Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11].[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[SH:19]>>[CH3:13][N:14]1[CH:18]=[CH:17][N:16]=[C:15]1[S:19][C:2]1[S:6][C:5]([C:7](=[O:9])[CH3:8])=[CH:4][C:3]=1[N+:10]([O-:12])=[O:11]
Reactant: Cn1ccnc1S
Reactant: CC(=O)c1cc([N+](=O)[O-])c(Cl)s1
Product: CC(=O)c1cc([N+](=O)[O-])c(Sc2nccn2C)s1

Procedure:
Prepared according to the procedure described for example 14 from 1-(5-Chloro-4-nitro-2-thienyl)ethanone (0.1 g, 0.49 mmol) and N-methyl imidazole-2-thiol (0.056 g, 0.49 mmol). The title compound was obtained as a solid (50 mg, 36% yield). 1H NMR (400 MHz, d6-DMSO) δ: 8.48 (2H, s) 7.64 (2H, dd) 7.28 (2H, dd), 3.42 (3H, s), 2.52 (3H, s). MS m/z: 283.9 [M+H]+.
Reaction SMILES: [CH:1]([N:5]1[C:10]2[N:11]=[C:12](S(C)(=O)=O)[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[CH3:22])[C:9]=2[CH:8]=[CH:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2].[NH2:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31]>>[CH:1]([N:5]1[C:10]2[N:11]=[C:12]([NH:28][CH:29]([CH2:32][OH:33])[CH2:30][OH:31])[N:13]=[C:14]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=3[CH3:22])[C:9]=2[CH:8]=[CH:7][C:6]1=[O:27])([CH2:3][CH3:4])[CH3:2]
Reactant: NC(CO)CO
Reactant: CCC(C)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(S(C)(=O)=O)nc21
Product: CCC(C)n1c(=O)ccc2c(-c3ccc(F)cc3C)nc(NC(CO)CO)nc21

Procedure:
The product of Example 55, and serinol were reacted by the procedure of Example 60 to afford the title compound 8-sec-butyl-4-(4-fluoro-2-methyl-phenyl)-2-(2-hydroxy-1-hydroxymethyl ethylamino)-8H-pyrido[2,3-d]pyrimidin-7-one. 1H-NMR: δ 0.80 (m, 3H), 1.37 (m, 3H), 2.21 (m, 3H), 2.73 (m, 2H), 3.96 (m, 4H), 4.20 (m, 1H), 5.52 (m, 1H), 6.29 (m, 1H), 6.59 (br s, 1H), 6.91-7.40 (m, 4H). LC MS (m/e)=401 (MH+).
Reaction SMILES: C(C1C=C(C(C)(C)CC(O)(C(F)(F)F)C[N:14]2[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[C:17](=[O:24])[CH:16]=[CH:15]2)C=CC=1)(=O)C.C(=O)([O-])[O-].[K+].[K+].Cl.NO>CO>[NH:14]1[C:23]2[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=2)[C:17](=[O:24])[CH:16]=[CH:15]1
Reactant: CC(=O)c1cccc(C(C)(C)CC(O)(Cn2ccc(=O)c3ccccc32)C(F)(F)F)c1
Agent: Cl
Agent: NO
Agent: O=C([O-])[O-]
Solvent: CO
Product: O=c1cc[nH]c2ccccc12
Temperature: 65 °C

