Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([O:12]C)=[CH:4][N:3]=1>B(Br)(Br)Br>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5]([OH:12])=[CH:4][N:3]=1
Reactant: COc1cnc(Cl)c2ccccc12
Agent: BrB(Br)Br
Product: Oc1cnc(Cl)c2ccccc12

Procedure:
6-Chloro-1,3-Oxazino[5,6-d]soquinoline was prepared by the procedure of Miyoko Toyama and Hirotaka Otomasu starting from 1-chloro-4-hydroxy isoquinoline. The starting material: 1-chloro-4-hydroxy isoquinoline (Example 226c) was prepared by the synthetic sequence shown above. MCPBA oxidation of 4-methoxy isoquinoline (Example 222a) was carried as usual to give 79.1% of the corresponding N-oxide (Example 226a). The material was converted into the 1-chloro derivative immediately afterward in POCl3 to give the chloride (Example 226b) in essentially quantitative yield. The crude 1-chloro-4-methoxy isoquinoline was de-methylated in BBr3 at room temperature to give the corresponding 1-chloro-4-hydroxy isoquinoline (Example 226c) after treating the crude BBr3 mixture with anhydrous methanol at room temperature, followed by evaporation to get rid of excess of borate residues. The reaction of Miyoko Toyama and Hirotaka Otomasu gave 266 mg of 6-chloro-1,3-oxazino[5,6-c]isoquinoline (Example 226d, 62.3%) overall yield from 300 mg of 4-methoxy isoquinoline in 4 steps. LC/MS Rt-min ([M−HCHO]H+) [method D]: 2.45 (192). 1H NMR (400 MHz, CHLOROFORM-D) δ ppm 5.02 (s, 2H) 5.41 (s, 2H) 7.68 (m, 1H) 7.77 (ddd, J=8.25, 6.91, 1.22 Hz, 1H) 8.10 (d, J=8.31 Hz, 1H) 8.26 (d, J=8.56 Hz, 1H).
Reaction SMILES: Br[CH:2]1[C:7](=[O:8])[NH:6][C:5]2[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Br:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH3:21])=[CH:16][CH:15]=1.[Sn](Cl)(Cl)(Cl)Cl>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([O:20][CH3:21])=[C:18]([CH:2]2[C:7](=[O:8])[NH:6][C:5]3[CH:9]=[CH:10][CH:11]=[CH:12][C:4]=3[O:3]2)[CH:19]=1
Reactant: COc1ccc(Br)cc1
Reactant: O=C1Nc2ccccc2OC1Br
Agent: Cl[Sn](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Br)cc1C1Oc2ccccc2NC1=O

Procedure:
To 2-bromo-2H-1,4-benzoxazin-3(4H)-one (I10) (1.40 g, 6.14 mmoles) in methylene chloride (20 mL) was added 4-bromoanisole and then tin (IV) chloride. Addition of tin (IV) chloride caused a brown solution to form. The solution was refluxed for 5 hours, diluted with methylene chloride (100 mL) and washed with water (2×50 mL). After drying over Magnesium sulphate the mixture was concentrated until the product (I11) precipitated (0.58 g). Concentration of the mother liquors and chromatography on silica gel afforded an additional amount of product (I11) (0.55 g).
Reaction SMILES: Cl.[CH2:2]([O:4][C:5](=[O:14])[C@H:6]([CH2:8][C:9]([O:11][CH2:12]C)=[O:10])[NH2:7])C>C(=O)([O-])[O-].[Na+].[Na+]>[NH2:7][C@H:6]([C:5]([O:4][CH3:2])=[O:14])[CH2:8][C:9]([O:11][CH3:12])=[O:10]
Reactant: CCOC(=O)C[C@H](N)C(=O)OCC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Product: COC(=O)C[C@H](N)C(=O)OC
Yield: 84.3 %

