Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.[C:7]([NH:14][C@H:15]([C:23](O)=[O:24])[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]>>[C:7]([NH:14][C@H:15]([C:23]([N:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1)=[O:24])[CH2:16][C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)([O:9][C:10]([CH3:12])([CH3:11])[CH3:13])=[O:8]
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)O
Reactant: C1COCCN1
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)C(=O)N1CCOCC1

Procedure:
In substantially the same manner as Working Example 2, morpholine (1.64 ml, manufactured by Tokyo Kasei) was condensed with Boc-L-phenylalanine (5.00 g) to give Boc-L-phenylalanylmorpholine (6.00 g) as a white powdery product (yield 95%). Taking a portion (2.00 g) of this product, the Boc group was deprotected with TFA, followed by concentration to dryness. The concentrate was dissolved in water, and the solution was allowed to pass through IRA-402 (Cl type, 250 ml, manufactured by Amberlite Inc.), and the solution was concentrated and lyophilized to give L-phenylalanylmorpholine hydrochloride (1.68 g) as a white powdery product (yield: quantitative). A portion (923 mg) of this product was dissolved in dichloromethane (23 ml). To the solution were added, under ice-cooling, (2S,3S)-ethyl hydrogen N-Z-aziridine-2,3-dicarboxylate produced in Working Example 1 (Compound 1, 1.00 g), HOBT (507 mg), WSC (719 mg) and triethylamine (1.02 ml). The mixture was stirred for 14 hours at room temperature. The reaction mixture was concentrated, to which was added ethyl acetate. The mixture was washed with a 10% aqueous solution of citric acid, water, a saturated aqueous solution of sodium hydrogen carbonate, a 2% aqueous solution of sodium hydrogen carbonate, water and a saturated aqueous saline solution, respectively, followed by drying over anhydrous sodium sulfate, which was concentrated. The concentrate was subjected to a silica gel column chromatography (100 ml). The column was subjected to elution with solutions prepared by adding ethyl acetate to hexane in sequence. The eluate with 60% to 70% (v/v) ethyl acetate was concentrated to give the above-titled compound (Compound 8; 940 mg) as a white powdery product (yield 54%).
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:39]=[CH:38][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]2[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=2[C@@H:21]2[CH2:30][CH2:29][C:28]3[CH:27]=[C:26]([O:31]C(=O)C(C)(C)C)[CH:25]=[CH:24][C:23]=3[CH2:22]2)=[CH:7][CH:6]=1)(O)=O.Cl.[CH:41]12[NH:47][CH:44]([CH2:45][CH2:46]1)[CH2:43][CH2:42]2>>[CH:44]12[N:47]([CH2:1][CH2:4][C:5]3[CH:6]=[CH:7][C:8]([CH2:9][CH2:10][CH2:11][NH:12][C:13]4[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:14]=4[C@@H:21]4[CH2:30][CH2:29][C:28]5[CH:27]=[C:26]([OH:31])[CH:25]=[CH:24][C:23]=5[CH2:22]4)=[CH:38][CH:39]=3)[CH:41]([CH2:46][CH2:45]1)[CH2:42][CH2:43]2
Reactant: C1CC2CCC1N2
Reactant: COc1ccc([C@@H]2CCc3cc(OC(=O)C(C)(C)C)ccc3C2)c(NCCCc2ccc(CC(=O)O)cc2)c1
Agent: Cl
Product: COc1ccc([C@@H]2CCc3cc(O)ccc3C2)c(NCCCc2ccc(CCN3C4CCC3CC4)cc2)c1
Yield: 6 %

