Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([OH:12])=O)=[CH:5][C:4]=1[CH3:14])#[N:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:36]1([CH3:54])[CH:41]=[CH:40][CH:39]=[C:38]([C:42]2[C:47]([CH2:48][NH2:49])=[CH:46][CH:45]=[C:44]([C:50]([F:53])([F:52])[F:51])[N:43]=2)[CH:37]=1.C(N(CC)CC)C>C(#N)C.C(OC(=O)C)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]([CH3:13])[C:10]([NH:49][CH2:48][C:47]2[C:42]([C:38]3[CH:37]=[C:36]([CH3:54])[CH:41]=[CH:40][CH:39]=3)=[N:43][C:44]([C:50]([F:53])([F:51])[F:52])=[CH:45][CH:46]=2)=[O:12])=[CH:5][C:4]=1[CH3:14])#[N:2]
Reactant: Cc1cc(C(C)C(=O)O)ccc1C#N
Reactant: Cc1cccc(-c2nc(C(F)(F)F)ccc2CN)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: Cc1cccc(-c2nc(C(F)(F)F)ccc2CNC(=O)C(C)c2ccc(C#N)c(C)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.6 %

Procedure:
To a stirred solution of 2-(4-cyano-3-methylphenyl)propanoic acid (100 mg, 0.53 mmol) in acetonitrile were added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide (152 mg, 0.80 mmol), 1-hydroxybenzotriazole (107 mg, 0.80 mmol), (2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methanamine (155 mg, 0.58 mmol) and triethylamine (0.18 mL, 1.33 mmol). The reaction mixture was stirred for overnight at room temperature. The mixture was diluted with ethylacetate and washed with water and brine. The organic layer was dried over magnesium sulfate and filtered. The filtrate removed in vacuo. The crude was purified by column chromatography. 2-(4-Cyano-3-methylphenyl)-N-((2-m-tolyl-6-(trifluoromethyl)pyridin-3-yl)methyl)propanamide (152 mg) was obtained as 86% yield.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8]2[CH:9]=[C:10]3[C:14](=[CH:15][CH:16]=2)[N:13]([CH3:17])[C:12]2[N:18]([CH3:31])[C:19](=[O:30])[C:20]([C:22]4[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][C:23]=4[Cl:29])=[CH:21][C:11]3=2)[N:7]=1.[CH3:32][S:33](Cl)(=[O:35])=[O:34]>>[Cl:29][C:23]1[CH:24]=[C:25]([Cl:28])[CH:26]=[CH:27][C:22]=1[C:20]1[C:19](=[O:30])[N:18]([CH3:31])[C:12]2[N:13]([CH3:17])[C:14]3[C:10]([C:11]=2[CH:21]=1)=[CH:9][C:8]([C:6]1[N:7]=[C:3]([CH2:2][NH:1][S:33]([CH3:32])(=[O:35])=[O:34])[S:4][CH:5]=1)=[CH:16][CH:15]=3
Reactant: CS(=O)(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CN)n4)ccc3n(C)c21
Product: Cn1c(=O)c(-c2ccc(Cl)cc2Cl)cc2c3cc(-c4csc(CNS(C)(=O)=O)n4)ccc3n(C)c21

Procedure:
The process is carried out as indicated in Example 99 above, with the compound from Example 147, 6-(2-aminomethylthiazol-4-yl)-3-(2,4-dichlorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one, and methanesulphonyl chloride.
Reaction SMILES: C(N(CC)CC)C.[CH:8]#[C:9][CH2:10][CH2:11][CH2:12][CH3:13].Cl[C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1>C1COCC1.[Cu]I>[C:8]([C:15]1[CH:20]=[CH:19][N:18]([C@@H:21]2[O:36][C@H:35]([CH2:37][O:38][C:39](=[O:46])[C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C@@H:25]([O:26][C:27](=[O:34])[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C@H:22]2[O:23][CH3:24])[C:17](=[O:47])[N:16]=1)#[C:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: C#CCCCC
Reactant: CO[C@@H]1[C@H](OC(=O)c2ccccc2)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1ccc(Cl)nc1=O
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCCCC#Cc1ccn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@H]2OC)c(=O)n1
Reaction time: 0.08 h

