Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P([O-])([O-])([O-])=O.[K+].[K+].[K+].[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1)(=[O:12])=[O:11].[C@@H]1(N)CCCC[C@H]1N.[NH:28]1[C:32]2=[N:33][CH:34]=[CH:35][CH:36]=[C:31]2[C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:29]1>CCCCCCCCCCCC.O1CCOCC1.ClCCl>[CH3:9][S:10]([C:13]1[CH:18]=[CH:17][C:16]([N:28]2[C:32]3=[N:33][CH:34]=[CH:35][CH:36]=[C:31]3[C:30]([C:37]([O:39][CH3:40])=[O:38])=[CH:29]2)=[CH:15][CH:14]=1)(=[O:12])=[O:11]
Reactant: CS(=O)(=O)c1ccc(Br)cc1
Reactant: COC(=O)c1c[nH]c2ncccc12
Agent: N[C@@H]1CCCC[C@H]1N
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCCCCCCCCCCC
Solvent: ClCCl
Solvent: C1COCCO1
Product: COC(=O)c1cn(-c2ccc(S(C)(=O)=O)cc2)c2ncccc12
Temperature: 110 °C
Reaction time: 48 h

Procedure:
0.038 g (0.2 mmol) of cuprous iodide, 0.891 g (4.2 mmol) of potassium phosphate, 0.47 g (2 mmol) of 4-bromophenyl methyl sulfone and 0.24 cm3 (2 mmol) of trans-1,2-cyclohexanediamine were added, under an argon atmosphere, to 0.405 g (2.3 mmol) of methyl 1H-pyrrolo[2,3-b]pyridine-3-carboxylate in solution in 0.3 cm3 of dodecane and 6 cm3 of dioxane. After stirring at a temperature in the region of 110° C. for 48 h, the reaction mixture was concentrated to dryness under reduced pressure (2.7 kPa) to give a residue which was taken up in 20 cm3 of dichloromethane. The resulting organic solution was washed with 20 cm3 of 0.1N hydrochloric acid and filtered, then dried over magnesium sulfate and concentrated to dryness under reduced pressure (2.7 kPa). Methyl 1-(4-(methylsulfonyl)phenyl)-1H-pyrrolo[2,3-b]pyridine-3-carboxylate, characterized by LC/MS (m/z 331 [MH]+), was thus obtained, which was used directly in the following stage.
Reaction SMILES: I[C:2]1[N:25]([S:26]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)(=[O:28])=[O:27])[C:5]2=[N:6][CH:7]=[CH:8][C:9]([C:10]3[C:11]([C:16]4[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=4)=[N:12][N:13]([CH3:15])[CH:14]=3)=[C:4]2[CH:3]=1.[CH3:35][N:36]1[CH2:41][CH2:40][N:39]([C:42]2[N:47]=[CH:46][C:45](B3OC(C)(C)C(C)(C)O3)=[CH:44][N:43]=2)[CH2:38][CH2:37]1>>[CH3:15][N:13]1[CH:14]=[C:10]([C:9]2[CH:8]=[CH:7][N:6]=[C:5]3[N:25]([S:26]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)(=[O:27])=[O:28])[C:2]([C:45]4[CH:44]=[N:43][C:42]([N:39]5[CH2:40][CH2:41][N:36]([CH3:35])[CH2:37][CH2:38]5)=[N:47][CH:46]=4)=[CH:3][C:4]=23)[C:11]([C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[N:12]1
Reactant: CN1CCN(c2ncc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Reactant: Cn1cc(-c2ccnc3c2cc(I)n3S(=O)(=O)c2ccccc2)c(-c2ccc([N+](=O)[O-])cc2)n1
Product: CN1CCN(c2ncc(-c3cc4c(-c5cn(C)nc5-c5ccc([N+](=O)[O-])cc5)ccnc4n3S(=O)(=O)c3ccccc3)cn2)CC1

