Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([CH2:7][CH2:8][NH2:9])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Cl[C:11]1[N:16]=[CH:15][C:14]2[C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[O:18][CH:19]([CH2:20][CH3:21])[C:13]=2[C:12]=1[Cl:33].O1CCOC[CH2:35]1>>[Cl:33][C:12]1[C:13]2[CH:19]([CH2:20][CH2:21][CH3:35])[O:18][C:17](=[C:22]3[C:30]4[C:25](=[CH:26][CH:27]=[C:28]([F:31])[CH:29]=4)[NH:24][C:23]3=[O:32])[C:14]=2[CH:15]=[N:16][C:11]=1[NH:9][CH2:8][CH2:7][N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1
Reactant: C1COCCO1
Reactant: CCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(Cl)c(Cl)c21
Reactant: NCCN1CCOCC1
Product: CCCC1OC(=C2C(=O)Nc3ccc(F)cc32)c2cnc(NCCN3CCOCC3)c(Cl)c21
Temperature: 100 °C
Yield: 24 %

Procedure:
A solution of 2-morpholin-4-yl-ethylamine (320 mg, 2.45 mmol) in 3 mL of dioxane is treated with 3-(6,7-dichloro-1-ethyl-1H-furo[3,4-c]pyridin-3-ylidene)-5-fluoro-1,3-dihydro-indol-2-one (100 mg, 0.26 mmol) in one portion and the reaction mixture is heated to 100° C. overnight. The reaction mixture is concentrated and the residue is purified by chromatography (silica gel, 5% MeOH/EtOAc). The product containing fractions are concentrated to give the title compound as a yellow solid (29 mg, 24%).
Reaction SMILES: [C:1](O)(=O)C.FC(F)(F)C(O)=O.[CH3:12][O:13][C:14]1[CH:15]=[C:16]([CH2:22][CH2:23][NH2:24])[CH:17]=[CH:18][C:19]=1[O:20][CH3:21].C1N2CN3CN(C2)CN1C3>O>[CH3:12][O:13][C:14]1[CH:15]=[C:16]2[C:17](=[CH:18][C:19]=1[O:20][CH3:21])[CH:1]=[N:24][CH2:23][CH2:22]2
Reactant: COc1ccc(CCN)cc1OC
Reactant: CC(=O)O
Agent: C1N2CN3CN1CN(C2)C3
Solvent: O=C(O)C(F)(F)F
Solvent: O
Product: COc1cc2c(cc1OC)CCN=C2
Yield: 95 %

Procedure:
Acetic acid/trifluoroacetic acid (100 mL) was added to a solution of 2-(3,4-dimethoxyphenyl)ethanamine (20 g, 110.38 mmol, 1.00 equiv) and hexamethylenetetramine (31 g, 221.11 mmol, 2.00 equiv). The resulting solution was heated at reflux for about 5 hours in an oil bath. After adding water (100 mL), the solution was extracted with dichloromethane (3×200 mL), and the organic layers were combined and dried over anhydrous sodium sulfate. Solids were removed by filtration, and the resulting filtrate was concentrated in vacuo to give the title product as a yellow oil (20 g, yield=95%). LC-MS: m/z=192 (MH)+.
Reaction SMILES: C(N(C(C)C)CC)(C)C.[CH3:10][O:11][CH2:12][C:13](Cl)=[O:14].[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][NH:38][CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:24])=[O:23])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl>[C:16]1([S:22]([N:25]2[C:29]3=[N:30][CH:31]=[C:32]([NH:41][C:42](=[O:50])[CH2:43][C:44]4[C:45]([CH3:49])=[N:46][O:47][CH:48]=4)[C:33]([NH:34][CH:35]4[CH2:40][CH2:39][N:38]([C:13](=[O:14])[CH2:12][O:11][CH3:10])[CH2:37][CH2:36]4)=[C:28]3[CH:27]=[CH:26]2)(=[O:23])=[O:24])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: Cc1nocc1CC(=O)Nc1cnc2c(ccn2S(=O)(=O)c2ccccc2)c1NC1CCNCC1
Reactant: COCC(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COCC(=O)N1CCC(Nc2c(NC(=O)Cc3conc3C)cnc3c2ccn3S(=O)(=O)c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Diisopropylethylamine (0.107 ml, 0.615 mmol) and methoxyacetyl chloride (0.028 ml, 0.308 mmol) were added sequentially to a solution of N-[1-benzenesulfonyl-4-(piperidin-4-ylamino)-1H-pyrrolo[2,3-b]pyridin-5-yl]-2-(3-methyl-isoxazol-4-yl)-acetamide (hydrochloride salt) (0.205 mmol) in CH2Cl2 (2 ml) at 25° C. The reaction mixture was stirred for 3 h at 25° C., then was partitioned between saturated NaHCO3 (6 ml) and CH2Cl2 (2 ml). The phases were separated using a phase separation column (Biotage) and the organic layer was concentrated under reduced pressure to give crude N-{1-benzenesulfonyl-4-[1-(2-methoxy-acetyl)-piperidin-4-ylamino]-1H-pyrrolo[2,3-b]pyridin-5-yl}-2-(3-methyl-isoxazol-4-yl)-acetamide as a brown oil/solid. LCMS (Method G, ESI): RT=0.73 min, m+H=567.3. This material was used in the next step below without additional purification or characterization.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]2[S:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]=12.[NH2:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1>CN1C(=O)CCC1.O.C(Cl)Cl>[Cl:8][C:6]1[N:5]=[C:4]2[S:9][CH:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:3]2=[C:2]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:7]=1
Reactant: Clc1cc(Cl)c2c(-c3ccccc3)csc2n1
Reactant: NCc1ccccn1
Solvent: CN1CCCC1=O
Solvent: ClCCl
Solvent: O
Product: Clc1cc(NCc2ccccn2)c2c(-c3ccccc3)csc2n1
Temperature: 200 °C

