Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH2:6][CH:5]=[C:4]([C:7]2[C:8]([O:13][C:14]3[CH:19]=[CH:18][C:17]([NH:20][C:21]4[C:26]([CH3:27])=[CH:25][CH:24]=[CH:23][N:22]=4)=[CH:16][CH:15]=3)=[N:9][CH:10]=[CH:11][CH:12]=2)[CH2:3][CH2:2]1>CCOC(C)=O.[OH-].[OH-].[Pd+2]>[CH3:27][C:26]1[C:21]([NH:20][C:17]2[CH:18]=[CH:19][C:14]([O:13][C:8]3[C:7]([CH:4]4[CH2:5][CH2:6][O:1][CH2:2][CH2:3]4)=[CH:12][CH:11]=[CH:10][N:9]=3)=[CH:15][CH:16]=2)=[N:22][CH:23]=[CH:24][CH:25]=1
Reactant: Cc1cccnc1Nc1ccc(Oc2ncccc2C2=CCOCC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: Cc1cccnc1Nc1ccc(Oc2ncccc2C2CCOCC2)cc1

Procedure:
To a pressure vessel was added N-(4-(3-(3,6-dihydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)-3-methylpyridin-2-amine (0.2400 g, 0.668 mmol) and palladium hydroxide on carbon (0.047 g, 0.067 mmol) in EtOAc (2.226 mL). The rbf was flushed with nitrogen and then placed under vacuum three times. Reaction was placed under 40 psi. Reaction mixture was filtered through celite. The crude product was adsorbed onto a plug of silica gel and chromatographed to provide 3-methyl-N-(4-(3-(tetrahydro-2H-pyran-4-yl)pyridin-2-yloxy)phenyl)pyridin-2-amine. MS (ESI, pos. ion) m/z: 362.1. IC50 (uM) 0.006873.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:18])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([O:7]CC#C)=[O:6].[OH-].[Na+]>C(O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:11]=[C:12]([F:18])[C:13]=1[O:14][CH2:15][C:16]#[CH:17])[C:5]([OH:7])=[O:6]
Reactant: C#CCOC(=O)c1cc(F)c(OCC#C)c(F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: C#CCOc1c(F)cc(C(=O)O)cc1F
Temperature: 50 °C
Reaction time: 1 h
Yield: 96.5 %

Procedure:
To 10 ml of ethanol were added 2.2 g of 2-propynyl 3,5-difluoro-4-(2-propynyloxy)benzoate and 6 ml of 15% aqueous sodium hydroxide solution, and the mixture obtained was stirred at 50° C. for 1 hour. Then, the reaction mixture was concentrated under reduced pressure. Hydrochloric acid was added to the residue for acidification. Crystals precipitated were collected by filtration and dried to obtain 1.8 g of 3,5-difluoro-4-(2-propynyloxy)benzoic acid.
Reaction SMILES: [NH2:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12.[C:36]([O:55]/[N:56]=[C:57](/[C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:79]=[CH:78][CH:77]=[CH:76][CH:75]=2)[C:68]2[CH:73]=[CH:72][CH:71]=[CH:70][CH:69]=2)[S:64][CH:65]=1)\[C:58](O)=[O:59])([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1)[C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl.CN(C)C=O>[C:36]([O:55][N:56]=[C:57]([C:61]1[N:62]=[C:63]([NH:66][C:67]([C:80]2[CH:85]=[CH:84][CH:83]=[CH:82][CH:81]=2)([C:74]2[CH:75]=[CH:76][CH:77]=[CH:78][CH:79]=2)[C:68]2[CH:69]=[CH:70][CH:71]=[CH:72][CH:73]=2)[S:64][CH:65]=1)[C:58]([NH:1][CH:2]1[C:34](=[O:35])[N:4]2[C:5]([C:18]([O:20][CH:21]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:19])=[C:6]([CH:9]=[CH:10][S:11][C:12]3[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=3)[CH2:7][S:8][C@H:3]12)=[O:59])([C:49]1[CH:50]=[CH:51][CH:52]=[CH:53][CH:54]=1)([C:37]1[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1
Reactant: O=C(O)/C(=N\OC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1
Reactant: NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: O=C(NC1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(C=CSc3ccncc3)CS[C@H]12)C(=NOC(c1ccccc1)(c1ccccc1)c1ccccc1)c1csc(NC(c2ccccc2)(c2ccccc2)c2ccccc2)n1

