Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[Na+].Cl[C:11]1[N:16]=[C:15]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[N:14]=[C:13]([N:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[N:25]=[C:24]2[CH:32]([F:34])[F:33])[N:12]=1.COCCOCCN(CCOCCOC)CCOCCOC>O.O1CCOCC1>[F:34][CH:32]([F:33])[C:24]1[N:23]([C:13]2[N:14]=[C:15]([N:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[N:16]=[C:11]([S:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:12]=2)[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=1
Reactant: FC(F)c1nc2ccccc2n1-c1nc(Cl)nc(N2CCOCC2)n1
Reactant: Sc1ccccc1
Agent: COCCOCCN(CCOCCOC)CCOCCOC
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: FC(F)c1nc2ccccc2n1-c1nc(Sc2ccccc2)nc(N2CCOCC2)n1
Yield: 75.8 %

Procedure:
Thiophenol (230 mg, 2.1 mmol) and NaOH (85 mg, 2.1 mmol) were combined in water to give a clear solution, which was then evaporated to dryness. 1-[4-Chloro-6-(4-morpholinyl)-1,3,5-triazin-2-yl]-2-(difluoromethyl)-1H-benzimidazole (184 mg, 0.5 mmol) and tris[2-(2-methoxyethoxy)ethyl]amine (TDA-1; 16 mg, 0.05 mmol) were added and the mixture was heated under reflux in dioxane (10 mL) for 2 hr. After cooling, the mixture was diluted with water to give a solid, which was recrystallised from EtOH to give 167 mg (76% yield) of 2-(difluoromethyl)-1-[4-(4-morpholinyl)-6-(phenylsulfanyl)-1,3,5-triazin-2-yl]-1H-benzimidazole: mp 245-248° C.; 1H NMR (CDCl3) δ 7.83 (t, J=8.6 Hz, 2H), 7.67 (dd, J=8.1, 1.3 Hz, 2H), 7.58 (br t, J=7.4 Hz, 1H), 7.52 (br t, J=7.3 Hz, 2H), 7.34 (dt, J=7.9, 1.2 Hz, 1H), 7.25 (dd, J=7.8, 1.2 Hz, 1H), 6.91 (t, JHF=53.5 Hz, 1H), 3.89 (m, 4H), 3.82-3.77 (m, 4H); Anal. Calc. for C21H18F2N6OS: C, 57.3; H, 4.1; N, 19.1. Found: C, 57.2; H, 4.1; N, 19.2%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8](C#N)[C:9](=[O:20])[CH2:10][C:11]([CH3:19])([CH3:18])[CH2:12][C:13]([O:15]CC)=O)[CH:5]=[CH:6][CH:7]=1.C(O)(=O)C.S(=O)(=O)(O)O>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]2[C:9](=[O:20])[CH2:10][C:11]([CH3:18])([CH3:19])[CH2:12][C:13]2=[O:15])[CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)CC(C)(C)CC(=O)C(C#N)c1cccc(Cl)c1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CC(=O)O
Product: CC1(C)CC(=O)C(c2cccc(Cl)c2)C(=O)C1
Yield: 46.4 %