Procedure:
A mixture of 1-[4-(3-acetylphenyl)-2-hydroxy-4-methyl-2-trifluoromethylpentyl]-1-H-quinolin-4-one (60 mg, 0.14 mmol), potassium carbonate (79 mg, 0.57 mmol), and hydroxylamine hydrochloride (39 mg, 0.55 mmol) in methanol (1 mL) was heated at 65° C. for 3 hours, cooled to room temperature, and concentrated in vacuo. The residue was diluted with water and extracted with ethyl acetate. The combined organic layers were washed with brine, dried over sodium sulfate, and concentrated in vacuo. The residue was purified by flash chromatography to afford 1-(2-hydroxy-4-{3-[1-(hydroxyimino)ethyl]phenyl)}-4-methyl-2-trifluoromethylpentyl)-1H-quinolin-4-one. Yield: 38 mg.
Reaction SMILES: O=[C:2]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][CH2:16][N:17]2[CH2:22][CH2:21][N:20]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=3)[CH2:19][CH2:18]2)=[CH:10][CH:9]=1)[CH2:3][CH2:4][C:5](O)=[O:6].[CH2:30]([NH2:32])[CH3:31]>>[CH2:30]([N:32]1[CH:2]([C:8]2[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][CH2:16][N:17]3[CH2:22][CH2:21][N:20]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([CH3:29])[CH:24]=4)[CH2:19][CH2:18]3)=[CH:12][CH:13]=2)[CH2:3][CH2:4][C:5]1=[O:6])[CH3:31]
Reactant: Cc1cccc(N2CCN(CCCc3ccc(C(=O)CCC(=O)O)cc3)CC2)c1
Reactant: CCN
Product: CCN1C(=O)CCC1c1ccc(CCCN2CCN(c3cccc(C)c3)CC2)cc1

Procedure:
4-Oxo-4-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]butyric acid and ethylamine are reacted together to give N-ethyl-5-[4-(3-(4-(3-methylphenyl)piperazin-1-yl)propyl)phenyl]pyrrolidin-2-one.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc(Br)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
To a solution of 4-bromo-2-nitrophenol 13.A (1.00 g, 4.59 mmol, available from Aldrich) and benzyl bromide (0.55 mL, 5.05 mmol) in DMF (10 mL) was added cesium carbonate (2.2 g, 6.9 mmol). The mixture was stirred overnight at room temperature and then partitioned between AcOEt and water. The organic phase was concentrated to afford 1-((4-bromo-2-nitrophenoxy)methyl)benzene 13.B (1.40 g, 99% yield) which was used in the next step without any further purification.
Reaction SMILES: [C:1]1([NH:7][C:8]([CH:10]2[CH2:13][N:12]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:11]2)=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.B>C1COCC1>[C:14]([N:12]1[CH2:13][CH:10]([CH2:8][NH:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:11]1)([O:16][C:17]([CH3:19])([CH3:20])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)Nc2ccccc2)C1
Agent: B
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(CNc2ccccc2)C1
Yield: 84.3 %

Procedure:
1-Boc-Azetidine-3-carboxylic acid phenylamide 47 (650 mg, 2.35 mmol) in 5 mL of dry THF was added slowly to 5 mL of 1.0 M borane in THF while stirring in an ice bath. The mixture was refluxed for 3 hours, then cooled in ice bath and quenched with 5 mL of aqueous HCl (10%), then treated with NaOH (10%) to pH 10. The mixture was extracted with ethyl acetate (3×20 mL). The extracts were combined and washed with brine (2×10 mL), and dried over anhydrous sodium sulfate. After the solvent was removed, the remaining oily residue was passed through a short column (silica gel, ethyl acetate) to afford N-(1-Boc-azetidine-3-ylmethyl)aniline 48 as a colorless oil (520 mg, 84%).
Reaction SMILES: [N:1]([C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[CH:6]=[CH:5][C:4]=1[OH:17])=O.[S:18]([O-:21])([OH:20])=[O:19].[Na+].[OH-].[Na+]>O>[NH2:1][C:3]1[C:12]2[C:7](=[CH:8][C:9]([C:13]([O:15][CH3:16])=[O:14])=[CH:10][CH:11]=2)[C:6]([S:18]([OH:21])(=[O:20])=[O:19])=[CH:5][C:4]=1[OH:17]
Reactant: COC(=O)c1ccc2c(N=O)c(O)ccc2c1
Reactant: O=S([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1ccc2c(N)c(O)cc(S(=O)(=O)O)c2c1
Temperature: 40 °C
Yield: 64 %

