Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[S:10][CH2:9][CH2:8][CH:7]=1)=[O:5])[CH3:2].[C-:11]#[N:12].[Na+].O>CN(C)C=O>[C:11]([C@H:7]1[C@H:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[S:10][CH2:9][CH2:8]1)#[N:12]
Reactant: [C-]#N
Reactant: CCOC(=O)C1=CCCS1
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)[C@@H]1SCC[C@H]1C#N
Temperature: 25 °C
Reaction time: 48 h
Yield: 22.2 %

Procedure:
To a stirred solution of 5-ethoxycarbonyl-2,3-dihydrothiophene (500 mg) in dimethylformamide (3 ml), sodium cyanide (187 mg) was added under nitrogen atmosphere and the mixture was stirred for 2 days at room temperature. Water was added to the mixture and extracted with diethyl ether. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and concentrated in vacuo. The oily residue was purified by a silica gel column chromatography to give 130 mg (24%) of trans-4-cyano-5-ethoxycarbonyltetrahydrothiophene.
Reaction SMILES: OC(C(F)(F)F)=O.[CH3:8][C:9]1[C:14]([O:15][C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18]([OH:20])=O)=[CH:13][CH:12]=[CH:11][N:10]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH2:53][C:54]1[CH:55]=[C:56]([S:60]([NH2:63])(=[O:62])=[O:61])[CH:57]=[CH:58][CH:59]=1.C(N(CC)CC)C>CN(C=O)C>[CH3:8][C:9]1[C:14]([O:15][C:16]2[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][C:17]=2[C:18]([NH:53][C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([S:60](=[O:62])(=[O:61])[NH2:63])[CH:55]=2)=[O:20])=[CH:13][CH:12]=[CH:11][N:10]=1
Reactant: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C(=O)O
Reactant: Nc1cccc(S(N)(=O)=O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: Cc1ncccc1Oc1cc(C(F)(F)F)ccc1C(=O)Nc1cccc(S(N)(=O)=O)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A solution of 2-(2-methylpyridin-3-yloxy)-4-(trifluoromethyl)benzoic acid TFA salt (54 mg, 0.13 mmol) and HATU (50 mg, 0.13 mmol) in DMF (1 mL) was stirred at room temperature 3 min. To this solution was added 3-amino-benzenesulfonamide (23 mg, 0.13 mmol) and triethylamine (46 μL, 0.33 mmol). The reaction was stirred at room temperature for 16 h and purified by preparative reverse phase HPLC using 10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA) to give 2-(2-methylpyridin-3-yloxy)-N-(3-sulfamoylphenyl)-4-(trifluoromethyl)benzamide. LC/MS: m/z 452.3 (M+H)+ at 1.07 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([OH:18])=O)[CH:11]=[N:12][CH:13]=2)=[CH:4][CH:3]=1.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[CH3:43][N:44]([CH2:51][C@H:52]1[CH2:57][CH2:56][C@H:55]([NH2:58])[CH2:54][CH2:53]1)[CH:45]1[CH2:50][CH2:49][O:48][CH2:47][CH2:46]1.C1CCN2C(=NCCC2)CC1>C(#N)C.C(N(CC)CC)C>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:9]=[C:10](/[CH:14]=[CH:15]/[C:16]([NH:58][C@H:55]3[CH2:54][CH2:53][C@H:52]([CH2:51][N:44]([CH3:43])[CH:45]4[CH2:50][CH2:49][O:48][CH2:47][CH2:46]4)[CH2:57][CH2:56]3)=[O:18])[CH:11]=[N:12][CH:13]=2)=[CH:6][CH:7]=1
Reactant: CN(C[C@H]1CC[C@H](N)CC1)C1CCOCC1
Reactant: Cc1ccc(-c2cncc(/C=C/C(=O)O)c2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: Cc1ccc(-c2cncc(/C=C/C(=O)N[C@H]3CC[C@H](CN(C)C4CCOCC4)CC3)c2)cc1
Reaction time: 2 h

