Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21]O)=[C:17]([O:23][CH3:24])[CH:16]=2)=[CH:9][C:8]=1[F:25])[CH3:2].P(Br)(Br)[Br:28]>ClCCl.O>[Br:28][CH2:21][C:18]1[CH:19]=[CH:20][C:15]([CH2:14][O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([O:3][CH2:1][CH3:2])=[O:26])=[C:8]([F:25])[CH:9]=2)=[CH:16][C:17]=1[O:23][CH3:24]
Reactant: BrP(Br)Br
Reactant: CCOC(=O)CCc1ccc(OCc2ccc(CO)c(OC)c2)cc1F
Solvent: ClCCl
Solvent: O
Product: CCOC(=O)CCc1ccc(OCc2ccc(CBr)c(OC)c2)cc1F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 93.7 %

Procedure:
To a solution of 3-[2-fluoro-4-(4-hydroxymethyl-3-methoxy-benzyloxy)-phenyl]-propionic acid ethyl ester (1.0 g, 2.76 mmol) in dichloromethane (25 mL) is added phosphorus tribromide (0.4 mL, 4.41 mmol) at 0° C. and the reaction mixture is stirred for 15 min at 0° C. The mixture is cooled to 0° C., diluted with water, and extracted with dichloromethane (2×100 mL). The combined extracts are washed with saturated brine, dried over Na2SO4, filtered, and concentrated to give the title compound (1.1 g, crude). 1H NMR (DMSO, 400 MHz) δ 7.34-7.32 (d, J=8 Hz, 1H), 7.12-7.08 (t, J=8 Hz, 1H), 6.96-6.94 (d, J=8 Hz, 2H), 6.67-6.64 (d, J=12 Hz, 2H), 4.98 (s, 2H), 4.55 (s, 2H), 4.12-4.09 (q, 2H), 2.90-2.88 (t, 2H), 2.60-2.56 (t, J=8 Hz, 2H), 1.25-1.22 (t, J=8 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[OH:11].C(=S)=S.[Br:15]Br>O>[Br:15][C:6]1[CH:5]=[C:4]([OH:11])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[O:9][CH3:10]
Reactant: BrBr
Reactant: COc1ccc(O)c(OC)c1
Solvent: O
Solvent: S=C=S
Product: COc1cc(OC)c(Br)cc1O
Temperature: 25 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
To a mixed solution comprising 8.6 g of 2,4-dimethoxyphenol and 80 ml of carbon disulfide (CS2) was added dropwise 2.86 ml of bromine at 10° to 15° C. After stirring the mixture at room temperature for one hour, water was added to the reaction mixture and the reaction mixture was extracted with diethyl ether. The extract was washed and dried, and the solvent was removed under reduced pressure. Hexane was added to the obtained residue and the precipitated crystals were collected by filtration to give 12.0 g of 3-bromo-4,6-dimethoxyphenol (yield: 92%, melting point: 78°-80° C.).
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][C:5](/[C:8](/[C:25]2[CH:30]=[CH:29][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:27][CH:26]=2)=[CH:9]\[CH2:10][O:11][C:12]2[CH:23]=[CH:22][C:15]([O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[C:14]([CH3:24])[CH:13]=2)=[CH:4][CH:3]=1.[CH2:35]([N:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1)[C:36]#[CH:37].C(NC(C)C)(C)C>O1CCCC1.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>[CH3:24][C:14]1[CH:13]=[C:12]([O:11][CH2:10]/[CH:9]=[C:8](\[C:5]2[CH:4]=[CH:3][C:2]([C:37]#[C:36][CH2:35][N:38]3[CH2:43][CH2:42][O:41][CH2:40][CH2:39]3)=[CH:7][CH:6]=2)/[C:25]2[CH:26]=[CH:27][C:28]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:30]=2)[CH:23]=[CH:22][C:15]=1[O:16][CH2:17][C:18]([O:20][CH3:21])=[O:19]
Reactant: COC(=O)COc1ccc(OC/C=C(\c2ccc(I)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Reactant: C#CCN1CCOCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(\c2ccc(C#CCN3CCOCC3)cc2)c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of the above ester (13.9 g, 23.9 mmol), N-propargylmorpholine (5.98 g, 47.7 mmol) and N,N-diisopropylamine (11.35 g, 112 mmol) in tetrahydrofuran (250 mL) was cooled down and degassed; bis(triphenylphosphine)palladium(II) dichloride (0.84 g, 1.19 mmol) and copper(I) iodide (0.365 g, 1.9 mmol) were added. The reaction mixture was stirred at ambient temperature for 18 h. The mixture was evaporated in vacuo and the residue was purified by column chromatography (silica gel Fluka 60, hexanes/ethyl acetate/methanol 64:32:4) yielding the title compound as a white crystals.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[CH:6][C:7]([O:11][C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)=[C:8]([CH:10]=1)[NH2:9])[CH3:2].CC(C)([O-])C.[K+].[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28]Br.O>CN(C)C=O>[F:25][C:26]1[CH:33]=[CH:32][C:31]([F:34])=[CH:30][C:27]=1[CH2:28][O:18][C:15]1[CH:16]=[CH:17][C:12]([O:11][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH2:1][CH3:2])=[CH:10][C:8]=2[NH2:9])=[CH:13][CH:14]=1
Reactant: Fc1ccc(F)c(CBr)c1
Reactant: CCOc1ccc(Oc2ccc(O)cc2)c(N)c1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOc1ccc(Oc2ccc(OCc3cc(F)ccc3F)cc2)c(N)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 77 %

