Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Li+].[OH-].C([O:5][C:6]([C:8]1[C:9]([O:23][CH2:24][CH3:25])=[N:10][C:11]2[C:16]([C:17]=1[CH3:18])=[CH:15][CH:14]=[C:13]([C:19]([F:22])([F:21])[F:20])[CH:12]=2)=[O:7])C>CO.C1COCC1>[CH2:24]([O:23][C:9]1[C:8]([C:6]([OH:7])=[O:5])=[C:17]([CH3:18])[C:16]2[C:11](=[CH:12][C:13]([C:19]([F:22])([F:20])[F:21])=[CH:14][CH:15]=2)[N:10]=1)[CH3:25]
Reactant: CCOC(=O)c1c(OCC)nc2cc(C(F)(F)F)ccc2c1C
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCOc1nc2cc(C(F)(F)F)ccc2c(C)c1C(=O)O
Temperature: 60 °C
Yield: 94.8 %

Procedure:
2M aq. LiOH sol. (38 ml) was added to a solution of 5.1 g (15.5 mmol) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid ethyl ester in a MeOH/THF mixture (in each case 38 ml) and subsequently heated to 60° C. for 16 h. The organic solvents were removed as far as possible in a vacuum and the obtained aqueous solution was washed with EtOAc, set at pH 2 with 2M hydrochloric acid and diluted with EtOAc. The organic phase was separated and washed with brine, dried over MgSO4 and concentrated in a vacuum. 4.4 g (14.7 mmol, 95%) 2-ethoxy-4-methyl-7-(trifluoromethyl)quinoline-3-carboxylic acid was obtained as a residue. The raw product was further converted without additional purification.
Reaction SMILES: [C:1]1([C:7]2[CH:25]=[C:24]3[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]4[S:23][CH2:22][C:16]5([CH2:21][CH2:20][NH:19][CH2:18][CH2:17]5)[O:15][C:14]=43)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]2[CH2:37][O:36]2)=[CH:31][CH:30]=1>>[F:28][C:29]1[CH:39]=[CH:38][C:32]([O:33][CH2:34][C@@H:35]([OH:36])[CH2:37][N:19]2[CH2:20][CH2:21][C:16]3([O:15][C:14]4[C:24]5[C:10]([C:11](=[O:27])[C:12](=[O:26])[C:13]=4[S:23][CH2:22]3)=[CH:9][CH:8]=[C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)[CH:25]=5)[CH2:17][CH2:18]2)=[CH:31][CH:30]=1
Reactant: Fc1ccc(OC[C@@H]2CO2)cc1
Reactant: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCNCC1)O2
Product: O=C1C(=O)c2ccc(-c3ccccc3)cc2C2=C1SCC1(CCN(C[C@H](O)COc3ccc(F)cc3)CC1)O2

Procedure:
Compound 225 was synthesized using 9-phenylspiro[naphtho[1,2-b][1,4]oxathiine-2,4′-piperidine]-5,6-dione, (2S)-2-[(4-fluorophenoxy)methyl]oxirane and conditions outlined in procedure Z. M.p.=173-175° C.; 400 MHz 1H NMR (DMSO-d6) δ: 8.01 (d, J=1.2 Hz, 1H), 7.98 (d, J=8.8 Hz, 1H), 7.87 (dd, J=1.6, 7.6 Hz, 1H), 7.76 (d, J=7.6 Hz, 2H), 7.57 (dd, J=7.6, 7.6 Hz, 2H), 7.52-7.47 (m, 1H), 7.10 (dd, J=8.8, 8.8 Hz, 2H), 6.94 (dd, J=4.4, 8.8 Hz, 2H), 4.88 (d, J=4.8 Hz, 1H), 3.97-3.95 (m, 2H), 3.87-3.82 (m, 1H), 3.11 (s, 2H), 2.87-2.78 (m, 2H), 2.54-2.39 (m, 4H), 2.03 (d, J=14.4 Hz, 2H), 1.87-1.81 (m, 2H); LCMS: 546 [M+H].
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:13][C:14]#[N:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.Cl.ClC1C=CC=CC=1C1C=CC=CC=1CC(N)=[NH:32]>>[ClH:1].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:13][C:14]([NH2:32])=[NH:15])[CH2:12][CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: N=C(N)Cc1ccccc1-c1ccccc1Cl
Reactant: N#CCC1(c2ccc(Cl)cc2)CCCC1
Agent: Cl
Product: N=C(N)CC1(c2ccc(Cl)cc2)CCCC1
Yield: 80.21 %

