Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[Cl-].CC(C)CCCCCCCCCCC[NH2+]CC1C=CC=CC=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])[C:34](Cl)([Cl:36])[Cl:35]>ClC1C=CC=CC=1>[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]([C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=1[Cl:44])=[C:34]([Cl:35])[Cl:36]
Reactant: Clc1ccccc1C(c1ccccc1Cl)C(Cl)(Cl)Cl
Agent: CC(C)CCCCCCCCCCC[NH2+]Cc1ccccc1
Agent: [Cl-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: ClC(Cl)=C(c1ccccc1Cl)c1ccccc1Cl
Temperature: 90 °C
Yield: 97.8 %

Procedure:
201.5 g of 28% strength aqueous sodium hydroxide and 2.0 g of dimethyllaurylbenzylammonium chloride were added to a solution of 250 g of 1,1-bis(chlorophenyl)-2,2,2-trichloroethane in 100 g of monochlorobenzene at 50° C. The mixture was heated at reflux (90° C.) for 20 hours. The organic phase was separated by phase separation and was washed three times with 100 g of water. After distillation of the monochlorobenzene, 219.3 g of 1,1-bis(chlorophenyl)-2,2-dichloroethylene were obtained (y=97.8%) with 0.10% of 1,1-bis(chlorophenyl)-2,2,2-trichloroethane.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)[CH2:13][CH:12]([C:26]([OH:28])=O)[CH2:11]2)=[O:9])[CH2:4][CH2:3]1.O[N:30]=[C:31]([NH2:36])[CH2:32][CH2:33][O:34][CH3:35]>>[OH:1][CH:2]1[CH2:3][CH2:4][N:5]([C:8]([N:10]2[CH2:15][CH:14]([C:16]3[CH:17]=[CH:18][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:20][CH:21]=3)[CH2:13][CH:12]([C:26]3[O:28][N:36]=[C:31]([CH2:32][CH2:33][O:34][CH3:35])[N:30]=3)[CH2:11]2)=[O:9])[CH2:6][CH2:7]1
Reactant: COCCC(N)=NO
Reactant: O=C(O)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCC(O)CC2)C1
Product: COCCc1noc(C2CC(c3ccc(C(F)(F)F)cc3)CN(C(=O)N3CCC(O)CC3)C2)n1
Yield: 18.3 %

Procedure:
250 mg (0.624 mmol) of 1-[(4-hydroxypiperidin-1-yl)carbonyl]-5-[4-(trifluoromethyl)phenyl]piperidine-3-carboxylic acid (Example 99A) and 108 mg (0.687 mmol, 75% pure) of N′-hydroxy-3-methoxypropanimidamide (Example 64A) were reacted according to the General Method 1. Enantiomer separation of the racemate according to Method 16D gave 56.0 mg of the title compound from Example 275 and 55.0 mg of the title compound from Example 276 (36% of theory).
Reaction SMILES: [Cl:1][C:2]1[C:11]([S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([O:6]C)=[O:5].[OH-].[Na+]>>[Cl:1][C:2]1[C:11]([S:12]([NH:15][CH2:16][CH3:17])(=[O:14])=[O:13])=[CH:10][CH:9]=[CH:8][C:3]=1[C:4]([OH:6])=[O:5]
Reactant: CCNS(=O)(=O)c1cccc(C(=O)OC)c1Cl
Agent: [Na+]
Agent: [OH-]
Product: CCNS(=O)(=O)c1cccc(C(=O)O)c1Cl