Procedure:
Following the procedure described for Intermediate 241 using 2-iodo-4-[1-methyl-3-(4-nitrophenyl)-1H-pyrazol-4-yl]-1-(phenylsulfonyl)-1H-pyrrolo[2,3-b]pyridine and 2-(4-methyl-1-piperazinyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyrimidine provided the title compound. ESMS [M+H]+: 636.0.
Reaction SMILES: CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.[C:23]([O:27][C:28]([N:30]1[C@H:37]([CH2:38][OH:39])[CH2:36][C@H:35]2[C@@H:31]1[CH2:32][CH2:33][CH2:34]2)=[O:29])([CH3:26])([CH3:25])[CH3:24].O.[OH-].[Na+]>C(Cl)Cl.CCOCC>[C:23]([O:27][C:28]([N:30]1[C@H:37]([CH:38]=[O:39])[CH2:36][C@H:35]2[C@@H:31]1[CH2:32][CH2:33][CH2:34]2)=[O:29])([CH3:26])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N1[C@H](CO)C[C@@H]2CCC[C@@H]21
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@H](C=O)C[C@@H]2CCC[C@@H]21

Procedure:
A solution of Dess-Martin periodinane (4.14 mmol, 2.2 eq) in DCM (10 ml) is treated with a solution of (1S,3S,5S)-3-hydroxymethyl-2-azabicyclo[3.3.0]octane-2-carboxylic acid tert-butyl ester (1.85 mmol, 1.0 eq) in DCM (4 mL) and some drops of water. After 5 h ether and aqueous NaOH solution (1.0 M) are added and the layers are separated. The organic layer is washed with aqueous citric acid (10%) and brine, dried over MgSO4 and concentrated in vacuo to give the desired aldehyde which is used without further purification.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.[CH3:18][O:19][CH:20]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][O:33][CH:34]1CCCC[O:35]1)C(OCC)=O.O>CO>[CH3:18][O:19][CH:20]1[C:26]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:32][O:33][C:34]1=[O:35]
Reactant: CCOC(=O)C(OC)c1ccccc1COC1CCCCO1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Solvent: O
Product: COC1C(=O)OCc2ccccc21
Temperature: 25 °C
Yield: 74.2 %

Procedure:
Pyridinium p-toluenesulfonate (0.30 g) was added to a solution of ethyl α-methoxy-2-(tetrahydropyran-2-yloxy-methyl)phenylacetate (14.00 g, 45.4 mmol) in methanol (50 ml), and the mixture was heated under reflux for 1 hour. The mixture was cooled to room temperature, and water (50 ml) was added. The mixture was extracted with methylene chloride and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was purified by recrystallization from n-hexane/ethyl acetate (=1/1) to give the desired compound 4-methoxy-3-isochromanone (6.00 g, 74.2%) as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:20]1[CH2:24][N:23]([C:25]([CH2:27][N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[O:26])[CH2:22][CH2:21]1>>[Cl:1][C:2]1[CH:19]=[CH:18][C:5]2[O:6][C:7]3[CH:17]=[CH:16][CH:15]=[CH:14][C:8]=3[CH2:9][N:10]([C:11]([N:31]3[CH2:30][CH2:29][N:28]([CH2:27][C:25]([N:23]4[CH2:22][CH2:21][CH2:20][CH2:24]4)=[O:26])[CH2:33][CH2:32]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: O=C(Cl)N1Cc2ccccc2Oc2ccc(Cl)cc21
Reactant: O=C(CN1CCNCC1)N1CCCC1
Product: O=C(CN1CCN(C(=O)N2Cc3ccccc3Oc3ccc(Cl)cc32)CC1)N1CCCC1
Yield: 93.1 %

Procedure:
The title compound of Example 2 (0.75 g, 2.55 mmol) was reacted with 1-(1-piperazinylacetyl) pyrrolidine (0.50 g, 2.55 mmol) by the method of Example 4. Following chromatographic separation, 1.08 g of clear oil title product was obtained.
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1)(=O)C.C1(C)C=CC(S(O)(=O)=O)=CC=1.[OH-].[Na+]>CO.O.C(O)C>[CH3:1][O:4][CH2:5][C:6]1[C:7]([CH2:15][CH2:16][C:17]([OH:19])=[O:18])=[CH:8][C:9]2[O:13][CH2:12][O:11][C:10]=2[CH:14]=1
Reactant: CC(=O)OCc1cc2c(cc1CCC(=O)O)OCO2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Solvent: CO
Product: COCc1cc2c(cc1CCC(=O)O)OCO2
Yield: 87.3 %

