Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[F:8].C(Cl)(=O)C(Cl)=O.[NH2:19][C:20](=[N:26]O)[C:21]([O:23][CH2:24][CH3:25])=[O:22].C(N(CC)C(C)C)(C)C>ClCCl.N1C=CC=CC=1.CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[F:8])[CH2:9][C:10]1[O:12][N:26]=[C:20]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[N:19]=1
Reactant: O=C(O)Cc1ccc(F)c(F)c1
Reactant: CCOC(=O)C(N)=NO
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)c1noc(Cc2ccc(F)c(F)c2)n1
Yield: 34.1 %

Procedure:
This compound was prepared according to general method 2 with (step I) 2-(3,4-difluorophenyl)acetic acid (0.651 g; 3.78 mmol) and oxalyl chloride (0.352 mL; 4.16 mmol) in dichloromethane (8 mL) with few drops of DMF and (step II) ethyl 2-amino-2-(hydroxyimino)acetate (0.5 g; 3.78 mmol) and N,N diisopropylethylamine (1.05 mL; 6.06 mmol) in dichloromethane (10 mL), and (step III) pyridine (18 mL). The crude material was purified by flash chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) to yield 0.346 g (34%) of ethyl 5-(3,4-difluorobenzyl)-1,2,4-oxadiazole-3-carboxylate as a yellow solid.
Reaction SMILES: Br[C:2](=[CH2:13])[CH2:3][CH2:4][O:5][Si:6]([C:9]([CH3:12])([CH3:11])[CH3:10])([CH3:8])[CH3:7].C([Li])(C)(C)C.[Si:19]([O:26][CH2:27]/[CH:28]=[N:29]/[S@:30]([C:32]([CH3:35])([CH3:34])[CH3:33])=[O:31])([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]>C1COCC1>[CH3:33][C:32]([S@@:30]([NH:29][C@@H:28]([C:2](=[CH2:13])[CH2:3][CH2:4][O:5][Si:6]([CH3:8])([CH3:7])[C:9]([CH3:10])([CH3:11])[CH3:12])[CH2:27][O:26][Si:19]([CH3:21])([CH3:20])[C:22]([CH3:25])([CH3:24])[CH3:23])=[O:31])([CH3:35])[CH3:34]
Reactant: C=C(Br)CCO[Si](C)(C)C(C)(C)C
Reactant: CC(C)(C)[S@](=O)/N=C/CO[Si](C)(C)C(C)(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C=C(CCO[Si](C)(C)C(C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)N[S@@](=O)C(C)(C)C
Temperature: -78 °C
Reaction time: 0.75 h
Yield: 73.3 %

Procedure:
To a solution of ((3-bromobut-3-en-1-yl)oxy)(tert-butyl)dimethylsilane (Intermediate 273, 24.66 g, 92.97 mmol) in THF (200 mL) at −78° C. was added tert-butyllithium (1.7M in pentane) (120 mL, 204.54 mmol) dropwise via cannula. The reaction mixture was stirred for 45 minutes at −78° C. The (S,E)-N-(2-((tert-butyldimethylsilyl)oxy)ethylidene)-2-methylpropane-2-sulfinamide (Intermediate 274, 17.2 g, 61.98 mmol) in THF (50 mL) was added dropwise. The reaction mixture was stirred for ˜1.5 hours at −78° C. The reaction was quenched with saturated sodium bicarbonate and extracted twice with ether. The combined organic extracts were dried over magnesium sulfate, filtered and concentrated. Silica gel chromatography (0%-15% ethyl acetate/hexanes) afforded the title compound (21.07 g, 73.3%) as a colorless oil.
Reaction SMILES: [NH2-].[Na+].[Br-].[C:4]([CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([O:6][CH2:7][CH3:8])=[O:5].[N+:39]([C:42]1[CH:43]=[C:44]([CH:47]=[CH:48][CH:49]=1)[CH:45]=O)([O-:41])=[O:40].CCOCC>O1CCCC1.O>[CH2:7]([O:6][C:4](=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH:18]=[CH:45][C:44]1[CH:47]=[CH:48][CH:49]=[C:42]([N+:39]([O-:41])=[O:40])[CH:43]=1)[CH3:8]
Reactant: CCOC(=O)CCCCCCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=Cc1cccc([N+](=O)[O-])c1
Agent: [Br-]
Agent: [NH2-]
Agent: [Na+]
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)CCCCCCCCCC=Cc1cccc([N+](=O)[O-])c1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 42.3 %

