Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:11])[O:6][C:4](=O)[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[C:12]1([C:18]2[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C(O)C>[C:12]1([C:18]2[CH2:23][C:22](=[C:24]3[C:1](=[O:11])[C:2]4[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=4)[C:4]3=[O:6])[CH:21]=[CH:20][N:19]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: Cc1ccnc(-c2ccccc2)c1
Reactant: O=C1OC(=O)c2ccccc21
Solvent: CCO
Product: O=C1C(=C2C=CN=C(c3ccccc3)C2)C(=O)c2ccccc21
Temperature: 200 °C
Reaction time: 14 h
Yield: 36.3 %

Procedure:
Under exclusion of air, a mixture of phthalic anhydride (4.38 g, 29.5 mmol) and 2-phenyl-4-picoline (5.0 g, 29.5 mmol) was heated to 200° C. The reaction melt was stirred at 200° C. for 14 h until a yellow precipitate was formed. The reaction was cooled to 100° C. and ethanol (300 mL) was added. The resultant brown mass was refluxed in ethanol for 1 h and sonicated in a water bath to break up the compound. The precipitate was filtered and triturated in ethanol (100 mL) to give the title compound as a yellow solid (3.2 g, 10.7 mmol, 36% yield). 1H-NMR (DMSO-d6) 12.06 (broad s, 1H), 9.04 (d, J=1.3, 1H), 8.68 (dd, J=6.7, 1.3, 1H), 8.17 (d, J=6.7, 1H), 7.79 (dd, J=8.0, 5.2, 2H), 7.61 to 7.64 (m, 3H), 7.45 to 7.53 (m, 4H); MS ES 300 (M+H)+, calc. 299; TLC (1:2:8 v/v methanol-acetone-dichloromethane) Rf=0.32.
Reaction SMILES: F[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=[C:4]([F:11])[N:3]=1.Cl.[C:13]([N:23]1[CH2:28][CH2:27][NH:26][CH:25]([C:29]([OH:31])=[O:30])[CH2:24]1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14].C(N(CC)CC)C>CS(C)=O>[F:11][C:4]1[N:3]=[C:2]([N:26]2[CH2:27][CH2:28][N:23]([C:13]([O:15][CH2:16][C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)=[O:14])[CH2:24][CH:25]2[C:29]([OH:31])=[O:30])[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][CH:5]=1
Reactant: O=[N+]([O-])c1ccc(F)nc1F
Reactant: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: O=C(O)C1CN(C(=O)OCc2ccccc2)CCN1c1nc(F)ccc1[N+](=O)[O-]

Procedure:
In a similar procedure to that described in Example 1, from 6.0 g. of 2,6-difluoro-3-nitropyridine, 9.0 g. of 4-carbobenzoxypiperazine-2-carboxylic acid, hydrochloride, 20 ml. of triethylamine and 150 ml. of dimethyl sulfoxide, there is obtained 14 g. of the title product as a viscous orange glass. Thin layer chromatographic analysis of this material shows essentially one spot.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=2)[N:5]=[C:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[OH:19])[N:3]=1.[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][NH:33][CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C=O)C.C(N(CC)CC)C>[CH2:20]([O:27][CH2:28][C@H:29]1[CH2:34][N:33]([C:2]2[C:11]3[C:6](=[CH:7][C:8]([CH3:12])=[CH:9][CH:10]=3)[N:5]=[C:4]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[OH:19])[N:3]=2)[CH2:32][CH2:31][N:30]1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: Cc1ccc2c(Cl)nc(-c3ccccc3O)nc2c1
Reactant: CC(C)(C)OC(=O)N1CCNC[C@@H]1COCc1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1ccc2c(N3CCN(C(=O)OC(C)(C)C)[C@@H](COCc4ccccc4)C3)nc(-c3ccccc3O)nc2c1
Temperature: 85 °C
Yield: 84.7 %

