Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][OH:11])[CH:5]=[C:6]([Br:8])[CH:7]=1.I[CH3:13].[H-].[Na+]>>[Br:1][C:2]1[CH:3]=[C:4]([CH2:9][CH2:10][O:11][CH3:13])[CH:5]=[C:6]([Br:8])[CH:7]=1
Reactant: CI
Reactant: OCCc1cc(Br)cc(Br)c1
Agent: [H-]
Agent: [Na+]
Product: COCCc1cc(Br)cc(Br)c1
Yield: 86 %

Procedure:
In analogy to the procedure described for Building Block AW, the alkylation of 2-(3,5-dibromo-phenyl)-ethanol with iodomethane using sodium hydride as the base yielded the title compound 86% yield as a light yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[C:20]1([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C1CCN2C(=NCCC2)CC1>O1CCCC1>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:29]2[CH2:30][CH2:31][N:26]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:27][CH2:28]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Solvent: C1CCOC1
Solvent: C1CCC2=NCCCN2CC1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccccc2)CC1
Temperature: 70 °C
Reaction time: 7 h
Yield: 81.9 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate (30 mg, 0.11 mmol) and 1-phenylpiperazine (24 mg, 0.15 mmol) were dissolved in tetrahydrofuran (2 ml) at room temperature and thereto DBU (23 mg, 0.15 mmol) was added. The resulting mixture was stirred at 70° C. for 7 hours and concentrated under the reduced pressure to remove the solvent, and purified by SiO2 column chromatography. Extraction of the residue with a n-hexane:ethyl acetate (2:1) mixture and concentration gave 34 mg of the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.43 (s, 3H), 3.22-3.29 (m, 4H), 3.73-3.87 (m, 4H), 4.13 (s, 3H), 6.87-7.74 (m, 9H).
Reaction SMILES: Cl.[NH2:2][N:3]1[CH2:8][CH2:7][N:6]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:5][CH2:4]1.C([O:23][C@@H:24]1[C@H:28]([O:29]C(=O)C2C=CC=CC=2)[C@@H:27]([CH2:38][O:39]C(=O)C2C=CC=CC=2)[O:26][C@H:25]1[N:48]1[CH:56]=[N:55][C:54]2[C:49]1=[N:50][C:51]([Cl:58])=[N:52][C:53]=2Cl)(=O)C1C=CC=CC=1.N>>[Cl:58][C:51]1[N:52]=[C:53]([NH:2][N:3]2[CH2:4][CH2:5][N:6]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[CH2:7][CH2:8]2)[C:54]2[N:55]=[CH:56][N:48]([C:49]=2[N:50]=1)[C@@H:25]1[O:26][C@H:27]([CH2:38][OH:39])[C@@H:28]([OH:29])[C@H:24]1[OH:23]
Reactant: O=C(OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(=O)c2ccccc2)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reactant: NN1CCN(c2ccccc2)CC1
Agent: Cl
Agent: N
Product: OC[C@H]1O[C@@H](n2cnc3c(NN4CCN(c5ccccc5)CC4)nc(Cl)nc32)[C@H](O)[C@@H]1O
Yield: 60 %

Procedure:
The title compound was prepared according to method A as described in Example 6 by reacting 1-amino-4-phenylpiperazine hydrochloride (also prepared using the method described by Overberger, C. G. and Herin, L. P., Journal of Organic Chemistry, 1962, 27, 417) (0.77 g, 3.0 mmol) with 9-(2',3',5'-tri-O-benzoyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (1.90 g, 3.0 mmol), followed by debenzoylation of the purified product using methanolic ammonia. This provided the title 2-chloro-N-(4-phenyl-1-piperazinyl)adenosine (0.81 g, 60%) (after column chromatography) as a foam, 1H NMR (DMSO-d6) δ3.53-3.60 (1H, m, H-5'a), 3.63-3.70 (1H, m, H-5'b), 3.95 (1H, q, H-4'), 4.13 (1H, q, H-3'), 4.51 (1H, q, H-2'), 5.07 (1H, t, 5'-OH), 5.22, 5.50 (2H, 2d, 2'- and 3'-OH), 5.85 (1H, d, H-1'), 6.77-7.26 (5H, 3m, Ar-H), 8.44 (1H, s, H-8), 9.50 (1H, s, N-H).
Reaction SMILES: [H-].[Na+].Br[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([Br:10])[C:5]=1[S:11]([NH:14][C:15]([CH3:18])([CH3:17])[CH3:16])(=[O:13])=[O:12].[Li]CCCC.CN(C)[CH:26]=[O:27]>O1CCCC1>[Br:10][C:6]1[C:5]2[S:11](=[O:13])(=[O:12])[N:14]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:26]([OH:27])[C:4]=2[CH:9]=[CH:8][CH:7]=1
Reactant: CN(C)C=O
Reactant: CC(C)(C)NS(=O)(=O)c1c(Br)cccc1Br
Agent: [H-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)N1C(O)c2cccc(Br)c2S1(=O)=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 55 %

