Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1O)[CH:5]=[O:6].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].[C:22]([O-:25])([O-])=O.[K+].[K+]>CC(C)=O>[CH2:12]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:25][CH2:22][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:5]=[O:6])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: O=C([O-])[O-]
Reactant: CCCCCCCCCCBr
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [K+]
Solvent: CC(C)=O
Product: CCCCCCCCCCOc1ccc(C=O)cc1OCCCCCCCCCC
Temperature: 25 °C
Reaction time: 24 h
Yield: 52.9 %

Procedure:
3,4-Dihydroxybenzaldehyde (10 g., 72.4 mmol, 1 equiv.) is dissolved in 150 mL of acetone. 1-Bromodecane (45.1 mL, 0.217 mol, 3 equiv.) is added, followed by K2CO3 (10 g., 72.4 mmol, 1 equiv.), and the mixture heated to reflux for 24 hrs. At this time the reaction was incomplete, and another 10 grams of K2CO3 was added and heating continued for 24 hours. The mixture is allowed to cool to room temperature, and is partitioned between ether and water. The aqueous layer is extracted thrice with ether, and the combined organic phases are washed with brine, dried (MgSO4), and evaporated. Upon evaporation, tan crystals formed, and these were collected. Further evaporation yielded another crop of crystals. A total of 16 grams of 3,4-didecyloxybenzaldehyde (38.3 mmol, 53%) was obtained (for an alternative synthesis of this compound see Strzelecka, H.; et al. Mol. Cryst. Liq. Cryst. 1988, 156 (Part A), 347): mp=59.5°-60.5° C.; UVmax (EtOH) 232 nm (ε=15472), 276 nm (ε=11079), 206 nm (ε=9806), 310 nm (ε=9273); 1H NMR (300 MHz, CDCl3) δ 9.81 (s, 1H, CHO), 7.39 (dd, J=2, 8 Hz, 1H, ArH), 7.37 (d, J=2 Hz, 1H, ArH), 6.93 (d, J=8 Hz, 1H, ArH), 4.04 (m, 4H, RCH2O), 1.83 (m, 4H, RCH2CH2O), 1.46 (m, 4H, decyl), 1.25 (m, 24H, decyl), 0.86 (m, 6H, 2×CH3); 13C NMR (75 MHz, CDCl3) δ 190.98 (C=O), 154.68, 149.44, 129.87, 126.57, 111.76, 110.97, 69.13, 31.90, 29.57, 29.34, 29.07, 28.98, 25.97, 25.94, 22.68, 14.10; IR (KBr) 2956, 2922, 2850, 1688, 1674, 1596, 1586, 1510, 1278, 1134, 808 cm-1 ; MS (DCI) m/e 419 (MH+). Anal. Calcd for C27H46O3 : C, 77.46; H, 11.07. Found: C, 77.19; H, 10.99.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14].C(Cl)(=O)C([Cl:18])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11]([Cl:18])=[O:12])[CH:9]=[CH:10][C:5]=2[O:4][C:3]1=[O:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: Cn1c(=O)oc2ccc(C(=O)O)cc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cn1c(=O)oc2ccc(C(=O)Cl)cc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carboxylic acid (935 mg, obtained in Example 116, step 5) in CH2Cl2 (15 mL) were added two drops of DMF and oxalylchloride (0.66 mL). The mixture was stirred at room temperature for 1 hour and was then concentrated to dryness. 1,2-Dimethoxyethane (20 mL) was added and the solvent was evaporated again. The resulting solid was dried at high vacuum over night to give the crude acid chloride (3-methyl-2-oxo-2,3-dihydro-benzooxazole-5-carbonyl chloride). To a suspension of zinc powder (633 mg) in 1,2-dimethoxyethane (10 mL) was added tetrakis(triphenyl-phosphine)palladium(0) (56 mg). A suspension of the acid chloride in 1,2-dimethoxyethane (10 mL) was added. The mixture was cooled in an ice bath and a solution of 4-bromo-1-bromomethyl-2-trifluoromethyl-benzene (1.54 g, [CAS Reg. No. 335013-18-8]) in 1,2-dimethoxyethane (10 mL) was slowly added over a period of 15 minutes. The mixture was stirred for 10 minutes at 0° C. and then for 18 hours at r.t. The reaction mixture was poured into ice and basified with sat. NaHCO3. The aqueous phase was then extracted two times with ethyl acetate and the organic layers were washed with brine, dried over Na2SO4, filtered and the solvent was evaporated. The residue was purified by flash chromatography (silica gel, heptane:ethyl acetate=1:1) to give the title compound as a yellow oil (944 mg, 47%). MS (neg. ion, m/e)=414.1 [(M−H)−].