Procedure:
Starting with 108.08 g (0.351 mol) of ethyl 6-(3'-chlorophenyl)-6-cyano-5-keto-3,3-dimethylhexanoate, 316 ml of acetic acid, 105 ml of water, and 105 ml of concentrated sulfuric acid, and utilizing the procedure described in Example 1, Part B, 40.82 g (46% yield) of 2-(3'-chlorophenyl)-5,5-dimethyl-1,3-cyclohexanedione was obtained as a white solid, m.p. 155°-58° C.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:16][C@H:17]([CH2:21][CH:22]2[CH2:24][CH2:23]2)[C:18]([NH2:20])=[O:19])=[N:7][C:8]=1[NH:9][C:10]1[S:14][N:13]=[C:12]([CH3:15])[CH:11]=1)#[N:2].[OH-].[Na+].OO.CC(O)=[O:31]>CCO.CS(C)=O>[NH2:20][C:18](=[O:19])[C@H:17]([NH:16][C:6]1[N:7]=[C:8]([NH:9][C:10]2[S:14][N:13]=[C:12]([CH3:15])[CH:11]=2)[C:3]([C:1]([NH2:2])=[O:31])=[N:4][CH:5]=1)[CH2:21][CH:22]1[CH2:23][CH2:24]1
Reactant: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C#N)sn1
Reactant: CC(=O)O
Agent: OO
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: CS(C)=O
Product: Cc1cc(Nc2nc(N[C@H](CC3CC3)C(N)=O)cnc2C(N)=O)sn1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The compound (R)-2-(5-cyano-6-(3-methylisothiazol-5-ylamino)pyrazin-2-ylamino)-3-cyclopropylpropanamide (143 mg, 0.323 mmol) was dissolved in EtOH (2 mL) and DMSO (1 mL), aq. 1N NaOH (1.0 mL) and aq. H2O2 (30%, 1.0 mL) were added. The mixture was stirred at room temperature for 15 min. HOAc (0.1 mL) was added. The mixture was then concentrated in vacuo. The residue was purified by HPLC to give the titled compound (39 mg). MS found for C15H19N7O2S as (M+H)+ MS 362.2; UV 205.4, 275.6, 324.4 nm; t 0.418 min. 1H NMR: (CD3OD) δ 7.51 (s, 1H), 6.69 (s, 1H), 4.68-4.60 (m, 1H), 2.28 (s, 3H), 1.84-1.75 (m, 1H), 1.65-1.57 (m, 1H), 0.82-0.72 (m, 1H), 0.40-0.28 (m, 2H), 0.10-0.0 (m, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([Cl:16])=[CH:12][CH:11]=2)=[O:9])=[CH:4][CH:3]=1.CCN(CC)CC.Cl[C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28].C([O-])([O-])=O.[K+].[K+]>C(Cl)Cl>[Cl:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:32])[CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[CH:3][CH:4]=2)=[O:9])=[CH:11][CH:12]=1
Reactant: Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Reactant: CCOC(=O)CC(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC(=O)Nc1ccc(C(=O)c2ccc(Cl)cc2)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
A 5-L 4-neck flask equipped with a thermocouple controller, a mechanical stirrer, a condenser, and a nitrogen inlet/outlet adapter was charged with (4-aminophenyl)(4-chlorophenyl)methanone (86.6 g, 370.1 mmol), DCM (2.61 L), and Et3N (70.3 mL, 499.6 mmol). After the solution was cooled to 5° C. in an ice-bath, ethyl 3-chloro-3-oxopropanoate (64.5 mL, 407.1 mmol) was added dropwise over 60 min. The resulting mixture was stirred at 0° C. for 1 h. Additional ethyl 3-chloro-3-oxopropanoate (12.9 mL) was added dropwise and the mixture was stirred at 0° C. for an additional 2 h. The reaction was cooled to 0° C. and ice-water (2 L) was added, followed by solid K2CO3 (60 g) until the solution was basic (pH=9-10). After phase separation, the organic layer was concentrated at 40° C. (to remove DCM) and then at 60° C. (to remove ex Et3N) to yield ethyl 3-((4-(4-chlorobenzoyl)phenyl)amino)-3-oxopropanoate as a slightly yellowish solid, which was used in the next step without further purification. (ES, m/z) 346, 348 (M+H)+
Reaction SMILES: [OH:1][CH:2]1[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]1.[H-].[Na+].[Cl:16][C:17]1[C:18]([C:26]([NH2:28])=[O:27])=[N:19][C:20]([CH2:24][CH3:25])=[C:21](Cl)[N:22]=1>CN(C)C=O>[C:26]([C:18]1[N:19]=[C:20]([CH2:24][CH3:25])[C:21]([O:1][CH:2]2[CH2:6][CH2:5][N:4]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:3]2)=[N:22][C:17]=1[Cl:16])(=[O:27])[NH2:28]
Reactant: CC(C)(C)OC(=O)N1CCC(O)C1
Reactant: CCc1nc(C(N)=O)c(Cl)nc1Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1nc(C(N)=O)c(Cl)nc1OC1CCN(C(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 40.1 %

