Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:32])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15](SC)=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[CH3:33][CH:34]([NH2:39])[C:35]([CH3:38])([CH3:37])[CH3:36].C(N(CC)CC)C>C(#N)C>[F:32][C:2]([F:1])([F:31])[C:3]1[CH:4]=[C:5]([N:13]([C:15]([NH:39][CH:34]([CH3:33])[C:35]([CH3:38])([CH3:37])[CH3:36])=[C:16]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=2)(=[O:21])=[O:20])[C:17]#[N:18])[CH3:14])[CH:6]=[C:7]([C:9]([F:11])([F:10])[F:12])[CH:8]=1
Reactant: CC(N)C(C)(C)C
Reactant: CSC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC(NC(=C(C#N)S(=O)(=O)c1ccc(Cl)cc1)N(C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)C(C)(C)C
Temperature: 80 °C
Reaction time: 68 h
Yield: 43.1 %

Procedure:
To a solution of 3-[N-(3,5-Bis(trifluoromethyl)phenyl)-N-methylamino]-2-(4-chlorophenylsulfonyl)-3-methylsulfanyl-2-propenenitrile (0.300 g, 0.58 mmol) in dry acetonitrile (2 ml) was added 1,2,2-trimethylpropylamine (0.12 g) and dry triethylamine (89 μl). The mixture was stirred for 68 h at 80° C. under nitrogen. The reaction mixture was concentrated. Purification by flash chromatography using ethyl acetate/heptane 1:4 and 1:3 as eluent gave a syrup (142 mg) which was crystallised in ethanol/water to give 110 mg (33%) of the title compound. Mp 151.5-154° C. 1H NMR (300 MHz, CDCl3): δ=0.9 (s, 9H), 1.10 (d, 3H), 3.10 (m, 1H), 3.30 (s, 3H), 7.10 (s, 2H), 7.46 (s, 1H), 7.55 (d, 2H), 7.85 (d, 2H), 8.1 (br d, 1H); MA calc for C24H24ClF6N3O2S: C, 50.75%; H, 4.26%; N, 7.40%; Cl, 6.24%. Found: C, 50.79%; H, 4.28%; N, 7.24%; Cl, 6.19%.
Reaction SMILES: [F-].[Cs+].[CH3:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][C:13]=1[CH:14]1[C:23]2[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[N:21][N:20]([CH3:30])[C:19]=2[CH2:18][C:17](=[O:31])[CH2:16][CH2:15]1)[C:7]([O:9][CH3:10])=[O:8].[F:32][C:33]([Si](C)(C)C)([F:35])[F:34].[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C1COCC1>COCCOC>[OH:31][C@:17]1([C:33]([F:35])([F:34])[F:32])[CH2:18][C:19]2[N:20]([CH3:30])[N:21]=[C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][N:25]=3)[C:23]=2[C@@H:14]([C:13]2[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=2[CH3:3])[CH2:15][CH2:16]1
Reactant: C[Si](C)(C)C(F)(F)F
Reactant: COC(=O)c1ccc(C2CCC(=O)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Solvent: C1CCOC1
Product: COC(=O)c1ccc([C@H]2CC[C@@](O)(C(F)(F)F)Cc3c2c(-c2ccccn2)nn3C)c(C)c1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 8 %