Procedure:
To sodium hydride (0.52 g, 12.9 mmol) in tetrahydrofuran (20 mL) at 0° C. was added 2,6-dibromo-N-(1,1-dimethylethyl) benzenesulfonamide (4.0 g, 10.8 mmol). The resulting mixture was stirred at ambient temperature for 2-3 h, cooled to −780° C. and treated with n-BuLi (1.6 M in hexanes, 7.4 mL, 11.9 mmol) over a period of 20 min. The reaction was continued to stir for 40 min and treated with N,N-dimethyl formamide (0.9 mL, 11.9 mL). The cooling bath was removed and the mixture continued to stir over a period of 20 min. The work-up consisted of slowly quenching the reaction with 1N NaCl, dilution with water and extraction with ethyl acetate. Drying over sodium sulfate and concentrating under reduced pressure provided the crude product that was purified by the flash chromatography (ethyl acetate/hexane, 1:4) to afford the 7-bromo-2-(1,1-dimethylethyl)-2,3-dihydro-1,2-benzisothiazol-3-ol 1,1-dioxide (2.1 g, 55 %). 1H NMR (CD3OD): δ1.61 (s, 9H), 6.02 (s, 1H), 7.61 (m, 2H), 7.77 (m, 1H).
Reaction SMILES: [Na].[OH:2][N:3]1[C:7](=[O:8])[C:6]2=[CH:9][CH:10]=[CH:11][CH:12]=[C:5]2[C:4]1=[O:13].[CH3:14][N:15]=[C:16](Cl)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.O>CN(C=O)C>[O:8]=[C:7]1[C:6]2[C:5](=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:13])[N:3]1[O:2][C:16](=[N:15][CH3:14])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C1c2ccccc2C(=O)N1O
Reactant: CN=C(Cl)c1ccccc1
Agent: [Na]
Solvent: O
Solvent: CN(C)C=O
Product: CN=C(ON1C(=O)c2ccccc2C1=O)c1ccccc1

Procedure:
N-hydroxy phthalimide sodium salt (46.25 g.; 0.25 mol), is dissolved in dry DMF (220 ml), to the resulting suspension 38.8 g (0.25 mol) of N-methyl benzimidoyl chloride (prepared according to J. C. S. Perkin II, 1324, (1980)) are slowly added at room temperature, on stirring. The reaction mixture is stirred at room temperature for 19 h and then poured into 1.5 l of water. The so formed precipitate is sucked off and dried in vacuo to obtain 66.06 g of a a crude product which is then taken up in 250 ml of acetonitrile. After filtration 58.7 g of N-methyl-benzimidic acid 1,3-dioxo-1,3-dihydro-isoindol-2-yl ester are obtained in form of colorless crystals, mp. 174-176° C.
Reaction SMILES: [CH3:1][NH:2][CH3:3].[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH:14]=[CH2:15])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]>CO.C1COCC1>[Cl:4][C:5]1[CH:10]=[C:9]([S:11]([CH2:14][CH2:15][N:2]([CH3:3])[CH3:1])(=[O:13])=[O:12])[CH:8]=[CH:7][C:6]=1[NH:16][C:17](=[O:25])[C@:18]([OH:24])([CH3:23])[C:19]([F:22])([F:21])[F:20]
Reactant: CNC
Reactant: C=CS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CCS(=O)(=O)c1ccc(NC(=O)[C@@](C)(O)C(F)(F)F)c(Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89 %