Procedure:
Synthesized from pivalic acid (R)-6-{2-[(4-carboxymethylbenzyl)ethylamino]-4-methoxyphenyl}-5,6,7,8-tetrahydronaphthalen-2-yl ester (19 mg) and 7-azabicyclo[2.2.1]heptane hydrochloride (20 mg) according to an analogous synthetic method to Example 715 and purified by LC-MS, the title compound (1.1 mg) was obtained.
Reaction SMILES: [N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([NH:24][C:25]2[NH:26][C:27](=[O:47])[C:28]3[N:29]=[CH:30][N:31]([CH2:34][O:35][CH:36]([CH2:42][O:43]C(=O)C)[CH2:37][O:38]C(=O)C)[C:32]=3[N:33]=2)([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:7][CH:6]=1>CO.[OH-].[NH4+]>[N:1]#[N:2].[CH3:3][O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]([NH:24][C:25]2[NH:26][C:27](=[O:47])[C:28]3[N:29]=[CH:30][N:31]([CH2:34][O:35][CH:36]([CH2:37][OH:38])[CH2:42][OH:43])[C:32]=3[N:33]=2)([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(C(Nc2nc3c(ncn3COC(COC(C)=O)COC(C)=O)c(=O)[nH]2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: [NH4+]
Agent: [OH-]
Solvent: CO
Product: COc1ccc(C(Nc2nc3c(ncn3COC(CO)CO)c(=O)[nH]2)(c2ccccc2)c2ccccc2)cc1
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 100.7 %

Procedure:
A solution of 4.0 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-diacetoxy-2-propoxymethyl)guanine in 100 ml of methanol plus 20 ml of concentrated ammonium hydroxide was magnetically stirred at 22° C. for 16 hours then at 50° C. for 2.5 hours. An additional 10 ml of ammonium hydroxide were then added and the solution stirred another 2.5 hours at 50° C. Next, the solution was concentrated at reduced pressure and the residual solid recrystallized from methanol:ethyl acetate to give 3.5 g of N2 -(4-methoxyphenyldiphenylmethyl)-9-(1,3-dihydroxy-2-propoxymethyl)guanine, m.p. 148°-151° C.
Reaction SMILES: [F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]2[CH2:13][O:12]2)=[CH:4][CH:3]=1.[OH:14][CH:15]([C:23]1[CH:32]=[CH:31][C:26]2[C:27](=[O:30])[O:28][CH2:29][C:25]=2[C:24]=1[CH3:33])[CH2:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>CCO>[F:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([CH:11]([OH:12])[CH2:13][N:20]2[CH2:21][CH2:22][N:17]([CH2:16][CH:15]([OH:14])[C:23]3[CH:32]=[CH:31][C:26]4[C:27](=[O:30])[O:28][CH2:29][C:25]=4[C:24]=3[CH3:33])[CH2:18][CH2:19]2)=[CH:4][CH:3]=1
Reactant: Cc1c(C2CO2)ccc(F)c1C#N
Reactant: Cc1c(C(O)CN2CCNCC2)ccc2c1COC2=O
Solvent: CCO
Product: Cc1c(C(O)CN2CCN(CC(O)c3ccc4c(c3C)COC4=O)CC2)ccc(F)c1C#N

Procedure:
6-Fluoro-2-methyl-3-oxiran-2-ylbenzonitrile (69.2 mg, 0.391 mmol), 5-(1-hydroxy-2-piperazin-1-ylethyl)-4-methyl-2-benzofuran-1(3H)-one (54.0 mg, 0.195 mmol) was dissolved in EtOH (5 ml) then microwaved at 150° C. for 1 hr. Evaporated off ethanol and the residue was purified by mass directed hplc to yield 6-fluoro-3-(1-hydroxy-2-{4-[2-hydroxy-2-(4-methyl-1-oxo-1,3-dihydro-2-benzofuran-5-yl)ethyl]piperazin-1-yl}ethyl)-2-methylbenzonitrile.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[N:14]=[C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)[NH:12][C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([CH2:27][CH2:28][C:29](O)=[O:30])[CH2:22]2)=[C:10]1[C:32]([O:34][CH2:35][CH3:36])=[O:33].Cl.[CH3:38][NH2:39]>>[Br:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[CH:9]1[C:10]([C:32]([O:34][CH2:35][CH3:36])=[O:33])=[C:11]([CH2:20][N:21]2[CH2:26][CH2:25][O:24][CH:23]([CH2:27][CH2:28][C:29]([NH:39][CH3:38])=[O:30])[CH2:22]2)[NH:12][C:13]([C:15]2[S:16][CH:17]=[CH:18][N:19]=2)=[N:14]1
Reactant: CCOC(=O)C1=C(CN2CCOC(CCC(=O)O)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Reactant: CN
Agent: Cl
Product: CCOC(=O)C1=C(CN2CCOC(CCC(=O)NC)C2)NC(c2nccs2)=NC1c1ccc(F)cc1Br
Yield: 38.2 %

