Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[C:13]([C:18]([F:21])([F:20])[F:19])[CH:14]=[CH:15][CH:16]=3)[N:11]=[CH:10][C:9]=2[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:23])[CH:5]=[CH:6][CH:7]=1.C[O:31][C:32]([C:34]1[CH:42]=[C:41]2[C:37]([C:38]([CH:43]=O)=[CH:39][NH:40]2)=[CH:36][CH:35]=1)=[O:33]>>[C:22]([C:9]1[CH:10]=[N:11][C:12]2[C:17]([C:8]=1[C:4]1[CH:3]=[C:2]([NH:1][CH2:43][C:38]3[C:37]4[C:41](=[CH:42][C:34]([C:32]([OH:33])=[O:31])=[CH:35][CH:36]=4)[NH:40][CH:39]=3)[CH:7]=[CH:6][CH:5]=1)=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([F:21])([F:19])[F:20])(=[O:23])[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COC(=O)c1ccc2c(C=O)c[nH]c2c1
Reactant: Nc1cccc(-c2c(C(=O)c3ccccc3)cnc3c(C(F)(F)F)cccc23)c1
Product: O=C(O)c1ccc2c(CNc3cccc(-c4c(C(=O)c5ccccc5)cnc5c(C(F)(F)F)cccc45)c3)c[nH]c2c1

Procedure:
The title compound was prepared from [4-(3-aminophenyl)-8-(trifluoromethyl)quinolin-3-yl](phenyl)methanone and 3-formyl-1H-indole-6-carboxylic acid methyl ester according to the procedure of Example 66. MS (ESI) m/z 564.
Reaction SMILES: [C:1]1([S:7](Cl)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][NH:31][CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:15][CH2:14]1>>[CH3:12][N:13]1[CH2:14][CH2:15][N:16]([C:19]2[CH:24]=[C:23]([C:25]3[CH:34]=[C:33]4[C:28]([CH2:29][CH2:30][N:31]([S:7]([C:1]5[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=5)(=[O:9])=[O:8])[CH2:32]4)=[CH:27][CH:26]=3)[N:22]=[C:21]([NH2:35])[N:20]=2)[CH2:17][CH2:18]1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CN1CCN(c2cc(-c3ccc4c(c3)CNCC4)nc(N)n2)CC1
Agent: Cl
Product: CN1CCN(c2cc(-c3ccc4c(c3)CN(S(=O)(=O)c3ccccc3)CC4)nc(N)n2)CC1

Procedure:
This compound was prepared from benzenesulfonyl chloride and 4-(4-methylpiperazin-1-yl)-6-(1,2,3,4-tetrahydroisoquinolin-7-yl)pyrimidin-2-amine HCl salt using procedures analogous to those for Example 2. Analytic LCMS (M+H)+: m/z=465.3.
Reaction SMILES: [CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([O:39]COC)[CH:21]=2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.O1CCCC1.C(O)C>C(OCC)(=O)C>[CH2:1]([N:8]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:10]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]3[N:29]=[C:30]([C:34]4[O:35][CH:36]=[CH:37][CH:38]=4)[O:31][C:32]=3[CH3:33])=[C:22]([OH:39])[CH:21]=2)=[N:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(OCOC)c1
Agent: Cl
Solvent: CCO
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cn(Cc2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccco3)oc2C)c(O)c1
Temperature: 50 °C
Reaction time: 5 h
Yield: 67.2 %

Procedure:
A mixture of ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-(methoxymethoxy)benzyl)oxy]-1H-pyrazole-4-carboxylate (8.65 g), 1N hydrochloric acid (50 mL), tetrahydrofuran (100 mL) and ethanol (100 mL) was stirred at 50° C. for 5 hrs. The reaction mixture was diluted with ethyl acetate, and washed successively with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography and eluted with ethyl acetate-hexane (2:3, v/v) to give ethyl 1-benzyl-3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-hydroxybenzyl)oxy]-1H-pyrazole-4-carboxylate as colorless crystals (5.37 g, yield 67%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 134-135° C.
Reaction SMILES: [C:1]([CH2:9][C:10]([O:12][CH3:13])=[O:11])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H][H]>CO>[OH:8][C@H:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH2:9][C:10]([O:12][CH3:13])=[O:11]
Reactant: [H][H]
Reactant: COC(=O)CC(=O)c1ccccc1
Solvent: CO
Product: COC(=O)C[C@H](O)c1ccccc1
Temperature: 80 °C
Reaction time: 5.5 h
Yield: 94.7 %

