Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]1([S:19]([N:22]2[C:26]3=[CH:27][N:28]=[CH:29][CH:30]=[C:25]3[CH:24]=[CH:23]2)(=[O:21])=[O:20])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.CN(C)CCN(C)C.[CH:39]1[C:43]([CH:44]=[O:45])=[CH:42][O:41][CH:40]=1.[Cl-].[NH4+]>O1CCCC1>[O:41]1[CH:40]=[CH:39][C:43]([CH:44]([C:23]2[N:22]([S:19]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)(=[O:21])=[O:20])[C:26]3=[CH:27][N:28]=[CH:29][CH:30]=[C:25]3[CH:24]=2)[OH:45])=[CH:42]1
Reactant: O=S(=O)(c1ccccc1)n1ccc2ccncc21
Reactant: O=Cc1ccoc1
Agent: CN(C)CCN(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: O=S(=O)(c1ccccc1)n1c(C(O)c2ccoc2)cc2ccncc21
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 37.9 %

Procedure:
A solution of diisopropylamine (0.43 mL, 3.07 mmol) in tetrahydrofuran (4 mL) was cooled to −78° C. under a nitrogen atmosphere. n-Butyllithium (1.24 mL of a 2.5 M solution in hexanes) was added dropwise and the reaction mixture was stirred for 30 minutes at −78° C. and then warmed to −30° C. A solution of 1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridine (Reference Example 12) (400 mg, 1.55 mmol) and N,N,N′,N′-tetramethylethylenediamine (0.24 mL, 1.59 mmol) in tetrahydrofuran (4 mL) was added and the reaction mixture was stirred for 45 minutes. A solution of 3-furfural (0.27 mL, 3.12 mmol) in tetrahydrofuran (3 mL) was added dropwise. The reaction mixture was allowed to warm to ambient temperature over 2 h. Saturated ammonium chloride solution (5 mL) was added to quench the reaction mixture. The reaction mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×25 mL). The combined organic extracts were washed successively with water and brine, dried over sodium sulfate and concentrated to dryness. Recrystallization from methanol gave 3-furyl[1-(phenylsulfonyl)-1H-pyrrolo[2,3-c]pyridin-2-yl]methanol (208 mg, 38%) as an off-white solid: mp 168-171° C.; 1H NMR (500 MHz, DMSO-d6) δ 6.24 (1H, d, J=5.8 Hz), 6.40 (1H, d, J=5.8 Hz), 6.48 (1H, d, J=1.1 Hz), 6.84 (1H, s), 7.55-7.62 (5H, m), 7.68-7.71 (1H, m), 7.92-7.94 (2H, m), 8.35 (1H, d, J=5.2 Hz), 9.23 (1H, s); ESI MS m/z 355 [C18H14N2O4S+H]+; HPLC (Method A) >99% (AUC), tR=15.4 min.
Reaction SMILES: Cl.[F:2][C:3]([F:27])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][NH:20][CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:16])[F:15])=[CH:9][CH:8]=1.C(=O)([O-])[O-].[CH:32]([N:35]=[C:36]=[O:37])([CH3:34])[CH3:33]>C(Cl)Cl>[F:27][C:3]([F:2])([F:26])[C:4]1[CH:25]=[CH:24][CH:23]=[CH:22][C:5]=1[CH:6]([O:17][CH:18]1[CH2:21][N:20]([C:36]([NH:35][CH:32]([CH3:34])[CH3:33])=[O:37])[CH2:19]1)[C:7]1[CH:12]=[CH:11][C:10]([O:13][CH:14]([F:15])[F:16])=[CH:9][CH:8]=1
Reactant: CC(C)N=C=O
Reactant: FC(F)Oc1ccc(C(OC2CNC2)c2ccccc2C(F)(F)F)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: CC(C)NC(=O)N1CC(OC(c2ccc(OC(F)F)cc2)c2ccccc2C(F)(F)F)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 67.3 %

