Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][CH:8]=[CH:7][C:6]=2[CH:10]=1.C([Li])CCC.[C:16]([O:20][C:21]([N:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[S:9][C:8]([C:26]3([OH:29])[CH2:25][CH2:24][N:23]([C:21]([O:20][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:22])[CH2:28][CH2:27]3)=[CH:7][C:6]=2[CH:10]=1
Reactant: Clc1ccc2sccc2c1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(O)(c2cc3cc(Cl)ccc3s2)CC1
Temperature: -78 °C
Reaction time: 1 h
Yield: 83.2 %

Procedure:
A solution of 0.60 gm (3.56 mMol) 5-chlorobenzothiophene 1.55 mL in 20 mL freshly distilled tetrahydrofuran was cooled to -78° C. under a nitrogen atmosphere. To this was then added a solution of 2.94 mL (3.56 mMol) n-butyllithium and the reaction mixture was stirred at -78° C. for 1 hour. To the resulting anion solution was added dropwise a solution of 0.779 gm (3.91 mMol) 1-tert-butoxycarbonyl-4-piperidone and then the reaction mixture was allowed to warm to 0° C. The reaction mixture was then quenched with saturated aqueous sodium bicarbonate, diluted with 1:1 hexanes:diethyl ether and the phases separated. The organic phase was washed with saturated aqueous sodium chloride, dried over sodium sulfate and concentrated under reduced pressure. The residue was subjected to flash silica chromatography, eluting with toluene containing 10% ethyl acetate. Fractions shown to contain product were combined and concentrated under reduced pressure to give 1.09 gm of the desired compound as a colorless foam contaminated with 20% 1-tert-butoxycarbonyl-4-piperidone.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[Cl:7][C:8]1[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[N+:20]([O-:22])=[O:21])=[N:10][NH:11][CH:12]=1.[CH3:23][Si:24]([CH2:27]Cl)([CH3:26])[CH3:25]>CN(C)C=O.CCCCCCC.C(OCC)(=O)C>[CH3:23][Si:24]([CH2:27][N:11]1[CH:12]=[C:8]([Cl:7])[C:9]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:19])[C:14]=2[N+:20]([O-:22])=[O:21])=[N:10]1)([CH3:26])[CH3:25]
Reactant: C[Si](C)(C)CCl
Reactant: O=[N+]([O-])c1c(Cl)cccc1-c1n[nH]cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: C[Si](C)(C)Cn1cc(Cl)c(-c2cccc(Cl)c2[N+](=O)[O-])n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
0.85 g of anhydrous potassium carbonate is added to a solution of 1.30 g of 4-chloro-3-(2-nitro-3-chlorophenyl)pyrazole and 0.70 g of (trimethylsilyl)methyl chloride in 30 ml of N,N-dimethylformamide. The reaction mixture is stirred for 12 hours at room temperature and diluted with 100 ml of an ether/H2O (1/1) mixture. The ether phase is dried over MgSO4 and concentrated under reduced pressure. The residual oil is purified by liquid chromatography on a Silica column (eluent: heptane/ethyl acetate [50/50]).
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].C(O[CH:8]=[CH:9][C:10](=O)[C:11]([F:14])([F:13])[F:12])C.FC(F)(F)C(Cl)=O.C(OCC)=C.Cl>CO>[F:12][C:11]([F:14])([F:13])[C:10]1[NH:4][C:2](=[O:3])[N:1]=[CH:8][CH:9]=1
Reactant: NC(N)=O
Reactant: CCOC=CC(=O)C(F)(F)F
Agent: C=COCC
Agent: Cl
Agent: O=C(Cl)C(F)(F)F
Solvent: CO
Product: O=c1nccc(C(F)(F)F)[nH]1
Temperature: 60 °C
Reaction time: 0.25 h

