Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[Na+].[N:3]1([CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13]([NH:15]C(=O)C2C=CC=CC=2)=[O:14])[CH2:7][CH2:6][CH2:5][CH2:4]1>>[N:3]1([CH2:8][C:9]#[C:10][CH2:11][NH:12][C:13]([NH2:15])=[O:14])[CH2:4][CH2:5][CH2:6][CH2:7]1
Reactant: O=C(NCC#CCN1CCCC1)NC(=O)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Product: NC(=O)NCC#CCN1CCCC1
Reaction time: 0.2 h

Procedure:
To a solution of sodium hydroxide (0.1 mol) at 80° C. is added N-[[[4-(1-pyrrolidinyl)-2-butynyl]amino]-carbonyl]-benzamide (4.3 g, 0.015 mol) (Example 1f) in one portion. The solution is allowed to stir for 12 minutes, cooled, extracted with chloroform, dried over magnesium sulfate and concentrated to give an oil which solidifies upon standing; mp 71°-73° C.
Reaction SMILES: [I:1]Cl.[CH3:3][O:4][C:5]([C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([Si](C)(C)C)=[CH:28][C:27]=1[F:36])=[O:6]>C(Cl)Cl>[CH3:3][O:4][C:5]([C:7]1[N:15]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([O:23][CH3:24])=[CH:19][CH:18]=2)[C:14]2[CH:13]=[CH:12][N:11]=[CH:10][C:9]=2[C:8]=1[NH:25][C:26]1[CH:31]=[CH:30][C:29]([I:1])=[CH:28][C:27]=1[F:36])=[O:6]
Reactant: ClI
Reactant: COC(=O)c1c(Nc2ccc([Si](C)(C)C)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Solvent: ClCCl
Product: COC(=O)c1c(Nc2ccc(I)cc2F)c2cnccc2n1Cc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 80 %

Procedure:
Iodine monochloride (1M in DCM, 1.13 mL) was added dropwise over 10 minutes to a cooled (−10° C.) solution of 3-(2-fluoro-4-trimethylsilanyl-phenylamino)-1-(4-methoxy-benzyl)-1H-pyrrolo[3,2-c]pyridine-2-carboxylic acid methyl ester (269 mg, 0.56 mmol) in DCM (5 mL). The mixture was allowed to warm to ambient temperature and stirred for 20 minutes then quenched by the addition of saturated sodium thiosulphate solution (1 mL). The solution was partitioned between DCM (30 mL) and water (20 mL), the organic layer was separated, dried (Na2SO4), filtered and evaporated to give an orange oil. The oil was purified by flash column chromatography on silica (Si-PPC, cyclohexane:EtOAc, gradient 90:10 to 40:60) to provide the title compound as a yellow solid (240 mg, 80%). LCMS (method B): RT=2.59 min, M+H+=532.
Reaction SMILES: [CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CCCCCC>[CH2:1]([N:5]([CH2:19][CH2:20][CH2:21][CH3:22])[CH2:6][CH2:7][CH2:8][O:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:15])=[CH:12][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCN(CCCC)CCCOc1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCCCCC
Product: CCCCN(CCCC)CCCOc1ccc(C(=O)Nc2ccccc2)cc1
Temperature: 50 °C
Reaction time: 4 h
Yield: 85 %

