Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[C:9]([OH:11])=O.C(Cl)(=O)C(Cl)=O.Cl.[CH3:28][O:29][C:30](=[O:36])[C@H:31]([CH:33]([CH3:35])[CH3:34])[NH2:32].C(N(CC)CC)C>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:12]2[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=2)[CH:6]=[CH:7][C:8]=1[C:9]([NH:32][C@H:31]([C:30]([O:29][CH3:28])=[O:36])[CH:33]([CH3:35])[CH3:34])=[O:11]
Reactant: COC(=O)[C@@H](N)C(C)C
Reactant: COc1cc(-c2ccc([N+](=O)[O-])cc2)ccc1C(=O)O
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H](NC(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1OC)C(C)C
Temperature: 50 °C
Reaction time: 0.75 h

Procedure:
3-Methoxy-4′-nitrobiphenyl-4-carboxylic acid (0.28 g, 1.0 mmol) was dissolved in methylene chloride (10 mL), and then oxalyl chloride (0.13 mL, 1.51 mmol) was added, followed by one drop of DMF. The resulting mixture was stirred at 50° C. for 45 min and then concentrated under reduced pressure. The residue was dissolved in methylene chloride (5 mL) and added dropwise to an ice-cold mixture of L-valine methyl ester hydrochloride (0.21 g, 1.2 mmol), methylene chloride (10 mL), and triethylamine (0.57 mL, 4.1 mmol). The resulting solution was stirred at rt for 18 h. The mixture was concentrated under reduced pressure, and the residue was purified by column chromatography (33% EtOAc in hexanes). LC/MS m/z 387.0 (MH+), retention time 3.40 min. 1H NMR (400 MHz, CD2Cl2) δ 1.05 (t, 6H), 2.32-2.39 (m, 1H), 3.78 (s, 3H), 4.10 (s, 3H), 4.71-4.78 (m, 1H), 7.22 (s, 1H), 7.38 (d, 1H), 7.80 (d, 2H), 8.22-8.37 (m, 4H).
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH2:13][O:14][CH2:15][CH2:16][NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=O)=O)=CC=1.[CH2:25]([NH:27][CH2:28][CH3:29])[CH3:26].[OH-].[Na+]>C1COCC1>[C:21]([O:20][C:18](=[O:19])[NH:17][CH2:16][CH2:15][O:14][CH2:13][CH2:12][N:27]([CH2:28][CH3:29])[CH2:25][CH3:26])([CH3:22])([CH3:23])[CH3:24]
Reactant: Cc1ccc(S(=O)(=O)OCCOCCNC(=O)OC(C)(C)C)cc1
Reactant: CCNCC
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCN(CC)CCOCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{2-[(tert-butoxycarbonyl)amino]ethoxy}ethyl 4-methylbenzenesulfonate (5.00 g) in THF (40 mL) was added diethylamine (14.5 mL). The reaction mixture was stirred at room temperature overnight, and 1N aqueous sodium hydroxide solution was added. The mixture was extracted with ethyl acetate, dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure to give the title compound (3.77 g).
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH:17]C(=O)OC(C)(C)C)=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1.FC(F)(F)C(O)=O>ClCCl>[CH3:1][C:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([CH2:16][NH2:17])=[N:14][N:15]=3)[N:12]=2)[O:4][N:3]=1
Reactant: Cc1cc(-c2ccc3nnc(CNC(=O)OC(C)(C)C)n3n2)on1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2ccc3nnc(CN)n3n2)on1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl (6-(3-methylisoxazol-5-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3-yl)methylcarbamate (3.63 g, 11.0 mmol) in dichloromethane (50 mL) was added trifluoroacetic acid (16.9 ml, 220 mmol) and the mixture was stirred at room temperature for one hour. The mixture was concentrated, taken up in a solution of ammonia in methanol (2.0 M) and purified by MPLC chromatography (eluted with 0-10% (1:10:90 NH4OH:MeOH:DCM) in DCM) to yield the product as a brown solid. MS m/z=230.8 [M+1]+. Calc'd for C10H10N6O: 230.1.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6](Br)[CH:5]=[CH:4][C:3]=1[CH:9]([O:12][CH:13]([CH3:15])[CH3:14])[O:10][CH3:11].C([Li])CCC.CCCCCC.[Cl-].[NH4+]>C1(C)C=CC=CC=1.C(OC)(C)(C)C>[Br:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]([O:12][CH:13]([CH3:15])[CH3:14])[O:10][CH3:11]
Reactant: COC(OC(C)C)c1ccc(Br)cc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Solvent: COC(C)(C)C
Solvent: Cc1ccccc1
Product: COC(OC(C)C)c1ccccc1Br