Procedure:
92.4 g (0.4 mol) of crude 1-nitroso-6-methoxycarbonyl-β-naphthol were added at room temperature to a solution of 360 g (1.11 mol) of 40%-strength aqueous sodium hydrogen sulfite and 4.4 g (0.11 mol) or sodium hydroxide in 1610 ml of water. The suspension was heated for 24 h at 40° C. and then 2.4 g; (2.6% of the amount taken) of residue were separated off. The clear solution was then acidified at 25° C. with 142 g (1.39 mol) of 36%-strength sulfuric acid and the product was crystallized out for 48 hours at room temperature. After filtration by suction and drying, 76.0 g (64%) of product is obtained.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([O:23][CH2:24][CH2:25][CH3:26])=[C:7]([C:9]2[NH:10][C:11](=[O:22])[C:12]3[N:17]([CH3:18])[N:16]=[C:15]([CH2:19][CH2:20][CH3:21])[C:13]=3[N:14]=2)[CH:8]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>>[CH3:18][N:17]1[C:12]2[C:11](=[O:22])[NH:10][C:9]([C:7]3[CH:8]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[CH:4]=[CH:5][C:6]=3[O:23][CH2:24][CH2:25][CH3:26])=[N:14][C:13]=2[C:15]([CH2:19][CH2:20][CH3:21])=[N:16]1
Reactant: CCCOc1ccc(CCl)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1
Reactant: CN1CCNCC1
Product: CCCOc1ccc(CN2CCN(C)CC2)cc1-c1nc2c(CCC)nn(C)c2c(=O)[nH]1

Procedure:
The title compound was prepared from 5-(5-chloromethyl-2-n-propoxyphenyl)-1-methyl-3-n-propyl-1,6-dihydro-7H-pyrazolo[4,3-d]pyrimidin-7-one and 1-methylpiperazine, following the procedure of Example 34, and was obtained as a colourless solid (36%), m.p. 149°-150° C. Found: C,65.68; H,7.83; N,19.10. C24H34N6O2 requires C,65.73; H,7.81; N,19.16%.
Reaction SMILES: Cl.Cl[C:3]1[N:12]=[C:11]([N:13]([C:15]2[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=2)[CH3:14])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1.[NH2:23][CH2:24][CH2:25][CH2:26][OH:27].C(Cl)(Cl)Cl>CCCCO>[CH3:22][O:21][C:18]1[CH:19]=[CH:20][C:15]([N:13]([CH3:14])[C:11]2[C:10]3[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=3)[N:4]=[C:3]([NH:23][CH2:24][CH2:25][CH2:26][OH:27])[N:12]=2)=[CH:16][CH:17]=1
Reactant: NCCCO
Reactant: COc1ccc(N(C)c2nc(Cl)nc3ccccc23)cc1
Agent: Cl
Solvent: CCCCO
Solvent: ClC(Cl)Cl
Product: COc1ccc(N(C)c2nc(NCCCO)nc3ccccc23)cc1
Temperature: 115 °C
Yield: 79.6 %

Procedure:
A mixture of (2-chloro-quinazolin-4-yl)-(4-methoxy-phenyl)-methyl-amine hydrochloride (88 mg, 0.26 mmol) and 3-amino-propan-1-ol (62 μL, 0.82 mmol) in n-BuOH (2 mL) was heated at 115° C. for 29 h then concd in vacuo. Chloroform (5 mL) was added and this washed with satd NaHCO3 (1×2 mL); then dried (MgSO4), filtered through silica with a wash of 100:10:1 CHCl3:MeOH:concd NH4OH, concd then purified by MPLC (amine column (Isco 60-2203-201)/0-100% i-PrOH in CHCl3) yielding the title compound as a pale yellow oil (70 mg; 79%). 1H NMR (CDCl3) δ 7.43 (m, 1H), 7.38 (m, 1H), 7.12 (m, 2H), 6.92 (m, 2H), 6.80 (m, 1H), 6.69 (m, 1H), 3.84 (s, 3H), 3.78-3.66 (m, 4H), 3.52 (s(br), 3H), 1.81 (m, 2H); LC-MS (ESI+; 339 ([M+H]+)).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C@@H:15]([OH:41])[C@@H:16]([N:26]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:13][O:12][C:11]1([CH3:43])[CH3:42])=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH2:44](Br)[C:45]1[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=1.[Cl-].[NH4+]>CN(C)C=O>[C:3]([O:7][C:8]([N:10]1[C@@H:14]([C@@H:15]([O:41][CH2:44][C:45]2[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=2)[C@@H:16]([N:26]([CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH2:17][C:18]2[CH:23]=[C:22]([F:24])[CH:21]=[C:20]([F:25])[CH:19]=2)[CH2:13][O:12][C:11]1([CH3:43])[CH3:42])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@@H](O)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Reactant: BrCc1ccccc1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1[C@@H]([C@@H](OCc2ccccc2)[C@H](Cc2cc(F)cc(F)c2)N(Cc2ccccc2)Cc2ccccc2)COC1(C)C
Reaction time: 0.25 h