Procedure:
Diethylaspartate hydrochloride (3, 85.31 g, 0.432 mol) was dissolved in a saturated solution of aqueous sodium carbonate (200 mL) and extracted with ethyl acetate (10×250 mL) in a separatory funnel. The combined organic phases were dried by filtration through magnesium sulfate and sodium sulfate and concentrated in vacuo to provide dimethyl aspartate (58.73 g, 0.364 mol, 84%) as a pale yellow oil. This material provided satisfactory 1H NMR data and was used immediately in the preparation of N-benzyloxycarbonylglycyl-L-α-aspartic acid dimethyl ester (5).
Reaction SMILES: C(N(CC)CC)C.[C:8](Cl)(=[O:10])[CH3:9].[Cl:12][C:13]1[CH:14]=[C:15]([C:20]2([CH:24]([N:31]([CH3:33])[CH3:32])[C:25](=[O:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22][CH2:21]2)[CH:16]=[CH:17][C:18]=1[Cl:19]>CCOCC>[C:8]([O:29][CH2:28][CH2:27][CH2:26][C:25](=[O:30])[CH:24]([C:20]1([C:15]2[CH:16]=[CH:17][C:18]([Cl:19])=[C:13]([Cl:12])[CH:14]=2)[CH2:23][CH2:22][CH2:21]1)[N:31]([CH3:33])[CH3:32])(=[O:10])[CH3:9]
Reactant: CC(=O)Cl
Reactant: CN(C)C(C(=O)CCCO)C1(c2ccc(Cl)c(Cl)c2)CCC1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: CC(=O)OCCCC(=O)C(N(C)C)C1(c2ccc(Cl)c(Cl)c2)CCC1

Procedure:
Triethylamine and then a solution of acetyl chloride in ether were added dropwise to a solution of the product of Example 45 in ether and the mixture was heated under reflux for 90 minutes, cooled and filtered. The filtrate was diluted with water and extracted with ether. The extract was washed, dried and evaporated to give an oil which was distilled on a Buchi Kugelrohr apparatus (200°/0.5 mm) to give 5-[1-(3,4-dichlorophenyl)cyclobutyl]-5-dimethylamino-4-oxopentyl acetate.
Reaction SMILES: [F:1][C:2]([F:41])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:39])([F:38])[F:37])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[CH:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[OH:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O>C(Cl)Cl.CCOCC.[OH-].[Na+]>[F:41][C:2]([F:1])([F:40])[C:3]1[CH:4]=[C:5]([CH:33]=[C:34]([C:36]([F:37])([F:38])[F:39])[CH:35]=1)[CH2:6][N:7]([CH2:14][C:15]1[CH:20]=[C:19]([C:21]([F:24])([F:23])[F:22])[CH:18]=[CH:17][C:16]=1[C:25]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)=[O:26])[C:8]1[N:9]=[N:10][N:11]([CH3:13])[N:12]=1
Reactant: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(O)C2CCCCC2)n1
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: ClCCl
Product: Cn1nnc(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)Cc2cc(C(F)(F)F)ccc2C(=O)C2CCCCC2)n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.5 %

Procedure:
To a solution of (2-{[(3,5-bis-trifluoromethyl-benzyl)-(2-methyl-2H-tetrazol-5-yl)-amino]-methyl}-4-trifluoromethyl-phenyl)-cyclohexyl-methanol (5.46 g, 9.17 mmol) in methylene chloride (150 mL) at room temperature was added Dess-Martin periodinane (4.36 g, 10.3 mmol). The mixture was stirred at room temperature for 2 hours, diluted with ether (50 mL) and 1N sodium hydroxide (40 mL) was added. The mixture was extracted with ethyl acetate (2×100 mL). Combined organic layers were washed with 1N sodium hydroxide (2×40 mL), brine (50 mL), dried with sodium sulfate and concentrated in vacuo. The crude was purified by chromatography over 40+M Biotage silica column (eluted with 0-30% ethyl acetate in heptane) to afford the title compound as a pale yellow oil (5.2 g, 96%). 1H NMR (400 MHz, CDCl3) δ ppm 1.16-1.42 (m, 5H) 1.70 (d, J=12.03 Hz, 1H) 1.80 (d, J=9.54 Hz, 4H) 2.96-3.05 (m, 1H) 4.18 (s, 3H) 4.79 (s, 2H) 4.82 (s, 2H) 7.53 (s, 1H) 7.57 (d, J=8.30 Hz, 1H) 7.64 (d, J=7.88 Hz, 1H) 7.66 (s, 2H) 7.72 (s, 1H). MS (ES+) Calc: 593.2, Found: 594.5 (M+1)
Reaction SMILES: [Cl:1][B:2]([Cl:4])Cl.[CH:5]([NH:8][CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6].C(N(CC)CC)C>C(Cl)Cl>[CH:5]([N:8]([B:2]([Cl:4])[Cl:1])[CH:9]([CH3:11])[CH3:10])([CH3:7])[CH3:6]
Reactant: ClB(Cl)Cl
Reactant: CC(C)NC(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)N(B(Cl)Cl)C(C)C
Temperature: 25 °C
Reaction time: 1 h
Yield: 50.6 %

