Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([OH:11])=[O:10])[CH:4]=[N:3]1.S(=O)(=O)(O)O.[C:17](=O)([O-])[O-].[Na+].[Na+]>CO>[CH3:1][N:2]1[CH:6]=[C:5]([CH:7]=[CH:8][C:9]([O:11][CH3:17])=[O:10])[CH:4]=[N:3]1
Reactant: Cn1cc(C=CC(=O)O)cn1
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CO
Product: COC(=O)C=Cc1cnn(C)c1

Procedure:
3-(1-Methylpyrazol-4-yl)acrylic acid (18.86 g) was added to a solution of sulphuric acid (15 ml) in methanol (150 ml), and the mixture refluxed for 2 hours, cooled, and poured onto ice. The acid was neutralised with solid sodium carbonate and the product extracted into dichloromethane, which was dried and evaporated. Crystallisation from ether/petrol gave methyl 3-(1-methylpyrazol-4-yl)acrylate (16.0 g). 1H-NMR (d6-DMSO) δ 3.77 (3H, s), 3.91 (3H, s), 6.16 (1H, d), 7.54 (1H, s), 7.56 (1H, d), 7.69 (1H, s). (APCI) M+H=167. C8H10N2O2 requires 166.
Reaction SMILES: CC(C)([O-])C.[K+].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[CH:13]=O.[Cl-].[CH3:16][O:17][CH2:18][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>C1COCC1>[CH3:16][O:17][CH:18]=[CH:13][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][N:7]=1
Reactant: O=Cc1ccccn1
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: C1CCOC1
Product: COC=Cc1ccccn1
Temperature: 0 °C
Reaction time: 1 h
Yield: 59.6 %

Procedure:
(for Example 11): Potassium t-butoxide (8.40 g) was added under argon to a stirred, ice-cooled, mixture of 2-pyridinecarboxaldehyde (5.36 g) and (methoxymethyl)triphenylphosphonium chloride (25.65 g) in dry THF (100 ml). The mixture was stirred for 1 hour and was then poured into ice-water (100 ml). The mixture was extracted with ether (3×50 ml) and the organic solution extracted with 2M hydrochloric acid (3×25 ml). These acid extracts were washed with ether (25 ml), basified to pH 11 with 2M sodium hydroxide and extracted with ether (1×100 ml). These combined extracts were washed with water (25 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated. Flash chromatography, eluting with ether, gave 1-methoxy-2-(2-pyridyl)ethene as a yellow oil (4.03 g). A solution of this oil (810 mg) and methyl 4(Z)-6-(4-o-methylsulphonyloxyphenyl-2,2-dimethyl-1,3-dioxan-cis-5-yl)hexenoate (1.65 g) in acetonitrile (10 ml) was treated with p-toluenesulphonic acid monohydrate (1.25 g) and the mixture stirred at 80° C. for 18 hours. Ether (100 ml) was added to the cooled solution and the mixture washed with 5% w/v sodium bicarbonate (1×40 ml), saturated brine (2×25 ml), dried (MgSO4) and evaporated. Purification of the residue by MPLC, eluting with ethyl acetate/hexane (75:25) gave methyl 4(Z)-6-([2,4,5-cis]-4-o-methylsulphonyloxphenyl-2-[2-pyridylmethyl]-1,3-dioxan-5-yl)hexenoate as a pale yellow oil (1.50 g); NMR (CDCl3): 1.51 (1H, m), 1.88 (1H, m), 2.25 (4H, m), 2.41 (1H, m), 3.22 (3H, s), 3.29 (2H, d J=5 Hz), 3.68 (3H, s), 3.91 (1H, dm J=11 Hz), 4.06 (1H, bd J=11 Hz), 5.26 (4H, m), 7.15 (1H, m), 7.32 (4H, m), 7.60 (2H, m), 8.56 (1H, dd J=5, 0.5 Hz); m/e 476 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([O:7][CH2:8][CH:9]([OH:23])[CH2:10][NH:11][CH:12]([CH3:22])[CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])=[CH:5][CH:4]=1.CN(C)[CH:28]=[O:29]>>[Si:15]([O:14][CH2:13][CH:12]([N:11]1[CH2:10][CH:9]([CH2:8][O:7][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[CH:25][CH:24]=2)[O:23][C:28]1=[O:29])[CH3:22])([C:18]([CH3:19])([CH3:20])[CH3:21])([CH3:16])[CH3:17]
Reactant: CN(C)C=O
Reactant: COc1ccc(OCC(O)CNC(C)CO[Si](C)(C)C(C)(C)C)cc1
Product: COc1ccc(OCC2CN(C(C)CO[Si](C)(C)C(C)(C)C)C(=O)O2)cc1