Procedure:
Sodium amide (0.40 g, 9.74 mmol) was weighed directly into a flame-dried 50 ml round-bottomed flask filled with argon. 11-Carbethoxyundecyltriphenylphosphonium bromide (5.00 g, 9.0 mmol) was added followed by anhydrous tetrahydrofuran (THF, 15 ml). The mixture was cooled to -30° C. After the reaction mixture had stirred for 30 minutes at -30° C., a solution of m-nitrobenzaldehyde (1.4 g, 9.30 mmol) in anhydrous THF (5 ml) was added dropwise. The reaction mixture was allowed to warm to room temperature and was stirred for 4 hours. Ether was added. The reaction mixture was cooled to 0° C., and H2O was cautiously added to destroy residual base. The ether layer was removed, washed with H2O, 2% NaHSO4 and brine, and dried (MgSO4). The solvent was evaporated under reduced pressure to yield an oily residue. Purification by column chromatography (150 g silica gel, hexanes:ethyl acetate, 15:1) gave the pure compound 4, ethyl-12-(m-nitrophenyl)-11-dodecenoate (1.323 g, 42% yield).
Reaction SMILES: Cl.[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH2:6].C(N(CC)CC)C.S=[C:20]1[CH2:24][S:23][C:22](=[O:25])[NH:21]1>C(O)C>[CH3:2][N:3]([CH3:11])[C:4](=[O:10])[C@@H:5]([CH:7]([CH3:9])[CH3:8])[NH:6][C:20]1[CH2:24][S:23][C:22](=[O:25])[N:21]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)[C@@H](N)C(=O)N(C)C
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: CC(C)[C@@H](NC1=NC(=O)SC1)C(=O)N(C)C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of the crude product (19.6 g) containing N,N-dimethyl-D-valinamide hydrochloride obtained in B) and triethylamine (44.0 g) in ethanol (150 mL) was added 4-thioxothiazolidin-2-one (14.4 g) at room temperature. The reaction mixture was stirred at room temperature for 3 hr, and the solvent was evaporated under reduced pressure. The obtained solid was suspended in THF, and the suspension was filtered through celite pad and silica gel pad. The filtrate was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (NH, ethyl acetate) to give the title compound (4.2 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:16]3[C:11](=[N:12][CH:13]=[N:14][C:15]=3[NH2:17])[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:29][CH2:28][N:27]([CH3:30])[CH2:26][CH2:25]4)[CH2:20][CH2:19]3)[N:9]=2)=[CH:4][C:3]=1[O:31][CH3:32].C(N(CC)CC)C.[C:40](Cl)(=[O:49])[CH2:41][CH2:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>ClCCl>[NH2:17][C:15]1[N:14]=[CH:13][N:12]=[C:11]2[N:10]([C@H:18]3[CH2:23][CH2:22][C@@H:21]([N:24]4[CH2:25][CH2:26][N:27]([CH3:30])[CH2:28][CH2:29]4)[CH2:20][CH2:19]3)[N:9]=[C:8]([C:5]3[CH:6]=[CH:7][C:2]([NH:1][C:40](=[O:49])[CH2:41][CH2:42][C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)=[C:3]([O:31][CH3:32])[CH:4]=3)[C:16]=12
Reactant: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1N
Reactant: O=C(Cl)CCc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(-c2nn([C@H]3CC[C@@H](N4CCN(C)CC4)CC3)c3ncnc(N)c23)ccc1NC(=O)CCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of cis-3-(4-amino-3-methoxyphenyl)-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-4-amine (75 mg, 0.17 mmol) and triethylamine (34 mg, 0.34 mmol) in dichloromethane (2.5 ml) was added hydrocinnamoyl chloride (34 mg, 0.20 mmol) in dichloromethane (0.5 ml) dropwise. The solution was stirred at room temperature for 48 hr and a further equivalent of hydrocinnamoyl chloride was then added. The reaction mixture was stirred for a further 24 hr. The resulting mixture was partitioned between dichloromethane (4 ml) and 2N NaOH (1.5 ml) and passed through an Empore extraction cartridge. Evaporation of the solvent gave an oily solid which was purified by silica gel chromatography using 10-20% MeOH/dichloromethane to give cis-N1-(4-{4-amino-1-[4-(4-methylpiperazino)cyclohexyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)-3-phenylpropanamide (12 mg, 13%). 1H NMR (CDCl3): δ H 8.55 (1H, d), 8.36 (1H, s), 7.75 (1H, s), 7.25 (7H, m), 5.51 (2H, bs), 4.91 (1H, m), 3.92 (3H, s), 3.09 (2H, m), 2.76 (2H, m), 2.34-2.59 (9H, m), 2.29 (3H, s), 2.16 (2H, m), 1.85 (4H, m), 1.66 (2H, m). LCMS (Micromass-Column: Pecosphere, C18, 3 um, 33×4.6 mm. Eluents: 0% B/A to 100% B/A in 4.5 min.(B: acetonitrile, A: 50 mM ammonia acetate buffer, PH 4.5), 3.5 mL/min.) Rt=1.92 mins, MH+=569.6.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[CH2:17]([O:19][C:20](=[O:37])[CH2:21][C:22]1[CH:27]=[CH:26][C:25](B2OC(C)(C)C(C)(C)O2)=[CH:24][CH:23]=1)[CH3:18].C(=O)(O)[O-].[Na+]>O1CCOCC1.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>[CH2:17]([O:19][C:20]([CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:2]2[CH:7]=[CH:6][C:5]([C:8]3[O:12][N:11]=[C:10]([CH3:13])[C:9]=3[C:14]([OH:16])=[O:15])=[CH:4][CH:3]=2)=[CH:24][CH:23]=1)=[O:37])[CH3:18]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(=O)O
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: O
Solvent: C1COCCO1
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3C(=O)O)cc2)cc1