Procedure:
Cesium fluoride (0.037 g, 0.244 mmol) was added to a solution of rac-methyl 3-methyl-4-(1-methyl-7-oxo-3-(pyridin-2-yl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)benzoate (0.190 g, 0.488 mmol) in DME (50 mL). The mixture was stirred at rt for about 20 min then it was cooled in an ice bath and (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added in a dropwise manner. After about 30 min, (trifluoromethyl)trimethylsilane (1.44 mL, 9.76 mmol) was added. After about 45 min, the mixture was partitioned between EtOAc (100 mL) and saturated aqueous NH4Cl solution (100 mL). The organic layer was washed with brine (100 mL), dried with Na2SO4, filtered and concentrated in vacuo. The residue was dissolved in EtOAc (20 mL) and 1 M tetrabutylammonium fluoride in THF (0.54 mL, 0.54 mmol) was added. The mixture was stirred at rt for about 1 h then it was washed with saturated NH4Cl (2×50 mL) and brine (50 mL). The organic layer was dried with Na2SO4, filtered and concentrated in vacuo. The residue was purified by column chromatography (SiO2, 25-50% EtOAc/heptane) to give rac-methyl 4-((4R,7S)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.018 g, 8%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.31-8.27 (m, 1H), 7.75-7.72 (m, 1H), 7.69-7.67 (m, 1H), 7.65-7.60 (m, 1H), 7.53-7.49 (m, 1H), 7.10-7.05 (m, 1H), 6.95 (d, J=8.1 Hz, 1H), 6.30 (s, 1H), 5.22-5.14 (m, 1H), 3.85 (s, 3H), 3.76 (s, 3H), 3.34-3.32 (m, 2H), 2.62 (s, 3H), 2.20-2.08 (m, 1H), 1.98-1.90 (m, 1H), 1.86-1.74 (m, 2H). and rac-methyl 4-((4R,7R)-7-hydroxy-1-methyl-3-(pyridin-2-yl)-7-(trifluoromethyl)-1,4,5,6,7,8-hexahydrocyclohepta[c]pyrazol-4-yl)-3-methylbenzoate (0.034 g, 15%): LC-MS (Table 1, Method g) Rt=2.28 min, m/z 460 (M+H)+; 1H-NMR (DMSO, Bruker 400 MHz) δ 8.35-8.38 (m, 1H), 7.77-7.74 (m, 1H), 7.71-7.69 (m, 1H), 7.68-7.63 (m, 1H), 7.57-7.52 (m, 1H), 7.14-7.10 (m, 1H), 6.96-6.93 (m, 1H), 6.18 (s, 1H), 5.51-5.45 (m, 1H), 3.90 (s, 3H), 3.76 (s, 3H), 3.36-3.17 (m, 2H), 2.56 (s, 3H), 2.29-2.20 (m, 1H), 1.90-1.79 (m, 1H), 1.76-1.65 (m, 2H).
Reaction SMILES: [H-].[Na+].[OH:3][C:4]1[C:5]2[N:6]([CH:10]=[C:11]([CH3:13])[N:12]=2)[CH:7]=[CH:8][CH:9]=1.[N+:14]([C:17]1[CH:24]=[CH:23][C:20]([CH2:21]Br)=[CH:19][CH:18]=1)([O-:16])=[O:15].O>CS(C)=O>[CH3:13][C:11]1[N:12]=[C:5]2[C:4]([O:3][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([N+:14]([O-:16])=[O:15])=[CH:18][CH:19]=3)=[CH:9][CH:8]=[CH:7][N:6]2[CH:10]=1
Reactant: Cc1cn2cccc(O)c2n1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cn2cccc(OCc3ccc([N+](=O)[O-])cc3)c2n1
Reaction time: 0.5 h
Yield: 40.3 %

Procedure:
A 60% dispersion of sodium hydride in mineral oil (0.3 g) was added portionwise to a suspension of 8-hydroxy-2-methylimidazo[1,2-a]pyridine (1.0 g) in dimethyl sulfoxide (10 ml) at room temperature over a period of 15 minutes. After being stirred for 30 minutes, 4-nitrobenzyl bromide (1.6 g) was added in one portion to the mixture and then the resultant mixture was stirred for 24 hours at room temperature. The mixture was poured into water and the resulting precipitate was collected by filtration. The crude product was purified by column chromatography on silica gel (30 g) with methylene chloride as an eluent to afford a solid, which was recrystallized from a mixture of ethyl acetate and n-hexane to give 2-methyl-8-(4-nitrobenzyloxy)imidazo[1,2-a]pyridine (0.77 g).
Reaction SMILES: [N:1]([CH2:4][C@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1)=[N+]=[N-]>CO.O1CCCC1.[Pd]>[NH2:1][CH2:4][C@H:5]1[CH2:9][N:8]([C:10]2[CH:11]=[CH:12][C:13]3[O:14][CH2:15][C:16](=[O:20])[NH:17][C:18]=3[N:19]=2)[C:7](=[O:21])[CH2:6]1
Reactant: [N-]=[N+]=NC[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Product: NC[C@@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reaction time: 2 h
Yield: 81.7 %