Procedure:
Into a 1-L autoclave was introduced methanol (360 mL) in a nitrogen stream. Then, [{RuCl((R)-SEGPHOS)}2(μ-Cl)3][Me2NH2] (82 mg: 0.1 mmol) and methyl benzoylacetate (178 g: 1.0 mol) were added. After hydrogen (4.0 MPa) was forced into the autoclave, the reaction mixture was heated to 80° C. and stirred for 5.5 hours to carry out asymmetric hydrogenation reaction. After cooling, methanol was removed from the reaction mixture, and the residue was distilled under reduced pressure (94-99° C./133 Pa) to obtain 170.6 g (yield, 95.3%) of methyl (S)-3-hydroxy-3-phenylpropionate. The asymmetric yield thereof was determined with the HPLC (CHIRALCEL OD-H, 4.6 mm×250 mm; hexane/isopropyl alcohol=95/5; flow rate, 1.0 mL/min; detection wavelength, UV-254 nm), and was found to be 97.2%.
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([N:8]2[CH2:13][CH2:12][CH:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]2)=[O:7])=[CH:4][CH:3]=1.[CH3:19][Mg]Br>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([N:8]2[CH2:9][CH2:10][CH:11]([C:14](=[O:16])[CH3:19])[CH2:12][CH2:13]2)=[O:7])=[CH:17][CH:18]=1
Reactant: C[Mg]Br
Reactant: O=C(O)C1CCN(C(=O)c2ccc(F)cc2)CC1
Product: CC(=O)C1CCN(C(=O)c2ccc(F)cc2)CC1

Procedure:
In a manner similar to that described in Preparation 4, 1-(4-fluorobenzoyl)piperidine-4-carboxylic acid is reacted with methylmagnesium bromide to afford the title compound.
Reaction SMILES: [CH3:1][N:2]1[CH:7]=[CH:6][C:5]([O:8]CC2C=CC=CC=2)=[C:4]([N+:16]([O-])=O)[C:3]1=[O:19].CCO.CN(C=O)C.[ClH:28]>CO.[Pd]>[ClH:28].[NH2:16][C:4]1[C:3](=[O:19])[N:2]([CH3:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: Cn1ccc(OCc2ccccc2)c([N+](=O)[O-])c1=O
Agent: [Pd]
Agent: Cl
Solvent: CCO
Solvent: CN(C)C=O
Solvent: CO
Product: Cn1ccc(O)c(N)c1=O
Yield: 95 %

Procedure:
To the title compound of step 2 (2.00 g, 7.69 mmol, 1.00 Eq) in MeOH (50 mL)/EtOH (50 mL)/DMF (10 mL) was added Pd—C (10%, 0.2 g) under N2. The suspension was purged with H2 three times and hydrogenated under a balloon for 5 h. The catalyst was removed by fitration, and anhydrous HCl in methanol (10 mL, 1.25 M) was added. Concentration left a residue which was treated a second time with HCl in methanol. Evaporation of the volatile components and triturtion with DCM (30 mL)/hexane (30 mL) gave the title compound (1.29 g, 7.30 mmol, yield: 95%) as a pink HCl salt after drying. 1H NMR: (DMSO-d6, 400 MHz) δ: 9.45-8.02 (br, 3H), 7.64 (d, J=7.6 Hz, 1H), 3.27 (d, J=7.6 Hz, 1H), 3.43 (s, 3H). LCMS: 163.0 (M+Na)+
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH2:9])=[N:4][C:5]([CH3:8])=[CH:6][N:7]=1.[Cl:10][CH2:11][C:12](=O)[CH2:13]Cl>CCO>[Cl:10][CH2:11][C:12]1[N:9]=[C:3]2[C:2]([CH3:1])=[N:7][CH:6]=[C:5]([CH3:8])[N:4]2[CH:13]=1
Reactant: Cc1cnc(C)c(N)n1
Reactant: O=C(CCl)CCl
Solvent: CCO
Product: Cc1ncc(C)n2cc(CCl)nc12
Yield: 36 %

