Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:8]([OH:10])=O)[CH2:3][CH2:4][C:5]([OH:7])=[O:6].C1(C)C(S(O)(=O)=O)=CC=CC=1.[CH2:22]([O:29][C:30](=[O:39])[CH2:31][NH:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(N1CCOCC1)C.C1(N=C=NC2CCCCC2)CCCCC1>ClCCl.CN(C=O)C.ClCCl>[CH2:22]([O:29][C:30](=[O:39])[CH2:31][N:32]([C:8](=[O:10])[C@H:2]([CH2:3][CH2:4][C:5](=[O:6])[OH:7])[NH2:1])[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)[C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(CNc1ccccc1)OCc1ccccc1
Reactant: N[C@@H](CCC(=O)O)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CCN1CCOCC1
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N[C@@H](CCC(=O)O)C(=O)N(CC(=O)OCc1ccccc1)c1ccccc1

Procedure:
A solution of 20 mmoles of pyro-L-glutamic acid and 20 mmoles phenylglycine benzyl ester toluene sulfonic acid, neutrallized with N-ethyl morpholine, in dichloromethane:DMF (4:1) is cooled in an ice bath with stirring. A solution of 20 mmoles of dicyclohexylcarbodiimide in dichloromethane is added to the above reaction mixture. The reaction mixture is stirred in an ice water bath for 1 hour and then at room temperature overnight. Dicyclohexylurea is removed by filtration and the product is washed in ethyl acetate. Solvents of the combined filtrates are removed under reduced pressure with a rotary evaporator at 40° C. Ethyl acetate is added to the residue and the organic solution is washed until neutral. The organic phase is dried over anhydrous MgSO4, filtered and then the solvent is removed with a rotary evaporator. The material is crystallized from isopropanol and ether yielding the named product.
Reaction SMILES: [CH3:1][C:2]1=[CH:3][CH2:4][C:5]([CH3:15])([CH3:14])[CH:6]=[CH:7][CH2:8][C:9]([CH3:13])=[CH:10][CH2:11][CH2:12]1.CC1C23CC=C(C)C2C3C(C(C)C)CC1.CC1[C@@H]2C[C@H](C(C)=C)CC[C@@]2(C)CCC=1.CC1C2CC(CCC2(C)CCC=1)=C(C)C.CC1CCC2[C@H]([C@H](C(C)C)CCC=2C)C=1.C[C@@H]1C2CC[C@H](C)C=2C[C@H](C(C)=C)CC1>>[CH3:13][C:9]1=[CH:10][CH2:11][CH2:12][C:2]([CH3:1])=[CH:3][CH:4]=[C:6]([CH:5]([CH3:14])[CH3:15])[CH2:7][CH2:8]1
Reactant: CC1=CCCC(C)=CCC(C)(C)C=CC1
Agent: C/C1=C\C=C(\C(C)C)CC/C(C)=C/CC1
Agent: C/C1=C\CC/C(C)=C/CC(C)(C)/C=C/C1
Agent: C=C(C)[C@@H]1CC[C@@]2(C)CCC=C(C)[C@@H]2C1
Product: CC1=CC=C(C(C)C)CCC(C)=CCC1

Procedure:
The sources of authentic terpene standards were as follows: α-longipinene, cyclosativene, sativene and α-ylangene were from Abies balsamea oleoresin; δ-selinene was from Abies alba oleoresin; α-, β-, and γ-himachalene, α- and δ-amorphene, α-muurolene, guaia-6,9-diene, α-cadinene, δ-selinene, germacrene A, β-ylangene, β-longipinene, E-α- and β-bisabolene were gifts from Larry Cool (University of California, Berkeley); germacrene B, and black pepper oleoresin containing a-cubebene and α-copaene, were gifts from Robert Adams (Baylor University); γ-humulene was from allspice seeds and as a gift from Ron Binder (USDA, Albany, Cailf.); sibirene and longicyclene were from Pinus sibirica oleoresin; longifolene was purchased from Sigma Chemical Co.; E-β-farnesene was from parsley leaf oil; germacrene D was from the essential oil of caraway and Nepeta mussini; β-caryophyllene was a gift from Rudolf Hopp (Haarmann and Reimer GmbH); γ-bisabolene was isolated from carrot roots; α-humulene was purchased from Fluka Chemical Co.; α-cubebene was from the essential oil of Valencia orange peels; α-selinene and seli-3,7(11)-diene were from celery seed; δ-cadinene was a gift from Margaret Essenberg (Oklahoma State University); α-guaiene was from patchouli essential oil; germacrene C was isolated from tomato leaf oil; bicyclogermacrene was from the essential oil of marjoram; and β-gurjunene was from ginger root. All other biochemicals and reagents were purchased from Sigma Chemical Co. or Aldrich Chemical Co., unless otherwise noted.