Procedure:
Bis-triphenylphosphine palladium (II) dichloride (422 mg, 4.3 mmole) and copper (I) iodide (114 mg, 4.3 mmole) were suspended in anhydrous THF (100 ml) and degassed with argon for 10 min. The orange suspension was treated with triethylamine (5 ml) and 1-hexyne (2.96 g, 41 mmole) and stirred for 5 min. A solution of 4-chloro-1-(2-O-methyl-3,5,-di-O-benzoyl-β-D-ribofuranosyl)pyrimidin-2-one (6.74 g, 13.9 mmole) in THF (25 ml) was added all at once. The reaction mixture was stirred for 2 hours at room temperature and evaporated to an oil. The residue was purified by silica gel column chromatography. Elution with chloroform (500 ml) and then chloroform/acetone (98:2, 21), pooling of appropriate fractions and evaporation gave a yield of 3.84 g (52.7%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([O-:28])=[O:27])=[CH:4][CH:3]=1.FC1C=CC(C2C3C(=CC=CC=3)C(C3C=CC4OCOC=4C=3)=C2C(OCC)=O)=CC=1>CCO.[Pd]>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH:10]([C:17]3[CH:22]=[CH:21][C:20]4[O:23][CH2:24][O:25][C:19]=4[CH:18]=3)[CH:9]2[C:26]([OH:28])=[O:27])=[CH:4][CH:3]=1
Reactant: O=C([O-])C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Agent: [Pd]
Agent: CCOC(=O)C1=C(c2ccc3c(c2)OCO3)c2ccccc2C1c1ccc(F)cc1
Solvent: CCO
Product: O=C(O)C1C(c2ccc(F)cc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 8 h
Yield: 100 %

Procedure:
Ethyl (1RS, 2RS, 3SR)-1-(4-Fluorophenyl)-3-(3,4-methylenedioxyphenyl)indane-2-carboxylate. To a solution of ethyl (RS)-1-(4-fluorophenyl)-3-(3,4-methylenedioxyphenyl)indene-2-carboxylate (40 mg, 0.10 mmol) in EtOH (3 ml) was added 10% palladium on activated carbon (45 mg). The resulting suspension was stirred under an atmosphere of H2 overnight, then was filtered through a pad of Celite. The filtrate was concentrated under reduced pressure to afford the title compound (40 mg, 100%), which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH:20]=O)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29].[N:30]1[CH:35]=[CH:34][CH:33]=[N:32][C:31]=1[N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:39]2[CH2:40][CH2:41][N:36]([C:31]4[N:30]=[CH:35][CH:34]=[CH:33][N:32]=4)[CH2:37][CH2:38]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:29]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(C=O)ccc21
Reactant: c1cnc(N2CCNCC2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)(C)OC(=O)n1c(-c2ccc(Cl)c3c2C(=O)NC3)cc2cc(CN3CCN(c4ncccn4)CC3)ccc21

Procedure:
In a similar manner to Step 1 of Example 56, 4-chloro-7-[1-(tert-butoxycarbonyl)-5-formylindol-2-yl]isoindolinone (20.0 mg, 0.0487 mmol) was dissolved in dichloromethane (0.5 mL). The solution was treated with 1-(2-pyrimidyl)piperazine (33 mg, 0.20 mmol) and sodium triacetoxyborohydride (32 mg, 0.15 mmol) to obtain 4-chloro-7-(1-(tert-butoxycarbonyl)-5-[4-(pyrimidin-2-yl)piperazin-1-ylmethyl]indol-2-yl)isoindolinone.
Reaction SMILES: C[O:2][C:3](=[O:33])[CH2:4][O:5][C:6]1[C:15]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=2[C:9]([S:16][CH2:17][C:18]2[CH:22]=[C:21]([C:23]3[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=3)[O:20][N:19]=2)=[CH:8][CH:7]=1.COC(=O)COC1C2CCCCC=2C(S)=CC=1>>[F:32][C:29]([F:30])([F:31])[C:26]1[CH:27]=[CH:28][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][S:16][C:9]3[C:10]4[CH2:11][CH2:12][CH2:13][CH2:14][C:15]=4[C:6]([O:5][CH2:4][C:3]([OH:33])=[O:2])=[CH:7][CH:8]=3)[CH:22]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)c2c1CCCC2
Agent: COC(=O)COc1ccc(S)c2c1CCCC2
Product: O=C(O)COc1ccc(SCc2cc(-c3ccc(C(F)(F)F)cc3)on2)c2c1CCCC2