Procedure:
To a solution of 2-(4-chloro-7-methylquinazolin-2-yl)phenol (450 mg, 1.66 mmol) in 10 mL DMF was added a solution of (R)-tert-butyl 2-((benzyloxy)methyl)piperazine-1-carboxylate (610 mg, 1.99 mmol) in DMF and triethylamine (0.46 mL). The reaction mixture was then refluxed at 85° C. for 30 minutes, quenched with water, extracted twice with CH2Cl2, dried over Na2SO4, and concentrated to give (R)-tert-butyl 2-((benzyloxy)methyl)-4-(2-(2-hydroxyphenyl)-7-methylquinazolin-4-yl)piperazine-1-carboxylate (760 mg, 85%). This material was used in the next step without further purification. LC/MS: m/z 541.5 (M+H)+ at 3.37 min (10%-99% CH3CN (0.035% TFA)/H2O (0.05% TFA)).
Reaction SMILES: [CH:1]([NH2:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[Cl:12][C:13]1[C:18]([Cl:19])=[CH:17][CH:16]=[CH:15][C:14]=1[NH:20][C:21]([C:23]1[CH:33]=[CH:32][C:26]([O:27][CH2:28][C:29](Cl)=[O:30])=[CH:25][CH:24]=1)=[O:22]>O1CCOCC1>[CH:1]([NH:4][C:29](=[O:30])[CH2:28][O:27][C:26]1[CH:32]=[CH:33][C:23]([C:21](=[O:22])[NH:20][C:14]2[CH:15]=[CH:16][CH:17]=[C:18]([Cl:19])[C:13]=2[Cl:12])=[CH:24][CH:25]=1)([CH3:3])[CH3:2]
Reactant: O=C(Cl)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(C)NC(=O)COc1ccc(C(=O)Nc2cccc(Cl)c2Cl)cc1
Reaction time: 5 h

Procedure:
0.71 g of isopropylamine and 3.0 g of triethylamine were dissolved in 20 ml of dioxane. To this solution, a solution prepared by dissolving 4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetyl chloride prepared in the same manner as in Example 3 in 5 ml of dioxane, was dropwise added over a period of about 5 minutes at room temperature under stirring. After completion of the dropwise addition, the stirring was continued at room temperature for further 5 hours. After completion of the reaction, the reaction solution was treated in the same manner as in Example 3 to obtain 3.8 g of desired N-isopropyl-4-(2,3-dichlorophenyl-carbamoyl)-phenoxyacetamide.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:34])[N:6]([CH3:33])[C:7]2[C:12]([C:13]=1[NH:14][C:15](=O)[CH3:16])=[CH:11][C:10]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=1)=[C:9]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=1[Cl:32])[N:8]=2)(=O)[CH3:2].[CH2:35]([NH2:42])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>ClCCCl.C(Cl)Cl>[CH2:35]([N:42]1[CH:1]([CH3:2])[C:4]2[C:5](=[O:34])[N:6]([CH3:33])[C:7]3[N:8]=[C:9]([C:25]4[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][C:26]=4[Cl:32])[C:10]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)=[CH:11][C:12]=3[C:13]=2[N:14]=[C:15]1[CH3:16])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1
Reactant: CC(=O)Nc1c(C(C)=O)c(=O)n(C)c2nc(-c3ccc(Cl)cc3Cl)c(-c3ccc(Cl)cc3)cc12
Reactant: NCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC1=Nc2c(c(=O)n(C)c3nc(-c4ccc(Cl)cc4Cl)c(-c4ccc(Cl)cc4)cc23)C(C)N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The product of Example 1 (80 mg) in 1,2-dichlorethane (1.5 mL) was combined with benzyl amine (16 μL), sodium triacetoxyborohydride (32 mg) and acetic acid (8.5 μL). The reaction was stirred for two days at room temperature. The reaction mixture was diluted with CH2Cl2 and washed with aqueous NaOH (1 M) and brine. The concentrated residue was purified by preparative TLC on silica gel eluted with 30% EtOAc in CH2Cl2 affording the title compound. HPLC/MS: 587.1 (M+1), 589.1 (M+3); Rt=3.86 min.
Reaction SMILES: [CH:1]1[CH:6]=[CH:5][C:4]([CH2:7][O:8][C:9]([NH:11][CH2:12][C:13]([O:15]C2C=CC([N+]([O-])=O)=CC=2)=O)=[O:10])=[CH:3][CH:2]=1.[NH2:25][C@H:26]([C:28]([N:30]1[CH2:41][CH2:40][CH2:39][C@H:31]1[C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])=[O:29])[CH3:27].C(Cl)(Cl)Cl.CO>C(OCC)(=O)C>[NH:11]([C:9]([O:8][CH2:7][C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)=[O:10])[CH2:12][C:13]([NH:25][C@H:26]([C:28]([N:30]1[CH2:41][CH2:40][CH2:39][C@H:31]1[C:32]([O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:33])=[O:29])[CH3:27])=[O:15]
Reactant: C[C@H](N)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reactant: O=C(CNC(=O)OCc1ccccc1)Oc1ccc([N+](=O)[O-])cc1
Solvent: CCOC(C)=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)OCc1ccccc1)C(=O)N1CCC[C@H]1C(=O)OC(C)(C)C
Reaction time: 20 h

