Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])[N:9]=[CH:8][NH:7][C:6]2=O.CN(C=O)C.C1(C)C=CC=CC=1.C(=O)([O-])O.[Na+].S(Cl)([Cl:41])=O>>[Cl:41][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][S:17]([CH3:20])(=[O:19])=[O:18])=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][N:7]=1
Reactant: COc1cc2c(=O)[nH]cnc2cc1OCCCS(C)(=O)=O
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: COc1cc2c(Cl)ncnc2cc1OCCCS(C)(=O)=O
Temperature: 0 °C
Yield: 88 %

Procedure:
6-Methoxy-7-(3-methylsulphonylpropoxy)-3,4-dihydroquinazolin-4-one (3.6 g, 11.5 mmol) was suspended in thionyl chloride (40 ml). DMF (1.8 ml) was added under argon and the mixture was heated at reflux for 1.5 hours. The thionyl chloride was eliminated by several azeotropic distillations using toluene. The solid residue was suspended in ice/water and a saturated solution of sodium hydrogen carbonate was added to adjust the mixture to pH7. The solid was collected by filtration, washed with water and dried in a vacuum dessicator over phosphorus pentoxide to give 4-chloro-6-methoxy-7-(3-methylsulphonylpropoxy)quinazoline (3.35 g, 88%).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.S(=O)(=O)(O)O>CO.[Pd]>[NH:1]1[C:9]2[C:4](=[CH:5][C:6]([C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: COC(=O)c1ccc2[nH]ccc2c1
Agent: [Pd]
Agent: O=S(=O)(O)O
Solvent: CO
Product: COC(=O)c1ccc2c(c1)CCN2
Reaction time: 48 h

Procedure:
Methyl indole-5-carboxylate (5 g) was dissolved in methanol (300 ml) containing concentrated sulphuric acid (12 ml) and 10% palladium on charcoal (1.0 g) added. The reaction mixture was hydrogenated in a Parr bottle at 65 p.s.i. with shaking for 48 hours. The catalyst was filtered off through Celite. The solution was made basic by addition of ammonia solution (0.880) and evaporated in vacuo. The product was extracted from water into ethyl acetate, the organic extracts dried over anhydrous magnesium sulphate, filtered and evaporated in vacuo to give methyl indoline-5-carboxylate, m.p. 70°-72° C.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[CH3:9])[NH2:5].[N+:10]([C:13]1[CH:18]=[C:17]([N+:19]([O-:21])=[O:20])[C:16]([OH:22])=[CH:15][C:14]=1F)([O-:12])=[O:11]>C(O)C>[CH3:1][C:2]1[CH:3]=[C:4]([NH:5][C:14]2[CH:15]=[C:16]([OH:22])[C:17]([N+:19]([O-:21])=[O:20])=[CH:18][C:13]=2[N+:10]([O-:12])=[O:11])[CH:6]=[CH:7][C:8]=1[CH3:9]
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(F)cc1O
Reactant: Cc1ccc(N)cc1C
Solvent: CCO
Product: Cc1ccc(Nc2cc(O)c([N+](=O)[O-])cc2[N+](=O)[O-])cc1C
Temperature: 40 °C
Reaction time: 168 h