Procedure:
A procedure similar to that described in Preparation 11 was repeated, except that 3.36 g of 1-(4-methoxyphenoxymethyl)-2-(2-t-butyldimethylsilyloxy-1-methylethylamino)ethanol (prepared as described in Preparation 75), 1.78 g of N,N'-carbonyldiimidazole and 30 ml of anhydrous dimethylformamide were used, to give 1.42 g of the title compound having an Rf value of 0.41 (on silica gel thin layer chromatography, using a 1:2 by volume mixture of ethyl acetate and hexane as the developing solvent) from a polar diastereomer and 1.62 g of the title compound, melting at 81° C. to 85° C. from a less polar diastereomer.
Reaction SMILES: BrC[C:3]1[CH:8]=[CH:7][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:5][CH:4]=1.[C:17]([O-:20])(=[O:19])[CH3:18].[K+]>CN1CCCC1=O.O.[I-].[K+]>[C:17]([O:20][C:3]1[CH:4]=[CH:5][C:6]([C:9](=[CH:14][O:15][CH3:16])[C:10]([O:12][CH3:13])=[O:11])=[CH:7][CH:8]=1)(=[O:19])[CH3:18]
Reactant: CC(=O)[O-]
Reactant: COC=C(C(=O)OC)c1ccc(CBr)cc1
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN1CCCC1=O
Product: COC=C(C(=O)OC)c1ccc(OC(C)=O)cc1
Reaction time: 3 h
Yield: 82.9 %

Procedure:
3 g (10.5 mmol) of methyl 2-(p-bromomethylphenyl)-3-methoxyacrylate (prepared similarly to EP 226 917), 1.1 g (11.2 mmol) of potassium acetate and 50 mg of potassium iodide in 70 ml of N-methylpyrrolidone are stirred for 3 hours at 70°-80° C. The reaction mixture is diluted with water and extracted three times with ether. The combined ether phases are washed with water, dried over MgSO4 and evaporated down. Purification of the residue by column chromatography gives 2.3 g (8.7 mmol, 83%) of the title compound as colorless crystals (mp.= 69°-70° C.).
Reaction SMILES: [H-].[Na+].[SH:3][C:4]1[N:8]([CH3:9])[N:7]=[N:6][N:5]=1.[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C@H:20]([CH2:36]OS(C)(=O)=O)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]>CN(C)C=O>[Si:10]([O:17][C@H:18]1[CH2:22][N:21]([C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[C@H:20]([CH2:36][S:3][C:4]2[N:8]([CH3:9])[N:7]=[N:6][N:5]=2)[CH2:19]1)([C:13]([CH3:16])([CH3:15])[CH3:14])([CH3:12])[CH3:11]
Reactant: CC(C)(C)[Si](C)(C)O[C@@H]1C[C@@H](COS(C)(=O)=O)N(C(=O)OCc2ccc([N+](=O)[O-])cc2)C1
Reactant: Cn1nnnc1S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cn1nnnc1SC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CN1C(=O)OCc1ccc([N+](=O)[O-])cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 53.8 %

