Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][CH:13]=2)[S:5][C:6]=1[C:7]([O:9][CH2:10][CH3:11])=[O:8].C([O-])=O.[NH4+]>[Pd].CO>[NH2:18][C:15]1[CH:14]=[CH:13][C:12]([C:4]2[S:5][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[C:2]([CH3:1])[N:3]=2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)c1sc(-c2ccc([N+](=O)[O-])cc2)nc1C
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CCOC(=O)c1sc(-c2ccc(N)cc2)nc1C
Yield: 75.7 %

Procedure:
The same operation as in Example (90d) was performed using ethyl 4-methyl-2-(4-nitrophenyl)-1,3-thiazole-5-carboxylate obtained in Example (94a) (0.40 g, 1.36 mmol), 10% Pd/C (wet, 1.2 g), ammonium formate (0.52 g, 8.22 mmol) and methanol (10 mL), to obtain 0.27 g of the crude title compound as a light yellow solid (75%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=O)[O:18][CH:17]3[CH3:22])[N:4]=1.COC1C=CC(P2(=S)SP(C3C=CC(OC)=CC=3)(=S)[S:32]2)=CC=1>C1(C)C(C)=CC=CC=1>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[N:6]=[C:5]([O:11][C:12]2[CH:13]=[CH:14][CH:15]=[C:16]3[C:21]=2[C:19](=[S:32])[O:18][CH:17]3[CH3:22])[N:4]=1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Reactant: COc1cc(OC)nc(Oc2cccc3c2C(=O)OC3C)n1
Solvent: Cc1ccccc1C
Product: COc1cc(OC)nc(Oc2cccc3c2C(=S)OC3C)n1

Procedure:
A mixture of 6.35 g of 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methyl-phthalide (see Example 1) and 8.92 g of 2,4-bis(4-methoxyphenyl)-2,4-dithioxo-1,3,2,4-dithia-diphosphetan (Lawesson reagent) is maintained at reflux temperature for approximately 16 hours in 40 ml of xylene. The reaction material is then filtered over silica gel (eluant: 30% diethyl ether/n-hexane) and recrystallised from ethyl acetate/n-hexane to yield 7-[(4,6-dimethoxy-pyrimidin-2-yl)oxy]-3-methyl-isobenzofuran-1(3H)-thione in the form of yellow crystals, m.p. 163°-164° C.; IR spectrum (CHCl3): 1602, 1570, 1358, 1304, 1195 cm-1 ; 1H-NMR (CDCl3): 5.80 ppm (q, 1H), 1.71 ppm (d, 3H).
Reaction SMILES: [CH2:1]([N:3]([CH2:18][CH3:19])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12]([CH:15]=O)[NH:11][C:10]=1[CH3:17])=[O:8])[CH3:2].[F:20][C:21]1[CH:22]=[C:23]2[C:27](=[CH:28][CH:29]=1)[NH:26][C:25](=[O:30])[CH2:24]2.C(OC(C)C)(C)C.N1CCCC1>CCOCC.C(OC)(C)(C)C>[CH3:2][CH2:1][N:3]([CH2:4][CH2:5][NH:6][C:7]([C:9]1[C:13]([CH3:14])=[C:12](/[CH:15]=[C:24]2/[C:23]3[CH:22]=[C:21]([F:20])[CH:29]=[CH:28][C:27]=3[NH:26][C:25]/2=[O:30])[NH:11][C:10]=1[CH3:17])=[O:8])[CH2:18][CH3:19]
Reactant: CCN(CC)CCNC(=O)c1c(C)[nH]c(C=O)c1C
Reactant: O=C1Cc2cc(F)ccc2N1
Solvent: COC(C)(C)C
Solvent: CC(C)OC(C)C
Solvent: C1CCNC1
Product: CCN(CC)CCNC(=O)c1c(C)[nH]c(/C=C2\C(=O)Nc3ccc(F)cc32)c1C

