Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[CH:9]1[O:14]CCCO1.[Li][CH2:16]CCC.CI>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH3:16])[C:3]=1[CH:9]=[O:14]
Reactant: [Li]CCCC
Reactant: Brc1cccc(Br)c1C1OCCCO1
Solvent: C1CCOC1
Solvent: CI
Product: Cc1cccc(Br)c1C=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 96 %

Procedure:
1H NMR (500 MHz, CDCl3) δ [ppm] 7.55 (d, 3J=8.0 Hz 2 H, ar), 7.00 (t, 3J=8.0 Hz 1 H, ar), 6.19 (s, 1 H, CH), 4.33-4.29 (m, 2 H, CH2), 4.02-3.97 (m, 2 H, CH2), 2.44-2.34 (m, 1 H, CH2), 1.44-1.40 (m, 1 H, CH2); 13C{1} NMR (125.77 MHz, CDCl3) δ [ppm] 133.9, 132.5, 129.8, 122.9, 101.6, 66.7, 24.1. The acetal (10.1 g, 31.25 mmol) was dissolved in THF, abs. (200 ml). At −78° C. n-BuLi (15.1 ml, 2.5 M in hexane, 37.8 mmol) was added within 25 min, followed by 90 min additional stirring at that temperature. Then the reaction mixture was treated with methyliodide (5.99 g, 42.2 mmol) and stirred for 25 min at −78° C. Next the reaction mixture was allowed to warm to ambient temperature within 1.5 h. The resulting solution was quenched with HCl (290 ml of a 5 N solution) and stirred for 1.5 h at ambient temperature. The complete deprotection of the aldehyde was checked via GC analysis. Then the reaction mixture was subsequently extracted with diethylether (4×100 ml), the combined organic layers were washed with a 10% solution of sodium thiosulfate (100 ml), water (100 ml), dried over MgSO4, filtered and the volatiles removed in vacuo. The resulting slightly yellow solid was purified via Kugelrohr distillation to afford 50 (5.97 g, 96%) as white crystals. Rf 0.56 (cyclohexane:ethylacetate 10:1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][NH:20][C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[Si]([N-][Si](C)(C)C)(C)C.[Na+].Br[CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38].CCOC(C)=O>C1COCC1.CCCCCC.CCOC(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:23]=[C:22]3[C:17]([CH2:18][CH2:19][N:20]([CH2:36][C:37]([O:39][CH2:40][CH3:41])=[O:38])[C:21]3=[O:24])=[CH:16][CH:15]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc3c(c2)C(=O)NCC3)CC1
Reactant: CCOC(=O)CBr
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCc2ccc(N3CCN(C(=O)OC(C)(C)C)CC3)cc2C1=O
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 7-(4-t-butoxycarbonylpiperazin-1-yl)-3,4-dihydro-1(1H)-isoquinolinone (1-3) (2.37 g, 7.16 mmol) in THF (30 mL) at -78° C. under argon was treated with NaHMDS (1M solution in THF; 7.88 mL, 7.88 mmol) and the temperature was allowed to rise to -50° C. over 30 minutes. The solution was cooled back to -78° C. and ethyl bromoacetate (1.19 mL, 10.7 mmol) was added in one lot. After stirring at ambient temperature for 3 hours, the mixture was poured into EtOAc, extracted with 1N HCl, washed with brine (twice), dried (MgSO4) and evaporated to give an oil. Column chromatography (hexane/EtOAc 1:1 then 1:2) gave 1-4 as a solid. Rf (silica; hexane/EtOAc 1:1)=0.38.
Reaction SMILES: [CH:1]1[C:6]([NH2:7])=[CH:5][CH:4]=[C:3]([As:8]([OH:11])([OH:10])=[O:9])[CH:2]=1.C(=O)([O-])[O-].[Na+].[Na+].[Br:18][CH2:19][C:20](Br)=[O:21]>O.ClCCl>[Br:18][CH2:19][C:20]([NH:7][C:6]1[CH:1]=[CH:2][C:3]([As:8]([OH:10])(=[O:11])[OH:9])=[CH:4][CH:5]=1)=[O:21]
Reactant: Nc1ccc([As](=O)(O)O)cc1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: O=C(CBr)Nc1ccc([As](=O)(O)O)cc1
Temperature: 4 °C
Reaction time: 0.04 h