Procedure:
To a solution of 8.74 moles of urea in 2.2L of methanol in a 3-necked flask, equipped with a mechanical stirrer, a reflux condenser and a dropping funnel was added dropwise over about 3 hours under N2 atmosphere an equimolar amount of 4-ethoxy-1,1,1-trifluoro-3-buten-2-one (ETFBO) which had been manufactured by addition of trifluoroacetyl chloride to ethyl vinyl ether. The temperature of the reaction mixture was kept below 15° C. After 15 min, 1.35 L of a concentrated HCl solution (32%) was added to the cooled suspension obtained and a clear solution was obtained. The solution was slowly heated to 60° C. and after 2 hours stirring, a suspension was formed. After overnight stirring at 60° C. and subsequently 1 h stirring at 0 to 5° C., the precipitate was filtered off. The residue was washed with water until neutral pH and subsequently with hexane (ca. 500 ml). After overnight drying on a rotary evaporator under reduced pressure in a 2-L flask, 6-(trifluoromethyl)pyrimidin-2(1H)-on was obtained as colorless crystals. The yield was 1.2 kg (85% of the theoretical yield).
Reaction SMILES: [Cl:1][C:2]1[N:3]=[N:4][C:5]([Cl:9])=[CH:6][C:7]=1Cl.[NH3:10]>>[NH2:10][C:7]1[CH:6]=[C:5]([Cl:9])[N:4]=[N:3][C:2]=1[Cl:1]
Reactant: N
Reactant: Clc1cc(Cl)c(Cl)nn1
Product: Nc1cc(Cl)nnc1Cl

Procedure:
A suspension of 3,4,6-trichloropyridazine (prepared by the method of B. Kasnar et al, Nucleosides and Nucleotides, 1994, 13, 459) (10.0 g) in conc. aqueous ammonia (1 L) was heated at 75° C. for 16 h. The mixture was concentrated to a small volume and extracted several times with ethyl acetate. The extracts were washed with brine, dried and evaporated. The crude product was recrystallised from ethyl acetate to give the product (5.03 g).
Reaction SMILES: [F:1][CH:2]([F:33])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:24]=[CH:23][C:22]([CH:25]5[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]5)=[CH:21][CH:20]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[C:5]([O:31][CH3:32])[CH:4]=1.Cl[CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37]>>[F:33][CH:2]([F:1])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]3[N:11]([N:15]=[C:16]([NH:18][C:19]4[CH:20]=[CH:21][C:22]([CH:25]5[CH2:26][CH2:27][N:28]([CH2:35][C:36]([N:38]([CH3:40])[CH3:39])=[O:37])[CH2:29][CH2:30]5)=[CH:23][CH:24]=4)[N:17]=3)[CH:12]=[CH:13][CH:14]=2)=[C:5]([O:31][CH3:32])[CH:4]=1
Reactant: CN(C)C(=O)CCl
Reactant: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCNCC4)cc3)nc12
Product: COc1cc(C(F)F)ccc1-c1cccn2nc(Nc3ccc(C4CCN(CC(=O)N(C)C)CC4)cc3)nc12