Reaction SMILES: Br[C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7].[C:13](P(C(C)(C)C)C1C=CC=CC=1)(C)(C)[CH3:14].C1(C(N)C2CCCCC2)CCCCC1.C=C.Cl>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CC(N(C)C)=O>[CH:13]([C:2]1[C:3]([C:9]([F:12])([F:11])[F:10])=[N:4][N:5]([CH3:8])[C:6]=1[CH3:7])=[CH2:14]
Reactant: Cc1c(Br)c(C(F)(F)F)nn1C
Reactant: CC(C)(C)P(c1ccccc1)C(C)(C)C
Agent: [Pd+2]
Agent: C=C
Agent: CC(=O)[O-]
Solvent: CC(=O)N(C)C
Product: C=Cc1c(C(F)(F)F)nn(C)c1C
Temperature: 130 °C
Reaction time: 30 h
Yield: 83 %

Procedure:
10.0 g (41.2 mmol) of 4-bromo-1,5-dimethyl-3-(trifluoromethyl)-1H-pyrazole, 92.4 mg (0.41 mmol) of palladium acetate and 302 mg (0.82 mmol) of tetra-n-butylammonium bromide are weighed into the glass insert of an autoclave together with 366 mg (1.65 mmol) of di(tert-butyl)phenylphosphine, 8.84 g (45.3 mmol) of dicyclohexylmethylamine and dimethylacetamide (34.3 ml), and placed under a protective gas atmosphere. Subsequently, 30 bar of ethylene are injected at 20° C. and the reaction mixture is stirred at 130° C. for 30 h. After the end of the reaction, the mixture is cooled, poured onto cold dilute hydrochloric acid and extracted with CH2C12. The combined organic phases which have been dried over magnesium sulphate are concentrated. The product is obtained as a brown oil in an 83% yield.
Reaction SMILES: C([O:3][C:4](=[O:36])[C:5]([CH3:35])([CH3:34])[CH2:6][NH:7][C:8]([C:10]1[N:11]=[C:12]([C:32]#[N:33])[C:13]2[C:18]([C:19]=1[OH:20])=[CH:17][CH:16]=[C:15]([O:21][C:22]1[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=1)[CH:14]=2)=[O:9])C.O.CCOC(C)=O.Cl>CO.[OH-].[Na+]>[C:32]([C:12]1[C:13]2[C:18](=[CH:17][CH:16]=[C:15]([O:21][C:22]3[CH:31]=[CH:30][C:29]4[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH:23]=3)[CH:14]=2)[C:19]([OH:20])=[C:10]([C:8]([NH:7][CH2:6][C:5]([CH3:35])([CH3:34])[C:4]([OH:36])=[O:3])=[O:9])[N:11]=1)#[N:33]
Reactant: CCOC(=O)C(C)(C)CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CO
Product: CC(C)(CNC(=O)c1nc(C#N)c2cc(Oc3ccc4ccccc4c3)ccc2c1O)C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
3-{[1-Cyano-4-hydroxy-7-(naphthalen-2-yloxy)-isoquinoline-3-carbonyl]-amino}-2,2-dimethyl-propionic acid ethyl ester (18 mg, 0.04 mmol) was dissolved in MeOH (3 mL) and 2 N NaOH (3 mL). After stirring for 4 hours at room temperature, H2O (15 mL) and EtOAc (15 mL) were added. To the stirred mixture was added 1 N hydrochloric acid until pH was 1. The layers were separated and the aqueous layer was extracted twice with EtOAc. The combined organic layers were dried over MgSO4, concentrated, and purified by flash chromatography (0-30% MeOH/CH2Cl2) to give the title compound in 10 mg. MS: (−) m/z 453.90 (M−1).
