Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH2:22])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][O:24][C:25]1[CH:26]=[C:27]2[C:32](=[CH:33][CH:34]=1)[C:31]([C:35](Cl)=[O:36])=[CH:30][CH:29]=[CH:28]2.[OH2:38]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[CH2:1]([C:8]1[C:9]([N:22]([C:35]([C:31]2[C:32]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[CH:34][CH:33]=3)[CH:28]=[CH:29][CH:30]=2)=[O:38])[C:35]([C:31]2[C:32]3[C:27](=[CH:26][C:25]([O:24][CH3:23])=[CH:34][CH:33]=3)[CH:28]=[CH:29][CH:30]=2)=[O:36])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(-c2cnc(N)c(Cc3ccccc3)n2)cc1
Reactant: COc1ccc2c(C(=O)Cl)cccc2c1
Reactant: O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: COc1ccc(-c2cnc(N(C(=O)c3cccc4cc(OC)ccc34)C(=O)c3cccc4cc(OC)ccc34)c(Cc3ccccc3)n2)cc1
Temperature: 50 °C
Yield: 68.3 %

Procedure:
Under an argon atmosphere, to a solution of 3-benzyl-5-(4-methoxyphenyl)pyrazin-2-amine (12) (synthesized by the process of M. Adamczyk, et al., Org. Prep. Proced. Int., 33, 477-485 (2001)) (500 mg, 1.72 mmol) in pyridine (5 mL) were successively added 4-(dimethylamino)pyridine (21.0 mg, 172 μmol) and 6-methoxy-1-naphthoyl chloride (22) prepared above at room temperature, and the mixture was heated with stirring at 50° C. 18 hours. After cooling to room temperature, to the mixture was added water and the product was extracted with dichloromethane (×3). The combined organic extract was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residual pyridine was azeotropically removed with toluene (×3). The residue was successively purified twice by column chromatography (silica gel 50 g, dichloromethane/ethyl acetate=9/1, and silica gel 50 g, n-hexane/ethyl acetate=2/1) to give Compound 11z (775 mg, 1.17 mmol, <68.3%) as a brown foamy solid containing some impurities. Rf=0.21 (n-hexane/ethyl acetate=2/1); 1H NMR (400 MHz, DMSO-d6) δ 3.82 (s, 3H), 3.83 (s, 6H), 4.39 (s, 2H), 7.04-7.09 (AA′BB′, 2H), 7.15-7.23 (m, 6H), 7.26-7.31 (m, 1H), 7.34-7.41 (m, 4H), 7.63-7.69 (m, 2H), 7.75-7.80 (AA′BB′, 2H), 8.02-8.08 (m, 4H), 9.07 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[C:3](F)=[CH:4][C:5]([Br:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[Br:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: CCOC(=S)[S-]
Reactant: Cc1nn(-c2cc(N)c(F)cc2Br)c(=O)n1C(F)F
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2Br)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 48 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-2-bromo-4-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 7 h, cooled, and poured into 100 mL ice water slurry. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 48% yield as a white solid after filtration.
Reaction SMILES: [CH:1]([Mg]Br)([CH3:3])[CH3:2].[CH:6]([N:19]1[CH2:22][C:21](=[O:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C([O-])(O)=O.[Na+]>C1COCC1>[CH:6]([N:19]1[CH2:22][C:21]([CH:1]([CH3:3])[CH3:2])([OH:23])[CH2:20]1)([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)[Mg]Br
Reactant: O=C1CN(C(c2ccccc2)c2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)C1(O)CN(C(c2ccccc2)c2ccccc2)C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 28 %

