Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:3][C@@H:2]1[CH2:4][OH:5].[NH2:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:26])[F:25])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1>C(O)C>[OH:3][C@H:2]([CH2:4][OH:5])[CH2:1][NH:6][C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[C:24]([F:27])([F:25])[F:26])[NH:13][C:14]2=[O:17])=[CH:9][CH:8]=1
Reactant: Nc1ccc2cc(-c3ccccc3C(F)(F)F)[nH]c(=O)c2c1
Reactant: OC[C@@H]1CO1
Solvent: CCO
Product: O=c1[nH]c(-c2ccccc2C(F)(F)F)cc2ccc(NC[C@H](O)CO)cc12
Yield: 68 %

Procedure:
132.6 μl (20 mmol) of (R)-glycidol was added to an ethanol solution (10 ml) containing 608.5 mg (2.0 mmol) of the 7-amino-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one obtained in Example 38. The obtained mixture was stirred under heating to reflux overnight. The residue obtained by concentration of the reaction solution was purified by silica gel column chromatography (methylene chloride:methanol=20:1), so as to obtain 514.3 mg (68%) of 7-((S)-2,3-dihydroxypropylamino)-3-(2-trifluoromethylphenyl)-2H-isoquinolin-1-one in the form of a light yellow amorphous substance.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:33][CH3:34])=[CH:20][C:21]([CH:23]([C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31][CH3:32])O)=[CH:22][C:12]=3[N:11]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].II.[PH2](=O)O.C(OCC)(=O)C>C(O)(=O)C>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:15][CH2:16][O:17][CH3:18])[C:13]3[C:19]([O:33][CH3:34])=[CH:20][C:21]([CH2:23][C:25]4[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=4[S:31][CH3:32])=[CH:22][C:12]=3[N:11]=2)=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(C(O)c3ccccc3SC)cc(OC)c21
Agent: II
Agent: O=[PH2]O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: COCCn1c(-c2ccc(C(C)C)cc2)nc2cc(Cc3ccccc3SC)cc(OC)c21
Temperature: 60 °C
Reaction time: 1 h
Yield: 118.8 %

Procedure:
To a mixture of 797 mg (1.67 mmol) [2-(4-isopropyl-phenyl)-7-methoxy-1-(2-methoxy-ethyl)-1H-benzoimidazol-5-yl]-(2-methylsulfanyl-phenyl)-methanol, 436 mg iodine in 13 ml acetic acid (100%), 0.88 ml of phosphinic acid (ca. 5 equiv.) is added at room temperature. The mixture is heated to 60° C. and stirred for 1 h. After that the reaction mixture is allowed to cool to room temperature and 100 ml ethyl acetate is added. The combined organic layers are washed with 4N NaOH-solution (4×), water (2×) and brine, dried over MgSO4, filtered and the filtrate is concentrated in vacuo to afford 914 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([N+:10]([O-])=O)[CH:3]=1>C(OCC)(=O)C.[C].[Pd]>[NH2:10][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[O:8][CH3:9]
Reactant: COc1ccc(F)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccc(F)cc1N
Yield: 100.5 %

Procedure:
A solution of 20.5 g of 4-fluoro-2-nitroanisole in ethyl acetate was hydrogenated over 5% palladium carbon (2 g) at room temperature for 16 hours. The catalyst was removed by filtration and the filtrate evaporated to leave 17 g of the title compound as a brown oil.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[S:3](Cl)(=[O:5])=[O:4].[Li+:9].[Li+].[Li+].[NH2-:12].CN(C=O)C>COCCOC>[N-:12]([S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4])[S:3]([C:2]([F:8])([F:7])[F:1])(=[O:5])=[O:4].[Li+:9]
Reactant: [NH2-]
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: [Li+]
Solvent: COCCOC
Solvent: CN(C)C=O
Product: O=S(=O)([N-]S(=O)(=O)C(F)(F)F)C(F)(F)F
Temperature: 25 °C

