Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([O:4][C:5]([C:7]1([NH:10][C:11]([C:13]2[N:17]3[C@@:18]([CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]#[N:40])=[CH:35][CH:34]=4)([CH3:31])[C:19](=[O:30])[N:20]([C:21]4[CH:26]=[C:25]([Cl:27])[C:24]([F:28])=[C:23]([Cl:29])[CH:22]=4)[C:16]3=[N:15][CH:14]=2)=[O:12])[CH2:9][CH2:8]1)=[O:6])C=C.N1CCOCC1>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1COCC1>[C:39]([C:36]1[CH:37]=[CH:38][C:33]([CH2:32][C@@:18]2([CH3:31])[N:17]3[C:13]([C:11]([NH:10][C:7]4([C:5]([OH:6])=[O:4])[CH2:8][CH2:9]4)=[O:12])=[CH:14][N:15]=[C:16]3[N:20]([C:21]3[CH:22]=[C:23]([Cl:29])[C:24]([F:28])=[C:25]([Cl:27])[CH:26]=3)[C:19]2=[O:30])=[CH:34][CH:35]=1)#[N:40]
Reactant: C=CCOC(=O)C1(NC(=O)c2cnc3n2[C@](C)(Cc2ccc(C#N)cc2)C(=O)N3c2cc(Cl)c(F)c(Cl)c2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: C1COCCN1
Product: C[C@@]1(Cc2ccc(C#N)cc2)C(=O)N(c2cc(Cl)c(F)c(Cl)c2)c2ncc(C(=O)NC3(C(=O)O)CC3)n21
Temperature: 25 °C
Reaction time: 16 h

Procedure:
The ester obtained (12.6 g, 22 mmol) was combined with THF (100 mL). Morpholine (18.6 mL, 210 mmol) and Pd(PPh3)4 (500 mg, 0.40 mmol) were added and the reaction was allowed to stir at room temperature for 16 h. The solution was filtered through diatomaceous earth and then concentrated. The residue was diluted with ethyl acetate (150 mL) washed with water (2×50 mL), 1M HCl (2×50 mL), brine (1×50 mL) and then dried (MgSO4), filtered and concentrated. The residue was purified by flash chromatography (silica-gel) using 10-100% ethyl acetate in hexanes to provide 10.4 g of the title compound.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([O:21][C:22]([F:25])([F:24])[F:23])[CH:5]=[C:6]2[C:11]=1[O:10][CH:9]([C:12]([F:15])([F:14])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]2.[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(Cl)Cl>C1(C)C=CC=CC=1.[Cl-].[Na+].O.[Cu]I.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:26]1([C:32]#[C:33][C:2]2[CH:3]=[C:4]([O:21][C:22]([F:23])([F:25])[F:24])[CH:5]=[C:6]3[C:11]=2[O:10][CH:9]([C:12]([F:14])([F:15])[F:13])[C:8]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:7]3)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(I)c2OC1C(F)(F)F
Reactant: C#Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [Fe+2]
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: O
Product: CCOC(=O)C1=Cc2cc(OC(F)(F)F)cc(C#Cc3ccccc3)c2OC1C(F)(F)F
Yield: 85 %

