Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: I.[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1.[C:24](O)(=[O:33])[CH2:25][CH2:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.Cl.CN(C)CCCN=C=NCC.ON1C2N=CC=CC=2N=N1.C(N(CC)CC)C>CN(C)C1C=CN=CC=1.CN(C)C=O>[Cl:2][C:3]1[C:4]2[C:5]3[C:6](=[C:20]([CH3:23])[O:21][N:22]=3)[C:7](=[O:19])[N:8]([CH:13]3[CH2:18][CH2:17][CH2:16][N:15]([C:24](=[O:33])[CH2:25][CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:14]3)[C:9]=2[CH:10]=[CH:11][CH:12]=1
Reactant: O=C(O)CCc1ccccc1
Reactant: Cc1onc2c1c(=O)n(C1CCCNC1)c1cccc(Cl)c21
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1onc2c1c(=O)n(C1CCCN(C(=O)CCc3ccccc3)C1)c1cccc(Cl)c21
Yield: 79.4 %

Procedure:
Add 9-chloro-3-methyl-5-piperidin-3-yl-5H-isoxazolo[4,3-c]quinolin-4-one hydroiodide (50 mg, 0.11 mmol), hydrocinnamic acid (20 mg, 0.13 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (26 mg, 0.13 mmol), 1-hydroxy-7-azabenzotriazole (18 mg, 0.13 mmol), 4-dimethylamino-pyridine (1 mg, 0.01 mmol), and dimethylformamide (3 mL) to a dry roundbottom flask. Stir the reaction under nitrogen, and add triethylamine (30 μL, 0.22 mmol) dropwise. Stir the solution under nitrogen at room temperature overnight. Concentrate the solution and dissolve in 20% isopropanol/chloroform; wash with 1.0N HCl, saturated aqueous sodium bicarbonate solution, brine; dry over magnesium sulfate; and concentrate. Purify by flash chromatography on silica gel (eluting with 0–1% methanol/chloroform) to give 39.3 mg of the title compound as a white solid, 78% yield. 1H NMR: consistent with structure. MS (ion spray) 450 (M+).
Reaction SMILES: C(OCC1C=N[C:9]2[NH:10][C:11](=[O:15])[NH:12][C:13](=[O:14])[C:8]=2[C:7]=1[CH2:18][NH:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:21]=1[O:28][CH3:29])(=O)C>C1(OC2C=CC=CC=2)C=CC=CC=1.C(O)C.C(OCC)C>[CH3:29][O:28][C:21]1[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:20]=1[N:19]1[CH2:9][C:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:7]=2[CH2:18]1
Reactant: COc1ccc(OC)c(NCc2c(COC(C)=O)cnc3[nH]c(=O)[nH]c(=O)c23)c1
Solvent: c1ccc(Oc2ccccc2)cc1
Solvent: CCOCC
Solvent: CCO
Product: COc1ccc(OC)c(N2Cc3[nH]c(=O)[nH]c(=O)c3C2)c1
Yield: 107.5 %

