Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)=[O:2].[CH3:31][Li]>C1COCC1.C(OCC)C>[OH:2][CH:1]([C:3]1[CH:8]=[C:7]([C@@H:9]([NH:12][C:13]([C:15]2[C:16]3[CH:23]=[N:22][N:21]([C:24]4[CH:25]=[CH:26][C:27]([F:30])=[CH:28][CH:29]=4)[C:17]=3[CH:18]=[N:19][CH:20]=2)=[O:14])[CH2:10][CH3:11])[CH:6]=[CH:5][N:4]=1)[CH3:31]
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C=O)c1
Reactant: [Li]C
Solvent: CCOCC
Solvent: C1CCOC1
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(C(C)O)c1
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
To a chilled (−78° C.) solution of 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-formyl-pyridin-4-yl)-propyl]-amide (368 mg, 0.91 mmol) in anhydrous THF (8 mL) was added a solution of 1.6 N methyl lithium (2.28 mL, 3.65 mmol) in diethyl ether and the mixture was slowly warmed to room temperature. After 3.5 hours, the reaction mixture was cooled to −78° C., quenched with saturated aqueous ammonium chloride and extracted with EtOAc (4×60 mL). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated in vacuo. The residue was purified by silica gel chromatography eluting with a gradient of 0-10% MeOH in DCM to afford 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid {(S)-1-[2-(1-hydroxy-ethyl)-pyridin-4-yl]-propyl}-amide as a light yellow foam.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1.C1CCN2C(=NCCC2)CC1>>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:27]3[CH2:32][CH2:31][O:30][CH2:29][CH2:28]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Solvent: C1CCC2=NCCCN2CC1
Product: COc1cc2c3c(cccc3c1N1CCOCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-5-methoxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted with morpholine (3 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.25 g of 2-benzyloxy-5-methoxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione. Hydrogenation of 2-benzyloxy-5-methoxy-6-(morpholin-4-yl)-benzo[de]isoquinoline-1,3-dione (0.25 g, 0.6 mmol) was performed as described in Example 18, to give 0.17 g of the title compound, mp 329-241° C. (dec.);
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][OH:5].[C:6]1([C:12](Cl)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[CH3:1][N:2]([C:12]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)[CH2:3][CH2:4][OH:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CNCCO
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCO)C(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 88.5 %

Procedure:
A mixture of 2-methylamino-ethanol (5.0 gr, 66.6 mmol) and triphenylmethyl chloride (18.6 g, 66.6 mmol) in 150 mL of CH2Cl2 was treated with triethylamine (9.3 mL, 66.6 mmol) and stirred at room temperature for 2 h. The solvent was removed in vacuum and the residue was dissolved in EtOAc (200 mL). The organic solution was washed with water (100 mL) and brine (50 mL), dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on a Flash 40M silica gel (90 g, 32-63 μm) cartridge, eluting with 20% EtOAc in n-heptane, and those fractions with Rf=0.5 by TLC (EtOAc/hexane, 3/7) were combined and concentrated in vacuo to give 18.7 g of the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].[CH3:22][Si:23]([CH3:30])([CH3:29])[CH2:24][CH2:25][O:26][CH2:27]Cl>CN(C)C=O.O1CCCC1>[Br:1][C:2]1[CH:10]=[C:9]2[C:5](/[C:6](=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[CH:14]=3)/[C:7](=[O:11])[N:8]2[CH2:27][O:26][CH2:25][CH2:24][Si:23]([CH3:30])([CH3:29])[CH3:22])=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCN1C(=O)/C(=C\c2cccc(Cl)c2)c2ccc(Br)cc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 60.5 %