Procedure:
Condition 4: Under a nitrogen atmosphere, 2,4-dibromo-1-(1-methoxy-1-methylethoxymethyl)benzene (500 mg, 1.48 mmol) was dissolved in toluene (3.65 ml) and t-butylmethyl ether (0.35 ml). To the solution was added dropwise n-butyllithium in hexane (1.6 M, 1.01 ml, 1.62 mmol) at 0° C. over 30 minutes. After completion of the addition, a saturated aqueous solution of ammonium chloride was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure to give a product containing 4-bromide and 2-bromide as an oil (373 mg). According to 1H-NMR analysis of the product, the ratio of 4-bromide:2-bromide was determined as 40:1, which was calculated based on the integration ratio of peaks of protons at benzyl position.
Reaction SMILES: Cl[CH2:2][CH:3]=O.[F:5][C:6]([F:16])([F:15])[C:7](=[O:14])[CH2:8][C:9]([O:11]CC)=O.Cl>N1C=CC=CC=1>[F:16][C:6]([F:5])([F:15])[C:7]1[O:14][CH:2]=[CH:3][C:8]=1[CH2:9][OH:11]
Reactant: CCOC(=O)CC(=O)C(F)(F)F
Reactant: O=CCCl
Agent: Cl
Solvent: c1ccncc1
Product: OCc1ccoc1C(F)(F)F
Reaction time: 52 h

Procedure:
210 ml of chloroacetaldehyde were added over 30 minutes at 20° C. to 36.5 ml of ethyl 4,4,4-trifluoroacetoacetate in 600 ml of pyridine and the mixture was stirred for 52 hours. The reaction mixture was poured into 650 ml of concentrated hydrochloric acid and ice, stirred for 5 minutes and extracted with isopropyl ether. The extract was dried and the solvent was evaporated to obtain after chromatography on silica (eluent: 7/3 hexane/ethyl acetate), 43 g of the expected product.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.Br[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([OH:19])=[O:18].O.C(=O)([O-])[O-].[Na+].[Na+].[CH2:27](O)[CH3:28]>>[N:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[NH:6][C:2]=1[S:1][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][C:17]([O:19][CH2:27][CH3:28])=[O:18]
Reactant: Sc1nc2ccccc2[nH]1
Reactant: CCO
Reactant: O=C(O)CCCCCBr
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: CCOC(=O)CCCCCSc1nc2ccccc2[nH]1

