Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13]Br)[CH:5]=[CH:4][CH:3]=1.[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[K+]>CN(C=O)C>[Cl:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[C:6]([NH:11][C:12](=[O:15])[CH2:13][NH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:5]=[CH:4][CH:3]=1
Reactant: O=C(CBr)Nc1cccc(Cl)c1C(=O)O
Reactant: Nc1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=C(CNc1ccccc1)Nc1cccc(Cl)c1C(=O)O
Temperature: 25 °C
Yield: 82 %

Procedure:
A solution of 6-chloro-2-(bromoacetamido)benzoic acid from Example 42 (7 g, 0.024 mol), aniline (5.6 g, 6 mL, 250 mol %) and DMF (40 mL) was heated at 100° C. for 5 h. The reaction mixture was cooled to rt, poured onto ice and the resulting crystalline product was solubilized by adding 5% KOH (70 mL, pH=9). The resulting milky homogenous solution was extracted with CH2Cl2 (3×100 mL), and the aqueous layer was acidified to pH=3 with 5% HBr and extracted with EtOAc (4×100 mL). Combined EtOAc washings were dried and concentrated. Recrystallization of the resulting solid from EtOAc/Hex, afforded 6 g (82%) of the title compound as white crystals, 176°-178.2° C.; 1H NMR (DMSO-d6) δ 9.93 (s, 1H , COOH), 7.97 (d, 1H, J=8), 7.42 (t, 1H, J=8), 7.30 (d, 1H, J=7.6), 7.12 (t, 2H, J=7.2), 6.65 (t, 3H, J=7.2), 3.82 (s, 2H); 13C NMR (DMSO-d6) 170.19, 166.30, 148.15, 136.56, 131.12, 130.53, 128.98, 125.51, 121.39, 117.23, 112.71, 48.13; MS (EI, m/z) 304 (M+).
Reaction SMILES: [CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40]Cl)(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4].C(SCC(OC)CNS(CCC[I:69])(=O)=O)CCCCCCCCCCCCCCC>>[CH2:1]([O:5][C:6]([NH:8][CH:9]([CH2:33][NH:34][S:35]([CH2:38][CH2:39][CH2:40][I:69])(=[O:37])=[O:36])[CH2:10][O:11][C:12](=[O:32])[NH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH3:31])=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCCCCCCCCCCCCCSCC(CNS(=O)(=O)CCCI)OC
Reactant: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCCl)NC(=O)OCCCC
Product: CCCCCCCCCCCCCCCCCCNC(=O)OCC(CNS(=O)(=O)CCCI)NC(=O)OCCCC

Procedure:
2-Butoxycarbonylamino-3-(3-chloropropylsulfonylamino)-1-octadecylcarbamoyloxypropane III e2 is allowed to react and worked up by the same procedure as described in (5). m.p. 96°-98° C. The summary of the experimental condition and the physical data of the product are listed in Table 8.
Reaction SMILES: Cl.C(N=C=NCCCN(C)C)C.[S:13]1[C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[CH:15]=[C:14]1[C:22]([OH:24])=O.[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH2:41])[CH2:40][CH2:39][CH2:38][CH2:37][CH2:36]2)=[O:34])[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.ON1C2C=CC=CC=2N=N1>C(Cl)Cl>[C:25]1([CH2:31][O:32][C:33]([C:35]2([NH:41][C:22]([C:14]3[S:13][C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH:15]=3)=[O:24])[CH2:36][CH2:37][CH2:38][CH2:39][CH2:40]2)=[O:34])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=C(O)c1cc2ccccc2s1
Reactant: NC1(C(=O)OCc2ccccc2)CCCCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NC1(C(=O)OCc2ccccc2)CCCCC1)c1cc2ccccc2s1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.8 %

