Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([O:7][C@@H:8]([C@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:34]([O:36]CC=C)=[O:35])=[C:14]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[C:28]5[CH:29]=[CH:30][CH:31]=[C:20]([C:21]=45)[S:19]3(=[O:33])=[O:32])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9])=O)C=C.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(C(CCCC)C([O-])=O)C.[Na+:71].C(OCC)(=O)C.C(C(CCCC)C(O)=O)C>C(OCC)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>[OH:7][C@@H:8]([C@H:10]1[C:40](=[O:41])[N:12]2[C:13]([C:34]([O-:36])=[O:35])=[C:14]([CH2:17][N:18]3[C:23](=[O:24])[C:22]4[CH:25]=[CH:26][CH:27]=[C:28]5[CH:29]=[CH:30][CH:31]=[C:20]([C:21]=45)[S:19]3(=[O:32])=[O:33])[C@H:15]([CH3:16])[C@H:11]12)[CH3:9].[Na+:71]
Reactant: C=CCOC(=O)O[C@H](C)[C@H]1C(=O)N2C(C(=O)OCC=C)=C(CN3C(=O)c4cccc5cccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: CCCCC(CC)C(=O)O
Agent: CCCCC(CC)C(=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: C[C@@H](O)[C@H]1C(=O)N2C(C(=O)[O-])=C(CN3C(=O)c4cccc5cccc(c45)S3(=O)=O)[C@H](C)[C@H]12
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
The product from step 1 (56 mg, 0.0961 mmol), triphenylphosphine (15 mg, 0.0577 mmol), 0.5M sodium 2-ethyl-hexanoate in ethyl acetate (0.211 mL, 0.106 mmol), 2-ethyl-hexanoic acid (0.0146 mL, 0.106 mmol), and tetrakis(triphenylphosphine)palladium(0) (22 mg, 0.0192 mmol) were combined in anhydrous dimethylfromamide (1 mL). The mixture was stirred at room temperature for 5 minutes, then cooled in an ice bath and stirred at 0-5° C. for 2 hours. The mixture was diluted with diethyl ether (12 mL) to precipitate a solid. The solid was collected by centrifugation, washed with ether (5 mL), and dried under vacuum. The solid was dissolved in water (5 mL) and added to a column (1×20 cm) of Amberchrom CG-161 resin. The column was eluted with water followed by a progressive gradient of acetonitrile in water. The product containing fractions were combined and lyophilized to a white, amorphous solid (18 mg). This material was further purified by preparative layer chromatography on a 1 mm×20 cm×20 cm RPSF plate, developing with 7:3 water-acetonitrile in an ice cooled tank. The product band was located by UV, removed and eluted with 4:1 acetonitrile-water. The eluent was washed with hexanes, filtered through a 0.45 micon disc, concentrated under vacuum to remove the acetonitrile, and lyophilized to afford the title compound (17.9 mg) as a white amorphous solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Cl[CH2:8][CH2:9][CH2:10][O:11][C:12]1[CH:25]=[CH:24][C:15]([CH2:16][CH:17]2[CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)=[CH:14][CH:13]=1.[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1>CN(C)C=O>[O:23]=[C:20]1[CH2:21][CH2:22][CH:17]([CH2:16][C:15]2[CH:24]=[CH:25][C:12]([O:11][CH2:10][CH2:9][CH2:8][N:26]3[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]3)=[CH:13][CH:14]=2)[CH2:18][CH2:19]1
Reactant: C1CCNCC1
Reactant: O=C1CCC(Cc2ccc(OCCCCl)cc2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCC(Cc2ccc(OCCCN3CCCCC3)cc2)CC1

