Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:10]2([C:22]3[C:13](=[CH:14][C:15]4[O:20][CH2:19][CH2:18][O:17][C:16]=4[CH:21]=3)[O:12][CH2:11]2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]1[CH2:23][C:24]1[O:28][C:27]([C:29]([OH:31])=O)=[CH:26][CH:25]=1.Cl.[CH3:33][NH:34][CH3:35].O.ON1C2C=CC=CC=2N=N1.CN1CCOCC1>CN(C)C=O>[CH3:33][N:34]([CH3:35])[C:29]([C:27]1[O:28][C:24]([CH2:23][N:3]2[C:4]3[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=3)[C:10]3([C:22]4[C:13](=[CH:14][C:15]5[O:20][CH2:19][CH2:18][O:17][C:16]=5[CH:21]=4)[O:12][CH2:11]3)[C:2]2=[O:1])=[CH:25][CH:26]=1)=[O:31]
Reactant: O=C(O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Reactant: CNC
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: O
Product: CN(C)C(=O)c1ccc(CN2C(=O)C3(COc4cc5c(cc43)OCCO5)c3ccccc32)o1
Yield: 76.2 %

Procedure:
A solution of 5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxylic acid (0.42 g, 1.00 mmol), dimethylamine hydrochloride (0.17 g, 2.04 mmol), N-(3-dimethylaminopropyl)-W-ethylcarbodiimide hydrochloride (0.26 g, 1.35 mmol), 1-hydroxybenzotriazole hydrate (0.21 g, 1.54 mmol) and 4-methylmorpholine (0.30 mL, 2.7 mmol) in N,N-dimethylformamide (10 mL) was stirred at ambient temperature for 16 h. The solvent was removed under reduced pressure, the residue was taken up into ethyl acetate (75 mL) and washed sequentially with 1 M hydrochloric acid (2×50 mL), water (50 mL) and brine (50 mL). The organic phase was further diluted with dichloromethane until all the material was in solution, then was dried over sodium sulfate, filtered and concentrated under reduced pressure. Purification by flash column chromatography with dichloromethane/methanol (29:1) afforded N,N-dimethyl-5-[(2′-oxo-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-1′(2′H)-yl)methyl]furan-2-carboxamide (0.34 g, 77%) as a colorless solid: mp 224-226° C. (diethyl ether/hexanes); 1H NMR (300 MHz, DMSO-d6) δ7.32 (dd, J=7.5, 7.5 Hz, 1H), 7.22-7.14 (m, 2H), 7.05 (dd, J=7.8, 7.5 Hz, 1H), 6.96 (m, 1H), 6.62 (m, 1H), 6.51 (s, 1H), 6.06 (s, 1H), 5.06 (d, J=16.4 Hz, 1H), 4.97 (d, J=16.4 Hz, 1H), 4.76 (d, J=9.3 Hz, 1H), 4.66 (d, J=9.3 Hz, 1H), 4.22-4.14 (m, 2H), 4.14-4.06 (m, 2H), 3.05 (br s, 3H), 2.94 (br s, 3H); 13C NMR (75 MHz, DMSO-d6) δ176.4, 158.9, 154.6, 150.8, 147.2, 144.2, 141.8, 137.8, 131.6, 128.8, 123.6, 123.3, 121.2, 116.5, 111.0, 109.9, 109.4, 98.8, 79.3, 64.2, 63.6, 57.2, 37.7, 36.7, 35.8; MS (ES+) m/z 446.9 (M+1).
Reaction SMILES: [CH:1]1([NH:4][C:5]([C:7]2[C:15]3[CH:14]=[C:13]([C:16]4[C:21]([Br:22])=[CH:20][N:19]=[C:18](Cl)[N:17]=4)[S:12][C:11]=3[CH:10]=[CH:9][CH:8]=2)=[O:6])[CH2:3][CH2:2]1.[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH2:40])([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25].C(N(C(C)C)CC)(C)C>O1CCOCC1>[C:24]([O:28][C:29]([N:31]1[CH2:36][CH2:35][C:34]([CH2:38][CH2:39][NH:40][C:18]2[N:17]=[C:16]([C:13]3[S:12][C:11]4[CH:10]=[CH:9][CH:8]=[C:7]([C:5](=[O:6])[NH:4][CH:1]5[CH2:3][CH2:2]5)[C:15]=4[CH:14]=3)[C:21]([Br:22])=[CH:20][N:19]=2)([CH3:37])[CH2:33][CH2:32]1)=[O:30])([CH3:27])([CH3:26])[CH3:25]
Reactant: O=C(NC1CC1)c1cccc2sc(-c3nc(Cl)ncc3Br)cc12
Reactant: CC1(CCN)CCN(C(=O)OC(C)(C)C)CC1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC1(CCNc2ncc(Br)c(-c3cc4c(C(=O)NC5CC5)cccc4s3)n2)CCN(C(=O)OC(C)(C)C)CC1
Temperature: 90 °C
Yield: 100.1 %

