Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:33][CH2:32][CH:31]([CH2:34][CH:35]=O)[CH2:30][CH2:29]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH:48]1([O:53][C:54](=[O:61])[C@H:55]([CH2:57][CH:58]([CH3:60])[CH3:59])[NH2:56])[CH2:52][CH2:51][CH2:50][CH2:49]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].CCCCCCC>ClC(Cl)C>[CH2:1]([O:8][C:9]1[CH:14]=[C:13]([O:15][CH2:16][C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:12]([C:23]([CH3:25])=[CH2:24])=[CH:11][C:10]=1[C:26]([N:28]1[CH2:29][CH2:30][CH:31]([CH2:34][CH2:35][NH:56][C@H:55]([C:54]([O:53][CH:48]2[CH2:49][CH2:50][CH2:51][CH2:52]2)=[O:61])[CH2:57][CH:58]([CH3:59])[CH3:60])[CH2:32][CH2:33]1)=[O:27])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@H](N)C(=O)OC1CCCC1
Reactant: C=C(C)c1cc(C(=O)N2CCC(CC=O)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Solvent: CCCCCCC
Solvent: CC(Cl)Cl
Product: C=C(C)c1cc(C(=O)N2CCC(CCN[C@@H](CC(C)C)C(=O)OC3CCCC3)CC2)c(OCc2ccccc2)cc1OCc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
To a solution of Intermediate D (0.245 g, 0.5 mmol) in dichloroethane (10 mL) was added L-leucine cyclopentyl ester tosylate (0.398 g, 1.07 mmol) and sodium triacetoxyborohydride (0.417 g, 1.97 mmol). The mixture was stirred for one hour then loaded directly onto a silica gel column and eluted with 7:3 ethyl acetate:heptane to yield the desired product (0.250 g, 75% yield). LC/MS: m/z 667.25 [M+H]+
Reaction SMILES: Cl.[NH2:2][C@H:3]([C@@H:5]1[CH2:9][CH2:8][N:7]([C:10]([O:12][CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:11])[CH2:6]1)[CH3:4].C([O:24][C:25]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:38]=[CH:37][C:36]([CH2:39][N:40]2[C:48]3[C:43](=[CH:44][C:45]([C:49](O)=[O:50])=[CH:46][CH:47]=3)[C:42]([CH3:52])=[C:41]2[CH3:53])=[CH:35][CH:34]=1)=[O:26])(C)(C)C>>[CH2:13]([O:12][C:10]([N:7]1[CH2:8][CH2:9][C@@H:5]([C@@H:3]([NH:2][C:49]([C:45]2[CH:44]=[C:43]3[C:48](=[CH:47][CH:46]=2)[N:40]([CH2:39][C:36]2[CH:35]=[CH:34][C:33]([C:28]4[C:27]([C:25]([OH:26])=[O:24])=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:38][CH:37]=2)[C:41]([CH3:53])=[C:42]3[CH3:52])=[O:50])[CH3:4])[CH2:6]1)=[O:11])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)OC(C)(C)C)cc2)c2ccc(C(=O)O)cc12
Reactant: C[C@H](N)[C@@H]1CCN(C(=O)OCc2ccccc2)C1
Agent: Cl
Product: Cc1c(C)n(Cc2ccc(-c3ccccc3C(=O)O)cc2)c2ccc(C(=O)N[C@@H](C)[C@@H]3CCN(C(=O)OCc4ccccc4)C3)cc12

Procedure:
The title compound was prepared following the same general protocol as described in Step 8-9, Example 1, using the (R)-benzyl 3-((S)-1-aminoethyl)pyrrolidine-1-carboxylate hydrochloride and the 1-((2′-(tert-butoxycarbonyl)-[1,1′-biphenyl]-4-yl)methyl)-2,3-dimethyl-1H-indole-5-carboxylic acid. ESI-MS (m/z): 630 [M+H]+.
Reaction SMILES: [N:1]1[N:2]2[CH2:13][CH2:12][CH2:11][C:3]2=[CH:4][C:5]=1[C:6]([O:8]CC)=[O:7].[OH-].[Na+].Cl>O1CCOCC1>[N:1]1[N:2]2[CH2:13][CH2:12][CH2:11][C:3]2=[CH:4][C:5]=1[C:6]([OH:8])=[O:7]
Reactant: CCOC(=O)c1cc2n(n1)CCC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: O=C(O)c1cc2n(n1)CCC2
Temperature: 65 °C
Yield: 57 %