Procedure:
To a mixture of tert-butyl 3-hydroxypyrrolidine-1-carboxylate (1 g) and N,N-dimethylformamide (30 mL) was added 55% oily sodium hydride (233 mg) under ice-cooling. After stirring for 30 minutes under ice-cooling, 3,5-dichloro-6-ethylpyrazine-2-carboxamide (1.18 g) was added thereto, followed by further stirring for 1 hour under ice-cooling. The reaction mixture was poured into ice water, followed by extraction with ethyl acetate. The organic phase was washed with saturated brine and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent: chloroform) to obtain tert-butyl 3-[(5-carbamoyl-6-chloro-3-ethylpyrazin-2-yl)oxy]pyrrolidine-1-carboxylate (795 mg) as a pale yellow solid.
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11].[N-:18]=[N+:19]=[N-:20].[Na+]>CN(C)C=O>[N:18]([CH2:2][C:3]1[CH:8]=[CH:7][C:6]([F:9])=[CH:5][C:4]=1[C:10]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)=[O:11])=[N+:19]=[N-:20]
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(c1cc(F)ccc1CBr)N1CCOCC1
Agent: [Na+]
Solvent: CN(C)C=O
Product: [N-]=[N+]=NCc1ccc(F)cc1C(=O)N1CCOCC1
Reaction time: 1 h
Yield: 87.8 %

Procedure:
To a solution of intermediate 42, (2-(bromomethyl)-5-fluorophenyl)(morpholino)methanone, (1.0 g, 3.32 mmol) in dimethylformamide (10 mL) was added sodium azide (230 mg, 3.5 mmol) and the mixture stirred under a nitrogen atmosphere for 1 h. The solvent was evaporated in vacuo, and the residue dissolved in CH2Cl2, then washed with water. The organic phase was dried (Na2SO4), filtered, concentrated, and the residue purified by column chromatography (SiO2, CH2Cl2) to provide 770 mg (Yield 88%) of the title compound as an oil: 1H NMR (300 MHz, CDCl3) δ ppm: 3.27 (2H, s) 3.51-3.65 (2H, m) 3.66-3.97 (4H, m) 4.38 (2H, brs) 6.92 (1H, dd, J=8.2, 2.7 Hz) 7.07 (1H, dt, J=8.5, 3 Hz) 7.34 (1H, dd, J=8.4, 5.5 Hz); LC/MS m/z 265 (M+H).
Reaction SMILES: I[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12].C(Cl)Cl.[CH2:16]([Mg]Br)[C:17]([CH3:20])([CH3:19])[CH3:18]>C1COCC1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:16]([C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][CH2:7][CH2:6][CH:5]2[OH:12])[C:17]([CH3:20])([CH3:19])[CH3:18]
Reactant: CC(C)(C)C[Mg]Br
Reactant: OC1CCOc2ccc(I)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(C)(C)Cc1ccc2c(c1)C(O)CCO2
Reaction time: 8 h
Yield: 45.4 %