Procedure:
6.6 g of 3,4-dimethylaniline was added to a suspension that consists of 4 g of 4,6-dinitro-3-fluorophenol (J. Org. Chem. 1991, 5958) in 100 ml of ethanol, and it was stirred for 7 days at 40° C. After cooling, it was suctioned off, and the residue was recrystallized from ethanol.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[NH:20]1[CH2:24][CH2:23][C@@H:22]([CH2:25][OH:26])[CH2:21]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][C@@H:22]([CH2:25][OH:26])[CH2:21]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: OC[C@@H]1CCNC1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: OC[C@@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 135 mg (1.34 mmol) (3R)-pyrrolidin-3-ylmethanol and 112.1 mg (1.34 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 92 mg (48%).
Reaction SMILES: [CH:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][C:9]2[C:21]([CH3:22])=[CH:20][C:19]([CH3:23])=[CH:18][C:10]=2[O:11][C:12]([CH3:17])([CH3:16])[C:13](O)=[O:14])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].C(Cl)(=O)C(Cl)=O.[Cl-].[Al+3].[Cl-].[Cl-]>C1COCC1.CN(C=O)C.ClCCl>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH2:8][C:9]2[C:10]3[O:11][C:12]([CH3:17])([CH3:16])[C:13](=[O:14])[C:18]=3[C:19]([CH3:23])=[CH:20][C:21]=2[CH3:22])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: Cc1cc(C)c(Cc2ccc(C(C)C)cc2)c(OC(C)(C)C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(C)c2c(c1Cc1ccc(C(C)C)cc1)OC(C)(C)C2=O
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 64 %

Procedure:
To a solution of 2-(2-(4-isopropylbenzyl)-3,5-dimethylphenoxy)-2-methylpropanoic acid obtained in Reference Example 156 (5.55 g, 16.3 mmol) in THF (50 mL) was added dropwise oxalyl chloride (2.13 mL, 24.5 mmol) with ice-cooling. The mixture was stirred for 20 minutes, and DMF (3 drops) was added thereto, and the mixture was stirred with ice-cooling for 30 minutes, and then, was warmed to room temperature. The solvent was removed by concentration under reduced pressure, and to a solution of the residue in dichloromethane (50 mL) was added aluminum chloride (3.26 g, 24.5 mmol) at −78° C., and the mixture was slowly warmed to room temperature. Ice was added to the reaction solution to separate the organic layer, and the aqueous layer was extracted with ethyl acetate. The combined organic layer was washed with a saturated sodium hydrogen carbonate solution, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:4) to obtain 3.35 g (yield 64%) of 7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)-one as crude product. To a solution of this compound (3.35 g, 10.4 mmol) in acetonitrile (40 mL) was added N-bromosuccinimide (1.85 g, 10.4 mmol) with ice-cooling, and the mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature, to which water was added, which was extracted with ethyl acetate. The combined organic layer was washed with a saturated brine, dried over anhydrous sodium sulfate, filtered, and then concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=1:19) to obtain 2.76 g (yield 66%) of 5-bromo-7-(4-isopropylbenzyl)-2,2,4,6-tetramethyl-1-benzofuran-3 (2H)-one as crude product.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([O:21]C(C)(C)C)=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]>C(O)(C(F)(F)F)=O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[C:4]([OH:26])=[C:5]([C:15]([NH:17][CH2:18][C:19]([OH:21])=[O:20])=[O:16])[C:6](=[O:14])[C:7]2([CH3:13])[CH3:12]
Reactant: CC(C)(C)OC(=O)CNC(=O)C1=C(O)c2c(F)cccc2C(C)(C)C1=O
Solvent: O=C(O)C(F)(F)F
Product: CC1(C)C(=O)C(C(=O)NCC(=O)O)=C(O)c2c(F)cccc21

Procedure:
1,1-Dimethylethyl N-((5-fluoro-4-hydroxy-1,1-dimethyl-2-oxo-naphthalen-3-yl)carbonyl)glycinate (116 mg, 319 μmol) was stirred in TFA (5 mL) for 15 minutes. The solvent was then removed in vacuo, and the residue was partitioned between DCM and water. The DCM layer was removed, and the solvent was removed in vacuo to give the product as a light yellow solid. MS m/e=308 (M+H)+. Calculated for C15H14FNO5 307.09.
Reaction SMILES: [O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:10][C:9]([C:11]2[CH:12]=[C:13]([CH:25]=[C:26]([O:28][C@@H:29]([CH3:33])[CH2:30][O:31]C)[CH:27]=2)[O:14][C:15]2[CH:16]=[CH:17][C:18]([S:21]([CH3:24])(=[O:23])=[O:22])=[N:19][CH:20]=2)=[CH:8][CH:7]=1.B(Br)(Br)Br.[Cl-].[NH4+]>C(Cl)Cl>[O:1]1[CH2:5][CH2:4][N:3]=[C:2]1[C:6]1[NH:10][C:9]([C:11]2[CH:27]=[C:26]([CH:25]=[C:13]([O:14][C:15]3[CH:20]=[N:19][C:18]([S:21]([CH3:24])(=[O:22])=[O:23])=[CH:17][CH:16]=3)[CH:12]=2)[O:28][C@@H:29]([CH3:33])[CH2:30][OH:31])=[CH:8][CH:7]=1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NCCO3)[nH]2)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 75.8 %

