Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=O)=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[N:6][CH:7]=1.N1C=CC=CC=1.Cl.[NH2:29][OH:30]>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([CH:14]=[N:29][OH:30])=[C:12]([CH3:16])[N:11]=[C:10]3[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:9]=23)[CH:5]=[N:6][CH:7]=1
Reactant: NO
Reactant: CCn1ncc2c(-c3cncc(Br)c3)c(C=O)c(C)nc21
Agent: Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: O
Product: CCn1ncc2c(-c3cncc(Br)c3)c(C=NO)c(C)nc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.7 %

Procedure:
To a solution of 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (34 mg) in DMF (1 ml) was added pyridine (0.032 ml) and hydroxylamine hydrochloride (13.7 mg) at room temperature and the mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted with water and extracted with EtOAc. The organic layer was washed with water, brine, dried over anhydrous MgSO4 and concentrated in vacuo to give 4-(5-bromo-3-pyridyl)-1-ethyl-6-methyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde oxime (35 mg) as a yellow crystal.
Reaction SMILES: [P:1]([O-:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4].[H-].[Na+].Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:17]1[C:26](=[O:27])[C:25]2[N:24]([CH2:28][O:29][CH2:30][CH3:31])[CH:23]=[N:22][C:21]=2[N:20]([CH3:32])[C:18]1=[O:19]>CN(C)C=O>[CH2:30]([O:29][CH2:28][N:24]1[C:25]2[C:26](=[O:27])[N:17]([CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][P:1](=[O:8])([O:5][CH2:6][CH3:7])[O:2][CH2:3][CH3:4])[C:18](=[O:19])[N:20]([CH3:32])[C:21]=2[N:22]=[CH:23]1)[CH3:31]
Reactant: CCOP([O-])OCC
Reactant: CCOCn1cnc2c1c(=O)n(CCCCCBr)c(=O)n2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOCn1cnc2c1c(=O)n(CCCCCP(=O)(OCC)OCC)c(=O)n2C
Temperature: 20 °C
Reaction time: 0.5 h

