Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[C:7]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:6][N:5]2[N:14]=[CH:15][N:16]=[C:4]2[N:3]=1.[C:17]([O:21][C:22](=[O:40])[NH:23][CH2:24][C:25]1[CH:30]=[CH:29][C:28](B2OC(C)(C)C(C)(C)O2)=[CH:27][CH:26]=1)([CH3:20])([CH3:19])[CH3:18]>O1CCOCC1.C(Cl)Cl.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[C:17]([O:21][C:22](=[O:40])[NH:23][CH2:24][C:25]1[CH:26]=[CH:27][C:28]([C:2]2[C:7]([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)=[CH:6][N:5]3[N:14]=[CH:15][N:16]=[C:4]3[N:3]=2)=[CH:29][CH:30]=1)([CH3:20])([CH3:18])[CH3:19]
Reactant: Clc1nc2ncnn2cc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)NCc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [CH]1[CH][CH][C](P(c2ccccc2)c2ccccc2)[CH]1
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCc1ccc(-c2nc3ncnn3cc2-c2ccccc2)cc1
Temperature: 100 °C
Yield: 47.7 %

Procedure:
A mixture of compound 3-4 (60 mg 0.24 mmol), [4-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzyl]-carbamic acid tert-butyl ester (100 mg, 0.3 mmol), aq.Na2 CO3 (2M, 0.70 mmol, 0.35 mL) and Pd(DPPF)Cl2 (10 mg) in dioxane (3 mL) was heated at 100° C. in microwave system under N2 atmosphere for 30 min. After cooling, the mixture was diluted with 15 mL of DCM, the combined organic phase was washed with 0.1N HClaq and brine, dried over anhydrous Na2SO4 and concentrated. The residue was purified by prep.TLC to give 46 mg of 3-5. MS (ESI) m/e (M+H) 402.1
Reaction SMILES: C(OC1C=CC(C#CC(C2CCCC2)(O)CC2OC(C)(C)OC(=O)C=2)=CC=1COC(=O)C)(=O)C.C1(C(O)(CC2OC(C)(C)OC(=O)C=2)C#CC2C=CC(C(C)(C)C#N)=C(F)C=2)CCCC1.[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][O:89]C)[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1>>[CH:66]1([C:71]2([CH2:79][CH2:80][C:81]3[CH:86]=[CH:85][C:84]([OH:87])=[C:83]([CH2:88][OH:89])[CH:82]=3)[O:76][C:75](=[O:77])[CH2:74][C:73](=[O:78])[CH2:72]2)[CH2:70][CH2:69][CH2:68][CH2:67]1
Reactant: COCc1cc(CCC2(C3CCCC3)CC(=O)CC(=O)O2)ccc1O
Agent: CC(=O)OCc1cc(C#CC(O)(CC2=CC(=O)OC(C)(C)O2)C2CCCC2)ccc1OC(C)=O
Agent: CC1(C)OC(=O)C=C(CC(O)(C#Cc2ccc(C(C)(C)C#N)c(F)c2)C2CCCC2)O1
Product: O=C1CC(=O)OC(CCc2ccc(O)c(CO)c2)(C2CCCC2)C1

Procedure:
The title compound was prepared analogously to step 4 from Example A(97) where Acetic acid 2-acetoxy-5-[3-cyclopentyl-4-(2,2-dimethyl-6-oxo-6H-[1,3]dioxin-4-yl)-3-hydroxy-but-1-ynyl]-benzyl ester (from step 2 below) was substituted in place of 2-{4-[3-cyclopentyl-4-(2,2-dimethyl-4-oxo-4H-1,3-dioxin-6-yl)-3-hydroxybut-1-ynyl]-2-fluorophenyl}-2-methylpropanenitrile. The product was obtained together with compound from Example A(194). 6-Cyclopentyl-6-[2-(4-hydroxy-3-methoxymethyl-phenyl)-ethyl]-dihydro-pyran-2,4-dione above 1H NMR (400 MHz, CDCl3): δ 1.30-1.80 (m, 9H), 1.83-1.86 (m, 2H), 2.15-2.18 (m, 1H), 2.49-2.54 (m, 2H), 2.67 (s, 2H), 3.33 (s, 2H), 4.76 (s, 2H), 6.71-6.91 (m, 3H). ESIMS (MH−): 331.
Reaction SMILES: [C:1]1(=[O:11])[NH:5][C:4](=[O:6])[C:3]2=[CH:7][CH:8]=[CH:9][CH:10]=[C:2]12.[K].Br[CH2:14][CH2:15][CH:16]=[C:17]([CH3:19])[CH3:18].O>CN(C)C=O>[CH3:18][C:17]([CH3:19])=[CH:16][CH2:15][CH2:14][N:5]1[C:1](=[O:11])[C:2]2=[CH:10][CH:9]=[CH:8][CH:7]=[C:3]2[C:4]1=[O:6]
Reactant: CC(C)=CCCBr
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)=CCCN1C(=O)c2ccccc2C1=O
Temperature: 90 °C
Reaction time: 4 h