Procedure:
5-{3-[5-(4,5-Dihydro-1,3-oxazol-2-yl)-1H-pyrrol-2-yl]-5-[(1S)-2-methoxy-1-methylethoxy]phenoxy}-2-(methylsulfonyl)pyridine (230 mg, 0.49 mmol) synthesized in Example (78l) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 0.75 mL, 0.75 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 1.5 hours under nitrogen atmosphere. To this reaction solution, a saturated aqueous ammonium chloride solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=2%-4%) to afford the desired compound (170 mg, yield 76%) as a white solid.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[OH:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]1[C:27]2[C:22](=[CH:23][C:24]([O:28][CH3:29])=[CH:25][CH:26]=2)[S:21][CH2:20][C:19]1([C:31]1[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][CH:32]=1)[CH3:30].C(N(CC)CC)C>ClCCl.O>[CH3:29][O:28][C:24]1[CH:23]=[C:22]2[C:27]([CH:18]([CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH:12]=[O:11])[C:19]([C:31]3[CH:32]=[CH:33][C:34]([O:37][CH3:38])=[CH:35][CH:36]=3)([CH3:30])[CH2:20][S:21]2)=[CH:26][CH:25]=1
Reactant: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCCO)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C2(C)CSc3cc(OC)ccc3C2CCCCCC=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 94 %

Procedure:
To a solution of oxalyl chloride (238 mg, 1.88 mmol) in dichloromethane (5 ml) was added dimethylsulfoxide (316 mg, 3.75 mmol) in dichloromethane (1 ml) at −70° C., which was then stirred at the same temperature for 10 minutes. Next, to the solution was added 4-(6-hydroxyhexyl)-7-methoxy-3-(4-methoxyphenyl)-3-methylthiochroman (500 mg, 1.25 mmol) in dichloromethane (5 ml) at −70° C., which was then stirred at the same temperature for 30 minutes. Then, to the reaction mixture was added triethylamine (1.0 ml, 7.5 mmol) at the same temperature and stirred for 30 minutes and warmed to room temperature. After the reaction was completed, water was added to the reaction mixture, and the resulting mixture was extracted with ethyl acetate. The extract was dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was used to next step without purification (470 mg, yield: 94%).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:7]([NH:9][C:10]2[O:11][C:12]([C:15]3[O:16][CH:17]=[CH:18][CH:19]=3)=[N:13][N:14]=2)=[O:8])[S:5][CH:6]=1.[C:20]1([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:25]=[CH:24][C:23](B(O)O)=[CH:22][CH:21]=1>>[C:20]1([C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:25]=[CH:24][C:23]([C:2]2[CH:3]=[C:4]([C:7]([NH:9][C:10]3[O:11][C:12]([C:15]4[O:16][CH:17]=[CH:18][CH:19]=4)=[N:13][N:14]=3)=[O:8])[S:5][CH:6]=2)=[CH:22][CH:21]=1
Reactant: O=C(Nc1nnc(-c2ccco2)o1)c1cc(Br)cs1
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Product: O=C(Nc1nnc(-c2ccco2)o1)c1cc(-c2ccc(-c3ccccc3)cc2)cs1

