Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:6]([O:10][CH3:11])(=[O:9])[CH:7]=[CH2:8]>>[N:1]1([CH2:8][CH2:7][C:6]([O:10][CH3:11])=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C=CC(=O)OC
Reactant: C1CCNC1
Product: COC(=O)CCN1CCCC1
Yield: 95 %

Procedure:
Pyrrolidine, 71.1 g, was added to 86.1 g of methyl acrylate at 20° C. and reacted for 24 hours. Purification by vacuum distillation yielded 149 g of methyl 3-(1-pyrrolidinyl)propionate, designated [B-17] (boiling point: 74° C./800 Pa, yield: 95%).
Reaction SMILES: [CH3:1][C:2](O)([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4].S(=O)(=O)(O)O>O1CCOCC1>[CH2:1]=[C:2]([C:6]1[CH:18]=[CH:17][C:16]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][C:8]=2[CH:7]=1)[C:3]([OH:5])=[O:4]
Reactant: CC(O)(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Product: C=C(C(=O)O)c1ccc2c(c1)Cc1ccccc1-2
Temperature: 0 °C
Yield: 98.2 %

Procedure:
A solution of α-methyl-α-hydroxyfluorene-2-acetic acid (5.7 g) and sulfuric acid (11.4 ml) in dioxane (300 ml) is refluxed for 2 hours. The reaction mixture is poured into ice water and extracted with ether. The ether extracts are washed with water, dried (MgSO4), and evaporated to give the title compound (5.2 g, mp 183°-185°). The analytical sample is prepared by recrystallization from 95% ethanol, mp 190°-191°, λKBr 880 cm-1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]([OH:12])[C:8]([F:11])([F:10])[F:9])[S:5][CH:6]=1.CC1(C)COB([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)OC1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=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>[F:9][C:8]([F:11])([F:10])[CH:7]([C:4]1[S:5][CH:6]=[C:2]([C:20]2[CH:21]=[C:22]3[C:27](=[CH:28][CH:29]=2)[N:26]=[CH:25][CH:24]=[N:23]3)[CH:3]=1)[OH:12]
Reactant: CC1(C)COB(c2ccc3nccnc3c2)OC1
Reactant: OC(c1cc(Br)cs1)C(F)(F)F
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: CN(C)C=O
Product: OC(c1cc(-c2ccc3nccnc3c2)cs1)C(F)(F)F
Temperature: 90 °C

Procedure:
A mixture of the alcohol (E1) (1.0 eq.) and the crude boronic ester (E2) (1.3 eq.) in DMF (1.0M), together with 2N Na2CO3 aqueous solution (2.0 eq.) was degassed with a stream of Ar for 10 min. Pd(PPh3)4 (0.05 eq) was added and the reaction heated overnight at 90° C. The reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography on silica using 500% EtOAc/Petroleum ether to yield the desired compound as a power. 1H NMR (400 MHz, CDCl3, 300K) δ 8.81 (2H, m), 8.20 (1H, d, J=2.0 Hz), 8.10 (1H, d, J=8.8 Hz), 7.98 (1H, dd, J=8.8, 2.0 Hz), 7.68 (1H, s), 7.61 (1H, s), 5.38 (1H, q, J=6.4 Hz). MS (ES) C14H9F3N2OS requires: 310, found: 311 (M+H+).
Reaction SMILES: CO[C:3](=[O:20])[C:4]([C:9](=[O:19])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([CH3:18])[CH:11]=1)=[CH:5]OCC.[NH2:21][C:22]1[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=1.C1(OC2C=CC=CC=2)C=CC=CC=1>>[CH3:17][O:16][C:13]1[CH:14]=[CH:15][C:10]([C:9]([C:4]2[C:3](=[O:20])[C:23]3[C:22](=[CH:27][CH:26]=[CH:25][N:24]=3)[NH:21][CH:5]=2)=[O:19])=[CH:11][C:12]=1[CH3:18]
Reactant: CCOC=C(C(=O)OC)C(=O)c1ccc(OC)c(C)c1
Reactant: Nc1cccnc1
Solvent: c1ccc(Oc2ccccc2)cc1
Product: COc1ccc(C(=O)c2c[nH]c3cccnc3c2=O)cc1C
Yield: 65.1 %

