Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14].[O:16]1[CH2:21][CH2:20]OCC1.[CH2:22]([CH2:25]OC)OC>>[O:16]=[C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14])[CH2:20][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:22][CH3:25]
Reactant: NCCCCCCCCCCCC(=O)O
Reactant: C1COCCO1
Reactant: COCCOC
Product: CCCCCCCCCCCCCCCC(=O)NCCCCCCCCCCCC(=O)O
Yield: 72 %

Procedure:
A sample of 5.13 g (20.0 mmol) hexadecanoic acid, 2.30 g (20.0 mmol) N-hydroxysuccinimide and 4.53 g (22.0 mmol) dicyclohexylcarbodiimide (DOC) was dissolved in 20 ml dry tetrahydrofurane or methylenechloride. The temperature of the reaction mixture was kept at 20° C. and the mixture stirred overnight under an atmosphere of nitrogen. The precipitate was removed by filtration and the filtrate concentrated by rotoevaporation to dryness to yield 6.0 g (85%) of the succinimidylester. 180 mg (0.509 mmol) of this active ester and 110 mg (0.510 mmol) 12-aminododecanoic acid were suspended in 3 ml dry dimethoxyethane or dioxane and stirred at 50°-60° C. for ca. 4 h. The reaction mixture was filtered hot and diluted with ice water. The precipitate was removed by filtration and purified by crystallization from methanol to yield 165 mg (72%) of the product as colourless cystals, m.p. 119°-121° C.
Reaction SMILES: [C:1](Cl)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Br:21][C:22]1[CH:27]=[C:26]([CH2:28][OH:29])[CH:25]=[CH:24][C:23]=1[CH2:30][OH:31].C(N([CH2:37][CH3:38])CC)C>CN(C=O)C.CN(C1C=CN=CC=1)C>[Br:21][C:22]1[CH:27]=[C:26]([CH2:28][O:29][C:1]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)[CH:25]=[CH:24][C:23]=1[CH2:30][O:31][C:1]([C:38]1[CH:37]=[CH:19][CH:14]=[CH:15][CH:16]=1)([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CCN(CC)CC
Reactant: OCc1ccc(CO)c(Br)c1
Agent: CN(C)c1ccncc1
Solvent: CN(C)C=O
Product: Brc1cc(COC(c2ccccc2)(c2ccccc2)c2ccccc2)ccc1COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18.1 %

Procedure:
Under a nitrogen stream, to a solution of trityl chloride (11.58 g, 41.6 mmol) and (2-bromo-4-hydroxymethylphenyl)methanol (4.1 g, 18.9 mmol) in DMF (12 ml), triethylamine (5.8 ml, 41.6 mmol) and DMAP (369.2 mg, 3.02 mmol) were added and the mixture was stirred for 18 hours at room temperature. The reaction mixture was evaporated under reduced pressure to remove the solvent and then extracted with methylene chloride. The organic layer was washed with water and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, and then evaporated under reduced pressure to remove the solvent. The resulting residue was purified by silica gel column chromatography (developing solution=ethyl acetate:n-hexane (1:2)) to give the titled compound (2.4 g, 18%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(N(CCCC)CCCC)CCC.[C:24]([NH:32][C:33]1[CH:45]=[C:44]([CH:46]=[CH2:47])[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:41])([CH3:40])[CH3:39])=[O:36])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.CN(C)C(=O)C>[C:24]([NH:32][C:33]1[CH:45]=[C:44](/[CH:46]=[CH:47]/[C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=2)[CH:43]=[CH:42][C:34]=1[C:35]([O:37][C:38]([CH3:40])([CH3:41])[CH3:39])=[O:36])(=[O:31])[C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Reactant: C=Cc1ccc(C(=O)OC(C)(C)C)c(NC(=O)c2ccccc2)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Solvent: CCCCN(CCCC)CCCC
Product: CC(C)(C)OC(=O)c1ccc(/C=C/c2ccc([N+](=O)[O-])cc2)cc1NC(=O)c1ccccc1
Temperature: 110 °C
Reaction time: 0.33 h
Yield: 72.8 %

