Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1.CC1(C)C(C)(C)OB([C:34]2[CH:40]=[CH:39][CH:38]=[CH:37][C:35]=2[NH2:36])O1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1COCC1.O.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[NH2:36][C:35]1[CH:37]=[CH:38][CH:39]=[CH:40][C:34]=1[C:2]1[CH:7]=[CH:6][N:5]2[C:8]([C:11]3[CH:12]=[C:13]([NH:17][C:18]([NH:20][CH2:21][C:22]([F:25])([F:24])[F:23])=[O:19])[CH:14]=[CH:15][CH:16]=3)=[CH:9][N:10]=[C:4]2[CH:3]=1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(Cl)ccn23)c1
Reactant: CC1(C)OB(c2ccccc2N)OC1(C)C
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: C1CCOC1
Product: Nc1ccccc1-c1ccn2c(-c3cccc(NC(=O)NCC(F)(F)F)c3)cnc2c1
Temperature: 125 °C
Yield: 90.4 %

Procedure:
To a mixture of 1-(3-(7-chloroimidazo[1,2-a]pyridin-3-yl)phenyl)-3-(2,2,2-trifluoroethyl)urea (20 mg, 0.052 mmol), 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (15 mg, 0.066 mmol) and cesium carbonate (51 mg, 0.156 mmol) in THF/H2O mixture (2/1, 0.75 ml) was added Pd(PtBu3)2 (3 mg, 0.005 mmol). The vial was degassed for 5 minutes then capped and heated to 125° C. for 20 minutes in a microwave. After cooling to ambient temperature, the reaction mixture was filtered through a celite pad and purified via flash cromatography (0-10% MeOH/DCM gradient containing 10% NH4OH) to yield the title compound (20 mg, 90% yield). MS (ES+) C22H18F3N5O requires: 425. Found: 426 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][C:7]=1[CH3:13].Cl[CH2:19][C:20]1[N:21]=[C:22]([C:26]2[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=2)[O:23][C:24]=1[CH3:25].C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+]>>[CH3:1][O:2][C:3](=[O:17])[C@@H:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:19][C:20]2[N:21]=[C:22]([C:26]3[CH:31]=[CH:30][C:29]([O:32][CH:33]([CH3:35])[CH3:34])=[CH:28][CH:27]=3)[O:23][C:24]=2[CH3:25])=[CH:8][C:7]=1[CH3:13]
Reactant: CCO[C@@H](Cc1ccc(O)cc1C)C(=O)OC
Reactant: Cc1oc(-c2ccc(OC(C)C)cc2)nc1CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Product: CCO[C@@H](Cc1ccc(OCc2nc(-c3ccc(OC(C)C)cc3)oc2C)cc1C)C(=O)OC

Procedure:
In analogy to the procedure described in example 1 f], (2S)-2-ethoxy-3-(4-hydroxy-2-methyl-phenyl)-propionic acid methyl ester (example 1 d]) was reacted with 4-chloromethyl-2-(4-isopropoxy-phenyl)-5-methyl-oxazole in the presence of cesium carbonate and potassium iodide to yield (S)-2-ethoxy-3-{4-[2-(4-isopropoxy-phenyl)-5-methyl-oxazol-4-ylmethoxy]-2-methyl-phenyl}-propionic acid methyl ester as colorless liquid.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:17][CH2:18][CH2:19][CH3:20]>CN(C)C=O>[CH2:17]([O:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][CH:3]=1)[CH2:18][CH2:19][CH3:20]
Reactant: O=Cc1ccc(O)cc1
Reactant: CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCCCOc1ccc(C=O)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 107.7 %