Procedure:
To a solution of E/Z 6-Bromo-3-(3-chloro-benzylidene)-1,3-dihydro-indol-2-one (5.3 g, 16 mmol) prepared in example 157a in N,N-dimethyl-formamide (50 mL) at 0° C. was added NaH (60% in mineral oil) (0.64 g, 16 mmol), followed by the dropwise addition of 2-(trimethylsilyl)ethoxymethyl chloride (2.65 g, 16 mmol) in tetrahydrofuran (40 mL). The reaction mixture was stirred at 0° C. for 0.5 h, then poured into ice-water. The crude was extracted with ethyl acetate twice. The combined organic layer was dried over Na2SO4. The solvent was removed and the residue was purified by chromatography (hexanes) to give E/Z-6-Bromo-3-(3-chloro-benzylidene)-1-(2-trimethylsilanyl-ethoxymethyl)-1,3-dihydro-indole-2-one as a yellow oil (Yield 4.5 g, 60%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([OH:15])=O.C(O)(=O)C(O)=O.[F:22][C:23]([F:36])([F:35])[C:24]1[CH:29]=[CH:28][C:27]([CH:30]2[CH2:34][CH2:33][NH:32][CH2:31]2)=[CH:26][CH:25]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][N:11]=[CH:10][C:9]=1[C:13]([N:32]1[CH2:33][CH2:34][CH:30]([C:27]2[CH:28]=[CH:29][C:24]([C:23]([F:22])([F:35])[F:36])=[CH:25][CH:26]=2)[CH2:31]1)=[O:15]
Reactant: O=C(O)c1cnoc1-c1ccccc1Cl
Reactant: FC(F)(F)c1ccc(C2CCNC2)cc1
Agent: O=C(O)C(=O)O
Product: O=C(c1cnoc1-c1ccccc1Cl)N1CCC(c2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared from 5-(2-chlorophenyl)isoxazole-4-carboxylic acid (11.2 mg, 0.050 mmol) and 3-[4-(trifluoromethyl)phenyl]pyrrolidine oxalate (15.1 mg, 0.050 mmol) as described in synthetic method C and thereafter purified by preparative HPLC method B to give a solid (3.8 mg). Calcd for C21H16ClF3N2O2: 420.0852, found 420.0855.
Reaction SMILES: [CH3:1][N:2]1[N:6]=[N:5][C:4]([C:7]2[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][CH:8]=2)=[N:3]1.[Br:14]N1C(=O)CCC1=O>>[Br:14][CH2:13][C:10]1[CH:11]=[CH:12][C:7]([C:4]2[N:5]=[N:6][N:2]([CH3:1])[N:3]=2)=[CH:8][CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2nnn(C)n2)cc1
Product: Cn1nnc(-c2ccc(CBr)cc2)n1

Procedure:
In a first step as depicted in Scheme 2, an appropriately substituted phenyl derivative, for example, the known compound 2-methyl-5-(4-methylphenyl)-1,2,3,4-tetrazole, is brominated with, for example N-bromosuccinimide and light, to afford the corresponding 5-[4-(bromomethyl)phenyl]-2-methyl-1,2,3,4-tetrazole (A1). Intermediate (A1) is then reacted under basic conditions with an appropriately substituted cyclic amine derivative, for example, the known compound 4-piperidone hydrochloride monohydrate, to afford the corresponding 1-{[4-(2-methyl-1,2,3,4-tetrazol-5-yl)phenyl]methyl}piperidin-4-one (B1). Intermediate (B1) is then reacted under acidic conditions with, for example sodium cyanide, to afford the corresponding nitrile compound, 4-hydroxy-1-{[4-(2-methyl(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carbonitrile (C1). Intermediate (C1) is esterified under acidic conditions with, for example ethanol, to afford the corresponding ethyl 4-hydroxy-1-{[4-(2-methyl-(1,2,3,4-tetrazol-5-yl))phenyl]methyl}piperidine-4-carboxylate (D1). The Grignard of an appropriately substituted halophenyl derivative, for example 4-trifluoromethoxybromobenzene, is reacted with intermediate (D1) to provide compounds of formula I-B, wherein X and Y are, for example hydroxyl. Example 2, set forth below, provides detailed methods to how compounds of formula I (-B) shown in Scheme 2 were prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)COC)(=[O:10])=[O:9])=[CH:4][C:3]=1[C:35]([F:38])([F:37])[F:36].O>Cl.O1CCOCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C:15]2[C:16]([C:22](=[O:34])[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[C:29]3[O:30][CH:31]=[CH:32][N:33]=3)=[N:17][CH:18]=[C:19]([Cl:21])[CH:20]=2)(=[O:9])=[O:10])=[CH:4][C:3]=1[C:35]([F:37])([F:38])[F:36]
Reactant: COCN(c1cc(Cl)cnc1C(=O)c1ccccc1-c1ncco1)S(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=C(c1ccccc1-c1ncco1)c1ncc(Cl)cc1NS(=O)(=O)c1ccc(Cl)c(C(F)(F)F)c1
Temperature: 25 °C
Yield: 57.7 %

