Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: B(F)(F)F.[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[CH:9][C:7]=1[OH:8].[C:15](O)(=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C([O-])(=O)C.[Na+]>C1C=CC=CC=1.C(Cl)Cl>[CH3:5][C:6]1[C:12]([CH3:13])=[C:11]([OH:14])[CH:10]=[C:9]([C:15](=[O:29])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]=1[OH:8]
Reactant: CCCCCCCCCCCCCC(=O)O
Reactant: Cc1c(O)ccc(O)c1C
Agent: CC(=O)[O-]
Agent: FB(F)F
Agent: [Na+]
Solvent: c1ccccc1
Solvent: ClCCl
Product: CCCCCCCCCCCCCC(=O)c1cc(O)c(C)c(C)c1O
Temperature: 50 °C
Reaction time: 8 h

Procedure:
Boron trifluoride was introduced with vigorous refluxing (bath temperature 50° C.) into a mixture of 138 g (1 mole) of 2,3-dimethylhydroquinone, 370 g (1.62 moles) of myristic acid and 700 ml of methylene chloride until saturation. After standing overnight the reaction mixture was decomposed by pouring into 3 l of a 10% by weight sodium acetate solution with stirring. The methylene chloride was evaporated by means of steam. The residual oily layer solidified after cooling to a melt cake that was isolated by decantation. It was melted up and added with stirring to 2 l of high-boiling benzine. The precipitate was filtered with suction and washed with benzine (boiling range: 50°-75° C.). After being dried the precipitate was stirred with acetonitrile and filtered with suction.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]2)=[CH:25][CH:24]=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[F:22][C:23]1[CH:28]=[CH:27][C:26]([CH:29]2[CH2:30][CH2:31][N:32]([C:2]3[C:7]([C:8]#[N:9])=[C:6]([NH:10][CH2:11][CH2:12][OH:13])[N:5]=[C:4]([NH:14][CH2:15][C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:3]=3)[CH2:33][CH2:34]2)=[CH:25][CH:24]=1
Reactant: N#Cc1c(Cl)nc(NCc2cccnc2)nc1NCCO
Reactant: Fc1ccc(C2CCNCC2)cc1
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: N#Cc1c(NCCO)nc(NCc2cccnc2)nc1N1CCC(c2ccc(F)cc2)CC1

Procedure:
In analogy to the procedure described in example 47b, the crude 4-chloro-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile (example 49a) was treated with the 4-(4-fluorophenyl)-piperidine in dioxane in the presence of N-ethyl-diisopropylamine at 100° C. to yield 4-[4-(4-fluoro-phenyl)-piperidin-1-yl]-6-(2-hydroxy-ethylamino)-2-[(pyridin-3-ylmethyl)-amino]-pyrimidine-5-carbonitrile as an amorphous, light brown; MS: [M+H]+=448.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-])=O.[NH2:14][CH2:15][CH2:16][OH:17]>C1COCC1>[NH2:1][C:4]1[CH:5]=[C:6]([S:10]([NH:14][CH2:15][CH2:16][OH:17])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Reactant: NCCO
Solvent: C1CCOC1
Product: Nc1cccc(S(=O)(=O)NCCO)c1
Reaction time: 8 h
Yield: 50.8 %

Procedure:
3-Nitrobenzenesulfonyl chloride (2.22 g) dissolved in 20 mL of THF was added to a solution of 2-aminoethanol (2.0 g) and tryethylamine (2.0 g) in 20 mL of THF. The reaction mixture was kept at ambient temperature overnight. The solvent was removed and the residue was dissolved in water (20 mL) and then extracted with EtOAc (2×50 mL). The solvent of the organic layer was removed and the residue was dissolved in 50 mL of EtOH and a catalytic amount of Raney-Nickel was added, followed by the addition of hydrazine hydrate (2 mL). The reaction mixture was kept at ambient temperature under argon overnight, filtered through a celite cake. The solvent of the filtrate was removed yielding 1.1 g of 3-amino-N-(2-hydroxyethyl)benzenesulfonamide which was used in the next step without further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]1[C:4]([NH2:9])=[N:5][CH:6]=[CH:7][CH:8]=1.Br[CH:11]([C:14]1[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[CH:16][CH:15]=1)[CH:12]=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[OH:1][CH2:2][C:3]1[C:4]2[N:5]([CH:12]=[C:11]([C:14]3[CH:15]=[CH:16][C:17]([N+:20]([O-:22])=[O:21])=[CH:18][CH:19]=3)[N:9]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: O=CC(Br)c1ccc([N+](=O)[O-])cc1
Reactant: Nc1ncccc1CO
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: O=[N+]([O-])c1ccc(-c2cn3cccc(CO)c3n2)cc1
Yield: 70.3 %