Procedure:
To a solution of 5-ethoxy-2-(4-hydroxyphenoxy)aniline (3.68 g, 15 mmol) in N,N-dimethylformamide (50 ml) were added potassium tert-butoxide (2.02 g, 18 mmol) and 2,5-difluorobenzyl bromide (3.11 g, 15 mmol), followed by stirring at room temperature overnight. The reaction solution was poured into water and extracted with ethyl acetate. The organic layer was washed with water and a saturated aqueous sodium chloride solution, and after drying, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography [eluent; ethyl acetate-hexane (1:4)] to give the title compound (4.29 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1Br.[NH2:9][C:10]1[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=1>>[N:13]1[CH:14]=[CH:15][C:10]([NH:9][C:3]2[C:2]([NH:9][C:10]3[CH:15]=[CH:14][N:13]=[CH:12][CH:11]=3)=[CH:7][CH:6]=[CH:5][CH:4]=2)=[CH:11][CH:12]=1
Reactant: Nc1ccncc1
Reactant: Brc1ccccc1Br
Product: c1ccc(Nc2ccncc2)c(Nc2ccncc2)c1
Yield: 73.3 %

Procedure:
The synthesis is carried out in accordance with the general procedure of Example 2 from 56.6 g (240 mmol) of 1,2-dibromobenzene and 47.5 g (505 mmol) of 4-aminopyridine. The precipitated solid is recrystallised from toluene/acetonitrile (5:1), and the residue is washed with MeOH, giving 46.2 g (176 mmol) of a crystalline solid. The total yield is 73%.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[CH:33]1([CH2:32][O:1][C:2]2[CH:24]=[CH:23][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:35][CH2:34]1
Reactant: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of N-{3-[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]-1-methylpropyl}acetamide (0.49 g) in DMF (15 mL) were added potassium carbonate (0.41 g) and (bromomethyl)cyclopropane (0.41 g), and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/methanol to give the title compound (313 mg).
Reaction SMILES: I([O-])(=O)(=O)=O.[Na+].[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=C)[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1.[Mn]([O-])(=O)(=O)=[O:27].[K+]>O.O1CCOCC1>[Cl:7][C:8]1[N:13]=[C:12]([C:14]([O:16][CH2:17][CH3:18])=[O:27])[CH:11]=[C:10]([CH2:19][O:20][CH2:21][C:22]([F:25])([F:24])[F:23])[N:9]=1
Reactant: O=[Mn](=O)(=O)[O-]
Reactant: C=C(OCC)c1cc(COCC(F)(F)F)nc(Cl)n1
Agent: [K+]
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(COCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium metaperiodate (701 mg, 3.28 mmol) was suspended in water (10 mL) and sonicated until a clear solution was obtained. 2-Chloro-4-(1-ethoxyvinyl)-6-((2,2,2-trifluoroethoxy)methyl)pyrimidine (486 mg, 1.64 mmol) in 1,4-dioxane (20 mL) and potassium permanganate (39 mg, 0.25 mmol) were added and the mixture was stirred at rt for 30 min. The mixture was filtered, precipitate was washed by dioxane and DCM. DCM an solid sodium bicarbonate (s) were added to the filtrate. The mixture was extracted with DCM (×2). The organic phase was dried over sodium sulfate and concentrated. The residue was purified by column chromatography on silica eluting with DC ti give the title compound as a solid, 385 mg (79%).
Reaction SMILES: [CH3:1][CH:2]([OH:5])[C:3]#[CH:4].C([Li])CCC.[CH2:11]([O:13][C:14]([N:16]1[CH2:21][CH2:20][C:19](=[O:22])[CH2:18][CH2:17]1)=[O:15])[CH3:12].[NH4+].[Cl-]>C1COCC1.CCCCCC>[OH:5][CH:2]([CH3:1])[C:3]#[C:4][C:19]1([OH:22])[CH2:18][CH2:17][N:16]([C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH2:21][CH2:20]1
Reactant: CCOC(=O)N1CCC(=O)CC1
