Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH3:30])[C:5]([CH2:8][N:9]([CH2:19][C:20]2[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[CH:22][C:21]=2[CH2:28][OH:29])[C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[N:6][CH:7]=1.[Li+].[BH4-].[OH-].[Na+].C(Cl)Cl>C1COCC1>[NH2:25][CH2:24][C:23]1[CH:26]=[CH:27][C:20]([CH2:19][N:9]([CH2:8][C:5]2[C:4]([CH3:30])=[CH:3][C:2]([Cl:1])=[CH:7][N:6]=2)[C:10]([CH3:18])([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH3:11])=[C:21]([CH2:28][OH:29])[CH:22]=1
Reactant: Cc1cc(Cl)cnc1CN(Cc1ccc(C#N)cc1CO)C(C)(C)c1ccccn1
Agent: [BH4-]
Agent: [Li+]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cc(Cl)cnc1CN(Cc1ccc(CN)cc1CO)C(C)(C)c1ccccn1
Temperature: 70 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
To a solution of 4-{[(5-chloro-3-methyl-pyridin-2-ylmethyl)-(1-methyl-1-pyridin-2-yl-ethyl)-amino]-methyl}-3-hydroxymethyl-benzonitrile (0.5371 g, 1.2 mmol) in THF (12 mL) at 0° C. was added LiBH4 (0.2086 g, 9.6 mmol), then heated to 70° C. and stirred for 18 hours. 1N NaOH (25 mL) and CH2Cl2 (50 mL) were added and stirred for 10 minutes. The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×50 mL). The combined organic extracts were dried (Na2SO4), filtered, and concentrated. Purification of the crude material by column chromatography on silica gel (75:1:1 CH2Cl2-MeOH—NH4OH) provided 0.2330 g (48%) of COMPOUND 402 as a white solid. 1H NMR (CDCl3) δ 1.61 (s, 5H), 2.07 (s, 6H), 3.69 (s, 2H), 3.73 (s, 2H), 3.91 (s, 2H), 4.55 (s, 2H), 6.69-6.78 (bs, 1H), 6.94-6.97 (m, 1H), 7.02-7.08 (m, 3H), 7.21 (d, 1H, J=1.5 Hz), 7.49-7.55 (m, 1H), 7.77 (d, 1H, J=8.1 Hz), 8.05 (d, 1H, J=2.1 Hz), 8.45-8.48 (m, 1H). 13C NMR (CDCl3) δ 18.71, 24.43, 46.39, 51.43, 53.95, 63.49, 64.78, 122.10, 123.09, 126.25, 129.32, 130.26, 131.30, 132.25, 136.21, 137.16, 137.26, 141.33, 143.29, 144.59, 147.94, 156.80, 165.90. ES-MS m/z 425.4 (M+H). Anal. Calcd. for C24H29N4ClO.0.3H2O: C, 66.98; H, 6.93; N, 13.02; Cl, 8.24. Found: C, 67.11; H, 6.54; N, 12.13; Cl, 8.99.
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][NH:8][C:7]1=[O:21])=[O:5])[CH3:2].F[B-](F)(F)F.[CH3:27][O+](C)C.C(=O)([O-])[O-].[K+].[K+].O>C(Cl)(Cl)Cl>[CH3:27][O:21][C:7]1[CH:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])[CH2:11][C@H:10]([CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=2)[CH2:9][N:8]=1
Reactant: C[O+](C)C
Reactant: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CNC1=O
Agent: F[B-](F)(F)F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: O
Product: CCOC(=O)C1C[C@H](CCc2ccc(Br)cc2)CN=C1OC
Temperature: 25 °C
Yield: 53.4 %