Procedure:
A 2M solution of dimethylamine (0.06 ml) in anhydrous methanol was added to a deoxygenated solution of (R)-N-[2-chloro-4-(ethenylsulphonyl)phenyl]-2-hydroxy-2-methyl-3,3,3-trifluoropropanamide (Example 283) (0.044 g) in anhydrous THF (1 ml). The mixture was allowed to stir at ambient temperature under argon for 2 hours then volatile material was removed by evaporation to give the title compound (in 89% yield) as a solid. NMR: 1.69 (s, 3H), 2.65 (s, 6H), 2.55 (t, 2H), 3.55 (t, 2H), 7.9 (d, 1H), 8.08 (s, 1H), 8.34 (d, 1H); MS (ESP−): 403.
Reaction SMILES: [O:1]1[CH2:31][CH:2]1[CH2:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][CH2:26][C:27]#[N:28])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1.[CH3:32][NH:33][CH3:34].O>CN(C=O)C>[CH3:32][N:33]([CH2:31][CH:2]([OH:1])[CH2:3][O:4][C:5]1[CH:30]=[CH:29][C:8]([NH:9][C:10]2[CH:15]=[C:14]([N:16]([CH2:25][CH2:26][C:27]#[N:28])[C:17]3[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:18]=3[Cl:24])[N:13]=[CH:12][N:11]=2)=[CH:7][CH:6]=1)[CH3:34]
Reactant: N#CCCN(c1cc(Nc2ccc(OCC3CO3)cc2)ncn1)c1cc(Cl)ccc1Cl
Reactant: CNC
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)CC(O)COc1ccc(Nc2cc(N(CCC#N)c3cc(Cl)ccc3Cl)ncn2)cc1
Reaction time: 6 h
Yield: 84 %

Procedure:
To a solution of 4-{4-[2,3-epoxypropoxy]anilino}-6-[N-(2-cyanoethyl)-2,5-dichloroanilino]pyrimidine (Reference Example 7, 396 mg) in DMF (2 ml) was added dimethylamine (2M in MeOH, 3.5 ml) and the reaction stirred for 6 hours. The mixture was poured into water and extracted with EtOAc. The organic extract was dried (MgSO4) and evaporated. The residue was purified by column chromatography eluting with DCM:MeOH:concentrated ammonia; 91:8:1 to give the product (366 mg, 84%) as a colourless oil. NMR: 2.15 (6H, s), 2.20-2.42 (2H, m), 2.84 (2H, m), 3.72-4.22 (5H, m), 4.77 (1H, d), 5.27 (1H, s), 6.81 (2H, d), 7.37 (2H, d), 7.56 (1H, dd), 7.76 (2H, m), 8.22 (1H, s), 8.88 (1H, s); m/z 501 (MH+).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]2[NH:8][N:9]=[C:10]([C:11]3[CH:16]=[CH:15][N:14]=[C:13]([S:17][CH3:18])[N:12]=3)[C:5]2=[CH:4][N:3]=1.[O:19]1[CH2:24][CH2:23][N:22]([CH2:25][CH2:26][NH2:27])[CH2:21][CH2:20]1.C(N(CC)CC)C>CC(O)C>[CH3:18][S:17][C:13]1[N:12]=[C:11]([C:10]2[C:5]3[C:6](=[N:7][C:2]([NH:27][CH2:26][CH2:25][N:22]4[CH2:23][CH2:24][O:19][CH2:20][CH2:21]4)=[N:3][CH:4]=3)[NH:8][N:9]=2)[CH:16]=[CH:15][N:14]=1
Reactant: NCCN1CCOCC1
Reactant: CSc1nccc(-c2n[nH]c3nc(Cl)ncc23)n1
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: CSc1nccc(-c2n[nH]c3nc(NCCN4CCOCC4)ncc23)n1