Reaction SMILES: [CH3:1][O:2][CH:3]([O:15][CH3:16])[CH2:4][NH:5][CH2:6][CH2:7][CH2:8][N:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27](O)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[Cl:17][C:18]1[CH:19]=[C:20]([NH:25][CH:26]([CH3:30])[C:27]([N:5]([CH2:4][CH:3]([O:15][CH3:16])[O:2][CH3:1])[CH2:6][CH2:7][CH2:8][N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[O:28])[CH:21]=[CH:22][C:23]=1[Cl:24]
Reactant: CC(Nc1ccc(Cl)c(Cl)c1)C(=O)O
Reactant: COC(CNCCCN1CCCCC1)OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: COC(CN(CCCN1CCCCC1)C(=O)C(C)Nc1ccc(Cl)c(Cl)c1)OC
Yield: 70.2 %

Procedure:
To a solution of (2,2-dimethoxy-ethyl)-(3-piperidin-1-yl-propyl)-amine (400 mg, 1.74 mmol) in N,N-dimethylformamide (4 mL) were added 2-(3,4-dichloro-phenylamino)-propionic acid (intermediate 11; 337 mg, 1.91 mmol), 4-methylmorpholine (527 mg, 5.21 mmol) and O-(7-azabenzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (990 mg, 2.61 mmol) at RT, then after 2 h the reaction mixture was partitioned between EtOAc and sat. aq. NaHCO3 solution. The organic layer was washed with brine, dried (MgSO4), and evaporated. Chromatography (SiO2; CH2Cl2/MeOH/25% aq. ammonia solution 90:10:0.25) afforded the title compound (545 mg, 70%). Yellow viscous oil, MS: 446.2 (M+H)+.
Reaction SMILES: [N:1]1([C:6]2[C:7]3[N:8]([C:16]([C:19]([OH:21])=O)=[CH:17][N:18]=3)[CH:9]=[C:10]([C:12]([F:15])([F:14])[F:13])[CH:11]=2)[CH:5]=[N:4][CH:3]=[N:2]1.FC(F)(F)C(O)=O.[CH:29]12[CH2:35][CH:33]([NH:34]1)[CH2:32][O:31][CH2:30]2.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(=O)(O)[O-].[Na+]>CN(C=O)C.C(N(CC)CC)C>[CH:33]12[CH2:35][CH:29]([N:34]1[C:19]([C:16]1[N:8]3[CH:9]=[C:10]([C:12]([F:14])([F:13])[F:15])[CH:11]=[C:6]([N:1]4[CH:5]=[N:4][CH:3]=[N:2]4)[C:7]3=[N:18][CH:17]=1)=[O:21])[CH2:30][O:31][CH2:32]2
Reactant: O=C(O)c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12
Reactant: C1OCC2CC1N2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CN(C)C=O
Solvent: O=C(O)C(F)(F)F
Solvent: CCN(CC)CC
Product: O=C(c1cnc2c(-n3cncn3)cc(C(F)(F)F)cn12)N1C2COCC1C2
Temperature: 25 °C
Reaction time: 12 h
Yield: 57.9 %

Procedure:
A mixture of 8-(1H-1,2,4-triazol-1-yl)-6-(trifluoromethyl)imidazo[1,2-a]pyridine-3-carboxylic acid (80 mg), 3-oxa-6-azabicyclo[3.1.1]heptane 2,2,2-trifluoroacetate (75 mg), HATU (133 mg), triethylamine (150 μL) and anhydrous DMF (3 mL) was stirred at room temperature for 12 hr, saturated aqueous sodium bicarbonate solution was added thereto, and the mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane), and the obtained solid was recrystallized from ethyl acetate/hexane to give the title compound (59 mg).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][C@H:13]1[C:21]2[C:20]([N:22]3[CH2:27][CH2:26][N:25]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[CH2:24][CH2:23]3)=[N:19][CH:18]=[N:17][C:16]=2[CH2:15][CH2:14]1.C([O-])(O)=O.[Na+].[O-]S([O-])(=S)=O.[Na+].[Na+].C([O-])([O-])=O.[Na+].[Na+]>C(Cl)(Cl)Cl.O>[C:31]([O:30][C:28]([N:25]1[CH2:24][CH2:23][N:22]([C:20]2[N:19]=[CH:18][N+:17]([O-:9])=[C:16]3[CH2:15][CH2:14][C@@H:13]([CH3:12])[C:21]=23)[CH2:27][CH2:26]1)=[O:29])([CH3:33])([CH3:32])[CH3:34]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: C[C@@H]1CCc2ncnc(N3CCN(C(=O)OC(C)(C)C)CC3)c21
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: O=S([O-])([O-])=S
Solvent: ClC(Cl)Cl
Solvent: O
Product: C[C@@H]1CCc2c1c(N1CCN(C(=O)OC(C)(C)C)CC1)nc[n+]2[O-]
Temperature: 25 °C
Reaction time: 7.5 h
Yield: 100 %

Procedure:
Solid 77% max. m-chloroperbenzoic acid (“m-CPBA”; 23.9 g, 107 mmol) was added portionwise to a 0° C. solution of (R)-tert-butyl 4-(5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidin-4-yl)piperazine-1-carboxylate (20.0 g, 62.8 mmol) in CHCl3 (310 mL). The reaction mixture was stirred 5 for minutes, then warmed to room temperature and stirred for an additional 90 minutes. HPLC looked similar after 7.5 hours. The reaction mixture was cooled to 0° C., and then NaHCO3 (13.2 g, 157 mmol) and another 0.5 equivalents of m-CPBA were added. The reaction mixture was stirred overnight (14 hours). The reaction mixture was cooled to 0° C., and a solution of Na2S2O3 (29.8 g, 188 mmol) in H2O (50 mL) was added dropwise by addition funnel. This was followed by a solution of Na2CO3 (24.6 g, 232 mmol) in H2O (70 mL) by addition funnel (mixture turns homogeneous). The reaction mixture was stirred for 30 minutes, and then the mixture was extracted with CHCl3 (3×150 mL). The combined extracts were dried (Na2SO4), filtered, and concentrated to give (R)-4-(4-(tert-butoxycarbonyl)piperazin-1-yl)-5-methyl-6,7-dihydro-5H-cyclopenta[d]pyrimidine 1-oxide (21.0 g, 100%). LC/MS (APCI+) m/z 335.1 [M+H]+.