Procedure:
A 25-mL round-bottomed flask equipped with a reflux condenser was charged with ethyl 5,6-dihydro-4H-pyrrolo[1,2-b]pyrazole-2-carboxylate (540 mg, 3.0 mmol), 2N Aqueous sodium hydroxide solution (3.5 mL), and 1,4-dioxane (3.0 mL). The system was heated at 65° C. for 2.5 h. It was then cooled to room temperature and adjusted the pH to 2-3 with concentrated HCl. The solid was collected by filtration to afford 162a (260 mg, 57%) as a yellow solid. MS-ESI: [M+H]+ 153.3
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N:8]1[C:12]([C:13]2[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=O)=[CH:15][CH:14]=2)=[CH:11][CH:10]=[N:9]1.[Br:22][C:23]1[CH:28]=[CH:27][C:26]([CH2:29]C#N)=[CH:25][CH:24]=1>>[Br:22][C:23]1[CH:28]=[CH:27][C:26]([C:29]2[O:21][N:19]=[C:16]3[CH:15]=[CH:14][C:13]([C:12]4[N:8]([C:3]5[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=5[F:1])[N:9]=[CH:10][CH:11]=4)=[CH:18][C:17]=23)=[CH:25][CH:24]=1
Reactant: O=[N+]([O-])c1ccc(-c2ccnn2-c2ccccc2F)cc1
Reactant: N#CCc1ccc(Br)cc1
Product: Fc1ccccc1-n1nccc1-c1ccc2noc(-c3ccc(Br)cc3)c2c1

Procedure:
The title compound, light yellow solid (108 mg, 71%), MS (ISP) m/z=434.2 [(M+H)+], mp 202° C., was prepared in accordance with the general method of example 1 from 1-(2-fluoro-phenyl)-5-(4-nitro-phenyl)-1H-pyrazole (intermediate B) (100 mg, 353 μmol) and commercially available 2-(4-bromo-phenyl)-acetonitrile.
Reaction SMILES: C1(=O)[N:5]([CH:6]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=2)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][N:16]2C(=O)C3=CC=CC=C3C2=O)C(=O)C2=CC=CC=C12.NN>C(O)C>[NH2:5][CH:6]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][NH2:16]
Reactant: O=C1c2ccccc2C(=O)N1CCCCCCCCCC(c1ccccn1)N1C(=O)c2ccccc2C1=O
Agent: NN
Solvent: CCO
Product: NCCCCCCCCCC(N)c1ccccn1
Temperature: 25 °C

Procedure:
1,10-diphthalimido-1-pyridinyldecane (1 equiv.) and hydrazine (2 equiv.) are stirred in ethanol at reflux. The reaction mixture is cooled to room temperature and the resulting solid is filtered off. The filtrate is purified by silica gel chromatography to yield 1,10-diamino-1-pyridinyldecane.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH2:25])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[C:28](OC(=O)C)(=[O:30])[CH3:29]>N1C=CC=CC=1>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[CH:10]=[C:11]([O:15][C:16]3[C:21]4[N:22]=[C:23]([NH:25][C:28](=[O:30])[CH3:29])[S:24][C:20]=4[CH:19]=[CH:18][CH:17]=3)[CH:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1
Reactant: Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)c3)cccc2s1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Nc1nc2c(Oc3cncc(-c4ccc(C(F)(F)F)cc4)c3)cccc2s1

Procedure:
A solution of 4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-benzothiazol-2-ylamine (12 mg, 0.031 mmol), acetic anhydride (10 uL, 0.074 mmol) and pyridine (1 mL) was heated at 60° C. for 18 h. The solution was concentrated under an N2 stream and the resulting mixture was purified by prep LC (10-90% CH3CN/H2O modified with 0.1% TFA) to give N-{4-[5-(4-trifluoromethyl-phenyl)-pyridin-3-yloxy]-benzothiazol-2-yl}-acetamide as a white solid [MS (ESI, pos. ion) m/z: 430 (M+1)].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([NH:15][CH3:16])[CH2:13][CH2:12][C:11](=[O:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[BH4-].[Na+].[CH2:19]=O>CO>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([N:15]([CH3:19])[CH3:16])[CH2:9][CH2:10][C:11](=[O:14])[CH2:12][CH2:13]2)=[CH:6][CH:7]=1
Reactant: CNC1(c2ccc(Cl)cc2)CCC(=O)CC1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CN(C)C1(c2ccc(Cl)cc2)CCC(=O)CC1
Yield: 59 %