Procedure:
Into a suspension of (E)-3-[5-(4-methylphenyl)pyridin-3-yl]acrylic acid (150 mg) and 1-hydroxybenzotriazole (134 mg) in acetonitrile (15 ml) was added at room temperature 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.19 g), and the resulting mixture was stirred for 2 hours. Into the reaction mixture was added a solution of trans-4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexylamine dihydrochloride (198 mg), 1,8-diazabicyclo[5,4,0]-7-undecene (0.2 g) and triethylamine (0.18 ml) in acetonitrile (20 ml), and the resulting mixture was stirred for 64 hours. After the reaction mixture was concentrated under reduced pressure, water was added to the residue, and the resulting mixture was extracted with chloroform. The organic layer was washed with an aqueous saturated solution of sodium chloride and was dried with magnesium sulfate. After the resulting organic layer was concentrated under reduced pressure to remove the solvent, the precipitated crystals were purified by recrystallization (ethanol/ethyl acetate) to obtain (trans, E)-3-[5-(4-methylphenyl)pyridin-3-yl]-N-[4-[N-methyl-N-(tetrahydropyran-4-yl)aminomethyl]cyclohexyl]acrylamide (compound 73) (226 mg) as colorless crystals.
Reaction SMILES: O=[C:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].C1(C)C=CC=CC=1.[NH:15]1[CH2:19][CH2:18][CH2:17][C:16]1=[O:20]>O>[O:20]=[C:16]1[CH2:17][CH2:18][CH2:19][N:15]1/[C:2](=[CH:6]\[CH3:7])/[C:3]([OH:5])=[O:4]
Reactant: O=C1CCCN1
Reactant: CCC(=O)C(=O)O
Solvent: O
Solvent: Cc1ccccc1
Product: C/C=C(/C(=O)O)N1CCCC1=O
Temperature: 25 °C
Yield: 67.6 %

Procedure:
A1 l flask fitted with a magnetic stirring bar and a Dean-Stark trap was charged with 2-oxobutanoic acid (25 g, 245 mmol), toluene (500 ml, 20 vol) and 2-pyrrolidinone (37.2 ml, 490 mmol, 2 equiv). The reaction mixture was stirred under reflux with azeotropic removal of water via the Dean-Stark trap for 5.5 hours. The solution was then concentrated to ca. 90 ml (3.6 vol) and allowed to cool slowly to ambient temperature. Off-white solid started to come out of solution at around 55° C. The solid was filtered, the cake was washed with toluene (2×1 vol) followed by dichloromethane (3×1 vol) and dried on the filter under vacuum for 5 min to afford crude material (28 g, 70% yield). The crude product was dissolved in acetone (450 ml, 16 vol) at reflux, cooled slowly to ambient temperature and allowed to crystallise over 12 hrs at −15 to −20° C. Pure product was obtained as a white crystalline solid (21 g, 51% overall yield).
Reaction SMILES: Cl.Cl[C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)=[C:10](OC)[CH:11]=2)[N:6]=[N:5][CH:4]=1.[F:24][C:25]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[CH:28][C:26]=1[NH2:27].C[CH:35]([OH:39])CCC>>[F:24][C:25]1[CH:31]=[C:30]([CH3:32])[C:29]([OH:33])=[CH:28][C:26]=1[NH:27][C:3]1[C:12]2[C:7](=[CH:8][C:9]([O:15][CH2:16][CH2:17][CH2:18][N:19]3[CH2:20][CH2:21][CH2:22][CH2:23]3)=[CH:10][CH:11]=2)[N:6]=[N:5][C:4]=1[O:39][CH3:35]
Reactant: COc1cc2c(Cl)cnnc2cc1OCCCN1CCCC1
Reactant: Cc1cc(F)c(N)cc1O
Reactant: CCCC(C)O
Agent: Cl
Product: COc1nnc2cc(OCCCN3CCCC3)ccc2c1Nc1cc(O)c(C)cc1F

