Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([O:7]C)=[O:6].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[S:12]([CH3:15])(=[O:14])=[O:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(C)c1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1cc(C(=O)O)ccc1S(C)(=O)=O
Temperature: 75 °C
Yield: 97.4 %

Procedure:
To a mixture of methyl 3-methyl-4-methylsulfonyl-benzoate (5.8 g, 25.4 mmol) in dioxane (25 mL) was added NaOH (20 g, 125.0 mmol) (aq. 25%) and the reaction mixture was heated at 75° C. for 1 hour. The reaction mixture was cooled and was concentrated in vacuo to half the volume and adjusted to pH 2 with 6N HCl solution. The aqueous layer was extracted with ethyl acetate (3×100 mL). The organics were washed with brine solution (50 mL), dried over MgSO4 and concentrated in vacuo to give 3-methyl-4-methylsulfonyl-benzoic acid (5.3 g, 97%) as a white solid. ESI-MS m/z calc. 214.5. Found 215.5 (M+1)+; Retention time: 0.67 minutes (3 min run); 1H NMR (400 MHz, DMSO) δ 13.48 (s, 1H), 8.13-7.81 (m, 3H), 3.33 (s, 3H), 2.70 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2Cl)=[CH:6][CH:5]=1.[F:30][C@@H:31]1[CH2:35][CH2:34][NH:33][CH2:32]1.Cl.CCN(C(C)C)C(C)C>CC#N>[F:1][C:2]([F:29])([F:28])[O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([N+:18]([O-:20])=[O:19])[C:15]([NH:21][CH2:22][CH:23]([F:25])[F:24])=[CH:14][C:13]=2[N:33]2[CH2:34][CH2:35][C@@H:31]([F:30])[CH2:32]2)=[CH:6][CH:5]=1
Reactant: F[C@@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1Cl
Agent: Cl
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cc([N+](=O)[O-])c(NCC(F)F)cc1N1CC[C@@H](F)C1

Procedure:
The sub-title compound is prepared in analogy to 6a from N-(4-trifluoromethoxy-phenyl)-2-chloro-4-(2,2-difluoro-ethylamino)-5-nitro-benzoic acid amide (177 mg, 0.40 mmol), (R)-3-fluoro-pyrrolidine×HCl (56 mg, 0.44 mmol), DIPEA (0.55 mL, 3.2 mmol) and MeCN (5 mL).
Reaction SMILES: [CH:1]1([NH2:4])[CH2:3][CH2:2]1.Cl.Cl[CH2:7][C:8]1[C:13]([O:14][CH3:15])=[C:12]([O:16][CH3:17])[CH:11]=[CH:10][NH+:9]=1.ClCCl.CO>C(O)C.C(=O)([O-])O.[Na+]>[CH3:15][O:14][C:13]1[C:8]([CH2:7][NH:4][CH:1]2[CH2:3][CH2:2]2)=[N:9][CH:10]=[CH:11][C:12]=1[O:16][CH3:17]
Reactant: COc1cc[nH+]c(CCl)c1OC
Reactant: NC1CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: CO
Product: COc1ccnc(CNC2CC2)c1OC
Temperature: 58 °C
Reaction time: 1.5 h
Yield: 47.5 %

Procedure:
1.05 ml (14.9 mmol) of cyclopropylamine was added to a solution of 695 mg (2.66 mmol) of 2-chloromethyl-3,4-dimethoxypyridinium hydrochloride in 4 ml ethanol and 4 ml of saturated aqueous sodium hydrogen carbonate. The reaction mixture was stirred for 1.5 hrs at 58° C. and extracted with ethyl acetate (3×10 ml). The combined organic layers were dried over magnesium sulphate and concentrated in vacuum. Column chromatography (gradient dichloromethane/methanol) yielded 263 mg (42% yield) of N-[(3,4-dimethoxypyridin-2-yl)methyl]cyclopropylamine.
Reaction SMILES: [C:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>O1CCCC1.[O-]S(C(F)(F)F)(=O)=O.[Sc+3].[O-]S(C(F)(F)F)(=O)=O.[O-]S(C(F)(F)F)(=O)=O>[N:12]1([CH2:8][C:7]2[CH:10]=[CH:11][C:4]([C:1](=[O:3])[CH3:2])=[CH:5][CH:6]=2)[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1
Reactant: C1COCCN1
Reactant: CC(=O)c1ccc(C=O)cc1
Agent: O=S(=O)([O-])C(F)(F)F
Agent: [Sc+3]
Solvent: C1CCOC1
Product: CC(=O)c1ccc(CN2CCOCC2)cc1

