Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:16]([N:18]([CH3:20])[CH3:19])=[O:17])=[C:6]([S:8]([NH:11][C:12]([CH3:15])([CH3:14])[CH3:13])(=[O:10])=[O:9])[CH:7]=1.[C:21](Cl)(=[O:24])[CH2:22][CH3:23].C(N(CC)CC)C>CN(C=O)C.C(OCC)(=O)C>[C:12]([NH:11][S:8]([C:6]1[CH:7]=[C:2]([NH:1][C:21](=[O:24])[CH2:22][CH3:23])[CH:3]=[CH:4][C:5]=1[C:16]([N:18]([CH3:20])[CH3:19])=[O:17])(=[O:9])=[O:10])([CH3:15])([CH3:14])[CH3:13]
Reactant: CN(C)C(=O)c1ccc(N)cc1S(=O)(=O)NC(C)(C)C
Reactant: CCC(=O)Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CCC(=O)Nc1ccc(C(=O)N(C)C)c(S(=O)(=O)NC(C)(C)C)c1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
0.85 g of 5-amino-N-tert.-butyl-2-dimethylaminocarbonyl-benzenesulfonamide (Example e) is dissolved in 3.5 ml of DMF at 0° C., and 0.28 g of propionyl chloride and 0.50 ml of triethylamine are added. After the mixture has been stirred at 5° C. for 1 hour, it is taken up in ethyl acetate and washed successively with dilute hydrochloric acid and water. After the mixture has been dried over MgSO4 and the organic phase has been concentrated, 0.60 g of a highly viscous substance, which is employed in subsequent reactions without further purification (Example k), is obtained.
Reaction SMILES: Br[CH:2]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH:15]([NH:28][C:29](=[O:37])[N:30]([CH3:36])[CH:31]1[CH2:35][CH2:34][NH:33][CH2:32]1)([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C([O-])([O-])=O.[K+].[K+]>CC(=O)CC>[CH:15]([NH:28][C:29](=[O:37])[N:30]([C@@H:31]1[CH2:35][CH2:34][N:33]([CH:2]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:32]1)[CH3:36])([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: CN(C(=O)NC(c1ccccc1)c1ccccc1)C1CCNC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CN(C(=O)NC(c1ccccc1)c1ccccc1)[C@@H]1CCN(C(c2ccccc2)c2ccccc2)C1

Procedure:
To a solution of bromodiphenylmethane (0.43 g, 1.75 mmol) in butanone (10 ml) was added 3-benzhydryl-1-methyl-1-pyrrolidin-3-yl-urea(0.65 g, 2.1 mmol), K2CO3 (0.24, 1.75 mmol) and KI (0.29 g, 1.75 mmol). The mixture was heated under reflux for 18 hours, then filtered and the solvent was removed in vacuo. The residue was dissolved in CH2Cl2 (50 ml) and washed with water (10 ml). Drying over MgSO4 and removal of solvent under reduced pressure followed by column chromatography using Hex:EtOAc (1:1) gives the desired product.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[CH2:8][CH:7]1[C:11]([O:13][CH2:14][CH3:15])=[O:12].S(OOS([O-])(=O)=O)([O-])(=O)=O.[K+].[K+].P([O-])([O-])(O)=O.[Na+].[Na+].O>C(#N)C>[O:10]=[C:9]1[NH:6][CH:7]([C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH2:8]1
Reactant: CCOC(=O)C1CC(=O)N1Cc1ccc(OC)cc1OC
Agent: O=P([O-])([O-])O
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: CCOC(=O)C1CC(=O)N1
Yield: 41 %