Procedure:
2-Mercaptobenzimidazole (6.3 g) and 6-bromocaproic acid (7.8 g) were dissolved in ethanol (35 ml), and the solution ws heated under reflux for 12 hours. After cooling, the reaction was added with water, and the mixture was adjusted to pH 8 with aqueous sodium carbonate. The deposited crystals were collected by filtration, and dried to obtain 11.2 g of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH2:11])=[O:10])=[CH:4][C:3]=1[C:12]([F:15])([F:14])[F:13].N12CCCN=C1CCCCC2.N[C:28]1[CH:44]=[CH:43][C:31]([O:32][C:33]2[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][CH3:42])=[O:40])[CH:34]=2)=[CH:30][CH:29]=1.CS(C)=O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:10])[NH:11][C:28]2[CH:44]=[CH:43][C:31]([O:32][C:33]3[CH:38]=[CH:37][N:36]=[C:35]([C:39]([NH:41][CH3:42])=[O:40])[CH:34]=3)=[CH:30][CH:29]=2)=[CH:4][C:3]=1[C:12]([F:13])([F:14])[F:15]
Reactant: CNC(=O)c1cc(Oc2ccc(N)cc2)ccn1
Reactant: NC(=O)Nc1ccc(Cl)c(C(F)(F)F)c1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Solvent: CS(C)=O
Product: CNC(=O)c1cc(Oc2ccc(NC(=O)Nc3ccc(Cl)c(C(F)(F)F)c3)cc2)ccn1
Temperature: 115 °C
Yield: 59.9 %

Procedure:
1-(4-chloro-3-(trifluoromethyl)phenyl)urea (15 g, 0.0628 mol), 1,8-diazabicyclo[5.4.0]undec-7-ene (11.75 ml, 0.078 mol) and 4-(4-aminophenoxy)-N-methylpicolinamide (15.27 g, 0.0628 mol) were mixed with dimethyl sulfoxide (45 ml) and the reaction mass was then heated to 110-120° C. for 12-18 hours. The reaction mass was cooled to room temperature and quenched in water (250 ml). The quenched mass was extracted repeatedly with ethyl acetate and the combined ethyl acetate layer was then back washed with water. It was dried over sodium sulfate and evaporated under vacuum to obtain solid. The obtained solid was slurried in acetonitrile (150 ml) at ambient temperature and filtered to give 4-(4-(3-(4-chloro-3-(trifluoromethyl)phenyl) ureido) phenoxy)-N-methylpicolinamide (sorafenib base) (17.5 g).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:31](=[CH:32][CH:33]=1)[O:30][CH2:29][C:25]1([CH2:28][O:27][CH2:26]1)[C:5]12[CH2:9][O:8][C:7]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[N:6]1.CC1(C)C(C)(C)OB([C:42]2[CH2:43][CH2:44][O:45][CH2:46][CH:47]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:14]([O:13][C:11]([N:10]([C:7]1[O:8][CH2:9][C:5]2([N:6]=1)[C:25]1([CH2:26][O:27][CH2:28]1)[CH2:29][O:30][C:31]1[C:4]2=[CH:3][C:2]([C:42]2[CH2:47][CH2:46][O:45][CH2:44][CH:43]=2)=[CH:33][CH:32]=1)[C:18]([O:20][C:21]([CH3:22])([CH3:24])[CH3:23])=[O:19])=[O:12])([CH3:16])([CH3:15])[CH3:17]
Reactant: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(Br)ccc1OCC21COC1
Reactant: CC1(C)OB(C2=CCOCC2)OC1(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(C(=O)OC(C)(C)C)C1=NC2(CO1)c1cc(C3=CCOCC3)ccc1OCC21COC1
Temperature: 100 °C
Reaction time: 1 h

