Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[I:8].[C:11](=O)([O-])[O-].[K+].[K+].CI>CC(C)=O>[CH3:11][O:10][C:4]1[CH:5]=[C:6]([CH3:9])[C:7]([I:8])=[C:2]([CH3:1])[CH:3]=1
Reactant: Cc1cc(O)cc(C)c1I
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CI
Product: COc1cc(C)c(I)c(C)c1
Temperature: 25 °C

Procedure:
O-Methyl-3,5-dimethyl-4-iodophenol was prepared by etherifying 3,5-dimethyl-4-iodophenol as follows: In a 1 l three-necked flask equipped with an overhead stirrer were placed 63.7 g (257 mmol) of 3,5-dimethyl-4-iodophenol, 70.9 g (513 mmol) potassium carbonate, 400 ml acetone and 47.5 ml (108 g, 760 mmol) methyl iodide. The reaction mixture was refluxed for 15 hours, cooled, the precipitate filtered and washed with acetone. The combined acetone washes were concentrated under reduced pressure, dissolved in methylene chloride, washed successively with 5% sodium hydroxide, saturated sodium bisulfite and water. After drying over magnesium sulfate and filtering, the solvent was removed under reduced pressure to afford a tan oil. Recrystallization from hot methanol with cooling to room temperature and then -78° C. afforded 58.2 g (86% yield) of white needles, mp 33°-34° C., which were identified as O-methyl-3,5-dimethy-4-iodophenol. 1H NMR analysis indicated: (δ, CDCl3) 6.56 (s, 2H), 3.67 (s, 3H) and 2.37 (s, 6H). Mass spectrum analysis indicated: (m/e) 262 (m+, 100%), 247, 219, 135 and 91.
Reaction SMILES: [CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:11])[C:6](=[O:18])[N:5]1[CH3:19])[CH:2]=[CH2:3].C([C@]1(C2C=CC=CC=2)CCN([C@H](C2CCCCC2)C)C(=[O:43])N1)C=C>>[CH:12]1([C@@H:10]([N:7]2[CH2:8][CH2:9][C@:4]([CH2:1][CH2:2][CH2:3][OH:43])([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[N:5]([CH3:19])[C:6]2=[O:18])[CH3:11])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1.[CH2:1]([C@:4]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9][CH2:8][N:7]([C@H:10]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)[CH3:11])[C:6](=[O:18])[N:5]1[CH3:19])[CH:2]=[CH2:3]
Reactant: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)C2CCCCC2)C(=O)N1
Agent: C=CC[C@]1(c2ccccc2)CCN([C@@H](C)C2CCCCC2)C(=O)N1C
Product: C[C@@H](C1CCCCC1)N1CC[C@](CCCO)(c2ccccc2)N(C)C1=O

Procedure:
The title compound was prepared from (R)-4-allyl-1-((S)-1-cyclohexylethyl)-3-methyl-4-phenyltetrahydropyrimidin-2(1H)-one following a procedure analogous to that described in Example 7. (R)-4-allyl-1-((S)-1-cyclohexylethyl)-3-methyl-4-phenyltetrahydropyrimidin-2(1H)-one was prepared from (R)-4-allyl-1-((S)-1-cyclohexylethyl)-4-phenyltetrahydropyrimidin-2(1H)-one following a procedure analogous to that described in Example 3. LC-MS Method 2 tR=1.408 min, m/z=359.1; 1H NMR (CDCl3) δ=1.06 (m, 3H), 1.10 (m, 3H), 1.23 (m, 3H), 1.52 (m, 7H), 1.75 (m, 2H), 1.98 (m, 1H), 2.15 (m, 2H), 2.60 (m, 1H), 2.87 (m, 3H), 3.70 (m, 2H), 4.22 (m, 11-1), 7.17 (m, 4H), 7.28 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[N:21]=[C:20]([Cl:22])[C:19](O)=[C:18]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH:25]2[CH2:30][OH:31])[N:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCOCC1>[Cl:22][C:20]1[C:19]2[O:31][CH2:30][CH:25]3[N:24]([CH2:29][CH2:28][O:27][CH2:26]3)[C:18]=2[N:17]=[C:16]([Cl:15])[N:21]=1
Reactant: OCC1COCCN1c1nc(Cl)nc(Cl)c1O
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: Clc1nc(Cl)c2c(n1)N1CCOCC1CO2
Temperature: 25 °C
Reaction time: 1 h
Yield: 38.2 %