Procedure:
6 g. (20.5 mmoles) of ethyl 1-(2,4-dimethoxybenzyl)-4-oxo-2-azetidine-carboxylate prepared according to Example 10, 11 g. (41 mmoles) of potassium peroxidisulfate and 14.5 g, (82 mmoles) of disodium hydrogenphosphate×2H2O are boiled in a mixture of 60 ml. of water and 90 ml. of acetonitrile for 6 hours. The biphase reaction mixture is separated, the aqueous phase is shaken with 100 ml. of benzene and the combined organic phase is extracted with three 30-ml. portions of a saturated aqueous sodium chloride solution. The organic phase is dried with magnesium sulfate, filtered and the filtrate is evaporated. The obtained oily product is subjected to column chromatography (Kieselgel 60, 0.063-0.200 mm., benzene followed by a 99:1 mixture of benzene and acetone). 1.21 g. (41%) of the named compound are obtained.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][C:6]1[CH:11]=[CH:10][C:9]([S:12][C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][C:14]=2[N+:23]([O-])=O)=[CH:8][CH:7]=1)=[O:4].COC(=O)C1C=CC(SC2C=CC(NC(OC(C)(C)C)=O)=CC=2)=C([N+]([O-])=O)C=1>>[NH2:23][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:13]=1[S:12][C:9]1[CH:10]=[CH:11][C:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])=[CH:7][CH:8]=1)[C:17]([O:19][CH3:20])=[O:18]
Reactant: COC(=O)Nc1ccc(Sc2ccc(C(=O)OC)cc2[N+](=O)[O-])cc1
Agent: COC(=O)c1ccc(Sc2ccc(NC(=O)OC(C)(C)C)cc2)c([N+](=O)[O-])c1
Product: COC(=O)Nc1ccc(Sc2ccc(C(=O)OC)cc2N)cc1
Yield: 88 %

Procedure:
The title compound was prepared by the procedure in Example 385C substituting the product from Example 441A for the product of Example 385B. The reaction was purified by silica gel chromatography (ethyl acetate/CHCl3=1/9) to give the title compound (yield 88%).
Reaction SMILES: [C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28](=[O:36])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[OH:35])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22].[F:37][C:38]1[CH:43]=[C:42]([F:44])[CH:41]=[CH:40][C:39]=1C1C=CC(O)=C(C(O)=O)C=1>>[C:1]([NH:24][CH2:25][CH2:26][NH:27][C:28]([C:29]1[CH:34]=[C:33]([C:41]2[CH:40]=[CH:39][C:38]([F:37])=[CH:43][C:42]=2[F:44])[CH:32]=[CH:31][C:30]=1[OH:35])=[O:36])(=[O:23])[CH2:2][CH2:3]/[CH:4]=[CH:5]\[CH2:6]/[CH:7]=[CH:8]\[CH2:9]/[CH:10]=[CH:11]\[CH2:12]/[CH:13]=[CH:14]\[CH2:15]/[CH:16]=[CH:17]\[CH2:18]/[CH:19]=[CH:20]\[CH2:21][CH3:22]
Reactant: O=C(O)c1cc(-c2ccc(F)cc2F)ccc1O
Reactant: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1ccccc1O
Product: CC/C=C\C/C=C\C/C=C\C/C=C\C/C=C\C/C=C\CCC(=O)NCCNC(=O)c1cc(-c2ccc(F)cc2F)ccc1O

Procedure:
N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2′,4′-difluoro-4-hydroxybiphenyl-3-carboxamide was prepared in a similar fashion as N-(2-(4Z,7Z,10Z,13Z,16Z,19Z)-docosa-4,7,10,13,16,19-hexaenamidoethyl)-2-hydroxybenzamide, using the appropriate 2′,4′-difluoro-4-hydroxybiphenyl-3-carboxylic acid starting material. Mass calculated for C37H44F2N2O3=602.75. found: [M+H]+=603.3.
Reaction SMILES: O[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16](O)[CH3:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)[CH3:3].C(C1C=C(O)C(=CC=1)O)(C)(C)C.CC1C=CC=CC=1C>O>[CH:2]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([CH:16]=[CH2:17])=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)=[CH2:3]
Reactant: CC(O)c1ccc(-c2ccc(C(C)O)cc2)cc1
Agent: CC(C)(C)c1ccc(O)c(O)c1
Solvent: O
Solvent: Cc1ccccc1C
Product: C=Cc1ccc(-c2ccc(C=C)cc2)cc1

Procedure:
The mixture of 5.0020 g (0.02064 mole) of 4,4′-di-(1-hydroxyethyl)biphenyl (DHEBP), 0.0050 g (0.1% of DHEBP weight) of 4-tert-butyl catechol, 00742 g (1.483% of DHEBP weight or 4.11 mmol/L) of TSA, and 90 mL of o-xylene was heated at the boiling temperature for 40 minutes. Water released during the dehydration was azeotroped from the system. Then, the reaction mixture was treated as described in Example 1. The yield of the unsaturated composition riched with 4,4′-divinylbiphenyl (DVBP) was 3.8 g (89.3% of theor.). According to reversed phase chromatography, the content of components was as follows, wt-%: Monomer M1 (DVBP) 77, its unsaturated dimer 17, its insaturated trimer 5%, tetramers and higher oligomers <1%. The pure DVBP (purity was >99.5%), mp 150-153° C. was obtained by sublimation of the monomer at 160° C. for 1 hour under vacuum (1-2 mm Hg).
Reaction SMILES: [CH2:1]([N:4]([CH:18]1[CH2:27][CH2:26][C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[OH:28])[CH2:19]1)[CH2:5][CH2:6][N:7]1[C:15](=O)[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[C:8]1=O)[CH2:2][CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:8]1[C:9]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:15][N:7]1[CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH:18]1[CH2:27][CH2:26][C:25]2[C:24]([OH:28])=[CH:23][CH:22]=[CH:21][C:20]=2[CH2:19]1
Reactant: CCCN(CCN1C(=O)c2ccccc2C1=O)C1CCc2c(O)cccc2C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCN(CCN1Cc2ccccc2C1)C1CCc2c(O)cccc2C1