Procedure:
To a solution of 6-[(4R)-4-(azidomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (230 mg, 0.877 mmol) in methanol-tetrahydrofuran (5 ml-2.5 ml) was added 10% palladium on carbon catalyst (about 50% aqueous, 130 mg) at room temperature and the mixture was stirred at the same temperature for 2 hours under a hydrogen atmosphere. The catalyst was removed by filtration and washed with methanol, and the filtrate was concentrated under reduced pressure. The obtained residue was dissolved in dichloromethane and dried over anhydrous sodium sulfate. After removing the drying agent by filtration, the filtrate was concentrated under reduced pressure so as to yield 188 mg (90%) of the title compound in the form of a colorless solid.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.C([Li])CCC.C[O:16][B:17](OC)[O:18]C.Cl>O1CCCC1>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([B:17]([OH:18])[OH:16])=[CH:3][CH:4]=1)#[N:7]
Reactant: COB(OC)OC
Reactant: N#Cc1ccc(Br)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: N#Cc1ccc(B(O)O)cc1
Reaction time: 0.33 h
Yield: 71 %

Procedure:
To a stirred solution of 4-bromobenzonitrile (1.807 g, 0.009929 mol) in anhydrous tetrahydrofuran (30 mL) at −85° C. under nitrogen was added dropwise over 15 minutes a 2.1 M solution of n-butyl lithium in hexanes (4.7 mL, 0.0099 mol), and the mixture was stirred. After 20 minutes, trimethylborate (1.0 mL, 0.0088 mol) was added in one portion, and the mixture was allowed to slowly warm. After 40 minutes, the reaction was quenched with 1 M aqueous hydrochloric acid (2.2 mL, 0.0022 mol) and stirred. Solids began crystallizing after 1 hour. The solids were filtered, washed with diethyl ether, and dried under house vacuum (air bleed, T=40° C.) to give 0.918 g of crude (4-cyano-phenyl)boronic acid. This material was used in the next reaction without further purification.
Reaction SMILES: [CH:1]1([C:6]2[CH:7]=[CH:8][C:9]([C:17]([OH:19])=O)=[N:10][C:11]=2[O:12][CH2:13][CH:14]2[CH2:16][CH2:15]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:20][C:21]([CH2:28][CH3:29])([CH2:26][CH3:27])[C:22]([NH:24][CH3:25])=[O:23]>>[CH2:26]([C:21]([NH:20][C:17]([C:9]1[CH:8]=[CH:7][C:6]([CH:1]2[CH2:2][CH2:3][CH2:4][CH2:5]2)=[C:11]([O:12][CH2:13][CH:14]2[CH2:15][CH2:16]2)[N:10]=1)=[O:19])([C:22](=[O:23])[NH:24][CH3:25])[CH2:28][CH3:29])[CH3:27]
Reactant: O=C(O)c1ccc(C2CCCC2)c(OCC2CC2)n1
Reactant: CCC(N)(CC)C(=O)NC
Product: CCC(CC)(NC(=O)c1ccc(C2CCCC2)c(OCC2CC2)n1)C(=O)NC

Procedure:
The title compound was synthesized in analogy to Example 1, using 5-cyclopentyl-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 39 b) and 2-amino-2-ethyl-N-methyl-butyramide (Example 70 b) as starting materials, MS (EI): m/e=388.2 [M+H]+.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH2:18])=[CH:12][CH:11]=1.C(N(CC)CC)C.Cl>CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([CH2:16][CH2:17][NH:18][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[O:6])=[CH:12][CH:11]=1
Reactant: COc1ccc(CCN)cc1
Reactant: O=C(Cl)C1CCC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(CCNC(=O)C2CCC2)cc1
Reaction time: 8 h
Yield: 88.3 %

