Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1([CH3:18])[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1.[H][H]>[Pd].C(O)C>[CH3:1][C:2]1([CH3:18])[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([CH:12]([CH3:17])[C:13]([O:15][CH3:16])=[O:14])[CH:8]=2)[NH:3]1
Reactant: [H][H]
Reactant: COC(=O)C(C)c1ccc2c(c1)C=CC(C)(C)N2
Agent: [Pd]
Solvent: CCO
Product: COC(=O)C(C)c1ccc2c(c1)CCC(C)(C)N2
Yield: 102.5 %

Procedure:
3 g of methyl 2-(1,2-dihydro-2,2-dimethylquinolin-6-yl)propionate (Compound 7) were added to absolute ethanol. Palladium-on-carbon was further added to the solution, and the mixture was reacted with bubbling hydrogen gas at room temperature for 4 hours with stirring. After the reaction, the catalyst was filtered off and ethanol was distilled off to give 3.1 g of methyl 2-(1,2,3,4-tetrahydro-2,2-dimethylquinolin-6-yl)propionate (Compound 11).
Reaction SMILES: Cl.[NH2:2][OH:3].C([O-])(=O)C.[Na+].CO.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=O)[CH2:20][CH3:21])=[CH:15][CH:14]=1>O>[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19](=[N:2][OH:3])[CH2:20][CH3:21])=[CH:15][CH:14]=1
Reactant: NO
Reactant: CCC(=O)c1ccc(OC)cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CCC(=NO)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 111.7 %

Procedure:
Hydroxylamine hydrochloride (7.0 g, 100 mmol) and sodium acetate (8.2 g, 100 mmol) were added to 50 mL of methanol and the resulting white slurry was stirred at room temperature for 30 min. 1-(4-Methoxyphenyl)propan-1-one (15 g, 91.4 mmol) was added and the mixture was stirred at room temperature for 20 hours, and then refluxed for 20 hours. Water (50 mL) was added and the mixture was stirred for 10 min. The product was extracted with EtOAc and the organic layer was washed with saturated NaHCO3 solution and dried over MgSO4. The solvent was evaporated in vacuo to give 18.3 g of the title compound. MS: (+) m/z 180.39 (M+1).
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:29][N:30](C)[C:31](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])[CH:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:45]>C(OCC)(=O)C.CC(O)C>[ClH:45].[F:1][C:2]1[C:3]([CH2:29][NH:30][CH3:31])=[CH:4][N:5]([S:14]([C:17]2[CH:18]=[C:19]([CH:20]=[CH:21][CH:22]=2)[C:23]([NH:25][CH2:26][CH2:27][OH:28])=[O:24])(=[O:15])=[O:16])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: CN(Cc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F)C(=O)OC(C)(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cccc(C(=O)NCCO)c2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 50 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(3-{[(2-hydroxyethyl)amino]carbonyl}phenyl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (226 mg) in ethyl acetate (3 mL) and 2-propanol (2 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (6 mL), and the mixture was stirred at room temperature for 2 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethanol to give the title compound as a white solid (yield 99 mg, 50%).
Reaction SMILES: [CH3:1][N:2]([CH3:13])[CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)N(C)C.C([Cl:17])(=O)C>CCOCC>[Cl-:17].[CH:3](=[N+:2]([CH3:13])[CH3:1])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: CN(C)C(c1ccccc1)N(C)C
Reactant: CC(=O)Cl
Solvent: CCOCC
Product: C[N+](C)=Cc1ccccc1
Product: [Cl-]
Temperature: 0 °C
Reaction time: 15 h
Yield: 81 %

