Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([CH:23]=O)=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:28]OS(O)(=O)=O>C(#N)C.O>[C:1]([O:5][C:6]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([C:18]3[S:19][C:20]([C:23]#[N:28])=[CH:21][CH:22]=3)=[CH:15][CH:16]=2)[C:11]([CH3:25])=[CH:10][C:9]1([CH3:27])[CH3:26])=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C=O)s3)cc21
Reactant: NOS(=O)(=O)O
Solvent: O
Solvent: CC#N
Product: CC1=CC(C)(C)N(C(=O)OC(C)(C)C)c2ccc(-c3ccc(C#N)s3)cc21
Temperature: 65 °C
Yield: 43.8 %

Procedure:
To a solution of 1-tert-butyloxycarbonyl-6-(5-formyl-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline (12 mg, 0.03 mmol) in acetonitrile/water (10 ml/0.5 ml) was added hydroxylamine-O-sulphonic acid (5 mg, 0.04 mmol). The reaction mixture was heated to 65° C. for 1 h. The reaction was quenched with 10% NaOH (5 mL) and extracted with EtOAc (10 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4), and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 5 mg (40%) of 1-tert-butyloxycarbonyl-6-(5-cyano-2-thienyl)-1,2-dihydro-2,2,4-trimethylquinoline as a yellow oil. This product was dissolved in CH2Cl2 (5 mL) and treated with TFA (0.1 ml) at rt with stirring. After 2 h, the reaction was quenched with 10% NaOH (5 mL). The organic layer was washed with water and brine (3×5 mL each), dried (Na2SO4) and concentrated in vacuo to afford the crude product as a yellow oil. The crude product was purified by prep. TLC (20×20 cm, 250 μm, 25% EtOAc:hexane) to afford 2 mg (60%) of Compound 451 as a yellow oil. Data for Compound 451: Rf 0.3 (silica gel, 25% EtOAc:Hex); 1H NMR(400 MHz, CDCl3) 7.52 (d, J=4.0, 1H), 7.23 (s, 1H), 7.22 (d, J=7.4, 1H), 7.07 (d, J=4.0, 1H), 6.43 (d, J=7.4, 1H), 5.38 (s, 1H), 2.02 (s, 3H), 1.31 (s, 6H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]([CH2:7][CH:8]([C:11]#[N:12])[C:9]#[N:10])=[CH:5][CH:4]=1.[H-].[Na+].FC(F)(F)S(O[CH2:25][C:26]([F:35])([F:34])[C:27]([F:33])([F:32])[C:28]([F:31])([F:30])[F:29])(=O)=O>CN(C)C=O>[F:34][C:26]([F:35])([C:27]([F:32])([F:33])[C:28]([F:29])([F:31])[F:30])[CH2:25][C:8]([CH2:7][C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:15])([F:16])[F:1])=[CH:14][CH:13]=1)([C:11]#[N:12])[C:9]#[N:10]
Reactant: O=S(=O)(OCC(F)(F)C(F)(F)C(F)(F)F)C(F)(F)F
Reactant: N#CC(C#N)Cc1ccc(C(F)(F)F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(Cc1ccc(C(F)(F)F)cc1)CC(F)(F)C(F)(F)C(F)(F)F
Yield: 8.1 %

Procedure:
Using 0.50 g of (4-(trifluoromethyl)benzyl)malononitrile, 5 ml of N,N-dimethylformamide, 59 mg of sodium hydride (60% in oil), and 0.77 g of 2,2,3,3,4,4,4-heptafluorobutyl trifluoromethanesulfonate, and according to the process described in the Production Example 1, there was obtained 73 mg of 2-(2,2,3,3,4,4,4-heptafluorobutyl)-2-(4-(trifluoromethyl)benzyl)malononitrile (the present compound (77)).
Reaction SMILES: [CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([OH:21])=O)[CH2:3][CH2:2]1.[NH2:22][C:23]([NH2:25])=[NH:24]>>[CH:1]1([C:4]2[N:8]([C:9]3[CH:18]=[CH:17][CH:16]=[C:15]4[C:10]=3[CH:11]=[CH:12][CH:13]=[N:14]4)[N:7]=[CH:6][C:5]=2[C:19]([NH:24][C:23]([NH2:25])=[NH:22])=[O:21])[CH2:3][CH2:2]1
Reactant: O=C(O)c1cnn(-c2cccc3ncccc23)c1C1CC1
Reactant: N=C(N)N
Product: N=C(N)NC(=O)c1cnn(-c2cccc3ncccc23)c1C1CC1