Procedure:
To a suspension of phthalimide, potassium derivative (11.5 g, 0.062 mol) in dry dimethylformamide (60 mL) was added 1-bromo-4-methyl-3-pentene (10.0 g, 0.061 mol) and the suspension was stirred under N2 at 90° C. for 4 h. The reaction mixture was poured into water (300 mL) and the precipitated solid was filtered and washed with water and the solid was dried under vacuum. Yield: 12.8 g (91%). mp 95-97° C., MS: (M+H)+=229.9.
Reaction SMILES: C(O)(=O)C.[OH:5][C:6]1[C:13](O)=[CH:12]C=C[C:7]=1[CH:8]=[O:9].C([O-])(=O)C.[Na+].[N+:20]([CH2:23][CH3:24])([O-])=O>O.C(OCC)(=O)C>[OH:9][C:8]1[CH:7]=[C:6]([OH:5])[CH:13]=[CH:12][C:24]=1[C:23]#[N:20]
Reactant: O=Cc1cccc(O)c1O
Reactant: CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: N#Cc1ccc(O)cc1O
Yield: 64.1 %

Procedure:
In an acetic acid (10 mL) solvent, a solution including 2,3-dihydroxybenzaldehyde (3.0 g, 21.7 mmol), sodium acetate (NaOAc) (3.54 g, 43.4 mmol), and nitroethane (3.24 g, 43.4 mmol) was refluxed for 8 hours. After cooling, the reaction mixture was distributed between ethyl acetate and water. Until a pH of the residual aqueous layer reached 8, an organic layer was washed with a saturated NaHCO3 solution. The organic layer was evaporated, the residual was purified by silica gel column chromatography using hexane and ethyl acetate (2:1) as a developer to obtain Compound 101a (1.88 g, 59%).
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]([C:10]3[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=3)=[CH:8][O:9][C:4]=2[CH:3]=1.Br[CH:21]([CH3:27])[C:22]([O:24][CH2:25][CH3:26])=O.C(=O)([O-])[O-:29].[K+].[K+]>CN(C)C=O>[CH2:25]([O:24][CH:22]([O:1][C:2]1[CH:19]=[CH:18][C:5]2[C:6](=[O:17])[C:7]([C:10]3[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=3)=[CH:8][O:9][C:4]=2[CH:3]=1)[CH:21]=[C:27]=[O:29])[CH3:26]
Reactant: CCOC(=O)C(C)Br
Reactant: O=c1c(-c2ccc(O)cc2)coc2cc(O)ccc12
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(C=C=O)Oc1ccc2c(=O)c(-c3ccc(O)cc3)coc2c1
Temperature: 80 °C
Yield: 54.1 %