Procedure:
A mixture of ethyl 8-iodo-6-(trifluoromethoxy)-2-(trifluoromethyl)-2H-chromene-3-carboxylate prepared as in Example 21a, Step 2 (1.00 g, 2.07 mmole), phenylacetylene (0.455 mL, 4.15 mmole), CuI (39.5 mg, 0.207 mmole), PdCl2(dppf)2.CH2Cl2 (169 mg, 0.207 mmole) and TEA (0.867 mL, 6.22 mmole) in anhydrous toluene (10 mL) was stirred at room temperature for 18.5 h. The mixture was then poured into brine (100 mL) and extracted with EtOAc. The EtOAc layer was separated, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica chromatography (9:1 hexanes:EtOAc) to give 0.802 g (85% yield) of the product as a yellow crystalline solid: EIHRMS m/z 456.0781 (M+, C14H14F6O4, Calc'd 456.0796).
Reaction SMILES: [NH2:1][C:2]1[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=1[C:12]#[N:13].[CH:14]([NH2:16])=O>O>[NH2:13][C:12]1[N:16]=[CH:14][N:1]=[C:2]2[N:7]([CH3:8])[C:6](=[O:9])[N:5]([CH3:10])[C:4](=[O:11])[C:3]=12
Reactant: Cn1c(N)c(C#N)c(=O)n(C)c1=O
Reactant: NC=O
Solvent: O
Product: Cn1c(=O)c2c(N)ncnc2n(C)c1=O
Yield: 58 %

Procedure:
0.3 g (1.7 mmol) of 6-amino-5-cyano-1,3-dimethyluracil was added to 2 ml of formamide followed by refluxing for 2 hours. 10 ml of water was added to the solution and the crystalline precipitate was filtered off. The crude product was recrystallized from methanol to give 0.2 g of 5-amino-1,3-dimethylpyrimido[4,5-d]pyrimidine-2,4-dione (compound 9) in a 58% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[CH:10]=[C:9]([C:12]#[N:13])[O:8][C:7]=2[CH:6]=[CH:5][CH:4]=1.Cl.[NH2:15][OH:16].C(=O)([O-])O.[Na+]>C(O)C>[OH:16][N:15]=[C:12]([NH2:13])[C:9]1[O:8][C:7]2[CH:6]=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:11]=2[CH:10]=1
Reactant: COc1cccc2oc(C#N)cc12
Reactant: NO
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cccc2oc(C(N)=NO)cc12
Yield: 102 %

Procedure:
To a solution (40 ml) of 4-methoxybenzo(b)furan-2-carbonitrile (2.8 g) in ethanol were added hydroxylamine hydrochloride (1.2 g) and sodium hydrogencarbonate (3.0 g). The mixture was refluxed under heating for 1.5 hr. The inorganic material was filtered off and the reaction mixture was concentrated under reduced pressure to give the title compound (3.4 g) as brown crystals.
Reaction SMILES: Cl.[O:2]1[C:10]2[CH2:9][CH2:8][NH:7][CH2:6][C:5]=2[CH:4]=[CH:3]1.[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23](O)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1.C(N(CC)CC)C.C(P(=O)(OCC)OCC)#N>ClCCl.O>[CH3:11][O:12][C:13]1[CH:29]=[CH:28][C:16]([C:17]([C:19]2[CH:27]=[CH:26][C:22]([C:23]([N:7]3[CH2:8][CH2:9][C:10]4[O:2][CH:3]=[CH:4][C:5]=4[CH2:6]3)=[O:24])=[CH:21][CH:20]=2)=[O:18])=[CH:15][CH:14]=1
Reactant: c1cc2c(o1)CCNC2
Reactant: COc1ccc(C(=O)c2ccc(C(=O)O)cc2)cc1
Agent: CCOP(=O)(C#N)OCC
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: COc1ccc(C(=O)c2ccc(C(=O)N3CCc4occc4C3)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 0.160 g (1.000 mmol) of 4,5,6,7-tetrahydrofuro[3,2-c]pyridine hydrochloride, 0.308 g (1.2 mmol) of 4-(4-methoxybenzoyl)benzoic acid and 0.55 ml (4.0 mmol) of triethylamine in 30 ml of dichloromethane, 0.24 g (1.5 mmol) of diethyl cyanophosphonate was added dropwise under ice-cooling, followed by overnight stirring at room temperature. The reaction mixture was poured into water and extracted with dichloromethane 2 times. The combined organic layer was washed with water and dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (hexane/ethyl acetate=2/1) to yield the desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][NH:15][CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1.F[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=1.C(N(CC)C(C)C)(C)C>CS(C)=O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][C@H:9]2[C@H:13]3[CH2:14][N:15]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([C:25]([F:28])([F:27])[F:26])[N:20]=4)[CH2:16][CH2:17][N:12]3[CH2:11][CH2:10]2)=[N:6][CH:7]=1
Reactant: Fc1cccc(C(F)(F)F)n1
Reactant: Clc1ccc(O[C@@H]2CCN3CCNC[C@H]23)nc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: FC(F)(F)c1cccc(N2CCN3CC[C@@H](Oc4ccc(Cl)cn4)[C@H]3C2)n1
Temperature: 90 °C
Reaction time: 16 h