Procedure:
To a solution of 6-iodochroman-4-ol (1.0 g, 3.6 mmol) in 18 ml of THF, at 0° C., was added the Pd(dppf)Cl2.CH2Cl2 (0.15 g, 0.18 mmol), followed by neopentylmagnesium bromide (10.8 ml, 10.8 mmol, 1.0 M in Et2O). The cold bath was maintained for 10 min., then removed and stirring continued overnight. The mixture was quenched with NH4Cl (30 ml) and extracted with EtOAc (3×50 ml). The combined organic layers were dried over MgSO4 and concentrated in vacuo to yield a brown oil. The crude oil was absorbed onto silica gel followed by flash chromatography (biotage 40S) 10% EtOAc/heptanes to yield 0.36 g (46%) of 6-neopentylchroman-4-ol as a white solid. Rf=0.11. HRMS (ESI+) calcd for C14H20O2 m/z 220.1463 (M+H)+; found 220.1460.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:26]=[C:27]([O:31][CH3:32])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)([CH2:13][CH2:14]OS(C)(=O)=O)[CH2:9]1)=[O:7].I.[CH3:34][N:35]([N:39]1[C:43]2[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=2[N:41]=[C:40]1[N:48]1[CH2:54][CH2:53][CH2:52][NH:51][CH2:50][CH2:49]1)[C:36](=[O:38])[CH3:37]>CO.ClCCl>[CH3:32][O:31][C:27]1[CH:26]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:28]=1[O:29][CH3:30])[C:6]([N:8]1[CH2:12][CH2:11][C:10]([CH2:13][CH2:14][N:51]2[CH2:52][CH2:53][CH2:54][N:48]([C:40]3[N:39]([N:35]([CH3:34])[C:36](=[O:38])[CH3:37])[C:43]4[CH:44]=[CH:45][CH:46]=[CH:47][C:42]=4[N:41]=3)[CH2:49][CH2:50]2)([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:9]1)=[O:7]
Reactant: COc1cc(C(=O)N2CCC(CCOS(C)(=O)=O)(c3ccccc3)C2)cc(OC)c1OC
Reactant: CC(=O)N(C)n1c(N2CCCNCC2)nc2ccccc21
Agent: I
Solvent: ClCCl
Solvent: CO
Product: COc1cc(C(=O)N2CCC(CCN3CCCN(c4nc5ccccc5n4N(C)C(C)=O)CC3)(c3ccccc3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of Example 45.1 using 1-(3,4,5-trimethoxybenzoyl)-3-phenyl-3-(2-methanesulfonyloxyethyl)pyrrolidine (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) and 4-(1-(N-methylacetamido)-1H-benzimidazol-2-yl)[1,4]diazepane hydriodic acid salt to give, after chromatography on silica gel eluting with 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution, the title compound: Rf=0.32 (silica gel, 5% methanol/dichloromethane/0.5% concentrated aqueous ammonia solution).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:17][C:18]1[C:23]([CH3:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>CN(C)C=O.CCOCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([O:25][C:19]2[CH:20]=[CH:21][CH:22]=[C:23]([CH3:24])[C:18]=2[CH3:17])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: Cc1cccc(O)c1C
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Cc1cccc(Oc2ccc([N+](=O)[O-])cc2)c1C
Temperature: 100 °C
Yield: 100.5 %

Procedure:
In a microwave vial 1-fluoro-4-nitrobenzene (500 mg, 3.54 mmol) was dissolved in N,N-Dimethylformamide (10 mL) to give a pale yellow solution. Potassium carbonate (1469 mg, 10.63 mmol) and 2,3-dimethylphenol (433 mg, 3.54 mmol) were added. The reaction vessel was sealed and heated in Biotage Initiator at 100° C. for 1 hour. After cooling the reaction was diluted with 25 mL of Et2O. The organic phase was washed with 3 times 25 mL of water, 10 mL of saturated brine, dried over sodium sulphate, filtered and evaporated under vacuum to afford the title compound as a yellow solid (865.1 mg).
Reaction SMILES: [OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4].C([O-])([O-])=[O:14].[Ca+2]>>[CH2:11]([OH:12])[C@H:9]([OH:10])[C@@H:7]([OH:8])[C@H:5]([OH:6])[C:3]([C:2]([OH:14])=[O:1])=[O:4]
Reactant: O=C([O-])[O-]
Reactant: O=C(CO)[C@@H](O)[C@H](O)[C@@H](O)CO
Agent: [Ca+2]
Product: O=C(O)C(=O)[C@@H](O)[C@H](O)[C@@H](O)CO
Temperature: 30 °C
Reaction time: 48 h

