Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:12]3([OH:22])[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:9][C:10]=2Br)[CH:5]=[CH:6][N:7]=1.CC1(C)C(C)(C)OB([C:31]2[CH:49]=[CH:48][C:34]([C:35]([NH:37][C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][N:39]=3)=[O:36])=[CH:33][CH:32]=2)O1.C([O-])([O-])=O.[K+].[K+].O1CCOCC1>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O>[NH2:1][C:2]1[C:3]2[N:4]([C:8]([C:12]3([OH:22])[CH2:20][CH2:19][CH2:18][C:17]4[N:16]([CH3:21])[N:15]=[CH:14][C:13]3=4)=[N:9][C:10]=2[C:31]2[CH:49]=[CH:48][C:34]([C:35]([NH:37][C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[CH:40][N:39]=3)=[O:36])=[CH:33][CH:32]=2)[CH:5]=[CH:6][N:7]=1
Reactant: CC1(C)OB(c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)OC1(C)C
Reactant: Cn1ncc2c1CCCC2(O)c1nc(Br)c2c(N)nccn12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: Cn1ncc2c1CCCC2(O)c1nc(-c2ccc(C(=O)Nc3cc(C(F)(F)F)ccn3)cc2)c2c(N)nccn12
Temperature: 110 °C
Reaction time: 1.5 h

Procedure:
The reaction mixture of 4-(8-amino-1-bromoimidazo[1,5-a]pyrazin-3-yl)-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-ol (580 mg, 1.6 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide (2 mmol), Pd(dppf)Cl2 (80 mg) and K2CO3 (830 mg, 6 mmol) in a mixed solvent of dioxane (15 mL) and H2O (2 mL) was stirred at 110° C. for 1.5 hrs under N2 protection. After cooling, the resulting mixture was filtered and the filtrate was evaporated under reduce pressure to dryness. The residue was purified by preparative TLC to afford 4-(8-amino-3-(4-hydroxy-1-methyl-4,5,6,7-tetrahydro-1H-indazol-4-yl)imidazo[1,5-a]pyrazin-1-yl)-N-(4-(trifluoromethyl)pyridin-2-yl)benzamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].S(Cl)(Cl)=O.[CH2:21]([O:28][C:29]1[CH:30]=[CH:31][C:32]([Br:36])=[C:33]([NH2:35])[CH:34]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[NH:35][C:33]2[CH:34]=[C:29]([O:28][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH:30]=[CH:31][C:32]=2[Br:36])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Reactant: Nc1cc(OCc2ccccc2)ccc1Br
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: O=S(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC(C(=O)Nc2cc(OCc3ccccc3)ccc2Br)CC1

Procedure:
Piperidine-1,4-dicarboxylic acid mono-tert-butyl ester (2.25 g, 9.80 mmol) was dissolved in dry methylene chloride (18 mL) and dry pyridine (2.02 mL). To the reaction mixture was then added thionyl chloride (1.40 g, 11.76 mmol) under nitrogen atmosphere and the reaction mixture was stirred at room temperature for 30 minutes. To the reaction mixture was then added successively, under nitrogen atmosphere, 5-benzyloxy-2-bromo-phenylamine (3.0 g, 10.78 mmol), dry triethylamine (3.50 g, 34.32 mmol), dry methylene chloride (20 mL), 4-(dimethylamino)pyridine (0.12 g, 0.98 mmol) and the reaction mixture was stirred at room temperature for 24 hours. The reaction mixture was then partitioned with aqueous 2N HCl and tert-butyl methyl ether. The organic layer was washed with aqueous 2N HCl, aqueous NaHCO3, brine, dried with Na2SO4, filtered and the solvent evaporated in vacuo to yield a crude oil. The crude oil was recrystallized from ethyl acetate/hexanes to yield the title compound as a solid.
Reaction SMILES: C(O[C:6]([N:8]([C:39](OC(C)(C)C)=O)[C:9](=[O:38])[C:10]1[CH:15]=[C:14]([N:16]2[CH2:20][CH2:19][CH2:18][C:17]2=[O:21])[CH:13]=[CH:12][C:11]=1[C:22]([N:24]1[CH2:29][CH2:28][N:27]([C:30]2[C:35]([CH3:36])=[CH:34][C:33]([CH3:37])=[CH:32][N:31]=2)[CH2:26][CH2:25]1)=[O:23])=O)(C)(C)C.N1CC[CH2:48][CH2:47]1>>[CH3:36][C:35]1[C:30]([N:27]2[CH2:28][CH2:29][N:24]([C:22]([C:11]3[CH:12]=[CH:13][C:14]([N:16]4[CH2:20][CH2:19][CH2:18][C:17]4=[O:21])=[CH:15][C:10]=3[C:9]([N:8]3[CH2:6][CH2:48][CH2:47][CH2:39]3)=[O:38])=[O:23])[CH2:25][CH2:26]2)=[N:31][CH:32]=[C:33]([CH3:37])[CH:34]=1
Reactant: C1CCNC1
Reactant: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)CC2)c(C)c1
Product: Cc1cnc(N2CCN(C(=O)c3ccc(N4CCCC4=O)cc3C(=O)N3CCCC3)CC2)c(C)c1