Procedure:
Under ice-cooling, 5.9 g (31 mmol) of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride was added to a solution of 5 g (28 mmol) of 2-benzothiophenecarboxylic acid, 6.5 g (28 mmol) of 1-aminocyclohexanecarboxylic acid phenylmethyl ester and 4.5 g (29 mmol) of 1-hydroxybenzotriazole in methylene chloride. After the mixture was stirred at room temperature overnight, the reaction solvent was distilled off under reduced pressure. Water was added to the residue, and the mixture was extracted with ethyl acetate twice. The obtained organic layer was washed with a 10% aqueous potassium hydrogensulfate solution, a saturated aqueous sodium hydrogencarbonate solution and then saturated brine, and it was dried with anhydrous sodium sulfate. The solvent was distilled off under reduced pressure, diethyl ether was added to the obtained residue, and the mixture was stirred overnight. The crystal was collected by filtration and heated/dried under reduced pressure to obtain 10 g (91%) of the title compound.
Reaction SMILES: [OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:16]=[CH:15][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:13][CH:12]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24]([O:26]CC)=[O:25].[OH-].[Na+].C(O)C.Cl>O>[OH:1][C:2]1[N:7]2[N:8]=[CH:9][C:10]([C:11]3[CH:12]=[CH:13][C:14]([S:17][C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:15][CH:16]=3)=[C:6]2[N:5]=[CH:4][C:3]=1[C:24]([OH:26])=[O:25]
Reactant: CCOC(=O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1cnc2c(-c3ccc(Sc4ccccc4)cc3)cnn2c1O
Reaction time: 2 h
Yield: 98.5 %

Procedure:
A mixture of 10.30 g of 7-hydroxy-6-ethoxycarbonyl-3-(4-phenylthiophenyl)pyrazolo[1,5-a]pyrimidine, 6.59 g of sodium hydroxide, 300 ml of ethanol and 300 ml of water was heated and stirred for 2 hours. To the reaction mixture, 400 ml of water was added, and hydrochloric acid was also added while ice-cooling to adjust the pH to 1 to 2, and after stirring for 30 minutes, the precipitate was filtered, washed in water, and dried, thereby obtaining the title compound (9.42 g ).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([Cl:12])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH3:13][N:14](C=O)C>[C-]#N.[Zn+2].[C-]#N.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].[Zn].C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[Cl:12][C:5]1[CH:4]=[CH:3][C:2]([C:13]#[N:14])=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)c1cc(Br)ccc1Cl
Reactant: CN(C)C=O
Agent: [Fe+2]
Agent: [Pd]
Agent: CC(=O)[O-]
Product: COC(=O)c1cc(C#N)ccc1Cl
Temperature: 90 °C
Yield: 98 %

Procedure:
Methyl 5-bromo-2-chlorobenzoate (2 g; 8.02 mmol; 1 eq.), zinc cyanide (564.79 mg; 4.81 mmol; 0.60 eq.), tris(dibenzylideneacetone)dipalladium(0) (58.73 mg; 0.06 mmol; 0.01 eq.), 1,1′-bis(diphenylphosphino)ferrocene (71.11 mg; 0.13 mmol; 0.02 eq.), zinc (20.97 mg; 0.32 mmol; 0.04 eq.) and zinc acetate (58.83 mg; 0.32 mmol; 0.04 eq.) were put in dry DMF (20 mL). The reaction mixture was purged with N2 and then heated to 90° C. for 3 hours. The reaction mixture was cooled to RT, filtered over a pad of celite and washed with EtOAc. The organic phase was washed with water, brine, dried over MgSO4 and concentrated to afford a brown solid purified by flash chromatography eluting with cHex-EtOAc 8:2 affording the title compound as a yellow solid. It was washed with EtOH and dried under vacuum affording the title compound as a yellow solid (1.55 g, 98%). 1H NMR (DMSO-d6, 300 MHz) δ 8.29 (m, 1H), 8.09-8.06 (m, 1H), 7.83-7.81 (m, 1H), 3.89 (s, 3H). LC/MS (Method B): 197.0 (M+H)+. HPLC (Method A) Rt 3.70 min (Purity: 83.7%)
Reaction SMILES: C1(C(N2C3C(=CC(S(N)(=O)=O)=CC=3)CC2)=O)CCCCC1.[NH:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:33])=[O:32])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1.[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[F:45])[C:39](Cl)=[O:40]>>[F:35][C:36]1[CH:37]=[C:38]([CH:42]=[CH:43][C:44]=1[F:45])[C:39]([N:22]1[C:30]2[C:25](=[CH:26][C:27]([S:31]([NH2:34])(=[O:32])=[O:33])=[CH:28][CH:29]=2)[CH2:24][CH2:23]1)=[O:40]
Reactant: NS(=O)(=O)c1ccc2c(c1)CCN2
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Agent: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)C1CCCCC1
Product: NS(=O)(=O)c1ccc2c(c1)CCN2C(=O)c1ccc(F)c(F)c1
Yield: 78.8 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 55, indoline-5-sulfonamide (Intermediate 54A, 90 mg, 0.45 mmol) and 3,4-difluorobenzoyl chloride (69 μL, 0.54 mmol) were converted to the title compound (120 mg, 78%). 1H NMR (DMSO-d6) δ 7.60-7.21 (m, 6H), 7.01 (s, 2H), 3.85 (t, J=8.6 Hz, 2H), 2.92 (t, J=8.6 Hz, 2H); MS(ESI+) m/z 338.9 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[C:8]([O:10][CH:11]3[CH2:14][O:13][CH2:12]3)[N:7]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([NH2:21])[N:16]=3)[C:6]=2[CH:22]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[CH:25]=1>>[NH2:21][C:17]1[N:16]=[C:15]([N:7]2[C:6]3[CH:22]=[C:2]([C:32]#[C:31][C@:29]([C:26]4[CH:25]=[C:24]([CH3:23])[O:28][N:27]=4)([OH:33])[CH3:30])[CH:3]=[CH:4][C:5]=3[N:9]=[C:8]2[O:10][CH:11]2[CH2:14][O:13][CH2:12]2)[CH:20]=[CH:19][N:18]=1
Reactant: Nc1nccc(-n2c(OC3COC3)nc3ccc(Br)cc32)n1
Reactant: C#C[C@@](C)(O)c1cc(C)on1
Product: Cc1cc([C@](C)(O)C#Cc2ccc3nc(OC4COC4)n(-c4ccnc(N)n4)c3c2)no1