Procedure:
4-Hydroxybenzaldehyde (3 g, 24.6 mmol) and potassium carbonate (10.2 g, 73.8 mmol) were suspended in N,N-dimethylformamide (60 mL). 1-Bromobutane (3.17 mL, 29.5 mmol) was added to this suspension, and stirred for 17 hours at room temperature. The mixture was partitioned into ethyl acetate and water. The organic layer was separated, washed with water, dried over anhydrous magnesium sulfate, and filtered. The filtrate was concentrated under a reduced pressure to obtain the title compound (4.72 g).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH:8]([NH:12][C:13](=[O:22])[O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH2:7][CH2:6]2.CC1(C)COB([C:30]2[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:43])([F:42])[F:41])[CH:39]=2)[C:33]([O:35][CH3:36])=[O:34])OC1.C(=O)([O-])[O-].[Na+].[Na+]>C1COCC1.O.C(OCC)(=O)C.C1C(=O)[N-]C(=O)C1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.Br[Pd+]>[CH2:15]([O:14][C:13]([NH:12][CH:8]1[C:9]2[C:5](=[CH:4][C:3]([CH2:2][C:30]3[CH:31]=[C:32]([CH:37]=[C:38]([C:40]([F:41])([F:43])[F:42])[CH:39]=3)[C:33]([O:35][CH3:36])=[O:34])=[CH:11][CH:10]=2)[CH2:6][CH2:7]1)=[O:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C(NC1CCc2cc(CCl)ccc21)OCc1ccccc1
Reactant: COC(=O)c1cc(B2OCC(C)(C)CO2)cc(C(F)(F)F)c1
Agent: Br[Pd+]
Agent: O=C([O-])[O-]
Agent: O=C1CCC(=O)[N-]1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(Cc2ccc3c(c2)CCC3NC(=O)OCc2ccccc2)cc(C(F)(F)F)c1
Temperature: 80 °C
Yield: 86.4 %

Procedure:
A mixture of benzyl 5-(chloromethyl)-2,3-dihydro-1H-inden-1-ylcarbamate (2.10 g, 6.7 mmol), methyl 3-(5,5-dimethyl-1,3,2-dioxaborinan-2-yl)-5-(trifluoromethyl)benzoate (2.21 g, 7.0 mmol), trans-Bromo(N-succinimidyl)bis(triphenylphosphine)palladium(II) (269 mg, 0.3 mmol), and sodium carbonate (3.52 g, 33.2 mmol) in degassed THF (40 mL) and water (20 mL) was stirred at 80° C. After 3 h the reaction was cooled to rt and diluted with ethyl acetate (200 mL) and washed with brine (2×200 mL). The aqueous phases were extracted once more with ethyl acetate (1×100 mL). The combined organic extracts were dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a grey solid. The material was purified by silica flash column chromatography (100 g silica, EtOAc/heptane, from 0% to 25% of EtOAc) to afford the title compound as a white solid (2.8 g, 87%). MS (ESI): m/z [M+NH4]+ 501.2.
Reaction SMILES: C(N(C(C)C)C(C)C)C.C([Li])CCC.CCCCCC.[CH3:21][C:22]1[CH:27]=[C:26]([CH3:28])[CH:25]=[C:24]([CH3:29])[C:23]=1[C:30]1[C:31](=[O:37])[CH2:32][CH2:33][C:34]=1[O:35][CH3:36].[O:38]1[CH2:43][CH2:42][CH:41]([CH:44]=[O:45])[CH2:40][CH2:39]1>C1COCC1>[OH:45][CH:44]([CH:41]1[CH2:42][CH2:43][O:38][CH2:39][CH2:40]1)[CH:32]1[C:31](=[O:37])[C:30]([C:23]2[C:24]([CH3:29])=[CH:25][C:26]([CH3:28])=[CH:27][C:22]=2[CH3:21])=[C:34]([O:35][CH3:36])[CH2:33]1
Reactant: COC1=C(c2c(C)cc(C)cc2C)C(=O)CC1
Reactant: O=CC1CCOCC1
Agent: [Li]CCCC
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CCCCCC
Product: COC1=C(c2c(C)cc(C)cc2C)C(=O)C(C(O)C2CCOCC2)C1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 62.7 %

