Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(N(CC)CC)C.[O:8]([C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([O:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)=O)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].[Cl:34][C:35]12[CH2:44][CH:39]3[CH2:40][CH:41]([CH2:43][CH:37]([C:38]3=O)[CH2:36]1)[CH2:42]2>C1COCC1.CCCCCC.[Ti](Cl)(Cl)(Cl)Cl.[Zn]>[O:8]([C:16]1[CH:17]=[C:18]([C:19](=[C:40]2[CH:41]3[CH2:43][CH:37]4[CH2:36][C:35]([Cl:34])([CH2:44][CH:39]2[CH2:38]4)[CH2:42]3)[O:21][CH2:22][CH2:23][O:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:31]=[CH:32][CH:33]=1)[Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: O=C1C2CC3CC1CC(Cl)(C3)C2
Reactant: CC(C)(C)[Si](C)(C)Oc1cccc(C(=O)OCCOc2ccccc2)c1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [Zn]
Solvent: CCN(CC)CC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)Oc1cccc(C(OCCOc2ccccc2)=C2C3CC4CC2CC(Cl)(C4)C3)c1
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
Into a 500 mL three-neck flask equipped with magnetic stirrer, pressure-equalizing addition funnel and nitrogen line was charged with 150 mL anhydrous THF. Titanium tetrachloride(12 mL) was added dropwise over a period of 30 minutes. After stirring the suspension for 20 minutes, 18 parts of zinc was added in small portions. The reaction mixture was heated under reflux for 2 hours and 29 mL of triethylamine was added dropwise. After refluxing one hour a solution 5.0 parts of ester (54) and 3.0 parts of 5-chloroadamantan-2-one in 35 mL of dry THF was added over a period of 45 minutes. The reaction mixture was heated for one hour. TLC on silica gel plate of the mixture showed the presence of starting ester. One part of 5-chloroadamantan-2-one in 20 mL of dry THF was added dropwise over 30 minutes and refluxed for two hours. The mixture was cooled to room temperature, diluted with 400 mL of hexane and decanated. The residue was washed three times with 150 mL of hexane. The combined hexane layer was filtered and evaporated under reduced pressure to give an oily material which was purified by chromatography on silica gel column using 5% ethyl acetate/hexane as an eluant. The fractions were checked by TLC on silica gel plate and the desired fractions were combined. The solvent was evaporated under reduced pressure to give an oil, yield 4.9 parts. The structure was confirmed by 1H NMR. The reaction proceeded as follows:
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[O:12])[C:5]2[S:10][C:9](=[O:11])[NH:8][C:6]=2[N:7]=1.[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[CH:25](OC)[O:24]1)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[C:13]([O:21][CH2:22][C@@H:23]1[CH2:27][C@@H:26]([N:28]2[CH2:32][CH2:31][CH2:30][CH2:29]2)[C@H:25]([N:8]2[C:6]3[N:7]=[C:2]([NH2:1])[NH:3][C:4](=[O:12])[C:5]=3[S:10][C:9]2=[O:11])[O:24]1)(=[O:20])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: COC1O[C@H](COC(=O)c2ccccc2)C[C@H]1N1CCCC1
Reactant: Nc1nc2[nH]c(=O)sc2c(=O)[nH]1
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: Nc1nc2c(sc(=O)n2[C@@H]2O[C@H](COC(=O)c3ccccc3)C[C@H]2N2CCCC2)c(=O)[nH]1
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 72.9 %

