Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([CH:12]=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15].CC(=CC)C.[O-:21]Cl=O.[Na+]>CC(O)(C)C.O>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[C:10]([C:12]([OH:21])=[O:13])=[CH:9][CH:8]=[C:7]2[O:14][CH3:15]
Reactant: [O-][Cl+][O-]
Reactant: COc1ccc(C=O)c2c(Cl)cccc12
Agent: CC=C(C)C
Agent: [Na+]
Solvent: CC(C)(C)O
Solvent: O
Product: COc1ccc(C(=O)O)c2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 79.3 %

Procedure:
To a mixture of 8-chloro-4-methoxy-1-naphthaldehyde (step-3 intermediate) (2.0 g, 9.06 mmol) in tBuOH (20 mL) and 2-methyl-2-butene (14.4 mL, 136.0 mmol) at 0° C. was added a solution of NaClO2 (4.1 g, 45.3 mmol) and NaH2PO4.H2O (6.3 g, 45.3 mmol) in H2O (16 mL) dropwise. The resulting solution was stirred at RT for 24 h. The solvent was evaporated and the crude mixture was basified with 10% NaOH solution and then washed with EtOAc. The aqueous layer was acidified with 1 N HCl and again extracted with EtOAc. The combined organic layer was washed with water, brine, dried (Na2SO4) and filtered. The solvent was evaporated to provide the desired acid as pale yellow solid (1.7 g, 80%).
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1.C(N(CC)CC)C.[CH3:26][C:27]([CH3:32])=[CH:28][C:29](Cl)=[O:30]>ClCCl>[CH3:26][C:27]([CH3:32])=[CH:28][C:29]([N:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][N:4]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[CH2:3][CH2:2]1)=[O:30]
Reactant: CC(C)(C)OC(=O)N1CCNc2ccccc2C1
Reactant: CC(C)=CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)=CC(=O)N1CCN(C(=O)OC(C)(C)C)Cc2ccccc21
Temperature: 25 °C
Yield: 95.1 %

Procedure:
1 g (4.04 mmol) of tert-butyl 2,3-dihydro-1H-benzo[e][1,4]diazepine-4(5H)-carboxylate was dissolved in 20 mL of dichloromethane and treated with 1.54 mL (8.86 mL) of triethylamine followed by 0.53 mL (4.83 mmol) of 3-methylbut-2-enoyl chloride. The reaction mixture was stirred over night at room temperature, poured onto water (50 mL) and extracted three times with 50 mL of dichloromethane each. The organic phases were combined, washed with a saturated solution of sodium chloride, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica (eluent: 5-10% methanol in dichloromethane) to yield 1.27 g of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)=[O:3].[CH3:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([NH2:32])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)[CH:18]=[CH:19][CH:20]=1.C(=O)([O-])O.[Na+]>CN(C)C1C=CN=CC=1.CN(C)C(=O)C>[CH3:14][C:15]1[CH:16]=[C:17]([C:21]2[N:22]=[C:23]([NH:32][C:2]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)=[O:3])[S:24][C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][N:27]=2)[CH:18]=[CH:19][CH:20]=1
Reactant: Cc1cccc(-c2nc(N)sc2-c2ccncn2)c1
Reactant: COC(=O)c1ccc(C(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1ccc(C(=O)Nc2nc(-c3cccc(C)c3)c(-c3ccncn3)s2)cc1
Temperature: 70 °C
Reaction time: 14 h
Yield: 65 %

Procedure:
Methyl 4-chloroformylbenzoate (1.1 g, 5.6 mmol) was added to a solution of [4-(3-methylphenyl)-5-(4-pyrimidinyl)-1,3-thiazol-2-yl]amine and 4-dimethylaminopyridine (0.14 g, 1.1 mmol) in N,N-dimethylacetamide (10 mL), and the mixture was stirred at 70° C. for 14 hrs. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture and the precipitated solids were collected by filtration. Crude crystals were washed with water, dried and recrystallized from pyridine to give the title compound (1.0 g, yield 65%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20](S(C)(=O)=O)[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.[CH3:28][C:29]1([C:33](O)=[O:34])[CH2:32][O:31][CH2:30]1>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([C:11]3[N:16]=[C:15]([NH:17][C@H:18]4[CH2:22][CH2:21][N:20]([C:33]([C:29]5([CH3:28])[CH2:32][O:31][CH2:30]5)=[O:34])[CH2:19]4)[C:14]([F:27])=[CH:13][N:12]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CS(=O)(=O)N1CC[C@H](Nc2nc(-c3c[nH]c4ncc(Cl)cc34)ncc2F)C1
Reactant: CC1(C(=O)O)COC1
Product: CC1(C(=O)N2CC[C@H](Nc3nc(-c4c[nH]c5ncc(Cl)cc45)ncc3F)C2)COC1
Yield: 42 %

