Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]=[C:7]([C:23]#[N:24])[C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH:9]=2)=O.[C:25]([O:29][C:30]([C:32]1([CH2:39][NH2:40])[CH2:37][CH2:36][S:35](=[O:38])[CH2:34][CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]>CCO>[C:25]([O:29][C:30]([C:32]1([CH2:39][NH:40][C:3]([C:5]2[N:6]=[C:7]([C:23]#[N:24])[C:8]3[C:13]([C:14]=2[OH:15])=[CH:12][CH:11]=[C:10]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:9]=3)=[O:2])[CH2:33][CH2:34][S:35](=[O:38])[CH2:36][CH2:37]1)=[O:31])([CH3:28])([CH3:27])[CH3:26]
Reactant: COC(=O)c1nc(C#N)c2cc(Oc3ccccc3)ccc2c1O
Reactant: CC(C)(C)OC(=O)C1(CN)CCS(=O)CC1
Solvent: CCO
Product: CC(C)(C)OC(=O)C1(CNC(=O)c2nc(C#N)c3cc(Oc4ccccc4)ccc3c2O)CCS(=O)CC1
Yield: 39.3 %

Procedure:
A mixture of 4-cyano-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (193 mg) and Raney Ni (0.5 mL in water) in MeOH (30 mL) was stirred at rt under H2 atmosphere (balloon) overnight. Then the reaction mixture was filtered over Celite pad, filtrate was concentrated to give the desired product 4-aminomethyl-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (195 mg), which was used in the next step. A mixture of 1-cyano-4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (35 mg) and 4-aminomethyl-1-oxo-hexahydro-1λ4-thiopyran-4-carboxylic acid tert-butyl ester (52 mg) in EtOH (1.5 mL) was refluxed overnight. The mixture was cooled, concentrated and the residue was column purified to give the desired product (23 mg). LC MS ESI+: 536 (M+1)+.
Reaction SMILES: [N:1]([O-:3])=O.[Na+].[CH:5]1([O:10][C:11]2[CH:12]=[C:13]([CH:24]=[CH:25][C:26]=2[O:27][CH3:28])[CH2:14][N:15]2[C:22]([NH2:23])=[CH:21][C:19](=[O:20])[NH:18][C:16]2=[O:17])[CH2:9][CH2:8][CH2:7][CH2:6]1>C(O)(=O)C>[NH2:23][C:22]1[N:15]([CH2:14][C:13]2[CH:24]=[CH:25][C:26]([O:27][CH3:28])=[C:11]([O:10][CH:5]3[CH2:9][CH2:8][CH2:7][CH2:6]3)[CH:12]=2)[C:16](=[O:17])[NH:18][C:19](=[O:20])[C:21]=1[N:1]=[O:3]
Reactant: COc1ccc(Cn2c(N)cc(=O)[nH]c2=O)cc1OC1CCCC1
Reactant: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: COc1ccc(Cn2c(N)c(N=O)c(=O)[nH]c2=O)cc1OC1CCCC1
Temperature: 25 °C

Procedure:
15.81 ml of 4N sodium nitrite solution was added dropwise at 65°-70° C. over 8 minutes to a solution of 20.53 g of 1-(3-cyclopentyloxy-4-methoxy-benzyl) 6-amino uracil in 300 ml of acetic acid. After 30 minutes the suspension was cooled to room temperature and the solid collected and washed with water to give the title compound (19.36 g) as pink crystals. The filtrate was evaporated to dryness, the residue suspended in 100 ml of water and the solid collected to give 1.98 g as a second crop.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][CH:8]=[CH:7]2.[C:11]([C:14]1[CH:19]=[CH:18][C:17](B(O)O)=[CH:16][CH:15]=1)(=[O:13])[CH3:12]>>[NH:9]1[C:10]2[C:6](=[CH:5][CH:4]=[CH:3][C:2]=2[C:17]2[CH:18]=[CH:19][C:14]([C:11](=[O:13])[CH3:12])=[CH:15][CH:16]=2)[CH:7]=[CH:8]1
Reactant: Brc1cccc2cc[nH]c12
Reactant: CC(=O)c1ccc(B(O)O)cc1
Product: CC(=O)c1ccc(-c2cccc3cc[nH]c23)cc1

