Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([OH:25])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].I[CH2:42][CH3:43].O>CN(C=O)C>[CH2:1]([S:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]([C:19]1[C:24]([O:25][CH2:42][CH3:43])=[CH:23][C:22]([C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([F:32])[CH:27]=3)=[C:21]([F:33])[CH:20]=1)[C:14](=[O:34])[CH:13]=[CH:12]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=c1ccc2cc(SCc3ccccc3)ccc2n1-c1cc(F)c(-c2cccc(F)c2)cc1O
Reactant: CCI
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOc1cc(-c2cccc(F)c2)c(F)cc1-n1c(=O)ccc2cc(SCc3ccccc3)ccc21
Temperature: 25 °C
Reaction time: 24 h
Yield: 98.8 %

Procedure:
6-(Benzylthio)-1-(2,3′-difluoro-5-hydroxy-[1,1′-biphenyl]-4-yl)quinolin-2(1H)-one (510 mg, 1.082 mmol) was dissolved in DMF (2163 μl). Then potassium carbonate (149 mg, 1.082 mmol) was added followed by iodoethane (96 μl, 1.190 mmol). After stirring at rt for 1 d, water was added. A gummy solid was collected with an aid of water, and dried. The crude material was absorbed onto a plug of silica gel and purified by chromatography through a Redi-Sep pre-packed silica gel column (40 g), eluting with a gradient of 0% to 50% EtOAc in heptane, to provide 6-(benzylthio)-1-(5-ethoxy-2,3′-difluoro-[1,1′-biphenyl]-4-yl)quinolin-2(1 H)-one (534 mg, 99% yield) as white solid. Ink (ESI) [M+H]+=500.0. NMR (400 MHz, DMSO-d6) δ ppm 1.00 (t, J=6.94 Hz, 3 H) 4.01-4.13 (m, 2 H) 4.24 (s, 2 H) 6.60 (d, J=8.80 Hz, 1 H) 6.70 (d, J=9.59 Hz, 1 H) 7.18-7.35 (m, 6 H) 7.38-7.48 (m, 3 H) 7.49-7.63 (m, 3 H) 7.79 (d, J=2.15 Hz, 1 H) 7.96 (d, J=9.59 Hz, 1 H).
Reaction SMILES: [C:1]([NH2:5])([CH3:4])([CH3:3])[CH3:2].Cl[S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18]Cl>ClCCCl>[C:1]([NH:5][S:7][S:8][S:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][S:16][S:17][S:18][NH:5][C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClSSSCCCCCCSSSCl
Reactant: CC(C)(C)N
Solvent: ClCCCl
Product: CC(C)(C)NSSSCCCCCCSSSNC(C)(C)C

Procedure:
70.0 ml (736 mmol) of tert-butylamine are used as initial charge in 1,2-dichloroethane in an inertized three-necked flask with dropping funnel, reflux condenser with hose coupling at its upper end, a tap with hose coupling and a Teflon stirrer bar, in a countercurrent of argon. 10.2 g (29.3 mmol) of 1,6-bis(chlorotrisulphanyl)hexane in 50 ml of 1,2-dichloroethane are then added dropwise, with stirring. The reaction mixture is stirred at room temperature for 4 hours. The resultant salt is filtered off, and the organic phase is washed three times with water and dried over sodium sulphate. After removal of the solvent on a rotary evaporator and drying in the vacuum generated by a rotary-vane pump, 1,6-bis(tert-butylaminotrisulphanyl)hexane precipitates in the form of a yellow oil. The crude yield is 11.9 g (97%). Elemental analysis was carried out on the crude product.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[NH:8][N:7]=1)=[O:5])[CH3:2].C(OC(C1N([CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])N=C(COC2C=CC=CC=2)C=1)=O)C>>[CH2:1]([O:3][C:4]([C:6]1[C:10]([I:11])=[C:9]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[N:8]([CH2:35][CH2:36][NH:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[N:7]=1)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1n[nH]c(C(=O)OCC)c1I
Reactant: CCOC(=O)c1cc(COc2ccccc2)nn1CCNC(=O)OC(C)(C)C
Product: CCOC(=O)c1nn(CCNC(=O)OC(C)(C)C)c(C(=O)OCC)c1I

