Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([C:12]=1[NH:13][C:14]1[CH:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][C:15]=1[Cl:23])=[CH:10][C:9]([O:24][CH3:25])=[C:8]([NH:26]C(=O)C)[CH:7]=2)#[N:2]>Cl>[NH2:26][C:8]1[CH:7]=[C:6]2[C:11]([C:12]([NH:13][C:14]3[CH:19]=[C:18]([O:20][CH3:21])[C:17]([Cl:22])=[CH:16][C:15]=3[Cl:23])=[C:3]([C:1]#[N:2])[CH:4]=[N:5]2)=[CH:10][C:9]=1[O:24][CH3:25]
Reactant: COc1cc(Nc2c(C#N)cnc3cc(NC(C)=O)c(OC)cc23)c(Cl)cc1Cl
Agent: Cl
Product: COc1cc2c(Nc3cc(OC)c(Cl)cc3Cl)c(C#N)cnc2cc1N
Temperature: 65 °C
Yield: 40.7 %

Procedure:
An amount of 5 g (0.012 mol) of N-[3-cyano-4-(2,4-dichloro-5-methoxyanilino)-6-methoxy-7-quinolinyl]acetamide was stirred in 37% hydrochloric acid (500 mL), and heated at 65° C. for 1 hour. The mixture was evaporated to a slurry, stirred in saturated sodium bicarbonate solution, and extracted with ethyl acetate. The organic phase was dried over sodium sulfate, filtered through a pad of silica gel, and evaporated to dryness to give a tan solid (1.9 g, 42% yield), mp 265° C. decomp.; 1H NMR (DMSO-d6) δ 9.29 (s, 1H), 8.27 (s, 1H), 7.70 (s, 1H), 7.66 (s, 1H), 7.23 (s, 1H), 6.98 (s, 1H), 5.93 (s, 2H), 3.96 (s, 3H), 3.84 (s, 3H); MS (ES) m/z 389.2 (M+1). Analysis for C18H14Cl2N4O2: Found: C, 55.80; H, 3.78; N, 14.67. Calcd: C, 55.54; H, 3.63; N, 14.39.
Reaction SMILES: [CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:31])=[O:30])[C:25](O)=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.C1C=[N:43]C2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C.[NH4+].[Cl-].CCN=C=NCCCN(C)C>CN(C=O)C>[CH:1]1([NH:6][CH2:7][C:8]2[CH:17]=[C:16]3[C:11]([C@H:12]([N:18]4[CH:22]=[C:21]([CH2:23][C@@H:24]([NH:28][S:29]([C:32]5[CH:37]=[CH:36][C:35]([CH3:38])=[CH:34][CH:33]=5)(=[O:30])=[O:31])[C:25]([NH2:43])=[O:26])[N:20]=[N:19]4)[CH2:13][CH2:14][O:15]3)=[CH:10][CH:9]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(=O)O)cc1
Reactant: On1nnc2cccnc21
Agent: CCN=C=NCCCN(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(S(=O)(=O)N[C@H](Cc2cn([C@@H]3CCOc4cc(CNC5CCCC5)ccc43)nn2)C(N)=O)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of (R)-3-(1-((R)-7-((cyclopentylamino)methyl)-3,4-dihydro-2H-chromen-4-yl)-1H-1,2,3-triazol-4-yl)-2-(4-methylphenylsulfonamido)propanoic acid (61 mg, 0.11 mol), HOAt (18 mg, 0.12 mmol), i-Pr2NEt (60. mL, 0.45 mmol), NH4Cl (25 mg, 0.45 mmol), and EDCI (24 mg, 0.12 mmol) in 5 mL DMF was stirred for 24 h at RT. The reaction mixture was concentrated, taken up in H2O, and the white solid was filtered and air-dried to afford the title compound. MS (m/z, m+1): 539.4.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5](=[O:18])[C:6]2[C:11]([CH3:12])=[C:10]([C:13]([O:15]CC)=[O:14])[S:9][C:7]=2[N:8]=1.[NH:19]1[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]1>>[CH3:12][C:11]1[C:6]2[C:5](=[O:18])[NH:4][C:3]([CH2:2][N:19]3[CH2:24][CH2:23][C:22](=[O:25])[CH2:21][CH2:20]3)=[N:8][C:7]=2[S:9][C:10]=1[C:13]([OH:15])=[O:14]
Reactant: O=C1CCNCC1
Reactant: CCOC(=O)c1sc2nc(CCl)[nH]c(=O)c2c1C
Product: Cc1c(C(=O)O)sc2nc(CN3CCC(=O)CC3)[nH]c(=O)c12