Procedure:
A mixture of 4,6-dichloro-3-phenyl-thieno[2,3-b]pyridine (400 mg, 1.43 mmol) and 2-aminomethylpyridine (294 μl, 1.86 mmol) in NMP (1 ml) were heated in the microwave at 200° C. for 1 h. The reaction was diluted with water (30 ml) and DCM (30 ml). The DCM layer was separated and washed with water (6×50 ml), dried (Na2SO4), and concentrated. The residue was columned on silica, eluting (EtOAc/Hexane 0-100%). The first isolated fraction gave (6-chloro-3-phenyl-thieno[2,3-b]pyridin-4-yl)-pyridin-2-ylmethyl-amine (19) as colourless crystals. Yield=288 mg (57.3%). The second isolated fraction gave (4-Chloro-3-phenyl-thieno[2,3-b]pyridin-6-yl)-pyridin-2-ylmethyl-amine (20) as an orange oil. Yield=24 mg (4.7%).
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([OH:21])=[C:8]([CH2:18][CH:19]=[CH2:20])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1.CC1C2C(OCC=C)=CC=C(C(C3SC=CC=3)=O)C=2OC=1.[H][H]>C(O)C.[Pd]>[CH3:1][C:2]1[C:6]2[C:7]([OH:21])=[C:8]([CH2:18][CH2:19][CH3:20])[CH:9]=[C:10]([C:11]([C:13]3[S:14][CH:15]=[CH:16][CH:17]=3)=[O:12])[C:5]=2[O:4][CH:3]=1
Reactant: [H][H]
Reactant: C=CCc1cc(C(=O)c2cccs2)c2occ(C)c2c1O
Agent: [Pd]
Agent: C=CCOc1ccc(C(=O)c2cccs2)c2occ(C)c12
Solvent: CCO
Product: CCCc1cc(C(=O)c2cccs2)c2occ(C)c2c1O

