Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([OH:13])[CH:6]=1)[CH3:2].[CH2:15]([O:17][CH2:18][CH2:19]Br)[CH3:16].C([O-])([O-])=O.[K+].[K+].[Na+].[I-]>CC#N>[CH2:1]([O:3][C:4](=[O:14])[C:5]1[CH:10]=[CH:9][C:8]([O:11][CH3:12])=[C:7]([O:13][CH2:16][CH2:15][O:17][CH2:18][CH3:19])[CH:6]=1)[CH3:2]
Reactant: CCOCCBr
Reactant: CCOC(=O)c1ccc(OC)c(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: CCOCCOc1cc(C(=O)OCC)ccc1OC
Reaction time: 8 h

Procedure:
A mixture of 3-hydroxy-4-methoxy-benzoic acid ethyl ester (1.60 g, 8.16 mmol), 2-bromoethyl ethyl ether (1.38 mL, 12.2 mmol) and anhydrous K2CO3 (1.69 g, 12.2 mmol) in MeCN (35 mL) is refluxed overnight. In order to complete the reaction, an additional aliquot of 2-bromoethyl ethyl ether (1.38 mL, 12.2 mmol) and a catalytic amount of NaI are added, and reflux is continued overnight. After cooling, the mixture is filtered and the filtrates are concentrated. The residue is taken up in CH2Cl2, the organic layer is washed with 0.5M NaOH and water, dried (Na2SO4) and concentrated. The title compound is obtained after flash chromatography (hexane/AcOEt 8:2) as colorless oil. MS: 269.0 [M+H]+. tR (HPLC, Nucleosil C18HD column, 5-100% CH3CN/H2O/6 min, 100% CH3CN/2 min, CH3CN and H2O containing 0.1% TFA, flow: 1 mL/min): 4.92 min. 1H-NMR (CDCl3): δ 1.27 (m, 3H), 1.41 (m, 3H), 3.64 (m, 2H), 3.87 (m, 2H), 3.94 (s, 3H), 4.26 (m, 2H), 4.38 (m, 2H), 9.91 (dd, 1H), 7.63 (d, 1H), 7.72 (dd, 1H) ppm.
Reaction SMILES: COC[O:4][C:5]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:6]=1/[CH:7]=[C:8]1/[C:9](=[O:26])[N:10]([S:16]([C:19]2[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][CH:20]=2)(=[O:18])=[O:17])[CH2:11][C:12](=[O:15])[NH:13][CH2:14]/1.FC(F)(F)C(O)=O>C(Cl)Cl>[OH:4][C:5]1[CH:30]=[CH:29][C:28]([CH3:31])=[CH:27][C:6]=1/[CH:7]=[C:8]1/[C:9](=[O:26])[N:10]([S:16]([C:19]2[CH:20]=[CH:21][C:22]([Cl:25])=[CH:23][CH:24]=2)(=[O:17])=[O:18])[CH2:11][C:12](=[O:15])[NH:13][CH2:14]/1
Reactant: COCOc1ccc(C)cc1/C=C1\CNC(=O)CN(S(=O)(=O)c2ccc(Cl)cc2)C1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc(O)c(/C=C2\CNC(=O)CN(S(=O)(=O)c3ccc(Cl)cc3)C2=O)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 101.2 %

