Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][C:3]1[N:13]([CH2:14][C:15]([CH3:18])([CH3:17])[CH3:16])[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=1.[NH:19]1[CH:23]=[N:22][N:21]=[N:20]1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH3:16][C:15]([CH3:18])([CH3:17])[CH2:14][N:13]1[C:6]2[N:7]=[C:8]([C:11]#[N:12])[N:9]=[CH:10][C:5]=2[CH:4]=[C:3]1[CH2:2][N:19]1[CH:23]=[N:22][N:21]=[N:20]1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Reactant: c1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(Cn2cnnn2)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 23 h
Yield: 45 %

Procedure:
6-Bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile (0.33 mmol) and 1H-tetrazole (0.65 mmol) are dissolved in DMF (3 ml). To the solution, K2CO3 (0.98 mmol) is added and the mixture is stirred at room temperature under nitrogen atmosphere for 23 h. The reaction mixture is diluted with water and extracted with AcOEt. The organic layer is washed with brine, dried over sodium sulfate, and concentrated. The crude product is purified by silica gel column chromatography to give A in 45% yield and B in 48% yield in the order of elution.
Reaction SMILES: [C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][C:14](=O)[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2].[CH2:17]([O:24][C:25]1[CH:30]=[CH:29][C:28]([CH:31]([O:34][CH2:35][CH2:36][OH:37])[CH2:32][NH2:33])=[CH:27][CH:26]=1)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:1]([CH2:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH:14]([NH:33][CH2:32][CH:31]([C:28]2[CH:29]=[CH:30][C:25]([O:24][CH2:17][C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:26][CH:27]=2)[O:34][CH2:35][CH2:36][OH:37])[CH3:15])=[CH:9][CH:8]=1)([O:3][CH3:4])=[O:2]
Reactant: NCC(OCCO)c1ccc(OCc2ccccc2)cc1
Reactant: COC(=O)COc1ccc(CC(C)=O)cc1
Product: COC(=O)COc1ccc(CC(C)NCC(OCCO)c2ccc(OCc3ccccc3)cc2)cc1

Procedure:
The title compound was prepared as an oil from 1-(4-carbomethoxymethoxyphenyl)propan-2-one (4.52 g) and 2-(4-benzyloxyphenyl)-2-(2-hydroxyethoxy)ethanamine (5.84 g) as described in Example 1.
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1)([O-])=O>CO.[OH-].[OH-].[Pd+2]>[NH2:1][C:4]1[CH:13]=[C:12]2[C:7]([CH2:8][CH2:9][N:10]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=[CH:6][CH:5]=1
Reactant: CC(C)(C)OC(=O)N1CCc2ccc([N+](=O)[O-])cc2C1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCc2ccc(N)cc2C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 67.1 %

Procedure:
Pd(OH)2 (330.0 mg) was added to a stirring solution of tert-butyl 3,4-dihydro-7-nitroisoquinoline-2(1H)-carboxylate (3.3 g, 12.0 mmol) in MeOH (56 mL) under N2 atmosphere. The reaction mixture was stirred under H2 (1 atm) at room temperature for 72 h. The solid was removed by filtration through Celite. The filtrate was concentrated and purified by column chromatography (15-35% EtOAc-Hexanes) to provide tert-butyl 7-amino-3,4-dihydroisoquinoline-2(1H)-carboxylate (DC-6) as a pink oil (2.0 g, 69%). 1H NMR (400 MHz, DMSO-d6) δ 6.79 (d, J=8.1 Hz, 1H), 6.40 (dd, J=8.1, 2.3 Hz, 1H), 6.31 (s, 1H), 4.88 (s, 2H), 4.33 (s, 2H), 3.48 (t, J=5.9 Hz, 2H), 2.58 (t, J=5.9 Hz, 2H), 1.42 (s, 9H); HPLC ret. time 2.13 min, 10-99% CH3CN, 5 min run; ESI-MS 249.0 m/z (MH+).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:16])([CH3:15])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:30](=[O:31])[CH2:29][CH2:28][C:27]4=[O:32])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].I[CH2:35][CH3:36]>>[CH2:35]([O:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:15])([CH3:16])[C:13](=[O:17])[N:12]([CH:18]3[CH2:23][CH2:22][N:21]([C:24](=[O:33])[CH2:25][N:26]4[C:27](=[O:32])[CH2:28][CH2:29][C:30]4=[O:31])[CH2:20][CH2:19]3)[N:11]=2)[CH:5]=[CH:6][C:7]=1[O:8][CH3:9])[CH3:36]
Reactant: COc1ccc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)cc1O
Reactant: CCI
Product: CCOc1cc(C2=NN(C3CCN(C(=O)CN4C(=O)CCC4=O)CC3)C(=O)C2(C)C)ccc1OC