Procedure:
4.8 g (0.035 mol) of diethyl phosphite were cooled to 0° C. in 100 ml of dry dimethylformamide and slowly treated with 0.8 g (0.035 mol) of sodium hydride. The solution was stirred at 20° C. for 0.5 hours to complete the deprotonation and then treated with 10 g (0.0268 mol) of 1-(5-bromopentyl)-7-ethoxymethyl-3-methylxanthine, dissolved in a little dimethyl-formamide. After 4 hours at 20° C., the reaction mixture was quenched with a little saturated ammonium chloride solution, concentrated and chromatographed on silica gel (eluent: dichloromethane/methanol 15:1).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:8])[C:4]([F:7])([F:6])[F:5].[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17](S(CC)(=O)=O)[CH:16]=[C:15]2[O:25]CC1C=CC(OC)=CC=1.N1C2C(=CC=CC=2)C=CC=1>C1COCC1.C(Cl)Cl.FC(F)(F)C(O)=O>[Cl:9][C:10]1[CH:11]=[CH:12][CH:13]=[C:14]2[C:19]=1[N:18]=[C:17]([O:8][CH2:3][C:4]([F:7])([F:6])[F:5])[CH:16]=[C:15]2[OH:25]
Reactant: OCC(F)(F)F
Reactant: CCS(=O)(=O)c1cc(OCc2ccc(OC)cc2)c2cccc(Cl)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Oc1cc(OCC(F)(F)F)nc2c(Cl)cccc12
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
To a solution of sodium hydride (60 wt %, 177 mg, 7.7 mmol) in THF (3 mL) was added trifluoroethanol and 8-chloro-2-ethanesulfonyl-4-(4-methoxy-benzyloxy)-quinoline (300 mg, 0.77 mmol). The reaction was stirred at room temperature for 1 h, quenched with H2O, then diluted with EtOAc and washed with brine. The resulting organic layer was dried over sodium sulfate and concentrated to provide crude 8-Chloro-4-(4-methoxy-benzyloxy)-2-(2,2,2-trifluoro-ethoxy)-quinoline. LCMS found 397.9 [M+H]+. The crude quinoline was then dissolved in CH2Cl2 (4 mL) and trifluoroacetic acid (4 mL). After stirring for 15 min the reaction was concentrated. The crude product was purified by column chromatography (10-30% EtOAc/hexanes) to provide 8-chloro-2-(2,2,2-trifluoro-ethoxy)-quinolin-4-ol (220 mg, 100% yield). LCMS found 278.3 [M+M]+.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)#[N:2].N.S(=O)(=O)(O)[OH:17]>>[C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1)(=[O:17])[NH2:2]
Reactant: O=S(=O)(O)O
Reactant: N#Cc1ccccc1N1CCNCC1
Agent: N
Product: NC(=O)c1ccccc1N1CCNCC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1-(2-Cyanophenyl)piperazine (1.8 g, 9.8 mmol) was dissolved in 90% sulfuric acid aqueous solution (20 ml) and stirred at a room temperature for 24 hours. The reaction solution was slowly added dropwise to a mixture of ice (75 g) and 28% aqueous ammonia (75 ml), and the reaction product was extracted with chloroform. The extract was washed with saturated brine and dried with sodium sulfate. Then the compound obtained by the evaporation of the solvent under a reduced pressure was separated by an aluminum column chromatography to obtain colorless crystals. By further recrystallizing the thus obtained crystals from ethyl acetate, 680 mg of the title compound was obtained (3.1 mmol, 32% in yield).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17].[N-:18]=[N+:19]=[N-:20].[Na+].CN(C=O)C>O>[N:18]([C:2]1[CH:3]=[CH:4][N:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]2=[O:17])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: CCOC(=O)c1ccc2cc(Cl)ccn2c1=O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2cc(N=[N+]=[N-])ccn2c1=O
Temperature: 40 °C
Reaction time: 1 h
Yield: 84.4 %

Procedure:
An oven-dried 25 ml round-bottom flask was purged with argon and charged with ethyl 8-chloro-4-oxo-4H-quinolizine-3-carboxylate (2) (250 mg, 1 mmol), NaN3 (300 mg, 4.6 mmol), and 5 ml DMF. The reaction mixture was stirred at 40° C. for 1 h, cooled to room temperature, and poured into 100 ml water. The aqueous layer was extracted three times with 100 ml chloroform, and the combined organic layers were washed three times with 100 ml water. The organic solvent was evaporated and the crude product was purified by flash chromatography (ethyl acetate) to give a deep red crystalline solid (218 mg, 85%). M.p. 145-150° C. 1H NMR (δ, CDCl3): 1.42 (t, J=7 Hz, 3H), 4.41 (q, J=7 Hz, 2H), 6.53 (d, J=8 Hz, 1H), 6.84 (dd, J=2 Hz, J=7 Hz, 1H), 7.08 (d, J=2 Hz, 1H), 8.37 (d, J=8 Hz, 1H), 9.36 (d, J=7 Hz, 1H). MS: m/z 258.0751; required for C12H10N4O3: 258.0753.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]2[C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=1.[Cl:22][C:23]1[S:27][C:26]([C:28]([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)=[O:29])=[CH:25][CH:24]=1>>[Cl:22][C:23]1[S:27][C:26]([C:28]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([O:12][CH3:13])[CH:6]=[C:5]3[C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([O:20][CH3:21])[CH:15]=2)([C:30]2[N:31]([CH3:35])[CH:32]=[N:33][CH:34]=2)[OH:29])=[CH:25][CH:24]=1
Reactant: Cn1cncc1C(=O)c1ccc(Cl)s1
Reactant: COc1cccc(-c2cc(OC)nc3ccc(Br)cc23)c1
Product: COc1cccc(-c2cc(OC)nc3ccc(C(O)(c4ccc(Cl)s4)c4cncn4C)cc23)c1
Yield: 80.1 %

