Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:4][CH:3]=1.C(N(CC)C(C)C)(C)C.[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46]Cl.[Na+].[Cl-]>C(Cl)Cl>[CH3:41][Si:42]([CH3:49])([CH3:48])[CH2:43][CH2:44][O:45][CH2:46][O:1][C:2]1[CH:3]=[CH:4][C:5]([S:8][C@@H:9]2[O:26][C@H:25]([CH2:27][O:28][C:29](=[O:31])[CH3:30])[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@H:15]([O:16][C:17](=[O:19])[CH3:18])[C@H:10]2[O:11][C:12](=[O:14])[CH3:13])=[CH:6][CH:7]=1
Reactant: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(O)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: C[Si](C)(C)CCOCCl
Agent: [Cl-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](Sc2ccc(OCOCC[Si](C)(C)C)cc2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 88 %

Procedure:
To a solution of thioglycoside 78 (1.40 g, 3.10 mmol) in 15 mL of methylene chloride is added N,N-diisopropylethylamine (0.64 mL, 3.70 mmol), followed by 2-(trimethylsilyl)ethoxymethyl chloride (0.60 mL, 3.40 mmol). The mixture is stirred at room temperature for 2 h, poured into saturated NaCl (50 mL) and extracted with CH2Cl2 (2×50 mL), dried over Na2SO4, concentrated, and purified by flash chromatography (40% EtOAc/hexane) to give 1.60 g (89%) of 1-deoxy-1-{4-[2(trimethylsilyl)ethoxymethoxy]phenylthio}-2,3,4,6-tetra-O-acetyl-β-D-galactopyranose 79 as a colorless oil: Rf 0.4 (33% EtOAc/hexane); 1H NMR (CDCl3, 270 MHz) δ 7.46 (d, J=8.4 Hz, 2H), 6.98 (d, J=8.4 Hz, 2H), 5.40 (d, J=3.3 Hz, 1H, H-4), 5.22 (s, 2H, SEM), 5.20 (dd, J=9.9, 9.9 Hz, 1H, H-2), 5.02 (dd, J=3.3, 9.9 Hz, 1H, H-3), 4.58 (d, J=9.9 Hz, 1H, H-1), 4.18 (dd, J=6.6, 11.2 Hz, 1H), 4.10 (dd, J=6.6, 11.2 Hz, 1H), 3.89 (dd, J=6.6, 6.6 Hz, 1H, H-5), 3.75 (t, J=8.4 Hz, 2H, SEM), 2.11 (s, 3H, OAc), 2.10 (s, 3H, OAc), 2.04 (s, 3H, OAc), 1.98 (s, 3H, OAc), 0.94 (t, J=8.4 Hz, 2H, CH2 --TMS), 0.01 (s, 9H, SiMe3).
Reaction SMILES: O[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([CH3:13])([OH:12])[CH3:11].OS(O)(=O)=O>O>[CH3:11][C:10]1([CH3:13])[CH2:9][CH2:8][C:3]2[C:4](=[CH:5][CH:6]=[CH:7][CH:2]=2)[O:12]1
Reactant: CC(C)(O)CCc1ccccc1O
Agent: O=S(=O)(O)O
Solvent: O
Product: CC1(C)CCc2ccccc2O1

Procedure:
A mixture of 16 g (89 mmol) of 4-(2-hydroxyphenyl)-2-methyl-2-butanol, (Compound 55), 40 ml of conc. H2SO4 and 160 ml of water was heated at reflux for 4 hours. The mixture was cooled, diluted with 300 ml of water and extracted with 2×100 ml of hexane. The organic extracts were combined, washed successively with water and saturated NaCl solution and then dried. The solution was then filtered and the filtrate concentrated in-vacuo to give the title compound as a yellow oil. PMR (CDCl3) : & 1.32 (6H, s), 1.78 (2H, t, J~6.8 Hz), 2.76 (2H, t, J~6.8 Hz), 6.74-6.85 (2H, m), 7.01-7.12 (2H, m).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[NH:10][S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4].[H-].[Na+].[CH2:24](Br)[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>CN(C=O)C>[CH3:1][O:2][C:3]([C:5]1[S:6][CH:7]=[CH:8][C:9]=1[N:10]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[S:11]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1)(=[O:13])=[O:12])=[O:4]
Reactant: COC(=O)c1sccc1NS(=O)(=O)c1ccc(OC)cc1
Reactant: BrCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1sccc1N(Cc1ccccc1)S(=O)(=O)c1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 63.4 %

