Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[C:2]1[C:10]([O:12]CC)=O.[H-].[Na+].[C:17]([O:21][CH2:22][CH3:23])(=[O:20])[CH:18]=[CH2:19]>C1(C)C=CC=CC=1>[O:12]=[C:10]1[C:2]2=[CH:3][C:4]3[CH:5]=[CH:6][CH:7]=[CH:8][C:9]=3[N:1]2[CH2:19][CH:18]1[C:17]([O:21][CH2:22][CH3:23])=[O:20]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)c1cc2ccccc2[nH]1
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C1Cn2c(cc3ccccc32)C1=O

Procedure:
A stirred solution of ethyl indole-2-carboxylate (5.67 g, 30 mmol) in 400 ml of toluene under N was treated with sodium hydride (1.44 g, 36 mmol). Ethyl acrylate (3.6 ml, 33 mol) was added and the mixture was heated at reflux. Additional portions of ethyl acrylate (6 mmol) and sodium hydride (16 mmol) were added after 3 hr. After a total time of 6 hr, t.l.c. indicated that all starting material are consumed. The mixture was quenched with ethanol and treated with water, dilute HCl, and methylene chloride. The organic phase was washed with brine, dried over sodium sulfate, filtered, and concentrated to give 2,3-dihydro-1-oxo-2-ethoxycarbonyl-1H-pyrrolo[1,2-a]indole, which was used directly in the next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([N:20]2[CH2:25][CH2:24][C:23]3[CH:26]=[CH:27][S:28][C:22]=3[C:21]2=[O:29])[CH:6]=[CH:7][C:8]=1[O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:16])[CH3:15])[CH:11]([CH3:13])[CH3:12].C(=O)=O.CC(C)=O.[Br:37]C(F)(F)C(Br)(F)F.[Li]C(C)(C)C.C([O-])(O)=O.[Na+]>C1COCC1>[Br:37][C:27]1[S:28][C:22]2[C:21](=[O:29])[N:20]([C:5]3[CH:6]=[CH:7][C:8]([O:9][Si:10]([CH:17]([CH3:19])[CH3:18])([CH:14]([CH3:15])[CH3:16])[CH:11]([CH3:12])[CH3:13])=[C:3]([O:2][CH3:1])[CH:4]=3)[CH2:25][CH2:24][C:23]=2[CH:26]=1
Reactant: FC(F)(Br)C(F)(F)Br
Reactant: COc1cc(N2CCc3ccsc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Agent: O=C([O-])O
Agent: O=C=O
Agent: [Li]C(C)(C)C
Solvent: CC(C)=O
Solvent: C1CCOC1
Product: COc1cc(N2CCc3cc(Br)sc3C2=O)ccc1O[Si](C(C)C)(C(C)C)C(C)C
Reaction time: 0.12 h
Yield: 46.9 %

Procedure:
Dissolve 6-(3-methoxy-4-triisopropylsilanyloxy-phenyl)-5,6-dihydro-4H-thieno[2,3-c]pyridin-7-one (5 g, 11.6 mmol) in THF (100 mL) in a three neck round bottom flask. Cool the solution in a dry ice/acetone bath. In one neck, set up a chilled (dry ice/acetone) addition funnel containing 1,2-dibromo-1,1,2,2-tetrafluoro-ethane (2.8 mL, 23.2 mmol) in 10 mL THF. Add t-BuLi (9.7 mL of 1.2 M solution in pentane, 11.6 mmol) quickly through one of the side necks allowing the solution to run down the inside of the flask. Within 30 sec of completion of the t-BuLi addition, open the addition funnel containing the electrophile. Stir 5-10 min, then pour into aqueous NaHCO3 (300 mL) and extract with EtOAc (2×300 mL). Wash the combined organic layers with brine (200 mL). Concentrate and purify via silica gel chromatography using a 0-25% gradient of EtOAc/hexanes to give 2.78 g (47%) of the desired product. MS/ES m/z (79Br) δ 10.0 [M+H]+; Rf=0.52 in 4:1 Hexanes:EtOAc.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N:5][C:4]2[S:13][C:14]3[CH2:19][N:18]([CH3:20])[CH2:17][CH2:16][C:15]=3[C:3]1=2.P(Cl)(Cl)([Cl:23])=O>>[Cl:23][C:2]1[C:3]2[C:15]3[CH2:16][CH2:17][N:18]([CH3:20])[CH2:19][C:14]=3[S:13][C:4]=2[N:5]=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1
Reactant: CCOC(=O)c1nc2sc3c(c2c(=O)[nH]1)CCN(C)C3
Reactant: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc(Cl)c2c3c(sc2n1)CN(C)CC3
Temperature: 90 °C
Reaction time: 3 h

