5H), 2.20 (s, 3H), 1.90-1.92 (m, 2H), 1.79-1.80 (m, 2H)
Reaction SMILES: [S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[CH:10][C:9]([CH2:12][N:13]([NH:38]C(OC(C)(C)C)=O)[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:7]=1>C(O)=O>[S:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:7]=[CH:8][C:9]([CH2:12][N:13]([NH2:38])[CH2:14][C@H:15]([OH:37])[C@@H:16]([NH:24][C:25](=[O:36])[C@H:26]([C@H:32]([CH2:34][CH3:35])[CH3:33])[NH:27][C:28]([O:30][CH3:31])=[O:29])[CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:10][CH:11]=1
Reactant: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(Cc1ccc(-c2nccs2)cc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Product: CC[C@H](C)[C@H](NC(=O)OC)C(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CN(N)Cc1ccc(-c2nccs2)cc1

Procedure:
761 mg (1.2 mmol) of 1-[4-(thiazol-2-yl)-phenyl]-4(S)-hydroxy-2-(tert-butoxycarbonyl)amino-5(S)-N-(N-methoxycarbonyl-(L)-iso-leucyl)amino-6-phenyl-2-azahexane and 12 ml of formic acid are stirred at room temperature for 7 hours and worked up analogously to Example 2d to form the title compound.
Reaction SMILES: P(Cl)(Cl)([Cl:3])=O.[F:6][C:7]1[CH:12]=[C:11]([F:13])[CH:10]=[CH:9][C:8]=1[C:14]1[NH:19][C:18](=O)[N:17]2[N:21]=[C:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[N:23]=[C:16]2[CH:15]=1>[Cl-].C([N+](CC)(CC)CC)C1C=CC=CC=1>[ClH:3].[Cl:3][C:18]1[N:17]2[N:21]=[C:22]([CH:24]3[CH2:29][CH2:28][N:27]([CH:30]([CH3:32])[CH3:31])[CH2:26][CH2:25]3)[N:23]=[C:16]2[CH:15]=[C:14]([C:8]2[CH:9]=[CH:10][C:11]([F:13])=[CH:12][C:7]=2[F:6])[N:19]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)[nH]c(=O)n3n2)CC1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: [Cl-]
Product: CC(C)N1CCC(c2nc3cc(-c4ccc(F)cc4F)nc(Cl)n3n2)CC1
Product: Cl
Temperature: 120 °C
Reaction time: 7 h

Procedure:
4.5 ml of phosphoryl chloride were added to 670 mg (1.72 mmol) of 7-(2,4-difluorophenyl)-2-[1-(propan-2-yl)piperidin-4-yl][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (Example 51A), 785 mg (3.45 mmol) of benzyltriethylammonium chloride were added and the reaction mixture was stirred at 120° C. for 7 h. The reaction mixture was concentrated and carefully, with vigorous stirring, added to ice. Three times, the aqueous phase was extracted with dichloromethane. The combined organic phases were freed from the solvent and used without further purification. This gave 590 mg (80% of theory) of the product.