Reaction SMILES: [N+](=[C:3]([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5])=[N-].[CH3:12][C:13](=[C:15]([CH3:17])[CH3:16])[CH3:14]>[Hg]>[CH3:12][C:13]1([CH3:14])[C:15]([CH3:17])([CH3:16])[C:3]1([C:8]([O:10][CH3:11])=[O:9])[C:4]([O:6][CH3:7])=[O:5]
Reactant: CC(C)=C(C)C
Reactant: COC(=O)C(=[N+]=[N-])C(=O)OC
Agent: [Hg]
Product: COC(=O)C1(C(=O)OC)C(C)(C)C1(C)C
Yield: 30.8 %

Procedure:
A mixture of 20.0 grams (0.13 mole) of dimethyl diazomalonate and 164.35 grams (1.95 moles) of 2,3-dimethyl-2-butene was photolyzed at room temperature for a period of approximately 47 hours in the presence of a 100-watt Hanovia mercury lamp. Most of the unreacted 2,3-dimethyl-2-butene was removed by distillation, at atmospheric pressure, to a head temperature of 73° C. and the still residue was subjected to flash chromatography on a silica gel column to give 9.00 grams (0.04 mole) of dimethyl 2,2,3,3-tetramethylcyclopropanedicarboxylate. NMR analysis of the product indicated the following:
Reaction SMILES: Br[C:2]1[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=1.[CH:13]1(B(O)O)[CH2:15][CH2:14]1.C1(P(C2CCCCC2)C2CCCCC2)CCCCC1.C(=O)([O-])[O-].[K+].[K+].[OH-].[NH4+]>C1(C)C=CC=CC=1.O.CCCCCCC.C(OCC)(=O)C>[CH:13]1([C:2]2[CH:10]=[C:9]([CH3:11])[C:5]([C:6]([NH2:8])=[O:7])=[C:4]([F:12])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: Cc1cc(Br)cc(F)c1C(N)=O
Reactant: OB(O)C1CC1
Agent: C1CCC(P(C2CCCCC2)C2CCCCC2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cc(C2CC2)cc(F)c1C(N)=O
Temperature: 60 °C

Procedure:
A mixture of 4-bromo-2-fluoro-6-methylbenzamide (10 g), cyclopropylboronic acid (4.87 g, 1.25 eq), tricyclohexylphosphine (725 mg, 0.06 eq), tris (dibenzyllideneacetone)dipalladium(0) chloroform adduct (446 mg, 0.01 eq) and potassium carbonate (17.9 g, 3 eq) in toluene (100 ml) and water (10 ml) was stirred under reflux in an inert (nitrogen) environment for about 24 h. The reaction mixture was then cooled to about 60° C. and treated with 10% aqueous ammonium hydroxide (60 ml) and then with ethyl acetate (60 ml). Layers were separated, the organic phase was washed with brine and filtered to remove particulate material. The extract was concentrated under reduced pressure to about 30 ml to obtain a slurry. This was diluted with heptane (80 ml) and ethyl acetate (20 ml) and then heated to reflux to dissolve all solids. The resulting solution cooled slowly to room temperature to allow the product to crystallize out. The precipitated product was isolated by filtration, washed with ethyl acetate-heptane (1:1) mixture (60 ml), dried under vacuum at about 60° C. to obtain 6.85 g (82.3% isolated yield) of product.
Reaction SMILES: [CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH2:15])=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2.Cl[C:17]1[N:22]=[CH:21][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:19][N:18]=1.C(=O)([O-])[O-].[K+].[K+]>O>[CH3:1][C:2]12[C:14]3[C:6](=[CH:7][C:8]([NH:15][C:17]4[N:18]=[CH:19][C:20]([C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:21][N:22]=4)=[CH:9][C:10]=3[CH2:11][CH2:12][CH2:13]1)[CH2:5][CH2:4][CH2:3]2
Reactant: CCOC(=O)c1cnc(Cl)nc1
Reactant: CC12CCCc3cc(N)cc(c31)CCC2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CCOC(=O)c1cnc(Nc2cc3c4c(c2)CCCC4(C)CCC3)nc1
Temperature: 110 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