Procedure:
Experimental conditions analogous to those described for Step 1 of Example 1 were used with 0.60 g (2.27 mmol) of 3-ethoxy-2-(4-methoxy-3-methyl-benzoyl)-acrylic acid methyl ester, 0.214 g (2.27 mmol) of 3-aminopyridine, and 15 mL of diphenyl ether to yield 0.435 g of 3-(4-Methoxy-3-methyl-benzoyl)-1H-[1,5]naphthyridin-4-one.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:15]=[CH:14][C:13](=[O:16])[CH:12]=[CH:11]2)=[CH:6][CH:5]=1)([O-])=O>C(OCC)(=O)C.C(O)C>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:11]=[CH:12][C:13](=[O:16])[CH:14]=[CH:15]2)=[CH:6][CH:5]=1
Reactant: O=c1ccn(-c2ccc([N+](=O)[O-])cc2)cc1
Solvent: CCO
Solvent: CCOC(C)=O
Product: Nc1ccc(-n2ccc(=O)cc2)cc1
Temperature: 25 °C

Procedure:
To a solution of 10 g 1-(4-Nitro-phenyl)-1H-pyridin-4-one in 510 mL ethyl acetate and 26 mL ethanol, 52.1 g SnCl2 dihydrate were added and the reaction mixture was heated to reflux for 6 h. Then, after cooling to RT the solvents were removed under reduced pressure. The residue was taken-up in 100 mL aqueous NaHCO3 solution and 200 mL ethyl acetate were added. The inorganic precipitate was filtered off and the solids were washed with ethyl acetate. After separation of the organic layer, the aqueous layer of the filtrate was extracted with ethyl acetate (2×100 ml) and with DCM (3×150 ml). The combined organic layers were dried over Na2SO4 and the solvents were removed under reduced pressure. The remaining product was pure enough for the next reaction step. Yield: 6 g.
Reaction SMILES: Cl[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3].[CH3:24][NH:25][CH3:26]>>[CH3:24][N:25]([CH3:26])[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[N:15]3[CH2:16][CH2:17][C:18]4[NH:19][C:20](=[O:23])[CH:21]=[CH:22][C:13]([C:14]=43)=[CH:12][N:11]=2)=[CH:6][CH:5]=1)[CH3:3]
Reactant: CC(Cl)c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1
Reactant: CNC
Product: CC(c1ccc(C2=NC=C3C=CC(=O)NC4=C3N2CC4)cc1)N(C)C
Temperature: 80 °C

Procedure:
This compound was prepared from intermediate 245b and dimethylamine according to the procedure described in Example 171, with the exception of heating to 80° C. Received 69 mg (77%)
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)=[N:10][N:11]3[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=23)[CH:5]=[CH:4][N:3]=1.C(N(CC)CC)C.[CH:31]1([NH2:35])[CH2:34][CH2:33][CH2:32]1>ClCCl>[CH:31]1([NH:35][C:2]2[N:7]=[C:6]([C:8]3[C:9]([C:17]4[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=4)=[N:10][N:11]4[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=34)[CH:5]=[CH:4][N:3]=2)[CH2:34][CH2:33][CH2:32]1
Reactant: Fc1ccc(-c2nn3c(c2-c2ccnc(Cl)n2)CCCC3)cc1
Reactant: NC1CCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Fc1ccc(-c2nn3c(c2-c2ccnc(NC4CCC4)n2)CCCC3)cc1
Temperature: 65 °C
Reaction time: 18 h