Procedure:
A stirred mixture of 2-(5-bromo-2-chloropyrimidin-4-yl)-benzo[b]thiophene-4-carboxylic acid cyclopropylamide (400 mg, 0.979 mmol), 4-(2-aminoethyl)-4-methyl-piperidine-1-carboxylic acid tert-butyl ester (474 mg, 1.96 mmol) and diisopropylethylamine (253 mg, 1.96 mmol) in 1,4-dioxane (10 mL) is heated at 90° C. under nitrogen for 18 hours. At room temperature the mixture is concentrated and the crude product is chromatographed on silica gel, eluting with 3% 2 M NH3/MeOH in dichloromethane, to give 602 mg of 4-{2-[5-bromo-4-(4-cyclopropylcarbamoylbenzo[b]thiophen-2-yl)-pyrimidin-2-ylamino]-ethyl}-4-methylpiperidine-1-carboxylic acid tert-butyl ester. It is then subject to deprotection by dissolving the material (132 mg, 0.220 mmol) in MeOH (10 mL) and dichloromethane (5 mL) and bubbling anhydrous HCl gas for 5 minutes. The hot, yellow solution is allowed to sit at room temperature for 1.5 hours, then concentrated to give the title compound as a yellow solid (126 mg, 100% yield). ES+(m/z) 514 (79Br) and 516 (81Br) [M(free base)+H].
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:48])[CH2:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([C:25]3[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([O:38][Si](C(C)(C)C)(C)C)[C:34]([CH3:37])([CH3:36])[CH3:35])=[C:27]([CH3:46])[CH:26]=3)([CH2:23][CH3:24])[CH2:21][CH3:22])=[CH:16][C:15]=2[CH3:47])=[CH:10][CH:9]=1.P([O-])(O)(O)=O.[Na+].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.CO>[CH2:21]([C:20]([C:17]1[CH:18]=[CH:19][C:14]([C:11]2[CH:10]=[CH:9][C:8]([CH2:7][CH2:6][C:5]([OH:48])=[O:4])=[CH:13][CH:12]=2)=[C:15]([CH3:47])[CH:16]=1)([C:25]1[CH:30]=[CH:29][C:28]([CH2:31][CH2:32][CH:33]([OH:38])[C:34]([CH3:36])([CH3:37])[CH3:35])=[C:27]([CH3:46])[CH:26]=1)[CH2:23][CH3:24])[CH3:22]
Reactant: CCC(CC)(c1ccc(CCC(O[Si](C)(C)C(C)(C)C)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CCC(=O)OC)cc2)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=P([O-])(O)O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(CCC(O)C(C)(C)C)c(C)c1)c1ccc(-c2ccc(CCC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Yield: 68 %