Procedure:
A mixture of 4-Chloro-N-[5-chloro-2-(2-oxazol-2-yl-benzoyl)-pyridin-3-yl]-N-methoxymethyl-3-trifluoromethyl-benzenesulfonamide(15 mg) in 2 mL of 4M HCl in dioxane and 1 mL of water was refluxed for 2 hours. After cooling to rt the mixture was concentrated, diluted with water and then sodium bicarbonate was added until pH was 6. The mixture was extracted with ethyl acetate, dried and concentrated. The residue was purified via flash column (35% ethyl acetate in hexane) to afford 8.0 mg of title compound as an off white solid. MS: (M+H)/z=542.3.
Reaction SMILES: [C:1]1([C:7]2[NH:8][CH:9]=[CH:10][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].Br[CH2:15][CH2:16][CH2:17][N:18]1[C:22](=[O:23])[C:21]2=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]2[C:19]1=[O:28]>CN(C=O)C>[C:1]1([C:7]2[N:11]([CH2:15][CH2:16][CH2:17][N:18]3[C:22](=[O:23])[C:21]4=[CH:24][CH:25]=[CH:26][CH:27]=[C:20]4[C:19]3=[O:28])[CH:10]=[CH:9][N:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Reactant: c1ccc(-c2ncc[nH]2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCn1ccnc1-c1ccccc1
Temperature: 100 °C

Procedure:
A solution of 2-phenylimidazole (14.4 g) in dry DMF (25 ml) was added dropwise to a stirred suspension of sodium hydride (4.0 g, 60% dispersion in oil) in dry DMF (125 ml) at ambient temperature under nitrogen for 2 hours. A slurry of N-(3-bromopropyl)phthalimide (25.5 g) in dry DMF (40 ml) was added and the mixture heated at 100° C. for 16 hours. The solvent was evaporated off and the residue was extracted with hot toluene. The combined toluene extracts were evaporated to dryness and the residue triturated with ether and dried to give N-[3-(2-phenylimidazol-1-yl)propyl]phthalimide, m.p. 109°-110.5° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[N:6][C:7]2[CH2:8][CH2:9][C:10](=O)[CH2:11][C:12]=2[CH:13]=1)([O-:3])=[O:2].[CH3:15][NH:16][CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl>[CH3:15][N:16]([CH2:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:10]1[CH2:9][CH2:8][C:7]2[N:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:13][C:12]=2[CH2:11]1
Reactant: CNCCc1ccccc1
Reactant: O=C1CCc2ncc([N+](=O)[O-])cc2C1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: CN(CCc1ccccc1)C1CCc2ncc([N+](=O)[O-])cc2C1
Temperature: 25 °C
Reaction time: 40 h
Yield: 18 %

Procedure:
A100 mL flask, equipped with a magnetic stirbar, was charged with 3-nitro-7,8-dihydroquinolin-6(5H)-one (2.5 g, 13.0 mmol), N-methyl-2-phenylethanamine (1.76 g, 13.0 mmol), and 1,2-dichloroethane (73 mL). Sodium triacetoxyborohydride (4.13 g, 19.5 mmol) was added as a solid. The mixture was stirred at ambient temperature for 40 hours. Saturated NaHCO3 (aq) was added until the pH=8. The mixture was extracted with dichloromethane (3×50 mL). The combined organic portions were dried (Na2SO4) and concentrated. The residue was purified by silica gel chromatography (0 to 10% MeOH in dichloromethane) to provide the title compound (0.73 g, 18%). 1H NMR (400 MHz, CD3OD), δ9.16 (d, 1H, J=2.6), 8.13 (d, 1H, J=2.6), 7.30-7.17 (m, 5H), 3.19 (ddd, 2H, J=19, 6, 4), 2.96-2.89 (m, 6H), 2.45 (s, 3H), 2.21-2.12 (m, 2H), 1.89-1.84 (m, 1H). MS [M+H]+=312.2 m/z.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:9])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].[Cl:12][C:13]1[CH:18]=[C:17]([N+]([O-])=O)[CH:16]=[CH:15][N:14]=1>>[Cl:12][C:13]1[CH:18]=[C:17]([O:9][C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=2)[CH:16]=[CH:15][N:14]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: COc1cccc(O)c1
Agent: [H-]
Agent: [Na+]
Product: COc1cccc(Oc2ccnc(Cl)c2)c1
Yield: 95.2 %