Procedure:
To (6E)-6-[2-(methoxymethoxy)-5-methylbenzylidene]-4-[(4-chlorophenyl)sulfonyl]-1,4-diazepan-2,5-dione (95 mg), synthesized by using, instead of the starting material of Reference Example 117, that is, the compound S6, the compound S11 for the similar procedure as in Reference Example 117, Reference Example 122, and Example 1, in methylene chloride (0.48 ml) solution, trifluoroacetic acid (0.48 ml) was added and the mixture was stirred at room temperature for 45 minutes. Next, the reaction solution was concentrated, and the residue was recrystallized from hexane/ethyl acetate to obtain the title compound (87 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]([F:22])([F:21])[F:20])=[CH:13][CH:12]=2)[C:4](=[O:23])[CH:3]=1.C([O-])(=O)C.[Na+].[Br:29]Br.O>C(O)(=O)C>[NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][CH3:10])[N:5]([C:11]2[CH:12]=[CH:13][C:14]([O:17][CH2:18][C:19]([F:21])([F:22])[F:20])=[CH:15][CH:16]=2)[C:4](=[O:23])[C:3]=1[Br:29]
Reactant: CCSc1nc(N)cc(=O)n1-c1ccc(OCC(F)(F)F)cc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCSc1nc(N)c(Br)c(=O)n1-c1ccc(OCC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 6-amino-2-(ethylsulfanyl)-3-[4-(2,2,2-trifluoroethoxy)phenyl]pyrimidin-4(3H)-one (0.5 g) and sodium acetate (0.143 g) in acetic acid (10 mL) was added dropwise bromine (0.09 mL), and the mixture was stirred at room temperature for 2 hr. To the reaction mixture was added water, and the precipitated crystals were collected by filtration to give the title compound (0.1 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=O)=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:4][CH:3]=1.[N:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]([CH3:21])[S:9]([C:12]2[CH:13]=[CH:14][C:15]([C:16]([NH:33][C:30]3[S:31][CH:32]=[C:28]([C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][N:22]=4)[N:29]=3)=[O:18])=[CH:19][CH:20]=2)(=[O:10])=[O:11])=[CH:6][CH:7]=1
Reactant: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)O)cc1
Reactant: Nc1nc(-c2ccccn2)cs1
Product: CN(c1ccc(Cl)cc1)S(=O)(=O)c1ccc(C(=O)Nc2nc(-c3ccccn3)cs2)cc1

Procedure:
4-(N-(4-chlorophenyl)-N-methylsulfamoyl)benzoic acid (5) (100 mg, 0.31 mmol) was treated with 4-(pyridin-2-yl)thiazol-2-amine (45 mg, 0.26 mmol) using method C. The residue was purified using flash chromatography eluting with EtOAc. The resulting solid was triturated with diethyl ether to give 4-(N-(4-chlorophenyl)-N-methylsulfamoyl)-N-(4-(pyridin-2-yl)thiazol-2-yl)benzamide as a yellow solid. Yield: 18 mg (15%). 1H-NMR: 8.64-8.61 (m, 1H), 8.29 (d, J=8.5 Hz, 2H), 8.02 (d, J=8.0 Hz, 1H), 7.95-7.87 (m, 2H), 7.68 (d, J=8.5 Hz, 2H), 7.46-7.41 (m, 2H), 7.35 (ddd, J=7.5, 5.0, 1.0 Hz, 1H), 7.19-7.14 (m, 2H), 3.19 (s, 3H).
Reaction SMILES: [CH3:1][Si:2]([CH3:7])([CH3:6])[C:3]#[C:4][CH3:5].CN(C)C(N(C)C)C.C([Li])(C)(C)C.CCCCC.[Si:26]([O:33][C@H:34]([CH2:43][O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])/[CH:35]=[N:36]/[S@:37]([C:39]([CH3:42])([CH3:41])[CH3:40])=[O:38])([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27]>C(OCC)C.C1COCC1>[Si:45]([O:44][CH2:43][C@@H:34]([O:33][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])[C@@H:35]([NH:36][S@:37]([C:39]([CH3:40])([CH3:41])[CH3:42])=[O:38])[CH2:5][C:4]#[C:3][Si:2]([CH3:7])([CH3:6])[CH3:1])([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46]
Reactant: CC#C[Si](C)(C)C
Reactant: CC(C)(C)[S@](=O)/N=C/[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Agent: CC(N(C)C)N(C)C
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCC
Product: CC(C)(C)[S@](=O)N[C@@H](CC#C[Si](C)(C)C)[C@@H](CO[Si](C)(C)C(C)(C)C)O[Si](C)(C)C(C)(C)C
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Trimethyl(prop-1-ynyl)silane (4 mL, 28 mmol) and N,N,N′,N′-tetramethylethanediamine (5 mL, 36 mmol) were dissolved in dry diethyl ether (50 mL) and cooled to −78° C. Tert-butyllithium, 1.7 M solution in pentane (17 mL, 28 mmol) was added dropwise and the heterogenous solution was allowed to warm to 0° C. for 15 min to give a clear yellow solution, which was recooled to −78 C. Azeotropically (S,E)-N—((S)-2,3-bis(tert-butyldimethylsilyloxy)propylidene)-2-methylpropane-2-sulfinamide (3.0 g, 7 mmol) in dry THF (20 μL) was added dropwise and the solution was stirred for 1 h until the starting material was consumed. The reaction mixture as quenched with NH4Cl and extracted with EtOAc. The combined organics were washed with water, brine, dried over Na2SO4, filtered, and concentrated to afford a yellow oil as (S)—N-((2S,3S)-1,2-bis(tert-butyldimethylsilyloxy)-6-(trimethylsilyl)hex-5-yn-3-yl)-2-methylpropane-2-sulfinamide.
Reaction SMILES: C([C:4]1([CH2:11][CH2:12][C:13]([O:15][CH2:16][CH3:17])=[O:14])[CH2:9][CH2:8][CH2:7][CH2:6][C:5]1=[O:10])(=O)C.OO.S(=O)(=O)(O)[OH:21]>C(O)(C)(C)C>[CH2:16]([O:15][C:13]([CH2:12][CH2:11][C:4]1([C:5]([OH:10])=[O:21])[CH2:9][CH2:8][CH2:7][CH2:6]1)=[O:14])[CH3:17]
Reactant: O=S(=O)(O)O
Reactant: CCOC(=O)CCC1(C(C)=O)CCCCC1=O
Agent: OO
Solvent: CC(C)(C)O
Product: CCOC(=O)CCC1(C(=O)O)CCCC1
Reaction time: 24 h

