Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([P:5](Cl)[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]>[Cu]Cl>[C:1]([P:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:6]([CH3:9])([CH3:8])[CH3:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)P(Cl)C(C)(C)C
Agent: Cl[Cu]
Product: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Yield: 54.4 %

Procedure:
The same operations as in Example 15 were carried out, except that the amount of copper(I) chloride added was changed to 0.75 g (corresponding to 15% by mol based on the di-tert-butylphosphinous chloride), and after the reaction and the treatment, the solvent and a low-boiling component were distilled off under reduced pressure. As a result, 5.9 g (purity: 93.8%) of tri-tert-butylphosphine was obtained as an oily substance. The yield was 54.4%.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:22](=[O:23])[NH:21][C:20](=[O:24])[CH:19]=[N:18]3)[C:12]=2[Cl:25])[C:9]#[N:10])=[CH:4][C:3]=1[C:26]([F:29])([F:28])[F:27].Cl[CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36].C(N(CC)CC)C.O>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N:17]3[C:22](=[O:23])[N:21]([CH2:31][O:32][CH2:33][CH2:34][O:35][CH3:36])[C:20](=[O:24])[CH:19]=[N:18]3)[C:12]=2[Cl:25])[C:9]#[N:10])=[CH:4][C:3]=1[C:26]([F:29])([F:27])[F:28]
Reactant: COCCOCCl
Reactant: N#CC(c1ccc(Cl)c(C(F)(F)F)c1)c1cccc(-n2ncc(=O)[nH]c2=O)c1Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Solvent: O
Product: COCCOCn1c(=O)cnn(-c2cccc(C(C#N)c3ccc(Cl)c(C(F)(F)F)c3)c2Cl)c1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 118.5 %

Procedure:
A mixture of (±)-4-chloro-α-[2-chloro-3-(4,5-dihydro-3,5-dioxo-1,2,4-triazin-2-(3H)-yl)phenyl]-3-(trifluoromethyl)benzeneacetonitrile (0.00542 mol), 1-(chloromethoxy)-2-methoxyethane (0.006 mol) and triethylamine (0.0065 mol) in THF (15 ml) was stirred at RT for 2 hours. The mixture was poured out into water and extracted with EtOAc. The organic layer was separated, dried, filtered and the solvent was evaporated, yielding 3.4 g of (±)-4-chloro-α-[2-chloro-3-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]phenyl]-3-(trifluoromethyl)benzeneacetonitrile (interm. 22). (±)-2-chloro-α-(4-chlorophenyl)-4-[4,5-dihydro-4-[(2-methoxyethoxy)methyl]-3,5-dioxo-1,2,4-triazin-2(3H)-yl]benzeneacetonitrile was prepared in an analogous way (interm. 39).
Reaction SMILES: [CH3:1][C:2]1([CH3:24])[NH:7][C:6](=[O:8])[C:5]2[S:9][C:10]([N:12]3[C:17]4[CH:18]=[CH:19][C:20]([O:22][CH3:23])=[CH:21][C:16]=4[O:15][CH2:14][CH2:13]3)=[N:11][C:4]=2[CH2:3]1.[Br:25]N1C(=O)CCC1=O>CC#N.C1COCC1>[Br:25][C:19]1[C:20]([O:22][CH3:23])=[CH:21][C:16]2[O:15][CH2:14][CH2:13][N:12]([C:10]3[S:9][C:5]4[C:6](=[O:8])[NH:7][C:2]([CH3:24])([CH3:1])[CH2:3][C:4]=4[N:11]=3)[C:17]=2[CH:18]=1
Reactant: COc1ccc2c(c1)OCCN2c1nc2c(s1)C(=O)NC(C)(C)C2
Reactant: O=C1CCC(=O)N1Br
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1cc2c(cc1Br)N(c1nc3c(s1)C(=O)NC(C)(C)C3)CCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.8 %