Procedure:
coupling said 5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carboxylic acid with guanidine to form N-(5-cyclopropyl-1-quinolin-5-yl-1H-pyrazole-4-carbonyl)-guanidine.
Reaction SMILES: C[O:2][C:3]1[CH:4]=[CH:5][C:6]([C:15]2[C:28]3[C:29]4=[C:30]5[C:25](=[CH:26][CH:27]=3)[CH:24]=[CH:23][CH:22]=[C:21]5[CH:20]=[CH:19][C:18]4=[CH:17][CH:16]=2)=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.B(Br)(Br)Br>ClCCl>[C:15]1([C:6]2[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[CH:8][C:3]([OH:2])=[CH:4][CH:5]=2)[C:28]2[C:29]3=[C:30]4[C:25](=[CH:26][CH:27]=2)[CH:24]=[CH:23][CH:22]=[C:21]4[CH:20]=[CH:19][C:18]3=[CH:17][CH:16]=1
Reactant: COc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)c(-c2ccccc2)c1
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Oc1ccc(-c2ccc3ccc4cccc5ccc2c3c45)c(-c2ccccc2)c1
Temperature: -78 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
In a 1000 ml three-necked flask that had been degassed and filled with nitrogen, 12.4 g (32.2 mmol) of 1-(5-methoxybiphenyl-2-yl)pyrene was dissolved in anhydrous dichloromethane (200 ml), the solution was cooled to −78° C., and 24.2 g (96.6 mmol) boron tribromide was added slowly. The solution was warmed to room temperature and stirred overnight. 200 g Ice was carefully added to quench unreacted boron tribromide. The organic layer was extracted with dichloromethane and water, dried with anhydrous magnesium sulfate, the solvent was removed to give product 10.8 g (91%).
Reaction SMILES: [CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH2:13])=[CH:8][CH:7]=1)[CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24].O>CN(C=O)C>[CH3:1][CH:2]([S:5][C:6]1[CH:15]=[CH:14][C:9]([O:10][CH2:11][CH2:12][NH:13][C:23](=[O:24])[O:25][CH2:26][CH3:27])=[CH:8][CH:7]=1)[CH2:3][CH3:4]
Reactant: CCC(C)Sc1ccc(OCCN)cc1
Reactant: CCOC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)NCCOc1ccc(SC(C)CC)cc1
Reaction time: 1.5 h

Procedure:
To a solution of the above amine (2.41 g, 10.0 mmol) in 10 ml DMF, cooled to 0° and under N2, is added potassium carbonate (1.66 g, 12.0 mmol) followed by dropwise addition of ethyl chloroformate (1.2 ml, 12.0 mmol) in 5 ml of DMF. After 1.5 hours, water is added and the aqueous phase is extracted with ether. The combined organic layers are washed with water and brine, dried, rotoevaporated and the residue is purified by column chromatography to give ethyl N-{2-[4-(1methylpropylthio)phenoxy]ethyl}carbamate (compound 40, Table A).
Reaction SMILES: Cl[C:2]1[C:7]2[CH2:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1.[N:17]1C=CC=C[CH:18]=1>C(Cl)Cl>[CH:5]1[C:6]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][CH2:8][C:7]=2[C:2]([C:18]#[N:17])=[CH:3][CH:4]=1
Reactant: Clc1cccc2c1CCCc1ccccc1-2
Reactant: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cccc2c1CCCc1ccccc1-2

