Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:14][CH2:15][CH3:16])[CH2:5][C:6]1([C:12]#[N:13])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1)[CH3:2].[Na].O>C(O)C>[NH2:13][CH2:12][C:6]1([CH2:5][CH:4]([O:3][CH2:1][CH3:2])[O:14][CH2:15][CH3:16])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(CC1(C#N)CCCCC1)OCC
Agent: [Na]
Solvent: O
Solvent: CCO
Product: CCOC(CC1(CN)CCCCC1)OCC

Procedure:
90 g of di-(ethyloxy)ethyl-cyclohexane-carbonitrile are dissolved in 1 l of ethanol, and 60 g of sodium are added. After dissolution of the metal, 100 ml of water are added, and the solvent is substantially removed in vacuo. 300 ml of water are added to the residue, and it is extracted three times with 200 ml of ether. The ethereal phase is dried over sodium sulfate, concentrated, and distilled in vacuo.
Reaction SMILES: [F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16](Cl)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1.CCN(C(C)C)C(C)C.Cl.Cl.[N:36]1([CH:41]2[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:40][CH2:39][CH2:38][CH2:37]1>>[F:1][C:2]1([F:24])[CH2:7][CH2:6][CH2:5][CH:4]([CH2:8][NH:9][C:10]([C:12]2[C:13]3[CH:14]=[CH:15][C:16]([N:43]4[CH2:44][CH2:45][CH:41]([N:36]5[CH2:40][CH2:39][CH2:38][CH2:37]5)[CH2:42]4)=[N:17][C:18]=3[CH:19]=[CH:20][C:21]=2[Cl:22])=[O:11])[CH2:3]1
Reactant: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(Cl)ccc12
Reactant: C1CCN(C2CCNC2)C1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC1CCCC(F)(F)C1)c1c(Cl)ccc2nc(N3CCC(N4CCCC4)C3)ccc12

Procedure:
The title compound was synthesized according to the procedure described in example 1 using 2,6-dichloro-quinoline-5-carboxylic acid (3,3-difluoro-cyclohexylmethyl)-amide, DIPEA and 3-pyrrolidinyl-pyrrolidine dihydrochloride. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.75 (1H), 7.48 (2H), 6.69 (1H), 3.89 (m, 1H), 3.70 (m, 1H), 3.45 (m, 1H), 3.26 (m, 2H), 2.85 (m, 1H), 2.54 (m, 4H), 2.15 (m, 1H), 2.06 (m, 2H), 1.85 (m, 3H), 1.74-1.76 (m, 5H), 1.27-1.32 (m, 2H). m/z: 478 [M+H]
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[OH:5][CH2:6][CH2:7][NH:8][N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1C=CC=CC=1>C(OCC)(=O)C>[C:1]([N:8]([CH2:7][CH2:6][OH:5])[N:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Cl
Reactant: OCCNN=Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)N(CCO)N=Cc1ccccc1

Procedure:
0.78 g (10-2 moles) of acetyl chloride is added dropwise to a solution containing 10-2 moles of benzaldehyde (2-hydroxyethyl)hydrazone and 0.79 g (10-2 moles) of anhydrous pyridine in 20 ml of anhydrous ethyl acetate, with stirring in the cold.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18])([O-])=O.FC(F)(F)C(O)=O.[H][H]>[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13](=[O:16])[NH:14][N:15]=2)=[CH:6][C:5]=1[C:17]([F:20])([F:19])[F:18]
Reactant: [H][H]
Reactant: O=c1ccc(-c2ccc([N+](=O)[O-])c(C(F)(F)F)c2)n[nH]1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Product: Nc1ccc(-c2ccc(=O)[nH]n2)cc1C(F)(F)F