Procedure:
The compound was prepared from 4-iodo-1H-pyrazole-3,5-dicarboxylic acid diethyl ester and 2-(2-tert-butoxycarbonylamino)ethyl bromide using the method described in the preceding example 5 (2-(2-tert-butoxycarbonylamino-ethyl)-5-phenoxymethyl-2H-pyrazole-3-carboxylic acid ethyl ester).
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[C:20]1([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH:26]=O)[CH:21]=1>>[C:20]1([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][N:1]2[CH:2]([C:10]3[C:15]([O:16][CH3:17])=[CH:14][N:13]=[CH:12][C:11]=3[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]2=[O:8])[CH:21]=1
Reactant: COC(=O)CCCC(N)c1c(OC)cncc1OC
Reactant: O=Cc1cccc(-c2ccccc2)c1
Product: COc1cncc(OC)c1C1CCCC(=O)N1Cc1cccc(-c2ccccc2)c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(3,5-dimethoxypyridin-4-yl)pentanoate with commercially available [1,1′-biphenyl]-3-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.64 min.; [M+H]+: 402.69 g/mol.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:21])=O>>[CH3:1][C:2]1[CH:10]=[C:9]([S:11]([CH3:14])(=[O:13])=[O:12])[C:8]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:7][C:3]=1[C:4]([Cl:21])=[O:5]
Reactant: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)O
Reactant: O=S(Cl)Cl
Product: Cc1cc(S(C)(=O)=O)c(S(C)(=O)=O)cc1C(=O)Cl

Procedure:
in stage d) 2-methyl-4,5-di(methylsulfonyl)benzoic acid is reacted with thionyl chloride to give 2-methyl-4,5-di (methylsulfonyl)benzoyl chloride, and
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8](F)=[C:7]([F:12])[CH:6]=1)(=[O:4])=[O:3].[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[C:18]([OH:20])[CH:19]=1>>[Cl:13][C:14]1[CH:15]=[C:16]([CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[C:18]([O:20][C:8]2[CH:9]=[CH:10][C:5]([S:2]([CH3:1])(=[O:4])=[O:3])=[CH:6][C:7]=2[F:12])[CH:19]=1
Reactant: CS(=O)(=O)c1ccc(F)c(F)c1
Reactant: O=C(O)Cc1cc(O)cc(Cl)c1
Product: CS(=O)(=O)c1ccc(Oc2cc(Cl)cc(CC(=O)O)c2)c(F)c1

Procedure:
The title compound was prepared by the method of example 2 step (iii) using 3,4-difluorophenyl methyl sulfone and the product of example 18 step (iv).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][CH:10]=2)[CH:6]=[CH:7][CH:8]=1.C(=O)(O)[O-:20].[Na+].O.ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][C:10]2=[O:20])[CH:6]=[CH:7][CH:8]=1
Reactant: O=C([O-])O
Reactant: COc1cccc(C2=CCCc3ccccc32)c1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: COc1cccc(C2C(=O)CCc3ccccc32)c1
Reaction time: 2 h
Yield: 93.9 %

Procedure:
To a 2-phase mixture of 25.1 g (0.106 mol) of 1-(3-methoxyphenyl)-3,4-dihydronaphthalene, 20 g (0.238 mol) of sodium bicarbonate, 200 ml of water, and 400 ml of methylene chloride at 5° C. was added 24.4 g of 80-85% m-chloroperbenzoic acid portion-wise over 15 minutes. The internal temperature rose to 10° C. After the addition was complete, the mixture was stirred at 0°-5° C. for 2 hr. The layers were separated and the aqueous layer was extracted with 100 ml of methylene chloride. The combined organic layers were extracted with 200 ml of 10% sodium carbonate and then with 100 ml of water, dried over MgSO4 and evaporated to an oil. IR, NMR, and thin layer chromatography indicated the presence of a mixture of epoxide and 1,2-diol monoester. The crude mixture was stirred 3 hours at room temperature in 1M solution of sodium hydroxide in 5:1 ethanol-water. After adjusting the pH to 8 with HCl, the bulk of the solvent was evaporated. The residue was taken up in 500 ml of ether, which was then washed with 50 ml of water, dried over MgSO4, and evaporated. The oily residue was dissolved in 300 ml of dry toluene containing 0.050 g of p-toluenesulfonic acid and refluxed 3 hour in a Dean-Stark apparatus. The solution was washed with 50 ml of 5% sodium bicarbonate and with 50 ml of water, dried over MgSO4 and evaporated to give 25.1 g of the title compound, which was characterized as its 2,4-dinitrophenyl hydrazone derivative, m.p. 161°-161.5° C. (ethanol).
Reaction SMILES: NC(N)=O.[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][CH2:29][CH3:30])=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH:34]4CCN(C(OCC)=O)C[CH2:35]4)[N:32]=[CH:33][C:14]=13)[CH2:6]2.NC1C=[CH:56][C:49]([C:50]([NH:52][N:53]([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=1.NC1C=CC=CC=1>>[CH:5]12[O:12][CH:9]([CH2:10][CH2:11]1)[CH2:8][N:7]([C:13]1[N:18]=[C:17]([C:19]3[CH:24]=[CH:23][C:22]([NH:25][C:26]([NH:28][C:29]4[CH:30]=[CH:56][C:49]([C:50]([NH:52][N:53]([CH3:55])[CH3:54])=[O:51])=[CH:48][CH:47]=4)=[O:27])=[CH:21][CH:20]=3)[N:16]=[C:15]3[N:31]([CH2:34][CH3:35])[N:32]=[CH:33][C:14]=13)[CH2:6]2
Reactant: CN(C)NC(=O)c1ccc(N)cc1
Reactant: CCNC(=O)Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(C(=O)OCC)CC4)c3n2)cc1
Agent: NC(N)=O
Solvent: Nc1ccccc1
Product: CCn1ncc2c(N3CC4CCC(C3)O4)nc(-c3ccc(NC(=O)Nc4ccc(C(=O)NN(C)C)cc4)cc3)nc21

