Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][CH2:12][CH2:13][C@H:14]2[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[C:34](Cl)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1>C(Cl)Cl>[C:34]([N:11]([S:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=1)(=[O:9])=[O:10])[CH2:12][CH2:13][C@H:14]1[CH2:19][CH2:18][C@H:17]([O:20][CH2:21][C:22]([O:24][CH2:25][CH3:26])=[O:23])[CH2:16][CH2:15]1)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CCOC(=O)CO[C@H]1CC[C@H](CCNS(=O)(=O)c2ccc(Cl)cc2)CC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CO[C@H]1CC[C@H](CCN(C(=O)c2ccccc2)S(=O)(=O)c2ccc(Cl)cc2)CC1
Temperature: 0 °C

Procedure:
To an ice-cold mixture of 4.0 g. (10 mMol) ethyl trans-4-[2-(4-chlorobenzenesulphonylamino)-ethyl]-cyclohexyloxyacetate, 50 ml. methylene chloride and 1.5 g. (15 mMol) triethylamine is added dropwise a mixture of 1.4 g. (10 mMol) benzoyl chloride and 30 ml. methylene chloride. The reaction mixture is maintained for 4 hours at reflux temperature, cooled, filtered and the filtrate washed with dilute hydrochloric acid and water. It is then dried with anhydrous sodium sulphate and evaporated. After purification over silica gel/cyclohexane/diethyl ether (2:1 v/v), there is obtained a yield of 1.7 g. (67% of theory); m.p. 81°-82° C.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[CH:7]=[C:8]([C:11](O)=[O:12])[CH:9]=[CH:10][C:5]=2[N:4]=[C:3]1[NH:14][C:15]1[S:16][C:17]2[CH:23]=[C:22]([O:24][C:25]([F:28])([F:27])[F:26])[CH:21]=[CH:20][C:18]=2[N:19]=1.[NH2:29][CH2:30][CH2:31][O:32][CH2:33][CH2:34][OH:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[OH:35][CH2:34][CH2:33][O:32][CH2:31][CH2:30][NH:29][C:11]([C:8]1[CH:9]=[CH:10][C:5]2[N:4]=[C:3]([NH:14][C:15]3[S:16][C:17]4[CH:23]=[C:22]([O:24][C:25]([F:27])([F:28])[F:26])[CH:21]=[CH:20][C:18]=4[N:19]=3)[N:2]([CH3:1])[C:6]=2[CH:7]=1)=[O:12]
Reactant: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)O)cc21
Reactant: NCCOCCO
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2ccc(C(=O)NCCOCCO)cc21
Yield: 51.5 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid [2-(2-hydroxy-ethoxy)-ethyl]-amide (50 mg) was prepared by following General Procedure F starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-benzoimidazole-5-carboxylic acid (80 mg), 2-(2-amino-ethoxy)-ethanol (24 mg), HBTU (80 mg), and DIEA (70 uL) in DMF (1 mL). LC/MS: m/z 495.5.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([OH:15])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2].S(=O)(=O)(O)O.[CH2:22](O)[CH3:23]>>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]2[O:12][CH:11]([C:13]([O:15][CH2:22][CH3:23])=[O:14])[CH2:10][CH2:9][C:8]=2[CH:16]=1)([O-:3])=[O:2]
Reactant: O=C(O)C1CCc2cc([N+](=O)[O-])ccc2O1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1CCc2cc([N+](=O)[O-])ccc2O1
Reaction time: 2 h
Yield: 95 %

Procedure:
A mixture of 60 parts of 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylic acid, 480 parts of ethanol and 5.52 parts of concentrate sulfuric acid was stirred for 2 hours at reflux temperature. The reaction mixture was evaporated. The residue was crystallized from 2,2'-oxybispropane (activated charcoal). The product was filtered off and dried, yielding 65 parts (95%) of ethyl 3,4-dihydro-6-nitro-2H-1-benzopyran-2-carboxylate; mp. 80.8° C. (intermediate 23).
Reaction SMILES: [CH2:1]([NH2:4])[CH2:2][NH2:3].C[Al](C)C.[F:9][C:10]([CH3:41])([CH3:40])[CH2:11][CH2:12][CH:13]1[C:17](=O)[O:16][CH:15]([CH:19]([NH:27][C:28]([C:30]2[CH:39]=[N:38][C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]=2)=[O:29])[CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH2:14]1>C1(C)C=CC=CC=1>[CH2:20]([CH:19]([NH:27][C:28]([C:30]1[CH:39]=[N:38][C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]=1)=[O:29])[CH:15]([OH:16])[CH2:14][CH:13]([C:17]1[NH:3][CH2:2][CH2:1][N:4]=1)[CH2:12][CH2:11][C:10]([F:9])([CH3:41])[CH3:40])[C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: NCCN
Reactant: CC(C)(F)CCC1CC(C(Cc2ccccc2)NC(=O)c2cnc3ccccc3n2)OC1=O
Agent: C[Al](C)C
Solvent: Cc1ccccc1
Product: CC(C)(F)CCC(CC(O)C(Cc1ccccc1)NC(=O)c1cnc2ccccc2n1)C1=NCCN1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 27.1 %