Procedure:
Prepared by Procedure I and Scheme T using 7-bromo-1H-indole and 4-acetylphenylboronic acid: ESMS m/e: 235.2 (M+H)+.
Reaction SMILES: [S:1]1[C:9]2[CH:8]([OH:10])[CH2:7][NH:6][CH2:5][C:4]=2[CH:3]=[CH:2]1.[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15](F)=[CH:14][CH:13]=1>>[Br:11][C:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:15]([O:10][CH:8]2[CH2:7][NH:6][CH2:5][C:4]3[CH:3]=[CH:2][S:1][C:9]2=3)=[CH:14][CH:13]=1
Reactant: Fc1ccc(Br)c2ccccc12
Reactant: OC1CNCc2ccsc21
Product: Brc1ccc(OC2CNCc3ccsc32)c2ccccc12

Procedure:
The same method as in Example 1 was conducted using 4,5,6,7-tetrahydrothieno[3,2-c]pyridin-7-ol (Reference Example 13) instead of 6-methyl-4,5,6,7-tetrahydrothieno[2,3-c]pyridin-4-ol (Reference Example 6) and was conducted using 1-bromo-4-fluoronaphthalene instead of 1-fluoronaphthalene to give the objective compound.
Reaction SMILES: [F:1][C:2]1[C:10]2[S:9][C:8]([C:11]([O:13]C)=[O:12])=[CH:7][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1.[OH-].[Na+].CO>O>[F:1][C:2]1[C:10]2[S:9][C:8]([C:11]([OH:13])=[O:12])=[CH:7][C:6]=2[C:5]([O:15][CH3:16])=[CH:4][CH:3]=1
Reactant: COC(=O)c1cc2c(OC)ccc(F)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COc1ccc(F)c2sc(C(=O)O)cc12
Temperature: 0 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
A mixture of methyl 7-fluoro-4-methoxy-1-benzothiophene-2-carboxylate (67.2 g, 280 mmol), sodium hydroxide (45 g, 1.12 mol), methanol (800 mL) and water (400 mL) were stirred at ambient overnight. The methanol was evaporated and the mixture cooled to 0° C. Acidified with concentrated hydrochloric acid and stirred for 20 mins. The yellow solid was filtered, washing with water (3×100 mL). Dried under vacuum at 45° C. overnight, over phosphorus pentoxide to give the title compound (61.4 g, 97%); δH (300 MHz, d6-DMSO) 8.10 (1H, d, ArH) 7.44 (1H, t, ArH) 7.00 (1H, m, ArH) and 4.02 (3H, s, OCH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[NH:10][C:9]1=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:20]>CN(C=O)C>[C:1]([O:5][C:6]([N:8]1[CH:12]2[CH2:13][CH2:14][CH2:15][CH:11]2[N:10]([CH3:20])[C:9]1=[O:16])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1C(=O)NC2CCCC21
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN1C(=O)N(C(=O)OC(C)(C)C)C2CCCC21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 106.1 %