Procedure:
A mixture of [4-(2,6-dichloro-5-methoxy-pyrimidin-4-yl)-morpholin-3-yl]-methanol (614 mg, 2.09 mmol) and lithium chloride (246 mg, 5.80 mmol) in anhydrous DMF (5 mL) was heated at 160° C. for 10 mins in a microwave reactor, then concentrated in vacuo to give 2,4-dichloro-6-(3-hydroxymethyl-morpholin-4-yl)-pyrimidin-5-ol. DIAD (452 μL, 2.3 mmol) was added to a solution of 2,4-dichloro-6-(3-hydroxymethyl-morpholin-4-yl)-pyrimidin-5-ol (2 mmol) and triphenyl phosphine (603 mg, 2.3 mmol) in 1,4-dioxane (5 mL) and the mixture stirred at RT for 1 h, then concentrated in vacuo. The resulting residue was purified by column chromatography (SiO2, 0 to 50% ethyl acetate in cyclohexane) affording 1,3-Dichloro-5,6,8a,9-tetrahydro-8H-7,10-dioxa-2,4,4b-triaza-phenanthrene (200 mg, 37%). LCMS (method A): RT=2.91 min, [M+H]−=262/264.
Reaction SMILES: [C:1]1([CH2:7][C:8]([OH:10])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[F:35][C:36]1[CH:41]=[CH:40][C:39]([C:42]2[C:50]3[O:49][C:48]([NH2:51])=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:38][CH:37]=1>C1COCC1.O1CCOCC1.CN(C=O)C>[F:35][C:36]1[CH:37]=[CH:38][C:39]([C:42]2[C:50]3[O:49][C:48]([NH:51][C:8](=[O:10])[CH2:7][C:1]4[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=4)=[N:47][C:46]=3[C:45]([O:52][CH3:53])=[CH:44][CH:43]=2)=[CH:40][CH:41]=1
Reactant: O=C(O)Cc1ccccc1
Reactant: COc1ccc(-c2ccc(F)cc2)c2oc(N)nc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(F)cc2)c2oc(NC(=O)Cc3ccccc3)nc12

Procedure:
From phenylacetic acid, HATU and N-diethylisopropylamine in THF, then treatment with 7-(4-fluoro-phenyl)-4-methoxy-benzooxazol-2-yl-amine in dioxane and DMF. ES-MS m/e (%): 377 (M+H+, 100).
Reaction SMILES: Cl.[C:2]1([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:7]=[CH:6][C:5]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:28][CH2:29][CH3:30])[C:22]([O:24]CC)=[O:23])=[CH:16][CH:15]=2)=[O:9])=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[C:2]1([C:31]2[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=2)[CH:3]=[CH:4][C:5]([C:8]([NH:10][CH2:11][CH2:12][O:13][C:14]2[CH:19]=[CH:18][C:17]([CH2:20][CH:21]([NH:27][CH2:28][CH2:29][CH3:30])[C:22]([OH:24])=[O:23])=[CH:16][CH:15]=2)=[O:9])=[CH:6][CH:7]=1
Reactant: CCCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCNC(Cc1ccc(OCCNC(=O)c2ccc(-c3ccccc3)cc2)cc1)C(=O)O

