Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-:1].[K+].CC(C[C:16]1[CH:25]=[CH:24][C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[CH:17]=1)(C(OCC)=O)C(OCC)=O.Cl.[OH2:27]>C(O)C.C(OCC)(=O)C>[CH3:17][CH:18]([CH2:23][C:19]1[C:18]2[C:23](=[CH:24][CH:25]=[CH:16][CH:17]=2)[CH:22]=[CH:21][CH:20]=1)[C:19]([OH:27])=[O:1]
Reactant: O
Reactant: [OH-]
Reactant: CCOC(=O)C(C)(Cc1ccc2ccccc2c1)C(=O)OCC
Agent: Cl
Agent: [K+]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(Cc1cccc2ccccc12)C(=O)O
Temperature: 175 °C
Yield: 94 %

Procedure:
A solution of 23.7 g (422 mmol) of potassium hydroxide in 50 ml of water was added to 33.2 g (105 mmol) of the compound 1 in 70 ml of ethanol, and the mixture was heated under reflux for 4 hours. After the solvent had been stripped off, the solid residue was taken up in ethyl acetate, water was added and the pH was brought to 1 with hydrochloric acid. The aqueous phase was extracted several times with ethyl acetate. After drying over magnesium sulfate, the combined organic phases were evaporated completely. The residue was stirred with hexane for crystallization. For decarboxylation, the beige-colored solid was heated at 175° C. until the evolution of gas had ended. 21 g (94%) of the product 2 were obtained as a beige-colored solid.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH:3]1[CH2:8][CH2:9][C:10]#[N:11].C(C1CCCC([Cl:22])C1=O)(C)(C)C>>[Cl:22][CH:7]1[CH2:6][CH2:5][CH2:4][CH:3]([CH2:8][CH2:9][C:10]#[N:11])[C:2]1=[O:1]
Reactant: CC(C)(C)C1CCCC(Cl)C1=O
Reactant: N#CCCC1CCCCC1=O
Product: N#CCCC1CCCC(Cl)C1=O

Procedure:
The chlorination of 2-oxo-1-cyclohexanepropionitrile takes place in a manner similar to that described above for the preparation of 2-tert-butyl-6-chloro-cyclohexanone. The title compound is reacted as a crude product without further characterization.
Reaction SMILES: FC(F)(F)C(O)=O.ClC1C2C(=CC(S(N[C@H](C(O)=O)CCC(=O)N)(=O)=O)=CC=2)C(NC(N)=N)=[N:11]C=1.Cl.[NH2:37][C:38]([NH2:40])=[NH:39].[C:41]([O:45][C:46](=[O:69])[C@H:47]([CH2:64][CH2:65][C:66](=[O:68])[NH2:67])[NH:48][S:49]([C:52]1[CH:61]=[C:60]2[C:55]([C:56]([Cl:63])=[CH:57][N:58]=[C:59]2Cl)=[CH:54][CH:53]=1)(=[O:51])=[O:50])([CH3:44])([CH3:43])[CH3:42].O>CS(C)=O>[NH3:11].[C:41]([O:45][C:46](=[O:69])[C@H:47]([CH2:64][CH2:65][C:66](=[O:68])[NH2:67])[NH:48][S:49]([C:52]1[CH:61]=[C:60]2[C:55]([C:56]([Cl:63])=[CH:57][N:58]=[C:59]2[NH:39][C:38]([NH2:40])=[NH:37])=[CH:54][CH:53]=1)(=[O:50])=[O:51])([CH3:44])([CH3:42])[CH3:43]
Reactant: N=C(N)N
Reactant: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)N[C@@H](CCC(N)=O)C(=O)O)cc12
Reactant: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NS(=O)(=O)c1ccc2c(Cl)cnc(Cl)c2c1
Agent: Cl
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: CC(C)(C)OC(=O)[C@H](CCC(N)=O)NS(=O)(=O)c1ccc2c(Cl)cnc(NC(=N)N)c2c1
Product: N
Temperature: 50 °C
Reaction time: 1 h
Yield: 18.8 %