Procedure:
A reaction solution consisting of 5.68 gm. (0.0201 mole) 4-(p-chlorophenyl)-4-methylaminocyclohexanone, ethylene ketal (prepared in Part G, above), 22 ml. 37 percent formalin (aqueous formaldehyde), and 75 ml. methanol is heated at the reflux temperature for four (4) hours, after which heating the solution is allowed to cool and then chilled in an ice-bath. Small portions of sodium borohydride are cautiously added with stirring to a total of 2.89 gm. (0.076 mole). Stirring is continued for two (2) hours at 25° C. when the solution is concentrated by removing most of the solvent under reduced pressure. The concentrate is diluted with a mixture of 100 ml. methylene chloride and 20 ml. water. The aqueous phase that separates is discarded, and the organic phase is washed successively with water and then with brine. The methylene chloride solvent is then removed by evaporation under reduced pressure. The residue thus obtained is dissolved in the formalin and methanol as initially, heated at the reflux temperature, cooled in an ice bath, and treated again with the sodium borohydride as previously. Following the same work-up as described, the crude 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal free base obtained following the removal of the methylene chloride is dissolved in a small amount of diethyl ether, and the ether solution is treated with 3 N hydrogen chloride in ether. A precipitate forms which is recrystallized from methylene chloride and ethyl acetate to give 3.96 gm. (59% yield) of object compound 4-(p-chlorophenyl)-4-dimethylaminocyclohexanone, ethylene ketal hydrochloride having a melting point at 261° to 262° C. (with decomposition).
Reaction SMILES: [CH3:1][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH2:14])=[CH:7][CH:6]=1)[CH3:3].[O:15]([C:22](OC1C=CC=CC=1)=[CH:23][N+:24]([O-:26])=[O:25])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[CH3:3][N:2]([CH2:4][C:5]1[O:9][C:8]([CH2:10][S:11][CH2:12][CH2:13][NH:14][C:22]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[CH:23][N+:24]([O-:26])=[O:25])=[CH:7][CH:6]=1)[CH3:1]
Reactant: CN(C)Cc1ccc(CSCCN)o1
Reactant: O=[N+]([O-])C=C(Oc1ccccc1)Oc1ccccc1
Solvent: CC#N
Product: CN(C)Cc1ccc(CSCCNC(=C[N+](=O)[O-])Oc2ccccc2)o1
Yield: 81 %

Procedure:
A solution of 2·14 g (10 mmol) of 2-[[[5-[(dimethylamino)methyl]-2-furanyl]methyl]thio]ethylamine and 2·57 g (10 mmol) of 1,1-diphenoxy-2-nitroethene in 20 ml of acetonitrile is boiled for 2 hours. After concentration of the solution by evaporation under vacuum, the oily residue is chromatographically purified as described in Example 1 and yields 3·06 g (81%) of the title compound as a pale yellow oil which according to thin layer chromatography and 1H-NMR spectrum is identical to the compound from Example 1.
Reaction SMILES: Br[C:2]1C=CC(C(OC)=O)=C(C)C=1.[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([OH:20])=[O:19])=[CH:16][C:15]=1[I:23]>>[F:13][C:14]1[CH:22]=[CH:21][C:17]([C:18]([O:20][CH3:2])=[O:19])=[CH:16][C:15]=1[I:23]
Reactant: COC(=O)c1ccc(Br)cc1C
Reactant: O=C(O)c1ccc(F)c(I)c1
Product: COC(=O)c1ccc(F)c(I)c1