Procedure:
Ethyl 3-[4-[2-(biphenyl-4-carbonylamino)ethoxy]phenyl]-2-propylaminopropionate hydrochloride, which is the product of Example 185(b), is hydrolyzed by sodium hydroxide in methanol to give the title compound.
Reaction SMILES: C(=O)([O-])[O-].[Ba+2].C(=O)=O.BrBr.[O:11]=[CH:12][C@@H:13]([C@H:15]([C@@H:17]([C@@H:19]([CH2:21][OH:22])[OH:20])[OH:18])[OH:16])[OH:14]>>[CH2:21]([OH:22])[C@H:19]1[O:20][C:12](=[O:11])[C@H:13]([OH:14])[C@@H:15]([OH:16])[C@@H:17]1[OH:18]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: BrBr
Agent: O=C([O-])[O-]
Agent: O=C=O
Product: O=C1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Then, 8,000 parts by mass of a 12% aqueous solution of barium carbonate were saturated with carbon dioxide, and 330 parts by mass of bromine and 300 parts by mass of the glucose obtained above were added and agitated for 30 minutes at 25° C. to obtain 250 parts by mass of gluconolactone represented by the following chemical formula (III):
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12]1[NH:13][CH2:14][CH2:15][N:16]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)[O:18]1.C([O-])(=O)C.[K+].O1CCOCC1>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.CN(C=O)C>[NH:13]1[CH2:14][CH2:15][N:16]=[C:12]1[CH:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[C:2]([OH:18])[C:3]=2[CH2:4][CH2:5][O:6]1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Brc1cccc2c1CCOC2C1=NCCN1
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: CC(=O)[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: Oc1cccc2c1CCOC2C1=NCCN1
Temperature: 160 °C
Reaction time: 0.5 h

Procedure:
A mixture of 2-(5-bromoisochroman-1-yl)-4,5-dihydro-1H-imidazole (720 mg), bis(pinacolato)diboron (715 mg) bis(tri-t-butylphosphine)palladium(0) (39 mg), potassiumacetate (503 mg), dioxane (9 ml) and DMF (0.75 ml) was stirred under inert atmosphere in microwave reactor at 160° C. for 30 minutes. Additional bis(tri-t-butylphosphine)palladium(0) (21 mg) was added and heating continued for 15 minutes. The intermediate 2-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)isochroman-1-yl)-4,5-dihydro-1H-imidazole (680 mg) was purified with separation method A and stirred with EtOAc (2 ml), water (2 mil) and hydrogen peroxide (35%, 0.07 ml) at ice bath temperature for 2 hrs. The title compound was purified with separation methods A and E. (Yield 45 mg).
Reaction SMILES: [O:1]([C:5]1[C:13]([CH3:14])=[CH:12][CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=O)[C:2]([CH3:4])=[O:3].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[CH2:39]([O:41][C:42]([C:44]1([NH2:53])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45]1)=[O:43])[CH3:40].CCN(C(C)C)C(C)C>CC(O)C.C(Cl)Cl.C(Cl)Cl>[CH2:39]([O:41][C:42]([C:44]1([NH:53][C:7](=[O:9])[C:6]2[CH:10]=[CH:11][CH:12]=[C:13]([CH3:14])[C:5]=2[O:1][C:2](=[O:3])[CH3:4])[CH2:52][C:51]2[C:46](=[CH:47][CH:48]=[CH:49][CH:50]=2)[CH2:45]1)=[O:43])[CH3:40]
Reactant: CCOC(=O)C1(N)Cc2ccccc2C1
Reactant: CC(=O)Oc1c(C)cccc1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)C1(NC(=O)c2cccc(C)c2OC(C)=O)Cc2ccccc2C1
Reaction time: 0.08 h
Yield: 161.5 %