6a-Methyl-5,6,6a,7,8,9-hexahydro-4H-2-phenalenylamine (0.111 g) was added with ethyl 2-chloropyrimidine-5-carboxylate (0.104 g) and potassium carbonate (0.400 g), and the mixture was stirred overnight at 110° C. The reaction mixture was left to cool and then added with water, and the mixture was extracted with chloroform. The organic layer was washed successively with water and saturated brine, and dried over anhydrous sodium sulfate. The organic layer was concentrated under reduced pressure, and the resulting residue was purified by silica gel column chromatography (developing solvent: ethyl acetate:n-hexane=1:20) to obtain the title compound (0.162 g, yield: 84%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)C(C)C)(C)C.[CH3:22][O:23][CH2:24][C:25](Cl)=[O:26].C(=O)(O)[O-].[Na+]>C1COCC1>[NH2:1][C:2]1[C:11]([NH:12][C:25](=[O:26])[CH2:24][O:23][CH3:22])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cccc(N)c1N
Reactant: COCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc(C(=O)OC)c1N

Procedure:
To a solution of methyl 2,3-diaminobenzoate (3.0 g) in THF (50 mL) was added N,N-diisopropylethylamine (4.0 mL). The solution was stirred under ice-cooling, methoxyacetyl chloride (1.81 mL) in THF (10 mL) was added dropwise slowly, and it was stirred for 3 hours at the same temperature. To the reaction mixture was added saturated aqueous sodium bicarbonate, and THF was removed under reduced pressure. To the residue was added saturated aqueous sodium bicarbonate, and it was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue was purified on silica gel column chromatography to obtain the titled compound (3.60 g) as pale yellow powder.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]([C:6]([N:8]([CH:34]([CH3:36])[CH3:35])[C:9]2[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=2[CH:17]2[CH2:26][CH2:25][C:24]3[CH:23]=[C:22]([O:27]C(=O)C(C)(C)C)[CH:21]=[CH:20][C:19]=3[CH2:18]2)=O)=[CH:4][CH:3]=1.Cl[CH2:40][C:41]([NH:43][CH:44]1[CH2:46][CH2:45]1)=O.C(=O)([O-])[O-].[Cs+].[Cs+].[I-].[K+].B.O1CCCC1.Cl.[OH-].[Na+]>O.O1CCCC1>[CH:44]1([NH:43][CH2:41][CH2:40][O:1][C:2]2[CH:3]=[CH:4][C:5]([CH2:6][N:8]([CH:34]([CH3:36])[CH3:35])[C:9]3[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=[CH:11][C:10]=3[CH:17]3[CH2:26][CH2:25][C:24]4[CH:23]=[C:22]([OH:27])[CH:21]=[CH:20][C:19]=4[CH2:18]3)=[CH:37][CH:38]=2)[CH2:46][CH2:45]1
Reactant: O=C(CCl)NC1CC1
Reactant: COc1ccc(C2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(N(C(=O)c2ccc(O)cc2)C(C)C)c1
Agent: B
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(C2CCc3cc(O)ccc3C2)c(N(Cc2ccc(OCCNC3CC3)cc2)C(C)C)c1
Temperature: 60 °C
Reaction time: 5 h
Yield: 37.1 %

Procedure:
A mixture of pivalic acid 6-{2-[(4-hydroxybenzoyl)isopropylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (25 mg), 2-chloro-N-cyclopropylacetamide (13 mg), cesium carbonate (32 mg), potassium iodide (5.0 mg) and tetrahydrofuran (2 ml) was stirred for 5 hours at 60° C. To the reaction solution was added dropwise borane-tetrahydrofuran complex (1.0 M solution in tetrahydrofuran) (0.49 ml), and the solution was stirred at 60° C. for one day and one night. The reaction solution was cooled to room temperature, concentrated hydrochloric acid (0.08 ml) was added thereto, the solution was stirred for 1.5 hours at 60° C., then an aqueous solution of 5N sodium hydroxide (1 ml) was added thereto, and the solution was stirred for 8 hours at 60° C. The reaction solution was diluted with water, then extracted with ethyl acetate. The organic layer was concentrated under a nitrogen stream; purified from a solution of the resulting residue in N,N-dimethylformamide by LC-MS, the title compound (9.0 mg) was obtained.