Procedure:
A solution of 515 mg of the product of Example 4 and 236 mg of trimethyloxonium tetrafluoroborate in 3 ml of chloroform was heated under reflux for four hours. The mixture was then cooled to ambient temperature, and 2 ml of 50% aqueous potassium carbonate was added. Then 10 ml of water and 10 ml of chloroform were added, and the organic phase, containing solids, was dried with magnesium sulfate. The solids were removed by filtration, and the supernatant was concentrated under vacuum. The residue was purified by spinning plate thin layer chromatography on a 2 mm silica gel plate, with 1:1 ethyl acetate:hexane, to obtain 286 mg of (3RS,5S)-2-methoxy-3-ethoxycarbonyl-5-[2-(4-bromophenyl)ethyl]-3,4,5,6-tetrahydropyridine, as a 1:1 mixture of the 3-position diastereomers.
Reaction SMILES: C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CC(OC(/N=N/C(OC(C)C)=O)=O)C.[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37]O.[N+:40]([C:43]1[CH:44]=[CH:45][C:46]([NH:49][CH2:50][CH2:51][NH:52][S:53]([C:56]2[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=2[N+:62]([O-:64])=[O:63])(=[O:55])=[O:54])=[N:47][CH:48]=1)([O-:42])=[O:41]>C(Cl)Cl>[CH3:34][N:35]([CH3:39])[CH2:36][CH2:37][N:52]([CH2:51][CH2:50][NH:49][C:46]1[CH:45]=[CH:44][C:43]([N+:40]([O-:42])=[O:41])=[CH:48][N:47]=1)[S:53]([C:56]1[CH:61]=[CH:60][CH:59]=[CH:58][C:57]=1[N+:62]([O-:64])=[O:63])(=[O:55])=[O:54]
Reactant: O=[N+]([O-])c1ccc(NCCNS(=O)(=O)c2ccccc2[N+](=O)[O-])nc1
Reactant: CN(C)CCO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CN(C)CCN(CCNc1ccc([N+](=O)[O-])cn1)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 23 °C
Reaction time: 12 h

Procedure:
To a solution of Ph3P (11 g, 42 mmol) and CH2Cl2 (20 mL) at 23° C. was added DIAD (6.6 mL, 42 mmol) and the resulting yellow solution was maintained at 23° C. for 30 min. To this solution was added 2-(dimethylamino)-ethanol (4.2 mL, 42 mmol) and the resulting solution was maintained at 23° C. for 5 min. then added to a suspension of resin-bound {2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine (3.0 g, 2.1 mmol) and CH2Cl2 (30 mL). The resulting mixture was shaken at 23° C. for 12 h, filtered, washed with NMP, H2O and CH2Cl2 and air dried to yield polymer-bound [2-(dimethylamino)ethyl]{2-[(5-nitro(2-pyridyl))amino]ethyl}[(2-nitrophenyl)sulfonyl]amine.
Reaction SMILES: [NH2:1][CH:2]1[C:22](=[O:23])[N:4]2[C:5]([C:9]([O:11][CH2:12][C:13]3[CH:18]=[CH:17][C:16]([N+:19]([O-:21])=[O:20])=[CH:15][CH:14]=3)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]12.C[Si](CC(N)=O)(C)C.[F:32][C:33]([F:57])([F:56])[C:34]([NH:36][C:37]1[S:38][CH:39]=[C:40]([C:42](=NOCC2C=CC(C)=CC=2)[C:43](O)=[O:44])[N:41]=1)=[O:35].P(Cl)(Cl)(Cl)=O>O1CCCC1.CN(C)C=O>[F:57][C:33]([F:32])([F:56])[C:34]([NH:36][C:37]1[S:38][CH:39]=[C:40]([CH2:42][C:43]([NH:1][CH:2]2[C:22](=[O:23])[N:4]3[C:5]([C:9]([O:11][CH2:12][C:13]4[CH:14]=[CH:15][C:16]([N+:19]([O-:21])=[O:20])=[CH:17][CH:18]=4)=[O:10])=[CH:6][CH2:7][S:8][C@H:3]23)=[O:44])[N:41]=1)=[O:35]
Reactant: Cc1ccc(CON=C(C(=O)O)c2csc(NC(=O)C(F)(F)F)n2)cc1
Reactant: NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Agent: C[Si](C)(C)CC(N)=O
Solvent: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cc1csc(NC(=O)C(F)(F)F)n1)NC1C(=O)N2C(C(=O)OCc3ccc([N+](=O)[O-])cc3)=CCS[C@H]12
Yield: 129.4 %

