Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([N+:12]([O-])=O)=[N:10][CH:11]=2)[CH2:3]1>C(O)C.C(OCC)(=O)C>[CH3:1][CH:2]1[CH2:5][N:4]([C:6]2[CH:7]=[CH:8][C:9]([NH2:12])=[N:10][CH:11]=2)[CH2:3]1
Reactant: CC1CN(c2ccc([N+](=O)[O-])nc2)C1
Solvent: CCOC(C)=O
Solvent: CCO
Product: CC1CN(c2ccc(N)nc2)C1
Reaction time: 3 h
Yield: 101 %

Procedure:
A 250-mL Parr reactor bottle was purged with nitrogen and charged with 10% palladium on carbon (50% wet, 800 mg dry weight) and a solution of 236a (2.58 g, 13.4 mmol) in a mixture of ethanol (25 mL) and ethyl acetate (25 mL). The bottle was attached to a Parr hydrogenator, evacuated, charged with hydrogen gas to a pressure of 50 psi and shaken for 3 h. After this time, the hydrogen was evacuated, and nitrogen was charged into the bottle. Celite 521 (3.50 g) was added, and the mixture was filtered through a pad of Celite 521. The filter cake was washed with ethanol (2×50 mL), and the combined filtrates were concentrated to dryness under reduced pressure to afford a quantitative yield of 236b (2.21 g) as a purple oil: 1H NMR (500 MHz, DMSO-d6) d 7.19 (d, 1H, J=3.0 Hz), 6.66 (dd, 1H, J=9.0, 3.0 Hz), 6.36 (d, 1H, J=8.5 Hz), 5.13 (br s, 2H), 3.81 (t, 2H, J=7.5 Hz), 3.21 (t, 2H, J=6.5 Hz), 2.70 (m, 1H), 1.18 (d, 3H, J=7.0 Hz); MS (ESI+) m/z 164.1 (M+H).
Reaction SMILES: [C:1]([NH:4][CH2:5][CH2:6][SH:7])(=[O:3])[CH3:2].C1CCN2C(=NCCC2)CC1.[CH3:19][N:20]([CH3:49])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:35]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[CH:33]=[C:32]([CH2:43]OS(C)(=O)=O)[N:31]=2)=[CH:26][CH:25]=1)=[O:22]>C(#N)C>[CH3:49][N:20]([CH3:19])[C:21]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]2[N:31]=[C:32]([CH2:43][S:7][CH2:6][CH2:5][NH:4][C:1](=[O:3])[CH3:2])[CH:33]=[C:34]([N:36]3[CH2:41][CH2:40][O:39][CH2:38][C@@H:37]3[CH3:42])[N:35]=2)=[CH:26][CH:25]=1)=[O:22]
Reactant: C[C@H]1COCCN1c1cc(COS(C)(=O)=O)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Reactant: CC(=O)NCCS
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: CC(=O)NCCSCc1cc(N2CCOC[C@@H]2C)nc(-c2ccc(NC(=O)N(C)C)cc2)n1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
N-Acetylcysteamine (0.064 mL) was dissolved in acetonitrile (5 mL). DBU (0.141 mL) was then added to the solution and was allowed to stir at RT for 5 minutes. 1,1-Dimethyl-3-[4-[4-[(3S)-3-methylmorpholin-4-yl]-6-(methylsulfonyloxymethyl)pyrimidin-2-yl]phenyl]urea (154 mg) was suspended in acetonitrile (5 mL) and added to the thiol. The reaction was left to stir at RT of 1 hour then concentrated in vacuo to give the desired material.
Reaction SMILES: [NH2:1][C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:9])[NH2:8].[OH-].[Na+].[C:15](Cl)(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26].[C:29]([OH:32])(=O)[CH3:30]>O.CC(C)=O>[C:15]([N:1]([C:29](=[O:32])[CH2:30][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24])[C@H:2]([C:10]([OH:12])=[O:11])[CH2:3][CH2:4][CH2:5][NH:6][C:7](=[NH:8])[NH2:9])(=[O:27])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(=O)O
Reactant: N=C(N)NCCC[C@H](N)C(=O)O
Reactant: CCCCCCCCCCCC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: CCCCCCCCCCCC(=O)N(C(=O)CCCCCCCCCCC)[C@@H](CCCNC(=N)N)C(=O)O
Reaction time: 8 h