Procedure:
6.5 g of 4-(3-dibutylaminopropoxyl)benzoyl chloride (V) (0.02 mol) is dissolved in 60 mL of n-hexane. 1.86 g of aniline (0.02 mol, 1 eq) and 2.76 g of potassium carbonate (0.02 mol, 1 eq) are added. The reaction mixture is heated to 50° C. and stirred for 4 hours. After the reaction the solid inorganic salt is filtered, washed with 2×10 mL of n-hexane and the filtrate is concentrated. The residue is purified by column chromatography (spheric silica; eluent: toluene:MTBE:methanol=5:4:1) to give 6.50 g of the title compound (VIe) (85%) as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1)([O-:15])=[O:14].C(O)(C(F)(F)F)=O>>[N+:13]([C:16]1[CH:23]=[CH:22][C:19]([CH:20]2[C:5]3[NH:6][C:7]4[C:12](=[CH:11][CH:10]=[CH:9][CH:8]=4)[C:4]=3[CH2:3][CH2:2][NH:1]2)=[CH:18][CH:17]=1)([O-:15])=[O:14]
Reactant: O=Cc1ccc([N+](=O)[O-])cc1
Reactant: NCCc1c[nH]c2ccccc12
Solvent: O=C(O)C(F)(F)F
Product: O=[N+]([O-])c1ccc(C2NCCc3c2[nH]c2ccccc32)cc1
Yield: 85 %

Procedure:
This product was prepared using the same procedure as for Intermediate 1 with tryptamine (2.0 g, 12.5 mmol), 4-nitrobenzaldehyde (1.88 g, 1 equiv.) and TFA (1.9 mL, 2 equiv.) to give the title compound (3.1 g, 86%) as a yellow powder. MP: 190° C.
Reaction SMILES: [CH3:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Br)=[O:5].[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH2:16])[CH3:12].C(=O)(O)[O-].[Na+]>CC(C)=O>[CH2:11]([O:13][C:14]1[CH:20]=[CH:19][CH:18]=[CH:17][C:15]=1[NH:16][C:4](=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[CH3:1])[CH3:12]
Reactant: CCOc1ccccc1N
Reactant: Cc1ccccc1C(=O)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Product: CCOc1ccccc1NC(=O)c1ccccc1C
Temperature: 40 °C
Yield: 94.5 %

Procedure:
A 19.9 g (0.1 mol) portion of o-methylbenzoyl bromide was added dropwise with cooling to a mixture of 13.7 g (0.1 mol) of o-ethoxyaniline and 8.4 g (0.1 mol) of sodium bicarbonate in 200 ml of acetone with stirring. After addition of the o-methylbenzoyl bromide, the reaction mixture was warmed to 40°C and the mixture was refluxed and stirred for another 40 hours. After filtering, the ether was distilled from the reaction mixture and the residual material was re-dissolved in ether and washed with water. The ether layer was dried over anhydrous sodium sulfate, the ether was removed and the product was distilled to obtain 24.1 g (94.5%) of a clear pink liquid having a boiling point of 148°C/0.04 mm Hg and nD20 of 1.5929. IR cm-1 (film) νNH 3295(S), νCO 1655,1615(S).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.CCN(C(C)C)C(C)C.Br[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1>CS(C)=O>[CH3:1][N:2]([CH2:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[C:21]1[N:26]=[C:25](/[CH:27]=[C:28]2/[C:29](=[O:34])[NH:30][C:31](=[O:33])[S:32]/2)[CH:24]=[CH:23][CH:22]=1
Reactant: O=C1NC(=O)/C(=C/c2cccc(Br)n2)S1
Reactant: CNCCc1ccccc1
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(CCc1ccccc1)c1cccc(/C=C2\SC(=O)NC2=O)n1
Temperature: 110 °C
Reaction time: 48 h

