Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18].C([Sn](CCCC)(CCCC)[C:27]([O:29]CC)=[CH2:28])CCC>O1CCOCC1.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>[C:27]([C:2]1[CH:3]=[C:4]([C:19]([OH:21])=[O:20])[CH:5]=[C:6]2[C:11]=1[O:10][C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[CH:8][C:7]2=[O:18])(=[O:29])[CH3:28]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: O=C(O)c1cc(Br)c2oc(N3CCOCC3)cc(=O)c2c1
Agent: Cl[Pd]Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(=O)c1cc(C(=O)O)cc2c(=O)cc(N3CCOCC3)oc12
Temperature: 100 °C
Reaction time: 3 h
Yield: 103.3 %

Procedure:
Bis(triphenylphosphine) palladium (II) chloride (12.78 mg, 0.02 mmol) was added to a stirred mixture of 8-bromo-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (215 mg, 0.61 mmol) and tributyl(1-ethoxyvinyl)stannane (0.226 mL, 0.67 mmol) in 1,4-dioxane (5 mL) and the mixture was purged with nitrogen. The resulting mixture was stirred at 100° C. for 3 hrs. HC12N (0.5 mL) was added and the reaction mixture was stirred at 50° C. for 25 minutes then allowed to cool to room temperature and concentrated under vacuum. The product was diluted with diethyl ether and pentane to afford a solid, which was collected by filtration and washed with ether/pentane to give 8-acetyl-2-morpholino-4-oxo-4H-chromene-6-carboxylic acid (200 mg, 104%) as a beige solid. Mass Spectrum: M+H+ 318.
Reaction SMILES: C([O:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd].C(O)C>[OH:8][C:9]1[CH:23]=[CH:22][CH:21]=[CH:20][C:10]=1[O:11][CH2:12][CH2:13][CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: [H][H]
Reactant: CCOC(=O)CCCOc1ccccc1OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCCOc1ccccc1O

Procedure:
A mixture of (3) (1.57 g, 5.0 mM), ethanol (50 mL), glacial acetic acid (7 drops) and 10% palladium on carbon (0.7 g) was reacted in a hydrogen atmosphere (40 p.s.i.) at room temperature until hydrogen uptake ceased. Concentration of the filtered mixture yielded the product (4) as an oil.
Reaction SMILES: C(#N)C1C=CC=C(C#N)C=1.N.[C:12](#[N:21])[C:13]1[CH:20]=[CH:19][C:16]([C:17]#[N:18])=[CH:15][CH:14]=1>O1CCOCC1>[CH3:12][C:13]1[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1.[C:13]1([CH2:12][NH2:21])[CH:20]=[CH:19][C:16]([CH2:17][NH2:18])=[CH:15][CH:14]=1
Reactant: N#Cc1ccc(C#N)cc1
Agent: N
Agent: N#Cc1cccc(C#N)c1
Solvent: C1COCCO1
Product: Cc1ccc(CN)cc1
Product: NCc1ccc(CN)cc1

Procedure:
In place of 26.8 g of isophthalonitrile and 30 g of ammonia in Example 1, 24.6 g of terephthalonitrile, 52 g of dioxane and 25 g of ammonia were changed into the same autocLave and subjected to reaction in the same manner as in Example 1. It was found that the yield of 1,4-BAC was 88.2%, the yields of 4-methylbenzylamine and paraxylylenediamine were 7.2% and 2.1%, respectively, and that of other lower boiling and higher boiling products was 2.5%.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH2:10][CH2:11][C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([O:22][CH3:23])=[C:16]([O:24][CH3:25])[CH:15]=3)=[CH:4][C:3]=2[O:2]1.FC(F)(F)C(O)=O>ClCCl.C(OCC)(=O)C>[CH3:21][O:20][C:18]1[C:19]2[C:6]3[CH:7]=[C:8]4[O:9][CH2:1][O:2][C:3]4=[CH:4][C:5]=3[CH2:10][CH2:11][C:12]([C:31]([O:33][CH2:34][CH3:35])=[O:32])([C:26]([O:28][CH2:29][CH3:30])=[O:27])[CH2:13][C:14]=2[CH:15]=[C:16]([O:24][CH3:25])[C:17]=1[O:22][CH3:23]
Reactant: CCOC(=O)C(CCc1ccc2c(c1)OCO2)(Cc1cc(OC)c(OC)c(OC)c1)C(=O)OCC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(C(=O)OCC)CCc2cc3c(cc2-c2c(cc(OC)c(OC)c2OC)C1)OCO3
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61 %