Procedure:
1.65 g of Z-Gly-ONP and 1.09 g of H-Ala-Pro-OtBu in 20 ml of ethyl acetate are allowed to stand for one hour at 0° C. and 20 hours at room temperature. The mix is then diluted with ethyl acetate, washed with 50% saturated potassium carbonate solution and with water, dried over sodium sulphate and evaporated. 2.06 g of an oil which is homogeneous according to thin layer chromatography result. Rf = 0.8 in the system chloroform-methanol (1:1) on silica gel.
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1.N1CCC[C@H]1C(O)=O>[Cu]I.CS(C)=O>[C:2]1([N:8]2[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C1COCCN1
Reactant: Ic1ccccc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CS(C)=O
Product: c1ccc(N2CCOCC2)cc1
Temperature: 90 °C
Reaction time: 4 h
Yield: 44.4 %

Procedure:
1-iodobenzene (28.12 g, 137.84 mmol) was added to morpholine (12.0 g, 137.93 mmol). L-Proline (3.12 g, 27.13 mmol) was then added, followed by the addition of CuI (2.6 g, 13.68 mmol) and DMSO (120 mL). The resulting solution was stirred at 90° C. for 4 hours, and then the reaction mixture was then quenched by the addition of 300 mL of iced water. The resulting solution was extracted using dichloromethane (2×200 mL), and the organic layers combined, dried (Na2SO4) and concentrated. The residue was purified by column chromatography using a petroleum ether solvent system. The collected fractions were combined and concentrated to give 10 g (42%) of 4-phenylmorpholine as a white solid.
Reaction SMILES: [CH3:1][C:2]1[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:16])[F:15])[CH:9]=2)[C:6](=[O:18])[C:5]([C:19]([OH:21])=O)=[CH:4][C:3]=1[C:22]1[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=1.CN(C(O[N:36]1N=[N:43][C:38]2C=CC=C[C:37]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.NCC#N>O1CCOCC1>[C:37]([CH2:38][NH:43][C:19]([C:5]1[C:6](=[O:18])[N:7]([C:8]2[CH:13]=[CH:12][CH:11]=[C:10]([C:14]([F:17])([F:15])[F:16])[CH:9]=2)[C:2]([CH3:1])=[C:3]([C:22]2[N:23]([CH3:27])[N:24]=[CH:25][CH:26]=2)[CH:4]=1)=[O:21])#[N:36]
Reactant: Cc1c(-c2ccnn2C)cc(C(=O)O)c(=O)n1-c1cccc(C(F)(F)F)c1
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Agent: N#CCN
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(-c2ccnn2C)cc(C(=O)NCC#N)c(=O)n1-c1cccc(C(F)(F)F)c1
Reaction time: 0.17 h
Yield: 72.2 %

