Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:3]([CH2:25][N:26](C)[C:27](=O)OC(C)(C)C)=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1.C(OCC)(=O)C.[ClH:41]>C(OCC)(=O)C.CC(O)C>[ClH:41].[F:1][C:2]1[C:3]([CH2:25][NH:26][CH3:27])=[CH:4][N:5]([S:14]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)(=[O:16])=[O:15])[C:6]=1[C:7]1[C:8]([F:13])=[N:9][CH:10]=[CH:11][CH:12]=1
Reactant: COc1ccnc(S(=O)(=O)n2cc(CN(C)C(=O)OC(C)(C)C)c(F)c2-c2cccnc2F)c1
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CC(C)O
Product: CNCc1cn(S(=O)(=O)c2cc(OC)ccn2)c(-c2cccnc2F)c1F
Temperature: 25 °C
Reaction time: 4 h
Yield: 79 %

Procedure:
To a solution of tert-butyl ({4-fluoro-5-(2-fluoropyridin-3-yl)-1-[(4-methoxypyridin-2-yl)sulfonyl]-1H-pyrrol-3-yl}methyl)methylcarbamate (94 mg) in ethyl acetate (2 mL) and 2-propanol (1 mL) was added 4 mol/L hydrogen chloride-ethyl acetate solution (2 mL), and the mixture was stirred at room temperature for 4 hr. The reaction mixture was concentrated under reduced pressure, and the residue was recrystallized from ethyl acetate-ethanol to give the title compound as a white solid (yield 65 mg, 79%).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([N:16]3[CH2:20][CH2:19][CH2:18][CH2:17]3)=[C:12]([CH:15]=2)[C:13]#[N:14])[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=1)[C:25]([NH2:27])=[O:26]>CN1C(=O)CCC1>[C:13]([C:12]1[CH:15]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([NH:21][C:22]3[CH:23]=[C:24]([CH:28]=[CH:29][CH:30]=3)[C:25]([NH2:27])=[O:26])[N:7]=2)[CH:9]=[CH:10][C:11]=1[N:16]1[CH2:20][CH2:19][CH2:18][CH2:17]1)#[N:14]
Reactant: NC(=O)c1cccc(N)c1
Reactant: N#Cc1cc(-c2ccnc(Cl)n2)ccc1N1CCCC1
Solvent: CN1CCCC1=O
Product: N#Cc1cc(-c2ccnc(Nc3cccc(C(N)=O)c3)n2)ccc1N1CCCC1
Temperature: 140 °C

Procedure:
5-(2-Chloro-pyrimidin-4-yl)-2-pyrrolidin-1-yl-benzonitrile (50 mg, 0.18 mmol) was dissolved in NMP (1 mL). 3-Aminobenzamide (100 mg, 0.734 mmol) was added and the mixture was heated at 140° C. in the microwave (300 W, stirring) for 45 minutes. The solvent was evaporated in vacuo (Genevac™). The residue was dissolved in DMSO (1.5 mL) and the crude product purified by reversed phase preparative LC-MS. Fractions containing desired product were combined and the solvents evaporated in vacuo (Genevac™). The title compound was afforded as an off-white solid (15.3 mg, 23%); LC-MS, Rt=8.00 min (ANALpH2_MeOH_QC), m/z 400 (MH+).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH2:19][OH:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1>O1CCCC1.CC(C)=O.O=[Mn]=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([CH:19]=[O:20])=[CH:11][C:12]3[NH:16][CH:15]=[N:14][C:13]=3[C:17]=2[F:18])=[C:4]([Cl:21])[CH:3]=1
Reactant: OCc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: O=Cc1cc2[nH]cnc2c(F)c1Nc1ccc(Br)cc1Cl
Temperature: 50 °C
Reaction time: 10 h
Yield: 85.2 %