Procedure:
Using N,N-di-tert-butyloxycarbonyl-2-[4-(3,5-dimethylpyridin-2-yl)piperazine-1-carbonyl]-5-(2-oxopyrrolidin-1-yl)benzamide (249 mg) described in Example 769 and pyrrolidine (40 μL) and by the reaction and treatment in the same manner as in Example 770, the title compound (138 mg) was obtained.
Reaction SMILES: C([N:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+].Cl>CO.O.C(O)(C)C.[Pd]>[NH:8]1[CH2:12][CH2:11][CH:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[CH2:9]1
Reactant: c1ccc(CN2CCC(c3ccccn3)C2)cc1
Agent: [Pd]
Agent: Cl
Agent: O=C[O-]
Solvent: CO
Solvent: CC(C)O
Solvent: O
Product: c1ccc(C2CCNC2)nc1
Temperature: 68 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
To 2-(1-benzylpyrrolidin-3-yl)pyridine enantiomer 1 a1-64 (10.01 g, 41.96 mmol, 1 eq) in methanol (340 ml) is added Pd/C (5%, 1.98 g). A solution of ammonium formate (10.69 g, 167.83 mmol, 4 eq) in water (55 ml) is then added dropwise over a period of 10 minutes. The reaction mixture is heated for 45 mins at 68° C., then cooled to room temperature. The catalyst is filtered off using Celite, washed with methanol (60 ml) and the pooled filtrates evaporated to dryness. The residue is retaken in methanol (50 ml) and evaporated again. Dichloromethane (100 ml) is added to the residue, the solid obtained is filtered, washed with dichloromethane (30 ml) and the pooled filtrates are evaporated to dryness to give a yellow oil. This oil is dissolved in isopropanol (60 ml) and a mixture of isopropanol (21 ml)/aqueous HCl 6N (21 ml, 3 eq) is added slowly over a period of 15 minutes to the solution. The mixture is stirred at room temperature overnight, the precipitate obtained is filtered, washed with isopropanol (10 ml) and dried under vacuum for 4 hours at 40° C. to afford 7.90 g of 2-(pyrrolidin-3-yl)pyridine enantiomer 1 dihydrochloride a1-66. Yield: 85%.
Reaction SMILES: [C:1]([NH:6][C@@H:7]([C:10]([OH:12])=[O:11])[CH2:8][SH:9])(=[O:5])[CH:2]([CH3:4])[CH3:3].OO>CO>[CH3:3][CH:2]([CH3:4])[C:1]([NH:6][C@H:7]([CH2:8][S:9][S:9][CH2:8][C@@H:7]([NH:6][C:1](=[O:5])[CH:2]([CH3:3])[CH3:4])[C:10]([OH:12])=[O:11])[C:10]([OH:12])=[O:11])=[O:5]
Reactant: CC(C)C(=O)N[C@H](CS)C(=O)O
Agent: OO
Solvent: CO
Product: CC(C)C(=O)N[C@H](CSSC[C@@H](NC(=O)C(C)C)C(=O)O)C(=O)O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
N-isobutyryl-D-cysteine (1 g, 5.2 mmol) was dissolved in 10 ml of methanol. Hydrogen peroxide (30%, 0.3 ml, 2.6 mmol) was added and the reaction mixture was stirred at room temperature for 6 hours. After evaporation of the solvent under reduced pressure, a white crystallised oil was obtained. Recrystallisation from ethyl acetate furnished the title compound as a white solid which was dried in vacuo.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([OH:15])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:26])[CH3:25])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH:30]([CH3:32])[CH3:31]>>[CH2:1]([O:8][C:9]1[C:14]([O:15][CH:30]([CH3:32])[CH3:31])=[CH:13][C:12]([CH2:16][CH3:17])=[C:11]([O:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][C:24]([C:27]#[N:28])([CH3:25])[CH3:26])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)I
Reactant: CCc1cc(O)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Product: CCc1cc(OC(C)C)c(OCc2ccccc2)cc1OCCCCCC(C)(C)C#N
Yield: 100 %

