Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].C([O-])([O-])=O.[Na+].[Na+].Cl[C:20]([O:22][CH3:23])=[O:21]>[OH-].[Na+]>[CH3:23][O:22][C:20]([NH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4])=[O:21]
Reactant: COC(=O)Cl
Reactant: NC(Cc1ccccc1)C(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Agent: [OH-]
Product: COC(=O)NC(Cc1ccccc1)C(=O)O
Temperature: 0 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
2-Amino-3-phenyl-propionic acid (1.65 g) was dissolved in 1 N NaOH (10 mL), and Na2CO3 (530 mg) was added. The mixture was cooled to 0° C. and methyl chloroformate was added slowly, and then stirred for overnight at room temperature. The mixture was washed with DCM and acidified with 3 mL of 2N HCl, and then was taken up in ether (200 mL). The organic phase was dried over sodium sulfate. Removing the solvent to give 2-Methoxycarbonylamino-3-phenyl-propionic acid (1.95 g, 87%) as an off-white solid.
Reaction SMILES: [NH2:1][C:2]1[C:15]([O:16][CH3:17])=[CH:14][C:5]2[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=2[CH:3]=1.Cl[C:19]1[N:24]=[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:37]3[CH2:42][CH2:41][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:39][CH2:38]3)=[C:30]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[CH2:31]3)[C:22]([Cl:46])=[CH:21][N:20]=1>>[Cl:46][C:22]1[C:23]([NH:25][C:26]2[CH:27]=[CH:28][C:29]([N:37]3[CH2:38][CH2:39][N:40]([CH:43]([CH3:45])[CH3:44])[CH2:41][CH2:42]3)=[C:30]3[C:34]=2[C:33](=[O:35])[N:32]([CH3:36])[CH2:31]3)=[N:24][C:19]([NH:1][C:2]2[C:15]([O:16][CH3:17])=[CH:14][C:5]3[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][OH:13])[CH2:9][CH2:10][C:4]=3[CH:3]=2)=[N:20][CH:21]=1
Reactant: CC(C)N1CCN(c2ccc(Nc3nc(Cl)ncc3Cl)c3c2CN(C)C3=O)CC1
Reactant: COc1cc2c(cc1N)CCN(CCO)CC2
Product: COc1cc2c(cc1Nc1ncc(Cl)c(Nc3ccc(N4CCN(C(C)C)CC4)c4c3C(=O)N(C)C4)n1)CCN(CCO)CC2

Procedure:
The title compound was prepared from 2-(7-amino-8-methoxy-1,2,4,5-tetrahydro-3-benzazepin-3-yl)-ethanol (40 mg, 0.20 mmol) and 7-(2,5-dichloropyrimidin-4-ylamino)-4-(4-isopropylpiperazin-1-yl)-2-methyl-2,3-dihydroisoindol-1-one (74 mg, 0.17 mmol) in an analogous manner to Example 946 to afford an off-white solid (75 mg, 70%). Mp: 198-200° C. LCMS (m/e) 635 (M+1); 1H-NMR (CDCl3, 400 MHz) δ 10.55 (s, 1H), 8.67 (d, J=9 Hz, 1H), 8.11 (s, 2H), 7.40 (s, 1H), 7.10 (d, J=9 Hz, 1H), 6.68 (s, 1H), 4.40 (s, 2H), 3.91 (s, 3H), 3.70 (m, 2H), 3.20 (s, 3H), 3.08 (m, 4H), 2.92 (m, 5H), 2.82-2.64 (m, 11H), 1.13 (d, J=6 Hz, 6H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]=[O:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15].Br[C:37]1[CH:42]=[CH:41][C:40]([O:43][C:44]([F:47])([F:46])[F:45])=[CH:39][CH:38]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4]([CH:34]([C:37]1[CH:38]=[CH:39][C:40]([O:43][C:44]([F:45])([F:46])[F:47])=[CH:41][CH:42]=1)[OH:35])=[CH:5][N:6]2[C@@H:11]1[O:28][C@H:27]([CH2:29][O:30][C:31](=[O:33])[CH3:32])[C@@H:22]([O:23][C:24](=[O:26])[CH3:25])[C@H:17]([O:18][C:19](=[O:21])[CH3:20])[C@H:12]1[O:13][C:14](=[O:16])[CH3:15]
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cc(C=O)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: FC(F)(F)Oc1ccc(Br)cc1
Product: CC(=O)OC[C@H]1O[C@@H](n2cc(C(O)c3ccc(OC(F)(F)F)cc3)c3c(Cl)cccc32)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O

