Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][C:10]=1[N+:11]([O-:13])=[O:12])[N:7]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6](=[O:19])[C:5]2([CH3:21])[CH3:20].[CH3:22][O:23][C:24]1[CH:32]=[CH:31][C:27]([C:28](Cl)=[O:29])=[CH:26][CH:25]=1>C(Cl)Cl.CO>[CH3:20][C:5]1([CH3:21])[C:4]2[C:8](=[CH:9][C:10]([N+:11]([O-:13])=[O:12])=[C:2]([NH:1][C:28](=[O:29])[C:27]3[CH:31]=[CH:32][C:24]([O:23][CH3:22])=[CH:25][CH:26]=3)[CH:3]=2)[N:7]([CH2:14][CH2:15][CH:16]([CH3:17])[CH3:18])[C:6]1=[O:19]
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)CCN1C(=O)C(C)(C)c2cc(N)c([N+](=O)[O-])cc21
Solvent: CO
Solvent: ClCCl
Product: COc1ccc(C(=O)Nc2cc3c(cc2[N+](=O)[O-])N(CCC(C)C)C(=O)C3(C)C)cc1
Yield: 27.3 %

Procedure:
N-[3,3-Dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide is prepared from A9 (419 mg) and 4-methoxy-benzoyl chloride (491 mg; 2.88 mmol) as described in Example 1a. N-[3,3-dimethyl-1-(3-methyl-butyl)-6-nitro-2-oxo-2,3-dihydro-1H-indol-5-yl]-4-methoxy-benzamide (167 mg) is obtained by flash chromatography on silica gel eluting with CH2Cl2/MeOH (50:1)
Reaction SMILES: [F:1][C:2]([F:11])([F:10])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[CH2:8][OH:9].C1(C)C(S(O)(=O)=[O:19])=CC=CC=1.[C:23]1([CH3:29])C=CC=CC=1>>[F:11][C:2]([F:1])([F:10])[C:3]1[O:4][CH:5]=[CH:6][C:7]=1[C:8]([O:19][CH2:23][CH3:29])=[O:9]
Reactant: Cc1ccccc1
Reactant: Cc1ccccc1S(=O)(=O)O
Reactant: OCc1ccoc1C(F)(F)F
Product: CCOC(=O)c1ccoc1C(F)(F)F

Procedure:
43.g of the product of Stage A were refluxed for 2 and a half hours in 250 ml of toluene and 3.1 g of toluenesulfonic acid and the reaction mixture was allowed to cool and was chromatographed on silica (eluent: 9/1 hexane/ethyl acetate) to obtain after evaporation of the solvent at 40° C. under 80 mm of Hg, 20 g of the expected product.
Reaction SMILES: [N:1]1([CH:6]2[CH2:11][CH2:10][NH:9][CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[S:12](N)([NH2:15])(=[O:14])=[O:13]>O1CCOCC1>[N:1]1([CH:6]2[CH2:11][CH2:10][N:9]([S:12]([NH2:15])(=[O:14])=[O:13])[CH2:8][CH2:7]2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: NS(N)(=O)=O
Reactant: C1CCN(C2CCNCC2)C1
Solvent: C1COCCO1
Product: NS(=O)(=O)N1CCC(N2CCCC2)CC1