Procedure:
1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl -6-isopropoxy benzene was prepared in 100% yield as a white solid from 1-Benzyloxy-3-(6-cyano-6-methylheptyloxy)-4-ethyl-6-hydroxy benzene and 2-iodo-propane.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([C:10]([OH:12])=O)=[CH:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1c[nH]c2ccccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1c[nH]c2ccccc12)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 35 %

Procedure:
The title compound is prepared from 1H-indole-3-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 35% of theory; LC (method 4): tR=1.99 min; Mass spectrum (ESI+): m/z=317 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1.[C:12](Cl)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]>N1C=CC=CC=1>[C:12]([NH:1][C:2]1[NH:7][C:6]2=[N:8][CH:9]=[CH:10][C:5]2=[C:4]([Cl:11])[N:3]=1)(=[O:17])[C:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: Nc1nc(Cl)c2ccnc-2[nH]1
Reactant: CC(C)(C)C(=O)Cl
Solvent: c1ccncc1
Product: CC(C)(C)C(=O)Nc1nc(Cl)c2ccnc-2[nH]1
Yield: 73.8 %

Procedure:
A solution of 2-amino-4-chloro-pyrrolo[2,3-d]pyrimidine (20 g, 118 mmol) and pivaloyl chloride (14.3 g, 118 mmol) in pyridine (150 mL) was stirred for 18 hours at ambient temperature. The resulting dark red solution was evaporated to an amber solid which was co-evaporated with water (20 mL, 3×). The resulting solid was filtered, washed with cold water and then dried over KOH in vacuo to yield 22 g (83%) of 2-pivaloylamino-4-chloro-pyrrolo[2,3-d]pyrimidine as a reddish solid. 1H-NMR (DMSO-d6): δ 12.35 (bs, 1, N (7)-H); 10.07 (s,1, N (2)-H); 7.56 (m,1, H-6); 6.58 (m,1, H-5); 1.24 (s, 9, pivaloyl methyls). mp>210° C.
Reaction SMILES: [Cl:1][C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.N1C=CC=CC=1.[C:19]1([CH2:25][CH2:26][CH2:27][OH:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C1(C)C=CC=CC=1>[C:19]1([CH2:25][CH2:26][CH2:27][O:28][C:2]([Cl:1])=[O:4])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: OCCCc1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: O=C(Cl)OCCCc1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.8 %

Procedure:
In a four necked round bottom flask, triphosgene (5.45 g, 55.1 mmol) was dissolved in toluene (80 mL) under argon. After cooling at 0° C., pyridine (4.8 mL, 58.8 mmol) was added dropwise during 1 h and the resulting suspension stirred for further 1 h at 0° C. 3-phenyl-1-propanol (5 mL, 36.8 mmol) was added dropwise in 30 min. After stirring at rt for 24 h, the solid was filtered off and the solvent removed under vacuum, yielding the title compound (6.2 g, 85%) as pale yellow oil, which was used in the next step without further purification. FTIR (cm−1): 3086, 3065, 3027, 2995, 2932, 2862, 1776, 1743, 1603, 1496, 1454, 1262, 1148, 745, 699.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[NH:4][N:3]=1.[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[C:16]([C:22]([F:25])([F:24])[F:23])[CH:15]=1>>[Cl:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:4]2[C:5]3[C:10](=[CH:9][C:8]([CH:11]=[O:12])=[CH:7][CH:6]=3)[C:2]([I:1])=[N:3]2)=[C:16]([C:22]([F:23])([F:24])[F:25])[CH:15]=1
Reactant: FC(F)(F)c1cc(Cl)ccc1CBr
Reactant: O=Cc1ccc2[nH]nc(I)c2c1
Product: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(Cl)cc1C(F)(F)F

Procedure:
1-[4-Chloro-2-(trifluoromethyl)benzyl]-3-iodo-1H-indazol-5-carbaldehyde was prepared from 3-iodo-1H-indazol-5-carbaldehyde and 4-chloro-2-(trifluoromethyl)benzyl bromide following General Procedure A.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]1[O:16][C:15](=[O:17])[CH:14]([C:18](O)=O)[CH:13]1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[Na+].C=O.C(NCC)C>C(O)(=O)C>[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][CH:12]1[O:16][C:15](=[O:17])[C:14](=[CH2:18])[CH:13]1[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)C1C(=O)OC(CCCOCc2ccccc2)C1c1ccccc1
Agent: C=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCNCC
Solvent: CC(=O)O
Product: C=C1C(=O)OC(CCCOCc2ccccc2)C1c1ccccc1
Temperature: 100 °C
Yield: 76.9 %

