Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]([Mg]Cl)=[CH2:2].Br[C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16][CH3:17])[CH:14]=2)[N:9]=[CH:8][CH:7]=1>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:17][O:16][C:13]1[CH:14]=[C:15]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[C:6]2[CH:1]=[CH2:2]
Reactant: COc1ccc2nccc(Br)c2c1
Reactant: C=C[Mg]Cl
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: C1CCOC1
Product: C=Cc1ccnc2ccc(OC)cc12
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 21.6 %

Procedure:
InCl3 (1.1 g, 5 mmol) was dried under HV by heating with a heat gun. After cooling under N2 atmosphere, THF (25 mL) was added and the mixture sonicated until a solution had formed. This solution was cooled to −78° C., and a 1.7M solution of vinyl magnesium chloride (15 mmol) was added dropwise. The mixture was stirred at −78° C. for 15 min, warmed to rt and the resulting solution was added to a refluxing mixture of 4-bromo-6-methoxy-quinoline (1.85 g, 10 mmol) and Pd(dppf)Cl2.CH2Cl2 complex (0.408 g) in THF (25 mL). The mixture was refluxed for 2 h until tlc indicated complete conversion. The mixture was cooled to rt, quenched by addition of a few drops of MeOH and SiO2 (20 g) was added. The volatiles were removed under reduced pressure and the residue was chromatographed over SiO2 (Hex/EA 1:1) to give the desired compound (0.4 g, 21% yield) as a yellowish oil.
Reaction SMILES: [Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:22])([F:21])[F:20])[CH:10]=2)=[O:7])=[C:4]([OH:25])[CH:3]=1.[N:26]1([C:32](Cl)=[O:33])[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>>[Cl:1][C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[C:11]([C:19]([F:20])([F:21])[F:22])[CH:10]=2)=[O:7])=[C:4]([O:25][C:32]([N:26]2[CH2:31][CH2:30][O:29][CH2:28][CH2:27]2)=[O:33])[CH:3]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1O
Reactant: O=C(Cl)N1CCOCC1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ccc(Cl)cc1OC(=O)N1CCOCC1
Yield: 84.1 %

Procedure:
Using 4-chloro-2-hydroxy-N-[3,5-bis(trifluoromethyl)phenyl]benzamide and morpholine-4-carbonyl chloride as the raw materials, the same operation as the Example 71 gave the title compound.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[F:15][C:16]([F:30])([F:29])[C:17]1[CH:18]=[C:19]([CH:22]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:24]=1)[CH:20]=O.C(O)(=O)C.[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH2:53])[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36].C(=O)(O)[O-].[Na+]>ClC(Cl)C>[CH:35]([O:38][C:39]([N:41]1[C:50]2[C:45](=[N:46][C:47]([O:51][CH3:52])=[CH:48][CH:49]=2)[C@H:44]([NH:53][CH2:20][C:19]2[CH:18]=[C:17]([C:16]([F:30])([F:29])[F:15])[CH:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=2)[CH2:43][C@@H:42]1[CH3:54])=[O:40])([CH3:37])[CH3:36]
Reactant: COc1ccc2c(n1)[C@H](N)C[C@H](C)N2C(=O)OC(C)C
Reactant: O=Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: COc1ccc2c(n1)[C@H](NCc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C[C@H](C)N2C(=O)OC(C)C
Temperature: 25 °C
Reaction time: 14 h
Yield: 81.6 %

Procedure:
Add sodium triacetoxyborohydride (1.160 g, 5.50 mmol) to a mixture of 3,5-bis(trifluoromethyl)benzaldehyde (0.217 mL, 1.32 mmol), acetic acid (0.010 mL, 1.65 mmol), and (+/−)-cis-4-amino-6-methoxy-2-methyl-3,4-dihydro-2H-[1,5]naphthyridine-1-carboxylic acid isopropyl ester (0.318 mg, 1.12 mmol) in dichloroethane (10 mL). Stir thie mixture at room temperature under an atmosphere of nitrogen for 14 h. Add a saturated solution of sodium bicarbonate, separate the layers, and extract the aqueous layer with dichioromethane. Dry the combined organic layers over anhydrous sodium sulfate, filter, and remove the solvent under reduced pressure. Purify the residue by flash chromatography, eluting with hexanes/ethyl acetate (gradient eluent, 0-60% ethyl acetate in hexane), to afford the title compound (0.462 g, 83%). MS (ES+): 506 (M+H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[OH:9].Cl[C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[O:9][C:11]1[S:15][C:14]([C:16]([O:18][CH3:19])=[O:17])=[CH:13][C:12]=1[N+:20]([O-:22])=[O:21]
Reactant: COC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Reactant: Oc1c(Cl)cccc1Cl
Product: COC(=O)c1cc([N+](=O)[O-])c(Oc2c(Cl)cccc2Cl)s1

