Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:3][CH:4]=[C:5]([CH2:7][N:8]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[N:10]([CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)[C:9]2=[NH:28])[N:6]=1.[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1.C([O-])([O-])=O.[K+].[K+]>CN1CCCC1=O.[Cu]I>[C:29]1([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][N:36]1[CH2:37][CH2:38][N:39]([C:2]2[S:3][CH:4]=[C:5]([CH2:7][N:8]3[C:12]4[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=4[N:10]([CH2:17][CH2:18][CH2:19][O:20][C:21]4[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=4)[C:9]3=[NH:28])[N:6]=2)[CH2:40][CH2:41]1
Reactant: c1ccc(-c2ccccc2CN2CCNCC2)cc1
Reactant: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(Cl)n1
Agent: [Cu]I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Product: N=c1n(CCCOc2ccc(F)cc2)c2ccccc2n1Cc1csc(N2CCN(Cc3ccccc3-c3ccccc3)CC2)n1
Temperature: 190 °C
Yield: 7.9 %

Procedure:
To a solution of 1-(2-chloro-thiazol-4-ylmethyl)-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (30 mg, 0.072 mmol) in N-methylpyrrolidinone (2 ml) was added 1-biphenyl-2-ylmethyl-piperazine (18 mg, 0.072 mmol), CuI (14 mg, 0.072 mmol) and K2CO3 (15 mg, 0.11 mmol). The reaction was heated in a microwave at 190° C. for a total of 1.5 h. After this time, the suspension was cooled to rt and filtered through Celite®. The collected solids were washed with dichloromethane and then the combined filtrate and washings were washed with H2O. The aqueous phase was extracted with additional dichloromethane and the combined organic fractions were then washed with brine, dried (Na2SO4) and filtered. The filtrate was concentrated under reduced pressure and the crude product was purified by preparative HPLC. The product was free-based by partitioning between a saturated solution of NaHCO3 and dichloromethane. The organic layer was then separated, dried (Na2SO4), filtered and concentrated under reduced pressure to give 1-[2-(4-biphenyl-2-ylmethyl-piperazin-1-yl)-thiazol-4-ylmethyl]-3-[3-(4-fluoro-phenoxy)-propyl]-1,3-dihydro-benzoimidazol-2-ylideneamine (3.6 mg, 8%). HPLC-MS 633 [M+1]+, 317 (100%).
Reaction SMILES: [CH2:1]([Li])CCC.[C:6]([CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][C:11]1=O)([CH3:9])([CH3:8])[CH3:7]>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CCOCC>[CH2:1]=[C:11]1[CH2:12][CH2:13][CH2:14][CH2:15][CH:10]1[C:6]([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)C1CCCCC1=O
Reactant: [Li]CCCC
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Solvent: CCOCC
Product: C=C1CCCCC1C(C)(C)C
Yield: 44.6 %

Procedure:
Methyltriphenylphosphonium bromide (346 g, 0.97 mole) was suspended in ether (1500 ml) and treated with n-butyllithium (2.5M in ether; 388 ml, 0.97 mole), followed by 2-t-butylcyclohexanone (50 g, 0.324 mole), following the procedure described in Example 12, Part A. The reaction mixture was heated under reflux for 2 days and then worked up in the usual manner. The crude product was fractionated to provide methylene-2-t-butylcyclohexane (22 g), which was pure by GC.
Reaction SMILES: [N+](C1C=CC(COC([NH:12][CH:13]([CH2:24][CH2:25][P:26]([O:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)([O:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:27])[C:14]([O:16]CC2C=CC=CC=2)=[O:15])=O)=CC=1)([O-])=O.[H][H]>C(O)(=O)C.[C].[Pd]>[NH2:12][CH:13]([CH2:24][CH2:25][P:26]([O:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)([O:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)=[O:27])[C:14]([OH:16])=[O:15]
Reactant: O=C(NC(CCP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)OCc1ccccc1)OCc1ccc([N+](=O)[O-])cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Product: NC(CCP(=O)(Oc1ccccc1)Oc1ccccc1)C(=O)O
Yield: 36.6 %