Procedure:
To a stirred solution of Example 489 (0.05 g, 0.145 mmol) in MeCN (1 mL) and THF (1 mL) was added N-bromosuccinimide (0.026 g, 0.145 mmol). The mixture was stirred at r.t. overnight and then concentrated in vacuo. EtOAc (10 mL) and 1% aqueous sodium sulfite (5 mL) were added and the mixture was rapidly stirred for 10 minutes. The aqueous layer was extracted with EtOAc (10 mL) and then DCM (2×10 mL). The EtOAc extracts were concentrated in vacuo and the residue was dissolved in DCM (5 mL). The combined organic fractions were washed with brine (10 mL), dried (MgSO4), filtered and the solvent was evaporated in vacuo to give the title compound (0.062 g, 100%) as a light brown solid. δH (CDCl3) 8.17 (1H, s), 6.52 (1H, s), 5.22 (1H, s), 4.35-4.30 (2H, m), 4.10-4.05 (2H, m), 3.86 (3H, s), 2.88 (2H, s), 1.39 (6H, s). LCMS (ES+) 424.1, 426.0 (M+H)+, RT 3.47 minutes (Method 1).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[C:3]1SC>CO.[Ni].O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([NH:9][CH3:10])[N:4]=[CH:3]1
Reactant: CNc1cc(=O)n(C)c(SC)n1
Agent: [Ni]
Solvent: CO
Solvent: O
Product: CNc1cc(=O)n(C)cn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Referring to scheme 1, 3-methyl-6-(methylamino)-2-(methylthio)pyrimidin-4(3H)-one (compound 1A; 650 mg, 0.35 mmol, 1 eq) was suspended in methanol (5 ml). A large excess of Raney Nickel slurried in water was added (approx 5 ml) and the mixture stirred at room temperature overnight to yield compound 1B. The product was confirmed by LC-MS. The mixture was filtered and the solid washed several times with methanol. The filtrate was then removed in vacuo and the residue was purified by flash chromatography with 1:10 MeOH:DCM to leave 3-methyl-6-(methylamino)pyrimidin-4(3H)-one (compound 1B) as a yellow/green solid (380 mg, 86%). 1H NMR (400 MHz, MeOD) δ ppm 2.78 (s, 3H) 3.35 (s, 3H) 5.22 (br. s., 1H) 8.10 (br. s., 1H); [M+H] calc'd for C5H7N3O, 126. found, 126.
Reaction SMILES: C([O:5][C:6](=[O:25])/[CH:7]=[CH:8]/[C:9]1[CH:24]=[N:23][C:12]2[NH:13][C:14](=[O:22])[N:15]([CH2:17][CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][C:11]=2[CH:10]=1)(C)(C)C.C(O)(C(F)(F)F)=O.[ClH:33]>C(Cl)Cl>[ClH:33].[CH3:21][N:19]([CH3:20])[CH2:18][CH2:17][N:15]1[CH2:16][C:11]2[CH:10]=[C:9](/[CH:8]=[CH:7]/[C:6]([OH:25])=[O:5])[CH:24]=[N:23][C:12]=2[NH:13][C:14]1=[O:22]
Reactant: CN(C)CCN1Cc2cc(/C=C/C(=O)OC(C)(C)C)cnc2NC1=O
Agent: Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CN(C)CCN1Cc2cc(/C=C/C(=O)O)cnc2NC1=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 113.2 %

Procedure:
A solution of (E)-3-[3-(2-dimethylamino-ethyl)-2-oxo-1,2,3,4-tetrahydro-pyrido[2,3-d]pyrimidin-6-yl]acrylic acid tert-butyl ester (145 mg, 0.419 mmol) in CH2Cl2 (4 mL) was treated with TFA (2 mL). After stirring at room temperature for 30 min, the clear tan solution was concentrated in vacuo. The resulting oil was treated with anhydrous HCl (4.0 mL of 4 M solution in dioxane, 16 mmol) and stirred until the oil was converted to a solid. The solid was isolated by filtration, washed with Et2O and dried under vacuum over night to give the title compound (155 mg, quantitative) as a pale yellow solid: 1H NMR (300 MHz, DMSO-d6) δ 10.18 (s, 1H), 9.70 (br s, 1H), 8.36 (d, J=1.4 Hz, 1H), 7.92 (s, 1H), 7.55 (d, J=16.0 Hz, 1H), 6.48 (d, J=16.0 Hz, 1H), 4.53 (s, 2H), 4.50 (br s, 2H), 3.71 (t, J=5.6 Hz, 2H), 3.31 (t, J=5.6 Hz, 2H), 2.84 (s, 3H), 2.82 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[K+].[K+].[C:14]([O:18][C:19](=[O:23])[CH:20](Br)[CH3:21])([CH3:17])([CH3:16])[CH3:15]>CN(C=O)C.O>[O:1]=[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]1[CH:20]([CH3:21])[C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:23]
Reactant: CC(Br)C(=O)OC(C)(C)C
Reactant: Oc1ccccn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C(=O)OC(C)(C)C)n1ccccc1=O
Temperature: 25 °C
Reaction time: 7 h
Yield: 71.7 %