Procedure:
A mixture of 3-(2-chloro-4-pyrimidinyl)-2-(4-fluorophenyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyridine (i.e. the product of Step B) (200 mg, 0.54 mmol), triethylamine (55 mg, 0.54 mmol) and cyclobutylamine (5.0 mL) was stirred at 65° C. for 18 h. The reaction mixture was diluted with dichloromethane (50 mL) and treated with silica gel (20.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (1:9 to 1:0) as eluant to give 70 mg of the title product, a compound of the present invention, as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.S(Cl)(Cl)=O.[CH2:16](O)[CH3:17]>>[CH2:16]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])[CH3:17]
Reactant: O=C(O)c1ccc(F)cc1O
Reactant: CCO
Solvent: O=S(Cl)Cl
Product: CCOC(=O)c1ccc(F)cc1O

Procedure:
To a solution of 4-fluoro-2-hydroxybenzoic acid (3.0 g) in ethanol (40 mL) was added thionyl chloride (5.61 mL) at 0° C., and the mixture was heated under reflux for 24 hours. The reaction mixture was concentrated under reduced pressure. This residue was poured into water, and the resulting mixture was extracted with ethyl acetate. The organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure to give the title compound (3.5 g).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][O:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22]3[C:27](Cl)=[CH:26][CH:25]=[CH:24][C:23]=3Cl)=[CH:16][CH:15]=2)[CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[CH2:20]([C:17]1[CH:18]=[CH:19][C:14]([CH:10]2[O:11][CH2:12][CH2:13][NH:8][CH2:9]2)=[CH:15][CH:16]=1)[CH2:21][C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: Clc1cccc(Cl)c1C=Cc1ccc(C2CN(Cc3ccccc3)CCO2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(CCc2ccc(C3CNCCO3)cc2)cc1
Yield: 100.1 %

Procedure:
A mixture of 4-benzyl-2-{4-[2-(2,6-dichloro-phenyl)-vinyl]-phenyl}-morpholine (0.54 g; 1.27 mmol) and palladium hydroxide (0.04 g; 0.25 mmol) in MeOH (25 mL) was treated with H2, at normal pressure, overnight. The resulting mixture was filtered over Kieselguhr and the solvents evaporated to afford 2-(4-phenethyl-phenyl)-morpholine (0.34 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1.C(N(CC)CC)C.[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27](O)=[O:28].CCN=C=NCCCN(C)C.Cl>C(Cl)Cl>[CH3:25][C:26](=[CH:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C:27]([NH:2][C@H:3]([C:14]([O:16][CH3:17])=[O:15])[CH2:4][C:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[NH:7][CH:6]=1)=[O:28]
Reactant: CC(=Cc1ccccc1)C(=O)O
Reactant: COC(=O)[C@@H](N)Cc1c[nH]c2ccccc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C(C)=Cc1ccccc1
Yield: 93.7 %

Procedure:
The same procedures as in Example 146 were carried out from methyl L-tryptophanate hydrochloride (3.0 g), triethylamine (2.0 mL), α-methylcinnamic acid (2.3 g), WSC.HCl (2.7 g), and methylene chloride (80 mL), to give the captioned compound (4.0 g, 94%) as an oily product.
Reaction SMILES: [OH-].[Na+].CC(O)C.[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:20]=[CH:19][C:14]=1[C:15]([O:17]C)=[O:16])=[O:11].[ClH:46]>O>[ClH:46].[OH:7][C:8]1[CH:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][N:36]2[CH2:41][CH2:40][N:39]([S:42]([CH3:45])(=[O:44])=[O:43])[CH2:38][CH2:37]2)=[CH:29][C:9]=1[C:10]([NH:12][C:13]1[CH:22]=[C:21]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:20]=[CH:19][C:14]=1[C:15]([OH:17])=[O:16])=[O:11]
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCN2CCN(S(C)(=O)=O)CC2)ccc1O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)O
Product: CS(=O)(=O)N1CCN(CCOc2ccc(O)c(C(=O)Nc3cc(-c4ccccc4)ccc3C(=O)O)c2)CC1
Temperature: 50 °C
Reaction time: 2 h