Procedure:
To a solution of (3aSR,6aRS)-2-oxo-hexahydro-cyclopentaimidazole-1-carboxylic acid tert-butyl ester (Example 106, step 1) (1.82 g, 8.04 mmol) in 30 ml of DMF was added a 60% suspension of sodium hydride in mineral oil (386 mg, 9.65 mmol, 1.2 equiv.). The suspension was stirred for 45 minutes at room temperature (gas evolution), then iodomethane (0.604 ml, 9.65 mmol, 1.2 equiv.) was added and the mixture was stirred at room temperature overnight. After concentration in vacuo and workup with ethyl acetate/water, 2.05 g of a yellow oil were obtained containing mineral-oil drops which was directly used in the next step without further characterisation.
Reaction SMILES: [CH2:1]([NH:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([C:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH:26]=4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:6]=1)[CH3:2]>C(O)C.CN(C=O)C.[Pd]>[CH2:1]([NH:3][C:4](=[O:27])[C:5]1[CH:10]=[CH:9][C:8]([CH3:11])=[C:7]([C:12]2[CH:20]=[C:19]3[C:15]([C:16]([CH:21]4[CH2:22][CH2:23][NH:24][CH2:25][CH2:26]4)=[N:17][NH:18]3)=[CH:14][CH:13]=2)[CH:6]=1)[CH3:2]
Reactant: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4=CCNCC4)n[nH]c3c2)c1
Agent: [Pd]
Solvent: CCO
Solvent: CN(C)C=O
Product: CCNC(=O)c1ccc(C)c(-c2ccc3c(C4CCNCC4)n[nH]c3c2)c1
Yield: 58 %

Procedure:
A solution of N-ethyl-4-methyl-3-[3-(1,2,3,6-tetrahydro-4-pyridinyl)-1H-indazol-6-yl]benzamide (Intermediate 15, 360 mg) in ethanol (10 ml) and DMF (3 ml) was stirred with 10% palladium on carbon (50 mg) under an atmosphere of hydrogen for 24 h. The catalyst was removed by filtration, the solvent was evaporated and the residue was dissolved in methanol and applied to an SCX ion exchange cartridge. The cartridge was eluted with a solution of aqueous ammonia (0.88) in methanol (10%) and the resultant product was further purified on a column of silica, eluting with a dichloromethane/methanol gradient, to give the title compound (210 mg).
Reaction SMILES: [OH-].[Li+].C[O:4][C:5](=[O:30])[CH2:6][C:7]1[C:8]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][C:18]3[CH:22]=[C:21]([C:23]4[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=4)[O:20][N:19]=3)[C:9]=2[S:10][CH:11]=1.Cl>O1CCCC1.O.O>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[O:20][N:19]=[C:18]([CH2:17][O:16][C:12]3[C:9]4[S:10][CH:11]=[C:7]([CH2:6][C:5]([OH:30])=[O:4])[C:8]=4[CH:15]=[CH:14][CH:13]=3)[CH:22]=2)=[CH:24][CH:25]=1
Reactant: COC(=O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)Cc1csc2c(OCc3cc(-c4ccc(Cl)cc4)on3)cccc12
Yield: 69 %

Procedure:
Lithium hydroxide (0.024 g, 0.58 mmol) was added to a stirred suspension of compound 77C from the preceding step (0.06 g, 0.15 mmol) in 8 mL of tetrahydrofuran/water (3:2) at room temperature. After 18 hours the resulting clear solution was diluted with 75 mL of water, stirred, and acidified with aq HCl. After −1 hour the precipitate was filtered off, rinsed 3× with water, and dried to afford 0.04 g (69% yield) of the title compound as a white solid; mp 229-230° C. (dec).
Reaction SMILES: [N+:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=O)=[CH:6][CH:5]=1)([O-:3])=[O:2].[N:12]([CH2:15][C:16]([O:18][CH3:19])=[O:17])=[N+:13]=[N-:14]>>[CH3:19][O:18][C:16](=[O:17])[C:15]([N:12]=[N+:13]=[N-:14])=[CH:8][C:7]1[CH:10]=[CH:11][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: COC(=O)CN=[N+]=[N-]
Product: COC(=O)C(=Cc1ccc([N+](=O)[O-])cc1)N=[N+]=[N-]