Procedure:
10 g of ethyl 5,6,7,8-tetrahydro-4-oxo-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-2-carboxylate was added to 60 ml of phosphorus oxychloride, and stirred at 80 to 100° C. for 3 hours. After phosphorus oxychloride was distilled off under reduced pressure, 100 ml of cool water was added to the reaction residue. The reaction solution was made alkaline with an aqueous saturated solution of sodium hydrogen carbonate, and extracted with chloroform. The organic layer was washed with saturated salt water and dried over anhydrous magnesium sulfate. After magnesium sulfate was filtered off, the filtrate was concentrated under reduced pressure to give 9.5 g of ethyl 5,6,7,8-tetrahydro-4-chloro-7-methylpyrido[4′,3′:4,5]thieno[2,3-d]pyrimidine-2-carboxylate.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1.CO.[CH3:19][NH2:20]>CO>[CH3:19][NH:20][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][N:7]([C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH2:6][CH2:5]1
Reactant: CN
Reactant: CC(C)(C)OC(=O)N1CCN(CCCl)CC1
Solvent: CO
Product: CNCCN1CCN(C(=O)OC(C)(C)C)CC1
Yield: 98 %

Procedure:
Tert-butyl 4-(2-chloroethyl)piperazine-1-carboxylate (3.13 g, 12.58 mmol) was dissolved in methanol (20 ml), to which 40% methylamine methanol solution (30 ml) was added, and the mixture was heated under reflux for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was dissolved in methylene chloride. The mixture was washed with saturated sodium hydrogencarbonate aqueous solution. The organic layer was dried over magnesium sulfate, and then filtered, and the filtrate was concentrated under reduced pressure to afford tert-butyl 4-(2-methylaminoethyl)piperazine-1-carboxylate (3.0 g, yield 98%) as a pale yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[C:7]2=[O:14].[F:20][C:21]([F:33])([F:32])[C:22]1[CH:27]=[CH:26][C:25]([CH2:28][C:29](O)=[O:30])=[CH:24][CH:23]=1.C(N(CC)C(C)C)(C)C.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.CN(C)C=O>>[CH3:13][O:12][C:11]1[C:2]([NH:1][C:29](=[O:30])[CH2:28][C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:32])([F:20])[F:33])=[CH:27][CH:26]=2)=[C:3]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[N:6]([C@H:15]([CH3:19])[C:16]([NH2:18])=[O:17])[CH:5]=[CH:4]2
Reactant: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1N
Reactant: O=C(O)Cc1ccc(C(F)(F)F)cc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(=O)n([C@H](C)C(N)=O)ccc2c1NC(=O)Cc1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (R)-2-(5-amino-6-methoxy-1-oxoisoquinolin-2(1H)-yl)propanamide (98.34 mg, 0.0003764 mol), 2-(4-(trifluoromethyl)phenyl)acetic acid (115.2 mg, 0.0005646 mol), N,N-diisopropylethylamine (163.9 μL, 0.0009409 mol), N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (357.8 mg, 0.0009409 mol) and N,N-dimethylformamide (2 mL, 0.02 mol) was stirred at room temperature overnight. The reaction was only 40% complete. The solvent was removed and the residue purified by preparative HPLC (reverse phase) to obtain the pure product as a light yellow solid. MS m/z=448.3 (M+H). 1H NMR (400 MHz; DMSO-d6) δ 9.71 (s, 1H), 8.17 (d, J=8.87 Hz, 1H), 7.74 (d, J=7.76 Hz, 2H), 7.62 (d, J=7.76 Hz, 2H), 7.34-7.29 (m, 2H), 7.20 (s, 1H), 6.28 (d, J=8.48 Hz, 1H), 5.45 (q, J=7.07 Hz, 1H), 3.90 (s, 3H), 3.84 (s, 2H), 1.49 (d, J=7.39 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[N:6](C(NC)=O)[CH:5]=[N:4][C:3]=1[C:11]([NH2:13])=[O:12].CCN(CC)CC>CO>[NH2:1][C:2]1[NH:6][CH:5]=[N:4][C:3]=1[C:11]([NH2:13])=[O:12]
Reactant: CNC(=O)n1cnc(C(N)=O)c1N
Solvent: CO
Solvent: CCN(CC)CC
Product: NC(=O)c1nc[nH]c1N
Temperature: 80 °C
Reaction time: 2 h

