Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2([CH2:14][NH2:15])[O:13][CH2:12][CH2:11][O:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[Cl:25][C:26]1[CH:27]=[C:28]2[CH:34]=[C:33]([C:35](O)=[O:36])[NH:32][C:29]2=[CH:30][N:31]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>ClCCl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2([CH2:14][NH:15][C:35]([C:33]3[NH:32][C:29]4=[CH:30][N:31]=[C:26]([Cl:25])[CH:27]=[C:28]4[CH:34]=3)=[O:36])[O:10][CH2:11][CH2:12][O:13]2)=[CH:7][CH:8]=1
Reactant: COc1ccc(C2(CN)OCCO2)cc1
Reactant: O=C(O)c1cc2cc(Cl)ncc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: COc1ccc(C2(CNC(=O)c3cc4cc(Cl)ncc4[nH]3)OCCO2)cc1
Reaction time: 0.03 h

Procedure:
To a solution of [2-(4-methoxyphenyl)-[1,3]-dioxolan-2-yl]methylamine (Preparation 45, 0.117 g, 0.56 mmol) in dichloromethane (5 mL) was added DIPEA (213 μL, 1.22 mmol), 5-chloro-1H-pyrrolo[2,3-c]pyridine-2-carboxylic acid (Preparation 18, 0.100 g, 0.51 mmol) and HOBT (0.076 g, 0.56 mmol). The resulting solution was stirred for 2 min then EDCI (0.117 g, 0.61 mmol) was added and stirring was continued for 18 h at rt. The reaction mixture was partitioned between dichloromethane (30 mL) and water (20 mL) and the layers separated. The aqueous phase was extracted with dichloromethane (3×20 mL) then the combined organics were washed with brine (20 mL), dried (MgSO4), filtered and concentrated in vacuo. Recrystallisation from methanol/dichloromethane gave the title compound as an orange solid. δH (CDCl3): 3.81 (3H, s), 3.84-3.91 (4H, m), 4.05 (2H, m), 6.56 (1H, t), 6.76 (1H,s), 6.89 (2H, d), 7.44 (2H, d), 7.57 (1H, s), 8.68 (1H, s), 9.94 (1H, br s).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([OH:12])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:18]O>S(=O)(=O)(O)O.O>[CH2:1]([C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[C:10]([O:12][CH3:18])=[O:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CO
Reactant: CCCCCCc1cc(C(=O)O)ccc1OC
Agent: O=S(=O)(O)O
Solvent: O
Product: CCCCCCc1cc(C(=O)OC)ccc1OC

Procedure:
A crude product of 3-hexyl-4-methoxybenzoic acid and methanol (4 ml) were mixed. To this solution was added conc. sulfuric acid (2 drops), and the mixture was refluxed under heating for 20 hours. Water (10 ml) was added and methanol was evaporated under reduced pressure. The aqueous layer was extracted 3 times with ethyl acetate (20 ml). The organic layers were combined, and washed 3 times with saturated brine (20 ml). This solution was dried over anhydrous magnesium sulfate, and the drying agent was filtered off. The filtrate was concentrated under reduced pressure, and the obtained residue was purified by column chromatography (hexane/ethyl acetate=10/1) to give methyl 3-hexyl-4-methoxybenzoate (96.2 g) as a colorless oil.
Reaction SMILES: CCN(P1(N(C)CCCN1C)=NC(C)(C)C)CC.[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[NH:25][C:24]=1[CH3:32].[CH2:34](Br)[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>CN(C=O)C>[CH3:19][O:20][C:21](=[O:33])[CH2:22][C:23]1[C:31]2[C:26](=[N:27][CH:28]=[CH:29][CH:30]=2)[N:25]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:24]=1[CH3:32]
Reactant: COC(=O)Cc1c(C)[nH]c2ncccc12
Reactant: BrCc1ccccc1
Agent: CCN(CC)P1(=NC(C)(C)C)N(C)CCCN1C
Solvent: CN(C)C=O
Product: COC(=O)Cc1c(C)n(Cc2ccccc2)c2ncccc12
Reaction time: 0.5 h

