Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:10]([Cl:11])=[C:9]2[C:5]([CH2:6][C:7]([CH:14]3[CH2:18][CH2:17][CH2:16][CH2:15]3)([CH3:13])[C:8]2=[O:12])=[CH:4][C:3]=1[OH:19].C(=O)([O-])[O-].[K+].[K+].[F:26][C:27]([F:33])([F:32])[S:28](Cl)(=[O:30])=[O:29]>CC(C)=O>[CH:14]1([C:7]2([CH3:13])[CH2:6][C:5]3[C:9](=[C:10]([Cl:11])[C:2]([Cl:1])=[C:3]([O:19][S:28]([C:27]([F:33])([F:32])[F:26])(=[O:30])=[O:29])[CH:4]=3)[C:8]2=[O:12])[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: CC1(C2CCCC2)Cc2cc(O)c(Cl)c(Cl)c2C1=O
Reactant: O=S(=O)(Cl)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CC1(C2CCCC2)Cc2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c(Cl)c2C1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of 6,7-dichloro-2-cyclopentyl-5-hydroxy-2-methyl-1-indanone (20.93 g., 0.07 mole), anhydrous potassium carbonate (25.99 g., 0.188 mole) and dry acetone (350 ml) are stirred at room temperature and treated with trifluoromethane sulfonyl chloride (12.70 g., 0.0754 mmole) in portions. Reaction is complete in about 15 minutes after the completion of the addition. The mixture is filtered and evaporated to dryness. The residue is dissolved in methylene chloride, the solution dried (MgSO4) and evaporated under vacuum to an oil giving 28.45 g. (94%),
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][OH:15])[N:11]=[C:4]2[N:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[C:36]1[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O.O1CCCC1>[CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[N:5]2[N:9]=[C:10]([S:12][CH2:13][CH2:14][O:15][C:36]3[CH:41]=[CH:40][N:39]=[CH:38][CH:37]=3)[N:11]=[C:4]2[N:3]=1
Reactant: Oc1ccncc1
Reactant: Cc1cc(C)n2nc(SCCO)nc2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C)n2nc(SCCOc3ccncc3)nc2n1
Reaction time: 0.25 h

Procedure:
A mixture of 2-({5,7-dimethyl-[1,2,4]triazolo[1,5-a]pyrimidin-2-yl}sulfanyl)ethan-1-ol (100 mg, 0.446 mmol), triphenylphosphine (175 mg, 0.670 mmol), 4-hydroxypyridine (55 mg, 0.58 mmol), and tetrahydrofuran (0.5 mL) was added to a 20 mL scintillation vial. The mixture was placed in a sonicating bath, and diisopropyl azodicarboxylate (0.133 mL, 0.67 mmol) was added dropwise. Sonication was allowed to continue for 15 min, and progress of the reaction was monitored by HPLC with UV detection at 215 nm. Water (5 mL) was added to the mixture, stirred, and decanted. The oily residue was dissolved in 50 mL of ethyl acetate and extracted with 3 mL of 1 M aqueous HCl. The acidic layer was separated, and the pH was adjusted to basic with saturated aqueous sodium bicarbonate. The basic layer was extracted with 4 mL of ethyl acetate which was dried (Na2SO4), filtered, and concentrated under reduced pressure. The crude material was purified by silical gel chromatography using a gradient elution of 0-10% methanol in dichloromethane. The title compound was obtained as a white powder (0.025 g, 19% yield). EM (calc.): 301.1; MS (ESI) m/e: 302.1 (M+H)+. 1H NMR (DMSO-d6, 400 MHz) δ ppm: 8.38 (dd, 2H), 7.13 (s, 1H), 7.04 (dd, 2H), 4.43 (t, 2H), 3.62 (t, 2H), 2.67 (s, 3H), 2.55 (s, 3H).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:10][C:11](=[O:20])[NH:12][C:13]1[C:14]([OH:19])=[N:15][CH:16]=[CH:17][CH:18]=1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.Br[CH2:22][C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24]>C1COCC1>[C:26]([O:25][C:23](=[O:24])[CH2:22][N:15]1[CH:16]=[CH:17][CH:18]=[C:13]([NH:12][C:11]([O:10][CH2:3][C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)=[O:20])[C:14]1=[O:19])([CH3:29])([CH3:28])[CH3:27]
Reactant: O=C(Nc1cccnc1O)OCc1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Cn1cccc(NC(=O)OCc2ccccc2)c1=O
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 85 %