Procedure:
To a suspension of sodium hydride (62.8% suspension in oil) (0.38 g) in N,N-dimethylformamide (12 ml) was added 5-mercapto-1-methyl-1H-tetrazole (1.14 g) under ice-cooling. The mixture was stirred at the same temperature for 30 minutes. This solution was added dropwise to a solution of (2S,4R)-4-t-butyldimethylsilyloxy-2-methanesulfonyloxymethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (3.0 g) in N,N-dimethylformamide (60 ml) under ice-cooling. The mixture was stirred at 60°-70° C. for 2 hours. The reaction mixture was poured into ice-water (200 ml) and extracted 3 times with ethyl acetate (100 ml). The extracts were combined, washed with saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated in vacuo. The resulting residue was chromatographed on silica gel (100 g) eluting with a mixture of dichloromethane and acetone (40:1, V/V). The fractions containing the desired compound were collected and concentrated under reduced pressure to give (2S,4R)-4-t-butyldimethylsilyloxy-2-(1-methyl-1H-tetrazol- 5-yl)thiomethyl-1-(4-nitrobenzyloxycarbonyl)pyrrolidine (1.68 g).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([C:13](=O)[CH3:14])=[CH:7]2.C([O-])(=O)C.[NH4+].C([BH3-])#[N:22].[Na+]>CO>[F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH:13]([NH2:22])[CH3:14])=[CH:7]2
Reactant: CC(=O)c1ccc2c(F)cc(F)cc2c1
Reactant: [BH3-]C#N
Agent: CC(=O)[O-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CO
Product: CC(N)c1ccc2c(F)cc(F)cc2c1
Temperature: 25 °C
Reaction time: 48 h
Yield: 41.3 %

Procedure:
The above ketone (760 mg, 3.689 mmol) was dissolved in methanol (40 ml). Then, ammonium acetate (2.841 g, 36.896 mmol), sodium cyanoborohydride (232 mg, 3.389 mmol) and molecular sieves (3 Å, 7.6 g) were added. The mixture was stirred at room temperature for two days. The solid was filtered and the filtrate was concentrated. The residue was dissolved in water and concentrated aqueous HCl was added dropwise until the pH≈2. The mixture was then extracted with ethyl acetate to remove the unfinished ketone and other by-products. The water layer was basified to pH≈10 with aqueous sodium hydroxide (1M), and was extracted with dichloromethane and the organic layers were combined, dried over magnesium sulfate and concentrated to afford 290 mg of 1-(5,7-difluoro-naphthalen-2-yl)-ethylamine (38% yield).
Reaction SMILES: [CH2:1]1[CH:5]2[CH2:6][NH:7][CH2:8][CH:4]2[CH2:3][N:2]1[C:9]([C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:17]1[S:18][CH:19]=[CH:20][CH:21]=1)=[O:10].Cl[C:23]1[C:32]([CH3:33])=[N:31][C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[N:24]=1>>[CH3:33][C:32]1[C:23]([N:7]2[CH2:8][CH:4]3[CH:5]([CH2:1][N:2]([C:9]([C:11]4[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=4[C:17]4[S:18][CH:19]=[CH:20][CH:21]=4)=[O:10])[CH2:3]3)[CH2:6]2)=[N:24][C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[N:31]=1
Reactant: O=C(c1ccccc1-c1cccs1)N1CC2CNCC2C1
Reactant: Cc1nc2ccccc2nc1Cl
Product: Cc1nc2ccccc2nc1N1CC2CN(C(=O)c3ccccc3-c3cccs3)CC2C1

