Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[C:17]([CH2:19][N:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[CH:16]=[CH:15][N:14]=2)[CH:6]=[C:7]([O:11][CH3:12])[C:8]=1[O:9][CH3:10].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29](Cl)=[O:30]>>[ClH:26].[Cl:26][C:27]1[CH:35]=[C:34]([Cl:36])[CH:33]=[C:32]([Cl:37])[C:28]=1[C:29]([N:23]1[CH2:24][CH2:25][N:20]([CH2:19][C:17]2[CH:16]=[CH:15][N:14]=[C:13]([C:5]3[CH:6]=[C:7]([O:11][CH3:12])[C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH:18]=2)[CH2:21][CH2:22]1)=[O:30].[ClH:26]
Reactant: COc1cc(-c2cc(CN3CCNCC3)ccn2)cc(OC)c1OC
Reactant: O=C(Cl)c1c(Cl)cc(Cl)cc1Cl
Product: COc1cc(-c2cc(CN3CCN(C(=O)c4c(Cl)cc(Cl)cc4Cl)CC3)ccn2)cc(OC)c1OC
Product: Cl

Procedure:
1-[[2-(3,4,5-Trimethoxyphenyl)pyridin-4-yl]methyl]-piperazine (103 mg) and 2,4,6-trichlorobenzoyl chloride (95 mg) were reacted in the same manner as in Example 46 to obtain the title compound as a hydrochloride.
Reaction SMILES: CS(O[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([Br:13])=[C:9]([C:14]([F:17])([F:16])[F:15])[CH:8]=1)(=O)=O.[C-:18]#[N:19].[K+]>C(O)C.O>[Br:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][C:18]#[N:19])=[CH:8][C:9]=1[C:14]([F:17])([F:16])[F:15]
Reactant: [C-]#N
Reactant: CS(=O)(=O)OCc1ccc(Br)c(C(F)(F)F)c1
Agent: [K+]
Solvent: CCO
Solvent: O
Product: N#CCc1ccc(Br)c(C(F)(F)F)c1
Temperature: 25 °C

Procedure:
To a solution of 4-bromo-3-(trifluoromethyl)benzyl methanesulfonate 46-4 (1.295 g, 3.75 mmol) in ethanol (10 mL) was added a solution of potassium cyanide (364 mg, 5.6 mmol) in water (2 mL). The mixture was refluxed for 2 hours. After the mixture was cooled down to the room temperature, all the solvents were evaporated and the residue was redissolved in dichloromethane (50 mL), washed with water and brine, dried over Na2SO4, and concentrated to dryness to give 2-(4-bromo-3-(trifluoromethyl)phenyl)acetonitrile 46-5 as dark brown oil, which was used for next step directly. MS m/z 264.1 (M+1)
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:10]1[C:15]([OH:16])=[CH:14][CH:13]=[CH:12][C:11]=1[CH3:17].C(N(CC)CC)C>CCOCC>[C:1]([O:16][C:15]1[CH:14]=[CH:13][CH:12]=[C:11]([CH3:17])[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: Cc1cccc(O)c1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: Cc1cccc(OC(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 212 %

Procedure:
A solution of benzoyl chloride (32.5 g, Aldrich) in ether (200 ml) was added dropwise to a stirred solution of m-cresol (25.0 g, Aldrich) and triethylamine (27.2 g, Aldrich) in ether (500 ml). The reaction mixture was stirred at room temperature for 1 hour then filtered. The ethereal filtrate was washed with saturated NaHCO3 and water then dried over Na2SO4. The ether layer was separated, dried and concentrated in vacuo to give the desired product (104.0 g) as a white solid, mp 45-47C. 1H NMR consistent with the desired structure.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[N+:7]([C:10]1[S:14]C(C(O)=O)=[N:12][CH:11]=1)([O-:9])=[O:8].CN(C)C=O>C(Cl)Cl>[N+:7]([C:10]1[S:14][C:1]([C:2]([Cl:4])=[O:3])=[N:12][CH:11]=1)([O-:9])=[O:8]
Reactant: O=C(O)c1ncc([N+](=O)[O-])s1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1ncc([N+](=O)[O-])s1
Reaction time: 0.5 h