Procedure:
Prepared according to the procedure described for step A of example 18 from 2,6-dichloro-phenol (368 mg, 2.26 mmol) and methyl 5-chloro-4-nitro-thiophene-2-carboxylate (500 mg, 2.26 mmol). The title compound was obtained as a white solid (500 mg, 65% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.12 (1H, m), 7.80 (2H, m), 7.58 (1H, m), 3.80 (3H, s). MS m/z: 365.07, 367.00 [M+H]+.
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])=[CH:9][C:10](=[O:17])[N:11]2[CH2:14][CH:15]=O)=[CH:6][CH:5]=1.[O:20]1[C:25]2[CH:26]=[CH:27][C:28]([CH2:30][N:31]([CH:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:32](=[O:38])[O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[CH:29][C:24]=2[O:23][CH2:22][CH2:21]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)(Cl)Cl.O.C(O)(=O)C.ClCCl>[F:1][CH:2]([F:19])[O:3][C:4]1[CH:13]=[C:12]2[C:7]([C:8]([CH3:18])=[CH:9][C:10](=[O:17])[N:11]2[CH2:14][CH2:15][N:42]2[CH2:43][CH2:44][CH:39]([N:31]([CH2:30][C:28]3[CH:27]=[CH:26][C:25]4[O:20][CH2:21][CH2:22][O:23][C:24]=4[CH:29]=3)[C:32](=[O:38])[O:33][C:34]([CH3:36])([CH3:35])[CH3:37])[CH2:40][CH2:41]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Reactant: Cc1cc(=O)n(CC=O)c2cc(OC(F)F)ccc12
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: O
Product: Cc1cc(=O)n(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2cc(OC(F)F)ccc12
Reaction time: 0.08 h
Yield: 0.1 %

Procedure:
To 1.5 mL of dichloromethane solution containing 0.12 g of (7-(difluoromethoxy)-4-methyl-2-oxoquinolin-1(2H)-yl)acetaldehyde, 0.16 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate and 15 μL of acetic acid were added, and stirred for 5 min. To the reaction mixture, 0.14 g of sodium triacetoxyborohydride was added, and stirred for 40 min. Water, chloroform and aqueous saturated sodium hydrogen carbonate solution were added, the organic layer was separated, washed sequentially with water and aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [eluent; hexane:ethyl acetate=2:3], to give 0.19 mg of tert-butyl (1-(2-(7-(difluoromethoxy)-4-methyl-2-oxo-1,2-dihydroquinolin-1-yl)ethyl)piperidin-4-yl)(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)carbamate as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([CH:8]=[O:9])[CH:5]=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([CH2:14][C:15]([N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)=[O:16])#[C-:13]>CO>[Cl:1][C:2]1[CH:7]=[C:6]([C@@H:8]2[O:9][CH:13]=[N:12][C@H:14]2[C:15]([N:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)=[O:16])[CH:5]=[CH:4][N:3]=1
Reactant: O=Cc1ccnc(Cl)c1
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Product: O=C([C@@H]1N=CO[C@H]1c1ccnc(Cl)c1)N1CCCC1
Reaction time: 24 h
Yield: 66 %

