Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.Cl.Cl[C:4]1[CH:5]=[C:6]2[C:12]3([CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)[CH2:11][N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][C@@H:24](O)[C:20]=4[N:21]=[CH:22][N:23]=3)[C:7]2=[CH:8][CH:9]=1.C=O>>[CH2:12]([N:15]1[CH2:16][CH2:17][C:12]2([C:6]3[C:7](=[CH:8][CH:9]=[CH:4][C:5]=3[CH2:22][NH:21][CH:20]([CH3:24])[CH3:19])[N:10]([C:18]3[C:19]4[C@H:26]([CH3:27])[CH2:25][CH2:24][C:20]=4[N:21]=[CH:22][N:23]=3)[CH2:11]2)[CH2:13][CH2:14]1)[C:6]1[CH:7]=[CH:8][CH:9]=[CH:4][CH:5]=1
Reactant: C[C@@H]1C[C@@H](O)c2ncnc(N3CC4(CCNCC4)c4cc(Cl)ccc43)c21
Agent: C=O
Agent: Cl
Product: CC(C)NCc1cccc2c1C1(CCN(Cc3ccccc3)CC1)CN2c1ncnc2c1[C@H](C)CC2
Yield: 60 %

Procedure:
(R)-N-((1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methyl)propan-2-amine (33 mg, 60%) was prepared by the procedures described in Example 18, substituting (R)-(1′-benzyl-1-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)spiro[indoline-3,4′-piperidine]-4-yl)methanamine trihydrochloride trihydrochloride for (5R,7R)-4-(5-chlorospiro[indoline-3,4′-piperidine]-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-7-ol dihydrochloride, and substituting acetone for formaldehyde. LCMS (APCI+) m/z 482 [M+H]+; Rt=2.59 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([Cl:11])=[N:4][CH:5]=[C:6]([CH:10]=1)[C:7]([OH:9])=O.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH:24]([NH2:27])([CH3:26])[CH3:25]>>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([NH:27][CH:24]([CH3:26])[CH3:25])=[O:9])[CH:5]=[N:4][C:3]=1[Cl:11]
Reactant: O=C(O)c1cnc(Cl)c(Cl)c1
Reactant: CC(C)N
Agent: O=C(n1ccnc1)n1ccnc1
Product: CC(C)NC(=O)c1cnc(Cl)c(Cl)c1

Procedure:
The product was prepared from 5,6-dichloro-nicotinic acid (0.86 g), carbonyldiimidazole (0.8 g) and isopropylamine (0.52 ml) using the method of example 115 step (i). Yield 0.69 g.
Reaction SMILES: C1(S([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([NH:19][CH3:20])[C:13]=3[C:12]([C:21]([C:23]3[C:24]([F:37])=[N:25][C:26]([NH:29][C:30]4[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=4)=[CH:27][CH:28]=3)=[O:22])=[CH:11]2)(=O)=O)C=CC=CC=1.FC(F)(F)C(O)=O.[OH-].[K+]>CO>[F:37][C:24]1[C:23]([C:21]([C:12]2[C:13]3[C:18]([NH:19][CH3:20])=[N:17][CH:16]=[N:15][C:14]=3[NH:10][CH:11]=2)=[O:22])=[CH:28][CH:27]=[C:26]([NH:29][C:30]2[CH:31]=[N:32][C:33]([CH3:36])=[CH:34][CH:35]=2)[N:25]=1
Reactant: CNc1ncnc2c1c(C(=O)c1ccc(Nc3ccc(C)nc3)nc1F)cn2S(=O)(=O)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O=C(O)C(F)(F)F
Product: CNc1ncnc2[nH]cc(C(=O)c3ccc(Nc4ccc(C)nc4)nc3F)c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To [7-(benzenesulfonyl)-4-methylamino-pyrrolo[2,3-d]pyrimidin-5-yl]-[2-fluoro-6-[(6-methyl-3-pyridyl)amino]-3-pyridyl]methanone; 2,2,2-trifluoroacetic acid (88, 80 mg, 0.09 mmol) in Methanol (6 ml) was added KOH (0.1 g, 1.78 mmol). The reaction was stirred at room temperature for 1 hour. The reaction mixture was concentrated and purified with silica gel column chromatography eluting with 2% to 25% methanol in methylene chloride to give product (P-4115, 9.6 mg, 27.3%). MS (ESI) [M+H+]+=377.9.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4](OB(O)O)[CH:5]=[CH:6][C:7]=1[F:8].Br[C:14]1[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][N:15]=1.C(O)C.C(=O)([O-])[O-].[Na+].[Na+]>C1C=CC=CC=1>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=2)=[N:15][CH:16]=1
Reactant: OB(O)Oc1ccc(F)c(F)c1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: c1ccccc1
Solvent: CCO
Product: Fc1ccc(-c2ccc(Br)cn2)cc1F

