Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([NH:5][S:6]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]2[N:16]=[CH:17][N:18]([C:20]3[N:25]=[C:24]([C:26]([F:29])([F:28])[F:27])[CH:23]=[C:22]([C:30]4[CH:35]=[CH:34][C:33]([F:36])=[CH:32][CH:31]=4)[N:21]=3)[CH:19]=2)[CH:10]=1)(=[O:8])=[O:7])(C)(C)C.C(O)(C(F)(F)F)=O>ClCCl>[F:36][C:33]1[CH:32]=[CH:31][C:30]([C:22]2[CH:23]=[C:24]([C:26]([F:27])([F:28])[F:29])[N:25]=[C:20]([N:18]3[CH:19]=[C:15]([C:11]4[CH:10]=[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])[CH:14]=[CH:13][CH:12]=4)[N:16]=[CH:17]3)[N:21]=2)=[CH:35][CH:34]=1
Reactant: CC(C)(C)NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NS(=O)(=O)c1cccc(-c2cn(-c3nc(-c4ccc(F)cc4)cc(C(F)(F)F)n3)cn2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 28 %

Procedure:
To a cooled and stirred solution of N-tert-butyl-3-{1-[6-(4-fluoro-phenyl)-4-trifluoromethyl-pyrimidin-2-yl]-1H-imidazol-4-yl}-benzenesulfonamide (0.52 g) in dichloromethane (4 ml) was added TFA (4 ml) and the reaction mixture was allowed to stir at room temperature for 15 h. The mixture was evaporated to dryness, poured into 2N NaHCO3 solution (25 ml) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 ml), dried (MgSO4) and evaporated. Further purification by flash chromatography on silica gel (dichloromethane/MeOH) and crystallization (ethyl acetate/heptane) yielded the title compound as an off-white solid (0.13 g, 48%). MS (ISN) 462.0 [(M−H)−]; mp 260° C.
Reaction SMILES: [F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14]([O:16]C(C)(C)C)=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:21](O)(C(F)(F)F)=O.C(OC(=O)C)(=O)C>C(Cl)Cl>[F:1][C:2]1[C:7]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][N:9]2[C:14](=[O:16])[CH3:21])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCCCC1c1cccnc1F
Reactant: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: CC(=O)N1CCCCC1c1cccnc1F
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 2-(2-fluoropyridin-3-yl)piperidine-1-carboxylate (70 mg, 0.250 mmol) and DCM (5 mL) was added TFA (0.50 mL, 6.49 mmol). After 1 hour, the reaction was washed with 10% Na2CO3. The organic layer was treated with TEA (0.070 mL, 0.499 mmol), then acetic anhydride (0.024 mL, 0.250 mmol). After 15 minutes, LC-MS shows conversion to the desired product [M+1=223]. The reaction was washed with water and concentrated in vacuo to give 1-(2-(2-fluoropyridin-3-yl)piperidin-1-yl)ethanone as a yellow oil.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]([O:32]CC)=[O:31])[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:24]2)=[CH:17][CH:16]=1.[OH-].[Na+].C(O)C.Cl>O1CCCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][N:23]2[CH:27]=[C:26]([CH2:28][CH2:29][C:30]([OH:32])=[O:31])[C:25]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)=[N:24]2)=[CH:17][CH:16]=1
Reactant: CCOC(=O)CCc1cn(CCc2ccc(OCc3nc(-c4ccccc4)oc3C)cc2)nc1-c1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1oc(-c2ccccc2)nc1COc1ccc(CCn2cc(CCC(=O)O)c(-c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 100.8 %

Procedure:
A mixture of ethyl 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionate (900 mg), 1N aqueous sodium hydroxide solution (3.4 ml), ethanol (3 ml) and tetrahydrofuran (3 ml) was stirred at room temperature for 2 hours. The reaction mixture was acidified with dilute hydrochloric acid, which was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium chloride solution, dried (MgSO4), then concentrated. The crystals obtained were collected by filtration to yield 3-[1-[2-[4-(5-methyl-2-phenyl-4-oxazolylmethoxy)phenyl]ethyl]-3-phenyl-1H-pyrazol-4-yl]propionic acid (860 mg, yield: 91%). This was recrystallized from ethyl acetate-hexane. Melting point: 85–86° C.
Reaction SMILES: C(N1C=CN=C1)(N1C=CN=C1)=O.[C:13]1(/[CH:19]=[CH:20]/[CH:21]=[CH:22]/[C:23]([OH:25])=O)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(N(CC)CC)C.Cl.[NH2:34][CH2:35][CH2:36][S:37][CH2:38][CH2:39][C:40]([O:42][CH3:43])=[O:41]>O1CCCC1>[CH3:43][O:42][C:40](=[O:41])[CH2:39][CH2:38][S:37][CH2:36][CH2:35][NH:34][C:23](=[O:25])/[CH:22]=[CH:21]/[CH:20]=[CH:19]/[C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: O=C(O)/C=C/C=C/c1ccccc1
Reactant: COC(=O)CCSCCN
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COC(=O)CCSCCNC(=O)/C=C/C=C/c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 67 %