Procedure:
SLA 07174 was prepared in accordance with method D using 2-chloropyridine-4-carbaldehyde SLA 07156 (0.12 g, 1.05 mmol), KOH (0.06 g, 1.05 mmol) in methanol (10 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.146 g, 1.05 mmol). The solution was stirred 24 h with continued cooling. After work-up trans-(5-(2-chloropyridin-4-yl)-4,5-dihydrooxazol-4-yl)(pyrrolidin-1-yl)methanone SLA 07174 was obtained as a yellow solid (0.19 g, 66% yield).
Reaction SMILES: [I-].ClC1C=CC=C[N+]=1C.CCN(C(C)C)C(C)C.[C:19]1([CH3:31])[CH:24]=[CH:23][C:22]([C:25]2[N:26]=[C:27]([NH2:30])[S:28][CH:29]=2)=[CH:21][CH:20]=1.[C:32]([O:36][C:37]([NH:39][C:40]1[S:41][C:42]([C:45](O)=[O:46])=[CH:43][N:44]=1)=[O:38])([CH3:35])([CH3:34])[CH3:33]>CN(C=O)C.CCOC(C)=O>[C:19]1([CH3:31])[CH:20]=[CH:21][C:22]([C:25]2[N:26]=[C:27]([NH:30][C:45]([C:42]3[S:41][C:40]([NH:39][C:37](=[O:38])[O:36][C:32]([CH3:34])([CH3:33])[CH3:35])=[N:44][CH:43]=3)=[O:46])[S:28][CH:29]=2)=[CH:23][CH:24]=1
Reactant: CC(C)(C)OC(=O)Nc1ncc(C(=O)O)s1
Reactant: Cc1ccc(-c2csc(N)n2)cc1
Agent: C[n+]1ccccc1Cl
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2csc(NC(=O)c3cnc(NC(=O)OC(C)(C)C)s3)n2)cc1
Temperature: 25 °C
Yield: 15.6 %

Procedure:
2-Chloro-1-methylpyridinium iodide (0.47 g, 1.84 mmol), DIEA (0.44 mL, 2.5 mmol) and 4-p-tolylthiazol-2-amine (0.24 g, 1.23 mmol) were added to a solution of 2-(tert-butoxycarbonylamino)thiazole-5-carboxylic acid (0.30 g, 1.23 mmol) in DMF (5 mL). The resulting solution was stirred at RT until completion of the reaction. Then the reaction mixture was diluted with AcOEt, washed with water, dried with Na2SO4 and concentrated. The crude product was purified by column (100% AcOEt), yielding tert-butyl 5-(4-p-tolylthiazol-2-ylcarbamoyl)thiazol-2-ylcarbamate (80 mg, 17%) as a solid.
Reaction SMILES: I[C:2]1[C:7]([O:8][CH3:9])=[CH:6][CH:5]=[CH:4][C:3]=1[O:10][CH3:11].[Li]CCCC.[C:17]([S:21]([N:23]=[CH:24][CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28])=[O:22])([CH3:20])([CH3:19])[CH3:18].[NH4+].[Cl-]>C1COCC1.O.CCOCC>[CH3:11][O:10][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]([O:8][CH3:9])[C:2]=1[CH:24]([NH:23][S:21]([C:17]([CH3:20])([CH3:19])[CH3:18])=[O:22])[CH2:25][CH2:26][C:27]([O:29][CH3:30])=[O:28]
Reactant: COc1cccc(OC)c1I
Reactant: COC(=O)CCC=NS(=O)C(C)(C)C
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: COC(=O)CCC(NS(=O)C(C)(C)C)c1c(OC)cccc1OC
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A cooled (−78° C.) yellow solution of 2-iodo-1,3-dimethoxybenzene (13.798 g; 52.25 mmol) in anh. THF (200 ml), under nitrogen, was treated dropwise with a solution of 1.6 M n-BuLi in hexanes (32.66 ml; 52.25 mmol). The resulting slightly yellow solution was further stirred at −78° C. for 15 min. A yellow solution of methyl 4-((tert-butylsulfinyl)imino)butanoate (7.640 g; 34.83 mmol) in anh. THF (50 ml) was then added dropwise to the cooled reaction mixture, and stirring at −78° C. was continued for 45 min. The resulting yellow reaction mixture was treated successively with aq. sat. NH4Cl (20 ml), Et2O (250 ml) and water (75 ml). The separated yellow organic layer was then washed with brine (75 ml), dried over anh. MgSO4, filtered, and concentrated to dryness under reduced pressure. Purification by FC (DCM/MeOH=30/1) afforded methyl 4-(2,6-dimethoxyphenyl)-4-(1,1-dimethylethylsulfinamido)butanoate as a yellow oil. LC-MS (conditions A): tR=0.73 min.; [M+H]+: 358.34 g/mol.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([C:7]([CH3:15])([CH3:14])[CH2:8][CH2:9][C:10]2=O)=[CH:5][C:4]=1[CH3:16].[CH3:17][CH2:18][Mg+].[Br-]>>[CH2:17]([C:10]1[C:11]2[C:6](=[CH:5][C:4]([CH3:16])=[C:3]([O:2][CH3:1])[CH:12]=2)[C:7]([CH3:15])([CH3:14])[CH2:8][CH:9]=1)[CH3:18]
Reactant: COc1cc2c(cc1C)C(C)(C)CCC2=O
Reactant: CC[Mg+]
Agent: [Br-]
Product: CCC1=CCC(C)(C)c2cc(C)c(OC)cc21
Yield: 62.3 %

