Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CO.[OH-].[K+].[Br:5][C:6]1[C:11]2[CH:12]=[C:13]([C:15]([CH3:18])([CH3:17])[CH3:16])[O:14][C:10]=2[C:9]([C:19]([O:21]C)=[O:20])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O1CCCC1>[Br:5][C:6]1[C:11]2[CH:12]=[C:13]([C:15]([CH3:17])([CH3:18])[CH3:16])[O:14][C:10]=2[C:9]([C:19]([OH:21])=[O:20])=[CH:8][C:7]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: COC(=O)c1cc(-c2ccccc2)c(Br)c2cc(C(C)(C)C)oc12
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)c1cc2c(Br)c(-c3ccccc3)cc(C(=O)O)c2o1
Temperature: 25 °C
Reaction time: 3.5 h
Yield: 94.4 %

Procedure:
A methanol (12 ml) solution of potassium hydroxide (1.26 g, 22.5 mol) was put into a tetrahydrofuran (50 ml) solution of methyl 4-bromo-2-tert-butyl-5-phenyl-1-benzofuran-7-carboxylate (I-255) (2.90 g, 7.49 mmol), followed by stirring at room temperature for 3.5 hours. The reaction liquid was concentrated under reduced pressure, then 1 N hydrochloric acid (100 ml) and water (100 ml) were added, the product was extracted with ethyl acetate (200 ml×2). The organic layer was washed with saturated brine (50 ml×2), then dried over anhydrous magnesium sulfate, concentrated under reduced pressure to obtain the entitled compound (2.64 g, 95%) as a yellow white solid.
Reaction SMILES: C(OC([N:11]1[CH2:15][CH2:14][CH2:13][C@@H:12]1[C:16]1[O:17][C:18]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)=[C:19]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[N:20]=1)=O)C1C=CC=CC=1>C(O)C.[Pd]>[C:21]1([C:19]2[N:20]=[C:16]([C@H:12]3[CH2:13][CH2:14][CH2:15][NH:11]3)[O:17][C:18]=2[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1c1nc(-c2ccccc2)c(-c2ccccc2)o1
Agent: [Pd]
Solvent: CCO
Product: c1ccc(-c2nc([C@H]3CCCN3)oc2-c2ccccc2)cc1
Reaction time: 10 h

Procedure:
A mixture of (2R)-1-benzyloxycarbonyl-2-(4,5-diphenyloxazol-2-yl)pyrrolidine (4 g) and 10% Pd/C (0.5 g) in ethanol (120 ml) was stirred under H2 for 10 hours. The catalyst was filtered off and filtrate was evaporated in vacuo to give (2R)-2-(4,5-diphenyloxazol-2-yl)pyrrolidine. NMR (CDCl3, δ): 1.7-2.3 (4H, m), 2.9-3.2 (2H, m), 3.6-3.8 (1H, m), 4.44 (1H, t, J=6.0 Hz), 7.2-7.7 (10H, m)
Reaction SMILES: [F:1][C:2]1[C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH:19]([CH3:21])[CH3:20])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.Cl.[O:60]([NH2:62])[CH3:61].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F>CN(C)C=O>[F:1][C:2]1[C:25]([C:26]([NH:62][O:60][CH3:61])=[O:28])=[CH:24][CH:23]=[CH:22][C:3]=1[O:4][C:5]1[C:10]2=[C:11]([CH:19]([CH3:21])[CH3:20])[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:13][N:9]2[N:8]=[CH:7][N:6]=1
Reactant: CCOC(=O)c1cn2ncnc(Oc3cccc(C(=O)O)c3F)c2c1C(C)C
Reactant: CON
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)c1cn2ncnc(Oc3cccc(C(=O)NOC)c3F)c2c1C(C)C
Reaction time: 8 h
Yield: 93.4 %

