Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([OH:7])[CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1.N1C=CC=CC=1.Cl[C:15]([O:17][CH2:18][Cl:19])=[O:16]>CCOCC>[C:15](=[O:16])([O:7][CH2:1][CH:2]1[O:6][CH2:5][CH2:4][CH2:3]1)[O:17][CH2:18][Cl:19]
Reactant: OCC1CCCO1
Reactant: O=C(Cl)OCCl
Solvent: CCOCC
Solvent: c1ccncc1
Product: O=C(OCCl)OCC1CCCO1
Temperature: 25 °C
Reaction time: 17 h
Yield: 91.7 %

Procedure:
Tetrahydrofurfuryl alcohol (19.4 g) was dissolved in anhydrous ether (500 ml) and, after adding pyridine (15 g) under ice cooling, chloromethyl chloroformate (25 g) was added dropwise. After the reaction mixture was stirred at room temperature for 17 hours, the deposited pyridine hydrochloride was removed by filtration and the filtrate was washed with ether (50 ml×2). The washings and the filtrate were combined, washed with water (300 ml×2) and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain chloromethyl (2,3,4,5-tetrahydrofurfuryl) carbonate (33.9 g) as a colorless oily product.
Reaction SMILES: [C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:17]=[CH:16][C:15]([C:18]3[C:19]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)=[CH:20][C:21]4[NH:26][C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:14][CH:13]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].Br[CH2:39][CH2:40][O:41][CH3:42].C([O-])(O)=O.[Na+]>CN(C=O)C>[C:1]([O:5][C:6](=[O:35])[NH:7][C:8]1([C:12]2[CH:13]=[CH:14][C:15]([C:18]3[C:19]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)=[CH:20][C:21]4[N:26]([CH2:39][CH2:40][O:41][CH3:42])[C:25](=[O:27])[CH2:24][O:23][C:22]=4[N:28]=3)=[CH:16][CH:17]=2)[CH2:11][CH2:10][CH2:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3nc4c(cc3-c3ccccc3)NC(=O)CO4)cc2)CCC1
Reactant: COCCBr
Agent: O=C([O-])O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCN1C(=O)COc2nc(-c3ccc(C4(NC(=O)OC(C)(C)C)CCC4)cc3)c(-c3ccccc3)cc21
Temperature: 80 °C
Reaction time: 2 h
Yield: 18.9 %

Procedure:
To a solution of tert-butyl(1-(4-(2-oxo-7-phenyl-2,3-dihydro-1H-pyrido[2,3-b][1,4]oxazin-6-yl)phenyl)cyclobutyl)carbamate (48 mg, 0.10 mmol) in dry DMF (1 mL) was added sodium hydride (16 mg, 0.41 mmol) and 1-bromo-2-methoxyethane (28 mg, 0.20 mmol) under nitrogen. The resulting mixture was stirred for 2 hours at 80° C. A saturated solution of NaHCO3 was added and the mixture was extracted with dichloromethane (3×10 ml) using a phase separator (Isolute® SPE). The combined organic phases were concentrated to dryness under reduced pressure. The resulting residue was purified by Biotage silica gel chromatography (gradient 0 to 40% EtOAc in cyclohexane) to give the title compound (10 mg, 18%). 1H NMR (500 MHz, CDCl3): 7.49 (1H, s), 7.23-7.17 (7H, m), 7.12-7.11 (2H, m), 4.95 (1H, s), 4.82 (2H, s), 4.05 (2H, t), 3.61 (2H, t), 3.29 (3H, s), 2.52-2.20 (4H, m), 2.00-1.95 (1H, m), 1.79-1.65 (1H, m), 1.40-1.10 (9H, br).
Reaction SMILES: [CH2:1]([N:5]([CH:11]([CH3:13])[CH3:12])[C:6](=[O:10])[O:7][CH2:8]Cl)[CH:2]([CH3:4])[CH3:3].[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O-:36])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16].[Na+]>>[OH:14][C@@H:15]([C@H:17]1[C:37](=[O:38])[N:19]2[C:20]([C:34]([O:36][CH2:8][O:7][C:6]([N:5]([CH2:1][CH:2]([CH3:4])[CH3:3])[CH:11]([CH3:13])[CH3:12])=[O:10])=[O:35])=[C:21]([S:24]/[CH:25]=[CH:26]\[C:27]3[S:31][CH:30]=[N:29][C:28]=3[CH2:32][OH:33])[C@H:22]([CH3:23])[C@H:18]12)[CH3:16]
Reactant: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(S/C=C\c3scnc3CO)[C@H](C)[C@H]12
Reactant: CC(C)CN(C(=O)OCCl)C(C)C
Agent: [Na+]
Product: CC(C)CN(C(=O)OCOC(=O)C1=C(S/C=C\c2scnc2CO)[C@H](C)[C@@H]2[C@@H]([C@@H](C)O)C(=O)N12)C(C)C
Yield: 67.9 %