Reactant: C#CC(C)O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)N1CCC(O)(C#CC(C)O)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 3-butyn-2-ol (42 g, 0.6 mol) in dry THF (8OO ml) under nitrogen was cooled with a dry-ice/acetone bath. n-Butyl lithium (390 ml of 2.5M and 230 ml of 1.5M) in hexane was added rapidly, dropwise. The suspension became gelatinous and another 800 mls of dry THF was added. The reaction was stirred at approximately -78° for 1 hour and then at 0° for 20 minutes. The reaction was cooled to -78° and 1-ethoxycarbonyl-4-piperidinone (104 g, 0.607 mol) in 300 ml of dry THF was added rapidly dropwise. The reaction mixture was allowed to warm to room temperature and then stirred overnight. The reaction mixture was cooled in an ice-bath, diluted with THF (1.51), decomposed with saturated NH4Cl, and the THF layer was washed three times with 200 ml of saturated ammonium chloride. The aqueous layers were back-washed with THF (200 ml×3). The organic layers were combined and dried over MgSO4 and evaporated to give an oil. A one-fifth portion of the oil was purified by flash chromatography on silica gel and elution with 30% ethyl acetate/ether afforded the desired product diol (19.7 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]=[C:12]([N+]([O-])=O)[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C.CO.S(=O)(=O)(O)[OH:21]>[Pd].O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][C:12](=[O:21])[CH3:13])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(C=C(C)[N+](=O)[O-])cc1OC
Agent: [Pd]
Solvent: O
Solvent: CO
Product: COc1ccc(CC(C)=O)cc1OC

Procedure:
(3,4-Dimethoxyphenyl)-2-nitropropene (11) (200 g, 0.90 mol), palladium 10%/charcoal (10.0 g, either fresh or recycled), methanol (750 ml), water (220 ml) and sulfuric acid (96%, 28 ml) are charged to a steel autoclave thermostatted at 15° C.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:11])[CH:7]=[CH:8][C:9]=1Cl)([O-:3])=[O:2].[C:12]([NH:15][C:16]1[CH:21]=[CH:20][C:19]([SH:22])=[CH:18][CH:17]=1)(=[O:14])[CH3:13].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[OH:11][C:6]1[CH:7]=[CH:8][C:9]([S:22][C:19]2[CH:18]=[CH:17][C:16]([NH:15][C:12](=[O:14])[CH3:13])=[CH:21][CH:20]=2)=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1
Reactant: O=[N+]([O-])c1cc(O)ccc1Cl
Reactant: CC(=O)Nc1ccc(S)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(=O)Nc1ccc(Sc2ccc(O)cc2[N+](=O)[O-])cc1
Temperature: 100 °C
Yield: 98.9 %

Procedure:
A mixture of 3-nitro-4-chloro phenol (1.59 g, 8.97 mmol), 4-acetamidothiophenol (2 g, 10.76 mmol) and cesium carbonate (7.0 g, 21.53 mmol) in DMF (20 mL) was heated 2.5 h at 100° C. The mixture was cooled, poured onto ice and the resulting solid is collected by filtration and dried under vacuum the title compound leaving a yellow solid (2.7 g, 100%).
Reaction SMILES: S1C=CN=[CH:2]1.[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][CH:25]=[C:26]([CH2:28]C)[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12.BrC(C)C(=O)C>>[NH2:6][C:7]1[N:12]=[CH:11][N:10]=[C:9]2[N:13]([C@H:30]3[CH2:35][CH2:34][C@@H:33]([N:36]4[CH2:37][CH2:38][N:39]([CH3:42])[CH2:40][CH2:41]4)[CH2:32][CH2:31]3)[N:14]=[C:15]([C:16]3[CH:21]=[CH:20][C:19]([NH:22][C:23]4[S:24][C:25]([CH3:2])=[C:26]([CH3:28])[N:27]=4)=[CH:18][CH:17]=3)[C:8]=12
Reactant: c1cscn1
Reactant: CCc1csc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)n1
Agent: CC(=O)C(C)Br
Product: Cc1nc(Nc2ccc(-c3nn([C@H]4CC[C@@H](N5CCN(C)CC5)CC4)c4ncnc(N)c34)cc2)sc1C
Reaction time: 24 h