Procedure:
A mixture of 4.0 g of 7-hydroxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one, 3.42 g of ethyl 2-bromopropionate, 60 ml of dimethylformamide and 4.3 g of potassium carbonate was stirred well with heating at 80° C. for 2 hours, poured into ice water and extracted with ethyl acetate. The extract was washed with water and concentrated and the residue was recrystallized from dichloroethane to give 3.0 g of 7-(1-ethoxy- carbonylethyl)oxy-3-(4-hydroxyphenyl)-4H-1-benzopyran-4-one as white crystals. m.p. 172°-173° C.
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].C([Li])CCC.C[C:16]1[N:21]=[C:20]([CH:22]=[O:23])[CH:19]=[CH:18][CH:17]=1.[Cl-].[NH4+].C[CH2:27][O:28]CC>CCCCCC>[OH:5][CH2:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([O:28][CH3:27])[C:2]=1[CH:22]([C:20]1[CH:19]=[CH:18][CH:17]=[CH:16][N:21]=1)[OH:23]
Reactant: CCOCC
Reactant: Cc1cccc(C=O)n1
Reactant: OCc1ccccc1Br
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: CCCCCC
Product: COc1cccc(CO)c1C(O)c1ccccn1
Temperature: -20 °C
Reaction time: 1 h
Yield: 70.5 %

Procedure:
To a mixture of 28.3 g (0.15 mol) of o-bromobenzyl alcohol in 1 L of ether cooled to -20° C. was added in portions 32.5 ml (0.32 mol) of n-butyllithium (10M) in hexane over a 20 min period and the reaction mixture was stirred for 1 hr. The above reaction mixture was cooled to -20° C., 19.9 g (0.165 mol) of 6-methyl-2-pyridinecarboxaldehyde was added to the mixture, and the resulting reaction mixture was allowed to warm to room temperature. After 1 hour, ammonium chloride solution was added to the mixture. The diol was extracted with ethyl acetate, washed with brine, the ethyl acetate phase was dried over sodium sulfate, and the solvent was removed in vacuo to afford 21.9 g (70.5%) of 2-[1-hydroxy-(2'-hydroxymethyl)-benzyl]-6-methyl-pyridine (Formula XIII: R1 =6--CH3 ; R2 =R7 =H).
Reaction SMILES: C(N(CC)CC)C.[CH3:8][C:9]1[N:10]([CH2:20][CH2:21][OH:22])[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=1.[C:23](Cl)(=[O:25])[CH3:24]>ClCCl>[C:23]([O:22][CH2:21][CH2:20][N:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:13]=[C:9]1[CH3:8])(=[O:25])[CH3:24]
Reactant: Cc1cc(-c2ccccc2)cn1CCO
Reactant: CC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)OCCn1cc(-c2ccccc2)cc1C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Triethylamine (0.5 mL, 3.59 mmol) was added dropwise to a solution of 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethanol (260 mg, 1.29 mmol) in dry dichloromethane (20 mL) at 0 to 5° C. followed by the addition of acetyl chloride (0.2 mL, 2.81 mmol). The reaction mixture was stirred for 30 min and then quenched into ice water (30 mL) and ethyl acetate (20 mL) and stirred for 15 min. The organic layer was separated and washed with water (2×25 mL), brine (2×25 mL), dried over anhydrous sodium sulphate and concentrated in vacuo to afford 2-(2-methyl-4-phenyl-pyrrol-1-yl)ethyl acetate (300 mg, 96%) as a brown liquid.
Reaction SMILES: CN([CH:9]=[O:10])C1C=CC=CC=1.[CH3:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[C:27](=[O:28])[CH:26]=[C:25]3[C:20]([C:21]4[CH:31]=[CH:30][S:29][C:22]=4[CH2:23][CH2:24]3)=[N:19]2)=[CH:14][CH:13]=1>O(Cl)Cl>[OH:10][CH2:9][C:30]1[S:29][C:22]2[CH2:23][CH2:24][C:25]3[C:20]([C:21]=2[CH:31]=1)=[N:19][N:18]([C:15]1[CH:16]=[CH:17][C:12]([CH3:11])=[CH:13][CH:14]=1)[C:27](=[O:28])[CH:26]=3
Reactant: CN(C=O)c1ccccc1
Reactant: Cc1ccc(-n2nc3c(cc2=O)CCc2sccc2-3)cc1
Agent: ClOCl
Product: Cc1ccc(-n2nc3c(cc2=O)CCc2sc(CO)cc2-3)cc1
Temperature: 25 °C
Yield: 9.1 %