Procedure:
Under a dry nitrogen atmosphere a mixture of 4-chloro-6,7-dihydro-5H-dibenzo[a,c]cycloheptene (1.6 grams, 0.007 mole), cuprous cyanide (0.95 gram, 0.011 mole), and pyridine (0.8 gram, 0.01 mole) was stirred and heated at 195° for approximately 16 hours. The mixture was cooled, dissolved in methylene chloride (150 ml), and the resultant solution was washed with three 70 ml portions of concentrated ammonium hydroxide. The organic phase was dried over anhydrous magnesium sulfate and filtered. The filtrate was evaporated under reduced pressure to give a brown solid. Recrystallization from n-hexane gave 6,7-dihydro-5H-dibenzo[a,c]cycloheptene-4-carbonitrile (mp 109°-111°).
Reaction SMILES: [CH3:1][C:2]([O:16][C:17](=[O:28])[CH2:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([CH3:15])[C:3]([C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1)=O.C1CCN2C(=NCCC2)CC1.ClCCl>C(#N)C>[F:27][C:21]1[CH:22]=[C:23]([F:26])[CH:24]=[CH:25][C:20]=1[O:19][C:18]1[C:17](=[O:28])[O:16][C:2]([CH3:15])([CH3:1])[C:3]=1[C:5]1[CH:10]=[CH:9][C:8]([S:11]([CH3:14])(=[O:13])=[O:12])=[CH:7][CH:6]=1
Reactant: CC(C)(OC(=O)COc1ccc(F)cc1F)C(=O)c1ccc(S(C)(=O)=O)cc1
Solvent: ClCCl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: CC1(C)OC(=O)C(Oc2ccc(F)cc2F)=C1c1ccc(S(C)(=O)=O)cc1
Temperature: 50 °C
Yield: 27.1 %

Procedure:
To a solution of 2-(2,4-difluorophenoxy)acetic acid 2-methyl-1-(4-(methylsulfonyl)phenyl)propan-1-one-2-yl ester (Step 2) (470 mg, 1.14 mmol) in acetonitrile (7 mL) was added DBU (187 μL, 1.25 mmol) and the resulting solution was heated at 50° C. for 20 minutes. After cooling to r.t. dichloromethane was added and the mixture was washed with 1 N HCl, brine, filtered over cotton and the solvent evaporated under vacuum. Purification by silica gel chromatography followed by a swish in EtOAc/Et2O afforded 122 mg of the title compound.
Reaction SMILES: [CH:1]1([C:4]2[N:31]=[C:7]3[NH:8][C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:3][CH2:2]1.CI.[C:34](=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH:1]1([C:4]2[N:31]=[C:7]3[N:8]([CH3:34])[C:9](=[O:30])[C:10]([CH2:15][C:16]4[CH:21]=[CH:20][C:19]([C:22]5[C:23]([C:28]#[N:29])=[CH:24][CH:25]=[CH:26][CH:27]=5)=[CH:18][CH:17]=4)=[C:11]([CH2:12][CH2:13][CH3:14])[N:6]3[N:5]=2)[CH2:2][CH2:3]1
Reactant: O=C([O-])[O-]
Reactant: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)[nH]c2nc(C3CC3)nn12
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Solvent: CCOC(C)=O
Product: CCCc1c(Cc2ccc(-c3ccccc3C#N)cc2)c(=O)n(C)c2nc(C3CC3)nn12
Temperature: 25 °C
Reaction time: 16 h
Yield: 107.4 %