Procedure:
A suspension of potassium carbonate (369 mg) in a solution of 4-[4-(3-chloropropoxy)benzyl]cyclohexanone (250 mg) and piperidine (264 μL) in N,N-dimethylformamide (6 mL) is heated for three hours at a temperature close to 80° C., then for two days at a temperature close to 50° C. Solvent is evaporated and the residue partioned between ethyl acetate (10 mL) and water (10 mL). The organic phase is separated by decantation, washed with a saturated aqueous solution of sodium chloride, dried over magnesium sulfate, concentrated under reduced pressure and purified by column chromatography using a gradient dichloromethane/methanol/ammonia from 99/1/0.1 to 98/2/0.2 to give 270 mg of 1-{3-[4-(4-oxocyclohex-1-yl)methylphenoxy]propyl}piperidine.
Reaction SMILES: O1[CH:5]=[CH:4][C:3]([C:6]2[C:7]([O:28][CH3:29])=[C:8]([C:14]([CH2:17][S:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3C)(=[O:20])=[O:19])=[CH:15][CH:16]=2)[C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:2]1.[C:30]1(S(CC2C(C(OCC)=O)=C(OC)C(Br)=CC=2)(=O)=O)C=CC=C[CH:31]=1.C1(B(O)O)C=CC=CC=1>>[C:21]1([S:18]([CH2:17][C:14]2[C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[C:7]([O:28][CH3:29])[C:6]([C:3]3[CH:2]=[CH:31][CH:30]=[CH:5][CH:4]=3)=[CH:16][CH:15]=2)(=[O:19])=[O:20])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2C)ccc(-c2ccoc2)c1OC
Reactant: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(Br)c1OC
Agent: OB(O)c1ccccc1
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccccc2)ccc(-c2ccccc2)c1OC

Procedure:
Prepared by proceeding in a similar manner to Intermediate 28, starting from ethyl 6-(benzenesulphonylmethyl)-3-bromo-2-methoxybenzoate (Intermediate 61) and phenylboronic acid.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:10]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[CH3:11].[Cl-].[Al+3].[Cl-].[Cl-]>ClCCCl>[CH2:10]([C:12]1[CH:13]=[C:14]([CH:15]=[CH:16][C:17]=1[CH2:18][CH3:19])[C:1]([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:8])[CH3:11]
Reactant: CCc1ccccc1CC
Reactant: O=C(Cl)c1ccccc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CCc1ccc(C(=O)c2ccccc2)cc1CC

Procedure:
A mixture of benzoyl chloride (1 eq) and 3,4-diethylbenzene (1.15 eq) was dissolved in 1,2-dichloroethane in a dry flask under argon and cooled in an ice bath with stirring. Aluminum chloride (1.3 eq) was added in portions to the reaction mixture at a rate to maintain the temperature below 10° C. Upon complete addition of the aluminum chloride, the ice bath was removed and the reaction mixture was stirred at room temperature for 18 h, then poured into cold water (100 mL) and extracted into ether (2×100 mL). The combined ether extracts were washed with water (25 mL), sodium bicarbonate solution (2×25 mL), water (25 mL), brine (25 mL), dried (MgSO4) and concentrated to provide the title compound as an oil.
Reaction SMILES: [CH:1]([O:4][C:5]1[CH:12]=[CH:11][C:10]([C:13]([N:15]2[CH2:20][CH2:19][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:17][CH2:16]2)=[O:14])=[CH:9][C:6]=1[CH:7]=[O:8])([CH3:3])[CH3:2].[Li+].[BH4-]>C1COCC1>[OH:8][CH2:7][C:6]1[CH:9]=[C:10]([C:13]([N:15]2[CH2:16][CH2:17][C:18]3([C:32]4[CH:31]=[N:30][N:29]([CH3:33])[C:28]=4[C:27]4[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=4[O:21]3)[CH2:19][CH2:20]2)=[O:14])[CH:11]=[CH:12][C:5]=1[O:4][CH:1]([CH3:2])[CH3:3]
Reactant: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1C=O
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(C(=O)N2CCC3(CC2)Oc2ccccc2-c2c3cnn2C)cc1CO
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 66.1 %