Procedure:
Oxalyl chloride (13 ml) was added dropwise to a stirred suspension of 5-nitrothiazole-2-carboxylic acid (12.9 g; Chem. Ber. 1973, 106, 722) in a mixture of methylene chloride (80 ml and dimethylformamide (20 ml). The mixture was stirred at laboratory temperature for 30 minutes and evaporated to dryness to give 5-nitrothiazole-2-carbonyl chloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH2:9])=[CH:5][CH:4]=1.N1C=CC=CC=1.[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24](Cl)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:34])([F:33])[F:32]>CN(C)C1C=CN=CC=1.CCOC(C)=O>[Cl:16][C:17]1[C:22]([Cl:23])=[C:21]([S:24]([NH:9][C:6]2[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)(=[O:26])=[O:25])[CH:20]=[CH:19][C:18]=1[NH:28][C:29](=[O:37])[C@:30]([OH:36])([CH3:35])[C:31]([F:32])([F:33])[F:34]
Reactant: COc1ccc(N)cc1
Reactant: C[C@@](O)(C(=O)Nc1ccc(S(=O)(=O)Cl)c(Cl)c1Cl)C(F)(F)F
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: COc1ccc(NS(=O)(=O)c2ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c2Cl)cc1
Yield: 46 %

Procedure:
To a stirred solution of p-anisidine (74 mg, 0.6 mmol), pyridine (0.14 ml, 1.0 mmol) and 4-dimethylaminopyridine (10 mg) in EtOAc (10 ml) was added a solution of (R)-N-[2,3-dichloro-4-(chlorosulphonyl)phenyl]-3,3,3-trifluoro-2-hydroxy-2-methylpropanamide (200 mg, 0.5 mmol) (Method 1) in EtOAc (10 ml). The resultant mixture was stirred at ambient temperature overnight, washed with 1 M aqueous hydrochloric acid, saturated sodium hydrogen carbonate solution and brine, dried and evaporated. The residue was chromatographed on a Bond Elut column (using 10% EtOAc in DCM as eluent) to give the title compound as a foam (114 mg, 0.23 mmol); NMR: 1.6 (s, 3H), 3.6 (s, 3H), 6.8 (d, 2H), 7.0 (d, 2H), 7.95 (d, 1H), 8.1 (d, 1H); m/z 485.
Reaction SMILES: [O-]CC.[Na+].[CH3:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=1)=[O:7].[C:15](OCC)(=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(O)(=O)C>C(O)C>[Cl:14][C:11]1[CH:12]=[CH:13][C:8]([C:6](=[O:7])[CH2:5][C:15](=[O:21])[C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:9][CH:10]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CC(=O)O
Product: CCOC(=O)C(=O)CC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 100.9 %

Procedure:
To a solution of sodium ethoxide (4.4 g, 64.6 mmol) in absolute ethanol (60 mL) was added 4-chloroacetophenone (5.0 g, 32.3 mmol) and the reaction mixture was stirred for five minutes at room temperature. Diethyl oxalate (7.0 mL, 51.7 mmol) in absolute ethanol (10 mL) was added and the reaction mixture was heated to reflux for 4 hours. After cooling to room temperature, acetic acid (7.0 mL) was added and the resulting light yellow solid was filtered, washed with ethanol and dried in vacuo to obtain ethyl 4-(4-chlorophenyl)-2,4-dioxobutanoate (8.3 g, 32.6 mmol).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([N:8]([CH2:14][C:15]2[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=2)[CH2:9][C:10]([O:12]C)=O)[C:5]([N+:25]([O-])=O)=[C:4]([S:28][CH3:29])[N:3]=1.CO>C(O)(=O)C.C(Cl)Cl.[Fe]>[NH2:1][C:2]1[N:3]=[C:4]([S:28][CH3:29])[C:5]2[NH:25][C:10](=[O:12])[CH2:9][N:8]([CH2:14][C:15]3[C:20]([CH3:21])=[C:19]([O:22][CH3:23])[C:18]([CH3:24])=[CH:17][N:16]=3)[C:6]=2[N:7]=1
Reactant: COC(=O)CN(Cc1ncc(C)c(OC)c1C)c1nc(N)nc(SC)c1[N+](=O)[O-]
Agent: [Fe]
Solvent: CC(=O)O
Solvent: CO
Solvent: ClCCl
Product: COc1c(C)cnc(CN2CC(=O)Nc3c(SC)nc(N)nc32)c1C
Temperature: 70 °C
Yield: 28.7 %

