Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4](=O)[C:5]([NH2:28])([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C@H:18]3[CH2:23][CH2:22][C@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:20][CH2:19]3)[CH:13]=2)[N:8]=1)[CH3:6])C.[BH4-].[Na+]>CO.O1CCCC1>[NH2:28][C:5]([C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:17][C@H:18]3[CH2:19][CH2:20][C@H:21]([C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:22][CH2:23]3)[CH:13]=2)[N:8]=1)([CH3:6])[CH2:4][OH:3]
Reactant: CCOC(=O)C(C)(N)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: CC(N)(CO)c1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2n1
Reaction time: 2 h

Procedure:
2-Amino-2-[6-(trans-4-tert-butyl-cyclohexyloxy)-quinolin-2-yl]-propionic acid ethyl ester (18 mg as TFA salt, 0.000035 mol) was dissolved in a mixture of methanol (2.0 mL, Acros) and tetrahydrofuran (2.0 mL, Acros), then sodium tetrahydroborate (3.8 mg, 0.00010 mol, Aldrich) was added. After 2 h, additional sodium tetrahydroborate (8.1 mg, 0.00021 mol, Aldrich) was added. After an additional 2 h, the reaction mixture was quenched with 250 uL of to saturated NH4Cl, and solvents were removed under vacuum. DMSO (½ mL) was added to the residue but it did not completely solubilize. The material was partitioned between methylene chloride and water. The emulsion was broken up by adding saturated sodium chloride and solid sodium chloride. The organics were dried with magnesium sulfate, filtered and evaporated. The residue was purified via preparative HPLC to give pure product (6.3 mg, 38%) as TFA salt. MS: m/z=357.20 [M+H]+. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm: 8.19 (d, J=8.5 Hz, 1H), 7.96 (d, J=9.3 Hz, 1H), 7.39-7.46 (m, 2H), 7.13 (d, J=2.8 Hz, 1H), 4.24-4.36 (m, 1H), 4.12-4.21 (m, 2H), 2.23-2.32 (m, 2H), 1.88-1.96 (m, 2H), 1.78 (s, 3H), 1.41-1.54 (m, 2H), 1.10-1.27 (m, 3H), 0.91 (s, 9H).
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[OH:10])[CH:2]=[CH2:3].Br[CH2:12][C:13](OC)=[O:14].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[O:10][CH2:12][CH2:13][OH:14])[CH:2]=[CH2:3]
Reactant: C=CCc1ccccc1O
Reactant: COC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCc1ccccc1OCCO
Temperature: 100 °C
Reaction time: 8 h
Yield: 0.1 %

Procedure:
2-Allylphenol (5.066 g) was dissolved in N,N-dimethylformamide (70 ml), followed by the addition of methyl 2-bromoacetate (6.931 g) and potassium carbonate (7.88 g), and the resulting mixture was stirred at 100° C. overnight. The reaction mixture was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was dissolved in tetrahydrofuran (40 ml), followed by the addition of lithium aluminium hydride (1.442 g) in small portions under ice-cooling. The resulting mixture was stirred for 5 min. To the reaction mixture were sequentially added water (1.5 ml), 5N sodium hydroxide (1.5 ml) and water (4.5 ml), and the resulting insoluble matters were filtered off through Celite. The resulting filtrate was partitioned between ethyl acetate and water. The organic layer was washed with water, dried (over MgSO4) and evaporated. The resulting residue was purified by (NH) silica gel column chromatography (ethyl acetate/hexane system), to give the title compound as a colorless oil (5.248 mg, yield; 76%).
Reaction SMILES: [OH-].[Na+].[CH:3]1[C:8]([N+:9]([O-:11])=[O:10])=[CH:7][CH:6]=[C:5]([OH:12])[CH:4]=1.Cl[CH2:14][CH2:15][OH:16]>CN(C=O)C>[N+:9]([C:8]1[CH:7]=[CH:6][C:5]([O:12][CH2:14][CH2:15][OH:16])=[CH:4][CH:3]=1)([O-:11])=[O:10]
Reactant: O=[N+]([O-])c1ccc(O)cc1
Reactant: OCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(OCCO)cc1
Temperature: 100 °C
Yield: 92 %