Procedure:
Following the general procedure of PREPARATION 61 and making non-critical variations but starting with p-nitrobenzaldehyde (10 g) and methyl azidoacetate (30.4 g), the title compound is obtained, NMR 8.34, 8.07, 7.02, and 4.07 δ.
Reaction SMILES: [CH2:1]([O:8][CH2:9][C@@H:10]1[CH2:14][C@@H:13]([S:15]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:12][N:11]1[S:35]([CH3:38])(=[O:37])=[O:36])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(O)(C(F)(F)F)=O>[CH2:1]([O:8][CH2:9][C@H:10]1[N:11]([S:35]([CH3:38])(=[O:37])=[O:36])[CH2:12][C@H:13]([SH:15])[CH2:14]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)N1C[C@H](SC(c2ccccc2)(c2ccccc2)c2ccccc2)C[C@H]1COCc1ccccc1
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)N1C[C@H](S)C[C@H]1COCc1ccccc1
Reaction time: 18 h
Yield: 75 %

Procedure:
9.07 g (20 mmol) of (2S,4R)-(1-methanesulfonyl-4-tritylsulfanyl-pyrrolidin-2-yl)-methanol and 9.5 ml (80 mmol) of benzylbromide were dissolved in 660 ml DMF, cooled to 0° C. and treated with 1.4 g (32 mmol) of 55% NaH over 15 min in 4 portions. The reaction was warmed up over night and treated with 4.75 ml (40 mmol) benzylbromide/700 mg (16 mmol) 55% NaH and 6 h later again with the same amount of benzylbromide/NaH. After further 16 h at room temperature the reaction was quenched with saturated NH4Cl solution/EtOAc (3x). The organic phase was washed with aqueous 10% NaCl solution, dried over Na2SO4 and evaporated to give 25 g crude product. Flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) gave 6.43 g (59%) of (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine, MS: 544 (MH+). 6.4 g (11.77 mmol) (2S,4R)-2-benzyloxymethyl-1-methanesulfonyl-4-tritylsulfanyl-pyrrolidine were dissolved in 170 ml TFA and treated at 0° C. with 18.75 ml (117.7 mmol) of triethylsilane. After 18 h at 0° C., the mixture was evaporated and purified by flash-chromatography on silica gel (Hexane/EtOAc 4:1 to 1:4) to give 2.66 g (72%) of (3R,5S)-5-benzyloxymethyl-1-methanesulfonyl-pyrrolidine-3-thiol, MS: 302 (MH+).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].[Br:10]Br>C(O)(=O)C>[CH2:2]([Br:10])[C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3]
Reactant: CC(=O)c1ccccc1
Reactant: BrBr
Solvent: CC(=O)O
Product: O=C(CBr)c1ccccc1

Procedure:
Synthesis of 2-amino-4-arylimidazolamine of the formula (48) (wherein R4, R5, R6, R7 R8 and R9 are as defined above) is described in Scheme 9. Thus, reaction of acetophenone derivative of formula (45) with bromine in acetic acid gives phenacyl bromide, which on reaction with acetyl guanidine in acetonitrile at reflux temperature gives N-acetyl imidazole of the formula (47). The N-deacetylation of (47) under acidic conditions affords 2-amino-4-arylimidazoles of the formula (48). This is similar to the procedure reported by Thomas, L. et al in J. Org. Chem., 1994, 59, 7299-7305.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:10]=[C:11]([F:13])[CH:12]=1)[C@H:5]([OH:9])[C:6]([OH:8])=O.Cl.[NH2:15][C@H:16]([C:18]([CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]([NH2:29])=[N:23][C:22]2[CH:30]=[CH:31][CH:32]([CH3:35])[C:33](=[O:34])[C:21]1=2)=[O:19])[CH3:17]>>[F:13][C:11]1[CH:10]=[C:4]([CH:3]=[C:2]([F:1])[CH:12]=1)[C@H:5]([OH:9])[C:6]([NH:15][C@H:16]([C:18]([CH:20]1[CH2:26][C:25]([CH3:28])([CH3:27])[C:24]([NH2:29])=[N:23][C:22]2[CH:30]=[CH:31][CH:32]([CH3:35])[C:33](=[O:34])[C:21]1=2)=[O:19])[CH3:17])=[O:8]
Reactant: CC1C=CC2=C(C1=O)C(C(=O)[C@H](C)N)CC(C)(C)C(N)=N2
Reactant: O=C(O)[C@@H](O)c1cc(F)cc(F)c1
Agent: Cl
Product: CC1C=CC2=C(C1=O)C(C(=O)[C@H](C)NC(=O)[C@@H](O)c1cc(F)cc(F)c1)CC(C)(C)C(N)=N2