Procedure:
A solution of 4-nitrobenzyl 7-amino-3-cephem-4-carboxylate (2.01 g.), trimethylsilylacetamide (5.51 g.) and tetrahydrofuran (40 ml.) and a solution of 2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-2-(4-methylbenzyloxyimino)acetic acid (syn isomer, 2.32 g.), phosphoryl chloride (1.20 g.) and N,N-dimethylformamide (570 mg.) in tetrahydrofuran (12 ml.) were treated in a similar manner to that of Example of Example 1-(1) to give 4-nitrobenzyl 7-[2-[2-(2,2,2-trifluoroacetamido)thiazol-4-yl]-acetamido]-3-cephem-4-carboxylate (syn isomer, 4.43 g.).
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]2[CH2:20][CH2:19][N:18]([CH:21]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:22]3=[O:34])[CH2:17][CH:16]2[OH:35])=[CH:11][CH:10]=1)C1C=CC=CC=1.[H][H]>[Pd].CO>[F:33][C:30]1[CH:31]=[CH:32][C:27]([CH2:26][N:23]2[CH2:24][CH2:25][CH:21]([N:18]3[CH2:19][CH2:20][C@H:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[CH:10][CH:11]=4)[C@H:16]([OH:35])[CH2:17]3)[C:22]2=[O:34])=[CH:28][CH:29]=1
Reactant: O=C1C(N2CCC(c3ccc(OCc4ccccc4)cc3)C(O)C2)CCN1Cc1ccc(F)cc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: O=C1C(N2CC[C@H](c3ccc(O)cc3)[C@H](O)C2)CCN1Cc1ccc(F)cc1
Yield: 101.2 %

Procedure:
A mixture of 3-(4-(4-(benzyloxy)phenyl)-3-hydroxypiperidin-1-yl)-1-(4-fluorobenzyl)-pyrrolidin-2-one (D2 from step E, 85 mg, 0.18 mmol), methanol (5 mL), and 38 mg 10% Pd/C was stirred in a pressure vessel overnight under 125 psi hydrogen pressure. The catalyst was removed by filtration through Celite and the filtrate was evaporated to dryness to yield 70 mg of racemic 1-(4-fluorobenzyl)-3-(cis-3-hydroxy-4-(4-hydroxyphenyl)-piperidin-1-yl)pyrrolidin-2-one. LCMS (method J) RT=0.63 (52% AP), 0.66 (31% AP) min, m/z 385.4 (MH+); 1H NMR (400 MHz, DMSO-d6) δ ppm 7.27-7.28 (m, 2H), 7.15-7.19 (m, 2H), 7.06 (d, J=8.4, 2H), 6.45 (d, J=8.4, 2H), 4.39 (d, J=15, 1H), 4.32 (d, J=15, 1H), 3.74-3.76 (m, 1H), 3.66 (m, 1H), 3.47 (m, 1H), 3.10-3.18 (m, 2H), 3.01 (m, 1H), 2.85-2.88 (m, 1H), 2.76 (m, 1H), 2.30-2.40 (m, 1H), 2.06-2.11 (m, 2H), 1.80-1.95 (m, 1H), 1.46 (d, J=12, 1H). The complete relative stereochemistry was not determined.
Reaction SMILES: C([O:3][C:4](=[O:37])[CH:5]([O:34][CH2:35][CH3:36])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([N:20]3[CH2:25][CH2:24][N:23]([CH2:26][C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[CH2:22][CH2:21]3)[N:17]=[C:16]([NH2:33])[N:15]=2)=[CH:9][CH:8]=1)C>O1CCCC1.O.[K]>[NH2:33][C:16]1[N:15]=[C:14]([O:13][C:10]2[CH:11]=[CH:12][C:7]([CH2:6][CH:5]([O:34][CH2:35][CH3:36])[C:4]([OH:37])=[O:3])=[CH:8][CH:9]=2)[CH:19]=[C:18]([N:20]2[CH2:25][CH2:24][N:23]([CH2:26][C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:22][CH2:21]2)[N:17]=1
Reactant: CCOC(=O)C(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)OCC
Agent: [K]
Solvent: C1CCOC1
Solvent: O
Product: CCOC(Cc1ccc(Oc2cc(N3CCN(Cc4ccccc4)CC3)nc(N)n2)cc1)C(=O)O
Reaction time: 20 h