Procedure:
A mixture of 4-pyrrolidin-1-ylpiperidine (0.67 g) and sulfamide (0.46 g) were heated at 115° C. in dry 1,4-dioxane (30 ml) for 16 h. The solvents were evaporated in vacuo and the residue partitioned between EtOAc (containing a little methanol) and H2O. The organic phase was collected and the aqueous layer further extracted with EtOAc (×2). The combined organic phases collected, dried (MgSO4) and the solvent evaporated. The residue was triturated with Et2O and filtered to give the subtitle product as a beige solid. Yield: 0.43 g
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[CH:7][C:5]=2[N:6]=1.[C:13]([C:16]1[S:17][C:18](B(O)O)=[CH:19][CH:20]=1)([OH:15])=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.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>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:5]2[N:6]=[C:2]([C:18]3[S:17][C:16]([C:13]([OH:15])=[O:14])=[CH:20][CH:19]=3)[S:3][C:4]=2[CH:10]=1
Reactant: COc1ccc2nc(Br)sc2c1
Reactant: O=C(O)c1ccc(B(O)O)s1
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: O
Solvent: CN(C)C=O
Product: COc1ccc2nc(-c3ccc(C(=O)O)s3)sc2c1
Temperature: 120 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
2-Bromo-6-methoxy-benzothiazole (1.22 g, 5.00 mmol), 2-carboxythiophene-5-boronic acid (860 mg, 5.00 mmol), sodium carbonate (2.65 g, 25.00 mmol) and tetrakis(triphenylphosphine)palladium (300 mg, 0.25 mmol) were dissolved in a mixture of 80 mL N,N-dimethylformamide and 80 mL water. The mixture was stirred at 120° C. under argon for 2 h. The reaction mixture was evaporated and the residue was partitioned between 100 mL of water and 100 mL of dichloromethane. A considerable amount of white solid precipitated between the layers and was filtered off and triturated with diethyl ether, affording the title compound (550 mg, 1.89 mmol, 38%) as a white powder.
Reaction SMILES: [C:1]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N:28]=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:13][CH2:12]1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].ClC1C=CC=C(C(OO)=[O:39])C=1>C(Cl)Cl.C(Cl)CCl>[C:1]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[N:18]3[CH:30]=[CH:29][N+:28]([O-:39])=[C:19]3[S:20][C:21]3[CH:27]=[CH:26][CH:25]=[CH:24][C:22]=3[N:23]=2)[CH2:15][CH2:16]1)([O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)=[O:2]
Reactant: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3nccn32)CC1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: O=C(OCc1ccccc1)N1CCN(C2=Nc3ccccc3Sc3n2cc[n+]3[O-])CC1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
To the solution of 0.5 g of 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine in 5 ml of methylene chloride, cooled at 0° C., is added dropwise a solution of 0.26 g of m-chloroperbenzoic acid dissolved in 2 ml of ethylene chloride. The mixture is stirred at 0° C. for 1.5 hrs., the solids are filtered, and the filtrates are washed with 10% aqueous potassium carbonate and water, then dried over magnesium sulfate and evaporated to dryness to give 5-(4-carbobenzoxypiperazino)-imidazo[2,1-b][1,3,5]benzothiadiazepine 1-oxide.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.[Cl:7][C:8]1[C:16]([F:17])=[CH:15][C:11]([C:12]([OH:14])=O)=[C:10]([F:18])[CH:9]=1.C(=O)([O-])[O-].[K+].[K+].[CH:25]1([C@H:28]([NH2:30])[CH3:29])[CH2:27][CH2:26]1>O.C(Cl)Cl.CN(C=O)C>[Cl:7][C:8]1[C:16]([F:17])=[CH:15][C:11]([C:12]([NH:30][C@@H:28]([CH:25]2[CH2:27][CH2:26]2)[CH3:29])=[O:14])=[C:10]([F:18])[CH:9]=1
Reactant: O=C(O)c1cc(F)c(Cl)cc1F
Reactant: C[C@@H](N)C1CC1
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: ClCCl
Product: C[C@@H](NC(=O)c1cc(F)c(Cl)cc1F)C1CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 96.3 %