Procedure:
To a solution of 2.0 g (6.116 mmol) of the product of Example 1 in 25 mL of DMF was added 0.257 g (6.422 mmol) of 60% sodium hydride. The resulting mixture was stirred for 30 min at room temperature and then 0.76 mL (6.422 mmol) of benzyl bromide was added. This reaction mixture was stirred overnight at room temperature, poured into water and then extracted with ether. The combined organics were washed with water and brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was chromatographed on silica gel eluting with EtOAc/Hexanes (1:3) to provide 1.62 g (65%) of the desired product as white crystals. CI Mass Spec: 418 (M+H).
Reaction SMILES: [NH:1](C(OC(C)(C)C)=O)[C@H:2]([C:10]([NH:12][C@@H:13]([C:31]([NH:33][C@H:34]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH2:43][C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)=[CH:38][CH:37]=1)=[O:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:30])[NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:22])=[O:21])=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[NH:67]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:68]([C:78]([OH:80])=O)[CH2:69][O:70][CH2:71][C:72]1[CH:77]=[CH:76][CH:75]=[CH:74][CH:73]=1.C1C2C3C(=O)N(O)C(=O)C3C1C=C2.C1CCC(N=C=NC2CCCCC2)CC1>>[NH:67]([C:81]([O:83][C:84]([CH3:87])([CH3:86])[CH3:85])=[O:82])[C@H:68]([C:78]([NH:1][C@H:2]([C:10]([NH:12][C@@H:13]([C:31]([NH:33][C@H:34]([C:50]([O:52][CH2:53][C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1)=[O:51])[CH2:35][C:36]1[CH:37]=[CH:38][C:39]([O:42][CH2:43][C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)=[CH:40][CH:41]=1)=[O:32])[CH2:14][CH2:15][CH2:16][NH:17][C:18](=[NH:30])[NH:19][S:20]([C:23]1[CH:29]=[CH:28][C:26]([CH3:27])=[CH:25][CH:24]=1)(=[O:21])=[O:22])=[O:11])[CH2:3][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1)=[O:80])[CH2:69][O:70][CH2:71][C:72]1[CH:73]=[CH:74][CH:75]=[CH:76][CH:77]=1
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=C1C2C3C=CC(C3)C2C(=O)N1O
Product: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@@H](NC(=O)[C@H](Cc2ccccc2)NC(=O)[C@H](COCc2ccccc2)NC(=O)OC(C)(C)C)C(=O)N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)OCc2ccccc2)cc1

Procedure:
Using 3.90 g Boc-Phe-D-Arg(Tos)-Tyr(Bzl)-OBzl, 1.60 g Boc-Ser(Bzl)-OH, 1.08 g HONB and 1.24 g DCC, the desired product was obtained in exactly the same manner as in Example 1-(III).
Reaction SMILES: [CH3:1][CH:2]([CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])[CH2:3][CH2:4][C:5]1([CH2:20][O:21][C:22]2[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=2)[CH2:14][C:13](=[O:15])[C:12]2[C:7](=[C:8]([CH3:19])[C:9]([CH3:18])=[C:10]([OH:17])[C:11]=2[CH3:16])[O:6]1.[C:37](OC(=O)C)(=[O:39])[CH3:38].N1C=CC=CC=1>C1C=CC=CC=1>[C:37]([O:17][C:10]1[C:11]([CH3:16])=[C:12]2[C:7](=[C:8]([CH3:19])[C:9]=1[CH3:18])[O:6][C:5]([CH2:4][CH2:3][CH:2]([CH3:1])[CH2:31][CH2:32][CH2:33][CH:34]([CH3:36])[CH3:35])([CH2:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N+:28]([O-:30])=[O:29])=[CH:24][CH:23]=1)[CH2:14][C:13]2=[O:15])(=[O:39])[CH3:38]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)c(C)c2c(c1C)C(=O)CC(CCC(C)CCCC(C)C)(COc1ccc([N+](=O)[O-])cc1)O2