Procedure:
Following General Procedure A, 7-methoxy-4,4,6-trimethyl-3,4-dihydro-2H-naphthalen-1-one (Compound 6, 0.5 g, 2.3 mmol) was reacted with a solution of 3 M EtMgBr (2.3 mL, 6.9 mmol), and the crude product was purified by flash chromatography (hexane:ethyl acetate=4:1) to give 0.33 g (63%) of the title compound as a clear oil. PNMR (300 MHz, CDCl3) δ 1.32 (t,3 H, J=6.3 Hz), 1.38 (s, 6 H), 2.32 (d, 2 H, J=4.5 Hz), 2.42 (s, 3 H), 2.65 (m, 2 H), 3.98 (s, 3 H), 5.88 (t, 1 H, J=2.5 Hz), 6.96 (s, 1 H), 7.28 (s, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][C:10]2=[O:13])=[CH:6][CH:5]=1)([O-:3])=[O:2].[BH4-].[Na+]>CO>[N+:1]([C:4]1[CH:12]=[C:11]2[C:7]([CH2:8][CH2:9][CH:10]2[OH:13])=[CH:6][CH:5]=1)([O-:3])=[O:2]
Reactant: O=C1CCc2ccc([N+](=O)[O-])cc21
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: O=[N+]([O-])c1ccc2c(c1)C(O)CC2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 6-nitro-1-indanone (18.9 g, 107 mmol) in methanol (300 mL) was cooled to 0° C. and sodium borohydride (4.04 g, 107 mmol) was added in several small portions. The reaction was then stirred overnight at 25° C. The solution was quenched at 0° C. with methanolic hydrochloric acid (200 mL), concentrated under reduced pressure, redissolved in dichloromethane, washed with water, and the organic layer reconcentrated to provide the crude alcohol as a brown solid which was used without further purification in Preparation 3.
Reaction SMILES: [CH3:1][C:2]([S@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[Si:8]([O:15][CH2:16][CH:17]=O)([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]>C(Cl)Cl.[O-]S([O-])(=O)=O.[Cu+2]>[Si:8]([O:15][CH2:16][CH:17]=[N:7][S@@:5]([C:2]([CH3:4])([CH3:3])[CH3:1])=[O:6])([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9]
Reactant: CC(C)(C)[Si](C)(C)OCC=O
Reactant: CC(C)(C)[S@](N)=O
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: ClCCl
Product: CC(C)(C)[S@@](=O)N=CCO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (R)-2-methylpropane-2-sulfinamide (2.5 g, 20.6 mmol) and {[tert-butyl(dimethyl)silyl]oxy}acetaldehyde (4.32 ml, 22.7 mmol) in CH2Cl2 (30 ml) was added CuSO4 (7.23 g, 45.32 mmol). The reaction mixture was stirred at room temperature for 2 days. The mixture was filtered through Centel), washed with CH2Cl2 and concentrated in vacuo. Column chromatography (0-30% EtOAc in hexanes) gave the desired product (R)—N-(2-{[tert-butyl(dimethyl)silyl]oxy}ethylidene)-2-methylpropane-2-sulfinamide (Tetrahedron Lett. 2001, 42, 2051-54). 1H NMR (300 MHz, CDCl3) δ 7.86-8.24 (m, 1H) 4.53 (d, J=3.01 Hz, 2H) 1.15-1.23 (m, 9H) 0.90 (s, 9H) 0.08 (s, 6H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)(O)[O-:23].[Na+].ClC1C=CC=C(C(OO)=O)C=1.[I-].[K+]>C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][S:14]2=[O:23])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)SCc1ccccc12
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [I-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1CCC2(CC1)c1ccccc1CS2=O
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
In 420 ml of chloroform, 42.0 g (0.14 mole) of the 1′-tert-butoxycarbonyl-spiro[benzo[c]thiophene-1(3H),4′-piperidine] obtained in Referential Example 1(a) were dissolved, followed by the addition of 12.7 g (0.15 mole) of sodium bicarbonate. To the resulting mixture, 28.0 g (85% content, 0.14 mole) of m-chloroperbenzoic acid were added in small portions under ice-cooling. After stirring of the mixture for 30 minutes under ice-cooling, 10 g of potassium iodide were added thereto and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was washed with water and a saturated aqueous solution of sodium chloride and dried over anhydrous sodium sulfate, and the solvent was removed by distillation under reduced pressure to obtain a residue. The residue was purified by chromatography on a silica gel column (eluting solvent; n-hexane: ethyl acetate=1:1), whereby 42 g of the title compound were obtained as white crystals.
Reaction SMILES: [CH2:1]([C:3]1[N:8]=[C:7]([C:9]([NH2:11])=[O:10])[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][O:22][CH2:21][CH2:20]3)=[CH:15][C:14]=2[CH3:25])=[N:5][C:4]=1[O:26][C:27]1[CH:32]=[CH:31][CH:30]=[C:29]([N+:33]([O-])=O)[CH:28]=1)[CH3:2].C(O)C>[Pd].O1CCCC1>[NH2:33][C:29]1[CH:28]=[C:27]([CH:32]=[CH:31][CH:30]=1)[O:26][C:4]1[N:5]=[C:6]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][O:22][CH2:23][CH2:24]3)=[CH:15][C:14]=2[CH3:25])[C:7]([C:9]([NH2:11])=[O:10])=[N:8][C:3]=1[CH2:1][CH3:2]
Reactant: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc([N+](=O)[O-])c1
Agent: [Pd]
Solvent: CCO
Solvent: C1CCOC1
Product: CCc1nc(C(N)=O)c(Nc2ccc(N3CCOCC3)cc2C)nc1Oc1cccc(N)c1
Reaction time: 5 h
Yield: 99.3 %

