Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([I:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13].[O:17]=[C:18]([C:27]1[CH:32]=[CH:31][N:30]=[N:29][CH:28]=1)[CH2:19][C:20](OC(C)(C)C)=[O:21]>>[I:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:13])([CH3:15])[CH3:14])=[C:2]([NH:1][C:20](=[O:21])[CH2:19][C:18](=[O:17])[C:27]2[CH:32]=[CH:31][N:30]=[N:29][CH:28]=2)[CH:7]=1
Reactant: CC(C)(C)OC(=O)Nc1ccc(I)cc1N
Reactant: CC(C)(C)OC(=O)CC(=O)c1ccnnc1
Product: CC(C)(C)OC(=O)Nc1ccc(I)cc1NC(=O)CC(=O)c1ccnnc1

Procedure:
The title compound was prepared from the reaction of tert-butyl 2-amino-4-iodophenylcarbamate (Example B3; 1 mmol) and tert-butyl 3-oxo-3-(pyridazin-4-yl)propanoate (Example C1; 1 mmol) according to the general procedure D. Obtained as a yellow solid (87%), MS (EI) 483 [(M+1)+].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=O)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:38])([CH3:37])[CH3:36])[N:27]=1.[NH:39]1[CH2:43][CH2:42][CH2:41][CH2:40]1>C(Cl)Cl.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:39]2[CH2:43][CH2:42][CH2:41][CH2:40]2)=[CH:4][C:3]=1[C:10]1[O:14][C:13]([C:15]2[C:20]([CH3:21])=[CH:19][N:18]=[C:17]([NH:22][C:23](=[O:25])[CH3:24])[CH:16]=2)=[CH:12][C:11]=1[C:26]1[N:30]=[CH:29][N:28]([CH2:31][O:32][CH2:33][CH2:34][Si:35]([CH3:37])([CH3:38])[CH3:36])[N:27]=1
Reactant: C1CCNC1
Reactant: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(C=O)ccc3Cl)o2)c(C)cn1
Solvent: ClCCl
Solvent: O
Product: CC(=O)Nc1cc(-c2cc(-c3ncn(COCC[Si](C)(C)C)n3)c(-c3cc(CN4CCCC4)ccc3Cl)o2)c(C)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.9 %

Procedure:
To a solution of N-{4-[5-(2-chloro-5-formylphenyl)-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl]-5-methylpyridin-2-yl}acetamide (0.19 g, 0.34 mmol) in DCM (10 mL) was added pyrrolidine (0.14 mL, 1.68 mmol) and STAB (0.21 g, 1.01 mmol). The mixture was allowed to stir at rt overnight. The mixture was diluted with water and extracted with DCM. The organic solutions were combined, dried over MgSO4, filtered and concentrated. The residue was purified by column chromatography to give N-(4-{5-[2-chloro-5-(pyrrolidin-1-ylmethyl)phenyl]-4-(1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-1,2,4-triazol-3-yl)-2-furyl}-5-methylpyridin-2-yl)acetamide (0.20 g, 100%). LCMS (FA): m/z=607.7 (M+H).
Reaction SMILES: Br[CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4].[CH3:12][O:13][CH2:14][CH2:15][NH2:16].[ClH:17]>CCOCC>[ClH:17].[CH3:12][O:13][CH2:14][CH2:15][NH:16][CH:2]([CH3:11])[C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:4]
Reactant: CC(Br)C(=O)c1ccccc1
Reactant: COCCN
Agent: Cl
Solvent: CCOCC
Product: COCCNC(C)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A solution of α-bromopropiophenone (2.13 g, 0.010 mole) in ether (10 ml) was added dropwise to a stirred solution of 2-methoxyethylamine (1.50 g, 0.020 mole) in ether (20 ml). The mixture was then stirred at ambient temperature for 18 hr. The ether layer was decanted from an insoluble oil, washed with water (20 ml), and then extracted with 2N hydrochloric acid solution (20 ml). The acid extract was basified to pH 10 with 6N sodium hydroxide solution, and this solution extracted with ether (50 ml). The extract was dried over magnesium sulfate and concentrated to give a clear yellow oil. The oil was dissolved in ether and treated with excess ethereal hydrogen chloride. The product separated from solution as an oil, but solidified upon trituration. The yield was 0.85 g (35%), m.p. 133°-134° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:11]([C:12]2[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([NH2:18])=[C:8]([NH2:19])[N:7]=1.[CH2:20](OC(OCC)OCC)C.[OH-].[Na+].C(OCC)(=O)C>C(O)(=O)C>[O:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[N:7]=[C:8]2[NH:19][CH:20]=[N:18][C:9]2=[CH:10][C:11]=1[C:12]1[CH:17]=[CH:16][N:15]=[CH:14][CH:13]=1
Reactant: Nc1cc(-c2ccncc2)c(-c2ncco2)nc1N
Reactant: CCOC(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: c1cc(-c2cc3nc[nH]c3nc2-c2ncco2)ccn1
Temperature: 140 °C
Reaction time: 2 h
Yield: 45.8 %

