Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([Si:5]([O:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([C:16]#[CH:17])[C:11]=1[F:18])([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.CCCCCC.Cl[C:31]([O:33][CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)=[O:32].[Cl-].[NH4+]>C1COCC1>[Si:5]([O:8][CH2:9][C:10]1[C:11]([F:18])=[C:12]([C:16]#[C:17][C:31]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)=[O:32])[CH:13]=[CH:14][CH:15]=1)([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: C#Cc1cccc(CO[Si](C)(C)C(C)(C)C)c1F
Reactant: O=C(Cl)OCc1ccccc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)(C)[Si](C)(C)OCc1cccc(C#CC(=O)OCc2ccccc2)c1F
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
tert-Butyl [(3-ethynyl-2-fluorobenzyl)oxy]dimethylsilane (1 g) was mixed with THF (20 ml), and a 1.65M n-butyl lithium/hexane solution (2.5 ml) was added dropwise thereto at −78° C., followed by stirring at −78° C. for 30 minutes. Benzyl chloroformate (774 mg) was added dropwise thereto at the same temperature, followed by stirring overnight while raising the temperature to room temperature. A saturated aqueous ammonium chloride solution was added thereto at 0° C., followed by extraction with CHCl3. The organic layer was washed with water and saturated brine, and dried over Na2SO4, and the solvent was concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (EtOAc/hexane) to obtain benzyl 3-[3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-2-fluorophenyl]prop-2-ynoate (1.41 g).
Reaction SMILES: [CH:1]([C:4]1[NH:5][CH:6]=[C:7]([C:9]([CH3:20])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:10])[N:8]=1)([CH3:3])[CH3:2].[C:21](=O)([O-])[O-].[K+].[K+].IC>C1COCC1>[CH:1]([C:4]1[N:5]([CH3:21])[CH:6]=[C:7]([C:9]([CH3:10])([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[CH3:20])[N:8]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)c[nH]1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)c1nc(C(C)(C)c2cccc([N+](=O)[O-])c2)cn1C
Temperature: 50 °C
Yield: 54.4 %

Procedure:
To a solution of 2-isopropyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.35 g, 1.28 mmol) in THF (2 mL) was added potassium carbonate (0.21 g, 1.5 mmol) and iodomethane (0.12 mL, 1.92 mmol). The mixture was heated at 50° C. for 5 h then concentrated in vacuo. The residue was partitioned between water and DCM then the organic phase was dried over sodium sulfate and evaporated to afford 2-isopropyl-1-methyl-4-[1-methyl-1-(3-nitro-phenyl)-ethyl]-1H-imidazole (0.2 g, 56%) as colourless semisolid.
Reaction SMILES: [CH3:1][NH:2][N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6].C(=O)([O-])[O-].[K+].[K+].[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([CH2:26][C:27](Cl)=[O:28])=[C:20]([CH2:30][CH3:31])[CH:19]=1>C(#N)C>[Cl:17][C:18]1[CH:23]=[C:22]([CH2:24][CH3:25])[C:21]([CH2:26][C:27]([N:2]([CH3:1])[N:3]=[C:4]([CH3:10])[C:5]([O:7][CH2:8][CH3:9])=[O:6])=[O:28])=[C:20]([CH2:30][CH3:31])[CH:19]=1
Reactant: CCOC(=O)C(C)=NNC
Reactant: CCc1cc(Cl)cc(CC)c1CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCOC(=O)C(C)=NN(C)C(=O)Cc1c(CC)cc(Cl)cc1CC
Yield: 66.2 %

Procedure:
To a solution of 1.1 g of ethyl 2-(methylhydrazono)propanoate in 20 mL of acetonitrile was added 0.68 g of potassium carbonate. The mixture was stirred under ice cooling. To the mixture was added dropwise a solution of 1.26 g of 4-chloro-2,6-diethylphenylacetyl chloride in 8 mL of acetonitrile over about 10 minutes. The mixture was further stirred at room temperature for 3 hours. Then, the reaction mixture was concentrated under reduced pressure. To the residue was added 20 mL of ice water, followed by extraction with ethyl acetate (20 mL, 10 mL×2). The extracts were combined, washed with an aqueous saturated sodium chloride solution (20 mL×2), dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to basic alumina column chromatography (ethyl acetate:hexane=1:6) to give 1.2 g of a light yellow solid. The solid was washed with cold hexane and air dried to give 0.79 g of the title compound as a white powder.
Reaction SMILES: [C:1]([NH:5][OH:6])(=[O:4])[CH2:2][CH3:3].[CH2:7]([N:9]=[C:10]=[O:11])[CH3:8]>C(N(CC)CC)C.C(Cl)Cl>[CH2:7]([NH:9][C:10]([N:5]([O:6][C:10]([NH:9][CH2:7][CH3:8])=[O:11])[C:1](=[O:4])[CH2:2][CH3:3])=[O:11])[CH3:8]
Reactant: CCC(=O)NO
Reactant: CCN=C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCNC(=O)ON(C(=O)CC)C(=O)NCC
Reaction time: 12 h

