Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=O.[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH2:30])[CH:29]=1)=[CH:17]2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>C(Cl)Cl.C(O)(=O)C>[F:13][C:14]1[CH:15]=[C:16]2[C:20](=[CH:21][C:22]=1[F:23])[NH:19][C:18]([C:24]1[CH:25]=[CH:26][C:27]([O:31][CH3:32])=[C:28]([NH:30][CH2:5][C:4]3[CH:7]=[CH:8][C:9]([N+:10]([O-:12])=[O:11])=[C:2]([OH:1])[CH:3]=3)[CH:29]=1)=[CH:17]2
Reactant: O=Cc1ccc([N+](=O)[O-])c(O)c1
Reactant: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1N
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc(-c2cc3cc(F)c(F)cc3[nH]2)cc1NCc1ccc([N+](=O)[O-])c(O)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.1 %

Procedure:
3-Hydroxy-4-nitrobenzaldehyde (0.334 g, 2.0 mmol) was added to a stirred mixture of 5-(5,6-difluoro-1H-indol-2-yl)-2-methoxy-phenylamine (0.548 g, 2.0 mmol) in methylene chloride (125 mL), followed by acetic acid (0.2 g). The resulting mixture was stirred at room temperature for 1 hour. Sodium triacetoxyborohydride (0.46 g, 2.2 mmol) was added in one portion, and the resulting homogeneous solution was stirred at room temperature for 3 days. Saturated aqueous sodium bicarbonate solution (100 mL), was added and the mixture was stirred for 2 hours. The mixture was shaken; the organic layer was separated and dried over Na2SO4. The solvent was evaporated to give a red-orange gum. Recrystallization from methanol gave the product (350 mg), mp 170-171° C.
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]1)([CH3:3])=[CH2:2].[CH2:11]([Zn]CC)C.ICI.[NH4+].[Cl-]>CCCCCC>[CH3:2][C:1]1([CH:4]2[CH2:9][CH2:8][C:7](=[O:10])[CH2:6][CH2:5]2)[CH2:11][CH2:3]1
Reactant: CC[Zn]CC
Reactant: C=C(C)C1CCC(=O)CC1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ICI
Solvent: CCCCCC
Product: CC1(C2CCC(=O)CC2)CC1
Temperature: -60 °C
Reaction time: 2 h

Procedure:
5.0 g (0.036 mol) of 4-isopropenylcyclohexanone (precursor to Example 4) were placed under inert gas in 150 ml of hexane, and 16.5 g (0.134 mol) of diethylzinc (1M in hexane) followed by 58.0 g (0.22 mol) of diiodomethane were added dropwise at -20° C. The mixture was stirred at -60° C. for 2 hours and then at 0° C. for 6 hours. The reaction solution was kept in a refrigerator overnight and was worked up by pouring it into cold NH4Cl solution and carrying out extraction with ether. The organic phase was washed with sodium thiosulfate solution and water, dried and concentrated. 5.3 g (96% of theory) of a colorless oil were obtained which was reacted without further purification.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][NH:10][C:9]2=O)=[O:5])[CH3:2].O=P(Cl)(Cl)[Cl:19].CCN(C(C)C)C(C)C.OP([O-])([O-])=O.[K+].[K+]>O.C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1[C:7]([CH3:16])=[C:8]2[N:13]([CH:14]=1)[N:12]=[CH:11][N:10]=[C:9]2[Cl:19])=[O:5])[CH3:2]
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCOC(=O)c1cn2nc[nH]c(=O)c2c1C
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)c1cn2ncnc(Cl)c2c1C
Temperature: 111 °C
Reaction time: 0.33 h