Procedure:
Following General Procedure D and using (S)-3,5-difluoromandelic acid (Example L) and 5-(L-alaninyl)-amino-3,3,7-trimethyl-5,7-dihydro-6H-benz[b]azepin-6-one hydrochloride (Example 6-B), the title compound was prepared. The product was purified by chromatography (silica, 3% MeOH/CHCl3).
Reaction SMILES: [F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH2:20])=[CH:4][CH:3]=1.[N+:23]([C:26]1[CH:31]=[CH:30][C:29]([N:32]=[C:33]=[O:34])=[CH:28][CH:27]=1)([O-:25])=[O:24]>>[F:1][C:2]1[CH:22]=[CH:21][C:5]([CH2:6][CH:7]2[CH2:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[CH2:9][N:8]2[CH2:17][CH2:18][CH2:19][NH:20][C:33]([NH:32][C:29]2[CH:28]=[CH:27][C:26]([N+:23]([O-:25])=[O:24])=[CH:31][CH:30]=2)=[O:34])=[CH:4][CH:3]=1
Reactant: NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1
Reactant: O=C=Nc1ccc([N+](=O)[O-])cc1
Product: O=C(NCCCN1Cc2ccccc2CC1Cc1ccc(F)cc1)Nc1ccc([N+](=O)[O-])cc1

Procedure:
The reaction and treatment were carried out in the same manner as in Example 208 using 3-[3-(4-fluorobenzyl)-3,4-dihydroisoquinolin-2(1H)-yl]propanamine obtained in Example 214-b) as a starting material, and using 4-nitrophenyl isocyanate instead of phenyl isocyanate to obtain a title compound as a pale yellow amorphous substance.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]1[O:21][CH2:20]1)[CH:9]=2.[CH:27]([NH2:30])([CH3:29])[CH3:28]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[C:6]1[O:7][C:8]2[C:13]([C:14](=[O:16])[CH:15]=1)=[CH:12][CH:11]=[C:10]([O:17][CH2:18][CH:19]([OH:21])[CH2:20][NH:30][CH:27]([CH3:29])[CH3:28])[CH:9]=2
Reactant: CC(C)N
Reactant: COc1ccc(-c2cc(=O)c3ccc(OCC4CO4)cc3o2)cc1OC
Solvent: CO
Product: COc1ccc(-c2cc(=O)c3ccc(OCC(O)CNC(C)C)cc3o2)cc1OC

Procedure:
3′,4′-Dimethoxy-7-(2,3-epoxy-propoxy)-flavone, 33 (300 mg, 0.85 mmol) and iso-propyl amine (0.15 mL, 1.7 mmol) in dry methanol (80 mL) were reacted in a similar manner to that described under 34 to afford 46. Yield 290 mg (83%); mp 144-145° C.; MS (FAB) 414 (M++1); IR (KBr) 3410, 1634; 1H NMR (200 MHz, CDCl3) δ 8.03 (d, J=9.5 Hz, 1H), 7.51 (dd, J=8.5 Hz, 1.7 Hz, 1H), 7.36 (d, J=1.7 Hz, 1H), 6.96-6.92 (m, 3H), 6.74 (s, 1H), 4.18-4.12 (m, 3H), 3.97 (s, 3H), 3.96 (s, 3H), 3.99 (s, (m, 3H), 1.23 (d, J=6.3 Hz, 6H). Analysis Calcd for C23H27NO6: C, 66.81; H, 6.58; N, 3.39. Found: C, 66.67; H, 6.65; N, 3.53.
Reaction SMILES: [F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4](O)=[O:5].S(Cl)(Cl)=O.[Cl:15][C:16]1[C:21]([NH2:22])=[CH:20][C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])=[CH:18][CH:17]=1.[OH-].[Na+]>CN(C)C(=O)C>[F:1][C:2]([F:10])([F:9])[C:3]([OH:8])([CH3:7])[C:4]([NH:22][C:21]1[C:16]([Cl:15])=[CH:17][CH:18]=[C:19]([S:23]([C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=[O:25])=[O:24])[CH:20]=1)=[O:5]
Reactant: CC(O)(C(=O)O)C(F)(F)F
Reactant: Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Solvent: O=S(Cl)Cl
Product: CC(O)(C(=O)Nc1cc(S(=O)(=O)c2ccccc2)ccc1Cl)C(F)(F)F
Temperature: -20 °C
Reaction time: 1 h
Yield: 33.9 %