Procedure:
To a solution of 3,6-dimethylpyrazin-2-amine (1.0 g, 8.1 mmol) in EtOH (20 mL) was added 1,3-dichloropropan-2-one (1.03 g, 8.1 mmol). The reaction mixture was stirred at reflux for 1 h. Then the solvent was removed. The product was purified by reverse column chromatography to give the title compound as a brown solid (570 mg, yield 85%). ESI MS: m/z 196 [M+H]+. 1H NMR (400 MHz, DMSO-d6): δ 8.10 (s, 1H), 7.65 (s, 1H), 4.94 (s, 2H), 2.70 (s, 3H), 2.54 (s, 3H).
Reaction SMILES: CC([O-])=O.[Na+].C([O:9][CH2:10][C:11]1[CH:16]=[C:15]([Cl:17])[C:14]([CH2:18][C:19]2[CH:24]=[CH:23][C:22]([CH2:25][CH3:26])=[CH:21][CH:20]=2)=[CH:13][C:12]=1[C@H:27]1[C@H:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C@@H:31]([O:41][CH2:42][C:43]2[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=2)[C@H:30]([O:49][CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=2)[C@@H:29]([CH2:57][O:58][CH2:59][C:60]2[CH:65]=[CH:64][CH:63]=[CH:62][CH:61]=2)[O:28]1)C=C>CC(O)=O.O.Cl[Pd]Cl>[Cl:17][C:15]1[C:14]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([CH2:25][CH3:26])=[CH:23][CH:24]=2)=[CH:13][C:12]([C@H:27]2[C@H:32]([O:33][CH2:34][C:35]3[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=3)[C@@H:31]([O:41][CH2:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)[C@H:30]([O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[C@@H:29]([CH2:57][O:58][CH2:59][C:60]3[CH:61]=[CH:62][CH:63]=[CH:64][CH:65]=3)[O:28]2)=[C:11]([CH2:10][OH:9])[CH:16]=1
Reactant: C=CCOCc1cc(Cl)c(Cc2ccc(CC)cc2)cc1[C@@H]1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: Cl[Pd]Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCc1ccc(Cc2cc([C@@H]3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(CO)cc2Cl)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
PdCl2 (23.7 mg, 0.133 mmol, 2.2 eq) and NaOAc (76 mg, 0.285 mmol, 4 eq) were added to a solution of (2S,3S,4R,5R,6R)-2-(2-(allyloxymethyl)-4-chloro-5-(4-ethylbenzyl)phenyl)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran (intermediate O-1) (50 mg, 0.061 mmol) in HOAc:H2O (9:1) (1 mL), and the mixture was stirred at 70° C. for 1 h. Then the mixture was cooled to room temperature, extracted with ethyl acetate, and the combined organic layers were washed with water, dried over anhydrous Na2SO4, concentrated and purified by preparative TLC to obtain 30 mg of intermediate V-1.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][NH:11][N:10]=2)=[CH:4][CH:3]=1.O=[S:18]1(=O)[CH2:23][CH2:22][C:21](=[CH:24][C:25]#[N:26])[CH2:20][CH2:19]1.C1CCN2C(=NCCC2)CC1>CC#N>[C:25]([CH2:24][C:21]1([N:11]2[CH:12]=[C:13]([C:14]([NH2:16])=[O:15])[C:9]([NH:8][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)=[N:10]2)[CH2:22][CH2:23][S:18][CH2:19][CH2:20]1)#[N:26]
Reactant: N#CC=C1CCS(=O)(=O)CC1
Reactant: NC(=O)c1c[nH]nc1Nc1ccc(F)cc1
Solvent: CC#N
Solvent: C1CCC2=NCCCN2CC1
Product: N#CCC1(n2cc(C(N)=O)c(Nc3ccc(F)cc3)n2)CCSCC1
Temperature: 80 °C