Procedure:
The product of Example 13 was reduced with LAH in dry THF and, after purification, the isolated compound was characterized by its HCl.salt NMR, (CD3OD) δ7.7 (m, 4H), 6.9 (m, 1H), 6.6 (m, 2H), 1.0 (t, 3H).
Reaction SMILES: [F:1][CH:2]([F:19])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][C:12]2[CH:13]=[C:14]([OH:18])[CH:15]=[CH:16][CH:17]=2)=[CH:6][CH:5]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[Na+].Br[CH2:29][CH2:30][CH:31]=[C:32]([F:34])[F:33]>CCCCCCCC[N+](CCCCCCCC)(CCCCCCCC)C.[Cl-].C(C(C)=O)C.ClCCl>[F:33][C:32]([F:34])=[CH:31][CH2:30][CH2:29][O:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:11]#[C:10][C:7]2[CH:6]=[CH:5][C:4]([O:3][CH:2]([F:19])[F:1])=[CH:9][CH:8]=2)[CH:13]=1
Reactant: Oc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Reactant: FC(F)=CCCBr
Agent: CCCCCCCC[N+](C)(CCCCCCCC)CCCCCCCC
Agent: O=C([O-])[O-]
Agent: [Cl-]
Solvent: CCC(C)=O
Solvent: ClCCl
Product: FC(F)=CCCOc1cccc(C#Cc2ccc(OC(F)F)cc2)c1
Temperature: 80 °C
Yield: 46.2 %

Procedure:
A mixture of 3-((4-(difluoromethoxy)phenyl)ethynyl)phenol (900 mg), potassium carbonate (636 mg), Aliquat 336 (4 drops), sodium iodide (catalytic) and 4-bromo-1,1-difluoro-1-butene (591 μL) in methyl ethyl ketone was placed in a pressure vessel, heated at 80° C. for 15 h, cooled to room temperature, diluted with dichloromethane and filtered. The filtrate was concentrated in vacuo. The resultant residue was purified by flash chromatography (silica gel, eluant: 2.5% ethyl acetate/hexane to afford 1-(4,4-difluorobut-3-enyloxy)-3-((4-(difluoromethoxy)phenyl)-ethynyl)benzene, 560 mg (46.2% yield); 1H NMR (chloroform-d1): δ 7.51 (d, J=8.8 Hz, 2H), 7.24 (m, 1H), 7.10 (m, 1H), 7.08 (d, J=8.8 Hz, 2H), 7.03 (m, 1H), 6.87 (m, 1H), 6.52 (t, J=73.5 Hz, 1H), 4.32 (m, 1H), 3.97 (t, J=6.4 Hz, 2H) and 2.47 (m, J=6.4 Hz, 2H); MS (ES pos) m/z 350.
Reaction SMILES: [C:1]([C:3]([O:5][CH2:6][CH2:7][CH2:8][CH3:9])=[O:4])#[N:2].C1(N=[CH:17][C:18]2[O:19][CH:20]=[CH:21][C:22]=2[CH3:23])C=CC=CC=1>C1(C)C(C)=CC=CC=1>[CH2:6]([O:5][C:3]([C:1]1[CH:23]=[C:22]2[CH:21]=[CH:20][O:19][C:18]2=[CH:17][N:2]=1)=[O:4])[CH2:7][CH2:8][CH3:9]
Reactant: CCCCOC(=O)C#N
Reactant: Cc1ccoc1C=Nc1ccccc1
Solvent: Cc1ccccc1C
Product: CCCCOC(=O)c1cc2ccoc2cn1
Temperature: 130 °C
Yield: 45.8 %

