Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]([C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=2[Cl:25])(=[O:18])=[O:17])[C:11]=1OC)(C)[C:4]([O:6]CC)=[O:5])#N>I.C(O)(=O)C>[CH3:1][CH:3]1[C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([S:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[Cl:25])(=[O:18])=[O:17])[C:11]=2[O:6][C:4]1=[O:5]
Reactant: CCOC(=O)C(C)(C#N)c1cccc(S(=O)(=O)c2ccccc2Cl)c1OC
Agent: I
Solvent: CC(=O)O
Product: CC1C(=O)Oc2c1cccc2S(=O)(=O)c1ccccc1Cl
Yield: 77.2 %

Procedure:
A solution of ethyl 2-cyano-2-[2-methoxy-3-(2-chlorobenzenesulfonyl)phenyl]propionate (3.6 g) in hydriodic acid (58%, 10 ml) and glacial acetic acid (30 ml) was refluxed under heating for 21 hours. After cooling, the reaction mixture was concentrated under reduced pressure. To the residue was added dil. aqueous sodium hydrogen sulfite, and the mixture was extracted with diethyl ether. The extract was washed with dil. aqueous sodium hydrogen sulfite and water in turn, dried and evaporated under reduced pressure. To the oily residue was added acetic anhydride (5 ml), and the mixture was refluxed under heating for 10 minutes and then evaporated under reduced pressure. The resultant residue was crystallized with ethanol to give 3-methyl-7-(2-chlorobenzenesulfonyl)-2,3-dihydrobenzofuran-2-one (2.2 g), mp. 94°-96° C.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CN(C)C=O.Cl[C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][C:14]=1[N+:23]([O-:25])=[O:24]>O>[N+:23]([C:14]1[CH:15]=[C:16]([C:19]([F:20])([F:21])[F:22])[CH:17]=[CH:18][C:13]=1[N:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)([O-:25])=[O:24]
Reactant: O=[N+]([O-])c1cc(C(F)(F)F)ccc1Cl
Reactant: C1CCNCC1
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(C(F)(F)F)ccc1N1CCCCC1
Reaction time: 0.67 h

Procedure:
Piperidine (5.50 ml, 55.5 mmol, commercially available product) was added at 0° C. to an N,N-dimethylformamide (DMF; 7 ml) solution of 1-chloro-2-nitro-4-(trifluoromethyl)benzene (5.00 g, 22.4 mmol, commercially available product). The resulting mixture was stirred for 40 minutes. Water was added to the mixture, and the resulting mixture was extracted three times with ethyl acetate. The obtained organic layer was washed with a saturated sodium chloride solution, dried over anhydrous sodium sulfate, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (200 g, hexane/ethyl acetate=8/1). Thus, 1-[2-nitro-4-(trifluoromethyl)phenyl]piperidine (6.13 g, quant.) was yielded as an orange-colored solid.
Reaction SMILES: [OH:1][CH2:2][CH:3]1[CH2:6][CH2:5][O:4]1.[C:7]1([CH3:17])[CH:12]=[CH:11][C:10]([S:13](Cl)(=[O:15])=[O:14])=[CH:9][CH:8]=1>C(Cl)Cl.N1C=CC=CC=1>[CH3:17][C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:1][CH2:2][CH:3]2[CH2:6][CH2:5][O:4]2)(=[O:15])=[O:14])=[CH:9][CH:8]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OCC1CCO1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCC2CCO2)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 2-hydroxymethyloxetane (TCI-US, 2.0 g, 23 mmol) in 10 mL of CH2Cl2 and 10 mL of pyridine was added p-toluenesulfonyl chloride (6.5 g, 34 mmol) in portions over 15 minutes. The mixture was stirred at ambient temperature for 3 hours and was quenched with 10 mL of saturated, aqueous NaHCO3. The layers were separated and the aqueous layer was extracted with three 5 mL portions of CH2Cl2. The combined organic extracts were dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure. Purification via column chromatography (SiO2, 70% hexanes in ethyl acetate) afforded the title compound. MS (DCI/NH3) m/z 243 (M+H)+, 260 (M+NH4)+.