Procedure:
To a methylene chloride solution of trichloroborane (1.0 M, 100 ml, 0.10 mole) was added dropwise at −78° C. diisopropylamine (13.108 ml, 0.100 mole) over a 30 minute period. The solution was allowed to stir for 1 hour, during which a white precipitate formed. The mixture was allowed to warm to room temperature, and solvent was removed under reduced pressure. The residue was dissolved in 100 ml of dry toluene, triethylamine (13.94 ml, 0.10 mole) was added and the solution was stirred overnight at room temperature. The mixture was filtered, the residue was washed with 20 ml of toluene. Solvent was removed under reduced pressure from the combined filtrates, and the resulting oil was purified by vacuum distillation (25-28° C., 13 Pa, 0.1 mm) to give 9.2 g (51 percent) of product as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:34]=[C:8]2[NH:9][C:10]([C:20]3[CH:25]=[CH:24][C:23]([O:26][CH2:27][C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)=[CH:22][CH:21]=3)=[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)[C:12](=[O:13])[N:7]2[N:6]=1)=[O:4].CO.[C:37]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O>O1CCCC1>[CH3:1][O:2][C:3]([C:5]1[CH:34]=[C:8]2[N:9]=[C:10]([C:20]3[CH:21]=[CH:22][C:23]([O:26][CH2:27][C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=4)=[CH:24][CH:25]=3)[C:11]([CH:14]3[CH2:19][CH2:18][CH2:17][CH2:16][CH2:15]3)=[C:12]([O:13][CH3:37])[N:7]2[N:6]=1)=[O:4]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: COC(=O)c1cc2[nH]c(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(=O)n2n1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Solvent: CO
Solvent: C1CCOC1
Product: COC(=O)c1cc2nc(-c3ccc(OCc4ccccc4)cc3)c(C3CCCCC3)c(OC)n2n1
Temperature: 25 °C
Reaction time: 2 h
Yield: 106 %

Procedure:
To an ice cold mixture of 22 mg (0.048 mmol) of 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-oxo-4,7-dihydro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester in 3 mL of tetrahydrofuran (THF) was added 0.008 mL (0.192 mmol) of methanol (MeOH), 50 mg (0.192 mmol) of triphenylphosphine (PPh3), followed by 0.038 mL (0.192 mmol) of diisopropyl azodicarboxylate (DIAD) and the mixture was allowed to warm up to rt and stirred at rt for 2 h when analysis by thin layer chromatography (TLC) revealed complete consumption of starting material. The reaction mixture was then concentrated and the residue was chromatographed on silica gel (Biotage; gradient elution dichloromethane (DCM) to 10% ethyl acetate in DCM) to give 24 mg of desired 5-(4-benzyloxy-phenyl)-6-cyclohexyl-7-methoxy-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid methyl ester as indicated by 1H-NMR (containing traces of impurities).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][CH2:10][C:11]([N:13]2[CH2:19]CCC[CH:15]([NH:20][C:21]3[C:22]4[CH:29]=[CH:28][NH:27][C:23]=4[N:24]=[CH:25][N:26]=3)[CH2:14]2)=[O:12])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CO>C(Cl)Cl>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][CH:15]2[CH2:14][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)[CH2:19]2)=[N:26][CH:25]=1
Reactant: O=C(CNc1cc(Cl)cc(Cl)c1)N1CCCCC(Nc2ncnc3[nH]ccc23)C1
Solvent: CO
Solvent: ClCCl
Product: O=C(CNc1cc(Cl)cc(Cl)c1)N1CC(Nc2ncnc3[nH]ccc23)C1
Yield: 51 %