Procedure:
A urea formation procedure similar to that used for the synthesis of ethyl 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-6-(4-(3-ethylureido)phenyl)-1H-pyrazolo[3,4-d]pyrimidin-1-yl)piperidine-1-carboxylate is used, utilizing 4-amino-N′,N′-dimethylbenzohydrazide as the aniline component. (37%, MS=556.3 (M+H))
Reaction SMILES: II.[OH:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]=[C:11]([SH:15])[C:12]([OH:14])=[O:13])=[CH:6][C:5]=1[O:16][CH3:17].S(=O)(O)[O-].[Na+]>C(O)C>[OH:3][C:4]1[C:5]([O:16][CH3:17])=[CH:6][C:7]2[CH:10]=[C:11]([C:12]([OH:14])=[O:13])[S:15][C:8]=2[CH:9]=1
Reactant: COc1cc(C=C(S)C(=O)O)ccc1O
Agent: II
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CCO
Product: COc1cc2cc(C(=O)O)sc2cc1O

Procedure:
Iodine (90 g) was added to a stirred mixture of the product from Step B (73 g) and 90% ethanol (2000 mL). The resultant dark mixture was heated at reflux for 24 hours. Saturated sodium bisulfite solution (200 mL) was added to the cooled reaction mixture and the ethanol was removed in vacuo. The aqueous residue was diluted to 1500 ml with water and extracted with ethyl acetate (4×400 mL). The combined extracts were evaporated in vacuo and the residue was heated on the steam bath with lN sodium hydroxide solution (1500 mL) for 3 hours. The solution was treated with charcoal, filtered, diluted to 2500 mL with water and acidified with concentrated hydrochloric acid. The precipitated solid was collected, washed with water and dried; yield 36.8 g.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:11][C:12](=[O:20])[C:13]2[CH:18]=[CH:17][C:16](Cl)=[N:15][CH:14]=2)[CH:8]=[CH:9][CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[NH:21]1[CH2:31][CH2:30][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH2:23][CH2:22]1.C(OC(C1CCN(C2C=CC(C(=O)NC3C=CC(C)=C(I)C=3)=CN=2)CC1)=O)C>CCOC(C)=O>[CH2:28]([O:27][C:25]([CH:24]1[CH2:30][CH2:31][N:21]([C:16]2[CH:17]=[CH:18][C:13]([C:12](=[O:20])[NH:11][C:7]3[CH:8]=[CH:9][CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=3)=[CH:14][N:15]=2)[CH2:22][CH2:23]1)=[O:26])[CH3:29]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(C)(C)c1cccc(NC(=O)c2ccc(Cl)nc2)c1
Agent: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3ccc(C)c(I)c3)cn2)CC1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CCN(c2ccc(C(=O)Nc3cccc(C(C)(C)C)c3)cn2)CC1

