Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1)#[N:2].[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21](Br)[N:20]=1)([CH3:15])([CH3:14])[CH3:13].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:12]([O:16][C:17](=[O:26])[NH:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:6]2[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=2)[N:20]=1)([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)OC(=O)Nc1cccc(Br)n1
Reactant: N#Cc1ccc(B(O)O)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1cccc(-c2ccc(C#N)cc2)n1
Temperature: 80 °C
Reaction time: 8 h
Yield: 47.4 %

Procedure:
A mixture of 4-cyanobenzeneboronic acid (7.35 g, 50 mmol), (6-bromo-pyridin-2-yl)carbamic acid tert-butyl ester (13.8 g, 50 mmol), Pd(Ph3P)4 (5.8 g, 0.15 mmol) and K2CO3 (10.4 g, 75 mmol) in DMF/H2O (1:1, 250 mL) was stirred under argon at 80° C. overnight. DMF was evaporated off under reduced pressure and the residue was dissolved in EtOAc (200 mL). The mixture was washed with water and brine, dried over Na2SO4, and concentrated to dryness. The residue was purified by column (Petroleum Ether/EtOAc 50:1) on silica gel to give [6-(4-cyano-phenyl)-pyridin-2-yl]carbamic acid tert-butyl ester (7.0 g, 60%). 1H NMR (300 MHz, CDCl3) δ 8.02-8.07 (m, 2 H), 7.95 (d, J=8.4 Hz, 1 H), 7.71-7.79 (m, 3 H), 7.37-7.44 (m, 2 H), 1.53 (s, 9 H).
Reaction SMILES: O=[CH:2][CH2:3][CH:4]1[C:9]2[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=2[CH2:7][CH2:6][O:5]1.[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][NH:30][C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[F:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[C:23]([N:27]1[CH2:32][CH2:31][N:30]([CH2:2][CH2:3][CH:4]3[C:9]4[CH:10]=[CH:11][C:12]([C:14]#[N:15])=[CH:13][C:8]=4[CH2:7][CH2:6][O:5]3)[C@H:29]([CH3:33])[CH2:28]1)=[CH:22][CH:21]=[CH:20]2
Reactant: N#Cc1ccc2c(c1)CCOC2CC=O
Reactant: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C[C@@H]1CN(c2cccc3cc(F)ccc23)CCN1CCC1OCCc2cc(C#N)ccc21
Reaction time: 0.17 h

Procedure:
To a stirred solution of 1-(2-oxoethyl)-3,4-dihydro-1H-2-benzopyran-6-carbonitrile (0.454 g, 2.26 mmol) in methanol (30 mL) was added (3R)-1-(6-fluoro-1-naphthyl)-3-methylpiperazine (0.61 g, 2.49 mmol), and the mixture stirred for 10 min. Sodium cyanoborohydride (0.157 g, 2.49 mmol) and acetic acid (0.25 mL) were added and the mixture stirred for 18 h. A further portion of sodium cyanoborohydride (0.20 g) was added and the reaction stirred for 6 h. The mixture was quenched with water, and the solvent removed in vacuo. Water was added and the mixture extracted with chloroform, the organic extracts dried (MgSO4), filtered and evaporated in vacuo. The crude product was purified by preparative LC-MS to yield the title compound as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([OH:11])=O)[NH:5][C:6]=1[CH2:7][CH3:8].S(Cl)(Cl)=O.[NH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=2)=[CH:19][CH:18]=1>N1C=CC=CC=1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:16][C:17]2[CH:18]=[CH:19][C:20]([C:23]3[O:24][CH:25]=[C:26]([C:28]([O:30][CH3:31])=[O:29])[N:27]=3)=[CH:21][CH:22]=2)=[O:11])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCc1[nH]c(C(=O)O)nc1Cl
Reactant: COC(=O)c1coc(-c2ccc(N)cc2)n1
Solvent: c1ccncc1
Solvent: O=S(Cl)Cl
Product: CCc1[nH]c(C(=O)Nc2ccc(-c3nc(C(=O)OC)co3)cc2)nc1Cl
Yield: 46.4 %