Procedure:
2-[1-(4-chlorophenyl)-cyclopentyl]-acetamidine HCl salt (26-02) (6 g, 80.21%) was synthesized from [1-(4-chlorophenyl)-cyclopentyl]-acetonitrile (25-02) (6 g, 27.39 mmol) as a white gummy solid as a crude product following the procedure as described for 2-(2′-chloro-biphenyl-2-yl)-acetamidine hydrochloride salt (5-02).
Reaction SMILES: I[C:2]1[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[CH3:12][O:13][C:14]1[CH:15]=[C:16](B(O)O)[CH:17]=[CH:18][CH:19]=1.C(=O)([O-])[O-].[Na+].[Na+]>COCCOC.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>[CH3:12][O:13][C:14]1[CH:19]=[C:18]([C:2]2[CH:3]=[CH:4][C:5]([NH2:11])=[C:6]([CH:10]=2)[C:7]([OH:9])=[O:8])[CH:17]=[CH:16][CH:15]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Nc1ccc(I)cc1C(=O)O
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: COCCOC
Product: COc1cccc(-c2ccc(N)c(C(=O)O)c2)c1
Temperature: 80 °C

Procedure:
To a solution of 5-iodo-2-aminobenzoic acid (2.6g; 10 mmol) in ethylene glycol dimethyl ether (DME, 20 mL) add tetrakis(triphenylphosphine)palladium(0) (150 mg) under argon. After the catalyst dissolved completely, add successively 3-methoxybenzeneboronic acid (1.65 g; 11 mmol) and sodium carbonate (1M in water, 30 mL). Heat the mixture at 80° C. for 1 hour. Cool the reaction mixture then wash with 50% EtOAc in hexane. Filter the aqueous layer through a short pad of celite to remove palladium black and carefully pour the filtrate into cold 3N hydrochloric acid (25 mL) under stirring. Collect the precipitate by filtration and air-dry to obtain 5-(3-methoxyphenyl)-2-aminobenzoic acid as a white solid.
Reaction SMILES: [CH2:1]([C:3]1[C:4](N[C@@H]2C3C(=CC=CC=3)C[C@@H]2O)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2].[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]([NH2:34])[CH2:29][CH2:28][CH2:27]2>>[CH2:1]([C:3]1[C:4]([NH:34][CH:30]2[C:31]3[C:26](=[CH:25][C:24]([O:23][CH3:22])=[CH:33][CH:32]=3)[CH2:27][CH2:28][CH2:29]2)=[N:5][C:6]([CH2:9][CH3:10])=[CH:7][N:8]=1)[CH3:2]
Reactant: CCc1cnc(CC)c(N[C@@H]2c3ccccc3C[C@@H]2O)n1
Reactant: COc1ccc2c(c1)CCCC2N
Product: CCc1cnc(CC)c(NC2CCCc3cc(OC)ccc32)n1

Procedure:
Following the procedure for the preparation of (1R,2S)-1-[(3,6-diethylpyrazin-2-yl)amino]-2,3-dihydro-1H-inden-2-ol but substituting 6-methoxy-1,2,3,4-tetrahydronaphthalen-1-amine and making non-critical variations provided the title compound as a oil: HRMS (FAB) calcd for C19H25N3O+H 312.2076, found 312.2075; Anal. Calcd for C19H25N3O: C, 73.28; H, 8.09; N, 13.49. Found C, 73.38; H, 8.11; N, 13.32.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH:5]=O.C([O-])(=O)C.[NH4+].[N+:17]([CH3:20])([O-:19])=[O:18]>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:20][N+:17]([O-:19])=[O:18])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11]
Reactant: C[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1F
Agent: CC(=O)[O-]
Agent: [NH4+]
Product: COc1ccc(C=C[N+](=O)[O-])cc1F