Procedure:
To a solution of methyl 2-chloro-3-(chlorosulfonyl)benzoate (608 mg, 2.26 mmol) and K2CO3 (770 mg, 5.6 mmol) in 10 mL benzene was added ethylamine (5.6 mL, 11.2 mmol). Purification of the product provided methyl 2-chloro-3-[(ethylamino)sulfonyl]benzoate (335 mg, 53%) as a solid. 1H NMR (400 MHz, CDCl3), δ 8.24 (dd, 1H, J=8.0, 1.7 Hz), 7.90 (dd, 1H, J=7.8, 1.7 Hz), 7.47 (t, 1H, J=7.8 Hz), 5.14 (t, 1H, J=5.9 Hz), 3.94 (s, 3H), 2.98 (qd, 2H, J=7.3, 6.0 Hz), 1.09 (t, 3H, J=7.2 Hz); ESI-MS 278 (M+H), 300 (M+Na). Methyl 2-chloro-3-[(ethylamino)sulfonyl]benzoate was hydrolyzed using aqueous NaOH to provide 2-chloro-3-[(ethylamino)sulfonyl]benzoic acid as a solid, which was used without further purification. ESI-MS 264 (M+H), 286 (M+Na).
Reaction SMILES: [OH:1][CH:2]([C:6]1[O:10][N:9]=[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[C:7]=1[CH3:16])[CH2:3][CH:4]=[CH2:5].[CH:17](=O)[CH3:18].[Si](OS(C(F)(F)F)(=O)=O)(C)(C)C.[Cl-].[NH4+]>C(Cl)Cl>[CH3:16][C:7]1[C:8]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:9][O:10][C:6]=1[CH:2]1[CH2:3][CH:4]=[CH:5][CH:17]([CH3:18])[O:1]1
Reactant: C=CCC(O)c1onc(C(=O)OCC)c1C
Reactant: CC=O
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Product: CCOC(=O)c1noc(C2CC=CC(C)O2)c1C
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of ethyl 5-(1-hydroxybut-3-en-1-yl)-4-methylisoxazole-3-carboxylate (35 mg, 0.155 mmol) in DCM (1 mL) was treated with acetaldehyde (8.72 μl, 0.155 mmol) and the reaction mixture was cooled to 0° C. A solution of TMSOTf (80.4 μL, 0.465 mmol) in DCM (1.5 mL) cooled to 0° C. was added and the reaction mixture was stirred at 0° C. for 30 minutes and at room temperature overnight. To the resulting mixture was added a saturated solution of ammonium chloride (aq) (2 mL) and this was extracted with DCM (×3). The combined organic extracts were passed through a phase separating cartridge and the eluent was concentrated under reduced pressure. The crude material was adsorbed onto silica and purification by chromatography eluting with 0-100% EtOAc in iso-hexane afforded the title compound;
Reaction SMILES: C[Al](C)C.[CH:5]([NH2:8])([CH3:7])[CH3:6].C.[CH3:10][C:11]1[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:14]=[C:13]([NH:20][C:21]([NH:23][S:24]([C:27]2[CH:36]=[CH:35][CH:34]=[CH:33][C:28]=2[C:29](OC)=[O:30])(=[O:26])=[O:25])=[O:22])[N:12]=1>CCCCCC.C(Cl)Cl.C1(C)C=CC=CC=1>[CH:5]([NH:8][C:29]([C:28]1[CH:33]=[CH:34][CH:35]=[CH:36][C:27]=1[S:24]([NH:23][C:21]([NH:20][C:13]1[N:12]=[C:11]([CH3:10])[C:16]2[CH2:17][CH2:18][CH2:19][C:15]=2[N:14]=1)=[O:22])(=[O:26])=[O:25])=[O:30])([CH3:7])[CH3:6]
Reactant: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2c(n1)CCC2
Reactant: CC(C)N
Agent: C
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Solvent: ClCCl
Solvent: CCCCCC
Product: Cc1nc(NC(=O)NS(=O)(=O)c2ccccc2C(=O)NC(C)C)nc2c1CCC2
Reaction time: 2 h

