Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[CH:12][CH:13]=[C:8]2[C:7]([C:14]2[N:15]=[N:16][C:17]([NH2:21])=[C:18]([NH2:20])[N:19]=2)=[N:6]1.Cl[C:27]([O:29][CH3:30])=[O:28].C(N(CC)CC)C>ClCCl>[NH2:20][C:18]1[N:19]=[C:14]([C:7]2[C:8]3[C:9](=[N:10][CH:11]=[CH:12][CH:13]=3)[N:5]([CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[F:1])[N:6]=2)[N:15]=[N:16][C:17]=1[NH:21][C:27](=[O:28])[O:29][CH3:30]
Reactant: COC(=O)Cl
Reactant: Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)Nc1nnc(-c2nn(Cc3ccccc3F)c3ncccc23)nc1N
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
200 mg (purity 67%, 0.398 mmol) of 3-[1-(2-fluorobenzyl)-1H-pyrazolo[3,4-b]pyridin-3-yl]-1,2,4-triazine-5,6-diamine were admixed with 4 ml of dichloromethane and cooled to 0° C. 151 mg (1.594 mmol) of methyl chloroformate dissolved in 1 ml of dichloromethane and 161 mg (1.594 mmol) of triethylamine were added and the mixture was stirred at RT for 15 min. The precipitate was filtered off with suction and dried under high vacuum. This gave 97 mg (61% of theory) of the target compound.
Reaction SMILES: [OH-].[Li+].[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH2:24][CH2:25][CH2:26][C:27]([O:29]C)=[O:28])[CH:13]=[C:14]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]3[CH3:23])[CH:8]=[CH:9][CH:10]=1)#[N:4].O>C1COCC1>[C:3]([C:5]1[CH:6]=[C:7]([C:11]2[N:12]([CH2:24][CH2:25][CH2:26][C:27]([OH:29])=[O:28])[CH:13]=[C:14]3[C:19]=2[C:18](=[O:20])[N:17]([CH3:21])[C:16](=[O:22])[N:15]3[CH3:23])[CH:8]=[CH:9][CH:10]=1)#[N:4]
Reactant: COC(=O)CCCn1cc2c(c1-c1cccc(C#N)c1)c(=O)n(C)c(=O)n2C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cn1c(=O)c2c(-c3cccc(C#N)c3)n(CCCC(=O)O)cc2n(C)c1=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Lithium hydroxide (965 mg, 23.0 mmol) was added to a suspension of methyl 4-(5-(3-cyanophenyl)-1,3-dimethyl-2,4-dioxo-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)butanoate (Step 5) (1.75 g, 4.6 mmol) in THF (9 mL)/water (9 mL). The mixture was stirred at room temperature for 4 hours. The organic solvent was largely removed under vacuum, the residue was acidified to pH 1, using 2M HCl. The resulting slurry was diluted with water (100 mL). The mixture was reduced under vacuum to give a white solid, which was further dried under vacuum at 50° C. overnight.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][C@@H:11]2[CH2:13][O:14][C:15](=[O:16])[C@@H:10]2[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:17]([NH2:20])([CH3:19])[CH3:18]>[Cl-].[Cl-].[Zn+2]>[CH:17]([NH:20][C:15]([C@H:10]1[C@@H:11]([CH2:13][OH:14])[CH2:12][N:8]([CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH2:9]1)=[O:16])([CH3:19])[CH3:18]
Reactant: CC(C)N
Reactant: O=C1OC[C@H]2CN(Cc3ccccc3)C[C@@H]12
Agent: [Cl-]
Agent: [Zn+2]
Product: CC(C)NC(=O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1CO