Procedure:
Sodium hydride (0.070 g of a 60% suspension in mineral oil, 1.75 mmol, 1.0 equiv) was added to a solution of (2-hydroxypyridin-3-yl)carbamic acid benzyl ester prepared as described in Example 1) (0.415 g, 1.70 mmol, 1 equiv) in THF (20 mL) at 0° C. The reaction mixture was stirred for 20 min at 0° C., then tert-butyl bromoacetate (0.275 mL, 1.86 mmol, 1.1 equiv) was added. The reaction mixture was warmed to 23° C. for 45 min, then was partitioned between 0.5 M HCl (150 mL) and EtOAc (2×100 mL). The organic layers were dried over Na2SO4 and were concentrated. Purification of the residue by flash column chromatography (30% EtOAc in hexanes) provided the title compound (0.485 g, 85%) as an off-white solid: mp=88-90° C.; IR (cm−1) 3380, 1739, 1652, 1604; 1H NMR (CDCl3) δ 1.48 (s, 9H), 4.57 (s, 2H), 5.20 (s, 2H), 6.25 (t, 1H, J=7.1), 6.87 (dd, 1H, J=6.9, 1.7), 7.27-7.41 (m, 5H), 7.86 (s, br, 1H), 8.05 (d, br, 1H J=6.8); Anal. C19H22N2O5: C, H, N.
Reaction SMILES: [CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[NH:7][C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2].[CH3:16][C:17]1[CH:24]=[CH:23][C:20]([CH:21]=[CH2:22])=[CH:19][CH:18]=1.[H-].[Na+]>CN(C=O)C>[CH2:1]([N:3]1[CH2:15][CH2:14][C:6]2[N:7]([CH2:22][CH2:21][C:20]3[CH:23]=[CH:24][C:17]([CH3:16])=[CH:18][CH:19]=3)[C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][C:13]=3[C:5]=2[CH2:4]1)[CH3:2]
Reactant: C=Cc1ccc(C)cc1
Reactant: CCN1CCc2[nH]c3ccccc3c2C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1CCc2c(c3ccccc3n2CCc2ccc(C)cc2)C1
Yield: 10 %

Procedure:
The title compound was prepared according to General Method 2. 2-Ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole was prepared from 2-ethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (Sec Example 5) (100 mg, 0.5 mmol), 4-methylstyrene (1 mL, 6.72 mmol) and NaH (200 mg, 5 mmol) in DMF (4 ml) at 150° C. for 16 h to obtain 16 mg of 2-ethyl-2,3,4,5-tetrahydro-5-(4-methylphenethyl)-1H-pyrido[4,3-b]indole after purification.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH:7]([CH:15](C(C)=O)[C:16]([O:18]CC)=[O:17])[CH:8](C(C)=O)[C:9]([O-:11])=[O:10])=[CH:5][CH:4]=1.C(O)C.[OH-].[Na+]>O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH:7]([CH2:15][C:16]([OH:18])=[O:17])[CH2:8][C:9]([OH:11])=[O:10])=[CH:24][CH:25]=1
Reactant: CCOC(=O)C(C(C)=O)C(c1ccc(OC)cc1)C(C(C)=O)C(=O)[O-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COc1ccc(C(CC(=O)O)CC(=O)O)cc1
Yield: 16.1 %

