Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2N)[CH:5]=[N:4][CH:3]=1.N([O-])=[O:14].[Na+].O.N>S(=O)(=O)(O)O>[CH3:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][C:10]=2[OH:14])[CH:5]=[N:4][CH:3]=1
Reactant: Cc1cncc2cccc(N)c12
Reactant: O=N[O-]
Agent: N
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Product: Cc1cncc2cccc(O)c12
Yield: 63.9 %

Procedure:
A solution of 4-methyl-5-aminoisoquinoline (869 mg) in concentrated sulfuric acid (8 ml) was added with sodium nitrite (379 mg) with ice cooling and stirring and stirred for 0.5 hours. The reaction mixture was added with water (12 ml) and then stirred at 130° C. for 16 hours. The reaction mixture was neutralized with 28% aqueous ammonia solution and extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (chloroform:methanol=30:1) to obtain the title compound (559 mg).
Reaction SMILES: C[O:2][C:3](=O)[C@H:4]([OH:21])[C@@H:5]([NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[BH4-].[Na+].Cl>C(O)C>[C:17]([O:16][C:14]([NH:13][C@@H:5]([CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)[C@@H:4]([OH:21])[CH2:3][OH:2])=[O:15])([CH3:20])([CH3:18])[CH3:19]
Reactant: COC(=O)[C@H](O)[C@H](Cc1ccccc1)NC(=O)OC(C)(C)C
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)CO
Temperature: 30 °C
Reaction time: 3 h

Procedure:
A solution of N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenylbutyric acid methyl ester 85.1 kg dissolved in ethanol 220 kg was kept at 10-20° C. and mixed with sodium borohydride 13.5 kg and stirred at 15-45° C. for 3 hrs. The reaction solution was cooled, adjusted with 3N-HCl to pH 2.5-3.5, concentrated under a reduced pressure, and washed with ethyl acetate and water to separate an organic phase, which was washed with aqueous 10% sodium chloride solution and concentrated under an reduced pressure to obtain the crude N-tert-butoxycarbonyl-3(S)-amino-2(R)-hydroxy-4-phenyl-1-butanol.
Reaction SMILES: [NH2:1][C:2]1([CH2:17][CH3:18])[C:7](=[O:8])[N:6]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)[C:5](=[O:15])[NH:4][C:3]1=[O:16].C(N1C(=O)C(C)(N2[C:36](=[O:37])[C:35]3[C:30](=[C:31]([F:41])[C:32]([F:40])=[C:33]([F:39])[C:34]=3[F:38])[C:29]2=[O:42])C(=O)NC1=O)C>>[CH:9]1([N:6]2[C:7](=[O:8])[C:2]([CH2:17][CH3:18])([N:1]3[C:29](=[O:42])[C:30]4[C:35](=[C:34]([F:38])[C:33]([F:39])=[C:32]([F:40])[C:31]=4[F:41])[C:36]3=[O:37])[C:3](=[O:16])[NH:4][C:5]2=[O:15])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCN1C(=O)NC(=O)C(C)(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C1=O
Reactant: CCC1(N)C(=O)NC(=O)N(C2CCCCC2)C1=O
Product: CCC1(N2C(=O)c3c(F)c(F)c(F)c(F)c3C2=O)C(=O)NC(=O)N(C2CCCCC2)C1=O

Procedure:
Compound 19i was prepared from 5-amino-1-cyclohexyl-5-ethylbarbituric acid (0.38 g, 1.50 mmol) using the same procedure described for 19f. The crude product was recrystallized from EtOH to give 1-cyclohexyl-5-ethyl-5-(tetrafluorophthalimido)barbituric acid (19i) as white crystals.
Reaction SMILES: C([O:4][C:5]1[C:10]([CH2:11][CH3:12])=[CH:9][C:8]([OH:13])=[C:7]([C:14](=[O:16])[CH3:15])[C:6]=1[CH2:17][CH3:18])(=O)C.[C:19]1(=O)[CH2:22][CH2:21][CH2:20]1.N1CCCC1>C1(C)C=CC=CC=1>[CH2:17]([C:6]1[C:5]([OH:4])=[C:10]([CH2:11][CH3:12])[CH:9]=[C:8]2[C:7]=1[C:14](=[O:16])[CH2:15][C:19]1([O:13]2)[CH2:22][CH2:21][CH2:20]1)[CH3:18]
Reactant: CCc1cc(O)c(C(C)=O)c(CC)c1OC(C)=O
Reactant: O=C1CCC1
Solvent: Cc1ccccc1
Solvent: C1CCNC1
Product: CCc1cc2c(c(CC)c1O)C(=O)CC1(CCC1)O2
Temperature: 25 °C
Reaction time: 16 h
Yield: 43.3 %

