Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([N:8]([CH3:28])[CH:9]1[CH2:14][CH2:13][CH:12]([NH:15][CH2:16][C:17]2[CH:18]=[C:19](B(O)O)[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[NH2:29][C:30]1[CH:35]=[CH:34][C:33](Br)=[CH:32][N:31]=1>Cl>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:19]2[CH:20]=[CH:21][C:22]([O:23][CH3:24])=[C:17]([CH:18]=2)[CH2:16][NH:15][CH:12]2[CH2:13][CH2:14][CH:9]([N:8]([CH3:28])[C:1](=[O:2])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[CH2:10][CH2:11]2)=[CH:34][CH:35]=1
Reactant: Nc1ccc(Br)cn1
Reactant: COc1ccc(B(O)O)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: Cl
Product: COc1ccc(-c2ccc(N)nc2)cc1CNC1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 4 (900 mg, 2.29 mmol) is coupled to 2-amino-5-bromopyridine (475 mg, 2.74 mmol) using Method A. On completion, the cooled reaction mixture is diluted with 1 M HCl (10 mL) and extracted with TBME (3×10 mL). The aqueous phase is then basified to pH 9 by careful addition of solid NaHCO3 and extracted into EtOAc (50 mL) and DCM (3×50 mL). The combined organic phases are dried over Na2SO4 and reduced in vacuo to yield the crude title product.
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10].C(N(C(C)C)C(C)C)C.[Br:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](Cl)=[O:31])=[CH:28][CH:27]=1>C(Cl)Cl>[C:12]([O:11][C:9]([N:2]1[CH2:3][CH:4]2[CH:5]([CH2:6][N:7]([C:30](=[O:31])[C:29]3[CH:33]=[CH:34][C:26]([Br:25])=[CH:27][CH:28]=3)[CH2:8]2)[CH2:1]1)=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC2CN(C(=O)c3ccc(Br)cc3)CC2C1
Temperature: 0 °C
Reaction time: 14 h
Yield: 90.9 %

Procedure:
1.1 tert-Butyl hexahydropyrrolo[3,4-c]pyrrole-2(1H)-carboxylate (0.65 g; 3.06 mmol) is dissolved in 20 ml of DCM. N-Ethyldiisopropylamine for synthesis (1.56 ml; 9.19 mmol) is added and the mixture cooled to 0° C. Now 4-bromobenzoyl chloride for synthesis (0.74 g; 3.37 mmol) is dissolved in 10 ml of DCM and added dropwise to the reaction, followed by stirring at RT for 14 h. The reaction mixture is extracted with 50 ml of water. The organic layer is separated, dried over MgSO4, filtered off and then reduced to dryness under vacuo to afford 1.10 g (90.9%) 5-(4-bromo-benzoyl)-hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester 1 as a slight orange oil.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH3:12])=[N:7]2.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Br:28])[CH:23]=2)[CH:17]=[CH:16][C:15]=1[S:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:32][CH:31]=1>C(O)C>[Br:28][C:24]1[CH:23]=[C:22]([CH:27]=[CH:26][CH:25]=1)[CH2:21][O:20][C:18]1[CH:17]=[CH:16][C:15]([S:29][C:30]2[CH:31]=[CH:32][C:33]([NH:36][C:37](=[O:39])[CH3:38])=[CH:34][CH:35]=2)=[C:14]([NH:13][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH3:12])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:19]=1
Reactant: Cc1ccc2c(Cl)ccnc2n1
Reactant: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2N)cc1
Solvent: CCO
Product: CC(=O)Nc1ccc(Sc2ccc(OCc3cccc(Br)c3)cc2Nc2ccnc3nc(C)ccc23)cc1