Procedure:
A mixture of ethyl 2,2'-(4-methoxybenzal)-bis-acetoacetate (30 g), ethanol (450 ml) and 50% sodium hydroxide (450 g) is refluxed vigorously for 1.0 hour. Water (150 ml) is added and most of the ethanol is removed by distillation in vacuo. The concentrate is acidified with concentrated hydrochloric acid and is extracted with ethyl acetate. The ethyl acetate solution is washed with brine, dried, evaporated and the residue is crystallized from benzene-methanol to afford 3.3 g of 3-(4-methoxyphenyl)glutaric acid, melting point 147°-150° C.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]([CH3:10])=[C:5]([CH3:9])[C:6]=1[C:7]#[N:8].[CH3:11]OC(OC)N(C)C.C1(C)C=CC=CC=1.C(O)(=O)C.[NH2:30][C:31]1[CH:32]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[Se:34][C:35]=1[CH3:36]>C(O)(=O)C>[CH3:9][C:5]1[C:6]2[C:7]([NH:30][C:31]3[CH:32]=[C:33]([C:37]([O:39][CH3:40])=[O:38])[Se:34][C:35]=3[CH3:36])=[N:8][CH:11]=[N:1][C:2]=2[NH:3][C:4]=1[CH3:10]
Reactant: COC(OC)N(C)C
Reactant: COC(=O)c1cc(N)c(C)[se]1
Reactant: Cc1[nH]c(N)c(C#N)c1C
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: COC(=O)c1cc(Nc2ncnc3[nH]c(C)c(C)c23)c(C)[se]1

Procedure:
As shown in scheme K, 2-amino-4,5-dimethyl-1H-pyrrole-3-carbonitrile (Fischer, R. W. et. al., Org. Proc. Res. Dev., 2001, 5, 581-586) is reacted with N,N-dimethylformamide-dimethylacetal in the presence of toluene/acetic acid, followed by methyl 4-amino-5-methylselenophene-2-carboxylate in acetic acid to yield methyl 4-(5,6-dimethyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-5-methylselenophene-2-carboxylate.
Reaction SMILES: [I-].C([O:6][C:7](=O)[CH2:8][CH2:9][C:10]([O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[O+:18]=[C:17]2[C:27]([C:30]3[CH:39]=[CH:38][C:33]4[O:34][CH2:35][CH2:36][O:37][C:32]=4[CH:31]=3)=[CH:28][S:29][C:16]=12)=[O:11])(C)(C)C.[ClH:41].S(Cl)([Cl:44])=O>ClCCl>[Cl-:44].[Cl:41][C:7](=[O:6])[CH2:8][CH2:9][C:10]([O:12][CH2:13][O:14][C:15]1[CH:20]=[C:19]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)[O+:18]=[C:17]2[C:27]([C:30]3[CH:39]=[CH:38][C:33]4[O:34][CH2:35][CH2:36][O:37][C:32]=4[CH:31]=3)=[CH:28][S:29][C:16]=12)=[O:11]
Reactant: Cl
Reactant: CC(C)(C)OC(=O)CCC(=O)OCOc1cc(N2CCOCC2)[o+]c2c(-c3ccc4c(c3)OCCO4)csc12
Reactant: O=S(Cl)Cl
Agent: [I-]
Solvent: ClCCl
Product: O=C(Cl)CCC(=O)OCOc1cc(N2CCOCC2)[o+]c2c(-c3ccc4c(c3)OCCO4)csc12
Product: [Cl-]
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 134.9 %

Procedure:
A vial was charged with a magnetic stirring bar, 7-((4-tert-butoxy-4-oxobutanoyloxy)methoxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium iodide (81) (1.02 g, 1.49 mmol), dichloromethane (4.7 mL) and hydrochloric acid (4 M in dioxane, 1.49 mL, 5.95 mmol). The solution was magnetically stirred at room temperature for 30 minutes. The reaction was charged with thionyl chloride (1.63 mL, 2.98 mmol) and stirred at room temperature overnight. The reaction solution was concentrated in mow to give 7-((4-chloro-4-oxobutanoyloxy)methoxy)-3-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-5-morpholinothieno[3,2-b]pyran-4-ium chloride (82) (1.12 g, 2.01 mmol) as a crunchy yellow solid.
Reaction SMILES: Cl.[NH2:2][CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([CH3:6])=O.[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]#[N:23].C(N(CC)CC)C>C(O)C>[ClH:13].[Cl:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([Cl:20])[C:15]=1[NH:21][C:22]1[NH:2][C:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:4]([CH3:6])[N:23]=1
Reactant: CC(=O)C(N)c1ccccc1
Reactant: N#CNc1c(Cl)cccc1Cl
Agent: Cl
Solvent: CCO
Solvent: CCN(CC)CC
Product: Cc1nc(Nc2c(Cl)cccc2Cl)[nH]c1-c1ccccc1
Yield: 14.7 %