Procedure:
4.7 g of 1,4-dihydro-2,6-dimethyl-3,5-pyridinecarboxylate and 1.3 g of scandium triflate were added to 2.75 g of 4-acetylbenzaldehyde (18.56 mmol), 1.7 ml of morpholine and 3 g of 4 Å molecular sieves in 100 ml of tetrahydrofuran under argon, and the mixture was heated to reflux for 3 hours. The mixture was concentrated. The residue was mixed with ethyl acetate and washed with sat. NaHCO3 solution and sat. NaCl solution. Drying and evaporation of the mixture resulted in a crude product which was purified by chromatography on silica gel (eluent: cyclohexane/ethyl acetate 40-80%). 1.85 g of a yellowish oil were obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)[C:14](=[O:24])[CH2:13][CH2:12]1.Br[C:26]1[S:27][CH:28]=[CH:29][N:30]=1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C)(C(=O)CC(=O)C(C)(C)C)C>CN1C(=O)CCC1.Cl[Cu].C1(C)C=CC=CC=1.CCOC(C)=O.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([O:9][CH3:10])[C:4]=1[CH:11]1[N:15]([CH2:16][C:17]2[CH:18]=[CH:19][C:20]([O:23][C:26]3[S:27][CH:28]=[CH:29][N:30]=3)=[CH:21][CH:22]=2)[C:14](=[O:24])[CH2:13][CH2:12]1
Reactant: Brc1nccs1
Reactant: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(O)cc1
Agent: Cl[Cu]
Agent: CC(C)(C)C(=O)CC(=O)C(C)(C)C
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Solvent: CN1CCCC1=O
Solvent: CCOC(C)=O
Product: COc1cccc(OC)c1C1CCC(=O)N1Cc1ccc(Oc2nccs2)cc1

Procedure:
In a microwave tube, a mixture of 5-(2,6-dimethoxyphenyl)-1-(4-hydroxybenzyl)pyrrolidin-2-one (60 mg; 0.18 mmol), commercially available 2-bromothiazole (60 mg; 0.36 mmol), Cs2CO3 (66 mg; 0.20 mmol), CuCl (9 mg; 0.09 mmol), and commercially available 2,2,6,6-tetramethylheptane-3,5-dione (34 mg; 0.18 mmol) in anh. NMP (1 ml) was sealed and irradiated by microwave (175° C.; 10 min.). Water (1 ml), AcOEt (2 ml), and toluene (1 ml) were added, and the resulting suspension was filtered over a pad of celite. The separated organic layer was dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.79 min.; [M+H]+: 411.07 g/mol.
Reaction SMILES: [OH-].[K+].[NH2:3][C:4]1[S:5][CH:6]=[C:7]([CH3:14])[C:8]=1[C:9]([O:11][CH2:12]C)=[O:10].ClC(OC(Cl)(Cl)Cl)=[O:17]>O>[CH3:14][C:7]1[C:8]2[C:9](=[O:10])[O:11][C:12](=[O:17])[NH:3][C:4]=2[S:5][CH:6]=1
Reactant: CCOC(=O)c1c(C)csc1N
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cc1csc2[nH]c(=O)oc(=O)c12
Temperature: 100 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
Potassium hydroxide (14.77 g, 0.26 mol) was dissolved in 500 mL water. To this solution was added ethyl 2-amino-4-methyl-thiophene-3-carboxylate (24.38 g, 0.13 mol). The solution was heated at 100° C. for 16 hours. The solution was then cooled to 0° C. and trichloromethyl chloroformate (23.8 mL, 0.20 mol) was added slowly. The solution was allowed to come to room temperature and further stirred for 5 hours. The precipitated solid was collected by vacuum filtration to yield 16.0 g (66%) of 5-methyl-1H-thieno[2,3-d][1,3]oxazine-2,4-dione. MP 220° C. 1H-NMR (DMSO-d6) δ 2.30 (d, J=1.2 Hz, 3H), 6.78 (d, J=1.2 Hz, 1H), 12.55 (b, 1H) ppm; EIMS m/z 184 (M+1).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:11]2([CH2:14][N:13]([C@H:15]3[C:23]4[C:18](=[CH:19][C:20](Br)=[CH:21][CH:22]=4)[CH2:17][CH2:16]3)[CH2:12]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])(=O)C.[K+].Cl[C:33]1[N:38]=[CH:37][C:36]([CH2:39][CH3:40])=[CH:35][N:34]=1.C([O-])([O-])=O.[K+].[K+]>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].O1CCOCC1>[CH2:39]([C:36]1[CH:35]=[N:34][C:33]([C:20]2[CH:19]=[C:18]3[C:23](=[CH:22][CH:21]=2)[C@H:15]([N:13]2[CH2:14][C:11]4([CH2:25][CH2:26][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9][CH2:10]4)[CH2:12]2)[CH2:16][CH2:17]3)=[N:38][CH:37]=1)[CH3:40]
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN([C@@H]1CCc3cc(Br)ccc31)C2
Reactant: CCc1cnc(Cl)nc1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)[O-]
Solvent: C1COCCO1
Product: CCc1cnc(-c2ccc3c(c2)CC[C@H]3N2CC3(CCN(C(=O)OC(C)(C)C)CC3)C2)nc1
Temperature: 110 °C
Yield: 91.5 %