Procedure:
Prepared analogously as described for example 5 using 1-(2-{4-[3-(3-hydroxy-4-methoxyphenyl)-4,4-dimethyl-5-oxo-4,5-dihydro-1H-pyrazol-1-yl]piperidin-1-yl}-2-oxoethyl)pyrrolidine-2,5-dione (compound A4) and iodoethane as starting compounds.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:26](=[O:27])[C:25]5[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=5)[C:19]4=[O:28])[N:17]=[C:13]3[NH:12][C:11]([CH3:29])=[C:10]2[C:30]#[N:31])=[C:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:4]=1)#[N:2].[F:36][C:37]([F:48])([F:47])[C:38]1[CH:39]=[C:40](B(O)O)[CH:41]=[CH:42][CH:43]=1.C(N(CC)CC)C.N1C(C)=CC=CC=1C>C([O-])(=O)C.[Cu+2].C([O-])(=O)C.[Cu].N1C=CC=CC=1.ClCCl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[N:14]3[N:15]=[C:16]([N:18]4[C:19](=[O:28])[C:20]5[C:25](=[CH:24][CH:23]=[CH:22][CH:21]=5)[C:26]4=[O:27])[N:17]=[C:13]3[N:12]([C:42]3[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:48])([F:47])[F:36])[CH:43]=3)[C:11]([CH3:29])=[C:10]2[C:30]#[N:31])=[C:5]([S:32]([CH3:35])(=[O:34])=[O:33])[CH:4]=1)#[N:2]
Reactant: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1
Reactant: OB(O)c1cccc(C(F)(F)F)c1
Agent: [Cu+2]
Agent: [Cu]
Agent: CC(=O)[O-]
Solvent: c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC1=C(C#N)C(c2ccc(C#N)cc2S(C)(=O)=O)n2nc(N3C(=O)c4ccccc4C3=O)nc2N1c1cccc(C(F)(F)F)c1
Reaction time: 12 h

Procedure:
Under an atmosphere of argon protective gas, (rac)-7-[4-cyano-2-(methylsulfonyl)phenyl]-2-(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)-5-methyl-4,7-dihydro[1,2,4]triazolo[1,5-a]pyrimidine-6-carbonitrile (600 mg, 1.2 mmol) was stirred in abs. dichloromethane (50 ml) with molecular sieve (0.5 g, 4 Å) for 15 min 3-(Trifluoromethyl)phenylboronic acid (704 mg, 3.7 mmol, 3 eq.) was added together with anhydrous copper(II) acetate (673 mg, 3.7 mmol, 3 eq.). Abs. pyridine (60 ml) and triethylamine (571 μl, 3.7 mmol, 3 eq.) were then added, and the mixture was stirred for 12 h. 2,6-Lutidine (864 μl, 7.4 mmol, 6 eq.) was then added, and the reaction mixture initially stirred under an atmosphere of dry air for 12 h and then left under an atmosphere of argon for 3 d. More 3-(trifluoromethyl)phenylboronic acid (235 mg, 1.2 mmol, 1 eq.), anhydrous copper(II) acetate (225 mg, 1.2 mmol, 1 eq.), 2,6-lutidine (432 μl, 3.7 mmol, 3 eq.) and a catalytic amount (spatula tip) of activated copper were then added, and the mixture was stirred under an atmosphere of dry air for 5 d. The reaction mixture was then concentrated to dryness, and the residue was applied to silica gel using dichloromethane (˜50 ml) to silica gel and purified by flash chromatography (silica gel; mobile phase: cyclohexane/ethyl acetate 1:2). The product was obtained as a solid (102 mg, 13.1% of theory).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH2:13][CH2:12][CH2:11][CH:10]([N:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)[CH2:9]2)=[N:6][CH:7]=1.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[CH:33])=[N:30][CH:31]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([C:26]2[CH:27]=[CH:28][C:29]([C:32]#[C:33][C:2]3[CH:3]=[CH:4][C:5]([N:8]4[CH2:13][CH2:12][CH2:11][CH:10]([N:14]5[CH2:18][CH2:17][CH2:16][CH2:15]5)[CH2:9]4)=[N:6][CH:7]=3)=[N:30][CH:31]=2)=[CH:24][CH:25]=1
Reactant: Ic1ccc(N2CCCC(N3CCCC3)C2)nc1
Reactant: C#Cc1ccc(-c2ccc(Cl)cc2)cn1
Product: Clc1ccc(-c2ccc(C#Cc3ccc(N4CCCC(N5CCCC5)C4)nc3)nc2)cc1

