Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].Cl.[CH2:3]([N:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH:17]([CH3:33])[C:18]([C:20]1[CH:29]=[CH:28][C:27]2[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=2[Cl:30])[CH:21]=1)=[O:19].C(N(CC)CC)C>C1C=CC=CC=1>[ClH:30].[ClH:1].[CH2:3]([N:10]1[CH2:15][CH2:14][N:13]([CH:17]([C:18]([C:20]2[CH:29]=[CH:28][C:27]3[C:22](=[CH:23][CH:24]=[C:25]([O:31][CH3:32])[C:26]=3[Cl:30])[CH:21]=2)=[O:19])[CH3:33])[CH2:12][CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: COc1ccc2cc(C(=O)C(C)Br)ccc2c1Cl
Agent: Cl
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Product: COc1ccc2cc(C(=O)C(C)N3CCN(Cc4ccccc4)CC3)ccc2c1Cl
Yield: 101.5 %

Procedure:
A mixture of N-benzyl piperazine dihydrochloride (1.5 g, 7.05 mmol), 2-bromo-1-(5-chloro-6-methoxynaphthalen-2-yl) propan-1-one (2.8 g, 8.5 mmol) and triethyl-amine (2.38 g, 23.5 mmol) in benzene (150 ml) was treated according to the general preparation 2 to obtain 2.14 g of N1-benzyl-N4-[1-(5-chloro-6-methoxy-2-naphthoyl)ethyl] piperazine dihydrochloride, yield 60%, mp 252-253° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([CH3:9])[N:6]=[C:5]([NH:10][Si](C)(C)C)[N:4]=1.C1C=CC(O[C:22](Cl)=[S:23])=CC=1>C1(C)C=CC=CC=1>[N:10]([C:5]1[N:4]=[C:3]([O:2][CH3:1])[CH:8]=[C:7]([CH3:9])[N:6]=1)=[C:22]=[S:23]
Reactant: S=C(Cl)Oc1ccccc1
Reactant: COc1cc(C)nc(N[Si](C)(C)C)n1
Solvent: Cc1ccccc1
Product: COc1cc(C)nc(N=C=S)n1
Temperature: 80 °C
Yield: 63.9 %

Procedure:
A mixture of 4.2 g of 4-methoxy-6-methyl-2-trimethylsilylaminopyrimidine and 3.5 g of phenyl chlorothionocarbonate in 30 ml of toluene is stirred with heating at ca. 80° C. for 5.5 hours. The reaction solution is cooled to room temperature and filtered to remove the precipitate. The filtrate is concentrated under reduced pressure, and the residue is purified by silica gel chromatography (eluent: ethyl acetate: toluene =1:3) to give the title compound (2.3 g). mp 54°~55° C.
Reaction SMILES: [NH:1]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18](O)=[O:19])=[CH:16][CH:15]=1)#[N:13].C(N(CC)CC)C>CN(C)C1C=CN=CC=1>[C:12]([C:14]1[CH:22]=[CH:21][C:17]([C:18]([N:1]2[C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=3[CH2:5][CH2:4][CH2:3][CH2:2]2)=[O:19])=[CH:16][CH:15]=1)#[N:13]
Reactant: N#Cc1ccc(C(=O)O)cc1
Reactant: c1ccc2c(c1)CCCCN2
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Product: N#Cc1ccc(C(=O)N2CCCCc3ccccc32)cc1