Procedure:
A 40 mL vial containing a stirring bar is charged with 2-acetoxyl-3-methyl-benzoic acid (1 g, 4.87 mmol) and dry DCM (14 mL), and stirring is initiated. After dissolution is complete, HBTU (1.85 g, 4.87 mmoles) is added. After 5 min, 2-amino-indane-2-carboxylic acid ethyl ester (1 g, 4.87 mmol) is added followed by DIPEA (2.1 mL, 12.18 mmol). The reaction is allowed to stir for 110 h. Analysis by tlc of the reaction mixture (silica, 5% iPrOH/DCM) indicates complete consumption of the starting amine. The contents of the reaction flask are transferred to a reparatory funnel and diluted with EtOAc (100 mL). This is washed consecutively with dilute aqueous HCl (3%, 40 mL), saturated aqueous NaHCO3 (50 mL) and brine (50 mL), dried over MgSO4, filtered and evaporated in vacuo to provide 3 g of a light orange solid. This material is dissolved in 15 mL of DCM. This material is purified utilizing an ISCO Companion with an 80 g cartridge of silica. The gradient is 10% EtOAc in heptanes over 3 column volumes followed by a linear gradient to 50% EtOAc over 12 column volumes. Fractions 19 through 27 are combined and evaporated in vacuo to give 1.38 g of white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34](C4C=CC(OC)=C(OC)C=4)=[CH:33][CH:32]=[C:31]([C:45]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:46])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[N+:52]([C:55]1[CH:60]=[CH:59][C:58](B(O)O)=[CH:57][CH:56]=1)([O-:54])=[O:53]>>[CH:1]1([N:7]2[C:11]3[CH:12]=[CH:13][C:14]([C:16]([OH:18])=[O:17])=[CH:15][C:10]=3[N:9]=[C:8]2[C:19]2[CH:20]=[C:21]3[C:26](=[CH:27][CH:28]=2)[N:25]=[C:24]([C:29]2[C:34]([C:58]4[CH:59]=[CH:60][C:55]([N+:52]([O-:54])=[O:53])=[CH:56][CH:57]=4)=[CH:33][CH:32]=[C:31]([C:45]([N:47]4[CH2:51][CH2:50][CH2:49][CH2:48]4)=[O:46])[CH:30]=2)[CH:23]=[CH:22]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: COc1ccc(-c2ccc(C(=O)N3CCCC3)cc2-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4C4CCCCC4)ccc3n2)cc1OC
Product: O=C(O)c1ccc2c(c1)nc(-c1ccc3nc(-c4cc(C(=O)N5CCCC5)ccc4-c4ccc([N+](=O)[O-])cc4)ccc3c1)n2C1CCCCC1

Procedure:
The title compound (5.2 mg yield) was prepared as described for Compound 419 using 4-nitrophenylboronic acid in place of 3,4-dimethoxyphenylboronic acid.
Reaction SMILES: S(=O)(=O)(O)O.[NH2:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17])=[CH:9][CH:8]=1.Cl.[CH3:20][CH2:21]O>>[CH2:20]([O:17][C:16](=[O:18])[CH2:15][CH2:14][CH2:13][C:10]1[CH:9]=[CH:8][C:7]([NH2:6])=[CH:12][CH:11]=1)[CH3:21]
Reactant: Nc1ccc(CCCC(=O)O)cc1
Reactant: CCO
Agent: Cl
Agent: O=S(=O)(O)O
Product: CCOC(=O)CCCc1ccc(N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Catalytic sulfuric acid was added to a solution of 4-(4-aminophenyl) butyric acid (6.0 g, 33.48 mmol) in EtOH. The reaction mixture was stirred at room temperature for 24 h. HCl (5 mL, 6N) was added and the reaction mixture was heated at reflux for 24 h. The reaction mixture was concentrated in vacuo and CH2Cl2 and water were added. The pH was adjusted to 7.0 with aqueous NaHCO3 (satd). The organic solution was washed with water (1×) and brine (1×), dried over MgSO4, filtered, and concentrated to afford 4-(4-amino-phenyl)-butyric acid ethyl ester (1.53 g). 1H NMR (400 MHz, CDCl3) δ6.95 (d, 2H), 6.61 (d, 2H), 4.10 (q, 2H), 3.66 (bs, 2H), 2.53 (t, 2H), 2.29 (t, 2H), 1.88 (m, 2H), 1.24 (t, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][N:11](C(OC(C)(C)C)=O)[CH2:10][CH2:9]2)[C:5]([NH2:21])=[C:4]([SH:22])[N:3]=1.[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33](O)=O)=[CH:26][CH:25]=1>>[F:23][C:24]1[CH:29]=[CH:28][C:27]([CH2:30][CH2:31][CH2:32][C:33]2[S:22][C:4]3[N:3]=[C:2]([NH2:1])[N:7]=[C:6]([N:8]4[CH2:9][CH2:10][NH:11][CH2:12][CH2:13]4)[C:5]=3[N:21]=2)=[CH:26][CH:25]=1
Reactant: O=C(O)CCCc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCN(c2nc(N)nc(S)c2N)CC1
Product: Nc1nc(N2CCNCC2)c2nc(CCCc3ccc(F)cc3)sc2n1
Yield: 48 %