Procedure:
6-Acetoxymethyl-5-(2,5-dimethoxyanilino)methylpyrido[2,3-d]-pyrimidine-2,4(1H,3H)-dione (400 mg, 1 mmol) in diphenyl ether is heated at 210° C. for 2 hours under nitrogen. The resulting clear solution is cooled and then is diluted with a 1:1 mixture of ethanol and diethyl ether (100 mL). The yellow precipitate is collected by filtration and is washed with boiling mixture of chloroform and ethanol (1:1 v/v) to give 6-(2,5-dimethoxyphenyl)-6,7-dihydropyrrolo[3,4-d]pyrimidine-2,4(1H,3H)-dione (311 mg, 91%), mp 308°-310° C. 1H NMR (Me2SO-d6) d 3.70 (3H, s, OMe), 3.74 (3H, s, OMe), 4.67 (2H, brs, CH2), 4.98 (2H, brs, CH2), 6.28 (1H, s, H-6'), 6.31 and 6.87 (each 1H, d, H-3' and H-4' ), 8.53 (1H, s, H-2), 11.43 and 11.61 (each 1H, brs, NH, exchangeable).
Reaction SMILES: [C:1]([O:8]CC)(=[O:7])[C:2]([O:4]CC)=O.[O-]CC.[Na+].[C:15]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)(=[O:17])[CH3:16]>C(O)C>[O:4]=[C:2]([CH2:16][C:15](=[O:17])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:1]([OH:8])=[O:7]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: O=C(O)C(=O)CC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a stirred solution of diethyl oxalate (21.9 g, 150 mmol) and sodium ethoxide (168 mL, 21% wt. solution, 450 mmol) was added dropwise a solution of acetophenone (18 g, 150 mmol) in ethanol (120 mL). The reaction mixture was allowed to stir at ambient temperature for 15 h. The reaction mixture was concentrated to ca. 70 mL and partitioned between diethyl ether (50 mL) and water (200 mL). The phases were separated, and the aqueous layer adjusted to pH=1 with conc. HCl before being extracted with diethyl ether (3×100 mL). The combined ether extracts were dried over MgSO4 and evaporated to yield 2,4-dioxo-4-phenylbutanoic acid. 1H NMR (DMSO-d6, 300 MHz) δ 8.05 (d, J=7.2 Hz, 1.8H enol form), 7.96 (d, J=6.9 Hz, 0.2H keto form), 7.69 (t, J=7.5 Hz, 1H), 7.56 (t, J=8.1 Hz, 2H), 7.08 (s, 0.9H enol form), 4.56 (s, 0.1H keto form). 13C NMR (DMSO-d6, 75 MHz) δ 190.7, 170.7, 163.6, 135.1, 134.6, 129.7, 128.4, 98.5.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)=[N:2]1.[NH2:21][CH2:22][CH2:23][CH2:24][N:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.O.ON1C2C=CC=CC=2N=N1.[ClH:42].C(N=C=NCCCN(C)C)C.CN1CCOCC1>>[ClH:42].[ClH:42].[O:28]1[CH2:29][CH2:30][N:25]([CH2:24][CH2:23][CH2:22][NH:21][C:16](=[O:18])[C:15]2[CH:14]=[CH:13][C:12](/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)=[CH:20][CH:19]=2)[CH2:26][CH2:27]1
Reactant: NCCCN1CCOCC1
Reactant: O=C(O)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: O
Product: O=C(NCCCN1CCOCC1)c1ccc(/C=C/c2n[nH]c3ccccc23)cc1

Procedure:
The crude product obtained using (E)-4-[2-(1H-indazol-3-yl)vinyl]benzoic acid (500 mg, 1.89 mmol) obtained in Step 6 of Example 1, N-(3-aminopropyl)morpholine (0.365 mL, 2.50 mmol), 1-hydroxybenzotriazole monohydrate (333 mg, 2.46 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (510 mg, 2.67 mmol) and N-methylmorpholine (0.75 mL, 6.82 mmol) in a similar manner to Example 5, was purified by silica gel column chromatography (hexane/ethyl acetate) to obtain a free base of Compound 97. Then the free base of Compound 97 was dissolved in ethyl acetate (5.00 mL), and the solution was added with 4 mol/L hydrogen chloride-ethyl acetate solution (1.00 mL), followed by stirring at room temperature for 30 minutes. The precipitate in the reaction mixture was filtered to obtain Compound 97 (340 mg, 78%).
Reaction SMILES: [CH2:1]([C:3]1[CH:13]=[CH:12][C:6]([NH:7][CH2:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1)[CH3:2].[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]>N1C=CC=CC=1>[Br:14][C:15]1[CH:24]=[CH:23][C:22]([S:25](=[O:27])(=[O:26])[N:7]([C:6]2[CH:12]=[CH:13][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=2)[CH2:8][CH:9]([CH3:10])[CH3:11])=[CH:21][C:16]=1[C:17]([O:19][CH3:20])=[O:18]
Reactant: CCc1ccc(NCC(C)C)cc1
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1Br
Solvent: c1ccncc1
Product: CCc1ccc(N(CC(C)C)S(=O)(=O)c2ccc(Br)c(C(=O)OC)c2)cc1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 58.5 %