Procedure:
According to the procedure for compound 398 using 3-methyloxetane-3-carboxylic acid (15 mg, 0.13 mmol) afforded 17.7 mg (42% yield) of 482, as a solid.
Reaction SMILES: C1(P(=O)(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O.C([S:43][CH:44]([CH2:77][N:78]1[CH2:83][CH2:82][S:81][CH2:80][CH2:79]1)[CH2:45][NH:46][C:47]([C:49]1[NH:50][C:51]2[C:56]([CH:57]=1)=[CH:55][C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:64])=[O:63])=[CH:53][C:52]=2[N:66]([CH3:76])[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:69])=[O:68])=O)C1C=CC=CC=1.C1(SC)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[CH3:76][N:66]([C:52]1[CH:53]=[C:54]([O:58][CH2:59][CH2:60][CH2:61][S:62]([CH3:65])(=[O:63])=[O:64])[CH:55]=[C:56]2[C:51]=1[NH:50][C:49]([C:47]1[S:43][CH:44]([CH2:77][N:78]3[CH2:83][CH2:82][S:81][CH2:80][CH2:79]3)[CH2:45][N:46]=1)=[CH:57]2)[S:67]([C:70]1[CH:75]=[CH:74][CH:73]=[CH:72][N:71]=1)(=[O:68])=[O:69]
Reactant: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C(=O)NCC(CN3CCSCC3)SCc3ccccc3)[nH]c12)S(=O)(=O)c1ccccn1
Agent: O=P(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CSc1ccccc1
Product: CN(c1cc(OCCCS(C)(=O)=O)cc2cc(C3=NCC(CN4CCSCC4)S3)[nH]c12)S(=O)(=O)c1ccccn1
Reaction time: 0.5 h
Yield: 54.8 %

Procedure:
To a solution of triphenylphosphine oxide (0.70 g) in dichloromethane (3 mL) was slowly added trifluoromethanesulfonic anhydride (0.41 mL) under ice-cooling, and the mixture was stirred for 30 min. A solution of N-[2-(benzylthio)-3-thiomorpholinopropyl]-7-[methyl(pyridin-2-ylsulfonyl)amino]-5-[3-(methylsulfonyl)propoxy]-1H-indole-2-carboxamide (0.75 g) and thioanisole (0.30 mL) in dichloromethane (10 mL) was added dropwise, and the mixture was stirred for 30 min under ice-cooling. The reaction solution was diluted with ethyl acetate, washed with aqueous sodium hydrogencarbonate solution and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was subjected to silica gel column chromatography (ethyl acetate:hexane=50:50-90:10) to give the title compound (350 mg, yield: 54%) as a colorless amorphous solid. MS: 625 (MH+).
Reaction SMILES: [CH3:1][N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:27])([CH3:26])[C:16]=2[CH:15]=1)[C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[CH3:28]C1C=CC(C(OCC)=O)=C(NC2C(C)=CC3C(C)=CCC(C)(C)C=3C=2)C=1.C(O)C.[OH-].[K+]>O>[CH2:1]([N:2]([C:14]1[C:23]([CH3:24])=[CH:22][C:21]2[C:20]([CH3:25])=[CH:19][CH2:18][C:17]([CH3:26])([CH3:27])[C:16]=2[CH:15]=1)[C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:12][CH:13]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(N(C)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Reactant: CCOC(=O)c1ccc(C)cc1Nc1cc2c(cc1C)C(C)=CCC2(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1ccc(N(CC)c2cc3c(cc2C)C(C)=CCC3(C)C)cc1
Temperature: 60 °C
Yield: 92 %