Procedure:
To a solution of 2,3,4,5-tetrahydro-1H-1-benzazepine (1.05 g, 7.14 mmol) in dichloromethans (40 ml) were added 4-cyanobenzoic acid (1.26 g, 8.57 mmol), triethylamine (1.00 g, 7.14 mmol), 4-(dimethylamino)pyridine (0.87 g, 7.14 mmol) and WSCDI (2.86 g, 14.28 mmol). The mixture was stirred at reflux for 18 h, cooled and evaporated in vacuo. The residue was partitioned between EtOAc and 1M KHSO4. The organic layer was washed with saturated sodium bicarbonate solution and brine, dried over MgSO4, and concentrated in vacuo to give a white solid; yield 1.50 g (76%).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1.[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:43]=[CH:42][C:41](O)=[CH:40][CH:39]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C1COCC1>[CH2:17]([C@H:24]1[CH2:28][O:27][C:26](=[O:29])[N:25]1[C:30](=[O:45])[CH2:31][C@@H:32]([C:38]1[CH:39]=[CH:40][C:41]([O:1][CH2:2][C:3]2[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])[CH:6]=[CH:7][CH:8]=2)=[CH:42][CH:43]=1)[C:33]1[CH:37]=[CH:36][O:35][N:34]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)Nc1cccc(CO)c1
Reactant: O=C(C[C@@H](c1ccc(O)cc1)c1ccon1)N1C(=O)OC[C@@H]1Cc1ccccc1
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cccc(COc2ccc([C@H](CC(=O)N3C(=O)OC[C@@H]3Cc3ccccc3)c3ccon3)cc2)c1
Reaction time: 16 h
Yield: 96.2 %

Procedure:
To a solution of alcohol 27.1 (179 mg, 0.765 mmol) in THF (7 mL), was added phenol 7.5 (300 mg, 0.765 mmol), DIAD (0.155 mL, 0.803 mmol), and triphenylphosphine (211 mg, 0.803 mmol). The solution was stirred for 16 hours and then concentrated to a reduced volume. The residue was purified by medium pressure chromatography (silica gel, 0 to 50% EtOAc:hexanes) to give 27.2 (440 mg). MS ESI (pos.) m/e 598.2 (M+H). 1H NMR (400 MHz, CDCl3) δ ppm 8.20 (1 H, d, J=1.6 Hz), 7.38 (1 H, s), 7.08-7.29 (8 H, m), 7.00 (1 H, d), 6.82 (2 H, d, J=8.6 Hz), 6.54 (1 H, s), 6.33 (1 H, br. s.), 6.05 (1 H, d, J=1.6 Hz), 4.92 (2 H, s), 4.85-4.90 (1 H, m), 4.66 (1 H, dd, J=1.6 Hz), 4.49-4.58 (1 H, m), 4.01-4.04 (1 H, m), 3.93 (1 H, dd, J=17.6, 8.2 Hz), 3.45 (1 H, dd, J=17.6, 6.7 Hz), 3.11 (1 H, dd, J=13.5, 3.3 Hz), 2.68 (1 H, dd, J=13.3, 9.4 Hz), 1.43 (9 H, s).
Reaction SMILES: [C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH2:16])[C:11]=1[NH2:17])([CH3:4])([CH3:3])[CH3:2].CO[C:22](=N)[C:23]([Cl:26])([Cl:25])[Cl:24]>>[C:1]([Si:5]([CH3:19])([CH3:18])[O:6][CH2:7][CH2:8][O:9][C:10]1[C:11]2[N:17]=[C:22]([C:23]([Cl:26])([Cl:25])[Cl:24])[NH:16][C:12]=2[CH:13]=[CH:14][CH:15]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=N)C(Cl)(Cl)Cl
Reactant: CC(C)(C)[Si](C)(C)OCCOc1cccc(N)c1N
Product: CC(C)(C)[Si](C)(C)OCCOc1cccc2[nH]c(C(Cl)(Cl)Cl)nc12

Procedure:
4-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-2-trichloromethyl-1H-benzoimidazole was prepared by a procedure according to example 108 (iii) starting from 503 mg (1.78 mmol) 3-[2-(tert-Butyl-dimethyl-silanyloxy)-ethoxy]-benzene-1,2-diamine and 0.31 mL (2.49 mmol) 2,2,2-trichloro-acetimidic acid methyl ester. Yield: 680 mg MS (ES+): m/e=409, chloro pattern.
Reaction SMILES: Cl[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1.Cl.[CH2:18]([NH2:20])[CH3:19].C(N(CC)CC)C>C(O)(C)C>[CH2:18]([NH:20][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[N:3]=1)[CH3:19]
Reactant: O=[N+]([O-])c1cnc(-c2ccccc2)nc1Cl
Reactant: CCN
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CCNc1nc(-c2ccccc2)ncc1[N+](=O)[O-]
Yield: 93.3 %