Procedure:
The title compound was synthesized in accordance with the synthesis method of compound Ia-50, using 4-bromo-N-[5-(2-furyl)-1,3,4-oxadiazol-2-yl]-2-thiophenecarboxamide prepared in Reference Example 12 instead of compound Ia-50 and using commercially available 4-biphenylboronic acid instead of 1-methyl-5-indoleboronic acid pinacol ester.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][CH:4]=1.Br[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=1[CH3:23].C([O-])([O-])=O.[Cs+].[Cs+].O>O1CCOCC1.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>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[CH3:23])=[CH:5][CH:4]=1
Reactant: COc1ccc(B(O)O)cc1
Reactant: COC(=O)c1ccc(Br)c(C)c1
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: [Cs+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)c(C)c1
Temperature: 100 °C
Reaction time: 8 h

Procedure:
Into a 10000-mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen was placed a solution of (4-methoxyphenyl)boronic acid (350 g, 2.30 mol, 1.00 equiv) in 1,4-dioxane (3500 mL), methyl 4-bromo-3-methylbenzoate (527 g, 2.30 mol, 1.00 equiv), Pd(PPh3)4 (79.8 g, 69.06 mmol, 0.03 equiv), Cs2CO3 (1501 g, 4.60 mol, 2.00 equiv), water (850 mL). The resulting solution was stirred overnight at 100° C. in an oil bath. The reaction was then cooled and quenched by the addition of 3000 mL of water. The resulting solution was extracted with 2×2000 mL of ethyl acetate. The organic layers were combined, washed with 1×2000 mL of brine, dried and concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:50-1:20). This resulted in 471.6 g (crude) of methyl 4-(4-methoxyphenyl)-3-methylbenzoate as a red solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:27][CH2:28][CH3:29])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:26])[C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][NH:18][CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)=[CH:13][CH:12]=1)[CH2:2][CH3:3].[CH3:30][N:31]1[CH:35]=[CH:34][N:33]=[C:32]1[CH:36]=O.C([BH3-])#N.[Na+].C(O)(=O)C>CO>[CH2:27]([N:4]([CH2:1][CH2:2][CH3:3])[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([CH3:26])[C:10](=[O:25])[C:11]1[CH:16]=[CH:15][C:14]([CH2:17][N:18]([CH2:19][C:20]2[NH:21][CH:22]=[CH:23][N:24]=2)[CH2:36][C:32]2[N:31]([CH3:30])[CH:35]=[CH:34][N:33]=2)=[CH:13][CH:12]=1)[CH2:28][CH3:29]
Reactant: Cn1ccnc1C=O
Reactant: CCCN(CCC)CCCCN(C)C(=O)c1ccc(CNCc2ncc[nH]2)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: CCCN(CCC)CCCCN(C)C(=O)c1ccc(CN(Cc2ncc[nH]2)Cc2nccn2C)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
The compound (266.9 mg) obtained in Example 111-1 was dissolved in anhydrous methanol (11 ml) and then added with 1-methyl-2-imidazole carboxaldehyde (110.1 mg) and sodium cyanoborohydride (84.2 mg). Then, the solution was adjusted to pH 5 with acetic acid, followed by stirring at room temperature for 3 days. After the reaction, the solvent was distilled off. The residue was added with a 1 mol/l sodium hydroxide aqueous solution (1.0 ml) and extracted with chloroform. The extract was dried with magnesium sulfate. The solvent was distilled off. Then, the residue was purified through silica gel column chromatography (chloroform/methanol) and treated with hydrochloric acid, thereby obtaining hydrochloride (234.9 mg) of the subject compound as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:7]2[NH:23][C:10]3=[CH:11][C:12]4[C:13]([CH3:22])([CH3:21])[C:14](=[O:20])[N:15]([CH2:18][CH3:19])[C:16]=4[CH:17]=[C:9]3[N:8]=2)=[N:4][NH:5][CH:6]=1.[F:24][C:25]1[CH:26]=[C:27]([CH:31]=[C:32]([F:34])[CH:33]=1)[C:28](Cl)=[O:29]>>[CH2:18]([N:15]1[C:16]2[CH:17]=[C:9]3[N:8]=[C:7]([C:3]4[C:2]([NH:1][C:28](=[O:29])[C:27]5[CH:26]=[C:25]([F:24])[CH:33]=[C:32]([F:34])[CH:31]=5)=[CH:6][NH:5][N:4]=4)[NH:23][C:10]3=[CH:11][C:12]=2[C:13]([CH3:22])([CH3:21])[C:14]1=[O:20])[CH3:19]
Reactant: O=C(Cl)c1cc(F)cc(F)c1
Reactant: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4N)nc3cc21
Product: CCN1C(=O)C(C)(C)c2cc3[nH]c(-c4n[nH]cc4NC(=O)c4cc(F)cc(F)c4)nc3cc21

