Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O-].[Na+].[Na].[OH:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1.[CH2:14](Br)[CH:15]=[CH2:16]>CS(C)=O.CO>[CH2:16]([O:5][C:6]1[C:7]([CH2:12][OH:13])=[N:8][CH:9]=[CH:10][CH:11]=1)[CH:15]=[CH2:14]
Reactant: C=CCBr
Reactant: OCc1ncccc1O
Agent: C[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CO
Solvent: CS(C)=O
Product: C=CCOc1cccnc1CO
Reaction time: 2 h

Procedure:
To a sodium methoxide, methanol mixture made from 1.43 g (62 mmole) sodium metal and 100 ml methanol was added 5.9 g (31 mmole) 3-hydroxy-2-hydroxymethylpyridine and the methanol removed in vacuo. The resulting residue was dissolved in 80 ml dimethylsulfoxide (DMSO) and 3.0 ml (34.7 mmole) allyl bromide in 20 ml DMSO was added over 20 minutes at room temperature. The mixture was stirred for two hours, the DMSO distilled in vacuo and the reside partitioned between chloroform/water. The aqueous phase was adjusted to pH 7.5 and extracted three times with chloroform. The combined organic layers were washed with water, brine, dried (Na2SO4) and concentrated to give 3.48 g (68%) of the desired ether.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:4]=[C:5]([C:9]2[CH:18]=[N:17][C:12]3[O:13][CH2:14][CH2:15][NH:16][C:11]=3[CH:10]=2)[CH:6]=[CH:7][CH:8]=1.[Br:21][C:22]1[CH:23]=[C:24]([CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32])[C:25](Cl)=[O:26].C(N(CC)CC)C>ClCCl>[Br:21][C:22]1[CH:23]=[C:24]([C:25]([N:16]2[CH2:15][CH2:14][O:13][C:12]3[N:17]=[CH:18][C:9]([C:5]4[CH:6]=[CH:7][CH:8]=[C:3]([C:2]([F:19])([F:1])[F:20])[CH:4]=4)=[CH:10][C:11]2=3)=[O:26])[CH:28]=[C:29]([Br:33])[C:30]=1[O:31][CH3:32]
Reactant: FC(F)(F)c1cccc(-c2cnc3c(c2)NCCO3)c1
Reactant: COc1c(Br)cc(C(=O)Cl)cc1Br
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(Br)cc(C(=O)N2CCOc3ncc(-c4cccc(C(F)(F)F)c4)cc32)cc1Br
Yield: 95.9 %

Procedure:
By the same method as in the step c) of Example 45, 7-(3-trifluoromethyl-phenyl)-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazine (99 mg, 0.35 mmol), 3,5-dibromo-4-methoxy-benzoyl chloride (139 mg, 0.42 mmol) and triethylamine (98.5 μl, 0.71 mmol) were dissolved in dichloromethane (3 ml) and reacted at room temperature for 3 hours to obtain (3,5-dibromo-4-methoxy-phenyl)-[7-(3-trifluoromethyl-phenyl)-2,3-dihydro-pyrido[2,3-b][1,4]oxazin-1-yl]-methanone as white solid (192 mg, 95%).
Reaction SMILES: Cl.[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][NH:23][CH2:22]3.C(N(CC)CC)C.Cl[CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[CH:45]=1.CC1C=C(C=CC=1)CBr>C(Cl)Cl>[F:2][C@@:3]12[C@:16]3([CH3:17])[C:11](=[CH:12][C:13](=[O:18])[CH:14]=[CH:15]3)[C@@H:10]([F:19])[CH2:9][C@H:8]1[C@@H:7]1[CH2:20][C@@H:21]3[C@:25]([C:26](=[O:32])[CH2:27][O:28][C:29](=[O:31])[CH3:30])([C@@:6]1([CH3:33])[CH2:5][C@@H:4]2[OH:34])[CH2:24][N:23]([CH2:43][C:44]1[CH:49]=[CH:48][CH:47]=[C:46]([CH3:50])[CH:45]=1)[CH2:22]3
Reactant: Cc1cccc(CCl)c1
Reactant: CC(=O)OCC(=O)[C@@]12CNC[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Agent: Cc1cccc(CBr)c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCC(=O)[C@@]12CN(Cc3cccc(C)c3)C[C@@H]1C[C@H]1[C@@H]3C[C@H](F)C4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]12C
Temperature: 40 °C
Reaction time: 2 h
Yield: 57.3 %