Procedure:
5-Amino-N1-methyl-1H-imidazole-1,4-dicarboxamide 15 (10.72 g, 0.057 mol, 97% pure against a standard sample by HPLC analysis), Et3N (5 mL) and MeOH (100 mL) were placed into a 250 mL round-bottom flask equipped with a magnetic stir bar. The heterogeneous reaction mixture was heated at 80° C. (oil bath) for 4 hour with vigorous stirring, gradually cooled to room temperature (the reaction mixture is a dark homogeneous solution), and concentrated under reduced pressure. The residue (a viscous oil) was treated with t-BuOMe/acetone/MeOH (50 mL/20 mL/5 mL) and stirred for 2 hour. Precipitation was induced by scratching the glass surface. The precipitate was collected by vacuum filtration to yield 7.21 g of 5-amino-1H-imidazole-4-carboxamide (as free base). The free base was converted into 5-amino-1H-imidazole-4-carboxamide hydrochloride 16.HCl by slurrying in HCl/MeOH (2.6 M, 40 mL, 0.104 mol, prepared by bubbling HCl gas into MeOH). The solid product 16.HCl was collected by filtration and air dried (2 hour) to yield 8.5 g of product (0.051 mmol, 97% pure against an Aldrich sample by HPLC analysis). 1H NMR (400 MHz, D2O, δ): 8.21 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][N:9]2[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]2)=[C:4]([F:27])[CH:3]=1.[N+:28]([C:31]1C=[CH:35][C:34](B(O)O)=[CH:33][CH:32]=1)([O-])=O.C(=O)([O-])[O-].[K+].[K+].Cl>O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1>[F:27][C:4]1[CH:3]=[C:2]([C:33]2[CH:32]=[CH:31][N:28]=[CH:35][CH:34]=2)[CH:7]=[CH:6][C:5]=1[CH2:8][N:9]1[C:14](=[O:15])[C:13]([C:16]([NH:18][CH2:19][C:20]([OH:22])=[O:21])=[O:17])=[C:12]([OH:23])[C:11]([CH:24]([CH3:26])[CH3:25])=[N:10]1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
Reactant: CC(C)c1nn(Cc2ccc(Br)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)c1nn(Cc2ccc(-c3ccncc3)cc2F)c(=O)c(C(=O)NCC(=O)O)c1O
Yield: 25.6 %