Procedure:
The title compound was prepared using standard chemical manipulations and procedures similar to those used for the preparation of compound 6.1, except 4-fluoro-3-iodobenzoic acid was used in place of 4-bromo-2-methylbenzoic acid.
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[NH:10][C:9]=2[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2.C([BH3-])#N.[Na+].O>C(O)(=O)C>[CH3:1][C:2]1([CH3:18])[C@H:17]2[C@H:9]([NH:10][C:11]3[CH:12]=[CH:13][CH:14]=[CH:15][C:16]=32)[C:8]2[C:3]1=[CH:4][CH:5]=[CH:6][CH:7]=2
Reactant: CC1(C)c2ccccc2-c2[nH]c3ccccc3c21
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)c2ccccc2[C@H]2Nc3ccccc3[C@H]21
Reaction time: 0.5 h

Procedure:
5,10-Dihydro-10,10-dimethylindeno [1,2-b]indole (1.00 g, 4.29 mmol) was reacted with sodium cyanoborohydride (1.0 g, 16 mmol) in glacial acetic acid (20 cm3), for 10 minutes. The solution was poured into water, stirred for 30 minutes, and extracted into diethylether. The organic phase was washed 10 times with water, dried (Na2SO4), and the solvent removed in vacuo. The residue was dissolved in 5% ethylacetate/petrol (60°-80° C.) and filtered through a pad of "flash" silica, yielding, on removal of solvent, a gum which solidified on the oil pump, to give the title compound as a colourless solid. Yield: 0.98 g, (98%) M.p. 57°-59° C. 1H NMR (CDCl3) δ: 1.17 (3H, s,), 1.43 (3H, s,), 3.86 (1H, d,), 3.9 (1H, br,), 5.29 (1H, d,), 6.59 (1H, d,), 6.71 (1H, ddd,), 7.02 (1H, ddd,), 7.2-7.3 (5H, m,).
Reaction SMILES: [N:1]1([C:7]2[N:12]=[C:11]([OH:13])[CH:10]=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.O>O1CCOCC1>[C:18]([O:17][C:15]([N:4]1[CH2:3][CH2:2][N:1]([C:7]2[CH:8]=[CH:9][CH:10]=[C:11]([OH:13])[N:12]=2)[CH2:6][CH2:5]1)=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: Oc1cccc(N2CCNCC2)n1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2cccc(O)n2)CC1
Temperature: 75 °C

Procedure:
To a stirring solution of 6-piperazin-1-yl-pyridin-2-ol (0.6 g, 3.30 mmol—Pavia, M. R., Taylor, C. P., Hershenson, F. M., Lobbestael, S. J. J. Med. Chem. 1987, 30(7), 1210) in 1,4-dioxane (15 ml) was added t-BOC2O (0.80 g, 3.68 mmol) and H2O (3 ml). The reaction mixture was heated at 75° C. for 8 h and cooled to RT. The heterogenous mixture was filtered and concentrated. Purification by flash silica gel chromatography afforded the title compound as a red solid, 0.90 g (97%). MS (ESI) 280.4 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:5]2[O:9][CH:8]([CH2:10][OH:11])[CH2:7][C:6]=2[CH:12]=1.[C:19]1([CH3:29])[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>CN(C)C1C=CN=CC=1>[CH3:29][C:19]1[CH:24]=[CH:23][C:22]([S:25]([O:11][CH2:10][CH:8]2[CH2:7][C:6]3[CH:12]=[C:2]([Cl:1])[CH:3]=[C:4]([CH:13]4[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]4)[C:5]=3[O:9]2)(=[O:27])=[O:26])=[CH:21][CH:20]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1Cc2cc(Cl)cc(C3CCCCC3)c2O1
Agent: CN(C)c1ccncc1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(C4CCCCC4)c3O2)cc1

