Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11](C1C=C(C3C=CC(C#N)=CC=3)C=C(F)C=1)[C:10]([CH3:32])([CH3:31])[CH2:9]2)=[O:5])C.O.[OH-].[Li+].O.Cl>CO.O1CCCC1>[CH3:31][C:10]1([CH3:32])[CH2:9][C:8]2[C:13](=[CH:14][CH:15]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=2)[NH:12][CH2:11]1
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cc(F)cc(-c3ccc(C#N)cc3)c1)N2
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC1(C)CNc2ccc(C(=O)O)cc2C1
Temperature: 60 °C
Reaction time: 12 h
Yield: 69.6 %

Procedure:
A mixture of 2-(4′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.15 g, 0.35 mmol), lithium hydroxide hydrate (0.15 g, 3.5 mmol), water (1 mL) in methanol (3 mL) and tetrahydrofuran (10 mL) was stirred at 60° C. for 12 h. The mixture was neutralized with a 3 N aqueous hydrochloric acid solution and extracted with ethyl acetate (2×50 mL), washed with water, dried over anhydrous sodium sulfate and then concentrated in vacuo. Purification by Waters automated flash system (column: Xterra 30 mm×100 mm, sample manager 2767, pump 2525, detector: ZQ mass and UV 2487, solvent system: acetonitrile and 0.1% formic acid in water) afforded 244′-cyano-5-fluoro-biphenyl-3-yl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid (50 mg, 36%) as a white solid: LC/MS m/e calcd for C25H21FN2O2 (M+H)+: 401.5, observed: 401.3.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[NH:7][N:6]=[C:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)[CH:4]=1.[CH2:20](I)[CH3:21].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH2:20]([N:7]1[C:3]([C:2]([F:18])([F:1])[F:19])=[CH:4][C:5]([C:8]2[S:12][C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:10][CH:9]=2)=[N:6]1)[CH3:21]
Reactant: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)[nH]n2)s1
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc(-c2cc(C(F)(F)F)n(CC)n2)s1
Temperature: 25 °C
Reaction time: 9 h

Procedure:
A mixture of ethyl 5-(5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate, ethyl iodide, potassium carbonate and DMF was stirred at room temperature for 9 hours. The residue obtained by a usual treatment was eluted by silica gel chromatography (eluent; n-hexane:ethyl acetate=15:1) to give ethyl 5-(1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylate as colorless needle crystals. Also, by changing the eluent of the silica gel chromatography to n-hexane:ethyl acetate=10:1, ethyl 5-(1-ethyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylate was obtained as a light yellow oil. By hydrolyzing these compounds with a base in the usual way, a) 5-(1-ethyl-5-trifluoromethyl-1H-pyrazol-3-yl)thiophene-2-carboxylic acid and b) 5-(1-ethyl-3-trifluoromethyl-1H-pyrazol-5-yl)thiophene-2-carboxylic acid were obtained.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:21])([F:20])[F:19])[N:15]=[C:14]([CH:22]=[O:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[BH4-].[Na+]>C(O)(C)C>[O:4]1[C:5]2([CH2:10][CH2:9][CH:8]([O:11][C:12]3[N:17]=[C:16]([C:18]([F:20])([F:21])[F:19])[N:15]=[C:14]([CH2:22][OH:23])[CH:13]=3)[CH2:7][CH2:6]2)[O:1][CH2:2][CH2:3]1
Reactant: O=Cc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: OCc1cc(OC2CCC3(CC2)OCCO3)nc(C(F)(F)F)n1
Temperature: 0 °C
Reaction time: 5 h

