Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][CH:12]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1(C2[O:36]N2S(C2C=CC=CC=2)(=O)=O)C=CC=CC=1.[NH4+].[Cl-]>C1COCC1.C1(C)C=CC=CC=1>[Cl:1][C:2]1[C:7]([CH:8]([OH:36])[C:9]([C:11]2[CH:12]=[CH:13][C:14]([F:17])=[CH:15][CH:16]=2)=[O:10])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: O=S(=O)(c1ccccc1)N1OC1c1ccccc1
Reactant: O=C(Cc1cccnc1Cl)c1ccc(F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: O=C(c1ccc(F)cc1)C(O)c1cccnc1Cl
Reaction time: 0.17 h
Yield: 37.4 %

Procedure:
To a stirred solution of the title compound of Step C (0.73 g, 2.92 mmol) in anhydrous THF (10 mL) at -78° C. under N2 was added potassium bis(trimethylsilyl)amide (6.43 mL of a 0.5M solution in toluene, 3.22 mmol). After 10 min, a solution of 3-phenyl-2-(phenylsulfonyl)oxaziridine (1.14 g, 4.38 mmol) in THF (10 mL) was added via syringe causing the brown solution to turn yellow. After 20 min, 10% aqueous NH4Cl was added and the aqueous layer was extracted with ether (2×60 mL). The combined organic extracts were dried over MgSO4 and concentrated in vacuo to an oily solid. This solid was triturated with hexanes and filtered off. Purification of the filtrate by column chromatography eluting with 4-25% ethyl acetate/hexanes afforded the title compound of Step D as a colorless oil (0.29 g). 1H NMR (CDCl3, 300 MHz) δ8.36 (dd, 1H), 7.9-8.1 (m,2H), 7.51 (m, 1H), 7.22 (m, 1H), 7.05-7.18 (m,2H), 6.32 (m, 1H), 4.21 (br s, 1H). APCI+ found 266 (M+1); calc 265 (M).
Reaction SMILES: [NH:1]1[CH:5]=[N:4][C:3]([C:6]([NH2:8])=[O:7])=[N:2]1.N1C(C)=CC=CC=1C.FC(F)(F)S(O[Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[CH2:24][CH3:25])(=O)=O>ClCCCl.ClCCl>[CH2:24]([Si:23]([CH2:28][CH3:29])([CH2:26][CH3:27])[NH:8][C:6]([C:3]1[N:4]=[CH:5][NH:1][N:2]=1)=[O:7])[CH3:25]
Reactant: CC[Si](CC)(CC)OS(=O)(=O)C(F)(F)F
Reactant: NC(=O)c1nc[nH]n1
Solvent: Cc1cccc(C)n1
Solvent: ClCCl
Solvent: ClCCCl
Product: CC[Si](CC)(CC)NC(=O)c1nc[nH]n1
Temperature: 50 °C
Yield: 67.7 %

Procedure:
A stirred mixture of 1H-1,2,4-triazole-3-carboxamide (500 mg, 4.46 mmol) in 1,2-dichloroethane (4.46 mL) treated at room temperature with 2,6-lutidine (2.08 mL, 17.84 mmol) and triethylsilyl trifluoromethanesulfonate (3.03 mL, 13.38 mmol) and heated under a nitrogen atmosphere at 50° C. After 4 hours of heating the reaction solution allowed to cool to room temperature and diluted with dichloromethane (25 mL), washed with water (25 mL), 0.5M hydrochloric acid (25 mL), water (25 mL), dried over MgSO4, filtered, and evaporated to solid. The solid was flash chromatographed (silica gel, 10-65% ethyl acetate:hexane) to give the product as a white solid (683 mg).
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][CH:15]=[CH:14][C:5]=1[C:6]([CH2:8][C:9](OCC)=O)=[O:7])([O-:3])=[O:2].ClC[CH2:20][OH:21].[OH-].[Na+].[OH-].C([N+](C)(C)C)C1C=CC=CC=1>O>[OH:21][CH2:20][CH2:9][CH2:8][C:6]([C:5]1[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=1[N+:1]([O-:3])=[O:2])=[O:7]
Reactant: CCOC(=O)CC(=O)c1ccccc1[N+](=O)[O-]
Reactant: OCCCl
Agent: C[N+](C)(C)Cc1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(CCCO)c1ccccc1[N+](=O)[O-]