Procedure:
N-[(4-Chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine trifluoroacetate ##STR79## NaH (25 mg, 80% dispersion in mineral oil, 0.83 mmol) was added to a solution of guanidine hydrochloride (128 mg, 1.34 mmol) in DMSO (2 ml) and stirred at 50° C. for 1 h. N-[(1,4-Dichloro-7-isoquinolinyl)sulphonyl]-L-glutamine tert-butyl ester (150 mg, 0.32 mmol) was added and the resultant solution stirred at 100° C. for 6 h, allowed to cool and then poured into water. The aqueous mixture was extracted with EtOAc (3×30 ml) and concentrated in vacuo. The residue was purified by column chromatography upon silica gel using CH2Cl2 -MeOH-0.880 NH3 (90:10:1) as eluant to give N-[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]-L-glutamine tert-butyl ester (30 mg, 0.06 mmol) as a buff-coloured powder.
Reaction SMILES: FC(F)(F)S(O[C:7]1[C:11]2[C:12]([O:16][CH3:17])=[N:13][CH:14]=[CH:15][C:10]=2[N:9]([CH:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)[N:8]=1)(=O)=O.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=2)O1.C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.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>[CH:18]1([N:9]2[C:10]3[CH:15]=[CH:14][N:13]=[C:12]([O:16][CH3:17])[C:11]=3[C:7]([C:33]3[CH:34]=[C:35]([S:39]([NH2:42])(=[O:41])=[O:40])[CH:36]=[CH:37][CH:38]=3)=[N:8]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COc1nccc2c1c(OS(=O)(=O)C(F)(F)F)nn2C1CCCC1
Reactant: CC1(C)OB(c2cccc(S(N)(=O)=O)c2)OC1(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: COc1nccc2c1c(-c1cccc(S(N)(=O)=O)c1)nn2C1CCCC1
Yield: 43.8 %

Procedure:
A solution of 1-cyclopentyl-4-methoxy-1H-pyrazolo[4,3-c]pyridin-3-yl trifluoromethanesulfonate (80.0 mg) obtained in Step C of Example 12, 3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzenesulfonamide (93.0 mg), tetrakis(triphenylphosphine)palladium(0) (25.3 mg) and 2M aqueous sodium carbonate solution (0.550 mL) in DME (10 mL) was heated overnight with reflux under nitrogen atmosphere. To the reaction mixture was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed successively with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (35.7 mg).
Reaction SMILES: O[CH2:2][C@@H:3](N)[CH2:4][CH:5]([CH3:7])[CH3:6].COC(=O)[C@H](CC(C)C)N.OCCN.CC(C)C[C@H](NCC(C)C)CO.[Cl-].[CH2:36]([NH3+:40])[CH:37]([CH3:39])[CH3:38].[N+:41]([C:44]1[CH:49]=[CH:48][C:47]([N:50]=[C:51]=[S:52])=[CH:46][CH:45]=1)([O-:43])=[O:42]>>[N+:41]([C:44]1[CH:45]=[CH:46][C:47]([N:50]=[C:51]2[N:40]([CH2:36][CH:37]([CH3:39])[CH3:38])[CH2:2][CH:3]([CH2:4][CH:5]([CH3:7])[CH3:6])[S:52]2)=[CH:48][CH:49]=1)([O-:43])=[O:42]
Reactant: CC(C)C[NH3+]
Reactant: O=[N+]([O-])c1ccc(N=C=S)cc1
Reactant: CC(C)C[C@H](N)CO
Agent: CC(C)CN[C@H](CO)CC(C)C
Agent: COC(=O)[C@@H](N)CC(C)C
Agent: [Cl-]
Solvent: NCCO
Product: CC(C)CC1CN(CC(C)C)C(=Nc2ccc([N+](=O)[O-])cc2)S1