Procedure:
To a solution of 4-ethyl-N-isobutylaniline (400 mg, 2.256 mmol) in pyridine (2 mL) was added methyl 2-bromo-5-(chlorosulfonyl)benzoate (707 mg, 2.256 mmol) portionwise, over 30 minutes. The reaction mixture was stirred at 20° C. for 30 minutes then stood at room temperature, in air, for 16 hours. The solvent was evaporated in vacuo to give a crude yellow solid. The crude was then triturated with methanol, filtered and dried in vacuo to give the desired product (600 mg) as a white solid. LCMS (M+1) 454/456, RT 1.41 mins.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([O:20]CC)=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[K+].Cl>O1CCOCC1.O>[CH2:1]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[C:12]([C:18]([OH:20])=[O:19])[NH:13]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: O=C(O)c1cc2c(OCc3ccccc3)cccc2[nH]1
Temperature: 0 °C
Yield: 99.4 %

Procedure:
Ethyl 4-benzyloxyindol-2-carboxylate (10 g) was dissolved in a mixed solvent (200 ml) of dioxane-water (1:1) and potassium hydroxide (3.8 g) was added. The mixture was refluxed under heating for 2 hr. The reaction mixture was poured into ice water, made acidic with hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give 4-benzyloxyindol-2-carboxylic acid as pale-yellow crystals (9.0 g). The crystals were dissolved in dimethylformamide (100 ml) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (WSC, 7.6 g), 1-hydroxybenzotriazole hydrochloride (HOBt, 6.9 g), triethylamine (7.0 ml) and acetohydrazine (2.6 g) were added thereto. The mixture was stirred at room temperature for 6 hr. The reaction mixture was poured into ice water and the precipitated crystals were collected by filtration to give the title compound (10 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[C:7]([C:22]([O-])=[O:23])[C:8]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9]2)=[N:4][CH:3]=1.[CH3:25]C(C[AlH]CC(C)C)C>C(Cl)Cl>[CH3:25][CH:22]([C:7]1[C:8]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[S:18]([CH3:21])(=[O:20])=[O:19])=[N:9][C:10]2[C:5]([CH:6]=1)=[N:4][CH:3]=[C:2]([F:1])[CH:11]=2)[OH:23]
Reactant: CC(C)C[AlH]CC(C)C
Reactant: CS(=O)(=O)c1ccccc1-c1nc2cc(F)cnc2cc1C(=O)[O-]
Solvent: ClCCl
Product: CC(O)c1cc2ncc(F)cc2nc1-c1ccccc1S(C)(=O)=O
Reaction time: 4 h

Procedure:
To a solution of 7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridine-3-carboxylate (1.2 g, 3.33 mmol) in DCM (27 mL) was added DIBAL-H (34 mL, 33.3 mmol) at −78° C. The reaction mixture was stirred for 4 h at same temperature. The reaction mixture was quenched with satd solution of ammonium chloride and extracted with EtOAc. The organic layer was concentrated in vacuo to give methyl (7-fluoro-2-(2-(methylsulfonyl)phenyl)-1,5-naphthyridin-3-yl)methanol: LC-MS (ESI) m/z 333.1 [M+H]+. It was carried on crude for next step.
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:15][CH2:14][N:13]([CH:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)[CH2:12][CH2:11]1)=[O:9])[CH3:2].[C:49]1([CH3:59])[CH:54]=[CH:53][C:52]([S:55]([OH:58])(=[O:57])=[O:56])=[CH:51][CH:50]=1.CO>CC(C)=O>[CH2:1]([C:3]1[CH:4]=[C:5]([CH:44]=[CH:45][C:46]=1[CH2:47][CH3:48])[CH2:6][C@@H:7]([NH:23][C:24]([N:26]1[CH2:31][CH2:30][CH:29]([N:32]2[CH2:38][CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[NH:34][C:33]2=[O:43])[CH2:28][CH2:27]1)=[O:25])[C:8]([N:10]1[CH2:11][CH2:12][N:13]([CH:16]2[CH2:17][CH2:18][N:19]([CH3:22])[CH2:20][CH2:21]2)[CH2:14][CH2:15]1)=[O:9])[CH3:2].[C:49]1([CH3:59])[CH:50]=[CH:51][C:52]([S:55]([O-:58])(=[O:56])=[O:57])=[CH:53][CH:54]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: CCc1ccc(C[C@@H](NC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)N2CCN(C3CCN(C)CC3)CC2)cc1CC
Solvent: CC(C)=O
Solvent: CO
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C