Procedure:
Using the method of Example 3, Step A, 3-methoxyphenol (2.35 g, 18.9 mmol), 60% sodium hydride in mineral oil (0.757 g, 18.9 mmol), and 2-chloro-4-nitropyridine (3.00 g, 18.9 mmol) were reacted to provide 2-chloro-4-(3-methoxyphenoxy)pyridine (4.24 g, 95.1% yield) as a thick oil. 1H NMR (CDCl3) 6 (8.23 (d, 1H), 7.34 (t, 1H), 6.80-6.85 (m, 3H), 6.63-6.69 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12]([C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[CH3:27][Si](C)(C)[N-][Si](C)(C)C.[K+].IC>O1CCCC1>[C:1]([O:5][C:6](=[O:26])[N:7]([CH2:8][CH2:9][N:10]1[C:18]2[C:13](=[CH:14][CH:15]=[C:16]([Cl:19])[CH:17]=2)[C:12]([C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[CH:11]1)[CH3:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)NCCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21
Agent: [K+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(CCn1cc(C(=O)C(F)(F)F)c2ccc(Cl)cc21)C(=O)OC(C)(C)C
Reaction time: 0.33 h

Procedure:
To a solution of 14.1 g (36.1 mmol) {2-[6-chloro-3-(2,2,2-trifluoro-acetyl)-indol-1-yl]-ethyl}-carbamic acid tert-butyl ester in 360 ml dry tetrahydrofuran were slowly added 44 ml (40 mmol) of a 0.91 M solution of potassium hexamethyldisilazide in tetrahydrofuran at −78° C. After stirring for 20 min. were added 2.5 ml (40 mmol) iodomethane at −78° C. Stirring was continued for 15 min. at −78° C. The cooling bath was removed and the mixture was stirred for another 3 h at room temperature. Quenching with water was followed by evaporation of the solvent in a rotary evaporator. The residue was diluted with a mixture of 200 ml water and 100 ml of a saturated aqueous solution of ammonium chloride. After extraction with three 250-ml portions of tert-butyl methyl ether the combined organic extracts were washed with 200 ml of an ice-cold 0.2 M aqueous solution of hydrochloric acid and 100 ml brine, dried over sodium sulfate and concentrated in vacuo to give 14.9 g of the crude product as a brown oil.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[NH:7][C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1.[H-].[Na+].[CH3:20]I>C1COCC1>[CH3:20][N:7]([CH:2]1[CH2:3][CH2:4][CH2:5][CH2:6][O:1]1)[C:8]1[S:9][C:10]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][N:12]=1
Reactant: CI
Reactant: CCOC(=O)c1cnc(NC2CCCCO2)s1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1cnc(N(C)C2CCCCO2)s1
Yield: 40.4 %

Procedure:
Ethyl 2-(tetrahydro-2H-pyran-2-ylamino)thiazole-5-carboxylate (4.73 g, 18.5 mmol) was added to a suspension of NaH (740 mg, 18.5 mmol) in THF (20 mL) at 0° C., followed by methyl iodide (1.15 mL, 18.5 mmol). The resulting mixture was heated at reflux during 3 hrs. After quenching with water and extracting with AcOEt, the crude product was purified by column chromatography (50% AcOEt/PE), yielding ethyl 2-(methyl(tetrahydro-2H-pyran-2-yl)amino)thiazole-5-carboxylate (2.02 g, 40%) as an oil.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:16]([CH3:17])=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:18]1[C:27]2[C:22]3=[C:23]([CH2:28][CH2:29][O:30][C:21]3=[CH:20][CH:19]=1)[CH:24]=[CH:25][N:26]=2)(=O)=O.[CH2:33]([Sn](CCCC)(CCCC)C=C)[CH2:34]CC.[Li+].[Cl-]>O1CCOCC1.C(OCC)(=O)C.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>[CH3:17][C:16]1[C:7]([CH:33]=[CH2:34])=[C:8]([C:18]2[C:27]3[C:22]4=[C:23]([CH2:28][CH2:29][O:30][C:21]4=[CH:20][CH:19]=2)[CH:24]=[CH:25][N:26]=3)[C:9]2[C:14]([CH:15]=1)=[CH:13][CH:12]=[CH:11][CH:10]=2
Reactant: Cc1cc2ccccc2c(-c2ccc3c4c(ccnc24)CCO3)c1OS(=O)(=O)C(F)(F)F
Reactant: C=C[Sn](CCCC)(CCCC)CCCC
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: C=Cc1c(C)cc2ccccc2c1-c1ccc2c3c(ccnc13)CCO2
Yield: 113 %

