Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9](O)=[CH:10][C:11](=O)[C:12]([F:15])([F:14])[F:13].[NH2:18][NH2:19]>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[NH:19][N:18]=[C:11]([C:12]([F:15])([F:14])[F:13])[CH:10]=1
Reactant: O=C(C=C(O)c1ccc(F)cc1F)C(F)(F)F
Reactant: NN
Solvent: CC(=O)O
Product: Fc1ccc(-c2cc(C(F)(F)F)n[nH]2)c(F)c1
Temperature: 95 °C
Yield: 93.1 %

Procedure:
At 24° C., 15.0 g (0.06 mole) of the product of step A was dissolved in 50 mL glacial acetic acid and treated with 2 mL (0.064 mole) anhydrous hydrazine, added over a period of 5 minutes. The reaction was heated to 95° C. for 30 minutes. The reaction was cooled and poured into 300 mL ice water. The slurry was filtered and the cake washed with water and air dried to give 13.86 g (94%) of 5-(2,4-difluorophenyl)-3-(trifluoromethyl)-1H-pyrazole as a white solid, mp 157-158° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[I:10]I.[OH-].[Na+]>O>[OH:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][N:5]=[CH:4][C:3]=1[I:10]
Reactant: II
Reactant: N#Cc1cnccc1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: N#Cc1cncc(I)c1O
Temperature: 85 °C
Yield: 61.3 %

Procedure:
A mixture of 4-hydroxynicotinonitrile (45.7 g, 381 mmol), iodine (96.6 g, 381 mmol) and NaOH (19.8 g, 825 mmol) in water (600 mL) was heated at 85° C. overnight, cooled to r.t. and diluted with water. The precipitate was collected by filtration and washed with water to give 57.5 g (61%) of 4-hydroxy-5-iodonicotinonitrile as a tan solid. Mp>245° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CC(C)([O-])C.[K+].[O:30]=[C:31]1[CH2:36][CH2:35][CH2:34][CH2:33][N:32]1[C:37]1[C:42]([CH:43]=O)=[CH:41][CH:40]=[CH:39][N:38]=1>O1CCCC1.CO>[CH3:2][O:3][CH:4]=[CH:43][C:42]1[C:37]([N:32]2[CH2:33][CH2:34][CH2:35][CH2:36][C:31]2=[O:30])=[N:38][CH:39]=[CH:40][CH:41]=1
Reactant: O=Cc1cccnc1N1CCCCC1=O
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CO
Solvent: C1CCOC1
Product: COC=Cc1cccnc1N1CCCCC1=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 11 %

Procedure:
Methoxymethyl-triphenylphosphonium chloride (3.59 g, 10.48 mmol, 1.3 eq) is dissolved in dry tetrahydrofuran (150 ml) under nitrogen. This solution is cooled at 0° C. and potassium tert-butoxide (1.085 g, 9.67 mmol, 1.2 eq) is added. The reaction mixture is stirred at 0° C. for 30 min. A solution of crude 2-(2-oxopiperidin-1-yl)pyridine-3-carbaldehyde a4-1 (4.2 g, 8.06 mmol, 1 eq) in dry THF (50 ml) is added, then the reaction mixture is warmed up to room temperature and stirred for 1 hour. The solvent is removed under reduced pressure, the residue is taken with ethyl acetate, stirred, filtered and the solid cake washed with ethyl acetate (2 times). The filtrate is evaporated under reduced pressure. The residue is purified by chromatography over silicagel (gradient: CH2Cl2/MeOH/NH4OH 100/0/0 to 97/3/0.3). The product obtained is redissolved in methanol, catched over an acidic column, washed with methanol and then released with ammonia 1M in methanol. The solvent is evaporated under reduced pressure to afford 540 mg of 1-[3-(2-methoxyethenyl)pyridin-2-yl]piperidin-2-one a4-2.
Reaction SMILES: [C:1]([Si:5]([C:11]([CH3:14])([CH3:13])[CH3:12])([C:7](O)([CH3:9])C)C)([CH3:4])([CH3:3])[CH3:2].[C:15]([Si:19]([C:22]([CH3:25])([CH3:24])[CH3:23])([F:21])[F:20])([CH3:18])([CH3:17])[CH3:16].[CH2:26]([O:28]C=C[Li])[CH3:27].C[Li]>C1COCC1>[C:22]([Si:19]([C:15]([CH3:18])([CH3:17])[CH3:16])([F:21])[F:20])([CH3:25])([CH3:24])[CH3:23].[C:11]([SiH:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:7][C:9]([O:28][CH2:26][CH3:27])=[CH2:15])([CH3:12])([CH3:13])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C(C)(C)C)C(C)(C)O
Reactant: [Li]C=COCC
Agent: CC(C)(C)[Si](F)(F)C(C)(C)C
Agent: [Li]C
Solvent: C1CCOC1
Product: C=C(C[SiH](C(C)(C)C)C(C)(C)C)OCC
Yield: 14 %