Procedure:
A mixture of 3-methyl-4-hydroxy-5-(2-propen-1-yl)-7-(2-thienoyl)benzofuran, compound 4 (0.228 g, 0.76 mmol) and 5% Pd/C (0.020 g) in absolute ethanol (5 mL) was hydrogenated at 3 atmospheres pressure. After 0.5 hours the requisite amount of hydrogen had been taken up. The catalyst was removed by filtration through celite and the filtrate concentrated to an oil that slowly solidified. Recrystallization of this material from ether/hexane afforded pure 3-methyl-4-hydroxy-5-propyl-7-(2-thienoyl)benzofuran, compound 5 as an off white solid. 1H NMR d 0.98 (3H, t, J=8 Hz), 1.67 (2H, m), 2.40 (3H, s), 2.64 (2H, t, J=6 Hz), 7.14 (1H, m), 7.30 (1H, s), 7.48 (1H, s), 7.63 (1H, d, J=4 Hz), 7.68 (1H, d, J= 4 Hz).
Reaction SMILES: [N:1]1([C:6]2[CH:27]=[CH:26][C:9]([CH2:10][C:11]3[C:12]([CH:23]4[CH2:25][CH2:24]4)=[CH:13][C:14]([CH:21]=O)=[C:15]([CH:20]=3)[C:16](OC)=[O:17])=[CH:8][CH:7]=2)[CH:5]=[CH:4][CH:3]=[N:2]1.Cl.[NH2:29][C@@H:30]1[CH2:34][CH2:33][CH2:32][C@H:31]1[OH:35].C(N(CC)CC)C.S([O-])([O-])(=O)=O.[Mg+2]>C1COCC1>[CH:23]1([C:12]2[CH:13]=[C:14]3[C:15](=[CH:20][C:11]=2[CH2:10][C:9]2[CH:26]=[CH:27][C:6]([N:1]4[CH:5]=[CH:4][CH:3]=[N:2]4)=[CH:7][CH:8]=2)[C:16](=[O:17])[N:29]([C@@H:30]2[CH2:34][CH2:33][CH2:32][C@H:31]2[OH:35])[CH2:21]3)[CH2:24][CH2:25]1
Reactant: N[C@@H]1CCC[C@H]1O
Reactant: COC(=O)c1cc(Cc2ccc(-n3cccn3)cc2)c(C2CC2)cc1C=O
Agent: Cl
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C1c2cc(Cc3ccc(-n4cccn4)cc3)c(C3CC3)cc2CN1[C@@H]1CCC[C@H]1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 49.9 %

Procedure:
A solution of methyl 5-(4-(1H-pyrazol-1-yl)benzyl)-4-cyclopropyl-2-formylbenzoate (0.11 g), trans-2-aminocyclopentanol hydrochloride (0.04 g), triethylamine (0.04 mL) and anhydrous magnesium sulfate (0.07 g) in THF (2.20 mL) was stirred at room temperature for 5 hr. The insoluble substance was removed by filtration, and the filtrate was concentrated under reduced pressure. The residue was diluted with methanol (2.20 mL) and THF (2.20 mL), sodium triacetoxyborohydride (0.13 g) was added thereto, and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, and the mixture was washed with water and saturated brine. The organic layer was dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (0.06 g).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=1.[OH:11][C:12]1[CH:19]=[CH:18][C:15]([CH:16]=[O:17])=[CH:14][CH:13]=1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH:16]([C:15]1[CH:18]=[CH:19][C:12]([O:11][C:2]2[CH:10]=[CH:9][C:5]([C:6]([NH2:8])=[O:7])=[CH:4][N:3]=2)=[CH:13][CH:14]=1)=[O:17]
Reactant: NC(=O)c1ccc(Cl)nc1
Reactant: O=Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 130 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
Combine 6-chloronicotinamide (4.53 g, 28.9 mmol), 4-hydroxybenzaldehyde (3.5 g, 28.9 mmol), potassium carbonate (6 g, 43.4 mmol), and dimethylformamide (200 mL). Heat the reaction mixture to 130° C. under nitrogen, and stir for 18 h. Dilute the reaction mixture with 200 mL of water, extract with diethyl ether (4×100 mL) and dichloroethane (2×100 mL). Combine the organics, and dry over magnesium sulfate. Filter, and concentrate in vacuo. Adsorb the residue on silica, and purify by Biotage Flash 40L (elute with 50:50 hexanes/ethyl acetate to 100% ethyl acetate) to afford the title compound as a white solid (3.2 g, 46%): 1H NMR (DMSO-d6): 10.0 (s, 1H), 8.59 (d, 1H), 8.26-8.22 (dd, 1H), 7.98-7.95 (m, 2H), 7.10-7.07 (d, 1H), 6.15-5.65 (br m, 2H).
Reaction SMILES: [CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([OH:21])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:31]([CH:32]([CH3:34])[CH3:33])=[CH:30][CH:29]=[CH:28][C:27]=2[CH:35]([CH3:37])[CH3:36])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].[I-].[K+].I[CH2:48][CH2:49][CH3:50]>CN(C=O)C.O>[CH2:1]([N:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][N:13]=2)[C:8]([C:15]2[CH:20]=[CH:19][CH:18]=[C:17]([O:21][CH2:48][CH2:49][CH3:50])[CH:16]=2)=[C:7]([NH:22][C:23]([NH:25][C:26]2[C:27]([CH:35]([CH3:37])[CH3:36])=[CH:28][CH:29]=[CH:30][C:31]=2[CH:32]([CH3:33])[CH3:34])=[O:24])[C:6]1=[O:38])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(O)c2)c2cccnc21
Reactant: CCCI
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCn1c(=O)c(NC(=O)Nc2c(C(C)C)cccc2C(C)C)c(-c2cccc(OCCC)c2)c2cccnc21
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a suspension of N-{1-butyl-4-(3-hydroxyphenyl)-1,2-dihydro-2-oxo-1,8-naphthyridin-3-yl }-N'-(2,6-diisopropylphenyl)urea (300 mg, 0.58 mmol), potassium carbonate (96 mg, 0.7 mmol) and potassium iodide (19 mg) in DMF (5 ml) was added 1-iodopropane (99 mg, 0.58 mmol) at room temperature, and the mixture was stirred at 40°-50° C. for five hours. After allowed to stand for cooling, the mixture was poured into water, and the mixture was extracted with ethyl acetate. The extracted was washed with water, washed with a saturated aqueous sodium chloride solution, and dried over anhydrous magnesium sulfate. The resultant was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (20% ethyl acetate in hexane), and crystallized from ether/hexane to give the title compound (253 mg, 0.48 mmol).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH2:13][CH2:14][N:15]1[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1)[N:8]=[CH:7]2)([O-])=O.[Cl-].[NH4+]>[Fe].C(O)C.O>[N:15]1([CH2:14][CH2:13][N:9]2[C:10]3[C:6](=[CH:5][C:4]([NH2:1])=[CH:12][CH:11]=3)[CH:7]=[N:8]2)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: O=[N+]([O-])c1ccc2c(cnn2CCN2CCCCC2)c1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCO
Product: Nc1ccc2c(cnn2CCN2CCCCC2)c1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 87 %