Procedure:
To a mixture of 6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}-5-(3-nitrophenoxy)pyrazine-2-carboxamide (145 mg), ethanol (2 mL), and tetrahydrofuran (6 mL) was added 10% palladium-supported carbon (50% wet product) (30 mg), followed by stirring for 5 hours under a hydrogen gas atmosphere (1 atm). The reaction mixture was filtered through celite and then the solvent was evaporated under reduced pressure to obtain 5-(3-aminophenoxy)-6-ethyl-3-{[2-methyl-4-(morpholin-4-yl)phenyl]amino}pyrazine-2-carboxamide (135 mg) as a solid.
Reaction SMILES: C1(C)C=CC(S(O)(=O)=[O:8])=CC=1.[CH3:12][S:13][CH:14]([S:28]([CH3:30])=O)[C:15](=O)[CH:16]=[CH:17][C:18]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20][CH:19]=1.C(=O)([O-])O.[Na+]>O1CCCC1.C1C=CC=CC=1>[CH3:12][S:13][C:14]1([S:28][CH3:30])[C:19]2[NH:20][C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[C:18]=2[CH2:17][C:16](=[O:8])[CH2:15]1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CSC(C(=O)C=Cc1c[nH]c2ccccc12)S(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Solvent: C1CCOC1
Product: CSC1(SC)CC(=O)Cc2c1[nH]c1ccccc21
Yield: 885.5 %