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][NH:13][CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15].C(N(CC)CC)C.[S:24]1[CH:28]=[CH:27][CH:26]=[C:25]1[S:29](Cl)(=[O:31])=[O:30]>C(Cl)Cl>[CH3:1][C:2]1([CH3:16])[N:7]([CH2:8][C@H:9]2[CH2:14][N:13]([S:29]([C:25]3[S:24][CH:28]=[CH:27][CH:26]=3)(=[O:31])=[O:30])[CH2:12][CH2:11][NH:10]2)[CH2:6][CH2:5][NH:4][C:3]1=[O:15]
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: CC1(C)C(=O)NCCN1C[C@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1(C)C(=O)NCCN1C[C@H]1CN(S(=O)(=O)c2cccs2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.7 %

Procedure:
A 20-mL vial was charged with 3,3-dimethyl-4-((2R)-2-piperazinylmethyl)-2-piperazinone (0.104 g, 0.461 mmol), triethylamine (0.200 mL, 1.44 mmol), and CH2Cl2 (3 mL). To this mixture thiophene-2-sulfonyl chloride (0.0951 g, 0.521 mmol, Sigma-Aldrich, St. Louis, Mo.) in CH2Cl2 (1 mL) was added drop wise at room temperature. The clear solution was stirred at room temperature for 30 min and then the mixture was concentrated and dissolved in CH2Cl2 (20 mL). The organic phase was washed with water (2×20 mL) and saturated aqueous NaCl (20 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated in vacuo to afford 3,3-dimethyl-4-(((2S)-4-(2-thiophenylsulfonyl)-2-piperazinyl)methyl)-2-piperazinone (0.166 g) as an off-white foam.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23].O.[CH3:28][N:29](C)C=O>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-]#N.[Zn+2].[C-]#N>[C:28]([C:2]1[N:7]2[N:8]=[C:9]([CH3:20])[C:10]([C:11]3[C:16]([CH3:17])=[CH:15][C:14]([CH3:18])=[CH:13][C:12]=3[CH3:19])=[C:6]2[N:5]=[C:4]([CH3:21])[C:3]=1[C:22]([O:24][CH2:25][CH3:26])=[O:23])#[N:29]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Solvent: O
Product: CCOC(=O)c1c(C)nc2c(-c3c(C)cc(C)cc3C)c(C)nn2c1C#N
Temperature: 150 °C
Reaction time: 4 h

Procedure:
Tetrakis(triphenylphosphine)palladium (0) (691 mg, 0.592 mmol) and zinc cyanide (402 mg, 3.25 mmol) were added to a solution of ethyl 7-chloro-3-mesityl-2,5-dimethylpyrazolo[1,5-a]pyrimidin-6-carboxylate (1.1 g, 2.96 mmol) in N,N-dimethylformamide (10 mL), followed by stirring at 150° C. for four hours. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with brine, dried over anhydrous magnesium sulfate and evaporated, and the residue was purified by silica gel column chromatography (15% ethyl acetate/hexane), to give the title compound (1 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[NH:11][C:12]([NH2:14])=[NH:13].O=[C:16]([C:23]1[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=1)[CH2:17][C:18](OCC)=[O:19]>CN1CCCC1=O.C(O)C>[OH:19][C:18]1[N:14]=[C:12]([NH:11][C:3]2[CH:4]=[C:5]([N+:8]([O-:10])=[O:9])[CH:6]=[CH:7][C:2]=2[CH3:1])[N:13]=[C:16]([C:23]2[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:17]=1
Reactant: CCOC(=O)CC(=O)c1cccnc1
Reactant: Cc1ccc([N+](=O)[O-])cc1NC(=N)N
Solvent: CN1CCCC1=O
Solvent: CCO
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nc(O)cc(-c2cccnc2)n1
Temperature: 150 °C

Procedure:
40 g (2-methyl-5-nitrophenyl)guanidine in 160 mL N-methyl pyrrolidone is dissolved. The mixture is heated to 150° C. and ethyl β-oxo-3-pyridine propionate is added portionwise, to 50 g total in a time period of 5 hours, distillating about 15 g of by-products under a nitrogen flow. At the end of the reaction, the mixture is cooled and diluted with ethanol. The precipitate is filtrated, yielding, upon drying, 46.4 g of product with HPLC purity of 99% (A %), identified through LC-MS and 1H-NMR.