Procedure:
A mixture of ethyl 2-(o-nitrobenzoyl)acetate (11.9 g, 0.05 mol), 2-chloroethanol (8 g, 0.1 mol), 50% sodium hydroxide solution (8.8 g, 4.4 g real, 0.11 mol) and 40% benzyltrimethylammonium hydroxide solution (4.2 PG,12 g, 1.7 g, real, 0.01 mol) in water (50 mL) is heated at 50°-65° C. for 4-8 hours, cooled and extracted with methylene chloride. The combined organic extracts are concentrated in vacuo to give the title product, identified by 1HNMR and 13CNMR analyses.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH2:6][CH2:5]2.Cl[C:12]1[C:21]2[C:16](=[CH:17][C:18]([O:24][CH3:25])=[C:19]([O:22][CH3:23])[CH:20]=2)[N:15]=[CH:14][N:13]=1>CC(O)C>[CH3:23][O:22][C:19]1[CH:20]=[C:21]2[C:16](=[CH:17][C:18]=1[O:24][CH3:25])[N:15]=[CH:14][N:13]=[C:12]2[N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][CH:9]=2)[CH2:5][CH2:6]1
Reactant: COc1cc2ncnc(Cl)c2cc1OC
Reactant: Cc1ccc2c(c1)CCN2
Solvent: CC(C)O
Product: COc1cc2ncnc(N3CCc4cc(C)ccc43)c2cc1OC
Yield: 94 %

Procedure:
Utilizing a procedure analogous to that described in Example 1, this product was prepared in 94% yield from 5-methyl-indoline (1.1 eq.) and 4-chloro-6,7-dimethoxy-quinazoline (1.0 eq) in i-PrOH. (M.P. 180°-181° C.; GC/MS: 321 (M+); anal. RP18-HPLC RT: 4.37 min.).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)=[CH:4][C:3]=1[F:17].CC1(C)C(C)(C)OB([C:26]2[CH:31]=[CH:30][C:29]([O:32][C:33]([F:36])([F:35])[F:34])=[CH:28][CH:27]=2)O1.[F-].[Cs+].O>O1CCOCC1.CCOCC>[F:17][C:3]1[CH:4]=[C:5]([C:8]2[N:13]=[CH:12][C:11]([CH2:14][CH2:15][CH3:16])=[CH:10][N:9]=2)[CH:6]=[N:7][C:2]=1[C:26]1[CH:27]=[CH:28][C:29]([O:32][C:33]([F:34])([F:35])[F:36])=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(OC(F)(F)F)cc2)OC1(C)C
Reactant: CCCc1cnc(-c2cnc(Cl)c(F)c2)nc1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOCC
Solvent: C1COCCO1
Solvent: O
Product: CCCc1cnc(-c2cnc(-c3ccc(OC(F)(F)F)cc3)c(F)c2)nc1
Temperature: 100 °C

Procedure:
10.2 mmol of 2-(6-chloro-5-fluoropyridin-3-yl)-5-propylpyrimidine and 10.2 mmol of 4,4,5,5-tetramethyl-2-(4-trifluoromethoxyphenyl)-1,3,2-dioxaborolane are dissolved in 30 ml of dioxane, and 20.4 mmol of caesium fluoride and 0.5 mmol of bis(tricyclohexylphosphine)palladium dichloride catalyst are added. The mixture is heated at 100° C. for 18 hours with stirring. Water and MTB ether are added to the batch, and the organic phase is washed with water, dried using sodium sulfate and evaporated. The residue is purified by chromatography on silica gel with heptane/MTB ether 2/1 and recrystallised from isopropanol, giving 2-[5-fluoro-6-(4-trifluoromethoxyphenyl)pyridin-3-yl]-5-propylpyrimidine.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@H:5]([CH2:7][C:8]([OH:10])=O)[C:4](=[O:11])[O:3]1.[CH2:13]([SH:15])[CH3:14].C1CCC(N=C=NC2CCCCC2)CC1.C(O)(=O)C>C(Cl)Cl.CN(C)C1C=CN=CC=1.CCOCC>[CH3:12][C:2]1([CH3:1])[O:6][C@H:5]([CH2:7][C:8](=[O:10])[S:15][CH2:13][CH3:14])[C:4](=[O:11])[O:3]1
Reactant: CCS
Reactant: CC1(C)OC(=O)[C@@H](CC(=O)O)O1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOCC
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCSC(=O)C[C@H]1OC(C)(C)OC1=O
Reaction time: 1 h
Yield: 71.5 %