Procedure:
This compound was synthesized from tert-butyl 4-(2,5-diamino-6-mercaptopyrimidin-4-yl)piperazine-1-carboxylate using 4-(4-fluorophenyl)butanoic acid, yielding the title compound in 48% yield.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[C:6]([F:9])[CH:5]=[CH:4][C:3]=1Br.[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[CH:14].O.Cl>CN(C=O)C.C(N(CC)CC)C.[Cu](I)I>[CH3:11][C:12]([OH:16])([CH3:15])[C:13]#[C:14][C:3]1[CH:4]=[CH:5][C:6]([F:9])=[C:7]([F:8])[C:2]=1[F:1]
Reactant: C#CC(C)(C)O
Reactant: Fc1ccc(Br)c(F)c1F
Agent: I[Cu]I
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(O)C#Cc1ccc(F)c(F)c1F
Temperature: 70 °C
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Under nitrogen replacement, 247 g of 2,3,4-trifluorobromobenzene was dissolved in 740 ml of DMF, into which 247 mL of triethylamine, 3.7 g of tetrakistriphenylphosphine palladium (0), and 4.4 g of copper iodide (I) were added, and heated to 70° C. To this, 108 g of 3-methyl-1-butyne-3-ol was added dropwise for 1 hour, and the mixutre was then stirred for 2 hours at room temperature, for 1 hour at 50° C., for 30 minutes at 60° C., and for 2 hours at 80° C. Then, 500 mL of water was added and cooled to room temperature, to which 200 mL of concentrated hydrochloric acid was added. After this was extracted twice using ethyl acetate, the extract and the organic layer were mixed together, washed using water and a saturated saline solution in that order, and dried using anhydrous magnesium sulfate. After the solvent was evaporated under a reduced pressure, the residue was purified by distillation under a reduced pressure (78 to 84° C./0.65 to 0.70 mmHg) to obtain 229 g of 1-(3-methyl-3-hydroxy-1-butynyl)-2,3,4-trifluorobenzene as a yellow solid.
Reaction SMILES: C[O:2][C:3](=[O:29])[C:4]([CH3:28])([CH3:27])/[CH:5]=[CH:6]/[C:7]1[CH:16]=[C:15]2[C:10]([CH:11]=[N:12][C:13]([CH:17]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH3:18])=[N:14]2)=[CH:9][CH:8]=1.[OH-].[Li+]>O1CCCC1.O>[C:23]([Si:20]([CH3:22])([CH3:21])[O:19][CH:17]([C:13]1[N:12]=[CH:11][C:10]2[C:15](=[CH:16][C:7](/[CH:6]=[CH:5]/[C:4]([CH3:28])([CH3:27])[C:3]([OH:29])=[O:2])=[CH:8][CH:9]=2)[N:14]=1)[CH3:18])([CH3:26])([CH3:25])[CH3:24]
Reactant: COC(=O)C(C)(C)/C=C/c1ccc2cnc(C(C)O[Si](C)(C)C(C)(C)C)nc2c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(O[Si](C)(C)C(C)(C)C)c1ncc2ccc(/C=C/C(C)(C)C(=O)O)cc2n1
Temperature: 25 °C
Reaction time: 20 h
Yield: 58.5 %