Procedure:
0.14 g of 1-bromo-4-nitrobenzene, 0.22 mL of tributylamine and 5.2 mg of palladium acetate were added to 2.0 mL of N,N-dimethylacetamide solution containing 0.15 g of tert-butyl 2-(benzamido)-4-vinylbenzoate at room temperature and stirred under nitrogen atmosphere at 110° C. for 1 hour and 20 minutes. After the reaction mixture was cooled to room temperature, 10% citric acid aqueous solution and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 10% citric acid aqueous solution, a saturated sodium thiosulfate aqueous solution and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufactured by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain 0.15 g of tert-butyl 2-(benzamido)-4-((E)-2-(4-nitrophenyl)vinyl)benzoate as yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][NH:4][C:5]1[N:13]=[C:12]([Cl:14])[N:11]=[C:10]2[C:6]=1[N:7]=[CH:8][N:9]2[CH:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1.CO.[F:22][C:23]([F:33])([F:32])[C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1.[BH3-]C#N.[Na+]>C(O)(=O)C>[Cl:14][C:12]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[C:5]([NH:4][CH2:3][CH2:2][NH:1][CH2:28][C:27]2[CH:26]=[CH:25][C:24]([C:23]([F:22])([F:32])[F:33])=[CH:31][CH:30]=2)[N:13]=1
Reactant: NCCNc1nc(Cl)nc2c1ncn2C1CCCC1
Reactant: O=Cc1ccc(C(F)(F)F)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: FC(F)(F)c1ccc(CNCCNc2nc(Cl)nc3c2ncn3C2CCCC2)cc1
Reaction time: 0.5 h

Procedure:
281 mg of the product obtained in Stage 1 of Example 7, 4 ml of methanol, 0.19 ml of 4-trifluoromethyl-benzaldehyde and 0.2 ml of acetic acid are mixed together, the reaction medium is agitated for 2 hours and 30 minutes, 0.1 g of NaBH3CN is added and agitation is carried out at ambient temperature for 1 hour. After evaporating the solvent, the residue is chromatographed on silica eluting with CH2Cl2/methanol/ammonium hydroxide (95/0.5/0.33) and 146 mg of expected product is obtained.
Reaction SMILES: CCCCCC.S(Cl)([Cl:10])(=O)=O.[CH2:12]([N:15]1[C:20](=[O:21])[CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[N:17]=[C:16]1[NH:26][C:27]1[CH:32]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:30]=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:13]=[CH2:14].C(=O)(O)[O-].[Na+]>CCOCC.C(O)(=O)C>[CH2:12]([N:15]1[C:20](=[O:21])[C:19]([Cl:10])=[C:18]([C:22]([F:25])([F:23])[F:24])[N:17]=[C:16]1[NH:26][C:27]1[CH:32]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:30]=[CH:29][C:28]=1[C:37]([F:40])([F:39])[F:38])[CH:13]=[CH2:14]
Reactant: C=CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)cc1=O
Reactant: O=S(=O)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCCC
Solvent: CC(=O)O
Solvent: CCOCC
Product: C=CCn1c(Nc2cc(C(F)(F)F)ccc2C(F)(F)F)nc(C(F)(F)F)c(Cl)c1=O
Reaction time: 1 h
Yield: 86.3 %