Procedure:
1.6 g of 3-(6-acetoxymethyl-1,3-benzodioxole-5-yl)propionic acid was dissolved in 100 ml of methanol. A catalytic amount of p-toluenesulfonic acid was added to the solution and the mixture was heated under reflux for 4 h and 15 min. The solvent was distillef off from the reaction mixture. A solution of 1 g of sodium hydroxide in a mixture of 5 ml of water and 45 ml of ethanol was added to the residue and the mixture was heated under reflux for 20 min. The reaction mixture was concentrated. 200 ml of ethyl acetate and 200 ml of water were added to the concentrate. The mixture was acidified with concentrated hydrochloric acid. The layers thus formed were separated. The product was washed with water three times and then dried over anhydrous sodium sulfate. The solvent was distilled off to obtain 1.25 g of the intended compound in the form of a white powder.
Reaction SMILES: [N+:1](F)([O-:3])=[O:2].S1(CCCC1)(=O)=O.B(F)(F)F.[CH3:16][N:17]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:20][CH:19]([F:35])[C:18]1=[O:36]>>[CH3:16][N:17]1[C:23]2[CH:24]=[CH:25][C:26]([N+:1]([O-:3])=[O:2])=[CH:27][C:22]=2[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Cl:34])=[N:20][CH:19]([F:35])[C:18]1=[O:36]
Reactant: O=[N+]([O-])F
Reactant: CN1C(=O)C(F)N=C(c2ccccc2Cl)c2ccccc21
Agent: FB(F)F
Solvent: O=S1(=O)CCCC1
Product: CN1C(=O)C(F)N=C(c2ccccc2Cl)c2cc([N+](=O)[O-])ccc21
Reaction time: 1 h

Procedure:
A solution of 0.8 g. of NO2F in 13 ml. of sulfolane is saturated with BF3 at 5°-10°. This solution is added dropwise to a stirred solution of 3.03 g. of 1-methyl-3-fluoro-5-o-chlorophenyl-2,3-dihydro-1H-1,4-benzodiazepin-2-one, obtainable from the corresponding 3-chloro compound and AgF, in 15 ml. of sulfolane at 10°-15°. The mixture is stirred for 1 hour more at 15°-25° and worked up in the customary manner to give 1-methyl-3-fluoro-5-o-chlorophenyl-7-nitro-2,3-dihydro-1H-1,4-benzodiazepin-2-one.
Reaction SMILES: [C:1](Cl)(=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16].[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([OH:39])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1.C(N(CC)CC)C>ClCCl>[Cl:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[C:26]1([CH:29]2[C:38]3[C:33](=[CH:34][C:35]([O:40][CH3:41])=[C:36]([O:39][C:1](=[O:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[CH:37]=3)[CH2:32][CH2:31][N:30]2[CH3:42])[CH2:28][CH2:27]1
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Reactant: COc1cc2c(cc1O)C(C1(c3ccccc3Cl)CC1)N(C)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCCCCCCCCCCCCC(=O)Oc1cc2c(cc1OC)CCN(C)C2C1(c2ccccc2Cl)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Hexadecanoyl chloride (0.83 g) in dichloromethane (5 ml) was added dropwise to a stirring solution of 1-[1-(2-chlorophenyl)cyclopropyl]-7-hydroxy-6-methoxy-2-methyl-1,2,3,4-tetrahydroisoquinoline (1.04 g, prepared from the (+)-enantiomer of the hydrobromide salt, prepared in a similar manner to that described in Example 77), triethylamine (0.91 g) and dichloromethane (20 ml). The mixture was stirred at ambient temperature for 2 hours, then washed with dilute sodium hydroxide solution, water and brine. The organic phase was dried over magnesium sulphate, filtered and concentrated in vacuo. The resulting oil was dissolved in petroleum ether (b.p. 60°-80° C.) and washed repeatedly with water. The organic layer was dried over magnesium sulphate, filtered and concentrated in vacuo to yield (+)-1-[1-(2-chlorophenyl)cyclopropyl]-7-hexadecanoyloxy-6-methoxy-2-methyl-1,2,3,4-tetrahydro-isoquinoline (1.45 g) which had a specific optical rotation αD of +21.18°.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=2)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=1.O.Cl.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:21]=1>C(=O)([O-])[O-].[K+].[K+]>[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([S:26]([NH:1][C:2]2[CH:3]=[C:4]([C:8]3[NH:9][C:10](=[O:17])[C:11](=[CH:15][CH:16]=3)[C:12]([OH:14])=[O:13])[CH:5]=[CH:6][CH:7]=2)(=[O:28])=[O:27])[CH:21]=1
Reactant: Nc1cccc(-c2ccc(C(=O)O)c(=O)[nH]2)c1
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=C(O)c1ccc(-c2cccc(NS(=O)(=O)c3cccnc3)c2)[nH]c1=O
Temperature: 25 °C
Yield: 81.9 %

