Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:38])[CH2:29][O:30]CC1C=CC=CC=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO>[CH2:1]([C@H:8]1[CH2:13][N:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[C:16]([O:22][CH:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)[CH:15]=2)[CH2:11][CH2:10][N:9]1[C:28](=[O:38])[CH2:29][OH:30])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(N2CCN(C(=O)COCc3ccccc3)C(Cc3ccccc3)C2)cc1OC1CCCC1
Solvent: CO
Product: COc1ccc(N2CCN(C(=O)CO)[C@@H](Cc3ccccc3)C2)cc1OC1CCCC1
Yield: 17.7 %

Procedure:
Intermediate 1-[2-Benzyl-4-(3-cyclopentyloxy-4-methoxy-phenyl)-piperazin-1-yl]-2-benzyloxy-ethanone (60 mg, 0.12 mmol) was dissolved in MeOH (20 mL), purged with a stream of nitrogen, treated with 20% Pd/C (140 mg, 50% water content) and hydrogenated under 40 psi pressure of hydrogen for 4 h. The crude reaction mixture was then purged with nitrogen, filtered, evaporated, and purified by silica gel flash chromatography with 40% then 75% EtOAc/hexane as eluant to afford the title compound as an oil (9 mg, 18%). LC/MS (Method A) 6.55 min, [M+1]+ 425.
Reaction SMILES: [C:1](=[O:6])=[N:2][C:3](Cl)=[O:4].[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][NH:36][OH:37])=[CH:31][CH:30]=2)=[CH:25][CH:24]=1.O1CCCC1.Cl>O>[CH3:7][C:8]1[O:12][C:11]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:21])([F:20])[F:22])=[CH:15][CH:14]=2)=[N:10][C:9]=1[C:23]1[CH:28]=[CH:27][C:26]([C:29]2[CH:34]=[CH:33][C:32]([CH2:35][N:36]3[C:3](=[O:4])[NH:2][C:1](=[O:6])[O:37]3)=[CH:31][CH:30]=2)=[CH:25][CH:24]=1
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(CNO)cc2)cc1
Reactant: O=C=NC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1-c1ccc(-c2ccc(Cn3oc(=O)[nH]c3=O)cc2)cc1
Reaction time: 0.5 h
Yield: 53 %

Procedure:
N-(Chlorocarbonyl)isocyanate (0.2 mL, 2.6 mmol) was added dropwise into a cold (−5° C.) mixture of N-{4′-[5-methyl-2-(4-trifluoromethyl-phenyl)-oxazol-4-yl]-biphenyl-4-ylmethyl}-hydroxylamine (1.1, 2.6 mmol), and tetrahydrofuran (20.0 mL). The reaction mixture was stirred for 30 minutes, poured into water, acidified with HCl (2 N), and extracted with ethyl acetate. The organic extracts were dried over MgSO4. Evaporation and purification by flash chromatography on acidic silica gel (hexanes/EtOAc 2:1) gave a white solid (0.68 g, 53% yield): mp 196–198; MS m/e 493 (M+);
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([Cl:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O>C(O)(=O)C>[Cl:15][C:12]1[CH:13]=[CH:14][C:9]([C:8]2[O:16][N:23]=[C:2]3[C:7]=2[CH:6]=[N:5][C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]3=2)=[CH:10][CH:11]=1
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(Cl)cc3)cnc21
Reactant: NO
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccc(Cl)cc4)c3cnc21
Reaction time: 8 h
Yield: 43 %