Procedure:
In a nitrogen atmosphere, intermediate 6 (200 mg, 0.400 mmol) was dissolved in DCM (5 ml), triethylamine (166 μL, 1.20 mmol) and 1-(chloromethyl)-3-methylbenzene (79 μL, 0.60 mmol) were added, and the mixture was heated at 40° C. for 2 hours and at RT for 16 hours. Then triethylamine (138 μL, 1.00 mmol) and 3-methylbenzyl bromide (54 μL, 0.40 mmol) were added to the mixture, and stirring was continued for 2 hours. The reaction mixture was partitioned between water and DCM, and the aqueous layer was extracted with DCM (3×15 mL), and the organic phase was collected and concentrated. The crude was purified by silica gel flash chromatography (eluent DCM/MeOH 99:1) to yield the title compound (130 mg, 57.2% yield).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]([C:7]1[S:8][CH:9]=[CH:10][C:11]=1[NH:12][C:13]1[CH:18]=[CH:17][N:16]=[C:15]2[NH:19][CH:20]=[CH:21][C:14]=12)=[O:6].[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CO>[CH3:22][O:23][C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH:1][CH2:2][CH2:3][NH:4][C:5]([C:7]2[S:8][CH:9]=[CH:10][C:11]=2[NH:12][C:13]2[CH:18]=[CH:17][N:16]=[C:15]3[NH:19][CH:20]=[CH:21][C:14]=23)=[O:6])=[CH:26][CH:25]=1
Reactant: COc1ccc(C=O)cc1
Reactant: NCCNC(=O)c1sccc1Nc1ccnc2[nH]ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COc1ccc(CNCCNC(=O)c2sccc2Nc2ccnc3[nH]ccc23)cc1
Temperature: 50 °C
Reaction time: 18 h
Yield: 102.2 %

Procedure:
To a solution of 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid (2-amino-ethyl)-amide (45 mg, 0.13 mmol), 4-methoxy benzaldehyde (16 uL, 0.13 mmol), and glacial acetic acid (8 uL, 0.13 mmol) in methanol (1 mL) was added sodium triacetoxy borohydride (84 mg, 0.4 mmol) portionwise. The solution was stirred at 50° C. for 18 h. The solution was absorbed onto Celite and purified by ISCO Companion (silica 0-10% methanol, methylene chloride, 1% ammonium hydroxide) to afford 3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carboxylic acid [2-(4-methoxy-benzylamino)-ethyl]-amide (56 mg, 75%) LCMS (ESI) 422 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 10.26 (1H, br. s.) 7.98-8.07 (2H, m) 7.77 (1H, d, J=5.47 Hz) 7.46 (1H, d, J=5.47 Hz) 7.30 (1H, d, J=3.32 Hz) 7.19 (2H, d, J=8.59 Hz) 6.76-6.84 (2H, m) 6.43 (1H, d, J=3.51 Hz) 3.69 (3H, s) 3.60 (2H, s) 3.33 (2H, q, J=6.25 Hz) 2.61 (2H, t, J=6.64 Hz)
Reaction SMILES: C([O:4][CH2:5][C:6]([NH:8][C:9]1[C:10]([Cl:32])=[C:11]([C:28]([Cl:31])=[CH:29][CH:30]=1)[C:12]([NH:14][C:15]1[C:23]2[O:22][C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:13])=[O:7])(=O)C.[OH-].[Na+]>ClCCl.CO>[Cl:32][C:10]1[C:9]([NH:8][C:6](=[O:7])[CH2:5][OH:4])=[CH:30][CH:29]=[C:28]([Cl:31])[C:11]=1[C:12]([NH:14][C:15]1[C:23]2[O:22][C:21]3[CH2:24][CH2:25][CH2:26][CH2:27][C:20]=3[C:19]=2[CH:18]=[CH:17][CH:16]=1)=[O:13]
Reactant: CC(=O)OCC(=O)Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: O=C(CO)Nc1ccc(Cl)c(C(=O)Nc2cccc3c4c(oc23)CCCC4)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 49.1 %