Procedure:
rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionic acid ethyl ester was dissolved in tetrahydrofuran (THF)/alcohol solvent in the presence of an excess of aqueous potassium hydrate, the reaction is allowed to proceed for about 20 h. After most of the solve was removed in vacuo, the aqueous solution was acidified to pH 6, the white product was precipitated, then filtered through celite, rac-3-{4-[2-Amino-6-(4-benzyl-piperazin-1-yl)-pyrimidin-4-yloxy]-phenyl}-2-ethoxy-propionic acid (95%) was collected.
Reaction SMILES: C([O:4][CH2:5][C:6]1[C:15]([CH3:16])=[C:14]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:25])[CH:12]=2)[N:7]=1)(=O)C.[OH-].[Na+]>C1COCC1.CO>[CH2:18]([O:17][C:14]1[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([CH3:25])[CH:12]=2)[N:7]=[C:6]([CH2:5][OH:4])[C:15]=1[CH3:16])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CC(=O)OCc1nc2ccc(C)cc2c(OCc2ccccc2)c1C
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1ccc2nc(CO)c(C)c(OCc3ccccc3)c2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 85.7 %

Procedure:
To a solution of [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methyl acetate (1.20 g) in THF-methanol (1:3, 24 mL) was added a 1M aqueous sodium hydroxide solution (5.5 mL), followed by stirring at room temperature for 3 hours. The reaction solution was concentrated under reduced pressure and water was then added to the residue. The precipitated solid was collected by filtration, washed with water, and dried to obtain [4-(benzyloxy)-3,6-dimethylquinolin-2-yl]methanol (900 mg).
Reaction SMILES: [Na].[NH2:2][C:3]1[CH:13]=[CH:12][C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][CH:4]=1.[CH2:14](O)C=C>CCCCCC>[NH2:2][C:3]1[CH:4]=[CH:5][C:6]([C:7]([O:9][CH2:10][CH:11]=[CH2:14])=[O:8])=[CH:12][CH:13]=1
Reactant: C=CCO
Reactant: CCOC(=O)c1ccc(N)cc1
Agent: [Na]
Solvent: CCCCCC
Product: C=CCOC(=O)c1ccc(N)cc1

Procedure:
50 ml of allyl alcohol are introduced into a round-bottomed flask, 750 mg (22 mmol) of sodium are added in small portions and the mixture is stirred until the metal has reacted completely. 30.2 g (0.2 mol) of ethyl 4-aminobenzoate, dissolved in 200 ml of allyl alcohol, are then introduced and the mixture is heated to reflux and distilled until 180 ml of distillate have been obtained. The reaction medium is evaporated, the residue is taken up with water and ethyl ether and the organic phase is separated after settling has taken place, dried over magnesium sulphate and evaporated. The residue obtained is ground in 200 ml of hexane and filtered off. 29 g (82%) of allyl ester, melting point 48°-50° C., are collected.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1.N1C=CC=CC=1.[CH3:18][O:19][CH2:20][CH2:21][S:22](Cl)(=[O:24])=[O:23]>C(OCC)(=O)C>[CH3:18][O:19][CH2:20][CH2:21][S:22]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH3:10])=[N:7][C:6]=2[CH:11]=1)(=[O:24])=[O:23]
Reactant: COCCS(=O)(=O)Cl
Reactant: Cc1nc2cc(N)ccc2o1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: COCCS(=O)(=O)Nc1ccc2oc(C)nc2c1
Temperature: 0 °C
Yield: 77.6 %

