Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([Li])[CH2:2][CH2:3][CH3:4].[CH:6]1[CH:7]=[CH:8][C:9]2[S:14]C=[CH:12][C:10]=2[CH:11]=1.C(Br)C=C.[NH4+].[Cl-]>C1COCC1>[CH3:4][CH:3]=[CH:2][C:1]1[S:14][C:9]2[CH:8]=[CH:7][CH:6]=[CH:11][C:10]=2[CH:12]=1
Reactant: [Li]CCCC
Reactant: c1ccc2sccc2c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: C=CCBr
Solvent: C1CCOC1
Product: CC=Cc1cc2ccccc2s1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
n-Butyl lithium (16.7 ml, 2.5 N in hexanes) was added dropwise to a stirred solution of thianaphthene (5.0 g, 37.3 mmol) in THF (80 mL) at -78° C. under a dry N2 atmosphere. After the addition wascompleted, the mixture was warmed up and stirred at 0° C. for 30 min. Allylbromide (16.1 mL, 186.5 mmol ) was added. After an additional 3.5 h., sat. aq. NH4Cl was added and the reaction mixture was partitioned between water and ether. The ether phase was washed with brine and dried. Silica gel (120 mL) was added. Solvents were removed and the silica adsorbate was flash chromatographed (eluent petroleum ether) to provide the title compound as an oil (3.74 g, 58%): NMR (CDCl3); δ 7.76 (d, J=9 Hz, 1H), 7.66 (d, J=9 Hz, 1H), 7.36-7.20 (m, 2H), 7.02 (s, 1H), 6.14-5.96 (m, 1H), 5.22 (dd, J=2, 17 Hz, 1H), 5.16 (dd, J=2, 17 Hz, 1H), 3.66 (d, J=8 Hz, 2H); MS (EI): [M+] 174 (100%); Anal. Calc. for C11H10S: C, 75.82, H, 5.78, N, 0.00. Found: C, 72.88, H, 5.56, N, 0.13.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1.[CH3:10][CH:11]([NH2:20])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]>>[CH3:10][CH:11]([NH:20][C:2]1[CH:7]=[C:6]([O:8][CH3:9])[N:5]=[CH:4][N:3]=1)[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH3:19]
Reactant: COc1cc(Cl)ncn1
Reactant: CCCCCCCCC(C)N
Product: CCCCCCCCC(C)Nc1cc(OC)ncn1
Yield: 60.3 %

Procedure:
7.2 g (0.05 mol ) of 4-chloro-6-methoxypyrimidine and 15.7 g (0.1 mol) of 2-decylamine were heated at 100° C. for 2 hours. The mixture was worked up using a water/methylene chloride mixture, and purification by chromatography (silica gel/ethyl acetate) gave 8.0 g (58.8% of theory) of 4-(2-decylamino)-6-methoxypyrimidine in the form of a yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:14]=[CH:13][C:10]([CH:11]=[O:12])=[CH:9][CH:8]=1.[BH4-].[Na+]>>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:8]=[CH:9][C:10]([CH2:11][OH:12])=[CH:13][CH:14]=1
Reactant: O=Cc1ccc(-c2ccccn2)cc1
Agent: [BH4-]
Agent: [Na+]
Product: OCc1ccc(-c2ccccn2)cc1
Yield: 73.6 %

Procedure:
4-(2-Pyridinyl)benzaldehyde (2 gm, 11 mmole), and NaBH4 (0.42 gm, 11 mmole) were stirred at room temperature for 2 hr, ethanol was evaporated, residue dissolved in ethyl acetate washed with saturated NaHCO3 solution, and saturated NaCl solution, dried using Na2SO4 and evaporated to produce white solid (1.5 gm, 75%).
Reaction SMILES: [CH2:1]([N:8]([CH2:16][C@@:17]1([CH2:27][F:28])[CH2:21][CH2:20][N:19](C(OCC)=O)[CH2:18]1)[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>C(O)(C)C>[CH2:1]([N:8]([CH2:16][C@@:17]1([CH2:27][F:28])[CH2:21][CH2:20][NH:19][CH2:18]1)[CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)N1CC[C@](CF)(CN(Cc2ccccc2)Cc2ccccc2)C1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)O
Product: FC[C@]1(CN(Cc2ccccc2)Cc2ccccc2)CCNC1