Procedure:
5-(3-Benzyloxypropyl)-2-oxo-4-phenyltetrahydro-3-furancarboxylic acid (1 g) was dissolved in a solution (5 ml) prepared from sodium acetate (105 mg), acetic acid (4 ml), formalin (2.92 ml) and diethylamine (1 ml), and the solution was heated on a water bath (100° C.) for 30 minutes. After cooling, the reaction mixture was poured into ice water and extracted with ether. The extract was washed with 5% sodium bicarbonate and water and dried over magnesium sulfate. The solvent was then distilled off to give 5-(3-benzyloxypropyl)-3-methylene-4-phenyltetrahydro-2-furanone (0.7 g) as a colorless oil.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][C:23](O)=[O:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2].B>O1CCCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]([CH2:22][CH2:23][OH:24])[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:9]2[C:14]=1[CH:13]=[CH:12][C:11]([Cl:15])=[CH:10]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CC(=O)O
Agent: B
Solvent: C1CCOC1
Product: CCOC(=O)c1c2ccc(Cl)cc2c(-c2ccccc2)n1CCO
Temperature: 25 °C
Reaction time: 60 h

Procedure:
A solution of 10.8 g. of 1-ethoxycarbonyl-5-chloro-3-phenylisoindole-2-acetic acid in 100 ml. of tetrahydrofuran is added dropwise under argon at 15°-20° C. to 72 ml. of a 1-M solution of borane in tetrahydrofuran. After stirring at room temperature for 60 hours, the clear solution is treated at 15°-20° C. with 30 ml. of ethanol and evaporated to dryness under reduced pressure. The solid residue is dissolved in methylene chloride and the obtained solution washed with a 5% sodium bicarbonate solution and then with water. The solution is dried over sodium sulfate, evaporated and the solid crude product obtained chromatographed on 700 g. of silica gel with methylene chloride/ethyl acetate (4:1) as the eluant. The uniform fractions yield 5-chloro-2-(2-hydroxyethyl)-3-phenylisoindole-1-carboxylic acid ethyl ester; melting point 114°-116° C. Recrystallization from ether/pentane does not increase the melting point.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[CH:6][C:5]=1[F:11])=[O:3].C([Si](C(C)C)(C(C)C)[S:16][C:17]1[CH:18]=[C:19]([C:23]2([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]2)[CH:20]=[CH:21][CH:22]=1)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)([O-])C.[K+].Cl>C(OCC)(=O)C.C1(C)C=CC=CC=1>[C:2]([C:4]1[CH:9]=[CH:8][C:7]([S:16][C:17]2[CH:18]=[C:19]([C:23]3([C:29]([NH2:31])=[O:30])[CH2:28][CH2:27][O:26][CH2:25][CH2:24]3)[CH:20]=[CH:21][CH:22]=2)=[CH:6][C:5]=1[F:11])(=[O:3])[CH3:1]
Reactant: CC(=O)c1ccc(F)cc1F
Reactant: CC(C)[Si](Sc1cccc(C2(C(N)=O)CCOCC2)c1)(C(C)C)C(C)C
Agent: CC(C)(C)[O-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(=O)c1ccc(Sc2cccc(C3(C(N)=O)CCOCC3)c2)cc1F
Temperature: 25 °C
Reaction time: 4 h

Procedure:
2,4-Difluoroacetophenone (0.40 g, 2.54 mmols), 4-{3-[(triisopropylsilyl)thio]phenyl}-tetra-hydro-2H-pyran-4-carboxamide (1.0 g, 2.54 mmols), tetrabutylammonium fluoride (0.66 g, 2.54 mmols), and potassium tert-butoxide (1.0 M in THF, 2.54 ml, 2.54 mmols) were added to anhydrous toluene (10 ml). The mixture was warmed to 90 degrees Celcius and stirred for 4 hours. After cooling to room temperature, ethyl acetate was added (100 ml) along with 1.0 N HCl (6 ml). The mixture was then stirred for 30 minutes and a beige precipate was collected by suction filtration. The crude product was purified further on silica gel eluting with a 70:30 mixture of methylene chloride and acetone. The appropriate fractions were concentrated to a light brown solid, (0.61 g, 64%).
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([O:18]C)=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]>O1CCCC1.CO>[CH2:3]([O:7][C:8]1[CH:13]=[C:12]([CH2:14][CH2:15][C:16]([OH:18])=[O:17])[CH:11]=[CH:10][C:9]=1[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([N:26]([CH3:37])[C:27]([NH:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:28])[CH:21]=1)[CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OC)cc2OCCCC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2OCCCC)c1
Yield: 64 %