Procedure:
The colonies treated with the mutagen on the complete medium plate were streaked onto a fresh complete medium plate over a length of about 2 cm at the rate of 12 strains per plate. After incubation at 28° C. for 2 days, one loopful of the grown cells were transferred to a test tube containing 3 ml of a medium (pH 6.5) composed of 7.0% of L-sorbose (separately sterilized), 1.0% of dried yeast 10% of peptone, 0 1% of ferrous chloride and 3.0% of CaCO3 and incubated with shaking at 30° C. for 4 days. Among the tested mutant strains, the strain TH14-86 was found to produce 2-keto-L-gulonic acid twice as much as the parental strain K591s under the above conditions. This strain TH14-86 (IFO 14466; FERM BP-1128) was chosen as an oxidative strain with an augmented ability to oxidize L-sorbose.
Reaction SMILES: [F:1][C:2]1[CH:19]=[CH:18][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]([C:13]([NH:15][CH3:16])=[O:14])[CH2:9][C:8]2=[O:17])=[CH:4][CH:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:30]([O:37]CC)(=O)[C:31]([O:33]CC)=O>CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][N:10]3[C:13](=[O:14])[N:15]([CH3:16])[C:31](=[O:33])[C:30]([OH:37])=[C:9]3[C:8]2=[O:17])=[CH:18][CH:19]=1
Reactant: CCOC(=O)C(=O)OCC
Reactant: CNC(=O)N1CCN(Cc2ccc(F)cc2)C(=O)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CN(C)C=O
Product: Cn1c(=O)c(O)c2n(c1=O)CCN(Cc1ccc(F)cc1)C2=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
4-(4-Fluorobenzyl)-N-methyl-3-oxopiperazine-1-carboxamide (200 mg, 0.75 mmol) was dissolved in anhydrous DMF (1.5 mL) under nitrogen and chilled to 0° C. in an ice-water bath. Lithium bis(trimethylsilyl)amide (0.91 mL, 0.91 mmol, 1M solution in THF) was added dropwise and then diethyl oxalate (0.15 mL, 1.13 mmol) was immediately added. The reaction was allowed to warm to room temperature and stirred for one hour. The solvent was removed in vacuo and the residue partitioned between aqueous HCl and ethyl acetate. The layers were separated and the aqueous phase was extracted twice more with ethyl acetate. The combined organic extracts were concentrated in vacuo. The residue was triturated with ethyl acetate and the solids were collected by vacuum filtration to yield the title compound as an off-white solid. 1H NMR (400 MHz, d6 DMSO) δ 11.82 (bs, 1H), 7.40 (m, 2H), 7.21 (m, 2H), 4.69 (s, 2H), 3.94 (m, 2H), 3.58 (m, 2H), and 3.21 (s, 3H). HRMS (FT-ICR) C15H14FN3O4+H=320.1047; calculated 320.1041.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][N:8]=[C:9]2[O:12]C)=[CH:4][C:3]=1[O:14][CH:15]1[CH2:20][C@@H:19]2[CH2:21][C@H:16]1[CH2:17][C@@:18]2([CH:28]([NH2:31])[CH2:29][CH3:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.CC(O)C.Cl>O>[NH2:31][CH:28]([C@@:18]1([C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[CH2:17][C@@H:16]2[CH2:21][C@H:19]1[CH2:20][CH:15]2[O:14][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[Cl:1])[C:9](=[O:12])[NH:8][CH:7]=[CH:6]2)[CH2:29][CH3:30]
Reactant: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2ccnc(OC)c2cc1Cl
Agent: Cl
Solvent: O
Solvent: CC(C)O
Product: CCC(N)[C@@]1(c2ccccc2)C[C@@H]2C[C@H]1CC2Oc1cc2cc[nH]c(=O)c2cc1Cl
Temperature: 100 °C
Yield: 100.4 %

Procedure:
35 mg of 1-[(1S,2S,4S)-5-(7-Chloro-1-methoxy-isoquinolin-6-yloxy)-2-phenyl-bicyclo[2.2.1]hept-2-yl]-propylamine (90) were dissolved using 1 mL of 2-propanol and 1 mL of a 1N aqueous HCl-solution. The mixture was heated to 100° C. for 1 h under microwave irradiation. Afterwards, 20 mL of water were added and the mixture freeze dried. The residue was once again treated with 20 mL of water and freeze dried to yield 34 mg of the desired product as its hydrochloride. Rt=0.75 min (Method 18). Detected mass: 423.2 (M+H+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:8]([CH3:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH2:11](O)[CH2:12][OH:13].C1(C)C=CC(S(O)(=O)=O)=CC=1.O>C1C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]([C:8]2([CH3:10])[O:13][CH2:12][CH2:11][O:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)c1cccc(Br)c1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: c1ccccc1
Product: CC1(c2cccc(Br)c2)OCCO1