Procedure:
To 21.2 ml of 25% trimethylaluminum in hexane (2.36 molar) under nitrogen is added 2.9 g of isopropyl amine in 100 ml of dried methylene chloride. The mixture is stirred at ambient temperature until evolution of methane gas ceases and then 19.5 g of methyl 2[[(6,7-dihydro-4-methyl-5H-cyclopentapyrimidin-2-yl)aminocarbonyl]aminosulfonyl]benzoate and 200 ml of dry toluene is added. The resulting mixture is heated to distill off the methylene chloride and hexane, after which heating is continued at the reflux temperature of toluene. After 2 hours, the toluene is removed in vacuo, and 200 ml of methylene chloride and 100 ml of 10% hydrochloric acid are added. The phases are separated, and the methylene chloride phase is washed once with water, dried over magnesium sulfate, and filtered, and the methylene chloride distilled to yield the desired compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH2:7][CH2:8]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Br)(Br)(Br)[Br:30].C(OCC)C>O1CCCC1>[Br:30][CH2:8][CH2:7][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=1
Reactant: OCCc1ccccn1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: C1CCOC1
Product: BrCCc1ccccn1
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of 2-pyridineethanol (1.00 ml) in tetrahydrofuran (20 ml) were successively added triphenylphosphine (3.51 g) and carbon tetrabromide (4.44 g) with stirring at room temperature, and the resulting mixture was stirred at room temperature overnight. After stirring, to the reaction mixture was added diethyl ether, and insoluble materials were filtered off, and the organic layer was washed successively with a saturated aqueous sodium hydrogencarbonate solution and a saturated aqueous sodium chloride solution, dried over anhydrous magnesium sulfate and evaporated in vacuo. The residue obtained was purified by chromatography on a silica gel column using a mixed solvent of hexane and ethyl acetate (1:3) as the eluent to afford the title compound (1.30 g, yield: 78%) as a yellow oil.
Reaction SMILES: [C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18][CH:19]=O)[CH2:14]2)[N:11]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:9])#[N:2].Cl.[NH2:29][OH:30].C([O-])(=O)C.[Na+]>C(O)C.O.[Cl-].[Na+].O>[C:1]([C@@H:3]1[CH2:7][CH2:6][CH2:5][N:4]1[C:8]([C@@H:10]1[C@H:15]2[CH2:16][C@H:12]([C@H:13]([O:17][CH2:18]/[CH:19]=[N:29]/[OH:30])[CH2:14]2)[N:11]1[C:21]([O:23][C:24]([CH3:25])([CH3:26])[CH3:27])=[O:22])=[O:9])#[N:2]
Reactant: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OCC=O)[C@H]1C(=O)N1CCC[C@H]1C#N
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: CC(C)(C)OC(=O)N1[C@@H]2C[C@@H](C[C@H]2OC/C=N/O)[C@H]1C(=O)N1CCC[C@H]1C#N
Yield: 77.3 %

Procedure:
To a solution of tert-butyl (1R,3S,4S,6R)-3-{[(2S)-2-cyano-1-pyrrolidinyl]carbonyl}-6-(2-oxoethoxy)-2-azabicyclo[2.2.1]heptane-2-carboxylate obtained in Example 25-1 (163 mg) in ethanol (6 mL) and water (1 mL), were added hydroxylamine hydrochloride (36 mg) and sodium acetate (46 mg). The mixture was stirred at reflux for 20 minutes. To the resulting mixture, brine was added. The mixture extracted with ethyl acetate. The combined organic phase was washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed on silica gel eluting with ethyl acetate to give the target compound (131 mg).
Reaction SMILES: [C:1]1([C:14](O)=O)[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.OCC1C2CC3C(=CC=CC=3)C=2C=CC=1.P(Br)(Br)[Br:33].O>C1COCC1>[Br:33][CH2:14][C:1]1[C:13]2[CH2:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: O=C(O)c1cccc2c1Cc1ccccc1-2
Agent: OCc1cccc2c1Cc1ccccc1-2
Solvent: C1CCOC1
Solvent: O
Product: BrCc1cccc2c1Cc1ccccc1-2
Temperature: -5 °C
Reaction time: 1.5 h

Procedure:
Fluorene-1-carboxylic acid was purchased from Aldrich. It was reduced as described in J. Am. Chem. Soc. 1961, 83, 417 via the methyl ester to 1-hydroxymethylfluorene 1H NMR (CDCl3): δ 4.84 ppm (CH2), 3.89 ppm (CH2). 4.1 g (21 mmol) 1-hydroxymethylfluorene dissolved in 60 ml THF was slowly added to 2.54 g PBr3 in 10 ml THF at −5° C. The orange solution was stirred for 1.5 hrs at −5° C. then stirred for 16 hrs at room temperature. This was then poured into iced water, allowed to settle and 5.1 g of 1-bromomethylfluorene was isolated on a frit as an off-white powder. 1H NMR (CDCl3): δ 4.65 ppm (CH2), 3.97 ppm (CH2).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1.[CH3:18][CH2:19][O:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([NH2:27])[CH:22]=1.Cl.[OH-].[Na+]>O.C(O)C>[CH2:19]([O:20][C:21]1[CH:22]=[C:23]([CH:24]=[CH:25][CH:26]=1)[NH:27][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[N:5]=[C:4]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:3]=1)[CH3:18]
Reactant: FC(F)(F)c1cc(Cl)nc(-c2ccccn2)n1
Reactant: CCOc1cccc(N)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOc1cccc(Nc2cc(C(F)(F)F)nc(-c3ccccn3)n2)c1
Yield: 63.6 %