Procedure:
In a manner similar to that of Example (19g), by reaction of 200 mg (5.0 mmol, ˜8 eq) of sodium hydroxide and methyl 3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoate, prepared in the preceding step, in 6 ml of a tetrahydrofuran/methanol mixture (8/2), and after crystallization from pentane, 200 mg of 3-[2-butoxy-3′-(3-heptyl-1-methylureido)biphenyl-4-yl]propanoic acid are obtained in the form of a white powder (m.p.=77-78° C.). Yield=64% over the two steps a and b.
Reaction SMILES: [BH4-].[Na+].[Cl:3][C:4]1[N:5]=[C:6]([CH:9]([C:17]2[NH:18][C:19]([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=23)[C:10]([CH3:16])([CH3:15])[C:11](OC)=[O:12])[S:7][CH:8]=1.[Cl-].[Li+]>CO>[Cl:3][C:4]1[N:5]=[C:6]([CH:9]([C:17]2[NH:18][C:19]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=3)=[C:20]3[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[N:22]([CH3:29])[C:21]=23)[C:10]([CH3:16])([CH3:15])[CH2:11][OH:12])[S:7][CH:8]=1
Reactant: COC(=O)C(C)(C)C(c1nc(Cl)cs1)c1[nH]c(-c2ccccc2)c2c(=O)n(C)c(=O)n(C)c12
Agent: [BH4-]
Agent: [Cl-]
Agent: [Li+]
Solvent: CO
Product: Cn1c(=O)c2c(-c3ccccc3)[nH]c(C(c3nc(Cl)cs3)C(C)(C)CO)c2n(C)c1=O
Reaction time: 0.5 h

Procedure:
Sodium borohydride (46.6 mg, 1.232 mmol) was added to a mixture of methyl 3-(4-chloro thiazol-2-yl)-3-(1,3-dimethyl-2,4-dioxo-5-phenyl-2,3,4,6-tetrahydro-1H-pyrrolo[3,4-d]pyrimidin-7-yl)-2,2-dimethylpropanoate (120 mg, 0.246 mmol) and lithium chloride (52.2 mg, 1.232 mmol) in methanol (10 mL). The mixture was stirred at room temp. for 30 mins. The reaction was quenched with saturated NaHCO3(aq) and extracted with DCM (3×). The combined organic extracts were passed through a hydrophobic frit and evaporated under vacuum to afford the title compound.
Reaction SMILES: C([O:3][C:4](=[O:21])[CH2:5][N:6]1[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:8]([CH:17]2[CH2:19][CH2:18]2)[C:7]1=[O:20])C.[OH-].[K+]>CO>[CH:17]1([N:8]2[C:9]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)=[CH:10][N:6]([CH2:5][C:4]([OH:21])=[O:3])[C:7]2=[O:20])[CH2:19][CH2:18]1
Reactant: CCOC(=O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)Cn1cc(-c2ccccc2)n(C2CC2)c1=O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
350 mg (1.222 mmol) of ethyl (3-cyclopropyl-2-oxo-4-phenyl-2,3-dihydro-1H-imidazol-1-yl)-acetate from Example 123A are placed in 2 ml methanol, treated with 0.5 ml 20% aqueous potassium hydroxide and stirred for two hours at room temperature. The methanol is removed on the rotary evaporator, and the residue acidified with 2 N hydrochloric acid and extracted with dichloromethane. The organic phase is separated, dried over sodium sulphate and concentrated. It is purified by flash chromatography on silica gel (eluent: dichloromethane/methanol first 50:1, then 25:1). 166 mg (53% of theory) of the target compound are thus obtained.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][NH:7][C:6]2=[O:13])#[N:2].[Cl-].[NH4+].[N-:16]=[N+:17]=[N-:18].[Na+]>CN(C)C=O.C(OCC)(=O)C>[NH:16]1[C:1]([C:3]2[CH:4]=[C:5]3[C:10](=[CH:11][CH:12]=2)[N:9]=[CH:8][NH:7][C:6]3=[O:13])=[N:2][N:18]=[N:17]1
Reactant: N#Cc1ccc2nc[nH]c(=O)c2c1
Reactant: [N-]=[N+]=[N-]
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=c1[nH]cnc2ccc(-c3nnn[nH]3)cc12
Temperature: 100 °C
Yield: 89.5 %