Procedure:
According to the process of the present invention, 5-Formyl-2,4-dimethyl-1H-pyrrole-3-carboxylic acid (2-diethylaminoethyl)-amide (IX) and 5-Fluoro-1,3-dihydro-indol-2-one (X) in ether solvents like diethyl ether, isopropyl ether or methyl tertiary butyl ether are reacted in presence of catalytic amount of pyrrolidine as base at reflux temperature for 3-9 hours. The resultant Sunitinib base is again triturated with the same solvent at reflux temperature for 1-2 hours and isolated at a temperature ranging from 20-45° C., preferably at 25-35° and most preferably at 25-30° C. and dried at 60° C. for 5-20 hours to get Sunitinib base (I) as orange crystalline solid.
Reaction SMILES: Br[C:2]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]2[N:6]([CH3:24])[C:7]([CH2:9][CH2:10][N:11]3[CH2:16][CH2:15]N(CC4C=CC=CC=4)[CH2:13][CH2:12]3)=[N:8][C:4]=2[CH:3]=1.[OH-].[Na+].[H][H]>[Pd].O1CCCC1>[CH3:24][N:6]1[C:5]2[C:25]3[C:30]([CH:2]=[CH:3][C:4]=2[N:8]=[C:7]1[CH2:9][CH2:10][N:11]1[CH2:12][CH2:13][CH:26]([C:25]2[CH:30]=[CH:2][CH:3]=[CH:4][CH:5]=2)[CH2:15][CH2:16]1)=[CH:29][CH:28]=[CH:27][CH:26]=3
Reactant: [H][H]
Reactant: Cn1c(CCN2CCN(Cc3ccccc3)CC2)nc2cc(Br)c3ccccc3c21
Agent: [Pd]
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: Cn1c(CCN2CCC(c3ccccc3)CC2)nc2ccc3ccccc3c21

Procedure:
A mixture of 8.32 g (0.0185 mole) of the compound of Example 16, 0.9 g of 10% Pd-C catalyst, and 150 cc of tetrahydrofuran containing 20 cc of 1 M NaOH is shaken in a Paar hydrogenator under about 5.4 atm. of hydrogen pressure until hydrogenolysis is completed. The catalyst is filtered and the mother liquor is concentrated to remove the solvent. The residue is taken up with methylene chloride, and washed with water. Upon evaporating the solvent, 6.1 g of a crude product are obtained which is recrystallized from acetone yielding 4.74 g of the compound of the title. M.p. 181.5°-182.5° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=1.[CH:12]1([CH:17]([OH:20])[CH:18]=[CH2:19])[CH2:16][CH2:15][CH2:14][CH2:13]1.C(=O)(O)[O-].[Na+]>CN1CCCC1=O>[CH:12]1([C:17](=[O:20])[CH2:18][CH2:19][C:2]2[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[C:4]([CH2:10][CH3:11])[CH:3]=2)[CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: C=CC(O)C1CCCC1
Reactant: CCc1cc(Br)ccc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN1CCCC1=O
Product: CCc1cc(CCC(=O)C2CCCC2)ccc1OC
Temperature: 140 °C
Yield: 47.2 %

Procedure:
A mixture of bromide (1.3 g, 6.02 mmol, from step 1), 1-Cyclopentyl-2-propen-1-ol (1.14 g, 9.07 mmol), dichlorobis (triphenylphosphine) palladium (II) (85 mg, 0.12 mmol), sodium bicarbonate (0.61 g, 7.25 mmol) in N-methylpyrrolidinone (12 mL) was heated to 140° C. under N2 for 5 h. The reaction mixture was partitioned between 1N HCl and EtOAc. The organic layer was washed with saturated NaHCO3, brine, dried over Na2SO4 and concentrated to a brown oil. The oil was purifed by silica gel chromatography to give the title compound as a yellow oil (0.74 g, 47%).
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]1[N:14]2[C:15](=[O:28])[C:16](=[O:27])[NH:17][C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:21]([NH2:22])=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].CO[CH:31]1[CH2:35][CH2:34][CH:33](OC)O1>>[CH2:6]([O:5][P:4]([CH:9]1[N:14]2[C:15](=[O:28])[C:16](=[O:27])[NH:17][C:18]3[CH:19]=[C:20]([C:23]([F:26])([F:25])[F:24])[C:21]([N:22]4[CH:31]=[CH:35][CH:34]=[CH:33]4)=[C:12]([C:13]=32)[CH2:11][CH2:10]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: COC1CCC(OC)O1
Reactant: CCOP(=O)(OCC)C1CCc2c(N)c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23
Product: CCOP(=O)(OCC)C1CCc2c(-n3cccc3)c(C(F)(F)F)cc3[nH]c(=O)c(=O)n1c23