Procedure:
The above 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indole-3-carboxaldehyde and 1-bromo-4-(trifluoro-methoxy)benzene were treated in a manner similar to Example 25-(2) to give crude 4-chloro-1-(2,3,4,6-tetra-O-acetyl-β-D-gluco-pyranosyl)indol-3-yl 4-(trifluoromethoxy)phenyl methanol, which was used in the subsequent step without further purification.
Reaction SMILES: [Mg].Cl[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].C[Mg]Br.[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][CH2:31][CH:32]=[O:33]>C(OCC)C.C(Br)C>[O:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH:23]1[O:28][CH2:29][CH2:30][CH2:31][CH:32]([OH:33])[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH3:3]
Reactant: CCCCCCCCCCCCCCCCCl
Reactant: O=CCCCOC1CCCCO1
Agent: C[Mg]Br
Agent: [Mg]
Solvent: CCBr
Solvent: CCOCC
Product: CCCCCCCCCCCCCCCCC(O)CCCOC1CCCCO1
Yield: 70 %

Procedure:
To a refluxing mixture of 1.26 g of magnesium turnings, 15.5 ml of 1-chlorohexadecane, and 100 ml of anhydrous diethyl ether were added 0.5 ml of a 3.2 M solution of methylmagnesium bromide in diethyl ether and 0.05 ml of ethyl bromide. The reaction mixture was refluxed for a period of 6 hours. A solution of 3.0 g of 4-[(tetrahydro-2H-pyran-2-yl)oxy]butanal in 10 ml of diethyl ether was added, and the reaction mixture refluxed for an additional hour. The reaction mixture was poured into a mixture of ice and a saturated aqueous solution of ammonium chloride, and filtered. Upon standing the filtrate separated into organic and inorganic phases. The organic phase was dried over anhydrous sodium sulfate and concentrated to an oil. Flash chromatography of the oil utilizing 25% diethyl ether/petroleum ether yielded 4.8 g (70%) of 1-[(tetrahydro-2H-pyran-2-yl)oxy]eicosan-4-ol as a solid, mp 39-43°.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([CH2:11][C:12]([OH:14])=O)[CH:8]=[CH:9][CH:10]=1)=[O:4].[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH2:27])[CH2:21]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)C(C)C)(C)C>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:19][N:20]1[CH2:25][CH2:24][O:23][CH:22]([CH2:26][NH:27][C:12](=[O:14])[CH2:11][C:7]2[CH:6]=[C:5]([CH:10]=[CH:9][CH:8]=2)[C:3]([O:2][CH3:1])=[O:4])[CH2:21]1
Reactant: COC(=O)c1cccc(CC(=O)O)c1
Reactant: NCC1CN(Cc2ccc(Cl)c(Cl)c2)CCO1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COC(=O)c1cccc(CC(=O)NCC2CN(Cc3ccc(Cl)c(Cl)c3)CCO2)c1
Temperature: 20 °C
Reaction time: 8 h
Yield: 57.2 %