Procedure:
Following previously described General Procedure E, to a solution of ethyl 4-[methyl-(3,5,8,8-tetramethyl-7,8-dihydronaphthalen-2-yl)amino]benzoate (Compound 40, 0.05 g, 0.14 mmol) and 2 mL of absolute ethyl alcohol was added aqueous 5 M KOH (0.3 mL). The resulting solution was heated in an 60° C. bath for 24 h. The solution was cooled to room temperature, diluted with water and washed once with 2:1 hexane:ethyl acetate solution, and the layers were separated. The aqueous layer was acidified with HCl 2 N to pH=0-1 and the product extracted three times with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, and filtered. The solvent was removed to give 0.042 g (92%) of the title compound as a dark green solid. PNMR (300 MHz, CDCl3) δ—1.24 (s, 6 H), 2.12 (s, 3 H), 2.14 (s, 3 H), 2.22 (d, 2 H, J=2.4 Hz), 3.32 (s, 3 H), 5.81 (s, 1 H), 6.52 (d, 2 H, J=7.5 Hz), 7.08 (s, 1 H), 7.19 (s, 1 H), 7.92 (d, 2 H, J=7.5 Hz).
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[NH:19][C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:29])([F:28])[F:27])[CH:3]=1.Br.Br[CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>>[Cl:1][C:2]1[CH:25]=[CH:24][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12](/[CH:16]=[C:17]4/[C:18](=[O:23])[N:19]([CH2:32][CH2:33][N:34]5[CH2:38][CH2:37][CH2:36][CH2:35]5)[C:20](=[O:22])[S:21]/4)=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:26]([F:27])([F:29])[F:28])[CH:3]=1
Reactant: BrCCN1CCCC1
Reactant: O=C1NC(=O)/C(=C/c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Agent: Br
Product: O=C1S/C(=C\c2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)C(=O)N1CCN1CCCC1

Procedure:
(5Z)-5-({1-[4-Chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-3-(2-pyrrolidin-1-ylethyl)-1,3-thiazolidine-2,4-dione was prepared from [(5Z)-5-({1-[4-chloro-2-(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-2,4-dioxo-1,3-thiazolidine (from Example 1) and 1-(2-bromoethyl)pyrrolidine hydrobromide following General Procedure H.
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C@@H:7]([O:9][S:10]([CH3:13])(=[O:12])=[O:11])[CH2:6][N:5]1[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=1)=[O:15])(=[O:3])[NH2:2].CO[CH:29](OC)[N:30]([CH3:32])[CH3:31].C(OCC)(=O)C>ClCCl>[CH3:13][S:10]([O:9][C@H:7]1[CH2:6][N:5]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=2)=[O:15])[C@H:4]([C:1](=[O:3])[N:2]=[CH:29][N:30]([CH3:32])[CH3:31])[CH2:8]1)(=[O:11])=[O:12]
Reactant: CS(=O)(=O)O[C@@H]1C[C@@H](C(N)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: COC(OC)N(C)C
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C=NC(=O)[C@@H]1C[C@@H](OS(C)(=O)=O)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 120 °C
Reaction time: 1 h