Procedure:
5-(4-Bromo-phenyl)-3-methyl-isoxazole-4-carboxylic acid (2.0 g, 7.07 mmol), [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (2.46 g, 8.5 mmol), tetrakis(triphenylphosphine)palladium(0) (0.80 g, 0.70 mmol), and sodium bicarbonate (4.3 g, 52 mmol) were combined in 1,4-dioxane (50 mL) and water (10 mL), and the reaction was stirred overnight at 80° C. to give the title compound.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:33])[CH3:32])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][N:35]=[N+]=[N-])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:12][C@@H:11]([CH2:13][N:14]([CH:31]([CH3:32])[CH3:33])[C:15](=[O:30])[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[C:18]([O:24][CH2:25][CH2:26][CH2:27][O:28][CH3:29])[CH:17]=2)[C@H:10]([CH2:34][NH2:35])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN=[N+]=[N-])C(C)C)ccc1OC
Agent: [Pd]
Solvent: CO
Product: COCCCOc1cc(C(=O)N(C[C@@H]2CN(C(=O)OC(C)(C)C)C[C@H]2CN)C(C)C)ccc1OC

Procedure:
A solution of (3S,4R)-3-azidomethyl-4-({isopropyl-[4-methoxy-3-(3-methoxy-propoxy)-benzoyl]-amino}-methyl)-pyrrolidine-1-carboxylic acid tert-butyl ester (1.86 g, 3.58 mmol) in MeOH (40 mL) is hydrogenated overnight in the presence of Pd/C 10% (0.6 g; Engelhard 4505) at room temperature under atmospheric pressure to give, after filtration and drying in vacuo, the title compound as colorless oil. MS: 494.2 [M+H]+. tR (HPLC, Nucleosil C18HD column, 20-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 3.73 min.
Reaction SMILES: [N:1]([CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][C:11]([O:13]C)=[O:12])=[N+:2]=[N-:3].Cl>O1CCCC1>[N:1]([CH2:4][C:5]1[CH:9]=[CH:8][S:7][C:6]=1[CH2:10][C:11]([OH:13])=[O:12])=[N+:2]=[N-:3]
Reactant: COC(=O)Cc1sccc1CN=[N+]=[N-]
Agent: Cl
Solvent: C1CCOC1
Product: [N-]=[N+]=NCc1ccsc1CC(=O)O
Yield: 72 %

Procedure:
A solution of 15.6 g. of the above ester in 200 ml. of tetrahydrofuran and 30 ml. of 3 N hydrochloric acid is heated under reflux for 5 hours. The cooled solution is then basified to pH 10 and the mixture is extracted with ether. The ether is discarded and the pH of the residual aqueous phase is lowered to 2. The product is then extracted into ether. The ether is dried and evaporated to give 10.5 g. (72% yield) of the acid as an oily solid.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([OH:19])=O)[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1.S(Cl)(Cl)=O.[NH2:26][CH:27]([CH3:29])[CH3:28]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]2[O:6][C@H:7]([C:17]([NH:26][CH:27]([CH3:29])[CH3:28])=[O:19])[O:8][C@@H:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[F:16])[C:4]=2[CH:3]=1
Reactant: O=C(O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Reactant: CC(C)N
Solvent: O=S(Cl)Cl
Solvent: CN(C)C=O
Product: CC(C)NC(=O)[C@H]1Oc2ccc(Cl)cc2[C@H](c2ccccc2F)O1
Reaction time: 16 h