Procedure:
[6-(4-Bromo-2-chloro-phenylamino)-7-fluoro-3H-benzoimidazol-5-yl]-methanol 10e (0.96 g, 2.58 mmol) is dissolved in tetrahydrofuran/acetone (1:1, 15 mL), and MnO2 (2.24 g, 25.8 mmol) is added. The reaction mixture is stirred at 50° C. for 10 hours under N2. The reaction mixture is filtered through silica gel and eluted with methylene chloride/methanol (10:1, 1 L). The filtrate is concentrated under reduced pressure to a small volume and then filtered through an Acrodisc syringe filter to remove small amounts of MnO2 that passed through the silica gel. The filtrate is concentrated under reduced pressure and the residue is purified by flash column chromatography (eluting with 20:1 methylene chloride:methanol) to yield 0.81 g (85%) of the pure desired product as a bright yellow solid. MS ESI (+) m/z 368, 370 (M+, Br pattern) detected.
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]([OH:9])=O)=[CH:4][CH:3]=1.[NH2:10][C:11]1[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=1[CH3:21])[C:14]([O:16][CH3:17])=[O:15]>>[Br:1][C:2]1[S:6][C:5]([C:7]([NH:10][C:11]2[CH:12]=[C:13]([CH:18]=[CH:19][C:20]=2[CH3:21])[C:14]([O:16][CH3:17])=[O:15])=[O:9])=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(C)c(N)c1
Reactant: O=C(O)c1ccc(Br)s1
Product: COC(=O)c1ccc(C)c(NC(=O)c2ccc(Br)s2)c1
Yield: 88 %

Procedure:
Compound a was prepared by coupling 5-bromothiophene-2-carboxylic acid with commercially available methyl 3-amino-4-methylbenzoate using the method described in Example 128 to afford a white solid in 88% yield. HPLC Ret time=3.25 min. LCMS [M+H]+ 355.2.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.[CH3:12][N+:13]1[C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=[CH:15][C:14]=1SC.[CH2:25]([N:32]1[C:36](=[O:37])[CH2:35][S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[CH2:25]([N:32]1[C:36](=[O:37])[C:35](=[C:14]2[CH:15]=[CH:16][C:17]3[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=3)[N:13]2[CH3:12])[S:34][C:33]1=[N:38][C:39]1[CH:40]=[C:41]([CH:44]=[CH:45][C:46]=1[NH:47][CH2:48][CH3:49])[C:42]#[N:43])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: CCNc1ccc(C#N)cc1N=C1SCC(=O)N1Cc1ccccc1
Reactant: CSc1ccc2ccccc2[n+]1C
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Product: CCNc1ccc(C#N)cc1N=C1SC(=C2C=Cc3ccccc3N2C)C(=O)N1Cc1ccccc1

Procedure:
In a manner similar to Example 45, intermediate 1-methyl-2-methylthioquinolinium p-toluenesulfonate was condensed with 3-(3-benzyl-4-oxothiazolidin-2-ylideneamino)-4-ethylaminobenzonitrile to afford the title compound. 1H-NMR (CDCl3): δ 7.41–7.58 (4H, m), 7.20–7.38 (9H, m), 6.49 (1H, d), 5.16 (2H, s), 3.79 (3, brs), 3.01 (2H, q), 1.02 (3H, t); MS(ESI): 492 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:7](N)=[C:6]([Br:9])[C:5]([CH3:10])=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[Cl:18])[N:3]=1.C(ON=O)(C)(C)C>C1COCC1>[Br:9][C:6]1[CH:7]=[C:2]([Br:1])[N:3]=[C:4]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[Cl:18])[C:5]=1[CH3:10]
Reactant: Cc1c(-c2ccc(F)cc2Cl)nc(Br)c(N)c1Br
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: Cc1c(Br)cc(Br)nc1-c1ccc(F)cc1Cl
Temperature: 60 °C
Reaction time: 1.75 h