Procedure:
To a solution of N-ethyl-N,N-diisopropylamine (527 μl, 3.76 mmol) in THF (5 ml) under N2 at −78° C. is added, dropwise, a 2.5M solution of butyllithium in hexane (1.32 ml, 3.3 mmol) and the reaction allowed to stir at −78° C. for 20 minutes. This pale yellow solution is then added dropwise, over a period of 10 minutes, to a solution of 2-(2,4,6-trimethylphenyl)-3-methoxy-cyclopent-2-enone (691 ml, 3 mmol) in THF (5 ml) under N2, which is pre-cooled to −78° C. The resulting solution is allowed to stir at −78° C. for 40 minutes. A solution of tetrahydropyran-4-carbaldehyde (377 mg, 3.3 mmol) in THF (1 ml) is then added in one portion, the reaction mixture is stirred at −78° C. for 30 minutes before being allowed to warm to room temperature over a period of 60 minutes. The reaction was quenched by the addition of saturated aqueous ammonium chloride (50 ml) and extracted with ethyl acetate (2×50 ml). The combined organics were purified by flash chromatography to give 5-[hydroxy-(tetrahydro-pyran-4-yl)-methyl]-3-methoxy-2-(2,4,6-trimethyl-phenyl)-cyclopent-2-enone (648 mg).
Reaction SMILES: [NH2:1][CH:2]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4].[Cl:15][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1.[ClH:25]>C(O)C>[ClH:15].[ClH:25].[CH3:13][CH:12]([CH3:14])[CH2:11][CH:2]([NH:1][CH2:16][CH2:17][CH2:18][N:19]1[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)[CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[OH:4]
Reactant: CC(C)CC(N)C(O)c1ccccc1
Reactant: ClCCCN1CCCCC1
Agent: Cl
Solvent: CCO
Product: CC(C)CC(NCCCN1CCCCC1)C(O)c1ccccc1
Yield: 72 %

Procedure:
A mixture of (1RS,2SR)-2-amino-4-methyl-1-phenylpentane-1-ol (40.6 g, 210 mmol) and 1-(3-chloropropyl)piperidine (34.0 g, 210 mmol) was melted together at 50° to 70° C. in a nitrogen atmosphere. The mixture was then heated on an oil bath of 110° to 120° C. for 3 hours. After being cooled, the reaction mixture was dissolved with heating in ethanol (750 ml), followed by addition of concentrated hydrochloric acid (17 ml). The mixture was cooled and precipitated crystals were collected by filtration. The crystals were agian suspended in ethanol (1,200 ml) and heated under reflux for one hour. The mixture was cooled and the resulting crystals were collected by filtration, washed and then dried to obtain 58.8 g of the intended compound as white crystals [yield: 72%, m.p.: 268°-270° C. (decomposed)].
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][CH:16]2[CH2:18][CH2:17]2)[N:3]=1.[F:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[CH:16]1([CH2:15][NH:14][C:4]2[N:3]=[C:2]([N:29]3[CH2:28][CH2:27][N:26]([C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][CH:24]=4)[CH2:31][CH2:30]3)[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=2)[CH2:18][CH2:17]1
Reactant: Fc1ccc(N2CCNCC2)cc1
Reactant: N#Cc1c(Cl)nc(NCC2CC2)nc1NCCO
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: N#Cc1c(NCCO)nc(NCC2CC2)nc1N1CCN(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, 4-chloro-2-(cyclopropylmethyl-amino)-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile (example 48a) was treated with the 1-(4-fluorophenyl)-piperazine in dioxane in the presence of N-ethyl-diisopropyl-amine at 100° C. to yield 2-(cyclopropylmethyl-amino)-4-[4-(4-fluoro-phenyl)-piperazin-1-yl]-6-(2-hydroxy-ethylamino)-pyrimidine-5-carbonitrile as an amorphous, white solid; MS: [M+H]+=412.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]1[N:5]=[CH:6][NH:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10].[C:14](Cl)([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:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>O1CCCC1.C(OCC)(=O)C>[CH3:3][C:4]1[N:5]([C:14]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)([C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:6]=[N:7][C:8]=1[C:9]([O:11][CH2:12][CH3:13])=[O:10]
Reactant: CCOC(=O)c1[nH]cnc1C
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)c1C
Reaction time: 0.17 h
Yield: 10.2 %