Procedure:
A sodium hydroxide aqueous solution (1 M, 0.5 mL, 0.5 mmol) was added to a mixture of 3-[4′-(1-{4-[3-(t-butyl-dimethyl-silanyloxy)-4,4-dimethyl-pentyl]-3-methyl-phenyl}-1-ethyl-propyl)-2′-methyl-biphenyl-4-yl]-propionic acid methyl ester (Example 11-(3); 0.013 g, 0.02 mmol), tetrahydrofuran (0.5 mL) and methanol (1.0 mL) while stirring at room temperature, and the mixture was stirred at the same temperature for two hours. A 30% sodium dihydrogenphosphate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. Tetra-n-butylammonium fluoride (1 M solution in tetrahydrofuran, 0.1 mL, 0.1 mmol) and tetrahydrofuran (1 mL) were added to the resulting residue, and the mixture was stirred at 60° C. for four hours. A 30% sodium dihydrogenphosphate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed with a 30% sodium dihydrogenphosphate aqueous solution and brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue was purified by preparative TLC (dichloromethane/methanol=10/1) to give the title compound (0.007 g, 67%).
Reaction SMILES: O1CCN(C([N:9]2[C:14](=[O:15])[C:13]([CH2:16][CH:17]([CH3:19])[CH3:18])=[N:12][C:11]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])=[N:10]2)C)CC1.C([O-])(=O)C([O-])=O>>[Cl:26][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=1[C:11]1[N:12]=[C:13]([CH2:16][CH:17]([CH3:18])[CH3:19])[C:14](=[O:15])[NH:9][N:10]=1
Reactant: CC(C)Cc1nc(-c2ccccc2Cl)nn(C(C)N2CCOCC2)c1=O
Agent: O=C([O-])C(=O)[O-]
Product: CC(C)Cc1nc(-c2ccccc2Cl)n[nH]c1=O

Procedure:
1-MORPHOLINOETHYL-3-(2-CHLOROPHENYL)-5-ISOBUTYL-1,2,4-TRIAZIN-6-ONE in the form of the acid oxalate
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:33])=[O:32])[C:7]=2[CH:36]=1)#[N:2].Cl[CH2:38][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][C:40]=1[O:49][CH3:50].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[Na+]>CN(C=O)C.CCOC(C)=O>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[N:12]([CH2:38][C:39]3[C:48]4[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=4)[CH:42]=[CH:41][C:40]=3[O:49][CH3:50])[C:11](=[O:13])[C@@H:10]([NH:14][C:15](=[O:27])[C@@H:16]([N:18]([CH3:26])[C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:22])[CH3:23])[CH3:17])[C@H:9]([CH3:28])[N:8]([C:29](=[O:35])[CH2:30][S:31]([CH3:34])(=[O:32])=[O:33])[C:7]=2[CH:36]=1)#[N:2]
Reactant: C[C@@H](C(=O)N[C@@H]1C(=O)Nc2ccc(C#N)cc2N(C(=O)CS(C)(=O)=O)[C@H]1C)N(C)C(=O)OC(C)(C)C
Reactant: COc1ccc2ccccc2c1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc2ccccc2c1CN1C(=O)[C@@H](NC(=O)[C@H](C)N(C)C(=O)OC(C)(C)C)[C@H](C)N(C(=O)CS(C)(=O)=O)c2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 38.4 %

Procedure:
To a rt solution of tert-butyl(S)-1-((2S,3S)-8-cyano-2-methyl-1-(2-(methylsulfonyl)acetyl)-4-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (108 mg, 207 μmol) in DMF (518 μl) was added 1-(chloromethyl)-2-methoxynaphthalene (47.1 mg, 228 μmol), cesium carbonate (81.0 mg, 248 μmol), and sodium iodide (37.2 mg, 248 μmol). The reaction was stirred at rt for 1.5 h, then diluted with EtOAc, washed with H2O and sat. aq. NaCl, dried over Na2SO4, filtered, and concentrated. The crude material was purified by flash chromatography then reverse phase preparative HPLC to provide tert-butyl(S)-1-((3S,4S)-7-cyano-1-((2-methoxynaphthalen-1-yl)methyl)-4-methyl-5-(2-(methylsulfonyl)acetyl)-2-oxo-2,3,4,5-tetrahydro-1H-benzo[b][1,4]diazepin-3-ylamino)-1-oxopropan-2-yl(methyl)carbamate (55 mg, 38%) as a white solid. MS m/z 714 (MNa)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][CH:4]=1.[Cl:16][S:17](O)(=[O:19])=[O:18]>>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][CH2:11][O:12][C:7]=2[C:6]([C:13]([OH:15])=[O:14])=[CH:5][C:4]=1[S:17]([Cl:16])(=[O:19])=[O:18]
Reactant: O=S(=O)(O)Cl
Reactant: COc1ccc(C(=O)O)c2c1OCCO2
Product: COc1c(S(=O)(=O)Cl)cc(C(=O)O)c2c1OCCO2
Temperature: 25 °C
Yield: 98 %