Procedure:
2-Isopropoxy-5-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-carbonyl)benzaldehyde (110 mg, 0.25 mmol) was dissolved in THF (3 mL) and LiBH4 (11 mg, 0.50 mmol) was added. The reaction was stirred at room temperature for 1.5 h before being quenched with methanol (3 mL). The reaction was neutralized by the addition of a saturated sodium bicarbonate solution and was extracted with ethyl acetate (3×). The combined organic layers were dried over Na2SO4, filtered and the solvent was evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel (0-100% ethyl acetate in hexane) to yield [3-(hydroxymethyl)-4-isopropoxy-phenyl]-(1-methylspiro[chromeno[4,3-c]pyrazole-4,4′-piperidine]-1′-yl)methanone (74 mg, 65%) as a white solid. ESI-MS m/z calc. 447.5, found 448.3 (M+1)+. Retention time: 1.59 minutes (3 min run).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:36])([F:35])[F:34])[CH:28]=5)[CH:24]=[C:23]([C:37]([NH2:39])=[O:38])[C:19]=4[NH:20][C:21]=3[CH:22]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO.C(Cl)Cl.[Pd]>[N:11]1([C:14]2[CH:15]=[CH:16][C:17]3[C:18]4[N:26]=[C:25]([C:27]5[CH:32]=[CH:31][CH:30]=[C:29]([C:33]([F:34])([F:36])[F:35])[CH:28]=5)[CH:24]=[C:23]([C:37]([NH2:39])=[O:38])[C:19]=4[NH:20][C:21]=3[CH:22]=2)[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3CCN(Cc4ccccc4)CC3)ccc12
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CO
Product: NC(=O)c1cc(-c2cccc(C(F)(F)F)c2)nc2c1[nH]c1cc(N3CCNCC3)ccc12
Temperature: 25 °C
Yield: 52.6 %

Procedure:
A mixture of 7-(4-benzylpiperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (20 mg, 0.038 mmol), 10% Pd on carbon (7 mg) and ammonium formate (12 mg, 0.19 mmol) in MeOH (3 mL) was heated at reflux for 0.5 hr. The reaction was cooled to RT, diluted with DCM and filtered. The solvents were removed to leave 7-(piperazin-1-yl)-2-(3-(trifluoromethyl)phenyl)-5H-pyrido[3,2-b]indole-4-carboxamide (9 mg, 0.02 mmol, 52% yield). MS (ESI) m/z 440.16 (M+H). 1H NMR (500 MHz, DMSO-d6) δ ppm 11.32 (1H, s), 8.53-8.65 (3H, m), 8.41 (1H, s), 8.07 (1H, d, J=8.85 Hz), 7.88 (1H, s), 7.69-7.83 (2H, m), 7.21 (1H, d, J=1.83 Hz), 7.00 (1H, dd, J=8.70, 1.98 Hz), 3.13-3.25 (4H, m), 2.82-3.00 (4H, m).
Reaction SMILES: [C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(OCC)(O[CH2:19][CH3:20])(=O)=O.[Cl-].[Al+3].[Cl-].[Cl-]>>[CH2:19]([C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][CH:5]=1)[C:1]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])[CH3:20]
Reactant: O=C(c1ccccc1)c1ccccc1
Reactant: CCOS(=O)(=O)OCC
Agent: [Al+3]
Agent: [Cl-]
Product: CCc1cccc(C(=O)c2ccccc2)c1

Procedure:
Friedel-Crafts alkylation is carried out with benzophenone and diethyl sulfate in the presence of aluminum chloride to form 3-ethylbenzophenone. It is then subjected to bromination using N-bromosuccinimide to produce 3-(1-bromoethyl)benzophenone, which is then subjected to alkali hydrolysis to obtain 3-(1-hydroxyethyl)benzophenone. This compound is further reacted with carbon monoxide to obtain ketoprofen (Spanish Patent No. 452,500). ##STR4##
Reaction SMILES: [CH3:1][N:2]([CH3:22])[CH2:3][C:4]([CH3:21])([CH3:20])[CH2:5][NH:6][C:7](=[O:19])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]([O-])=O)=[C:10]([O:17][CH3:18])[CH:9]=1>CCO.[Pd]>[NH2:14][C:11]1[CH:12]=[CH:13][C:8]([C:7]([NH:6][CH2:5][C:4]([CH3:20])([CH3:21])[CH2:3][N:2]([CH3:1])[CH3:22])=[O:19])=[CH:9][C:10]=1[O:17][CH3:18]
Reactant: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Product: COc1cc(C(=O)NCC(C)(C)CN(C)C)ccc1N
Temperature: 40 °C
Reaction time: 16 h
Yield: 104.3 %