Procedure:
3-(4-((6-(2-bromo-4-fluorophenyl)-5-(ethoxycarbonyl)-2-(thiazol-2-yl)-3,6-dihydropyrimidin-4-yl)methyl)morpholin-2-yl)propanoic acid (0.69 g, 1.19 mmol) was reacted with methanamine hydrochloride (0.12 g, 1.8 mmol) according to the procedure as described in Example 62, Step B to give the title compound as a yellow solid (0.27 g, 38%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17]Br)[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][OH:21]>FC(F)(F)S([O-])(=O)=O.[Ag+].C(=O)([O-])[O-].[Ag+2]>[C:1]([O:5][C:6]([N:8]1[CH2:15][CH:14]2[CH:10]([CH2:11][CH:12]([C:16](=[O:19])[CH2:17][O:21][CH3:20])[CH2:13]2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N1CC2CC(C(=O)CBr)CC2C1
Agent: [Ag+2]
Agent: [Ag+]
Agent: O=C([O-])[O-]
Product: COCC(=O)C1CC2CN(C(=O)OC(C)(C)C)CC2C1
Temperature: 25 °C
Reaction time: 48 h
Yield: 61 %

Procedure:
A mixture of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-bromo-1-ethanone (0.126 g, 0.360 mmol), silver trifluoromethanesulfonate (0.10 g, 0.39 mmol), and silver carbonate (0.10 g, 0.36 mmol) in methanol (4.0 mL) was stirred in the dark for 2 days at ambient temperature. The reaction was filtered, and the filtrate was concentrated and purified by silica gel column chromatography, eluting with 30-40% ethyl acetate in hexanes, to obtain 0.062 g (61% yield) of 1-(3-(tert-butoxycarbonyl)-3-azabicyclo[3.3.0]oct-7-yl)-2-methoxy-1-ethanone as an oil. This was dissolved in dichloromethane (2.0 mL), treated with TFA (0.5 mL), and was stirred at ambient temperature for 2 h. The volatiles were evaporated, and the residue was vacuum dried to obtain 0.045 g of 1-(3-azabicyclo[3.3.0]oct-7-yl)-2-methoxy-1-ethanone trifluoroacetate, as an off-white solid (mixture of cis and trans isomers) (1H NMR (CD3OD, 300 MHz): δ 4.17 (s, 2H), 3.39 (s, 3H), 3.36-3.30 (m, 2H), 3.19-3.12 (m, 3H), 3.00-2.91 (m, 2H), 2.30-2.20 (m, 2H), 1.64-1.75 (m, 2H); MS (m/z): 184 (M+1)). This material exhibited Ki values at rat and human α4β2 of 32 nM and 31 nM respectively and did not pass HIS for α7.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[N:2].[Na].[CH3:10][NH:11][NH:12][C:13](=O)[C:14]1[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=1>CO>[CH3:10][N:11]1[C:1]([C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:2][C:13]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[N:12]1
Reactant: N#Cc1ccccn1
Reactant: CNNC(=O)c1ccncc1
Agent: [Na]
Solvent: CO
Product: Cn1nc(-c2ccncc2)nc1-c1ccccn1
Reaction time: 0.5 h