Procedure:
The title compound was prepared by the method described in Example 142-b, by reacting 4-[6-bromo-2-(oxetan-3-yloxy)-1H-1,3-benzodiazol-1-yl]pyrimidin-2-amine with (2R)-2-(5-methyl-1,2-oxazol-3-yl)but-3-yn-2-ol: 1H NMR (500 MHz, DMSO) delta 1.81 (3H, s), 2.40 (3H, s), 4.80-4.71 (2H, m), 4.96 (2H, t, J=7.1 Hz), 5.87-5.78 (1H, m), 6.37 (1H, s), 6.46 (1 H, s), 7.22-7.04 (3H, m), 7.28 (1H, dd, J=8.2, 1.5 Hz), 7.45 (1H, d, J=8.2 Hz), 8.18 (1H, s), 8.42 (1 H, d, J=5.5 Hz); LC-MS: m/z=+433.15 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C@H:18]([OH:30])[C@@H:17]2[C@H:15]1[C@H:16]2[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.O1CCCC1.C(=O)(O)[O-].[Na+]>>[C:6]([O:10][C:11]([NH:13][C@@:14]1([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[C@H:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=2)[C@H:18]([O:30][S:2]([CH3:1])(=[O:4])=[O:3])[C@@H:17]2[C@H:15]1[C@H:16]2[C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])=[O:12])([CH3:9])([CH3:7])[CH3:8]
Reactant: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@]1(C(=O)OC(C)(C)C)[C@@H]2[C@@H](C(=O)OC(C)(C)C)[C@@H]2[C@@H](OS(C)(=O)=O)[C@H]1OCc1ccc(Cl)c(Cl)c1
Yield: 61.8 %