Procedure:
{4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid methyl ester (compound 102A) The title compound was prepared in the manner analogous to Example 1F using (4-mercapto-5,6,7,8-tetrahydro-naphthalen-1-yloxy)-acetic acid methyl ester and the product from Example 42C; recrystallization from methanol afforded the title compound. MS m/z 478 (M+1). Step 2. {4-[5-(4-trifluoromethyl-phenyl)-isoxazol-3-ylmethylsulfanyl]-5,6,7,8-tetrahydro-naphthalen-1-yloxy}-acetic acid (compound 102) The title compound was prepared in the manner analogous to Example 1 using the product from Example 102A. mp 167-170° C.; 400 MHz 1H NMR (DMSO-d6) δ 8.01 (d, 2H, J=8 Hz), 7.83 (d, 2H, J=8.3 Hz), 7.14 (d, 2H, J=8.5 Hz), 7.07 (s, 1H), 6.58 (d, 2H, J=8.8 Hz), 4.56 (s, 2H), 4.07 (s, 2H), 2.64 (m, 2H), 2.53 (m, 2H), 1.60 (m, 4H); MS m/z 464 (M+1). The compounds of the present invention can also be prepared using combinatorial chemistry methods. In particular, compounds of Examples 103-134 were prepared using combinatorial chemistry analogous to that previously described in Examples 1-102. The combinatorial chemistry methods useful in the present invention include those where an activated alcohol is contacted with a thiol followed by saponification of the resulting ester to afford the desired products. Such methods can be illustrated by previously described Scheme 1 where compound D is an exemplary thiol, compound Y is an exemplary activated alcohol, and compound F is an exemplary desired product.
Reaction SMILES: C(O)[C@H]1OC(O)[C@H](O)[C@@H](O)[C@@H]1O.O.O.O.O.O.O.[Cl-].[Mg+2].[Cl-].[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C:31](=[O:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:24])[CH3:23].C1C=[N+]([C@@H]2O[C@H](COP(OP(OC[C@H]3O[C@@H](N4C5N=CN=C(N)C=5N=C4)[C@H](O)[C@@H]3O)(O)=O)([O-])=O)[C@@H](O)[C@H]2O)C=C(C(N)=O)C=1.O=C[C@@H]([C@H]([C@@H]([C@@H](CO)O)O)O)O.[OH-].[Na+]>C1N(CCS(O)(=O)=O)CCOC1.CCCCCCC>[C:22]([O:26][C:27]([N:29]1[CH2:36][CH2:35][C:32]2([CH2:34][CH2:33]2)[C@H:31]([OH:37])[CH2:30]1)=[O:28])([CH3:25])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC2)C(=O)C1
Agent: NC(=O)c1ccc[n+]([C@@H]2O[C@H](COP(=O)([O-])OP(=O)(O)OC[C@H]3O[C@@H](n4cnc5c(N)ncnc54)[C@H](O)[C@@H]3O)[C@@H](O)[C@H]2O)c1
Agent: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=S(=O)(O)CCN1CCOCC1
Solvent: CCCCCCC
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC2(CC2)[C@H](O)C1
Temperature: 35 °C
Yield: 93 %