Procedure:
A suspension of (3aR*,6aS*)-5-benzyl-hexahydro-furo[3,4-c]pyrrol-1-one (1.50 g, 6.90 mmol) and ZnCl2 (0.94 g, 6.90 mmol) in iPrNH2 (20 mL) is refluxed overnight under a nitrogen atmosphere. The crude material is filtered over a pad of Celite and concentrated. The crude material is purified by flash chromatography on silica gel (eluent: CH2Cl2/MeOH/NH4OH 70:25:5) to give the title product. TLC, Rf (CH2Cl2/MeOH 95:5)=0.38. MS (LC-MS): 277.2 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:7]1=[O:21])=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[CH3:27][O:21][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][N:8]=1
Reactant: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CNC1=O
Reactant: C[O+](C)C
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CN=C1OC
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of 515 mg of the product of Example 4 and 236 mg of trimethyloxonium tetrafluoroborate in 3 ml of chloroform was heated under reflux for four hours. The mixture was then cooled to ambient temperature, and 2 ml of 50% aqueous potassium carbonate was added. Then 10 ml of water and 10 ml of chloroform were added, and the organic phase, containing solids, was dried with magnesium sulfate. The solids were removed by filtration, and the supernatant was concentrated under vacuum. The residue was purified by spinning plate thin layer chromatography on a 2 mm silica gel plate, with 1:1 ethyl acetate:hexane, to obtain 286 mg of (3RS,5S)-2-methoxy-3-ethoxycarbonyl-5-[2-(4-bromophenyl)ethyl]-3,4,5,6-tetrahydropyridine, as a 1:1 mixture of the 3-position diastereomers.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[Na+].Br[CH2:7][C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:16](=[O:25])[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]=2[CH3:26])[N:9]=1>CN(C)C=O>[C:1]([S:3][CH2:7][C:8]1[N:17]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[C:16](=[O:25])[C:15]2[C:10](=[CH:11][C:12]([CH3:32])=[C:13]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:14]=2[CH3:26])[N:9]=1)(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: CCOC(=O)c1c(C)cc2nc(CBr)n(-c3ccccc3Cl)c(=O)c2c1C
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(C)cc2nc(CSC(C)=O)n(-c3ccccc3Cl)c(=O)c2c1C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 62.6 %

Procedure:
Sodium thioacetate (235 mg) was added to an ice-cooled, stirred solution of 1 g of 2-bromomethyl-3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-4(3H)-quinazolinone in 4 ml of dimethylformamide. After stirring for an additional 30 minutes, the mixture was poured into ice-water. The resulting precipitate was filtered off, washed with water, and dried in vacuo. The crude product was chromatographed on a column of silica gel using 5% ethyl acetate in benzene as an eluent to give 619 mg (yield, 62.5%) of 2-(acetylmercaptomethyl)-3-(2-chlorophenyl)-6-ethoxycarbonyl-5,7-dimethyl-4(3H)-quinazolinone melting at 103°-105° C. (recrystallized from methanol).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[C:11]3[CH:17]=[CH:16][NH:15][C:12]3=[N:13][CH:14]=2)O1.Cl[C:20]1[N:25]=[C:24]([NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=[N:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>O1CCOCC1.C(Cl)(Cl)Cl>[NH:15]1[C:12]2=[N:13][CH:14]=[C:9]([C:20]3[N:25]=[C:24]([NH:26][CH2:27][CH2:28][N:29]([CH3:31])[CH3:30])[CH:23]=[N:22][CH:21]=3)[CH:10]=[C:11]2[CH:17]=[CH:16]1
Reactant: CC1(C)OB(c2cnc3[nH]ccc3c2)OC1(C)C
Reactant: CN(C)CCNc1cncc(Cl)n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Solvent: ClC(Cl)Cl
Product: CN(C)CCNc1cncc(-c2cnc3[nH]ccc3c2)n1
Temperature: 100 °C