Procedure:
4-Chloro-5-(4-chlorobenzoyl)-1-ethyl-1H-pyrazolo[3,4-b]pyridine (3.76 g) was suspended in 75 ml of glacial acetic acid, and to this was added 1.05 g of hydroxylamine hydrochloride. The reaction mixture was stirred overnight at 80° and the next morning yet another 1.05 g of hydroxylamine hydrochloride was added. After stirring the mixture for additional two hours the solvent was evaporated and the residue washed first with sodium bicarbonate solution and then methanol. The resulting product was then chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane), giving 1.51 g of product, mp 248°-250° C.
Reaction SMILES: [NH2:1][C@@H:2]1[C:33](=[O:34])[N:4]2[C:5]([C:17]([O:19][CH:20]([C:27]3[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=3)[C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])=[C:6]([S:9][CH2:10][C:11]3[CH:16]=[CH:15][N:14]=[CH:13][CH:12]=3)[CH2:7][S:8][C@H:3]12.C[Si](C([Si](C)(C)C)C(N)=O)(C)C.Cl.[NH2:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:58]/[O:59][C:60](=[O:62])[CH3:61])/[C:55](Cl)=[O:56])[N:53]=1.[OH-].[Na+]>ClCCl.CO.O>[NH2:48][C:49]1[S:50][CH:51]=[C:52](/[C:54](=[N:58]/[O:59][C:60](=[O:62])[CH3:61])/[C:55]([NH:1][C@@H:2]2[C:33](=[O:34])[N:4]3[C:5]([C:17]([O:19][CH:20]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=4)=[O:18])=[C:6]([S:9][CH2:10][C:11]4[CH:12]=[CH:13][N:14]=[CH:15][CH:16]=4)[CH2:7][S:8][C@H:3]23)=[O:56])[N:53]=1
Reactant: CC(=O)O/N=C(\C(=O)Cl)c1csc(N)n1
Reactant: N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12
Agent: C[Si](C)(C)C(C(N)=O)[Si](C)(C)C
Agent: Cl
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: CC(=O)O/N=C(\C(=O)N[C@@H]1C(=O)N2C(C(=O)OC(c3ccccc3)c3ccccc3)=C(SCc3ccncc3)CS[C@H]12)c1csc(N)n1
Temperature: 5 °C
Reaction time: 16 h
Yield: 77 %

Procedure:
Diphenylmethyl 7β-amino-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (2.15 g, 4.39 m mol) was dissolved in dichloromethane (50 ml) by addition of bis(trimethylsilyl)acetamide (1.79 g, 8.78 m mol). To a resulting solution was added 2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetyl chloride hydrochloride (1.50 g, 5.27 m mol) at 5° C. and the mixture was stirred at 5° C. for 1.5 hours and at room temperature for 16 hours. The mixture was poured into a mixture of water and methanol and adjusted to pH 7 by addition of 1N NaOH aq. The organic layer was separated, washed with brine, dried over magnesium sulfate and evaporated in vacuo to give diphenylmethyl 7β-[2-(2-aminothiazol-4-yl)-2-(Z)-(acetoxyimino)acetamido]-3-[(4-pyridyl)methylthio]-3-cephem-4-carboxylate (2.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:14][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:12]2)=[C:6]([CH:10]=1)[C:7](O)=[O:8].Cl.[NH2:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]([N:11]2[CH2:12][CH:13]([NH:15][C:16]3[CH:21]=[CH:20][C:19]([F:22])=[CH:18][CH:17]=3)[CH2:14]2)=[C:6]([CH:10]=1)[C:7]([NH:24][C:25]1([C:28]2[CH:37]=[CH:36][C:31]([C:32]([O:34][CH3:35])=[O:33])=[CH:30][CH:29]=2)[CH2:27][CH2:26]1)=[O:8]
Reactant: COC(=O)c1ccc(C2(N)CC2)cc1
Reactant: O=C(O)c1cc(Cl)cnc1N1CC(Nc2ccc(F)cc2)C1
Agent: Cl
Product: COC(=O)c1ccc(C2(NC(=O)c3cc(Cl)cnc3N3CC(Nc4ccc(F)cc4)C3)CC2)cc1
Yield: 40 %