Procedure:
0.2 g (0.30 mmol) 4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidine-1-carboxylic acid-{(R)-1-(3,4-diethyl-benzyl)-2-[4-(1-methyl-piperidin-4-yl)-piperazin-1-yl]-2-oxo-ethyl}-amide and 57.8 mg (0.30 mmol) p-toluenesulphonic acid are suspended in 10 ml acetone and refluxed. 1 ml of methanol is added to this suspension, whereupon the substance goes into solution completely. After cooling to ambient temperature the solid formed is filtered off, washed with acetone and dried for 12 hours at 40° C.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.O1CCOCC1.Cl>CO>[ClH:24].[NH2:7][CH2:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([NH:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[CH2:13][CH2:12]1)=[O:10]
Reactant: CC(C)(C)OC(=O)NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: NCC(=O)N1CCC(Nc2ccccc2Cl)CC1
Yield: 201.4 %

Procedure:
To a stirred mixture of glycine (30 g, 0.3996 mole) in 1N aqueous NaOH (39.96 g, 0.999 mole) was added tert-butanol (270 mL). The mixture was cooled to 0° C. and di-tert-butyl dicarbonate (96.42 g, 0.4395 mole) was added dropwise. The mixture was stirred at ambient temperature for 5 hours. The reaction mixture was then concentrated under reduced pressure and the resulting residue was acidified with citric acid. The product was extracted with ethyl acetate. the organic layer was washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure to afford 49 g (70%) of tert-butoxycarbonylamino-acetic acid. 1H NMR (DMSO-d6): δ 12.8-12.0 (bs, 1H), 7.1 (t, 1H), 3.6 (d, 2H), 1.4 (s 9H). To a stirred solution of tert-butoxycarbonylamino-acetic acid (0.2 g, 0.00114 mol) in DMF (5 mL) was added DIPEA (0.59 g, 0.00457 mol), HOBt (0.193 g, 0.001427 mol) and EDCI.HCl (0.274 g, 0.00143 mol) at ambient temperature. After 5 minutes (2-chloro-phenyl)-piperidin-4-yl-amine dihydrochloride (0.283 g, 0.00114 mol) was added and the resulting mixture was stirred overnight. The reaction mixture was then diluted with cold water. The resulting precipitate was isolated by filtration and purified by column chromatography using basic aluminium oxide (60% ethyl acetate in hexane) to afford 0.41 g (98%) of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester. LCMS: 368.18 (M+1)+, 93.53%. A solution of {2-[4-(2-chloro-phenylamino)-piperidin-1-yl]-2-oxo-ethyl}-carbamic acid tert-butyl ester (0.41 g, 0.00111 mole) in methanol (10 mL) was added dioxane.HCl (5 mL) and the resulting mixture was stirred at ambient temperature for 10 minutes. The mixture was then concentrated under reduced and the resulting residue was washed with ether to afford 0.34 g (98%) of 2-amino-1-[4-(2-chloro-phenylamino)-piperidin-1-yl]-ethanone hydrochloride. LCMS: 268.11 (M+1)+, 84.63%.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:34])[S:5]([C:8]1[CH:33]=[CH:32][C:11]([CH2:12][NH:13][C:14]([C:16]2[C:17]3[CH:24]=[N:23][N:22]([C:25]4[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=4)[C:18]=3[CH:19]=[N:20][CH:21]=2)=[O:15])=[CH:10][CH:9]=1)(=[O:7])=[O:6].CCN(CC)CC.[C:42](Cl)(=[O:44])[CH3:43]>ClCCl.CCOC(C)=O>[F:31][C:28]1[CH:29]=[CH:30][C:25]([N:22]2[C:18]3[CH:19]=[N:20][CH:21]=[C:16]([C:14]([NH:13][CH2:12][C:11]4[CH:10]=[CH:9][C:8]([S:5]([N:4]([CH3:34])[CH2:3][CH2:2][O:1][C:42](=[O:44])[CH3:43])(=[O:6])=[O:7])=[CH:33][CH:32]=4)=[O:15])[C:17]=3[CH:24]=[N:23]2)=[CH:26][CH:27]=1
Reactant: CN(CCO)S(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc1
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CC(=O)OCCN(C)S(=O)(=O)c1ccc(CNC(=O)c2cncc3c2cnn3-c2ccc(F)cc2)cc1
Reaction time: 4 h