Procedure:
To a stirred solution of 9.5 g (0.10 mol) of 2-hydroxypyridine in 250 mL of DMF was added 16.6 g (0.120 mol) of potassium carbonate followed by 25.0 g (0.120 mol) of 2-bromopropionic acid tert-butyl ester. The resulting mixture was stirred at ambient temperature for 7 h then diluted with 1 L of water. The aqueous phase was extracted with ethyl acetate (3×200 mL) and the combined organics were washed with water (2×100 mL), brine (100 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The crude residue was purified by silica gel chromatography eluting with 25% ethyl acetate in hexanes to afford the title compound as a clear gum 16 g (72%). LC-MS: m/z (ES) 224 (MH)+
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16](Cl)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.[NH:20]1[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]1.C(=O)([O-])O.[Na+]>C(O)CCC>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[CH:3]=[C:2]1[C:10]1[N:14]2[N:15]=[C:16]([N:20]3[CH2:24][CH2:23][C@H:22]([OH:25])[CH2:21]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Clc1ccc2ncc(-c3cc4ccccc4o3)n2n1
Reactant: O[C@H]1CCNC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCCCO
Product: O[C@H]1CCN(c2ccc3ncc(-c4cc5ccccc5o4)n3n2)C1

Procedure:
150 mg (0.56 mmol) 3-(1-benzofur-2-yl)-6-chloroimidazo[1,2-b]pyridazine, 116.3 mg (1.34 mmol) (3S)-pyrrolidin-3-ol and 112.1 mg (1.34 mmol) sodium hydrogencarbonate in 4.0 mL butan-1-ol were stirred 72 h at 150° C. The solvent was removed. The residue was purified by HPLC to yield 22 mg (12%).
Reaction SMILES: O[CH2:2][C:3]1[CH:4]=[CH:5][C:6]2=[C:7]([CH:21]=1)[O:8][CH2:9][C:10]1[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=1/[C:12]/2=[C:13](\[CH3:16])/[C:14]#[N:15].[CH3:22][C:23]1[NH:33][C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O>C1COCC1>[CH3:22][C:23]1[N:33]([CH2:2][C:3]2[CH:4]=[CH:5][C:6]3=[C:7]([CH:21]=2)[O:8][CH2:9][C:10]2[CH:20]=[CH:19][CH:18]=[CH:17][C:11]=2/[C:12]/3=[C:13](\[CH3:16])/[C:14]#[N:15])[C:26]2=[N:27][C:28]([CH3:32])=[CH:29][C:30]([CH3:31])=[C:25]2[N:24]=1
Reactant: C/C(C#N)=C1\c2ccccc2COc2cc(CO)ccc21
Reactant: Cc1cc(C)c2nc(C)[nH]c2n1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C/C(C#N)=C1\c2ccccc2COc2cc(Cn3c(C)nc4c(C)cc(C)nc43)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 51 %