Procedure:
A solution of 4-chloro-6-methoxy-7-(3-pyrrolidinopropoxy)cinnoline hydrochloride (158 mg, 0.4 mmol),(prepared as described for the starting material in Example 13), and 2-fluoro-5-hydroxy-4-methylaniline (67 mg, 0.48 mmol), (prepared as described for the starting material in Example 11), in 2-pentanol (5 ml) was heated at reflux for 1 hour. After cooling, the solid was filtered off, washed with isopropanol, ether and dried under vacuum to give 4-(2-fluoro-5-hydroxy-4-methylanilino)-methoxy-7 (3-pyrrolidinopropoxy)cinnoline as the hydrochloride salt (yellow solid, 55 mg, 27%).
Reaction SMILES: [C:1]([O:4][CH:5]([C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH2:31])[CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])(=[O:3])[CH3:2].[C:33]([CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][C:42](O)=[O:43])([OH:35])=[O:34].C(N=C=NC(C)C)(C)C.OC1C2N=NNC=2C=CC=1>C(Cl)Cl>[C:1]([O:4][CH:5]([CH:6]([O:19][C:20](=[O:22])[CH3:21])[CH:7]([O:15][C:16](=[O:18])[CH3:17])[CH:8]([O:11][C:12](=[O:14])[CH3:13])[CH2:9][OH:10])[C:23](=[O:32])[CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][NH:31][C:42]([CH2:41][O:40][CH2:39][CH2:38][O:37][CH2:36][C:33]([OH:35])=[O:34])=[O:43])(=[O:3])[CH3:2]
Reactant: O=C(O)COCCOCC(=O)O
Reactant: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCN
Agent: CC(C)N=C=NC(C)C
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Product: CC(=O)OC(CO)C(OC(C)=O)C(OC(C)=O)C(OC(C)=O)C(=O)COCCOCCNC(=O)COCCOCC(=O)O

Procedure:
25 is prepared similarly to 24 starting from 500 mg of 2,3,4-triacetoxy-1-{2-[2-(2-aminoethoxy)ethoxy]acetyl}-5-hydroxypentyl acetate 23, 927 mg of (2-carboxymethoxyethoxy)acetic acid, 400 μl of diisopropylcarbodiimide and 288 mg of hydroxybenzotriazole in 20 ml of methylene chloride. This gives 25:
Reaction SMILES: C([BH3-])#N.[Na+].[CH3:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12]1[CH:17]=[CH:16][C:15]([C:18]2[O:22][N:21]=[C:20]([C:23]3[CH:30]=[CH:29][C:26]([CH:27]=O)=[CH:25][CH:24]=3)[N:19]=2)=[CH:14][C:13]=1[C:31]([F:34])([F:33])[F:32].[NH2:35][CH2:36][C:37]([OH:39])=[O:38].[CH3:40][C:41]([CH3:43])=O>CO.CC(O)=O.C(Cl)Cl>[CH:41]([N:35]([CH2:36][C:37]([OH:39])=[O:38])[CH2:27][C:26]1[CH:25]=[CH:24][C:23]([C:20]2[N:19]=[C:18]([C:15]3[CH:16]=[CH:17][C:12]([C:7]4[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=4[CH3:5])=[C:13]([C:31]([F:32])([F:33])[F:34])[CH:14]=3)[O:22][N:21]=2)=[CH:30][CH:29]=1)([CH3:43])[CH3:40]
Reactant: NCC(=O)O
Reactant: CC(C)=O
Reactant: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(C=O)cc3)no2)cc1C(F)(F)F
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: CO
Product: Cc1ccccc1-c1ccc(-c2nc(-c3ccc(CN(CC(=O)O)C(C)C)cc3)no2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Sodium cyanoborohydride (18 mg, 0.28 mmol) was added to a solution of 4-(5-(2′-methyl-2-(trifluoromethyl)biphenyl-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (0.25 mmol) and 2-aminoacetic acid (23 mg, 0.25 mmol) in a mixture of methanol (3 mL), DCM (3 mL) and acetic acid (38 μl). The mixture was stirred at room temperature overnight and was filtered through a frit under positive pressure. To the filtrate was added acetone (67 mg; 1.5 mmol) followed by addition of AcOH until the pH was in the range of 3-4 (240 mL). To the resulting mixture was added sodium cyanoborohydride (79 mg, 1.26 mmol), the mixture stirred for 16 hours, the solvent removed in vacuo and the residue purified by reverse phase HPLC to give a white solid as the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 8.55-8.53 (1H, m), 8.53-8.48 (1H, m), 8.13-8.09 (2H, m), 7.71 (1H, d, J=7.9 Hz), 7.63 (2H, d, J=8.0 Hz), 7.37-7.34 (2H, m), 7.28-7.24 (1H, m), 7.15 (1H, d, J=7.5 Hz), 4.02 (2H, s), 3.24-3.22 (3H, m), 2.01 (3H, s), 1.11 (6H, d, J=6.5 Hz). LC/MS (Method A): 510 (M+H)+. HPLC (Method F) Rt=3.39 min (Purity: 99.1%).
Reaction SMILES: [CH3:1][NH:2][S:3]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:13][C:14]#[C:15][CH3:16])=[CH:8][CH:7]=1)(=[O:5])=[O:4].C[Si](C)(C)[N-][Si](C)(C)C.[Na+].Br[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30].O>CN(C=O)C>[CH2:13]([O:12][C:9]1[CH:10]=[CH:11][C:6]([S:3]([N:2]([CH3:1])[CH:28]([CH2:33][CH2:34][CH2:35][Cl:36])[C:29]([O:31][CH3:32])=[O:30])(=[O:5])=[O:4])=[CH:7][CH:8]=1)[C:14]#[C:15][CH3:16]
Reactant: CC#CCOc1ccc(S(=O)(=O)NC)cc1
Reactant: COC(=O)C(Br)CCCCl
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)C(CCCCl)C(=O)OC)cc1
Reaction time: 0.25 h

