Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH2:16])[C:8]=32)=[N:3]1.C(N(CC)CC)C.[C:24](OC(=O)C)(=[O:26])[CH3:25]>O1CCCC1.C(=O)([O-])O.[Na+].C(OCC)(=O)C>[CH3:1][N:2]1[CH:10]=[C:9]2[C:4]([CH:5]=[CH:6][C:7]3[CH2:13][CH2:12][C:11](=[CH:14][CH2:15][NH:16][C:24](=[O:26])[CH3:25])[C:8]=32)=[N:3]1
Reactant: CC(=O)OC(C)=O
Reactant: Cn1cc2c3c(ccc2n1)CCC3=CCN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)NCC=C1CCc2ccc3nn(C)cc3c21
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
2-(2-Methyl-6,7-dihydrocyclopenta[e]indazol-8(2H)-ylidene)ethanamine (400 mg, 1.88 mmol) was dissolved in tetrahydrofuran (19 mL), triethylamine (287 μL, 2.06 mmol) and acetic anhydride (195 μL, 2.06 mmol) were added under ice-cooling, and the mixture was stirred for 15 min. The reaction solution was diluted with saturated aqueous sodium hydrogen carbonate solution, diluted with ethyl acetate, washed with water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography (methanol/ethyl acetate=0/100→10/90) to give the title compound (393 mg, yield 82%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[N:8]=[CH:7][C:6]([CH:9]=O)=[CH:5][CH:4]=1.[CH2:13]([O:20][C:21]([NH:23][CH:24](P(OC)(OC)=O)[C:25]([O:27][CH3:28])=[O:26])=[O:22])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1COCC1>[CH2:13]([O:20][C:21]([NH:23]/[C:24](=[CH:9]\[C:6]1[CH:7]=[N:8][C:3]([C:2]([F:12])([F:11])[F:1])=[CH:4][CH:5]=1)/[C:25]([O:27][CH3:28])=[O:26])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=Cc1ccc(C(F)(F)F)nc1
Reactant: COC(=O)C(NC(=O)OCc1ccccc1)P(=O)(OC)OC
Solvent: C1CCOC1
Product: COC(=O)/C(=C/c1ccc(C(F)(F)F)nc1)NC(=O)OCc1ccccc1
Temperature: -70 °C
Reaction time: 12 h

Procedure:
6-Trifluoromethylpyridine-3-carbaldehyde (4.85 g, 27.70 mmol) and methyl {[benzyloxycarbonyl]amino}(dimethoxyphosphoryl)acetate (9.17 g, 27.70 mmol, 1.0 equivalent) are dissolved in THF (70 ml) and cooled to −70° C. At −70° C., N,N,N,N-tetramethylguanidine (6.38 g, 55.39 mmol, 6.95 ml, 2.0 equivalents) is slowly added dropwise and then the mixture is stirred at −70° C. for 4 h, subsequently at RT for 12 h. The reaction mixture is concentrated, and extracted with ethyl acetate (2×100 ml) against water. The combined organic phases are washed with a saturated sodium chloride solution, dried over sodium sulfate and filtered. After concentration, the crude product is chromatographed (silica gel, eluent: toluene, then toluene: ethyl acetate 10:1). 6.93 g (66% of theory) of the title compound are obtained.
Reaction SMILES: [CH2:1]([N:3]([CH2:11][CH3:12])[C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)[CH3:2].CS(C)=O.[OH-].[Na+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25]>C1(C)C=CC=CC=1>[CH2:11]([N:3]([CH2:1][CH3:2])[C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:20][CH2:21][CH2:22][Si:23]([O:28][CH3:29])([O:26][CH3:27])[O:24][CH3:25])[CH3:12]
Reactant: CO[Si](CCCCl)(OC)OC
Reactant: CCN(CC)c1cccc(O)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CS(C)=O
Product: CCN(CC)c1cccc(OCCC[Si](OC)(OC)OC)c1
Temperature: 88 °C

