Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][C:3]=1[C:11]#[C:12][C:13]1[CH:14]=[N:15][C:16]2[C:21]([CH:22]=1)=[CH:20][CH:19]=[CH:18][CH:17]=2.Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[Cl:45][C:46]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:47]=1[C:48]([NH:50][NH2:51])=[O:49]>CN(C)C=O>[Cl:45][C:46]1[CH:55]=[C:54]([Cl:56])[CH:53]=[C:52]([Cl:57])[C:47]=1[C:48]([N:50]([C:6](=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([CH3:1])=[C:3]([C:11]#[C:12][C:13]2[CH:14]=[N:15][C:16]3[C:21]([CH:22]=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH:4]=1)[NH2:51])=[O:49]
Reactant: NNC(=O)c1c(Cl)cc(Cl)cc1Cl
Reactant: Cc1ccc(C(=O)O)cc1C#Cc1cnc2ccccc2c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Product: Cc1ccc(C(=O)N(N)C(=O)c2c(Cl)cc(Cl)cc2Cl)cc1C#Cc1cnc2ccccc2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A mixture of 4-methyl-3-[(quinolin-3-yl)ethynyl]benzoic acid (0.15 g, 0.5 mmol), N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.15 g, 0.7 mmol) and 1-hydroxybenzotriazole (0.1 g, 0.7 mmol) in N,N-dimethylformamide (15 ml) was stirred at ambient temperature for 1 hr. 2,4,6-Trichlorobenzohydrazide (0.125 g, 0.5 mmol) was added and the mixture stirred for 12 hrs at ambient temperature. Concentration and trituration of the residue with water produced a solid which was filtered, washed with water and the crude product was purified by flash chromatography on silica gel (elution with 10% methanol in dichloromethane) to get 2,4,6-trichloro-N-[4-methyl-3-[2-(3-quinolyl)ethynyl]benzoyl]benzohydrazide as a white solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]2[C:8]3[C:9]([NH:17]CC4C=CC(OC)=CC=4)=[N:10][CH:11]=[C:12]([C:15]#[N:16])[C:13]=3[S:14][C:4]=2[CH:3]=1.[CH3:27][N:28](C=O)C>[C-]#N.[C-]#N.[Zn+2].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>[NH2:17][C:9]1[C:8]2[C:5]3[CH:6]=[CH:7][C:2]([C:27]#[N:28])=[CH:3][C:4]=3[S:14][C:13]=2[C:12]([C:15]#[N:16])=[CH:11][N:10]=1
Reactant: COc1ccc(CNc2ncc(C#N)c3sc4cc(Br)ccc4c23)cc1
Reactant: CN(C)C=O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [C-]#N
Agent: [Zn+2]
Product: N#Cc1ccc2c(c1)sc1c(C#N)cnc(N)c12
Reaction time: 0.08 h

Procedure:
To a microwave reaction vessel was added 7-bromo-1-[(4-methoxybenzyl)amino][1]benzothieno[3,2-c]pyridine-4-carbonitrile (Example 12, Step 9), Zn(CN)2 (1.3 equiv), Pd(Ph3P)4 (0.1 equiv), and DMF (0.06 M). After sealing, the tube was degassed via a needle through the septum, and the reaction was set up on the Smith Creator microwave machine for 5 min at 150° C. The mixture was then added to H2O and the resulting solid was collected by filtration and dried under vacuum. The crude was then stirred with 1:10 EtOAc:hexanes containing a trace of acetone, to give after filtration, a pale brown solid which was used as such for the next step.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([S:8][CH2:9][C:10]([NH2:12])=[O:11])[C:5]([C:13]#[N:14])=[C:4]([C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[C:3]=1[C:20]#[N:21].[N:22]1([CH2:27][CH2:28][CH2:29]N)[CH2:26][CH2:25][CH2:24][CH2:23]1>>[NH2:14][C:13]1[C:5]2[C:6](=[N:7][C:2]([NH:1][CH2:29][CH2:28][CH2:27][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[C:3]([C:20]#[N:21])[C:4]=2[C:15]2[O:16][CH:17]=[CH:18][CH:19]=2)[S:8][C:9]=1[C:10]([NH2:12])=[O:11]
Reactant: N#Cc1c(N)nc(SCC(N)=O)c(C#N)c1-c1ccco1
Reactant: NCCCN1CCCC1
Product: N#Cc1c(NCCCN2CCCC2)nc2sc(C(N)=O)c(N)c2c1-c1ccco1