Procedure:
10 g (56 mmole) of N,N,N′, N′-tetramethyl-C-phenylmethanediamine (J. Am. Chem. Soc. 77 (1955) 1114-1116) were dissolved in 100 ml ether and the solution was cooled to 0° C. in an ice-bath. 4.0 ml (56 mmole) acetyl chloride were added dropwise under nitrogen. After the first drops, a white salt precipitated out and the temperature increased slightly. After 15 hours at RT, the mixture was decanted and the solid was washed three times with 100 ml ether each time, filtered over an inert gas frit under nitrogen and dried to constant weight under an oil-pump vacuum. 7.7 g benzylidenedimethylammonium chloride (80.9% of theoretical) were obtained in this manner.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](I)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1.C1(C)C=CC=CC=1>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.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:32]2[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=2)[C:5]2[O:10][CH:9]([C:11]([F:14])([F:13])[F:12])[C:8]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][C:6]=2[CH:20]=1
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(I)c2OC1C(F)(F)F
Reactant: OB(O)c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1=Cc2cc(Cl)cc(-c3ccc(Cl)cc3)c2OC1C(F)(F)F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
Ethyl 6-chloro-8-iodo-2-(trifluoromethyl)-2H-1-benzopyran-3-carboxylate (Example 73, Step 2)(1.3 g, 3.02 mmol), potassium carbonate (1.25 g, 9.06 mmol), 4-chorophenylboronic acid (0.52 g, 3.33 mmol), and tetrakis(triphenylphosphine)palladium(0) (0.174 g, 0,151 mmol) were added to toluene (30 mL) and the resulting solution was heated to reflux for 18 hours. After cooling to room temperature the reaction mixture was poured into ethyl acetate (50 mL). It was washed with 1 N HCl (2×25 mL), saturated aqueous sodium bicarbonate (2×25 mL), and water (2×25 mL). The organic phase was dried over MgSO4, filtered, and concentrated in vacuo to yield a brown oil. The crude material was purified by flash chromatography using 1% ethyl acetate in hexane yielding a white solid. Recrystallization from hexane afforded the ester as a white solid (0.79 g, 64%): mp 114.2–115.9° C. 1H NMR (CDCl3/300 MHz) 7.69 (s, 1H), 7.41 (s, 4H), 7.30 (d, 1H, J=2.4 Hz), 7.22 (d, 1H, J=2.6 Hz), 5.70 (q, 1H, J=6.9 Hz), 4.37–4.29 (m, 2H), 1.35 (t, 3H, J=7.1 Hz). ESLRMS m/z 434 (M+NH4+). FABHRMS m/z 434.0574 (M+NH4+, Calc'd. 434.0538). Anal. Calc'd. for C19H13Cl2F3O3: C, 54.70; H, 3.14; Cl, 17.00. Found: C, 54.79; H, 3.18; Cl, 16.65.
Reaction SMILES: [N:1]1([C:5]2[C:10]([C:11]#[N:12])=[C:9]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][OH:22])=[CH:15][CH:14]=3)[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=2)[CH2:4][CH2:3][CH2:2]1.[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49](O)=[O:50])[CH3:48])=[O:45])([CH3:42])([CH3:41])[CH3:40].C1COCC1.Cl.CN(C)CCCN=C=NCC>CN(C)C1C=CN=CC=1.CN(C=O)C>[C:39]([O:43][C:44]([NH:46][C@H:47]([C:49]([O:22][CH2:21][CH2:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([C:9]2[C:8]([C:23]#[N:24])=[C:7]([S:25][CH2:26][C:27]3[N:28]=[C:29]([C:32]4[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=4)[S:30][CH:31]=3)[N:6]=[C:5]([N:1]3[CH2:2][CH2:3][CH2:4]3)[C:10]=2[C:11]#[N:12])=[CH:14][CH:15]=1)=[O:50])[CH3:48])=[O:45])([CH3:41])([CH3:42])[CH3:40]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Reactant: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc(N2CCC2)c(C#N)c1-c1ccc(OCCO)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: C[C@H](NC(=O)OC(C)(C)C)C(=O)OCCOc1ccc(-c2c(C#N)c(SCc3csc(-c4ccc(Cl)cc4)n3)nc(N3CCC3)c2C#N)cc1
Temperature: 40 °C
Reaction time: 8 h