Procedure:
Into a 1-neck round-bottom flask, 6-(1,4-dioxaspiro[4.5]dec-8-yloxy)-2-(trifluoromethyl)pyrimidine-4-carbaldehyde (3.00 g, 9.03 mmol) was dissolved in isopropyl alcohol (40 mL) and cooled to 0° C. To this solution, NaBH4 (0.27 g, 7.2 mmol) was added, and the reaction was stirred for 5 hours until LCMS analysis of the reaction mixture showed no starting material present. The reaction was transferred to a separatory funnel and partitioned between water and EtOAc, the phases were separated and the aqueous phase was washed with EtOAc. The combined organic phase was washed with water, then saturated NaCl, dried over MgSO4 and filtered and stripped to dryness to leave the crude product. MS (ES): 335 (M+1).
Reaction SMILES: Cl.[O:2]=[C:3]1[N:12]([CH2:13][CH2:14][CH2:15][N:16]([CH2:20][CH2:21][CH2:22][CH2:23][NH:24][CH2:25][CH2:26][CH2:27][N:28]2[C:37](=[O:38])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]2=[O:39])[C:17](=[O:19])[CH3:18])[C:11](=[O:40])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4]1.Cl[C:42]([O:44][CH2:45][CH3:46])=[O:43].C(OC(=O)C)(=O)C>ClCCl.N1C=CC=CC=1>[CH2:45]([O:44][C:42](=[O:43])[N:24]([CH2:23][CH2:22][CH2:21][CH2:20][N:16]([C:17](=[O:19])[CH3:18])[CH2:15][CH2:14][CH2:13][N:12]1[C:11](=[O:40])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[NH:4][C:3]1=[O:2])[CH2:25][CH2:26][CH2:27][N:28]1[C:37](=[O:38])[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[NH:30][C:29]1=[O:39])[CH3:46]
Reactant: CC(=O)N(CCCCNCCCn1c(=O)[nH]c2ccccc2c1=O)CCCn1c(=O)[nH]c2ccccc2c1=O
Reactant: CCOC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CCOC(=O)N(CCCCN(CCCn1c(=O)[nH]c2ccccc2c1=O)C(C)=O)CCCn1c(=O)[nH]c2ccccc2c1=O

Procedure:
In the above Example 4, hydrochloric acid salt of N-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propyl]-N-{4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butyl}acetamide 3 g (5.3 mmol) and ethyl chloroformate 0.6 mL (6.3 mmol) were used, instead of 3-(3-4-[3-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)propylamino]butylaminopropyl)-1H-quinazoline-2,4-dione and acetic anhydride. The same procedure of the above Example 4 was performed to give the title compound of white solid (1.1 g, 34%) in the mix-solvent of pyridine and dichloromethane.
Reaction SMILES: O1CCCC1.B.CS(O)(=O)=O.[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH:14]=[C:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25].N>O>[O:12]=[C:13]([N:27]1[CH2:32][CH2:31][N:30]2[C:33]([C:36]([F:39])([F:38])[F:37])=[N:34][N:35]=[C:29]2[CH2:28]1)[CH2:14][CH:15]([NH2:26])[CH2:16][C:17]1[CH:22]=[C:21]([F:23])[C:20]([F:24])=[CH:19][C:18]=1[F:25]
Reactant: NC(=CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Agent: B
Agent: CS(=O)(=O)O
Agent: N
Solvent: O
Solvent: C1CCOC1
Product: NC(CC(=O)N1CCn2c(nnc2C(F)(F)F)C1)Cc1cc(F)c(F)cc1F
Temperature: -10 °C
Reaction time: 1 h