Procedure:
The title compound (D167) (43 mg) was prepared according to the experimental procedure described in Description 146 starting from 5-chloro-2-(3-((4-fluorophenyl)amino)azetidin-1-yl)nicotinic acid (D117) (70 mg, 0.217 mmol) and methyl 4-(1-aminocyclopropyl)benzoate (D7) (50 mg, 0.217 mmol).
Reaction SMILES: C([O:8][C:9]([C:11]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:15]([C:26]([O:28][CH2:29][CH2:30][C:31]#[N:32])=[O:27])=[C:14]([CH3:33])[NH:13][C:12]=1[CH3:34])=[O:10])C1C=CC=CC=1.C(O)=O.CO>C(Cl)(Cl)Cl.[Pd]>[C:31]([CH2:30][CH2:29][O:28][C:26]([C:15]1[CH:16]([C:17]2[CH:22]=[CH:21][C:20]([N+:23]([O-:25])=[O:24])=[CH:19][CH:18]=2)[C:11]([C:9]([OH:10])=[O:8])=[C:12]([CH3:34])[NH:13][C:14]=1[CH3:33])=[O:27])#[N:32]
Reactant: CC1=C(C(=O)OCCC#N)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCc2ccccc2)=C(C)N1
Agent: [Pd]
Solvent: ClC(Cl)Cl
Solvent: CO
Solvent: O=CO
Product: CC1=C(C(=O)O)C(c2ccc([N+](=O)[O-])cc2)C(C(=O)OCCC#N)=C(C)N1

Procedure:
A solution of 3-benzyloxycarbonyl-5-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine (3.24 g, 7.02 mmol) in 160 ml of 4.4% (w/w) formic acid/MeOH mixture was stirred with Pd/C (10%, 3.24 g) for 30 min., the reaction was quenched by addition of 10 ml of CHCl3. The mixture was filtered and concentrated to give a yellow powder, which was dissolved in CHCl3 (100 ml), washed with water (25 ml) and aqueous 1N HCl (25 ml). After drying (Na2SO4) and evaporation of solvent, 3-(2-cyanoethoxy)carbonyl-1,4-dihydro-2,6-dimethyl-4-(4-nitrophenyl)pyridine-5-carboxylic acid was obtained as a yellow powder (1.94 g, 75%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[NH:9][CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1.I[CH3:20].O>CN(C)C=O>[F:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][CH:12]=1)[N:9]([CH3:20])[CH:8]=[C:7]2[CH:13]1[CH2:17][CH2:16][C:15](=[O:18])[CH2:14]1
Reactant: O=C1CCC(c2c[nH]c3ccc(F)cc23)C1
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Cn1cc(C2CCC(=O)C2)c2cc(F)ccc21
Temperature: 25 °C
Yield: 75.2 %

Procedure:
A suspension of sodium hydride (60% dispersion in oil, 0.335 g, 8.2 mmol) in dimethylformamide (20 mL) was stirred at room temperature. A solution of 3-(5-fluoro-1H-indol-3-yl)-cyclopentanone (1.5 g, 6.9 mmol) in 10 mL of DMF was added dropwise over 10 min. The reaction mixture was stirred at room temperature for an additional 30 min, then iodomethane (3.1 g, 21.8 mmol) was added. After stirring at room temperature for 24 hours, the reaction mixture was poured into water (100 mL) and extracted with ethyl acetate (2×100 mL). The combined organic layers were washed with water (50 mL) and brine (50 mL), then were dried over anhydrous sodium sulfate, filtered, and concentrated to give 1.6 g of crude product. Flash chromatography on silica gel (50% ethyl acetate/hexane) afforded 1.2 g (81%) of the title compound as a thick oil which solidified on standing. An analytical sample was recrystallized from ethyl acetate/hexane: mp 104–105° C.; MS (ESI) m/z 232 [M+H]+.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7](Cl)[CH:6]=1)[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH:20]([NH2:23])([CH3:22])[CH3:21].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1>[CH2:1]([O:3][C:4](=[O:13])[C:5]1[CH:10]=[C:9]([CH3:11])[N:8]=[C:7]([NH:23][CH:20]([CH3:22])[CH3:21])[CH:6]=1)[CH3:2]
Reactant: CCOC(=O)c1cc(C)nc(Cl)c1
Reactant: CC(C)N
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(C)nc(NC(C)C)c1
Temperature: 85 °C
Reaction time: 18 h
Yield: 67.7 %