Procedure:
(S)-3-(N,N-Dibenzylaminomethyl)-1-ethoxycarbonyl-3-fluoromethylpyrrolidine (52 g) was dissolved in isopropyl alcohol (500 ml), and sodium hydroxide (27 g) was added. The mixture was refluxed for 40 hours with stirring. After concentration, water (300 ml) was added to the concentrate and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried and concentrated to give the object compound as an oil.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH2:24][C:25]1[C:26]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1>>[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:21]=[C:20]([S:22][CH3:23])[CH:19]=[CH:18][C:14]=1[C:15]([NH:24][C:25]1[C:26]([C:31]([NH:33][C:34]2[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][N:35]=2)=[O:32])=[N:27][CH:28]=[CH:29][CH:30]=1)=[O:17])=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: Nc1cccnc1C(=O)Nc1ccc(Cl)cn1
Reactant: CSc1ccc(C(=O)O)c(OCCCNC(=O)OC(C)(C)C)c1
Product: CSc1ccc(C(=O)Nc2cccnc2C(=O)Nc2ccc(Cl)cn2)c(OCCCNC(=O)OC(C)(C)C)c1

Procedure:
Using a procedure analogous to Example 1-G, 2-(3-tert-butoxycarbonylaminopropoxy)-4-(methylthio)benzoic acid and 3-amino-N-(5-chloropyridin-2-yl)pyridine-2-carboxamide gave the desired product as a solid which was purified by HPLC (2.2 g, 28%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH:11]=[CH:12][CH2:13][CH:14]2[CH2:17]OS(C2C=CC(C)=CC=2)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[N-:29]=[N+:30]=[N-:31].[Na+]>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:16][CH:15]2[CH:10]([CH:11]=[CH:12][CH2:13][CH:14]2[CH2:17][N:29]=[N+:30]=[N-:31])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1ccc(S(=O)(=O)OCC2CC=CC3CN(C(=O)OC(C)(C)C)CC32)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2C=CCC(CN=[N+]=[N-])C2C1

Procedure:
A solution of 33 g (0.08 mol) of (1RS,2RS,6RS)-8-tert-butyloxycarbonyl-2-(4-toluenesulphonyloxymethyl)-8-azabicyclo[4.3.0]non-4-ene (title compound from Example K.5.) and 15.8 g (0.24 mol) of sodium azide in 200 ml of N,N-dimethylformamide is stirred at 70° C. for 40 h. After cooling, the solution is diluted with water (500 ml) and extracted three times with 250 ml of petroleum ether on each occasion. The combined organic phase is washed with 5% strength sodium hydrogen carbonate solution, dried (sodium sulphate) and concentrated.
Reaction SMILES: [CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17]O)[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4].P(Cl)(Cl)(Cl)(Cl)[Cl:38].N1C=CC=CC=1>C(Cl)Cl>[CH:1](=[N:9][CH:10]1[C:35](=[O:36])[N:12]2[C:13]([C:19]([O:21][CH:22]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:20])=[C:14]([CH2:17][Cl:38])[CH2:15][S:16][C@H:11]12)[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[OH:4]
Reactant: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CO)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Reactant: ClP(Cl)(Cl)(Cl)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: O=C(OC(c1ccccc1)c1ccccc1)C1=C(CCl)CS[C@@H]2C(N=Cc3ccccc3O)C(=O)N12
Temperature: -30 °C
Yield: 85.9 %