Procedure:
1045 cm3 of chlorosulfonic acid were introduced into a balloon flask provided with an agitator, a thermometer and a condenser and then, in portions, 110 g of 8-methoxy-1,4-benzodioxane-5-carboxylic acid were added with the temperature being maintained at from 5°-10° C. The mixture was agitated at ambient temperature and then poured on ice. The precipitate was dried off, washed and dried. 159 g of 8-methoxy-7-chlorosulfonyl-1,4-benzodioxane-5-carboxylic acid were obtained (yield: 98%).
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([O:6][CH2:7][CH3:8])=[O:5].[Br:14][C:15]1[C:20]([CH3:21])=[CH:19][C:18](I)=[CH:17][N:16]=1>>[Br:14][C:15]1[N:16]=[CH:17][C:18]([NH:1][C:2]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=2[C:4]([O:6][CH2:7][CH3:8])=[O:5])=[CH:19][C:20]=1[CH3:21]
Reactant: Cc1cc(I)cnc1Br
Reactant: CCOC(=O)c1cc(C)ccc1N
Product: CCOC(=O)c1cc(C)ccc1Nc1cnc(Br)c(C)c1
Yield: 25 %

Procedure:
Obtained (0.050 g, yield 25%) following the procedure described in Intermediate 16 starting with ethyl 2-amino-5-methylbenzoate (0.56 mmol, 0.100 g) and 2-bromo-5-iodo-3-methylpyridine (1.0 mmol, 0.166 g).
Reaction SMILES: [C:1](O)(=[O:5])[C:2]([CH3:4])=[CH2:3].C(OC(Cl)=O)C.C(N(CC)CC)C.[NH2:20][C:21]1[CH:29]=[CH:28][C:24]([C:25]([OH:27])=[O:26])=[CH:23][CH:22]=1.Cl>C(#N)C>[C:25]([C:24]1[CH:28]=[CH:29][C:21]([NH:20][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:22][CH:23]=1)([OH:27])=[O:26]
Reactant: C=C(C)C(=O)O
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(CC)CC
Product: C=C(C)C(=O)Nc1ccc(C(=O)O)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 83.3 %

Procedure:
Into a 1 liter flask 600 ml of acetonitrile, 95.2 g (1.1 mol) of methacrylic acid and 120.1 g (1.1 mol) of chloroformic acid ethyl ester were added. To this mixture 111.8 g (1.1 mol) of triethylamine was added over a period of 1 hour in a cold bath. Stirring was continued for 1 hour at room temperature. 137.1 g (1 mol) of 4-aminobezoic acid was added to the mixture. The mixture was heated for 2 hours at 50° C. The mixture was poured into 5 liter of 1% HCl solution. The deposit was filtered, washed and dried to produce 170.9 g of N-(4-carboxyphenyl)-methacrylamide.
Reaction SMILES: [CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([OH:11])=O)=[C:7]([CH3:20])[CH:6]=2)[CH2:4][CH2:3][CH2:2]1.Cl.[NH:22]1[CH2:27][CH2:26][CH:25]([C:28]2[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH:1]1([C:5]2[C:13]([C:14]3[NH:18][C:17]([CH3:19])=[N:16][N:15]=3)=[CH:12][C:8]([C:9]([N:22]3[CH2:27][CH2:26][CH:25]([C:28]4[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=4)[CH2:24][CH2:23]3)=[O:11])=[C:7]([CH3:20])[CH:6]=2)[CH2:2][CH2:3][CH2:4]1
Reactant: N#Cc1ccc(C2CCNCC2)cc1
Reactant: Cc1nnc(-c2cc(C(=O)O)c(C)cc2C2CCC2)[nH]1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: Cc1nnc(-c2cc(C(=O)N3CCC(c4ccc(C#N)cc4)CC3)c(C)cc2C2CCC2)[nH]1
Temperature: 25 °C
Reaction time: 16 h
Yield: 46.2 %