Procedure:
n-Butyl cyanoformate(13.7 g, 0.108 mol) and 3-methylfuran-2-carbaldehyde-N-phenylimine(5.0 g, 27.0 mmol) were mixed at room temperature in xylene (25 mL) then heated to reflux at 120 to 140° C. with stirring. A xylene (15 mL) solution of 7.40 g (54.2 mol) of n-butyl chlorofornate was added dropwise for an hour to the resulting mixture. After all the solution had been added, the reaction mixture was heated to reflux for 2 hours, it was allowed to cool to room temperature, and the solvent was distilled off to give 7.10 g of crude product. This product was purified by column chromatography on silica gel, giving 2.71 g (45.8% yield) of 5-n-butoxycarbonylfuro[2,3-c]pyridine.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[C:12](Br)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:20][N:21](C)P(N(C)C)(N(C)C)=O>C(Cl)Cl>[CH2:1]([O:8][C:9]1([C:20]#[N:21])[C:18]2[CH2:17][CH2:16][CH2:15][CH2:14][C:13]=2[CH:12]=[CH:11][CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)P(=O)(N(C)C)N(C)C
Reactant: Brc1ccc(OCc2ccccc2)c2c1CCCC2
Solvent: ClCCl
Product: N#CC1(OCc2ccccc2)CC=CC2=C1CCCC2

Procedure:
1-Benzyloxy-4-bromo-5,6,7,8-tetrahydronaphthalene (4.5 g, 14.2 mM), cuprous cyanide (1.71 g, 8.67 mM) pyridine (1 ml) and hexamethylphosphoramide (0.25 ml) was stirred at 170° C. for 16 hours. The resultant viscous mixture was dissolved in methylene chloride and washed with ammonium hydroxide solution, saturated brine solution, dried (sodium sulphate) and evaporated to give an oil (4.6 g). This oil was chromatographed on alumina (eluted with methylene chloride:petroleum ether, 1:1) to give the nitrile (5) as a solid (2.4 g) m pt 74°-75.5° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH:13]C(=O)C)=[CH:10][CH:9]=[C:8]2[S:17]([OH:20])(=[O:19])=[O:18].Cl>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:12]=1[C:11]([NH2:13])=[CH:10][CH:9]=[C:8]2[S:17]([OH:20])(=[O:19])=[O:18]
Reactant: COc1cccc2c(S(=O)(=O)O)ccc(NC(C)=O)c12
Agent: Cl
Product: COc1cccc2c(S(=O)(=O)O)ccc(N)c12

Procedure:
8-Methoxy-1-acetylaminonaphthalene-4-sulfonic acid is suspended in 20%-strength hydrochloric acid and the suspension is heated under a reflux condenser while stirring at 90°-100° C. After approx 1-11/2 hours, the deacetylation is complete. The mixture is allowed to cool to 20°-25° C., the slightly pink-colored crystals are filtered off by suction, they are washed on the sintered disk filter funnel with water and then dried in a vacuum drying oven at 50°-60° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=1.[CH3:30][C:31]1[N:36]=[C:35]([O:37][CH3:38])[C:34](B(O)O)=[CH:33][CH:32]=1>>[C:26]([C:4]1[C:5]([O:24][CH3:25])=[C:6](/[CH:8]=[CH:9]/[C:10]2[CH:15]=[CH:14][C:13]([NH:16][S:17]([CH3:20])(=[O:19])=[O:18])=[CH:12][C:11]=2[CH2:21][O:22][CH3:23])[CH:7]=[C:2]([C:34]2[C:35]([O:37][CH3:38])=[N:36][C:31]([CH3:30])=[CH:32][CH:33]=2)[CH:3]=1)([CH3:29])([CH3:27])[CH3:28]
Reactant: COc1nc(C)ccc1B(O)O
Reactant: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(Br)cc(C(C)(C)C)c1OC
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(C)nc2OC)cc(C(C)(C)C)c1OC

Procedure:
step 1—Cross coupling of 315 and 6-methyl-2-methoxy-3-pyridine boronic acid (316, CASRN 1000802-754) was carried out in accord with the procedure in step 4 of example 38 except 107 was replaced with 316 which afforded N-(4-{(E)-2-[3-tert-butyl-2-methoxy-5-(2-methoxy-6-methyl-pyridin-3-yl)-phenyl]-vinyl}-3-methoxymethyl-phenyl)-methanesulfonamide (318).
Reaction SMILES: I[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1.[C:13]([OH:18])(=[O:17])[CH2:14][CH:15]=[CH2:16].CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Cl>C(OC(=O)C)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(#N)C.C(N(CC)CC)C>[C:13]([CH2:14]/[CH:15]=[CH:16]/[C:2]1[CH:12]=[CH:11][C:5]([C:6]([O:8][CH2:9][CH3:10])=[O:7])=[CH:4][CH:3]=1)([OH:18])=[O:17]
Reactant: CCOC(=O)c1ccc(I)cc1
Reactant: C=CCC(=O)O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CCOC(C)=O
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)c1ccc(/C=C/CC(=O)O)cc1
Temperature: 100 °C
Reaction time: 8 h
Yield: 51.2 %