Procedure:
The same operation as in Example (91c) was performed using 4-chloro-5-ethyl-1H-imidazole-2-carboxylic acid (0.13 g, 0.75 mmol), thionyl chloride (5 mL), methyl 2-(4-aminophenyl)-1,3-oxazole-4-carboxylate obtained in Example (96b) (0.15 g, 0.69 mmol) and pyridine (5 mL), to obtain 0.12 g of the title compound as a light purple solid (47%).
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=1[CH3:25])[C:12]([OH:14])=O)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[C:26]([C:28]1[CH:37]=[CH:36][C:31]([C:32]([NH:34][NH2:35])=[O:33])=[CH:30][CH:29]=1)#[N:27].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC>C1COCC1>[Si:1]([O:8][CH2:9][CH2:10][C@@H:11]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]#[N:23])=[C:18]([Cl:24])[C:17]=1[CH3:25])[C:12]([NH:35][NH:34][C:32](=[O:33])[C:31]1[CH:30]=[CH:29][C:28]([C:26]#[N:27])=[CH:37][CH:36]=1)=[O:14])([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:2])[CH3:3]
Reactant: N#Cc1ccc(C(=O)NN)cc1
Reactant: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)O)ccc(C#N)c1Cl
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: C1CCOC1
Product: Cc1c(N[C@H](CCO[Si](C)(C)C(C)(C)C)C(=O)NNC(=O)c2ccc(C#N)cc2)ccc(C#N)c1Cl
Temperature: -15 °C
Reaction time: 0.33 h
Yield: 52.5 %

Procedure:
(R)-4-(tert-butyldimethylsilyloxy)-2-(3-chloro-4-cyano-2-methylphenylamino)butanoic acid (840 mg, 2.19 mmol) and 4-cyanobenzohydrazide (329 mg, 2.41 mmol) were mixed together in THF (100 ml) and cooled to −15° C. under N2 atmosphere. To the pre-cooled reaction mixture were added hydroxybenzotriazole (HOBT) (296 mg, 2.19 mmol), TEA (0.458 mL, 3.29 mmol) followed by N-(3-Dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (EDCI) (630 mg, 3.29 mmol). The reaction mixture was allowed to stir at −20° C. for 20 min and then at room temperature overnight. After the reaction was complete based on TLC, the urea was filtered off and the solution was washed with water, 5% citric acid followed by 5% NaHCO3 to provide the crude product as a yellow solid (0.95 g). Purification by flash column chromatography [EtOAc-hexanes (1:1) as eluent] afforded the title compound as a white crystalline solid (605 mg, 53%). 1H NMR (400 MHz, Acetone-d6, δ in ppm) 9.78 (br s, 2H), 8.03 (d, J=9 Hz, 2H), 7.87 (d, J=9 Hz, 2H), 7.48 (d, J=9 Hz, 1H), 6.63 (d, J=9 Hz, 1H), 5.87 (d, J=9 Hz, 1H), 4.40-4.34 (m, 1H), 4.03-3.82 (m, 2H), 2.31 (s, 3H), 2.29-2.04 (m, 2H), 0.81 (s, 9H), 0.1 (s, 3H) and 0.00 (s, 3H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([CH:10]=[O:11])=[CH:7][CH:8]=2)[CH:3]=[N:2]1.[OH-].[Na+].[I:14]I>O1CCOCC1.O>[I:14][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[C:6]([CH:10]=[O:11])[CH:5]=2)[NH:1][N:2]=1
Reactant: II
Reactant: O=Cc1ccc2[nH]ncc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=Cc1ccc2[nH]nc(I)c2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.4 %