Procedure:
To a solution containing 3,3,3-trifluoro-2-hydroxy-2-methylpropanoic acid (2.00 g) in N,N-dimethylacetamide (40 mL) cooled to -20° C. was added thionyl chloride (1.50 g) and the mixture was stirred for 1.0 hour. 6-chloro-3-phenylsulfonylaniline (2.42 g) was added in one portion and mixture was stirred for 48 hours at room temperature. The reaction mixture was poured into aqueous sodium hydroxide (1.0N, 250 mL) and extracted with ethyl acetate. The combined ethyl acetate extracts were washed (aqueous sodium hydroxide, brine) and evaporated. Chromatography, with hexane:ethyl acetate as the eluent (4:1 then 2:1) yielded the title compound as a white solid (1.25 g); mp: 79°-80° C.; NMR (250 MHz): 1.61 (s,3), 7.69 (m,3), 7.82 (m,2), 7.94 (d,1, J=9), 7.98 (m,2), 8.52 (s,1), 9.93 (s,1); MS: m/z=408(M+1). Analysis for C16H13ClF3NO4S: Calculated: C, 47.11; H, 3.19; N, 3.44; Found: C, 47.10; H, 3.28; N, 3.38.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][C:11]=3[C:12](=[O:15])[C:13]=2[OH:14])=[CH:4][CH:3]=1>C(Cl)(Cl)Cl.CO>[OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:9][C:10]3[CH:19]=[CH:18][C:17]([NH:20][C:21](=[O:23])[CH3:22])=[CH:16][C:11]=3[C:12](=[O:15])[C:13]=2[O:14][CH2:8][C:5]2[CH:6]=[CH:7][CH:2]=[CH:3][CH:4]=2)=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(O)c(=O)c2c1
Solvent: CO
Solvent: ClC(Cl)Cl
Product: CC(=O)Nc1ccc2oc(-c3ccc(O)cc3)c(OCc3ccccc3)c(=O)c2c1
Yield: 84 %

Procedure:
Prepared analogously to Example 5d, starting from 2-(4-hydroxyphenyl)-3-hydroxy-6-acetamido-4H-1-benzopyran-4-one. Yield: 84%; Rf (9/1 Chloroform/Methanol): 0.59, 1H-NMR (d6-DMSO): 10.38 (s broad, 1H), 8.40 (d, 1H), 8.1-7.9 (m, 3H), 7.70 (d, 1H); 7.55-7.25 (m, 10H); 7.17 (d, 2H); 5.22 (s, 2H), 5.07 (s, 2H); 2.11 (s, 3H).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:41]=[CH:40][C:39]([F:42])=[CH:38][CH:37]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:12]([Cl:43])[CH:11]=1)(=O)=O.[N-:44]=[N+:45]=[N-:46].[Na+]>CN(C=O)C>[N:44]([CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:15]=[C:14]([F:16])[C:13]([CH2:17][S:18][C:19]2[N:20]([C:36]3[CH:37]=[CH:38][C:39]([F:42])=[CH:40][CH:41]=3)[C:21]([C:24]([C:27]3[CH:32]=[CH:31][C:30]([F:33])=[C:29]([O:34][CH3:35])[CH:28]=3)([CH3:26])[CH3:25])=[CH:22][N:23]=2)=[C:12]([Cl:43])[CH:11]=1)=[N+:45]=[N-:46]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCOS(C)(=O)=O)cc3Cl)n2-c2ccc(F)cc2)ccc1F
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc(C(C)(C)c2cnc(SCc3c(F)cc(OCCCN=[N+]=[N-])cc3Cl)n2-c2ccc(F)cc2)ccc1F
Reaction time: 16 h
Yield: 79.4 %