Procedure:
A mixture of 5-nitro-1-(2-piperidin-1-yl-ethyl)-1H-indazole (4.3 g, 16 mmol), iron powder (8.8 g, 157 mmol), and ammonium chloride (430 mg, 8 mmol) in a 4:1 ethanol/H2O solution (75 mL) was heated to reflux for 3 hours, cooled to room temperature and concentrated under reduced pressure. The residue was stirred in triethylamine/ethyl acetate (1/4, 50 mL) for 15 minutes, filtered through a plug of silica gel which was rinsed with triethylamine/ethyl acetate (1/4). The filtrate was concentrated under reduced pressure to provide the title compound (3.4 g, 93%). 1H NMR (300 MHz, DMSO-d6) ppm 1.34–1.45 (m, 6H), 2.36 (m, 4H), 2.64 (t, J=6.44, 2H), 4.35 (t, J=6.44, 2H), 4.76 (s, 2H), 6.71 (m, 1H), 6.79 (m, 11H), 7.35 (m, 1H), 7.67 (m, 1H); MS (DCI/NH3) m/z 245 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5](Br)[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH2:26]C)[CH:20]=[CH:21][CH:22]=1.C[O-:32].[Na+]>CO>[NH2:1][C:2]1[N:10]=[C:9]([O:11][CH2:12][CH2:13][CH2:14][CH3:15])[N:8]=[C:7]2[C:3]=1[N:4]=[C:5]([OH:32])[N:6]2[CH2:16][C:17]1[CH:18]=[C:19]([CH2:23][P:24]([CH3:29])(=[O:28])[O:25][CH3:26])[CH:20]=[CH:21][CH:22]=1
Reactant: C[O-]
Reactant: CCCCOc1nc(N)c2nc(Br)n(Cc3cccc(CP(C)(=O)OCC)c3)c2n1
Agent: [Na+]
Solvent: CO
Product: CCCCOc1nc(N)c2nc(O)n(Cc3cccc(CP(C)(=O)OC)c3)c2n1
Temperature: 70 °C
Reaction time: 16 h