Procedure:
Benzhydryl 7-salicylideneamino-3-hydroxymethyl-3-cephem-4-carboxylate (1.01 g) was dissolved in methylene chloride (10 ml) and cooled to -30° C. To this solution was added phosphorus pentachloride (0.46 g), followed by addition of pyridine (0.18 ml). The reaction mixture was stirred for an hour at -30° to -20° C. and poured into ice-water. The separated organic layer was washed with water and an aqueous sodium chloride, followed by drying over magnesium sulfate. The solvent was evaporated in vacuo to give benzhydryl 7-salicylideneamino-3-chloromethyl-3-cephem-4-carboxylate (0.9 g).
Reaction SMILES: Br[CH2:2][CH:3]1[CH:5]([CH3:6])[O:4]1.[C:7]1([CH:13]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[NH2:14])[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>CO>[CH:13]([N:14]1[CH2:2][CH:3]([OH:4])[CH:5]1[CH3:6])([C:15]1[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: NC(c1ccccc1)c1ccccc1
Reactant: CC1OC1CBr
Solvent: CO
Product: CC1C(O)CN1C(c1ccccc1)c1ccccc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 38 %

Procedure:
A 500-mL round-bottom flask was charged with 2-(bromomethyl)-3-methyloxirane (42.4 g, 280 mmol), methanol (120 mL), and diphenylmethanamine (44 mL, 260 mmol), and the resulting solution stirred overnight at 80° C. The reaction mixture was cooled to room temperature and concentrated. The residue was purified via column chromatography on silica gel (eluting with 50:1, dichloromethane/methanol) to afford 1-benzhydryl-2-methylazetidin-3-ol (25 g, 35%) as a white solid. MS (ESI, pos. ion) m/z 254 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[C:10]1(=[O:16])[O:15][C:13](=[O:14])[CH2:12][CH2:11]1.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][C:10](=[O:16])[CH2:11][CH2:12][C:13]([OH:15])=[O:14])=[CH:4][CH:3]=1
Reactant: Cc1ccc(CO)cc1
Reactant: O=C1CCC(=O)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: Cc1ccc(COC(=O)CCC(=O)O)cc1
Temperature: 25 °C
Yield: 90.5 %

Procedure:
A mixture of 2.44 g (0.02 mol) of 4-methylbenzyl alcohol, 2.00 g (0.02 mol) of succinic acid anhydride, 6.50 g (0.02 mol) of cesium carbonate, and 150 mL of dioxane was stirred at reflux temperature for 4 hours. The mixture was cooled to room temperature and filtered to remove the solid portion. The solvent was removed under reduced pressure. The crude product was purified by column chromatography on silica gel (ethyl acetate-hexane) to provide 4.022 g of succinic acid mono-(4-methylbenzyl) ester (90.58%).
Reaction SMILES: [CH3:1][C:2]([CH3:27])([CH3:26])[C:3](=[O:25])[CH:4]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:5]([C:13]1[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=1)[S:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+]>C(O)(C)C>[CH3:1][C:2]([CH3:27])([CH3:26])[CH:3]([OH:25])[CH:4]([N:20]1[CH:24]=[N:23][CH:22]=[N:21]1)[CH:5]([C:13]1[CH:14]=[CH:15][C:16]([F:19])=[CH:17][CH:18]=1)[S:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: CC(C)(C)C(=O)C(C(Sc1ccccc1)c1ccc(F)cc1)n1cncn1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)C(O)C(C(Sc1ccccc1)c1ccc(F)cc1)n1cncn1
Reaction time: 48 h
Yield: 77.8 %

