Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([Cl:12])[CH:11]=1)[CH2:8][N:7]([CH3:13])[CH2:6][CH:5]2[C:14]1[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C[CH2:25][N:26]([CH:30]([CH3:32])C)[CH:27]([CH3:29])C.[CH2:33]([NH2:38])[CH2:34][CH2:35][CH2:36][NH2:37]>C(Cl)(Cl)Cl>[CH2:33]([NH:38][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:32]2[C:4]3[C:29](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:27][N:26]([CH3:25])[CH2:30]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21])[CH2:34][CH2:35][CH2:36][NH:37][S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:5]2[C:4]3[C:9](=[C:10]([Cl:12])[CH:11]=[C:2]([Cl:1])[CH:3]=3)[CH2:8][N:7]([CH3:13])[CH2:6]2)=[CH:15][CH:16]=1)(=[O:22])=[O:21]
Reactant: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)Cl)cc2)C1
Reactant: CCN(C(C)C)C(C)C
Reactant: NCCCCN
Solvent: ClC(Cl)Cl
Product: CN1Cc2c(Cl)cc(Cl)cc2C(c2ccc(S(=O)(=O)NCCCCNS(=O)(=O)c3ccc(C4CN(C)Cc5c(Cl)cc(Cl)cc54)cc3)cc2)C1
Reaction time: 8 h
Yield: 13.1 %

Procedure:
To a solution of 4-(6,8-dichloro-2-methyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (intermediate 10.6) (150 mg, 0.353 mmol) in chloroform (0.706 mL) was added DIEA (182 mg, 1.412 mmol) and a solution of butane-1,4-diamine (15.5 mg, 0.176 mmol) in chloroform (0.176 mL). The reaction was stirred overnight at which point the solvent was removed and the resulting residue brought up in 50% IPA/H2O. Purification by preparative HPLC gave the title compound (18.4 mg) as a TFA salt. 1H-NMR (400 MHz, CD3OD): δ7.86 (d, 4H), 7.53 (s, 2H), 7.45 (d, 4H), 6.84 (s, 2H), 4.73 (m, 3H), 4.46 (d, 2H), 3.86 (dd, 2H), 3.57 (t, 2H), 3.12 (s, 6H), 2.84 (m, 4H), 1.41 (m, 4H). MS (m/z): 797.15 (M+H).
Reaction SMILES: [ClH:1].[NH2:2][C:3]1[NH:4][CH2:5][CH2:6][CH2:7][N:8]=1.[OH-].[Na+].[O-:11]S([O-])(=O)=O.[Na+].[Na+].[CH3:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[C:20]=1[N:26]=[C:27]=[O:28]>C1COCC1.C(Cl)Cl>[OH2:11].[ClH:1].[CH3:25][C:21]1[CH:22]=[CH:23][CH:24]=[C:19]([CH3:18])[C:20]=1[NH:26][C:27]([NH:2][C:3]1[NH:8][CH2:7][CH2:6][CH2:5][N:4]=1)=[O:28]
Reactant: O=S(=O)([O-])[O-]
Reactant: NC1=NCCCN1
Reactant: Cc1cccc(C)c1N=C=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: C1CCOC1
Product: Cc1cccc(C)c1NC(=O)NC1=NCCCN1
Product: O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of 8.13 g (0.060 mol) of 2-amino-1,4,5,6-tetrahydropyrimidine hydrochloride, 5.0 g (0.0625 mol) of 50% NaOH and 75 ml of THF was stirred for 0.5 hours at room temperature and then 10.0 g Na2SO4 was added. After stirring for 0.5 hours, a solution of 5.89 g (0.040 mol) of 2,6-dimethylphenyl isocyanate in 50 ml of THF was added over a period of 0.5 hours. After stirring for 1 hour, the reaction mixture was diluted with 100 ml of CH2Cl2, filtered, the filtrate evaporated in vacuo and the residue dissolved in 25 ml of 10% HCl and 50 ml of H2O with warming. After filtration through a pad of diatomaceous earth, chilling in ice gave the crystalline hydrochloride which was recrystallized from cold H2O affording 8.78 g (55%). This material was dried in vacuo (20° C., 5 mm Hg) to constant weight giving N-(2,6-dimethylphenyl)-N'-(1,4,5,6-tetrahydropyrimidin-2-yl)urea monohydrochloride hydrate (10:10:11); m.p. (110) 214.5°-216.5° C. dec.; IR (CHCl3) 3226, 1710, 1676, 1641 cm-1 ; UV max. (MeOH) 270 shl (ε1,000) and 233 nm (ε18,300).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14].[F:16][C:17]1[CH:22]=[CH:21][C:20](I)=[CH:19][CH:18]=1.C([O-])([O-])=O.[K+].[K+].CN1CCCC1=O>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([C:20]1[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=1)[CH:6]=[C:5]2[CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: O=C(O)CCc1c[nH]c2ccc(Cl)cc12