Procedure:
Di-tert-butyldifluorosilane was prepared according to the procedure of B. Rempfer et al., J. Am. Chem. Soc. 1986, 108, 3893-3897. Following the general procedure of Example 7, di-tert-butyl(1-hydroxy-1-methylethyl)methylsilane was prepared from di-tert-butyldifluorosilane (11.8 g, 65.4 mmol), ethoxyvinyl lithium (prepared from ethyl vinyl ether (4.68 g, 64.9 mmol) and tert-butyl lithium (1.6 M in pentane, 40.6 ml, 65.0 mmol)) in THF (100 ml)) and methyl lithium (1.6 M in Et2O, 280 ml, 448 mmol). The crude product was distilled twice to furnish at 57° C./1.7 mbar 2.10 g (14%) of di-tert-butyl(1-ethoxyvinyl)methylsilane, of which 2.00 g (8.76 mmol) were hydrolysed with acetone/1 N HCl (2:1, 10 ml). Purification by silica-gel chromatography (silica-gel 35-70 μm, hexane/EtOAc, 9:1) followed by bulb-to-bulb distillation (120° C., 80 mbar) afforded 0.93 g (53%) of acetyl(di-tert-butyl)methylsilane (m.p. 35° C.), of which 0.90 g (4.49 mmol) was reacted with methyl lithium (1.6 M in Et2O, 60.0 ml, 96.0 mmol) according to Example 1 to furnish after purification by repeated silica-gel flash chromatography (silica-gel 15-40 μm, hexane/EtOAc, 9:1) 204 mg (21%) of the odoriferous title compound (m.p. 122-123° C.).
Reaction SMILES: [NH2:1][C:2]1C=[CH:9][C:5](C(O)=O)=[CH:4][C:3]=1O.[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([OH:23])=O)=[CH:20][C:15]=2[N:14]=[CH:13]1.C(OC(OCC)OCC)(=O)C.O1C2C=C(C(N3CC=CCC3)=O)C=CC=2N=C1.N1CC=CCC1>>[O:12]1[C:16]2[CH:17]=[CH:18][C:19]([C:21]([N:1]3[CH2:2][CH:3]=[CH:4][CH2:5][CH2:9]3)=[O:23])=[CH:20][C:15]=2[N:14]=[CH:13]1
Reactant: Nc1ccc(C(=O)O)cc1O
Reactant: O=C(O)c1ccc2ocnc2c1
Agent: C1=CCNCC1
Agent: CCOC(OCC)OC(C)=O
Agent: O=C(c1ccc2ncoc2c1)N1CC=CCC1
Product: O=C(c1ccc2ocnc2c1)N1CC=CCC1

Procedure:
4-Amino-3-hydroxybenzoic acid is converted into 1,3-benzoxazol-5-carboxylic acid by treating with diethoxymethyl acetate as described for the preparation of Invention Compound. IX. EMIS m/z=163 (parent), 146 (base), 118, 90, and 63. Coupling of the acid with 1,2,3,6-tetrahydropyridine is performed in the same manner as described for the preparation of isomeric Invention Compound IX. 1H NMR δ 2.1-2.4 (br, 4), 3.4-4.3 (br m, 4), 5.5-5.95 (br m, 2), 7.45 (dd, 1, J=8.17, 1.41 Hz), 7.70 (d, 1, J=0.96 Hz), 7.83 (d, 1, J=8.16 Hz), and 8.18 ppm (s, 1).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[O:3].[C:8](=[O:18])([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[NH2:9].O>C1(C)C=CC=CC=1>[CH2:11]([O:10][C:8]([NH:9][CH:2]([OH:3])[C:1]([O:5][CH2:6][CH3:7])=[O:4])=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NC(=O)OCc1ccccc1
Reactant: CCOC(=O)C=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)C(O)NC(=O)OCc1ccccc1
Yield: 64.9 %