Procedure:
To a 5 ml microwave tube was added N-{[2-[(4-bromo-2-fluorophenyl)methyl]-5-hydroxy-6-(1-methylethyl)-3-oxo-2,3-dihydro-4-pyridazinyl]carbonyl}glycine (example 46(b), 40 mg, 0.09 mmol), (4-nitrophenyl)boronic acid (18.1 mg, 0.11 mmol), potassium carbonate (38 mg, 0.272 mmol), tetrakis(triphenylphosphine)palladium (0) (3 mg, 2.7 μmol), 1,4-Dioxane (1.5 ml) and Water (0.500 ml). The mixture was irradiated at 100° C. for 20 minutes. The reaction mixture was diluted with water (5 ml), acidified with 1N HCl (2 ml), and extracted with ethyl acetate (20 ml). The organic phase was dried over MgSO4, filtered, and solvents removed under reduced pressure. The crude residue was purified by HPLC chromatography (ODS silica, gradient 15-95% acetonitrile/water (0.1% TFA)) to afford the title compound (10 mg, 0.023 mmol, 25% yield) as a white powder. 1H NMR (400 MHz, DMSO-d6) d ppm 15.93 (s, 1H), 12.99 (s, 1H), 10.13 (t, J=5.43 Hz, 1H), 8.73 (d, J=5.81 Hz, 2H), 7.91 (d, J=5.56 Hz, 2H), 7.81 (dd, J=11.37, 1.52 Hz, 1 H), 7.70 (dd, J=8.08, 1.52 Hz, 1H), 7.43 (t, J=8.08 Hz, 1H), 5.38 (s, 2H), 4.10 (d, J=5.56 Hz, 2 H), 3.19 (m, 1H), 1.19 (d, J=6.82 Hz, 6H). MS (ES+) m/e 441 [M+H]+.
Reaction SMILES: Cl[CH2:2][C:3](=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8].[C:10]1([P:16](C2C=CC=CC=2)C2C=CC=CC=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>C(Cl)(Cl)Cl>[C:3]([CH:2]=[PH2:16][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)(=[O:9])[CH2:4][CH2:5][CH2:6][CH2:7][CH3:8]
Reactant: CCCCCC(=O)CCl
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)Cl
Product: CCCCCC(=O)C=[PH2]c1ccccc1
Reaction time: 24 h
Yield: 34.4 %

Procedure:
A solution of 1-chloroheptan-2-one (33 g.) and triphenylphosphine (60 g.) in chloroform (50 ml.) was saturated with nitrogen and refluxed under nitrogen overnight. The chloroform was removed in vacuo and the residue was dissolved in dichloromethane (150 ml.). Dry diethyl ether (600 ml.) was added to precipitate 2-oxoheptyltriphenylphosphonium chloride (60 g.), m.p. 165°-168° C. This compound (23 g.) was added portionwise to a solution of sodium carbonate (25 g.) in water (250 ml.) and the mixture was stirred vigorously for 24 hours. The solution was extracted with diethyl ether, and the ethereal extracts were dried over magnesium sulphate. The solvent was removed by evaporation and the residue was cooled and triturated with petroleum ether (b.p. 40°-60° C.). The solid thus obtained was recrystallised from petroleum ether (b.p. 60°-80° C.) to give hexanoylmethylenephenylphosphorane (17 g.), m.p. 73°-74° C.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:8][C:9]([CH3:13])([CH3:12])[CH2:10]O>>[CH3:10][C:9]1([CH3:13])[NH:8][C:1]2([CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]2)[O:7][CH2:12]1
Reactant: CC(C)(N)CO
Reactant: O=C1CCCCC1
Product: CC1(C)COC2(CCCCC2)N1

Procedure:
Reaction of cyclohexanone with 2-amino-2-methyl-1-propanol to form 3,3-dimethyl-1-oxa-4-azaspiro[4.5]decane.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH2:9][NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:5]=[C:6]([Cl:8])[CH:7]=1.CC1(C)C(C)(C)OB(/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])O1.C(=O)([O-])[O-].[Na+].[Na+].[NH4+].[Cl-]>C(O)CC.CN(C=O)C>[Cl:8][C:6]1[CH:5]=[C:4]([CH2:9][NH:10][CH:11]2[CH2:13][CH2:12]2)[CH:3]=[C:2](/[CH:22]=[CH:23]/[CH2:24][O:25][CH3:26])[CH:7]=1
Reactant: COC/C=C/B1OC(C)(C)C(C)(C)O1
Reactant: Clc1cc(Br)cc(CNC2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Solvent: CCCO
Product: COC/C=C/c1cc(Cl)cc(CNC2CC2)c1
Temperature: 100 °C