Procedure:
Using ethyl 2-chloromethyl-5-methyl-4-oxo-3,4-dihydrothieno-[2,3-d]pyrimidine-6-carboxylate and piperidin-4-one, a substitution reaction was carried out similarly to later appearing Production Example 21. Successively the reaction product was hydrolyzed similarly to Example 33, without intervening isolation of the reaction product, to provide the title compound.
Reaction SMILES: [F:1][C:2]([F:30])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([C@@H:19]([O:21][CH3:22])[CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([O:23]C2CCCCO2)=[CH:13][C:12]=1[CH2:11][CH2:10]3.C(O)(=O)C(O)=O>CO.O>[F:1][C:2]([F:30])=[C:3]1[CH2:8][CH2:7][C@H:6]2[C@H:9]3[C@H:18]([C@@H:19]([O:21][CH3:22])[CH2:20][C@:4]12[CH3:5])[C:17]1[CH:16]=[CH:15][C:14]([OH:23])=[CH:13][C:12]=1[CH2:11][CH2:10]3
Reactant: CO[C@H]1C[C@]2(C)C(=C(F)F)CC[C@H]2[C@@H]2CCc3cc(OC4CCCCO4)ccc3[C@H]21
Agent: O=C(O)C(=O)O
Solvent: CO
Solvent: O
Product: CO[C@H]1C[C@]2(C)C(=C(F)F)CC[C@H]2[C@@H]2CCc3cc(O)ccc3[C@H]21
Yield: 93.9 %

Procedure:
A suspension of 1.2 g of 17-difluoromethylene-11β-methoxy-3-tetrahydropyranyloxy-estra-1,3,5(10)-triene in 25 ml of methanol and 2.6 ml of water is refluxed with 1.2 g of oxalic acid for 0.5 hour at a bath temperature of 100° C. Then, it is concentrated by evaporation in a vacuum diluted with ethyl acetate, washed with water, sodium bicarbonate solution as well as with saturated sodium chloride solution, dried on sodium sulfate, concentrated by evaporation in a vacuum and chromatographed on silica gel with hexane/acetone. After crystallization from hexane, 0.9 g of 17-difluoromethylene-11β-methoxy-estra-1,3,5(10)-trien-3-ol is obtained as colorless crystals with a melting point of 245-247° C., [α]D22 +77.3° (c=0.535% in pyridine).
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:15]=[C:16]([O:21][S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=1.[C:32]([C:34]1[CH:35]=[C:36]([CH:39]=[CH:40][CH:41]=1)[CH2:37]O)#[N:33].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>O1CCCC1>[C:32]([C:34]1[CH:35]=[C:36]([CH2:37][O:13][C:14]2[CH:15]=[C:16]([O:21][S:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:31])(=[O:24])=[O:23])[CH:17]=[C:18]([CH3:20])[CH:19]=2)[CH:39]=[CH:40][CH:41]=1)#[N:33]
Reactant: N#Cc1cccc(CO)c1
Reactant: Cc1cc(O)cc(OS(=O)(=O)c2ccccc2Cl)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: Cc1cc(OCc2cccc(C#N)c2)cc(OS(=O)(=O)c2ccccc2Cl)c1
Temperature: 0 °C
Reaction time: 3 h
Yield: 88.6 %

