Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[H-].[Na+].CS(O[CH2:36][CH2:37][O:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][N:45]1[CH2:49][C@@H:48]([C:50]2[CH:61]=[CH:60][C:53]3[O:54][C:55]([CH3:59])([CH3:58])[O:56][CH2:57][C:52]=3[CH:51]=2)[O:47][C:46]1=[O:62])(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:58][C:55]1([CH3:59])[O:54][C:53]2[CH:60]=[CH:61][C:50]([C@H:48]3[O:47][C:46](=[O:62])[N:45]([CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][O:38][CH2:37][CH2:36][O:1][CH2:2][C:3]4[CH:4]=[C:5]([S:9]([N:12]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:19])([CH3:20])[CH3:18])(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=4)[CH2:49]3)=[CH:51][C:52]=2[CH2:57][O:56]1
Reactant: C[Si](C)(C)CCOCN(COCC[Si](C)(C)C)S(=O)(=O)c1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOS(C)(=O)=O)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCCCCCOCCOCc4cccc(S(=O)(=O)N(COCC[Si](C)(C)C)COCC[Si](C)(C)C)c4)C(=O)O3)ccc2O1
Reaction time: 0.5 h
Yield: 63.8 %

Procedure:
A solution of 3-(hydroxymethyl)-N,N-bis{[2-(trimethylsilyl)ethoxy]methyl}benzenesulfonamide (512 mg) in DMF (4 ml) under nitrogen was treated with sodium hydride (1.295 g, 60% in oil) and the mixture was stirred at 20° for 30 min. A solution of 2-({6-[(5R)-5-(2,2-dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]hexyl}oxy)ethyl methanesulfonate (359 mg) in DMF (1 ml) was added and the mixture was stirred at 20° for 18 h. Phosphate buffer solution (25 ml, pH6.5) was added and the mixture was extracted with EtOAc. The extract was washed with water, dried (Na2SO4) and the solvent evaporated in vacuo to give a residue. The residue was purified by chromatography on flash silica gel (30 mm diameter column). Elution with EtOAc-cyclohexane (2:3) then (1:1) gave the title compound (400 mg). LCMS RT=4.43 min.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].[CH2:10](Br)[CH:11]=[CH2:12]>CC(C)=O>[CH2:12]([O:9][C:6]1[CH:7]=[CH:8][C:3]([C:1]#[N:2])=[CH:4][CH:5]=1)[CH:11]=[CH2:10]
Reactant: N#Cc1ccc(O)cc1
Reactant: C=CCBr
Solvent: CC(C)=O
Product: C=CCOc1ccc(C#N)cc1

Procedure:
A solution of 4-cyanophenol (50 g), allyl bromide (27.2 ml) potassium carbonate (47.8 g) in acetone (100 ml) was heated at reflux for 16 hours. The reaction mixture was evaporated, water was added to the residue and the aqueous mixture was extracted with diethyl ether. The diethyl ether extract was washed with dilute aqueous sodium hydroxide solution, dried (MgSO4) and evaporated to give 4-cyanophenyl allyl ether as a solid, m.p. 41.6° C.; microanalysis, found: C 75.1; H, 5.8; N, 8.7%; C10H9NO2 requires: C, 75.5; H, 5.7; N, 8.8%; NMR: 4.55-4.65(2H,m), 5.2-5.4(2H,m), 5.9-6.05(1H,m), 7.0-7.1(2H,m) and 7.65-7.75(2H,m).
Reaction SMILES: [F:1][C:2]([F:22])([CH2:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][C:10]=1[C:18]([F:21])([F:20])[F:19])[C:3]([O:5][CH2:6][CH3:7])=[O:4].CC(=O)OCC>CO.[Pd]>[NH2:15][C:12]1[CH:13]=[CH:14][C:9]([CH2:8][C:2]([F:1])([F:22])[C:3]([O:5][CH2:6][CH3:7])=[O:4])=[C:10]([C:18]([F:19])([F:20])[F:21])[CH:11]=1
Reactant: CCOC(=O)C(F)(F)Cc1ccc([N+](=O)[O-])cc1C(F)(F)F
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CCOC(=O)C(F)(F)Cc1ccc(N)cc1C(F)(F)F
Reaction time: 1 h
Yield: 85.3 %