Procedure:
Methanesulfonyl chloride (0.841 mL, 1.25 g, 10.87 mmol) is added to di-tert-butyl (1S,2R,3S,4R,5R,6R)-2-[(tert-butoxycarbonyl)amino]-3-[(3,4-dichlorobenzyl)oxy]-4-hydroxybicyclo[3.1.0]hexane-2,6-dicarboxylate (2.00 g, 3.40 mmol), triethylamine (1.66 mL, 1.20 g, 11.89 mmol), and tetrahydrofuran (33.98 mL, 30.11 g, 417.61 mmol) at 0° C. and stirred. Gradually warm the reaction to room temperature and stir overnight. Dilute the reaction with saturated aqueous sodium bicarbonate then extract with ethyl acetate (3×100 mL). The combined organic extracts are washed with brine, dried over magnesium sulfate, filtered, and then concentrated under reduced pressure to yield a residue. The residue is purified by flash chromatography using eluting with 5-60% ethyl acetate in hexanes to give the title compound (1.40 g, 2.10 mmol, 62%).
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]([C:5]1[C:13]2[C:8](=[CH:9][C:10]([O:14][CH3:15])=[CH:11][CH:12]=2)[NH:7][C:6]=1[CH3:16])=[O:4].[CH2:19](I)[CH3:20].[H-].[Na+]>C1COCC1>[CH2:19]([N:7]1[C:8]2[C:13](=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:5]([C:3](=[O:4])[C:2]([F:1])([F:17])[F:18])=[C:6]1[CH3:16])[CH3:20]
Reactant: CCI
Reactant: COc1ccc2c(C(=O)C(F)(F)F)c(C)[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCn1c(C)c(C(=O)C(F)(F)F)c2ccc(OC)cc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 40.3 %

Procedure:
To a solution of 2,2,2-trifluoro-1-(6-methoxy-2-methyl-1H-indol-3-yl)-ethanone 71a (1.3 g, 5.05 mmole) in 20 ml anhydrous THF was added ethyl iodide (2.36 g, 15.15 mmole) and sodium hydride (404 mg, 60% in mineral oil, 10.1 mmole) with ice bath cooling. The mixture was warmed slowly to room temperature and stirred for an additional four hours. The reaction was quenched with water and extracted with EtOAc. The combined organic layer was dried over Na2SO4, filtered and concentrated under rot vap. The residue was purified by column chromatography (eluting with 20-30% EtOAc in hexanes) to give a brown oil (580 mg, 40% yield). 1H NMR (300 MHz, CDCl3) δ7.91 (1H, d, J=8.9 Hz), 6.93 (1H, dd, J=2.3, 8.9 Hz), 6.82 (1H, d, J=2.3 Hz), 4.18 (2H, m), 3.88 (3H, s), 2.76 (3H, s), 1.40 (3H, m).
Reaction SMILES: C([O-])([O-])=O.[Ca+2:5].[OH:6][P:7]([OH:10])([OH:9])=[O:8].[O:11]=[P:12]12[O:23]P3(OP(OP(O3)([O:19]1)=O)(=O)[O:13]2)=O>>[P:7]([O-:10])([O-:9])([O-:8])=[O:6].[Ca+2:5].[P:12]([O-:23])([O-:19])([O-:13])=[O:11].[Ca+2:5].[Ca+2:5]
Reactant: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Reactant: O=P(O)(O)O
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Product: O=P([O-])([O-])[O-]

Procedure:
CaCO3 and H3PO4 were mixed in such amounts that correspond to 47 mol % (26% by weight) of CaO and 53 mol % (74% by weight) of P2O5, respectively. The mixture was treated in the same manner as in Example 1 to obtain calcium phosphate type crystallizable glass. The glass was subjected to crystallizing treatment at 650° C. for 20 hours. The properties of the crystallized glass having an atomic ratio of Ca/P of 0.44 thereby obtained, are shown in Table 1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH:14]1([CH2:17][S:18][C:19]([CH3:23])([CH3:22])[CH:20]=O)[CH2:16][CH2:15]1>>[CH:14]1([CH2:17][S:18][C:19]([CH3:23])([CH3:22])[CH2:20][NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[NH:8][CH2:9][C:10]([SH:13])([CH3:11])[CH3:12])[CH2:16][CH2:15]1
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: CC(C)(C=O)SCC1CC1
Product: CC(C)(S)CNc1ccccc1NCC(C)(C)SCC1CC1
Yield: 85 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.43 g, 2.19×10-3 mol) and 0.82 g (5.19×10-3 mol, 237 M %) 2-cyclopropylmethylthio-2-methylpropanal were reacted by the method of Example 2 to yield 0.63 g (85%) of 1-(2-cyclopropylmethylthio-2-methylpropylamino)-2-(2-mercapto-2-methylpropylamino)benzene as an oily product after purification by filtration through flash silica in a 350 ml sintered glass funnel, eluting with 200 ml portions of 2×100% hexane, 3×90% hexane/ether, 2×80% hexane/ether.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([C:19](=[O:23])[C:20]([NH2:22])=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH:19]([OH:23])[C:20]([NH2:22])=[O:21])=[CH:6][N:7]2[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: COc1cccc2c1c(C(=O)C(N)=O)cn2Cc1ccccc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2c1c(C(O)C(N)=O)cn2Cc1ccccc1
Reaction time: 20 h
Yield: 43 %