Procedure:
Into a 1.0 L round bottom flask equipped with mechanical stirrer, addition funnel, thermometer and nitrogen inlet tube was placed 100 grams (0.67 Mol) of 5-amino-2-methylbenzoxazole and 350 mL of pyridine. The slurry was stirred in an ice/ethanol bath at 0° C. then 110 grams (0.69 Mol) of Intermediate 1 was added dropwise so as to maintain a reaction temperature below 7° C. The reaction was stirred at 0° C. for two hours then the resulting red colored mixture was poured into 1.0 L of ethyl acetate. The slurry was stirred for 30 minutes then filtered and the collected solids were discarded. The filtrate was extracted with 4×200 mL of 10% hydrochloric acid and the organic phase was collected and dried over magnesium sulfate. The solvents were removed in vacuo to afford 140 grams (0.52 Mol, 76.7% yield) of desired product as a tan solid.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][Cl:8].[CH2:9](Br)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.CN(C=O)C>C(N(CC)CC)C>[Cl:2][CH2:3][CH2:4][N:5]([CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:6][CH2:7][Cl:8]
Reactant: BrCc1ccccc1
Reactant: ClCCNCCCl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: ClCCN(CCCl)Cc1ccccc1
Reaction time: 8 h

Procedure:
An ice bath is used to cool a mixture of 150 g of N,N-bis(2-chloroethyl)amine hydrochloride and 100 ml of benzyl bromide in 1 000 ml of DMF and then 120 ml of triethylamine are added dropwise and the mixture is left with stirring at AT overnight. The reaction mixture is concentrated under vacuum, the residue is taken up in water and extracted 3 times with ether, the organic phases are dried over Na2SO4 and the solvent is evaporated under vacuum. This gives 113 g of the expected product.
Reaction SMILES: [CH2:1]([C:3]1[N:7]([CH3:8])[C:6]2[CH:9]=[C:10]([N:13]3[CH:18]=[CH:17][C:16]([OH:19])=[CH:15][C:14]3=[O:20])[CH:11]=[CH:12][C:5]=2[N:4]=1)[CH3:2].[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28]O)=[CH:24][C:23]=1[F:30].C(P(CCCC)CCCC)CCC.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O>C1COCC1.O>[Cl:21][C:22]1[CH:27]=[CH:26][C:25]([CH2:28][O:19][C:16]2[CH:17]=[CH:18][N:13]([C:10]3[CH:11]=[CH:12][C:5]4[N:4]=[C:3]([CH2:1][CH3:2])[N:7]([CH3:8])[C:6]=4[CH:9]=3)[C:14](=[O:20])[CH:15]=2)=[CH:24][C:23]=1[F:30]
Reactant: OCc1ccc(Cl)c(F)c1
Reactant: CCc1nc2ccc(-n3ccc(O)cc3=O)cc2n1C
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Solvent: O
Product: CCc1nc2ccc(-n3ccc(OCc4ccc(Cl)c(F)c4)cc3=O)cc2n1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 34.7 %

Procedure:
To a solution of 1-(2-ethyl-1-methyl-1H-benzimidazol-6-yl)-4-hydroxypyridin-2(1H)-one (500 mg), (4-chloro-3-fluorophenyl)methanol (596 mg) and tributylphosphine (1.13 g) in THF (20 ml) was added 1,1′-(azodicarbonyl)dipiperidine (1.41 g), and the reaction mixture was stirred at 60° C. for 2 h. The reaction mixture was cooled to room temperature. The mixture was poured into water and extracted with EtOAc. The extract was washed with brine, dried over MgSO4, concentrated and purified by NH silica gel column chromatography (hexane/EtOAc then EtOAc/MeOH). The resulting solid was recrystallized from EtOH-water to give the title compound (265 mg) as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH:10]([O:13][C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:22][C:23]([O:25][CH2:26][CH3:27])=[O:24].[H-].[Na+]>O1CCCC1>[CH2:26]([O:25][C:23](=[O:24])[CH2:22][O:20][C:17]1[CH:18]=[CH:19][C:14]([O:13][CH:10]2[CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9]2)=[CH:15][CH:16]=1)[CH3:27]
Reactant: CCOC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(O)cc2)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)COc1ccc(OC2CCN(C(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 4-(1-tert-butoxycarbonylpyrrolidin-3-yloxy)phenol (2.14 g) in tetrahydrofuran (43 l) were added ethyl bromoacetate (1.1 ml) and 60% sodium hydride (368 mg) with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, ice water was added and the mixture was extracted with ethyl acetate and washed with 10% aqueous citric acid solution. The organic layer was dried over anhydrous magnesium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=7:3) and dried under reduced pressure to give the title compound (2.605 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][N:13]=[C:12](S(C)(=O)=O)[N:11]=1)=[O:9].O1[CH2:38][CH2:37]OCC1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:28]=[C:29]([O:31][CH3:32])[CH:30]=1)[CH2:6][N:7]([CH3:27])[C:8]([C:10]1[C:15]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[CH3:22])=[CH:14][N:13]=[C:12]([N:11]2[CH2:38][CH2:37][N:7]([CH3:6])[CH2:8][CH2:10]2)[N:11]=1)=[O:9]
Reactant: C1COCCO1
Reactant: COc1cc(CN(C)C(=O)c2nc(S(C)(=O)=O)ncc2-c2ccccc2C)cc(OC)c1
Product: COc1cc(CN(C)C(=O)c2nc(N3CCN(C)CC3)ncc2-c2ccccc2C)cc(OC)c1
Reaction time: 16 h
Yield: 168.2 %

