Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([C:13](OCC)=[O:14])=[CH:7]2)([O-:3])=[O:2].[OH-].[K+].C(N1C=CN=C1)(N1C=CN=C1)=O.[BH4-].[Na+]>CO.O>[N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][C:8]([CH2:13][OH:14])=[CH:7]2)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2cc([N+](=O)[O-])ccc2[nH]1
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [BH4-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=[N+]([O-])c1ccc2[nH]c(CO)cc2c1
Reaction time: 0.67 h

Procedure:
To a solution of ethyl 5-nitro-1H-indole-2-carboxylate (9.8 g, 42.0 mmol) in methanol (300 mL) was added a solution of 2 M potassium hydroxide (31 mL, 63.0 mmol). The reaction mixture was heated at reflux for 2 h and then the hot solution was filtered, poured onto ice, and acidified. The resultant fine pale brown precipitate was collected by filtration and dried. The crude acid was dissolved in tetrahydrofuran (250 mL) and stirred with 1,1′-carbonyldiimidazole (10.2 g, 63.0 mmol) with gentle warming for 2 h. Water (100 mL) was added and then solid sodium borohydride (7.9 g, 0.21 mol) was added portionwise over 30 min, the reaction mixture was stirred for a further 40 min and then it was quenched with 1 M hydrochloric acid. The tetrahydrofuran was removed at reduced pressure and the residue was dissolved in ethyl acetate, washed, dried, and concentrated to give (5-nitro-1H-indol-2-yl)methanol (903). This material was used without purification in the next step.
Reaction SMILES: [CH:1]1[C:6]([C:7]([CH2:9][NH2:10])=O)=[CH:5][CH:4]=[C:3]([Br:11])[CH:2]=1.Cl.C([O-])(=O)C.[Na+].C(O)(=O)C.[NH:22]=[C:23](SC)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C([O-])(O)=O.[Na+]>O1CCOCC1>[Br:11][C:3]1[CH:4]=[CH:5][C:6]([C:7]2[N:22]=[C:23]([C:24]([O:26][CH2:27][CH3:28])=[O:25])[NH:10][CH:9]=2)=[CH:1][CH:2]=1
Reactant: NCC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)C(=N)SC
Agent: CC(=O)[O-]
Agent: Cl
Agent: O=C([O-])O
Solvent: CC(=O)O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc(-c2ccc(Br)cc2)c[nH]1
Temperature: 95 °C
Reaction time: 8 h
Yield: 74.8 %

Procedure:
A mixture of 2-amino-4-bromoacetophenone hydrochloride (4.0 g, 16.0 mmol), sodium acetate (6.1 g, 90.0 mmol), acetic acid (4.6 mL, 80.0 mmol) and ethyl 2-imino-2-(methylthio)acetate (7.7 g, 32.0 mmol) in dioxane (40 mL) was stirred at 95° C. overnight. The reaction mixture was carefully neutralized with saturated NaHCO3 solution and extracted with ethyl acetate. The organic solution was dried over sodium sulfate and concentrated. Purification by silica gel column chromatography (ethyl acetate:hexanes 1:1) afforded ethyl 4-(4-bromophenyl)-1H-imidazole-2-carboxylate (3.53 g, 75.0%). MS (EI) for C12H11BrN2O2: 296 (MH+).
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH2:21])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].[CH3:25][O:26][C:27]1[CH:32]=[CH:31][C:30]([CH2:33][C:34](Cl)=[O:35])=[CH:29][CH:28]=1>CO>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:22])=[C:16]([NH:21][C:34](=[O:35])[CH2:33][C:30]4[CH:31]=[CH:32][C:27]([O:26][CH3:25])=[CH:28][CH:29]=4)[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:24])[CH3:23])=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: Cc1c(C)c2c(c(C)c1N)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Reactant: COc1ccc(CC(=O)Cl)cc1
Solvent: CO
Product: COc1ccc(CC(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Yield: 74 %