Procedure:
Oxalyl chloride (250.0 μL, 2.954 mmol) was added to a solution of 4-chloro-2,5-difluorobenzoic acid (0.0578 g, 0.300 mmol) in dichloromethylene (3 mL), followed by 15 μL of DMF. The mixture was stirred at room temperature for 1 hour. The volatiles were removed under reduced pressure. The residue was diluted with dichloromethylene (5 mL). To the solution was added potassium carbonate (82.9 mg, 0.600 mmol) in water (1 mL), and (1R)-1-cyclopropylethanamine (41.6 μL, 0.450 mmol). The mixture was stirred at room temperature for 30 minutes, and diluted with DCM, washed with water and brine. The organic layer was dried over MgSO4, filtered and concentrated under reduced pressure to afford the desired product (0.075 g, 96%) which was directly used in the next step reaction without further purification. LCMS (M+H)+: m/z=260.0.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH:9](=O)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(O)C>[CH:9](=[N:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1ccccc1O
Solvent: CCO
Product: Oc1ccccc1N=Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-aminophenol (28.55 g, 261.61 mmol) in ethanol (40 mL), was added benzaldehyde (30 mL, 31.32 g, 295.14 mmol), and this reaction mixture was refluxed for two hours, and left stirring at room temperature overnight. The creamy white precipitate was filtered, washed with ethanol and dried in vacuum oven at 80° C. for 4 hours. Giving 40.27 g (78% yields).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10](=O)[CH2:11][C:12]2[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=2)=[CH:6][CH:5]=1)[CH3:2].F[P-](F)(F)(F)(F)F.[NH2:30][N+:31]1[CH:36]=[CH:35][CH:34]=[CH:33][N:32]=1.CN1CCCC1=O.CN(CCN(C)C)C>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]([C:12]3[CH:17]=[CH:16][C:15]([S:18]([CH3:21])(=[O:20])=[O:19])=[CH:14][CH:13]=3)[CH:36]3[N:31]([N:32]=[CH:33][CH:34]=[CH:35]3)[N:30]=2)=[CH:6][CH:5]=1)[CH3:2]
Reactant: N[n+]1ccccn1
Reactant: CCOc1ccc(C(=O)Cc2ccc(S(C)(=O)=O)cc2)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: CN(C)CCN(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN1CCCC1=O
Solvent: ClCCl
Product: CCOc1ccc(C2=NN3N=CC=CC3C2c2ccc(S(C)(=O)=O)cc2)cc1
Reaction time: 1 h

Procedure:
Titanium tetrachloride (3.45 mL) was added to a stirred mixture of 1-(4-ethoxyphenyl)-2-(4-methanesulfonyl-phenyl)-ethanone (10.0 g), N-amino-pyridazinium hexafluorophosphate (7.95 g) in dichloromethane (150 mL) at about 20° C. N-Methyl-pyrrolidinone (3.0 mL) was added at about 20° C. TMEDA (6.7 mL) was then added over a period of about 4 hours at about 20° C. After stirring the mixture for about 1 hour, a second portion of TMEDA (12.3 mL) was added over about 20 minutes, and the reaction mixture was stirred at about 20° C. for about 16 hours.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\NC1C=CC(C2CCN(C)CC2)=CC=1.BrC1C=C2C(=CC=1)[C:36](=[O:40])NC(=O)C2=C[NH:43][C:44]1[CH:49]=[CH:48][C:47]([N:50]2[CH2:55][CH:54]([CH3:56])[NH:53][CH:52]([CH3:57])[CH2:51]2)=[CH:46][CH:45]=1>>[I:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/[O:40][CH3:36].[CH3:56][CH:54]1[NH:53][CH:52]([CH3:57])[CH2:51][N:50]([C:47]2[CH:48]=[CH:49][C:44]([NH2:43])=[CH:45][CH:46]=2)[CH2:55]1
Reactant: CC1CN(c2ccc(NC=C3C(=O)NC(=O)c4ccc(Br)cc43)cc2)CC(C)N1
Reactant: CN1CCC(c2ccc(N/C=C3\C(=O)NC(=O)c4ccc(I)cc43)cc2)CC1
Product: CC1CN(c2ccc(N)cc2)CC(C)N1
Product: CO/C=C1/C(=O)NC(=O)c2ccc(I)cc21