Procedure:
Using the general procedure described in the preceding Example 1, a reactor was charged with 90.75 g (0.55 mole) m-diethylaminophenol, 112 cc dimethylsulfoxide, 120 cc toluene and 43.28 g of a 50% aqueous sodium hydroxide solution. All of the water present in the reactor was removed by azeotropic distillation. The reaction mixture was allowed to cool to 80° C., at which time 109 g (0.55 mole) of chloropropyl trimethoxysilane were gradually added over a period of 2 hours. The temperature of the reaction mixture increased to 88° C. during the addition. Following completion of the addition, external heating was applied to maintain the temperature of the reaction mixture at 80° C. for 16 hours. The reaction mixture was then allowed to cool and was filtered. The liquid phase was recovered and evaporated under a pressure of 5 mm of mercury to remove the toluene and dimethylsulfoxide. The pressure inside the reactor was reduced to 2 mm and the product, 3(m-diethylaminophenoxy)propyl trimethoxysilane, distilled at a temperature of 185°-187° C. Analysis by vapor phase chromatography demonstrated that the product was 97% pure.
Reaction SMILES: Cl.[C:2]([NH:6][OH:7])([CH3:5])([CH3:4])[CH3:3].C=O.[P:10]([O-:27])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[C:28](=O)(O)[O-].[Na+]>O1CCCC1>[C:2]([N:6]([CH2:28][P:10](=[O:27])([O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[OH:7])([CH3:5])([CH3:4])[CH3:3]
Reactant: [O-]P(OCc1ccccc1)OCc1ccccc1
Reactant: O=C([O-])O
Reactant: CC(C)(C)NO
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N(O)CP(=O)(OCc1ccccc1)OCc1ccccc1
Temperature: 55 °C
Yield: 63.3 %

Procedure:
Using the procedure of Example 1, the above-named compound is prepared from 5.0 g (40 mmol) of N-tert-butylhydroxylamine hydrochloride, 2.4 g (80 mmol) of paraformaldehyde, 9.0 g (41 mmol) of dibenzyl phosphite, 3.0 g (40 mmol) of sodium bicarbonate and 200 ml of tetrahydrofuran (THF) by heating at 55° C. for 14 hours. The residue is purified by recrystallization from a mixture of methylene chloride and hexane to give 9.2 g (64% yield) of a white solid melting at 106°-107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH:9]([CH3:28])[C:10]([C:16]1[CH:17]=[CH:18][C:19]2[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=2[CH:27]=1)([OH:15])[C:11]([F:14])([F:13])[F:12].[CH2:29]([O:31][C:32]([C:34]1[CH:35]=[C:36](B(O)O)[CH:37]=[CH:38][CH:39]=1)=[O:33])[CH3:30].N1C=CC=CC=1>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH2:29]([O:31][C:32](=[O:33])[C:34]1[CH:35]=[CH:36][CH:37]=[C:38]([O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([CH:9]([CH3:28])[C:10]([OH:15])([C:16]3[CH:17]=[CH:18][C:19]4[O:24][CH2:23][C:22](=[O:25])[N:21]([CH3:26])[C:20]=4[CH:27]=3)[C:11]([F:12])([F:13])[F:14])[CH:4]=2)[CH:39]=1)[CH3:30]
Reactant: CC(c1cc(O)ccc1Cl)C(O)(c1ccc2c(c1)N(C)C(=O)CO2)C(F)(F)F
Reactant: CCOC(=O)c1cccc(B(O)O)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1cccc(Oc2ccc(Cl)c(C(C)C(O)(c3ccc4c(c3)N(C)C(=O)CO4)C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 95.8 %