Procedure:
The compound obtained in step (a) (0.2 g, 0.53 mmol) was dissolved in 1,4-dioxane (5 ml), HBTU (0.19 g, 0.5 mmol) and DIEA (0.32 g, 2.5 mmol). The mixture was stirred for 10 minutes and aminoacetonitrile hydrochloride (0.55 g, 0.6 mmol) was added. After 1 h the mixture was evaporated and the residue purified by chromatography on silica to give the amide (0.15 g, 72%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH2:8])=[CH:4][N:3]=[CH:2]1.N1C=CC=CC=1.[C:19](Cl)(=[O:21])[CH3:20]>ClCCl>[NH:3]1[CH:4]=[C:5]([C:6]2[CH:12]=[CH:11][CH:10]=[CH:9][C:7]=2[NH:8][C:19](=[O:21])[CH3:20])[N:1]=[CH:2]1
Reactant: Nc1ccccc1-c1cnc[nH]1
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccccc1-c1c[nH]cn1
Temperature: 25 °C
Reaction time: 16 h
Yield: 44.2 %

Procedure:
To a solution of 2-(1H-imidazol-5-yl)aniline (18 mg, 0.113 mmol) in dichloromethane (3 mL) was added pyridine (47 μL, 0.339 mmol) and acetyl chloride (19 μL, 0.271 mmol). The reaction was stirred at room temperature for 16 h. The solvent was removed under reduced pressure. The crude product was dissolved in methanol (4 mL) and refluxed for 2 h. The solution was concentrated and the residue was purified by flash column chromatography (silica gel, 5%-30% MeOH/DCM as eluent) to afford the desired product as a white solid (10 mg, 0.050 mmol, 44%). 1H NMR (MeOH-d4): 2.17 (s, 3H), 7.05-7.26 (m, 2H), 7.46 (s, 1H), 7.62 (d, 1H, J=7.8 Hz), 7.78 (s, 1H), 8.18 (s, 1H).
Reaction SMILES: [CH:1](O)=[O:2].[N+:4]([CH2:6][C:7]([O:9][CH3:10])=[O:8])#[C-:5].CC(C)([O-])C.[K+]>C1COCC1>[O:2]1[CH:1]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[N:4]=[CH:5]1
Reactant: O=CO
Reactant: [C-]#[N+]CC(=O)OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC(=O)c1cocn1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 37 %

Procedure:
To a suspension of 1,1-carbonyldiimidazole (90 g, 0.555 mol) in 400 mL of THF at 0° C. was added dropwise formic acid 25.5 g (0.555 mol) in 100 mL of THF over a 15 min period. The mixture was warmed to room temperature and stirred for 1.5 h. The resulting solution was added via a canula to the anion of methyl isocyanoacetate (generated by addition of the methyl isocyanoacetate in 75 mL of THF to a suspension of potassium t-butoxide at 0° C. and stirring for 15 min) at 0° C. During the addition (exothermic), the reaction mixture reached to 20° C. and the ice-bath was removed, stirring was continued at room temperature for 1 h. The above mixture was quenched with 100 mL of acetic acid followed by 200 mL of water, THF was removed in vacuo, and 1000 mL of chloroform was added to the residual mixture. The organic layer was washed with water (2×200 mL), saturated sodium bicarbonate solution (1×100 mL), water, brine, and dried over sodium sulfate and concentrated in vacuo. The resulting residue was chromatographed on silica (methylene chloride/hexane/ether 7:2:1) to afford 23.5 g (37%) of methyl 4-oxazolecarboxylate.
Reaction SMILES: Br[CH:2]1[C@@H:5]([CH2:6][CH:7]=[CH2:8])[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3]1=[O:17].C(O)(=O)C>C(Cl)Cl.C(OCC)(=O)C.[Zn]>[CH2:6]([C@H:5]1[N:4]([C:9](=[C:14]([CH3:16])[CH3:15])[C:10]([O:12][CH3:13])=[O:11])[C:3](=[O:17])[CH2:2]1)[CH:7]=[CH2:8]
Reactant: C=CC[C@@H]1C(Br)C(=O)N1C(C(=O)OC)=C(C)C
Agent: [Zn]
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: C=CC[C@@H]1CC(=O)N1C(C(=O)OC)=C(C)C
Temperature: 5 °C
Reaction time: 0.5 h
Yield: 28 %