Procedure:
Diethyl azodicarboxylate (349 mg, 2.0 mmol) was added to a solution of 2-chlorobenzenesulfonic acid 3-hydroxy-5-methylphenyl ester (900 mg, 3.0 mmol), as prepared in step (c) of Example 1, 3-cyanobenzyl alcohol (400 mg, 3.0 mmol; Yoon et al., J. Org. Chem. 38:2786-2792 (1973)), and triphenylphosphine (525 mg, 2.0 mmol) in tetrahydrofuran (20 mL) at 0° C. The mixture was stirred at 0° C. for 2 h and at room temperature for 3 h. The reaction mixture was quenched with water (50 mL) and extracted with ethyl acetate (3×50 mL). The organic phase was washed with saturated NaHCO3 (2×50 mL), brine (2×50 mL) and dried over Na2SO4. The solvent was removed in vacuo and the residue was purified by flash column chromatography (2:1 ethyl acetate/hexane) to give the title compound as awhite solid (1.10 g, 89%). 1H-NMR (300 MHz, CDCl3) δ 2.26 (s, 3H), 4.99 (s, 2H), 6.55 (t, 1H, J=2.3 Hz), 6.60 (t, 1H, J=0.7 Hz), 6.67 (t, 1H, J=0.7 Hz), 7.39 (m, 1H), 7.50 (t, 1H, J=7.7 Hz), 7.61 (m, 5H), and 7.96 (d, 1H, J=1.3 Hz).
Reaction SMILES: CN(C)CCOC1C=C[C:9]([NH:12][C:13]([C:15]2[C:16]3[N:17]=[CH:18][CH:19]=[N:20][C:21]=3[C:22]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[F:31])=[CH:23][CH:24]=2)=[O:14])=CC=1>C(Cl)Cl.CO>[NH:17]1[CH:16]=[CH:21][N:20]=[C:9]1[NH:12][C:13]([C:15]1[C:16]2[N:17]=[CH:18][CH:19]=[N:20][C:21]=2[C:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[F:31])=[CH:23][CH:24]=1)=[O:14]
Reactant: CN(C)CCOc1ccc(NC(=O)c2ccc(-c3ccccc3F)c3nccnc23)cc1
Solvent: CO
Solvent: ClCCl
Product: O=C(Nc1ncc[nH]1)c1ccc(-c2ccccc2F)c2nccnc12

Procedure:
The title compound was prepared in analogy to the procedure described in Example 14 but using 8-(2-fluoro-phenyl)-quinoxaline-5-carboxylic acid (Example 44) in Step 14.1. Title compound: ESI-MS: 334.0 [M+H]+; tR=3.39 min (System 1); TLC: Rf=0.54 (DCM/MeOH, 9:1).
Reaction SMILES: [Cl:1][C:2]1[C:6]([NH:7][C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1.[CH3:20][CH:21]([CH2:25][S:26][CH3:27])[C:22](Cl)=[O:23]>ClCCCl>[Cl:1][C:2]1[C:6]([N:7]([C:8](=[O:13])[CH2:9][CH2:10][S:11][CH3:12])[C:22](=[O:23])[CH:21]([CH3:20])[CH2:25][S:26][CH3:27])=[CH:5][N:4]([C:14]2[CH:15]=[N:16][CH:17]=[CH:18][CH:19]=2)[N:3]=1
Reactant: CSCCC(=O)Nc1cn(-c2cccnc2)nc1Cl
Reactant: CSCC(C)C(=O)Cl
Solvent: ClCCCl
Product: CSCCC(=O)N(C(=O)C(C)CSC)c1cn(-c2cccnc2)nc1Cl
Reaction time: 3 h
Yield: 22.3 %