Procedure:
Following the same procedure as that described in example 1E, 6-bromo4-(3-methoxy-phenyl)-2-methoxy-quinoline (1 g, 2.91 mmol) and (5-chloro-thiophen-2-yl)-(3-methyl-3H-imidazol-4-yl)-methanone (0.78 g, 3.49 mmol) generated the title compound of 31A (1.147 g, 80.2% yield).
Reaction SMILES: [O:1]=[C:2]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:8]=[C:7]([C:18]3[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=3)[N:6]=[C:5]([C:24]([O:26]CC)=O)[C:4]=2[NH:3]1.ClC1N=C(C(OCC)=O)C2NC(=O)CN(C3C=CC=CC=3)C=2[N:31]=1.C([Sn](CCCC)(CCCC)C1C=CN=CC=1)CCC>CN(C=O)C.C(Cl)Cl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[O:1]=[C:2]1[CH2:11][N:10]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:9]2[N:8]=[C:7]([C:18]3[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=3)[N:6]=[C:5]([C:24]([NH2:31])=[O:26])[C:4]=2[NH:3]1
Reactant: CCOC(=O)c1nc(Cl)nc2c1NC(=O)CN2c1ccccc1
Reactant: CCOC(=O)c1nc(-c2ccncc2)nc2c1NC(=O)CN2c1ccccc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccncc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: NC(=O)c1nc(-c2ccncc2)nc2c1NC(=O)CN2c1ccccc1
Temperature: 120 °C
Yield: 50 %

Procedure:
Ethyl 6-oxo-8-phenyl-2-(pyridin-4-yl)-5,6,7,8-tetrahydropteridine-4-carboxylate. To a solution of ethyl 2-chloro-6-oxo-8-phenyl-5,6,7,8-tetrahydropteridine-4-carboxylate (0.160 g, 0.48 mmol) in anhydrous DMF (6.7 mL) was added 4-(tributylstannyl)pyridine (0.884 g, 2.40 mmol), and dichlorobis(triphenylphosphine)palladium(II) (0.170 g, 0.24 mmol). The solution was purged with nitrogen then heated in a Biotage Emrys Optimizer microwave reactor for 30 min at 120° C. The volatiles were evaporated and the resulting residue was purified by chromatography on a normal phase silica gel column (1-10% methanol in dichloromethane). Fractions containing product were combined and the solvent evaporated. The material was re-purified using reverse-phase preparatory HPLC (10-70% acetonitrile+0.1% TFA in H2O+0.1% TFA, over 30 min). Fractions containing the desired material were combined and concentrated under reduced pressure to afford a residue. The residue was dissolved in methylene chloride (100 mL) which was washed with aqueous potassium carbonate solution (saturated, 10 mL) and dried over sodium sulfate. The organic phase was concentrated and the resulting solid was dried under high vacuum at 60° C. to afford the title compound (0.090 g, 0.24 mmol, 50% yield). MS (ESI) m/z 376.4 [M+1]+.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Na+].[I-].C(N(CC)CC)C.[CH2:16]([NH2:19])[CH:17]=[CH2:18].Br[CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23]>CN(C=O)C>[CH2:16]([NH:19][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:17]=[CH2:18]
Reactant: C=CCN
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCNCC(=O)OCC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice cold solution of K2CO3 (331.7 g, 2.4 mol), NaI (360 g, 2.4 mol), DMF (1 L), triethylamine (484.8 g, 4.8 mol) and prop-2-en-1-amine (82 g, 1.44 mol) was slowly added a solution of ethyl bromoacetate (200 g, 1.2 mol) in DMF (100 mL) via addition funnel over 0.5 hr. The ice bath was removed upon completion of addition, and the mixture was stirred at room temperature overnight. The mixture was filtered and rinsed with Et2O. Cold saturated NaCl aq. (2 L) was added to filtrate and the mixture was extracted with Et2O (1 L*3). The combined organic extracts were dried over Na2SO4, filtered and concentrated which gave the title compound XId (150 g, 87.3%) as a yellow oil, which was directly utilized for next reaction without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:12]=2)[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].Br[CH2:22][CH2:23][O:24][Si:25]([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]>CN(C)C=O>[Si:25]([O:24][CH2:23][CH2:22][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([C:8]2[O:9][CH2:10][C@@H:11]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)[N:12]=2)[CH:3]=1)([C:28]([CH3:31])([CH3:30])[CH3:29])([CH3:27])[CH3:26]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: Oc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc(C2=N[C@H](c3ccccc3)CO2)c1
Reaction time: 1 h
Yield: 85.7 %