Procedure:
Next, 0.64 g (1.06 mmol) of benzyl 2-(N-4-nitrobenzyloxycarbonylamino)-4-(diphenylphosphono)butanoate was dissolved in 20 mL of acetic acid and mixed with 86 mg of 10% palladium-carbon and hydrogen gas was introduced at room temperature for 2 hours. Thereafter, the palladium-carbon was removed by Celite filtration and the filtrate was vacuum-concentrated, and the residue was crystallized from a solvent mixture of acetonitrile and water to obtain 2-amino-4-(diphenylphosphono)butanoic acid (0.13 g, yield 37%) as a colorless solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][C:9]2[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]3[C:20](=[O:35])[N:21]([C:28]4[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=4)[CH:22]=[CH:23][C:24]=3[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[CH:37]1([C:40]([NH2:42])=[O:41])[CH2:39][CH2:38]1.C([O-])([O-])=O.[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH:37]1([C:40]([NH:42][C:2]2[CH:7]=[C:6]([O:8][C:9]3[C:14]([F:15])=[CH:13][C:12]([NH:16][C:17]([C:19]4[C:20](=[O:35])[N:21]([C:28]5[CH:33]=[CH:32][C:31]([F:34])=[CH:30][CH:29]=5)[CH:22]=[CH:23][C:24]=4[O:25][CH2:26][CH3:27])=[O:18])=[C:11]([F:36])[CH:10]=3)[CH:5]=[CH:4][N:3]=2)=[O:41])[CH2:39][CH2:38]1
Reactant: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(Cl)c2)cc1F
Reactant: NC(=O)C1CC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: CCOc1ccn(-c2ccc(F)cc2)c(=O)c1C(=O)Nc1cc(F)c(Oc2ccnc(NC(=O)C3CC3)c2)cc1F
Temperature: 100 °C
Yield: 30.1 %

Procedure:
A mixture of N-(4-((2-chloropyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (0.100 g, 0.194 mmol, see: Example 1), cyclopropanecarboxamide (0.033 g, 0.388 mmol), Cs2CO3 (0.095 g, 0.291 μmol) and Xantphos (5.05 mg, 8.72 μmol) in dioxane (2 mL) was sparged with argon, treated with Pd2(dba)3 (2.66 mg, 2.91 μmol), sparged again with argon, then fitted with a reflux condensor capped with an argon-filled balloon and heated to 100° C. overnight. The mixture was cooled to RT and partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, concentrated to dryness and purified via silica gel chromatography (EtOAc/Hex) to afford N-(4-((2-(cyclopropanecarboxamido)pyridin-4-yl)oxy)-2,5-difluorophenyl)-4-ethoxy-1-(4-fluorophenyl)-2-oxo-1,2-dihydropyridine-3-carboxamide (33 mg, 30% yield) as a solid. MS (ESI) m/z: 565.2 (M+H+).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)=[C:9]([O:12][CH3:13])[CH:10]=2)[N:5]=[CH:4][N:3]=1.[OH:23][C:24]1[CH:33]=[C:32]2[C:27]([C:28]([CH3:35])=[CH:29][C:30]([CH3:34])=[N:31]2)=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[CH3:34][C:30]1[CH:29]=[C:28]([CH3:35])[C:27]2[C:32](=[CH:33][C:24]([O:23][C:2]3[C:11]4[C:6](=[CH:7][C:8]([O:14][CH2:15][CH2:16][CH2:17][N:18]5[CH2:22][CH2:21][CH2:20][CH2:19]5)=[C:9]([O:12][CH3:13])[CH:10]=4)[N:5]=[CH:4][N:3]=3)=[CH:25][CH:26]=2)[N:31]=1
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCN1CCCC1
Reactant: Cc1cc(C)c2ccc(O)cc2n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(Oc3ccc4c(C)cc(C)nc4c3)ncnc2cc1OCCCN1CCCC1
Temperature: 90 °C
Yield: 35.2 %