Procedure:
2-(4-{4-[8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-ylamino]-phenyl}-piperidin-1-yl)-N,N-dimethyl-acetamide was prepared from [8-(4-difluoromethyl-2-methoxy-phenyl)-[1,2,4]-triazolo[1,5-a]pyridin-2-yl]-(4-piperidin-4-yl-phenyl)-amine (0.160 g, 0.356 mmol) and 2-chloro-N,N-dimethyl-acetamide (0.055 mL, 0.534 mmol) in a manner analogous to Example 313 to give product (0.035 g, 18%).
Reaction SMILES: [NH2:1][C:2]1[CH:29]=[CH:28][C:5]([O:6][C:7]2[C:12]3=[C:13]([CH3:27])[C:14]([C:16]([NH:18][CH2:19][CH2:20][N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[O:17])=[CH:15][N:11]3[N:10]=[CH:9][N:8]=2)=[C:4]([F:30])[CH:3]=1.CCN(CC)CC.[F:38][C:39]1[CH:47]=[CH:46][C:45]([CH3:48])=[CH:44][C:40]=1[C:41]([Cl:43])=[O:42]>C1COCC1>[ClH:43].[F:30][C:4]1[CH:3]=[C:2]([NH:1][C:41](=[O:42])[C:40]2[CH:44]=[C:45]([CH3:48])[CH:46]=[CH:47][C:39]=2[F:38])[CH:29]=[CH:28][C:5]=1[O:6][C:7]1[C:12]2=[C:13]([CH3:27])[C:14]([C:16]([NH:18][CH2:19][CH2:20][N:21]3[CH2:26][CH2:25][O:24][CH2:23][CH2:22]3)=[O:17])=[CH:15][N:11]2[N:10]=[CH:9][N:8]=1
Reactant: Cc1c(C(=O)NCCN2CCOCC2)cn2ncnc(Oc3ccc(N)cc3F)c12
Reactant: Cc1ccc(F)c(C(=O)Cl)c1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cc1ccc(F)c(C(=O)Nc2ccc(Oc3ncnn4cc(C(=O)NCCN5CCOCC5)c(C)c34)c(F)c2)c1
Product: Cl
Reaction time: 1 h
Yield: 22.7 %

Procedure:
To a solution of 4-(4-amino-2-fluorophenoxy)-5-methyl-N-(2-morpholinoethyl)pyrrolo[2,1-f][1,2,4]triazine-6-carboxamide (25 mg, 0.06 mmol) in 1 mL of THF were added Et3N (0.2 mL) and a solution of 2-fluoro-5-methylbenzoyl chloride (20 mg, 0.11 mmol) in 1 mL of THF at room temperature. The mixture was allowed to stir for 1 h and HPLC analysis indicated the consumption of the starting material. The reaction was quenched with MeOH. The solution was then concentrated in vacuo and the residue was purified by preparative HPLC to give the title compound (8.0 mg, 23%) as a HCl salt. 1H NMR (CD3OD) δ 8.48 (d, 1H), 7.83 (m, 3H), 7.28 (m, 3H), 7.00 (m, 1H), 2.90-4.00 (m, 12H), 2.76 (s, 3H), 2.33 (s, 3H); MS(ESI+) m/z 551.2 (M+H)+.
Reaction SMILES: [CH:1]1([S:4]([C:7]2[CH:12]=[CH:11][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32]O)=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:20][CH2:19][O:18][CH2:17][CH2:16]3)=[CH:9][CH:8]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1.CC(C)(O)[C:36]#[N:37].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>O1CCCC1.C(OCC)(=O)C>[CH:1]1([S:4]([C:7]2[CH:8]=[CH:9][C:10]([CH:13]([C:21]3[NH:25][C:24]([C:26]4[N:31]=[CH:30][C:29]([CH2:32][C:36]#[N:37])=[CH:28][CH:27]=4)=[CH:23][CH:22]=3)[CH2:14][CH:15]3[CH2:16][CH2:17][O:18][CH2:19][CH2:20]3)=[CH:11][CH:12]=2)(=[O:6])=[O:5])[CH2:3][CH2:2]1
Reactant: CC(C)(O)C#N
Reactant: O=S(=O)(c1ccc(C(CC2CCOCC2)c2ccc(-c3ccc(CO)cn3)[nH]2)cc1)C1CC1
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: N#CCc1ccc(-c2ccc(C(CC3CCOCC3)c3ccc(S(=O)(=O)C4CC4)cc3)[nH]2)nc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 22.8 %