Procedure:
A solution of 7.17 g (30 mmol) N-methyl-[4-(2-butynyloxy)-phenyl]sulfonamide] in 25 ml of DMF was cooled 0° C. and 30 ml of 1M sodium hexamethyldisilazide (30 mmol) was slowly added and this mixture was stirred for 15 min and then added to a solution of 6.89 g (30 mmol) of methyl 2-bromo-5-chloropentanoate in 25 ml of DMF and was stirred at room temperature for 18 hours. The mixture was combined with water and the precipitate was collected and purified by chromatography on silica gel using hexane-ethyl acetate, 4:1 to give methyl 2-[{[4-(2-butynyloxy)phenyl]sulfonyl}(methyl)-amino]-5-chloropentanoate Electrospray Mass Spec 410.2 (M+Na)+
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:4]=[C:5]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[CH:6]=[CH:7][CH:8]=1.C(N(CC)CC)C.C(Cl)CCl.[Cl:26][CH2:27][C:28](O)=[O:29]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:26][CH2:27][C:28]([N:12]1[CH2:13][CH2:14][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Cl:2])[CH:4]=2)[CH2:10][CH2:11]1)=[O:29]
Reactant: O=C(O)CCl
Reactant: Clc1cccc(N2CCNCC2)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: ClCCCl
Product: O=C(CCl)N1CCN(c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.4 %

Procedure:
To solution of 1-(3-chlorophenyl)piperazine hydrochloride (1.2 g, 5.2 mmol) in DCM (10 mL) was added triethylamine (1.0 mL, 7.3 mmol), EDC (1.9 g, 10 mmol), DMAP (cat.) and chloroacetic acid (0.4 g, 5.2 mmol). The reaction was stirred at RT overnight and DCM was removed. The resultant residue was partitioned between EtOAc (50 mL) and H2O (50 mL). The organic layer was dried over Na2SO4 and concentrated to provide 1.0 g of pure 2-chloro-1-(4-(3-chlorophenyl)piperazin-1-yl)ethanone, (yield: 70%).
Reaction SMILES: [F:1][S:2]([O:5][CH3:6])(=[O:4])=[O:3].Br.COC1C=CC(N(S(C2C=CC(CCCCC(O)=O)=CC=2)(=O)=O)C(C2C3C(N=C4C=2C=CC=C4)=CC=CC=3)=O)=CC=1.[C:49]1(=[O:91])[N:53]([O:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([N:63]([S:80]([C:83]3[CH:88]=[CH:87][C:86]([CH3:89])=[CH:85][CH:84]=3)(=[O:82])=[O:81])[C:64]([C:66]3[C:67]4[C:72]([N:73]=[C:74]5[C:79]=3[CH:78]=[CH:77][CH:76]=[CH:75]5)=[CH:71][CH:70]=[CH:69][CH:68]=4)=[O:65])=[CH:59][CH:58]=2)=[O:56])[C:52](=[O:90])[CH2:51][CH2:50]1>ClCCCl>[F:1][S:2]([O-:5])(=[O:4])=[O:3].[C:52]1(=[O:90])[N:53]([O:54][C:55]([C:57]2[CH:62]=[CH:61][C:60]([N:63]([S:80]([C:83]3[CH:84]=[CH:85][C:86]([CH3:89])=[CH:87][CH:88]=3)(=[O:81])=[O:82])[C:64]([C:66]3[C:79]4[C:74]([N+:73]([CH3:6])=[C:72]5[C:67]=3[CH:68]=[CH:69][CH:70]=[CH:71]5)=[CH:75][CH:76]=[CH:77][CH:78]=4)=[O:65])=[CH:59][CH:58]=2)=[O:56])[C:49](=[O:91])[CH2:50][CH2:51]1
Reactant: COS(=O)(=O)F
Reactant: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3nc3ccccc23)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Agent: Br
Agent: COc1ccc(N(C(=O)c2c3ccccc3nc3ccccc23)S(=O)(=O)c2ccc(CCCCC(=O)O)cc2)cc1
Solvent: ClCCCl
Product: Cc1ccc(S(=O)(=O)N(C(=O)c2c3ccccc3[n+](C)c3ccccc23)c2ccc(C(=O)ON3C(=O)CCC3=O)cc2)cc1
Product: O=S(=O)([O-])F