Procedure:
To a solution of 2-acetyl-2-[2-(ethoxycarbonyl)-ethyl]-cyclohexanone (see Preparation 4) (40 g, 0.16 mol) in tert-butanol (85 ml) was added, dropwise, a 30% aqueous solution of hydrogen peroxide (21.7 ml, 0.19 mol) and concentrated sulfuric acid (0.25 ml, 98% w/w) at room temperature. The mixture was further stirred for 24 hours, partitioned between dichloromethane (100 ml) and distilled water (100 ml) and the layers separated. The dichloromethane layer was washed with 5% aqueous sodium sulphite solution, dried over magnesium sulphate, filtered and concentrated under reduced pressure to give a yellow oil, (34.35 g). Purification of this material by chromatography on silica by eluting with ethyl acetate/hexane (1:2 changing to 1:1), followed by neat ethyl acetate in the latter stages, gave, after combination and evaporation of appropriate fractions, the title compound as a yellow oil, (22.96 g, 67%). RF. 0.28 (silica, ethyl acetate/hexane, 1:1). 1H-NMR (300 MHz, CDCl3):=1.31 (t, 3H), 1.47-1.62 (m, 2H), 1.62-1.82 (m, 4H), 1.92-2.08 (m, 2H), 2.10-2.27 (m, 2H), 2.32-2.46 (m, 2H), 4.19 (q, 2H) ppm. 13 C-NMR (75.5 MHz, CDCl3):=14.26, 25.15, 31.21, 33.56, 36.15, 53.21, 60.49, 173.38, 183.52 ppm.
Reaction SMILES: [CH2:1]([O:4][NH:5][C:6](=[O:9])[CH2:7][Cl:8])[CH2:2][CH3:3].[C:10]1([N:16]=[C:17]=[O:18])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C([O-])(=O)CCCCCCCCCCC.C([O-])(=O)CCCCCCCCCCC.C([Sn+2]CCCC)CCC.C1C=CC=CC=1>[Cl:8][CH2:7][C:6]([O:9][C:17](=[O:18])[NH:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[N:5][O:4][CH2:1][CH2:2][CH3:3]
Reactant: O=C=Nc1ccccc1
Reactant: CCCONC(=O)CCl
Agent: CCCCCCCCCCCC(=O)[O-]
Agent: CCCC[Sn+2]CCCC
Solvent: c1ccccc1
Product: CCCON=C(CCl)OC(=O)Nc1ccccc1
Temperature: 25 °C