Procedure:
A mixture of 4-chloro-5-nitro-2-phenylpyrimidine (3 g), ethylamine hydrochloride (1.6 g), triethylamine (3.9 g) and isopropanol (60 ml) is refluxed for three hours. The reaction mixture is concentrated under reduced pressure, and to the residue are added chloroform and water. The chloroform layer is separated, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (eluent; chloroform), and recrystallized from isopropanol to give the desired compound (2.9 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12].NC1C=CC2CCCC=2C=1C(OC)=O.N1C=CC=CC=1.Cl[C:36]([O:38][CH:39]([CH3:41])[CH3:40])=[O:37].Cl>C(Cl)Cl>[CH:39]([O:38][C:36]([NH:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][CH2:8]2)=[CH:4][C:3]=1[C:11]([O:13][CH3:14])=[O:12])=[O:37])([CH3:41])[CH3:40]
Reactant: CC(C)OC(=O)Cl
Reactant: COC(=O)c1cc2c(cc1N)CCC2
Agent: COC(=O)c1c(N)ccc2c1CCC2
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC(=O)c1cc2c(cc1NC(=O)OC(C)C)CCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of a mixture of methyl 6-aminoindane-5-carboxylate and methyl 5-aminoindane-4-carboxylate (760 mg, 3.98 mmol), and pyridine (805 uL, 9.95 mmol) in CH2Cl2 (8 mL) at 0° C. under N2 was added isopropyl chloroformate (1 M in toluene) (3.98 mL, 3.98 mmol). The resulting mixture was stirred at room temperature for 16 h. 1M HCl was added to the reaction mixture and the organic layer was separated. The aqueous layer was extracted with CH2Cl2 (2×). The combined organic layers were dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (Si, hexanes/EtOAc) to afford methyl 6-[(isopropoxycarbonyl)amino]indane-5-carboxylate. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) δ 10.43 (s, 1H); 8.34 (s, 1H); 7.86 (s, 1H); 5.06-5.00 (m, 1H); 3.92 (s, 3H); 2.96 (t, J=7.5 Hz, 2H); 2.88 (t, J=7.4 Hz, 2H); 2.13-2.07 (m, 2H); 1.33 (d, J=6.2 Hz, 6H). Methyl 5-[(isopropoxycarbonyl)amino]indane-4-carboxylate was isolated as a by-product. LCMS calc.=300.1; found=299.9 (M+Na)+. 1H NMR (500 MHz, CDCl3) a 10.07 (s, 1H); 8.21 (d, J=8.4 Hz, 1H); 7.36 (d, J=8.4 Hz, 1H); 5.06-5.00 (m, 1H); 3.93 (s, 3H); 3.19 (t, J=7.5 Hz, 2H); 2.89 (t, J=7.5 Hz, 2H); 2.08-2.02 (m, 2H); 1.32 (d, J=6.2 Hz, 6H).
Reaction SMILES: [CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]#[N:15])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1.[OH:18]O.[OH-].[Na+].O>CS(C)=O>[CH:1]1([C:4]([NH:7][C:8]2[C:13]([C:14]([NH2:15])=[O:18])=[CH:12][N:11]=[C:10]([S:16][CH3:17])[N:9]=2)([CH3:6])[CH3:5])[CH2:3][CH2:2]1
Reactant: OO
Reactant: CSc1ncc(C#N)c(NC(C)(C)C2CC2)n1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: CSc1ncc(C(N)=O)c(NC(C)(C)C2CC2)n1
Temperature: 50 °C
Reaction time: 0.2 h
Yield: 55 %

Procedure:
To a stirring solution of 4-((2-cyclopropylpropan-2-yl)amino)-2-(methylthio)pyrimidine-5-carbonitrile (665 mg, 2.68 mmol) in DMSO (4 mL) was added aqueous hydrogen peroxide solution (0.162 mL, 30%) and aqueous sodium hydroxide (2.2 mL, 6 mol/L) solution. The resulting mixture was stirred at 50° C. for 12 min, and then water was added. The desired product was filtered and dried in vacuo to give the crude product (392 mg, 1.47 mmol, 55% yield) as a white solid. MS (ESI) m/z 267.3 [M+H]+.
Reaction SMILES: [CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15](O)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.C1CCC(N=C=NC2CCCCC2)CC1.[NH:35]1[CH2:40][CH2:39][O:38][CH2:37][CH2:36]1.C(O)(C(F)(F)F)=O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH3:1][N:2]1[CH2:19][CH2:18][C:5]2[N:6]([CH2:14][C:15]([N:35]3[CH2:40][CH2:39][O:38][CH2:37][CH2:36]3)=[O:16])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: Cc1ccc2c(c1)c1c(n2CC(=O)O)CCN(C)C1
Reactant: C1COCCN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)c1c(n2CC(=O)N2CCOCC2)CCN(C)C1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 8 %

