Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:25]=[C:24](Br)[CH:23]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:2].[S:44]1[CH:48]=[CH:47][C:46](B(O)O)=[CH:45]1.C(=O)([O-])[O-].[Cs+].[Cs+]>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]>[CH2:1]([O:3][C:4](=[O:43])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:23]=[C:24]([C:46]3[CH:47]=[CH:48][S:44][CH:45]=3)[CH:25]=[C:26]([O:28][CH2:29][CH:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)[CH:27]=2)[C:10]=1[CH2:36][CH2:37][C:38]([O:40][CH2:41][CH3:42])=[O:39])[CH3:2]
Reactant: OB(O)c1ccsc1
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(Br)cc(OCC3CCCC3)c2)c1CCC(=O)OCC
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Product: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC3CCCC3)cc(-c3ccsc3)c2)c1CCC(=O)OCC
Yield: 97 %

Procedure:
A similar procedure as described in Example 43, step 4 was used, starting from 4-[3-[6-(3-bromo-5-cyclopentylmethoxy-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (136 mg, 0.2 mmol), 3-thiophenylboronic acid (53 mg, 0.41 mmol), [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) (73 mg, 0.1 mmol), and cesium carbonate (134 mg, 0.41 mmol) to obtain 4-[3-[6-(3-cyclopentylmethoxy-5-thiophen-3-yl-phenoxy)-hexyl]-2-(2-ethoxycarbonyl-ethyl)-phenoxy]-butyric acid ethyl ester (129 mg, 95%) as a colorless viscous oil: ES(+)-HRMS m/e calcd for C39H52O7S (M+Na)+ 687.3326. found 687.3328.
Reaction SMILES: [C:1]([Si:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[C:11]([CH3:16])[CH:10]=1)([CH3:7])[CH3:6])([CH3:4])([CH3:3])[CH3:2].[Br:17]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>[Br:17][CH2:16][C:11]1[CH:10]=[C:9]([CH:14]=[CH:13][C:12]=1[F:15])[O:8][Si:5]([C:1]([CH3:4])([CH3:3])[CH3:2])([CH3:7])[CH3:6]
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1cc(O[Si](C)(C)C(C)(C)C)ccc1F
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(F)c(CBr)c1
Temperature: 0 °C
Yield: 65.2 %

Procedure:
A mixture of tert-butyl(4-fluoro-3-methylphenoxy)dimethylsilane (step 1, 30 g, 0.12 mol), N-bromosuccinimide (24 g, 0.13 mol) and benzoylperoxide (1.5 g, 6.2 mmol) in carbon tetrachloride (75 mL) was reflux under nitrogen atmosphere for 4 h. The reaction mixture was cooled at 0° C., and the white precipitate was filtered. The filtrate washed with sodium bicarbonate aqueous solution, dried over magnesium sulfate, and evaporated. The residue was purified by column chromatography on silica gel eluting with hexane to afford 25 g (65%) of the title compound as a colorless oil:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[NH2:28][C:29]1[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:28][C:29]2[CH:34]=[CH:33][N:32]=[C:31]([CH3:35])[N:30]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1Cl
Reactant: Cc1nccc(N)n1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: ClCCl
Product: Cc1nccc(NC(=O)C(CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)n1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 24.9 %

Procedure:
A solution of 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (200 mg, 0.61 mmol) in methylene chloride (2 mL) was treated with N,N-dimethylformamide (I drop) and then cooled to 0° C. The reaction mixture was then treated dropwise with a 2M solution of oxalyl chloride in methylene chloride (0.45 mL, 0.91 mmol) and stirred at 0° C. for 30 min. The resulting reaction mixture was then treated with a solution of 4-amino-2-methylpyrimidine (98.9 mg, 0.91 mmol) and pyridine (0.25 mL, 3.03 mmol) in N,N-dimethylformamide (5 mL). The resulting reaction mixture was allowed to warm to 25° C. where it was stirred for 16 h. The reaction mixture was then diluted with water (10 mL) and extracted with ethyl acetate (3×15 mL). The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo. Biotage chromatography (FLASH 40S, Silica, 55/45 hexanes/ethyl acetate) afforded 2-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(2-methyl-pyrimidin-4-yl)-propionamide (64 mg, 25%) as a colorless oil: EI-HRMS m/e calcd for C20H24ClN3O3S (M+) 421.1227, found 421.1230.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[OH:20].O.[OH-].[Li+].S(=O)(=O)(O)O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.O.C1(C)C=CC=CC=1>[Cl:6][C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH:15]=[C:16]([Cl:18])[Cl:17])[CH:10]=[C:9]([Cl:19])[C:8]=1[O:20][CH2:2][CH2:3][CH2:4][OH:5]
Reactant: OCCCBr
Reactant: Oc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)(O)O
Agent: [Br-]
Solvent: O
Solvent: Cc1ccccc1
Product: OCCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 60 °C
Reaction time: 6 h
Yield: 84 %