Procedure:
A mixture of 2-(1,3-oxazol-2-yl)-3,4′-bipyridine-5,6-diamine (Intermediate 10, 0.100 g, 0.39 mmol) and triethylorthoformate (0.117 g, 0.79 mmol) in glacial acetic acid (2 mL) was heated in a sealed tube to 140° C. After stirring for 2 hours, the mixture was cooled and taken to pH 7 with 6N aqueous sodium hydroxide solution. Ethyl acetate was added to the mixture and, after stirring for 30 minutes, the separated solid was filtered, washed with diethyl ether and dried in vacuo to give the title compound (0.047 g, 49%) as an off-white solid.
Reaction SMILES: [CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([O:20]CC)=[O:19])=[O:15])[C:10](=[O:23])[NH:9][C:8]2=[O:24])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:31][C:32]1[CH:39]=[C:38]([CH3:40])[CH:37]=[CH:36][C:33]=1[CH2:34]Br.Cl>CN(C)C=O>[CH:1]1([N:7]2[C:12]([OH:13])=[C:11]([C:14]([NH:16][CH2:17][C:18]([OH:20])=[O:19])=[O:15])[C:10](=[O:23])[N:9]([CH2:34][C:33]3[CH:36]=[CH:37][C:38]([CH3:40])=[CH:39][C:32]=3[CH3:31])[C:8]2=[O:24])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(CBr)c(C)c1
Reactant: CCOC(=O)CNC(=O)c1c(O)n(C2CCCCC2)c(=O)[nH]c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1ccc(Cn2c(=O)c(C(=O)NCC(=O)O)c(O)n(C3CCCCC3)c2=O)c(C)c1
Reaction time: 8 h
Yield: 40.3 %

Procedure:
A mixture of ethyl N-[(1-cyclohexyl-6-hydroxy-2,4-dioxo-1,2,3,4-tetrahydro-5-pyrimidinyl)carbonyl]glycinate (340 mg, 1.0 mmoles), pulv. Potassium carbonate (740 mg, 5.35 mmoles) and 2,4-dimethylbenzyl bromide (400 mg, 2.0 mmoles) in dimethylformamide (5 mL) was vigorously stirred at 100° C. for 3 hours. The mixture was poured into 1 molar hydrochloric acid and extracted with ethyl acetate. The organic solution was washed with 1 molar hydrochloric acid and evaporated. The residue was purified by flash chromatography (10-50% ethyl acetate in hexane), the required fractions evaporated, dissolved in ethanol (5 mL) and 1 molar sodium hydroxide solution (1.0 mL) and 6 molar sodium hydroxide solution (1.0 mL) added. The mixture was stirred overnight, acidified and extracted with ethyl acetate (×2), the combined extracts washed with 1 molar hydrochloric acid, dried and evaporated to give the title compound (173 mg, 40%). 1H NMR (400 MHz, DMSO-d6) δ ppm 13.10 (br. s., 1 H), 10.15 (br. s., 1 H), 2.31 (s, 3 H), 2.18-2.29 (m, 5 H), 1.78 (d, J=13.14 Hz, 2 H), 1.62 (d, J=10.36 Hz, 3 H), 1.28 (q, J=12.72 Hz, 2 H), 1.12 (t, J=12.88 Hz, 1 H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O.Cl[C:23]1[C:24]2[C:31]([CH3:32])=[C:30]([CH3:33])[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1>O>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][C:23]1[C:24]2[C:31]([CH3:32])=[C:30]([CH3:33])[NH:29][C:25]=2[N:26]=[CH:27][N:28]=1)([O-:3])=[O:2]
Reactant: O=[N+]([O-])c1cccc(O)c1
Reactant: Cc1[nH]c2ncnc(Cl)c2c1C
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1[nH]c2ncnc(Oc3cccc([N+](=O)[O-])c3)c2c1C
Reaction time: 72 h
Yield: 46.9 %