Procedure:
To a solution of methyl 2-[(2-amino-6-methylsulfanyl-5-nitro-pyrimidin-4-yl)-[(4-methoxy-3,5-dimethyl-pyridin-2-yl)methyl]amino]acetate (Intermediate 26)(212 mg) in glacial acetic acid (5 mL) stirred at 70° C. was added iron powder (120 mg). The reaction mixture was heated at 70° C. for 30 minutes then allowed to cool to room temperature. The reaction mixture was filtered, the filtrate evaporated to dryness and azeotroped with toluene to give a brown gum. This material was stirred with 5% methanol in DCM (10 mL) and then filtered to remove iron residues. The filtrate was purified by flash chromatography on silica eluting with an increasingly polar gradient of methanol/DCM (0/100 to 5/95) to give the title compound (52 mg) as a beige solid. 1H NMR spectrum (400 MHz, DMSO-d6) 2.11 (6H, s), 2.37 (3H, s), 3.66 (3H, s), 3.88 (2H, s), 4.68 (2H, s), 5.80 (2H, s), 8.07 (1H, s), 9.34 (1H, s); Mass spectrum: (M+H)+ 361.44.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](C(C)OCC)[CH:11]=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.CN(C)CCN(C)C.C([Li])CCC.CN(C)[CH:41]=[O:42]>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]([CH:41]=[O:42])=[N:10][C:9]=2[C:18]2[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=2)=[CH:6][CH:7]=1
Reactant: CN(C)C=O
Reactant: CCOC(C)n1cnc(-c2ccc(SC)cc2)c1-c1ccc(F)cc1
Agent: CN(C)CCN(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CSc1ccc(-c2nc(C=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: -70 °C
Reaction time: 0.25 h
Yield: 80 %

Procedure:
A solution of the compound from step 2 (500 mg, 1.4 mmol) and tetramethylethylenediamine (TMEDA) (186 mg, 1.6 mmol) in tetrahydrofuran (8 ml) was cooled to -70° C. under an argon atmosphere. n-Butyllithium (1.2 ml of 1.6M solution in hexane, 1.9 mmol) was added and the solution stirred at -70° C. for 15 minutes. Dimethylformamide (DMF) (140 mg, 1.9 mmol) was added and the solution was warmed to 0° C. The reaction was quenched by the addition of saturated NaHCO3 solution (2 ml) and extracted with diethyl ether. The organic phase was separated and dried (Na2SO4). The drying agent was filtered and the filtrate concentrated in vacuo. The residue was treated with 2N HCl (5 ml) in EtOH (10 ml) at room temperature for 24 hours. The reaction solution was made basic with NaHCO3, diluted with water (20 ml) and extracted with methylene chloride. After evaporation, the residue was chromatographed on silica gel, eluting with toluene/methanol (90/10), to give 350 mg (70%) of titled compound which was used immediately without further purification.
Reaction SMILES: FC(F)(F)C(OC1C(F)=C(F)C(F)=C(F)C=1F)=O.[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41](O)=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1.N1C=CC=CC=1.[F:50][C:51]1[CH:57]=[CH:56][CH:55]=[CH:54][C:52]=1[NH2:53].Cl>CN(C)C=O>[Cl:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([NH:34][C:35]3[CH:36]=[N:37][N:38]([CH2:40][C:41]([NH:53][C:52]4[CH:54]=[CH:55][CH:56]=[CH:57][C:51]=4[F:50])=[O:42])[CH:39]=3)=[N:29][CH:30]=[N:31]2)=[CH:26][CH:25]=1
Reactant: Nc1ccccc1F
Reactant: O=C(O)Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1
Agent: Cl
Agent: O=C(Oc1c(F)c(F)c(F)c(F)c1F)C(F)(F)F
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: O=C(Cn1cc(Nc2ncnc3cc(OCCCCl)ccc23)cn1)Nc1ccccc1F
Reaction time: 5 h