Procedure:
BRAA was prepared by a modification of the method described in Donoghue et al (2000) and WO 01/21628. p-Arsanilic acid (20.6 g, 95 mmol) was added in portions to a solution of sodium carbonate (20 g, 189 mmol) in water (200 mL). When all solids had dissolved, the solution was found to be pH 10, and was chilled at 4° C. for 2 hours. Bromoacetyl bromide (15 mL, 173 mmol) in dry dichloromethane (35 mL) was added in two portions, each addition followed by vigorous shaking for 2 to 3 min. The mixture was allowed to stand for a few minutes, and the lower organic layer was drained off. 4-(N-(Bromoacetyl)amino)benzenearsonic acid (BRAA) was precipitated by acidification of the solution to about pH 2-3 with the dropwise addition of 98% sulfuric acid, collected by vacuum filtration, and dried, giving BRAA as a white solid.
Reaction SMILES: [N:1]([C:4]([C:7]1[CH:12]=[CH:11][C:10]([C:13]2[NH:14][C:15](=[O:23])[C:16]3[N:17]([CH:19]=[C:20]([F:22])[CH:21]=3)[CH:18]=2)=[CH:9][CH:8]=1)([CH3:6])[CH3:5])=[N+]=[N-].[C:24]([OH:27])(=[O:26])C>C1COCC1.[Zn]>[CH:24]([OH:27])=[O:26].[NH2:1][C:4]([C:7]1[CH:8]=[CH:9][C:10]([C:13]2[NH:14][C:15](=[O:23])[C:16]3[N:17]([CH:19]=[C:20]([F:22])[CH:21]=3)[CH:18]=2)=[CH:11][CH:12]=1)([CH3:6])[CH3:5]
Reactant: CC(C)(N=[N+]=[N-])c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Reactant: CC(=O)O
Agent: [Zn]
Solvent: C1CCOC1
Product: CC(C)(N)c1ccc(-c2cn3cc(F)cc3c(=O)[nH]2)cc1
Product: O=CO
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a slurry of 103 mg (0.33 mmol) 3-[4-(1-azido-1-methyl-ethyl)-phenyl]-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one and 90 mg (1.38 mmol) zinc dust in 2 ml THF is added 175 ml (3.1 mmol) acetic acid and the mixture is stirred for 3 hours at room temperature. The suspension is quenched with THF/dichloromethane/ethyl acetate. The mixture is filtered with suction and the residue is washed with methanol. The filtrate is evaporated and the residue is purified by preparative HPLC to afford 3-[4-(1-amino-1-methyl-ethyl)-phenyl]-7-fluoro-2H-pyrrolo[1,2-a]pyrazin-1-one formate salt as white solid; HPLC/MS 1.57 min (B), [M+H] 268;
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH:13]=[CH:12][N:11]=[CH:10]2)=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1)[CH3:2].[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]>C1COCC1>[Br-:17].[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([N+:9]2[CH:13]=[CH:12][N:11]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=2)=[C:5]([C:14]([OH:16])=[O:15])[CH:4]=1)[CH3:2]
Reactant: CCCCCCBr
Reactant: CCc1ccc(-n2ccnc2)c(C(=O)O)c1
Solvent: C1CCOC1
Product: CCCCCCn1cc[n+](-c2ccc(CC)cc2C(=O)O)c1
Product: [Br-]

Procedure:
According to the general synthesis procedure, 1.62 mmol (0.350 g) 1-(4-ethylcarboxyphenyl)imidazole and 1.78 mmol (0.294 g, 0.25 ml) 1-bromohexane are dissolved in 5 ml THF and heated for 2.5 h to 100° C.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH2:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:13][NH:14][C:16]1[N:21]=[CH:20][C:19]([Cl:22])=[CH:18][N:17]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CN
Reactant: Clc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CNc1ncc(Cl)cn1
Yield: 48.6 %

Procedure:
(S)-2-Aminomethylpyrrolidine-1-carboxylic acid tert-butyl ester (3.38 g), 2,5-dichloropyrimidine (2.50 g), potassium carbonate (4.67 g) and diisopropylethylamine (8.79 ml) were heated in xylene (60 ml) at 100° C. for 3.75 h. The cooled reaction mixture was filtered and the filtrate evaporated to a gum which was chromatographed on silica gel, eluting with ethyl acetate-pentane fractions, to afford the title compound as a pale yellow solid (2.55 g). Mass Spectrum (API+): Found 213 (MH+-tBoc). C14H2135ClN4O2 requires 312.
Reaction SMILES: [C:1]([C:4]1[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=1)(=[S:3])[NH2:2].[F:14][C:15]([F:28])([F:27])[O:16][C:17]1[CH:26]=[CH:25][C:20]([C:21](=O)[CH2:22]Br)=[CH:19][CH:18]=1>>[F:14][C:15]([F:27])([F:28])[O:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]2[N:2]=[C:1]([C:4]3[CH:13]=[CH:12][C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][CH:5]=3)[S:3][CH:22]=2)=[CH:25][CH:26]=1
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: COC(=O)c1ccc(C(N)=S)cc1
Product: COC(=O)c1ccc(-c2nc(-c3ccc(OC(F)(F)F)cc3)cs2)cc1
Yield: 60 %