Procedure:
22 ml of trifluoromethanesulfonyl chloride were added to a suspension of 3.5 g of lithium nitride in 100 ml of a mixture of DMF and DME (50/50). The nitride dissolved in a few minutes with stirring at ambient temperature. The reaction took place according to the following reaction scheme:
Reaction SMILES: FC(F)(F)C(O)=O.[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([O:37]C(OC(C)(C)C)=O)[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([O:22]C(C)(C)C)=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1>>[S:8]1[C:12]2[CH:13]=[CH:14][C:15]([NH:17][C:18]3[CH:30]=[C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[C:33]([OH:37])[CH:32]=4)[CH:28]=[CH:27][C:19]=3[C:20]([OH:22])=[O:21])=[CH:16][C:11]=2[CH:10]=[CH:9]1
Reactant: CC(C)(C)OC(=O)Oc1cccc(-c2ccc(C(=O)OC(C)(C)C)c(Nc3ccc4sccc4c3)c2)c1
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)c1ccc(-c2cccc(O)c2)cc1Nc1ccc2sccc2c1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Trifluoroacetic acid 5.0 mL was added to the obtained tert-butyl 2-((benzothiophen-5-yl)amino)-4-(3-(tert-butoxycarbonyloxy)phenyl)benzoate, and it was stirred at room temperature for 3 hours. The solvent was removed under reduced pressure,diisopropyl ether was added to the obtained residue, and solid matter was filtrated to give 2-((benzothiophen-5-yl)amino)-4-(3-hydroxyphenyl)benzoic acid 30 mg of a yellow solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:21]([C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])[NH2:22]>>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:22][NH:21][C:23]([C@H:25]1[CH2:29][CH2:28][C:27](=[O:30])[N:26]1[C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])=[O:24])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NN
Product: CC(C)(C)OC(=O)N1C(=O)CC[C@@H]1C(=O)NNC(=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Yield: 60.9 %

Procedure:
Following a procedure analogous to Example 27, the carboxylic acid (6b, 390 mg, 1.41 mmol) of Example 9 or 16 and (R)-tert-butyl 2-(hydrazinecarbonyl)-5-oxopyrrolidine-1-carboxylate (730 mg, prepared following a procedure analogous to Reference Example 6 from the compound described in Reference Example 4), 431.2 mg of the title compound was afforded (yield 60.9%).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:22][CH2:21][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:19]=2[CH2:18]1)(=[O:3])N.[OH-].[Na+].C([O:34]CCOCCO)C>O>[C:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:18][CH2:19][C:20]2[C:23]3[CH:29]=[CH:28][CH:27]=[CH:26][C:24]=3[O:25][C:21]=2[CH2:22]1)([OH:3])=[O:34]
Reactant: CCOCCOCCO
Reactant: NC(=O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(O)c1ccc2[nH]cc(CCCCN3CCc4c(oc5ccccc45)C3)c2c1
Reaction time: 16 h

Procedure:
A mixture of 38.7 g of 2-[4-(5-carbamoyl-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine, 27.1 g of NaOH, 525 ml of water and 450 ml of diethylene glycol monoethyl ether is boiled, with stirring, for 16 hours. The mixture is cooled, the usual working up followed by acidification is carried out, and 2-[4-(5-carboxy-3-indolyl)butyl]-1,2,3,4-tetrahydrobenzofuro[2,3-c]pyridine is obtained.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14](OCC)=[O:15])[CH2:9]1>C1COCC1>[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][OH:15])[CH2:9]1
Reactant: CCOC(=O)C1CCCC(N)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: NC1CCCC(CO)C1
Temperature: 27.5 °C
Reaction time: 15 h
Yield: 82.8 %

Procedure:
LAH (107 mg, 2.8 mmol) was added portionwise to a solution of ethyl 3-aminocyclohexanecarboxylate (320 mg, 1.87 mmol) in THF (5 mL) at 0° C. and continued stirring at 25-30° C. for 15 h. The reaction mixture was quenched with aqueous saturated sodium sulphate solution, filtered the solid precipitate, washed the solid with THF; the filtrate collected was concentrated under reduced pressure to afford 200 mg of the title compound.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]2[C@H:13]([CH3:14])[CH2:12][O:11][C@H:10]([CH2:15][N:16]([CH3:18])[CH3:17])[CH2:9]2)[N:5]=[C:4]([NH:19][CH3:20])[N:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][C:26](B(O)O)=[CH:25][C:24]=1[F:32])#[N:22]>O1CCOCC1.C([O-])(O)=O.[Na+].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>[CH3:17][N:16]([CH2:15][C@H:10]1[O:11][CH2:12][C@@H:13]([CH3:14])[N:8]([C:6]2[N:5]=[C:4]([NH:19][CH3:20])[N:3]=[C:2]([C:26]3[CH:27]=[CH:28][C:23]([C:21]#[N:22])=[C:24]([F:32])[CH:25]=3)[CH:7]=2)[CH2:9]1)[CH3:18]
Reactant: N#Cc1ccc(B(O)O)cc1F
Reactant: CNc1nc(Cl)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
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: C1COCCO1
Product: CNc1nc(-c2ccc(C#N)c(F)c2)cc(N2C[C@@H](CN(C)C)OC[C@H]2C)n1
Temperature: 100 °C
Reaction time: 15 h
Yield: 75.4 %

