Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][N:10]1[CH:14](O)[CH2:13][NH:12][C:11]1=[O:16])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:7][CH2:8][CH2:9][N:10]1[CH:14]=[CH:13][NH:12][C:11]1=[O:16]
Reactant: CC(C)(C)OC(=O)NCCN1C(=O)NCC1O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: NCCn1cc[nH]c1=O
Reaction time: 16 h
Yield: 90 %

Procedure:
[2-(5-Hydroxy-2-oxo-imidazolidin-1-yl)-ethyl]-carbamic acid tert-butyl ester (7.85 g, 32 mmol) was suspended in DCM (250 mL) and a solution of TFA (100 mL) in DCM (250 mL) was added over 10 min to the stirred suspension, which dissolved. The solution was stirred for 16 h, concentrated, and azeotroped with MeCN. The resulting TFA salt of the product was dissolved in MeOH (10 mL) and purified on 50 g of SCX resin, washing with MeOH and eluting off with 2 M NH3 in MeOH. Concentration gave the product as a pale yellow oil (3.66 g, 90%). MS (M+H)+ 128.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[C:7]([CH3:9])[CH:6]=[C:5]([CH2:10][CH3:11])[C:4]=1[C:12](=[O:17])[C:13]([NH:15][NH2:16])=[O:14])[CH3:2].[CH:18](=O)[CH3:19]>CO>[CH:18](=[N:16][NH:15][C:13](=[O:14])[C:12]([C:4]1[C:5]([CH2:10][CH3:11])=[CH:6][C:7]([CH3:9])=[CH:8][C:3]=1[CH2:1][CH3:2])=[O:17])[CH3:19]
Reactant: CC=O
Reactant: CCc1cc(C)cc(CC)c1C(=O)C(=O)NN
Solvent: CO
Product: CC=NNC(=O)C(=O)c1c(CC)cc(C)cc1CC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a 100 mL volume three-necked flask, 10.0 g of 2-(2,6-diethyl-4-methylphenyl)-2-oxoacetohydrazide ((12-1)-(11)-39), 38 ml of methanol and 4.79 ml of acetaldehyde were added and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was washed with hexane and dried under reduced pressure to give 9.71 g of 2-ethylidene-1-[2-(2,6-diethyl-4-methylphenyl)-2-oxoacetyl]hydrazine ((40-a)-(14)-2) as a mixture (5:1) of geometrical isomer.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:19])/[CH:11]=[CH:12]/C1C=CC=CC=1.[Cl-].[Cl-].[Cl-].[Al+3].BrC1C=C2C(C=CC(=O)N2)=CC=1>>[F:8][C:7]1[C:2]([F:1])=[C:3]2[C:4]([CH:12]=[CH:11][C:10](=[O:19])[NH:9]2)=[CH:5][CH:6]=1
Reactant: O=C(/C=C/c1ccccc1)Nc1cccc(F)c1F
Agent: O=c1ccc2ccc(Br)cc2[nH]1
Agent: [Al+3]
Agent: [Cl-]
Product: O=c1ccc2ccc(F)c(F)c2[nH]1