Procedure:
A mixture of [3-(methoxycarbonyl)phenyl]acetic acid (0.200 g), Intermediate 1 (0.284 g), 1-hydroxybenzotriazole (0.182 g) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.316 g) was stirred in dichloromethane (10 ml), and N,N-diisopropylethylamine (0.352 ml) was added to the solution. Stirring at 20° C. under nitrogen was continued for 8 h. The mixture was purified by solid phase extraction (2×10 g Varian Bondelut silica gel cartridges), eluting successively with one column volume of dichloromethane, chloroform, ether, ethyl acetate, acetone, acetonitrile and methanol, to give the title compound as a colourless gum, (0.266 g).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH3:29])[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[O:30]1[CH2:32][C@@H:31]1[CH2:33][O:34][C:35]1[CH:44]=[CH:43][CH:42]=[C:41]2[C:36]=1[CH:37]=[CH:38][CH:39]=[N:40]2>C(O)(C)C>[C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([NH:20][C:21]([CH:23]2[CH2:28][CH2:27][N:26]([CH2:29][CH2:32][C@@H:31]([OH:30])[CH2:33][O:34][C:35]3[CH:44]=[CH:43][CH:42]=[C:41]4[C:36]=3[CH:37]=[CH:38][CH:39]=[N:40]4)[CH2:25][CH2:24]2)=[O:22])[CH2:11][CH2:12][CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN1CCC(C(=O)NC(CCCc2ccccc2)CCCc2ccccc2)CC1
Reactant: c1cc(OC[C@H]2CO2)c2cccnc2c1
Solvent: CC(C)O
Product: O=C(NC(CCCc1ccccc1)CCCc1ccccc1)C1CCN(CC[C@@H](O)COc2cccc3ncccc23)CC1
Temperature: 70 °C
Yield: 82.6 %

Procedure:
Methylpiperidine-4-carboxylic acid [4-phenyl-1-(3-phenyl-propyl)-butyl]-amide (57) (150 mg; 0.382 mmol) is dissolved in isopropanol (10 mL) at ambient temperature. (R)-5-Oxiranylmethoxy-quinoline (2) (77.5 mg; 0.382 mmol) is added, then the mixture is heated to 70° C. and maintained for 18 hours. After cooling to ambient temperature, the solution is concentrated in vacuo at 40° C. The residue is purified via silica gel chromatography with gradient elution (0%→25% methanol in methylene chloride) affording the desired product (187.4 mg) as a solid foam. ESMS:MH+ 594.4 (base).
Reaction SMILES: CC(C)([O-])C.[K+].[N+]([O-])(O)=O.[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18](=[NH:20])[NH2:19])[N:13]=1.[N:21]([CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]=[S:23]>CS(C)=O>[CH3:11][C:12]1[CH:16]=[C:15]([CH3:17])[N:14]([C:18]([NH:19][C:22]([NH:21][CH2:24][CH2:25][NH:26][C:27](=[O:33])[O:28][C:29]([CH3:31])([CH3:30])[CH3:32])=[S:23])=[NH:20])[N:13]=1
Reactant: Cc1cc(C)n(C(=N)N)n1
Reactant: CC(C)(C)OC(=O)NCCN=C=S
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O=[N+]([O-])O
Solvent: CS(C)=O
Product: Cc1cc(C)n(C(=N)NC(=S)NCCNC(=O)OC(C)(C)C)n1
Temperature: 60 °C
Reaction time: 0.08 h

Procedure:
554.7 mg (4.94 mmol) of potassium tert-butoxide are dissolved in 12 ml of DMSO while cooling slightly in ice, and then 596.8 mg (2.96 mmol) of 3,5-dimethyl-1H-pyrazole-1-carboximidamide nitrate are added. A clear solution is produced after stirring for about 5 minutes. Then 500 mg (2.47 mmol) of tert-butyl (2-isothiocyanatoethyl)carbamate are added, and the icebath is removed. The mixture is heated at 60° C. for a further 3 h and the solution obtained in this way is employed for the further subsequent reactions.
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([CH2:8][CH3:9])[CH2:3]1.[CH3:10][C:11]1[CH:12]=[C:13]2[C:18](=O)[O:17][C:15](=[O:16])[C:14]2=[CH:20][CH:21]=1>>[CH2:8]([N:4]1[CH2:5][CH2:6][CH2:7][CH:2]([N:1]2[C:18](=[O:17])[C:13]3=[CH:12][C:11]([CH3:10])=[CH:21][CH:20]=[C:14]3[C:15]2=[O:16])[CH2:3]1)[CH3:9]
Reactant: CCN1CCCC(N)C1
Reactant: Cc1ccc2c(c1)C(=O)OC2=O
Product: CCN1CCCC(N2C(=O)c3ccc(C)cc3C2=O)C1