Procedure:
To a suspension of 5-amino-3,6-dihydrothiazolo[4,5-d]pyrimidine-2,7-dione (138 mg, 0.75 mmol) in ACN (5 mL) was added BSA (535 mg, 2.6 mmol). The resulting reaction mixture was then stirred at 70° C. under argon for 0.5 hour to form a clear solution. After the solution was cooled to room temperature, [(2S,4R)-5-methoxy-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32d, 230 mg, 0.75 mmol) and TMSOTf (832 mg, 3.75 mmol) were added in sequence. After being heated with stirring at 70° C. for 14 hours, the solvent was removed in vacuo. The residue was partitioned between EtOAc and saturated NaHCO3 solution (30 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (30 mL) twice. The combined organic layers were washed with brine, dried over Na2SO4 and concentrated in vacuo to afford 250 mg crude product of [(2S,4R,5R)-5-(5-amino-2,7-dioxo-6H-thiazolo[4,5-d]pyrimidin-3-yl)-4-pyrrolidin-1-yl-tetrahydrofuran-2-yl]methyl benzoate (compound 32e) as a yellow solid. MS obsd. (ESI+) [(M+H)+]: 458.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[CH2:13]([C@H:16]1[CH2:21][CH2:20][C@H:19]([C@H:22]2[CH2:27][CH2:26][C@H:25]([C:28]3[CH:33]=[C:32]([F:34])[C:31]([OH:35])=[C:30]([F:36])[CH:29]=3)[CH2:24][CH2:23]2)[CH2:18][CH2:17]1)[CH2:14][CH3:15].[CH3:37][C@H:38](O)[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl.C1COCC1>[CH2:13]([C@H:16]1[CH2:17][CH2:18][C@H:19]([C@H:22]2[CH2:23][CH2:24][C@H:25]([C:28]3[CH:29]=[C:30]([F:36])[C:31]([O:35][C@H:38]([CH3:37])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH3:44])=[C:32]([F:34])[CH:33]=3)[CH2:26][CH2:27]2)[CH2:20][CH2:21]1)[CH2:14][CH3:15]
Reactant: CCCCCC[C@H](C)O
Reactant: CCC[C@H]1CC[C@H]([C@H]2CC[C@H](c3cc(F)c(O)c(F)c3)CC2)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CCCCCC[C@@H](C)Oc1c(F)cc([C@H]2CC[C@H]([C@H]3CC[C@H](CCC)CC3)CC2)cc1F
Reaction time: 2 h

Procedure:
2.6 ml (16 mmol) of diethyl azodicarboxylate are added dropwise at room temperature to a mixture of 5 g (15 mmol) of 4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-2,6-difluorophenol, 2.1 g (16 mmol) of (S)-(+)-2-octanol, 4.3 g of triphenylphosphine and 80 ml of THF. The mixture is stirred for 2 hours and subjected to customary work-up. Chromatography gives (R)-(-)-4-[trans-4-(trans-4-propylcyclohexyl)cyclohexyl]-1-(1-methylheptyloxy)-2,6-difluorobenzene, C 29 SB 42 Ch 73.8 I, HTP=-7.7, [α]D20 =-6.9 (CH2Cl2).
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8](O)=[O:9])=[O:4].C([BH-](CC)CC)C.[Li+]>>[OH:9][CH2:8][C:7]1[CH:6]=[C:5]([CH:13]=[CH:12][CH:11]=1)[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1cccc(C(=O)O)c1
Agent: CC[BH-](CC)CC
Agent: [Li+]
Product: O=C(O)c1cccc(CO)c1
Yield: 89.4 %

Procedure:
To 3-[(methyloxy)carbonyl]benzoic acid (0.18 g, 1.0 mmol) was added lithium triethyl borohydride (3.0 mL, 1.0 M in THF, 3.0 mmol) while stirring. The mixture was stirred for 3 h and then quenched with NH4Cl (sat.) and acidified with HCl (aq.). This solution was extracted with EtOAc, and the extract was dried over Na2SO4, filtered and concentrated to afford the title compound 0.136 g (89%). LC-MS m/z 153 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[C:8]([CH2:17][CH3:18])=[N:7]2.CC1(C)C(C)(C)OB([C:27]2[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=2)O1.CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.CO.C(Cl)Cl>O1CCOCC1.O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:13]([NH:12][C:9]1[C:8]([CH2:17][CH3:18])=[N:7][C:6]2[C:11]([N:10]=1)=[C:2]([C:27]1[NH:35][C:34]3[CH2:33][CH2:32][NH:31][C:30](=[O:36])[C:29]=3[CH:28]=1)[CH:3]=[CH:4][CH:5]=2)([CH3:16])([CH3:15])[CH3:14]
Reactant: CCc1nc2cccc(Br)c2nc1NC(C)(C)C
Reactant: CC1(C)OB(c2cc3c([nH]2)CCNC3=O)OC1(C)C
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Solvent: ClCCl
Solvent: CO
Product: CCc1nc2cccc(-c3cc4c([nH]3)CCNC4=O)c2nc1NC(C)(C)C
Temperature: 100 °C
Reaction time: 1 h
Yield: 4.1 %