Procedure:
(1S)-1-(Hydroxymethyl)-3-methylbutylamine was made from (L)-leucine methyl ester as described in Method B1b. The 2-hydroxyethylamine was converted to (2S)-4-methyl-2-(isobutylamino)pentanol as described in Method B4c, Steps 1-2. The alcohol was converted to N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride as described in Method B7c. 4-Nitrophenyl isothiocyanate was reacted with N-(1S)-1-(chloromethyl)-3-methylbutyl)-N-(isobutyl)ammonium chloride according to Method C1f to give 2-(4-nitrophenylimino)-3,5-diisobutyl-1,3-thiazolidine.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1OS(C(F)(F)F)(=O)=O)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2].[C:28]1([C:34]2[CH:39]=[CH:38][C:37](B(O)O)=[CH:36][CH:35]=2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.C(OCC)(=O)C.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>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[N:8][C:9]2[C:14]([C:15]=1[C:37]1[CH:38]=[CH:39][C:34]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[CH:35][CH:36]=1)=[CH:13][CH:12]=[C:11]([C:24]([F:27])([F:26])[F:25])[CH:10]=2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1OS(=O)(=O)C(F)(F)F
Reactant: OB(O)c1ccc(-c2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1cnc2cc(C(F)(F)F)ccc2c1-c1ccc(-c2ccccc2)cc1

Procedure:
4-Trifluoromethanesulfonyloxy-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester (208 mg, 0.5 mmol), 4-phenylphenylboronic acid (109 mg, 0.55 mmol), tetrakis(triphenylphosphine)palladium(0) (29 mg) and potassium phosphate (159 mg, 0.75 mmol) were heated together in dioxane (5 mL) to 80° C. overnight. The reaction mixture was then diluted with ethyl acetate and washed with brine twice. The organic layer was dried over sodium sulfate, concentrated, and the residue purified by flash column eluted with 30% ethyl acetate in hexane to yield 4-biphenyl-4-yl-7-trifluoromethyl-quinoline-3-carboxylic acid ethyl ester as a white solid.
Reaction SMILES: C(OC(=O)COC1C=CC(Cl)=CC=1C#C)(C)(C)C.C[Si](C)(C)[C:21]#[C:22][C:23]1[CH:28]=[C:27]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:31])=[O:30])[CH:26]=[CH:25][C:24]=1[CH3:35]>>[C:22]([C:23]1[CH:28]=[C:27]([S:29]([CH2:32][CH2:33][CH3:34])(=[O:30])=[O:31])[CH:26]=[CH:25][C:24]=1[CH3:35])#[CH:21]
Reactant: CCCS(=O)(=O)c1ccc(C)c(C#C[Si](C)(C)C)c1
Agent: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Product: C#Cc1cc(S(=O)(=O)CCC)ccc1C

Procedure:
Following the general method as outlined in Intermediate 3, starting from 2-trimethylsilylethynyl-1-methyl-4-(propylsulfonyl)benzene (Intermediate 39), the title compound was obtained as a brown liquid after purification by column chromatography (silica) eluting with petroleum ether and ethyl acetate.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[NH2:12][C:13]1[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])=[CH:15][C:14]=1[CH3:28].[C:29]([C:31]1[CH:41]=[CH:40][C:34]([C:35]([N:37]=[C:38]=[O:39])=[O:36])=[CH:33][CH:32]=1)#[N:30].C(N(C(C)C)CC)(C)C>C(#N)C>[C:29]([C:31]1[CH:32]=[CH:33][C:34]([C:35]([NH:37][C:38](=[O:39])[NH:12][C:13]2[CH:27]=[CH:26][C:16]([O:17][CH2:18][C:19]([O:21][C:22]([CH3:24])([CH3:25])[CH3:23])=[O:20])=[CH:15][C:14]=2[CH3:28])=[O:36])=[CH:40][CH:41]=1)#[N:30]
Reactant: Cc1cc(OCC(=O)OC(C)(C)C)ccc1N
Reactant: N#Cc1ccc(C(=O)N=C=O)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: Cc1cc(OCC(=O)OC(C)(C)C)ccc1NC(=O)NC(=O)c1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 21.1 %

