Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]2[C:10](I)=[CH:9][N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[C:4]=2[N:5]=[CH:6][N:7]=1.[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.O.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>[CH2:22]([O:29][C:30]1[CH:35]=[CH:34][C:33]([C:10]2[C:3]3[C:2]([Cl:1])=[N:7][CH:6]=[N:5][C:4]=3[N:8]([CH:12]3[CH2:21][CH2:20][C:15]4([O:19][CH2:18][CH2:17][O:16]4)[CH2:14][CH2:13]3)[CH:9]=2)=[CH:32][CH:31]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Clc1ncnc2c1c(I)cn2C1CCC2(CC1)OCCO2
Reactant: OB(O)c1ccc(OCc2ccccc2)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: Clc1ncnc2c1c(-c1ccc(OCc3ccccc3)cc1)cn2C1CCC2(CC1)OCCO2
Temperature: 80 °C
Reaction time: 5 h
Yield: 60.5 %

Procedure:
A mixture of 4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-5-iodo-7H-pyrrolo[2,3-d]pyrimidine (3.0 g, 7.15 mmol) in ethylene glycol dimethyl ether (100 mL) was treated with 4-(benzyloxy)phenylboronic acid (1.79 g, 7.87 mmol), tetrakis(triphenylphosphine)palladium (0.496 g, 0.429 mmol), and a solution of sodium carbonate (1.83 g, 17.16 mmol) in water (50 mL). A precipitate formed after 20 minutes. Reaction was stirred for 5 hours at 80° C. under a nitrogen atmosphere. The mixture was allowed to cool to room temperature and the organic solvent was removed under reduced pressure. The product was partitioned between the aqueous sodium carbonate layer and ethyl acetate. The aqueous layer was further extracted with ethyl acetate three times. The organic layers were combined, washed with water and brine, dried over magnesium sulfate, and partially concentrated until a precipitate formed. The solid was filtered, washed with ethyl acetate, and dried under a high vacuum. Yielded 2.06 g (61%) of 5-[4-(benzyloxy)phenyl]-4-chloro-7-(1,4-dioxaspiro[4.5]dec-8-yl)-7H-pyrrolo[2,3-d]pyrimidine. 1H NMR (DMSO-d6, 400 MHz) δ 8.64(s, 1H), 7.88(s, 1H), 7.52-7.33(m, 7H), 7.08-7.05(d, 2H, J=12 Hz), 5.15(s, 2H), 4.82-4.78 (m, 1H), 3.95-3.89(m, 4H), 2.21-2.13(m, 2H), 1.98-1.96(m, 2H), 1.85-1.75(m, 4H); Waters 2690 Alliance HPLC (Symmetry Shield RP18 3.5 μm, 2.1×50 mm; 5%-95% acetonitrile-0.1 M ammonium acetate over 15 min, 0.5 mL/min) Rt 8.356 min.
Reaction SMILES: [ClH:1].[F:2][C:3]([F:20])([F:19])[CH2:4][CH2:5][C@@H:6]([NH:10][C@@H](C1C=CC=CC=1)C)[C:7]([NH2:9])=[O:8].CO.O>[Pd].[OH-].[OH-].[Pd+2].ClCCl>[ClH:1].[NH2:10][C@H:6]([CH2:5][CH2:4][C:3]([F:2])([F:19])[F:20])[C:7]([NH2:9])=[O:8]
Reactant: C[C@@H](N[C@H](CCC(F)(F)F)C(N)=O)c1ccccc1
Agent: [Pd+2]
Agent: [Pd]
Agent: Cl
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: NC(=O)[C@H](N)CCC(F)(F)F
Temperature: 32.5 °C
Yield: 91.8 %