Procedure:
To a solution of 1H-indazole-5-carboxaldehyde (3.75 g, 25.7 mmol) in dioxane (120 mL) was added a solution of NaOH (15.48 g, 384.9 mmol) in water (120 mL). To this solution, iodine (8.2 g, 32 mmol) was added. After 1 hr at rt, more iodine (8.2 g, 32 mmol) was added, and the reaction mixture was stirred for an additional 1 hr at rt. After removal of most of the dioxane in vacuo, the reaction mixture was extracted with EtOAc, washed with brine, dried, and concentrated. The crude product was purified by flash chromatography to afford 3-iodo-1H-indazole-5-carboxaldehyde (4.5 g, 64.5%).
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:12]=[C:11]([F:13])[C:10]([F:14])=[CH:9][C:8]=1[CH3:15].[B:16](OC)([O:19]C)[O:17]C>O1CCCC1>[F:14][C:10]1[C:11]([F:13])=[CH:12][C:7]([B:16]([OH:19])[OH:17])=[C:8]([CH3:15])[CH:9]=1
Reactant: Cc1cc(F)c(F)cc1Br
Reactant: COB(OC)OC
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1cc(F)c(F)cc1B(O)O
Reaction time: 1 h

Procedure:
n-Butyl lithium (4.6 mL, 11.5 mmol) is added to the mixture of 1-bromo-4,5-difluoro-2-methylbenzene (2.0 g, 9.6 mmol) and trimethyl borate (1.5 g, 14.5 mmol) in anhydrous tetrahydrofuran (30 mL), drop wise, at −78° C. over one hour, under an atmosphere of argon. The reaction mixture is stirred for another hour at the same temperature, quenched and acidified with 1 N HCl. The resulting mixture is extracted with ethyl acetate(3×). The combined organic layer is washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)Br.C(N(CC)CC)C.[NH:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1>O1CCCC1>[CH3:1][O:2][C:3](=[O:12])[CH:4]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[N:20]1[CH2:25][CH2:24][S:23][CH2:22][CH2:21]1
Reactant: COC(=O)C(Br)c1ccccc1
Reactant: C1CSCCN1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)C(c1ccccc1)N1CCSCC1
Temperature: 25 °C
Yield: 97 %

Procedure:
To a solution of racemic α-bromophenylacetic acid methyl ester, 5.0 g (22.0 mmol) in 120 mL of tetrahydrofuran was added 3.4 mL (22.0 mmol) of triethylamine and 6.7 g (66.0 mmol) of thiomorpholine. The reaction mixture was refluxed for four hours, cooled to ambient temperature and concentrated to dryness. The residue was partitioned between 20% isopropanol/chloroform and water. The mixture was washed with saturated sodium bicarbonate, washed with brine, dried over sodium sulfate, filtered and concentrated to dryness. The residue was purified by chromatography using a methanol/chloroform gradient as eluent. A second purification was performed using chloroform as eluent and was concentrated to dryness to yield 5.36 g (97%) of the desired mixture of isomers as a yellow oil. MS (ion spray) 252.1 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.S([O-])([O-])(=O)=O.[Na+].[Na+].[NH2:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21].[BH4-].[Na+]>ClCCl.CO>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][NH:17][CH:18]([CH2:22][CH2:23][CH3:24])[CH2:19][CH2:20][CH3:21]
Reactant: O=Cc1ccccc1Br
Reactant: CCCC(N)CCC
Agent: O=S(=O)([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: CCCC(CCC)NCc1ccccc1Br
Reaction time: 2 h
Yield: 95 %