Procedure:
A mixture of ethyl 4-iodobenzoate (1.38 g), 3-butenoic acid (1.08 g), palladium(II) acetate (0.11 g), tris(2-methylphenyl)phosphine (0.30 g), triethylamine (4 mL) and acetonitrile (5 mL) was stirred at 100° C. under an argon atmosphere overnight. The reaction mixture was diluted with ethylacetate. To the mixture was added 2 mol/L hydrochloric acid (20 mL), and the mixture was stirred at room temperature for 10 minutes. The insoluble material was removed by filtration, and the filtrate was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1-1/1) to give ethyl 4-((1E)-3-carboxyprop-1-enyl)benzoate (0.60 g). This material was dissolved in ethyl acetate (9 mL). To the solution was added 10% palladium-carbon powder (0.60 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 3 hours. The insoluble material was removed by filtration, and the solvent was removed under reduced pressure. The residue was dissolved in tetra hydrofuran (10 mL). To the solution was added borane tetra hydrofuran complex (1.0 mol/L tetra hydrofuran solution, 3.56 mL) under ice-cooling, and the mixture was stirred at room temperature for 2 hours. To the reaction mixture was added 20% aqueous potassium carbonate solution under ice-cooling, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The residue was dissolved in N,N-dimethylformamide (5 mL). To the solution were added imidazole (0.32 g) and tert-butyl-chlorodiphenylsilane (0.68 mL), and the mixture was stirred at room temperature overnight. The reaction mixture was poured into water, and the resulting mixture was extracted with diethyl ether. The extract was washed with water and brine successively, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=10/1) to give ethyl 4-[4-(tert-butyldiphenylsilyloxy)-butyl]benzoate (0.95 g). The title compound was prepared in a similar manner to that described in Step 2 of Reference Example 51 using this material instead of methyl 4-[3-(benzyl-oxy)phenyl]benzoate.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][C:14]([O:16]CC)=[O:15])=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=[CH:4][N:3]=1.[OH-].[Na+].Cl>C(O)C>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[S:12][C:11]([CH2:13][C:14]([OH:16])=[O:15])=[N:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([CH3:25])[CH:20]=2)[CH:5]=[CH:4][N:3]=1
Reactant: CCOC(=O)Cc1nc(-c2cccc(C)c2)c(-c2ccnc(N)c2)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: Cc1cccc(-c2nc(CC(=O)O)sc2-c2ccnc(N)c2)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.7 %

Procedure:
To a suspension of ethyl [5-(2-amino-4-pyridyl)-4-(3-methylphenyl)-1,3-thiazol-2-yl]acetate (7.00 g, 19.8 mmol) in ethanol (40 mL) was added a 1N aqueous sodium hydroxide solution (40 mL), and the mixture was stirred for 2 hours at the room temperature under the same condition, The reaction mixture was neutralized with 2N hydrochloric acid (20 mL), then, the produced solid was collected by filtration. The crude product was washed with water, and dried to obtain a title compound (6.10 g, yield: 95%).
Reaction SMILES: Br[C:2]1[N:3]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[N:5]=2.[CH3:25][O-:26].[Na+]>CO>[CH3:25][O:26][C:2]1[N:3]([CH:19]2[CH2:24][CH2:23][CH2:22][CH2:21][O:20]2)[C:4]2[C:9]([N:10]=1)=[C:8]([NH2:11])[N:7]=[C:6]([O:12][CH2:13][CH:14]1[CH2:18][CH2:17][CH2:16][O:15]1)[N:5]=2
Reactant: Nc1nc(OCC2CCCO2)nc2c1nc(Br)n2C1CCCCO1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1nc2c(N)nc(OCC3CCCO3)nc2n1C1CCCCO1