Reaction SMILES: C([O:5][C:6](=[O:25])[CH2:7][N:8]([C:12](=[O:24])[CH:13]([S:15][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:14])[CH:9]1[CH2:11][CH2:10]1)(C)(C)C.C1CCC(NC2CCCCC2)CC1>C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.CCOCC>[C:16]([S:15][CH:13]([CH3:14])[C:12]([N:8]([CH:9]1[CH2:11][CH2:10]1)[CH2:7][C:6]([OH:25])=[O:5])=[O:24])(=[O:23])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: CC(SC(=O)c1ccccc1)C(=O)N(CC(=O)OC(C)(C)C)C1CC1
Agent: C1CCC(NC2CCCCC2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: COc1ccccc1
Solvent: CCOCC
Product: CC(SC(=O)c1ccccc1)C(=O)N(CC(=O)O)C1CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Crude N-(2-benzoylthiopropanoyl)-N-cyclopropylglycine tert-butyl ester (17.1 g) was dissolved in a mixture of anisole (25 ml) and trifluoroacetic acid (100 ml). The resulting solution was stirred at room temperature for two hours. Trifluoroacetic acid was removed in vacuo and the residue was distributed between ethyl acetate and saturated sodium bicarbonate. The aqueous bicarbonate phase was separated and washed twice with ethyl acetate and then acidified cautiously to pH 4-6 with concentrated hydrochloric acid. The precipitated product was extracted into chloroform and washed twice with water. The organic phase was dried over magnesium sulfate, filtered and evaporated to give crude product as a pale yellow oil. The product was characterized as its DCHA salt which was prepared in ether to give colorless crystals, m.p. 140°-143° C.
Reaction SMILES: C(OC([NH:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH2:32][CH3:33])=O)C1C=CC=CC=1>[Pd].CO>[NH2:11][C@H:12]1[CH2:17][CH2:16][N:15]([C:18]2[O:19][C:20]([CH3:30])=[C:21]([C:23]([O:25][CH2:26][CH2:27][CH2:28][CH3:29])=[O:24])[N:22]=2)[CH2:14][C@H:13]1[O:31][CH2:32][CH3:33]
Reactant: CCCCOC(=O)c1nc(N2CC[C@H](NC(=O)OCc3ccccc3)[C@H](OCC)C2)oc1C
Agent: [Pd]
Solvent: CO
Product: CCCCOC(=O)c1nc(N2CC[C@H](N)[C@H](OCC)C2)oc1C
Yield: 96.6 %

Procedure:
The same operation as in Example (95b) was performed using butyl cis(±)-2-(4-{[(benzyloxy)carbonyl]amino}-3-ethoxypiperidin-1-yl)-5-methyl-1,3-oxazole-4-carboxylate obtained in Example (112g) (1.05 g, 2.1 mmol), 10% Pd/C (0.25 g) and methanol (15 mL), to obtain 0.66 g of the title compound as a light brown oily substance (88%).