Procedure:
Following the same procedure as described in Preparation 16, 1.8 g of 2-(3,7-dimethyloctyl)-6-hydroxy-5,7,8-trimethyl-2-(4-nitrophenoxymethyl)chroman-4-one (prepared as described in Preparation 30), 0.5 g of acetic anhydride, 5 ml of pyridine and 10 ml of benzene were reacted, to give the title compound.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[F:7][C:8]1[C:9]([N:18]2[CH2:22][CH2:21][CH2:20][CH2:19]2)=[N:10][CH:11]=[C:12]([CH:17]=1)[C:13](OC)=[O:14].C(=O)([O-])O.[Na+]>C1COCC1>[F:7][C:8]1[CH:17]=[C:12]([CH2:13][OH:14])[CH:11]=[N:10][C:9]=1[N:18]1[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: COC(=O)c1cnc(N2CCCC2)c(F)c1
Agent: O=C([O-])O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCc1cnc(N2CCCC2)c(F)c1
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 111 %

Procedure:
To a solution of 0.24 g of lithium aluminum hydride in 5 mL of THF, a solution of 0.70 g of methyl 5-fluoro-6-(pyrrolidin-1-yl)nicotinate in 5 mL of tetrahydrofuran was dropped under cooling with ice. After warming to room temperature, the mixture was stirred for 45 minutes, thereto was dropped a saturated aqueous sodium hydrogen carbonate solution under cooling with ice, and the mixture was stirred for 10 minutes. The reaction mixture was filtered, and the filtration residue was washed with ethyl acetate and water. The organic layer of the filtrate was separated, and the aqueous layer was extracted with ethyl acetate. The organic layer and the extract were combined, the resultant solution was washed with water and a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure to obtain 0.68 g of (5-fluoro-6-(pyrrolidin-1-yl)pyridin-3-yl)methanol as a brown oily substance.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH2:13][OH:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)=[CH:4][CH:3]=1>ClC(Cl)(Cl)Cl.[O-2].[O-2].[Mn+4]>[Cl:1][C:2]1[S:6][C:5]([C:7]2[C:12]([CH:13]=[O:14])=[C:11]([CH:15]([CH3:17])[CH3:16])[N:10]=[C:9]3[N:18]([CH2:21][CH3:22])[N:19]=[CH:20][C:8]=23)=[CH:4][CH:3]=1
Reactant: CCn1ncc2c(-c3ccc(Cl)s3)c(CO)c(C(C)C)nc21
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClC(Cl)(Cl)Cl
Product: CCn1ncc2c(-c3ccc(Cl)s3)c(C=O)c(C(C)C)nc21
Yield: 55.8 %

Procedure:
A mixture of [4-(5-chloro-2-thienyl)-1-ethyl-6-isopropyl-1H-pyrazolo[3,4-b]pyridin-5-yl]methanol (2.526 g), activated manganese dioxide (13.1 g) in tetrachloromethane (50 ml) was refluxed for 12 hours. Another activated manganese dioxide (26.1 g) was added and the mixture was refluxed for 10 hours. After cooling, the mixture was filtered through celite and the filtrate was concentrated in vacuo. The residue was purified by flash column chromatography on silica gel eluting with a mixture of EtOAc and n-hexane (1:20) to give 4-(5-chloro-2-thienyl)-1-ethyl-6-isopropyl-1H-pyrazolo[3,4-b]pyridine-5-carbaldehyde (1.4 g) as a yellow crystal.
Reaction SMILES: [CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9](O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O=S(Cl)[Cl:21]>>[CH2:1]([CH:8]([CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:9]([Cl:21])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(O)C(Cc1ccccc1)Cc1ccccc1
Reactant: O=S(Cl)Cl
Product: O=C(Cl)C(Cc1ccccc1)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.1 %