Procedure:
8-Bromo-2-[(tetrahydro-2-furanylmethyl)oxy]-9-(tetrahydro-2H-pyran-2-yl)-9H-purin-6-amine (1.3748 g) was dissolved in methanol (10.2 mL) and treated with 25% (w/v) sodium methoxide in methanol (2.2 mL). This was heated to reflux under nitrogen for 3.5 hours. The reaction mixture was evaporated under reduced pressure to dryness and saturated ammonium chloride solution was added (100 mL). This was then extracted with ethyl acetate (100 mL, 3 times). The organic layers were combined and washed with brine (100 mL) and then dried by passing through a hydrophobic frit after separating the aqueous layer. The organic was evaporated under reduced pressure to give the title compound as white foam (1.1614 g) and used in the next stage without requiring purification.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=1.[C:9]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1>C1(C)C=CC=CC=1>[C:17]1([C:9]2[CH:10]=[CH:11][C:12]([CH:15]=[N:1][C:2]3[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][CH:3]=3)=[CH:13][CH:14]=2)[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: Cc1ccc(N)cc1
Reactant: O=Cc1ccc(-c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: Cc1ccc(N=Cc2ccc(-c3ccccc3)cc2)cc1

Procedure:
p-toluidine (0.20 mole), 4-biphenylaldehyde (0.20 mole), and IRC-50 (weakly acidic) ion exchange resin (0.5 g.) are azeotropically refluxed in toluene (150 cc). The required amount of water is removed after about 3 hours. The solvent is removed on the rotary, and the residue is recrystallized with 95% ethanol to yield N-[(p-phenyl)benzylidene]-p-methylaniline. m.p. 137°-139° C.
Reaction SMILES: Br[C:2]1[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=[C:6]([Br:8])[N:7]=1.[O:16]1[CH2:21][CH2:20][CH:19]([CH2:22][NH2:23])[CH2:18][CH2:17]1.C(N(CC)C(C)C)(C)C.CS(C)=O>CO>[Br:8][C:6]1[N:7]=[C:2]([NH:23][CH2:22][CH:19]2[CH2:20][CH2:21][O:16][CH2:17][CH2:18]2)[C:3]([NH:9][CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])=[N:4][CH:5]=1
Reactant: NCC1CCOCC1
Reactant: CCOC(=O)CNc1ncc(Br)nc1Br
Solvent: CO
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)CNc1ncc(Br)nc1NCC1CCOCC1
Temperature: 150 °C
Yield: 71.7 %

Procedure:
Ethyl 2-(3,5-dibromopyrazin-2-ylamino)acetate (2.00 g, 5.90 mmol), (tetrahydro-2H-pyran-4-yl)methanamine (0.713 g, 6.19 mmol), N,N-diisopropylethylamine (3.08 mL, 17.70 mmol) and dimethylsulfoxide (4 mL) were combined in a microwave vial with a stirbar and heated in a Biotage Emrys Optimizer microwave reactor at 150° C. for 1 h. The resulting mixture was transferred to a round bottom flask with methanol. The methanol and N,N-diisopropylethylamine were removed under reduced pressure and the residue purified using Biotage flash chromatography (5-100% ethyl acetate in hexane). Fractions containing the desired product were combined in a separatory funnel and washed twice with water and once with brine. The organics were dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was dried under high vacuum at 50° C. to give impure desired product (1.578 g) as an amber waxy solid which was taken on to the next step without further purification. MS (ESI) m/z 373.4 [M]+, 375.4 [M+2]+.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]([OH:14])=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.O[NH:28][C:29]([C:31]1[S:32][C:33]([S:36](=[O:39])(=[O:38])[NH2:37])=[CH:34][CH:35]=1)=[NH:30]>>[F:26][C:2]([F:25])([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]3[O:14][N:30]=[C:29]([C:31]4[S:32][C:33]([S:36]([NH2:37])(=[O:39])=[O:38])=[CH:34][CH:35]=4)[N:28]=3)=[C:7]2[N:6]=[C:5]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:19][CH:20]=2)[CH:4]=1
Reactant: N=C(NO)c1ccc(S(N)(=O)=O)s1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: NS(=O)(=O)c1ccc(-c2noc(-c3cnn4c(C(F)(F)F)cc(-c5ccc(C(F)(F)F)cc5)nc34)n2)s1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and N-hydroxy-5-sulfamoyl-thiophene-2-carboxamidine (example B.2) (166 mg, 0.75 mmol) according to general procedure II. Obtained after purification by flash chromatography (ethyl acetate/heptane) and crystallization (dichloromethane) as an off-white solid (130 mg, 46%). MS (ISN) 558.0 [(M−H)−]; mp 276° C.