Procedure:
The product from Example 1d (18 mg, 0.085 mmol) was reacted in ethanol (1 mL) with the product from Example 154a (37 mg, 0.085 mmol) for 18 h following the procedure from Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (15 mg, 30%). 1H NMR (300 MHz, DMSO-d6) δ ppm: 0.97 (t, J=7.35 Hz, 3H) 1.65-1.90 (m, 2H) 2.02 (s, 3H) 2.99 (t, J=7.54 Hz, 2H) 5.17 (s, 2H) 6.29 (d, J=6.99 Hz, 1H) 7.14 (d, J=8.82 Hz, 2H) 7.17-7.27 (m, 2H) 7.28-7.40 (m, 3H) 7.42 (d, J=8.46 Hz, 2H) 7.55 (d, J=7.72 Hz, 1H) 7.66 (s, 1H) 7.80 (d, J=8.46 Hz, 1H) 8.37 (d, J=6.99 Hz, 1H) 8.97 (d, J=8.82 Hz, 1H) 9.98 (s, 1H) 11.00 (s, 1H) 14.37 (s, 1H); MS (ESI+) m/z 613 (M+H)+.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1.[CH:19](=O)[CH:20]([CH3:22])[CH3:21].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH2:19]([NH:1][C@@H:2]1[CH2:7][N:6]([C:8]([O:10][C:11]([CH3:12])([CH3:13])[CH3:14])=[O:9])[CH2:5][C@H:4]([C:15]([O:17][CH3:18])=[O:16])[CH2:3]1)[CH:20]([CH3:22])[CH3:21]
Reactant: COC(=O)[C@@H]1C[C@H](N)CN(C(=O)OC(C)(C)C)C1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: COC(=O)[C@@H]1C[C@H](NCC(C)C)CN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
1-tert-Butyl 3-methyl (3R,5S)-5-aminopiperidine-1,3-dicarboxylate (1.83 g), isobutyraldehyde (0.78 ml) and acetic acid (0.49 ml) were dissolved in methanol (50 ml), and the mixture was stirred at room temperature for 30 min. Sodium triacetoxyborohydride (3.80 g) was added to the reaction mixture, and the mixture was stirred at room temperature for 7 hr. The reaction mixture was concentrated under reduced pressure, the concentrated solution was basified with aqueous sodium hydrogen carbonate, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography. The fraction eluted with ethyl acetate-hexane (1:1) to ethyl acetate 100% to ethyl acetate-methanol (9:1) was concentrated under reduced pressure to give the object compound (1.42 g) as an oil.
Reaction SMILES: [C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)([O:3]C)=O.N(C[C@@H]1CCCN1)[C:20]1[CH:25]=CC=C[CH:21]=1.[Cl-].[Mg+2].[Cl-].C([Mg]Br)(C)C>C1COCC1.CCOCC>[C:1]([CH:5]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:11][CH:10]2[N:6]1[CH2:7][CH2:8][CH2:9]2)(=[O:3])[CH:20]([CH3:25])[CH3:21]
Reactant: c1ccc(NC[C@@H]2CCCN2)cc1
Reactant: COC(=O)C1N(c2ccccc2)CC2CCCN21
Agent: CC(C)[Mg]Br
Agent: [Cl-]
Agent: [Mg+2]
Solvent: C1CCOC1
Solvent: CCOCC
Product: CC(C)C(=O)C1N(c2ccccc2)CC2CCCN21
Temperature: -70 °C
Yield: 79 %

Procedure:
2-Carbomethoxy-3-phenyl-1,3-diazabicyclo[3,3,0]octane prepared from 637 mg of (S)-2-(anilinomethyl)pyrrolidine was dissolved in 18 ml of THF, then admixed with 378 mg of anhydrous magnesium chloride, and refluxed for 10 minutes by heating. To the mixture cooled to -70° C., was added dropwise an ether solution containing 1.37 equivalents of isopropylmagnesium bromide. The resulting mixture was treated as in Example 12 to obtain 731 mg (79%) of 2-isobutyryl-3-phenyl-1,3-diazabicyclo[3,3,0]octane. NMR peaks: δ (ppm)=0.9 (3H, doublet), 1.1 (3H, doublet), 1.5-2.2 (4H, multiplet), 2.4-3.3 (4H, multiplet), 3.5-3.9 (2H, multiplet), 4.4 (1H, singlet), 6.2-7.1 (5H, multiplet).
Reaction SMILES: Cl.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH3:14])[N:9]([CH2:15][CH2:16][NH:17]C(=O)C1C=CC([N+]([O-])=O)=CC=1)[CH2:8][CH2:7]2.[N+:29]([C:32]1[CH:37]=[CH:36][C:35]([S:38]([Cl:41])(=[O:40])=[O:39])=[CH:34][CH:33]=1)([O-:31])=[O:30]>>[ClH:41].[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH:10]([CH3:14])[N:9]([CH2:15][CH2:16][NH:17][S:38]([C:35]1[CH:34]=[CH:33][C:32]([N+:29]([O-:31])=[O:30])=[CH:37][CH:36]=1)(=[O:39])=[O:40])[CH2:8][CH2:7]2
Reactant: O=[N+]([O-])c1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCN(CCNC(=O)c1ccc([N+](=O)[O-])cc1)C2C
Agent: Cl
Product: COc1ccc2c(c1)CCN(CCNS(=O)(=O)c1ccc([N+](=O)[O-])cc1)C2C