Procedure:
A mixture of 1.4 g (4.5 mmol) of 4-methoxy-alpha-oxo-1-(phenylmethyl)-1H-indole-3-acetamide and 213 mg (5.6 mmol) of sodium borohydride and 50 mL of ethanol was stirred for 20 hours, 213 mg (5.6 mmol), of sodium borohydride added and stirred an additional 20 hours and the mixture filtered and evaporated at reduced pressure. The residue was stirred with ethyl acetate and water and the insoluble material was filtered to give 600 mg (43%) of 4-methoxy-alpha-hydroxy-1-(phenylmethyl)-1H-indole-3-acetamide, mp, 179-182° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[C:17]([NH2:18])=[CH:16][C:15]([C:19]#[N:20])=[CH:14][N:13]=2)[CH2:8][CH2:7]1)[CH3:2].[Cl:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][CH:31]=1)[C:26](Cl)=[O:27]>C(#N)C>[CH2:1]([O:3][C:4](=[O:21])[CH2:5][CH:6]1[CH2:7][CH2:8][N:9]([C:12]2[C:17]([NH:18][C:26](=[O:27])[C:25]3[CH:29]=[CH:30][CH:31]=[C:23]([Cl:22])[CH:24]=3)=[CH:16][C:15]([C:19]#[N:20])=[CH:14][N:13]=2)[CH2:10][CH2:11]1)[CH3:2]
Reactant: CCOC(=O)CC1CCN(c2ncc(C#N)cc2N)CC1
Reactant: O=C(Cl)c1cccc(Cl)c1
Solvent: CC#N
Product: CCOC(=O)CC1CCN(c2ncc(C#N)cc2NC(=O)c2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 68.8 %

Procedure:
To a solution of 0.043 g (0.15 mol) of (3′-amino-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl)-acetic acid ethyl ester in acetonitrile (3 mL) is added 0.021 mL (0.16 mmol) of 3-chlorobenzoyl chloride. The mixture is stirred at room temperature for 2 hours then concentrated under reduced pressure. The residue is taken up in a saturated aqueous solution of ammonium chloride and extracted with ethyl acetate. The combined organic phase is dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue is purified by flash silica gel chromatography to give 0.047 g (73%) of [3′-(3-chloro-benzoylamino)-5′-cyano-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-yl]-acetic acid ethyl ester as a light yellow solid.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:8]=[CH:7][C:6]([N:9]=[C:10]=[O:11])=[CH:5][CH:4]=1.[NH2:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1>C1COCC1>[F:1][C:2]([F:12])([F:13])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10](=[O:11])[NH:14][CH:15]2[CH2:16][CH2:17][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:19][CH2:20]2)=[CH:7][CH:8]=1
Reactant: O=C=Nc1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(N)CC1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(NC(=O)Nc2ccc(C(F)(F)F)cc2)CC1
Reaction time: 12 h
Yield: 87.8 %