Procedure:
The starting material 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine (124) (70 mg, 0.286 mmol, 1 eq) and N1-(6-chloropyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine (66) (457 mg, 0.286 mmol, 1 eq) in 1,4-dioxane (5 mL) was degassed and purged under argon atmosphere for 10 min. To this reaction mixture was charged Cs2CO3 (150 mg, 0.614 mmol, 1.5 eq) followed by addition of Pd(dpp)Cl2 (6.2 mg, 0.0086 mmol, 0.03 eq) and degassing and purging under argon for additional 10 min. The reaction mixture was heated at 100° C. for 12 h in a sealed tube. After completion of the reaction, the reaction mixture was diluted with CHCl3 and filtered through oCelite. The solvents were distilled off and the crude material was submitted for flash column purification in neutral alumina using 1% MeOH/CHCl3 to obtain pale yellow solid compound N1-(6-(1H-pyrrolo[2,3-b]pyridin-5-yl)pyrazin-2-yl)-N2,N2-dimethylethane-1,2-diamine 127 in 10 mg quantity. The compound 127 was confirmed by 1HNMR and LCMS. 1H NMR (400 MHz, CDCl3) δ: 11.78 (s, 1H), 8.90 (d, J=1.82, 1H), 8.57 (s, 1H), 8.30 (s, 1H), 7.89 (s, 1H), 7.51 (m, J=151.58, 1H), 7.01 (m, J=201.21, 1H), 6.53 (m, J=191.45, 1H), 3.48 (m, J=5.85, 2H), 2.22 (s, 6-H); MS m/z 283 (M+H)+.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6](=[O:32])[CH:7]([NH2:31])[CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1)C>CO>[NH2:31][CH:7]([CH2:8][C:9]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:20][CH:19]=3)[CH:16]=2)[NH:11][CH:10]=1)[C:6]([OH:32])=[O:5]
Reactant: CCOC(=O)C(N)Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: NC(Cc1c[nH]c2ccc(-c3ccc(Oc4ccccc4)cc3)cc12)C(=O)O
Temperature: 30 °C
Reaction time: 24 h

Procedure:
2-Amino-3-[5-(4-phenoxyphenyl)-1H-indol-3-yl]propionic acid (9) was prepared as follows: NaOH (2N aqueous, 1 mL) was added to a solution of compound 7 prepared in Example 1 (0.2 g) in MeOH (4 mL) at 0° C. The reaction mixture was shaken at 30° C. for 24 hours. The solvents were evaporated under vacuum. The residues were dissolved in CHCl3 (40 mL) and neutralized to pH ˜2 with 1N HCl aqueous. The organic layer was separated, washed with brine and concentrated to get a sticky oil, which was washed with Et2O, and dried under vacuum to afford compound 9 as a HCl-salt (white solid, 7 0 mg, 35%): 1H-NMR (400 MHz, CD3OD) δ: 7.88 (s, 1H), 7.58-7.72 (m, 2H), 7.25-7.41 (m, 4H), 6.88-7.05 (m, 5H), 3.47-3.72 (m, 1H), 3.25-3.28 (m, 1H), 2.81-2.88 (m, 1H); LC/MS: m/z=358 [M+H]+ (Calc: 372.4).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]=1.[N+:15]([O-])([O-:17])=[O:16].[Na+]>OS(O)(=O)=O>[N+:15]([C:6]1[CH:7]=[CH:8][CH:9]=[C:10]2[C:5]=1[CH:4]=[C:3]([C:11]([O:13][CH3:14])=[O:12])[N:2]=[CH:1]2)([O-:17])=[O:16]
Reactant: COC(=O)c1cc2ccccc2cn1
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: COC(=O)c1cc2c([N+](=O)[O-])cccc2cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.2 %

Procedure:
Methyl isoquinoline-3-carboxylate (9.58 g, 51.2 mmol) in concentrated H2SO4 (100 mL) at 0° C. was treated with sodium nitrate (4.79 g, 56.4 mmol) in small portions such that the temperature was maintained below 5° C. Ten minutes after addition was complete, the reaction mixture was allowed to warm to room temperature and stirred for 2 hours. The mixture was poured over ice and adjusted to pH between 7 and 8 and filtered to afford the title compound as a bright yellow solid (11.44 g, 96%). MS (ESI+) m/z 233 (M+H)+; 1H NMR (DMSO, 300 MHz) δ 3.97 (s, 3H), 8.06 (t, J 8.2, 1H), 8.72 (dt, J 1.0, 8.2, 1H), 8.78 (dd, J 1.0, 7.8, 1H), 9.11 (s, 1H), 9.65 (s, 1H).
Reaction SMILES: [C:1]([O:9][CH2:10][CH3:11])(=[O:8])[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].C(=O)([O-])[O-].[K+].[K+].[CH2:18](Br)[CH:19]=[CH2:20]>CC#N>[CH2:20]([CH:2]([C:3]([O:5][CH2:6][CH3:7])=[O:4])[C:1]([O:9][CH2:10][CH3:11])=[O:8])[CH:19]=[CH2:18]
Reactant: C=CCBr
Reactant: CCOC(=O)CC(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: C=CCC(C(=O)OCC)C(=O)OCC
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 96 %