Reaction SMILES: [CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22]O)[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4].[CH2:25]([N:27](CC)CC)C.S(Cl)(C1C=CC(C)=CC=1)(=O)=O.[C-]#N.[Na+]>CN(C=O)C.N1C=CC=CC=1>[CH2:1]([O:5][C:6]1[N:14]=[C:13]2[C:9]([N:10]=[CH:11][N:12]2[CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([CH2:22][C:25]#[N:27])[CH:17]=2)=[C:8]([NH2:24])[N:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCOc1nc(N)c2ncn(Cc3cccc(CO)c3)c2n1
Reactant: CCN(CC)CC
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: [C-]#N
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CCCCOc1nc(N)c2ncn(Cc3cccc(CC#N)c3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 44.4 %

Procedure:
2-Butoxy-9-(3-hydroxymethylbenzyl)adenine (0.09 g, 0.27 mmol), triethylamine (0.20 g, 1.98 mmol), tosyl chloride (0.30 g, 1.57 mmol) and pyridine (0.4 ml) were added to DMF (10 ml), and the mixture was stirred at room temperature for 24 hours. To the reaction mixture was added sodium cyanide (0.40 g, 9.16 mmol), and the mixture was stirred at 80° C. for 18 hours. After removing the solvent, the residue was poured into water and extracted with dichloromethane. The organic layer was dried over anhydrous magnesium sulfate, concentrated and the residue was purified by column chromatography (SiO2 20 g, eluting solvent: CHCl3/MeOH=100/1) to give 2-butoxy-9-(3-cyanomethylbenzyl)adenine (0.04 g, 0.12 mmol, yield: 44%) as a white solid.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]2([CH3:17])[CH3:16])(=[O:3])[CH3:2].[CH:18]([C:20]1[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][CH:21]=1)=O>[OH-].[Na+].CO>[C:24]([C:23]1[CH:28]=[CH:29][C:20]([CH:18]=[CH:2][C:1]([C:4]2[CH:13]=[CH:12][C:11]3[C:10]([CH3:15])([CH3:14])[CH2:9][CH2:8][C:7]([CH3:17])([CH3:16])[C:6]=3[CH:5]=2)=[O:3])=[CH:21][CH:22]=1)([O:26][CH3:27])=[O:25]
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: CC(=O)c1ccc2c(c1)C(C)(C)CCC2(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: COC(=O)c1ccc(C=CC(=O)c2ccc3c(c2)C(C)(C)CCC3(C)C)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 58.4 %

Procedure:
138 g (0.6 mole) of 6-acetyl-1,2,3,4-tetrahydro-1,1,4,4-tetramethylnaphthalene and 98.5 g (0.6 mole) of methyl 4-formylbenzoate in a mixture of 16 g of sodium hydroxide and 690 ml of methanol were stirred for 16 hours at room temperature. The precipitated crystals were filtered off under suction and dried to give 132 g of 3-(4-carbomethoxyphenyl)-1-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-prop-2-en-1-one of melting point 89°-91° C.
Reaction SMILES: [Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19]C)=[O:18])[CH:5]=2.[Li+].[OH-].Cl>CO.C1COCC1.O.O>[Br:1][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([OH:19])=[O:18])[CH:5]=2