Procedure:
Prepared according to general working method I from 5′-iodo-3-pyrrolidin-1-yl-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl (179 mg, 0.50 mmol) and 5-(4-chloro-phenyl)-2-ethynyl-pyridine (107 mg, 0.50 mmol).
Reaction SMILES: [C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)([OH:3])=O.C(N(CC)CC)C.S(Cl)(Cl)=O.[CH3:30][NH:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1>C(Cl)(Cl)Cl>[CH3:30][N:31]([CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)[C:1]([CH2:4][CH2:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[NH:14][C:13](=[O:18])[CH:12]=[CH:11]2)=[O:3]
Reactant: CNC1CCCCC1
Reactant: O=C(O)CCCOc1ccc2[nH]c(=O)ccc2c1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CN(C(=O)CCCOc1ccc2[nH]c(=O)ccc2c1)C1CCCCC1
Reaction time: 1 h

Procedure:
2.5 Grams of 6-(3-carboxypropoxy)carbostyril is suspended in 200 ml of chloroform, followed by addition of 1.5 ml of triethylamine, and then 1.2 g of thionyl chloride is added dropwise to the solution under agitation while maintaining the internal temperature at 0° to 20° C. After this addition, the mixture is agitated at the same temperature for 1 hour and then added dropwise with 2 ml of N-methylcyclohexylamine, followed by additional 3-hour agitation at room temperature. The reaction solution is washed well with a 5% aqueous K2CO3 solution, then further washed with water and diluted hydrochloric acid and then dried with anhydrous Na2SO4. After removing the solvent by distillation, the residue is refined by silica gel column chromatography (silica gel: Wakogel C-200; eluent: 10:1 chloroform/methanol (V/V)) and then recrystallized from chloroform-ethanol to obtain 0.4 g of 6-[3-(N-methyl-N-cyclohexylaminocarbonyl)propoxy]-carbostyril with melting point of 184.5°-186° C.
Reaction SMILES: [CH3:1][C:2]([S@@:5]([NH2:7])=[O:6])([CH3:4])[CH3:3].[CH:8]([C:10]1[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:11]=1)=O.O>C(Cl)Cl.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4]>[C:2]([S@@:5](/[N:7]=[CH:8]/[C:10]1[S:14][C:13]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])=[CH:12][CH:11]=1)=[O:6])([CH3:4])([CH3:3])[CH3:1]
Reactant: CC(C)(C)OC(=O)c1ccc(C=O)s1
Reactant: CC(C)(C)[S@@](N)=O
Agent: [Ti+4]
Agent: CC(C)[O-]
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1ccc(/C=N/[S@@](=O)C(C)(C)C)s1
Temperature: 0 °C
Reaction time: 16 h
Yield: 86.9 %

Procedure:
To a 500-mL round-bottom flask was added (S)-(−)-2-methyl-2-propanesulfinamide (1.62 g, 13.4 mmol), and tert-butyl 5-formylthiophene-2-carboxylate (2.37 g, 11.2 mmol), and DCM (100 mL). The mixture was cooled to 0° C., then titanium tetraisopropoxide (19.8 mL, 67.0 mmol) was added. After the solution was warmed to rt and stirred for 16 h, the reaction mixture was diluted with DCM (200 mL). To the flask was added water (19.8 mL) slowly. The mixture was vigorously stirred at rt for 30 min, then filtered through a pad of Celite. The filtrate was concentrated to give a solid. Purification via flash chromatography (hexanes to 10% EtOAc-hexanes) afforded (S,E)-tert-butyl 5-((tert-butylsulfinylimino)methyl)thiophene-2-carboxylate (3.07 g, 87%) as a white solid. 1H NMR (CDCl3, 400 MHz) δ 8.65 (s, 1H), 7.72 (d, J=4.0 Hz, 1H), 7.65 (d, J=3.8 Hz, 1H), 1.58 (s, 9H), 1.24 (s, 9H).
Reaction SMILES: C[N:2]1[CH2:11][CH2:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]3[C:14](=[O:15])[C:13](=[O:16])[NH:12][C:8]3=2)[CH2:3]1.ClC(OC(Cl)=O)C>ClCCCl>[NH:12]1[C:8]2=[C:9]3[C:4](=[CH:5][CH:6]=[C:7]2[C:14](=[O:15])[C:13]1=[O:16])[CH2:3][NH:2][CH2:11][CH2:10]3
Reactant: CN1CCc2c(ccc3c2NC(=O)C3=O)C1
Agent: CC(Cl)OC(=O)Cl
Solvent: ClCCCl
Product: O=C1Nc2c(ccc3c2CCNC3)C1=O
Temperature: 25 °C