Procedure:
BEMP (182 μL, 0.63 mmol) is added to a stirring solution of (2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester prepared as described in U.S. Pat. No. 3,320,268 (80 mg, 0.39 mmol) in DMF (2.4 mL). After 30 minutes, benzyl bromide (75 μL, 0.63 mmol) is added and the reaction stirred for 3 days, before partitioning between water and 1:1 EtOAc/ether. The organic layer is washed with brine then reduced in vacuo. The residue is purified by flash column chromatography (3:1 iso-hexane/EtOAc elution) to furnish (1-benzyl-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-acetic acid methyl ester; MH+=295.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:16])[C:4]1[CH:13]=[C:12]([F:14])[C:7]([C:8]([O:10][CH3:11])=[O:9])=[CH:6][C:5]=1[NH2:15].Br[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C1C=CC(P(C2C=CC3C(=CC=CC=3)C=2C2C3C(=CC=CC=3)C=CC=2P(C2C=CC=CC=2)C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1(C)C=CC=CC=1>[CH3:11][O:10][C:8](=[O:9])[C:7]1[CH:6]=[C:5]([NH:15][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:4]([C:3]([O:2][CH3:1])=[O:16])=[CH:13][C:12]=1[F:14]
Reactant: COC(=O)c1cc(F)c(C(=O)OC)cc1N
Reactant: Brc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(Nc2ccccc2)c(C(=O)OC)cc1F
Temperature: 90 °C
Yield: 80.2 %

Procedure:
To a mixture of 174B (10.0 g, 44.0 mmol), bromobenzene (4.6 mL, 44.0 mmol), (S)-(−)-2,2′-Bis(diphenylphosphino)-1,1′-binaphthyl (2.06 g, 3.30 mmol), and toluene (250 mL) was added cesium carbonate (20.0 g, 44.0 mmol) followed by palladium(II) acetate (0.494 g, 2.20 mmol). The mixture was heated at 90° C. for 24 h. HPLC indicated that the reaction was complete. The reaction mixture was cooled to room temperature, and filtered under reduced pressure through a pad of Celite topped with a pad of silica gel, and the Celite/Silica gel pad was rinsed with EtOAc. The filtrate was concentrated under reduced pressure and purified by silica gel chromatography using a 1:10 mixture of EtOAc and hexane to give 10.7 g (80%) of compound 174C as a pale yellow solid. HPLC retention time=3.72 min. (Condition A). 1H-NMR (400 MHz, CDCl3) δ 3.89 (s, 3H), 3.93 (s, 3H), 7.12 (m, 1H), 7.22 (m, 2H), 7.37 (m, 2H), 7.74 (m, 2H), and 9.22 (br s, 1H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH2:8][CH2:7]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:22][CH3:23])=[CH:19][CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:18]1[CH:17]=[C:16]2[C:21]([C:12]([N:9]3[C:10]4[C:6](=[CH:5][CH:4]=[CH:3][C:2]=4[CH3:1])[CH2:7][CH2:8]3)=[N:13][CH:14]=[N:15]2)=[CH:20][CH:19]=1
Reactant: COc1ccc2c(Cl)ncnc2c1
Reactant: Cc1cccc2c1NCC2
Solvent: CC(C)O
Product: COc1ccc2c(N3CCc4cccc(C)c43)ncnc2c1
Yield: 79 %

Procedure:
Utilizing a procedure analogous to that described in Example 1 this product was prepared in 79% yield from 7-methyl-indoline (1.1 eq.), and 4-chloro-7-methoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 157°-160° C. (dec); LC-MS: 292 (MH+); anal. RP18-HPLC RT: 4.30 min.).
Reaction SMILES: [C:1]([CH:4]1[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=O)(=O)[CH3:2].[NH2:11][C:12]1[NH:16][N:15]=[C:14]([CH2:17][OH:18])[N:13]=1>COCCO>[CH3:2][C:1]1[C:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=2[N:16]2[N:15]=[C:14]([CH2:17][OH:18])[N:13]=[C:12]2[N:11]=1
Reactant: Nc1nc(CO)n[nH]1
Reactant: CC(=O)C1CCCCC1=O
Solvent: COCCO
Product: Cc1nc2nc(CO)nn2c2c1CCCC2
Temperature: 23 °C
Yield: 50.8 %