Procedure:
In 3 ml of dichloromethane, 102 mg of diethyl 4-(3,4-methylenedioxyphenyl)-1-(3,4,5-trimethoxyphenyl)-butane-2,2-dicarboxylate [0.205 mmol, A. S. Kende and L. S. Liebeskind, J. Am. Chem. Soc., 98, 267 (1976)] were dissolved. The solution was added with 0.3 ml of trifluoroacetic acid and 210 mg (0.45 mmol) of ferric perchlorate, followed by stirring at room temperature for 1.5 hours. The reaction mixture was dissolved in 10 ml of ethyl acetate. After the resulting solution was washed with 2N-HCl and then saturated NaCl, the organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, whereby brown oil was obtained. The oil thus obtained was purified by TLC (silica gel: "MERCK #5744", eluent: 1:3 mixed solvent of ethyl acetate and hexane), whereby 62 mg of the title compound were obtained as colorless oil (yield: 61%).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]1([C@H:19]([N:21]2[CH:25]=[CH:24][N:23]=[N:22]2)[CH3:20])[CH2:18][O:17]1.O>CN(C)C=O.C(OCC)(=O)C>[F:8][C:9]1[CH:14]=[C:13]([F:15])[CH:12]=[CH:11][C:10]=1[C@:16]([OH:17])([C@H:19]([N:21]1[CH:25]=[CH:24][N:23]=[N:22]1)[CH3:20])[CH2:18][N:1]1[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: c1nc[nH]n1
Reactant: C[C@@H](n1ccnn1)[C@@]1(c2ccc(F)cc2F)CO1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C[C@@H](n1ccnn1)[C@](O)(Cn1cncn1)c1ccc(F)cc1F
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 44.6 %

Procedure:
1H-1,2,4-Triazole (63 mg) was added under ice-cooling to a dispersion of 60% sodium hydride in oil (36 mg) in dimethylformamide (1.5 ml) and the resulting mixture was stirred for 10 minutes at room temperature. To the mixture was added a solution of (2S)-2-(2,4-difluorophenyl)-2-[(1R)-1-(1H-1,2,3-triazol-1-yl)ethyl]oxirane (116 mg) in dimethylformamide (0.8 ml), followed by heating for 5 hours at 50° C. and cooling. Cold water (10 ml) and ethyl acetate (20 ml) were added to the reaction mixture. The separated aqueous layer was extracted twice with ethyl acetate. The combined ethyl acetate layers were washed with water and saturated saline, dried over anhydrous magnesium sulfate and distilled under reduced pressure. The residue was purified by silica gel column chromatography (acetone/dichlormethane=1:2→1:1). The obtained crystals were recrystallized from diisopropyl ether to give the title compound (Compound 6, 66 mg, 45%) as colorless crystals.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[F:30][C:31]([F:42])([F:41])[C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>>[CH:18]1([N:13]2[C:12]([C:35]3[CH:36]=[CH:37][C:32]([C:31]([F:42])([F:41])[F:30])=[CH:33][CH:34]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccc(C(F)(F)F)cc1
Product: FC(F)(F)c1ccc(-c2c3c(nn2C2CCC2)CCNCC3)cc1
Yield: 47.6 %