Procedure:
[step 1] (Z)-2-(3-Hydroxymethyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene)propiononitrile (400 mg, 1.44 mmol) obtained in Reference Example B6 and 2,5,7-trimethyl-3H-imidazo[4,5-b]pyridine (U.S. Pat. No. 5,332,744; 349 mg, 2.16 mmol) were dissolved in THF (14 mL), polymer-supported triphenylphosphine (962 mg, 2.88 mmol) and di-tert-butyl azodicarboxylate (664 mg, 2.88 mmol) were added at 0° C., and the mixture was stirred at room temperature for 2 hr. The mixture was filtered, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=4/6) to give (Z)-2-[3-(2,5,7-trimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl-6,11-dihydrodibenzo[b,e]oxepin-11-ylidene]propiononitrile (310 mg, 51%).
Reaction SMILES: [F:1][C:2]1([F:33])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[N:12](CCOC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[NH:21][C:22]([C:24]2[CH:25]=[N:26][N:27]3[CH:32]=[CH:31][CH:30]=[N:29][C:28]=23)=[O:23])[CH2:3]1.Cl>C(O)C.O>[F:33][C:2]1([F:1])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[C:9]([NH:21][C:22]([C:24]3[CH:25]=[N:26][N:27]4[CH:32]=[CH:31][CH:30]=[N:29][C:28]=34)=[O:23])=[CH:10][NH:11][N:12]=2)[CH2:3]1
Reactant: C[Si](C)(C)COCCn1ncc(NC(=O)c2cnn3cccnc23)c1N1CCCC(F)(F)C1
Agent: Cl
Solvent: CCO
Solvent: O
Product: O=C(Nc1c[nH]nc1N1CCCC(F)(F)C1)c1cnn2cccnc12
Temperature: 70 °C
Reaction time: 1 h
Yield: 105.6 %

Procedure:
To a solution of N-(5-(3,3-difluoropiperidin-1-yl)-1-(2-((trimethylsilyl)methoxy)ethyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (1.0 g, 2.1 mmol) in 50 mL of ethanol was added HCl (1.75 mL of a 6 M solution in water, 10.5 mmol). The reaction mixture was stirred at 70° C. for 1 hour. After cooling to room temperature, a light yellow precipitate formed, which was filtered off and rinsed with methanol and diethyl ether. The filtrate was then reduced in volume, and more solid product isolated by filteration. The combined collected solids were dried under vacuum to afford 0.77 g (94%) of N-(3-(3,3-difluoropiperidin-1-yl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide. LCMS (ESI) m+H=348.1; 1H NMR (400 MHz, CDCl3) δ: 9.59 (s, 1H), 9.37 (dd, 1H), 8.84 (m, 2H), 8.01 (s, 1H), 7.32 (dd, 1H), 3.74 (s, 1H), 3.33 (m, 2H), 3.12 (m, 2H), 2.10 (m, 2H), 2.00 (m, 2H).
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[NH:9][CH:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)=[O:4].[H-].[Na+].[CH3:16][S:17](Cl)(=[O:19])=[O:18].Cl.[CH3:22][OH:23]>C(N(CC)CC)C>[CH3:22][O:23][C:3]([C:5]1[N:9]([S:17]([CH3:16])(=[O:19])=[O:18])[CH:8]=[C:7]([CH:10]=[O:11])[CH:6]=1)=[O:4]
Reactant: CS(=O)(=O)Cl
Reactant: O=Cc1c[nH]c(C(=O)C(Cl)(Cl)Cl)c1
Reactant: CO
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: COC(=O)c1cc(C=O)cn1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 82 %

Procedure:
To a solution of 5-trichloroacetyl-1H-pyrrole-3-carbaldehyde (3.6 g, 14.97 mmol) in MeOH (60 mL) was added triethylamine (2 mL). The reaction mixture was stirred at room temperature for 3 hours. The solvent was removed and the residue was dried on the vacuum pump for 6 hours. This crude product was then dissolved in 60 mL of anhydrous THF. To the resulting solution was added NaH (720 mg, 18 mmol) at room temperature. The suspension was then stirred at room temperature for 1 hour before addition of MsCl (2.6 g, 22.70 mmol). The mixture was left at room temperature overnight and then poured into 2N HCl solution (100 mL). The aqueous solution was extracted with EtOAc (3×60 mL), the combined organic layers were dried over MgSO4, the solvent was removed by evaporation, and the residue was purified by flash column eluting with 30% EtOAc/hexanes to afford the title compound as a white solid (2.85 g, 82%). 1H NMR (500 MHz, DMSO-d6) δ9.88 (s, 1H), 8.40 (s, 1H), 7.40 (s, 1H), 3.96 (s, 3H), 3.85 (s, 3H) ppm. MS (ES+): m/e=232.1 (M+H); LC/Method A/2.61 min.
Reaction SMILES: [CH3:1][N:2]([CH3:11])[C:3]1[N:8]=[C:7]([OH:9])[CH:6]=[C:5]([OH:10])[N:4]=1.S(OCC)(O[CH2:16][CH3:17])(=O)=O>[OH-].[Na+]>[CH3:1][N:2]([CH3:11])[C:3]1[N:4]=[C:5]([O:10][CH2:16][CH3:17])[CH:6]=[C:7]([OH:9])[N:8]=1
Reactant: CN(C)c1nc(O)cc(O)n1
Reactant: CCOS(=O)(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(O)nc(N(C)C)n1
Reaction time: 6 h