Procedure:
To a stirred solution of 2,4-dibromo-6-(2-chloro-4-fluorophenyl)-5-methylpyridin-3-amine (4.8 g, 12.2 mmol, 1 eq) in THF (50 mL) was added tert-butylnitrite (2.2 mL, 18.25 mmol, 1.5 eq). The mixture was warmed to 60° C. and mild gas evolution was observed. After 1.75 h the heating bath was turned off and the mixture was allowed to stir overnight. Additional tert-butylnitrite (1 mL) was added and the mixture was again warmed to 60° C. After 2 h no starting material was left as assessed by HPLC analysis. The mixture was cooled and the solvent removed under reduced pressure. The product was purified by flash column chromatography on silica gel eluting with 2% Et2O in hexanes to give 4,6-dibromo-2-(2-chloro-4-fluorophenyl)-3-methylpyridine. Mass spectrum (ESI) 378.0 (M+1); 380.0 (M+3); 382.0 (M+5).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4](O)[C:3]=1[CH3:9].[CH3:10][O:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>>[Cl:1][C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:16][C:15]2[CH:17]=[CH:18][C:12]([O:11][CH3:10])=[CH:13][CH:14]=2)[C:3]=1[CH3:9]
Reactant: Cc1c(O)ncnc1Cl
Reactant: COc1ccc(N)cc1
Product: COc1ccc(Nc2ncnc(Cl)c2C)cc1

Procedure:
Synthesized according to the method of reagent preparation 49 using 6-chloro-5-methylpyrimidin-4-ol and 4-methoxyaniline in step 1.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17](Br)=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CNCCNC.[Na+].[I-:28]>O1CCOCC1.[Cu]I>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][S:11][CH:10]([C:14]2[CH:19]=[CH:18][C:17]([I:28])=[CH:16][CH:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: [I-]
Reactant: CC(C)(C)OC(=O)N1CCSC(c2ccc(Br)cc2)C1
Agent: [Cu]I
Agent: CNCCNC
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCSC(c2ccc(I)cc2)C1
Temperature: 130 °C
Yield: 41.3 %

Procedure:
To a degassed solution of 2-(4-bromo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (0.75 g; 2.09 mmol) and N,N′-dimethylethylenediamine (0.11 mL; 1.05 mmol) in 1,4-dioxane (10 mL) was added CuI (39.9 mg; 0.21 mmol) and NaI (0.78 g; 5.23 mmol). The resulting mixture was heated in a closed vessel, at 130° C., for 3 days. After cooling to room temperature the mixture was concentrated in vacuo, and the residue was purified by column chromatography (SiO2, CH2Cl2/hexanes 1:1) to afford 2-(4-iodo-phenyl)-thiomorpholine-4-carboxylic acid tert-butyl ester (0.35 g).
Reaction SMILES: [NH2:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[CH2:11][CH:12]2[CH2:17][CH2:16][O:15]C[O:13]2)=[C:4](Cl)[N:3]=1.[OH-:19].[NH4+]>Cl>[OH:13][CH:12]([CH2:17][CH2:16][OH:15])[CH2:11][N:8]1[CH:7]=[N:6][C:5]2[C:4](=[O:19])[NH:3][C:2]([NH2:1])=[N:10][C:9]1=2
Reactant: [OH-]
Reactant: Nc1nc(Cl)c2ncn(CC3CCOCO3)c2n1
Agent: Cl
Agent: [NH4+]
Product: Nc1nc2c(ncn2CC(O)CCO)c(=O)[nH]1

Procedure:
4-(2-amino-6-chloropurin-9-yl)methyl-1,3-dioxane (prepared according to Example 5) was dissolved in hydrochloric acid (1 mol/l) and refluxed for four hours. The solution was made alkaline with diluted ammonium hydroxide and evaporated to dryness at reduced pressure. The residue was dissolved in water and purified with preparative HPLC on a reversed phase column (μ Bondapack C18)eluted with a mixture of methanol and water (1:3). The product obtained was a white crystalline solid. M.p. 226°-8° C. (dec) (uncorrected) UV spectra (hydrochloric acid 0.01 mol/l): λmax (nm) 277, 254 (ε=10700).
Reaction SMILES: [Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([OH:26])[CH2:24][CH3:25])=[CH:4][CH:3]=1.N(C(N1CCCCC1)=O)=NC(N1CCCCC1)=O.C(P(CCCC)CCCC)CCC.[F:58][C:59]([F:63])([F:62])[CH2:60]O>O1CCCC1>[Cl:1][C:2]1[C:10]2[N:9]=[C:8]3[N:11]([C:15]4[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][C:16]=4[Cl:22])[CH2:12][CH2:13][CH2:14][N:7]3[C:6]=2[C:5]([CH:23]([O:26][CH2:60][C:59]([F:63])([F:62])[F:58])[CH2:24][CH3:25])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Reactant: OCC(F)(F)F
Agent: CCCCP(CCCC)CCCC
Agent: O=C(N=NC(=O)N1CCCCC1)N1CCCCC1
Solvent: C1CCOC1
Product: CCC(OCC(F)(F)F)c1ccc(Cl)c2nc3n(c12)CCCN3c1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 35 %