Procedure:
The title compound was prepared in a manner analogous to Example 15 utilizing Intermediate 37 and 2-chloro-3-methyl-quinoxaline. MS (ESI) mass calcd. for C26H24N4OS, 440.56; m/z found, 441.1 [M+H]+. 1H NMR (CDCl3): rotamers observed 7.77 (d, J=7.9 Hz, 1H), 7.64 (d, J=7.9 Hz, 1H), 7.51-7.40 (m, 2H), 7.40-7.25 (m, 4H), 7.20-7.14 (m, 2H), 6.93 (br s, 1H), 3.86-3.74 (m, 2H), 3.70-3.60 (br m, 1.3H), 3.58-3.40 (br m, 1.6H), 3.26-3.10 (m, 1.7H), 2.95-2.82 (br m, 1.7H), 2.76 (br m, 1.5H), 2.62 (s, 3H).
Reaction SMILES: C(OC(=O)[N:7]([CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26](=O)[N:27]=[CH:28][N:29](C)C)=[CH:22][C:21]=2[CH3:33])=[CH:16][CH:15]=1)[CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])(C)(C)C.O.[NH2:36]N.[ClH:38]>C(O)(=O)C.CO.O1CCOCC1>[ClH:38].[CH3:33][C:21]1[CH:22]=[C:23]([C:26]2[NH:27][CH:28]=[N:29][N:36]=2)[CH:24]=[CH:25][C:20]=1[C:17]1[CH:16]=[CH:15][C:14]([CH2:13][NH:7][CH2:8][CH2:9][CH:10]([CH3:12])[CH3:11])=[CH:19][CH:18]=1
Reactant: Cc1cc(C(=O)N=CN(C)C)ccc1-c1ccc(CN(CCC(C)C)C(=O)OC(C)(C)C)cc1
Reactant: NN
Agent: Cl
Solvent: C1COCCO1
Solvent: CC(=O)O
Solvent: O
Product: Cc1cc(-c2nnc[nH]2)ccc1-c1ccc(CNCCC(C)C)cc1
Temperature: 90 °C
Reaction time: 2 h

