Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:10]=[CH:9][C:6]([CH2:7][NH2:8])=[CH:5][CH:4]=1.[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24](O)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1.C1C2C(=C(CC(O)=O)C=CC=2)C=CN=1>>[CH:13]1[C:22]2[C:17](=[C:18]([CH:23]([CH3:27])[C:24]([NH:8][CH2:7][C:6]3[CH:9]=[CH:10][C:3]([C:2]([F:11])([F:12])[F:1])=[CH:4][CH:5]=3)=[O:25])[CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CC(C(=O)O)c1cccc2cnccc12
Agent: O=C(O)Cc1cccc2cnccc12
Product: CC(C(=O)NCc1ccc(C(F)(F)F)cc1)c1cccc2cnccc12

Procedure:
The title compound was prepared using the procedure described in Example 222B using 4-(trifluoromethyl)benzylamine and 2-(5-isoquinolinyl)propanoic acid instead of 4-(trifluoromethoxy)benzylamine and 5-isoquinolinylacetic acid. MS (ESI+) m/z 359 (M+H)+; MS (ESI−) m/z 357 (M−H)−; 1H NMR (DMSO, 300 MHz) δ 1.59 (d, J 7.1, 3H), 4.35 (d, J 6.1, 2H), 4.69 (q, J 7.1, 1H), 7.40 (d, J 8.1, 1H), 7.65 (d, J 8.1, 1H), 7.78 (m, 2H), 8.03 (t, 1H), 8.20 (d, J 7.1, 1H), 8.47 (d, J 7.8, 1H), 8.65 (br s, 1H), 8.75 (s, 1H), 9.05 (t, J 5.8, 1H), 9.93 (s, 1H); Anal. Calcd for C20H17F3N2O+1.6HCl+1.3H2O: C, 54.58; H, 4.86. Found: C, 54.70; H, 5.10.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:9]([C:11]2[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1)#[N:2].[CH3:18][N:19]([CH3:23])[C:20](Cl)=[S:21]>>[CH3:18][N:19]([CH3:23])[C:20](=[S:21])[O:17][C:14]1[CH:13]=[CH:12][C:11]([C:9](=[O:10])[C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[N:2])[CH:4]=2)=[CH:16][CH:15]=1
Reactant: N#Cc1cccc(C(=O)c2ccc(O)cc2)c1
Reactant: CN(C)C(=S)Cl
Product: CN(C)C(=S)Oc1ccc(C(=O)c2cccc(C#N)c2)cc1
Yield: 93.2 %

Procedure:
Following the procedure described in Preparation I and starting from 27 g (0.121 mol) of 3-cyanophenyl 4-hydroxyphenyl methanone and 17.2 g (0.138 mol) of dimethylthiocarbamoyl chloride, 35 g (yield: 88%) of O-4-(3-cyanobenzoyl)phenyl dimethylthiocarbamate melting at 160° C. are obtained.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:7][OH:8])[O:5][CH:6]=1.[H-].[Na+].I[CH3:12]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH2:7][O:8][CH3:12])[O:5][CH:6]=1
Reactant: CI
Reactant: OCc1cc(Br)co1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: COCc1cc(Br)co1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 1.062 g (4-bromo-furan-2-yl)-methanol in 10 ml dimethylsulfoxide was added 0.288 of sodium hydride (55%) in oil and 0.56 ml of iodomethane and the reaction mixtures was stirred at room temperature for 18 h. The reaction mixture was partitioned between ethyl acetate and water. The phases were separated; the organic phase was washed with citric acid (10% in water), water, satd. sodiumbicarbonate and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by chromatography on silica gel to yield 0.731 g of a light yellow liquid.
Reaction SMILES: [F:1][C:2]([F:17])([F:16])[C:3]1[CH:8]=[CH:7][C:6]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)=[CH:5][CH:4]=1.[H-].[Na+].Cl[C:21]1[N:26]=[C:25]([C:27]([NH:29][CH:30]2[CH2:35][CH2:34][N:33]([CH2:36][C:37]3[CH:42]=[CH:41][N:40]=[CH:39][CH:38]=3)[CH2:32][CH2:31]2)=[O:28])[CH:24]=[CH:23][CH:22]=1.C(Cl)Cl>CN(C=O)C.C(OCC)C.CO.C(Cl)Cl>[N:40]1[CH:39]=[CH:38][C:37]([CH2:36][N:33]2[CH2:34][CH2:35][CH:30]([NH:29][C:27](=[O:28])[C:25]3[CH:24]=[CH:23][CH:22]=[C:21]([O:15][CH:12]4[CH2:13][CH2:14][N:9]([C:6]5[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:16])[F:17])=[CH:8][CH:7]=5)[CH2:10][CH2:11]4)[N:26]=3)[CH2:31][CH2:32]2)=[CH:42][CH:41]=1
Reactant: OC1CCN(c2ccc(C(F)(F)F)cc2)CC1
Reactant: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(NC1CCN(Cc2ccncc2)CC1)c1cccc(OC2CCN(c3ccc(C(F)(F)F)cc3)CC2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 25 %

