Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C@H:20]([C:32]([OH:34])=[O:33])[CH2:21][CH2:22][CH2:23][NH:24][C:25](OC(C)(C)C)=O)=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1.Cl.O1[CH2:43][CH2:42]OCC1>CO>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[NH:11][CH2:12][C:13]2[CH:36]=[CH:35][C:16]([C:17]([NH:19][C@@H:20]([CH2:21][CH2:22][CH2:23][NH:24][CH2:25][C:43]3[CH:42]=[CH:4][CH:3]=[CH:2][N:1]=3)[C:32]([OH:34])=[O:33])=[O:18])=[CH:15][CH:14]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: CC(C)(C)OC(=O)NCCC[C@H](NC(=O)c1ccc(CNc2cccc3cccnc23)cc1)C(=O)O
Reactant: C1COCCO1
Agent: Cl
Solvent: CO
Product: O=C(N[C@@H](CCCNCc1ccccn1)C(=O)O)c1ccc(CNc2cccc3cccnc23)cc1
Reaction time: 15 h

Procedure:
The compound obtained in Example 16-3 (122.6 mg) was dissolved in methanol (1.2 ml) and 4 mol/l hydrochloric acid/dioxane solution (1.2 ml) was added. After the reaction for 1 hour, the reaction solution was concentrated and dried under reduced pressure. The resulting residue was dissolved in methanol (2 ml), and pyridine-2-aldehyde (18 μl) and triethylamine (27 μl) were added. After 15 hours, the reaction solution was concentrated and dried under reduced pressure. The residue was again dissolved in methanol (2 ml) and sodium borohydride (22 mg) was added. After the reaction for 1 hour, the reaction solution was concentrated. The residue was purified by silica gel column chromatography (4 g, chloroform/methanol/water=7/3/0.5) to obtain the title compound (114.0 mg) as an orange solid.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([NH:17][C@@H:18]1[C@H:23]2[CH2:24][C@H:20]([CH2:21][CH2:22]2)[C@H:19]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([O:33]C)=[O:32])(=[O:16])=[O:15].[OH-].[K+].Cl>CO.O1CCCC1>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][C:2]=1[S:14]([NH:17][C@@H:18]1[C@H:23]2[CH2:24][C@H:20]([CH2:21][CH2:22]2)[C@H:19]1[CH2:25]/[CH:26]=[CH:27]\[CH2:28][CH2:29][CH2:30][C:31]([OH:33])=[O:32])(=[O:15])=[O:16]
Reactant: COC(=O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)CCC/C=C\C[C@@H]1[C@H]2CC[C@H](C2)[C@H]1NS(=O)(=O)c1ccc2oc3ccccc3c2c1
Temperature: 25 °C
Yield: 86.8 %

Procedure:
Methyl (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoate (1a-1) (234 mg, 0.50 mmol) was dissolved in methanol (6 ml)/tetrahydrofuran (4 ml). To the solution was added 1 N potassium hydroxide (1.50 ml, 1.50 mmol) under ice-cooling. After the reaction mixture was warmed up to room temperature, it was allowed to react for 16 hr and concentrated to remove the solvent. To the residue were added ethyl acetate (50 ml) and water (10 ml), and then 1 N HCl (2.00 ml, 2.00 mmol), and the organic layer was separated. The organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated. The residue was purified by column chromatography on silica gel (n-hexane/ethyl acetate (1:1) containing 0.2% acetic acid) to yield (Z)-7-[(1S,2R,3R,4R)-3-(2-dibezofuryl)sulfonylaminobicyclo[2.2.1]hept-2-yl]-5-heptenoic acid (1a-2) (203 mg, 0.434 mmol). Yield 87%, oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH3:13])[C:10]([OH:12])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].CN(C)CCCN=C=NCC.OC1C2N=NNC=2C=CC=1.Cl.[F:36][C@@H:37]1[CH2:41][CH2:40][NH:39][CH2:38]1.C(N(CC)C(C)C)(C)C>CN(C=O)C.C(OCC)(=O)C>[C:1]([O:5][C:6](=[O:7])[NH:8][C@H:9]([CH3:13])[C:10]([N:39]1[CH2:40][CH2:41][C@@H:37]([F:36])[CH2:38]1)=[O:12])([CH3:2])([CH3:3])[CH3:4]
Reactant: C[C@@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: F[C@@H]1CCNC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@@H](NC(=O)OC(C)(C)C)C(=O)N1CC[C@@H](F)C1
Temperature: 25 °C
Reaction time: 16 h
Yield: 94.2 %