Procedure:
A 2.0 mol/L aqueous solution of sodium hydroxide (0.17 mL) was added to 2-propanol (1.2 mL) suspension of the obtained methyl 2-(2-hydroxy-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoate (0.063 g), followed by stirring at 50° C. for 2 hours. The reaction mixture was cooled to room temperature, and then water was added thereto. After adjusting the pH to 6.5 with 1.0 mol/L hydrochloric acid, the solid substance was collected by filtration. Ethyl acetate (2.0 mL) and a 4.0 mol/L hydrogen chloride-dioxane solution (0.10 mL) were added to the obtained solid substance, followed by stirring at room temperature for 1 hour. The solid substance was collected from the reaction mixture by filtration to obtain 0.025 g of 2-(2-hydroxy-5-(2-(4-(methylsulfonyl)piperazin-1-yl)ethoxy)benzamido)-4-phenylbenzoic acid hydrochloride as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](O)=[O:24])=[CH:17][CH:16]=2)=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([N:35](CC)[CH2:36]C)C.CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CNC>C(Cl)Cl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH:9]([C:28](=[O:32])[N:29]([CH3:31])[CH3:30])[C:10]1[CH:27]=[CH:26][C:13]([O:14][C:15]2[CH:16]=[CH:17][C:18]([CH2:21][CH2:22][C:23](=[O:24])[N:35]([CH3:36])[CH3:33])=[CH:19][CH:20]=2)=[CH:12][CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: CCN(CC)CC
Reactant: CN(C)C(=O)C(NC(=O)OC(C)(C)C)c1ccc(Oc2ccc(CCC(=O)O)cc2)cc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: CNC
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Product: CN(C)C(=O)CCc1ccc(Oc2ccc(C(NC(=O)OC(C)(C)C)C(=O)N(C)C)cc2)cc1
Temperature: 25 °C
Yield: 94.3 %

Procedure:
Acid compound 33 (0.7 g, 1.58 mmol) was dissolved in DCM (20 mL) and stirred at room temp under an atmosphere of argon. Triethylamine (0.26 mL, 1.9 mmol) and BOP reagent (0.77 g, 1.74 mmol) were added and the reaction mixture was stirred for 15 min. Dimethylamine (2.0 M solution in THF, 4.0 mL, 7.9 mmol) was added and the resulting solution was stirred at room temp for about 2-3 h. The solvent was removed under reduced pressure and the resulting oil was taken up in EtOAc (200 mL). The organic layer was extracted with 0.5 N NaOH (1×30 mL), water (2×100 mL) and brine (1×100 mL). Drying and concentration of the organic layer gave the desired amide 40 (0.7 g, 94.5%). 1H NMR (400 MHz, DMSO-d6): 7.33 (d, J=8.4 Hz, 2H), 7.26 (d, J=8.4 Hz, 2H), 7.11 (d, J=8.0 Hz, 1H), 6.93 (overlapped d, J=8.4 Hz, 2H), 6.92 (overlapped d, J=8.4 Hz, 2H), 5.50 (d, J=7.6 Hz, 2H), 2.93 (s, 3H), 2.90 (s, 3H), 2.84 (s, 3H), 2.82 (s, 3H), 2.79 (t, J=8.0 Hz, 2H), 2.59 (t, J=8.0 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]1[N:18]=[CH:17][NH:16][N:15]=1.[CH3:19][Si:20]([CH2:23][CH2:24][O:25][CH2:26]Cl)([CH3:22])[CH3:21].[I-].[K+].[H-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[O:12][C:11]([I:13])=[N:10][C:9]=1[C:14]1[N:18]([CH2:26][O:25][CH2:24][CH2:23][Si:20]([CH3:22])([CH3:21])[CH3:19])[CH:17]=[N:16][N:15]=1
Reactant: Clc1ccccc1-c1oc(I)nc1-c1nc[nH]n1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[Si](C)(C)CCOCn1cnnc1-c1nc(I)oc1-c1ccccc1Cl
Temperature: 25 °C
Yield: 11.1 %