Procedure:
D(+)-glucose monoydrate (300 g) and magnesium chloride hexahydrate (1.0 g) were dissolved in 10 mM MES buffer pH 6.5 (2.4 L; Sigma M3671). After addition of 4-oxo-6-aza-spiro[2.5]octane-6-carboxylic acid tert-butyl ester (300 g; 1.33 mmol) and β-NAD (3.0 g; free acid; Roche Diagnostics Cat. No. 10 004 626) the pH was re-adjusted and the suspension heated to 35° C. The reaction was started by adding ketoreductase KRED-NADH-117 (3.0 g; former Biocatalytics, now Codexis) and glucose dehydrogenase GDH-102 (300 mg; Biocatalytics). The suspension was vigorously stirred at 35° C. keeping the pH constant at 6.5 by the controlled addition (pH-stat) of 1.0 M aq. sodium hydroxide solution. After a consumption of 1.307 L (corresponding to 98% conversion; after 17 h) the reaction mixture was extracted with ethyl acetate (10 L). The organic phase was dried over sodium sulfate and concentrated in vacuo (200 mbar/45° C.) until evaporation fell off. Upon cooling the oily residue (411 g) started to crystallize and was stirred with heptane (1 L) for 2 h. The crystals were filtered off and the filtrate evaporated to dryness, redissolved in ethyl acetate (150 ml) and concentrated in vacuo as described above. The crystal suspension formed again upon cooling was stirred with heptane (200 ml; 2 h) and the crystals filtered off. Both crops of crystals were washed with heptane and dried under high vacuum to yield the title compound in 93% yield (250.77 g and 34.60 g white crystals), each having a purity of >98.5% GC and 99.8% ee. [α]D=−44.97° (c=1.00, CHCl3).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][C:9]=1[NH:10]C(=O)C(F)(F)F)=[O:4].C(=O)([O-])[O-].[K+].[K+]>>[CH3:1][O:2][C:3]([C:5]1[S:6][C:7]([C:17]([CH:19]2[CH2:24][CH2:23][O:22][CH2:21][CH2:20]2)=[O:18])=[CH:8][C:9]=1[NH2:10])=[O:4]
Reactant: COC(=O)c1sc(C(=O)C2CCOCC2)cc1NC(=O)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Product: COC(=O)c1sc(C(=O)C2CCOCC2)cc1N

Procedure:
5-(Tetrahydropyran-4-carbonyl)-3-(2,2,2-trifluoroacetylamino)thiophene-2-carboxylic acid methyl ester and potassium carbonate were reacted by method X. The product with the molecular weight of 269.32 (C12H15NO4S) was obtained in this way; MS (ESI): 270 (M+H+).
Reaction SMILES: [F:1][CH:2]([F:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[NH:8][C:7](=S)[C:6]([CH3:11])([CH3:10])[O:5][CH2:4]1.CO.[NH3:22]>>[F:1][CH:2]([F:19])[C:3]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:4][O:5][C:6]([CH3:11])([CH3:10])[C:7]([NH2:22])=[N:8]1
Reactant: CC1(C)OCC(c2ccccc2F)(C(F)F)NC1=S
Reactant: N
Solvent: CO
Product: CC1(C)OCC(c2ccccc2F)(C(F)F)N=C1N
Temperature: 80 °C

Procedure:
5-Difluoromethyl-5-(2-fluoro-phenyl)-2,2-dimethyl-morpholine-3-thione (2.50 g, 8.64 mmol) was dissolved in NH3 solution 7 mol/L in methanol (40.7 mL, 285 mmol). The sealed reaction vessel was heated to 80° C. for 7 h, then the temperature was lowered to 70° C. and the reaction mixture was stirred over night. The reaction mixture was evaporated and purified on a silica gel column by eluting with CH2Cl2/1-4% EtOH:NH3 9:1 to give 2.09 g of the title compound as an off-white solid.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]2[N:13]([S:16]([C:19]3[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:14]=[CH:15][C:3]=12.[CH:26]1([NH2:32])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CCCCO.O.C(Cl)Cl>[CH:26]1([NH:32][C:2]2[C:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:6][N:5]=[C:4]3[N:13]([S:16]([C:19]4[CH:25]=[CH:24][C:22]([CH3:23])=[CH:21][CH:20]=4)(=[O:18])=[O:17])[CH:14]=[CH:15][C:3]=23)[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1Cl
Reactant: NC1CCCCC1
Solvent: CCCCO
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)c1cnc2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1NC1CCCCC1
Temperature: 110 °C
Yield: 72.7 %