Procedure:
To a solution of benzhydryl 7-amino-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (a mixture of cis- and trans-isomers) (1.0 g) in a mixture of methylene chloride (10 ml) and dimethylformamide (1.0 ml) were added (Z)-2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetic acid (1.46 g) and DCC (dicyclohexylcarbodiimide) (450 mg) and the resultant mixture was stirred at room temperature for 2 hours. After completion of the reaction, the dicyclohexylurea was filtered off and the filtrate was diluted with ethyl acetate (50 ml), washed with saturated aqueous solution of sodium hydrogen carbonate and saturated aqueous solution of sodium chloride and dried over magnesium sulfate. The solvent was then distilled off under reduced pressure to give a crude product (2.65 g). This crude product was chromatographed on a column of silica gel and eluted with benzene-ethyl acetate to provide benzhydryl 7-[2-trityloxyimino-2-(2-tritylaminothiazol-4-yl)acetamido]-3-[2-(4-pyridyl)thiovinyl]-3-cephem-4-carboxylate (1.6 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[N:8]=[C:7]2[CH:9]=[CH:10][NH:11][C:6]2=[CH:5][CH:4]=1.C(=O)([O-])[O-].[K+].[K+].I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.[Cl-].[NH4+]>CS(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[Cu]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH:9]=[CH:10][N:11]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[C:6]2=[CH:7][N:8]=1
Reactant: COc1ccc2[nH]ccc2n1
Reactant: Ic1ccccc1
Agent: [Cu]
Agent: CC(=O)/C=C(/C)O
Agent: O=C([O-])[O-]
Solvent: CS(C)=O
Product: COc1cc2ccn(-c3ccccc3)c2cn1
Temperature: 130 °C
Reaction time: 10 h
Yield: 92.8 %

Procedure:
To a mixture of 5-methoxy-1H-pyrrolo[2,3-c]pyridine (6.00 g, 40.5 mmol; cf. D. Mazéas et al., Heterocycles 50 (1999), 1065), copper(II) acetylacetonate (1.06 g, 4.05 mmol) and potassium carbonate (11.2 g, 81.0 mmol) in DMSO (63 ml) was added iodobenzene (4.99 ml, 44.6 mmol). The reaction mixture was stirred at 130° C. for 10 h. The mixture was then cooled to room temperature, and a solution of ammonium chloride (20% in water) was added. The mixture was filtered through celite and the filtrate extracted three times with EA. The organic layers were combined, dried over sodium sulfate, filtered and evaporated under reduced pressure. Column chromatography of the residue on silica gel (EA/HEP) gave 8.43 g of the title compound.
Reaction SMILES: [CH2:1]([O:4][C@H:5]1[O:34][C@H:33]([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[C@@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:6]1[O:7][CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH:2]=[CH2:3].C12BC(CCC1)CCC2.[OH-:56].[Na+].OO>O1CCCC1.O>[CH2:8]([O:7][C@@H:6]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:24]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:33]([CH2:35][O:36][S:37]([C:40]2[CH:46]=[CH:45][C:43]([CH3:44])=[CH:42][CH:41]=2)(=[O:39])=[O:38])[O:34][C@@H:5]1[O:4][CH2:1][CH2:2][CH2:3][OH:56])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: C=CCO[C@H]1O[C@H](COS(=O)(=O)c2ccc(C)cc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: [OH-]
Agent: B1C2CCCC1CCC2
Agent: OO
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: Cc1ccc(S(=O)(=O)OC[C@H]2O[C@H](OCCCO)[C@H](OCc3ccccc3)[C@@H](OCc3ccccc3)[C@@H]2OCc2ccccc2)cc1
Reaction time: 10 h