Reactant: Fc1ccc(I)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: O=C(O)CCc1cn(-c2ccc(F)cc2)c2ccc(Cl)cc12
Temperature: 165 °C
Yield: 104.9 %

Procedure:
A mixture of 3-(5-chloro-3-1H-indolyl)propanoic acid (17.5 g, 0.078 mol), 4-fluoroiodobenzene (20.8 g, 0.094 mol), Cul (2.4 g), K2CO3 (21.6 g, 0.16 mol) and N-methyl-2-pyrrolidone (0.20 L) was heated at 165° C. for 7 h. The reaction mixture was cooled to room temperature and water (0.25 L) was added. After acidification with concentrated hydrochloric acid, the mixture was extracted with diethyl ether (2×0.30 L) . The combined organic phases were washed with brine (3×0.40 L) and dried (Na2SO4). Evaporation of the solvents afforded crude 3-[5-chloro-1-(4-fluorophenyl)-3-1H-indolyl]propanoic acid (26 g) as an oil. The oil was dissolved in dry diethyl ether and added to a suspension of lithium aluminum hydride (15 g, 0.40 mol) in dry diethyl ether (0.20 L) over 30 min. After reflux for further 2 h the reaction mixture was cooled to 0° C. and carefully treated with water (15 ml), 4N aqueous NaOH (15 ml) and then water (75 mL). The resulting mixture was filtered and dried (Na2SO4). Evaporation of the solvents afforded the title compound (1a) as an oil (17.6 g, 74%). An analytical sample was crystallized from heptane: mp. 67°-69° C.; 1H NMR (CDCl3) δ 1.55 (broad s, 1 H), 2.00 (qui, 2 H), 2.90 (t, 2 H), 3.75 (t, 2 H), 7.10 (s, 1 H), 7.15 (broad d, 1 H), 7.20 (t, 2 H), 7.35 (d, 1 H), 7.40 (dd, 2 H), 7.60 (broad s,1 H). Anal. (C17H15ClFNO) C, H, N.
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[NH:30]1[CH2:35][CH2:34][CH2:33][CH:32]([C:36](N)=O)[CH2:31]1>C(Cl)Cl>[NH2:1][C@@H:2]([C:13]([N:15]1[CH2:22][CH2:21][CH2:20][C@@H:16]1[C:17]([OH:19])=[O:18])=[O:14])[CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[CH3:36][CH:32]1[CH2:33][CH2:34][CH2:35][N:30]([C:13]([NH2:15])=[O:14])[CH2:31]1
Reactant: NC(=O)C1CCCNC1
Reactant: CC(C)(C)OC(=O)N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Solvent: ClCCl
Product: CC1CCCN(C(N)=O)C1
Product: N[C@H](Cc1c[nH]c2ccccc12)C(=O)N1CCC[C@@H]1C(=O)O
Yield: 68.3 %

Procedure:
Under N2 atmosphere, the Boc-DTrp-DPro-3-piperidinamide was dissolved in 25 ml of CH2Cl2 and 10 ml of trifluoracetic was added while being stirred. The reaction mixture was stirred for 30 min. All volatiles were removed under vacuum and the residue was dissolved in 30 ml of CH2Cl2 and washed with 10 ml saturated NaHCO3 aqueous solution. The organic layer was removed and the aqueous layer was extracted with CH2Cl2 (3×10 ml). The organic layer was dried over anhydrous sodium sulfate, filtered and the solvent removed in vacuum. The residue was further purified by column chromatography (SiO2, CHCl3/MeOH, 85:15) to afford 0.43 mmol (68.3%) of compound (2) which was characterized by TLC and mass spectra, M+=382.46.