Procedure:
Sodium hydroxide (6.22 g) is added to a solution of p-nitrophenol (21.45 g) in DMF (300 mL) and stirred until the reagents are fully dissolved. After a dropwise addition of 2-chloroethanol (10.66 ml), the reaction mixture is heated to 100° C. for 72 hours. After filtering and evaporating the solvent under reduced pressure, the resulting oil is recrystallized in a methanol/water mixture and filtered to afford 21.62 g (92%) of 2-(4-nitrophenoxy)-1-ethanol. A mixture of 2-(4-nitrophenoxy)-1-ethanol (6.17 g) and palladium on carbon (0.08 g) in EtOH (120 mL) is hydrogenated in a 500 mL Parr jar at 33 psi for 18 hrs. Vacuum filtration through celite and evaporation under reduced pressure affords 5.00 g (96%) of 2-(4-aminophenoxy)-1-ethanol. This material is combined with diethyl ethoxymethylenemalonate (7 mL) and heated to 130° C. for 1 hr in a round bottom flask under a gentle stream of nitrogen. The mixture is cooled, diluted with 1:1 cyclohexane/toluene (20 mL), and filtered to afford 9.1 g (86%) of diethyl 2-{[4-(2-hydroxyethoxy)anilinorlmethylene}-malonate. A solution the resulting malonate (8.59 g) in acetic acid (15 mL) and acetic anhydride (4 mL) is heated to 60° C. for 36 hrs. The reaction mixture is diluted with water, extracted with ethyl acetate and washed with saturated sodium bicarbonate. Evaporation under reduced pressure leaves a brown oil which is recrystallized from 1:1 methanol/water and filtered to afford 7.09 g (73%) diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate. Diethyl 2-({4-[2-(acetyloxy)ethoxy]anilino}methylene)malonate (6.55 g) is dissolved in diphenyl ether (75 mL) and refluxed at 250° C. for 1 hr. After the mixture is cooled and diluted with 250 mL toluene, the resulting precipitate is collected by filtration, washed with toluene and recrystallized from aqueous acetic acid. This procedure yielded 0.50 g (9%) of ethyl 6-[2-(acetyloxy)ethoxy]-4-hydroxy-3-quinolinecarboxylate. The resulting carboxylate ester (0.49 g) and 4-chlorobenzylamine (0.90 mL) are heated to 175° C. for 2 hrs. After the reaction mixture is cooled and diluted with xylenes, the dark solid is filtered. Recrystallization from acetic acid and water affords 0.150 g (26%) of the title compound as a beige solid.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][C:5]1[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:10]([O-])=[CH:9][C:8]=2[N:18]=1.[NH4+:33].[OH-].C1(C)C=CC(S(Cl)(=O)=O)=CC=1.C(Cl)Cl>ClCCCl>[NH2:33][C:9]1[C:8]2[N:18]=[C:5]([CH2:4][CH2:3][O:2][CH3:1])[N:6]([CH2:19][CH2:20][O:21][CH2:22][CH2:23][N:24]([CH3:32])[C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C:7]=2[C:16]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N:10]=1
Reactant: COCCc1nc2c[n+]([O-])c3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reactant: [NH4+]
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [OH-]
Solvent: ClCCCl
Solvent: ClCCl
Product: COCCc1nc2c(N)nc3ccccc3c2n1CCOCCN(C)C(=O)OC(C)(C)C
Reaction time: 4 h