Procedure:
In a similar manner to Example 1, starting material step (a), the product of step (b) (2.9 g), 4-cyanobenzoyl isocyanate (1.23 g), diisopropylethylamine (1.23 ml) and acetonitrile (125 ml total) were reacted to give, after stirring at ambient temperature overnight, a solid, which was crystallised from acetonitrile/ether to give t-butyl 4-[3-(4-cyanobenzoyl)ureido]-3-methylphenoxyacetate (611 mg) as an off-white solid: NMR Spectrum (DMSO-d6) 1.44 (9H, s), 2.27 (3H, s), 4.61 (2H, s), 6.73 (1H, dd), 6.81 (1H, d), 7.72 (1H, d), 8.00 (2H, d), 8.13 (2H, d), 10.41 (1H, s), 11.23 (1H, s); Mass Spectrum m/Z 432 (M+Na)+.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([O:14]C)=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17].[Br-].[Li+].C(N(CC)CC)C>C(#N)C.O>[F:1][C:2]1[CH:3]=[C:4]([CH:20]=[C:21]([C:23]([F:26])([F:24])[F:25])[CH:22]=1)[CH2:5][CH:6]1[CH2:11][CH:10]([C:12]([OH:14])=[O:13])[CH2:9][CH2:8][N:7]1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)C1CCN(C(=O)OC)C(Cc2cc(F)cc(C(F)(F)F)c2)C1
Agent: [Br-]
Agent: [Li+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)N1CCC(C(=O)O)CC1Cc1cc(F)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 96.3 %

Procedure:
To a solution of dimethyl 2-(3-fluoro-5-(trifluoromethyl)benzyl)piperidine-1,4-dicarboxylate (4.94 g, 13.09 mmol) in acetonitrile (60 mL) and water (1.2 mL) was added lithium bromide (9.10 g, 104.74 mmol) and triethylamine (7.26 mL, 52.37 mmol). The resulting mixture was heated under reflux for 2 h, then cooled to room temperature. Water was added and acetonitrile removed by evaporation. The aqueous layer was further diluted with water, then washed with MTBE. The organic layer was extracted with water. The combined aqueous layers were acidified with 3.8 M HCl, a colorless precipitate formed. The aqueous layer was extracted with DCM three times. The combined organic layers were dried over MgSO4 and evaporated. 2-(3-Fluoro-5-(trifluoromethyl)benzyl)-1-(methoxycarbonyl)piperidine-4-carboxylic acid (4.58 g, 96%) was isolated as a pale yellow viscous oil. MS m/z 364 (M+H)+
Reaction SMILES: [C:1]([C:3]1[CH:14]=[CH:13][C:6]2[CH:7]=[C:8]([C:10]([OH:12])=O)[O:9][C:5]=2[CH:4]=1)#[N:2].Cl.[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1)(=[O:29])=[O:28])[CH:21]=[CH:20]2>>[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[CH:25][CH:26]=1)[CH:23]=[C:22]([S:27]([N:30]1[CH2:31][CH2:32][N:33]([C:10]([C:8]3[O:9][C:5]4[CH:4]=[C:3]([C:1]#[N:2])[CH:14]=[CH:13][C:6]=4[CH:7]=3)=[O:12])[CH2:34][CH2:35]1)(=[O:28])=[O:29])[CH:21]=[CH:20]2
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Reactant: N#Cc1ccc2cc(C(=O)O)oc2c1
Agent: Cl
Product: N#Cc1ccc2cc(C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)oc2c1