Procedure:
A 2L 3-neck flask was charged with 5-methyl-4-oxo-3,4-dihydro-pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid ethyl ester (50 g, 226 mmol) and dry toluene (750 ml). POCl3 (41.6 g, 271.5 mmol) was added in one portion, followed by slow addition of DIEA (32.2 g, 248.9 mmol) at a rate, which maintained the temperature below 30° C. The resulting suspension was heated to 111° C. for 24 h becoming homogeneous at 80° C. The reaction was monitored by HPLC after quenching with 2 M MeNH2/THF (10 μl reaction mixture, 20 μl MeNH2/THF in 200 μl acetonitrile). Upon completion, reaction was cooled to −8° C. and a solution of K2HPO4 in H2O (170 g/775 ml) was added maintaining temperature below 1° C. The mixture was stirred for 20 min at −8° C. then warmed to ambient temperature for 1 h. The resulting light suspension was filtered through a pad of celite and the layers were separated. The organic layer was washed with K2HPO4 in H2O (27 g/130 ml), followed by water (250 ml) and dried (Na2SO4). The solution was filtered and concentrated to a yellow foam 4A (54.0 g, 100%). MS: 235 (MeNH2 adduct) (M+H)+; HPLC Ret Time (MeNH2 adduct): 2.240 min (YMC S5 ODS 4.6×50 mm column, 4 min gradient, 3 mL/min).
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([NH:8][C:9](=[O:13])[CH:10]=NO)[CH:5]=[CH:6][CH:7]=1.[OH:16]S(O)(=O)=O>>[Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:5]([C:10](=[O:16])[C:9](=[O:13])[NH:8]2)=[CH:6][CH:7]=1
Reactant: O=S(=O)(O)O
Reactant: COc1c(Br)cccc1NC(=O)C=NO
Product: COc1c(Br)ccc2c1NC(=O)C2=O
Temperature: 0 °C

Procedure:
A mixture of N-(3-Bromo-2-methoxy-phenyl)-2-hydroxyimino-acetamide (36 g, 0.132 mol), conc.H2SO4 (193 mL) is stirred at 80° C. for 1 hour. After reaction, poured the reaction mixture into ice water (2 L). The mixture is filtered and the solid is dried under vacuum to give the desired product.
Reaction SMILES: Br[C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[CH:10]2[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]2)=[N:4][CH:3]=1.[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([SH:34])=[N:32][CH:33]=1)=[O:28])[CH3:25]>>[CH2:24]([O:26][C:27]([C:29]1[N:30]([CH3:35])[C:31]([S:34][C:2]2[S:6][C:5]([NH:7][C:8]([N:9]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH:10]3[CH2:15][CH2:14][CH:13]([CH3:16])[CH2:12][CH2:11]3)=[O:23])=[N:4][CH:3]=2)=[N:32][CH:33]=1)=[O:28])[CH3:25]
Reactant: CCOC(=O)c1cnc(S)n1C
Reactant: CC1CCC(N(C(=O)Nc2ncc(Br)s2)C2CCCCC2)CC1
Product: CCOC(=O)c1cnc(Sc2cnc(NC(=O)N(C3CCCCC3)C3CCC(C)CC3)s2)n1C

Procedure:
Prepared as described in general procedure (E) from 3-(5-bromothiazol-2-yl)-1-cyclohexyl-1-(4-methylcyclohexyl)-urea (Example 242) and 2-mercapto-3-methyl-3H-imidazole-4-carboxylic acid ethyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:37])[N:7]([NH:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)[C:8]([C@H:12]([NH:15][CH2:16][CH2:17][CH2:18][N:19]3C(=O)C4C(=CC=CC=4)C3=O)[CH2:13][CH3:14])=[N:9]2)=[CH:4][CH:3]=1.[CH:38](=O)[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>>[NH2:19][CH2:18][CH2:17][CH2:16][N:15]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[C@@H:12]([C:8]1[N:7]([NH:30][C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[C:6](=[O:37])[C:5]2[C:10](=[CH:11][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:9]=1)[CH2:13][CH3:14]
Reactant: O=Cc1ccccc1
Reactant: CC[C@@H](NCCCN1C(=O)c2ccccc2C1=O)c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1
Product: CC[C@H](c1nc2cc(Cl)ccc2c(=O)n1Nc1ccccc1)N(CCCN)Cc1ccccc1