Procedure:
To a solution of 3-acetyl-2,6-diethyl-4-hydroxyphenyl acetate (4.0 g) and cyclobutanone (1.23 g) in toluene (150 mL) was added pyrrolidine (568 mg). The solution was left at room temperature for 16 hours, refluxed for two hours, and then a Dean-Stark was used to remove the water. After evaporation, the residue was dissolved in methanol and a lithium hydroxide solution (10%) was added until the solution reached a pH value greater than 9. The solution was stirred at room temperature for 2 hours and then neutralized to pH 7 using diluted hydrochloric acid. Work up and chromatography (silica gel, hexane-ethyl acetate 2% to 8%) gave 1.8 g of 5,7-diethyl-6-hydroxyspiro[chroman-2,1′-cyclobutan]-4-one. 1H-NMR (300 MHz, CDCl3) δ=6.67 (s, 1H), 5.14 (s, 1H), 4.01 (s, 3H), 3.11 (q, J=7.4 Hz, 2H), 2.84 (s, 2H), 2.65 (q, J=7.4 Hz, 2H), 2.30-1.65 (m, 6H), 1.30-1.10 (m, 6H) ppm. 13C-NMR (75 MHz, CDCl3) δ=194.3, 155.0, 146.0, 139.9, 130.6, 117.0, 115.8, 79.8, 47.7, 33.0, 23.8, 19.8, 13.9, 13.2, 12.1 ppm.
Reaction SMILES: [CH:1]1([C:7]2[C:15]3[C:10](=[N:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=3)[N:9]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[Br:27]N1C(=O)CCC1=O>C(Cl)(Cl)(Cl)Cl>[Br:27][C:8]1[N:9]([CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[C:10]2=[N:11][C:12]([C:16]([O:18][CH2:19][CH3:20])=[O:17])=[CH:13][CH:14]=[C:15]2[C:7]=1[CH:1]1[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cn1cc(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Solvent: ClC(Cl)(Cl)Cl
Product: CCOC(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OCC)nc21
Temperature: 25 °C
Yield: 78 %

Procedure:
To a solution of ethyl 3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (463 mg, 1.34 mmol) in carbon tetrachloride (10 ml) was added N-bromosuccinimide (287 mg, 1.61 mmol), and the mixture was heated under reflux for 4 hr. The mixture was allowed to cool to room temperature and the solvent was evaporated under reduced pressure. The residue was purified by silica gel chromatography (hexane:ethyl acetate-5:1) to give ethyl 2-bromo-3-cyclohexyl-1-ethoxycarbonylmethyl-1H-pyrrolo[2,3-b]pyridine-6-carboxylate (457 mg, yield 64%).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]4[CH2:31][CH2:30][O:29][CH2:28][CH2:27]4)=[N:20][CH:21]=3)[N:16]([CH3:32])[N:15]=2)=[CH:10][C:9]=1[CH3:33])(C)(C)C>FC(F)(F)C(O)=O>[NH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:22]3[C:17](=[N:18][C:19]([NH:23][CH2:24][CH2:25][N:26]4[CH2:27][CH2:28][O:29][CH2:30][CH2:31]4)=[N:20][CH:21]=3)[N:16]([CH3:32])[N:15]=2)=[CH:10][C:9]=1[CH3:33]
Reactant: Cc1cc(-c2nn(C)c3nc(NCCN4CCOCC4)ncc23)ccc1NC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nn(C)c3nc(NCCN4CCOCC4)ncc23)ccc1N