Procedure:
N-[3-(5-Ethyl-7,7-dimethyl-6-oxo-1,5,6,7-tetrahydro-imidazo[4,5-f]indol-2-yl)-1H-pyrazol-4-yl]-3,5-difluoro-benzamide was prepared using 2-(4-amino-1H-pyrazol-3-yl)-5-ethyl-7,7-dimethyl-5,7-dihydro-1H-imidazo[4,5-f]indol-6-one (250 mg, 0.81 mmol) and 3,5-difluorobenzoyl chloride (111 ml, 0.89 mmol). The title compound was obtained as brown powder (112 mg, 31%).
Reaction SMILES: C[O:2][C:3](=[O:34])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH2:10][C:11]([NH:14][CH2:15][C@H:16]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=2)([CH3:13])[CH3:12])[CH:5]=1.[OH-].[Na+].O>O1CCOCC1>[Si:27]([O:26][C@H:16]([C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([CH2:24][OH:25])[CH:18]=1)[CH2:15][NH:14][C:11]([CH3:13])([CH3:12])[CH2:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:34])=[O:2])([C:30]([CH3:31])([CH3:32])[CH3:33])([CH3:29])[CH3:28]
Reactant: COC(=O)c1cccc(CC(C)(C)NC[C@H](O[Si](C)(C)C(C)(C)C)c2ccc(O)c(CO)c2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(Cc1cccc(C(=O)O)c1)NC[C@H](O[Si](C)(C)C(C)(C)C)c1ccc(O)c(CO)c1
Yield: 87.7 %

Procedure:
3-{2-[(2R)-2-(tert-butyldimethylsilanyloxy)-2-(4-hydroxy-3-hydroxymethyl-phenyl)ethylamino]-2-methylpropyl}benzoic acid methyl ester (Preparation 36) (1.50 g, 3.08 mmol), aqueous sodium hydroxide solution (5M, 3.07 ml, 15.0 mmol), water (2 ml) and dioxane (20 ml) were stirred at room temperature for 18 hours. The solvent was removed in vacuo and the residue dissolved in water (30 ml) and acidified with aqueous hydrochloric acid (1N, 15.38 ml). The resulting white precipitate was filtered off and dried in vacuo for 72 hours to furnish the title compound as a white solid (1.28 g). 1H NMR (400 MHz, CD3OD) δ=7.88 (1H, d), 7.81 (1H, bs), 7.38-7.28 (3H, m), 7.10 (1H, dd), 6.77 (1H, d), 4.92 (1H, m, partially under solvent peak), 4.61 (2H, dd), 3.23-3.12 (2H, m), 2.95 (2H, dd), 1.08 (6H, s), 0.81 (9H, s), −0.04 (3H, s), −0.15 (3H, s). LRMS (electrospray) m/z 474 [M+H]+
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27](O)=[O:28])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[C:53]([NH2:57])([CH3:56])([CH3:55])[CH3:54]>ClCCl>[C:1]([O:5][C:6]([N:8]1[CH:12]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[CH:11]([CH2:20][CH:21]2[CH:26]([C:27](=[O:28])[NH:57][C:53]([CH3:56])([CH3:55])[CH3:54])[CH2:25][CH:24]=[CH:23][CH2:22]2)[O:10][C:9]1([CH3:31])[CH3:30])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1C(Cc2ccccc2)C(CC2CC=CCC2C(=O)O)OC1(C)C
Reactant: CC(C)(C)N
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: CC(C)(C)NC(=O)C1CC=CCC1CC1OC(C)(C)N(C(=O)OC(C)(C)C)C1Cc1ccccc1
Temperature: 25 °C
Yield: 9512.6 %