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: O=C(O)c1ccc2c(C3CCCCC3)c(Br)[nH]c2c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 2-bromo-3-cyclohexyl-1H-indole-6-carboxylate (20 g, 60 mmol) and LiOH (3.8 g, 160 mmol) in MeOH/THF/H2O (1:1:1, 300 mL) was heated at 90° C. for 2 h. The reaction mixture was cooled in an ice/H2O bath, neutralized with 1M HCl (˜160 mL) diluted with H2O (250 mL) and stirred for 1 h at rt. The precipitates were collected by filtration rinse with H2O and dried to yield 2-bromo-3-cyclohexyl-1H-indole-6-carboxylic acid (quant.) which was used without further purification.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1.Cl.[F:24][C:25]([F:34])([F:33])[C:26]([NH:28][CH:29]1[CH2:32][NH:31][CH2:30]1)=[O:27].C(N(CC)CC)C>CS(C)=O.O>[CH:1]1([N:4]2[C:13]3[C:8](=[CH:9][C:10]([F:16])=[C:11]([N:31]4[CH2:32][CH:29]([NH:28][C:26](=[O:27])[C:25]([F:34])([F:33])[F:24])[CH2:30]4)[C:12]=3[F:14])[C:7](=[O:17])[C:6]([C:18]([O:20][CH2:21][CH3:22])=[O:19])=[CH:5]2)[CH2:3][CH2:2]1
Reactant: O=C(NC1CNC1)C(F)(F)F
Reactant: CCOC(=O)c1cn(C2CC2)c2c(F)c(F)c(F)cc2c1=O
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: O
Product: CCOC(=O)c1cn(C2CC2)c2c(F)c(N3CC(NC(=O)C(F)(F)F)C3)c(F)cc2c1=O
Yield: 22 %

Procedure:
A mixture of 1 g (3.2 mmoles) of ethyl 1-cyclopropyl-6,7,8-trifluoro-4-oxo-1,4-dihydro-quinoline-3-carboxylate, 0.98 g (4.8 mmoles) of 3-trifluoroacetamidoazetidine hydrochloride and 2 ml of triethylamine is heated in 15 ml of dimethyl sulphoxide for 4 hours at 80°-5° C. It is diluted with water and extracted with chloroform. The organic phase is washed with water and evaporated yielding 0.31 g (22% of ethyl 1-cyclopropyl-6,8-difluoro-1,4-dihydro-7-(3-trifluoroacetamido-1-azetidinyl)-4-oxo-3-quinolinecarboxylate which is then hydrolysed by heating a mixture of 0.1 g (0.22 mmoles) of this ester with 5 ml of 1N sodium hydroxide and 5 ml of ethanol. The mixture is cooled, evaporated and acidified with acetic acid. Filtering and washing with water yields 70 mg (96%) of 1-cyclopropyl-6,8-difluoro-7-(3-amino-1-azetidinyl)-1,4-dihydro-4-oxo-3-quinolinecarboxylic acid, melting at 214°-6° C.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]([C:9]1[CH:10]=[C:11](B(O)O)[CH:12]=[N:13][CH:14]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].Br[C:21]1[CH:22]=[C:23]2[C:28](=[CH:29][CH:30]=1)[N:27]1[CH:31]=[N:32][N:33]=[C:26]1[CH2:25][CH2:24]2.C(=O)([O-])[O-].[K+].[K+]>C(O)(C)(C)C.O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[CH:31]1[N:27]2[C:28]3[C:23]([CH2:24][CH2:25][C:26]2=[N:33][N:32]=1)=[CH:22][C:21]([C:11]1[CH:10]=[C:9]([C:3]([OH:8])([C:4]([F:7])([F:6])[F:5])[C:2]([F:19])([F:18])[F:1])[CH:14]=[N:13][CH:12]=1)=[CH:30][CH:29]=3
Reactant: OB(O)c1cncc(C(O)(C(F)(F)F)C(F)(F)F)c1
Reactant: Brc1ccc2c(c1)CCc1nncn1-2
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: CC(C)(C)O
Product: OC(c1cncc(-c2ccc3c(c2)CCc2nncn2-3)c1)(C(F)(F)F)C(F)(F)F
Temperature: 80 °C

Procedure:
A vial containing the title compound from Example 61 Step B (15 mg, 0.05 mmol), the title compound from Example 22 Step B (11.7 mg, 0.047 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (3.68 mg, 5.19 μmol) and potassium carbonate (21.5 mg, 0.156 mmol) in tert-butanol (577 μL) and water (72 μL) was flushed with nitrogen, sealed tightly and heated to 80° C. overnight. The reaction solution was then cooled to room temperature and concentrated under reduced pressure. The resulting residue was diluted with acetonitrile and purified