Procedure:
To a solution of 4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoic acid (compound 152.8, 260 mg, 0.95 mmol) in DMF (4 mL) were added 4-(piperidin-4-yl)benzonitrile hydrochloride salt (compound 1.5, 232 mg, 1.045 mmol), EDC (272 mg, 1.425 mmol), HOBt (39 mg, 0.285 mmol), and DIEA (367.7 mg, 2.85 mmol). The resulting mixture was stirred at room temperature for 16 hours. The mixture was quenched with saturated aqueous NaHCO3 (20 mL) and extracted with ethyl acetate (2×50 mL). The combined organic layers were washed with brine (50 mL), dried over Na2SO4, filtered, and concentrated in vacuo. Purification via SiO2 column chromatography (dichloromethane/methanol=95/5) afforded 4-(1-(4-cyclobutyl-2-methyl-5-(5-methyl-4H-1,2,4-triazol-3-yl)benzoyl)piperidin-4-yl)benzonitrile as a white solid (193 mg, 44% yield). m/z (ES+) 440 (M+H)+. 1H NMR (300 MHz, CD3OD): δ 7.69 (d, J=5.4 Hz. 2H), 7.56-7.30 (m, 4H), 1 proton obscured by methanol solvent peak, 4.10-3.98 (m, 1H), 3.64 (t, J=10.7 Hz, 1H), 3.33-3.21 (m, 1H), 3.00 (t, J=8.9 Hz, 2H), 2.58 (s, 3H), 2.48 and 2.38 (2 singlets, amide rotamers, ArCH3, 3H), 2.28-1.92 (m, 6H), 1.92-1.55 (m, 4H). 1H NMR (400 MHz, DMSO-d6): δ 13.66 (s, 1H), 7.77 (d, J=8.0 Hz, 2H), 7.62-7.34 (m, 4H), 4.78-4.63 (m, 1H), 4.31 (br s, 1H), 3.45 (br s, 1H), 3.15 (app t, J=12.3 Hz, 1H), 2.99-2.78 (m, 2H), 2.44-1.80 (m, 12H), 1.80-1.37 (m, 4H).
Reaction SMILES: [O-]CC.[Na+].[CH2:5]([O:7][C:8](=[O:22])[CH2:9][C:10]([NH:12][CH2:13][C:14]1([C:17]([O:19]CC)=O)[CH2:16][CH2:15]1)=[O:11])[CH3:6]>C1(C)C=CC=CC=1.O>[O:11]=[C:10]1[CH:9]([C:8]([O:7][CH2:5][CH3:6])=[O:22])[C:17](=[O:19])[C:14]2([CH2:15][CH2:16]2)[CH2:13][NH:12]1
Reactant: CCOC(=O)CC(=O)NCC1(C(=O)OCC)CC1
Agent: CC[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C1C(=O)NCC2(CC2)C1=O
Temperature: 25 °C
Yield: 91.2 %