Procedure:
211 mg of 8-amino-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester and 66 mg of 2,5-dimethoxytetrahydrofuran are reacted for one hour at 140° C. bath temperature. After recrystallization from ethanol, 123 mg of 8-(1-pyrrolyl)-9-trifluoromethyl-2,3-dioxo-1,2,3,5,6,7-hexahydro-pyrido[1,2,3-de]quinoxaline-5-phosphonic acid diethyl ester of melting point 268° C. is obtained.
Reaction SMILES: [N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[CH:14]3[CH2:17][CH2:18][CH2:19][C:13]3=[N:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]>C(OCC)(=O)C.C(OCC)C>[N+:1]([C:4]1[CH:25]=[CH:24][C:7]([CH2:8][N:9]2[C:15](=[O:16])[C@H:14]3[CH2:17][CH2:18][CH2:19][C@H:13]3[NH:12][C:11]3[CH:20]=[CH:21][CH:22]=[CH:23][C:10]2=3)=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1C2CCCC2=Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: O=C1[C@H]2CCC[C@H]2Nc2ccccc2N1Cc1ccc([N+](=O)[O-])cc1
Yield: 46 %

Procedure:
Using 9-(4-nitrobenzyl)-2,3,9,10a-tetrahydrobenzo[b]cyclopenta[e][1,4]diazepin-10(1H)-one, synthesis was conducted by substantially the same procedure as in Working Example 24. The compound thus synthesized was purified by silica-gel column chromatography to afford the titled compound (yield 46%), m.p. 154°-155° C. (ethyl acetate-diethyl ether).
Reaction SMILES: [NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[C:9](Br)[N:8]([C@@H:14]3[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:32])[C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[C@@H:20]([CH3:33])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1.C([O-])=O.[NH4+]>CCO.[Pd]>[NH2:1][C:2]1[C:3]2[C:10]([C:11]#[N:12])=[CH:9][N:8]([C@@H:14]3[O:22][C@H:21]([CH2:23][O:24][C:25](=[O:32])[C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[C@@H:20]([CH3:33])[C@H:15]3[O:16][C:17](=[O:19])[CH3:18])[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1c(Br)c(C#N)c2c(N)ncnc21
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: CC(=O)O[C@@H]1[C@H](C)[C@@H](COC(=O)c2ccccc2)O[C@H]1n1cc(C#N)c2c(N)ncnc21
Yield: 68.9 %

Procedure:
To a suspension of the title compound from Step A (183 mg, 0.35 mmol) in EtOH (9 mL) were added ammonium formate (0.23 g, 3.6 mmol) and 10% palladium on activated carbon (20 mg) and the mixture was heated at reflux for 1.5 h. The hot reaction mixture was filtered through Celite and washed with hot EtOH. The solvent was removed and the residue treated with MeOH. The pale yellow solid was filtered thus yielding 105 mg of pure title compound. The filtrate was evaporated and purified on a silica gel column with a solvent system of CH2Cl2/MeOH: 50/1 to afford an additional 63 mg of title compound as a white solid.
Reaction SMILES: Cl.CC[O:4]CCO.[Cl:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:10]=1[C:11]([C:13]1[C:22]([OH:23])=[CH:21][C:16]2[C:17]([C:19]#[N:20])=[CH:18][C:15]=2[CH:14]=1)=[O:12]>O>[Cl:8][C:9]1[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:10]=1[C:11]([C:13]1[C:22]([OH:23])=[CH:21][C:16]2[C:17]([C:19]([NH2:20])=[O:4])=[CH:18][C:15]=2[CH:14]=1)=[O:12]
Reactant: CCOCCO
Reactant: N#CC1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Agent: Cl
Solvent: O
Product: NC(=O)C1=Cc2cc(C(=O)c3c(Cl)cccc3Cl)c(O)cc21
Reaction time: 48 h