Procedure:
A mixture 10 g. of 6-[4-nitro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone in 50 ml. of trifluoroacetic acid is reduced with hydrogen and palladium on carbon to give 6-[4-amino-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone. The preceding compound is converted to 6-[4-fluoro-3-(trifluoromethyl)phenyl]-3(2H)-pyridazinone by the procedure described in J. Org. Chem., 26, 468 (1961). The preceding compound is reacted with phosphorus oxychloride as described in Example 47 to give 3-chloro-6-[4-fluoro-3-(trifluoromethyl)phenyl]pyridazine., which is reacted with formylhydrazine as described in Example 48 to give the product of the example.
Reaction SMILES: [CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([O-:11])(=O)=[O:9])[N:6]=1.[Na+].P(Cl)(Cl)(Cl)(Cl)[Cl:14]>P(Cl)(Cl)(Cl)=O>[CH3:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][S:8]([Cl:14])(=[O:11])=[O:9])[N:6]=1
Reactant: ClP(Cl)(Cl)(Cl)Cl
Reactant: Cc1nc(CS(=O)(=O)[O-])cs1
Agent: [Na+]
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc(CS(=O)(=O)Cl)cs1
Temperature: 50 °C
Reaction time: 3 h
Yield: 27 %

Procedure:
Sodium (2-methylthiazol-4-yl)methanesulfonate (357 mg, 1.66 mmol) is dissolved in phosphorous oxychloride (6 mL) and is treated with phosphorous pentachloride (345 mg, 1.66 mmol). The reaction mixture is stirred at 50° C. for 3 hours, then allowed to cool to room temperature. The solvent is removed under reduced pressure and the residue is re-dissolved in CH2Cl2 (40 mL) and is washed with sat. NaHCO3 and brine. The organic layer is dried over MgSO4, filtered, and the solvent removed in vacuo to afford 0.095 g of the desired product as a brown oil. LC/MS ESI+211 (M+1). Intermediates are obtained in sufficient purity to be carried forward according to Scheme IX without the need for further purification.
Reaction SMILES: [OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20](Br)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4].COCCOC.C(=O)([O-])[O-].[Cs+].[Cs+].[C:37]1(B(O)O)[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.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>[OH:1][CH2:2][C:3]([NH:6][C:7]([C:9]1[C:10]2[CH2:11][C@@H:12]3[CH2:24][C@@H:13]3[C:14]=2[N:15]([C:17]2[CH:22]=[CH:21][C:20]([C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)=[CH:19][N:18]=2)[N:16]=1)=[O:8])([CH3:5])[CH3:4]
Reactant: OB(O)c1ccccc1
Reactant: CC(C)(CO)NC(=O)c1nn(-c2ccc(Br)cn2)c2c1C[C@@H]1C[C@H]21
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: [Cs+]
Solvent: O
Solvent: COCCOC
Product: CC(C)(CO)NC(=O)c1nn(-c2ccc(-c3ccccc3)cn2)c2c1C[C@@H]1C[C@H]21
Temperature: 120 °C
Yield: 60.6 %