Procedure:
680 mg of p-toluenesulfonic acid was added to a mixture of 10.6 g of 3-(4-methylthio-4-methylsulfinyl-3-oxobutene-1-yl)indole, as obtained in Example 1(b), in 150 ml of tetrahydrofuran and 40 ml of benzene. The reaction mixture was next refluxed for 3 hours and then neutralized by the addition of a saturated aqueous solution of sodium hydrogencarbonate. The solvent was removed from the resulting mixture by evaporation under reduced pressure and ethyl acetate was added to the residue. The aqueous layer was then extracted with ethyl acetate, and the organic extract was washed with a saturated aqueous solution of sodium chloride, dried over anhydrous magnesium sulfate and concentrated by evaporation under reduced pressure. The resulting residue was subjected to column chromatography using 300 g of silica gel with a 9:1 v/v mixture of hexane and ethyl acetate as the eluent, to yield 9.7 g of the title compound as an amorphous solid.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@H:13]2[CH3:18])[N:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.CN([CH:32]=[O:33])C.Cl>C1COCC1>[Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([CH:32]=[O:33])[N:8]2[CH3:11])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][C@H:13]2[CH3:18])[N:3]=1
Reactant: C[C@@H]1COCCN1c1nc(Cl)nc2c1ncn2C
Reactant: CN(C)C=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: C[C@@H]1COCCN1c1nc(Cl)nc2c1nc(C=O)n2C
Temperature: 25 °C

Procedure:
To a solution of 2-chloro-9-methyl-6-((R)-3-methylmorpholin-4-yl)-9H-purine (550 mg, 2.05 mmol) in THF (20 mL) at −78° C. was added LiHMDS (3.1 mL, 3.08 mmol, 1M solution in THF). The resulting mixture was allowed to stir for 45 min before the addition of DMF (800 μL, 10.33 mmol). The reaction mixture was warmed to r.t. over 1.5 h then poured onto 0.5M HCl. The resulting precipitate was collected by filtration and washed with H2O then Et2O affording the title compound as a yellow solid (406 mg, 67%). LCMS (method H): RT 3.35 min [M+H]+ 296.3
Reaction SMILES: Br[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1.[CH2:9]([NH:11][CH2:12][CH3:13])[CH3:10]>CS(C)=O.CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-]>[CH2:9]([N:11]([CH2:12][CH3:13])[C:2]1[O:6][C:5]([CH:7]=[O:8])=[CH:4][CH:3]=1)[CH3:10]
Reactant: O=Cc1ccc(Br)o1
Reactant: CCNCC
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: [Cl-]
Solvent: CS(C)=O
Product: CCN(CC)c1ccc(C=O)o1
Yield: 85 %

Procedure:
5-Bromofuraldehyde was dissolved in dimethylsulfoxide (DMSO) and 1-2 drops of Aliquart 336 (tricaprylylmethylammonium chloride, produced by Aldrich Co.) was added to the solution. 10 Equivalents diethylamine was added to the mixture and refluxed for 4 days. The remaining diethylamine was removed from the reaction mixture and subjected to extraction and column chromatography to obtain 5-diethylamino-2-furaldehyde with a yield of 85%.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:11][C:12]([O:14]CC)=[O:13])[C:6]=2[CH:23]=1.[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([I:34])[C:26]=1[C:27](O)=[O:28]>>[F:24][C:25]1[CH:33]=[CH:32][CH:31]=[C:30]([I:34])[C:26]=1[C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:9]=[CH:8][N:7]([CH:10]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=3)[CH2:11][C:12]([OH:14])=[O:13])[C:6]=2[CH:23]=1)=[O:28]
Reactant: O=C(O)c1c(F)cccc1I
Reactant: CCOC(=O)CC(c1ccccc1)n1cnc2ccc(N)cc21
Product: O=C(O)CC(c1ccccc1)n1cnc2ccc(NC(=O)c3c(F)cccc3I)cc21

