Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N:9]=O)=[C:4]([NH2:11])[N:3]=1.C(=O)([O-])[O-].[K+].[K+].[Cl:18][C:19]1[CH:20]=[C:21]([CH2:26][C:27](=O)[CH3:28])[CH:22]=[CH:23][C:24]=1[Cl:25]>CN(C)C=O>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]2[C:4](=[N:11][C:27]([CH3:28])=[C:26]([C:21]3[CH:22]=[CH:23][C:24]([Cl:25])=[C:19]([Cl:18])[CH:20]=3)[N:9]=2)[N:3]=1
Reactant: CC(=O)Cc1ccc(Cl)c(Cl)c1
Reactant: Nc1nc(N)c(N=O)c(N)n1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nc2nc(N)nc(N)c2nc1-c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A stirred solution of 1.0 gram (0.007 mole) of 2,4,6-triamino-5nitrosopyrimidine and 2.7 grams (0.020 mole) of potassium carbonate in 30 mL of N,N-dimethylformamide was heated to 95°-100° C., and 2.0 grams (0.010 mole) of (3,4-dichlorophenyl)acetone was added in one portion. Upon completion of addition, the reaction mixture was allowed to cool to ambient temperature, where it was allowed to stir for about 18 hours. After this time the reaction mixture was concentrated under reduced pressure. The residue was triturated with 250 mL of water, and the remaining solid was collected by filtration. The solid was further triturated with 50 mL of 20% methanol in methylene chloride. The remaining solid was collected by filtration, yielding 0.5 gram of 2,4-diamino-6-(3,4-dichlorophenyl)-7-methylpteridine. The NMR spectrum was consistent with the proposed structure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH:4]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])P(OC)(OC)=O.CN(C)C(=N)N(C)C.[N+:28]([C:31]1[C:32]([CH:37]=O)=[N:33][CH:34]=[CH:35][CH:36]=1)([O-:30])=[O:29]>C1COCC1.O>[C:15]([O:14][C:12]([NH:11][C:4](=[CH:37][C:32]1[C:31]([N+:28]([O-:30])=[O:29])=[CH:36][CH:35]=[CH:34][N:33]=1)[C:3]([O:2][CH3:1])=[O:19])=[O:13])([CH3:16])([CH3:17])[CH3:18]
Reactant: O=Cc1ncccc1[N+](=O)[O-]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)P(=O)(OC)OC
Agent: CN(C)C(=N)N(C)C
Solvent: O
Solvent: C1CCOC1
Product: COC(=O)C(=Cc1ncccc1[N+](=O)[O-])NC(=O)OC(C)(C)C
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
Methyl[(tert-butoxycarbonyl)amino](dimethoxyphosphoryl)acetate (1.33 g, 4.46 mmol) was dissolved in dry THF (20 mL) and cooled to −78° C. under nitrogen. Tetramethylguanidine (490 mg, 4.26 mmol) was added and the solution stirred at −78° C. for a further 10 mins. A solution of 3-nitropyridine-2-carbaldehyde (Tetrahedron vol 0.54 (1998) p 6311) (618 mg, 4.06 mmol) in dry THF (5 mL.) was added drop wise. After stirring the solution for 2 hours. at −78° C. (50 mL) it was diluted with water (150 mL) and extracted with ethyl acetate. The combined extracts were washed with water (2×20 mL) and brine (20 mL), dried (MgSO4) and evaporated under reduced pressure to give a yellow oil, which was purified by column chromatography (DCM) to give the title compound as a 4:1 mixture of Z/E isomers (1.1 g, 84%).
Reaction SMILES: C(Cl)(Cl)Cl.Br[CH2:6][C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1)=[O:8].[C:19]1([CH:25]2[CH2:30][C:29](=[O:31])[CH2:28][C:27](=[O:32])[CH2:26]2)[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[OH:32][C:27]1[CH2:26][CH:25]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:30][C:29](=[O:31])[C:28]=1[CH2:6][C:7](=[O:8])[C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([C:15]([F:18])([F:17])[F:16])[CH:10]=1
Reactant: O=C1CC(=O)CC(c2ccccc2)C1
Reactant: O=C(CBr)c1cccc(C(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C1CC(c2ccccc2)CC(O)=C1CC(=O)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 34.4 %