Procedure:
350 mg (0.625 mmol) of 2-(azetidin-1-yl)-6-({(2-(4-chlorophenyl)-1,3-thiazol-4-yl)methyl}sulfanyl)-4-(4-(2-hydroxyethoxy)phenyl)pyridine-3,5-dicarbonitrile (Example 8), 354.7 mg (1.875 mmol) of N-(tert-butoxycarbonyl)-L-alanine and 38.17 mg (0.312 mmol) of 4-dimethylaminopyridine were initially charged in 3.3 ml of DMF. 3.3 ml of THF and 155.7 mg (0.812 mmol) of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride were added, and the reaction solution was then stirred at 40° C. overnight. After cooling, the reaction solution was purified by preparative HPLC (acetonitrile/water+0.1% TFA). This gave 377 mg (83% of theory) of the target compound.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[CH:24][CH:23]=2)(=[O:21])=[O:20])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C>C1COCC1.CO.[OH-].[Na+]>[CH2:12]([N:9]1[CH2:10][CH2:11][C:6]([S:19]([C:22]2[CH:27]=[CH:26][C:25]([O:28][C:29]3[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=3)=[CH:24][CH:23]=2)(=[O:20])=[O:21])([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)C1(S(=O)(=O)c2ccc(Oc3ccc(Cl)cc3)cc2)CCN(Cc2ccccc2)CC1

Procedure:
1-Benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperdine-4-carboxylic acid was prepared starting from 1-benzyl-4-[4-(4-chloro-phenoxy)-benzenesulfonyl]-piperidine-4- carboxylic acid ethyl ester (2.11 g, 4.1 mmol) dissolved in THF:methanol (3:1 150 ml) and 10N NaOH (20 ml). The resulting reaction mixture was worked up as outlined in example 83. Yield 1.11 g (56%); white solid; mp 201° C.; MS: 485.9 (M+H)+
Reaction SMILES: [O:1]1[CH2:16][CH:2]1[CH2:3][N:4]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:5][CH:6]1[O:8][CH2:7]1.[CH2:17]([OH:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.O1CCOCC1.[H-].[Na+]>O>[C:18]1([CH2:17][O:24][CH2:7][CH:6]2[CH2:5][N:4]([CH2:9][C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=3)[CH2:3][CH:2]([CH2:16][OH:1])[O:8]2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OCc1ccccc1
Reactant: c1ccc(CN(CC2CO2)CC2CO2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: OCC1CN(Cc2ccccc2)CC(COCc2ccccc2)O1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
5.48 G (0.025 mole) of N,N-bis(2,3-epoxypropyl)benzylamine is added to a mixture of 2.70 g (0.025 mole) of benzyl alcohol in 75 ml of dioxane containing 1 equivalent of sodium hydride. The reaction is allowed to cool below 40° with an ice-bath for approximately 1/2 hour and is then heated at reflux overnight. After cooling to room temperature, the entire mixture is poured slowly, with stirring, into 150 ml of water. The aqueous mixture is extracted with 3×125 ml portions of chloroform. The CHCl3 extracts are combined, washed with 200 ml of water and 200 ml of saturated NaCl solution. The CHCl3 layer is then dried over anhydrous NaSO4, evaporated in vacuo to yield 6.1 g (74%) of crude product as a pale yellow oil. The oil is chromatographed on 300 g of neutral Alumina III to give 5.6 g (68%) of 6-[(phenylmethoxy)methyl]-4-(phenylmethyl)-2-morpholinemethanol.
Reaction SMILES: [C:1]1(=[O:14])[CH:9]2[CH:4]([CH:5]3[CH2:11][CH2:10][CH:8]2[CH:7]2[CH2:12][CH:6]32)[C:3](=[O:13])[NH:2]1.[Cl:15][C:16]1[C:17]([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)=[N:18][CH:19]=[CH:20][N:21]=1>>[ClH:15].[Cl:15][C:16]1[C:17]([N:22]2[CH2:23][CH2:24][N:25]([CH2:3][CH2:4][CH2:5][CH2:6][N:2]3[C:3](=[O:13])[CH:4]4[CH:9]([CH:8]5[CH2:10][CH2:11][CH:5]4[CH:6]4[CH2:12][CH:7]54)[C:1]3=[O:14])[CH2:26][CH2:27]2)=[N:18][CH:19]=[CH:20][N:21]=1
Reactant: O=C1NC(=O)C2C3CCC(C4CC43)C12
Reactant: Clc1nccnc1N1CCNCC1
Product: Cl
Product: O=C1C2C3CCC(C4CC43)C2C(=O)N1CCCCN1CCN(c2nccnc2Cl)CC1