Procedure:
(4′-{[1-Dimethylamino-methylidene]-carbamoyl}-2′-methyl-biphenyl-4-ylmethyl)-(3-methyl-butyl)-carbamic acid tert-butyl ester (I-7a-1: 222 mg, 0.477 mmol) was dissolved in acetic acid (5 ml) and treated with hydrazine monohydrate (0.035 ml, 0.715 mmol). After the reaction mixture was heated at 90° C. for 2 hours, the volatiles were removed and the residue was taken up in ethyl acetate and washed with a saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified using preparative thin layer chromatography eluting with 50% ethyl acetate in hexanes. The product-containing band was isolated and extracted, and the extracts were concentrated under reduced pressure to afford a residue. The residue was dissolved in methanol and treated with 4M HCl in dioxane. After 2 hours, the volatiles were removed under reduced pressure and the resulting solid triturated with hexanes to provide a suspension. The solid was isolated by filtration to afford the title compound (E7-01) as a colorless solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11][C:12]2[C:16](=[CH:17][CH2:18][CH2:19][C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:15][CH2:14][C:13]=2[C:26]([OH:28])=O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].C(Cl)(=O)C(Cl)=O.C[Si](C)(C)[O:37][NH2:38].Cl>ClCCl>[OH:37][NH:38][C:26]([C:13]1[CH2:14][CH2:15][C:16](=[CH:17][CH2:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:12]=1[S:11][C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:28]
Reactant: COc1ccc(SC2=C(C(=O)O)CCC2=CCCc2ccccc2)cc1OC
Reactant: C[Si](C)(C)ON
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Product: COc1ccc(SC2=C(C(=O)NO)CCC2=CCCc2ccccc2)cc1OC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxylic acid (0.6 g, 1.5 mmol) in dichloromethane (20 mL) is added 2 M oxalyl chloride (1.5 mL, 3 mmol). The mixture is stirred at room temperature for 15 minutes. The solvent is removed in vacuo and the residue is dissolved in dichloromethane and O-(trimethylsilyl)hydroxylamine (0.3 mL, 3 mmol) is added. The mixture is stirred at room temperature for 30 minutes. The mixture is poured into 5% HCl and is extracted with dichloromethane. The organic layer is washed with water and is dried over MgSO4. The solvent is removed in vacuo and the residue is chromatographed on silica gel (100% ethyl acetate). The product is dissolved in the minimum amount of ethyl acetate and the solution is diluted to the cloudy point with hexane to precipitate N-hydroxy-2-[(3,4-dimethoxyphenyl)thio]-3-(3-phenylpropyl-1-yl)-1-cyclopentenecarboxamide on standing at room temperature overnight (0.1 g, 16%): m.p. 44-6° C. Anal. (C23H27NO4S.1/4H2O) C,H,N: 1H-NMR (300 MHz, CDCl3) δ (TMS) 1.42-1.78 (m, 5H), 1.90-2.08 (m, 1H), 2.38-2.50 (m, 2H), 2.59-2.78 (m, 3H), 3.82 (s, 3H), 3.90 (s, 3H), 6.72-6.79 (d, 1H), 6.88-6.98 (m, 2H), 6.98-7.10 (d, 2H), 7.10-7.30 (m, 3H), 9.02 (s, 1H); MS (Ion Spray) m/e 413 (M+H)+.
Reaction SMILES: [CH3:1][O:2][CH2:3][C@H:4]([CH3:31])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]([OH:30])=O)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.[NH2:32][C@H:33]([CH2:37][OH:38])[C@@H:34]([CH3:36])[OH:35].[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>CO>[OH:35][C@H:34]([CH3:36])[C@H:33]([NH:32][C:28]([C:26]1[NH:27][C:23]([C:8]2[CH:9]=[C:10]([O:12][C:13]3[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=3)[CH:11]=[C:6]([O:5][C@@H:4]([CH3:31])[CH2:3][O:2][CH3:1])[CH:7]=2)=[CH:24][CH:25]=1)=[O:30])[CH2:37][OH:38]
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)O)[nH]2)c1
Reactant: C[C@@H](O)[C@H](N)CO
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Product: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C(=O)N[C@H](CO)[C@@H](C)O)[nH]2)c1
Reaction time: 3.5 h
Yield: 61.5 %

Procedure:
5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrole-2-carboxylic acid (1.20 g, 2.69 mmol) synthesized in Example (78k) and commercially available L-threoninol (0.57 g, 5.38 mmol) were dissolved in methanol (25 mL), and 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride n hydrate (1.70 g, 5.38 mmol) was added at room temperature, followed by stirring for 3.5 hours under nitrogen atmosphere. The solvent was distilled off under reduced pressure, and the resulting residue was diluted with ethyl acetate (100 mL). After washing with 1N hydrochloric acid, a saturated aqueous sodium hydrogencarbonate solution and saturated brine, drying was carried out over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=0%-6%) to afford the desired compound (883 mg, 62%) as a white solid.
Reaction SMILES: [CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([O:31]C)=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:11][CH:10]=1)[CH2:2][CH2:3][CH3:4].[OH-].[Na+].Cl>C1COCC1.CO>[CH2:1]([O:5][CH2:6][CH2:7][O:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:16]=[CH:17][C:18]3[N:24]([CH2:25][CH:26]([CH3:28])[CH3:27])[CH2:23][CH2:22][C:21]([C:29]([OH:31])=[O:30])=[CH:20][C:19]=3[CH:33]=2)=[CH:13][CH:14]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)OC)CCN3CC(C)C)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CCCCOCCOc1ccc(-c2ccc3c(c2)C=C(C(=O)O)CCN3CC(C)C)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 83.9 %