Procedure:
A mixture of 4-chloro-2-(2-pyridinyl)-6-(trifluoromethyl)pyrimidine (25 mg, 0.096 mmol), m-phenetidine (19 μl, 0.144 mmol), and 2N HCl (75 μl) in water:ethanol (2:1, 5 ml) was refluxed for 24 h. The mixture was cooled to room temperature and basified with aqueous 2N NaOH to pH 10–12. The resulting precipitate was filtered, washed with water, water:ethanol (2:1) and dried to give a yellow solid (22 mg, 63%). 1H NMR (CDCl3): 8.88–8.85 (m, 1H), 8.58 (d, J=8.1 Hz, 1H), 7.93–7.88 (m, 1H), 7.61 (s, 1H), 7.48–7.44 (m, 1H), 7.35 (t, J=8.4 Hz, 1H), 7.05 (s, 1H), 6.89–6.81 (m, 3H), 4.07 (q, J=7.1 Hz, 2H), 1.45 (t, J=7.1 Hz, 3H).
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[Cl:12][C:13]1[CH:14]=[C:15]([NH:28][C:29]2[C:34]3=[C:35]([CH2:38][S:39][CH2:40][CH2:41][OH:42])[CH:36]=[CH:37][N:33]3[N:32]=[CH:31][N:30]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1>C(Cl)(Cl)Cl>[Cl:12][C:13]1[CH:14]=[C:15]([NH:28][C:29]2[C:34]3=[C:35]([CH2:38][S:39]([CH2:40][CH2:41][OH:42])=[O:9])[CH:36]=[CH:37][N:33]3[N:32]=[CH:31][N:30]=2)[CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([F:27])[CH:22]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: OCCSCc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Solvent: ClC(Cl)Cl
Product: O=S(CCO)Cc1ccn2ncnc(Nc3ccc(OCc4cccc(F)c4)c(Cl)c3)c12
Temperature: 0 °C
Reaction time: 1 h
Yield: 42.1 %

Procedure:
A solution of thioacetic acid S-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethyl}ester (80 mg, 0.175 mmole) in dry THF (4 mL) was sparged with N2 for 15 min. NaOMe (0.40 mL, 0.5 M in MeOH, 1.1 equiv), 2-bromoethanol (0.013 mL, 1 equiv) were added and the reaction was left stirring at RT. After 16 h, the solvents were removed and the residue was partitioned between DCM and water. The organic phase was separated, dried (Na2SO4), and the solvent removed. Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2% MeOH) afforded 2-{4-[3-chloro-4-(3-fluoro-benzyloxy)-phenylamino]-pyrrolo[2,1-f][1,2,4]triazin-5-ylmethylsulfanyl}-ethanol (35 mg, 44%): 1H NMR (CDCl3) δ 2.73 (t, 2H, J=5.9 Hz), 3.81 (t, 2H, J=5.9 Hz), 4.11 (s, 2H), 5.13 (s, 2H), 6.55 (d, 1H, J=2.6 Hz), 6.92–7.93 (m, 10H), 8.99 (s, 1H). Solid m-chloroperbenzoic acid (19 mg, 58 to 70%, 1 equiv) was added to an ice-cooled solution of the alcohol (35 mg, 0.18 mmole) in CHCl3 (4 mL). After 1 h, this was removed from the bath and washed with a 6% aq. solution of NaHSO3, sat. aq. NaHCO3 (3×) and then dried (Na2SO4). Radial chromatography (silica gel plate eluted with DCM containing 0, 0.5, 1, 2, 3% MeOH) afforded the title compound (22 mg, 60%): MS: 475 (M+H)+; HPLC Ret Time: 1.66 min (YMC Xterra C18 S7, 3.0×50 mm column, 2 min gradient, 5 mL/min).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)(=[O:26])=[O:25])[CH2:12]1)(C(C)(C)C)(C)C.C(=O)([O-])O.[Na+].[CH3:42][S:43](Cl)(=[O:45])=[O:44].Cl>C(O)(=O)C.O1CCCC1.O.CN(C)C1C=CN=CC=1>[CH3:42][S:43]([O:8][CH2:9][CH2:10][C@H:11]1[O:15][CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[N:13]([S:24]([C:27]2[CH:32]=[CH:31][C:30]([O:33][CH3:34])=[C:29]([O:35][CH3:36])[CH:28]=2)(=[O:26])=[O:25])[CH2:12]1)(=[O:45])=[O:44]
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc(S(=O)(=O)N2C[C@@H](CCO[Si](C)(C)C(C)(C)C)OC2c2ccc(Cl)c(Cl)c2)cc1OC
Agent: CN(C)c1ccncc1
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(S(=O)(=O)N2C[C@@H](CCOS(C)(=O)=O)OC2c2ccc(Cl)c(Cl)c2)cc1OC
Temperature: 80 °C
Reaction time: 2 h
Yield: 89.1 %