Procedure:
An ice-cooled, stirred solution of 4-benzyl-5-(6-carboxy-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (3.0 g) in dichloromethane (70 ml) was treated with 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloide (1.61 g), 1-hydroxybenzotriazole and tert-butylamine (1.12 g). The reaction mixture was allowed to stir and warm to ambient temperature during 16 hours. The reaction mixture was then washed sequentially with 2M aqueous hydrochloric acid, 10% aqueous sodium bicarbonate solution, water and saturated aqueous sodium chloride solution, dried (anhydrous magnesium sulfate) and evaporated to give 4-benzyl-5-(6-tert-butylcarbamoyl-cyclohex-3-enylmethyl)-2,2-dimethyl-oxazolidine-3-carboxylic acid tert-butyl ester (322 g, 95%)
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][CH:3]([CH3:5])[CH3:4].[Na+].[CH2:9]([C@H:11]1[CH2:16][C@H:15]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH3:14])[C@H:12]1[O:30][C:31](=[O:34])[CH2:32]Br)[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)[CH3:10].CN(C=O)C>O.CC(C)=O>[CH2:9]([C@H:11]1[CH2:16][C@H:15]2[C@H:17]3[C@H:26]([CH2:27][CH2:28][C@:13]2([CH3:14])[C@H:12]1[O:30][C:31](=[O:34])[CH2:32][O:6][C:1](=[O:7])[CH2:2][CH:3]([CH3:5])[CH3:4])[C@@H:25]1[C:20](=[CH:21][C:22](=[O:29])[CH2:23][CH2:24]1)[CH2:19][CH2:18]3)[CH3:10]
Reactant: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)CBr
Reactant: CC(C)CC(=O)[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Solvent: O
Product: CC[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)CC[C@@H]4[C@H]3CC[C@]2(C)[C@H]1OC(=O)COC(=O)CC(C)C
Yield: 87.8 %

Procedure:
In a mixture of 2 ml of water and 2 ml of acetone is dissolved 0.26 g of sodium isovalerate, and 0.45 g of 16β-ethyl-17β-bromoacetoxy-4-estren-3-one and 10 ml of DMF are added to the above solution. The mixture is refluxed for 6 hours, and thereafter treated in the same manner as Example 26. The reaction mixture is then subjected to column chromatography. Following passage of 100 ml of diisopropyl ether-n-hexane (2:8), elution is carried out with 400 ml of a 1:1 mixture of the same solvents. The elutate is evaporated under reduced pressure to remove the solvent, giving 0.415 g of the above-identified compound as a colorless viscous oil.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:6]([C:26](OC)=[O:27])=[C:7]([C:18]2[CH:23]=[CH:22][C:21]([O:24][CH3:25])=[CH:20][CH:19]=2)[N:8]2[C:17]=1[CH2:16][C:15]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:9]2)=O.[H-].[H-].[H-].[H-].[Li+].[Al+3]>ClCCl.C(OCC)C>[OH:27][CH2:26][C:6]1[C:5]([CH2:3][OH:2])=[C:17]2[CH2:16][C:15]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[CH2:9][N:8]2[C:7]=1[C:18]1[CH:19]=[CH:20][C:21]([O:24][CH3:25])=[CH:22][CH:23]=1
Reactant: COC(=O)c1c(C(=O)OC)c(-c2ccc(OC)cc2)n2c1Cc1ccccc1C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: ClCCl
Product: COc1ccc(-c2c(CO)c(CO)c3n2Cc2ccccc2C3)cc1
Reaction time: 2 h