Procedure:
{2-Methyl-4-[1-methyl-6-(2-morpholin-4-yl-ethylamino)-1H-pyrazolo[3,4-d]pyrimidin-3-yl]-phenyl}-carbamic acid tert-butyl ester (468 mg, 1 mmol) was dissolved in 10 mL of trifluoroacetic acid. After 1 hour the reaction mixture was evaporated, and methanol (10 mL) followed by water (10 mL) was added. The reaction mixture was then neutralised with 1 M NaOH to pH˜8 and product was filtered and dryed to give pure [3-(4-amino-3-methyl-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; LC/MS (m/e)=368.2 (MH+), Rt=1.02 min.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][CH:3]=1.Cl.Cl.[NH:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:20]2[S:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=2)[CH2:15][CH2:14]1.C(N(CC)CC)C.C(=O)([O-])O.[Na+]>CN(C=O)C>[Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([N:13]2[CH2:14][CH2:15][CH:16]([NH:19][C:20]3[S:21][CH:22]=[C:23](/[CH:25]=[CH:26]/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[N:24]=3)[CH2:17][CH2:18]2)=[O:7])=[CH:4][CH:3]=1
Reactant: CCOC(=O)/C=C/c1csc(NC2CCNCC2)n1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)/C=C/c1csc(NC2CCN(C(=O)c3ccc(Cl)cc3)CC2)n1
Reaction time: 4.5 h

Procedure:
4-Chlorobenzoyl chloride (0.19 mL) was added to a mixture of ethyl (2E)-3-[2-(4-piperidylamino)-1,3-thiazol-4-yl]acrylate dihydrochloride (0.5 g) and triethylamine (0.63 mL) in DMF (10 ml) under ice-cooling and the mixture was stirred at same temperature for 4.5 hours. The reaction mixture was poured into saturated aqueous sodium hydrogen carbonate and the mixture was extracted with an AcOEt. The extract layer was washed with water, dried over magnesium sulfate and evaporated in vacuo to give ethyl (2E)-3-(2-{[1-(4-chlorobenzoyl)-4-piperidyl]amino}-1,3-thiazol-4-yl)acrylate (0.48 g).
Reaction SMILES: [Li+].[OH-].[CH3:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([O:19]C)=[O:18])=[O:11])[CH2:6][CH2:5]1.Cl>O.O1CCCC1>[CH3:3][N:4]1[CH2:5][CH2:6][N:7]([C:10]([C:12]2[CH:13]=[CH:14][C:15]([O:22][CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)=[C:16]([CH:21]=2)[C:17]([OH:19])=[O:18])=[O:11])[CH2:8][CH2:9]1
Reactant: COC(=O)c1cc(C(=O)N2CCN(C)CC2)ccc1OCc1ccccc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CN1CCN(C(=O)c2ccc(OCc3ccccc3)c(C(=O)O)c2)CC1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of LiOH (393 mg, 9.36 mmol) in water (10 ml) was added to a stirred solution of methyl 5-[(4-methyl-1-piperazinyl)carbonyl]-2-[(phenylmethyl)oxy]benzoate (may be prepared as described in Description 50; 345 mg, 0.94 mmol) in tetrahydrofuran (2.5 ml) at room temperature. The mixture was stirred at room temperature for 3 h. The mixture was acidified by HCl (6 mol/L). The solvent was evaporated in vacuo to afford the crude product. The crude product was used directly in the next step without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([OH:18])=O)[CH3:15])=[N:9]2)=[CH:4][CH:3]=1.[C:19](N1C=CN=C1)([N:21]1C=CN=C1)=O.CN>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[CH:12]=[N:11][C:10]([O:13][CH:14]([C:16]([NH:21][CH3:19])=[O:18])[CH3:15])=[N:9]2)=[CH:6][CH:7]=1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CC(Oc1ncn(-c2ccc(Br)cc2)n1)C(=O)O
Agent: CN
Product: CNC(=O)C(C)Oc1ncn(-c2ccc(Br)cc2)n1
Yield: 80 %