Procedure:
In the same manner as in Referential Example 319, a reaction was effected using 6-cyanobenzofuran-2-carboxylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as starting materials, whereby the title compound was obtained.
Reaction SMILES: [ClH:1].[C:2]([NH:10][CH2:11][C:12]([OH:14])=O)(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.P(Cl)(Cl)(Cl)(Cl)[Cl:16]>C(Cl)Cl>[ClH:16].[C:2]([NH:10][CH2:11][C:12]([Cl:1])=[O:14])(=[NH:9])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: N=C(NCC(=O)O)c1ccccc1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Agent: Cl
Solvent: ClCCl
Product: N=C(NCC(=O)Cl)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To benzimidoylaminoacetic acid hydrochloride (2.2 g., 10 m moles) in 40 ml. of dry methylene chloride is added 2.5 g. (12 m moles) of phosphorous pentachloride, and the reaction mixture allowed to stir overnight at room temperature. The product is filtered, washed successively with methylene chloride (50 ml.), chloroform 2 × 75 ml.) and hexane (50 ml.) and dried in vacuo, 2.5 g. (99% yield).
Reaction SMILES: [H-].[Na+].Br.Cl[C:5]1[CH:6]=[CH:7][C:8]2[N:9]([C:11]([NH2:14])=[N:12][N:13]=2)[N:10]=1.O.[CH:16]1([OH:20])[CH2:19][CH2:18][CH2:17]1>>[CH:16]1([O:20][C:5]2[CH:6]=[CH:7][C:8]3[N:9]([C:11]([NH2:14])=[N:12][N:13]=3)[N:10]=2)[CH2:19][CH2:18][CH2:17]1
Reactant: OC1CCC1
Reactant: Nc1nnc2ccc(Cl)nn12
Agent: Br
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: Nc1nnc2ccc(OC3CCC3)nn12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Cyclobutanol (2.43 ml) was initially charged at RT with stirring and cooled almost to 0° C. with an ice bath. Subsequently, the mixture was admixed with portions of sodium hydride (146 mg). The suspension formed was heated to 55° C. for 30 min and admixed with portions of 6-chloro-[1,2,4]triazolo[4,3-b]pyridazin-3-ylamine hydrobromide (W2.001, 200 mg), suspended in cyclobutanol (5 ml). After stirring at 55° C. for 1.5 h, the mixture was left to stand at RT overnight and then admixed with water and extracted three times with dichloromethane. The combined organic phases were dried over sodium sulfate and, after the desiccant had been filtered off, dried under reduced pressure. 136 mg of the title compound were obtained in solid form.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:10][CH2:9][CH2:8]C(C#N)(O[Si](C)(C)C)[C:6]=2[CH:18]=1.[C:20]([OH:23])(=[O:22])[CH3:21]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([Cl:19])[C:5]2[O:10][CH2:9][CH2:8][CH:21]([C:20]([OH:23])=[O:22])[C:6]=2[CH:18]=1
Reactant: C[Si](C)(C)OC1(C#N)CCOc2c(Cl)cc(Cl)cc21
Reactant: CC(=O)O
Product: Cl
Product: O=C(O)C1CCOc2c(Cl)cc(Cl)cc21

Procedure:
Following the procedure of Example 2, 6,8-dichloro-4-cyano-4-trimethylsilyloxy-3,4-dihydro-2H-1-benzopyran (3.0 g.) and stannous chloride dihydrate (15.0 g.) were reacted in glacial acetic acid (25 ml.) and concentrated hydrochloric acid (25 ml.) to form 6,8-dichloro-3,4-dihydro-2H-1-benzopyran-4-carboxylic acid. Recrystallization from cyclohexane yielded 1.33 g. of product, m.p. 124.5°-126° C.
Reaction SMILES: Cl[CH:2]([C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[C:3]([NH:5][O:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:4].[O:21]1[CH:25]=[CH:24][CH:23]=[CH:22]1.[CH3:26]COC(C)=O>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C@@H:2]2[C@@H:26]3[C:25](=[O:21])[C@H:24]([CH:23]=[CH:22]3)[N:5]([O:6][CH2:7][C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:3]2=[O:4])=[CH:15][CH:16]=1
Reactant: c1ccoc1
Reactant: O=C(NOCc1ccccc1)C(Cl)c1ccc(Cl)cc1
Reactant: CCOC(C)=O
Product: O=C1[C@@H]2C=C[C@@H]1N(OCc1ccccc1)C(=O)[C@@H]2c1ccc(Cl)cc1
Yield: 53 %