Procedure:
To a 4:1 (v/v) DMF:n-propanol solution (0.15 M) of N-[(3-bromo-5-chlorophenyl)methyl]cyclopropanamine (1 eq.) from the previous step and 4,4,5,5-tetramethyl-2-[(1E)-3-(methyloxy)-1-propen-1-yl]-1,3,2-dioxaborolane (2 eq.) was added trans-dibromobis(triphenylphosphine) palladium(II) (0.05 eq.) followed by sodium carbonate (2 M aqueous solution, 3 eq.). The reaction vessel was evacuated and purged with nitrogen five times and then heated at 100° C. for 2 h. The cooled reaction mixture was poured into aq. sat. NH4Cl and then extracted with EtOAc. The combined organic extracts were washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. Purification of the crude product thus obtained by way of flash chromatography (SiO2, 3:7 (v/v) Hex:EtOAc→EtOAc) afforded the title compound as an oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])=[C:5]([CH:8]=[C:9](B2OC(C)(C)C(C)(C)O2)[CH:10]=1)[CH:6]=[O:7].[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[C:45]1[CH:50]=[C:49](Cl)[N:48]=[N:47][C:46]=1[O:52][CH3:53])=[O:35])([CH3:32])([CH3:31])[CH3:30]>>[C:29]([O:33][C:34]([N:36]1[C:44]2[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:38]=[C:37]1[C:45]1[CH:50]=[C:49]([C:9]2[CH:10]=[C:3]([O:2][CH3:1])[C:4]([O:20][CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])=[C:5]([CH:6]=[O:7])[CH:8]=2)[N:48]=[N:47][C:46]=1[O:52][CH3:53])=[O:35])([CH3:32])([CH3:31])[CH3:30]
Reactant: COc1nnc(Cl)cc1-c1cc2ccccc2n1C(=O)OC(C)(C)C
Reactant: COc1cc(B2OC(C)(C)C(C)(C)O2)cc(C=O)c1OCOCC[Si](C)(C)C
Product: COc1cc(-c2cc(-c3cc4ccccc4n3C(=O)OC(C)(C)C)c(OC)nn2)cc(C=O)c1OCOCC[Si](C)(C)C

Procedure:
400 mg of 3-Methoxy-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2-(2-trimethylsilanyl-ethoxymethoxy)-benzaldehyde and 353 mg of 2-(6-Chloro-3-methoxy-pyridazin-4-yl)-indole-1-carboxylic acid tert-butyl ester is reacted analogously to the procedure described in Example 126(a). Yield 377 mg. LC-MS (ES+) 606 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:39])([F:38])[F:37])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([N:11](CC2C=CC(OC)=CC=2OC)[C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1.Cl>O1CCOCC1>[Cl:1][C:2]1[C:3]([S:29][C:30]2[CH:35]=[CH:34][CH:33]=[C:32]([C:36]([F:38])([F:39])[F:37])[CH:31]=2)=[CH:4][C:5]([F:28])=[C:6]([S:8]([NH:11][C:12]2[S:13][CH:14]=[N:15][N:16]=2)(=[O:10])=[O:9])[CH:7]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Sc3cccc(C(F)(F)F)c3)cc2F)c(OC)c1
Agent: Cl
Solvent: C1COCCO1
Product: O=S(=O)(Nc1nncs1)c1cc(Cl)c(Sc2cccc(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 5-chloro-N-(2,4-dimethoxybenzyl)-2-fluoro-N-1,3,4-thiadiazol-2-yl-4-{[3-(trifluoromethyl)phenyl]thio}benzenesulfonamide (Preparation 3, 0.215 g, 0.347 mmol) was added a 4M solution of hydrogen chloride in 1,4-dioxane (5.04 mL). The reaction was stirred at ambient temperature for 5 hours before concentrating in vacuo. The residue was solubilised in dimethylsulfoxide (1 mL) and purified by the B-HPLC method to afford the title compound.
Reaction SMILES: [H-].[Li+].[Al+3].[H-].[H-].[H-].[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18][CH2:17][CH2:16][NH:15][C:14](=O)[C:13]=2[CH:20]=1.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][O:8][C:9]1[CH:10]=[CH:11][C:12]2[S:18][CH2:17][CH2:16][NH:15][CH2:14][C:13]=2[CH:20]=1
Reactant: COc1ccc2c(c1)C(=O)NCCS2
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: COc1ccc2c(c1)CNCCS2
Yield: 94.3 %