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-piperidin-4-ol (0.1 g, 0.4 mmol) in anhydrous DMF, NaH (60% in mineral oil, 18 mg, 0.45 mmol) was added. The mixture was allowed to stir at room temperature under N2 atmosphere for 10 min, followed by the addition of 6-chloro-N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)picolinamide (0.15 g, 0.4 mmol). The resulting reaction mixture was then stirred with heating at 105° C. overnight. A significant amount of starting material was still present and hence, an additional amount of NaH was added (82 mg, 2.1 mmol). The reaction mixture was allowed to stir at 105° C. for an additional 8 h, and quenched with saturated sodium bicarbonate solution (20 mL). The aqueous layer was extracted with ethyl acetate (3×20 mL), and the combined organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried (MgSO4), filtered and concentrated to give a yellow residue. Column chromatography (100% CH2Cl2→3% MeOH/CH2Cl2) provided a yellow solid, which upon trituration with ethyl ether, yielded N-(1-(pyridin-4-ylmethyl)piperidin-4-yl)-6-(1-(4-(trifluoromethyl)phenyl)piperidin-4-yloxy)picolinamide as a tan solid (54 mg, 25%). 1H NMR (CD3OD) δ 8.53 (d, J=4.1 Hz, 2H), 8.28 (d, J=7.4 Hz, 1H), 7.80 (t, J=7.7 Hz, 1H), 7.65 (d, J=7.2 Hz, 1H), 7.51 (d, J=4.1 Hz, 2H), 7.46 (d, J=8.5 Hz, 2H), 7.05 (d, J=8.3 Hz, 2H), 6.96 (d, J=8.3 Hz, 1H), 5.43 (br s, 1H), 4.10-3.95 (m, 1H), 3.90 (s, 2H), 3.77-3.56 (m, 2H), 3.23-2.98 (m, 3H), 2.71-2.57 (m, 2H), 2.23-1.81 (m, 9H). MS (m/z): 540 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:21])[CH3:20])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]#[N:15])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1.[OH-:25].[Na+].Cl>CCO.O.O>[NH2:1][C:2]1[C:7]([O:8][C:9]2[C:10]([CH:19]([CH3:20])[CH3:21])=[CH:11][C:12]([O:17][CH3:18])=[C:13]([CH:16]=2)[C:14]([NH2:15])=[O:25])=[CH:6][N:5]=[C:4]([NH:22][CH2:23][CH3:24])[N:3]=1
Reactant: [OH-]
Reactant: CCNc1ncc(Oc2cc(C#N)c(OC)cc2C(C)C)c(N)n1
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCNc1ncc(Oc2cc(C(N)=O)c(OC)cc2C(C)C)c(N)n1
Temperature: 100 °C
Yield: 27.1 %