Procedure:
1,1′-Carbonyldiimidazole (0.36 g, 2.2 mmol) was added to a solution of 5-phenyl-penta-2E,4E-dienoic acid (1/1) (0.35 g, 2 mmol) in dry tetrahydrofuran (10 ml) and the obtained mixture was stirred for 1 hour at ambient temperature. To the mixture triethylamine (0.30 g 3.0 mmol) and methyl 3-(2-amino-ethylsulfanyl)-propionate hydrochloride (2e) (2.2 mmol) were added and the resultant suspension was stirred for 6 hours at ambient temperature. The solvent was removed under reduced pressure, to the residue water (15 ml) was added and the precipitate was filtered off, washed with water and dried, to give the title product. Yield 67%, m.p. 58-60° C. 1H NMR (90 MHz, DMSO-d6) δ: 2.54-2.89 (6H, m, CH2); 2.96-3.45 (2H, m, CH2); 3.61 (3H, s, CH3); 6.14 (1H, d, J=14.5 Hz, CH); 6.81-7.16 (2H, m, CH—CH); 7.11-7.69 (6H, m, C6H5, CH); 8.18 (1H, t, J=5.4 Hz, NH).
Reaction SMILES: [CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13](Br)[CH:12]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3].[F:24][C:25]1[CH:30]=[C:29]([F:31])[CH:28]=[CH:27][C:26]=1B(O)O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1>[CH2:1]([C:4]1([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:9][C:8](=[O:10])[N:7]([C:11]2[CH:12]=[C:13]([C:28]3[CH:27]=[CH:26][C:25]([F:24])=[CH:30][C:29]=3[F:31])[CH:14]=[CH:15][CH:16]=2)[CH2:6][CH2:5]1)[CH:2]=[CH2:3]
Reactant: C=CCC1(c2ccccc2)CCN(c2cccc(Br)c2)C(=O)O1
Reactant: OB(O)c1ccc(F)cc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: C=CCC1(c2ccccc2)CCN(c2cccc(-c3ccc(F)cc3F)c2)C(=O)O1
Yield: 18.4 %

Procedure:
To a solution of 6-allyl-3-(3-bromophenyl)-6-phenyl-1,3-oxazinan-2-one (50 mg, 0.134 mmol) and 2,4-difluorophenylboronic acid (40 mg, 0.215 mmol), K2CO3 (0.5 mL, 2 M) in 1,4-dioxane (1.5 ml) was slowly added Pd(Ph3)2Cl2 (10 mg, 20%) at 0° C. under N2. The mixture was refluxed overnight. The mixture was concentrated to give the crude product, which was purified by TLC and preparative HPLC to afford 6-allyl-3-(2′,4′-difluorobiphenyl-3-yl)-6-phenyl-1,3-oxazinan-2-one (10 mg, 18%). 1H NMR (400 MHz, CDCl3): δ=2.40 (m, 2H), 2.55-2.72 (m, 2H), 3.26 (m, 1H), 3.47 (m, 1H), 5.05 (m, 2H), 5.76 (m, 1H), 6.76-6.90 (m, 2H), 7.04 (m, 1H), 7.28 (m, 4H), 7.36 (m, 2H).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][CH2:4][C@H:3]1[NH:13][C:14]([NH:16][C:17]1[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=1)=[O:15].I[CH2:25][C:26]([N:28]1[CH2:33][CH:32]([CH3:34])[CH2:31][CH:30]([CH3:35])[CH2:29]1)=[O:27]>C1COCC1>[CH3:35][CH:30]1[CH2:31][CH:32]([CH3:34])[CH2:33][N:28]([C:26](=[O:27])[CH2:25][N:8]2[C:7]3[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=3[O:5][CH2:4][C@@H:3]([NH:13][C:14]([NH:16][C:17]3[CH:18]=[C:19]([CH3:23])[CH:20]=[CH:21][CH:22]=3)=[O:15])[C:2]2=[O:1])[CH2:29]1
Reactant: Cc1cccc(NC(=O)N[C@@H]2COc3ccccc3NC2=O)c1
Reactant: CC1CC(C)CN(C(=O)CI)C1
Solvent: C1CCOC1
Product: Cc1cccc(NC(=O)N[C@@H]2COc3ccccc3N(CC(=O)N3CC(C)CC(C)C3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 72 %