Procedure:
3-[(4-Fluorophenyl)amino]-1H-pyrazole-4-carboxamide (Intermediate 31-7) (100 mg, 0.45 mmol) was added to a mixture of 2-(1,1-dioxidodihydro-2H-thiopyran-4(3H)-ylidene)acetonitrile (160 mg, 0.91 mmol) in MeCN (1.51 mL). DBU (0.068 mL, 0.45 mmol) was then added, the reaction vessel was capped and the reaction mixture was heated to 80° C. for 4 hours. The reaction mixture was cooled to ambient temperature, and purified by reverse phase preparative HPLC (using a gradient elution of MeCN/water, with 0.1% v/v TFA modifier). Desired fractions were combined, basified with saturated aqueous NaHCO3, and extracted with EtOAc. The organic layer was dried over anhydrous NaSO4, filtered, and concentrated in vacuo to afford the title compound, Example #7.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:38])[CH:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]3[CH:36]=[CH:35][C:34]([OH:37])=[CH:33][CH:32]=3)(=[O:30])=[O:29])=[CH:24][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[CH:5][C:4]=1[N+:39]([O-:41])=[O:40])[NH2:2].Cl.[CH2:43]([O:45][C:46]([CH2:48][C:49](=N)[O:50]CC)=O)[CH3:44]>>[N+:39]([C:4]1[CH:5]=[C:6]([NH:9][C:10](=[O:38])[CH:11]([O:21][C:22]2[CH:27]=[CH:26][C:25]([S:28]([C:31]3[CH:32]=[CH:33][C:34]([OH:37])=[CH:35][CH:36]=3)(=[O:29])=[O:30])=[CH:24][CH:23]=2)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH:7]=[CH:8][C:3]=1[N:1]1[C:49](=[O:50])[CH:48]=[C:46]([O:45][CH2:43][CH3:44])[NH:2]1)([O-:41])=[O:40]
Reactant: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(NN)c([N+](=O)[O-])c1
Reactant: CCOC(=N)CC(=O)OCC
Agent: Cl
Product: CCCCCCCCCC(Oc1ccc(S(=O)(=O)c2ccc(O)cc2)cc1)C(=O)Nc1ccc(-n2[nH]c(OCC)cc2=O)c([N+](=O)[O-])c1
Yield: 29 %

Procedure:
N-[3-nitro-4-(3-ethoxy-5-pyrazolon-1-yl)phenyl]2- [4-(4-hydroxyphenylsulphonyl)phenoxy]undecylamide was prepared by the method in (2b) from N-(4-hydrazino-3-nitrophenyl)- 2-[4-(4-hydroxyphenylsulphonyl)phenoxy]undecylamide (3b) and O-ethyl 2-ethoxycarbonylacetimidate hydrochloride (prepared from ethyl cyanoacetate and ethanol as in method (2a)). The crude product was partially purified by column chromatography using 63-200 mesh silica gel and ethyl acetate/60°-80° C. petroleum ether (1:1) as the eluent. The yield was 29% over the two stages (3a) to (3c).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([NH2:15])=[O:14])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:18][CH2:19][C:20]([CH2:22]Cl)=O>>[CH2:1]([O:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]2[O:14][CH:22]=[C:20]([CH2:19][Cl:18])[N:15]=2)=[CH:16][CH:17]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(CCl)CCl
Reactant: NC(=O)c1ccc(OCc2ccccc2)cc1
Product: ClCc1coc(-c2ccc(OCc3ccccc3)cc2)n1
Yield: 33 %

Procedure:
In substantially the same manner as in Reference Example 31, 4-benzyloxybenzamide was allowed to react with 1,3-dichloroacetone to give 2-(4-benzyloxyphenyl)-4-chloromethyloxazole. The yield was 33%. Recrystallization from ethyl acetate-hexane gave colorless prisms, mp 119-120° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([OH:13])[C:6](=[CH:11][CH:12]=1)[C:7]([O:9][CH3:10])=[O:8].[N+:14]([O-])([OH:16])=[O:15].O>C(O)(=O)C>[OH:13][C:5]1[C:4]([N+:14]([O-:16])=[O:15])=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=1[C:7]([O:9][CH3:10])=[O:8]
Reactant: O=[N+]([O-])O
Reactant: COC(=O)c1ccc(OC)cc1O
Solvent: CC(=O)O
Solvent: O
Product: COC(=O)c1ccc(OC)c([N+](=O)[O-])c1O
Reaction time: 2 h