Procedure:
To an oven-dried round-bottomed flask was added (R)-tert-butyl-2-(5-bromo-2,3-dihydro-1H-inden-1-yl)-2,7-diazaspiro[3.5]nonane-7-carboxylate (3-1a, 600 mg, 1.42 mmol), bispinacolatodiboron (398 mg, 1.71 mmol), 559 mg potassium acetate (559 mg, 5.70 mmol) and anhydrous dioxane (20 mL). The resulting mixture was purged with nitrogen (3×). Pd(dppf)Cl2 (58.0 mg, 0.07 mmol) was added and the reaction mixture was purged with nitrogen (3×). The reaction was heated under nitrogen at 110° C. for 4 hours at which time LCMS showed conversion to the desired boronate intermediate. Pd(dppf)Cl2 catalyst (58.0 mg, 0.07 mmol), 2-chloro-5-ethylpyrimidine (224 mg, 1.57 mmol) and aqueous K2CO3 solution (de-oxygenated with nitrogen for 15 minutes prior to addition, 2M, 5.0 mL) were added to the reaction mixture. The reaction was purged with nitrogen (3×) and heated for 6 hours at 110° C. The reaction was cooled to room temperature and the dioxane solvent was removed under reduced pressure. The residue was partitioned between 100 mL of ethyl acetate and 100 mL of 1N NaOH solution. The organic layer was washed with 100 mL of brine, dried (Na2SO4) and concentrated to afford thecrude product as a dark brown oil. The crude product was purified on an Analogix (Analogix Inc., Burlington, Wis.) 8 g silica column, eluted with 0-10% MeOH in CH2Cl2 over 20 minutes to afford 583 mg (92%) of the desired product (3-1b) as a brown foam. MS (ES+) 449.5 (M+H)+. 1H NMR (CDCl3) δ 1.23 (t, 3H), 1.40 (s, 9H), 1.56-1.67 (m, 4H), 1.83-1.91 (m, 1H), 2.07-2.16 (m, 1H), 2.59 (q, 2H), 2.76-2.85 (m, 1H), 2.99-3.13 (m, 5H), 3.24-3.31 (m, 4H), 3.91 (dd, 1H), 7.27-7.34 (m, 1H), 8.17-8.23 (m, 2H), 8.56 (s, 2H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH2:19][C:20]([C:22]2[CH:31]=[CH:30][C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[CH:23]=2)=[O:21])[C:3]1=[O:32].[C:33]1([CH3:42])[CH:38]=[CH:37][CH:36]=[C:35]([N:39]=[C:40]=[O:41])[CH:34]=1>>[CH:23]1[C:24]2[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:30]=[CH:31][C:22]=1[C:20]([CH2:19][N:4]1[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8][CH:2]([NH:1][C:40]([NH:39][C:35]2[CH:34]=[C:33]([CH3:42])[CH:38]=[CH:37][CH:36]=2)=[O:41])[C:3]1=[O:32])=[O:21]
Reactant: Cc1cccc(N=C=O)c1
Reactant: NC1N=C(c2ccccc2)c2ccccc2N(CC(=O)c2ccc3ccccc3c2)C1=O
Product: Cc1cccc(NC(=O)NC2N=C(c3ccccc3)c3ccccc3N(CC(=O)c3ccc4ccccc4c3)C2=O)c1