Procedure:
To a solution of 6-[2-(2-chloro-5-hydroxy-phenyl)-1-hydroxy-1-trifluoromethyl-propyl]-4-methyl-4H-benzo[1,4]oxazin-3-one (Example 1, step 4, 150 mg) in CH2Cl2 (3 ml) were added 3-ethoxycarbonylphenylboronic acid (210 mg), copper-(II)-acetate (197 mg), molecular sieve and pyridine (143 mg). The mixture was stirred at room temperature under an air atmosphere with exclusion of moisture for 18 hours. The mixture was filtered, diluted with CH2Cl2 and washed with 1 M aqueous HCl. The organic phase was dried (MgSO4), filtered and concentrated to dryness. The product was purified by chromatography (SiO2, cyclohexane/EtOAc 1:0=>1:1) to give the title compound (195 mg) as a colorless foam. MS (m/e)=564.2 [M+H+].
Reaction SMILES: C(N(CC)CC)C.[C:8](OC(=O)C)(=[O:10])[CH3:9].[CH3:15][C:16]1([CH3:30])[C:20]([CH3:22])([CH3:21])[O:19][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH2:29])=[N:27][CH:28]=2)[O:17]1>CN(C)C1C=CN=CC=1.ClCCl>[CH3:22][C:20]1([CH3:21])[C:16]([CH3:30])([CH3:15])[O:17][B:18]([C:23]2[CH:24]=[CH:25][C:26]([NH:29][C:8](=[O:10])[CH3:9])=[N:27][CH:28]=2)[O:19]1
Reactant: CC(=O)OC(C)=O
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)Nc1ccc(B2OC(C)(C)C(C)(C)O2)cn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.1 %

Procedure:
4-dimethylaminopyridine (17 mg, 0.139 mmol), triethylamine (0.19 mL, 1.36 mmol) and acetic anhydride (153 mg, 1.50 mmol) were added sequentially to a solution of 5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-amine (300 mg, 1.36 mmol) in dichloromethane (15 mL). The reaction mixture was stirred at room temperature for 0.5 h, then diluted with 30 mL of dichloromethane, washed with 50 mL of a saturated aqueous solution of ammonium chloride. The organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated to give 225 mg of the product.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][C:5](=[O:8])[CH:4]([CH3:9])[CH2:3]1.[H-].[Na+].Br[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=1)=[CH2:15]>CN(C=O)C>[F:22][C:19]1[CH:20]=[CH:21][C:16]([C:14](=[CH2:15])[CH2:13][C:4]2([CH3:9])[C:5](=[O:8])[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]2)=[CH:17][CH:18]=1
Reactant: CC1CN(C)CCC1=O
Reactant: C=C(CBr)c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=C(CC1(C)CN(C)CCC1=O)c1ccc(F)cc1
Reaction time: 0.08 h
Yield: 52.1 %

Procedure:
To a stirred solution of 1,3-dimethylpiperidin-4-one (2.8 g, 22.04 mmol) in DMF (10 mL) was added sodium hydride (970 mg, 24.25 mmol) at 0° C. After stiffing for 5 min, 1-(1-bromomethyl-vinyl)-4-fluoro-benzene (4.74 g, 22.04 mmol) was added dropwise and stirring was continued for 30 min. The reaction was quenched with ice water and extracted with EtOAc (2×100 mL). The combined organic layer was washed with water (4×100 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was purified by column chromatography using silica (100:200) and 10% EtOAc-Hex as eluent to yield 3 g of 3-[2-(4-fluoro-phenyl)-allyl]-1,3-dimethyl-piperidin-4-one.
Reaction SMILES: [NH2:1][C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6].[C:10](Cl)([O:12][CH2:13][CH:14]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]2[C:15]1=[CH:16][CH:17]=[CH:18][CH:19]=2)=[O:11].O>O1CCOCC1>[NH:1]([C:10]([O:12][CH2:13][CH:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21]2[C:26]1=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:11])[C@@H:2]([C:7]([OH:9])=[O:8])[CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCC[C@@H](N)C(=O)O
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Solvent: C1COCCO1
Solvent: O
Product: CCCC[C@@H](NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Yield: 34.3 %