Procedure:
To a room temperature solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid 4-[(2-hydroxy-ethyl)-methyl-sulfamoyl]-benzylamide (50 mg, 0.1 mmol), Et3N (16 μL, 0.14 mmol) in dichloromethane was added acetyl chloride (0.010 mL, 0.11 mmol). After 4 hours, the mixture was diluted with EtOAc and the organic layer was washed with saturated aqueous sodium bicarbonate, 1 N aqueous HCl, water, brine, dried over magnesium sulfate, filtered and concentrated to afford the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[NH:11][CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2].Cl[C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15].C(N(CC)CC)C>O1CCCC1>[CH2:1]([O:3][C:4]([CH:6]1[N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[CH2:10][CH2:9][NH:8][C:7]1=[O:12])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1NCCNC1=O
Reactant: O=C(Cl)OCc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C1C(=O)NCCN1C(=O)OCc1ccccc1
Reaction time: 0.5 h
Yield: 52.9 %

Procedure:
To a cold (-20° C.) solution of above 2-oxopiperazine-3-carboxylic acid ethyl ester (0.34 g) in tetrahydrofuran are dropwise added benzyl chloroformate (340 mg) and triethylamine (202 mg). After standing for 30 minutes the reaction mixture is concentrated in vacuum, diluted with ethyl acetate, and chromatographed to give oily 2-oxo-4-benzyloxycarbonylpiperazine-3-carboxylic acid ethyl ester (320 mg) as oil.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][OH:6].C([O-])([O-])=O.[K+].[K+].[C:16]1([CH3:26])[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH3:1][O:2][C:3](=[O:9])[C:4]([CH3:8])([CH3:7])[CH2:5][O:6][S:22]([C:19]1[CH:20]=[CH:21][C:16]([CH3:26])=[CH:17][CH:18]=1)(=[O:24])=[O:23]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COC(=O)C(C)(C)CO
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: COC(=O)C(C)(C)COS(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 52.4 %

Procedure:
To a mixture of 3-hydroxy-2,2-dimethyl-propionic acid methyl ester (13.2 g, 0.1 mol), K2CO3 (20 g, 0.14 mol) and DMAP (6.2 g, 0.05 mol) in DCM (100 mL) was added p-toluenesulfonyl chloride (19 g, 0.1 mol). The mixture was stirred at room temperature overnight, then filtered. The filtrate was washed with HCl aq. (1 M) and water, dried over anhydrous Na2SO4 and concentrated to give the title compound (15 g).
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:27]=[N:26][C:8]2[N:9]([CH3:25])[C:10](=[O:24])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:12](=[O:13])[C:7]=2[CH:6]=1)([CH3:3])[CH3:2].[Li+].CC([N-]C(C)C)C.[CH3:36][CH:37]([CH3:41])[CH2:38][CH:39]=[O:40]>C1COCC1>[OH:40][CH:39]([C:6]1[C:7]2[C:12](=[O:13])[N:11]([CH2:14][CH2:15][CH2:16][O:17][CH:18]3[CH2:23][CH2:22][CH2:21][CH2:20][O:19]3)[C:10](=[O:24])[N:9]([CH3:25])[C:8]=2[N:26]=[CH:27][C:5]=1[O:4][CH:1]([CH3:3])[CH3:2])[CH2:38][CH:37]([CH3:41])[CH3:36]
Reactant: CC(C)Oc1cnc2c(c1)c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Reactant: CC(C)CC=O
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)CC(O)c1c(OC(C)C)cnc2c1c(=O)n(CCCOC1CCCCO1)c(=O)n2C
Temperature: -78 °C
Reaction time: 1 h
Yield: 32.4 %