Procedure:
1-Amino-1-phenylacetone hydrochloride (189 mg), 2,6-dichlorophenylcyanamide (187 mg, prepared as described in J. Med. Chem., 1975, 18, 90-99) and triethylamine (101 mg) were kept at the reflux temperature in ethanol (10 ml) for 3 hours. Cooling was followed by drying in vacuo and purification by preparative HPLC. The product-containing fractions were combined, the acetonitrile was stripped in a rotary evaporator, and the aqueous residue was neutralized with potassium carbonate and extracted three times with ethyl acetate. Drying over magnesium sulfate was followed by evaporation to dryness and, after addition of hydrochloric acid, freeze drying. 26 mg of the title compound were obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=[O:8])[C:5]([SH:11])=[CH:4][CH:3]=1.Cl[CH2:13][C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15].[OH-].[Na+].C(O)C>O>[CH2:13]([S:11][C:5]1[CH:4]=[CH:3][C:2]([Cl:1])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:15]
Reactant: O=C(O)c1cc(Cl)ccc1S
Reactant: O=C(CCl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(CSc1ccc(Cl)cc1C(=O)O)c1ccccc1

Procedure:
A solution of 18.9 g. (0.1 mole) of 5-chlorothiosalicylic acid, 15.4 g. (0.1 mole) of α-chloroacetophenone and 8 g. (0.2 mole) of sodium hydroxide in 200 ml. of ethanol containing 45 ml. of water is heated to reflux for 2 hours. After removing one-fourth the alcohol under reduced pressure, the mixture is acidified with hydrochloric acid and the resulting precipitated product filtered, 5.0 g., m.p. 154°-156° C. The analytical sample has a melting point of 156°-157.5° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9](=[O:39])[N:10]([C@H:12]2[C@H:16]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)[CH2:15][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([OH:38])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:13]2)[CH3:11])=[CH:4][CH:3]=1.[C:40](Cl)(=[O:42])[CH3:41]>>[Cl:23][C:20]1[CH:19]=[CH:18][C:17]([C@H:16]2[C@H:12]([N:10]([C:9]([O:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=3)=[O:39])[CH3:11])[CH2:13][N:14]([C:24]([CH:26]3[CH2:31][CH2:30][N:29]([C:32]4[CH:37]=[CH:36][C:35]([O:38][C:40](=[O:42])[CH3:41])=[CH:34][N:33]=4)[CH2:28][CH2:27]3)=[O:25])[CH2:15]2)=[CH:22][CH:21]=1
Reactant: CN(C(=O)Oc1ccc(F)cc1)[C@@H]1CN(C(=O)C2CCN(c3ccc(O)cn3)CC2)C[C@H]1c1ccc(Cl)cc1
Reactant: CC(=O)Cl
Product: CC(=O)Oc1ccc(N2CCC(C(=O)N3C[C@@H](N(C)C(=O)Oc4ccc(F)cc4)[C@H](c4ccc(Cl)cc4)C3)CC2)nc1

Procedure:
A mixture of [(3S,4R)-4-(4-Chloro-phenyl)-1-(5′-hydroxy-3,4,5,6-tetrahydro-2H-[1,2′]bipyridinyl-4-carbonyl)-pyrrolidin-3-yl]-methyl-carbamic acid 4-fluoro-phenyl ester (example 320, crude) was treated with acetyl chloride and the mixture was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile, water and NEt3 to yield after evaporation of the product containing fractions the title compound as light yellow solid. MS m/e: 595.4 [M+H]+.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=1.Br[CH2:9][CH2:10][CH2:11][N:12]1[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]2[C:13]1=[O:22].C1CCN2C(=NCCC2)CC1>CN(C=O)C>[C:13]1(=[O:22])[N:12]([CH2:11][CH2:10][CH2:9][O:1][C:2]2[CH:7]=[CH:6][N:5]=[CH:4][CH:3]=2)[C:16](=[O:17])[C:15]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:14]12
Reactant: Oc1ccncc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C1c2ccccc2C(=O)N1CCCOc1ccncc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 16.4 %