Procedure:
To a stirred solution of 4,5-dihydro-2-(3-hydroxyphenyl)-4(R)-phenyloxazole (3.3 g, 13.8 mmol) in N,N-dimethylformamide (30 ml) was added sodium hydride (60% in mineral oil, 0.62 g, 16 mmol) portionwise over 5 min. at ambient temperature. The mixture was stirred for 1 hour, and then a solution of 2-bromo-1-(tert-butyldimethylsilyloxy)ethane (4.94 g, 21 mmol) in N,N-dimethylformamide (5 ml) was added dropwise over 5 min. and the reaction mixture stayed overnight. The reaction mixture was partitioned between ethyl acetate (50 ml) and water (50 ml), the aqueous layer was separated, extracted with ethyl acetate (2×50 ml) and the combined organic phase washed with 1N HCl (100 ml), aqueous 4% NaHCO3 solution (100 ml) and brine (100 ml), dried (MgSO4) and evaporated. The resulting residue was purified by column chromatography on silica gel eluting with ethyl acetate/n-hexane (=1:6) to afford 1-(tert-butyldimethylsilyloxy)-2-[3-(4,5-dihydro-4(R)-phenyloxazol-2-yl)phenoxy]ethane (4.7 g, 86%) as a colorless oil.
Reaction SMILES: CC1C=CC(S([O:11][C@H:12]2[C@@:16]3([CH3:22])[O:17][C:18]([CH3:21])([CH3:20])[O:19][CH:15]3[O:14][C@@H:13]2[CH2:23][O:24][Si:25]([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1>C1COCC1>[Si:25]([O:24][CH2:23][C@H:13]1[O:14][CH:15]2[C@:16]([CH3:22])([O:17][C:18]([CH3:21])([CH3:20])[O:19]2)[C@@H:12]1[OH:11])([C:38]([CH3:41])([CH3:40])[CH3:39])([C:32]1[CH:33]=[CH:34][CH:35]=[CH:36][CH:37]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Cc1ccc(S(=O)(=O)O[C@@H]2[C@@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)OC3OC(C)(C)O[C@@]32C)cc1
Solvent: C1CCOC1
Product: CC1(C)OC2O[C@H](CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)[C@@H](O)[C@@]2(C)O1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
The mixture of (5R,6R,6aR)-5-((tert-butyldiphenylsilyloxy)methyl)-2,2,6a-trimethyl-tetrahydrofuro[3,2-d][1,3]dioxol-6-yl 4-methylbenzenesulfonate (from step 4) (56 g, 0.094 mol) and 1M solution of Li(Et)3BH (376.4 mL, 0.376 mol) in 800 mL of THF was refluxed for 12 h. The reaction mixture was cooled to room temperature and quenched carefully with 200 mL of saturated ammonium chloride solution. Diluted with 500 mL of ethyl acetate and washed with 1N HCl (500 mL) and brine (300 mL). The organic layers were dried over anhydrous Na2SO4, filtered and concentrated. The crude residue was dissolved in ethyl acetate and passed through a pad of celite to remove salts. Purified by column chromatography using hexane and ethyl acetate as a gradient mixture to give 38.4 g of the title compound (93% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21](Br)=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2].[CH:30]([Sn](CCCC)(CCCC)CCCC)=[CH2:31]>C1(C)C=CC=CC=1>[CH2:1]([O:3][C:4]([C:6]1([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:10][CH2:9][CH2:8][N:7]1[C:11]1[CH:12]=[N:13][C:14]([O:17][C:18]2[CH:23]=[CH:22][C:21]([CH:30]=[CH2:31])=[CH:20][CH:19]=2)=[CH:15][CH:16]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(C(=O)OCC)CCCN1c1ccc(Oc2ccc(Br)cc2)nc1
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Solvent: Cc1ccccc1
Product: C=Cc1ccc(Oc2ccc(N3CCCC3(C(=O)OCC)C(=O)OCC)cn2)cc1
Temperature: 25 °C
Yield: 95.9 %