Procedure:
A similar procedure was used as describe for the synthesis of 2-(3,5-dichlorophenylamino)-1-(3-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino) azepan-1-yl) ethanone to give a residue, that was subjected to column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford (107 mg, 51%) the titled compound. 1H NMR (DMSO-d6, 400 MHz): 11.70 (s, 1H), 8.14 (s, 1H), 7.96 (d, J=2.0 Hz, 1H), 7.16 (s, 1H), 6.64 (s, 3H), 6.56 (s, 1H), 6.40 (bs, 1H), 4.94-4.80 (m, 1H), 4.58 (t, J=8.0 Hz, 1H), 4.30 (t, J=8.0 Hz, 1H), 4.16-4.04 (m, 1H), 3.98-3.86 (m, 1H), 3.78 (d, J=1.6 Hz, 2H). LC-MS: m/z [M+1]=391.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[O:17][CH:16]([C:18]([OH:20])=[O:19])[CH2:15][C:8]3([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]3)[C:6]=2[CH:7]=1.[CH2:21](O)[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33].C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:21]([O:19][C:18]([CH:16]1[CH2:15][C:8]2([C:12](=[O:13])[NH:11][C:10](=[O:14])[NH:9]2)[C:6]2[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=2[O:17]1)=[O:20])[CH2:22][O:23][CH2:24][CH2:25][O:26][CH2:27][CH2:28][O:29][CH2:30][CH2:31][O:32][CH3:33]
Reactant: O=C1NC(=O)C2(CC(C(=O)O)Oc3ccc(F)cc32)N1
Reactant: COCCOCCOCCOCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: COCCOCCOCCOCCOC(=O)C1CC2(NC(=O)NC2=O)c2cc(F)ccc2O1

Procedure:
A mixture consisting of 6-fluoro-2,3-dihydro-2',5'-dioxo-spiro[4H-1-benzopyran-4,4'-imidazolidine]-2-carboxylic acid (2.8 g, 0.01 mol) (obtained through the process as described in Example 1), 3,6,9,12-tetraoxatridecanol (2.1 g, 0.01 mol) and p-toluenesulfonic acid (1.9 g, 0.01 mol) in 80 ml of toluene was heated at reflux temperature for 7.0 hours under a Dean-Stark trap. The reaction mixture was evaporated in vacuo to give a semi-solid residue which was partitioned between 50 ml of chloroform and 50 ml of water. The organic layer was dried over anhydrous sodium sulfate, filtered and evaporated in vacuo to give a pale yellow oil which was chromatographed on silica gel, eluting with ethyl acetate to give 3.9 g (82.5%) of the desired refined compound as a colorless oil.
Reaction SMILES: I.CS[C:4](=[N:19][CH3:20])[NH:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.[CH3:21][NH2:22]>C(O)C>[CH3:20][NH:19][C:4]([NH:22][CH3:21])=[N:5][C:6]1[CH:11]=[C:10]([CH3:12])[CH:9]=[CH:8][C:7]=1[N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: CN=C(Nc1cc(C)ccc1N1CCOCC1)SC
Reactant: CN
Agent: I
Solvent: CCO
Product: CNC(=Nc1cc(C)ccc1N1CCOCC1)NC
Reaction time: 504 h

Procedure:
A mixture of 2-methyl-1-(5-methyl-2-morpholinophenyl)-3-methyl-2-thiopseudourea hydroiodide (6 g) and 33% methylamine in absolute ethanol solution (250 ml) was kept at room temperature for 21 days to yield 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine as an oil which was dissolved in methanol (60 ml) and treated with fumaric acid (1.7 g) to give 1,3-dimethyl-2-(5-methyl-2-morpholinophenyl)guanidine fumarate (1.2 g) as a colourless solid which was recrystallised form a 1:1 mixture of methanol and ether (m.p. 201°-202° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][OH:14])=[CH:5][CH:4]=1.[CH3:15][S:16](Cl)(=[O:18])=[O:17].C(N(CC)CC)C>ClCCl>[CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][CH:9]2[CH2:12][CH2:13][O:14][S:16]([CH3:15])(=[O:18])=[O:17])=[CH:5][CH:4]=1
Reactant: CS(=O)(=O)Cl
Reactant: COc1ccc2c(c1)C(CCO)CC2
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc2c(c1)C(CCOS(C)(=O)=O)CC2
Temperature: 25 °C
Reaction time: 3 h