Procedure:
Two grams (0.01148 mole) of L-(+) arginine were dissolved in a solution of 30 ml of water and 20 ml of acetone. To this solution were added, at room temperature, 10 ml of a 5M sodium hydroxide solution, followed immediately by the addition of one-half of a solution prepared by dissolving 5.02 gram (0.02296 mole) of lauroyl chloride in 10 ml of acetone. Fifteen minutes later, identical portions of the sodium hydroxide and lauroyl chloride solutions were added. The reaction mixture was allowed to stir overnight. The pH of the reaction mixture was then adjusted to 6 with glacial acetic acid which resulted in the precipitation of a white solid. The solid was collected by filtration and was washed with water. The washed solid then was air-dried and recrystallized from chloroform-acetone. The yield of Nα,NG -dilauroylarginine having the formula below was 0.980 gram (24.4%). ##STR4## Exactly the same procedure was used to prepare the following Nα,NG -diacyl derivatives of arginine:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([OH:28])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:29]1(P(C2C=CC=CC=2)C2C=CC=CC=2)[CH:34]=CC=C[CH:30]=1.C(O)(C)C.CC(OC(/N=N/C(OC(C)C)=O)=O)C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:25]=[C:26]([O:28][CH:29]([CH3:34])[CH3:30])[CH:27]=1)[C:12]([NH:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([O:23][CH3:24])=[O:22])=[CH:17][CH:16]=1)=[O:13])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1ccc(NC(=O)c2cc(O)cc(OCc3ccccc3)c2)nc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Solvent: C1CCOC1
Solvent: CC(C)O
Product: COC(=O)c1ccc(NC(=O)c2cc(OCc3ccccc3)cc(OC(C)C)c2)nc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 78.5 %

Procedure:
Methyl 6-[(3-benzyloxy-5-hydroxybenzoyl)amino]-3-pyridinecarboxylate(2.20 g, 5.81 mM), triphenylphosphine (1.59 g, 6.10 mM), iso-propanol (0.445 ml, 5.81 mM) and THF (50 ml) were combined and diisopropylazodicarboxylate (1.2 ml, 6.10 mM) was added dropwise. The reaction was stirred for 72 hours at ambient temperature. The mixture was concentrated in vacuo and the resulting brown oil was purified by column chromatography on Kieselgel 60, eluting with a gradient of 50–100% methylene chloride in iso-hexane and then 5% EtOAc in methylene chloride to give methyl 6-[(3-benzyloxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate as a colourless oil (1.92 g); H1 NMR δ (d6-CDCl3) 1.36 (6H d) 3.95 (3H s) 4.60 (1H sept) 5.09 (2H s) 6.72 (1H s) 7.02 (1H s) 7.10 (1H s) 7.30–7.50 (4H m) 8.39 (2H ddd) 8.68 (1H s br) 8.92 (1H s). [M+H] 421; [M-H] 419.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[CH:6][CH:7]=1.[OH:11][C:12]1[CH:17]=[CH:16][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:14][CH:13]=1.C(N(CC)CC)C>CN(C=O)C.C(O[Cu]OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:11][C:12]1[CH:13]=[CH:14][C:15]([C@@H:18]2[C:23]3=[N:24][S:25](=[O:29])(=[O:28])[CH2:26][CH2:27][N:22]3[CH2:21][CH2:20][CH2:19]2)=[CH:16][CH:17]=1
Reactant: OB(O)c1cccc(Cl)c1
Reactant: O=S1(=O)CCN2CCC[C@H](c3ccc(O)cc3)C2=N1
Agent: CC(=O)O[Cu]OC(C)=O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@H](c3ccc(Oc4cccc(Cl)c4)cc3)C2=N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
A mixture of 3-chlorophenylboronic acid (167 mg), (9R)-9-(4-hydroxyphenyl)-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazine 2,2-dioxide (100 mg), diacetoxycopper (130 mg), triethylamine (0.248 mL), and powdered 4A MS (1.50 g) in DMF (10 mL) was stirred at room temperature overnight. The mixture was added with NH silica gel, concentrated in vacuo, and purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) to give the title compound (32.0 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[S:22][C:23]=1[C:24]([O:26]CC)=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].O>C1COCC1.CO>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH:11]([C:19]1[N:20]=[C:21]([N:29]2[CH2:30][CH2:31][O:32][CH2:33][CH2:34]2)[S:22][C:23]=1[C:24]([OH:26])=[O:25])[C:12]1[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1sc(N2CCOCC2)nc1C(CCNC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(C)(C)OC(=O)NCCC(c1ccc(Cl)cc1)c1nc(N2CCOCC2)sc1C(=O)O
Temperature: 25 °C
Reaction time: 72 h
Yield: 105.5 %