Procedure:
To (2S,4R)-2-carbamoyl-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3 g) was added N,N-dimethylformamide dimethylacetal (3 ml) and the mixture was stirred at 120° C. for 1 hour. The mixture was poured into a mixture of ethyl acetate and dichloromethane, washed with water and brine successively, and evaporated in vacuo to give (2S,4R)-4-methanesulfonyloxy-2-[N-(N,N-dimethylaminomethylene)carbamoyl]-1-(4-nitrobenzyloxycarbonyl)pyrrolidine. The compound obtained above was dissolved in acetic acid (30 ml) and to this solution was added hydrazine hydrate (0.36 ml) at room temperature. After stirring at the same temperature for 2 hours, the mixture was poured into water and ethyl acetate. The organic layer was washed with saturated aqueous sodium bicarbonate and brine successively, dried over magnesium sulfate, and evaporated in vacuo. The oily residue was subjected to a column chromatography on silica gel (90 g) eluting with a mixture of methanol and dichloromethane (1:20 V/V) to give (2S,4R)-4-methanesulfonyloxy-1-(4-nitrobenzyloxycarbonyl)-2-(1H-1,2,4-triazol-3-yl)pyrrolidine (1.5 g).
Reaction SMILES: Cl[C@H:2]([C@H:8]([OH:12])[CH2:9][CH2:10][CH3:11])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C(O)C.C(=O)([O-])[O-].[K+].[K+]>C(OC)(C)(C)C>[CH2:9]([C@H:8]1[O:12][C@@H:2]1[C:3]([O:5][CH2:6][CH3:7])=[O:4])[CH2:10][CH3:11]
Reactant: CCC[C@@H](O)[C@@H](Cl)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Solvent: COC(C)(C)C
Product: CCC[C@H]1O[C@@H]1C(=O)OCC
Temperature: 15 °C
Reaction time: 14 h
Yield: 104.9 %

Procedure:
Ethyl (2R,3R)-2-chloro-3-hydroxyhexanoate (1.0 g, 5 mmol), ethanol (10 ml) and potassium carbonate (2.1 g, 15 mmol) were mixed, and the mixture was stirred at 15° C. for 14 hours. Methyl tert-butyl ether (20 ml) was added. The mixture was washed with water (10 ml) three times. The organic layer was concentrated under reduced pressure to obtain the title compound (0.83 g, yield: 100%).
Reaction SMILES: [C:1]([O:11][CH2:12][C:13]1[CH:18]=[C:17]([N+:19]([O-])=O)[CH:16]=[C:15]([N+:22]([O-])=O)[CH:14]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[H][H]>>[C:1]([O:11][CH2:12][C:13]1[CH:14]=[C:15]([NH2:22])[CH:16]=[C:17]([NH2:19])[CH:18]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9]
Reactant: CCCCCCCCC(=O)OCc1cc([N+](=O)[O-])cc([N+](=O)[O-])c1
Reactant: [H][H]
Product: CCCCCCCCC(=O)OCc1cc(N)cc(N)c1
Yield: 100.1 %

Procedure:
39.6 g (0.2mol) of 3,5-dinitrobenzyl alcohol, 23.7 g (0.3 mol) of pyridine and 200 ml of methyl ethyl ketone were introduced into a reactor and dissolved by stirring under a nitrogen gas stream at about 70° C. 35.3 g (0.2 mol) of pelargonic acid chloride was dissolved in 100 ml of methyl ethyl ketone and the resultant solution was added dropwise into the reactor as described above. After the completion of the addition, the mixture was refluxed and stirred under nitrogen for about 2 hours. Then the reactor was cooled by allowing to stand and pyridine hydrochloride was removed by filtration. The filtrate was concentrated and purified by using a column to give 50.8 g of 3,5-dinitrobenzyl pelargonate. 33.8 g of 3,5-dinitrobenzyl pelargonate and 4 g of a catalyst (5% palladium carried on active carbon) were introduced into a hydrogenation apparatus and reduced with hydrogen. After filtration and concentration, 27.8 g (0.1 mol) of 3,5-diaminobenzyl pelargonate was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[N:9]2)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[S:18][C:19]([C:25]2[C:30]([F:31])=[CH:29][C:28]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:27][C:26]=2[F:36])=[CH:20][C:21]=1[C:22]([NH2:24])=[O:23]>>[F:36][C:26]1[CH:27]=[C:28]([C:32]([OH:35])([CH3:34])[CH3:33])[CH:29]=[C:30]([F:31])[C:25]=1[C:19]1[S:18][C:17]([NH:16][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([N:8]3[CH:12]=[C:11]([CH2:13][CH2:14][OH:15])[N:10]=[N:9]3)[N:7]=2)=[C:21]([C:22]([NH2:24])=[O:23])[CH:20]=1
Reactant: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(N)s2)c(F)c1
Reactant: OCCc1cn(-c2cccc(Cl)n2)nn1
Product: CC(C)(O)c1cc(F)c(-c2cc(C(N)=O)c(Nc3cccc(-n4cc(CCO)nn4)n3)s2)c(F)c1