Procedure:
To a mixture of ethyl 2,2-difluoro-3-(4-nitro-2-(trifluoromethyl)phenyl)propanoate (220 mg, 0.672 mmol) in MeOH (10 mL) was added Pd/C (71.6 mg, 0.672 mmol) under N2. The mixture was then stirred under a H2 atmosphere for 1 h. LCMS and TLC (PE/EA=5:1, Rf=0.3) showed the reaction was finished. The mixture was filtered and the filtrate was concentrated to give ethyl 3-(4-amino-2-(trifluoromethyl)phenyl)-2,2-difluoropropanoate (190 mg, 0.573 mmol, 85% yield): NMR (400 MHz, CD3OD-d4) δ 7.15 (s, 1H), 6.97 (d, J=2.2 Hz, 1H), 6.81 (dd, J=2.1, 8.4 Hz, 1H), 4.24 (q, J=7.1 Hz, 2H), 3.42 (t, J=16.8 Hz, 2H), 1.24 (t, J=7.1 Hz, 3H). ES-LCMS m/z 298 (M+H).
Reaction SMILES: [C:1]([C:3]([CH2:13][CH3:14])([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4](Br)=[O:5])#[N:2].[CH2:15]([NH2:18])[CH2:16][CH3:17].N1C=CC=CC=1>C1C=CC=CC=1>[CH2:15]([NH:18][C:4](=[O:5])[C:3]([C:1]#[N:2])([CH2:13][CH3:14])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[CH2:16][CH3:17]
Reactant: CCC(C#N)(C(=O)Br)c1ccccc1
Reactant: CCCN
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CCCNC(=O)C(C#N)(CC)c1ccccc1
Yield: 78.6 %

Procedure:
11 g of 2-cyano-2-ethyl-2-phenylacetyl bromide are added dropwise under cooling, at 20° to 30° C., to a solution of 3 g of n-propylamine and 4 g of pyridine in 20 ml of dry benzene. The reaction mixture is refluxed for 30 minutes and then processed as described in Example 3. 7.9 g (68.3%) of N-(n-propyl)-2-cyano-2-ethyl-2-phenylacetic acid amide are obtained; m.p.: 55°-56° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[CH2:7][N:8]([C@H:19]1[CH2:23][CH2:22][N:21]([CH2:24][C:25]2[CH:29]=[C:28]([C:30]#[N:31])[S:27][CH:26]=2)[C:20]1=[O:32])[S:9]([C:12]1[S:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=1)(=[O:11])=[O:10])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:30]([C:28]1[S:27][CH:26]=[C:25]([CH2:24][N:21]2[CH2:22][CH2:23][C@H:19]([N:8]([S:9]([C:12]3[S:13][C:14]([Cl:18])=[C:15]([Cl:17])[CH:16]=3)(=[O:10])=[O:11])[CH2:7][C:6]([OH:33])=[O:5])[C:20]2=[O:32])[CH:29]=1)#[N:31]
Reactant: CC(C)(C)OC(=O)CN([C@H]1CCN(Cc2csc(C#N)c2)C1=O)S(=O)(=O)c1cc(Cl)c(Cl)s1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#Cc1cc(CN2CC[C@H](N(CC(=O)O)S(=O)(=O)c3cc(Cl)c(Cl)s3)C2=O)cs1
Reaction time: 2 h

Procedure:
To a solution of 2-[[1-(5-cyanothiophene-3-ylmethyl)-2-oxopyrrolidin-3-(S)-yl]-(4,5-dichlorothiophene-2-sulfonyl)amino]acetic acid tert-butyl ester (0.40 g, 0.72 mmol) in 15 mL of CH2Cl2 is added 5 mL of TFA. After 2 hours, the solution is concentrated to give the title compound as a white foam.
Reaction SMILES: [C:1](#[N:4])[CH:2]=[CH2:3].[NH:5]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=1)[NH2:6]>>[N:9]1[CH:10]=[CH:11][CH:12]=[C:7]([N:5]2[CH2:3][CH2:2][C:1]([NH2:4])=[N:6]2)[CH:8]=1
Reactant: C=CC#N
Reactant: NNc1cccnc1
Product: NC1=NN(c2cccnc2)CC1