Procedure:
Sodium hydride (900 mg, 80% oil dispersion, 30 mmol) was added in portions over 5 minutes to a stirred solution of ethyl 4-methyl-imidazole-5-carboxylate (3.85 g, 25 mmol) in dry tetrahydrofuran (100 ml) at room temperature under nitrogen. After 10 minutes, trityl chloride (8.36 g, 30 mmol) was added in one portion. After 1 h, the mixture was diluted with ethyl acetate (500 ml) and washed with water (200 ml). The washings were extracted with ethyl acetate (2×75 ml) and the combined organic solutions were dried (MgSO4) and concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with hexane/ethyl acetate to give ethyl 5-methyl-1-(triphenylmethyl)imidazole-4-carboxylate (1.01 g, 10%) as a white solid.
Reaction SMILES: N1C=CC=C(COC(=O)[NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([C:18]([NH:20][C:21]3[C:26]([NH:27][C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])=[CH:25][CH:24]=[C:23]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:22]=3)=[O:19])=[CH:14][CH:13]=2)C=1.C(O)=O>CCO.[Pd]>[C:31]([O:30][C:28](=[O:29])[NH:27][C:26]1[C:21]([NH:20][C:18](=[O:19])[C:15]2[CH:14]=[CH:13][C:12]([CH2:11][NH2:10])=[CH:17][CH:16]=2)=[N:22][C:23]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[CH:24][CH:25]=1)([CH3:34])([CH3:32])[CH3:33]
Reactant: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CNC(=O)OCc2cccnc2)cc1
Agent: [Pd]
Solvent: O=CO
Solvent: CCO
Product: CC(C)(C)OC(=O)Nc1ccc(-c2ccccc2)nc1NC(=O)c1ccc(CN)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
pyridin-3-ylmethyl{4-[({3-[(tert-butoxycarbonyl)amino]-6-phenylpyridin-2-yl}amino)carbonyl]benzyl}carbamate (1.5 g, 2.71 mmol) was taken up in EtOH (10.84 mL) at 0° C., evacuated and backfilled with N2. Pd/C (0.288 g, 0.27 mmol) was added and the reaction was again purged and backfilled with N2. Formic acid (2 mL, 53 mmol) was added and the reaction was stirred at RT and monitored by LC/MS. Reaction was complete in 2 h. The reaction was filtered through Celite and evaporated. The residue was taken up in DCM and washed with satd NaHCO3 solution (2×50 mL). The combined organic fractions were dried over Na2SO4, filtered and evaporated in vacuo to provide tert-butyl(2-{[4-(aminomethyl)benzoyl]amino}-6-phenylpyridin-3-yl)carbamate. MS: cal'd 419 (MH+), exp 419 (MH+).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23]([O:24]CC)=[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH:21]=[N:20][C:18]=3[N:19]=2)[CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32](I)[CH3:33]>>[CH2:1]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[N:15]=[CH:16][C:17]3[C:23](=[O:24])[C:22]([C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:21][N:20]([CH2:32][CH3:33])[C:18]=3[N:19]=2)[CH2:12][CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cnc2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1OCC
Reactant: CCI
Product: CCOC(=O)c1cn(CC)c2nc(N3CCN(Cc4ccccc4)CC3)ncc2c1=O

Procedure:
Following the procedure described in Example 37 using ethyl 2-(4-benzyl-1-piperazinyl)-5-ethoxypyrido[2,3-d] pyrimidine-6-carboxylate with ethyl iodide, there is obtained the product, m.p. 151° - 153°C.
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:24]3[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]4)=[CH:26][CH:25]=3)[C@H:8]([C:13]3[C:18]([F:19])=[C:17]([F:20])[C:16]([F:21])=[C:15]([F:22])[C:14]=3[F:23])[CH2:9][O:10]2)=[CH:5][CH:4]=1.Cl.N1C=CC=CC=1>>[OH:2][C:3]1[CH:12]=[C:11]2[C:6]([C@H:7]([C:24]3[CH:25]=[CH:26][C:27]([O:30][CH2:31][CH2:32][N:33]4[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38]4)=[CH:28][CH:29]=3)[C@H:8]([C:13]3[C:14]([F:23])=[C:15]([F:22])[C:16]([F:21])=[C:17]([F:20])[C:18]=3[F:19])[CH2:9][O:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2c(c1)OC[C@@H](c1c(F)c(F)c(F)c(F)c1F)[C@H]2c1ccc(OCCN2CCCCC2)cc1
Agent: Cl
Solvent: c1ccncc1
Product: Oc1ccc2c(c1)OC[C@@H](c1c(F)c(F)c(F)c(F)c1F)[C@H]2c1ccc(OCCN2CCCCC2)cc1