Procedure:
N-Propoxychloroacetamide (15.1 grams; 0.1 mole), benzene (80 ml) and dibutyltin dilaurate (1 drop) are charged into a glass reaction flask equipped with a mechanical stirrer, thermometer and reflux condenser. Phenylisocyanate (12.1 grams; 0.12 mole) dissolved in benzene (25 ml) is incrementally added to the reaction mixture, with stirring, at room temperature. After the addition is completed the reaction mixture is heated at reflux for a period of about 20 hours. After this time the reaction mixture is distilled to remove benzene and unreacted starting material thereby yielding the desired product 1-chloro-2-(N-phenylcarbamoyloxy)-2-propoxyiminoethane.
Reaction SMILES: C(OC([NH:8][CH2:9][CH2:10][C:11]([O:13][CH:14]1[CH2:19][CH2:18][N:17]([CH3:20])[CH2:16][CH2:15]1)=[O:12])=O)(C)(C)C.[ClH:21].NCCCC(OC1C(C)=CC=CC=1C)=O>>[ClH:21].[NH2:8][CH2:9][CH2:10][C:11]([O:13][CH:14]1[CH2:15][CH2:16][N:17]([CH3:20])[CH2:18][CH2:19]1)=[O:12]
Reactant: CN1CCC(OC(=O)CCNC(=O)OC(C)(C)C)CC1
Agent: Cc1cccc(C)c1OC(=O)CCCN
Agent: Cl
Product: CN1CCC(OC(=O)CCN)CC1

Procedure:
The title compound was prepared from 1-methylpiperidin-4-yl N-(tert-butoxycarbonyl)-β-alaninate in a similar manner as described for 2,6-dimethylphenyl 4-aminobutanoate hydrochloride. Mass Spectrum M+H+ 188.17.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)(=[O:10])=[O:9])[CH:3]=1.[N+:18]([O-:21])([OH:20])=[O:19]>CO.C(#N)C>[CH3:1][C:2]1[O:6][N:5]=[C:4]([NH:7][S:8]([C:11]2[CH:16]=[CH:15][C:14]([NH2:17])=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:3]=1.[N+:18]([O-:21])([O-:20])=[O:19]
Reactant: O=[N+]([O-])O
Agent: Cc1cc(NS(=O)(=O)c2ccc(N)cc2)no1
Solvent: CO
Solvent: CC#N
Product: O=[N+]([O-])[O-]

Procedure:
The compound is prepared by starting from a Sulfamethoxazole solution (2 g, 7.9 mmoli) in methanol (100 ml), addition of a 65% nitric acid solution (0.500 ml) in acetonitrile (5 ml), following the procedure reported in Example 5. Sulfamethoxazole nitrate as amorphous solid is obtained. Yield 60%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][NH:16][CH:17]=3)=[C:11]([C:18]([F:21])([F:20])[F:19])[O:10][N:9]=2)=[CH:4][CH:3]=1.F[C:23]1[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([C:13]3[N:14]=[CH:15][N:16]([C:23]4[CH:28]=[CH:27][C:26]([C:29]([F:32])([F:31])[F:30])=[CH:25][CH:24]=4)[CH:17]=3)=[C:11]([C:18]([F:21])([F:19])[F:20])[O:10][N:9]=2)=[CH:4][CH:3]=1
Reactant: Fc1ccc(C(F)(F)F)cc1
Reactant: FC(F)(F)c1onc(-c2ccc(Cl)cc2)c1-c1c[nH]cn1
Product: FC(F)(F)c1ccc(-n2cnc(-c3c(-c4ccc(Cl)cc4)noc3C(F)(F)F)c2)cc1
Yield: 34 %