Procedure:
To a solution of 3-(3-chloro-5-fluoro-4-((5-(2-(4-fluoro-3-methoxyphenyl)propan-2-yl)-1-(4-fluorophenyl)-1H-imidazol-2-ylthio)methyl)phenoxy)propyl methanesulfonate (470 mg, 0.72 mmol) in DMF (3 mL) at 0° C. was added NaN3 (186 mg, 2.87 mmol). After stirring for 16 h, the mixture was partitioned in EtOAc (20 mL) and water (20 mL). The separated organic layer was washed with 1M HCl (10 mL) and water (10 mL) successively, dried over MgSO4, filtered and evaporated. The mixture was purified by column chromatography (EtOAc/Hex=1:3) to provide 2-(4-(3-azidopropoxy)-2-chloro-6-fluorobenzylthio)-5-(2-(4-fluoro-3-methoxyphenyl)-propan-2-yl)-1-(4-fluorophenyl)-1H-imidazole (344 mg, 80% yield) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.21 (s, 1H), 6.87 (dd, J=10.99, 8.49 Hz, 1H), 6.76 (t, J=8.49 Hz, 2H), 6.67 (s, 1H), 6.58 (dd, J=8.15, 2.15 Hz, 1H), 6.52-6.42 (m, 2H), 6.38-6.29 (m, 2H), 4.16 (t, J=4.34 Hz, 2H), 3.98 (t, J=5.89 Hz, 2H), 3.77 (d, J=5.67 Hz, 3H), 3.50 (t, J=6.51 Hz, 2H), 2.17 (s, 1H), 2.13-1.97 (m, 3H), 1.60 (s, 2H), 1.49 (s, 6H).
Reaction SMILES: [CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15]#[N:16])[N:7]=1)[CH3:2].Cl.[C:19](=O)([O-])[O-:20].[K+].[K+]>CO.C(Cl)(Cl)Cl>[CH2:1]([N:3]=[C:4]([NH2:17])[NH:5][C:6]1[CH:10]=[N:9][N:8]([CH2:11][CH2:12][CH2:13][CH2:14][C:15](=[NH:16])[O:20][CH3:19])[N:7]=1)[CH3:2]
Reactant: O=C([O-])[O-]
Reactant: CCN=C(N)Nc1cnn(CCCCC#N)n1
Agent: Cl
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCN=C(N)Nc1cnn(CCCCC(=N)OC)n1
Reaction time: 60 h