Procedure:
30.1 g (151 mmol) of (3-bromophenyl)methyl ketone and 13.8 g (222 mmol) of ethylene glycol are dissolved in 120 mL of benzene, mixed with 60 mg of 4-toluenesulphonic acid and boiled under reflux at a water separator (Dean-Stark apparatus) until no more water is separated off. The reaction solution is washed with 50 mL of a 0.5 M NaHCO3 solution, the organic phase is separated off and dried over anhydrous MgSO4. After removal of the benzene in a rotary evaporator, the residue becomes the product with a purity (GC) of 97% in nearly quantitative yield as colorless oily liquid. C10H11O2Br.
Reaction SMILES: [C:1]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(OCC)=[O:2].C1COCC1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[OH:2][CH2:1][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([NH:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[O:25][CH3:26])[CH:12]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: CCOC(=O)CCCCCN1CCCC(NCc2ccccc2OC)C1c1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COc1ccccc1CNC1CCCN(CCCCCCO)C1c1ccccc1
Reaction time: 0.17 h
Yield: 56.2 %

Procedure:
Under a nitrogen atmosphere in a round-bottom flask were placed 95 mg (0.22 mmol) of the title compound of Example 97 and 1 ml of THF. The system was cooled in an ice/acetone bath, 0.44 ml (0.44 mmol) of 1M lithium aluminum hydride in ether was added to the system and the mixture was stirred fro 10 minutes. The cold bath was removed, the mixture was stirred at room temperature for 20 minutes and the cold bath was replaced. The the system was added cautiously ca. 0.4 ml of 2M aqueous sodium hydroxide, and the mixture was stirred at room temperatre for 20 minutes. Sodium sulfate was added tothe system, the mixture was stirred for 30 minutes, solides were removed by suction filtration and the filtrate was concentrated. The crude material was purified by flash column chromatography (5 g of silica gel) usign 3:47 methanol/chloroform as the eluant to obtain 49 mg of the title compound.
Reaction SMILES: [CH3:1][C:2]([CH3:33])([CH3:32])[CH2:3][C:4]([NH:6][C:7]1[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]2[O:14][CH2:13][CH:12]([C:15]3[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23](OCC)=[O:24])=[CH:17][CH:16]=3)[C:11]=2[C:28]=1[CH3:29])=[O:5]>C(OCC)(=O)C.CCCCCC>[OH:24][CH2:23][CH2:22][CH2:21][C:18]1[CH:17]=[CH:16][C:15]([CH:12]2[C:11]3[C:28]([CH3:29])=[C:7]([NH:6][C:4](=[O:5])[CH2:3][C:2]([CH3:1])([CH3:33])[CH3:32])[C:8]([CH3:31])=[C:9]([CH3:30])[C:10]=3[O:14][CH2:13]2)=[CH:20][CH:19]=1
Reactant: CCOC(=O)CCc1ccc(C2COc3c(C)c(C)c(NC(=O)CC(C)(C)C)c(C)c32)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: Cc1c(C)c2c(c(C)c1NC(=O)CC(C)(C)C)C(c1ccc(CCCO)cc1)CO2
Yield: 77 %

