Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:21][CH2:20][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:18][CH2:19]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1.CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1>CO>[OH:7][C:8]1[CH:9]=[C:10]([C:14]23[CH2:19][CH2:18][C:17]([CH2:22][CH2:23][O:24][CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])([CH2:20][CH2:21]2)[CH2:16][O:15]3)[CH:11]=[CH:12][CH:13]=1
Reactant: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(OC4CCCCO4)c3)(CC1)OC2
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CO
Product: CC(C)(C)OC(=O)COCCC12CCC(c3cccc(O)c3)(CC1)OC2
Temperature: 50 °C
Reaction time: 3 h
Yield: 89 %

Procedure:
A mixture of tert-butyl 2-(2-(1-(3-(tetrahydro-2H-pyran-2-yloxy)phenyl)-2-oxabicyclo[2.2.2]octan-4-yl)ethoxy)acetate (1000 mg, 2.24 mmol) and PPTS (169 mg, 0.672 mmol) in MeOH (10 ml) was stirred at 50° C. for 3 h. The reaction was concentrated in vacuo. The crude oil was purified by flash chromatography on SiO2 (0 to 30% EtOAc:hexanes) to afford the title compound (723 mg, 89% yield) as a white solid. LCMS, [M−H]+=361.4. 1H NMR (500 MHz, CDCl3) δ 7.19 (t, J=8.1 Hz, 1H), 6.96-6.91 (m, 2H), 6.71 (ddd, J=8.0, 2.5, 1.0 Hz, 1H), 4.83 (s, 1H), 3.96 (s, 2H), 3.89 (s, 2H), 3.59 (t, J=6.9 Hz, 2H), 2.06-2.00 (m, 4H), 1.78-1.71 (m, 4H), 1.54 (t, J=7.0 Hz, 2H), 1.51 (s, 9H).
Reaction SMILES: [C:1]1([S:7][CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:26])[F:25])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C[OH:29]>O>[C:1]1([S:7]([CH2:8][CH2:9][N:10]([CH2:23][C:24]([F:27])([F:25])[F:26])[C:11]2[CH:18]=[CH:17][C:14]([C:15]#[N:16])=[C:13]([C:19]([F:20])([F:21])[F:22])[CH:12]=2)=[O:29])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: N#Cc1ccc(N(CCSc2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Reactant: CO
Solvent: O
Product: N#Cc1ccc(N(CCS(=O)c2ccccc2)CC(F)(F)F)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h
Yield: 88 %

Procedure:
To a solution of 4-[[2-(phenylthio)ethyl](2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (0.039 g, 0.096 mmol) in MeOH (3 mL) was added a solution of NaIO4 (0.041 g, 0.193 mmol) in water (1 mL) and stirred at rt. After 1 h, additional NaIO4 (0.041 g, 0.19 mmol) dissolved in water (1 mL) was added and the reaction mixture diluted with MeOH (1 mL). After stirring at rt for 12 h, the mixture was partitioned between EtOAc and brine. The organic phase was washed with water and brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (1-10% MeOH/CH2Cl2 gradient) to give the title compound (0.037 g, 88% yield): MS (ES) m/z 421 (M+1).
Reaction SMILES: [OH:1][CH:2]([CH:11]1[C:15](=[O:16])[C:14]([S:17][CH3:18])=[CH:13][C:12]1([OH:30])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[CH:3]=[CH:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9].ClC1C=CC=C(C(OO)=[O:39])C=1.C(=O)([O-])O.[Na+]>ClCCl>[OH:1][CH:2]([CH:11]1[C:15](=[O:16])[C:14]([S:17]([CH3:18])=[O:39])=[CH:13][C:12]1([OH:30])[CH2:19][CH2:20][CH2:21][CH2:22][O:23][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)[CH:3]=[CH:4][CH:5]([OH:10])[CH2:6][CH2:7][CH2:8][OH:9]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSC1=CC(O)(CCCCOc2ccccc2)C(C(O)C=CC(O)CCCO)C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CS(=O)C1=CC(O)(CCCCOc2ccccc2)C(C(O)C=CC(O)CCCO)C1=O
Reaction time: 3 h
Yield: 20.1 %