Procedure:
(R)-2-tert-Butoxycarbonylamino-propionic acid (1.0 g, 5.3 mmol), 1-(3-(dimethylamino)-propyl)-3-ethylcarbodiimide (2.33 g, 12.2 mmol) and hydroxybenzotriazole (1.64 g, 12.2 mmol) were dissolved in DMF (50 ml). (R)-3-Fluoropyrrolidine hydrochloride (1.66 g, 13.2 mmol) and N,N-diisopropylethylamine (2.95 ml, 16.9 mmol) were added and the mixture was stirred at room temperature for 16 h. Ethyl acetate was added and the solution was washed with 10% citric acid solution three times. The organic layer was washed with sodium bicarbonate solution which was then back-extracted with ethyl acetate four times. The combined organic layers were then washed further with lithium chloride solution, sodium chloride solution, and dried over magnesium sulfate. Concentration of the solution gave 1.3 g (94%) of [(R)-2-((R)-3-fluoro-pyrrolidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:31][CH2:30][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:28][CH2:27]3)=[O:25])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1.[CH2:38]([S:40]([NH2:43])(=[O:42])=[O:41])[CH3:39]>>[CH3:1][N:2]1[C:10]2[C:5](=[CH:6][C:7]([NH:11][C:12]3[N:17]4[N:18]=[CH:19][C:20]([C:21]([NH:43][S:40]([CH2:38][CH3:39])(=[O:42])=[O:41])=[O:23])=[C:16]4[N:15]=[CH:14][C:13]=3[C:24]([N:26]3[CH2:27][CH2:28][CH:29]([C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[CH2:30][CH2:31]3)=[O:25])=[CH:8][CH:9]=2)[CH:4]=[CH:3]1
Reactant: Cn1ccc2cc(Nc3c(C(=O)N4CCC(c5ccccc5)CC4)cnc4c(C(=O)O)cnn34)ccc21
Reactant: CCS(N)(=O)=O
Product: CCS(=O)(=O)NC(=O)c1cnn2c(Nc3ccc4c(ccn4C)c3)c(C(=O)N3CCC(c4ccccc4)CC3)cnc12
Yield: 47.8 %

Procedure:
In the same manner as in Example 1, step 6 and using 7-(1-methyl-5-indolylamino)-6-(4-phenylpiperidine-1-carbonyl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.05 g, 0.10 mmol) obtained in step 2 and ethanesulfonamide (0.065 g, 0.6 mmol), the title compound (0.028 g, 47%) was obtained.
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11]1[CH:12]=[C:13]2[C:17](=[CH:18][CH:19]=1)[NH:16][C:15]([C:20]([O:22][CH3:23])=[O:21])=[CH:14]2)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[Cl:24][C:25]1[CH:26]=[C:27]([S:32](Cl)(=[O:34])=[O:33])[CH:28]=[CH:29][C:30]=1[Cl:31]>CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]([S:32]([N:16]2[C:17]3[C:13](=[CH:12][C:11]([O:10][CH2:3][C:4]4[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=4)=[CH:19][CH:18]=3)[CH:14]=[C:15]2[C:20]([O:22][CH3:23])=[O:21])(=[O:33])=[O:34])[CH:28]=[CH:29][C:30]=1[Cl:31]
Reactant: COC(=O)c1cc2cc(OCc3ccccc3)ccc2[nH]1
Reactant: O=S(=O)(Cl)c1ccc(Cl)c(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccc(Cl)c(Cl)c1
Reaction time: 1 h
Yield: 55.7 %