Procedure:
A solution of 3.38 g (10.9 mmoles) of trans-6-chloro-4-(2-fluorophenyl)-1,3-benzodioxan-2-carboxylic acid, 10.0 ml (16.4 g, 137 mmoles) of thionyl chloride, and 5 drops of anhydrous DMF in 200 ml of anhydrous Ch2Cl2 was refluxed for 2 hours; the solvent and excess SOCl2 were removed under reduced pressure and the residue was flashed down with 3 portions of anhydrous benzene to remove traces of SOCl2. The acid chloride was redissolved in 100 ml of anhydrous CH2Cl2 and 5.57 ml (3.86 g, 65.4 mmoles) of 2-aminopropane was added all at once; heat was evolved. The reaction mixture stood in a stoppered flask for 16 hours.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[N:21](S(C2C=CC(C)=CC=2)(=O)=O)[C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1.[OH-].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH3:12])[CH:7]=[C:6]2[C:13]1[NH:21][C:16]2=[N:17][CH:18]=[CH:19][CH:20]=[C:15]2[CH:14]=1
Reactant: COc1ccc2c(c1)c(-c1cc3cccnc3n1S(=O)(=O)c1ccc(C)cc1)cn2C
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc2c(c1)c(-c1cc3cccnc3[nH]1)cn2C
Yield: 80.5 %

Procedure:
A solution of 2-(5-methoxy-1-methyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine [1.45 g, Reference Example 13(b)] in methanol (100 mL) was treated with potassium hydroxide (5N, 15 mL) then heated at reflux for 2 hours. The reaction mixture was cooled then evaporated. The residue was treated with water (150 mL) and the resulting solid was filtered then dried to give the title compound (0.75 g) as a tan solid, m.p. 226-227° C. MS: 278 (MH+).
Reaction SMILES: [OH:1][C:2]1[C:7]([CH2:8][CH2:9][CH3:10])=[C:6]([OH:11])[CH:5]=[CH:4][C:3]=1[C:12](=[O:14])[CH3:13].[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35]Cl)[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(C)=O.CN(C)C=O>[CH2:15]([O:17][C:18](=[O:40])[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27](=[O:29])[CH3:28])=[C:23]([O:30][CH2:31][CH2:32][O:33][CH2:34][CH2:35][O:11][C:6]2[CH:5]=[CH:4][C:3]([C:12](=[O:14])[CH3:13])=[C:2]([OH:1])[C:7]=2[CH2:8][CH2:9][CH3:10])[C:22]=1[CH2:37][CH2:38][CH3:39])[CH3:16]
Reactant: CCCc1c(OCC(=O)OCC)ccc(C(C)=O)c1OCCOCCCl
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCOCCOc2c(C(C)=O)ccc(OCC(=O)OCC)c2CCC)ccc(C(C)=O)c1O
Yield: 70.4 %

Procedure:
A mixture of 2.94 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone, 5.85 g of [4-acetyl-3-[2-(2-chloroethoxy)ethoxy]-2-propylphenoxy]acetic acid ethyl ester, 4.2 g of anhydrous potassium carbonate, and 2.25 g of potassium iodide in 100 ml of anhydrous acetone and 50 ml of anhydrous dimethylformamide was stirred at reflux. Additional 2.0 g portions of potassium carbonate were added after 19, 26 and 51 hours. Reflux was continued for a total of 8 days and then the reaction mixture was concentrated in vacuo. The crude product was purified by liquid chromatography using 35% ethyl acetate-hexane to give 5.8 g (70% yield) of [4-acetyl-3-[2-[2-(4-acetyl-3-hydroxy-2-propylphenoxy)ethoxy]ethoxy]-2-propylphenoxy]acetic acid ethyl ester.
Reaction SMILES: Cl/[CH:2]=[C:3](/[C:13]1[S:14][C:15]([CH3:18])=[CH:16][CH:17]=1)\[O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([O:11][CH3:12])[CH:6]=1.[F-].[Cs+].C(=O)([O-])[O-].[Cs+].[Cs+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O(C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1)C1C=CC=CC=1P(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:12][O:11][C:7]1[CH:8]=[CH:9][C:10]2[CH:2]=[C:3]([C:13]3[S:14][C:15]([CH3:18])=[CH:16][CH:17]=3)[O:4][C:5]=2[CH:6]=1
Reactant: COc1cccc(O/C(=C\Cl)c2ccc(C)s2)c1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Product: COc1ccc2cc(-c3ccc(C)s3)oc2c1
Yield: 82.6 %