Procedure:
The title compound (73 mg) was prepared according to Example 263 using 201 mg of 2-cyclobutyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 276, Step A) and 122 mg of 4-trifluoromethylphenylboronic acid. MS (ESI): exact mass calculated for C18H20F3N3, 335.16. found, m/z 336.4 [M+H]+. 1H NMR (500 MHz, CD3OD): 7.86-7.85 (m, 2H), 7.52-7.50 (m, 2H), 4.65-4.58 (m, 1H), 3.45-3.41 (m, 2H), 3.22-3.20 (m, 2H), 2.81-2.79 (m, 2H), 2.67-2.62 (m, 2H), 2.30-2.24 (m, 2H), 1.84-1.74 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:5](=[C:6]([Br:11])[CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]=1[C:12]([NH2:14])=[O:13].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[Br:11][C:6]1[C:5]2[NH:4][C:3]3[C:12](=[O:13])[NH:14][C:16](=[O:15])[NH:1][C:2]=3[C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: NC(=O)c1[nH]c2c(Br)cccc2c1N
Solvent: C1COCCO1
Solvent: O
Product: O=c1[nH]c(=O)c2[nH]c3c(Br)cccc3c2[nH]1
Temperature: 25 °C
Yield: 100.4 %

Procedure:
8.0 g (32 mmol) 3-amino-7-bromo-1H-indole-2-carboxylic acid amide was suspended in 50 ml dioxan, and refluxed after the addition of 3.8 ml (32 mmol) diphosgene for 3 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was then sucked off. 9.0 g (32%) 6-bromo-1H-pyrimido[5,4-b]indole-2,4(3H,5H)-dione was obtained. ESI-MS [m/z]: 278, 280 [M−H]−
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Cl[C:12]1[N:13]=[C:14]([N:33]2[CH2:38][CH2:37][O:36][CH2:35][CH2:34]2)[C:15]2[N:21]=[C:20]([CH2:22][N:23]3[CH2:28][CH2:27][CH:26]([C:29]([OH:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]3)[CH:19]=[CH:18][C:16]=2[N:17]=1>>[CH3:1][C:2]1[N:6]([C:12]2[N:13]=[C:14]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)[C:15]3[N:21]=[C:20]([CH2:22][N:23]4[CH2:28][CH2:27][CH:26]([C:29]([OH:32])([CH3:31])[CH3:30])[CH2:25][CH2:24]4)[CH:19]=[CH:18][C:16]=3[N:17]=2)[C:5]2[CH:7]=[CH:8][CH:9]=[CH:10][C:4]=2[N:3]=1
Reactant: CC(C)(O)C1CCN(Cc2ccc3nc(Cl)nc(N4CCOCC4)c3n2)CC1
Reactant: Cc1nc2ccccc2[nH]1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCC(C(C)(C)O)CC3)ccc2n1

Procedure:
Following General Procedure C, 2-methylbenzimidazole and 2-(1-((2-chloro-4-morpholinopyrido[3,2-d]pyrimidin-6-yl)methyl)piperidin-4-yl)propan-2-ol from Example 8 were reacted to give 101. LCMS (MH+)=502.3. 1H-NMR (DMSO-d6): δ 8.20 (m, 2H), 7.89 (m, 1H), 7.62 (m, 1H), 7.27 (m, 2H), 4.56 (s, 4H), 4.08 (s, 1H), 3.84 (m, 4H), 3.73 (s, 2H), 2.92 (m, 2H), 2.88 (s, 3H), 1.98 (m, 2H), 1.67 (m, 2H), 1.29 (m, 2H), 1.18 (m, 1H), 1.04 (s, 6H)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([NH2:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[C:12]([O-:15])(=[O:14])[CH3:13].[Na+].C(Cl)Cl.[C:20]([O:23][C:24]1[CH:32]=[CH:31][CH:30]=[CH:29][C:25]=1[C:26](Cl)=[O:27])(=[O:22])[CH3:21]>O>[C:12]([O:15][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:1][C:2]1[CH:10]=[C:9]([NH:11][C:26](=[O:27])[C:25]2[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=2[O:23][C:20](=[O:22])[CH3:21])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])=[O:5])(=[O:14])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: CC(=O)Oc1ccccc1C(=O)Cl
Reactant: Nc1ccc(C(=O)O)c(N)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CC(=O)Oc1ccccc1C(=O)Nc1ccc(C(=O)O)c(NC(=O)c2ccccc2OC(C)=O)c1
Yield: 97.8 %