Procedure:
In a 250 mL round bottom flask 1.0 M Borane tetrahydrofuran (37 mL) was taken. It was cooled to −10° C. and TEA (5.15 mL) was added dropwise at −10 to 5° C. After 30 min. methanesulfonic acid (6.0 mL) was added dropwise at −10 to 5° C. over a period of 15-30 min. 4-oxo-4-[3-(trifluoromethyl)-5,6-dihydro[1,2,4]triazolo[4,3-a]pyrazin-7(8H)-yl]-1-(2,4,5-trifluorophenyl)but-2-en-2-amine (5.0 g) was added in small portions into the reaction mixture, keeping the temperature between −10 to −5° C. It was stirred for 1 h at −10 to −5° C. Reaction mixture was poured into cold water. It was basified by adding aq. ammonia solution. Product was extracted in ethyl acetate. The organic layer was collected. It was washed with water and dried over anhydrous sodium sulfate. Solvent was evaporated at reduced pressure to obtain the product. (Wt.-4.2 g; % Y-83.6%; % Purity by HPLC-31%).
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:30][CH2:29][CH:28]([NH2:31])[CH2:27][CH2:26]3)=[N:19]2)=[CH:14][CH:13]=1.[N+:32]([C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][C:36]=1[S:41](Cl)(=[O:43])=[O:42])([O-:34])=[O:33]>ClCCl>[CH3:10][O:11][C:12]1[CH:21]=[C:20]2[C:15]([N:16]=[CH:17][C:18]([S:22][CH2:23][CH2:24][N:25]3[CH2:26][CH2:27][CH:28]([NH:31][S:41]([C:36]4[CH:37]=[CH:38][CH:39]=[CH:40][C:35]=4[N+:32]([O-:34])=[O:33])(=[O:42])=[O:43])[CH2:29][CH2:30]3)=[N:19]2)=[CH:14][CH:13]=1
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Reactant: COc1ccc2ncc(SCCN3CCC(N)CC3)nc2c1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc2ncc(SCCN3CCC(NS(=O)(=O)c4ccccc4[N+](=O)[O-])CC3)nc2c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
N,N-Diisopropylethylamine (318 μL, 1.82 mmol, 2.5 eq) is added at room temperature to a stirred solution of 1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-ylamine (237 mg, 0.73 mmol, 1.0 eq) in dichloromethane (4 mL), followed by 2-nitro-benzenesulfonyl chloride (183 mg, 0.80 mmol, 1.1 eq). After 2 hours stirring at room temperature, the reaction mixture is extracted with dichloromethane (3×10 mL) and water (10 mL). The combined organic layers are dried over sodium sulfate, filtered and concentrated to give a residue that is purified by column chromatography (silica gel, eluent: ethyl acetate 100%) to afford N-{1-[2-(7-methoxy-quinoxalin-2-ylsulfanyl)-ethyl]-piperidin-4-yl}-2-nitro-benzenesulfonamide as a yellow waxy solid (307 mg, 82% yield).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][C:3]=1[CH3:9].[C:10](OC(=O)C)(=[O:12])[CH3:11]>[OH-].[Na+]>[C:10]([O:8][C:5]1[CH:6]=[CH:7][C:2]([Br:1])=[C:3]([CH3:9])[CH:4]=1)(=[O:12])[CH3:11]
Reactant: Cc1cc(O)ccc1Br
Reactant: CC(=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)Oc1ccc(Br)c(C)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A stirred mixture of 4-bromo-3-methylphenol (184.1 g) and aqueous NaOH (850 ml, 2M) at 20° C. is treated with acetic anhydride (136 ml) and stirred at room temperature for 1 h. The suspension is extracted with diethyl ether (3×300 ml) and the combined extracts are washed with aqueous NaOH (2×100 ml 2M), dried (Na2SO4) and filtered. The solvent is evaporated off under reduced pressure to yield the title compound as an oil.
Reaction SMILES: [Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([OH:16])[CH:10]=3.[CH2:28](Cl)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[S:12][C:11]3[C:6]4=[C:7]([C:17](=[O:27])[C:18]([CH2:20][C:21]5[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=5)=[CH:19][N:5]4[C:4]=2[CH:3]=1)[CH:8]=[C:9]([O:16][CH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[CH:10]=3
Reactant: O=c1c(Cc2cccnc2)cn2c3c(cc(O)cc13)Sc1ccc(Br)cc1-2
Reactant: ClCc1ccccc1
Product: O=c1c(Cc2cccnc2)cn2c3c(cc(OCc4ccccc4)cc13)Sc1ccc(Br)cc1-2
Yield: 48 %

Procedure:
According to Example 34, the compound (100 mg) produced in Example 37 was reacted with benzyl chloride (39 μl) to obtain the title compound (58 mg; 48%).
Reaction SMILES: C1(C(=[N:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])C2C=CC=CC=2)C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C)C=CC=CC=1.Br[CH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:50][C:49]([CH3:52])([CH3:51])[C:48]([CH3:54])([CH3:53])[O:47]2)=[C:42]([F:55])[CH:41]=1>C1COCC1.O.Cl>[NH2:14][CH:15]([CH2:39][C:40]1[CH:45]=[CH:44][C:43]([B:46]2[O:50][C:49]([CH3:52])([CH3:51])[C:48]([CH3:54])([CH3:53])[O:47]2)=[C:42]([F:55])[CH:41]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)CN=C(c1ccccc1)c1ccccc1
Reactant: CC1(C)OB(c2ccc(CBr)cc2F)OC1(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [K+]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C(N)Cc1ccc(B2OC(C)(C)C(C)(C)O2)c(F)c1
Temperature: -20 °C
Reaction time: 0.25 h
Yield: 46.9 %