Procedure:
A 500 mL three necked round bottom flask was charged with diethyl malonate (20 g), dry potassium carbonate (43 g) and dry CH3CN (200 mL) under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 10 minutes and allylbromide (23 g) was slowly added to the reaction mixture at room temperature. The reaction mixture was heated to 80° C. for 24 hours. The reaction mixture was cooled to room temperature and filtered through celite bed. The celite bed was washed with acetonitrile (100 mL) and the combined filtrate was concentrated to give diethyl 2-allylmalonate (24 g) as colorless liquid. 1H NMR (CDCl3): δ 1.26 (t, 6H), 2.61-2.67 (m, 2H), 3.42 (t, 1H), 4.20 (q, 4H), 5.03-5.16 (m, 2H), 5.70-5.85 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[OH-].[Na+].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>CN(C=O)C.CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:31]=[C:30]([O:32][CH3:33])[CH:29]=[CH:28][C:4]=1[CH2:5][N:6]1[C:10]2[N:11]=[CH:12][N:13]=[C:14]([NH:15][CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][O:42][CH2:41][CH2:40]3)[C:9]=2[C:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[C:7]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: ClCCN1CCOCC1
Reactant: COc1ccc(Cn2c(-c3ccccc3)c(-c3ccccc3)c3c(N)ncnc32)c(OC)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(Cn2c(-c3ccccc3)c(-c3ccccc3)c3c(NCCN4CCOCC4)ncnc32)c(OC)c1
Temperature: 150 °C
Reaction time: 0.08 h

Procedure:
To a solution of 7-(2,4-dimethoxybenzyl)-5,6-diphenyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamine (43.7 mg, 0.1 mmol) and sodium hydroxide powder (20 mg, 0.50 mmol) in DMF (1 mL) was added N-(2-chloroethyl)morpholine (30 mg, 0.2 mmol). The mixture was stirred for 5 minutes at 150° C. under microwave irradiation (using powerMAX™). The reaction mixture was then cooled and diluted with EtOAc (25 mL). The mixture was extracted twice with water (10 mL) and then brine. The organic layer was dried over MgSO4, filtered and the filtrate was concentrated. The residue was purified by column chromatography on silica gel to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](OC2C=CC([N+]([O-])=O)=CC=2)=[O:30])[CH:5]=[CH:6][C:7]=1[F:8].Cl.Cl.[NH2:43][CH2:44][CH2:45][CH2:46][N:47]1[CH2:52][CH2:51][C:50]([C:55]2[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=2[C:61]#[N:62])([C:53]#[N:54])[CH2:49][CH2:48]1.C(N(C(C)C)CC)(C)C>C(Cl)(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[N:12]([CH2:19][C:20]3[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=3)[C:11](=[O:28])[N:10]2[C:29](=[O:30])[NH:43][CH2:44][CH2:45][CH2:46][N:47]2[CH2:48][CH2:49][C:50]([C:53]#[N:54])([C:55]3[CH:60]=[CH:59][CH:58]=[CH:57][C:56]=3[C:61]#[N:62])[CH2:51][CH2:52]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: N#Cc1ccccc1C1(C#N)CCN(CCCN)CC1
Reactant: COc1ccc(CN2C(=O)N(C(=O)Oc3ccc([N+](=O)[O-])cc3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClC(Cl)Cl
Product: COc1ccc(CN2C(=O)N(C(=O)NCCCN3CCC(C#N)(c4ccccc4C#N)CC3)C(c3ccc(F)c(F)c3)c3ccccc32)cc1
Reaction time: 2 h

