Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[C:6](O)=[C:5]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[S:4]1(=[O:17])=[O:16])[CH3:2].CN(C=O)C.C(Cl)(=O)C([Cl:26])=O>C(Cl)Cl>[Cl:26][C:6]1[C:7](=[O:8])[N:3]([CH2:1][CH3:2])[S:4](=[O:17])(=[O:16])[C:5]=1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCN1C(=O)C(O)=C(c2ccccc2)S1(=O)=O
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Temperature: 0 °C
Yield: 292.4 %

Procedure:
2-Ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide (5 g, 19.76 mmol) was dissolved in dry DCM (250 mL) and cooled to 0° C. under N2. Dry DMF (15 mL) was added, followed by oxalyl chloride (3 mL, 34.4 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc and washed with water (3×25 mL) and brine, dried over Na2SO4 and evaporated. Another (16 g, 63.24 mmol) of 2-ethyl-4-hydroxy-5-phenylisothiazol-3(2H)-one 1,1-dioxide was dissolved in dry DCM (500 mL) and cooled to 0° C. under N2. Dry DMF (20 mL) was added followed by oxalyl chloride (9 mL, 103.2 mmol). The ice-bath was removed and the mixture was refluxed at 50° C. under N2 for 4 h. The reaction mixture was evaporated and the residue was diluted with EtOAc and washed with water (3×50 mL) and brine, dried over Na2SO4 and evaporated where by red solid was obtained. The crude material from both batches were combined and purified by column chromatography on silica gel using 2.5-3% EtOAc in petroleum ether as eluant, and recrystallised from MeOH to give the title compound (15.7 g, 70%) as a white solid; 1H NMR (400 MHz, CD3OD) δ 1.42 (t, 3H, J=7.3 Hz), 3.84 (q, 2H, J=7.3 Hz), 7.6-7.7 (m, 3H), 7.9-8.0 (m, 2H); Mass Spectrum: M+H+ 272.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12](I)[C:10]([NH2:11])=[N:9][C:7]1=[O:8].[CH2:15]([NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:16]#[CH:17].CO>ClCCl>[OH:1][CH2:2][CH2:3][O:4][CH2:5][N:6]1[CH:13]=[C:12]([C:17]#[C:16][CH2:15][NH:18][C:19](=[O:24])[C:20]([F:23])([F:22])[F:21])[C:10]([NH2:11])=[N:9][C:7]1=[O:8]
Reactant: Nc1nc(=O)n(COCCO)cc1I
Reactant: C#CCNC(=O)C(F)(F)F
Solvent: ClCCl
Solvent: CO
Product: Nc1nc(=O)n(COCCO)cc1C#CCNC(=O)C(F)(F)F
Yield: 23 %

Procedure:
Iodide 68 (311 mg, 1.00 mmol) was coupled to N-propargyltrifluoroacetamide (43) according to the general procedure described in Example 1C. Flash chromatography on silica gel (3×20 cm) with 5%, 10% and 20% methanol in dichlormethane afforded alkynylamino nucleotide 69 as a pale yellow foam (77.4 mg, 23%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH2:24][N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)[N:18]=[CH:17]3)=[O:12])=[CH:6][CH:5]=1)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[N:19]([CH2:23][CH2:24][N:25]2[CH2:26][CH2:27][CH2:28][CH2:29]2)[N:18]=[CH:17]3)=[O:12])=[CH:6][CH:5]=1
Reactant: O=C(Nc1ccc([N+](=O)[O-])cc1)Nc1ccc2c(cnn2CCN2CCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc(NC(=O)Nc2ccc3c(cnn3CCN3CCCC3)c2)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 91.5 %