Procedure:
A solution of tert-butyl 2-{2-[2-(2-methoxyethyl)-5-oxido-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate (7.05 g, 15.9 mmol) in 100 mL of 1,2-dichloroethane was heated to 80° C. and treated with 5 mL of concentrated NH4OH solution. To the rapidly stirred solution was added solid p-toluenesulfonyl chloride (3.33 g, 17.5 mmol) over a 10 min period. The reaction mixture was treated with an additional 5 mL concentrated NH4OH solution and then sealed in a pressure vessel and heating was continued for 4 h. The reaction mixture was then cooled and treated with 100 mL of CH2Cl2. The reaction mixture was then washed with H2O, 1% Na2CO3 solution (3×) and brine. The organic portion was dried over Na2SO4 and concentrated to give 6.50 g of tert-butyl 2-{2-[4-amino-2-(2-methoxyethyl)-1H-imidazo[4,5-c]quinolin-1-yl]ethoxy}ethyl(methyl)carbamate as a brown oil.
Reaction SMILES: [CH2:1]([OH:5])[CH2:2][C:3]#[CH:4].C1(C)C=CC(S(O)(=O)=O)=CC=1.[O:17]1[CH:22]=[CH:21][CH2:20][CH2:19][CH2:18]1>CCOCC>[O:17]1[CH2:18][CH2:19][CH2:20][CH2:21][CH:22]1[O:5][CH2:1][CH2:2][C:3]#[CH:4]
Reactant: C#CCCO
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCOCC
Product: C#CCCOC1CCCCO1
Reaction time: 16 h
Yield: 95.8 %

Procedure:
3-Butyn-1-ol (3) (7.0 g, 100 mmol) was dissolved in 50 mL dry ether, and the solution was cooled to 0°. A few crystals of p-toluenesulphonic acid were added, followed by dropwise addition of 9.24 g (110 mmol) of dihydropyran. The resulting solution was warmed to 20°, stirred for 16 hr, and extracted with saturated aqueous NaHCO3 (20 mL) and brine (20 mL). The solution was dried (MgSO4), concentrated in vacuo, and distilled to give 7 (14.78 g, 96% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[C:4]1[CH:9]=[C:8](I)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17].C([Sn](CCCC)(CCCC)[C:25]1[CH:26]=[C:27]([CH:30]=[CH:31][CH:32]=1)[C:28]#[N:29])CCC>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]([C:4]1[CH:9]=[C:8]([C:25]2[CH:32]=[CH:31][CH:30]=[C:27]([C:28]#[N:29])[CH:26]=2)[C:7]([C:11]([F:14])([F:13])[F:12])=[CH:6][C:5]=1[NH:15][C:16](=[O:18])[CH3:17])=[O:19]
Reactant: COC(=O)c1cc(I)c(C(F)(F)F)cc1NC(C)=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1cccc(C#N)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: COC(=O)c1cc(-c2cccc(C#N)c2)c(C(F)(F)F)cc1NC(C)=O
Temperature: 25 °C
Yield: 42.6 %

Procedure:
A solution of 2-acetylamino-5-iodo-4-trifluoromethyl-benzoic acid methyl ester (3 g, 7.75 mmol), tetrakis(triphenylphosphine)palladium (0.446 g, 0.775 mmol), and 3-tributylstannanyl-benzonitrile (3.65 g, 9.3 mmol) in dioxane (100 mL) was heated to 110° C. for 96 h under nitrogen. The mixture was allowed to cool to r.t., and then filtered. The filtrate was concentrated in vacuo and the crude product was purified by column chromatography (silica gel 60, hexanes/DCM 9:1) to give 4-acetylamino-3′-cyano-6-trifluoromethyl-biphenyl-3-carboxylic acid methyl ester (1.2 g, 3.3 mmol, 43%) as a yellow oil, ESI-MS: m/z 363 [M+H]+.
Reaction SMILES: [NH:1]1[CH:5]=[N:4][CH:3]=[N:2]1.[H-].[Na+].[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:33])([F:32])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24](F)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1.O>CN(C=O)C>[Cl:8][C:9]1[CH:10]=[C:11]([C:16]2([C:30]([F:32])([F:33])[F:31])[CH2:20][CH2:19][N:18]([C:21]3[CH:22]=[CH:23][C:24]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)=[C:25]([CH:28]=3)[C:26]#[N:27])[CH2:17]2)[CH:12]=[C:13]([Cl:15])[CH:14]=1
Reactant: c1nc[nH]n1
Reactant: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1F
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: N#Cc1cc(N2CCC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1-n1cncn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 53.5 %