Procedure:
To a chloroform solution (2 mL) of 2-bromo-3′-trifluoromethylacetophenone (534.1 mg, 2 mmol) and 5-phenyl-1,3-cyclohexanedione (376.5 mg, 2 mmol) was added potassium carbonate (276.4 mg, 2 mmol) and stirred under suspension at room temperature over night. The reaction liquid was added with ethyl acetate (5 mL), to filter off undissolved substance, followed by concentration of thus obtained organic layer under reduced pressure and purification of concentrated residue using silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain a crude product, which was further purified by suspension (hexane 1 ml/ethyl acetate about 0.2 ml) to obtain an objective compound (257.8 mg, 35.0%).
Reaction SMILES: Br.[CH2:2]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7]Br)[CH3:3].[SH:13][C:14]1[NH:15][C:16]2[C:17](=[CH:19][S:20][CH:21]=2)[N:18]=1>CC(C)=O>[CH2:2]([NH:4][C:5]1[CH:12]=[CH:11][CH:10]=[CH:9][C:6]=1[CH2:7][S:13][C:14]1[NH:18][C:17]2=[CH:19][S:20][CH:21]=[C:16]2[N:15]=1)[CH3:3]
Reactant: CCNc1ccccc1CBr
Reactant: Sc1nc2cscc2[nH]1
Agent: Br
Solvent: CC(C)=O
Product: CCNc1ccccc1CSc1nc2cscc2[nH]1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.12 g of 2-ethylaminobenzyl bromide hydrobromide are added to a solution of 0.60 g of 2-mercaptothieno-[3,4-d]imidazole in 100 ml of acetone. After the mixture has been stirred at room temperature for 24 hours, the solvent is removed by distillation in vacuo, and the crystalline residue is washed with acetone. Then 1N NH4OH solution is added to the product, the mixture is stirred for 2 hours, and the solid is filtered off with suction and washed wit water. The residue which has been dried in air is dissolved in methylene chloride, active charcoal is added, and the mixture is filtered. Concentration in vacuo results in the clorless crystalline product.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[C:14]3[CH:15]=[CH:16][S:17][C:13]=3[C:12](=[N:18]O)[CH2:11][CH2:10]2)[CH:5]=[CH:6][C:7]=1[Cl:8].[OH2:20]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:9]2[CH2:10][CH2:11][NH:18][C:12](=[O:20])[C:13]3[S:17][CH:16]=[CH:15][C:14]2=3)[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: ON=C1CCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Reactant: O
Solvent: CCOC(C)=O
Product: O=C1NCCC(c2ccc(Cl)c(Cl)c2)c2ccsc21
Temperature: 130 °C
Reaction time: 4 h
Yield: 86 %

Procedure:
In a 250-ml round bottomed flask equipped with a stirbar was placed 4-(3,4-dichlorophenyl)-N-hydroxy-5,6-dihydro-1-benzothiophen-7(4H)-imine (1.25 g, 4.00 mmol) and polyphosphoric acid (40 g, 200 mmol). The resulting mixture was heated at 130° C. under an atmosphere of nitrogen with stirring for ˜4 hours, leaving a dark brown mixture. The mixture was allowed to cool to rt then water and ethyl acetate were added. The mixture was stirred briefly then transferred to a separatory funnel. The organic layer was separated then the aqueous layer was extracted with additional ethyl acetate. The organic layers were combined, washed with brine, dried over sodium sulfate, filtered, and evaporated to leave crude product as a brown oil. The residue was purified using column chromatography on silica gel (120 g RediSep column, gradient 0% ethyl acetate in dichloromethane to 90% ethyl acetate in dichloromethane over 20 minutes) give the product 1.08 g (86% yield) product as a light tan solid. LCMS: (FA) ES+ 312, 314. 1H NMR (400 MHz, DMSO) δ 8.24-8.12 (s, 1H), 7.65-7.59 (d, J=5.2 Hz, 1H), 7.60-7.51 (d, J=8.3 Hz, 1H), 7.45-7.36 (d, J=2.1 Hz, 1H), 7.11-7.01 (dd, J=8.3, 2.1 Hz, 1H), 6.64-6.51 (d, J=5.2 Hz, 1H), 4.56-4.42 (dd, J=8.8, 5.5 Hz, 1H), 3.25-3.03 (m, 2H), 2.34-2.18 (m, 1H), 2.10-1.95 (m, 1H).
Reaction SMILES: [F:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[CH:5]=[CH:4][N:3]=1.C(O)(=O)C.[H][H]>C(OCC)(=O)C.[Pd]>[NH2:8][C:7]1[C:2]([F:1])=[N:3][CH:4]=[CH:5][C:6]=1[CH3:11]
Reactant: Cc1ccnc(F)c1[N+](=O)[O-]
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Product: Cc1ccnc(F)c1N