Procedure:
5′-(3-tert-Butyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester was prepared from N-(3-tert-butyl-phenyl)-6-chloro-nicotinamide and ethyl isonipecotate following a procedure similar to the one described in the synthesis of 5′-(3-iodo-4-methyl-phenylcarbamoyl)-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4 carboxylic acid ethyl ester above. The product was isolated by silica gel column purification with 20-30% EtOAc in hexanes gradient. FIRMS m/z calcd for C24H31N3O3 [M+H]+: 410.2438. Found: 410.2436
Reaction SMILES: [F:1][C:2]([F:18])([C:9]([F:17])([F:16])[C:10]([F:15])([F:14])[CH:11]([F:13])[F:12])[CH2:3][CH:4]([C:7]#[N:8])[C:5]#[N:6].[CH2:19](Br)[CH:20]=[CH2:21].C(=O)([O-])[O-].[K+].[K+].Cl>CS(C)=O>[CH2:21]([C:4]([CH2:3][C:2]([F:18])([F:1])[C:9]([F:16])([F:17])[C:10]([F:14])([F:15])[CH:11]([F:13])[F:12])([C:7]#[N:8])[C:5]#[N:6])[CH:20]=[CH2:19]
Reactant: N#CC(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Reactant: C=CCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: C=CCC(C#N)(C#N)CC(F)(F)C(F)(F)C(F)(F)C(F)F
Temperature: 25 °C
Reaction time: 5 h
Yield: 23.4 %

Procedure:
0.56 g of 2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile and 0.30 g of allyl bromide were dissolved in 5 ml of dimethyl sulfoxide, 0.28 g of potassium carbonate was added, and the mixture was stirred at room temperature for 5 hours. Thereafter, dilute hydrochloric acid was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was washed successively with water and aqueous saturated sodium chloride, dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The residue was subjected to silica gel column chromatography to obtain 0.15 g of 2-(allyl)-2-(2,2,3,3,4,4,5,5-octafluoropentyl)malononitrile (hereinafter, referred to as the present compound (47)).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8]([CH3:10])[C:5]([C:6]#[N:7])=[C:4]([Cl:11])[N:3]=1.CN(C=O)C.[H-].[Na+].[F:19][C:20]1([F:35])[O:24][C:23]2[CH:25]=[CH:26][C:27]([C:29]3([C:32](Cl)=[O:33])[CH2:31][CH2:30]3)=[CH:28][C:22]=2[O:21]1>O1CCCC1.O>[Cl:11][C:4]1[N:3]=[C:2]([NH:1][C:32]([C:29]2([C:27]3[CH:26]=[CH:25][C:23]4[O:24][C:20]([F:35])([F:19])[O:21][C:22]=4[CH:28]=3)[CH2:31][CH2:30]2)=[O:33])[CH:9]=[C:8]([CH3:10])[C:5]=1[C:6]#[N:7]
Reactant: Cc1cc(N)nc(Cl)c1C#N
Reactant: O=C(Cl)C1(c2ccc3c(c2)OC(F)(F)O3)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc(Cl)c1C#N
Reaction time: 0.08 h
Yield: 100.2 %

Procedure:
6-Amino-2-chloro-4-methylnicotinonitrile (252 mg, 1.50 mmol) was dissolved in a mixture of anhydrous N,N′ dimtheylformamide (DMF, 0.5 mL) and anhydrous tetrahydrofuran (THF, 4.5 mL). The reaction tube was placed in a beaker full of room temperature water to help maintain the reaction temperature. Sodium hydride (84.23 mg, 2.106 mmol, 60% by weight in mineral oil) was added and the resulting suspension was allowed to stir for 5 minutes. 1-(2,2-Difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (392.0 mg, 1.5 mmol) was added and the reaction mixture turned dark red. The crude material was evaporated to dryness, re-dissolved in a minimum of dichloromethane, and purified on 12 g of silica utilizing a gradient of 0-50% ethyl acetate in hexanes to yield the pure product as a pale yellow solid (0.589 g, 63%). ESI-MS m/z calc. 391.0. found 392.0 (M+1)+. Retention time 2.06 minutes.
Reaction SMILES: I[C:2]1[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=1.[Br:15][C:16]1[CH:21]=[CH:20][C:19](B(O)O)=[CH:18][CH:17]=1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Br:15][C:16]1[CH:21]=[CH:20][C:19]([C:2]2[N:7]=[CH:6][C:5]([C:8]([NH:11][C:12](=[O:14])[CH3:13])([CH3:10])[CH3:9])=[CH:4][CH:3]=2)=[CH:18][CH:17]=1
Reactant: OB(O)c1ccc(Br)cc1
Reactant: CC(=O)NC(C)(C)c1ccc(I)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(=O)NC(C)(C)c1ccc(-c2ccc(Br)cc2)nc1
Temperature: 95 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-(2-(6-iodopyridin-3-yl)propan-2-yl)acetamide, 33-d, (22 g, 72.4 mmol) in dioxane (100 ml) was added 4-bromophenylboronic acid (16 g, 79.6 mmol) and Pd(PPh3)4 (4.2 g, 3.62 mmol) and aq Na2CO3 (2N) (25.3 g, 238.8 mmol). The reaction mixture was then stirred at 95° C. for 3 hours. The reaction mixture was then cooled to room temperature and concentrated under vacuo. The concentrate was extracted with ethyl acetate, washed with brine, and re-concentrated. Purification by silica gel (petroleum ether:ethyl acetate=1:1-ethyl acetate) gave the solid, 33-e, (18 g, 75%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[C:5](=[O:19])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2].[F:21][C:22]([Si](C)(C)C)([F:24])[F:23].[F-].C([N+](CCCC)(CCCC)CCCC)CCC>[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O1CCCC1>[CH2:1]([O:3][C:4](=[O:20])[C:5]([OH:19])([C:22]([F:24])([F:23])[F:21])[CH2:6][C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([CH3:16])[C:11]=1[O:17][CH3:18])([CH3:9])[CH3:8])[CH3:2]
Reactant: CCOC(=O)C(=O)CC(C)(C)c1cccc(C)c1OC
Reactant: C[Si](C)(C)C(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: CCOC(=O)C(O)(CC(C)(C)c1cccc(C)c1OC)C(F)(F)F
Temperature: 35 °C
Reaction time: 8 h
Yield: 65.2 %