Procedure:
A mixture of 8-bromo-N-(tert-butyl)-3-ethylquinoxalin-2-amine (312b; 134.8 mg, 0.437 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (609) (345 mg, 0.90 mmol), K2PO4 (279 mg, 1.31 mmol), X-Phos (Strem Chemicals, Inc.) (20 mg, 0.04 mmol), and Pd2dba3 (Aldrich, 20 mg, 0.022 mmol) in a mixture of 1,4-dioxane (5.0 mL) and water (1.00 mL) was stirred under argon at 100° C. for 1 h. The reaction mixture was then concentrated onto silica gel and chromatographically purified (silica gel, 0-100% EtOAc/hexanes, then 0-10% MeOH/DCM) to provide 2-(3-(tert-butylamino)-2-ethylquinoxalin-5-yl)-6,7-dihydro-1H-pyrrolo[3,2-c]pyridin-4(5H)-one (6.7 mg, 0.018 mmol, 4% yield) as a yellow-orange solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 12.00 (1H, br. s.), 7.82 (1H, dd, J=7.4, 1.2 Hz), 7.60 (1H, dd, J=8.1, 1.3 Hz), 7.33 (1H, t, J=7.8 Hz), 7.02 (1H, d, J=2.0 Hz), 6.96 (1H, br. s.), 6.04 (1H, s), 3.42 (2H, td, J=6.9, 2.2 Hz), 2.90 (2H, q, J=7.2 Hz), 2.85 (2H, t, J=7.0 Hz), 1.56 (9H, s), 1.29 (3H, t, J=7.2 Hz). m/z (ESI, +ve) 364.1 (M+H)+.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[C:5]([NH:8][CH:9]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:10]1)(=[O:7])[CH3:6].[Cl-].[Al+3].[Cl-].[Cl-].Cl>C(Cl)CCl>[CH3:2][C:1]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[CH2:17][CH:9]([NH:8][C:5](=[O:7])[CH3:6])[CH2:10]2)=[O:3]
Reactant: CC(=O)Cl
Reactant: CC(=O)NC1Cc2ccccc2C1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)NC1Cc2ccc(C(C)=O)cc2C1
Reaction time: 3 h

Procedure:
24.4 g (0.31 mol) of acetyl chloride, followed by 35.5 g (0.20 mol) of 2-acetamido-indane are added, with stirring, to a suspension of 68 g (0.51 mol) of anhydrous aluminium chloride in 350 ml of ethylene chloride. In the course of this the reaction temperature rises to approx. 50° C. Stirring is continued for a further 3 hours, the product is decomposed by means of ice and concentrated hydrochloric acid, and the organic phase is separated off and evaporated.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[CH:7]2)([O-:3])=[O:2].N1CCCC1.[CH2:18]([N:25]1[CH2:30][CH2:29][C:28](=O)[CH2:27][CH2:26]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>C(O)C>[CH2:18]([N:25]1[CH2:26][CH:27]=[C:28]([C:7]2[C:6]3[C:10](=[CH:11][CH:12]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=3)[NH:9][CH:8]=2)[CH2:29][CH2:30]1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: O=[N+]([O-])c1ccc2[nH]ccc2c1
Reactant: O=C1CCN(Cc2ccccc2)CC1
Solvent: CCO
Solvent: C1CCNC1
Product: O=[N+]([O-])c1ccc2[nH]cc(C3=CCN(Cc4ccccc4)CC3)c2c1
Yield: 45 %