Procedure:
A mixture of 0.53 g of 3-bromopropanol, 5.0 g of toluene and 0.06 q of tetra-n-butylammonium bromide was heated to 60° C. Thereto was added dropwise a mixed solution of 1.0 q of 2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenol, 5.0 g of water and 0.16 g of lithium hydroxide monohydrate with stirring over 6 hours. After completion of the addition, the mixture was further stirred at 60° C. for 10 hours. The reaction mixture was then cooled to 20° C. After 2.0 g of a 20% aqueous sulfuric acid solution was added thereto, the mixture was stirred and then separated. The obtained organic layer was washed with 5.0 g of water and concentrated under reduced pressure to give 1.1 g of 3-(2,6-dichloro-4-(3,3-dichloro-2-propenyloxy)phenoxy)-1-propyl alcohol (purity: 93%, yield: 84%).
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][CH2:12][CH2:13][O:14][CH3:15])=[CH:4][CH:3]=1.[Br:16]N1C(=O)CCC1=O>O1CCCC1>[Br:16][C:6]1[C:5]2[C:9](=[CH:10][C:2]([Br:1])=[CH:3][CH:4]=2)[N:8]([CH2:11][CH2:12][CH2:13][O:14][CH3:15])[CH:7]=1
Reactant: COCCCn1ccc2ccc(Br)cc21
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Product: COCCCn1cc(Br)c2ccc(Br)cc21
Temperature: -78 °C
Reaction time: 1.7 h

Procedure:
A solution of 10.39 g of 6-bromo-1-(3-methoxypropyl)-1H-indole (building block 5) in 1.5 l of tetrahydrofuran is cooled to −78° C., and 7.05 g of N-bromosuccinimide are added. The mixture is stirred at −78° C. for 1.7 hours and then warmed to room temperature. The reaction mixture is evaporated. The title compound is obtained as an orange oil from the residue by flash chromatography (SiO2 60 F). Rf=0.31 (EtOAc-heptane 1:4); Rt=5.65 (Gradient I).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]4[O:28][C:27]([CH3:30])([CH3:29])[CH:26](O)[C:25]=4[C:32]=3[CH3:33])[CH2:17][CH2:16]2)=[CH:11][CH:10]=1>>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([N:15]2[CH2:20][CH2:19][N:18]([C:21]3[C:22]([CH3:35])=[C:23]([CH3:34])[C:24]4[O:28][C:27]([CH3:29])([CH3:30])[CH:26]([N:1]5[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]5)[C:25]=4[C:32]=3[CH3:33])[CH2:17][CH2:16]2)=[CH:13][CH:14]=1
Reactant: C1CCNCC1
Reactant: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(O)C(C)(C)O4)CC2)cc1
Product: COc1ccc(N2CCN(c3c(C)c(C)c4c(c3C)C(N3CCCCC3)C(C)(C)O4)CC2)cc1
Yield: 80 %

Procedure:
Using piperidine and 5-(4-(4-methoxyphenyl)piperazin-1-yl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-3-ol obtained in Reference Example 18, the title compound was synthesized in the same manner as in Example 57. Yield 80%.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[C:5]2[CH2:6][N:7]([CH2:10][CH2:11][C:12]#[N:13])[CH2:8][CH2:9][N:4]2[N:3]=1.Br[C:16]1[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=[C:20]([Br:22])[CH:21]=1>>[Br:22][C:20]1[CH:21]=[C:16]([NH:1][C:2]2[CH:14]=[C:5]3[CH2:6][N:7]([CH2:10][CH2:11][C:12]#[N:13])[CH2:8][CH2:9][N:4]3[N:3]=2)[C:17](=[O:24])[N:18]([CH3:23])[CH:19]=1
Reactant: N#CCCN1CCn2nc(N)cc2C1
Reactant: Cn1cc(Br)cc(Br)c1=O
Product: Cn1cc(Br)cc(Nc2cc3n(n2)CCN(CCC#N)C3)c1=O
Yield: 63.1 %