Procedure:
(R)-2-(2,2-Dimethyl-5-oxo-1,3-dioxolan-4-yl)acetic acid (25 g, 144 mmol) was dissolved in CH2Cl2 (500 mL) and cooled in an ice bath. Ethanethiol (21.2 mL, 287 mmol) and N,N-dimethylpyridin-4-amine (0.351 g, 2.87 mmol) were added followed by DCC (35.5 g, 172 mmol). This mixture was stirred in ice bath for 1 hour, and then 2 hours at ambient temperature. Acetic acid (45 mL) was added and then stirred the mixture for 10 minutes. The reaction mixture was then poured into vigorously stirred ether (400 mL) and filtered. The filtrate was washed with 10% sodium carbonate, water, 0.5 N HCl, water and brine. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was purified over silica gel (1-5-10% EtOAc in hexanes) to afford (R)—S-ethyl 2-(2,2-dimethyl-5-oxo-1,3-dioxolan-4-yl)ethanethioate (22.5 g, 103 mmol, 71.8% yield) as a clear colorless oil that solidified to a white solid.
Reaction SMILES: [CH:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([O:11]C)=[O:10])([CH3:3])[CH3:2].[OH-].[K+]>CO.O>[CH:1]([C:4]1[O:8][CH:7]=[N:6][C:5]=1[C:9]([OH:11])=[O:10])([CH3:3])[CH3:2]
Reactant: COC(=O)c1ncoc1C(C)C
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)c1ocnc1C(=O)O
Temperature: 25 °C
Yield: 85 %

Procedure:
23.1 g of 5-isopropyl-4-methoxycarbonyloxazole are dissolved in a mixture of 200 ml of methanol and 200 ml of water, and 15.3 g of potassium hydroxide are added thereto. The mixture is stirred at room temperature over night, and condensed under reduced pressure to remove methanol. The residue is dissolved in water and the aqueous solution is adjusted to pH 2-3 with conc. hydrochloric acid. Said solution is extracted with ethyl acetate, and the extract is washed with water, dried and then evaporated to remove solvent. 18 g of 5-isopropyl-4-oxazolecarboxylic acid are obtained. Yield: 85.3%.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].N1C=CN=C1>CN(C=O)C>[Si:16]([O:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:14]#[N:15])[CH2:13][CH2:12][O:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: N#CC1(c2ccc(O)cc2)CCOCC1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2(C#N)CCOCC2)cc1
Reaction time: 0.5 h

Procedure:
A solution of 4-(4-hydroxy-phenyl)-tetrahydro-pyran-4-carbonitrile (5 g, 25 mmol), t-butyldimethylsilyl chloride (4.46 g, 29 mmol) and imidazole (2.34 g, 34 mmol) were stirred in DMF (15 ml) at room temperature. After 30 minutes, a yellow suspension was observed. The reaction was partitioned between ether (75 ml) and water (100 ml). The ether was then washed further with water (4×50 ml), dried over sodium sulphate, filtered and concentrated in vacuo. The title compound was isolated as a pale orange waxy solid (7 g, 90%).
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH:34]=O>>[CH:21]1[C:29]2[C:28]3[CH:30]=[CH:31][CH:32]=[CH:33][C:27]=3[O:26][C:25]=2[CH:24]=[CH:23][C:22]=1[CH2:34][N:1]1[CH:2]([C:11]2[C:12]([O:19][CH3:20])=[CH:13][CH:14]=[CH:15][C:16]=2[O:17][CH3:18])[CH2:3][CH:4]([CH3:10])[C:5]1=[O:7]
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Reactant: O=Cc1ccc2oc3ccccc3c2c1
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc2oc3ccccc3c2c1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available dibenzo[b,d]furan-2-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.96 min.; [M+H]+: 416.03 g/mol.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][O:5][CH2:6][CH2:7][NH2:8].[C:9](N1C=CN=C1)(N1C=CN=C1)=[S:10].O>CN(C=O)C>[N:8]([CH2:7][CH2:6][O:5][CH2:4][CH2:3][O:2][CH3:1])=[C:9]=[S:10]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: COCCOCCN
Solvent: CN(C)C=O
Solvent: O
Product: COCCOCCN=C=S
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 61.2 %