Procedure:
To a solution of 35 mg of 5-(1,4,7-trihydroxy-2-heptenyl)-4-hydroxy-2-methylthio-4-(4-phenoxybutyl)-2-cyclopentenone obtained in Example 72 dissolved in 2 ml of dichloromethane was added 16 mg of 3-chloroperbenzoic acid, and the mixture was stirred for 3 hours. Saturated aqueous sodium hydrogencarbonate was added, and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered and concentrated, followed by silica gel column chromatography to give 7.3 mg (yield 46%) of 5-(1,4,7-trihydroxy-2-heptenyl)-4-hydroxy-2-methylsulfinyl-4-(4-phenoxybutyl)-2-cyclopentenone.
Reaction SMILES: [O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([C:22]#N)=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.[PH2]([O-])=[O:25].[Na+]>N1C=CC=CC=1.O.[Ni]>[O:1]=[C:2]1[C@@:10]2([CH2:12][C@H:11]2[C:13]2[CH:21]=[C:20]3[C:16]([C:17]([CH:22]=[O:25])=[N:18][NH:19]3)=[CH:15][CH:14]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1
Reactant: O=[PH2][O-]
Reactant: N#Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Agent: [Ni]
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Product: O=Cc1n[nH]c2cc([C@@H]3C[C@@]34C(=O)Nc3ccccc34)ccc12
Reaction time: 8 h
Yield: 30 %

Procedure:
To a solution of 6-((1R*,2S*)-2′-oxospiro[cyclopropane-1,3′-indoline]-2-yl)-1H-indazole-3-carbonitrile (1 g, 3.3 mmol) in pyridine (30 mL) acetic acid (8 mL) and water (8 mL) and Raney Nickel (1 g). Sodium hypophosphite (1.8 g, 21 mmol) was dissolved in water (10 mL) and added dropwise and the reaction was stirred overnight. The product was extracted into ethyl acetate (300 mL), washed with brine (50 mL), dried over MgSO4 and concentrated to dryness. The residue was purified by silica gel chromatography (95:5 CH2Cl2/MeOH) to give the title compound as a yellow solid (300 mg, 30%). 1H NMR (400 MHz, CD3OD) δ 10.17 (s, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.55 (s, 1H), 7.17 (d, J=8.5 Hz, 1H) 7.08-7.04 (m, 1H), 6.94 (d, J=8.3 Hz, 1H), 6.56 (t, J=7.6 Hz, 1H), 5.93 (d, J=7.5 Hz, 1H), 3.38-3.34 (m, 1H), 2.27-2.17 (m, 1H).
Reaction SMILES: [CH:1]([NH2:14])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[Br:22][CH2:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1.O>ClCCl>[CH:1]([NH:14][S:30]([C:27]1[CH:26]=[CH:25][C:24]([CH2:23][Br:22])=[CH:29][CH:28]=1)(=[O:31])=[O:32])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(CBr)cc1
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=S(=O)(NC(c1ccccc1)c1ccccc1)c1ccc(CBr)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Benzhydrylamine (640 μL) was dissolved in dichloromethane (5.0 mL). To the solution, triethylamine (645 μl) and 4-(bromomethyl)benzenesulfonyl chloride (1.0 g) were added at 0° C., and the mixture was stirred at room temperature for 2 hours. To the reaction mixture, water (10 mL) was added, and the resultant mixture was then extracted with chloroform (30 mL). The organic layer was washed with brine (15 mL), dried over anhydrous sodium sulfate, and then concentrated under reduced pressure. The residue was purified by silica gel column chromatography (40% ethyl acetate/hexane) to obtain the title compound (753 mg).
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([C:8]([F:11])([F:10])[F:9])=[N:6][CH:7]=1.[OH:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.O.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]>[F:9][C:8]([F:11])([F:10])[C:5]1[N:6]=[CH:7][C:2]([C:16]2[CH:17]=[CH:18][C:13]([OH:12])=[CH:14][CH:15]=2)=[CH:3][CH:4]=1
Reactant: OB(O)c1ccc(O)cc1
Reactant: FC(F)(F)c1ccc(Br)cn1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Oc1ccc(-c2ccc(C(F)(F)F)nc2)cc1
Temperature: 70 °C
Yield: 94.1 %