Procedure:
The title compound was prepared by Method A using 2-(2-aminoethyl)-1,2,3,4-tetrahydro-6-methoxy-1-methylisoquinoline (described in Example 178) and 4-nitrobenzenesulfonyl chloride to produce the desired product in 100% yield. This material was purified by flash silica gel chromatography using 10-100% EtOAc in hexane. The material obtained was treated with HCl/2-propanol (1.1 eq) to afford a beige solid; mp 167°-172° C.; IR (KBr) 1611, 1531,1507,1443,1347,1309,1248,1232,1168,1092,1029,852,745,739 and 607 cm-1.
Reaction SMILES: [CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47](O)[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2].C(N(S(F)(F)[F:62])CC)C.C(#N)C>C1COCC1>[CH2:1]([CH:3]1[CH:29]=[C:28]([CH3:30])[CH2:27][CH:26]([CH3:31])[CH2:25][CH:24]([O:32][CH3:33])[CH:23]2[O:34][C:19]([OH:38])([CH:20]([CH3:37])[CH2:21][CH:22]2[O:35][CH3:36])[C:18](=[O:39])[C:17](=[O:40])[N:16]2[CH:11]([CH2:12][CH2:13][CH2:14][CH2:15]2)[C:10](=[O:41])[O:9][CH:8]([C:42]([CH3:53])=[CH:43][CH:44]2[CH2:49][CH2:48][CH:47]([F:62])[CH:46]([O:51][CH3:52])[CH2:45]2)[CH:7]([CH3:54])[CH2:6][CH2:5][C:4]1=[O:55])[CH3:2]
Reactant: CCN(CC)S(F)(F)F
Reactant: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(O)C(OC)C3)C(C)CCC1=O)C(C)CC2OC
Solvent: C1CCOC1
Solvent: CC#N
Product: CCC1C=C(C)CC(C)CC(OC)C2OC(O)(C(=O)C(=O)N3CCCCC3C(=O)OC(C(C)=CC3CCC(F)C(OC)C3)C(C)CCC1=O)C(C)CC2OC

Procedure:
Treatment of 17-ethyl-1-hydroxy-12-[2'-(4"-hydroxy-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone with diethylaminosulfur trifluoride (DAST) in THF followed by 48% aqueous HF/acetonitrile as in Example 64 yields 17-ethyl-1-hydroxy-12-[2'-(4"-fluoro-3"-methoxycyclohexyl)-1'-methylvinyl]-23,25-dimethoxy-13,19,21,27-tetramethyl-11,28-dioxa-4-azatricyclo-[22.3.1.04,9 ]octacos-18-ene-2,3,10,16-tetraone.
Reaction SMILES: [NH2:1][C:2]1[CH:12]=[CH:11][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:4][CH:3]=1.[F:13][C:14]([F:21])([F:20])[C:15](OCC)=[O:16].C(N(CC)CC)C.Cl>CO>[F:13][C:14]([F:21])([F:20])[C:15]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([CH:6]=[CH:7][C:8]([OH:10])=[O:9])=[CH:11][CH:12]=1)=[O:16]
Reactant: CCOC(=O)C(F)(F)F
Reactant: Nc1ccc(C=CC(=O)O)cc1
Agent: Cl
Solvent: CO
Solvent: CCN(CC)CC
Product: O=C(O)C=Cc1ccc(NC(=O)C(F)(F)F)cc1
Yield: 94 %

