Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])O[CH:13]=2)=[CH:4][CH:3]=1.Cl.[OH-].[NH4+:21]>>[Cl:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][O:7][C:8]2[C:9](=[O:16])[CH:10]=[C:11]([CH2:14][OH:15])[NH:21][CH:13]=2)=[CH:4][CH:3]=1
Reactant: O=c1cc(CO)occ1OCc1ccc(Cl)cc1
Reactant: [NH4+]
Agent: Cl
Agent: [OH-]
Product: O=c1cc(CO)[nH]cc1OCc1ccc(Cl)cc1
Temperature: 90 °C

Procedure:
5-(4-Chloro-benzyloxy)-2-hydroxymethyl-pyran-4-one (638, 8.00 g, 3.00 mmol) was suspended in ammonium hydroxide (200 mL) in an 80 mL sealed tube. The reaction was heated at 90° C. overnight. Upon cooling, the reaction was lowered to pH 10 with 6N HCl to provide a beige solid that was collected by filtration (639, 7.8 g, 98%).
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)=O.ClC1C=CC=[C:15]([C:19]([O:21]O)=[O:20])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl.C(OCC)C>[C:19]([O:21][C:4]1[CH:9]=[CH:8][C:7]([F:10])=[C:6]([Br:11])[CH:5]=1)(=[O:20])[CH3:15]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(=O)Oc1ccc(F)c(Br)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 68 %

Procedure:
A solution of 1.09 gm (5 mMol) 3-bromo-4-fluoroacetophenone and 3.45 gm (20 mMol) m-chloroperbenzoic acid (70%) in 15 mL dichloromethane was heated at reflux for 18 hours. An additional 3.45 gm m-chloroperbenzoic acid were added and reflux continued for about 12 hours. At this point an additional 1.4 gm m-chloroperbenzoic acid were added and reflux continued for 18 hours. The reaction mixture was cooled to room temperature and was then diluted with 50 mL diethyl ether. The resulting mixture was cooled to 0° C. and was then treated with 15 mL 20% aqueous sodium thiosulfate. The resulting slurry was stirred for about 1 hour and then the phases separated. The organic phase was washed sequentially with 3×20 mL 20% aqueous sodium thiosulfate followed by 3×20 mL saturated aqueous sodium chloride. The organic phase was then dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel chromatography, eluting with 10:1 hexane:diethyl ether. Fractions containing product were combined and concentrated under reduced pressure to provide 68% of the desired compound.
Reaction SMILES: Cl[C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1.Cl.[CH3:20][O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH2:28].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH3:20][O:21][C:22](=[O:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:2]1[C:3]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=3)=[CH:9][O:8][C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: COC(=O)CCCCCN
Reactant: COc1ccc(-c2coc3ncnc(Cl)c23)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCCCNc1ncnc2occ(-c3ccc(OC)cc3)c12
Temperature: 25 °C

Procedure:
Dissolve 7.1 g (27.2 mol) 4-chloro-5-(4-methoxyphenyl)furo[2,3-d]pyrimidine in 250 ml acetonitrile and add 5.9 g (32.7 mmol) 6-aminohexanoic acid methyl ester hydrochloride and 9.4 g (68.1 mmol) potassium carbonate. Heat the mixture under reflux for 18 hours and then filter after cooling to room temperature. Mix the residue three times in 50 ml water each time, filter and dry under vacuum. 4.1 g (41% of theor.) of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][CH:9]=[CH:8]2)=[O:4].[H-].[Na+].[CH3:16][Si:17]([CH3:25])([CH3:24])[CH2:18][CH2:19][S:20](Cl)(=[O:22])=[O:21].C(O)(=O)C>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[N:10]([S:20]([CH2:19][CH2:18][Si:17]([CH3:25])([CH3:24])[CH3:16])(=[O:22])=[O:21])[CH:9]=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Reactant: C[Si](C)(C)CCS(=O)(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: COC(=O)c1ccc2c(ccn2S(=O)(=O)CC[Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 77.6 %