Procedure:
3-Amino-1,3-dihydro-1-(2-naphthoylmethyl)-5-phenyl-2H-1,4-benzodiazepin-2-one, and 3-tolyl isocyanate
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][C:7]([NH:10][C:11](=[O:31])[CH2:12][S:13][CH:14]2[C:18]([CH3:19])=[C:17]([CH3:20])[C:16](=[O:21])[N:15]2[CH2:22][C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)=[N:6][CH:5]=1.N[C:34]1C=CC=C(C)N=1>>[CH3:30][O:29][C:26]1[CH:27]=[CH:28][C:23]([CH2:22][N:15]2[C:16](=[O:21])[C:17]([CH3:20])=[C:18]([CH3:19])[CH:14]2[S:13][CH2:12][C:11]([NH:10][C:7]2[CH:8]=[CH:9][CH:4]=[C:5]([CH3:34])[N:6]=2)=[O:31])=[CH:24][CH:25]=1
Reactant: Cc1cccc(N)n1
Reactant: COC(=O)c1ccc(NC(=O)CSC2C(C)=C(C)C(=O)N2Cc2ccc(OC)cc2)nc1
Product: COc1ccc(CN2C(=O)C(C)=C(C)C2SCC(=O)Nc2cccc(C)n2)cc1

Procedure:
The product from Example 1, Part C (0.3 g, 0.93 mmol) and 2-amino-6-picoline (0.152 g, 1.4 mmol) were converted to the title compound by the method described in Part B of Example 16 (271 mg, 70%). 1H NMR (300 MHz, CDCl3) δ 8.50 (broad s, 1H); 8.12 (d, J=5 Hz, 1H), 7.96 (s, 1H); 7.20 (d, J=8.4 Hz, 2H); 6.88 (d, J=5 Hz, 1H); 6.84 (d, J=8.4 Hz, 2H); 5.10 (d, J=14.6 Hz, 1H), 4.61 (s, 1H); 4.16 (d, 14.9 Hz, 1H); 3.76 (s, 3H); 2.90 (s, 2H); 2.36 (s, 3H); 1.95 (s, 3H); 1.84 (s, 3H). MS: m/z (MH+) 412.
Reaction SMILES: [H-].[Na+].Cl.[NH2:4][C:5]1([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]2[NH:10][C:9](=[O:15])[CH:8]=[CH:7][C:6]1=2.CI.[C:19](O)(=O)/C=C/C(O)=O.[OH-].[Na+]>CN(C)C=O>[NH2:4][C:5]1([CH3:16])[CH2:14][CH2:13][CH2:12][C:11]2[N:10]([CH3:19])[C:9](=[O:15])[CH:8]=[CH:7][C:6]1=2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CC1(N)CCCc2[nH]c(=O)ccc21
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: Cn1c2c(ccc1=O)C(C)(N)CCC2
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 23 %

Procedure:
A mixture of sodium hydride (50% in oil, 2.9 g), 5-amino-5,6,7,8-tetrahydro-5-methyl-2(1H)-quinolinone hydrochloride (5.43 g), and dimethylformamide (370 ml) was stirred at room temperature for 1.5 hrs. Methyl iodide (3.97 g) was added, and the mixture was allow to stand at room temperature for 20 hrs. The reaction mixture was concentrated in vacuo, and the residue was washed with dichloromethane. The washings were concentrated, the residue was dissolved in a mixture of ethyl acetate and methanol and treated with 0.5 equivalents of fumaric acid. The precipitate (2.65 g) was combined with a 1.9 g-sample obtained in another experiment, and the combined material was treated with 5% sodium hydroxide solution and extracted with dichloromethane. The extract was concentrated. Recrystallization of the residue from ethyl acetate gave 2.1 g (23%) of product, mp 166-167.5 C.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][C:12]3[CH:13]=[C:14]([NH:18][C:19](=[O:31])[C:20]4[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([C:29]#[N:30])([CH3:28])[CH3:27])[CH:21]=4)[CH:15]=[CH:16][CH:17]=3)[CH:8]=[CH:7][C:5]=2[N:6]=1.[CH:32]1([C:35](Cl)=[O:36])[CH2:34][CH2:33]1>N1C=CC=CC=1.CN(C)C1C=CN=CC=1.CO.[OH-].[Na+]>[C:29]([C:26]([C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][CH:23]=1)[C:19]([NH:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([O:11][C:9]2[CH:8]=[CH:7][C:5]3[N:6]=[C:2]([NH:1][C:35]([CH:32]4[CH2:34][CH2:33]4)=[O:36])[S:3][C:4]=3[CH:10]=2)[CH:13]=1)=[O:31])([CH3:27])[CH3:28])#[N:30]
Reactant: O=C(Cl)C1CC1
Reactant: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(N)sc4c3)c2)c1
Agent: CN(C)c1ccncc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: c1ccncc1
Product: CC(C)(C#N)c1cccc(C(=O)Nc2cccc(Oc3ccc4nc(NC(=O)C5CC5)sc4c3)c2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 73.8 %