Procedure:
A mixture of 16.0 g (80 mmole) of 1-bromo-4-nitrobenzene, 11.2 ml (ca. 120 mmole) of ethyl vinyl ether, 179.2 mg of lead(II) acetate, 484 mg of tri-o-tolylphosphine, and 22 ml (ca. 160 mmole) of triethylamine was placed in a bomb, purged with nitrogen, and heated at 100° for eight hours. The reaction mixture was partitioned between diethyl ether and water and clarified by filtration. The organic layer was washed with water, dried over magnesium sulfate, filtered, and concentrated in vacuo. Chromatography of the residue on silica gel (using toluene-hexane as eluant) yielded three principle components (in order of elution): 2.1 g of 4-(1-ethoxyvinyl)nitrobenzene, 3.0 g of the cis isomer of 4-(2-ethoxyviny)nitrobenzene, and 7.2 g of the trans isomer of 4-(2-ethoxyvinyl)nitrobenzene. A solution of 3.0 g (15 mmole) of 4-(2-ethoxyvinyl)nitrobenzene (as a mixture of cis and trans isomers) in 30 ml of diethyl ether was cooled to - 15°. Bromine (2.48 ml, ca. 15 mmole) was added dropwise as the temperature was maintained at or below -10°. The reaction mixture was poured into 50 ml of water containing 5 g of sodium bicarbonate. After two hours of stirring, the mixture was allowed to separate into layers. The organic layer was washed with water, dried over sodium sulfate, filtered, and concentrated in vacuo to yield 3.9 g of 2-bromo-2-(4-nitrophenyl)acetaldehyde as an oil. A mixture of 1.98 g (15 mmole) of 3-hydroxymethyl-2-pyridinamine and 3.9 g (15 mmole) of 2-bromo-2-(4-nitrophenyl)acetaldehyde was warmed to initiate an exothermic reactiion. After cooling, the mixture was shaken with aqueous potassium carbonate and dichloromethane. The solid was collected, washed with water and dichloromethane, and air dried to yield 2.84 g of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine, as confirmed by the nmr and infrared spectra. The title compound (100 mg) was prepared by the method described in Example 6 using 1.4 g (5.2 mmole) of 8-hydroxymethyl-2-(4-nitrophenyl)imidazo[1,2-a]pyridine instead of 8-hydroxymethylimidazo[1,2-a]pyridine. Structure assignment was supported by the nmr and infrared spectra and by elemental analysis.
Reaction SMILES: [NH2:1][C:2]1[O:3][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:5](=[O:7])[N:6]=1.[CH:14]1(N)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1>>[CH:14]1([NH:1][C:2]2[O:3][CH:4]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:5](=[O:7])[N:6]=2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: NC1CCCCCC1
Reactant: NC1=NC(=O)C(c2ccccc2)O1
Product: O=C1N=C(NC2CCCCCC2)OC1c1ccccc1

Procedure:
Synthesis was performed from 2-amino-5-phenyl-1,3-oxazol-4(5H)-one and cycloheptylamine according to Method G+H.
Reaction SMILES: [F:1][C:2]([F:15])([F:14])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][NH:8][CH:9]([CH3:11])[CH3:10])=[CH:5][CH:4]=1.[Cl:16][CH:17]([Cl:21])[C:18](Cl)=[O:19]>>[F:1][C:2]([F:14])([F:15])[C:3]1[CH:13]=[CH:12][C:6]([CH2:7][N:8]([CH:9]([CH3:11])[CH3:10])[C:18](=[O:19])[CH:17]([Cl:21])[Cl:16])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(Cl)Cl
Reactant: CC(C)NCc1ccc(C(F)(F)F)cc1
Product: CC(C)N(Cc1ccc(C(F)(F)F)cc1)C(=O)C(Cl)Cl
Reaction time: 0.5 h
Yield: 66.3 %