Procedure:
Using the procedure described for the preparation of 4Z)-6-bromo-4-({[4-(3,5-dimethylpiperazin-1-yl)phenyl]amino}methylene)isoquinoline-1,3(2H,4H)-dione, after purified from HPLC, 0.064 g (53.4% yield) of light brown solid is obtained from 0.082 g (0.25 mmol) of (4E)-6-iodo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and [4-(3,5-dimethylpiperazin-1-yl)phenyl]amine (0.048 g, 0.25 mmol): mp 215-216° C.; MS (ESI) m/z 488.1 (M+H)+1
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([O:13]C)[CH:10]=[CH:9][C:4]=1[C:5]([NH:7][NH2:8])=O.[N+:15]([C:18]1[CH:23]=[CH:22][C:21]([N:24]=[C:25]=[S:26])=[CH:20][CH:19]=1)([O-:17])=[O:16]>>[OH:2][C:3]1[CH:12]=[C:11]([OH:13])[CH:10]=[CH:9][C:4]=1[C:5]1[N:24]([C:21]2[CH:20]=[CH:19][C:18]([N+:15]([O-:17])=[O:16])=[CH:23][CH:22]=2)[C:25]([SH:26])=[N:8][N:7]=1
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: COc1ccc(C(=O)NN)c(OC)c1
Product: O=[N+]([O-])c1ccc(-n2c(S)nnc2-c2ccc(O)cc2O)cc1