Procedure:
A mixture of 6.2 g of 3,4-difluorophenylboric acid, 8.5 g of 2,5-dibromopyridine, 0.31 g of tetrakistriphenylphosphine palladium, 60 ml of ethanol, 120 ml of benzene and 120 ml of 2N sodium carbonate solution is heated to boiling (66° C.) for 7 hours while stirring. After cooling the mixture is extracted with diethyl ether. The organic phase is washed with 100 ml of saturated sodium hydrogen carbonate solution and 100 ml of water, dried over sodium sulphite, filtered and concentrated. Purification of the residue by chromatography on silica gel with hexane/ethyl acetate 19:1 yields pure 5-bromo-2-(3,4-difluorophenyl)pyridine.
Reaction SMILES: [CH:1]([CH:3]=O)=O.[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]([NH2:13])[C:7]=1[NH2:14]>CCO>[Br:5][C:6]1[CH:11]=[CH:10][C:9]([Br:12])=[C:8]2[C:7]=1[N:14]=[CH:1][CH:3]=[N:13]2
Reactant: Nc1c(Br)ccc(Br)c1N
Reactant: O=CC=O
Solvent: CCO
Product: Brc1ccc(Br)c2nccnc12
Temperature: 25 °C
Yield: 79.5 %

Procedure:
A 40% aqueous solution of glyoxal (8.8 M, 6.3 mL, 55.1 mmol, 1.3 equiv) was added to a suspension of 3,6-dibromo-benzene-1,2-diamine (Step 179.6) (11.3 g, 42.4 mmol) in EtOH (280 mL). The reaction mixture was heated to reflux for 3 h and allowed to cool to rt overnight. Vacuum filtration of the reaction mixture afforded 9.7 g of the title compound as a yellow solid: APCI-MS: 286/288/291 [M-1]−; tR=4.40 min (System 1).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH2:20])[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].Br[C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=1>>[CH3:1][S:2]([C:5]1[CH:6]=[C:7]([C:11]2[N:16]3[N:17]=[C:18]([NH:20][C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([O:28][CH3:29])[CH:23]=4)[N:19]=[C:15]3[CH:14]=[CH:13][CH:12]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])=[O:4]
Reactant: COc1cccc(Br)c1
Reactant: CS(=O)(=O)c1cccc(-c2cccc3nc(N)nn23)c1
Product: COc1cccc(Nc2nc3cccc(-c4cccc(S(C)(=O)=O)c4)n3n2)c1
Yield: 75.3 %

