Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:13]=[C:14]2[C:18](=[CH:19][CH:20]=1)[N:17]([CH3:21])[CH:16]=[CH:15]2.C(N(CC)CC)C>O1CCCC1>[CH3:21][N:17]1[C:18]2[C:14](=[CH:13][C:12]([NH:11][C:2](=[O:3])[O:4][C:5]3[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=3)=[CH:20][CH:19]=2)[CH:15]=[CH:16]1
Reactant: Cn1ccc2cc(N)ccc21
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1ccc2cc(NC(=O)Oc3ccccc3)ccc21
Temperature: -20 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
To a solution of phenyl chloroformate (2.21 ml; 17.4 mM) in dry tetrahydrofuran (30 ml), cooled in a carbon tetrachloride/solid carbon dioxide bath, was added 5-amino-1-methylindole (D3) (2.31 g; 15.8 mM) followed by triethylamine (2.40 ml; 17.4 mM). The mixture was stirred for 45 min at -20° C. (bath temp.), then evaporated and the residue was dissolved in ethyl acetate, washed with brine, dried and evaporated to give the title compound (4.29 g; 100%), m.p. 103°-107° C. (EtOAc/petrol).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1.C(OCC)(=[O:30])C.C(=O)([O-])O.[Na+]>CO.O>[CH3:1][S:2]([C:3]1[C:4](=[O:27])[C:5](=[CH:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([O:25][CH3:26])=[O:24])[CH:6]([CH:8]=[CH:9][CH:10]([OH:16])[CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH:7]=1)=[O:30]
Reactant: CCCCCC(O)C=CC1C=C(SC)C(=O)C1=CCCCCCC(=O)OC
Reactant: CCOC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CCCCCC(O)C=CC1C=C(S(C)=O)C(=O)C1=CCCCCCC(=O)OC
Reaction time: 0.5 h
Yield: 16 %

Procedure:
To a solution of 17.6 mg of 2-methylthio-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone obtained in Example 34 in methanol (0.5 ml) was added a solution of 2KHSO5 ·KHSO4 ·K2SO4 (27.4 mg) in water (0.2 ml) at 0° C., and the mixture was stirred for 30 minutes. To the reaction mixture were added ethyl acetate and saturated aqueous sodium hydrogencarbonate, and the product was extracted into the organic layer. The extract was washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and filtered, followed by concentration. The concentrate was subjected to silica gel chromatography to obtain 3 mg (yield 16%) of 2-methylsulfinyl-5-(6-methoxycarbonylhexylidene)-4-(3-hydroxy-1-octenyl)-2-cyclopentenone.
Reaction SMILES: ClC(Cl)(Cl)CO[C:5]([NH:7][C:8]1[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=[C:10]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:9]=1)=[O:6].[NH2:26][C:27]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([C:37]2[CH:38]=[N:39][C:40]([CH2:43][N:44]3[CH2:49][CH2:48][O:47][CH2:46][CH2:45]3)=[CH:41][CH:42]=2)=[CH:29][CH:28]=1.CS(C)=O>C(OCC)(=O)C>[C:20]([C:10]1[CH:9]=[C:8]([NH:7][C:5]([NH:26][C:27]2[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[C:30]([C:37]3[CH:38]=[N:39][C:40]([CH2:43][N:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[CH:41][CH:42]=3)=[CH:29][CH:28]=2)=[O:6])[N:12]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[N:11]=1)([CH3:22])([CH3:21])[CH3:23]
Reactant: Nc1ccc(-c2ccc(CN3CCOCC3)nc2)c2ccccc12
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)OCC(Cl)(Cl)Cl)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Nc2ccc(-c3ccc(CN4CCOCC4)nc3)c3ccccc23)cc1
Reaction time: 5 h