Procedure:
In an manner analogous to that described in step 5 for Example 10, (±)-cis-7-methoxy-3-(2,3,4,5,6-pentafluorophenyl)-4-(4-(2-piperidinoethoxy)phenyl)chromane (0.428 g, 0.75 mmol) was de-methylated by heating with pyridine hydrochloride to give the title compound as an off-white foam.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]([C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[CH:20]([CH3:22])[CH3:21])O)=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[C:7]([CH2:8][C:10]2[CH:15]=[C:14]([O:16][CH3:17])[C:13]([O:18][CH3:19])=[CH:12][C:11]=2[CH:20]([CH3:21])[CH3:22])=[CH:6][N:5]=[C:4]([S:23][CH3:24])[N:3]=1
Reactant: COc1cc(C(C)C)c(C(O)c2cnc(SC)nc2Cl)cc1OC
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cc(Cc2cnc(SC)nc2Cl)c(C(C)C)cc1OC
Yield: 90.2 %

Procedure:
To a solution of (4-chloro-2-methylsulfanyl-pyrimidin-5-yl)-(2-isopropyl-4,5-dimethoxy-phenyl)-methanol (6.5 g, 17.6 mmol) in 200 mL CH2Cl2 was added triethylsilane (28.0 mL, 176 mmol) and trifluoroacetic acid (TFA) (70 mL, 881 mmol). After 2 hours the solution was concentrated in vacuo, 10% K2CO3 was added and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. Purification via flash chromatography (4:1 hexanes/ethyl acetate) afforded 4-chloro-5-(2-isopropyl-4,5-dimethoxy-benzyl)-2-methylsulfanyl-pyrimidine (5.60 g, 91%) as a clear oil.
Reaction SMILES: [CH2:1]([N:4]([CH2:15][CH:16]([OH:24])[CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:5](=[O:14])[C:6]1[CH:11]=[C:10]([I:12])[CH:9]=[CH:8][C:7]=1O)[CH:2]=[CH2:3].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[CH2:1]([N:4]1[CH2:15][CH:16]([CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:24][C:7]2[CH:8]=[CH:9][C:10]([I:12])=[CH:11][C:6]=2[C:5]1=[O:14])[CH:2]=[CH2:3]
Reactant: C=CCN(CC(O)Cc1ccccc1)C(=O)c1cc(I)ccc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C=CCN1CC(Cc2ccccc2)Oc2ccc(I)cc2C1=O
Temperature: 25 °C
Yield: 38.1 %