Procedure:
In a typical reaction, 3-hydrazinopyridine•dihydrochloride and an anhydrous alcohol are introduced into a reaction vessel and the alkoxide base is gradually added. The mixture is stirred and the acrylonitrile is added. The mixture is stirred at about 60° C. until most of the 3-hydrazinopyridine has reacted. The mixture is allowed to cool and the excess base is neutralized with acid. The crude 1-(pyridin-3-yl)-4,5-dihydro-1H-pyrazol-3-amine (9a) is conveniently isolated and purified by standard techniques.
Reaction SMILES: [F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]3)=[N:7][O:8][C:4]=2[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[C:23]([NH:26][C:27]1[CH:28]=[C:29]([CH:35]=[CH:36][CH:37]=1)[O:30][CH2:31][CH2:32][CH2:33]Br)(=[O:25])[CH3:24].[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42]>C(#N)C.C(O)C>[C:38]([OH:45])(=[O:44])/[CH:39]=[CH:40]/[C:41]([OH:43])=[O:42].[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1.[F:1][C:2]1[CH:16]=[CH:15][C:5]2[C:6]([CH:9]3[CH2:10][CH2:11][N:12]([CH2:33][CH2:32][CH2:31][O:30][C:29]4[CH:28]=[C:27]([NH:26][C:23](=[O:25])[CH3:24])[CH:37]=[CH:36][CH:35]=4)[CH2:13][CH2:14]3)=[N:7][O:8][C:4]=2[CH:3]=1
Reactant: CC(=O)Nc1cccc(OCCCBr)c1
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C(O)/C=C/C(=O)O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: CCO
Product: CC(=O)Nc1cccc(OCCCN2CCC(c3noc4cc(F)ccc34)CC2)c1

Procedure:
A stirred mixture of 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (9.25 g, 42 mmol), K2CO3 (8 g, 58 mmol) and 3-(3-acetamidophenoxy)propyl bromide (11.4 g, 42 mmol) in acetonitrile (350 ml) was heated at reflux for 3 hours. At the end of the reaction, the reaction was cooled, filtered and the solids washed with dichloromethane (100 ml). The organic solvent was removed on a rotary evaporator to leave a crude oil (18 g). Purification was by flash chromatography on a silica gel column. The product thus purified was an oil, 12.2 g, 70%. Analytically pure sample was prepared by dissolving 3 g of free base in ethanol and treating with fumaric acid solution in ethanol (850 mg:5 ml). The N-[3-[3-[4-(6-fluoro-1,2-benzisoxazol-3-yl)-1-piperidinyl]propoxy]phenyl]acetamide hemifumarate crystals obtained weighed 2.73 g, m.p.=184°-186° C.
Reaction SMILES: O[C@H]([C@H]([C:10](=[O:26])[CH:11]([C:13]1[CH:22]=[CH:21][C:20]2[C:15](=[CH:16][CH:17]=[C:18]([O:24][CH3:25])[C:19]=2[Br:23])[CH:14]=1)[CH3:12])C(O)=O)C(O)=O.Cl.[O:28]1CCOCC1>>[Br:23][C:19]1[C:18]([O:24][CH3:25])=[CH:17][CH:16]=[C:15]2[C:20]=1[CH:21]=[CH:22][C:13]([C@H:11]([CH3:12])[C:10]([OH:26])=[O:28])=[CH:14]2
Reactant: COc1ccc2cc(C(C)C(=O)[C@H](C(=O)O)[C@@H](O)C(=O)O)ccc2c1Br
Reactant: C1COCCO1
Agent: Cl
Product: COc1ccc2cc([C@H](C)C(=O)O)ccc2c1Br
Temperature: 90 °C
Reaction time: 2 h

Procedure:
A mixture of pure 2(R)-hydroxy-3(R)-[2-(5-bromo-6-methoxy-2-naphthyl)propanoyl]-butanedioic acid (0.441 g, 1 mmol), 1,4-dioxane (8 ml), and of conc. HCl (8 ml) was heated, under stirring, at 90° C. for 2 hours. The reaction mixture was worked up as described in example 52, to give pure 2(S)-(5-bromo-6-methoxy-2-naphthyl)-propionic acid in 98% enantiomeric excess, determined by HPLC and by 1H-NMR carried out as described in example 57.
Reaction SMILES: [CH2:1]([CH:8]([C:11]#[N:12])[C:9]#[N:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:16][CH2:17][C:18]([F:22])=[C:19]([F:21])[F:20]>CN(C)C=O>[CH2:1]([C:8]([CH2:16][CH2:17][C:18]([F:22])=[C:19]([F:21])[F:20])([C:9]#[N:10])[C:11]#[N:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: FC(F)=C(F)CCBr
Reactant: N#CC(C#N)Cc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: N#CC(C#N)(CCC(F)=C(F)F)Cc1ccccc1
Yield: 75.1 %