Procedure:
An 8 mL round-bottomed vial was charged with N-methyl-2-phenylethanamine (43 mg, 0.318 mmol, 1 equiv.) and DMSO (1 mL, 0.3 M), DiPEA (105 μL, 0.636 mmol, 2 equiv.), (Z)-5-((6-bromopyridin-2-yl)methylene)thiazolidine-2,4-dione (91 mg, 0.318 mmol, 1 equiv.), and the vial was purged with argon. The mixture was shaken for 48 h at 110° C. The reaction mixture was then partitioned between CH2Cl2 (10 mL) and sat. NaCl (20 mL). The aqueous layer was back extracted with CH2Cl2 (2×15 mL) and the combined organic layer was dried over xxx and concentrated under reduced pressure to provide an orange residue. The orange residue was triturated with ether (3×15 mL) to provide (Z)-5-((6-(methyl(phenethyl)amino)pyridin-2-yl)methylene)thiazolidine-2,4-dione as an orange film (2.6 mg, 175 mg theoretical, 5%). LC-MS m/z: 340 (M+1).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([OH:20])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C(=O)([O-])[O-].[K+].[K+].[C:32]([O:36][CH:37](Cl)[CH3:38])(=[O:35])[CH2:33][CH3:34].C(OCC)(=O)C>CS(C)=O>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:23][O:24][CH3:25])[C:8]([NH:10][CH:11]2[C:21](=[O:22])[N:13]3[C:14]([C:18]([O:20][CH:37]([O:36][C:32](=[O:35])[CH2:33][CH3:34])[CH3:38])=[O:19])=[CH:15][CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: CCC(=O)OC(C)Cl
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=CCS[C@H]12)c1csc(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CCC(=O)OC(C)OC(=O)C1=CCS[C@@H]2C(NC(=O)C(=NOC)c3csc(N)n3)C(=O)N12
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
To a solution of 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylic acid (syn-isomer, 100 g) in dimethylsulfoxide (650 ml) was added potassium carbonate (21.6 g). Thereto was added 1-chloroethyl propionate (42.8 g) at 40° C. and the mixture was stirred at the same temperature for 2 hours. The reaction mixture was poured into a mixture of ice-water (3 l) and ethyl acetate (2 l), and the separated organic layer was washed in turn with 5% aqueous sodium bicarbonate (300 ml×2), water (300 ml) and an aqueous sodium chloride, followed by drying over magnesium sulfate. After treating with activated charcoal, the solvent was removed by evaporation, and the residue was pulverized with diisopropyl ether to give 1-propionyloxyethyl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-cephem-4-carboxylate (syn-isomer, 80 g).
Reaction SMILES: [C:1]([NH:4][C@H:5]1[C@@H:11]([OH:12])[C@H:10]([OH:13])[C@@H:9]([CH2:14][OH:15])[O:8][CH:6]1[OH:7])(=[O:3])[CH3:2].C([CH2:18][C:19]([O-])=[O:20])=C.C(OCC)(=O)C.CO>CN(C=O)C>[C:19]([O:15][CH2:14][C@H:9]1[O:8][CH:6]([OH:7])[C@@H:5]([NH:4][C:1](=[O:3])[CH3:2])[C@@H:11]([OH:12])[C@@H:10]1[OH:13])(=[O:20])[CH3:18]
Reactant: C=CCC(=O)[O-]
Reactant: CC(=O)N[C@@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Solvent: CO
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H]1C(O)O[C@H](COC(C)=O)[C@@H](O)[C@@H]1O
Temperature: 25 °C
Reaction time: 5 h
Yield: 92 %

Procedure:
In 2 mL of DMF were suspended 500 mg (2.2 mmol) of N-acetylmannosamine. Vinylacetate (1 mL, 5 equivalent) and 160 mg of subtilisin mutant 8399 [Zhong et al., J. Am. Chem. Soc., 113:683 (1991)] were then added and the suspension was stirred vigorously at room temperature. The reaction progress was monitored by TLC with ethyl acetate/methanol (2/1). After 5 hours when the formation of the di-acetylated derivatives began, the reaction was stopped by evaporating the vinylacetate and DMF. Methanol was then added to dissolve the sugar. After the enzyme and salt were filtered off, the filtrate was concentrated. The residual syrup was chromatographed on a silica gel, with ethyl acetate/methanol (10/1) to give 6-O-Acetyl N-acetylmannosamine (92 percent) as α/β mixture (3:1) based on the NMR spectrum.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:13](=[CH:14][CH:15]=1)[CH:12]=[CH:11][C:10]1[CH:9]=[CH:8][C:7]([OH:16])=[CH:6][C:5]2=1.Br[CH2:18][CH:19]1[CH2:21][CH2:20]1.C(=O)([O-])[O-].[K+].[K+].O>CC(C)=O.[I-].[K+]>[Br:1][C:2]1[CH:15]=[CH:14][C:13]2[CH:12]=[CH:11][C:10]3[C:5]([C:4]=2[CH:3]=1)=[CH:6][C:7]([O:16][CH2:18][CH:19]1[CH2:21][CH2:20]1)=[CH:8][CH:9]=3
Reactant: Oc1ccc2ccc3ccc(Br)cc3c2c1
Reactant: BrCC1CC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CC(C)=O
Product: Brc1ccc2ccc3ccc(OCC4CC4)cc3c2c1
Yield: 86.9 %