Procedure:
9.5 g (25 millimols) of 4,4-dimethyl-1-(4-fluorophenyl)-1-phenylthio-2-(1,2,4-triazol-1-yl)-pentan-3-one (Example 3) were suspended in 150 ml of isopropyl alcohol and 0.5 g (12.5 millimols) of sodium borohydride were added in portions. After 2 days, the mixture was evaporated down in vacuo and the residue was decomposed with dilute acetic acid. The organic phase was taken up in methylene chloride, and the methylene chloride solution was washed with water, dried over sodium sulphate, filtered and evaporated down in vacuo. The crystalline residue was stirred with diisopropyl ether; the crystals were filtered off and dried. 7.5 g (77.9% of theory) of 4,4-dimethyl-1-(4-fluorophenyl)-1-phenylthio-2-(1,2,4-triazol-1-yl)-pentan-3-ol, of melting point 171° C., were obtained.
Reaction SMILES: [ClH:1].Cl.[NH2:3][C@@H:4]1[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]2[C:21]3[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=3)[CH:15]=[CH:14][C:13]2=[O:24])[CH2:6][C@@H:5]1[OH:25].[O:26]1[C:35]2[CH:34]=[C:33]([CH:36]=O)[N:32]=[CH:31][C:30]=2[O:29][CH2:28][CH2:27]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(Cl)Cl.C(N(CC)CC)C.CO.C(Cl)(Cl)Cl>[ClH:1].[O:26]1[C:35]2[CH:34]=[C:33]([CH2:36][NH:3][C@@H:4]3[CH2:9][CH2:8][N:7]([CH2:10][CH2:11][N:12]4[C:21]5[C:16](=[N:17][CH:18]=[C:19]([O:22][CH3:23])[CH:20]=5)[CH:15]=[CH:14][C:13]4=[O:24])[CH2:6][C@@H:5]3[OH:25])[N:32]=[CH:31][C:30]=2[O:29][CH2:28][CH2:27]1
Reactant: O=Cc1cc2c(cn1)OCCO2
Reactant: COc1cnc2ccc(=O)n(CCN3CC[C@@H](N)[C@@H](O)C3)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: COc1cnc2ccc(=O)n(CCN3CC[C@@H](NCc4cc5c(cn4)OCCO5)[C@@H](O)C3)c2c1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
1-{2-[(3S,4R)-4-amino-3-hydroxy-1-piperidinyl]ethyl}-7-(methyloxy)-1,5-naphthyridin-2(1H)-one dihydrochloride (209 mg) was stirred in 9:1 v:v chloroform:MeOH (5 ml) at rt under argon and triethylamine (25011) was added. The mixture was stirred at rt for 10 mins., then 2,3-dihydro[1,4]dioxino[2,3-c]pyridine-7-carboxaldehyde (88 mg, for a synthesis see WO2004058144, Example 2(c) or WO03/087098, Example 19(d)) was added and the mixture was stirred at rt for 4 hours before being treated with sodium triacetoxyborohydride (360 mg) added in one portion. The mixture was then stirred at rt overnight. Saturated aqueous sodium hydrogen cabonate (2 ml) was then added and the organic phase was diluted with DCM to bring the total volume to ca. 50 ml. The organic phase was separated using a hydrophobic frit and the aqueous phase was extracted with DCM (2×10 ml). The combined organic extracts were evaporated under reduced pressure and purified by MDAP to give the free base of the title compound as colourless gum (30 mg).
Reaction SMILES: C1(P(C2C=CC=CC=2)(C2C=CC=CC=2)=[CH:8][C:9]([O:11][CH2:12][CH3:13])=[O:10])C=CC=CC=1.[CH:26]1([CH:30]=O)[CH2:29][CH2:28][CH2:27]1>ClCCl>[CH:26]1(/[CH:30]=[CH:8]/[C:9]([O:11][CH2:12][CH3:13])=[O:10])[CH2:27][CH2:28][CH2:29]1
Reactant: CCOC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: O=CC1CCC1
Solvent: ClCCl
Product: CCOC(=O)/C=C/C1CCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 23 %

Procedure:
Ethyl 2-triphenylphosphoranylideneacetate (9.32 g, 26.74 mmol) was added to a solution of cyclobutanecarbaldehyde, 45a, (1.50 g, 17.83 mmol) in dichloromethane (30 mL). The reaction mixture was briefly purged with nitrogen and capped allowed to stir at room temperature overnight. All volatiles were removed at reduced pressure and the residue was dissolved in Et2O (100 mL) and hexanes (25 mL). The resulting pink precipitate was filtered off and discarded. The solvent was removed from the filtrate at reduced pressure. The crude product was purified via silica gel chromatography (0-20% EtOAc/Hexanes gradient) to afford 646 mg (23%) of the desired product: 1H NMR (400 MHz, CDCl3) δ 7.05 (dd, J=15.6, 6.8 Hz, 1H), 5.73 (dd, J=15.6, 1.4 Hz, 1H), 4.29-4.09 (m, 2H), 3.20-2.98 (m, 1H), 2.28-2.09 (m, 2H), 2.04-1.78 (m, 4H), 1.36-1.18 (m, 3H).
Reaction SMILES: NC1C=CC=CC=1.C1(O)CCCCC1.C1(=O)CCCCC1.[C:22]1(=[N:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1.[N+](C1C=CC=CC=1)([O-])=O>C([O-])(=O)C.[Zn+2].C([O-])(=O)C>[CH:29]1([NH:28][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:34][CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: c1ccc(N=C2CCCCC2)cc1
Agent: CC(=O)[O-]
Agent: [Zn+2]
Solvent: Nc1ccccc1
Solvent: OC1CCCCC1
Solvent: O=C1CCCCC1
Product: c1ccc(NC2CCCCC2)cc1