Procedure:
In the same manner as in Example 28, methyl 4-thiocarbamoylbenzoate was reacted with 4-trifluoromethoxyphenacyl bromide to obtain methyl 4-[4-(4-trifluoromethoxyphenyl)-2-thiazolyl]benzoate. The product was recrystallized from ethanol. Yield: 60%. Pale yellow prisms. Melting point: 138 to 139° C.
Reaction SMILES: [Cl-].[CH3:2][O:3][CH2:4][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C([Li])CCC.[Cl:29][C:30]1[N:31]=[C:32]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:33]2[S:38][C:37]([CH:39]=O)=[CH:36][C:34]=2[N:35]=1>C1COCC1>[Cl:29][C:30]1[N:31]=[C:32]([N:41]2[CH2:46][CH2:45][O:44][CH2:43][CH2:42]2)[C:33]2[S:38][C:37]([CH:39]=[CH:2][O:3][CH3:4])=[CH:36][C:34]=2[N:35]=1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Agent: [Cl-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC=Cc1cc2nc(Cl)nc(N3CCOCC3)c2s1
Temperature: 0 °C
Reaction time: 1 h
Yield: 101.9 %

Procedure:
To a suspension of methoxymethyl triphenylphosphonium chloride (7.24 g) in THF (100 mL) at 0° C. was added n-butyllithium (6.76 mL of a 2.M solution in hexanes). The reaction mixture was stirred at 0° C. for 1 h and then a suspension of 2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine-6-carbaldehyde 10 (2 g) in THF (30 mL) was added dropwise. The reaction mixture was stirred at room temperature for 16 h and then quenched with water (80 mL) and extracted with ethyl acetate (2×80 mL). The combined organics were washed with aqueous brine solution (2×80 mL), dried (MgSO4), concentrated and purified using column chromatography to give 2-chloro-6-(2-methoxy-vinyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (mixture of cis/trans isomers) as a yellow solid (2.24 g).
Reaction SMILES: [C:1]([NH2:4])(=[O:3])[CH3:2].[CH2:5](Cl)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1>CN(C)C=O>[CH2:5]([NH:4][C:1](=[O:3])[CH3:2])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1
Reactant: ClCc1ccccc1
Reactant: CC(N)=O
Solvent: CN(C)C=O
Product: CC(=O)NCc1ccccc1
Reaction time: 4 h
Yield: 72.6 %