Procedure:
If steps 1.1 and 1.2 according to Example 1 are carried out analogously with furan-2-carbaldehyde as “E1”, 2-(6-amino-4-furan-2-yl-3,5-dicyanopyridin-2-ylsulfanyl)acetamide (“2a”) is obtained. “2a” is subsequently reacted analogously to steps 2.1 to 2.3 according to Example 2, using 3-pyrrolidin-1-ylpropylamine as “E2” in step 2.2. 3-Amino-5-cyano-4-furan-2-yl-6-(3-pyrrolidin-1-ylpropylamino)thieno[2,3-b]pyridine-2-carboxamide “A51” is obtained.
Reaction SMILES: OO.NC(N)=[O:5].FC(F)(F)C(OC(=O)C(F)(F)F)=O.[Br:20][C:21]1[C:22]([CH3:29])=[N:23][C:24]([Cl:28])=[CH:25][C:26]=1[CH3:27].CSC>C(Cl)Cl.O>[Br:20][C:21]1[C:22]([CH3:29])=[N+:23]([O-:5])[C:24]([Cl:28])=[CH:25][C:26]=1[CH3:27]
Reactant: NC(N)=O
Reactant: Cc1cc(Cl)nc(C)c1Br
Agent: OO
Solvent: ClCCl
Solvent: O
Solvent: CSC
Product: Cc1cc(Cl)[n+]([O-])c(C)c1Br
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A suspension of urea hydrogen peroxide (33.9 g, 360 mmol) in CH2Cl2 (1.985 L) was cooled to 0° C. Trifluoracetic anhydride (25.4 mL, 180 mmol) was added and the reaction was warmed to r.t. and stirred for 10 minutes. Next, 3-bromo-6-chloro-2,4-dimethylpyridine (39.7 g, 180 mmol) was added as a solution in CH2Cl2 (198 mL). The reaction was stirred for 2.5 hours at room temperature and then dimethyl sulfide (170 mL, 2305 mmol) was added and stirring was continued for an additional 30 minutes. Next, water (2 L) was added, and the mixture was stirred for 10 minutes. The layers were separated and the aqueous layer was extracted with CH2Cl2 (3×500 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated. Purification of the residue by flash chromatography on silica gel with 0 to 75% EtOAc/heptanes afforded 3-bromo-6-chloro-2,4-dimethylpyridine 1-oxide. LCMS=235.9 and 237.9 (M+H)+ 1H NMR (CDCl3, 500 MHz) δ 7.29 (s, 1H), 2.79 (s, 3H), 2.40 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8](N)=[CH:7][CH:6]=1.N([O-])=[O:14].[Na+].[OH-].[Na+].O=C1O[C@H]([C@H](CO)O)C([O-])=C1O.[Na+]>S(=O)(=O)(O)O.O.C(OCC)C>[Cl:1][C:2]1([Cl:12])[CH2:4][CH:3]1[C:5]1[CH:11]=[CH:10][C:8]([OH:14])=[CH:7][CH:6]=1
Reactant: Nc1ccc(C2CC2(Cl)Cl)cc1
Reactant: O=N[O-]
Agent: O=C1O[C@H]([C@@H](O)CO)C([O-])=C1O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOCC
Product: Oc1ccc(C2CC2(Cl)Cl)cc1
Reaction time: 8 h
Yield: 94.4 %