Procedure:
To a solution of 6-chloro-3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidine (from Example 7 supra) (2 g, 7.19 mmol) in 2-propanol (100 mL) was added 2-morpholinoethanamine (1.0 g, 7.9 mmol) followed by triethylamine (800 mg, 7.9 mmol). The reaction mixture was stirred with heating at reflux for 6 hours. The solvent was then removed under reduced pressure. The residue was washed with 2-propanol and water to afford [3-(2-methylsulfanyl-pyrimidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine. (Yield 2.1 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][NH2:9])[CH:5]=[CH:6][CH:7]=1.O[C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:13]=2[N:14]=[N:15][N:16]=1>>[F:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][CH:7]=1)[CH2:8][NH:9][C:11]1[C:12]2[CH:20]=[CH:19][CH:18]=[C:17]([C:21]([NH2:23])=[O:22])[C:13]=2[N:14]=[N:15][N:16]=1
Reactant: NCc1cccc(F)c1
Reactant: NC(=O)c1cccc2c(O)nnnc12
Product: NC(=O)c1cccc2c(NCc3cccc(F)c3)nnnc12

Procedure:
Compound 9 was prepared following general synthetic scheme 7 wherein (3-fluorophenyl)methanamine was reacted with 4-hydroxybenzo[d][1,2,3]-triazine-8-carboxamide to give the title compound. LC-MS [298 (M+1)], 1H NMR (400 MHz, DMSO-d6): 9.39 (s, 1H), 9.32 (s, 1H), 8.55-8.50 (m, 2H), 8.05 (s, 1H), 7.99 (t, 1H), 7.41-7.35 (m, 1H), 7.26-7.23 (m, 2H), 7.11-7.09 (m, 1H), 4.93 (d, 2H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=3)[CH2:9][CH2:8]2)[CH2:3][CH2:2]1.[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1>>[CH3:21][O:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28][N:1]2[CH2:2][CH2:3][CH:4]([N:7]3[C:15]4[C:10](=[CH:11][CH:12]=[C:13]([CH2:16][NH:17][C:18](=[O:20])[CH3:19])[CH:14]=4)[CH2:9][CH2:8]3)[CH2:5][CH2:6]2)=[CH:25][CH:24]=1
Reactant: CC(=O)NCc1ccc2c(c1)N(C1CCNCC1)CC2
Reactant: COc1ccc(CCBr)cc1
Product: COc1ccc(CCN2CCC(N3CCc4ccc(CNC(C)=O)cc43)CC2)cc1
Yield: 53.7 %

Procedure:
1-(Piperidin-4-yl)-6-acetamidomethylindoline (250 mg) and 4-methoxyphenethyl bromide (240 mg) were treated as in Example 2 to give the title compound (200 mg) as a white powder (yield: 53%).
Reaction SMILES: [Br:1][C:2]1[N:6]=[C:5]([C:7]([O:9]C)=O)[NH:4][N:3]=1.CO.[NH3:13]>>[Br:1][C:2]1[N:6]=[C:5]([C:7]([NH2:13])=[O:9])[NH:4][N:3]=1
Reactant: COC(=O)c1nc(Br)n[nH]1
Reactant: N
Solvent: CO
Product: NC(=O)c1nc(Br)n[nH]1

Procedure:
A solution of methyl 3-bromo-1H-1,2,4-triazole-5-carboxylate from Step 1 (250 mg, 1.21 mmol) in 7M ammonia in methanol (4 mL, 28 mmol) was heated at 125° C. under microwave conditions for 40 minutes. The reaction solution was concentrated under vacuum to give the title compound as a solid.
Reaction SMILES: BrC1C=C[C:5](NCC(OC)=O)=[N:6]C=1.[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH:25]=O.CN1C2C(=CC=CC=2)C(C)=C1C=O>>[Cl:14][C:15]1[CH:16]=[CH:17][CH:18]=[C:19]2[C:23]=1[N:22]([CH3:24])[CH:21]=[C:20]2[CH2:25][NH:6][CH3:5]
Reactant: COC(=O)CNc1ccc(Br)cn1
Reactant: Cn1cc(C=O)c2cccc(Cl)c21
Agent: Cc1c(C=O)n(C)c2ccccc12
Product: CNCc1cn(C)c2c(Cl)cccc12
Yield: 93 %