Procedure:
A mixture of 6-(3-acetoxyacetylamino-2,6-dichlorobenzoylamino)-1,2,3,4-tetrahydrodibenzofuran (67 mg) and aqueous 1N-sodium hydroxide (0.5 ml) in a mixture of dichloromethane (1 ml) and methanol (1 ml) was stirred at ambient temperature for 1 hour. The mixture was partitioned between a mixture of dichloromethane and ethanol (8:2) and water. The organic layer was separated, washed with brine, dried over sodium sulfate and concentrated in vacuo. The residue was crystallized from ethanol to give 6-(2,6-dichloro-3-hydroxyacetylamino-benzoylamino)-1,2,3,4-tetrahydrodibenzofuran (30 mg).
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[CH:19][CH:18]=[CH:17][C:3]=1[CH2:4][N:5]1[C:9]2[CH:10]=[N:11][C:12]([C:14]([OH:16])=O)=[CH:13][C:8]=2[N:7]=[CH:6]1.[CH2:22]([O:25][NH2:26])[CH:23]=[CH2:24]>>[CH2:22]([O:25][NH:26][C:14]([C:12]1[N:11]=[CH:10][C:9]2[N:5]([CH2:4][C:3]3[CH:17]=[CH:18][CH:19]=[C:20]([F:21])[C:2]=3[F:1])[CH:6]=[N:7][C:8]=2[CH:13]=1)=[O:16])[CH:23]=[CH2:24]
Reactant: C=CCON
Reactant: O=C(O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1
Product: C=CCONC(=O)c1cc2ncn(Cc3cccc(F)c3F)c2cn1

Procedure:
The title compound can be prepared by coupling of 3-(2,3-difluorobenzyl)-3H-imidazo[4,5-c]pyridine-6-carboxylic acid and N-allyloxyamine under the same conditions as those in step (c) of example 1.
Reaction SMILES: C([C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[C@H:18]([O:22][C:23](=[O:28])[C:24]([CH3:27])([CH3:26])[CH3:25])[CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:29][C:30](=[O:35])[C:31]([CH3:34])([CH3:33])[CH3:32])(=O)C.ClC1C=CC=[C:39]([C:43]([O:45]O)=[O:44])C=1.C(=O)(O)[O-].[Na+]>ClCCl>[C:43]([O:45][C:4]1[CH:5]=[CH:6][C:7]2[CH2:8][CH2:9][C@@H:10]3[C@@H:19]([C:20]=2[CH:21]=1)[C@H:18]([O:22][C:23](=[O:28])[C:24]([CH3:26])([CH3:25])[CH3:27])[CH2:17][C@@:15]1([CH3:16])[C@H:11]3[CH2:12][CH2:13][C@@H:14]1[O:29][C:30](=[O:35])[C:31]([CH3:33])([CH3:32])[CH3:34])(=[O:44])[CH3:39]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(=O)c1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(=O)Oc1ccc2c(c1)[C@@H]1[C@@H](CC2)[C@@H]2CC[C@H](OC(=O)C(C)(C)C)[C@@]2(C)C[C@H]1OC(=O)C(C)(C)C
Yield: 31.5 %

Procedure:
A solution of the ketone (27) (40 mg. 0.83 mmol) and m-chloroperbenzoic acid (43 mg, 0.248 mmol) in dichloromethane (1 ml) was stirred for four days at room temperature in the dark. Addition of saturated sodium bicarbonate solution was followed by the usual working up procedure with methylene chloride to give a residue which was chromatographed on silica (2 g). Elution with ether-light petroleum (1:20) gave the product (28) (39 mg, 94%), m.p. 143°-146° C. (from ether-light petroleum), νmax 1720 cm-1 (C=O), δ (250 MHz) 7.10 (1 H, d, J 8 Hz, 4-proton), 6.86 (1 H, dd, J 8 and 2.5 Hz, 3-proton), 6.71 (1 H, d, J 2.5 Hz, 1-proton), 5.35 (1 H, dt, J 10.5 and 5 Hz, 11-proton), 4.65 (1 H, dd, J 8.5 and 7.5 Hz, 17-proton), 2.82 (2 H, t, J 7 Hz, 6-proton), 2.54 (1 H, t, J 10.5 Hz, 9-proton), 2.24 (3 H, s, CH3CO), 1.21 (9 H, s, OBut), 1.19 (9 H, s, OBut), 0.89 (3 H, s, 18-CH3), M+ (ammonia chemical ionization) 516 (M+NH3).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50](Cl)(=[O:52])=[O:51])#[N:43]>C(#N)C>[C:42]([C:44]1[CH:49]=[CH:48][CH:47]=[CH:46][C:45]=1[S:50]([O:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34])(=[O:52])=[O:51])#[N:43]
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(O)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: N#Cc1ccccc1S(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(C)(C)OC(=O)n1c(-c2ccc(OS(=O)(=O)c3ccccc3C#N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 87.8 %