Procedure:
A mixture of 1-(4-nitro-phenyl)-3-[1-(2-pyrrolidin-1-yl-ethyl)-1H-indazol-5-yl]-urea (3.1 g, 7.8 mmol), iron powder (3.5 g, 63 mmol), and ammonium chloride (0.21 g, 3.9 mmol) in a 4:1 ethanol/H2O solution (50 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was taken up and stirred in triethylamine/ethyl acetate (1/4, 30 mL) for 15 minutes followed by filteration through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (2.6 g, 92%). 1H NMR (300 MHz, DMSO-d6) ppm 1.89 (m, 4H), 3.06 (m, 4H), 3.64(m, 2H), 4.75 (d, J=6.44, 2H), 6.52 (m, 2H), 7.09 (m, 2H), 7.39 (m, 1H), 7.66 (m, 1H), 7.92 (m, 1H), 8.06 (s, 1H), 8.31 (m, 1H), 8.70 (s, 1H); MS (DCI/NH3) m/z 365 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]2[CH:16]=[CH:15][CH:14]=[CH:13][C:10]=2[C:11]#[N:12])[CH:5]=[CH:6][C:7]=1[NH2:8].[F:17][C:18]([F:26])([F:25])[C:19]([F:24])([F:23])[C:20](O)=O>>[C:11]([C:10]1[CH:13]=[CH:14][CH:15]=[CH:16][C:9]=1[C:4]1[CH:5]=[CH:6][C:7]2[NH:8][C:20]([C:19]([F:24])([F:23])[C:18]([F:26])([F:25])[F:17])=[N:1][C:2]=2[CH:3]=1)#[N:12]
Reactant: N#Cc1ccccc1-c1ccc(N)c(N)c1
Reactant: O=C(O)C(F)(F)C(F)(F)F
Product: N#Cc1ccccc1-c1ccc2[nH]c(C(F)(F)C(F)(F)F)nc2c1
Temperature: 115 °C

Procedure:
2-(3,4-Diaminophenyl)benzonitrile (9.6 mmoles, 2.0 g) was dissolved in 40 ml of pentafluoropropionic acid and heated at 115° C. for 20 hours. After cooling, the solvent was removed in vacuo. The residue was dissolved in ethyl acetate. The ethyl acetate solution was added slowly to saturated sodium bicarbonate. The intermediate was extracted with ethyl acetate, washed with brine, dried over sodium sulfate and concentrated. The residue was chromatographed over silica gel eluded with 25% ethyl acetate in hexane to yield 1.1 g of 5-(2-cyanophenyl)-2-pentafluoroethyl-1H-benzimidazole. (MS).
Reaction SMILES: [Cl:1][C:2]1[NH:3][C:4](I)=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.C(N(CC)CC)C.[H][H]>C(O)C.[C].[Pd]>[Cl:1][C:2]1[NH:3][CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1nc(Cl)[nH]c1I
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1c[nH]c(Cl)n1
Yield: 83.7 %

Procedure:
2-Chloro-5-iodo-4-nitroimidazole (545 mg) was dissolved in ethanol (10 ml), then triethylamine (840 μl) and 10% palladium-carbon (54 mg) were added, the reaction mixture was subjected to hydrogenation at hydrogen pressure of 4 kg/cm2 by use of Pearl reduction equipment, there was obtained 2-chloro-4-nitroimidazole (246 mg, yield: 83.4%) as colorless solid matter.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=1.Cl.[F:17][C:18]1([F:24])[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]1>>[F:17][C:18]1([F:24])[CH2:23][CH2:22][N:21]([C:13]([C:9]2[CH:10]=[N:11][O:12][C:8]=2[C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)=[O:15])[CH2:20][CH2:19]1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Reactant: FC1(F)CCNCC1
Agent: Cl
Product: Cc1ccc(-c2oncc2C(=O)N2CCC(F)(F)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 4,4-difluoropiperidine hydrochloride (9.5 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (3.2 mg). Calcd for C16H16F2N2O2: 306.1180, found 306.1179.
Reaction SMILES: [CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][C:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)=[O:21])[CH2:15][CH2:14]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2].Cl.[NH2:35]O>>[CH2:1]([N:3]1[C:12]2[C:7](=[CH:8][C:9]([F:29])=[C:10]([N:13]3[CH2:14][CH2:15][N:16]([C:19](=[NH:35])[CH:20]([C:22]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=4)[OH:21])[CH2:17][CH2:18]3)[CH:11]=2)[C:6](=[O:30])[C:5]([C:31]([OH:33])=[O:32])=[CH:4]1)[CH3:2]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(CC(=O)c4ccc(F)cc4)CC3)cc21
Reactant: NO
Agent: Cl
Product: CCn1cc(C(=O)O)c(=O)c2cc(F)c(N3CCN(C(=N)C(O)c4ccc(F)cc4)CC3)cc21