Procedure:
(Z)-2-(2-chloro-1-(3-methoxyphenoxy)vinyl)-5-methylthiophene (97) (4.7 g, 16.74 mmol), Pd2 dba3 (0.178 g, 0.399 mmol), (oxybis(2,1-phenylene))bis(diphenylphosphine) (0.429 g, 0.797 mmol), cesium fluoride (7.27 g, 47.8 mmol) and cesium carbonate (15.58 g, 47.8 mmol) were placed into a 250-mL three-neck rbf, sealed with a septum and purged with argon for 20-30 minutes. 100 mL dioxane was added. The solution was vigorously stirred and brought to reflux for 18 hours and cooled. The layers were separated and the aqueous layer was extracted with DCM once more. The combined organic layers were washed with brine, dried with anhydrous MgSO4, filtered and concentrated. The product was purified by column to provide (98) (3.38 g, 13.83 mmol, 87% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[CH:15][C:5]([CH2:6][NH:7][C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([Cl:14])[N:9]=2)=[CH:4][CH:3]=1.[Br:17]N1C(=O)CCC1=O.O>C(#N)C>[Br:17][C:11]1[CH:12]=[CH:13][C:8]([NH:7][CH2:6][C:5]2[CH:15]=[CH:16][C:2]([Cl:1])=[CH:3][CH:4]=2)=[N:9][C:10]=1[Cl:14]
Reactant: O=C1CCC(=O)N1Br
Reactant: Clc1ccc(CNc2cccc(Cl)n2)cc1
Solvent: O
Solvent: CC#N
Product: Clc1ccc(CNc2ccc(Br)c(Cl)n2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To (4-chloro-benzyl)-(6-chloro-pyridin-2-yl)-amine (538, 4.00 g, 0.0158 mol) in acetonitrile (66.7 mL, 1.28 mol) under an atmosphere of nitrogen, N-bromosuccinimide (2.81 g, 0.0158 mol) in acetonitrile (20 mL) was added slowly. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over sodium sulfate, concentrated and crystallized with ethyl acetate in hexane to give a white solid (539, 2.60 g, 95.3%).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]1[CH:18]=[N:17][C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[N:10]=1.[F:19][C:20]([F:37])([F:36])[C:21]1[CH:26]=[CH:25][C:24]([C:27]2[C:28]([C:33](O)=[O:34])=[CH:29][CH:30]=[CH:31][CH:32]=2)=[CH:23][CH:22]=1>>[N:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:17]=[CH:18][C:9]=1[N:2]1[CH2:3][CH:4]2[CH2:8][N:7]([C:33]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=3[C:24]3[CH:25]=[CH:26][C:21]([C:20]([F:19])([F:36])[F:37])=[CH:22][CH:23]=3)=[O:34])[CH2:6][CH:5]2[CH2:1]1
Reactant: c1ccc2nc(N3CC4CNCC4C3)cnc2c1
Reactant: O=C(O)c1ccccc1-c1ccc(C(F)(F)F)cc1
Product: O=C(c1ccccc1-c1ccc(C(F)(F)F)cc1)N1CC2CN(c3cnc4ccccc4n3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 35 and 4′-trifluoromethyl-biphenyl-2-carboxylic acid. MS (ESI): mass calculated for C28H23F3N4O, 488.50; m/z found 489.2 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]([OH:9])=[O:8])=[CH:5][CH:4]=1.S(=O)(=O)(O)O.[CH2:17](O)[CH3:18]>>[OH:1][CH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:17][CH3:18])=[O:8])=[CH:10][CH:11]=1
Reactant: CCO
Reactant: O=C(O)c1ccc(CO)cc1
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1ccc(CO)cc1