Procedure:
Sodium Hydride (60% dispersion, 444 mg) was added to a stirred solution of methyl 5-benzyloxyindole-2-carboxylate (2.08 g) in DMF (50 ml) at room temperature. After 1 hour, 3,4-dichlorobenzenesulphonyl chloride (2.72 g) was added. Stirring was continued for 2 hours after which the reaction mixture was partitioned between water and ethyl acetate. Combined organic extracts were dried and concentrated in vacuo and the residue purified by column chromatography using isohexane-20% ethyl acetate as eluent to give the desired product as a white solid (2.02 g, 56%). NMR: δ3.85 (s, 3H), 5.1 (s, 2H), 7.2 (m, 1H), 7.4 (m, 7H), 7.9 (s, 2H), 8.0 (d, 1H), 8.2 (s, 1H); m/z 489.8 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][C:6]1[C:11]([NH:12][CH2:13][CH2:14][O:15][CH3:16])=[N:10][C:9]([C:17]#[N:18])=[C:8]([C:19]#[N:20])[N:7]=1.Cl[C:22]1[C:27](Cl)=[N:26][C:25]([C:29]#[N:30])=[C:24]([C:31]#[N:32])[N:23]=1.COCCOCCOC>C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>[CH3:1][O:2][CH2:3][CH2:4][N:5]1[C:6]2[N:7]=[C:8]([C:19]#[N:20])[C:9]([C:17]#[N:18])=[N:10][C:11]=2[N:12]([CH2:13][CH2:14][O:15][CH3:16])[C:22]2[N:23]=[C:24]([C:31]#[N:32])[C:25]([C:29]#[N:30])=[N:26][C:27]1=2
Reactant: COCCNc1nc(C#N)c(C#N)nc1NCCOC
Reactant: N#Cc1nc(Cl)c(Cl)nc1C#N
Solvent: COCCOCCOC
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: COCCN1c2nc(C#N)c(C#N)nc2N(CCOC)c2nc(C#N)c(C#N)nc21

Procedure:
FIG. 17 shows the reaction pathway. In a 100 mL round-bottom flask having a magnetic stir-bar and with 14/20 glass joint attached to an air-condenser was add 0.48 g [0.002 mole] of 2,3-bis(2-methoxyethylamino)-5,6-dicyanopyrazine 1101, 2,3-dichloro-5,6-dicyanopyrazine 301 and 5 mL of diglyme 901 [diethyleneglycoldimethylether]. The reaction was stirred for about an hour until all the solids had dissolved. To this solution was added 0.6 g of diisopropylethylamine 902 drop-wise with stirring. The reaction was then brought to reflux using a sand-bath at ˜180°. All under a nitrogen sweep. The solution acquired a dark gray orange color as heating took place. Reaction was monitored by TLC or column chromatography [silica plates] using ethyl acetate; the bright blue fluorescent starting material spot at Rf: 0.45 slowly faded and was converted to a bright yellow spot at Rf: 0.98 identical to the material formed from dimerization. After 5 hours the starting material spot remained though the yellow spot corresponding to the expected product at solvent front in TLC or column chromatography was present. Solution cooled to rt and poured, with good stirring into 40 mL of water/ice mixture having ˜0.5 mL of 10% HCl. Dark mixture was allowed to stand ˜24 hrs and filtered by suction and washed with water. Material was dried in vac. drying oven at 70°. There was obtained 0.6 g of yellow brown powder having both starting material and desired tetracyanodipyrazinepyrazine. Exact mass 402.2 [calc 402.13].
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH:12]2[CH2:14][CH2:13]2)[CH:7]=1)=[O:5])[CH3:2].[N+]([O-])([O-])=O.[Ce+4].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[I:37]I>C(#N)C.O.C(OCC)(=O)C>[CH2:1]([O:3][C:4]([C:6]1[N:10]([CH3:11])[N:9]=[C:8]([CH:12]2[CH2:13][CH2:14]2)[C:7]=1[I:37])=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cc(C2CC2)nn1C
Reactant: II
Agent: O=[N+]([O-])[O-]
Agent: [Ce+4]
Agent: [NH4+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: CCOC(=O)c1c(I)c(C2CC2)nn1C
Temperature: 25 °C
Yield: 103.3 %