Procedure:
To a solution of ethyl 4-chloro-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (2.28 g, 5.42 mmol) in n-BuOH (21 mL) was added cyclohexanamine (1.24 mL, 10.8 mmol). The resulting solution was heated at about 110° C. for about 18 h. The reaction mixture was cooled to ambient temperature and diluted with water and DCM (50 mL each). The layers were separated and the organic layer was dried over anhydrous Na2SO4, filtered, and concd to dryness under reduced pressure. The residue was triturated with heptane and the precipitates were filtered to give ethyl 4-(cyclohexylamino)-1-tosyl-1H-pyrrolo[2,3-b]pyridine-5-carboxylate (1.74 g, 73%) as a light yellow solid: LC/MS (Table 1, Method b) Rt=3.18 min; MS m/z: 442 (M+H)+.
Reaction SMILES: [CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[NH:9][C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2].Br.Br[CH2:31][C:32]([C:34]1[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=1)=[O:33].CN(C)C=O.[H-].[Na+]>O.C(OCC)(=O)C>[CH2:1]([C:3]1[S:28][C:6]2[N:7]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([C:20]4[C:21]([C:26]#[N:27])=[CH:22][CH:23]=[CH:24][CH:25]=4)=[CH:16][CH:15]=3)[C:8](=[O:12])[N:9]([CH2:31][C:32](=[O:33])[C:34]3[CH:39]=[CH:38][N:37]=[CH:36][CH:35]=3)[C:10](=[O:11])[C:5]=2[CH:4]=1)[CH3:2]
Reactant: O=C(CBr)c1ccncc1
Reactant: CCc1cc2c(=O)[nH]c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCc1cc2c(=O)n(CC(=O)c3ccncc3)c(=O)n(Cc3ccc(-c4ccccc4C#N)cc3)c2s1
Temperature: 25 °C
Reaction time: 20 h
Yield: 15.3 %

Procedure:
To a mixture of 4′-[(6-ethyl-2,4-dioxo-3,4-dihydrothieno[2,3-d]pyrimidin-1(2H)-yl)methyl]biphenyl-2-carbonitrile (1.0 g), 2-bromo-1-pyridin-4-yl-ethanone hydrogen bromide (1.09 g) and N,N-dimethylformamide (8 mL) was added 60% sodium hydride (0.31 g), and the mixture was stirred at room temperature for 20 hr. After allowing to cool to room temperature, ethyl acetate and water were added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was successively washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography to give the title compound as a pale-yellow amorphous solid (0.20 g, 15%).
Reaction SMILES: [C:1]([C:3]1([NH:10][C:11](=[O:30])[CH:12]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C:14]([N:16]([CH2:21][CH3:22])[CH2:17][CH2:18][O:19]C)=[O:15])[CH2:5][CH:4]1[CH2:6]N(C)C)#[N:2].N1C=CC=CC=1.[O:37](S(C(F)(F)F)(=O)=O)S(C(F)(F)F)(=O)=O>ClCCl>[C:1]([C:3]1([NH:10][C:11](=[O:30])[CH:12]([CH2:23][CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH2:13][C:14]([N:16]2[CH2:21][CH2:22][O:19][CH2:18][CH2:17]2)=[O:15])[CH2:5][CH:4]1[CH2:6][OH:37])#[N:2]
Reactant: CCN(CCOC)C(=O)CC(CC1CCCCC1)C(=O)NC1(C#N)CC1CN(C)C
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Solvent: c1ccncc1
Product: N#CC1(NC(=O)C(CC(=O)N2CCOCC2)CC2CCCCC2)CC1CO
Temperature: 25 °C
Reaction time: 1 h
Yield: 34.3 %