Procedure:
To a solution of 11 (0.060 g, 0.109 mmol) in 10 ml of CHCl3 was added N-(3-amino)propyl-4-(2-cyanophenyl)-4-cyanopiperidine dihydrochloride (Example 1) and diisopropyl ethylamine (0.057 mL, 0.329 mmol). The resulting solution was stirred for 2 hours and the crude material purified by PCTLC (5% MeOH in CHCl3/2%NH4OH) affording the title compound.
Reaction SMILES: CN1CCOCC1.[C:8]([O:12][C:13]([NH:15][C@H:16]([C:22]([O:24][CH3:25])=[O:23])[CH2:17][CH2:18][C:19]([OH:21])=O)=[O:14])([CH3:11])([CH3:10])[CH3:9].[C:26]([O:30][C:31]([NH:33][CH2:34][CH2:35][NH:36][CH2:37][CH2:38][NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:32])([CH3:29])([CH3:28])[CH3:27]>C(Cl)Cl>[C:42]([O:41][C:40]([NH:39][CH2:38][CH2:37][N:36]([CH2:35][CH2:34][NH:33][C:31]([O:30][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:32])[C:19]([CH2:18][CH2:17][C@H:16]([NH:15][C:13]([O:12][C:8]([CH3:9])([CH3:10])[CH3:11])=[O:14])[C:22]([O:24][CH3:25])=[O:23])=[O:21])=[O:46])([CH3:45])([CH3:44])[CH3:43]
Reactant: CC(C)(C)OC(=O)NCCNCCNC(=O)OC(C)(C)C
Reactant: COC(=O)[C@H](CCC(=O)O)NC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COC(=O)[C@H](CCC(=O)N(CCNC(=O)OC(C)(C)C)CCNC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C
Reaction time: 0.17 h
Yield: 72 %

Procedure:
To a solution of CDMT (2.22 g, 12.62 mmol) in DCM (40 mL) and cooled to 0° C. was added N-methylmorpholine (1.38 mL, 12.63 mmol). The mixture was stirred for 10 min before adding (4S)-4-{[(tert-butoxy)carbonyl]amino}-5-methoxy-5-oxopentanoic acid (3.0 g, 11.48 mmol). The solution was stirred for 60 min at 0° C. The tert-butyl N-{2-[(2-{[(tert-butoxy)carbonyl]amino}ethyl)amino]ethyl}carbamate XIV was then added and the mixture stirred at room temperature overnight. The solution was washed with 1 M aq. K2CO3, 1 M aq. HCl, brine and dried over anhydrous MgSO4. The crude product was crystallized from DCM/hexane to give methyl (2S)-4-[bis(2-{[(tert-butoxy)carbonyl]amino}ethyl)carbamoyl]-2-{[(tert-butoxy)carbonyl]amino}butanoate (XV) (4.91 g, 8.98 mmol, 72% yield). 1H NMR (DMSO-d6) δ ppm 1.35-1.47 (m, 27H), 1.80-1.91 (m, 1H), 2.19-2.32 (m, 1H), 2.33-2.42 (m, 1H), 2.46-2.57 (m, 1H), 3.11-3.38 (m, 6H), 3.40-3.53 (m, 1H), 3.54-3.62 (m, 1H), 3.73 (s, 3H), 4.26-4.38 (m, 1H), 4.99-5.09 (brs, 1H), 5.31-5.46 (m, 2H); ESIMS found for C25H46N4O9 m/z 547 (M+H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[CH:9]2)([O-:5])=[O:4].[O:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH:16]1Cl>CN(C)C=O>[N+:3]([C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[N:11]([CH:16]1[CH2:17][CH2:18][CH2:19][CH2:20][O:15]1)[CH:10]=[CH:9]2)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: ClC1CCCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2c(ccn2C2CCCCO2)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 62.6 %