Procedure:
Following the procedure of Example 309c, and starting with 338b (120 mg, 0.63 mmol) and 3,5-dibromo-1-methylpyridin-2(1H)-one (169 mg, 0.63 mmol) afforded 338c as a yellow solid (150 mg, 63%). MS-ESI: [M+H]+ 377.2
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1.[CH3:12]OS(OC)(=O)=O.C([O-])([O-])=O.[K+].[K+]>CC(C)=O>[Cl:1][C:2]1[CH:10]=[C:6]([C:7]([O:9][CH3:12])=[O:8])[C:5]([NH2:11])=[CH:4][CH:3]=1
Reactant: Nc1ccc(Cl)cc1C(=O)O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)c1cc(Cl)ccc1N
Yield: 96.1 %

Procedure:
5-Chloroanthranilic acid (15.0 g), (CH3)2SO4 (11.6 g) and K2CO3 (12.7 g) were refluxed in acetone (150 g) for 30 minutes. The mixture was concentrated to about 90 g, and thereto was added water (90 g). The mixture was extracted with toluene (75 g), and the organic layer was concentrated to give methyl 5-chloroanthranilate (15.6 g, 96%).
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].[C:7]([O:11][C:12]([NH:14][C:15]1[C:23]([F:24])=[CH:22][CH:21]=[CH:20][C:16]=1[C:17]([OH:19])=[O:18])=[O:13])([CH3:10])([CH3:9])[CH3:8].Br[CH2:26][CH2:27][O:28][Si:29]([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30].[I-].[Na+]>CN(C=O)C>[Si:29]([O:28][CH2:27][CH2:26][O:18][C:17](=[O:19])[C:16]1[CH:20]=[CH:21][CH:22]=[C:23]([F:24])[C:15]=1[NH:14][C:12]([O:11][C:7]([CH3:10])([CH3:8])[CH3:9])=[O:13])([C:32]([CH3:35])([CH3:34])[CH3:33])([CH3:31])[CH3:30]
Reactant: CC(C)(C)[Si](C)(C)OCCBr
Reactant: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)Nc1c(F)cccc1C(=O)OCCO[Si](C)(C)C(C)(C)C
Temperature: 65 °C

Procedure:
To a solution of caesium carbonate (1.63 g, 5.0 mmol) in DMF (10 ml) was added 2-tert-butoxycarbonylamino-3-fluoro-benzoic acid from Example 19A (1.15 g, 4.5 mmol), (2-bromoethoxy)-tert-butyldimethylsilane (1.08 g, 4.5 ml) and sodium iodide (680 mg, 4.5 ml). The mixture was heated at 65° C. for 3 h and evaporated in vacuo. The residue was partitioned between chloroform and brine and the organic phase was dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc: pet. ether 15:85) to give a colourless gum; yield 1.1 g, 59%.
Reaction SMILES: [NH2:1][C:2]1[C:3]2[N:4]([C:8]([C@@H:26]3[CH2:30][CH2:29][CH2:28][NH:27]3)=[N:9][C:10]=2[C:11]2[CH:25]=[CH:24][C:14]([C:15]([NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[O:16])=[CH:13][CH:12]=2)[CH:5]=[CH:6][N:7]=1.[C:31]([S:34][CH2:35][C:36](ON1C(=O)CCC1=O)=[O:37])(=[O:33])[CH3:32]>>[C:31](=[O:33])([S:34][CH2:35][C:36]([N:27]1[CH2:28][CH2:29][CH2:30][C@H:26]1[C:8]1[N:4]2[CH:5]=[CH:6][N:7]=[C:2]([NH2:1])[C:3]2=[C:10]([C:11]2[CH:25]=[CH:24][C:14]([C:15](=[O:16])[NH:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[CH:13][CH:12]=2)[N:9]=1)=[O:37])[CH3:32]
Reactant: Nc1nccn2c([C@@H]3CCCN3)nc(-c3ccc(C(=O)Nc4ccccn4)cc3)c12
Reactant: CC(=O)SCC(=O)ON1C(=O)CCC1=O
Product: CC(=O)SCC(=O)N1CCC[C@H]1c1nc(-c2ccc(C(=O)Nc3ccccn3)cc2)c2c(N)nccn12
Yield: 31.8 %