Procedure:
To a freshly prepared solution of sodium ethoxide [made from sodium (21 mg, 0.9338 mmol) and EtOH (0.5 mL)] was added a solution of ethyl 1-((3-ethoxy-3-oxopropanamido)methyl)cyclopropanecarboxylate (200 mg, 0.7782 mmol) in toluene (2 mL), and the resulting mixture was heated at reflux for 4 h. The mixture was cooled to RT, diluted with water (5 mL), and extracted with EtOAc (2×5 mL). The combined organic extracts were dried over Na2SO4 and concentrated in vacuo to provide ethyl 6,8-dioxo-5-azaspiro[2.5]octane-7-carboxylate (150 mg, 0.710 mmol, 91% yield): m/z (ESI, +ve) 212.3 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:15][CH3:16])[CH2:9][N:10]2[CH2:14][CH2:13][CH2:12][CH2:11]2)[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[CH:19]=[C:20]([N:25]([CH3:30])[CH2:26][C:27]([OH:29])=O)[CH:21]=[CH:22][C:23]=1[Cl:24].C(N(CC)CC)C.O>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]([N:15]([CH3:16])[C:27](=[O:29])[CH2:26][N:25]([C:20]2[CH:21]=[CH:22][C:23]([Cl:24])=[C:18]([Cl:17])[CH:19]=2)[CH3:30])[CH2:9][N:10]2[CH2:11][CH2:12][CH2:13][CH2:14]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN(CC(=O)O)c1ccc(Cl)c(Cl)c1
Reactant: CNC(CN1CCCC1)c1cccc(Br)c1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CN(CC(=O)N(C)C(CN1CCCC1)c1cccc(Br)c1)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 54 %

Procedure:
[1-(3-Bromophenyl)-2-(1-pyrrolidinyl)ethyl]methylamine (0.65 g, 2.30 mmol) was added to a solution of N-(3,4-dichlorophenyl)-N-methylglycine (0.65 g, 2.30 mmol), (benzotriazol-1-yloxy) tris(dimethylamino) phosphonium-hexaflurophosphate (BOP) (1.52 g, 3.40 mmol) and triethylamine (TEA) (0.70 g, 6.90 mmol) in N,N-dimethyl-formamide (DMF) (10 mL). The reaction mixture was stirred at RT for 12 h. Water (10 mL) was then added an the crude compound precipitated, was filtered and crystallized from ether and hexane to give the title compound as an off-white solid (0.62 g, 54%). MS (ES) m/e 499[M+H]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[CH2:16]([NH2:18])[CH3:17]>C(O)CCC>[CH2:16]([NH:18][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:12])[NH:7][CH:8]=[N:9]2)=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14])[CH3:17]
Reactant: CCN
Reactant: O=c1[nH]cnc2cc(Cl)c([N+](=O)[O-])cc12
Solvent: CCCCO
Product: CCNc1cc2nc[nH]c(=O)c2cc1[N+](=O)[O-]
Temperature: 100 °C
Reaction time: 0.25 h
Yield: 40 %