Procedure:
To a 1.0 M isopropylmagnesium bromide in THF (5.0 mL, 5.0 mmol), 1-benzhydryl-azetidin-3-one (237 mg, 1 mmol) in THF (5 mL) was added dropwise at 0° C. The reaction mixture was stirred at 0° C. for 1 hr. Then it was added 10% NaHCO3 solution and extracted with ether (2×30 mL). The organic layers were combined, dried (MgSO4) and concentrated to give an orange oil. The crude product was purified by Prep. HPLC column using CH3CN—H2O-ammonium acetate solvent system. Fractions were collected and concentrated. Then it was extracted with ethyl acetate (2×30 mL). The organic layers were combined, dried (MgSO4) and concentrated to give a light yellow oil as Grignard reaction product. (80 mg, 28% yield). MS m/z 282(MH+), Retention time: 1.485 min. 1H NMR (300 MHz, MeOD) δ ppm 0.93 (d, J=6.95 Hz, 6 H) 1.90-2.04 (m, 1 H) 3.00 (d, J=9.15 Hz, 2 H) 3.28 (d, J=9.15 Hz, 2 H) 4.49 (s, 1 H) 7.14-7.22 (m, 2 H) 7.23-7.33 (m, 4 H) 7.37-7.46 (m, 4 H).
Reaction SMILES: Cl.[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3].[CH3:17][C:18]1[C:26]([CH3:27])=[C:25]([CH3:28])[CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21]>>[CH:2]([NH:5][CH2:6][C:7]([C:9]1[CH:14]=[CH:13][C:12]([O:15][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][C:25]([CH3:28])=[C:26]([CH3:27])[C:18]=2[CH3:17])=[C:11]([OH:16])[CH:10]=1)=[O:8])([CH3:4])[CH3:3]
Reactant: Cc1ccc(C(=O)Cl)c(C)c1C
Reactant: CC(C)NCC(=O)c1ccc(O)c(O)c1
Agent: Cl
Product: Cc1ccc(C(=O)Oc2ccc(C(=O)CNC(C)C)cc2O)c(C)c1C

Procedure:
Following the procedure described above in Example 58A but using 3,4-dihydroxyphenyl isopropylaminomethyl ketone hydrochloride instead of 3,4-dihydroxyphenyl tert-butylaminomethyl ketone hydrochloride and 2,3,4-trimethylbenzoyl chloride instead of isovaleryl chloride, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)phenyl isopropylaminomethyl ketone; and by interaction of this base with hydrochloric acid there is obtained the hydrochloride salt. When this hydrochloride is catalytically hydrogenated, using a procedure similar to that described above in Example 2B, there is obtained 3-hydroxy-4-(2,3,4-trimethylbenzoyloxy)-alpha-(isopropylaminomethyl)benzyl alcohol hydrochloride.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7](O)=[O:8])[CH3:2].O=S(Cl)[Cl:18]>C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([CH:10]=[CH:11][C:12]=1[O:13][CH2:14][CH3:15])[C:7]([Cl:18])=[O:8])[CH3:2]
Reactant: O=S(Cl)Cl
Reactant: CCOc1ccc(C(=O)O)cc1OCC
Solvent: ClCCl
Product: CCOc1ccc(C(=O)Cl)cc1OCC

Procedure:
To a stirred solution of 3,4-diethoxybenzoic acid (0.71 mmol, 150 mg) in CH2Cl2 was added SOCl2 at room temperature; the reaction was refluxed for 1.5 h and the mixture concentrated under reduced pressure to yield 3,4-diethoxybenzoylchloride quantitatively. To a stirred suspension of Na2CO3 (1.42 mmol, 150.52 mg) and pyridine-4-carbohydrazide (0.71 mmol, 97 mg) in NMP (0.8 mL) was added a solution of the 3,4-diethoxybenzoylchloride in NMP (0.8 mL) and the reaction was stirred for 12 h at room temperature. The mixture was poured into 20 mL of cold H2O and filtered. The precipitated intermediate was dried in vacuum. The solid was added to POCl3 (5 mL) and heated to 70-72° C. for 6 h. The solution was poured into an ice-water container and neutralized with a solution of NaOH (2M). The precipitated product was filtered and purified by column chromatography using CH2Cl2:MeOH (9:1) to yield the product as white solid in 67% yield (150 mg). 1H NMR (400 MHz, CDCl3): δ 8.84 (bs, 2H), 7.99 (d, J=4.4 Hz, 2H), 7.67 (dd, J1=2.0, J2=8.4 Hz, 1H), 7.64 (d, J=2.0 Hz, 1H), 6.98 (d, J=8.4 Hz, 1H), 4.20 (q, J=7.2 Hz, 2H), 4.18 (q, J=7.2 Hz, 2H), 1.51 (t, J=7.2 Hz, 3H), 1.50 (t, J=7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3): δ165.81, 162.46, 152.51, 150.84, 149.20, 131.52, 128.05, 120.97, 115.77, 112.78, 111.58, 65.05, 64.80, 14.92, 14.85. MS (EI) m/z: 312 (M+), HRMS (EI) for C17H17N3O3 (M+): calcd 312.1343, found 312.1350.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[Se](=O)=[O:13].CCCCC.CCOC(C)=O>CO>[N:8]1[C:9]2[C:4](=[CH:3][C:2]([CH:1]=[O:13])=[CH:11][CH:10]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[Se]=O
Reactant: Cc1ccc2ncccc2c1
Solvent: CCCCC
Solvent: CO
Solvent: CCOC(C)=O
Product: O=Cc1ccc2ncccc2c1
Temperature: 100 °C
Yield: 21.5 %