Procedure:
1-Ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-hydroxy-iminoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinoline-carboxylic acid was prepared from 1-ethyl-6-fluoro-7-{4-[2-(4-fluorophenyl)-2-oxoethyl]-1-piperazinyl}-4-oxo-1,4-dihydro-3-quinolinecarboxylic acid (0.23 g, 0.5 mmole) and hydroxylamine hydrochloride (0.07 g, 1 mmol) by a method similar to that described for Example 3 (66% yield). 1H NMR (DMSO-d6): δ 1.39 (t, 3H, J=7.2), 2.62 and 3.25 (two m, 8H), 3.44 and 3.73 (two s, 2H), 4.57 (q, 2H, J=7.2), 7.15 (d, 1H, J=7.2), 7.42-7.83 (m, 4H),7.89 (d, 1H, J=13.3), 8.93 (s, 1H), 11.19 and 11.62 (two s, 1H), 15.23 (br s, 1H) Anal. Calcd. for C24H24F2N4O4•0.5 H2O: C, 60.12; H, 5.26; N, 11.68. Found: C, 60.01; H, 5.24; N, 11.60.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:28]=[CH:27][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=3)[C:21]([O:23]C)=[O:22])=[O:14])=[CH:11][CH:10]=2)[CH2:4][CH2:3]1.[OH-].[Li+]>O.C1COCC1>[CH3:1][N:2]1[CH2:3][CH2:4][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([C:13]([NH:15][C:16]3[CH:17]=[CH:18][C:19]([CH3:26])=[C:20]([CH:25]=3)[C:21]([OH:23])=[O:22])=[O:14])=[CH:27][CH:28]=2)[CH2:6][CH2:7]1
Reactant: COC(=O)c1cc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)ccc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1C(=O)O
Temperature: 25 °C
Reaction time: 6 h
Yield: 52.3 %

Procedure:
A reactor is charged with 0.5 g (1.3 mmol) of the solid obtained in step 2, 20 ml of a mixture water/THF (1/1) and 0.55 g (13 mmol) of lithium hydroxide. The mixture is stirred at room temperature for 6 hours. The solution is concentrated under reduced pressure and then diluted in 100 ml of water. The aqueous phase is extracted by 3*30 ml of ethyl acetate and acidified with chlorhydric acid 32% until pH comprised between 2 and 3. the aqueous phase is extracted with 3*30 ml ethyl acetate. The organic phases are combined, dried on sodium sulphate and evaporated under reduced pressure. 250 mg of a solid is obtained (52%).
Reaction SMILES: [O:1]=[S:2]1(=[O:19])[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[CH:15]=[CH:14][C:10]([C:11]([OH:13])=O)=[C:9]([N+:16]([O-:18])=[O:17])[CH:8]=1.[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:20][C:21]1[CH:26]=[C:25]([CH3:27])[CH:24]=[CH:23][C:22]=1[N:28]1[CH2:29][CH2:30][N:31]([C:11]([C:10]2[CH:14]=[CH:15][C:7]([N:3]3[CH2:4][CH2:5][CH2:6][S:2]3(=[O:1])=[O:19])=[CH:8][C:9]=2[N+:16]([O-:18])=[O:17])=[O:13])[CH2:32][CH2:33]1
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Reactant: O=C(O)c1ccc(N2CCCS2(=O)=O)cc1[N+](=O)[O-]
Product: Cc1ccc(N2CCN(C(=O)c3ccc(N4CCCS4(=O)=O)cc3[N+](=O)[O-])CC2)c(C)c1
Yield: 16.2 %