Procedure:
As described for Example 44, 3-(4-chloro-phenyl)-4-(1H-imidazol-4-yl)-5-trifluoromethyl-isoxazole (100 mg, 0.32 mmol), using 4-fluorobenzotrifluoride instead of 4-fluoroacetophenone, was converted to the title compound (50 mg, 34%) which was obtained as a white solid. MS: m/e=458.1 [M+H]+.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH2:6][CH:7]([N:14]([CH3:18])[CH2:15][C:16]#[CH:17])[CH2:8]OS(C)(=O)=O.[F-:19]>>[F:19][CH2:8][CH:7]([N:14]([CH3:18])[CH2:15][C:16]#[CH:17])[CH2:6][C:2]1[O:1][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: C#CCN(C)C(COS(C)(=O)=O)Cc1ccco1
Product: C#CCN(C)C(CF)Cc1ccco1

Procedure:
Compound 3e is synthesized by general procedure A from starting material 3c with F-18 fluoride 0.96 GBq. The desired compound is obtained (124 MBq).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C@H:11](O)[CH2:10][C@H:9]1[C:14]([N:16]1[CH2:20][CH2:19][S:18][CH2:17]1)=[O:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].C([N:23](CC)CC)C>ClCCl>[NH2:23][C@@H:11]1[CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[C@H:9]([C:14]([N:16]2[CH2:20][CH2:19][S:18][CH2:17]2)=[O:15])[CH2:10]1
Reactant: CC(C)(C)OC(=O)N1C[C@H](O)C[C@H]1C(=O)N1CCSC1
Reactant: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1C[C@@H](N)C[C@H]1C(=O)N1CCSC1

Procedure:
3-((2S,4R)-1-tert-Butoxycarbonyl-4-hydroxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (title compound of Reference Example 9, 56.3 g) and triethylamine (28.5 mL) were dissolved in dichloromethane (1.0 l), and methanesulfonyl chloride (15.1 mL) was added thereto under ice-cooling. After stirring under ice-cooling for 1 hr, the reaction mixture was washed with water and dried. The solvent was evaporated under reduced pressure to give 3-((2S,4R)-1-tert-butoxycarbonyl-4-methanesulfonyloxy-2-pyrrolidinylcarbonyl)-1,3-thiazolidine (70.5 g) as an oil.
Reaction SMILES: FC1(F)CCN(C(C2NC3C(C=2)=CC(OC2CCN(C(C)C)CC2)=CC=3)=O)CC1.Cl.BrC1C=C2C(C=C(C(O)=O)N2)=CC=1OC1CCN(C(C)C)CC1.[Br:54][C:55]1[CH:63]=[C:62]2[C:58]([CH:59]=[C:60]([C:71]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[O:72])[N:61]2C2C=CN=C(Cl)C=2)=[CH:57][C:56]=1[O:79][CH:80]1[CH2:85][CH2:84][N:83]([CH:86]([CH3:88])[CH3:87])[CH2:82][CH2:81]1.N1CCOCC1>>[Br:54][C:55]1[CH:63]=[C:62]2[C:58]([CH:59]=[C:60]([C:71]([N:73]3[CH2:78][CH2:77][O:76][CH2:75][CH2:74]3)=[O:72])[NH:61]2)=[CH:57][C:56]=1[O:79][CH:80]1[CH2:81][CH2:82][N:83]([CH:86]([CH3:88])[CH3:87])[CH2:84][CH2:85]1
Reactant: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)n(-c4ccnc(Cl)c4)c3cc2Br)CC1
Agent: CC(C)N1CCC(Oc2cc3cc(C(=O)O)[nH]c3cc2Br)CC1
Agent: CC(C)N1CCC(Oc2ccc3[nH]c(C(=O)N4CCC(F)(F)CC4)cc3c2)CC1
Agent: Cl
Solvent: C1COCCN1
Product: CC(C)N1CCC(Oc2cc3cc(C(=O)N4CCOCC4)[nH]c3cc2Br)CC1