Procedure:
5-Bromo-2-(trifluoromethyl)pyridine (1.18 g, 5.51 mmol), 4-hydroxyphenylboronic acid (775 mg, 5.51 mmol) and sodium carbonate (2.34 g, 22.0 mmol) were combined and dissolved in a mixture of dioxane/water (30 mL/6 mL). The reaction mixture was degassed and then tetrakistriphenylphosphinepalladium (0) (322 mg, 0.275 mmol) was added and the reaction mixture was heated at 70° C. for 18 hours. The cooled reaction mixture was partitioned between ethyl acetate and water. The organic layer was separated and washed with brine, dried over anhydrous MgSO4 and concentrated in vacuo. The residue was purified on silica gel by Biotage™ (7% to 60% EtOAc in heptane over 20 CV) to give the title compound (1.24 g, 95%) as a white solid.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=[O:13])=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[NH2:27][C:28]1[CH:29]=[C:30]([S:35]([NH2:38])(=[O:37])=[O:36])[C:31]([CH3:34])=[CH:32][CH:33]=1>>[CH3:34][C:31]1[CH:32]=[CH:33][C:28]([NH:27][C:12]([C:11]2[CH:10]=[N:9][N:8]3[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=4)=[N:6][C:7]=23)=[O:13])=[CH:29][C:30]=1[S:35](=[O:36])(=[O:37])[NH2:38]
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: Cc1ccc(N)cc1S(N)(=O)=O
Product: Cc1ccc(NC(=O)c2cnn3c(C(F)(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)cc1S(N)(=O)=O

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) and 3-amino-6-methyl-benzenesulfonamide [CAS-No. 6973-09-7] according to general procedure II. Yellow solid. MS (ISP) 544.0 [(M+H+]; mp 297° C.
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11](=[NH:15])[N:12]([OH:14])[CH3:13])[N:6]=1.C(N(CC)CC)C.Cl[C:30](OC1C=CC(F)=CC=1)=[O:31]>CN(C=O)C>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][O:8]/[N:9]=[C:10](/[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)\[C:11]2[N:12]([CH3:13])[O:14][C:30](=[O:31])[N:15]=2)[N:6]=1
Reactant: O=C(Cl)Oc1ccc(F)cc1
Reactant: CN(O)C(=N)/C(=N\OCc1csc(N)n1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cn1oc(=O)nc1/C(=N\OCc1csc(N)n1)c1ccccc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 104.2 %

Procedure:
To a solution of (2Z)-2-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}-N-hydroxy-N-methyl-2-phenylethanimidamide (5.00 g, 16.37 mmol, 1 eq.) and triethylamine (2.28 ml, 16.37 mmol, 1 eq) in DMF (100 ml) at 0° C., was added dropwise 4-fluorophenyl chloroformate (28.58 g, 16.37 mmol, 1 eq.). After stirring at 0° C. for 1 hour, the reaction was quenched by addition of water (50 ml) and extracted with EtOAc (2×150 ml). The organics were combined, dried over MgSO4 and concentrated. The residue was purified by chromatography on silica gel to give 3-[(Z)-{[(2-amino-1,3-thiazol-4-yl)methoxy]imino}(phenyl)methyl]-2-methyl-1,2,4-oxadiazol-5(2H)-one (5.65 g, 96% yield).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]2[O:10]C[N:8]([C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:7][C:6]=2[CH:15]=1.[N:22]1[CH:27]=[CH:26][C:25](B(O)O)=[CH:24][CH:23]=1.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)C.O>[C:11]([NH:8][CH2:7][C:6]1[CH:15]=[C:2]([C:25]2[CH:26]=[CH:27][N:22]=[CH:23][CH:24]=2)[CH:3]=[C:4]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:5]=1[OH:10])([CH3:14])([CH3:12])[CH3:13]
Reactant: CC(C)(C)N1COc2c(cc(Br)cc2-c2ccccc2)C1
Reactant: OB(O)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)O
Solvent: O
Product: CC(C)(C)NCc1cc(-c2ccncc2)cc(-c2ccccc2)c1O
Temperature: 55 °C
Yield: 32.4 %