Procedure:
To a round bottomed flask was loaded 4.2 grams of 2-acetylcyclohexanone, 3.52 grams of (5-Amino-1H-[1,2,4]triazol-3-yl)-methanol and 50 ml 2-methoxyethanol. The mixture was refluxed for 18 hours. Then it was cooled down to 23° C. and concentrated to 5 ml. Then 50 ml ethyl ether was added and the precipitate was filtered and vacuum dried to yielded 3.32 grams of product Yield. 49%. This compound was used directly for the next step. MS: 219.2(M+H). H-NMR(DMSO): δ 5.49(t, 1H, OH, J=6 Hz), 4.61(d, 2H, J=6 Hz), 3.24 (m, 2H), 2.93 (m, 2H), 2.69 (s, 3H), 2.52 (s, 2H), 1.84 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:46])[CH2:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:44])=[O:43])[CH:37]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][NH:25][CH2:26][CH2:27][O:28][CH3:29])=[CH:20][N:19]=3)[S:17][C:10]=12.[C:47](OC(=O)C)(=[O:49])[CH3:48]>>[F:1][C:2]1[CH:3]=[C:4]([NH:30][C:31](=[O:46])[CH2:32][C:33]([NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[C:38]([S:42]([CH3:45])(=[O:43])=[O:44])[CH:37]=2)=[O:34])[CH:5]=[CH:6][C:7]=1[O:8][C:9]1[CH:14]=[CH:13][N:12]=[C:11]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][C:21]([CH2:24][N:25]([CH2:26][CH2:27][O:28][CH3:29])[C:47](=[O:49])[CH3:48])=[CH:20][N:19]=3)[S:17][C:10]=12
Reactant: CC(=O)OC(C)=O
Reactant: COCCNCc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5cccc(S(C)(=O)=O)c5)cc4F)c3s2)nc1
Product: COCCN(Cc1ccc(-c2cc3nccc(Oc4ccc(NC(=O)CC(=O)Nc5cccc(S(C)(=O)=O)c5)cc4F)c3s2)nc1)C(C)=O
Yield: 32.4 %

Procedure:
A solution of compound 345 (18.5 mg, 0.028 mmol) in acetic anhydride (1.31 ml, 13.9 mmol) was stirred at room temperature for 60 h. The solvent was removed under reduced pressure and the residue was triturated with water for 3 h. The solid suspension was filtered, the precipitate was rinsed with water and dried under high vacuum to afford compound 346 (6.4 mg, 9.07 μmol, 32.5%) as a beige solid. 1H NMR (400 MHz, DMSO-d6) δ (ppm): mixture of rotamers, 10.64 (s, 1H), 10.60 (s, 1H), 8.55-8.49 (m, 2H), 8.38-8.21 (m, 3H), 7.91-7.86 (m, 2H), 7.78 (td, J=8.8, 2.0 Hz, 1H), 7.66-7.60 (m, 2H), 7.51 (t, J=8.8 Hz, 1H), 7.44 (dd, J=9.2, 1.6 Hz, 1H), 6.71-6.67 (m, 1H), 4.71 and 4.59 (2s, 2H), 3.58-3.23 (m, 14H), 3.21 (s, 3H), 2.13 and 2.05 (2s, 3H). MS (m/z): 706.5 (M+H).
Reaction SMILES: C1(S([N:10]2[C:18]3[C:13](=[CH:14][C:15]([NH:19][C:20]4[C:21]5[S:28][C:27]([C:29]6[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=6)=[CH:26][C:22]=5[N:23]=[CH:24][N:25]=4)=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=O)=O)C=CC=CC=1.[CH2:35]([N:37]([CH:40](O)[CH2:41][CH3:42])[CH2:38][CH3:39])[CH3:36]>>[CH2:35]([N:37]([CH2:38][CH3:39])[CH2:40][CH2:41][CH2:42][N:10]1[C:18]2[C:13](=[CH:14][C:15]([NH:19][C:20]3[C:21]4[S:28][C:27]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)=[CH:26][C:22]=4[N:23]=[CH:24][N:25]=3)=[CH:16][CH:17]=2)[CH:12]=[CH:11]1)[CH3:36]
Reactant: CCC(O)N(CC)CC
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(Nc3ncnc4cc(-c5ccccc5)sc34)ccc21
Product: CCN(CC)CCCn1ccc2cc(Nc3ncnc4cc(-c5ccccc5)sc34)ccc21