Procedure:
To a solution of ethyl 4-{3-[(tert-butoxycarbonyl)amino]-1-(4-chlorophenyl)propyl}-2-(morpholin-4-yl)-1,3-thiazole-5-carboxylate (0.322 g, 0.631 mmol) in THF (7.8 mL) and MeOH (2.6 mL) was added a solution of sodium hydroxide in water (1 M, 7.76 mL, 7.76 mmol). The solution was stirred at room temperature for 3 days. The solvents were evaporated and the residue was diluted with water then 1N hydrogen chloride aqueous solution was added until pH 7 was reached. The mixture was extracted twice with EA and the combined organic layers were washed with brine then dried over anhydrous sodium sulfate and concentrated to give the product (0.321 g, 105%) which was used directly in the next step. LCMS: (AA) ES+ 482, 484.
Reaction SMILES: [C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([OH:13])=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:18]1([C:24]([O:26]O)=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(OCC)C.ClCCl.C(OCC)C>[C:1]([O:5][C:6]([O:8][C:9]1[CH:17]=[CH:16][CH:15]=[CH:14][C:10]=1[C:11]([O:13][O:26][C:24](=[O:25])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:12])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Oc1ccccc1C(=O)O
Reactant: O=C(OO)c1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)Oc1ccccc1C(=O)OOC(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 3 h
Yield: 47.2 %

Procedure:
3 g (13 mmol) of 2-(tert-butoxycarbonyloxy)benzoic acid and 1.8 g (13 mmol) of benzenecarboperoxoic acid (prepared as described in Example 1-3) are dissolved in a diethyl ether/dichloromethane 6/4 mixture. The solution is cooled to 0° C. and then 2.6 g (13 mmol) of N,N′-dicyclohexylcarbodiimide dissolved in 50 ml of diethyl ether are added dropwise. After stirring at 0° C. for 3 hours, the reaction medium is filtered and then concentrated to dryness. The residue is purified by chromatography on silica gel eluted with a pentane/dichloromethane 4/6 mixture. 2.2 g of (2-(tert-butoxycarbonyloxy)benzoyl)benzoyl peroxide are obtained in the form of a white solid with a yield of 49%.
Reaction SMILES: [I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[NH:4][N:3]=1.C(N=C(N(C)C)N(C)C)(C)(C)C.Cl.Cl[CH2:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]([F:38])([F:37])[F:36])=[CH:31][N:30]=1>CC#N>[I:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[N+:11]([O-:13])=[O:12])[N:4]([CH2:28][C:29]2[CH:34]=[CH:33][C:32]([C:35]([F:37])([F:36])[F:38])=[CH:31][N:30]=2)[N:3]=1
Reactant: O=[N+]([O-])c1cccc2[nH]nc(I)c12
Reactant: FC(F)(F)c1ccc(CCl)nc1
Agent: CN(C)C(=NC(C)(C)C)N(C)C
Agent: Cl
Solvent: CC#N
Product: O=[N+]([O-])c1cccc2c1c(I)nn2Cc1ccc(C(F)(F)F)cn1
Reaction time: 0.08 h
Yield: 54.4 %