Procedure:
[5-(3-Methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxyphenyl)-amine was prepared from 5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-ylamine (100 mg, 0.35 mmol) and 1-bromo-3-methoxy benzene (52 μL, 0.42 mmol) in a manner analogous to Example 77 to yield [5-(3-methanesulfonyl-phenyl)-[1,2,4]triazolo[1,5-a]pyridin-2-yl]-(3-methoxyphenyl)-amine (104 mg, 75%) as a yellow powder following purification on a 12 g Isco silica gel column using 0-5% methanol in dichloromethane as an eluent. MP=180° C. 1H NMR (400 MHz, (D3C)2SO, δ, ppm): 9.66 (s, 1H), 8.62 (m, 1H), 8.40 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.0 Hz, 1H), 7.87 (t, J=16.1 Hz, 8.0 Hz, 1H), 7.68 (m, 2H), 7.32 (m, 2H), 7.25 (d, J=8.6 Hz, 1H), 7.15 (t, J=16.5 Hz, 8.0 Hz, 1H), 6.45 (dd, J=8.0 Hz, 2.7 Hz, 1H), 3.69 (s, 3H), 3.33 (s, 3H). MS=395 (MH)+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]=O.[C:9]([NH2:17])([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:11])[CH3:10].O>C(Cl)Cl>[CH3:10][C:9](/[N:17]=[CH:7]/[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1)([CH2:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH3:11]
Reactant: O=Cc1ccccn1
Reactant: CC(C)(C)CC(C)(C)N
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)CC(C)(C)/N=C/c1ccccn1
Yield: 94.1 %

Procedure:
In air, to a solution of 2-pyridinecarboxaldehyde (0.338 g, 0.300 mL, 3.15 mmol, 1.01 equiv) in CH2Cl2 (10 mL) was added tert-octylamine (0.402 g, 0.500 mL, 3.11 mmol, 1.00 equiv). After heating at reflux for 1.5 h with azeotropic removal of water using a Dean-Stark trap, the reaction mixture was concentrated under reduced pressure. The residue was purified by bulb-to-bulb distillation (250 mTorr, 140° C.) to give the title compound as a colorless oil (0.639 g, 94% yield).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([OH:17])=[C:15]([C:18]([O:20][CH3:21])=[O:19])[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].S(OCC)(O[CH2:26][CH3:27])(=O)=O>CN(C=O)C>[CH2:26]([O:17][C:16]1[N:12]([C:9]2[CH:8]=[CH:7][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:11][CH:10]=2)[N:13]=[N:14][C:15]=1[C:18]([O:20][CH3:21])=[O:19])[CH3:27]
Reactant: CCOS(=O)(=O)OCC
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2O)cc1
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)OC)c2OCC)cc1
Yield: 33 %

Procedure:
A solution of methyl 1-{4-[(ethylamino)carbonyl]phenyl}-5-hydroxy-1H-1,2,3-triazole-4-carboxylate (580 mg, 2 mmol) obtained in Example 1211a) and diethyl sulfate (339 mg, 2.2 mmol, 1.1 eq.) in DMF (5 ml) was stirred at 90° C. for 15 hr. The reaction mixture was concentrated to dryness, and chloroform (20 ml) and water (10 ml) were added to the residue. After partitioning, the organic layer was dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column (hexane/ethyl acetate=1/1 to ethyl acetate/methanol=4/1) to give the title compound as a white powder (210 mg, 33%).
Reaction SMILES: [Br:1][C:2]1[C:3](F)=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6].C(=O)([O-])[O-].[K+].[K+].[CH3:18][C:19]([SH:22])([CH3:21])[CH3:20].O>CN(C=O)C>[Br:1][C:2]1[C:3]([S:22][C:19]([CH3:21])([CH3:20])[CH3:18])=[C:4]([CH:7]=[CH:8][C:9]=1[I:10])[CH:5]=[O:6]
Reactant: CC(C)(C)S
Reactant: O=Cc1ccc(I)c(Br)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Sc1c(C=O)ccc(I)c1Br
Temperature: 80 °C
Yield: 62.6 %