Procedure:
A solution of 17.3 g (0.169 mole) of ethyl glyoxylate and 23.0 g (0.152 mole) of benzyl carbamate in 250 ml of toluene was heated under reflux for 6 hours, with removal of water using a Dean-Stark trap. The resulting reaction mixture was concentrated in vacuo, and diethyl ether was added to the residue. The mixture was filtered, and the diethyl ether solution was evaporated in vacuo to give 25.0 g of ethyl 2-(benzyloxycarbonylamino)-2-(hydroxy)acetate as a sticky solid.
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8]([O:14][CH3:15])(=[O:13])[C:9](OC)=[O:10]>O([Ti](OC1C=CC=CC=1)(OC1C=CC=CC=1)OC1C=CC=CC=1)C1C=CC=CC=1>[C:8]([O:14][C:15]1[CH:5]=[CH:6][CH:1]=[CH:2][CH:3]=1)(=[O:13])[C:9]([O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)=[O:10]
Reactant: COC(=O)C(=O)OC
Reactant: Oc1ccccc1
Agent: c1ccc(O[Ti](Oc2ccccc2)(Oc2ccccc2)Oc2ccccc2)cc1
Product: O=C(Oc1ccccc1)C(=O)Oc1ccccc1
Temperature: 190 °C

Procedure:
A solution comprising 54.1% by weight of phenol, 45.3% by weight of dimethyl oxalate and 0.5% by weight of tetraphenoxytitanium was fed into the twelfth step from the top of a first fifty-plate Oldershaw-type reactive distillation column provided with a one liter bottom flask and having an inner diameter of 32 mm, at a flow rate of 600 ml/hr, and the bottom flask was heated by a mantle heater to a temperature of 190° C., while withdrawing a resultant vapor fraction from the top portion of the first column at a reflux ratio of 2 and condensing the withdrawn vapor fraction by a cooler, to transesterify dimethyl oxalate with phenol and to produce diphenyl oxalate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH:7]=[CH:8][NH:9]2)=[CH:5][CH:4]=1.ClS([N:16]=[C:17]=O)(=O)=O>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:17]#[N:16])=[CH:8][NH:9]2)=[CH:5][CH:4]=1
Reactant: COc1ccc2cc[nH]c2c1
Reactant: O=C=NS(=O)(=O)Cl
Solvent: CN(C)C=O
Product: COc1ccc2c(C#N)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
A solution of 6-methoxyindole (10.0 g, 68.0 mmol) in DMF (120 mL) was cooled to 0° C. and treated with chlorosulfonyl isocyanate (7.72 mL, 88.4 mmol). After the addition, the reaction mixture was stirred at this temperature for 1 h. The dark solution was poured into ice water (600 mL) and the light brown solid was collected by filtration, washed with additional H2O and dried to afford 9.9 g (85%) of 6-methoxy-1H-indole-3-carbonitrile as a light brown solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]2[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][N:3]=1.[S:24]([NH2:34])(=[O:33])([C:26]1[CH:31]=[CH:30][C:29]([NH2:32])=[CH:28][CH:27]=1)=[O:25].CO>C(O)CCC>[S:24]([C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:2]2[N:7]=[C:6]([N:8]([CH2:17][CH2:18][CH2:19][C:20]([F:23])([F:22])[F:21])[C:9]3[CH:14]=[C:13]([CH3:15])[CH:12]=[CH:11][C:10]=3[F:16])[CH:5]=[CH:4][N:3]=2)=[CH:28][CH:27]=1)(=[O:25])(=[O:33])[NH2:34]
Reactant: Nc1ccc(S(N)(=O)=O)cc1
Reactant: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Cl)n2)c1
Solvent: CCCCO
Solvent: CO
Product: Cc1ccc(F)c(N(CCCC(F)(F)F)c2ccnc(Nc3ccc(S(N)(=O)=O)cc3)n2)c1
Temperature: 95 °C
Yield: 54.6 %