Procedure:
To a solution of 2-(1, 2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)acetic acid (100 mg, 0.38 mmol) in DCM (10 ml) was added DCC (95 mg, 0.46 mmol), DMAP (56 mg, 0.46 mmol), and stirred for 5 min at RT, morpholine (1 ml, 11.5 mmol) was added and stirred at 25 deg C. for 14 h. The reaction mixture was concentrated to dryness and The resulting crude was purified by reverse-phase chromatography (C-18, 500 mm×50 mm, Mobile Phase A=0.05% TFA in water, B=0.05% TFA in acetonitrile, Gradient: 10% B to 80% B in 30 min, injection vol. 5 mL) to obtain 10 mg (Yield 5.8%) of 2-(1,2,3,4-tetrahydro-2,8-dimethylpyrido[4,3-b]indol-5-yl)-1-morpholino ethanone as TFA salt.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:9]3[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=4[F:29])[C:10]=3[N:11]=[C:12](S(C)(=O)=O)[N:13]=2)=[C:4]([CH3:30])[CH:3]=1.[CH2:31]([NH2:33])[CH3:32]>C1COCC1>[CH2:31]([NH:33][C:12]1[N:13]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=2[CH3:30])[C:9]2[CH:21]=[CH:20][C:19](=[O:22])[N:18]([C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=3[F:29])[C:10]=2[N:11]=1)[CH3:32]
Reactant: CCN
Reactant: Cc1cc(F)ccc1-c1nc(S(C)(=O)=O)nc2c1ccc(=O)n2-c1ccccc1F
Solvent: C1CCOC1
Product: CCNc1nc(-c2ccc(F)cc2C)c2ccc(=O)n(-c3ccccc3F)c2n1

Procedure:
The product of Example 59 (200 mg, 0.47 mmol) was combined and stirred with 5 mL of a 2M solution of ethylamine in THF. After 5 min the solvents were removed in vacuo, and the residue was partitioned between EtOAc and H2O. The organic phase was washed with H2O, satd aq NaCl, dried over anhyd Na2SO4, filtered and evaporated to give the crude product. Flash chromatography eluted with 0-2% EtOAc/CH2Cl2 followed by recrystallization from CH2Cl2/hexane gave the product as a light-yellow crystalline solid. mp 176-177°, LC MS m/z=393 (MH+) Retention time=2.38 min.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1)=O.CO.CC([O-])=O.[Na+].[NH2:29][OH:30].Cl>O>[OH:30][N:29]=[CH:1][C:3]1[N:8]=[C:7]2[CH2:9][O:10][C:11]3([CH2:14][N:13]([C:15]([O:17][C:18]([CH3:19])([CH3:20])[CH3:21])=[O:16])[CH2:12]3)[C:6]2=[CH:5][CH:4]=1
Reactant: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=O)ccc12
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)N1CC2(C1)OCc1nc(C=NO)ccc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 100.2 %