Procedure:
According to the procedure of Preparation 13 (c), except substituting 7-chloro-1-methyl-1H-indole-3-carboxaldehyde for the 1,3-dimethyl-1H-indole-2-carboxaldehyde, the title compound (2.0 g, 93%) was obtained as an amber oil: MS (ES) m/e 209.2 (M+H)+.
Reaction SMILES: [CH2:1]([C:8]1O[C:10]([O:20]CC)=[C:11]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[N:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O:23]1[CH2:27][CH:26]=[CH:25][CH2:24]1>>[CH2:1]([C:8]1[C:25]2[CH2:24][O:23][CH2:27][C:26]=2[C:10]([OH:20])=[C:11]([CH2:13][C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)[N:12]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1=CCOC1
Reactant: CCOc1oc(Cc2ccccc2)nc1Cc1ccccc1
Product: Oc1c(Cc2ccccc2)nc(Cc2ccccc2)c2c1COC2
Yield: 37 %

Procedure:
44 g (150 millimoles) of 2,4-dibenzyl-5-ethoxyoxazole and 210 g (3 moles) of 2,5-dihydrofuran are heated for 8 hours at 180° C. Excess 2,5-dihydrofuran is distilled off and the residue is digested in ether. The undissolved constituent is recrystallized from ethanol. 17.6 g of 4,6-dibenzyl-1,3-dihydro-furo[3,4-c]pyridin-7-ol are obtained; melting point 204°-205° C.
Reaction SMILES: [C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[C:8](N)=[C:7]([Cl:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].S(=O)(=O)(O)O.N([O-])=O.[Na+]>C(O)C>[C:1]([C:5]1[CH:11]=[C:10]([CH3:12])[CH:8]=[C:7]([Cl:13])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc(C(C)(C)C)cc(Cl)c1N
Agent: O=N[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(Cl)cc(C(C)(C)C)c1

Procedure:
4-t-Butyl-2-chloro-6-methylaniline (1.97 g) was dissolved in ethanol (50 ml), sulphuric acid (1.88 ml, conc.) was added dropwise and the resulting blue solution was heated at reflux. Sodium nitrite (1.72 g) was added portionwise over 30 min. The resulting mixture was heated at reflux for a further 30 rain, then cooled and was poured onto ice water and extracted with ether (2×50 ml). The ethereal extract was dried (MgSO4) and evaporated and the residue was purified on silica using hexane as eluent to afford 3-t-butyl-5-chlorotoluene as a colourless oil. 1H NMR (360 MHz, CDCl3) δ1.29 (9H, s, (CH3)3), 2.31 (3H, s, CH3), 6.98 (1H, brs, ArH), 7.05 (1H, brs, ArH), 7.15 (1H, brs, ARH). MS (CI-) m/z 181 (M+ -H, 100%).
Reaction SMILES: [C:1]([O:10]CC)(=[O:9])[CH2:2][CH2:3][C:4]([O:6]CC)=[O:5].[C:13]1([CH:23]=O)[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1.[H-].[Na+].[OH-].[Na+]>C(O)C>[C:13]1([CH:23]=[C:3]([CH2:2][C:1]([OH:10])=[O:9])[C:4]([OH:6])=[O:5])[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)CCC(=O)OCC
Reactant: O=Cc1cccc2ccccc12
Agent: [H-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: O=C(O)CC(=Cc1cccc2ccccc12)C(=O)O
Yield: 55.8 %

Procedure:
To a solution of 32.3 g of diethyl succinate and 29.0 g of 1-naphthaldehyde in 100 ml of absolute ethanol was added 10.7 g of sodium hydride (50% dispersion in mineral oil) under ice-cooling, and then the mixture was heated under reflux for 0.5 hours. To the reaction was added 230 ml of 1N-aqueous sodium hydroxide solution, and the mixture was heated under reflux for 1 hour. The reaction mixture was evaporated under reduced pressure, and water was added to the residue. The mixture was extracted with diethyl ether to remove neutral substances. The aqueous layer was acidified by adding concentrated hydrochloric acid, and extracted with diethyl ether. The ethereal layer was washed a saturated sodium chloride aqueous solution, dried over anhydrous magnesium sulfate, and evaporated under reduced pressure. Benzene was added to the residue, and the precipitated crystals were collected by flitration to obtain 26.5 g of 2-(1-naphthylmethylene)succinic acid as yellow crystals.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[OH:11].[F-].[K+].Br[CH:15]([F:21])[C:16](OCC)=[O:17]>CN(C)C=O.C(OCC)(=O)C>[F:21][CH:15]1[C:16](=[O:17])[NH:1][C:2]2[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=2[O:11]1
Reactant: CCOC(=O)C(F)Br
Reactant: Nc1ccc([N+](=O)[O-])cc1O
Agent: [F-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C1Nc2ccc([N+](=O)[O-])cc2OC1F
Temperature: 60 °C
Reaction time: 44 h
Yield: 41.8 %