Procedure:
Propiohydroxamic acid (4.5 grams), ethyl isocyanate (8.0 grams), and a few drops of triethylamine were added to 100 ml of methylene chloride and allowed to stand at room temperature for about 12 hours. The solvent was then removed under vacuum leaving a residue which was recrystallized from a solution of methylene chloride and hexane leaving the desired, N-((ethylamino)carbonyl)-N-(((ethylamino)carbonyl)oxy)propionamide as white crystals, m.p. 104°-106° C.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][N:7]=[C:6]([C:10]([OH:12])=O)[CH:5]=1)([CH3:3])[CH3:2].[NH2:13][C:14]1[NH:18][N:17]=[N:16][N:15]=1>>[NH:15]1[C:14]([NH:13][C:10]([C:6]2[CH:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[CH:9]=[CH:8][N:7]=2)=[O:12])=[N:18][N:17]=[N:16]1
Reactant: Nc1nnn[nH]1
Reactant: CC(C)c1ccnc(C(=O)O)c1
Product: CC(C)c1ccnc(C(=O)Nc2nnn[nH]2)c1
Yield: 28.8 %

Procedure:
0.42 g of 4-isopropyl-2-pyridinecarboxylic acid, 0.42 g of N,N'-carbonyldiimidazole and 0.24 g of 5-aminotetrazole are treated in the same manner as described in Example 2. The crude product thus obtained is recrystallized from a mixture of dimethylformamide and water, whereby 0.17 g of N-(5-tetrazolyl)-4-isopropyl-2-pyridinecarboxamide is obtained.
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:24]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])(=[O:27])[CH:25]=[CH2:26].O>CS(C)=O>[C:29]([O:28][C:24](=[O:27])[CH2:25][CH2:26][NH:2][C@H:3]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)([CH3:32])([CH3:31])[CH3:30]
Reactant: C=CC(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)[C@@H](N)Cc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)CCN[C@@H](Cc1ccccc1)C(=O)OC(C)(C)C
Temperature: 150 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl L-phenylalaninate hydrochloride (800 mg) in dimethyl sulfoxide (3.20 mL) were added potassium carbonate (429 mg) and tert-butyl acrylate (0.901 mL), followed by stirring at 150° C. for 1 hour under microwave. After cooling to room temperature, water was added thereto, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl N-(3-tert-butoxy-3-oxopropyl)-L-phenylalaninate (266 mg).
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH2:5][CH2:6][CH:7]1[CH2:9][CH2:8]1>>[CH:7]1([CH2:6][NH:5][CH2:3][CH2:2][C:1]#[N:4])[CH2:9][CH2:8]1
Reactant: NCC1CC1
Reactant: C=CC#N
Product: N#CCCNCC1CC1

Procedure:
With stirring and cooling in an ice-bath to maintain a temperature of 8–10° C., acrylonitrile (0.614 ml) was added to aminomethylcyclopropane (0.651 g). The resultant mixture was stirred at room temperature for 15 h to give the title compound (1.02 g) as a yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11](=[O:16])[C:12]([CH3:15])([CH3:14])[CH3:13].[OH-].[Na+]>CO.C(O)C>[CH3:13][C:12]([CH3:15])([CH3:14])[C:11](=[O:16])[CH:10]=[CH:6][C:5]1[CH:8]=[CH:9][C:2]([Cl:1])=[CH:3][CH:4]=1
Reactant: CC(=O)C(C)(C)C
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: CCO
Product: CC(C)(C)C(=O)C=Cc1ccc(Cl)cc1