Procedure:
(-)-4-(2,2-Dichlorocyclopropyl)aniline (5 g, 0.024 mol) from the above resolution was dissolved in concentrated sulphuric acid (25 ml) and added in aliquots (1 ml) to iced water (100 ml). The mixture was allowed to stand overnight and the resulting precipitate then removed by filtration. The solid was suspended with stirring in sulphuric acid (0.05M, 70 ml) whilst being cooled to below 5° C. and a solution of sodium nitrite (2.2 g, 0.032 mol) in sulphuric acid (0.05M, 30 ml) added. After stirring for 1.5 hours the remaining precipitate was dissolved by addition of concentrated sulphuric acid (2.4 ml) and stirring maintained for a further 1.5 hours. The pH of the solution was then adjusted to 2 by addition of an aqueous solution of sodium hydroxide (10M) before being added to a stirred mixture of cupric nitrate hemipentahydrate (50 g, 0.21 mol) and sodium ascorbate (2.3 g, 0.012 mol) in distilled water (440 ml) and diethyl ether (150 ml). The mixture was stirred for 10 minutes before the organic phase was removed and the aqueous phase extracted with diethyl ether (3×100 ml). The combined organic phases were washed with distilled water, dried over anhydrous magnesium sulphate and the solvent removed by evaporation under reduced pressure to afford the crude (-)-4-(2,2-dichlorocyclopropyl)phenol (4.6 g) which was used directly in the following reaction.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][N:21]4C3CCCCO3)=[CH:11][CH:10]=2)=[C:4]([O:32][CH3:33])[CH:3]=1.Cl.CCOC(C)=O.O>CO>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH2:16][C:17]3[CH:25]=[CH:24][CH:23]=[C:22]4[C:18]=3[CH:19]=[N:20][NH:21]4)=[CH:13][CH:14]=2)=[C:4]([O:32][CH3:33])[CH:3]=1
Reactant: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3c2cnn3C2CCCCO2)cc1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cc(F)c(F)cc1-c1ccc(OCc2cccc3[nH]ncc23)cc1
Yield: 73.8 %

Procedure:
4-(4′,5′-Difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1-(tetrahydro-pyran-2-yl)-1H-indazole (0.4 g, 0.888 mmol) and 1N HCl (1.8 mL, 1.8 mmol) in 10 mL MeOH were heated to reflux for 5 hrs. The reaction was cooled and distributed between EtOAc and H2O. The water layer was made basic to pH 12 and the organic layer was separated and concentrated in vacuo. The crude product was purified by flash chromatography with a gradient from 20-100% ethyl acetate in hexanes to yield 4-(4′,5′-difluoro-2′-methoxy-biphenyl-4-yloxymethyl)-1H-indazole as a white solid (240 mg, 73.7%). LC-MS (ES) calculated for C21H16F2N2O2, 366.37; found m/z 367 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][CH2:9][NH:10][CH2:11][C:12]2[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=2)[C:5]2[C:20](I)=[N:21][N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:4]=2[CH:3]=1.CC([O-])(C)C.[Na+].C1COCC1>CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.CCOC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]2[N:22]([C:23]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)([C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[N:21]=[C:20]3[C:5]2=[C:6]([CH2:8][CH2:9][N:10]3[CH2:11][C:12]2[CH:13]=[CH:14][C:15]([O:18][CH3:19])=[CH:16][CH:17]=2)[N:7]=1
Reactant: COc1ccc(CNCCc2nc(Cl)cc3c2c(I)nn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CC(C)(C)[O-]
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: COc1ccc(CN2CCc3nc(Cl)cc4c3c2nn4C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 55 °C

Procedure:
2-(6-chloro-3-iodo-1-trityl-1H-pyrazolo[4,3-c]pyridin-4-yl)-N-(4-methoxybenzyl)ethanamine (268 mg, 0.391 mmol) and RuPhos pre-catalyst (16 mg, 0.02 mmol) were charged in a 1 dram vial, evacuated and backfilled with nitrogen and taken in 1,4-dioxane (2 mL). Added a solution of 2M NaOtBu in THF (0.5 ml, 0.978 mmol) and reaction heated to 55° C. for 1 hour. The reaction mixture was diluted with EtOAc and washed with water, brine, dried with sodium sulfate and concentrated. Purification of the residue by flash column (0-25% EtOAc-hexanes) gave 7-chloro-3-(4-methoxybenzyl)-1-trityl-1,3,4,5-tetrahydropyrazolo[3,4,5-de][1,6]naphthyridine. MS ESI calc'd. for C35H29 ClN4O [M+H]+ 558. found 558.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]#[N:6].[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH:11]([CH3:13])[CH3:12])[C:5]([NH:14][OH:15])=[NH:6]
Reactant: CC(C)Oc1ccc(C#N)cc1Cl
Reactant: NO
Solvent: CCO
Product: CC(C)Oc1ccc(C(=N)NO)cc1Cl
Temperature: 60 °C
Yield: 98.4 %