Procedure:
The process was carried out as was Example 45, starting with 3 g of the compound of Example 37, 2.3 g of carbonyldiimidazole and 2 ml of 40% aqueous methylamine. The product was recrystallized from ethanol to obtain 2.5 g of the desired product, m.p. 176°-178°.
Reaction SMILES: [O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7](/[N:9]=[C:10](\[CH3:23])/[CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1Br)[C:12]([O:14][CH3:15])=[O:13])[CH3:8].CC(C)([O-])C.[Na+]>O1CCOCC1>[O:1]1[CH2:6][CH2:5][O:4][CH2:3][CH:2]1[CH:7]([N:9]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:11]([C:12]([O:14][CH3:15])=[O:13])=[C:10]1[CH3:23])[CH3:8]
Reactant: COC(=O)C(/C(C)=N/C(C)C1COCCO1)c1ccccc1Br
Agent: CC(C)(C)[O-]
Agent: [Na+]
Solvent: C1COCCO1
Product: COC(=O)c1c(C)n(C(C)C2COCCO2)c2ccccc12
Temperature: 120 °C
Reaction time: 0.5 h
Yield: 84.5 %

Procedure:
To a solution of (E)-methyl 3-((1-(1,4-dioxan-2-yl)ethyl)imino)-2-(2-bromophenyl)butanoate (400 mg, 1.1 mmol) in dioxane (3 mL) was added Chloro[2-(dicyclohexylphosphino)-3,6-dimethoxy-2′,4′,6′-triisopropylbiphenyl][2-(2-aminoethyl)phenyl]Pd(II) (160 mg, 0.2 mmol), 2-Dicyclohexyphosphino-2′,6′-diisopropoxybiphenyl (93 mg, 0.2 mmol) and sodium tert-butoxide (192 mg, 2 mmol). The resulting reaction mixture was heated to 120° C. with stirring for 30 mins in a microwave. The reaction mixture was quenched by adding water and was extracted with ethyl acetate (25 mL×3). The combined organic phase was dried by anhydrous sodium sulphate, and then filtered. The filtrate was concentrated and purified by column chromatograph on silica gel (eluted: petrol ether Iacetic ester 10:1→5:1→2:1) to afford the title compound (282 mg, 89%) as yellow solid. LCMS (M+H+) m/z: calcd. 303.15. found 303.9.
Reaction SMILES: [F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:12])[CH:3]=1.OS(O)(=O)=O.[CH3:18]O>>[F:1][C:2]1[C:10]([F:11])=[CH:9][C:5]([C:6]([O:8][CH3:18])=[O:7])=[C:4]([OH:12])[CH:3]=1
Reactant: O=C(O)c1cc(F)c(F)cc1O
Reactant: CO
Agent: O=S(=O)(O)O
Product: COC(=O)c1cc(F)c(F)cc1O
Yield: 74 %

Procedure:
A mixture of 4,5-difluoro-2-hydroxybenzoic acid (20 mmol), methanol (100 ml) and concentrated H2SO4 (5 ml) was refluxed for 48 h. Then, the reaction mixture was concentrated. The residue was dissolved in ethyl acetate, washed with brine and a saturated NaHCO3 solution and neutralized with citric acid. The organic layer was dried over MgSO4 and concentrated in vacuo to give the product. Yield: 2.8 g (97% purity, 74% yield).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]([NH:19][S:20]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[N+:29]([O-])=O)(=[O:22])=[O:21])=[C:15]2[C:10]=1[CH:11]=[CH:12][CH:13]=[N:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl>CCO>[NH2:29][C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][C:23]=1[S:20]([NH:19][C:16]1[CH:17]=[CH:18][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[C:10]2[C:15]=1[N:14]=[CH:13][CH:12]=[CH:11]2)(=[O:21])=[O:22]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Nc1ccc(OCc2ccccc2)c2cccnc12
Agent: Cl[Sn]Cl
Solvent: CCO
Product: Nc1ccccc1S(=O)(=O)Nc1ccc(OCc2ccccc2)c2cccnc12
Yield: 86.4 %