Procedure:
To a solution of 2-(2-methoxyethoxyl)ethanamine (0.820 g, 6.88 mmol) in DMF (69 mL) at 0° C. was added dropwise a solution of 1,1′-thiocarbonyldiimidazole (1.349 g, 7.57 mmol) in 21 mL of DMF. The mixture was warmed to RT and stirred for 90 min. The mixture was poured into water (130 mL) and extracted with Et2O (70 mL). The Et2O layer was washed with water, dried over Na2SO4, and filtered. The filtrate was concentrated in vacuo (325 torr, bath temp: 24° C.) to afford 1-isothiocyanato-2-(2-methoxyethoxyl)ethane (0.678 g, 4.21 mmol, 61% yield) as a yellow oil. The crude material was used in next step.
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([N:6]=[CH:7][C:8]([N:12]3[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])(=[O:20])=[O:19])[CH2:14][CH2:13]3)=[N:9]2)=[CH:4][CH:3]=1.B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.C([O-])(=O)C.[K+].Br[C:53]1[CH:54]=[C:55]([NH:61][S:62]([CH:65]2[CH2:67][CH2:66]2)(=[O:64])=[O:63])[C:56]([O:59][CH3:60])=[N:57][CH:58]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:60][O:59][C:56]1[C:55]([NH:61][S:62]([CH:65]2[CH2:66][CH2:67]2)(=[O:63])=[O:64])=[CH:54][C:53]([C:2]2[CH:11]=[C:10]3[C:5](=[CH:4][CH:3]=2)[N:6]=[CH:7][C:8]([N:12]2[CH2:17][CH2:16][N:15]([S:18]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:27][CH3:28])(=[O:20])=[O:19])[CH2:14][CH2:13]2)=[N:9]3)=[CH:58][N:57]=1
Reactant: COc1ncc(Br)cc1NS(=O)(=O)C1CC1
Reactant: COc1ccccc1S(=O)(=O)N1CCN(c2cnc3ccc(Br)cc3n2)CC1
Agent: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: COc1ccccc1S(=O)(=O)N1CCN(c2cnc3ccc(-c4cnc(OC)c(NS(=O)(=O)C5CC5)c4)cc3n2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 37.9 %

Procedure:
A slurry of 7-bromo-2-(4-{[2-(methyloxy)phenyl]sulfonyl}-1-piperazinyl)quinoxaline (0.54 mmol), bis(pinacolato)diboron (0.81 mmol), potassium acetate (2.15 mmol), and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (1:1) (0.05 mmol) in 1,4-dioxane (4 ml) was heated at 100° C. After the reaction stirred for 1 hour, N-[5-bromo-2-(methyloxy)-3-pyridinyl]cyclopropanesulfonamide (0.81 mmol) and 2M solution potassium carbonate (2 ml) was added and continued to stir for 1 hour. The reaction was cooled to ambient temperature, separated the organic layer and purified directly on silica by column chromatography (30-100% ethyl acetate/hexanes). The desired fractions were combined and concentrated to give the title compound (125 mg, 38% yield) as a pale tan solid. MS(ES)+ m/e 611.2 [M+H]+.
Reaction SMILES: C(=O)([O-])[O-].[Sr+2:5].[C:6]([OH:14])(=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]>O>[C:6]([O-:14])(=[O:13])[CH2:7][CH2:8][CH2:9][C:10]([O-:12])=[O:11].[Sr+2:5]
Reactant: O=C(O)CCCC(=O)O
Agent: O=C([O-])[O-]
Agent: [Sr+2]
Solvent: O
Product: O=C([O-])CCCC(=O)[O-]