Procedure:
0.85 g (7.5 mmol) of methyl fluorosulfonate is added, while stirring at 25° C., to a solution of 0.59 9 (1 mmol) of N-(4-succinimidyloxycarbonylphenyl)-N-(4-toluenesulfonyl)acridine-9-carboxamide in 30 ml of 1,2-dichloroethane. The reaction product precipitates out within 4 hours. Filtration with suction and drying result in 0.43 g (60.8% of theory) of the desired product.
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=[C:4]2[CH:3]=[CH:2]1.Cl.[CH3:13][NH:14][CH3:15].[CH2:16]=O>C(O)(C)C>[CH3:13][N:14]([CH2:16][C:3]1[C:4]2[C:5](=[N:6][CH:7]=[C:8]([C:10]#[N:11])[CH:9]=2)[NH:1][CH:2]=1)[CH3:15]
Reactant: CNC
Reactant: C=O
Reactant: N#Cc1cnc2[nH]ccc2c1
Agent: Cl
Solvent: CC(C)O
Product: CN(C)Cc1c[nH]c2ncc(C#N)cc12
Yield: 47.6 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine-5-carbonitrile (632, 3.00 g, 0.0210 mol) in isopropyl alcohol (120 mL) were added dimethylamine hydrochloride (1.91 g, 0.0235 mol) and formaldehyde (0.708 g, 0.0236 mol). The reaction was heated to reflux overnight, then concentrated, poured into water, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 5% to 30% methanol in dichloromethane containing 0.3% triethyl amine to give the desired compound (633, 2.0 g, 48%).
Reaction SMILES: [C:1]([C:3]([CH3:10])([CH3:9])[CH:4]([OH:8])[CH2:5][CH2:6][OH:7])#[N:2].C(=O)([O-])[O-].[K+].[K+].CO[C:19](OC)([CH3:21])[CH3:20]>C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:3]([CH:4]1[CH2:5][CH2:6][O:7][C:19]([CH3:21])([CH3:20])[O:8]1)([CH3:10])[CH3:9])#[N:2]
Reactant: CC(C)(C#N)C(O)CCO
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC1(C)OCCC(C(C)(C)C#N)O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol (500 mg, 3.49 mmol) was dissolved in 2,2-dimethoxypropane (5 mL) and p-toluenesulfonic acid (50 mg) was added. The mixture was stirred at room temperature for 30 min. Thereto was added a powder of potassium carbonate (100 mg) to neutralize the reaction mixture. The mixture was filtrated and concentrated under reduced pressure to give optically active 4-(1-cyano-1-methylethyl)-2,2-dimethyl-1,3-dioxane (614 mg, 3.35 mmol) (yield relative to optically active 4-cyano-4-methyl-3-hydroxy-1-pentanol: 96%).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[CH:28]=[CH:27][C:7]([CH2:8][N:9]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10]2)=[CH:6][CH:5]=1.Cl[CH2:30][C:31]1[N:32]=[C:33]([C:36]2[S:37][CH:38]=[CH:39][CH:40]=2)[S:34][CH:35]=1.O>CN(C)C=O>[C:14]1([C:12]2[C:11]([CH2:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])=[CH:10][N:9]([CH2:8][C:7]3[CH:27]=[CH:28][C:4]([O:3][CH2:30][C:31]4[N:32]=[C:33]([C:36]5[S:37][CH:38]=[CH:39][CH:40]=5)[S:34][CH:35]=4)=[CH:5][CH:6]=3)[CH:13]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1csc(-c2cccs2)n1
Reactant: CCOC(=O)CCc1cn(Cc2ccc(O)cc2)cc1-c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCc1cn(Cc2ccc(OCc3csc(-c4cccs4)n3)cc2)cc1-c1ccccc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 74.4 %