Procedure:
20 ml of concentrated hydrochloric acid and 10 ml of Cellosolve are added to 2 g of 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carbonitrile and stirring is carried out for 2 days at room temperature. 100 ml of water are added with stirring and the whole is filtered with suction and recrystallised from ether/hexane. 4-(2,6-dichlorobenzoyl)-5-hydroxybenzocyclobutene-1-carboxamide is obtained having a melting point of 174°.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1.Br[CH2:24][CH2:25][CH2:26][N:27]1[C:31](=[O:32])[C:30]2=[CH:33][CH:34]=[CH:35][CH:36]=[C:29]2[C:28]1=[O:37]>>[NH2:3][C:4]1[C:19]([Cl:20])=[CH:18][C:7]([C:8]([NH:10][CH2:11][CH:12]2[CH2:13][CH2:14][N:15]([CH2:24][CH2:25][CH2:26][N:27]3[C:31](=[O:32])[C:30]4[C:29](=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:28]3=[O:37])[CH2:16][CH2:17]2)=[O:9])=[C:6]([O:21][CH3:22])[CH:5]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: COc1cc(N)c(Cl)cc1C(=O)NCC1CCNCC1
Agent: Cl
Product: COc1cc(N)c(Cl)cc1C(=O)NCC1CCN(CCCN2C(=O)c3ccccc3C2=O)CC1
Yield: 53.2 %

Procedure:
4-Amino-5-chloro-2-methoxy-N-(piperidin-4-ylmethyl)benzamide dihydrochloride (11.1 g) and N-(3-bromopropyl)phthalimide (8.0 g) were reacted and treated in the same manner as in Preparation Example 150 to give 7.7 g of 4-amino-5-chloro-N-(1-(3-(2,3-dihydro-1,3-dioxo-1 H-isoindol-2-yl)propyl)piperidin-4-ylmethyl)-2-methoxybenzamide.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[CH:17])=[CH:14][C:13]([C:18]3[CH:19]=[N:20][C:21]([N:24]4[CH2:29][CH2:28][C:27]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:26][CH2:25]4)=[N:22][CH:23]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2].Br[C:35]1[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=1.CCN(C(C)C)C(C)C.CCCCCC>CN(C=O)C.[Cu]I.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>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[S:8][C:9]2[C:15]([C:16]#[C:17][C:35]3[CH:40]=[CH:39][CH:38]=[C:37]([O:41][CH3:42])[N:36]=3)=[CH:14][C:13]([C:18]3[CH:23]=[N:22][C:21]([N:24]4[CH2:25][CH2:26][C:27]([CH3:33])([C:30]([OH:32])=[O:31])[CH2:28][CH2:29]4)=[N:20][CH:19]=3)=[CH:12][C:10]=2[N:11]=1)=[O:5])[CH3:2]
Reactant: C#Cc1cc(-c2cnc(N3CCC(C)(C(=O)O)CC3)nc2)cc2nc(NC(=O)NCC)sc12
Reactant: COc1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)O)CC4)nc3)cc(C#Cc3cccc(OC)n3)c2s1
Temperature: 80 °C
Yield: 4.5 %