Procedure:
To a solution of 69 (130.4, 0.26 mmol) in methanol (10 mL) was slowly added sodium methoxide (283.8 mg, 5.25 mmol). The mixture was heated to 70° C. for 3 hours at which time Dowex resin was added to quench any remaining methoxide. The resin was filtered off and the solvent evaporated. The product was stirred in 6N HCl over night (16 hr) after which time the solvent was evaporated to give 70 as a white solid, the crude product was carried through to the next step. LCMS: m/z for C20H28N5O4P++H observed 420.2 at 1.92 minutes of a 3.5 minute run, eluting 5-95% CH3CN in H2O.
Reaction SMILES: C[O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]2[CH:18]=[C:17]([C:19]3[S:20][C:21]([Cl:24])=[CH:22][CH:23]=3)[O:16][N:15]=2)[C:7]([CH2:10][O:11][CH3:12])=[N:8][CH:9]=1)=[O:4].O.[OH-].[Li+]>C1COCC1.O>[Cl:24][C:21]1[S:20][C:19]([C:17]2[O:16][N:15]=[C:14]([CH2:13][N:6]3[C:5]([C:3]([OH:4])=[O:2])=[CH:9][N:8]=[C:7]3[CH2:10][O:11][CH3:12])[CH:18]=2)=[CH:23][CH:22]=1
Reactant: COCc1ncc(C(=O)OC)n1Cc1cc(-c2ccc(Cl)s2)on1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: COCc1ncc(C(=O)O)n1Cc1cc(-c2ccc(Cl)s2)on1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
To a solution of 400 mg 3-[5-(5-Chloro-thiophen-2-yl)-isoxazol-3-ylmethyl]-2-methoxymethyl-3H-imidazole-4-carboxylic acid methyl ester in 5 ml THF and 1 ml water, 10.0 mg lithium hydroxide monohydrate were added. After stirring for 2 h at 60° C. the reaction was cooled to RT and concentrated under reduced pressure. The residue was acidified with half concentrated hydrochloric acid and filtered through a RP-18 cartridge eluting with H2O/MeCN gradient. The fractions containing the product were evaporated and lyophilized to yield a white solid.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1C=O.C(OP([CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])[CH3:17])(=O)OCC)C.[CH3:26][O-].[Na+]>CN(C)C=O>[S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[CH:16]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[C:24]#[N:25])[CH:17]=[CH2:26]
Reactant: C[O-]
Reactant: CCOP(=O)(OCC)C(C)c1ccccc1C#N
Reactant: O=Cc1cccs1
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CC(c1cccs1)c1ccccc1C#N
Reaction time: 1 h

Procedure:
A solution of 73.0 g of 2-thiophenaldehyde and 170 g of diethyl-1-(o-cyanophenyl)ethylphosphonate in 800 ml of anhydrous dimethyl formamide was added dropwise in a nitrogen atmosphere at 20°-30°to a suspension of 39.0 g of sodium methylate in 500 ml of anhydrous dimethyl formamide. The mixture was further stirred for 1 hour at 40°, cooled to 10°-15° and treated with ca. 5 1 of icewater. Working up gave 2-[1-(2-thienyl)-2-propenyl]benzonitrile, B.Pt. (0.1 to 0.2 mm Hg) = 200°-210° .
Reaction SMILES: [Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH:29]C(=O)C(F)(F)F)[CH2:21][CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(=O)([O-])[O-].[K+].[K+]>O.CCOC(C)=O>[Si:1]([O:18][C@H:19]1[C:28]2[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=2)[C@H:22]([NH2:29])[CH2:21][CH2:20]1)([C:14]([CH3:16])([CH3:17])[CH3:15])([C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[Si](O[C@@H]1CC[C@@H](NC(=O)C(F)(F)F)c2ccccc21)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)[Si](O[C@@H]1CC[C@@H](N)c2ccccc21)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.2 %