Procedure:
Added to a solution of 7.4 g of 2-bromobenzaldehyde in 80 cm3 of dichloromethane are 6.25 g of sodium sulfate and 5.07 g of 4-aminoheptane at a temperature close to 20° C. After stirring for 2 h, the reaction mixture is filtered through a cartridge and washed with 2 lots of 10 cm3 of dichloromethane. The filtrate is concentrated using a rotary evaporator under reduced pressure (5 kPa). The oil obtained is dissolved in 80 cm3 of methanol. 0.757 g of sodium borohydride is added in 3 lots. The reaction mixture is stirred for 1 h at 20° C., then 0.757 g of sodium borohydride is again added. This operation is carried out twice. After stirring at 20° C. for 20 h, the reaction mixture is concentrated using a rotary evaporator under reduced pressure (5 kPa). The concentration residue is taken up in 100 cm3 of dichloromethane and 50 cm3 of water. The organic phase is washed with 2 lots of 50 cm3 of a saturated aqueous solution of sodium chloride, dried over magnesium sulfate and concentrated using a rotary evaporator under reduced pressure (5 kPa). The 10.8 g of colorless oil obtained are purified by filtration through a pellet of 150 g of silica with 1 dm3 of an 80% heptane/20% ethyl acetate mixture. After concentrating the fractions under reduced pressure, 9.75 g of N-(2-bromobenzyl)heptan-4-amine are obtained in the form of a colorless clear oil.
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH3:30]>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH3:30])[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: CCC(=N)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: CCc1noc(N2CCC(N(C(=O)c3ccc(-c4cnco4)cc3)C3CC3)CC2)n1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-propionamidine following a procedure analogous to that described in Example 1. LC (method 6): tR=1.56 min; Mass spectrum (ESI+): m/z=408 [M+H]+.
Reaction SMILES: C([O:3][C:4](=[O:16])[C:5]#[C:6][C:7]1[CH:8]=[N:9][CH:10]=[C:11]([O:13][CH2:14][CH3:15])[CH:12]=1)C.C(OC([N:24]1[C:33]2[C:28](=[CH:29][CH:30]=[C:31]([CH2:34][CH2:35][O:36][C:37]3[CH:38]=[C:39]4[C:43](=[CH:44][CH:45]=3)[NH:42][CH:41]=[CH:40]4)[N:32]=2)[CH2:27][CH2:26][CH2:25]1)=O)(C)(C)C>>[CH2:14]([O:13][C:11]1[CH:12]=[C:7]([CH:6]([N:42]2[C:43]3[C:39](=[CH:38][C:37]([O:36][CH2:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]5[CH2:27][CH2:26][CH2:25][NH:24][C:33]=5[N:32]=4)=[CH:45][CH:44]=3)[CH:40]=[CH:41]2)[CH2:5][C:4]([OH:3])=[O:16])[CH:8]=[N:9][CH:10]=1)[CH3:15]
Reactant: CC(C)(C)OC(=O)N1CCCc2ccc(CCOc3ccc4[nH]ccc4c3)nc21
Reactant: CCOC(=O)C#Cc1cncc(OCC)c1
Product: CCOc1cncc(C(CC(=O)O)n2ccc3cc(OCCc4ccc5c(n4)NCCC5)ccc32)c1
Yield: 70 %