Procedure:
7-Chloro-6-nitro-4(3H)-quinazolinone (20.0 g, 88.7 mmol) was suspended in n-butanol (150 ml), 70% aqueous ethylamine solution (120 ml) was added thereto, and the mixture was stirred for 15 minutes to give a clear solution which was then heated for 9 hours in a sealed tube in an oil bath (oil bath temperature set at 100° C. ). After the reaction was completed, the reaction mixture was left and cooled to precipitate yellow solids (first crystal) which were then filtered off. The first crystal was washed with methanol and ether and dried to give the desired title compound (8.27 g, 40%). The filtrate obtained at the time of acquisition of the first crystal was concentrated to precipitate crystal which was then filtered off and subjected to the same procedures as above to give second crystal as the desired title compound (5.84 g, 24%).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:31][CH3:32])=[CH:4][C:5]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:27]([F:30])([F:29])[F:28])[CH:11]=2)=[N:6][C:7]=1[C:8]#[N:9].Cl.[N:34]([O-])=O.[Na+]>O1CCOCC1.O>[C:8]([C:7]1[C:2]2[N:1]=[N:34][N:31]([CH3:32])[C:3]=2[CH:4]=[C:5]([C:10]2[CH:26]=[CH:25][C:13]([O:14][CH2:15][CH2:16][NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[C:12]([C:27]([F:28])([F:29])[F:30])[CH:11]=2)[N:6]=1)#[N:9]
Reactant: O=N[O-]
Reactant: CNc1cc(-c2ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c2)nc(C#N)c1N
Agent: Cl
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: Cn1nnc2c(C#N)nc(-c3ccc(OCCNC(=O)OC(C)(C)C)c(C(F)(F)F)c3)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 2-(4-(5-amino-6-cyano-4-(methylamino)pyridin-2-yl)-2-(trifluoromethyl)phenoxy)ethylcarbamate (1.130 mmol, 0.51 g) was dissolved in 1M Hydrochloric Acid (2.259 mmol, 2.259 ml) and dioxane (5 ml). Sodium nitrite (1.582 mmol, 0.109 g) in water (5.00 ml) was added to the reaction mixture and it was stirred at room temperature for 1 hr. The reaction mixture was filtered and the solid washed with water to afford tert-butyl 2-(4-(4-cyano-1-methyl-1H-[1,2,3]triazolo[4,5-c]pyridin-6-yl)-2-(trifluoromethyl)phenoxy)ethylcarbamate. (0.61 g)
Reaction SMILES: CS(O[CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=O)=O.[CH3:48][NH:49][CH3:50]>CN(C=O)C.CCOC(C)=O>[CH3:48][N:49]([CH2:6][C@H:7]([N:29]1[C:37]([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)=[C:36]2[C:31]([N:32]([CH3:47])[C:33](=[O:46])[N:34]([CH3:45])[C:35]2=[O:44])=[CH:30]1)[CH2:8][S:9][C:10]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:50]
Reactant: Cn1c(=O)c2c(-c3ccccc3)n([C@@H](COS(C)(=O)=O)CSC(c3ccccc3)(c3ccccc3)c3ccccc3)cc2n(C)c1=O
Reactant: CNC
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CN(C)C[C@@H](CSC(c1ccccc1)(c1ccccc1)c1ccccc1)n1cc2c(c1-c1ccccc1)c(=O)n(C)c(=O)n2C
Temperature: 120 °C

Procedure:
(S)-2-(1,3-Dimethyl-2,4-dioxo-5-phenyl-3,4-dihydro-1H-pyrrolo[3,4-d]pyrimidin-6(2H)-yl)-3-(tritylthio)propyl methanesulfonate (step 3)(1.7 g, 2.55 mmol) was dissolved in DMF (12 mL) and dimethylamine (40% wt. aqueous solution) (1.455 mL, 11.49 mmol) was added. The mixture was heated under microwave irradiation at 120° C. for 15 h. The reaction mixture was diluted with EtOAc and washed with brine (4×). The organic phase was dried over sodium sulphate and evaporated under vacuum. The residue was redissolved in DCM and evaporated onto silica. Purification by chromatography on silica, eluting with 20-100% EtOAc in iso-hexane gave the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[N:13]([CH3:20])[CH:14]=[C:15]([N+:17]([O-])=O)[N:16]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4].[CH3:23][C:24]([O:27][C:28]([NH:30][C:31]1[CH:35]=[C:34]([C:36](ON2N=NC3C2=CC=CC=3)=[O:37])[N:33]([CH3:48])[CH:32]=1)=[O:29])([CH3:26])[CH3:25].CCN(C(C)C)C(C)C>CN(C=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[CH:22]=[CH:21][C:8]2[NH:9][C:10]([C:12]3[N:13]([CH3:20])[CH:14]=[C:15]([NH:17][C:36]([C:34]4[N:33]([CH3:48])[CH:32]=[C:31]([NH:30][C:28]([O:27][C:24]([CH3:25])([CH3:23])[CH3:26])=[O:29])[CH:35]=4)=[O:37])[N:16]=3)=[N:11][C:7]=2[CH:6]=1)=[O:4]
Reactant: COC(=O)c1ccc2[nH]c(-c3nc([N+](=O)[O-])cn3C)nc2c1
Reactant: Cn1cc(NC(=O)OC(C)(C)C)cc1C(=O)On1nnc2ccccc21
Agent: [Pd]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2[nH]c(-c3nc(NC(=O)c4cc(NC(=O)OC(C)(C)C)cn4C)cn3C)nc2c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 25 %