Procedure:
A solution of 21.7 g of N-(4-trifluoromethylbenzyl)-N-isopropylamine is added while stirring in a 4 neck-flask with 20 ml of 20% sodium-hydroxide solution. The reaction-mixture is then cooled while stirring in an alcohol/CO2 -bath to a temperature of from -10° to -5° whereupon 14.7 g of dichloroacetyl chloride is added slowly, dropwise thereto. After about 1/2 hour, when everything is added, the cooling-bath is removed and the reaction mixture is stirred for 2 hours until it reaches room temperature. It is then poured into ice/water and the organic material is extracted with toluene. The toluene-phases are collected, washed first with diluted sodium hydroxide, then with diluted hydrochloric acid and eventually twice with water, dried over sodium sulfate and concentrated in a rotatory evaporator. A clear oil is thus obtained, which becomes solid after a while. The solid mass is then triturated with hexane and filtered to yield 21.7 g of cristalline N-(4-trifluoromethylbenzyl)-N-isopropyl-dichloroacetamide, melting at 92° to 93°.
Reaction SMILES: [S].[SH:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1.[F:8][C:9]([F:13])=[C:10]([F:12])[F:11]>>[F:8][C:9]([F:13])([S:2][C:3]1[NH:4][CH:5]=[CH:6][N:7]=1)[CH:10]([F:12])[F:11]
Reactant: FC(F)=C(F)F
Reactant: Sc1ncc[nH]1
Agent: [S]
Product: FC(F)C(F)(F)Sc1ncc[nH]1

Procedure:
The appropriate R1 moiety can then be introduced onto the sulfur by a suitable alkylating agent such as tetrafluoroethylene or difluorocarbene. For example, the 2-mercaptoimidazole derivative of Reaction (2) can be reacted with tetrafluoroethylene to form the 2-(1,1,2,2-tetrafluoroethylthio)imidazole derivative. ##STR10## The reaction is carried out under heat and pressure with a slight excess of the fluorocarbon reactant. Typically, the reaction is carried out in a closed reaction vessel at a temperature of 50° C. at an initial pressure of about 50 p.s.i. which falls to about 13 p.s.i. as the reaction proceeds. Similar addition reactions of tetrafluoroethylene and other fluorinated olefins are described by England, D. C. et al., J. Am. Chem. Soc., 82, 5116 (1960) and Rapp, K. E., et. al., J. Am. Chem. Soc., 72, 3642 (1950). Within the context of the invention, tetrafluoroethylene and other fluorinated olefins used are considered alkylating agents.
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][NH:34][CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:37](N(CC)CC)C.IC>CN(C=O)C>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH:30]5[CH2:33][N:34]([CH3:37])[CH2:35][CH2:36][N:29]5[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: Nc1ncnn2c(C3CN4CCNCC4CO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Solvent: CI
Solvent: CN(C)C=O
Product: CN1CCN2CC(c3cc(-c4ccc5cn(Cc6ccccc6)nc5c4)c4c(N)ncnn34)OCC2C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 33.7 %