Procedure:
A solution of (E)-4-{2-[1-(tert-butyl-dimethyl-silanyloxy)-ethyl]-quinazolin-7-yl}-2,2-dimethyl-but-3-enoic acid methyl ester (1.07 g, 2.58 mmol) in tetrahydrofuran (50 mL) was cooled to 0° C. before adding an aqueous solution of lithium hydroxide (1 M, 8 mL, 8 mmol). The reaction mixture was allowed to warm to room temperature and was stirred for 20 h. The reaction mixture was diluted with water (50 mL) then washed with diethyl ether (60 mL) before acidifying to pH 2 with a saturated solution of potassium bisulfate. The resulting mixture was extracted with diethyl ether (3×30 mL). The extract was dried over anhydrous sodium sulfate, filtered and evaporated to yield the title product (0.605 g, 59%) as a yellow gum. 1H NMR (300 MHz, CDCl3) δ 0.06 (s, 3H), 0.08 (s, 3H), 0.90 (s, 9H), 1.53 (s, 6H), 1.64 (d, J=6.5 Hz, 3H), 5.22 (q, J=6.5 Hz, 1H), 6.64-6.81 (m, 2H), 7.73, 7.87 (ABq, J=8.5 Hz, 2H), 7.99 (s, 1H), 9.40 (s, 1H). LCMS (m/z) 401.2 [M+H], Tr=3.43 min.
Reaction SMILES: [CH:1]1([C:4]2[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=2)[CH2:3][CH2:2]1.Br[C:13]1C=CC(C2CCC2)=CC=1.[Li]CCCC.CCCCCC.CN(C=O)C>>[CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([CH:8]=[O:9])=[CH:10][CH:11]=2)[CH2:3][CH2:2][CH2:13]1
Reactant: Brc1ccc(C2CCC2)cc1
Reactant: O=Cc1ccc(C2CC2)cc1
Agent: [Li]CCCC
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: O=Cc1ccc(C2CCC2)cc1
Yield: 67 %