Procedure:
6-Methyl-quinoline (Aldrich Chemical Co.) (1 g, 7.0 mmol) and selenium dioxide (2.32 g, 21.0 mmol) were combined in the absence of solvent and heated at 100° C. under a nitrogen atmosphere for 16 h. The reaction mixture was allowed to cool to room temperature, taken up in MeOH and presorbed onto silica gel. Chromatography using a 3:1 mixture of pentane: EtOAc provided the title product (236 mg, 21%); 1HNMR (400 MHz, CDCl3) δ: 7.46-7.52 (m, 2H), 7.98 (d, 1H), 8.33-8.37 (m, 2H), 9.03 (d, 1H), 10.18 (s, 1H); m/z (ES−) 315 (2 MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[C:5](OC)=O.[CH3:12][C:13]([CH3:15])=[O:14].[CH3:16][O-:17].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][N:11]=1)[CH2:5][C:16](=[O:17])[CH2:12][C:13](=[O:14])[CH3:15]
Reactant: COC(=O)c1ccnc(Cl)c1
Reactant: C[O-]
Reactant: CC(C)=O
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)CC(=O)Cc1ccnc(Cl)c1
Yield: 83 %

Procedure:
To solution of methyl 2-chloroisonicotinate (12.0 g, 0.07 mol) and acetone (12.2 g, 0.21 mol) in 100 mL of dry THF at 35 C was added sodium methoxide portionwise. After heating the reaction mixture at reflux for 4 h, the solvent was removed. The residue was dissolved with 500 mL of water, acidified with acetic acid to pH=6 and extracted with ethyl acetate. The organic layer was washed with brine, dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo to give 11.46 g (83% yield) of product was a brown solid.
Reaction SMILES: Br[C:2]1[CH:26]=[CH:25][C:5]2[N:6]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=3[C:15]3[N:16]=[N:17][N:18]([CH3:20])[N:19]=3)=[N:8][C:4]=2[CH:3]=1.[NH2:27][C:28]1[N:33]=[CH:32][C:31](B2OC(C)(C)C(C)(C)O2)=[CH:30][N:29]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=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>[C:21]([N:6]1[C:5]2[CH:25]=[CH:26][C:2]([C:31]3[CH:30]=[N:29][C:28]([NH2:27])=[N:33][CH:32]=3)=[CH:3][C:4]=2[N:8]=[C:7]1[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[C:15]1[N:16]=[N:17][N:18]([CH3:20])[N:19]=1)([CH3:24])([CH3:22])[CH3:23]
Reactant: Cn1nnc(-c2ccccc2-c2nc3cc(Br)ccc3n2C(C)(C)C)n1
Reactant: CC1(C)OB(c2cnc(N)nc2)OC1(C)C
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: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cn1nnc(-c2ccccc2-c2nc3cc(-c4cnc(N)nc4)ccc3n2C(C)(C)C)n1
Temperature: 110 °C
Yield: 63.1 %