Procedure:
Pentafluorophenyl trifluoroacetate (0.325 g, 1.16 mmol) was added dropwise, at room temperature, to a stirred suspension of (4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)acetic acid (0.300 g, 0.83 mmol) and pyridine (0.092 g, 1.16 mmol) in dimethylformamide (3 ml). After stirring for 5 minutes 2-fluoroaniline (0.184 g, 1.66 mmol) was added and the reaction stirred for 5 hours. The mixture was poured into 0.2N aqueous hydrochloric acid (25 ml) to give 2-(4-{[7-(3-chloropropoxy)quinazolin-4-yl]amino}-1H-pyrazol-1-yl)-N-(2-fluorophenyl)acetamide as a cream coloured solid: MS (+ve ESI): 455 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([CH2:10][C:11]([OH:13])=[O:12])[NH2:9])[CH:5]=[CH:6][CH:7]=1.C(N(CC)CC)C.[C:21]1([CH2:27][C:28](Cl)=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O.CC(C)=O>[C:21]1([CH2:27][C:28]([NH:9][CH:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[CH2:10][C:11]([OH:13])=[O:12])=[O:29])[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: NC(CC(=O)O)c1cccc(Cl)c1
Reactant: O=C(Cl)Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)CC(NC(=O)Cc1ccccc1)c1cccc(Cl)c1
Temperature: -5 °C
Reaction time: 2 h

Procedure:
To a solution, in a 3/1 mixture of water/acetone, of 10 mmol of (±)-3-(3-chlorophenyl)-β-alanine described in Step A of Example 1 there are added 24 mmol of triethylamine and then, at −5° C., 13 mmol of phenylacetyl chloride. After stirring for 2 hours at −5° C. and then for 3 hours at ambient temperature, the solution is filtered; the acetone is evaporated off, the aqueous phase is washed with ether and is then acidified to pH=1 and extracted with ethyl acetate. The combined organic phases are dried and then evaporated. The residue obtained is washed with hexane, precipitated in a minimum of ether and then filtered to yield the expected product.
Reaction SMILES: C(OC(=O)[N:7]([CH2:11][C:12]1[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=2[O:16][C:15]2[CH:23]=[CH:24][CH:25]=[CH:26][C:14]=2[CH:13]=1)[CH2:8][C:9]#[CH:10])(C)(C)C.CS(O)(=O)=O.[OH-].[Na+].[Cl:35]CCl>O1CCOCC1>[ClH:35].[CH:26]1[C:14]2[CH:13]=[C:12]([CH2:11][NH:7][CH2:8][C:9]#[CH:10])[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=3[O:16][C:15]=2[CH:23]=[CH:24][CH:25]=1
Reactant: ClCCl
Reactant: C#CCN(CC1=Cc2ccccc2Oc2ccccc21)C(=O)OC(C)(C)C
Agent: CS(=O)(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: C#CCNCC1=Cc2ccccc2Oc2ccccc21
Product: Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 42 %