Procedure:
The procedure for thiazole synthesis, described in the preparation of cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4-ethyl-1,3-thiazol-2-amine, was employed with the exception that 3-bromo-2-butanone (0.183 g, 1.21 mmol) was used as the alkylating agent, and the alkylation reaction was conducted at 40° C. for 24 h. Purification of the product by preparative HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 20 min at 21 mL/min using an 8μ Hypersil HS C18, 250×21 mm column, Rt 6.7-7.7 min) afforded cis-N2-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}phenyl)-4,5-dimethyl-1,3-thiazol-2-amine as an off-white powder (0.069 g, 0.133 mmol); RP-HPLC (25 to 100% acetonitrile in 0.1 M aqueous ammonium acetate over 10 min at 1 mL/min using a 5μ Hypersil HS C18, 250×4.6 mm column) Rt 6.83 min; MS (MH)+ 518.
Reaction SMILES: Cl.N[C:3]1[O:4][C:5]2[C:19]([C:20]([CH3:23])([CH3:22])[CH3:21])=[CH:18][C:17]([C:24]([CH3:27])([CH3:26])[CH3:25])=[CH:16][C:6]=2[C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=1.C[OH:29]>O>[C:24]([C:17]1[CH:18]=[C:19]([C:20]([CH3:22])([CH3:23])[CH3:21])[C:5]2[O:4][C:3](=[O:29])[CH:7]([C:8]3[CH:13]=[CH:12][C:11]([CH3:14])=[C:10]([CH3:15])[CH:9]=3)[C:6]=2[CH:16]=1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CO
Reactant: Cc1ccc(-c2c(N)oc3c(C(C)(C)C)cc(C(C)(C)C)cc23)cc1C
Agent: Cl
Solvent: O
Product: Cc1ccc(C2C(=O)Oc3c2cc(C(C)(C)C)cc3C(C)(C)C)cc1C
Temperature: 25 °C
Reaction time: 2 h

Procedure:
0.35 ml (0.70 mmol) of 2N HCl is added at room temperature to a solution of 0.22 g (0.63 mmol) of 2-amino-5,7-di-tert-butyl-3-(3,4-dimethylphenyl)-benzofurane [compound (302), Table 3, prepared according to Example 2a] in 5 ml methanol and stirred at room temperature for 2 hours. The reaction mixture is diluted with water and extracted three times with ethyl acetate. The organic phases are combined, dried over sodium sulfate and concentrated using a vacuum rotary evaporator. Crystallisation of the residue from ethanol yields 200 mg (96%) of 5,7-di-tert-butyl-3-(3,4-dimethylphenyl-3H-benzofuran-2-one (compound (102), Table 1), m.p. 130-132° C.
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[CH:5][O:4][C:3]=1[C:7]([OH:9])=O.S(Cl)(Cl)=O.[NH2:14][C:15]1[CH:16]=[C:17]([CH:30]=[CH:31][CH:32]=1)[C:18]([C:20]1[CH:28]=[C:27]2[C:23]([CH2:24][C:25](=[O:29])[NH:26]2)=[CH:22][CH:21]=1)=[O:19]>C1COCC1>[O:29]=[C:25]1[CH2:24][C:23]2[C:27](=[CH:28][C:20]([C:18]([C:17]3[CH:16]=[C:15]([NH:14][C:7]([C:3]4[O:4][CH:5]=[CH:6][C:2]=4[CH3:1])=[O:9])[CH:32]=[CH:31][CH:30]=3)=[O:19])=[CH:21][CH:22]=2)[NH:26]1
Reactant: Cc1ccoc1C(=O)O
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Temperature: 79 °C
Reaction time: 3 h
Yield: 87.1 %