Procedure:
To an ice cooled stirred suspension of 6,7,8,9-tetrahydro-7-methyl-1H-pyrrolo[2,3-f]isoquinoline-2,3-dione (500 mg) in 1,2-dichloroethane (10 ml) was added α-chloroethylchloroformate (0.25 ml). The mixture was then brought to reflux for 1 hour, whereafter it was cooled to room temperature and filtered. The filtrate was evaporated, the residue dissolved in methanol (10 ml) and refluxed for 10 min. Evaporation of the solvent left the crude title compound as a solid, M.p. 270° C.
Reaction SMILES: O=C1C2C(=CC=CC=2)N=C(C(OCC)=O)N1.[O:17]=[C:18]1[NH:23][C:22]([C:24]([O:26]CC)=O)=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[C:19]1=2.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)N2C=NC(CCCOC3C=C(CN)C=CN=3)=N2)C=CC=CC=1.C1(C(C2C=CC=CC=2)(C2C=CC=CC=2)[N:80]2[CH:84]=[N:83][C:82]([O:85][CH2:86][CH2:87][O:88][C:89]3[CH:90]=[C:91]([CH2:95][NH2:96])[CH:92]=[CH:93][CH:94]=3)=[N:81]2)C=CC=CC=1>>[O:17]=[C:18]1[NH:23][C:22]([C:24]([NH:96][CH2:95][C:91]2[CH:92]=[CH:93][CH:94]=[C:89]([O:88][CH2:87][CH2:86][O:85][C:82]3[N:83]=[CH:84][NH:80][N:81]=3)[CH:90]=2)=[O:26])=[N:21][C:20]2[S:29][CH:30]=[C:31]([C:32]3[CH:36]=[CH:35][S:34][CH:33]=3)[C:19]1=2
Reactant: NCc1cccc(OCCOc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Reactant: CCOC(=O)c1nc2scc(-c3ccsc3)c2c(=O)[nH]1
Agent: CCOC(=O)c1nc2ccccc2c(=O)[nH]1
Agent: NCc1ccnc(OCCCc2ncn(C(c3ccccc3)(c3ccccc3)c3ccccc3)n2)c1
Product: O=C(NCc1cccc(OCCOc2nc[nH]n2)c1)c1nc2scc(-c3ccsc3)c2c(=O)[nH]1

Procedure:
By a method similar to that in Example 22, and using, instead of ethyl 4-oxo-3,4-dihydro-2-quinazolinecarboxylate, ethyl 4-oxo-5-(3-thienyl)-3,4-dihydrothieno[2,3-d]pyrimidine-2-carboxylate obtained in Reference Example 65 and using, instead of 1-[2-({3-[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]propyl}oxy)pyridin-4-yl]methaneamine, 1-{3-[(2-{[1-(triphenylmethyl)-1H-1,2,4-triazol-3-yl]oxy}ethyl)oxy]phenyl}methanamine obtained in Reference Example 32, the title compound was obtained as a white powder (48.0 mg, 34%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]([C:14](=O)[CH3:15])[C:11](=[O:13])[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9].Cl.[NH2:18]O>C(O)C.CCOCC>[Br:1][C:2]1[CH:3]=[C:4]([C:10]2[C:14]([CH3:15])=[N:18][O:13][C:11]=2[CH3:12])[CH:5]=[CH:6][C:7]=1[O:8][CH3:9]
Reactant: NO
Reactant: COc1ccc(C(C(C)=O)C(C)=O)cc1Br
Agent: Cl
Solvent: CCO
Solvent: CCOCC
Product: COc1ccc(-c2c(C)noc2C)cc1Br
Temperature: 25 °C
Yield: 70.9 %