Procedure:
A mixture of 3-bromo-2-fluoro-4-iodo-benzaldehyde (1.3 g, 4.0 mmol), potassium carbonate (0.66 g, 4.7 mmol), and 2-methylpropane-2-thiol (0.53 mL, 4.7 mmol) in dry DMF (2 mL) was heated at 80° C. in a sealed tube for 16 h. The reaction mixture was cooled to RT, water was added, and the mixture was extracted with dichloromethane (2×30 mL). The combined organic fractions were washed with water (60 mL), dried over sodium sulfate, filtered, and concentrated. Purification of the residue by column chromatography (5% ethyl acetate:hexanes) afforded 1.0 g (64%) of the title compound. 1H NMR (300 MHz, CDCl3): δ 1.30 (s, 9H), 7.54 (d, J=8.1 Hz, 1H), 7.87 (d, J=8.1 Hz, 1H), 10.29 (s, 1H).
Reaction SMILES: [O:1]=[C:2]([C:10]1[CH:15]=[CH:14][N:13]=[N:12][CH:11]=1)[CH2:3]P(=O)(OC)OC.C(N(CC)CC)C.[Br:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>C1COCC1>[Br:23][C:24]1[CH:31]=[CH:30][C:27](/[CH:28]=[CH:3]/[C:2]([C:10]2[CH:15]=[CH:14][N:13]=[N:12][CH:11]=2)=[O:1])=[CH:26][CH:25]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: COP(=O)(CC(=O)c1ccnnc1)OC
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(/C=C/c1ccc(Br)cc1)c1ccnnc1
Yield: 7 %

Procedure:
To a solution of dimethyl 2-oxo-2-(pyridazin-4-yl)ethylphosphonate (1.83 g, 7.95 mmol) in THF (18 mL) was added triethylamine (885 mg, 8.75 mmol) and 4-bromobenzaldehyde (1.49 g, 7.95 mmol) at 0° C. After 6 h the reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate, filtered, and evaporated. The residue was suspended in ethyl acetate and the title compound (824 mg, 36%) collected by filtration. Chromatography of the mother liquor (SiO2; ethyl acetate) produced a second crop of product (160 mg, 7%). Light yellow solid, MS: 288.9 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][C:8]([C:11](Cl)=[O:12])=[CH:7][C:5]=2[N:6]=1.[CH3:14][Mg]Cl.Cl>O1CCCC1.O>[C:11]([C:8]1[CH:9]=[CH:10][C:4]2[S:3][C:2]([Cl:1])=[N:6][C:5]=2[CH:7]=1)(=[O:12])[CH3:14]
Reactant: C[Mg]Cl
Reactant: O=C(Cl)c1ccc2sc(Cl)nc2c1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(=O)c1ccc2sc(Cl)nc2c1
Reaction time: 0.5 h

Procedure:
A solution of 2-chloro-5-(chlorocarbonyl)benzothiazole (321 mg, 1.38 mmol, prepared according to U.S. Pat. No. 3,654,296) and ferric acetylacetonate (14.7 mg, 0.042 mmol) in anhydrous tetrahydrofuran (13.8 mL) was cooled in an ice-methanol bath (−20° C.), stirred under a nitrogen atmosphere, and treated dropwise over 5 minutes with 1M methyl magnesium chloride in tetrahydrofuran (1.38 mL). The resulting mixture was stirred at −15° C. for 15 minutes then at room temperature for 30 minutes. The mixture was treated with 2N hydrochloric acid (1.38 mL), diluted with water, and extracted with ethyl acetate. The extracts were washed with 5% aqueous sodium bicarbonate and brine, dried over magnesium sulfate, filtered, and evaporated in vacuo to white solid (299 mg). The crude product was purified by flash chromatography on silica gel (25 g, loaded as a dichloromethane solution and eluted with 2% ethyl acetate in dichlormethane) to afford 5-acetyl-2-chlorobenzothiazole (201 mg) as a white solid.
Reaction SMILES: [CH2:1]([NH:4][C:5](/[CH:7]=[CH:8]/[C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])(=[O:28])=[O:27])=[O:24])=[CH:21][C:20]=2[O:38][CH3:39])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3].C(N(CC)CC)C.[H][H]>[Pd].C(O)C>[CH2:1]([NH:4][C:5]([CH2:7][CH2:8][C:9]1[CH:17]=[C:16]2[C:12]([CH:13]=[CH:14][N:15]2[CH2:18][C:19]2[CH:37]=[CH:36][C:22]([C:23]([NH:25][S:26]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=3[CH3:35])(=[O:28])=[O:27])=[O:24])=[CH:21][C:20]=2[O:38][CH3:39])=[CH:11][CH:10]=1)=[O:6])[CH2:2][CH3:3]
Reactant: [H][H]
Reactant: CCCNC(=O)/C=C/c1ccc2ccn(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCNC(=O)CCc1ccc2ccn(Cc3ccc(C(=O)NS(=O)(=O)c4ccccc4C)cc3OC)c2c1
Yield: 79.7 %