Procedure:
Into a round bottom flask was added 3-chloro-4-isopropoxy-benzonitrile (5.00 g, 25.6 mmol), hydroxylamine (50% by weight in water, 1.86 mL, 28.1 mmol) and ethanol (150 mL). The mixture was heated at about 60° C. overnight. Upon completion of the reaction, the mixture was concentrated to dryness under reduced pressure to give 3-chloro-N-hydroxy-4-isopropoxy-benzamidine (5.76 g, 94%) as a light yellow solid.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)([O:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[CH:35]=[CH:34][C:33]([C:36]3[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=3)=[CH:32][CH:31]=2)=[N:27][C:26]=1[CH2:42][CH2:43]OS(C1C=CC(C)=CC=1)(=O)=O.C([O-])([O-])=O.[K+].[K+].[OH-].[Na+]>C(O)C>[C:33]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:34]=[CH:35][C:30]([C:28]2[O:29][C:25]([CH3:24])=[C:26]([CH2:42][CH2:43][O:22][C:19]3[CH:20]=[CH:21][C:16]([CH2:15][C:5]([O:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)([CH2:6][CH3:7])[C:4]([OH:3])=[O:23])=[CH:17][CH:18]=3)[N:27]=2)=[CH:31][CH:32]=1
Reactant: CCOC(=O)C(CC)(Cc1ccc(O)cc1)Oc1ccccc1
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Product: CCC(Cc1ccc(OCCc2nc(-c3ccc(-c4ccccc4)cc3)oc2C)cc1)(Oc1ccccc1)C(=O)O

Procedure:
A mixture of 2-(4-hydroxybenzyl)-2-phenoxybutyric acid ethyl ester (0.030 mmol), toluene-4-sulfonic acid 2-(5-methyl-2-biphenyl-4-yl-oxazol-4-yl)ethyl ester (0.030 mmol) (see Ex. 1, Part I) and 325 mesh K2CO3 (0.084 g, 0.60 mmol) in ethanol (2 mL) was heated to reflux for 24 h under N2. Aqueous 5N NaOH (0.5 mL) and additional ethanol (1 mL) was added to the reaction mixture and it was heated at reflux for an additional 2 h. The reaction was cooled and the solvent removed in vacuo. The residue was acidified with aqueous 1 N HCl (5 mL), extracted with water and CH2Cl2 and the organic layer dried by passing it through a Varian Chem Elut 1003 cartridge. The solvent was removed in vacuo to give 2-{4-[2-(2-Biphenyl-4-yl-5-methyl-oxazol-4-yl)-ethoxy]-benzyl}-2-phenoxy-butyric acid. 1H NMR (400 MHz, CDCl3) δ 8.05–8.03 (m, 2H), 7.68–7.61 (m, 4H), 7.48–7.44 (m, 2H), 7.40–7.35 (m, 1H), 7.32–7.25 (m, 2H), 7.09–6.96 (m, 5H), 6.79–6.70 (m, 2H), 4.19 (t, 2H, J=6.4 Hz), 3.29 (s, 2H), 2.99 (t, 2H, J=6.4 Hz), 2.39 (s, 3H), 2.14 (qd, 1H, J=14.8, 7.6 Hz), 2.07 (qd, 1H, J=14.8, 7.6 Hz), 0.91 (t, 3H, J=7.6 Hz).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][OH:28])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][C:15]=2[C:16]([O:18][CH3:19])=[O:17])[CH:10]([CH2:27][O:28][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1CO
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1cc([N+](=O)[O-])ccc1N1CCN(Cc2ccccc2)CC1COS(C)(=O)=O
Reaction time: 0.17 h