Procedure:
A mixture of di-tert-butyl (6′-bromodispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl)imidodicarbonate (300 mg, 0.571 mmol), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,6-dihydro-2H-pyran (360 mg, 1.71 mmol), bis(triphenylphosphine)palladium(II) dichloride (40.1 mg, 0.057 mmol) and Na2CO3 (182 mg, 1.71 mmol) in dioxane (3.6 mL) and water (0.9 mL) was stirred for 1 hour at 100° C. The mixture was cooled down to ambient temperature and partitioned between EtOAc and water. The organic layer was washed with brine, dried over MgSO4, diluted with hexane, and filtered through silica gel pad (eluted with 50% EtOAc in hexane). The filtrate was concentrated at reduced pressure to give crude di-tert-butyl[6′-(3,6-dihydro-2H-pyran-4-yl)dispiro[1,3-oxazole-4,4′-chromene-3′,3″-oxetan]-2-yl]imidodicarbonate which was used for the next reaction without further purification.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C@H:11]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]3[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=3[Cl:32])=[CH:16][CH:15]=2)[C@@H:10]([C:33](=[O:47])[N:34]([CH:44]2[CH2:46][CH2:45]2)[CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[CH2:9]1)=O)(C)(C)C.Cl>C(Cl)Cl.O1CCOCC1>[CH:44]1([N:34]([CH2:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([CH3:42])[C:37]=2[CH3:43])[C:33]([C@@H:10]2[C@@H:11]([C:14]3[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][O:23][C:24]4[C:29]([Cl:30])=[CH:28][C:27]([CH3:31])=[CH:26][C:25]=4[Cl:32])=[CH:18][CH:19]=3)[CH2:12][CH2:13][NH:8][CH2:9]2)=[O:47])[CH2:45][CH2:46]1
Reactant: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCN(C(=O)OC(C)(C)C)C[C@@H]3C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: Cc1cc(Cl)c(OCCOc2ccc([C@H]3CCNC[C@@H]3C(=O)N(Cc3cccc(C)c3C)C3CC3)cc2)c(Cl)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 63.6 %

Procedure:
Compound D3 (0.068 g, 0.10 mmol) was dissolved in CH2Cl2 (1 mL) and the sol. was cooled to 0° C. 4M HCl in dioxane (1 mL) was added and the reaction mixture was stirred for 1 h at rt. The solvents were evaporated under reduced pressure. Purification of the residue by HPLC yielded the title compound (37 mg, 63%). LC-MS: tR=0.95 min, ES+=581.44.
Reaction SMILES: [OH:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[O:5][C:4](=[O:12])[CH:3]=1.[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21](O)[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)[CH3:14].B(F)(F)F.CCOCC>O1CCOCC1>[CH2:13]([C:15]1[CH:20]=[CH:19][C:18]([CH:21]([C:3]2[C:4](=[O:12])[O:5][C:6]3[C:11]([C:2]=2[OH:1])=[CH:10][CH:9]=[CH:8][CH:7]=3)[CH2:22][CH2:23][CH3:24])=[CH:17][CH:16]=1)[CH3:14]
Reactant: CCCC(O)c1ccc(CC)cc1
Reactant: O=c1cc(O)c2ccccc2o1
Agent: FB(F)F
Solvent: CCOCC
Solvent: C1COCCO1
Product: CCCC(c1ccc(CC)cc1)c1c(O)c2ccccc2oc1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a flame-dried flask containing a mixture of 325 mg of 4-hydroxycoumarin and 500 mg of 1-(4-ethylphenyl)-butan-1-ol of Preparation 21 in 10 mL of dioxane under an argon atmosphere is added 1.25 mL of boron trifluoride etherate. The resulting yellow solution is left to stir at room temperature overnight. The volatiles are removed and the residue is partioned between diethyl ether and 1N sodium hydroxide. The basic aqueous phase is washed with diethyl ether and acidified to pH=1 with 6N hydrochloric acid. The resulting precipitant is repeatedly extracted with dichloromethane (methanol-chloroform co-solvents). The combined dichloromethane extracts are washed once with dilute sodium bicarbonate to remove most of the unreacted 4-hydroxycoumarin, then brine, dried (magnesium sulfate), and finally concentrated under reduced pressure. The residue is flash column chromatographed with 40% ethyl acetate in hexane to yield 360 mg of the title product as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11].Cl[C:19]1[CH:20]=[C:21]([CH:27]=[CH:28][N:29]=1)[C:22]([O:24][CH2:25][CH3:26])=[O:23]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:19]2[CH:20]=[C:21]([CH:27]=[CH:28][N:29]=2)[C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:6]=[C:7]([O:13][CH3:14])[C:8]=1[O:9][CH:10]([CH3:12])[CH3:11]
Reactant: COc1cc(B(O)O)cc(OC)c1OC(C)C
Reactant: CCOC(=O)c1ccnc(Cl)c1
Product: CCOC(=O)c1ccnc(-c2cc(OC)c(OC(C)C)c(OC)c2)c1