Procedure:
Prepared in 53% yield (54.4 mg, 0.16 mmol) from the reaction of 2-choro-2-(4-chlorophenyl)-N-(phenylmethoxy)acetamide (95.5 mg, 0.31 mmol) with furan via general procedure B. Rf=0.48 (3:1, hexanes:EtOAc); 1H-NMR (500 MHz, CDCl3): δ 7.50-7.44 (m, 2H), 7.44-7.34 (m, 3H), 7.28 (ABd, J=8.5 Hz, 2H), 7.05 (ABd, J=8.5 Hz, 2H), 6.55 (dd, J=6.0, 1.1 Hz, 1H), 6.19 (dd, J=6.0, 1.7 Hz, 1H), 5.36 (d, J=1.3 Hz, 1H), 5.05 (d, J=11.0 Hz, 1H), 4.96 (d, J=11.0 Hz, 1H), 4.94 (dd, J=5.3, 1.8 Hz, 1H), and 4.38 (d, J=5.3 Hz, 1H); 13C-NMR (126 MHz, CDCl3): δ 169.7, 136.0, 136.0, 135.6, 133.8, 133.8, 132.0, 131.1, 129.83, 129.1, 128.8, 128.7, 91.8, 91.8, 83.1, 83.1, 78.3, and 56.5; IR (film) 3089, 3064, 3031, 2924, 1688, 1492, 1454, 1368, 1275, 1260, 1211, 1091, 1059, 1017 cm-1. HR-ESIMS: calculated for C19H17ClNO3 (M+H)+ 342.0891, observed 342.0886.
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[C:5]([CH3:7])[CH:4]=[C:3]([CH3:8])[CH:2]=1.C(O[O:15][C:16]([CH3:19])(C)C)(C)(C)C.[C]=O.[CH2:22]([OH:24])C>>[CH3:9][C:1]1[CH:6]=[C:5]([CH2:7][C:22]([O:15][CH2:16][CH3:19])=[O:24])[CH:4]=[C:3]([CH3:8])[CH:2]=1
Reactant: CCO
Reactant: CC(C)(C)OOC(C)(C)C
Reactant: Cc1cc(C)cc(C)c1
Agent: [C]=O
Product: CCOC(=O)Cc1cc(C)cc(C)c1
Temperature: 120 °C
Reaction time: 16 h
Yield: 88.6 %

Procedure:
Mesitylene (1.8 g), ethanol (46 mg), di-tert-butyl peroxide (73 mg, 1 equivalent), and Pd(Xantphos)Cl2 (3.8 mg, 1 mol %) were added into a reaction kettle, into which 10 atm carbon monoxide was introduced. The reaction was heated to 120° C., and stirred at this constant temperature for 16 h. After the reaction was completed, carbon monoxide was discharged, and 85 mg ethyl 3,5-dimethylphenylacetate was obtained by column chromatography, in a yield of 89%. 1HNMR (400 MHz, CDCl3) δ 1.24 (t, J=7.2 Hz, 3H), 2.30 (s, 6H), 3.53 (s, 2H), 4.12 (q, J=7.2 Hz, 2H), 6.84-6.95 (m, 3H); 13CNMR (100 MHz, CDCl3) δ 14.2, 21.3, 41.3, 60.8, 127.0, 128.7, 133.9, 138.1, 171.9; HRMS (ESI) calcd. for C12H16NaO2 [M+Na]: 215.1043. found: 215.1040. The ethyl 3,5-dimethylphenylacetate obtained was dissolved in 1,4-dioxane. 6 N sodium hydroxide solution was added, and the reaction was heated to 60° C. After 2 h of reaction, the pH value was adjusted to 1 by adding 2 N hydrochloric acid. After removing the organic solvent under reduced pressure, 70 mg product 3,5-dimethylphenylacetic acid was obtained by extraction with ethyl acetate, and the yield of hydrolysis was 96%.
Reaction SMILES: [Br:1][CH:2]1[CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[CH:7][C:8]=2[C:11]2[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=2)[C:3]1=[O:21].[CH3:22][NH:23][C:24]([NH:26][CH3:27])=[S:25]>CC(C)=O>[BrH:1].[CH3:27][N:26]1[C:3]2([OH:21])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)[C:9]=3[CH2:10][CH:2]2[S:25][C:24]1=[N:23][CH3:22].[CH3:27][N:26]1[C:3]2([OH:21])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]([C:11]4[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][CH:12]=4)[C:9]=3[CH2:10][CH:2]2[S:25][C:24]1=[N:23][CH3:22]
Reactant: O=C1c2cccc(-c3ccc(C(F)(F)F)cc3)c2CC1Br
Reactant: CNC(=S)NC
Solvent: CC(C)=O
Product: Br
Product: CN=C1SC2Cc3c(-c4ccc(C(F)(F)F)cc4)cccc3C2(O)N1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
426 mg (1.2 mmol) of 2-bromo-4-(4-trifluoromethylphenyl)-1-indanone and 130.2 mg (1.25 mmol) of N, N′-dimethylthiourea are dissolved in 10 ml of acetone and stirred at room temperature for 4 h. The precipitate is filtered off with suction, washed with acetone and dried in vacuo. The hydrobrornide of 3-methyl-2-methylimino-7-(4-trifluoromethylphenyl)-2,3,8,8a-tetrahydroindeno[1,2-d]thiazol-3a-ol is obtained with a melting point of 202-204° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:46]=[CH:45][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13](B4OC(C)(C)C(C)(C)O4)=[CH:14][CH:15]=3)[C:10]([C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[CH:30]=3)=[N:9]2)=[CH:5][CH:4]=1.[OH:47]O>CCOC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([OH:47])=[CH:14][CH:15]=3)[C:10]([C:26]3[N:27]=[N:28][N:29]([C:31]4[CH:36]=[CH:35][C:34]([C:37]([N:39]5[CH2:44][CH2:43][O:42][CH2:41][CH2:40]5)=[O:38])=[CH:33][CH:32]=4)[CH:30]=3)=[N:9]2)=[CH:45][CH:46]=1
Reactant: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(B4OC(C)(C)C(C)(C)O4)ccc32)cc1
Reactant: OO
Solvent: CCOC(C)=O
Product: COc1ccc(Cn2nc(-c3cn(-c4ccc(C(=O)N5CCOCC5)cc4)nn3)c3cc(O)ccc32)cc1
Yield: 67.8 %