Procedure:
A solution of methyl 4-methoxysalicylate (50 g) in glacial acetic acid (700 ml) was treated dropwise with concentrated nitric acid (50 ml) over 15 minutes. After stirring for 2 hours, then standing at room temperature for 18 hours, the mixture was treated with a further aliquot of concentrated nitric acid (10 ml) then stirred for 6 hours. The reaction mixture was diluted with ice then poured into water (1000 ml), then filtered. The solid was dried then subjected to flash chromatography on silica eluting with a mixture of toluene and dichloromethane (2:1, v/v) to give the title compound as a while solid, m.p. 185-187° C.
Reaction SMILES: Cl[CH2:2][C:3]1[C:4]([CH:19]2[CH2:21][CH2:20]2)=[N:5][C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)=[N:7][CH:8]=1.[C-:22]#[N:23].[Na+]>>[CH:19]1([C:4]2[C:3]([CH2:2][C:22]#[N:23])=[CH:8][N:7]=[C:6]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([F:17])([F:16])[F:18])=[CH:11][CH:10]=3)[N:5]=2)[CH2:20][CH2:21]1
Reactant: FC(F)(F)c1ccc(-c2ncc(CCl)c(C3CC3)n2)cc1
Reactant: [C-]#N
Agent: [Na+]
Product: N#CCc1cnc(-c2ccc(C(F)(F)F)cc2)nc1C1CC1

Procedure:
In analogy to the procedure described in example 8 b], 5-chloromethyl-4-cyclopropyl-2-(4-trifluoromethyl-phenyl)-pyrimidine (example 3 d]) was reacted with sodium cyanide to give the title compound as white crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=O)[CH2:9][CH2:10][CH2:11][CH2:12][N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=2)[CH2:15][CH2:14]1.Cl.[F:33][C:34]([F:45])([F:44])[O:35][C:36]1[CH:41]=[CH:40][C:39]([NH:42]N)=[CH:38][CH:37]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[NH:42][C:39]2[C:40]([C:9]=1[CH2:10][CH2:11][CH2:12][N:13]1[CH2:14][CH2:15][CH:16]([C:19]3[CH:20]=[C:21]([NH:25][C:26](=[O:30])[CH:27]([CH3:29])[CH3:28])[CH:22]=[CH:23][CH:24]=3)[CH2:17][CH2:18]1)=[CH:41][C:36]([O:35][C:34]([F:33])([F:44])[F:45])=[CH:37][CH:38]=2
Reactant: CC(C)C(=O)Nc1cccc(C2CCN(CCCCC(=O)c3ccccc3Cl)CC2)c1
Reactant: NNc1ccc(OC(F)(F)F)cc1
Agent: Cl
Product: CC(C)C(=O)Nc1cccc(C2CCN(CCCc3c(-c4ccccc4Cl)[nH]c4ccc(OC(F)(F)F)cc34)CC2)c1

Procedure:
Prepared by Procedure E and Scheme M using N-(3-{1-[5-(2-chlorophenyl)-5-oxopentyl]-4-piperidinyl}phenyl)-2-methylpropanamide and 4-(trifluoromethoxy)phenylhydrazine hydrochloride: ESMS m/e: 598.2 (M+H)+.
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[C:6]([O:12][CH3:13])[CH:5]=1.[C:14]([O:17][C@@H:18]1[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[O:20][C@@H:19]1Br)(=[O:16])[CH3:15]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)(Cl)Cl>[CH3:13][O:12][C:6]1[CH:5]=[C:4]([O:3][C@@H:19]2[O:20][C@H:21]([CH2:32][O:33][C:34](=[O:36])[CH3:35])[C@@H:22]([O:28][C:29](=[O:31])[CH3:30])[C@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:17][C:14](=[O:16])[CH3:15])[CH:11]=[CH:10][C:7]=1[CH:8]=[O:9]
Reactant: CC(=O)OC[C@H]1O[C@H](Br)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reactant: COc1cc(O)ccc1C=O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: COc1cc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)ccc1C=O
Reaction time: 1 h
Yield: 34.4 %