Procedure:
To a solution of 1H-indole-5-carboxylic acid methyl ester (3.6 g, 20.6 mmol) in tetrahydrofuran (180 mL) at 0° C., was added sodium hydride (0.65 g, 21.9 mmol). After 10 min., 2-trimethylsilanylethanesulfonyl chloride (4.4 g, 21.9 mmol) was added and the reaction mixture was allowed to warm to room temperature. After 3 h, acetic acid (1.6 mL, 26.8 mmol) was added and the reaction mixture was concentrated. The crude product was chromatographed (Biotage 40M column, 2.5% ethyl acetate-hexanes) to afford 1-(2-trimethylsilanylethanesulfonyl)-indole-5-carboxylic acid methyl ester (5.43 g) as a white solid.
Reaction SMILES: [CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([OH:29])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:3])[CH3:2].[C:42](Cl)(=[O:45])[CH2:43][CH3:44]>C1COCC1.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH:1]([O:4][C:5](=[O:41])[C@@H:6]([N:8]=[P:9]([O:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][C:13]=1[O:22][CH2:23][C@:24]1([F:40])[C@@H:28]([O:29][C:42](=[O:45])[CH2:43][CH3:44])[C@:27]([F:31])([CH3:30])[C@H:26]([N:32]2[CH:37]=[CH:36][C:35](=[O:38])[NH:34][C:33]2=[O:39])[O:25]1)=[O:10])[CH3:7])([CH3:2])[CH3:3]
Reactant: CCC(=O)Cl
Reactant: CC(C)OC(=O)[C@H](C)N=[P+]([O-])Oc1c(OC[C@@]2(F)O[C@@H](n3ccc(=O)[nH]c3=O)[C@](C)(F)[C@@H]2O)ccc2ccccc12
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCC(=O)O[C@H]1[C@@](C)(F)[C@H](n2ccc(=O)[nH]c2=O)O[C@]1(F)COc1ccc2ccccc2c1O[P+]([O-])=N[C@@H](C)C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 5 h
Yield: 48 %

Procedure:
To a solution of (S)-2-[[(2S,3S,4R,5R)-5-(2,4-dioxo-3,4-dihydro-2H-pyrimidin-1-yl)-2,4-difluoro-3-hydroxy-4-methyl-tetrahydro-furan-2-ylmethoxy]-(naphthalen-1-yloxy)-phosphorylamino]-propionic acid isopropyl ester prepared in Example 2 (86 mg, 144 μmol) in THF (10 mL) were added propionyl chloride (66.6 mg, 720 μmol) and DMAP (87.9 mg, 720 μmol). The reaction mixture was stirred at room temperature for 5 h. The mixture was diluted with ethyl acetate, washed with water, brine. The organic layer was separated, dried over MgSO4, and concentrated. The residue was purified by flash chromatography (silica gel, 40 g, 0-15% MeOH in DCM) to give the title compound as white solid (45 mg, 48%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10].[CH3:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[CH3:12][C:13]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:14]=1[NH:15][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=[O:10]
Reactant: O=C(O)Cc1ccccc1Br
Reactant: Cc1cccc(N)c1C
Product: Cc1cccc(Nc2ccccc2CC(=O)O)c1C

Procedure:
In the manner described in example 3, 2-bromophenylacetic acid is condensed with 2,3-dimethylaniline to yield 2-[(2,3-dimethylphenyl)amino]phenylacetic acid.
Reaction SMILES: CO[C:3]1[CH:28]=[CH:27][C:6]([CH2:7][N:8]2[C:16]([S:17][CH3:18])=[C:15]3[C:10]([N:11]([CH2:22][C:23]([CH3:26])([CH3:25])[CH3:24])[C:12](=[O:21])[N:13]([CH3:20])[C:14]3=[O:19])=[N:9]2)=[CH:5][CH:4]=1.ClCC1C=CC([CH:37]2[CH2:42][CH2:41][CH2:40][CH2:39][N:38]2[CH3:43])=CC=1>>[CH3:20][N:13]1[C:14](=[O:19])[C:15]2=[C:16]([S:17][CH3:18])[N:8]([CH2:7][C:6]3[CH:27]=[CH:28][C:3]([CH:37]4[CH2:42][CH2:41][CH2:40][CH2:39][N:38]4[CH3:43])=[CH:4][CH:5]=3)[N:9]=[C:10]2[N:11]([CH2:22][C:23]([CH3:25])([CH3:24])[CH3:26])[C:12]1=[O:21]
Reactant: COc1ccc(Cn2nc3c(c2SC)c(=O)n(C)c(=O)n3CC(C)(C)C)cc1
Reactant: CN1CCCCC1c1ccc(CCl)cc1
Product: CSc1c2c(=O)n(C)c(=O)n(CC(C)(C)C)c2nn1Cc1ccc(C2CCCCN2C)cc1