Procedure:
To a solution of 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzonitrile (0.3 g, 0.92 mmol) in EtOH/H2O (1:1,10 ml) was added a solution of NaOH (0.37 g, 9.17 mmol) in H2O (1 ml). The reaction mixture was heated at 100° C. for 24 hrs and neutralized with 3N HCl. Ethanol was removed in vacuo and the remaining aqueous solution was extracted into methylene chloride. The combined extract was washed with water, dried over Na2SO4, filtered and concentrated. Flash chromatography on silica gel (3 to 8% EtOAc in Hexanes) gave 5-(4-Amino-2-ethylamino-pyrimidin-5-yloxy)-4-isopropyl-2-methoxy-benzamide (0.086 g, 27% ) as a white solid. (M+H)=346.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[C:7]1([CH2:13][CH2:14][CH2:15][C:16](O)=[O:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.S(=O)(=O)(O)O>O1CCCC1>[C:7]1([CH2:13][CH2:14][CH2:15][CH2:16][OH:17])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: O=C(O)CCCc1ccccc1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCCCCc1ccccc1
Temperature: 0 °C

Procedure:
To a suspension of lithium aluminum hydride (67.2 g) in dry tetrahydrofuran (2.5 l), a solution of 4-phenylbutyric acid (225 g, 1.37 mmoles) in dry tetrahydrofuran was added dropwise at 15°-25° C. under nitrogen. The resultant mixture was stirred for 1 h at room temperature, then poured into ice-cold H2O (3 l) and sulfuric acid (200 g) and extracted thrice with ethyl acetate. The organic extract was dried over anhydrous N2SO4, evaporated, and then the residue was distilled under reduced pressure to give the title compound as a colorless oil; yield: 191 g; bp 113°-115° C./0.5 mmHg (Lit. bp 92°-93° C./0.3 mmHg; B. H. Baker, W. B. Martin, J. Org. Chem., 25, 1496 (1960)).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][C:9]1=[O:19])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([NH:25][C:26]1[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=1)=[O:24].C([O-])([O-])=O.[Cs+].[Cs+].O>CN(C=O)C>[C:1]([O:5][C:6](=[O:20])[CH2:7][N:8]1[C:17](=[O:18])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]([CH2:22][C:23](=[O:24])[NH:25][C:26]2[CH:31]=[C:30]([Cl:32])[N:29]=[C:28]([Cl:33])[CH:27]=2)[C:9]1=[O:19])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)Nc1cc(Cl)nc(Cl)c1
Reactant: CC(C)(C)OC(=O)Cn1c(=O)[nH]c2ccccc2c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)Cn1c(=O)c2ccccc2n(CC(=O)Nc2cc(Cl)nc(Cl)c2)c1=O