Procedure:
Using 4-(1,1-dioxo-1λ6-isothiazolidin-2-yl)-2-nitrobenzoic acid (967 mg) described in Preparation Example 24 and 1-(2,4-dimethylphenyl)piperazine (639 mg) and by the reaction and treatment in the same manner as in Example 87, the title compound (250 mg) was obtained.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]2[O:12][N:11]=[C:10]([CH2:13][C:14]3[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=3)[CH:9]=2)=[CH:6][CH:5]=[C:4]([NH2:21])[N:3]=1.CO.[OH-].[Na+].Cl[CH2:27][C:28]1[CH:33]=[C:32]([CH3:34])[CH:31]=[CH:30][N:29]=1>CN(C)C=O>[CH3:34][C:32]1[CH:31]=[CH:30][N:29]=[C:28]([CH2:27][O:20][C:17]2[CH:18]=[CH:19][C:14]([CH2:13][C:10]3[CH:9]=[C:8]([C:7]4[C:2]([NH2:1])=[N:3][C:4]([NH2:21])=[CH:5][CH:6]=4)[O:12][N:11]=3)=[CH:15][CH:16]=2)[CH:33]=1
Reactant: Nc1ccc(-c2cc(Cc3ccc(O)cc3)no2)c(N)n1
Reactant: Cc1ccnc(CCl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: CO
Product: Cc1ccnc(COc2ccc(Cc3cc(-c4ccc(N)nc4N)on3)cc2)c1
Temperature: 60 °C
Reaction time: 0.17 h
Yield: 36.9 %

Procedure:
To 4-(5-(2,6-diamino-pyridin-3-yl)-isoxazol-3-ylmethyl)-phenol (80 mg, 0.28 mmol) described in Manufacturing Example 18-1-1 were added methanol (4 mL) and 1 N aqueous sodium hydroxide solution (0.29 mL), which was then dissolved by irradiating ultrasonic wave. This solution was concentrated under a reduced pressure. To the resulting residue was added 2-chloromethyl-4-methyl-pyridine (50.9 mg, 0.36 mol.) described in Manufacturing Example 11-1-4 and N,N-dimethylformamide (3 mL), which was stirred for 10 minutes at 60° C. The reaction solution was partitioned into water and ethyl acetate. The organic layer was evaporated under a reduced pressure. The residue was purified by NH silica gel column chromatography (heptane:ethyl acetate=1:2, then ethyl acetate) to obtain the title compound (40 mg, 36.5%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([CH:7]=[CH:8][C:9]=1[F:10])[NH2:6].C(N(CC)CC)C.Cl.[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[C:25](Cl)=[O:26].[OH-].[Na+]>ClCCl>[F:10][C:9]1[CH:8]=[CH:7][C:5]([NH:6][C:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=2)=[O:26])=[CH:4][C:3]=1[CH2:2][OH:1]
Reactant: Nc1ccc(F)c(CO)c1
Reactant: O=C(Cl)c1ccccn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(F)c(CO)c1)c1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 16.7 %