Procedure:
In a similar fashion using route 19 general procedure 29, N-(5-benzyloxy-quinolin-8-yl)-2-nitro-benzenesulfonamide 566 (519 mg, 1.19 mmol), SnCl2 (1.08 g, 4.77 mmol), and EtOH (10 ml) gave the title compound (417 mg, 86%) which was used in the next step without further purification.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:9][C@@H:8]([S:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[C:19]([F:22])([F:21])[F:20])(=[O:12])=[O:11])[CH2:7][N:6]1[C:23]1[N:24]([C:31]2[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=2)[N:25]=[C:26]([CH:28]2[CH2:30][CH2:29]2)[CH:27]=1)=[O:4].[OH-].[Li+]>>[CH:28]1([C:26]2[CH:27]=[C:23]([N:6]3[CH2:7][C@H:8]([S:10]([C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=4[C:19]([F:21])([F:22])[F:20])(=[O:12])=[O:11])[CH2:9][C@H:5]3[C:3]([OH:4])=[O:2])[N:24]([C:31]3[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=3)[N:25]=2)[CH2:30][CH2:29]1
Reactant: COC(=O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1-c1ccc(C(F)(F)F)cc1
Agent: [Li+]
Agent: [OH-]
Product: O=C(O)[C@@H]1C[C@@H](S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cc(C2CC2)nn1-c1ccc(C(F)(F)F)cc1

Procedure:
In analogy to the procedure described in example 253e, (2S,4R)-1-[5-cyclopropyl-2-(4-trifluoromethyl-phenyl)-2H-pyrazol-3-yl]-4-(2-trifluoromethyl-benzenesulfonyl)-pyrrolidine-2-carboxylic acid methyl ester was saponified in the presence of lithium hydroxide to give the title compound as white solid which was used in the next step without further purification. MS (ESI): m/z=574.3 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]2[CH:13]=[C:14]([C:16]([O:18]CC)=[O:17])[N:15]=[C:4]2[CH:3]=1.[OH-].[Na+].C(COC)OC.Cl>C(O)C>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([Cl:12])=[CH:9][CH:10]=2)[N:5]2[CH:13]=[C:14]([C:16]([OH:18])=[O:17])[N:15]=[C:4]2[CH:3]=1
Reactant: CCOC(=O)c1cn2c(cc(Cl)c3ccc(Cl)cc32)n1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: COCCOC
Product: O=C(O)c1cn2c(cc(Cl)c3ccc(Cl)cc32)n1

Procedure:
1.24 g of ethyl 5,8-dichloroimidazo-[1,2-a]-quinoline-2-carboxylate were hydrolyzed with 3 ml of 2 N sodium hydroxide solution in 120 ml of 50--50 mixture of dimethoxyethane and ethanol. The resultant mixture was neutralized with 3.3 ml of 2 N hydrochloric acid by the method of Example 20 to obtain fine off-white crystals of 5,8-dichloroimidazo-[1,2-a]-quinoline-2-carboxylic acid melting at ≈305° C. (decomp).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH3:19].[Br:21]N1C(=O)CCC1=O.C(Cl)(Cl)(Cl)Cl.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>CCOCC>[CH3:1][O:2][C:3](=[O:20])[C:4]1[CH:9]=[CH:8][C:7]([O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][CH:12]=2)=[CH:6][C:5]=1[CH2:19][Br:21]
Reactant: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1C
Reactant: O=C1CCC(=O)N1Br
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOCC
Product: COC(=O)c1ccc(Oc2ccc(OC)cc2)cc1CBr
Temperature: 25 °C
Yield: 82.9 %

Procedure:
To a mixture of 4-(4-Methoxy-phenoxy)-2-methyl-benzoic acid methyl ester (2.8 grams, 10.3 mmol), N-bromosuccinimide (2.14 grams, 12 mmol) and carbon tetrachloride (12 mL) was added a crystal of benzoyl peroxide. The mixture was heated to reflux for 2 hours, and an additional 2.1 grams of N-bromosuccinimide was added. After refluxing for an additional 4 hours, the mixture was cooled to room temperature, diluted with ether, and the organic phase was washed with water, dried over magnesium sulfate, filtered and concentrated, affording 3 grams of 2-Bromomethyl-4-(4-methoxy-phenoxy)-benzoic acid methyl ester as a colorless oil. 1H NMR (CDCl3, 500 MHz): δ 7.96 (d, 1H, J=8.8 Hz), 7.05-6.90 (m, 6H), 6.87 (dd, 1H, J=2.6, 8.3 Hz), 4.92 (s, 2H), 3.93 (s, 3H), 3.85(s, 3H) ppm.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([F:9])=[C:4]([F:10])[C:3]=1[CH2:11][O:12][CH:13]1[CH2:18][CH2:17][CH2:16][CH2:15][O:14]1.C([Li])CCC.CN(C)[CH:26]=[O:27].[Cl-].[Na+]>O1CCCC1.CCCCCC>[F:9][C:5]1[C:4]([F:10])=[C:3]([CH2:11][O:12][CH:13]2[CH2:18][CH2:17][CH2:16][CH2:15][O:14]2)[C:2]([F:1])=[C:7]([F:8])[C:6]=1[CH:26]=[O:27]
Reactant: Fc1cc(F)c(F)c(COC2CCCCO2)c1F
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1c(F)c(F)c(COC2CCCCO2)c(F)c1F
Temperature: -55 °C
Reaction time: 1 h