Procedure:
The title compound was prepared from [1-benzenesulfonyl-1H-indol-5-yl]-(6-phenyl-thieno[3,2-d]pyrimidin-4-yl )-amine (246 mg, 1.00 mmol) and diethylamino-propanol (120 mg, 0.939 mmol) by a procedure analogous to example 69. RP18-HPLC RT: 4.55 minutes; API MS: 455.63 (M+1) MP: 178-180° C.
Reaction SMILES: Cl.[CH3:2][CH:3]([O:5][C:6]1[CH:11]=[CH:10][C:9]([C:12]2[C:16]([CH:17]=[O:18])=[CH:15][NH:14][N:13]=2)=[CH:8][CH:7]=1)[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH:26]1[CH2:29][CH2:28][CH2:27]1.O>C(#N)C.CCOC(C)=O>[CH:26]1([N:14]2[CH:15]=[C:16]([CH:17]=[O:18])[C:12]([C:9]3[CH:10]=[CH:11][C:6]([O:5][CH:3]([CH3:2])[CH3:4])=[CH:7][CH:8]=3)=[N:13]2)[CH2:29][CH2:28][CH2:27]1
Reactant: BrC1CCC1
Reactant: CC(C)Oc1ccc(-c2n[nH]cc2C=O)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: O
Product: CC(C)Oc1ccc(-c2nn(C3CCC3)cc2C=O)cc1
Temperature: 2.5 °C
Reaction time: 1 h
Yield: 85.2 %

Procedure:
A mixture of 3-[4-(propan-2-yloxy)phenyl]-1H-pyrazole-4-carbaldehyde hydrochloride (250 mg, 0.9 mmol) and K2CO3 (626 mg, 4.5 mmol) in acetonitrile (5 ml) was stirred at 0-5° C. for 1 h. Bromocyclobutane (158 mg, 1.16 mmol) was added and the reaction mixture stirred at ambient temperature for 34 h. The reaction was poured into water (200 mL) and extracted with EtOAc (50 mL×3). The combined extracts was washed with brine (100 mL), dried, and concentrated under vacuum. The residue was purified by SGC using Hexane: EtOAc (0%-40%) as eluent to afford 1-cyclobutyl-3-(4-isopropoxyphenyl)-1H-pyrazole-4-carbaldehyde (218 mg, Yield: 71%) as a white solid. LCMS (method C): RT=2.54 min, m/z=285.2 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([CH3:16])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]#[N:15])=[CH:10][CH:9]=1)=[O:5].[CH2:17]([N:19]1[C:31]2[CH:30]=[CH:29][C:28]([C:32](O)=[O:33])=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH3:18].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.O>CN(C=O)C>[C:14]([C:11]1[CH:10]=[CH:9][C:8]([CH2:7][NH:6][C:4](=[O:5])[CH:3]([CH3:16])[CH2:2][NH:1][C:32]([C:28]2[CH:29]=[CH:30][C:31]3[N:19]([CH2:17][CH3:18])[C:20]4[C:25]([C:26]=3[CH:27]=2)=[CH:24][CH:23]=[CH:22][CH:21]=4)=[O:33])=[CH:13][CH:12]=1)#[N:15]
Reactant: CCn1c2ccccc2c2cc(C(=O)O)ccc21
Reactant: CC(CN)C(=O)NCc1ccc(C#N)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Product: CCn1c2ccccc2c2cc(C(=O)NCC(C)C(=O)NCc3ccc(C#N)cc3)ccc21
Yield: 69.2 %