Procedure:
155.2 g (1 mol) of 2-dimethylamino-4,6-dihydroxypyrimidine are added while stirring to 1000 cc of 1N sodium hydroxide solution 1N and the mixture is heated to 50° over a short period. 170 g (1.1 mol) of diethyl sulphate are subsequently added dropwise, over the course of 2 hours, at 40°-45°. During the dropwise addition the pH value is kept at between 7.5 and 8.0 by further addition of 1N sodium hydroxide solution. Approximately 500 cc of 1N sodium hydroxide solution are additionally required. The mixture is stirred at 40° for 6 hours, filtered off, washed with a small amount of water and dried at 90° in a high vacuum. The compound may be recrystallized from benzene. M.P. 194°-195°. The aqueous phase may be extracted with chloroform in order to obtain better yields. The chloroform solution is dried with sodium sulphate and after evaporation crystals are obtained which may be recrystallized from benzene.
Reaction SMILES: C([O:3][C:4](=[O:30])[CH:5](CC)[CH2:6][CH2:7][N:8]1[C:25](=[S:26])[N:11]2[C:12]3[CH:13]=[C:14]([C:18]4[CH:23]=[CH:22][C:21]([Cl:24])=[CH:20][CH:19]=4)[O:15][C:16]=3[CH:17]=[C:10]2[C:9]1=[O:27])C.O>C(O)(C(F)(F)F)=O>[Cl:24][C:21]1[CH:22]=[CH:23][C:18]([C:14]2[O:15][C:16]3[CH:17]=[C:10]4[C:9](=[O:27])[N:8]([CH2:7][CH2:6][CH2:5][C:4]([OH:30])=[O:3])[C:25](=[S:26])[N:11]4[C:12]=3[CH:13]=2)=[CH:19][CH:20]=1
Reactant: CCOC(=O)C(CC)CCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)CCCN1C(=O)c2cc3oc(-c4ccc(Cl)cc4)cc3n2C1=S
Temperature: 70 °C
Yield: 91.9 %

Procedure:
Compound 4 (17.5 mg, 0.042 mmol) was dissolved in TFA (2 ml), to give a clear red solution. Water (0.5 ml) was added and the mixture was heated at 70° C. overnight. Additional water (2 ml) was added and the solvents of the reaction mixture reaction mixture were evaporated under reduced pressure to afford Compound 5 as a yellow-brown solid (15 mg, 90% yield).
Reaction SMILES: [CH3:1][N:2]1[C:10]([C:11]([OH:13])=O)=[C:9]2[C:4]([CH:5]=[CH:6][CH:7]=[CH:8]2)=[N:3]1.CN(C=O)C.C(Cl)(=O)C(Cl)=O.[NH2:25][C:26]1[C:31]([Cl:32])=[CH:30][C:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])=[C:28]([F:39])[CH:27]=1.C(N(CC)CC)C>C1C=CC=CC=1>[Cl:32][C:31]1[C:26]([NH:25][C:11]([C:10]2[N:2]([CH3:1])[N:3]=[C:4]3[C:9]=2[CH:8]=[CH:7][CH:6]=[CH:5]3)=[O:13])=[CH:27][C:28]([F:39])=[C:29]([CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:30]=1
Reactant: Cn1nc2ccccc2c1C(=O)O
Reactant: CCOC(=O)Cc1cc(Cl)c(N)cc1F
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Solvent: c1ccccc1
Product: CCOC(=O)Cc1cc(Cl)c(NC(=O)c2c3ccccc3nn2C)cc1F
Temperature: 25 °C
Yield: 27.1 %