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]1[C@@H:13]2[C@@H:8]([C@@:9]([OH:23])([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4].[N:24]1([CH2:30][C:31](O)=[O:32])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>>[CH3:1][O:2][C:3]([N:5]1[C@H:13]2[C@H:8]([C@:9]([O:23][C:31](=[O:32])[CH2:30][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)([C:14]#[C:15][C:16]3[CH:17]=[C:18]([CH3:22])[CH:19]=[CH:20][CH:21]=3)[CH2:10][CH2:11][CH2:12]2)[CH2:7][CH2:6]1)=[O:4]
Reactant: O=C(O)CN1CCOCC1
Reactant: COC(=O)N1CC[C@H]2[C@@H]1CCC[C@]2(O)C#Cc1cccc(C)c1
Product: COC(=O)N1CC[C@@H]2[C@H]1CCC[C@]2(C#Cc1cccc(C)c1)OC(=O)CN1CCOCC1

Procedure:
Synthesis in analogy to the General Method 1 starting from (3aS,4R,7aS)-4-hydroxy-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester and morpholin-4-yl-acetic acid to yield (3aR,4S,7aR)-4-(2-morpholin-4-yl-acetoxy)-4-m-tolylethynyl-octahydro-indole-1-carboxylic acid methyl ester. MS [M+H]=296 (ester elimination ion); RT=6.574 min; LC-MS Method III
Reaction SMILES: Cl[CH:2]([CH3:5])[CH:3]=[CH2:4].[CH3:6][O:7][CH:8]([O:16][CH3:17])[CH2:9][NH:10][C:11](=[O:15])[O:12][CH2:13][CH3:14].[OH-].[K+].O>CN(C)C=O>[CH2:4]=[CH:3][CH:2]([N:10]([CH2:9][CH:8]([O:7][CH3:6])[O:16][CH3:17])[C:11](=[O:15])[O:12][CH2:13][CH3:14])[CH3:5]
Reactant: CCOC(=O)NCC(OC)OC
Reactant: C=CC(C)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Product: C=CC(C)N(CC(OC)OC)C(=O)OCC

Procedure:
22 g (0.24 mol) of 3-chloro-1-butene are added to 35.5 g (0.2 mol) of ethyl N-(2,2-dimethoxyethyl)-carbamate and 26 g of powdered potassium hydroxide in 400 ml of dimethylformamide and the mixture is warmed overnight to 40° C. The salts are dissolved with water and the mixture is extracted several times with methylene chloride. The organic extracts are dried over potassium carbonate and concentrated, and the residue is distilled.