Procedure:
Using 0.1 g of benzylmalononitrile, 5 ml of N,N-dimethylformamide, 0.010 g of sodium hydride (60% in oil), and 0.04 g of 4-bromo-1,1,2-trifluoro-1-butene, and according to the process described in the Production Example 1, there was obtained 0.042 g of 2-benzyl-2-(3,4,4-trifluoro-3-butenyl)malononitrile (the present compound (4)).
Reaction SMILES: CS(C)=O.[CH3:5][NH:6][C@H:7]1[CH2:11][CH2:10][NH:9][CH2:8]1.[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17](F)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13].C(N(CC)CC)C>[Cl-].[Na+].O>[C:12]([C:14]1[C:19]2[N:20]=[C:21]([C:23]([N:25]([CH3:27])[CH3:26])=[O:24])[O:22][C:18]=2[C:17]([N:9]2[CH2:10][CH2:11][C@H:7]([NH:6][CH3:5])[CH2:8]2)=[C:16]([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:15]=1[CH3:35])#[N:13]
Reactant: Cc1c(-c2ccccc2)c(F)c2oc(C(=O)N(C)C)nc2c1C#N
Reactant: CN[C@H]1CCNC1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CN[C@H]1CCN(c2c(-c3ccccc3)c(C)c(C#N)c3nc(C(=O)N(C)C)oc23)C1
Reaction time: 4 h

Procedure:
Under nitrogen atmosphere, a dimethyl sulfoxide (3 ml) solution (3S)-3-methylaminopyrrolidine (139 μl, 1.40 mmol) was added at 150° C. to a dimethyl sulfoxide (18 ml) solution of 4-cyano-7-fluoro-N,N,5-trimethyl-6-phenyl-1,3-benzoxazole-2-carboxamide (I-114) (350 mg, 1.08 mmol) and triethylamine (201 μl, 1.30 mmol), followed by stirring at the same temperature for 4 hours. After cooling, saturated brine was added to the reaction liquid, and the reaction liquid was extracted with ethyl acetate. Next, the combined organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, filtered, and the filtrate was concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography, and the eluate with chloroform/methanol (4:1, v/v) gave a crude product of the entitled compound as a solid, and the solid was suspended and washed in diisopropyl ether to obtain the entitled compound (147 mg, 34%) as a pale yellow solid.
Reaction SMILES: [C@@H:1]1([N:9]2[CH:16]=[CH:15][C:13]([NH2:14])=[N:12][C:10]2=[O:11])[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.Cl[CH2:18][CH:19]=O>CS(C)=O>[CH2:2]1[C@H:1]([N:9]2[C:10](=[O:11])[N:12]3[C:13](=[N:14][CH:18]=[CH:19]3)[CH:15]=[CH:16]2)[O:8][C@H:5]([CH2:6][OH:7])[C@H:3]1[OH:4]
Reactant: O=CCCl
Reactant: Nc1ccn([C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)n1
Solvent: CS(C)=O
Product: O=c1n([C@H]2C[C@H](O)[C@@H](CO)O2)ccc2nccn12
Temperature: 70 °C
Reaction time: 1 h