Procedure:
The compound was prepared from (2E)-N-(2,3-difluorophenyl)-3-phenylacrylamide (Intermediate 22) (7.4 g, 28.5 mmol) and aluminium trichloride (19 g, 142 mmol) as described for Intermediate 17. The crude cyclization product was obtained as a single regioisomer, which was used without further purification, 2 g light brown solid (37%).
Reaction SMILES: [CH2:1]1[C:14]2[C:13]3[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=3[NH:7][C:6]=2[CH2:5][CH2:4][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:2]1.CN(C)C=O.[H-].[Na+].Br[CH2:30][C:31]([O:33][CH2:34][CH3:35])=[O:32]>O>[CH2:34]([O:33][C:31](=[O:32])[CH2:30][N:7]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=2[C:14]2[CH2:1][CH2:2][N:3]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:4][CH2:5][C:6]1=2)[CH3:35]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCc2[nH]c3ccccc3c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)Cn1c2c(c3ccccc31)CCN(C(=O)OC(C)(C)C)CC2
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a mixture of tert-butyl 1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (3.557 g, 12.42 mmol) and N,N-dimethylformamide (30 mL) was added 60% sodium hydride (0.596 g, 14.90 mmol). The mixture stirred for 1 h, and then cooled in a 0° C. bath. Ethyl bromoacetate was added, and the mixture warmed to room temperature. Water then was added and the mixture was evaporated in vacuo. The residue was taken up in ethyl acetate and washed with water. Evaporation and trituration with hexanes provided 3.289 g of the title compound, the structure of which is shown in FIG. 6 as (23) (where n=1).
Reaction SMILES: CS(O[CH:6]([C:8]1[CH:21]=[C:20]2[C:11]([O:12][CH2:13][CH2:14][N:15]3[C:19]2=[N:18][C:17]([C:22]2[N:23]([CH:28]([CH3:30])[CH3:29])[CH:24]=[C:25]([CH3:27])[N:26]=2)=[CH:16]3)=[CH:10][CH:9]=1)[CH3:7])(=O)=O.[NH:31]1[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]1>O1CCOCC1>[CH:28]([N:23]1[CH:24]=[C:25]([CH3:27])[N:26]=[C:22]1[C:17]1[N:18]=[C:19]2[C:20]3[CH:21]=[C:8]([CH:6]([N:31]4[CH2:36][CH2:35][CH:34]([C:37]([OH:40])([CH3:39])[CH3:38])[CH2:33][CH2:32]4)[CH3:7])[CH:9]=[CH:10][C:11]=3[O:12][CH2:13][CH2:14][N:15]2[CH:16]=1)([CH3:29])[CH3:30]
Reactant: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)OS(C)(=O)=O)ccc2OCC3)n1
Reactant: CC(C)(O)C1CCNCC1
Solvent: C1COCCO1
Product: Cc1cn(C(C)C)c(-c2cn3c(n2)-c2cc(C(C)N4CCC(C(C)(C)O)CC4)ccc2OCC3)n1
Temperature: 90 °C
Yield: 18.7 %

Procedure:
To a solution of 1-{4-[4-methyl-1-(propan-2-yl)-1H-imidazol-2-yl]-9-oxa-3,6-diazatricyclo[8.4.0.02,6]tetradeca-1(14),2,4,10,12-pentaen-13-yl}ethyl methanesulfonate (12 mg, 0.028 mmol) in dioxane (2 mL) was added 2-(piperidin-4-yl)propan-2-ol (40 mg, 0.280 mmol). The resulting mixture was heated at 90° C. overnight. The solvent was removed under reduce pressure and the residue was purified by prep-HPLC (Gilson GX 281, Shim-pack PRC-ODS 250 mm×20 mm×2, gradient: CH3CN/10 mm/L NH4HCO3, 17 min) to afford 202 (2.5 mg, 18% yield) as a white solid. LCMS (ESI): RT=5.23 min, m/z: 478.4 [M+H+]. 1H NMR (500 MHz, DMSO-d6) δ 8.36 (s, 1H), 7.55 (s, 1H), 7.30-7.28 (d, J=9.0 Hz, 1H), 7.05-7.04 (d, J=8.0 Hz, 1H), 7.02 (s, 1H), 5.48 (m, 1H), 4.52 (s, 4H), 3.57 (m, 1H), 3.21-3.18 (m, 1H), 2.99 (m, 1H), 2.23 (s, 3H), 2.10-1.60 (m, 4H), 1.52-1.47 (m, 10H), 1.35-1.22 (m, 3H), 1.13 (s, 6H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[N:9]([CH2:20][C:21]([OH:23])=O)[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:12])=[O:11].[CH2:24]([NH:26][CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[CH3:25]>>[CH2:24]([N:26]([CH2:27][C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1)[C:21](=[O:23])[CH2:20][N:9]([C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[S:10]([C:13]1[C:14]([CH3:19])=[CH:15][CH:16]=[CH:17][CH:18]=1)(=[O:11])=[O:12])[CH3:25]
Reactant: COc1ccccc1N(CC(=O)O)S(=O)(=O)c1ccccc1C
Reactant: CCNCc1cccnc1
Product: CCN(Cc1cccnc1)C(=O)CN(c1ccccc1OC)S(=O)(=O)c1ccccc1C