Procedure:
To a solution of 6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (See Compound 36, step 3, 150 mg, 0.4 mmol) in THF (6 mL) at −78° C. was added LDA (2M in THF, 1.0 mL, 2.0 mmol) dropwise. The reaction was stirred at −78° C. for 1 h then 3-methylbutanal (68.8 mg, 0.8 mmol) in THF (1.5 mL) was added. The reaction was stirred at −78° C. for 1 h, quenched with aq. NH4Cl (5 mL) diluted with water (13 mL) then extracted with EA (30 mL). The organic layer was dried over Na2SO4 and concentrated to a residue which was purified by Prep TLC eluted with PE/EA (2:1) to give 5-(1-hydroxy-3-methylbutyl)-6-isopropoxy-1-methyl-3-(3-(tetrahydro-2H-pyran-2-yloxy)propyl)pyrido[2,3-d]pyrimidine-2,4(1H,3H)-dione (60 mg, 32.4% yield) as a white solid. LCMS: [M+-THP-OH] 362 and TR=2.616 min.
Reaction SMILES: [CH3:1][C:2]([C:4](OC1[C@@]2(C)C(C)(C)[C@H](CC2)C1)=[O:5])=[CH2:3].CN(CCC[CH:23]=[C:24]([CH3:28])[C:25]([NH2:27])=[O:26])C.C(=O)(O)[O-].[Na+].S(S([O-])=O)([O-])(=O)=O.[Na+].[Na+].S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(O)(C)C.O>[CH2:4]([O:5][CH2:28][C:24](=[CH2:23])[C:25]([NH2:27])=[O:26])[CH:2]([CH3:3])[CH3:1]
Reactant: C=C(C)C(=O)OC1C[C@H]2CC[C@]1(C)C2(C)C
Reactant: CC(=CCCCN(C)C)C(N)=O
Agent: O=C([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=S([O-])S(=O)(=O)[O-]
Solvent: CC(C)O
Solvent: O
Product: C=C(COCC(C)C)C(N)=O
Yield: 45 %