Procedure:
A mixture of 3-(3-bromo-4-methoxyphenyl)pentane-2,4-dione (40 mg, 0.14 mmol) and hydroxylamine hydrochloride (30 mg, 0.43 mmol) in 95% ethanol (0.50 mL) was refluxed for 4 h. After cooling to RT, the mixture was taken up in 30 mL of ether and washed with 10 mL of saturated sodium bicarbonate solution followed by 10 mL of brine. Drying over sodium sulfate and concentration afforded 40 mg of crude product which was purified by flash column chromatography, eluting with 50% dichloromethane in hexane, to yield 28 mg of the title compound as a white solid. Mass spectrum (NH3/CI): m/z=282 (M+1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1.[CH3:13][NH:14][C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1>>[CH3:13][N:14]([C:15]1[CH:23]=[CH:22][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=1)[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[C:4]([CH3:12])[N:3]=1
Reactant: Cc1nc(Cl)c2ccccc2n1
Reactant: CNc1ccc(C(=O)O)cc1
Product: Cc1nc(N(C)c2ccc(C(=O)O)cc2)c2ccccc2n1

Procedure:
The title compound was prepared from 4-chloro-2-methylquinazoline and 4-(methylamino)benzoic acid by a procedure described for Example 1b. 1H NMR (CDCl3): 8.42-8.39 (m, 1H), 8.28 (m, 2H), 7.84 (m, 1H), 7.45 (m, 2H), 7.37 (m, 1H), 7.22 (m, 1H), 6.84 (d, J=1H, 8.4), 3.91 (s, 3H), 3.01 (s, 3H).
Reaction SMILES: COC1C=CC(C[S:10][C:11]2[N:12]([CH2:31][CH:32]=[CH2:33])[CH:13]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=3)[C:14]([C:18]([O:20][CH3:21])=[O:19])=[C:15]([CH3:17])[N:16]=2)=CC=1.FC(F)(F)C(O)=O.C(S)C>ClCCl>[CH3:17][C:15]1[NH:16][C:11](=[S:10])[N:12]([CH2:31][CH:32]=[CH2:33])[CH:13]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:14]=1[C:18]([O:20][CH3:21])=[O:19]
Reactant: C=CCN1C(SCc2ccc(OC)cc2)=NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Solvent: CCS
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: C=CCN1C(=S)NC(C)=C(C(=O)OC)C1c1cccc([N+](=O)[O-])c1
Reaction time: 2 h

Procedure:
1,6-Dihydro-2-[[(4-methoxyphenyl)methyl]thio]-4-methyl-6-(3-nitrophenyl)-1-(2-propenyl)-5-pyrimidinecarboxylic acid, methyl ester (1.0 g, 2.14 mmol) in 15 ml of dichloromethane under argon at room temperature was treated with trifluoroacetic acid (0.6 ml, 0.85 g, 7.7 mmole) and ethanethiol (0.4 ml, 0.33 g, 5.4 mmole). No change (tlc) occurred within 2 hours. Heating at reflux temperature, however, effected complete reaction in several hours.
Reaction SMILES: C([N:8]1[CH:13]=[CH:12][C:11](=[O:14])[C:10]2[C:15]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:16]([Si:18]([CH2:23][CH3:24])([CH2:21][CH3:22])[CH2:19][CH3:20])[O:17][C:9]1=2)C1C=CC=CC=1>C(OCC)(=O)C.CO.[OH-].[OH-].[Pd+2]>[C:25]1([C:15]2[C:10]3[C:11](=[O:14])[CH:12]=[CH:13][NH:8][C:9]=3[O:17][C:16]=2[Si:18]([CH2:21][CH3:22])([CH2:23][CH3:24])[CH2:19][CH3:20])[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC[Si](CC)(CC)c1oc2c(c1-c1ccccc1)c(=O)ccn2Cc1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CC[Si](CC)(CC)c1oc2[nH]ccc(=O)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A mixture of 7-benzyl-3-phenyl-2-(triethylsilanyl)-7H-furo[2,3-b]pyridin-4-one (1) and Pd(OH)2 (0.11 g 20% on C, 0.11 mmol) in ethyl acetate (10 mL) and methanol (10 mL) was degassed and stirred under hydrogen at room temperature for 2.5 hr. The catalyst was filtered off and the solvent was removed to give the title compound. MS (m/z), M+H+ 326.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH:19]=[CH:20][CH2:21][C@@H:22]([OH:27])[C:23]([F:26])([F:25])[F:24])=[CH:18][C:13]=3[O:12][CH:11]=2)[CH2:5]1>C(O)C.[Pd]>[CH3:1][O:2][CH2:3][C@@H:4]1[O:8][C:7](=[O:9])[N:6]([C:10]2[C:14]3[CH:15]=[CH:16][C:17]([CH2:19][CH2:20][CH2:21][C@@H:22]([OH:27])[C:23]([F:24])([F:25])[F:26])=[CH:18][C:13]=3[O:12][CH:11]=2)[CH2:5]1
Reactant: COC[C@H]1CN(c2coc3cc(C=CC[C@@H](O)C(F)(F)F)ccc23)C(=O)O1
Agent: [Pd]
Solvent: CCO
Product: COC[C@H]1CN(c2coc3cc(CCC[C@@H](O)C(F)(F)F)ccc23)C(=O)O1
Reaction time: 18 h