Procedure:
Sodium hydride (60%, oily, 60.0 mg) was added to a solution of ethyl 3-[1-(4-hydroxybenzyl)-4-phenyl-3-pyrrolyl]propionate (524 mg) in N,N-dimethylformamide (10 ml) at 0° C., and the mixture was stirred at room temperature for 15 minutes. 4-Chloromethyl-2-(2-thienyl)thiazole (324 mg) was added to the mixture, which was stirred at room temperature for 30 minutes. 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 ethyl 3-[4-phenyl-1-[4-[2-(2-thienyl)-4-thiazolylmethoxy]benzyl]-3-pyrrolyl]propionate (590 mg, yield: 74%) was obtained as an oily substance from the fraction eluted with ethyl acetate-hexane (1:3, volume ratio).
Reaction SMILES: [C:1]1([CH:7]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][NH2:18])[CH2:11][CH2:10]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl[C:27]1[CH:28]=[CH:29][C:30]2[N:31]([N:33]=[CH:34][N:35]=2)[N:32]=1.C(=O)(O)[O-].[Na+]>>[C:20]1([CH:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[O:8][CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH:16]([OH:19])[CH2:17][NH:18][C:27]3[CH:28]=[CH:29][C:30]4[N:31]([N:33]=[CH:34][N:35]=4)[N:32]=3)[CH2:11][CH2:10]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: NCC(O)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Reactant: Clc1ccc2ncnn2n1
Agent: O=C([O-])O
Agent: [Na+]
Product: OC(CNc1ccc2ncnn2n1)CN1CCC(OC(c2ccccc2)c2ccccc2)CC1
Yield: 56 %

Procedure:
0.675 g of 3-[4-(diphenylmethoxy)piperidino]-2-hydroxypropylamine and 0.335 g of 6-chloro[1,2,4]triazolo [1,5-b]pyridazine were stirred at 135-140° C. for 3 hours. After cooling, aqueous sodium bicarbonate was added, followed by extraction with ethyl acetate-tetrahydrofuran (2:1); the extract was washed with saline and dried with sodium sulfate. The dry product was concentrated under reduced pressure; the residue was subjected to silica gel column chromatography and eluted with ethyl acetate:methanol:triethylamine (90:10:1). The desired fraction was collected, recrystallized from ethyl acetate and dried to yield 0.509 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH2:20])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.[F:21][C:22]([F:38])([F:37])[C:23]1[O:27][N:26]=[C:25]([C:28]2[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=2)[C:31](O)=[O:32])[N:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:13]3([CH2:19][NH:20][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:25]5[N:24]=[C:23]([C:22]([F:38])([F:37])[F:21])[O:27][N:26]=5)[CH:29]=4)[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)[S:11][CH:12]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)c1cccc(-c2noc(C(F)(F)F)n2)c1
Reactant: NCC1(c2nc(-c3ccc(Cl)cc3)cs2)CCOCC1
Product: O=C(NCC1(c2nc(-c3ccc(Cl)cc3)cs2)CCOCC1)c1cccc(-c2noc(C(F)(F)F)n2)c1
Yield: 42 %

Procedure:
This compound was synthesized (4-(4-(4-chlorophenyl)thiazol-2-yl)tetrahydro-2H-pyran-4-yl)methanamine and 3-(5-(trifluoromethyl)-1,2,4-oxadiazol-3-yl)benzoic acid as described in example 8 step 6 (75 mg, yield 42%). 1H NMR (400 MHz, CDCl3) δ 8.47 (s, 1H), 8.26 (d, J=7.8 Hz, 1H), 7.99 (d, J=9 Hz, 1H), 7.83 (m, 2H), 7.59 (t, J=7.8 Hz, 1H), 7.52 (s, 1H), 7.42 (t, J=5.4 Hz, 1H), 7.35 (d, J=8.5 Hz, 2H), 3.99-3.94 (m, 2H), 3.58 (d, J=5.8 Hz, 2H), 3.77-3.71 (m, 2H), 2.35-2.29 (m, 2H), 2.08-2.05 (m, 2H). MS (ESI) m/z: Calculated for C26H20ClF3N4O3S: 548.09. found: 549.0 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:26][O:27][C:28]1[CH:35]=[CH:34][C:31]([CH2:32]Cl)=[CH:30][CH:29]=1>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:12]([CH2:16][CH:17]([CH3:19])[CH3:18])[C:13]([NH2:15])=[O:14])[CH2:32][C:31]2[CH:34]=[CH:35][C:28]([O:27][CH3:26])=[CH:29][CH:30]=2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CC(C)C[C@@H](NS(=O)(=O)c1ccc(Cl)cc1)C(N)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(CN([C@H](CC(C)C)C(N)=O)S(=O)(=O)c2ccc(Cl)cc2)cc1
Yield: 69.9 %