Procedure:
To a solution of 2-chloro-6-methyl-isonicotinic acid ethyl ester (5.20 g, 26.0 mmol) in dioxane (200 mL), Cs2CO3 (25.5 g, 78.1 mmol) and isopropylamine (9.24 g, 156.3 mmol) is added. The mixture is degassed and put under N2 before Xantphos (5.43 g, 9.38 mmol) and Pd(II) acetate (1.17 g, 5.26 mmol) are added. The mixture is stirred in a sealed vessel at 85° C. for 18 h. The mixture is cooled to rt, filtered and concentrated. The crude product is purified by CC on silica gel eluting with heptane:EA 7:3 to give 2-isopropylamino-6-methyl-isonicotinic acid ethyl ester (3.91 g) as an orange solid; LC-MS: tR=0.67 min; [M+1]+=223.10.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[C:22](=[NH:23])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[C:26](OC(=O)C)(=[O:28])[CH3:27]>COC(C)(C)C>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[C:22](=[N:23][C:26](=[O:28])[CH3:27])[N:21]([CH2:24][CH3:25])[C:14]3[N:15]=[C:16]([S:19][CH3:20])[N:17]=[CH:18][C:13]=3[CH:12]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: CCn1c(=N)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Reactant: CC(=O)OC(C)=O
Solvent: COC(C)(C)C
Product: CCn1c(=NC(C)=O)c(-c2cc(OC)cc(OC)c2)cc2cnc(SC)nc21
Yield: 78 %

Procedure:
A mixture of the product of Example 4, 6-(3,5-dimethoxy-phenyl)-8-ethyl-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-ylideneamine (50.0 g, 0.145 mol), and acetic anhydride (150 mL) were heated with stirring until reflux at which point all the starting material dissolved. The reaction mixture was heated at reflux for 5 minutes, cooled in an ice bath, and t-butyl methyl ether added. The product was collected by filtration, washed with acetic anhydride (50 mL) and ether (100 mL) to afford 43.7 g (78% yield) of the titled compound. mp 145–150° C.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([OH:25])=O)[CH:13]=2)[CH2:3][CH2:2]1.[NH:26]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]1>>[O:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([O:11][C:12]2[C:20]3[N:19]=[C:18]([CH3:21])[N:17]([CH3:22])[C:16]=3[CH:15]=[C:14]([C:23]([N:26]3[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27]3)=[O:25])[CH:13]=2)[CH2:3][CH2:2]1
Reactant: O[C@H]1CCNC1
Reactant: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)O)cc2n1C
Product: Cc1nc2c(OC3CCOc4ccccc43)cc(C(=O)N3CC[C@H](O)C3)cc2n1C
Yield: 25 %

Procedure:
The title compound was prepared as a white solid in 25% yield (30 mg) from 4-(3,4-dihydro-2H-chromen-4-yloxy)-1,2-dimethyl-1H-benzimidazole-6-carboxylic acid (100 mg, 0.30 mmol, STEP 2 of Example 11) and (S)-(+)-3-pyrrolidinol (77 mg, 0.63 mmol) by the same manner in STEP 3 of Example 11:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[OH:8].[CH2:9]([O:11][C:12](=[O:16])[C:13]#[C:14][CH3:15])[CH3:10].N12CCCN=C1CCCCC2>O1CCCC1>[CH2:9]([O:11][C:12](=[O:16])/[CH:13]=[C:14](/[O:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[CH3:1])\[CH3:15])[CH3:10]
Reactant: CC#CC(=O)OCC
Reactant: Cc1ccccc1O
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCOC(=O)/C=C(\C)Oc1ccccc1C