Procedure:
To a mixture of 4.9 g of 2,4-diaminobenzoic acid, 12 g of sodium acetate, 90 ml of methylene chloride and 90 ml of water was added 19.2 g of 2-acetoxybenzoylchloride while stirring at 5° - 10°C, followed by continuing the stirring at 5° - 15°C for 4 hours. The precipitated crystals were recovered by filtration, washed with water and then with methylene chloride and thoroughly mixed with 70 ml of methanol. To the mixture was added 30 ml of water, followed by allowing to stand to precipitate crystals. The crystals were recovered by filtration and recrystallized from 90% aqueous methanol to obtain 7.5 g of 2,4-bis(2'-acetoxybenzamido)-benzoic acid having a melting point between 194° - 195°C.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([O:14][C:15]3[CH:20]=[CH:19][N:18]=[C:17]4[CH:21]=[C:22]([C:24]5[CH:29]=[CH:28][C:27]([CH2:30][N:31]6[CH2:36][CH2:35][N:34]([C:37](=[O:40])[CH2:38][OH:39])[CH2:33][CH2:32]6)=[CH:26][N:25]=5)[S:23][C:16]=34)=[C:10]([F:41])[CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[C:42]([NH:49][C@H:50]([C:54](O)=[O:55])[CH:51]([CH3:53])[CH3:52])([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43].C1CCC(N=C=NC2CCCCC2)CC1.CO.C(Cl)Cl>CN(C1C=CN=CC=1)C.CN(C=O)C>[C:45]([O:44][C:42]([NH:49][C@@H:50]([CH:51]([CH3:53])[CH3:52])[C:54]([O:39][CH2:38][C:37]([N:34]1[CH2:33][CH2:32][N:31]([CH2:30][C:27]2[CH:26]=[N:25][C:24]([C:22]3[S:23][C:16]4[C:17](=[N:18][CH:19]=[CH:20][C:15]=4[O:14][C:11]4[CH:12]=[CH:13][C:8]([NH:7][C:5]([NH:4][CH:1]5[CH2:2][CH2:3]5)=[O:6])=[CH:9][C:10]=4[F:41])[CH:21]=3)=[CH:29][CH:28]=2)[CH2:36][CH2:35]1)=[O:40])=[O:55])=[O:43])([CH3:48])([CH3:47])[CH3:46]
Reactant: O=C(Nc1ccc(Oc2ccnc3cc(-c4ccc(CN5CCN(C(=O)CO)CC5)cn4)sc23)c(F)c1)NC1CC1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CO
Solvent: CN(C)C=O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC(=O)N1CCN(Cc2ccc(-c3cc4nccc(Oc5ccc(NC(=O)NC6CC6)cc5F)c4s3)nc2)CC1
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.5 %