Procedure:
A mixture comprising (2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-acetic acid tert-butyl ester (Intermediate L) (226.7 mg, 0.82 mmol), 2-bromo-N-(2,6-dichloro-pyridine-4-yl)-acetamide (Intermediate N) (256.5 mg, 0.902 mmol) and Cs2CO3 (545.1 mg, 1.64 mmol) in DMF (5 ml) is stirred at RT for 3 hours. The resulting mixture is treated with water and the precipitate is filtered under vacuum. The solid is washed with water, iso-hexane and then dried to give the title compound, [M+H]+ 479
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([CH2:8][N:9]2[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]3=[N:19][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:21](=[O:22])[C:11]3=[CH:10]2)=[N:6][CH:7]=1.C1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[CH3:64][C:65]1[C:70](B(O)O)=[CH:69][CH:68]=[CH:67][N:66]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[F:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[N:20]1[C:21](=[O:22])[C:11]2=[CH:10][N:9]([CH2:8][C:5]3[N:6]=[CH:7][C:2]([C:70]4[C:65]([CH3:64])=[N:66][CH:67]=[CH:68][CH:69]=4)=[CH:3][CH:4]=3)[C:18]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:12]2=[N:19]1
Reactant: O=c1c2cn(Cc3ccc(Br)cn3)c3ccccc3c-2nn1-c1ccccc1F
Reactant: Cc1ncccc1B(O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Solvent: CS(C)=O
Product: Cc1ncccc1-c1ccc(Cn2cc3c(=O)n(-c4ccccc4F)nc-3c3ccccc32)nc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
5-[(5-Bromopyridin-2-yl)methyl]-2-(2-fluorophenyl)-2,5-dihydro-3H-pyrazolo[4,3-c]quinolin-3-one (51 mg, 0.11 mmol), 2-dicyclohexylphosphino-2′,4′,6′-tri-iso-propyl-1,1′-biphenyl (16 mg, 0.034 mmol, 0.3 equiv), (2-methylpyridin-3-yl)boronic acid (26 mg, 0.19 mmol, 1.7 equiv), palladium(II) acetate (2.6 mg, 0.011 mmol, 0.1 equiv) and an aqueous solution (0.1 mL) of potassium carbonate (39 mg, 0.28 mmol, 2.5 equiv) were combined in dimethylsulfoxide (0.5 mL) and placed into a preheated oil bath at 85° C. for 90 minutes. The mixture was cooled to ambient temperature, stirred with Quadrapure® (50 mg, 1 wt equiv) for 1 hour, filtered and purified by reverse phase HPLC (80:20 to 5:95; water containing 0.1% trifluoroacetic acid:acetonitrile containing 0.1% trifluoroacetic acid), providing the titled compound: 1H-NMR (500 MHz, d6-DMSO) δ 9.10 (1H, s), 8.57 (1H, d, J=2.1 Hz), 8.55 (1H, d, J=4.6 Hz), 8.21 (1H, dd, J=7.9, 1.4 Hz), 7.96 (1H, dd, J=8.1, 2.4 Hz), 7.84 (1H, d, J=8.7 Hz), 7.80 (1H, br s), 7.72 (1H, d, J=8.3 Hz), 7.65 (1H, ddd, J=8.6, 7.3, 1.5 Hz), 7.61 (1H, td, J=7.8, 1.6 Hz), 7.54 (1H, br t, J=7.6 Hz), 7.48-7.38 (3H, m), 7.34 (1H, td, J=7.6, 1.5 Hz), 5.92 (2H, s), 2.44 (3H, s) ppm; low resolution mass spectrometry (ES+) m/z 462.1709 [(M+H)+; calculated for C28H21FN5O: 462.1725].
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:7]=[CH:6][C:3]=1[CH:4]=O.[Br-].[O:16]1CCO[CH:17]1[CH2:21][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.COCCOCCN(CCOCCOC)CCOCCOC>ClCCl.C([O-])([O-])=O.[K+].[K+]>[F:1][C:2]1[CH:9]=[C:8]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)[CH:7]=[CH:6][C:3]=1/[CH:4]=[CH:21]/[CH:17]=[O:16]
Reactant: c1ccc([P+](CC2OCCO2)(c2ccccc2)c2ccccc2)cc1
Reactant: O=Cc1ccc(-n2cccn2)cc1F
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: O=C([O-])[O-]
Agent: [Br-]
Solvent: ClCCl
Product: O=C/C=C/c1ccc(-n2cccn2)cc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 69.8 %

Procedure:
A mixture of 2-fluoro-4-(1H-pyrazol-1-yl)benzaldehyde (1.06 g, 5.57 mmol, prepared as described in Reference Example 8), (1,3-dioxolan-2-ylmethyl)triphenylphosphonium bromide (3.60 g, 8.39 mmol), and TDA-1 (1.80 mL, 5.63 mmol) in dichloromethane (30 mL) and sat. aq. K2CO3 (30 mL) was heated to reflux for 20 h. The layers were separated and the aqueous layer was extracted with dichloromethane (2×15 mL). The combined organic layers were washed with water (30 mL) and brine (30 mL), dried (Na2SO4), and concentrated. THF (15 mL) and 10% HCl (15 mL) were added and the mixture was stirred for 1 h at rt. The mixture was cooled to 0° C., the precipitated solids were removed by filtration, washed with water and dried in vacuo. Recrystallization from IPA provided 0.84 g (70%) of the title compound as tan needles. MS 217 (M+H)+.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8]([C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)=O)[CH:2]([CH3:4])[CH3:3].Cl.[NH2:38][OH:39].N1C=CC=CC=1.C(Cl)(Cl)Cl>C(O)C.O>[CH2:1]([O:5][C:6]1[CH:31]=[C:30]([O:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH:29]=[CH:28][C:7]=1[C:8](=[N:38][OH:39])[C:10]1[CH:11]=[CH:12][C:13]([O:23][CH2:24][CH:25]([CH3:27])[CH3:26])=[C:14]([CH2:16][CH2:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:15]=1)[CH:2]([CH3:4])[CH3:3]
Reactant: NO
Reactant: CCOC(=O)CCc1cc(C(=O)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Agent: Cl
Solvent: CCO
Solvent: O
Solvent: ClC(Cl)Cl
Product: CCOC(=O)CCc1cc(C(=NO)c2ccc(OCC(C)C)cc2OCC(C)C)ccc1OCC(C)C
Temperature: 25 °C
Yield: 99 %