Procedure:
To a solution of 3-[2-(trifluoromethyl)-4′-(difluoromethoxy)benzhydryloxy]azetidine hydrochloride (175) (100 mg, 0.24 mmol) in anhydrous DCM (4 mL) was added MP-carbonate (2.62 mmol/g; 280 mg, 0.72 mmol), molecular sieves and iso-propyl isocyanate (25 μL, 0.24 mmol). After shaking at ambient temperature for 2 h, the mixture was poured onto a DCM-wet SCX-2 cartridge (2 g). Elution with DCM (20 mL) and evaporation afforded the desired product (74 mg, 66%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.[Br:18][C:19]1[CH:24]=[CH:23][C:22]([O:25]C)=[CH:21][CH:20]=1.[Al+3].[Cl-].[Cl-].[Cl-]>ClCCl.CN(C=O)C>[Br:18][C:19]1[CH:20]=[CH:21][C:22]([OH:25])=[C:23]([C:9](=[O:11])[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH:24]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C(O)Cc1ccccc1F
Agent: O=C(Cl)C(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cc1ccccc1F)c1cc(Br)ccc1O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
2-Fluorophenylacetic acid (2.96 g, 19.24 mmoles) was dissolved in 50 ml dichloromethane. To this mixture, oxalylchloride (2.1 ml, 24.05 mmoles) and DMF (3 drops) were added at 0° C. and stirred for 30 min. The solvent was evaporated and dissolved in 30 ml dichloromethane. To this mixture, 4-bromoanisole (3.0 g, 16.03 mmoles) was added and cooled to 0° C. At 0° C. AlCl3 (3.21 g, 24.05 mmoles) was added and the reaction mixture was warmed to RT and stirred for 12 h. The reaction mixture was quenched by the addition of 2N HCl and extracted with ethyl acetate, dried over sodium sulphate and concentrated. The crude product was purified by column chromatography with ethyl acetate:petroleum ether to afford the title compound as off-white solid (4.0 g, 81% yield. 1H-NMR (δ ppm, CDCl3, 400 MHz): δ 11.97 (s, 1H), 8.01 (d, J=1.7 Hz, 1H), 7.58 (dd, J=8.8, 2.3.1 Hz, 1H), 7.35 (m, 1H), 7.23 (d, J=7.3 Hz, 1H), 7.17 (m, 2H), 6.92 (d, J=8.9 Hz, 1H), 4.33 (s, 2H).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.[S:10]1[CH:14]=[CH:13][N:12]=[CH:11]1.C([O-])(=O)C.[K+]>CC(N(C)C)=O.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>[S:10]1[C:14]([C:2]2[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=2)=[CH:13][N:12]=[CH:11]1
Reactant: c1cscn1
Reactant: O=Cc1ccc(Br)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: O=Cc1ccc(-c2cncs2)cc1
Temperature: 150 °C
Reaction time: 12 h

Procedure:
In a bomb tube, a mixture of 3.7 g (20 mmol) of 4-bromobenzaldehyde (Fluka, Buchs, Switzerland), 6.64 ml (93 mmol) of thiazole, 2.94 g of potassium acetate and 1.16 g (1 mmol) of Pd(PPh3)4 in 50 ml of dimethylacetamide is stirred at 150° C. for 12 hours. The reaction mixture is concentrated by evaporation. Water is added to the residue and the mixture is extracted 3× with methylene chloride. The organic phases are filtered through cotton wadding, concentrated by evaporation and chromatographed (SiO2; hexane/ethyl acetate 1:2), yielding the title compound: HPLC20-100: tRet=11.4; 1H-NMR (CD3OD) δ 9.98 (s, HCO), 9.03 (s, H(2)thiazole), 8.32 (s, H(4)thiazole), 7.95 and 7.85 (2d, J=8, each 2H); additionally also signals of the hydrate (≈12%): 8.92 (s, H(2)thiazole), 8.15 (s, H(4)thiazole), 7.62 and 7.53 (2d, J=8, each 2H), 5.54 (s, HC(OH)2).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[OH:9][C:10]1[C:15]([C:16](=[O:18])[CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[O:25]1[CH2:30][CH2:29][CH:28]([C:31](OC)=[O:32])[CH2:27][CH2:26]1>O1CCCC1>[OH:9][C:10]1[C:15]([C:16](=[O:18])[CH2:17][C:31]([CH:28]2[CH2:29][CH2:30][O:25][CH2:26][CH2:27]2)=[O:32])=[CH:14][CH:13]=[CH:12][C:11]=1[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)c1cccc(-c2ccccc2)c1O
Reactant: COC(=O)C1CCOCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(CC(=O)C1CCOCC1)c1cccc(-c2ccccc2)c1O
Temperature: 0 °C