Reaction SMILES: [NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:37])[C:16]([N:19]([CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:20](=[O:29])[O:21][CH2:22][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[CH:17][N:18]=[C:13]2[CH2:12][CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51]>C1COCC1>[NH:1]([C:8]([C@H:10]1[N:14]2[C:15](=[O:37])[C:16]([N:19]([CH2:30][C:31]3[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=3)[C:20]([O:21][CH2:22][C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:29])=[CH:17][N:18]=[C:13]2[C@@H:12]([CH2:49][C:50]([O:52][C:53]([CH3:56])([CH3:55])[CH3:54])=[O:51])[CH2:11]1)=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Nc1ccccc1)[C@@H]1CCc2ncc(N(Cc3ccccc3)C(=O)OCc3ccccc3)c(=O)n21
Reactant: CC(C)(C)OC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)C[C@H]1C[C@@H](C(=O)Nc2ccccc2)n2c1ncc(N(Cc1ccccc1)C(=O)OCc1ccccc1)c2=O
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 88.7 %

Procedure:
To a solution of 112a (101.6 mg, 0.205 mmol) in 1 mL THF at −78° C., was added 1N LiHMDS in THF (0.431 mL, 0.431 mmol). The mixture was stirred at −78° C. for 10 min, then t-butyl bromoacetate (30.3 μL, 0.205 mmol) was added, dropwise. The mixture was stirred at −78° C. for 5 h, then quenched with sat. NH4Cl. The mixture was diluted with EtOAc and washed with sat. NH4Cl and brine, dried (Na2SO4), and concentrated. The crude product was purified by flash chromatography to afford 110.7 mg (89%) of 112b. 1H NMR (300 MHz, CDCl3) δ9.38 (br s, 1H), 7.63 (br s, 1H), 7.45 (d, J=8.1, 2H), 7.33-7.17 (m, 12H), 7.02 (t, J=7.3, 1H), 5.17-5.11 (m, 3H), 4.84 (br s, 1H), 4.69 (br s, 1H), 3.62-3.51 (m, 1H), 2.84 (d, J=6.9, 2H), 2.79-2.67 (m, 1H), 2.40 (br s, 1H), 1.43 (s, 9H); MS (ESI) 609.2 (M+H+), 631.2 (M+Na+), 607.2 (M−H+).
Reaction SMILES: [CH2:1]([CH:10]([CH2:49][C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:31])[CH2:17][C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)=[O:19])[CH:13]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:44]=[CH:43][C:42]([N+:45]([O-:47])=[O:46])=[CH:41][CH:40]=2)=[O:36])[CH3:33])[C:12]1=[O:48])[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.C(C1C=CC(S([N:70]=[N+:71]=[N-])(=O)=O)=CC=1)(O)=O.C(N(CC)CC)C>C(#N)C.C(OCC)(=O)C>[CH2:49]([CH:10]([CH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1)[N:11]1[CH:14]([CH2:15][C:16](=[O:31])[C:17]([C:18]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][C:25]([N+:28]([O-:30])=[O:29])=[CH:26][CH:27]=2)=[O:19])=[N+:70]=[N-:71])[CH:13]([CH:32]([O:34][C:35]([O:37][CH2:38][C:39]2[CH:40]=[CH:41][C:42]([N+:45]([O-:47])=[O:46])=[CH:43][CH:44]=2)=[O:36])[CH3:33])[C:12]1=[O:48])[C:50]1[CH:55]=[CH:54][C:53]([O:56][CH3:57])=[CH:52][CH:51]=1
Reactant: [N-]=[N+]=NS(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)CC(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Solvent: CC#N
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: COc1ccc(CC(Cc2ccc(OC)cc2)N2C(=O)C(C(C)OC(=O)OCc3ccc([N+](=O)[O-])cc3)C2CC(=O)C(=[N+]=[N-])C(=O)OCc2ccc([N+](=O)[O-])cc2)cc1
Reaction time: 0.25 h

Procedure:
1.9 g of 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxopropyl]-2-azetidinone and 660 mg of p-carboxybenzenesulfonyl azide were dissolved in 50 ml of dried acetonitrile, and 1.4 ml of triethylamine was added thereto dropwise in a nitrogen stream under ice-cooling. After stirring at that temperature for 15 minutes, the reaction mixture was diluted with ethyl acetate, and the thus formed precipitate was filtered. The filtrate was concentrated under reduced pressure, and the resulting oily residue was subjected to silica gel chromatography to obtain 1-(di-p-anisylmethyl)-3-(1-p-nitrobenzyloxycarbonyloxyethyl)-4-[3-(p-nitrobenzyloxycarbonyl)-2-oxo-3-diazopropyl]-2-azetidinone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[H-].[Na+].[CH3:16]I>O>[CH3:16][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[CH3:16][N:2]1[CH:3]=[C:4]2[C:9]([CH:8]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:6]=[CH:5]2)=[N:1]1
Reactant: CI
Reactant: COC(=O)c1ccc2cn[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: COC(=O)c1ccc2cn(C)nc2c1
Product: COC(=O)c1ccc2cnn(C)c2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of methyl 1H-indazole-6-carboxylate (566 mg, 3.21 mmol) was added NaH (154 mg, 3.85 mmol), the mixture was then stirred at room temperature for 30 min. Methyl iodide (547 mg, 3.85 mmol) was added drop wise, and the reaction mixture was stirred overnight. Cooled to 0° C., added water and extracted with ethyl acetate. The organic phase was concentrated and purified by gel chromatograph to provide 130 mg of methyl 1-methyl-1H-indazole-6-carboxylate and 230 mg of methyl 2-methyl-2H-indazole-6-carboxylate, 59%. 1H NMR for methyl 1-methyl-1H-indazole-6-carboxylate: 1H NMR (400 MHz, CDCl3): δ 3.97 (3H, s), 4.14 (3H, s), 7.74-7.82 (2H, m), 8.02 (1H, s), 8.17 (1H, d, J=0.8 Hz). 1H NMR for methyl 2-methyl-2H-indazole-6-carboxylate: 1H NMR (400 MHz, CDCl3): δ 3.94 (3H, s), 4.25 (3H, s), 7.65-7.72 (2H, m), 7.92 (1H, s), 8.47 (1H, d, J=1.2 Hz). [M+H] Calc'd for C10H10N2O2, 191; Found, 191.
Reaction SMILES: C([Sn](CCCC)(CCCC)[C:6]([O:8]CC)=[CH2:7])CCC.Br[C:20]1[CH:21]=[C:22]([O:34][CH2:35][CH3:36])[C:23]([O:30]COC)=[C:24]([C:26]([CH3:29])([CH3:28])[CH3:27])[CH:25]=1.C(OCC)(=O)C>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([C:24]1[CH:25]=[C:20]([C:6](=[O:8])[CH3:7])[CH:21]=[C:22]([O:34][CH2:35][CH3:36])[C:23]=1[OH:30])([CH3:27])([CH3:28])[CH3:29]
Reactant: C=C(OCC)[Sn](CCCC)(CCCC)CCCC
Reactant: CCOc1cc(Br)cc(C(C)(C)C)c1OCOC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CCOc1cc(C(C)=O)cc(C(C)(C)C)c1O
Temperature: 100 °C
Reaction time: 18 h
Yield: 65.8 %

Procedure:
Tributyl(1-ethoxyvinyl)tin (7.77 g, 21.52 mmol) and Pd(PPh3)4 (1.18 g, 1.02 mmol) were added to a solution of the 5-bromo-1-(tert-butyl)-3-ethoxy-2-(methoxymethoxy)benzene (6.5 g, 20.4 mmol) in toluene (68 ml) and the mixture was stirred at 100° C. for 18 hours. The reaction mixture was cooled to room temperature, ethyl acetate was added, the mixture was washed with 20% aqueous KF and filtered through celite, and the organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. A 1 N HCl aqueous solution (15 ml) was added to a solution of the residue in methanol (80 ml), and the mixture was stirred at room temperature for 2 hours. Saturated sodium hydrogencarbonate solution was added to be basic and extraction was performed with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (3.17 g) as colorless crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([OH:23])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25].Br[CH2:28][C:29]([O:31][CH3:32])=[O:30]>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[CH2:9][N:10]1[C:22]2[CH:21]=[CH:20][CH:19]=[C:18]([O:23][CH2:28][C:29]([O:31][CH3:32])=[O:30])[C:17]=2[C:16]2[C:11]1=[CH:12][CH:13]=[CH:14][C:15]=2[C:24](=[O:26])[NH2:25]