Procedure:
To a solution of the compound (5) (29.0 g, 45.0 mmol) in anhydrous tetrahydrofuran (THF, 150 ml), added was a solution of 0.5 M 9-borabicyclo[3,3,1]nonane (9-BBN) in tetrahydrofuran (180 ml, 90.0 mmol) at 0° C. in an argon atmosphere. After a lapse of 1 hour, the reaction liquid was returned to room temperature, and continuously stirred for 10 hours. The reaction liquid was cooled again to 0° C., to which water (20 ml) was added firstly, and then 3 M sodium hydroxide solution (70 ml) and 35% hydrogen peroxide solution (70 ml) were added sequentially. After a lapse of 1 hour, the reaction liquid was returned to room temperature, and stirred for 12 hours. After the sufficient progress of the reaction was confirmed, the solution was extracted with ethyl acetate (3×100 ml), the organic layers were combined and washed with saturated saline (2×100 ml), dried with sodium sulfate, filtered, and concentrated under reduced pressure. The obtained residue was purified with silica gel chromatography (hexane-ethyl acetate, 3:2→1:1→2:3) to obtain the title compound (6) in the form of a colorless oily substance {28.2 g (42.5 mmol), 94.4%}.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([CH3:8])[CH2:4][CH2:3]1.[CH2:9]([N:17]1[CH:21]=[C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[N:19]=[C:18]1[CH:28]=O)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])([O-])=O.[Na+].[Na+]>CS(O)(=O)=O.C(Cl)(Cl)Cl>[CH3:8][N:5]1[CH2:6][CH2:7][CH:2]([O:1][CH:28]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:11]=3[CH2:10][CH2:9][N:17]3[C:18]2=[N:19][C:20]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:21]3)[CH2:3][CH2:4]1
Reactant: O=Cc1nc(-c2ccccc2)cn1CCc1ccccc1
Reactant: CN1CCC(O)CC1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CN1CCC(OC2c3ccccc3CCn3cc(-c4ccccc4)nc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 4-hydroxy-N-methylpiperidine (275 mg, 2.39 mmoles) in methanesulfonic acid (2 mL) at 0° C. is added a solution of 1-phenethyl-4-phenyl-imidazole-2-carbaldehyde (example 4B) (250 mg, 0.904 mmoles) in chloroform (2 mL). The reaction mixture is stirred at room temperature overnight, then heated to reflux for 6 h. A saturated solution of Na2CO3 is added to reach pH 10. The aqueous phase is extracted three times with CH2Cl2. The organic phase is dried over magnesium sulphate, filtered and the solvent is removed under reduced pressure. The residue is purified by silica gel chromatography using (CH2Cl2:MeOH) (90:10) to give 4-(1-methylpiperidin-4-yloxy)-2-phenyl-9,10-dihydro-4H-3,10a-diaza-benzo[f]azulene melting at 113° C.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[N:14]=[C:15]([O:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[S:16][C:17]=3[C:18]#[N:19])[CH:10]=[N:9]2)=CC=1>C(O)(C(F)(F)F)=O>[NH:8]1[CH:12]=[C:11]([C:13]2[N:14]=[C:15]([O:20][C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[S:16][C:17]=2[C:18]#[N:19])[CH:10]=[N:9]1
Reactant: COc1ccc(Cn2cc(-c3nc(Oc4ccccn4)sc3C#N)cn2)cc1
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1sc(Oc2ccccn2)nc1-c1cn[nH]c1
Temperature: 25 °C
Yield: 41.4 %

Procedure:
According to Scheme 7, Step 6: A solution of 4-(1-(4-methoxybenzyl)-1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile (0.26 mmol, 153 mg) in TFA (5 mL) was stirred at 100° C. for 10 minutes under microwave conditions. After cooling to room temperature, the mixture was concentrated under reduced pressure. The residue was diluted with EtOAc and was washed with a saturated aqueous solution of NaHCO3. The organic phase was dried over MgSO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC to give 4-(1H-pyrazol-4-yl)-2-(pyridin-2-yloxy)thiazole-5-carbonitrile as a white solid (29 mg, 28%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([OH:20])=O)=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1.[CH:27]1([NH2:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1.F[P-](F)(F)(F)(F)F.Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1.C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]([CH:17]([CH:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)[C:18]([NH:33][CH:27]3[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]3)=[O:20])=[C:15]3[C:10]([CH:11]=[CH:12][CH:13]=[CH:14]3)=[N:9]2)=[CH:4][CH:3]=1
Reactant: O=C(O)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Reactant: NC1CCCCC1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(NC1CCCCC1)C(c1c2ccccc2nn1-c1ccc(Cl)cc1)C1CCCCC1
Temperature: 25 °C
Reaction time: 120 h
Yield: 46 %