Procedure:
The title compound is prepared following the procedure of Example 1, using hexahydro-4,6-ethanocycloprop[f]isoindole-1,3-(2H,3aH)-dione instead of hexahydro-4,7-ethenocycloprop[f]isoindole-1,3(2H,3aH)-dione and 1-(3-chloro-2-pyrazinyl)piperazine instead of 1-(6-chloro-2-pyrazinyl)piperazine hydrochloride and is converted to the hydrochloride salt; m.p. 245°-246° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[NH2:7][C:8]1[CH:9]=[C:10]([SH:14])[CH:11]=[CH:12][CH:13]=1.Cl[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[C:18]([CH:25]([O:28][CH3:29])[O:26][CH3:27])[CH:17]=1.O>CC(N(C)C)=O>[CH3:29][O:28][CH:25]([O:26][CH3:27])[C:18]1[CH:17]=[C:16]([S:14][C:10]2[CH:9]=[C:8]([NH2:7])[CH:13]=[CH:12][CH:11]=2)[CH:21]=[CH:20][C:19]=1[N+:22]([O-:24])=[O:23]
Reactant: COC(OC)c1cc(Cl)ccc1[N+](=O)[O-]
Reactant: Nc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COC(OC)c1cc(Sc2cccc(N)c2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 2 h

Procedure:
K2CO3 (0.085 mol) was added to a mixture of 3-aminothiophenol (0.075 mol) in DMA (150 mL), then 4-chloro-2-dimethoxymethyl-1-nitrobenzene (0.050 mol) was added and the reaction mixture was stirred for 2 hours at 80° C. H2O was added and the mixture was extracted with diisopropyl ether. The crude product was purified by column chromatography (eluent: 70:30 CH2Cl2:hexane up to 99:1 CH2Cl2:CH3OH). The product fractions were collected and the solvent was evaporated to yield the title compound as a residue which contained about 10% of an impurity. (The product was used in subsequent steps without further purification.)
Reaction SMILES: C(C(C(O)=O)(O)C(C(=O)C1C=CC=CC=1)(O)C(O)=O)(=O)C1C=CC=CC=1.[OH:27][C@@H:28]1[CH2:33][CH2:32][CH2:31][NH:30][C@@H:29]1[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.[CH2:40]([O:47][C:48](Cl)=[O:49])[C:41]1[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1.[OH-].[Na+]>ClCCl>[C:41]1([CH2:40][O:47][C:48]([N:30]2[CH2:31][CH2:32][CH2:33][C@@H:28]([OH:27])[C@H:29]2[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)=[O:49])[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1
Reactant: O[C@@H]1CCCN[C@@H]1c1ccccc1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C(O)C(O)(C(=O)c1ccccc1)C(O)(C(=O)O)C(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCC[C@@H](O)[C@H]1c1ccccc1
Reaction time: 1 h
Yield: 95 %