Procedure:
A solution of 1-(2,3-dihydropyrano[4,3,2-de]quinolin-7-yl)-3-methylnaphthalen-2-yltrifluoromethanesulfonate (5E) (89 mg, 0.194 mmol), tributyl(vinyl)tin (0.23 mL, 0/776 mmol), Pd(PPh3)4 (34 mg, 0.029 mmol) and LiCl (16 mg, 0.39 mmol) in dioxane (3 mL) was stirred at 110° C. under Ar for 5 hours. The reaction mixture was cooled, diluted with ethyl acetate and washed with saturated NaHCO3 solution (2×), brine and dried (MgSO4), filtered, concentrated and purified by flash column chromatography (silica gel, hexanes) to give 5F as a white solid (74 mg, 91%). LCMS-ESI+ (m/z): [M+H]+ calcd for C24H20NO: 338.42. Found: 338.2.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12]([CH:14]([O:16]C(=O)C)[CH3:15])=[O:13])[NH:7][C:6](=[O:20])[CH2:5]2.[OH-].[Na+].[CH3:23]O>O>[F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[NH:11][C:12](=[O:13])[C:14]([OH:16])([CH3:15])[CH3:23])[NH:7][C:6](=[O:20])[CH2:5]2
Reactant: CC(=O)OC(C)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Reactant: CO
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(O)C(=O)Nc1cc2c(cc1F)CC(=O)N2
Temperature: 25 °C
Reaction time: 8 h
Yield: 35.6 %

Procedure:
A stirred mixture of acetic acid 1-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-ylcarbamoyl)-ethyl ester (720 mg, 2.45 mmol) in methanol (5 ml) and water (5 ml) was added with sodium hydroxide (200 mg, 50 mmol). The resulting mixture was stirred at room temperature overnight and concentrated under reduced pressure. The residue was extracted with ethyl acetate (100×3) and water (100×3). The organic extracts were dried with anhydrous sodium sulfate, filtered and concentrated under reduced pressure to give N-(5-fluoro-2-oxo-2,3-dihydro-1H-indol-6-yl)-2-hydroxy-2-methyl-propionamide (220 mg, 35.6%) as a white solid.
Reaction SMILES: [C:1](#[N:6])[CH2:2][CH2:3][CH2:4][CH3:5].C([Sn](=O)CCCC)CCC.C[Si]([N:21]=[N+:22]=[N-:23])(C)C>C1(C)C=CC=CC=1>[CH2:2]([C:1]1[NH:23][N:22]=[N:21][N:6]=1)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCC#N
Reactant: C[Si](C)(C)N=[N+]=[N-]
Agent: CCCC[Sn](=O)CCCC
Solvent: Cc1ccccc1
Product: CCCCc1nnn[nH]1
Yield: 84.9 %