Procedure:
To 20 mL of SOCl2 was added in portions 3.14 g (13.1 mmol) of di-benzylacetic acid and the solution stirred at room temperature overnight. The SOCl2 was removed under reduced pressure and the residue taken up in Et2O and the solvent removed again. There was obtained 3.18 g (94.1% yield) of the product as an oil. The structure was confirmed by NMR spectroscopy.
Reaction SMILES: [CH2:1]([O:3][C:4]1[NH:5][C:6]2[C:12]([CH3:13])=[CH:11][C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)=[CH:9][C:7]=2[N:8]=1)[CH3:2].CC(C)([O-])C.[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[C:44]2[N:45]=[N:46][N:47]([C:49]([C:62]3[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=3)([C:56]3[CH:61]=[CH:60][CH:59]=[CH:58][CH:57]=3)[C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)[N:48]=2)=[CH:34][CH:33]=1.[Cl-].[Na+]>CS(C)=O>[CH2:1]([O:3][C:4]1[N:8]([CH2:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]3[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=3[C:44]3[N:45]=[N:46][N:47]([C:49]([C:62]4[CH:67]=[CH:66][CH:65]=[CH:64][CH:63]=4)([C:56]4[CH:57]=[CH:58][CH:59]=[CH:60][CH:61]=4)[C:50]4[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=4)[N:48]=3)=[CH:36][CH:37]=2)[C:7]2[CH:9]=[C:10]([C:14]3[N:18]([CH3:19])[C:17]4[CH:20]=[CH:21][CH:22]=[CH:23][C:16]=4[N:15]=3)[CH:11]=[C:12]([CH3:13])[C:6]=2[N:5]=1)[CH3:2]
Reactant: CCOc1nc2cc(-c3nc4ccccc4n3C)cc(C)c2[nH]1
Reactant: BrCc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CS(C)=O
Product: CCOc1nc2c(C)cc(-c3nc4ccccc4n3C)cc2n1Cc1ccc(-c2ccccc2-c2nnn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 570 mg (1.86 mMol) of 2-ethoxy-4-methyl-6-(1-methyl-benzimidazol-2-yl)-benzimidazole in 20 ml of dimethylsulphoxide are added 224 mg (2.0 mMol) of potassium tert.butoxide and the mixture is stirred for 15 minutes at ambient temperature. Then 1.11 g (2.0 mMol) of 4'-bromomethyl-2-(2-triphenylmethyl-tetrazol-5-yl)-biphenyl are added and the mixture is stirred for a further 3 hours at ambient temperature. Then the mixture is stirred into about 50 ml of saturated sodium chloride solution, the crude product precipitated is suction filtered and purified by column chromatography (100 g silica gel; eluant: ethyl acetate/petroleum ether=4:1).
Reaction SMILES: Br[C:2]1[N:3]([CH2:10][C:11]2([CH3:14])[CH2:13][O:12]2)[CH:4]=[C:5]([N+:7]([O-:9])=[O:8])[N:6]=1.[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH2:20])=[CH:18][CH:17]=1>C(#N)C.O.O.O.O.O.O.[Co](Cl)Cl>[I:15][C:16]1[CH:22]=[CH:21][C:19]([NH:20][CH2:13][C:11]2([CH3:14])[O:12][C:2]3=[N:6][C:5]([N+:7]([O-:9])=[O:8])=[CH:4][N:3]3[CH2:10]2)=[CH:18][CH:17]=1
Reactant: Nc1ccc(I)cc1
Reactant: CC1(Cn2cc([N+](=O)[O-])nc2Br)CO1
Agent: Cl[Co]Cl
Solvent: CC#N
Solvent: O
Product: CC1(CNc2ccc(I)cc2)Cn2cc([N+](=O)[O-])nc2O1
Temperature: 60 °C
Reaction time: 3 h
Yield: 11.2 %