Procedure:
To a solution of 10.1 g (grams) (65 mmol (millimole)) of 2-fluoro-4-methyl-3-nitropyridine in 200 mL (milliliter) of ethyl acetate was added 25 g (0.40 mol) of acetic acid and 0.8 g of 5 percent palladium on carbon catalyst. This mixture was shaken under 50 psig (pounds per square inch gauge, 2400 kiloPascals) pressure of hydrogen for 18 hours, was filtered, and was concentrated by evaporation under reduced pressure to obtain an oil. This oil was partitioned between dilute aqueous sodium bicarbonate and ether. The organic phase was separated, dried over magnesium sulfate, and filtered. The filtrate was concentrated by evaporation under reduced pressure and the residue was purified by column chromatography to obtain 7.2 g (88 percent of theory) of the title compound as a colorless solid melting at 63°-64° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH:18]=O)=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[CH2:23][CH2:24][C:25]([O:27]C)=[O:26])[CH:5]=[CH:6][CH:7]=1.Cl.[NH2:30][OH:31]>O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH:18]=[N:30][OH:31])=[CH:15][CH:16]=3)[N:11]([CH2:20][CH3:21])[C:10](=[O:22])[C:9]=2[CH2:23][CH2:24][C:25]([OH:27])=[O:26])[CH:5]=[CH:6][CH:7]=1
Reactant: CCn1c(=O)c(CCC(=O)OC)c(-c2cccc(Cl)c2)c2ccc(C=O)nc21
Reactant: NO
Agent: Cl
Solvent: O
Product: CCn1c(=O)c(CCC(=O)O)c(-c2cccc(Cl)c2)c2ccc(C=NO)nc21
Reaction time: 1 h
Yield: 4.8 %

Procedure:
To a 33 ml methanol-pyridine (10:1) solution containing 1.50 g of methyl 3-[4-(3-chlorophenyl)-1-ethyl-7-formyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoate was added 300 mg of hydroxylamine hydrochloride under ice cooling. After stirring for 1 hour, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic layer was washed with water and saturated brine and then the solvent was evaporated. The resulting residue was treated in a similar manner to Example 2 to obtain 72 mg of 3-[4-(3-chlorophenyl)-1-ethyl-7-hydroxyiminomethyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]propanoic acid as colorless crystals.
Reaction SMILES: [CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2].[OH-].[Na+]>FC(F)(F)C(O)=O.O.[Pt](=O)=O>[CH:1]([NH:4][N:5]1[C:17]2[C:16]3[CH2:15][CH2:14][CH2:13][CH2:12][C:11]=3[N:10]=[C:9]([NH2:18])[C:8]=2[N:7]=[C:6]1[CH2:19][CH2:20][CH3:21])([CH3:3])[CH3:2]
Reactant: CCCc1nc2c(N)nc3ccccc3c2n1NC(C)C
Agent: O=[Pt]=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCCc1nc2c(N)nc3c(c2n1NC(C)C)CCCC3
Reaction time: 144 h
Yield: 38.1 %