Procedure:
0.05 g of palladium-on-charcoal is added to a solution in 8.5 ml of ethanol of 0.26 g (0.67 mmol) of (R,R)-5-(methoxymethyl)-3-[6-(5,5,5-trifluoro-4-hydroxypent-1-enyl)benzofuran-3-yl]oxazolidin-2-one obtained in Example 8. The mixture is placed under a hydrogen atmosphere for 18 hours, the palladium-on-charcoal is removed by filtration and the filtrate is concentrated under reduced pressure. The product is then purifiedtran by chromatography on silica gel with a 60/40 mixture of cyclohexane and ethyl acetate. 0.14 g of product is recovered after crystallization from diisopropyl ether.
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]4[CH2:31][CH2:30][C:25]5(OCC[O:26]5)[CH2:24][CH2:23]4)=[N:19][C:18]=3[CH3:32])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Cl.C([O-])(O)=O.[Na+]>>[CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([C:13]([C:17]3[S:21][C:20]([N:22]4[CH2:31][CH2:30][C:25](=[O:26])[CH2:24][CH2:23]4)=[N:19][C:18]=3[CH3:32])=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCC5(CC4)OCCO5)nc3C)c(C)nc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Product: CCC(CC)c1cc(C)nn2c(-c3sc(N4CCC(=O)CC4)nc3C)c(C)nc12
Yield: 53.8 %

Procedure:
70 mg of 8-{5-[8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazin-3-yl]-4-methyl-thiazol-2-yl}-1,4-dioxa-8-aza-spiro[4.5]decane (0.15 mmol) is dissolved in 10. ml of conc. HCl and stirred at room temperature for 2 h. The reaction mixture is neutralized with sat. NaHCO3, extracted with CH2Cl2, dried over Na2SO4 and evaporated. The crude product is applied onto a silica-gel chromatography column (Hexane:AcOEt=2:1) to give 33.2 mg of the title compound. Yield 52%. mass spectrum (m/e): 412 (M+1) 1H NMR (CDCl3): δ 6.70 (s, 1H), 3.94 (t, J=6.2 Hz, 4H), 3.35 (m, 1H), 2.67 (t, J=6.5 Hz, 4H), 2.57 (s, 3H), 2.47 (s, 3H), 2.21 (s, 3H), 1.86 (m, 4H), 0.91 (t, J=7.1 Hz, 6H).
Reaction SMILES: [C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:12][CH2:11][C:10]([C:15]([F:18])([F:17])[F:16])([CH:13]=O)[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2].[CH3:21][C:22]([S:25]([NH2:27])=[O:26])([CH3:24])[CH3:23].C([O-])(O)=O.[Na+]>[O-]CC.[Ti+4].[O-]CC.[O-]CC.[O-]CC.C1COCC1>[C:1]([Si:5]([CH3:20])([CH3:19])[O:6][CH:7]1[CH2:12][CH2:11][C:10]([CH:13]=[N:27][S:25]([C:22]([CH3:24])([CH3:23])[CH3:21])=[O:26])([C:15]([F:18])([F:17])[F:16])[CH2:9][CH2:8]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(C=O)(C(F)(F)F)CC1
Reactant: CC(C)(C)S(N)=O
Agent: [Ti+4]
Agent: CC[O-]
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: CC(C)(C)S(=O)N=CC1(C(F)(F)F)CCC(O[Si](C)(C)C(C)(C)C)CC1
Yield: 91.5 %