Procedure:
To an ice cold solution of [2-(4-chloro-phenyl)-2H-indazol-3-yl]-cyclohexyl-acetic acid (9 mg, 24 μmol and cyclohexylamine (2.3 μl, 24 μmol; CAS Reg. No. 108-91-8) in CH2Cl2 (1 ml) under an argon atmosphere was added bromotripyrrolidinophosphonium hexafluorophosphate (17 mg, 36 umol) and N,N-diisopropylethylamine (10 ul, 72 umol). The reaction mixture was stirred for 5 d at ambient temperature, poured onto ice water/1 N aqueous NaOH solution 1/1 and extracted two times with iPrOAc. The combined extracts were washed with ice water/1 N aqueous HCl solution 1/1 and brine and dried over Na2SO4. After filtration the solvent was removed under reduced pressure and the residue was purified by preparative thin layer chromatography (silica gel, iPrOAc/heptane) to give the title compound (5 mg, 11 μmol; 46%) as colorless foam. MS: m/e=450.3 [M+H+].
Reaction SMILES: C([CH2:4][C:5]1[N:12]2[C:8]([CH2:9][CH2:10][CH2:11]2)=[C:7]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C:6]=1[C:19]1(C(O)=O)[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]1)(O)=O.C(=O)=O.C(OC(C)C)(C)C>>[CH:19]1([C:6]2[C:7]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)=[C:8]3[N:12]([CH2:11][CH2:10][CH2:9]3)[C:5]=2[CH3:4])[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: O=C(O)Cc1c(C2(C(=O)O)CCCCC2)c(-c2ccccc2)c2n1CCC2
Agent: O=C=O
Solvent: CC(C)OC(C)C
Product: Cc1c(C2CCCCC2)c(-c2ccccc2)c2n1CCC2

Procedure:
1-(3-Carboxymethyl-1-phenyl-6,7-dihydro-5H-pyrrolizin-2-yl)cyclohexanecarboxylic acid (1.5 g, 3.7 mmol) is immersed in an oil bath of 150° C. for 30 min in a 25 ml flask. The release of CO2 is checked via a bubble counter. The still warm melt is digested with diisopropyl ether (15 ml). The insoluble crystalline residue is filtered off with suction and dried. 0.84 g (82% of theory) of decarboxylation product 6-cyclohexyl-5-methyl-7-phenyl-2,3-dihydro-1H-pyrrolizine (TLC: SiO2, ether-n-hexane (1:1): starting material Rf 0-0.2, product 0.9) is obtained.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:17]=[C:16]2[C:11]([C:12](=[O:26])[N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:24])([CH3:23])[CH3:22])[CH:14]=[N:15]2)=[CH:10][C:9]=1[O:27][CH3:28].[O:29]1[CH2:34][CH2:33][N:32]([CH2:35][CH2:36][CH2:37]Cl)[CH2:31][CH2:30]1>CN(C)C=O>[CH3:28][O:27][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][C:8]=1[O:7][CH2:37][CH2:36][CH2:35][N:32]1[CH2:33][CH2:34][O:29][CH2:30][CH2:31]1)[N:15]=[CH:14][N:13]([CH2:18][O:19][C:20](=[O:25])[C:21]([CH3:22])([CH3:23])[CH3:24])[C:12]2=[O:26]
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Reactant: ClCCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCCN1CCOCC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 65.4 %