Procedure:
To a solution of 4-[2-fluoro-3-carboxyphenoxy]-5-(1-methylethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxylic acid, ethyl ester (14 mg, 0.036 mmol) in dimethyl formamide at RT were added EDCI (14 mg, 0.07 mmol), DIPEA (20 μL, 0.11 mmol), HOBt (9.7 mg, 0.07 mmol), and methoxylamine hydrochloride (6 mg, 0.07 mmol). After stirring overnight, HPLC analysis revealed that only 10% product was formed. BOP reagent (0.1 mmol) was added. After 6 h, all the starting material was consumed. The mixture was purified by reverse phase preparative HPLC to afford the desired product (14 mg, 93%). LC/MS: (M+H)+=417.
Reaction SMILES: [CH3:1][C:2]1[C:41]([CH3:42])=[CH:40][C:5]2[N:6]([C:21]([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]([CH:9]([OH:20])[C:10]3[C:11]([F:19])=[C:12]([OH:18])[CH:13]=[C:14]([CH2:16][CH3:17])[CH:15]=3)=[N:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].I[CH2:50][CH3:51]>CN(C=O)C.CCOC(C)=O>[CH3:1][C:2]1[C:41]([CH3:42])=[CH:40][C:5]2[N:6]([C:21]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)([C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:7]([CH:9]([C:10]3[CH:15]=[C:14]([CH2:16][CH3:17])[CH:13]=[C:12]([O:18][CH2:50][CH3:51])[C:11]=3[F:19])[OH:20])=[N:8][C:4]=2[CH:3]=1
Reactant: CCI
Reactant: CCc1cc(O)c(F)c(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOc1cc(CC)cc(C(O)c2nc3cc(C)c(C)cc3n2C(c2ccccc2)(c2ccccc2)c2ccccc2)c1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 100.1 %

Procedure:
To a solution of this phenol (34 mg, 0.061 mmol) in 2 mL DMF, were added K2CO3 (10 mg, 0.073 mmol) and iodoethane (15 μL, 0.18 mmol). The mixture was stirred at rt for 16 h, then was diluted with EtOAc. The organic phase was washed with H2O and brine, dried (Na2SO4), filtered through a 1″ pad of silica gel and concentrated to afford 35.7 mg of Intermediate 415.3. LCMS (2 min gradient) RT=1.97 min, 585.47 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:14]=[C:13]([CH:15]([CH3:17])[CH3:16])[CH:12]=[C:11]2[C:3]=1[C:4](=[O:18])[CH2:5][C:6]1([O:10]2)[CH2:9][CH2:8][CH2:7]1.[CH3:19][O:20]C(Cl)Cl>[Ti](Cl)(Cl)(Cl)Cl.ClCCl>[OH:1][C:2]1[C:14]([CH:19]=[O:20])=[C:13]([CH:15]([CH3:16])[CH3:17])[CH:12]=[C:11]2[C:3]=1[C:4](=[O:18])[CH2:5][C:6]1([O:10]2)[CH2:7][CH2:8][CH2:9]1
Reactant: CC(C)c1cc(O)c2c(c1)OC1(CCC1)CC2=O
Reactant: COC(Cl)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: CC(C)c1cc2c(c(O)c1C=O)C(=O)CC1(CCC1)O2
Temperature: -70 °C
Reaction time: 3 h