Procedure:
A suspension of N-(3-dimethylamino-2,2-dimethyl-propyl)-3-methoxy-4-nitro-benzamide (Intermediate 23; 5.7 g, 18.40 mmol), 5% Pd on charcoal (569 mg) in EtOH (300 mL) was stirred at 40° C. under a hydrogen atmosphere for 16 h. The reaction mixture was then filtered through celite, washed with copious MeOH and the volatiles removed under reduced pressure to afford the title compound (5.36 g, Quant.) as a foam.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@@H:9]1[CH2:14][O:15][C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][S:23](=[O:26])(=[O:25])[NH2:24])[C:17]=1[C:27]#[N:28])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>C(O)C>[NH2:28][C:27]1[C:17]2[C:16]([O:15][CH2:14][C@H:9]3[CH2:10][CH2:11][CH2:12][CH2:13][N:8]3[C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])=[CH:21][CH:20]=[CH:19][C:18]=2[NH:22][S:23](=[O:26])(=[O:25])[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc(NS(N)(=O)=O)c1C#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CC(C)(C)OC(=O)N1CCCC[C@@H]1COc1cccc2c1C(N)=NS(=O)(=O)N2
Temperature: 25 °C

Procedure:
To a solution of (R)-tert-butyl-2-((2-cyano-3-(sulfamoylamino)phenoxy)methyl)piperidine-1-carboxylate (Example 15c, 10.7 g, 26.1 mmol) in ethanol (130 mL) was added aqueous NaOH (2N, 130 mL, 26.1 mmol). The solution was refluxed for 18 hours under nitrogen. After cooling to room temperature, the solution was cooled to 0° C. and neutralized with 1N HCl. The mixture was partially concentrated and the product was collected by filtration to afford (R)-tert-butyl 2-(((4-amino-2,2-dioxido-1H-benzo[c][1,2,6]thiadiazin-5-yl)oxy)methyl)piperidine-1-carboxylate, which was used immediately in the next step. MS 311 (MH+-boc).
Reaction SMILES: [CH:1]1([CH2:4][NH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]5[N:27](CC6C=CC(OC)=CC=6)[N:28]=[C:29]([CH3:30])[C:22]=45)=[C:16]([F:40])[CH:15]=3)=[CH:8][N:7]=2)[CH2:3][CH2:2]1>C(O)(C(F)(F)F)=O>[CH:1]1([CH2:4][NH:5][C:6]2[N:11]([CH3:12])[C:10](=[O:13])[C:9]([C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]4[CH:26]=[CH:25][N:24]=[C:23]5[NH:27][N:28]=[C:29]([CH3:30])[C:22]=45)=[C:16]([F:40])[CH:15]=3)=[CH:8][N:7]=2)[CH2:3][CH2:2]1
Reactant: COc1ccc(Cn2nc(C)c3c(Oc4ccc(-c5cnc(NCC6CC6)n(C)c5=O)cc4F)ccnc32)cc1
Solvent: O=C(O)C(F)(F)F
Product: Cc1n[nH]c2nccc(Oc3ccc(-c4cnc(NCC5CC5)n(C)c4=O)cc3F)c12
Temperature: 80 °C
Reaction time: 1 h
Yield: 45.9 %