Procedure:
Methyl 2-[(4R)-3-bromo-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (840 mg) was dissolved in methylene chloride (6 ml) and cooled to 5° C. To this cooled solution were added acetic acid (0.5 ml) and zinc powder (0.60 g), and the mixture was allowed to warm to room temperature. After stirring for 30 minutes, the reaction mixture was diluted with ethyl acetate (6 ml) and filtered through a pad of Celite. The filtrate was further diluted with ethyl acetate (50 ml) and washed successively with water, dilute sodium bicarbonate and brine. Drying over magnesium sulfate and evaporation left an oil, which was chromatographed on silica gel (20 g) eluting with a mixture of benzene and acetone (5:1) to give methyl 2-[(4R)-4-allyl-2-oxoazetidin-1-yl]-3-methyl-2-butenoate (174 mg) as an oil.
Reaction SMILES: CO.[F:3][C:4]1[CH:31]=[CH:30][C:7]([NH:8][C:9]2[CH:17]=[C:16](/[CH:18]=[CH:19]/[C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:6][CH:5]=1>[C].[Pd].C(OCC)(=O)C>[F:3][C:4]1[CH:5]=[CH:6][C:7]([NH:8][C:9]2[CH:17]=[C:16]([CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:22][CH:21]=3)[CH:15]=[CH:14][C:10]=2[C:11]([OH:13])=[O:12])=[CH:30][CH:31]=1
Reactant: O=C(O)c1ccc(/C=C/c2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C(O)c1ccc(CCc2ccc(C(F)(F)F)cc2)cc1Nc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 10 h
Yield: 92.9 %

Procedure:
To a mixed solution of methanol 4.0 mL and ethyl acetate 4.0 mL of 2-(4-fluoroanilino)-4-((E)-2-(4-(trifluoromethyl)phenyl)vinyl)benzoic acid 15 mg was added 5% palladium-carbon 8.0 mg at room temperature, and it was stirred under hydrogen atmosphere at room temperature for 10 hours. The solvent was removed under reduced pressure after insoluble matter was filtrated to give 2-(4-fluoroanilino)-4-(2-(4-(trifluoromethyl)phenyl)ethyl)benzoic acid 14 mg of white solid.
Reaction SMILES: [CH:1]1([S:7][CH:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=2)[C:9]#[N:10])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Br[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][Cl:27]>>[Cl:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][C:8]([S:7][CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1)([C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[C:13]([O:19][CH3:20])[CH:12]=1)[C:9]#[N:10]
Reactant: COc1ccc(C(C#N)SC2CCCCC2)cc1OC
Reactant: ClCCCCCBr
Product: COc1ccc(C(C#N)(CCCCCCl)SC2CCCCC2)cc1OC

Procedure:
The procedure of Example 2 is repeated using 3.0 g of α-(cyclohexylthio)-3,4-dimethoxy benzeneacetonitrile and 2.0 mL of bromo-5-chloropentane. This affords 3.1 g of the desired product as a colorless oil.
Reaction SMILES: [OH-].[Li+].[CH2:3]([O:10][CH2:11][CH:12]([CH3:43])[CH2:13][CH2:14][C@@H:15]([N:22]1[CH2:27][CH2:26][C@@H:25]([CH2:28][C:29]([O:31]C)=[O:30])[CH2:24][C@H:23]1[C:33]1[CH:38]=[CH:37][C:36]([C:39]([F:42])([F:41])[F:40])=[CH:35][CH:34]=1)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Cl.C([O-])(O)=O.[Na+]>O.C1COCC1>[CH2:3]([O:10][CH2:11][CH:12]([CH3:43])[CH2:13][CH2:14][C@@H:15]([N:22]1[CH2:27][CH2:26][C@@H:25]([CH2:28][C:29]([OH:31])=[O:30])[CH2:24][C@H:23]1[C:33]1[CH:34]=[CH:35][C:36]([C:39]([F:42])([F:40])[F:41])=[CH:37][CH:38]=1)[CH2:16][CH2:17][C:18]([F:21])([F:20])[F:19])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)C[C@@H]1CCN([C@H](CCC(C)COCc2ccccc2)CCC(F)(F)F)[C@H](c2ccc(C(F)(F)F)cc2)C1
Agent: Cl
Agent: O=C([O-])O
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(CC[C@H](CCC(F)(F)F)N1CC[C@@H](CC(=O)O)C[C@H]1c1ccc(C(F)(F)F)cc1)COCc1ccccc1
Temperature: 25 °C
Yield: 92.3 %