Procedure:
A solution of 5-nitroindole (38) (1.0 g, 6.167 mmol) in dry ethanol (20 mL) was treated with pyrrolidine (1.54 mL, 18.501 mmol), N-benzyl-4-piperidone (2.2 mL, 12.3 mmol) at room temperature and the resulting solution was refluxed for 4 days. The reaction was brought to room temperature and solvent was evaporated. The crude product was purified by column chromatography (2 M NH3 in methanol: CH2Cl2, 5:95) to obtain compound 71 (0.925 g, 45%) as a solid. mp 168-170° C.; 1H NMR (DMSO-d6) δ 2.51-2.55 (m, 2H), 2.66 (t, 2H, J=5.4 Hz), 3.12-3.18 (m, 2H), 3.60 (s, 2H), 6.17 (s, 1H), 7.23-7.38 (m, 5H), 7.55 (d, 1H, J=9.0 Hz), 7.65 (s, 1H), 8.01 (dd, 1H, J=2.1, 8.7 Hz), 8.68 (d, 1H, J=2.1 Hz), 11.87 (s, 1H); ESI-MS m/z (%): 334 (M+, 100).
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([CH:12]=1)[C:8](OC)=[O:9].[H-].[Al+3].[Li+].[H-].[H-].[H-].[Cl-].[NH4+]>C(OCC)C.O>[CH3:1][S:2][C:3]1[CH:12]=[C:7]([CH2:8][OH:9])[CH:6]=[N:5][CH:4]=1
Reactant: COC(=O)c1cncc(SC)c1
Agent: [Al+3]
Agent: [Cl-]
Agent: [H-]
Solvent: O
Solvent: CCOCC
Product: CSc1cncc(CO)c1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 7 %

Procedure:
Methyl 5-methylsulphanylnicotinate (916 mg, 5 mmol) is dissolved in 150 mL of diethyl ether, admixed at 0° C. with lithium aluminium hydride (660 mg, 18 mmol) and subsequently stirred at room temperature for 90 minutes. The reaction is discontinued by addition of 10% ammonium chloride solution at 0° C. The batch is diluted with water and the aqueous phase is extracted with ether. Drying of the organic phase over sodium sulphate, concentrating the solvent and also chromatographic purification of the residue (silica gel, n-hexane/ethyl acetate: 50→100% ethyl acetate) gives the desired product in 7% yield (50 mg).
Reaction SMILES: C([O:5][C:6](=[O:13])[CH2:7][CH2:8][NH:9][C:10](=[O:12])[CH3:11])(C)(C)C.C(O)C.O.[NH4+].[OH-]>>[C:10]([NH:9][CH2:8][CH2:7][C:6]([OH:13])=[O:5])(=[O:12])[CH3:11]
Reactant: CC(=O)NCCC(=O)OC(C)(C)C
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC(=O)NCCC(=O)O
Yield: 116.4 %

Procedure:
Utilizing the procedure for converting 40a to 41a, 127 (0.10 g, 0.19 mmol) gave 128 (29 mg, 39%) as a fluffy solid after flash chromotography (silica, 10:1.2:1.2 ethanol/H2O/NH4OH).
Reaction SMILES: [CH2:1]([C:16]1[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=1)[C:20](O)=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15].[H-].[Al+3].[Li+].[H-].[H-].[H-].C(OCC)(=O)C>O1CCCC1>[CH2:1]([C:16]1[CH:17]=[C:18]([OH:25])[C:19](=[CH:23][CH:24]=1)[CH2:20][OH:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15]
Reactant: CCCCCCCCCCCCCCCc1ccc(C(=O)O)c(O)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCc1ccc(CO)c(O)c1