Procedure:
To a solution of 1-[9-chloro-1-(2,4-dichlorophenyl)-1,2,3,4-tetrahydropyrimido[1,2-a]benzimidazol-6-yl]propan-1-ol (100 mg, 0.243 mmol) and 1,1′-(azodicarbonyl)dipiperidine (123 mg, 0.49 mmol) in tetrahydrofuran (5.0 mL) was added tri(n-butyl)phosphine (0.122 mL, 0.49 mmol) at room temperature. After the mixture was stirred at room temperature for 10 min under nitrogen atmosphere, 2,2,2-trifluoroethanol (0.177 mL, 2.32 mmol) was added to the reaction mixture. The mixture was stirred at 60° C. for 8 hr under nitrogen atmosphere. The mixture was concentrated in vacuo and diethyl ether was added to the residue. The solid was removed by filtration and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with a 10-40% ethyl acetate/n-hexane gradient mixture and recrystallization from 2-propanol/n-hexane to give the title compound (41.8 mg, 0.085 mmol, 35%) as colorless crystals.
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.ClC[C:45]1[CH:50]=[CH:49][CH:48]=C[C:46]=1[O:51][CH3:52]>>[C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][C:15]3[CH:48]=[CH:49][CH:50]=[CH:45][C:46]=3[O:51][CH3:52])[C:9]=2[N:10]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Reactant: COc1ccccc1CCl
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: COc1ccccc1Cn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-(chloromethyl)-2-methoxybenzene and isolated as light-yellow gum (5.7 mg, 34%). MS (m/e): 403.4 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([NH:14][C:15](=[O:26])[C:16]#[C:17][C:18]3[CH:23]=[CH:22][C:21]([CH2:24][OH:25])=[CH:20][CH:19]=3)=[CH:10][CH:9]=2)=[C:4]([F:27])[CH:3]=1.[CH3:28][S:29](Cl)(=[O:31])=[O:30].ClCCl.CO.N>>[CH3:28][S:29]([O:25][CH2:24][C:21]1[CH:22]=[CH:23][C:18]([C:17]#[C:16][C:15](=[O:26])[NH:14][C:11]2[CH:12]=[CH:13][C:8]([C:5]3[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][C:4]=3[F:27])=[CH:9][CH:10]=2)=[CH:19][CH:20]=1)(=[O:31])=[O:30]
Reactant: O=C(C#Cc1ccc(CO)cc1)Nc1ccc(-c2ccc(Cl)cc2F)cc1
Reactant: CS(=O)(=O)Cl
Agent: N
Solvent: CO
Solvent: ClCCl
Product: CS(=O)(=O)OCc1ccc(C#CC(=O)Nc2ccc(-c3ccc(Cl)cc3F)cc2)cc1