Procedure:
To a suitable pressure vessel, (R)-5,5,5-trifluoro-2-((R)-1-phenylethylamino)-pentanamide hydrochloride (1.50 kg) was charged along with methanol (15.0 L). This was followed by the addition of water (701.0 mL) followed by 20% palladium hydroxide on carbon (225 g). Similarly, palladium on carbon (Pd/C) could be used as the hydrogenation catalyst. The vessel was flushed with nitrogen three times, and then hydrogen gas was pressurized into the vessel (3-4 kg/cm2) at 60° C. The reaction was monitored for completion by HPLC. Upon completion, the reaction mixture was allowed to cool to 30-35° C. and filtered through a Celite pad, then washed with methanol. The filtrate was then concentrated under reduced pressure. After complete concentration, the remaining reaction mixture was treated with dichloromethane (2.5 L per wash), filtered and dried at 45° C. for 12 hours, giving the title compound (915 g, 91.0%; Purity=97%). 1H NMR (DMSO-d6) (400 MHz) δ 2.00 (m, 2H, CH2), 2.30-2.40 (m, 211 of CH2—CF3), 3.85-3.88 (m, 1H, —(CONH2)CH(NH), 7.64 & 8.11 (br s, 1H, each of CONH2), 8.44 (br s, 311, 13C NMR (DMSO-d6) (100.0 MHz) δ 169.57, 131.20, 128.45, 125.71, 122.97, 50.91, 29.46, 29.18, 28.89, 28.61, 23.56, 23.53.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[F:10])[CH2:5]O.[CH2:11]([O:13][C:14]([CH:16]=[PH3])=[O:15])[CH3:12]>C1(C)C=CC=CC=1.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:16][C:14]([O:13][CH2:11][CH3:12])=[O:15])[CH:7]=[CH:8][C:9]=1[F:10]
Reactant: CCOC(=O)C=[PH3]
Reactant: OCc1ccc(F)c(Br)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: Cc1ccccc1
Product: CCOC(=O)C=Cc1ccc(F)c(Br)c1
Reaction time: 8 h

Procedure:
9.65 g (111 mmol) of manganese dioxide were added to a solution of 6.5 g (31.7 mmol) of 3-bromo-4-fluorobenzyl alcohol and 13.25 g (38 mmol) of ethoxycarbonylmethylenephosphorane in 390 ml of toluene. The reaction mixture was heated at reflux, a further 9.65 g of manganese dioxide were added after 1 h and heating under reflux was continued overnight. After cooling, the mixture was filtered through celite and the filtrate was concentrated. The residue was purified by flash chromatography on silica gel (mobile phase cylclohexane/ethyl acetate 5:1). This gave 7.05 g (81% of theory) of the target product in the form of an E/Z isomer mixture.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=O)=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1.[CH2:28]([N:30]([CH2:41][CH3:42])[CH2:31][CH2:32][N:33]([CH3:40])[C:34]1[S:35][CH2:36][C:37](=[O:39])[N:38]=1)[CH3:29]>>[F:1][C:2]([F:26])([F:27])[C:3]1[CH:21]=[C:20]([C:22]([F:24])([F:23])[F:25])[CH:19]=[CH:18][C:4]=1[CH2:5][N:6]1[C:14]2[C:9](=[CH:10][C:11]([CH:15]=[C:36]3[S:35][C:34]([N:33]([CH2:32][CH2:31][N:30]([CH2:41][CH3:42])[CH2:28][CH3:29])[CH3:40])=[N:38][C:37]3=[O:39])=[CH:12][CH:13]=2)[C:8]([I:17])=[N:7]1
Reactant: CCN(CC)CCN(C)C1=NC(=O)CS1
Reactant: O=Cc1ccc2c(c1)c(I)nn2Cc1ccc(C(F)(F)F)cc1C(F)(F)F
Product: CCN(CC)CCN(C)C1=NC(=O)C(=Cc2ccc3c(c2)c(I)nn3Cc2ccc(C(F)(F)F)cc2C(F)(F)F)S1