Procedure:
6.3 g of 55% NaH are added, at 0° C., under an argon atmosphere, to 20 g of 5-nitroindole in solution in 200 ml of dimethylformamide. After stirring for 15 minutes at 0° C., 27.1 g of tetrahydropyranyl chloride are added to the reaction mixture. After stirring for 24 hours at room temperature, the reaction mixture is poured onto 1200 ml of ice-cold water and extracted with ethyl acetate. The combined organic phases are dried over sodium sulphate and evaporated to dryness. The residue is purified by chromatography on a column of silica gel eluted with a 4/1 (v/v) cyclohexane/ethyl acetate mixture, to provide 19 g of 5-nitro-1-tetrahydropyran-2-ylindole. 1H NMR (DMSO): 1.34-2.12 (m, 6H), 3.67-4.48 (m, 2H), 5.70 (dd, J=2.0, 10.2, 1H), 6.75 (d, J=3.4, 1H), 7.72-7.76 (m, 2H), 8.02 (dd, J=2.2, 9.2, 1H), 8.54 (d, J=2.2, 1H).
Reaction SMILES: Cl[CH2:2][C:3]1[O:4][C:5]([C:8]2[CH:9]=[CH:10][C:11]3[O:15][CH2:14][CH2:13][C:12]=3[CH:16]=2)=[N:6][N:7]=1.[F:17][C:18]1[CH:19]=[C:20]([SH:24])[CH:21]=[CH:22][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[O:15]1[C:11]2[CH:10]=[CH:9][C:8]([C:5]3[O:4][C:3]([CH2:2][S:24][C:20]4[CH:21]=[CH:22][CH:23]=[C:18]([F:17])[CH:19]=4)=[N:7][N:6]=3)=[CH:16][C:12]=2[CH2:13][CH2:14]1
Reactant: ClCc1nnc(-c2ccc3c(c2)CCO3)o1
Reactant: Fc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Fc1cccc(SCc2nnc(-c3ccc4c(c3)CCO4)o2)c1
Yield: 14.3 %

Procedure:
A solution of 2-(chloromethyl)-5-(2,3-dihydro-1-benzofuran-5-yl)-1,3,4-oxadiazole (0.16 g, 0.68 mmol), 3-fluorothiophenol (57 μL, 0.68 mmol) and potassium carbonate (0.10 g, 0.75 mmol) in N,N-dimethylformamide (5 mL) was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) and recrystallized from hexane/ethyl acetate to give the title compound (32 mg, yield 14%) as colorless crystals.
Reaction SMILES: [I:1][C:2]1[CH:3]=[N:4][NH:5][CH:6]=1.Br[CH2:8][C:9]([O:11][CH2:12][CH3:13])=[O:10].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:12]([O:11][C:9](=[O:10])[CH2:8][N:4]1[CH:3]=[C:2]([I:1])[CH:6]=[N:5]1)[CH3:13]
Reactant: Ic1cn[nH]c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cn1cc(I)cn1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
4-Iodo-1H-pyrazole (2 g, 10.3 mmol), ethyl bromoacetate (2.3 mL, 20.6 mmol) and cesium carbonate (5 g, 15.5 mmol) were combined in DMF (20 mL). After stirring at room temperature for 30 minutes the reaction was diluted with EtOAc/hexanes (1:1) and washed with H2O/brine, with back-extraction. The organic layer was dried over MgSO4, concentrated and filtered via silica gel chromatography (0-20% EtOAc in hexanes) to give the title compound.
Reaction SMILES: O=[C:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2.[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH2:31].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[F:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[CH2:29][CH2:30][NH:31][CH:2]1[CH2:11][CH2:10][CH2:9][C:8]2[CH:7]=[C:6]([O:12][C:13]3[CH:21]=[CH:20][C:16]([C:17]([NH2:19])=[O:18])=[CH:15][N:14]=3)[CH:5]=[CH:4][C:3]1=2
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3=O)nc1
Reactant: NCCc1ccccc1F
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCCC3NCCc2ccccc2F)nc1
Yield: 83 %