Procedure:
2-Chloro-4-(N-4,4,4,-trifluorobutyl-2-fluoro-5-methylanilino)pyrimidine (215 mg, 0.62 mmol) was dissolved in n-butanol (2 ml) and sulphanilamide (85 mg, 0.50 mmol) was added. The resulting suspension was treated with methanol until all the solid dissolved. The reaction mixture was heated at 95° C. for 12 hours and allowed to cool to ambient temperature. The solid that had precipitated was collected by filtration, washed with a small volume of methanol and dried in vacuo to yield a white solid (132 mg). NMR (400 MHz@373K): 1.85 (m, 2H), 2.31 (m, 2H), 2.35 (s, 3H), 3.97 (t, 2H), 6.04 (d, 1H), 7.29 (m, 3H) 8.02 (d, 1H), 10.00 (br s, 1H); MS (M+H)+: 484.4.
Reaction SMILES: [CH2:1]([Li])[CH2:2]CC.[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[C:20](=O)[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CCCCCC.[Br-].C([P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)C.O1CCCC1>[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1/[C:20](=[CH:1]\[CH3:2])/[C:21]([O:23][CH3:24])=[O:22])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COC(=O)C(=O)c1ccccc1OCc1ccccc1
Reactant: [Li]CCCC
Agent: CC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: C/C=C(/C(=O)OC)c1ccccc1OCc1ccccc1
Reaction time: 0.5 h
Yield: 57 %

Procedure:
At 0° C. and under nitrogen, 32 ml (50 mmol) of a 1.6 molar solution of n-butyllithium in hexane is slowly added to 18.5 g (50 mmol) of ethyltriphenylphosphonium bromide in 100 ml of absolute tetrahydrofuran. After the mixture has been stirred for 30 minutes, 13.5 g (50 mmol) of methyl 2-(benzyloxy)-phenylglyoxylate in 25 ml of absolute tetrahydrofuran is dripped in at 0° C. The mixture is stirred for 16 hours at room temperature. After concentration, the residue is taken up in dichloromethane and washed several times with water. After drying over Na2SO4 the solvent is evaporated off. The crude product obtained is purified by chromatography (a 9:1 mixture of cyclohexane and ethyl acetate). There is obtained 8.0 g (57%) of the methyl crotonate (trans:cis ratio=9:1) as an oil.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[O:8][C:6](=O)[C:5]2=[CH:11][CH:12]=1.C1(N=C=N)CCCCC1.Cl.[CH3:23][O:24][C:25]1[CH:26]=[C:27]([N:39]2C(=O)C3C(=CC=C(OC4C=CC=CC=4)C=3)C2=O)[CH:28]=[CH:29][C:30]=1[O:31][CH2:32][CH2:33][N:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:3]=[C:4]2[C:5](=[CH:11][CH:12]=1)[C:6](=[O:8])[N:39]([C:27]1[CH:28]=[CH:29][C:30]([O:31][CH2:32][CH2:33][N:34]3[CH2:35][CH2:36][CH2:37][CH2:38]3)=[C:25]([O:24][CH3:23])[CH:26]=1)[C:9]2=[O:10]
Reactant: COc1cc(N2C(=O)c3ccc(Oc4ccccc4)cc3C2=O)ccc1OCCN1CCCC1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: N=C=NC1CCCCC1
Solvent: ClCCl
Product: COc1cc(N2C(=O)c3ccc(F)cc3C2=O)ccc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
4-Fluorophthalic anhydride [Acros] (0.84 g, 5 mmol) was dissolved in dichloromethane (30 ml) and polymer bound N-cyclohexylcarbodiimide [Argonaut Technologies] (1.69 mol. eq./g, 3 g) was added, followed by a solution of 3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenylamine [Example A4] (1.18 g, 5.0 mmol) and a catalytic amount of 4-dimethylaminopyridine. The mixture was stirred for 16 h at ambient temperature. The resin was filtered off over filter-aid, and washed with dichloromethane. The filtrate was evaporated in vacuo and purified by chromatography using a Biotage Flash40M cartridge, eluting with dichloromethane-methanol to give the 5-fluoro-2-[3-methoxy-4-(2-pyrrolidin-1-yl-ethoxy)-phenyl]-isoindole-1,3-dione;
Reaction SMILES: [NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4](Cl)[CH:3]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25]>CN1C(=O)CCC1.O>[NH2:1][C:2]1[C:19]([N+:20]([O-:22])=[O:21])=[CH:18][C:5]([C:6]([NH:8][C:9]2[CH:17]=[C:16]3[C:12]([CH:13]=[N:14][NH:15]3)=[CH:11][CH:10]=2)=[O:7])=[C:4]([N:26]([CH2:27][CH3:28])[CH2:24][CH3:25])[CH:3]=1
Reactant: CCNCC
Reactant: Nc1cc(Cl)c(C(=O)Nc2ccc3cn[nH]c3c2)cc1[N+](=O)[O-]
Solvent: O
Solvent: CN1CCCC1=O
Product: CCN(CC)c1cc(N)c([N+](=O)[O-])cc1C(=O)Nc1ccc2cn[nH]c2c1
Temperature: 25 °C