by HPLC (C18 column, 10 to 100% acetonitrile/water, both 0.1% v/v trifluoroacetic acid). Fractions containing product were combined, aqueous 1 M hydrochloric acid solution was added and the solution concentrated under reduced pressure to provide the title compound: LCMS m/z 414.79 [M+H]+; 1H NMR (500 MHz, d6-DMSO) δ 9.38 (s, 1H), 9.11 (s, 1H), 8.85 (s, 1H), 8.27 (s, 1H), 7.92 (d, J=8.34 Hz, 1H) 7.87 (d, J=1.71 Hz, 1H), 7.81 (dd, J=1.94, 8.34 Hz, 1H), 3.15 (s, 4H).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:27])[CH3:26])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([OH:24])[CH:15]=1)[CH2:2][CH2:3][CH3:4].[H-].[Na+].[CH3:41][S:42][CH2:43]Cl>CN(C)C=O>[CH2:1]([NH:5][C:6](=[O:38])[CH:7]([CH3:37])[CH2:8][C@H:9]([OH:36])[C@@H:10]([NH:28][C:29]([O:31][C:32]([CH3:34])([CH3:33])[CH3:35])=[O:30])[CH2:11][C@@H:12]([CH:25]([CH3:26])[CH3:27])[CH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([CH3:23])([CH3:22])[CH3:21])=[C:16]([O:24][CH2:41][S:42][CH3:43])[CH:15]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(O)c1)C(C)C)NC(=O)OC(C)(C)C
Reactant: CSCCl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCNC(=O)C(C)C[C@H](O)[C@H](C[C@H](Cc1ccc(C(C)(C)C)c(OCSC)c1)C(C)C)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 100 mg of N-tert-butoxycarbonyl-2(R,S)-methyl-4(S)-hydroxy-5(S)-amino-7(S)-isopropyl-8-(3-hydroxy-4-tert-butyl-phenyl)-octanoic acid (N-butyl)amide (Example 5a) in 5 ml of dimethylformamide is added dropwise to a suspension, stirred at room temperature, of 7.6 mg of a 65% NaH dispersion in 3 ml of dimethylformamide. The reaction mixture is stirred for a further 30 minutes at room temperature and then a solution of 0.0 17 ml of chlorodimethyl sulfide in 2 ml of dimethylformamide is added thereto. The reaction mixture is stirred for a further 24 hours and then concentrated by evaporation. The residue is partitioned between ether and water. The organic phases are concentrated by evaporation and the title compound is obtained from the residue by FC (12 g of silica gel, dichloromethane/diethyl ether=2:1): Rf (dichloromethane/diethyl ether=2:1)=0.33.
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]2[N:8]=[CH:7][C:6]3[N:12]([CH3:23])[C:13](=[O:22])[N:14]([C:15]4[C:16]([CH3:21])=[N:17][N:18]([CH3:20])[CH:19]=4)[C:5]=3[C:4]=2[CH:3]=1.[C:24]1(=[O:29])[CH2:28][CH2:27][CH2:26][CH2:25]1>>[CH3:20][N:18]1[CH:19]=[C:15]([N:14]2[C:5]3[C:4]4[CH:3]=[C:2]([C:6]5[CH:7]=[N:8][CH:9]=[C:4]([C:24]6([OH:29])[CH2:28][CH2:27][CH2:26][CH2:25]6)[CH:5]=5)[CH:11]=[CH:10][C:9]=4[N:8]=[CH:7][C:6]=3[N:12]([CH3:23])[C:13]2=[O:22])[C:16]([CH3:21])=[N:17]1
Reactant: O=C1CCCC1
Reactant: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(Br)cc3c21
Product: Cc1nn(C)cc1-n1c(=O)n(C)c2cnc3ccc(-c4cncc(C5(O)CCCC5)c4)cc3c21

Procedure:
The title compound was synthesized in a similar manner as described for Example 1.1 using 8-bromo-1-(1,3-dimethyl-1H-pyrazol-4-yl)-3-methyl-1,3-dihydro-imidazo[4,5-c]quinolin-2-one (Intermediate A) and cyclopentanone (Fluka, Buchs, Switzerland) to give the title compound as a white solid. (HPLC: tR 2.14 min (Method A); M+H=455 MS-ES; 1H-NMR (d6-DMSO, 400 MHz) 8.99 (s, 1H), 8.71-8.68 (m, 1H), 8.61-8.58 (m, 1H), 8.16-8.11 (m, 2H), 8.01-7.96 (m, 1H), 7.85-7.81 (m, 1H), 7.63-7.59 (m, 1H), 5.05 (s, 1H), 3.90 (s, 3H), 3.58 (s, 3H), 1.98-1.77 (m, 8H), 1.95 (s, 3H))