Procedure:
An oven-dried 100 mL round-bottom flask was charged with a magnetic stirring bar, tetrahydrofuran (10 mL) and lithium diisopropylamide (2.0M in hexanes, 6.9 mL, 13.8 mmol). The mixture was magnetically stirred and cooled to 0° C. under argon gas. 1-(2-Hydroxybiphenyl-3-yl)ethanone (0.92 g, 4.34 mmol) was added, and the reaction was stirred at 0° C. for 1 hour. A solution of methyl tetrahydro-2H-pyran-4-carboxylate (1.0 g, 6.94 mmol) in tetrahydrofuran (2 mL) was added dropwise over 5 minutes and the reaction was allowed to warm to room temperature overnight. The reaction was quenched by the addition of aqueous 10% hydrochloric acid solution (20 mL) until pH=3. The resulting solution was transferred to a separatory funnel, diluted with water (80 mL), and extracted three times with dichloromethane (100 mL). The organic layers were combined, dried over magnesium sulfate, filtered, and concentrated in vacuo to give crude 1-(2-hydroxybiphenyl-3-yl)-3-(tetrahydro-2H-pyran-4-yl)propane-1,3-dione as a brown oil. The crude product was used as is without further purification.
Reaction SMILES: Cl[C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1.Cl.[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[NH:25][CH2:24][CH2:23]2>>[Br:17][C:18]1[CH:19]=[C:20]([O:27][CH3:28])[CH:21]=[C:22]2[C:26]=1[N:25]([C:2]1[C:3](=[O:15])[N:4]([C@H:9]([CH2:12][O:13][CH3:14])[CH2:10][CH3:11])[CH:5]=[C:6]([Cl:8])[N:7]=1)[CH2:24][CH2:23]2
Reactant: CC[C@@H](COC)n1cc(Cl)nc(Cl)c1=O
Reactant: COc1cc(Br)c2c(c1)CCN2
Agent: Cl
Product: CC[C@@H](COC)n1cc(Cl)nc(N2CCc3cc(OC)cc(Br)c32)c1=O

Procedure:
Prepared in a similar fashion as described for Example 413 using 3,5-dichloro-1-[(1S)-1-(methoxymethyl)propyl]-2(1H)-pyrazinone and 7-bromo-5-methoxyindoline hydrochloride as the starting materials. mp 100–102° C.; 1H NMR (300 MHz, CDCl3): δ 7.00 (s, 1 H), 6.92 (d, J=2.5 Hz, 1 H), 6.78 (d, J=2.6 Hz, 1 H), 4.99–4.90 (m, 1 H), 4.35 (t, J=7.7 Hz, 2 H), 3.78 (s, 3 H), 3.67 (dd, J=10.6, 5.7 Hz, 1 H), 3.56 (dd, J=10.6, 3.5 Hz, 1 H), 3.35 (s, 3 H), 3.10 (t, J=7.7 Hz, 2 H), 1.92–1.72 (m, 2 H), 0.93 (t, J=7.3 Hz, 3 H); HRMS (ESI) calcd for C18H22N3O3BrCl (M+H)+: 442.0533; found m/z 442.0516.
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[CH:9][N:10]=[C:6]2[C:5]([CH2:11][CH2:12][O:13][CH2:14][CH3:15])=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:3]=1.[N-:22]=[N+:23]=[N-:24].[Na+].O>CS(C)=O>[CH2:14]([O:13][CH2:12][CH2:11][C:5]1[C:6]2[N:7]([N:8]=[CH:9][N:10]=2)[C:2]2[N:3]([N:22]=[N:23][N:24]=2)[C:4]=1[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH3:15]
Reactant: CCOCCc1c(-c2ccccc2)nc(Cl)n2ncnc12
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CCOCCc1c(-c2ccccc2)n2nnnc2n2ncnc12
Reaction time: 5 h