Procedure:
This compound was synthesized as described in general procedure C except 2-{3-[(R)-1-(7-chloro-4-oxo-3-phenylamino-3,4-dihydro-quinazolin-2-yl)-propylamino]-propyl}-isoindole-1,3-dione was used instead of (R)-2-(3-(1-(7-chloro-4-oxo-3-(phenylamino)-3,4-dihydroquinazolin-2-yl)but-3-ynylamino)propyl)isoindoline-1,3-dione and benzaldehyde was used instead of 4-methyl benzaldehyde. Yield (16%). LCMS: m/e 477.04 [M+H].
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:16]\[N:17](C)C)[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.ON.CC([OH:26])C>C1COCC1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11](/[N:15]=[CH:16]\[NH:17][OH:26])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)/C=N\c1cc(OCc2ccccc2)ccn1
Reactant: CC(C)O
Agent: Cl
Agent: NO
Solvent: C1CCOC1
Product: ON/C=N\c1cc(OCc2ccccc2)ccn1
Temperature: 50 °C

Procedure:
A 100 mL, single-neck, round-bottomed flask was charged with (Z)-N′-(4-(benzyloxy)pyridin-2-yl)-N,N-dimethylformamidine (7.66 g, 30.0 mmol), hydroxyl amine hydrochloride (2.40 g, 34.5 mmol), propan-2-ol (33.3 ml), and THF (5 ml). The reaction was heated to 50° C. for 7 hours, then concentrated. The residue was titrated with EtOAc/THF and filtered. The filtrate was concentrated and triturated with dichloromethane to provide the product as a white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[C:21]([C:44]([F:47])([F:46])[F:45])=[N:22][N:23](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[CH:24]=4)[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:4])=[O:3].FC(F)(F)C(O)=O.ClCCl.[OH-].[Na+]>O.C(OCC)(=O)C>[CH3:1][S:2]([C:5]1[S:9][C:8]([C:10]2[C:19]3[C:14](=[CH:15][CH:16]=[C:17]([C:20]4[C:21]([C:44]([F:47])([F:45])[F:46])=[N:22][NH:23][CH:24]=4)[CH:18]=3)[N:13]=[CH:12][CH:11]=2)=[CH:7][CH:6]=1)(=[O:3])=[O:4]
Reactant: CS(=O)(=O)c1ccc(-c2ccnc3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)nc4C(F)(F)F)cc23)s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(-c2ccnc3ccc(-c4c[nH]nc4C(F)(F)F)cc23)s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.8 %

Procedure:
A mixture of 58 mg 4-(5-methylsulfonyl 2-thienyl)-6-(3-trifluoromethyl-1-trityl-1H-4-pyrazolyl)qui noline obtained in Example 158, 1 mL trifluoroacetic acid and 3 mL dichloromethane was stirred overnight at room temperature. The reaction solution was cooled with iced water and basified with 5 N aqueous sodium hydroxide, then ethyl acetate and water were added thereto, and the organic layer was separated. The aqueous layer was then extracted with ethyl acetate, and the combined organic layer was washed with water and an aqueous brine and dried over anhydrous sodium sulfate. The drying agent was filtered off, and the filtrate was evaporated. The residue was triturated with diethyl ether, and the crystals were separated by filtration to give 18 mg of the title compound as pale yellow crystals.
Reaction SMILES: CC(C)([O-])C.[K+].[C:7]([O:11][C:12](=[O:37])[NH:13][C:14]([CH3:36])([CH3:35])[CH2:15][N:16]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1[O:27][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:17](=[O:20])[CH2:18]Br)([CH3:10])([CH3:9])[CH3:8].[Cl-].[NH4+].O>O1CCCC1>[C:7]([O:11][C:12]([N:13]1[CH2:18][C:17](=[O:20])[N:16]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=2[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:15][C:14]1([CH3:36])[CH3:35])=[O:37])([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(CN(C(=O)CBr)c1ccccc1OCc1ccccc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(=O)N(c2ccccc2OCc2ccccc2)CC1(C)C
Reaction time: 0.17 h
Yield: 86.4 %