Procedure:
To the solution of 1H-1,2,4-triazole (0.06 g) in DMF was added sodium hydride (0.04 g) while cooling with ice, and the mixture was warmed to room temperature and then stirred for 0.5 hr. To this solution was added the solution of 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]2-fluorobenzonitrile (0.30 g) in DMF, and the mixture was heated to reflux for 6 hours. The mixture was cooled to room temperature and then poured into water, which was then extracted twice with ethyl acetate. The organic layer was combined, which was then washed with water and dried over anhydrous magnesium sulfate. After the drying agent was filtered off, the solvent was distilled away under the reduced pressure, and the residue was then purified by silica gel chromatography to yield 5-[3-(3,5-dichlorophenyl)-3-(trifluoromethyl)pyrrolidin-1-yl]-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.18 g). 1H-NMR (DMSO-d6) δ: 2.62-2.73 (1H, m), 2.95-3.03 (1H, m), 3.49-3.55 (2H, m), 3.90 (1H, d), 4.31 (1H, d), 7.09 (1H, dd), 7.29 (1H, d), 7.61 (1H, d), 7.68 (2H, d), 7.71 (1H, t), 8.26 (1H, s), 8.98 (1H, s)
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:5](=[O:17])[NH:6][C@@H:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:8]([O:10]CC)=[O:9].[OH-].[Li+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1.C(O)C>[OH:1][CH2:2][CH2:3][N:4]([CH2:18][CH2:19][C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:5](=[O:17])[NH:6][C@@H:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:8]([OH:10])=[O:9]
Reactant: CCOC(=O)[C@H](CC(C)C)NC(=O)N(CCO)CCc1ccccc1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: CC(C)C[C@H](NC(=O)N(CCO)CCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Ethyl (2S)-2-[3-(2-hydroxyethyl)-3-phenethylureido]-4-methylvalerate (Compound No. 1-31, 1.00 g) is dissolved in a mixed solvent of tetrahydrofuran (3.5 ml)-ethanol (2.8 ml). A 2 N aqueous lithium hydroxide solution (1.7 ml) is added thereto under ice cooling, and the mixture is stirred under ice cooling for 25 minutes and further at room temperature for one hour. A 5% aqueous citric acid solution is added to the reaction mixture, and the whole is extracted with ethyl acetate. The organic layer is washed with water and saturated brine successively, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give 1.02 g (quantitatively) of the titled compound (Compound No. 15-1).
Reaction SMILES: [OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:21][C:22]1[C:23]([CH:32]2[CH2:34][O:33]2)=[CH:24][C:25]2[CH2:29][O:28][C:27](=[O:30])[C:26]=2[CH:31]=1>>[OH:1][C@H:2]([C:10]1[CH:19]=[CH:18][C:13]2[C:14](=[O:17])[O:15][CH2:16][C:12]=2[C:11]=1[CH3:20])[CH2:3][N:4]1[CH2:9][CH2:8][N:7]([CH2:34][CH:32]([OH:33])[C:23]2[C:22]([CH3:21])=[CH:31][C:26]3[C:27](=[O:30])[O:28][CH2:29][C:25]=3[CH:24]=2)[CH2:6][CH2:5]1
Reactant: Cc1c([C@@H](O)CN2CCNCC2)ccc2c1COC2=O
Reactant: Cc1cc2c(cc1C1CO1)COC2=O
Product: Cc1cc2c(cc1C(O)CN1CCN(C[C@H](O)c3ccc4c(c3C)COC4=O)CC1)COC2=O