Procedure:
The reaction was carried out using the same apparatus and the same procedure as in Example 1 except that zinc acetate was not employed. In this case, the distilled aniline layer contained as impurities of 200-400 ppm of cyclohexanol, 1300-2200 ppm of cyclohexanone, 80-150 ppm of cyclohexylideneaniline and 20 ppm of nitrobenzene, and the purity of the aniline was only 99.68-99.80%. Furthermore, in the liquid phase in the reactor, N-cyclohexylaniline was formed rapidly and its content reached about 1.7% after 9 hours had elapsed from the start of the reaction, although the content of nitrobenzene in this liquid phase was maintained at 0.01% or less.
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19](B4OC(C)(C)C(C)(C)O4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2].Br[C:32]1[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][N:33]=1>>[CH:1]([O:4][C:5]([N:7]1[CH2:12][CH2:11][CH:10]([CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([C:32]4[CH:37]=[CH:36][C:35]([S:38]([CH3:41])(=[O:40])=[O:39])=[CH:34][N:33]=4)[CH:20]=[CH:21][C:15]=3[O:14]2)[CH2:9][CH2:8]1)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)c1ccc(Br)nc1
Reactant: CC(C)OC(=O)N1CCC(C2Cc3cc(B4OC(C)(C)C(C)(C)O4)ccc3O2)CC1
Product: CC(C)OC(=O)N1CCC(C2Cc3cc(-c4ccc(S(C)(=O)=O)cn4)ccc3O2)CC1
Yield: 58 %

Procedure:
The title compound is prepared from 4-[5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,3-dihydro-benzofuran-2-yl]-piperidine-1-carboxylic acid isopropyl ester and 2-bromo-5-methanesulfonyl-pyridine following a procedure analogous to that described in Example 1.
Reaction SMILES: C(O)(=O)C(O)=O.[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:15]([NH2:26])=[N:16][NH:17][C:18]=1[C:19]1[CH:24]=[CH:23][C:22]([CH3:25])=[CH:21][CH:20]=1)[CH2:8]CC.Cl.CO[CH:31](OC)[CH2:32][CH:33](OC)OC.C(=O)([O-])[O-].[K+].[K+]>C(O)C.O>[CH2:7]([O:11][C:12](=[O:27])[CH2:13][C:14]1[C:18]([C:19]2[CH:20]=[CH:21][C:22]([CH3:25])=[CH:23][CH:24]=2)=[N:17][N:16]2[CH:33]=[CH:32][CH:31]=[N:26][C:15]=12)[CH3:8]
Reactant: COC(CC(OC)OC)OC
Reactant: CCCCOC(=O)Cc1c(N)n[nH]c1-c1ccc(C)cc1
Agent: Cl
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CCO
Solvent: O
Product: CCOC(=O)Cc1c(-c2ccc(C)cc2)nn2cccnc12
Temperature: 25 °C
Reaction time: 24 h
Yield: 85 %