Reaction SMILES: [S:1](=[O:39])(=[O:38])([O:3][CH2:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)[C:14]=3[CH:13]=[CH:12]2)[CH2:8][C@@H:7]1[O:30][Si](C(C)(C)C)(C)C)[NH2:2].N1C=CC=CC=1.O1CCCC1.F.N1C=CC=CC=1>>[S:1](=[O:39])(=[O:38])([O:3][CH2:4][CH2:5][C@@H:6]1[CH2:10][C@@H:9]([N:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([NH:20][C@@H:21]4[C:29]5[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=5)[CH2:23][CH2:22]4)[C:14]=3[CH:13]=[CH:12]2)[CH2:8][C@@H:7]1[OH:30])[NH2:2]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1C[C@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@H]1CCOS(N)(=O)=O
Agent: F
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: NS(=O)(=O)OCC[C@@H]1C[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)C[C@@H]1O
Temperature: 0 °C
Reaction time: 1 h
Yield: 12.9 %

Procedure:
2-((1S,2S,4R)-2-{[tert-Butyl(dimethyl)silyl]oxy}-4-{4-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-7H-pyrrolo[2,3-d]pyrimidin-7-yl}cyclopentyl)ethyl sulfamate (0.0442 g, 0.0773 mmol) was dissolved in pyridine (0.344 mL, 4.25 mmol) and tetrahydrofuran (0.345 mL, 4.25 mmol). The solution was cooled to 0° C. Pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added dropwise. The solution was warmed to room temperature. After one hour, pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. After two hours, pyridine hydrofluoride (0.500 mL, 5.55 mmol) was added. The solution was stirred for 24 h. The reaction was quenched with dropwise addition of saturated sodium bicarbonate, and the mixture was extracted with EtOAc. The combined organic extracts were dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by silica gel chromatography, eluting with 0 to 5% MeOH in EtOAc, to give the title compound (0.005 g, 0.01 mmol). 1H NMR (CD3OD, 400 MHz, δ): 8.17 (s, 1H), 7.28-7.12 (m, 5H) 6.67 (d, J=3.61 Hz 1H) 5.58 (t, J=7.44, 7.44 Hz 1H), 5.48-5.40 (m, 1H), 4.40-4.35 (m, 1H), 4.28-4.17 (m, 2H), 3.10-3.02 (m, 1H), 2.98-2.88 (m, 1H), 2.68-2.47 (m, 1H), 2.57-2.47 (m, 1H), 2.38-1.98 (m, 5H), 1.89-1.80 (m, 1H) ppm. LC/MS: Rt=1.25 min, ES+ 458 (FA standard).
Reaction SMILES: [C:1]([NH:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28]CC=C)([O:3][CH2:4][CH:5]1[C:17]2[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=2)[C:11]2[C:6]1=[CH:7][CH:8]=[CH:9][CH:10]=2)=[O:2].C(N([CH2:37][CH3:38])CC)C.CCCCCCC.[OH2:46]>ClCCl.CO>[C:1]([N:18]([CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[CH2:38][CH:37]=[O:46])([O:3][CH2:4][CH:5]1[C:6]2[C:11](=[CH:12][CH:13]=[CH:14][CH:7]=2)[C:10]2[C:17]1=[CH:16][CH:15]=[CH:8][CH:9]=2)=[O:2]
Reactant: C=CCCCCCCCCCCCNC(=O)OCC1c2ccccc2-c2ccccc21
Reactant: CCN(CC)CC
Reactant: O
Solvent: CO
Solvent: ClCCl
Solvent: CCCCCCC
Product: CCCCCCCCCCN(CC=O)C(=O)OCC1c2ccccc2-c2ccccc21
Temperature: -65 °C
Reaction time: 3 h
Yield: 61 %

Procedure:
A three-necked, 1000 mL round bottom flask equipped with a magnetic stir bar and a gas inlet tubing was charged with N-FMOC-N-allyldecylamine (˜0.099 mol) in dichloromethane (280 mL) and methanol (50 mL). The mixture was cooled in a −65° C. dry ice-chloroform bath and purged with a stream of dilute ozone in oxygen for 2.5 hours (internal temperature about −55° C.; flow rate for dilute ozone in oxygen about 1.0 L/min). The reaction was monitored by HPLC (retention time for starting material=7.96 min; retention time for