Procedure:
In the same manner as in step b) in Example 125, 279 mg of the title compound was prepared from 177 mg of chloromethyl N-isobutyl-N-isopropylcarbamate and 300 mg of sodium (1R,5S,6S)-6-((1R)-1-hydroxyethyl)-2-[[(Z)-2-(4-hydroxymethyl-thiazol-5-yl)ethen-1-yl]thio]-1-methyl-1-carbapen-2-em-3-carboxylate.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13](Cl)(=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C>C(Cl)Cl>[C:1]([O:5][C:6](=[O:12])[NH:7][CH2:8][CH2:9][CH2:10][NH:11][C:13](=[O:20])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)NCCCN
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCCNC(=O)c1ccccc1

Procedure:
(3-Amino-propyl)-carbamic acid tert-butyl ester (1.6 g) was treated with benzoyl chloride (1.1 eq.) and triethylamine (1.5 eq) in methylene chloride (50 mL). The reaction mixture was washed with 1 N HCl, sat, NaHCO3, and sat NaCl and the solvent removed to give product. LC-MS showed the product had the expected M+H+ of 279.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([CH3:14])(C(O)=O)[CH2:6][CH2:5]2.C([N:17](CC)CC)C.C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C[Si](C)(C)[O-].[Na+].[OH-].[Na+]>C1(C)C=CC=CC=1>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7]([NH2:17])([CH3:14])[CH2:6][CH2:5]2
Reactant: CCN(CC)CC
Reactant: CC1(C(=O)O)CCc2cc(Br)ccc21
Agent: C[Si](C)(C)[O-]
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CC1(N)CCc2cc(Br)ccc21
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 90.8 %

Procedure:
To a solution of (rac)-5-bromo-1-methyl-indan-1-carboxylic acid (1.197 g, 4.69 mmol) in dry toluene (65 ml) was added triethylamine (570 mg, 475 μl, 5.63 mmol) and diphenylphosphoryl azide (1.33 g, 1.04 ml, 4.69 mmol) and the colorless solution was heated to reflux for 3 h. After cooling to 0° C., sodium trimethylsilanolate (9.38 ml, 9.38 mmol, 1M solution in THF) was added and the mixture was stirred for 30 minutes at room temperature. After quenching the reaction with 5% citric acid (100 ml), the pH was adjusted to 12-13 by addition of 3N NaOH and the mixture was extracted three times with CH2Cl2. The combined organic layers were washed with brine, dried with Na2SO4 and evaporated. The remaining crude material was partitioned between 0.1N HCl and diethylether and the aqueous layer was extracted with diethylether. The pH of the aqueous layer was adjusted to 12 by addition of 0.1N NaOH and the aqueous layer was extracted three times with CH2Cl2. The combined CH2Cl2-layers were washed with brine, dried with Na2SO4 and evaporated to obtain the title compound as light yellow oil (963 mg, 91%). MS: 209.1 [M+H−NH3]+.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6]([CH2:12][CH2:13][CH3:14])=[N:7]2.[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH2:28])[CH:17]=1>>[CH3:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([NH:28][C:2]2[C:3]3[C:8](=[N:7][C:6]([CH2:12][CH2:13][CH3:14])=[CH:5][CH:4]=3)[N:9]=[CH:10][CH:11]=2)[CH:17]=1
Reactant: CCCc1ccc2c(Cl)ccnc2n1
Reactant: Cc1ccc(-c2ccccc2)c(N)c1
Product: CCCc1ccc2c(Nc3cc(C)ccc3-c3ccccc3)ccnc2n1