Procedure:
A mixture of 1.1 g (3.044 mmol) of N-(dibenz[b,f]oxepin-10-ylmethyl-prop-2-ynyl-carbamic acid tert-butyl ester and 1.45 ml of methanesulfonic acid in 1 ml of dioxane and 9 ml of dichloromethane is stirred for 1hour at room temperature, 2N sodium hydroxide solution is added and the mixture is extracted 2× with dichloromethane. The organic phase is concentrated using a rotary evaporator, taken up in ethyl acetate and extracted 3× with 1N hydrochloric acid, and the aqueous phase is rendered basic with potassium hydroxide pellets, extracted 3× with dichloromethane, dried over sodium sulfate and concentrated. The crude light-brown oil is dissolved in 2N ethereal hydrochloric acid and concentrated. The crude hydrochloride (beige crystals) is recrystallised from ethyl acetate/methanol. 386 mg (1.30 mmol)=42% of N-(dibenz[b,f]oxepin-10-ylmethyl)-N-prop-2-ynylamine hydrochloride alias 10-propargylaminomethyldibenz[b,f]oxepine hydrochloride are obtained in the form of white crystals; melting point: 181°-183° C.; MS: 261 (M+, free base), 222, 181, 165, 152.
Reaction SMILES: [N:1]1([CH2:6][CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:16](=[CH:17][CH:18]=2)[C:15](=[O:19])[CH2:14][CH2:13][CH2:12]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=O)[S:24][CH:25]=1>[OH-].[K+].CCO>[Br:20][C:21]1[CH:22]=[C:23]([CH:26]=[C:14]2[CH2:13][CH2:12][C:11]3[C:16](=[CH:17][CH:18]=[C:9]([O:8][CH2:7][CH2:6][N:1]4[CH:5]=[CH:4][N:3]=[CH:2]4)[CH:10]=3)[C:15]2=[O:19])[S:24][CH:25]=1
Reactant: O=Cc1cc(Br)cs1
Reactant: O=C1CCCc2cc(OCCn3ccnc3)ccc21
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=C1C(=Cc2cc(Br)cs2)CCc2cc(OCCn3ccnc3)ccc21
Yield: 43 %

Procedure:
According to the method of Example 4, 6-(2-imidazole-1-yl-ethoxy)-3,4-dihydro-2H-naphthalen-1-one (0.252 g, 0.98 mmol) was reacted with 4-bromothiophene-2-carboxaldehyde (0.282 g, 1.5 mmol) in 5 mL of 4% KOH in EtOH to afford 0.181 g (43%) of the title compound as a light tan powder, mp 164-166° C.: CI-MS m/e 428, 430 (M+); 429, 431 (M++1);
Reaction SMILES: S(Cl)([Cl:3])=O.[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24]O>C1C=CC=CC=1>[Cl:5][C:6]1[N:10]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:9]=[C:8]([C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[C:7]=1[CH2:24][Cl:3]
Reactant: O=S(Cl)Cl
Reactant: OCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Solvent: c1ccccc1
Product: ClCc1c(-c2ccc(Cl)cc2)nn(-c2ccccc2)c1Cl
Reaction time: 0.5 h
Yield: 98.5 %

Procedure:
17.6 g of thionyl chloride are added to a suspension of 45 g of 5-chloro-3-p-chlorophenyl-4-hydroxymethyl-1-phenyl-pyrazole in 45 ml of benzene, there being a considerable evolution of gas and solution occurs. Following this heating is carried out for 30 minutes at boiling point for completion of the reaction. The solvent is distilled off in vacuo and this operation is carried out with the addition of benzene. The residue is caused to crystallise with the help of petroleum ether. 5-Chloro-4-chloromethyl-3-p-chlorophenyl-1-phenyl-pyrazole is obtained with a 98.5% yield; F 96.5°-97°.
Reaction SMILES: [C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3](Cl)[CH3:4].[C:17]([O-:21])(=[O:20])[CH:18]=[CH2:19].[K+]>CN(C)C=O.C1OCCOCCOCCOCCOCCOC1>[C:1](=[O:16])([O:6][CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12](=[O:15])[CH:13]=[CH2:14])[O:2][CH:3]([O:21][C:17](=[O:20])[CH:18]=[CH2:19])[CH3:4]
Reactant: C=CC(=O)[O-]
Reactant: C=CC(=O)OCCCCOC(=O)OC(C)Cl
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CC(=O)OCCCCOC(=O)OC(C)OC(=O)C=C
Yield: 89.4 %