Procedure:
Aluminum lithium hydride (2.739) and the abovementioned 7-methoxy-5-oxo-2,3,4,5-tetrahydro-1,4-benzothiazepine (5.0 g) were added to THF (150 ml) under ice cooling and heated at reflux for 3 hours. After adding an excess amount of sodium sulfate.10 hydrates, a celite filtration was made. The resulting filtrate was concentrated to give 7-methoxy-2,3,4,5-tetrahydro-1,4-benzothiazepine (4.4 g).
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:16])[C:8](=[O:15])[N:9]2[CH2:12][CH2:13][CH3:14])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18].[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1.[OH-].[K+].Cl>O.CS(C)=O>[N+:17]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:24]1[CH:25]=[CH:26][C:21](=[O:20])[CH:22]=[CH:23]1)[N:9]([CH2:12][CH2:13][CH3:14])[C:8](=[O:15])[C:7](=[O:16])[NH:6]2)([O-:19])=[O:18]
Reactant: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(F)cc21
Reactant: Oc1ccncc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCCn1c(=O)c(=O)[nH]c2cc([N+](=O)[O-])c(-n3ccc(=O)cc3)cc21
Temperature: 130 °C
Reaction time: 3.5 h
Yield: 67.8 %

Procedure:
First, 1.244 g of 7-fluoro-6-nitro-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione, 952 mg of 4-hydroxypyridine, and 711 mg of powdered potassium hydroxide were added to 10 ml of dry dimethylsulfoxide. The mixture was stirred at 130° C. for 3.5 hours in a nitrogen atmosphere. Then, 50 ml of water was added to the reaction mixture and the mixture was made acidic (pH 2 to 3) with 4N hydrochloric acid to give a yellow precipitate. The precipitate was filtered and recrystallized with dimethylformaldehyde to give 1.08 g of 6-nitro-7-(4-oxo-4H-pyridin-1-yl)-1-(n-propyl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: Cl[C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1.[CH3:16][CH:17]([NH2:21])[C:18]([OH:20])=[O:19]>>[C:18]([CH:17]([NH:21][C:2]1[C:11]([C:12]([OH:14])=[O:13])=[CH:10][C:9]2[C:4](=[CH:5][CH:6]=[C:7]([Cl:15])[CH:8]=2)[N:3]=1)[CH3:16])([OH:20])=[O:19]
Reactant: CC(N)C(=O)O
Reactant: O=C(O)c1cc2cc(Cl)ccc2nc1Cl
Product: CC(Nc1nc2ccc(Cl)cc2cc1C(=O)O)C(=O)O
Yield: 14 %

Procedure:
In close analogy to the procedure described in Example 1, 2,6-dichloroquinoline-3-carboxylic acid is reacted with DL-2-aminopropionic acid to provide the title compound in 14% yield as yellow needles (flash chromatography on SiO2, eluent CHCl3, MeOH, AcOH—10, 1, 0.2 and recrystallization from DMF/water).
Reaction SMILES: [N+:1]([C:4]1[C:9]([CH:10]=[N:11][OH:12])=[CH:8][C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=1)([O-:3])=[O:2].C[O-].[Na+].[CH2:20](Cl)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CN(C)C=O>[CH2:20]([C:8]1[C:7]([O:13][CH3:14])=[C:6]([O:15][CH3:16])[CH:5]=[C:4]([N+:1]([O-:3])=[O:2])[C:9]=1[CH:10]=[N:11][OH:12])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: COc1cc(C=NO)c([N+](=O)[O-])cc1OC
Reactant: ClCc1ccccc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1cc([N+](=O)[O-])c(C=NO)c(Cc2ccccc2)c1OC
Reaction time: 4 h