Procedure:
To a solution of N-{3-[(2-amino-1,3-benzothiazol-6-yl)oxy]phenyl}-3-(1-cyano-1-methylethyl)benzamide (5.13 g, 12.0 mmol) in pyridine (50 mL) were added cyclopropanecarbonyl chloride (2.5 mL, 27.6 mmol) and N,N-dimethylpyridine-4-amine (89.3 mg, 731 μmol), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was diluted with methanol (50 mL), 2N aqueous sodium hydroxide solution (10 mL) was added, and the mixture was stirred at room temperature for 3 hr. The reaction mixture was concentrated under reduced pressure, and the residue was suspended in ethyl acetate (300 mL), and washed successively with water (150 mL), dilute hydrochloric acid (100 mL), saturated aqueous sodium hydrogencarbonate solution (100 mL) and saturated brine (100 mL), successively. The organic layer was dried over anhydrous magnesium sulfate, the insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (hexane/ethyl acetate=95/5→50/50) and recrystallized from ethyl acetate/diisopropyl ether to give the title compound (4.4 g, 88%) as colorless crystals.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[OH:9].[N+:10]([O-])([OH:12])=[O:11].O>C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([N+:10]([O-:12])=[O:11])[CH:5]=[C:4]([F:8])[C:3]=1[OH:9]
Reactant: O=[N+]([O-])O
Reactant: Oc1c(F)cccc1F
Solvent: CC(=O)O
Solvent: O
Product: O=[N+]([O-])c1cc(F)c(O)c(F)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 51 %

Procedure:
To a solution of 2,6-difluorophenol (2.00 g) in acetic acid (20 ml) was added dropwise 60% nitric acid (1.20 ml) in an ice bath and the mixture was stirred at room temperature for 1 hour. After pouring into iced water, the reaction mixture was extracted with ethyl acetate. The extract was washed with brine. The organic layer was dried over anhydrous magnesium sulfate, filtered and the filtrate concentrated in vacuo. The residue was purified by chromatography on a silica gel column using hexane/ethyl acetate=3/1→2/1 as an eluant to give the desired compound (1.37 g, yield 51%) as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:19])([F:18])[F:17])[CH:13]=[CH:12][C:11]=1[S:20](Cl)(=[O:22])=[O:21]>>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]([F:18])([F:17])[F:19])[CH:13]=[CH:12][C:11]=1[S:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1)(=[O:22])=[O:21]
Reactant: O=S(=O)(Cl)c1ccc(C(F)(F)F)cc1Cl
Reactant: Nc1ccc(O)cc1
Product: O=S(=O)(Nc1ccc(O)cc1)c1ccc(C(F)(F)F)cc1Cl

Procedure:
2-Chloro-N-(4-hydroxy-phenyl)-4-trifluoromethyl-benzenesulfonamide was synthesized (98%) from 4-aminophenol (Aldrich) and 2-chloro-4-trifluoromethylbenzenesulfonyl chloride in a similar manner as described in Example 421.
Reaction SMILES: ClCCl.[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[CH:11]=[CH:10][C:6]=1[C:7]([OH:9])=[O:8].C(=O)([O-])O.[Na+].[I:20](Cl)(=O)=O.I(Cl)(=O)=O.C([N+](C)(C)C)C1C=CC=CC=1>CO>[NH2:4][C:5]1[CH:13]=[C:12]([F:14])[C:11]([I:20])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8]
Reactant: O=I(=O)Cl
Reactant: Nc1cc(F)ccc1C(=O)O
Agent: C[N+](C)(C)Cc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Product: Nc1cc(F)c(I)cc1C(=O)O
Reaction time: 48 h
Yield: 77 %