Procedure:
6-Cyanoquinazolin-4-one (0.5 g) in dimethylformamide (5 ml) was treated with ammonium chloride (0.33 g) and sodium azide (0.38 g) and heated at 100° C. under nitrogen for 45 minutes. The resulting mixture was cooled, diluted with ethyl acetate and filtered. The filter cake was washed with dimethylformamide and ethyl acetate to give the title compound (0.56 g) as a cream solid; δH [2H6]DMSO 13.00(1H, bs), 8.70(1H, d), 8.40(1H, dd), 8.38(1H, bs), 8.05(1H, s), 7.68(1H, d); m/z (M−1+) 213.
Reaction SMILES: C[C:2]1(C)[O:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])O1.CO.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.C(N(CC)C(C)C)(C)C.O[N:45]=[C:46]([NH2:53])[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>CC#N.CCOC(C)=O>[C:47]1([C:46]2[N:53]=[C:4]([CH2:5][C:6]([O:7][CH3:2])=[O:8])[O:9][N:45]=2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: NC(=NO)c1ccccc1
Reactant: CC1(C)OC(=O)CC(=O)O1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CC#N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)Cc1nc(-c2ccccc2)no1
Temperature: 80 °C
Reaction time: 18 h
Yield: 37.7 %

Procedure:
A mixture of 2,2-dimethyl-1,3-dioxane-4,6-dione (5.0 g, 34.6 mmol) and MeOH (1.4 mL, 34.6 mmol) was heated at 80° C. for 18 h. The reaction was concentrated, the residue (2.05 g, 17.3 mmol) was dissolved in CH3CN (10 mL) and added to a solution of HOBt (2.3 g, 17.3 mmol), EDCI.HCl (3.3 g, 17.3 mmol), N,N-diisopropylethylamine (3.01 mL, 17.3 mmol) and N′-hydroxybenzimidamide (2.0 g, 8.5 mmol) in CH3CN (5 mL). The reaction was stirred at 40° C. for 18 h under N2, and upon completion, diluted with EtOAc and washed with H2O (2×). The combined organic layers were dried over Na2SO4, concentrated and purified by flash-chromatography (0-50% EtOAc in Hexane). The resulting residue was dissolved in CH3CN (10 mL), and heated in a microwave reactor (110° C., 30 min). Upon completion, the solvent was removed in vacuo and the residue was purified by flash-chromatography (0-50% EtOAc in Hexane) to yield methyl 2-(3-phenyl-1,2,4-oxadiazol-5-yl)acetate as a yellow oil (700 mg, 38%). 1H NMR (500 MHz, DMSO-d6): δ 3.72 (s, 3H), 4.41 (s, 2H), 7.56-7.62 (m, 3H), 8.01-8.04 (m, 2H). MS(M+H, 219).
Reaction SMILES: ClCCCO[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1/[CH:12]=[CH:13]/[C:14]1[O:15][C:16]2[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=2[N:18]=1.[CH3:23][N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1>>[CH3:23][N:24]1[CH2:29][CH2:28][N:27]([CH2:12][CH2:13][CH2:14][O:15][C:9]2[CH:8]=[C:7](/[CH:12]=[CH:13]/[C:14]3[O:15][C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[N:18]=3)[CH:6]=[CH:11][CH:10]=2)[CH2:26][CH2:25]1
Reactant: CN1CCNCC1
Reactant: ClCCCOc1ccccc1/C=C/c1nc2ccccc2o1
Product: CN1CCN(CCCOc2cccc(/C=C/c3nc4ccccc4o3)c2)CC1

Procedure:
The title compound was prepared as described in Example 1 starting with (A) of Example 1 (2.0 g, 6.4 mmol) and using N-methylpiperazine in place of dibutylamine to produce 0.56 g (25% yield of the free base of the title compound which was converted to the HCl salt, mp 250°-252° C. IR: 1600 cm-1. MS: 378(MH+). 1H NMR (CDCl3): δ 7.82-7.00 (m, 10H), 4.13 (t, J=5.2 Hz, 2H), 3.31 (m, 13H), 2.41 (m, 2H).