Procedure:
Add sodium hydride (4.4 g, 110 mmol, 60% in mineral oil) portionwise to a room temperature maintained solution of (R)-4-[(1S,2S)-2-dibenzylamino-3-(3,5-difluorophenyl)-1-hydroxypropyl]-2,2-dimethyloxazolidine-3-carboxylic acid tert-butyl ester (50.5 g, 89.222 mmol) and benzyl bromide (22 mL, 184.96 mmol) in N,N-dimethylformamide (400 mL). Stir for 15 minutes and pour into saturated aqueous ammonium chloride. Extract with ethyl acetate, dry (magnesium sulfate), filter, concentrate and purify (silica gel chromatography, eluting with 2:98 to 4:96 ethyl acetate:hexanes) to give the title compound as a viscous oil that solidifies upon standing (48.5 g, 83%).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=[O:7])=[CH:4][C:3]=1[O:10][CH3:11].N1C=CC=CC=1.I[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:11][O:10][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][C:2]=1[O:1][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH:6]=[O:7]
Reactant: Ic1ccccc1
Reactant: COc1cc(C=O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COc1cc(C=O)ccc1Oc1ccccc1
Temperature: 145 °C
Yield: 12 %

Procedure:
6.0 g of 4-hydroxy-3-methoxybenzaldehyde, 75 ml of pyridine, 12.0 g of iodobenzene, 10.9 g of potassium carbonate and 6.24 g of cupric oxide were mixed and heated at 145° C. for 18 hours in a sealed tube. The reaction solution was left to cool to room temperature and then diluted with ethyl acetate and subjected to celite filtration. The filtrate was distilled off under reduced pressure, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=3/1) to obtain 1.11 g (yield: 12%) of the above identified compound as a colorless oily substance.
Reaction SMILES: [C:1]([C:5]1[CH:36]=[CH:35][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][C:19](Cl)=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:31][CH:32]([CH3:34])[CH3:33])[C:28]([OH:30])=[O:29])=[O:10])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd].C(O)C>[C:1]([C:5]1[CH:6]=[CH:7][C:8]([C:9]([N:11]2[C@@H:15]([C:16]3[S:20][CH:19]=[N:18][CH:17]=3)[C@@H:14]([C:22]3[CH:27]=[N:26][CH:25]=[CH:24][N:23]=3)[CH2:13][C@@:12]2([CH2:31][CH:32]([CH3:33])[CH3:34])[C:28]([OH:30])=[O:29])=[O:10])=[CH:35][CH:36]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2cnc(Cl)s2)N1C(=O)c1ccc(C(C)(C)C)cc1
Agent: [Pd]
Solvent: CCO
Product: CC(C)C[C@@]1(C(=O)O)C[C@H](c2cnccn2)[C@H](c2cncs2)N1C(=O)c1ccc(C(C)(C)C)cc1

Procedure:
A mixture of Example 27 (40 mg, 0.076 mmol) and 10% palladium on carbon catalyst (40 mg) in ethanol (5 mL) was hydrogenated over 5 days. The catalyst was removed by filtration and washed with ethanol. Following evaporation of the solvent the title compound was purified by reverse phase HPLC on a C18 column using a two-solvent gradient elution with (A) water containing formic acid (0.1%) and (B) acetonitrile-water (95:5 v/v) containing formic acid (0.05%) as the eluents, and analysis of the fractions by electrospray mass spectroscopy.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][C:15](=O)[N:14]([C:18]3[C:19]([CH3:38])=[C:20]([CH3:37])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[C@H:23]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:22]=4[C:35]=3[CH3:36])[C:13](=O)[CH2:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]>CCCCCC>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:12][CH2:13][N:14]([C:18]3[C:19]([CH3:38])=[C:20]([CH3:37])[C:21]4[O:25][C:24]([CH3:27])([CH3:26])[C@H:23]([C:28]5[CH:33]=[CH:32][C:31]([CH3:34])=[CH:30][CH:29]=5)[C:22]=4[C:35]=3[CH3:36])[CH2:15][CH2:16]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(C2CC(=O)N(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)C(=O)C2)cc1OC
Solvent: CCCCCC
Product: COc1ccc(C2CCN(c3c(C)c(C)c4c(c3C)[C@@H](c3ccc(C)cc3)C(C)(C)O4)CC2)cc1OC
Yield: 54 %