Procedure:
To a sealed vial is added 5-bromo-1-tert-butyl-2-[2-(2-methyl-2H-tetrazol-5-yl)-phenyl]-1H-benzimidazole (55 mg, 0.134 mmol) in DMF (3 mL), followed by the addition of 2-aminopyrimidine-5-boronic acid pinacol ester (35 mg, 0.158 mmol), tetrakis(triphenylphosphine)palladium(0) (15 mg, 0.013 mmol) and 2M aq. Na2CO3 (0.3 mL, 0.6 mmol). The reaction mixture is heated under Argon at 110° C. for 6 hours. The residue is diluted with EtOAc, washed with brine, dried under Na2SO4, filtered and concentrated. The residue is loaded onto a silica gel column. The column is eluted with 0-5% 7M NH3 in MeOH/CH2Cl2. The product fractions are collected and concentrated to afford the title compound (36 mg, 63%) as a off-white solid. LCMS (ESMS): m/z 426.70 (M++1)
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:19]>ClCCl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH3:10])(=[O:19])=[O:9])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: CS(=O)c1ccc(F)cc1[N+](=O)[O-]
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CS(=O)(=O)c1ccc(F)cc1[N+](=O)[O-]
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 85.6 %

Procedure:
4-Fluoro-1-methylsulfonyl-2-nitrobenzene can be obtained in the following way: 1.3 g of 4-fluoro-1-methylsulfinyl-2-nitrobenzene in 15 ml of dichloromethane are added dropwise to a suspension, stirred at a temperature in the region of −5° C. under argon, of 1.5 g of 3-chloroperoxybenzoic acid in 15 ml of dichloromethane. The reaction mixture is then stirred at a temperature in the region of 0° C. for 30 minutes and is then left to reheat to a temperature in the region of 20° C. It is then filtered through sintered glass and the solid is washed with dichloromethane. The filtrate is washed with an aqueous sodium hydrogencarbonate solution then with water, dried over magnesium sulfate, treated with 3S black, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue thus obtained is purified by chromatography on a column of 125 g of silice (particle size 40-63 μm), eluting with pure dichloromethane. The fractions containing the expected product are pooled and concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.2 g of 4-fluoro-1-methylsulfonyl-2-nitrobenzene are thus obtained in the form of a yellow foam (Rf=0.43, silica gel thin layer chromatography, eluent: dichloromethane)).
Reaction SMILES: [CH2:1]([NH:10][C:11]1[CH:21]=[CH:20][C:14]([C:15]([O:17]CC)=[O:16])=[CH:13][CH:12]=1)[CH:2]=[CH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[K+].C(O)C.O.Cl>O>[CH2:1]([NH:10][C:11]1[CH:12]=[CH:13][C:14]([C:15]([OH:17])=[O:16])=[CH:20][CH:21]=1)[CH:2]=[CH:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(=O)c1ccc(NCC=Cc2ccccc2)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: O=C(O)c1ccc(NCC=Cc2ccccc2)cc1

Procedure:
A mixture of 10 g. of ethyl p-(cinnamylamino)benzoate (prepared as described in Example 24), 10 g. of potassium hydroxide and 200 ml. of ethanol-water (9:1) is refluxed for 3 hours. The solution is acidified while hot with concentrated hydrochloric acid, diluted with water, cooled and filtered to give off-white crystals. Recrystallization from ethanol gives pale yellow crystals, m.p. 200°-202° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([NH:12][C:13]2[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=2)[C:3]=1[F:19].[CH:20]1([C:23]2([F:27])[CH2:26][NH:25][CH2:24]2)[CH2:22][CH2:21]1>C(#N)C.C(OC(=O)C)C.O>[CH:20]1([C:23]2([F:27])[CH2:26][N:25]([C:2]3[N:7]=[C:6]([S:8]([CH3:11])(=[O:10])=[O:9])[N:5]=[C:4]([NH:12][C:13]4[NH:17][N:16]=[C:15]([CH3:18])[CH:14]=4)[C:3]=3[F:19])[CH2:24]2)[CH2:22][CH2:21]1
Reactant: Cc1cc(Nc2nc(S(C)(=O)=O)nc(Cl)c2F)[nH]n1
Reactant: FC1(C2CC2)CNC1
Solvent: CCOC(C)=O
Solvent: O
Solvent: CC#N
Product: Cc1cc(Nc2nc(S(C)(=O)=O)nc(N3CC(F)(C4CC4)C3)c2F)[nH]n1
Temperature: 50 °C
Reaction time: 1 h