Procedure:
To a 250 ml round bottom flask containing 4 g (8.0 mmol) of N-((1R,4R)-4-(tert-butyldiphenylsilyloxy)-1,2,3,4-tetrahydronaphthalen-1-yl)-2,2,2-trifluoroacetamide was added 160 ml of MeOH. To this solution was added a solution of 8.34 g (60 mmol) potassium carbonate in 16 ml of water. The reaction mixture was stirred at room temp overnight. The reaction mixture was diluted with 150 ml EtOAc, and after separation, the aqueous phase was extracted several times with EtOAc. The organic phase was dried over MgSO4 and concentrated in vacuo to afford 3.09 g (96%) of the title compound, whose purity was good enough to use crude. (Note: On separate occasion, this hydrolysis became sluggish, and 30 ml of 3M NaOH was added, upon which the reaction was completed in a few hours.)
Reaction SMILES: [C:1]1([CH:8]=[CH:7][CH:6]=[C:4]([OH:5])[CH:3]=1)[OH:2].[CH2:9]([O:13][C:14](=[O:28])[CH:15](OC(=O)C)[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][CH3:12].B(F)(F)F.CCOCC>C(Cl)Cl>[CH2:9]([O:13][C:14](=[O:28])[CH:15]([C:6]1[CH:7]=[CH:8][C:1]([OH:2])=[CH:3][C:4]=1[OH:5])[NH:16][C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:10][CH2:11][CH3:12]
Reactant: Oc1cccc(O)c1
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)OC(C)=O
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a stirred mixture of 11.0 g. (0.1 mol.) of resorcinol and 24.7 g. (0.085 mol.) of N-t-butoxycarbonyl-2-acetoxyglycine n-butyl ester in 250 ml. of methylene chloride at 0° was added 1 ml. of boron trifluoride etherate. The reaction mixture was allowed to warm to room temperature during a 30 minute period, then it was stirred for an additional 3 hours. The reaction mixture was washed five times with equal volumes of water, dried (Na2SO4) and concentrated in vacuo to give N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[NH2:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]2[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]2)=[CH:14][CH:13]=1>>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([N:18]3[CH2:22][CH2:21][CH:20]([N:23]([CH3:25])[CH3:24])[CH2:19]3)=[CH:14][CH:13]=2)=[O:8])=[CH:4][N:3]=1
Reactant: O=C(O)c1ccc(Cl)nc1
Reactant: CN(C)C1CCN(c2ccc(N)cc2)C1
Product: CN(C)C1CCN(c2ccc(NC(=O)c3ccc(Cl)nc3)cc2)C1

Procedure:
6-Chloronicotinic acid was reacted with [1-(4-amino-phenyl)pyrrolidin-3-yl]dimethylamine by method E-b. This resulted in the product with the molecular weight of 344.14 (C18H21CIN4O); MS (ESI): 345 (M+H+) as hydrotrifluoroacetate.
Reaction SMILES: [CH:1]1[C:15](=[O:16])[N:14]=C2[N:3]([C@@H:4]3[O:8][C@H:7]([CH2:9][OH:10])[C@@H:6]([OH:11])[C@@H:5]3O2)[CH:2]=1.[CH3:17][SH:18].[CH3:19]N(C)C(N(C)C)=N>CN(C=O)C>[CH3:19][C@@H:5]1[C@H:6]([OH:11])[C@@H:7]([CH2:9][OH:10])[O:8][C@H:4]1[N:3]1[CH:2]=[CH:1][C:15](=[O:16])[NH:14][C:17]1=[S:18]
Reactant: CS
Reactant: O=c1ccn2c(n1)O[C@H]1[C@H](O)[C@@H](CO)O[C@H]12
Reactant: CN(C)C(=N)N(C)C
Solvent: CN(C)C=O
Product: C[C@@H]1[C@H](O)[C@@H](CO)O[C@H]1n1ccc(=O)[nH]c1=S
Reaction time: 12 h
Yield: 80.1 %