Procedure:
A mixture of 4-chloro-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (100 mg, 0.31 mmol), (prepared as described for the starting material in Example 9), and 7-hydroxy-2,4-dimethylquinoline (64 mg, 0.36 mmol), (Chem. Berichte, 1903, 36, 4016), in DMF (3 ml) containing potassium carbonate (86 mg, 0.62 mmol) was heated at 90° C. for 3 hours. After cooling, the mixture was poured onto a column of silica and eluted with 2.5M ammonia in methanol/methylene chloride (5/95) to give 4-(2,4-dimethylquinolin-7-yloxy)-6-methoxy-7-(3-pyrrolidin-1-ylpropoxy)quinazoline (50 mg, 35%).
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([O:16]CC)=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1.[OH-].[Na+].Cl>CO>[O:1]=[C:2]1[N:6]([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][C:14]([OH:16])=[O:15])[CH2:9][CH2:8]2)[C:5]2[CH:19]=[CH:20][CH:21]=[CH:22][C:4]=2[NH:3]1
Reactant: CCOC(=O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CN1CCC(n2c(=O)[nH]c3ccccc32)CC1
Temperature: 25 °C
Yield: 146 %

Procedure:
A solution of ethyl (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetate (13.0 g, 42.8 mmol) in methanol (150 mL) was treated with an aqueous solution of sodium hydroxide (3 N, 30 mL, 90 mmol) and heated at reflux for 2 hours. The solution was cooled to room temperature and neutralized with the addition of concentrated hydrochloric acid (12 N, 7.5 mL). The solvent was evaporated in vacuo, and the resultant amorphous solid was dried in vacuo with heating (˜50° C.) overnight to give (4-(2-keto-1-benzimidazolinyl)piperidin-1-yl)acetic acid (17.2 g) which was used in the subsequent step without purification. MS m/z 304 (MH+); NMR(DMSO-d6): δ 1.74 (br d, 2 H), 2.53-2.67 (m, 2 H), 2.74-2.86 (m, 2 H), 3.33 (s, 2 H), 4.29-4.42 (m, 1 H), 6.97-7.05 (m, 3 H) and 7.38-7.43 (m, 1 H).
Reaction SMILES: [CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=O)[C:5]=2[CH:4]=[CH:3][CH:2]=1.Cl.[NH2:26][OH:27].CCOC(C)=O.CCCCCC>CCO.O>[CH:1]1[C:11]2[CH2:10][CH2:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[CH:16][C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH:19]=[N:26][OH:27])[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: NO
Reactant: O=Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Agent: Cl
Solvent: CCCCCC
Solvent: CCO
Solvent: O
Product: ON=Cc1ccccc1C=C1c2ccccc2CCc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 72 %

Procedure:
Dissolve 2-(10,11-dihydro-dibenzo[a,d]cyclohepten-5-ylidenemethyl)-benzaldehyde (110 mg,0.35 mmol) in EtOH (4 mL). In a separate flask, dissolve hydroxylamine hydrochloride (35 mg, 0.5 mmol) in water (1 mL). Add this solution the aldehyde solution and stir at room temperature for 18 h. Pour the reaction into water (300 mL) and extract the product into EtOAc. Dry (MgSO4) and concentrate to give 140 mg crude product. Purity on silica gel using EtOAc/hexane to give 82 mg (72%) title compound as a white solid. 1H NMR (CDCl3) δ 3.31 (br s, 4H), 6.73-7.33 (m, 11H), 7.55 (m, 1H), 7.70 (dd, 1H), 8.58 (s, 1H); MS (ES) 326 (M+1), 324 (M−1). HPLC shows 98% purity.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:15]=[C:16]([CH:20]=[CH:21][CH:22]=2)[C:17](O)=[O:18])[CH:10]([O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>>[CH2:35]([NH:42][C:17]([C:16]1[CH:15]=[C:14]([CH:11]2[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH:10]2[O:23][CH2:24][C:25]2[CH:34]=[CH:33][C:32]3[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH:26]=2)[CH:22]=[CH:21][CH:20]=1)=[O:18])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)O)c2)C(OCc2ccc3ccccc3c2)C1
Product: CC(C)(C)OC(=O)N1CCC(c2cccc(C(=O)NCc3ccccc3)c2)C(OCc2ccc3ccccc3c2)C1