Reactant: NC(=O)c1cccc2c1c1c(O)cccc1n2Cc1c(Cl)cccc1Cl
Reactant: COC(=O)CBr
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2c1c1c(C(N)=O)cccc1n2Cc1c(Cl)cccc1Cl
Reaction time: 0.25 h
Yield: 47.9 %

Procedure:
40% Methanolic Triton B (0.23 mL, 0.49 mM) was added to a solution of the 9-[(2,6-dichlorophenyl)methyl]-4-hydroxy-5-carbamoyl carbazole (146 mg, 0.38 mM) in 5 mL DMF at room temperature. After 15 minutes, methyl bromoacetate (119 mg, 0.76 mM) was added and the resultant mixture stirred at room temperature for 17 hours. The mixture was diluted with ethyl acetate, washed with H2O, 1 N HCl, H2O, sat. NaHCO3, and saturated brine, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by column chromatography on silica gel (elution with ethyl acetate) to afford 83 mg (48%) of the {9-[(2,6-dichlorophenyl)methyl]-5-carbamoylcarbazol-4-yl}oxyacetic acid, methyl ester as a tan solid. 1H NMR (DMSO-d6) δ7.5-7.0 (m, 10H), 6.55 (d, 1H, J=8 Hz), 5.8 (s, 2H), 4.9 (s, 2H), and 3.75 (s, 3H). IR (KBr, cm−1). MS (ES) m/e 457, 459.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[CH:6][CH:7]=1)(=[O:15])[CH3:14]
Reactant: CC(=O)OC(C)=O
Reactant: COC(=O)Cc1ccc(O)cc1
Solvent: c1ccncc1
Product: COC(=O)Cc1ccc(OC(C)=O)cc1
Reaction time: 2 h

Procedure:
10 g (0.06 mol) of methyl 4-hydroxyphenylacetate are treated with 18.36 g (0.18 mol) of acetic anhydride (17 ml) and 1 ml of pyridine and the mixture is heated to boiling for 2 hours. The solvents are largely evaporated in vacuo, the residue is taken up in water and the solution is extracted with ethyl acetate. After drying using sodium sulphate, the solvent is distilled off in vacuo and a pale yellow, thin oil is obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([I:8])=[CH:4][N:3]=1.Cl[CH2:10][CH:11]=O>C(O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[CH:11][N:1]=2)[CH:4]=1
Reactant: O=CCCl
Reactant: Nc1ccc(I)cn1
Solvent: CCO
Product: Ic1ccc2nccn2c1
Temperature: 85 °C

Procedure:
To a solution of the product (480 mg, 2.18 mmol) from Step A in ethanol (12 mL) was added chloroacetaldehyde (50 wt. % in water, 0.336 mL) and the mixture was heated at 85° C. for 3 h. After cooling to room temperature, the solution was concentrated under reduced pressure. The residue was partitioned between saturated aqueous sodium bicarbonate solution and dichloromethane. The organic phase was separated, dried (magnesium sulfate) and concentrated in vacuo to yield the product as light-brown solid which was used without further purification. LC/MS 244.8 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][C:16]([N:18]2[CH2:23][CH2:22][CH2:21][C@@H:20]([C:24](=[O:39])[NH:25][C@H:26]([C:32]3[CH:33]=[N:34][CH:35]=[C:36]([OH:38])[CH:37]=3)[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH2:19]2)=[O:17])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:43][C:44]1[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([F:52])[CH:45]=1.O>CN(C=O)C.[Cl-].[Na+].O.C(OCC)(=O)C>[C:48]([C:47]1[CH:50]=[CH:51][C:44]([CH2:43][O:38][C:36]2[CH:37]=[C:32]([C@@H:26]([NH:25][C:24]([C@@H:20]3[CH2:21][CH2:22][CH2:23][N:18]([C:16](=[O:17])[CH2:15][CH2:14][CH:11]4[CH2:10][CH2:9][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:13][CH2:12]4)[CH2:19]3)=[O:39])[CH2:27][C:28]([O:30][CH3:31])=[O:29])[CH:33]=[N:34][CH:35]=2)=[CH:45][C:46]=1[F:52])#[N:49]
Reactant: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(O)c1