Procedure:
In THF (15.0 ml)/methanol (15.0 ml) was dissolved methyl 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylate (0.75 g). To the solution was added 1N sodium hydroxide solution (7.5 ml), and the mixture was stirred at room temperature for 20 hours. pH was adjusted to approximate 4 with 1N hydrochloric acid, and the solvent was concentrated to half under reduced pressure. The concentrated material was extracted with ethyl acetate, washed with saturated brine and dried with magnesium sulfate. The solvent was removed under reduced pressure, and the resulting residue was washed with hexane/ethyl acetate (=6/1) to give 7-[4-(2-butoxyethoxy)phenyl]-1-isobutyl-2,3-dihydro-1-benzazepine-4-carboxylic acid (0.61 g).
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH:14]C=O)[S:11][N:10]=1)[C:5]([O:7]C)=[O:6].[OH-].[Na+].Cl>O>[CH3:1][O:2][N:3]=[C:4]([C:9]1[N:13]=[C:12]([NH2:14])[S:11][N:10]=1)[C:5]([OH:7])=[O:6]
Reactant: CON=C(C(=O)OC)c1nsc(NC=O)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CON=C(C(=O)O)c1nsc(N)n1
Temperature: 0 °C
Yield: 137411.2 %

Procedure:
To a suspension of methyl 2-methoxyimino-2-(5-formamido-1,2,4-thiadiazole-3-yl)-acetate (syn-isomer) (146 g, 0.60 mmol) in water (720 g) was cooled to an internal temperature of 0° C. and then 10% aqueous sodium hydroxide solution (720 ml) was added dropwise thereto. The mixture was allowed to react at a temperature in the range of 0°±1° C. for 1 hr., then heated to an internal temperature of 45° to 50° C. to react for 2 hrs. The reaction mixture was then neutralized with concentrated hydrochloric acid (62.4 g) to pH 6.5 to 7.5., and concentrated at an internal temperature of below 60° C. and then adjusted to pH 3 with concentrated hydrochloric acid (62 g). After that, it was decolorized and purified with activated carbon (14.6 g), followed by the addition of concentrated hydrochloric acid (62.4 g). It was then cooled to separate crystals which were collected by filtration and dried to give 2-methoxyimino-2-(5-amino-1,2,4-thiadiazole-3-yl) acetic acid (syn-isomer) (166.7 g, yield: 88.0%, and purity by HPLC: 99.4%).
Reaction SMILES: [C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[NH:11][C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[C:5]1=[O:30])(=[O:3])[CH3:2].[CH3:31]I.[H-].[Na+].O>CN(C)C=O>[C:1]([N:4]1[C:8]2([C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]([CH3:31])[C:10](=[O:18])[N:9]2[CH3:19])[C:7](=[O:20])[N:6]([CH2:21][O:22][CH2:23][C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:5]1=[O:30])(=[O:3])[CH3:2]
Reactant: CI
Reactant: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1NC(=O)N2C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)N1C(=O)N(COCc2ccccc2)C(=O)C12c1ccccc1N(C)C(=O)N2C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94.5 %

Procedure:
3'-Acetyl-1'-benzyloxymethyl-3-methyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'trione (3.06 g) is dissolved in dimethylformamide (20 ml) and thereto is added methyl iodide (1 ml) and further added in portions sodium hydride (60%) (0.3 g) under ice-cooling, and the mixture is stirred at room temperature for 30 minutes. To the reaction mixture is added water, and the mixture is extracted with ethyl acetate. The extract is dried and distilled to remove the solvent. The residue is purified by silica gel column chromatography (solvent: chloroform) to give 3'-acetyl-1'-benzyloxymethyl-1,3-dimethyl-spiro[1,2,3,4-tetrahydroquinazoline-4,4'-imidazolidine]-2,2',5'-trione (3 g, yield: 94.5%) as an oily substance.
Reaction SMILES: Br[C:2]1[N:3]=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][N:8]([CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17])[C:7](=[O:21])[CH:6]=2.[C:22]1([CH2:28][C:29]#[CH:30])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>CN(C)C=O.[Cu]I.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>[O:21]=[C:7]1[CH:6]=[C:5]2[C:10]([CH:11]=[C:2]([C:30]#[C:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[N:3]=[CH:4]2)=[CH:9][N:8]1[CH2:12][C:13]1[CH:14]=[C:15]([CH:18]=[CH:19][CH:20]=1)[C:16]#[N:17]
Reactant: N#Cc1cccc(Cn2cc3cc(Br)ncc3cc2=O)c1
Reactant: C#CCc1ccccc1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: N#Cc1cccc(Cn2cc3cc(C#CCc4ccccc4)ncc3cc2=O)c1