Procedure:
5-[(1R)-1-hydroxy-2-{4-[2-hydroxy-2-(6-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl]-4-methyl-2-benzofuran-1(3H)-one was prepared in a similar fashion to that described for the synthesis of EXAMPLE 58 starting from 5-[(1R)-1-hydroxy-2-(piperazin-1-yl)ethyl]-4-methyl-2-benzofuran-1(3H)-one and isomer B of 6-methyl-5-oxiran-2-yl-2-benzofuran-1(3H)-one (65B).
Reaction SMILES: [CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH:18]C(OCC2C=CC=CC=2)=O)[CH2:8][C@H:7]1[CH3:29])=[O:5])[CH3:2]>C(O)C.O1CCCC1.[Pd]>[CH2:1]([O:3][C:4]([N:6]1[C:15]2[C:10](=[N:11][C:12]([O:16][CH3:17])=[CH:13][CH:14]=2)[C@@H:9]([NH2:18])[CH2:8][C@H:7]1[CH3:29])=[O:5])[CH3:2]
Reactant: CCOC(=O)N1c2ccc(OC)nc2[C@@H](NC(=O)OCc2ccccc2)C[C@H]1C
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCOC(=O)N1c2ccc(OC)nc2[C@@H](N)C[C@H]1C
Temperature: 25 °C
Reaction time: 7 h
Yield: 99.4 %

Procedure:
(2R*,4S*)-4-Benzyloxycarbonylamino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (5.83 g) is dissolved in a mixture solvent of ethanol (60 ml) and tetrahydrofuran (60 ml), then thereto is added 10% palladium/carbon (500 mg), and the mixture is stirred at room temperature under hydrogen for 7 hours. The catalyst is removed by filtration, the filtrate is concentrated under reduced pressure to give (2R*,4S*)-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid ethyl ester (3.85 g). MS (m/z): 266 [M+H]+
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Cl[C:22]1[C:31]2[C:26](=[CH:27][C:28]([O:34][CH3:35])=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][N:23]=1.Cl>O.CS(C)=O>[CH3:33][O:32][C:29]1[CH:30]=[C:31]2[C:26](=[CH:27][C:28]=1[O:34][CH3:35])[N:25]=[CH:24][N:23]=[C:22]2[O:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([C:12]([OH:14])=[O:13])=[CH:7][CH:6]=[CH:5]2
Reactant: O=C(O)c1cccc2cc(O)ccc12
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: COc1cc2ncnc(Oc3ccc4c(C(=O)O)cccc4c3)c2cc1OC
Temperature: 140 °C
Yield: 58.7 %

Procedure:
6-Hydroxy-1-naphthoic acid (1.43 g, 7.6 mmol) and 38 ml of DMSO were stirred at room temperature while cesium carbonate (7.5 g, 22.9 mmol) and 4-chloro-6,7-dimethoxy-quinazoline (2.05 g, 9.14 mmol) were added. The mixture was heated at 140° C. for 3 hours. The mixture was cooled to room temperature and diluted with 40 mL of H2O. The mixture was neutralized with 2 N HCl to 6.5. The deposited solids were collected by vacuum filtration, washed with H2O, dried under vacuum and recrystallized from methanol to give the title compound (1.68 g, 59% yield) as a brown solid. LC-MS (m/z) 377 (M+1).
Reaction SMILES: [C:1]([N:9]1[CH2:13][C@@H:12]([O:14][CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)[C@H:11](Br)[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1(C)C(C)=CC=CC=1>[C:1]([N:9]1[CH2:13][C@@H:12]2[C@@H:11]([N:36]([CH2:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH2:16][CH2:15][O:14]2)[CH2:10]1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCCO[C@@H]2CN(C(=O)c3ccccc3)C[C@H]2Br)cc1
Reactant: NCc1ccccc1
Solvent: Cc1ccccc1C
Product: O=C(c1ccccc1)N1C[C@H]2OCCN(Cc3ccccc3)[C@H]2C1