Procedure:
To a solution of Example 101B (53 mg, 0.21 mmol) and 2-fluoro-6-(trifluoromethyl)pyridine (41 mg, 0.25 mmol) in dimethyl sulfoxide (0.7 mL) was added N,N-diisopropylethylamine (0.3 mL, 1.73 mmol). The mixture was heated to 90° C. and stirred for 16 hours and then concentrated. The residue was purified via HPLC (Gilson®, Xbridge™ 30×100 mm column, eluted with pH=10 aqueous ammonium bicarbonate-ammonium hydroxide/methanol, UV=248 nm) to give the title compound. 1H NMR (300 MHz, methanol-d4) δ ppm 1.81-1.96 (m, 1 H), 2.13-2.31 (m, 3 H), 2.40-2.53 (m, 1 H), 2.94-3.05 (m, 2 H), 3.16-3.25 (m, 2 H), 4.34-4.43 (m, 1 H), 4.50 (dd, 1H, J=12, 3 Hz), 5.59 (ddd, 1H, J=7, 4, 2 Hz), 6.81 (d, 1H, J=8 Hz), 6.96 (dd, 2H, J=8, 5 Hz), 7.61-7.71 (m, 2 H), 8.12 (d, 1H, J=2 Hz); MS (DCI) m/z 399 (M+H)+.
Reaction SMILES: C([O:3][C:4]([C:6]1[N:14]2[C:9]([CH:10]=[N:11][CH:12]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])C.[OH-].[Na+].Cl>O1CCCC1.N1C=CC=CC=1.O>[N:13]1[N:14]2[C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=[C:9]2[CH:10]=[N:11][CH:12]=1
Reactant: CCOC(=O)c1ccc2cncnn12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc2cncnn12
Temperature: 70 °C
Yield: 43.9 %

Procedure:
A mixture of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid ethyl ester (40 mg) and an aqueous solution of sodium hydroxide (6 M, 1 mL) in a mixture of tetrahydrofuran and methanol (1/1, 1 mL) was heated at 70° C. for 1 hour. The reaction mixture was then cooled, acidified by addition of an aqueous solution of hydrochloric acid (6 M) and evaporated under reduced pressure. The residue was dissolved in a mixture of dichloromethane and water (10/1, 5.5 mL), the organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated under reduced pressure to give 15 mg of pyrrolo[2,1-f][1,2,4]triazine-7-carboxylic acid.
Reaction SMILES: I[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[CH3:13][O:14][C:15]1[CH:20]=[CH:19][C:18](B(O)O)=[CH:17][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CCOC(C)=O>O.CCO.C1(C)C=CC=CC=1.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCCCCC>[Cl:12][C:3]1[CH:4]=[C:5]([C:6]([O:8][CH3:9])=[O:7])[CH:10]=[CH:11][C:2]=1[C:18]1[CH:19]=[CH:20][C:15]([O:14][CH3:13])=[CH:16][CH:17]=1
Reactant: COC(=O)c1ccc(I)c(Cl)c1
Reactant: COc1ccc(B(O)O)cc1
Agent: [Pd]
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CCO
Product: COC(=O)c1ccc(-c2ccc(OC)cc2)c(Cl)c1