Procedure:
5-[1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazol-5ylmethylene]-2-[(2-diethylamino-ethyl)-methyl-amino]-thiazol-4-one was prepared from 1-(2,4-Bis-trifluoromethyl-benzyl)-3-iodo-1H-indazole-5-carbaldehyde and 2-[(2-Diethylamino-ethyl)-methyl-amino]-thiazol-4-one following General Procedure E.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:13][O:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][C:24]=2[Cl:30])=[CH:17][CH:16]=1)=O)(C)(C)C.Cl.CCOCC>CO>[ClH:29].[Cl:30][C:24]1[CH:25]=[C:26]([Cl:29])[CH:27]=[CH:28][C:23]=1[CH2:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([O:14][CH2:13][C@H:9]2[CH2:10][CH2:11][CH2:12][NH:8]2)=[CH:16][CH:17]=1
Reactant: CC(C)(C)OC(=O)N1CCC[C@@H]1COc1ccc(OCc2ccc(Cl)cc2Cl)cc1
Agent: Cl
Solvent: CCOCC
Solvent: CO
Product: Clc1ccc(COc2ccc(OC[C@H]3CCCN3)cc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 205.8 %

Procedure:
To a 25 mL vial which contained a solution of the product from step 2 (120 mg, 0.26 mmol) in MeOH (2 mL) was added HCl (2 N in ether, 4 mL) at 0° C. The mixture was allowed to warm to rt and stir at rt for 24 h. The ether (10 mL) was added to the mixture and the solid which formed was filtered out to provide the crude which was further purified by recrystallization with MeOH-ether to yield the title product, (104 mg, 95%); LCMS; 100% APCI+, Calcd: 352.3; Found m/z 352.3 (M); 1H NMR (400 MHz, DMSO-d6); δ 1.68-1.75 (m, 1H), 1.84-2.02 (m, 2H), 2.07-2.16 (m, 1H), 3.13-3.26 (m, 2H), 3.80-3.90 (m, 1H), 4.05-4.10 (m, 1H), 4.18 (dd, J1=10.4 Hz, J2=3.6 Hz, 1H), 5.09 (s, 2H), 6.94-7.01 (m, 4H), 7.48 (dd, J1=8.0 Hz, J2=2.0 Hz, 1H), 7.60 (d, J=8.4 Hz, 1H), 7.68 (d, 1H, J=2.0 Hz):
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[S:10]1[CH2:14][C:13](=[O:15])[NH:12][C:11]1=[O:16]>>[OH:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[C:14]2\[C:13](=[O:15])[NH:12][C:11](=[O:16])[S:10]\2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(O)cc1
Reactant: O=C1CSC(=O)N1
Product: O=C1NC(=O)/C(=C\c2ccc(O)cc2)S1

Procedure:
A compounds of Formula 3A can be synthesized according to Scheme 1A, wherein 4-hydroxybenzaldehyde is condensed with thiazolidine-2,4-dione under Knoevenagel conditions to produce (E)-5-(4-hydroxybenzylidene)thiazolidine-2,4-dione. This intermediate can then be reduced to the compound of Formula 3A by, for example, hydrogenation.
Reaction SMILES: [N:1]1([CH2:6][C@@H:7]([O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:21](=[O:25])[CH2:20][CH2:19][CH2:18][C:17]=3[C:16]=2[CH2:26][S:27][C:28]2[CH:36]=[CH:35][CH:34]=[CH:33][C:29]=2[C:30]([OH:32])=O)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:5]=[CH:4][N:3]=[CH:2]1.[NH2:37][CH2:38][C@@H:39]([OH:41])[CH3:40]>>[OH:41][C@@H:39]([CH3:40])[CH2:38][NH:37][C:30](=[O:32])[C:29]1[CH:33]=[CH:34][CH:35]=[CH:36][C:28]=1[S:27][CH2:26][C:16]1[C:17]2[CH2:18][CH2:19][CH2:20][C:21](=[O:25])[C:22]=2[CH:23]=[CH:24][C:15]=1[O:14][C@@H:7]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH2:6][N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: O=C(O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Reactant: C[C@H](O)CN
Product: C[C@H](O)CNC(=O)c1ccccc1SCc1c(O[C@H](Cn2ccnc2)c2ccccc2)ccc2c1CCCC2=O
Yield: 66.6 %