Procedure:
124 g (0.265 mol) of trans-1-benzoyl-3-bromo-4-(2-tosyloxyethoxy)-pyrrolidine are re-fluxed overnight with 86 g (0.8 mol) of benzylamine in 1.5 l of xylene. The benzylamine salts are suctioned off and the filtrate concentrated.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([O:10]C)=[O:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14].[OH-].[Na+]>O1CCCC1.O>[Cl:1][C:2]1[CH:7]=[C:6]([CH:5]=[C:4]([Cl:12])[C:3]=1[C:13]([O:15][CH3:16])=[O:14])[C:8]([OH:10])=[O:9]
Reactant: COC(=O)c1cc(Cl)c(C(=O)OC)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1c(Cl)cc(C(=O)O)cc1Cl
Temperature: 25 °C
Reaction time: 16 h
Yield: 79.2 %

Procedure:
To the stirred solution of dimethyl 2,6-dichlorobenzene-1,4-dicarboxylate (2 g, 7.6 mmol, Step b) in tetrahydrofuran and water (1:1, 20 mL), sodium hydroxide (304 mg, 7.6 mmol) was added and the reaction mixture was stirred at room temperature for 16 hours. The reaction mixture was concentrated under vacuum and the residue was neutralized using cold hydrochloric acid (1N). The precipitated solid was filtered under suction, washed with hexane and dried to afford 3,5-dichloro-4-(methoxycarbonyl)benzoic acid as an white solid (1.5 g, 85%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=O)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1.[F:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1/[CH:19]=[CH:20]/[CH:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:10][N:24]2[CH2:25][CH2:26][CH:21](/[CH:20]=[CH:19]/[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=3[F:12])[CH2:22][CH2:23]2)[C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COc1ncc(Cl)cc1C=O
Reactant: Fc1ccccc1/C=C/C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: COc1ncc(Cl)cc1CN1CCC(/C=C/c2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 58.2 %

Procedure:
200 mg of 5-chloro-2-methoxy-3-pyridinecarboxaldehyde and 263 mg of 4-[(E)-2-(2-fluorophenyl)-1-ethenyl]piperidine were dissolved in 5 ml of 1,2-dichloroethane. To the mixture were added 0.09 ml of acetic acid and 339 mg of sodium triacetoxyborohydride, followed by stirring at room temperature for 2.5 hours. The reaction solution was filtered through NH-form silica gel, and the filtrate was evaporated. Ethyl acetate was added to the residue, and the mixture was filtered through alumina, and the filtrate was evaporated. The crude product was purified by silica gel column chromatography (n-hexane:ethyl acetate=10:1), to give 245 mg of the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:9])[CH:5]=[C:6]([F:8])[CH:7]=1.[F:10][C:11]1[CH:18]=[CH:17][C:14]([CH2:15]Br)=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[F:1][C:2]1[CH:3]=[C:4]([O:9][CH2:15][C:14]2[CH:17]=[CH:18][C:11]([F:10])=[CH:12][CH:13]=2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: Oc1cc(F)cc(F)c1
Reactant: Fc1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: Fc1ccc(COc2cc(F)cc(F)c2)cc1
Temperature: 25 °C
Yield: 103.2 %