Procedure:
prepared by reaction of [(2-methoxy-phenyl)-(toluene-2-sulfonyl)-amino]-acetic acid with ethyl-pyridin-3-ylmethyl-amine
Reaction SMILES: [N+](C1C=CC(O[C:11](=[O:23])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])=CC=1)([O-])=O.[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)=[O:27].CO>C1(C)C(C)=CC=CC=1>[CH3:24][O:25][C:26]([C:28]1[N:29]=[C:30]([NH:33][C:11](=[O:23])[C:12]2[CH:17]=[C:16]([O:18][CH3:19])[C:15]([O:20][CH3:21])=[CH:14][C:13]=2[OH:22])[S:31][CH:32]=1)=[O:27]
Reactant: COC(=O)c1csc(N)n1
Reactant: COc1cc(O)c(C(=O)Oc2ccc([N+](=O)[O-])cc2)cc1OC
Solvent: Cc1ccccc1C
Solvent: CO
Product: COC(=O)c1csc(NC(=O)c2cc(OC)c(OC)cc2O)n1
Temperature: 130 °C
Reaction time: 12 h
Yield: 84.9 %

Procedure:
In 1 mL of xylene were suspended 200 mg of 2-hydroxy-4,5-dimethoxybenzoic acid 4-nitrophenyl ester and 119 mg of 2-amino-1,3-thiazole-4-carboxylic acid methyl ester in a stream of argon, which was then stirred at 130° C. for 12 hours. The reaction mixture was allowed to stand to cool, to which 1 mL of methanol was then added, followed by heating to reflux for one hour. The resultant reaction mixture was allowed to stand to cool, followed by collecting the precipitated crystal by filtration at 30° C. or lower before drying under reduced pressure to provide 180 mg of the title compound (5a) at a yield of 80%.
Reaction SMILES: I[C:2]1[N:9]2[C:5]([S:6][C:7]([C:10]3[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([N:19]4[CH2:24][CH2:23][O:22][CH2:21][CH2:20]4)(=[O:18])=[O:17])[CH:11]=3)=[N:8]2)=[N:4][CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[C:36]([NH2:39])=[N:37][CH:38]=2)O1.C([O-])([O-])=O.[K+].[K+]>COCCOC.C(Cl)Cl.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[N:19]1([S:16]([C:12]2[CH:11]=[C:10]([C:7]3[S:6][C:5]4=[N:4][CH:3]=[C:2]([C:33]5[CH:34]=[C:35]([C:40]([F:43])([F:42])[F:41])[C:36]([NH2:39])=[N:37][CH:38]=5)[N:9]4[N:8]=3)[CH:15]=[CH:14][CH:13]=2)(=[O:18])=[O:17])[CH2:24][CH2:23][O:22][CH2:21][CH2:20]1
Reactant: O=S(=O)(c1cccc(-c2nn3c(I)cnc3s2)c1)N1CCOCC1
Reactant: CC1(C)OB(c2cnc(N)c(C(F)(F)F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: ClCCl
Product: Nc1ncc(-c2cnc3sc(-c4cccc(S(=O)(=O)N5CCOCC5)c4)nn23)cc1C(F)(F)F
Temperature: 120 °C
Yield: 22.9 %