Procedure:
To a stirred solution of tert-butyl 2′-formyl-7′H-spiro[azetidine-3,5′-furo[3,4-b]pyridine]-1-carboxylate (0.5 g, 1.7 mmol, 1 eq.) in mixture of methanol (12 mL):water (12 mL) was added NaOAc (0.28 g, 3.45 mmol, 2 eq.) followed by addition of NH2OH.HCl (0.24 g, 3.45 mmol, 2 eq.) at room temperature. Resulting reaction mixture was stirred at room temperature for 18 hours under nitrogen atmosphere. After complete consumption starting material, reaction mixture was concentrated under reduced pressure; resulting residue was diluted with water (50 mL) and extracted by ethyl acetate (3×100 mL). Combined organic layer was dried over sodium sulphate and concentrated under reduced pressure to afford title compound as brown solid (0.520 g, 99%). 1H NMR (400 MHz, CDCl3) δ: 1.47 (s, 9H), 4.12 (d, J=9.88 Hz, 2H), 4.34 (d, J=10.12 Hz, 2H), 5.08 (s, 2H), 7.73 (d, J=7.92 Hz, 1H), 7.79 (d, J=7.96 Hz, 1H), 8.21 (s, 1H). LC-MS (m/z): 306.3 (M+H).
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=1.[C:9]1(B(O)O)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(=O)([O-])[O-].[K+].[K+]>C(COC)OC.O>[C:9]1([C:2]2[CH:7]=[C:6]([Br:8])[CH:5]=[CH:4][N:3]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: Brc1ccnc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: O
Product: Brc1ccnc(-c2ccccc2)c1
Yield: 43.3 %

Procedure:
A mixture was prepared of 2,4-dibromopyridine (10 g, 42.21 mmol), phenylboronic acid (5.1 g, 42.21 mmol), and potassium carbonate (11.7 g, 84.42 mmol) in 100 mL dimethoxyethane and 40 mL of water. Nitrogen was bubbled directly into the mixture for 30 minutes. Next, tetrakis(triphenylphosphine)palladium(0) was added (244 mg, 2.11 mmol) and the mixture was heated to reflux under nitrogen overnight. The mixture was cooled and diluted with ethyl acetate and water. The layers were separated and the aqueous layer was extracted with ethyl acetate. The organic layers were washed with brine, dried over magnesium sulfate, filtered, and evaporated to a residue. The residue was purified by column chromatography eluting with 0, 2, and 5% ethyl acetate/hexanes. Obtained 4.28 g of a yellow liquid (43%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[C:17](=[O:18])[C:16]3[C:15]4[C:10](=[CH:11][C:12]([C:19]#[N:20])=[CH:13][CH:14]=4)[NH:9][C:8]=3[C:7]([CH3:22])([CH3:21])[C:6]=2[CH:23]=1.[F:24][C:25]([F:31])([F:30])[S:26](O)(=[O:28])=[O:27].O>N1C=CC=CC=1>[C:19]([C:12]1[CH:11]=[C:10]2[C:15]([C:16]3[C:17](=[O:18])[C:5]4[CH:4]=[CH:3][C:2]([O:1][S:26]([C:25]([F:31])([F:30])[F:24])(=[O:28])=[O:27])=[CH:23][C:6]=4[C:7]([CH3:21])([CH3:22])[C:8]=3[NH:9]2)=[CH:14][CH:13]=1)#[N:20]
Reactant: CC1(C)c2cc(O)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Reactant: O=S(=O)(O)C(F)(F)F
Solvent: O
Solvent: c1ccncc1
Product: CC1(C)c2cc(OS(=O)(=O)C(F)(F)F)ccc2C(=O)c2c1[nH]c1cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
8-Hydroxy-6,6-dimethyl-11-oxo-6,11-dihydro-5H-benzo[b]carbazole-3-carbonitrile (Compound A6, 550 mg, 0.189 mmol) was dissolved in pyridine (18 mL), added with anhydrous trifluoromethane sulfonic acid (0.758 ml, 3 eq.), and stirred at room temperature for 30 minutes. The reaction solution was poured into water and then extracted with dichloromethane. The organic layer was dried over magnesium sulfate. The drying agent was removed by filtration and the residues obtained after concentration under reduced pressure were purified by silica gel column chromatography (ethyl acetate/hexane) to obtain the target compound (white powder, 641 mg, 81%).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][O:15][Si](C(C)(C)C)(C)C)[CH2:11][CH:10]([CH:23]=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][OH:26].Cl.CC([O-])=O.[Na+].O>CCO>[CH2:1]([N:8]1[CH2:13][CH:12]([CH2:14][OH:15])[CH2:11][CH:10](/[CH:23]=[N:25]\[OH:26])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](C)(C)OCC1CC(C=O)CN(Cc2ccccc2)C1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: OCC1CC(/C=N\O)CN(Cc2ccccc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 136.7 %