Procedure:
To a solution of 4.76 g (50 mmol) of 4-hydroxypyridine and 14.75 g (55 mmol) of N-(3-bromopropyl)phthalimide in 80 ml of DMF was added 8.23 ml (55 mmol) of 1,8-diazabicyclo[5.4.0]-7-undecene. The mixture was stirred at room temperature for 6 hours. After the solvent was distilled off, the mixture was poured into water and extracted with ethyl acetate. The mixture was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off. The residue was purified by column chromatography (eluent: ethyl acetate) to obtain 2.32 g of the desired compound (yield: 16.4%, colorless crystals).
Reaction SMILES: [F:1][C:2]([F:21])([F:20])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][NH:17][CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:5][CH:4]=1.Cl[C:23]1[C:28]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=1.C(N(CC)C(C)C)(C)C>>[F:21][C:2]([F:1])([F:20])[C:3]1[CH:4]=[CH:5][C:6]([NH:9][C:10]2[C:11]3[CH2:19][CH2:18][N:17]([C:23]4[C:28]([S:29]([CH:32]([CH3:34])[CH3:33])(=[O:31])=[O:30])=[CH:27][CH:26]=[CH:25][N:24]=4)[CH2:16][C:12]=3[N:13]=[CH:14][N:15]=2)=[CH:7][CH:8]=1
Reactant: FC(F)(F)c1ccc(Nc2ncnc3c2CCNC3)cc1
Reactant: CC(C)S(=O)(=O)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)S(=O)(=O)c1cccnc1N1CCc2c(ncnc2Nc2ccc(C(F)(F)F)cc2)C1

Procedure:
The title compound was prepared according to the procedure given for Example 9 using N-(4-(trifluoromethyl)phenyl)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-4-amine (0.073 g, 0.25 mmol), 2-chloro-3-(isopropylsulfonyl)pyridine (0.070 g, 0.32 mmol) and N,N-diisopropylethylamine (0.082 mL, 0.47 mmol) to obtain 0.073 g of a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][NH:9]2)=[CH:5][CH:4]=1.[H-].[Na+].[CH2:16](I)[CH3:17]>CN(C=O)C.O>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([C:7]([C:12]#[N:13])=[CH:8][N:9]2[CH2:16][CH3:17])=[CH:5][CH:4]=1
Reactant: COc1ccc2c(C#N)c[nH]c2c1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCn1cc(C#N)c2ccc(OC)cc21
Reaction time: 0.25 h

Procedure:
To a solution of 6-methoxy-1H-indole-3-carbonitrile (9.9 g, 57.6 mmol) in DMF (150 mL) is added NaH (60% dispersion in mineral oil, 3.45 g, 86.3 mmol). The reaction mixture is stirred for 15 min and then ethyl iodide (5.53 mL, 69.1 mmol) is added and the mixture is stirred at room temperature overnight. The reaction mixture is then diluted with H2O and extracted with EtOAc (2×). The organic phases are washed with H2O (3×) and saturated NaCl and then dried and concentrated to a semi-solid. The crude product is purified via column chromatography on silica gel (200 g) using CH2Cl2/hexanes (50-100%) as eluent to yield 6-methoxy-1-ethyl-1H-indole-3-carbonitrile as a tan solid.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5])#[N:2].[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH2:25].[CH2:31](OC(OCC)OCC)C>C(O)(C)C>[Cl:17][CH2:18][CH2:19][CH2:20][O:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[NH:25][CH:31]=[C:3]([C:1]#[N:2])[C:4]([NH:6][C:7]1[CH:12]=[C:11]([O:13][CH3:14])[C:10]([Cl:15])=[CH:9][C:8]=1[Cl:16])=[O:5]
Reactant: COc1ccc(N)cc1OCCCCl
Reactant: COc1cc(NC(=O)CC#N)c(Cl)cc1Cl
Reactant: CCOC(OCC)OCC
Solvent: CC(C)O
Product: COc1cc(NC(=O)C(C#N)=CNc2ccc(OC)c(OCCCCl)c2)c(Cl)cc1Cl
Yield: 44.3 %