Procedure:
To a 15 mL capacity reaction tube was added 2-(cyclopropylmethylamino)-5-(3-fluoro-4-(1-(4-methoxybenzyl)-3-methyl-1H-pyrazolo[3,4-b]pyridin-4-yloxy)phenyl)-3-methylpyrimidin-4(3H)-one (23.8 mg, 0.044 mmol) and the solids were dissolved in TFA (0.5 mL, excess). The reaction mixture was stirred at 80° C. for 1 hour in a sealed tube. The excess solvent was evaporated and the crude residue was purified by silica gel chromatography (Biotage 12M) loading with EtOAc and eluting with 3% MeOH/EtOAc to give the title compound as pink solid (8.5 mg, 46%). LRMS (APCI pos) m/e 421.3 (M+1). 1H NMR (400 MHz, DMSO-d6) δ 13.29 (s, 1H), 8.27 (d, J=5.5 Hz, 1H), 8.10 (s, 1H), 7.85 (br d, 1H), 7.65 (d, J=8.6 Hz, 1H), 7.53 (t, J=5.5 Hz, 1H), 7.43 (t, J=8.6 Hz, 1H), 6.23 (d, J=5.5 Hz, 1H), 3.38 (s, 3H), 3.28 (t, J=6.2 Hz, 2H), 2.63 (s, 3H), 1.17 (t, J=7.2 Hz, 1H), 0.46 (q, J=6.8 Hz, 2H), 0.28 (q, J=4.9 Hz, 2H).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:19]2[S:23][C:22]([CH2:24]O)=[N:21][CH:20]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1C(=O)N([Br:52])C(=O)C1>ClCCl>[Br:52][CH2:24][C:22]1[S:23][C:19]([C:4]2[CH:5]=[C:6]([NH:8][C:9]3[N:14]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:12]=[CH:11][N:10]=3)[CH:7]=[C:2]([CH3:1])[CH:3]=2)=[CH:20][N:21]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CO)s2)c1
Reactant: O=C1CCC(=O)N1Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(CBr)s2)c1
Temperature: 0 °C
Yield: 49.3 %

Procedure:
To [5-(3-methyl-5-{[4-(trifluoromethyl)pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]methanol (0.13 g, 0.34 mmol) was added dichloromethane (3.5 mL) and triphenylphosphine (0.11 g, 0.41 mmol). The solution was cooled to 0° C. and n-bromosuccinimide (0.067 g, 0.38 mmol) was added and the reaction was allowed to warm slowly to room temperature. Once the reaction was complete, silica gel (1.3 g) was added and the slurry was concentrated. The solid was purified by silica gel chromatography to yield N-{3-[2-(bromomethyl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (0.072 g, 49%). MS ESI: [M+H]+ m/z 430.9. 1H NMR (500 MHz, DMSO-d6) δ 10.29 (s, 1H), 8.84 (d, J=4.9, 1H), 8.07 (s, 1H), 7.99 (s, 1H), 7.49 (s, 1H), 7.29 (d, J=4.9, 1H), 7.21 (s, 1H), 5.04 (s, 2H), 2.32 (s, 3H). rhSYK activity=+++
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[C:7]([C:21]2[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=2[O:28]C)[C:8]([O:13]CC2C=CC=CC=2)=[C:9]([CH:11]=O)[CH:10]=1)=[O:4].Cl.[NH2:31][C:32]1[CH:33]=[C:34]([CH:38]=[CH:39][C:40]=1[NH2:41])[C:35]([NH2:37])=[NH:36]>>[C:35]([C:34]1[CH:38]=[CH:39][C:40]2[NH:41][C:11]([C:9]3[CH:10]=[C:5]([C:3]([OH:2])=[O:4])[CH:6]=[C:7]([C:21]4[CH:26]=[C:25]([F:27])[CH:24]=[CH:23][C:22]=4[OH:28])[C:8]=3[OH:13])=[N:31][C:32]=2[CH:33]=1)(=[NH:36])[NH2:37]
Reactant: N=C(N)c1ccc(N)c(N)c1
Reactant: COC(=O)c1cc(C=O)c(OCc2ccccc2)c(-c2cc(F)ccc2OC)c1
Agent: Cl
Product: N=C(N)c1ccc2[nH]c(-c3cc(C(=O)O)cc(-c4cc(F)ccc4O)c3O)nc2c1
Yield: 58.2 %