Procedure:
The title compound was synthesized from 2-[1-(6-chloropyridin-2-yl)-1H-1,2,3-triazol-4-yl]ethanol (90 mg, 0.40 mmol) and 2-amino-5-[2,6-difluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (125 mg, 0.40 mmol) according to the general procedure in Example 1.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1.[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17](C1C=CC=C2C=1C(C#N)=CN2)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]>>[CH2:12]([O:14][C:15](=[O:35])[CH:16]=[C:17]([C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH3:11])=[CH:4][CH:3]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH3:13]
Reactant: CCOC(=O)C=C(c1ccccc1)c1cccc2[nH]cc(C#N)c12
Reactant: Cn1ccc2ccc(Br)cc21
Product: CCOC(=O)C=C(c1ccccc1)c1ccc2ccn(C)c2c1
Yield: 78 %

Procedure:
3-(1-Methyl-1H-indol-6-yl)-3-phenyl-acrylic acid ethyl ester CXLIII (78% yield) was prepared from 6-bromo-1-methyl-1H-indole using the procedure described above for preparation of 3-(3-cyano-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LVIII (Example 14).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[NH:4][C:5](=[O:13])[C:6]2[CH2:12][O:11][CH2:10][CH2:9][C:7]=2[N:8]=1.[CH2:14]([O:16][C:17]1[CH:34]=[CH:33][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30](O)=[O:31])[CH2:25][CH2:24]2)=[O:22])=[CH:19][CH:18]=1)[CH3:15]>>[CH2:14]([O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][C:30]([NH:1][CH2:2][C:3]3[NH:4][C:5](=[O:13])[C:6]4[CH2:12][O:11][CH2:10][CH2:9][C:7]=4[N:8]=3)=[O:31])[CH2:25][CH2:24]2)=[O:22])=[CH:33][CH:34]=1)[CH3:15]
Reactant: NCc1nc2c(c(=O)[nH]1)COCC2
Reactant: CCOc1ccc(C(=O)C2CCN(CC(=O)O)CC2)cc1
Product: CCOc1ccc(C(=O)C2CCN(CC(=O)NCc3nc4c(c(=O)[nH]3)COCC4)CC2)cc1
Yield: 19.9 %

