Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH:13]([CH:14]3[CH2:16][CH2:15]3)[O:12][C:11](=[O:17])[NH:10]2)[CH:5]=[CH:6][C:7]=1[F:8].C([Li])CCC.CCCCCC.[CH:29]1[C:34]([N+:35]([O-:37])=[O:36])=[CH:33][CH:32]=[C:31]([Cl-]C([O-])=O)[CH:30]=1.[C:42](=O)([OH:44])[O-:43].[Na+]>C1COCC1>[N+:35]([C:34]1[CH:29]=[CH:30][C:31]([O:44][C:42]([N:10]2[CH:9]([C:4]3[CH:5]=[CH:6][C:7]([F:8])=[C:2]([F:1])[CH:3]=3)[CH:13]([CH:14]3[CH2:15][CH2:16]3)[O:12][C:11]2=[O:17])=[O:43])=[CH:32][CH:33]=1)([O-:37])=[O:36]
Reactant: O=C([O-])O
Reactant: O=C1NC(c2ccc(F)c(F)c2)C(C2CC2)O1
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1C(=O)OC(C2CC2)C1c1ccc(F)c(F)c1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-(3,4-difluorophenyl)-5-cyclopropyl-oxazolidin-2-one (2 g, 8.3 mmol) in 100 mL THF was added a solution of n-butyllithium in hexane (9.1 mmol) dropwise via a syringe under an argon atmosphere at −78° C. The resulting yellow solution was stirred at −78° C. for 10 min. To this solution was then added dropwise via syringe 4-nitrophenylchloroformate (1.03 g, 5.1 mmol) in 20 mL of THF. The reaction was stirred at −78° for 10 min. The reaction mixture was poured into saturated sodium bicarbonate and extracted with ethyl acetate (2×200 mL). The organic extracts were washed with brine, and the organic layer was dried over Na2SO4. The solvent was removed after filtration, and the residue was purified by column chromatography on silica gel 30% ethyl acetate hexane. The material was rechromatographed on silica gel eluting with 2% acetone/methylene chloride ti) give 1.2 g the product as a thick syrup which solidified upon standing.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2)#[N:2].[H-].[Na+].[Cl:15][C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1.Cl>CN(C=O)C.O>[ClH:15].[C:1]([C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH:6]2[C:16]1[C:25]2[C:20](=[CH:21][C:22]([O:28][CH2:29][CH2:30][CH2:31][N:32]3[CH2:33][CH2:34][O:35][CH2:36][CH2:37]3)=[C:23]([O:26][CH3:27])[CH:24]=2)[N:19]=[CH:18][N:17]=1)#[N:2]
Reactant: N#Cc1ccc2c(c1)CC(=O)N2
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(C3C(=O)Nc4ccc(C#N)cc43)ncnc2cc1OCCCN1CCOCC1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 53.8 %

Procedure:
A solution of 5-cyanooxindole (213 mg, 1.35 mmol), (Tet. Lett., 1987, 28, 4027), in DMF (3 ml) was added dropwise to a suspension of sodium hydride (54 mg, 1.35 mmol, prewashed with hexane) in DMF (2 ml). The mixture was stirred for 20 minutes at ambient temperature, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (152 mg, 0.45 mmol), (prepared as described for the starting material in Example 5), was added and the mixture was heated at 70° C. for 1 hour. The mixture was allowed to cool and then was diluted with water and adjusted to pH1 with 2M hydrochloric acid. The solution was washed with ether and then basified with aqueous sodium hydrogen carbonate solution. The resulting precipitate was collected by filtration, washed with water, ether and dried under vacuum. The solid was purified by flash chromatography eluting with methylene chloride/methanol (90/10 followed by 80/20). The purified solid was dissolved in methylene chloride/methanol and 5M methanolic hydrogen chloride (0.5 ml) was added. The solution was concentrated by evaporation to a total volume of 2 ml and ether (15 ml) was added. The resulting solid was collected by filtration, washed with ether and dried under vacuum to give 4-(5-cyanooxindol-3-yl)-6-methoxy-7-(3-morpholinopropoxy)quinazoline hydrochloride (120 mg, 50%).
Reaction SMILES: [SH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[K+].Cl[CH:14]([OH:16])[CH3:15]>CO>[OH:16][CH2:14][CH2:15][S:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1
Reactant: CC(O)Cl
Reactant: O=C(O)c1ccc(S)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)c1ccc(SCCO)cc1
Yield: 62566.4 %