Procedure:
To a round bottom flask was added 3-iodo-4-nitro-1H-indazole (0.580 g, 2.01 mmol) and CH3CN (10 mL). 2-tert-Butyl-1,1,3,3-tetramethylguanidine (0.890 mL, 4.41 mmol) was added and the mixture was stirred for 5 minutes. 2-(Chloromethyl)-5-(trifluoromethyl)pyridine hydrochloride (0.512 g, 2.21 mmol) was added as a CH3CN solution (4 mL) and the mixture was stirred at ambient temperature overnight. The mixture was concentrated and diluted with saturated aqueous NH4Cl (20 mL) and EtOAc (60 mL). The layers were mixed and separated and the organic phase was washed with brine, dried over Na2SO4, filtered and concentrated. The crude product was purified by column chromatography (50% EtOAc/hexane) to provide 0.490 g (54%) of the product as an orange solid.
Reaction SMILES: [CH:1]1[C:6]([C:7]([O:9]OC(C)(C)C)=[O:8])=[CH:5]C=CC=1.N([CH2:22][CH2:23][CH2:24][C:25]#N)=N[CH2:17][CH2:18][CH2:19][C:20]#N.[C:27]1(C)[CH:32]=CC=[CH:29][CH:28]=1>>[CH3:32][CH2:27][CH2:28][CH2:29][CH:23]([CH2:22][O:9][C:7]([CH:6]=[CH2:5])=[O:8])[CH2:24][CH3:25].[CH3:17][CH2:18][CH2:19][CH2:20][O:9][C:7]([CH:6]=[CH2:1])=[O:8]
Reactant: N#CCCCN=NCCCC#N
Reactant: Cc1ccccc1
Reactant: CC(C)(C)OOC(=O)c1ccccc1
Product: C=CC(=O)OCC(CC)CCCC
Product: C=CC(=O)OCCCC
Temperature: 100 °C
Reaction time: 10 h

Procedure:
To a monomeric mixture of the formulation shown in Table 8 were added 10 g of tert-butyl perbenzoate and 30 g of azobisbutyronitrile. The mixture was then added dropwise over the course of 4 hours to 1,000 ml of toluene heated at 100° C. The reaction was further continued for 10 hours at 100° C, and then the toluene was removed to provide an acrylic copolymer resin having a number average molecular weight of about 20,000 and an oxirane group content of 2,150 g·eq/106 g and a softening point of 110° C. Powder paints were prepared in the same way as in Example 1 except that the polyester and the acrylic resin in the amounts shown in Table 9 were used instead of the polyester A and triglycidyl isocyanurate. The powder paints were coated, and baked at a temperature of 200° C for 30 minutes. The resulting coatings had a film thickness of 60 to 65μ and the properties shown in Table 10.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)[Cl:2].[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9][SH:10]>>[Cl:6][CH2:7][CH:8]([OH:11])[CH2:9][S:10][CH2:4][CH:3]([OH:5])[CH2:1][Cl:2]
Reactant: ClCC1CO1
Reactant: OC(CS)CCl
Product: OC(CCl)CSCC(O)CCl

Procedure:
Epichlorohydrin (5563 g, 60.12 mol) and methanol (2500 g) were put into a 10-liter reactor. The reaction temperature was adjusted to 6° C. When the reaction temperature reached 6° C., sodium hydroxide (50% aq., 5 g) was added to the mixture. NaSH.xH2O (70% NaSH, 3660 g, 45.75 mol), methanol (1000 g) and water (500 g) were completely dissolved with stirring in another 10-liter reactor, and hydrochloric acid was slowly added dropwise thereto to generate hydrogen sulfide gas. The hydrogen sulfide gas was added to the epichlorohydrin solution to obtain bis(3-chloro-2-hydroxypropyl)sulfide. The completion of the reaction was defined as the time when epichlorohydrin and 3-chloro-2-hydroxy-propane-1-thiol disappeared completely and bis(3-chloro-2-hydroxypropyl)sulfide was formed, which was confirmed by GC. When 3-chloro-2-hydroxy-propane-1-thiol was present, the content of the thiol compound was calculated from the relative integral ratio by GC and epichlorohydrin was further added in an amount corresponding to the calculated content. The reaction of epichlorohydrin and the thiol compound afforded bis(3-chloro-2-hydroxypropyl)sulfide (BCPS).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1.[CH2:18]([N:20]=[C:21]=[O:22])[CH3:19]>C(Cl)(Cl)Cl>[CH2:18]([NH:20][C:21]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]1[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]1)=[O:22])[CH3:19]
Reactant: CCN=C=O
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Solvent: ClC(Cl)Cl
Product: CCNC(=O)Nc1ccc2[nH]cc(C3CCN(C)CC3)c2c1
Yield: 81.8 %