Procedure:
To a solution containing 30.2 g of 5-chloro-8-(2-ethoxyethyl)-7-phenyl[1,2,4]triazolo[1,5-c]pyrimidine (0.1 moles) dissolved in 200 ml of dimethylsulfoxide is added 20 g of sodium azide (0.3 moles). The resulting reaction mixture is heated to 65°-70° C. and then stirred for 5 hours. The reaction mixture is then stirred overnight at room temperature. The reaction mixture is then stirred into 1 liter of water and a precipitate forms. The mixture is filtered and the precipitate is washed with water and dried yielding a crude product. The crude product is chromatographed on silica gel and recrystallized from diethylether to yield 6-(2-ethoxyethyl)-5-phenyltetrazolo[1,5-a][1,2,4]triazolo[1,5-c]pyrimidine having the structural formula ##STR20## and the azido tautomer thereof as a white solid having a melting point of 114° C. and the following elemental analysis:
Reaction SMILES: [OH-].[K+].[CH3:3][C:4](=[O:9])[CH2:5][C:6](=[O:8])[CH3:7].[C:10](#[N:13])[CH:11]=[CH2:12]>CO>[C:6]([C:5]([C:4](=[O:9])[CH3:3])([CH2:12][CH2:11][C:10]#[N:13])[CH2:12][CH2:11][C:10]#[N:13])(=[O:8])[CH3:7]
Reactant: C=CC#N
Reactant: CC(=O)CC(C)=O
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: CC(=O)C(CCC#N)(CCC#N)C(C)=O

Procedure:
After addition of 0.25 g of KOH, dissolved in 2.5 ml of methanol, to 15.0 g of 2,4-pentandione, 35.0 g of acrylonitrile was added dropwise with the reaction temperature not exceeding 40° C. The product which was precipitated during the process was filtered off, washed with a small amount of acetone, and dried. Melting point: 185–186° C. Purity>98%. The product was colorless.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5](Cl)=[O:6].[F:9][C:10]1[CH:11]=[C:12]([CH:22]=[CH:23][CH:24]=1)[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([NH2:21])=[CH:17][CH:16]=1.Cl>ClCCl.N1C=CC=CC=1.O>[CH3:1][O:2][C:3](=[O:8])[CH2:4][C:5]([NH:21][C:18]1[CH:17]=[CH:16][C:15]([O:14][CH2:13][C:12]2[CH:22]=[CH:23][CH:24]=[C:10]([F:9])[CH:11]=2)=[CH:20][CH:19]=1)=[O:6]
Reactant: COC(=O)CC(=O)Cl
Reactant: Nc1ccc(OCc2cccc(F)c2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Solvent: O
Product: COC(=O)CC(=O)Nc1ccc(OCc2cccc(F)c2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 19.4 %

Procedure:
A solution of 242 mg (1.77 mmol) chlorocarbonyl-acetic acid methyl ester in 2 ml dichloromethane is added dropwise to an ice-cooled solution of 350 mg (1.61 mmol) 4-(3-fluoro-benzyloxy)-phenylamine in 7 ml of pyridine. The mixture is then stirred for 2 h at room temperature, diluted with water, acidified with dil. hydrochloric acid and extracted with ethyl acetate. The organic phase is dried. Chromatography (silica gel, ethyl acetate/hexane 1:1) yields 99 mg (19%) of the title compound. Yellowish solid; MS: m/e=418.1 (M++H).
Reaction SMILES: Cl.C1(C(=[N:15][CH:16]2[CH2:21][CH2:20][CH2:19][C:18]([CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=3)([C:22]([O:24][CH3:25])=[O:23])[CH2:17]2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[NH2:15][CH:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH2:26][C:27]2[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=2)([C:22]([O:24][CH3:25])=[O:23])[CH2:17]1
Reactant: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N=C(c2ccccc2)c2ccccc2)C1
Agent: Cl
Solvent: C1CCOC1
Product: COC(=O)C1(Cc2ccc(F)cc2)CCCC(N)C1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
In a flask, methyl 3-(diphenylmethyleneamino)-1-(4-fluorobenzyl)cyclohexanecarboxylate (crude, from previous step) was dissolved in tetrahydrofuran (15 mL). Concentrated hydrochloric acid (1.2 mL) was added to the reaction. The reaction was stirred at room temperature for 5 hours. The resulting reaction mixture was concentrated to yield the crude product. The crude product was progressed to the next step without further purification.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[C:30](=[O:31])[N:7]2[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[C:9]3[NH:10][C:11]4[C:16]([C:17]=3[CH2:18][C:6]2([CH3:32])[C:5]1=[O:33])=[CH:15][C:14]([O:19][CH:20]([F:22])[F:21])=[CH:13][CH:12]=4.[CH3:34][NH2:35]>O1CCCC1>[F:21][CH:20]([F:22])[O:19][C:14]1[CH:15]=[C:16]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]1[CH:8]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([OH:29])[CH:24]=3)[N:7]3[C:30](=[O:31])[N:4]([CH2:3][CH2:2][NH:35][CH3:34])[C:5](=[O:33])[C:6]3([CH3:32])[CH2:18][C:17]2=1
Reactant: CN
Reactant: CC12Cc3c([nH]c4ccc(OC(F)F)cc34)C(c3cccc(O)c3)N1C(=O)N(CCBr)C2=O
Solvent: C1CCOC1
Product: CNCCN1C(=O)N2C(c3cccc(O)c3)c3[nH]c4ccc(OC(F)F)cc4c3CC2(C)C1=O