Reactant: N#Cc1ccc(CBr)cc1F
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C[C@H](NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1)c1cncc(OCc2ccc(C#N)c(F)c2)c1
Temperature: 0 °C
Yield: 4.5 %

Procedure:
To tert-butyl-4-{3-[(3R)-3-{[(1S)-1-(5-hydroxypyridin-3-yl)-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate (example 5e, 200 mg, 0.37 mmol) in DMF (5 mL) was added sodium hydride (60%, 9.6 mg, 0.24 mmol) and the mixture was cooled to 0° C. 4-(Bromomethyl)-2-fluorobenzonitrile (70.5 mg, 0.33 mmol) in DMF (3 mL) was added while stirring and the mixture was warmed to room temperature. After one hour water, brine and ethyl acetate were added. Phases were separated and the aqueous phase was extracted with ethyl acetate. The combined extracts were dried over sodium sulfate and concentrated in vacuum. The residue was purified by preparative HPLC to yield 10 mg of tert-butyl 4-{3-[(3R)-3-{[(1S)-1-{5-[(4-cyano-3-fluorobenzyl)oxy]pyridin-3-yl}-3-methoxy-3-oxopropyl]carbamoyl}piperidin-1-yl]-3-oxopropyl}piperidine-1-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])([CH3:4])(C)C.FC(F)(F)C(O)=O.[C:22]1(OC)[CH:27]=[CH:26]C=[CH:24][CH:23]=1>ClCCl>[CH2:1]([O:5][C:6]([NH:8][C@H:9]1[C@H:12]([CH3:13])[NH:11][C:10]1=[O:14])=[O:7])[C:4]1[CH:26]=[CH:27][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1NC(=O)[C@H]1NC(=O)OC(C)(C)C
Reactant: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@@H]1NC(=O)[C@H]1NC(=O)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
A solution of 3.3 g of (3S-trans)-3-t-butoxycarbonylamino-4-methylazetidinone in 10 ml each of dichloromethane and anisole was cooled to 0° C. and 112 ml of trifluoroacetic acid was added. The solution was stirred for 90 minutes and evaporated in vacuo (benzene added and evaporated three times). The residue was dissolved in 70 ml of acetone and the solution was adjusted to pH 7 with 5% sodium bicarbonate solution. A total of 5.33 g of benzyl chloroformate was added over 1 hour at pH 6.5-7.5. The mixture was stirred for 30 minutes at pH 7, diluted with 100 ml of saturated salt, and extracted with ethyl acetate (three 400 ml portions). The residue obtained by evaporation was chromatographed on a 1 liter silica gel column. Elution with chloroform-ethyl acetate (4:1) gave 2.19 g of compound. Crystallization from ether-hexane yielded 1.125 g of the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[N:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=2)=[CH:4][N:3]=1.Cl[C:16]([O:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)=[O:17].O>N1C=CC=CC=1>[OH:14][C:11]1[CH:12]=[CH:13][C:8]([C:5]2[N:6]=[CH:7][C:2]([NH:1][C:16](=[O:17])[O:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[N:3][CH:4]=2)=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: Nc1cnc(-c2ccc(O)cc2)cn1
Solvent: O
Solvent: c1ccncc1
Product: O=C(Nc1cnc(-c2ccc(O)cc2)cn1)Oc1ccccc1
Reaction time: 1 h

Procedure:
To solution of 2-amino-5-(4-hydroxyphenyl)pyrazine (283 mg) in pyridine (20 mL) was added under ice-cooling phenyl chloroformate (199 μL) and the mixture was stirred for 1 hour. The reaction mixture was poured into water (30 mL) and extracted with ethyl acetate (20 mL×3). The organic layer was washed with saturated saline solution and then dried over anhydrous Na2SO4. The concentration of the solvent left a crystal residue, which was washed with diethyl ether (10 mL) to give the subject compound (314 mg).