product=5.82 min). Upon disappearance of the allyl starting material, ozone purging was discontinued and the mixture was purged with nitrogen for 20 minutes to remove excess ozone. The reaction mixture was then treated with triethylamine (24.8 mL, 0.178 mol) at −55° C., warmed to 21° C., and stirred for 3 hours. The reaction mixture was washed with water (50 mL); 0.01 N HCl (50 mL) and the organic layer was concentrated in vacuo to give an oil. Heptane (150 mL) was added and the mixture was concentrated in vacuo to azeotropically remove water and dichloromethane. This azeotropic procedure was repeated two more times using heptane (150 mL) to give a final volume of about 100 mL. The resulting organic solution was charged to a 200 mL three-necked round bottom flask and cooled to 15° C. in a water bath. Pieces of ice were added slowly to the water bath to cool the mixture to 5° C. in a period of 40 minutes (the mixture was seeded at approximately 10° C.). The cloudy mixture was further cooled to −10° C. and stirred for 2.5 hours. The resulting suspension was filtered through a Buchner funnel and the precipitate was washed with ice cold heptane (20 mL×2). The precipitate was collected and dried in vacuo (25 mmHg) for 6 hours to give N-FMOC-2-(n-decylamino)acetaldehyde (25.6 g; 61% yield; 99% purity) as a white waxy powder.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4](SC)[N:3]=1.OO.Cl.[CH3:23][CH:24]([CH:26]1[CH2:30][CH2:29][CH2:28][NH:27]1)[CH3:25].[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32]>C(N(CC)CC)C.O1CCOCC1>[C:31]([OH:37])([C:33]([F:36])([F:35])[F:34])=[O:32].[NH2:1][C:2]1[N:7]=[C:6]([C:8]2[CH:16]=[C:15]3[C:11]([C:12]([NH2:17])=[N:13][NH:14]3)=[CH:10][CH:9]=2)[CH:5]=[C:4]([N:27]2[CH2:28][CH2:29][CH2:30][CH:26]2[CH:24]([CH3:25])[CH3:23])[N:3]=1
Reactant: CC(C)C1CCCN1
Reactant: CSc1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Agent: Cl
Agent: OO
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CC(C)C1CCCN1c1cc(-c2ccc3c(N)n[nH]c3c2)nc(N)n1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To 6-[2-amino-6-(methylthio)-4-pyrimidinyl]-1H-indazol-3-amine (0.25 g, 0.92 mmol) in TFA (8.74 mL) at 0° C. was added aqueous H2O2 (0.375 mL, 3.67 mmol, 30% (w/w)) dropwise over 2 minutes. Upon completion of the addition, the reaction was allowed to warm to room temperature. After 2 hours, the reaction mixture was cooled back to 0° C. and quenched with dimethyl sulfide (0.54 mL, 7.34 mmol, dropwise addition). The reaction was allowed to warm to room temperature and stirred for 1 hour. The mixture was cooled to 0° C. and diluted with Et2O (5 mL) Et2O and hexane (15 mL). The resulting orange precipitate was filtered and transferred to a 25 mL sealable tube under nitrogen. 1,4-Dioxane (5.83 mL), 2-(1-methylethyl)pyrrolidine hydrochloride (0.275 g, 1.84 mmol), and triethylamine (0.51 mL, 3.67 mmol) were added, the tube was sealed, and the reaction mixture was stirred overnight at 95° C. Since LCMS showed a minimal amount of product, additional triethylamine (1 mL) was added, and the reaction mixture was stirred overnight at 95° C. The reaction was cooled to room temperature and decanted. The solution was concentrated, and the resulting oil was dissolved in a mixture of 50/50 CH3CN/H2O w/0.1 mL TFA. The resulting mixture was filtered through a 0.45μ frit and purified on a Gilson RPHPLC (CH3CN/H2O w/0.1% TFA) to afford a TFA salt of the title compound (12 mg) as a yellow solid as a mixture of rotamers. LC-MS (ES) m/z=338 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 0.75-0.99 (m, 6H), 1.79-2.04 (m, 4H), 3.58-3.88 (m, 3H), 4.26 (m, 1H), 4-5 (bs), [6.59 (s) and 6.65 (s)] (1H), [7.33 (d, J=8.6 Hz) and 7.37 (d, J=8.6 Hz)] (1H), [7.69 (s) and 7.73 (s)] (1H), 7.91 (d, J=8.6 Hz, 1H), 12.04 (bs, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][CH:7]=[C:6]([C:13]([NH:15][N:16]1[CH2:20][CH2:19][N:18]([S:21]([NH:24][C:25]([N:27]3[CH2:30][CH:29]([NH:31][C:32](=[O:41])OCC4C=CC=CC=4)[C:28]3=[O:42])=[O:26])(=[O:23])=[O:22])[C:17]1=[O:43])=[O:14])[CH2:5]2.CN([Si](C)(C)C)C(=[O:51])C(F)(F)F.[NH2:56][C:57]1[S:58][CH:59]=[C:60](/[C:62](=[N:66]/[O:67][C:68]([CH3:86])([CH3:85])[C:69]([O:71][CH:72]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C:73]2[CH:78]=[CH:77][CH:76]=[CH:75][CH:74]=2)=[O:70])/C(O)=O)[N:61]=1>CN(C)C=O.[Pd]>[NH2:56][C:57]1[S:58][CH:59]=[C:60]([C:62](=[N:66][O:67][C:68]([CH3:86])([CH3:85])[C:69]([O:71][CH:72]([C:79]2[CH:84]=[CH:83][CH:82]=[CH:81][CH:80]=2)[C:73]2[CH:74]=[CH:75][CH:76]=[CH:77][CH:78]=2)=[O:70])[C:32]([NH:31][CH:29]2[CH2:30][N:27]([C:25]([NH:24][S:21]([N:18]3[CH2:19][CH2:20][N:16]([NH:15][C:13]([C:6]4[C:5](=[O:51])[C:4]5[C:9](=[CH:10][C:11]([OH:12])=[C:2]([OH:1])[CH:3]=5)[NH:8][CH:7]=4)=[O:14])[C:17]3=[O:43])(=[O:23])=[O:22])=[O:26])[C:28]2=[O:42])=[O:41])[N:61]=1
Reactant: O=C(NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)C3=CNc4cc(O)c(O)cc4C3)C2=O)C1=O)OCc1ccccc1
Reactant: CC(C)(O/N=C(\C(=O)O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)C(F)(F)F)[Si](C)(C)C
Agent: [Pd]
Solvent: CN(C)C=O
Product: CC(C)(ON=C(C(=O)NC1CN(C(=O)NS(=O)(=O)N2CCN(NC(=O)c3c[nH]c4cc(O)c(O)cc4c3=O)C2=O)C1=O)c1csc(N)n1)C(=O)OC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
To a solution of [1-[[[[3-[[(1,4-dihydro-6,7-dihydroxy-3-quinolinyl)carbonyl]amino]-2-oxo-1-imidazolidinyl]sulfonyl]amino]carbonyl]-2-oxo-3-azetidinyl]carbamic acid, phenylmethyl ester (3.35 g, 5.3 mmol) in 60 ml of N,N-dimethylformamide, N-methyl-N-trimethylsilyl trifluoroacetamide (5.28 g, 26.5 mmol) was added. After 30 minutes, 1.68 g of palladium on carbon was added, and the mixture was hydrogenolyzed for 1 hour. The catalyst was removed by filtration and the filtrate added to a solution of (Z)-2-amino-α-[[2-(diphenylmethoxy)-1,1-dimethyl-2-oxoethoxy]imino]-4-thiazoleacetic acid, 1-benzotriazole ester (2.96 g, 5.3 mmol) in 30 ml of N,N-dimethylformamide. After stirring for 20 hours, the solvent was distilled off and the residue triturated with 60 ml of water and 75 ml of ethyl acetate. The resulting crystals were filtered off, washed with water and dried in vacuo to give 3.27 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[C:24]([NH2:25])=[CH:23][N:22]=[CH:21][N:20]=2)=[CH:14][CH:13]=1.C1N=CN([C:31](N2C=NC=C2)=[O:32])C=1>C1COCC1>[CH3:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[O:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:31](=[O:32])[NH:25][C:24]3[C:19]2=[N:20][CH:21]=[N:22][CH:23]=3)=[CH:14][CH:13]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: Cn1c(Oc2ccc(Nc3ncncc3N)cc2)nc2ccccc21
Solvent: C1CCOC1
Product: Cn1c(Oc2ccc(-n3c(=O)[nH]c4cncnc43)cc2)nc2ccccc21
Yield: 65 %

Procedure:
A solution of N4-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}pyrimidine-4,5-diamine (80 mg) and CDI (39 mg) in THF (20 mL) was refluxed for 3 h. CDI (39 mg) was added to the mixture. After refluxing overnight, the mixture was concentrated in vacuo. The residual solid was washed with AcOEt to give 9-{4-[(1-methyl-1H-benzimidazol-2-yl)oxy]phenyl}-7,9-dihydro-8H-purin-8-one (56 mg) as white crystals.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:9]=[CH:8][CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[C:4]=1[NH2:5].Cl[C:14]([O:16][CH2:17][C:18](Cl)(Cl)Cl)=[O:15].C(O)[C:23]1[CH:28]=[CH:27]C=[CH:25][CH:24]=1>C1COCC1>[CH2:17]([O:16][C:14](=[O:15])[NH:5][C:4]1[C:6]([N+:10]([O-:12])=[O:11])=[CH:7][CH:8]=[CH:9][C:3]=1[O:2][CH3:1])[C:18]1[CH:27]=[CH:28][CH:23]=[CH:24][CH:25]=1
Reactant: OCc1ccccc1
Reactant: COc1cccc([N+](=O)[O-])c1N
Reactant: O=C(Cl)OCC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: COc1cccc([N+](=O)[O-])c1NC(=O)OCc1ccccc1
Temperature: 60 °C

Procedure:
To a solution of 2-methoxy-6-nitroaniline (2g; 0.0119 moles) in anhydrous THF (20 ml), trichloroethyl chloroformate (1.43 ml; 0.01189 moles) was added dropwise. The reaction was heated for 45 minutes at 60° C., the solvent was then removed under vacuum and the crude residue was dissolved in dioxane (20 ml). To this solution, benzyl alcohol (2.46 ml; 0.0237 mmoles) was added and the reaction mixture was refluxed for 8 hours. The solvent was then removed under vacuum and the crude residue was poured into diluted 10% HCl. The title compound was extracted into ethyl ether. The crude brown oil was crystallized with diisopropyl ether to give a light brown solid. 1.9 g; m.p. 78-80° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][NH:15][C:17]1[CH:26]=[CH:25][C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CN
Reactant: Clc1ccc2ccccc2n1
Product: CC(C)(C)OC(=O)N1CCCCC1CNc1ccc2ccccc2n1
Yield: 5.6 %

Procedure:
The title compound (0.11 g) was prepared from (S) 2-aminomethyl-piperidine-1-carboxylic acid tert butyl ester (1.23 g) and 2-chloroquinoline (1 g) according to the procedure of D8.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[C:12]([CH2:18][N:19]3[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]([CH:28]([CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH2:29][CH2:30][CH3:31])[C:20]3=[O:37])[CH:13]=[C:14]([Br:17])[CH:15]=2)[CH:10]=[C:9]1[O:38]C(OC(C)(C)C)=O)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH3:36][O:35][C:33](=[O:34])[CH2:32][CH:28]([N:21]1[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[N:19]([CH2:18][C:12]2[CH:13]=[C:14]([Br:17])[CH:15]=[C:16]3[C:11]=2[CH2:10][C:9](=[O:38])[NH:8]3)[C:20]1=[O:37])[CH2:29][CH2:30][CH3:31]
Reactant: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2cc(OC(=O)OC(C)(C)C)n3C(=O)OC(C)(C)C)c2ccccc21
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCC(CC(=O)OC)n1c(=O)n(Cc2cc(Br)cc3c2CC(=O)N3)c2ccccc21
Reaction time: 1 h
Yield: 46.4 %

Procedure:
6-Bromo-2-tert-butoxycarbonyloxy-4-[3-(1-methoxycarbonylmethyl-butyl)-2-oxo-2,3-dihydro-benzoimidazol-1-ylmethyl]-indole-1-carboxylic acid tert-butyl ester (200 mg, 0.28 mmol) is dissolved in dichloromethane (5 mL) and then trifluoroacetic acid is added (2 mL). The reaction is stirred for 1 hour then evaporated in vacuo to give an oil that is purified by preparative reverse phase LC to give the title compound (63 mg 0.13 mmol 44%). LCMS (ESMS): m/z 487.6 (M+H+).