Procedure:
To 200 ml of N,N-dimethylformamide, were added 12 g of acetamide, 105 g of LEVATIT MP-500, which was also used in Example 68, and 32 g of benzylchloride. They were .reacted at 50° C. for 4 hours with stirring. After the reaction, the reaction solution was treated in the same manner as in Example 69, the resulting distillation residue was recrystallized from benzene, thereby providing 22 g of N-benzylacetamide having a melting point of 61°-62° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[CH2:20][CH2:19][N:18]([C:21]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([C:30]([O:32]CC)=[O:31])=[CH:26][CH:25]=2)=[O:22])[CH2:17][CH2:16]1.O.[OH-].[Li+].O>O1CCOCC1>[C:30]([C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:21]([N:18]2[CH2:19][CH2:20][N:15]([C:6]3[C:5]4[C:10](=[CH:11][C:12]([O:13][CH3:14])=[C:3]([O:2][CH3:1])[CH:4]=4)[N:9]=[CH:8][N:7]=3)[CH2:16][CH2:17]2)=[O:22])=[CH:25][CH:26]=1)([OH:32])=[O:31]
Reactant: CCOC(=O)c1ccc(NC(=O)N2CCN(c3ncnc4cc(OC)c(OC)cc34)CC2)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2ncnc(N3CCN(C(=O)Nc4ccc(C(=O)O)cc4)CC3)c2cc1OC
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To a solution of 390 mg (0.84 mmol) of 4-(6,7-dimethoxy-4-quinazolinyl)-N-(4-ethoxycarbonylphenyl)-1-piperazinecarboxamide obtained in Example 89 in 10 ml of 1,4-dioxane were added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate and 1 ml of water, followed by stirring at room temperature for 4.5 hours. To the resulting mixture was further added 70.4 mg (1.68 mmol) of lithium hydroxide monohydrate, followed by overnight stirring at room temperature. After the solvent was evaporated, water was added to the residue, and the resulting mixture was adjusted to pH 4 with 4 N hydrochloric acid. The precipitated crystals were collected by filtration, washed with water, and dried, followed by purification by silica gel column chromatography to give the desired compound as colorless crystals. F Yield: 100%
Reaction SMILES: C(N(CC)C([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[C:11]2[C:15]=1[NH:14][CH:13]=[C:12]2[CH2:16][CH2:17][NH:18][C@@H:19]([CH3:29])[C@H:20]([OH:28])[C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)=O)C.P([O-])([O-])(O)=O.[Na+].[Na+].F[B-](F)(F)F.[CH2:44]([O+:46](CC)CC)[CH3:45].C(Cl)Cl.C(=O)([O-])[OH:55].[Na+]>C(#N)C>[OH:28][C@H:20]([C:21]1[CH:26]=[CH:25][C:24]([OH:27])=[CH:23][CH:22]=1)[C@@H:19]([NH:18][CH2:17][CH2:16][C:12]1[C:11]2[C:15](=[C:7]([C:6]([O:46][CH2:44][CH3:45])=[O:55])[CH:8]=[CH:9][CH:10]=2)[NH:14][CH:13]=1)[CH3:29]
Reactant: O=C([O-])O
Reactant: CC[O+](CC)CC
Reactant: CCN(CC)C(=O)Cc1cccc2c(CCN[C@@H](C)[C@H](O)c3ccc(O)cc3)c[nH]c12
Agent: F[B-](F)(F)F
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC#N
Product: CCOC(=O)c1cccc2c(CCN[C@@H](C)[C@H](O)c3ccc(O)cc3)c[nH]c12
Temperature: 25 °C
Reaction time: 15 h
Yield: 64 %

Procedure:
To a solution of N,N-diethyl-3-(2-(((1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-methylethyl)amino)ethyl)-1H-indole-7-carboxyamide (215.5 mg, 0.526 mmol) in acetonitrile (18 mL) is added disodium hydrogen phosphate (112 mg, 0.789 mmol) under nitrogen atmosphere, and thereto is further added a 1N solution of triethyloxonium tetra-fluoroborate in methylene chloride (1.58 mL, 1.58 mmol), and the mixture is stirred at room temperature for 15 hours. To the reaction solution are added a saturated aqueous sodium hydrogen carbonate solution (18 mL) and sodium hydrogen carbonate (200 mg), and the mixture is further stirred for 2 hours. The mixture is separated into water and chloroform, and the organic layer is washed with a saturated aqueous sodium hydrogen carbonate solution and dried over anhydrous sodium sulfate. The solvent is evaporated, and the obtained crude product is purified by silica gel column chromatography (chloroform: methanol=50:1 5:1) to give ethyl 3-{2-[(1S,2R)-2-hydroxy-2-(4-hydroxyphenyl)-1-(methyl) ethylamino]ethyl}-1H-indole-7-carboxylate (128.4 mg, 0.336 mmol, 64%).
Reaction SMILES: CO[C:3](=[O:9])[CH:4]=[C:5]([NH2:8])OC.[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[CH2:14][NH:15][NH2:16]>O1CCOCC1>[NH2:8][C:5]1[NH:16][N:15]([CH2:14][C:13]2[CH:17]=[CH:18][C:19]([Cl:20])=[C:11]([Cl:10])[CH:12]=2)[C:3](=[O:9])[CH:4]=1
Reactant: COC(=O)C=C(N)OC
Reactant: NNCc1ccc(Cl)c(Cl)c1
Solvent: C1COCCO1
Product: Nc1cc(=O)n(Cc2ccc(Cl)c(Cl)c2)[nH]1
Reaction time: 2 h