Procedure:
A solution of 0.100 g (0.000325M) (R)-(8-oxo-6,7,8,9-tetrahydro-5-oxa-9-aza-benzocyclohepten-7-yl)-3-m-tolyl-urea in 5 ml of THF was cooled to -78° C. under a nitrogen atmosphere. To this solution was added dropwise 0.321 mL (0.000325M) of lithium bis-hexamethyldisilylamide (1M solution in THF) and the reaction was stirred for 15 minutes. To this mixture was added 0.090 ml (0.000325M) of N-iodoacetyl-3,5-dimethyl piperidine. After addition was complete, the reaction was warmed to room temperature and stirred for 30 minutes. The reaction mixture was quenched with 5 mL of water, and extracted with ethyl acetate. The ethyl acetate extracts were dried and evaporated. The residue was chromatographed on 15 g of silica using 10:1 chloroform:methanol as the eluant. The appropriate fractions were combined and evaporated to yield 109 mg (72% yield) of product as a white solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:20][OH:21])[CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:13][CH:14]=1.Cl[C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[C:6]([F:19])[C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]([C:15]([F:16])([F:17])[F:18])=[CH:13][CH:14]=1)[CH2:20][O:21][C:23]1[CH:24]=[C:25]2[N:32]([CH3:33])[C:31]([CH3:35])([CH3:34])[CH2:30][N:26]2[C:27](=[O:29])[N:28]=1
Reactant: OCc1cc(F)c(Oc2ccc(C(F)(F)F)nc2)c(F)c1
Reactant: CN1c2cc(Cl)nc(=O)n2CC1(C)C
Product: CN1c2cc(OCc3cc(F)c(Oc4ccc(C(F)(F)F)nc4)c(F)c3)nc(=O)n2CC1(C)C

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (3,5-difluoro-4-((6-(trifluoromethyl)pyridin-3-yl)oxy)phenyl)methanol and 7-chlo-ro-1,2,2-trimethyl-2,3-dihydroimidazo[1,2-c]pyrimidin-5(1H)-one.
Reaction SMILES: [C:1]([C@H:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:5]([OH:9])[C:6]([OH:8])=[O:7])([OH:3])=[O:2].F[C:15](F)(F)C(OC(=O)C(F)(F)F)=O>>[C:1]([C@H:4]([CH2:10][CH:11]([CH3:13])[CH3:12])[C@H:5]([OH:9])[C:6]([O:8][CH3:15])=[O:7])([OH:3])=[O:2]
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](O)C(=O)O
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Product: COC(=O)[C@@H](O)[C@@H](CC(C)C)C(=O)O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.48 g of 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoic acid were stirred under nitrogen in 10 ml of trifluoroacetic anhydride for 1.5 hours. The solvent was evaporated and the residue was dissolved in 20 ml of dry methanol and stirred overnight at room temperature. The solvent was evaporated to give 5.3 g of methyl 3(R)-carboxy-2(S)-hydroxy-5-methylhexanoate in the form of an orange oil.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([CH:8]([N:11]2[CH2:16][CH2:15][O:14][CH2:13][CH2:12]2)[CH2:9][F:10])[CH:5]=[CH:4][CH:3]=1.[NH2:17][C:18]1[S:19][C:20]([C:26]2[CH:31]=[CH:30][C:29]([C:32]([OH:35])([CH3:34])[CH3:33])=[CH:28][C:27]=2[F:36])=[CH:21][C:22]=1[C:23]([NH2:25])=[O:24]>>[F:36][C:27]1[CH:28]=[C:29]([C:32]([OH:35])([CH3:33])[CH3:34])[CH:30]=[CH:31][C:26]=1[C:20]1[S:19][C:18]([NH:17][C:2]2[CH:3]=[CH:4][CH:5]=[C:6]([CH:8]([N:11]3[CH2:16][CH2:15][O:14][CH2:13][CH2:12]3)[CH2:9][F:10])[N:7]=2)=[C:22]([C:23]([NH2:25])=[O:24])[CH:21]=1
Reactant: FCC(c1cccc(Br)n1)N1CCOCC1
Reactant: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(N)s2)c(F)c1
Product: CC(C)(O)c1ccc(-c2cc(C(N)=O)c(Nc3cccc(C(CF)N4CCOCC4)n3)s2)c(F)c1