Procedure:
3-Fluoro-4-methoxy-benzaldehyde (10 g) was dissolved in 100 mL of nitromethane along with 5 g of ammonium acetate. The mixture was refluxed for 2 hours. The nitromethane was removed by rotary evaporation and the residue recrystallized from ethanol to give 7.6 g of the expected product. LC-MS showed the product had the expected M+H+ of 198.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][N:4]1[C:12]2[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=2[C:6]2[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]1=2.C(N(C(C)C)CC)(C)C.[C:34]1([S:40](Cl)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1.C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C1COCC1>[C:34]1([S:40]([NH:1][CH2:2][CH2:3][N:4]2[C:12]3[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=3[C:6]3[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17][C:5]2=3)(=[O:42])=[O:41])[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2c(n(CCN)c3ccccc23)CC1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCc2c(n(CCNS(=O)(=O)c3ccccc3)c3ccccc23)CC1
Reaction time: 19 h
Yield: 75.1 %

Procedure:
tert-Butyl 6-(2-aminoethyl)-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0403 g, 0.122 mmol) was dissolved in THF (2 mL) at rt under N2. Diisopropylethylamine (0.043 mL, 0.0316 g, 0.245 mmol, 2.00 equiv.) and benzenesulfonyl chloride (0.023 mL, 0.0324 g, 0.183 mmol, 1.50 equiv.) were added, then the reaction mixture was stirred for 19 h. Citric acid (10%) was added and the reaction mixture was stirred for 15 min. The reaction mixture was extracted with EtOAc, and the organic layer was washed sequentially with 10% citric acid, saturated aqueous NaHCO3 and brine. The organic layer was dried over MgSO4, filtered, and concentrated. The crude product (0.0649 g) was chromatographed (SiO2 25 g, eluted with 2:1 hexane:EtOAc) to give tert-butyl 6-{2-[(phenylsulfonyl)amino]ethyl}-1,4,5,6-tetrahydroazepino[4,5-b]indole-3(2H)-carboxylate (0.0430 g) in 75% yield. 1H NMR (300 MHz, CDCl3) δ 1.46, 1.52, 2.95-3.02, 3.22-3.30, 3.63-3.75, 4.24-4.31, 4.63, 4.79, 7.09-7.26, 7.45-7.51, 7.48, 7.58, 7.79; MS (ESI+) for C25H31N3O4S m/z 470.0 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3](C(OC)=O)=[CH:2]1.[H-].[Na+].CI.[CH3:18][N:19]([CH:21]=O)[CH3:20]>O>[CH3:18][N:19]1[C:20]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:2][NH:1][CH3:9])=[CH:21]1
Reactant: CN(C)C=O
Reactant: COC(=O)c1c[nH]c2ccccc12
Agent: [H-]
Agent: [Na+]
Solvent: CI
Solvent: O
Product: CNCc1cn(C)c2ccccc12
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 96 %

Procedure:
Methyl 1-methyl-1H-indole-3-carboxylate NaH (60% dispersion in mineral oil, 8.56 g, 214.0 mmole) was added portionwise, allowing for gas evolution, to a solution of methyl 1H-indole-3-carboxylate (25.00 g, 142.7 mmole) in DMF (350 mL) at 0° C. When the NaH addition was complete, methyl iodide (44.4 mL, 713.5 mmole) was added at 0° C. The reaction was stirred at 0° C. for 15 minutes then at RT overnight. The reaction was diluted with water and extracted with ethyl acetate. The combined extracts were dried over K2CO3 and concentrated to afford the title compound (26.00 g, 96%) as an orange solid: MS (ES) m/e 190 (M+H)+.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.[CH3:8][C:9]([C:11]1[CH:12]=[CH:13][C:14](O)=[CH:15][C:16]=1[OH:17])=[O:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(Cl)Cl.CCOCC>[OH:17][C:16]1[CH:15]=[C:14]([O:7][CH:4]2[CH2:5][CH2:6][O:1][CH2:2][CH2:3]2)[CH:13]=[CH:12][C:11]=1[C:9](=[O:10])[CH3:8]
Reactant: OC1CCOCC1
Reactant: CC(=O)c1ccc(O)cc1O
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: CC(=O)c1ccc(OC2CCOCC2)cc1O
Temperature: 20 °C
Reaction time: 20 h
Yield: 31.3 %