Procedure:
A 1N sodium hydroxide aqueous solution (10.4 mL) was added to a solution of 666 mg (4.38 mmol) of 4-hydroxy-2-methoxybenzaldehyde, 1.50 g (3.65 mmol) of 2,3,4,6-tetra-O-acetyl-α-D-glucopyranosyl bromide, and 1.18 g (3.66 mmol) of tetrabutylammonium bromide in chloroform (11 mL) at room temperature, and the mixture was vigorously stirred for 1 hour. The reaction mixture was subjected to extraction with ethyl acetate. After washing with a saturated sodium bicarbonate solution and then with saturated brine, drying over magnesium sulfate was performed. After filtration, the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=75/25 to 60/40) to give 606 mg (40% yield) of 2-methoxy-4-[(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyl) oxy]benzaldehyde as a white powder.
Reaction SMILES: [CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[CH:4].I[C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2>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.CN(C=O)C.CCN(CC)CC>[CH3:1][C:2]([OH:9])([CH2:5][CH:6]([CH3:8])[CH3:7])[C:3]#[C:4][C:11]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:12]=1/[C:13](=[CH:21]/[C:22]1[NH:23][CH:24]=[CH:25][C:26]=1[O:27][CH3:28])/[C:14](=[O:20])[NH:15]2
Reactant: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(I)c21
Reactant: C#CC(C)(O)CC(C)C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc[nH]c1/C=C1\C(=O)Nc2cccc(C#CC(C)(O)CC(C)C)c21

Procedure:
Using Method C above, 3,5-dimethyl-1-hexyn-3-ol (61 mg, 0.48 mmol) (Aldrich) was coupled with (Z)-1,3-dihydro-4-iodo-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one (Starting Material 2 supra) (146 mg, 0.4 mmol) using (Ph3P)2PdCl2 (20 mg) and Cul (10 mg) as catalyst in DMF (2 mL) and Et3N (2 mL) as solvent at 70° C. for 15 h to yield rac-(Z)-1,3-dihydro-4-(3,5-dimethyl-3-hydroxy-1-hexynyl)-3-[(3-methoxy-1H-pyrrol-2-yl)methylene]-2H-indol-2-one. (Yield 87 mg, 60%).
Reaction SMILES: O=[C:2]([CH2:16][CH2:17][C:18]([O-:20])=[O:19])[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([N+:13]([O-:15])=[O:14])=[CH:9][CH:8]=1)=[O:4].[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][NH:34][C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[I-].ClC1C=CC=C[N+]=1C.C(N(CC)CC)C>ClCCl>[CH2:21]([O:28][C:29]([NH:31][C@@H:32]1[CH2:36][O:35][N:34]([C:2]2([C:3]([O:5][CH2:6][C:7]3[CH:8]=[CH:9][C:10]([N+:13]([O-:15])=[O:14])=[CH:11][CH:12]=3)=[O:4])[CH2:16][CH2:17][C:18](=[O:19])[O:20]2)[C:33]1=[O:37])=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])CCC(=O)C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: O=C(N[C@@H]1CONC1=O)OCc1ccccc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C1CCC(C(=O)OCc2ccc([N+](=O)[O-])cc2)(N2OC[C@@H](NC(=O)OCc3ccccc3)C2=O)O1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 24.4 %

Procedure:
In 2 ml of dichloromethane were dissolved 85 mg of Compound (1) and 60 mg of (4R)-4-benzyloxycarbonylamino-3-isoxazolidinone. To the solution were added 77 mg of 2-chloro-1-methylpyridinium iodide and 84 μ1 of triethylamine. The mixture was stirred at room temperature for 40 minutes, followed by concentration under reduced pressure. The residue was dissolved in ethyl acetate, followed by conducting workup similar to that in Example 8(a) to give 31 mg of the subject Compound (8).
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6].[H-].[Na+].[CH3:30][OH:31]>O1CCOCC1.CN(C=O)C>[CH3:30][O:31][C:2]1[CH:3]=[C:4]([CH:25]=[CH:26][N:27]=1)[C:5]([NH:7][C:8]1[S:9][C:10]2[C:16]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[CH:15][CH:14]=[C:13]([O:23][CH3:24])[C:11]=2[N:12]=1)=[O:6]
Reactant: CO
Reactant: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccnc(Cl)c3)nc12
Agent: [H-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)ccn1