Procedure:
A solution of N1-isopropyl-2-propyl-1H-imidazo[4,5-c]quinoline-1,4-diamine (0.59 g, 2.1 mmol) in 15 mL of trifluoroacetic acid was treated with platinum(IV) oxide (0.55 g, 2.4 mmol) and shaken under an atmosphere of hydrogen (3.8×105 Pa). After 6 days, the reaction mixture was filtered through a pad of CELITE filter agent and rinsed with a mixture of 85:15:0.1 CHCl3:MeOH:TFA until the filtrate ran clear. The filtrate was concentrated under reduced pressure to yield a white foam. The material was suspended in water and treated with 50% NaOH solution until the pH reached 13. A white solid precipitated and was triturated in the basic mixture for 1 h. The white solid was collected by vacuum filtration. The solid was purified by chromatography (SiO2, 95:5:0.1 CHCl3:MeOH:NH4OH) to yield 0.23 g of N1-isopropyl-2-propyl-6,7,8,9-tetrahydro-1H-imidazo[4,5-c]quinoline-1,4-diamine as a white solid.
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22](Br)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]1[CH2:37][CH2:36][N:35]2C(=NC[CH2:33][CH2:34]2)CC1>N1CCCCC1>[CH2:1]([O:8][N:9]1[C:18](=[O:19])[C:17]2[CH:20]=[C:21]([O:24][CH3:25])[C:22]([N:35]3[CH2:34][CH2:33][CH2:27][CH2:37][CH2:36]3)=[C:15]3[C:16]=2[C:11](=[CH:12][CH:13]=[CH:14]3)[C:10]1=[O:26])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc2c3c(cccc3c1Br)C(=O)N(OCc1ccccc1)C2=O
Reactant: C1CCC2=NCCCN2CC1
Solvent: C1CCNCC1
Product: COc1cc2c3c(cccc3c1N1CCCCC1)C(=O)N(OCc1ccccc1)C2=O

Procedure:
2-Benzyloxy-5-methoxy-6-bromo-benzo[de]isoquinoline-1,3-dione (0.5 g, 1.2 mmol, from Example Z) was reacted in piperidine (3 mL) in the presence of DBU (0.05 mL) following the procedure of Example 18 to give 0.3 g of 2-benzyloxy-5-methoxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione. The hydrogenation of 2-benzyloxy-5-methoxy-6-(piperidin-1-yl)-benzo[de]isoquinoline-1,3-dione (0.3 g, 0.7 mmol) was performed as described in Example 18 to give 0.17 g of the title compound, mp 204-205° C.;
Reaction SMILES: [N:1]([CH:4]1[CH2:11][CH2:10][CH:9](Br)[CH:8]2[N:13]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:5]1[CH2:6][CH2:7]2)=[N+]=[N-].N(C1CCC2N(CC3C=CC=CC=3)C1CCC2Br)=[N+]=[N-]>>[CH2:14]([N:13]1[CH:9]2[CH:8]3[NH:1][CH:4]([CH2:11][CH2:10]2)[CH:5]1[CH2:6][CH2:7]3)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: [N-]=[N+]=NC1CCC(Br)C2CCC1N2Cc1ccccc1
Agent: [N-]=[N+]=NC1CCC2C(Br)CCC1N2Cc1ccccc1
Product: c1ccc(CN2C3CCC4NC3CCC42)cc1
Yield: 68 %

Procedure:
The synthesis described in Ex. 2.1 was repeated, but substituting the azide (1.1A) with the compound (1.1B) obtained in Ex. 1.1. The compound 2-benzyl-2,7-diaza-tricyclo-[4.4.0.03,8]decane is obtained. Yield: 68%. 1H-NMR (CDCl3) δ 1.50-2.00 (m, 8H); 2.70-2.80 (m, 2H); 3.00-3.10 (m, 2H); 3.90 (AB system, 2H, J=13.8 Hz); 7.20-7.42 (m, 5H). Anal. calc. for C15H20N2: C, 78.90; H, 8.83; N, 12.27. Found: C, 78.78; H, 8.81; N, 12.26.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:10]=[CH:11][C:12]=1[Cl:13])[C:5]([O:7]CC)=O.[Cl:14][C:15]1[N:20]=[C:19]([CH3:21])[CH:18]=[CH:17][CH:16]=1>>[Br:1][C:2]1[CH:3]=[C:4]([C:5](=[O:7])[CH2:21][C:19]2[CH:18]=[CH:17][CH:16]=[C:15]([Cl:14])[N:20]=2)[CH:10]=[CH:11][C:12]=1[Cl:13]
Reactant: Cc1cccc(Cl)n1
Reactant: CCOC(=O)c1ccc(Cl)c(Br)c1
Product: O=C(Cc1cccc(Cl)n1)c1ccc(Cl)c(Br)c1