Procedure:
A mixture of methyl 4-iodo-3-chlorobenzoate (1.20 g, 4.05 mmol) from Step A, 4-methoxy phenyl boronic acid (1.23 g, 8.1 mmol), tetrakis(triphenylphosphine) palladium (0.23 g, 5% mol) and sodium carbonate (0.94 g, 8.9 mmol) in 50 ml of water/EtOH/toluene (1:2:4) was heated to reflux overnight. TLC (EtOAc:hexane/1:9) showed that the reaction was over. The solvents were removed. Water (30 ml) was added. The organic was extracted with methylene chloride (3×50 ml). The combined methylene chloride layers were washed with brine, and dried over sodium sulfate. The title compound was obtained after flash column using EtOAc:hexane/1:9 as the eluant. 1H NMR (CDCl3, 500 MHz): δ 8.16 (d, J=1.5 Hz, 1H), 7.97 (dd, J=8, 1.5 Hz, 1H), 7.43 (m, 3H), 7.01 (d, J=6.5 Hz, 2H), 4.00 (s, 3H), 3.91 (s, 3H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2.[Si:12]([C:16]#[CH:17])([CH3:15])([CH3:14])[CH3:13]>CN(C=O)C.[Cu]I.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>[CH3:13][Si:12]([C:16]#[C:17][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[CH2:5]2)([CH3:15])[CH3:14]
Reactant: O=C1Cc2cc(I)ccc2N1
Reactant: C#C[Si](C)(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CN(C)C=O
Product: C[Si](C)(C)C#Cc1ccc2c(c1)CC(=O)N2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a solution of 5-iodoindolin-2-one (518 mg, 2 mmol), TEA (3 ml) and CuI (38 mg) in DMF (3 ml) was added to PdCl2(PPh3)2 (70 mg). The mixture was cooled to 0° C. and a solution of TMS-acetylene (1 ml). The mixture was maintained same temperature for 3 h, then warmed to rt. After stirring for overnight, the reaction mixture was concentrated in vacuo. The residue was purified by silica gel column chromatography to give 5-((trimethylsilyl)ethynyl)indolin-2-one (451 mg).
Reaction SMILES: [H-].[Na+].[CH2:3]([OH:10])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Br:11][CH2:12][CH2:13][CH2:14][C:15](Cl)=[O:16]>O1CCCC1>[Br:11][CH2:12][CH2:13][CH2:14][C:15]([O:10][CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:16]
Reactant: OCc1ccccc1
Reactant: O=C(Cl)CCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(CCCBr)OCc1ccccc1
Temperature: -70 °C
Reaction time: 1 h

Procedure:
80% Sodium hydride dispersion in oil (0.18 g, 5.9 mmol) was added portionwise to a stirred solution of benzyl alcohol (0.64 g, 5.9 mmol) in anhydrous tetrahydrofuran (10 ml) under nitrogen. After a further 1 hour at room temperature, the reaction mixture was cooled to -70° C. and a solution of 4-bromobutanoyl chloride (1.0 g, 5.4 mmol) in anhydrous tetrahydrofuran (3 ml) added dropwise. After 0.5 hour, the cooling bath was removed and the reaction mixture quenched at room temperature with 5% aqueous ammonium chloride solution (20 ml) and then extracted with dichloromethane (3×20 ml). The combined extracts were washed with saturated brine, dried (Na2SO4) and evaporated under reduced pressure, then the residue was purified by column chromatography on silica gel, eluting with dichloromethane, to give the required ester as a gum. Rf 0.60 (SS 16).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]([CH:7]2[CH2:16][CH2:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[CH2:8]2)[C:3]1=[S:17].[C:18](OC(=O)C)(=[O:20])[CH3:19]>>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][CH2:16][CH:7]1[N:4]1[C:3](=[S:17])[N:2]([NH:1][C:18](=[O:20])[CH3:19])[CH:6]=[N:5]1
Reactant: Nn1cnn(C2CCc3ccccc3C2)c1=S
Reactant: CC(=O)OC(C)=O
Product: CC(=O)Nn1cnn(C2CCc3ccccc3C2)c1=S