Procedure:
144 g (10% excess) of β-amino-β-methoxyacrylic acid methyl ester are introduced into 500 ml of dioxane. 191 g of 3,4-dichlorobenzylhydrazine are introduced into the reaction mixture while flushing with nitrogen. The mixture is stirred for 2 hours at 60°, the solvent is driven off on a rotary evaporator, the residue is worked with 600 ml of 2 N NaOH and extracted with ether, and the aqueous phase is stirred with animal charcoal for 1/2 hour. After filtration, the mixture is adjusted to pH 5 with dilute acetic acid. The product which initially is obtained as an oil becomes crystalline on rubbing and is finally purified by recrystallising it again from alcohol. 139 g, corresponding to about 54% of theory, of the compound identified above, as felted colorless needles of melting point 159° are obtained.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[N:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:15][NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:10][CH:11]([OH:14])CO)[CH3:8])([CH3:4])([CH3:3])[CH3:2].I([O-])(=O)(=O)=O.[Na+]>O1CCCC1.O>[C:1]([O:5][C:6](=[O:30])[N:7]([C:9]([C:22]1[CH:27]=[CH:26][C:25]([Cl:28])=[C:24]([Cl:29])[CH:23]=1)([CH2:15][NH:16][C:17](=[O:21])[CH2:18][CH2:19][CH3:20])[CH2:10][CH:11]=[O:14])[CH3:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCCC(=O)NCC(CC(O)CO)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: C1CCOC1
Solvent: O
Product: CCCC(=O)NCC(CC=O)(c1ccc(Cl)c(Cl)c1)N(C)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 103.5 %

Procedure:
tert-Butyl{1-(3,4-dichlorophenyl)-3,4-dihydroxy-1-[(methylpropionylamino)-methyl]-butyl}-methyl-carbamate (1.09 g) was dissolved in a mixture solvent of tetrahydrofuran (8 mL) and water (8 mL). Sodium periodate (1.0 g) was added thereto, and the mixture was stirred for 1 hour at room temperature. The reaction mixture was concentrated under reduced pressure, and water was added to the residue, followed by extraction with ethyl acetate. The organic layer was washed with saturated brine, dried over sodium sulfate anhydrate, and concentrated under reduced pressure, to thereby give the title compound (1.05 g, quantative amount). The compound was used in the next step without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1.[Na].[CH2:10](O)C>>[CH2:1]([O:2][C:3]1[CH2:7][NH:6][C:5](=[O:8])[CH:4]=1)[CH3:10]
Reactant: COC1=CC(=O)NC1
Reactant: CCO
Agent: [Na]
Product: CCOC1=CC(=O)NC1
Yield: 65 %

Procedure:
A solution of 4-methoxy-3-pyrrolin-2-one (3 g; 26.52 mmols) in absolute ethanol (60 ml) is treated with sodium ethoxyde (2.17 g; 31.82 mmols) under nitrogen atmosphere. The solution is refluxed for 2 hours and then poured into a 30% NaH2PO4 solution (200 ml). The resulting mixture is extracted with ethyl acetate (3×150 ml) and the organic phase is shaken with brine, dried over sodium sulphate and evaporated to dryness to obtain 4-ethoxy-3-pyrrolin-2-one (2.19 g; 17.24 mmols). Yield: 65%.
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20]Cl)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:33])[CH3:32])[CH:26]=2)=[C:4]([F:37])[CH:3]=1.C(N(CC)CC)C.[CH2:45]([N:47]1[CH2:52][CH2:51][NH:50][CH2:49][CH2:48]1)[CH3:46]>O1CCCC1.C(OCC)(=O)C>[Cl:1][C:2]1[C:7]([O:8][C:9]2[N:14]=[C:13]3[S:15][C:16]([NH:18][C:19](=[O:22])[CH2:20][N:50]4[CH2:51][CH2:52][N:47]([CH2:45][CH3:46])[CH2:48][CH2:49]4)=[N:17][C:12]3=[CH:11][CH:10]=2)=[CH:6][C:5]([NH:23][C:24](=[O:36])[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([C:31]([C:34]#[N:35])([CH3:32])[CH3:33])[CH:26]=2)=[C:4]([F:37])[CH:3]=1
Reactant: CCN1CCNCC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)CCl)sc4n3)c(Cl)cc2F)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCN1CCN(CC(=O)Nc2nc3ccc(Oc4cc(NC(=O)c5cccc(C(C)(C)C#N)c5)c(F)cc4Cl)nc3s2)CC1
Temperature: 70 °C
Reaction time: 4 h
Yield: 67 %