Procedure:
A mixture of 6-bromo-3-(tert-butyl)-8-phenyl-3,4-dihydro-2H-benzo[e][1,3]oxazine (from Example 42, Step 2) (0.404 g, 1.17 mmol), pyridin-4-ylboronic acid (0.288 g, 2.0 equiv), and potassium carbonate (0.647 g, 4 equiv) in isopropanol (30 mL) and water (6 mL) was purged with nitrogen for 20 minutes. Tetrakis(triphenylphosphine)Pd (0) (88 mg, 6.5 mol %) was added and the resulting mixture was heated at 55° C. for 4 hours. The cooled reaction mixture was concentrated and the resulting residue was purified by column chromatograph to give 3-((tert-butylamino)methyl)-5-(pyridine-4-yl)-[1,1′-biphenyl]-2-ol (0.126 g).
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:18]3[CH:23]=[CH:22][N:21]=[N:20][CH:19]=3)=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=3)[N:10]=2)[N:7]=1.[CH:24]([N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1)([CH3:26])[CH3:25]>C(O)CCCC>[F:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:10]=[C:5]3[CH:4]=[CH:3][C:2]([N:30]4[CH2:31][CH2:32][N:27]([CH:24]([CH3:26])[CH3:25])[CH2:28][CH2:29]4)=[N:7][N:6]3[C:8]=2[C:18]2[CH:23]=[CH:22][N:21]=[N:20][CH:19]=2)=[CH:12][CH:13]=1
Reactant: Fc1ccc(-c2nc3ccc(Cl)nn3c2-c2ccnnc2)cc1
Reactant: CC(C)N1CCNCC1
Solvent: CCCCCO
Product: CC(C)N1CCN(c2ccc3nc(-c4ccc(F)cc4)c(-c4ccnnc4)n3n2)CC1
Temperature: 130 °C

Procedure:
The mixture of 0.26 g (0.8 mmol) of 6-chloro-2-(4-fluorophenyl)-3-(pyridazin-4-yl)imidazo[1,2-b]pyridazine and 0.66 g (3.2 mmol) of 1-isopropylpiperazine in 6 ml of pentanol is heated in a sealed tube at 130° C. for 10 hours.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[C:12]([CH3:14])([CH3:13])[C:11]2[CH:10]=[C:9]([C:15]([NH2:17])=[O:16])[CH:8]=[CH:7][C:6]=2[CH2:5][C@H:4]1[O:18][CH3:19].C(N(CC)CC)C.[CH2:27]([O:29][C:30](=[O:33])[CH:31]=[CH2:32])[CH3:28]>>[CH2:27]([O:29][C:30](=[O:33])[CH2:31][CH2:32][NH:2][C@H:3]1[C@H:4]([O:18][CH3:19])[CH2:5][C:6]2[C:11](=[CH:10][C:9]([C:15](=[O:16])[NH2:17])=[CH:8][CH:7]=2)[C:12]1([CH3:14])[CH3:13])[CH3:28]
Reactant: CO[C@@H]1Cc2ccc(C(N)=O)cc2C(C)(C)[C@H]1N
Reactant: C=CC(=O)OCC
Agent: Cl
Solvent: CCN(CC)CC
Product: CCOC(=O)CCN[C@H]1[C@H](OC)Cc2ccc(C(N)=O)cc2C1(C)C
Temperature: 70 °C
Reaction time: 23 h

Procedure:
A mixture of trans-7-amino-6-methoxy-8,8-dimethyl-5,6,7,8-tetrahydro-naphthalene-2-carboxylic acid amide hydrochloride (0.25 g, 0.88 mmol) anhydrous ethanol (0.90 mL), triethylamine (0.14 mL, 1.32 mmol) and acrylic acid ethyl ester (0.14 mL, 1.0 mmol) were heated at 70° C. After 23 h, additional acrylic acid ethyl ester (0.04 mL, 0.3 mmol) was added and heating was continued. Five hours after the addition, the reaction was cooled to room temperature, combined with another run (0.36 mmol scale) and concentrated under vacuum. The title compound (0.61 g) was used without further purification. (m/z): [M+H]− calcd for C19H28N2O4 349.21; found 349.0.
Reaction SMILES: [NH2:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:6](=[O:16])[N:5]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4](=[O:24])[CH:3]=1.C(O)=O.N([O-])=O.[Na+].S(S([O-])=O)([O-])=O.[Na+].[Na+].[CH:40]([NH2:42])=O>>[CH2:17]([N:5]1[C:4](=[O:24])[C:3]2[NH:42][CH:40]=[N:1][C:2]=2[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH3:15])[CH:9]=2)[C:6]1=[O:16])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: NC=O
Reactant: COc1cccc(-n2c(N)cc(=O)n(Cc3ccccc3)c2=O)c1
Agent: O=N[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: O=CO
Product: COc1cccc(-n2c(=O)n(Cc3ccccc3)c(=O)c3[nH]cnc32)c1
Temperature: 100 °C