Procedure:
substituting 4-amino-2-(1,2,3,4-tetrahydronaphthalen-2-yl)-2,4-dihydro[1,2,4]triazole-3-thione and acetic anhydride gave N-[1-(1,2,3,4-tetrahydronaphthalen-2-yl)-5-thioxo-4,5-dihydro-1H-[1,2,4]triazol-4-yl]acetamide, m.p. 199°-201° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15](=[O:16])[NH:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1.[C:19](Cl)(=[O:28])[CH2:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([OH:18])=[C:7]3[C:15]([O:16][C:19](=[O:28])[CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:14][NH:13][C:12](=[O:17])[C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH][nH]c(=O)c2c(O)c3ccc(Cl)cc3nc12
Reactant: O=C(Cl)CCc1ccccc1
Solvent: c1ccncc1
Solvent: O
Product: O=C(CCc1ccccc1)Oc1n[nH]c(=O)c2nc3cc(Cl)ccc3c(O)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 7-chloro-2,3-dihydro-10-hydroxypyridazino[4,5-b]quinoline-1,4-dione (0.60 g, 2.3 mM), as prepared in Example 2, and hydrocinnamoyl chloride (1.15 g, 6.84 mM) in pyridine (9 mL) was refluxed for 1 hr. Upon cooling to room temperature, the solution solidified. After 2 hr at room temperature, the mixture was diluted with water (60 mL) and the solids broken up with a glass rod to provide a free-flowing aqueous suspension which was stirred for 1 hr. The solids were collected, washed with water (10 mL), and resuspended in 50% aqueous methanol (60 mL). After stirring for 15 minutes, this suspension was filtered and the collected solids were washed with 50% aqueous methanol (10 mL) and then sucked dry under a stream of nitrogen to provide a tan solid. This material was dried for 2.5 days in vacuo (50 mTorr) at 100° C. and then was recrystallized from dimethylsulfoxide/methanol. The title compound was obtained (0.40 g, 44%), after drying 24 hr in vacuo (50 mTorr) at 100° C., as an off-white powder, mp >300° C. Analysis for C20H14ClN3O4 ·0.3 H2O: Calculated: C, 60.0; H, 3.65; N, 10.50 Found: C, 60.1; H, 3.69; N, 10.56
Reaction SMILES: [O-:1][V:2](=[O:4])=[O:3].[Na+:5].[OH2:6]>>[O-:4][V:2](=[O:3])=[O:1].[Na+:5].[OH:3][V:2]([OH:6])([OH:1])=[O:4]
Reactant: O
Agent: O=[V](=O)[O-]
Agent: [Na+]
Product: O=[V](O)(O)O