Procedure:
By using 3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-amine and 4-methoxyphenylacetyl chloride, the title compound was synthesized according to Example 1b. Yield: 74%. Melting point: 171-173° C. (Methanol).
Reaction SMILES: [CH3:1][C:2]1[N:3]([CH2:21][C:22]2[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=2)[C:25](O)=[O:26])[C:4]2[C:9]([CH:10]=1)=[CH:8][C:7]([C:11]([OH:20])([C:16]([F:19])([F:18])[F:17])[C:12]([F:15])([F:14])[F:13])=[CH:6][CH:5]=2.Cl.[CH2:32]([O:34][C:35](=[O:39])[CH2:36][NH:37][CH3:38])[CH3:33]>>[CH2:32]([O:34][C:35](=[O:39])[CH2:36][N:37]([CH3:38])[C:25](=[O:26])[C:24]1[CH:28]=[CH:29][CH:30]=[C:22]([CH2:21][N:3]2[C:4]3[C:9](=[CH:8][C:7]([C:11]([OH:20])([C:12]([F:14])([F:13])[F:15])[C:16]([F:19])([F:18])[F:17])=[CH:6][CH:5]=3)[CH:10]=[C:2]2[CH3:1])[CH:23]=1)[CH3:33]
Reactant: CCOC(=O)CNC
Reactant: Cc1cc2cc(C(O)(C(F)(F)F)C(F)(F)F)ccc2n1Cc1cccc(C(=O)O)c1
Agent: Cl
Product: CCOC(=O)CN(C)C(=O)c1cccc(Cn2c(C)cc3cc(C(O)(C(F)(F)F)C(F)(F)F)ccc32)c1

Procedure:
In analogy to example 34, from 3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzoic acid (example 31) and sarcosine ethylester hydrochloride was prepared (methyl-{3-[2-methyl-5-(2,2,2-trifluoro-1-hydroxy-1-trifluoromethyl-ethyl)-indol-1-ylmethyl]-benzolyl}-amino)-acetic acid ethyl ester, colorless solid, MS: 531 (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[CH:4]=O.S(O)(O)(=O)=O.[NH2:16]O.C(Cl)Cl.C([O-])(O)=O.[Na+]>O>[OH:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([OH:10])[C:3]=1[C:4]#[N:16]
Reactant: O=Cc1c(O)cccc1O
Reactant: NO
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: N#Cc1c(O)cccc1O
Temperature: 25 °C
Reaction time: 0.75 h