Procedure:
A solution of 1.59 g of potassium t-butoxide (14.2 mmol) in tetrahydrofuran (100 ml) was added to a solution of 4.64 g of {2-[(2-benzyloxyphenyl)-(2-bromoacetyl)amino]-1,1-dimethylethyl}carbamic acid t-butyl ester obtained in Example (10b) (9.64 mmol) in tetrahydrofuran (100 ml) under a nitrogen atmosphere and under cooling in a dry ice-acetone bath over 30 minutes, and the mixture was stirred at the same temperature for 10 minutes. A saturated ammonium chloride aqueous solution was added to the reaction mixture. The mixture was returned to room temperature and then water was added, followed by extraction with ethyl acetate. Then, the organic layer was dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (elution solvent:methylene chloride/ethyl acetate=5/1) to obtain 3.42 g of the title compound (yield: 94%).
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.[CH3:18][S:19][C:20]1[CH:28]=[CH:27][C:23]([C:24](O)=[O:25])=[CH:22][CH:21]=1>>[CH3:18][S:19][C:20]1[CH:28]=[CH:27][C:23]([C:24]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[C:5]3[CH:11]2[CH2:16][CH2:15][N:14]([CH3:17])[CH2:13][CH2:12]2)=[O:25])=[CH:22][CH:21]=1
Reactant: CN1CCC(c2c[nH]c3ccc(N)cc23)CC1
Reactant: CSc1ccc(C(=O)O)cc1
Product: CSc1ccc(C(=O)Nc2ccc3[nH]cc(C4CCN(C)CC4)c3c2)cc1
Yield: 57.2 %

Procedure:
Beginning with 20.0 mg (0.087 mMol) 5-amino-3-(1-methylpiperidin-4-yl)-1H-indole and 44.0 mg (0.131 mMol) 4-(methylthio)benzoic acid, 18.9 mg (57.1%) of the title compound were recovered.
Reaction SMILES: Cl.CO[C:4](=N)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[N:12]1([CH2:19][C:20]2[S:21][C:22]([C:25]([NH:27][NH2:28])=[O:26])=[CH:23][CH:24]=2)[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>N1C=CC=CC=1>[C:5]1([C:4]2[O:26][C:25]([C:22]3[S:21][C:20]([CH2:19][N:12]4[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]4)=[CH:24][CH:23]=3)=[N:27][N:28]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: NNC(=O)c1ccc(CN2CCCCCC2)s1
Reactant: COC(=N)c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Product: c1ccc(-c2nnc(-c3ccc(CN4CCCCCC4)s3)o2)cc1
Yield: 16.2 %

Procedure:
687 mg (4.0 mmol) of methylbenzoimidate hydrochloride was added to 7 ml of pyridine solution containing 507 mg (2.0 mmol) of 2-(hexahydro-1H-azepin-1-yl)methylthiophene-5-carboxylic acid hydrazide, and the mixture was heated under reflux for 4 hours. The reaction solution was concentrated, chloroform was added to the resulting residue, followed by washing with water and drying over anhydrous magnesium sulfate. The solvent was evaporated and the resulting residue was purified by a silica gel column chromatography to give 110 mg of the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]2[CH2:28][O:27]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[NH:29]1[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]1>CC(O)C.O1CCOCC1.CN(C1C=CN=CC=1)C>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[O:17][N:16]=[C:15]3[C:18]4[C:23]([CH2:24][CH2:25][C:14]=23)=[CH:22][C:21]([CH:26]([OH:27])[CH2:28][N:29]2[CH2:34][CH2:33][CH2:32][C@H:31]([C:35]([O:37][CH2:38][CH3:39])=[O:36])[CH2:30]2)=[CH:20][CH:19]=4)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: CCOC(=O)[C@H]1CCCNC1
Reactant: CCOc1ccc(-c2onc3c2CCc2cc(C4CO4)ccc2-3)cc1OCC
Agent: CN(C)c1ccncc1
Solvent: CC(C)O
Solvent: C1COCCO1
Product: CCOC(=O)[C@H]1CCCN(CC(O)c2ccc3c(c2)CCc2c-3noc2-c2ccc(OCC)c(OCC)c2)C1
Temperature: 60 °C
Yield: 26.4 %