Procedure:
Palladium on carbon (10% w/w, 0.01 g) was added to a solution of E-4-[6-[2-(propylcarbamoyl)vinyl]indol-1-ylmethyl]-3-methoxy-N-(2-methylphenylsulfonyl)benzamide (0.1 g) and triethylamine (0.026 ml) in ethanol (5 ml). The mixture was vigorously stirred and hydrogenated at atmospheric pressure. When hydrogen uptake had ceased, the catalyst was removed by filtration through diatomaceous earth, the filter pad washed with ethanol, the filtrate diluted with water (10 ml) and acidified to pH 4 with 1M hydrochloric acid. The ethanol was evaporated; and the white solid which precipitated from the aqueous residue was isolated by filtration, washed with water and dried to give the title compound (80 mg, 80%) as a white solid; mp 110°.
Reaction SMILES: [NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12](=[O:31])[N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)[C:8]([OH:10])=O)=[CH:4][C:3]=1[Cl:38].[CH3:39][N:40]1[CH2:45][CH:44]2[CH2:46][CH:41]1[CH2:42][N:43]2[CH:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1>C(N(CC)CC)C>[NH2:1][C:2]1[C:33]([C:34]([F:37])([F:36])[F:35])=[CH:32][C:5]([CH2:6][C@@H:7]([CH2:11][C:12]([N:13]2[CH2:18][CH2:17][CH:16]([N:19]3[CH2:25][CH2:24][C:23]4[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=4[NH:21][C:20]3=[O:30])[CH2:15][CH2:14]2)=[O:31])[C:8]([N:50]2[CH2:49][CH2:48][CH:47]([N:43]3[CH2:42][CH:41]4[CH2:46][CH:44]3[CH2:45][N:40]4[CH3:39])[CH2:52][CH2:51]2)=[O:10])=[CH:4][C:3]=1[Cl:38]
Reactant: CN1CC2CC1CN2C1CCNCC1
Reactant: Nc1c(Cl)cc(C[C@@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)C(=O)O)cc1C(F)(F)F
Solvent: CCN(CC)CC
Product: CN1CC2CC1CN2C1CCN(C(=O)[C@H](CC(=O)N2CCC(N3CCc4ccccc4NC3=O)CC2)Cc2cc(Cl)c(N)c(C(F)(F)F)c2)CC1

Procedure:
Prepared analogously to Example 10.26 from 100 mg (0.18 mmol) (S)-2-(4-amino-3-chloro-5-trifluoromethyl-benzyl)-4-oxo-4-[4-(2-oxo-1,2,4,5-tetrahydro-1,3-benzodiazepin-3-yl)-piperidin-1-yl]-butanoic acid and 39.1 mg (0.2 mmol) 2-methyl-5-piperidin-4-yl-2,5-diaza-bicyclo[2.2.1]heptane using triethylamine as the base.
Reaction SMILES: [Br:1][CH2:2][C:3]1[C:19]([C:20]#[N:21])=[CH:18][C:6]([C:7]([N:9](C)[C:10](=O)OC(C)(C)C)=[O:8])=[C:5]([O:22][CH2:23][CH3:24])[CH:4]=1>ClCCl.FC(F)(F)C(O)=O>[CH3:10][NH:9][C:7](=[O:8])[C:6]1[CH:18]=[C:19]([C:20]#[N:21])[C:3]([CH2:2][Br:1])=[CH:4][C:5]=1[O:22][CH2:23][CH3:24]
Reactant: CCOc1cc(CBr)c(C#N)cc1C(=O)N(C)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1cc(CBr)c(C#N)cc1C(=O)NC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.2 %