Procedure:
Using (3R)-4-(3,4-dimethoxyphenyl)-1-(2,2,4,6,7-pentamethyl-3-(4-methylphenyl)-2,3-dihydro-1-benzofuran-5-yl)piperidine-2,6-dione obtained in Example 27, the title compound was synthesized in the same manner as in Example 28. Yield 54%. mp. 102–106° C. (hexane).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][OH:9])[CH2:3][CH2:2]1.[C:10]1([CH3:20])[CH:15]=[CH:14][C:13]([S:16](Cl)(=[O:18])=[O:17])=[CH:12][CH:11]=1>N1C=CC=CC=1>[O:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][O:9][S:16]([C:13]2[CH:14]=[CH:15][C:10]([CH3:20])=[CH:11][CH:12]=2)(=[O:18])=[O:17])[CH2:3][CH2:2]1
Reactant: OCCC1CCOCC1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCC2CCOCC2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 53.5 %

Procedure:
To a solution of 1.63 g (12.5 mmol) of 2-(tetrahydro-pyran-4-yl)-ethanol in pyridine (15 mL) are added 3.58 g (18.8 mmol) of p-toluenesulfonylchloride. The reaction is stirred at room temperature for 5 h. The reaction mixture is concentrated under reduced pressure. The residue is dissolved 2M aqueous HCl solution (20 mL) and extracted with ethyl acetate (3×50 mL). The combined organic extracts are dried over Na2SO4, filtered and the solvent is removed to give 1.9 g of toluene-4-sulfonic acid 2-(tetrahydro-pyran-4-yl)-ethyl ester as off-white crystalline solid. Yield: 53%; ES-MS: m/z 285 [M+H]
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([OH:15])[CH:13]=2)[N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2].[Cl:28][C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1>>[CH2:1]([O:3][C:4]([C:6]1[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([O:15][C:32]3[CH:33]=[CH:34][C:29]([Cl:28])=[CH:30][CH:31]=3)[CH:13]=2)[N:8]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:7]=1[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:5])[CH3:2]
Reactant: CCOC(=O)Cc1c(C(=O)OCC)c2cc(O)ccc2n1-c1ccccc1
Reactant: OB(O)c1ccc(Cl)cc1
Product: CCOC(=O)Cc1c(C(=O)OCC)c2cc(Oc3ccc(Cl)cc3)ccc2n1-c1ccccc1

Procedure:
The sub-title compound was prepared in accordance with step (c) Example 1 from 2-ethoxycarbonylmethyl-5-hydroxy-1-phenylindole-3-carboxylic acid ethyl ester (140 mg, 0.38 mmol, see step (b) Example 3) and 4-chlorophenylboronic acid (119 mg, 0.76 mmol). Yield 100 mg, 55%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH:26]=O)[CH:9]=1.CO.[CH3:30][NH2:31].[BH4-].[Na+].[ClH:34].C(=O)([O-])O.[Na+]>CO>[ClH:34].[F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8]1[N:12]([S:13]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([S:22]([CH3:25])(=[O:24])=[O:23])[CH:17]=2)(=[O:15])=[O:14])[CH:11]=[C:10]([CH2:26][NH:31][CH3:30])[CH:9]=1
Reactant: CS(=O)(=O)c1cccc(S(=O)(=O)n2cc(C=O)cc2-c2ccccc2F)c1
Reactant: CN
Agent: Cl
Agent: O=C([O-])O
Agent: [BH4-]
Solvent: CO
Product: CNCc1cc(-c2ccccc2F)n(S(=O)(=O)c2cccc(S(C)(=O)=O)c2)c1
Reaction time: 0.5 h
Yield: 65 %