Procedure:
A solution of 5-(2,2,2-trichloroethoxycarbonyl)amino-3-t-butyl-1-p-tolylpyrazole (26 mmol), 1-amino-4-[6-(morpholin-4-ylmethyl)pyridin-3-yl]naphthalene (26 mmol), duisopropylethylamine (25 mmol) and DMSO (75 mL) is heated to 55-90° C. and held for 2-8 h. To this solution, ethyl acetate (100 mL) is added. The organic layer is washed with brine (4×50 mL), and dried over MgSO4. The solvent is removed under reduced pressure, and residue is crystallized from a suitable solvent such as acetonitrile (50 mL) at 0° C. The product is collected by filtration and recrystallized from a suitable solvent such as isopropanol and dried in vacuum to constant weight.
Reaction SMILES: N[C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.N(OC(C)(C)C)=O.C(Br)(Br)[Br:22]>>[Br:22][C:2]1[CH:3]=[C:4]([CH2:12][OH:13])[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: BrC(Br)Br
Reactant: Nc1cc(CO)cc(C(F)(F)F)c1
Agent: CC(C)(C)ON=O
Product: OCc1cc(Br)cc(C(F)(F)F)c1
Temperature: 80 °C

Procedure:
[3-amino-5-(trifluoromethyl)phenyl]methanol (900 mg, 4.71 mmol) (Step A, Example 24) was suspended in CHBr3 (9 mL), and t-butyl nitrite (600 μL, 5.04 mmol) was added dropwise by syringe. The reaction was heated slowly to 80° C. and was maintained at this temperature for 10 minutes. The reaction was then cooled to room temperature, diluted with hexanes (50 mL), loaded on a silica gel column, and purified with 100% hexanes to 20% EtOAc/hexanes (2 columns) to afford [3-bromo-5-(trifluoromethyl) phenyl]methanol. Rf=0.31 (25% EtOAc/hexanes). 1H NMR (CDCl3, 500 MHz) δ 7.71 (s, 1H), 7.68 (s, 1H), 7.56 (s, 1H), 4.76 (d, J=5.5 Hz, 2H), 1.86 (t, J=5.7 Hz, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[C:11](=[O:20])[C:10]=2[CH:21]=1)(=[O:5])=[O:4].CO.[BH4-].[K+].[OH-].[K+]>O>[CH3:1][N:2]([CH3:22])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[CH:15]=[CH:14][C:13]3[CH:16]=[CH:17][CH:18]=[CH:19][C:12]=3[CH:11]([OH:20])[C:10]=2[CH:21]=1)(=[O:4])=[O:5]
Reactant: CN(C)S(=O)(=O)c1ccc2ccc3ccccc3c(=O)c2c1
Agent: [BH4-]
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc2c(c1)C(O)c1ccccc1C=C2

Procedure:
3-Dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-one (6.9 g., 0.022 mole) and 100 ml. of absolute methanol are stirred and heated to refluxing. A solution of 1.6 g. (0.0296 mole) of potassium borohydride in 12 ml. of water containing 1 pellet of potassium hydroxide is added dropwise at a rate such that reflux is maintained without external heating. After another 11/2 hours at reflux, the solution is evaporated to dryness under reduced pressure. The residual white solid is suspended in water, collected, and crystallized from 95% ethanol. The yield of 3-dimethylsulfamoyl-5H-dibenzo[a,d]cyclohepten-5-ol is 6.05 g. (87%), m.p. 150°-152°C. The melting point is unchanged by further recrystallization.
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][NH:10]2)=[CH:6][CH:5]=1.Br[CH2:14][CH3:15]>CN(C)C=O>[Br:3][C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[CH:9][N:10]2[CH2:14][CH3:15])=[CH:6][CH:5]=1
Reactant: CCBr
Reactant: Brc1ccc2cc[nH]c2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCn1ccc2ccc(Br)cc21
Yield: 101.9 %

Procedure:
Sodium hydride (480 mg of a 60% dispersion in mineral oil) was added to a stirred solution of 6-bromoindole (1.8 g, 9.2 mmol) in dimethylformamide (20 ml) at 0° C. under a nitrogen atmosphere. After 1 hour bromoethane (1.1 ml, 14.7 mmol) was added and the cooling bath removed. After 12 hours the dimethylformamide was removed in vacuo. The residue was purified directly by flash column chromatoraphy (using 95% hexane, 5% ethyl acetate as eluant) to give 2.1 g of the subtitle compound as a yellow oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13]O)[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9].S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[N-:26]=[N+:27]=[N-:28].[Na+]>>[F:1][C:2]1[CH:3]=[C:4]([CH2:11][CH2:12][CH2:13][N:26]=[N+:27]=[N-:28])[CH:5]=[C:6]([F:10])[C:7]=1[O:8][CH3:9]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1c(F)cc(CCCO)cc1F
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [Na+]
Product: COc1c(F)cc(CCCN=[N+]=[N-])cc1F
Yield: 94.1 %