Procedure:
The title compound was synthesized from (5-ethoxy-pyridin-3-yl)-propynoic acid ethyl ester and 7-[2-(1H-indol-5-yloxy)-ethyl]-3,4-dihydro-2H-[1,8]naphthyridine-1-carboxylic acid tert-butyl ester using the procedure described in Example 16, step (d1), in 70% yield. Mass Spectrum (LCMS, ESI) calculated for C35H40N4O6: 513.2 (M-Boc+H); found: 513.3 (-Boc).
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[F:9][C:10]([F:39])([F:38])[C:11]1[CH:37]=[CH:36][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29](=[O:32])(=[O:31])[NH2:30])=[O:21])=[CH:13][CH:12]=1>CN(C)C1C=CN=CC=1.O1CCCC1>[F:39][C:10]([F:9])([F:38])[C:11]1[CH:12]=[CH:13][C:14]([CH2:15][O:16][C:17]2[CH:18]=[C:19]([CH:33]=[CH:34][CH:35]=2)[C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[S:29]([NH:30][C:1](=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])(=[O:31])=[O:32])=[O:21])=[CH:36][CH:37]=1
Reactant: CCCCCC(=O)Cl
Reactant: NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: CCCCCC(=O)NS(=O)(=O)c1ccccc1NC(=O)c1cccc(OCc2ccc(C(F)(F)F)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
In a stream of nitrogen and at 0° C. 0.16 ml (1.10 mmol) of hexanoyl chloride was added to an anhydrous tetrahydrofuran (10 ml) solution containing 451 mg (1.00 mmol) of 3-(4-trifluoromethylbenzyloxy)-N-(2-sulfamoylphenyl)benzamide produced in Reference Example 8 and 249 mg (2.00 mmol) of 4-dimethylaminopyridine, the mixture was stirred at room temperature for 1 hour and then the solvent was evaporated under a reduced pressure. The resulting residue was dissolved in ethyl acetate, washed with water, a potassium hydrgensulfate aqueous solution and saturated brine in that order and dried over anhydrous sodium sulfate, and then the solvent was evaporated under a reduced pressure. The resulting residue was purified by a silica gel column chromatography to obtain 439 mg (yield: 80.0%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([O:21]C)=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[Na+].Cl>CCO.C1COCC1>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[C:23]2[CH2:28][C:27]([CH3:30])([CH3:29])[CH2:26][C:25]([CH3:32])([CH3:31])[CH2:24]2)[C:9]2[CH:14]=[CH:13][C:12]([C:15]#[C:16][CH2:17][CH2:18][C:19]([OH:21])=[O:20])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: COC(=O)CCC#Cc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(O)cc2)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: CC1(C)CC(=C(c2ccc(O)cc2)c2ccc(C#CCCC(=O)O)cc2)CC(C)(C)C1
Temperature: 60 °C
Reaction time: 2 h
Yield: 94.8 %

Procedure:
To a solution of methyl 5-{4-[(4-hydroxyphenyl)(3,3,5,5-tetramethylcyclohexylidene)methyl]phenyl}-4-pentynoate (243) (0.16 g, 0.38 mmol) in a mixture of EtOH (5 mL) and THF (5 mL) was added an aqueous solution of 1 N NaOH (6 mL). The mixture was stirred at 60° C. for 2 h. Upon cooling, the mixture was acidified to pH=2 with an aqueous solution of 1 N HCl. The mixture was extracted with EtOAc (2×50 mL). The combined organic extract was washed with brine and dried over Na2SO4. Concentration gave a white residue, which was triturated with hot hexanes containing 1% MeOH to yield the title compound (244) as white solid (0.15 g, 95%), mp 233-234° C. 1H NMR (400 MHz, CH3OH-d4): δ 0.91 (s, 6H), 0.92 (s, 6H), 1.29 (s, 2H), 1.94 (s, 2H), 1.98 (s, 2H), 2.50-2.60 (m, 2H), 2.60-2.70 (m, 2H), 6.68 (d, J=8.6 Hz, 2H), 6.94 (d, J=8.6 Hz, 2H), 7.07 (d, J=8.3 Hz, 2H), 7.25 (d, J=8.1 Hz, 2H). LCMS (ESI): m/z 417 (M+H)+, 415 (M−H)−.
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:21]=[CH:20][C:19](C=O)=[CH:18][N:17]=3)[N:12]=2)=[CH:7][CH:6]=1)[CH:2]([CH3:4])[CH3:3].C(C1C=CC(C2ON=C(C3N=CC([CH2:45][NH:46][CH:47]4[CH2:50][CH:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=NC=3)N=2)=CC=1)C(C)C>>[CH2:1]([C:5]1[CH:6]=[CH:7][C:8]([C:11]2[O:15][N:14]=[C:13]([C:16]3[N:21]=[CH:20][C:19]([CH2:45][NH:46][C@@H:47]4[CH2:50][C@H:49]([C:51]([OH:53])=[O:52])[CH2:48]4)=[CH:18][N:17]=3)[N:12]=2)=[CH:9][CH:10]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: CC(C)Cc1ccc(-c2nc(-c3ncc(C=O)cn3)no2)cc1
Reactant: CC(C)Cc1ccc(-c2nc(-c3cnc(CNC4CC(C(=O)O)C4)cn3)no2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(CN[C@H]4C[C@@H](C(=O)O)C4)cn3)no2)cc1