Procedure:
3-Amino-1-ethylpiperidine and 4-methylphthalic anhydride are reacted in a similar manner to that described in Example 3 to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH:17]([CH3:19])[CH3:18])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:20]1([CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[CH:17]([C@:11]1([C:14]([N:29]2[CH2:28][CH:27]=[C:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:31][CH2:30]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1)([CH3:19])[CH3:18]
Reactant: c1ccc(C2CCNCC2)cc1
Reactant: CC(C)[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)[C@]1(C(=O)N2CC=C(c3ccccc3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81 %

Procedure:
In a dried flask, (1S,3R)-3-[(tert-butoxycarbonyl)amino]-1-isopropylcyclopentanecarboxylic acid (200 mg, 0.7 mmol) and 4-phenyl-1,2,3,5-tetrahydropyridine (160 mg, 0.81 mmol) were suspended in methylene chloride (4 mL) under N2. Triethylamine (0.22 g, 2.2 mmol) was added followed by benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (0.36 g, 0.81 mmol). The reaction was stirred overnight at room temperature and quenched by addition of saturated NaHCO3 solution. The resulting solution was extracted with methylene chloride three times. The combined extracts were dried (MgSO4), filtered and concentrated. Purification by flash chromatography on silica gel (gradient: 0-45% B over 15 min. Bottle A=hexanes, bottle B=EtOAc) to give 234 mg (80%) of desired product. MS calculated for C25H36N2O3: (M+H) 413; found 413.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=3)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]=2[CH3:21])=[CH:4][CH:3]=1.[CH2:22]([O:24][C:25](=[O:30])[C:26](Br)([CH3:28])[CH3:27])[CH3:23]>>[CH2:22]([O:24][C:25](=[O:30])[C:26]([O:17][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[N:10]([CH2:18][CH2:19][CH3:20])[C:9]([CH3:21])=[C:8]2[C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([CH3:28])[CH3:27])[CH3:23]
Reactant: CCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(O)ccc21
Reactant: CCOC(=O)C(C)(C)Br
Product: CCCn1c(C)c(-c2ccc(Cl)cc2)c2cc(OC(C)(C)C(=O)OCC)ccc21

Procedure:
In accordance with a procedure analogous to that of Example 10, the above compound was prepared from 3-(4-chloro-phenyl)-2-methyl-1-propyl-1H-indole-5-ol and 2-bromo-2-methyl-propanoic acid ethylester.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([N+:8]([O-:10])=[O:9])[C:5]([F:11])=[CH:4][C:3]=1[OH:12].C(=O)([O-])[O-].[K+].[K+].Br[CH2:20][CH3:21].ICC>C(#N)C>[CH2:20]([O:12][C:3]1[CH:4]=[C:5]([F:11])[C:6]([N+:8]([O-:10])=[O:9])=[CH:7][C:2]=1[F:1])[CH3:21]
Reactant: CCBr
Reactant: O=[N+]([O-])c1cc(F)c(O)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCI
Solvent: CC#N
Product: CCOc1cc(F)c([N+](=O)[O-])cc1F
Temperature: 70 °C
Reaction time: 3.5 h
Yield: 88.2 %