Procedure:
To a stirred solution of 5-(2-benzyl-2H-indazol-6-yl)-7-(octahydropyrazino[2,1-c][1,4]oxazin-3-yl)pyrrolo[2,1-f][1,2,4]triazin-4-amine (85 mg, 0.18 mmol) and triethylamine (49 μL, 0.35 mmol) in DMF (1 mL) at −78° C., iodomethane (177 μL, 0.17 mmol, 1.0M in DMF) was added. The reaction was allowed to stir for 1 h while warming to rt. The mixture was partitioned between ethyl acetate (30 mL) and pH 14 saturated aqueous NaCl (10 mL). The layers were separated and the organic phase was washed, dried (Na2SO4), and concentrated to dryness. The residue was triturated with Et2O to obtain 30 mg (34%) of the desired product. 1H-NMR (DMSO-d6) 8.53 (s, 1H), 7.90 (s, 1H), 7.78 (d, 1H), 7.57 (s, 1H), 7.35-7.28 (m, 5H), 7.11 (d, 1H), 6.70 (s, 1H), 5.64 (s, 2H), 5.11 (dd, 1 H), 3.75 (dd, 1 H), 3.37-3.26 (m, 1H), 2.98 (dd, 1H), 2.70-2.65 (m, 2H), 2.56-2.50 (m, 1H), 2.47-2.30 (m, 1H), 2.26-2.18 (m, 2H), 2.14 (s, 3H), 2.11-2.01 (m, 1H), 1.61 (t, J=10.5 Hz, 1H); LC-MS [M+H]+=495, RT=2.10 min.
Reaction SMILES: C1(C([O:14][C:15](=[O:36])[C:16]([OH:35])=[CH:17][C:18]([C:20]2[C:28]3[C:23](=[CH:24][CH:25]=[C:26]([Cl:29])[CH:27]=3)[N:22]([C:30](=[O:34])[N:31]([CH3:33])[CH3:32])[CH:21]=2)=[O:19])C2C=CC=CC=2)C=CC=CC=1.FC(F)(F)C(O)=O>ClCCl>[CH3:33][N:31]([CH3:32])[C:30]([N:22]1[C:23]2[C:28](=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=2)[C:20]([C:18](=[O:19])[CH:17]=[C:16]([OH:35])[C:15]([OH:36])=[O:14])=[CH:21]1)=[O:34]
Reactant: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)OC(c2ccccc2)c2ccccc2)c2cc(Cl)ccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CN(C)C(=O)n1cc(C(=O)C=C(O)C(=O)O)c2cc(Cl)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
To a solution of 356 mg (0.7 mmol) of the ester derivative obtained in above (1) in dichloromethane (3.6 ml) was added under ice-cooling, 0.5 ml of trifluoroacetic acid. The mixture was stirred for 30 minutes under ice-cooling. The reaction solution was concentrated under reduced pressure. The residues was dissolved in ethyl acetate. The ethyl acetate was washed successively with water and brine, and then dried. The obtained residue was crystallized from ether and recrystallized from 95% ethanol to give 0.16 g of the titled compound. Yield: 67%.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[CH2:10][C@H:9]1[CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][OH:24])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:41]1([C:47](Cl)([C:54]2[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=2)[C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([O:13][Si:14]([C:17]([CH3:20])([CH3:18])[CH3:19])([CH3:15])[CH3:16])[CH2:10][C@H:9]1[CH:21]([CH2:25][NH:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:22][CH2:23][O:24][C:47]([C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1)([C:54]1[CH:55]=[CH:56][CH:57]=[CH:58][CH:59]=1)[C:48]1[CH:49]=[CH:50][CH:51]=[CH:52][CH:53]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCC(CCO)[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)NCC(CCOC(c1ccccc1)(c1ccccc1)c1ccccc1)[C@@H]1C[C@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (2S,4R)-N-tert-butoxycarbonyl-2-(1-tert-butoxycarbonylaminomethyl-3-hydroxypropyl)-4-tert-butyldimethylsiloxypyrrolidine diastereomer B prepared in REFERENCE EXAMPLE 24-1 (1.01 g, 2 mmol) in methylene chloride (20 ml) were added triethylamine (0.307 ml, 2.2 mmol) and triphenylmethyl chloride (584 mg, 2.1 mmol). The mixture was stirred for 3 h at room temperature under a nitrogen atmosphere. The reaction solution was washed successively with water and saturated aqueous sodium chloride, and dried over anhydrous sodium sulfate. The solvent was removed in vacuo. The residue was subjected to silica gel column chromatography (hexane-ethyl acetate) to give (2S,4S)-N-tert-butoxycarbonyl-2-(1-tert-butoxycarbonylaminomethyl-3-triphenylmethoxypropyl)-4-tert-butyldimethylsiloxypyrrolidine diastereomer B (1.48 g, yield: quantitative).
Reaction SMILES: [F:1][C:2]1[N:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:17][CH2:18][N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]1=[O:29].O>CN(C=O)C>[F:1][C:2]1[N:7]=[CH:6][C:5]([O:8][CH2:17][CH2:18][N:19]2[C:20](=[O:29])[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:27]2=[O:28])=[C:4]([I:9])[CH:3]=1
Reactant: Oc1cnc(F)cc1I
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCOc1cnc(F)cc1I
Temperature: 25 °C
Reaction time: 8 h
Yield: 58.3 %