Procedure:
Treatment of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methanol (4.5 g, 0.017 mol) with p-toluenesulfonyl chloride (4.8 g, 0.025 mol), diisopropylethylamine (4.36 g, 0.034 mol), and 4-(dimethylamino)pyridine (0.12 g, 0.98 mmol) generally according to the procedure described for Intermediate 45 gave (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate as a colorless oil. Treatment of the tosylate with sodium azide (4.03 g, 61.99 mmol) generally according to the procedure described for Intermediate 98 provided 3.45 g of (±)-2-(azidomethyl)-5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran. Treatment of the azide with sulfided platinum on carbon (0.75 g, 5 wt. %) generally according to the procedure described for Example 1 afforded 2.70 g (60%) of (±)-(5-chloro-7-cyclohexyl-2,3-dihydro-1-benzofuran-2-yl)methylamine as a white solid, hydrochloride salt. mp 210-213° C.; Anal. calcd for C15H20ClNOHCl: C, 59.61; H, 7.00; N, 4.63. Found: C, 57.29; H, 7.14; N, 4.78.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([F:11])[CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[NH3:12]>O>[F:11][C:4]1[CH:5]=[C:6]2[C:10](=[C:2]([NH2:12])[CH:3]=1)[NH:9][CH:8]=[CH:7]2
Reactant: Fc1cc(Br)c2[nH]ccc2c1
Reactant: N
Solvent: O
Product: Nc1cc(F)cc2cc[nH]c12
Temperature: 155 °C

Procedure:
A mixture of 7-bromo-5-fluoro-indole (1 g), Cu (0.31 g), CuBr (0.64 g) and NH3 (30 ml of a 33% aqueous solution) was heated in an autoclave for 1.5 h at 155° C. The mixture was diluted with water and extracted with EtOAc. The organic phase was dried and the solvent removed to give 5-fluoro-7-amino-indole as an oil which was used without further purification. UPLC/MS found for C8H7FN2 as (M+H)+ 151.0.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@H:10]([C:14]([OH:16])=O)[CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[C:19]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])(=[O:22])[NH:20][NH2:21].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.Cl>ClCCl>[C:24]([O:23][C:19]([NH:20][NH:21][C:14]([C@H:10]1[CH2:11][CH2:12][CH2:13][N:8]([C:6](=[O:7])[C:5]2[CH:4]=[CH:3][C:2]([F:1])=[CH:18][CH:17]=2)[CH2:9]1)=[O:16])=[O:22])([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)NN
Reactant: O=C(O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NNC(=O)[C@H]1CCCN(C(=O)c2ccc(F)cc2)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 46.9 %

Procedure:
A mixture of 1-(4-fluoro-benzoyl)-(S)-piperidine-3-carboxylic acid (1.05 g, 4.17 mmol), tert-butyl carbazate (0.55 g, 4.17 mmol), HOBT (0.562 g, 4.17 mmol), EDCI.HCl (1.2 g, 6.25 mmol) in dry dichloromethane (8 mL) was kept under stirring overnight at ambient temperature, under nitrogen atmosphere. HCl 1N (30 mL) was then added and the phases separated. The organic layer was washed with HCl 1N (30 mL), with NaOH 1N (30 mL×2 times), then with water (30 mL). Evaporation of the organic solvent afforded a crude yellow oil which was purified by flash chromatography (silica gel, eluent: DCM/MeOH 70/1) to give 0.715 g of N′-[1-(4-fluoro-benzoyl)-(S)-piperidine-3-carbonyl]-hydrazinecarboxylic acid-tert-butyl ester.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:18])=[C:6]([C@:8]2([CH3:17])[C:13]([F:15])([F:14])[CH2:12][O:11][C:10]([NH2:16])=[N:9]2)[CH:7]=1.[Cl:19][C:20]1[C:21]([C:30](O)=[O:31])=[N:22][N:23]([CH2:25][C:26]([F:29])([F:28])[F:27])[CH:24]=1>>[NH2:16][C:10]1[O:11][CH2:12][C:13]([F:14])([F:15])[C@:8]([C:6]2[CH:7]=[C:2]([NH:1][C:30]([C:21]3[C:20]([Cl:19])=[CH:24][N:23]([CH2:25][C:26]([F:28])([F:27])[F:29])[N:22]=3)=[O:31])[CH:3]=[CH:4][C:5]=2[F:18])([CH3:17])[N:9]=1
Reactant: C[C@]1(c2cc(N)ccc2F)N=C(N)OCC1(F)F
Reactant: O=C(O)c1nn(CC(F)(F)F)cc1Cl
Product: C[C@]1(c2cc(NC(=O)c3nn(CC(F)(F)F)cc3Cl)ccc2F)N=C(N)OCC1(F)F