Procedure:
After dissolving tert-butyl N-[4-(bromomethyl)-5-cyano-2-ethoxybenzoyl]-N-methylcarbamate (39.9 g) in dichloromethane (300 ml), trifluoroacetic acid (50 ml) was added and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated and the residue was purified by silica gel column chromatography (solvent: n-hexane-ethyl acetate) to yield the title compound (19.77 g) as a white solid.
Reaction SMILES: C1COC23OCCOC2([C@]2(CC[C@H]4[C@@H](C[C@H](C=O)C5[C@]4(C)CCCC5)[C@@H]2C3)C)[O:2]1.[CH2:30]=[C:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1>>[CH:30]([C@@H:31]1[CH:48]2[C@:43]([CH3:50])([CH2:44][CH2:45][C:46](=[O:49])[CH2:47]2)[C@@H:42]2[C@H:33]([C@H:34]3[C@@:38]([CH2:40][CH2:41]2)([CH3:39])[C:37](=[O:51])[CH2:36][CH2:35]3)[CH2:32]1)=[O:2]
Reactant: C=C1C[C@@H]2[C@H](CC[C@]3(C)C(=O)CC[C@@H]23)[C@@]2(C)CCC(=O)CC12
Reactant: C[C@]12CCCCC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@@]2(C)[C@H]1CC13OCCOC12OCCO3
Product: C[C@]12CCC(=O)CC1[C@@H](C=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Yield: 85 %

Procedure:
6α-Formylandrostane-3,17-dione was prepared in 85% yield from 3,3:17,17-bis(ethylendioxy)-6α-formylandrostane (Prepn. 14) by the procedure described above for the preparation of 6-methyleneandrostane-3,17-dione (II-ac, Prepn. 13). The combined organic extracts were washed with H2O, dried over Na2SO4 and evaporated to dryness to give 6α-formylandrostane-3,17-dione. 1H-NMR (300 MHz, acetone-d6, ppm from TMS): δ 9.50 (1H, d), 2.56-0.82 (21H, m), 1.16 (3H, s), 0.88 (3H, s).
Reaction SMILES: COC1C=CC(C[N:8](CC2C=CC(OC)=CC=2)[C:9]2[N:14]=[C:13]([C:15]3[C:16]([NH:29][C:30]4[CH:31]=[N:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=4)=[N:17][CH:18]=[C:19]([C:21]([N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)=[O:22])[CH:20]=3)[N:12]=[C:11]([CH3:38])[N:10]=2)=CC=1.OS(C(F)(F)F)(=O)=O>C(O)(C(F)(F)F)=O>[CH3:37][O:36][C:33]1[N:32]=[CH:31][C:30]([NH:29][C:16]2[C:15]([C:13]3[N:12]=[C:11]([CH3:38])[N:10]=[C:9]([NH2:8])[N:14]=3)=[CH:20][C:19]([C:21]([N:23]3[CH2:24][CH2:25][O:26][CH2:27][CH2:28]3)=[O:22])=[CH:18][N:17]=2)=[CH:35][CH:34]=1
Reactant: COc1ccc(CN(Cc2ccc(OC)cc2)c2nc(C)nc(-c3cc(C(=O)N4CCOCC4)cnc3Nc3ccc(OC)nc3)n2)cc1
Agent: O=S(=O)(O)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(Nc2ncc(C(=O)N3CCOCC3)cc2-c2nc(C)nc(N)n2)cn1
Temperature: 80 °C
Yield: 68.9 %