Procedure:
Cool a suspension of 6-fluoro-4-iodo-pyridin-3-ol (1.5 g, 6.28 mmol) and K2CO3 (4.38 g, 31.4 mmol) in DMF (10 mL) to 0° C. in an ice bath under nitrogen. Add 2-(2-bromo-ethyl)-isoindole-1,3-dione (3.19 g, 12.55 mmol). Stir the mixture at RT overnight. Add water. Extract with ethyl acetate. Wash the solution with aqueous saturated sodium chloride. Dry over sodium sulfate. Concentrate the solution in vacuo. Purify by column chromatography (hexane to 30% ethyl acetate in hexane) to afford the title compound as a yellow oil (1.51 g, 58%). MS (ES) m/z 413 [M+1]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:22][CH2:21][N:20](C(OCC)=O)[CH2:19][CH2:18]1.[OH-].[K+]>O.CC(O)C>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][N:7]1[C:11]2=[N:12][CH:13]=[CH:14][CH:15]=[C:10]2[N:9]=[C:8]1[NH:16][CH:17]1[CH2:18][CH2:19][NH:20][CH2:21][CH2:22]1
Reactant: CCOC(=O)N1CCC(Nc2nc3cccnc3n2Cc2ccco2)CC1
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)O
Solvent: O
Product: c1coc(Cn2c(NC3CCNCC3)nc3cccnc32)c1
Yield: 85 %

Procedure:
A mixture of 50 parts of ethyl 4-[[3-(2-furanylmethyl)-3H-imidazo[4,5-b]pyridin-2-yl]amino]-1-piperidinecarboxylate, 50 parts of potassium hydroxide, 400 parts of 2-propanol and 20 drops of water was stirred and refluxed for about 5 hours. The reaction mixture was evaporated and water was added to the residue. The product was extracted twice with 4-methyl-2-pentanone. The combined extracts were dried, filtered and evaporated. The solid residue was stirred in 1,1'-oxybisethane. The product was filtered off and dried, yielding 34 parts (85%) of 3-(2-furanylmethyl)-N-(4-piperidinyl)-3H-imidazo[4,5-b]pyridin-2-amine; mp. 159.0° C. (intermediate 68).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][OH:11].N1C=CN=C1.[CH:17]([Si:20](Cl)([CH:24]([CH3:26])[CH3:25])[CH:21]([CH3:23])[CH3:22])([CH3:19])[CH3:18]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][C:3]=1[CH2:10][O:11][Si:20]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:17]([CH3:19])[CH3:18]
Reactant: COc1ccc(Br)c(CO)c1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: COc1ccc(Br)c(CO[Si](C(C)C)(C(C)C)C(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
(2-Bromo-5-methoxyphenyl)methanol (1 eq.) was dissolved in anhydrous DMF (1.1M solution) and imidazole (1.05 eq.) was added. To the stirred solution triisopropylsilyl chloride (1.1 eq.) was added and the resulting mixture was left stirring at RT for 8 h. All volatiles were evaporated in vacuo and the residual material was filtered with PE/EtOAc (9:1) over a pad of silica gel. After evaporation in vacuo the product was obtained as a colorless oil (94%), which was used without further characterization in the next reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH2:24])[CH2:17][C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)[CH2:11][CH2:10]1.C(N(CC)CC)C.[CH:32]1([C:38](Cl)=[O:39])[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][C@H:16]([NH:24][C:38]([CH:32]2[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:39])[CH2:17][C:18]2[CH:19]=[CH:20][N:21]=[CH:22][CH:23]=2)[CH2:11][CH2:10]1
Reactant: COc1ccccc1N1CCN(C[C@H](N)Cc2ccncc2)CC1
Reactant: O=C(Cl)C1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccccc1N1CCN(C[C@@H](Cc2ccncc2)NC(=O)C2CCCCC2)CC1
Temperature: 25 °C
Yield: 57 %