Procedure:
A mixture of 2,6-dihydroxybenzaldehyde (300 mg, 2.17 mmol) and hydroxylamine sulfate (758 mg, 6.51 mmol) in water (30 mL) is stirred at RT for 45 min. Methylene chloride (60 mL) is added followed by NaHCO3 (911 mg, 10.85 mmol) and the mixture is stirred at RT for 30 min. The organic phase is separated and dried over sodium sulfate and the solvent removed under reduced pressure to give the title compound as a pale yellow solid.
Reaction SMILES: Cl[C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:17])[C:7]([C:14]([OH:16])=[O:15])=[CH:8][N:9]2[CH2:12][CH3:13])=[CH:4][C:3]=1[F:18].[CH3:19][CH:20]1[CH2:25][NH:24][CH2:23][CH2:22][NH:21]1.C(C(CCCC)C([O-])=O)C.[Na+:36]>C(OC(=O)C)C.C(Cl)(Cl)Cl>[Na+:36].[CH2:12]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([F:18])=[C:2]([N:24]3[CH2:23][CH2:22][NH:21][CH:20]([CH3:19])[CH2:25]3)[CH:11]=2)[C:6](=[O:17])[C:7]([C:14]([O-:16])=[O:15])=[CH:8]1)[CH3:13]
Reactant: CCn1cc(C(=O)O)c(=O)c2cc(F)c(Cl)cc21
Reactant: CC1CNCCN1
Agent: CCCCC(CC)C(=O)[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: CCn1cc(C(=O)[O-])c(=O)c2cc(F)c(N3CCNC(C)C3)cc21
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A mixture of 7-chloro-1-ethyl-6-fluoro-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid [J. Med. Chem., 23, 1358 (1980)] (0.52 g, 2 mmol) and 2-methylpiperazine (0.8 g, 8 mmol) was heated at 175° for 5 hours. The residue was dissolved in ethylacetate (10 mL) and chloroform (10 mL), and a solution of sodium-2-ethyl- hexanoate (0.33 g, 2 mmol) in ethyl acetate (20 mL) was added. The mixture was stirred for 30 minutes and the precipitate was collected. The crude product was purified by preparative liquid chromatography (C-18 reverse phase, gradient 0-40% acetonitrile in water) to give a pale yellow lyophilized solid (0.5 g, 75% yield).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH:12]([F:14])[F:13])[CH2:9][CH:10]=C)([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:25].[Na+].O=[O+][O-].[BH4-].[Na+]>C(Cl)Cl.CO.O=O>[C:1]([O:5][C:6](=[O:23])[NH:7][C:8]([C:15]1[CH:20]=[C:19]([Br:21])[CH:18]=[CH:17][C:16]=1[F:22])([CH:12]([F:14])[F:13])[CH2:9][CH2:10][OH:25])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C([O-])O
Reactant: C=CCC(NC(=O)OC(C)(C)C)(c1cc(Br)ccc1F)C(F)F
Agent: O=O
Agent: O=[O+][O-]
Agent: [BH4-]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(C)OC(=O)NC(CCO)(c1cc(Br)ccc1F)C(F)F
Temperature: -75 °C
Reaction time: 0.17 h
Yield: 92 %

Procedure:
A suspension of [1-(5-bromo-2-fluoro-phenyl)-1-difluoromethyl-but-3-enyl]-carbamic acid tert-butyl ester (5.11 g, 12.96 mmol) and NaHCO3 (1.63 g, 19.44 mmol) in 90 ml DCM and 30 ml MeOH was cooled to −75° C. A mixture of O3 in oxygen gas was introduced till the blue color persisted. The excess ozone was removed by bubbling through oxygen gas for 10 minutes. NaBH4 (0.981 g, 25.9 mmol) was added as a solid in three portions. The mixture was stirred 10 min at −75° C. and then allowed to warm to 0° C. After 30 min the mixture was poured onto ice-cold 1N HCl and extracted with TBME. The organic phase was washed with 1N HCl, brine, dried with MgSO4.H2O and evaporated. Chromatography on silica gel (hexanes/15-35% EtOAc) provided 4.75 g of the title compound as a colorless resin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](B(O)O)[CH:5]=[C:6]([Br:8])[CH:7]=1.Br[C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14].C([O-])([O-])=O.[K+].[K+]>C1COCC1.O.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:13]([C:15]([F:18])([F:17])[F:16])=[CH2:14])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: C=C(Br)C(F)(F)F
Reactant: OB(O)c1cc(Br)cc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Product: C=C(c1cc(Br)cc(Br)c1)C(F)(F)F
Temperature: 80 °C
Yield: 75.8 %