Procedure:
5.0 g (26.0 mmol) of crude 2-(6-methoxyindan-1-yl)ethanol are dissolved in 50 ml of dichloromethane and, while cooling with ice, 3.6 g (31 mmol) of methanesulphonic acid chloride and 3.1 g (31 mmol) of triethylamine are added dropwise. The mixture is stirred at room temperature for 3 hours, the triethylammonium chloride which has precipitated is filtered off and the filtrate is extracted by shaking with ice-water. The organic phases are washed with saturated sodium chloride solution, dried over magnesium sulphate and concentrated by evaporation at 40° under reduced pressure. Methanesulphonic acid 2-(6-methoxyindan-1-yl)ethyl ester is obtained which can be used without further purification.
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[CH:11]=[CH:12][C:13]3[O:17][N:16]=[C:15]([O:18][CH2:19][C:20]([OH:22])=O)[C:14]=3[CH:23]=2)=[CH:6][CH:5]=1.[NH:26]1[CH2:30][CH2:29][CH2:28][CH2:27]1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.C(OCC)(=O)C>[N:26]1([C:20](=[O:22])[CH2:19][O:18][C:15]2[C:14]3[CH:23]=[C:10]([C:7]4[CH:6]=[CH:5][C:4]([O:3][C:2]([F:1])([F:25])[F:24])=[CH:9][CH:8]=4)[CH:11]=[CH:12][C:13]=3[O:17][N:16]=2)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: O=C(O)COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12
Reactant: C1CCNC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COc1noc2ccc(-c3ccc(OC(F)(F)F)cc3)cc12)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51.4 %

Procedure:
2-((5-(4-(trifluoromethoxy)phenyl)benzo[d]isoxazol-3-yl)oxy)acetic acid (50 mg, 0.142 mmol) was dissolved in 3 mL DMF. Pyrrolidine (30 mg, 0.425 mmol) was added followed by addition of HATU (81 mg, 0.212 mmol). The mixture was stirred at ambient temperature overnight, then diluted with 60 mL ethyl acetate, washed with water and brine, and evaporated. The product was purified on 12 g silica gel with 0-100% ethyl acetate in hexane followed by recrystallization from acetonitrile/water to give the title compound (30 mg, 0.073 mmol).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H]1[C@H](C(O)=O)CC=CC1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.O>C(Cl)Cl>[CH2:1]([O:8][C:9](=[O:10])[NH2:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(N[C@H]1CC=CC[C@H]1C(=O)O)OCc1ccccc1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: ClCCl
Solvent: O
Product: NC(=O)OCc1ccccc1
Reaction time: 8 h
Yield: 155.6 %