Procedure:
To a vigorously stirred solution of Example 45E (1 g, 2.59 mmol) in dichloromethane (5.19 mL) was added triethylamine (0.542 mL, 3.89 mmol) and methanesulfonyl chloride (0.253 mL, 3.24 mmol). The reaction was stirred for 10 minutes and then quenched with brine, extracted twice with dichloromethane, dried over sodium sulfate, and the solvent was evaporated to afford the title compound. MS (ESI+) m/z 464.1 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([O:6][C:7]1[CH:8]=[C:9]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)[CH:10]=[CH:11][C:12]=1[O:13][CH3:14])[CH:3]1[O:5][CH2:4]1.[C:21]1([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[CH3:14][O:13][C:12]1[CH:11]=[CH:10][C:9]([CH:15]2[CH2:19][NH:18][C:17](=[O:20])[CH2:16]2)=[CH:8][C:7]=1[O:6][CH:2]([CH3:1])[CH:3]([OH:5])[CH2:4][N:30]1[CH2:31][CH2:32][N:27]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:28][CH2:29]1
Reactant: COc1ccc(C2CNC(=O)C2)cc1OC(C)C1CO1
Reactant: c1ccc(N2CCNCC2)cc1
Solvent: CCO
Product: COc1ccc(C2CNC(=O)C2)cc1OC(C)C(O)CN1CCN(c2ccccc2)CC1
Yield: 68 %

Procedure:
In accordance with the process set forth in Example 1, 10 mmol of 4-[3-(1-methyl-2,3-epoxypropoxy)-4-methoxyphenyl]-2-pyrrolidone and 10 mmol of 1-phenylpiperazine (95% strength) produce, in a 68% yield, 4-{4-methoxy-3-[3-(4-phenylpiperazin-1-yl)1-methyl-2-hydroxypropoxy]phenyl}-2-pyrrolidone, m.p. 116°-118° (ethanol).
Reaction SMILES: [CH:1]1[C:7](=[O:8])[NH:6][C:4](=[O:5])[NH:3][C:2]=1Cl.[SH:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1.[OH-].[K+]>C(O)C>[OH:17][C:14]1[CH:15]=[CH:16][C:11]([S:10][C:2]2[NH:3][C:4](=[O:5])[NH:6][C:7](=[O:8])[CH:1]=2)=[CH:12][CH:13]=1
Reactant: Oc1ccc(S)cc1
Reactant: O=c1cc(Cl)[nH]c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: O=c1cc(Sc2ccc(O)cc2)[nH]c(=O)[nH]1
Yield: 77.6 %

Procedure:
A mixture of 4-chlorouracil (0.87 g, 6.0 mmol), 4-mercaptophenol(0.834 g, 6.6 mmol) and KOH (0.435 g, 6.6 mmol) in ethanol (36 ml) was heated to reflux for 24 h. The reaction was allowed to cool, was concentrated in vacuo, and acidified with 1 n HCl. The solids were collected, washed with water and dried to give 6-[(4-hydroxyphenyl)thio]-2,4(1H,3H)-pyrimidinedione (1.1 g, 80%) as a white solid.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][S:8][C:4]=2[C:3]([C:9]2[NH:10][C:11]3[C:16]([CH:17]=2)=[CH:15][C:14]([C:18](=[O:21])[CH2:19][CH3:20])=[CH:13][CH:12]=3)=[N:2]1.[N:22]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[Mg]Br)[CH2:26][CH2:25][CH2:24][CH2:23]1>O1CCCC1>[N:22]1([CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:18]([C:14]2[CH:15]=[C:16]3[C:11](=[CH:12][CH:13]=2)[NH:10][C:9]([C:3]2[C:4]4[S:8][CH:7]=[CH:6][C:5]=4[NH:1][N:2]=2)=[CH:17]3)([OH:21])[CH2:19][CH3:20])[CH2:26][CH2:25][CH2:24][CH2:23]1
Reactant: Br[Mg]c1ccccc1CN1CCCC1
Reactant: CCC(=O)c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1
Solvent: C1CCOC1
Product: CCC(O)(c1ccc2[nH]c(-c3n[nH]c4ccsc34)cc2c1)c1ccccc1CN1CCCC1
Reaction time: 1 h