Procedure:
A mixture of 6-amino-3-benzyl-1-(3-methoxyphenyl)uracil (5.52 g), formic acid (3.2 ml) and sodium nitrite (1.45 g) in formamide (130 ml) was gradually heated up to 100° C. with stirring. Sodium dithionite (4.83 g) was then added in portions over a period of 10 min, the temperature being held at 100° C. The temperature was then raised to 190° C. and the mixture stirred at this temperature for 30 min. It was allowed to cool then extracted into chloroform. The chloroform solution was extracted into 2M sodium hydroxide solution and this washed with ether. The aqueous layer was acidified with concentrated hydrochloric acid to give a solid which was filtered off and washed with water. Recrystallisation from ethanol provided the title compound (1.55 g).
Reaction SMILES: [CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][OH:11])=[N:7][CH:8]=1)[CH3:2].C(N(CC)CC)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>C(Cl)Cl>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][O:11][S:20]([CH3:19])(=[O:22])=[O:21])=[N:7][CH:8]=1)[CH3:2]
Reactant: CCc1ccc(CCO)nc1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCc1ccc(CCOS(C)(=O)=O)nc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 2-(5-ethyl-pyridine-2-yl)-ethanol (25.34 g) and triethylamine (46.7 mL) in DCM (130 mL) at 0° C. under nitrogen was added methane sulfonyl chloride (15.56 mL), then the reaction mixture was allowed to warm to room temperature and stirred overnight. A further portion of methane sulfonyl chloride (3.88 mL) was added and the reaction stirred for 30 min. The reaction was diluted with DCM and washed with H2O and brine. The organic layer was dried (MgSO4) and the solution concentrated to give the title compound as a red oil (38.24 g). 1H NMR (400 MHz, CDCl3): δ 8.39 (d, J=2.2 Hz, 1H), 7.47 (dd, J=7.7, 2.3 Hz, 1H), 7.14 (d, J=7.7 Hz, 1H), 4.64 (t, J=6.5 Hz, 2H), 3.19 (t, J=6.5 Hz, 2H), 2.90 (s, 3H), 2.64 (q, J=7.6 Hz, 2H), 1.25 (t, J=7.6 Hz, 3H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9]([NH:10][CH:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])=[C:8]([C:20](=[O:22])[NH2:21])[CH:7]=[N:6][N:5]2[CH:23]=1.[C:24]1(B(O)O)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[Na+].[Na+].O>C1(C)C=CC=CC=1.[OH-].C([N+](CCCC)(CCCC)CCCC)CCC>[C:20]([C:8]1[CH:7]=[N:6][N:5]2[CH:23]=[C:2]([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:3]=[C:4]2[C:9]=1[NH:10][CH:11]([CH3:19])[C:12]([CH3:18])([CH3:17])[C:13]([O:15][CH3:16])=[O:14])(=[O:22])[NH2:21]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(Br)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: COC(=O)C(C)(C)C(C)Nc1c(C(N)=O)cnn2cc(-c3ccccc3)cc12
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 60.4 %