Procedure:
A solution (2.5 mL) of the compound obtained in Step 2 (112 mg, 0.52 mmol), 9-ethyl-9H-carbazole-3-carboxylic acid (123 mg, 0.52 mmol), HATU (255 mg, 0.67 mmol) and TEA (0.216 mL, 1.55 mmol) in DMF was stirred at room temperature for 16 hr. Water was poured into the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was dried, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (solvent; ethyl acetate) to give the title compound (158 mg, 0.360 mmol, 69.9%) as a white powder.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[CH:5]=[CH:6][NH:7]2.C=O.CNC.CI.[Si](C#N)(C)(C)C.CC[CH2:27][CH2:28][N+:29](CCCC)(CCCC)CCCC.[F-]>C(O)(=O)C.O.C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:4]=1[C:5]([CH2:27][C:28]#[N:29])=[CH:6][NH:7]2
Reactant: CCCC[N+](CCCC)(CCCC)CCCC
Reactant: COc1cccc2[nH]ccc12
Agent: C=O
Agent: CNC
Agent: C[Si](C)(C)C#N
Solvent: CC(=O)O
Solvent: O
Solvent: CI
Product: COc1cccc2[nH]cc(CC#N)c12
Temperature: 25 °C
Reaction time: 6 h
Yield: 63.2 %

Procedure:
To a solution of 4-methoxyindole (1.0 g, 6.8 mmol, 1.0 eq.) in a mixture of acetic acid (2 mL) and water (1 mL) were added, at 0° C., formaldehyde (720 μL, 37% in H2O, 8.9 mmol, 1.3 eq) and dimethylamine (1.23 mL, 40% in H2O, 10.9 mmol, 1.6 eq). The mixture was stirred at room temperature for 6 hours and then, quenched with ice and 5 M aqueous sodium hydroxide. The mixture was extracted with dichloromethane and then, the organic layer was dried over MgSO4 and partially evaporated. To the solution gramine in dichloromethane (20 mL) were added, under an argon atmosphere, anhydrous toluene (40 mL) and methyl iodide (845 μL, 13.6 mmol, 2.0 eq.). The mixture was stirred at room temperature for 12 hours and then, concentrated under reduced pressure. To the residue taken up in anhydrous THF (60 mL) were added, under an argon atmosphere, TMSCN (1.28 mL, 10.2 mmol, 1.5 eq.) and TBAF (20.4 mL, 1M, 20.4 mmol, 3.0 eq.). The mixture was stirred at room temperature for 4 hours and then, concentrated under reduced pressure. The crude was taken up in ethyl acetate and the organic layer was washed with aqueous bicarbonate solution and then dried over MgSO4. The solvent was removed under reduced pressure, and the residue purified by silica gel pad filtration (eluent: EtOAc) to afford (4-methoxy-1H-indol-3-yl)-acetonitrile as a beige solid (0.80 g, 68%).
Reaction SMILES: [CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH2:28][NH2:29])=[CH:26][CH:25]=1>>[CH2:1]([C:9]1[N:13]=[C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][NH:29][CH2:28][C:27]3[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=3)=[CH:16][CH:15]=2)[O:11][N:10]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: CCCCCCCCc1noc(-c2ccc(C=O)cc2)n1
Product: CCCCCCCCc1noc(-c2ccc(CNCc3ccc(C(F)(F)F)cc3)cc2)n1
Yield: 49 %