Procedure:
A solution of lithium hydroxide (41 mg, 1.702 mmol) in water (1 ml) was added to a stirred solution of methyl {(2S,4R)-1-[(1R,4R/S)-5-(benzyloxy)-4-methyl-1-(3,3,3-trifluoropropyl)pentyl]-2-[4-(trifluoromethyl)phenyl]piperidin-4-yl}acetate (Step 1, 200 mg, 0.340 mmol) in THF (2 ml) at RT. The mixture was stirred at RT o/n. 2N HCl (1 ml) was added The pH of the aqueous layer was adjusted to 7 with NaHCO3 (aq). The aqueous layer was extracted with DCM (×3). The combined extracts were dried (Na2SO4), filtered and evaporated. The residue was purified by chromatography (silica, 2-4% MeOH/DCM) to give the title compound (180 mg) as a colourless foam/M/Z 574 (MH+).
Reaction SMILES: CS(OS(C)(=O)=O)(=O)=O.O[CH2:11][C:12]1(CO)[CH2:17][C:16]2[CH:18]=[CH:19][S:20][C:15]=2[S:14](=[O:22])(=[O:21])[N:13]1[CH2:23][C:24]1[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=1.C(N(CC)CC)C.[NH:41]1[CH2:46][CH2:45][O:44][CH2:43][CH2:42]1>C1COCC1>[CH3:31][O:30][C:27]1[CH:28]=[CH:29][C:24]([CH2:23][N:13]2[C:12]([CH2:11][N:41]3[CH2:46][CH2:45][O:44][CH2:43][CH2:42]3)=[CH:17][C:16]3[CH:18]=[CH:19][S:20][C:15]=3[S:14]2(=[O:21])=[O:22])=[CH:25][CH:26]=1
Reactant: COc1ccc(CN2C(CO)(CO)Cc3ccsc3S2(=O)=O)cc1
Reactant: C1COCCN1
Agent: CS(=O)(=O)OS(C)(=O)=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: COc1ccc(CN2C(CN3CCOCC3)=Cc3ccsc3S2(=O)=O)cc1
Reaction time: 1 h
Yield: 88 %

Procedure:
Methanesulfonic anhydride (1.24 g, 7.13 mmol) was added to a solution of the product of Example 11, Step C (1.3 g, 3.86 mmol) and triethylamine (1.17 g, 11.6 mmol) in anhydrous THF (50 mL) at ambient temperature. After stirring for 1 h, morpholine (3 mL) was added and the reaction mixture was heated at reflux temperature for 1 h followed by removal of solvent. A saturated aqueous solution of sodium bicarbonate was added and the mixture was extracted with ethyl acetate (2×100 mL). The combined extracts were dried (MgSO4) and evaporated to an oil which was purified by column chromatography (silica, 30% to 60% ethyl acetate/hexane) to give a solid (1.39 g, 88%): mp 112°-114° C.
Reaction SMILES: Cl.[S:2]1[CH:6]=[CH:5][C:4]2[CH:7]([NH2:11])[CH2:8][CH2:9][CH2:10][C:3]1=2.[CH:12]1([N:18]=[C:19]=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1>O1CCCC1>[CH:12]1([NH:18][C:19]([NH:11][CH:7]2[C:4]3[CH:5]=[CH:6][S:2][C:3]=3[CH2:10][CH2:9][CH2:8]2)=[O:20])[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1
Reactant: NC1CCCc2sccc21
Reactant: O=C=NC1CCCCC1
Agent: Cl
Solvent: C1CCOC1
Product: O=C(NC1CCCCC1)NC1CCCc2sccc21