Procedure:
Potassium carbonate (4.51 g) was added to 7-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin4-one (2.0 g) in dimethylformamide (50 ml) followed by 3-morpholinopropyl chloride (1.3 g) and the reaction was stirred at 100° C. for 6 hours. After cooling the solid was removed by filtration and the filtrate was evaporated and was purified by eluting through a silica column with 10% methanol in methylene chloride to yield 6-methoxy-7-(3-morpholinopropoxy)-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one as a solid (1.85 g, 65%); NMR: 1.1 (s, 9H), 1.9 (m, 2H), 2.4 (broad m, 6H), 3.55 (m, 4H), 3.88 (s, 3H), 4.16 (m, 2H), 5.89 (s, 2H), 7.13 (s, 1H), 7.47 (s, 1H), 8.32 (s, 1H); m/s: M+H+ 434.
Reaction SMILES: [NH:1]([C:3]1[N:11]=[C:10]2[C:6]([N:7]=[CH:8][N:9]2[CH3:12])=[C:5]([NH:13][C:14]2[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=2)[N:4]=1)[NH2:2].[CH3:22][C:23](=O)[CH2:24][C:25](=O)[CH3:26]>>[CH3:22][C:23]1[CH:24]=[C:25]([CH3:26])[N:1]([C:3]2[N:11]=[C:10]3[C:6]([N:7]=[CH:8][N:9]3[CH3:12])=[C:5]([NH:13][C:14]3[CH:21]=[CH:20][C:17]([C:18]#[N:19])=[CH:16][CH:15]=3)[N:4]=2)[N:2]=1
Reactant: CC(=O)CC(C)=O
Reactant: Cn1cnc2c(Nc3ccc(C#N)cc3)nc(NN)nc21
Product: Cc1cc(C)n(-c2nc(Nc3ccc(C#N)cc3)c3ncn(C)c3n2)n1

Procedure:
Was prepared according to Example 9 from 4-(2-hydrazino-9-methyl-9H-purin-6-ylamino)-benzonitrile and 2,4-pentanedione.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:14][CH3:15])=[C:4]([C:9]([CH2:12]Br)=[CH:10][CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[S:16]([O-:19])([O-:18])=[O:17].[Na+:20].[Na+]>C(O)C.O>[Na+:20].[Br:1][C:2]1[CH:11]=[CH:10][C:9]([CH2:12][S:16]([O-:19])(=[O:18])=[O:17])=[C:4]([C:5]([O:7][CH3:8])=[O:6])[C:3]=1[O:14][CH3:15]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)c1c(CBr)ccc(Br)c1OC
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COC(=O)c1c(CS(=O)(=O)[O-])ccc(Br)c1OC
Yield: 100.1 %

Procedure:
A mixture of methyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 89, 1.0 g) and sodium sulphite (0.445 g) in ethanol (1 ml) and water (10 ml) was stirred and heated at reflux for 2 hours. After cooling, the mixture was evaporated to dryness to give (4-bromo-3-methoxy-2-methoxycarbonylphenyl)-methanesulphonic acid sodium salt (1.07 g) as a white solid which was used without further characterization.
Reaction SMILES: CN(C)C=[O:4].Cl[CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:20]=[C:19]2[C:14]([C:15]([O:21][C:22]3[C:23]([CH3:32])=[N:24][C:25]4[C:30]([CH:31]=3)=[CH:29][CH:28]=[CH:27][CH:26]=4)=[CH:16][CH:17]=[N:18]2)=[CH:13][C:12]=1[O:33][CH3:34].C(=O)([O-])[O-].[K+].[K+]>O>[CH3:34][O:33][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:11]=1[O:10][CH2:9][CH2:8][CH2:7][OH:4])[N:18]=[CH:17][CH:16]=[C:15]2[O:21][C:22]1[C:23]([CH3:32])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][CH:28]=[CH:27][CH:26]=2
Reactant: CN(C)C=O
Reactant: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: COc1cc2c(Oc3cc4ccccc4nc3C)ccnc2cc1OCCCO
Temperature: 80 °C
Reaction time: 72 h
Yield: 61 %