Procedure:
A mixture of 4′-[(2-cyclopropyl-5-oxo-7-propyl-4,5-dihydro[1,2,4]triazolo[1,5-a]pyrimidin-6-yl)methyl]biphenyl-2-carbonitrile (0.18 g), methyl iodide (0.033 mL), potassium carbonate (0.12 g) and N,N-dimethylformamide (10 mL) was stirred at room temperature for 16 hr. The reaction mixture was diluted with ethyl acetate, washed with 5% aqueous potassium hydrogensulfate solution and then with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel column chromatography to give the title compound as a colorless solid (0.2 g, 100%).
Reaction SMILES: [NH3:1].[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[S:10](Cl)(=[O:12])=[O:11].Cl>C(#N)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([Cl:9])=[CH:5][C:4]=1[S:10]([NH2:1])(=[O:12])=[O:11]
Reactant: O=S(=O)(Cl)c1cc(Cl)ccc1Cl
Reactant: N
Agent: Cl
Solvent: CC#N
Product: NS(=O)(=O)c1cc(Cl)ccc1Cl
Temperature: 5 °C

Procedure:
170 ml of aqueous solution of 25% ammonia and 500 ml of acetonitrile were ice-cooled and stirred while maintaining the internal temperature at 5° C. or lower. 126 g (0.513 mol) of commercially available 2,5-dichlorobenzenesulfonyl chloride was added dividedly in five times over 1 hour. After completion of the addition, additional 30 minutes' reaction was performed, and then the reaction mixture was poured in a mixed solution of 100 ml of concentrated hydrochloric acid and 1,000 ml of ice water under stirring. The precipitated crystal was collected by filtration, and washed with water. By drying, 100 g of 2,5-dichlorobenzenesulfonamide was obtained as a white crystal (yield 88%).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11].[H-].[Na+].[CH2:15](Br)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O.C(OCC)(=O)C>[CH2:15]([O:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:12])[O:5][C:6]2=[O:11])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1OC(=O)c2c(O)cccc21
Reactant: BrCc1ccccc1
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1OC(=O)c2c(OCc3ccccc3)cccc21
Reaction time: 72 h
Yield: 68.7 %

Procedure:
To a solution of 4-hydroxy-isobenzofuran-1,3-dione (0.51 g, 3.09 mmol) in anhydrous N,N-dimethylformamide (7 ml) under nitrogen was added sodium hydride (130 mg, 3.25 mmol). Immediate evolution of gas and bright yellow color was observed. The mixture was stirred for 5 minutes after which benzyl bromide (1.8 ml, 15.45 mmol) was added. The reaction was stirred for 72 h. Saturated sodium bicarbonate (2 ml) was added and the mixture stirred for 2 minutes, diluted in ethyl acetate (35 ml) and washed with saturated sodium bicarbonate (5 ml), 1N hydrochloric acid (5 ml), and brine (2×5 ml). The organic layer was dried (MgSO4), filtered and the solvent evaporated in vacuo. To the crude material was added hexane and the formed precipitate was filtered off, washed further with hexane and dried in vacuo to give 0.54 g (69%) of 4-(benzyloxy)-isobenzofuran-1,3-dione as a solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][O:11][C:12]1[CH:16]=[C:15]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[O:14][N:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:31](Cl)(=[O:33])[CH3:32]>O1CCCC1>[C:31]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:15]2[O:14][N:13]=[C:12]([O:11][CH2:10][CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:16]=2)=[CH:22][CH:21]=1)(=[O:33])[CH3:32]
Reactant: CC(=O)Cl
Reactant: CC(C)(C)OC(=O)NCCOc1cc(-c2ccc(O)cc2)on1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1ccc(-c2cc(OCCNC(=O)OC(C)(C)C)no2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 71 %