Procedure:
To a stirred solution of the intermediate alcohol from Example 22 (1.1 g, 2.7 mmol) and pyridine (0.44 mL, 5.2 mmol) in dichloromethane (15 mL) at 0° C. was added Tf2O (0.67 mL, 4 mmol) slowly. The mixture was allowed to warm to room temperature and stirred for 1 h. The reaction mixture was washed with brine, dried (sodium sulfate) and purified by chromatography on silica gel (dichloromethane/MeOH=20/1) to give the title compound (0.35 g, 34.6%).
Reaction SMILES: C(O)(C(F)(F)F)=O.[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([O:31]C(C)(C)C)=[O:30])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]([N:38]4[CH2:43][CH2:42][N:41]([C:44]5[CH:49]=[CH:48][C:47]([F:50])=[CH:46][CH:45]=5)[CH2:40][C@H:39]4[CH3:51])=[O:37])[CH:21]=3)[C:16]2=[O:52])=[CH:11][CH:10]=1>ClCCl>[F:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[C:24]([CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[C:20]([C:36]([N:38]4[CH2:43][CH2:42][N:41]([C:44]5[CH:45]=[CH:46][C:47]([F:50])=[CH:48][CH:49]=5)[CH2:40][C@H:39]4[CH3:51])=[O:37])[CH:21]=3)[C:16]2=[O:52])=[CH:11][CH:10]=1
Reactant: C[C@@H]1CN(c2ccc(F)cc2)CCN1C(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)OC(C)(C)C)cc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H]1CN(c2ccc(F)cc2)CCN1C(=O)c1ccc2c(=O)n(-c3ccc(F)cc3)c(CCCCC(=O)O)cc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.2 %

Procedure:
TFA (1 mL, 12.98 mmol) was added to a stirred, room temperature mixture of (R)-tert-butyl 5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoate (58 mg, 0.094 mmol) in dichloromethane (4 mL) and the mixture was stirred at room temperature for 2 hours. The mixture was concentrated to dryness, the residue was purified via PTLC (Emerck 1 mm), eluted with CH2Cl2/MeOH=10:1 to give (R)-5-(2-(4-fluorophenyl)-6-(4-(4-fluorophenyl)-2-methylpiperazine-1-carbonyl)-1-oxo-1,2-dihydroisoquinolin-3-yl)pentanoic acid (46 mg, 0.082 mmol) as a light yellow solid. LCMS [M+H]+=560. 1H NMR (500 MHz, CDCl3) δ ppm: 8.43 (d, J=8.28 Hz, 1H), 7.56 (d, J=1.32 Hz, 1H), 7.44 (dd, J=8.28, 1.32 Hz, 1H), 7.26 (m, 2H), 7.25 (m, 2H), 6.96-7.07 (m, 2H), 6.86-6.93 (m, 2H), 6.48 (s, 1H), 3.52 (m, 3H), 2.96 (m, 1H), 2.79 (m, 1H), 2.31 (m, 4H), 1.55-1.68 (m, 6H), 1.50 (d, 3H).
Reaction SMILES: CC[C@@H]([C@H]1NC(=O)[C@@H](NC([C@H](N(C([C@H]2N(C(C(O)C)=O)CCC2)=O)C)CC(C)C)=O)[C@@H](C)OC(=O)[C@H](CC2C=CC(OC)=CC=2)N(C)C(=O)[C@H]2N(CCC2)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H:11]([CH:76]([CH3:78])[CH3:77])[O:10]C(=O)C[C@@H]1O)C.[NH:80]1[CH2:87][CH2:86][CH2:85][C@H:81]1[C:82]([OH:84])=[O:83].C(OC(=O)C(C)C)(=O)C(C)C.C(N1CCC[C@H]1C(O)=O)(=O)CC>>[C:11]([N:80]1[CH2:87][CH2:86][CH2:85][C@H:81]1[C:82]([OH:84])=[O:83])(=[O:10])[CH:76]([CH3:78])[CH3:77]
Reactant: O=C(O)[C@@H]1CCCN1
Reactant: CC[C@H](C)[C@H]1NC(=O)[C@@H](NC(=O)[C@@H](CC(C)C)N(C)C(=O)[C@@H]2CCCN2C(=O)C(C)O)[C@@H](C)OC(=O)[C@H](Cc2ccc(OC)cc2)N(C)C(=O)[C@@H]2CCCN2C(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)C(=O)[C@H](C(C)C)OC(=O)C[C@@H]1O
Agent: CC(C)C(=O)OC(=O)C(C)C
Agent: CCC(=O)N1CCC[C@H]1C(=O)O
Product: CC(C)C(=O)N1CCC[C@H]1C(=O)O
Yield: 96 %