Procedure:
Proceeding as in Reference 23, but substituting 6-benzyloxy-5′-fluoro-5-formyl-2′-methoxybiphenyl-3-carboxylic acid methyl ester (1.3 g, 3.30 mmol) and 3,4-diaminobenzamidine hydrochloride (0.739 g, 3.96 mmol), gave 5-(5-carbamimidoyl-1H-benzoimidazol-2-yl)-5′-fluoro-6,2′-dihydroxy-biphenyl-3-carboxylic acid (0.780 g).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[Na+].[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24]SC2C=CC=CC=2)=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C(=O)(O)[O-].[Na+]>CC(N(C)C)=O.O>[Br:12][C:13]1[C:14]([O:32][CH3:33])=[C:15]([C:21]([CH2:24][S:8]([C:5]2[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=2)(=[O:10])=[O:9])=[CH:22][CH:23]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17]
Reactant: CCOC(=O)c1c(CSc2ccccc2)ccc(Br)c1OC
Reactant: O=S([O-])c1ccc(F)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)c1c(CS(=O)(=O)c2ccc(F)cc2)ccc(Br)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 81.8 %

Procedure:
Sodium 4-fluorobenzenesulphinate (0.517 g) was added to a suspension of ethyl 3-bromo-6-bromomethyl-2-methoxybenzoate (Intermediate 87, 0.4 g) and sodium bicarbonate (0.24 g) in dimethylacetamide (8 ml) and water (2 ml) and the mixture was stirred at room temperature for 3 hours. The resultant mixture was diluted with water and loaded onto a C-18 SPE column. The column was flushed with water then eluted with DCM and ethyl acetate. The organic eluent was dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of t-butyl methyl ether and cyclohexane with a gradient of 0-60% to give ethyl 3-bromo-6-(4-fluorobenzenesulphonyl-methyl)-2-methoxybenzoate (0.37 g) as a colourless gum.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[N:5]=[C:4]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[N:3]=1.[H][H]>C(O)C.[Pd]>[NH2:8][C:7]1[C:2]([CH3:1])=[N:3][C:4]([O:12][CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])=[N:5][C:6]=1[CH3:11]
Reactant: CCOC(=O)COc1nc(C)c([N+](=O)[O-])c(C)n1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)COc1nc(C)c(N)c(C)n1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 99.9 %

Procedure:
Compound 6 (75.98 g) and 5% Pd—C (7.598 g, N. E. CHEMCAT, STD Type) were suspended in ethanol (760 mL). Evacuation and replacement with hydrogen were repeated three times. Subsequently, the suspension was vigorously stirred at room temperature (20 to 30° C.) for 4.5 hours under hydrogen atmosphere. After the reaction was completed, the mixture was subjected to high precision pressure filtration (0.2 μm, PTFE) and the filtered product was washed with ethanol (474 mL). The filtrate was evaporated under reduced pressure to give 66.99 g (99.9% yield) of the desired product as a pale yellow solid.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].Br[CH2:8][CH2:9][Cl:10].[CH3:11][C@@H:12]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([OH:28])=[C:24]([O:29][CH3:30])[CH:23]=2)[CH2:14][CH2:13]1.[Cl-].[Na+]>CC(CC(C)C)=O.C(Cl)Cl>[CH3:11][C@@H:12]1[CH2:13][CH2:14][C@H:15]([NH:18][C:19](=[O:31])[CH:20]=[CH:21][C:22]2[CH:27]=[CH:26][C:25]([O:28][CH2:8][CH2:9][Cl:10])=[C:24]([O:29][CH3:30])[CH:23]=2)[CH2:16][CH2:17]1
Reactant: ClCCBr
Reactant: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1O
Agent: O=C([O-])[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CC(=O)CC(C)C
Solvent: ClCCl
Product: COc1cc(C=CC(=O)N[C@H]2CC[C@@H](C)CC2)ccc1OCCCl