Procedure:
In an analogous manner to that described in Example 36(b), by condensing (3RS,4RS)-3-(1 -tert-butoxycarbonyl-3-naphthalen-2-ylmethoxy-piperidin-4-yl)-benzoic acid with benzylamine using 1,1-carbonyidiimidazole as the condensation agent there was obtained tert-butyl (3RS,4RS)-4-(3-benzylcarbamoyl-phenyl)-3-(naphthalen-2-ylmethoxy)-piperidine-1-carboxylate as a colourless oil; MS: 551 (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:10][CH:9]2[C:11](N2C3CC4C(C)(C)C3(CC4)CS2(=O)=O)=[O:12])=[CH:4][CH:3]=1.[OH2:27].[OH-].[Li+].O>O1CCCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C@@H:8]2[CH2:10][C@H:9]2[C:11]([OH:12])=[O:27])=[CH:6][CH:7]=1
Reactant: CC1(C)C2CCC13CS(=O)(=O)N(C(=O)C1CC1c1ccc(F)cc1)C3C2
Reactant: O
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(O)[C@@H]1C[C@H]1c1ccc(F)cc1
Temperature: 50 °C
Reaction time: 24 h

Procedure:
A suspension of the product from step b) (3.74 g) and lithium hydroxide monohydrate (4.11 g) in tetrahydrofuran (100 ml)/water (3 ml) was stirred at 50° C. for 24 hours. The reaction mixture was concentrated in vacuo, and the residue dissolved in water (100 ml), acidified with 2N HCl and extracted into dichloromethane (3×75 ml). The organics were dried and concentrated. Purification (SiO2, isohexane:diethylether 2:1 as eluant) gave the subtitle compound as a colourless solid (1.78 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:12])[C:5](=[CH:10][CH:11]=1)[C:6]([O:8][CH3:9])=[O:7].N1C=CC=CC=1.[C:19]([CH2:23][CH2:24][C:25](Cl)=[O:26])([O:21][CH3:22])=[O:20]>C1C=CC=CC=1>[C:19]([CH2:23][CH2:24][C:25]([NH:12][C:4]1[C:5](=[CH:10][CH:11]=[C:2]([Cl:1])[CH:3]=1)[C:6]([O:8][CH3:9])=[O:7])=[O:26])([O:21][CH3:22])=[O:20]
Reactant: COC(=O)CCC(=O)Cl
Reactant: COC(=O)c1ccc(Cl)cc1N
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: COC(=O)CCC(=O)Nc1cc(Cl)ccc1C(=O)OC

Procedure:
To the solution of 444 g of methyl 4-chloro-anthranilate in 1.3 lt of benzene and 199 ml of pyridine, that of 406 g of 3-carbomethoxy-propionyl chloride in 200 ml of benzene is added dropwise while stirring and cooling with ice. The mixture is stirred for 19 hours at room temperature, filtered and the filtrate evaporated. The combined residues are taken up in 3 lt of chloroform, the solution washed with water, 1 lt of N hydrochloric acid, 1 lt of 10% aqueous sodium bicarbonate and again with water, dried, filtered, evaporated and the residue recrystallized from acetonitrile, to yield the methyl N-(3-carbomethoxypropionyl)-4-chloroanthranilate melting at 80°-84°.
Reaction SMILES: Cl.Cl[CH2:3][CH2:4][N:5]([CH2:7][CH2:8]Cl)[CH3:6].C(=O)([O-])[O-].[Na+].[Na+].[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[NH2:27]>C(O)CCC.ClCCl>[Br:16][C:17]1[CH:18]=[N:19][C:20]2[C:25]([CH:26]=1)=[CH:24][CH:23]=[CH:22][C:21]=2[N:27]1[CH2:8][CH2:7][N:5]([CH3:6])[CH2:4][CH2:3]1
Reactant: CN(CCCl)CCCl
Reactant: Nc1cccc2cc(Br)cnc12
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCCCO
Product: CN1CCN(c2cccc3cc(Br)cnc23)CC1
Temperature: 25 °C
Yield: 48.6 %