Procedure:
N-[4-Chloro-5-({2-[(chloroacetyl)amino][1,3]thiazolo[5,4-b]pyridin-5-yl}oxy)-2-fluorophenyl]-3-(1-cyano-1-methylethyl)benzamide synthesized above was dissolved in tetrahydrofuran (3.0 mL), triethylamine (128 μL, 0.933 mmol) and N-ethylpiperazine (118 μL, 0.933 mmol) were added, and the mixture was stirred at 70° C. for 4 hr. The reaction mixture was cooled to room temperature, diluted with ethyl acetate (10 mL), washed with water (10 mL) and saturated brine (10 mL), and dried over anhydrous sodium sulfate. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by basic silica gel column chromatography (ethyl acetate/methanol=100/0→85/15), and the obtained solution was concentrated under reduced pressure. The residue was triturated with ethyl acetate/hexane to give the title compound (133 mg, 67%) as a colorless powder.
Reaction SMILES: [Cl:1][C:2]([Cl:7])([CH2:5][Cl:6])[CH:3]=[O:4].[CH3:8][C:9]1([C:12](=[O:19])[CH2:13][N:14]2[CH:18]=[N:17][CH:16]=[N:15]2)[CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].O>O1CCCC1>[Cl:6][CH2:5][C:2]([Cl:7])([Cl:1])[CH:3]([OH:4])[CH:13]([N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[C:12]([C:9]1([CH3:8])[CH2:10][CH2:11]1)=[O:19]
Reactant: O=CC(Cl)(Cl)CCl
Reactant: CC1(C(=O)Cn2cncn2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C(=O)C(C(O)C(Cl)(Cl)CCl)n2cncn2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 30.1 %

Procedure:
11.3 g of 2,2,3-trichloropropionaldehyde were added dropwise to 9.2 g (0.056 mol) of 1-methyl-1-(1,2,4-triazol-1-yl-acetyl)-cyclopropane in 120 ml of tetrahydrofuran and 13.6 g (0.1 mol) of potassium carbonate, the temperature increasing slightly. The reaction solution was stirred overnight at room temperature and was thereafter introduced into 500 ml of water. The resulting precipitate was filtered off under suction and recrystallized from methanol. 5.5 g (30% of theory) of 1,2,2-trichloro-3-hydroxy-4-(1,2,4-triazol-1-yl)-5-(1-methylcycloprop-1-yl)-pentan-5-one of melting point 182° to 186° C. were obtained.
Reaction SMILES: Br[C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].CCCCCCC.[Li]CCCC.CCCCCC.[C:30](Cl)(=[O:34])[CH:31]([CH3:33])[CH3:32]>C1COCC1>[C:30]([C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5])(=[O:34])[CH:31]([CH3:33])[CH3:32]
Reactant: CC(C)C(=O)Cl
Reactant: Cc1cccc(C(=O)O)c1Br
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCCCCCC
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)O)c1C(=O)C(C)C
Reaction time: 0.5 h
Yield: 58.4 %

Procedure:
The solution of 2-bromo-3-methyl-benzoic acid (1.5 g, 6.98 mmol) in 10 mL THF is treated with 1M Bu2Mg/heptane at −15° C. under argon. After stirring for 30 min, 1.6M n-BuLi/hexane is added dropwise at −15° C. and the mixture is left for 1 hr. Then isobutyryl chloride (2.95 ml, 27.9 mmol) is added dropwise. After another 30 min stirring, the reaction is quenched with 2N HCl aqueous solution (2 ml). After concentration, the residue is purified by HPLC to give a pure product (227) as white solid (840 mg, 58%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[CH:8]=[N:7][CH:6]=[N:5]1)[CH3:3].C([Li])CCC.[C:14](=[O:16])=[O:15]>C1COCC1.CCCCCC>[CH3:1][CH:2]([N:4]1[C:8]([C:14]([OH:16])=[O:15])=[N:7][CH:6]=[N:5]1)[CH3:3]
Reactant: CC(C)n1cncn1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(C)n1ncnc1C(=O)O
Temperature: -78 °C
Reaction time: 1.5 h
Yield: 92.4 %

Procedure:
1-(1-Methylethyl)-1H-1,2,4-triazole (1 g) was dissolved in THF (15 ml) and cooled to −78° C. under nitrogen. A 1.6 M solution of butyllithium in hexane (5.9 ml) was added dropwise. The solution was stirred for 1.5 h at −78° C., then the solution was treated with solid carbon dioxide (2 g). After 30 min at −78° C. the solution was allowed to warm to RT and stirred overnight. The reaction was quenched with water (1 ml), concentrated in vacuo and dried in a vacuum oven for 1 day at 50° C. to give the title compound (1.29 g) as a white solid.