Procedure:
After adding 3-nitrophenol (243 mg), potassium carbonate (268 mg) and dimethylformamide (2 ml) to the 4-chloro-5,6-dimethyl-7H-pyrrolo[2,3-d]-pyrimidine (177 mg) described in journal of Medicinal Chemistry, 1996, Vol. 39, No. 12, 2285–2292, the mixture was stirred at 120–130° C. for 72 hours. This was returned to room temperature, water was added, extraction was performed with a tetrahydrofuran and ethyl acetate mixed solution, and then the organic layer was washed with saturated brine, dried over anhydrous sodium sulfate and concentrated to dryness. The obtained crystals were washed with diethyl ether to obtain the title compound (130 mg).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:13])([CH3:12])[C:10]#[N:11])[CH:5]=[CH:6][CH:7]=1.B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:8][C:9]([CH3:13])([CH3:12])[CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C#N)Cc1cccc(Br)c1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(CN)Cc1cccc(Br)c1
Temperature: 0 °C
Reaction time: 19 h
Yield: 75.4 %

Procedure:
To an ice-cold mixture of crude 3-(3-bromophenyl)-2,2-dimethylpropanenitrile (71) (3.0 g, 12.6 mmol) in anhydrous THF (20 mL) was added BH3-THF (20 mL of a 1M solution in THF, 20 mmol) slowly. The reaction was allowed to warm slowly and stirred for 19 h. The reaction was quenched with the dropwise addition of 6 M HCl then stirred for 1.5 h. Volatiles were removed under reduced pressure. The aqueous layer was extracted with diethyl ether twice then EtOAc was added and the mixture was made basic with 5 M aqueous KOH. The layers were separated and the aqueous layer was extracted with EtOAc twice. The combined organics were washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give 3-(3-bromophenyl)-2,2-dimethylpropan-1-amine as a light yellow oil (2.3 g). This material was taken on to the next step without further purification. 1H NMR (400 MHz, CDCl3) δ 7.32-7.35 (m, 1H), 7.30 (t, J=1.7 Hz, 1H), 7.13 (t, J=7.7 Hz, 1H), 7.06 (dd, J=7.6, 1.2 Hz, 1H), 2.50 (s, 2H), 2.47 (s, 2H), 0.84 (s, 6H).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([N+:16]([O-:18])=[O:17])=[CH:12][CH:11]=1)(=O)OCC)C.[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=O)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH:24]=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([N+:16]([O-:18])=[O:17])=[CH:14][CH:15]=2)=[CH:22][CH:21]=1
Reactant: CCOP(=O)(Cc1ccc([N+](=O)[O-])cc1)OCC
Reactant: O=Cc1ccc(Cl)cc1
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(Cl)cc2)cc1
Yield: 95 %

Procedure:
Prepared in analogy to example 56b) from (4-nitro-benzyl)-phosphonic acid diethyl ester and 4-chloro-benzaldehyde. Yellow solid. Yield=95%. MS: m/e=259.1 (M+).
Reaction SMILES: Cl.[NH:2]([C:4]1[CH:5]=[CH:6][C:7]2[S:11][CH:10]=[CH:9][C:8]=2[CH:12]=1)N.[NH:13]1[CH2:18][CH2:17][C:16](=O)[CH2:15][CH2:14]1>C(O)(C)C>[CH:9]1[C:8]2=[C:12]3[C:4](=[CH:5][CH:6]=[C:7]2[S:11][CH:10]=1)[NH:2][C:16]1[CH2:17][CH2:18][NH:13][CH2:14][C:15]3=1
Reactant: O=C1CCNCC1
Reactant: NNc1ccc2sccc2c1
Agent: Cl
Solvent: CC(C)O
Product: c1cc2c(ccc3[nH]c4c(c32)CNCC4)s1