Procedure:
evaporation. The yield in that procedure is only 59% of crude product. Apart from the poor yield, the complicated aqueous work up is a disadvantage. In DE-OS (German Published Specification) 2,737,489, a procedure is described, according to which p-chlorobenzaldehyde is reacted with pinacolone in the presence of sodium hydroxide in methanol/ethanol at maximum temperatures of up to 25° C. 4,4-Dimethyl-1-(p-chlorophenyl)-1-penten-3-one is formed as a solid, has to be filtered off with suction and washed with further solvent. The required low temperature results in an inhomogeneous, partially solid reaction mixture, which can only be stirred with difficulty. Furthermore, molar amounts of sodium hydroxide have to be used. A further disadvantage is that the portions of the reaction product which remain in the mother liquor have to be isolated in an additional workup step. To hydrogenate the double bond, the pentenone is dissolved in ethyl acetate and reacted with about 26% by weight of Raney nickel and with hydrogen at atmospheric pressure and a reaction time of about 14 1/2 hours. The very large amount of catalyst and the very long reaction time are the crucial disadvantages of this process. In all known procedures, the condensation product of pinacolone and p-chlorobenzaldehyde has to be isolated and purified as a solid and is only then subjected to hydrogenation in a second separate operation.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([S:8][C:9]2[C:17]3[C:16]([NH:18][C@H:19]([C:21]4[N:26]([C:27]5[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=5)[C:25](=[O:33])[C:24]5=[C:34]([CH3:37])[CH:35]=[CH:36][N:23]5[N:22]=4)[CH3:20])=[N:15][CH:14]=[N:13][C:12]=3[N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:45])([CH3:44])[CH3:43])[CH:10]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>>[CH3:37][C:34]1[CH:35]=[CH:36][N:23]2[C:24]=1[C:25](=[O:33])[N:26]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]([C@@H:19]([NH:18][C:16]1[C:17]3[C:9]([S:8][C:4]4[CH:3]=[C:2]([NH:1][S:47]([CH3:46])(=[O:49])=[O:48])[CH:7]=[CH:6][CH:5]=4)=[CH:10][N:11]([CH2:38][O:39][CH2:40][CH2:41][Si:42]([CH3:43])([CH3:45])[CH3:44])[C:12]=3[N:13]=[CH:14][N:15]=1)[CH3:20])=[N:22]2
Reactant: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(N)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Reactant: CS(=O)(=O)Cl
Product: Cc1ccn2nc([C@H](C)Nc3ncnc4c3c(Sc3cccc(NS(C)(=O)=O)c3)cn4COCC[Si](C)(C)C)n(-c3ccccc3)c(=O)c12
Yield: 21.5 %

Procedure:
(S)-2-(1-((5-((3-Aminophenyl)thio)-7-((2-(trimethylsilyl)ethoxy)methyl)-7H-pyrrolo[2,3-d]pyrimidin-4-yl)amino)ethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.13 mmol) was treated with methanesulfonyl chloride (10 μl, 0.14 mmol) according to the method described in Preparation 15b. The residue was purified by reverse phase using SP1® Purification System to give 20 mg (23% yield) of the title compound. Purity 98%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=1[NH2:8].[CH:11]1([C:14](O)=O)[CH2:13][CH2:12]1>>[CH:11]1([C:14]2[NH:1][C:2]3[CH:3]=[C:4]([OH:10])[CH:5]=[C:6]([CH3:9])[C:7]=3[N:8]=2)[CH2:13][CH2:12]1
Reactant: O=C(O)C1CC1
Reactant: Cc1cc(O)cc(N)c1N
Product: Cc1cc(O)cc2[nH]c(C3CC3)nc12

Procedure:
0.55 g (4.00 mmol) 3,4-diamino-5-methyl-phenol and 1.67 mL (20.00 mmol) cyclopropanecarboxylic acid were stirred for 1 h at 120° C. Then the reaction mixture w evaporated down i.vac. and further reacted as crude product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(N1C=CN=C1)(N1C=CN=C1)=O.Cl.[NH2:26][CH2:27][C:28]1[CH:37]=[CH:36][CH:35]=[C:34]2[C:29]=1[C:30](=[O:47])[N:31]([CH:39]1[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]1=[O:46])[C:32]([CH3:38])=[N:33]2>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([NH:26][CH2:27][C:28]2[CH:37]=[CH:36][CH:35]=[C:34]3[C:29]=2[C:30](=[O:47])[N:31]([CH:39]2[CH2:44][CH2:43][C:42](=[O:45])[NH:41][C:40]2=[O:46])[C:32]([CH3:38])=[N:33]3)=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: Cc1nc2cccc(CN)c2c(=O)n1C1CCC(=O)NC1=O
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: Cc1nc2cccc(CNC(=O)Cc3ccc(Cl)c(Cl)c3)c2c(=O)n1C1CCC(=O)NC1=O
Reaction time: 1 h
Yield: 73.9 %