Procedure:
1.19 g (2.06 mmole) of 2-[(5R)-(3,4-dichlorophenyl)-3-(3,4-dimethoxybenzenesulfonyl)oxazolidin-5-yl]ethanol t-butyldimethylsilyl ether [prepared as described in step (a) above] were dissolved in 20 ml of a 3:3:1 by volume mixture of acetic acid, tetrahydrofuran and water, and the resulting mixture was then heated at 80° C. for 2 hours under a nitrogen atmosphere. At the end of this time, the reaction mixture was then neutralised with a saturated aqueous solution of sodium hydrogencarbonate and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was dissolved in 10 ml of pyridine. 23 mg (0.19 mmole) of 4-dimethylaminopyridine and 0.22 ml (2.84 mmole) of methanesulfonyl chloride were then added to the resulting solution, whilst ice-cooling. The mixture was then stirred for 2 hours at 0° C. under a nitrogen atmosphere. At the end of this time, the reaction mixture was poured into 200 ml of ice-cooled 10% w/v aqueous hydrochloric acid, and then extracted with ethyl acetate. The organic extract was washed with a saturated aqueous solution of sodium chloride and then dried over anhydrous magnesium sulfate. The solvent was removed by distillation under reduced pressure, and the resulting residue was purified by silica gel column chromatography, using a gradient elution method, with mixtures of hexane and ethyl acetate ranging from 2:1 to 1:2 by volume as the eluent, to give 992 mg of the title compound as white crystals.
Reaction SMILES: [OH-].[K+].[OH:3][C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:20])[CH3:19].S(OC)(O[CH3:25])(=O)=O>O>[CH3:25][O:3][C:4]1[C:9]([S:10][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[F:17])=[CH:8][CH:7]=[CH:6][C:5]=1[CH:18]([OH:20])[CH3:19]
Reactant: CC(O)c1cccc(Sc2ccccc2F)c1O
Reactant: COS(=O)(=O)OC
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: COc1c(Sc2ccccc2F)cccc1C(C)O
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 45.2 %

Procedure:
A solution of potassium hydroxide (1.6 g) in water (20 ml) was added slowly to a mixture of 1-[2-hydroxy-3-(2-fluorophenylthio)phenyl]ethanol (2.1 g) and dimethyl sulfate (2 g), and the mixture was stirred at room temperature for 30 minutes and at 60° C. for an hour. To the reaction mixture was added water, and the mixture was extracted with diethyl ether. The extract was washed with dil. aqueous solution of sodium hydroxide and water in turn, dried and evaporated under reduced pressure. The oily residue (1.8 g) was purified by column chromatography (silica gel 30 g, toluene) to give 1-[2-methoxy-3-(2-fluorophenylthio) phenyl]ethanol (1 g).
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([O:11]C)=O)[CH:4]=1.[Cl-].[NH4+:14].CCOC(C)=O.O>N>[Cl:2][C:3]1[CH:8]=[CH:7][N:6]=[C:5]([C:9]([NH2:14])=[O:11])[CH:4]=1
Reactant: [NH4+]
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: Cl
Agent: N
Agent: [Cl-]
Solvent: O
Solvent: CCOC(C)=O
Product: NC(=O)c1cc(Cl)ccn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 214.4 %