Procedure:
A mixture of 1.9 g of N-methylformanilide in 1.3 ml of phosphrus oxychloride was stirred at room temperature for an hour and 2.0 g of 2-(4-methylphenyl)-5,6-dihydrothieno-[2,3-h]cinnolin-3(2H)-one was added thereto. After stirring at room temperature for 10 hours, the mixture was poured into ice-cold water and extracted with chloroform. The extract was washed with water, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was dissolved in methanol and 1.0 g of sodium borohydride was added thereto under ice-cooling. After stirring for an hour, the mixture was poured into diluted hydrochloric acid and extracted with chloroform. The extract was washed with brine, dried over anhydrous magnesium sulfate and concentrated in vacuo. The residue was chromatographed on a silica gel column using a mixed solvent of hexane and ethyl acetate (2:1) as an eluent. The solid was recrystallized from a mixed solvent of isopropyl alcohol and isopropyl ether to give 0.2 g of 8-hydroxymethyl-2-(4-methylphenyl)-5,6-dihydrothieno-[2,3-h]cinnolin3(2H)-one as a brown powder, melting at 166°-169° C.
Reaction SMILES: Cl[CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12].[I-:28].[Na+]>C(#N)C>[I:28][CH2:2][O:3][C:4](=[O:27])[C:5]([CH3:26])([CH3:25])[CH2:6][O:7][C:8](=[O:24])[C@@H:9]([CH:21]([CH3:23])[CH3:22])[NH:10][C:11]([O:13][CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:12]
Reactant: [I-]
Reactant: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCCl
Agent: [Na+]
Solvent: CC#N
Product: CC(C)[C@@H](NC(=O)OCc1ccccc1)C(=O)OCC(C)(C)C(=O)OCI

Procedure:
2,2-Dimethyl-3-(N-CBz-D-valyloxy)-propionic acid chloromethyl ester (2.4 g, 6 mmole) was dissolved in acetonitrile (30 ml). Sodium iodide (1.26 g, 8.4 mmole) was added to the solution. After reaction at 70° C. for 2 hr, the reaction mixture was filtered and the residue was dissolved in methylene chloride (20 ml) and refiltered. The solution was dried and gave the titled product. 2.68g.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[N:11]1)=[CH:6][N:7](C)C)C.[NH:16]([C:18]1[CH:23]=[C:22]([CH3:24])[CH:21]=[CH:20][N:19]=1)N.C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O>C(O)C>[CH3:24][C:22]1[CH:21]=[CH:20][N:19]=[C:18]([N:16]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[N:11]3)=[CH:6][NH:7]2)[CH:23]=1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnn1
Reactant: Cc1ccnc(NN)c1
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CCO
Product: Cc1ccnc(-n2[nH]cc(-n3ccnn3)c2=O)c1

Procedure:
250 mg (1.19 mmol) of the compound from Example 3A, 122 mg (0.99 mmol) of the compound from Example 1A and 23 mg (99 μmol) camphor-10-sulfonic acid are dissolved in 5 ml anhydrous ethanol and the mixture is heated under reflux overnight.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:8]([OH:13])=[CH:9][C:10]=1[O:11][CH3:12])[CH:6]=[O:7].C(=O)([O-])[O-].[K+].[K+].[CH3:20][N:21]([CH3:26])[S:22](Cl)(=[O:24])=[O:23].O>CN(C=O)C>[CH3:20][N:21]([CH3:26])[S:22](=[O:24])(=[O:23])[O:13][C:8]1[CH:9]=[C:10]([O:11][CH3:12])[C:3]([O:2][CH3:1])=[CH:4][C:5]=1[CH:6]=[O:7]
Reactant: COc1cc(O)c(C=O)cc1OC
Reactant: CN(C)S(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(C=O)c(OS(=O)(=O)N(C)C)cc1OC
Temperature: 10 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
Dissolve 16.2 g (0.0889 mol) of 3,4-dimethoxy-6-hydroxybenzaldehyde in 80 ml of DMF. Cool to 10° C. and add in portions 24.6 g (0.178 mol) of potassium carbonate. Allow to return to ambient temperature and stir for 30 minutes. Cool to approximately 10° C. and pour in dropwise 10.1 ml (0.093 mol) of N,N-dimethylsulphamoyl chloride. Allow to return to ambient temperature and stir for 2 h. Pour the reaction mixture into 600 g of water and ice and stir for 1 h at ambient temperature. The precipitate formed is filtered off and washed 3 times with 50 ml of water each time and then dried in vacuo. 21.3 g of title product are obtained.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].Cl.[NH2:8][OH:9].[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18]Br)=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]>CN(C)C=O>[C:10]([C:14]1[CH:21]=[CH:20][C:17]([CH2:18][N:8]([CH2:18][C:17]2[CH:20]=[CH:21][C:14]([C:10]([CH3:13])([CH3:12])[CH3:11])=[CH:15][CH:16]=2)[OH:9])=[CH:16][CH:15]=1)([CH3:13])([CH3:12])[CH3:11]
Reactant: NO
Reactant: CC(C)(C)c1ccc(CBr)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)c1ccc(CN(O)Cc2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C