Procedure:
At room temperature, hexane solution of sulfuryl chloride (1.2 M, 0.56 ml, 0.67 mmol) was added to a mixture of 3-allyl-2-(2,5-bis(trifluoromethyl)phenyl)amino-6-trifluoromethyl-4-(3H)-pyrimidinone (0.29 g, 0.67 mmol) and acetic acid (6 ml), followed by stirring for 1 hour. After completion of the reaction, ether (30 ml) and saturated sodium bicarbonate aqueous solution (10 ml) were added to the reaction solution to separate the organic layer, and the resulting aqueous layer was extracted with ether (20 ml×2). The organic layers were combined, washed with saturated sodium bicarbonate aqueous solution and saturated brine in that order and then dried over anhydrous sodium sulfate. The drying agent was removed by filtration, and the solvent was evaporated under a reduced pressure from the resulting filtrate. By purifying the thus obtained crude product by a silica gel column chromatography (hexane:ethyl acetate=3:1), 3-allyl-2-{2,5-bis(trifluoromethyl)phenyl}amino-5-chloro-6-trifluoromethyl-4(3H)-pyrimidinone [Compound No. 67] was obtained as a white solid.
Reaction SMILES: C([O:8][CH2:9][CH:10]1[O:24][C:14]2=[C:15]3[C:20](=[CH:21][CH:22]=[C:13]2[O:12][CH2:11]1)[N:19]=[C:18]([CH3:23])[CH:17]=[CH:16]3)C1C=CC=CC=1>C(Cl)Cl>[CH3:23][C:18]1[CH:17]=[CH:16][C:15]2[C:20](=[CH:21][CH:22]=[C:13]3[O:12][CH2:11][CH:10]([CH2:9][OH:8])[O:24][C:14]3=2)[N:19]=1
Reactant: Cc1ccc2c3c(ccc2n1)OCC(COCc1ccccc1)O3
Solvent: ClCCl
Product: Cc1ccc2c3c(ccc2n1)OCC(CO)O3
Reaction time: 1 h
Yield: 69 %

Procedure:
To a solution of 2[(benzyloxy)methyl-8-methyl-2,3-dihydro[1,4]dioxino[2,3-f]quinoline (0.30 g, 0.94 mmol) in CH2Cl2 (8 mL) being cooled in an ice-bath, FeCl3 (0.77 g, 4.7 mmol) was added. After 1 h, the ice-bath was removed and the reaction mixture was stirred for another 4 h. CH2Cl2 (30 mL) and 1N NaOH (25 mL) were added to result in a suspension which was then filtered. The filtered solid was washed with CH3OH (50 mL). The combined organic layers were concentrated in vacuo. Purification on SiO2, eluted with (10:1) CHCl3:iPrOH gave 0.15 g (68%) of the title compound as an off-white solid.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:6]=[C:7]([S:11](Cl)(=[O:13])=[O:12])[CH:8]=[CH:9][CH:10]=1)(=[O:4])=[O:3].[C:15]([O:19][C:20]([N:22]1[CH2:27][CH2:26][N:25]([C:28]2[C:37]3[O:36][CH2:35][CH2:34][NH:33][C:32]=3[CH:31]=[C:30]([Cl:38])[CH:29]=2)[CH2:24][CH2:23]1)=[O:21])([CH3:18])([CH3:17])[CH3:16].N1C=CC=CC=1.O>ClCCl>[C:15]([O:19][C:20]([N:22]1[CH2:23][CH2:24][N:25]([C:28]2[C:37]3[O:36][CH2:35][CH2:34][N:33]([S:11]([C:7]4[CH:8]=[CH:9][CH:10]=[C:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH:6]=4)(=[O:13])=[O:12])[C:32]=3[CH:31]=[C:30]([Cl:38])[CH:29]=2)[CH2:26][CH2:27]1)=[O:21])([CH3:18])([CH3:16])[CH3:17]
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)Cl)c1
Reactant: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3)CC1
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCN(c2cc(Cl)cc3c2OCCN3S(=O)(=O)c2cccc(S(C)(=O)=O)c2)CC1
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 92 %