Procedure:
To a stirred solution of 4-mercapto benzoic acid (10 g, 0.0645 mmol) in methanol (100 mL) was added KOH (10.8 g, 0.1935 mol) at 25-30° C. Chloroethanol (10.3 g, 0.1290 mol) was then added to it. Reaction mixture was refluxed for 4 hr. Excess methanol was evaporated and then quenched in dil.HCl. Product obtained was filtered. Drying afforded 8 g of titled compound in 62% yield.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(=O)([O-])[O-].[Cs+].[Cs+].Cl.[N:43]1[CH:48]=[CH:47][CH:46]=[C:45]([CH2:49]Cl)[CH:44]=1.O>C(#N)C>[Cl:1][C:2]1[C:10]([O:11][CH2:49][C:45]2[CH:44]=[N:43][CH:48]=[CH:47][CH:46]=2)=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: ClCc1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2cc(OCc3cccnc3)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 50 °C
Reaction time: 12 h
Yield: 60 %

Procedure:
4-Chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (70.0 mg, 0.141 mmol) was suspended in acetonitrile (3.5 mL), and the suspension was added with cesium carbonate (91.9 mg, 0.282 mmol) and 3-pyridylmethyl chloride hydrochloride (23.1 mg, 0.141 mmol), followed by stirring at 50° C. for 12 hours under nitrogen atmosphere. The reaction mixture was added with water. The obtained solid was collected by filtration and washed with water, followed by drying under reduced pressure to obtain 4-chloro-5-(3-pyridylmethoxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (49.7 mg, yield 60%).
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14](Br)=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.C([O-])(=O)CC([O-])=O.CC(C)(O[Mg+2])C.[C:37]([O:44][CH3:45])(=[O:43])[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CCOCC>[CH3:42][O:41][C:39](=[O:40])[CH:38]([C:14](=[O:15])[CH:13]([O:12][C:11]1[CH:18]=[CH:19][C:8]([O:7][C:6]2[CH:20]=[CH:21][C:3]([C:2]([F:23])([F:22])[F:1])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1)[CH3:17])[C:37]([O:44][CH3:45])=[O:43]
Reactant: COC(=O)CC(=O)OC
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)Br
Agent: CC(C)(C)O[Mg+2]
Agent: O=C([O-])CC(=O)[O-]
Solvent: CCOCC
Product: COC(=O)C(C(=O)OC)C(=O)C(C)Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1
Yield: 83.8 %

Procedure:
A 50% etheral solution of 39 g of 2-[4'-(4"-trifluoromethyl-phenoxy)-phenoxy]-propionyl-bromide is added dropwise under stirring to a mixture of dimethyl-ethoxy-magnesium-malonate prepared from 14.5 g of dimethyl malonate and 50 ml of ether. The addition of the acid bromide having been completed the reaction mixture is heated to boiling for an hour and worked up as described in Example 1. Thus 37 g of the desired compound are obtained in the form of a yellow viscous oil which solidifies on standing, mp.: 40°-44° C. Yield 84%.
Reaction SMILES: CO[CH2:3][N:4]([CH2:11][CH2:12][CH3:13])[CH2:5][CH2:6][Si](C)(C)C.[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]=C)=[N:19][CH:20]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Br:14][C:15]1[CH:16]=[N:17][C:18]([CH:21]2[CH2:6][CH2:5][N:4]([CH2:11][CH2:12][CH3:13])[CH2:3]2)=[N:19][CH:20]=1
Reactant: C=Cc1ncc(Br)cn1
Reactant: CCCN(CC[Si](C)(C)C)COC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCN1CCC(c2ncc(Br)cn2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 35.3 %