Procedure:
To 3-(3,4-diethoxyphenyl)-7-(oxiran-2-yl)-4,5-dihydronaphtho[1,2-c]isoxazole (Preparation 81A, 0.08 g, 0.212 mmol) in a mixture of 2-propanol (1 mL) and dioxane (1.000 mL) was added DMAP (5.18 mg, 0.042 mmol) followed by (S)-ethyl piperidine-3-carboxylate (0.033 mL, 0.212 mmol) at room temperature. The reaction mixture was heated at 60° C. (oil bath temp.) for 26 h, concentrated under reduced pressure, and purified by column chromatography using an ISCO setup (12 g, RediSep® silica gel column). The desired fractions were collected and concentrated to yield (0.03 g, 0.056 mmol, 26.5% yield) of the product as a diastereomeric mixture. The individual diastereomers were separated using a CHIRALCE1® OJ-H column under SFC conditions (25% MeOH with 0.1% diethylamine in CO2). Isomer 1 (7.7 mgs), retention time on chiral HPLC, 4.39 min; Isomer 2 (9 mgs), retention time on chiral HPLC, 6.15 min. The absolute stereochemistry at the carbon anchoring the secondary alcohol, of Isomer 1 and Isomer 2 was not determined.
Reaction SMILES: [F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([CH2:12][OH:13])[CH:3]=1.C(N(CC)CC)C.O>CS(C)=O>[F:1][C:2]1[C:7]([O:8][CH2:9][O:10][CH3:11])=[CH:6][N:5]=[C:4]([CH:12]=[O:13])[CH:3]=1
Reactant: COCOc1cnc(CO)cc1F
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: COCOc1cnc(C=O)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 68.4 %

Procedure:
To a solution of (4-fluoro-5-(methoxymethoxy)pyridin-2-yl)methanol (3.59 g) and triethylamine (8.02 mL) in DMSO (30 mL) was added sulfur trioxide pyridine complex (9.16 g), and the mixture was stirred at room temperature for 30 min. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (2.43 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([CH:14]([NH:16][C:17]2[N:22]=[C:21]([N:23]3[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=[CH:24]3)[CH:20]=[CH:19][N:18]=2)[CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[BH3-][C:33]#N.[Na+].C=O.O>CO.CC#N.CCOC(C)=O>[CH3:33][N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9][CH:10]1[CH:14]([NH:16][C:17]1[N:22]=[C:21]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[CH:24]2)[CH:20]=[CH:19][N:18]=1)[CH3:15]
Reactant: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1
Reactant: [BH3-]C#N
Agent: C=O
Agent: [Na+]
Solvent: CC#N
Solvent: CO
Solvent: O
Product: CC(Nc1nccc(-n2cnc3ccccc32)n1)C1CN(C(=O)OC(C)(C)C)CCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 85.4 %