Procedure:
Analogously to Example 8.1, reaction of 2,4-dimethoxybenzhydrazide and 4-nitrophenyl isothiocyanate gives the compound
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[O:6][C@@H:5]([C@H:7]([OH:9])[CH3:8])[CH2:4][O:3]1.[H-].[Na+].[Cl:13][C:14]1[CH:19]=[C:18](Cl)[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1>C1COCC1>[Cl:13][C:14]1[CH:19]=[C:18]([O:9][C@@H:7]([C@H:5]2[CH2:4][O:3][C:2]([CH3:10])([CH3:1])[O:6]2)[CH3:8])[N:17]=[C:16]([S:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:24]=2[F:30])[N:15]=1
Reactant: C[C@@H](O)[C@H]1COC(C)(C)O1
Reactant: Fc1cccc(CSc2nc(Cl)cc(Cl)n2)c1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@@H](Oc1cc(Cl)nc(SCc2cccc(F)c2F)n1)[C@H]1COC(C)(C)O1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (1R)-1-[(4R)-2,2-dimethyl-1,3-dioxolan-4-yl]ethanol (the product of step iv) (0.24 g) in dry THF (10 mL) at 0° C. was added in portions sodium hydride (91 mg as 60% dispersion in mineral oil) followed in portions by 4,6-dichloro-2-[(2,3-difluorobenzyl)thio]pyrimidine (the product of example 1 step ii) (0.50 g). The reaction mixture was stirred at room temperature for 48 h then quenched with saturated aqueous ammonium chloride (10 mL) and diluted with ethyl acetate. The layers were separated and the aqueous layer extracted with further ethyl acetate. The combined organic extracts were washed with brine, dried (MgSO4), filtered and evaporated. The residue was purified by column chromatography on silica gel using EtOAc/isohexane (1:19 to 1:9 gradient) as eluent to give the subtitle compound as a pale yellow solid. Yield: 0.42 g.
Reaction SMILES: [CH3:1][C:2]1([CH3:17])[C:11]2[C:6](=[CH:7][C:8](CCCCC)=[CH:9][CH:10]=2)[O:5][CH2:4][CH2:3]1.[CH2:18]([Li])[CH2:19][CH2:20][CH3:21].ClC1C=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=1>O1CCCC1.CCCCCC>[CH3:17][C:2]1([CH3:1])[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:21]#[C:20][C:19]3[CH:18]=[CH:33][C:27]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[CH:26][N:25]=3)[CH:10]=2)[O:5][CH2:4][CH2:3]1
Reactant: CCCCCc1ccc2c(c1)OCCC2(C)C
Reactant: CCOC(=O)c1ccc(Cl)nc1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCOC(=O)c1ccc(C#Cc2ccc3c(c2)C(C)(C)CCO3)nc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Reaction vessels used in this procedure were flame dried under vacuum and all operations were carried out in an oxygen-free, argon or nitrogen atmosphere. To a solution of 509.4 mg (2.74 mmol) of 4,4-dimethyl-6-ethynylchroman (Compound 4) in 4 ml of dry tetrahydrofuran at 0 degrees C. was added dropwise 1.72 ml of 1.6M (2.75 mmol) of n-butyl lithium in hexane. Stirring was commenced at 0 degrees C. for 30 minutes and at room temperature for 15 minutes, after which the solution was cooled again to 0 degrees C. and then treated with a solution of 380 mg (2.79 mmol) of fused zinc chloride in 5 ml of dry tetrahydrofuran using a double ended needle. The resulting solution was stirred at 0 degrees C. for 1 hour and then at room temperature for 15 minutes. A solution of 628.6 mg (2.74 mmol) of ethyl 6-chloronicotinate (Compound 98) in 4 ml of dry tetrahydrofuran was transferred by double ended needle into a suspension of 380 mg (0.33 mmol) of tetrakistriphenylphosphine palladium in 5 ml dry tetrahydrofuran and the mixture was stirred at room temperature for 15 minutes and then treated by double ended needle with the solution of alkynyl zinc prepared above. The mixture was stirred at room temperature for 20 hours and then quenched with ice and 30 ml of 3N hydrogen chloride. The mixture was extracted with 3×75 ml ether and ether extracts were combined and washed successively with saturated NaHCO3 and saturated NaCl and then dried (MgSO4). Solvent was removed in vacuo and the residue further purified by flash chromatography (silica; 10% ethyl acetate in hexane) to give the title compound as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:7]=[C:8]([C:19](=[O:22])[CH2:20][Cl:21])[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:17])[CH3:16])=[N:11][C:10]=2[CH:18]=1)([CH3:4])([CH3:3])[CH3:2]>CO.CN(C=O)C.CC1C=CC(C(C)C)=CC=1.CC1C=CC(S([N-][C@H]([C@@H](N)C2C=CC=CC=2)C2C=CC=CC=2)(=O)=O)=CC=1.Cl[Ru+]>[C:1]([O:5][C:6]1[CH:7]=[C:8]([C@@H:19]([OH:22])[CH2:20][Cl:21])[C:9]2[S:13][C:12]([O:14][CH:15]([CH3:16])[CH3:17])=[N:11][C:10]=2[CH:18]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)Oc1nc2cc(OC(C)(C)C)cc(C(=O)CCl)c2s1
Agent: Cl[Ru+]
Agent: Cc1ccc(S(=O)(=O)[N-][C@@H](c2ccccc2)[C@@H](N)c2ccccc2)cc1
Solvent: Cc1ccc(C(C)C)cc1
Solvent: CN(C)C=O
Solvent: CO
Product: CC(C)Oc1nc2cc(OC(C)(C)C)cc([C@@H](O)CCl)c2s1
Temperature: 30 °C
Yield: 102.2 %