Procedure:
A mixture of 5-Iodo-2-[3-(morpholine-4-sulfonyl)-phenyl]-imidazo[2,1-b][1,3,4]thiadiazole (18 mg, 0.053 mmol), 5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-3-trifluoromethyl-pyridin-2-ylamine (20 mg, 0.068 mmol), PdCl2(dppf) (9 mg, 0.011 mmol) and sat K2CO3 (0.22 mL) in DME (0.5 mL) was heated under microwave irradiation at 120° C. for 30 min. The reaction mixture was cooled, diluted with DCM and washed with water. The organic layer was dried (Na2SO4), filtered and evaporated. The residue was purified by column chromatography (5% MeOH in DCM) to give the desired product (6.2 mg, 19%). HPLC-MS (5-100% B in 8 min at 0.8 mL): tR=5.13 min, [M+H]+ m/z 511.1; 1H NMR (300 MHz, DMSO) δ 8.75 (s, 1H), 8.29 (s, 1H), 8.20 (d, J=7.6 Hz, 1H), 8.10 (s, 1H), 7.83 (m, 2H), 7.72 (s, 1H), 6.65 (s, 2H), 3.53 (m, 4H), 2.84 (m, 4H).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10](I)[C:3]=12.[CH3:21][O:22][C:23]1[CH:28]=[C:27](B2OC(C)(C)C(C)(C)O2)[CH:26]=[CH:25][C:24]=1[NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42].C(=O)([O-])[O-].[Na+].[Na+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]2[N:8]([C:12]3[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=3)[N:9]=[C:10]([C:27]3[CH:26]=[CH:25][C:24]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[C:23]([O:22][CH3:21])[CH:28]=3)[C:3]=12
Reactant: Nc1ncnc2c1c(I)nn2-c1ccc([N+](=O)[O-])cc1
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)ccc1NC(=O)OC(C)(C)C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(-c2nn(-c3ccc([N+](=O)[O-])cc3)c3ncnc(N)c23)ccc1NC(=O)OC(C)(C)C
Temperature: 85 °C
Reaction time: 26 h
Yield: 63 %

Procedure:
A suspension of 4-amino-1-[4-nitrophenyl]-3-iodo-1H-pyrazolo[3,4-d]pyrimidine (0.500 g, 1.31 mmol) in dimethylformamide (8 mL) was treated with tert-butyl N-[2-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]carbamate (0.915 g, 2.62 mmol), tetrakis(triphenylphosphine)palladium (0.091 g, 0.06 mmol), and a solution of sodium carbonate (0.333 g, 3.14 mmol) in water (4 mL). The reaction mixture stirred at 85° C. for 26 h under a nitrogen atmosphere. Water was added to the reaction mixture. The precipitate was filtered and washed with water. The solid was triturated with diethyl ether to give 0.431 g, (63%) of tert-butyl N-(4-{4-amino-1-[4-nitrophenyl]-1H-pyrazolo[3,4-d]pyrimidin-3-yl}-2-methoxyphenyl)carbamate. 1H NMR (DMSO-d6, 400 MHz) δ 8.6862-8.6634 (d, 2H, J=9.12 Hz), 8.4897-8.4423 (m, 3H), 8.1117 (s, 1H), 8.0074-7.9872 (d, 1H, J=8.08 Hz), 7.3743-7.3293 (m, 2H), 3.9189 (s, 3H), 1.4959 (s, 9H); LCMS (Perkin Elmer, Pecosphere C18 column, 3 um particle size, 33×4.6 mm; 100% 50 mM ammonium Acetate in Water to 100% Acetonitrile over 5 min, 3.0 to 3.5 mil/min) tR=4.38 min M+ 478.1.
Reaction SMILES: Br[C:2]1[S:3][C:4]2[C:10]([C:11]3[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=3)=[C:9]([C@H:18]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:8]([CH3:29])=[CH:7][C:5]=2[N:6]=1.[CH3:30][C:31]1[N:35]([C@H:36]2[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:47])([CH3:46])[CH3:45])=[O:42])[CH2:37]2)[C:34]2[CH:48]=[C:49](B3OC(C)(C)C(C)(C)O3)[CH:50]=[CH:51][C:33]=2[N:32]=1.C([O-])([O-])=O.[K+].[K+]>CCOC(C)=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:25]([O:24][C@@H:18]([C:9]1[C:8]([CH3:29])=[CH:7][C:5]2[N:6]=[C:2]([C:49]3[CH:50]=[CH:51][C:33]4[N:32]=[C:31]([CH3:30])[N:35]([C@H:36]5[CH2:40][CH2:39][N:38]([C:41]([O:43][C:44]([CH3:46])([CH3:45])[CH3:47])=[O:42])[CH2:37]5)[C:34]=4[CH:48]=3)[S:3][C:4]=2[C:10]=1[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=1)[C:19]([O:21][CH2:22][CH3:23])=[O:20])([CH3:28])([CH3:27])[CH3:26]
Reactant: Cc1nc2ccc(B3OC(C)(C)C(C)(C)O3)cc2n1[C@H]1CCN(C(=O)OC(C)(C)C)C1
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(Br)sc2c1-c1ccc(Cl)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccc4nc(C)n([C@H]5CCN(C(=O)OC(C)(C)C)C5)c4c3)sc2c1-c1ccc(Cl)cc1
Temperature: 100 °C