Procedure:
A mixture of tetrahydro-4H-pyran-4-ol (1.53 g, 15 mmol), 2,4-dihydroxyacetophenone (1.52 g, 10 mmol), and triphenylphosphine, polymerbound (5 g, 3 mmol P/g resin, 15 mmol) in CH2Cl2 (150 mL) was treated with diethylazodicarboxylate (2.61 g, 15 mmol) and stirred at 20° C. for 20 h. The reaction mixture was treated with ether (200 mL) and the resin was filtered off and discarded. The filtrate was concentrated in vacuo and purified by flash chromatography (silica gel, 4×7.5 cm, eluted with 25% ether in hexanes) to yield the white solid product (0.74 g, 31%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.C([Li])CCC.[O:14]1[CH2:17][C:16](=[O:18])[CH2:15]1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:16]2([OH:18])[CH2:17][O:14][CH2:15]2)=[N:3][CH:4]=1
Reactant: O=C1COC1
Reactant: Brc1ccc(Br)nc1
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: OC1(c2ccc(Br)cn2)COC1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 51.9 %

Procedure:
2,5-Dibromopyridine (10 g, 35.2 mmol) is dissolved in dry toluene (200 mL) under a nitrogen atmosphere and cooled to −78° C. n-Butyllithium (2.5M in hexanes, 2.5 mL, 38.7 mmol) is added at −78° C. over 20 minutes. The reaction mixture is stirred at −78° C. for 20 minutes. Oxetane-3-one (2.79 g, 38.7 mmol) in toluene (100 mL) is added then stirred at −78° C. for 30 minutes. Saturated aqueous ammonium chloride solution (50 mL) is added. The mixture extracted with ethyl acetate (2×200 mL), separated, washed with brine solution (50 mL) and the solvent evaporated under reduced pressure. The crude material is purified using flash chromatography (35% ethyl acetate in hexane) to give the title compound (4.2 g): 1H NMR (400 MHz, DMSO-d6):δ 4.64 (2H, d), 4.87 (2H, d), 6.68 (1H, s), 7.55 (1H, d), 8.06 (1H, dd), 8.76 (1H, d).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([CH:11]2[CH2:15][CH2:14][O:13][C:12]2=[O:16])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[Na+].I[CH3:20]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([C:11]2([CH3:20])[CH2:15][CH2:14][O:13][C:12]2=[O:16])(=[O:10])=[O:9])=[CH:6][CH:7]=1
Reactant: CI
Reactant: O=C1OCCC1S(=O)(=O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(S(=O)(=O)c2ccc(Cl)cc2)CCOC1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a mixture of 3-(4-chlorobenzenesulfonyl)-dihydro-furan-2-one (0.599 g; 2.29 mmol) in DMF (5 mL) at 0-5° C. was added portionwise NaH (0.23 g of a 60% dispersion in mineral oil; 5.74 mmol). The mixture stirred 30 minutes and iodomethane (0.43 mL; 6.89 mmol) was added. The reaction warmed to room temperature while stiffing overnight and was quenched with water. The solid was filtered and dried in vacuo to provide the desired product. Wt 0.488 g. 1H NMR (CDCl3) δ 7.82 (d, 2H), 7.56 (d, 2H), 4.56 (m, 1H), 4.39 (m, 1H), 3.32 (m, 1H), 2.42 (m, 1H), 1.51 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]2[O:10][C:9](=[O:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=2[CH:14]=1.[Cl:17][C:18]1[CH:23]=[CH:22][C:21]([CH2:24][N:25]2[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][CH2:33]Cl)[CH2:27][CH2:26]2)=[CH:20][CH:19]=1.C(O)(C)C.Cl>O>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:24][N:25]2[CH2:26][CH2:27][N:28]([CH2:31][CH2:32][CH2:33][O:1][C:2]3[C:3]([O:15][CH3:16])=[CH:4][C:5]4[O:10][C:9](=[O:11])[C:8]([CH3:12])=[C:7]([CH3:13])[C:6]=4[CH:14]=3)[CH2:29][CH2:30]2)=[CH:22][CH:23]=1
Reactant: COc1cc2oc(=O)c(C)c(C)c2cc1O
Reactant: ClCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: COc1cc2oc(=O)c(C)c(C)c2cc1OCCCN1CCN(Cc2ccc(Cl)cc2)CC1
Yield: 74 %