Procedure:
A solution of 4-aminocinnamic acid (1.88 g), ethyl trifluoroacetate (6.8 ml) and triethylamine (4.8 ml) in 20 ml methanol was stirred at room temperature for 4 hours, and 0.3 mol/l hydrochloric acid was added thereto, on ice, to precipitate a solid, which was then filtered, washed with water, and then dried by heating under reduced pressure to give 4-(trifluoroacetylamino)cinnamic acid (2.81 g, 94%).
Reaction SMILES: Cl.[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][NH:5]1.[C:10](#[N:13])[CH:11]=[CH2:12]>>[OH:2][CH2:3][C@H:4]1[CH2:8][C@H:7]([CH3:9])[CH2:6][N:5]1[CH2:12][CH2:11][C:10]#[N:13]
Reactant: C[C@@H]1CN[C@@H](CO)C1
Reactant: C=CC#N
Agent: Cl
Product: C[C@H]1C[C@H](CO)N(CCC#N)C1

Procedure:
(2R,4S)-4-Methylpyrrolidine-2-carboxylic acid described in J. Chem. Soc. C, pp. 514-522 (1971) is reacted with di-tert-butyl dicarbonate to give (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid. (2R,4S)-1-tert-Butoxycarbonyl-4-methylpyrrolidine-2-carboxylic acid is reacted with methyl iodide in the presence of potassium carbonate in acetonitrile solvent to give methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate. Methyl (2R,4S)-1-tert-butoxycarbonyl-4-methylpyrrolidine-2-carboxylate is reduced with lithium borohydride to give (2R,4S)-1-tert-butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine. (2R,4S)-1-tert-Butoxycarbonyl-2-hydroxymethyl-4-methylpyrrolidine is reacted with 4N hydrogen chloride-dioxane to give (2R,4S)-2-hydroxymethyl-4-methylpyrrolidine hydrochloride. (2R,4S)-2-Hydroxymethyl-4-methylpyrrolidine hydrochloride is reacted with acrylonitrile to give 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile. In the same manner as in Example 1b (e) and using 3-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]propionitrile and N,N-diethyl-2,3-dimethylbenzamide, 3-{2-[(2R,4S)-2-hydroxymethyl-4-methylpyrrolidin-1-yl]ethyl}-5-methyl-2H-isoquinolin-1-one is obtained.
Reaction SMILES: [C:1]1([N:7]([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[C:8]([O:10][CH2:11][CH2:12][C:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][CH:14]=2)=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].OO.C(OCC)(=[O:53])C>O1CCCC1.O>[C:41]1([N:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[C:8]([O:10][CH2:11][CH2:12][C@@H:13]2[C:22]3[C:17](=[C:18]([O:23][Si:24]([C:37]([CH3:40])([CH3:39])[CH3:38])([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=4)[CH:19]=[CH:20][CH:21]=3)[CH2:16][CH2:15][C@H:14]2[OH:53])=[O:9])[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(C)=O
Reactant: CC(C)(C)[Si](Oc1cccc2c1CCC=C2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)[Si](Oc1cccc2c1CC[C@@H](O)[C@@H]2CCOC(=O)N(c1ccccc1)c1ccccc1)(c1ccccc1)c1ccccc1
Reaction time: 4 h