Procedure:
A mixture of 3,5-dibromophenylboronic acid (2.58 g, 9.2 mmol), 2-bromo-3,3,3-trifluoroprop-1-ene (2.42 g, 13.8 mmol), K2CO3 (2.54 g, 18.4 mmol) and Pd(PPh3)2Cl2 (129 mg, 0.18 mmol) in THF (12 mL) and H2O (6 mL) was heated at 80° C. in a sealed tube for 4 h. The mixture was cooled to rt and partitioned between EA (50 mL) and H2O (50 mL). The aqueous layer was extracted with EA (50 mL) and the combined organic layers were dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by column chromatography on silica gel to give the crude desired product (2.3 g; 76% yield) as colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([S:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:22])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.CC1(C)C(C)(C)OB(B2OC(C)(C)C(C)(C)O2)[O:25]1.C1(P(C2CCCC2)C2CCCC2)CCCC1.[F-].[Cs+]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[Cl:22][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=1[S:15][C:4]1[CH:3]=[C:2]([OH:25])[CH:7]=[N:6][C:5]=1[NH:8][C:9]1[S:10][CH:11]=[C:12]([CH3:14])[N:13]=1
Reactant: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Reactant: Cc1csc(Nc2ncc(Br)cc2Sc2ccccc2Cl)n1
Agent: [Pd+2]
Agent: C1CCC(P(C2CCCC2)C2CCCC2)C1
Agent: CC(=O)[O-]
Solvent: CC#N
Product: Cc1csc(Nc2ncc(O)cc2Sc2ccccc2Cl)n1
Temperature: 90 °C

Procedure:
A degassed mixture of N-(5-bromo-3-(2-chlorophenylthio)pyridin-2-yl)-4-methylthiazol-2-amine (1.10 g, 2.66 mmol), 4,4,4′,4′,5,5,5′,5′-octamethyl-2,2′-bi(1,3,2-dioxaborolane) (1.35 g, 5.32 mmol), Pd(OAc)2 (60 mg, 0.27 mmol), tricyclopentylphosphine (93 mg. 0.40 mmol) and cesium fluoride (3.64 g, 23.9 mmol) in acetonitrile is heated at 90° C. for 5 hours. The reaction mixture is cooled and partitioned between ether and water. The crude product is dissolved in THF. N-morpholine N-oxide (1.40 g, 12.0 mmol) is added and the reaction mixture is heated at reflux for 12 hours. The reaction mixture is cooled and partitioned between ether and water. The organic layer is washed with water and brine, dried and concentrated. The residue is purified by silica gel chromatography, eluting with 10-20% EtOAc in hexanes to afford the title compound.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23](O)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[NH:26]1[C:35]2[CH2:34][CH2:33][NH:32][CH2:31][C:30]=2[CH:29]=[CH:28][C:27]1=[O:36]>>[C:1]([N:5]1[C:9]([C:10]2[CH:11]=[CH:12][C:13]([F:16])=[CH:14][CH:15]=2)=[C:8]([C:17]2[S:18][CH:19]=[C:20]([CH2:22][C:23]([N:32]3[CH2:33][CH2:34][C:35]4[NH:26][C:27](=[O:36])[CH:28]=[CH:29][C:30]=4[CH2:31]3)=[O:24])[N:21]=2)[CH:7]=[N:6]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)n1ncc(-c2nc(CC(=O)O)cs2)c1-c1ccc(F)cc1
Reactant: O=c1ccc2c([nH]1)CCNC2
Product: CC(C)(C)n1ncc(-c2nc(CC(=O)N3CCc4[nH]c(=O)ccc4C3)cs2)c1-c1ccc(F)cc1

Procedure:
Using 2-(2-(1-tert-butyl-5-(4-fluorophenyl)-1H-pyrazol-4-yl)thiazol-4-yl)acetic acid and 5,6,7,8-tetrahydro-1,6-naphthyridin-2(1H)-one and by reaction and purification in the same manner as in the method described in Example 1, step 7, the title compound was obtained.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1.[CH2:13]([O:15]C=C[Sn](CCCC)(CCCC)CCCC)[CH3:14].Cl.C([O-])(O)=O.[Na+]>C(#N)C.[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:13]([C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH2:11])(=[O:10])=[O:9])=[C:4]([Cl:12])[CH:3]=1)(=[O:15])[CH3:14]
Reactant: NS(=O)(=O)c1ccc(Br)cc1Cl
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: Cl
Solvent: CC#N
Product: CC(=O)c1ccc(S(N)(=O)=O)c(Cl)c1
Temperature: 100 °C
Reaction time: 0.33 h
Yield: 75.2 %