Procedure:
A solution of 500 mg (2.57 mmol) of ethyl-3-cyclopropyl-1-methyl-1H-pyrazole-5-carboxylate (prepared from ethyl-3-cyclopropyl-1H-pyrazole-5-carboxylate in accordance with Bioorg. Med. Chem. Lett. 1996, 6, 1819-1824) in 5 ml of acetonitrile is admixed with 706 mg (1.28 mmol) of ammonium cerium(IV) nitrate and 392 mg (1.53 mmol) of iodine and heated under reflux for three hours and afterstirred overnight at room temperature. The reaction mixture is diluted with water and ethyl acetate, and the organic phase is washed with saturated sodium thiosulphate solution, dried over sodium sulphate, filtered and concentrated by evaporation in vacuo. Chromatographic purification gives 506 mg of ethyl-3-cyclopropyl-4-iodo-1-methyl-1H-pyrazole-5-carboxylate (66%).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.[Cl-].C[Al+]C.[CH3:13][N:14]([CH3:39])[C:15]([C:17]1[N:18]=[CH:19][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](OCC)=[O:35])[CH:25]=2)=[N:21][CH:22]=1)=[O:16]>COC>[CH3:39][N:14]([CH3:13])[C:15]([C:17]1[CH:22]=[N:21][C:20]([O:23][C:24]2[C:29]3[CH:30]=[C:31]([CH3:33])[O:32][C:28]=3[CH:27]=[C:26]([C:34](=[O:35])[NH:8][C:5]3[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=3)[CH:25]=2)=[CH:19][N:18]=1)=[O:16]
Reactant: Cc1cnc(N)cn1
Reactant: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)C)cn2)c2cc(C)oc2c1
Agent: COC
Agent: C[Al+]C
Agent: [Cl-]
Product: Cc1cnc(NC(=O)c2cc(Oc3cnc(C(=O)N(C)C)cn3)c3cc(C)oc3c2)cn1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
5-methyl-2-aminopyrazine (6.8 g, 63 mmol) was taken up in 70 mL of dimethylether and cooled to 0° C. Dimethyaluminium chloride (131 mmol, 1 M in hexane) was added dropwise. The resulting mixture was warmed up to ambient temperature and stirred for 30 min. Ethyl 4-(5-(dimethylcarbamoyl)pyrazin-2-yloxy)-2-methylbenzofuran-6-carboxylate (I-1d: 10.1 g, 27.3 mmol) in dimethylether (70 mL) was then added to the activated amine solution via canula. The combined solution was heated to reflux overnight. The reaction was cooled on ice and slowly quenched by the dropwise addition of aqueous Rochelle's salt (concentrated, 100 mL). The mixture was stirred for 20 minutes. The mixture was separated. Organic layer was washed with aqueous Rochelle's salt (30 ml), 1N HCl (30 ml), brine (30 ml), dried over sodium sulfate, and concentrated in vacuo. The crude product was purified by column chromatography (silica gel, gradient of ethyl acetate from 50-100% in heptane) to give desired N,N-dimethyl-5-(2-methyl-6-((5-methylpyrazin-2-yl)carbamoyl)benzofuran-4-yloxy)pyrazine-2-carboxamide (1: 8.5 gram 72%).
Reaction SMILES: [C:1]([C:3]1[CH:30]=[CH:29][C:6]([O:7][C:8]2[N:16]=[C:15]([O:17][C:18]3[CH:23]=[CH:22][C:21]([O:24][C:25]([F:28])([F:27])[F:26])=[CH:20][CH:19]=3)[CH:14]=[CH:13][C:9]=2[C:10](O)=[O:11])=[CH:5][CH:4]=1)#[N:2].[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1)([CH3:34])([CH3:33])[CH3:32]>>[C:31]([O:35][C:36](=[O:46])[NH:37][CH2:38][CH2:39][CH:40]1[CH2:41][CH2:42][N:43]([C:10]([C:9]2[C:8]([O:7][C:6]3[CH:29]=[CH:30][C:3]([C:1]#[N:2])=[CH:4][CH:5]=3)=[N:16][C:15]([O:17][C:18]3[CH:19]=[CH:20][C:21]([O:24][C:25]([F:27])([F:26])[F:28])=[CH:22][CH:23]=3)=[CH:14][CH:13]=2)=[O:11])[CH2:44][CH2:45]1)([CH3:34])([CH3:32])[CH3:33]
Reactant: N#Cc1ccc(Oc2nc(Oc3ccc(OC(F)(F)F)cc3)ccc2C(=O)O)cc1
Reactant: CC(C)(C)OC(=O)NCCC1CCNCC1
Product: CC(C)(C)OC(=O)NCCC1CCN(C(=O)c2ccc(Oc3ccc(OC(F)(F)F)cc3)nc2Oc2ccc(C#N)cc2)CC1
Yield: 69.8 %