Procedure:
15 g of 5-hydrazinobenzothiophene hydrochloride and 15 g of 4-piperidone are boiled in 450 ml of isopropanol under a reflux condenser for 2 hours. After cooling the mixture, the precipitate which has separated out is filtered off and suspended in 2 N NaOH. A layer of methylene chloride is introduced under the suspension and the mixture is stirred; the layers are then separated and the organic phase is washed, dried and evaporated. After recrystallisation of the residue from isopropanol, 7,8,9,10-tetrahydrothieno[3,2-e]pyrido[4,3-b]indole of melting point 190° is obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH2:17])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:3])[CH3:2].[O:19]([C:26]([NH:28][C:29]1[C:30](=[CH:35][CH:36]=[CH:37][CH:38]=1)[C:31]([O:33][CH3:34])=[O:32])=O)C1C=CC=CC=1>>[C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:17][C:26]([NH:28][C:29]2[CH:38]=[CH:37][CH:36]=[CH:35][C:30]=2[C:31]([O:33][CH3:34])=[O:32])=[O:19])(=[O:16])=[O:15])=[CH:10][C:9]=1[OH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)c1ccccc1NC(=O)Oc1ccccc1
Reactant: CC(C)(C)OC(=O)c1ccc(S(N)(=O)=O)cc1O
Product: COC(=O)c1ccccc1NC(=O)NS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Yield: 77.8 %

Procedure:
618 mg (2.26 mmol) of 4-t-butoxycarbonyl-3-hydroxybenzenesulfonamide and 613 mg (2.26 mmol) of methyl 2-N-phenoxycarbonylanthranilate were treated in the same way as in Preparation Example 17 to obtain 792 mg (yield 78%) of methyl 2-{[(4-t-butoxycarbonyl-3-hydroxybenzene-sulfonylamino)carbonyl]amino}benzoate. Properties: colorless amorphous, PMR (δ ppm, CDCl3): 1.60 (9H, s), 3.97 (3H, s), 7.09 (1H, t), 7.49-7.52 (2H, m), 7.65 (1H, d), 7.90 (1H, d), 8.01 (1H, dd), 8.33 (1H, d), 10.98 (1H, s), 11.18 (1H, s).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17](Cl)[C:12]=3[C:11]([CH3:20])=[C:10]2[CH3:21])=[C:4]([CH3:22])[CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH2:24]1.C(N(CC)C(C)C)(C)C>CCO>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([N:9]2[C:13]3[N:14]=[C:15]([CH3:19])[N:16]=[C:17]([N:23]4[CH2:28][CH2:27][CH:26]([CH2:29][CH2:30][C:31]#[N:32])[CH2:25][CH2:24]4)[C:12]=3[C:11]([CH3:20])=[C:10]2[CH3:21])=[C:4]([CH3:22])[CH:3]=1
Reactant: Cc1nc(Cl)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Reactant: N#CCCC1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: Cc1nc(N2CCC(CCC#N)CC2)c2c(C)c(C)n(-c3c(C)cc(Br)cc3C)c2n1
Temperature: 100 °C
Yield: 78.8 %

Procedure:
A suspension of 7-(4-bromo-2,6-dimethyl-phenyl)-4-chloro-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidine (2.0 g), 3-(piperidin-4-yl)propionitrile (1.4 g) and N,N-diisopropylethylamine (1.4 g) in EtOH (4 mL) was heated at 100° C. in a sealed tube for 11 hours. After cooling to room temperature, the solvent was removed under reduced pressure. The residue was purified with column chromatography (silica gel: Wako gel C200, eluent: hexane:ethyl acetate:CHCl3=8/2/1) to obtain 3-{1-[7-(4-bromo-2,6-dimethyl-phenyl)-2,5,6-trimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-yl]-piperidin-4-yl}-propionitrile (2.0 g) as a white crystal.
Reaction SMILES: C([NH:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][NH:10]2)(=O)C.[C:17]([NH:20]C1CCC2C(=C(NC(=O)C)C=CC=2)C1=O)(=O)[CH3:18]>>[NH2:4][C:5]1[CH:14]=[CH:13][C:12]([CH3:15])=[C:11]2[C:6]=1[C:7](=[O:16])[CH2:8][CH2:9][N:10]2[CH2:18][CH2:17][NH2:20]
Reactant: CC(=O)Nc1ccc(C)c2c1C(=O)CCN2
Reactant: CC(=O)Nc1cccc2c1C(=O)C(NC(C)=O)CC2
Product: Cc1ccc(N)c2c1N(CCN)CCC2=O