Procedure:
Prepared analogously to Example 1.2.b. from 3-(4-hydroxymethylphenyl)propynoic acid-(4′-chloro-2′-fluorobiphenyl-4-yl)amide and methanesulfonic acid chloride. Yield: 0.23 g (50% of theory); C23H17ClFN2O2S (M=457.91); calc.: molecular ion peak (M+H)+: 456/458; found: molecular ion peak (M+H)+: 456/458; Rf value: 0.5 (silica gel, dichloromethane/methanol/ammonia (20:1:0.1)).
Reaction SMILES: P(OP(O)(O)=O)(O)(O)=O.[CH3:10][C:11]([C:13]1[C:18]([NH2:19])=[CH:17][C:16]2[O:20][CH2:21][O:22][C:15]=2[CH:14]=1)=[O:12].[O:23]1[CH:27]=[C:26]([C:28](Cl)=[O:29])[C:25]2[CH:31]=[CH:32][CH:33]=[CH:34][C:24]1=2>>[C:11]([C:13]1[C:18]([NH:19][C:28]([C:26]2[C:25]3[CH:31]=[CH:32][CH:33]=[CH:34][C:24]=3[O:23][CH:27]=2)=[O:29])=[CH:17][C:16]2[O:20][CH2:21][O:22][C:15]=2[CH:14]=1)(=[O:12])[CH3:10]
Reactant: O=C(Cl)c1coc2ccccc12
Reactant: CC(=O)c1cc2c(cc1N)OCO2
Agent: O=P(O)(O)OP(=O)(O)O
Product: CC(=O)c1cc2c(cc1NC(=O)c1coc3ccccc13)OCO2

Procedure:
The synthetic procedure of target compounds 158 is illustrated in Scheme 12. The starting 2-amino-4,5-methylenedioxy acetophenone (148) was first reacted with benzo[b]furan-3-carbonyl chloride (154) to give N-(6-Acetyl-1,3-benzodioxol-5-yl)-1-benzofuran-3-carboxamide (155). Then, the intermediates (155) was subjected to cyclization in dioxane, in the presence of NaOH, to afford 2-(3-Benzo[b]furyl)-6,7-methylenedioxyquinolin-4-one (156). Compound 156 was first reacted with tetrabenzylpyrophosphate in THF, in the presence of NaH, to yield dibenzyl 2-(3-benzo[b]furyl)-6,7-methylenedioxyquinolin-4-yl phosphate (157). Compound 157 was then subjected to catalytic hydrogenation in MeOH to give its diphosphoric acid (158).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1B(O)O.Br[C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1.C([O-])([O-])=O.[Na+].[Na+]>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:13]1[S:14][CH:15]=[C:16]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:17]=1
Reactant: CCOC(=O)c1csc(Br)n1
Reactant: COc1ccccc1B(O)O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: CCOC(=O)c1csc(-c2ccccc2OC)n1
Temperature: 25 °C

Procedure:
A suspension of 2-methoxyphenyl boronic acid (0.25 g, 1.65 mmol), ethyl 2-bromothiazole-4-carboxylate (0.33 g, 1.4 mmol), PdCl2(dppf)2 (0.11 g, 0.14 mmol) and 2M Na2CO3(aq) (2 mL) in DME (10 mL) was heated at reflux for 20 h, cooled to RT, filtered, concentrated by rotary evaporation and purified on silica gel (6:1 hexanes/EtOAc and 4:1 hexanes/EtOAc) to afford the title compound as a light-brown oil. EI-MS m/z 264 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]([N+:15]#[C-:16])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:8][CH3:9].Cl.[C:25](=O)([O-])[O-].[K+].[K+]>CO>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:17]=[C:18]([O:22][CH3:23])[C:19]=1[O:20][CH3:21])[CH2:6][C:7]([N:15]([CH3:25])[CH3:16])([C:10]1[S:11][CH:12]=[CH:13][CH:14]=1)[CH2:8][CH3:9]
Reactant: [C-]#[N+]C(CC)(Cc1cc(OC)c(OC)c(OC)c1)c1cccs1
Reactant: O=C([O-])[O-]
Agent: Cl
Agent: [K+]
Solvent: CO
Product: CCC(Cc1cc(OC)c(OC)c(OC)c1)(c1cccs1)N(C)C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
3.7 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propyl isocyanide are dissolved in 40 ml of methanol, and 5 ml of conc. hydrochloric acid are added to the solution. The mixture is stirred at 50°-60° C. for 2 hours. After the reaction, the mixture is evaporated to remove solvent and the residue (i.e., crude 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)propylamine hydrochloride) is dissolved in a mixture of 30 ml of methanol and 2.5 g of 35% formalin. 1.84 g of sodium cyanoborohydride are added to the solution and the mixture is stirred at room temperature for 3 hours. After the reaction, the mixture is evaporated to remove solvent and 10% hydrochloric acid is added to the residue. The mixture is stirred for 15 minutes. After the reaction, the mixture is alkalized with potassium carbonate and extracted with ethyl acetate. The extract is washed with an aqueous saturated sodium chloride solution, dried and evaporated to remove solvent. The residue is purified by silica gel column chromatography (solvent; n-hexane:ethyl acetate=2:1) to give 1.8 g of 1-(3,4,5-trimethoxybenzyl)-1-(2-thienyl)-N,N-dimethylpropylamine as a colorless oil. yield; 46.2%
Reaction SMILES: [C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12](Cl)[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2].[CH2:23]([NH:27][CH3:28])[CH:24]([CH3:26])[CH3:25].C(N(CC)CC)C>CS(C)=O>[C:1]([O:5][C:6](=[O:22])[NH:7][C:8]1[CH:13]=[C:12]([N:27]([CH2:23][CH:24]([CH3:26])[CH3:25])[CH3:28])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[N+:19]([O-:21])=[O:20])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1[N+](=O)[O-]
Reactant: CNCC(C)C
Solvent: CS(C)=O
Solvent: CCN(CC)CC
Product: CC(C)CN(C)c1cc(NC(=O)OC(C)(C)C)c([N+](=O)[O-])cc1C(F)(F)F