Procedure:
The product from Example 2g (0.106 g, 0.49 mmol) was reacted with the product from Example 213b (0.088 g, 0.49 mmol) for 65 h following the procedure of Example 1g giving the crude title compound which was purified by HPLC with TFA providing the product as a trifluoroacetic acid salt (0.122 g, 52%). 1H NMR (300 MHz, DMSO-d6) ppm: 0.96 (t, J=7.35 Hz, 3 H) 1.81 (d, J=7.72 Hz, 2 H) 2.43 (s, 3 H) 2.89-3.02 (m, 2 H) 6.31 (d, J=6.99 Hz, 1 H) 7.14-7.58 (m, 8 H) 7.77 (d, J=8.46 Hz, 1 H) 8.32 (d, J=7.35 Hz, 1 H) 8.91 (d, J=8.46 Hz, 1 H) 10.91-11.08 (m, 1 H); MS (ESI+) m/z 354.0 (M+H)+; (ESI−) m/z 351.9 (M−H)−.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:12]=[N:13][C:14]([O:18][CH:19]([CH3:21])[CH3:20])=[C:15]([Cl:17])[CH:16]=1)[C:5]#[N:6].[CH3:22][O:23][C:24]1[C:29](B(O)O)=[CH:28][CH:27]=[CH:26][N:25]=1.C(=O)([O-])[O-].[Na+].[Na+]>O1CCOCC1.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:17][C:15]1[CH:16]=[C:11]([O:10][C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[C:29]2[C:24]([O:23][CH3:22])=[N:25][CH:26]=[CH:27][CH:28]=2)[CH:12]=[N:13][C:14]=1[O:18][CH:19]([CH3:21])[CH3:20]
Reactant: CC(C)Oc1ncc(Oc2ccc(C#N)cc2Br)cc1Cl
Reactant: COc1ncccc1B(O)O
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: C1COCCO1
Product: COc1ncccc1-c1cc(C#N)ccc1Oc1cnc(OC(C)C)c(Cl)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 77.5 %

Procedure:
To a solution of 3-bromo-4-[(5-chloro-6-isopropoxypyridin-3-yl)oxy]benzonitrile (Preparation 25, 638 mg, 1.74 mmol) and 2-methoxy-3-pyridylboronic acid (265 mg, 1.74 mmol) in dioxan (10.5 mL) was added a 1 M aqueous solution of sodium carbonate (5.2 mL, 5.21 mmol). The reaction was sparged with nitrogen before the addition of tetrakis(triphenylphosphine)palladium(0) (200 mg, 0.17 mmol). The reaction mixture was heated to 100° C. and stirred for 16 hours and then concentrated in vacuo The residue was partitioned between water (30 mL) and EtOAc (25 mL). The aqueous phase was separated and extracted with EtOAc (2×25 mL). The combined organic extracts were dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to afford a yellow oil which was purified by silica gel column chromatography, eluting with 9:1 heptane/EtOAc. Fractions containing product were combined and concentrated in vacuo to obtain the title compound as a colourless oil (534 mg, 60%).
Reaction SMILES: [N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH2:11][OH:12])[N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1>C(Cl)(Cl)Cl.CO.O=[Mn]=O>[N:1]1([C:6]2[S:7][CH:8]=[C:9]([CH:11]=[O:12])[N:10]=2)[CH:5]=[N:4][CH:3]=[N:2]1
Reactant: OCc1csc(-n2cncn2)n1
Agent: O=[Mn]=O
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O=Cc1csc(-n2cncn2)n1

Procedure:
MnO2 (5.3 g; 60.9 mmol) was added to a solution of (2-[1,2,4]triazol-1-ylthiazole-4-yl)methanol (0.32 g; 2.25 mmol), prepared as described in the above step, in chloroform (15 ml) and methanol (1.5 ml).
Reaction SMILES: [C:1]([O:4][CH2:5][C:6]1[CH2:11][CH2:10][C:9]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)([CH2:12][NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])[CH2:8][CH:7]=1)(=[O:3])[CH3:2].[H][H]>CCOC(C)=O.[Pd]>[C:1]([O:4][CH2:5][CH:6]1[CH2:7][CH2:8][C:9]([C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)([CH2:12][NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[O:22][CH3:23])=[O:15])[CH2:10][CH2:11]1)(=[O:3])[CH3:2]
Reactant: COc1ccccc1C(=O)NCC1(c2ccccc2)CC=C(COC(C)=O)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Product: COc1ccccc1C(=O)NCC1(c2ccccc2)CCC(COC(C)=O)CC1