Procedure:
To a solution of 1-[5-[2-(ethylcarbamoylamino)-7-ethynyl-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylic acid (0.18 g, 0.39 mmol) in DMF (5 mL) was added 2-bromo-6-methoxy pyridine (0.15 g, 0.77 mmol) and DIPEA (0.16 mL, 1.16 mmol). The reaction mass was degassed by purging N2 for 15 min followed by addition of CuI (0.015 g, 0.077 mmol) and tetrakis(triphenylphosphine)palladium (0) (0.067 g, 0.058 mmol). The reaction mixture was again degassed for 10-15 min then heated up to 80° C. for 30 min under microwave irradiation. The mixture was then poured in 100 mL of ice-cold water, extracted with EtOAc (3×100 mL) and the combined organic layer washed with brine, dried over anhydrous Na2SO4, filtered and evaporated under reduced pressure. The crude residue was purified over 100-200 M silica-gel using 30% EtOAc:hexane to obtain Compound 152 as an off-white solid (0.01 g, 5% yield). 1H NMR (DMSO-d6): δ 1.09 (t, J=7.20 Hz, 3H), 1.19 (s, 3H), 1.41 (m, 2H), 2.02 (m, 2H), 3.19 (m, 2H), 3.30 (m, 2H), 3.90 (s, 3H), 4.30 (m, 2H), 6.77 (br s, 1H), 6.93 (d, J=8.40 Hz, 1H), 7.34 (d, J=7.20 Hz, 1H), 7.66-7.82 (m, 2H), 7.97 (s, 1H), 8.81 (s, 2H), 10.91 (br s, 1H) and 12.46 (br s, 1H). MS: 572.05 [M+H]+.
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][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25](SC)=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32].C(O)(C(F)(F)F)=[O:34].OO.NC(N)=O.FC(F)(F)C(OC(=O)C(F)(F)F)=O>CC#N>[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][CH:7]=[C:6]2[O:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[C:23](=[O:31])[N:24]([CH3:30])[C:25]([OH:34])=[N:26][CH:27]=2)=[CH:18][C:17]=1[F:32]
Reactant: COc1cc2nccc(Oc3ccc(-c4cnc(SC)n(C)c4=O)cc3F)c2cc1OC
Reactant: O=C(O)C(F)(F)F
Agent: NC(N)=O
Agent: OO
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: CC#N
Product: COc1cc2nccc(Oc3ccc(-c4cnc(O)n(C)c4=O)cc3F)c2cc1OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
5-(4-(6,7-Dimethoxyquinolin-4-yloxy)-3-fluorophenyl)-3-methyl-2-methylthio-3H-pyrimidin-4-one (Step 1, 1.048 g, 2.3 mmol) was dissolved in CH3CN (15 mL) and TFA (1.7 mL) and cooled to 0° C. Urea hydrogen peroxide (290 mg, 3.09 mmol) was added, and the reaction was stirred for 5 min. trifluoroacetic anhydride (0.43 mL, 3.09 mmol) was added, and the reaction was warmed to RT and stirred for 40 min. The mixture was quenched with H2O (10 mL) and EtOAc (25 mL) and allowed to stand overnight. Saturated NaHCO3 (10 mL) and EtOAc were added, and the layers were separated. The aqueous layer was extracted with EtOAc, and the organic layers were combined, dried over Na2SO4, filtered, concentrated, and purified on silica gel (EtOAc→1:1 EtOAc/MeOH) to give title compound. MS (ESI pos. ion) m/z: 411. Calc'd for C21H17FN3O5: 410.39.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([N:35]2[CH2:40][C@H:39]([CH3:41])[O:38][C@H:37]([CH3:42])[CH2:36]2)=[C:22]([F:34])[C:23]2[O:27][N:26]=[C:25]([C:28](OCC)=[O:29])[C:24]=2[CH:33]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[F:43][C:44]1([F:50])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[F:43][C:44]1([F:50])[CH2:49][CH2:48][N:47]([C:28]([C:25]2[C:24]3[CH:33]=[C:20]([CH2:19][OH:18])[C:21]([N:35]4[CH2:36][C@H:37]([CH3:42])[O:38][C@H:39]([CH3:41])[CH2:40]4)=[C:22]([F:34])[C:23]=3[O:27][N:26]=2)=[O:29])[CH2:46][CH2:45]1
Reactant: FC1(F)CCNCC1
Reactant: CCOC(=O)c1noc2c(F)c(N3C[C@@H](C)O[C@@H](C)C3)c(CO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)cc12
Product: C[C@@H]1CN(c2c(CO)cc3c(C(=O)N4CCC(F)(F)CC4)noc3c2F)C[C@H](C)O1

Procedure:
Starting materials: ethyl 5-((tert-butyldiphenylsilyloxy)methyl)-6-((2R,6S)-2,6-dimethylmorpholino)-7-fluorobenzo[d]isoxazole-3-carboxylate (Intermediate 204) and 4,4-difluoropiperidine
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH3:8])[C:3]=1[Cl:9].C1C(=O)N([Br:17])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C>C(Cl)(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([CH2:8][Br:17])[C:3]=1[Cl:9]
Reactant: Cc1cccc(Br)c1Cl
Reactant: O=C1CCC(=O)N1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: ClC(Cl)(Cl)Cl
Product: Clc1c(Br)cccc1CBr
Temperature: 25 °C