Procedure:
To a solution of N-(3-chloro-1-(pyridin-3-yl)-1H-pyrazol-4-yl)-3-(methylthio)propanamide (0.216 g, 0.728 mmol) in DCE (2.91 ml) in a 10 mL vial was added 2-methyl-3-(methylthio)propanoyl chloride (0.244 g, 1.601 mmol). The vial was capped and placed in a Biotage Initiator microwave reactor for 3 hours at 100° C., with external IR-sensor temperature monitoring from the side of the vessel. The crude mixture was concentrated and purified using reverse phase C-18 column chromatography (0-100% acetonitrile/water) to yield the title compound as a pale yellow oil (67 mg, 22%): IR (thin film) 2916 and 1714 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.96-8.92 (d, J=2.7 Hz, 1H), 8.64-8.59 (dd, J=4.9, 1.4 Hz, 1H), 8.07-7.99 (m, 2H), 7.50-7.40 (dd, J=8.4, 4.8 Hz, 1H), 3.39-3.28 (m, 1H), 3.10-2.99 (td, J=7.2, 3.9 Hz, 2H), 2.96-2.86 (dd, J=13.2, 8.7 Hz, 1H), 2.86-2.79 (t, J=7.3 Hz, 2H), 2.58-2.48 (dd, J=13.1, 5.8 Hz, 1H), 2.14-2.12 (s, 3H), 2.09-2.06 (s, 3H), 1.30-1.26 (d, J=6.9 Hz, 3H); ESIMS m/z 413 ([M+H]+).
Reaction SMILES: [C:1]([C@@H:4]1[CH2:8][C:7]([OH:10])([CH3:9])[CH2:6][N:5]1C(OC(C)(C)C)=O)(=[O:3])[NH2:2].[ClH:18].O1CCOCC1>>[ClH:18].[OH:10][C:7]1([CH3:9])[CH2:6][NH:5][C@H:4]([C:1]([NH2:2])=[O:3])[CH2:8]1
Reactant: CC1(O)C[C@@H](C(N)=O)N(C(=O)OC(C)(C)C)C1
Agent: Cl
Solvent: C1COCCO1
Product: CC1(O)CN[C@H](C(N)=O)C1

Procedure:
A solution of (2S)-tert-butyl 2-carbamoyl-4-hydroxy-4-methylpyrrolidine-1-carboxylate (Example 132 a, 46 mg, 188 μmol) in a solution of 4 M HCl in dioxane (942 μL, 3.8 mmol) was stirred at ambient temperature for 5 h. The solvent was removed in vacuo to give the title compound (36 mg, quant.) as light brown solid, MS (ESI) m/e=145.2 [MH+].
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([CH:8]([OH:32])[CH:9]([NH:24]C(=O)OC(C)(C)C)[CH2:10][C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:23])([F:22])[CH:19]([F:21])[F:20])[CH:12]=2)[CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O>[NH2:24][CH:9]([CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[C:13]([O:17][C:18]([F:22])([F:23])[CH:19]([F:20])[F:21])[CH:12]=1)[CH:8]([C:6]1[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=1)[OH:32]
Reactant: CC(C)(C)OC(=O)NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Solvent: O=C(O)C(F)(F)F
Product: NC(Cc1cccc(OC(F)(F)C(F)F)c1)C(O)c1cccc(F)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 103.7 %

Procedure:
To a solution of 1,1-dimethylethyl(1RS,2RS)-2-(6-fluoropyridin-2-yl)-2-hydroxy-1-((3-(1,1,2,2-tetrafluoroethoxy)phenyl)methyl)ethylcarbamate (1.6 g, 3.46 mmol) was added trifluoroacetic acid (20 ml), and the mixture was stirred at room temperature for 10 min. The reaction solution was concentrated under reduced pressure, and 1N aqueous sodium hydroxide solution (10 ml) was added. The mixture was extracted with ethyl acetate (20 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure to give (1RS,2RS)-2-amino-1-(6-fluoropyridin-2-yl)-3-(3-(1,1,2,2-tetrafluoroethoxy)phenyl)-1-propanol (1.3 g, 100%).
Reaction SMILES: [CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]=[C:12]=[O:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4].[ClH:14].Cl.[Cl:16][C:17]1[CH:33]=[CH:32][C:20]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][CH2:30][SH:31])[CH2:24][CH2:23]2)=[CH:19][CH:18]=1.C(N(CC)CC)C>C(Cl)Cl>[ClH:16].[ClH:14].[CH2:1]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12](=[SH:31][CH2:30][CH2:29][CH2:28][N:25]2[CH2:26][CH2:27][N:22]([CH2:21][C:20]3[CH:19]=[CH:18][C:17]([Cl:16])=[CH:33][CH:32]=3)[CH2:23][CH2:24]2)[OH:13])=[CH:7][CH:6]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCc1ccc(N=C=O)cc1
Reactant: SCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCCc1ccc(NC(O)=[SH]CCCN2CCN(Cc3ccc(Cl)cc3)CC2)cc1
Yield: 56.8 %