Procedure:
The title compound was prepared according to the general procedure in Example 1 using 4-[1-(6-bromopyridin-2-yl)-2-fluoroethyl]morpholine (36.3 mg, 0.13 mmol) and 2-amino-5-[2-fluoro-4-(1-hydroxy-1-methylethyl)phenyl]thiophene-3-carboxamide (37 mg, 0.13 mmol) as the starting materials.
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[S:10]([NH2:13])(=[O:12])=[O:11].[Br:14][C:15]1[CH:20]=[CH:19][C:18]([N:21]=[C:22]=[O:23])=[CH:17][CH:16]=1>>[Br:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:13][S:10]([C:2]2[O:1][C:5]3[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=3[CH:3]=2)(=[O:11])=[O:12])=[O:23])=[CH:17][CH:16]=1
Reactant: O=C=Nc1ccc(Br)cc1
Reactant: NS(=O)(=O)c1cc2ccccc2o1
Product: O=C(Nc1ccc(Br)cc1)NS(=O)(=O)c1cc2ccccc2o1
Yield: 76.6 %

Procedure:
2-Benzofuransulfonamide (7.6 mmol), prepared as described in Example 1, was reacted with 4-bromophenylisocyanate (7.6 mmol) as described in Method A to obtain 2.3 g of the title product as a solid. 1H NMR (CD3SOCD3): δ9.35 (s, 1 H), 7.87 (d, J =8 Hz, 1 H), 7.82 (s, 1 H), 7.78 (d, J =8 Hz, 1 H), 7.58 (dd, J =8, 8 Hz, 1 H), 7.46 (d, J =9 Hz, 2 H), 7.44 (dd, J =8, 8 Hz, 1 H), 7.38 (d, J =9 Hz, 2 H).
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[Cl:34])[N:30](COCC[Si](C)(C)C)[N:29]=[C:28]3[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(OCC)(=O)C>O1CCCC1>[C:19]1([C:25]2[CH:26]=[C:27]3[C:31](=[CH:32][C:33]=2[Cl:34])[NH:30][N:29]=[C:28]3[NH:43][C:44](=[O:48])[CH2:45][CH2:46][CH3:47])[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCCC(=O)Nc1nn(COCC[Si](C)(C)C)c2cc(Cl)c(-c3ccccc3)cc12
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CCCC(=O)Nc1n[nH]c2cc(Cl)c(-c3ccccc3)cc12
Temperature: 67 °C

Procedure:
8.8 cm3 of tetrabutylammonium fluoride as a 1M solution in tetrahydrofuran are added to 650 mg of N-[5-phenyl-6-chloro-1-[[2-(trimethylsilyl]ethoxy]methyl]-1H-indazol-3-yl]butanamide, described previously, in 25 cm3 of tetrahydrofuran. The medium is maintained at 67° C. for 20 hours and is then allowed to return to room temperature and 75 cm3 of ethyl acetate are added; the organic phase is washed with 75 cm3 of saturated aqueous sodium hydrogen carbonate solution and then with 2×75 cm3 of saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulphate, filtered and evaporated to dryness under reduced pressure (2 kPa; 45° C.). The residue is purified by chromatography under an argon pressure of 50 kPa, on a column of silica gel (particle size 40-60 μm; diameter 3.5 cm), eluting with a cyclohexane/ethyl acetate mixture (70/30 by volume). The fractions containing the expected product are combined and evaporated under reduced pressure (2 kPa; 50° C.) and the residue is taken up in 15 cm3 of diisopropyl ether, filtered off on a sinter funnel and washed successively with 10 cm3 of diisopropyl ether and with 5 cm3 of ethyl acetate. After drying under reduced pressure (90 Pa; 50° C.), 240 mg of N-(5-phenyl-6-chloro-1H-indazol-3-yl)butanamide are obtained in the form of a white solid melting at 235° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][NH:25][CH2:26][CH:27]([CH3:29])[CH3:28])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10].[C:34](O)(=[O:40])[CH2:35][CH2:36][C:37]([CH3:39])=[O:38].Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][NH:8][C:9]([C@H:11]([C@@H:21]([CH2:30][CH:31]([CH3:33])[CH3:32])[C:22]([NH:24][N:25]([C:34](=[O:40])[CH2:35][CH2:36][C:37](=[O:38])[CH3:39])[CH2:26][CH:27]([CH3:28])[CH3:29])=[O:23])[CH2:12]/[CH:13]=[CH:14]/[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]
Reactant: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Reactant: CC(=O)CCC(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Product: CC(=O)CCC(=O)N(CC(C)C)NC(=O)[C@H](CC(C)C)[C@H](C/C=C/c1ccccc1)C(=O)NOC1CCCCO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 102.3 %