Procedure:
5-(2-Fluorophenyl)-1-{[3-(methylsulfonyl)phenyl]sulfonyl}-1H-pyrrole-3-carbaldehyde (550 mg) was dissolved in methanol (55 mL), 40% methylamine methanol solution (1.05 g) was added at room temperature, and the mixture was stirred for 30 min. Sodium borohydride (154 mg) was added at room temperature, and the mixture was stirred for 10 min. 1 mol/L Hydrochloric acid (100 mL) was added, and the mixture was stirred for 5 min. The reaction mixture was alkalized with a saturated aqueous sodium hydrogencarbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was dissolved in methanol (10 mL). A 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL) was added, and the mixture was concentrated under reduced pressure. The residue was crystallized from ethyl acetate to give the title compound as colorless crystals (yield 400 mg, 65%).
Reaction SMILES: CC1C=CC(S(O[CH2:12][C:13]([F:16])([F:15])[F:14])(=O)=O)=CC=1.[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[C:22]([OH:24])[CH:23]=1.C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:17][C:18]1[CH:19]=[CH:20][C:21]([CH2:25][OH:26])=[C:22]([O:24][CH2:12][C:13]([F:16])([F:15])[F:14])[CH:23]=1
Reactant: OCc1ccc(Cl)cc1O
Reactant: Cc1ccc(S(=O)(=O)OCC(F)(F)F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCc1ccc(Cl)cc1OCC(F)(F)F
Temperature: 100 °C
Yield: 13 %

Procedure:
Charged 2,2,2-trifluoroethyl 4-methylbenzenesulfonate (1.62 g, 6.37 mmol), 5-chloro-2-(hydroxymethyl)phenol (1.01 g, 6.37 mmol, PREPARATION 7), K2CO3 (1.76 g, 12.74 mmol) and DMF (7 mL) to a flask; heated to 100° C. overnight. The reaction mixture was then poured into ice-water and extracted with EA twice, washed the organic phase with water twice, brine and dried with Na2SO4, concentrated for gel chromatograph to give the title compound (200 mg, 13%). 1H NMR (400 MHz, CDCl3): δ 4.39 (2H, q, J=8.0 Hz), 4.70 (2H, d, J=5.2 Hz), 6.83 (1H, d, J=1.6 Hz), 7.05 (1H, dd, J=1.6 Hz, 8.0 Hz), 7.33 (1H, d, J=7.6 Hz).
Reaction SMILES: [C:1]([O-:7])(=[O:6])[CH2:2][C:3]([O-:5])=[O:4].[Na+].[Na+].[CH:10]12[CH:18]=[CH:17][CH:14]([CH2:15][CH2:16]1)[CH2:13][CH2:12][CH:11]2[C:19](Cl)=[O:20]>>[CH:10]12[CH:16]=[CH:15][CH:14]([CH2:17][CH2:18]1)[CH2:13][CH2:12][CH:11]2[C:19]([CH:2]([C:1]([OH:7])=[O:6])[C:3]([OH:5])=[O:4])=[O:20]
Reactant: O=C([O-])CC(=O)[O-]
Reactant: O=C(Cl)C1CCC2C=CC1CC2
Agent: [Na+]
Product: O=C(O)C(C(=O)O)C(=O)C1CCC2C=CC1CC2
Yield: 87.5 %