Procedure:
The title compound was prepared from 2-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrimidine-5-carbaldehyde by procedures analogous to those described in Examples (1A-1B) for the preparation of 3-({5-[5-(4-isobutyl-phenyl)-[1,2,4]oxadiazol-3-yl]-pyrazin-2-ylmethyl}-amino)-cyclobutanecarboxylic acid.
Reaction SMILES: [CH2:1]([CH:3]([C:9]([O:11][CH2:12][CH3:13])=[O:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5])[CH3:2].[H-].[Na+].[CH2:16](Br)[CH:17]=[CH2:18]>C1COCC1>[CH2:7]([O:6][C:4](=[O:5])[C:3]([CH2:18][CH:17]=[CH2:16])([CH2:1][CH3:2])[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH3:8]
Reactant: CCOC(=O)C(CC)C(=O)OCC
Reactant: C=CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C=CCC(CC)(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1.25 h

Procedure:
To a stirred solution of diethyl ethylmalonate (43.0 mL, 0.228 mol) in THF (500 mL) at 0° C. was added sodium hydride (60%; 9.2 g, 0.228 mol) in portions. The mixture was warmed to rt and stirred at rt for 75 min, and was added allyl bromide (23.9 mL, 0.275 mol). The reaction was stirred at rt for 4 h, and then cooled to 0° C. and quenched with water (400 mL) and 6 N hydrochloric acid (80 mL). The product was extracted with diethyl ether (4×200 mL), and the extracts were washed with brine (2×200 mL), dried over sulfate and concentrated. The residue was distilled to give 2-allyl-2-ethylmalonic acid diethyl ester (b.p. 89-91° C./ca. 2 mm Hg).
Reaction SMILES: O[C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2.[OH-].[K+].[CH3:31][S:32](Cl)(=[O:34])=[O:33]>O.CN(C)C=O>[CH3:31][S:32]([C:2]1[CH:3]=[CH:4][C:5]([C:13](=[O:28])[CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)=[C:6]2[C:11]=1[NH:10][C:9](=[O:12])[CH2:8][CH2:7]2)(=[O:34])=[O:33]
Reactant: O=C1CCc2c(C(=O)CCN3CCN(c4ccccc4)CC3)ccc(O)c2N1
Reactant: CS(=O)(=O)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(C(=O)CCN2CCN(c3ccccc3)CC2)c2c1NC(=O)CC2