Procedure:
To a solution of [6-(5-{1-[4-(cyclopropylsulfonyl)phenyl]-2-(tetrahydro-2H-pyran-4-yl)ethyl}-1H-pyrrol-2-yl)pyridin-3-yl]methanol (0.500 g) in tetrahydrofuran (10 mL) were added acetone cyanohydrin (202 mg), tributylphosphine (466 mg) and 1,1′-(azodicarbonyl)dipiperidine (540 mg), and the mixture was stirred at room temperature for 12 hr. The reaction mixture was suspended in ethyl acetate and filtered to remove the precipitate, and the filtrate, and the suspension was concentrated under reduced pressure. The residue was successively purified by silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio) and basic silica gel column chromatography (ethyl acetate:hexane=20:80-100:0, volume ratio), and recrystallized from hexane-ethyl acetate to give the title compound (0.116 g, yield 23%) as colorless crystals. MS: 476 (MH+). melting point 139-141° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([Li])CCC.[C:20](=[O:22])=[O:21]>CCCCCC.O1CCCC1.O>[C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[N:11][CH:12]=[CH:13][C:14]=1[C:20]([OH:22])=[O:21])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C=O
Reactant: CC(C)(C)OC(=O)Nc1cccnc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)Nc1cnccc1C(=O)O
Reaction time: 0.25 h

Procedure:
While a mixture of 1.16 g of 3-(tert-butoxycarbonylamino)pyridine and 25 ml of tetrahydrofuran was cooled in a dry ice-acetone bath, 8.5 ml of 1.65 M hexane solution of n-butyllithium was added so that the temperature of the reaction mixture did not exceed −60° C. The reaction mixture was stirred for 15 minutes. Cooling was stopped. Then, the reaction mixture was stirred until the temperature became 0° C. The reaction mixture was cooled in a dry ice-acetone bath again. After injection of carbon dioxide, cooling was stopped, and the reaction mixture was stirred at room temperature for two hours. After water was added, most of tetrahydrofuran and hexane was removed by concentration under reduced pressure. The residue was ice-cooled and 3N hydrochloric acid was added so as to adjust pH to about 3. Extraction with a mixture solvent (4:1) of ethyl acetate to tetrahydrofuran was carried out several times. The combined organic layers were washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give 0.53 g of 3-(tert-butoxycarbonyl amino)isonicotinic acid.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[CH:19]=[CH:18][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:16][N:15]=2)[CH2:9]1)(C)(C)C.C(O)(C(F)(F)F)=O>>[ClH:39].[ClH:39].[ClH:39].[NH2:7][CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:15]=[CH:16][C:17]([NH:20][C:21]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([C:31]5[CH:36]=[C:35]([F:37])[C:34]([OH:38])=[C:33]([Cl:39])[CH:32]=5)[N:29]=4)[N:24]=[CH:23][C:22]=3[C:40](=[O:42])[CH3:41])=[CH:18][CH:19]=2)[CH2:9]1
Reactant: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(NC(=O)OC(C)(C)C)C2)nc1
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1cnc2ccc(-c3cc(F)c(O)c(Cl)c3)nc2c1Nc1ccc(N2CCCC(N)C2)nc1
Product: Cl
Yield: 107.1 %