Procedure:
Under argon, 9.60 g (39 mmol) of 5-hydroxy-7-isopropylspiro[chromen-2,1′-cyclobutan]-4(3H)-one (Example 46A) are dissolved in 400 ml of abs. dichloromethane and cooled to −70° C. At this temperature, 97.44 ml (97.44 mmol) of titanium(IV) chloride (1 M solution in dichloromethane) are added dropwise such that the temperature does not exceed −65° C. The mixture is stirred briefly at −70° C., 3.88 ml (42.87 mmol) of dichloromethyl methyl ether are then added and the mixture is subsequently warmed to 0° C. After 3 hours at this temperature, the reaction mixture is added carefully to ice-water and extracted four times with dichloromethane. The combined organic phases are washed three times with saturated sodium chloride solution, dried over magnesium sulfate, filtered and evaporated to dryness. The crude product obtained is adsorbed on silica gel and purified on a silica gel column (mobile phase: cyclohexane→cyclohexane/ethyl acetate 30:1). This gives 8.1 g (76% of theory) of the title compound in a purity of 77%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([OH:19])=O)=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][C:17]([Cl:23])=[O:19])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: O=C(O)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(Cl)CCc1ccc(Sc2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of acid from step 4 in CH2Cl2 (0.2M) was added oxalyl chloride (1.2 eq) and one drop of DMF. The mixture was stirred at rt for 3 h and the solvent evaporated. The crude acid chloride was used as such in the next step.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:9]([O:10][CH3:11])=[C:8]([S:12]([O:15][C:16]2[CH:21]=[CH:20][C:19]([C:22]3[C:34]4[C:33]([CH3:35])=[C:32]([CH3:36])[S:31][C:30]=4[C:29]([Br:37])=[C:28]4[C:23]=3[CH:24]=[CH:25][CH:26]=[CH:27]4)=[CH:18][C:17]=2[CH:38]2[CH2:42][CH2:41][CH2:40][CH2:39]2)(=[O:14])=[O:13])[S:7][CH:6]=1)=[O:4].[OH-].[K+]>C1COCC1.CO>[Br:37][C:29]1[C:30]2[S:31][C:32]([CH3:36])=[C:33]([CH3:35])[C:34]=2[C:22]([C:19]2[CH:20]=[CH:21][C:16]([O:15][S:12]([C:8]3[S:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:9]=3[O:10][CH3:11])(=[O:14])=[O:13])=[C:17]([CH:38]3[CH2:42][CH2:41][CH2:40][CH2:39]3)[CH:18]=2)=[C:23]2[C:28]=1[CH:27]=[CH:26][CH:25]=[CH:24]2
Reactant: COC(=O)c1csc(S(=O)(=O)Oc2ccc(-c3c4ccccc4c(Br)c4sc(C)c(C)c34)cc2C2CCCC2)c1OC
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1c(C(=O)O)csc1S(=O)(=O)Oc1ccc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc1C1CCCC1
Reaction time: 1.5 h
Yield: 84.5 %

Procedure:
At ambient temperature, to a stirred solution of 5-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2-cyclopentyl-phenoxysulfonyl]-4-methoxy-thiophene-3-carboxylic acid methyl ester (0.722 g, 1.05 mmol) in THF:MeOH (3:2, 10 mL) was added 1N KOH (5.26 mL). After 1.5 h, the reaction was quenched with 1N HCl (40 mL) and extracted with EtOAc. The combined organic extracts were dried (MgSO4) and concentrated. Purification on 2% H3PO4 /MeOH treated Biotage KP-Sil, eluting with 25% EtOAc/hexane gave 0.596 g (85%) of the title compound as a white solid, mp >225° C.; 1H NMR (DMSO-d6) δ 1.34-1.39 (m, 2 H), 1.49-1.54 (m, 5 H), 1.62-1.73 (m, 3 H), 1.79-1.83 (m, 1 H), 2.43 (s, 3 H), 3.23 (quintet, 1 H), 3.97 (s, 3 H), 7.24 (dd, 1 H), 7.30 (d, 1 H), 7.34-7.36 (m, 2 H), 7.49 (t, 1 H), 7.64 (t, 1 H), 8.19 (d, 1 H), 8.72 (s, 1 H), 13.34 (br. s, 1 H). IR (KBr) 3400, 2950, 1690, 1375 and 860 cm-1. mass spectrum (-ESI), m/z 669/671 (M-H). Anal. Calcd. for C31H27BrO6S3 : C, 55.44; H, 4.05 N, 0.00. Found: C, 55.25; H, 4.11 N, 0.01.
Reaction SMILES: [CH3:1][N:2]([CH3:13])[C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=O)=[CH:5][CH:4]=1.[CH2:14]([C@H:21]1[CH2:25][NH:24][C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[CH2:14]([C@H:21]1[CH2:25][N:24]([C:10](=[O:12])[CH2:9][C:6]2[CH:5]=[CH:4][C:3]([N:2]([CH3:1])[CH3:13])=[CH:8][CH:7]=2)[C@H:23]([C:26]([NH:28][C:29]2[CH:34]=[CH:33][C:32]([O:35][C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)=[CH:31][CH:30]=2)=[O:27])[CH2:22]1)[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: CN(C)c1ccc(CC(=O)O)cc1
Reactant: O=C(Nc1ccc(Oc2ccc(F)cc2)cc1)[C@@H]1C[C@@H](Cc2ccccc2)CN1
Product: CN(C)c1ccc(CC(=O)N2C[C@H](Cc3ccccc3)C[C@H]2C(=O)Nc2ccc(Oc3ccc(F)cc3)cc2)cc1
Yield: 7.6 %