Procedure:
3,N4 -Ethenodeoxycytidine is synthesized according to the published procedure of Eberle et al. (Carcinogenesis 10:2751-2756, 1989). To 2'-deoxycytidine (8 mg, available from Sigma Chemical Company) in 0.4 mL of DMSO is added 0.04 mL of a 45% aqueous solution of chloroacetaldehyde and the reaction mixture is stirred for 1 hour at 70° C. The reaction mixture is then evaporated to dryness and the resulting residue purified by reverse-phase HPLC on a Nucleosil C18 column (Altech) to yield 3,N4 -ethenodeoxycytidine.
Reaction SMILES: [CH3:1][N:2]([CH3:12])[C:3]1[CH:8]=[CH:7][C:6](B(O)O)=[CH:5][N:4]=1.N1C2C(=CC=CC=2)C=C(B(O)O)C=1.Br[C:27]1[CH:35]=[CH:34][CH:33]=[C:32]2[C:28]=1[C:29]1([C:55]3[C:46](=[CH:47][C:48]4[O:53][CH2:52][CH2:51][O:50][C:49]=4[CH:54]=3)[O:45][CH2:44]1)[C:30](=[O:43])[N:31]2[CH2:36][C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=1.BrC1C=CC=C2C=1C1(C3C(=CC4OCCOC=4C=3)OC1)C(=O)N2C(C1C=CC=CC=1)C1C=CC=CC=1>>[CH3:1][N:2]([CH3:12])[C:3]1[N:4]=[CH:5][C:6]([C:27]2[CH:35]=[CH:34][CH:33]=[C:32]3[C:28]=2[C:29]2([C:55]4=[CH:54][C:49]5[O:50][CH2:51][CH2:52][O:53][C:48]=5[CH:47]=[C:46]4[O:45][CH2:44]2)[C:30](=[O:43])[N:31]3[CH2:36][C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][N:38]=2)=[CH:7][CH:8]=1
Reactant: CN(C)c1ccc(B(O)O)cn1
Reactant: O=C1N(Cc2ccccn2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: O=C1N(C(c2ccccc2)c2ccccc2)c2cccc(Br)c2C12COc1cc3c(cc12)OCCO3
Agent: OB(O)c1cnc2ccccc2c1
Product: CN(C)c1ccc(-c2cccc3c2C2(COc4cc5c(cc42)OCCO5)C(=O)N3Cc2ccccn2)cn1

Procedure:
Following the procedure as described in EXAMPLE 2.46 and making non-critical variations using 2-(dimethylamino)pyridine-5-boronic acid to replace quinolin-3-ylboronic acid, and 4′-bromo-1′-(pyridin-2-ylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one to replace 4′-bromo-1′-(diphenylmethyl)-2,3-dihydrospiro[furo[2,3-g][1,4]benzodioxine-8,3′-indol]-2′(1′H)-one, 4′-(6-(dimethylamino)pyridin-3-yl)-1′-(pyridin-2-ylmethyl)-3,7-dihydro-2H-spiro[benzofuro[5,6-b][1,4]dioxine-8,3′-indolin]-2′-one was obtained (44%) as a colorless solid: mp 187-188° C. (methanol/dichloromethane); 1H NMR (300 MHz, CDCl3) δ 8.61-8.56 (m, 1H), 7.80-7.77 (m, 1H), 7.70-7.62 (m, 1H), 7.32-7.17 (m, 3H), 6.91-6.81 (m, 2H), 6.66 (dd, J=8.8, 2.5 Hz, 1H), 6.40 (s, 1H), 6.27 (s, 1H), 6.21 (d, J=8.8 Hz, 1H), 5.25 (d, J=15.8 Hz, 1H), 4.93 (d, J=15.8 Hz, 1H), 4.71 (d, J=9.0 Hz, 1H), 4.46 (d, J=9.0 Hz, 1H), 4.30-4.08 (m, 4H), 3.05 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 178.2, 158.5, 155.6, 155.4, 149.5, 147.4, 144.7, 142.7, 138.0, 137.6, 137.2, 137.1, 129.5, 128.8, 125.9, 122.8, 122.7, 122.0, 121.7, 111.2, 108.6, 104.3, 99.4, 64.6, 64.0, 58.4, 46.2, 38.1; MS (ES+) m/z 507.0 (M+1).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1.Cl[CH2:15][C:16]1[CH:17]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:19]=[CH:20][CH:21]=1.Cl(O)(=O)(=O)=O>>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=2)=[CH:9][CH:8]=1
Reactant: Oc1ccc(Cc2ncc[nH]2)cc1
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [O-][Cl+3]([O-])([O-])O
Product: FC(F)(F)c1cccc(COc2ccc(Cc3ncc[nH]3)cc2)c1

Procedure:
This substance is prepared in analogy to Example 2 from 4-(1-imidazolylmethyl)-phenol and 3-chloromethylbenzotrifluoride with the use of perchloric acid.
Reaction SMILES: [NH:1]([C:3]1[CH:8]=[N:7][CH:6]=[CH:5][N:4]=1)N.[Cl:9][C:10]1[CH:15]=[C:14]([C:16](=O)[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:13]=[CH:12][N:11]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Cl:9][C:10]1[CH:15]=[C:14]([C:16]2[NH:1][C:3]3=[N:4][CH:5]=[CH:6][N:7]=[C:8]3[C:17]=2[C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:13]=[CH:12][N:11]=1
Reactant: O=C(Cc1ccc(F)cc1)c1ccnc(Cl)c1
Reactant: NNc1cnccn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: Fc1ccc(-c2c(-c3ccnc(Cl)c3)[nH]c3nccnc23)cc1
Reaction time: 2 h
Yield: 26.5 %