Procedure:
The procedure described in Example 2 was followed, using 1.0 g of 4-n-butylphenyl isocyanate, 2.0 g of 3-[4-(4-chlorobenzyl)piperazin-1-yl]propanethiol dihydrochloride, 0.7 g of triethylamine and 50 ml of methylene chloride, to give 0.85 g (28% of theory) of N-(4-n-butylphenyl)-S-{3-[4-(4-chlorobenzyl)piperazin-1-yl]propyl}thiocarbamate dihydrochloride as a white crystalline solid, M.p. 243°-246° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][CH:8]=[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[F:19])[C:6]=2[CH:20]=1.[Br:21]Br>C(Cl)(Cl)(Cl)Cl>[Br:21][CH:9]1[CH:8]=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[F:19])[C:6]2[CH:20]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=2[NH:11][C:10]1=[O:12]
Reactant: O=C1CC=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: BrBr
Solvent: ClC(Cl)(Cl)Cl
Product: O=C1Nc2ccc(Cl)cc2C(c2ccccc2F)=CC1Br

Procedure:
A suspension of 7-chloro-5-(2-fluorophenyl)-1,3-dihydro-2H-1-benzazepin-2-one (0.378 g, 1.31 mmole) in 45 mL of dry carbon tetrachloride was heated to reflux, which generated a clear solution. Bromine (0.15 mL, 2.91 mmole) was added in two portions, 20 minutes apart, and the solution was heated at reflux for a total of 1 hour under a sunlamp. After cooling the reaction solution was washed sequentially with 5% aqueous sodium thiosulfate, dilute aqueous sodium bicarbonate, and 5% aqueous sodium thiosulfate. The organic phase was dried (sodium sulfate) and concentrated. The crude material was purified using a 2 mm chromatotron plate, eluting with 1:1 ethyl acetate-hexane, yielding 0.185 g (72%) of the title compund. IR(KBr): 3386, 1731, 1682 cm-1. Mass spec. (EI, m/z 367).
Reaction SMILES: Br[C:2]1[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=1.[CH3:9][O:10][C:11]1[CH:12]=[C:13](B(O)O)[CH:14]=[CH:15][CH:16]=1>>[CH3:9][O:10][C:11]1[CH:12]=[C:13]([C:2]2[CH2:7][CH2:6][CH2:5][C:4](=[O:8])[CH:3]=2)[CH:14]=[CH:15][CH:16]=1
Reactant: O=C1C=C(Br)CCC1
Reactant: COc1cccc(B(O)O)c1
Product: COc1cccc(C2=CC(=O)CCC2)c1
Yield: 88 %