Procedure:
To a stirred solution of ethyl 2-((diphenylmethylene)amino)acetate (300 mg, 1.12 mmol) in anhydrous THF (3 mL) at −78° C. was added 0.5 M KHMDS in toluene (2.46 mL, 1.23 mmol). After stirring for 15 min, 2-(4-(bromomethyl)-2-fluorophenyl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (353 mg, 1.12 mmol) was added. The reaction mixture was stirred at −78° C. for 3 h and warmed to −20° C. To the mixture was added 6 N Hydrochloric acid (0.5 mL) and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with water (5 mL) and 1 N HCl (5 mL) and then extracted with diethyl ether. The aqueous layer was basified with 1N NaOH and then extracted with EtOAc (3×10 mL). The combined organic extract was washed with water, brine and then dried over MgSO4. Filtration and concentration gave 177 mg (46%) of ethyl 2-amino-3-(3-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)propanoate which was used in the next step without purification. LCMS-ESI (m/z) calculated for C17H25BFNO4: 337.2. found 338.2 [M+H]+, tR=2.78 min (Method 1).
Reaction SMILES: N[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([O:16]CC)=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.N([O-])=O.[Na+].[BrH:23]>O>[Br:23][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Br
Reactant: CCOC(=O)C1CCN(c2ccc(N)cc2)CC1
Agent: O=N[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)C1CCN(c2ccc(Br)cc2)CC1
Reaction time: 0.25 h

Procedure:
To a solution of ethyl 1-(4-aminophenyl)piperidine-4-carboxylate (2.48 g, 10 mmol) in 40 mL of HBr 40%, a solution of NaNO2 (0.69 g, 10 mmol) in 7 mL of water was slowly added at 0° C. The mixture was stirred for 15 minutes and added to a solution of CuBr (0.79 g, 5.5 mmol) in 30 mL of HBr 40%. The resulting mixture was stirred and refluxed for 2 hours. The suspension thus obtained was partitioned between 2N NaOH and ethyl acetate. The organic layer was washed with aqueous NaCl, dried over Na2SO4 and concentrated to afford crude title compound 1.56 g. MS (m/z): 286 (M+2)+
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)=[CH:13][C:12]([CH2:23][N:24]([CH3:34])[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:35]1[CH2:39][C:38](=[O:40])[NH:37][C:36]1=[O:41]>>[CH2:1]([O:8][C:9]1[C:14]([C:15]2[CH:16]=[CH:17][C:18]([CH:21]=[C:39]3[S:35][C:36](=[O:41])[NH:37][C:38]3=[O:40])=[CH:19][CH:20]=2)=[CH:13][C:12]([CH2:23][N:24]([CH3:34])[C:25](=[O:33])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=O)cc2)c1
Reactant: O=C1CSC(=O)N1
Product: CCCCCCCC(=O)N(C)Cc1ccc(OCc2ccccc2)c(-c2ccc(C=C3SC(=O)NC3=O)cc2)c1

Procedure:
In a manner similar to that of Example 1(f), by reacting 11.5 g (22 mmol) of N-(6-benzyloxy-4′-formylbiphenyl-3-ylmethyl)-N-methyloctanamide and 2.5 g (22 mmol) of 2,4-thiazolidine dione, the expected product is obtained in the form of a pale yellow powder with a melting point of 162° C.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].N1C=CN=C1>CN(C)C=O>[Si:14]([O:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([CH:12]=[O:13])=[CH:4][CH:3]=1)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=Cc1ccc(O)c2ccccc12
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C=O)c2ccccc12