Procedure:
(2R,3R)-3-Hydroxy-2-phenylpiperidine dibenzoyltartrate (prepared by the method European Patent Specification number 0 528 495-A, 35.6 g, 0.1 mol) was added slowly to a mixture of benzylchloroformate (21.4 mL, 25.6 g, 0.15 mol), dichloromethane (50 mL) and aqueous sodium hydroxide (1M, 500 mL). The mixture was stirred vigorously for 1 h., then further benzylchloroformate (8.0 mL, 9.56 g, 56 mmol) in dichloromethane (50 mL) was added slowly. The mixture was stirred vigorously overnight, the layers were separated and the aqueous layer was extracted with dichloromethane (100 mL). The combined organic fractions were dried (MgSO4) and the solvent was evaporated under reduced pressure. The residue was triturated with hexane and the solid was collected and dried in vacuo to give the title compound as a colorless solid (29.53 g, 95%). 1H NMR (250 MHz, CDCl3) δ7.47-7.24 (10 H, m), 5.44 (1 H, d, J 5.7 Hz), 5.14 (1 H, d, J 12.4 Hz), 5.07 (1 H, d, J 12.4 Hz), 4.09 (2 H, m), 3.09 (1 H, m), and 1.88-1.58 (6 H, m).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6](O)[C:3]=1[CH:4]=[O:5].C(N([CH2:17][CH3:18])CC)C.F[C:20](F)(F)S(OS(C(F)(F)F)(=O)=O)(=O)=O>ClCCl.CN(C)C=O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[C:6]([C:20]#[C:17][CH3:18])[C:3]=1[CH:4]=[O:5]
Reactant: CCN(CC)CC
Reactant: O=Cc1c(O)cc(F)cc1F
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CC#Cc1cc(F)cc(F)c1C=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 83 %

Procedure:
To an ice-bath cooled mixture of 2,4-difluoro-6-hydroxybenzaldehyde (Description 70, 9.20 g; 58.2 mmol) and triethylamine (8.92 ml; 64.02 mmol) in anhydrous dichloromethane (100 ml) was added dropwise over 10 minutes trifluoromethanesulfonic anhydride (11.75 ml; 69.84 mmol) and the resulting mixture stirred at room temperature for 1 hour. The mixture was washed with water (300 ml), and the aqueous phase extracted with DCM (100 ml). The combined organic layers were washed with saturated NaCl (100 ml), dried over Na2SO4, filtered through a 1 inch plug of silica and evaporated. The residue (14.4 g; 49.6 mmol) and triethylamine (10.37 ml; 74.4 mmol) in anhydrous N,N-dimethylformamide (80 ml) contained within a large (200 ml capacity) sealed tube was cooled to −78° C. and propyne gas bubbled through until the volume had increased by approx 10 ml. To this mixture was added Pd(PPh3)2Cl2 (1.74 g; 2.48 mmol) and CuI (449 mg; 4.96 mmol), the lid was put in place and the tube allowed to reach room temperature. The reaction was stirred for 2 hours after which TLC showed reaction was complete. The mixture was poured onto water (500 ml) and extracted with EtOAc (3×150 ml); the combined EtOAc layers were washed with water (3×400 ml), saturated NaCl (150 ml), dried over Na2SO4, filtered through a 1 inch plug of silica and evaporated to give the title compound (8.7 g, 97%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]([C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)[C:4](=[O:18])[CH:3]=1.[Br:19]N1C(=O)CCC1=O.C([O-])([O-])=O.[K+].[K+].[F:33][C:34]1[CH:41]=[C:40]([F:42])[CH:39]=[CH:38][C:35]=1[CH2:36]Br>CN(C=O)C>[Br:19][C:3]1[C:4](=[O:18])[N:5]([C:9]2[O:13][C:12]([C:14]([O:16][CH3:17])=[O:15])=[CH:11][CH:10]=2)[C:6]([CH3:8])=[CH:7][C:2]=1[O:1][CH2:36][C:35]1[CH:38]=[CH:39][C:40]([F:42])=[CH:41][C:34]=1[F:33]
Reactant: O=C1CCC(=O)N1Br
Reactant: COC(=O)c1ccc(-n2c(C)cc(O)cc2=O)o1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(-n2c(C)cc(OCc3ccc(F)cc3F)c(Br)c2=O)o1
Reaction time: 1 h