Procedure:
2-(4-cyano phenoxy)-6-(4-trifluoromethoxy phenoxy)nicotinic acid (0.2 g, 0.48 mmol) and (2-Piperidin-4-yl-ethyl)-carbamic acid tert-butyl ester (0.11 g, 0.48 mmol) were coupled using the procedure of Example 5(c) to afford 0.21 g of the required product. Percentage purity (LCMS): 68.11%.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@H:4](/[CH:5]=[C:6](\[Br:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[C:17]([C@@H:19](O)[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:21]=1)#[N:18]>>[CH3:16][C:2]1([CH3:1])[C@H:4](/[CH:5]=[C:6](\[Br:12])/[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][C@H:19]([C:17]#[N:18])[C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([O:26][C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[CH:21]=1)=[O:14]
Reactant: N#C[C@@H](O)c1cccc(Oc2ccccc2)c1
Reactant: CCOC(=O)/C(Br)=C/[C@@H]1[C@@H](C(=O)O)C1(C)C
Product: CCOC(=O)/C(Br)=C/[C@@H]1[C@@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)C1(C)C

Procedure:
Using the procedure of Step B of Example 43, (1R,trans,Z) 2,2-dimethyl-3-(2-bromo-3-oxo-3-ethoxy-1-propenyl)-cyclopropane carboxylic acid and (S)α-cyano-3-phenoxy-benzyl alcohol were reacted to obtain (S)α-cyano-3-phenoxy-benzyl (1R,trans,Z) 2,2-dimethyl-3-(2-bromo-3-oxo-3-ethoxy-1-propenyl)-cyclopropanecarboxylate melting at 97° C. and having a specific rotation of [α]D20 =+5°±1° (c=1% in chloroform).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:15][CH2:14][C:11]([CH2:16][C:17]([OH:19])=[O:18])([CH2:12][CH2:13]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1.[CH3:20]C1C=CC(S(O)(=O)=O)=CC=1>CO>[OH:1][C:2]1[CH:3]=[C:4]([C:8]23[CH2:13][CH2:12][C:11]([CH2:16][C:17]([O:19][CH3:20])=[O:18])([CH2:14][CH2:15]2)[CH2:10][O:9]3)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: O=C(O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Solvent: CO
Product: COC(=O)CC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 60 °C
Reaction time: 18 h
Yield: 925.1 %

Procedure:
A mixture of 2-(1-(3-hydroxyphenyl)-2-oxabicyclo[2.2.2]octan-4-yl)acetic acid (910 mg, 3.47 mmol) and p-TsOH (66 mg, 0.347 mmol) in MeOH (10 mL) was stirred at 60° C. for 18 h. The reaction was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 50% EtOAc:hexanes) to afford the title compound (887 mg, 93% yield) as a clear oil. LCMS, [M+H]+=277.3. 1H NMR (500 MHz, CDCl3) δ 7.13 (t, J=7.9 Hz, 1H), 6.93-6.84 (m, 2H), 6.69-6.63 (m, 1H), 6.13 (s, 1H), 3.94 (s, 2H), 3.67 (s, 3H), 2.18 (s, 2H), 2.06-1.94 (m, 4H), 1.86-1.72 (m, 4H).
Reaction SMILES: [ClH:1].Cl.[C:3]1([NH2:11])[C:4]([NH2:10])=[CH:5][C:6]([NH2:9])=[CH:7][CH:8]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([C:21]([C:23]2[CH:28]=[CH:27][C:26]([OH:29])=[CH:25][CH:24]=2)=O)=O)=[CH:15][CH:14]=1>O1CCOCC1.O>[ClH:1].[ClH:1].[OH:12][C:13]1[CH:14]=[CH:15][C:16]([C:19]2[C:21]([C:23]3[CH:24]=[CH:25][C:26]([OH:29])=[CH:27][CH:28]=3)=[N:10][C:4]3[C:3](=[CH:8][CH:7]=[C:6]([NH2:9])[CH:5]=3)[N:11]=2)=[CH:17][CH:18]=1
Reactant: Nc1ccc(N)c(N)c1
Reactant: O=C(C(=O)c1ccc(O)cc1)c1ccc(O)cc1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: Nc1ccc2nc(-c3ccc(O)cc3)c(-c3ccc(O)cc3)nc2c1
Yield: 167.3 %