Procedure:
To a suspension of 2-cyano-N-(2,4-dichloro-5-methoxyphenyl)acetamide (738 mg, 2.84 mmol) in 100 mL of isopropanol was added 3-(3-chloropropoxy)-4-methoxyaniline (611 mg, 2.84 mmol). This mixture was heated to reflux and triethylorthoformate (3.0 mL, 18.0 mmol) was added dropwise. The reaction mixture was heated at reflux overnight. The mixture was filtered while still warm and the collected white solid was washed with isopropanol to give 610 mg of 3-(3-chloropropoxy)-4-methoxyanilino-N-(2,4-dichloro-5-methoxyphenyl)-2-cyano-2-propenamide, mp 185-192° C.; MS (ES) m/z 482.1, 484.2, 486.0 (M−H)−
Reaction SMILES: Br[CH:2]([CH2:12][Br:13])[CH2:3][P:4](=[O:11])([O:8][CH2:9][CH3:10])[O:5][CH2:6][CH3:7].CC(C)([O-])C.[K+]>C(O)(C)(C)C>[Br:13][CH2:12]/[CH:2]=[CH:3]\[P:4](=[O:11])([O:5][CH2:6][CH3:7])[O:8][CH2:9][CH3:10]
Reactant: CCOP(=O)(CC(Br)CBr)OCC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CC(C)(C)O
Product: CCOP(=O)(/C=C\CBr)OCC
Reaction time: 0.5 h
Yield: 0.4 %

Procedure:
To a solution of diethyl 2,3-dibromopropylphosphonate (3.34 g.) in tert.-butanol (10 ml.) was added dropwise a solution of potassium tert.-butoxide (K: 430 mg., tert.--C4H9OH: 14 ml.) at ambient temperature in the course of 15 minutes. The reaction mixture was stirred at the same temperature for 30 minutes. The resultant mixture was concentrated under reduced pressure and then the residue was shaken with a mixture of ethyl acetate (50 ml.) and water (30 ml.). The ethyl acetate layer was separated, wshed with water (30 ml.), dried over magnesium sulfate and evaporated to dryness under reduced pressure to give an oily mixture of isomeric diethyl 3-bromo-propenylphosphonates (2.13 g.). An aliquot (1.86 g.) of which was fractionated by subjecting to a column chromatography on silica gel (developing solvent: chloroform) into two fractions (i.e. fraction A and fraction B). The fraction A was evaporated to dryness under reduced pressure to give oily diethyl 3-bromo-cis-1-propenylphosphonate (10 mg.). The fraction B was evaporated to dryness under reduced pressure to give oily mixture (1.65 g.) of diethyl 3-bromo-2-propenylphosphonate and diethyl 3-bromo-trans-1-propenylphosphonate (molar ratio: ca 1:1).
Reaction SMILES: [H-].[Na+].[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4].[CH3:27]I>O1CCCC1>[C:3]([O:7][C:8]([N:10]1[CH2:15][CH2:14][CH:13]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[N:22]([CH3:27])[S:23]([CH3:26])(=[O:25])=[O:24])[CH2:12][CH2:11]1)=[O:9])([CH3:6])([CH3:5])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccccc2NS(C)(=O)=O)CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN(c1ccccc1C1CCN(C(=O)OC(C)(C)C)CC1)S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.1 %