Procedure:
In a similar manner to Step 1 of Example 227, 4-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.115 g, 0.249 mmol) was dissolved in acetonitrile (5.0 mL), and the solution was treated with triethylamine (0.104 mL, 0.747 mmol) and 2-cyanobenzenesulfonyl chloride (0.0750 g, 0.374 mmol) to obtain 4-(2-cyanobenzenesulfonyloxy)-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.137 g, yield 88%).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5](Cl)=[CH:6][CH:7]=1.[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[C:9]([O:13][C:14]([N:16]1[CH:20]=[C:19]([C:5]2[N:4]=[N:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[CH:18]=[N:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Clc1ccc(Cl)nn1
Reactant: CC(C)(C)OC(=O)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)n1cc(-c2ccc(Cl)nn2)cn1
Temperature: 70 °C
Yield: 4631.1 %

Procedure:
A mixture of 3,6-dichloro-pyridazine (1.06 g, 6.98 mmol) and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazole-1-carboxylic acid tert-butyl ester (1.47 g, 5.0 mmol) in 2.0 M potassium carbonate (10 mL, 20 mmol) and 1,4-dioxane (40 mL) was degassed by house vacuum for 15 min followed by bubbling with argon for ˜10 min, Peppsi-ipr (340 mg, 0.5 mmol) was then added. After flushing with argon for another ˜10 min, the mixture was heated at 70° C. for 4 h and allowed to cool to room temperature. The solid was removed by filtration through Celite, and the filtrate was separated. The aqueous solution was extracted with CH2Cl2 and the combined organic phases were dried over Na2SO4, concentrated, and purified by column to provide o.65 g desired product (46%). 1H NMR(DMSO) δ 9.08(s, 1H), 8.47 (s, 1H), 8.31 (d, J=9.0 Hz, 1H), 8.01 (d, J=9.0 Hz, 1H), 1.59 (s, 3H); MS (ES) m/z 280.8 (M+H+).
Reaction SMILES: C(N(CC)CC)C.Cl.[CH3:9][NH:10][O:11][CH3:12].[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16](Cl)=[O:17]>ClCCl>[F:13][C:14]1[CH:22]=[CH:21][CH:20]=[CH:19][C:15]=1[C:16]([N:10]([O:11][CH3:12])[CH3:9])=[O:17]
Reactant: CNOC
Reactant: O=C(Cl)c1ccccc1F
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CON(C)C(=O)c1ccccc1F
Reaction time: 0.17 h
Yield: 674.6 %