Procedure:
3.20 g (10.3 mmol) of 4-(tert-Butyl-dimethyl-silanyloxy)-1-trifluoromethyl-cyclohexanecarbaldehyde (71) were dissolved using 25 ml of anhydrous THF. 1.31 g (10.8 mmol) of 2-methyl-2-propanesulfinamide and 4.32 ml (20.6 mmol) of titanium (IV) ethoxide were added and the mixture heated for 4 h at reflux. The reaction mixture was poured into 75 ml of a saturated aqueous solution of NaHCO3 and the precipitate removed by filtration. The filtrate was extracted three times using 50 ml of ethyl acetate each. The organic layer was dried using MgSO4 and evaporated to yield 3.90 g of 72. Rt=1.02 min (Method Q).
Reaction SMILES: [CH2:1]([OH:4])[CH2:2][OH:3].[H-].[Na+].Br[CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=1.O>C1COCC1.CCOC(C)=O>[F:15][C:11]1[CH:10]=[C:9]([CH2:8][O:3][CH2:2][CH2:1][OH:4])[CH:14]=[CH:13][CH:12]=1
Reactant: OCCO
Reactant: Fc1cccc(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: OCCOCc1cccc(F)c1
Temperature: 60 °C
Yield: 25 %

Procedure:
Ethylene glycol (0.1 mL, 1.79 mmol) was added to NaH (46 mg, 1.81 mmol, 95% in oil) in THF (5 mL). 1-(Bromomethyl)-3-fluorobenzene (0.22 mL, 1.79 mmol) was added to the reaction, and the reaction was heated at 60° C. for 5 days. H2O (2 mL) and EtOAc (2 mL) were added, and the layers were separated via pipette. The aqueous layer was extracted with EtOAc (3×1 mL), and the combined organic layers were washed with saturated NaCl (1×2 mL), dried (Na2SO4), and concentrated. The crude product was purified on a SPE cartridge (5 g silica) eluting with the following 10 mL fractions: 30% EtOAc/hexanes (fractions 1,2), 50% EtOAc/hexanes (fraction 3), and 75% EtOAc/hexanes (fraction 4) to give the title compound (76.2 mg, 25%). The product was characterized by 1H NMR (400 MHz) in CDCl3.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]2[CH:15]=[CH:14][C:13]3[N:12]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:11][CH:10]([CH2:22][Cl:23])[C:9]=3[C:8]=2[CH:24]=1)(=[O:3])[CH3:2].OS(O)(=O)=O.[N+:30]([O-])([O-:32])=[O:31].[K+]>>[C:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:15]([N+:30]([O-:32])=[O:31])=[CH:14][C:13]3[N:12]([C:16](=[O:21])[C:17]([F:19])([F:18])[F:20])[CH2:11][CH:10]([CH2:22][Cl:23])[C:9]=3[C:8]=2[CH:24]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)c1ccc2ccc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Reactant: O=[N+]([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Product: CC(=O)c1ccc2c([N+](=O)[O-])cc3c(c2c1)C(CCl)CN3C(=O)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 39 %

Procedure:
Solid 174 (57 mg, 0.16 mmol) was dissolved in cone. H2SO4 (5 mL) at 0° C., then treated dropwise with a cold (0° C.) solution of KNO3 (16 mg, 0.16 mmol) in cone. H2SO4 (0.5 mL). After 15 min, the mixture was poured into ice water and extracted with CH2Cl2 (×6). The combined organic extracts were washed with water (×2), brine and dried. Chromatography eluting with petroleum ether/EtOAc (7:3) gave 8-acetyl-1-(chloromethyl)-5-nitro-3-(trifluoroacetyl)-1,2-dihydro-3H-benzo[e]indole (175) (25 mg, 39%) as an orange powder: mp (petroleum ether/EtOAc) 196-198° C.; 1H NMR (CDCl3) δ 9.23 (s, 1H), 8.58 (d, J=9.1 Hz, 1H, 8.49 (d, J=1.3 Hz, 1H), 8.17 (dd, J=9.1, 1.6 Hz, 1H), 4.73 (d, J=11.5 Hz, 1H), 4.56 (dd, J=11.4, 8.8 Hz, 1H), 4.47-4.39 (m, 1H), 3.98 (dd, J=11.6, 3.6 Hz, 1H), 3.77 (dd, J=11.6, 7.8 Hz, 1H), 2.78 (s, 3H). Anal. (C17H12ClF3N2O4) C, H, N.