Procedure:
Methoxymethyl-propyl-trimethylsilanylethyl-amine (14.13 g, 74.61 mmol) in CH2Cl2 (4 ml) was added dropwise to a 0° C. cooled solution of 5-bromo-2-vinyl-pyrimidine (2 g, 10.80 mmol) and TFA (210 μl, 2.72 mmol) in CH2Cl2 (45 ml) over a period of 20 min. The reaction mixture was then stirred at room temperature for 2 h. The crude material was diluted with CH2Cl2, washed with saturated aqueous NaHCO3 and the organic layer was dried over Na2SO4 and evaporated. The residue was chromatographied on silica gel (CH2Cl2:methanol, 97:3) to afford the title compound (1.03 g, 34%) as a brown oil.
Reaction SMILES: [CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[NH:15][C:16](=[O:23])[C:17]4[CH:18]=[CH:19][CH:20]=[N:21][C:22]=4[C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]>C(O)C.ClCCl.[Pd]>[CH2:1]([N:4]1[CH2:9][CH2:8][CH:7]([O:10][C:11]2[CH:25]=[CH:24][C:14]3[NH:15][C:16](=[O:23])[C:17]4[CH2:18][CH2:19][CH2:20][NH:21][C:22]=4[C:13]=3[CH:12]=2)[CH2:6][CH2:5]1)[CH2:2][CH3:3]
Reactant: CCCN1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCO
Product: CCCN1CCC(Oc2ccc3[nH]c(=O)c4c(c3c2)NCCC4)CC1
Reaction time: 24 h
Yield: 91.1 %

Procedure:
The compound (30 mg, 0.09 mmol) prepared in step 5 was dissolved in ethanol (4 ml)/dichloromethane (2 ml), added with 10%-palladium (Pd) (6 mg) at room temperature. The resulting mixture was stirred for one day under hydrogen gas. By using celite, 10%-palladium (Pd) was removed and the filtrate was concentrated under reduced pressure. Elthyl acetate was added and the precipitate was collected by filtration to obtain the title compound (28 mg, yield: 92%, white solid).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1.BrC1C=CC(I)=C(S(C)(=O)=O)C=1.[CH3:30][O:31]C1C=CC(B(O)O)=CC=1>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:31][CH3:30])=[CH:10][CH:9]=2)=[C:4]([S:14]([CH3:17])(=[O:16])=[O:15])[CH:3]=1
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccccc1
Reactant: COc1ccc(B(O)O)cc1
Agent: CS(=O)(=O)c1cc(Br)ccc1I
Product: COc1ccc(-c2ccc(Br)cc2S(C)(=O)=O)cc1
Yield: 73 %

Procedure:
Following the general method as outlined in Intermediate 203, starting from 4-bromo-1-iodo-2-(methylsulfonyl)benzene (Intermediate 202) and 4-methoxyphenylboronic acid, the title compound was obtained as a brown solid in 73% yield after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[CH:8][NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.[H-].[Na+].[CH2:13](Cl)[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C1COCC1.CCOC(C)=O>[CH2:15]([O:14][CH2:13][N:7]1[C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([CH3:1])[C:10]=2[N:9]=[CH:8]1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: ClCOCc1ccccc1
Reactant: Cc1cccc2[nH]cnc12
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cccc2c1ncn2COCc1ccccc1
Reaction time: 0.08 h
Yield: 24.2 %

Procedure:
To a solution of Intermediate 171.1 (130 mg, 0.984 mmol) in 3 mL THF at rt, was added sodium hydride (60%, 43 mg, 1.1 mmol). The mixture was stirred 5 min, then BOM-Cl (80%, 0.204 mL, 1.18 mmol) was added. The mixture was stirred at rt for 2 h, then was diluted with EtOAc, washed with H2O (2×) and brine, dried (Na2SO4) and concentrated. The crude product was purified by flash chromatography (0 to 100% EtOAc/hexanes gradient) to afford 60 mg of Intermediate 171.2.
Reaction SMILES: Br.[CH2:2]([CH:4]1[O:9][CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16]C)[CH:11]=2)[CH2:7][N:6]([CH2:18][CH2:19][CH3:20])[CH2:5]1)[CH3:3]>ClCCl.CO>[CH2:2]([CH:4]1[CH2:5][N:6]([CH2:18][CH2:19][CH3:20])[CH2:7][CH:8]([C:10]2[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=2)[O:9]1)[CH3:3]
Reactant: CCCN1CC(CC)OC(c2cccc(OC)c2)C1
Agent: Br
Solvent: CO
Solvent: ClCCl
Product: CCCN1CC(CC)OC(c2cccc(O)c2)C1
Yield: 68.4 %