Procedure:
To a 5 mL heavy-walled sealed tube with a stir bar were added (1aS,5aS)-2-(5-bromo-pyridin-2-yl)-1a,2,5,5a-tetrahydro-1H-2,3-diaza-cyclopropa[a]pentalene-4-carboxylic acid (2-hydroxy-1,1-dimethyl-ethyl)-amide (0.020 g, 0.051 mmol) and DME (0.31 mL, 0.051 mmol), cesium carbonate (0.033 g, 0.10 mmol), phenylboronic acid (0.0094 g, 0.077 mmol). Water (0.051 mL, 0.051 mmol) was added and the tube was flushed with argon. Tetrakis(triphenylphosphine)palladium(0) (0.0060 g, 0.0051 mmol) was added and tube was capped and again flushed with argon. The reaction was heated under microwave irradiation at 120° C. for 35 min. The sample was cooled and filtered. The filtrate was concentrated and the residue was purified by preparative HPLC to give the title compound as a tan solid (12 mg). LCMS m/z=389.5 [M+H]+; 1H NMR (400 MHz, CDCl3) δ ppm 0.51 (td, J=4.8 and 3.5 Hz, 1H), 1.26-1.33 (m, 1H), 1.41-1.47 (m, 6H), 2.28-2.36 (m, 1H), 2.80-2.87 (m, 1H), 2.94 (d, J=16.5 Hz, 1H), 3.03 (dd, J=16.5 and 6.3 Hz, 1H), 3.77 (s, 2H), 7.08 (bs, 1H), 7.42-7.47 (m, 1H), 7.52 (t, J=7.2 Hz, 2H), 7.60-7.65 (m, 2H), 7.96 (d, J=8.5 Hz, 1H), 8.05 (dd, J=8.5 and 2.4 Hz, 1H), 8.74 (d, J=2.3 Hz, 1H).
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32](S(C)=O)[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1.CCN(C(C)C)C(C)C>C1COCC1>[Cl:18][C:19]1[CH:20]=[C:21]2[C:27]([C:28]3[N:33]=[C:32]([NH:1][CH2:2][CH:3]4[CH2:8][C:7]([F:10])([F:9])[CH2:6][CH2:5][N:4]4[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:31]([F:37])=[CH:30][N:29]=3)=[CH:26][N:25]([S:38]([C:41]3[CH:46]=[CH:45][C:44]([CH3:47])=[CH:43][CH:42]=3)(=[O:40])=[O:39])[C:22]2=[N:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)N1CCC(F)(F)CC1CN
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(S(C)=O)n3)c3cc(Cl)cnc32)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: Cc1ccc(S(=O)(=O)n2cc(-c3ncc(F)c(NCC4CC(F)(F)CCN4C(=O)OC(C)(C)C)n3)c3cc(Cl)cnc32)cc1
Temperature: 130 °C

Procedure:
To a solution of tert-butyl 2-(aminomethyl)-4,4-difluoro-piperidine-1-carboxylate, 13i, (0.10 g, 0.41 mmol) and 5-chloro-3-(5-fluoro-4-methylsulfinyl-pyrimidin-2-yl)-1-(p-tolylsulfonyl)pyrrolo[2,3-b]pyridine (0.18 g, 0.38 mmol) in THF (2 mL) was added iPr2NEt (0.20 mL, 1.15 mmol). The reaction mixture was heated in microwave at 130° C. for 15 minutes. The reaction was cooled to room temperature and the volatiles were removed under reduced pressure. The crude residue was purified via silica gel chromatography (0-100% EtOAc/hexanes) to afford the desired product, 13j.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]2[C:21](C)=[CH:22][CH:23]=[CH:24][C:25]=2[Cl:26])=[CH:6][CH:5]=1)([O-:3])=[O:2].[Cl:29]C1C=CC=C(C)C=1NC1C=CC=CC=1CC(O)=O>>[N+:1]([C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11](=[O:28])[CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[NH:19][C:20]2[C:25]([Cl:26])=[CH:24][CH:23]=[CH:22][C:21]=2[Cl:29])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: Cc1cccc(Cl)c1Nc1ccccc1CC(=O)O
Product: O=C(Cc1ccccc1Nc1c(Cl)cccc1Cl)Oc1ccc([N+](=O)[O-])cc1

Procedure:
[o-(3-chloro-o-toluidino)-phenyl]-acetic acid-p-nitrophenyl ester, starting with [o-(3-chloro-o-toluidino)-phenyl]-acetic acid, M.P. 124° - 125° (from ether/petroleum ether).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[C:10](F)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1.C(OC([NH:29][CH:30]1[CH2:34][CH2:33][NH:32][CH2:31]1)=O)(C)(C)C.C(N(CC)CC)C>C(#N)C>[NH2:1][C:2]1[C:11]([F:12])=[C:10]([N:32]2[CH2:33][CH2:34][CH:30]([NH2:29])[CH2:31]2)[C:9]([Cl:14])=[C:8]2[C:3]=1[C:4](=[O:21])[C:5]([C:18]([OH:20])=[O:19])=[CH:6][N:7]2[CH:15]1[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)NC1CCNC1
Reactant: Nc1c(F)c(F)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Solvent: CC#N
Solvent: CCN(CC)CC
Product: Nc1c(F)c(N2CCC(N)C2)c(Cl)c2c1c(=O)c(C(=O)O)cn2C1CC1
Temperature: 100 °C
Yield: 63 %