Procedure:
98.04 mg (0.5 mmol) of 1,2,4-benzenetriamine dihydrochloride and 121.2 mg (0.5 mmol) of 4,4′-dihydroxybenzil were dissolved in 2 ml of 1:1 mixture of dioxane-water. The reaction was refluxed for 3 hours. Then solvent was removed in vacuo. The residue was dissolved in 2 ml of methanol and this solution was added dropwise to 40 ml of diethyl ether. The formed dark-red precipitate was collected, washed with ether and dried in vacuo to give 168.3 mg (83.7% yield) of the product. 98.7% purity by LC/MS (230 DAD). Mass-spec [ES+]=330.8. 1H NMR (500 MHz, MeOH-d4) 6.76–6.77 (2H, d), 6.87–6.89 (2H, d), 7.05–7.06 (1H, d), 7.29–7.31 (2H, d), 7.38–7.40 (2H, d), 7.50–7.52 (1H, m), 7.99–8.01 (1H, d).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[N:3]=1.[Cl:22][C:23]1[N:28]=[C:27](Cl)[CH:26]=[CH:25][N:24]=1.C(N(CC)CC)C>C(O)C>[NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH3:15])=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[C:4]([N:16]2[CH2:21][CH2:20][N:19]([C:25]3[CH:26]=[CH:27][N:28]=[C:23]([Cl:22])[N:24]=3)[CH2:18][CH2:17]2)[N:3]=1
Reactant: COc1cc2nc(N3CCNCC3)nc(N)c2cc1OC
Reactant: Clc1ccnc(Cl)n1
Solvent: CCN(CC)CC
Solvent: CCO
Product: COc1cc2nc(N3CCN(c4ccnc(Cl)n4)CC3)nc(N)c2cc1OC

Procedure:
4-Amino-6,7-dimethoxy-2-piperazino-quinazoline (30.0 g, 0.104 mole), 2,4-dichloropyrimidine (17.3 g, 0.117 mole) and triethylamine (20.5 g, 0.203 mole) in ethanol (1200 ml) were heated at reflux for three hours. The solid which separated on cooling was filtered, slurried in hot isopropanol (500 ml), filtered and washed with hot methanol. The product was partitioned between 5% by volume methanol in methylene chloride and 10% (w/w) aqueous sodium carbonate solution, the organic layer separated, washed with water, dried (Na2SO4) and evaporated in vacuo. The resulting solid was slurried in hot isopropanol, filtered and washed with hot isopropanol to afford 20 g. of the title compound, m.p. 266° C.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:23][CH2:22][O:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[CH2:34][C:33](=[O:35])[NH:32][N:31]=2)[CH:25]=1.[H-].[Na+]>CN(C=O)C>[CH3:13][O:12][C:9]1[CH:10]=[C:11]2[C:6](=[CH:7][C:8]=1[O:14][CH2:15][CH2:16][CH2:17][N:18]1[CH2:23][CH2:22][O:21][CH2:20][CH2:19]1)[N:5]=[CH:4][N:3]=[C:2]2[O:35][C:33]1[CH:34]=[C:30]([C:26]2[CH:25]=[N:24][CH:29]=[CH:28][CH:27]=2)[NH:31][N:32]=1
Reactant: O=C1CC(c2cccnc2)=NN1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3cc(-c4cccnc4)[nH]n3)ncnc2cc1OCCCN1CCOCC1
Yield: 59.5 %