Procedure:
bis-(2-Chloro-ethyl)-methyl-amine hydrochloride (3.7 g, 19.2 mmol) and sodium carbonate (9.0 g, 85 mmol) were added to a suspension of 3-bromo-quinolin-8-ylamine (3.9 g, 17.5 mmol) (for synthesis see Gershon et al., Monatsh. Chem., 1991, 122, 935) in n-butanol (70 ml). The stirred suspension was heated at reflux for 72 h. The reaction mixture was cooled to ambient temperature, diluted with dichloromethane (300 ml) and the solution washed with water (300 ml), dried (MgSO4) and concentrated in vacuo to an oil. The oil was purified by chromatography over silica gel eluting with a gradient of methanol/dichloromethane to afford the title compound (Dl) as an oil (2.6 g, 8.5 mmol, 49%);
Reaction SMILES: [OH:1][N:2]1[C:6](=[O:7])[C:5]2=[CH:8][CH:9]=[CH:10][CH:11]=[C:4]2[C:3]1=[O:12].C(N(CC)CC)C.[F:20][C:21]([F:46])([F:45])[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35]Cl)=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:26]=2[CH:44]=1>CC(N(C)C)=O>[F:46][C:21]([F:20])([F:45])[C:22]1[CH:23]=[CH:24][C:25]2[N:31]3[C:32]([CH2:35][O:1][N:2]4[C:3](=[O:12])[C:4]5=[CH:11][CH:10]=[CH:9][CH:8]=[C:5]5[C:6]4=[O:7])=[N:33][N:34]=[C:30]3[CH2:29][N:28]=[C:27]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][C:38]=3[Cl:43])[C:26]=2[CH:44]=1
Reactant: FC(F)(F)c1ccc2c(c1)C(c1ccccc1Cl)=NCc1nnc(CCl)n1-2
Reactant: O=C1c2ccccc2C(=O)N1O
Solvent: CC(=O)N(C)C
Solvent: CCN(CC)CC
Product: O=C1c2ccccc2C(=O)N1OCc1nnc2n1-c1ccc(C(F)(F)F)cc1C(c1ccccc1Cl)=NC2

Procedure:
In the manner given in Example 1, N-hydroxyphthalimide and triethylamine in dimethylacetamide is treated with 8-trifluoromethyl-6-(o-chlorophenyl)-1-(chloromethyl)-4H-s-triazolo[4,3-a][1,4]benzodiazepine to give 8-trifluoromethyl-6-(o-chlorophenyl)-1-[(phthalimidooxy)methyl]-4H-s-triazolo[4,3-a][1,4]benzodiazepine.
Reaction SMILES: C(O[C:4](=O)[C:5]([F:21])([F:20])[C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)=[CH:8][CH:7]=1)C.C(N(S(F)(F)F)CC)C.C([O:34][C:35](=[O:52])[C:36](C1C=CC(C2C=CC(OC)=CC=2)=CC=1)=O)C>ClCCl>[F:21][C:5]([F:20])([C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)=[CH:10][CH:11]=1)[CH2:4][CH2:36][C:35]([OH:52])=[O:34]
Reactant: CCOC(=O)C(F)(F)c1ccc(-c2ccc(OC)cc2)cc1
Reactant: CCOC(=O)C(=O)c1ccc(-c2ccc(OC)cc2)cc1
Agent: CCN(CC)S(F)(F)F
Solvent: ClCCl
Product: COc1ccc(-c2ccc(C(F)(F)CCC(=O)O)cc2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Difluoro-(4′-methoxy-biphenyl-4-yl)-acetic acid ethyl ester. Diethylaminosulfur trifluoride (5 mL) is added directly to (4′-methoxy-biphenyl-4-yl)-oxo-acetic acid ethyl ester (3.77 g, 13.3 mmol), prepared as described by Neidlin, et. al., Arzneim.-Forsch. 1983, 33, 691-3. Dichloromethane (2 mL) is added and the mixture is stirred overnight at room temperature. The reaction is diluted with dichloromethane and slowly added to ice water. This mixture is extracted with ethyl acetate twice. The combined organic extracts are dried over Na2SO4, filtered, and concentrated under reduced pressure. The crude product is purified by column chromatography (silica gel, 5% EtOAc/hexanes) to give the desired product as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[OH:9].[Br:10][C:11]1[CH:16]=[C:15](F)[CH:14]=[C:13]([Cl:18])[CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CN1C(=O)CCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[O:9][C:15]1[CH:14]=[C:13]([Cl:18])[CH:12]=[C:11]([Br:10])[CH:16]=1
Reactant: Oc1cc(F)ccc1Cl
Reactant: Fc1cc(Cl)cc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCCC1=O
Solvent: O
Product: Fc1ccc(Cl)c(Oc2cc(Cl)cc(Br)c2)c1
Temperature: 140 °C