Procedure:
In analogy to the procedure described for the synthesis of intermediate 1, step 4, the title compound was synthesized from 6-bromo-5-(1-isopropyl-piperidin-4-yloxy)-1H-indole-2-carboxylic acid hydrochloride salt with 1 eq. lithium chloride (example 41, step 5) and morpholine. The title compound was obtained in 75% yield as light yellow solid. MS (m/e): 450.1 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([OH:21])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:23]([O:26][CH2:27][CH2:28][CH2:29]Br)(=[O:25])[CH3:24]>>[CH2:1]([O:9][C:10]1[C:11](=[O:22])[O:12][C:13]2[C:20]([O:21][CH2:29][CH2:28][CH2:27][O:26][C:23](=[O:25])[CH3:24])=[CH:19][CH:18]=[CH:17][C:14]=2[C:15]=1[OH:16])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CC(=O)OCCCBr
Reactant: CCCCCCCCOc1c(O)c2cccc(O)c2oc1=O
Product: CCCCCCCCOc1c(O)c2cccc(OCCCOC(C)=O)c2oc1=O

Procedure:
In the same manner as in Reference Example 1, except that an equimolar amount of 3-octyloxy-4,8-dihydroxy-2H-1-benzopyran-2-one was used in place of 3-ethoxy-4,5-dihydroxy-2H-1-benzopyran-2-one, and 3-bromopropyl acetate was used in place of 2-bromoethyl acetate in Reference Example 1, 3-octyloxy-4-hydroxy-8-(3-acetoxypropyloxy)-2H-1-benzopyran-2-one was obtained.
Reaction SMILES: Cl.[Cl:2][C:3]1[N:4]=[C:5]([C:10]([NH:12][C@H:13]2[CH2:18][CH2:17][NH:16][CH2:15][C@H:14]2[O:19][CH2:20][CH3:21])=[O:11])[NH:6][C:7]=1[CH2:8][CH3:9].[C:22](O)(=[O:26])[C:23]([NH2:25])=[O:24].CCN=C=NCCCN(C)C.Cl.C(N(CC)CC)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.C(OCC)(=O)C>[NH2:25][C:23](=[O:24])[C:22]([N:16]1[CH2:17][CH2:18][C@H:13]([NH:12][C:10]([C:5]2[NH:6][C:7]([CH2:8][CH3:9])=[C:3]([Cl:2])[N:4]=2)=[O:11])[C@H:14]([O:19][CH2:20][CH3:21])[CH2:15]1)=[O:26]
Reactant: NC(=O)C(=O)O
Reactant: CCO[C@@H]1CNCC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCO[C@@H]1CN(C(=O)C(N)=O)CC[C@@H]1NC(=O)c1nc(Cl)c(CC)[nH]1
Temperature: 25 °C
Reaction time: 8 h
Yield: 60 %

Procedure:
cis(±)-4-Chloro-N-(3-ethoxypiperidin-4-yl)-5-ethyl-1H-imidazole-2-carboxamide hydrochloride obtained in Example (131a) (100 mg, 0.297 mmol), oxamic acid (26 mg, 0.29 mmol) and WSC hydrochloride (120 mg, 0.626 mmol) were suspended in DMF (3 mL). Triethylamine (0.040 mL, 0.29 mmol) and HOBT (40 mg, 0.30 mmol) were added, and the mixture was stirred at room temperature overnight. The reaction solution was diluted with ethyl acetate, washed with saturated aqueous sodium bicarbonate solution, water and brine, and dried over anhydrous sodium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: dichloromethane/methanol=1/0→9/1) to obtain 64.7 mg of the title compound as a colorless solid (59%).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:17])[CH3:16])[N:6]=[C:5]2[C:19]#[C:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>C(O)C.[Pd]>[NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][O:12][CH2:13][CH2:14][Si:15]([CH3:18])([CH3:16])[CH3:17])[N:6]=[C:5]2[CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: C[Si](C)(C)CCOCn1nc(C#Cc2ccccc2)c2cc(N)ccc21
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: C[Si](C)(C)CCOCn1nc(CCc2ccccc2)c2cc(N)ccc21
Yield: 91.2 %