Procedure:
A solution 4-amino-2-chloro-N-(1H-indazol-6-yl)-5-nitrobenzamide (1 mmol; see Example 48) in NMP (2 mL) was added with diethylamine (1.0 mL), and the resulting mixture was subjected to microwave irradiation at 70° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with water (20 mL). The solid formed was collected by filtration, washed with water, and dried in vacuo to provide 4-amino-2-diethylamino-N-(1H-indazol-6-yl)-5-nitrobenzamide.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18]Cl.[CH3:21][CH:22]([CH3:38])[C:23]([NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([CH:32]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]2)[CH:27]=1)=[O:24]>>[Br:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[O:20])[CH2:15][CH2:16][CH2:17][CH2:18][N:35]1[CH2:36][CH2:37][CH:32]([C:28]2[CH:27]=[C:26]([NH:25][C:23](=[O:24])[CH:22]([CH3:21])[CH3:38])[CH:31]=[CH:30][CH:29]=2)[CH2:33][CH2:34]1
Reactant: CC(C)C(=O)Nc1cccc(C2CCNCC2)c1
Reactant: O=C(CCCCCl)c1ccccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Br)CC2)c1

Procedure:
Prepared by Procedure K and Scheme B1 (K2CO3) using 1-(2-bromophenyl)-5-chloro-1-pentanone and 2-methyl-N-[3-(4-piperidinyl)phenyl]propanamide: ESMS m/e: 485.1 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[O:9]1[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[O:9]1[CH2:14][CH2:13][CH:12]([NH:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[OH:8])[CH2:11][CH2:10]1
Reactant: O=C1CCOCC1
Reactant: Nc1ccccc1O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Product: Oc1ccccc1NC1CCOCC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 39 %

Procedure:
A mixture of 2-aminophenol (1 g, 9.164 mmol), tetrahydropyran-4-one (1.099 ml, 11.913 mmol), and sodium triacetoxy-borohydride (0.71 g, 3.42 mmol) in DCE (50 ml) was stirred at r.t. for 16 h. The crude was filtered over diatomaceous earth, washed with DCM and the filtrate was evaporated in vacuo to yield D7 (0.69 g) that was used as such in the next reaction step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6].[OH-].[K+].[CH2:14](Br)[CH3:15]>C(O)C.O>[CH2:14]([O:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=[O:6])[CH3:15]
Reactant: COc1ccc(C=O)cc1O
Reactant: CCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCOc1cc(C=O)ccc1OC
Reaction time: 8 h
Yield: 93 %