Procedure:
Using a method similar to Example 1, using 6-(5-oxo-5,6,7,8-tetrahydro-naphthalen-2-yloxy)-nicotinamide (Intermediate 2, 846 mg, 3.00 mmol), 2-(2-fluorophenyl)ethylamine (501 mg, 3.60 mmol), Ti(iPrO)4 (1.70 g, 6.00 mmol), TiCl4 (1.0M/DCM, 6.00 ml, 6.00 mmol), and NaBH3CN (377 mg, 6.00 mmol) gives the title compound (1.01 g) as a white solid. Mass spectrum (ion spray): m/z=406 (M+1); 1HNMR (CDCl3): 8.59 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.26-7.16 (m, 2H), 7.09-6.99 (m, 2H), 6.93 (d, 1H), 6.89 (d, 1H), 6.84 (s, 1H), 5.89 (br. s, 2H), 3.81 (t, 1H), 3.07-2.85 (m, 4H), 2.83-2.67 (m, 2H), 1.98-1.80 (m, 3H), 1.73 (m, 1H).
Reaction SMILES: C[O:2][C:3](=[O:17])/[CH:4]=[CH:5]/[CH:6]=[C:7](/[C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)\[CH3:8].[OH-].[Na+]>CO>[CH3:16][O:15][C:12]1[CH:11]=[CH:10][C:9](/[C:7](/[CH3:8])=[CH:6]/[CH:5]=[CH:4]/[C:3]([OH:17])=[O:2])=[CH:14][CH:13]=1
Reactant: COC(=O)/C=C/C=C(\C)c1ccc(OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(/C(C)=C/C=C/C(=O)O)cc1
Reaction time: 2.5 h
Yield: 95.5 %

Procedure:
As described in Example 99, (E,E)-5-(4-methoxyphenyl)-2,4-hexadienoic acid methyl ester (6.8 g) was saponified in a refluxing mixture of methanol (30 mL) and 2N NaOH (30 mL). After 2.5 hours the reaction was worked up in the normal manner to give 6.1 g of (E,E)-5-(4-methoxyphenyl)-2,4-hexadienoic acid. Crystallization of a portion from 2-propanol furnished the analytical sample, mp 174°-177° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13](=[O:14])[C:12]([C:15](Cl)=[O:16])=[C:11]([C:18]3[CH:23]=[CH:22][C:21]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=4)=[CH:20][CH:19]=3)[N:10]2[CH3:30])=[CH:5][CH:4]=1)#[N:2].C(N(CC)CC)C.[NH:38]1[CH2:43][CH2:42][CH:41]([O:44][CH2:45][C:46]([O:48]CC)=[O:47])[CH2:40][CH2:39]1>O1CCCC1>[C:46]([CH2:45][O:44][CH:41]1[CH2:40][CH2:39][N:38]([C:15]([C:12]2[C:13](=[O:14])[N:9]([C:6]3[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)[N:10]([CH3:30])[C:11]=2[C:18]2[CH:23]=[CH:22][C:21]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)=[O:16])[CH2:43][CH2:42]1)([OH:48])=[O:47]
Reactant: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)Cl)c(=O)n1-c1ccc(C#N)cc1
Reactant: CCOC(=O)COC1CCNCC1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1c(-c2ccc(-c3ccccn3)cc2)c(C(=O)N2CCC(OCC(=O)O)CC2)c(=O)n1-c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 11.9 %

Procedure:
A mixture of 1.62 g of 1-(4-cyanophenyl)-4-chlorocarbonyl-2-methyl-3-[4-(2-pyridyl)phenyl]-2H-pyrazol-5-one, 2.04 g of triethylamine, 20 ml of tetrahydrofuran and 1.35 g of ethyl 4-piperidinoxyacetate was stirred at room temperature for 16 hours. The reaction solution was evaporated under reduced pressure, and the resulting residue was extracted with chloroform. The organic layer was washed with saturated aqueous sodium chloride and dried over sodium sulfate. The insolubles were filtered off, and the solvent was removed by evaporation. The resulting residue was crystallized in chloroform-methanol-ethyl acetate to give 250 mg of the title compound as pale yellow crystals. The mother liquor was evaporated under reduced pressure, and the resulting residue was purified by silica gel chromatography (eluent;ethyl acetate:methanol 9:1). The resulting crude crystals were recrystallized in chloroform-methanol-ethyl acetate to give 601 mg of the title compound as pale pink crystals.