Procedure:
3-(2-(N-tert-Butoxycarbonylamino)ethoxy)-5-(4-hydroxyphenyl)isoxazole (0.15 g) was dissolved in tetrahydrofuran (1.5 ml), and triethylamine (0.07 ml) and acetyl chloride (0.04 ml) were added dropwise thereto at 5° C. under a nitrogen atmosphere, followed by stirring of the resulting mixture at room temperature for 30 minutes. The reaction mixture was poured into ice-cold water and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous NaCl solution and dried over anhydrous magnesium sulfate. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (eluent: hexane/ethyl acetate=2/1) to obtain the title compound (0.12 g, 71%) as a colorless powder.
Reaction SMILES: CO[CH2:3][N:4]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH2:5][Si](C)(C)C.[CH2:17]([O:19][C:20](=[O:31])/[C:21](/[CH3:30])=[CH:22]/[C:23]1[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=1)[CH3:18].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:17]([O:19][C:20]([C:21]1([CH3:30])[CH:22]([C:23]2[CH:24]=[CH:25][C:26]([Cl:29])=[CH:27][CH:28]=2)[CH2:3][N:4]([CH2:10][C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH2:5]1)=[O:31])[CH3:18]
Reactant: CCOC(=O)/C(C)=C/c1ccc(Cl)cc1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOC(=O)C1(C)CN(Cc2ccccc2)CC1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 24 h
Yield: 53.4 %

Procedure:
A solution of N-(methoxymethyl)-N-(phenylmethyl)-N-(trimethylsilyl)methylamine (1.55 g, 6.54 mmol) in CH2Cl2 (5 mL) was added dropwise, over a 30 minutes period, to a stirred solution of (E)-3-(4-Chloro-phenyl)-2-methyl-acrylic acid ethyl ester (1.00 g, 4.45 mmol; preparation described in J. Org. Chem. 1966, 31: 4043-4047) and trifluoroacetic acid (0.034 mL, 0.44 mmol) in CH2Cl2 (10 mL) at 0° C. The ice bath was removed, and the solution was stirred at 25° C. for an additional 24 h. It was then concentrated and purification by flash chromatography (SiO2, EtOAc/H 1:8) afforded 0.85 g (54%) of the title compound as a colorless oil. ES-MS m/e: 358.2 (M+H+).
Reaction SMILES: C(Cl)Cl.[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14](B2OC(C)(C)C(C)(C)O2)[CH:13]=1)(=[O:11])=[O:10])([CH3:7])([CH3:6])[CH3:5].Br[C:28]1[N:33]=[C:32]([NH:34][C:35]2[CH:39]=[C:38]([CH:40]3[CH2:42][CH2:41]3)[NH:37][N:36]=2)[C:31]([C:43]#[C:44][Si](C)(C)C)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:4]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:28]2[N:33]=[C:32]([NH:34][C:35]3[NH:36][N:37]=[C:38]([CH:40]4[CH2:42][CH2:41]4)[CH:39]=3)[C:31]([C:43]#[CH:44])=[CH:30][N:29]=2)[CH:13]=1)(=[O:10])=[O:11])([CH3:5])([CH3:6])[CH3:7]
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1
Reactant: C[Si](C)(C)C#Cc1cnc(Br)nc1Nc1cc(C2CC2)[nH]n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: C#Cc1cnc(-c2cccc(S(=O)(=O)NC(C)(C)C)c2)nc1Nc1cc(C2CC2)n[nH]1
Temperature: 25 °C
Yield: 22.9 %

Procedure:
A mixture of Pd(dppf)Cl2.CH2Cl2 (65.3 mg, 0.08 mmol, 0.1 equiv.), N-tert-butyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (542 g, 1.60 mmol, 2.0 equiv.), 2-Bromo-N-(5-cyclopropyl-1H-pyrazol-3-yl)-5-((trimethyl silyl)ethynyl) pyrimidin-4-amine (300 mg, 0.80 mmol, 1.0 equiv.) and saturated aq Na2CO3 (10 mL) in dioxane (30 mL) was heated to 90° C. for 1 h under nitrogen atmosphere. The reaction mixture was cooled to room temperature and extracted with THF. The combined layers were concentrated and the residue was purified by silica gel chromatography (EtOAc/Petroleum ether from 10:1 to 1:1) to afford compound N-tert-butyl-3-(4-(3-cyclopropyl-1H-pyrazol-5-ylamino)-5-ethynylpyrimidin-2-yl)benzenesulfonamide (80 mg, 23%). LC-MS (m/z)=437.1 [M+H]+.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:18]=1[O:19][CH3:20])[N:15]=[CH:14][N:13]=[C:12]2[O:21][C:22]1[C:23]([F:31])=[C:24]2[C:28](=[CH:29][CH:30]=1)[NH:27][CH:26]=[CH:25]2)C1C=CC=CC=1.C([O-])=O.[NH4+].O>[Pd].CN(C=O)C>[F:31][C:23]1[C:22]([O:21][C:12]2[C:11]3[C:16](=[CH:17][C:18]([O:19][CH3:20])=[C:9]([OH:8])[CH:10]=3)[N:15]=[CH:14][N:13]=2)=[CH:30][CH:29]=[C:28]2[C:24]=1[CH:25]=[CH:26][NH:27]2
Reactant: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1OCc1ccccc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1cc2ncnc(Oc3ccc4[nH]ccc4c3F)c2cc1O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 80.4 %