Procedure:
A solution of the 3-(4-methoxyphenyl)-5,10-dihydropyrrolo[1,2-b]isoquinoline-1,2-dicarboxylic acid dimethyl ester (3.91 g, 10 mmol) in anhydrous dichloromethane (20 mL) was added dropwise to a stirred suspension of LiAlH4 (0.87 g, 23 mmol) in anhydrous diethyl ether (30 mL) at 10-15° C. The reaction mixture was further stirred for 2 hours after the addition was completed. The mixture was cooled in an ice bath and the excess hydride was destroyed by the sequential addition of water (1.2 mL), 15% aqueous NaOH (1.2 mL), and water (3.6 mL) at 0° C. The inorganic salt was removed by filtration, was washed with hot THF (300 mL), and the combined filtrate and washings was evaporated under reduced pressure to dryness. The solid residue was recrystallized from dichloromethane/ether to give [2-hydroxymethyl-3-(4-methoxyphenyl)-5,10-dihydropyrrolo[1,2-b]-isoquinolin-1-yl]methanol (DA-1106), 2.29 g (68.4%); mp 174-176° C.; 1H NMR (DMSO-d6) δ 3.82 (3H, s, OMe), 4.05 (2H, s, CH2), 4.26 (2H, d, J=5.0 Hz, CH2), 4.45-4.54 (4H, m, CH2 and exchangeable, 2×OH), 4.93 (2H, s, CH2), 7.05 (2H, d, J=8.4 Hz, ArH), 7.17-7.21 (1H, m, ArH), 7.25-7.28 (2H, m, ArH), 7.38 (2H, d, J=8.4 Hz, ArH), 7.37-7.39 (1H, m, ArH); m/z 451.9 (M+H)+ Anal. Calcld. for C21H21NO3 0.2H2O: C, 74.40; H, 6.36; N, 4.13. Found: C, 74.41; H, 6.30; N, 4.13.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]2[C:8](=[C:9]([CH3:11])[CH:10]=1)[NH:7][CH:6]=[C:5]2[C:12](=[O:16])[C:13]([O-:15])=O.[K+].[C:18]([N:26]1[CH2:31][CH2:30][NH:29][C@H:28]([CH3:32])[CH2:27]1)(=[O:25])[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[C:18]([N:26]1[CH2:31][CH2:30][N:29]([C:13](=[O:15])[C:12]([C:5]2[C:4]3[C:8](=[C:9]([CH3:11])[CH:10]=[C:2]([Cl:1])[N:3]=3)[NH:7][CH:6]=2)=[O:16])[C@H:28]([CH3:32])[CH2:27]1)(=[O:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: C[C@@H]1CN(C(=O)c2ccccc2)CCN1
Reactant: Cc1cc(Cl)nc2c(C(=O)C(=O)[O-])c[nH]c12
Agent: [K+]
Product: Cc1cc(Cl)nc2c(C(=O)C(=O)N3CCN(C(=O)c4ccccc4)C[C@H]3C)c[nH]c12

Procedure:
Precursor 5e, 1-benzoyl-3-(R)-methyl-4-[(5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetyl]piperazine was prepared by the same method as Precursor 5a, starting from Potassium (5-chloro-7-methyl-4-azaindol-3-yl)-oxoacetate, Precursor 4f, and 1-benzoyl-3-(R)-methyl piperazine. MS m/z: (M+H)+ calcd for C22H22ClN4O3 425.24, found 425.04. HPLC retention time: 1.72 minutes (column B).