Procedure:
A suspension of 11.5 g (50 mmol) of 6-(3-aminophenyl)-1,2-dihydro-2-oxonicotinic acid and 300 ml of water is stirred at room temperature and 21 g (0.15 mol) of potassium carbonate is added. The solution is cooled to 25° and 13.0 g (61 mmol) of 3-pyridinesulfonyl chloride hydrochloride is slowly added. The solution is clarified by filtration and the pH of the filtrate adjusted to 5.3 with hydrochloric acid. The precipitated solid is filtered, washed with water and dissolved in 300 ml of water containing 10 g (72 mmol) of potassium carbonate. The solution is stirred at room temperature and 10 g (47 mmol) of 3-pyridinesulfonyl chloride hydrochloride is gradually added along with portions of potassium carbonate to maintain a pH of 8. Altogether 10 g (72 mmol) of potassium carbonate is added. The reaction is stirred for 30 min at room temperature and filtered. The pH of the filtrate is adjusted to 6 with hydrochloric acid and the solids filtered and washed with water. A second crop is obtained by lowering the pH of the filtrate to 4.0 and the solid is filtered. The two crops are combined with 200 ml of 1 N sodium hydroxide and heated on the steam bath for 1 hour and filtered. The filtrate is acidified to pH 5.7 with 1 N hydrochloric acid and the solid is filtered, washed with water, methanol, and ether and dried under high vacuum to give 15.2 g of 6-[3-(3-pyridinylsulfonylamino)phenyl]-1,2-dihydro-2-oxonicotinic acid; mp 305° dec.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[C:5]#[N:6].Br.Br[CH:14]([C:16]1[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]2[C:25]=1[O:24][C:23]([N:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1)=[CH:22][C:21]2=[O:32])[CH3:15]>>[C:5]([C:4]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:2]([NH:1][CH:14]([C:16]2[CH:17]=[C:18]([C:33]([N:35]([CH3:37])[CH3:36])=[O:34])[CH:19]=[C:20]3[C:25]=2[O:24][C:23]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[CH:22][C:21]3=[O:32])[CH3:15])[CH:3]=1)#[N:6]
Reactant: COc1ccc(C#N)cc1N
Reactant: CC(Br)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Agent: Br
Product: COc1ccc(C#N)cc1NC(C)c1cc(C(=O)N(C)C)cc2c(=O)cc(N3CCOCC3)oc12
Yield: 52.5 %