Procedure:
A microwave vial was charged with (S)-ethyl 2-(2-bromo-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-6-yl)-2-tert-butoxyacetate (50 mg, 0.10 mmol), (S)-tert-butyl 3-(2-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazol-1-yl)pyrrolidine-1-carboxylate (181 mg, 0.42 mmol), then Pd(PPh3)4 (23 mg, 0.02 mmol). The vial was flushed with argon, diluted with dioxane (2 mL) and to this was added 2M aqueous K2CO3 (0.2 mL, 0.4 mmol). The vial was sealed then heated to 100° C. for 16 hours and then allowed to cool to room temperature. The mixture was diluted with EtOAc, dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel column chromatography (0-100% THF/CH2Cl2 gradient) to afford the desired product. LCMS-ESI+: calc'd for C39H46ClN4O5S: 717.3 (M+H+); Found: 717.1 (M+H+).
Reaction SMILES: C([N:8]1[CH2:15][CH2:14][C:13]2([F:16])[CH:9]1[CH2:10][N:11]([CH3:17])[CH2:12]2)C1C=CC=CC=1>C(O)C.[Pd]>[F:16][C:13]12[CH2:12][N:11]([CH3:17])[CH2:10][CH:9]1[NH:8][CH2:15][CH2:14]2
Reactant: CN1CC2N(Cc3ccccc3)CCC2(F)C1
Agent: [Pd]
Solvent: CCO
Product: CN1CC2NCCC2(F)C1

Procedure:
11 g (43.7 mmol, 93% pure) of 2-benzyl-5-fluoro-7-methyl-2,7-diazabicyclo[3.3.0]octane in 100 ml of ethanol are hydrogenated at 100° C. and 100 bar on 2 g of palladium-active carbon (10% Pd). The catalyst is filtered off with suction, the filtrate is concentrated and the residue is distilled.
Reaction SMILES: [C:1](O)(=[O:9])[C:2]1[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=1)[SH:4].[C:11]1([CH:18]=[CH:17][C:15]([OH:16])=[CH:14][CH:13]=1)[OH:12].C(=O)(O)[O-].[Na+].Cl>S(=O)(=O)(O)O>[OH:12][C:11]1[C:18]2[C:1](=[O:9])[C:2]3[C:3](=[CH:5][CH:6]=[CH:7][CH:8]=3)[S:4][C:17]=2[C:15]([OH:16])=[CH:14][CH:13]=1
Reactant: Oc1ccc(O)cc1
Reactant: O=C(O)c1ccccc1S
Agent: Cl
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Product: O=c1c2ccccc2sc2c(O)ccc(O)c12
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.8 %

Procedure:
A suspension of thiosalicylic acid (5.0 g) and hydroquinone (5.0 g) in concentrated sulfuric acid (100 ml) is stirred at room temperature for 4 h. The red suspension is poured on ice and allowed to reach ambient temperature when it is then filtered. The solid obtained is treated with saturated sodium bicarbonate and the solution was carefully neutralized with 20% hydrochloric acid. The solid is filtered, dissolved in acetone and filtered again through a plug of silica gel. The solution is concentrated and the solid purified by column chromatography with silica gel using a mixture of hexanes: ethyl acetate (1:1) as the eluent. The fraction containing the product is concentrated under reduced pressure to provide the yellow title compound (2.36 g, 30%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:13]2[N:12]=[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:10][C:9]=2[C:8]([OH:21])=[CH:7][CH:6]=1)=[O:4].O[Li].O>C1COCC1.CO.O>[Cl:20][C:17]1[CH:16]=[CH:15][C:14]([C:11]2[NH:10][C:9]3[C:8]([OH:21])=[CH:7][CH:6]=[C:5]([C:3]([OH:4])=[O:2])[C:13]=3[N:12]=2)=[CH:19][CH:18]=1
Reactant: COC(=O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Agent: [Li]O
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(O)c2[nH]c(-c3ccc(Cl)cc3)nc12
Temperature: 25 °C
Yield: 89.4 %