Procedure:
Triethylamine (5.32 mL, 37.84 mmol) was added dropwise to a solution of N,O-dimethylhydroxylamine hydrochloride (2.768 g, 28.38 mmol) in anhydrous dichloromethane (45 mL) at 0° C. After stirring for 10 min, 2-fluorobenzoyl chloride (0.303 mL, 2.52 mmol) in anhydrous dichloromethane (15 mL) was added dropwise. The reaction mixture was returned to room temperature and stirred for 5 h. The reaction mixture was quenched with water (60 mL) and the products were extracted with dichloromethane (2×60 mL). The combined organic phases were washed with brine, dried over anhydrous sodium sulfate, and the solvent was removed under reduced pressure. Purification using flash chromatography (silica gel, hexanes:ethyl acetate, gradient 93:7 to 60:40) afforded 2-Fluoro-N-methoxy-N-methyl-benzamide (3.116, 17 mmol) in a 90% yield.
Reaction SMILES: CC([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([CH:10]([CH3:12])[CH3:11])[C:5]=1[CH2:13][C:14]([C:16]1[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:29])(=[O:28])[NH2:27])[C:19]([CH:22]([CH3:24])[CH3:23])=[CH:20][CH:21]=1)=[O:15])C.[CH:33](C1C=CC=C(C(C)C)C=1CC(O)=O)([CH3:35])[CH3:34].C1C2C(C(O)=O)C3C(=CC=CC=3)C=2C=CC=1>>[CH:4]1[C:5]2[CH:13]([C:14]([C:16]3[C:17]([CH:30]([CH3:32])[CH3:31])=[C:18]([O:25][S:26](=[O:28])(=[O:29])[NH2:27])[C:19]([CH:22]([CH3:23])[CH3:24])=[CH:20][CH:21]=3)=[O:15])[C:11]3[C:10](=[CH:12][CH:34]=[CH:33][CH:35]=3)[C:6]=2[CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)c1ccc(C(C)C)c(OS(N)(=O)=O)c1C(C)C
Reactant: CC(C)c1cccc(C(C)C)c1CC(=O)O
Agent: O=C(O)C1c2ccccc2-c2ccccc21
Product: CC(C)c1ccc(C(=O)C2c3ccccc3-c3ccccc32)c(C(C)C)c1OS(N)(=O)=O

Procedure:
This compound was prepared in the same manner as for the title compound of Example 1, except that 2,6-diisopropylphenylacetic acid was replaced with 9-fluorenecarboxylic acid, mp 146°-147° C.
Reaction SMILES: [CH:1]([N:3]1[CH:7]=[N:6][CH:5]=[N:4]1)=[CH2:2].[CH2:8]([O:15][C:16]1[CH:21]=[C:20](I)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(N(CC)CC)C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:8]([O:15][C:16]1[CH:21]=[C:20](/[CH:2]=[CH:1]/[N:3]2[CH:7]=[N:6][CH:5]=[N:4]2)[CH:19]=[CH:18][C:17]=1[N:23]1[S:27](=[O:29])(=[O:28])[NH:26][C:25](=[O:30])[CH2:24]1)[C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1
Reactant: O=C1CN(c2ccc(I)cc2OCc2ccccc2)S(=O)(=O)N1
Reactant: C=Cn1cncn1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Solvent: CCN(CC)CC
Solvent: CC#N
Product: O=C1CN(c2ccc(/C=C/n3cncn3)cc2OCc2ccccc2)S(=O)(=O)N1
Temperature: 110 °C

Procedure:
A mixture of 1-vinyl-1,2,4-triazole (0.100 g, 1.06 mmol), 5-(2-benzyloxy-4-iodophenyl)-1,1-dioxo-1,2,5-thiadiazolidin-3-one (0.236 g, 0.531 mmol), palladium acetate (0.024 g, 0.107 mmol), triethylamine (0.295 mL, 2.09 mmol) in acetonitrile is heated in a microwave apparatus at 110° C. for 30 min. The mixture is filtered over Celite, washed with acetonitrile, and concentrated. The residue is purified by column chromatography using a gradient of 10-60% EtOH/water as eluent to afford the title compound: (M−1)−=410.
Reaction SMILES: Br[C@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4].[C:9]([O-:17])(=[S:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.[Cs+]>CN(C=O)C.CCOCC>[C:9]([S:16][C@@H:2]([CH:6]([CH3:8])[CH3:7])[C:3]([OH:5])=[O:4])(=[O:17])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CC(C)[C@@H](Br)C(=O)O
Reactant: [O-]C(=S)c1ccccc1
Agent: [Cs+]
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CC(C)[C@H](SC(=O)c1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 20 h
Yield: 72.6 %