Procedure:
A solution of 1-acetoxymethyl-4-phenyl-4-(3-(2-methoxyphenyl)-3-oxo-2-azaprop-1-yl)-cyclohex-1-ene (Example 200, 11.5 mg, 0.029 mmol) in 5 mL of EtOAc was shaken with Pd/C (5 mg, 10%) under 50 psi of hydrogen for 14 h. The mixture was filtered through silica gel, concentrated and purified by HPLC (Waters RCM, μ Porosil, 25 mm×10 cm) using a mixture of (5:4:1 hexane-methyl tert-butyl ether-acetonitrile:hexane, 4.5/8.0 mL/min) to give the 2 isomers of the title compound
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:25]=[CH:24][C:6]([CH2:7][N:8]2[C:13](=O)[CH:12]3[CH:10]([CH:11]3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[C:9]2=O)=[CH:5][CH:4]=1.[BH4-].[Na+].B(F)(F)F.N1CCNCC1>C1COCC1.O.[Cl-].[Na+].O>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][N:8]2[CH2:9][CH:10]3[CH:12]([CH:11]3[C:15]3[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[CH:17][CH:16]=3)[CH2:13]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CN2C(=O)C3C(C2=O)C3c2ccc(OC)cc2)cc1
Agent: C1CNCCN1
Agent: FB(F)F
Agent: [BH4-]
Solvent: O
Solvent: C1CCOC1
Product: COc1ccc(CN2CC3C(C2)C3c2ccc(OC)cc2)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 63.4 %

Procedure:
A mixture of 3-(4-methoxybenzyl)-6-(4-methoxyphenyl)-3-azabicyclo[3.1.0]hexane-2,4-dione (0.86 g, 2.6 mmol), NaBH4 (0.296 g, 7.8 mmol) and BF3 etherate (1.0 mL, 7.8 mmol) in THF was heated under reflux overnight. After cooling to 0° C., a solution of piperazine (2 g) in H2O (20 mL) was added. The mixture was stirred at room temperature for 2 h, poured into H2O and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered and then concentrated. The residue was purified by flash column chromatography with EtOAc in hexane (10%, 20%, then 30%) to give a white solid. To a suspension of the solid in THF (20 mL) and H2O (10 mL) was added piperazine (3 g). After heating the mixture under reflux overnight, it was poured into brine and extracted with EtOAc (3×). The combined organic extract was dried over MgSO4, filtered and concentrated to give the title compound as white solid (0.51 g, 65% yield). MS [M+H]+: 310.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]3([CH:16]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[CH3:24])[CH2:15][C:14](=[O:25])[CH2:13][CH:12]3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1.[NH2:33]O.Cl.[OH-].[Na+].C1(C)C=CC(S(Cl)(=O)=O)=CC=1>CCO.O.ClCCl.CCOC(C)=O>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C@@:6]3([C@H:16]([C:17]4[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=4[CH3:24])[CH2:15][C:14](=[O:25])[NH:33][CH2:13][C@@H:12]3[C:26]3[CH:31]=[CH:30][CH:29]=[C:28]([Cl:32])[CH:27]=3)[C:7](=[O:11])[NH:8]2)=[CH:4][CH:3]=1
Reactant: Cc1ccc(F)cc1C1CC(=O)CC(c2cccc(Cl)c2)C12C(=O)Nc1cc(Cl)ccc12
Reactant: NO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(F)cc1[C@@H]1CC(=O)NC[C@H](c2cccc(Cl)c2)[C@@]12C(=O)Nc1cc(Cl)ccc12
Temperature: 100 °C
Yield: 11.7 %