Procedure:
A sample of (1R,6S)-6-benzyloxycarbonylamino-cyclohex-3-enecarboxylic acid (72 g) was dissolved in CH2Cl2 (750 mL) prior to the addition of CDI (50.9 g). After 2.5 h water was added, and the solution was extracted with CH2Cl2. The combined organic layers were dried, filtered, and concentrated. The resulting material was dissolved in CH2Cl2 and ammonia gas was bubbled through the solution for 1.5 h. After stirring overnight, the majority of the solvent was removed and Et2O was added. The product precipitated as a white solid and was collected to give (1R,6S)-6-carbamoyl-cyclohex-3-enyl)-carbamic acid benzyl ester (61.5 g). MS found: (M+H)+=275.3.
Reaction SMILES: [CH3:1][Li].[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[C:10]3([CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]3)[C:7]2=[N:8][CH:9]=1.[Cl-].[NH4+]>O1CCCC1>[Br:3][C:4]1[CH:5]=[C:6]2[NH:12][C:11](=[O:13])[C:10]3([CH2:18][CH2:17][C:16]([OH:19])([CH3:1])[CH2:15][CH2:14]3)[C:7]2=[N:8][CH:9]=1
Reactant: [Li]C
Reactant: O=C1CCC2(CC1)C(=O)Nc1cc(Br)cnc12
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC1(O)CCC2(CC1)C(=O)Nc1cc(Br)cnc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
Methyllithium (1.6 M in diethyl ether, 4.88 mL, 7.81 mmol) was added dropwise to a stirred solution of 6′-bromospiro[cyclohexane-1,3′-pyrrolo[3,2-b]pyridine]-2′,4(1′H)-dione (preparation 18, 1.00 g, 3.39 mmol) in tetrahydrofuran (30 mL) at −78° C. The mixture was warmed to 0° C. over 3 h and stirred overnight at ambient temperature. Additional methyllithium (1.6 M in diethyl ether, 4.24 mL, 6.78 mmol) was added dropwise at −78° C. and the mixture was warmed to ambient temperature stirred overnight at ambient temperature. Saturated aqueous ammonium chloride solution (20 mL) was added to the reaction and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated. Purification of the residue by flash chromatography (0.1% Et3N in 1:1 to 3:1 ethyl acetate/hexanes) gave the two pure isomers of the title compound.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([OH:15])=O)(=[O:11])=[O:10])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1.[NH2:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24].O.OC1C2N=NNC=2C=CC=1.C(N(CC)CC)C.C1(N=C=NC2CCCCC2)CCCCC1>O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([CH2:12][C:13]([NH:20][CH2:21][CH2:22][S:23]([OH:26])(=[O:25])=[O:24])=[O:15])(=[O:10])=[O:11])=[C:4]([C:16]([F:19])([F:18])[F:17])[CH:3]=1
Reactant: O=C(O)CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F
Reactant: NCCS(=O)(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Oc1cccc2[nH]nnc12
Solvent: O
Solvent: CCN(CC)CC
Product: O=C(CS(=O)(=O)Nc1ccc(F)cc1C(F)(F)F)NCCS(=O)(=O)O

Procedure:
Under the conditions of Example 2(a), 3.012 g (10 mmol) of 2-[N-(4-fluoro-2-trifluoromethylphenyl)sulfamoyl]acetic acid, 1.252 g (10 mmol) of 2aminoethanesulfonic acid, 1.531 g (10 mmol) of hydroxybenzotriazole, hydrate, as well as 1.012 g (10 mmol) of triethylamine and 2.063 g (10 mmol) of dicyclohexylcarbodiimide are reacted and worked up analogously. The crude product is dissolved in distilled water, extracted with ethyl acetate, and converted into the free acid by treatment with acidic cation exchanger. The title compound is obtained by freeze-drying the aqueous solution.
Reaction SMILES: [Si]([O:18][CH2:19][C:20]1[C:21]([C:25]#[N:26])=[CH:22][NH:23][CH:24]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34](F)=[CH:33][CH:32]=1)[CH3:28].C(=O)([O-])[O-].[Cs+].[Cs+].O>CN(C)C=O>[CH2:27]([O:29][C:30](=[O:38])[C:31]1[CH:36]=[CH:35][C:34]([N:23]2[CH:24]=[C:20]([CH2:19][OH:18])[C:21]([C:25]#[N:26])=[CH:22]2)=[CH:33][CH:32]=1)[CH3:28]
Reactant: CCOC(=O)c1ccc(F)cc1
Reactant: CC(C)(C)[Si](OCc1c[nH]cc1C#N)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1ccc(-n2cc(C#N)c(CO)c2)cc1
Temperature: 70 °C
Reaction time: 8 h
Yield: 13.8 %