Reaction SMILES: [CH3:1][N:2]([CH3:4])[CH3:3].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([Cl:15])[N:7]=1>CN(C)C=O>[Cl-:15].[NH2:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][CH:11]=[N:12]2)=[C:8]([N+:2]([CH3:4])([CH3:3])[CH3:1])[N:7]=1
Reactant: Nc1nc(Cl)c2[nH]cnc2n1
Reactant: CN(C)C
Solvent: CN(C)C=O
Product: C[N+](C)(C)c1nc(N)nc2nc[nH]c12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Anhydrous trimethylamine was bubbled through a solution of 2-amino-6-chloropurine (10 g, 59 mmol) in anhydrous N,N-dimethylformamide (80 ml) for 30 min and the reaction stirred at room temperature for 12 h under a stream of nitrogen. The crude product was collected by filtration, dissolved in the minimum amount of cold water and the product precipitated out by the addition of acetone. The title compound was collected as a white solid (9.96 g, 74%)(m.p. 205-206° C.). (Found C, 41.8; H, 5.6; N, 36.9 C10H13N5O requires C, 42.1; H, 5.7; N, 36.8%). νmax/cm−1 3460 (NH2), 3320 (NH), 1640 (C═C), 1570 (C═C); λmax (CH3OH)/nm 316; δH (200 MHz, d6-DMSO) 13.40 (1H, br s, NH), 8.35 (1H, s, C(8)H), 7.10 (2H, s, NH2), 3.70 (9H, s, N(CH3)3); δC (50.3 MHz, d6-DMSO) 159.5 (C6), 154.9 (C2), 153.5 (C4), 135.0 (C8), 113.6 (C5), 37.8 (3×CH3); m/z (FAB) 192 (M+—Cl, 8%), 178 (MH+—CH3Cl, 72), 163 (MH+—(CH3)2Cl, 35), 149 (MH2+—(CH3)3Cl, 100), 134 (MH+—N(CH3)3Cl, 45).
Reaction SMILES: O[C:2]1[C:3]2[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[NH2:16][C@@H:17]([C:33]1[CH:38]=[CH:37][C:36]([F:39])=[C:35]([CH3:40])[CH:34]=1)[CH2:18][N:19]([CH3:32])S(C1C=CC([N+]([O-])=O)=CC=1)(=O)=O>>[F:39][C:36]1[CH:37]=[CH:38][C:33]([C@H:17]([NH:16][C:2]2[C:3]3[N:11]=[CH:10][CH:9]=[C:8]([C:12]([NH2:14])=[O:13])[C:4]=3[N:5]=[CH:6][N:7]=2)[CH2:18][NH:19][CH3:32])=[CH:34][C:35]=1[CH3:40]
Reactant: Cc1cc([C@H](N)CN(C)S(=O)(=O)c2ccc([N+](=O)[O-])cc2)ccc1F
Reactant: NC(=O)c1ccnc2c(O)ncnc12
Agent: Cl
Product: CNC[C@@H](Nc1ncnc2c(C(N)=O)ccnc12)c1ccc(F)c(C)c1

Procedure:
Compound 67 was prepared following general synthesis scheme 7 wherein 4-hydroxypyrido[3,2-d]pyrimidine-8-carboxamide (G) was reacted with N—[(S)-2-Amino-2-(4-fluoro-3-methyl-phenyl)-ethyl]-N-methyl-4-nitro-benzenesulfonamide hydrochloride to give the title compound. LC/MS [355 (M+H)]1H NMR (400 MHz, DMSO-d6) δ 9.97 (s, 1H), 9.07 (s, 1H), 8.99 (d, 1H), 8.54 (s, 1H), 8.38 (d, 1H), 8.17 (s, 1H), 7.38 (m, 1H), 7.30 (m, 1H), 7.07 (m, 1H), 5.45 (s, 1H), 3.15 (dd, 1H), 2.89 (dd, 1H), 2.32 (s, 3H), 2.21 (s, 3H).