Procedure:
The condensation of (R)-4-(5-amino-2-fluoro-phenyl)-5,5-difluoro-4-methyl-5,6-dihydro-4H-[1,3]oxazin-2-ylamine (intermediate XI-1) and 4-chloro-1-(2,2,2-trifluoro-ethyl)-1H-pyrazole-3-carboxylic acid (CAS1006448-63-0) following procedure I yielded the title compound as a white solid. MS (ISP): m/z=470.2 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[C:10]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[C].[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C@H:10]([C:20]([OH:22])=[O:21])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2)=C(C(=O)O)C1
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](c2ccccc2)[C@H](C(=O)O)C1
Reaction time: 2 h
Yield: 84 %

Procedure:
1-(tert-Butoxycarbonyl)-4-phenyl-1,2,5,6-tetrahydropyridin-3-carboxylic acid (5.63 g) was dissolved in methanol (60 ml), and thereto was added palladium-carbon (4.06 g), and the mixture was stirred under hydrogen atmosphere for 2 hours. The reaction solution was filtered on celite, and concentrated under reduced pressure to give the title compound (4.76 g).
Reaction SMILES: [C:1]([CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:25])[F:24])[CH:18]=3)[CH2:10][C:11]([CH3:16])([CH3:15])[O:12]2)=[CH:7][CH:6]=1)#[N:2].[BrH:27]>[Pd].C(O)C>[BrH:27].[NH2:2][CH2:1][CH2:3][O:4][C:5]1[CH:14]=[C:13]2[C:8]([CH:9]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([F:26])([F:24])[F:25])[CH:18]=3)[CH2:10][C:11]([CH3:15])([CH3:16])[O:12]2)=[CH:7][CH:6]=1
Reactant: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCC#N)cc2O1
Agent: [Pd]
Agent: Br
Solvent: CCO
Product: CC1(C)CC(c2cccc(C(F)(F)F)c2)c2ccc(OCCN)cc2O1

Procedure:
A solution of 7-cyanomethyloxy-2,2-dimethyl-4-(3-trifluoromethylphenyl) chroman (5.4 g) and 10% palladium on charcoal (0.5 g) in ethanol (75 ml) was hydrogenated at atmospheric pressure. The catalyst was removed by filtration and the filtrate evaporated under reduced pressure to give an oil which was treated with ethereal hydrogen bromide to give the title compound (4 g) as a very hygroscopic non-crystalline compound.
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH2:24][C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:48]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1>C1COCC1.C1(C)C=CC=CC=1>[CH3:1][C:2]1([CH3:29])[CH2:7][CH2:6][N:5]([C:8]2[N:13]3[N:14]=[C:15]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=4)[N:16]=[C:12]3[N:11]=[C:10]([CH3:23])[C:9]=2[CH:24]([OH:48])[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3]1
Reactant: COC(=O)Cc1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: COC(=O)C(O)c1c(C)nc2nc(-c3ccccc3)nn2c1N1CCC(C)(C)CC1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 49.8 %