Procedure:
Wang resin-supported 2-(4-chloro-phenyl)-7-hydroxy-1H-benzoimidazole-4-carboxylic acid methyl ester (570 mg, 0.47 mmol) obtained in step 5 was dissolved in THF, LiOH.H2O (99 mg, 2.35 mmol) in MeOH—H2O (1:1) was added thereto and the resulting mixture was refluxed for 5 hours. The resulting solution was cooled to room temperature and filtered. The filtrate was washed with MeOH and CH2Cl2, and dried to obtain the title compound (551 mg, 0.42 mmol) in a yield of 90%.
Reaction SMILES: [C:1]1([C:7]2([CH2:13][CH2:14][CH2:15][OH:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Cl)Cl.CC(C)=[O:22]>>[C:1]1([C:7]2([CH2:13][CH2:14][C:15]([OH:22])=[O:16])[CH2:12][CH2:11][CH2:10][CH2:9][O:8]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CC(C)=O
Reactant: OCCCC1(c2ccccc2)CCCCO1
Solvent: ClCCl
Product: O=C(O)CCC1(c2ccccc2)CCCCO1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 3-(2-phenyltetrahydro-2H-pyran-2-yl)propan-1-ol (640 mg, 2.91 mmol) in acetone (10 mL) at 0° C. was added 4.15 mL of 0.7 M Jone's reagent, and the mixture was stirred for 30 mins at 0° C. and for 1 hr at room temperature. It was added to CH2Cl2 and washed with water twice. The extract was dried over Na2SO4 and evaporated to give an oily residue. The residue was purified by Combiflash (40 g silica gel) eluting with 4:6 EtOAc-hexane to 3-(2-phenyltetrahydro-2H-pyran-2-yl)propanoic acid (346 mg). LC/MS: m/e 235.21 (M+H)+.
Reaction SMILES: [N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:4]=2[NH:3][CH:2]=1.Cl[CH2:16][CH2:17][N:18]([CH2:21][CH3:22])[CH2:19][CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:17]([N:18]([CH2:21][CH2:22][N:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([O:12][CH2:13][CH3:14])=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1)[CH2:19][CH3:20])[CH3:16]
Reactant: CCN(CC)CCCl
Reactant: CCOC(=O)c1ccc2nc[nH]c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)ncn2CCN(CC)CC

Procedure:
5.4 g (28.4 mmol) of ethyl benzimidazole-5-carboxylate, 9.8 g (56.8 mmol) of N-(2-chloro-1-ethyl)-N,N-diethylamine and 7.9 g (56.8 mmol) of potassium carbonate were heated in 100 ml of dimethylformamide at 100° C. for 4 hours. The mixture was then filtered, the filtrate was concentrated in vacuo, and the resulting residue was purified by chromatography (mobile phase: ethyl acetate/acetone=1/1). 2.6 g of an isomer mixture containing ethyl 3-(2-(N,N-diethylamino)-1-ethyl)benzimidazole-5-carboxylate in addition to the product were obtained.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:4][CH:3]=1.Cl.O1CCOC[CH2:15]1>CO>[CH3:15][O:11][C:10](=[O:12])[CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([OH:1])=[CH:7][CH:6]=1
Reactant: C1COCCO1
Reactant: O=C(O)CCc1ccc(O)cc1
Agent: Cl
Solvent: CO
Product: COC(=O)CCc1ccc(O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 100.5 %

Procedure:
After 3-(4-hydroxy-phenyl)propionic acid (3 g, 18 mmol) was added with MeOH (6 mL), 4M HCl/dioxane solution (18 mL, 72 mmol) was added thereto, and the mixture was stirred at room temperature for 3 hours. The reactant was concentrated, added with EtOAc, and then washed with NaCl aqueous solution. The organic layer was separated, dried with MgSO4, and filtered to obtain the title compound (3.26 g, 99%).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:15]=[CH:14][C:13]([C:16]([OH:18])=O)=[CH:12][CH:11]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(Cl)(=O)C(Cl)=O.Cl.[CH3:26][NH:27][C@H:28]([C:32]([O:34][CH3:35])=[O:33])[CH:29]([CH3:31])[CH3:30].C(N(CC)CC)C>C(Cl)Cl.CN(C)C=O>[CH3:26][N:27]([C:16]([C:13]1[CH:12]=[CH:11][C:10]([C:7]2[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:9][CH:8]=2)=[CH:15][CH:14]=1)=[O:18])[C@H:28]([C:32]([O:34][CH3:35])=[O:33])[CH:29]([CH3:31])[CH3:30]
Reactant: O=C(O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Reactant: CN[C@H](C(=O)OC)C(C)C
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@H](C(C)C)N(C)C(=O)c1ccc(-c2ccc([N+](=O)[O-])cc2)cc1
Temperature: 50 °C
Reaction time: 1 h
Yield: 94.5 %