Procedure:
The title compound was prepared from (5-chloro-2-nitro-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example B5) (4.00 g, 11.7 mmol), N-isobutyl-methyl-amine (1.54 g, 17.6 mmol) and triethylamine (5.73 ml, 41.1 mmol) in DMSO (30 mL) at RT according to the general procedure C. Obtained as a yellow solid (4.18 g, 91%).
Reaction SMILES: CC1(C)[O:6][C:5]2[CH:7]=[C:8]([CH2:11][C@H:12]([NH:16]C(OCC3C4C(=CC=CC=4)C4C3=CC=CC=4)=O)[C:13]([OH:15])=[O:14])[CH:9]=[CH:10][C:4]=2[O:3]1.N1CCCCC1.O>C(Cl)Cl.C(O)(C(F)(F)F)=O>[O:14]=[C:13]([C@H:12]([CH2:11][C:8]1[CH:7]=[C:5]([OH:6])[C:4]([OH:3])=[CH:10][CH:9]=1)[NH2:16])[OH:15]
Reactant: CC1(C)Oc2ccc(C[C@H](NC(=O)OCC3c4ccccc4-c4ccccc43)C(=O)O)cc2O1
Solvent: C1CCNCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N[C@@H](Cc1ccc(O)c(O)c1)C(=O)O

Procedure:
To unambiguously determine the chirality of the synthesized Fmoc-DOPA(acetonide)-OH, it was cleaved by 25% piperidine in DCM and TFA/TIS/H2O (95:2.5:2.5) to give a raw free DOPA product, which was subjected to chiral HPLC analysis (CHIROBIOTIC T, Aldrich) using commercially available L- and D/L-DOPA as reference.26 The absence of the D-DOPA peak in the chromatogram confirmed the optical purity of the synthesized Fmoc-DOPA(acetonide)-OH and that L-DOPA retained its chirality under the conditions of refluxing with DMP in the presence of TsOH.27
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[CH:11][C:6]2[C:7](=[O:10])[CH2:8][O:9][C:5]=2[C:4]=1[C:13]#[C:14][CH:15]1[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]1.[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30]([CH:37]=O)=[N:29]1>CO.N1CCCCC1>[NH:28]1[C:36]2[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=2)[C:30](/[CH:37]=[C:8]2\[O:9][C:5]3[C:4]([C:13]#[C:14][CH:15]4[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]4)=[C:3]([O:2][CH3:1])[CH:12]=[CH:11][C:6]=3[C:7]\2=[O:10])=[N:29]1
Reactant: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)OCC2=O
Reactant: O=Cc1n[nH]c2ccccc12
Solvent: C1CCNCC1
Solvent: CO
Product: COc1ccc2c(c1C#CC1CCN(C(=O)OC(C)(C)C)CC1)O/C(=C\c1n[nH]c3ccccc13)C2=O
Temperature: 60 °C
Reaction time: 2 h
Yield: 79.6 %