Procedure:
Using the procedure of Preparation 21, the title compound (48 mg) was prepared from ethyl 3-(6-amino-1H-benzimidazol-1-yl)-3-phenylpropanoate and 2-fluoro-6-iodobenzoic acid. [LCMS (Method A, Mobile Phase I) RT=4.33 min, MH+ 530].
Reaction SMILES: [CH3:1][C@@:2]1([OH:29])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=2[C:15]([OH:23])=[C:14]2[C@@H:3]1[CH2:4][C@@H:5]1[C@:11](O)([C:12]2=[O:13])[C:10]([OH:25])=[C:9]([C:26]([NH2:28])=[O:27])[C:7](=[O:8])[CH2:6]1>N.[Zn]>[CH3:1][C@@:2]1([OH:29])[C:17]2[CH:18]=[CH:19][CH:20]=[C:21]([OH:22])[C:16]=2[C:15]([OH:23])=[C:14]2[C@@H:3]1[CH2:4][C@@H:5]1[C@H:11]([C:12]2=[O:13])[C:10]([OH:25])=[C:9]([C:26]([NH2:28])=[O:27])[C:7](=[O:8])[CH2:6]1
Reactant: C[C@@]1(O)c2cccc(O)c2C(O)=C2C(=O)[C@]3(O)C(O)=C(C(N)=O)C(=O)C[C@@H]3C[C@@H]21
Agent: N
Agent: [Zn]
Product: C[C@@]1(O)c2cccc(O)c2C(O)=C2C(=O)[C@@H]3C(O)=C(C(N)=O)C(=O)C[C@@H]3C[C@@H]21
Yield: 18.2 %

Procedure:
A solution was prepared by dissolving 20.0 g (50 mmoles) of 4-dedimethylaminotetracycline in 500 ml of a 15% aqueous ammonia solution. To the resulting solution 40 g of zinc dust was added and the mixture was vigorously stirred. After being stirred for twenty two (22) hours, the reaction mixture was filtered to remove excess zinc dust. The filtrate was neutralized with concentrated hydrochloric acid under ice-cooling. The precipitated solid was collected by filtration, washed with water, dried, and then purified and isolated by column chromatography, to provide 3.5 g of 4-dedimethylamino-12a-deoxytetracycline (yield: 18%) as a mixture of 2 isomers. The mixture was separated by HPLC to give isomer-A and isomer-B. Their properties are shown below.
Reaction SMILES: [CH3:1][N:2]([CH3:20])[C:3]1[CH:19]=[CH:18][C:6]([C:7]([C:9]2[C:10]([C:15]([OH:17])=O)=[N:11][CH:12]=[CH:13][N:14]=2)=[O:8])=[CH:5][CH:4]=1.[CH3:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([NH:35][C:36]2[CH:41]=[CH:40][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:38][CH:37]=2)=[CH:31][CH:30]=1.C(OC(=O)C)(=O)C>>[CH3:20][N:2]([CH3:1])[C:3]1[CH:4]=[CH:5][C:6]([C:7]2([N:35]([C:36]3[CH:37]=[CH:38][C:39]([CH2:42][CH2:43][CH2:44][CH2:45][CH2:46][CH2:47][CH2:48][CH3:49])=[CH:40][CH:41]=3)[C:32]3[CH:31]=[CH:30][C:29]([CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH3:21])=[CH:34][CH:33]=3)[C:9]3=[N:14][CH:13]=[CH:12][N:11]=[C:10]3[C:15](=[O:17])[O:8]2)=[CH:18][CH:19]=1
Reactant: CCCCCCCCc1ccc(Nc2ccc(CCCCCCCC)cc2)cc1
Reactant: CN(C)c1ccc(C(=O)c2nccnc2C(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Product: CCCCCCCCc1ccc(N(c2ccc(CCCCCCCC)cc2)C2(c3ccc(N(C)C)cc3)OC(=O)c3nccnc32)cc1

Procedure:
A mixture containing 0.7 g. of 3-[4-(dimethylamino)benzoyl]-2-pyrazinecarboxylic acid, 1.0 g. of 4,4'-dioctyldiphenylamine and 7 ml. of acetic anhydride was stirred and gently heated in a warm bath for one hour. The product, 7-[4-(dimethylamino)phenyl]-7-[bis(4-octylphenyl)amino]furo[3,4-b]pyrazine-5(7H)-one was isolated by column chromatography as a rust-colored solid, m.p. 158°-168° C. A toluene solution of the product contacted with acidic clay or phenolic resin developed a reddish-brown image.