Procedure:
Hydrobromic acid (48% aq., 5 mL) and the product from example 46A (0.10 g, 0.38 mmol) were heated at 80° C. for 16 hours. After cooling the reaction mixture was concentrated in vacuo. The residue was partitioned between aqueous ammonia (0.880, 15 mL) and dichloromethane (15 mL), the layers were separated and the aqueous layer re-extracted with dichloromethane (2×15 mL). The organic extracts were combined, dried over anhydrous magnesium sulphate, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica eluting with dichloromethane, then dichloromethane:methanol (99:1 to 95:5) to yield the title compound as a clear oil (65 mg, 0.26 mmol, 69%) as the single diastereoisomer. 1H NMR (CDCl3, 400 MHz) δ: 0.95 (m 6H), 1.60 (m, 3H), 1.85 (m, 1H), 2.25 (m, 2H), 2.45 (m, 2H), 2.55 (q, 1H), 2.75 (d, 1H), 3.75 (s, 1H), 4.80 (m, 1H), 6.70 (d, 1H), 6.90 (s, 1H), 7.00 (1H, d), 7.25 (t, 1H). LRMS (APCl): m/z 250 (MH+). Analysis found C, 70.94%; H, 9.16%; N, 5.53%. C15H23NO2.0.3H2O requires C, 70.72%; H, 9.34%; N, 5.50%.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH2:9][C:10]1[CH:14]=[C:13]([S:15]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]#[N:25])[CH:19]=2)(=[O:17])=[O:16])[N:12]([C:26]2[C:27]([F:32])=[N:28][CH:29]=[CH:30][CH:31]=2)[N:11]=1)C)(C)(C)C.C(OCC)(=O)C.[ClH:40]>C(OCC)(=O)C.CC(O)C>[ClH:40].[F:32][C:27]1[C:26]([N:12]2[C:13]([S:15]([C:18]3[CH:19]=[C:20]([CH:21]=[CH:22][CH:23]=3)[C:24]#[N:25])(=[O:16])=[O:17])=[CH:14][C:10]([CH2:9][NH:7][CH3:6])=[N:11]2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: CN(Cc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CC(C)O
Solvent: CCOC(C)=O
Product: CNCc1cc(S(=O)(=O)c2cccc(C#N)c2)n(-c2cccnc2F)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 86 %

Procedure:
tert-Butyl({5-[(3-cyanophenyl)sulfonyl]-1-(2-fluoropyridin-3-yl)-1H-pyrazol-3-yl}methyl)methylcarbamate (247 mg) was dissolved in ethyl acetate (2 mL) and 2-propanol (1 mL), and 4 mol/L hydrogen chloride-ethyl acetate solution (3 mL) was added. After stirring at room temperature for 3 hr, the reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from a mixed solvent of ethanol and water to give the title compound as colorless crystals (yield 184 mg, yield 86%). melting point 237-240° C.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH:14]=O)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:49][CH2:48][O:47][CH2:46][CH2:45]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[N:21]=2)=[O:19])=[CH:4][CH:3]=1.[CH3:50][N:51]1[CH2:56][CH2:55][NH:54][CH2:53][CH2:52]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([CH2:14][N:54]3[CH2:55][CH2:56][N:51]([CH3:50])[CH2:52][CH2:53]3)[CH:9]=2)=[CH:6][C:5]([CH2:16][NH:17][C:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([NH:28][CH2:29][C:30]3[C:31]([NH:43][CH:44]4[CH2:45][CH2:46][O:47][CH2:48][CH2:49]4)=[C:32]4[CH:40]=[N:39][N:38]([CH2:41][CH3:42])[C:33]4=[N:34][C:35]=3[CH2:36][CH3:37])=[O:27])[N:21]=2)=[O:19])=[CH:4][CH:3]=1
Reactant: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(C=O)c3)c2)n1
Reactant: CN1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1nc2c(cnn2CC)c(NC2CCOCC2)c1CNC(=O)c1cccc(C(=O)NCc2ccc(Cl)c(-c3cccc(CN4CCN(C)CC4)c3)c2)n1
Temperature: 25 °C
Yield: 33.6 %