Procedure:
A mixture of 4-chloro-6-{(2R,5R)-2-[(dimethylamino)methyl]-5-methyl-4-morpholinyl}-N-methyl-2-pyrimidinamine (60 mg, 0.20 mmol), (4-cyano-3-fluorophenyl)boronic acid (73 mg, 0.44 mmol), and Pd(PPh3)4 (12 mg, 0.010 mmol) in 1,4-dioxane (2 mL) and saturated aqueous NaHCO3 (1 mL) was degassed with nitrogen for 10 minutes. The vial was then capped and stirred at 100° C. for 15 hours. The mixture was cooled, diluted with saturated aqueous NaHCO3 (5 mL) and water (5 mL), and extracted with EtOAc (2×10 mL). The extracts were washed with brine (10 mL), dried (Na2SO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography (10 g SiO2, CH2Cl2 to 95/5/0.5 CH2Cl2/CH3OH/NH4OH gradient) to give the title compound (58 mg, about 85% purity) as a yellow oil. LC-MS (ES) m/z=385 [M+H]+.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[NH2:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27].C(N(CC)CC)C>ClCCl>[C:1]([NH:22][C@H:23]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:30])[CH3:31])=[O:27])([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)CC[C@H](N)C(=O)OC(C)(C)C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)CC[C@H](NC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.7 %

Procedure:
Tritylchloride (2.05 g. 7.36 mmol) was added to a solution of di-tert-butyl L-glutamate hydrochloride (2.15 g, 7.27 mmol) and triethylamine (5 mL, 36 mmol) in dichloromethane (20 mL). The solution was stirred for overnight (16 h) at room temperature. The solution was washed with sodium bicarbonate solution (3×10 mL) and water (2×5 mL). After drying over sodium sulphate, the solvent was evaporated. The crude product was purified by flash chromatography (ethyl acetate/n-hexane: 2/98 to 3/97) to give di-tert-butyl N-trityl-L-glutamate (3.2 g, 88%) as a white foam.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9]([C:11]1[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=1)=[O:10].[CH:17]([O:20][C:21]1[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=1)([CH3:19])[CH3:18]>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][S:27]([C:24]2[CH:23]=[CH:22][C:21]([O:20][CH:17]([CH3:19])[CH3:18])=[CH:26][CH:25]=2)(=[O:29])=[O:28])=[C:3]([C:9]([C:11]2[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=2)=[O:10])[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)c1ccncc1
Reactant: CC(C)Oc1ccc(S(=O)(=O)Cl)cc1
Product: CC(C)Oc1ccc(S(=O)(=O)Nc2ccc(Cl)cc2C(=O)c2ccncc2)cc1

Procedure:
The title compound was prepared according to the general procedure for the synthesis of N-Aryl-benzenesulfonamides previously described using 116 mg of (2-Amino-5-chloro-phenyl)-pyridin-4-yl-methanone and 117 mg of 4-Isopropoxy-benzenesulfonyl chloride. 1H-NMR (400 MHz, CDCl3): δ 1.01 (d, 6H, J=5.6 Hz), 4.27 (m, 1H), 6.51 (d, 2H, J=8.8 Hz), 6.87 (d, 1H, J=8.8 Hz), 7.15-7.25 (m, 4H), 7.60 (d, 2H, J=6.0 Hz), 8.64 (d, 2H, J=6 Hz), 9.60 (s, 1H). MS: m/z 431.9 (M++1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([CH3:12])[CH:10]=2)[C:5](O)=[CH:4][N:3]=1.[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27]S(C)(=O)=O)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:16])[CH3:15].C([O-])([O-])=O.[K+].[K+].C(O)(=O)C>CN(C)C=O.O.CO>[C:14]([O:18][C:19]([N:21]1[CH2:26][CH2:25][CH:24]([O:27][C:8]2[CH:7]=[C:6]3[C:11](=[CH:10][C:9]=2[CH3:12])[C:2]([NH2:1])=[N:3][CH:4]=[CH:5]3)[CH2:23][CH2:22]1)=[O:20])([CH3:17])([CH3:15])[CH3:16]
Reactant: CC(C)(C)OC(=O)N1CCC(OS(C)(=O)=O)CC1
Reactant: Cc1ccc2c(O)cnc(N)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc2c(N)nccc2cc1OC1CCN(C(=O)OC(C)(C)C)CC1
Yield: 38.1 %