Procedure:
Synthesized from 3-bromocyclohex-2-enone and 3-methoxyphenylboronic acid according to the general procedure described for the Suzuki coupling. Purification by automated flash chromatography using gradient elution (0 to 80% ethyl acetate/hexanes) yielded the product (141 mg, 88%) as a pale yellow solid. 1H NMR (300 MHz, CDCl3): δ 7.30 (t, J=8.0 Hz, 1H), 7.10 (dd, J=8.0, 0.8 Hz, 1H), 7.03 (t, J=2.2 Hz, 1H), 6.93 (dd, J=8.3, 2.5 Hz, 1H), 6.39 (bs, 1H), 3.82 (s, 3H), 2.75 (td, J=6.1, 0.8 Hz, 2H), 2.48 (t, J=6.3 Hz, 2H), 2.14 (quintet, J=6.1 Hz, 2H).
Reaction SMILES: [C:1]([C:4]1[N:9]=[N:8][C:7]([NH:10][C@@H:11]2[CH2:16][CH2:15][CH2:14][CH2:13][C@@H:12]2[NH:17]C(=O)OC(C)(C)C)=[CH:6][C:5]=1[NH:25][C:26]1[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[N:27]=1)(=[O:3])[NH2:2].FC(F)(F)C(O)=O>ClCCl>[NH2:17][C@H:12]1[CH2:13][CH2:14][CH2:15][CH2:16][C@H:11]1[NH:10][C:7]1[N:8]=[N:9][C:4]([C:1]([NH2:2])=[O:3])=[C:5]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[C:28]([O:32][CH2:33][CH3:34])[N:27]=2)[CH:6]=1
Reactant: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3NC(=O)OC(C)(C)C)nnc2C(N)=O)n1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCOc1cccc(Nc2cc(N[C@@H]3CCCC[C@@H]3N)nnc2C(N)=O)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 65.6 %

Procedure:
tert-Butyl (1S,2R)-2-(6-carbamoyl-5-(6-ethoxypyridin-2-ylamino)pyridazin-3-ylamino)cyclohexylcarbamate (32.2 mg, 51.2 μmol) was dissolved in dichloromethane (1 mL) and treated with trifluoroacetic acid (744 mg, 0.5 mL, 6.53 mmol). The reaction was stirred at 25° C. for 3 h then concentrated in vacuo to a brown oil. This oil was dissolved in dichloromethane, washed with 1N NaOH (3×5 mL) and brine (5 mL), then the organic phase was dried (Na2SO4), filtered and concentrated to give an off-white solid. The solid was triturated with Et2O (3×5 mL) and dried overnight in vacuo to give an off-white solid, 6-((1R,2S)-2-aminocyclohexylamino)-4-(6-ethoxypyridin-2-ylamino)pyridazine-3-carboxamide (12.6 mg, 33.6 μmol, 66% yield), 1H NMR (DMSO-d6) δ: 11.65 (br. s., 1H), 8.40 (br. s., 1H), 7.71 (s, 1H), 7.64 (t, J=7.9 Hz, 2H), 6.77 (d, J=7.8 Hz, 1H), 6.54 (d, J=7.8 Hz, 1H), 6.36-6.42 (m, 1H), 4.35 (q, J=7.0 Hz, 2H), 3.85 (br. s., 1H), 3.09 (br. s., 1H), 1.48-1.74 (m, 6H), 1.20-1.40 (m, 5H); MS (EI/CI) m/z: 372.3 [M+H].
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:16]=[CH:17][CH:18]=1)[O:5][CH2:6][C:7]1[CH:8]=[C:9]([C:13]([OH:15])=[O:14])[O:10][C:11]=1[CH3:12].[F:19][C:20]([F:31])([F:30])[C:21]1[CH:22]=[C:23](B(O)O)[CH:24]=[CH:25][CH:26]=1>>[CH3:12][C:11]1[O:10][C:9]([C:13]([OH:15])=[O:14])=[CH:8][C:7]=1[CH2:6][O:5][C:4]1[CH:3]=[C:2]([C:25]2[CH:24]=[CH:23][CH:22]=[C:21]([C:20]([F:31])([F:30])[F:19])[CH:26]=2)[CH:18]=[CH:17][CH:16]=1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Reactant: Cc1oc(C(=O)O)cc1COc1cccc(I)c1
Product: Cc1oc(C(=O)O)cc1COc1cccc(-c2cccc(C(F)(F)F)c2)c1

Procedure:
Compound (109) was prepared from compound (107) and (3-trifluoromethyl-phenyl)-boronic acid by adapting the procedure of Example 26A(c). LC/MS System B; Rt=1.97 mins, m/z (ES−)=375 (M−H for C20H15F3O4).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][CH:3]=1.[CH3:11][NH:12][CH2:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:12]([CH3:11])[CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][N:16]=2)=[O:8])=[CH:9][CH:10]=1
Reactant: CNCCc1ccccn1
Reactant: Nc1ccc(C(=O)O)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccn1)C(=O)c1ccc(N)cc1
Reaction time: 3 h