Procedure:
Method D (5 h at 90° C.); starting materials: 6-hydroxy-7-methoxy-3,4-dimethyl-2H-1-benzopyran-2-one (example 103) and 1-[(4-chlorophenyl)methyl]-4-(3-chloropropyl)piperazine; yield: 74%; fusion point 96°-97° C. (from isopropanol and petroleum ether). Hydrochloride (x 2 HCl): method G; yield 95%; fusion point 255°-260° C. (from isopropanol and water).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][N:5]([CH2:7][CH:8]2[CH2:10][CH2:9]2)[N:6]=1.[CH:11]1[C:24]2[CH:23]([C:25](Cl)=[O:26])[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[O:16][C:15]=2[CH:14]=[CH:13][CH:12]=1>>[CH:8]1([CH2:7][N:5]2[N:4]=[N:3][C:2]([NH:1][C:25]([CH:23]3[C:24]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=4[O:16][C:17]4[C:22]3=[CH:21][CH:20]=[CH:19][CH:18]=4)=[O:26])=[N:6]2)[CH2:10][CH2:9]1
Reactant: Nc1nnn(CC2CC2)n1
Reactant: O=C(Cl)C1c2ccccc2Oc2ccccc21
Product: O=C(Nc1nnn(CC2CC2)n1)C1c2ccccc2Oc2ccccc21

Procedure:
The title compound, white solid, m.p. 222-224° C. and MS: (neg. ions): m/e=346.2 (M+−H) was prepared in accordance with the general method of example 1 from 5-amino-2-cyclopropylmethyl-2H-tetrazole and 9H-xanthene-9-carbonyl chloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][C:10]2[C:18]([O:19][CH3:20])=[CH:17][CH:16]=[CH:15][C:11]=2[C:12]([OH:14])=O)[CH:5]=[CH:6][CH:7]=1.O=S(Cl)Cl.[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]2[C:12](=[O:14])[C:11]3[CH:15]=[CH:16][CH:17]=[C:18]([O:19][CH3:20])[C:10]=3[CH2:9][CH2:8][C:4]=2[CH:3]=1
Reactant: COc1cccc(C(=O)O)c1CCc1cccc(Cl)c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=S(Cl)Cl
Solvent: ClCCl
Product: COc1cccc2c1CCc1cc(Cl)ccc1C2=O

Procedure:
For the synthesis of the title compound, 16.6 g (0.057 mol) of [2-(3-chlorophenyl)-ethyl]-3-methoxybenzoic acid, 7.25 g (0.06 mol) of SOCl2, 250 ml of methylene chloride and 10 g of AlCl3 are employed in method K. Purification is carried out by column chromatography (flash; SiO2; hexane 90%/ethyl acetate 10%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH:25]=[CH2:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2].[H][H]>CO.[Pd]>[CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C:13]2[S:14][CH:15]=[C:16]([C:18]3[CH:23]=[C:22]([CH2:24][CH2:25][CH3:26])[C:21]([OH:27])=[C:20]([C:28]([OH:30])=[O:29])[CH:19]=3)[N:17]=2)[CH:7]=[CH:8][C:9]=1[O:10][CH2:11][CH3:12])[CH3:2]
Reactant: [H][H]
Reactant: C=CCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Agent: [Pd]
Solvent: CO
Product: CCCc1cc(-c2csc(-c3ccc(OCC)c(OCC)c3)n2)cc(C(=O)O)c1O
Yield: 76.8 %