Procedure:
To a mixture of 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-1H-1,2,4-triazole (26.0 g, 70.0 mmol), SEM-Cl (16.6 g, 100.0 mmol) and potassium iodide (1.6 g, 10.0 mmol) in DMF (400 mL) was added NaH (4.0 g, 100 mmol). The reaction mixture was allowed to stir at rt until the reaction was complete (as judged by TLC analysis). The reaction mixture was poured into water and extracted with EtOAc. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give 3-[5-(2-chlorophenyl)-2-iodo-1,3-oxazol-4-yl]-4-{[2-(trimethylsilyl)-ethoxy]methyl}-4H-1,2,4-triazole (3.9 g, 11%) plus two other SEM regioisomers (9.39 g, 26.2%). All three isomers could be separated and could be used for the following steps.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8]C(=O)C(C)(C)C)=[C:4]([CH3:15])[C:3]=1[C:16]([F:19])([F:18])[F:17].Cl>C(O)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([CH3:15])[C:3]=1[C:16]([F:17])([F:18])[F:19]
Reactant: Cc1c(NC(=O)C(C)(C)C)ccc(Cl)c1C(F)(F)F
Agent: Cl
Solvent: CCO
Product: Cc1c(N)ccc(Cl)c1C(F)(F)F
Yield: 75.8 %

Procedure:
N-(4-Chloro-2-methyl-3-trifluoromethylphenyl)-2,2-dimethyl-propionamide 1.0 g, 3.4 mmol) was added to a 1:1 mixture (15 mL) of concentrated HCl and ethanol and heated at reflux for overnight. The reaction was cooled and concentrated in vacuo to give a tan solid which was then partitioned between EtOAc and saturated NaHCO3. The organic layer was separated, washed with water, brine, dried (Na2SO4), filtered and concentrated to give compound 760C (0.54g, 76%) as a brown oily solid.
Reaction SMILES: Cl[CH2:2][C:3](Cl)=[O:4].C(O)(=O)C.C[O:11][C:12]([C@H:14]1[CH2:19][CH2:18][C@H:17]([CH2:20][NH:21][C:22](=[O:30])[C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[NH2:29])[CH2:16][CH2:15]1)=[O:13].Cl.[H-].[Na+].[Cl-].[NH4+]>C(Cl)Cl.CN(C=O)C>[O:4]=[C:3]1[NH:29][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=2[C:22](=[O:30])[N:21]([CH2:20][C@H:17]2[CH2:18][CH2:19][C@H:14]([C:12]([OH:13])=[O:11])[CH2:15][CH2:16]2)[CH2:2]1
Reactant: O=C(Cl)CCl
Reactant: COC(=O)[C@H]1CC[C@H](CNC(=O)c2ccccc2N)CC1
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: CN(C)C=O
Solvent: CC(=O)O
Solvent: ClCCl
Product: O=C1CN(C[C@H]2CC[C@H](C(=O)O)CC2)C(=O)c2ccccc2N1
Temperature: 80 °C
Reaction time: 0.5 h

Procedure:
A solution of chloroacetyl chloride (470 μL) in dry DCM (6 mL) was added dropwise to a stirred solution of trans-4-[(2-Amino-benzoylamino)-methyl]-cyclohexanecarboxylic acid methyl ester acetate (3 mmol, 0.850 g) and TEA (9 mmol, 1.2 mL) in dry DCM (44 mL) under argon at 0° C. The mixture was allowed to reach room temperature within 30 minutes. After reaction completion, the reaction mixture was poured into 2N HCl solution (10 mL) and extracted with DCM (3×40 mL). The organic layer was washed with a saturated solution of NaHCO3 (1×30 mL) and brine (2×30 mL). Finally, the solvent was removed under reduced pressure. NaH (60% on mineral oil 13.5 mmol, 0.54 g) was added to a solution of the crude product in dry DMF (11 mL) and the mixture was heated at 80° C. for 4 h, then the reaction mixture was allowed to reach room temperature. A saturated ammonium chloride solution (10 mL) was added to the mixture and the final mixture was washed with DCM (2×20 mL) and then the mixture was acidified with (2 N) HCl and extracted with DCM (3×10 mL). The organic layer was washed with brine (2×10 mL) dried over Na2SO4 anhydrous, concentrated under reduced pressure and filtrate on silica pad. The silica pad was washed 3 times with a DCM-MeOH 95-5 all the washings were collected together and the solvent was removed under reduced pressure to afford the titled compound (0.49 g, yield 57%).
Reaction SMILES: O=P(Cl)(Cl)[Cl:3].[C:6]([CH2:9][S:10][C:11]1[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=1[C:13](O)=O)(O)=O.[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:25]>CN(C=O)C>[CH3:20][N+:21]([CH3:24])=[CH:22][Cl:23].[Cl-:3].[Cl:25][C:13]1[C:12]2[CH:16]=[CH:17][CH:18]=[CH:19][C:11]=2[S:10][C:9]=1[CH2:6][NH:21][CH3:20]
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=C(O)CSc1ccccc1C(=O)O
Agent: C[N+](C)=CCl
Agent: [Cl-]
Solvent: CN(C)C=O
Product: CNCc1sc2ccccc2c1Cl
Temperature: 25 °C
Yield: 68 %