Procedure:
A suspension of 1-amino-7-methylisoquinolin4-ol (430 mg, 2.4 mmol), 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester (1.0 g) and K2CO3 (510 mg, 3.7 mmol) in anhydrous N, N-dimethylformamide (8 ml) were microwaved at 100° C. for 10 minutes. A further equivalent of 4-methanesulfonyloxypiperidine-1-carboxylic acid tert-butyl ester in N, N-dimethylformamide (4 ml) was added and the mixture microwaved at 100° C. for a further 10 minutes. The mixture was diluted with water, acidified with acetic acid and further diluted with methanol. The mixture was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol. The crude product was isolated and further purified using flash chromatography on silica (eluent: 9:1:0.1 dichloromethane : methanol :ammonium hydroxide) to afford 4-(1-amino-7-methylisoquinolin-6-yloxy)piperidine-1-carboxylic acid tert-butyl ester (327 mg). A mixture of the 4-(1-amino-7-methylisoquinolin-6-yloxy)-piperidine-1-carboxylic acid tert-butyl ester in dichloromethane (5 ml) and trifluoroacetic acid (2 ml) was stirred at ambient temperature overnight. The mixture was concentrated in vacuo to give a residue. The residue was loaded onto a pre-acidified SCX column, washed with methanol and then eluted with 2M ammonia in methanol to give 7-methyl-6-(piperidin-4-yloxy)isoquinolin-1-ylamine (270 mg), El-MS: m/z=258.4 [M+H]+.
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[C:9]([CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])(=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[BH3-]C#N.[Na+]>CO>[C:10]1([CH:9]([NH:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ccccc1
Reactant: CCOC(=O)CC(=O)c1ccccc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCOC(=O)CC(Nc1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 61.4 %

Procedure:
To a solution of aniline hydrochloride (3.37 g, 26 mmol) and ethyl benzoylacetate (5 mL, 26 mmol) in MeOH (70 mL) was added NaBH3CN (1.75 g) and the mixture was stirred at room temperature for 18 h. The solvent was removed and the residue partitioned between 0.5N HCl and Et20. The aqueous phase was made basic with 1N NaOH and extracted with CHCl3. The organic phase was dried and concentrated to a residue. Purification by chromatography on silica gel (hexane: EtOAc, 5%) afforded ethyl 3-phenyl-3-(phenylamino)propionate (4.3 g, 62%). This compound was then hydrolized under basic conditions to give the title compound as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[H-].[Na+].[C:13]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])([CH3:15])[CH3:14].O>C1COCC1>[C:13]([Si:17]([CH3:19])([CH3:18])[N:7]1[C:8]2[C:4](=[CH:3][C:2]([F:1])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Fc1ccc2[nH]ccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)[Si](C)(C)n1ccc2cc(F)ccc21
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
To a solution of 5-fluoro-1H-indole (30.0 g, 0.222 mol) in anhydrous THF (250 mL) was added sodium hydride (60% suspension in mineral oil, 10.22 g, 0.255 mol) portionwise and maintaining the solution at 0° C. The reaction mixture was stirred at 0° C. for 20 min, then a solution of tert-butyl-chloro-dimethyl-silane (40.15 g, 0.266 mol) in anhydrous THF (20 mL) was added and the solution stirred at RT for 25 h. The reaction mixture was poured into H2O and the layers separated. The aqueous layer was extracted with EtOAc and the combined organic layers were dried (MgSO4), then concentrated in vacuo. The resultant residue was purified by column chromatography (silica gel, cyclohexane:DCM 100% to 50:50) to provide the title compound was obtained as a colourless oil (41.2 g, 74%).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:5][C:6]=1[CH2:7]O.[NH:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[Cl-].[NH4+]>O1CCCC1>[CH3:1][C:2]1[O:3][C:4]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=2)=[CH:5][C:6]=1[CH2:7][N:19]1[CH:23]=[C:22]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH:21]=[N:20]1
Reactant: CCOC(=O)c1cn[nH]c1
Reactant: Cc1oc(-c2cccc(C(F)(F)F)c2)cc1CO
Agent: CCOC(=O)N=NC(=O)OCC
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnn(Cc2cc(-c3cccc(C(F)(F)F)c3)oc2C)c1
Reaction time: 1 h
Yield: 59.3 %