Procedure:
Following general procedure IV-2, tert-butyl[1-(5-{[3-acetyl-6-(3-chloro-5-fluoro-4-hydroxyphenyl)-1,5-naphthyridin-4-yl]amino}pyridin-2-yl)piperidin-3-yl]carbamate (0.20 mmol) was reacted with TFA (2 mL) followed by formation of the trihydrochloride salt to afford the desired product (33 mg, 33% over two steps) as an orange solid: 1H NMR (500 MHz, CD3OD) δ 9.38 (s, 1H), 8.48 (d, J=9.5 Hz, 1H), 8.41 (d, J=9.5 Hz), 8.25 (d, J=2.5 Hz, 1H), 7.91 (dd, J=9.5, 2.5 Hz, 1H), 7.41-7.37 (m, 2H), 7.28 (d, J=9.5 Hz, 1H), 4.37 (d, J=10.7 Hz, 1H), 4.03-3.99 (m, 1H), 3.52-3.32 (m, 3H), 2.84 (s, 3H), 2.28-2.20 (m, 1H), 2.08-1.98 (m, 1H), 1.84-1.78 (m, 2H); ESI MS m/z 507 [M+H]+; HPLC>99% (AUC), tR=9.38 min.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]([C:6]1[C:15]([O:16][CH3:17])=[CH:14][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:8][C:7]=1[O:18][CH3:19])=[O:5].[C:20](OCC)(OCC)(OCC)[CH3:21]>>[CH3:20][C:21]1[O:5][C:4]([C:6]2[C:7]([O:18][CH3:19])=[CH:8][C:9]([C:10]([O:12][CH3:13])=[O:11])=[CH:14][C:15]=2[O:16][CH3:17])=[CH:3][N:2]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: COC(=O)c1cc(OC)c(C(=O)CN)c(OC)c1
Agent: Cl
Product: COC(=O)c1cc(OC)c(-c2cnc(C)o2)c(OC)c1
Temperature: 140 °C
Reaction time: 6 h

Procedure:
Methyl 4-(aminoacetyl)-3,5-dimethoxybenzoate hydrochloride was dissolved in triethyl orthoacetate, paratoluenesulfonic acid monohydrate (10 mg) was added to it, and stirred at 140° C. for 6 hours. The reaction liquid was cooled to room temperature, then triethyl orthoacetate was evaporated away under reduced pressure, and the residue was purified through silica gel column chromatography (hexane/ethyl acetate=100/0 to 30/70) to obtain the title compound.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10](OS(C)(=O)=O)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18](#[N:20])C>[C-]#N.C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([N:8]1[CH2:12][CH2:11][C@H:10]([C:18]#[N:20])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)O[C@@H]1CCN(Cc2ccccc2)C1
Reactant: CC#N
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [C-]#N
Product: N#C[C@H]1CCN(Cc2ccccc2)C1
Temperature: 65 °C
Yield: 85 %

Procedure:
(R)-1-Benzyl-3-mesyloxypyrrolidine (5.0 g, 20 mmol) was dissolved in acetonitrile (6 mL) and tetrabutylammonium cyanide (11.1 g, 41.4 mmol) was added. The mixture was heated at 65° C. for 3 hours and then cooled to room temperature and extracted with ethyl ether (100 mL). The organic layer was washed with saturated NaHCO3 (2×50 mL), dried over MgSO4, and concentrated under reduced pressure to give (S)-1-benzyl-3-cyanopyrrolidine (3.1 g, 85%) as a yellow oil: VPC: 100%;
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:15][CH2:14][CH:13]([CH2:16][CH2:17][C:18]3[C:19](=[O:24])[NH:20][CH:21]=[CH:22][CH:23]=3)[CH2:12][CH2:11]2)=[CH:7][CH:6]=[CH:5][N:4]=1.Br[CH2:26][CH2:27][CH2:28][C:29]#[N:30].C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C=O>[CH3:1][O:2][C:3]1[C:8]([CH2:9][N:10]2[CH2:11][CH2:12][CH:13]([CH2:16][CH2:17][C:18]3[C:19]([O:24][CH2:26][CH2:27][CH2:28][C:29]#[N:30])=[N:20][CH:21]=[CH:22][CH:23]=3)[CH2:14][CH2:15]2)=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COc1ncccc1CN1CCC(CCc2ccc[nH]c2=O)CC1
Reactant: N#CCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ncccc1CN1CCC(CCc2cccnc2OCCCC#N)CC1
Temperature: 60 °C
Reaction time: 4 h
Yield: 60.2 %