Procedure:
A mixture of 6-bromophenanthren-3-ol (0.823 g, 3.02 mmol) from Step 1 above, (bromomethyl)cyclopropane (0.5 mL, 5.4 mmol), potassium carbonate (2.5 g, 18 mmol) and potassium iodide (5 mg) in acetone (50 mL) was heated at reflux for 3 days. Water was then added and the reaction mixture extracted with ethyl acetate The organic layer washed with brine, dried over MgSO4, filtered and concentrated. The crude material was purified by flash chromatography on silica (100% hexanes) to provide 3-bromo-6-(cyclopropylmethoxy)phenanthrene (0.859 g, 87%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=2)=[N:6][CH:7]=1.O[C@H:18]1[CH2:22][CH2:21][NH:20][C:19]1=[O:23].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.CCOC(/N=N/C(OCC)=O)=O>C(OCC)(=O)C.C1COCC1>[O:23]=[C:19]1[C@H:18]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:8]3[S:9][C:10]([C:13]([O:15][CH3:16])=[O:14])=[CH:11][N:12]=3)=[N:6][CH:7]=2)[CH2:22][CH2:21][NH:20]1
Reactant: O=C1NCC[C@@H]1O
Reactant: COC(=O)c1cnc(-c2ccc(O)cn2)s1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(-c2ccc(O[C@@H]3CCNC3=O)cn2)s1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a round-bottomed flask was added methyl 2-(5-hydroxypyridin-2-yl)thiazole-5-carboxylate (400 mg), (S)-3-hydroxy-pyrrolidin-2-one (188 mg), PPh3 (443 mg), and THF (10 mL). DEAD (299 mg) was added dropwise at 0° C. under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 12 hours. After being diluted with ethyl acetate (50 mL), the organic layer was washed with water (20 mL×2) and brine (10 mL) and dried over anhydrous Na2SO4. After filtration and evaporation of the solvent, the residue obtained was purified by silica gel column chromatography eluting with petroleum ether/ethyl acetate (4:1 to 1:3) to afford the subtitle compound. MS ESI+: m/z=320 [M-FH]+.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].ClOC(C)(C)C.[CH3:15][S:16][CH:17]([C:19]1[N:24]=[C:23]([O:25][CH3:26])[CH:22]=[C:21]([O:27][CH3:28])[N:20]=1)[CH3:18].C[O-].[Na+]>ClCCl.O.CO>[CH3:15][S:16][C:17]([C:19]1[N:20]=[C:21]([O:27][CH3:28])[CH:22]=[C:23]([O:25][CH3:26])[N:24]=1)([C:5]1[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[C:3]=1[NH2:4])[CH3:18]
Reactant: COc1cc(OC)nc(C(C)SC)n1
Reactant: Nc1ccccc1Cl
Agent: CC(C)(C)OCl
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: ClCCl
Solvent: O
Product: COc1cc(OC)nc(C(C)(SC)c2cccc(Cl)c2N)n1
Temperature: -65 °C
Reaction time: 0.17 h
Yield: 90 %