Procedure:
First, an 8% by weight solution of sodium metavanadate (NaVO3) was prepared by dissolving an appropriate amount of NaVO3 powder in water. The NaVO3 and water were stirred for several hours until the NaVO3 powder was completely dissolved. 4700 grams of the sodium metavanadate solution was acidified using 3600 milliliters of Amberlite IR-120 ion exchange resin (commercially available from Fluka Chemical Corp., New York) to form a solution of vanadic acid having a pH less than 2. Immediately following acidification, approximately 4500 grams of the vanadic acid solution was partially neutralized with a 12% weight solution of lithium hydroxide monohydrate (LiOH.H2O) in water. The resulting acidic lithium vanadate solution had a pH of about 5.30. The ratio of lithium to vanadium in the solution was measured using inductively coupled plasma emission spectroscopy and was found to be 0.53 to 1.00. The lithium vadadate solution had a solids content of 3% by weight. A 760 gram aliquot of the acidic lithium vanadate solution was dried by rotary vacuum evaporation at 40° C. to form an orange solid. The solid was dissolved in 380 grams of ethanol. Dissolution in ethanol was carried out by stirring at room temperature for several hours, followed by refluxing at the boiling point for at least an hour. Following refluxing, a small amount of undissolved solid remained and was allowed to settle, leaving a transparent orange vanadium oxide precursor solution.
Reaction SMILES: C=O.[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][NH:25][C@@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1.[C:35](O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>C(Cl)Cl.CC(O)=O.C(Cl)Cl>[Cl:3][C:4]1[C:5]([F:34])=[C:6]([NH:10][C:11]2[C:20]3[C:15](=[CH:16][C:17]([O:32][CH3:33])=[C:18]([O:21][C@@H:22]4[CH2:27][CH2:26][N:25]([CH3:35])[C@@H:24]([C:28]([NH:30][CH3:31])=[O:29])[CH2:23]4)[CH:19]=3)[N:14]=[CH:13][N:12]=2)[CH:7]=[CH:8][CH:9]=1
Reactant: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Reactant: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1
Agent: C=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CNC(=O)[C@H]1C[C@H](Oc2cc3c(Nc4cccc(Cl)c4F)ncnc3cc2OC)CCN1C
Yield: 48.4 %

Procedure:
Molecular sieves (5 g) followed by aqueous formaldehyde (10 ml) were added to a stirred solution of (2R,4R)-4-({4-[(3-chloro-2-fluorophenyl)amino]-7-methoxyquinazolin-6-yl}oxy)-N-methylpiperidine-2-carboxamide (3.6 g, 7.84 mmol) in DCM-AcOH (100:10 ml) at room temperature. The reaction mixture was stirred for 1-2 minutes before solid sodium triacetoxyborohydride (3.31 g, 15.7 mmol) was added portionwise over 5 minutes. The reaction was essentially complete after all the sodium triacetoxyborohydride reducing agent had been added. DCM was added (100 ml) and the reaction was carefully neutralised with saturated aqueous NaHCO3(aq). The organic extract was washed with brine, dried (MgSO4) and concentrated to a yellow foam. The residue was purified by flash chromatography (silica gel, DCM-NH3/MeOH 2%) to give the title product as a white solid (1.8 g, 49%): 1H NMR Spectrum: (DMSO d6) 1.85-1.96 (m, 3H), 2.07 (m, 1H), 2.15 (s, 3H), 2.45-2.50 (m, 1H), 2.59 (d, 3H), 2.71 (m, 1H), 2.84 (m, 1H), 3.96 (s, 3H), 4.81 (m, 1H), 7.23 (s, 1H), 7.28 (t, 1H), 7.47-7.53 (m, 2H), 7.81 (s, 2H), 8.37 (s, 1H), 9.59 (s, 1H); Mass Spectrum: (M+H)+ 474.1.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30](O)=[O:31])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:37]1([NH2:40])[CH2:39][CH2:38]1>>[CH:37]1([NH:40][C:30](=[O:31])[C:29]2[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=2[S:27][CH2:26][C:16]2[C:17]3[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=3[CH:23]=[CH:24][C:15]=2[O:14][C@@H:7]([C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH2:6][N:1]2[CH:5]=[CH:4][N:3]=[CH:2]2)[CH2:39][CH2:38]1
Reactant: NC1CC1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Product: O=C(NC1CC1)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 80 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and cyclopropylamine (17 mg, 0.30 mmol, 0.6M in DMF) were combined to give 43 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 538 [M+H]+.
Reaction SMILES: [CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26](O)=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1.F[P-](F)(F)(F)(F)F.C[N:42](C(N(C)C)=[N+]1C2C(=NC=CC=2)[N+]([O-])=N1)C.C(N(C(C)C)CC)(C)C.[Cl-].[NH4+]>O.C(OCC)(=O)C.CN(C)C=O>[CH:1]1([N:6]2[CH2:12][C:11]([F:14])([F:13])[C:10](=[O:15])[N:9]([CH3:16])[C:8]3[CH:17]=[N:18][C:19]([NH:21][C:22]4[CH:30]=[CH:29][C:25]([C:26]([NH2:42])=[O:27])=[CH:24][C:23]=4[O:31][CH2:32][CH3:33])=[N:20][C:7]2=3)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CCOc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reactant: CN(C)C(N(C)C)=[N+]1N=[N+]([O-])c2ncccc21
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N(C1CCCC1)CC(F)(F)C(=O)N2C
Reaction time: 0.33 h
Yield: 78.6 %