Procedure:
13 g of 2-[(2,3,5,6-tetrafluorophenyl)-methoxy]-tetra hydropyran in 200 ml of tetrahydrofuran were cooled to -60 C. and 35.1 ml of butyllithium (1,6M) in hexane were added dropwise over the course of 30 minutes. The mixture was stirred for 1 hour at -55° C. and 5 ml of dimethylformamide dissolved in 10 ml of tetrahydrofuran were added over the course of 5 minutes. The mixture was stirred for 1/2hours at this temperature and 50 ml of a saturated aqueous sodium chloride solution were added. Extraction was carried out with isopropyl ether and the extract was dried and the solvents removed under reduced pressure to obtain 14.4 g of the expected product which was used as is in the following step.
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20](SCC)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1.[N:32]1([CH2:38][C:39]([NH2:41])=[O:40])[CH2:37][CH2:36][NH:35][CH2:34][CH2:33]1>>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([CH:16]=[C:17]4[S:21][C:20]([N:35]5[CH2:36][CH2:37][N:32]([CH2:38][C:39]([NH2:41])=[O:40])[CH2:33][CH2:34]5)=[N:19][C:18]4=[O:25])=[CH:13][CH:14]=3)[CH:9]=[N:8]2)=[C:4]([C:28]([F:31])([F:30])[F:29])[CH:3]=1
Reactant: CCSC1=NC(=O)C(=Cc2ccc3c(cnn3Cc3ccc(Cl)cc3C(F)(F)F)c2)S1
Reactant: NC(=O)CN1CCNCC1
Product: NC(=O)CN1CCN(C2=NC(=O)C(=Cc3ccc4c(cnn4Cc4ccc(Cl)cc4C(F)(F)F)c3)S2)CC1

Procedure:
2-(4-{5-[1-(4-Chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-4-oxo-4,5-dihydro-thiazol-2-yl}-piperazin-1-yl)-acetamide was prepared from 5-[1-(4-chloro-2-trifluoromethyl-benzyl)-1H-indazol-5-ylmethylene]-2-ethylsulfanyl-thiazol-4-one and 2-piperazin-1-yl-acetamide following General Procedure C.
Reaction SMILES: [C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:23])([CH2:10]/[C:11](=[CH:16]\[CH2:17][CH:18]3OCC[O:19]3)/[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2].C([O-])(O)=O.[Na+]>CC1C=CC(S(O)(=O)=O)=CC=1.C(#N)C.O>[C:1]([O:4][CH2:5][C@@H:6]1[C@:14]2([CH3:15])[C@@:9]([OH:23])([CH2:10]/[C:11](=[CH:16]\[CH2:17][CH2:18][OH:19])/[CH2:12][CH2:13]2)[CH2:8][CH2:7]1)(=[O:3])[CH3:2]
Reactant: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C\CC3OCCO3)CC[C@]12C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CC(=O)OC[C@H]1CC[C@]2(O)C/C(=C\CCO)CC[C@]12C
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.1 %