Procedure:
In 20 ml of ethanol is dissolved 10.00 g of ethyl 3-[5-(2,4-diisobutoxybenzoyl)-2-isobutoxyphenyl]-propanoate, to which are added 5.59 g of hydroxylamine hydrochloride and 7 ml of pyridine. The mixture is heated under reflux for 4.5 hours with stirring. After cooling the mixture to ambient temperature, chloroform and water are added, and the organic layer is separated. The organic layer thus obtained is washed with water and saturated aqueous solution of sodium chloride successively and dried over anhydrous magnesium sulfate, and the solvent is distilled off under reduced pressure. The residue thus obtained is purified by silica gel column chromatography (eluent; n-hexane:ethyl acetate=5:1) to obtain 10.20 g of ethyl 3-{5-[(2,4-diisobutoxyphenyl)(hydroxyimino)-methyl]-2-isobutoxyphenyl}propanoate as a light brown oily product.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=1.[C:9]([C:11]1[C:12]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][C:21]#[CH:22])=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10]>C(NCC)C.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.[Cu]I>[C:9]([C:11]1[C:12]([NH:17][C:18](=[O:23])[CH2:19][CH2:20][C:21]#[C:22][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[CH:6][CH:7]=2)=[N:13][CH:14]=[CH:15][CH:16]=1)#[N:10]
Reactant: C#CCCC(=O)Nc1ncccc1C#N
Reactant: Cc1cccc(I)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCNCC
Product: Cc1cccc(C#CCCC(=O)Nc2ncccc2C#N)c1

Procedure:
Under an atmosphere of argon, bis(triphenylphosphine)palladium(II) chloride ([13965-03-2], 326 mg) and copper(I) iodide (44 mg) were added to a solution of 3-iodotoluene ([625-95-6], 506 mg, 2 mmol) and pent-4-ynoic acid (3-cyano-pyridin-2-yl)-amide (508 mg, 3 mmol) in diethylamine (15 ml). The mixture was kept at r.t. (3d). The volatiles were evaporated, and the residue was taken up in ethyl acetate. After washing (H2O) and drying (Na2SO4), the solvent was evaporated and 5-m-tolyl-pent-4-ynoic acid (3-cyano-pyridin-2-yl)-amide was isolated from the reaction mixture by column chromatography (silica gel, ethyl acetate/heptane). MS: m/e=290.1 [M+H+].
Reaction SMILES: [CH:1]1([O:5][C:6]2[C:15](B3OC(C)(C)C(C)(C)O3)=[CH:14][CH:13]=[C:12]3[C:7]=2[CH2:8][CH2:9][C@H:10]([CH3:29])[N:11]3[C:25]([O:27][CH3:28])=[O:26])[CH2:4][CH2:3][CH2:2]1.Br[C:31]1[N:32]=[C:33]([C:36]2([OH:49])[CH2:41][CH2:40][N:39]([C:42]([O:44][C:45]([CH3:48])([CH3:47])[CH3:46])=[O:43])[CH2:38][CH2:37]2)[S:34][CH:35]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CC(C1C=C(C(C)C)C(C2C=CC=C(P(C3CCCCC3)C3CCCCC3)C=2)=C(C(C)C)C=1)C.C1C=[C-]C(C2C(N)=CC=CC=2)=CC=1.Cl[Pd+].O1CCOCC1.O>[C:45]([O:44][C:42]([N:39]1[CH2:38][CH2:37][C:36]([C:33]2[S:34][CH:35]=[C:31]([C:15]3[C:6]([O:5][CH:1]4[CH2:2][CH2:3][CH2:4]4)=[C:7]4[C:12](=[CH:13][CH:14]=3)[N:11]([C:25]([O:27][CH3:28])=[O:26])[C@@H:10]([CH3:29])[CH2:9][CH2:8]4)[N:32]=2)([OH:49])[CH2:41][CH2:40]1)=[O:43])([CH3:48])([CH3:46])[CH3:47]
Reactant: COC(=O)N1c2ccc(B3OC(C)(C)C(C)(C)O3)c(OC3CCC3)c2CC[C@@H]1C
Reactant: CC(C)(C)OC(=O)N1CCC(O)(c2nc(Br)cs2)CC1
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2cccc(P(C3CCCCC3)C3CCCCC3)c2)c(C(C)C)c1
Agent: Nc1ccccc1-c1[c-]cccc1
Solvent: O
Solvent: C1COCCO1
Product: COC(=O)N1c2ccc(-c3csc(C4(O)CCN(C(=O)OC(C)(C)C)CC4)n3)c(OC3CCC3)c2CC[C@@H]1C
Temperature: 100 °C
Yield: 92.5 %