Procedure:
In a similar manner, as described in Example 1, 4,5,6,7-tetrahydrobenzo[b]thiophen-4-amine hydrochloride is allowed to react with cyclohexyl isocyanate in dry tetrahydrofuran to afford 7 grams of 1-cyclohexyl-3-(4,5,6,7-tetrahydrobenzo[b]thien-4-yl)urea, melting point 222° C. to 225° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[N:7]=N[N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)=[O:5])[CH3:2].B1C2CCC[CH:31]1CCC2.C(=O)([O-])[O-].[K+].[K+].C(C1C=CC=CC=1I)(=O)C>C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C1COCC1>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[CH:31][N:9]([C:11]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=1)=[O:5])[CH3:2]
Reactant: B1C2CCCC1CCC2
Reactant: CCOC(=O)c1nnn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: CC(=O)c1ccccc1I
Solvent: C1CCOC1
Product: CCOC(=O)c1ncn(C(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To Resin A (30 mg) was added THF (0.4 ml). To the mixture was added 9-BBN (0.5M in THF, 0.4 ml). The mixture was stirred at room temperature for 4 hours. To the mixture was added an aqueous solution of potassium carbonate (2M, 0.1 ml), 2-acetyliodobenzene (41 mg, 0.2 mmol) and PdCl2(dppf) (3 mg). The mixture was stirred at 50° C. for 20 hours. The obtained resin was washed with DMF, water, methanol and methylene chloride to give Resin B.
Reaction SMILES: Br[C:2]1[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=1)=[O:8].B(O)(O)[C:28]1[CH:29]=[CH:30][C:31]([CH3:34])=[CH:32][CH:33]=1.C([O-])([O-])=O.[Na+].[Na+].O1CCCC1>O>[C:31]1([CH3:34])[CH:32]=[CH:33][C:28]([C:2]2[C:3]([O:21][CH2:22][C:23]([F:26])([F:25])[F:24])=[N:4][CH:5]=[C:6]([CH:20]=2)[C:7]([NH:9][CH2:10][C:11]2[O:15][N:14]=[C:13]([C:16]([F:19])([F:18])[F:17])[N:12]=2)=[O:8])=[CH:29][CH:30]=1
Reactant: O=C(NCc1nc(C(F)(F)F)no1)c1cnc(OCC(F)(F)F)c(Br)c1
Reactant: Cc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(-c2cc(C(=O)NCc3nc(C(F)(F)F)no3)cnc2OCC(F)(F)F)cc1
Temperature: 90 °C
Reaction time: 15 h
Yield: 46.8 %

Procedure:
5-Bromo-6-(2,2,2-trifluoroethoxy)-N-((3-(trifluoromethyl)-1,2,4-oxadiazol-5-yl)methyl)nicotinamide (example BP; 100 mg, 223 μmol), p-tolylboronic acid (CAN 5720-05-8; 33 mg, 243 μmol), 1,1′-bis(diphenylphosphino)-ferrocene-palladium(II)dichloride dichloromethane complex (4 mg, 5.27 μmol) and Na2CO3 (35 mg, 330 μmol) were combined with tetrahydrofuran (5 mL) and water (1.5 mL). The reaction mixture was heated to 90° C., stirred for 15 h, cooled down and poured into 25 mL H2O. The mixture was extracted with ethyl acetate (2×25 mL). The organic layers were combined, washed with brine (1×25 mL), dried with MgSO4 and concentrated in vacuo. The crude material was purified twice by flash chromatography (silica gel, 20 g, 0% to 40% ethyl acetate in hexanes) to give 48 mg (46%) of the title compound as a light yellow solid; MS (ESI): 459.090 (M−H)−.