Procedure:
A solution of N,N-bis(4-methoxybenzyl)-4-(2-((6-methoxy-3-pyridinyl)amino)-5-(4-morpholinylcarbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine (0.128 g, 0.193 mmol) in TFA (2.00 mL) at ambient temperature was treated with triflic acid (0.051 mL, 0.579 mmol) and heated for 4 h at 80° C. The reaction mixture was concentrated, but not to dryness. A few ice cubes were added and saturated NaHCO3 (aq.) was added until pH was about 7. The solid was collected by filtration, washed with water and CH2Cl2, and dried under vacuum to give 4-(2-((6-methoxy-3-pyridinyl)amino)-5-(4-morpholinylcarbonyl)-3-pyridinyl)-6-methyl-1,3,5-triazin-2-amine (0.056 g, 0.133 mmol, 68.6% yield) as a brown solid. 1H NMR (400 MHz, d6-DMSO) δ 11.92 (s, 1H); 8.87 (s, 1H); 8.52 (s, 1H); 8.38 (s, 1H); 8.11-8.22 (m, 1H); 7.92 (br. s., 1H); 7.78 (br. s., 1H); 6.85 (d, J=8.80 Hz, 1H); 3.84 (s, 3H); 3.54-3.65 (m, 8H); 2.44 (s, 3H). m/z (ESI, +ve ion) 423.1 (M+H)+.
Reaction SMILES: [C:1]1([CH3:23])[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]([N:10]2[C@H:14]3[C:15]4[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=4[CH2:21][C@H:13]3[O:12][C:11]2=[O:22])=[O:9])[CH:2]=1.C[Si](C)(C)N[Si](C)(C)C.[Na].[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[N:45]=[C:44]([CH2:55]I)[CH:43]=2)[CH:38]=[CH:39][C:40]=1[Cl:41]>C1COCC1>[Cl:34][C:35]1[CH:36]=[C:37]([C:42]2[N:46]([C:47]3[CH:52]=[CH:51][C:50]([O:53][CH3:54])=[CH:49][CH:48]=3)[N:45]=[C:44]([CH2:55][C@@H:7]([C:3]3[CH:2]=[C:1]([CH3:23])[CH:6]=[CH:5][CH:4]=3)[C:8]([N:10]3[C@H:14]4[C:15]5[CH:16]=[CH:17][CH:18]=[CH:19][C:20]=5[CH2:21][C@H:13]4[O:12][C:11]3=[O:22])=[O:9])[CH:43]=2)[CH:38]=[CH:39][C:40]=1[Cl:41]
Reactant: COc1ccc(-n2nc(CI)cc2-c2ccc(Cl)c(Cl)c2)cc1
Reactant: Cc1cccc(CC(=O)N2C(=O)O[C@@H]3Cc4ccccc4[C@@H]32)c1
Agent: C[Si](C)(C)N[Si](C)(C)C
Agent: [Na]
Solvent: C1CCOC1
Product: COc1ccc(-n2nc(C[C@H](C(=O)N3C(=O)O[C@@H]4Cc5ccccc5[C@@H]43)c3cccc(C)c3)cc2-c2ccc(Cl)c(Cl)c2)cc1
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 83.1 %