Procedure:
To a suspension of 23.0 g of anhydrous sodium carbonate in 75 ml of dry dimethylformamide is added 3.78 g of hydroxylamine hydrochloride followed by 24.72 g of p-tert-butylbenzyl bromide. After stirring at room temperature, the insoluble inorganic residue is removed by filtration and the mixture is concentrated under reduced pressure. Preparative liquid chromatography on the crude product affords a white solid, mp 108°-110° C.
Reaction SMILES: [CH:1]1([OH:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24](Cl)=[O:25].Cl.C(N(CC)CC)C>C1(C)C=CC=CC=1.C(OCC)C>[Cl:15][C:16]1[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:17]=1[O:18][C:19]1[CH:20]=[CH:21][C:22]([N+:28]([O-:30])=[O:29])=[C:23]([CH:27]=1)[C:24]([O:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)=[O:25]
Reactant: O=C(Cl)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]
Reactant: OC1CCCCC1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: O=C(OC1CCCCC1)c1cc(Oc2ccc(Cl)cc2Cl)ccc1[N+](=O)[O-]

Procedure:
To a stirred solution of cyclohexanol (1.05g., 0.0105 mole) and triethylamine (1.10g., 0.011 mole) in toluene (30 ml.) was added 5-(2',4'-dichlorophenoxy)-2-nitrobenzoyl chloride (3.47g., 0.01 mole). A precipitate of triethylamine hydrochloride occurred immediately. The reaction solution was heated to reflux for one hour, cooled and diluted with diethyl ether (150 ml.). After filtering the triethylamine hydrochloride, the solvent was evaporated to give 4.1g. of a brown oil. A small amount of additional precipitate was filtered off. The ether was again stripped to yield 3.5g. of brown oil.
Reaction SMILES: Cl[C:2]1[N:11]=[CH:10][C:9]2[N:8]([CH3:12])[C:7](=[O:13])[C@@H:6]([CH2:14][CH3:15])[N:5]([CH:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)[C:4]=2[N:3]=1.[CH3:21][N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1>CS(C)=O.O>[CH:16]1([N:5]2[C:4]3[N:3]=[C:2]([N:25]4[CH2:26][CH2:27][N:22]([CH3:21])[CH2:23][CH2:24]4)[N:11]=[CH:10][C:9]=3[N:8]([CH3:12])[C:7](=[O:13])[C@H:6]2[CH2:14][CH3:15])[CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: CN1CCNCC1
Reactant: CC[C@@H]1C(=O)N(C)c2cnc(Cl)nc2N1C1CCCC1
Solvent: CS(C)=O
Solvent: O
Product: CC[C@@H]1C(=O)N(C)c2cnc(N3CCN(C)CC3)nc2N1C1CCCC1

Procedure:
Intermediate B (114 mg, 0.39 mmol) and N-methylpiperazine (2 mmol, 6 eq, 204 mg, 0.22 mL) in 1 mL of DMSO was heated at 120° C. in a microwave for 2 h. The reaction was diluted with water and extracted with EtOAc. The organic extracts were washed 5× with water, then dried with MgSO4 and evaporated. The residue was purified by reverse-phase HPLC (eluting with 10-30% acetonitrile in water with 0.1% TFA over 20 min; Phenomenex Luna C-18 column, 25×2 cm) to give the title compound after lyophylization. LCMS: 359.2 m/z (M+H)+; ret. Time: 6.72 min (Analytical Method A); 1H NMR (400 MHz, CDCl3) δ: 7.6 (s, 1H), 4.3 (ddd, 1H), 4.1 (dd, 1H), 4.8 (broad s, 4H), 3.3 (s, 3H), 2.5 (broad s, 4H), 2.3 (s, 3H), 2.1-1.6 (m, 10H) and 0.9 ppm (dd, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[OH:13].Br[CH2:15][CH:16]1[CH2:18][CH2:17]1>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([O:9][CH2:10][O:11][CH3:12])=[CH:4][C:3]=1[O:13][CH2:15][CH:16]1[CH2:18][CH2:17]1
Reactant: COCOc1cc(O)c(Br)cc1F
Reactant: BrCC1CC1
Product: COCOc1cc(OCC2CC2)c(Br)cc1F