Procedure:
A mixture of (S)-methyl 5-cyclobutoxy-2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydroquinoline-1(2H)-carboxylate (0.109 g, 0.273 mmol), tert-butyl 4-(4-bromothiazol-2-yl)-4-hydroxypiperidine-1-carboxylate (0.090 g, 0.248 mmol), XPhos Precatalyst 2nd Generation (0.019 g, 0.025 mmol), and cesium carbonate (0.242 g, 0.743 mmol) in 1,4-dioxane (1.0 mL) and water (0.2 mL) was heated at 100° C. for 2.5 h. The reaction mixture was cooled to room temperature, filtered through a pad of Celite, and concentrated. The residue was purified via column chromatography on silica gel (Biotage 25 g column, gradient elution with 5-50% ethyl acetate-hexane) to afford (S)-methyl 6-(2-(1-(tert-butoxycarbonyl)-4-hydroxypiperidin-4-yl)thiazol-4-yl)-5-cyclobutoxy-2-methyl-3,4-dihydroquinoline-1(2H)-carboxylate (0.128 g, 93%). MS (ESI, pos. ion) m/z 558 [M+H]+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([N:13]=[N+:14]=[N-:15])[C@H:9]1[C:16](=[O:27])[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([Cl:25])[C:20]=1[F:26])=O)(C)(C)C.[C:28]([OH:34])([C:30]([F:33])([F:32])[F:31])=[O:29].CO>C(Cl)Cl>[F:31][C:30]([F:33])([F:32])[C:28]([OH:34])=[O:29].[Cl:25][C:21]1[C:20]([F:26])=[C:19]([CH:24]=[CH:23][CH:22]=1)[CH2:18][NH:17][C:16]([C@@H:9]1[C@H:10]([N:13]=[N+:14]=[N-:15])[CH2:11][CH2:12][NH:8]1)=[O:27]
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](N=[N+]=[N-])[C@H]1C(=O)NCc1cccc(Cl)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Product: [N-]=[N+]=N[C@@H]1CCN[C@@H]1C(=O)NCc1cccc(Cl)c1F
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of (2S,3R)-3-azido-2-(3-chloro-2-fluoro-benzylcarbamoyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (560 mg, 1.41 mmol) in CH2Cl2 (8 mL) was added TFA (4 mL), and the solution was stirred at RT for 2 h. Methanol was added then added, and volatiles were removed under reduced pressure. The residue was taken up in methanol and concentrated in vacuo to afford the crude title compound as a yellow resin. MS (LC/MS): 298.0 [M+H]+; tR (HPLC conditions c): 3.59 min. The product was used directly in the next step without further purification.
Reaction SMILES: [OH:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[C:11]([CH3:19])[C:3]=1[C:4]([CH2:6][CH2:7][C:8]([OH:10])=[O:9])=O.Cl.O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:14]([O:15][CH3:16])=[C:13]([O:17][CH3:18])[CH:12]=[C:11]([CH3:19])[C:3]=1[CH2:4][CH2:6][CH2:7][C:8]([OH:10])=[O:9]
Reactant: COc1cc(C)c(C(=O)CCC(=O)O)c(O)c1OC
Agent: Cl
Solvent: Cc1ccccc1
Solvent: O
Product: COc1cc(C)c(CCCC(=O)O)c(O)c1OC