Procedure:
To a mixture of 1-benzyl-5-((tert-butyldimethylsilyloxy)methyl)piperidine-3-carbaldehyde (3.39 g, 9.75 mmol) in EtOH (50 mL) was added an aqueous solution of NH2OH—HCl (3.75M, 3.12 mL, 11.7 mmol) followed by an aqueous solution of NaOAc (1.5M, 5.2 mL, 7.8 mmol). The reaction mixture was stirred at room temperature for 18 h. H2O (30 mL) was then added and the EtOH was partially removed in vacuo (˜40 mL). The reaction mixture was diluted with ethyl acetate and washed with saturated NaHCO3. The combined aqueous fractions were extracted with ethyl acetate (3×50 mL) and the combined organic fractions were washed with brine and dried (MgSO4) and concentrated in vacuo to afford 3.31 g (94% yield) of the title compound. 1H NMR (400 MHz, CDCl3) δ ppm 7.25-7.35 (6 H, m), 3.58 (2 H, d, J=4.5 Hz), 3.43-3.54 (2 H, m), 3.03 (2 H, d, J=4.5 Hz), 2.57-2.68 (1 H, m) 1.90-2.01 (2 H, m), 1.80-1.89 (1 H, m), 1.65-1.77 (2 H, m), 0.93-1.01 (1 H, m). LCMS (+ESI, M+H+) m/z 249.
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:12]=[CH:11][CH:10]=[CH:9][C:5]=1[C:6]([OH:8])=[O:7])N.[CH3:13][C:14](=O)[CH2:15][CH3:16].Cl>C(O)(=O)C.O>[CH3:13][C:14]1[NH:2][C:4]2[C:12]([C:15]=1[CH3:16])=[CH:11][CH:10]=[CH:9][C:5]=2[C:6]([OH:8])=[O:7]
Reactant: NNc1ccccc1C(=O)O
Reactant: CCC(C)=O
Agent: Cl
Solvent: CC(=O)O
Solvent: O
Product: Cc1[nH]c2c(C(=O)O)cccc2c1C
Temperature: 100 °C

Procedure:
To a suspension of 2-hydrazinobenzoic acid hydrochloride (2.0 g) in acetic acid (8 ml) was added dropwise a solution of 2-butanone (0.9 ml) in acetic acid (2 ml), and the resultant mixture was heated at 80° C. for one hour. After 6N-hydrochloric acid (8 ml) was added to the reaction mixture, the mixture was heated at 100° C. for 5 hours. The mixture was diluted with water (18 ml), and allowed to cool to 40° C. The resultant precipitate was collected by filtration, washed with a small amount of diisopropyl ether and dried in vacuo to give 2,3-dimethyl-1H-indole-7-carboxylic acid (0.78 g).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10][CH2:11][CH2:12]Br.[OH-].[Na+].C(O)C>ClCCl>[Br:10][CH2:11][CH2:12][O:9][C:3]1[CH:4]=[CH:5][C:6]([I:8])=[CH:7][C:2]=1[CH3:1]
Reactant: Cc1cc(I)ccc1O
Reactant: BrCCBr
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCO
Product: Cc1cc(I)ccc1OCCBr

Procedure:
A mixture of 2-methyl-4-iodophenol (5.00 grams), 1,2-dibromoethane (2.76 mL), sodium hydroxide (1.3 grams) and ethanol (100 mL) was stirred at reflux for 5 hours before being poured into ice. The crude solid was dissolved in dichloromethane and washed with 1N NaOH. The organic layer was evaporated in vacuo to give 2-Bromo-1-(2-methyl-4-iodophenoxy)ethane Compound 21a as a tan solid. 1H NMR (CDCl3) δ 6.54 (d, 1H), 4.25 (t, 2H), 3.66 (t, 2H), 2.20 (s, 3H).
Reaction SMILES: CN1CCOCC1.CN(C1C=CC=CN=1)C.[C:17]([NH:21][C:22]([C:24]1[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=1[C:32]([OH:34])=O)=[O:23])([CH3:20])([CH3:19])[CH3:18]>ClCCl>[C:17]([N:21]1[C:22](=[O:23])[C:24]2[S:28][N:27]=[C:26]([CH:29]([CH3:31])[CH3:30])[C:25]=2[C:32]1=[O:34])([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)c1nsc(C(=O)NC(C)(C)C)c1C(=O)O
Agent: CN(C)c1ccccn1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CC(C)c1nsc2c1C(=O)N(C(C)(C)C)C2=O
Yield: 95.1 %