Procedure:
A dry flask was charged with 3-Methyl-furan-2-carboxylic acid (0.500 g, 3.96 mmol) and thionyl chloride (10 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (40 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 1.00 g, 3.96 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 3-Methyl-furan-2-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (1.242 g, 3.45 mmol, 87%).
Reaction SMILES: [NH2:1][CH:2]([CH2:13][CH2:14][CH:15]([OH:28])[CH2:16][NH:17][C:18]([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19])[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4].[C:29]1([CH2:35][CH2:36][C:37](=O)[C:38]([OH:40])=[O:39])[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.[OH-].[Na+].C([BH3-])#N.[Na+]>C(O)C.O>[CH2:21]([O:20][C:18]([NH:17][CH2:16][CH:15]([OH:28])[CH2:14][CH2:13][CH:2]([NH:1][CH:37]([C:38]([OH:40])=[O:39])[CH2:36][CH2:35][C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[C:3]([N:5]1[CH2:12][CH2:11][CH2:10][C@H:6]1[C:7]([OH:9])=[O:8])=[O:4])=[O:19])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: O=C(O)C(=O)CCc1ccccc1
Reactant: NC(CCC(O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(NCC(O)CCC(NC(CCc1ccccc1)C(=O)O)C(=O)N1CCC[C@H]1C(=O)O)OCc1ccccc1
Reaction time: 1 h

Procedure:
Compound VI and 4-phenyl-2-oxobutanoic acid (5 eq) were mixed with water (10 ml) and concentrated NaOH was added to raise the pH to 7.5. Ethanol was added (10 ml) and a solution of sodium cyanoborohydride (3 eq) in ethanol (4 ml) was added dropwise over 15 hours. Dowex 50W-2X (H+) (25 cc) was added with stirring. After 1 hour, the slurry was added to a column of Dowex (50 cc), the column was washed with ethanol and water and the product was eluted with 3% pyridine in water. After concentration and purfication over an LH-20 column, freeze drying gave V.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH3:12][C@@H:13](O)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19].[N+](C1C=CC=CC=1O)([O-])=O>>[CH3:12][C@H:13]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1)[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: CCCCCC[C@@H](C)O
Reactant: Cc1ccc(O)cc1[N+](=O)[O-]
Agent: O=[N+]([O-])c1ccccc1O
Product: CCCCCC[C@H](C)Oc1ccc(C)c([N+](=O)[O-])c1

Procedure:
4-Methyl-3-nitrophenol (Compound 33, Scheme VI) was coupled with (R)-2-octanol using the same procedure as that given for alkylation of phenol 9, Scheme I, to give (S)-4-(1-methylheptyloxy)-2-nitro-toluene (Compound 34, Scheme VI, R1 =(S)--OCH(CH3)C6H13) as a yellow liquid; Rf [Hexanes/ethyl acetate 99/1]: 0.26; 1H NMR (300 MHz,CDCl3): δ 0.87(t, 3 H, J=6.6 Hz), 1.16-1.65(m, 12 H), 1.70(m, 1 H), 2.50(s, 3 H), 4.37(m, 1 H), 7.02(dd, 1 H ,J=2.7 Hz, J=8.5 Hz), 7.19(d, 1 H, J=8.5 Hz), 7.47(d, 1 H, J=2.7 Hz); 13C NMR (300 MHz, CDCl3): δ 13.97, 19.41, 19.63, 22.51, 25.32, 29.14, 31.69, 36.20, 74.72, 111.05, 121.44, 125.12, 133.44, 149.5, 156.77; IR (CHCl3): 3020, 2940, 2850, 1620, 1550, 1525, 1490, 1375, 1300, 1240, 1220, 1110, 1050, 975, 860, 825 cm-1 ; Mass spectrum, m/z(rel.intensity): 265(M+ 11), 153(33), 136(100), 112(21), 71(40), 57(70), 51(11), 43(78), 41(66).
Reaction SMILES: [Cl:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[N:9]1[CH:14]=[CH:13][C:12]([CH2:15]O)=[CH:11][CH:10]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C>O1CCCC1>[Cl:1][C:2]1[C:7]([O:8][CH2:15][C:12]2[CH:13]=[CH:14][N:9]=[CH:10][CH:11]=2)=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccncc1
Reactant: Oc1cccnc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Clc1ncccc1OCc1ccncc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.8 %