Procedure:
A stirred slurry of 50.2 g (0.133 mole) of 3-amino-5-(4-methylphenyl)-1H-pyrazole-4-acetic acid butyl ester ethanedioate (1:1) in 500 mL of 190 ethanol was treated first with 5 mL of hydrochloric acid (37%) and then with 21.8 g (0.133 mole) of malonaldehyde bis(dimethyl acetal). After stirring for 24 hours at ambient temperature, the reaction mixture was concentrated in vacuo. The residue was dissolved in 500 mL of methylene chloride and washed with saturated sodium bicarbonate solution. The combined aqueous layers were extracted with methylene chloride then the methylene chloride solutions were combined and washed with water. After drying the methylene chloride solution was concentrated in vacuo. The residue was dissolved in 500 mL of 200 ethanol, treated with 1 mL of concentrated sulfuric acid, and heated on a steam bath for 24 hours. The ethanol solution was treated with 50 g of potassium carbonate and 5 mL of H2O. After stirring for 30 minutes, the inorganic material was removed by filtration and the filtrate concentrated in vacuo to a black tar-like residue. The residue was dissolved in 2-propyl ether, filtered, and treated with ethereal hydrogen chloride. The salt which precipitated was collected by filtration, yielding 44 g of crude yellow-green product. The crude product was dissolved in 190 ethanol, diluted with water, then treated with 20 g of potassium carbonate. The precipitated product was collected by filtration in 2 batches to yield 33.4 g (85%) of tan product, mp 69°-71.5° C. An analytical sample was recrystallized from ethanol-water with charcoal treatment yielding a pale yellow crystalline powder, mp 71°-73° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([O:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]=3[CH:9]=2)[CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][CH2:31][CH3:32]>C(#N)C>[CH2:30]([N:1]1[CH2:2][CH2:3][CH:4]([O:7][C:8]2[CH:22]=[CH:21][C:11]3[NH:12][C:13](=[O:20])[C:14]4[CH:15]=[CH:16][CH:17]=[N:18][C:19]=4[C:10]=3[CH:9]=2)[CH2:5][CH2:6]1)[CH2:31][CH3:32]
Reactant: O=c1[nH]c2ccc(OC3CCNCC3)cc2c2ncccc12
Reactant: CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCCN1CCC(Oc2ccc3[nH]c(=O)c4cccnc4c3c2)CC1
Temperature: 60 °C
Reaction time: 8 h
Yield: 59.3 %

Procedure:
Compound (55 mg, 0.17 mmol) prepared in step 4 and potassium carbonate (70 mg, 0.50 mmol) were dissolved in acetonitrile (10 ml), added with 1-bromopropane (53 μl, 0.058 mol) at room temperature. The resulting mixture was stirred overnight at 60° C. and extracted with chloroform. The organic layer was washed with brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was then purified by flash column chromatography (chloroform:methanol=5:1) to obtain the title compound (34 mg, yield: 61%, white solid).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N+:4]([O-:31])[CH:5]=[C:6]([Cl:30])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH:28]=O)=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1.[NH2:32][CH:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)[C:34]([O:36][CH:37]1[CH2:43][CH:42]2[N:44]([CH3:45])[CH:39]([CH2:40][CH2:41]2)[CH2:38]1)=[O:35].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[Cl:30][C:6]1[CH:5]=[N+:4]([O-:31])[CH:3]=[C:2]([Cl:1])[C:7]=1[CH2:8][C@H:9]([O:20][C:21]([C:23]1[S:24][C:25]([CH2:28][NH:32][CH:33]([C:46]2[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=2)[C:34]([O:36][CH:37]2[CH2:38][CH:39]3[N:44]([CH3:45])[CH:42]([CH2:41][CH2:40]3)[CH2:43]2)=[O:35])=[CH:26][CH:27]=1)=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH3:19])[CH:11]=1
Reactant: CN1C2CCC1CC(OC(=O)C(N)c1ccccc1)C2
Reactant: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(C=O)s2)cc1OC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: COc1ccc([C@H](Cc2c(Cl)c[n+]([O-])cc2Cl)OC(=O)c2ccc(CNC(C(=O)OC3CC4CCC(C3)N4C)c3ccccc3)s2)cc1OC
Temperature: 25 °C
Reaction time: 20 h
Yield: 27.8 %