Procedure:
Starting from 2-bromo-4-fluoro-5-methoxymethoxy-phenol (example A7) and bromomethyl-cyclopropane the title compound is obtained as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([CH2:8][C:9]([C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)=O)[CH:5]=[CH:4][N:3]=1.[CH3:24][CH:25]([CH3:29])[C:26](=[S:28])[NH2:27]>>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[S:28][C:26]([CH:25]([CH3:29])[CH3:24])=[N:27][C:9]=2[C:11]2[CH:12]=[C:13]([NH:17][C:18](=[O:23])[O:19][CH2:20][CH:21]=[CH2:22])[CH:14]=[CH:15][CH:16]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CC(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)C)sc2-c2ccnc(Cl)n2)c1
Yield: 45.9 %

Procedure:
Following a procedure analogous to the procedure described in Intermediate 6, using 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]phenyl}carbamate (10.0 g, 30.14 mmol), and 2-methylpropanethioamide (3.73 g, 36.17 mmol), prepared by a procedure analogous to Intermediate 1, 5.74 g of the title compound was obtained. MS (ESI): 415 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15](O)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1.Cl.CN(C)CCCN=C=NCC.[CH3:35][N:36]1[C:41]([CH3:43])([CH3:42])[CH2:40][CH:39]([NH2:44])[CH2:38][C:37]1([CH3:46])[CH3:45]>CN(C=O)C.C1COCC1.C1COCC1>[Cl:1][C:2]1[C:21]([Cl:22])=[CH:20][C:5]2[N:6]=[C:7]([C:9]3[CH:14]=[CH:13][C:12]([C:15]([NH:44][CH:39]4[CH2:38][C:37]([CH3:45])([CH3:46])[N:36]([CH3:35])[C:41]([CH3:43])([CH3:42])[CH2:40]4)=[O:16])=[CH:11][C:10]=3[O:18][CH3:19])[NH:8][C:4]=2[CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CN1C(C)(C)CC(N)CC1(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1cc(C(=O)NC2CC(C)(C)N(C)C(C)(C)C2)ccc1-c1nc2cc(Cl)c(Cl)cc2[nH]1
Reaction time: 1 h
Yield: 47.6 %

Procedure:
A solution of 5,6-dichloro-2-(4-carboxy-2-methoxyphenyl)benzimidazole (0.8 g, 2,36 mmol), prepared as described in Preparation 6,1-hydroxybenzotriazole (0.32 g, 2.36 mmol) and N-(3-dimethylaminopropyl)-N′-ethylcarbodiimide hydrochloride (0.56 g, 2.9 mmol) in 80 ml of DMF/THF (50:50) was refluxed for 5 h. A solution of 1,2,2,6,6-pentamethyl-4-aminopiperidine (0.5 g, 2.9 mmol) in THF (5 ml) was added dropwise and the reaction was refluxed for additional 3 h. After cooling, solvent was removed under reduced pressure and the residue was treated with 1N NaOH (10 ml) and extracted with dichloromethane (50 ml). The organic layer was washed with water, dried over Na2SO4, filtered and evaporated under reduced pressure. The residue was triturated with diisopropyl ether (150 ml), stirred for 1 h, filtered to give 0.55 g of the title compound (yield 47.6%), mp=285–286° C.
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([CH2:9][C@H:10]([NH:14][C:15](=[O:24])OCC2C=CC=CC=2)[C@H:11]2[CH2:13][O:12]2)[CH:5]=[C:6](F)[CH:7]=1.[CH3:25][O:26][C:27]1[CH:36]=[C:35]2[C:30](CCC[CH:34]2[NH2:37])=[CH:29][CH:28]=1.C([N:41](CCC)[C:42]([C:44]1[CH:45]=[C:46]([CH:50]=[C:51](CC)[CH:52]=1)C(O)=O)=O)CC>>[CH2:9]([C@H:10]([NH:14][C:15](=[O:24])[C:51]1[CH:50]=[CH:46][CH:45]=[C:44]([C:42]#[N:41])[CH:52]=1)[C@H:11]([OH:12])[CH2:13][NH:37][CH2:34][C:35]1[CH:30]=[CH:29][CH:28]=[C:27]([O:26][CH3:25])[CH:36]=1)[C:4]1[CH:3]=[CH:2][CH:7]=[CH:6][CH:5]=1
Reactant: CCCN(CCC)C(=O)c1cc(CC)cc(C(=O)O)c1
Reactant: O=C(N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1)OCc1ccccc1
Reactant: COc1ccc2c(c1)C(N)CCC2
Product: COc1cccc(CNC[C@@H](O)[C@H](Cc2ccccc2)NC(=O)c2cccc(C#N)c2)c1