Procedure:
Cyclobutanecarbonyl chloride (5.5 g) was added to a solution of 2-(4-methoxyphenyl)ethylamine (7 g) and triethylamine (6.5 ml) in ether (300 ml) at ambient temperature. The mixture was stirred overnight, poured onto water and acidified with 2M hydrochloric acid, then the mixture was extracted with ethyl acetate (3×100 ml). The combined extracts were washed with brine, dried and the solvents removed in vacuo to give a residue. This was washed with petroleum ether and dried in vacuo to give N-[2-(4-methoxyphenyl)ethyl]cyclobutanecarboxamide as a solid (9.54 g), mp 118°-20° C.
Reaction SMILES: [F:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:3]=1[C:4]([NH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[C:13](=[C:17]([CH3:21])[C:18]([OH:20])=[O:19])[CH2:12][CH2:11][CH2:10]2)=[O:5].[CH3:27][Si](C)(C)C=[N+]=[N-]>C(OCC)C>[CH3:27][O:19][C:18](=[O:20])[C:17](=[C:13]1[C:14]2[C:9](=[CH:8][C:7]([NH:6][C:4](=[O:5])[C:3]3[C:2]([F:1])=[CH:25][CH:24]=[CH:23][C:22]=3[F:26])=[CH:16][CH:15]=2)[CH2:10][CH2:11][CH2:12]1)[CH3:21]
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C(=O)O)=C1CCCc2cc(NC(=O)c3c(F)cccc3F)ccc21
Solvent: CCOCC
Product: COC(=O)C(C)=C1CCCc2cc(NC(=O)c3c(F)cccc3F)ccc21
Reaction time: 0.25 h
Yield: 75 %

Procedure:
2-[6-(2,6-Difluoro-benzoylamino)-3,4-dihydro-2H-naphthalen-1-ylidene]-propionic acid (Compound 1) (13 mg, 0.036 mmol) was then dissolved in diethylether and excess trimethyl-silyl diazomethane (TMSCHN2) was added at room temperature. After 15 min, the reaction was quenched with acetic acid and concentrated under reduced pressure. The product, 2-[6-(2,6-difluoro-benzoylamino)-3,4-dihydro-2H-naphthalen-1-ylidene]-propionic acid methyl ester (10 mg, 75% yield) was obtained by silica gel chromatography purification using ethyl acetate/hexane as eluent.
Reaction SMILES: [Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].OS(O)(=O)=O.[N+:18]([O-])([O-:20])=[O:19].[K+]>>[Cl:1][C:2]1[C:10]([CH3:11])=[C:9]([Cl:12])[C:8]([N+:18]([O-:20])=[O:19])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: Cc1c(Cl)ccc(C(=O)O)c1Cl
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: Cc1c(Cl)c(C(=O)O)cc([N+](=O)[O-])c1Cl
Temperature: 50 °C

Procedure:
30 g of 2,4-dichloro-3-methylbenzoic acid are initially introduced into 83 ml of concentrated H2SO4. 16.7 g of KNO3 are added in portions with ice cooling. The mixture is subsequently warmed at 50° C. for a further 2 hours and then poured onto ice. The nitro compound is isolated and recrystallized from toluene. Melting point 152°-4° C., yield: 24 g.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18](Br)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[CH3:26][N:27]([CH3:39])[C:28]([C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)=[O:29].C([O-])([O-])=O.[K+].[K+]>CN(C)C=O>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:15][C:16]4[CH:21]=[CH:20][C:19]([CH2:22][C:23]#[N:24])=[C:18]([C:33]5[CH:34]=[CH:35][C:30]([C:28]([N:27]([CH3:39])[CH3:26])=[O:29])=[CH:31][CH:32]=5)[CH:17]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: CN(C)C(=O)c1ccc(B(O)O)cc1
Reactant: N#CCc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1ccc(-c2cc(NC(=O)C3(c4ccc5c(c4)OCO5)CC3)ccc2CC#N)cc1
Yield: 19.5 %