Procedure:
6-Benzyloxy-4-(4-fluoroindol-5-yloxy)-7-methoxyquinazoline (0.75 g, 1.8 mmol), ammonium formate (1.14 g, 18 mmol) and 10% palladium on carbon (115 mg) in DMF (8 ml) containing water (1.5 ml) was stirred at ambient temperature for 2.5 hours. The mixture was filtered over diatomaceous earth and the filtrate was evaporated. The residue was triturated under diethyl ether, filtered, washed with water, followed by diethyl ether and dried overnight over P2O5 to give 4-(4-fluoroindol-5-yloxy)-6-hydroxy-7-methoxyquinazoline (0.471 g, 80%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:20])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([OH:18])[CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[O:27]1[CH:32]2[CH:28]1[CH2:29][O:30][CH2:31]2>CN(C)C=O>[Cl:20][C:6]1[CH:5]=[N:4][CH:3]=[C:2]([Cl:1])[C:7]=1[NH:8][C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:32]2[CH:28]([OH:27])[CH2:29][O:30][CH2:31]2)[CH:11]=1
Reactant: C1OCC2OC12
Reactant: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1COCC1O
Temperature: 120 °C
Yield: 27.1 %

Procedure:
400 mg (1.2 mmol) of N-(3,5-dichloropyridin-4-yl)-3-hydroxy-4-methoxybenzamide (starting compound A16) and 540 mg (3.85 mmol) of potassium carbonate are stirred under a nitrogen atmosphere at RT for 1 h in 5 ml of dimethylformamide. The mixture is heated to 120° C. and 115 mg (1.3 mmol) of 3,4-epoxytetrahydrofuran are added to the reaction mixture 4×at an interval of 6 h in each case. The mixture is concentrated, 50 ml of water are added, it is acidified with 2 N HCl and extracted with 3×50 ml of ethyl acetate. The combined organic phases are washed with saturated sodium chloride solution, dried over magnesium sulfate, concentrated and the residue is chromatographed on silica gel [toluene/ethyl acetate=1:2]. The product-containing fractions are concentrated and the residue is crystallized from diethyl ether. 130 mg of the title compound of m.p. 183-185° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:25])[F:24])[CH2:9][C:10]([C:12]2[CH:13]=[N:14][C:15]([O:18]C)=[CH:16][CH:17]=2)=[O:11])=[CH:4][CH:3]=1.Cl>O1CCOCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([CH2:20][CH2:21][CH2:22][C:23]([F:26])([F:24])[F:25])[CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](=[O:18])[NH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)CC(CCCC(F)(F)F)c2ccc(Br)cc2)cn1
Agent: Cl
Solvent: C1COCCO1
Product: O=C(CC(CCCC(F)(F)F)c1ccc(Br)cc1)c1ccc(=O)[nH]c1