Procedure:
To 1.57 g (5 mmol) of 5-amino-8-chloro-1-cyclopropyl-6,7-difluoro-1,4-dihydro-4-oxo-3-quinoline carboxylic acid in 20 ml of acetonitrile was added 0.93 g (5 mmol) of 3-[(t-butoxycarbonyl)amino]pyrrolidine and 1.0 g (10 mmol) of triethylamine. The mixture was refluxed for three hours, cooled, and filtered. The solids were washed with acetonitrile and ether, then dissolved in 10 ml of acetic acid and 2 ml of 3N hydrochloric acid. The mixture was heated at 100° C. for four hours, concentrated, and triturated with 2-propanol. The solid that formed was filtered and washed with ether to give 1.2 g of the title compound.
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[S:3]([O:6][C:7]1[CH:16]=[CH:15][C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]=1[C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][C:18]=1OS(C(F)(F)F)(=O)=O)(=[O:5])=[O:4].[PH3:37]=[O:38]>[Pd]>[PH2:37]([C:18]1[CH:19]=[CH:20][C:21]2[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:17]=1[C:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][C:7]=1[O:6][S:3]([C:2]([F:1])([F:36])[F:35])(=[O:4])=[O:5])=[O:38]
Reactant: O=S(=O)(Oc1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12)C(F)(F)F
Reactant: O=[PH3]
Agent: [Pd]
Product: O=[PH2]c1ccc2ccccc2c1-c1c(OS(=O)(=O)C(F)(F)F)ccc2ccccc12

Procedure:
More specifically, following Tetrahedron Letters, 31, 6321-6324 (1990), trifluoromethanesulfonic anhydride (4) is reacted with 1,1-bi-2-naphthol (3) to form 2,2'-bis(trifluoromethanesulfonyloxy)-1,1'-binaphthyl (5). This compound (5) is reacted with phosphine oxide (6) in the presence of a palladium catalyst to form 2-phosphinyl-2'-trifluoromethanesulfonyloxy-1,1'-binaphthyl (7). Compound (7) is then reduced in the presence of triethylamine, followed by hydrolysis of the reduction product to form 2-phosphino-2'-hydroxy-1,1'-binaphthyl (8). Further, this compound (8) is reacted with chlorophosphine (9) in the presence of triethylamine, whereby the phosphine compound (I) of the present invention is prepared.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10](=[NH:13])[NH:11][OH:12])[CH:5]=[N:6][C:7]=1[S:8][CH3:9].[CH3:14][C:15]([CH3:20])([CH3:19])[C:16](Cl)=O>C1(C)C=CC=CC=1>[C:15]([C:20]1[O:12][N:11]=[C:10]([C:4]2[CH:5]=[N:6][C:7]([S:8][CH3:9])=[C:2]([Cl:1])[CH:3]=2)[N:13]=1)([CH3:19])([CH3:16])[CH3:14]
Reactant: CSc1ncc(C(=N)NO)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: Cc1ccccc1
Product: CSc1ncc(-c2noc(C(C)(C)C)n2)cc1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 59 %