Procedure:
1-(Benzo[d][1,3]dioxol-5-yl)-N-(3-bromo-4-(cyanomethyl)phenyl)cyclopropane-carboxamide (40 mg, 0.10 mmol), 4-(dimethylcarbamoyl)phenylboronic acid (29 mg, 0.15 mmol), 1 M K2CO3 (0.2 mL, 0.2 mmol), Pd-FibreCat 1007 (8 mg, 0.1 mmol), and N,N-dimethylformamide (1 mL) were combined. The mixture was irradiated in the microwave at 150° C. for 10 minutes. Volatiles were removed in vacuo and crude product was purified by chromatography on silica gel (eluting with 0-100% ethyl acetate in hexanes) to afford 5′-(1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-2′-(cyanomethyl)-N,N-dimethylbiphenyl-4-carboxamide (9.1 mg, 20%). ESI-MS m/z calc. 467.2, found 468.5 (M+1)+; retention time 2.96 minutes.
Reaction SMILES: Br[C:2]1[C:10]2[O:9][CH2:8][CH:7]([C:11]3[CH:16]=[CH:15][C:14]([CH:17]([CH3:19])[CH3:18])=[CH:13][CH:12]=3)[C:6]=2[C:5]([CH3:20])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:27])([CH3:26])[CH3:25])[C:3]=1[CH3:29].[N:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1>>[CH:17]([C:14]1[CH:13]=[CH:12][C:11]([CH:7]2[C:2]3[C:3]([CH3:29])=[C:4]([NH:21][C:22](=[O:28])[CH2:23][C:24]([CH3:26])([CH3:25])[CH3:27])[C:5]([CH3:20])=[C:6]([C:33]4[CH:34]=[CH:35][N:30]=[CH:31][CH:32]=4)[C:10]=3[O:9][CH2:8]2)=[CH:16][CH:15]=1)([CH3:18])[CH3:19]
Reactant: OB(O)c1ccncc1
Reactant: Cc1c(Br)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(C(C)C)cc1)CO2
Product: Cc1c(NC(=O)CC(C)(C)C)c(C)c2c(c1-c1ccncc1)OCC2c1ccc(C(C)C)cc1
Yield: 72 %

Procedure:
Using N-(7-bromo-3-(4-isopropylphenyl)-4,6-dimethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 35 and pyridin-4-ylboronic acid, the title compound was obtained in the same as in Example 107.
Reaction SMILES: [OH:1][C@@H:2]([C@H:4]1[CH2:8][N:7]([C@@H:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)[CH3:10])[C:6](=[O:19])[CH2:5]1)[CH3:3].CC(C)([O-])C.[K+].[Br:26][C:27]1[N:32]=[C:31](Cl)[C:30]2[N:34]([CH3:37])[CH:35]=[N:36][C:29]=2[CH:28]=1>C1COCC1>[Br:26][C:27]1[N:32]=[C:31]([O:1][C@@H:2]([C@H:4]2[CH2:8][N:7]([C@@H:9]([C:11]3[CH:12]=[CH:13][C:14]([O:17][CH3:18])=[CH:15][CH:16]=3)[CH3:10])[C:6](=[O:19])[CH2:5]2)[CH3:3])[C:30]2[N:34]([CH3:37])[CH:35]=[N:36][C:29]=2[CH:28]=1
Reactant: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)O)CC2=O)cc1
Reactant: Cn1cnc2cc(Br)nc(Cl)c21
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc([C@@H](C)N2C[C@H]([C@@H](C)Oc3nc(Br)cc4ncn(C)c34)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of (R)-4-((R)-1-hydroxyethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 1.04 (135 mg, 0.51 mmol) in dry THF (6 mL) was added potassium tert-butoxide (72 mg, 0.64 mmol) and the reaction mixture was stirred at rt for 5 min. Then 6-bromo-4-chloro-3-methyl-3H-imidazo[4,5-c]pyridine 2.60 (105 mg, 0.43 mmol) was added and reaction mixture was heated to 60° C. After 12 h, cooled to rt, quenched the reaction mixture with water (0.5 mL) and concentrated. The residue was purified by flash column chromatography (SiO2, 0% MeOH/EtOAc to 20% EtOAc/hexanes) to give ((R)-4-((R)-1-(6-bromo-3-methyl-3H-imidazo[4,5-c]pyridin-4-yloxy)ethyl)-1-((R)-1-(4-methoxyphenyl)ethyl)pyrrolidin-2-one 2.61.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1.Br[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][Cl:39].[OH-].[Na+].O>CC(C)=O>[Cl:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:32])[C:13]3[CH:14]=[CH:15][C:16]([O:18][CH2:19][O:20][CH3:21])=[CH:17][C:12]=3[O:11][CH2:10][CH:9]2[C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:29][O:30][CH3:31])=[CH:24][CH:23]=2)=[CH:4][CH:3]=1
Reactant: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(O)cc2)cc1
Reactant: ClCCCCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: COCOc1ccc(C2COc3cc(OCOC)ccc3C2(O)c2ccc(OCCCCCCl)cc2)cc1
Temperature: 25 °C
Yield: 113.7 %