Procedure:
3-Methanesulfonyl-benzenesulfonyl chloride (80 mg, 0.314 mmol) was added in small portions under nitrogen to an ice-cold solution of 4-(6-chloro-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl)-piperazine-1-carboxylic acid tert-butyl ester (101 mg, 0.285 mmol) and pyridine (50 mg, 0.628 mmol) in dichlormethane (2 mL). After 1.5 hours at ambient temperature, water was added. The layers were separated and the organic phase was washed with saturated aqueous solution of sodium bicarbonate (20 mL), dried (Na2SO4) and concentrated to give 4-[6-chloro-4-(3-methanesulfonyl-benzenesulfonyl)-3,4-dihydro-2H-benzo[1,4]oxazin-8-yl]-piperazine-1-carboxylic acid tert-butyl ester as an oil (150 mg, 91%).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20](=[N:22]O)[NH2:21]>>[Br:14][C:15]1[CH:19]=[CH:18][S:17][C:16]=1[C:20]1[N:22]=[C:7]([C:6]2[CH:10]=[CH:11][C:3]([C:2]([F:13])([F:12])[F:1])=[CH:4][CH:5]=2)[O:8][N:21]=1
Reactant: O=C(Cl)c1ccc(C(F)(F)F)cc1
Reactant: NC(=NO)c1sccc1Br
Product: FC(F)(F)c1ccc(-c2nc(-c3sccc3Br)no2)cc1

Procedure:
The title compound was prepared from 4-trifluoromethyl-benzoyl chloride (66 μL, 0.44 mmol) and 3-bromo-thiophene-2-amidoxime (98 mg, 0.44 mmol) similar to Example 16, and yielded 130 mg (78%) of white solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][NH:12][CH2:11]1)[CH2:8][CH3:9])([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)C(C)C)C.[CH3:33][S:34]([N:37]1[CH2:42][CH2:41][N:40]([C:43](Cl)=[O:44])[CH2:39][CH2:38]1)(=[O:36])=[O:35]>C(Cl)Cl>[C:1]([O:5][C:6](=[O:23])[N:7]([C@H:10]1[C@H:14]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=2)[CH2:13][N:12]([C:43]([N:40]2[CH2:39][CH2:38][N:37]([S:34]([CH3:33])(=[O:36])=[O:35])[CH2:42][CH2:41]2)=[O:44])[CH2:11]1)[CH2:8][CH3:9])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCN(C(=O)OC(C)(C)C)[C@@H]1CNC[C@H]1c1ccc(Cl)c(Cl)c1
Reactant: CS(=O)(=O)N1CCN(C(=O)Cl)CC1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCN(C(=O)OC(C)(C)C)[C@@H]1CN(C(=O)N2CCN(S(C)(=O)=O)CC2)C[C@H]1c1ccc(Cl)c(Cl)c1
Yield: 97.6 %

Procedure:
To a solution of rac-[(3S,4R)-4-(3,4-dichloro-phenyl)-pyrrolidin-3-yl]-ethyl-carbamic acid tert-butyl ester (0.25 g, 0.69 mmol) in CH2Cl2 (5 ml) was added ethyl-diisopropyl-amine (0.20 ml, 1.1 mmol) and 4-methanesulfonyl-piperazine-1-carbonyl chloride (189 mg, 0.83 mmol). Stirring was continued over night at RT, concentrated under vacuo and purification by flash chromatography (SiO2, EtOAc) afforded 0.37 g (97%) of the title compound as a white solid. ES-MS m/e: 549.3 (M+H+).
Reaction SMILES: Cl[S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3].[CH2:15]([NH2:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.N1C=CC=CC=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:15]([NH:22][S:2]([C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9](=[O:14])[CH2:8]2)(=[O:4])=[O:3])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=C1Cc2cc(S(=O)(=O)Cl)ccc2N1
Reactant: NCc1ccccc1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: O=C1Cc2cc(S(=O)(=O)NCc3ccccc3)ccc2N1
Temperature: 25 °C
Reaction time: 4 h
Yield: 66.1 %