Procedure:
4-Hydroxynaphthalene-1-carbaldehyde (2.00 g, 11.63 mmol), tert-butyldimethylsilyl chloride (1.93 g, 12.80 mmol), imidazole (983 mg, 15.12 mmol) and N,N-dimethylaminopyridine (4 mg) in N,N-dimethylformamide (20 ml) were stirred at RT for 20 h. The solvent was removed and the mixture suspended in ethyl acetate (20 ml) and washed with water (20 ml). The aqueous phase was extracted with ethyl acetate (20 ml) and the combined organics washed with brine (2×20 ml) and dried (MgSO4). The solvent was removed leaving the product as a brown oil which solidified on standing.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:3]=1.[OH-].[Na+].C(=O)(O)[O-:19].[Na+]>S(=O)(=O)(O)O.O>[Cl:1][C:2]1[C:7]([C:8]([NH2:9])=[O:19])=[C:6]([CH3:10])[CH:5]=[C:4]([N:11]2[CH:15]=[CH:14][N:13]=[CH:12]2)[N:3]=1
Reactant: Cc1cc(-n2ccnc2)nc(Cl)c1C#N
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cc1cc(-n2ccnc2)nc(Cl)c1C(N)=O
Temperature: 25 °C

Procedure:
A solution of 2-chloro-3-cyano-6-(imidazol-1-yl)-4-methylpyridine (2.1 g) in concentrated sulfuric acid (5 mL) was heated at 130° C. for 15 minutes. The mixture was cooled to room temperature, diluted with water (10 mL), and adjusted to pH 7 with 20% sodium hydroxide solution followed by solid sodium bicarbonate. The crystalline product was removed by filtration and dried to give 2.35 g of the title compound, suitable for use in the next reaction.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.Br[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[O:8][CH2:10][CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14]
Reactant: Oc1cccc(F)c1
Reactant: CCOC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(F)c1
Temperature: 25 °C
Yield: 99.1 %

Procedure:
A mixture of 3-fluorophenol (6.00 g, 53.5 mmol), ethyl 4-bromobutanoate (15.70 g, 80.5 mmol) and Cs2CO3 (26.20 g, 80.4 mmol) in DMF (25 mL) under N2 was refluxed overnight. The mixture was then cooled to rt and 150 mL of water was added. The resulting mixture was extracted with DCM (100 mL×2) and the combined organic phases were washed with brine (100 mL×2), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=10:1) to give the title compound as colorless oil (12.0 g, 99%).
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9])=[O:2].[BH4-].[Na+].C(OCC)(=O)C.O>CO>[OH:2][CH2:1][C:3]1[CH:4]=[C:5]([CH:13]=[CH:14][CH:15]=1)[O:6][C@H:7]([CH3:12])[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)[C@@H](C)Oc1cccc(C=O)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](C)Oc1cccc(CO)c1
Reaction time: 0.5 h

Procedure:
2.50 g of 3-hydroxybenzaldehyde, 2.77 g of methyl L-(−)-lactate, and 6.44 g of triphenylphosphine were dissolved in 25.0 mL of THF, and 22.2 mL of a 2.2 M diethyl azodicarboxylate/toluene solution was added thereto under ice-cooling, followed by stirring at room temperature overnight. To the reaction liquid was added an aqueous saturated sodium hydrogen carbonate solution, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3 to 1:1) to obtain 1.67 g of methyl (2R)-2-(3-formylphenoxy)propionate. The obtained methyl (2R)-2-(3-formylphenoxy)propionate was dissolved in 33.3 mL of methanol, and 394 mg of sodium borohydride was added thereto under ice-cooling, followed by stirring for 30 minutes. To the reaction liquid were added ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure to obtain 1.68 g of methyl (2R)-2-[3-(hydroxymethyl)phenoxy]propionate.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][CH:16]=[CH:15][CH:14]=4)=[CH:4][CH:3]=1.[C:24](Cl)(=[O:27])[CH2:25][CH3:26]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:21](=[O:22])[N:20]([CH3:23])[C:11]3[N:12]([CH3:19])[C:13]4[C:18]([C:10]=3[CH:9]=2)=[CH:17][C:16]([C:24](=[O:27])[CH2:25][CH3:26])=[CH:15][CH:14]=4)=[CH:6][CH:7]=1
Reactant: CCC(=O)Cl
Reactant: Cn1c(=O)c(-c2ccc(F)cc2)cc2c3ccccc3n(C)c21
Product: CCC(=O)c1ccc2c(c1)c1cc(-c3ccc(F)cc3)c(=O)n(C)c1n2C