Procedure:
A mixture of 3-(2'-hydroxy-3',4'-dimethoxy-6'-methylbenzoyl)propionic acid (formula II-1 wherein R=H3CO, X=H, Y=OH, n=2 in the free form) (0.536 part), zinc amalgam (1 part), concentrated hydrochloric acid (1 volume part), water (2 volume parts) and toluene (2 volume parts) was refluxed for 5 hours and, after cooling, the reaction mixture was extracted with diethyl ether. The extract was washed with water and dried. The solvents were distilled off under reduced pressure and the residue was recrystallized from diethyl ether-hexane. The procedure provided 4-(2'-hydroxy-3',4'-dimethoxy-6'-methylphenyl)butyric acid (formula II-2 wherein R=H3CO, X=H, Y=OH, n=2, in the free form) (0.34 part) as colorless needles melting at 98°-100° C.
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1.[Li+].[Br-:13]>CC(C)=O>[Br:13][CH2:2][C:3]1[N:4]([CH3:11])[CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[N:7]=1
Reactant: [Br-]
Reactant: Cn1cc([N+](=O)[O-])nc1CCl
Agent: [Li+]
Solvent: CC(C)=O
Product: Cn1cc([N+](=O)[O-])nc1CBr
Yield: 94.9 %

Procedure:
A mixture of 2-(chloromethyl)-1-methyl-4-nitro-1H-imidazole (485 mg, 2.76 mmol) and LiBr (4.80 g, 55.2 mmol) in acetone was heated at reflux for 5 hours before all the solvent was removed under reduced pressure. The residue was partitioned between ethyl acetate and water. The aqueous phase was extracted with ethyl acetate twice. The combined organic phase was washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude product was recrystallised from DCM/hexane to give 2-(bromomethyl)-1-methyl-4-nitro-1H-imidazole (105) (576 mg, 95%) as an off-white solid, m.p. 130-132° C. 1H NMR (CDCl3, 400 MHz) δ 7.74 (s, 1H), 4.50 (s, 2H), 3.83 (s, 3H). Analysis found: C, 27.81; H, 3.27; N, 19.05. C5H6BrN3O2.0.04hexane requires: C, 28.16; H, 2.96; N, 18.80. HRMS (FAB+) found: 219.97220, 221.97018 (M+1), calcd. for C5H779/81BrN3O2: 219.97216, 221.97012.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8](Br)[CH:7]=[CH:6][C:5]=1[OH:11].[Cl:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][C:19]=1[F:20].C(OC)(=O)C1C=CC=CC=1.[Li+].[OH-].O.C1COCC1.C(O)C>>[CH3:1][O:2][C:3]([C:4]1[CH:9]=[C:8]([C:16]2[CH:17]=[CH:18][C:19]([F:20])=[C:14]([Cl:13])[CH:15]=2)[CH:7]=[CH:6][C:5]=1[OH:11])=[O:12]
Reactant: COC(=O)c1cc(Br)ccc1O
Reactant: OB(O)c1ccc(F)c(Cl)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Solvent: COC(=O)c1ccccc1
Product: COC(=O)c1cc(-c2ccc(F)c(Cl)c2)ccc1O

Procedure:
The resin-bound 3′-chloro-4′-fluoro-4-hydroxy-biphenyl-3-carboxylic acid methyl ester was prepared with 1.0 g (3.0 mmol) of above resin-bound 5-bromo-2-hydroxy-benzoic acid methyl ester and 1.6 g (9.0 mmol) of 3-chloro-4-fluoro-phenylboronic acid as described in Procedure K. The resulting resin-bound methyl benzoate was hydrolyzed with LiOH/H2O/THF/ethanol at rt for 3 days.