Procedure:
2-Chloroaniline 7 g (32.7 mmol) was dissolved in dichloromethane 100 ml and the solution was cooled to −65° C. To the solution a solution of t-butyl hypochlorite 3.55 g (32.7 mmol) in dichloromethane 10 ml was added dropwise and the solution was stirred at the same temperature for 10 minutes. Then a solution of 2-(1-methylthioethyl)-4,6-dimethoxypyrimidine in dichloromethane was added thereto dropwise and the solution was stirred at the same temperature for 1 hour. After a methanol solution of sodium methoxide 12.6 g (65.3 mmol) had been added dropwise and the mixed solution had been stirred at the same temperature for 10 minutes, the reaction solution was stirred until it came to room temperature. The reaction solution was poured into water and extracted with dichloromethane. The solvent was distilled off and the residue was purified with column chromatography (hexane/ethyl acetate=5/1) to obtain 2-{1-methylthio-1-(2-amino-3-chlorophenyl)ethyl}-4,6-dimethoxypyrimidine 10.0 g (90%).
Reaction SMILES: Cl[C:2]1[N:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([F:15])([F:14])[CH2:8][N:7]([CH:16]3[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]3)[C:6]=2[N:22]=1.O.C1(C)C(S(O)(=O)=O)=CC=CC=1.[NH2:35][C:36]1[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]2[CH2:48][CH2:47][N:46]([CH2:49][CH2:50][OH:51])[CH2:45][CH2:44]2)=[O:41])=[CH:38][C:37]=1[O:54][CH3:55]>C(O)(C)C>[CH:16]1([N:7]2[CH2:8][C:9]([F:15])([F:14])[C:10](=[O:13])[N:11]([CH3:12])[C:5]3[CH:4]=[N:3][C:2]([NH:35][C:36]4[CH:53]=[CH:52][C:39]([C:40]([NH:42][CH:43]5[CH2:44][CH2:45][N:46]([CH2:49][CH2:50][OH:51])[CH2:47][CH2:48]5)=[O:41])=[CH:38][C:37]=4[O:54][CH3:55])=[N:22][C:6]2=3)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]1
Reactant: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1N
Reactant: CN1C(=O)C(F)(F)CN(C2CCCCC2)c2nc(Cl)ncc21
Agent: Cc1ccccc1S(=O)(=O)O
Solvent: O
Solvent: CC(C)O
Product: COc1cc(C(=O)NC2CCN(CCO)CC2)ccc1Nc1ncc2c(n1)N(C1CCCCC1)CC(F)(F)C(=O)N2C
Yield: 20 %

Procedure:
A mixture of 0.112 g (0.34 mmole) 2-chloro-9-cyclohexyl-7,7-difluoro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-246), 0.097 g (0.51 mmole) of toluenesulfonic acid monohydrate, 0.10 g (0.34 mmole) of 4-amino-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide and 1 mL of isopropanol was heated in a sealed vessel at 170 degrees in a microwave reactor for 2 hours, cooled and concentrated under reduced pressure. The residue taken up in ethyl acetate and washed successively with 50 mL of saturated aqueous sodium bicarbonate, 50 mL of water, 50 mL of brine. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was by preparative thin layer chromatography, eluting with dichloromethane-methanol (90:10) to give 0.040 g of 4-(9-cyclohexyl-7,7-difluoro-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino)-N-[1-(2-hydroxy-ethyl)-piperidin-4-yl]-3-methoxy-benzamide (I-267).
Reaction SMILES: [Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=O.Cl.[NH2:14][OH:15]>C(O)C>[Cl:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[N:14][OH:15]
Reactant: COc1ccc(C=O)c(Cl)c1O
Reactant: NO
Agent: Cl
Solvent: CCO
Product: COc1ccc(C=NO)c(Cl)c1O