Procedure:
Following the procedure described in Example 21, valeronitrile (845 mg, 10.16 mmol) was reacted with dibutyltin oxide (254 mg, 1.02 mmol) and trimethylsilyl azide (2.70 ml, 19.8 mmol) in toluene (20 mL) to give 1.088 g (85%) of the title compound. 1H NMR (CDCl3, 300 MHz) δ0.95 (t, J=7 Hz, 3H), 1.43 (sextet, J=7 Hz, 2H), 1.87 (pentet, J=7 Hz, 2H), 3.12 (t, J=7 Hz, 2H). 13C NMR (CDCl3, 75 MHz) 13.42, 22.04, 23.08, 29.62, 156.94. IR (CDCl3) 2900, 1555 cm-1. MS (DCl/NH3) m/e 127 (M+H)+, 144 (M+H+NH3)+. Anal calcd for C5H10N4 : C, 47.60; H, 7.99; N, 44.41. Found: C, 47.14; H, 7.99; N, 43.75.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[F:7][C:8]1[CH:13]=[CH:12][C:11]([OH:14])=[CH:10][CH:9]=1.Br[CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18]>C(C(C)=O)C>[F:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])=[CH:10][CH:9]=1
Reactant: CCOC(=O)CBr
Reactant: Oc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)COc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 13.8 g (0.1 mole) potassium carbonate, 11.3 g (0.01 mole) 4-fluorophenol and 13.0 ml (19.6 g [0.11 mole]) ethyl bromoacetate in 100 ml methyl ethyl ketone were stirred overnight at room temperature and then heated at reflux for 5 hours. After the reaction mixture cooled to room temperature, it was filtered. The filtrate was concentrated to remove solvent. The concentrate was used as a whole without further isolation in Example 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.C[N:29](C)C=O.C(Cl)(=O)C(Cl)=O>ClCCl>[Cl:1][C:2]1[CH:3]=[C:4]([C:9]2([C:24]([F:27])([F:26])[F:25])[S:13][N:12]=[C:11]([C:14]3[CH:22]=[CH:21][C:17]([C:18]([NH2:29])=[O:19])=[C:16]([CH3:23])[CH:15]=3)[CH2:10]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: CN(C)C=O
Reactant: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(=O)O
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: Cc1cc(C2=NSC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2)ccc1C(N)=O
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of 4-[5-(3,5-dichlorophenyl)-5-(trifluoromethyl)-4H-isothiazol-3-yl]-2-methyl-benzoic acid (1.65 g) was suspended in dichloromethane (16 mL). A catalytic amount of N,N-dimethylformamide (“DMF”) and oxalyl chloride (1.2 eq.) were added to the suspension. The reaction mixture was stirred at ambient temperature for 1.5 hour. The reaction mixture was concentrated and the residue dissolved in dry tetrahydrofuran (16 mL). To the solution was added a solution of ammonium hydroxide (8 mL, 25%). The reaction mixture was stirred at ambient temperature for two hours. It was then quenched by addition of water and extracted with ethyl acetate. The organic extract was washed with a saturated solution of sodium hydrogenocarbonate, dried over magnesium sulfate and concentrated in vacuo. The crude residue was triturated with tert-butylmethylether then the precipitate was filtered and dried under vacuo to give the title compound (841 mg) as a solid. 1H-NMR (CDCl3, 400 MHz): δ=7.50-7.61 (m, 2 H), 7.39-7.50 (m, 1 H), 7.29-7.39 (m, 1 H), 7.14-7.27 (m, 2 H), 6.40 (br. s., 1 H), 6.05 (br. s., 1 H), 4.16 (m, J=17.4, 1 H), 3.74-3.91 (m, 1 H), 2.44-2.49 (m, 3 H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].[CH2:28]([C:35]1[CH:40]=[CH:39][CH:38]=[C:37](Br)[CH:36]=1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:37]4[CH:38]=[CH:39][CH:40]=[C:35]([CH2:28][C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[CH:36]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Reactant: Brc1cccc(Cc2ccccc2)c1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(Cc5ccccc5)c4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 41, Step 2, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 1-benzyl-3-bromo-benzene.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([OH:24])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2].CI.N1(C2CCCCCCCCCC2)CCCCCCCC[CH2:35]N1>C(Cl)Cl>[C:1]([C:3]1[CH:4]=[C:5]([CH:28]=[CH:29][CH:30]=1)[O:6][C:7]1[N:12]=[C:11]([O:13][C:14]2[CH:15]=[C:16]([CH2:20][CH2:21][C:22]([O:24][CH3:35])=[O:23])[CH:17]=[CH:18][CH:19]=2)[C:10]([F:25])=[C:9]([CH3:26])[C:8]=1[F:27])#[N:2]
Reactant: C1CCCCCC(N2CCCCCCCCCN2)CCCC1
Reactant: Cc1c(F)c(Oc2cccc(C#N)c2)nc(Oc2cccc(CCC(=O)O)c2)c1F
Solvent: ClCCl
Solvent: CI
Product: COC(=O)CCc1cccc(Oc2nc(Oc3cccc(C#N)c3)c(F)c(C)c2F)c1
Reaction time: 15 h

Procedure:
To 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid (0.50 g, 1.2 mmol) in methylene chloride (20 mL) was added methyl iodide (0.26 g, 1.8 mmol) and diazabicycloundecane (2.8 g, 1.8 mmol). After stirring for 15 hours, the solution was concentrated in vacuo and chromatographed on silica gel with ethyl acetate/hexane (1/4) to give 3-[(6-(3-cyanophenoxy)-3,5-difluoro-4-methylpyridin-2-yl)oxy]benzenepropionic acid, methyl ester; NMR (CDCl3) 7.3 (m,5), 7.05 (d,1), 6.85 (m,2), 3.68 (s,3), 2.9 (t,2), 2.55 (t,2), 2.4 (s,3) ppm.