Procedure:
To a solution of 2-[1-(4-(tert-butyloxycarbonyl)piperazine-2-yl)-ethylamino]-4-(benzimidazol-1-yl)-pyrimidine (EXAMPLE 17, Step C; 17 mg) in 1 mL of MeOH and 1 mL of CH3CN was added NaBH3CN (5 mg) and 37% aqueous formaldehyde (20 μL). The mixture was stirred overnight at room temperature, then diluted with 5 mL of EtOAc and poured into 10 mL of water. The phases were separated and the aqueous phase was extracted with 2×5 mL of EtOAc. The aqueous phase was basified (pH>10) by addition of 5 N NaOH, then extracted with 5×5 mL of EtOAc. The combined organic extracts were washed with 5 mL of brine, dried over Na2SO4, and concentrated to yield 15 mg of the title compound.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4](/[CH:7]=[C:8]2/[C:9](=[O:23])[CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][C:17]([CH3:21])=[CH:16][C:15]=3[CH3:22])[C:11](=[O:13])[CH2:12]/2)[CH2:3][CH2:2]1>C(O)C.[Pd]>[O:1]1[CH2:2][CH2:3][CH:4]([CH2:7][CH:8]2[CH2:12][C:11](=[O:13])[CH:10]([C:14]3[C:15]([CH3:22])=[CH:16][C:17]([CH3:21])=[CH:18][C:19]=3[CH3:20])[C:9]2=[O:23])[CH2:5][CH2:6]1
Reactant: Cc1cc(C)c(C2C(=O)C/C(=C\C3CCOCC3)C2=O)c(C)c1
Agent: [Pd]
Solvent: CCO
Product: Cc1cc(C)c(C2C(=O)CC(CC3CCOCC3)C2=O)c(C)c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.4 %

Procedure:
To a solution of 4-[1-(tetrahydro-pyran-4-yl)-meth-(E)-ylidene]-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (270 mg, 0.86 mmol) in ethanol (10 ml) was added 10% palladium on charcoal (27 mg) and the resulting solution stirred under hydrogen (3 bar) for 5 hours at room temperature. The reaction mixture was then filtered through a pad of celite, which was washed with methanol, and the filtrated concentrated in vacuuo to give 4-(tetrahydro-pyran-4-ylmethyl)-2-(2,4,6-trimethyl-phenyl)-cyclopentane-1,3-dione (258 mg).
Reaction SMILES: [SH:1][CH2:2][CH:3]([SH:6])[CH2:4][SH:5].O=[C:8]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH2:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:14]([O:13][C:11](=[O:12])[CH2:10][CH2:9][C:8]1([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[S:6][CH:3]([CH2:4][SH:5])[CH2:2][S:1]1)[CH3:15]
Reactant: SCC(S)CS
Reactant: CCOC(=O)CCC(=O)CCC(=O)OCC
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCOC(=O)CCC1(CCC(=O)OCC)SCC(CS)S1
Temperature: 25 °C
Reaction time: 72 h
Yield: 40 %

Procedure:
A stirred solution of 1,2,3-trimercaptopropane (10.0 g, 0.071 mol) and diethyl 4-oxopimelate (16.43 g, 0.071 mol) in methylene chloride (300 ml) under nitrogen atmosphere was treated with boron trifluoride etherate (2 ml). After stirring for 3 days at room temperature, the reaction was quenched by addition of 200 ml of 5% sodium bicarbonate solution. The organic phase was separated and dried over anhydrous sodium sulfate. The drying agent was filtered and the filtrate concentrated on the rotary evaporator. The residue was chromatographed on silica gel using 5% ethyl acetate/hexane as eluent to give 10 g (40%) of the title compound as an oil.
Reaction SMILES: C(N)(=O)C=C.C([NH:10][C@@H:11]1[C@@H:17]([OH:18])[C@H:16]([OH:19])[C@@H:15]([CH2:20][OH:21])[O:14][CH:12]1[OH:13])(=O)C=C.C(NN[C@@H]1[C@@H](O)[C@H](O)[C@@H](CO)OC1O)(=O)C=C.SCCNC(=O)C(NC(=O)C1C=CC(C(=O)C2C=CC=CC=2)=CC=1)CCCCNC(=O)C1C=CC(C(=O)C2C=CC=CC=2)=CC=1.CC(N=NC(C#N)(C)C)(C#N)C.CN(CCN(C)C)C>O>[OH:13][CH:12]1[O:14][C@H:15]([CH2:20][OH:21])[C@@H:16]([OH:19])[C@H:17]([OH:18])[C@H:11]1[NH2:10]
Reactant: C=CC(=O)N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: C=CC(=O)NN[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Agent: C=CC(N)=O
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: O
Product: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O