Procedure:
2-Bromo-1-(2-methyl-oxiranylmethyl)-4-nitro-1H-imidazole (prepared as described by Goto, F.; et al: WO 2004035547; 0.54 g, 2 mmol), 4-iodoaniline (1.31 g, 6 mmol) and cobalt (II) chloride hexahydrate were suspended in 15 mL acetonitrile and stirred at 60° C. for 3 hours. The resulting mixture was filtered through a Celite pad and washed with EtOAc. Upon removing solvent, brown solid precipitated out. The precipitate (˜200 mg) was dried and dissolved in 5 mL DMF. The solution was cooled to −78° C. before NaH (20 mg, 60% in mineral oil) was added quickly. The resulting mixture was warmed up to room temperature and stirred for one hour, before it was quenched with 1 mL water and partitioned in 50 mL EtOAc/50 mL water. The organic layer was washed with brine and dried over Na2SO4. The concentrated residue was purified by aolumn chromatography (EtOAc/Hexanes, v/v, 1/1 to 4/1) to give the titled product (90 mg) as yellow solid. ESI MS m/z 401 (M+H). 1H NMR (400 MHz, MeCN-d3) δ 7.66 (s, 1H), 7.39 (d, J=5.2 Hz, 2H), 6.52 (d, J=5.2 Hz, 2H), 4.75-4.91 (m, 1H), 4.20 (d, J=10.4 Hz, 1H), 4.02 (d, J=10.4 Hz, 1H), 3.37-3.58 (m, 2H), 1.63 (s, 3H).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[S:11]([NH:14][CH2:15][C:16]([NH:18][CH:19]([CH2:23][NH:24][C:25]([CH:27]1[CH2:32][CH2:31][N:30]([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][CH:34]=2)[CH2:29][CH2:28]1)=[O:26])[C:20](O)=[O:21])=[O:17])(=[O:13])=[O:12].[NH:39]1[CH2:44][CH2:43][O:42][CH2:41][CH2:40]1>>[O:42]1[CH2:43][CH2:44][N:39]([C:20]([CH:19]([NH:18][C:16](=[O:17])[CH2:15][NH:14][S:11]([C:2]2[CH:1]=[CH:10][C:5]3[C:4](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:3]=2)(=[O:12])=[O:13])[CH2:23][NH:24][C:25]([CH:27]2[CH2:32][CH2:31][N:30]([C:33]3[CH:34]=[CH:35][N:36]=[CH:37][CH:38]=3)[CH2:29][CH2:28]2)=[O:26])=[O:21])[CH2:40][CH2:41]1
Reactant: C1COCCN1
Reactant: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)O
Product: O=C(CNS(=O)(=O)c1ccc2ccccc2c1)NC(CNC(=O)C1CCN(c2ccncc2)CC1)C(=O)N1CCOCC1
Yield: 36 %

Procedure:
Using an analogous procedure to that described in Example 20, 2-[2-(2-naphthalenesulphonamido)acetamido]-3-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]propionic acid was reacted with morpholine to give N-{1-morpholinocarbonyl-2-[1-(4-pyridyl)piperidin-4-ylcarbonylamino]-ethyl}-2-(2-naphthalenesulphonamido)acetamide in 36% yield.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[NH:5][N:4]=1.Br[CH2:16][CH2:17][O:18][CH3:19].CN(C=O)C.[H-].[Na+]>CCCC[N+](CCCC)(CCCC)CCCC.[I-].O>[CH3:1][O:2][C:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]([CH2:16][CH2:17][O:18][CH3:19])[N:4]=1
Reactant: COc1n[nH]c2ccc([N+](=O)[O-])cc12
Reactant: COCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCn1nc(OC)c2cc([N+](=O)[O-])ccc21
Temperature: 100 °C
Reaction time: 1 h