Procedure:
To a solution containing sodium malonate (17.1 g) which was prepared according to the same procedure as in Example 7, bicyclo[3,2,2]non-8-ene-2-carbonyl chloride (18.4 g) obtained in Preparation Example 3 is slowly added, and the reaction mixture is reacted at −20° C. in a nitrogen atmosphere for 1 hour, and further reacted at 45° C. for 8 hours. Then, the mixture is worked up as in the procedure of Example 1, to obtain 22 g of the pure title compound (purity: 99%, yield: 87%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([SH:11])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Cl[CH2:13][C:14]#[N:15].C([O-])([O-])=O.[K+].[K+].CCOC(C)=O>CN(C=O)C.CN(C1C=CN=CC=1)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][CH2:13][C:14]#[N:15])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(S)cc1OC
Reactant: N#CCCl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(SCC#N)cc1OC
Temperature: 80 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
To a solution of 3,4-dimethoxythiophenol (5.0 g, 29.4 mmol) in dry DMF (150 ml), were added chloroacetonitrile (1.85 ml, 29.4 mmol), anhydrous K2CO3 (6.09 g, 44.1 mmol) and DMAP (358 mg, 2.9 mmol). The reaction mixture was stirred at 80° C. for 20 h under nitrogen. After cooling, the mixture was filtered and concentrated in vacuo. The residue was combined with H2O, extracted with CH2Cl2, the combined organic phases were dried over anhydrous MgSO4, filtered and concentrated to give a crude oil. Flash chromatography (AcOEt) gave the title product (5.16 g, 84%).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6](F)[C:3]=1[CH:4]=[O:5].[C:11]1([OH:17])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([O:17][C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:3]=1[CH:4]=[O:5]
Reactant: Oc1ccccc1
Reactant: O=Cc1c(F)cccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: O=Cc1c(Cl)cccc1Oc1ccccc1
Yield: 83.6 %

Procedure:
A mixture of 15.8 g (100 mmol) of 2-chloro-6-fluorobenzaldehyde, 9.4 g (100 mmol) of phenol and 20.7 g (150 mmol) of potassium carbonate in 150 ml of dimethylacetamide is heated under reflux for 4 hours The mixture is allowed to cool, water is added and the mixture is extracted 3× with tert-butyl methyl ether. The organic phases are washed with 2N sodium hydroxide solution and brine, dried over sodium sulfate and concentrated. Bulb tube distillation (175° C., 0.04 mbar) yields 19.46 g (83.64 mmol)=83.6% of 2-chloro-6-phenoxy-benzaldehyde in the form of a yellow oil, 1H-NMR (CDCl3, 200 MHz): 6.75-7.45 (m, 8H); 10.58 (s, 1H).
Reaction SMILES: [Li][CH2:2][CH2:3][CH2:4][CH3:5].CCCCCC.C([O:14][CH:15](OCC)[C:16]1[CH:21]=[C:20](Br)[CH:19]=[CH:18][C:17]=1[O:23][CH3:24])C.COB(OC)OC>C1COCC1>[CH2:2]([C:20]1[CH:19]=[CH:18][C:17]([O:23][CH3:24])=[C:16]([CH:21]=1)[CH:15]=[O:14])[CH2:3][CH2:4][CH3:5]
Reactant: CCOC(OCC)c1cc(Br)ccc1OC
Reactant: [Li]CCCC
Agent: COB(OC)OC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCc1ccc(OC)c(C=O)c1
Temperature: 0 °C
Reaction time: 4 h
Yield: 43 %

Procedure:
n-BuLi in hexane (1.6M, 15.4 mL, 24.6 mmol) was added dropwise over 15 min to a -70° C. solution of 5-bromo-2-methoxybenzaldehyde diethylacetal in 50 mL of THF. Once the addition was complete, the mixture was stirred and allowed to warm up to 0° C. over 1.5 h. The mixture was then cooled to -70° C. and a solution of trimethylborate (5.4 mL, 48 mmol) in 25 mL of THF was added rapidly through a double-ended needle. The reaction was kept at -70° C. for 4 h and was then allowed to warm to 0° C. slowly before being quenched by the addition of 70 mL of 2.0N aqueous hydrochloric acid. After the mixture had been stirred for 1 h, the layers were separated and the aqueous layer was extracted with 3×100 mL of ethyl acetate. The combined organic layers were dried (sodium sulfate), decanted, and evaporated. The residue was then dissolved in ethyl acetate (100 mL) and extracted with 4×44 mL of 2.0N sodium hydroxide. The ethyl acetate layer was dried (sodium sulfate), decanted, and evaporated. The crude material was purified by flash column chromatography on silica gel, eluting with 10-20% dichloromethane in hexane to yield 5-butyl-2-methoxybenzaldehyde (1.87 g, 43% yield) as an amber liquid.