Procedure:
N,N-Dimethylformamide (2 ml) was added to 7-(3-chloro-propoxy)-6-methoxy-4-(2-methyl-quinolin-3-yloxy)-quinoline (compound 375) (69 mg), potassium carbonate (70 mg), and water (10 mg), and the mixture was stirred at 80° C. for 3 days. The reaction solution was cooled to room temperature, water was added to the reaction solution, and the mixture was extracted with chloroform. The chloroform layer was washed with water and was then dried over anhydrous sodium sulfate. The solvent was removed by distillation under the reduced pressure, and the residue was purified by thin layer chromatography using chloroform-methanol to give the title compound (40 mg, yield 61%).
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][NH:5][C@@H:4]([C:7]([OH:9])=[O:8])[CH2:3]1.C(N(CC)CC)C.[CH3:17][O:18][C:19]1[CH:24]=[CH:23][C:22]([S:25](Cl)(=[O:27])=[O:26])=[CH:21][CH:20]=1>O.O1CCOCC1.CN(C)C1C=CN=CC=1>[CH3:17][O:18][C:19]1[CH:20]=[CH:21][C:22]([S:25]([N:5]2[CH2:6][C@H:2]([OH:1])[CH2:3][C@@H:4]2[C:7]([OH:9])=[O:8])(=[O:27])=[O:26])=[CH:23][CH:24]=1
Reactant: O=C(O)[C@H]1C[C@@H](O)CN1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(S(=O)(=O)N2C[C@H](O)C[C@@H]2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Cis-4-hydroxy-D-proline (9.0 g, 68.6 mmol) is dissolved in 100 mL mixture of water and p-dioxane (1:1) and then triethyl amine (19.1 mL, 137.3 mmol), 4-methoxyphenylsulfonyl chloride (15.6 g, 75.5 mmol), and 4-dimethylaminopyridine (0.86 g, 6.86 mmol) are added. The solution is stirred at room temperature overnight. The reaction mixture is washed with sodium bicarbonate and extracted once with ether. The water layer is acidified with 1N HCl until pH~2 is achieved and then the solution is extracted three times with ethyl acetate. The ethyl acetate layers are washed with ammonium chloride, and dried (MsSO4), filtered and evaporated to give the crude acid. Cl+ MS: m/z (rel intensity) 302.0(M+ +H, 100).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.Cl[CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1.CN(C)C=O.[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[SH:29]>O>[Br:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[S:29][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][O:14][CH2:13][CH2:12]1
Reactant: ClCCN1CCOCC1
Reactant: Sc1ccccc1Br
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: Brc1ccccc1SCCN1CCOCC1
Temperature: 100 °C

Procedure:
Potassium carbonate (10.95 g) and 2-chloroethylmorpholine hydrochloride (5.9 g) were mixed with dimethylformamide (56 ml) and 2-bromothiophenol was added before the mixture was heated to 100° C. for 3 days. The mixture was allowed to cool before water (500 ml) was added. The product was extracted into diethyl ether (×3). The combined extracts were dried over sodium sulphate and filtered before evaporation. The product was purified by column chromatography eluting with ethyl acetate/hexane mixtures to give a red/brown oil (6.024 g).
Reaction SMILES: [O-]CC.[Na+].C1(C)C=CC=CC=1.C([O:14][C:15](=[O:32])[CH2:16][C:17]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH3:31])[N:26]=1)=[N:18][N:19]1[CH2:23][CH2:22][CH2:21][C:20]1=O)C.Cl>O>[CH3:31][C:27]1[N:26]=[C:25]([C:17]2[C:16]([C:15]([OH:14])=[O:32])=[C:23]3[CH2:22][CH2:21][CH2:20][N:19]3[N:18]=2)[CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CC(=NN1CCCC1=O)c1cccc(C)n1
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: O
Product: Cc1cccc(-c2nn3c(c2C(=O)O)CCC3)n1
Temperature: 100 °C
Yield: 85.8 %