Procedure:
The synthetic procedure of this compound is analogous to EXAMPLE 5 wherein 2-(4-methoxybenzyl)-5-methyl-3-(methylthio)-7-neopentyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione is used instead of 2-(4-methoxybenzyl)-5-methyl-7-neopentyl-3-(phenylthio)-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione, and 2-(4-(chloromethyl)phenyl)-1-methylpiperidine is used instead of 1-(4-(bromomethyl)phenyl)-1H-1,2,4-triazole. MS (ESI) m/z 439.2 [M+H]+.
Reaction SMILES: [C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:6]=[CH:5][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([N:11](CC4C=CC(OC)=CC=4)[C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:3][CH:2]=1.[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.O=[N+]([O-])[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[O-][N+](=O)[O-].[Ce+4].[NH4+].[NH4+]>C1COCC1.O>[C:1]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:2]=[CH:3][C:4]([CH2:7][N:8]2[CH:16]=[C:15]3[C:10]([NH:11][C:12](=[O:19])[N:13]([CH3:18])[C:14]3=[O:17])=[N:9]2)=[CH:5][CH:6]=1
Reactant: COc1ccc(Cn2c(=O)n(C)c(=O)c3cn(Cc4ccc(-c5ccccc5)cc4)nc32)cc1
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)[nH]c2nn(Cc3ccc(-c4ccccc4)cc3)cc2c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(biphenyl-4-ylmethyl)-7-(4-methoxybenzyl)-5-methyl-2H-pyrazolo[3,4-d]pyrimidine-4,6(5H,7H)-dione (300 mg, 0.663 mmol) in THF (9 mL), a solution of ammonium cerium (IV) nitrate (1.82 g, 3.32 mmol) in water (3 mL) is added. The resulting orange solution is stirred at room temperature overnight. Another batch of CAN (1.82 g, 3.32 mmol) is added and the mixture is stirred for 6 hours, and then the third batch of CAN (1.82 g) is added, and the mixture is stirred at r.t. overnight. The reaction mixture is evaporated to dryness. The residue is treated with brine, and extracted with methylene chloride five times. The organic phase is combined and concentrated. The residue is purified by chromatography to give product as white solids with a high yield. 1H NMR (400 MHz, DMDO-d6) 153.16 (s, 3H), 5.37 (s, 2H), 7.38 (m, 3H), 7.46 (m, 2H), 7.65 (m, 4H), 8.59 (s, 1H), 11.6 (s, 1H). MS (FAB) m/z 333.3 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]([F:45])([F:44])[F:43])[C@H:9]([CH3:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20](=[O:22])[NH2:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([O:28]C)=O)[CH2:15][CH2:14]2)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH3:46].[C-]#N.[Na+]>CO>[C:1]([O:5][C:6]([N:8]([CH2:31][CH2:32][O:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[O:40][CH2:41][C:42]([F:43])([F:45])[F:44])[C@H:9]([CH3:30])[CH2:10][C:11]1[CH:12]=[C:13]2[C:17](=[C:18]([C:20](=[O:22])[NH2:21])[CH:19]=1)[N:16]([CH2:23][CH2:24][CH2:25][C:26]([NH2:46])=[O:28])[CH2:15][CH2:14]2)=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CCCN1CCc2cc(C[C@@H](C)N(CCOc3ccccc3OCC(F)(F)F)C(=O)OC(C)(C)C)cc(C(N)=O)c21
Reactant: N
Agent: [C-]#N
Agent: [Na+]
Solvent: CO
Product: C[C@H](Cc1cc2c(c(C(N)=O)c1)N(CCCC(N)=O)CC2)N(CCOc1ccccc1OCC(F)(F)F)C(=O)OC(C)(C)C
Temperature: 50 °C
Reaction time: 71 h

Procedure:
To a solution of methyl (R)-(-)-4-[5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-carbamoylindolin-1-yl]butyrate (187 mg) in a saturated ammonia in methanol (2 ml) was added sodium cyanide (2 mg), and the mixture was stirred in a sealed tube at 50° C. for 71 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by medium pressure liquid column chromatography on silica gel using a mixture of methylene chloride, diethyl ether and methanol (5/5/1) as eluent to give 145 mg of (R)-(-)-4-[5-[2-[N-tert-butoxycarbonyl-2-[2-(2,2,2-trifluoroethoxy)phenoxy]ethylamino]propyl]-7-carbamoylindolin-1-yl]butyramide as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([OH:18])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1.C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C1C=CC=CC=1>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:19])([CH:16]([O:18][S:28]([CH3:27])(=[O:30])=[O:29])[CH3:17])[CH2:10][N:11]1[CH:15]=[CH:14][N:13]=[N:12]1
Reactant: CS(=O)(=O)Cl
Reactant: CC(O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: CC(OS(C)(=O)=O)C(O)(Cn1ccnn1)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 100.4 %