Procedure:
Sodium hydride (60% dispersion in mineral oil, 73.4 mg) was added to a solution of N-[2-(1-t-butoxycarbonylpiperidin-4-yl)phenyl]methanesulfonamide (650 mg) in tetrahydrofuran (50 mL) and the mixture was stirred at room temperature for 1 h. Methyl iodide (260 mg) was added and the mixture was stirred at room temperature for 36 h. The solvent was evaporated under reduced pressure, and the residue was partitioned between water and ethyl acetate (100 mL). The organic layer was separated, dried (MgSO4) and the solvent was evaporated under reduced pressure to give the title compound as colorless solid (662 mg), δH (CDCl3) 1.48 (9H, s), 1.73 (2H, m), 1.88 (2H, m), 2.84 (2H, m), 2.97 (3H, s), 3.25 (3H, s), 3.33 (1H, m), 4.13 (2H, m), 7.21-7.36 (4H, m). m/e (ES+) 369 (MH+).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5](N)=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19].S(=O)(=O)(O)[OH:21].N([O-])=O.[Na+].NC(N)=O>O.C(O)(=O)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:21])=[CH:4][C:3]=1[N:9]1[C:13](=[O:14])[C:12]2[CH2:15][CH2:16][CH2:17][CH2:18][C:11]=2[C:10]1=[O:19]
Reactant: O=S(=O)(O)O
Reactant: Nc1ccc(F)c(N2C(=O)C3=C(CCCC3)C2=O)c1
Agent: NC(N)=O
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: O=C1C2=C(CCCC2)C(=O)N1c1cc(O)ccc1F
Reaction time: 0.25 h
Yield: 26.8 %

Procedure:
To N-(2-fluoro-5-aminophenyl)-3,4,5,6-tetrahydrophthalimide (VIII) (2.6 g), acetic acid (26 g) and conc. sulfuric acid (2.5 g) were added, and the resultant mixture was kept at a temperature below 10° C. A solution of sodium nitrite (1.0 g) in water (10 g) was added dropwise thereto at a temperature of 5° to 10° C. The resulting mixture was stirred for 15 minutes, followed by decomposition of excess of sodium nitrite with urea (0.3 g). A solution of cupric nitrate (38.6 g) in water (100 g) was added dropwise thereto at room temperature. After addition of cuprous oxide (1.5 g), the resultant mixture was stirred vigorously at room temperature for 10 minutes. The reaction mixture was extracted with ethyl acetate, and the solvent was removed by distillation under reduced pressure. The residue was purified by silica gel chromatography using a mixture of n-hexane and ethyl acetate as an eluent to give 0.7 g of N-(2-fluoro-5-hydroxyphenyl)-3,4,5,6-tetrahydrophthalimide (VI). M.P., 164.6° C. M.P., 164.6° C.
Reaction SMILES: [OH:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18](O)=[O:19].O>CCCCCC>[CH3:10][CH:11]([CH3:21])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][C:18]([O:7][CH2:6][C:5]1[CH:8]=[CH:9][C:2]([OH:1])=[CH:3][CH:4]=1)=[O:19]
Reactant: OCc1ccc(O)cc1
Reactant: CC(C)CCCCCCC(=O)O
Solvent: CCCCCC
Solvent: O
Product: CC(C)CCCCCCC(=O)OCc1ccc(O)cc1
Temperature: 50 °C
Yield: 67.2 %

Procedure:
4-Hydroxybenzyl alcohol (651 mg, 5.24 mmol), 8-methylnonanoic acid (948 mg, 5.50 mmol) and Novozyme 435 (50 mg) were measured and placed in a flask (25 ml). The mixture was stirred with heating in an oil bath at 50° C. for 16 hr without plugging the flask. After stirring with heating for 2 to 3 hr, attachment of water onto the upper wall of the flask was observed. The reaction mixture was allowed to cool to room temperature, hexane (50 ml) was added, and Novozyme 435 and the insoluble material were removed by filtration. Hexane (25 ml) was added to the filtrate, and the mixture was washed with 5% aqueous citric acid solution (25 ml×2) and saturated brine (25 ml) and dried over anhydrous magnesium sulfate. Magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure to give 4-hydroxybenzyl 8-methylnonanoate (0.98 g, yield 67.3%) as a thin-yellow oil.