Procedure:
To 2-methylindazole-3-carboxylic acid (650 mg, 3.69 mmol) and DMF (29.0 μl, 0.37 mmol) was added benzene (20 ml). Under stirring at room temperature, oxalyl chloride (0.39 ml, 4.43 mmol) was added dropwise to the resulting mixture. After completion of the dropwise addition, the reaction mixture was stirred for further 1 hour at room temperature. A solution of ethyl (4-amino-5-chloro-2-fluorophenyl)acetate (855 mg, 3.69 mmol) and triethylamine (3.09 ml, 22.1 mmol) in benzene (3.0 ml), which had been prepared in advance, was added dropwise to the reaction mixture, and the mixture was heated under reflux for 16 hours. The reaction mixture was then cooled to room temperature, followed by extraction with ethyl acetate. The extract was washed with saturated brine, dried over anhydrous sodium sulfate, and distilled under reduced pressure to remove the solvent. The residue was purified by chromatography on a silica gel column, whereby from n-hexane-ethyl acetate (5:1, v/v) eluate fractions, ethyl (5-chloro-2-fluoro-4-((2-methyl-3-indazolylcarbonyl)amino)phenyl)acetate (390 mg, 27%) was obtained as a pale yellow solid.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])=[CH:5][C:4]=1[N+:18]([O-])=O)#[N:2].[H][H]>[Pd].C(O)C>[NH2:18][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:7]=[CH:8][C:3]=1[C:1]#[N:2]
Reactant: CC(C)(C)OC(=O)/C=C/c1ccc(C#N)c([N+](=O)[O-])c1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CC(C)(C)OC(=O)CCc1ccc(C#N)c(N)c1

Procedure:
4.9 mg of palladium on carbon (10%) were added to a solution of 48.9 mg (0.18 mmol) of tert-butyl (2E)-3-(4-cyano-3-nitrophenyl)acrylate in 4.4 ml of ethanol. The reaction mixture was hydrogenated using a hydrogen pressure of 1 bar at RT overnight. The mixture was then filtered through celite and the filtrate was concentrated. This gave 43.5 mg (99% of theory) of the target compound of a purity of 85%.
Reaction SMILES: [Br-].[C:2]([CH2:5][CH2:6][CH2:7][CH2:8][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)([OH:4])=[O:3].C([Li])CCC.CCCCCC.[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:45]([CH:48]=O)=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42]>O1CCCC1.O>[CH2:39]([C:43]1[N:44]([CH2:50][C:51]2[CH:56]=[CH:55][CH:54]=[CH:53][C:52]=2[Cl:57])[C:45]([CH2:48][CH:8]=[CH:7][CH2:6][CH2:5][C:2]([OH:4])=[O:3])=[CH:46][N:47]=1)[CH2:40][CH2:41][CH3:42]
Reactant: CCCCc1ncc(C=O)n1Cc1ccccc1Cl
Reactant: O=C(O)CCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCCCc1ncc(CC=CCCC(=O)O)n1Cc1ccccc1Cl
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 36.7 %

Procedure:
To a suspension of (4-carboxybutyl)triphenyl-phosphonium bromide (1.04 g, 2.35 mmol) in dry tetrahydrofuran (25 mL) at 0° C. under argon was added n-butyl lithium in hexane (1.8 mL of 2.5M, 4.6 mmol). The reaction mixture was stirred for 15 minutes at 0° C. and then a solution of 2-n-butyl-1-(2-chlorophenyl)methyl-1H-imidazol-5-carboxaldehyde [Example 6 (iii)] (0.5 g, 1.81 mmol) in tetrahydrofuran (25 mL) was added dropwise. The mixture was stirred an additional hour at 0° C. and then at ambient temperature for 3 days. Water was added and the mixture was extracted with diethyl ether. The aqueous layer was acidified to pH 3 with aqueous hydrochloric acid solution. The product was extracted into ethyl acetate, washed with water, dried, concentrated, and chromatographed over silica gel eluting with 5-10% methanol in methylene chloride to give 0.24 g of 6-[2-n-butyl-1-{(2-chlorophenyl)methyl}-1H-imidazol-5-yl]-4-hexenoic acid.
Reaction SMILES: C[O:2][C:3](=[O:18])[CH2:4][CH2:5][C:6](=[O:17])[NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16].[OH-].[Na+]>CO>[O:17]=[C:6]([NH:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[O:16])[CH2:5][CH2:4][C:3]([OH:18])=[O:2]
Reactant: COC(=O)CCC(=O)NCCCN1CCCC1=O
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(O)CCC(=O)NCCCN1CCCC1=O
Temperature: 25 °C
Reaction time: 4 h
Yield: 99.9 %