Procedure:
3-Methoxy-5-nitro-1H-indazole (97 mg), 1-bromo-2-methoxyethane (70 μl, and TBAI (2 mg) were added to a DMF (1 ml) suspension containing sodium hydride (60% in oil) (24 mg) under ice cooling, followed by stirring at 100° C. for 1 hour. Water was added to the reaction solution, followed by extraction with ethyl acetate. The organic layers were washed with water and saturated saline and dried over anhydrous sodium sulfate. Then, the solvent was distilled away under reduced pressure, and the obtained residue was purified by silica gel chromatography (n-hexane:ethyl acetate=1:0 to 1:1). A 3-methoxy-1-(2-methoxyethyl)-5-nitro-1H-indazole (50 mg) was thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([OH:14])=O)[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17].FC1C(OC(N(C)C)=[N+](C)C)=C(F)C(F)=C(F)C=1F.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C.[OH:63][CH2:64][C@@H:65]1[CH2:69][CH2:68][CH2:67][NH:66]1>CS(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[C:12]([N:66]1[CH2:67][CH2:68][CH2:69][C@H:65]1[CH2:64][OH:63])=[O:14])[N:8]=[CH:7][N:6]=[C:5]2[NH:15][CH:16]([C:18]1[NH:22][C:21]2[CH:23]=[CH:24][C:25]([Cl:27])=[CH:26][C:20]=2[N:19]=1)[CH3:17]
Reactant: CC(Nc1ncnc2cc(C(=O)O)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1
Reactant: OC[C@@H]1CCCN1
Agent: CN(C)C(Oc1c(F)c(F)c(F)c(F)c1F)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Product: CC(Nc1ncnc2cc(C(=O)N3CCC[C@H]3CO)c(Cl)cc12)c1nc2cc(Cl)ccc2[nH]1

Procedure:
Prepared analogously to Example 37a from 6-chloro-4-[1-(5-chloro-1H-benzimidazol-2-yl)-ethylamino]-7-hydroxycarbonyl-quinazoline, pentafluorophenyl-tetramethyluronium-hexafluorophosphate (PFTU), diisopropylethylamine and (2S)-2-hydroxymethyl-pyrrolidine in DMSO at ambient temperature.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]([O:18]CC)=[O:17])[CH:12]=[N:11]1.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14]([CH3:15])=[C:13]([C:16]([OH:18])=[O:17])[CH:12]=[N:11]1
Reactant: CCOC(=O)c1cnn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cc1c(C(=O)O)cnn1-c1c(Cl)cc(Cl)cc1Cl
Yield: 71.5 %

Procedure:
By the method of Example 1, Step D, 40.0 g (0.12 mole) of 1-(2,4,6-trichlorophenyl)-4-ethoxycarbonyl-5-methyl-1H-pyrazole and 5.75 g (0.14 mole) of sodium hydroxide were reacted in 40 mL of ethanol and 30 mL of water, yielding 26.2 g of 1-(2,4,6-trichlorophenyl)-4-carboxy-5-methyl-1H-pyrazole as a light tan solid; mp 184°-186.5° C. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[NH:10]1[CH2:14][CH2:13][CH2:12][CH2:11]1>>[NH:10]1[CH2:14][CH2:13][CH2:12][CH:11]1[C:3]([CH3:5])=[CH:2][C:1]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: CCOC(=O)CC(C)=O
Reactant: C1CCNC1
Product: CCOC(=O)C=C(C)C1CCCN1

Procedure:
Ethyl 3-tetrahydropyrrolyl-2-butenoate was prepared (21 g, 99%) from ethyl acetoacetate (15.0 g, 115.26 mmol) and pyrrolidine (71.1 mL, 345.78 mmol) in the same manner as described in the above Example 1 (1), and the obtained product was identified with the following NMR data.
Reaction SMILES: [CH3:1][N:2]1[CH:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[S:16][CH3:17])[C:6]2[C:18](=[O:21])[CH2:19][CH2:20][C:5]=2[N:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[CH:23]=2)[C:3]1=[O:32].ClC1C=C(C=CC=1)C(OO)=[O:38]>ClCCl>[CH3:1][N:2]1[CH:7]([C:8]2[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[CH:10][C:9]=2[S:16]([CH3:17])=[O:38])[C:6]2[C:18](=[O:21])[CH2:19][CH2:20][C:5]=2[N:4]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([F:30])([F:31])[F:29])[CH:23]=2)[C:3]1=[O:32]
Reactant: CSc1cc(C#N)ccc1C1C2=C(CCC2=O)N(c2cccc(C(F)(F)F)c2)C(=O)N1C
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CN1C(=O)N(c2cccc(C(F)(F)F)c2)C2=C(C(=O)CC2)C1c1ccc(C#N)cc1S(C)=O
Temperature: 25 °C
Reaction time: 0.33 h