Procedure:
Using the method in Example 172, 2-{[(2-{[(1S)-2-(1H-imidazol-1-yl)-1-phenylethyl]oxy}-5-oxo-5,6,7,8-tetrahydro-1-naphthalenyl)methyl]sulfanyl}benzoic acid (50 mg, 0.10 mmol, 0.20M in DMF) and (S)-1-amino-2-propanol (23 mg, 0.30 mmol, 0.6M in DMF) were combined to give 37 mg of the desired compound: Low resolution mass spectrum (LC-MS, APCI) m/z 556 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:5](=O)[CH2:4][CH2:3]1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[CH3:1][C:2]1([C:9]([OH:11])=[O:10])[CH2:7][CH2:6][C:5]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)=[CH:4][CH2:3]1
Reactant: CC1(C(=O)O)CCC(=O)CC1
Reactant: C1COCCN1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1(C(=O)O)CC=C(N2CCOCC2)CC1
Yield: 103.3 %

Procedure:
The solution of methyl 4-oxocyclohexanecarboxylic acid (172.0 g, 1.01 mol), morpholine (97.0 g, 1.11 mol) and p-toluenesulfonic acid (200 mg) in toluene (500 mL) was stirred 18 h at reflux. The reaction mixture was concentrated in vacuum to give 235 g methyl 4-morpholinocyclohex-3-enecarboxylic acid. The compound was used in the next reaction without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH2:12])=[NH:11].[C:14]([N:18]=[C:19]=[O:20])([CH3:17])([CH3:16])[CH3:15]>C1(C)C(C)=CC=CC=1>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([CH3:13])[C:10]([NH:12][C:19]([NH:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])=[NH:11]
Reactant: CN(C(=N)N)c1c(Cl)cccc1Cl
Reactant: CC(C)(C)N=C=O
Solvent: Cc1ccccc1C
Product: CN(C(=N)NC(=O)NC(C)(C)C)c1c(Cl)cccc1Cl

Procedure:
To a mixture of 10.9 g (0.05 mole) of 1-(2,6-dichlorophenyl)-1-methylguanidine and 10 ml xylene is added 5 g of t-butylisocyanate (0.05 mole) and the mixture is refluxed for 2 hours. The reaction product is cooled, triturated with heptane and filtered. Recrystallization from 1:1 isopropanol/water results in 1-(2,6-dichlorophenyl-N-methylamidino)-3-(t-butyl)urea.
Reaction SMILES: O1CCOCC1.O.C([O:14][C@@H:15]1[C:20]([C:21]2[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=2)=[CH:19][CH2:18][NH:17][CH2:16]1)(=O)C(C)(C)C.O.[OH-].[Li+]>C(OCC)(=O)C>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C:20]2[C@@H:15]([OH:14])[CH2:16][NH:17][CH2:18][CH:19]=2)=[CH:22][CH:23]=1
Reactant: CC(C)(C)C(=O)O[C@H]1CNCC=C1c1ccc(F)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: O
Solvent: C1COCCO1
Product: O[C@H]1CNCC=C1c1ccc(F)cc1
Yield: 74 %

Procedure:
To a 1,4-dioxane (4.5 mL)-water (2.5 mL) solution of the crude product of (R)-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridin-3-yl pivalate synthesized in Reference Synthesis Example 132, lithium hydroxide monohydrate (229 mg, 5.45 mmol) was added and the resultant mixture was stirred at 115° C. for 3 hours. After completion of the reaction, water was added to the reaction solution and extraction from the resultant mixture with ethyl acetate was performed. The organic layer was concentrated under reduced pressure and the obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=49/1→7/3) to obtain the title compound (640 mg, two step yield 74%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]([C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[C:20](=[O:29])[C:21]#[C:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:13]=1>>[CH3:9][O:10][C:11](=[O:36])[C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][N:19]2[C:30]3[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=3)/[C:21](=[C:22](\[C:3]3[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=3[Cl:1])/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=3)/[C:20]2=[O:29])[CH:13]=1
Reactant: Clc1ccccc1I
Reactant: COC(=O)c1cccc(CN(C(=O)C#Cc2ccccc2)c2ccccc2)c1
Product: COC(=O)c1cccc(CN2C(=O)/C(=C(\c3ccccc3)c3ccccc3Cl)c3ccccc32)c1