Procedure:
A suspension of 5-chlorosulfonyl-2-oxindole (1.62 g, 7 mmol), benzylamine (0.918 mL, 8.4 mmol) and pyridine (1 mL) in dichloromethane (20 mL) was stirred at room temperature for 4 hours. The reaction mixture was diluted with ethyl acetate (300 mL) and acidified with 1 N hydrochloric acid (16 mL). The organic layer was then washed with sodium bicarbonate and brine, dried and concentrated. The residue was washed with ethanol (3 mL) and was then purified by chromatography on silica gel eluting with methanol:dichloromethane 1:9 to give 1.4 g (66%) of 2-oxo-2,3-dihydro-1H-indole-5-sulfonic acid benzylamide.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH:11]([C:14]([N:16]2[CH2:20][C@H:19]([N:21]([CH2:32][CH3:33])[C:22]([O:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)=[O:23])[C@@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17]2)=[O:15])[CH2:10][CH2:9]1)=O)(C)(C)C.C(O)(C(F)(F)F)=O.O.[OH-].[Na+]>C(Cl)Cl>[F:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:22](=[O:23])[N:21]([C@@H:19]2[C@@H:18]([C:34]3[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=3)[CH2:17][N:16]([C:14]([CH:11]3[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]3)=[O:15])[CH2:20]2)[CH2:32][CH3:33])=[CH:26][CH:27]=1
Reactant: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCN(C(=O)OC(C)(C)C)CC2)C[C@@H]1c1ccc(Cl)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCN(C(=O)Oc1ccc(F)cc1)[C@H]1CN(C(=O)C2CCNCC2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 87 %

Procedure:
A mixture of 804 mg (1.4 mmol) 4-{(3S,4R)-3-(4-Chloro-phenyl)-4-[ethyl-(4-fluoro-phenoxycarbonyl)-amino]-pyrrolidine-1-carbonyl}-piperidine-1-carboxylic acid tert-butyl ester and 1.6 g (14 mmol) TFA in 25 mL DCM was stirred for 5 h at room temperature. Water and 2N NaOH aq. was added and the mixture was extracted with DCM. The combined organic layers were dried over Na2SO4, filtered off and evaporated to yield 577 mg (87%) of the title compound as yellow foam. MS m/e: 474.3 [M+H]+.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]([C:6]1[CH:20]=[CH:19][C:9]2[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=2[CH:7]=1)=[O:5].C(N([CH2:26][CH3:27])CC)C.[N-:28]=[C:29]=[O:30]>CN(C=O)C>[CH3:7][C:6]1[CH:4]=[C:3]([NH:28][C:29]([NH:1][CH2:2][CH2:3][C:4]([C:6]2[CH:20]=[CH:19][C:9]3[N:10]=[C:11]([NH:13][C:14]([NH:16][CH2:17][CH3:18])=[O:15])[S:12][C:8]=3[CH:7]=2)=[O:5])=[O:30])[CH:2]=[CH:26][CH:27]=1
Reactant: CCN(CC)CC
Reactant: [N-]=C=O
Reactant: CCNC(=O)Nc1nc2ccc(C(=O)CCN)cc2s1
Solvent: CN(C)C=O
Product: CCNC(=O)Nc1nc2ccc(C(=O)CCNC(=O)Nc3cccc(C)c3)cc2s1
Yield: 25 %

Procedure:
Similar to the synthesis of Example 249, a mixture of 1-(6-(3-aminopropanoyl)-2-benzothiazolyl)-3-ethylurea, triethylamine and 3-methylphenhyl isocyanate in DMF was reacted to give the desired compound 0.021 g (25%). LC/MS 426.1 (M+1); LC retention time 2.94 min.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:6][CH:7]=1.Cl.[NH2:16][C@H:17]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH3:18].C(N(CC)CC)C.O>CN(C)C=O>[C:22]([O:21][C:19](=[O:20])[C@@H:17]([NH:16][CH2:2][C:3]1[CH:4]=[C:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[S:6][CH:7]=1)[CH3:18])([CH3:25])([CH3:24])[CH3:23]
Reactant: C[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)(C)OC(=O)c1cc(CBr)cs1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@H](NCc1csc(C(=O)OC(C)(C)C)c1)C(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 53.2 %