Procedure:
Vilsmeier reagent was prepared via the dropwise addition of POCl3 (7.9 mL, 84 mmol) into ice-cold DMF (14 mL). A solution of 2-carboxymethylsulfanyl-benzoic acid (3.0 g, 14 mmol) in DMF (15 mL) was added dropwise to the Vilsmeier reagent. The resulting mixture was warmed to room temperature and then heated to 80° C. for 3.5 h. The reaction mixture was cooled to ambient temperature. Crushed ice was added until a bright yellow precipitate appeared. The solid was isolated by filtration. Purification by flash column chromatography (silica gel, hexanes/ethyl acetate 3:2) gave the title compound (1.87 g, 68%) as a yellow powder: 1H NMR (300 MHz, CDCl3) δ 10.36 (s, 1H), 8.03 (m, 1H), 7.86 (m, 1H), 7.59-7.53 (m, 2H).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[C:8]([O:11][C:12]3[CH:21]=[CH:20][N:19]=[C:18]4[C:13]=3[C:14]3[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=3[C:16](=[O:22])[NH:17]4)[CH:9]=[CH:10][C:5]=2[NH:4][CH2:3][CH2:2]1.[N:27]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=1)=[C:28]=[O:29]>>[F:37][C:36]([F:38])([F:39])[C:32]1[CH:31]=[C:30]([NH:27][C:28]([N:4]2[C:5]3[CH:10]=[CH:9][C:8]([O:11][C:12]4[CH:21]=[CH:20][N:19]=[C:18]5[C:13]=4[C:14]4[CH:26]=[CH:25][CH:24]=[CH:23][C:15]=4[C:16](=[O:22])[NH:17]5)=[CH:7][C:6]=3[O:1][CH2:2][CH2:3]2)=[O:29])[CH:35]=[CH:34][CH:33]=1
Reactant: O=c1[nH]c2nccc(Oc3ccc4c(c3)OCCN4)c2c2ccccc12
Reactant: O=C=Nc1cccc(C(F)(F)F)c1
Product: O=C(Nc1cccc(C(F)(F)F)c1)N1CCOc2cc(Oc3ccnc4[nH]c(=O)c5ccccc5c34)ccc21
Yield: 22.8 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 221 using 218 (50 mg, 0.14 mmol) and 1-isocyanato-3-trifluoromethyl-benzene (41 mg, 0.22 mmol) to provide 224 (17 mg, 22% yield) as a tan solid. LC-MS (M+H=533, obsd.=533).
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.[CH3:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1>ClCCl>[CH3:1][NH:2][C:3]([NH:32][NH:31][C:29](=[O:30])[C:28]1[CH:27]=[CH:26][C:25]([CH3:24])=[CH:34][CH:33]=1)=[O:4]
Reactant: Cc1ccc(C(=O)NN)cc1
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)NNC(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
653 mg (3.33 mmol) of 4-nitrophenyl methylcarbamate and 473 mg (3.22 mmol) of N,N-diisopropylethylamine are added to 500 mg (3.33 mmol) of 4-methylbenzoic acid hydrazide in 15 ml dichloromethane and the mixture stirred overnight at room temperature. The precipitate formed is recovered by filtration, washed with diethyl ether and dried in vacuo. 602 mg (87% of theory) of the target compound are thus obtained.