Procedure:
To a solution of 15.0 mg (0.0655 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole in 3.0 mL chloroform were added 9.3 mg (0.131 mMol) ethyl isocyanate. The reaction was mixed for 48 hours and to it were then added 0.23 gm (0.131 mMol) aminomethylated polystyrene and the reaction mixed for an additional 18 hours. The reaction mixture was then filtered and the volatiles evaporated to give 16.1 mg (82%) of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([SH:13])[N:5]=1.Cl[CH2:15][CH:16]([OH:39])[CH2:17][N:18]1[CH2:23][CH2:22][N:21]([CH:24]([C:32]2[CH:37]=[CH:36][C:35]([F:38])=[CH:34][CH:33]=2)[C:25]2[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=2)[CH2:20][CH2:19]1.CO>CN(C=O)C.C(Cl)Cl>[CH3:3][C:4]1[N:12]=[C:11]2[C:7]([NH:8][CH:9]=[N:10]2)=[C:6]([S:13][CH2:15][CH:16]([OH:39])[CH2:17][N:18]2[CH2:19][CH2:20][N:21]([CH:24]([C:32]3[CH:33]=[CH:34][C:35]([F:38])=[CH:36][CH:37]=3)[C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:22][CH2:23]2)[N:5]=1
Reactant: OC(CCl)CN1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Reactant: Cc1nc(S)c2[nH]cnc2n1
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1nc(SCC(O)CN2CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC2)c2[nH]cnc2n1
Reaction time: 72 h
Yield: 23.7 %

Procedure:
To NaH (2.4 mmol, 115 mg, 50% in oil, pentane washed and decanted), in DMF (5 mL) was added 2-methyl-6-mercaptopurine (400 mg, 2.4 mmol) in portions, at 0° After stirring 2 h 1-(1-chloro-2-hydroxy-3-propanyl)-4-(4,4'- difluorobenzhydryl)piperazine (2.4 mmol, 0.914 g) was added in DMF (5 mL) dropwise over 15 min, at 0° C., under nitrogen. After three days, the solution was filtered and the DMF removed from the filtrate in vacuo (vacuum oven, 1 mm Hg, 60° C.) to give the crude product. Silica gel flash column chromatography using 10% MeOH:CH2Cl2 gave the product with DMF. This product was dried 72 h in vacuo (room temperature, 1 mm Hg) to give pure product (290 mg, 23.2%). mp 83°-86° C. (dec.) DCI/MS (M+1)=511. (300 MHz) 1H NMR (CDCl3)δ: 8.1 (s, 1H), 7.3 (m, 4H), 6.95 (m, 4H), 4.2 (s, 1H), 4.15 (m, 1H), 3.4 and 3.6 (d of d, 2H), 2.65 (s, 3H), 2.6 (M, 6H), 2.4 (m, 4H).
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[OH:27])=[CH:10][CH:9]=1)=[O:5])[CH3:2].Br[CH2:29][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:31]=1>>[CH2:1]([O:3][C:4]([CH:6]=[CH:7][C:8]1[CH:9]=[CH:10][C:11]([CH:14]2[CH2:19][CH2:18][N:17]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:16][CH:15]2[O:27][CH2:29][C:30]2[CH:39]=[CH:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[CH:31]=2)=[CH:12][CH:13]=1)=[O:5])[CH3:2]
Reactant: BrCc1ccc2ccccc2c1
Reactant: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2O)cc1
Product: CCOC(=O)C=Cc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2ccc3ccccc3c2)cc1