Reaction SMILES: C(OC([NH:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:20]4[S:26][CH:25]([CH3:27])[N:21]43)=[CH:16][C:15]=2[F:34])[CH2:10]1)=O)(C)(C)C.Cl.[OH-].[Na+]>>[NH2:8][C@H:9]1[CH2:13][CH2:12][N:11]([C:14]2[C:23]([F:24])=[C:22]3[C:17]([C:18](=[O:33])[C:19]([C:28]([O:30][CH2:31][CH3:32])=[O:29])=[C:20]4[S:26][CH:25]([CH3:27])[N:21]43)=[CH:16][C:15]=2[F:34])[CH2:10]1
Reactant: CCOC(=O)c1c2n(c3c(F)c(N4CC[C@H](NC(=O)OC(C)(C)C)C4)c(F)cc3c1=O)C(C)S2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Product: CCOC(=O)c1c2n(c3c(F)c(N4CC[C@H](N)C4)c(F)cc3c1=O)C(C)S2
Temperature: 80 °C
Yield: 90.9 %

Procedure:
A mixture of 0.40 g of ethyl 7-[(S)-3-(tert-butoxycabonyl amino)-1-pyrrolidinyl)-6,8-difluoro-1-methyl-4-oxo-1H,4H-[1,3]thiazeto[3,2-a]quinoline-3-carboxylate and 4.0 ml of 35% hydrochloric acid was heated at 80° C. for 10 minutes with stirring. The reaction mixture was neutralized with 20% aqueous sodium hydroxide. The precipitate was collected by filtration to give 0.29 g of the desired compound, which was recrystallized from ethanol to give pale brown crystals, m.p. 225°-230° C. (decomp.).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](B(O)O)=[CH:4][C:3]=1[F:11].FC(F)(F)S(O[C:18]1[CH:23]=[CH:22][C:21]([C@H:24]2[C:29]3=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]3[CH2:27][CH2:26][CH2:25]2)=[CH:20][CH:19]=1)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>CCO.O.CN(C=O)C.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>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:18]2[CH:19]=[CH:20][C:21]([C@H:24]3[C:29]4=[N:30][S:31](=[O:35])(=[O:34])[CH2:32][CH2:33][N:28]4[CH2:27][CH2:26][CH2:25]3)=[CH:22][CH:23]=2)=[CH:4][C:3]=1[F:11]
Reactant: OB(O)c1ccc(Cl)c(F)c1
Reactant: O=S1(=O)CCN2CCC[C@@H](c3ccc(OS(=O)(=O)C(F)(F)F)cc3)C2=N1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CN(C)C=O
Product: O=S1(=O)CCN2CCC[C@@H](c3ccc(-c4ccc(Cl)c(F)c4)cc3)C2=N1
Temperature: 50 °C
Reaction time: 16 h
Yield: 5.2 %

Procedure:
Tetrakis(triphenylphosphine)palladium(0) (16.0 mg) was added to a mixture of (4-chloro-3-fluorophenyl)boronic acid (85.0 mg), 4-[(95)-2,2-dioxido-3,4,6,7,8,9-hexahydropyrido[2,1-c][1,2,4]thiadiazin-9-yl]phenyl trifluoromethanesulfonate (100 mg) and sodium carbonate (51.4 mg) in EtOH (3 mL), water (1.5 mL) and DMF (dry) (2 mL). The mixture was stirred at 50° C. under nitrogen for 16 hr. Silica-gel was added and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH silica gel, eluted with MeOH in EtOAc) and concentrated. The residue was dissolved in MeCN/DMSO (1900/100 μM) and purified by preparative HPLC (C18, eluted with water in acetonitrile containing 0.1% TFA). The desired fractions were neutralized with sat. NaHCO3 aq., extracted with EtOAc and washed with brine. The organic layer was separated, dried over anhydrous magnesium sulfate and concentrated in vacuo to give the title compound (5.00 mg) as a white solid.