Procedure:
A mixture of [(1S)-2-(3,5-dichloro-1-oxido-pyridin-1-ium-4-yl)-1-(3,4-dimethoxyphenyl)ethyl]5-formylthiophene-2-carboxylate (0.17 g, 0.35 mmol), (8-methyl-8-azabicyclo[3.2.1]octan-3-yl) 2-amino-2-phenyl-acetate (0.14 g, 0.53 mmol) and acetic acid (40 μL, 0.71 mmol) in dichloromethane (8 mL) was stirred at room temperature for 20 h. Sodium triacetoxyborohydride was added and the reaction mixture was stirred at room temperature for a further 24 h. The mixture was diluted with dichloromethane (10 mL) and washed with saturated sodium bicarbonate solution (2×10 mL) and saturated sodium chloride solution (10 mL). The organic layer was separated and filtered through a phase separator and the solvent was removed by evaporation under reduced pressure. Purification by preparative HPLC gave the title compound (mixture of diastereoisomers) as a pale yellow solid (72 mg, 28%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][CH2:10][C:11]([F:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[CH3:15].[CH3:16][C:17]1[C:26](B2OC(C)(C)C(C)(C)O2)=[CH:25][CH:24]=[CH:23][C:18]=1[C:19]([O:21][CH3:22])=[O:20].C1(P(C2CCCCC2)C2C=CC=CC=2C2C(OC)=CC=CC=2OC)CCCCC1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.O.C1(C)C=CC=CC=1>[F:14][C:11]([CH3:13])([CH3:12])[CH2:10][CH2:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2[CH:25]=[CH:24][CH:23]=[C:18]([C:19]([O:21][CH3:22])=[O:20])[C:17]=2[CH3:16])=[C:3]([CH3:15])[CH:4]=1
Reactant: Cc1cc(OCCC(C)(C)F)ccc1Br
Reactant: COC(=O)c1cccc(B2OC(C)(C)C(C)(C)O2)c1C
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: COc1cccc(OC)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)c1cccc(-c2ccc(OCCC(C)(C)F)cc2C)c1C
Temperature: 80 °C
Reaction time: 12 h

Procedure:
In an atmosphere of nitrogen, a mixture of 1-bromo-4-(3-fluoro-3-methylbutoxy)-2-methylbenzene, methyl 2-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzoate, palladium acetate, dicyclohexyl(2′,6′-dimethoxybiphenyl-2-yl)phosphine, tripotassium phosphate, toluene and water was stirred at 80° C. for 12 hours to obtain methyl 4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-carboxylate. Lithium aluminum hydride was added to a THF solution of the resulting methyl 4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-carboxylate under ice-cooling, followed by warming up to room temperature and stirring for 1 hour to obtain [4′-(3-fluoro-3-methylbutoxy)-2,2′-dimethylbiphenyl-3-yl]methanol.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]2=[O:17])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:24][C:25]1[CH:32]=[CH:31][C:28]([CH2:29][NH2:30])=[CH:27][CH:26]=1>CN(C)C=O.O.C(OCC)(=O)C>[Cl:8][C:6]1[N:7]=[C:2]([NH:30][CH2:29][C:28]2[CH:31]=[CH:32][C:25]([CH3:24])=[CH:26][CH:27]=2)[N:3]=[C:4]([NH:9][CH:10]2[NH:14][C:13](=[O:15])[N:12]([CH3:16])[C:11]2=[O:17])[N:5]=1
Reactant: CN1C(=O)NC(Nc2nc(Cl)nc(Cl)n2)C1=O
Reactant: Cc1ccc(CN)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cc1ccc(CNc2nc(Cl)nc(NC3NC(=O)N(C)C3=O)n2)cc1
Reaction time: 24 h

Procedure:
To a stirred suspension of 5-(4,6-dichloro-[1,3,5]triazin-2-ylamino)-3-methyl-imidazolidine-2,4-dione (Example 1.3, Part D) (200 mg, 0.72 mmol) and potassium carbonate (219 mg, 1.59 mmol) in dimethylformamide (5 mL) at room temperature was added 4-methyl-benzylamine (0.1 mL, 0.79 mmol). The reaction mixture was stirred at 35° for 24 h and then diluted with water and ethyl acetate. The ethyl acetate layer was separated, dried and evaporated to give the crude product which was used directly in the next step.