Procedure:
In a similar manner as described in Example 1 from ethyl 3-bromo-4-chlorobenzoate (42.6 g, 171 mmol) and 6-chloro-2-picoline (18.7 mL, 171 mmol), 1-(3-bromo-4-chlorophenyl)-2-(-6-chloro-2-pyridinyl)ethanone was obtained as a pale yellow solid existing as a mixture of ketone and enol tautomers. 1H NMR (CDCl3) of ketone: δ 8.30 (d, 1H), 7.92 (dd, 1H), 7.69–7.54 (m, 2H), 7.24 (m, 2H), 4.42 (s, 2H); MS m/z 344 (M+1).
Reaction SMILES: C([O:4][CH:5]([C:14](=[O:16])[NH2:15])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=O)C.C(OC[C@H](C1C=CC=CC=1)CC(=O)N)(=O)C>>[C:14]([CH:5]([OH:4])[CH:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[CH3:7])(=[O:16])[NH2:15]
Reactant: CC(=O)OC(C(N)=O)C(C)c1ccccc1
Agent: CC(=O)OC[C@@H](CC(N)=O)c1ccccc1
Product: CC(c1ccccc1)C(O)C(N)=O

Procedure:
Except for using (S)-3-N-morphoryl carbamoyl-2-phenyl propanol acetate, instead of (S)-3-carbamoyl-2-phenyl propanol acetate as the starting material, the same procedure with that of Example 38 was repeated.
Reaction SMILES: [C:1]([C:9]1[N:13]([CH3:14])[C:12]([CH:15]([C:21]2[CH:26]=[CH:25][C:24]([NH2:27])=[CH:23][C:22]=2[F:28])C(OCC)=O)=[CH:11][C:10]=1[CH3:29])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO.C1COCC1>[F:28][C:22]1[CH:23]=[C:24]([CH:25]=[CH:26][C:21]=1[CH2:15][C:12]1[N:13]([CH3:14])[C:9]([C:1](=[O:8])[C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[C:10]([CH3:29])[CH:11]=1)[NH2:27]
Reactant: CCOC(=O)C(c1ccc(N)cc1F)c1cc(C)c(C(=O)c2ccccc2)n1C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1cc(Cc2ccc(N)cc2F)n(C)c1C(=O)c1ccccc1
Yield: 72.2 %

Procedure:
Ethyl 2-(5-benzoyl-1,4-dimethylpyrrol-2-yl)-2-(2-fluoro-4-aminophenyl)acetate (5.3 g, 13,4 mmol) [prepared as in Example 1, Step (c)] and 50% aqueous NaOH (5 ml) were dissolved in a 1:1 mixture of methanol/THF (100 ml), and the reaction mixture was refluxed for 30 min. After removing the solvents in vacuo, the residue was diluted with water and acidified with concentrated HCl. The product was extracted into ethyl acetate, and the organic layer was washed with brine, dried over sodium sulfate, and the solvent was removed under reduced pressure. The residue was re-dissolved in DMF (200 ml) and refluxed for 30 min. The reaction mixture was cooled, poured into water/ice, and the product was extracted into ethyl acetate. The organic layer was washed with water and dried over sodium sulfate. Evaporation of the solvent gave 3-fluoro-4-[5-benzoyl-1,4-dimethyl-1H-pyrrol-2-ylmethyl]aniline (3.12 g, 69%) as a solid.
Reaction SMILES: C[O:2][C:3]1[CH:20]=[CH:19][C:6]([O:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[O:15][CH:16]=[N:17][N:18]=3)=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.N[C@H](C(O)=O)CCSC.CS(O)(=O)=O>C(=O)(O)[O-].[Na+]>[O:15]1[CH:16]=[N:17][N:18]=[C:14]1[C:11]1[CH:12]=[CH:13][C:8]([O:7][C:6]2[CH:19]=[CH:20][C:3]([OH:2])=[CH:4][CH:5]=2)=[CH:9][CH:10]=1
Reactant: COc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Agent: CS(=O)(=O)O
Agent: CSCC[C@H](N)C(=O)O
Agent: O=C([O-])O
Product: Oc1ccc(Oc2ccc(-c3nnco3)cc2)cc1
Temperature: 50 °C
Yield: 87.3 %