Procedure:
3-Hydroxymethyl-4-fluoroaniline (34.2 g, 243 mmol) was dissolved in dichloromethane (600 mL) under anhydrous conditions and cooled to 0° C. Triethylamine (120 mL, 0.861 mol) was added, followed by a solution of picolinic acid chloride hydrochloride (86.0 g, 0.483 mol) in methylene chloride (300 mL). The reaction mixture was stirred at 0° C. for 0.5 hours and at room temperature for 1 hour, and poured into ice water (2 L). The resulting mixture was basified with 1N sodium hydroxide solution, extracted with methylene chloride (3×800 mL), washed with brine, and dried over magnesium sulfate to give a brown oil, which was purified by flash chromatography (6 in diameter column, elution with 25% ethyl acetate in petroleum ether) to give the title compound (10.0 g, 18%, mp 99°-122° C.) as the first compound of the column, followed by 2-pyridinecarboxylic acid [[2-fluoro-4-[[(2-pyridinyl)oxomethyl]-amino]phenyl]methyl] ester (46.5 g, 52%, mp 116°-118° C.). Additional title compound can be obtained by treating the ester (25.0 g, 71 mmol) with potassium carbonate (19.8 g, 143 mmol) in water (20 mL), methanol (200 mL), and tetrahydrofuran (200 mL). The mixture was left for 2 days and then concentrated in vacuo. The residue was partitioned between ethyl acetate (500 mL) and water (500 ml) and the aqueous layer was extracted again with ethyl acetate (2×200 mL). The organic layer was washed with 2.5N sodium hydroxide solution (500 mL) and brine (500 mL), dried, and concentrated to afford more N-(4-fluoro-3-hydroxymethylphenyl)-2-pyridinecarboxamide (15 g, 90%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:28])[N:12]2[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([O:26]C)=[O:25])[CH:19]=2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4].CO.[OH-].[K+].Cl>O>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([NH:10][C:11](=[O:28])[N:12]2[CH2:15][CH2:16][O:17][C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([OH:26])=[O:25])[CH:19]=2)=[C:8]([NH2:29])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3cccc(C(=O)OC)c3)c2n1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCCOc1nc(N)c2[nH]c(=O)n(CCOc3cccc(C(=O)O)c3)c2n1
Temperature: 85 °C
Reaction time: 4.5 h
Yield: 100 %

Procedure:
To 2-butoxy-8-oxo-9-[2-(3-methoxycarbonylphenoxy)ethyl]adenine (50 mg, 0.12 mmol) obtained in Example 1 were added methanol (2.5 ml) and 2.5N potassium hydroxide (5 m), and the mixture was stirred at 85° C. for 4.5 hours. After cooling, water was added and the resultant was made to pH 5 by concentrated hydrochloric acid. The precipitated crystal was collected by filtration to give 49 mg (0.12 mmol) of the titled compound as a white solid. Yield: 100%.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH:5]([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1.Cl[CH2:17][C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]=[C:20]([CH3:28])[CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:15])[CH:4]([CH3:14])[CH:5]([OH:13])[C:6]1[CH:11]=[CH:10][C:9]([O:12][CH2:17][C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[N:21]=[C:20]([CH3:28])[CH:19]=2)=[CH:8][CH:7]=1
Reactant: Cc1cc(CCl)c2ccccc2n1
Reactant: COC(=O)C(C)C(O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: COC(=O)C(C)C(O)c1ccc(OCc2cc(C)nc3ccccc23)cc1
Reaction time: 18 h
Yield: 84.5 %