Procedure:
Pd/C (10 wt. %, 150 mg) was added to a solution of nitro-ester 21a (1.00 g, 3.32 mmol) in DMF (100 mL) and the mixture was hydrogenated at 450 psi for 2 h at ambient temperature. The reaction mixture was filtered through Celite to remove the catalyst and the filtrate was treated immediately with Boc-Py-OBt (27a, 1.42 g, 3.98 mmol) and DIEA (20 mL) and stirred at 60° C. for 18 h. The resulting yellow solution was poured into ice water and extracted with EtOAc. The organic phase was washed with 10% citric acid, brine, and saturated aqueous sodium bicarbonate and dried with MgSO4. Evaporation of the solvent yielded the crude product as a yellow foam which was purified by column chromatography on silica gel (n-hexane/EtOAc 1:2) to give the title compound as a beige solid (409 mg, 25%). 1H NMR (300 MHz, [D6] DMSO): δ=1.45 (s, 9H), 3.82 (s, 3H), 3.87 (s, 3H), 4.16 (s, 3H), 6.88 (s, 1H), 6.99 (s, 1H), 7.60-8.20 (m, 4H), 9.11 (s, 1H), 10.23 (s, 1H), 13.03 (br s, 1H); MS (ESI): m/z: 494 [M+H]+; HR-MS (FAB): calcd for C24H28N7O5: 494.2151; found: 494.2143 [M+H]+.
Reaction SMILES: [CH2:1]1[CH2:6][C@H:5]([C:7]([OH:9])=[O:8])[CH2:4][CH2:3][C@H:2]1[CH2:10][NH2:11].[CH3:12][C:13]([CH3:31])([CH3:30])[C:14]([O:16][CH:17]([O:19][C:20](ON1C(=O)CCC1=O)=[O:21])[CH3:18])=[O:15]>CC(OC)(C)C.CC(C)=O.O>[CH3:30][C:13]([CH3:12])([CH3:31])[C:14]([O:16][CH:17]([O:19][C:20]([NH:11][CH2:10][C@H:2]1[CH2:3][CH2:4][C@H:5]([C:7]([OH:9])=[O:8])[CH2:6][CH2:1]1)=[O:21])[CH3:18])=[O:15]
Reactant: CC(OC(=O)ON1C(=O)CCC1=O)OC(=O)C(C)(C)C
Reactant: NC[C@H]1CC[C@H](C(=O)O)CC1
Solvent: CC(C)=O
Solvent: O
Solvent: COC(C)(C)C
Product: CC(OC(=O)NC[C@H]1CC[C@H](C(=O)O)CC1)OC(=O)C(C)(C)C

Procedure:
Following the general nucleophilic carbamoylation procedure, tranexamic acid (1.1 g, 7 mmol) and 1-[(2,5-dioxopyrrolidinyl)oxycarbonyloxy]ethyl 2,2-dimethylpropanoate (1.1 g, 3.8 mmol) were reacted in the MTBE/acetone/water mixture (16 mL) to yield the title compound 21 (200 mg, 16% yield) as a white powder after work-up and mass-guided preparative HPLC purification. 1H NMR (400 MHz, DMSO-d6): δ=0.86-0.99 (m, 2H), 1.14 (s, 9H), 1.21-1.39 (br. m, 3H), 1.42 (d, J=5.2 Hz, 3H), 1.71-1.74 (m, 2H), 1.89-1.91 (m, 2H), 2.13 (tt, J=12, 3.6 Hz, 1H), 2.81-2.89 (m, 2H), 6.64 (q, J=5.6 Hz, 1H), 7.49 (t, J=6.0 Hz, 1H), 12.01 (br. s, 1H). MS (ESI) m/z 352.16 (M+Na)+; 328.14 (M−H)−.