Procedure:
4 g (26.3 mmol) of 4-(hydroxymethyl)benzoic acid in 1,000 ml of absolute ethanol are heated under reflux of the solvent for 15 hours in the presence of approximately 1 g of concentrated sulfuric acid. The ethyl alcohol is then evaporated off and the residue taken up with water. After extraction of the aqueous phase with 3×100 ml of ethyl ether, the organic phases are washed to neutrality with saturated sodium hydrogen carbonate solution. After removal of the solvent, 4.56 g of a yellow oil, which soon crystallizes, remains.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].C([Mg]Cl)(C)C.[C:12]([O:16][C:17]([N:19]1[CH2:24][CH2:23][C:22]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)(C(O)=O)[CH2:21][CH2:20]1)=[O:18])([CH3:15])([CH3:14])[CH3:13].C(N1C=CN=C1)(N1C=CN=C1)=O>C1COCC1.CC(O)=O.O>[C:12]([O:16][C:17]([N:19]1[CH2:20][CH2:21][C:22]([C:4](=[O:6])[CH2:3][C:1]#[N:2])([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:23][CH2:24]1)=[O:18])([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)O)(c2ccccc2)CC1
Reactant: N#CCC(=O)O
Agent: CC(C)[Mg]Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CC(=O)O
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C(=O)CC#N)(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 2.52 g (30 mmol) of cyanoacetic acid in 80 mL of dry THF was stirred at −78° C. as 24.6 mL (49.2 mmol) of 2.0 M i-PrMgCl in THF was added. After 1 h, a solution of 3.00 g (10 mmol) 1-tert-butoxycarbonyl-4-phenylpiperidine-4-carboxylic acid (Maybridge, cat. no. JFD 01929) and 1.93 g (12 mmol) of 1,1′-carbonyldiimidazole in 20 mL of THF was added. The reaction mixture was allowed to warm to rt. After 16 h, the mixture was poured into 300 mL of water and the pH lowered to 4 with conc. AcOH. The mixture was then extracted with EtOAc, dried over MgSO4 and concentrated. Purification on silica gel using 1:1 EtOAc-hexanes as eluant afforded 4-(2-cyanoacetyl)-4-phenylpiperidine-1-carboxylic acid tert-butyl ester.
Reaction SMILES: [CH2:1]([C@@H:8]([CH2:12][CH2:13][C@H:14]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@H:52]([C:53]([F:56])([F:55])[F:54])[N:44]2[C:43]1=[O:57]>>[CH2:34]([C@@H:14]([CH2:13][CH2:12][C@H:8]([CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:9]([NH:41][C@H:42]1[CH2:48][CH2:47][S:46][C@H:45]2[CH2:49][CH2:50][CH2:51][C@H:52]([C:53]([F:54])([F:56])[F:55])[N:44]2[C:43]1=[O:57])=[O:10])[C:15]([NH:17][C@H:18]1[CH2:24][CH2:23][CH2:22][CH2:21][N:20]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[O:31][CH3:32])[C:19]1=[O:33])=[O:16])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@H]1CCS[C@H]2CCC[C@H](C(F)(F)F)N2C1=O
Reactant: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)O)Cc2ccccc2)C1=O
Product: COc1ccccc1N1CCCC[C@H](NC(=O)[C@H](CC[C@H](Cc2ccccc2)C(=O)N[C@H]2CCS[C@H]3CCC[C@H](C(F)(F)F)N3C2=O)Cc2ccccc2)C1=O

Procedure:
(2R,5R)-2,5-Dibenzyl-N1-((S)-1-(2-methoxyphenyl)-2-oxoazepan-3-yl)-N6-((4S,7R,10aS)-5-oxo-7-(trifluoromethyl)octahydro-2H-pyrido[2,1-b][1,3]thiazepin-4-yl)hexanediamide was synthesized as described in General Procedure H using Intermediate 70 (21 mg, 0.039 mmol) and Intermediate 78 (10 mg, 0.037 mmol) to give a white solid (26 mg, 83% yield). Anal. Calcd. for C43H51F3N4O5S m/z 792.7. found: 793.4 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 7.37-6.99 (m, 12H), 6.99-6.86 (m, 3H), 6.77 (s, 1H), 5.27 (t, 1H), 5.02-4.80 (m, 2H), 4.75 (dd, J=10.2, 6.6 Hz, 1H), 3.96-3.81 (m, 1H), 3.80 (s, 3H), 3.38 (s, 1H), 3.24-3.07 (m, 1H), 2.91-2.46 (m, 7H), 2.36 (dd, J=12.8, 8.4 Hz, 4H), 2.14-1.58 (m, 9H), 1.58-1.20 (m, 5H).