Procedure:
To a solution of 2,5-difluoro-4-nitro-phenol (4.86 g, 28.2 mmol) in acetonitrile (50 mL), potassium carbonate (4.7 g, 34 mmol) and bromoethane (4.21 mL, 56.4 mmol) were added. After stirring at 70° C. for 3.5 hours, iodoethane (2.73, 33.8 mmol) was added and mixture was stirred at 80° C. After 20 hours, mixture was concentrated and extracted with methylene chloride and 2M NaOH solution. Organic phases were dried over magnesium sulfate, filtered, and concentrated to give 1-ethoxy-2,5-difluoro-4-nitro-benzene as a yellow solid (5.05 g, 88%). 1HNMR (CDCl3, 400 MHz) δ 7.92-7.88 (m, 1H), 6.82-6.78 (m, 1H), 4.21-4.16 (q, 1H), 4.13-4.07 (q, J=7.0 Hz, 2H), 1.54-1.51 (t, J=7.0 Hz, 3H).
Reaction SMILES: [Na].C(O)C.[CH:5]1[C:17]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]=2[CH:8]=[CH:7][C:6]=1[CH:18]=O.[N:20]([CH2:23][C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+:21]=[N-:22]>O1CCCC1>[N:20]([C:23](=[CH:18][C:6]1[CH:7]=[CH:8][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[CH2:16][C:17]=2[CH:5]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[N+:21]=[N-:22]
Reactant: CCOC(=O)CN=[N+]=[N-]
Reactant: O=Cc1ccc2c(c1)Cc1ccccc1-2
Agent: [Na]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)C(=Cc1ccc2c(c1)Cc1ccccc1-2)N=[N+]=[N-]
Temperature: 25 °C
Yield: 37 %

Procedure:
Sodium (1.7 eq) was added to absolute ethanol stirred under nitrogen at room temperature. When dissolution was complete the reaction was cooled to -10° C. and fluorene-2-carboxaldehyde (1 eq) and ethyl azidoacetate (3 eq) dissolved together in the minimum of tetrahydrofuran were added dropwise. The mixture was stirred at -10° C. for 20 h and then quenched by the addition of water and dichloromethane. The combined organic extracts were dried (MgSO4) and evaporated in vacuo. Flash chromatography yielded the pure product (37%) νmax (CHCl3)cm-1 2120 and 1765.
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]([C:8]([O:10]C)=[O:9])=[N:6][CH:7]=1.[CH2:12]([OH:15])[CH:13]=[CH2:14].[OH-].[K+:17]>>[K+:17].[CH2:12]([O:15][C:2]1[N:3]=[CH:4][C:5]([C:8]([O-:10])=[O:9])=[N:6][CH:7]=1)[CH:13]=[CH2:14]
Reactant: COC(=O)c1cnc(Cl)cn1
Reactant: C=CCO
Agent: [K+]
Agent: [OH-]
Product: C=CCOc1cnc(C(=O)[O-])cn1
Temperature: 95 °C
Reaction time: 0.17 h
Yield: 100.8 %

Procedure:
A mixture of methyl 5-chloropyrazine-2-carboxylate (1.7 g, 10 mmol) and allyl alcohol (10 mL, 147 mmol) was heated with stirring to 95° C. and then treated with pulverized potassium hydroxide (1.3 g, 23 mmol). Within 10 min, a thick paste developed. The heating was continued for 2 h. The reaction mixture was concentrated in vacuo to dryness, and the residue was further concentrated in vacuo to dryness from toluene (2×50 mL). The 5-allyloxy-pyrazine-2-carboxylic acid potassium salt (2.2 g) that was isolated was used without further purification and characterization.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:17](=[O:18])[C:16]2[C@H:15]3[C:19]([CH3:21])([CH3:20])[C@:12]([CH3:22])([CH2:13][CH2:14]3)[C:11]=2[NH:10]1.[CH2:23](I)[CH:24]=[CH2:25]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CN(C)C=O>[CH2:25]([N:10]1[C:11]2[C@:12]3([CH3:22])[C:19]([CH3:21])([CH3:20])[C@@H:15]([CH2:14][CH2:13]3)[C:16]=2[C:17](=[O:18])[N:9]1[C:3]1[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=1[F:1])[CH:24]=[CH2:23]
Reactant: C=CCI
Reactant: CC1(C)[C@H]2CC[C@]1(C)c1[nH]n(-c3ccc(F)cc3F)c(=O)c12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: CN(C)C=O
Product: C=CCn1c2c(c(=O)n1-c1ccc(F)cc1F)[C@@H]1CC[C@@]2(C)C1(C)C
Temperature: 100 °C
Yield: 29.8 %