Procedure:
3-(3,5-Difluoro-4-methoxyphenyl)propanol (0.073 mol), tosyl chloride (0.146 mol) and sodium azide (0.146 mol) were reacted substantially as described in Example 7E above to obtain 15.6 g (95%) yellow oil.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([C:6]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=3)=[C:7]([CH:14]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[C:15]([O:17]C)=[O:16])[N:8]([CH3:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.[Br-].[CH2:33]([Zn+])[CH:34]([CH3:36])[CH3:35]>>[CH3:23][C:20]([O:19][CH:14]([C:7]1[N:8]([CH3:13])[C:9](=[O:12])[C:10]2[C:5]([C:6]=1[C:24]1[CH:29]=[CH:28][C:27]([CH3:30])=[C:26]([CH3:31])[CH:25]=1)=[CH:4][CH:3]=[C:2]([CH2:33][CH:34]([CH3:36])[CH3:35])[CH:11]=2)[C:15]([OH:17])=[O:16])([CH3:21])[CH3:22]
Reactant: COC(=O)C(OC(C)(C)C)c1c(-c2ccc(C)c(C)c2)c2ccc(Br)cc2c(=O)n1C
Reactant: CC(C)C[Zn+]
Agent: [Br-]
Product: Cc1ccc(-c2c(C(OC(C)(C)C)C(=O)O)n(C)c(=O)c3cc(CC(C)C)ccc23)cc1C

Procedure:
The title compound was prepared in two steps in a manner similar to that described in Example 171 from methyl 2-(7-bromo-4-(3,4-dimethylphenyl)-2-methyl-1-oxo-1,2-dihydroisoquinolin-3-yl)-2-(tert-butoxy)acetate and isobutylzinc(II) bromide and was isolated as a white solid (11.7 mg, 37%) after reverse phase chromatography: 1H NMR (400 MHz, CHLOROFORM-d) δ=8.27 (s, 1 H), 7.42-7.22 (m, 3 H), 7.16-7.00 (m, 2 H), 5.35 (m, 1 H), 3.70 (s, 3 H), 2.61 (m, 2 H), 2.36 (m, 3 H), 2.32 (m, 3 H), 2.00-1.85 (m, 1 H), 1.07 (m, 9 H), 0.96-0.85 (m, 6 H); LC/MS (m/z) ES+=450 (M+1).
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[CH:4][C:3]=1[C:10]1[CH:25]=[CH:24][C:13]2[C@:14]3([CH3:23])[C@@H:19]([CH2:20][CH2:21][C:12]=2[CH:11]=1)[NH:18][C:17](=[O:22])[CH2:16][CH2:15]3.[C:26](O)(C)(C)C.CC(C)([O-])C.[K+].CI>C(OCC)(=O)C>[CH3:26][N:18]1[C@H:19]2[C@@:14]([CH3:23])([C:13]3[CH:24]=[CH:25][C:10]([C:3]4[CH:4]=[C:5]([F:9])[CH:6]=[C:7]([F:8])[C:2]=4[F:1])=[CH:11][C:12]=3[CH2:21][CH2:20]2)[CH2:15][CH2:16][C:17]1=[O:22]
Reactant: C[C@]12CCC(=O)N[C@@H]1CCc1cc(-c3cc(F)cc(F)c3F)ccc12
Reactant: CC(C)(C)O
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOC(C)=O
Product: CN1C(=O)CC[C@]2(C)c3ccc(-c4cc(F)cc(F)c4F)cc3CC[C@@H]12
Temperature: 25 °C
Reaction time: 4 h
Yield: 83 %