Procedure:
The 3-hydroxy-3-(4-hydroxy-phenyl)-2-methyl-propionic acid methyl ester (0.24 g, 1.14 mmol) was combined with the 4-chloromethyl-2-methyl-quinoline (0.313 g, 1.37 mmol) and cesium carbonate (1.1 g, 3.42 mmol) in DMSO (5 mL) at room temperature under a nitrogen atmosphere. The reaction was stirred for 18 h, filtered to remove the solids, and then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried over magnesium sulfate, and concentrated to give a mixture of diasteromers. The product was purified by FCC on silica gel eluting with ethyl acetate:hexane (60:40, v: v) to give 3-hydroxy-2-methyl-3-[4-(2-methyl-quinolin-4-ylmethoxy)-phenyl]-propionic acid methyl ester (0.352 g, 84%) as a glass. MS found: (M+H)+=366.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][NH:13][C:12](=[O:15])[CH2:11][CH2:10]1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].O([CH2:34][C:35]([F:38])([F:37])[F:36])S(C(F)(F)F)(=O)=O>C1COCC1.CN1C(=O)CCC1>[F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[CH:9]1[CH2:14][N:13]([CH2:34][C:35]([F:38])([F:37])[F:36])[C:12](=[O:15])[CH2:11][CH2:10]1
Reactant: O=S(=O)(OCC(F)(F)F)C(F)(F)F
Reactant: O=C1CCC(c2cccc(F)c2F)CN1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CN1CCCC1=O
Product: O=C1CCC(c2cccc(F)c2F)CN1CC(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 5-(2,3-difluorophenyl)piperidin-2-one (8.88 g, 42 mmol) in THF (250 mL) and NMP (170 mL) at 0° C. was added lithium bis(trimethylsilyl)amide (1.0 M in THF, 48 mL, 48 mmol) over 5 min, keeping the internal temperature of the reaction mixture below 5° C. The resulting mixture was stirred at 0° C. for 15 min, then 2,2,2-trifluoroethyl triflate (11.2 g, 48 mmol) was added dropwise, keeping the internal temperature of the reaction mixture below 5° C. The reaction mixture was allowed to warm slowly to ambient temperature and stirring was continued for 3 h. The resulting mixture was partitioned between saturated aqueous sodium bicarbonate (800 mL) and EtOAc (1 L). The organic layer was removed and the aqueous phase was extracted further with EtOAc (500 mL). The combined organic extracts were washed with water, then brine, then dried over sodium sulfate, filtered, and concentrated to dryness in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of hexanes:EtOAc—100:0 to 0:100, to give the title compound. MS: m/z=293.9 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=O)=[CH:5][CH:4]=1.[CH3:19][C:20]1([CH3:29])[CH2:25][C:24]([CH3:27])([CH3:26])[CH2:23][C:22](=O)[CH2:21]1>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9](=[C:22]2[CH2:23][C:24]([CH3:27])([CH3:26])[CH2:25][C:20]([CH3:29])([CH3:19])[CH2:21]2)[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[CH:13][CH:12]=2)=[CH:5][CH:4]=1
Reactant: CC1(C)CC(=O)CC(C)(C)C1
Reactant: COc1ccc(C(=O)c2ccc(C#N)cc2)cc1
Product: COc1ccc(C(=C2CC(C)(C)CC(C)(C)C2)c2ccc(C#N)cc2)cc1
Yield: 50.2 %

Procedure:
The general McMurry protocol, described for 14 was used. The reaction was conducted between 4-{[4-(methyloxy)phenyl]carbonyl}benzonitrile (1.00 g, 4.21 mmol) and 3,3,5,5-tetramethylcyclohexanone (1.95 g, 12.64 mmol) to afford 0.760 g (50%) of the title compound 209 as a white solid. 1H NMR (300 MHz, CDCl3): δ 7.58 (d, J=8.4 Hz, 2H), 7.29 (d, J=8.1 Hz, 2H), 7.07 (d, J=8.7 Hz, 2H), 6.85 (d, J=8.7 Hz, 2H), 3.81 (s, 3H), 2.01 (s, 2H), 1.95 (s, 2H), 1.32 (s, 2H), 0.96 (s, 6H), 0.95 (s, 6H).
Reaction SMILES: [SH:1][CH2:2][C:3]([NH2:5])=[O:4].[H-].[Na+].[NH2:8][CH2:9][C:10]1[N:11]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:12](=[O:27])[C:13]2[C:18]([C:19]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)=[CH:17][C:16](Br)=[CH:15][CH:14]=2>CN(C)C=O>[NH2:8][CH2:9][C:10]1[N:11]([CH2:28][CH:29]([CH3:31])[CH3:30])[C:12](=[O:27])[C:13]2[C:18]([C:19]=1[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)=[CH:17][C:16]([S:1][CH2:2][C:3]([NH2:5])=[O:4])=[CH:15][CH:14]=2
Reactant: NC(=O)CS
Reactant: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(Br)ccc2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CN)c(-c2ccccc2)c2cc(SCC(N)=O)ccc2c1=O
Yield: 49.8 %