Procedure:
200 mg of 1-[(2-methoxy-3-pyridyl)methyl]-4-[2-(2-oxo-1,2-dihydro-3-pyridinyl)ethyl]piperidine obtained in Example 47,95 mg of γ-bromobutyronitrile and 169 mg of potassium carbonate were suspended in 5 ml of N,N-dimethylformamide, and the mixture was stirred at 60° C. for 4 hours. Ethyl acetate was added thereto, the resulting salt was filtered off, and the solvent was evaporated. The crude product was purified by NH form silica gel column chromatography (ethyl acetate:hexane=1:4), to give 77 mg of the title compound as a colorless oil.
Reaction SMILES: [CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12]Cl)[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[I-:15].[Na+]>C(C(C)=O)C>[CH3:1][C:2]([CH3:14])([CH2:9][CH2:10][CH2:11][CH2:12][I:15])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: [I-]
Reactant: CCOC(=O)CC(C)(C)CCCCCl
Agent: [Na+]
Solvent: CCC(C)=O
Product: CCOC(=O)CC(C)(C)CCCCI

Procedure:
To a solution of 3.57 g. (0.0162 mole) of ethyl 3,3-dimethyl-7-chloroheptanoate in 100 ml. of methyl ethyl ketone is added 4 g. of sodium iodide and the mixture heated at reflux for 18 hours. The reaction mixture is cooled, filtered and concentrated. The residue is partitioned between ether and water. The aqueous phase is extracted several times with ether. The extract is washed with sodium bisulfite solution, water and saline. The organic solution is dried over magnesium sulfate and concentrated to give 4.182 g. of a yellow oil. The material is purified by distillation, b.p. 86°-87° C. (0.18 Torr).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl.[NH2:8][C:9]1[CH:10]=[CH:11][C:12]2[C:21]([CH:22]=1)=[N:20][C:19]1[C:14](=[CH:15][CH:16]=[C:17]([NH2:23])[CH:18]=1)[CH:13]=2.[CH2:24](Br)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43].O>CN1C(=O)N(C)CC1>[CH2:24]([NH:23][C:17]1[CH:16]=[CH:15][C:14]2[C:19]([CH:18]=1)=[N:20][C:21]1[C:12](=[CH:11][CH:10]=[C:9]([NH:8][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH2:28][CH2:27][CH2:26][CH2:25][CH3:24])[CH:22]=1)[CH:13]=2)[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH3:43]
Reactant: CCCCCCCCCCCCCCCCCCCCBr
Reactant: Nc1ccc2cc3ccc(N)cc3nc2c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN1CCN(C)C1=O
Solvent: O
Product: CCCCCCCCCCCCCCCCCCCCNc1ccc2cc3ccc(NCCCCCCCCCCCCCCCCCCCC)cc3nc2c1
Temperature: 50 °C
Reaction time: 86 h

Procedure:
2.53 g of anhydrous potassium carbonate are added to a solution of 2.5 g of 3,6-diaminoacridine hydrochloride and 2.95 g of 1-eicosyl bromide in 20 ml of N,N'-dimethylethyleneurea, and the mixture is stirred at 50° C. for 86 hours. The cooled reaction mixture is subsequently poured into water, and the orange-brown suspension is extracted with methylene chloride. The organic phase is washed with water and dried over sodium sulfate. After evaporation, 2N HCl is added to the brown oil. The red precipitate formed is filtered off, washed with water and then dried in a high vacuum. The resultant red-brown crystals are taken up in methylene chloride/methanol (10:1) and chromatographed on silica gel. After evaporation, the residue is taken up in diethyl ether/methanol (10:1) and re-chromatographed on silica gel, giving the title compound as red crystals, absorption spectrum (ethanol): λmax =472 nm; ε=42 200.
Reaction SMILES: CO[C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[C:12]1[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1.[NH2-:19].[Li+]>O1CCCC1>[NH2:19][C:3]1[C:8]([O:9][CH3:10])=[CH:7][C:6]([CH3:11])=[CH:5][C:4]=1[C:12]1[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=1
Reactant: [NH2-]
Reactant: COc1cc(C)cc(C2=NC(C)(C)CO2)c1OC
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1cc(C)cc(C2=NC(C)(C)CO2)c1N
Temperature: 25 °C
Reaction time: 72 h
Yield: 25.5 %