Procedure:
A solution of 1-bromo-2-chloro-3-methyl-benzene (3.90 g, 19.00 mmol), NBS (3.60 g, 20.20 mmol) and a catalytic amount of AIBN (50 mg) in CCl4 was refluxed for 30 minutes. The reaction mixture was cooled to room temperature and filtered. The precipitate was washed with pentane. The solvent was distilled off and the residue was purified by column chromatography using pentane as the eluant to afford the title compound. Spectroscopic data: 1H NMR (300 MHz, CDCl3) δ 4.62 (s, 2H), 7.14 (t, J=7.62 Hz, 1H), 7.39 (dd, J=7.62 Hz, 1H), 7.60 (dd, J=7.91 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][OH:10].Cl[C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH2:9][O:10][C:12]1[CH:13]=[C:14]2[N:21]([CH3:22])[C:20]([CH3:24])([CH3:23])[CH2:19][N:15]2[C:16](=[O:18])[N:17]=1
Reactant: OCc1cc(F)ccc1F
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)ccc3F)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (2,5-difluorophenyl)methanol and 7-chloro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: O=C1C2C(=CC=CC=2)C(=O)[N:3]1[CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([C:29]([O:31]CC)=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1.C(O)C.[OH-].[K+]>C(O)(=O)C>[NH2:3][CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[N:28]=[C:27]([C:29]([OH:31])=[O:30])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[N:20]=2)=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1nc(-c2ccc(CN3C(=O)c4ccccc4C3=O)cc2)nc2ccccc12
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)O
Product: NCc1ccc(-c2nc(C(=O)O)c3ccccc3n2)cc1
Temperature: 100 °C
Reaction time: 24 h

Procedure:
Into a 500-mL round-bottom flask, was placed ethyl 2-[4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]phenyl]quinazoline-4-carboxylate (4 g, 9.14 mmol, 1.00 equiv), ethanol (40 mL) and 1N KOH (70 mL). The resulting solution was stirred for 24 h at 100° C. in an oil bath. The pH value of the solution was adjusted to 7 with acetic acid. The resulting mixture was concentrated under vacuum. This resulted in 2.6 g (crude) of 2-[4-(aminomethyl)phenyl]quinazoline-4-carboxylic acid as a white solid. MS (ESI) m/z 280 ([M+H]+).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[CH:4][C:3]=1[CH:8]=O.C([O-])([O-])=O.[K+].[K+].[C:16]([O:20][CH3:21])(=[O:19])[CH2:17][SH:18]>CN(C=O)C.O>[CH3:21][O:20][C:16]([C:17]1[S:18][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][C:3]=2[CH:8]=1)=[O:19]
Reactant: COC(=O)CS
Reactant: O=Cc1cnccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc2cnccc2s1
Temperature: 45 °C
Reaction time: 1 h