Procedure:
To a solution of methyl 3-(6-bromo-3-carbamoylpyrrolo[1,2-b]pyridazin-4-ylamino)-2,2-dimethylbutanoate (1.0 g, 2.61 mmol) in toluene (10 ml) was added phenyl boronic acid (0.44 g, 3.91 mmol) and stirred for 10 minutes at RT. Sodium carbonate (0.553 gm, 5.22 mmol), Pd(dppf)2 (0.10 gm, 3.91 mmol), water (2.0 ml) and tetrabutyl ammonium hydroxide (1 drop) was added at room temperature under nitrogen atmosphere and the reaction mixture was degassed with nitrogen for 15 minutes. The reaction mixture was stirred at 110° C. in a CEM microwave synthesizer for 8 hours. Upon completion, the reaction mixture was cooled to room temperature and the layers were separated. The aqueous layer was washed with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (25 ml), dried over anhyd. sodium sulfate, filtered and concentrated under vacuum. The crude compound was purified by column chromatography using 30% ethyl acetate in hexanes as the eluting solvent to give the title compound (600 mg, 60%). 1H NMR (400 MHz, DMSO-d6): δ 1.32-1.34 (m, 6H), 1.37-1.39 (m, 3H), 3.73 (s, 3H), 4.68-4.70 (m, 1H), 7.157-7.161 (d, J=1.6 Hz, 1H), 7.27-7.31 (m, 1H), 7.41-7.44 (m, 2H), 7.62-7.65 (m, 2H), 7.87-7.88 (m, 2H). 10.60-10.63 (d, J=10 Hz, 1H).
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:10]3[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=3[C:8]([CH3:17])([CH3:16])[O:7][C:6]=2[C:5]([C:18](=[O:20])[CH3:19])=[C:4]([OH:21])[CH:3]=1.[C:22](OCC)(=O)[C:23]([O:25]CC)=[O:24].[Na].Cl>C(O)C>[C:23]([C:22]1[O:21][C:4]2[CH:3]=[C:2]([CH3:1])[C:11]3[C:10]4[CH:12]=[CH:13][CH:14]=[CH:15][C:9]=4[C:8]([CH3:17])([CH3:16])[O:7][C:6]=3[C:5]=2[C:18](=[O:20])[CH:19]=1)([OH:25])=[O:24]
Reactant: CCOC(=O)C(=O)OCC
Reactant: CC(=O)c1c(O)cc(C)c2c1OC(C)(C)c1ccccc1-2
Agent: Cl
Agent: [Na]
Solvent: CCO
Product: Cc1cc2oc(C(=O)O)cc(=O)c2c2c1-c1ccccc1C(C)(C)O2
Temperature: 10 °C

Procedure:
A solution of 1.2 gm (4.3 millimols) of 1-methyl-3-hydroxy-4-acetyl-6,6-dimethyl-6H-dibenzo-[b,d]-pyran and 1.2 gm (8.3 millimols) of diethyl oxalate in 10 ml of ethanol was poured at 40° C into a solution of 1.03 gm (45 millimols) of sodium in 20 ml of ethanol. The mixture was refluxed for 1 hour, cooled to 10° C and acidified with 2 N hydrochloric acid. The raw reaction product was extracted twice with 15 ml of ether each, the combined extracts were dried, and the solvent was evaporated. The orange residue was refluxed for 13/4hours in 18.2 ml of a mixture of acetic acid and hydrochloric acid (1.2 : 1), the reaction mixture was then cooled, and the precipitate formed thereby was recrystallized from ethanol. 1.1 gm (77% of theory) of the compound named in the heading, m.p. 231°-232° C, were obtained.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([OH:16])=O)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:19][C:20]1[CH:21]=[C:22]([C:27]2([CH2:33][CH2:34][OH:35])[O:32][CH2:31][CH2:30][NH:29][CH2:28]2)[CH:23]=[CH:24][C:25]=1[Cl:26]>C(#N)C>[F:1][C:2]([F:18])([F:17])[C:3]1[CH:4]=[C:5]([CH2:13][C:14]([N:29]2[CH2:30][CH2:31][O:32][C:27]([CH2:33][CH2:34][OH:35])([C:22]3[CH:23]=[CH:24][C:25]([Cl:26])=[C:20]([Cl:19])[CH:21]=3)[CH2:28]2)=[O:16])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: OCCC1(c2ccc(Cl)c(Cl)c2)CNCCO1
Reactant: O=C(O)Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Solvent: CC#N
Product: O=C(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)N1CCOC(CCO)(c2ccc(Cl)c(Cl)c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.6 %