Procedure:
The title compound (150 mg) was prepared following the general procedure of Example 1 from 2-aminomethyl-3,5,7,8-tetrahydro-pyrano[4,3-d]pyrimidin-4-one (300 mg, 1.66 mmol) and 2-(4-(4-ethoxybenzoyl)piperidin-1-yl)acetic acid (603 mg, 1.66 mmol). 1H NMR (400 MHz, CDC3) δ 10.67 (s, 1H), 8.07 (t, J=6.0 Hz, 1H), 7.92 (d, J=9.0 Hz, 2H), 6.94 (t, J=9.0 Hz, 2H), 4.56 (s, 2H), 4.37 (d, J=6.0 Hz, 2H), 4.10 (q, J=7.0 Hz, 2H), 3.95 (t, J=5.5 Hz, 2H), 3.20-3.29 (m, 1H), 2.91-3.00 (m, 2H), 2.66-2.72 (m, 2H), 2.30-2.40 (m, 2H), 1.80-1.90 (m, 4H), 1.45 (t, J=7.0 Hz, 3H). HRMS calculated for C24H30N4O5 455.2294. found (ESI, [M+H]+), 455.2308. MS m/z 455.2 (M+1), retention time=2.70 min.
Reaction SMILES: [N:1]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([OH:12])=O)[CH:4]=[N:3][CH:2]=1.[F:16][C:17]([F:27])([F:26])[CH2:18][C:19]1[CH:25]=[CH:24][C:22]([NH2:23])=[CH:21][CH:20]=1>C(Cl)Cl>[N:3]1[CH:4]=[C:5]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][CH:15]=2)[C:10]([NH:23][C:22]2[CH:24]=[CH:25][C:19]([CH2:18][C:17]([F:16])([F:26])[F:27])=[CH:20][CH:21]=2)=[O:12])[CH:6]=[N:1][CH:2]=1
Reactant: O=C(O)c1cccc(-c2cncnc2)c1
Reactant: Nc1ccc(CC(F)(F)F)cc1
Solvent: ClCCl
Product: O=C(Nc1ccc(CC(F)(F)F)cc1)c1cccc(-c2cncnc2)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 3-pyrimidin-5-yl-benzoic acid (100 mg, 0.50 mmol) SOCl2 (73 μL, 1.0 mmol) was heated under reflux for 4 h. The solvent was evaporated off under reduced pressure and the residue was dissolved in DCM (5 mL) and slowly added to a mixture of 4-(2,2,2-trifluoroethyl)aniline (105 mg, 0.60 mmol) and TEA (140 μL, 1.0 mmol) in DCM (5 mL). The mixture was stirred at RT overnight. The solvent was evaporated off under reduced pressure and the residue was suspended in water (20 mL) filtered and dried under vacuum to afford the title compound. LC-MS (Condition 4) tR=1.05 min, m/z=375.8 [M+H]+; 1H-NMR (400 MHz, CDCl3) δ ppm 3.40 (q, J=10.76 Hz, 2H) 7.35 (d, J=8.56 Hz, 2H) 7.65-7.71 (m, 3H) 7.80 (d, J=7.82 Hz, 1H) 7.87-7.98 (m, 2H) 8.15 (s, 1H) 9.03 (s, 2H) 9.28 (s, 1H).
Reaction SMILES: N[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]1)[C:7](=[O:36])[NH:6][C:5]2=[O:37].[C:38](O)(=O)C.C=O.[C:44]([BH3-])#[N:45].[Na+]>CO>[CH3:38][N:45]([CH3:44])[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][CH2:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][CH:19]([O:22][CH:23]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH2:18][CH2:17]1)[C:7](=[O:36])[NH:6][C:5]2=[O:37]
Reactant: Nc1ccc2c(c1)c(=O)[nH]c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: [BH3-]C#N
Reactant: CC(=O)O
Agent: C=O
Agent: [Na+]
Solvent: CO
Product: CN(C)c1ccc2c(c1)c(=O)[nH]c(=O)n2CCCCN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reaction time: 1.5 h
Yield: 50 %

Procedure:
6-Amino-2,4-dioxo-1-[4-(4-diphenylmethoxypiperidino)butyl)-1,2,3,4-tetrahydroquinazoline (800 mg) obtained in Example 40 was suspended in methanol (8.0 ml), and to this mixture acetic acid (0.8 ml) and 37% formaldehyde (0.8 ml) were added and the mixture was stirred for 1.5 hours. A solution of sodium cyanoborohydride (141 mg) in methanol (4.0 ml) was added dropwise and the mixture was stirred at room temperature for 27 hours. The reaction mixture was concentrated under reduced pressure, diluted with ethyl acetate, washed with water, dried (Na2SO4) and then the solvent was distilled off under reduced pressure. The residue was subjected to a column chromatography on a silica gel eluting with n-hexane-ethyl acetate (5:1,v/v) to give the title compound (420 mg, 50%). Recrystallization from ethyl acetate-ethyl ether yielded a yellow crystal having a melting point of 165 to 167° C.
Reaction SMILES: C([O:8][C:9](=[O:28])[CH:10]([NH:20]C(OC(C)(C)C)=O)[CH2:11][NH:12]C(OC(C)(C)C)=O)C1C=CC=CC=1.[ClH:29]>C(#N)C>[ClH:29].[ClH:29].[ClH:29].[NH2:20][CH:10]([CH2:11][NH2:12])[C:9]([OH:28])=[O:8]
Reactant: CC(C)(C)OC(=O)NCC(NC(=O)OC(C)(C)C)C(=O)OCc1ccccc1
Agent: Cl
Solvent: CC#N
Product: NCC(N)C(=O)O
Reaction time: 0.25 h