Procedure:
A suspension of 1-(5-tert-butoxy-2-isopropoxybenzo[d]thiazol-7-yl)-2-chloro-ethanone (70 g, 204.8 mmol) and RuCl(p-cymene)[(S,S)-Ts-DPEN] (1.954 g, 3.07 mmol) in methanol/DMF (1330 ml/70 ml) was degassed and refilled with N2 three times. A degassed preformed mixture of formic acid (28.3 g) in Et3N (124.3 g) was added slowly while keeping the internal temperature between 15 to 20° C. The resulting yellow suspension was warmed up to 30° C. After 2 h the reaction mixture is cooled to 25° C., water (750 ml) was then added into the reaction mixture followed by the addition of acetic acid (56 ml) in one portion. The mixture was concentrated and then diluted with TBME (1000 ml). Aqueous phase was separated and extracted with TBME (1000 ml). The combined organic phase was washed sequentially with water and brine and then dried with Na2SO4 and concentrated under vacuum to give (R)-1-(5-tert-Butoxy-2-isopropoxy-benzothiazol-7-yl)-2-chloro-ethanol (72 g).
Reaction SMILES: [C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[CH:9]=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:3])[CH3:2].C1C(=O)N([Br:35])C(=O)C1>CN(C=O)C.O>[C:1]([N:5]1[CH2:26][CH2:25][CH2:24][CH2:23][C:8]2[C:9]([Br:35])=[C:10]3[C:19]4[CH:18]=[C:17]([Br:20])[C:16]([O:21][CH3:22])=[CH:15][C:14]=4[CH2:13][CH2:12][N:11]3[C:7]=2[C:6]1=[O:27])([CH3:4])([CH3:2])[CH3:3]
Reactant: COc1cc2c(cc1Br)-c1cc3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reactant: O=C1CCC(=O)N1Br
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc2c(cc1Br)-c1c(Br)c3c(n1CC2)C(=O)N(C(C)(C)C)CCCC3
Reaction time: 0.75 h
Yield: 90.7 %

Procedure:
A solution of 506 mg of 19d in 4 ml of DMF was treated with 210 mg of NBS. The reaction was stirred for 45 min, then diluted with water, and stirred for an additional 15 min. The white precipitate was filtered and dried, to provide 543 mg of dibromide 25a.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH:8]=[N:9][NH:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1>CN(C)C=O>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:11]([CH:12]=1)=[N:10][N:9]([CH2:21][CH2:22][N:23]1[CH2:27][CH2:26][CH2:25][CH2:24]1)[CH:8]=2)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1ccc2cn[nH]c2c1
Reactant: ClCCN1CCCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc2cn(CCN3CCCC3)nc2c1
Temperature: 60 °C

Procedure:
6-Nitroindazole (2.00 g, 12.3 mmol) was treated with potassium carbonate (5.00 g 36.2 mmol) in N,N-dimethylformamide (40 mL) for 30 minutes and then 1-(2-chloro-ethyl)-pyrrolidine hydrochloride (3.20 g 18.8 mmol) was added. The reaction mixture was heated to 60° C. for 6 hours, then cooled to room temperature. The reaction mixture was filtered through a plug of silica gel and rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, triethylamine/ethyl acetate 1/30) to afford the title compound. 1H NMR (300 MHz, DMSO-d6) ppm 1.65 (m, 4H) 2.48 (m, 4H), 3.00 (t, 2H, J=6.44), 4.64 (t, 2H, J=6.44), 7.80 (m, 1H), 7.97 (m, 1H), 8.62 (s, 1H), 8.68 (s, 1H); MS (DCI/NH3) m/z 261 [M+H]+.
Reaction SMILES: [C-:1]#[N:2].[K+].[CH3:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([C:10](=O)[CH:11]=[CH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[CH:8][CH:7]=1.CC(O)=[O:24]>O.COCCO>[CH3:4][O:5][C:6]1[CH:21]=[CH:20][C:9]([CH:10]([C:11](=[O:24])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:1]#[N:2])=[CH:8][CH:7]=1
Reactant: [C-]#N
Reactant: CC(=O)O
Reactant: COc1ccc(C(=O)C=Cc2ccccc2)cc1
Agent: [K+]
Solvent: COCCO
Solvent: O
Product: COc1ccc(C(C#N)C(=O)Cc2ccccc2)cc1
Temperature: 25 °C
Yield: 75.6 %