Procedure:
D-Nle-OH (1.01 g) was dissolved in 30 ml of 10% NaCO3 and 10 ml of dioxan. While stirring, a solution of Fmoc-Cl (2.0 g) in 10 ml of dioxan was added to the solution. After stirring at room temperature for 2 hours, 400 ml of water was added to the mixture. The reaction mixture was extracted twice with 200 ml of ether to remove by-products. Ice was added to the aqueous phase and the mixture was neutralized with conc. hydrochloric acid. After extracting with ethyl acetate, the extract was washed with water. Crystallization from ether gave 933 mg of Fmoc-D-Nle-OH.
Reaction SMILES: [CH:1]1([CH2:6][N:7]([C:20]2[CH:25]=[CH:24][C:23](S(C)(=O)=O)=[CH:22][CH:21]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1(CNC2C=CC=CC=2[Br:43])CCCC1.C([O:46][C:47](=[O:56])[CH2:48][S:49]C1SC(N)=NC=1)C>>[Br:43][C:25]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:7]([CH2:6][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5]1)[C:8](=[O:19])[NH:9][C:10]1[S:11][C:12]([S:49][CH2:48][C:47]([OH:46])=[O:56])=[CH:13][N:14]=1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Reactant: Brc1ccccc1NCC1CCCC1
Product: O=C(O)CSc1cnc(NC(=O)N(CC2CCCC2)c2ccccc2Br)s1

Procedure:
The title compound was prepared via {2-[3-(2-bromo-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(2-bromo-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: CC(O)CNCC(O)C.C(OC(OCC)[N:14]1[CH:18]=[CH:17][N:16]=[CH:15]1)C.[N:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[CH2:32][O:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][N:42]2[CH2:47][CH2:46][C:45](=[C:48]3[C:54]4[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=4[CH2:52][CH2:51][N:50]4[C:59]([CH:62]=[O:63])=[CH:60][N:61]=[C:49]34)[CH2:44][CH2:43]2)=[CH:36][CH:35]=1.C([O-])([O-])=O.[K+].[K+]>C1COCC1.C(O)(=O)C>[NH:14]1[CH:18]=[CH:17][N:16]=[C:15]1[CH:62]([C:59]1[N:50]2[C:49]([C:48](=[C:45]3[CH2:44][CH2:43][N:42]([CH2:41][CH2:40][C:37]4[CH:38]=[CH:39][C:34]([O:33][CH2:32][C:23]5[CH:24]=[CH:25][C:26]6[C:31](=[CH:30][CH:29]=[CH:28][CH:27]=6)[N:22]=5)=[CH:35][CH:36]=4)[CH2:47][CH2:46]3)[C:54]3[CH:55]=[CH:56][CH:57]=[CH:58][C:53]=3[CH2:52][CH2:51]2)=[N:61][CH:60]=1)[OH:63]
Reactant: O=Cc1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Reactant: CCOC(OCC)n1ccnc1
Agent: CC(O)CNCC(C)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: OC(c1ncc[nH]1)c1cnc2n1CCc1ccccc1C2=C1CCN(CCc2ccc(OCc3ccc4ccccc4n3)cc2)CC1
Temperature: -78 °C
Yield: 98.1 %

Procedure:
A mixture of diisopropanolamine (1.13 g) in TBF was stirred under nitrogen at −78° C. N-Butillithium (2.5 M in hexanes, 4.3 ml) was added portionwise at −70° C. and the mixture was stirred for 15 minutes. 1-(Diethoxymethyl)-1H-imidazole (1.81 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. Compound 4 (5.54 g) dissolved in THF was added dropwise at −70° C. and the mixture was stirred at −70° C. for 1 hour. The mixture was brought till room temperature and it was stirred at room temperature overnight. Acetic acid (5 ml) was added and the mixture was stirred at room temperature for 20 minutes. K2CO3 (5 g) was added and the mixture was evaporated. The residue was taken up in water and DCM and the layers were separated. The aqueous layer was extracted with DCM. The combined organic layers were dried, filtered off and the solvent was evaporated, yielding 6.1 g (97%) of 6,11-dihydro-α-(1H-imidazol-2-yl)-11-[1-[2-[4-(2-quinolinylmethoxy)phenyl]ethyl]-4-piperidinylidene]-5H-imidazo[2,1-b][3]benzazepine-3-methanol (compound 46).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[CH:7]=[CH:6][C:5]=1[O:13][CH3:14].CO.[H][H]>[Pt]=O.O1CCCC1>[CH3:1][O:2][C:3](=[O:15])[C:4]1[CH:9]=[C:8]([NH2:10])[CH:7]=[CH:6][C:5]=1[O:13][CH3:14]
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1OC
Reactant: [H][H]
Agent: O=[Pt]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(N)ccc1OC