Procedure:
A mixture of 30 g of 2-chloro-3-hydroxy-p-anisaldehyde and 230 ml of ethanol is stirred at 70° for 4 hours in the presence of 12.3 g of hydroxylamine hydrochloride, the reaction mixture is subsequently evaporated, the residue is dried in a high vacuum and recrystallized from methanol/water. There is obtained 2-chloro-3-hydroxy-p-anisaldehyde oxime of m.p. 174°-176°.
Reaction SMILES: CO[C:3]([C:5]1[N:6]=[C:7]([C:24]#[N:25])[C:8]2[C:13]([C:14]=1[OH:15])=[C:12]([O:16][C:17]1[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=1)[CH:11]=[CH:10][CH:9]=2)=[O:4].[NH2:26][CH2:27][C:28]([OH:30])=[O:29]>>[C:24]([C:7]1[C:8]2[C:13](=[C:12]([O:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[CH:19][CH:18]=3)[CH:11]=[CH:10][CH:9]=2)[C:14]([OH:15])=[C:5]([C:3]([NH:26][CH2:27][C:28]([OH:30])=[O:29])=[O:4])[N:6]=1)#[N:25]
Reactant: NCC(=O)O
Reactant: COC(=O)c1nc(C#N)c2cccc(Oc3ccc(F)cc3)c2c1O
Product: N#Cc1nc(C(=O)NCC(=O)O)c(O)c2c(Oc3ccc(F)cc3)cccc12

Procedure:
The title compound was synthesized from 1-cyano-5-(4-fluoro-phenoxy)-4-hydroxy-isoquinoline-3-carboxylic acid methyl ester and glycine in analogy to example 1b; MS-(−)-ion: M−1=380.4.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8].C([O-])([O-])=O.[Na+].[Na+].[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21](Cl)=[O:22])=[CH:19][CH:18]=1>O>[Br:16][C:17]1[CH:25]=[CH:24][C:20]([C:21]([NH:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][C:7]([OH:9])=[O:8])=[O:22])=[CH:19][CH:18]=1
Reactant: NCCCCCC(=O)O
Reactant: O=C(Cl)c1ccc(Br)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)CCCCCNC(=O)c1ccc(Br)cc1
Reaction time: 4 h
Yield: 61.7 %

Procedure:
To a solution of 6-aminohexanoic acid (5.0 g, 38.7 mmol), Na2CO3 (4.1 g, 38.7 mmoL) in water (100 mL) was added drop-wise 4-bromobenzoyl chloride (8.5 g, 38.7 mmoL, dissolved in 80 mL THF) at 0° C. and stirred for 4 hours. The mixture was concentrated under reduced pressure. The pH value of the solution was adjusted to 1 by concentrated HCl. The resulting mixture was extracted by EtOAc (200 mL×3). The organic layers were combined and dried over Na2SO4, then concentrated to give the desired compound (7.5 g, yield 61.7%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([C:12](C)(C)[O:13][SiH2]C(C)(C)C)=[CH:9][CH2:8][CH:7]([NH:21]C(OC(C)(C)C)=O)[C:6]1=[O:29].C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:30])[CH2:4][N:5]1[CH2:11][C:10]([CH2:12][OH:13])=[CH:9][CH2:8][CH:7]([NH2:21])[C:6]1=[O:29]
Reactant: COC(=O)CN1CC(C(C)(C)O[SiH2]C(C)(C)C)=CCC(NC(=O)OC(C)(C)C)C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)CN1CC(CO)=CCC(N)C1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of [3-tert-Butoxycarbonylamino-6-(tert-butyl-dimethyl-silanyloxymethyl)-oxo-2,3,4,7-tetrahydro-azepin-1-yl]-acetic acid methyl ester, 17, (4.32 g, 9.7 mmol) in CH2Cl2 (20 mL) is treated with wet TFA (5 mL) and stirred at rt for 30 min. The solution is concentrated in vacuo using toluene to azeotrope off the solvent. The crude product is used without further purification.
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26]C=3)[C@H:16]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.S([O-])([O-])(=O)=O.[Mg+2].C([N:44](CC)CC)C.C(C=O)=O>C(O)C>[F:34][C:2]([F:35])([F:1])[C:3]1[CH:4]=[C:5]([CH2:13][O:14][C@H:15]2[CH2:20][CH2:19][CH2:18][N:17]([CH2:21][C:22]3[N:23]=[N:24][CH:25]=[CH:26][N:44]=3)[C@H:16]2[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:6]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:8]=1
Reactant: CCN(CC)CC
Reactant: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3cccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Agent: O=CC=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CCO
Product: FC(F)(F)c1cc(CO[C@H]2CCCN(Cc3nccnn3)[C@H]2c2ccccc2)cc(C(F)(F)F)c1
Reaction time: 0.5 h