Procedure:
A suspension of 6-chloro-5-fluoro-N-(3-methyl-1H-pyrazol-5-yl)-2-(methylsulfonyl)pyrimidin-4-amine (100 mg, 0.33 mmol) and 3-cyclopropyl-3-fluoroazetidine (50 mg, 0.33 mmol) in acetonitrile (5 ml) was heated to 50° C. and stirred for 1 hr. The mixture was allowed to cool and diluted with ethylacetate (20 ml) and water (20 ml). The organic layer was dried (Na2SO4) and concentrated to give a solid. Purification by flash column chromatography eluting with 40% ethylacetate/hexanes and ethyl acetate gave the title compound as an off white solid (64 mg, 51%). 1H NMR (DMSO, 400 MHz) 0.51-0.52 (2H, m), 0.68-0.76 (2H, m), 1.42-1.59 (1H, m), 2.29 (3H, s), 3.31 (3H, s), 4.20-4.36 (4H, m), 6.41 (1H, s), 9.98 (1H, s), 12.13 (1H, s). ES+385.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:29])[C@H:10]([NH:14][S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]1[O:34][C:33]2[CH:35]=[C:36]([CH2:39]O)[CH:37]=[CH:38][C:32]=2[O:31]1.C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1C=CC=CC=1>[CH2:1]([O:8][C:9](=[O:29])[C@H:10]([N:14]([CH2:39][C:36]1[CH:37]=[CH:38][C:32]2[O:31][CH2:30][O:34][C:33]=2[CH:35]=1)[S:15]([C:18]1[C:23]([CH3:24])=[CH:22][C:21]([O:25][CH3:26])=[C:20]([CH3:27])[C:19]=1[CH3:28])(=[O:17])=[O:16])[CH:11]([CH3:13])[CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OCc1ccc2c(c1)OCO2
Reactant: COc1cc(C)c(S(=O)(=O)N[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: c1ccccc1
Product: COc1cc(C)c(S(=O)(=O)N(Cc2ccc3c(c2)OCO3)[C@@H](C(=O)OCc2ccccc2)C(C)C)c(C)c1C
Yield: 80.9 %

Procedure:
To a mixture of 2(R)-(4-methoxy-2,3,6-trimethylbenzenesulfonylamino)-3-methylbutyric acid benzyl ester (4.5 g, 10.72 mmol), 3,4-(methylenedioxy)phenylmethanol (2.04 g, 13.41 mmol), and tributylphosphine (3.35 mL, 13.4 mmol) in dry benzene (60 mL) cooled in an ice bath was added 1,1′-(azodicarbonyl)dipiperidine (3.38 g, 13.4 mmol). The reaction mixture was stirred overnight to room temperature and then flash chromatographed on a silica gel column (5-10% ethyl acetate/hexanes) to give 2(R)-[(3,4-methylenedioxy-benzyl)-(4-methoxy-2,3,6-trimethylbenzenesulfonyl)amino]-3-methylbutyric acid benzyl ester (4.8 g) as a white solid.
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=1.[F:9][C:10]([F:22])([F:21])[O:11][C:12]1[CH:13]=[C:14](B(O)O)[CH:15]=[CH:16][CH:17]=1>>[F:9][C:10]([F:21])([F:22])[O:11][C:12]1[CH:17]=[C:16]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][CH:3]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: Nc1ccc(Br)cc1
Reactant: OB(O)c1cccc(OC(F)(F)F)c1
Product: Nc1ccc(-c2cccc(OC(F)(F)F)c2)cc1
Yield: 63.5 %

Procedure:
The title compound (280 mg) was prepared from 4-bromoaniline (300 mg, 1.74 mmol) and 3-(trifluoromethoxy)phenylboronic acid (466 mg, 2.26 mmol) as a pale-yellow liquid.
Reaction SMILES: Br[CH2:2][CH2:3][N:4]1[CH2:9][C:8]2[CH:10]=[C:11]([F:14])[CH:12]=[CH:13][C:7]=2[N:6]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[F:21])[S:5]1(=[O:23])=[O:22].[CH3:24][NH2:25].Cl>>[F:14][C:11]1[CH:12]=[CH:13][C:7]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[F:21])[S:5](=[O:23])(=[O:22])[N:4]([CH2:3][CH2:2][NH:25][CH3:24])[CH2:9][C:8]=2[CH:10]=1
Reactant: O=S1(=O)N(CCBr)Cc2cc(F)ccc2N1c1ccccc1F
Reactant: CN
Agent: Cl
Product: CNCCN1Cc2cc(F)ccc2N(c2ccccc2F)S1(=O)=O
Yield: 92 %