Procedure:
5-Chloro-6-methylthio-N-hydroxy-3-pyridinecarboximidamide (1.0 g, 4.6 mmol) was slurried in toluene (20 mL) and trimethylacetyl chloride (0.61 g, 5.1 mmol) added. The mixture was stirred at room temperature for one hour and then heated under reflux conditions for four hours. This was then cooled and filtered through Celite, washing with additional toluene (20 mL). Evaporation of the solvent under reduced pressure and purification of the residue by chromatography over silica (0-10% ethyl acetate:hexane) gave the desired product as a white solid (0.77 g, 59%).
Reaction SMILES: [NH2:1][C:2]([CH3:9])([CH:6]([CH3:8])[CH3:7])[C:3]([NH2:5])=[O:4].[O:10]1[C:14]2=[N:15][C:16]3[C:22](=[O:23])[O:21][C:19](=[O:20])[C:17]=3[CH:18]=[C:13]2[CH:12]=[CH:11]1>O1CCCC1>[C:3]([C:2]([NH:1][C:22]([C:16]1[N:15]=[C:14]2[O:10][CH:11]=[CH:12][C:13]2=[CH:18][C:17]=1[C:19]([OH:21])=[O:20])=[O:23])([CH3:9])[CH:6]([CH3:8])[CH3:7])(=[O:4])[NH2:5]
Reactant: CC(C)C(C)(N)C(N)=O
Reactant: O=C1OC(=O)c2nc3occc3cc21
Solvent: C1CCOC1
Product: CC(C)C(C)(NC(=O)c1nc2occc2cc1C(=O)O)C(N)=O
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
2-Amino-2,3-dimethylbutyramide (2.1 g, 0.016 mol) is added to a stirred suspension of furo[2,3-b]pyridine-5,6-dicarboxylic acid anhydride (3.0 g, 0.016 mol) in tetrahydrofuran (7.5 mL) and the mixture allowed to stir at room temperature for 16 hours. The reaction mixture is then stirred at 60° C. for one hour, cooled to room temperature, either added, and the solid filtered off and dried to give 5 g of 6-[(1-carbamoyl-1,2-dimethylpropyl)carbamoyl]furo[2,3-b]pyridine-5-carboxylic acid mp 192°-196° C. (dec).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([OH:14])=[O:13])[CH:6]=[CH:5]2.S(=O)(=O)(O)O.O.[CH3:21]COCC>CO>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[CH:8]=[C:7]([C:12]([O:14][CH3:21])=[O:13])[CH:6]=[CH:5]2
Reactant: CCOCC
Reactant: O=C(O)c1ccc2cc(Cl)ccc2c1
Agent: O=S(=O)(O)O
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc2cc(Cl)ccc2c1
Reaction time: 72 h

Procedure:
A suspension of the 6-chloro-2-naphthoic acid (41.2 g.) in a mixture of methanol (500 ml.) and concentrated sulphuric acid (50 ml.) is heated under reflux for 3 hours, stored at ambient temperature for 3 days, then warmed until a solution is obtained. Water (2 1.) and ether (1 1.) are added. The ethereal layer is separated, and is washed in turn with water, N-aqueous sodium hydroxide, and water, dried with magnesium sulphate, and evaporated to give methyl 6-chloro-2-naphthoate (38.8 g.) m.p. 97°-98° C., which may be further purified by recrystallisation from light petroleum (b.p. 40°-60° C.) to give material of m.p. 100°-101° C.
Reaction SMILES: [C:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17](Cl)[C:16]=3[CH:15]=[C:14]2[C:23]([O:25][CH3:26])=[O:24])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[CH2:29]([O:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1)[CH3:30].[F-].[K+]>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[C:1]([O:5][C:6]1[CH:28]=[CH:27][C:9]([O:10][CH2:11][CH2:12][N:13]2[C:21]3[CH:20]=[CH:19][N:18]=[C:17]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([O:31][CH2:29][CH3:30])[CH:37]=4)[C:16]=3[CH:15]=[C:14]2[C:23]([O:25][CH3:26])=[O:24])=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc2c(Cl)nccc2n1CCOc1ccc(OC(C)(C)C)cc1
Reactant: CCOc1cccc(B(O)O)c1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [F-]
Agent: [K+]
Solvent: C1COCCO1
Product: CCOc1cccc(-c2nccc3c2cc(C(=O)OC)n3CCOc2ccc(OC(C)(C)C)cc2)c1
Temperature: 25 °C
Yield: 77.4 %