Reaction SMILES: [S:1]1[C:5]([CH2:6][O:7][C:8]([NH:10][C@@H:11]([CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH2:12][NH:13][CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]2[S:32][CH:31]=[N:30][CH:29]=2)=[O:25])[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[O:9])=[CH:4][N:3]=[CH:2]1.[CH3:40][CH:41]([CH3:44])[CH:42]=O.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl>[CH3:40][CH:41]([CH3:44])[CH2:42][N:13]([CH2:14][C@@H:15]([NH:23][C:24]([O:26][CH2:27][C:28]1[S:32][CH:31]=[N:30][CH:29]=1)=[O:25])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH2:12][C@@H:11]([NH:10][C:8]([O:7][CH2:6][C:5]1[S:1][CH:2]=[N:3][CH:4]=1)=[O:9])[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=C(N[C@H](CNC[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)Cc1ccccc1)OCc1cncs1
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)CN(C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1)C[C@H](Cc1ccccc1)NC(=O)OCc1cncs1
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
The product from Example 35 (180 mg, 0.32 mmol) in 1,2-dichloroethane (2.0 mL) was treated with 2-methylpropanal (36 μl, 0.38 mmol) at ambient temperature. After stirring for 15 minutes, the mixture was treated with acetic acid (22 μl, 0.38 mmol) and sodium triacetoxyborohydride (108 mg, 0.51 mmol) at ambient temperature. After stirring for 2 hours, the mixture was treated with aqueous 10% sodium bicarbonate (2.0 mL) and extracted with ethyl acetate (3×5 mL). The ethyl acetate extracts were combined, washed with brine (5 mL), dried over sodium sulfate, filtered, and the filtrate was concentrated. The residue was purified by column chromatography on silica gel eluting with (chloroform:methanol, 99:1) to provide the title compound (155 mg, 78%). 1H NMR (CDCl3) δ 8.73 (s, 2H), 7.75 (s, 2H), 7.31-7.11 (m, 10H), 5.33 (br s, 2H), 5.18 (q, 4H), 3.96 (br s, 2H), 2.83 (m, 2H), 2.71 (dd, 2H), 2.42 (t, 2H), 2.21 (dd, 2H), 2.05-1.83 (m, 2H), 1.46 (m, 1H), 0.72 (dd, 6H); MS (ESI+) m/z 622 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([OH:28])=O)[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].Cl.[CH3:31][NH:32][CH3:33]>>[Cl:1][C:2]1[C:3]([CH3:29])=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[N:22]=[C:23]([C:26]([N:32]([CH3:33])[CH3:31])=[O:28])[S:24][CH:25]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: CNC
Reactant: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(=O)O)n3)n2)ccc(C#N)c1Cl
Agent: Cl
Product: Cc1c(-c2ccn(C[C@H](C)NC(=O)c3csc(C(=O)N(C)C)n3)n2)ccc(C#N)c1Cl
Yield: 4.18 %

Procedure:
(S)—N4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-yl)-N2,N2-dimethylthiazole-2,4-dicarboxamide was prepared using the method of Example 34(d) starting from (S)-4-(1-(3-(3-chloro-4-cyano-2-methylphenyl)-1H-pyrazol-1-yl)propan-2-ylcarbamoyl)thiazole-2-carboxylic acid (0.2 g, 0.340 mmol) and dimethylamine hydrochloride (0.023 g, 0.283 mmol). The product was purified by Flash-chromatography and triturated using diethyl ether, respectively. Yield 4.18%. 1H-NMR (400 MHz; CDCl3): δ 1.27 (d, 3H), 2.51 (s, 3H), 3.09 (s, 3H), 3.24 (s, 3H), 4.23 (dd, 1H), 4.45 (dd, 1H), 4.62 (m, 1H), 6.41 (d, 1H), 7.48 (d, 1H), 7.51 (d, 1H), 7.54 (dd, 1H), 7.85 (d, 1H), 8.27 (s, 1H).