Procedure:
The process is carried out as indicated in preparation 1.1E above, with compound from Example 63A, 3-(4-fluorophenyl)-1,9-dimethyl-1,9-dihydropyrido[2,3-b]indol-2-one and propionyl chloride
Reaction SMILES: [N:1]1([CH2:6][CH:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[C:14]1[CH:21]=[CH:20][C:17]([CH:18]=[O:19])=[CH:16][C:15]=1[N+:22]([O-:24])=[O:23]>>[N+:22]([C:15]1[CH:16]=[C:17]([CH:20]=[CH:21][C:14]=1[N:10]1[CH2:11][CH2:12][CH:7]([CH2:6][N:1]2[CH2:5][CH2:4][CH2:3][CH2:2]2)[CH2:8][CH2:9]1)[CH:18]=[O:19])([O-:24])=[O:23]
Reactant: C1CCN(CC2CCNCC2)C1
Reactant: O=Cc1ccc(F)c([N+](=O)[O-])c1
Product: O=Cc1ccc(N2CCC(CN3CCCC3)CC2)c([N+](=O)[O-])c1

Procedure:
Prepared from the product of Example 4 and 4-fluoro-3-nitro-benzaldehyde.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13]O)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH2:13][Br:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc(OCc2ccccc2)cc1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: BrCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 92.6 %

Procedure:
To 4-benzyloxybenzyl alcohol (8.1 g, 37.8 mmol) in dichloromethane (160 mL) was added N-bromosuccinimide (7.4 g, 41.6 mmol) followed by portionwise addition of triphenylphosphine (10.9 g, 41.6 mmol). The reaction mixture was stirred at room temperature for 5 minutes, and was then concentrated in vacuo. Purification by flash chromatography, eluting with 80:20 hexanes/ethyl acetate, provided 9.7 g (92%) of 1 as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([C:12](O)=[O:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN1CCOCC1.ClC(OCC)=O.[BH4-].[Na+]>O1CCCC1.CO>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH2:15][CH:11]([CH2:12][OH:13])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)CC1
Agent: CCOC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC(C)(C)OC(=O)N1CCC(CO)CC1
Reaction time: 0.5 h
Yield: 92.4 %

Procedure:
A solution of 1-tert-butoxycarbonyl isonipecotic acid (40 g, 0.17 mol) and N-methylmorpholine (19 mL, 0.17 mol) in tetrahydrofuran (900 mL) at −10° C. was treated with ethyl chloroformate (17 mL, 0.17 mol). After 0.5 h, sodium borohydride was added (19.8 g, 0.5 mol) in one portion followed by slow addition of methanol. After gas evolution ceased, the mixture was concentrated and the residue was diluted with 10% aqueous acetic acid and partitioned between ethyl acetate and water. The aqueous layer was washed with EtOAc (2×) and the combined organic extracts were dried with magnesium sulfate, filtered, and concentrated to a solid residue which was purified by column chromatography (SiO2: 10 to 50% EtOAc:hexanes) providing the title compound (33.8 g, 90%) as a white solid.
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.[CH:13]([B-](F)(F)F)=[CH2:14].[K+].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C([O-])([O-])=O.[Cs+].[Cs+]>Cl[Pd]Cl.O.C1COCC1>[CH:13]([C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1)=[CH2:14]
Reactant: C=C[B-](F)(F)F
Reactant: O=Cc1c[nH]c2cc(Br)ccc12
Agent: Cl[Pd]Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: O
Product: C=Cc1ccc2c(C=O)c[nH]c2c1
Temperature: 85 °C

Procedure:
6-bromoindole-3-carboxaldehyde (5 g, 22.3 mmol), potassium vinyltrifluoroborate (4.48 g, 33.5 mmol), PdCl2 (396 mg, 2.23 mmol), PPh3 (1.75 mg, 6.7 mmol) and Cs2CO3 (2.18 mg, 66.9 mmol) were combined in a 500 mL flask placed under a nitrogen atmosphere. THF (135 mL) and H2O (15 mL) were added and the yellow solution was heated at 85° C. for 2 days. The reaction was allowed to cool to RT, water was added and the mixture was extracted twice with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered and concentrated. The crude residue was purified by flash column chromatography on silica gel (c-hexane to c-hexane/EtOAc 1:1) to give the title compound. TLC, Rf (c-hexane/EtOAc 1:1)=0.4; MS (LC/MS): 172.0 [M+H]+ 170.1 [M−H]−; tR (HPLC conditions a): 2.95 min.