Procedure:
1-Chloroethyl 4-acryloyloxybutyl carbonate (1.253 g, 5.00 mmol) is added to a suspension of freeze dried potassium acrylate (0.606 g, 5.50mmol) and 18-crown-6 (0.066 g, 0.25 mmol) in dimethylformamide (50 ml) under a dry N2 atmosphere. After 5 days at 20° C. the solvent is removed under reduced pressure and the residue dissolved by adding dichloromethane (60 ml) and water (30 ml). After separating the phases the aqueous layer is extracted with dichloromethane (3×30 ml) and the combined organic phase washed with saturated aqueous sodium hydrogen carbonate (50 ml). The organic phase is dried (MgSO4) and the solvent removed under reduced pressure to give 1.28 g (89%) of the title product. 1H NMR (60 MHz, CDCl3): δ1.58 (3H, d, J=5 Hz, CH3 --CH), 1.80 (4H, m, CH2 --CH2), 4.24 (4H, m, 2×CH2 --O), 5.7-6.7 (6H, m, 2×CH=CH2), 6.87 (1H, k, J=5 Hz, CH--CH3).
Reaction SMILES: [Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11](O)[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:24])([F:23])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(Cl)C(=O)C([Cl:55])=C(Cl)C(=O)C=1Cl.O>C(#N)C>[Cl:1][C:2]1[C:7]2[CH:8]=[C:9]([CH:11]([Cl:55])[CH3:12])[O:10][C:6]=2[C:5]([N:14]2[C:19](=[O:20])[CH:18]=[C:17]([C:21]([F:23])([F:24])[F:22])[N:16]([CH3:25])[C:15]2=[O:26])=[C:4]([F:27])[CH:3]=1
Reactant: CC(O)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Reactant: O=C1C(Cl)=C(Cl)C(=O)C(Cl)=C1Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CC#N
Solvent: O
Product: CC(Cl)c1cc2c(Cl)cc(F)c(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c2o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98 %

Procedure:
0.50 g (1.2 mmol) of 3-[4-chloro-2-(1-hydroxyethyl)-6-fluorobenzofuran-7-yl]-1-methyl-6-trifluoromethyluracil and 0.64 g (2.5 mmol) of triphenylphosphine were dissolved in 20 ml of acetonitrile, and 0.60 g (2.5 mmol) of chloranil was added thereto at room temperature. After stirring at room temperature for 2 hours, the reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed sequentially with water and a 5% potassium carbonate aqueous solution and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure. Then, the obtained residue was purified by silica gel column chromatography to obtain 0.50 g (yield: 96.2%) of the desired product as a pale brown glassy substance. Refractive index: 1.5639 (20° C.).
Reaction SMILES: CS[C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)[N:11]=[C:10]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1.[O-][Mn](=O)(=O)=O.[K+].[O-:37][S:38]([O-:40])=O.[Na+].[Na+].[CH3:43]C(C)=O>CC(O)=O.O.C(Cl)(Cl)Cl>[CH3:43][S:38]([C:3]1[N:7]([C:8]2[N:13]=[C:12]([N:14]3[CH2:15][CH2:16][O:17][CH2:18][CH2:19]3)[N:11]=[C:10]([NH:20][C:21]3[CH:22]=[N:23][CH:24]=[CH:25][CH:26]=3)[N:9]=2)[C:6]2[CH:27]=[CH:28][CH:29]=[CH:30][C:5]=2[N:4]=1)(=[O:40])=[O:37]
Reactant: O=S([O-])[O-]
Reactant: CSc1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reactant: CC(C)=O
Agent: O=[Mn](=O)(=O)[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: ClC(Cl)Cl
Solvent: CC(=O)O
Product: CS(=O)(=O)c1nc2ccccc2n1-c1nc(Nc2cccnc2)nc(N2CCOCC2)n1
Reaction time: 0.5 h
Yield: 31 %