Procedure:
To a solution of 2-chloro-5-fluorophenol (82.3 g, 562 mmol) and 1-bromo-3-chloro-5-fluorobenzene (124 g, 590 mmol) in NMP (200 mL) was added potassium carbonate (155 g, 1.123 mol). The resulting mixture was then heated to 140° C. and maintained at 140° C. for hours, after which the mixture was poured into water (1500 mL) and extracted with EtOAc (2500+1500 mL). The combined extracts were washed with water and brine. This solution was concentrated on the rotary evaporator and the residue was distilled at high vacuum at 135-190° C. to give the title compound as a clear, colorless liquid. 1H NMR (CDCl3) δ 7.45 (dd, 1H, J=9.0 and 4.5 hz), 7.28 (dd, 1H, J=1.7 Hz), 7.26 (s, 1H), 7.00 (dd, 1 h, J=1.95 Hz), 6.92 (ddd, 1H, J=10.5, 7.6 and 2.7 Hz), 6.89 (dd, 1H, J=1.95 Hz).
Reaction SMILES: [BH4-].[Na+].C1COCC1.[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[C:16](=[O:18])[CH3:17].Cl>CO>[Br:8][C:9]1[CH:14]=[C:13]([Cl:15])[CH:12]=[CH:11][C:10]=1[CH:16]([OH:18])[CH3:17]
Reactant: CC(=O)c1ccc(Cl)cc1Br
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(O)c1ccc(Cl)cc1Br

Procedure:
Solid NaBH4 (354 mg, 9.4 mmol) was added to a 0° C., THF (5 mL) and MeOH (15 mL) solution of 1-(2-bromo-4-chlorophenyl)ethanone (1.8 g, 7.8 mmol). After 30 min 2N aqueous HCl was slowly added, and the resulting mixture was extracted with EtOAc. The combined organic extracts were dried (Na2SO4), concentrated, and purified via column chromatography to yield the title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH3:6])=[O:4].[OH:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:6][O:5][C:3](=[O:4])[CH2:2][O:7][C:8]1[CH:9]=[CH:10][CH:11]=[C:12]2[C:17]=1[NH:16][C:15](=[O:18])[CH:14]=[CH:13]2
Reactant: COC(=O)CBr
Reactant: O=c1ccc2cccc(O)c2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)COc1cccc2ccc(=O)[nH]c12
Temperature: 25 °C
Yield: 53.6 %