Procedure:
To cooled (−40° C.) solution of 1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-one (110 mg, 0.372 mmol, Example 28) in anhydrous tetrahydrofuran (2 mL) is added (2-(1-pyrrolidinylmethyl)phenyl)magnesium bromide (0.25 M in tetrahydrofuran) under nitrogen. After 1 h, the cooling bath is removed and the reaction temperature brought to room temperature. After overnight it is quenched by the addition of saturated ammonium chloride (2 mL). The resulting precipitate is dissolved with water and extracted three times with ethyl acetate (2 mL). The combined extracts are washed with brine and dried over sodium sulfate. Purification by chromatography (10 silica gel cartridge, 1:1 ethyl acetate/heptane) afforded 1-(2-pyrrolidin-1-ylmethyl-phenyl)-1-[2-(1H-thieno[3,2-c]pyrazol-3-yl)-1H-indol-5-yl]-propan-1-ol (50 mg, Example 34) as white powder; 1H NMR [(CD3)2SO)]: δ 13.22 (1H, s), 11.48 (1H, s), 8.73 (1H, s), 7.74 (2H, m), 7.45 (1H, s), 7.41 (1H, t), 7.39-7.25 (4H, m), 6.93 (1H, d), 6.59 (1H, s), 2.68 (1H, d), 2.45 (2H), 2.25 (4H), 2.08 (1H), 1.74 (4H, m), 0.75 (3H, t); LC/MS: 457 (M+H).
Reaction SMILES: C1(C[N:8]2[CH2:12][CH2:11][CH:10]([CH2:13][NH:14][CH2:15][CH2:16][CH3:17])[CH2:9]2)C=CC=CC=1.[H][H]>[Pd].CO>[CH2:15]([NH:14][CH2:13][CH:10]1[CH2:11][CH2:12][NH:8][CH2:9]1)[CH2:16][CH3:17]
Reactant: [H][H]
Reactant: CCCNCC1CCN(Cc2ccccc2)C1
Agent: [Pd]
Solvent: CO
Product: CCCNCC1CCNC1
Yield: 83.2 %

Procedure:
A mixture of 14.0 g (60.0 mmole) of 1-(phenylmethyl)-N-propyl-3-pyrrolidinemethanamine, 1.0 g of 20% palladium on carbon and 140 ml of methanol was shaken in an atmosphere of hydrogen at about 4.5×105Pa and room temperature for 24 hours. The catalyst was removed by filtering through Celite, the filtrate concentrated and distilled in vacuo to give 7.1 g of N-propyl-3-pyrrolidinemethanamine, bp 49°-50° C./0.25 mm.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5](/[CH:7]=[CH:8]/[C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3]1>C(O)C.[Pd]>[CH3:1][N:2]1[CH:6]=[C:5]([CH2:7][CH2:8][C:9]([O:11][CH3:12])=[O:10])[CH:4]=[N:3]1
Reactant: COC(=O)/C=C/c1cnn(C)c1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)CCc1cnn(C)c1
Temperature: 40 °C
Reaction time: 12 h
Yield: 98 %

Procedure:
To a solution of methyl ((E)-Methyl 3-(1-methyl-1H-pyrazol-4-yl)acrylate (18 g, 108 mmol) in ethanol (300 ml) was added Pd/C (4 g, 37.6 mmol) at room temperature. The reaction mixture was stirred at 40° C. for 12 h under hydrogen. The reaction mixture was cooled to room temperature, then the solid was removed by filtration. The filtrate was concentrated in vacuo to give the title compound as colorless oil (17.8 g, 80% yield). LCMS: rt=1.27 min, [M+H+]=169
Reaction SMILES: Cl.[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][C@@H:12]2[C:32](=[O:33])[N:14]3[C:15]([C:29]([O-:31])=[O:30])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:28])[C:22]([NH:25]C=O)=[CH:23][CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1.C(OCC)C>CO>[NH2:2][C:3]1[S:4][CH:5]=[C:6]([C:8](=[N:34][O:35][CH3:36])[C:9]([NH:11][C@@H:12]2[C:32](=[O:33])[N:14]3[C:15]([C:29]([O-:31])=[O:30])=[C:16]([CH2:19][N+:20]4[N:21]([CH3:28])[C:22]([NH2:25])=[CH:23][CH:24]=4)[CH2:17][S:18][C@H:13]23)=[O:10])[N:7]=1
Reactant: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(NC=O)n3C)CS[C@H]12)c1csc(N)n1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CON=C(C(=O)N[C@@H]1C(=O)N2C(C(=O)[O-])=C(C[n+]3ccc(N)n3C)CS[C@H]12)c1csc(N)n1
Reaction time: 3 h