Procedure:
To a solution of methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)acetate (106 mg, 0.269 mmol) in anhydrous THF (5 ml) at −78° C. was added dropwise KHMDS (0.808 mL, 0.404 mmol) in toluene. Reaction mixture was stirred at −78° C. for 30 min and to this was added dropwise 3-phenyl-2-(phenylsulfonyl)-1,2-oxaziridine (106 mg, 0.404 mmol) in THF (2 mL) and the contents were stirred at −78° C. for 30 min and allowed slowly to warm to room temperature, then quenched with a drop of saturated ammonium chloride solution. Evaporated to remove the solvent. Purified by prep HPLC to afford methyl 2-(7-(4,4-dimethylpiperidin-1-yl)-5-methyl-2-phenyl-[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (56 mg, 0.134 mmol, 49.8% yield) as white solid. 1H-NMR (500 MHz, CDCl3) δ 1.15 (6 H, s), 1.69-1.75 (4 H, m), 2.62 (3 H, s), 3.77-3.79 (2 H, m), 3.81-3.83 (2 H, m), 3.85 (3 H, s), 5.49 (1 H, s), 7.56-7.60 (3 H, m), 8.20-8.22 (2 H, m).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5]Br.[OH:7][CH:8]([CH3:41])[CH2:9][S:10]([C:13]1[CH:14]=[C:15]([C@H:24]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:34]=[C:33]([O:35][CH3:36])[C:32]([O:37][CH3:38])=[C:31]([O:39][CH3:40])[CH:30]=3)[O:25]2)[CH:16]=[C:17]([OH:23])[C:18]=1[O:19][CH2:20][CH2:21][CH3:22])(=[O:12])=[O:11].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[OH:7][CH:8]([CH3:41])[CH2:9][S:10]([C:13]1[CH:14]=[C:15]([C@H:24]2[CH2:28][CH2:27][C@H:26]([C:29]3[CH:30]=[C:31]([O:39][CH3:40])[C:32]([O:37][CH3:38])=[C:33]([O:35][CH3:36])[CH:34]=3)[O:25]2)[CH:16]=[C:17]([O:23][CH2:5][CH2:4][CH2:3][CH2:2][Br:1])[C:18]=1[O:19][CH2:20][CH2:21][CH3:22])(=[O:11])=[O:12]
Reactant: CCCOc1c(O)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Reactant: BrCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCOc1c(OCCCCBr)cc([C@H]2CC[C@H](c3cc(OC)c(OC)c(OC)c3)O2)cc1S(=O)(=O)CC(C)O
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
1,4-Dibromobutane (75 uL, 0.63 mmol) was added to a solution of trans-2-[3-(2-hydroxy-n-propylsulfonyl)-4-n-propoxy-5-hydroxyphenyl]-5-(3,4,5-trimethoxyphenyl)tetrahydrofuran (75 mg, 0.15 mmol) in DMF (0.5 mL) containing potassium carbonate (75 mg, 0.54 mmol). The reaction mixture was heated with stirring under nitrogen at 70° C. for 1.5 h, cooled, and partitioned between ethyl ether and water. The ethereal layer was separated and the aqueous layer was re-extracted twice with ether. The organic extracts were combined, dried, and evaporated to a residue. Purification by preparative TLC (hexane-ethyl acetate; 1:1, v/v) gave the title compound as a colorless viscous oil: Rf 0.5; NMR (CDCl3) δ 1.25 (d, CH2CHOHCH3).
Reaction SMILES: [CH2:1]1[C:13]2[C:12]3[CH:11]=[CH:10][CH:9]=[C:8]([S:14][C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)[C:7]=3[NH:6][C:5]=2[CH2:4][CH2:3][NH:2]1.[CH2:22]=O.[BH4-].[Na+]>CO>[CH3:22][N:2]1[CH2:3][CH2:4][C:5]2[NH:6][C:7]3[C:8]([S:14][C:15]4[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][CH:16]=4)=[CH:9][CH:10]=[CH:11][C:12]=3[C:13]=2[CH2:1]1
Reactant: Cc1ccc(Sc2cccc3c4c([nH]c23)CCNC4)cc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: Cc1ccc(Sc2cccc3c4c([nH]c23)CCN(C)C4)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 76 %

Procedure:
4-Methylphenyl 2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indol-6-yl sulfide (200 mg, 0.68 mmol) was brought to reflux with formaldehyde (37% aq., 0.68 mL) in MeOH (1.8 mL) for 30 minutes. The reaction was then cooled to 0° C. and sodium borohydride (89 mg, 1.3 mmol) was added slowly. The solution was allowed to stir at room temperature for 2 hours. Ice chips were then added and the reaction partitioned between CHCl3 and water. The aqueous layer was extracted with CHCl3 (3×10 mL). The combined extracts were washed with sat. NaCl (10 mL) and dried (MgSO4) and evaporated. The residue was dissolved in 1 mL EtOH and 1N HCl-Ether was added until no further precipitation was seen. The solid was filtered affording 2-methyl-6-[(4-methylphenyl)sulfanyl]-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole as a light tan solid (178 mg, 76%). 1H NMR (CD3OD, 300 MHz) δ 7.49 (d, 1H, J=8.1 Hz), 7.26 (d, 1H, J=7.6 Hz), 7.07 (t, 1H, J=7.7 Hz), 6.97-7.02 (m, 4H), 4.42 (s, 2H), 3.58 (t, 2H, J=6.2 Hz), 3.05-3.21 (m, 5H), 2.25 (s, 3H) ppm.