Procedure:
37.9 Grams of 8-hydroxy-5-[1-oxo-3-(4-phenylpiperazinyl)propyl]-3,4-dihydrocarbostyril and 5.9 g of potassium hydroxide were dissolved in 400 ml of water and the solution was concentraed under a reduced pressure to obtain a residue. The residue was dissolved in 400 ml of dimethylformamide and the 12.0 g of methane-sulfonyl chloride was added dropwise to the solution under cooling condition. One hour after the addition either was added to the reaction mixture to obtain crystals. The crystals were collected by filtration and washed with acetone, then recrystallized from isopropanol to obtain 35.9 g of 8-methanesulfonyl-5-[1-oxo-3-(4-phenyl-1-piperazinyl)propyl]-3,4-dihydrocarbostyril in light brown needle-like crystals. Melting point: 165°-167° C.
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][N:5]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[C@H:4]([C:14](N(OC)C)=[O:15])[CH2:3]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C.O1CCCC1>[CH:14]([C@@H:4]1[CH2:3][C@@H:2]([OH:1])[CH2:6][N:5]1[C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])=[O:15]
Reactant: CON(C)C(=O)[C@@H]1C[C@@H](O)CN1C(=O)OC(C)(C)C
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C=O
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
0.9 g of tert-butyl (2S,4R)-4-hydroxy-2-{[methoxy(methyl)amino]carbonyl}pyrrolidine-1-carboxylate is dissolved in 31 ml of diethyl ether under N2. The reaction medium is placed at 0° C. and 3.41 ml of 1N lithium aluminium hydride in tetrahydrofuran is carefully added. The mixture is stirred at 0° C. for 2 h. After hydrolysis with an aqueous potassium sulphate solution, extraction is carried out with diethyl ether until the aqueous phase is completely depleted. Drying over MgSO4 and concentration to dryness are carried out. The crude obtained is chromatographed on silica gel, elution being carried out with a 9/1 mixture of dichloromethane and methanol. 0.45 g of tert-butyl (2S,4R)-2-formyl-4-hydroxypyrrolidine-1-carboxylate is obtained.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:9](=O)[CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:5].[C:12](=[NH:19])(OCC)[CH2:13][CH2:14][CH3:15]>C(O)C>[CH3:10][C:9]1[N:19]=[C:12]([CH2:13][CH2:14][CH3:15])[NH:2][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCCC(=N)OCC
Reactant: CCOC(=O)C(N)C(C)=O
Agent: Cl
Solvent: CCO
Product: CCCc1nc(C)c(C(=O)OCC)[nH]1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.5 %

Procedure:
Ethyl 2-amino-3-oxobutanoate hydrochloride (10 g) was added to a stirring solution of ethyl butaneimidate (83.5 g) in ethanol (800 ml, freshly distilled from magnesium ethoxide) and triethylamine (85 ml) and the resultant yellow mixture stirred at room temperature for 48 h. The solvent was removed in vacuo and the residue diluted with water (500 ml) and extracted into ethyl acetate (3×200 ml). The combined organic extracts were washed with water (2×100 ml), dried and concentrated in vacuo. The resultant residue was purified by trituration with ether (5×50 ml) and the residual buff solid dried to afford the title compound (4.05 g)
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH:8]([CH3:10])[CH3:9])[CH:5]=[CH:4][C:3]=1[C:11]1([NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27])[C:19](=[O:20])[C:18]2[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:12]1=[O:21].C(N(CC)CC)C.[C:36](Cl)(=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38]>C(Cl)Cl>[O:21]=[C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:19](=[O:20])[C:11]1([C:3]1[CH:4]=[CH:5][C:6]([CH:8]([CH3:10])[CH3:9])=[CH:7][C:2]=1[O:1][C:36](=[O:41])[C:37]([CH3:40])([CH3:39])[CH3:38])[NH:22][C:23](=[O:28])[CH2:24][CH2:25][CH2:26][CH3:27]
Reactant: CCCCC(=O)NC1(c2ccc(C(C)C)cc2O)C(=O)c2ccccc2C1=O
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCC(=O)NC1(c2ccc(C(C)C)cc2OC(=O)C(C)(C)C)C(=O)c2ccccc2C1=O
Reaction time: 2 h
Yield: 91.3 %

Procedure:
A solution of pentanoic acid [2-(2-hydroxy-4-isopropyl-phenyl)-1,3-dioxo-indan-2-yl]-amide (0.10 g, 0.26 mmol) in anhydrous methylene chloride (10 ml) was added triethylamine (0.03 g, 0.31 mmol) and pivaloyl chloride (0.047 g, 0.39 mmol) and then stirred for 2 hrs. The reaction mixture was concented and extracted with ethylacetate. The concentrated organic layer was purified using silica gel column chromatography (ethylacetate:hexane=1:4) to afford the title compound (0.11 g, 91%).