Procedure:
Concentrated hydrochloric acid (0.136 ml) was added to a suspension of 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-formamido-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate (syn isomer) (0.2 g) in methanol (1 ml) at ambient temperature. After being stirred at the same temperature for 3 hours, the mixture was added dropwise to diethyl ether (100 ml), and the precipitate was collected by filtration. The precipitate was dissolved in water and subjected to column chromatography on macroporous non-ionic adsorption resin "Diaion HP-20". The desired product was eluted with water, and lyophilized to give 7β-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-(3-amino-2-methyl-1-pyrazolio)methyl-3-cephem-4-carboxylate.trihydrochloride (syn isomer) (71.20 mg).
Reaction SMILES: [OH-].[K+].[CH3:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[C:17]([O:19]CC)=[O:18].Cl>C(O)C>[CH3:3][C:4]1[C:16]2[NH:15][C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[C:8]=2[CH:7]=[CH:6][C:5]=1[C:17]([OH:19])=[O:18]
Reactant: CCOC(=O)c1ccc2c([nH]c3ccccc32)c1C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: Cc1c(C(=O)O)ccc2c1[nH]c1ccccc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.1 %

Procedure:
4 ml of ethanol and 4 ml of a 2N aqueous solution of potassium hydroxide were added to 100 mg of ethyl 1-methylcarbazole-2-carboxylate (obtained according to the procedures described in C. J. Moody and K. F. Rahimtoola, J. Chem. Soc. Parkin. Trans. I, 673 (1990)]. The reaction mixture was stirred for 2 hours at room temperature, and then acidified by the addition of a 1N aqueous solution of hydrochloric acid, after which it was concentrated by evaporation under reduced pressure. Ethyl acetate was added to the residue. The aqueous layer was 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 recrystallized from ethyl acetate and hexane, to yield 81 mg of the title compound, melting at >240° C.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH:3]([CH:7]=O)[CH2:2]1.[NH2:9][CH2:10][CH2:11][CH2:12][N:13]1[C:21]([O:22][CH3:23])=[N:20][C:19]2[C:14]1=[N:15][C:16]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[N:17][C:18]=2[NH2:24].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl>[CH2:26]([O:25][C:16]1[N:15]=[C:14]2[C:19]([N:20]=[C:21]([O:22][CH3:23])[N:13]2[CH2:12][CH2:11][CH2:10][NH:9][CH2:7][CH:3]2[CH2:4][CH2:5][CH2:6][O:1][CH2:2]2)=[C:18]([NH2:24])[N:17]=1)[CH2:27][CH2:28][CH3:29]
Reactant: O=CC1CCCOC1
Reactant: CCCCOc1nc(N)c2nc(OC)n(CCCN)c2n1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCCCOc1nc(N)c2nc(OC)n(CCCNCC3CCCOC3)c2n1
Temperature: 20 °C
Reaction time: 5 h
Yield: 70.4 %

Procedure:
Tetrahydro-2H-pyran-3-carbaldehyde (19.39 mg, 0.17 mmol) was added to 9-(3-aminopropyl)-2-(butyloxy)-8-(methyloxy)-9H-purin-6-amine (50 mg, 0.17 mmol) in DCM (1 ml). Sodium triacetoxyborohydride (72.0 mg, 0.34 mmol) and DCM (1 ml) was added followed by acetic acid (0.024 ml, 0.425 mmol). The mixture was stirred at 20° C. under nitrogen for 5 hours. The mixture was quenched with NaHCO3 (5 ml) and diluted with DCM (2 ml). The organic layer was separated using a hydrophobic frit and the solvent removed in vacuo. The sample was dissolved in 1:1 MeOH:DMSO (1 ml) and purified by Mass Directed AutoPrep (Method A). The solvent was dried under a stream of nitrogen to give the title compound as white solid (47 mg).