Procedure:
To a solution of 4-bromo-pyridine-3-carbaldehyde (1.50 g, 8.06 mmol) in DMF (10 mL) and water (1 mL) was added K2CO3 (1.34 g, 9.68 mmol) and methyl thioglycolate (0.87 mL, 9.68 mmol). The mixture was heated at 45° C. for 18 hours. The reaction mixture was removed from the heating bath and diluted with water (50 mL). After 1 hour, the fluffy solid that formed was filtered and washed with water. The material thus obtained was dried in a 60° C. vacuum oven to a constant weight of 0.92 g (59%). MS m/z 194 (M+H)+.
Reaction SMILES: [Li]CCCC.[C:6]1([CH3:20])[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[F:19].CON(C)[C:24]([C@@H:26]1[CH2:31][CH2:30][CH2:29][N:28]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:27]1)=[O:25]>C1COCC1>[C:35]([O:34][C:32]([N:28]1[CH2:29][CH2:30][CH2:31][C@@H:26]([C:24](=[O:25])[C:15]2[CH:16]=[CH:17][CH:18]=[C:13]([O:12][C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH3:20])[C:14]=2[F:19])[CH2:27]1)=[O:33])([CH3:38])([CH3:37])[CH3:36]
Reactant: Cc1ccccc1Oc1ccccc1F
Reactant: CON(C)C(=O)[C@@H]1CCCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: Cc1ccccc1Oc1cccc(C(=O)[C@@H]2CCCN(C(=O)OC(C)(C)C)C2)c1F
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 2.0 mL of 2.0 M n-BuLi (2.0 mL, 4.0 mmol) was added dropwise to a solution of 1-(o-tolyloxy)-2-fluorobenzene (0.7009 g, 3.5 mmol) in THF (15 mL); the internal temperature was maintained below −70° C. during the addition. A pale, yellow slurry resulted. Confirmation of proton abstraction was confirmed by quenching an aliquot on solid I2. A solution of (R)-tert-butyl 3-(N-methoxy-N-methylcarbamoyl)piperidine-1-carboxylate (1.1159 g, 4.1 mmol) in THF (15 mL) was added dropwise. The reaction was permitted to warm to rt and stirred at for 12 h. The reaction was quenched at 0° C. with satd aq NH4Cl and extracted with Et2O. The Et2O extracts were washed with aq NH4Cl and brine and dried over Na2SO4. Removal of the solvent left crude (3R)-1-tert-butoxycarbonyl-3-(2-fluoro-3-(o-tolyloxy)benzoyl)piperidine (1.79 g, ˜80% pure, quantitative) which was used directly without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:16])=[O:15])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[CH3:28][CH:29]([C:31]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][CH:39]([CH2:42]O)[CH2:38][CH2:37]2)[O:33][N:32]=1)[CH3:30].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>C1COCC1>[CH3:30][CH:29]([C:31]1[N:35]=[C:34]([N:36]2[CH2:37][CH2:38][CH:39]([CH2:42][O:1][C:2]3[CH:7]=[CH:6][C:5]([C:8]4[CH:9]=[CH:10][C:11]([S:14]([NH:17][CH2:18][CH2:19][NH:20][C:21](=[O:27])[O:22][C:23]([CH3:24])([CH3:26])[CH3:25])(=[O:15])=[O:16])=[CH:12][CH:13]=4)=[CH:4][CH:3]=3)[CH2:40][CH2:41]2)[O:33][N:32]=1)[CH3:28]
Reactant: CC(C)(C)OC(=O)NCCNS(=O)(=O)c1ccc(-c2ccc(O)cc2)cc1
Reactant: CC(C)c1noc(N2CCC(CO)CC2)n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)c1noc(N2CCC(COc3ccc(-c4ccc(S(=O)(=O)NCCNC(=O)OC(C)(C)C)cc4)cc3)CC2)n1
Yield: 44.7 %

Procedure:
The title compound (169 mg, 45%) was prepared as a white solid from 1,1-dimethylethyl (2-{[(4′-hydroxy-4-biphenylyl)sulfonyl]amino}ethyl)carbamate (246 mg, 0.63 mmol), {1-[3-(1-methylethyl)-1,2,4-oxadiazol-5-yl]-4-piperidinyl}methanol (prepared as in Example 20, Step 3, 214 mg, 0.95 mmol) and Ph3P (249 mg, 0.95 mmol) in THF (5 mL) followed by diisopropyl azodicarboxylate (0.187 mL, 0.95 mmol) in a manner similar to Example 1, Step 2. 1H NMR (400 MHz, DMSO-d6) δ 7.84-7.72 (m, 4H), 7.70-7.60 (m, 3H), 7.03 (d, 2H, J=8.8 Hz), 6.76 (t, 1H, J=5.4 Hz), 4.03-3.91 (m, 2H), 3.90 (d, 2H, J=6.4 Hz), 3.15-3.05 (m, 2H), 2.98-2.88 (m, 2H), 2.83-2.67 (m, 3H), 2.06-1.94 (m, 1H), 1.89-1.79 (m, 2H), 1.38-1.24 (m, 11H), 1.14 (d, 6H, J=7.0 Hz); LRMS (ESI), m/z 600 (M+H).