Procedure:
To a stirred solution of (3,4-dichloro-phenyl)-acetic acid (0.30 g, 1.5 mmol) in DMF (8 mL) in a 40° C. oil bath, was added 1,1′carbonyldiimidazole (0.26 g, 1.6 mmol) and stirred for one hour. To the mixture, 3-(5-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) was added, and the mixture was stirred for 15 minutes. The solvent was evaporated, and the residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 2-(3,4-dichloro-phenyl)-N-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-5-ylmethyl]-acetamide as a yellow solid (540 mg, 74% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.41 min (98.4%); mp, 262-264° C.; 1HNMR (DMSO-d6)2.14-2.19 (m, 1H, CHH), 2.57-2.89 (m, 6H, CHCH2, CH3), 3.57 (s, 2H, ArCH2), 4.69-4.85 (m, 2H, CH2NH), 5.24 (dd, J=6, 11 Hz, 1H, CH), 7.26-7.73 (m, 6H, Ar), 8.42 (t, J=6 Hz, 1H, CH2NH), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 20.73, 23.28, 30.60, 40.98, 41.76, 56.49, 117.70, 124.84, 125.65, 129.06, 129.55, 130.27, 130.63, 131.11, 133.82, 137.43, 140.52, 148.46, 154.81, 160.90, 169.42, 169.49, 172.59. LCMS MH=487, 489; Anal Calcd For C23H20N4O4Cl2: C, 56.69; H, 4.14; N, 11.50; Cl, 14.55. Found: C, 56.50; H, 3.95; N, 11.25; Cl, 14.29.
Reaction SMILES: [Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[NH:8][CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1.[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>>[Br:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][C:7]2[N:8]([CH2:29][C:28]3[CH:31]=[CH:32][C:25]([N+:22]([O-:24])=[O:23])=[CH:26][CH:27]=3)[CH:9]=[C:10]([C:12]3[CH:17]=[CH:16][C:15]([Cl:18])=[CH:14][C:13]=3[Cl:19])[N:11]=2)=[CH:4][CH:3]=1
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Reactant: Clc1ccc(-c2c[nH]c(Cc3ccc(Br)cc3)n2)c(Cl)c1
Product: O=[N+]([O-])c1ccc(Cn2cc(-c3ccc(Cl)cc3Cl)nc2Cc2ccc(Br)cc2)cc1

Procedure:
4-Bromophenylacetic acid (10.7 g, 50 mmol) was treated according to general procedure A using 2,4-dichlorophenacyl bromide to give 2-(4-bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole. 2-(4-Bromo-benzyl)-4-(2,4-dichloro-phenyl)-1H-imidazole (3.8 g, 10 m mol) was reacted with 4-nitro benzylbromide (2.5 g, 12 mmol) as described in general procedure B to give 2-(4-bromobenzyl)-4-(2,4-dichloro-phenyl)-1-(4-nitro-benzyl)-1H-imidazole.
Reaction SMILES: [C:1]([CH:3]([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:4][C:5]([NH:7][C:8]1[C:13]([O:14][CH3:15])=[CH:12][C:11]([O:16][CH3:17])=[CH:10][C:9]=1[O:18][CH3:19])=[O:6])#[N:2].C([Sn]([N:39]=[N+:40]=[N-:41])(CCCC)CCCC)CCC>O1CCOCC1>[NH:39]1[C:1]([CH:3]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH2:4][C:5]([NH:7][C:8]2[C:9]([O:18][CH3:19])=[CH:10][C:11]([O:16][CH3:17])=[CH:12][C:13]=2[O:14][CH3:15])=[O:6])=[N:2][N:41]=[N:40]1
Reactant: CCCC[Sn](CCCC)(CCCC)N=[N+]=[N-]
Reactant: COc1cc(OC)c(NC(=O)CC(C#N)c2ccccc2)c(OC)c1
Solvent: C1COCCO1
Product: COc1cc(OC)c(NC(=O)CC(c2ccccc2)c2nnn[nH]2)c(OC)c1
Reaction time: 0.5 h
Yield: 34.2 %