Procedure:
To a stirred solution of 74 (117 mg, 0.20 mmol), Boc-L-valine (132 mg, 0.61 mmol) and DMAP (25 mg, 0.20 mmol) in anhydrous DMF (4 ml) under nitrogen was added DCC reagent (251 mg, 1.22 mmol), and the reaction mixture was stirred at rt for 24 h. The reaction mixture was partitioned between AcOEt and a saturated aqueous solution of sodium bicarbonate. After separation, the organic layer was successively washed with a saturated aqueous solution of sodium bicarbonate, a saturated aqueous solution of ammonium chloride and brine, dried over anhydrous magnesium sulfate, filtered and concentrated. The residue was purified by Biotage (Snap 25 g cartridge; MeOH/DCM: 1/99 to 10/90 over 20 CV, then 10/90 over 5 CV), to afford the desired product 74-A (151 mg, 0.195 mmol, 96% yield) as a colorless-white sticky foam. MS (m/z): 776.7 (M+H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=S)[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.F[B-](F)(F)F.C([O+](CC)CC)C.[N:39]#[C:40][NH2:41].C(N(CC)CC)C>ClCCl.O>[Cl:1][C:2]1[C:3]([CH3:26])=[C:4]([S:8]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([C:17](=[N:41][C:40]#[N:39])[NH:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)[CH2:12]2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: N#CN
Reactant: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=S)NC2CCCCC2)C1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1c(Cl)cccc1S(=O)(=O)N1CCC[C@H](C(=NC#N)NC2CCCCC2)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of Example 34 (200 mg, 0.48 mmol) in dichloromethane (15 mL) was added triethyloxonium tetrafluoroborate (0.96 mL, 0.96 mmol, 1 Min dichloromethane) and the mixture was stirred at room temperature for overnight. The reaction mixture was then heated to 50° C. for 3 more days with continued stirring. The reaction mixture was cooled, concentrated and triturated in ether. The obtained product was dissolved in ethanol (2 mL) and cyanamide (61 mg, 1.4 mmol) and triethylamine (0.2 mL, 1.4 mmol) were added. After stirring, at 80° C. for 16 hours, the reaction mixture was cooled, diluted with water (10 mL) and extracted with ethyl acetate (3×10 mL). The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by column chromatography using an Analogix® Intelliflash 280™ (SiO2, 0-100% of ethyl acetate in hexanes). 1H NMR (300 MHz, DMSO-d6) δ ppm 1.04-1.34 (m, 5H), 1.44-1.91 (m, 9H), 2.60 (s, 3H), 2.60-2.70 (m, 1H), 2.83-2.98 (m, 1H), 3.08 (t, J=11.4 Hz, 1H), 3.64 (t, 3H), 7.47 (t, J=8.3 Hz, 1H), 7.80 (dd, J=8.1, 1.0 Hz, 1H), 7.83-7.89 (m, 1H), 8.31 (d, J=7.5 Hz, 1H); MS (ESI+) m/z 423 (M+H)+. Anal. Calculated for C20H27ClN4O2S: C, 56.79; H, 6.43; N, 13.29. Found: C, 56.42; H, 6.41; N, 12.98.
Reaction SMILES: S([NH:11][C:12]([NH:14][C:15]1[N:37]=[C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:17]2[N:16]=1)=[O:13])(C1C=CC(C)=CC=1)(=O)=O.[CH2:38](N)[CH3:39].CCN(CC)CC>C1COCC1.CN(C=O)C>[CH2:38]([NH:11][C:12]([NH:14][C:15]1[N:37]=[C:18]2[CH:19]=[C:20]([C:31]3[CH:32]=[N:33][CH:34]=[CH:35][CH:36]=3)[CH:21]=[C:22]([NH:23][CH:24]3[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]3)[N:17]2[N:16]=1)=[O:13])[CH3:39]
Reactant: CCN
Reactant: Cc1ccc(S(=O)(=O)NC(=O)Nc2nc3cc(-c4cccnc4)cc(NC4CCN(C)CC4)n3n2)cc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cccnc3)cc(NC3CCN(C)CC3)n2n1

Procedure:
The product of Step 2 (312 mg, 0.60 mol) and ethyl amine (3 mL of a 2 M solution in THF) in DMF (2 mL) was microwaved at 100° C. for 1 h. The homogeneous solution was pre-adsorbed onto SiO2. Silica gel chromatography (5% NEt3/0-5% MeOH/EtOAc) gave an oil which was triturated with EtOAc/hexane to afford the target compound 1-ethyl-3-[5-(1-methyl-piperidin-4-ylamino)-7-pyridin-3-yl[1,2,4]triazolo[1,5-a]pyridin-2-yl]-urea. MS m/z 395 (M+H+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]1([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:17][O:16][C:15]([CH3:19])([CH3:18])[O:14][CH2:13]1)[CH:6]=[CH:5]2.[F:28][C:29]([F:40])([F:39])[C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1.C(Cl)Cl>C(N(CC)CC)C>[CH3:18][C:15]1([CH3:19])[O:16][CH2:17][C:12]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])([C:7]2[CH:6]=[CH:5][C:4]3[C:9](=[CH:10][CH:11]=[C:2]([O:1][C:34]4[CH:33]=[CH:32][CH:31]=[C:30]([C:29]([F:40])([F:39])[F:28])[CH:35]=4)[CH:3]=3)[CH:8]=2)[CH2:13][O:14]1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc3cc(O)ccc3c2)COC(C)(C)OC1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NC1(c2ccc3cc(Oc4cccc(C(F)(F)F)c4)ccc3c2)COC(C)(C)OC1
Reaction time: 10 h
Yield: 62 %