Procedure:
The title compound is prepared similarly as described for example 30 using (3aSR,10RS)-2-(2-Bromoethyl)-6-(1,1-difluoro-methoxy)-10-(3-hydroxy-phenyl)-3a-methyl-3a,4,9,10-tetrahydro-2,9,10a-triaza-cyclopenta[b]fluorene-1,3-dione (example 36) and a 2 M solution of methyl amine in tetrahydrofurane as starting materials. MS: m/z (MH+)=471.2
Reaction SMILES: [CH2:1]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=[O:13])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[CH2:1]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([O:14][CH2:22][CH3:23])=[O:13])=[CH:15][CH:16]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(O)c1ccc(Cc2ccccc2)cc1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(Cc2ccccc2)cc1

Procedure:
By using 4-benzylbenzoic acid (211.58 g), ethanol (1.8 l) and concentrated sulfuric acid (20 ml), there was prepared the title compound (232.55 g).
Reaction SMILES: [H-].[Na+].[C:3]([CH:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4].[CH2:27](I)[CH2:28][CH2:29][CH3:30]>CN(C)C=O>[C:3]([C:5]([C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[CH3:24])[C:12]=1[O:25][CH3:26])([CH2:27][CH2:28][CH2:29][CH3:30])[C:6]([O:8][CH2:9][CH3:10])=[O:7])#[N:4]
Reactant: CCOC(=O)C(C#N)c1cccc(Oc2ccccc2C)c1OC
Reactant: CCCCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(C#N)(C(=O)OCC)c1cccc(Oc2ccccc2C)c1OC
Yield: 110.9 %

Procedure:
A suspension of sodium hydride (65%, 600 mg) in dimethylformamide (30 ml), a solution of ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]acetate (5 g) in dimethylformamide (10 ml) and n-butyl iodide (5.7 g) were treated in a similar manner to that of Example 25-(1) to give oily ethyl 2-cyano-2-[2-methoxy-3-(o-tolyloxy)phenyl]n-hexanoate (6.5 g).
Reaction SMILES: [BH4-].[Li+].[CH3:3][C:4]([CH3:48])([CH2:46][CH3:47])[CH2:5][C:6]1[N:7]=[C:8]([CH2:30][C:31]([C:33]2[CH:38]=[CH:37][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:35][CH:34]=2)=[O:32])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:10]=1>CO>[CH3:3][C:4]([CH3:48])([CH2:46][CH3:47])[CH2:5][C:6]1[N:7]=[C:8]([CH2:30][CH:31]([C:33]2[CH:34]=[CH:35][C:36]([C:39]3[CH:44]=[CH:43][C:42]([F:45])=[CH:41][N:40]=3)=[CH:37][CH:38]=2)[OH:32])[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:10]=1
Reactant: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(=O)c2ccc(-c3ccc(F)cn3)cc2)n1
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Product: CCC(C)(C)Cc1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c(CC(O)c2ccc(-c3ccc(F)cn3)cc2)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
Lithium borohydride (22 mg, 1 mmol) was added to a −78° C. solution of 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanone (200 mg, 0.33 mmol) in methanol (20 mL). After stirring at ambient temperature for 1.5 h, the reaction mixture was quenched with acetone (1 mL) and concentrated in vacuo. Chromatography over silica eluting with 0-30% ethyl acetate/hexane afforded 2-[4-(2,2-dimethylbutyl)-1-trityl-1H-imidazol-2-yl]-1-[4-(5-fluoropyridin-2-yl)phenyl]ethanol.
Reaction SMILES: [CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([O:27]C)[CH:23]=3)[CH:18]=2)[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1>Br>[CH:1]1([CH2:7][CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[CH2:14][CH:15]([C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[C:22]([OH:27])[CH:23]=3)[CH:18]=2)[CH3:16])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1ccc2cc(C(C)CN3CCCCC3CC3CCCCC3)ccc2c1
Agent: Br
Product: CC(CN1CCCCC1CC1CCCCC1)c1ccc2cc(O)ccc2c1