Procedure:
A mixture of N-[(6-chloro-3′-formyl-3-biphenylyl)methyl]-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide (50 mg, 0.074 mmol), 1-methylpiperazine (7.36 mg, 0.074 mmol), sodium triacetoxyborohydride (31.2 mg, 0.147 mmol) and acetic acid (5.05 μL, 0.088 mmol) in DCM (1 mL) was stirred at room temperature over the weekend. The reaction mixture was quenched with saturated NaHCO3, and extracted with DCM twice. The combined organic layers were concentrated under vacuum to give a crude residue. It was purified with a Gilson HPLC (with 0.1% TFA in the solvents), eluting with 10 to 70% CH3CN in water at a flow rate of 20 mL/min. The product fractions were combined, converted to the free base with saturated NaHCO3 and the basified solution was extracted with ethyl acetate twice. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and then concentrated under vacuum to give N-({6-chloro-3′-[(4-methyl-1-piperazinyl)methyl]-3-biphenylyl}methyl)-N′-{[1,6-diethyl-4-(tetrahydro-2H-pyran-4-ylamino)-1H-pyrazolo[3,4-b]pyridin-5-yl]methyl}-2,6-pyridinedicarboxamide as a solid (19 mg, 33.8%). LC-MS m/z 765 (M+H)+, 1.44 min (ret time).
Reaction SMILES: [C:1](#[N:5])[CH2:2][C:3]#[N:4].C(=O)([O-])[O-].[K+].[K+].FC(F)(F)S(O[CH2:18][C:19]([F:24])([F:23])[CH:20]([F:22])[F:21])(=O)=O.O>CN(C)C=O>[F:23][C:19]([F:24])([CH:20]([F:22])[F:21])[CH2:18][C:2]([CH2:18][C:19]([F:23])([F:24])[CH:20]([F:21])[F:22])([C:1]#[N:5])[C:3]#[N:4]
Reactant: O=S(=O)(OCC(F)(F)C(F)F)C(F)(F)F
Reactant: N#CCC#N
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: N#CC(C#N)(CC(F)(F)C(F)F)CC(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 1.4 %

Procedure:
7.5 g of malononitrile was dissolved in 50 ml of N,N-dimethylformamide and 10.4 g of potassium carbonate was added. The mixture was stirred at room temperature for 1 hour, 10.0 g of 2,2,3,3-tetrafluoropropyl trifluoromethanesulfonate dissolved in 20 ml of N,N-dimethylformamide was added dropwise, and the mixture was stirred overnight. Thereafter, the reaction mixture was poured to water and extracted with diethyl ether. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography. The resulting fraction was washed with chloroform to obtain 0.08 g of 2,2-bis(2,2,3,3-tetrafluoropropyl)malononitrile (hereinafter, referred to as the present compound (50)).
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[N:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:8]=1[C:9]([OH:11])=[O:10].[C:17](=O)([O-])O.[Na+]>CO>[CH3:17][O:10][C:9](=[O:11])[C:8]1[CH:12]=[CH:13][C:14]([Cl:16])=[N:15][C:7]=1[NH2:6]
Reactant: O=C([O-])O
Reactant: Nc1nc(Cl)ccc1C(=O)O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)c1ccc(Cl)nc1N
Temperature: 70 °C
Reaction time: 5 h
Yield: 68 %

Procedure:
Concentrated sulfuric acid (25 mL) and 2-amino-6-chloronicotinic acid (4.3 g, 25 mmol) described in Manufacturing Example 26-1-1 were added to methanol (50 mL) on an ice bath, and stirred at 70° C. for 5 hours. The reaction mixture was cooled and then neutralized by addition of aqueous sodium hydrogen carbonate (90 g) solution. The precipitated solids were filtered to obtain the title compound (3.2 g, 17 mmol, 68%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([OH:19])=O.[NH2:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:31]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:40])[CH3:39])[CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25]1>>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][C:13](=[O:15])[NH:12][C:11]([CH3:16])=[C:10]1[C:17]([NH:20][CH2:21][CH2:22][CH2:23][N:24]1[CH2:29][CH2:28][CH:27]([C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([NH:36][C:37](=[O:41])[CH:38]([CH3:39])[CH3:40])[CH:31]=2)[CH2:26][CH2:25]1)=[O:19]
Reactant: CC1=C(C(=O)O)C(c2ccc(F)cc2F)CC(=O)N1
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCN)CC2)c1
Product: CC1=C(C(=O)NCCCN2CCC(c3cccc(NC(=O)C(C)C)c3)CC2)C(c2ccc(F)cc2F)CC(=O)N1