Procedure:
2-Chloro-3-pyridinol (500 mg, 3.86 mmol) was dissolved in 20 mL of tetrahydrofuran along with 4-pyridyl methanol (465 mg, 4.26 mmol) and triphenylphosphine (1.15 g, 4.38 mmol). To this solution was added diisopropylazodicarboxylate (840 μL, 4.27 mmol). The reaction was stirred at room temperature overnight under a nitrogen atmosphere. The solvent was removed under vacuum and the residue was dissolved in 50 mL of ethyl acetate. The reaction mixture was washed 4 times with 25 mL portions of water. Then, the product was extracted by washing 3 times with 25 mL portions of 0.5 M HCl. The acidic washes were neutralized with 1.0 M NaOH and the product was extracted back into ethyl acetate with 3 washes of 25 mL. The combined organic fractions were dried with magnesium sulfate and concentrated under vacuum to give 620 mg of 2-chloro-3-(pyridin-4-ylmethoxy)pyridine as a yellow solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][N:3]=1.N1C=CC=CC=1.[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>ClCCl>[CH3:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:20](=[O:21])[C:19]2[CH:23]=[CH:24][CH:25]=[CH:26][C:18]=2[N+:15]([O-:17])=[O:16])=[N:3][CH:4]=1
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Cc1ccc(N)nc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(NC(=O)c2ccccc2[N+](=O)[O-])nc1
Reaction time: 4 h
Yield: 52.3 %

Procedure:
To a stirring solution of 2-amino-5-methylpyridine (3.1 g, 29 mmol) and pyridine (7.3 mL, 90 mmol) in dichloromethane (200 mL) was added 2-nitrobenzoyl chloride (5.7 g, 30 mmol). After 4 h, the solvent was removed in vacuo and the residue was partitioned between ethyl acetate (500 mL) and water (250 mL). The organic phase was separated and washed again with water (250 mL) followed by brine (250 mL) and then dried with MgSO4, filtered and partially concentrated in vacuo, which resulted in the formation of a precipitate. After standing overnight, the solid was filtered and dried in vacuo to give 3.9 g (52%) of white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:22])=[O:21])=[CH:4][CH:3]=1.Br[CH:24]([CH3:30])[C:25]([O:27][CH2:28][CH3:29])=[O:26].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:13](=[O:14])[N:12]([CH3:15])[C:11]3[CH:16]=[C:17]([O:20][CH:24]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH3:30])[CH:18]=[CH:19][C:10]=3[S:9]2(=[O:21])=[O:22])=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(C)Br
Reactant: CN1C(=O)N(c2ccc(Cl)cc2)S(=O)(=O)c2ccc(O)cc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc2c(c1)N(C)C(=O)N(c1ccc(Cl)cc1)S2(=O)=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 93 %

Procedure:
A mixture of 2-(4-chlorophenyl)-6-hydroxy-4-methyl-2H-1,2,4-benzothiadiazine-3(4H)-one 1,1-dioxide (678 mg), ethyl 2-bromopropionate (362 mg), and potassium carbonate (207 mg) in dry N,N-dimethyl formamide (2 ml) was stirred overnight at ambient temperature. The mixture was poured into water and extracted twice with ethyl acetate. The organic layers were washed with water, dried, and evaporated under reduced pressure. The residue was crystallized from n-hexane to yield 2-(4-chlorophenyl)-6-[1-(ethoxycarbonyl)ethoxy]-4-methyl-2H-1,2,4-benzothiadiazine -3(4H)-one 1,1-dioxide (816 mg). (R,S mixture)
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].[NH2:8][C:9]1[C:10]([CH3:31])=[C:11]([C:18]([C:20]2[CH:25]=[CH:24][C:23]([N+:26]([O-:28])=[O:27])=[C:22]([O:29][CH3:30])[CH:21]=2)=[O:19])[N:12]2[C:17]=1[CH:16]=[CH:15][CH:14]=[CH:13]2>ClCCl>[CH3:30][O:29][C:22]1[CH:21]=[C:20]([CH:25]=[CH:24][C:23]=1[N+:26]([O-:28])=[O:27])[C:18]([C:11]1[N:12]2[C:17]([CH:16]=[CH:15][CH:14]=[CH:13]2)=[C:9]([NH:8][C:1](=[O:3])[CH3:2])[C:10]=1[CH3:31])=[O:19]
Reactant: CC(=O)OC(C)=O
Reactant: COc1cc(C(=O)c2c(C)c(N)c3ccccn23)ccc1[N+](=O)[O-]
Solvent: ClCCl
Product: COc1cc(C(=O)c2c(C)c(NC(C)=O)c3ccccn23)ccc1[N+](=O)[O-]

Procedure:
1.20 ml (12.60 mmol) of acetic anhydride are added to 410 mg (1.26 mmol) of (1-amino-2-methylindolizin-3-yl)(3-methoxy-4-nitrophenyl)methanone dissolved in 10 ml of dichloromethane.