Procedure:
To a solution of (R)-(+)-2-bromo-3-methylbutyric acid (4.20 g, 23.2 mmol) in DMF (41 mL) was added cesium thiobenzoate (6.08 g, 22.5 mmol). The mixture was stirred at rt for 20 h. The resulting solution was diluted with ether (200 mL) and washed with H2O (4×40 mL). The ethereal layer was dried (Na2SO4), and concentrated. The crude residue was recrystallized from hexanes to afford (S)-2-benzoylthio-3-methylbutanoic acid as a pale yellow solid (3.89 g, 72%); 1H NMR (300 MHz, CDCl3) δ 1.09 (d, J=7.4 Hz, 3H), 1.11 (d, J=7.4 Hz, 3H), 2.40 (m, 1H), 4.37 (d, J=5.9 Hz, 1H), 7.45 (t, J=7.4 Hz, 2H), 7.57 (t, J=7.4 Hz, 1H), 7.97 (d, J=7.4 Hz, 2H), 12.0 (br s, 1H); 13C NMR (75 MHz, CDCl3) δ 19.8, 20.6, 30.5, 53.1, 127.6, 128.8, 133.9, 136.3, 177.9, 190.3; IR (neat) 3100, 2967, 1709, 1669 cm−1; [α]D22=−94.2 (c 1, CH2Cl2).
Reaction SMILES: CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([OH:42])=O)[CH:36]=1.[NH2:43][C@H:44]1[C:52]2[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=2)[CH2:46][CH2:45]1>ClCCl>[CH3:34][C:35]1[O:39][N:38]=[C:37]([C:40]([NH:43][C@H:44]2[C:52]3[C:47](=[CH:48][CH:49]=[C:50]([C:53]([O:55][CH3:56])=[O:54])[CH:51]=3)[CH2:46][CH2:45]2)=[O:42])[CH:36]=1
Reactant: Cc1cc(C(=O)O)no1
Reactant: COC(=O)c1ccc2c(c1)[C@H](N)CC2
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1ccc2c(c1)[C@H](NC(=O)c1cc(C)on1)CC2
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 68 %

Procedure:
HATU (4.4 g, 11.7 mmol, 1.5 eq) and DIPEA (3.0 ml, 15.6 mmol, 2 eq) were added to an ice-cooled solution of 5-methylisoxazole-3-carboxylic acid (990 mg, 7.8 mmol, 1 eq) in dichloromethane (80 ml), and stirring was carried out for 30 min. (R)-Methyl 3-amino-2,3-dihydro-1H-indene-5-carboxylate (A-07) (7.8 mmol, 1 eq) was dissolved in dichloromethane (20 ml) and added dropwise to the reaction solution, and stirring was carried out for 16 h at RT. The reaction solution was diluted with dichloromethane (250 ml), washed with sat. sodium hydrogen carbonate solution (50 ml), sat. ammonium chloride solution (50 ml), water (50 ml) and sat. NaCl solution (50 ml), dried over sodium sulfate and concentrated under reduced pressure. After purification by column chromatography (silica gel, 2% MeOH in dichloro-methane), the desired product was obtained in the form of a yellowish solid. Yield: 68% (1.6 g, 5.3 mmol).
Reaction SMILES: [Na].C(O)C.[C:5]([O:13][CH2:14][CH3:15])(=[O:12])[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].Cl[C:17]1[CH:30]=[CH:29][C:20]([C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)=[O:22])=[CH:19][C:18]=1[N+:31]([O-:33])=[O:32]>C(Cl)Cl>[N+:31]([C:18]1[CH:19]=[C:20]([C:21](=[O:22])[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:29]=[CH:30][C:17]=1[CH:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:5]([O:13][CH2:14][CH3:15])=[O:12])([O-:33])=[O:32]
Reactant: CCOC(=O)CC(=O)OCC
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: [Na]
Solvent: ClCCl
Solvent: CCO
Product: CCOC(=O)C(C(=O)OCC)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of sodium ethoxide, formed by reacting 4.6 g. (0.2 mole) of sodium metal with 200 ml. of ethanol, at 0° C. was added 32 g. (0.2 mole) of diethyl malonate followed by 26.1 g. (0.1 mole) of 4-chloro-3-nitrobenzophenone. The mixture was allowed to stir at room temperature for 2 hours and was then poured into 400 ml. of ice cold 2N hydrochloric acid and 300 ml. of methylene chloride. The organic layer was separated, dried over magnesium sulfate and concentrated to an oil. The residual oil was induced to crystallize by trituration with hexane containing trace amounts of diisopropyl ether, 34.75 g., m.p. 68°-70° C. The sample was further purified by trituration with hot hexanediisopropyl ether, 30.84 g. (80% yield).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17](N)=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10].[OH-:26].[Na+]>C1COCC1.CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:21][CH2:22][C:23]([CH3:25])=[CH2:24])=[C:6]([CH:20]=1)[CH2:7][N:8]([C:11]1[N:16]=[N:15][C:14]([C:17]([OH:26])=[O:18])=[CH:13][CH:12]=1)[CH2:9][CH3:10]
Reactant: [OH-]
Reactant: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(N)=O)nn1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: C=C(C)COc1ccc(Br)cc1CN(CC)c1ccc(C(=O)O)nn1
Reaction time: 16 h
Yield: 87 %