Procedure:
A solution of 0.459 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-isobutyl-4-methylvalerohydrazide in 5 ml of dimethylformamide was treated with 0.232 g of levulinic acid and 0.384 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred overnight at room temperature and evaporated. The residue in ethyl acetate was washed with 5% aqueous citric acid solution, 5% aqueous sodium hydrogen carbonate solution, saturated sodium chloride solution, and then dried over anhydrous magnesium sulphate and evaporated to give 0.570 g of (E)-2(R)-[1(S)-[(tetrahydro-2(RS)-pyranyloxy)carbamoyl]-4-phenyl-3-butenyl]-2′-(4-oxovaleryl)-2′-isobutyl-4-methylvalerohydrazide in the form of a white foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[CH:22])=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23].Br[C:25]1[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:15])([F:17])[F:16])[N:11]3[N:18]=[CH:19][C:20]([C:21]#[C:22][C:25]4[CH:26]=[C:27]([S:31]([NH2:34])(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=4)=[C:10]3[N:9]=2)=[CH:4][C:3]=1[CH3:23]
Reactant: NS(=O)(=O)c1cccc(Br)c1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)c(C)c3)nc12
Product: Cc1cc(-c2cc(C(F)(F)F)n3ncc(C#Cc4cccc(S(N)(=O)=O)c4)c3n2)ccc1Cl

Procedure:
The title compound was prepared from 5-(4-chloro-3-methyl-phenyl)-3-ethynyl-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine (example C.11) (168 mg, 0.5 mmol) and commercially available 3-bromo-benzenesulfonamide (118 mg, 0.5 mmol) according to general procedure II. Obtained as a yellow solid (114 mg, 46%). MS (ISN) 489.2 [(M−H)−]; mp 234° C.
Reaction SMILES: [C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([CH2:21][CH2:22][CH2:23][N:24]2[CH2:29][CH2:28][CH:27]([CH2:30][C:31]3[CH:36]=[CH:35][C:34]([NH2:37])=[CH:33][CH:32]=3)[CH2:26][CH2:25]2)[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].C(N(CC)CC)C.[CH3:45][S:46](Cl)(=[O:48])=[O:47].[OH-].[Na+]>O1CCCC1>[C:1]([N:4]1[CH2:9][CH2:8][CH:7]([C:10]([N:12]([C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([Cl:20])[CH:14]=2)[CH2:21][CH2:22][CH2:23][N:24]2[CH2:25][CH2:26][CH:27]([CH2:30][C:31]3[CH:32]=[CH:33][C:34]([NH:37][S:46]([CH3:45])(=[O:48])=[O:47])=[CH:35][CH:36]=3)[CH2:28][CH2:29]2)=[O:11])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(N)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CC(=O)N1CCC(C(=O)N(CCCN2CCC(Cc3ccc(NS(C)(=O)=O)cc3)CC2)c2ccc(Cl)c(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 78.8 %

Procedure:
1-Acetyl-N-{3-[4-(4-aminobenzyl)-1-piperidinyl]propyl}-N-(3,4-dichlorophenyl)-4-piperidinecarboxamide (Example 303) (18 mg, 0.033 mmol) was dissolved in tetrahydrofuran (0.3 mL). To the solution were added triethylamine (5.0 mg, 0.050 mmol) and methanesulfonyl chloride (4.9 mg, 0.043 mmol), and the mixture was stirred at room temperature for 30 minutes. To the reaction mixture was added aqueous solution of 1N-sodium hydroxide (5 mL), and the mixture was extracted with ethyl acetate (5 mL×2). The organic layer was dried over magnesium sulfate and concentrated under reduced pressure. The concentrate was subjected to alumina column chromatography (alumina 2 g, ethyl acetate), and the desired fraction was concentrated under reduced pressure to give the titled compound (16 mg, 0.026 mmol, Yield 78%) as a colorless oily substance.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:16]=[CH:15][C:11]([C:12]([OH:14])=O)=[CH:10][CH:9]=1)[CH3:7].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:49][CH2:50][C:51]1[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=1[CH3:57]>ClCCl>[Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[O:5][CH:6]([C:8]1[CH:9]=[CH:10][C:11]([C:12]([NH:49][CH2:50][C:51]2[C:52]([OH:59])=[N:53][C:54]([CH3:58])=[CH:55][C:56]=2[CH3:57])=[O:14])=[CH:15][CH:16]=1)[CH3:7]
Reactant: CC(Oc1cccc(Br)c1)c1ccc(C(=O)O)cc1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)Oc3cccc(Br)c3)cc2)c(O)n1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 94.1 %