Procedure:
To a stirred mixture of 2-methyl-phenol (4.90 g, 0.045 mol) and ethyl-2-butynoate (10.1 g, 0.09 mol) in tetrahydrofuran (15 mL) was added 1,8-diazabicyclo[5.4.0]undec-7-ene (6.80 g, 0.045 mol) slowly. After addition was complete the mixture was stirred at reflux for 6 h. Upon completion of the reaction the tetrahydrofuran was removed in vacuo and the residue was diluted in diethyl ether and washed first with 1N aqueous hydrochloric acid, then 10% aqueous sodium hydroxide solution, a saturated sodium chloride solution and dried over magnesium sulfate. The crude product, (E)-3-o-tolyloxy-but-2-enoic acid ethyl ester, was obtained as a brown oil (6.45 g, 65%) and used without further purification.
Reaction SMILES: [Cl:1]Cl.[CH3:3][CH:4]1[C:8]2[CH:9]=[CH:10][C:11]([N:13]([CH3:18])[CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:12][C:7]=2[O:6][C:5]1=[O:19]>C(Cl)(Cl)Cl>[Cl:1][C:10]1[C:11]([N:13]([CH3:18])[CH:14]([CH2:16][CH3:17])[CH3:15])=[CH:12][C:7]2[O:6][C:5](=[O:19])[CH:4]([CH3:3])[C:8]=2[CH:9]=1
Reactant: CCC(C)N(C)c1ccc2c(c1)OC(=O)C2C
Reactant: ClCl
Solvent: ClC(Cl)Cl
Product: CCC(C)N(C)c1cc2c(cc1Cl)C(C)C(=O)O2

Procedure:
A cold solution of chlorine in chloroform is added dropwise at 0° to 5° C., while stirring, to a mixture of 14.7 g (0.063 mole) of 3-methyl-6-(N-methyl-N-2-butylamino)-benzofuran-2(3H)-one in 100 ml of chloroform until no more educt is visible in the thin layer chromatograph. The reaction mixture is washed with methylene chloride, dilute sodium bicarbonate solution and water. The crude product remaining after drying and concentration by evaporation of the organic phase is chromatographed over silica gel with petroleum ether/ether. Recrystallisation of the pure fractions from ether/petroleum ether yields 5-chloro-3-methyl-6-(N-methyl-N-2-butylamino)-benzofuran-2(3H)-one in the form of a colourless oil, b.p. 0.05, 190° C.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]2=[N:6][CH:7]=1.[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][NH:25][C:26]2=[O:31].CNCCNC.C(=O)([O-])[O-].[K+].[K+]>CCOC(C)=O.[Cu]I>[Cl:21][C:22]1[CH:30]=[CH:29][CH:28]=[C:27]2[C:23]=1[CH2:24][N:25]([C:2]1[N:3]=[C:4]3[C:10]([CH:11]=[O:12])=[CH:9][N:8]([CH2:13][O:14][CH2:15][CH2:16][Si:17]([CH3:20])([CH3:19])[CH3:18])[C:5]3=[N:6][CH:7]=1)[C:26]2=[O:31]
Reactant: C[Si](C)(C)CCOCn1cc(C=O)c2nc(Br)cnc21
Reactant: O=C1NCc2c(Cl)cccc21
Agent: [Cu]I
Agent: CNCCNC
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Product: C[Si](C)(C)CCOCn1cc(C=O)c2nc(N3Cc4c(Cl)cccc4C3=O)cnc21
Temperature: 100 °C
Yield: 19.6 %

Procedure:
A 10 mL flask was charged with 2-bromo-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde (700 mg, 1.96 mmol), 4-chloro-2,3-dihydro-isoindol-1-one (395 mg, 2.36 mmol), N,N′-dimethylethylenediamine (42 μL, 0.39 mmol) and potassium carbonate (543 mg, 3.93 mmol) under argon atmosphere. Copper(I) iodide (37 mg, 0.20 mmol) was added and the reaction mixture was heated at 100° C. for 24 h. The reaction mixture was allowed to reach room temperature and then diluted with EtOAc (50 mL). The slurry was filtered over a celite pad and the filtrate was evaporated under vacuum. The crude residue was purified by column chromatography (SiO2, 100 g, EtOAc:hexanes, 0-70% in 30 min) to provide 170 mg (20%) of 2-(4-chloro-1-oxo-1,3-dihydro-isoindol-2-yl)-5-(2-trimethylsilanyl-ethoxymethyl)-5H-pyrrolo[2,3-b]pyrazine-7-carbaldehyde as an off-white solid and 400 mg of recovered starting material.
Reaction SMILES: CCCC[N+](CCCC)(CCCC)CCCC.[F-].[Si]([O:26][CH:27]([C:29]1[O:30][C:31](=[O:45])[C:32]2[C:37]([C:38]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:28])(C(C)(C)C)(C)C>C1COCC1.C(Cl)Cl.O>[OH:26][CH:27]([C:29]1[O:30][C:31](=[O:45])[C:32]2[C:37]([C:38]=1[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][N:40]=1)=[CH:36][CH:35]=[CH:34][CH:33]=2)[CH3:28]
Reactant: CC(O[Si](C)(C)C(C)(C)C)c1oc(=O)c2ccccc2c1-c1ccccn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Solvent: O
Solvent: ClCCl
Product: CC(O)c1oc(=O)c2ccccc2c1-c1ccccn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 81.5 %