Procedure:
Acrylamide (400mg, 5.6 mmole) was dissolved in 10 ml of dimethylsulfoxide(DMSO). To that solution was added 400 mg (1.48 mmole) of N-acryloylglucosamine (Compound VI). Additionally were added 34 mg of N-(2-mercaptoethyl)-2,6-bis(4-benzoylbenzamido)hexanamide, 200 mg of AIBN and 50 μl of TEMED. The solution was sparged with nitrogen, then placed in a 55° C. oven overnight. The resulting polymer solution was dialyzed against deionized water using SpectraPor 1 (Spectrum) dialysis membrane. After dialysis, the solution was lyophilized. The dried polymer obtained was 0.58 gm by weight. At 0.1 mg/ml in deionized water, the polymer had an absorbance at 265 nm of 0.202.
Reaction SMILES: [CH:1]([C@:4]1([C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:26])[F:25])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:14][CH2:13]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH2:9])[CH2:5]1)([CH3:3])[CH3:2].[CH3:29][O:30][CH:31]1[C:36](=O)[CH2:35][CH2:34][O:33][CH2:32]1.C(N(CC)CC)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH:1]([C@:4]1([C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[CH:23]=[C:22]([C:24]([F:27])([F:25])[F:26])[CH:21]=[C:20]([CH3:28])[N:19]=3)[CH2:16][CH2:17]2)=[O:11])[CH2:8][CH2:7][C@@H:6]([NH:9][CH:36]2[CH2:35][CH2:34][O:33][CH2:32][CH:31]2[O:30][CH3:29])[CH2:5]1)([CH3:3])[CH3:2]
Reactant: COC1COCCC1=O
Reactant: Cc1cc(C(F)(F)F)cc(N2CCN(C(=O)[C@@]3(C(C)C)CC[C@@H](N)C3)CC2)n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC1COCCC1N[C@@H]1CC[C@@](C(=O)N2CCN(c3cc(C(F)(F)F)cc(C)n3)CC2)(C(C)C)C1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (1R,3S)-3-isopropyl-3-(4-[6-methyl-4-(trifluoromethyl)pyridin-2-yl]piperazin-1-ylcarbonyl)cyclopentanamine (120 mg, 0.30 mmol), 3-methoxytetrahydro-4H-pyran-4-one (120 mg, 0.90 mmol), and triethylamine (0.12 mL, 0.90 mmol) in methylene chloride (20 mL) was added sodium triacetoxyborohydride (0.19 g, 0.90 mmol). After being stirred at room temperature overnight, the reaction mixture was diluted with methylene chloride, washed with brine, dried over sodium sulfate, filtered and concentrated. The residue was purified by flash chromatography to provide the desired product as a mixture of cis/trans isomers. LCMS calculated for C26H40F3N4O3: (M+H) 513.3; found 513.2 for both isomers.
Reaction SMILES: [CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH2:10])[CH2:6][CH2:5]1)([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[C:44]1([C:50]2[NH:54][C:53]([C:55](O)=[O:56])=[CH:52][CH:51]=2)[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=1>C(Cl)Cl>[CH:1]([N:4]1[CH2:9][CH2:8][CH:7]([NH:10][C:55]([C:53]2[NH:54][C:50]([C:44]3[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=3)=[CH:51][CH:52]=2)=[O:56])[CH2:6][CH2:5]1)([CH3:3])[CH3:2]
Reactant: CC(C)N1CCC(N)CC1
Reactant: O=C(O)c1ccc(-c2ccccc2)[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N1CCC(NC(=O)c2ccc(-c3ccccc3)[nH]2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To 1-isopropyl-piperidin-4-ylamine (350 mg) in DCM (15 mL) was added DIEA (1.67 mL), followed by HATU (935 mg) and 5-phenyl-1H-pyrrole-2-carboxylic acid (461 mg). The mixture was stirred for 1 h at RT whereupon it was washed two times with saturated aqueous NaHCO3 solution, dried over MgSO4 and concentrated to give crude 5-phenyl-1H-pyrrole-2-carboxylic acid (1-isopropyl-piperidin-4-yl)-amide which was used directly in the following step.