Procedure:
A mixture of 0.0704 g (0.153 mmole) of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzoic acid (I-214), 4 mL of dimethylformamide, 0.0776 g (0.198 mmole) of 1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium-3-oxide hexafluorophosphate and 0.103 mg (0.804 mmole) of diisopropylethylamine was stirred for 20 minutes, then 0.0175 g (0.327 mmole) of ammonium chloride was added. The reaction mixture was stirred for 1.5 hours and then 150 mL of ethyl acetate and 25 mL of water was added. The organic layer was washed with 25 mL of ammonium chloride solution, 25 mL of water, 25 mL of brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 95:5-80:20) gave 0.0554 g of 4-(9-cyclopentyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-3-ethoxy-benzamide (I-223).
Reaction SMILES: [OH-].[Zn+2:2].[OH-].[NH2:4][C@H:5]([C:11]([OH:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10]>C(O)C>[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[NH2:4][C@H:5]([C:11]([O-:13])=[O:12])[CH2:6][CH2:7][CH2:8][CH2:9][NH2:10].[Zn+2:2]
Reactant: NCCCC[C@H](N)C(=O)O
Agent: [OH-]
Agent: [Zn+2]
Solvent: CCO
Product: NCCCC[C@H](N)C(=O)[O-]
Temperature: 25 °C
Yield: 92.4 %

Procedure:
A stirred mixture of zinc hydroxide (4.48 g, 45 mmol) and L-lysine (13.45 g, 92 mmol) in ethanol (300 mL) was refluxed for 4 h (became very thick and required mechanical stirring). The above mixture was cooled to room temperature and filtered (slowly), collected, and dried in vacuo. The wet solid was triturated from acetonitrile and dried to afford 14.80 g (92%) of zinc bis-lysinate as a white powder.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)#[CH:2].Br[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH2:22][CH3:23]>>[CH2:22]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[C:2]#[C:1][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:5][CH:4]=1)[CH3:23]
Reactant: C#Cc1ccc(CCC(=O)OC)cc1
Reactant: CCc1ccccc1Br
Product: CCc1ccccc1C#Cc1ccc(CCC(=O)OC)cc1

Procedure:
The title compound was prepared from methyl 3-(4-ethynylphenyl)propanoate (95 mg, 0.51 mmol) and 1-bromo-2-ethylbenzene (0.10 mL, 0.73 mmol) according to the general procedure IF to give 130 mg (87%) of a clear oil after purification by flash chromatography (SiO2, EtOAc:PE, 1:7): Rf=0.28 (EtOAc:PE, 1:4); 1H NMR (CDCl3) δ 7.50-7.48 (m, 1H), 7.46-7.44 (m, 2H), 7.26-7.22 (m, 2H), 7.20-7.14 (m, 3H), 3.67 (s, 3H), 2.96 (t, J=7.8 Hz, 2H), 2.88 (q, J=7.2 Hz, 2H), 2.63 (t, J=7.6 Hz, 2H), 1.29 (t, J=7.6 Hz, 3H); 13C NMR (CDCl3) δ 173.2, 146.3, 140.9, 132.2, 131.8, 128.6, 128.5, 128.1, 125.8, 122.5, 121.7, 92.9, 88.0, 51.8, 35.6, 31.0, 27.9, 14.9; ESI-MS m/z 315.1 (M+Na+).