Procedure:
Strontium carbonate (1.0 g, 6.77 mmol) and glutaric acid (0.89 g, 6.77 mmol) in water (30 ml) were stirred over night at 70° C. The mixture was filtered and the filtrate was evaporated to dryness and dried in vaccuo at ambient temperature. The title compound was isolated. Yield 1.23 g (83%).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]([C:11](OC)=[O:12])=[CH:9][CH:8]=[C:7]([C:15]([F:18])([F:17])[F:16])[N:6]=1)=O.[BH4-].[Na+].[Cl-].[Ca+2].[Cl-].Cl>CO>[OH:12][CH2:11][C:10]1[C:5]([CH2:3][OH:2])=[N:6][C:7]([C:15]([F:18])([F:16])[F:17])=[CH:8][CH:9]=1
Reactant: COC(=O)c1ccc(C(F)(F)F)nc1C(=O)OC
Agent: Cl
Agent: [BH4-]
Agent: [Ca+2]
Solvent: CO
Product: OCc1ccc(C(F)(F)F)nc1CO
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
A solution of 6 mmol 6-trifluoromethyl-pyridine-2,3-dicarboxylic acid dimethyl ester in 10 ml methanol was cooled to 0° C. 12 mmol of sodium borohydride and 6 mmol of calcium chloride were added and the resulting mixture stirred overnight at room temperature. After cooling again to 0° the reaction mixture was neutralized by addition of 5 ml 3M aqueous hydrochloric acid. The mixture is concentrated, diluted with water and extracted 3 times with ethyl acetate. The crude compound is purified by chromatography (SiO2; ethyl acetate/n-heptane 1:1) to give the title compound as a yellow oil. Yield: 72%. MS (m/e): 208.1 (MH+, 100%).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:7]=[C:8]([CH2:12][OH:13])[CH:9]=[CH:10][CH:11]=2)=[CH:2]1.N1C=CC=CC=1.[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26](Cl)=[O:27])[C:24]1([CH3:30])[CH3:29]>C(Cl)Cl>[Cl:20][C:21]([Cl:31])=[CH:22][C@@H:23]1[C@H:25]([C:26]([O:13][CH2:12][C:8]2[CH:9]=[CH:10][CH:11]=[C:6]([C:3]3[CH:4]=[CH:5][S:1][CH:2]=3)[CH:7]=2)=[O:27])[C:24]1([CH3:29])[CH3:30]
Reactant: OCc1cccc(-c2ccsc2)c1
Reactant: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC1(C)[C@H](C=C(Cl)Cl)[C@@H]1C(=O)OCc1cccc(-c2ccsc2)c1
Temperature: 25 °C
Reaction time: 17 h
Yield: 5.2 %

Procedure:
To a stirred solution of 1.0 g (0.005 mol) of 3-(3-thienyl)phenylmethanol and 0.5 g (0.005 mol) of pyridine in 25 mL of methylene chloride was added in one portion 1.2 g (0.005 mol) of cis-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropanecarbonyl chloride in 5 mL of methylene chloride. The reaction mixture was stirred at ambient temperature for 17 hours, then transferred to a separatory funnel, and diluted with 200 mL of methylene chloride. The solution was washed with 200 mL of aqueous 2 N hydrochloric acid, 200 mL of a saturated aqueous solution of sodium chloride, 200 mL of a cold aqueous 2 N solution of sodium hydroxide, and finally, 200 mL of a saturated aqueous solution of sodium chloride. The organic layer was dried with magnesium sulfate, filtered, and the filtrate concentrated under reduced pressure to give a residual oil. The oil was subjected to medium pressure liquid chromatography using petroleum ether:ethyl acetate (55:1) as the eluent. The appropriate fractions were combined and subjected to distillation under reduced pressure using a Kugelrohr distilling system to give 0.1 g of 3-(3-thienyl)-phenylmethyl cis-3-(2,2-dichloroetheny)-2,2-dimethylcyclopropanecarboxylate.
Reaction SMILES: [NH2:1][C:2]1(CO)[CH2:11][CH2:10][C:9]2[C:4](=[C:5]([Cl:12])[CH:6]=[CH:7][CH:8]=2)[CH2:3]1.[C:15]([C@:23]([C:38]([OH:40])=[O:39])(O)[C@:24](C(=O)C1C=CC=CC=1)(O)[C:25]([OH:27])=[O:26])(=[O:22])C1C=CC=CC=1.C(O)(=O)/C=C/C(O)=O>C(O)C>[C:38]([OH:40])(=[O:39])/[CH:23]=[CH:24]/[C:25]([OH:27])=[O:26].[NH2:1][CH:2]1[CH2:11][CH2:10][C:9]2[CH:8]=[CH:7][CH2:6][C:5]([CH2:15][OH:22])([Cl:12])[C:4]=2[CH2:3]1
Reactant: O=C(O)[C@](O)(C(=O)c1ccccc1)[C@](O)(C(=O)O)C(=O)c1ccccc1
Reactant: NC1(CO)CCc2cccc(Cl)c2C1
Agent: O=C(O)/C=C/C(=O)O
Solvent: CCO
Product: NC1CCC2=C(C1)C(Cl)(CO)CC=C2