Procedure:
Proceeding as in Example 1, but substituting 2-(4-(dimethylamino)phenyl)acetic acid and (2S,4R)-4-benzyl-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide, gave Compound 35, (2S,4R)-4-benzyl-1-(2-(4-(dimethylamino)phenyl)acetyl)-N-(4-(4-fluorophenoxy)phenyl)pyrrolidine-2-carboxamide (2.5 mg, 7.6%). 1H-NMR (400 MHz, DMSO-D6): σ 9.95 (s, 1H), 7.56 (m, 2H), 7.23 (t, 2H), 7.12 (m, 5H), 6.98 (m, 6H), 6.64 (m, 2H), 4.46 (m, 1H), 3.49 (s, 2H), 3.24 (m, 1H), 2.84 (s, 6H), 2.60 (m, 3H), 1.87 (m, 2H). MS (EI) for C34H34FN3O3: 552.6 (MH+).
Reaction SMILES: [CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][C:24]([OH:26])=[O:25])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:27])(=[O:6])=[O:5])([CH3:3])[CH3:2].[CH3:28]S(C)=O.[H-].[Na+].CI>O>[CH:1]([S:4]([N:7]1[C:11]2[CH:12]=[C:13]([C:16](=[CH:23][C:24]([O:26][CH3:28])=[O:25])[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH:14]=[CH:15][C:10]=2[N:9]=[C:8]1[NH2:27])(=[O:5])=[O:6])([CH3:3])[CH3:2]
Reactant: CC(C)S(=O)(=O)n1c(N)nc2ccc(C(=CC(=O)O)c3ccccc3)cc21
Reactant: CS(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: COC(=O)C=C(c1ccccc1)c1ccc2nc(N)n(S(=O)(=O)C(C)C)c2c1
Temperature: 25 °C

Procedure:
To a stirred solution of 0.77 g. of 1-isopropylsulfonyl-2-amino-6-(α-hydroxycarbonylmethylenebenzyl)benzimidazole (from Example 17) in 10 ml. of dimethylsulfoxide containing 0.1 g. of a fifty percent suspension of sodium hydride in mineral oil was added in one portion 0.3 g. of methyl iodide. The reaction mixture was stirred at room temperature for fifteen minutes, and then was diluted by the addition of 50 ml. of water. The aqueous mixture was extracted several times with ethyl acetate. The extracts were combined, washed with water, dried, and the solvent was removed by evaporation under reduced pressure to provide 1-isopropylsulfonyl-2-amino-6-(α-methoxycarbonylmethylenebenzyl)benzimidazole as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:5]=[CH:6][CH:7]=1.[Cl:17][C:18]1[N:23]=[C:22](Cl)[C:21]([F:25])=[CH:20][N:19]=1.CCN(C(C)C)C(C)C.CCCCCC.C(OCC)(=O)C>C(O)CCC.O>[Cl:17][C:18]1[N:23]=[C:22]([NH:1][C:2]2[CH:3]=[C:4]([N:8]([CH3:16])[C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH:5]=[CH:6][CH:7]=2)[C:21]([F:25])=[CH:20][N:19]=1
Reactant: Fc1cnc(Cl)nc1Cl
Reactant: CN(C(=O)OC(C)(C)C)c1cccc(N)c1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Solvent: O
Product: CN(C(=O)OC(C)(C)C)c1cccc(Nc2nc(Cl)ncc2F)c1
Temperature: 120 °C
Reaction time: 3 h
Yield: 60.8 %