Procedure:
A solution of 1.80 g of (1S,3aS,7aR)-1-acetoxymethyl-5-((Z)-2-(1,3-dioxolan-2-yl)ethyliden]-7a-methylperhydroinden-3a-ol in 20 ml of 1N PTSA in acetonitrile/water 85:15 was kept at room temperature for 8 hrs. The mixture was then neutralised with 5% aqueous NaHCO3, concentrated under reduced pressure and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure. The residue was dissolved in 5 ml of methanol and the solution cooled at 0° C. 0.33 g of NaBH4 were cautiously added and the mixture was stirred for 1 hr. It was then diluted with 10 ml of 5% aqueous NaH2PO4.H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated to dryness under reduced pressure to give 1.13 g of (1S,3aS,7aR)-1-acetoxymethyl-5-[(Z)-3-hydroxypropyliden]-7a-methylperhydroinden-3a-ol as a dense colourless off.
Reaction SMILES: C([O:3][C:4]([C:6]1[C:15](=[O:16])[C:14]2=[CH:17][C:18]([F:27])=[C:19]([N:20]3[CH2:25][CH2:24][NH:23][CH:22]([CH3:26])[CH2:21]3)[C:12]3=[C:13]2[N:8]([CH:9]([CH3:29])[CH2:10][C:11]3=[O:28])[CH:7]=1)=[O:5])C.N>C(O)C.Cl>[F:27][C:18]1[CH:17]=[C:14]2[C:13]3[N:8]([CH:7]=[C:6]([C:4]([OH:5])=[O:3])[C:15]2=[O:16])[CH:9]([CH3:29])[CH2:10][C:11](=[O:28])[C:12]=3[C:19]=1[N:20]1[CH2:25][CH2:24][NH:23][CH:22]([CH3:26])[CH2:21]1
Reactant: CCOC(=O)c1cn2c3c(c(N4CCNC(C)C4)c(F)cc3c1=O)C(=O)CC2C
Agent: Cl
Agent: N
Solvent: CCO
Product: CC1CN(c2c(F)cc3c(=O)c(C(=O)O)cn4c3c2C(=O)CC4C)CCN1
Reaction time: 5 h
Yield: 72 %

Procedure:
4.01 g (0.01 mole) of 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1, 7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid ethyl ester was suspended in a mixture of 20 ml of ethanol and 20 ml of 6N hydrochloric acid, and this suspension was stirred at 80°-90° C. for 5 hours to hydrolyze the starting material. The resulting reaction solution was adjusted to pH 7-8 by the addition of 28% aqueous ammonia under cooling with ice. The precipitate which separated out was collected by filtration and recrystallized from a water-ethanol mixture (with a volume ratio of 1:1) to obtain 2.69 g (72.0% yield) of 9-fluoro-5-methyl-8-(3-methyl-1-piperazinyl)-6,7-dihydro-1, 7-dioxo-1H, 5H-benzo[ij]quinolizine-2-carboxylic acid in the form of yellow crystals. These crystals had a melting point of 231°-234° C. (dec.) .
Reaction SMILES: [F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH2:13])[C@H:7]3[C:6]=2[C:5]([F:14])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:17]=[C:18]([CH:29]=[CH:30][CH:31]=1)[O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]=[C:27]=[S:28])=[N:24][CH:25]=1>C(#N)C>[F:1][C:2]1[C:11]2[O:10][CH2:9][C@H:8]3[C@@H:12]([NH:13][C:27]([NH:26][C:23]4[CH:22]=[CH:21][C:20]([O:19][C:18]5[CH:29]=[CH:30][CH:31]=[C:16]([F:15])[CH:17]=5)=[CH:25][N:24]=4)=[S:28])[C@H:7]3[C:6]=2[C:5]([F:14])=[CH:4][CH:3]=1
Reactant: Fc1cccc(Oc2ccc(N=C=S)nc2)c1
Reactant: N[C@@H]1[C@@H]2COc3c(F)ccc(F)c3[C@H]12
Solvent: CC#N
Product: Fc1cccc(Oc2ccc(NC(=S)N[C@@H]3[C@@H]4COc5c(F)ccc(F)c5[C@@H]43)nc2)c1
Temperature: 25 °C
Reaction time: 12 h
Yield: 38.3 %

Procedure:
(1S,1aR,7bR)-4,7-difluoro-1,1a,2,7b-tetrahydrocyclopropa[c]chromen-1-amine (20 mg, 0.1 mmol) was dissolved in dry acetonitrile (1 ml) and 5-(3-fluorophenoxy)-2-isothiocyanatopyridine (25 mg, 0.1 mmol) was added and the reaction mixture was stirred at ambient temperature for 12 h. The precipitate formed was collected by filtration and washed with acetonitrile and diethyl ether to give 17 mg (38% yield) of pure product as beige powder.