Procedure:
Heating a solution of 2-cyclohexylmethyl-1-[2-(6-methoxy-2-naphthyl)-2-methylethyl]piperidine in aqueous hydrobromic acid and isolation of the product from a neutral medium affords 2-cyclohexylmethyl-1-[2-(6-hydroxy-2-naphthyl)-2-methylethyl]piperidine.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:17])([F:16])[F:15])[CH:7]=2)=[CH:4][CH:3]=[N:2]1.O[C@H:19]([CH3:29])[CH2:20][NH:21]C(=O)OC(C)(C)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>>[NH2:21][CH2:20][C@@H:19]([N:2]1[CH:3]=[CH:4][C:5]([C:6]2[CH:13]=[CH:12][C:9]([C:10]#[N:11])=[C:8]([C:14]([F:15])([F:16])[F:17])[CH:7]=2)=[N:1]1)[CH3:29]
Reactant: N#Cc1ccc(-c2ccn[nH]2)cc1C(F)(F)F
Reactant: C[C@@H](O)CNC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Product: C[C@@H](CN)n1ccc(-c2ccc(C#N)c(C(F)(F)F)c2)n1

Procedure:
The title compound was prepared from 4-(1H-pyrazol-5-yl)-2-(trifluoromethyl)benzonitrile (1.4 g, 5.90 mmol), (R)-tert-butyl 2-hydroxypropylcarbamate (1.03 g, 5.90 mmol), triphenylphosphine (2.32 g, 8.85 mmol) and di-tert-butyl azodicarboxylate (2.04 g, 8.85 mmol) using the method of Example 34(c). Yield 0.429 g. 1H NMR (400 MHz; MeOD): δ 1.52 (d, 3H), 2.98 (dd, 1H), 3.12 (dd, 1H), 4.43 (m, 1H), 6.87 (d, 1H), 7.77 (d, 1H), 7.98 (m, 1H), 8.21 (m, 1H), 8.33 (m, 1H).
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C:11]2=[O:21])[CH2:3]1.[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([C:34](O)=[O:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]>>[C:23]([O:27][C:28]([N:30]1[CH2:33][CH:32]([C:34]([O:1][C@H:2]2[CH2:19][CH2:18][C@@:17]3([CH3:20])[CH:4]([C:5](=[O:22])[CH2:6][C@@H:7]4[C@@H:16]3[CH2:15][CH2:14][C@@:12]3([CH3:13])[C@H:8]4[CH2:9][CH2:10][C:11]3=[O:21])[CH2:3]2)=[O:35])[CH2:31]1)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C1
Reactant: C[C@]12CC[C@H](O)CC1C(=O)C[C@@H]1[C@@H]2CC[C@]2(C)C(=O)CC[C@@H]12
Product: CC(C)(C)OC(=O)N1CC(C(=O)O[C@H]2CC[C@@]3(C)C(C2)C(=O)C[C@@H]2[C@@H]3CC[C@]3(C)C(=O)CC[C@@H]23)C1
Yield: 65 %