Procedure:
To a solution of (1R)-2-[4-(2-Methoxy-phenyl)-piperazin-1-yl]-1-pyridin-4-ylmethyl-ethylamine (800 mg.; 2.45 mmol, from Example 8) in dichloromethane (30 mL) at 0° C. was added triethylamine (0.68 mL; 4.9 mmol) and cyclohexanecarbonyl chloride (0.33 mL; 2.45 mmol). The reaction mixture was stirred while allowing to warm to ambient temperature over 1 hour. The mixture was washed with saturated NaHCO3 (5 mL), dried over MgSO4, filtered, and the solvent removed in vacuo. The crude residue was purified by flash chromatography on silica gel (2% methanol/chloroform) to afford the free base of the title compound as a white gummy foam (610 mg; 57%). Treatment with an equimolar amount of maleic acid in ethanol yielded the maleate salt as an off-white amorphous solid, m.p. 145–147° C.; MS (+) FAB [M+H]+ @ m/z 437, [M+Na]+ @ m/z 459; 1H NMR, 400 MHz, DMSO-d6. Analysis for C26H36N4O2.C4H4O4.0.5H2O Calculated: C, 64.15; H, 7.36; N, 9.97 Found: C, 64.23; H, 7.37; N, 9.88
Reaction SMILES: [CH3:1][N:2]([CH3:7])[S:3](Cl)(=[O:5])=[O:4].Cl.Cl.[NH:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH3:1][N:2]([CH3:7])[S:3]([N:10]1[CH2:15][CH2:14][CH:13]([O:16][C:17]2[CH:18]=[C:19]3[C:24](=[CH:25][C:26]=2[O:27][CH3:28])[N:23]=[CH:22][N:21]=[C:20]3[NH:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:31]=2[F:37])[CH2:12][CH2:11]1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Cl
Reactant: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCNCC1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1cc2ncnc(Nc3cccc(Cl)c3F)c2cc1OC1CCN(S(=O)(=O)N(C)C)CC1
Temperature: 25 °C
Reaction time: 16 h
Yield: 85.8 %

Procedure:
Dimethylsulfamoyl chloride (90 mg) was added to a solution of 6-(piperidin-4-yloxy)-4-(3-chloro-2-fluoroanilino)-7-methoxyquinazoline dihydrochloride (250 mg) (starting material Example 16) and diisopropylethylamine (184 mg) in methylene chloride (10 ml). The reaction mixture was stirred for 16 hours at ambient temperature. The reaction mixture was adsorbed onto silica and the residue was purified by column chromatography on silica eluting with increasingly polar mixtures of methylene chloride/methanol (100/0 to 95/5). The fractions containing the expected product were combined and evaporated under vacuum and the residue triturated with diethylether to give the title product as a white solid (0.23 g); 1H NMR. Spectrum: (DMSO d6) 1.72-1.86 (m, 2H), 2.00-2.12 (m, 2H), 2.76 (s, 6H); 3.12-3.23 (m, 2H), 3.40-3.51 (m, 2H), 3.94 (s, 3H), 4.68 (m, 1H), 7.19-7.30 (m, 2H), 7.43-7.54 (m, 2H), 7.85 (s, 1H), 8.37 (s, 1H), 9.52 (s, 1H); Mass Spectrum: (M+H)+ 510.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][C:12](=O)[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[CH:16]1([NH2:19])[CH2:18][CH2:17]1>>[CH:16]1([NH:19][CH:12]2[CH2:13][CH2:14][N:9]([C:7]3[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=3)[CH2:10][CH2:11]2)[CH2:18][CH2:17]1
Reactant: NC1CC1
Reactant: CC(C)c1noc(N2CCC(=O)CC2)n1
Product: CC(C)c1noc(N2CCC(NC3CC3)CC2)n1

Procedure:
The title compound is prepared from 1-(3-isopropyl-[1,2,4]oxadiazol-5-yl)-piperidin-4-one and cyclopropylamine following a procedure analogous to that described in Intermediate 4. Mass spectrum (ESI+): m/z=251 [M+H]+.