Procedure:
Hydrazinopyrazine (6.2 g, 57 mmol) and 1-(2-chloropyridin-4-yl)-2-(4-fluorophenyl)ethanone (14 g, 57 mmol) were suspended in benzene (250 ml) and p-toluenesulfonic acid monohydrate (0.68 g) was added. The reaction mixture was then refluxed with azeotropic removal of water via Dean Stark trap. After 2 h, the benzene was removed in vacuo and di-ethylene glycol was added. The reaction mixture was heated at reflux. After 2 h, the reaction mixture was poured into ether with vigorous stirring. Water was added and the product was extracted into ether. The organic layer was dried over magnesium sulfate, filtered and concentrated in vacuo. Methanol was added and the solid was filtered off to give 6-(2-chloropyridin-4-yl)-7-(4-fluorophenyl)-5H-pyrrolo[2,3-b]pyrazine (4.9 g) as a solid.
Reaction SMILES: N1C=CC=CC=1.[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[CH2:23][CH2:22][CH2:21][NH:20][N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:8].Cl.[CH3:25][C:26]1[N:27]=[C:28]([C:34]2[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=2)[S:29][C:30]=1[C:31](Cl)=[O:32]>C(Cl)Cl>[CH2:7]([O:9][C:10]1[CH:11]=[C:12]([C:18]2[CH2:23][CH2:22][CH2:21][N:20]([C:31]([C:30]3[S:29][C:28]([C:34]4[CH:35]=[N:36][CH:37]=[CH:38][CH:39]=4)=[N:27][C:26]=3[CH3:25])=[O:32])[N:19]=2)[CH:13]=[CH:14][C:15]=1[O:16][CH3:17])[CH3:8]
Reactant: Cc1nc(-c2cccnc2)sc1C(=O)Cl
Reactant: CCOc1cc(C2=NNCCC2)ccc1OC
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOc1cc(C2=NN(C(=O)c3sc(-c4cccnc4)nc3C)CCC2)ccc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.3 %

Procedure:
1 ml of pyridine is added to a solution of 1.1 g of 3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazine in 20 ml of DCM, and 1.2 g of 4-methyl-2-pyridin-3-ylthiazole-5-carbonyl chloride, hydrochloride (“BA”) are subsequently added, and the mixture is stirred at room temperature for a further 16 hours. Conventional work-up gives 1.7 g of 1-[3-(3-ethoxy-4-methoxyphenyl)-5,6-dihydro-4H-pyridazin-1-yl]-1-(4-methyl-2-pyridin-3-ylthiazol-5-yl)methanone.
Reaction SMILES: [C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[CH:13]=[CH:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Li]CCCC.CN([CH:35]=[O:36])C.[NH4+].[Cl-]>C1COCC1>[C:1]1([CH2:7][O:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[N:14]([S:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)(=[O:20])=[O:19])[C:13]([CH:35]=[O:36])=[CH:12]3)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CN(C)C=O
Reactant: O=S(=O)(c1ccccc1)n1ccc2cc(OCc3ccccc3)ccc21
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: C1CCOC1
Product: O=Cc1cc2cc(OCc3ccccc3)ccc2n1S(=O)(=O)c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 76.9 %