Procedure:
To a suspension of 2-amino-5-nitrophenol (1.98 g) and potassium fluoride (2.24 g) in N,N-dimethylformamide (40 mL) was added ethyl bromofluoroacetate (2.85 g), and the mixture was stirred at 60° C. for 44 hours. After cooling, the reaction mixture was diluted with ethyl acetate, and the mixture was washed successively with water and brine. The organic layer was dried over magnesium sulfate and concentrated in vacuo. The resultant residue was purified by column chromatography on silica gel (solvent; n-hexane/ethyl acetate=19/1→1/1) and triturated with n-hexane/diisopropylether to give 2-fluoro-7-nitro-2H-1,4-benzoxazin-3(4H)-one (1.14 g) as a yellow powder.
Reaction SMILES: [Cl:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([S:13](Cl)(=O)=O)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.P(OC)(OC)O[CH3:21].CO.[OH-].[K+]>C1(C)C=CC=CC=1>[CH3:21][S:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([Cl:1])=[CH:3][CH:4]=2)=[CH:8][CH:9]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccc(Cl)cc2)cc1
Reactant: COP(OC)OC
Agent: [K+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CO
Product: CSc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 76.6 %

Procedure:
4-(4′-Chlorophenoxy)phenyl sulfonyl chloride (3.0 kg), 3, was dissolved in three liters of toluene and the solution was added dropwise, with stirring, to 3.6 kg of trimethyl phosphite which had been preheated to 60° C. The reaction was exothermic and the reaction was allowed to heat to 80°-90° C. during the addition. Thin layer chromatography indicated a mixture of the desired thioether and two baseline products. The mixture was refluxed until the pot temperature rose to ˜130° C. The mixture was cooled to ˜60° C. and 1 liter of methanol was added. Potassium hydroxide solution (4.5 kg of 45% aqueous solution) was added dropwise, slowly, with rapid stirring to the reaction mixture. The addition was very exothermic and the pot temperature was controlled to 65°-80° C. The mixture was then refluxed for 2 hrs. More toluene (6 liters) was added and the mixture cooled to 60° C. The lower aqueous layer was separated and the organic layer washed with 3 liters of water. The organic layer was stripped to a low volume and 9 liters of isopropanol charged to the hot mixture. The solution as distilled until ˜3.5 liters of distillate had been collected. The mixture was held at 45° C. for several hours and was then cooled to ˜−10° C. and stirred several hours. The white, crystalline product was collected, washed with cold isopropanol and dried to yield 1.9 kg of 4-(4′-chlorophenoxy)phenyl methyl sulfide, 4.
Reaction SMILES: [O-]CC.[Na+].[Na].[C:6]([C:14]1[CH:15]=[C:16]([CH2:20][C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[N:23](OCCC(C)C)=[O:24]>C(O)C.C(OCC)(=O)C>[C:6]([C:14]1[CH:15]=[C:16]([C:20](=[N:23][OH:24])[C:21]#[N:22])[CH:17]=[CH:18][CH:19]=1)(=[O:13])[C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1
Reactant: N#CCc1cccc(C(=O)c2ccccc2)c1
Reactant: CC(C)CCON=O
Agent: CC[O-]
Agent: [Na+]
Agent: [Na]
Solvent: CCO
Solvent: CCOC(C)=O
Product: N#CC(=NO)c1cccc(C(=O)c2ccccc2)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99 %