Procedure:
A mixture of 2-[4-(4-Methoxy-phenoxy)-phenyl]-[1,3,4]oxadiazole (1.1 g, 4.1 mmol), methionine (0.94 g, 4.9 mmol) and methanesulfonic acid (20.5 mL) was heated to 50° C. for 1.5 hours. The mixture was poured into ice cold 5M sodium hydroxide solution (60 mL), diluted with sodium bicarbonate solution (saturated aqueous), and was extracted three times into ethyl acetate. The combined organic phases were dried over sodium sulfate (Na2SO4), filtered and concentrated in vacuo, affording 4-(4-[1,3,4]oxadiazol-2-yl-phenoxy)-phenol as a colorless solid (0.91 g).
Reaction SMILES: [CH3:1][O:2][C:3]([O:6][CH3:7])([CH3:5])[CH3:4].CC1C=CC(S([O-])(=O)=O)=CC=1.C1C=C[NH+]=CC=1.[I:25][C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C@@H](O)CO)=[CH:28][CH:27]=1>CN(C=O)C>[I:25][C:26]1[CH:37]=[CH:36][C:29]([O:30][CH2:31][C@@H:1]2[CH2:7][O:6][C:3]([CH3:5])([CH3:4])[O:2]2)=[CH:28][CH:27]=1
Reactant: OC[C@H](O)COc1ccc(I)cc1
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(I)cc2)O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2,2-Dimethoxypropane (1.94 ml, 15.8 mmol) and PPTS (0.079 mg, 0.32 mmol) are added to a solution of (S)-3-(4-Iodo-phenoxy)-propane-1,2-diol (0.93 g, 3.16 mmol) in DMF (20 ml), and the resulting solution is left to stir at room temperature overnight. The solvent is removed in vacuo and the residue is purified by chromatography (SiO2, EtOAc:Iso-hexane) to afford (R)-4-(4-Iodo-phenoxymethyl)-2,2-dimethyl-[1,3]dioxolane as a colourless oil.
Reaction SMILES: [NH2:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]2[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=2)=[O:8])[CH2:3]1.[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27](O)=[O:28])[N:21]=[N:20]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C>CN(C)C=O>[NH:19]1[CH:23]=[C:22]([CH2:24][CH2:25][CH2:26][C:27]([NH:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][CH2:10][C:11]3[CH:16]=[C:15]([Cl:17])[CH:14]=[C:13]([Cl:18])[CH:12]=3)=[O:8])[CH2:3]2)=[O:28])[N:21]=[N:20]1
Reactant: O=C(O)CCCc1c[nH]nn1
Reactant: NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: O=C(CCCc1c[nH]nn1)NC1CCN(C(=O)OCc2cc(Cl)cc(Cl)c2)C1
Reaction time: 2 h

Procedure:
A mixture comprising of 3,5-dichlorobenzyl 3-aminopyrrolidine-1-carboxylate (1 equiv), 4-(1H-1,2,3-triazol-4-yl)butanoic acid (1 equiv.), HATU (1.5 equiv.) and triethylamine (5 equiv.) in dimethylformamide was stirred at RT for 18 hours. Another 1 equivalent of 4-(1H-1,2,3-triazol-4-yl)butanoic acid was added to the reaction mixture and stirring continued for a further 2 hours. The reaction mixture was concentrated under reduced pressure, diluted with water and extracted with DCM. The organic portion was separated, dried over MgSO4, filtered and concentrated under reduced pressure. The crude product was dry loaded using silica onto a 12 g ISCO column, eluting with 0-15% MeOH in DCM. The product fractions were combined and concentrated under reduced pressure. Further purification was carried our using preparative LC-MS. The product fractions were concentrated under reduced pressure to give an aqueous solution and extracted with EtOAc to afford the title compound;
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH3:26][O:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=1[N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1>C(#N)C>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH:10]([CH2:14][N:37]2[CH2:36][CH2:35][N:34]([C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][C:28]=3[O:27][CH3:26])[CH2:39][CH2:38]2)[CH2:9]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N1CCCC(COS(C)(=O)=O)C1
Reactant: COc1ccccc1N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1ccccc1N1CCN(CC2CCCN(C(=O)OC(C)(C)C)C2)CC1
Temperature: 25 °C