Procedure:
The title compound was prepared in analogy to Example 5 starting from 1-chloro-2-iodo-benzene (commercially available) and 3-{[phenyl-(3-phenyl propynoyl)-amino]-methyl}-benzoic acid methyl ester. 1H NMR (CDCl3, 300 MHz) δppm 8.01 (s, 1H), 7.92 (d, 1H), 7.50-7.52 (m, 4H), 7.37-7.42 (m, 7H), 7.07 (t, 1H), 6.62-6.69 (m, 1H), 6.05 (d, 1H), 4.96 (dd, 2H), 3.91 (s, 3H).
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[C:9]1([C:15]2[C:20]3=[CH:21][CH:22]=[C:23]4[C:32]([CH:31]=[C:30]5[C:25]([CH:26]=[CH:27][CH:28]=[CH:29]5)=[CH:24]4)=[C:19]3[CH:18]=[CH:17][CH:16]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.C(O)C>CN(C=O)C>[Br:1][C:24]1[C:23]2[C:32]([CH:31]=[C:30]3[C:25]=1[CH:26]=[CH:27][CH:28]=[CH:29]3)=[C:19]1[CH:18]=[CH:17][CH:16]=[C:15]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:20]1=[CH:21][CH:22]=2
Reactant: O=C1CCC(=O)N1Br
Reactant: c1ccc(-c2cccc3c2ccc2cc4ccccc4cc23)cc1
Solvent: CN(C)C=O
Solvent: CCO
Product: Brc1c2ccccc2cc2c1ccc1c(-c3ccccc3)cccc12
Reaction time: 3 h

Procedure:
16.9 g (95 mmol) of N-bromosuccinimide are added at 100° C. to a suspension of 18.2 g (45 mmol) of 4-phenylbenz[a]anthracene in 500 ml of DMF. After 3 h, 500 ml of ethanol are added at room temperature, and the solid is filtered off with suction, washed with ethanol and dried.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]2[CH:8]=[C:9]([C:18]3[CH:19]=[N:20][N:21]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH:22]=3)[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]=2[CH:3]=1.[NH2:30][C:31]1[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=1>>[C:26]([O:25][C:23]([N:21]1[CH:22]=[C:18]([C:9]2[N:10]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[C:4]3[CH:3]=[C:2]([NH:30][C:31]4[CH:38]=[CH:37][C:34]([C:35]#[N:36])=[CH:33][CH:32]=4)[N:7]=[CH:6][C:5]=3[CH:8]=2)[CH:19]=[N:20]1)=[O:24])([CH3:28])([CH3:27])[CH3:29]
Reactant: N#Cc1ccc(N)cc1
Reactant: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Br)cc3n2C(=O)OC(C)(C)C)cn1
Product: CC(C)(C)OC(=O)n1cc(-c2cc3cnc(Nc4ccc(C#N)cc4)cc3n2C(=O)OC(C)(C)C)cn1