Procedure:
To 2-cyanopyridine (2 g.) in methanol (30 ml.) is added sodium (0.1 g.). The solution is allowed to stand 0.5 hours at ambient temperature and is then added to a solution of 1-methyl-2-isonicotinoylhydrazine (3 g.) in methanol (50 ml.). The solution is heated at reflux 4 hours and concentrated to a gum. After chromatography on silica gel and recrystallization from acetonitrile-water 450 mg. of 1-methyl-3-(4-pyridyl)-5-(2-pyridyl)-1,2,4-triazole are obtained, melting at 145°-146° C.
Reaction SMILES: [Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9](I)=[C:4]2[C:3]=1[Cl:13].C(OC([N:21]1[CH2:26][CH2:25][CH:24]([N:27]2[CH:31]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:29]=[N:28]2)[CH2:23][CH2:22]1)=O)(C)(C)C>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:1][C:2]1[O:12][C:5]2=[C:6]([NH2:11])[N:7]=[CH:8][C:9]([C:30]3[CH:29]=[N:28][N:27]([CH:24]4[CH2:25][CH2:26][NH:21][CH2:22][CH2:23]4)[CH:31]=3)=[C:4]2[C:3]=1[Cl:13]
Reactant: Nc1ncc(I)c2c(Cl)c(Cl)oc12
Reactant: CC(C)(C)OC(=O)N1CCC(n2cc(B3OC(C)(C)C(C)(C)O3)cn2)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)c2c(Cl)c(Cl)oc12
Temperature: 100 °C

Procedure:
A mixture of 2,3-dichloro-4-iodo-furo[2,3-c]pyridin-7-ylamine (300.0 mg, 0.9121 mmol), 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-pyrazol-1-yl]-piperidine-1-carboxylic acid tert-butyl ester (516 mg, 1.37 mmol) and Pd(PPh3)4 (50 mg, 0.04 mmol) in 1,4-dioxane (20 mL) and H2O (2 mL) was degassed and refilled with argon (3×). The reaction was heated at 100° C. for 20 h using a Biotage Initiator microwave reactor. The reaction was concentrated in vacuo to give a solid which was purified by flash chromatography (30 to 60% EtOAc:hexanes), which afforded the desired intermediate. 1H NMR (400 MHz, CDCl3): δ 7.85 (s, 1H), 7.65 (s, 1H), 7.57 (s, 1H), 4.80 (br s, 2H), 4.32 (m, 3H), 2.99 (m, 2H), 2.18 (m, 2H), 1.97 (m, 2H), 1.47 (s, 9H); MS (ESI): 452.00 [M+H]+; HPLC tR=3.14 min.
Reaction SMILES: C1(O[C:8](=[O:27])[NH:9][C:10]2[S:11][C:12]3[C:13]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:14][CH:15]=[C:16]([O:19][CH3:20])[C:17]=3[N:18]=2)C=CC=CC=1.[OH:28][CH:29]1[CH2:34][CH2:33][NH:32][CH2:31][CH2:30]1>ClC(Cl)C.O1CCCC1>[CH3:20][O:19][C:16]1[C:17]2[N:18]=[C:10]([NH:9][C:8]([N:32]3[CH2:33][CH2:34][CH:29]([OH:28])[CH2:30][CH2:31]3)=[O:27])[S:11][C:12]=2[C:13]([N:21]2[CH2:26][CH2:25][O:24][CH2:23][CH2:22]2)=[N:14][CH:15]=1
Reactant: COc1cnc(N2CCOCC2)c2sc(NC(=O)Oc3ccccc3)nc12
Reactant: OC1CCNCC1
Solvent: C1CCOC1
Solvent: CC(Cl)Cl
Product: COc1cnc(N2CCOCC2)c2sc(NC(=O)N3CCC(O)CC3)nc12

Procedure:
From (7-methoxy-4-morpholin-4-yl-thiazolo[5,4-c]pyridin-2-yl)-carbamic acid phenyl ester with 4-hydroxypiperidine in dichloroethane and tetrahydrofuran. ES-MS m/e (%): 394 (M+H+, 100).
Reaction SMILES: O[C:2]1[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]2[CH2:15][CH2:14][CH2:13][CH:12]2[C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=3)[CH:17]=2)[N:3]=1.[NH2:27][C:28]1[CH:32]=[C:31]([CH:33]2[CH2:35][CH2:34]2)[NH:30][N:29]=1>>[CH:33]1([C:31]2[NH:30][N:29]=[C:28]([NH:27][C:2]3[CH:7]=[C:6]([CH2:8][O:9][CH3:10])[N:5]=[C:4]([N:11]4[CH2:15][CH2:14][CH2:13][CH:12]4[C:16]4[O:20][N:19]=[C:18]([C:21]5[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=5)[CH:17]=4)[N:3]=3)[CH:32]=2)[CH2:35][CH2:34]1
Reactant: Nc1cc(C2CC2)[nH]n1
Reactant: COCc1cc(O)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1
Product: COCc1cc(Nc2cc(C3CC3)[nH]n2)nc(N2CCCC2c2cc(-c3ccccn3)no2)n1