Reaction SMILES: [C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([OH:28])=O)#[N:2].C(Cl)(=O)C(Cl)=O.Cl.[OH:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][C:38]=1[O:45][CH3:46].C(N(C(C)C)CC)(C)C>C1COCC1.O.CN(C=O)C>[C:1]([C:3]1[C:11]2[C:6](=[N:7][C:8]([CH3:13])=[CH:9][C:10]=2[CH3:12])[N:5]([C@@H:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:17][CH2:16][CH2:15]2)[C:4]=1/[CH:24]=[CH:25]/[C:26]([NH:42][CH2:41][C:40]1[CH:43]=[CH:44][C:37]([OH:36])=[C:38]([O:45][CH3:46])[CH:39]=1)=[O:28])#[N:2]
Reactant: COc1cc(CN)ccc1O
Reactant: Cc1cc(C)c2c(C#N)c(/C=C/C(=O)O)n([C@H]3CCCc4ccccc43)c2n1
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COc1cc(CNC(=O)/C=C/c2c(C#N)c3c(C)cc(C)nc3n2[C@H]2CCCc3ccccc32)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2E)-3-{3-cyano-4,6-dimethyl-1-[(1S)-1,2,3,4-tetrahydronaphthalen-1-yl]-1H-pyrrolo[2,3-b]pyridin-2-yl}prop-2-enoic acid (300 mg, 0.808 mmol) in THF (3 ml) were added DMF (0.03 ml) and oxalylchloride (0.0846 ml, 0.970 mmol), the mixture was stirred at room temperature for 1 hour and the solvent was distilled off under reduced pressure. The residue was added under ice-cooling to a solution of 4-hydroxy-3-methoxybenzylamine hydrochloride (183 mg, 0.968 mmol), diisopropylethylamine (0.737 ml, 4.24 mmol) and THF (2 ml), and the mixture was stirred under ice-cooling for 2 hours and at room temperature for 12 hours. The reaction solution was poured into water and extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=1:1) to give the objective product as a solid material.
Reaction SMILES: [F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15](Br)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9].[C:29]1(B(O)O)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.O>[F:1][C:2]([F:28])([F:27])[C:3]1[CH:4]=[C:5]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:6][N:7]([CH3:19])[C:8]([C:10]1[C:15]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[CH:14][N:13]=[C:12]([S:17][CH3:18])[N:11]=1)=[O:9]
Reactant: CSc1ncc(Br)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OB(O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: CSc1ncc(-c2ccccc2)c(C(=O)N(C)Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Yield: 69 %

Procedure:
To a suspension of 3.50 g (7.17 mmol) 5-bromo-2-methylsulfanyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide, 0.213 g (0.2 mmol) tetrakis-(triphenylphosphin)palladium and 0.96 g (7.89 mmol) phenylboronic acid in 40 ml 1,2-dimethoxyethane a solution of 0.83 g (7.89 mmol) Na2CO3 in 15 ml H2O was added. The resulting reaction mixture was heated at reflux for 16 hrs. After evaporation of the 1,2-dimethoxyethan, the aqueous phase was extracted twice with 50 ml CH2Cl2. The combined organic layers were dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/ethyl acetate 40:1) and crystallised to give 2.4 g (69%) 2-methylsulfanyl-5-phenyl-pyrimidine-4-carboxylic acid (3,5-bis-trifluoromethyl-benzyl)-methyl-amide as off-white crystalls, m.p 109.7-110.7°.
Reaction SMILES: [CH2:1]([Li])[CH3:2].[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7]([OH:9])=O.[Cl-].[NH4+]>C1C=CC=CC=1.CCOCC>[CH3:4][C:5]([CH:10]=[CH:11][CH2:12][CH:13]([CH3:21])[CH2:14][CH2:15][CH2:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[CH:6][C:7](=[O:9])[CH2:1][CH3:2]
Reactant: CC(C=CCC(C)CCCC(C)(C)C)=CC(=O)O
Reactant: [Li]CC
Agent: [Cl-]
Agent: [NH4+]
Solvent: c1ccccc1
Solvent: CCOCC
Product: CCC(=O)C=C(C)C=CCC(C)CCCC(C)(C)C
Reaction time: 3 h

Procedure:
To a stirred solution of 9.5 ml. of a one molar solution of ethyllithium in benzene and 50 ml ether, under nitrogen is added at 0° 1.0 g. of 3,7,11,11-tetramethyldodeca-2,4-dienoic acid in 10 ml. ether. The reaction mixture is stirred for three hours and then is poured into a rapidly stirred saturated aqueous ammonium chloride solution followed by the addition of 50 ml. of ether. The organic layer is separated and then is washed with saturated sodium chloride. The solution is dried over magnesium sulfate and the solvent is removed to yield 5,9,13,13-tetramethyltetradeca-4,6-dien-3-one.