Procedure:
p-Aminobenzoic acid (1 g, 0.0073 mol) was dissolved in DMF (15 ml), methyl-(2-pyridin-2-yl-ethyl)amine (5 ml, 5 eq) was added, followed by DIPEA (1.91 ml, 1.5 eq), and HATU (4.1 g, 1.5 eq). After stirring for 3 h, TLC showed complete consumption of starting material. Water was added and the mixture extracted with CH2Cl2, the organic extracts were washed with NaHCO3 (sat), NH4Cl (sat), dried (MgSO4), concentrated under reduced pressure, and purified by flash chromatography (SiO2, EtOAc-EtOAc/MeOH 95:5) to give 1.43 g of 4-amino-N-methyl-N-(2-pyridin-2-ylethyl)benzamide. Step B: Preparation 1B (100 mg, 0.371 mmol) and the product of step A (142 mg, 1.5 eq) were dissolved in DMF (2 ml), potassium tert-butoxide (91 mg, 2.2 eq) was added and the mixture allowed to stir overnight. Water was added and the mixture extracted with EtOAc, dried (MgSO4), concentrated under reduced pressure, and the residue purified by flash chromatography (SiO2, hexane-EtOAc) to give 56 mg of the title compound. LCMS: MH+=489.3.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[C:5]([NH2:18])=[CH:6][C:7]=1[C:8]1[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=1.C(=O)([O-])[O-].[Na+].[Na+].[F:26][C:27]([F:35])([F:34])[C:28]([F:33])([F:32])[C:29](O)=O>O>[Cl:1][C:2]1[C:7]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([F:17])([F:16])[F:15])=[CH:10][CH:9]=2)=[CH:6][C:5]2[NH:18][C:29]([C:28]([F:33])([F:32])[C:27]([F:35])([F:34])[F:26])=[N:19][C:4]=2[CH:3]=1
Reactant: Nc1cc(Cl)c(-c2ccc(C(F)(F)F)cc2)cc1N
Reactant: O=C(O)C(F)(F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: FC(F)(F)c1ccc(-c2cc3[nH]c(C(F)(F)C(F)(F)F)nc3cc2Cl)cc1
Yield: 52 %