Procedure:
Starting materials: 4-hydroxy-6-methoxymethyl-2-[2-{3-(pyrid-2-yl)isoxazol-5-yl}pyrrolidin-1-yl]pyrimidine (Method 34) and 3-amino-5-cyclopropyl-1H-pyrazole (Method 7 of WO-03/048133).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:11][CH:10]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Br:39][C:40]1[CH:47]=[CH:46][CH:45]=[CH:44][C:41]=1[CH2:42][NH2:43]>>[C:1]([O:5][C:6](=[O:7])[NH:8][C:9]1[CH:10]=[CH:11][C:12]([S:15][C:16]2[CH:24]=[CH:23][C:19]([C:20](=[O:21])[NH:43][CH2:42][C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[Br:39])=[CH:18][C:17]=2[NH:25][C:26]2[C:27]3[CH:35]=[CH:34][C:33]([CH:36]([CH3:38])[CH3:37])=[N:32][C:28]=3[N:29]=[CH:30][N:31]=2)=[CH:13][CH:14]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: NCc1ccccc1Br
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)O)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)NCc4ccccc4Br)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1

Procedure:
According to the procedure in Example 385F, the title compound was prepared using 4-(4-tert-butoxycarbonylamino-phenylsulfanyl)-3-(7-isopropyl-pyrido[2,3-d]pyrimidin-4-ylamino)-benzoic acid (prepared in Example 385E) and o-bromobenzylamine.
Reaction SMILES: CN(C)C=O.[F:6][C:7]1[CH:14]=[C:13]([OH:15])[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10].[H-].[Na+].[N:18]1[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[CH2:24]Cl>O>[F:6][C:7]1[CH:14]=[C:13]([O:15][CH2:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][N:18]=2)[CH:12]=[CH:11][C:8]=1[CH:9]=[O:10]
Reactant: O=Cc1ccc(O)cc1F
Reactant: ClCc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(OCc2ccccn2)cc1F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.6 %

Procedure:
To an N,N-dimethylformamide (10.0 mL) solution of 2-fluoro-4-hydroxy-benzaldehyde (1.60 g, 11.4 mmol) was added sodium hydride (547 mg, 13.7 mmol, 60% in oil) under nitrogen atmosphere at 0° C., which was stirred for 30 minutes at room temperature. 2-Picolyl chloride (2.80 g, 17.1 mmol) was then added at room temperature and stirred for 1 hour at 70° C. Water was added to the reaction solution at room temperature, which was then extracted with ethyl acetate. The organic layer was washed with saturated aqueous sodium chloride, and the solvent was evaporated under a reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate:heptane=1:3) to obtain the title compound (1.07 g, 40.6%).
Reaction SMILES: C1(C2[O:12][C@H:11]3[CH2:13][C@H:14]([N:17]4[CH:22]=[CH:21][N:20]=[C:19]([C:23](OC)=[O:24])[C:18]4=[O:27])[CH2:15][O:16][C@@H:10]3[CH2:9][O:8]2)C=CC=CC=1.[NH3:28]>C(O)(=O)C.CO>[OH:12][C@@H:11]1[C@@H:10]([CH2:9][OH:8])[O:16][CH2:15][C@@H:14]([N:17]2[CH:22]=[CH:21][N:20]=[C:19]([C:23]([NH2:28])=[O:24])[C:18]2=[O:27])[CH2:13]1
Reactant: COC(=O)c1nccn([C@@H]2CO[C@@H]3COC(c4ccccc4)O[C@H]3C2)c1=O
Reactant: N
Solvent: CC(=O)O
Solvent: CO
Product: NC(=O)c1nccn([C@@H]2CO[C@H](CO)[C@@H](O)C2)c1=O
Temperature: 80 °C
Reaction time: 2 h