Procedure:
Alkylation of tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-hydroxy-piperidine-1-carboxylate with 2-bromomethylnaphthalene analogously to the procedure described in Example 22(i) gave tert-butyl (3RS,4RS)-4-[4-(2-ethoxycarbonyl-vinyl)-phenyl]-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a light yellow resin; MS: 516 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1([C:7]2[O:11][C:10]([CH2:12][N:13]3[CH:17]=[CH:16][C:15]([NH2:18])=[N:14]3)=[CH:9][CH:8]=2)[O:6]CCO1.[CH3:19][O:20][C:21]1[CH:26]=[CH:25][C:24](/[CH:27]=[CH:28]/[C:29](O)=[O:30])=[CH:23][CH:22]=1>>[C:2]([C:7]1[O:11][C:10]([CH2:12][N:13]2[CH:17]=[CH:16][C:15]([NH:18][C:29](=[O:30])/[CH:28]=[CH:27]/[C:24]3[CH:25]=[CH:26][C:21]([O:20][CH3:19])=[CH:22][CH:23]=3)=[N:14]2)=[CH:9][CH:8]=1)(=[O:6])[CH3:1]
Reactant: CC1(c2ccc(Cn3ccc(N)n3)o2)OCCO1
Reactant: COc1ccc(/C=C/C(=O)O)cc1
Product: COc1ccc(/C=C/C(=O)Nc2ccn(Cc3ccc(C(C)=O)o3)n2)cc1

Procedure:
Following general procedure B followed by either C or D, starting from 1-[5-(2-methyl-[1,3]dioxolan-2-yl)-furan-2-ylmethyl]-1H-pyrazol-3-ylamine and (E)-3-(4-methoxy-phenyl)-acrylic acid.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([N:27]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1.O.NN>C(O)C.C(#N)C>[NH2:1][C:2]1[N:7]=[C:6]([NH:8][C@H:9]([C:11]2[N:16]=[C:15]3[CH:17]=[CH:18][N:19]([CH3:20])[C:14]3=[CH:13][C:12]=2[N:21]2[CH2:26][CH2:25][CH2:24][C@H:23]([NH2:27])[CH2:22]2)[CH3:10])[C:5]([C:38]#[N:39])=[C:4]([CH3:40])[N:3]=1
Reactant: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@H](N3C(=O)c4ccccc4C3=O)C2)c1C#N
Agent: NN
Solvent: O
Solvent: CC#N
Solvent: CCO
Product: Cc1nc(N)nc(N[C@@H](C)c2nc3ccn(C)c3cc2N2CCC[C@H](N)C2)c1C#N
Temperature: 65 °C
Yield: 46 %

Procedure:
To a 25 mL pear flask were added 2-amino-4-(((S)-1-(6-((S)-3-(1,3-dioxoisoindolin-2-yl)piperidin-1-yl)-1-methyl-1H-pyrrolo[3,2-b]pyridin-5-yl)ethyl)amino)-6-methylpyrimidine-5-carbonitrile (20 mg, 0.037 mmol) and hydrazine monohydrate (0.081 mL, 1.7 mmol) in ethanol (1 mL). The mixture was heated to 65° C. for 4 hours. The mixture was diluted with acetonitrile and was then directly purified by preparative HPLC (basic mode, 25-45% ACN/water gradient). The product-containing fractions were combined and lyophilized to give the title compound as a light brown solid (6.9 mg, 46%). The absolute configuration of the stereocenter on the piperidine ring was not determined, but was assigned the opposite configuration of EXAMPLE 4. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.50-1.56 (m, 3H), 1.84-1.96 (m, 1H), 2.01-2.12 (m, 2H), 2.14-2.26 (m, 2H), 2.31 (s, 4H), 2.57 (d, J=4.55 Hz, 2H), 2.89-2.99 (m, 1H), 3.43-3.51 (m, 1H), 3.59-3.67 (m, 1H), 3.78-3.85 (m, 3H), 6.27 (s, 1H), 6.53-6.56 (m, 1H), 7.43-7.47 (m, 1H), 7.88 (s, 1H); ESI-MS m/z [M+H]+ calc'd for C21H27N9, 406. found 406.
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[C:10]([CH3:12])([CH3:11])[S:9][CH2:8][CH2:7][N:6]1[S:13]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)(=[O:15])=[O:14])=[O:4].[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34]O)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[CH2:23]([O:30][CH2:31][C:32]#[C:33][CH2:34][O:22][C:19]1[CH:18]=[CH:17][C:16]([S:13]([N:6]2[CH2:7][CH2:8][S:9][C:10]([CH3:12])([CH3:11])[CH:5]2[C:3]([O:2][CH3:1])=[O:4])(=[O:15])=[O:14])=[CH:21][CH:20]=1)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: COC(=O)C1N(S(=O)(=O)c2ccc(O)cc2)CCSC1(C)C
Reactant: OCC#CCOCc1ccccc1
Product: COC(=O)C1N(S(=O)(=O)c2ccc(OCC#CCOCc3ccccc3)cc2)CCSC1(C)C
Yield: 637.6 %