Procedure:
To a vigorously stirred solution of dichloromethane (700 ml), methanol (320 ml), and 2-amino-4-fluoro-benzoic acid (33.35 grams, 215 mmoles) was added solid sodium hydrogencarbonate (110 grams, 1.31 moles) followed by portion addition of benzyltrimethyl ammonium dichloroiodate (82.5 grams, 237 mmoles). The mixture was allowed to stir for 48 hours. The mixture was filtered to remove the insolubles. The remaining solid residue was washed with 200 ml of dichloromethane. The filtrate was concentrated and redissolved in a one to one mixture of ethyl acetate (1 liter) and a 0.2 N solution of sodium hydroxide (1 liter), added to a 2 liter separatory funnel and extracted. The organic layer was washed with an additional 200 ml of water. The aqueous layers were combined and acidified with 2N hydrochloric acid. The resulting precipitate was collected by suction filtration, washed with water and dried under vacuum at 60° C. to yield 46.5 grams (77%) of the title compound. 1H NMR (400 MHz, DMSO-d6) δ: 8.04 (d, 1H), 7.1 (s, broad, 2H), 6.63 (d, 1H). ESI-MS m/z 280 (M−1).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[C:10]([NH:13]C(NC3C=CC=CC=3)=O)[CH:11]=[CH:12][C:6]=2[N:5]=[C:4]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:3]1.C[C:39]([N:41](C)C)=O>O.[Zn].[C-]#N.[C-]#N.[Zn+2].C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[NH2:13][C:10]1[CH:11]=[CH:12][C:6]2[N:5]=[C:4]([C:23]3[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=3)[C:39]#[N:41])[CH2:3][C:2](=[O:1])[NH:8][C:7]=2[CH:9]=1
Reactant: CC(=O)N(C)C
Reactant: CC1(C)OB(c2cccc(C3=Nc4ccc(NC(=O)Nc5ccccc5)cc4NC(=O)C3)c2)OC1(C)C
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: [C-]#N
Solvent: O
Product: N#Cc1cccc(C2=Nc3ccc(N)cc3NC(=O)C2)c1
Temperature: 110 °C
Reaction time: 12 h
Yield: 62 %

Procedure:
To a stirred solution of compound 1 (Example 19, Step 2; 1.0 g, 3.03 mmol) in DMA (20 mL) were added Zn-powder (39.5 mg, 0.60 mmol), Zn(CN)2 (533 mg, 4.51 mmol) and xanthophos (630 mg, 1.12 mmol) at RT under N2 atmosphere. The reaction mixture was degassed with argon for 15 min and then Pd2(dba)3 (556 mg, 0.60 mmol) was added and again degassed for another 15 min. The resulting reaction mixture was heated to 110° C. and stirred for 12 h; progress of the reaction was monitored by TLC. The reaction mixture was cooled to RT; diluted with water (20 mL) and extracted with EtOAc (2×20 mL). The combined organic extracts were dried over anhydrous Na2SO4 and concentrated under reduced pressure to obtain the crude. The crude material was purified by silica gel column chromatography eluting with 70% EtOAc/Hexane to afford compound 2 (520 mg, 62%). 1H NMR (400 MHz, DMSO-d6): δ 10.34 (bs, 1H), 8.36 (s, 1H), 8.29 (d, J=8.0 Hz, 1H), 7.94 (d, J=7.6 Hz, 1H), 7.70 (t, J=7.6 Hz, 1H), 7.12 (d, J=8.4 Hz, 1H), 6.53-6.50 (m, 1H), 6.32 (d, J=2.4 Hz, 1H), 5.50 (s, 2H), 3.47 (s, 2H). MS (ESI): m/z 277 [M+1]+
Reaction SMILES: C(OC(=O)[NH:7][C@@H:8]([CH3:40])[C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][N:19]2[C:27]([S:28][C:29]3[C:37]([Br:38])=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[NH2:39])[CH2:13][CH2:12]1)=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][C@@H:8]([CH3:40])[C:9]([N:11]1[CH2:12][CH2:13][CH:14]([CH2:17][CH2:18][N:19]2[C:27]([S:28][C:29]3[C:37]([Br:38])=[CH:36][C:32]4[O:33][CH2:34][O:35][C:31]=4[CH:30]=3)=[N:26][C:25]3[C:20]2=[N:21][CH:22]=[N:23][C:24]=3[NH2:39])[CH2:15][CH2:16]1)=[O:10]
Reactant: C[C@H](NC(=O)OC(C)(C)C)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C[C@H](N)C(=O)N1CCC(CCn2c(Sc3cc4c(cc3Br)OCO4)nc3c(N)ncnc32)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 130.2 %