Procedure:
A mixture of 1-[6-(4-bromo-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester (5.8 g, 12.2 mmol), vinyltributyltin (3.9 mL, 12.3 mmol), tetrakistriphenylphosphine palladium (0) (0.60 g, 0.52 mmol) and 24 mL of toluene was heated to reflux for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and purified by silica gel chromatography (Flash 40, 20%-50% ethyl acetate-hexanes), affording 4.8 g of 1-[6-(4-Vinyl-phenoxy)-pyridin-3-yl]-pyrrolidine-2,2-dicarboxylic acid diethyl ester as a colorless syrup.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8]C(N(OC)C)=O)=[CH:6][CH:5]=[C:4]([CH3:15])[N:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[OH-:26].[Na+]>ClCCl>[Cl:1][C:2]1[N:3]=[C:4]([CH3:15])[CH:5]=[CH:6][C:7]=1[CH:8]=[O:26]
Reactant: [OH-]
Reactant: CON(C)C(=O)Cc1ccc(C)nc1Cl
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C=O)c(Cl)n1
Reaction time: 0.5 h
Yield: 91 %

Procedure:
A solution of 2-chloro-N-methoxy-N,6-dimethylpyridine-3-carboxyamide (1.30 g, 5.83 mmol) in dichloromethane (15 mL) was added with diisobutylaluminum hydride (0.99 M solution in toluene, 12 mL, 11.66 mmol) at −78° C., and the mixture was stirred at the same temperature for 30 minutes. The reaction mixture was added with 2 M aqueous sodium hydroxide, and the mixture was stirred at room temperature for 30 minutes, and then extracted with ethyl acetate. The organic layer was washed with saturated brine, then dried over anhydrous sodium sulfate, and concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=3:1) to obtain 2-chloro-6-methylnicotinaldehyde (828 mg, 91%) as pale yellow oil.
Reaction SMILES: [CH3:1][N:2]([CH2:33][CH2:34][C:35]([O:37]C(C)(C)C)=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1.C(O)(C(F)(F)F)=O>CC#N>[CH3:1][N:2]([CH2:33][CH2:34][C:35]([OH:37])=[O:36])[C:3](=[O:32])[C:4]1[CH:9]=[CH:8][C:7]([CH:10]([NH:14][C:15]2[CH:16]=[N:17][C:18]([N:21]3[CH:25]=[C:24]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[CH:23]=[N:22]3)=[CH:19][CH:20]=2)[CH2:11][CH2:12][CH3:13])=[CH:6][CH:5]=1
Reactant: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: CCCC(Nc1ccc(-n2cc(-c3ccccc3)cn2)nc1)c1ccc(C(=O)N(C)CCC(=O)O)cc1