Procedure:
To a suspension of 2-(2,4-dichlorophenyl)-3-hydroxy-1-(triazol-1-yl)butan-2-ol (1.0 g; 3.3 mmol) obtained in Reference Example 3 in benzene (10 ml) was added triethylamine (1.0 g; 9.9 mmol) and methanesulfonyl chloride (0.76 g; 6.6 mmol) at 25 to 40° C., and the mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into ice water and extracted with ethyl acetate. The organic layer was washed with aqueous sodium hydrogen bicarbonate and water, dried over magnesium sulfate and evaporated in vacuo to give 2-(2,4-dichlorophenyl)-3-mesyloxy-1-(triazol-1-yl)butan-2-ol (1.26 g, 100 %) as crystals m.p., 147-149° C.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]([O:12][CH2:13][CH2:14][OH:15])[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C(P(CCCC)CCCC)CCC.[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42](O)=[CH:41][CH:40]=1)[CH3:34].C1CCN(C(N=NC(N2CCCCC2)=O)=O)CC1>C1C=CC=CC=1.CCCCCCC>[CH2:33]([O:35][C:36](=[O:49])[CH:37]([O:46][CH2:47][CH3:48])[CH2:38][C:39]1[CH:44]=[CH:43][C:42]([O:15][CH2:14][CH2:13][O:12][CH:10]2[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][O:6][C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]2=3)=[CH:41][CH:40]=1)[CH3:34]
Reactant: CCOC(=O)C(Cc1ccc(O)cc1)OCC
Reactant: OCCOC1c2ccccc2COc2ccccc21
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: CCCCCCC
Solvent: c1ccccc1
Product: CCOC(=O)C(Cc1ccc(OCCOC2c3ccccc3COc3ccccc32)cc1)OCC
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 36.7 %

Procedure:
Under a nitrogen atmosphere, 2-(6,11-dihydrodibenzo[b,e]oxepin-11-yloxy)-ethanol (256 mg, 1.0 mmol), tributylphosphine (223 mg, 1.1 mmol) and 2-ethoxy-3-(4-hydroxy-phenyl)-propionic acid ethyl ester (262 mg, 1.1 mmol) were successively dissolved in dry benzene (10 mL). Solid azodicarboxylic dipiperidine (ADDP) (278 mg, 1.1 mmol) was added under stirring at 0° C. to the solution. After 10 min, the reaction mixture was brought to room temperature and the stirring was continued for 16 h. Heptane (10 mL) was added to the reaction mixture and dihydro-ADDP separated out was filtered off. After evaporation of the solvent the product was purified chromatography eluting with ethyl acetate/heptane (1:4) to give 175 mg (37%) of the title compound: 1H NMR (300 MHz, CDCl3) δ1.15 (t, 3H), 1.25 (t, 3H), 2.93 (d, 2H), 3.30-3.40 (m, 1H), 3.55-3.65 (m, 1H), 3.65-3.75 (m, 1H),3.78-3.88 (m,1 H), 3.95 (t, IH), 4.10 (t, 2H), 4.15 (q, 2H), 4.85 (d, 1H), 5.25 (s, 1H), 6.15 (d, 1H), 6.75 (d,2H), 6.85-6.95 (m, 2H), 7.10 (d, 2H), 7.15-7.40 (m, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([OH:17])=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=[O:21]>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][C:15]([O:17][CH2:19][C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=1)=[O:21])=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CC(=O)O
Reactant: N#Cc1cccc(C(=O)CBr)c1
Product: CC(C)(C)OC(=O)N1CCCCC1CC(=O)OCC(=O)c1cccc(C#N)c1
Yield: 82.7 %