Procedure:
A solution of tert-butyl 4-[(6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl)ethynyl]piperidine-1-carboxylate (0.103 g, 0.277 mmol) in methanol (5 mL) was added with 1H-indazole-3-carboxaldehyde (0.0386 g, 0.264 mmol) and piperidine (7 drops), and the mixture was stirred at 60° C. for 2 hours. The reaction mixture was concentrated, and the resulting residue was purified by silica gel column chromatography (chloroform/methanol) to obtain tert-butyl (Z)-4-({2-[(1H-indazol-3-yl)methylene]-6-methoxy-3-oxo-2,3-dihydrobenzofuran-7-yl}ethynyl)piperidine-1-carboxylate (0.105 g, 80%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:22]=[CH:23][CH:24]=1)[O:5][C:6]1[CH:15]=[C:14]2[C:9]([C:10]([OH:21])=[C:11]([C:17]([O:19][CH3:20])=[O:18])[N:12]=[C:13]2I)=[CH:8][CH:7]=1.[C:25]([Cu])#[N:26].C(Cl)Cl>CN(C=O)C>[C:25]([C:13]1[C:14]2[C:9](=[CH:8][CH:7]=[C:6]([O:5][C:4]3[CH:22]=[CH:23][CH:24]=[C:2]([F:1])[CH:3]=3)[CH:15]=2)[C:10]([OH:21])=[C:11]([C:17]([O:19][CH3:20])=[O:18])[N:12]=1)#[N:26]
Reactant: N#C[Cu]
Reactant: COC(=O)c1nc(I)c2cc(Oc3cccc(F)c3)ccc2c1O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)c1nc(C#N)c2cc(Oc3cccc(F)c3)ccc2c1O
Temperature: 120 °C
Reaction time: 0.17 h

Procedure:
Methyl 7-(3-fluorophenoxy)-4-hydroxy-1-iodoisoquinoline-3-carboxylate (100 mg, 0.23 mmol) and CuCN (41 mg, 0.46 mmol) were suspended in DMF (1.0 mL). The resulting mixture was heated at 120° C. for 7 minutes and then cooled to room temperature. The reaction crude was poured into CH2Cl2 (30 mL) and stirred vigorously for 10 minutes at room temperature. The resulting suspension was filtered through a pad of celite and the filtrate was washed with H2O and brine sequentially. The organic layer was dried over MgSO4, concentrated, and purified by flash chromatography (0-50% EtOAc/hexanes) to give the title compound in 67 mg. MS: (−) m/z 337.25 (M−1).
Reaction SMILES: F[C:2]1[CH:3]=[C:4]([C:9]2[CH:10]=[C:11]([C:20]([O:22]C)=[O:21])[C:12](=[O:19])[N:13](CC(C)C)[N:14]=2)[CH:5]=[CH:6][C:7]=1[F:8].[F:24]C1C=C(F)C=CC=1C(=O)CC(C(OCC)=O)(O)C(OCC)=O>>[C:20]([C:11]1[C:12](=[O:19])[NH:13][N:14]=[C:9]([C:4]2[CH:5]=[CH:6][C:7]([F:8])=[CH:2][C:3]=2[F:24])[CH:10]=1)([OH:22])=[O:21]
Reactant: CCOC(=O)C(O)(CC(=O)c1ccc(F)cc1F)C(=O)OCC
Reactant: COC(=O)c1cc(-c2ccc(F)c(F)c2)nn(CC(C)C)c1=O
Product: O=C(O)c1cc(-c2ccc(F)cc2F)n[nH]c1=O
Yield: 95.2 %

Procedure:
Following the procedure of Example 1 (4), ethyl 4-(2,4-difluorophenyl)-2-ethoxycarbonyl-2-hydroxy-4-oxo-butanoate was reacted to yield the title compound as a pale yellow crystalline powder (yield: 95.2%).