Procedure:
The reaction was carried out in the same manner as in Example 1-(4), except that 510 mg of the compound prepared in (1) above was used instead of 2,8-diacetylamino-1-tetralone of Example 1-(4), and post-treated to produce 220 mg of the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:16]3[C:11](=[CH:12][C:13]([NH2:17])=[CH:14][CH:15]=3)[C:10]([CH3:18])=[N:9]2)=[CH:5][CH:4]=1.CC1C=CC(S(O[CH2:32][CH2:33][C@@H:34]2[CH2:36][C@@H:35]2[CH:37]2[CH2:42][CH2:41][N:40]([C:43]3[N:48]=[CH:47][C:46]([Cl:49])=[CH:45][N:44]=3)[CH2:39][CH2:38]2)(=O)=O)=CC=1.[I-].[K+]>C(#N)C.O>[Cl:49][C:46]1[CH:45]=[N:44][C:43]([N:40]2[CH2:41][CH2:42][CH:37]([C@H:35]3[CH2:36][C@H:34]3[CH2:33][CH2:32][NH:17][C:13]3[CH:12]=[C:11]4[C:16](=[CH:15][CH:14]=3)[N:8]([CH2:7][C:6]3[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:20][CH:19]=3)[N:9]=[C:10]4[CH3:18])[CH2:38][CH2:39]2)=[N:48][CH:47]=1
Reactant: Cc1ccc(S(=O)(=O)OCC[C@@H]2C[C@@H]2C2CCN(c3ncc(Cl)cn3)CC2)cc1
Reactant: COc1ccc(Cn2nc(C)c3cc(N)ccc32)cc1
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(Cn2nc(C)c3cc(NCC[C@@H]4C[C@@H]4C4CCN(c5ncc(Cl)cn5)CC4)ccc32)cc1
Temperature: 110 °C
Reaction time: 1.33 h

Procedure:
1-(4-methoxybenzyl)-3-methyl-1H-indazol-5-amine (51 mg, 0.34 mmol) from step 2 of this example, 2-{(1S,2R)-2-[1-(5-chloropyrimidin-2-yl)piperidin-4-yl]cyclopropyl}ethyl 4-methylbenzenesulfonate from step 1 of Example 5 (75 mg, 0.17 mmol) and potassium iodide (3 mg, 0.017 mmol) combined and the solids slurried in acetonitrile. The slurry was reacted in the microwave with stirring for 80 minutes at 110° C. using normal power. The mixture was cooled to RT, diluted with 4:1 water:saturated sodium bicarbonate (40 ml), extracted with EtOAc (3×40 ml), the organic fractions combined, washed with brine, dried over Na2SO4, filtered and the volatiles removed in vacuum. The product was purified by chromatography on SiO2 eluting with 10% acetone:DCM to give the titled compound.
Reaction SMILES: [OH-].[Na+].C[O:4][C:5](=[O:41])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([CH2:38][CH3:39])([C:22]3[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]4([OH:36])[CH2:35][CH2:34][S:33][CH2:32][CH2:31]4)=[C:24]([CH3:37])[CH:23]=3)[CH2:20][CH3:21])=[CH:15][C:14]=2[CH3:40])=[CH:9][CH:8]=1.P([O-])(O)(O)=O.[Na+]>CO.O1CCCC1>[CH2:20]([C:19]([C:16]1[CH:17]=[CH:18][C:13]([C:10]2[CH:11]=[CH:12][C:7]([CH2:6][C:5]([OH:41])=[O:4])=[CH:8][CH:9]=2)=[C:14]([CH3:40])[CH:15]=1)([C:22]1[CH:27]=[CH:26][C:25]([C:28]#[C:29][C:30]2([OH:36])[CH2:31][CH2:32][S:33][CH2:34][CH2:35]2)=[C:24]([CH3:37])[CH:23]=1)[CH2:38][CH3:39])[CH3:21]
Reactant: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)OC)cc2)c(C)c1
Agent: O=P([O-])(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCC(CC)(c1ccc(C#CC2(O)CCSCC2)c(C)c1)c1ccc(-c2ccc(CC(=O)O)cc2)c(C)c1
Temperature: 25 °C
Reaction time: 13 h
Yield: 87.6 %