Procedure:
To a solution of 4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butyric acid methyl ester (900 mg) in methanol (10 ml) was added 2N sodium hydroxide (3 ml) under ice-cooling and the mixture was stirred at room temperature for 4 hours. The reaction mixture was concentrated, and the residue was dissolved in water and washed with ether. The aqueous layer was adjusted to pH 5 with 1N hydrochloric acid, and concentrated to dryness. Chloroform was added to the residue and the insoluble materials were filtered off. The filtrate was concentrated to give 850 mg of 4-oxo-4-[3-(2-oxo-1-pyrrolidinyl)propylamino]butyric acid.
Reaction SMILES: Cl.C([O:4][C:5](=[O:31])[CH:6]([NH:21][C:22]1[CH:27]=[CH:26][C:25]([C:28](=[NH:30])[NH2:29])=[CH:24][CH:23]=1)[C:7]1[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=1[F:20])C.[OH-].[Na+].Cl>C1COCC1>[C:28]([C:25]1[CH:24]=[CH:23][C:22]([NH:21][CH:6]([C:7]2[CH:12]=[C:11]([O:13][CH2:14][CH3:15])[C:10]([O:16][CH2:17][CH2:18][OH:19])=[CH:9][C:8]=2[F:20])[C:5]([OH:31])=[O:4])=[CH:27][CH:26]=1)(=[NH:29])[NH2:30]
Reactant: CCOC(=O)C(Nc1ccc(C(=N)N)cc1)c1cc(OCC)c(OCCO)cc1F
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCOc1cc(C(Nc2ccc(C(=N)N)cc2)C(=O)O)c(F)cc1OCCO
Temperature: 0 °C
Reaction time: 0.67 h
Yield: 87.4 %

Procedure:
The (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid ethyl ester hydrochloride (172 mg) described in example 1.6 was suspended in THF (1.1 ml). A solution of NaOH (0.82 ml, 1 M in H2O) was added and stirred for 30 min at 0° C. and for 40 min at room temperature. 1M HCl (0.41 ml) was added. The mixture was concentrated. The solid was washed with water and ether and dried to give 129 mg of (RS)-(4-carbamimidoyl-phenylamino)-[5-ethoxy-2-fluoro-4-(2-hydroxy-ethoxy)-phenyl]-acetic acid as a colorless solid. MS: 392 ([M+H]+).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH:10]([OH:15])[C:11]([F:14])([F:13])[F:12])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:16](Cl)(=[O:18])[CH3:17].O>N1C=CC=CC=1>[C:16]([O:15][CH:10]([CH2:9][CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[C:11]([F:13])([F:14])[F:12])(=[O:18])[CH3:17]
Reactant: OC(CCCc1ccccc1)C(F)(F)F
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)OC(CCCc1ccccc1)C(F)(F)F
Reaction time: 2 h
Yield: 98.1 %

Procedure:
18.5 g (85 mmol) of the above product (15-1) was dissolved in 100 ml of pyridine, then added with 7.1 g (90 mmol) of acetyl chloride at 0°-5° C. and stirred at the same temperature for 2 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The resulting organic layer was washed with 10% hydrochloric acid, water, a 5% sodium bicarbonate solution and brine successively in that order, then dried over anhydrous magnesium sulfate and concentrated under reduced pressure to obtain 21.7 g of 2-acetoxy-5-phenyl-1,1,1-trifluoropentane (16-1) as a pale yellow liquid. Yield: 98%.