Procedure:
A mixture of 3,5-difluorophenol (1 1.0 g, 84.6 mmol), 4-fluorobenzylbromide (16.5 g, 84.6 mmol) and potassium carbonate (12.7 g, 92.2 mmol) in acetone (50 mL) was heated under reflux for 6 h. After cooling to room temperature, the mixture was filtered and the filtrate evaporated. The residue was dissolved in diethyl ether, washed with sodium cabonate (saturated solution), dried over sodium sulfate, filtered and evaporated to leave the title compound (20.8 g, 96%) as a light yellow liquid. MS: m/e=238.1 (M+).
Reaction SMILES: [CH3:1][N:2]([CH3:17])[C:3]1[CH:16]=[CH:15][C:6]([C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[O:8])=[CH:5][CH:4]=1.O[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25]1[NH:26][C:27]2[C:32]([CH:33]=1)=[CH:31][CH:30]=[CH:29][CH:28]=2.N>P(Cl)(Cl)(Cl)=O>[C:9]1([C:7]2([C:6]3[CH:15]=[CH:16][C:3]([N:2]([CH3:17])[CH3:1])=[CH:4][CH:5]=3)[C:33]3[C:32]4[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=4)[NH:26][C:25]=3[C:20]3[C:21](=[CH:22][CH:23]=[CH:24][CH:19]=3)[O:8]2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: CN(C)c1ccc(C(=O)c2ccccc2)cc1
Reactant: Oc1ccccc1-c1cc2ccccc2[nH]1
Agent: N
Solvent: O=P(Cl)(Cl)Cl
Product: CN(C)c1ccc(C2(c3ccccc3)Oc3ccccc3-c3[nH]c4ccccc4c32)cc1
Yield: 80.2 %

Procedure:
11.26 g of 4-dimethylaminobenzophenone and 10.5 g of 2-(2'-hydroxypenyl)-indole are stirred in 50 ml of phosphorus oxychloride for 4 hours under reflux. The reaction mixture is poured onto ice and rendered alkaline with ammonia and the resulting precipitate is then filtered off. Repeated dissolving of the residue in methanol with the addition of a little 37% strength hydrochloric acid and precipitating with ammonia and water gives a slightly impure product, which is purified through a column, packed with 80 g of silica gel/ethyl acetate. Crystallisation from ethyl acetate/ethanol gives 16.7 g of 6-phenyl-6-(4-dimethylaminophenyl)-6H-chromeno[4,3-b]-indole of the formula ##STR17## in the form of yellowish crystals with a melting point of 229°-2 31° C. On silton clay, this colour-forming agent develops a blue colour with a λ max of 600 nm.
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].C(OC(=O)[N:14]([CH2:21][CH2:22][O:23][C:24]1[CH:29]=[C:28]([C:30](=[O:44])[N:31]([CH2:35][CH2:36][C:37](=[O:43])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33])[CH:27]=[C:26]([Cl:45])[CH:25]=1)[C:15]1[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=1)(C)(C)C>ClCCl.FC(F)(F)C(O)=O>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[Cl:45][C:26]1[CH:27]=[C:28]([CH:29]=[C:24]([O:23][CH2:22][CH2:21][NH:14][C:15]2[CH:16]=[CH:17][N:18]=[CH:19][CH:20]=2)[CH:25]=1)[C:30]([N:31]([CH2:35][CH2:36][C:37](=[O:43])[N:38]([CH2:41][CH3:42])[CH2:39][CH3:40])[CH:32]([CH3:34])[CH3:33])=[O:44]
Reactant: CCN(CC)C(=O)CCN(C(=O)c1cc(Cl)cc(OCCN(C(=O)OC(C)(C)C)c2ccncc2)c1)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCN(CC)C(=O)CCN(C(=O)c1cc(Cl)cc(OCCNc2ccncc2)c1)C(C)C
Reaction time: 3 h
Yield: 84.1 %

Procedure:
A solution of (2-{3-chloro-5-[(2-diethylcarbamoyl-ethyl)-isopropyl-carbamoyl]-phenoxy}-ethyl)-pyridin-4-yl-carbamic acid tert-butyl ester trifluoroacetate (0.06 g) in a mixture of dichloromethane (2 ml) and trifluoroacetic acid (1 ml) was stored at room temperature for 3 h and then concentrated under reduced pressure to give the title compound as a colourless oil (0.043 g).