Procedure:
In an analogous manner to Example 11 step 5, 3-(2-bromoethyl)-6-fluoro-1-(2-fluorophenyl)-3,4-dihydro-1H-2,1,3-benzothiadiazine 2,2-dioxide (0.1 g, 0.25 mmol) was reacted to methylamine and then treated with HCl to provide 2-[6-fluoro-1-(2-fluorophenyl)-2,2-dioxido-1,4-dihydro-3H-2,1,3-benzothiadiazin-3-yl]-N-methylethanamine (0.081 g, 92%) as a white solid:
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13].C(O[C:18]([C:20]1([OH:28])[CH2:25][CH2:24][N:23]([O:26][CH3:27])[CH2:22][CH2:21]1)=[O:19])C.CC(C)([O-])C.[K+]>C1COCC1>[OH:19][C:18]1[C:20]2([CH2:21][CH2:22][N:23]([O:26][CH3:27])[CH2:24][CH2:25]2)[O:28][C:3](=[O:2])[C:4]=1[C:5]1[CH:10]=[C:9]([CH3:11])[C:8]([CH3:12])=[CH:7][C:6]=1[CH3:13]
Reactant: COC(=O)Cc1cc(C)c(C)cc1C
Reactant: CCOC(=O)C1(O)CCN(OC)CC1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CON1CCC2(CC1)OC(=O)C(c1cc(C)c(C)cc1C)=C2O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of (2,4,5-trimethyl-phenyl)acetic acid methyl ester (0.6 g, 3.12 mmol) and 4-hydroxy-1-methoxy-piperidine-4-carboxylic acid ethyl ester (0.76 g, 3.74 mmol) in 7 ml anhydrous THF was added a 1 M solution of potassium tert-butoxide (6.9 ml, 8.87 mmol) in THF at room temperature. The suspension obtained was first stirred at room temperature for one hour, and then refluxed under argon for one hour. After cooling to room temperature, the reaction mixture was concentrated, water was added and the mixture acidified with little HCl (37%). The aqueous layer was extracted with dichloromethane, and the combined organic layers were then washed with brine and dried over sodium sulfate. After filtration and concentration under vacuum, the residue was purified by column chromatography (silica gel, ethyl acetate 100%). Yield: 280 mg of 4-hydroxy-8-methoxy-3-(2,4,5-trimethyl-phenyl)-1-oxa-8-aza-spiro[4.5]dec-3-en-2-one (title compound P2.2) as a white solid, mp 199-204° C.
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[CH:17]=[N:16][CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=O)=[C:4]([CH3:18])[CH:3]=1.CCN(C(C)C)C(C)C.Cl.[CH2:29]([O:31][NH2:32])[CH3:30]>CN(C=O)C>[CH2:29]([O:31][NH:32][C:11](=[O:13])[C:10]1[CH:14]=[CH:15][N:16]=[CH:17][C:9]=1[NH:8][C:5]1[CH:6]=[CH:7][C:2]([I:1])=[CH:3][C:4]=1[CH3:18])[CH3:30]
Reactant: Cc1cc(I)ccc1Nc1cnccc1C(=O)O
Reactant: CCON
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCONC(=O)c1ccncc1Nc1ccc(I)cc1C
Reaction time: 4 h
Yield: 53 %