Procedure:
The title compound was prepared from tert-butyl 6-bromo-2-(1-(tert-butoxycarbonyl)-1H-pyrazol-4-yl)-1H-pyrrolo[3,2-c]pyridine-1-carboxylate (10) (50 mg, 0.108 mmol) and 4-aminobenzonitrile (15.3 mg, 0.13 mmol, 1.2 eq) using the method described for Preparation 35 and using silica gel column chromatography eluting with EtOAc:hexane:triethylamine 10:10:1 (9 mg, 17%). 1H-NMR (500 MHz, CDCl3) 1.53 (s, 9H), 1.69 (s, 9H), 6.62 (s, 1H), 6.93 (s, 1H), 7.48 (d, J=8.8 Hz, 2H), 7.57 (d, J=8.8 Hz, 1H), 7.74 (s, 1H), 7.83 (s, 1H), 8.23 (s, 1H), 8.54 (s, 1H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([OH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:21])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[O:19][CH3:20].[C:22]1(C)C=C(C)C=C(C)C=1Cl>CN(C=O)C>[CH3:20][O:19][C:12]1[CH:13]=[C:14]([O:17][CH3:18])[CH:15]=[CH:16][C:11]=1[C:10]1[C:9](=[O:21])[C:3]2[C:2](=[CH:7][C:6]([OH:8])=[CH:5][CH:4]=2)[O:1][CH:22]=1
Reactant: Cc1cc(C)c(Cl)c(C)c1
Reactant: COc1ccc(CC(=O)c2ccc(O)cc2O)c(OC)c1
Solvent: CN(C)C=O
Product: COc1ccc(-c2coc3cc(O)ccc3c2=O)c(OC)c1
Temperature: 110 °C
Reaction time: 0.5 h
Yield: 70.6 %

Procedure:
BF3—OEt2 complex (14 ml, 112 mmol) was gradually added to a solution of 1-(2,4-dihydroxy-phenyl)-2-(2,4-dimethoxy-phenyl)-ethanone (8.1 gm, 28 mmol) in DMF at 0° C. The resulting solution was stirred for 30 min. Mesityl chloride (6.5 ml, 84 mmol) was then gradually added to it at 50° C. The solution was then heated up to 110° C. for 5 hours. The mixture was then concentrated. The residue was treated with ice and the solid obtained was purified with silica gel column chromatography using hexane-chloroform as the eluent to give 3-(2,4-dimethoxy-phenyl)-7-hydroxy-chromen-4-one (5.9 gm, 70%) as white solid.
Reaction SMILES: [OH:1][C:2]1[CH:17]=[CH:16][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.Cl[S:19]([C:22]1[CH:30]=[CH:29][C:25]([C:26]([OH:28])=[O:27])=[C:24]([OH:31])[CH:23]=1)(=[O:21])=[O:20]>C1COCC1>[OH:31][C:24]1[CH:23]=[C:22]([S:19]([O:1][C:2]2[CH:17]=[CH:16][C:5]([C:6](=[O:7])[C:8]3[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=3)=[CH:4][CH:3]=2)(=[O:21])=[O:20])[CH:30]=[CH:29][C:25]=1[C:26]([OH:28])=[O:27]
Reactant: O=C(O)c1ccc(S(=O)(=O)Cl)cc1O
Reactant: COc1ccc(C(=O)c2ccc(O)cc2)cc1
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(OS(=O)(=O)c3ccc(C(=O)O)c(O)c3)cc2)cc1
Yield: 54.3 %

Procedure:
The title compound was prepared according to the procedure in Example 4 using commercial 4-hydroxy-4'methoxybenzophenone (0.206 g, 0.903 mmol) and 4-chlorosulphonyl-2-hydroxybenzoic acid (0.427 g, 1.81 mmol) in THF (5 mL). Purification by preparative HPLC (C18, eluting with 60% CH3CN/H2O containing 0.1% TFA) and crystallization from EtOAc/hexane gave 0.21 g (54%) of the title compound as an off white solid, mp 73-75° C.; 1H NMR (DMSO-d6) δ 3.85 (s, 3H), 7.07 (d, 2H), 7.24 (d, 2H), 7.36-7.38 (m, 2H), 7.68-7.73 (m, 4H), 7.99 (s, 1 H). IR (KBr) 3400, 1700, 1650, 1000 and 1260 cm-1. mass spectrum (-ESI) m/z 427 (M-H).
Reaction SMILES: C([N:3]=[C:4]([C:9]1[CH:10]=[N:11][C:12]([NH2:15])=[CH:13][CH:14]=1)OCCC)#N.ClC1C=CC=CC=1CCN>CO.CN(C=O)C>[NH2:15][C:12]1[N:11]=[CH:10][C:9]([C:4]#[N:3])=[CH:14][CH:13]=1
Reactant: CCCOC(=NC#N)c1ccc(N)nc1
Agent: NCCc1ccccc1Cl
Solvent: CO
Solvent: CN(C)C=O
Product: N#Cc1ccc(N)nc1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 214.1 %