Procedure:
A 1 N sodium hydroxide aqueous solution (0.1 mL, 0.1 mmol) was added to a solution of (4′-{1-ethyl-1-[4-(4-hydroxy-tetrahydro-thiopyran-4-ylethynyl)-3-methyl-phenyl]-propyl}-2′-methyl-biphenyl-4-yl)-acetic acid methyl ester (Example 136-(6); 35 mg, 0.065 mmol) in methanol-tetrahydrofuran (1:1, 2 mL), and the mixture was stirred at room temperature for 13 hours. A 30% sodium dihydrogenphosphate aqueous solution was added to the reaction mixture, followed by extraction with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel chromatography (dichloromethane:methanol=20:1) to give the target compound as a colorless oil (30 mg, 88%).
Reaction SMILES: Br[C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[C:10]1(B(O)O)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]=[CH:12][CH:11]=1.O1CCCC1.C(=O)([O-])[O-].[K+].[K+]>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.O>[C:18]1([C:2]2[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=2[CH:4]=[O:5])[C:19]2[C:14](=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: O=Cc1ccccc1Br
Reactant: OB(O)c1cccc2ccccc12
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: C1CCOC1
Solvent: O
Product: O=Cc1ccccc1-c1cccc2ccccc12
Yield: 79.9 %

Procedure:
Into a 200-mL eggplant type flask were introduced 6.45 g (34.9 mmol) of 2-bromobenzaldehyde, 5.0 g (29.1 mmol) of 1-naphthylboronic acid, 0.15 g of tetrakis(triphenylphosphine)palladium, 60 mL of tetrahydrofuran, 10 g (73 mmol) of potassium carbonate, and 20 mL of water. This reaction mixture was heated with refluxing overnight. After washing with saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution and drying with anhydrous magnesium sulfate, the extract was concentrated to obtain yellow crystals. These crystals were purified by silica gel chromatography (solvent: hexane/toluene) to obtain 5.4 g of 2-(1-naphthyl)benzaldehyde (yield, 81%).
Reaction SMILES: [Li]CCCC.[O:6]1[C:10]2[CH:11]=[CH:12][C:13]([CH2:15][N:16]([CH2:33][C:34]3[CH:42]=[CH:41][C:37]4[O:38][CH2:39][O:40][C:36]=4[CH:35]=3)[CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[CH:21]=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)=[CH:14][C:9]=2[O:8][CH2:7]1.[CH3:43][C:44](OC(C)=O)=[O:45]>C1COCC1>[O:38]1[C:37]2[CH:41]=[CH:42][C:34]([CH2:33][N:16]([CH2:17][C:18]3[N:22]([CH2:23][CH2:24][CH2:25][CH3:26])[C:21]([C:44](=[O:45])[CH3:43])=[N:20][C:19]=3[C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[CH2:15][C:13]3[CH:12]=[CH:11][C:10]4[O:6][CH2:7][O:8][C:9]=4[CH:14]=3)=[CH:35][C:36]=2[O:40][CH2:39]1
Reactant: CCCCn1cnc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Reactant: CC(=O)OC(C)=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCCCn1c(C(C)=O)nc(-c2ccccc2)c1CN(Cc1ccc2c(c1)OCO2)Cc1ccc2c(c1)OCO2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
n-BuLi (1.2 equivalents in 175 μl hexane) is added to a solution of 1-(1,3-benzodioxol-5-yl)-N-(1,3-benzodioxol-5-ylmethyl)-N-[(1-butyl-4-phenyl-1H-imidazol-5-yl)methyl]methanamine (118 mg), obtained as a minor product in Example 2, step 4, in 10 mL anhydrous THF under N2 at −78° C. The resulting mixture is stirred at −78° C. for 1 hour. Ac2O (118.4 mg, 1.2 equivalents) is added. The reaction mixture is stirred at −78° C. for 2 more hours, warmed to room temperature, and stirred overnight. The reaction is quenched with 5 mL of H2O and diluted with 20 mL ethyl acetate. The organic phase is collected, washed with brine, dried and concentrated. Purification via silica gel chromatography provides the title compound (Compound 8).
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)OC)#[N:2].[N+]([O-])(O)=O.[O:16]([CH2:20][CH2:21][NH2:22])[N+:17]([O-:19])=[O:18].C[O-].[Na+]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:11]=[CH:10][O:9][CH:8]=1)=[N:22][CH2:21][CH2:20][O:16][N+:17]([O-:19])=[O:18])#[N:2]
Reactant: COC(=NC#N)c1ccoc1
Reactant: NCCO[N+](=O)[O-]
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O=[N+]([O-])O
Product: N#CNC(=NCCO[N+](=O)[O-])c1ccoc1
Temperature: 25 °C
Reaction time: 26 h
Yield: 8.2 %