Procedure:
To a room temperature solution of methyl 5-(4-hydroxy-6-methyl-2-oxopyridin-1(2H)-yl)-2-furoate (step 1) (3.19 g, 12.8 mmol) in DMF (14 mL) was added portion-wise solid N-bromosuccinimide (2.29 g, 12.9 mmol). The reaction was stirred vigorously for 1.0 h, followed by the sequential addition of K2CO3 (1.88 g, 13.6 mmol), DMF (4.0 mL), and 2,4 difluorobenzyl bromide (2.00 mL, 15.55 mmol). The resulting suspension was stirred for 9.0 hours until complete formation of desired product was seen by LCMS analysis. The reaction was then diluted with saturated brine (300 mL) and extracted with ethyl acetate (3×300 mL). The resulting organic extracts were Na2SO4 dried, filtered, and concentrated in vacuo to a residue that was subjected to SiO2 chromatography with a gradient elution using ethyl acetate/hexanes (40:60 to 60:40) to furnish a solid (3.20 mg, 55%). 1H NMR (400 MHz, d7-DMF) δ 7.78 (app q, J=8.6 Hz, 1H), 7.48 (app d, J=3.6 Hz, 1H), 7.33 (app dt, J=10.0, 2.4 Hz, 1H), 7.21 (app dt, J=8.5, 1.8 Hz, 1H), 6.92 (d, J=3.6 Hz, 1H), 6.81 (s, 1H), 5.47 (s, 2H), 3.88 (s, 3H), 2.15 (s, 3H); LC/MS C-18 column, tr=3.11 minutes (5 to 95% acetonitrile/water over 5 minutes at 1 ml/min with detection 254 nm, at 50° C.). ES-MS m/z 454 (M+H). ES-HRMS m/z 454.0117 (M+H calcd for C19H15BrF2N2O5 requires 454.0096).
Reaction SMILES: [OH-].[Li+].[CH2:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([CH3:35])[C:31]([O:33]C)=[O:32])[CH:25]=[CH:24]4)=[N:14][CH:15]=2)[S:8][CH:9]=1)[CH3:4].CO.O>C1COCC1>[CH2:3]([C:5]1[N:6]=[C:7]([C:10]2[CH:11]=[CH:12][C:13]([O:16][CH2:17][CH2:18][CH2:19][O:20][C:21]3[CH:22]=[C:23]4[C:27](=[CH:28][CH:29]=3)[N:26]([CH:30]([CH3:35])[C:31]([OH:33])=[O:32])[CH:25]=[CH:24]4)=[N:14][CH:15]=2)[S:8][CH:9]=1)[CH3:4]
Reactant: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)OC)c3)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CCc1csc(-c2ccc(OCCCOc3ccc4c(ccn4C(C)C(=O)O)c3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 83.3 %

Procedure:
Lithium hydroxide (0.05 g, 2.15 mmol) was added to a solution of methyl 2-[5-(3-{[5-(4-ethyl-1,3-thiazol-2-yl)-2-pyridinyl]oxy}propoxy)-1H-indol-1-yl]propanoate (Example 69, 0.1 g, 0.21 mmol) in a mixture of THF (2 mL), methanol (2 mL), and water (1 mL). The reaction mixture was stirred at rt for 18 h and then concentrated under reduced pressure. The residue was diluted with water and acidified with 5% H3PO4. The aqueous layer was extracted with ethyl acetate. The combined organic extracts were dried over Na2SO4, filtered, and concentrated to give the title compound as a solid (0.079 g, 82%). 1H NMR (400 MHz, CD2Cl2) δ 8.45 (dd, 1H), 7.94 (dd, 1H), 7.08-6.62 (m, 6H), 6.22 (d, 1H), 4.94 (qt, 1H), 4.37 (t, 2H), 4.00 (t, 2H), 2.66 (qt, 2H), 2.31-2.07 (m, 2H), 1.60 (d, 3H), 1.15 (t, 3H).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11].[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1B(O)O.C1(C)C=CC=CC=1>CCO>[F:19][C:20]1[CH:25]=[C:24]([F:26])[CH:23]=[CH:22][C:21]=1[C:8]1[N:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: OB(O)c1ccc(F)cc1F
Reactant: CCOC(=O)c1cccnc1Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccnc1-c1ccc(F)cc1F
Temperature: 82 °C
Reaction time: 8 h