Procedure:
A 15 mL round bottom flask was charged with (+)-(4aR)-(10bR)-8-(2,3,5-trifluorophenyl)-10b-methyl-1,2,3,4,4a,5,6,10b-octahydrobenzo[f]quinolin-3-one (35 mg, 0.10 mmol), 0.3 mL of t-butanol, and potassium t-butoxide (34 mg, 0.30 mmol). Methyl iodide (0.019 mL, 0.30 mmol) was added and the mixture was stirred at room temperature for 4 h. The mixture was diluted with ethyl acetate, and purified by silica gel chromatography (ethyl acetate eluent) to give 30 mg (83%) of the title compound as a foam. FDMS: m/e=359.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11](I)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.CO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([N:8]1[CH2:16][C:15]2([C:17]([O:19][CH3:20])=[O:18])[CH:10]([C:11]([C:32]3[CH:33]=[CH:34][C:29]([Br:28])=[CH:30][CH:31]=3)=[CH:12][CH2:13][CH:14]2[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)C12CN(Cc3ccccc3)CC1C(I)=CCC2c1ccccc1
Reactant: OB(O)c1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: COC(=O)C12CN(Cc3ccccc3)CC1C(c1ccc(Br)cc1)=CCC2c1ccccc1
Yield: 72.5 %

Procedure:
By carrying out the reaction as in Stage C of Example 45, but from 1 g of methyl (3aRS,4SR,7aRS)-2-benzyl-7-iodo-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate in 20 cm3 of toluene, from 120 mg of tetrakis(triphenylphosphine)palladium, from 0.46 g of 4-bromophenylboronic acid in 10 cm3 of methanol and from 15 cm3 of a 2N aqueous sodium carbonate solution at reflux for eighteen hours, 0.77 g (73%) of methyl (3aRS,4SR,7aRS)-2-benzyl-7-(4-bromophenyl)-4-phenyl-2,3,3a,4,5,7a-hexahydro-1H-isoindole-3a-carboxylate was obtained, after purification by flash chromatography on silica gel (230-400 mesh), elution was carried out with a mixture of cyclohexane and of ethyl acetate (90/10 by volume), in the form of a white foam, the characteristic of which was as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.Br[C:9]1[CH:10]=[CH:11][C:12]([O:29][CH2:30][CH3:31])=[C:13]([C:15]2[NH:16][C:17](=[O:28])[C:18]3[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=3[N:20]=2)[CH:14]=1>>[CH2:30]([O:29][C:12]1[CH:11]=[CH:10][C:9]([N:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH2:2]2)=[CH:14][C:13]=1[C:15]1[NH:16][C:17](=[O:28])[C:18]2[N:23]([CH3:24])[N:22]=[C:21]([CH2:25][CH2:26][CH3:27])[C:19]=2[N:20]=1)[CH3:31]
Reactant: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(Br)ccc3OCC)nc12
Reactant: Brc1ccccn1
Product: CCCc1nn(C)c2c(=O)[nH]c(-c3cc(N4C=CC=CC4)ccc3OCC)nc12

Procedure:
The title compound was prepared from 2-bromopyridine and 5-(5-bromo-2-ethoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one, following the procedure described in Example 82, and was obtained as an off-white solid (33%), m.p. 216-218° C. Found: C,67.61; H,5.81; N,17.63. C22H23N5O2 requires C,67.85; H,5.95; N,17.98%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH2:23][OH:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].C1C=C[NH+]=CC=1.[O-][Cr](Cl)(=O)=O.CCOCC>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][CH:23]=[O:24])=[CH:17][CH:16]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCOc1ccc(-c2ccc(CCCO)cc2)cc1
Agent: O=[Cr](=O)([O-])Cl
Agent: c1cc[nH+]cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCCCCOc1ccc(-c2ccc(CCC=O)cc2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 109.1 %