Procedure:
To a solution of tert-butyl 4-(bromomethyl)thiophene-2-carboxylate (2.00 g) in N,N-dimethylformamide (19.8 mL) were added tert-butyl L-alaninate hydrochloride (2.62 g) and triethylamine (4.02 mL), followed by heating at 60° C. for 12 hours. To the reaction suspension was added water, followed by extraction with ethyl acetate. The organic layer was washed with a saturated aqueous sodium chloride solution, then dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane-ethyl acetate) to obtain tert-butyl 4-({[(2S)-1-tert-butoxy-1-oxopropan-2-yl]amino}methyl)thiophene-2-carboxylate (1.31 g).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:22]=[CH:21][C:20]([O:23][C:24]([CH:26]3[CH2:35][CH2:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46])[CH:32]=4)[CH2:27]3)=[O:25])=[CH:19][CH:18]=2)=[CH:13][C:12]=1[F:47])=[O:10])C1C=CC=CC=1.[H][H]>[Pd].C1COCC1>[CH2:37]([O:36][C:31]1[CH:32]=[C:33]2[C:28](=[CH:29][CH:30]=1)[CH2:27][CH:26]([C:24]([O:23][C:20]1[CH:19]=[CH:18][C:17]([C:14]3[CH:15]=[CH:16][C:11]([C:9]([OH:10])=[O:8])=[C:12]([F:47])[CH:13]=3)=[CH:22][CH:21]=1)=[O:25])[CH2:35][CH2:34]2)[CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: CCCCCCCCCCOc1ccc2c(c1)CCC(C(=O)Oc1ccc(-c3ccc(C(=O)OCc4ccccc4)c(F)c3)cc1)C2
Reactant: [H][H]
Agent: [Pd]
Solvent: C1CCOC1
Product: CCCCCCCCCCOc1ccc2c(c1)CCC(C(=O)Oc1ccc(-c3ccc(C(=O)O)c(F)c3)cc1)C2
Reaction time: 72 h
Yield: 96.7 %

Procedure:
Into a mixture of 4.19 g (6.59 mmol) of the 4'-(6-decyloxy-1,2,3,4-tetrahydro-2-naphthalenecarbonyloxy)-3-fluoro-4-biphenylcarboxylic acid benzyl ester obtained in the fourth stage and 50 ml of a THF solution containing 0.838 g of 5% palladium/carbon was blown hydrogen gas with stirring for 3 days. The reaction mixture was filtered, and the filtrate thus obtained was concentrated to obtain 3.48 g (6.37 mmol) of 4'-(6-decyloxy-1,2,3,4-tetrahydro-2-naphthalenecarbonyloxy)-3-fluoro-4-biphenyl carboxylic acid as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([OH:15])=O)[CH:3]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.Cl.Cl.[N:50]1[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=1[C:56]1[S:60][C:59]([S:61]([N:64]2[CH2:69][CH2:68][CH:67]([CH2:70][NH2:71])[CH2:66][CH2:65]2)(=[O:63])=[O:62])=[CH:58][CH:57]=1>CN(C)C=O>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([O:10][CH2:11][CH3:12])[N:5]=[C:4]([C:13]([NH:71][CH2:70][CH:67]2[CH2:66][CH2:65][N:64]([S:61]([C:59]3[S:60][C:56]([C:51]4[CH:52]=[CH:53][CH:54]=[CH:55][N:50]=4)=[CH:57][CH:58]=3)(=[O:63])=[O:62])[CH2:69][CH2:68]2)=[O:15])[CH:3]=1
Reactant: NCC1CCN(S(=O)(=O)c2ccc(-c3ccccn3)s2)CC1
Reactant: CCOc1nc(C(=O)O)cc(N)c1C#N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOc1nc(C(=O)NCC2CCN(S(=O)(=O)c3ccc(-c4ccccn4)s3)CC2)cc(N)c1C#N
Reaction time: 0.25 h
Yield: 42.4 %