Procedure:
Using ethyl 3-(4-(5-((3,3-dimethylbutanoyl)amino)-4,6,7-trimethyl-2,3-dihydro-1-benzofuran-3-yl)phenyl)propanoate obtained in Example 181, the title compound was synthesized in the same manner as in Example 193. Yield: 77%. Melting point: 119-120° C. (ethyl acetate-hexane).
Reaction SMILES: [H-].[Na+].[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][NH:12][C:9]=3[C:10]=2[CH:11]=1.[CH3:23][Si:24]([CH2:27][CH2:28][O:29][CH2:30]Cl)([CH3:26])[CH3:25]>C1COCC1>[Br:3][C:4]1[S:5][C:6]2[CH2:7][C:8]3[C:14]([C:15]4[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=4)=[N:13][N:12]([CH2:30][O:29][CH2:28][CH2:27][Si:24]([CH3:26])([CH3:25])[CH3:23])[C:9]=3[C:10]=2[CH:11]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(-c2n[nH]c3c2Cc2sc(Br)cc2-3)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 75 %

Procedure:
At 0° C., NaH (60 percent, 1.3 g, 33 mmol) was added to a THF solution (40 mL) containing 2-Bromo-6-(4-methoxy-phenyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (8.3 g, 24 mmol). Then SEM-Cl (5.6 mL, 28 mmol) was added to the reaction mixture and the resulting mixture was stirred at 0° C. for 30 min, warmed up to 80° C. and stirred for 2 hr. The solution was cooled to room temperature and poured into ice water. The resulting mixture was extracted with ethyl acetate. The organic layer was collected and washed with saturated aqueous NH4Cl, dried over MgSO4(s), and concentrated under reduced pressure. The oily residue was purified by gravity column chromatography (20% EtOAc in hexane) to give 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (9.0 g, 18 mmol) as brown solid in 75% yield.
Reaction SMILES: [F:1][C:2]1[CH:28]=[CH:27][C:5]([CH2:6][O:7][C:8]2[CH:13]=[CH:12][N:11]([C:14]3[CH:15]=[CH:16][C:17]4[N:18]([C:20]([CH3:25])=[C:21]([CH2:23]O)[N:22]=4)[CH:19]=3)[C:10](=[O:26])[CH:9]=2)=[CH:4][CH:3]=1.S(Cl)([Cl:31])=O>C(Cl)Cl>[Cl:31][CH2:23][C:21]1[N:22]=[C:17]2[CH:16]=[CH:15][C:14]([N:11]3[CH:12]=[CH:13][C:8]([O:7][CH2:6][C:5]4[CH:27]=[CH:28][C:2]([F:1])=[CH:3][CH:4]=4)=[CH:9][C:10]3=[O:26])=[CH:19][N:18]2[C:20]=1[CH3:25]
Reactant: Cc1c(CO)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: Cc1c(CCl)nc2ccc(-n3ccc(OCc4ccc(F)cc4)cc3=O)cn12
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred solution of 4-((4-fluorobenzyl)oxy)-1-(2-(hydroxymethyl)-3-methylimidazo[1,2-a]pyridin-6-yl)pyridin-2(1H)-one (120 mg) in DCM (1 ml) was added thionyl chloride (1 ml), and the mixture was stirred at room temperature for 18 h. The reaction mixture was concentrated in vacuo, diluted with DCM and quenched with aqueous NaHCO3 under ice-cold condition. The organic layer was separated, washed successively with water and brine, dried over Na2SO4 and concentrated in vacuo to give the title compound (120 mg) as an off-white solid.
Reaction SMILES: [OH:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([CH3:14])[C:8]1=[O:15].[Cl:16][CH2:17][C:18](O)=[O:19].S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[Cl:16][CH2:17][C:18]([O:1][CH2:2][CH2:3][O:4][CH2:5][CH2:6][N:7]1[C:11](=[O:12])[C:10]([CH3:13])=[C:9]([CH3:14])[C:8]1=[O:15])=[O:19]
Reactant: CC1=C(C)C(=O)N(CCOCCO)C1=O
Reactant: O=C(O)CCl
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CC1=C(C)C(=O)N(CCOCCOC(=O)CCl)C1=O

Procedure:
A mixture of 90.6 g (0.41 mole) of N-(5-hydroxy-3-oxapentyl)dimethylmaleimide, 46.6 g of chloroacetic acid, 4.8 g of concentrated sulfuric acid and 400 ml of toluene are reacted and worked up as described in Example 1, affording 112 g of a slightly yellowish liquid.