Procedure:
A solution of 1-(4-methoxybenzyl)-3-{1-[4-(morpholin-4-ylcarbonyl)phenyl]-1H-1,2,3-triazol-4-yl}-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-indazole (239 mg; 0.39 mmol; 1.0 eq.) and hydrogen peroxide (52 mg, 1.54 mmol, 4 eq.) in EtOAc (4.8 mL) was stirred O/N at RT. Solvent was removed under reduced pressure and the crude was purified by preparative HPLC to give the title compound as a white powder (135 mg, 69%). UPLC/MS: (MS+) 511.1.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][C:27](O)=[O:28])[CH:5]=[N:6][C:7]=1[NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15](=[O:24])[NH:16][C:17]2[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=2)[CH2:11][CH2:10]1.[O:30]1[CH2:35][CH2:34][CH2:33][CH2:32][CH:31]1[O:36][NH2:37].CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.CCOC(C)=O.O>[Cl:1][C:2]1[C:7]([NH:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([NH:16][C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)=[O:24])[CH2:11][CH2:10]2)=[N:6][CH:5]=[C:4](/[CH:25]=[CH:26]/[C:27](=[O:28])[NH:37][O:36][CH:31]2[CH2:32][CH2:33][CH2:34][CH2:35][O:30]2)[CH:3]=1
Reactant: O=C(O)C=Cc1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1
Reactant: NOC1CCCCO1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=C(/C=C/c1cnc(NC2CCN(C(=O)Nc3ccc(Cl)cc3)CC2)c(Cl)c1)NOC1CCCCO1
Temperature: 23 °C
Reaction time: 8 h
Yield: 81.1 %

Procedure:
To a suspension of crude 3-{5-Chloro-6-[1-(4-chlorophenylcarbamoyl)-piperidin-4-ylamino]-pyridin-3-yl}-acrylic acid (247 mg) in DMF (3 ml) was added O-(tetrahydro-2H-pyran-2-yl)hydroxylamine (73.1 mg), EDCI (96.9 mg), HOBt (84.3 mg,), the mixture was stirred at 23° C. for 8 hours. The mixed solution was poured into a mixture of water (20 ml) and AcOEt (20 ml). The organic layer was separated, washed with water twice and brine, dried over sodium sulfate and concentrated in vacuo. The residue was purified by silica gel column chromatography eluted with 5% MeOH in dichloromethane to give 4-[(3-chloro-5-{(1E)-3-oxo-3-[(tetrahydro-2H-pyran-2-yloxy)amino]-1-propen-1-yl}-2-pyridyl)amino]-N-(4-chlorophenyl)-1-piperidinecarboxamide (246 mg).