Procedure:
Step B Add KCN (11.27 g, 0.173 mol) in water (25 mL) to a 100° C. solution of 4'-methoxychalcone (27.51 g 0.115 mol) and HOAc (7.5 mL, 0.128 mol) in 2-methoxyethanol (200 mL). The reaction is complete in <10 min. Cool the resulting solution to room temperature and pour into a mixture of ice and water (1 L). Extract the mixture with EtOAc. Combine the organic extracts, wash with water and brine, dry over Na2SO4, filter and concentrate in vacuo. Recrystallize the resulting solid from CH2Cl2 /MeOH to provide 23.07 g (75%) of 2-(4'-methoxyphenyl)-4-phenyl-3-oxobutyronitrile, mp 115°-116° C.
Reaction SMILES: [CH3:1][C:2]1[C:6]([NH:7][C:8]([O:10][C@@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[C:5]([C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][C:28]([C:31]4([C:34](O)=[O:35])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)=[CH:21][CH:20]=2)[O:4][N:3]=1.[CH3:37][S:38]([NH2:41])(=[O:40])=[O:39].C(N(C(C)C)CC)(C)C>C1COCC1>[C:13]1([C@H:11]([O:10][C:8](=[O:9])[NH:7][C:6]2[C:2]([CH3:1])=[N:3][O:4][C:5]=2[C:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:26]=[CH:27][C:28]([C:31]4([C:34]([NH:41][S:38]([CH3:37])(=[O:40])=[O:39])=[O:35])[CH2:32][CH2:33]4)=[CH:29][CH:30]=3)=[CH:21][CH:20]=2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CS(N)(=O)=O
Reactant: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1noc(-c2ccc(-c3ccc(C4(C(=O)NS(C)(=O)=O)CC4)cc3)cc2)c1NC(=O)O[C@H](C)c1ccccc1
Temperature: 65 °C
Reaction time: 8 h

Procedure:
1-{4′-[3-Methyl-4-((R)-1-phenyl-ethoxycarbonylamino)-isoxazol-5-yl]-biphenyl-4-yl}-cyclopropanecarboxylic acid (0.1 g, 0.2 mmol), methanesulfonamide (0.08 g, 0.8 mmol), and N,N′-carbonyldiimidazole (0.15 g, 0.6 mmol) were combined in THF (4 mL). Diisopropylethylamine (0.5 mL) was added, and the reaction was stirred at 65° C. overnight. The mixture was acidified and extracted with CH2Cl2. The crude material was purified by silica gel chromatography (0-50% EtOAc in hexanes) to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12](Br)[CH:11]=2)[O:7][N:6]=1)=[O:4].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.[CH3:39][CH:40]([OH:43])[CH:41]=[CH2:42].C(N(CC)CC)C>CN(C)C=O.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH3:1][O:2][C:3]([C:5]1[CH:9]=[C:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([CH2:42][CH2:41][C:40](=[O:43])[CH3:39])[CH:11]=2)[O:7][N:6]=1)=[O:4]
Reactant: C=CC(C)O
Reactant: COC(=O)c1cc(-c2cccc(Br)c2)on1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COC(=O)c1cc(-c2cccc(CCC(C)=O)c2)on1
Temperature: 100 °C
Yield: 59.4 %

Procedure:
To a mixture of 5-(3-Bromo-phenyl)-isoxazole-3-carboxylic acid methyl ester (1.5 g, 5.3 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), P(o-tolyl)3 (162 mg, 0.53 mmol) in anhydrous N,N-dimethylformamide (15 mL) in a pressure tube was added 3-buten-2-ol (0.92 mL, 10.6 mmol) and triethylamine (1.1 mL, 7.95 mmol). The mixture was flushed with nitrogen for 3 minutes, capped and heated to 100° C. for 30 minutes. The reaction mixture was allowed to cool to ambient temperature, partitioned between ethyl acetate and water (75 mL, 1:1). The organic layer was washed with brine (2×25 mL), dried (Na2SO4), filtered, concentrated under reduced pressure and purified on a Silica Gel MPLC eluting with 20–40% ethyl acetate/hexanes to provide the titled compound as a light yellow solid (860 mg, 59%). MS (ESI(+)) m/e 274 (M+H)+.