Procedure:
In 5.0 mL of 80% aqueous solution of acetic acid was dissolved 80 mg of methyl 4-[(4aR,7S,8aS)-2-phenylhexahydropyrano[3,2-d][1,3]dioxin-7-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxylate. The solution was heated at 80° C. for 2 hours and then allowed to cool, and the solvent was removed under reduced pressure. The residue was diluted with 20 mL of water and washed with diethyl ether, and water was distilled off from the aqueous layer. The residue thus obtained was dissolved in 4.0 mL of methanol, and gaseous ammonia was introduced until saturation at an ice-cooled temperature. After stirring the reaction mixture at room temperature for 2 hours, the solvent was removed under reduced pressure. The residue thus obtained was purified by column chromatography [eluent: chloroform:methanl=10:1] to obtain 24 mg of 4-[(3S,5S,6R)-5-hydroxy-6-(hydroxymethyl)tetrahydro-2H-pyran-3-yl]-3-oxo-3,4-dihydro-2-pyrazinecarboxamide as a solid product.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][NH2:36])=[O:34])=[CH:31][CH:32]=1)=[O:27].Cl.O>CN(C)C=O>[CH3:21][O:22][CH2:23][CH2:24][NH:25][C:26]([C:28]1[S:29][C:30]([C:33]([NH:35][N:36]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:34])=[CH:31][CH:32]=1)=[O:27]
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Reactant: COCCNC(=O)c1ccc(C(=O)NN)s1
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: COCCNC(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Reaction time: 15 h
Yield: 64.3 %

Procedure:
To 1-[4-hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (50 mg, 0.18 mmol) and 5-hydrazinocarbonylthiophene-2-carboxylic acid 2-methoxyethylamide (64 mg, 0.26 mmol) prepared in Reference Synthetic Example 5 in dimethylformamide (0.88 mL), concentrated hydrochloric acid (15 μL, 0.18 mmol) was added at room temperature, and the resulting mixture was stirred for 15 hours. After the reaction, water was added, and the resulting crystals were recovered by filtration and dried. Chloroform was added, and the resulting crystals were recovered by filtration to give 59 mg of the desired product (yield 66%).
Reaction SMILES: [CH:1]([O:3][CH2:4][CH2:5][OH:6])=[CH2:2].C(N(CC)CC)C.[C:14](Cl)(=[O:16])[CH3:15].C(OCC)C>O>[CH:1]([O:3][CH2:4][CH2:5][O:6][C:14]([CH3:15])=[O:16])=[CH2:2]
Reactant: CC(=O)Cl
Reactant: C=COCCO
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOCC
Product: C=COCCOC(C)=O

Procedure:
In a 1 L three neck flask fitted with a thermometer, a dropping funnel and a mechanical stirrer, there was added 1 mol (81.0 g) of ethylene glycol monovinyl ether and 1.05 mol (106.26 g) of triethylamine and 300 mL of tetrahydrofuran(THF). The mixture was cooled to 10°-15° C. using an ice-bath. To the cooled solution, there was added 1.05 mol (84.93 g) of acetyl chloride drop by drop over two hours such that the temperature of the reaction mixture was maintained below 15° C. and the reaction mixture was stirred constantly. After 10 hours of reaction, 500 mL of diethyl ether followed by 500 mL of deionized water was added to the reaction mixture. The organic layer was washed three times with 300 mL of deionized water, and dried using anhydrous magnesium sulfate for 24 hours. The dried organic layer was separated by filtration and diethyl ether was distilled off to obtain the crude product. It was purified by two subsequent distillations under reduced pressure. The compound has a boiling point of 33°-35° C./1 torr, 115°-116° C./20 torr. The yield after purification was 110.7 g (90%). The compound was characterized by IR and NMR. The infrared spectrum shows a strong peak at 1745 cm-1 (νc=0) and the NMR spectra has signals at2.1 ppm(3H), 3.89 ppm(2H), 4.05 ppm(1H), 4.22 ppm(1H), 4.3 ppm(2H), and 6.25 ppm(1H) confirming that the isolated compound is indeed 2-methanecarbonyloxyethyl vinyl ether.
Reaction SMILES: [C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12](SC)[N:11]=2)=[CH:8][C:7]([C:18]([NH2:20])=[O:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2].[C:21]1(B(O)O)[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.S1C=CC=C1C([O-])=O.[Cu+2].S1C=CC=C1C([O-])=O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:1]([N:5]1[C:9]([C:10]2[CH:15]=[CH:14][N:13]=[C:12]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:11]=2)=[CH:8][C:7]([C:18]([NH2:20])=[O:19])=[N:6]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CSc1nccc(-c2cc(C(N)=O)nn2C(C)(C)C)n1
Reactant: OB(O)c1ccccc1
Agent: [Cu+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])c1cccs1
Solvent: C1CCOC1
Product: CC(C)(C)n1nc(C(N)=O)cc1-c1ccnc(-c2ccccc2)n1
Temperature: 130 °C
Yield: 23 %