Procedure:
Methyl 1-[2-(4-tert-butoxyphenoxy)ethyl]-4-chloro-1H-pyrrolo[3,2-c]pyridine-2-carboxylate (1 g, 2.482 mmole), 3-ethoxyphenylboronic acid (0.618 g, 3.72 mmole), KF (0.433 g, 7.45 mmole), and bis(tri-t-butylphosphine)palladium(0) (0.127 g, 0.248 mmole) were combined in 1,4-dioxane (10 mL). The mixture was degassed (3× pump/N2) then heated to reflux. After 5 hr the mixture was cooled to RT, diluted with EtOAc, filtered through a pad of Celite washing with EtOAc, and concentrated. Flash column chromatography (Biotage-SNAP-50 g SiO2, 0-30% EtOAc/hexanes) gave the title compound (939 mg, 77%) as an off-white foam. 1H NMR (400 MHz, CDCl3): 8.52 (d, J=6.0 Hz, 1 H); 7.61 (d, J=0.9 Hz, 1 H); 7.52-7.47 (m, 2 H); 7.43 (d, J=7.2 Hz, 2
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[NH:14][C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1.IC.[CH3:39]COC(C)=O>C1COCC1>[Cl:3][C:4]1[CH:5]=[C:6]([CH:10]2[C:16]3[CH:17]=[C:18]([C:21]([C:29]4[CH:30]=[CH:31][C:32]([Cl:35])=[CH:33][CH:34]=4)([OH:28])[C:22]4[N:26]([CH3:27])[CH:25]=[N:24][CH:23]=4)[CH:19]=[CH:20][C:15]=3[N:14]([CH3:39])[C:13](=[O:36])[CH2:12][S:11]2)[CH:7]=[CH:8][CH:9]=1
Reactant: CCOC(C)=O
Reactant: Cn1cncc1C(O)(c1ccc(Cl)cc1)c1ccc2c(c1)C(c1cccc(Cl)c1)SCC(=O)N2
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CI
Product: CN1C(=O)CSC(c2cccc(Cl)c2)c2cc(C(O)(c3ccc(Cl)cc3)c3cncn3C)ccc21
Reaction time: 0.5 h
Yield: 67 %

Procedure:
NaH 60% (0.00917 mol) was added portionwise at 5° C. under N2 flow to a mixture of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-4,1-benzothiazepin-2(3H)-one (see Example B2) (0.00705 mol) in THF (50 ml). The mixture was stirred for 30 min. Iodomethane (0.00846 mol) was added dropwise. The mixture was stirred at 5° C. for 1 hour, at room temperature for 2 hours and hydrolyzed cold. EtOAc was added. The mixture was filtered over celite, washed with EtOAc and the filtrate was extracted with EtOAc. The organic layer was separated, washed with water, dried (MgSO4), filtered and the solvent was evaporated. The residue was crystallized from 2-propanone and diethyl ether. The precipitate was filtered off and dried in vacuo, yielding 2.5 g (67%) of 5-(3-chlorophenyl)-7-[(4-chlorophenyl)hydroxy(1-methyl-1H-imidazol-5-yl)methyl]-1,5-dihydro-1-methyl-4,1-benzothiazepin-2(3H)-one, mp. 186° C.
Reaction SMILES: [NH2:1][C:2]1[NH:6][N:5]=[C:4]([NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[CH:9]=2)[C:3]=1[C:15]([NH2:17])=[O:16].O[CH2:19][C:20]1[O:26][C:23]([CH:24]=[O:25])=[CH:22][CH:21]=1>CCO.N1CCCCC1>[Cl:14][C:10]1[CH:9]=[C:8]([NH:7][C:4]2[C:3]([C:15]([NH2:17])=[O:16])=[C:2]([N:1]=[CH:19][C:20]3[O:26][C:23]([CH2:24][OH:25])=[CH:22][CH:21]=3)[NH:6][N:5]=2)[CH:13]=[CH:12][CH:11]=1
Reactant: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N
Reactant: O=Cc1ccc(CO)o1
Solvent: C1CCNCC1
Solvent: CCO
Product: NC(=O)c1c(Nc2cccc(Cl)c2)n[nH]c1N=Cc1ccc(CO)o1