Procedure:
A solution of 4-(3-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylthio)benzonitrile (example 27.1, 20 mg, 0.04 mmol) in dichloromethane (3.0 mL) is treated with meta-chloroperoxybenzoic acid (77%, 10 mg, 0.04 mmol), and the mixture is stirred at room temperature for 20 min. All volatiles are removed under reduced pressure, and the residue is purified by reversed phase HPLC (Waters SunFire™-C18, gradient of acetonitrile in water, 0.1% TFA), whereupon the two diastereomers of 4-(3-methyl-2,5-dioxo-1-(3-(trifluoromethyl)phenyl)-2,3,4,5,6,7-hexahydro-1H-cyclopenta[d]pyrimidin-4-yl)-3-(methylsulfinyl)benzonitrile are separated.
Reaction SMILES: BrCC[C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O(CC1CCNCC1)C1C=CC=CC=1.C(N(C(C)C)C(C)C)C>O1CCOCC1>[NH:6]1[C:7]2[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=2)[CH:4]=[CH:5]1
Reactant: BrCCc1c[nH]c2ccccc12
Agent: c1ccc(OCC2CCNCC2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: c1ccc2[nH]ccc2c1
Yield: 41 %

Procedure:
A mixture of 8.96 g (0.04 mole) of 3-(2-bromoethyl)-indole, 7.65 g (0.04 mole) of 4-phenoxymethylpiperidine, 7.76 g (0.06 mole) of N-ethyl-diisopropylamine and 100 ml of dioxane is heated under reflux for 9 hours. After cooling, the reaction mixture is filtered, the filtrate is evaporated in a vacuum and the residue is taken up in diethy ether, washed with water, dried over anhydrous sodium sulfate and evaporated. After recrystallization from isopropanol/ligroin, there are obtained 5.55 g of 3-[2-(4-phenoxymethyl)-piperidino)-ethyl]-indole (41% of theory); m.p. 113°-114° C.
Reaction SMILES: O=[C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH2:13][NH:14][CH:3]12.O=P(Cl)(Cl)[Cl:17]>>[Cl:17][C:2]1[C:11]2[N:10]=[CH:9][N:8]=[CH:7][C:6]=2[CH:5]=[C:4]2[O:12][CH:13]=[N:14][C:3]=12
Reactant: O=C1c2ncncc2C=C2OCNC12
Reactant: O=P(Cl)(Cl)Cl
Product: Clc1c2ncncc2cc2ocnc12
Reaction time: 18 h
Yield: 22 %

Procedure:
A suspension of 4-oxo-3H-oxazolo[5,4-g]quinazoline (0.98 g, 5.24 mmol) in POCl3 (30 mL) is heated under reflux with vigorous stirring for 18 h, and then concentrated to dryness. The residue is partitioned between EtOAc and saturated aqueous NaHCO3 and the organic portion is worked up to give 4-chlorooxazolo[5,4-g]quinazoline (0.24 g, 22%) as a yellow solid which is used directly.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([N+:8]([O-])=O)[C:5]([NH2:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1>CCO>[Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[C:5]([NH2:11])=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1
Reactant: Nc1c([N+](=O)[O-])cc(Br)cc1[N+](=O)[O-]
Solvent: CCO
Product: Nc1cc(Br)cc([N+](=O)[O-])c1N
Temperature: 90 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
4-bromo-2,6-dinitrobenzenamine was dissolved in EtOH (50 mL) and (NH4)2S (2.2 mL) was added to the mixture. The reaction mixture was heated to 90° C. for 1 h. TLC showed a new compound and some remaining starting material remained. Additionally, another batch (NH4)2S (2.5 mL) was added. After 1 h, TLC analysis showed little starting material remained. The reaction mixture was concentrated to give a deep red solid. It was then purified by silica gel chromatography eluted with DCM to afford the desired product as a red solid (578 mg, 50%). 1H NMR (300 MHz, CDCl3) δ ppm 3.50 (br s, 2H), 5.93 (br s, 2H), 7.04 (d, 1H, J=1.8 Hz), 7.87 (d, 1H, J=1.8 Hz); LC-MS: m/e=232 [M+1]+.