Procedure:
2,2'Anhydrouridine (15.5 g, 68.2 mmol) [Rao and Reese, J. Chem. Soc., Chem. Commun., 997], methanethiol (15.7 g, 327 mmol), 1,1,3,3-tetramethylguanidine (39.2 g, 341 mmol) and DMF (150 mL) were heated at 60° C. After 12 hours, the reaction mixture was cooled and concentrated under reduced pressure. The residual oil was purified by flash column chromatography on silica gel (300 g). Concentration of the appropriate fractions, which were eluted with CH2Cl2 --MeOH (9:1), and drying the residue under reduced pressure gave 2'-deoxy-2'-methylthiouridine as a pale yellow solid (14.11 g, 75.4%). Attempts to crystallize the solids from EtOH-hexanes [as reported by Imazawa et al., Chem. Pharm. Bull., 23, 604 (1975)] failed and the material turned into a hygroscopic foam.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3.[C:18]([NH:28][C:29]([CH3:34])([C:31](O)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19].CCN=C=NCCCN(C)C.Cl>CN(C)C=O.N1C=CC=CC=1>[C:18]([NH:28][C:29]([CH3:34])([C:31]([NH:1][CH2:2][CH:3]1[O:17][C:6]2=[C:7]3[C:12](=[C:13]([CH3:15])[CH:14]=[C:5]2[CH2:4]1)[NH:11][C:10](=[O:16])[CH:9]=[CH:8]3)=[O:32])[CH3:30])([O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:19]
Reactant: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CN)C2
Reactant: CC(C)(NC(=O)OCc1ccccc1)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1cc2c(c3ccc(=O)[nH]c13)OC(CNC(=O)C(C)(C)NC(=O)OCc1ccccc1)C2
Temperature: 50 °C
Reaction time: 48 h
Yield: 43.6 %

Procedure:
2-Aminomethyl-5-methyl-2,3,6,7-tetrahydrofuro-[2,3-f]quinoline-7-one (3.00 g, 13.0 mmol) was dissolved in a solvent mixture of dimethylformamide (200 ml) and pyridine (100 ml). To this solution, N-carbobenzyloxy-α-methylalanine (4.64 g, 19.5 mmol) and WSC-HCl (3.48 g, 19.5 mmol) were added and the mixture was stirred at 50° C. for 48 hours. The reaction mixture was condensed under reduced pressure, and the residue was subjected to extraction using a solvent mixture (chloroform--methanol =4:1) combined with 1N-HCl. The organic phase was washed with saturated aqueous NaCl solution, followed by drying and condensing under reduced pressure. The resultant residue was purified by silica gel column chromatography (chloroform: methanol=25:1). The crude crystals were subjected to a recrystallizing procedure from chloroform--methanol. As a result, 2.55 g of the title compound was obtained as colorless powdery crystals (43.7%).
Reaction SMILES: [CH3:1][O:2][CH:3](O)[CH2:4][CH3:5].[H-].[Na+].Cl[C:10]1[C:15]([CH3:16])=[CH:14][N+:13]([O-:17])=[C:12]([CH3:18])[C:11]=1[CH3:19].CS(C)=[O:22]>>[CH3:1][O:2][CH2:3][CH2:4][CH2:5][O:22][C:10]1[C:15]([CH3:16])=[CH:14][N+:13]([O-:17])=[C:12]([CH3:18])[C:11]=1[CH3:19]
Reactant: CS(C)=O
Reactant: Cc1c[n+]([O-])c(C)c(C)c1Cl
Reactant: CCC(O)OC
Agent: [H-]
Agent: [Na+]
Product: COCCCOc1c(C)c[n+]([O-])c(C)c1C
Temperature: 60 °C
Reaction time: 1 h

Procedure:
4.5 g (0.05 mol) of methoxypropanol was dissolved in 45 ml of dimethyl sulfoxide to obtain a solution. 2.0 g of 60% sodium hydride was added to this solution at a room temperature in a nitrogen atmosphere. The obtained mixture was heated to 60° C. and stirred for one hour. After the completion of the reaction, a solution of 4.3 g (0.025 mol) of 4-chloro-2,3,5-trimethylpyridine 1-oxide in 15 ml of dimethyl sulfoxide was dropwise added to the reaction mixture at a room temperature. The obtained mixture was stirred at 60° C. for 5 hours, cooled and distilled to dryness to remove the solvent. 200 ml of water was added to the obtained residue. The obtained mixture was extracted with 150 ml of chloroform five times. The extract was dried over magnesium sulfate and filtered. The filtrate was distilled to remove the solvent. The residue was purified by silica gel column chromatography (ethyl acetate/n-hexane) to obtain 4.27 g of the title compound as an oil.