Procedure:
A solution of 2,3-bis-tert-butoxycarbonylamino propionic acid benzyl ester (1.8 g), 4N aqueous HCl (40 ml), and acetonitrile (50 ml) was stirred for 18 hours at room temperature. The solvent was removed under vacuum, and the mixture was diluted with ethyl acetate (100 ml) and water (50 ml) and stirred for 15 minutes. The layers were separated and the aqueous layer was evaporated to dryness (1.23 g of a foam/syrup). 1H NMR (300 MHz): 3.2-3.5 (m, 2H), 4.2-4.35 (m, 1H), 5.13-5.25 (q, 2H, J=11.8, 3.1 Hz).
Reaction SMILES: S(=[C:4]1[N:9]=[CH:8][CH:7]=[CH:6][NH:5]1)(=O)=O.[C:10]1([OH:16])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[O:16]([C:4]1[N:9]=[CH:8][CH:7]=[CH:6][N:5]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=S(=O)=c1nccc[nH]1
Reactant: Oc1ccccc1
Product: c1ccc(Oc2ncccn2)cc1

Procedure:
In step 1 of Scheme A, sulfanylpyrimidine compound a is treated with peracid or like oxidizing agent to afford sulfonylpyrimidine b. In step 2, sulfonylpyrimidine b is reacted with phenol compound c in the presence of base to provide phenoxypyrimidine compound d. Phenoxypyrimidine d is then treated with hydrazine in step 3 to yield hydrazinopyrimidine compound e. In step 4, hydrazinopyrimidine compound e undergoes a cyclization under basic conditions to afford a pyrazolone compound f. In step 5 the pyrazolone compound f is protected under basic conditions to give a protected pyrazol compound g. Partial deprotection of compound g in step 6 affords pyrazol compound h. In step 7 pyrazol compound h is reacted with alkylating agent i to give pyrazol ester compound j. In step 8 pyrazol ester i is deprotected to give a compound of formula II in accordance with the invention.
Reaction SMILES: [C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])(=[O:4])[CH2:2][CH3:3].[CH3:15][C:16]([CH3:20])([CH3:19])[CH:17]=[O:18]>>[OH:18][C@H:17]([C:16]([CH3:20])([CH3:19])[CH3:15])[C@@H:2]([CH3:3])[C:1]([N:5]1[C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=2[O:7][C:6]1=[O:14])=[O:4]
Reactant: CCC(=O)n1c(=O)oc2ccccc21
Reactant: CC(C)(C)C=O
Product: C[C@@H](C(=O)n1c(=O)oc2ccccc21)[C@H](O)C(C)(C)C

Procedure:
Prepared according to the method of paragraph C by reaction of N-propionyl-2-benzoxazolone with trimethylacetaldehyde. Slow addition of the aldehyde to the enolate solution over 1 hour at 0° C. gave a 9:1 ratio of the (2R*,3S*) and (2R*,3R*) isomers. The desired isomer was crystallized from 1:1 ether/hexanes, mp=90–2° C. 1H-NMR (CDCl3, 400 MHz): δ 8.04 (m, 1H), 7.23–7.29 (m, 3 H), 4.32 (dq,J=3, 7 Hz, 1H), 3.79 (d,J=10 Hz, 1H), 3.41 (dd, J=3,10 Hz, 1 H), 1.51 (d,J=7 Hz, 3 H), 0.94 (s, 9 H). 13C-NMR (CDCl3, 100 MHz): δ 178.2, 150.8, 142.0, 127.6, 125.7, 125.0, 116.3, 110.0, 84.0, 37.4, 36.2, 26.7, 18.1.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:4][N:3]=1.O.[NH2:15][NH2:16]>C(O)C>[CH3:11][C:10]([CH3:13])([CH3:12])[CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][NH2:16])=[N:3][CH:4]=1
Reactant: NN
Reactant: CC(C)(C)COc1ccc(Cl)nc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(NN)nc1

Procedure:
6.2 g (30.8 mmol) 2-chloro-5-(2,2-dimethylpropoxyl)pyridine together with 60 ml (1.2 mol) hydrazine hydrate are divided into four portions of equal size and 10 ml ethanol are added to each portion. Each portion is reacted in a single mode microwave (CEM Explorer) at 170° C. (200 watt) for in each case 12 h. Thereafter, the four mixtures are combined and the solvent is removed. The residue is taken up in ethyl acetate and the mixture is washed in each case once with saturated sodium bicarbonate solution and saturated sodium chloride solution. The mixture is dried over magnesium sulfate and the solvent is removed in vacuo.