Procedure:
To a solution of 5-chloro-4-iodo-2-nitroaniline (5.0 g, 16.75 mmol) in dioxane (200 ml) was added water (20 ml), Pd(PPh3)4 (924 mg, 0.80 mmol), K3PO4 (7.0 g, 32.98 mmol) and [4-(trifluoromethyl)phenyl]boronic acid (6.3 g, 33.17 mmol) with stirring overnight at 100° C. under nitrogen. The resulting mixture was concentrated under vacuum and dissolved in water (250 ml), extracted with ethyl acetate (3×200 ml) and the organic layers combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give the residue, which was re-crystallized from 50% ether in hexane to afford 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline as a yellow solid (4.2 g, crude). Next, to a solution of 5-chloro-2-nitro-4-[4-(trifluoromethyl)phenyl]aniline (3.7 g, crude) in ethanol (300 ml) and hydrogen chloride (3.0 ml) was added Zn powder (4.55 g, 70.0 mmol) in several bacthes with stirring for 20 min at room temperature. The resulting solution was stirred for 7 h at 85° C. The solids were filtered out and the filtrate was concentrated under vacuum to give a residue, which was dissolved in water (100 ml). The mixture was adjusted to pH 7 with saturated aqueous sodium carbonate, extracted with ethyl acetate (3×300 ml) and the organic layers combined and dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue that was purified by a silica gel column eluted with 10% to 50% ethyl acetate in petroleum ether to produce 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine as brown oil (2.9 g,). Finally, the solution of 4-chloro-5-[4-(trifluoromethyl)phenyl]benzene-1,2-diamine (150 mg, 0.52 mmol) in pentafluoropropanoic acid (1 ml) was stirred overnight at 80° C. The result mixture was diluted with water (50 ml) and adjusted to pH 7 with saturated aqueous sodium carbonate. The resulting solution was extracted with ethyl acetate (3×50 ml), combined, dried over anhydrous sodium sulfate and concentrated under vacuum to give a residue, which was purified by a silica gel column eluted with 0.5% to 6.5% ethyl acetate in petroleum ether to produce 5-chloro-2-(pentafluoroethyl)-6-[4-(trifluoromethyl)phenyl]-1H-1,3-benzodiazole as a white solid (112.6 mg, 52%).
Reaction SMILES: CO.C(N[C:12]1[CH:20]=[C:19](/C=C/C2C=CC=C(OC)C=2)[CH:18]=[CH:17][C:13]=1[C:14]([OH:16])=[O:15])(=O)C1C=CC=CC=1>[C].[Pd].C(OCC)(=O)C>[C:14]([OH:16])(=[O:15])[C:13]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:12]=1
Reactant: COc1cccc(/C=C/c2ccc(C(=O)O)c(NC(=O)c3ccccc3)c2)c1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1.0 mL of methanol, 2.0 mL of ethyl acetate and 2.0 mg of 5% palladium-carbon were added to the obtained 2-(benzamido)-4-((E)-2-(3-methoxyphenyl)vinyl)benzoic acid and stirred under hydrogen atmosphere at room temperature for 2 hours. Insoluble were removed by filtration, and the solvent was evaporated under reduced pressure to obtain 6.3 mg of 2-(benzamido)-4-(2-3-methoxyphenyl)ethyl)benzoic acid as white solid.
Reaction SMILES: [Br:1][CH:2]([CH:5]=O)[CH:3]=O.[NH2:7][C:8]1[CH:12]=[CH:11][NH:10][N:9]=1>C(O)(=O)C>[Br:1][C:2]1[CH:5]=[N:7][C:8]2[N:9]([N:10]=[CH:11][CH:12]=2)[CH:3]=1
Reactant: Nc1cc[nH]n1
Reactant: O=CC(Br)C=O
Solvent: CC(=O)O
Product: Brc1cnc2ccnn2c1
Yield: 11.2 %

Procedure:
Dissolve bromomalonaldehyde (Aldrich; 2.5 g, 16.5 mmol) and 3-aminopyrazole (Aldrich; 1.38 g, 16.5 mmol) in glacial acetic acid (25 mL) and reflux the resulting mixture under nitrogen for 2 h. Concentrate under reduced pressure. Dissolve the residue in absolute methanol (150 mL), vacuum filter through a pad diatomaceous earth and concentrate under reduced pressure. Chromatograph on flash silica using a gradient from neat hexane to 50% ethyl acetate/50% hexane to obtain 365 mgs (11%) of the subtitled compound as a light yellow solid. High Resolution Mass Spectrum: 197.9674 (M+1).
Reaction SMILES: [OH-].[Ca+2].[OH-].[C:4](=O)([O-])[O-:5].[Na+].[Na+].[Cl:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([Cl:17])[CH:16]=1.Cl>O.C(Cl)(Cl)Cl>[Cl:10][C:11]1[CH:12]=[C:13]([OH:18])[CH:14]=[C:15]([Cl:17])[C:16]=1[CH:4]=[O:5]
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [Ca+2]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: O=Cc1c(Cl)cc(O)cc1Cl
Yield: 4.5 %

Procedure:
To a stirred suspension of calcium hydroxide (61 gm), sodium carbonate (69.7 gm), and 3,5 dichlorophenol (20.97 gm) in water (436 ml) at 74° is added chloroform (45.3 gm) over 90 minutes. The solution is refluxed for 31/2 hours. After the slow addition of concentrated hydrochloric acid (170 ml), the acidic solution is steam distilled the aqueous residue is cooled and the solid which separates is filtered. Recrystallization from toluene gives 1.1 gm of 2,6-dichloro-4-hydroxybenzaldehyde.