Procedure:
A solution of 0.421 g (1 mmol) of 4-[2-(methylsulfanyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine (from Example 4) in 130 mL acetone and 20 mL HOAc was treated with 1 g KMnO4 in 10 mL water at room temperature. After 30 min, the reaction was decolorized with aq. Na2SO3 solution and the acetone was removed under vacuum. The residue was diluted with water and the pH adjusted to neutral to give a precipitate which was dissolved in CHCl3 and dried. Chromatography on alumina, eluting with CHCl3/EtOAc (9:1) gave 140 mg (31%) of 4-[2-(methylsulfonyl)-1H-benzimidazol-1-yl]-6-(4-morpholinyl)-N-(3-pyridinyl)-1,3,5-triazin-2-amine: mp (MeOH) 208-211° C.; 1H NMR (CDCl3) 8.88 (br s, 1H), 8.38 (dd, J=4.7, 1.4 Hz, 1H), 8.26 (d, J=7.9 Hz, 1H), 8.00 (d, J=7.8 Hz, 1H), 7.77 (dd, J=7.3, 1.2 Hz, 1H), 7.46-7.38 (m, 3H; 2H after D2O exchange), 7.31 (dd, J=8.3, 4.7 Hz, 1H), 4.08 (m, 2H), 3.83 (m, 2H), 3.76 (m, 4H), 3.62 (s, 3H); Anal. Calcd. for C20H20N8O3S 0.5H2O: C, 52.0; H, 4.6; N, 24.3. Found: C, 51.8; H, 4.6; N, 24.3%.
Reaction SMILES: [C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25](SC)[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2].C1C=C(Cl)C=C([C:43](OO)=[O:44])C=1.CO.C(N(CC)CC)C>C(Cl)Cl>[C:1]([C:5]1[CH:9]=[C:8]([NH:10][C:11]([NH:13][C:14]2[CH:19]=[C:18]([C:20]3[C:31](=[O:32])[N:30]([CH3:33])[C:23]4[N:24]=[C:25]([O:44][CH3:43])[N:26]=[CH:27][C:22]=4[CH:21]=3)[C:17]([CH3:34])=[CH:16][C:15]=2[F:35])=[O:12])[O:7][N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CO
Product: COc1ncc2cc(-c3cc(NC(=O)Nc4cc(C(C)(C)C)no4)c(F)cc3C)c(=O)n(C)c2n1
Reaction time: 0.5 h
Yield: 59 %

Procedure:
A suspension of 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-4-methyl-5-(8-methyl-2-(methylthio)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)phenyl)urea from Example 96 (15 mg, 0.030 mmol) in CH2Cl2 (1 mL) was treated with mCPBA (70%, 8.94 mg, 0.036 mmol). After 30 min, methanol (0.050 mL 1.2 mmol) and triethylamine (0.020 mL, 0.14 mmol) were added and the resultant mixture was heated to 40° C. overnight. The reaction was concentrated in vacuo and purified by chromatography to provide 1-(3-tert-butylisoxazol-5-yl)-3-(2-fluoro-5-(2-methoxy-8-methyl-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-6-yl)-4-methylphenyl)urea. (8.6 mg, 59% yield). 1H NMR (400 MHz, DMSO-d6): δ 10.32 (s, 1H), 8.93 (s, 1H), 8.72 (s, 1H), 7.93 (d, J=8.3 Hz, 1H), 7.90 (s, 1H), 7.20 (d, J=12.3 Hz, 1H), 6.00 (s, 1H), 4.02 (s, 3H), 3.63 (s, 3H), 2.09 (s, 3H), 1.21 (s, 9H); MS (ESI) m/z: 481.2 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:6][CH:7]=1.[C:12](=[O:14])=[O:13].CCOCC>O1CCCC1.O.C(OCC)C>[F:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[C:4]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:6][CH:7]=1
Reactant: O=C=O
Reactant: Fc1cccc(C(F)(F)F)c1
Solvent: O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=C(O)c1c(F)cccc1C(F)(F)F
Temperature: -78 °C
Reaction time: 5 h

Procedure:
A mixture of 3-fluorobenzotrifluoride (25.0 g, 0.15 mol) in tetrahydrofuran (200 ml) was cooled to -78° C. in a dry ice/acetone bath under nitrogen atmosphere. To this solution was added dropwise with rapid stirring N-butyl lithium (1.6M, 95.2 ml) at such rate that the temperature did not exceed -60° C. When the addition was complete, the mixture was allowed to stir at -78° C. for an additional five hours. The mixture was then poured over a slurry of dry ice/ether and allowed to come to room temperature. The solvent was removed by evaporation under reduced pressure to obtain a white solid residue. This solid was dissolved in a minimum amount of water, the solution was extracted with diethyl ether (2×100 ml) and the aqueous phase was acidified to pH 2 with dilute hydrochloric acid. An oil formed and this was dissolved in diethyl ether; the solution was washed several times with water and dried over magnesium sulfate. The solvent was removed by evaporation under reduced pressure to give a white solid. NMR analysis indicated this product was a mixture of the title compound and an isomer. A yield of 15.6 g (50 percent of theory) was obtained.