Procedure:
To a suspension of the material from step (a) (5.1 g, 0.016 mol) in dioxane (150 mL) at room temperature was added tri-n-butyltin azide (9.36 g, 0.016 mol) under N2 with stirring. The resulting solution was heated to reflux for 24 hours. The solution was then cooled and concentrated in vacuo. The residue was redissolved in ether and HCl gas was then passed through the solution for 30 minutes. This was then concentrated in vacuo to give β-(1H-tetrazol-5-yl)-N-(2,4,6-trimethoxyphenyl)benzene propanamide as a white solid (2.1 g) which was used without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]([O:22]C)=[O:21])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:6][CH:5]=1.[Li+].[OH-]>C1COCC1.O>[F:25][C:2]([F:1])([F:24])[O:3][C:4]1[CH:5]=[CH:6][C:7]([NH:10][C:11]2[C:12]3[CH:19]=[C:18]([C:20]([OH:22])=[O:21])[S:17][C:13]=3[N:14]=[CH:15][N:16]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1cc2c(Nc3ccc(OC(F)(F)F)cc3)ncnc2s1
Temperature: 60 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
A mixture of methyl 4-(4-(trifluoromethoxy)phenylamino)thieno[2,3-d]pyrimidine-6-carboxylate (152 mg, 0.43 mmol), LiOH (25.5 mg, 1.07 mmol) was dissolved in THF (4 ml) and H2O (1 mL). The mixture was stirred at 60° C. for 3 h. Acidified with acetic acid resulted brown solid which was collected by filtration. It was then dried in vacuo and used for the next step without any further purification (115 mg, 75% Yield). MS m/z 356.1 (M+1)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([I:9])[CH:3]=1.[CH2:10]([N:17]1[CH2:22][CH:21]=[C:20]([CH2:23]O)[CH2:19][CH2:18]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[CH2:10]([N:17]1[CH2:18][CH:19]=[C:20]([CH2:23][O:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=2[I:9])[CH2:21][CH2:22]1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: OCC1=CCN(Cc2ccccc2)CC1
Reactant: Oc1ccc(Cl)cc1I
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ccc(OCC2=CCN(Cc3ccccc3)CC2)c(I)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-chloro-2-iodo-phenol 4ii (20.32 g, 0.08 mol), (1-benzyl-1,2,3,6-tetrahydro-pyridin-4-yl)-methanol (20.5 g, 0.08 mol) and triphenylphosphine (23.58 g, 0.09 mol) in dry THF (150 mL) was added DEAD (17.4 g, 0.09 mol) at 0° C. under nitrogen atmosphere. After addition, the mixture was stirred at room temperature overnight. The mixture was concentrated to dryness and the residue was basified by Na2CO3 solution (10% 100 mL) and extracted with ethyl acetate (3×100 mL). The combined organic layers were washed with water (2×100 mL) and brine (200 mL), dried over Na2SO4, concentrated to dryness. The residue was purified by column on silica gel to afford 1-benzyl-4-(4-chloro-2-iodo-phenoxymethyl)-1,2,3,6-tetrahydro-pyridine 4iii (30 g). 1H NMR (400 MHz, CDCl3): δ 7.73 (d, J=2.4 Hz, 1H), 7.22-7.38 (m, 6H), 6.70 (d, J=8.8 Hz, 1H), 5.82 (s, 1H), 4.43 (s, 2H), 3.63 (s, 2H), 3.05 (s, 2H), 2.67 (t, J=5.6 Hz, 2H), 2.28 (s, 2H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH2:25])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[C:30](Cl)(=[O:34])[CH2:31][CH2:32][CH3:33]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([N:9]2[CH2:10][CH2:11][N:12]([C:15]3[C:16]([CH3:29])=[C:17]([CH3:28])[C:18]4[O:22][C:21]([CH2:24][NH:25][C:30](=[O:34])[CH2:31][CH2:32][CH3:33])([CH3:23])[CH2:20][C:19]=4[C:26]=3[CH3:27])[CH2:13][CH2:14]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)CC(C)(CN)O4)CC2)cc1
Reactant: CCCC(=O)Cl
Product: CCCC(=O)NCC1(C)Cc2c(C)c(N3CCN(c4ccc(OC)cc4)CC3)c(C)c(C)c2O1
Yield: 61.8 %