Procedure:
1.0 M TBAF in THF (1.43 mL, 1.43 mmol) was added dropwise to a solution of 3-(1-((tert-butyldimethylsilyl)oxy)ethyl)-4-(pyridin-2-yl)-1H-isochromen-1-one (intermediate B58.1, 0.394 g, 1.3 mmol) in THF (15 ml). The resulting mixture was stirred at RT for 2 hrs. The mixture was diluted with DCM and water was added. The mixture was extracted twice with DCM, the combined organic layers were dried over sodium sulfate and evaporated to dryness. The crude was purified by flash chromatography on silica gel Biotage cartridge (cyclohexane to cyclohexane:EtOAc=10:90) to afford title compound (0.284 g, 1.06 mmol)
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[NH:9][C:10](=O)[C:4]=2[CH:3]=1.P(Cl)(Cl)(Cl)=O.CN(C)C1C=CC=CC=1.[CH3:32][N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[S:17][C:5]2[O:6][C:7]3[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:8]=3[N:9]=[C:10]([N:36]3[CH2:37][CH2:38][N:33]([CH3:32])[CH2:34][CH2:35]3)[C:4]=2[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc2c(s1)Oc1c(C)cccc1NC2=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: Cc1cc2c(s1)Oc1c(C)cccc1N=C2N1CCN(C)CC1

Procedure:
In the same manner as in Example 125 and using 2,9-dimethylthieno[2,3-b][1,5]benzoxazepin-4(5H)-one, phosphorus oxychloride, N,N-dimethylaniline and 1-methylpiperazine, 2,9-dimethyl-4-(4-methylpiperazin-1-yl)thieno[2,3-b][1,5]benzoxazepine is obtained.
Reaction SMILES: [C:1]([OH:12])(=[O:11])[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[CH2:13]([OH:17])[CH2:14][CH2:15]O>>[OH:7][CH2:6][CH2:5][CH2:4][O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([C:1]([O:12][CH2:15][CH2:14][CH2:13][OH:17])=[O:11])=[CH:3][CH:4]=1
Reactant: O=C(O)c1ccc(C(=O)O)cc1
Reactant: OCCCO
Product: O=C(OCCCO)c1ccc(C(=O)OCCCO)cc1
Temperature: 245 °C
Reaction time: 3.5 h

Procedure:
50.6 kg of terephthalic acid (TPA) and 30.2 kg of 1,3-propanediol (PDO) were charged in an esterification vessel and stirred thoroughly at a stirring rate of 130 rpm in the presence of an esterification catalyst. Nitrogen was then introduced at a flow rate of 4 L/min, and the reaction pressure was maintained at 2 kg/cm2G. The internal temperature of the esterification vessel was increased to 245° C. During the esterification process, the byproducts water and 1,3-PDO were separated by using a separation tower such that 1,3-PDO was introduced to the esterification reaction system and that water was made to flow out from the top of the tower, which is then cooled and recovered. The total esterification reaction time was 3.5 hours. The esterified product BHPT was cooled and crushed, by which the saponification value can be determined, and the saponification value was then converted to have a calculated esterification conversion of 98.1%. The reaction conditions are summarized in Table 1.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[C:15]([CH3:16])=[CH:14][CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[NH:17]1[CH:21]=[CH:20][N:19]=[N:18]1>CN(C=O)C>[CH3:16][C:15]1[C:8]([N:18]2[N:19]=[CH:20][CH:21]=[N:17]2)=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#[N:11]
Reactant: c1c[nH]nn1
Reactant: Cc1cccc(C#N)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(C#N)c1-n1nccn1
Temperature: 120 °C