Procedure:
4-Pentadecylsalicylic acid (5.3 g) in dry tetrahydrofuran (60 cm3) is slowly added to stirred lithium aluminium hydride (2.5 g) in dry tetrahydrofuran (25 cm3) and the mixture then stirred and refluxed for five hours to complete the reduction. Work-up by recovery of the tetrahydrofuran, addition of a little ethyl acetate to the cooled residual material, followed by acidifiction and ethereal extraction yields the crude product which is crystallised from light petroleum (40°-60°) to give 4-pentadecylsalicyl alcohol as pale cream prisms, m.p. 94°-95°, (4.05 g).
Reaction SMILES: [CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)[CH2:3][CH2:2]1.Cl[CH2:17][CH2:18][N:19]([CH3:39])[C:20]([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:1]1([C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:10]2[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][N:19]([CH3:39])[C:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)([C:21]3[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:33]3[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=3)[CH2:14][CH2:15]2)[CH2:3][CH2:2]1
Reactant: CN(CCCl)C(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: c1ccc(N2CCNCC2)c(C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CN(CCN1CCN(c2ccccc2C2CC2)CC1)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 96 °C
Yield: 18.7 %

Procedure:
9.0 g (44.4 mmol) of 1-(2-cyclopropylphenyl)piperazine, 200 ml of dimethylformamide, 15 g (44.4 mmol) of 2-chloro-N-methyl-N-(triphenylmethyl)-ethanamine and 9 g of potassium carbonate are introduced into a 500-ml round bottom flask fitted with a condenser and placed under nitrogen and the mixture is heated to 96° C. for 6 h three times. The solvent is evaporated off, the residue is taken up with water and dichloromethane, the organic phase is separated off, is washed with water and is dried over sodium sulphate and the solvent is stripped off. 4.17 g of 2-[4-(2-cyclopropylphenyl)piperazin- 1-yl]-N-methyl-N-(triphenylmethyl)ethanamine are obtained in the form of oil, which is dissolved in 200 ml of methanol, gaseous hydrochloric acid is bubbled through it for 10 min, the mixture is concentrated, is allowed to stand for 2 days and the precipitate is separated off by filtration. 2.94 g of compound are obtained.
Reaction SMILES: [Br:1][CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:15])([CH3:14])[O:11][CH2:10][C:9]=2[CH:16]=1)=[O:4].B.C1COCC1>C1COCC1>[Br:1][CH2:2][C@@H:3]([C:5]1[CH:6]=[CH:7][C:8]2[O:13][C:12]([CH3:14])([CH3:15])[O:11][CH2:10][C:9]=2[CH:16]=1)[OH:4]
Reactant: CC1(C)OCc2cc(C(=O)CBr)ccc2O1
Agent: B
Solvent: C1CCOC1
Product: CC1(C)OCc2cc([C@@H](O)CBr)ccc2O1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To the product of step (c) (10 g, 35.1 mmol) in 100 mL of THF was added the solid catalyst of Preparation 13, step (c)(1) (0.97 g, 3.5 mmol). The solution was cooled to between −20° C. and −10° C. and BH3-THF (35 mL, 35 mmol) diluted with 50 mL THF was added dropwise via a dropping funnel. After the addition was complete, the reaction mixture was allowed to warm to ambient temperature. After 30 minutes, the reaction mixture was quenched by slow addition of 50 mL of methanol and then concentrated to a thick oil. The oil was purified by silica gel chromatography eluted with 1:2 ethyl acetate/hexanes. The fractions were combined and concentrated to give the title compound as an off-white solid.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[CH:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH:13](O)[CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[C:15]2[CH:16]=[CH:17][O:18][C:14]=2[CH2:13][CH2:12][CH:11]=1
Reactant: OC1CCC(c2cc3ccccc3o2)c2ccoc21
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: C1=C(c2cc3ccccc3o2)c2ccoc2CC1
Yield: 85.3 %