Procedure:
To a solution of 1-[2-(N,N-diphenylcarbamoyloxy)-ethyl]-5-t-butyldiphenylsilyloxy-3,4-dihydronaphthalene (2.0 g) in THF (tetrahydrofuran) (20 ml) was added BH3 (4.8 ml, 1M solution in THF) at 0° C. under N2. After being stirred for 12 hours at the room temperature, 2N-NaOH solution (1.5 ml) and H2O2 (1.0 ml, 35% solution) were added to the solution and stirred for 4 hours. The mixture was poured into a mixture of ethyl acetate and water. The organic layer was washed with 1N-HCl solution, sat. NaHCO3, and brine, dried over MgSO4, and evaporated in vacuo. The residue was purified by chromatography on silica gel to afford (trans)-1-[2-(N,N-diphenylcarbamoyl-oxy)ethyl]-2-hydroxy-5-t-butyldiphenylsilyloxy-1,2,3,4-tetrahydronaphthalene (1.1 g).
Reaction SMILES: [CH2:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[CH2:6][C:5]=2[CH2:4][CH:3]=[CH:2]1.C([Li])CCC.Cl[CH2:22][CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1>O1CCCC1.CCCCCC>[CH2:12]1[C:8]2[CH2:9][CH2:10][C:11]3[CH:1]=[CH:2][CH:3]=[CH:4][C:5]=3[CH:6]([CH2:22][CH2:23][N:24]3[CH2:28][CH2:27][CH2:26][CH2:25]3)[C:7]=2[CH2:15][CH:14]=[CH:13]1
Reactant: ClCCN1CCCC1
Reactant: C1=CCC2=C(C1)CCc1ccccc1C2
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C1=CCC2=C(C1)CCc1ccccc1C2CCN1CCCC1
Reaction time: 0.5 h

Procedure:
1.0 g of 1,4,10,11-tetrahydro-5H-dibenzo[a,d]cycloheptene in 20 ml of dry tetrahydrofuran are treated dropwise at between -70° and -60° with 9.0 ml of an about 0.85M solution of n-butyl lithium in hexane. The mixture is stirred at -70° for 60 minutes and at -30° for 30 minutes, a solution of 2.1 g of 2-chloroethylpyrrolidine in 5 ml of dry tetrahydrofuran at -30° is added dropwise thereto and subsequently the mixture is stirred at -30° for an additional 30 minutes, at 0° to 5° for 3 hours and at room temperature for 30 minutes. After evaporation of the mixture, the residue remaining is dissolved in toluene and washed ion-free with water. The organic phase is filtered over aluminum oxide (activity grade II, neutral) using toluene for the elution. Crude 1-[2-(4,5,10,11-tetrahydro-1H-dibenzo[a,d]cyclohepten-5-yl)ethyl]pyrrolidine is obtained.
Reaction SMILES: [CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.OO.CC(C)=[O:18].C(OCC)(=O)C>C(O)(=O)C.C(OCC)(=O)C.C(=O)([O-])[O-].[Na+].[Na+]>[CH2:1]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N+:9]=1[O-:18])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)=O
Reactant: c1ccc(Cc2ccccn2)cc1
Agent: O=C([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: [O-][n+]1ccccc1Cc1ccccc1
Temperature: 25 °C
Yield: 79 %

Procedure:
A stirred solution of 3.0 g (18 mmol) 2-benzylpyridine and 1.65 mL of 30% aqueous hydrogen peroxide in 5.0 mL of acetic acid was heated at 100° C. for 3 hr (S. Hibino and E. Sugino, J. Heterocycl Chem., 1990, 27, 175). After cooling to room temperature, the reaction was diluted with 30 mL ethyl acetate and neutralized with sodium carbonate. The sodium acetate was separated by filtration and the filtrate was dried (sodium carbonate) and concentrated to give a yellow oil. Flash column chromatography on 125 g of silica gel using 7 of L 20% acetone/ethyl acetate furnished 2,58 g (79% yield) of 2-benzylpyridine N-oxide as an amber syrup.
Reaction SMILES: [CH3:1][C:2]([O:41][CH2:42][C@@H:43]1[CH2:45][O:44]1)([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[NH:13]2)=[O:11])=[N:5]1.C(O)(C)C.[OH-].[NH4+:51]>C(Cl)Cl>[NH2:51][CH2:45][C@H:43]([OH:44])[CH2:42][O:41][C:2]([CH3:1])([CH3:40])[CH2:3][N:4]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([CH:12]2[CH:16]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([Cl:23])[C:18]=3[F:24])[C:15]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[F:34])([C:25]#[N:26])[CH:14]([CH2:35][C:36]([CH3:38])([CH3:39])[CH3:37])[NH:13]2)=[O:11])=[N:5]1
Reactant: [NH4+]
Reactant: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H]3CO3)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Agent: [OH-]
Solvent: ClCCl
Solvent: CC(C)O
Product: CC(C)(C)CC1NC(C(=O)Nc2ccn(CC(C)(C)OC[C@@H](O)CN)n2)C(c2cccc(Cl)c2F)C1(C#N)c1ccc(Cl)cc1F
Yield: 24.1 %