Procedure:
A mixture of (4R,7S)-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (Intermediate 42; 989 mg, 3.25 mmol), tetrabutylammonium iodide (600 mg, 1.63 mmol) and allyl iodide (1.05 mL, 9.75 mmol) in dimethylformamide (5.7 mL) was heated in an oil-bath at 100° C. overnight. The solvent was evaporated and dichloromethane (400 mL) was added. The solution was washed with aqueous sodium thiosulfate (2×100 mL) and the combined aqueous washes were back-extracted with dichloromethane (2×100 mL). The combined organic layers were washed with water (100 mL) and brine (100 mL), dried (magnesium sulfate), filtered, and purified using an ISCO 40 g column, eluting with 20-50% ethyl acetate/hexanes. Fractions homogeneous for the product were evaporated, and then co-evaporated successively with methanol, ether, and petroleum ether. The residue was triturated with hexane and the solid was dried under high vacuum at 70° C. overnight and then at 85° C. for 1 h to give (4R,7S)-1-allyl-2-(2,4-difluoro-phenyl)-7,8,8-trimethyl-1,2,4,5,6,7-hexahydro-4,7-methano-indazol-3-one (334 mg, 30%) as an off-white solid. APCI(+)-MS (M+H) 345.
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][NH:27][CH2:26]1)=[O:23])([CH3:20])([CH3:19])[CH3:18]>C(Cl)Cl>[C:17]([O:21][C:22]([NH:24][C@H:25]1[C@H:29]([CH3:30])[CH2:28][N:27]([C:8](=[O:15])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:26]1)=[O:23])([CH3:20])([CH3:18])[CH3:19]
Reactant: C[C@@H]1CNC[C@H]1NC(=O)OC(C)(C)C
Reactant: O=C(Cl)c1ccccc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C[C@@H]1CN(C(=O)c2ccccc2)C[C@H]1NC(=O)OC(C)(C)C
Yield: 97 %

Procedure:
In the presence of triethylamine, 59 g of benzoyl chloride was reacted at room temperature with 81.4 g of trans-3-tert-butoxycarbonylamino-4-methylpyrrolidine in methylene chloride, whereby 120 g of trans-3-tert-butoxycarbonylamino-4-methyl-1-benzoylpyrrolidine (a) was obtained. Hydrochloric acid was then reacted at room temperature with 123 g of the compound (a) in ethanol, so that 83 g of trans-3-amino-4-methyl-1-benzoylpyrrolidine (b) was obtained. In methylene chloride, 68.4 g of (R)-(-)mandelic acid was then reacted at room temperature with 83 g of the compound (b) in the presence of 87.3 g o 1-hydroxybenzotriazole, 87.4 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride and 46.5 g of triethylamine. 34 g of trans-3-(2-(R)-2-phenyl-2-hydroxyacetylamino)-4-methyl-1-benzoylpyrrolidine diastereomer (A), (c) was obtained. Acetic acid and hydrochloric acid were then reacted with the compound (c) under reflux, whereby 16.8 g of (-)-trans-3-amino-4-methylpyrrolidine dihydrochloride was obtained as a colorless solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18](SC2C=CC=CN=2)=[O:19])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1SC(=O)CC[CH:37]1[CH2:42][CH2:41][CH2:40][CH2:39]C1>>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][CH:11]([CH2:14][CH2:15][CH2:16][CH2:17][C:18]([CH:39]2[CH2:40][CH2:41][CH2:42][CH2:37]2)=[O:19])[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: O=C(CCC1CCCCC1)Sc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)Sc2ccccn2)CC1
Product: CC(C)(C)OC(=O)N1CCC(CCCCC(=O)C2CCCC2)CC1