Procedure:
Methyl bromoacetate (367 mg, 2.4 mmol) was added to a stirred mixture of 8-hydroxy-1H-quinolin-2-one [which was prepared according to literature procedure (Wang, T. C. et al, Synthesis, 1997, 87-90)], (322 mg, 2 mmol), K2CO3 (414 mg, 3 mmol) in DMF (10 ml) at room temperature. The reaction mixture was stirred at rt over night and then partitioned between dichloromethane and water. Water layer was extracted with dichloromethane (2×50 ml). The combined organic phase was washed with water (3×50 ml), brine and dried over sodium sulfate. After removal of solvent, the residue was washed with ether to give 250 mg of compound I-71.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([OH:23])[CH:5]=[CH:6][C:7]=1[CH:8]([CH3:22])[C:9]([C:15]1[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=1)([OH:14])[C:10]([F:13])([F:12])[F:11].[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([CH2:34]Br)=[CH:30][N:29]=1)=[O:27]>>[CH3:24][O:25][C:26]([C:28]1[CH:33]=[N:32][C:31]([CH2:34][O:23][C:4]2[CH:5]=[CH:6][C:7]([CH:8]([CH3:22])[C:9]([C:15]3[CH:20]=[CH:19][N:18]=[C:17]([Cl:21])[CH:16]=3)([OH:14])[C:10]([F:13])([F:12])[F:11])=[C:2]([Cl:1])[CH:3]=2)=[CH:30][N:29]=1)=[O:27]
Reactant: COC(=O)c1cnc(CBr)cn1
Reactant: CC(c1ccc(O)cc1Cl)C(O)(c1ccnc(Cl)c1)C(F)(F)F
Product: COC(=O)c1cnc(COc2ccc(C(C)C(O)(c3ccnc(Cl)c3)C(F)(F)F)c(Cl)c2)cn1

Procedure:
The title compound was prepared in analogy to Example 101 from 3-chloro-4-[2-(2-chloro-pyridin-4-yl)-3,3,3-trifluoro-2-hydroxy-1-methyl-propyl]-phenol (obtained in Example 19, step 5) and 5-bromomethyl-pyrazine-2-carboxylic acid methyl ester [CAS Reg. No. 193966-70-0]. MS (m/e)=516.3 [MH+].
Reaction SMILES: O.C(N(CC)CC)C.C([O:12][C@H:13]1[C@H:18]([O:19]C(=O)C)[C@@H:17]([O:23]C(=O)C)[C@H:16]([O:27][C:28]2[C:29]([O:48][CH3:49])=[CH:30][CH:31]=[C:32]3[C:37]=2[O:36][C:35](=[O:38])[CH:34]=[C:33]3[NH:39][C:40]2[C:45]([Cl:46])=[CH:44][N:43]=[CH:42][C:41]=2[Cl:47])[O:15][C@@H:14]1[CH2:50][O:51]C(=O)C)(=O)C>CO>[Cl:47][C:41]1[CH:42]=[N:43][CH:44]=[C:45]([Cl:46])[C:40]=1[NH:39][C:33]1[C:32]2[C:37](=[C:28]([O:27][C@H:16]3[C@H:17]([OH:23])[C@@H:18]([OH:19])[C@H:13]([OH:12])[C@@H:14]([CH2:50][OH:51])[O:15]3)[C:29]([O:48][CH3:49])=[CH:30][CH:31]=2)[O:36][C:35](=[O:38])[CH:34]=1
Reactant: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Solvent: CCN(CC)CC
Solvent: CO
Solvent: O
Product: COc1ccc2c(Nc3c(Cl)cncc3Cl)cc(=O)oc2c1O[C@@H]1O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Water (1.5 mL) and then triethylamine (1.5 mL) were added to a solution of (2R,3R,4S,5R,6S)-2-(acetoxymethyl)-6-(4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-2-oxo-2H-chromen-8-yloxy-tetrahydro-2H-pyran-3,4,5-triyl triacetate (0.137 g, 0.200 mmol Example 60) and MeOH (1.5 mL). The mixture was stirred at rt overnight, concentrated, and then purified by reverse-phase HPLC (25→100% MeCN/H2O) to give 4-(3,5-dichloropyridin-4-ylamino)-7-methoxy-8-((2S,3R,4S,5S,6R)-3,4,5-trihydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-2-yloxy)-2H-chromen-2-one: 1H NMR (400 MHz, CD3OD): δ 8.72 (s, 2H), 7.88 (d, 1H), 7.20 (d, 1H), 5.17 (d, 1H), 4.77 (s, 1H), 4.01 (s, 3H), 3.76 (dd, 1H), 3.63 (dd, 1H), 3.54 (dd, 1H), 3.43 (m, 2H), 3.25 (m, 1H); MS (ESI): 514.9.