Procedure:
The title compound (1.51 g) was prepared from (RS)-2-carboxymethyl-piperidine-1-carboxylic acid tert butyl ester (1.15 g) and 2-bromo-3′-cyanoacetophenone (1.06 g) according to the method of description 36.
Reaction SMILES: I[CH2:2][C@H:3]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6](=[O:15])[CH2:5][CH2:4]1.[Cl-].[Li+].[CH:18]([Mg]Cl)=[CH2:19].Cl>O1CCCC1>[C:9]1([CH2:8][N:7]2[C@H:3]([CH2:2][CH:18]=[CH2:19])[CH2:4][CH2:5][C:6]2=[O:15])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=C1CC[C@@H](CI)N1Cc1ccccc1
Reactant: C=C[Mg]Cl
Agent: Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CC[C@@H]1CCC(=O)N1Cc1ccccc1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of (S)-5-iodomethyl-1-(phenylmethyl)-2-pyrrolidinone (31.5 g, 0.1 mol) in 250 mL of anhydrous tetrahydrofuran was added a solution of Li2CuCl4 (7.5 mL of a 0.1M solution in tetrahydrofuran; prepared from anhydrous lithium chloride (85 mg) and anhydrous cupric chloride (134.5 mg) in 10 mL of tetrahydrofuran). The solution was cooled to -78° C. and vinyl magnesium chloride (200 mL of 1M solution in tetrahydrofuran) was added over a 25 min period. After stirring for 1 h at -78° C., a second portion of vinyl magnesium chloride (200 mL of 1M solution) was added as before. After stirring for another 1 h, a third portion (200 mL of 1M solution) was added as before, and the mixture was stirred at -78° C. overnight. The cold solution was then poured onto 1.5 kg of ice and was acidified with 100 mL of 6N hydrochloric acid (HCl). The mixture was extracted with methylene chloride, washed with saturated sodium bicarbonate and brine, and dried over MgSO4. The solution was concentrated on a rotary evaporator to give 23.8 g of crude (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone as a brown oil. The crude product was chromatographed on 700 g of silica gel, eluting with 50% ethyl acetate in hexanes to give 14.2 g (66% yield) of the pure (S)-1-(phenylmethyl)-5-(2-propenyl)-2-pyrrolidinone as a colorless oil. 1H NMR (CDCl3) δ 1.7-2.75 (m, 6 H, CH2 's), 3.51 (m, 1 H, NCH), 4.99 and 5.02 (AB, Jgem =15 Hz, 2 H, CH2Ph), 5.0-5.2 (m, 2 H, vinyl H), 5.4-5.9 (m, 1 H, vinyl H), 7.25-7.40 (m, 5 H, phenyl).
Reaction SMILES: Br[C:2]1[CH:17]=[CH:16][CH:15]=[C:14]([Si:18]([CH3:21])([CH3:20])[CH3:19])[C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH3:13])=[O:5].C1COCC1.[Li]C(CC)C.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1CCCCC1>[CH3:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=1[NH:6][C:4](=[O:5])[C:3]1[CH:2]=[CH:17][CH:16]=[CH:15][C:14]=1[Si:18]([CH3:21])([CH3:20])[CH3:19]
Reactant: Cc1ccccc1NC(=O)c1c(Br)cccc1[Si](C)(C)C
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]C(C)CC
Solvent: C1CCOC1
Solvent: C1CCCCC1
Product: Cc1ccccc1NC(=O)c1ccccc1[Si](C)(C)C
Reaction time: 0.5 h
Yield: 54 %

Procedure:
The compound of Example 120 (0.0021 mol, 0.75 g) and 50 mL THF were cooled to -78° C. in a nitrogen atmosphere with magnetic stirring. 1.3M s-BuLi (0.0026 mol, 2 mL) in cyclohexane was added dropwise. After stirring for 30 min, 25 mL of 25% citric acid were added. The mixture was then extracted three times with ethyl acetate, the extracts combined and washed with brine and twice with water, dried (MgSO4) and concentrated. The title compound was recrystallized as a white solid from ethyl acetate/hexanes in 54% yield. m.p. 117°-119° C.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][N:4]=[C:3]1SC.[CH3:9][NH:10][NH2:11]>>[CH3:9][N:10]([C:3]1[N:2]([CH3:1])[CH2:6][CH2:5][N:4]=1)[NH2:11]
Reactant: CSC1=NCCN1C
Reactant: CNN
Product: CN(N)C1=NCCN1C

Procedure:
N-Methyl-N-(1-methyl-4,5-dihydro-1H-imidazol-2-yl)-hydrazine is prepared according to Step B of Example 25 using 1-methyl-2-methylsulfanyl-4,5-dihydro-1H-imidazole and methyl hydrazine.
Reaction SMILES: [OH-].[Na+].[C:3]([O:7][C:8](=[O:25])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([NH:19]C(OCC)=O)=[S:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:5])[CH3:4]>O.CCO>[C:3]([O:7][C:8](=[O:25])[NH:9][C@H:10]1[CH2:15][CH2:14][C@H:13]([NH:16][C:17]([NH2:19])=[S:18])[CH2:12][CH2:11]1)([CH3:6])([CH3:4])[CH3:5]
Reactant: CCOC(=O)NC(=S)N[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N[C@H]1CC[C@H](NC(N)=S)CC1
Reaction time: 0.5 h