Procedure:
The expected product is obtained by resolving the compound obtained in stage D of Example 9 using (+)-dibenzoyl-D-tartaric acid by successive recrystallizations in ethanol. The enantiomeric purity is checked by chiral chromatography on a DIACEL-AD column, using an isopropanol/n-heptane/diethylamine mixture (40/1000/0.8) as eluent. The salt is then partitioned between 9N sodium hydroxide and dichloromethane. The aqueous phase is extracted with dichloromethane. After drying and evaporating the organic phases, the residue is dissolved in ethanol with one equivalent of fumaric acid and the mixture is brought to reflux. The expected product is then obtained after cooling, in the form of a white solid which is filtered off.
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:11][N:10]=1)(C)(C)C.[ClH:31]>CCOC(C)=O>[ClH:31].[NH2:7][CH2:8][C:9]1[C:18]2[C:13](=[CH:14][C:15]([O:21][CH3:22])=[C:16]([O:19][CH3:20])[CH:17]=2)[C:12]([C:23]([N:25]2[CH2:29][CH2:28][CH2:27][CH2:26]2)=[O:24])=[CH:11][N:10]=1
Reactant: COc1cc2c(C(=O)N3CCCC3)cnc(CNC(=O)OC(C)(C)C)c2cc1OC
Agent: Cl
Solvent: CCOC(C)=O
Product: COc1cc2c(C(=O)N3CCCC3)cnc(CN)c2cc1OC
Yield: 84 %

Procedure:
As described in example 1, a solution of [6,7-dimethoxy-4-(pyrrolidine-1-carbonyl)-isoquinolin-1-ylmethyl]-carbamic acid tert-butyl ester (59 mg) was treated with HCl in EtOAc to give 42 mg (84%) of (1-aminomethyl-6,7-dimethoxy-isoquinolin-4-yl)-pyrrolidin-1-yl-methanone hydrochloride: 1H NMR (DMSO-d6) δ 1.74-1.81 (m, 2H), 1.86-1.92 (m, 2H), 3.10 (t, 2H, J=6.41 Hz), 3.59 (t, 2H, J=6.50 Hz), 3.89 (s, 3H), 3.99 (s, 3H), 4.71 (m, 2H), 7.09 (s, 1H), 7.49 (s, 1H), 8.36 (s, 1H), 8.68 (br s, 3H); MS: APCI (M+H) calc'd for C17H21N3O3 316.2; found 316.1.
Reaction SMILES: [CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:25]([O:27]C)=[O:26])[CH:19]=4)[NH:14]3)[CH:10]=[CH:11][CH:12]=2)=[O:5])[CH2:3][CH2:2]1.[OH-].[Na+]>CO.O>[CH:1]1([C:4]([NH:6][C:7]2[CH:8]=[C:9]([CH:13]3[C:22]([CH3:24])([CH3:23])[CH2:21][C:20]4[C:15](=[CH:16][CH:17]=[C:18]([C:25]([OH:27])=[O:26])[CH:19]=4)[NH:14]3)[CH:10]=[CH:11][CH:12]=2)=[O:5])[CH2:2][CH2:3]1
Reactant: COC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(=O)C3CC3)c1)N2
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC1(C)Cc2cc(C(=O)O)ccc2NC1c1cccc(NC(=O)C2CC2)c1
Yield: 58.2 %