Reaction SMILES: C(OC([N:8]1[C@H:17]([C:18](=[O:40])[NH:19][C@H:20]([C:36]([O:38][CH3:39])=[O:37])[CH2:21][C:22]2[CH:27]=[CH:26][C:25]([C:28]3[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=3[CH3:35])=[CH:24][CH:23]=2)[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH:53]5[CH2:58][CH2:57][CH2:56][CH2:55][CH2:54]5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9]1)=O)(C)(C)C.[ClH:59]>C(Cl)Cl>[ClH:59].[ClH:59].[CH3:39][O:38][C:36](=[O:37])[C@@H:20]([NH:19][C:18]([C@@H:17]1[CH2:16][C:15]2[CH:14]=[C:13]3[O:41][CH2:42][C@H:43]([C:45]4[CH:50]=[CH:49][C:48]([O:51][CH2:52][CH:53]5[CH2:54][CH2:55][CH2:56][CH2:57][CH2:58]5)=[CH:47][CH:46]=4)[O:44][C:12]3=[CH:11][C:10]=2[CH2:9][NH:8]1)=[O:40])[CH2:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH:33]=[CH:32][N:31]=[C:30]([CH3:34])[C:29]=2[CH3:35])=[CH:24][CH:23]=1
Reactant: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1C(=O)OC(C)(C)C)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Agent: Cl
Solvent: ClCCl
Product: COC(=O)[C@H](Cc1ccc(-c2ccnc(C)c2C)cc1)NC(=O)[C@@H]1Cc2cc3c(cc2CN1)O[C@@H](c1ccc(OCC2CCCCC2)cc1)CO3
Temperature: 25 °C
Reaction time: 3 h

Procedure:
(3S,8S)-3-(4-Cyclohexylmethoxy-phenyl)-8-{(S)-2-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-1-methoxycarbonyl-ethylcarbamoyl}-2,3,8,9-tetrahydro-6H-[1,4]dioxino[2,3-g]isoquinoline-7-carboxylic acid tert-butyl ester (86 mg) was dissolved in 3 mL DCM and 3 mL 4 N HCl (dioxane) was added. The mixture stirred at room temperature for 3 hours, and the mixture was concentrated. DCM was added and the mixture was again concentrated. The solid was triturated with diethyl ether and dried under vacuum to provide (S)-2-{[(3S,8S)-3-(4-cyclohexylmethoxy-phenyl)-2,3,6,7,8,9-hexahydro-[1,4]dioxino[2,3-g]isoquinoline-8-carbonyl]-amino}-3-[4-(2,3-dimethyl-pyridin-4-yl)-phenyl]-propionic acid methyl ester bis hydrochloride (71 mg). LCMS: (m/z) 691.
Reaction SMILES: [C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH:36]=O)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2].[NH:38]1[CH2:43][CH2:42][O:41][CH2:40][CH2:39]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl.CC(O)=O>[C:1]([C:3]1[N:4]=[CH:5][C:6]([NH:9][C:10]2[CH:15]=[C:14]([NH:16][CH2:17][CH:18]3[CH2:23][CH2:22][CH2:21][N:20]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:19]3)[C:13]([N:31]3[CH:35]=[CH:34][C:33]([CH2:36][N:38]4[CH2:43][CH2:42][O:41][CH2:40][CH2:39]4)=[CH:32]3)=[CH:12][N:11]=2)=[N:7][CH:8]=1)#[N:2]
Reactant: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(C=O)c2)C1
Reactant: C1COCCN1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCCl
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(CNc2cc(Nc3cnc(C#N)cn3)ncc2-n2ccc(CN3CCOCC3)c2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Crude tert-butyl 3-((2-(5-cyanopyrazin-2-ylamino)-5-(3-formyl-1H-pyrrol-1-yl)pyridin-4-ylamino)methyl)piperidine-1-carboxylate (143 mg of 50% pure material, approx. 0.142 mmol) was dissolved in DCE (1.5 mL) and AcOH (0.15 mL). Morpholine (18.5 uL, 0.213 mmol) and sodium triacetoxyborohydride (75 mg, 0.355 mmol) were added and the reaction mixture was stirred at room temperature for 30 min. The reaction mixture was partitioned between dichloromethane and 10% aqueous NaHCO3. The two phases were separated and the aqueous phase was extracted with dichloromethane. The combined organic phases were evaporated to dryness and the product (90 mg) was used without further purification.