Procedure:
3-amino-4-methoxybenzonitrile (121 mg, 0.82 mmol) was reacted with 8-(1-bromoethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide hydrobromide (100 mg, 0.20 mmol) using an analogous procedure to the one described in Example 3.03 to give 8-(1-(5-cyano-2-methoxyphenylamino)ethyl)-N,N-dimethyl-2-morpholino-4-oxo-4H-chromene-6-carboxamide (50 mg, 51%) as a white solid. Mass Spectrum: M+H+ 477. NMR Spectrum (DMSOd6): 1.60 (d, 3H), 2.72 (bs, 3H), 2.94 (bs, 3H), 3.51-3.65 (m, 4H), 3.71-3.80 (m, 4H), 3.92 (s, 3H), 5.05-5.13 (m, 1H), 5.61 (s, 1H), 5.86 (d, 1H), 6.57 (d, 1H), 6.98 (d, 1H), 7.03 (dd, 1H), 7.57 (d, 1H), 7.79 (d, 1H).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH:12]1([NH2:15])[CH2:14][CH2:13]1>>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([NH:15][CH:12]2[CH2:14][CH2:13]2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: NC1CC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Cl
Product: O=[N+]([O-])c1cc(Cl)ccc1NC1CC1
Yield: 59 %

Procedure:
A mixture of 2,5-dichloronitrobenzene (2.00 g (10.4 mmol)) and cyclopropylamine (2.0 ml) was heated under reflux for 60 hours, and the excess cyclopropylamine was removed by concentration under reduced pressure. The residue was dissolved in ethyl acetate and the resulting solution was washed with aqueous 1% sodium hydroxide, saturated sodium chloride solution. The organic layer was dried over anhydrous magnesium sulfate and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography with ethyl acetate-hexane (1:10) as eluent to give 1.30 g (59%) of 4-chloro-N-cyclopropyl-2-nitroaniline as orange crystals.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9](O)=[O:10])=[C:7]([CH3:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:22])([F:21])[F:20])[CH:14]=2)[N:5]=1.[N:23]1([CH:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)[CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH3:1][O:2][CH2:3][C:4]1[C:8]([C:9]([N:31]2[CH2:32][CH2:33][CH:28]([N:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH2:29][CH2:30]2)=[O:10])=[C:7]([CH3:12])[N:6]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([C:19]([F:21])([F:20])[F:22])[CH:14]=2)[N:5]=1
Reactant: C1CCN(C2CCNCC2)C1
Reactant: COCc1nn(-c2cccc(C(F)(F)F)c2)c(C)c1C(=O)O
Product: COCc1nn(-c2cccc(C(F)(F)F)c2)c(C)c1C(=O)N1CCC(N2CCCC2)CC1
Yield: 94 %

Procedure:
In analogy to the procedure described in Example 18], 3-methoxymethyl-5-methyl-1-(3-trifluoromethyl-phenyl)-1H-pyrazole-4-carboxylic acid and 4-pyrrolidine-1-yl-piperidine gave the title compound in 94% yield as light yellow viscous oil. MS: 451.2 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([NH2:7])=O.[BH4-].[Na+].B(F)(F)F.CCOCC>O1CCCC1.C(OCC)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[CH2:5][NH2:7]
Reactant: COc1ccc(C(N)=O)cc1F
Agent: FB(F)F
Agent: [BH4-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccc(CN)cc1F
Temperature: 25 °C
Yield: 60 %

Procedure:
To a solution of 3-fluoro-4-(methyloxy)benzamide (100 mg, 0.60 mmol) in tetrahydrofuran (5 mL) was added sodium borohydride (115 mg, 3.0 mmol) followed by the drop-wise addition of a solution of borontrifluoride etherate (48% BF3 ca., 475 μl, 3.8 mmol) in tetrahydrofuran (3 mL). The mixture was stirred at reflux for 15 hours, then was cooled to room temperature and diluted with ethyl acetate. The organic portion was extracted with 20% aqueous citric acid. The aqueous portion was brought to pH 8 using solid sodium bicarbonate, then was extracted several times using ethyl acetate. The combined organic portion was washed with brine then dried over anhydrous sodium sulfate. Filtration and concentration afforded a yellow residue, which was purified by silica gel column chromatography using 10% methanol in dichloromethane as eluent. Purified fractions were pooled and concentrated to afford 56 mg, 0.36 mmol (61%) of 3-fluoro-4-methoxybenzylamine as a colorless residue. MS (EI) for C8H10FNO: 156 (MH+).
Reaction SMILES: [CH3:1][N:2]([CH3:27])[C:3]([CH2:5][O:6][N:7]([CH2:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=1)[C:8](=[O:18])[CH:9]=[C:10]1[C:14](=[O:15])[O:13]C(C)(C)[O:11]1)=[O:4].[OH-].[Li+].Cl>O1CCCC1>[CH3:27][N:2]([CH3:1])[C:3]([CH2:5][O:6][N:7]([CH2:19][C:20]1[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=1)[C:8]([CH:9]=[C:10]([OH:11])[C:14]([OH:15])=[O:13])=[O:18])=[O:4]
Reactant: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CN(C)C(=O)CON(Cc1ccc(F)cc1)C(=O)C=C(O)C(=O)O
Reaction time: 1 h
Yield: 74 %