Procedure:
To a solution of 3-methanesulfonyloxymethyl-piperidine-1-carboxylic acid tert-butyl ester (11.06 g, 0.04 mol) in acetonitrile (180 mL) was added potassium carbonate (26 g, 0.19 mol) followed by 1-(2-methoxy-phenyl) piperazine (7.25 g, 0.04 mol). After completion of addition the reaction mixture was heated to reflux. After 12 h the reaction mixture was cooled down to room temperature and quenched with water. The aqueous layer was extracted with ethyl acetate (3×100 mL). The combined organic layers were dried over sodium sulfate and concentrated to yield an oil. This crude material was purified using silica gel chromatography (7:3:0.05 Hexane:EtOAc:2M NH3 in EtOH) to afford the desired compound in good yield (8.0 g, 55%). C22H35N3O3,LRMS (m/z)=390 (MH+).
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][C@@H:10]([C:13]([O:15][C:16]2[CH:17]=[C:18]3[C:23](=[CH:24][C:25]=2[CH3:26])[CH2:22][N:21](CC2C=CC(OC)=CC=2)[CH:20]=[CH:19]3)=O)[CH2:9]1)=O)(C)(C)C.FC(F)(F)C(O)=[O:39]>>[CH3:26][C:25]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][NH:21][C:22]2=[O:39])=[CH:17][C:16]=1[O:15][CH2:13][C@@H:10]1[CH2:11][CH2:12][NH:8][CH2:9]1
Reactant: O=C(O)C(F)(F)F
Reactant: COc1ccc(CN2C=Cc3cc(OC(=O)[C@@H]4CCN(C(=O)OC(C)(C)C)C4)c(C)cc3C2)cc1
Product: Cc1cc2c(=O)[nH]ccc2cc1OC[C@@H]1CCNC1
Temperature: 150 °C
Yield: 38.7 %

Procedure:
0.53 g (1.1 mmol) (R)-3-[2-(4-Methoxy-benzyl)-7-methyl-1-oxo-1,2-dihydro-isoquinolin-6-yloxymethyl]-pyrrolidine-1-carboxylic acid tert-butyl ester were dissolved in 2.5 g (22 mmol) trifluoroacetic acid. After 1 h at room temperature the mixture was heated for 2 h in a microwave oven at 150° C. Then the excess trifluoroacetic acid was distilled off in vacuo and the residue was diluted with 10 ml 1 M hydrochloric acid. The aqueous phase was washed with methylene chloride twice and then it was freeze dried to give 0.11 g 7-Methyl-6-((R)-1-pyrrolidin-3-ylmethoxy)-2H-isoquinolin-1-one as the hydrochloride. Rt=0.82 min (Method B). Detected mass: 259.1 (M+H+).
Reaction SMILES: C[O:2][C:3]([C:5]1([O:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH:16]([C:23]3[N:24]([C:34]4[CH:39]=[CH:38][C:37]([Cl:40])=[CH:36][CH:35]=4)[N:25]=[C:26]4[C:31]=3[CH:30]=[C:29]([F:32])[C:28]([F:33])=[CH:27]4)[CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:11][CH:10]=2)[CH2:7][CH2:6]1)=[O:4].[OH-].[Li+]>C1COCC1.CO>[Cl:40][C:37]1[CH:38]=[CH:39][C:34]([N:24]2[C:23]([CH:16]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[O:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][C:5]4([C:3]([OH:4])=[O:2])[CH2:7][CH2:6]4)=[CH:10][CH:11]=3)=[C:31]3[C:26]([CH:27]=[C:28]([F:33])[C:29]([F:32])=[CH:30]3)=[N:25]2)=[CH:35][CH:36]=1
Reactant: COC(=O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)C1(Oc2ccc(OC(c3c4cc(F)c(F)cc4nn3-c3ccc(Cl)cc3)C3CCCCC3)cc2)CC1

Procedure:
In analogy to the procedure described in example 7.2, [rac]-1-(4-{[2-(4-chloro-phenyl)-5,6-difluoro-2H-indazol-3-yl]-cyclohexyl-methoxy}-phenoxy)-cyclopropanecarboxylic acid methyl ester was treated with 1 N aqueous lithium hydroxide solution in THF and MeOH to give the title compound as colorless liquid. MS: m/e=553.3 [M+H+].