Procedure:
To a stirred mixture of methyl 4-chloro-2-pyridinecarboxylate hydrochloride (1.0 g, 4.81 mmol) dissolved in conc. aqueous ammonia (32 mL) was added ammonium chloride (96.2 mg, 1.8 mmol, 0.37 equiv.), and the heterogeneous reaction mixture was stirred at ambient temperature for 16 h. The reaction mixture was poured into EtOAc (500 mL) and water (300 mL). The organic layer was washed with water (2×300 mL) and a saturated NaCl solution (1×300 mL), dried (MgSO4), concentrated in vacuo to give 4-chloro-2-pyridinecarboxamide as a beige solid (604.3 mg, 80.3%): TLC (50% EtOAc/hexane) Rf 0.20; 1H-NMR (DMSO-d6) δ 8.61 (d, J=5.4 Hz, 1H), 8.20 (broad s, 1H), 8.02 (d, J=1.8 Hz, 1H), 7.81 (broad s, 1H), 7.76 to 7.73 (m, 1H).
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[O:15][CH2:14][C:13](=[CH:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([OH:28])=[O:27])[CH:21]=1)[C:12]2=[O:29])C1C=CC=CC=1.[CH2:30]1COCC1.CO>[Pd]>[C:26]([C:22]1[CH:21]=[C:20]([CH2:19][CH:13]2[C:12](=[O:29])[C:11]3[C:16](=[CH:17][CH:18]=[C:9]([OH:8])[CH:10]=3)[O:15][CH2:14]2)[CH:25]=[CH:24][CH:23]=1)([O:28][CH3:30])=[O:27]
Reactant: O=C(O)c1cccc(C=C2COc3ccc(OCc4ccccc4)cc3C2=O)c1
Reactant: C1CCOC1
Agent: [Pd]
Solvent: CO
Product: COC(=O)c1cccc(CC2COc3ccc(O)cc3C2=O)c1
Temperature: 0 °C
Reaction time: 20 h
Yield: 63 %

Procedure:
To a solution of 6-benzyloxy-3-)3-carboxyphenylmethylene)-4-chromanone from Step 2 (1.54 g, 3.8 mmol) in 40 ml THF/MeOH (1:3) was added 150 mg of 10% Pd/C. The mixture was hydrogenated at 40 psi for 20 hr. The mixture was filtered through celite. The filtrate was evaporated to dryness and redissolved in THF. The THF solution was cooled to 0° C. and diazomethane was added until no acid remained. Then HOAc was added. The mixture was evaporated to give an oil which was chromatographed on silica gel and eluted with 40% EtOAc/hexane to give 750 mg (63%) of the title compound.
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[SH:9].[H-].[Na+].[Cl:14][C:15]1[CH:20]=[C:19]([N+]([O-])=O)[CH:18]=[CH:17][N:16]=1>>[Cl:14][C:15]1[CH:20]=[C:19]([S:9][C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:2]([F:1])([F:10])[F:11])[CH:18]=[CH:17][N:16]=1
Reactant: O=[N+]([O-])c1ccnc(Cl)c1
Reactant: FC(F)(F)c1ccccc1S
Agent: [H-]
Agent: [Na+]
Product: FC(F)(F)c1ccccc1Sc1ccnc(Cl)c1
Yield: 93 %