Procedure:
A solution (2 mL) of 2-mercaptoacetamide (0.27 g, 3.0 mmol) in N,N-dimethylformamide was ice-cooled under a nitrogen atmosphere and sodium hydride (0.12 g, 3.0 mmol) (60% in oil) was added thereto. The resulting mixture was stirred under ice-cooling for 30 min. To the obtained suspension was added 3-(aminomethyl)-6-bromo-2-isobutyl-4-phenyl-1(2H)-isoquinolinone (1.06 g, 2.74 mmol), and the mixture was stirred at 80° C. for 24 h. The reaction mixture was partitioned between water (100 mL) and ethyl acetate (50 mL), and the aqueous layer was extracted twice with ethyl acetate (50 mL). The extracts were combined and washed with saturated brine (20 mL), dried over anhydrous magnesium sulfate (12 g) and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:methanol=1:0–10:1 (v/v)) and recrystallized from n-hexane-ethyl acetate (1:1) to give the title compound (0.54 g, 50%) as a colorless powder.
Reaction SMILES: [S:1]([C:18]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:19]=1)([O:4][CH2:5][C@H:6]([OH:17])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:3])=[O:2].C(N(CC)CC)C.[Si:32](OS(C(F)(F)F)(=O)=O)([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33]>C(Cl)Cl>[S:1]([C:18]1[CH:19]=[CH:20][C:21]([CH3:22])=[CH:23][CH:24]=1)([O:4][CH2:5][C@H:6]([O:17][Si:32]([C:35]([CH3:38])([CH3:37])[CH3:36])([CH3:34])[CH3:33])[C@H:7]([CH3:16])[CH2:8][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:2])=[O:3]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: Cc1ccc(S(=O)(=O)OC[C@H](O)[C@H](C)CCc2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OC[C@H](O[Si](C)(C)C(C)(C)C)[C@H](C)CCc2ccccc2)cc1
Reaction time: 0.33 h

Procedure:
A solution of tosylate 18 (100 g, 0.29 mol) and triethylamine (81.0 mL, 0.58 mol) in CH2Cl2 (1200 mL) was treated with neat TBS-OTf (99 mL, 0.43 mol) dropwise with continued stirring for another 20 min. The reaction was washed twice with brine, dried over MgSO4 and concentrated to dryness. The oil was dissolved in a minimal amount of hexanes and filtered over a silica pad, eluting with hexanes:EtOAc (9:1) to yield the title compound as a slightly amber oil, 134 g.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](Br)[CH:7]=1.[F:9][C:10]1[CH:11]=[C:12](B(O)O)[CH:13]=[CH:14][CH:15]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].O>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.CN(C=O)C>[F:9][C:10]1[CH:15]=[C:14]([C:6]2[CH:7]=[C:2]([NH2:1])[CH:3]=[N:4][CH:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: OB(O)c1cccc(F)c1
Reactant: Nc1cncc(Br)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Nc1cncc(-c2cccc(F)c2)c1
Temperature: 180 °C
Yield: 83.1 %

Procedure:
To a microwave vial was added 3-amino-5-bromopyridine (LII) (0.400 g, 2.31 mmol), 3-fluorophenyl boronic acid (XLIX) (0.356 g, 2.54 mmol), tetrakis(triphenylphosphine)palladium(0) (0.133 g, 0.116 mmol), potassium phosphate (0.736 g, 3.47 mmol), water (1 mL), and DMF (5 mL). The reaction vial was capped, purged with argon and heated under microwave irradiation for 1 h at 180° C. The solution was filtered through a pad of Celite and concentrated under vacuum. The residue was purified by column chromatography (4:6 EtOAc:hexanes→7:3 EtOAc:hexanes) to afford the 5-(3-fluorophenyl)pyridin-3-amine (LIII) (0.360 g, 1.92 mmol, 83% yield) as a yellow-white solid. ESIMS found for C11H9FN2 m/z 189.1 (M+H).