Procedure:
To a mixture of 19.3 g of 4,5,6,7-tetrahydro-4-(2-benzofuryl)-benzofuran-7-ol in 400 ml of toluene was added 100 mg of p-toluene sulfonic acid, and the mixture was placed on a Rotovap®, and the solvent was distilled in vacuo (60° C.) until a residue was obtained. The residue was chromatographed on silica (hexane/methylene chloride 1.5:1) to afford 15.3 g (86%) of 6,7-dihydro-4-(2-benzofuryl)-benzofuran, (Formula III: ##STR9## R4 =2-benzofuryl) as an orange oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])N(OC)C)([CH3:4])([CH3:3])[CH3:2].Br[C:25]1[CH:30]=[CH:29][C:28]([Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1.C([Li])(C)(C)C>>[C:1]([O:5][C:6](=[O:23])[NH:7][CH:8]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)[C:9](=[O:14])[C:25]1[CH:30]=[CH:29][C:28]([Si:31]([CH3:34])([CH3:33])[CH3:32])=[CH:27][CH:26]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CON(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Cl)c(Cl)c1
Reactant: C[Si](C)(C)c1ccc(Br)cc1
Agent: [Li]C(C)(C)C
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc([Si](C)(C)C)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[(3,4-dichloro-phenyl)-(methoxy-methyl-carbamoyl)-methyl]-carbamic acid tert-butyl ester (Intermediate 9) and 1-bromo-4-(trimethylsilyl)benzene with tert-butyl-lithium instead of n-butyllithium in analogy to Example 1a): MS (ISP): 452.0 and 454.0 (M+H)+.
Reaction SMILES: C1(OC)C=CC=CC=1.[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[C:18](/[C:37]2[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=2)=[CH:19]/[C@@H:20]2[N:24](CC3C=CC(OC)=CC=3OC)[C:23](=[O:36])[CH2:22][CH2:21]2)=[N:14][C:15]=1[O:16][CH3:17]>FC(F)(F)C(O)=O>[Br:9][C:10]1[CH:11]=[CH:12][C:13](/[C:18](/[C:37]2[CH:38]=[CH:39][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:41][CH:42]=2)=[CH:19]/[C@@H:20]2[NH:24][C:23](=[O:36])[CH2:22][CH2:21]2)=[N:14][C:15]=1[O:16][CH3:17]
Reactant: COc1ccc(CN2C(=O)CC[C@@H]2/C=C(\c2ccc(C(C)(C)C)cc2)c2ccc(Br)c(OC)n2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: COc1nc(/C(=C/[C@H]2CCC(=O)N2)c2ccc(C(C)(C)C)cc2)ccc1Br
Temperature: 70 °C
Reaction time: 5 h

Procedure:
Trifluoroacetic acid (10 mL) and anisole (5 mL) were added to (5R)-5-[(E)-2-(5-bromo-6-methoxypyridin-2-yl)-2-(4-tert-butylphenyl)ethenyl]-1-(2,4-dimethoxybenzyl)pyrrolidin-2-one (950 mg), and the mixture was stirred at 70° C. for five hours. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=4:1→1:4) to give the title compound as a yellow amorphous (460 mg, 66%).
Reaction SMILES: Cl[C:2]1[C:11]([C:12]#[N:13])=[CH:10][C:9]2[C:4](=[CH:5][C:6]([O:14][CH3:15])=[CH:7][CH:8]=2)[N:3]=1.[NH2:16][C:17]1[CH:22]=[C:21]([OH:23])[C:20]([CH3:24])=[CH:19][CH:18]=1.Cl.N1C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>C(OCCO)C.O>[OH:23][C:21]1[CH:22]=[C:17]([NH:16][C:10]2[C:9]3[C:4](=[CH:5][C:6]([O:14][CH3:15])=[CH:7][CH:8]=3)[N:3]=[CH:2][C:11]=2[C:12]#[N:13])[CH:18]=[CH:19][C:20]=1[CH3:24]
Reactant: COc1ccc2cc(C#N)c(Cl)nc2c1
Reactant: Cc1ccc(N)cc1O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCOCCO
Solvent: O
Solvent: c1ccncc1
Product: COc1ccc2c(Nc3ccc(C)c(O)c3)c(C#N)cnc2c1