Procedure:
This compound was prepared, in an analogous manner as described in Example 1, from the compound described in intermediate 2b and 2,5-dioxopyrrolidin-1-yl 2-(acetylthio)acetate, to afford the title compound (12.3 mg, 31.8%). Data: UPLC (C) R: 1.51 min; m/z 516.3 (M+H)+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([CH:27]=[C:28]([C:30]([CH3:33])([CH3:32])[CH3:31])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15](=[O:22])[CH2:16][C:17]([O:19]CC)=O)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].[NH2:36]O.Cl>CO.O.C(Cl)Cl>[C:30]([C:28]1[CH:27]=[C:7]([CH:6]=[C:5]([C:1]([CH3:3])([CH3:4])[CH3:2])[CH:29]=1)[CH2:8][C@H:9]1[CH2:14][C@@H:13]([C:15]2[O:22][NH:36][C:17](=[O:19])[CH:16]=2)[CH2:12][CH2:11][N:10]1[C:23]([O:25][CH3:26])=[O:24])([CH3:33])([CH3:32])[CH3:31]
Reactant: NO
Reactant: CCOC(=O)CC(=O)[C@H]1CCN(C(=O)OC)[C@@H](Cc2cc(C(C)(C)C)cc(C(C)(C)C)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: COC(=O)N1CC[C@H](c2cc(=O)[nH]o2)C[C@@H]1Cc1cc(C(C)(C)C)cc(C(C)(C)C)c1
Temperature: -40 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-ethoxy-3-oxopropanoyl)piperidine-1-carboxylate (2.03 g, 4.42 mmol) was dissolved in MeOH (16 mL) and cooled to −40° C. under nitrogen. Sodium hydroxide (0.177 g, 4.42 mmol) dissolved in water (1.600 mL) was added during 10 min and the colourless solution continued to stir at −40° C. for 20 min. Hydroxylamine (50% by weight in water, 0.271 mL, 4.42 mmol) was added during 8 min. The resulting solution was stirred at −40° C. for 3.5 h. The mixture was then transferred into a prewarmed (80° C.) solution of 6 M hydrogen chloride (20 mL, 120.00 mmol) and the mixture continued to stir at 80° C. for 20 min. DCM and water were added. The phases were separated and the organic phase passed through a phase separator and evaporated to yield a yellow semi-solid. The compound was purified by preparative HPLC in 3 injections on a XBridge C18 column (10 μm 250×50 ID mm) using a gradient of 10-50% Acetonitrile in H2O/MeCN/NH3 95/5/0.2 buffer over 20 minutes with a flow of 100 mL/min. Cis-methyl 2-(3,5-di-tert-butylbenzyl)-4-(3-oxo-2,3-dihydroisoxazol-5-yl)piperidine-1-carboxylate (1.358 g, 72%) was isolated as a white solid. 1H NMR (600 MHz, cdcl3) δ 1.22-1.33 (m, 18H), 1.80-2.10 (m, 4H), 2.59-2.67 (m, 1H), 2.71-2.78 (m, 1H), 2.92-2.98 (m, 1H), 3.07-3.15 (m, 1H), 3.55 (s, 3H), 3.97 (dd, 1H), 4.18-4.27 (m, 1H), 5.68 (s, 1H), 6.92 (d, 2H), 7.22 (s, 1H). MS m/z 429 (M+H)+
Reaction SMILES: CO[C:3](=[O:5])[O-:4].[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.C1(=O)[O:19][C:17](=[O:18])[CH:16]=[CH:15]1>O>[C:3]([O-:4])(=[O:5])/[CH:15]=[CH:16]\[C:17]([O-:19])=[O:18].[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1.[CH3:6][N+:7]1([CH3:13])[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: O=C1C=CC(=O)O1
Reactant: COC(=O)[O-]
Agent: C[N+]1(C)CCCCC1
Solvent: O
Product: O=C([O-])/C=C\C(=O)[O-]
Yield: 133.9 %

Procedure:
By following the same procedure as Example 20 (2nd step) except that 18.9 g of N,N-dimethylpiperidinium methyl carbonate, 18.9 g of water, and 9.8 g of maleic anhydride were used, 22.9 g (yield of 100%) of N,N-dimethylpiperidinium maleate was obtained. The content of monomethyl maleate was less than 0.1% and the content of impurity ions were all less than 1 ppm.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[O:10][C:9]([CH:11](O)[CH2:12][CH:13]([CH3:15])[CH3:14])=[C:8]([CH3:17])[C:7]=2[CH:18]=1.N1C=CC=CC=1.S(Cl)([Cl:27])=O.C(=O)([O-])O.[Na+]>C1(C)C=CC=CC=1>[Cl:27][CH:11]([C:9]1[O:10][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:18][C:7]=2[C:8]=1[CH3:17])[CH2:12][CH:13]([CH3:15])[CH3:14]
Reactant: COc1ccc2oc(C(O)CC(C)C)c(C)c2c1
Reactant: O=S(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: COc1ccc2oc(C(Cl)CC(C)C)c(C)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94 %