Procedure:
The title compound was synthesized in analogy to 4-cyclopropyl benzaldehyde (described in example S53) using 830 mg of 1-bromo-4-cyclobutyl-benzene (3.93 mmol), 2.7 ml of a 1.6 molar solution of n-BuLi in hexane (4.32 mmol) and 605 μl of DMF (7.86 mmol). The isolated residue was purified by flash column chromatography (5:95 EtOAc/cyclohexane) to give 422 mg of 4-cyclobutyl-benzaldehyde (67%) as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.89 (m, 1H), 1.97-2.26 (m, 3H), 2.40 (m, 2H), 3.63 (quint, J=8.5 Hz, 1H), 7.36 (d, J=8.0 Hz, 2H), 7.81 (d, J=8.0 Hz, 2H), 9.97 (s, 1H).
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:20][C@H:21]([CH2:25][CH:26]2[CH2:28][CH2:27]2)[C:22]([NH2:24])=[O:23])=[N:7][C:8]=1[NH:9][C:10]1[CH:11]=[C:12]2[C:17](=[CH:18][CH:19]=1)[N:16]=[CH:15][CH:14]=[CH:13]2)#[N:2].[OH-].[Na+].OO.CC(O)=[O:35]>CCO.CS(C)=O>[NH2:24][C:22](=[O:23])[C@H:21]([NH:20][C:6]1[N:7]=[C:8]([NH:9][C:10]2[CH:11]=[C:12]3[C:17](=[CH:18][CH:19]=2)[N:16]=[CH:15][CH:14]=[CH:13]3)[C:3]([C:1]([NH2:2])=[O:35])=[N:4][CH:5]=1)[CH2:25][CH:26]1[CH2:27][CH2:28]1
Reactant: CC(=O)O
Reactant: N#Cc1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: NC(=O)c1ncc(N[C@H](CC2CC2)C(N)=O)nc1Nc1ccc2ncccc2c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A mixture of (R)-2-(6-chloro-5-cyanopyrazin-2-ylamino)-3-cyclopropylpropanamide (80 mg, 0.301 mmol), 6-aminoquinoline (60 mg, 0.416 mmol), K2CO3 (65 mg, 0.471 mmol), BINAP (25 mg, 0.040 mmol) and Pd(OAc)2 (10 mg, 0.044 mmol) in dioxane (2 mL) was degassed with Ar, then was stirred at 110 C for 20 h. Water and EtOAc were added. Organic phase was separated, dried over Na2SO4, concentrated in vacuo to give a crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg). The crude (R)-2-(5-cyano-6-(quinolin-6-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (130 mg) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (50%, 1.0 mL) were added. The mixture was stirred at room temperature for 30 min. HOAc (0.5 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (35 mg). MS 392.2 (M+H); UV 203.6, 266.4, 299.0, 358.5 nm; t 0.406 min.
Reaction SMILES: C([O:3][C:4](=[O:24])[C:5]([O:15][C:16]1[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=1)([CH3:14])[CH2:6][C:7]1[CH:12]=[CH:11][C:10](O)=[CH:9][CH:8]=1)C.[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38]S(C3C=CC(C)=CC=3)(=O)=O)[N:35]=2)[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]1>>[CH:25]1([C:31]2[O:32][C:33]([CH3:49])=[C:34]([CH2:36][CH2:37][O:38][C:10]3[CH:9]=[CH:8][C:7]([CH2:6][C:5]([O:15][C:16]4[CH:21]=[CH:20][C:19]([F:22])=[C:18]([F:23])[CH:17]=4)([CH3:14])[C:4]([OH:24])=[O:3])=[CH:12][CH:11]=3)[N:35]=2)[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]1
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccc(F)c(F)c1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(C3CCCCC3)oc2C)cc1
Product: Cc1oc(C2CCCCC2)nc1CCOc1ccc(CC(C)(Oc2ccc(F)c(F)c2)C(=O)O)cc1

Procedure:
The title compound was prepared from 2-(3,4-difluoro-phenoxy)-3-(4-hydroxy-phenyl)-2-methyl-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(2-cyclohexyl-5-methyloxazol-4-yl)-ethyl ester using the method of Example 56. 1H NMR (400 MHz, CDCl3) δ 9.37 (bs, 1H), 7.16 (d, 2H, J=8.4 Hz), 6.99 (dd, 1H, J=9.5 Hz), 6.78 (d, 2H, J=8.4 Hz), 6.77-6.72 (m, 1H), 6.63-6.58 (m, 1H), 4.12 (t, 2H, J=6.4 Hz), 3.21 and 3.08 (d of ABq, 2H, J=14.0 Hz), 2.97 (t, 2H, J=6.4 Hz), 2.91 (tt, 1H, J=12.0, 3.6 Hz), 2.32 (s, 3H), 2.04-1.98 (m, 2H), 1.85-1.78 (m, 2H), 1.76-1.68 (m, 1H), 1.62-1.49 (m, 2H), 1.41-1.19 (m, 3H), 1.37 (s, 3H).
Reaction SMILES: [C:1]([C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=O)=[CH:5][CH:4]=1)#[N:2].O.ON1C2C=CC=CC=2N=N1.[CH:23]1([N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]4)[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:26][CH2:25][CH2:24]1>ClCCl>[CH:23]1([N:27]2[CH2:33][CH2:32][C:31]3[CH:34]=[C:35]([O:38][CH:39]4[CH2:44][CH2:43][N:42]([C:7]([C:6]5[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:11][CH:10]=5)=[O:9])[CH2:41][CH2:40]4)[CH:36]=[CH:37][C:30]=3[CH2:29][CH2:28]2)[CH2:24][CH2:25][CH2:26]1
Reactant: c1cc2c(cc1OC1CCNCC1)CCN(C1CCC1)CC2
Reactant: N#Cc1ccc(C(=O)O)cc1
Agent: On1nnc2ccccc21
Solvent: O
Solvent: ClCCl
Product: N#Cc1ccc(C(=O)N2CCC(Oc3ccc4c(c3)CCN(C3CCC3)CC4)CC2)cc1
Reaction time: 16 h