Procedure:
To a solution of 3,5-dimethoxy-4-isopropoxyphenylboronic acid (1.23 g) and ethyl 2-chloroisonicotinate (0.95 g) were condensed in the same manner as described in Preparation Example 1 to give the title compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5](/[CH:6]=[N:7]\[OH:8])=[CH:4][CH:3]=1.[Cl:11]N1C(=O)CCC1=O>CN(C=O)C>[OH:8]/[N:7]=[C:6](\[Cl:11])/[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][CH:4]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O/N=C\c1ccc(F)cc1
Solvent: CN(C)C=O
Product: O/N=C(\Cl)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 100.2 %

Procedure:
To a solution of (E)- and/or (Z)-4-fluoro-benzaldehyde oxime (100 g, 719 mmol) in DMF (500 mL) was added N-chlorosuccinimide (110 g, 791 mmol) portionwise keeping the temperature below 70° C. The reaction mixture was stirred at room temperature for 2.5 h and then extracted with tert-butyl methyl ether to afford the title compound (125 g, 100%) which was obtained as a yellow oil. MS: m/e=173.1 [M]+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.[CH3:30][C:31]([CH3:33])=O>>[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]([NH:18][C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH:25]=[CH:26][NH:27]2)=[CH:23][CH:22]=1)=[O:20])[CH2:9][O:10][CH2:11][CH:12]1[CH2:17][CH2:16][N:15]([CH:31]([CH3:33])[CH3:30])[CH2:14][CH2:13]1
Reactant: O=C(NC(COCC1CCNCC1)c1ccccc1F)c1ccc2cc[nH]c2c1
Reactant: CC(C)=O
Product: CC(C)N1CCC(COCC(NC(=O)c2ccc3cc[nH]c3c2)c2ccccc2F)CC1

Procedure:
Using alkylation method A, N-[1-(2-fluorophenyl)-2-(piperidin-4-ylmethoxy)ethyl]-1H-indole-6-carboxamide (135 mg, 0.34 mmol) and acetone (1 mL, 14 mmol) afforded, after purification (SiO2: 10:2:2:1 DCM:EtOAc:hexane:isopropylamine), 90 mg (60%) of the title compound.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[O:12][CH2:11][CH:10]([CH2:14][N:15]3[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]3)[C:9]=2[CH:8]=[CH:7][CH:6]=1)=[O:4].O[Li].O>CO.C1COCC1.O>[C:24]([O:23][C:21]([N:18]1[CH2:19][CH2:20][N:15]([CH2:14][CH:10]2[C:9]3[CH:8]=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[O:12][CH2:11]2)[CH2:16][CH2:17]1)=[O:22])([CH3:27])([CH3:25])[CH3:26]
Reactant: COC(=O)c1cccc2c1OCC2CN1CCN(C(=O)OC(C)(C)C)CC1
Agent: [Li]O
Solvent: O
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCN(CC2COc3c(C(=O)O)cccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of tert-butyl 4-{[7-(methoxycarbonyl)-2,3-dihydro-1-benzofuran-3-yl]methyl}piperazine-1-carboxylate (250 mg, 0.66 mmol) in 20 mL of MeOH/THF/H2O (2/2/1) was added LiOH.H2O (139 mg, 3.32 mmol), and the mixture was stirred at ambient temperature overnight. The solvents were removed under vacuum, and the residue was added 30 mL of water and extracted with ether. The aqueous layer was then acidified with 4 N HCl to pH=7 in ice bath, and extracted with EtOAc. The combined organic phase was washed with brine, dried over anhydrous sodium sulfate and concentrated. The residue was re-crystallized from DCM to give 3-{[4-(tert-butoxycarbonyl)piperazin-1-yl]methyl}-2,3-dihydro-1-benzofuran-7-carboxylic acid.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[NH2:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16].N1C=CC=CC=1>ClCCl>[CH3:1][S:2]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([F:19])=[C:11]([CH:18]=1)[NH:12][C:13](=[O:17])[O:14][CH2:15][CH3:16])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: CCOC(=O)Nc1cc(N)ccc1F
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)Nc1cc(NS(C)(=O)=O)ccc1F
Temperature: 25 °C
Yield: 94 %