Procedure:
3-[(4-iodo-2-methylphenyl)amino]isonicotinic acid 2c (60 mg, 0.17 mmol) was dissolved in 6 ml dry DMF followed by the addition of DIPEA (0.20 mmol, 37 μl), ByBOP (0.20 mmol, 107 mg) and O-ethylhydroxylamine hydrochloride (0.34 mmol, 34 mg). The mixture was stirred for 4 h and the volatiles were removed in vacuo. The crude material was purified by preparative reversed phase HPLC to give 36 mg (91 μmol; 53% yield) of pure desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]#[N:9])=[N:6][CH:7]=1.ClC1C=CC(C2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19]N=2)=CN=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([C:8]2[N:21]=[C:20]([C:22]3[CH:27]=[CH:26][C:25]([CH2:28][CH:29]([CH3:31])[CH3:30])=[CH:24][CH:23]=3)[O:19][N:9]=2)=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Cl)cn1
Reactant: CC(C)Cc1ccc(-c2nc(-c3ccc(Cl)nc3)no2)cc1
Product: CC(C)Cc1ccc(-c2nc(-c3ncc(Cl)cn3)no2)cc1

Procedure:
The title compound was prepared from 5-chloropyrimidine-2-carbonitrile by procedures analogous to those described in Example 4A-4B for the preparation of 2-Chloro-5-[5-(4-isobutylphenyl)-1,2,4-oxadiazol-3-yl]pyridine.
Reaction SMILES: [Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[CH3:11][C:12]([S@:15]([NH2:17])=[O:16])([CH3:14])[CH3:13]>ClCCl.CC(C)[O-].[Ti+4].CC(C)[O-].CC(C)[O-].CC(C)[O-]>[Cl:1][C:2]1[C:9]([F:10])=[CH:8][CH:7]=[CH:6][C:3]=1/[CH:4]=[N:17]/[S:15]([C:12]([CH3:14])([CH3:13])[CH3:11])=[O:16]
Reactant: O=Cc1cccc(F)c1Cl
Reactant: CC(C)(C)[S@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: ClCCl
Product: CC(C)(C)S(=O)/N=C/c1cccc(F)c1Cl

Procedure:
2-Chloro-3-fluorobenzaldehyde (2.5 g) and (R)-(+)-2-methyl-2-propanesulfinamide were dissolved in dichloromethane (50 ml), and then titanium(IV) isopropoxide (23.6 ml) was added. The mixture was heated for three hours under reflux, then poured onto ice (150 g) and stirred vigorously for ten minutes. The mixture was filtered through kieselguhr and the filtrate was extracted with dichloromethane (3×50 ml). The organic phase was dried (Na2SO4), filtered and concentrated under reduced pressure. The product (4 g) was used further without further purification.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][N:6]=[CH:5][C:4]=1[C:9]1[NH:10][C:11]2[C:16]([CH:17]=1)=[CH:15][C:14]([C:18]#[N:19])=[CH:13][CH:12]=2.B(Br)(Br)[Br:21].C(Cl)Cl.C([O-])(O)=O.[Na+]>ClCCCl>[Br:21][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][C:9]=1[C:4]1[CH:5]=[N:6][CH:7]=[CH:8][C:3]=1[OH:2]
Reactant: BrB(Br)Br
Reactant: COc1ccncc1-c1cc2cc(C#N)ccc2[nH]1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Product: N#Cc1ccc2[nH]c(-c3cnccc3O)c(Br)c2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A flask is charged with 2-(4-methoxy-pyridin-3-yl)-1H-indole-5-carbonitrile (Example 90, 190 mg, 0.80 mmol) and DCE (8 mL), and 1.0 M BBr3 in DCM (4.8 mL, 4.8 mmol) is added. The mixture is stirred at room temperature overnight. The reaction mixture is poured into saturated aqueous NaHCO3 and extracted with DCM. The aqueous phase is concentrated, acidified with 1M HCl in water and concentrated in vacuo. The residue is purified with an Xbridge C18 eluting with a 1:9 to 9:1 acetonitrile-water gradient to give 3-bromo-2-(4-hydroxy-pyridin-3-yl)-1H-indole-5-carbonitrile. 1H NMR (400 MHz, DMSO-d6) δ ppm 6.40 (d, J=7.1 Hz, 1H), 7.48 (dd, J=8.5, 1.6 Hz, 1H), 7.71 (d, J=8.6 Hz, 1H), 7.81 (dd, J=7.1, 1.3 Hz, 1H), 7.86 (d, J=1.0 Hz, 1H), 8.67 (d, J=1.3 Hz, 1H). HRMS (ESI) m/z 313.9932 [(M+H)+ calcd for C14H9BrN3O: 313.9929].