Procedure:
A solution of 5-[4-[2-ethylguanidino)-1,2,3-triazol-2-yl]valeronitrile (1.35 g.) in MeOH (5 ml.) and chloroform (20 ml.) was saturated with gaseous HCl at 0° and the solution kept at 0° for 2.5 days. Evaporation of the solvent gave an oil which was basified with cold potassium carbonate solution and then extracted with chloroform to give methyl 5-[4-(2-ethylguanidino)1,2,3-triazol-2-yl]valerimidate (1.57 g.) which was used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[CH2:4][C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12].C=O.[C:16]([O-])(O)=[O:17].[Na+]>CS(C)=O>[CH3:1][O:2][C:3](=[O:13])[CH:4]([C:5]1[CH:10]=[CH:9][C:8]([Cl:11])=[CH:7][C:6]=1[Cl:12])[CH2:16][OH:17]
Reactant: COC(=O)Cc1ccc(Cl)cc1Cl
Reactant: O=C([O-])O
Agent: C=O
Agent: [Na+]
Solvent: CS(C)=O
Product: COC(=O)C(CO)c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a suspension of 2,4-dichlorophenylacetic acid methyl ester (1.38 mmol) and paraformaldehyde (1.45 mmol) in 2.7 mL DMSO was added NaHCO3 (0.07 mmol). The reaction mixture was stirred at RT for 2 h and then quenched with water. The mixture was neutralized with 1M HCl solution and extracted with EtOAc (2×). The combined organic layers were dried over MgSO4 and concentrated in vacuo. Purification by CC (KP-SIL™ from Biotage) using Hept to Hept/EtOAc (1/1) gives the desired compound as colorless oil;
Reaction SMILES: [N+:1]([O-:4])(O)=[O:2].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22].C(O)C.[OH-].[Na+]>C(OC(=O)C)(=O)C>[N+:1]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])([O-:4])=[O:2]
Reactant: O=[N+]([O-])O
Reactant: CCOC(=O)CCCCCCc1ccc2ccccc2c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Product: O=C(O)CCCCCCc1ccc2ccccc2c1[N+](=O)[O-]
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
Fuming nitric acid (81 ml) was ice-cooled and acetic anhydride (4.5 ml) was added dropwise. The mixture was cooled to -78° C. and a solution of ethyl 7-(2-naphthyl)heptanoate (10 g) in acetic anhydride (20 ml) was added. The temperature was then increased to -20° C. over a period of 2 hours, after which ethanol (10 ml) was added dropwise. The mixture was stirred for 30 minutes. Then, 2N aqueous sodium hydroxide solution (300 ml) was added under ice-cooling and the mixture was further stirred for 2 hours and, then, extracted with ether. The organic layer was washed with water, dried, and concentrated to dryness. The solid residue (11 g) was added to 5N aqueous sodium hydroxide solution (66 ml)-tetrahydrofuran (264 ml) and the mixture was refluxed for 6 hours. The reaction mixture was acidified with HCl and extracted with ethyl acetate. The organic layer was washed with water, dried, and concentrated to dryness and the residue was recrystallized from hexane-ethyl acetate to provide 7-(1-nitro-2-naphthyl)heptanoic acid (3.4 g).
Reaction SMILES: O=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1.[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH2:28].[BH3-]C#N.[Na+]>Cl[Ti](Cl)(Cl)Cl>[S:21]1[CH:25]=[CH:24][CH:23]=[C:22]1[CH2:26][CH2:27][NH:28][CH:2]1[C:10]2[C:5](=[CH:6][C:7]([O:11][C:12]3[CH:20]=[CH:19][C:15]([C:16]([NH2:18])=[O:17])=[CH:14][N:13]=3)=[CH:8][CH:9]=2)[CH2:4][CH2:3]1
Reactant: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3=O)nc1
Reactant: NCCc1cccs1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: [BH3-]C#N
Agent: [Na+]
Product: NC(=O)c1ccc(Oc2ccc3c(c2)CCC3NCCc2cccs2)nc1
Yield: 51.7 %

Procedure:
Using a method similar to Example 1, using 6-(1-oxo-indan-5-yloxy)-nicotinamide (Intermediate 4, 268 mg, 1.00 mmol), 2-thiopheneethylamine (152 mg, 1.20 mmol), Ti(iPrO)4 (568 mg, 2.00 mmol), TiCl4 (1.0M/DCM, 2.00 ml, 2.00 mmol), and NaBH3CN (125 mg, 2.00 mmol) gives the title compound (196 mg) as a white solid. Mass spectrum (ion spray): m/z=380 (M+1); 1HNMR (CDCl3): 8.58 (s, 1H), 8.15 (d, 1H), 7.35 (d, 1H), 7.16 (d, 1H); 6.99 (s, 1H), 6.96-6.93 (m, 3H), 6.86 (d, 1H), 5.81 (br. s, 2H), 4.28 (t, 1H), 3.11-2.96 (m, 5H), 2.83 (m, 1H), 2.46 (m, 1H), 1.87 (m, 1H).