Procedure:
4-(4-Hydroxyphenyl)-4-hydroxy-7-methoxymethyloxy-3-[4-(methoxymethyloxy)phenyl]-2,3-dihydro-4H-benzopyran (180 mg, 0.4 mmol), 1-bromo-5-chloropentane (0.39 ml, 2 mmol) and 2N aqueous sodium hydroxide solution (70 μl, 2 mmol) were dissolved in acetone (4 ml) and then refluxed for 6 hours. The reaction mixture was cooled to room temperature and, after adding water, extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and then concentrated under reduced pressure to remove the organic solvent. The concentrate was subjected to column chromatography (n-hexane:ethyl acetate=4:1) to obtain 247 mg (yield: 97%) of the title compound as a colorless oil.
Reaction SMILES: [CH:1]1[C:14]2[C:13]3([CH2:16][N:17]4[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]4)[CH2:15][CH:6]([C:7]4[C:12]3=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Br[C:25]1[C:26]([O:32][CH3:33])=[N:27][CH:28]=[C:29]([Br:31])[CH:30]=1>>[Br:31][C:29]1[CH:30]=[C:25]([C:20]2([OH:23])[CH2:21][CH2:22][N:17]([CH2:16][C:13]34[CH2:15][CH:6]([C:7]5[CH:8]=[CH:9][CH:10]=[CH:11][C:12]=53)[C:5]3[C:14]4=[CH:1][CH:2]=[CH:3][CH:4]=3)[CH2:18][CH2:19]2)[C:26]([O:32][CH3:33])=[N:27][CH:28]=1
Reactant: COc1ncc(Br)cc1Br
Reactant: O=C1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Product: COc1ncc(Br)cc1C1(O)CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Yield: 63 %

Procedure:
Using a procedure similar to that described in example 1 except starting with 1-(9,10-dihydro-9,10-methanoanthracen-9-ylmethyl)-4-piperidinone (described in example 5d) and employing 3,5-dibromo-2-methoxypyridine (literature preparation: J. M. Barger, J. K. Dulworth, M. T. Kenny, R. Massao, J. K. Daniel, T. Wilson, R. T. Sargent J. Med. Chem. 1986, 29, 1590), the title compound was formed in 63% yield as an off-white solid, mp 250°-251° C. (dec). free base: 1H NMR (CDCl3, 300 MHz) 8.08 (d, J=2.3 Hz, 1H), 7.61 (d, J=2.3 Hz, 1H), 7.21 (m, 4H), 6.90 (m, 4H), 4.26 (s, 1H), 3.97 (s, 3 H), 3.56 (s, 1H), 3.47 (s, 2H), 2.86 (m, 2H), 2.77 (dt, J=2.6, 11.4 Hz, 2H), 2.60 (d, J=1.4 Hz, 2H), 1.96 (m, 4H) MS (CI, CH4) m/z 491 (M+1,100), 483 (89), 492 (37), 494 (26), 521 (M+29, 13), 473 (28) hydrochloride salt:
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([OH:26])=O)=[O:5])[CH3:2].[CH:32]([NH:35][CH:36]([CH3:38])[CH3:37])([CH3:34])[CH3:33]>>[CH2:1]([O:3][C:4]([CH:6]=[C:7]([CH3:31])[CH2:8][CH2:9][CH:10]=[C:11]([CH3:30])[CH2:12][CH2:13][CH:14]=[C:15]([CH3:29])[CH2:16][CH2:17][CH:18]=[C:19]([CH3:28])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:27])[C:24]([N:35]([CH:36]([CH3:38])[CH3:37])[CH:32]([CH3:34])[CH3:33])=[O:26])=[O:5])[CH3:2]
Reactant: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)O
Reactant: CC(C)NC(C)C
Product: CCOC(=O)C=C(C)CCC=C(C)CCC=C(C)CCC=C(C)CCC=C(C)C(=O)N(C(C)C)C(C)C