Procedure:
A 2 liter Parr Bottle was charged with 11.6 grams (55 mmol) methyl-2-methoxy-5-nitrobenzoate, 450 mL of methanol and 150 mL of tetrahydrofuran (THF). Platinum oxide was added (460 mg) and the mixture was hydrogenated under 45 psi hydrogen for 1 hour. The reaction mixture was filtered through Celite® (diatomaceous earth) and evaporated. The reaction mixture was diluted with 500 mL of methylene chloride, and then washed with water and brine. The organic phase was dried and evaporated (9.9 grams). This material was used without further purification.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][C:7]([CH2:18][CH:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9].[CH2:25]=O.Cl.[CH3:28][NH:29][CH3:30]>>[CH3:28][N:29]([CH2:25][C:5]1[O:1][C:2]([CH2:6][C:7]([CH2:18][CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]2)([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[CH:3][CH:4]=1)[CH3:30]
Reactant: CCOC(=O)C(Cc1ccco1)(CC1CCCCC1)C(=O)OCC
Reactant: CNC
Reactant: C=O
Agent: Cl
Product: CCOC(=O)C(Cc1ccc(CN(C)C)o1)(CC1CCCCC1)C(=O)OCC

Procedure:
ethyl 3-(fur-2-yl)-2-cyclohexylmethyl-2-ethoxycarbonyl-propanoate, which by reaction with formaldehyde and dimethylamine hydrochloride yields ethyl 3-(5-dimethylaminomethyl-fur-2-yl)-2-cyclohexylmethyl-2-ethoxycarbonyl-propanoate.
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@@H:2]1[C:6]([NH:8][C@H:9]([C:11]1[CH:20]=[CH:19][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:13][CH:12]=1)[CH3:10])=[O:7].[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26]Br)=[CH:24][CH:23]=1.C([O-])([O-])=O.[Na+].[Na+]>>[F:21][C:22]1[CH:29]=[CH:28][C:25]([CH2:26][N:1]2[CH2:5][CH2:4][CH2:3][C@@H:2]2[C:6]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][C:14]([C:15]([O:17][CH3:18])=[O:16])=[CH:19][CH:20]=2)[CH3:10])=[O:7])=[CH:24][CH:23]=1
Reactant: Fc1ccc(CBr)cc1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)c1ccc([C@H](C)NC(=O)[C@H]2CCCN2Cc2ccc(F)cc2)cc1

Procedure:
The title compound (D145) (22 mg) was prepared according to the general procedure for substituted benzyl amines preparation starting from methyl 4-((S)-1-((R)-pyrrolidine-2-carboxamido)ethyl)benzoate (D103) (50 mg) and 4-Fluorobenzyl bromide (0.045 ml). (Na2CO3; reaction time: 5 hrs; 70° C.).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[NH:27]([C:29]([C:31]1[CH:38]=[CH:37][C:34]([CH:35]=O)=[CH:33][CH:32]=1)=[O:30])[NH2:28]>>[NH:27]([C:29]([C:31]1[CH:38]=[CH:37][C:34]([C:35]2[NH:10][C:9]3[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]4[CH:20]=[CH:19][C:18]([N:21]5[CH2:25][CH2:24][CH2:23][CH2:22]5)=[CH:17][CH:16]=4)=[CH:5][C:4]=3[N:1]=2)=[CH:33][CH:32]=1)=[O:30])[NH2:28]
Reactant: NNC(=O)c1ccc(C=O)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: NNC(=O)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 230 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-hydrazinylcarbonylbenzaldehyde. [M+H]+ calcd for C25H24N6O2: 441.21; found: 441.51.
Reaction SMILES: [CH3:1]CCCCC.C1C=CC=CC=1.[CH3:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[CH3:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27]>[Pt].C1(C)C(C)=CC=CC=1.C1(C)C=CC=CC=1>[CH2:21]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[CH3:20].[CH3:13][CH:14]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])[CH3:1]
Reactant: CCCCCC
Reactant: CCCCCCC
Reactant: CCCCCCCC
Agent: [Pt]
Solvent: Cc1ccccc1C
Solvent: c1ccccc1
Solvent: Cc1ccccc1
Product: CCCCCC(C)C
Product: CCc1ccccc1