Procedure:
4′-Nitro-1,1′-biphenyl-4-carboxylic acid (0.50 g, 2.0 mmol) was dissolved in methylene chloride (25 mL), and then oxalyl chloride (0.27 mL, 3.1 mmol) was added, followed by one drop of N,N-dimethylformamide. The resulting mixture was heated at 50° C. for 1 h, concentrated under reduced pressure, and further dried under vacuum for 30 min. The residue was dissolved in methylene chloride (20 mL) and added dropwise to an ice-cold mixture of methyl N-methyl-L-valinate hydrochloride (0.48 g, 2.6 mmol), methylene chloride (50 mL), and triethylamine (1.44 mL, 10.2 mmol). The resulting solution was stirred on ice for 1 h and then at rt overnight. The mixture was diluted with methylene chloride and washed with 1N aqueous HCl solution and brine. The organic layer was separated and concentrated under reduced pressure. The residue was purified by flash chromatography (Biotage® system, 3:1 hexanes/EtOAc) to afford methyl N-methyl-N-[(4′-nitro-1,1′-biphenyl-4-yl)carbonyl]-L-valinate (0.70 g, 92%). 1H NMR (400 MHz, CDCl3) δ 0.85 (dd, 3H), 1.06 (dd, 3H), 2.31 (m, 1H), 3.02 (d, 3H), 3.77 (d, 3H), 3.94 (d, 0.5H), 4.98 (d, 0.5H), 7.52 (m, 2H), 7.64 (m, 2H), 7.72 (t, 2H), 8.27 (d, 2H); LC-MS m/z 371.2 (MH+), retention time 3.27 minutes.
Reaction SMILES: [CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([CH:23]=[CH:24][C:25]=2[OH:26])[O:11][C:12]2[C:17]([CH3:18])=[CH:16][C:15]([NH:19][C:20]#[N:21])=[CH:14][C:13]=2[CH3:22])(=[O:7])=[O:6])[CH2:3][CH2:2]1.[N-:27]=[N+:28]=[N-:29].[Na+].[Cl-].[NH4+]>>[CH:1]1([CH2:4][S:5]([C:8]2[CH:9]=[C:10]([O:11][C:12]3[C:17]([CH3:18])=[CH:16][C:15]([NH:19][C:20]4[NH:29][N:28]=[N:27][N:21]=4)=[CH:14][C:13]=3[CH3:22])[CH:23]=[CH:24][C:25]=2[OH:26])(=[O:7])=[O:6])[CH2:3][CH2:2]1
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1cc(NC#N)cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: Cc1cc(Nc2nnn[nH]2)cc(C)c1Oc1ccc(O)c(S(=O)(=O)CC2CC2)c1
Temperature: 140 °C

Procedure:
2-Cyclopropylmethanesulfonyl-4-[2,6-dimethyl-4-(1H-tetrazol-5-ylamino)-phenoxy]-phenol was prepared from 4-(3-cyclopropylmethanesulfonyl-4-hydroxy-phenoxy)-3,5-dimethyl-phenyl-cyanamide according to a procedure analogous to that described in EXAMPLE 1, Step C. Sodium azide (1.5 equiv) and ammonium chloride (10 equiv) were used, and the reaction was heated to 140° C. for 20 hours. After the reaction had been acidified, the aqueous mixture was extracted with ethyl acetate (3×10 ml). The combined organic extracts were washed with aqueous 1N HCl (3×50 ml), and brine (50 ml). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by preparative TLC (methanol:water:dichloromethane=15:1.5:83.5) to afford the title product of Example 7. MS (APCI−) Calc.: 415.1, Found: 413.8 (M−1).