Procedure:
The same procedure as employed in the preparation of Example 223 (step b) but using 4-(3-octyl-1,2,4-oxadiazol-5-yl)benzaldehyde and 4-(trifluoromethyl)benzylamine gave the title compound as a colorless oil (49%). M+(LC/MS(ESI)): 446.4.
Reaction SMILES: [NH2:1][C:2](=[O:35])[CH2:3][CH2:4][N:5]([CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:30][CH2:29][C@H:28]([C:31]([CH3:34])([CH3:33])[CH3:32])[CH2:27][CH2:26]3)[CH:20]=2)[CH:15]=1)C(=O)OC(C)(C)C.[CH3:36][C:37](OC(C)=O)=[O:38]>CC(O)=O>[C:37]([NH:1][C:2](=[O:35])[CH2:3][CH2:4][NH:5][CH2:13][C:14]1[CH:23]=[CH:22][C:21]2[C:16](=[CH:17][CH:18]=[C:19]([O:24][C@H:25]3[CH2:26][CH2:27][C@H:28]([C:31]([CH3:33])([CH3:32])[CH3:34])[CH2:29][CH2:30]3)[CH:20]=2)[CH:15]=1)(=[O:38])[CH3:36]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)N(CCC(N)=O)Cc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Solvent: CC(=O)O
Product: CC(=O)NC(=O)CCNCc1ccc2cc(O[C@H]3CC[C@H](C(C)(C)C)CC3)ccc2c1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
The mixture of tert-butyl 3-amino-3-oxopropyl((6-((trans)-4-tert-butylcyclohexyloxy)naphthalen-2-yl)methyl)carbamate (241 mg, 0.5 mmol) in Ac2O and AcOH (6 mL, 1:5), was stirred at 90° C. for 2 h. The reaction mixture was concentrated in vacuum and the residue was purified by chromatography with silica gel (DCM/MeOH=15/1) to give the title compound as a white solid (100 mg, yield: 50%). ESI-MS (M+H+): 425.3. HPLC: 94.82%. 1H NMR (400 MHz, CDCl3) δ: 7.70 (d, 1H), 7.68 (d, 1H), 7.49 (s, 1H), 7.21 (d, 1H), 7.17-7.14 (m, 2H), 6.50 (br, 1H), 5.49 (br, 1H), 4.71 (s, 2H), 4.24-4.30 (m, 1H), 3.71 (t, 2H), 2.57 (t, 2H), 2.27 (d, 2H), 2.18 (s, 3H), 1.89 (d, 2H), 1.48-1.42 (m, 2H), 1.09-1.20 (m, 3H), 0.88 (s, 9H).
Reaction SMILES: Br[C:2]1[S:6][C:5]([C:7]([O:9][CH2:10]C)=[O:8])=[CH:4][CH:3]=1.[CH3:12][O:13][C@H:14]1[C@@H:19]([NH:20][C:21](=[O:30])[O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH2:18][CH2:17][NH:16][CH2:15]1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>C1(C)C=CC=CC=1.C(OCC)(=O)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:23]([O:22][C:21]([NH:20][C@H:19]1[CH2:18][CH2:17][N:16]([C:2]2[S:6][C:5]([C:7]([O:9][CH3:10])=[O:8])=[CH:4][CH:3]=2)[CH2:15][C@H:14]1[O:13][CH3:12])=[O:30])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CCOC(=O)c1ccc(Br)s1
Reactant: CO[C@@H]1CNCC[C@@H]1NC(=O)OCc1ccccc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: COC(=O)c1ccc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OC)C2)s1
Temperature: 110 °C
Reaction time: 39 h
Yield: 60.4 %

Procedure:
A suspension of ethyl 5-bromothiophene-2-carboxylate obtained in Example (244a) (100 mg, 0.45 mmol), benzyl cis(±)-(3-methoxypiperidin-4-yl)-carbamate obtained in Example (40b) (143 mg, 0.54 mmol), palladium acetate (10 mg, 0.05 mmol), BINAP (28 mg, 0.05 mmol) and cesium carbonate (206 mg, 0.63 mmol) in toluene was stirred at 110° C. for 39 hours. The reaction solution was diluted with ethyl acetate, washed with water and brine, and then dried over anhydrous magnesium sulfate. Following filtration, the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=2/1) to obtain 110 mg of the title compound as a yellow oily substance (60%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:10])[C:5]([NH:8][CH3:9])=[N:6][CH:7]=1.[N:11]([O-])=O.[Na+].[OH-].[Na+]>Cl.O>[Br:1][C:2]1[CH:3]=[C:4]2[N:10]=[N:11][N:8]([CH3:9])[C:5]2=[N:6][CH:7]=1
Reactant: CNc1ncc(Br)cc1N
Reactant: O=N[O-]
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Cn1nnc2cc(Br)cnc21
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
To a solution of 5-bromo-N*2*-methyl-pyridine-2,3-diamine (Stage 67.1.4, 1.2 g, 5.94 mmol) in 2 M aqueous HCl (70 ml) cooled with an ice-bath was added a solution of sodium nitrite (Fluka, Buchs, Switzerland, 492 mg, 7.13 mmol) in water (10 ml). The reaction mixture was stirred at 0° C. for 1 h and at rt for 75 min then basified with 2 M aqueous NaOH (75 ml) and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, filtered and evaporated. The crude product was dry loaded on silica gel and purified by MPLC (heptane/EtOAc 0%-30%) to give the title compound as a blue solid. (HPLC: tR 2.46 min (Method A); M+H=213, 215 MS-ES).
Reaction SMILES: [NH2:1][CH:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[O:13])=[CH:7][CH:6]=1)[CH2:3][OH:4].C([O-])(=O)C.[Na+].[N:27]#[C:28]Br.N>CO>[NH2:27][C:28]1[O:4][CH2:3][CH:2]([C:5]2[CH:6]=[CH:7][C:8]([NH:11][C:12]([NH:14][C:15]3[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=3)=[O:13])=[CH:9][CH:10]=2)[N:1]=1
Reactant: N#CBr
Reactant: NC(CO)c1ccc(NC(=O)Nc2ccc(Cl)cc2)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: [Na+]
Solvent: CO
Product: NC1=NC(c2ccc(NC(=O)Nc3ccc(Cl)cc3)cc2)CO1
Temperature: 25 °C
Reaction time: 16 h
Yield: 52.6 %