Procedure:
In dry tetrahydrofuran (80 ml) was dissolved 2-(2,3-dimethoxy-5-methylphenyl)-4,4-dimethyl-2-oxazoline (5 g). After addition of lithium amide (60 g), the mixture was stirred in a nitrogen gas stream at room temperature for 3 days. To the reaction mixture was added ice-water, followed by extraction with diethyl ether. The solvent layer was washed with water and dried over magnesium sulfate. The solvent was then distilled off to give a brown oil. This oil was chromatographed on silica gel to give colorless prisms (1.2 g) of 2-(2-amino-3-methoxy-5-methylphenyl)-4,4-dimethyl-2-oxazoline. m.p. 135°-137.5° C. (crystallized from diethyl ether)
Reaction SMILES: [CH2:1]([NH:5][S:6]([C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1)(=[O:8])=[O:7])[CH:2]([CH3:4])[CH3:3].[H-].[Na+].[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.O>CC(N(C)C)=O>[Cl:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[S:6]([C:9]2[CH:10]=[CH:11][C:12]([O:15][CH3:16])=[CH:13][CH:14]=2)(=[O:8])=[O:7])=[CH:22][CH:21]=1
Reactant: COc1ccc(S(=O)(=O)NCC(C)C)cc1
Reactant: Clc1ccc(CBr)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1ccc(S(=O)(=O)N(Cc2ccc(Cl)cc2)CC(C)C)cc1
Temperature: 90 °C
Reaction time: 0.17 h
Yield: 66.7 %

Procedure:
To a solution of N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 4.2 mmol) in anhydrous dimethylacetamide (20 mL) at 0° C. was added NaH (60% dispersion in mineral oil, 186 mg, 4.6 mmol) until no more gas evolved then stirred for a further 10 minutes. 4-Chlorobenzylbromide (951 mg, 4.6 mmol) was added and the reaction heated at 90° C. for 2 hours. The reaction was left to cool to room temperature, water was added, extracted with DCM, filtered through a phase separator, concentrated then purified by silica gel column chromatography (0-50% DCM in cyclohexane) to give N-(4-chloro-benzyl)-N-isobutyl-4-methoxy-benzenesulfonamide (1.03 g, 67%). LCMS (m/z, Method A)) ES+ 368 [M+1]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([O:24]CC)=O)=[CH:19][C:18]=3[CH:27]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([NH2:30])=O>CN1CCCC1=O>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[O:21][C:20]([C:22]([NH2:30])=[O:24])=[CH:19][C:18]=3[CH:27]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CCOC(=O)c1cc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2o1
Reactant: NC=O
Solvent: CN1CCCC1=O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc3oc(C(N)=O)cc3c2)CC1

Procedure:
According to the '614 patent, the preparation of 5-(1-pipearzinyl)benzofuran-2-carboxamide is carried out in four steps starting from ethyl 5-aminobenzofuran-2-carboxylate. According to first step, ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is prepared by reacting ethyl 5-aminobenzofuran-2-carboxylate with N,N-bis(2-chloroethyl)amine in dichloromethane to produce a reaction mass, followed by customary work-up using a solvent system (isopropanol/water 95:5). According to second step, the ethyl 5-(1-piperazinyl)benzofuran-2-carboxylate is subjected to BOC protection by reacting with di-tert-butyl dicarbonate in tetrahydrofuran to produce ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate. In third step, the ethyl 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-caboxylate is reacted with formamide in the presence of sodium alkoxide in N-methylpyrrolidone to produce 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide. In fourth step, the 5-(4-tert-butoxycarbonyl-1-piperazinyl)benzofuran-2-carboxamide is then deprotected with methanolic HCl to produce the 5-(1-pipearzinyl)benzofuran-2-carboxamide.