Procedure:
20 g (71.90) of ethyl-4-(2-methoxy-3-methylphenyl)-4-methyl-2-oxopentanoate and 12.3 g (86.28 mmol) of (trifluoromethyl)trimethylsilane are introduced into 117 ml of tetrahydrofuran. At room temperature, 180 mg of tetrabutylammonium fluoride is added (heating to about 35° C.). After stirring overnight, 22.7 g (71.90 mmol) of tetrabutylammonium fluoride is added, and the batch is stirred for three hours at room temperature. After dilution with methyl tert-butyl ether, the organic phase is washed three times with water and once with brine. After the solvent is dried and spun off, the residue is chromatographed on silica gel (mobile solvent: ethyl acetate/hexane). 16.33 g (65.2%) of the desired compound is isolated.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:17])[C:5]2[O:9][C:8]([C:10]([OH:12])=O)=[C:7]([CH3:13])[C:6]=2[C:14]=1[O:15][CH3:16].[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][C:41]([NH2:44])=[CH:40][CH:39]=2)=[CH:34][CH:33]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:21])([CH3:20])[CH3:19].F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C>CN(C=O)C>[C:18]([O:22][C:23](=[O:45])[C@@H:24]([NH:28][S:29]([C:32]1[CH:33]=[CH:34][C:35]([C:38]2[CH:39]=[CH:40][C:41]([NH:44][C:10]([C:8]3[O:9][C:5]4[C:4]([Cl:17])=[CH:3][C:2]([Cl:1])=[C:14]([O:15][CH3:16])[C:6]=4[C:7]=3[CH3:13])=[O:12])=[CH:42][CH:43]=2)=[CH:36][CH:37]=1)(=[O:31])=[O:30])[CH:25]([CH3:27])[CH3:26])([CH3:20])([CH3:21])[CH3:19]
Reactant: COc1c(Cl)cc(Cl)c2oc(C(=O)O)c(C)c12
Reactant: CC(C)[C@H](NS(=O)(=O)c1ccc(-c2ccc(N)cc2)cc1)C(=O)OC(C)(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1c(Cl)cc(Cl)c2oc(C(=O)Nc3ccc(-c4ccc(S(=O)(=O)N[C@H](C(=O)OC(C)(C)C)C(C)C)cc4)cc3)c(C)c12
Temperature: 25 °C
Reaction time: 48 h
Yield: 57.2 %

Procedure:
To 80 mg of 5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carboxylic acid was added 120 mg of (S)-2-(4′-amino-biphenyl-4-sulfonylamino)-3-methyl-butyric acid tert-butyl ester, 154 mg of BOP, 50 mg of N,N-diisopropylethylamine and 4 mL of DMF. The mixture was stirred at room temperature for 48 h. The mixture was washed with brine and was extracted with ethyl acetate. The combined ethyl acetate layers were washed with brine. Removal of the solvent in vacuo and purification of the residue by column chromatography on silica gel gave 110 mg (60% yield) of (S)-2-{4′-[(5,7-dichloro-4-methoxy-3-methyl-benzofuran-2-carbonyl)-amino]-biphenyl-4-sulfonylamino}-3-methyl-butyric acid tert-butyl ester as an off-white solid.
Reaction SMILES: C(N(CC)CC)C.[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.[C:17](Cl)(=[O:19])[CH3:18]>CCOCC>[CH3:8][O:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17](=[O:19])[CH3:18])=[CH:12][CH:11]=1
Reactant: COc1ccc(O)cc1
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: COc1ccc(OC(C)=O)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 107.3 %