Procedure:
In a pressure tube tert-butyl (3-aminophenyl)(methyl)carbamate (2.0 g), 2,4-dichloro-5-fluoropyrimidine (2.25 g) and DIPEA (2.32 g) were added in 1-butanol (15 ml). The reaction mixture was heated at 120° C. for 3 hr. The reaction was monitored on TLC using hexane:ethyl acetate (7:3) as mobile phase. The reaction was complete after 3 hr. After completion of the reaction, the reaction mixture was allowed to cool at room temperature. The reaction mixture was poured into water and extracted with ethyl acetate (3×25 ml). Ethyl acetate layer washed with brine solution, dried over sodium sulfate and concentrated under reduced pressure at 40° C. Crude material was purified by using Combiflash chromatography. Product was eluted with 14.8% ethyl acetate in hexane to give 1.93 g of tert-butyl (3-((2-chloro-5-fluoropyrimidin-4-yl)amino)phenyl)(methyl)carbamate. M+1=466.8.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][CH:7]2[CH2:12][CH2:11][N:10](C(OC(C)(C)C)=O)[CH2:9][CH2:8]2)=[C:4]([O:22][CH:23]([F:25])[F:24])[CH:3]=1.Cl.Cl[C:28]1[N:33]=[C:32]([NH:34][C@@H:35]2[CH2:43][C@H:42]3[N:38]([CH2:39][CH2:40][CH2:41]3)[C:37]([CH3:45])([CH3:44])[CH2:36]2)[C:31]([F:46])=[CH:30][N:29]=1.CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(O)C>[F:25][CH:23]([F:24])[O:22][C:4]1[CH:3]=[C:2]([NH:1][C:28]2[N:33]=[C:32]([NH:34][C@@H:35]3[CH2:43][C@H:42]4[N:38]([CH2:39][CH2:40][CH2:41]4)[C:37]([CH3:44])([CH3:45])[CH2:36]3)[C:31]([F:46])=[CH:30][N:29]=2)[CH:21]=[CH:20][C:5]=1[O:6][CH:7]1[CH2:8][CH2:9][NH:10][CH2:11][CH2:12]1
Reactant: CC1(C)C[C@H](Nc2nc(Cl)ncc2F)C[C@@H]2CCCN21
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(N)cc2OC(F)F)CC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: Cl
Solvent: CC(C)O
Solvent: O
Product: CC1(C)C[C@H](Nc2nc(Nc3ccc(OC4CCNCC4)c(OC(F)F)c3)ncc2F)C[C@@H]2CCCN21
Yield: 58.3 %

Procedure:
The general displacement procedure described herein was used with tert-butyl 4-(4-amino-2-(difluoromethoxy)phenoxy)piperidine-1-carboxylate (113 mg, 0.3 mmol), (7R,8aS)-N-(2-chloro-5-fluoropyrimidin-4-yl)-octahydro-5,5-dimethylindolizin-7-amine hydrochloride (106 mg, 0.3 mmol) and pTsOH.H2O (42 mg, 0.2 mmol) in IPA (3 mL) at reflux to give the product (91 mg, 55% yield) as a solid, after workup and purification by column chromatography on silica gel using DCM/2M NH3 in MeOH (1:0 to 85:15) as eluent.
Reaction SMILES: [C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH2:16])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:3])[CH3:2].[Cl:17][C:18]1[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:33])([CH3:32])[CH3:31])=[C:25]([F:35])[CH:24]=[CH:23][C:19]=1[C:20](O)=[O:21].C(Cl)(=O)C(Cl)=O.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[C:1]([NH:5][C:6]1[C:15]2[C:10](=[C:11]([NH:16][C:20](=[O:21])[C:19]3[CH:23]=[CH:24][C:25]([F:35])=[C:26]([CH2:27][NH:28][C:29](=[O:34])[C:30]([CH3:31])([CH3:32])[CH3:33])[C:18]=3[Cl:17])[CH:12]=[CH:13][CH:14]=2)[N:9]=[CH:8][N:7]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)C(=O)NCc1c(F)ccc(C(=O)O)c1Cl
Reactant: CC(C)(C)Nc1ncnc2c(N)cccc12
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(C)(C)Nc1ncnc2c(NC(=O)c3ccc(F)c(CNC(=O)C(C)(C)C)c3Cl)cccc12
Yield: 5.4 %