Procedure:
4-(Trifluoromethyl)phenyl isocyanate (1.068 g, 5.71 mmol) and 4-amino-1-Boc-piperidine (1.0 g, 5 mmol) was dissolved in THF (100 mL) and stirred for 12 h. The reaction was quenched by addition of water. The organic layer was isolated and the aqueous layer was extracted with EtOAc for 4 times. The combined organic layer was concentrated under vacuo and was further purified by flash chromatography (EtOAc:Hex/1:1) yielding final product (1.7 g, 4.39 mmol, 88%). 1H NMR (d6-DMSO, 300 Mhz): ∂ 8.77 (s, 1H), 7.55 (s, 4H), 6.26 (d, J=10 Hz, 1H), 3.80 (d, J=Hz, 2H), 3.64 (m, 1H), 2.88 (br, 2H), 1.78 (d, J=5 Hz, 2H), 1.38 (s, 9H), 1.23 (m, 2H).
Reaction SMILES: [CH3:1][C:2]1([CH3:13])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[CH2:5][CH2:4][CH2:3]1.C([OH:17])(C)C>C(O)(=O)C.O.[O-2].[Cr+6].[O-2].[O-2]>[O:17]=[C:5]1[C:6]2[C:11](=[CH:10][C:9]([CH3:12])=[CH:8][CH:7]=2)[C:2]([CH3:13])([CH3:1])[CH2:3][CH2:4]1
Reactant: Cc1ccc2c(c1)C(C)(C)CCC2
Reactant: CC(C)O
Agent: [Cr+6]
Agent: [O-2]
Solvent: O
Solvent: CC(=O)O
Product: Cc1ccc2c(c1)C(C)(C)CCC2=O
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of chromium(VI)oxide (86 g, 0.861 mol) in acetic acid (400 mL) and water (40 mL) was added dropwise to a stirred solution of 1,1,7-trimethyl-1,2,3,4-tetrahydronaphthalene in acetic acid (70 mL) and the reaction mixture stirred 2.5 hours at room temperature. Isopropanol (5 mL) was added and the whole concentrated in vacuo. The residue was dissolved in hexane and filtered over celite. The organic was washed with water and brine, dried (Mg2SO4), filtered and evaporated to give 40.3 g of 1-oxo-4,4,6-trimethyl-1,2,3,4-tetrahydronaphthalene and used without further purification in the bromination (step e). 1H NMR (300 MHz; CDCl3): 1.36 (s, 6 H), 1.98 (t, J=6.9 Hz, 2 H), 2.38 (s, 3 H), 2.68 (t, J=6.9 Hz, 2 H), 7.01 (dd, J1=0.6 Hz, J2=7.9 Hz, 1 H), 7.19 (d, J=0.6 Hz, 1 H), 7.90 (d, J=8.1 Hz, 1 H).
Reaction SMILES: [N:1]1([C@:4]23[CH2:40][CH2:39][C@@H:38]([C:41]([CH3:43])=[CH2:42])[C@@H:5]2[C@@H:6]2[C@@:19]([CH3:22])([CH2:20][CH2:21]3)[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:25])([CH3:24])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7]2)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.[NH:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1>O1CCOCC1>[CH3:22][C@:19]12[C@@:18]3([CH3:23])[C@@H:9]([C@:10]4([CH3:37])[C@@H:15]([CH2:16][CH2:17]3)[C:14]([CH3:24])([CH3:25])[C:13]([C:26]3[CH2:31][CH2:30][CH:29]([C:32]([O:34][CH2:35][CH3:36])=[O:33])[CH2:28][CH:27]=3)=[CH:12][CH2:11]4)[CH2:8][CH2:7][C@@H:6]1[C@H:5]1[C@H:38]([C:41]([CH3:43])=[CH2:42])[CH2:39][CH2:40][C@:4]1([NH:1][CH2:2][CH2:3][N:53]1[CH2:58][CH2:57][O:56][CH2:55][CH2:54]1)[CH2:21][CH2:20]2
Reactant: C1COCCN1
Reactant: C=C(C)[C@@H]1CC[C@]2(N3CC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: C=C(C)[C@@H]1CC[C@]2(NCCN3CCOCC3)CC[C@]3(C)[C@H](CC[C@@H]4[C@@]5(C)CC=C(C6=CCC(C(=O)OCC)CC6)C(C)(C)[C@@H]5CC[C@]43C)[C@@H]12
Temperature: 100 °C
Yield: 63.7 %