Procedure:
To a solution of 4-(1-(3-bromophenoxy)ethyl)benzoic acid (0.9 g, 2.8 mmol), 1-ethyl-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g, 4.0 mmol) and 1-hydroxybenzotriazole (0.54 g, 4.0 mmol) in dichloromethane (20 mL) was added triethylamine (0.8 g, 8.0 mmol). The reaction mixture was stirred for 15 minutes at room temperature, then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (0.76 g, 5 mmol) was added. The reaction mixture was stirred at room temperature for 12 hours. After the reaction, the mixture was washed with water (20 mL), concentrated and purified by column chromatography (silica gel: dichloromethane: methanol=20:1) to give pure product 4-(1-(3-bromophenoxy)ethyl)-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)benzamide (1.2 g, 93%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][C:9]([C:11]2([C:14]3[CH:24]=[CH:23][C:17]4[O:18][C:19]([F:22])([F:21])[O:20][C:16]=4[CH:15]=3)[CH2:13][CH2:12]2)=[O:10])[CH:5]=[CH:4][C:3]=1[CH3:25].[O:26]=[C:27]1[CH:32]=[CH:31][C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][N:28]1[CH2:42][C:43]#[N:44].C(=O)([O-])[O-].[K+].[K+]>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.COCCOC>[C:43]([CH2:42][N:28]1[C:27](=[O:26])[CH:32]=[CH:31][C:30]([C:2]2[N:7]=[C:6]([NH:8][C:9]([C:11]3([C:14]4[CH:24]=[CH:23][C:17]5[O:18][C:19]([F:21])([F:22])[O:20][C:16]=5[CH:15]=4)[CH2:13][CH2:12]3)=[O:10])[CH:5]=[CH:4][C:3]=2[CH3:25])=[CH:29]1)#[N:44]
Reactant: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1Cl
Reactant: CC1(C)OB(c2ccc(=O)n(CC#N)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: [K+]
Solvent: COCCOC
Product: Cc1ccc(NC(=O)C2(c3ccc4c(c3)OC(F)(F)O4)CC2)nc1-c1ccc(=O)n(CC#N)c1
Temperature: 80 °C
Yield: 6.1 %

Procedure:
N-(6-chloro-5-methylpyridin-2-yl)-1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamide (325.2 mg, 0.89 mmol), 2-(2-oxo-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-1(2H)-yl)acetonitrile (0.300 g, 1.15 mmol), tetrakis(triphenylphosphine)palladium (0) (51 mg, 0.044 mmol) and potassium carbonate (1.71 g, 1.11 mL of 2 M, 2.21 mmol) were combined in a scintillation vial containing 1,2-dimethoxyethane (8 mL). The reaction mixture was then stirred and heated to 80° C. overnight. The crude reaction mixture was purified by reverse-phase preparative liquid chromatography to yield the product (25.3 mg, 6.1%) as a trifluoracetic acid salt. ESI-MS m/z calc. 464.1. found 465.1 (M+1)+. Retention time 2.00 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([NH:20][N:21]1[C:27](=[O:28])[CH:26]([CH2:29][CH:30]2[CH2:32][CH2:31]2)[C:25]2[CH:33]=[CH:34][CH:35]=[CH:36][C:24]=2[C:23]2[CH:37]=[CH:38][CH:39]=[CH:40][C:22]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Reactant: C[C@H](N)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21
Agent: Cl
Product: C[C@H](NC(=O)[C@@H](O)c1cc(F)cc(F)c1)C(=O)NN1C(=O)C(CC2CC2)c2ccccc2-c2ccccc21

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-7-cyclopropylmethyl-5,7-dihydro-6H-dibenz[b,d]azepin-6-one hydrochloride (Example 7-R), the title compound was prepared. The product was purified by chromatography (silica, 2.5% MeOH/CHCl3).