Procedure:
According to the procedure of Step 4 of Example 243, Mitsunobu coupling of 0.345 g (1.0 mmol) of 4-(4-hydroxy-benzenesulfonyl)-2,2-dimethyl-thiomorpholine-3-carboxylic acid methyl ester and 0.211 g (1.2 mmol) of 4-(benzyloxy)-2-butyn-1-ol provided 3.211 g (42%) of methyl 4-[(4-{[4-(benzyloxy)-2-butynyl]oxy}phenyl)sulfonyl]-2,2-dimethyl-3-thiomorpholine carboxylate as a pale yellow oil. Electrospray Mass Spec: 504.2 (M+H)+.
Reaction SMILES: [N+:1]([C:4]1[CH:23]=[CH:22][C:7]([C:8]([O:10][C@H:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19](Cl)[C:14]=3[C@H:13]([CH3:21])[CH2:12]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][NH:31][C:28]2=[CH:29][CH:30]=1>>[Cl:24][C:25]1[CH:26]=[C:27]2[C:33]3([CH2:37][CH2:36][N:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:34]3)[CH2:32][N:31]([C:19]3[C:14]4[C@H:13]([CH3:21])[CH2:12][C@@H:11]([O:10][C:8](=[O:9])[C:7]5[CH:22]=[CH:23][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=5)[C:15]=4[N:16]=[CH:17][N:18]=3)[C:28]2=[CH:29][CH:30]=1
Reactant: CC(C)(C)OC(=O)N1CCC2(CNc3ccc(Cl)cc32)C1
Reactant: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(Cl)c21
Product: C[C@@H]1C[C@@H](OC(=O)c2ccc([N+](=O)[O-])cc2)c2ncnc(N3CC4(CCN(C(=O)OC(C)(C)C)C4)c4cc(Cl)ccc43)c21

Procedure:
tert-butyl 5-chloro-1-((5R,7R)-5-methyl-7-(4-nitrobenzoyloxy)-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,3′-pyrrolidine]-1′-carboxylate was prepared by the procedures described in Example 1, Step 8, substituting (R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine with (5R,7R)-4-chloro-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-yl 4-nitrobenzoate, and substituting tert-butyl 5-chloro spiro[indoline-3,4′-piperidine]-1′-carboxylate with tert-butyl 5-chlorospiro[indoline-3,3′-pyrrolidine]-1′-carboxylate. LCMS (APCI+) m/z 339.1 [M+H-Boc-pNO2 benzoic acid]+; Rt=4.74 min.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-])=O.[NH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[C:18]([O-])([O-])=[O:19].[K+].[K+]>CC#N>[C:3]1([N:8]2[C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3[NH:11][C:18]2=[O:19])[CH:4]=[CH:5][CH:6]=[CH:7][CH:2]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccccc1F
Reactant: Nc1ccccc1
Agent: [K+]
Solvent: CC#N
Product: O=c1[nH]c2ccccc2n1-c1ccccc1

Procedure:
2-fluoronitrobenzene was treated with aniline in the prescence of K2CO3 in CH3CN and heated to reflux for 12 h. The solution is cooled, filtered and the solvent removed. The nitro group is reduced with catalytic hydrogenation and the diamine treated with CDI to give 1-phenyl-1,3-dihydro-benzoimidazol-2-one.