Procedure:
To a stirred solution of (3aS,8aR)-3-(2-m-tolyl-acetyl)-3,3a,8,8a-tetrahydro-indeno[1,2-d]oxazol-2-one (product of Step F., 12 g, 0.039 mol) in THF (100 mL) was added 1.0 M sodium 1,1,1,3,3,3-hexamethyldisilazane (NaHMDS) (41 mL, 0.041 mol) in THF at −78° C. The mixture was stirred for 45 min at −78° C. then treated with 5-(3,4-dichloro-phenyl)-3-iodomethyl-1-(4-methoxy-phenyl)-1l-H-pyrazole (product of Step E., 18.4 g, 0.0405 mol) in THF (100 mL). The reaction mixture was allowed to warm to rt overnight and then was quenched with H2O (100 mL) and concentrated to half the volume. The aqueous layer was washed with EtOAc (3×75 mL). The extracted organic layer was washed with saturated NaCl, dried over Na2SO4, filtered and concentrated to an oil. The crude oil was purified by flash column chromatography (silica gel, 7:3 hexane/EtOAc) to obtain 20.7 g of the title compound (83%) as white foam. HPLC: Rt=11.38 (Method E). MS (ES+): mass calculated for C36H29Cl2N3O4, 638.55; m/z found 660.3 [M+Na]+. 1H NMR (400 MHz, CDCl3): 7.52 (d, J=7.6 Hz, 1H), 7.11-7.35 (m, 8H), 6.93-6.99 (m, 3H), 6.74-6.82 (m, 3H), 6.20 (s, 1H), 5.89 (d, J=6.8 Hz, 1H), 5.58 (q, J=6.1, 4.5 Hz, 1H), 5.11-5.15 (m, 1H), 3.8 (s, 3H), 3.72 (dd, J=10.6, 4.1 Hz, 1H), 3.33 (br, s, 2H), 3.07 (dd, J=9.8, 4.8 Hz, 1H), 2.37 (s, 3H).
Reaction SMILES: [NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([OH:5])=O.CN1CCOCC1.ClC(OCC)=O.[NH2:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:52])([CH3:51])[CH3:50])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CN(C=O)C>[NH:1]([C:6]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:7])[CH2:2][C:3]([NH:29][C@H:30]([C:38]([NH:40][C@H:41]([C:46]([O:48][C:49]([CH3:51])([CH3:50])[CH3:52])=[O:47])[CH2:42][CH:43]([CH3:45])[CH3:44])=[O:39])[CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5]
Reactant: CC(C)C[C@H](NC(=O)[C@@H](N)Cc1ccccc1)C(=O)OC(C)(C)C
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CCOC(=O)Cl
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](NC(=O)[C@H](Cc1ccccc1)NC(=O)CNC(=O)OCc1ccccc1)C(=O)OC(C)(C)C
Temperature: -10 °C
Reaction time: 0.05 h

Procedure:
Z-Gly-OH (25.2 g., 132 mM) was dissolved in DMF (300 ml.) and the solution was cooled to -10° C. N-methylmorpholine (14.8 ml., 132 mM) was added, followed by ethyl chloroformate (12.1 ml., 126 mM). After 3 minutes at -10° C., a solution of H-Phe-Leu-OBut (40.1 g., 120 mM) in DMF (100 ml.) was added, and the mixture was stirred at 0° C. overnight. The solvent was evaporated and the residue was dissolved in ethyl acetate (600 ml.) and washed successively with water (2×60 ml.), 2 N-aqueous potassium bicarbonate (3×60 ml.), and water (3×60 ml.). The solution was dried (MgSO4) and filtered. The solvent was evaporated to give Z-Gly-Phe-Leu-OBut.
Reaction SMILES: Br.C(O)(=O)C.C(O[C:11]([N:13]([C:15]1[CH:39]=[CH:38][C:18]([C:19]([N:21]2[CH2:26][CH2:25][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:23][CH2:22]2)=[O:20])=[CH:17][CH:16]=1)C)=O)(C)(C)C.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:11][NH:13][C:15]1[CH:16]=[CH:17][C:18]([C:19]([N:21]2[CH2:22][CH2:23][CH:24]([N:27]3[C:37]4[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=4)[CH2:31][CH2:30][C:28]3=[O:29])[CH2:25][CH2:26]2)=[O:20])=[CH:38][CH:39]=1
Reactant: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CNc1ccc(C(=O)N2CCC(N3C(=O)CCc4ccccc43)CC2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 85 %

Procedure:
A mixture (5 ml) of hydrobromic acid and acetic acid (35% solution) is added to 1-{1-[4-(N-t-butoxycarbonyl-N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihyrocarbostyril (1.8 g) and the mixture is stirred at room temperature overnight. The reaction mixture is poured into water and the pH value thereof is adjusted to pH 12-14 by adding potassium carbonate. The mixture is extracted with chloroform, dried with sodium carbonate and then purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=1:1). The resultant is recrystallized from n-hexane/ethanol to give 1-{1-[4-(N-methylamino)benzoyl]-4-piperidinyl}-3,4-dihydrocarbostyril (1.2 g), as white powder, m.p. 184°-186° C.