Procedure:
Methyl N-cyano-3-furancarboximidate (0.5 g, 3.3 mmol) was dissolved in methanol (10 ml), and 2-nitroxyethylamine nitrate (0.84 g, 5.0 mmol) and sodium methoxide (0.27 g, 5.0 mmol) were added. The mixture was stirred at room temperature for 26 hours. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was extracted with chloroform (60 ml×3). The chloroform layer was washed with water (100 ml), dried over anhydrous sodium sulfate and concentrated under reduced pressure. The residual concentrate was subjected to chromatography on a silica gel column (WAKO GEL C-200, 20 g) eluting with chloroform-methanol (100:1). The eluted fractions were concentrated under reduced pressure and crystallized from methanol diethyl ether to give the title compound (0.06 g, 0.27 mmol, yield: 8%) as colorless crystals.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:13][CH:14]([N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[CH3:15]>>[CH:14]([N:16]1[CH2:21][CH2:20][N:19]([C:2]2[CH:7]=[C:6]([N:8]([CH3:12])[C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:18][CH2:17]1)([CH3:15])[CH3:13]
Reactant: CC(=O)N(C)c1ccnc(Cl)c1
Reactant: CC(C)N1CCNCC1
Product: CC(=O)N(C)c1ccnc(N2CCN(C(C)C)CC2)c1
Temperature: 120 °C

Procedure:
A mixture of 4 g (22 mmol) N-(2-chloro-pyridin-4-yl)-N-methyl-acetamide and 2.8 g (22 mmol) 1-(2-propyl)-piperazine was heated to 120° C. for 24 h. The crude product was purified by flash column chromatography on silica elutingwith a gradient formed from heptane and ethyl acetate (0.1% NEt3) to yield after evaporation of the product fractions 2.5 g (41%) of the title compound as light brow oil. MS: (m/e): 277.2 (MH+).
Reaction SMILES: [C:1]1([C:7]2[O:11][C:10]([C:12]([OH:14])=O)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH2:15][C:16]1[CH:25]=[CH:24][C:23]([Cl:26])=[CH:22][C:17]=1[C:18]([O:20]C)=[O:19]>>[Cl:26][C:23]1[CH:24]=[CH:25][C:16]([NH:15][C:12]([C:10]2[O:11][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:8][CH:9]=2)=[O:14])=[C:17]([CH:22]=1)[C:18]([OH:20])=[O:19]
Reactant: O=C(O)c1ccc(-c2ccccc2)o1
Reactant: COC(=O)c1cc(Cl)ccc1N
Product: O=C(Nc1ccc(Cl)cc1C(=O)O)c1ccc(-c2ccccc2)o1
Yield: 77 %

Procedure:
Using the same method as in Example 3-(i), methyl 5-chloro-2-{[(5-phenylfuran-2-yl)carbonyl]amino}benzoate was obtained using 5-phenylfuran-2-carboxylic acid and methyl 2-amino-5-chlorobenzoate. Thereafter, using the same method as in Example 3-(ii), the target 5-chloro-2-{[(5-phenylfuran-2-yl)carbonyl]amino}benzoic acid was obtained (yield: 77%).