Procedure:
[Isobutyryl9 ]Didemnin B (33) and [Isobutyryl9, D-Pro8 ] Didemnin B (34). L-Pro (1.15 g, 0.01 mol) was treated with isobutyric anhydride in a procedure like the N-propionylproline synthesis to give N-isobutyrylproline (1.8 g, 96%): fine crystals, mp 80-82° C.; [α]D25 -8.7° (c 1.56, CHCl3). 1H NMR Anal. (C9H15NO3) C, H, N.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([C:21]#[N:22])[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)=[CH:11][CH:10]=1.[OH-].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2([CH2:21][NH2:22])[CH2:16][CH2:17][O:18][CH2:19][CH2:20]2)=[CH:11][CH:10]=1
Reactant: COc1ccc(C2(C#N)CCOCC2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(C2(CN)CCOCC2)cc1
Temperature: 7.5 °C

Procedure:
To a stirred suspension of LiAlH4 (79 g, 2.08 mol, 5 eq) in THF (900 ml) at 0 to 5° C. under an atmosphere of nitrogen was added 4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-carbonitrile (90 g, 0.414 mol) in THF (900 ml) over a 25 minutes maintaining the temperature at 5 to 10° C. The reaction mixture was allowed to warm to ambient temperature and stirred until complete. Sodium hydroxide (2N, 850 ml) was added dropwise, the resulting solids filtered and washed with THF (2×800 ml), the organics concentrated in vacuo at 40° C. The residue was dissolved in EtOAc (300 ml) and dried over MgSO4, filtered and concentrated in vacuo at 40° C. to provide {[4-(4-methoxyphenyl)-tetrahydro-2H-pyran-4-yl]methyl}amine as a light yellow oil (92 g, quantitative).
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)[NH2:2].[O:9]1[CH2:14][CH2:13][N:12]([C:15]2[C:20]([N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[CH:19][C:18](=O)[C:17](=[O:28])[CH:16]=2)[CH2:11][CH2:10]1>C(O)(=O)C>[O:24]1[CH2:25][CH2:26][N:21]([C:20]2[C:15]([N:12]3[CH2:11][CH2:10][O:9][CH2:14][CH2:13]3)=[CH:16][C:17]([OH:28])=[C:18]([N:2]=[N:1][C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=3)[CH:19]=2)[CH2:22][CH2:23]1
Reactant: O=C1C=C(N2CCOCC2)C(N2CCOCC2)=CC1=O
Reactant: NNc1ccccn1
Solvent: CC(=O)O
Product: Oc1cc(N2CCOCC2)c(N2CCOCC2)cc1N=Nc1ccccn1
Reaction time: 8 h

Procedure:
To 60 ml acetic acid were added in order 1.48 g (14 mmol) 2-hydrazinopyridine and 3.8 g (14 mmol) freshly prepared 4,5-di-morpholino-1,2-benzoquinone [Brackman and Havinga, Rec. trav. chim Pays-bas 74, 937 (1955)] at room temperature. The mixture was stirred overnight and the solvent taken off on a rotary evaporator. After dilution with water, the solid residue was filtered off, washed with water and air dried. The product was extracted twice with hot acetonitrile leaving 1.97 g product. The extract yielded another 1.02 g on cooling. Yield 3.0 g (59%).
Reaction SMILES: [C:1]1([C:7]2[C:8]([O:10][C:11](=[O:13])[CH:12]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:14]=[CH:15][CH:16]=[CH2:17]>C1(C)C=CC=CC=1>[C:1]1([C:7]23[C:8](=[O:9])[O:10][C:11](=[O:13])[CH:12]2[CH2:14][CH:15]=[CH:16][CH2:17]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C=CC=C
Reactant: O=C1C=C(c2ccccc2)C(=O)O1
Solvent: Cc1ccccc1
Product: O=C1OC(=O)C2(c3ccccc3)CC=CCC12
Temperature: 100 °C

Procedure:
A mixture of α-phenyl-maleic anhydride (20 g, 0.115 moles), butadiene (40 g, 0.74 moles) and 200 ml of toluene was heated at 100° C. in a sealed bomb for 15 hrs. The toluene solution was decanted from an insoluble, polymeric material and evaporated in vacuo to yield crude 1-phenyl-4-cyclohexene-1,2-dicarboxylic acid anhydride, bp 155° (0.3 mm).