Procedure:
At very high hexane conversions (99%), benzene was formed in over 94% yield. Similarly, n-heptane yielded 96% toluene. Consistent with the non-acidic nature of this platinum catalyst, n-octane yielded predominantly ethylbenzene and ortho-xylene, 2-methylheptane produced mostly meta-xylene, and 3-methylheptane formed mainly ethylbenzene, para-, and ortho-xylene.
Reaction SMILES: [CH2:1]([C:5]1[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:9](=[O:26])[C:8]([CH:27]=O)=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].C([O-])(=[O:31])C.[NH4+].[BH3-]C#[N:36].[Na+:37]>C(O)(C)C>[NH2:36][CH2:27][C:8]1[C:9](=[O:26])[N:10]([CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]#[N:25])=[CH:14][CH:13]=2)[C:5]([CH2:1][CH2:2][CH2:3][CH3:4])=[CH:6][CH:7]=1.[OH-:31].[Na+:37]
Reactant: [BH3-]C#N
Reactant: CCCCc1ccc(C=O)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Reactant: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CC(C)O
Product: CCCCc1ccc(CN)c(=O)n1Cc1ccc(-c2ccccc2C#N)cc1
Product: [OH-]
Reaction time: 72 h

Procedure:
A suspension of 370 mg of 6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-3-formyl-1,2-dihydro-2-oxopyridine, 770 mg of ammonium acetate, 61 mg of NaBH3CN and 400 mg of a powdered 3 Å molecular sieve in 10 ml of isopropanol is stirred under argon for 3 days at 20°. It is filtered, the material on the filter is washed with methanol and the filtrate is evaporated. 3-Aminomethyl-6-butyl-1-(2'-cyanobiphenyl-4-ylmethyl)-1,2-dihydro-2-oxopyridine is obtained after conventional working-up (sodium hydroxide solution/methylene chloride), m.p. 118°.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[N:6]2[C:7](=[O:10])[CH2:8][CH2:9][C@@H:5]2[CH2:4][O:3]1.C([N-]C(C)C)(C)C.[Li+].C1COCC1.CCCCCCC.C(C1C=CC=CC=1)C.[CH3:40][C:41]([CH3:43])=[O:42]>C1COCC1>[OH:42][C:41]([CH:8]1[C:7](=[O:10])[N:6]2[C:2]([CH3:11])([CH3:1])[O:3][CH2:4][C@H:5]2[CH2:9]1)([CH3:43])[CH3:40]
Reactant: CC(C)=O
Reactant: CC1(C)OC[C@H]2CCC(=O)N21
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: C1CCOC1
Solvent: CCc1ccccc1
Product: CC(C)(O)C1C[C@@H]2COC(C)(C)N2C1=O
Temperature: -78 °C
Reaction time: 1 h
Yield: 66.3 %