Procedure:
A suspension of 4-(tert-butyldiphenylsilanyloxymethyl)-1H-pyrrole-3-carbonitrile (0.3 g), 4-fluorobenzoic acid ethyl ester (0.35 g) and cesium carbonate (0.81 g) in N,N-dimethylformamide (2 mL) was stirred at 70° C. overnight. To this reaction mixture was added water, and this mixture was extracted with ethyl acetate. This organic layer was washed with water and brine, concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (eluent: hexane/ethyl acetate=80/20−30/70) to give the title compound (0.0310 g).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1.[C:30](Cl)(=[O:32])[CH3:31].C(N(CC)CC)C.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:30]([O:1][C:2]1[CH:3]=[C:4]2[C:9]3=[C:10]([C:12]([CH2:15][CH2:16][N:17]4[CH2:22][CH2:21][N:20]([C:23]5[CH:28]=[C:27]([CH3:29])[CH:26]=[CH:25][N:24]=5)[CH2:19][CH2:18]4)=[C:13]([CH3:14])[N:8]3[CH2:7][CH2:6][CH2:5]2)[CH:11]=1)(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: Cc1ccnc(N2CCN(CCc3c(C)n4c5c(cc(O)cc35)CCC4)CC2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(=O)Oc1cc2c3c(c1)c(CCN1CCN(c4cc(C)ccn4)CC1)c(C)n3CCC2
Yield: 73.9 %

Procedure:
2.2 g of 5,6-dihydro-2-methyl-8-hydroxy-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-4H-pyrrolo[3,2,1-ij]quinoline (preparation see Example 6), 0.884 g of acetyl chloride and 0.78 ml of triethylamine were heated under reflux for 5 hours in 15 ml of toluene. To work up the reaction mixture it was added to 50 ml of 10% strength aqueous sodium hydroxide solution. The toluene phase was separated and washed with water until neutral and concentrated. 2 g of crude product were obtained, which was purified by chromatography on a small silica gel column using first dichloromethane and then dichloromethane/ethanol 98:2. 1.8 g of oily title compound were obtained. This was converted into its hydrochloride as described in Example 1H). 1.72 g of 8-acetoxy-5,6-dihydro-2-methyl-1-{2-[4-(4-methylpyridin-2-yl)piperazin-1-yl]ethyl}-4H-pyrrolo-[3,2,1-ij]quinoline 2 HCl 22.5 H2O having a melting point of 220° C. were obtained.
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=1.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1.[CH3:32][O:33][C:34]1[CH:44]=[CH:43][C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)=[CH:41][C:35]=1[O:36][CH2:37][C:38](O)=[O:39]>ClCCl.O>[S:3]1[C:4]2[CH:10]=[CH:9][CH:8]=[CH:7][C:5]=2[N:6]=[C:2]1[NH:1][C:38](=[O:39])[CH2:37][O:36][C:35]1[CH:41]=[C:42](/[CH:45]=[CH:46]\[C:47]2[CH:52]=[C:51]([O:53][CH3:54])[C:50]([O:55][CH3:56])=[C:49]([O:57][CH3:58])[CH:48]=2)[CH:43]=[CH:44][C:34]=1[O:33][CH3:32]
Reactant: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)O
Reactant: Nc1nc2ccccc2s1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: O
Product: COc1ccc(/C=C\c2cc(OC)c(OC)c(OC)c2)cc1OCC(=O)Nc1nc2ccccc2s1
Yield: 78 %

Procedure:
To a solution of 2-aminobenzothiazole (150 mg, 1.0 mmol) in dichloromethane (20 mL) was added 1-Ethyl-3-(3-Dimethylaminopropyl)carbodiimide (EDC) (191 mg, 1.0 mmol) and 1-hydroxy-1,2,3-benzotriazole (HOBt) (13.5 mg, 0.1 mmol). Then added 2-{2-methoxy-5-[(Z)-2-(3,4,5-trimethoxyphenyl)-1-ethenyl]phenoxy}acetic acid (1) (374 mg, 1.0 mmol) and the reaction mixture was stirred at a temperature of 25° C. for 24 h and the reaction was monitored by TLC. Then to this water is added and extracted with dichloromethane. The solvent was evaporated under vacuum to afford the crude product. This was further purified by column chromatography using ethyl acetate and hexane as solvent system to obtain the pure product (8a) (395 mg, 80% yield).