Procedure:
The coupling of 3-(7-bromo-3-oxo-2H-6-azaisoquinolin-2-ylmethyl)benzonitrile (0.85 g, 2.51 mmol) with 3-phenyl-1-propyne (0.78 mL, 6.3 mmol) using triethylamine (0.70 mL, 5.0 mmol), CuI (0.034 g, 0.18 mmol), and Pd(Ph3P)4 (0.20 g, 0. 17 mmol) in dimethylformamide is carried out as described in Example 1, Step (2). Purification is carried out on a silica gel column eluted with hexanes/ethyl acetate 3:1 to give the desired product.
Reaction SMILES: Cl.CN(C)CCCN=C=NCC.[F:13][C:14]1[C:15]([C:20]([OH:22])=O)=[N:16][CH:17]=[CH:18][CH:19]=1.[NH2:23][C:24]1[N:29]=[C:28]([N:30]([CH3:38])[C:31]2[CH:36]=[CH:35][CH:34]=[C:33](C)[CH:32]=2)[N:27]=[C:26]([C:39]([NH:41]O)=[NH:40])[N:25]=1>N1C=CC=CC=1.CCOC(C)=O>[F:13][C:14]1[C:15]([C:20]2[O:22][N:41]=[C:39]([C:26]3[N:27]=[C:28]([N:30]([CH3:38])[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:29]=[C:24]([NH2:23])[N:25]=3)[N:40]=2)=[N:16][CH:17]=[CH:18][CH:19]=1
Reactant: Cc1cccc(N(C)c2nc(N)nc(C(=N)NO)n2)c1
Reactant: O=C(O)c1ncccc1F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CN(c1ccccc1)c1nc(N)nc(-c2noc(-c3ncccc3F)n2)n1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
N-[3-(Dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (633 mg, 3.3 mmol) was added to a solution of 3-fluoropyridine-2-carboxylic acid (400 mg, 2.83 mmol) in anhydrous pyridine (6 mL) in a sealed tube at room temperature under nitrogen. The reaction mixture was stirred at room temperature for 1 h. 4-Amino-N-hydroxy-6-(methyl-3-methylphenyl-amino)-[1,3,5]triazine-2-carboxamidine (prepared in an analogous manner to Intermediate 1, 611 mg, 2.36 mmol) was added and the mixture was stirred at room temperature for approximately 18 h. A solution of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (315 mg, 1.15 mmol) in anhydrous pyridine (1 mL) was added and the mixture was stirred for 2 h. Further N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride (100 mg, 0.52 mmol) and 3-fluoropyridine-2-carboxylic acid (70 mg, 0.5 mmol) were then added and the mixture was stirred at room temperature for 1 h and then at 60 C for approximately 18 h. The mixture was then diluted with EtOAc (75 mL) and washed with saturated aq. ammonium chloride (4×15 mL), then saturated aq. sodium bicarbonate (3×15 mL) and brine (15 mL). The organic layer was dried over sodium sulfate and evaporated under vacuum. The crude residue was purified by flash chromatography (0-2% MeOH in DCM) to afford the title compound (220 mg). 20 mg of this material was dissolved in hot DMSO (0.3 mL) and MeOH (0.5 mL) and then 1:1 MeCN:water (1 mL) was added. The resultant precipitate was filtered, the solids were washed with water (2×1 mL) and then dried under vacuum to afford the title compound as a white solid (14 mg, 2%).