Procedure:
6-Nitroveratraldoxime (113 g, 0.5 mole) was dissolved in 2500 ml of dimethylformamide. To this solution was added sodium methoxide (27 g, 0.5 mole). The suspension was treated with benzyl chloride (63 g, 0.5 mole) and stirring was continued for an additional 4 hr. The orange suspension was diluted with 3 l. of water and the solid was filtered, m.p. 109°-113°, yield: 110 g (78%). A small amount of the material was recrystallized from toluene to give an analytical sample melting at 116°-117°.
Reaction SMILES: [OH-].[Na+].[BH4-].[Na+].[CH3:5][O:6][C:7]([C:9]1([F:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][C:10]1=[O:16])=[O:8]>CO>[CH3:5][O:6][C:7]([C:9]1([F:17])[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[OH:16])=[O:8]
Reactant: COC(=O)C1(F)CCCCCC1=O
Agent: [BH4-]
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)C1(F)CCCCCC1O
Temperature: 25 °C
Reaction time: 2 h
Yield: 55.3 %

Procedure:
25 ml of methanol was cooled to 5° C. and 70 mg (1.8 mmol) of sodium hydroxide and 0.14 g (3.7 mmol) of sodium borohydride were added. To the resulting solution was added dropwise in the range of 5° C. to 10° C. 10 ml of a methanol solution of 2.5 g (13.3 mmol) of the 1-fluoro2-oxo-1-cycloheptanecarboxylic acid methyl ester. After stirring at room temperature for 2 hours, the contents were poured into saturated saline, followed by extraction with ethyl acetate. The extract was successively washed with diluted hydrochloric acid, saline, a saturated sodium bicarbonate solution and saline. The ethyl acetate layer was dried over anhydrous sodium sulfate and the solvent was distilled away to obtain 2.3 g of the crude product. The crude product was purified by silica gel column chromatography (developing solvent: hexane/isopropyl alcohol=99/1) to obtain 1.4 g (yield: 55.4%) of 1-fluoro-2-hydroxycycloheptanecarboxylic acid methyl ester in cis form (compound number 134a; the substance such that the substituent at the 2-position is supposed to take cis configuration when the methoxycarbonyl group at the 1-position is taken as a standard):
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH3:28])[CH2:24][CH2:23]2)[S:16]([CH3:19])(=[O:18])=[O:17])[C:9]([O-:11])=[O:10])[CH2:3][CH2:2]1.[Li+].C(Cl)CCl.O[CH2:35][C:36]([O:38][CH2:39][C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)=[O:37]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[C:8]([CH:12]=[CH:13][C:14]=2[N:15]([CH2:20][CH2:21][N:22]2[CH2:23][CH2:24][N:25]([CH3:28])[CH2:26][CH2:27]2)[S:16]([CH3:19])(=[O:17])=[O:18])[C:9]([O:11][CH2:35][C:36]([O:38][CH2:39][C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)=[O:37])=[O:10])[CH2:3][CH2:2]1
Reactant: O=C(CO)OCc1ccccc1
Reactant: CN1CCN(CCN(c2ccc(C(=O)[O-])cc2OCC2CC2)S(C)(=O)=O)CC1
Agent: CN(C)c1ccncc1
Agent: [Li+]
Solvent: ClCCCl
Solvent: ClCCl
Product: CN1CCN(CCN(c2ccc(C(=O)OCC(=O)OCc3ccccc3)cc2OCC2CC2)S(C)(=O)=O)CC1
Yield: 76 %

Procedure:
To a solution of lithium 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)methylsulfonamido)benzoate (theoric 0.869 mmol) and EDC (349 mg, 1.821 mmol) in dry DCM (3 ml), benzyl 2-hydroxyacetate (151 mg, 0.910 mmol) and DMAP (111 mg, 0.910 mmol) were added at RT. The final mixture was stirred for 2 days, then the solvent was evaporated, the residue was portioned between water and EtOAc, the organic layer was washed with NaHCO3 sat. sol. and brine, dried over Na2SO4 and evaporated. The crude was purified by flash chromatography on silica gel (eluent: DCM/MeOH/32% NH4OH 95/5/0.5) to give 2-(benzyloxy)-2-oxoethyl 3-(cyclopropylmethoxy)-4-(N-(2-(4-methylpiperazin-1-yl)ethyl)-methylsulfonamido)benzoate as a colorless oil (370 mg, 0.661 mmol, 76% yield over 2 steps, MS/ESI+ 560.1 [MH]+).