Procedure:
To a solution of sodium ethoxide prepared from sodium (1.70 g) and ethanol (40 ml) was added dropwise a solution of 2-(3-benzoylphenyl)acetonitrile (13.6 g) in ethanol (30 ml) at 0° C., and then isoamyl nitrite (12.4 ml) was added dropwise. After stirring at room temperature for 15 hours, the reaction mixture was diluted with ethyl acetate and washed successively with 1N hydrochloric acid and an aqueous saturated solution of sodium chloride. The ethyl acetate layer was dried (MgSO4) and concentrated to obtain 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile (15.2 g, yield 99%) as crystals. Recrystallization from ethyl acetate-hexane gave an isomer of 2-(3-benzoylphenyl)-2-(hydroxyimino)acetonitrile as colorless crystals. m.p. 175-176° C.
Reaction SMILES: O1CCCCC1[O:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18]Br.O1CCCCC1[O:26][C:27]1[CH:32]=[CH:31][C:30]([Mg]Br)=[CH:29][CH:28]=1.O1CCCCC1OC1C=CC(Br)=CC=1.[Mg]>O1CCCC1.Cl[Cu].C(OCC)C>[OH:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][C:30]1[CH:29]=[CH:28][C:27]([OH:26])=[CH:32][CH:31]=1
Reactant: Br[Mg]c1ccc(OC2CCCCO2)cc1
Reactant: BrCCCCCCCCCCCOC1CCCCO1
Agent: Cl[Cu]
Agent: Brc1ccc(OC2CCCCO2)cc1
Agent: [Mg]
Solvent: CCOCC
Solvent: C1CCOC1
Product: OCCCCCCCCCCCc1ccc(O)cc1
Yield: 36 %

Procedure:
0.4 g of CuCl and 29 g of 11-(tetrahydropyran-2-yloxy)-1-bromoundecane (B) were added to a filtered solution of 4-(tetrahydropyran-2-yloxy)phenyl magnesium bromide (A), prepared from 20.0 g of 4-(tetrahydropyran-2-yloxy)-1-bromobenzene and 3.16 g of magnesium, in 100 ml of tetrahydrofuran. After refluxing for 2 days, the reaction mixture was mixed with 100 ml of diethyl ether, followed by extraction with 100 ml of a saturated NH4Cl solution. After evaporation, the intermediate product C was refluxed for one hour with 40 ml of methanol and 1 ml of saturated hydrochloric acid. 15 ml of a saturated solution of NaHCO3 was added and the methanol was evaporated. 100 ml of diethyl ether was added. 7.4 g of 4-(11-hydroxyundecyl)phenol (D, 36%) was obtained after extraction with 50 ml of saturated sodium chloride, drying over magnesium sulphate, evaporation and recrystallisation from toluene.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:18])=[C:4]2[C:8](=[C:9]([CH3:15])[C:10]=1[CH2:11][C:12]([CH3:14])=[CH2:13])[N:7]([CH:16]=[O:17])[CH2:6][CH2:5]2.C(=O)([O-])[O-].[Ca+2].[I:24](Cl)(=O)=O.I(Cl)(=O)=O.C[NH+](C)C>CO.C1COCC1>[I:24][CH2:13][C:12]1([CH3:14])[O:1][C:2]2=[C:3]([CH3:18])[C:4]3[CH2:5][CH2:6][N:7]([CH:16]=[O:17])[C:8]=3[C:9]([CH3:15])=[C:10]2[CH2:11]1
Reactant: C=C(C)Cc1c(C)c2c(c(C)c1O)CCN2C=O
Reactant: O=I(=O)Cl
Agent: C[NH+](C)C
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c2c(c(C)c3c1OC(C)(CI)C3)N(C=O)CC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
2,3-Dihydro-5-hydroxy-4,7-dimethyl-6-(2-methyl-2-propenyl)-1H-indole-1-carbaldehyde (4.17 g, 17.0 mmol) was dissolved in methanol-THF solution (34 ml, 1:1). To the mixture was added calcium carbonate (2.21 g, 22.1 mmol) and then trimethylammonium dichloroiodate (6.51 g, 18.7 mmol) was added. After stirring for 1 hour at room temperature, the reaction mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was combined a 10% aqueous solution of sodium thiosulfate, and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain 5.52 g of the title compound.