Procedure:
To a solution of 0.18 g (0.4 mmol) 2-methanesulfonyl-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethoxy-benzyl)-methyl-amide in 10 ml dioxane 0.11 ml (0.99 mmol) 1-methylpiperazine was added. The reaction mixture was stirred for 16 hrs. After evaporation of the solvent, the residue was distributed between 50 ml CH2Cl2 and 50 ml H2O. The aqueous layer was extracted with 50 ml CH2Cl2, the combined organic layers dried (MgSO4), filtered and evaporated. The residue was purified by chromatography (SiO2, CH2Cl2/MeOH/NH4OH 110:10:1) to give 0.16 g (85%) 2-(4-methyl-piperazin-1-yl)-5-o-tolyl-pyrimidine-4-carboxylic acid (3,5-dimethoxy-benzyl)-methyl-amide as a colorless foam, MS (ISP): 476.3 (M+H+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([OH:9])=[O:8].[C:14](=O)([O-])[O-].[Cs+].[Cs+].CI.O>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[CH:5]=[CH:6][C:7]([O:9][CH3:14])=[O:8]
Reactant: O=C(O)C=Cc1ccc(Cl)c(Cl)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)C=Cc1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 138.5 %

Procedure:
To a solution of 3,4-dichlorocinnamic acid (21.7 g) and cesium carbonate (22.8 g) in DMF (200 mL) was added methyl iodide (7.47 mL) at 0° C., and the mixture was stirred at room temperature for 12 hr. The reaction mixture was poured into water, and the resultant product was extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium hydrogen carbonate solution, water, 1M KHSO4 solution and brine and dried, and the solvent was evaporated under reduced pressure to give methyl 3,4-dichlorocinnamate (22.4 g, 97%) as a white powder.
Reaction SMILES: Cl.[CH3:2][NH:3][O:4][CH3:5].[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:44])=[C:14]([CH2:16][O:17][C:18]2[CH:41]=[CH:40][C:21]([CH2:22][O:23][C:24]3[C:28](/[CH:29]=[CH:30]/[C:31](O)=[O:32])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)=[CH:20][C:19]=2[O:42][CH3:43])[N:15]=1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1>O.C(N(CC)CC)C.CN(C)C=O>[O:6]1[CH:10]=[CH:9][CH:8]=[C:7]1[C:11]1[O:12][C:13]([CH3:44])=[C:14]([CH2:16][O:17][C:18]2[CH:41]=[CH:40][C:21]([CH2:22][O:23][C:24]3[C:28](/[CH:29]=[CH:30]/[C:31]([N:3]([O:4][CH3:5])[CH3:2])=[O:32])=[CH:27][N:26]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=4)[N:25]=3)=[CH:20][C:19]=2[O:42][CH3:43])[N:15]=1
Reactant: CNOC
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)N(C)OC)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.25 h
Yield: 88.8 %