Procedure:
4-Cyanobenzoic acid (147 mg, 1 mmol), 1-hydroxy benzotriazole hydrate (154 mg, 1 mmol) and N-cyclohexylcarbodiimide N′-methyl polystyrene (1.8 mmol/g, 555 mg, 1 mmol) were stirred at room temperature in dichloromethane (5 ml) for 15 minutes. 3-cyclobutyl-7-(piperidin-4-yloxy)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (E6) (150 mg, 0.5 mmol) was added and stirring continued for 16 hours. The reaction mixture was applied to a SCX ion exchange cartridge (Varian bond-elute, 5 g) and washed with methanol and then a mixture of 0.880 ammonia:methanol (1:9). The combined basic fractions were concentrated in vacuo and the resulting residue was purified by column chromatography eluting with dichloromethane then a mixture of 0.880 ammonia:ethanol:dichloromethate (1:9:90) to afford the title product (E13). MS (ES+) m/e 430 [M+H]+.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15]O)[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH3:17][N:18]1[CH:22]=[CH:21][N:20]=[C:19]1[SH:23]>>[Si:1]([O:8][CH2:9][C:10]1([CH2:14][CH2:15][S:23][C:19]2[N:18]([CH3:17])[CH:22]=[CH:21][N:20]=2)[CH2:13][CH2:12][CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCC1(CCO)CCC1
Reactant: Cn1ccnc1S
Product: Cn1ccnc1SCCC1(CO[Si](C)(C)C(C)(C)C)CCC1

Procedure:
The title compound was prepared using the same experimental procedure as in example 19a using 2-[1-({[tert-butyl(dimethyl)silyl]oxy}methyl)cyclobutyl]ethanol and 1-methyl-1H-imidazole-2-thiol. 1H NMR (300 MHz, CDCl3) δ 7.22 (s, 1H), 7.01 (s, 1H), 3.58 (s, 3H), 3.43 (s, 2H), 1.85-1.73 (m, 6H), 2.91 (t, J=6 Hz, 2H), 1.48 (s, 9H), 1.21 (t, J=4 Hz, 2H), 0.04 (s, 6H). GC-MS m/z 341 (M+H).
Reaction SMILES: F[C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH2:17].CCN(C(C)C)C(C)C>C1COCC1>[CH3:12][O:13][C:14]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[CH:18][C:15]=1[CH2:16][NH:17][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10]
Reactant: COc1ccc(CN)c(OC)c1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: COc1ccc(CNc2cc(F)ccc2[N+](=O)[O-])c(OC)c1
Temperature: 25 °C

Procedure:
A solution of 2,4-difluoro-1-nitrobenzene (1.1 mL), 2,4-dimethoxy benzylamine (1.5 mL) and DIEA (5.2 mL), in THF (40 mL) was heated at 60° C. for 60 min, allowed to cool to RT, partitioned between EtOAc and H2O, separated, dried (MgSO4), filtered and evaporated to yield the titled product as a yellow solid (3.14 g). 1H-NMR (300 MHz, CDCl3) δ 8.5 (br s, 1H), 7.2 (dd, 1H), 7.2 (d, 1H), 6.6-6.4 (m, 3H), 6.3 (m, 1H), 4.3 (d, 2H), 3.9 (s, 3H), 3.8 (s, 3H).