Procedure:
61.1 g (533 mmol) of methanesulfonyl chloride was added dropwise to a mixture of 96.0 g (485 mmol) of ethyl 5-amino-2-fluorocarbanilate, 46.0 g (582 mmol) of pyridine and 700 ml of dichloromethane at a temperature of not higher than 5° C. Thereafter the temperature was raised to room temperature and the reaction was continued for one night. After the solvent was distilled off, the resultant product was dissolved in ethyl acetate and washed with diluted hydrochloric acid twice, then with water, and with saturated saline solution. The resultant solution was dried over anhydrous sodium sulfate, and the ethyl acetate was distilled off to obtain the crude procut (crystals). The crude product was washed with diisopropyl ether, thereby obtaining 126 g of the objective product (yield: 94%) in the form of light brown crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9]/[C:10](=[N:13]/[H])/[NH:11][OH:12].[O:15]=[C:16]1[C:21]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][CH2:19][CH2:18][N:17]1[CH2:34][C:35](O)=O.Cl.C(N=C=NCCCN(C)C)C>ClCCCl.C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]1[N:13]=[C:35]([CH2:34][N:17]2[CH2:18][CH2:19][CH2:20][C:21]([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:16]2=[O:15])[O:12][N:11]=1
Reactant: O=C(O)CN1CCCC(c2ccccc2)(c2ccccc2)C1=O
Reactant: [H]/N=C(/CCc1ccccc1Cl)NO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C1N(Cc2nc(CCc3ccccc3Cl)no2)CCCC1(c1ccccc1)c1ccccc1

Procedure:
A mixture of the product of Example 262A (180 mg, 0.91 mmol), the product of Example 68E (280 mg, 0.901 mmol), and N1-((ethylimino)methylene)-N3,N3-dimethylpropane-1,3-diamine hydrochloride (347 mg, 1.81 mmol) in 1,2-dichloroethane (4 mL) was stirred at ambient temperature for 3.5 hours and then heated to reflux for 16 hours. The cooled reaction mixture was diluted with CH2Cl2, washed with 1 N aqueous HCl and brine, dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was chromatographed on silica gel twice using ethyl acetate/hexanes as eluant, then finally purified by preparative HPLC on a Phenomenex® Luna® C8(2) 5 um 100 Å AXIA column (30 mm×75 mm). A gradient of acetonitrile (A) and 0.1% trifluoroacetic acid in water (B) was used, at a flow rate of 50 mL/minute (0-0.5 minutes 10% A, 0.5-7.0 minutes linear gradient 10-95% A, 7.0-10.0 minutes 95% A, 10.0-12.0 minutes linear gradient 95-10% A). Samples were injected in 1.5 mL dimethyl sulfoxide:methanol (1:1). The dried down fractions were taken up in CH2Cl2 and combined and concentrated in vacuo. Hexane was added to the residue, which caused the product to solidify. The resulting material was collected by vacuum filtration and dried in the vacuum oven at 50° C. for 4 hours to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ ppm 7.46-7.41 (m, 1H), 7.35-7.16 (m, 13H), 4.83 (s, 2H), 3.56 (t, J=6.3, 2H), 3.20-3.10 (m, 2H), 3.09-3.00 (m, 2H), 2.62-2.55 (m, 2H), 1.79-1.67 (m, 2H); MS (ESI+) m/z 472 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:8])[C:3]([O:5]CC)=O.C[O-].[Na+].[C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)(=[O:14])[CH3:13].Cl>CCOCC.C1COCC1>[F:8][CH:2]([F:1])[C:3](=[O:5])[CH2:13][C:12]([C:15]1[S:16][C:17]([Br:20])=[CH:18][CH:19]=1)=[O:14]
Reactant: CCOC(=O)C(F)F
Reactant: CC(=O)c1ccc(Br)s1
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCOCC
Solvent: C1CCOC1
Product: O=C(CC(=O)C(F)F)c1ccc(Br)s1
Yield: 73.3 %