Procedure:
To a solution (10 mL) of 1-(5-methoxy-3-methyl-1-benzofuran-2-yl)-3-methylbutan-1-ol (761 mg) synthesized above in toluene were added pyridine (297 μL) and thionyl chloride (268 μL), and the mixture was stirred at room temperature for 3 hr. Saturated aqueous sodium hydrogen carbonate solution was added to quench the reaction, and the reaction mixture was extracted with ethyl acetate. The extract was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure to give the title object compound (769 mg, 94%) as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([NH:8][CH2:9][CH2:10][NH2:11])=[CH:4][CH:3]=1.CS[C:14](SC)=[CH:15][N+:16]([O-:18])=[O:17].C(O)C>CO.ClCCl>[N+:16]([CH:15]=[C:14]1[NH:11][CH2:10][CH2:9][N:8]1[C:5]1[CH:6]=[N:7][C:2]([Cl:1])=[CH:3][CH:4]=1)([O-:18])=[O:17]
Reactant: CSC(=C[N+](=O)[O-])SC
Reactant: NCCNc1ccc(Cl)nc1
Solvent: CCO
Solvent: CO
Solvent: ClCCl
Product: O=[N+]([O-])C=C1NCCN1c1ccc(Cl)nc1
Yield: 22.8 %

Procedure:
A mixture of N-(6-chloro-3-pyridyl)-1,2-diaminoethane (0.7 g, 0.0041 mol)(ex Example 4), 1,1-bis(methylthio)-2-nitroethene (0.7 g, 0.0042 mol) and ethanol (25 ml) was heated under reflux for 24 hours. The resulting mixture was evaporated to leave a dark brown oil which was subjected to flash chromatography on a silica column using silica gel, 230 to 400 US mesh (0.062 mm to 0.037 mm), and with 2% w methanol in dichloromethane as eluent. The resulting product was recrystallized from ethanol to give 2-nitromethylene-1-(6-chloro-3-pyridyl)imidazolidine as a pale yellow solid (0.225 g, 25%), m.p. 201° C.
Reaction SMILES: [CH2:1]([O:5][C:6]1[C:11]2[O:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1)[C@H:2]1[O:4][CH2:3]1.[CH:20]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[CH:22][C:21]=1[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[OH:4][C@@H:2]([CH2:3][N:33]1[CH2:34][CH2:35][CH:30]([C:21]2[CH:22]=[CH:23][C:24]3[C:29](=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:20]=2)[CH2:31][CH2:32]1)[CH2:1][O:5][C:6]1[C:11]2[O:12][C:13]([C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:14][C:10]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CCOC(=O)c1cc2cccc(OC[C@@H]3CO3)c2o1
Reactant: c1ccc2cc(C3CCNCC3)ccc2c1
Product: CCOC(=O)c1cc2cccc(OC[C@@H](O)CN3CCC(c4ccc5ccccc5c4)CC3)c2o1
Yield: 77.3 %

Procedure:
By the reactions in the same manner as in Starting Material Synthesis Example 11 using ethyl (S)-7-(glycidyloxy)benzo(b)furan-2-carboxylate (5.3 g) and 4-(naphthalen-2-yl)piperidine (3.0 g), the title compound (5.2 g) was obtained as a brown oil.
Reaction SMILES: [OH:1][C@H:2]([CH2:7][OH:8])[CH2:3][C:4]([NH2:6])=[O:5].CN(C)C=O.[C:14](Cl)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[Cl-].[Ca+2].[Cl-]>O1CCCC1.N1C=CC=CC=1>[OH:1][CH:2]([CH2:7][O:8][C:14]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=1)[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)[CH2:3][C:4]([NH2:6])=[O:5]
Reactant: ClC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: NC(=O)C[C@H](O)CO
Agent: [Ca+2]
Agent: [Cl-]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: NC(=O)CC(O)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 36 h