Procedure:
The amidrazone hydrochloride of (b) above (200 mg) was dissolved in ethanol (2 ml). Magnesium sulphate was added (100 mg) and the mixture stirred for 30 min. Triethylamine (0.06 ml) was added followed by glyoxal (90 mg, trimeric dihydrate). This mixture was allowed to stir for 12 h. The solvent was removed in vacuo and the residue was dispersed between ethyl acetate and water. The organic layer was dried (MgSO4) and concentrated to afford a brown oil. This was purified by column chromatography on silica using hexane in ethyl acetate (95%) to afford the title compound. 1H NMR (360 MHz, CDCl3) δ1.53-1.72 (2H, m, CH2), 1.98-2.22 (2H, m, CH2), 2.42-2.53 (1H, m, NCHH), 3.14-3.22 (1H, m, NCHH), 3.61 (1H, bs, CHO), 3.74-3.81 (2H, m, NCHPh+OCHH), 4.04 (1H, d, J=12 Hz, NCHHtriazine), 4.19 (1H, d, J=12 Hz, OCHH), 4.47 (1H, d, J=12 Hz, NCHHtriazine), 7.24-7.37 (4H, m, ArH), 7.48-7.6 (4H, m, ArH), 7.70 (1H, s, ArH), 8.6 (1H, s, ArH). MS (CI+) m/z 497 (M+ +1, 100%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]([OH:8])=[N:6][CH:7]=1.Cl[C:10]([F:15])([F:14])C([O-])=O.[Na+].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:8][CH:10]([F:15])[F:14])=[N:6][CH:7]=1
Reactant: O=C([O-])C(F)(F)Cl
Reactant: Oc1ncc(Br)cn1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: CN(C)C=O
Product: FC(F)Oc1ncc(Br)cn1
Temperature: 65 °C
Reaction time: 15 h
Yield: 9.6 %

Procedure:
A reaction vial was charged with 5-bromopyrimidin-2-ol (1.50 g, 8.57 mmol), sodium 2-chloro-2,2-difluoroacetate (2.61 g, 17.14 mmol), potassium carbonate (2.1 equiv.) and DMF (10 mL). The resulting mixture was sparged with nitrogen for ˜5 min., then heated to 65° C. and stirred overnight (˜15 h). After cooling to rt, the resulting mixture was partitioned between EtOAc (300 mL) and water (100 mL). The layers were separated and the organic portion was washed with water (50 mL×2) then 80 mL of hexanes was added and washed again with water (50 mL×2), brine, then dried over sodium sulfate. The resulting solution was filtered and concentrated to remove solvent which afforded a colorless oil as the crude product mixture. This material was purified by ISCO silica gel chromatography (gradient Hex/EtOAc mixtures as eluant; 40 g column) Fractions containing the desired product were collected, combined and concentrated under vacuum to afford 186 mg (10%) of a colorless oil as the title compound. 1H NMR (400 MHz, METHANOL-d4) δ 8.95-8.71 (m, 2H), 7.83-7.27 (m, 1H).