Procedure:
A solution of 80 g IBMA, 100 g AMD, and 20 g dimethylaminopropyl methacrylamide (DMAPMA) in 600 ml of isopropyl alcohol and 450 ml of water is heated to 60° C. Sodium bicarbonate (3.5 g) is added to buffer the pH followed by solutions of sodium metabisulfite and ammonium persulfate (each 5.0 g in 15 ml of water). The resulting exothermic reaction is controlled by a cooling bath as needed. After the exotherm has ceased, heating is applied to keep the reaction mixture at reflux temperature (83° C.) for 30 minute after which isopropanol is distilled off until the reaction temperature has reached 90° C. Water is removed by evaporation under reduced pressure to give a 45-50% solution of polymer. The reaction mixture is cooled and adjusted to pH7. The material obtained has an average molecular weight of 7,000 and a surface tension of 35 dynes/cm as a 1.0% aqueous solution.
Reaction SMILES: [N+:1]([CH3:4])([O-:3])=[O:2].[H-].[Na+].[H-].[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[N:18]=[C:17](OP(N3CCOCC3)(N3CCOCC3)=O)[CH2:16][N:15]=[C:14]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]=2[CH:40]=1>CN(C)C=O>[Cl:8][C:9]1[CH:10]=[CH:11][C:12]2[NH:18][C:17](=[CH:4][N+:1]([O-:3])=[O:2])[CH2:16][N:15]=[C:14]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:13]=2[CH:40]=1
Reactant: O=P(OC1=Nc2ccc(Cl)cc2C(c2ccccc2)=NC1)(N1CCOCC1)N1CCOCC1
Reactant: C[N+](=O)[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])C=C1CN=C(c2ccccc2)c2cc(Cl)ccc2N1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of 1.0 ml. of nitromethane and 5 ml. of dry dimethylformamide was added 53 mg. of a 50% dispersion of sodium hydride in mineral oil (1.1 mmole hydride). After 1 hour at room temperature, under nitrogen, 489 mg. (1.0 mmole) of 7-chloro-2-di-(morpholino)phosphinyloxy-5-phenyl-3H-1,4-benzodiazepine was added. After stirring at room temperature for 2 hours, dimethylformamide was evaporated (about 80°). The residue was partitioned between methylene chloride and an aqueous layer which is acidified with a slight excess of acetic acid. The methylene chloride layer was dried (Na2SO4) and evaporated. Separation of the product mixture by preparative tlc (silica gel, developed in 10% methanol in ethylacetate v/v) afforded pure final product, which upon crystallization from methanol, had a m.p. of 178°-180°.
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH:8]=[CH:9][NH:10]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1.[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].CO>C(OCC)(=O)C>[C:28]([OH:33])(=[O:32])[C:29]([OH:31])=[O:30].[NH:10]1[C:11]2[C:7](=[C:6]([O:5][CH2:4][C@@H:2]([OH:1])[CH2:3][N:25]3[CH2:26][CH2:27][CH:22]([C:19]4[CH:18]=[CH:17][C:16]([CH3:15])=[CH:21][CH:20]=4)[CH2:23][CH2:24]3)[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9]1
Reactant: c1cc(OC[C@@H]2CO2)c2cc[nH]c2c1
Reactant: Cc1ccc(C2CCNCC2)cc1
Agent: O=C(O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CO
Product: Cc1ccc(C2CCN(C[C@H](O)COc3cccc4[nH]ccc34)CC2)cc1

Procedure:
The title compound was prepared in similar fashion from (S)-(+)-4-(oxiranylmethoxy)-1H-indole and 4-(4-methylphenyl)piperidine. The resulting free base was dissolved in ethyl acetate, and precipitated with one equivalent of oxalic acid in ethyl acetate in 78% overall yield. FDMS m/e=364 (M+ of free base). α[D]589 =-11.77 (c=0.34, methanol).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][N:12]([CH2:31][C:32]2[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([O:42]CC3C=CC=CC=3)[CH:33]=2)[C:13](=[O:30])[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][NH:19]C(OCC2C=CC=CC=2)=O)=[CH:7][C:6]=1[O:50]CC1C=CC=CC=1)=[O:4].Cl>CO.[Pd]>[NH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][C:13]([N:12]([CH2:11][C:8]1[CH:9]=[CH:10][C:5]([C:3]([O:2][CH3:1])=[O:4])=[C:6]([OH:50])[CH:7]=1)[CH2:31][C:32]1[CH:41]=[CH:40][C:35]([C:36]([O:38][CH3:39])=[O:37])=[C:34]([OH:42])[CH:33]=1)=[O:30]
Reactant: COC(=O)c1ccc(CN(Cc2ccc(C(=O)OC)c(OCc3ccccc3)c2)C(=O)CCCCCNC(=O)OCc2ccccc2)cc1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CO
Product: COC(=O)c1ccc(CN(Cc2ccc(C(=O)OC)c(O)c2)C(=O)CCCCCN)cc1O
Reaction time: 4 h
Yield: 102.1 %

Procedure:
Dissolved methyl 4-[(N-{[4-(methoxycarbonyl)-3-(phenylmethoxy)phenyl]-methyl}-6-[(phenylmethoxy)carbonylamino]hexanoylamino)methyl]-2-(phenylmethoxy)-benzoate (1.20 g, 1.56 mmole) in 400 mL of methanol and then added conc. HCl (400 uL) and a small scoop of palladium on carbon (10%). Hydrogenated for 4 hours using a Parr shaker at 40 psi. Filtered away the palladium on carbon and removed the methanol in vacuo. Collected 730 mg (95% yield) of the product as the hydrochloride salt.