Procedure:
11.9 g (0.10 mol) (S)-3,4-dihydroxy-butyramide was dissolved in 50 ml of tetrahydrofuran and 50 ml of dimethylformamide and 10 ml of pyridine followed by 30.6 g (0.11 mol) of trityl chloride was added to the flask. A drying tube filled with calcium chloride was used to exclude moisture. The reaction mixture was stirred at room temperature for 36 hours. After this period of time, it was filtered to remove the solid. The liquid was concentrated under reduced pressure to remove most of the solvent. The solution was poured into ice water, stirred for half an hour and the water layer was removed from the trityl protected amide. The product which was obtained as a semicrystalline liquid was dried under vacuum. The excess trityl chloride was washed away by trituration with hexane. The yield was 33.0 g (91%). Physical data: m.p. 59.0-60.0° C. (from solvent dichloromethane:hexane:acetone=6:3:0.5) [α]25D=−53.5° (c=0.5,, methanol). 1H NMR (300 MHz, CDCl3) δppm, 7.50-7.20 (m, 15 H), 6.17 (s, 1H), 5.62 (s, 1H), 4.19 (m, 1H), 3.17 (d, 2H, J=5.7 Hz), 2.41 (m, 2H). 13C NMR (75 MHz, CDCl3) δppm, 174.8, 143.5, 128.3, 127.5, 126.7, 86.3, 67.4, 39.2. FTIR cm−1 3345, 1667, 1600, 1490, 1448, 1218, 1074, 763, 703.
Reaction SMILES: [CH3:1][CH:2]([CH3:9])[C:3](=C=O)[CH2:4][C:5]#[N:6].[CH3:10][NH:11][NH2:12]>>[CH3:10][N:11]1[C:5]([NH2:6])=[CH:4][C:3]([CH:2]([CH3:1])[CH3:9])=[N:12]1
Reactant: CNN
Reactant: CC(C)C(=C=O)CC#N
Product: CC(C)c1cc(N)n(C)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 51.9 %

Procedure:
Under nitrogen atmosphere, the compound of Example 2A (8.03 g, 72 mmol) was dissolved in alcohol (50 mL). Methylhydrazine (3.32 g, 72 mmol) was added. The resultant mixture was slowly warmed and refluxed with stirring. The reaction was kept for 3 hr. The reaction was stopped and cooled to room temperature. Alcohol was rotary-evaporated to obtain a crude product as oil. The crude product was purified with column chromatography (eluant: petroleum ether/ethyl acetate=1:1) to give 5.2 g of the title compound. MS (ESI): m/z 140 (M+H)+
Reaction SMILES: [BH4-].[Na+].[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[C:6](=O)[CH2:5]1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:3][C:4]1([CH3:14])[O:9][C:8]2[CH:10]=[CH:11][S:12][C:7]=2[CH:6]=[CH:5]1
Reactant: CC1(C)CC(=O)c2sccc2O1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CC1(C)C=Cc2sccc2O1
Temperature: 0 °C
Reaction time: 1.5 h

Procedure:
Sodium borohydride (3.27 g, 86.3 mmol) was added to a solution of 5,6-dihydro-5,5-dimethyl-7H-thieno[3,2-b]-pyran-7-one (12.1 g, 66.4 mmol) in ethanol (100 mL) and the resultant mixture was stirred at rt for 17 h. The mixture was poured into water (400 mL) and extracted with dichloromethane (2×100 mL). The dichloromethane solution was washed with water (5×), dried over sodium sulfate, and filtered. Molecular sieves (12 g) and p-toluenesulfonic acid (1.2 g, 6.3 mmol) was added to the resultant solution and stirred at 0° C. for 1.5 h. The reaction mixture was filtered, washed with saturated aqueous sodium bicarbonate and dried over sodium sulfate. The solvent was evaporated in vacuo to give the product, 11.0 g (99%), as a red oil which was identical in all respects to the product described in Method A.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[F:9][C:10]1[CH:15]=[CH:14][C:13](B(O)O)=[CH:12][C:11]=1[CH:19]=[O:20]>>[Cl:1][C:2]1[N:7]=[C:6]([C:13]2[CH:14]=[CH:15][C:10]([F:9])=[C:11]([CH:12]=2)[CH:19]=[O:20])[CH:5]=[CH:4][N:3]=1
Reactant: Clc1ccnc(Cl)n1
Reactant: O=Cc1cc(B(O)O)ccc1F
Product: O=Cc1cc(-c2ccnc(Cl)n2)ccc1F
Yield: 40 %

Procedure:
2,4 dichloropyrimidine and 4-fluoro-3-formylphenylboronic acid was coupled following procedure A. The yield was 40%. LC-MS showed the product was >95% pure and had the expected M+H+ of 237.