Procedure:
To a solution of 100 g of 3-hydroxy-4-methoxybenzaldehyde in 200 ml ethanol was added to solution of 44 g KOH in 44 ml H2O. The mixture dissolved upon heating to reflux and 56 ml ethyl bromide was then added slowly. A yellow solid began to precipitate after 15 min and heating of the mixture at reflux was continued overnight. Excess ethyl bromide and solvent were removed in vacuo and the residue was distributed between water and CHCl3. The CHCl3 layer was dried and evaporated to give a pale yellow oil which crystallized from ethanol to give 112 g (93%) of 3-ethoxy-4-methoxybenzaldehyde, mp 49.5°-50.5°(Lit.12 mp 50° -51°).
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18](=[O:26])OC2C=CC=CC=2)[N:14]([C:27]2[CH:32]=[CH:31][C:30]([CH3:33])=[CH:29][CH:28]=2)[N:13]=1)([CH3:11])([CH3:10])[CH3:9].[CH2:34]([C:36]1[N:41]=[C:40]([NH:42][C:43]2[CH:48]=[C:47]([CH2:49][O:50][C:51]3[C:60]4[C:55](=[CH:56][CH:57]=[CH:58][CH:59]=4)[C:54]([NH:61]C(=O)OC(C)(C)C)=[CH:53][CH:52]=3)[CH:46]=[CH:45][N:44]=2)[CH:39]=[N:38][CH:37]=1)[CH3:35]>C1COCC1>[C:8]([C:12]1[CH:16]=[C:15]([NH:17][C:18]([NH:61][C:54]2[C:55]3[C:60](=[CH:59][CH:58]=[CH:57][CH:56]=3)[C:51]([O:50][CH2:49][C:47]3[CH:46]=[CH:45][N:44]=[C:43]([NH:42][C:40]4[CH:39]=[N:38][CH:37]=[C:36]([CH2:34][CH3:35])[N:41]=4)[CH:48]=3)=[CH:52][CH:53]=2)=[O:26])[N:14]([C:27]2[CH:28]=[CH:29][C:30]([CH3:33])=[CH:31][CH:32]=2)[N:13]=1)([CH3:10])([CH3:11])[CH3:9]
Reactant: Cc1ccc(-n2nc(C(C)(C)C)cc2NC(=O)Oc2ccccc2)cc1
Reactant: CCc1cncc(Nc2cc(COc3ccc(NC(=O)OC(C)(C)C)c4ccccc34)ccn2)n1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1cncc(Nc2cc(COc3ccc(NC(=O)Nc4cc(C(C)(C)C)nn4-c4ccc(C)cc4)c4ccccc34)ccn2)n1
Temperature: 40 °C
Reaction time: 0.67 h

Procedure:
Triethylamine (0.013 mL, 0.093 mmol) was added to a solution of phenyl (3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)carbamate (Intermediate B) (0.042 g, 0.121 mmol) and N-(4-(((4-aminonaphthalen-1-yl)oxy)methyl)pyridin-2-yl)-6-ethylpyrazin-2-amine (Intermediate D) (0.093 g, 0.250 mmol) in THF (1.5 mL) at 40° C. The reaction mixture was stirred at 40° C. for 40 min then cooled to RT and stirred for 3 days, and then concentrated in vacuo. The crude product was purified by silica gel chromatography (12 g column, 0 to 5% MeOH in DCM) to give an off white-brown solid. The product was re-purified by preparative HPLC (Gilson, Acidic (0.1% Formic acid), Acidic, Waters X-Select Prep-C18, 5 μm, 19×50 mm column, 45-75% MeCN in Water) to afford the title compound 1-(3-(tert-butyl)-1-(p-tolyl)-1H-pyrazol-5-yl)-3-(4-((2-((6-ethylpyrazin-2-yl)amino)pyridin-4-yl)methoxy)naphthalen-1-yl)urea as an off white solid (0.029 g, 49%); Rt 2.26 min (Method 1); m/z 627 (M+H)+ (ES+), 625 (M−H)− (ES−); 1H NMR δ: 1.18 (3H, t), 1.28 (9H, s), 2.40 (3H, s), 2.63 (2H, q), 5.36 (2H, s), 6.36 (1H, s), 7.02 (1H, d), 7.07 (1H, dd), 7.37 (2H, m), 7.45 (2H, m), 7.56-7.67 (3H, overlapping m), 7.94 (1H, m), 7.99 (1H, s), 8.02 (1H, s), 8.30 (1H, d), 8.39 (1H, m), 8.60 (1H, s), 8.81 (1H, s), 8.92 (1H, s), 10.08 (1H, s).
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:12]=[CH:11][C:10]([CH2:13][O:14][C:15]2([CH3:18])[CH2:17][CH2:16]2)=[C:9]([CH:19]([CH3:21])[CH3:20])[CH:8]=1)(=O)=O.[CH3:24][Si:25]([C:28]#[CH:29])([CH3:27])[CH3:26]>C(N(CC)CC)C.CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:19]([C:9]1[CH:8]=[C:7]([C:29]#[C:28][Si:25]([CH3:27])([CH3:26])[CH3:24])[CH:12]=[CH:11][C:10]=1[CH2:13][O:14][C:15]1([CH3:18])[CH2:17][CH2:16]1)([CH3:21])[CH3:20]
Reactant: C#C[Si](C)(C)C
Reactant: CC(C)c1cc(OS(=O)(=O)C(F)(F)F)ccc1COC1(C)CC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)c1cc(C#C[Si](C)(C)C)ccc1COC1(C)CC1
Temperature: 95 °C
Yield: 107.7 %