Procedure:
The title compound was prepared following the procedure described in Example-1 using N4-(tert-butyl)quinazoline-4,8-diamine (Intermediate-55, 100 mg, 0.46 mmol), 2-chloro-4-fluoro-3-(pivalamidomethyl)benzoic acid (Intermediate-64, 159 mg, 0.56 mmol), oxalyl chloride (117 mg, 0.93 mmol), DMF (1 drop) and DIPEA (178 mg, 1.38 mmol) in CH2Cl2 (5 mL) to afford 12 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 10.05 (s, 1H), 8.71-8.69 (d, J=7.2 Hz, 1H), 8.49 (s, 1H), 8.15-8.13 (d, J=7.8 Hz, 1H), 7.83 (t, 1H), 7.75-7.73 (m, 1H), 7.53-7.47 (m, 2H), 7.40-7.34 (t, J=8.7 Hz, 1H), 4.43 (d, 2H), 1.54 (s, 9H), 1.08 (s, 9H); MS [M+H]+: 486.56.
Reaction SMILES: [CH3:1][N:2]([CH3:25])[C:3]1[CH:4]=[C:5]([CH:13]=[C:14]([N:22]([CH3:24])[CH3:23])[C:15]=1[N:16]1[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1)[CH:6](O)CS(C)(=O)=O.C[O-].[Na+].[NH:29]([CH2:36][CH2:37][C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CS(C)=O>[NH:29]([CH:36]=[C:37]([CH2:6][C:5]1[CH:13]=[C:14]([N:22]([CH3:23])[CH3:24])[C:15]([N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[C:3]([N:2]([CH3:1])[CH3:25])[CH:4]=1)[C:38]#[N:39])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: N#CCCNc1ccccc1
Reactant: CN(C)c1cc(C(O)CS(C)(=O)=O)cc(N(C)C)c1N1CCCCC1
Agent: C[O-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CN(C)c1cc(CC(C#N)=CNc2ccccc2)cc(N(C)C)c1N1CCCCC1

Procedure:
A mixture of 7.4 g. of 3,5-bis(dimethylamino)-α-[(methylsulfonyl)methyl]-4-piperidinobenzyl alcohol, 1.64 g. of sodium methylate and 4.4 g. of β-anilinopropionitrile in 40 ml. of dimethylsulfoxide was stirred for 2 hours at 50° C. under nitrogen. The mixture was poured into 250 ml. of water, the precipitated product extracted with ethyl acetate, the ethyl acetate solution dried over sodium sulfate and evaporated. By purification of the residue over aluminum oxide with benzene and recrystallization from ethyl acetate/petroleum ether, there was obtained α-(anilinomethylene)-3,5-bis(dimethylamino)-4-piperidinohydrocinnamonitrile having a melting point of 200°-202° C.
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[S:15][C:16]1[CH:17]=[C:18]([CH:20]=[CH:21][CH:22]=1)[NH2:19].[CH:23]([C:26]1[O:30][N:29]=[C:28]([NH:31][C:32](=O)[O:33]C2C=CC=CC=2)[CH:27]=1)([CH3:25])[CH3:24]>>[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[S:15][C:16]1[CH:17]=[C:18]([NH:19][C:32]([NH:31][C:28]2[CH:27]=[C:26]([CH:23]([CH3:25])[CH3:24])[O:30][N:29]=2)=[O:33])[CH:20]=[CH:21][CH:22]=1
Reactant: CC(C)c1cc(NC(=O)Oc2ccccc2)no1
Reactant: COc1cc2ncnc(Sc3cccc(N)c3)c2cc1OC
Product: COc1cc2ncnc(Sc3cccc(NC(=O)Nc4cc(C(C)C)on4)c3)c2cc1OC
Yield: 69 %