Procedure:
To a nitrogen purged 3.0 L, 4-necked flask, fitted with an overhead stirrer, thermocouple, heating mantle, nitrogen outlet and reflux condenser, was charged Pd(Ph3)4 (5.0 g, 4.33 mmoles, 0.005 eq), sodium carbonate (92.6 g, 874 mmoles, 1.3 eq), ethyl 2-chloronicotinate, 1 (126.0 g, 678 moles, 1.0 eq), 2,4-difluorophenylboronic acid, 2 (125 g, 791 mmoles, 1.2 eq), followed by 0.5 L of toluene and 125 mL denatured EtOH. The reaction was heated to 82° C. with vigorous stirring under N2 overnight (completeness of reaction determined by HPLC and TLC). The reaction was cooled to room temperature, the mixture filtered through a small pad of Celite® and the solvents removed under vacuum at 55° C. The residue was dissolved in EtOAc, washed, dried (MgSO4), filtered through Celite® again, and concentrated. The product was obtained as a yellow solid.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([CH3:10])=[CH:4][C:3]=2[O:2]1.[N+:11]([O-])(O)=O.O>C(O)(=O)C>[CH2:1]1[O:2][C:3]2[CH:4]=[C:5]([CH3:10])[C:6]([NH2:11])=[CH:7][C:8]=2[O:9]1
Reactant: O=[N+]([O-])O
Reactant: Cc1ccc2c(c1)OCO2
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc2c(cc1N)OCO2
Reaction time: 0.75 h
Yield: 87 %

Procedure:
To a solution of (3,4-methylenedioxy)toluene (5 ml) in acetic acid (20 ml) cooled with a cold water bath was added, dropwise, nitric acid (70%, 5 ml). The mixture was stirred for 45 min. To work up, water (100 ml) was added and the resulting yellow precipitate was filtered and washed with water until the aqueous filtrate was colorless. The yellow solid was dissolved in EtOAc (250 ml) and dried (MgSO4), and the solid was filtered off. The filtrate was subjected to catalytic hydrogenation (1 0% Pd/C, 1 atm) for 1 2 hours. The reaction mixture was then filtered off the catalyst and the filtrate was concentrated on a rotavap to give (3,4-methylenedioxy)-6-methylaniline as a brownish grey solid (5.49 g, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[C:11](B(O)O)=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1.[NH4+].[Cl-].[OH2:17].OO>CCOCC>[Cl:1][C:2]1[C:11]([OH:17])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[N:3]=1
Reactant: OB(O)c1cc2ccccc2nc1Cl
Reactant: O
Agent: OO
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: Oc1cc2ccccc2nc1Cl
Reaction time: 16 h
Yield: 89 %

Procedure:
A suspension of 2-chloroquinoline-3-boronic acid (15 g, 72.3 mmol) and NH4Cl (7.16 g, 134 mmol) in Et2O:H2O (600 mL) was treated dropwise with aqueous H2O2 (30%, 62 mL, 709 mmol). The mixture was stirred for 16 h. Then, the precipitate was filtered, washed with water and Et2O, and dried at 60° C. over P2O5 to afford the title compound (11.5 g, 89%). LCMS (ES+) m/z 180 (M+H)+.