Procedure:
A solution of 4-amino-5-cyano-6-ethoxypicolinic acid (0.038 g) in N,N-dimethylformamide (2 mL) was treated with 1-ethyl-3-(3′-dimethylaminopropyl)carbodiimide hydrochloride (0.039 g), 1-hyroxybenzotriazole hydrate (0.031 g), followed by diisopropylethylamine (0.096 mL) at room temperature. After stirring for 15 minutes, the compound prepared in Example 244 (0.079 g) was added. Stirring was continued overnight, and the resulting mixture was washed with water, and the product extracted with ethyl acetate. The organic layer was separated, filtered, evaporated in vacuo and the residue triturated in 1:1 hexane-diethyl ether. The precipitated solids were collected by filtration to provide the title compound (0.041 g) having the following physical data.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([OH:17])=O)[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:18][CH:19]1[CH2:25][CH2:24][C:23]2[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=2[NH:21][C:20]1=[O:30]>>[C:1]([O:5][C:6]([NH:8][C:9]1([C:15]([NH:18][CH:19]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][CH:28]=[CH:29][C:22]=3[NH:21][C:20]2=[O:30])=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: NC1CCc2ccccc2NC1=O
Reactant: CC(C)(C)OC(=O)NC1(C(=O)O)CCCCC1
Product: CC(C)(C)OC(=O)NC1(C(=O)NC2CCc3ccccc3NC2=O)CCCCC1

Procedure:
Prepared from 1(t-butoxycarbonylamino)cyclohexanecarboxylic acid and 3-amino-2,3,4,5-tetrahydro-1H-[1]benzazepin-2-one (Example 1, Step A) by the procedure described in Example 25, Step A. 1H NMR (200 MHz, CDCl3): 1.1-2.2 (m,19 H), 2.00 (m,2 H), 2.50 (m,2 H), 4.55 (m,1 H), 6.9-7.2 (m,4 H). FAB-MS: calculated for C22H31N3O4 401; found 402 (M+H,40%).
Reaction SMILES: N1[CH:6]=[CH:5][CH:4]=[C:3]([CH:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)C=1.Br[C:15]1C=CC=C[N:16]=1.CC1(C)C(C)(C)OB(C2CCC3(OCCO3)CC=2)O1.[NH:40]1[CH2:43][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]2[C:57]3[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:61])([F:60])[F:59])[CH:56]=3)[N:51]=[CH:50][N:49]=2)[CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[N:16]1[CH:15]=[CH:6][CH:5]=[CH:4][C:3]=1[CH:7]1[CH2:8][CH2:9][CH:10]([N:40]2[CH2:41][CH:42]([NH:44][C:45](=[O:62])[CH2:46][NH:47][C:48]3[C:57]4[C:52](=[CH:53][CH:54]=[C:55]([C:58]([F:60])([F:59])[F:61])[CH:56]=4)[N:51]=[CH:50][N:49]=3)[CH2:43]2)[CH2:11][CH2:12]1
Reactant: Brc1ccccn1
Reactant: O=C1CCC(c2cccnc2)CC1
Reactant: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: CC1(C)OB(C2=CCC3(CC2)OCCO3)OC1(C)C
Agent: [Na+]
Product: O=C(CNc1ncnc2ccc(C(F)(F)F)cc12)NC1CN(C2CCC(c3ccccn3)CC2)C1

Procedure:
Reaction of 4-(pyridin-3-yl)cyclohexanone (prepared by the reaction of 2-bromopyridine with 8-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-1,4-dioxa-spiro[4.5]dec-7-ene using the sequence described in Example 1 Step A-C) with N-(azetidin-3-yl)-2-((6-(trifluoromethyl)quinazolin-4-yl)amino)acetamide (as prepared in Example 1 Step G) in the presence of TEA and NaBH(OAc)3 as described in Example 1, Step H afforded the product.