Procedure:
The title compound was prepared using the procedure described in Example 113C with 3-(6,7-dimethoxyquinazolin-4-ylthio)aniline described in Example 115B (94 mg, 0.3 mmol) and phenyl 5-isopropylisoxazol-3-ylcarbamate described in Example 133A (110 mg, 0.45 mmol). Precipitation of the desired product detected completion of reaction. The solid was filtered off and washed with diethyl ether to give 1-(3-(6,7-dimethoxyquinazolin-4-ylthio)phenyl)-3-(5-isopropylisoxazol-3-yl)urea (96.26 mg, 69%) as a solid. 1H NMR (300 MHz, DMSO-d6) δ 9.57 (s, 1H), 9.02 (s, 1H), 8.70 (s, 1H), 7.84 (s, 1H), 7.53-7.42 (m, 2H), 7.36-7.27 (m, 3H), 6.51 (s, 1H), 3.99 (s, 6H), 3.04-3.00 (m, 1H), 1.23 (d, 6H); LC-MS (ESI) m/z 466 (M+H)+.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([OH:41])=O)[CH:34]=1)C1C=CC=CC=1.[CH3:42][N:43]1[CH2:48][CH2:47][CH:46]([CH2:49][N:50]2[CH2:55][CH2:54][NH:53][CH2:52][CH2:51]2)[CH2:45][CH2:44]1>>[OH:8][C:9]1[CH:14]=[C:13]([OH:15])[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][O:31][CH3:32])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([N:53]2[CH2:52][CH2:51][N:50]([CH2:49][CH:46]3[CH2:47][CH2:48][N:43]([CH3:42])[CH2:44][CH2:45]3)[CH2:55][CH2:54]2)=[O:41])[CH:34]=1
Reactant: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CN1CCC(CN2CCNCC2)CC1
Product: COCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCN(CC4CCN(C)CC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-[1-(3-methoxy-propyl)-1H-tetrazol-5-yl]-biphenyl-3-carboxylic acid and 1-(N-methylpiperidin-4-yl-methyl)piperazine as described in general procedure D. LCMS: 550 [M+H].
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[C:4]([C:10]([F:13])([F:12])[F:11])[CH:3]=1>C(O)C.[Ni]>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[C:4]([C:10]([F:11])([F:12])[F:13])[CH:3]=1
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Agent: [Ni]
Solvent: CCO
Product: NCc1ccc(F)cc1C(F)(F)F
Reaction time: 2.5 h
Yield: 19.6 %

Procedure:
To a solution of 4-fluoro-2-(trifluoromethyl)benzonitrile (2.0 g) in ethanol (10.0 mL) was added Raney Ni (catalytic amount). The reaction mixture was subjected for hydrogenation in Parr apparatus under 50 psi for 2-3 h. The reaction mass, was filtered through celite and the filtrate was concentrated to afford 0.400 g of desired product. 1H NMR (CDCl3): δ 3.98 (s, 2H), 7.24 (t, J=9.0 Hz, 1H), 7.34 (d, J=8.7 Hz, 1H), 7.54 (t, J=7.8 Hz, 1H); MS [M+H]+: 194.03.
Reaction SMILES: O.Br[C:3]1[C:4]2[C:9]([CH:10]=[C:11]3[C:16]=1[CH:15]=[CH:14][CH:13]=[CH:12]3)=[CH:8][CH:7]=[CH:6][CH:5]=2>C(C1C=CC(B(O)O)=CC=1)(C)(C)C.P([O-])([O-])([O-])=O.[K+].[K+].[K+].[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CN(C)C=O>[C:11]([C:13]1[CH:12]=[CH:11][C:16]([C:3]2[C:4]3[C:9]([CH:10]=[C:9]4[C:4]=2[CH:5]=[CH:6][CH:7]=[CH:8]4)=[CH:8][CH:7]=[CH:6][CH:5]=3)=[CH:15][CH:14]=1)([CH3:16])([CH3:12])[CH3:10]
Reactant: Brc1c2ccccc2cc2ccccc12
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)c1ccc(B(O)O)cc1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)c1ccc(-c2c3ccccc3cc3ccccc23)cc1
Temperature: 130 °C
Reaction time: 5 h
Yield: 183.6 %

Procedure:
A solution of 12 g of 9-bromoanthracene, 10 g of 4-tert-butylphenylboronic acid, 19.9 g of tripotassium phosphate, 3.02 g of tetrabutylammonium bromide and 106 mg of palladium acetate in 300 ml of dimethylformamide as a solvent was heated while stirred under nitrogen atmosphere at a temperature of 130° C. for 5 hours. After cooling the solution to room temperature, 400 ml of water was injected thereto and filtered. The solid separated by filtration was purified by silica gel column chromatography and vacuum dried to thereafter obtain 13.3 g of 9-(4′-tert-butylphenyl)anthracene.