Procedure:
A mixture of rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethylpropyl)-pyrrolidine-2-carboxylic acid {1-[2-methyl-2-((S)-1-oxiranylmethoxy)-propyl]-1H-pyrazol-3-yl}-amide (203 mg, 0.307 mmol), isopropyl alcohol (2 mL), and ammonium hydroxide (2.5 mL) was microwaved at 130° C. for 15 min. The mixture was then diluted with CH2Cl2 and washed with water, brine. The organic phase was separated, filtered and dried over Na2SO4. The mixture was then concentrated and purified by reverse phase chromatography (20-95% of ACN/water) to give rac-(2R,3S,4R,5S)-3-(3-chloro-2-fluoro-phenyl)-4-(4-chloro-2-fluoro-phenyl)-4-cyano-5-(2,2-dimethyl-propyl)-pyrrolidine-2-carboxylic acid {1-[2-((S)-3-amino-2-hydroxy-propoxy)-2-methyl-propyl]-1H-pyrazol-3-yl}-amide (50.2 mg, 24.1%) as an white powder. HRMS (ES+) m/z Calcd for C33H40Cl2F2N6O3+H [(M+H)+]: 677.2580. found: 677.2577.
Reaction SMILES: O=[C:2]([CH3:13])[CH2:3][C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=O.[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1.Cl.C(N=C=NCCCN(C)C)C.N1C=CC=CC=1>C(Cl)(Cl)Cl>[CH3:14][O:15][C:16]1[CH:22]=[CH:21][C:19]([N:20]2[C:2]([CH3:13])=[CH:3][C:4]3[C:5](=[CH:9][CH:10]=[CH:11][CH:12]=3)[C:6]2=[O:8])=[CH:18][CH:17]=1
Reactant: COc1ccc(N)cc1
Reactant: CC(=O)Cc1ccccc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: ClC(Cl)Cl
Product: COc1ccc(-n2c(C)cc3ccccc3c2=O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
2-(2-oxopropyl)benzoic acid (100 mg, 0.56 mmol), 4-methoxyaniline (76 mg, 0.56 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.84 mmol) and pyridine (0.5 mL) were dissolved in chloroform (5 mL) and stirred at room temperature overnight. Chloroform was added, the organic phase was washed by aqueous citric acid solution, sodium hydrogen carbonate aqueous solution and saturated brine in that order, and dried with anhydrous sodium sulfate. The product was purified by silica gel column chromatography (hexane/ethyl acetate=10/0-3/7) to obtain the target compound (66 mg, 44%) as a light brown solid.
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]3[CH:15]=[CH:14][C:13]([C:16]([NH2:18])=[O:17])=[CH:12][C:10]=3[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:19][CH2:20][C:21]([CH2:23]Cl)=O>>[Cl:19][CH2:20][C:21]1[N:18]=[C:16]([C:13]2[CH:14]=[CH:15][C:9]3[O:8][C:7]([C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:11][C:10]=3[CH:12]=2)[O:17][CH:23]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc2oc(-c3ccccc3)nc2c1
Product: ClCc1coc(-c2ccc3oc(-c4ccccc4)nc3c2)n1
Yield: 65 %