Procedure:
To a solution of the product obtained in step 1 (1.0 g, 3.70 mmol) in ACN (8 ml) was added CuI (35 mg, 185 μmol), PdCl2(PPh3)2 (389 mg, 554 μmol) and 1-(ethoxyvinyl)tributyl-stannane (2.5 ml, 2.60 g, 7.39 mmol). The mixture was heated for 30 min at 100° C. using microwaves. After cooling, the reaction mixture was acidified with 1 N HCl (4 ml) and stirred for 20 min. The reaction mixture was adjusted to pH=7 using NaHCO3 and extracted with AcOEt. The organic phase was washed with brine, dried over Na2SO4 and evaporated. Purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane (1:1) gave the desired product (650 mg, 75%).
Reaction SMILES: [NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1I.C([Sn](CCCC)(CCCC)[S:27][CH3:28])CCC.[SnH4].O>CN(C=O)C.[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I.C(OCC)(=O)C>[NH2:1][C:2]1[C:7]([F:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[C:11]([F:16])[CH:10]=2)[N:5]=[C:4]([C:17]([O:19][CH3:20])=[O:18])[C:3]=1[S:27][CH3:28]
Reactant: CCCC[Sn](CCCC)(CCCC)SC
Reactant: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1I
Agent: Cl[Pd]Cl
Agent: [Cu]I
Agent: [SnH4]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1nc(-c2ccc(Cl)c(F)c2)c(F)c(N)c1SC
Temperature: 100 °C
Reaction time: 5 h
Yield: 76.2 %

Procedure:
Methyl 4-amino-6-(4-chloro-3-fluorophenyl)-5-fluoro-3-iodopicolinate (420 mg, 0.99 mmol) and tri-n-butylmethylthiostannane (530 mg, 1.6 mmol) were dissolved in 5 ml dry DMF. The solution was purged with a nitrogen stream for 10 m, treated with his (triphenylphosphine) palladium (II) chloride (70 mg, 0.01 mmol) and copper (I) iodide (19 mg, 0.01 mmol) and heated to 100° C. After 5 h, an additional 350 mg, 1.0 mmol, of the stannane were added and heating was continued for 8 h more. After cooling, the mixture was stirred with 10 ml water and 50 ml ethyl acetate and then filtered through a glass wool plug to remove yellow solids. The organic phase was separated and stirred with 25 ml 10% aq. potassium bifluoride solution for 30 m. After filtration through diatomaceous earth, the solution was washed with 10 ml water, 10 ml sat. NaCl, dried (Na2SO3) and evaporated. The crude material was purified by silica gel chromatography using a 0-40% ethyl acetate-hexane gradient. After evaporation of the solvents the oily product was stirred with hexane to produce a white solid which was collected by filtration and dried under vacuum to give 260 mg of the written product as a white solid: mp 125-126° C.; 1H NMR (400 MHz, CDCl3) δ 7.77 (dd, J=28.9, 9.5 Hz, 2H), 7.47 (m, 1H), 5.28 (s, 2H), 3.99 (s, 3H), 2.35 (s, 3H). 19F NMR (376 MHz, CDCl3) δ −115.10, −143.40; ESIMS m/z 345 ([M+H]+), 343 ([M−H]−).
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[C:6]([CH3:12])[CH:7]=[C:8]([CH3:11])[CH:9]=2)[C:4]([CH:13]=O)=[CH:3]1.[CH3:15][NH:16][CH3:17].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[CH3:15][N:16]([CH3:17])[CH2:13][C:4]1[C:5]2[C:10](=[CH:9][C:8]([CH3:11])=[CH:7][C:6]=2[CH3:12])[N:2]([CH3:1])[CH:3]=1
Reactant: CNC
Reactant: Cc1cc(C)c2c(C=O)cn(C)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1cc(C)c2c(CN(C)C)cn(C)c2c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,4,6-trimethyl-1H-indole-3-carbaldehyde (875 mg, 4.7 mmol) in CH2Cl2 (30 mL) and dimethylamine (2.0 M solution in MeOH) (4.7 mL, 9.3 mmol) was added sodium triacetoxyborohydride (NaBH(OAc)3) (2.9 g, 14 mmol) at 0° C. Upon complete addition the cooling bath was removed and the reaction mixture was stirred at room temperature for 48 h. When the reaction was complete, the mixture was diluted with CH2Cl2 and washed with saturated NaHCO3. The layers were separated and the organic phase was dried over MgSO4, filtered and concentrated. The residue was used in the next step of the synthesis without purification.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:37]=[CH:36][C:35]([S:38][CH2:39][C:40]5[N:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:42]=[CH:43][N:44]=5)=[CH:34][CH:33]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].ClC1C=CC=C(C(OO)=[O:58])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:27])[CH3:28])[CH2:23][CH2:22][C:21]([C:29]([NH:31][C:32]4[CH:33]=[CH:34][C:35]([S:38]([CH2:39][C:40]5[N:41]([CH2:45][CH:46]([CH3:48])[CH3:47])[CH:42]=[CH:43][N:44]=5)=[O:58])=[CH:36][CH:37]=4)=[O:30])=[CH:20][C:19]=3[CH:49]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(SCc4nccn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)Nc2ccc(S(=O)Cc4nccn4CC(C)C)cc2)CCN3CC(C)C)cc1
Reaction time: 0.5 h
Yield: 67.6 %