Procedure:
By using 1-{5-[4-(4-Methoxyphenyl)piperazin-1-yl]-2,4,6,7-tetramethyl-2,3-dihydro-1-benzofuran-2-yl}methaneamine (110 mg, 0.278 mmol) synthesized in Example 108 and butyryl chloride (32 mg, 0.304 mmol), the reaction was carried out in the same manner as Example 137 to synthesize 80 mg of the title compound (yield 68%). Melting point was 140 to 142° C.
Reaction SMILES: C(#N)C.[F:4][C:5]1[CH:6]=[C:7]([CH:10]=[C:11]([O:14][CH3:15])[C:12]=1[OH:13])[CH:8]=[O:9].[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[CH2:16]([O:13][C:12]1[C:11]([O:14][CH3:15])=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][C:5]=1[F:4])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C=O)cc(F)c1O
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COc1cc(C=O)cc(F)c1OCc1ccccc1
Yield: 67.2 %

Procedure:
To 40 ml of acetonitrile were added 7.3 g of 3-fluoro-4-hydroxy-5-methoxybenzaldehyde, 8.8 g of benzyl bromide, 16.8 g of cesium carbonate and 10 ml of DMF, and the mixture obtained was heated under reflux for 10 hours. The reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 7.5 g of 4-benzyloxy-3-fluoro-5-methoxybenzaldehyde represented by the formula:
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19]/[C:20](=[C:27]2\[C:28](=[O:36])[NH:29][C:30]3[C:35]\2=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)=[O:11])=O)(C)(C)C.C(OCC)(=O)C.[ClH:43]>ClCCl>[ClH:43].[NH2:8][CH2:9][C:10]([NH:12][C:13]1[CH:14]=[CH:15][C:16]([NH:19]/[C:20](=[C:27]2\[C:28](=[O:36])[NH:29][C:30]3[C:35]\2=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:17][CH:18]=1)=[O:11]
Reactant: CC(C)(C)OC(=O)NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: NCC(=O)Nc1ccc(N/C(=C2\C(=O)Nc3ccccc32)c2ccccc2)cc1

Procedure:
Prepared analogously to Example 29a from (Z)-3-[1-(4-tert.butoxycarbonylaminomethylcarbonylamino-phenylamino)-1-phenyl-methylidene]-2-indolinone and ethyl acetate/hydrogen chloride in dichloromethane.
Reaction SMILES: Cl[CH2:2][CH2:3][O:4][C:5]1[CH:6]=[C:7]2[C:12](=[CH:13][C:14]=1[O:15][CH3:16])[N:11]=[C:10]([C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[CH2:25][N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:18]=1)[N:9]=[C:8]2[NH:33][C:34]1[CH:35]=[C:36]2[C:40](=[CH:41][CH:42]=1)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]2.[NH:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1>CN(C=O)C.C1COCC1>[CH3:16][O:15][C:14]1[CH:13]=[C:12]2[C:7]([C:8]([NH:33][C:34]3[CH:35]=[C:36]4[C:40](=[CH:41][CH:42]=3)[N:39]([C:43]([O:45][C:46]([CH3:49])([CH3:48])[CH3:47])=[O:44])[N:38]=[CH:37]4)=[N:9][C:10]([C:17]3[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24](=[O:32])[CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)[CH:18]=3)=[N:11]2)=[CH:6][C:5]=1[O:4][CH2:3][CH2:2][N:50]1[CH2:54][CH2:53][CH2:52][CH2:51]1
Reactant: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCCl
Reactant: C1CCNC1
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc2nc(-c3cccc(NC(=O)CN4CCOCC4)c3)nc(Nc3ccc4c(cnn4C(=O)OC(C)(C)C)c3)c2cc1OCCN1CCCC1
Temperature: 25 °C
Yield: 29 %

Procedure:
To a mixture of tert-butyl 5-(6-(2-chloroethoxy)-7-methoxy-2-(3-(2-morpholinoacetamido)phenyl)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.280 g, 0.407 mmol) in DMF (2 mL) and THF (3 mL) was added pyrrolidine (0.8 mL). The resultant mixture was heated at 85° C. for 2 h, upon which it was allowed to cool to RT, the volatiles were removed in vacuo and the residue was taken up in ice-water (200 mL). The resulting precipitate was collected via filtration and subjected to preparative TLC (SiO2, CH2Cl2:MeOH 83:17) to give tert-butyl 5-(7-methoxy-2-(3-(2-morpholinoacetamido)-phenyl)-6-(2-(pyrrolidin-1-yl)ethoxy)quinazolin-4-ylamino)-1H-indazole-1-carboxylate (0.085 g, 0.118 mmol, 29%). HPLC retention time 3.81 minutes.