Procedure:
To a magnetically stirred solution of N-allyl-N-(2-hydroxy-5-iodobenzoyl)-2-hydroxy-3-phenylpropylamine (12.05 grams, 0.027 mol) in 100 mL THF was added triphenylphosphine (7.24 grams, 0.027 mol), and diethyl azodicarboxylate (4.7 grams, 0.027 mol). The mixture was heated to reflux overnight, allowed to cool to room temperature, and concentrated in vacuo. the resulting residue was dissolved in ethyl acetate (10 mL) and diluted with diethyl ether. The solids that form were filtered and the mother liquor was concentrated in vacuo. The yellow oil was purified by column chromatography (SiO2, using 15% diethyl ether/85% hexane to 1:1 diethyl ether/hexane as the eluting solvent gradient, Rf(product, 1:1 Et2O/heaxane)=0.64) to yield 4.31 grams (38%) of 2-allyl-4-benzyl-8-iodo-2,3,4,5-tetrahydro-1H-5-oxa-2-benzazepin-1-one. 1H NMR (CDCl3, dTMS) 8.10 (1H, d, 4JHH =2 Hz, C9-H), 7.69 (1H, dd, 4JHH =2 Hz, 3JHH =9 Hz, C7-H), 7.4-7.2 (5H, m, C6H5), 6.76 (1H, d, 3JHH =9 Hz, C6-H), 5.79 (1H, ddt, 3JHH =17 Hz, 3JHH =11 Hz, 3JHH =6 Hz, CH2CH=CH2), 5.2-5.0 (2H, m, CH=CH2), 5.71 (1H, m, CHOH), 4.31 (1H, ddt, 2JHH =15 Hz, 3JHH =6 Hz, 4JHH =1 Hz, NCHHCH=CH2), 4.00 (1H, ddt, 2JHH =15 Hz, 3JHH =6 Hz, 4JHH =1 Hz, NCHHCH=CH2), 3.34 (1H, dd, 2JHH =16 Hz, 3JHH =5.1 Hz, C3-H), 3.25 (1H, dd, 2JHH =16 Hz, 3JHH =4.2 Hz, C3-H), 3.09 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh), 2.73 (1H, dd, 2JHH =14 Hz, 3JHH =7 Hz, CHHPh). 13C NMR (CDCl3) 166.9, 152.7, 141.4, 139.6, 136.5, 132.6, 129.8, 129.1, 128.8, 127.0, 124.6, 118.4, 86.7, 84.7, 50.4, 48.9, 38.9. IR (NaCl, cm-1) 1641, 1589, 1463, 1430, 1264, 1217, 699.
Reaction SMILES: [N:1]1([C:6]2[CH:11]=[CH:10][C:9]([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=4)[C:15](=[O:22])[C:14](=[N:23]O)[CH:13]=3)=[CH:8][CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:25][N:26]1[C:34]2[C:29](=[CH:30][C:31]([N+:35]([O-:37])=[O:36])=[CH:32][CH:33]=2)[C:28]([CH3:39])([CH3:38])[C:27]1=[CH2:40]>C1(C)C=CC=CC=1>[CH3:25][N:26]1[C:27]2([O:22][C:15]3[C:16]4[C:21]([C:12]([C:9]5[CH:8]=[CH:7][C:6]([N:1]6[CH2:2][CH2:3][CH2:4][CH2:5]6)=[CH:11][CH:10]=5)=[CH:13][C:14]=3[N:23]=[CH:40]2)=[CH:20][CH:19]=[CH:18][CH:17]=4)[C:28]([CH3:38])([CH3:39])[C:29]2[C:34]1=[CH:33][CH:32]=[C:31]([N+:35]([O-:37])=[O:36])[CH:30]=2
Reactant: C=C1N(C)c2ccc([N+](=O)[O-])cc2C1(C)C
Reactant: O=C1C(=NO)C=C(c2ccc(N3CCCC3)cc2)c2ccccc21
Solvent: Cc1ccccc1
Product: CN1c2ccc([N+](=O)[O-])cc2C(C)(C)C12C=Nc1cc(-c3ccc(N4CCCC4)cc3)c3ccccc3c1O2
Yield: 8 %

Procedure:
From 4-(4-pyrrolidinophenyl)-1,2-naphthoquinone-2-oxime and 1,3,3-trimethyl-2-methylene-5-nitroindoline. Yield=8%, m.p.=259.5-261.5° C., λmax=592 and 470 (sh.) nm in PhMe upon irradiation.
Reaction SMILES: C[N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=2)[C:4](=[O:17])[N:3]1[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl.[F:25]C1C=CC(NN)=CC=1.C(N(CC)CC)C>C1C=CC=CC=1>[F:25][C:21]1[CH:22]=[CH:23][C:18]([N:3]2[C:4](=[O:17])[C:5]([C:7]3[CH:8]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:10]=[CH:11][CH:12]=3)=[CH:6][NH:2]2)=[CH:19][CH:20]=1
Reactant: NNc1ccc(F)cc1
Reactant: Cn1cc(-c2cccc(C(F)(F)F)c2)c(=O)n1-c1ccccc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: O=c1c(-c2cccc(C(F)(F)F)c2)c[nH]n1-c1ccc(F)cc1