Procedure:
From 2-chloro-N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-isonicotinamide with sodium hydride and methanol in dioxane and DMF. ES-MS m/e (%): 423 (M+Na+, 31), 401 (M+H+, 100).
Reaction SMILES: Br[C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][C:5]([Cl:11])=[CH:4][N:3]=1.[CH3:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([CH3:19])[C:14]=1[OH:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:11][C:5]1[CH:6]=[C:7]([NH2:8])[C:2]([O:20][C:14]2[C:15]([CH3:19])=[CH:16][CH:17]=[CH:18][C:13]=2[CH3:12])=[N:3][CH:4]=1
Reactant: O=[N+]([O-])c1cc(Cl)cnc1Br
Reactant: Cc1cccc(C)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C)c1Oc1ncc(Cl)cc1N
Temperature: 50 °C

Procedure:
2-Bromo-3-nitro-5-chloropyridine (4.8 g, 20 mmol) and 2,6-dimethylphenol (5.0 g, 41 mmol) were magnetically stirred in dry DMF (65 mL) and potassium carbonate (11.0 g, 80 mmol) was added. The mixture was heated at 50° C. for 4 days, allowed to cool to room temperature and added to ice; the product was extracted with ethyl acetate (3×100 mL). The extracts were washed with saturated aqueous NaHCO3 and dried (MgSO4), filtered and concentrated to provide the desired product.
Reaction SMILES: C([O:5][C:6]([C@H:8]1[CH2:12][CH2:11][CH2:10][N:9]1[C:13](=[O:40])[CH2:14][O:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH2:25][C:26]([N:28]2[CH2:32][CH2:31][CH2:30][C@@H:29]2[C:33]([O:35]C(C)(C)C)=[O:34])=[O:27])[CH:17]=1)=[O:7])(C)(C)C>FC(F)(F)C(O)=O>[C:33]([C@H:29]1[CH2:30][CH2:31][CH2:32][N:28]1[C:26](=[O:27])[CH2:25][O:24][C:18]1[CH:17]=[C:16]([CH:21]=[C:20]([O:22][CH3:23])[CH:19]=1)[O:15][CH2:14][C:13]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[C:6]([OH:7])=[O:5])=[O:40])([OH:35])=[O:34]
Reactant: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)cc(OCC(=O)N2CCC[C@@H]2C(=O)OC(C)(C)C)c1
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(OCC(=O)N2CCC[C@@H]2C(=O)O)cc(OCC(=O)N2CCC[C@@H]2C(=O)O)c1
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A solution of 370 mg (0.66 mmol) (R)-1-[[3-[2-[(R)-2-tert-butoxycarbonyl-pyrrolidin-1-yl]-2-oxo-ethoxy]-5-methoxy-phenoxy]-acetyl]-pyrrolidine-2-carboxylic acid tert-butyl ester in 4 ml trifluoroacetic acid was stirred for 3 h at room temperature. The solvent was removed in vacuo and the residue suspended in 10 ml ether. The resulting suspension was stirred overnight. Filtration and drying gave 287 mg (97%) of the title compound as a white powder. MS m/e (%): 473 (M+Na+, 45), 468 (M+NH4+, 30), 451 (M+H+, 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][SH:13])=[CH:10][CH:9]=1.Cl[CH2:17][C:18]([O:20][CH3:21])=[O:19].[I-].[K+]>CC(C)=O>[Cl:7][C:8]1[CH:15]=[CH:14][C:11]([CH2:12][S:13][CH2:17][C:18]([O:20][CH3:21])=[O:19])=[CH:10][CH:9]=1
Reactant: COC(=O)CCl
Reactant: SCc1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)CSCc1ccc(Cl)cc1
Yield: 100 %

Procedure:
Anhydrous acetone (100 ml), potassium carbonate (21 g), p-chlorobenzylmercaptan (19.5 ml), methyl chloroacetate (13.2 ml) and potassium iodide (0.1 g) are mixed in the cold. The mixture thus obtained is stirred and heated under reflux for 7 hours. It is cooled, the precipitate (K2CO3) is filtered off, the acetone is evaporated from the filtrate and the residue is taken up with ether. The ether solution is washed with 4 N NaOH and then with water until the wash waters have a neutral pH. The ether solution is then dried over MgSO4, the ether is evaporated and 34.5 g (100% yield) of methyl p-chlorobenzylmercapto-acetate are collected in the form of a chromatographically pure oil.