Procedure:
1H-NMR (500 MHz, DMSO): δ (ppm). 8.74(1H, d, J=2.4Hz, H-6), 8.04(1H, dd, J=2.4, 9.2Hz, H-4), 7.20(1H, brs, NH2), 6.53(1H, d, J=9.2Hz, H-3 ) , 4.27 (2H, t, J=6.7Hz, OCH2CH2CH3), 1.7 5 (2H, m, OCH2CH2CH3) , 0.97 (3H, t, J=7.3Hz, OCH2CH2CH3). Propyl N-cyano-6-amino-3-pyridinecarboximidate (200 mg, 0.98 mmol) and 2-(2-chlorophenyl)ethylamine (170 mg, 1.09 mmol) were dissolved in a mixture of methanol (10 ml) and DMF (1.5 ml), and the mixture was stirred at room temperature for 2.5 hours. The reaction mixture was concentrated under reduced pressure and subjected to silica gel column chromatography (Wako Gel C-200, 25 g), and elution was conducted with chloroform:methanol (30:1) to give the title compound (250 mg, yield 85%) as colorless powder.
Reaction SMILES: [NH2:1][C@@H:2]([CH2:5][S:6][CH2:7][CH:8]1[CH2:10][CH2:9]1)[CH2:3][OH:4].CO[CH:13](O)[C:14]([F:17])([F:16])[F:15].O>C1(C)C=CC=CC=1>[CH:8]1([CH2:7][S:6][CH2:5][CH:2]2[CH2:3][O:4][CH:13]([C:14]([F:17])([F:16])[F:15])[NH:1]2)[CH2:10][CH2:9]1
Reactant: N[C@H](CO)CSCC1CC1
Reactant: COC(O)C(F)(F)F
Solvent: Cc1ccccc1
Solvent: O
Product: FC(F)(F)C1NC(CSCC2CC2)CO1
Yield: 86.6 %

Procedure:
A solution of 2(R)-amino-3-cyclopropylmethylsulfanylpropan-1-ol (3.2 g, 20.0 mmol), prepared as described in Example 2, Steps 1 and 2 above, and trifluoroacetaldehyde methyl hemiacetal (2.6 g, 20.0 mmol) in toluene (20 mL) was heated at reflux with Dean Stark trapping of water for 24 h. The reaction mixture was concentrated to give 4-cyclopropylmethylsulfanylmethyl-2-trifluoromethyloxazolidine (4.18 g) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([CH2:11][CH3:12])=[CH:5]2.[C:13]1([CH3:23])[CH:18]=[CH:17][C:16]([S:19](Cl)(=[O:21])=[O:20])=[CH:15][CH:14]=1>C(N(CC)CC)C>[CH2:11]([C:6]1[NH:7][C:8]2[C:4]([CH:5]=1)=[CH:3][C:2]([NH:1][S:19]([C:16]1[CH:17]=[CH:18][C:13]([CH3:23])=[CH:14][CH:15]=1)(=[O:21])=[O:20])=[CH:10][CH:9]=2)[CH3:12]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CCc1cc2cc(N)ccc2[nH]1
Solvent: CCN(CC)CC
Product: CCc1cc2cc(NS(=O)(=O)c3ccc(C)cc3)ccc2[nH]1

Procedure:
The above compound could be synthesized by treating 5-amino-2-ethylindole with p-toluenesulfonyl chloride in the presence of triethylamine.
Reaction SMILES: [NH2:1][CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][C:17]=1[N+:26]([O-:28])=[O:27].C(N(CC)CC)C>ClCCl>[C:9]1([CH:2]([NH:1][S:22]([C:19]2[CH:20]=[CH:21][C:16]([Cl:15])=[C:17]([N+:26]([O-:28])=[O:27])[CH:18]=2)(=[O:23])=[O:24])[C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Reactant: NC(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=[N+]([O-])c1cc(S(=O)(=O)NC(c2ccccc2)c2ccccc2)ccc1Cl
Reaction time: 16 h
Yield: 74 %