Procedure:
7.4 ml of 4M NaOH are added to a suspension of 1.69 g of [trans-4-(3-ethoxycarbonyl-thioureido)cyclohexyl]carbamic acid tert-butyl ester in 10 ml of H2O and 15 ml of EtOH. The mixture obtained is kept at 90° for 30 minutes at RT. The precipitate formed is filtered and washed with diethylether. (trans-4-Thioureido-cyclohexyl)-carbamic acid tert-butyl ester is obtained.
Reaction SMILES: Cl[C:2]1[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=1[N+:13]([O-:15])=[O:14].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>CN(C=O)C>[C:17]1([NH:16][C:2]2[C:9]([N+:10]([O-:12])=[O:11])=[CH:8][C:5]([C:6]#[N:7])=[CH:4][C:3]=2[N+:13]([O-:15])=[O:14])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: N#Cc1cc([N+](=O)[O-])c(Cl)c([N+](=O)[O-])c1
Reactant: Nc1ccccc1
Solvent: CN(C)C=O
Product: N#Cc1cc([N+](=O)[O-])c(Nc2ccccc2)c([N+](=O)[O-])c1
Temperature: 0 °C

Procedure:
To a cooled (5° C.) solution of 4-chloro-3,5-dinitrobenzonitril (50 g, 0.22 mol) in anhydrous DMF (200 ml) was added aniline (40 ml, 0.44 mol) dropwise over 1 hour. The resultant mixture was stirred for additionally 1 hour at 0° C. and then poured into ice-water (1400 g). The precipitate was filtered off, washed with water and air-dried to afford N-phenyl-4-cyano-2,6-dinitroaniline, quantitatively.
Reaction SMILES: [F:1][C:2]1([F:33])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29](O)=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:34][S:35]([NH2:38])(=[O:37])=[O:36].C(Cl)CCl>CN(C1C=CN=CC=1)C.C(Cl)Cl>[F:33][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([CH3:32])=[C:21]([C:23]5[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([NH:38][S:35]([CH3:34])(=[O:37])=[O:36])=[O:30])[CH:24]=5)[CH:22]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)O)c1
Reactant: CS(N)(=O)=O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: ClCCCl
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)cc1-c1cccc(C(=O)NS(C)(=O)=O)c1
Reaction time: 18 h

Procedure:
To a mixture of 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methylbiphenyl-3-carboxylic acid (50 mg, 0.11 mmol), methansulfonamide (7.0 mg, 0.074 mmol), DMAP (13 mg, 0.11 mmol), and CH2Cl2 (1 mL) was added EDC (28 mg, 0.15 mmol) at ambient temperature. The mixture was allowed to stir for 18 h before it was concentrated. The residue was taken up in DMF (1 mL) and was purified by reverse phase preparatory HPLC to provide 5′-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-methyl-N-(methylsulfonyl)biphenyl-3-carboxamide as a white solid. ESI-MS m/z calc. 528.5, found 529.2 (M+1)+. Retention time 1.97 minutes.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1.Cl.[NH2:22][OH:23].C([O-])(=O)C.[Na+]>C(O)C.O>[OH:23][N:22]=[C:2]1[CH2:7][CH2:6][N:5]([C:8]([C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14][CH2:13]3)=[O:9])[CH2:4][CH2:3]1
Reactant: NO
Reactant: O=C1CCN(C(=O)c2ccc3c(c2)CCC(=O)N3)CC1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: O=C1CCc2cc(C(=O)N3CCC(=NO)CC3)ccc2N1

Procedure:
37 Grams of 6-(4-oxo-1-piperidylcarbonyl)-3,4-dihydrocarbostyril, 30.3 g of hydroxylamine.hydrochloride and 83.5 g of sodium acetate were dissolved in 600 ml of ethanol and 300 ml of water, the mixture was stirred overnight at room temperature. The crystals precipitated were collected by filtration, and recrystallized from ethanol to yield 16 g of 6-(4-hydroxylimino-1-piperidylcarbonyl)-3,4-dihydrocarbostyril.