Procedure:
To a solution of 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isobutylimidazol-2-yl)methyl]sulfanyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (600 mg) in dichloromethane (15 ml) was added dropwise 70% solution of 3-chloroperbenzoic acid (326 mg) in dichloromethane (15 ml) at −78° C. To the mixture was added an aqueous solution of sodium thiosulfate, and the mixture was allowed to be at room temperature, and stirred for 30 minutes, and extracted with ethyl acetate. The organic layer was washed with an aqueous solution of saturated sodium bicarbonate, and saturated brine, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The obtained residue was separated and purified by silica gel column chromatography (ethyl acetate→methanol:ethyl acetate=1:9), to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-N-[4-[[(1-isobutylimidazol-2-yl)methyl]sulfinyl]phenyl]-2,3-dihydro-1-benzazepine-4-carboxamide (415 mg) (Compound 350) as yellow amorphous.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[NH:8][C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1.O[CH2:13][C:14]1[CH:15]=[C:16]([NH:20][C:21](=[O:33])[O:22][CH2:23][CH2:24][CH2:25][N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:17]=[CH:18][CH:19]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[N:8]([CH2:13][C:14]3[CH:15]=[C:16]([NH:20][C:21](=[O:33])[O:22][CH2:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][N:29]([CH3:32])[CH2:30][CH2:31]4)[CH:17]=[CH:18][CH:19]=3)[C:9](=[O:11])[O:10][C:5]2=[CH:4][CH:3]=1
Reactant: Cc1ccc2oc(=O)[nH]c2n1
Reactant: CN1CCN(CCCOC(=O)Nc2cccc(CO)c2)CC1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: Cc1ccc2oc(=O)n(Cc3cccc(NC(=O)OCCCN4CCN(C)CC4)c3)c2n1
Reaction time: 0.5 h