Procedure:
To a solution of [(S)-2-(4-{2-[6-Amino-8-(6-bromo-benzo[1,3]dioxol-5-ylsulfanyl)-purin-9-yl]-ethyl}-piperidin-1-yl)-1-methyl-2-oxo-ethyl]-carbamic acid tert-butyl ester (0.014 g, 0.021 mmol) in DCM (3 mL) was added drop wise TFA (100 μL) and the resulting mixture was stirred for overnight at room temperature. After concentration under reduced pressure, the residual TFA was removed to afford a title product (0.015 g) as a TFA salt. 1H NMR (CD3OD) δ 8.34 (s, 1H), 7.28 (s, 1H), 7.23 (s, 1H), 6.09 (s, 2H), 4.54-4.44 (m, 2H), 4.39 (t, J=7.42 Hz, 2H), 3.85 (broad d, J=13.2 Hz, 1H), 3.19-3.08 (m, 1H), 2.75-2.63 (m, 1H), 2.00-1.80 (m, 4H), 1.70-1.58 (m, 1H), 1.44 (dd, J=14.8, 7.0 Hz, 3H), 1.35-1.13 (m, 2H); LC-MS [M+H]+ 548.2
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][OH:15].[O:16]1[CH:21]=[CH:20][CH2:19][CH2:18][CH2:17]1>C(Cl)Cl>[Br:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][CH2:14][O:15][C:17]1[O:16][CH2:21][CH2:20][CH2:19][CH:18]=1
Reactant: OCCCc1ccc2ccccc2c1Br
Reactant: C1=COCCC1
Solvent: ClCCl
Product: Brc1c(CCCOC2=CCCCO2)ccc2ccccc12
Yield: 95.9 %

Procedure:
A mixture of Example 10A (2.96 g, 11.2 mmol) and 3,4-dihydro-2H-pyran (2.04 mL, 22.4 mmol) in CH2Cl2 and was stirred at 0° C. for 10 minutes and at room temperature for 40 minutes. The reaction mixture was partitioned between CH2Cl2 and water, the organic layer dried (Na2SO4), filtered, concentrated, and purified on silica gel with 10% ethyl acetate/hexanes to provide 3.73 g (95%) of the desired compound as an yellow oil.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12]/[C:13](=N/N(C)C)/[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1.Cl.C([O-])(O)=[O:31].[Na+]>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([C@@:9]([NH:22][S@@:23]([C:25]([CH3:28])([CH3:27])[CH3:26])=[O:24])([CH2:12][C:13](=[O:31])[C:14]([F:17])([F:16])[F:15])[CH2:10][F:11])[C:5]([F:8])=[N:6][CH:7]=1
Reactant: O=C([O-])O
Reactant: CN(C)/N=C(/C[C@](CF)(N[S@](=O)C(C)(C)C)c1cc(Br)cnc1F)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@@](=O)N[C@@](CF)(CC(=O)C(F)(F)F)c1cc(Br)cnc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 76 %

Procedure:
(R)-N-((S,Z)-2-(5-bromo-2-fluoropyridin-3-yl)-4-(2,2-dimethylhydrazono)-1,5,5,5-tetrafluoropentan-2-yl)-2-methylpropane-2-sulfinamide (0.510 g, 1.034 mmol) was dissolved in THF 5 mL. Hydrochloric acid 1N solution (1.034 ml, 1.034 mmol) was added dropwise. The reaction mixture was stirred at room temperature overnight and worked up with saturated aqueous NaHCO3 and extracted with EtOAc three times. The combined organic layers were washed with brine, dried on sodium sulfate, filtered and concentrated. The crude material was purified by column chromatography using a gradient of 15-50% EtOAc/hexane to give (R)-N-((S)-2-(5-bromo-2-fluoropyridin-3-yl)-1,5,5,5-tetrafluoro-4-oxopentan-2-yl)-2-methylpropane-2-sulfinamide (0.356 g, 0.789 mmol, 76% yield). MS m/z=490.9 [M+CH3CN]+. Calculated for C14H16BrF5N2O2S: 451.250.