Procedure:
6-[N-(5-Bromo-2-(2-methylprop-2-en-1-yloxy)benzyl)-N-ethylamino]pyridazine-3-carboxamide (430 mg, 1.09 mmol) was dissolved in THF/methanol (30 ml, 1:1) and sodium hydroxide solution added (2.9 ml, 2M, 5.8 mmol). The mixture was heated at reflux for 72 hours, allowed to cool and evaporated. The residue was dissolved in water (25 ml) and acetic acid added to pH-4. The solution was stirred for 16 hours and then the resulting colourless precipitate collected by filtration, washed with water and dried under vacuum to give the title compound as a colourless powder (387 mg, 87%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]([NH:15][C:16](=[O:22])[O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:13][OH:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O.[C:27]1(C)[CH:32]=CC(S(O)(=O)=O)=C[CH:28]=1.COC(C)=C.C(=O)([O-])O.[Na+]>ClCCl>[CH2:1]([O:8][CH2:9][CH:10]([CH:23]([CH3:25])[CH3:24])[CH2:11][CH:12]1[CH2:13][O:14][C:27]([CH3:32])([CH3:28])[N:15]1[C:16]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:22])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)C(COCc1ccccc1)CC(CO)NC(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Agent: C=C(C)OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: CC(C)C(COCc1ccccc1)CC1COC(C)(C)N1C(=O)OC(C)(C)C
Reaction time: 22 h

Procedure:
A solution of 14.70 g of tert-butyl (3-benzyloxymethyl-1-hydroxymethyl-4-methylpentyl)carbamate and 0.24 g of p-toluenesulphonic acid monohydrate in 82 ml of dichloromethane at 0° C. is admixed with 8.2 ml of 2-methoxypropene. After 22 hours at room temperature, the mixture is poured onto 1M aqueous sodium hydrogencarbonate solution and extracted with tert-butyl methyl ether (2×)—the combined organic phases are washed with brine, dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as an orange oil from the residue by means of flash chromatography (SiO2 60F). Rt=6.30 (gradient I).
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][CH:5]=[CH:4][C:3]=1[C:12](=[O:21])[CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[N:22]([O-])=O.[Na+].O>CC(O)=O.OS(O)(=O)=O>[CH2:14]([C:13]1[N:22]=[N:1][C:2]2[C:3]([C:12]=1[OH:21])=[CH:4][CH:5]=[CH:6][C:7]=2[C:8]([F:9])([F:10])[F:11])[C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1
Reactant: O=N[O-]
Reactant: Nc1c(C(=O)CCc2ccccc2)cccc1C(F)(F)F
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: Oc1c(Cc2ccccc2)nnc2c(C(F)(F)F)cccc12
Temperature: 70 °C
Reaction time: 1.5 h

Procedure:
To a solution of 1-(2-amino-3-trifluoromethyl-phenyl)-3-phenyl-propan-1-one (4.2 g, 13.8 mmol) in AcOH (70 ml) and H2SO4 (10 ml) was added a solution of NaNO2 (1.8 g in 10 ml H2O). The reaction was then heated to 70° C. After 1.5 hr, the reaction was cooled, poured into water and extracted with EtOAc. The organic layer was dried (MgSO4) and concentrated to give 3-benzyl-8-trifluoromethyl-cinnolin-4-ol