Procedure:
6.2 g of potassium carbonate and 4.2 ml of 1-bromo-2-chloroethane were added to a solution of 8.67 g of N-(cis-4-methylcyclohexyl)-4-hydroxy-3-methoxycinnamamide (Example 105) in 200 ml of methylisobutylketone. The solution was reacted for 10 hours, while it was refluxed. After reaction, the reaction solution was allowed to cool, added with 200 ml of methylene chloride and 200 ml of an aqueous sodium chloride solution, and subjected to extraction. The aqueous layer was extracted twice with 100 ml of methylene chloride. The organic layer obtained was washed twice with an aqueous sodium chloride solution and dried over magnesium sulfate. Thereafter, the solvent was removed in vacuo. The product obtained was recrystallized from methylene chloride/ether, yielding 8.76 g of N-(cis-4-methylcyclohexyl)-4-(2-chloroethoxy)-3-methoxycinnamamide (a compound of the present invention) as white crystal, which had the following physiochemical properties:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:32])([CH3:31])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH2:36])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1.[CH3:37][C:38]1[N:46]=[CH:45][CH:44]=[CH:43][C:39]=1[C:40](O)=[O:41].C([O-])(=O)C.[NH4+]>>[Cl:8][C:9]1[CH:10]=[C:11]2[C:19](=[C:20]([NH:22][C:23]([C@@H:25]3[CH2:30][O:29][C:28]([CH3:31])([CH3:32])[CH2:27][N:26]3[CH2:33][C@@H:34]([NH:36][C:40]([C:39]3[C:38]([CH3:37])=[N:46][CH:45]=[CH:44][CH:43]=3)=[O:41])[CH3:35])=[O:24])[CH:21]=1)[NH:18][C:17]1[CH:16]=[N:15][CH:14]=[CH:13][C:12]2=1
Reactant: C[C@H](N)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Reactant: Cc1ncccc1C(=O)O
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O=C(O)C(F)(F)F
Product: Cc1ncccc1C(=O)N[C@@H](C)CN1CC(C)(C)OC[C@H]1C(=O)Nc1cc(Cl)cc2c1[nH]c1cnccc12
Yield: 75 %

Procedure:
The desired compound was prepared according to Method E from (S)-4-((S)-2-Amino-propyl)-6,6-dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide trifluoroacetate salt and 2-methyl-nicotinic acid in 75% yield. 1H-NMR (300 MHz, DMSO-d6): δ 1.21 (s,3H), 1.22 (d,3H), 1.36 (s,3H), 2.10 (d,1H), 2.42 (m,1H), 2.60 (m,1H), 2.99 (d,1H), 3.20 (m,1H), 3.92 (m,2H), 4.22 (m,1H), 7.22 (dd,1H), 7.65 (d,1H), 7.90 (s,1H), 8.16 (d,1H), 8.23 (s,1H), 8.31 (d,1H), 8.38 (d,1H), 8.45 (d,1H), 9.02 (s,1H), 10.04 (s,1H), 11.26 (s,1H). Retention Time (LC, method: ammonium acetate standard): 2.16 min. MS (M+H+): 535.5.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:20]3[CH2:23][CH:22]([OH:24])[CH2:21]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH2:29](Br)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:26][CH2:25][C:12]2=[C:13]([N:20]3[CH2:21][CH:22]([O:24][CH2:29][C:30]4[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH2:23]3)[N:14]3[C:18]([N:19]=[C:11]2[CH2:10][CH2:9]1)=[CH:17][CH:16]=[N:15]3)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCc1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(O)C3)c2CC1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCc2nc3ccnn3c(N3CC(OCc4ccccc4)C3)c2CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To 200 mg (0.56 mmol) 10-(3-hydroxy-azetidin-1-yl)-5,6,8,9-tetrahydro-1,4,7,10a-tetraaza-cyclohepta[f]indene-7-carboxylic acid tert-butyl ester in 10 mL anhydrous THF maintained at 0° C. for 30 minutes was added 320 mg (6.72 mmol, 60% dispersion in mineral oil) NaH under an atmosphere of nitrogen and the reaction was stirred at 0° C. for 30 minutes. 0.8 mL (6.80 mmol) benzyl bromide was added and the reaction was heated at 65° C. for 16 hours. The reaction mixture was allowed to cool to room temperature and the solvent was evaporated. 25 mL EtOAc was added and the organic layer was washed with H2O (2×20 mL), and dried over Na2SO4. After filtration and evaporation the product was purified by column chromatography (silica, heptane/EtOAc 3:7).