Procedure:
Prepared in 65% yield from 3β-hydroxyandrostane-6,17-dione and 1-(tert-butoxycarbonyl)-3-azetidinecarboxylic acid by the procedure described in Prepn. 43. 1H-NMR (300 MHz, DMSO-d6, ppm from TMS): δ 4.66 (1H, m), 4.50-1.00 (29H, m), 1.35 (9H, s), 0.78 (3H, s), 0.69 (3H, s).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:24])=[O:23])[C:18](B4OC(C)(C)C(C)(C)O4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:4][CH:3]=1.Br[C:37]1[CH:52]=[N:51][C:40]2[NH:41][CH:42]([C:46]3[S:47][CH:48]=[CH:49][CH:50]=3)[NH:43][C:44](=[O:45])[C:39]=2[CH:38]=1>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N:21]([CH3:26])[S:22]([CH3:25])(=[O:23])=[O:24])[C:18]([C:37]4[CH:52]=[N:51][C:40]5[NH:41][CH:42]([C:46]6[S:47][CH:48]=[CH:49][CH:50]=6)[NH:43][C:44](=[O:45])[C:39]=5[CH:38]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:15][CH3:16])=[O:14])=[CH:6][CH:7]=1
Reactant: O=C1NC(c2cccs2)Nc2ncc(Br)cc21
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(B3OC(C)(C)C(C)(C)O3)cc12
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1COCCO1
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc(N(C)S(C)(=O)=O)c(-c3cnc4c(c3)C(=O)NC(c3cccs3)N4)cc12
Temperature: 80 °C
Reaction time: 8 h
Yield: 22 %

Procedure:
To a mixture of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzofuran-3-carboxamide (150 mg, 0.30 mmol), compound 6-bromo-2-(thiophen-2-yl)-2,3-dihydropyrido[2,3-d]pyrimidin-4(1H)-one (112 mg, 0.36 mmol) and K3PO4.3H2O (239 mg, 0.90 mmol) in 1,4-dioxane (3 mL), Pd(dppf)Cl2 (20 mg) was added under N2 protection. After being stirred at 80° C. overnight, the reaction mixture was concentrated in vacuo, suspended in water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4 and concentrated. The residue was purified by prep-HPLC to give the product of 2-(4-fluorophenyl)-N-methyl-6-(N-methylmethylsulfonamido)-5-(4-oxo-2-(thiophen-2-yl)-1,2,3,4-tetrahydropyrido[2,3-d]pyrimidin-6-yl)benzofuran-3-carboxamide (40 mg, yield: 22%). 1H-NMR (DMSO-d6, 400 MHz) δ 8.80 (d, J=1.6 Hz, 1H), 8.51 (d, J=4.4 Hz, 1H), 8.26 (d, J=2.0 Hz, 1H), 8.22 (s, 1H), 7.95˜8.05 (m, 4H), 7.60 (s, 1H), 7.47 (dd, J=5.2, 1.2 Hz, 1H), 7.41 (t, J=8.8 Hz, 2H), 7.12 (d, J=2.8 Hz, 1H), 7.00 (dd, J=4.8, 3.2 Hz, 1H), 6.14 (d, J=2.4 Hz, 1H), 3.14 (s, 3H), 2.98 (s, 3H), 2.83 (d, J=4.4 Hz, 3H). MS (M+H)+: 606
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O:13]C)=[O:12])=[CH:4][CH:3]=1.[OH-].[K+:26]>>[K+:26].[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=2)[O:9][CH:10]([CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([O-:13])=[O:12])=[CH:4][CH:3]=1
Reactant: COC(=O)C(CC(C)C)OC(c1ccc(Br)cc1)c1cccnc1
Agent: [K+]
Agent: [OH-]
Product: CC(C)CC(OC(c1ccc(Br)cc1)c1cccnc1)C(=O)[O-]

Procedure:
Using the same protocol as described in example 17, step 5, methyl 2-[(4-bromophenyl)(pyridin-3-yl)methoxy]-4-methylpentanoate from step 2 (268 mg, 0.68 mmol) was hydrolysed with potassium hydroxide. The solid residue obtained was used as such in the next step.