Procedure:
In a manner similar to the method described in example 2 (method B), rac-(1S,2S,6R)-6′-chloro-2-(3-chlorophenyl)-6-(5-fluoro-2-methylphenyl)-spiro[cyclohexane-1,3′-[3H]indole]-2′,4(1′H)-dione (130.0 mg, 0.28 mmole) was reacted with NH2OH—HCl (97.3 mg, 1.40 mmol), NaOH (56.0 mg, 1.40 mmole) in EtOH-water (3/2, 5 mL) at refluxing for 3 hrs, followed by reacting with p-toluenesulfonyl chloride (114.4 mg, 0.60 mmol) in dichloromethane (10 mL) at room temperature for 2 hrs, and heating under microwave irradiation at 100° C. for 20 min. After diluted with AcOEt the mixture was washed with water, dried over Na2SO4 and concentrated. The residue was purified by chiral column chromatography to give (3R,4S,5S)-6′-chloro-3-(3-chlorophenyl)-5-(5-fluoro-2-methylphenyl)-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (15.9 mg): HRMS (ES+) m/z Calcd for C26H21Cl2FN2O2+H [(M+H)+]: 483.1037, Found: 483.1036; (3R,4S,5S)-6′-chloro-5-(3-chlorophenyl)-3-(5-fluoro-2-methylphenyl)-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (11.3 mg): HRMS (ES+) m/z Calcd for C26H21Cl2FN2O2+H [(M+H)+]: 483.1037, Found: 483.1037; (3S,4R,5R)-6′-chloro-5-(3-chlorophenyl)-3-(5-fluoro-2-methylphenyl)-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (8.3 mg): HRMS (ES+) m/z Calcd for C26H21Cl2FN2O2+H [(M+H)+]: 483.1037, Found: 483.1036; (3S,4R,5R)-6′-chloro-3-(3-chlorophenyl)-5-(5-fluoro-2-methylphenyl)-1,1′,2,2′,3,5,6,7-octahydrospiro[4H-azepine-4,3′-[3H]-indole]-2′,7-dione (12.5 mg): HRMS (ES+) m/z Calcd for C26H21Cl2FN2O2+H [(M+H)+]: 483.1037, Found: 483.1038.
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([O:21]C(C)(C)C)=[O:20])(=[O:14])=[O:13])=[CH:9][CH:10]=2)[C:5]([NH:29][C:30]([NH2:32])=[NH:31])=[N:4][CH:3]=1.[C:33]([C:37]([OH:39])=[O:38])([F:36])([F:35])[F:34]>C1(C)C=CC=CC=1>[F:34][C:33]([F:36])([F:35])[C:37]([OH:39])=[O:38].[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][C:8]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=3)[C:19]([OH:21])=[O:20])(=[O:13])=[O:14])=[CH:9][CH:10]=2)[C:5]([NH:29][C:30]([NH2:32])=[NH:31])=[N:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1cccc(NS(=O)(=O)c2ccc3c(Cl)cnc(NC(=N)N)c3c2)c1
Solvent: Cc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: N=C(N)Nc1ncc(Cl)c2ccc(S(=O)(=O)Nc3cccc(C(=O)O)c3)cc12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
tert-Butyl 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}benzoate (30 mg, 0.063 mmol) was dissolved in CF3CO2H (1.0 mL) and the mixture stirred at room temperature for 1 h. The mixture was diluted with PhMe and the solvents were evaporated in vacuo. The residue was triturated with Et2O and then azeotroped with CH2Cl2 to give 3-{[(4-chloro-1-guanidino-7-isoquinolinyl)sulphonyl]amino}-benzoic acid trifluoroacetate (29 mg, 0.055 mmol) as an off-white solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[NH:6][C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1.N1C2C(=CC=C3C=2N=CC=C3)C=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[CH:39]=[C:40]([C:42]1[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=1)[CH3:41]>CN(C=O)C.S([O-])([O-])(=O)=O.[Cu+2]>[CH3:1][N:2]1[CH2:15][CH2:14][C:5]2[N:6](/[CH:39]=[C:40](/[C:42]3[CH:47]=[CH:46][N:45]=[CH:44][CH:43]=3)\[CH3:41])[C:7]3[CH:8]=[CH:9][C:10]([CH3:13])=[CH:11][C:12]=3[C:4]=2[CH2:3]1
Reactant: CC(=CBr)c1ccncc1
Reactant: Cc1ccc2[nH]c3c(c2c1)CN(C)CC3
Agent: [Cu+2]
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Solvent: CN(C)C=O
Product: C/C(=C\n1c2c(c3cc(C)ccc31)CN(C)CC2)c1ccncc1
Temperature: 80 °C
Yield: 52.6 %