Procedure:
To a mixture of N,O-dimethylhydroxylamine hydrochloride (0.56 g) and N,N-dimethylformamide (30 mL) was added triethylamine (0.69 g) at room temperature, and the mixture was stirred for 15 min. To the reaction mixture were added (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (2.0 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (1.09 g) and 1-hydroxybenzotriazole monohydrate (0.87 g), and the mixture was further stirred at room temperature for 20 hr. Water was added to the reaction mixture and the precipitated crystals were collected by filtration to give (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-N-methoxy-N-methyl-2-propenamide as colorless crystals (1.92 g, yield 88%). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 173-174° C.
Reaction SMILES: C(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:9]([O:16][CH2:17][CH3:18])([O:13][CH2:14][CH3:15])OCC.Cl.C(OCC)C>C(O)C>[CH2:17]([O:16][CH:9]([O:13][CH2:14][CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[CH3:18]
Reactant: O=Cc1ccccc1
Reactant: CCOC(OCC)OCC
Agent: Cl
Solvent: CCOCC
Solvent: CCO
Product: CCOC(OCC)c1ccccc1
Yield: 82 %

Procedure:
A solution of benzaldehyde (6.82 mmol), triethyl orthoformate (3.3 g, 22.5 mmol), and conc. HCl (10 μL, 90 μmol) was refluxed in 3.7 mL of ethanol for 24 hrs. Diethyl ether was added and the organic layer was extracted with 3×2 M NaOH. The organic layer was dried over anhydrous Na2SO4. After removal of diethyl ether under reduced pressure, the crude mixture was distilled under vacuum (55-65° C./0.5 mmHg) to give pure benzaldehyde diethylacetal (82-91% yield). All acetals were characterized by 1H-NMR and used without further purification.
Reaction SMILES: C(O)C.[O:4]=[C:5]([N:25]1[CH2:29][C:28]2=[CH:30][S:31][CH:32]=[C:27]2[CH2:26]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([O:10]CC1C=CC=CC=1)=[O:9].[OH-].[Na+]>O1CCCC1>[O:4]=[C:5]([N:25]1[CH2:26][C:27]2=[CH:32][S:31][CH:30]=[C:28]2[CH2:29]1)[CH2:6][CH:7]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[C:8]([OH:10])=[O:9]
Reactant: O=C(OCc1ccccc1)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCO
Product: O=C(O)C(CC(=O)N1Cc2cscc2C1)Cc1ccccc1
Reaction time: 1 h
Yield: 75 %

Procedure:
15 ml of ethanol are added to a solution of 1.22 g (3 mmol) of phenylmethyl γ-oxo-α-(phenylmethyl)-5,6-dihydro-4H-thieno[3,4-c]pyrrole-5-butanoate in 15 ml of tetrahydrofuran, followed, at 0° C., by a solution of 0.36 g (9 mmol) of sodium hydroxide. After 1 h at room temperature, the medium is concentrated to about 15 ml, 15 ml of water are added and then the mixture is acidfied with 2N hydrochloric acid to pH 2 and extracted with three times 25 ml of ethyl acetate. The organic phases are pooled, washed with a saturated sodium chloride solution, dried over sodium sulphate and evaporated to dryness. The residue is triturated with diethyl ether to give 0.71 g of a white solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[CH:8]=[CH:9][S:10][C:3]=12.O.O.[SH2:13].[Na].Cl>CCO.O>[S:10]1[C:3]2[C:4](=[N:5][CH:6]=[CH:7][C:2]=2[SH:13])[CH:8]=[CH:9]1
Reactant: Clc1ccnc2ccsc12
Reactant: S
Agent: Cl
Agent: [Na]
Solvent: O
Solvent: CCO
Product: Sc1ccnc2ccsc12
Temperature: 90 °C
Reaction time: 20 h
Yield: 74 %

Procedure:
7-chlorothieno[3,2-b]pyridine (1.0 g, 5.9 mmol) in EtOH (15 mL) was treated with sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol). The solution was heated at 90° C. overnight. An additional amount of sodium hydrogen sulfide dihydrate (3.26 g, 35.4 mmol) was added and the reaction stirred an additional 20 hours at reflux. The solution was cooled to ambient temperature and diluted with water (100 mL) to dissolve the solids. The solution was cooled to 0° C. and concentrated hydrochloric acid solution was added slowly to adjust the pH to 1. The solution was then filtered and the solid was dried under high vacuum to provide thieno[3,2-b]pyridine-7-thiol (0.73 g, 74% yield) as a yellow solid.