Procedure:
Prepared by Procedure AC and Scheme AM using 4-(2,4-difluorophenyl)-2-methyl-6-oxo-1,4,5,6-tetrahydro-3-pyridinecarboxylic acid and N-{3-[1-(3-aminopropyl)-4-piperidinyl]phenyl}-2-methylpropanamide: ESMS m/e: 553.0 (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([CH:8]([CH2:18][CH3:19])[CH2:9][C:10]([OH:17])([C:13]([F:16])([F:15])[F:14])[CH:11]=O)[CH:5]=[CH:6][CH:7]=1.[NH2:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]2[C:24]=1[CH:25]=[N:26][C:27]([CH2:33][CH3:34])=[N:28]2>[O-]CC.[O-]CC.[O-]CC.[O-]CC.[Ti+4]>[CH2:33]([C:27]1[N:26]=[CH:25][C:24]2[C:29](=[CH:30][CH:31]=[CH:32][C:23]=2[N:22]=[CH:11][C:10]([C:13]([F:14])([F:15])[F:16])([OH:17])[CH2:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[C:3]=2[O:20][CH3:21])[CH2:18][CH3:19])[N:28]=1)[CH3:34]
Reactant: CCc1ncc2c(N)cccc2n1
Reactant: CCC(CC(O)(C=O)C(F)(F)F)c1cccc(F)c1OC
Agent: [Ti+4]
Agent: CC[O-]
Product: CCc1ncc2c(N=CC(O)(CC(CC)c3cccc(F)c3OC)C(F)(F)F)cccc2n1

Procedure:
In the same way as in Example 31, 112 mg (0.37 mmol) of (4-(3-fluoro-2-methoxyphenyl)-2-hydroxy-2-(trifluoromethyl)hexanal, 60 mg (0.37 mmol) of 5-amino-2-ethylquinazoline and 0.2 ml of titanium tetraethoxide are reacted to give 1-[(2-ethylquinazolin-5-yl)imino]-4-(3-fluoro-2-methoxyphenyl)-2-(trifluoromethyl)hexan-2-ol. 280 mg of crude imine are cyclized in the same way as in Example 31 at −20° C. with 2.4 ml (2.4 mmol) of 1 M boron tribromide solution to give the desired product. Purification by chromatography on silica gel (ethyl acetate) gives 4 mg of desired product and 11 mg of the 8α compound (Example 49).
Reaction SMILES: [CH:1]1([N:6]2[CH2:14][C:11]3([CH2:13][CH2:12]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.ON1C2C=CC=CC=2N=N1.F[P-](F)(F)(F)(F)F.CN(C(N(C)C)=[N+]1C2C=CC=CC=2[N+]([O-])=N1)C.C(N(C(C)C)C(C)C)C.[NH2:75][CH:76]1[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]1>CN(C)C=O>[CH:1]1([N:6]2[CH2:14][C:11]3([CH2:12][CH2:13]3)[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH:75][CH:76]5[CH2:81][CH2:80][N:79]([CH3:82])[CH2:78][CH2:77]5)=[O:27])=[CH:24][C:23]=4[CH3:31])=[N:20][C:7]2=3)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: Cc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reactant: CN1CCC(N)CC1
Agent: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ccccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(C(=O)NC2CCN(C)CC2)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC1(CC1)C(=O)N2C
Reaction time: 0.33 h
Yield: 65.4 %

Procedure:
To a suspension of 0.0262 g (0.000062 mole) of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methylbenzoic acid (I-60) in 3 mL of dimethylformamide was added 0.0144 g (0.000107 mole) of 1-hydroxybenzotriazole, 0.0365 g (0.000096 mole) of 1-[bis(dimethylamino)methylene]-1H-benzotriazolium 3-oxide hexafluorophosphate and 0.07 mL (0.000402 mole) of ethyldiisopropylamine. The mixture was stirred for 20 minutes and then 0.012 g (0.0001 mole) of 4-amino-1-methylpiperidine was added. The mixture was stirred for an additional 2.5 hours and then concentrated under reduced pressure. The residue was dissolved in ethyl acetate and washed successively with 1 M sodium hydroxide, brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with dichloromethane-methanol (98:2-80:20) to give 0.021 g of 4-[(9-cyclopentyl-6,7,8,9-tetrahydro-5-methyl-6-oxospiro[5H-pyrimido[4,5-b][1,4]diazepine-7,1′-cyclopropan]-2-yl)amino]-3-methyl-N-(1-methyl-4-piperidinyl)benzamide (I-61)