Procedure:
2,8-Dimethyl-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (200 mg, 1 mmol), copper sulfate (50 mg, 0.2 mmol), 1,10-phenanthroline (72 mg, 0.4 mmol), potassium phosphate (425 mg, 2 mmol) and 4-(1-bromoprop-1-en-2-yl)pyridine (237 mg, 1.2 mmol) were mixed in DMF (10 mL) and the reaction mixture was purged with nitrogen. The reaction mixture was heated overnight at 80° C. The reaction mixture was diluted with EtOAc and filtered through Celite. The filtrate was concentrated under reduced pressure and the residue was purified by silica gel chromatography (10% MeOH in DCM) to obtain (E)-2,8-dimethyl-5-(2-(pyridin-4-yl)prop-1-enyl)-2,3,4,5-tetrahydro-1H-pyrido[4,3-b]indole (167 mg) as a brown semi solid that was further purified by HPLC to obtain the product as the TFA salt. 1HNMR (DMSO, TFA salt) δ (ppm): 8.40 (m, 2H), 7.20 (s, 1H), 7.10 (m, 3H), 6.95 (d, 1H), 6.86 (d, 1H), 4.40 (m, 2H), 4.22 (m, 2H), 2.90 (s, 3H), 2.80 (m, 2H), 2.38 (s, 3H), 2.30 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:15])[CH3:14])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([OH:19])=O)[N:3]=1.Cl.C([O:25][C:26](=[O:35])[C@@H:27]([NH2:34])[CH2:28][O:29]C(C)(C)C)(C)(C)C>>[Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:12][CH:13]([CH3:14])[CH3:15])[CH:10]=2)[C:5]([OH:16])=[C:4]([C:17]([NH:34][C@@H:27]([CH2:28][OH:29])[C:26]([OH:35])=[O:25])=[O:19])[N:3]=1
Reactant: CC(C)(C)OC[C@H](N)C(=O)OC(C)(C)C
Reactant: CC(C)Oc1ccc2c(O)c(C(=O)O)nc(Cl)c2c1
Agent: Cl
Product: CC(C)Oc1ccc2c(O)c(C(=O)N[C@@H](CO)C(=O)O)nc(Cl)c2c1

Procedure:
Prepared in analogy to Example A-2 e) and f) from 1-chloro-4-hydroxy-7-isopropoxy-isoquinoline-3-carboxylic acid (can be obtained according to U.S. Pat. No. 6,093,730, October 1998, Weidmann et al.) and (S)-2-amino-3-tert-butoxy-propionic acid tert-butyl ester hydrochloride; MS-(+)-ion: M+1=369.0 amu.
Reaction SMILES: [O:1]1[CH2:6][CH2:5]O[CH2:3][CH2:2]1.Br[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12].C([Sn](CCCC)(CCCC)C1OC=CC=1)CCC.[F-].[K+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(OCC)(=O)C>[O:1]1[CH:6]=[CH:5][CH:3]=[C:2]1[C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][CH:15]=1)[CH:11]=[O:12]
Reactant: O=Cc1cccc(Br)c1
Reactant: C1COCCO1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: [F-]
Solvent: CCOC(C)=O
Product: O=Cc1cccc(-c2ccco2)c1
Reaction time: 18 h
Yield: 86 %