Procedure:
To a solution of (R)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.68 g, 43.0 mmol) in THF (100 mL) cooled to −78° C., was added lithium diisopropylamide, 2.0 M solution in THF/heptane/ethylbenzene (43.0 mL, 86 mmol) and stirred at −78° C. for 1 h. The resulting mixture was treated with acetone, 99.8%, extra dry, acroseal (6.32 mL, 86 mmol) at −78° C. and then allowed to warm up to room temperature for 16 h. The reaction was quenched with sat. NH4Cl and extracted with EtOAc (2×200 mL). The combined extracts were washed with brine, dried over Na2SO4, filtered and concentrated to provide (7aR)-6-(2-hydroxypropan-2-yl)-3,3-dimethyltetrahydropyrrolo[1,2-c]oxazol-5(3H)-one (6.088 g, 28.5 mmol, 66.3% yield) as a yellow oil. 1H NMR (400 MHz, DMSO-d6) δ 4.50 (s, 1H), 4.07-4.18 (m, 1H), 3.98 (dd, J=8.0, 5.7 Hz, 1H), 3.32-3.35 (m, 1H), 2.50-2.56 (m, 1H), 2.22 (ddd, J=13.4, 7.2, 2.0 Hz, 1H), 1.83 (ddd, J=13.3, 10.4, 7.6 Hz, 1H), 1.54 (s, 3H), 1.32 (s, 3H), 1.21 (s, 3H), 1.14 (s, 3H). m/z (ESI, +ve) 214 (M+H).
Reaction SMILES: C(N(C(C)C)CC)(C)C.[F:10][C:11]1([F:40])[CH2:16][C@@H:15]([C:17](O)=[O:18])[C@H:14]([C:20]2[C:24]([C:25]3[CH:30]=[CH:29][C:28]([S:31]([CH3:34])(=[O:33])=[O:32])=[CH:27][CH:26]=3)=[CH:23][N:22]([CH2:35][C:36]([F:39])([F:38])[F:37])[N:21]=2)[CH2:13][CH2:12]1.Cl.[NH2:42][C:43]1([C:46]#[N:47])[CH2:45][CH2:44]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[C:46]([C:43]1([NH:42][C:17]([C@@H:15]2[CH2:16][C:11]([F:10])([F:40])[CH2:12][CH2:13][C@H:14]2[C:20]2[C:24]([C:25]3[CH:26]=[CH:27][C:28]([S:31]([CH3:34])(=[O:32])=[O:33])=[CH:29][CH:30]=3)=[CH:23][N:22]([CH2:35][C:36]([F:39])([F:37])[F:38])[N:21]=2)=[O:18])[CH2:45][CH2:44]1)#[N:47]
Reactant: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)O)cc1
Reactant: N#CC1(N)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CS(=O)(=O)c1ccc(-c2cn(CC(F)(F)F)nc2[C@@H]2CCC(F)(F)C[C@H]2C(=O)NC2(C#N)CC2)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Diisopropylethylamine (3.2 mL, 18 mmol) was added in one portion to a solution of (1R,2R)-5,5-difluoro-2-[4-[4-(methylsulfonyl)phenyl]-1-(2,2,2-trifluoroethyl)-1H-pyrazol-3-yl]cyclohexanecarboxylic acid (1.69 g, 3.63 mmol), 1-aminocyclopropanecarbonitrile hydrochloride (1.16 g, 9.83 mmol) and HATU (1.72 g, 4.53 mmol) in DMF (10 mL) with stirring at rt for 2.5 h. The reaction vessel contents were then partitioned between ethyl acetate and water and the layers were separated. The aqueous phase was extracted with additional ethyl acetate and the combined organics were washed with 2 M HCl, 10% Na2CO3 and saturated NaCl aqueous solutions, followed by drying over Na2SO4. Concentration in vacuo and flash chromatography on silica gel eluting with 22.5/77.5 acetone/benzene provided the title compound as a colorless powder upon trituration with a mixture of hexanes and ether. 1H NMR (400 MHz, acetone d6) δ 8.03 (1H, s), 7.99 (2H, d, J= 8.5 Hz), 7.83 (1H, overlapped m), 7.81 (2H, d, J= 8.5 Hz), 5.05 (2H, q, J= 8.8 Hz), 3.36 (1H, m), 3.18 (3H, s), 3.12 (1H, m), 2.23 (1H, m), 2.15-1.95 (4H, m), 1.79 (1H, m), 1.37 (2H, m), 1.05 (1H, m), 0.81 (1H, m). MS: (+ESI) 531.0 [M+H]+.