Procedure:
In a round bottom flask, to a mixture of methyl 2-(3-(cyclopropane-carboxamido) phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylate (109 mg, 0.29 mmol) in methanol (5 mL) and water (2.5 mL) was added a solution of sodium hydroxide (196 mg, 4.90 mmol) in water (2.5 mL). The resultant mixture was heated for reflux for 1.5 hours. The methanol was removed under vacuum. The residue was acidified with 2 M hydrochloric acid to pH=5-6. The precipitates were collected by filtration, purified by preparative Thin layer chromatography (silica gel, petroleum ether/ethyl acetate=3:1) to afford 2-(3-(cyclopropanecarboxamido)phenyl)-3,3-dimethyl-1,2,3,4-tetrahydroquinoline-6-carboxylic acid as a solid product. (61 mg, yield: 58.2%). MS (ESI+APCI) M+1=347.2.
Reaction SMILES: FC(F)(F)C(=O)[CH2:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][C:16]([O:18]CC)=[O:17])[CH:11]=2)[O:6]1.[ClH:24]>>[ClH:24].[CH3:4][C@H:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[C:10]([CH2:15][C:16]([OH:18])=[O:17])[CH:11]=2)[O:6]1
Reactant: CCOC(=O)Cc1ccc2c(c1)CC[C@H](CC(=O)C(F)(F)F)O2
Agent: Cl
Product: C[C@H]1CCc2cc(CC(=O)O)ccc2O1
Temperature: 25 °C

Procedure:
The crude trifluoroacteyl protected amine of Example 5 was heated in 6N HCl (200 mL) at 80-95° C. for 2 hours under argon. The reaction became a white suspension after it was cooled down to room temperature. The solid was collected by vacuum filtration and dried by suction (5.95 g, 56%): 1H NMR (DMSO-d6) δ1.63 (m, 1H), 2.00 (m, 1H), 2.70 (m, 2H), 3.00 (m, 1H), 3.11 (m, 1H), 4.20 (m, 1H), 6.70 (d, J=8.7 Hz, 1H), 6.95 (d, J=9.0 Hz, 1H), 6.96 (s, 1H), 8.25 (s, broad, 3H); CI-MS m/z 222 (M+H+).
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:25])([CH3:24])[CH3:23].[CH2:27](Br)[C:28]#[CH:29].C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[O:1]=[C:2]1[N:8]([CH2:29][C:28]#[CH:27])[C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[O:5][C@H:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[C@@H:3]1[NH:19][C:20](=[O:26])[O:21][C:22]([CH3:23])([CH3:25])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H]1C(=O)Nc2ccccc2O[C@@H]1c1ccccc1
Reactant: C#CCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: C#CCN1C(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](c2ccccc2)Oc2ccccc21
Temperature: 25 °C
Reaction time: 18 h
Yield: 80.8 %

Procedure:
To a stirred solution of tert-butyl [(2R,3S)-4-oxo-2-phenyl-2,3,4,5-tetrahydro-1,5-benzoxazepin-3-yl]carbamate (67a) (160 mg, 0.451 mmol) in DMF (2 mL) was added propargyl bromide (80 mg, 0.672 mmol) and powdered cesium carbonate (219 mg, 0.672 mmol). The mixture was stirred under nitrogen at ambient temperature for 18 h. The reaction was diluted with water and extracted twice with ethyl acetate. The residue obtained from the combined organic extracts was purified by flash chromatography on silica gel eluting with 5:1 (v/v) hexane:ethyl acetate to afford the title compound (143 mg, 80%) as a white solid. TLC R1=0.19 (6:1 hexane:ethyl acetate). 1H NMR (300 MHz, CDCl3) δ1.38 (s, 9H), 2.30 (m, 1H), 4.69 (m, 2H), 4.96 (m, 2H), 5.66 (m, 1H), 7.28 (m, 3H), 7.39 (s, 5H), 7.48 (m, 1H). MS APCI, m/z=293 (M+1). LC/MS: 2.86 min.