Procedure:
Ethyl difluoroacetate (2.43 g, 19.6 mmol) was placed in a 100 mL round bottom flask, and dissolved in ether (15 mL). To the stirred solution was added 25 weight % sodium methoxide (4.23 g, 19.5 mmol) loll owed by 2-acetyl-5-bromothiophene (3.59 g, 17.5 mmol). After two hours a precipitate formed and THF (15 mL) was added to allow stirring to continue. The reaction was stirred at room temperature 6.2 hours, then treated with 3N HCl (20 mL). The organic layer was collected and washed with brine, dried over MgSO4, and concentrated in vacuo to give a yellow oil which was crystallized from methylene chloride/isooctane to give yellow needles (3.63 g, mp 83.5°-85°C., 73%). 1H NMR (CDCl3) 300 MHz 14.60 (br s, 1H), 7.53 (d, J=4.0 Hz, 1H), 7.15 (d, J=4.0 Hz, 1H), 7.19 (m, 1H), 6.32 (s, 1H), 6.04 (t, J=54.2 Hz, 1H); 19F NMR (CDCl3) 300 MHz: -127.00 (d); M+282.
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:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH2:26])=[CH:23]2)=[CH:18][CH:17]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[Cl:48][C:49]1[CH:57]=[CH:56][C:52]([C:53](O)=[O:54])=[CH:51][C:50]=1[C:58]([F:61])([F:60])[F:59].CCN(C(C)C)C(C)C>CN(C=O)C.O>[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:25]=[C:24]2[C:19]([CH:20]=[CH:21][C:22]([NH:26][C:53](=[O:54])[C:52]3[CH:56]=[CH:57][C:49]([Cl:48])=[C:50]([C:58]([F:61])([F:59])[F:60])[CH:51]=3)=[CH:23]2)=[CH:18][CH:17]=1
Reactant: O=C(O)c1ccc(Cl)c(C(F)(F)F)c1
Reactant: COc1cc2nccc(Oc3ccc4ccc(N)cc4c3)c2cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: COc1cc2nccc(Oc3ccc4ccc(NC(=O)c5ccc(Cl)c(C(F)(F)F)c5)cc4c3)c2cc1OC
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 7-(6,7-dimethoxyquinolin-4-yloxy)naphthalen-2-amine (0.137 g, 0.40 mmol) in 10 mL of DMF was added EDCI (0.077 g, 0.40 mmol), HOBt (0.054 g, 0.40 mmol), and 4-chloro-3-(trifluoromethyl)benzoic acid (0.099 g, 0.44 mmol). DIPEA (0.140 mL, 0.80 mmol) was added and the solution was stirred for 16 h at RT under an atmosphere of nitrogen. The reaction was diluted with water and extracted with EtOAc 3×. The organic layer was washed with brine, dried (Na2SO4), filtered and concentrated. The residue was purified using a Gilson Prep HPLC system. The fractions were collected, combined, treated with NaHCO3(aq) and extracted with EtOAc 3×. The organic layer was dried (Na2SO4), filtered and concentrated to afford the desired compound. MS (ESI, pos. ion) m/z: 553.0 (M+1). Mass Calc'd for C29H20ClF3N2O4: 552.934.