Procedure:
To a solution of 3,5-bis(trifluoromethyl)phenylacetic acid (2.0 g, 7.4 mmol) in acetonitrile (20 ml), N,N′-carbonyldiimidazole (1.3 g, 8.1 mmol) was added at room temperature, then 2-[2-(3,4-dichlorophenyl)morpholin-2-yl]ethanol (2.4 g, 8.8 mmol) was further added, and the resulting mixture was stirred at room temperature for one hour. After completion of the reaction, the reaction mixture was evaporated to dryness. To the obtained residue, methylene chloride (20 ml), water (20 ml) and concentrated hydrochloric acid (2 ml) were added, and the resulting mixture was partitioned. The separated organic layer was washed successively with a 5% aqueous solution of sodium hydroxide (25 ml) and water (20 ml) and evaporated to dryness to afford the title compound [2.3 g, yield: 58.6%] as an oil.
Reaction SMILES: C([C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)=O.[C:21](O)(=O)[CH2:22][C:23]([OH:25])=[O:24].N1CCCCC1.Cl>N1C=CC=CC=1>[C:23](/[CH:22]=[CH:21]/[C:3]1[C:12]2[O:11][C:10]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=3)=[C:9]([CH3:19])[C:8](=[O:20])[C:7]=2[CH:6]=[CH:5][CH:4]=1)([OH:25])=[O:24]
Reactant: Cc1c(-c2ccccc2)oc2c(C=O)cccc2c1=O
Reactant: O=C(O)CC(=O)O
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: Cc1c(-c2ccccc2)oc2c(/C=C/C(=O)O)cccc2c1=O
Temperature: 100 °C
Reaction time: 3 h

Procedure:
A mixture of 7.92 g of 8-formyl-3-methyl-4-oxo-2-phenyl-4H-1-benzopyran (prepared as described in Uneyama, K. et al., Bull. Chem. Soc. Jap. 58.; 2361, (1985)) 3.75 g of malonic acid and 0.46 ml of piperidine in 15 ml of anhydrous pyridine was stirred at 100° C. for 3 hours. After cooling to 20°-25° C. the reaction mixture was poured into a mixture of 90 g of crushed ice and 33 ml of hydrochloric acid (d=1.18). The resultant precipitate was collected by suction filtration, washed with water and crystallized twice from 95% ethanol to give 5.5 g of the title compound, m.p. 226°-229° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:8]=[N:9][C:10]([O:12][Si](C)(C)C)=[CH2:11].[Br:17][C:18]1[CH:26]=[C:25]2[C:21](/[C:22](=[CH:28]/[C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=3)/[C:23](=[O:27])[NH:24]2)=[CH:20][CH:19]=1.CO>C1(C)C=CC=CC=1>[Br:17][C:18]1[CH:26]=[C:25]2[NH:24][C:23](=[O:27])[C:22]3([CH:28]([C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([Cl:35])[CH:30]=4)[CH2:12][C:10](=[O:11])[NH:9][CH:8]3[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[CH3:1])[C:21]2=[CH:20][CH:19]=1
Reactant: O=C1Nc2cc(Br)ccc2/C1=C/c1cccc(Cl)c1
Reactant: C=C(N=Cc1ccccc1C)O[Si](C)(C)C
Solvent: CO
Solvent: Cc1ccccc1
Product: Cc1ccccc1C1NC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Br)ccc12
Temperature: 135 °C

Procedure:
To a solution of 1-(2-methylphenyl)-3-trimethylsilyoxy-2-aza-1,3-butadiene prepared in example 17a in toluene (20 mL) was added E/Z-6-bromo-3-(3-chloro-benzylidene)-2-oxo-2,3-dihydro-indole prepared in example 157a (0.3 g, 0.83 mmol). The reaction mixture was stirred and heated under microwave irradiation in a sealed tube at 135° C. for 0.5 h. After the solution was cooled to room temperature, methanol (50 mL) was added, and then the mixture was concentrated. The residue was purified by chromatography (EtOAc:CH2Cl2=1:3) to give racemic (2′R,3R,4′S)-6-bromo-4′-(3-chlorophenyl)-2′-(2-methylphenyl)spiro[3H-indole-3,3′-piperidine]-2,6′(1H)-dione as a white solid. (Yield 0.22 g, 53%).