Procedure:
5-Amino-3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole can be obtained in the following way: a solution of 0.9 g of 5-amino-3-phenylethynyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole in a mixture of 50 ml of absolute ethanol and of 2 ml of water containing 100 mg of 10% palladium-on-charcoal is hydrogenated under a pressure of 1000 kPa at a temperature in the region of 25° C. for 21.5 hours. After filtration of the catalyst through Celite® under argon and washing with ethanol, the filtrate is concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 0.83 g of crude 5-amino-3-phenethyl-1-(2-trimethylsilanylethoxymethyl)-1H-indazole is thus obtained in the form of a brown-colored oil (Cl mass analysis: m/z 368 (M+H)+).
Reaction SMILES: [OH:1][C@H:2]([CH2:26]O)[CH2:3][N:4]1[C:9](=[O:10])[C:8]2[C:11]([NH:17][C:18]3[CH:23]=[CH:22][C:21]([I:24])=[CH:20][C:19]=3[F:25])=[CH:12][C:13](=[O:16])[N:14]([CH3:15])[C:7]=2[N:6]=[CH:5]1.NC1C=CC(NC2C3C(=O)NC=NC=3N(C)C(=O)C=2)=C(F)C=1.BrCC(O)C>>[F:25][C:19]1[CH:20]=[C:21]([I:24])[CH:22]=[CH:23][C:18]=1[NH:17][C:11]1[C:8]2[C:9](=[O:10])[N:4]([CH2:3][CH:2]([OH:1])[CH3:26])[CH:5]=[N:6][C:7]=2[N:14]([CH3:15])[C:13](=[O:16])[CH:12]=1
Reactant: Cn1c(=O)cc(Nc2ccc(I)cc2F)c2c(=O)n(C[C@H](O)CO)cnc21
Agent: CC(O)CBr
Agent: Cn1c(=O)cc(Nc2ccc(N)cc2F)c2c(=O)[nH]cnc21
Product: CC(O)Cn1cnc2c(c(Nc3ccc(I)cc3F)cc(=O)n2C)c1=O

Procedure:
The title compound was prepared following the same procedure for the synthesis of Compound 5G using compound 5F and 1-bromopropan-2-ol as starting material. 1H NMR (400 MHz, CDCl3) δ 8.17 (s, 1H) 7.52 (m, 2H) 7.24 (t, J=8.84 Hz, 1H) 5.81 (s, 1H) 4.39 (m, 1H) 4.25 (m, 1H) 3.57 (m, 4H), 1.35 (d, J=6.32 Hz, 3H). [M+H] calc'd for C17H16FIN4O3, 471; found, 471.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH2:10][C:11]([OH:13])=O)[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].Cl.[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH2:22])[CH:16]([CH3:18])[CH3:17]>>[CH2:15]([O:19][C:20](=[O:24])[C@H:21]([CH3:23])[NH:22][C:11](=[O:13])[CH2:10][C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([N+:1]([O-:3])=[O:2])[CH:5]=1)[CH:16]([CH3:18])[CH3:17]
Reactant: CC(C)COC(=O)[C@H](C)N
Reactant: O=C(O)Cc1cccc([N+](=O)[O-])c1
Agent: Cl
Product: CC(C)COC(=O)[C@H](C)NC(=O)Cc1cccc([N+](=O)[O-])c1