Procedure:
The title compound was prepared analogously to step 7 of example B(29) where 4-[4-(pyridin-2-ylsulfanylcarbonyl)-butyl]-piperidine-1-carboxylic acid tert-butyl ester from step 5 above, was substituted in place 3-cyclohexyl-thiopropionic acid S-pyridin-2-yl ester. 1H NMR (400 MHz, CDCl3): δ 1–1.42 (m, 8H), 1.45 (s, 9H), 1.50–1.84 (m, 14H), 2.42–2.46 (m, 2H), 2.62–2.7 (m, 2H), 2.82–2.87 (m, 1H). ESIMS (MH+): 337.
Reaction SMILES: [OH:1][C:2]([CH2:28][CH2:29][CH3:30])([CH2:25][CH2:26][CH3:27])[CH2:3][NH:4][C:5]1[CH:6]=[C:7]([CH2:11][CH2:12][CH2:13][N:14]2C(=O)C3C(=CC=CC=3)C2=O)[CH:8]=[CH:9][CH:10]=1.O.NN>C(O)C>[NH2:14][CH2:13][CH2:12][CH2:11][C:7]1[CH:6]=[C:5]([NH:4][CH2:3][C:2]([OH:1])([CH2:28][CH2:29][CH3:30])[CH2:25][CH2:26][CH3:27])[CH:10]=[CH:9][CH:8]=1
Reactant: CCCC(O)(CCC)CNc1cccc(CCCN2C(=O)c3ccccc3C2=O)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: CCCC(O)(CCC)CNc1cccc(CCCN)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 2-(3-(3-(2-hydroxy-2-propylpentylamino)phenyl)propyl)isoindoline-1,3-dione (0.22 g, 0.71 mmol) and hydrazine hydrate (0.1 ml, 1.6 mmol) in ethanol was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. Purification by column chromatography (5% to 10% MeOH—CH2Cl2 gradient) gave 4-((3-(3-aminopropyl)phenylamino)methyl)heptan-4-ol as a light yellow semisolid. Yield (0.06 g, 18%); 1H NMR (400 MHz, DMSO-d6) δ 6.93 (t, J=7.6 Hz, 1H), 6.44-6.41 (m, 2H), 6.35 (d, J=7.6 Hz, 1H), 4.92 (t, J=5.2 Hz, 1H), 4.19 (bs, 1H), 2.87 (d, J=5.2 Hz, 2H), 2.54-2.50 (m, 2H), 2.44 (t, J=7.6 Hz, 2H), 1.55-1.62 (quintet, J=7.2 Hz, 2H), 1.42-1.33 (m, 4H), 1.32-1.27 (m, 4H), 0.85 (t, J=7.2 Hz, 6H); RP-HPLC (Method 3) tR=4.44 min, 97.48% (AUC); ESI MS m/z 279.31 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:8]([O:10]CC)=O)=[C:5]([CH3:7])[N:6]=1.Cl.[CH2:14]([NH2:16])[CH3:15].C(N(CC)CC)C>C(O)C>[CH2:14]([NH:16][C:8]([C:4]1[S:3][C:2]([CH3:1])=[N:6][C:5]=1[CH3:7])=[O:10])[CH3:15]
Reactant: CCOC(=O)c1sc(C)nc1C
Reactant: CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CCNC(=O)c1sc(C)nc1C
Temperature: 140 °C
Reaction time: 25 h
Yield: 50.3 %

Procedure:
3.0 g of ethyl 2,4-dimethylthiazole-5-carboxylate, 7.0 g of ethylamine hydrochloride, 6.0 g of triethylamine, and 100 mL of ethanol were added into a 250 mL of high-pressure reactor. And the reaction mixture was heated to 120-160° C. and stirred for 20 to 30 hours, and then extracted with ethyl acetate, the organic layer was separated while the aqueous layer was extracted with ethyl acetate twice. The organic phases were combined, and dried over anhydrous sodium sulfate after washed with an iced aqueous sodium chloride solution twice, then remove the solvent under reduced pressure to obtain 1.5 g N-ethyl-2,4-dimethylthiazole-5-carboxamide which was used in the next step directly without purification.