Procedure:
[5-(6-Hydroxy-naphthalen-2-yl)-2,2-dimethyl-1,3-dioxinan-5-yl]-carbamic acid tert-butyl ester (Example 13, 50.0 mg, 0.000134 mol), 3-(trifluoromethyl)phenylboronic acid (50.8 mg, 0.000268 mol), cupric acetate (24.3 mg, 0.000134 mol) were placed in a vial, purged with N2, following by methylene chloride (2 mL, 0.03 mol) and triethylamine to (0.0933 mL, 0.000669 mol) at 23° C. The reaction was allowed to stir for about for 10 hours, and filtrated. The crude material was then purified via chromatography (SiO2, 4 g, 0-35%) to give a pure product (43 mg, 62%). 1H NMR (CHLOROFORM-d) δ: 7.84 (d, J=8.8 Hz, 1H), 7.79 (s, 1H), 7.73 (d, J=8.5 Hz, 1H), 7.55 (dd, J=8.7, 1.6 Hz, 1H), 7.41-7.49 (m, 1H), 7.31-7.40 (m, 2H), 7.16-7.30 (m, 3H), 5.57 (br. s., 1H), 4.22-4.29 (m, 2H), 4.14 (d, J=11.3 Hz, 2H), 1.49-1.58 (m, 6H), 1.36 (br. s., 9H). MS (M-113): 404.20.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].[CH:14]([NH2:17])([CH3:16])[CH3:15].CCN(CC)CC>CO>[CH:14]([NH:17][S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11])([CH3:16])[CH3:15]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: CC(C)N
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)NS(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h
Yield: 63 %

Procedure:
To the solution of 2-nitrobenzene-1-sulfonyl chloride (1.11 g, 5.0 mmol) in MeOH (30 mL) was added isopropylamine (0.85 mL, 2.0 eq) and Et3N (1.4 mL, 2.0 eq). The mixture was stirred overnight at room temperature. The solvent was removed and the crude was purified by silica gel chromatography to obtain the desired product N-isopropyl-2-nitrobenzenesulfonamide (0.774 g, isolated yield 63%).
Reaction SMILES: Cl[C:2]([O:4][CH3:5])=[O:3].[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH2:18])[C:13]1=[O:19])[CH3:11])[CH3:7].CN1CCOCC1>ClCCl>[CH2:6]([O:8][C:9](=[O:20])[CH:10]([N:12]1[CH2:17][CH2:16][CH2:15][CH:14]([NH:18][C:2]([O:4][CH3:5])=[O:3])[C:13]1=[O:19])[CH3:11])[CH3:7]
Reactant: CCOC(=O)C(C)N1CCCC(N)C1=O
Reactant: COC(=O)Cl
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: CCOC(=O)C(C)N1CCCC(NC(=O)OC)C1=O
Yield: 75 %