Procedure:
A catalytic amount of 5% Pd-C was added to a solution of 250 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-allylphenyl)thiazole in 10 ml of methanol. The mixture was stirred in a hydrogen atmosphere at room temperature for 6 hours. After the completion of a reaction, the reaction mixture was filtered. The filtrate was concentrated. The residue was recrystallized from ethanol to obtain 193 mg of 2-(3,4-diethoxyphenyl)-4-(3-carboxy-4-hydroxy-5-propylphenyl)thiazole.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]([OH:10])=O)=[CH:6][C:5]([Br:11])=[CH:4][N:3]=1.[NH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[C:14]=1O.[OH-].[Na+]>O>[Br:11][C:5]1[CH:6]=[C:7]([C:8]2[O:10][C:14]3[C:15]([F:19])=[CH:16][CH:17]=[CH:18][C:13]=3[N:12]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)cc1C(=O)O
Reactant: Nc1cccc(F)c1O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: Nc1ncc(Br)cc1-c1nc2cccc(F)c2o1
Temperature: 200 °C
Reaction time: 5 h
Yield: 33.5 %

Procedure:
A mixture of 2-amino-5-bromo-pyridine-3-carboxylic acid (1 g), 2-amino-6-fluoro-phenol (0.586 g) and polyphosphoric acid (10 g) was stirred at 200° C. for 5 hours. The resulting mixture was cooled to room temperature, diluted with water (4 ml) and basified to pH 12 with aqueous NaOH 10N, then 2N. The precipitate was filtered, washed with water, diethyl ether, and dried. The compound was stirred in THF during 2 days, the insoluble was filtered, the filtrate was concentrated to dryness and dried under vacuum to give 5-bromo-3-(7-fluoro-1,3-benzoxazol-2-yl)pyridin-2-amine (0.475 g). NMR Spectrum: (DMSOd6) 7.37-7.48 (m, 2H), 7.69 (dd, 1H), 7.83 (bs, 2H), 8.34 (d, 1H), 8.38 (d, 1H); Mass spectrum: M+H+ 307-309
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1B1OC(C)(C)C(C)(C)O1)[O:6][CH2:7][C:8]([CH3:20])([CH3:19])[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].Br[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:42]=[C:43]([C:45]([F:48])([F:47])[F:46])[N:44]=2)=[CH:36][N:35]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:21]=[CH:22][C:23]=1[C:34]1[CH:39]=[CH:38][C:37]([C:40]2[N:41]([CH2:49][O:50][CH2:51][CH2:52][Si:53]([CH3:56])([CH3:55])[CH3:54])[CH:42]=[C:43]([C:45]([F:46])([F:47])[F:48])[N:44]=2)=[CH:36][N:35]=1)[O:6][CH2:7][C:8]([CH3:19])([CH3:20])[C:9]([O:11][CH2:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:10]
Reactant: C[Si](C)(C)CCOCn1cc(C(F)(F)F)nc1-c1ccc(Br)nc1
Reactant: COc1cc(OCC(C)(C)C(=O)OCc2ccccc2)ccc1B1OC(C)(C)C(C)(C)O1
Product: COc1cc(OCC(C)(C)C(=O)OCc2ccccc2)ccc1-c1ccc(-c2nc(C(F)(F)F)cn2COCC[Si](C)(C)C)cn1
Yield: 83.3 %