Procedure:
5-amino-3-((3-chlorophenyl)amino)-1H-pyrazole-4-carboxamide was then suspended in EtOH and 5-(hydroxymethyl)furfural (1 eq.) and piperidine (1 drop) were added. Stirred at reflux until intermediate was absent (HPLC). After reaction was complete (18 hrs) it was brought to room temperature and filtered to obtain product as a yellow powder. Powder was washed with EtOH. Product was allowed to dry under vacuum for 1 hr.
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7])([O-])=O>CO.C(Cl)Cl.[Pd]>[NH2:1][C:4]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:9][C:5]=1[C:6]([NH2:8])=[O:7]
Reactant: NC(=O)c1cc(N2CCCCC2)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(N2CCCCC2)ccc1N
Reaction time: 10 h
Yield: 57.1 %

Procedure:
To 2-Nitro-5-piperidin-1-yl-benzamide (948 mg, 4.07 mmol) in Methanol (100 mL) was added Pd/C (10%) followed by H2 (1 ATM). After 10 h, the solution was filtered and concentrated. Flash chromatography (0-5% methanol in methylene chloride) afforded the title compound as a white solid (510 mg, 51% yield). FIA m/z 220.1 (M+H) 218 (M-H)
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([NH:10]C(=O)C)[C:5]([CH3:9])=[C:6]([CH3:8])[CH:7]=1.Cl.[N:17]([O-])=O.[Na+]>CC(O)=O.O>[Cl:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]2[C:5]([CH:9]=[N:17][NH:10]2)=[C:6]([CH3:8])[CH:7]=1
Reactant: O=N[O-]
Reactant: COc1c(Cl)cc(C)c(C)c1NC(C)=O
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: COc1c(Cl)cc(C)c2cn[nH]c12
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
N-(3-Chloro-2-methoxy-5,6-dimethyl-phenyl)-acetamide (3.36 g, 17.4 mmol) is dissolved in HOAc (75 mL) and conc. HCl (30 mL) in a 1 L round bottom flask. The reaction is cooled to 0° C. with an ice/salt bath. Although some starting material crystallizes, a solution of NaNO2 (5.9 g, 86 mmol) in water (25 mL) is added portion-wise over 5 min. All material goes into solution and the reacion is stoppered and stirred 45 min. HPLC shows very little sm. Ice cold water (800 mL) is was added slowly and the reaction was stirred 1 h. A precipitate forms. The solid is filtered and washed with ice cold water (500 mL). The material is dried with suction and then pumped to a constant weight 3.3 g. The solid is partially dissolved in toluene (35 mL) and stirred under N2. After stirring 18 h, the reaction is heated for 4 hours and cooled. The reaction is diluted with EtOAc and washed with NaHCO3, brine, dried (MgSO4) and concentrated. The crude product is purified by column chromatography (silica, 30% EtOAc/hexanes) to provide the desired product, 6-chloro-7-methoxy-4-methyl-1H-indazole.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19](SCC)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1.[OH:35][C:36]1([C:42]([OH:44])=[O:43])[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1>>[F:34][C:2]([F:1])([F:33])[C:3]1[CH:28]=[C:27]([C:29]([F:30])([F:32])[F:31])[CH:26]=[CH:25][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:16]3[S:20][C:19]([N:39]4[CH2:40][CH2:41][C:36]([OH:35])([C:42]([OH:44])=[O:43])[CH2:37][CH2:38]4)=[N:18][C:17]3=[O:24])=[CH:12][CH:13]=2)[CH:8]=[N:7]1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(C(F)(F)F)cc3C(F)(F)F)c2)S1
Reactant: O=C(O)C1(O)CCNCC1
Product: O=C1N=C(N2CCC(O)(C(=O)O)CC2)SC1=Cc1ccc2c(cnn2Cc2ccc(C(F)(F)F)cc2C(F)(F)F)c1

Procedure:
1-[5-({1-[2,4-Bis(trifluoromethyl)benzyl]-1H-indazol-5-yl}methylidene)-4-oxo-4,5-dihydro-1,3-thiazol-2-yl]-4-hydroxypiperidine-4-carboxylic acid was prepared from 5-[1-(2,4-Bis-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 4-Hydroxy-piperidine-4-carboxylic acid following General Procedure C.