Procedure:
Starting materials: 19-ethoxycarbonyl-2,6,10,14,18-pentamethyl-2,6,10,14,18-nonadecapentaenoic acid and diisopropylamine.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]([C:8]([CH3:19])([CH3:18])[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][N:27]([CH3:34])[C:28]2=[O:33]>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:20][CH3:21])=[C:4]2[C:5](=[CH:6][CH:7]=1)[CH:11]([NH:22][C:23]1[CH:32]=[CH:31][CH:30]=[C:29]3[C:24]=1[CH:25]=[N:26][N:27]([CH3:34])[C:28]3=[O:33])[C:10]([OH:17])([C:13]([F:15])([F:16])[F:14])[CH2:9][C:8]2([CH3:19])[CH3:18]
Reactant: COc1c(Cl)cccc1C(C)(C)CC(O)(C=O)C(F)(F)F
Reactant: Cn1ncc2c(N)cccc2c1=O
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1c(Cl)ccc2c1C(C)(C)CC(O)(C(F)(F)F)C2Nc1cccc2c(=O)n(C)ncc12
Yield: 7.7 %

Procedure:
Analogously to Example 10, the corresponding imine is produced starting from 1.0 g of 4-(3-chloro-2-methoxyphenyl)-2-hydroxy-4-methyl-2-(trifluoromethyl)pentanal and 542 mg of 5-amino-2-methyl-phthalazin-1-one. As in Example 3, 840 mg of the imine is reacted by reaction with 43.6 ml of titanium tetrachloride (1 M in dichloromethane) in 40 ml of dichloromethane, and 114 mg of the title compound is obtained.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6]Cl.[OH:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1.CN(C)C1C=CC=CC=1>ClCCl>[CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][O:8][CH2:9][C:10]1[CH:11]=[C:12]([Si:15]([CH3:18])([CH3:17])[CH3:16])[O:13][CH:14]=1
Reactant: C[Si](C)(C)c1cc(CO)co1
Reactant: COCCOCCl
Solvent: CN(C)c1ccccc1
Solvent: ClCCl
Product: COCCOCOCc1coc([Si](C)(C)C)c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
2-Methoxyethoxymethyl chloride (0.11 ml, 0.96 mmol) was added to a solution of 4-hydroxymethyl-2-trimethylsilylfuran (Compound 25, also known as (2-trimethylsilyl-4-furyl)methanol, 162.8 mg, 0.96 mmol) and dimethylaniline (0 13 ml, 0.1 mmol) in dichloromethane (5 ml) at 0° After stirring at room temperature overnight (ca. 16 hours), the reaction mixture was washed successively with water, dilute hydrochloric acid and water. Evaporation of the dried (magnesium sulfate) dichloromethane layer gave an oil, which was purified by preparative silica TLC (developed with 30% ethyl ether/hexane) to give the title ether as a colorless oil.
Reaction SMILES: [OH-].[Na+].CO.C([O:7][C:8]([C:10]1[C:14]([C:15]2[CH:20]=[CH:19][C:18]([Br:21])=[CH:17][CH:16]=2)=[CH:13][S:12][C:11]=1[N:22]1[C:30](=[O:31])[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:23]1=[O:32])=[O:9])C.Cl>O>[Br:21][C:18]1[CH:19]=[CH:20][C:15]([C:14]2[C:10]([C:8]([OH:9])=[O:7])=[C:11]([N:22]3[C:30](=[O:31])[C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[C:23]3=[O:32])[S:12][CH:13]=2)=[CH:16][CH:17]=1
Reactant: CCOC(=O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1c(-c2ccc(Br)cc2)csc1N1C(=O)c2ccccc2C1=O

Procedure:
To a solution of NaOH (1.4 mmol) in a 1:1 mixture of methanol:H2O (6 mL) is added 4-(4-bromophenyl)-2-(1,3-dioxo-1,3-dihydroisoindol-2-yl)-thiophene-3-carboxylic acid ethyl ester (0.7 mmol, Example 21, Part C). The mixture is heated to reflux for 90 min, then diluted with water (12 mL), chilled in an ice bath, and acidified with concentrated HCl. The product that precipitates is collected by filtration, washed with water, and dried, affording the desired compound.