Procedure:
In analogy to example 162, step 2, 3-(4-bromo-phenyl)-7,7,7-trifluoro-1-(6-methoxy-pyridin-3-yl)-heptan-1-one was reacted with concentrated aqueous HCl in 1,4-dioxane to give the title compound as a light yellow oil, MS (ESI+): m/z=416.1 [M+H]+.
Reaction SMILES: NCC1N=C(N(C2C=CC(OC)=CC=2)C)C2C(=CC=CC=2)N=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([N:31]([CH3:54])[C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[C:34]([CH2:42][N:43]3C(=O)C4[C:45](=CC=CC=4)[C:44]3=[O:53])[N:33]=2)=[CH:27][CH:26]=1.O.NN.Cl>CCO>[CH3:23][O:24][C:25]1[CH:26]=[CH:27][C:28]([N:31]([CH3:54])[C:32]2[C:41]3[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=3)[N:35]=[C:34]([CH2:42][NH:43][C:44](=[O:53])[CH3:45])[N:33]=2)=[CH:29][CH:30]=1
Reactant: COc1ccc(N(C)c2nc(CN3C(=O)c4ccccc4C3=O)nc3ccccc23)cc1
Agent: COc1ccc(N(C)c2nc(CN)nc3ccccc23)cc1
Agent: Cl
Agent: NN
Solvent: CCO
Solvent: O
Product: COc1ccc(N(C)c2nc(CNC(C)=O)nc3ccccc23)cc1
Temperature: 60 °C
Yield: 45.6 %

Procedure:
(2-Aminomethyl-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine: A solution of 2-{4-[(4-methoxy-phenyl)-methyl-amino]-quinazolin-2-ylmethyl}-isoindole-1,3-dione (8.561 g, 20.2 mmol) in EtOH (100 mL) was treated with hydrazine mono-hydrate (3.0 mL, 61.8 mmol) and heated to 60° C. for 2 h. The reaction was cooled to rt, HCl (2 N, 50 mL) added and the reaction heated to 60° C. for 30 min. After cooling to rt the solid was filtered off. The filtrate was concentrated, basified with 5% NaOH and extracted with CH2Cl2. The organic layers were combined, dried (MgSO4), filtered and concentrated. The residue was purified by gradient reverse phase MPLC (MeCN/H2O with 0.1% TFA) and the free base re-extracted as above to yield 3.10 g (52%) of the title compound. 1H NMR (CDCl3) δ 7.76 (d, 1H), 7.54 (ddd, 1H), 7.08-7.16 (m, 2H), 6.95-7.05 (m, 2H), 6.86-6.94 (m, 2H), 4.07 (s, 2H), 3.84 (s, 3H), 3.60 (s, 3H), 2.00 (s(br), 2H); 13C NMR (CDCl3) δ 165.9, 162.0, 158.2, 152.2, 141.6, 132.0, 128.2, 127.6, 126.5, 124.4, 115.5, 115.4, 55.7, 49.1, 43.0; HRMS (ES) calcd for C17H18N4O (M+H) 295.1553, found 295.1506.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][CH2:14][C:15]([OH:17])=O)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1>O1CCCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]2[CH2:12][CH2:13][CH2:14][C:15]2=[O:17])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: O=C(O)CCCNS(=O)(=O)c1ccc(Cl)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C1CCCN1S(=O)(=O)c1ccc(Cl)cc1
Temperature: 0 °C
Reaction time: 21 h
Yield: 91.3 %

Procedure:
In 20 ml of tetrahydrofuran was dissolved 2.78 g of N-(4'-chlorobenzenesulfonyl)-4-aminobutyric acid (0.01 mole). To the stirred solution on an ice bath was added 2.06 g of dicyclohexylcarbodiimide (0.01 mole), and the mixture was stirred at 0° C. for 21 hours. The reaction mixture was filtered, and the solid material was washed with anhydrous tetrahydrofuran. The filtrate and the washings were combined, and tetrahydrofuran was removed under reduced pressure. The residue thus obtained was recrystallized from a mixed solvent of chloroform-ether to give 2.37 g of N-(4'-chlorobenzenesulfonyl)-2-pyrrolidone as crystals. Physical properties were identical with those in Synthetic Example 3.