Procedure:
A solution of N-dimethylcarbamoylmethoxy-2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-(4-fluorobenzyl)-acetamide (0.065 g, 0.17 mmol in tetrahydrofuran (3 ml) was treated at 0° C. with 0.34 ml (0.34 mmol) of 1 M aqueous lithium hydroxide. After 1 h, the reaction mixture was acidified with 1N hydrochloric acid and extracted with ethyl acetate. The organic phase was washed with brine, dried (magnesium sulphate) and evaporated in vacuo. Crystallisation of the residual solid from a mixture of ethyl acetate and hexane gave 0.043 g (74% yield) of the title material as a white solid: mp 118-120° C. 1HNMR 400 MHz (DMSO-d6) δ (ppm); (mixture of enol and keto forms, 7:3); enol form: 2.83 (3H, s, NCH3), 2.88 (3H, s, NCH3), 4.79 (2H, s, CH2), 4.94 (2H, s, CH2), 6.47 (1H, s, CH), 7.18 (2H, m, aromatics), 7.38 (2H, m, aromatics), 13.2 (1H, broad, OH), 13.7 (1H, broad, OH). HRMS (ES+) calculated for C15H18FN2O6[M+H]+: 341.114890. Found: 341.115095.
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Cl)(Cl)(Cl)=O.[CH3:27][C:28]1[NH:32][N:31]=[C:30]([NH2:33])[CH:29]=1.CCN(C(C)C)C(C)C>CN(C=O)C.CC(O)=O>[F:1][C:2]([F:21])([C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1)[C:3]1[N:12]=[C:11]([NH:33][C:30]2[CH:29]=[C:28]([CH3:27])[NH:32][N:31]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Cc1cc(N)n[nH]1
Reactant: Oc1nc(C(F)(F)c2ncc(F)cn2)nc2ccccc12
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1cc(Nc2nc(C(F)(F)c3ncc(F)cn3)nc3ccccc23)n[nH]1
Temperature: 95 °C
Reaction time: 8 h
Yield: 33.1 %