Procedure:
(2R)-2-(4-Chlorobenzenesulfonylamino)-4-methylpentanoic acid amide (300 mg, 1 mmol), K2CO3 (170 mg, 1.2 mmol), and 4-methoxybenzyl chloride (170 mg, 1.1 mmol) in DMF (25 mL) was heated to 60° C. for 18 h. The reaction was then diluted with EtOAc (150 mL) and washed with H2O, brine, dried over MgSO4 and concentrated to give a crude white wax. Further purification by flash chromatography (SiO2, 25% EtOAc/hexanes) afforded the titled compound (297 mg) as a white solid in 70% yield. [α]D=+44.2 (c 1.00, MeOH); MS (ESI), (M−H)˜422.9; 1H NMR (CDCl3) δ 7.63 (d, 2H, J=7.0), 7.42 (d, 2H, J=7.0), 7.25 (d, 2H, J=8.0), 6.79 (d, 2H, J=8.0), 6.25 (br s, 1H), 5.35 (br s, 1H), 4.36 (dd, 2H, J=50, 15), 4.26 (t, 1H, J=7.2), 3.78 (s, 3H), 1.83 (m, 1H), 1.18-1.34 (m, 2H), 0.75 (d, 3H, J=7.0), 0.67 (d, 3H, J=7.0); IR (KBr) 3480, 2959, 1693, 1674, 1514, 1333, 1158 cm−1.
Reaction SMILES: [CH2:1]([N:8]([CH2:21][C:22]1[CH:42]=[CH:41][C:25]([O:26][C:27]2[CH:40]=[CH:39][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36](O)=[O:37])=[CH:29][CH:28]=2)=[CH:24][CH:23]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:18])=[O:17])[C:10]=1[CH3:20])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.C([O:48][C:49](=[O:56])[C@H:50]([C@H:52]([CH2:54][CH3:55])[CH3:53])[NH2:51])(C)(C)C>>[CH2:1]([N:8]([CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][C:27]2[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][CH2:34][CH2:35][C:36]([NH:51][C@H:50]([C:49]([OH:48])=[O:56])[C@H:52]([CH2:54][CH3:55])[CH3:53])=[O:37])=[CH:39][CH:40]=2)=[CH:41][CH:42]=1)[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([NH:15][S:16]([CH3:19])(=[O:17])=[O:18])[C:10]=1[CH3:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1c(NS(C)(=O)=O)cccc1N(Cc1ccccc1)Cc1ccc(Oc2ccc(OCCCCC(=O)O)cc2)cc1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC(C)(C)C
Agent: Cl
Product: CC[C@H](C)[C@H](NC(=O)CCCCOc1ccc(Oc2ccc(CN(Cc3ccccc3)c3cccc(NS(C)(=O)=O)c3C)cc2)cc1)C(=O)O

Procedure:
The product from Example 234B and L-isoleucine tert-butyl ester hydrochloride were processed as described in Example 251A and 258B to provide the titled compound. 1H NMR (500 MHz, DMSO-d6) δ12.09-12.71 (br.s, 1 H), 8.94 (s, 1 H), 7.93 (d, 1 H), 7.23 (m, 7 H), 7.03 (t, 1 H), 6.94 (m, 6 H), 6.82 (d, 2 H), 4.19 (dd, 1 H), 4.04 (s, 2 H), 4.00 (s, 2 H), 3.93 (t, 2 H), 2.91 (s, 3 H), 2.38 (s, 3 H), 2.21 (m, 2 H), 1.59-1.80 (m, 5 H), 1.39 (m, 1 H), 1.20 (m, 1 H), 0.84 (m, 6 H); MS (ESI+) m/z 702 (M+H)+.