Procedure:
A 5.5 gram portion of the atropic ester of Example 1 was combined with 3.5 grams of 4-fluorophenylhydrazine hydrochloride and 2 grams triethylamine in 50 ml. benzene. The mixture was stirred at reflux temperature for 5 hours, after which about half of the benzene was allowed to evaporate and an equivalent amount of meta-xylene was added. The mixture was then stirred at reflux overnight, and the reaction mixture was evaporated to dryness under vacuum. The residue was partitioned between ethyl acetate and water, and the organic layer was dried over sodium sulfate and evaporated to dryness. The residue was chromatographed on silica gel with ethyl acetate as the eluant. The product containing fractions were combined and evaporated to dryness to produce about 3.5 grams of crude intermediate, which was recrystallized from methanol to produce 2.7 grams of purified 1-(4-fluorophenyl)-4-(α,α,α-trifluoro-3-tolyl)-3-pyrazolin-5-one, m.p. 171°-173° C.
Reaction SMILES: [N:1]([CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([Cl:22])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13])=[N+]=[N-]>[Pt]=O.C(OCC)(=O)C>[NH2:1][CH:4]1[C:10](=[O:11])[N:9]2[CH:5]1[CH2:6][C:7]([Cl:22])=[C:8]2[C:12]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:13]
Reactant: [N-]=[N+]=NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Agent: O=[Pt]
Solvent: CCOC(C)=O
Product: NC1C(=O)N2C(C(=O)OCc3ccccc3)=C(Cl)CC12
Reaction time: 0.5 h

Procedure:
A mixture of platinum oxide (100 mg), benzyl 6-azido-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate (80 mg), and ethyl acetate (2 ml) is hydrogenated on a Paar shaker for 30 mins at 45 psi. The resulting mixture is filtered through a pad of silica gel G which is washed with additional ethyl acetate. The filtrate is washed with water and brine, dried with magnesium sulfate, and evaporated under vacuum to afford benzyl 6-amino-3-chloro-1-azabicyclo[3.2.0]hept-2-en-7-one-2-carboxylate.
Reaction SMILES: Br[CH2:2][C:3]1[C:8]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])=[C:7]([O:16]C(OC(C)(C)C)=O)[C:6]([C:24]([F:27])([F:26])[F:25])=[CH:5][CH:4]=1.[OH:28][C:29]1[CH:34]=[CH:33][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([O:44]C)=[O:43])=[CH:37][C:36]=2[C:46](=[O:49])[CH2:47][CH3:48])=[CH:31][CH:30]=1>>[C:12]([O:11][C:9]([C:8]1[C:7]([OH:16])=[C:6]([C:24]([F:27])([F:25])[F:26])[CH:5]=[CH:4][C:3]=1[CH2:2][O:28][C:29]1[CH:30]=[CH:31][C:32]([C:35]2[CH:40]=[CH:39][C:38]([CH2:41][C:42]([OH:44])=[O:43])=[CH:37][C:36]=2[C:46](=[O:49])[CH2:47][CH3:48])=[CH:33][CH:34]=1)=[O:10])([CH3:13])([CH3:14])[CH3:15]
Reactant: CC(C)(C)OC(=O)Oc1c(C(F)(F)F)ccc(CBr)c1C(=O)OC(C)(C)C
Reactant: CCC(=O)c1cc(CC(=O)OC)ccc1-c1ccc(O)cc1
Product: CCC(=O)c1cc(CC(=O)O)ccc1-c1ccc(OCc2ccc(C(F)(F)F)c(O)c2C(=O)OC(C)(C)C)cc1

Procedure:
According to a method similar to Example (40-2), Example (33-5) and Example (17-4), from tert-butyl 6-(bromomethyl)-2-[(tert-butoxycarbonyl)oxy]-3-(trifluoromethyl)benzoate (289 mg, 0.688 mmol) obtained in Example (28-5) and methyl (4′-hydroxy-2-propionyl-1,1′-biphenyl-4-yl)acetate (174 mg, 0.626 mmol), the title compound was obtained as a colorless amorphous compound (194 mg, yield: 53%).