Procedure:
To 2-(difluoro(5-fluoropyrimidin-2-yl)methyl)quinazolin-4-ol (190 mg, 0.65 mmol) was added phosphorous oxychloride (4 mL) and the mixture was heated at 95° C. for 2 h. The mixture was concentrated under reduced pressure, toluene was added, and the solution was again concentrated under reduced pressure. The residue was diluted with EtOAc and washed with saturated aq NaHCO3. The organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (72 mg, 0.74 mmol), DIEA (0.14 mL, 0.78 mmol), and KI (40 mg, 0.24 mmol) in DMF (4 mL) and the mixture was stirred at rt overnight. AcOH (0.2 mL) was added and the mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluted with gradient of solvent B=0.05% AcOH/ACN and solvent A=0.05% AcOH/H2O) to afford 2-(difluoro(5-fluoropyrimidin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)quinazolin-4-amine (80 mg, 32%). 1H NMR (300 MHz, DMSO-d6) δ 12.19 (br s, 1H), 10.72 (s, 1H), 9.13 (s, 2H), 8.70 (d, J=8.1 Hz, 1H), 7.78-8.01 (m, 2H), 7.66 (t, J=7.3 Hz, 1H), 5.94 (s, 1H), 2.18 (s, 3H); LC-MS (ESI) m/z 372 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10][CH2:11][CH2:12][N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[N:7][C:6]=2[CH:19]=1.OO.C(=O)([O-])[OH:23].[Na+]>C(O)(=O)C.O.[O-][W]([O-])(=O)=O.[Na+].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([S:10]([CH2:11][CH2:12][N:13]3[CH2:14][CH2:15][O:16][CH2:17][CH2:18]3)=[O:23])=[N:7][C:6]=2[CH:19]=1
Reactant: O=C([O-])O
Reactant: Clc1ccc2sc(SCCN3CCOCC3)nc2c1
Agent: O=[W](=O)([O-])[O-]
Agent: OO
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: O=S(CCN1CCOCC1)c1nc2cc(Cl)ccc2s1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Dissolved in 4 ml of acetic acid were 0.80 g (2.5 mmol) of the compound obtained in Example 31, and 0.37 ml (3.3 mmol) of a 30% aqueous solution of hydrogen peroxide and a catalytic quantity of sodium tungstate were successively added to the solution, which was stirred at room temperature for 1 hour. The solution was poured in 80 ml of water, neutralized with sodium hydrogencarbonate and extracted with 80 ml of chloroform. After separation of the chloroform layer, the organic layer was dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residues were purified by silica gel chromatography to obtain 0.52 g of the title compound in the form of white crystalline powders (62% yield).
Reaction SMILES: [C:1]([C:3]1[CH:49]=[CH:48][C:6]2[N:7](COCC[Si](C)(C)C)[C:8]([CH:10]([C:18]3[C:26]([CH2:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]4[C:19]=3[CH:20]=[CH:21][N:22]4[S:30]([C:33]3[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=3)(=[O:32])=[O:31])[NH:11]S(C(C)(C)C)=O)=[N:9][C:5]=2[CH:4]=1)#[N:2].C(C1C=CC2N=C(C(C3C(CC)=CC(C)=C4C=3C=CN4S(C3C=CC(C)=CC=3)(=O)=O)NS(C(C)(C)C)=O)N(COCC[Si](C)(C)C)C=2C=1)#N.C([O-])(O)=O.[Na+]>Cl.CO>[NH2:11][CH:10]([C:18]1[C:26]([CH2:27][CH3:28])=[CH:25][C:24]([CH3:29])=[C:23]2[C:19]=1[CH:20]=[CH:21][N:22]2[S:30]([C:33]1[CH:39]=[CH:38][C:36]([CH3:37])=[CH:35][CH:34]=1)(=[O:32])=[O:31])[C:8]1[NH:7][C:6]2[CH:48]=[CH:49][C:3]([C:1]#[N:2])=[CH:4][C:5]=2[N:9]=1
Reactant: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NS(=O)C(C)(C)C)c1nc2cc(C#N)ccc2n1COCC[Si](C)(C)C
Agent: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(NS(=O)C(C)(C)C)c1nc2ccc(C#N)cc2n1COCC[Si](C)(C)C
Agent: Cl
Agent: O=C([O-])O
Solvent: CO
Product: CCc1cc(C)c2c(ccn2S(=O)(=O)c2ccc(C)cc2)c1C(N)c1nc2cc(C#N)ccc2[nH]1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of a mixture of (±)-N-((5-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide and (±)-N-((6-cyano-1-((2-(trimethylsilyl)ethoxy)methyl)-1H-benzo[d]imidazol-2-yl)(5-ethyl-7-methyl-1-tosyl-1H-indol-4-yl)methyl)-2-methylpropane-2-sulfinamide (574 mg, 0.8 mmol) in 1M HCl in MeOH (10 mL) was stirred at room temperature for 1.5 h, and then at 60° C. for 18 h. The reaction mixture was basified by 5% aq. NaHCO3. The layers were separated and the aqueous layer was extracted with CH2Cl2. The organic phase was successively washed with H2O and brine, dried over Na2SO4, and filtered. After concentration the residue was purified by silica gel flash column chromatography (heptanes/EtOAc=1/1 to 0/1) to give the title compound. MS (ESI+) m/z 484.2 (M+H).