Procedure:
Following the general procedure of EXAMPLEs 4, 5 and 6 and making non-critical variations but using tert-butyl 1-(2-oxiranyl)-2-phenylethylcarbamate (V), 3-methoxybenzylamine (VI) and 3-cyanobenzoic acid (IX), the title compound is obtained, MH+=430.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](/[CH:10]=[CH:11]/[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[N:18]2[CH:22]=[CH:21][C:20]([CH:23]=O)=[CH:19]2)=[N:2]1.[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C(O)(=O)C.[BH4-].[Na+]>ClC(Cl)C>[N:25]1([CH2:23][C:20]2[CH:21]=[CH:22][N:18]([C:13]3[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=3/[CH:11]=[CH:10]/[C:3]3[C:4]4[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=4)[NH:1][N:2]=3)[CH:19]=2)[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1
Reactant: O=Cc1ccn(-c2ccccc2/C=C/c2n[nH]c3ccccc23)c1
Reactant: C1COCCN1
Agent: [BH4-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(Cl)Cl
Product: C(=C/c1n[nH]c2ccccc12)\c1ccccc1-n1ccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40 %

Procedure:
Compound 167 (0.08 g, 0.26 mmol) was dissolved in dichloroethane (2.0 mL) and the solution was added with morpholine (67 μL, 0.77 mmol), acetic acid (84 μL, 0.77 mmol) and sodium borohydride (0.16 g, 0.77 mmol) followed by stirring at room temperature for 30 minutes. The reaction mixture was extracted with ethyl acetate, the organic layer was concentrated and the residue was purified by silica gel column chromatography (chloroform/methanol=9/1) to obtain Compound 182 (0.04 g, 41%).
Reaction SMILES: [CH3:1][NH:2][C:3]1[C:7]([NH:8][CH2:9][CH2:10][SH:11])=[N:6][S:5](=[O:13])(=[O:12])[N:4]=1.[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23]O)[N:22]=1)[CH3:16]>Cl>[CH3:14][N:15]([CH2:17][C:18]1[S:19][CH:20]=[C:21]([CH2:23][S:11][CH2:10][CH2:9][NH:8][C:7]2[C:3]([NH:2][CH3:1])=[N:4][S:5](=[O:13])(=[O:12])[N:6]=2)[N:22]=1)[CH3:16]
Reactant: CNC1=NS(=O)(=O)N=C1NCCS
Reactant: CN(C)Cc1nc(CO)cs1
Agent: Cl
Product: CNC1=NS(=O)(=O)N=C1NCCSCc1csc(CN(C)C)n1

Procedure:
Reaction of 3-methylamino-4-(2-mercaptoethylamino)-1,2,5-thiadiazole 1,1-dioxide [prepared in Example 25, Step A] with about one equivalent of 2-dimethylaminomethyl-4-hydroxymethylthiazole [prepared in Example 34, Step D] in concentrated hydrochloric acid, and then made basic and worked up, produces the title compound which is identical to the product prepared in Example 33.