Procedure:
Following General Procedure BH above and using 3-nitrophenylacetic acid (Aldrich) and L-alanine iso-butyl ester hydrochloride (from Example BB above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by recrystallization from butyl chloride.
Reaction SMILES: [CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:42])[CH:14]([CH3:41])[CH:15]2[CH2:27][CH2:28][C:29](=[O:40])[CH2:30][CH:31]([OH:39])[CH2:32][C:33]([O:35]CC=C)=[O:34])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(O)=O>O1CCCC1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:1]([O:8][N:9]=[C:10]1[CH2:19][CH2:18][CH:17]([O:20][C:21](=[O:26])[CH:22]([CH3:25])[CH2:23][CH3:24])[CH:16]2[C:11]1=[CH:12][C:13](=[O:42])[CH:14]([CH3:41])[CH:15]2[CH2:27][CH2:28][C:29](=[O:40])[CH2:30][CH:31]([OH:39])[CH2:32][C:33]([OH:35])=[O:34])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCOC(=O)CC(O)CC(=O)CCC1C(C)C(=O)C=C2C(=NOCc3ccccc3)CCC(OC(=O)C(C)CC)C21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O=CO
Product: CCC(C)C(=O)OC1CCC(=NOCc2ccccc2)C2=CC(=O)C(C)C(CCC(=O)CC(O)CC(=O)O)C21
Reaction time: 18 h
Yield: 48.9 %

Procedure:
239 mg (0.4 mmole) of allyl 7-[5-benzyloxyimino-2-methyl-8-(2-methylbutyryloxy)-3-oxo-1,2,3,5,6,7,8,8a-octahydro-1-naphthyl]-3-hydroxy-5-oxoheptanoate (prepared as described in Example 1a) were dissolved in 3.3 ml of anhydrous tetrahydrofuran, and 20.7 mg (0.02 mmole) of tetrakis(triphenylphosphine)palladium (0), 21.5 mg (0.08 mmole) of triphenylphosphine and 31 μl (0.82 mmole) of formic acid were added to the solution, and the resulting mixture was stirred for 18 hours under an atmosphere of nitrogen. At the end of this time, the reaction mixture was condensed by evaporation under reduced pressure, and the residue was dissolved in a 50% v/v aqueous solution of acetonitrile. The solution was filtered through a SEP-PAK C-18 Cartridge (Trade name for a product of Waters Co.) and extracted with ethyl acetate. The resulting ethyl acetate extract was dried over anhydrous magnesium sulfate, filtered and condensed by evaporation under reduced pressure. The resulting oily residue was purified through a reverse phase Lobar Column (RP-18, Size B, Merck), using as the eluent a buffer solution consisting of a 1:1 by volume mixture of acetonitrile and aqueous phosphoric acid (pH 3.0) containing 0.001M of triethylamine, to obtain 106 mg (yield 48%) of the title compound as an oily substance.
Reaction SMILES: Cl.[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[C:6](O)=O.[CH3:21][O:22][C:23]1[CH:24]=[CH:25][C:26]([CH:30]2[CH2:39][CH2:38][C:37]3[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=3)[CH2:31]2)=[C:27]([NH2:29])[CH:28]=1>>[F:2][C:3]1[CH:4]=[C:5]([CH:9]=[CH:10][C:11]=1[O:12][CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[CH2:6][NH:29][C:27]1[CH:28]=[C:23]([O:22][CH3:21])[CH:24]=[CH:25][C:26]=1[CH:30]1[CH2:39][CH2:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([O:40][CH3:41])[CH:36]=2)[CH2:31]1
Reactant: O=C(O)c1ccc(OCCN2CCCCC2)c(F)c1
Reactant: COc1ccc(C2CCc3cc(OC)ccc3C2)c(N)c1
Agent: Cl
Product: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCc1ccc(OCCN3CCCCC3)c(F)c1)C2
Yield: 70.1 %

Procedure:
Synthesized from 3-fluoro-4-(2-piperidin-1-ylethoxy)benzoic acid hydrochloride (1.2 g) and 5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenylamine (600 mg) according to an analogous synthetic method to Example 152, the title compound (770 mg) was obtained.