Procedure:
The title compound was prepared by a method analogous to that described in Step C of Example 1, using (+/−)-tert-butyl 3-(N-methyl-4-(1-(6-(4-phenyl-1H-pyrazol-1-yl)pyridin-3-ylamino)butyl)benzamido)propanoate. Column: Waters Atlantis dC18 4.6×50 mm, 5 μm. Modifier: TFA 0.05%. Gradient: 95% H20/5% MeCN linear to 5% H20/95% MeCN over 4.0 min, Hold at 5% H20/95% MeCN to 5.0 min. Flow: 2.0 mL/min. Retention time: 3.27 min. MS (M+1): 498.1.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([F:17])([F:16])[F:15])=[CH:7][CH:6]=1)(=[O:4])=[O:3].Cl.[CH3:21][C:22]1[CH:23]=[C:24]([NH:29][NH2:30])[CH:25]=[CH:26][C:27]=1[Cl:28].O>C(O)(=O)C>[Cl:28][C:27]1[CH:26]=[CH:25][C:24]([N:29]2[C:11]([C:8]3[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][CH:7]=3)=[CH:12][C:13]([C:14]([F:17])([F:16])[F:15])=[N:30]2)=[CH:23][C:22]=1[CH3:21]
Reactant: Cc1cc(NN)ccc1Cl
Reactant: CS(=O)(=O)c1ccc(C(=O)CC(=O)C(F)(F)F)cc1
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-n2nc(C(F)(F)F)cc2-c2ccc(S(C)(=O)=O)cc2)ccc1Cl
Reaction time: 0.5 h
Yield: 65.1 %

Procedure:
A mixture of 1-[4-(methylsulfonyl)phenyl]-4,4,4-trifluorobutane-1,3-dione (620 mg) and (3-methyl-4-chlorophenyl)hydrazine hydrochloride (425 mg) in acetic acid (2 ml) was refluxed for 1 hour. After cooling, the solvent was poured into water (50 ml) and stirred for 30 minutes. The resulting precipitates were collected by filtration and washed with water and dried in vacuo. The residue was recrystallized from ethanol to afford 1-(4-chloro-3-methylphenyl)-5-[4-(methylsulfonyl)phenyl]-3-(trifluoromethyl)pyrazole (569 mg).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N:4][CH:3]=1.C1C=C(Cl)C=C(C(OO)=[O:20])C=1>C(Cl)Cl>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[N+:4]([O-:20])[CH:3]=1
Reactant: Cc1cncc2ccccc12
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: Cc1c[n+]([O-])cc2ccccc12
Reaction time: 18 h
Yield: 97.5 %

Procedure:
To a solution of 4-methylisoquinoline (0.6 g, 4.19 mmol) in DCM (20 ml) was added m-CPBA (2.169 g, 12.57 mmol) at room temperature. The reaction mass was stirred at the same temperature for 18 h. The reaction mass was diluted with DCM and extracted with water. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get desired compound (0.65 g, 88%) as a semi solid. The crude compound was taken further without purification.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[NH2:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:15])([CH3:14])[CH2:11][C:10]=2[C:16]=1[CH3:17].C(N(CC)CC)C.O>O1CCCC1>[C:1]([NH:5][C:6]1[C:7]([CH3:19])=[C:8]([CH3:18])[C:9]2[O:13][C:12]([CH3:14])([CH3:15])[CH2:11][C:10]=2[C:16]=1[CH3:17])(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(C)O2
Solvent: O
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)Nc1c(C)c(C)c2c(c1C)CC(C)(C)O2
Reaction time: 4 h
Yield: 76.4 %