Procedure:
In substantially the same manner as in Reference Example 47, 2-phenyl-5-benzoxazolecarboxamide was allowed to react with 1,3-dichloroacetone to give 5-(4-chloromethyl-2-oxazolyl)-2-phenylbenzoxazole. The yield was 65%. Recrystallization from ethyl acetate-hexane gave brown needles, mp 194-195° C.
Reaction SMILES: [Cl:1][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5].Cl.[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH2:26].C(=O)([O-])O.[Na+].CS(C)=O>O>[ClH:1].[F:19][C:20]1[CH:21]=[C:22]([CH:27]=[C:28]([F:30])[CH:29]=1)[O:23][CH2:24][CH2:25][NH:26][C:2]1[N:9]=[C:8]([NH:10][C:11]2[CH:15]=[C:14]([CH3:16])[NH:13][N:12]=2)[CH:7]=[C:6]([CH3:17])[C:3]=1[C:4]#[N:5]
Reactant: Cc1cc(Nc2cc(C)c(C#N)c(Cl)n2)n[nH]1
Reactant: NCCOc1cc(F)cc(F)c1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(Nc2cc(C)c(C#N)c(NCCOc3cc(F)cc(F)c3)n2)n[nH]1
Temperature: 100 °C
Reaction time: 27 h
Yield: 10.9 %

Procedure:
Compound A (300 mg, 1.22 mmol), 2-(3,5-difluorophenoxy)ethylamine hydrochloride (767 mg) and sodium hydrogencarbonate (1.02 g) were added to DMSO (10 ml), and the mixture was stirred at 100° C. for 27 hr. After stirring, the reaction mixture was added to cold water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and concentrated, and the residue was washed by suspending in ethyl acetate. This was converted to hydrochloride to give the object compound of 2-(2-(3,5-difluorophenoxy)ethylamino)-6-(5-methyl-1H-pyrazol-3-ylamino)-4-methylnicotinonitrile hydrochloride (56 mg).
Reaction SMILES: [CH3:1][O:2][C:3]([N:5]=[C:6]=[O:7])=[O:4].[NH2:8][C:9]1[S:10][C:11]2[CH:17]=[CH:16][CH:15]=[C:14]([CH3:18])[C:12]=2[N:13]=1>C(Cl)Cl>[CH3:18][C:14]1[C:12]2[N:13]=[C:9]([NH:8][C:6](=[O:7])[NH:5][C:3]([O:2][CH3:1])=[O:4])[S:10][C:11]=2[CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)N=C=O
Reactant: Cc1cccc2sc(N)nc12
Solvent: ClCCl
Product: COC(=O)NC(=O)Nc1nc2c(C)cccc2s1
Temperature: 25 °C
Reaction time: 12 h
Yield: 37 %

Procedure:
Two and one half parts by weight of methoxycarbonyl isocyanate was added gradually with stirring to a solution of 4 parts by weight of 2-amino-4-methylbenzothiazole dissolved in 250 parts by weight of methylene chloride. The reaction mixture was stirred at room temperature for 12 hours. The solution was concentrated to one fifth the original volume and the solid isolated by filtration to give a 37% yield of methyl 4-(4-methylbenzothiazol-2-yl)allophanate having a melting point of 272°-280° with decomposition.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.[CH2:10]([O:12][C:13](=[O:24])[C:14](=[CH:20]OCC)[C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH3:11].CCCCCC>C1(C)C=CC=CC=1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH:20]=[C:14]([C:13]([O:12][CH2:10][CH3:11])=[O:24])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: N#Cc1ccc(N)cc1
Reactant: CCOC=C(C(=O)OCC)C(=O)OCC
Solvent: Cc1ccccc1
Solvent: CCCCCC
Product: CCOC(=O)C(=CNc1ccc(C#N)cc1)C(=O)OCC
Yield: 87.5 %

Procedure:
To 5.00 g (42.3 mmol) 4-aminobenzonitrile (Aldrich, 98%) was added 10.1 g (9.41 mL, 46.6 mmol, 1.1 eq) diethylethoxymethylenemalonate (Aldrich, 99%), and the mixture was dissolved in 50 mL toluene (HPLC grade). The solution was refluxed for four hours with a condensor open to the air. The solution was then poured into 200 mL hexane, and the resulting white precipitate was filtered and washed well with more hexane to yield 10.62 g (37.0 mmol, 85% yield) of the title compound as a slightly off-white solid (per LC/MS and 1H NMR). LC [MH+] 289, 97% purity.