Procedure:
Methyl chloroformate (192 μL, 2.5 mmol) was added to a solution of 2-(3-amino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (353 mg, 1.6 mmol) and 4-methylmorpholine (907 μL, 8.24 mmol) in dichloromethane (10 mL). After 15 minutes the mixture was diluted with dichloromethane (20 mL) and washed with water (10 mL), and aqueous hydrogen chloride (0.5 N, 10 mL). The organic phase was dried over sodium sulfate and filtered. The solvent was removed under reduced pressure to provide 2-(3-methoxycarbonylamino-2-oxo-piperidin-1-yl)-propionic acid ethyl ester (332 mg, 1.2 mmol, 75%). C12H20N2O5 calculated 272.1 observed [M+1]+ 273.0; rt=1.82 min.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([OH:28])=O)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.[CH3:34][NH:35][CH3:36].CN(C(ON1N=NC2C1=CC=CC=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C.Cl>CN(C)C=O>[CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:22][C:23]([C:29]4[S:30][CH:31]=[CH:32][N:33]=4)=[CH:24][C:25]=3[C:26]([N:35]([CH3:36])[CH3:34])=[O:28])[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:9][CH:8]=2)(=[O:5])=[O:6])[CH2:2][CH2:3]1
Reactant: CNC
Reactant: O=C(O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(-c2nccs2)[nH]c1C(CC1CCOCC1)c1ccc(S(=O)(=O)C2CC2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
To a solution of 2-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-5-(1,3-thiazol-2-yl)-1H-pyrrole-3-carboxylic acid (0.066 g) in N,N-dimethylformamide (5 mL) were added N,N-dimethylamine (0.038 mL), 0-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (57 mg) and N,N-diisopropylethylamine (0.069 mL), and the mixture was stirred at room temperature for 16 hr. To the reaction mixture was added 1M hydrochloric acid, and the mixture was extracted with ethyl acetate. The extract was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:hexane=70:30-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.058 g, yield 84%) as colorless crystals. MS: 514 (MH+). melting point 180-182° C.
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:11](=[O:12])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:9])[NH:7][C:5]1=[O:6].[C:25]1(C2(C3C=CC=CC=3)C(=O)NC(=O)NC2=O)C=CC=CC=1.COCN1C(=O)C(C2C=CC=CC=2)(C2C=CC=CC=2)C(=O)N(COC)C1=O>>[CH3:1][O:2][CH:3]([N:4]1[C:11](=[O:12])[C:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:8](=[O:9])[NH:7][C:5]1=[O:6])[CH3:25]
Reactant: O=C1NC(=O)C(c2ccccc2)(c2ccccc2)C(=O)N1
Reactant: COCN1C(=O)NC(=O)C(c2ccccc2)(c2ccccc2)C1=O
Agent: COCN1C(=O)N(COC)C(=O)C(c2ccccc2)(c2ccccc2)C1=O
Product: COC(C)N1C(=O)NC(=O)C(c2ccccc2)(c2ccccc2)C1=O

Procedure:
To the aqueous phase was added hydrochloric acid (32%, 0.32 L), while keeping the temperature below 20° C. The methanol was then distilled out of the mixture at reduced pressure, and the resulting precipitate was filtered and dried to provide a crude product (0.366 kg) containing 1-methoxymethyl-5,5-diphenylbarbituric acid (78% w/w), 5,5-diphenylbarbituric acid (6% w/w), and 1,3-bis(methoxymethyl)-5,5-diphenylbarbituric acid (2.7% w/w).
Reaction SMILES: [SH2]=N.C(O)(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[CH2:12]([NH:16][C:17](=[O:19])[OH:18])[CH2:13][CH2:14][CH3:15].C1(O)C=CC=CC=1.[OH-].[Na+]>O>[CH2:12]([NH:16][C:17](=[O:18])[O:19][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)[CH2:13][CH2:14][CH3:15]
Reactant: CCCCNC(=O)O
Reactant: O=C(O)c1ccccc1
Agent: N=[SH2]
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: Oc1ccccc1
Product: CCCCNC(=O)Oc1ccccc1
Reaction time: 5 h
Yield: 64.2 %

Procedure:
5 g N-butyl-carbamic acid benzoic acid sulfimide are suspended in the mixture of 1.67 g of phenol and 50 ml of water, then while stirring (5 hours), a solution of 0.71 g of sodium hydroxide in 50 ml water is added. After stirring another 3 hours, the mixture is extracted with 2×30 ml of ether. The ethereal extracts are dried with sodium sulfate, then the solvent is evaporated in a vacuum at a temperature not above 30° C. 2.15 g of phenyl N-butyl-carbamate are obtained, which can be distilled at 146°-148° C. at 2 mmHg.