Procedure:
Acetyl chloride (460 mg, 5.84 mmol) was added dropwise with ice cooling to a solution of 5-amino-2,2,4,6,7-pentamethyl-2,3-dihydrobenzofuran (100g, 4.87 mmol) and triethylamine (640 mg, 6.33 mmol) in tetrahydrofuran (20 ml). After the addition was completed, the mixture was stirred for 4 hours. Water was added to the reaction mixture and the mixture was extracted with chloroform. The extract was washed with saturated sodium bicarbonate solution and saturated saline, dried and concentrated. The residue was purified by column chromatography on silica gel (chloroform-methanol, 97:3) to obtain the desired compound (920 mg, yield: 76.4%). A part of it was recrystallized from dichloromethane-isopropyl ether, m.p. 190° C. (dichloromethane-isopropyl ether).
Reaction SMILES: [CH3:1][Si:2]([CH3:9])([CH2:6][CH:7]=[CH2:8])[CH2:3][CH:4]=[CH2:5].[C:10]1([PH:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:17]1([P:16]([CH2:5][CH2:4][CH2:3][Si:2]([CH2:6][CH2:7][CH2:8][P:16]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)([CH3:9])[CH3:1])[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: c1ccc(Pc2ccccc2)cc1
Reactant: C=CC[Si](C)(C)CC=C
Product: C[Si](C)(CCCP(c1ccccc1)c1ccccc1)CCCP(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
A mixture of 70 g (0.5 mole) dimethyl diallyl silane and 204.6 g (1.1 m mole, 10% excess over equivalent amounts) of diphenyl phosphine was reacted in the manner described in Example 1 at 40° C. The addition was slow. After 24 hours, only about 10% of the diphenyl phosphine reacted. The irradiation of the reaction mixture was continued for a total of 160 hours. A subsequent fractional distillation provided 46 g of monoadduct, as a clear, slightly viscous liquid monoadduct of bp. 122°-134° C. at 0.05 mm and 113 g of the desired diadduct (Table 1) as a clear, light yellow, viscous liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:27]=[CH:26][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH:13][C:14]([N:16]3[CH2:21][CH2:20][CH:19]([CH2:22][N:23]([CH3:25])[CH3:24])[CH2:18][CH2:17]3)=[O:15])[CH:8]=2)=[C:4]([F:28])[CH:3]=1.[F:29][C:30]1[CH:35]=[CH:34][C:33]([NH:36][C:37]([C:39]2([C:42](O)=[O:43])[CH2:41][CH2:40]2)=[O:38])=[CH:32][CH:31]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C)C=O>[CH3:24][N:23]([CH2:22][CH:19]1[CH2:18][CH2:17][N:16]([C:14]([NH:13][C:9]2[CH:8]=[C:7]([O:6][C:5]3[CH:26]=[CH:27][C:2]([NH:1][C:42]([C:39]4([C:37]([NH:36][C:33]5[CH:34]=[CH:35][C:30]([F:29])=[CH:31][CH:32]=5)=[O:38])[CH2:41][CH2:40]4)=[O:43])=[CH:3][C:4]=3[F:28])[CH:12]=[CH:11][N:10]=2)=[O:15])[CH2:21][CH2:20]1)[CH3:25]
Reactant: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(N)cc3F)ccn2)CC1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN(C)CC1CCN(C(=O)Nc2cc(Oc3ccc(NC(=O)C4(C(=O)Nc5ccc(F)cc5)CC4)cc3F)ccn2)CC1
Reaction time: 8 h
Yield: 29.6 %

Procedure:
4-(Dimethylaminomethyl)piperidine-1-carboxylic acid [4-(4-amino-2-fluorophenoxy)pyridin-2-yl]amide (88 mg) was dissolved in N,N-dimethylformamide (2.5 ml). 1-(4-Fluorophenylcarbamoyl)cyclopropanecarboxylic acid (101 mg), triethylamine (0.0633 ml) and benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (201 mg) were added under a nitrogen atmosphere at room temperature, followed by stirring overnight. Liquid-liquid separation was carried out after addition of ethyl acetate and water to the reaction mixture. The organic layer was washed with a 1N aqueous solution of sodium hydroxide and brine, and dried over anhydrous sodium sulfate. The solvent was removed and the resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, then ethyl acetate:methanol=98:2). Fractions containing the target compound were concentrated under reduced pressure. A solid was precipitated by addition of heptane to the resultant residue. The solid was collected by filtration, and dried under aeration to provide the titled compound as white powder (39.8 mg, 30%).