Procedure:
To a stirred solution of aminodiphenylmethane (1.9 g, 11 mmol) and 4-chloro-3-nitrobenzenesulfonyl chloride (2.56 g, 10 mmol) in 75 mL of dichloromethane was added triethylamine (2 mL, 14.4 mmol). The solution was stirred for 16 h. The reaction mixture was washed successively with 1M HCl and brine. The organic layer was dried over MgSO4, filtered and evaporated. The resulting yellow solid was recrystallized from ethyl acetate/hexane to give 2.98 g of product in (74%) yield as pale yellow crystals: 1H NMR (400 MHz, CDCl3) δ5.34 (d, 1H, J=7.0 Hz), 5.73 (d, 1H, J=7.0 Hz), 7.11-7.14 (m, 4H), 7.23-7.26 (m, 6H), 7.43 (d, 1H, J=8.5 Hz), 7.67 (dd, 1H, J=2.0, 8.5 Hz), 7.93 (d, 1H, J=2.0 Hz).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH3:9])=[CH:7][N:6]=[C:5]([CH2:10][S:11][C:12]2[NH:16][C:15]3[CH:17]=[C:18]4[C:22](=[CH:23][C:14]=3[N:13]=2)[C:21]([CH3:25])([CH3:24])[C:20](=O)[C:19]4([CH3:28])[CH3:27])[C:4]=1[CH3:29].[CH3:30][O:31][NH3+:32].[Cl-]>CO>[CH3:30][O:31][N:32]=[C:20]1[C:21]([CH3:25])([CH3:24])[C:22]2[C:18](=[CH:17][C:15]3[N:16]=[C:12]([S:11][CH2:10][C:5]4[C:4]([CH3:29])=[C:3]([O:2][CH3:1])[C:8]([CH3:9])=[CH:7][N:6]=4)[NH:13][C:14]=3[CH:23]=2)[C:19]1([CH3:28])[CH3:27]
Reactant: CO[NH3+]
Reactant: COc1c(C)cnc(CSc2nc3cc4c(cc3[nH]2)C(C)(C)C(=O)C4(C)C)c1C
Agent: [Cl-]
Solvent: CO
Product: CON=C1C(C)(C)c2cc3nc(SCc4ncc(C)c(OC)c4C)[nH]c3cc2C1(C)C

Procedure:
5 g of 5,7-dihydro-2-[[(4-methoxy-3,5-dimethyl-2-pyridyl)methyl]thio]-5,5,7,7-tetramethyli ndeno[5,6-d]imidazol-6(lH)-one and 40 g of 0-methylhydroxylamine hydrochloride in 250 ml of methanol were boiled at reflux for 16 hours under argon. After removing the solvent in vacuo the residue was partitioned between methylene chloride and water and the aqueous phase was extracted three times with methylene chloride. The combined organic extracts were made neutral with saturated sodium bicarbonate solution in the presence of ice and under argon gasification. After repeated extraction with methylene chloride the organic phases were dried over sodium sulfate and evaporated in vacuo. A red impurity was removed by chromatography on silica gel with ethyl acetate. The separation of the reaction product from starting material was carried out on silica gel using toluene/methyl isobutyl ketone/pyridine (80:18:2) as the elution agent. The purity of the fractions was assayed by thin-layer chromatography using the system ethyl acetate/ methyl isobutyl ketone/pyridine (80:18:2). By crystallization from acetone/water there was obtained 5,7-dihydro-2-[[(4- methoxy-3,5-dimethyl -2-pyridyl)methyl]thio]-5,5,7,7-tetramethylindeno[5,6-d]imidazol-6(lH)-one O-methyl oxime of melting point 110-112° .