Procedure:
To a solution of 5-[(phenylmethyl)oxy]-1-(phenylsulfonyl)-1H-indole (1.5 g, 4.12 mmol) in THF (20 mL), under N2, at −78° C., was added n-BuLi (2.5M solution in hexane, 2.15 mL, 5.37 mmol) dropwise. After stirring at −78° C. for 30 min, anhydrous DMF (0.54 g, 7.42 mmol) was added. After 5 min, the −78° C. bath was replaced with an ice bath. After 45 min, sat'd NH4Cl solution (20 mL) was added and the mixture was partitioned between Et2O and water. The organic phase was washed with water and sat'd brine, dried (Na2SO4) and concentrated in vacuo. The residue was purified by flash chromatography (20-70% CH2Cl2-hexanes gradient) to afford the title compound (1.24 g, 77% yield): 1H NMR (400 MHz, CDCl3) δ 10.5 (s, 1H), 8.14 (d, J=9.3 Hz, 1H), 7.74 (d, J=7.6 Hz, 2H), 7.53 (t, J=7.6 Hz, 1H), 7.43-7.31 (m, 8H), 7.22 (dd, J=9.3, 2.4 Hz, 1H), 7.06 (d, J=2.4 Hz, 1H), 5.06 (s, 2H); MS (ES) m/z 392 (M+1).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])/[CH:4]=[C:5]1\[C:6](=[CH2:27])[C@@H:7]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:22])[CH3:21])[CH2:8][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10]\1>CCCCCC>[CH3:1][O:2][C:3](=[O:28])/[CH:4]=[C:5]1/[C:6](=[CH2:27])[C@@H:7]([O:19][Si:20]([C:23]([CH3:26])([CH3:25])[CH3:24])([CH3:21])[CH3:22])[CH2:8][C@H:9]([O:11][Si:12]([C:15]([CH3:18])([CH3:17])[CH3:16])([CH3:14])[CH3:13])[CH2:10]/1
Reactant: C=C1/C(=C\C(=O)OC)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Solvent: CCCCCC
Product: C=C1/C(=C/C(=O)OC)C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@@H]1O[Si](C)(C)C(C)(C)C
Yield: 95.5 %

Procedure:
A solution of 4.45 g (0.01043 mole) of Z-(3S,5R)-[3,5-bis-(tert-butyl-dimethyl-silanyloxy)-2-methylene-cyclohexylidene]-acetic acid methyl ester (X) (A. Mourino, et al., Tetrahedron Letters, 38, pgs. 4713-4716 (1997)) in 100 ml hexane was irradiated with a UV-lamp for 3 hours. Evaporation gave 4.25 g (95.5%) of the title compound as colorless oil. NMR (CDCl3): δ0.06 (s, 3H), 0.07 (s, 9H), 0.85 (s, 9H), 0.89 (s, 9H), 1.76 (m, 1H), 1.84 (m, 1H), 2.70 (m, 1H), 3.36 (m, 1H), 3.70 (s, 3H), 4.26 (m, 1H), 4.58 (m, 1H), 5.07 (m, 2H), 5.91 (brs, 1H).
Reaction SMILES: C(O[C:6]([N:8](C)[NH:9][C:10](=[O:12])[CH3:11])=O)(C)(C)C.[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17]>C(Cl)Cl>[F:14][C:15]([F:20])([F:19])[C:16]([OH:18])=[O:17].[CH3:6][NH:8][NH:9][C:10](=[O:12])[CH3:11]
Reactant: CC(=O)NN(C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CNNC(C)=O
Reaction time: 1 h

Procedure:
To a solution of N'-acetyl-N-methylhydrazinecarboxylic acid tert-butyl ester (0.3 g, 1.59 mmol) in methylene chloride (2 ml) was added trifluoroacetic acid (2 ml) and the mixture was stirred for 60 min. The mixture was concentrated in vacuo and stripped three times with methylene chloride to give 0.32 g (100%) of acetic acid N'-methylhydrazide trifluoroacetic acid as a thin oil.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[S:8]([C:11]1[CH:12]=[CH:13][C:14]([OH:21])=[C:15]([CH:20]=1)[C:16]([O:18][CH3:19])=[O:17])(=[O:10])=[O:9]>ClCCl>[OH:21][C:14]1[CH:13]=[CH:12][C:11]([S:8]([N:1]2[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)(=[O:10])=[O:9])=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]
Reactant: COC(=O)c1cc(S(=O)(=O)Cl)ccc1O
Reactant: C1CCNCC1
Solvent: ClCCl
Product: COC(=O)c1cc(S(=O)(=O)N2CCCCC2)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Piperidine (849 mg, 9.97 mmol) was added dropwise to methyl 5-(chlorosulfonyl)-2-hydroxybenzoate (may be prepared as described in Description 60; 500 mg, 2.00 mmol) in dichloromethane (20 ml) at 25° C., and the mixture was allowed to stir at 25° C. for 2 h. The mixture was then concentrated in vacuo to yield the title compound as a crude product. 430 mg.