Procedure:
Using the method of Example 3, Step A, 2-(trifluoromethyl)benzenethiol (1.12 g, 6.31 mmol), 60% sodium hydride in mineral oil (252 mg, 6.31 mmol) and 2-chloro-4-nitropyridine (1.00 g, 12.6 mmol) were reacted to provide 2-chloro-4-(2-(trifluoromethyl)phenylthio)pyridine (1.70 g, 93% yield) as an oil. 1H NMR (CDCl3) δ 8.13 (d, 1H), 7.88 (m, 1H), 7.61-7.72 (m, 4H), 6.85 (s, 1H), 6.80 (m, 1H).
Reaction SMILES: [I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:6].[O-2].[O-2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:19]([C:30]2[CH:35]=[CH:34][C:33]([Cl:36])=[CH:32][CH:31]=2)=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[NH:24][C:23](=[O:29])[CH:22]=[CH:21]2)[CH2:16][OH:17])([CH3:13])([CH3:12])[CH3:11]>C(#N)C>[I:1]([OH:5])(=[O:4])(=[O:3])=[O:2].[O-2:14].[O-2:6].[O-2:2].[Cr+6:9].[C:10]([O:14][C@@H:15]([C:18]1[C:19]([C:30]2[CH:31]=[CH:32][C:33]([Cl:36])=[CH:34][CH:35]=2)=[C:20]2[C:25](=[CH:26][C:27]=1[CH3:28])[NH:24][C:23](=[O:29])[CH:22]=[CH:21]2)[C:16]([OH:6])=[O:17])([CH3:13])([CH3:11])[CH3:12]
Reactant: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@@H](CO)OC(C)(C)C
Agent: [Cr+6]
Agent: [O-2]
Agent: [O-][I+3]([O-])([O-])O
Solvent: CC#N
Product: Cc1cc2[nH]c(=O)ccc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A stock solution of periodic acid/chromium trioxide was prepared according to WO 99/52850 by dissolving periodic acid (11.4 g, 50.0 mmol) and chromium trioxide (23 mg, 1.2 mol %) in wet acetonitrile (0.75% H2O) to a volume of 114 mL. This stock solution (0.40 mL) was added to a solution of (S)-6-(1-tert-butoxy-2-hydroxyethyl)-5-(4-chlorophenyl)-7-methylquinolin-2(1H)-one (8K, 4.4 mg) in wet acetonitrile (1.5 mL, 0.75% H2O) at 0° C. After stirring for 60 min at 0° C., the reaction was quenched with 1.5 M K2HPO4 solution and extracted with ethyl acetate (2×). The combined organic layer was washed with 1:1 brine/H2O (2×), saturated NaHSO3/brine, and was dried (MgSO4). Concentration and purification by prep-HPLC gave (S)-2-tert-butoxy-2-(5-(4-chlorophenyl)-7-methyl-2-oxo-1,2-dihydroquinolin-6-yl)acetic acid (8L) (2 mg). 1H-NMR 300 MHz, (CD3OD) 7.56-7.53 (3H, m), 7.35 (1H, d, J=9.7 Hz), 7.28 (1H, d, J=8.2 Hz), 7.22 (1H, s), 6.43 (1H, d, J=9.8 Hz), 5.06 (1H, s), 2.55 (3H, s), 0.95 (9H, s). LCMS-ESI+ (m/z): [M+H]+ calcd for C22H23ClNO4: 400.9. Found: 400.2; LCMS-ESI− (m/z): [M−H]− calcd for C22H21ClNO4: 398.9. Found: 397.9.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:6]([O:16][C:17]1[CH:22]=[CH:21][C:20]([C:23](=[NH:25])[NH2:24])=[CH:19][C:18]=1[O:26][CH3:27])(=[O:15])[CH:7]=[CH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H][H]>[C].[Pd].CO>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[C:9]1([CH2:8][CH2:7][C:6]([O:16][C:17]2[CH:22]=[CH:21][C:20]([C:23](=[NH:24])[NH2:25])=[CH:19][C:18]=2[O:26][CH3:27])=[O:15])[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: COc1cc(C(=N)N)ccc1OC(=O)C=Cc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Agent: CS(=O)(=O)O
Solvent: CO
Product: COc1cc(C(=N)N)ccc1OC(=O)CCc1ccccc1
Yield: 74.6 %

Procedure:
To 100 ml of methanol, were added 2.0 g of 4-amidino-2-methoxyphenyl cinnamate methanesulfonate and 0.5 g of a 10% palladium-carbon. Hydrogen was fed to the mixture which was stirred vigorously to facilitate absorption. The reaction mixture was freed from the insolubles by filtration and from the solvent by distillation. The residue was recrystallized from ethanol to obtain 1.5 g of the same 4-amidino-2-methoxyphenyl 3-phenylpropionate methanesulfonate.