Procedure:
To a suspension of 200 mg (0.91 mmol) of -chloro-7-methoxy-3-quinolinecarbonitrile and 135.5 mg (1.10 mmol) of 5-amino-o-cresol in 10 mL of 2-ethoxy ethanol was added 105.6 mg (0.91 mmol) of pyridine hydrochloride. The resulting reaction mixture was refluxed for 1 hr, and then the solvent was removed to give a residue. To the residue was added about 30 mL of water and neutralized to pH 7-8 by addition of diluted sodium carbonate solution. The precipitate was collected by filtration and washed with water and ether. After drying in vacuo, this afforded 277 mg (99%) of the product as a yellow solid, m.p.>250° C., mass (electrospray, m/e): M+H 305.9.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:22])=[C:6]([NH:8][C:9]2[N:10]=[CH:11][C:12]3[N:17]=[C:16]([NH:18][C:19](=[O:21])[CH3:20])[S:15][C:13]=3[N:14]=2)[CH:7]=1.[CH3:23][C:24]([C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][CH:36]=1)[C:31](O)=[O:32])([CH3:27])[C:25]#[CH:26].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(=O)([O-])O.[Na+]>N1C=CC=CC=1>[C:19]([NH:18][C:16]1[S:15][C:13]2[N:14]=[C:9]([NH:8][C:6]3[CH:7]=[C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][CH:36]=[C:28]([C:24]([CH3:23])([CH3:27])[C:25]#[CH:26])[CH:29]=4)[CH:3]=[CH:4][C:5]=3[CH3:22])[N:10]=[CH:11][C:12]=2[N:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)Nc1nc2cnc(Nc3cc(N)ccc3C)nc2s1
Reactant: C#CC(C)(C)c1cccc(C(=O)O)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: c1ccncc1
Product: C#CC(C)(C)c1cccc(C(=O)Nc2ccc(C)c(Nc3ncc4nc(NC(C)=O)sc4n3)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.3 %

Procedure:
A solution of N-{5-[(5-amino-2-methylphenyl)amino][1,3]thiazolo[5,4-d]pyrimidin-2-yl}acetamide (120 mg, 382 μmol) produced in Example D35(v), 3-(1,1-dimethylprop-2-yn-1-yl)benzoic acid (458 mg, 458 μmol) produced in Example D20(iii) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (174 mg, 458 μmol) in pyridine (4 mL) was stirred at room temperature for 1 hr. To the reaction mixture was added saturated aqueous sodium hydrogen carbonate solution (15 mL), and the mixture was extracted with ethyl acetate (20 mL, 5 mL). The combined organic layer was washed with saturated brine (5 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained residue was purified by basic silica gel column chromatography (hexane/ethyl acetate=20/80→0/100), and the fractions containing the object product were concentrated under reduced pressure. The obtained residue was recrystallized from tetrahydrofuran to give the title compound (145 mg, 78%) as colorless crystals.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:11]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][C:14]=2[F:20])=[C:10]([CH3:21])[C:9](=[O:22])[N:8]([CH3:23])[C:7]=1[CH2:24]Br)=O)C.[NH2:26][NH2:27]>CO.CCOC(C)=O>[F:20][C:14]1[CH:15]=[C:16]([CH3:19])[CH:17]=[CH:18][C:13]=1[NH:12][C:11]1[C:6]2[C:4](=[O:3])[NH:27][NH:26][CH2:24][C:7]=2[N:8]([CH3:23])[C:9](=[O:22])[C:10]=1[CH3:21]
Reactant: CCOC(=O)c1c(Nc2ccc(C)cc2F)c(C)c(=O)n(C)c1CBr
Reactant: NN
Solvent: CO
Solvent: CCOC(C)=O
Product: Cc1ccc(Nc2c3c(n(C)c(=O)c2C)CNNC3=O)c(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 2-bromomethyl-4-(2-fluoro-4-methylphenylamino)-1,5-dimethyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid ethyl ester (1 equivalent) in MeOH is added hydrazine (1.10 equivalents). After stirring for 2 hours at room temperature, the reaction mixture is heated to 40° C. for 8 hours. The reaction mixture is diluted with EtOAc and washed with water. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give the crude material that is purified by trituration or flash column chromatography to afford the desired product as necessary.