Procedure:
To a stirred suspension of 1-[4-(1-amino-2-hydroxy-ethyl)-phenyl]-3-(4-chloro-phenyl)-urea (160 mg) and sodium acetate (129 mg) in methanol (8 ml) was added dropwise a solution of cyanogen bromide (72 mg) in methanol (0.5 ml). The resulting pale yellow solution was then stirred at room temperature for 16 h. Aqueous ammonia solution (0.4 ml, 25%) was added dropwise and stirring was continued for a further hour. The mixture was then concentrated in vacuo and the residue was purified by column chromatography (Isolute® Flash-NH2 from Separtis; gradient: heptane/dichloromethane/methanol) to give (RS)-1-[4-(2-amino-4,5-dihydro-oxazol-4-yl)-phenyl]-3-(4-chloro-phenyl)-urea (91 mg, 53%) as a white solid. MS (ISP): 333.2 ([{37Cl}M+H]+), 331.1 ([{35Cl}M+H]+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH:5]([C:10]1([CH:16](O)[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:40]1(=[O:50])[NH:44][C:43](=[O:45])[C:42]2=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]12.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[CH3:1][O:2][C:3](=[O:20])[CH:4]([CH3:19])[CH:5]([C:10]1([CH:16]([N:44]2[C:43](=[O:45])[C:42]3=[CH:46][CH:47]=[CH:48][CH:49]=[C:41]3[C:40]2=[O:50])[CH3:17])[S:15][CH2:14][CH2:13][CH2:12][S:11]1)[C:6]([F:9])([F:8])[F:7]
Reactant: COC(=O)C(C)C(C(F)(F)F)C1(C(C)O)SCCCS1
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: COC(=O)C(C)C(C(F)(F)F)C1(C(C)N2C(=O)c3ccccc3C2=O)SCCCS1

Procedure:
A solution of 462 mg (2 mMole) of the product of Example 4 in 20 ml of tetrahydrofuran is treated with 524 mg (2 mMole) of triphenylphosphine, 268 mg (2 mMole) of phthalimide, and 350 mg (2 mMole) of diethyl azodicarboxylate for 48 hours at 25° C. The solvent is evaporated and the product isolated by chromatography on silica gel affording 3-[2-(1-phthalimidoethyl)-1,3-dithian-2-yl]-4,4,4-trifluoro-2-methylbutyric acid methyl ester.
Reaction SMILES: [C:1]1([NH:7][CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[ClH:12].[CH3:13][CH2:14]O>>[ClH:12].[CH2:13]([N:7]([C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1)[CH2:8][C:9]([OH:11])=[O:10])[CH3:14]
Reactant: CCO
Reactant: O=C(O)CNc1ccccc1
Agent: Cl
Product: CCN(CC(=O)O)c1ccccc1

Procedure:
To a mixture of phenylglycine (15.00 gram (hereinafter g.), 0.1 mole (hereinafter mol)) in EtOH (100 miliLiters (hereinafter mL)) was added 20% ethanolic HCl (30 mL). The mixture was heated at reflux for about 20 hours (hereinafter h.), then allowed to cool. The solvent was removed in vacuo, and the residue was used without further purification.