Procedure:
To a cold (0° C.) stirred solution of 3-(4′-heptyloxybiphenyl-4-yl)propan-1-ol (2.26 g, 6.92 mmol) in CH2Cl2 (60 ml) were added molecular sieves 4A powder (5.17 g) and PCC (5.25 g, 24.4 mmol). After being stirred for 2 h at room temperature, Et2O (20 ml) was added to the mixture. The reaction mixture was transferred to a short silica gel column and eluted with CH2Cl2. The eluate was concentrated in vacuo to give 3-(4′-heptyloxybiphenyl-4-yl)propionaldehyde (crude, 2.45 g) which was used for the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:27][C:28](OC)=[O:29])[C:10]3[C:15]([C:16]=2[CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)=[CH:14][CH:13]=[C:12]([C:23]([O:25][CH3:26])=[O:24])[CH:11]=3)=[C:4]([CH2:32][NH:33][CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH:3]=1.CO[Na]>CO.CCOC(C)=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:8]3=[C:16]([CH:17]4[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]4)[C:15]4[CH:14]=[CH:13][C:12]([C:23]([O:25][CH3:26])=[O:24])=[CH:11][C:10]=4[N:9]3[CH2:27][C:28](=[O:29])[N:33]([CH2:34][CH2:35][N:36]([CH3:38])[CH3:37])[CH2:32][C:4]=2[CH:3]=1
Reactant: COC(=O)Cn1c(-c2ccc(Cl)cc2CNCCN(C)C)c(C2CCCCC2)c2ccc(C(=O)OC)cc21
Agent: CO[Na]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(=O)N(CCN(C)C)Cc1cc(Cl)ccc1-3
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of methyl 2-[4-chloro-2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl-3-cyclohexyl-1-(2-methoxy-2-oxoethyl)-1H-indole-6-carboxylate (from Step 5) in dry MeOH (0.05 M), 10% in weight of MeONa was added and the mixture stirred at RT overnight. The volume of the solution was reduced in vacuo before being diluted with EtOAc. The organic phase was washed with HCl 1 N, brine. The organic phase was dried over Na2SO4, filtered and the solvent evaporated in vacuo to afford the title compound. The crude was then used in the next step without any further purification (quant); MS (ES+) m/z 508 (M+H)+.
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][C:5]#[CH:6].N1C=CN=C1.[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].O>CN(C)C=O>[Si:13]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][C:5]#[CH:6])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: C#CCCCCO
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: C#CCCCCO[Si](C)(C)C(C)(C)C
Reaction time: 3 h
Yield: 96.1 %

Procedure:
To a solution of 5-hexyne-1-ol (4.81 g, 49.0 mmol) in N,N-dimethylformamide (100 ml) were added imidazole (4.0 g, 59.0 mmol) and t-butyldimethylsilylchloride (8.12 g, 54.0 mmol) at 0° C., which was then stirred at the same temperature for 3 hour After the reaction was completed, water was added to the reaction solution, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residue was subjected to column chromatography (n-hexane:ethyl acetate=10:1) to give the title compound (10.0 g, yield: 99%) as a colorless oil.
Reaction SMILES: COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:10])=CC=1.[Cl:23][C:24]1[C:25]([C:32]([NH:34][NH:35][C:36](=O)[CH2:37][C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=O)=[N:26][C:27]([S:30][CH3:31])=[N:28][CH:29]=1>N1C=CC=CC=1.O>[CH2:37]([C:36]1[S:10][C:32]([C:25]2[C:24]([Cl:23])=[CH:29][N:28]=[C:27]([S:30][CH3:31])[N:26]=2)=[N:34][N:35]=1)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: CSc1ncc(Cl)c(C(=O)NNC(=O)Cc2ccccc2)n1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Solvent: O
Solvent: c1ccncc1
Product: CSc1ncc(Cl)c(-c2nnc(Cc3ccccc3)s2)n1
Temperature: 100 °C
Yield: 47 %