Procedure:
7.5 g (74.1 mmol) of methylmorpholine, 2.4 g (20 mmol) of dimethylaminopyridine and 17.4 g of a 50% strength solution of propanephosphonic anhydride (27.3 mmol) in dichloromethane were added dropwise in succession to 5.4 g (20 mmol) of 5-tert-butylaminocarbonyl-3-isopropylisothiazole-4-carboxylic acid in 200 ml of dichloromethane at -5° C. and the mixture was then refluxed for 6 hours. Working up was carried out at described above for Example No. 1.003. 4.8 g (95%) of N-tert-butyl-3-isopropylisothiazole-4,5-dicarboximide were obtained as a solid of melting point 52°-53° C. (Example No. 3.001).
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH:10]=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16]CC)=[O:15]>>[OH:11][CH:10]([CH2:9][CH2:8][O:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:13][C:14]([OH:16])=[O:15]
Reactant: O=CCCOc1ccccc1
Reactant: CCOC(=O)CBr
Product: O=C(O)CC(O)CCOc1ccccc1

Procedure:
Magnetic microcapsules 71 were obtained in the same manner as in Example 64 except that the purified enzyme solution (1) in Example 64 was replaced by the crude enzyme solution (3) and (R)-3-hydroxybutyryl CoA was replaced by (R,S)-3-hydroxy-5-phenoxyvaleryl CoA (prepared by hydrolyzing 3-hydroxy-5-phenoxy valerate obtained through a Reformatsky reaction with zinc using 3-phenoxypropanal and ethyl bromoacetate as raw materials, which were synthesized according to a procedure described in J. Org. Chem., 55, 1490-1492, 1990, to produce 3-hydroxy-5-phenoxy valeric acid and then following a procedure described in Eur. J. Biochem., 250, 432-439, 1997). The drug content in the microcapsules is shown in Table 9.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8](B(O)O)[CH:9]=1)([CH3:3])[CH3:2].Br[C:16]1[CH:17]=[C:18]([CH:22]([C:27]2[O:28][C:29]([CH3:32])=[N:30][N:31]=2)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=[CH:20][CH:21]=1>CN(C=O)C.O.[NH4+].[Cl-].C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([O:13][CH3:14])=[C:8]([C:20]2[CH:21]=[CH:16][CH:17]=[C:18]([CH:22]([C:27]3[O:28][C:29]([CH3:32])=[N:30][N:31]=3)[CH2:23][C:24]([OH:26])=[O:25])[CH:19]=2)[CH:9]=1)([CH3:3])[CH3:2]
Reactant: COc1ccc(C(C)C)cc1B(O)O
Reactant: Cc1nnc(C(CC(=O)O)c2cccc(Br)c2)o1
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(C(C)C)cc1-c1cccc(C(CC(=O)O)c2nnc(C)o2)c1
Yield: 57 %

Procedure:
12.83 g (66.11 mmol) of 5-isopropyl-2-methoxybenzeneboronic acid, 48.97 g (150.3 mmol) and 18.7 g (60.1 mmol) of 3-(3-Bromo-phenyl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid are heated together with 3 mmol of bis(triphenylphosphine)palladium (II) dichloride in 200 ml of DMF and 30 ml of water for 10 hours at 100° C. The reaction mixture is diluted with conc. NH4Cl solution (200 ml) and extracted with methyl-tetrahydrofurane. The organic phase is filtrated over Celite and 100 g of SiO2 and the solvent is removed in vacuo. The obtained crude 3-(5′-Isopropyl-2′-methoxy-biphenyl-3-yl)-3-(5-methyl-[1,3,4]oxadiazol-2-yl)-propionic acid is used directly in the next step. (Yield=57%, 28 g)