Procedure:
A solution of the compound (0.40 g) obtained in Example 127b, ethyl 1H-pyrazole-4-carboxylate (0.26 g) and triphenylphosphine (0.49 g) in tetrahydrofuran (8 mL) was cooled in an ice bath, diethyl azodicarboxylate (0.30 mL) was added, and the mixture was stirred at the same temperature for 1 hr. Saturated aqueous ammonium chloride solution was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The obtained organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by column chromatography (carrier: silica gel, eluent: hexane/ethyl acetate) to give the title compound (0.35 g) as a solid.
Reaction SMILES: [C@H:1]12[CH2:6][C@H:5]1[CH2:4][NH:3][C@@H:2]2[CH2:7][NH:8][C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[CH3:15][C:16]1[S:17][C:18]([C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:13][C:10]([F:12])([F:11])[C:9]([NH:8][CH2:7][C@H:2]1[N:3]([C:21]([C:19]2[N:20]=[C:16]([CH3:15])[S:17][C:18]=2[C:24]2[CH:25]=[C:26]([CH3:30])[CH:27]=[CH:28][CH:29]=2)=[O:22])[CH2:4][C@H:5]2[C@@H:1]1[CH2:6]2)=[O:14]
Reactant: Cc1cccc(-c2sc(C)nc2C(=O)O)c1
Reactant: O=C(NC[C@H]1NC[C@@H]2C[C@@H]21)C(F)(F)F
Product: Cc1cccc(-c2sc(C)nc2C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)C(F)(F)F)c1

Procedure:
prepared by reaction of N-[(1S,2S,5R)-1-(3-Aza-bicyclo[3.1.0]hex-2-yl)methyl]-2,2,2-trifluoro-acetamide with 2-Methyl-5-m-tolyl-thiazole-4-carboxylic acid.
Reaction SMILES: [CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:28][N:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.ClCCCl>[CH:1]1([N:7]2[C:15]3[C:14](=[O:16])[NH:13][C:12]([C:17]4[CH:24]=[CH:23][C:20]([CH2:21][N:32]5[CH2:33][CH2:34][N:29]([CH3:28])[CH2:30][CH2:31]5)=[CH:19][C:18]=4[O:25][CH3:26])=[N:11][C:10]=3[C:9]([CH3:27])=[N:8]2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CN1CCNCC1
Reactant: COc1cc(C=O)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1cc(CN2CCN(C)CC2)ccc1-c1nc2c(C)nn(C3CCCCC3)c2c(=O)[nH]1
Temperature: 25 °C
Reaction time: 1 h
Yield: 76.2 %

Procedure:
To a 2 ml 1,2-dichloroethane solution of 61 mg (0.166 mmol) of the compound obtained in Example 233, 37 μl (0.332 mmol) of N-methylpiperazine, 10 μl of acetic acid, and 53 mg (0.252 mmol) of sodium triacetoxyborohydride were added, and the mixture was stirred at room temperature for 1 hour. Then, an aqueous solution of sodium hydrogen carbonate was added to the reaction mixture, and the mixture was extracted with dichloromethane. The organic layer was washed with water and a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate, whereafter the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (dichloromethane/methanol=10/1) to obtain 57 mg (76%) of the captioned compound.
Reaction SMILES: [C:1]([C:4]1[CH:23]=[CH:22][CH:21]=[CH:20][C:5]=1[C:6](C1C2C(=CC=CC=2)N(CC)C=1C)=[O:7])(O)=[O:2].C(OC1C=CC=C(NCCCC)C=1NCCCC)CCC>C(OC(=O)C)(=O)C>[C:1]1([C:4]2[C:5](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH2:6][O:7]1)=[O:2]
Reactant: CCn1c(C)c(C(=O)c2ccccc2C(=O)O)c2ccccc21
Agent: CCCCNc1cccc(OCCCC)c1NCCCC
Solvent: CC(=O)OC(C)=O
Product: O=C1OCc2ccccc21
Reaction time: 1 h
Yield: 416.6 %