Procedure:
EX-592A) To a dioxane (20 mL) solution of 3-bromobenzaldehyde (0.63 mL, 5.4 mmol) was added 2-(tributylstannyl)furan (1.89 mL, 6.00 mL) and Pd(PPh3)2Cl2 (0.21 g, 0.30 mmol). The mixture was heated to reflux under or 1.5 h. The cooled mixture was poured into a mixture of saturated KF and ethyl acetate and stirred 18 h. The slurry was filtered through celite. The organic layer was separated, washed with brine, dried (MgSO4) and evaporated to an oil. Purification by flash chromatography on silica gel eluting with 5% ethyl acetate in hexane gave 0.80 g (86%) of the desired 3-(2-furanyl)benzaldehyde product as an yellow oil which solidified upon standing. MS: m/z=173.1 [M+H]+.
Reaction SMILES: Br[C:2]1[N:3](C(OC(C)(C)C)=O)[C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2.[C:24](=[S:27])([O-:26])[CH3:25].[K+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.CCN(C(C)C)C(C)C.C(O)(C(F)(F)F)=O>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[C:24]([S:27][C:2]1[NH:3][C:4]2[C:9]([C:10]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:8][CH:7]=[CH:6][CH:5]=2)(=[O:26])[CH3:25]
Reactant: CCOC(=O)Cc1c(Br)n(C(=O)OC(C)(C)C)c2ccccc12
Reactant: CC([O-])=S
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)Cc1c(SC(C)=O)[nH]c2ccccc12
Reaction time: 1 h
Yield: 53.1 %

Procedure:
A solution of tert-butyl 2-bromo-3-(2-ethoxy-2-oxoethyl)-1H-indole-1-carboxylate (500 mg, 1.3 mmol), potassium ethanethioate (200 mg, 1.7 mmol), tris(dibenzylideneacetone)dipalladium(0) (60 mg, 0.065 mmol), xantphos (75 mg, 0.13 mmol) and DIPEA (0.5 ml, 2.6 mmol) in 1,4-dioxane (4 ml), was heated at 150° C. for 20 minutes in a microwave reactor. TFA (5 ml) was added to the mixture and stirred for 1 hour until Boc deprotection was complete. Filtered reaction mixture through celite and washed with EtOAc (2×50 ml). The organic layer was dried over Na2SO4, filtered and concentrated. The crude product was introduced to a silica gel loading column and purified by column chromatography (10-30% EtOAc/Hexanes) to provide the desired product (190 mg, 0.69 mmol), 52.8%. MS (m/z) 278 [M+H]+.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([OH:28])=O)=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19][CH3:20])C[CH2:4][CH2:3][CH2:2]1.[CH3:31][NH:32][CH2:33][CH2:34][C:35]([O:37]CC)=[O:36].Cl.C(N=C=NCCCN(C)C)C.O.OC1C2N=NNC=2C=CC=1>CN(C)C=O.C(OCC)(=O)C.C(N(CC)CC)C>[CH:6]1([CH:7]([NH:21][C:22]2[CH:30]=[CH:29][C:25]([C:26]([N:32]([CH3:31])[CH2:33][CH2:34][C:35]([OH:37])=[O:36])=[O:28])=[CH:24][CH:23]=2)[C:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[O:10][C:9]=2[CH2:19][CH3:20])[CH2:1][CH2:2][CH2:3][CH2:4]1
Reactant: CCc1oc(-c2ccccc2)cc1C(CC1CCCC1)Nc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)CCNC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCN(CC)CC
Product: CCc1oc(-c2ccccc2)cc1C(Nc1ccc(C(=O)N(C)CCC(=O)O)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 86.8 %

Procedure:
A solution of 4-{[2-cyclopentyl-1-(2-ethyl-5-phenylfuran-3-yl)ethyl]amino}benzoic acid (195 mg), ethyl 3-(methylamino)propanoate (79 mg), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (115 mg), hydroxybenzotriazole monohydrate (92 mg) and triethylamine (84 μL) in N,N-dimethylformamide (10 mL) was stirred at room temperature for 4 hr. Ethyl acetate was added, the mixture was washed with saturated aqueous sodium hydrogen carbonate solution and water, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure, and the organic layer was dried over magnesium sulfate. The solvent was evaporated under reduced pressure. To the residue were added ethanol (2 mL), tetrahydrofuran (2 mL) and 1N lithium hydroxide (1.0 mL), and the mixture was stirred at room temperature for 1 hr. The solvent was evaporated under reduced pressure, and water (10 mL) was added. The mixture was neutralized with 1N hydrochloric acid under ice-cooling, and stirred for 1 hr. The resulting precipitate was collected by filtration and dried to give the title compound (199 mg, 86%).