Procedure:
Using an analogous procedure to that described for Example 9, 4-chloro-6-methoxy-7-(3-morpholinopropoxy)quinazoline (134 mg, 0.4 mmol), (prepared as described for the starting material in Example 2), was reacted with 3-(3-pyridyl)-4,5-dihydro-1H-pyrazol-5-one (161 mg, 1 mmol) in the presence of sodium hydride (40 mg, 1 mmol, prewashed with THF) in DMF (3 ml) to give 6-methoxy-7-(3-morpholinopropoxy)-4-(5-(3-pyridyl)pyrazol-3-yloxy)quinazoline (110 mg, 59%).
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]1[C:10]([NH:11][C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1.I[CH2:31][CH2:32][CH3:33].O>CN(C=O)C>[CH3:3][O:4][C:5]1[C:10]([N:11]([CH2:31][CH2:32][CH3:33])[C:12](=[O:15])[CH2:13][CH3:14])=[CH:9][C:8]([CH3:16])=[C:7]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([F:27])([F:26])[F:25])=[CH:19][C:18]=2[O:28][CH3:29])[N:6]=1
Reactant: CCCI
Reactant: CCC(=O)Nc1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCN(C(=O)CC)c1cc(C)c(-c2ccc(OC(F)(F)F)cc2OC)nc1OC
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
60% NaH (23 mg, 0.58 mmol) is added to a solution of N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-propionamide (0.15 g, 0.39 mmol) in DMF (1 ml) at room temperature. After stirring at room temperature for 20 minutes, iodo propane (0.058 ml, 0.58 mmol) is added. The mixture is stirred at room temperature for 3 days. 20 ml of water is added and the mixture is extracted with EtOAc. The combined extracts are washed with brine and dried over Na2SO4. The solvent is removed under reduced pressure and the residue is purified by flash column chromatography to give N-[2-methoxy-6-(2-methoxy-4-trifluoromethoxy-phenyl)-5-methyl-pyridin-3-yl]-N-propyl-propionamide. Rf (hexane/EtOAc=2:1)=0.42.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11](I)=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.I[C:16]([F:20])=[C:17]([F:19])[F:18]>C1COCC1.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.[Pd].[Zn]>[F:20][C:16]([C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:16]([F:20])=[C:17]([F:19])[F:18])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1)=[C:17]([F:19])[F:18]
Reactant: Ic1ccc(-c2ccc(I)cc2)cc1
Reactant: FC(F)=C(F)I
Agent: [Pd]
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: FC(F)=C(F)c1ccc(-c2ccc(C(F)=C(F)F)cc2)cc1
Reaction time: 24 h

Procedure:
After 24 hours, a GC/MS of the mixture allows identification of all the reaction components. After 72 hours, the reaction seems to stop proceeding while excess diiodobiphenyl remains; another batch of iodotrifluoroethylene (25.0 g, 0.12 mole) is reacted with zinc in THF and added to the reaction mixture along with 1.0 g of palladium tetrakis(triphenylphosphine) catalyst. The reaction is allowed to stir an additional 12 hours, then is removed and evaporated to dryness under high vacuum on a rotary evaporator. REsidue from evaporation is added to a 3 fold volumetric excess of water. A heavy precipitate is formed which is filtered and air dried on a vacuum funnel. The precipitate is dissolved in THF and filtered. Resulting filtrate is coated on silica gel by adding the silica gel to the THF solution and evaporating to dryness. This silica gel is then eluted on a short silica gel column using hexane as eluent to remove the colored material from the product. A fine white crystalline material remains after evaporation of the hexane. This crystalline material is then chromatographed again carefully on an alumina column using hexane as an eluent. The first band to elute from the column is the desired monomer product CF2 =CF--Ph--Ph--CF=CF2. A total of 44.2 g of product is recovered (58.7% yield).