Procedure:
A mixture of 7.7 g of 3-(2'-carboxybenzoyl)-1-ethyl-2-methylindole and 7.9 g of bis(n-butylamino)phenol n-butyl ether in 30 g of acetic anhydride is stirred for 1 hour at 80°-85° C. Working up as described in Example 1 gives 14 g of a phthalide of formula ##STR11## This amorphous compound has a softening point of 40° C. and develops at once a lightfast blue image on acid-modified clay.
Reaction SMILES: [CH:1]([C:4]1[CH:12]=[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][N:6]2[N:5]=1)([CH3:3])[CH3:2].[CH2:13]([O:15][CH2:16][CH:17]([CH3:21])[C:18](Cl)=[O:19])[CH3:14].[Cl-].[Al+3].[Cl-].[Cl-].[OH-].[K+]>C(=S)=S.O>[CH2:13]([O:15][CH2:16][CH:17]([CH3:21])[C:18]([C:12]1[C:4]([CH:1]([CH3:3])[CH3:2])=[N:5][N:6]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=12)=[O:19])[CH3:14]
Reactant: CCOCC(C)C(=O)Cl
Reactant: CC(C)c1cc2ccccn2n1
Agent: [Al+3]
Agent: [Cl-]
Agent: [K+]
Solvent: O
Solvent: S=C=S
Product: CCOCC(C)C(=O)c1c(C(C)C)nn2ccccc12
Reaction time: 3 h
Yield: 32 %

Procedure:
A mixture of 2-isopropylpyrazolo[1,5-a]pyridine and β-ethoxy-α-methylpropionic chloride was dissolved in carbon disulfide. Aluminum chloride was added at 0° to the resulting solution. The reaction mixture was stirred for 3 hr, and poured into water. The solution was made basic with potassium hydroxide solution and extracted with chloroform. The chloroform solution was washed with water, dried over sodium sulfate and concentrated. The residue was distilled, bp 171°-173° (4 mmHg). Yield 32%.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([O:13][CH3:14])[CH:10]=[C:9]2[C:4]=1[C:5](=[O:27])[NH:6][C:7]([C:15]1[CH:20]=[CH:19][C:18]([N:21]3[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=1)=[N:8]2.CCN(CC)CC.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C(Cl)Cl>[C:35]([N:24]1[CH2:23][CH2:22][N:21]([C:18]2[CH:19]=[CH:20][C:15]([C:7]3[NH:6][C:5](=[O:27])[C:4]4[C:9](=[CH:10][C:11]([O:13][CH3:14])=[CH:12][C:3]=4[O:2][CH3:1])[N:8]=3)=[CH:16][CH:17]=2)[CH2:26][CH2:25]1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCNCC4)cc3)nc2c1
Reactant: O=C(Cl)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccc(N4CCN(C(=O)c5ccccc5)CC4)cc3)nc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 64.9 %

Procedure:
To a solution of 5,7-dimethoxy-2-(4-(piperazin-1-yl)phenyl)quinazolin-4(3H)-one (0.150 g, 0.40 mmol) in CH2Cl2 (10 mL) was added Et3N (0.08 mL, 0.60 mmol) and benzoyl chloride (0.04 mL, 0.36 mmol). The resulting solution was stirred at room temperature for 3 hours. The solution was concentrated in vacuo. The material was purified by flash chromatography on silica gel eluting with 0% to 10% of MeOH/EtOAc to afford the title compound (0.110 g, 64%). 1H NMR (300 MHz, DMSO-d6): δ 11.79 (s, 1H), 8.11 (d, J=8.7 Hz, 2H), 7.37-7.54 (m, 5H), 7.04 (d, J=8.9 Hz, 2H), 6.68 (s, 1H), 6.47 (s, 1H), 3.61-4.03 (m, 8H), 3.23-3.62 (m, 6H); ESI MS m/z 471 [M+H]+.