Procedure:
Lawesson's Reagent (0.487 g (1.2 mmol) and 5-chloro-2-(methylthio)-N′-(2-phenyl-acetyl)pyrimidine-4-carbohydrazide (0.442 g, 1.2 mmol) were dissolved in 8 mL pyridine. This solution was heated to 100° C. for 30 h, giving ˜50% conversion. Upon cooling, the reaction mixture was diluted with excess H2O. The aqueous layer was extracted with EtOAc. The combined organic layers were dried with magnesium sulfate and concentrated under vacuum. Flash chromatography was used to obtain 0.190 g (47% yield) product as a brown solid. MS (M+H)+ 335.
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][OH:4].[H-].[Na+].[Si:9]([O:16][C@@H:17]1[C:25]2[C:20](=[C:21]([C:27]3[C:28](F)=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:22]=[CH:23][C:24]=2[F:26])[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]>CN1CCCC1=O>[Si:9]([O:16][C@@H:17]1[C:25]2[C:20](=[C:21]([C:27]3[C:28]([O:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[N:29][CH:30]=[CH:31][CH:32]=3)[CH:22]=[CH:23][C:24]=2[F:26])[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: CC(C)(C)[Si](C)(C)O[C@H]1CCc2c(-c3cccnc3F)ccc(F)c21
Reactant: CC(C)(C)CO
Agent: [H-]
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CC(C)(C)COc1ncccc1-c1ccc(F)c2c1CC[C@@H]2O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
2,2-Dimethylpropan-1-ol (59 mg) is dissolved at 0° C. in N-methylpyrrolidone (NMP, 2 mL), treated with NaH (27 mg, 55% dispersion in mineral oil) and stirred for 15 minutes. The mixture is warmed to room temperature, treated with a solution of 3-((1S)-1-(tert-butyldimethylsilyloxy)-7-fluoro-2,3-dihydro-1H-inden-4-yl)-2-fluoropyridine (200 mg) in N-methylpyrrolidone (NMP, 1 mL) and stirred for 12 hours at 75° C. 2,2-Dimethylpropan-1-ol (59 mg) and NaH (27 mg, 55% dispersion in mineral oil) are added and the mixture is stirred for 4 hours at 80° C. The mixture thus obtained is directly used in the next step.
Reaction SMILES: [CH:1]1([N:7]=[C:8]=[N:9][CH:10]2[CH2:15][CH2:14][CH2:13]CC2)CCCCC1.[CH3:16]N(C)C=O>C(N(CC)CC)C.N1C=CC=CC=1>[CH3:16][N:7]([C:8]1[CH:13]=[CH:14][CH:15]=[CH:10][N:9]=1)[CH3:1]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: CN(C)C=O
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Product: CN(C)c1ccccn1

Procedure:
This condensation is carried out in solution either in dimethylformamide using triethylamine as catalyst for 20 to 24 hours, or in pyridine in the presence of dicyclohexylcarbodiimide for one night to three days or in the presence of dimethylaminopyridine to obtain ##STR28##
Reaction SMILES: [CH3:1][O:2][C:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=[C:5](OS(C(F)(F)F)(=O)=O)[CH:4]=1.[CH3:21][O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH2:26]>C(#N)C>[CH3:21][O:22][C:23](=[O:28])[CH:24]([CH3:27])[CH2:25][NH:26][C:5]1[CH:4]=[C:3]([O:2][CH3:1])[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]=1
Reactant: COC(=O)C(C)CN
Reactant: COc1cc(OS(=O)(=O)C(F)(F)F)nc2ccccc12
Solvent: CC#N
Product: COC(=O)C(C)CNc1cc(OC)c2ccccc2n1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
A solution of 1,1,1-trifluoromethanesulfonic acid 4-methoxyquinolin-2-yl ester [from Example 1b] (2.03 g, 6.61 mmol) and 3-amino-2-methyl-propionic acid methyl ester (1.5 eq, 1.52 g, 9.91 mmol) in acetonitrile (25 mL) was heated at reflux for five days. It was cooled to room temperature and evaporated to an oil. The crude product was purified via column chromatography on silica (1:1 ethyl acetate/hexane) to give the product (0.75 g, 42%) as an orange oil. [M+H]+ 275.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([OH:14])=O)=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH2:26])=[CH:16]1.ON1C2C=CC=CC=2N=N1.Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C>CN(C=O)C>[NH:15]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17]([CH2:24][CH2:25][NH:26][C:12]([C:3]2[C:2]([OH:1])=[C:11]3[C:6]([CH:7]=[CH:8][CH:9]=[N:10]3)=[CH:5][CH:4]=2)=[O:14])=[CH:16]1
Reactant: NCCc1c[nH]c2ccccc12
Reactant: O=C(O)c1ccc2cccnc2c1O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(NCCc1c[nH]c2ccccc12)c1ccc2cccnc2c1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 8-hydroxyquinoline-7-carboxylic acid (0.23 g, 1.25 mmol), 2-(1H-Indol-3-yl)ethylamine (0.20 g, 1.25 mmol), 1-hydroxybenzotriazole (0.18 g, 1.37 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.26 g, 1.37 mmol), and triethylamine (0.7 mL, 4.99 mmol) in DMF (12 mL) was stirred at room temp overnight. The reaction mixture was concentrated under vacuum. The residue was dissolved in DMSO and subjected to HPLC purification on C-18 stationary phase eluted with water/acetonitrile/TFA mobile phase. Collection and lyophilization of appropriate fractions provide the title compound as yellow solid.