Procedure:
By using benzyl 3-[3-methoxy-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenoxy]-2,2-dimethylpropanoate (1.03 g) and 2-bromo-5-[4-(trifluoromethyl)-1-{[2-(trimethylsilyl)ethoxy]methyl}-1H-imidazol-2-yl]pyridine (494 mg), the procedure was carried out in the same manner as in Reference example 1-3) to obtain benzyl 3-[3-methoxy-4-[5-[4-(trifluoromethyl)-1-(2-trimethylsilylethoxymethyl)imidazol-2-yl]-2-pyridyl]phenoxy]-2,2-dimethylpropanoate (639 mg).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([C:13]([OH:15])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2].C(Cl)(=O)C([Cl:19])=O>C(Cl)Cl.CN(C=O)C>[C:1]([C:3]1[CH:4]=[C:5]([C:13]([Cl:19])=[O:15])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=1)#[N:2]
Reactant: N#Cc1cc2c(c(C(=O)O)c1)CCCC2
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: N#Cc1cc2c(c(C(=O)Cl)c1)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.207 g, 1.03 mmol) in DCM (5 mL) was added oxalyl chloride (0.112 mL, 1.29 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h., the solvent was removed in vacuo and the 3-cyano-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:16]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C@H:15]([OH:25])[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[O:13][C@@H:10]1[O:11][CH3:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:35][CH2:36][O:37][CH2:38][CH3:39]>>[CH2:36]([O:37][C@@H:38]1[C@@H:36]([O:37][CH2:38][C:39]2[CH:4]=[CH:3][CH:2]=[CH:7][CH:6]=2)[C@H:35]([CH2:12][O:11][C:10](=[O:13])[CH3:9])[C@@H:15]([CH2:16][O:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[O:25][C@@H:39]1[O:25][C@@H:15]1[C@@H:14]([CH2:26][O:27][CH2:28][C:29]2[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=2)[O:13][C@H:10]([O:11][CH3:12])[C@H:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)[C@H:16]1[O:17][CH2:18][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:35]1[CH:31]=[CH:30][CH:29]=[CH:34][CH:33]=1
Reactant: CCOCC
Reactant: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Product: CO[C@H]1O[C@H](COCc2ccccc2)[C@@H](O[C@H]2O[C@H](COCc3ccccc3)[C@@H](COC(C)=O)[C@H](OCc3ccccc3)[C@H]2OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Temperature: -30 °C
Reaction time: 0.25 h
Yield: 60 %

Procedure:
Ethereal silver perchloride (0.08M, 9.58 mL, 7.67 mmol) was added with stirring at -30° C. to a solution of methyl 2,3,6-tri-O-benzyl-α-D-glucopyranoside (2.592 g, 5.59 mmol), 2,3,6-tri-O-benzyl-1,4-dideoxy-4-acetyloxymethyl-D-gluco-pyranosyl chloride (3.661 g, 6.98 mmol) in ether (20 mL). The mixture was stirred 15 min at -30° C. and silver chloride precipitated. The mixture was filtered through a celite pad, the solids were washed with ether, the filtrate was concentrated under reduced pressure. The residue was dissolved in methylene chloride and the organic layer was washed successively with aqueous sodium thiosulfate and water. The organic layer was dried over sodium sulfate, filtered and concentrated under reduced pressure to afford a foam. Flash chromatography on silica gel and elution with a graded mixture of hexane and ethyl acetate afforded mehyl 4-O-(2,3,6-tri-O-benzyl-4-deoxy-4-acetyloxymethyl-α-D-glucopyranosyl) -2,3,6-tri-O-benzyl-α-D-glucopyranoside (3.19 g, 60%) as a foam.
Reaction SMILES: [F:1][C:2]1([F:18])[CH2:7][O:6][C:5]([NH2:8])=[N:4][C@@:3]21[C:16]1[C:11](=[CH:12][CH:13]=[C:14]([NH2:17])[CH:15]=1)[CH2:10][CH2:9]2.[F:19][C:20]1[CH:21]=[CH:22][C:23]([C:26](O)=[O:27])=[N:24][CH:25]=1>>[NH2:8][C:5]1[O:6][CH2:7][C:2]([F:1])([F:18])[C@@:3]2([C:16]3[C:11](=[CH:12][CH:13]=[C:14]([NH:17][C:26](=[O:27])[C:23]4[CH:22]=[CH:21][C:20]([F:19])=[CH:25][N:24]=4)[CH:15]=3)[CH2:10][CH2:9]2)[N:4]=1
Reactant: NC1=N[C@@]2(CCc3ccc(N)cc32)C(F)(F)CO1
Reactant: O=C(O)c1ccc(F)cn1
Product: NC1=N[C@@]2(CCc3ccc(NC(=O)c4ccc(F)cn4)cc32)C(F)(F)CO1
Yield: 17 %

Procedure:
The condensation of (R)-5′,5′-difluoro-2,3,5′,6′-tetrahydrospiro[indene-1,4′-[1,3]oxazine]-2′,6-diamine (intermediate A7.3) and 5-fluoropicolinic acid yielded the title compound (17% yield) as an off-white solid. MS (ISP): m/z=377.2 [M+H]+.