Procedure:
Using General Procedure D; 3-isopropyl-4-(1-methyl-cyclopropoxymethyl)-phenyl 1,1,1-trifluoromethanesulfonate (Intermediate 164, 120.0 mg, 0.34 mmol) in triethylamine (2 mL) and anhydrous DMF (5 mL) was sparged with argon for 5 minutes. Trimethylsilyl acetylene (700.0 mg, 0.71 mmol) was then added followed by dichlorobis(triphenylphosphine)palladium(II) (24.0 mg, 0.03 mmol). The resulting reaction mixture was heated to 95° C. for 60 hours. The title compound 110.0 mg, (99%) was isolated by chromatography (0-1% EtOAc-hexanes).
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[N:6][CH:7]=1.[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH2:15])=[CH:12][CH:11]=1>>[CH3:8][O:9][C:10]1[CH:17]=[CH:16][C:13]([CH2:14][NH:15][C:2]2[CH:3]=[N:4][CH:5]=[N:6][CH:7]=2)=[CH:12][CH:11]=1
Reactant: Brc1cncnc1
Reactant: COc1ccc(CN)cc1
Product: COc1ccc(CNc2cncnc2)cc1
Yield: 85 %

Procedure:
Using the general procedure, 5-bromopyrimidine (159 mg, 1.0 mmol) was coupled with 4-methoxybenzylamine (196 μL, 1.5 mmol) at 90° C. for 22 h. Purification of the crude product by column chromatography on silica gel using dichloromethane(saturated with ammonia)/ethyl acetate (1:1) as eluent afforded the desired product as a white solid (183 mg, 85% yield). Rf=0.2 (dichloromethane(saturated with ammonia)/ethyl acetate 1:1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5](O)=[O:6].C(Cl)CCl.C1C=CC2N(O)N=[N:22][C:20]=2C=1.Cl.CN>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[OH:11])[C:5]([NH:22][CH3:20])=[O:6]
Reactant: O=C(O)c1ccc(O)c(Br)c1
Reactant: On1nnc2ccccc21
Agent: CN
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: CNC(=O)c1ccc(O)c(Br)c1
Reaction time: 16 h

Procedure:
To a stirred solution of 3-bromo-4-hydroxybenzoic acid (Commercial eg Aldrich) (2.0 g), EDC (2.65 g), HOBT (1.41 g) and TEA (6.2 ml) in DCM (60 ml) was added methylamine hydrochloride (1.87 g). This was stirred at 25-30 C for 16 h. The solvent was removed under reduced pressure. The residue was dissolved in water and extracted with ethyl acetate. The organics were dried (sodium sulphate) and concentrated in vacuo to yield the title compound, 0.57 g
Reaction SMILES: [NH2:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4].[C:14](Cl)(=[O:16])[CH3:15].Cl.C(O)(=O)C>[OH-].[Na+]>[C:14]([NH:1][C:2]([CH2:12][F:13])([CH2:6][C:7]1[NH:11][CH:10]=[N:9][CH:8]=1)[C:3]([OH:5])=[O:4])(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: NC(CF)(Cc1cnc[nH]1)C(=O)O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Product: CC(=O)NC(CF)(Cc1cnc[nH]1)C(=O)O
Temperature: 5 °C

Procedure:
A solution of 1.87 g (0.01 mole) of 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid in 10 ml of 2 N sodium hydroxide solution is cooled to 5° C. To this solution, maintained at 5° C., are added simultaneously from two syringes 1.0 g (0.013 mole) of acetyl chloride and 26 ml 2 N sodium hydroxide dropwise. After 2 hours the solution is neutralized by the addition of 8 ml of 5 N hydrochloric acid followed by 0.5 ml of acetic acid. The mixture is cooled to 0° C. and the resultant N-acetyl 2-amino-2-fluoromethyl-3-(5-imidazolyl)propionic acid filtered off.