Procedure:
50 mg (0.172 mmol) of 1-tert-butyl-5-[2-(methylsulfanyl)pyrimidin-4-yl]-1H-pyrazole-3-carboxamide, 42 mg (0.343 mmol) of phenyl boronic acid, 98 mg (0.515 mmol) of copper thiophencarboxylate and 20 mg (0.017 mmol) of palladium tetrakis were suspended in 1.5 mL of dry THF under argon atmosphere. The resulting suspension was heated a 130° C. for 1 h by microwave irradiation. The reaction mixture was then filtered on a silica plug, diluted with AcOEt and washed with aqueous NH4OH. The organic layer was washed with brine, dried over Na2SO4, filtered and concentrated under reduced pressure. The residue was purified by preparative HPLC/MS to provide the title compound (23%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([NH:13][C:14](=O)OCC)[CH2:6]2.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:8](=[CH:9][C:10]=1[O:11][CH3:12])[CH:7]([NH:13][CH3:14])[CH2:6]2
Reactant: CCOC(=O)NC1Cc2cc(OC)c(OC)cc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CNC1Cc2cc(OC)c(OC)cc21
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
3.2 g of the compound obtained in Step 2 dissolved in 30 mL of THF are added to a suspension of 0.9 g of LiAlH4 in 20 mL of THF. Refluxing is carried out for 1 hour 30 minutes, then hydrolysing using 0.6 ml of water and 0.5 mL of 20% sodium hydroxide solution and, finally, 2.3 mL of water. The mineral salts are then filtered off, rinsed with THF and then the filtrate obtained is evaporated to dryness. 2.3 g of the expected compound are obtained.
Reaction SMILES: [CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10](Br)[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4].[Cu][C:30]#[N:31].CN1CCCC1>>[CH2:1]([O:5][C:6]([C:8]1[N:9]=[C:10]([C:30]#[N:31])[C:11]2[C:16]([C:17]=1[OH:18])=[CH:15][CH:14]=[C:13]([O:19][C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:12]=2)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOC(=O)c1nc(Br)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Reactant: N#C[Cu]
Agent: CN1CCCC1
Product: CCCCOC(=O)c1nc(C#N)c2cc(Oc3ccc(OC)cc3)ccc2c1O
Temperature: 130 °C
Yield: 76.5 %

Procedure:
A mixture of 1-bromo-4-hydroxy-7-(4-methoxy-phenoxy)-isoquinoline-3-carboxylic acid butyl ester (190 mg, 0.43 mmol), copper(I) cyanide (76.3 mg, 0.85 mmol) and N-methyl-pyrrolidine (3 mL) was heated at 130° C. for 1 h. After cooled, reaction mixture was partitioned between ethyl acetate and water. Organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated. Crude product was purified by silica gel chromatography (eluting with 2%-25% ethyl acetate in methylene chloride) to give the title compound (129 mg). MS-(+)-ion: M+1=392.80.