Procedure:
K2CO3 (8.18 g, 59.2 mmol) was added to a RT solution of 2-fluoro-3-methylbenzonitrile (4.0 g, 29.6 mmol) and 1H-1,2,3-triazole (1.72 mL, 29.6 mmol) in DMF (80 mL) and the resulting suspension was heated to 120° C. for 4 h. The reaction mixture was cooled to RT and quenched with water before being extracted with EtOAc (3×). The combined organic extracts were washed with brine, dried over Na2SO4, filtered and evaporated in vacuo to give the crude product that was purified by flash chromatography (eluting with a gradient of 33% to 50% EtOAc in hexane) to give 3-methyl-2-(2H-1,2,3-triazol-2-yl)benzonitrile as a white solid. LC-MS B: tR=0.62 min; [M+H]+=185.16.
Reaction SMILES: [C:1]1([C:7]2[N:11]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=3)[C:10]([C:23]3[CH:24]=[C:25]4[C:30](=[CH:31][CH:32]=3)[CH:29]=[C:28]([OH:33])[CH:27]=[CH:26]4)=[CH:9][CH:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:34][O:35][C:36](=[O:53])[CH:37](OS(C(F)(F)F)(=O)=O)[CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[C:39]1([CH2:38][CH:37]([O:33][C:28]2[CH:27]=[CH:26][C:25]3[C:30](=[CH:31][CH:32]=[C:23]([C:10]4[N:11]([CH2:12][C:13]5[CH:14]=[CH:15][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:17][CH:18]=5)[C:7]([C:1]5[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=5)=[CH:8][CH:9]=4)[CH:24]=3)[CH:29]=2)[C:36]([O:35][CH3:34])=[O:53])[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: COC(=O)C(Cc1ccccc1)OS(=O)(=O)C(F)(F)F
Reactant: Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: COC(=O)C(Cc1ccccc1)Oc1ccc2cc(-c3ccc(-c4ccccc4)n3Cc3ccc(C(F)(F)F)cc3)ccc2c1
Yield: 89.6 %

Procedure:
In a similar manner as described in step 1 of Example 7, the title compound was prepared from 6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthol (0.300 g, 0.676 mmol), prepared in the previous step, 3-phenyl-2-trifluoromethanesulfonyloxypropionic acid methyl ester (0.317 g, 1.02 mmol) and cesium carbonate (0.441 g, 1.35 mmol). Purification on a Biotage Horizon™ system with a KP-Sil Flash 40+M column (100 g Silica Gel, 60 Å) using 25% to 65% methylene chloride in hexane as the eluent gave methyl 3-phenyl-2-[(6-{5-phenyl-1-[4-(trifluoromethyl)benzyl]-1H-pyrrol-2-yl}-2-naphthyl)oxy]propanoate as an off-white amorphous solid (0.367 g, 90%), mp 50–55° C. Elemental Analysis for C38H30F3NO3 Calc'd: C, 75.36; H, 4.99; N, 2.31. Found: C, 75.24; H, 5.16; N, 2.22.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:16])([CH3:15])[N:12]([OH:17])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.I[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30]I>>[CH2:1]([O:8][CH:9]1[CH2:14][C:13]([CH3:15])([CH3:16])[N:12]([O:17][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][O:17][N:12]2[C:11]([CH3:18])([CH3:19])[CH2:10][CH:9]([O:8][CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[CH2:14][C:13]2([CH3:16])[CH3:15])[C:11]([CH3:19])([CH3:18])[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: ICCCCCCCCCCI
Reactant: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1O
Product: CC1(C)CC(OCc2ccccc2)CC(C)(C)N1OCCCCCCCCCCON1C(C)(C)CC(OCc2ccccc2)CC1(C)C

Procedure:
The title compound is prepared from 4-benzyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine and 1,10-diiododecane according to the procedure of Example 5.