Procedure:
Add sodium ethoxide (90 g, 1.32 mol), toluene (5 L) and 3-[6-methyl-(pyridin-2-yl)]-3-(2-oxo-pyrrolidin-1-ylimino)-propionic acid ethyl ester (Preparation 2-B; 201 g, 0.661 mol) to a 22 L flask equipped with a mechanical stirrer, nitrogen inlet and a reflux condenser. Heat the mixture at 100° C. for 24 h then cool to room temperature. Add water (4 L) and adjust the pH to 4 with concentrated hydrochloric acid. Separate the organic layer and extract the aqueous portion with 10% isopropyl alcohol in chloroform (3×4.5 L). Combine the organic layers, dry (sodium sulfate), filter, and concentrate in vacuo to yield the subtitled product 138 g (86%) as a yellow solid in 78% purity by HPLC analysis. MS ES+ m/e 244 (M+1).
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([OH:10])=[O:9])[CH2:4][CH2:3]1.S(=O)(=O)(O)O.[NH4+].[OH-].[CH3:18]O>>[NH2:1][C@@H:2]1[CH2:7][CH2:6][C@H:5]([C:8]([O:10][CH3:18])=[O:9])[CH2:4][CH2:3]1
Reactant: CO
Reactant: N[C@H]1CC[C@@H](C(=O)O)CC1
Agent: O=S(=O)(O)O
Agent: [NH4+]
Agent: [OH-]
Product: COC(=O)[C@H]1CC[C@@H](N)CC1
Temperature: 80 °C
Reaction time: 24 h

Procedure:
A resealable pressure bottle was charged with cis-4-aminocyclohexanecarboxylic acid (10 g, 69.8 mmol), MeOH (100 mL), and sulfuric acid (7.45 mL, 140 mmol). The vessel was sealed and the mixture stirred at 80° C. for 24 hours. The mixture was cooled to 0° C. via an ice bath and made basic with NH4OH to a pH of approximately 10. The aqueous layer was extracted with DCM (4×50 mL) and the organic layers combined, dried over sodium sulfate and concentrated to afford cis-methyl 4-aminocyclohexanecarboxylate (9 g, 82% yield) as a colorless oil. MS m/z=158.2 [M+H]. Calc'd for C8H15NO2: 157.1.
Reaction SMILES: [F:1][C:2]1[C:8]([N:9]2[CH2:14][CH2:13][N:12]([CH3:15])[CH2:11][CH2:10]2)=[C:7]([F:16])[CH:6]=[C:5]([N+:17]([O-])=O)[C:3]=1[NH2:4]>C(O)C.[Pd]>[F:16][C:7]1[C:8]([N:9]2[CH2:10][CH2:11][N:12]([CH3:15])[CH2:13][CH2:14]2)=[C:2]([F:1])[C:3]([NH2:4])=[C:5]([NH2:17])[CH:6]=1
Reactant: CN1CCN(c2c(F)cc([N+](=O)[O-])c(N)c2F)CC1
Agent: [Pd]
Solvent: CCO
Product: CN1CCN(c2c(F)cc(N)c(N)c2F)CC1
Yield: 100.9 %

Procedure:
The nitroaniline derivative (10.0 g, 0.036 mol) (obtained in step 1 above) was hydrogenated using 10% Pd-C (2.0 g) in ethanol (40 mL), following an analogous procedure to that described in preparation 1 (step 4) to yield 4,6-difluoro-5-(4-methylpiperazin-1-yl)-1, 2-phenylenediamine (8.8 g, 98.7%) as a brown viscous oil, which was directly converted to 4,6-difluoro-5-(4-methylpiperazine-1-yl)-2-mercapto-1H-benzimidazole (6.7 g, 65%) by an analogous procedure to that described in preparation 1 (step 5) using carbon disulfide (5.5 g, 0.072 mol), potassium hydroxide (2.5 g, 0.043 mmol), ethanol (70 mL) and water (10 mL). mp 280-281° C.; IR (KBr) 3085, 1475 cm-1 ; 1H NMR (DMSO-d6) δd 2.22 (s, 3H, NCH3), 2.44 (m, 4H, N(CH2)2), 3.02 (m, 4H, N(CH2)2), 6.86 (d, J=12.8 Hz, 1H), 12.90 (brs, 1H, NH); Mass (m/z) 284 (M+.).