Procedure:
98 mg (0.65 mmol) of 5-methyl-3H-oxazolo[4,5-b]pyridin-2-one, 200 mg (0.65 mmol) of 3-(4-methylpiperazin-1-yl)propyl (3-hydroxymethylphenyl)carbamate and 325 mg (0.98 mmol) of polymer-bound triphenylphosphine (3 mmol/g) are suspended in 5 ml of DMF, and the mixture is shaken for 30 min. 229 mg (0.98 mmol) of di-tert-butyl azodicarboxylate are subsequently added. The reaction mixture is shaken at room temperature. The reaction mixture is filtered and rinsed with THF, and the filtrate is evaporated. The residue is purified by column chromatography on silica gel.
Reaction SMILES: [C:1]([OH:12])(=O)/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].[CH2:13]([NH:15][CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20])[CH3:14]>>[CH2:19]([N:18]([CH2:21][CH3:22])[CH2:17][CH2:16][N:15]([CH2:13][CH3:14])[C:1](=[O:12])/[CH:2]=[CH:3]/[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10])[CH3:20]
Reactant: CCNCCN(CC)CC
Reactant: CCCCCCC/C=C/C(=O)O
Product: CCCCCCC/C=C/C(=O)N(CC)CCN(CC)CC

Procedure:
The same operation as in Example 1-1 or 1-2 was carried out using trans-2-decenoic acid and N,N′,N′-triethylethylenediamine as starting materials to give the aimed compound.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[C:13]([OH:15])=[O:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:22]1(O)[CH2:26][CH2:25][CH2:24][CH2:23]1.CN(C1C=CC=CN=1)C.Cl.CN(C)CCCN=C=NCC>CN(C=O)C.CCOC(C)=O.O>[CH:22]1([O:14][C:13](=[O:15])[C@@H:12]([NH:11][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:10])[CH2:16][O:17][C:18]([CH3:21])([CH3:20])[CH3:19])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)O
Reactant: OC1CCCC1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC[C@H](NC(=O)OCc1ccccc1)C(=O)OC1CCCC1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 75.1 %

Procedure:
(S)-2-Benzyloxycarbonylamino-3-tert-butoxy-propionic acid (4 g, 0.014 mol) was dissolved in DMF (40 ml). Cyclopentanol (2.54 ml, 0.027 mol) and dimethylaminopyridine (0.165 g, 0.014 mol) were added. The solution was cooled to 0° C. using an ice bath and to it was added N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (2.73 g, 0.014 mol, 1.05 eq.). The mixture was stirred at 0° C. for 10 minutes and then allowed to warm to r.t. and stirred for a further 18 hours. To the reaction mixture was added water (20-30 ml) followed by EtOAc (40 ml). The layers were separated and the aqueous layer re-extracted with EtOAc (15 ml). The combined organic layers were washed with water (4×20 ml), dried (MgSO4) and the solvent removed in vacuo to give a residue. Purification by column chromatography (1:1 EtOAc/heptane) gave the product as a colourless oil (3.82 g, 78% yield). 1H NMR (300 MHz, CDCl3), δ: 1.15 (9H, s, CH3×3), 1.50-1.90 (8H, m, CH2×4), 3.57 (1H, dd, J=7.4, 1.2 Hz, CH), 3.85 (1H, dd, J=7.4, 1.2 Hz, CH), 4.45 (1H, m, CH), 5.15 (2H, s, CH2), 5.25 (1H, m, CH), 5.65 (1H, d, CH, J=7.6 Hz), 7.30-7.50 (5H, m, ArH×5).
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([O:19]CC)=[O:18])=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>CCO>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH3:16])=[C:8]2[C:17]([OH:19])=[O:18])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1c(C)c2ccccc2n1Cc1ccc(Cl)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)n(Cc2ccc(Cl)cc2)c2ccccc12
Temperature: 25 °C
Reaction time: 32 h

Procedure:
ethyl 1-(4-chlorobenzyl)-3-methyl-1H-indole-2-carboxylate (480 mg, 1.46 mmol) was dissolved in EtOH (15 mL) and 10% aq. NaOH was added (6 mL). The reaction was allowed to stir at rt for 32 h, at which time as much solvent was stripped off as possible, water was added, and the mixture cooled in an ice bath. The mixture was acidified with concentrated HCl and the precipitate collected over a filter. The title compound was obtained as a white powder that was not purified or characterized further. (Yield: 430 mg, 1.435 mmol, 98%)