Procedure:
Triethylamine (14.55 mL, 104.43 mmol) was added to an ice-bath cooled solution of 4-methoxyphenol (5.185 g, 41.77 mmol) in anhydrous ether (200 mL) under nitrogen atmosphere. Acetyl chloride (5.94 mL, 83.53 mmol) was added drop-wise and reaction mixture then allowed to warm to room temperature and stir for a further 10 min. The reaction mixture was partitioned between ethyl acetate and sat aqueous sodium bicarbonate solution. The phases were separated and the organic phase was dried over sodium sulphate, filtered and filtrate solvents removed in vacuo to afford the title compound (7.45 g, quant) as a brown liquid.
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[O:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[OH:23][CH2:24][C:25]([C:28]1[O:32][N:31]=[C:30]([NH:33][C:34](=O)[O:35]C2C=CC=CC=2)[CH:29]=1)([CH3:27])[CH3:26].COC1C=C2C(=CC=1OC)N=CN=C2OC1C=C(NC(NC2ON=C(C(C)C)C=2)=O)C=CC=1>>[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[O:15][C:16]1[CH:17]=[C:18]([NH:19][C:34]([NH:33][C:30]2[CH:29]=[C:28]([C:25]([CH3:27])([CH3:26])[CH2:24][OH:23])[O:32][N:31]=2)=[O:35])[CH:20]=[CH:21][CH:22]=1
Reactant: COc1cc2ncnc(Oc3cccc(N)c3)c2cc1OC
Reactant: CC(C)(CO)c1cc(NC(=O)Oc2ccccc2)no1
Agent: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)C)no4)c3)c2cc1OC
Product: COc1cc2ncnc(Oc3cccc(NC(=O)Nc4cc(C(C)(C)CO)on4)c3)c2cc1OC
Yield: 61 %

Procedure:
Prepared from 3-(6,7-dimethoxyquinazolin-4-yloxy)aniline from Example 113A (30 mg, 0.10 mmol) and phenyl 5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-ylcarbamate from the previous step (41 mg, 0.15 mmol) according to the method described for 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(3-isopropylisoxazol-5-yl)urea in Example 122B. Purification via preparative TLC eluting with 10% methanol in dichloromethane afforded 1-(3-(6,7-dimethoxyquinazolin-4-yloxy)phenyl)-3-(5-(1-hydroxy-2-methylpropan-2-yl)isoxazol-3-yl)urea as a colorless solid (30 mg, 61%). 1H NMR (300 MHz, DMSO-d6) δ 9.57 (brs, 1H), 8.99 (brs, 1H), 8.56 (s, 1H), 7.56-7.58 (m, 2H), 7.38-7.42 (m, 2H), 7.23-7.26 (m, 1H), 6.95-6.98 (m, 1H), 6.49 (s, 1H), 4.95 (brs, 1H), 3.98-3.99 (2×s, 6H), 3.43 (s, 2H), 1.20 (s, 6H); LC-MS (ESI) m/z 480 (M+H)+.
Reaction SMILES: O.[OH-].[Li+].[N:4]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([O:18]CC)=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1.Cl>CO.O>[N:4]1([C:9]2[N:14]=[CH:13][C:12]([CH2:15][C:16]([OH:18])=[O:17])=[CH:11][CH:10]=2)[CH2:8][CH2:7][CH2:6][CH2:5]1
Reactant: CCOC(=O)Cc1ccc(N2CCCC2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)Cc1ccc(N2CCCC2)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Lithium hydroxide monohydrate (36 mg, 0.85 mmol) was added to a solution of ethyl (6-pyrrolidin-1-ylpyridin-3-yl)acetate (100 mg, 0.4 mmol) in methanol (3.0 mL) and water (1.0 mL). The reaction mixture was stirred at r.t. overnight. The mixture was adjusted to pH=4 with aqueous HCl, and concentrated to afford the crude product which was directly used for next step without further purification. Analytic LCMS (M+H)+: m/z=207.1.