Procedure:
To a flask containing a suspension of ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-3a-(aziridin-1-yl)-5a,5b,8,8,11a-pentamethyl-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.202 g, 0.344 mmol) in 1,4-dioxane (3 mL) was added Hunig's base (0.421 mL, 2.408 mmol) followed by morpholine (0.150 mL, 1.720 mmol). The mixture was heated to 100° C. for 15.5 h then was cooled to rt. The mixture was directly purified by flash chromatography using a 0-40% ethyl acetate in hexanes gradient and a 25 g silica gel column. The fractions containing the expected product were combined and were concentrated under reduced pressure to give ethyl 4-((1R,3aS,5aR,5bR,7aR,11aS,11bR,13aR,13bR)-5a,5b,8,8,11a-pentamethyl-3a-((2-morpholinoethyl)amino)-1-(prop-1-en-2-yl)-2,3,3a,4,5,5a,5b,6,7,7a,8,11,11a,11b,12,13,13a,13b-octadecahydro-1H-cyclopenta[a]chrysen-9-yl)cyclohex-3-enecarboxylate (0.148 g, 0.219 mmol, 63.7% yield) as a white foam. LCMS: m/e 675.8 (M+H)+, 2.06 min (method 1).
Reaction SMILES: [C:1]([NH:4][CH:5]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2].[C:16]([C:18]1[CH:25]=[CH:24][C:21]([CH2:22]Br)=[CH:20][CH:19]=1)#[N:17].CC[O-].[Na+].O>CCO>[C:1]([NH:4][C:5]([CH2:22][C:21]1[CH:24]=[CH:25][C:18]([C:16]#[N:17])=[CH:19][CH:20]=1)([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:6]([O:8][CH2:9][CH3:10])=[O:7])(=[O:3])[CH3:2]
Reactant: CCOC(=O)C(NC(C)=O)C(=O)OCC
Reactant: N#Cc1ccc(CBr)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CCOC(=O)C(Cc1ccc(C#N)cc1)(NC(C)=O)C(=O)OCC

Procedure:
Diethyl 2-acetamidomalonate was treated with 4-cyanobenzyl bromide and NaOEt in EtOH, to give after dilution with H2O, and isolation of the resulting precipitate, diethyl 2-acetamido-2-(4-cyanobenzyl)malonate. This product was heated in HCl, and the mixture evaporated to give 4-carboxy-D,L-phenylalanine hydrochloride [D,L-Phe(4-CO2H)-OH.HCl]. This product was treated with MeOH and HCl gas to give after evaporation, D,L-Phe(4CO2Me)-OMeHCl. This product was treated with N-(toluene-4-sulfonyl)-L-Pro-OH, BOP, and NMM in DMF, to give after aqueous workup and flash chromatography, N-(toluene-4-sulfonyl)-L-Pro-D,L-Phe(4-CO2Me)-OMe. This product was treated with NaOH in dioxane and water, to give after acidification, extraction, drying with MgSO4, filtration and evaporation the title compound as a clear oil.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][C@H:4]([O:7][C:8]2[CH:9]=[C:10]([CH:15]=[C:16]([O:18]CC3C=CC=CC=3)[CH:17]=2)[C:11]([O:13][CH3:14])=[O:12])[C:3]1=[O:26]>[Pd].C1COCC1.CO>[OH:18][C:16]1[CH:15]=[C:10]([CH:9]=[C:8]([O:7][C@H:4]2[CH2:5][CH2:6][N:2]([CH3:1])[C:3]2=[O:26])[CH:17]=1)[C:11]([O:13][CH3:14])=[O:12]
Reactant: COC(=O)c1cc(OCc2ccccc2)cc(O[C@H]2CCN(C)C2=O)c1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1cc(O)cc(O[C@H]2CCN(C)C2=O)c1
Reaction time: 16 h
Yield: 99.9 %

Procedure:
A solution of methyl 3-[(3S)-1-methyl-2-oxo-pyrrolidin-3-yl]oxy-5-phenylmethoxy-benzoate (Intermediate 9) (1.42 g, 4.0 mmol) was added to a suspension of 10% palladium on carbon (140 mg, catalytic) in THF (40 mL) and methanol (40 mL). The mixture was stirred under an atmosphere of hydrogen for 16 hours. The mixture was filtered and the filtrate evaporated under reduced pressure to give the product (1.06 g, 100%). 1H NMR δ (300 MHz, CDCl3) 2.06-2.20 (m, 1H), 2.56-2.68 (m, 1H), 2.97 (s, 3H), 3.37-3.55 (m, 2H), 3.86 (s, 3H), 4.93 (t, 1H), 6.81 (s, 1H), 7.04 (s, 1H), 7.12 (s, 1H), 7.66 (s, 1H); m/z 266 (M+H)+