Procedure:
To a solution of ethylenediamine (0.040 mL, 0.598 mmol) in toluene (2 mL) at −10° C. was added trimethylaluminum (2.0 M in hexanes, 0.300 mL, 0.600 mmol) and stirred for 15 minutes. A solution of quinoxaline-2-carboxylic acid {1-[4-(3-fluoro-3-methyl-butyl)-5-oxo-tetrahydro-furan-2-yl]-2-phenyl-ethyl}-amide (250 mg, 0.556 mmol) in toluene (3 mL) was then added and the reaction warmed to ambient temperature, then heated to reflux for 3 hours. The reaction was cooled to ambient temperature and quenched carefully with water (1 mL). The solution was diluted with methylene chloride and methanol and then filtered, washing the filtrate with methanol. The organics were concentrated and the crude product was purified by chromatography on silica gel to give the title compound (74 mg, 17%).
Reaction SMILES: [CH3:1][Si:2]([CH3:17])([CH3:16])[CH2:3][CH2:4][O:5][CH2:6][O:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.[H-].[Na+].CS(O[CH2:25][CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([CH2:34][CH2:35][N:36]2[CH2:40][C@@H:39]([C:41]3[CH:52]=[CH:51][C:44]4[O:45][C:46]([CH3:50])([CH3:49])[O:47][CH2:48][C:43]=4[CH:42]=3)[O:38][C:37]2=[O:53])=[CH:30][CH:29]=1)(=O)=O.P([O-])([O-])([O-])=O>CN(C=O)C>[CH3:49][C:46]1([CH3:50])[O:45][C:44]2[CH:51]=[CH:52][C:41]([C@H:39]3[O:38][C:37](=[O:53])[N:36]([CH2:35][CH2:34][C:31]4[CH:30]=[CH:29][C:28]([O:27][CH2:26][CH2:25][O:15][CH2:14][C:10]5[CH:11]=[CH:12][CH:13]=[C:8]([O:7][CH2:6][O:5][CH2:4][CH2:3][Si:2]([CH3:17])([CH3:16])[CH3:1])[CH:9]=5)=[CH:33][CH:32]=4)[CH2:40]3)=[CH:42][C:43]=2[CH2:48][O:47]1
Reactant: C[Si](C)(C)CCOCOc1cccc(CO)c1
Reactant: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOS(C)(=O)=O)cc4)C(=O)O3)ccc2O1
Agent: O=P([O-])([O-])[O-]
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OCc2cc([C@@H]3CN(CCc4ccc(OCCOCc5cccc(OCOCC[Si](C)(C)C)c5)cc4)C(=O)O3)ccc2O1
Temperature: 20 °C
Reaction time: 0.25 h

Procedure:
A solution of (3-{[2-(trimethylsilyl)ethoxy]methoxy}phenyl)methanol in DMF (5 ml) under nitrogen was treated with sodium hydride (18 mg, 60% in oil) and the mixture was stirred at 20° C. for 15 min. 2-(4-{2-[(5R)-5-(2,2-Dimethyl-4H-1,3-benzodioxin-6-yl)-2-oxo-1,3-oxazolidin-3-yl]ethyl}phenoxy)ethyl methanesulfonate (150 mg) was added and the mixture was stirred at 20° C. for 20 h. Phosphate buffer solution (20 ml, pH6.5) was added and the mixture was extracted with EtOAc (30 ml). The organic extract was washed with water (2×20 ml) and dried (Na2SO4). The solvent was evaporated in vacuo to give a residue which was purified by chromatography on flash silica gel. Elution with EtOAc-petroleum ether 40°-60° (1:1) gave the title compound (90 mg) LCMS RT=4.07 min.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH2:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:15][CH:16]([N:18]=[C:19]=[O:20])[CH3:17]>O1CCCC1.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([C:10]([NH:12][C:19]([NH:18][CH:16]([CH3:17])[CH3:15])=[O:20])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: CC(C)N=C=O
Reactant: NC(=O)c1cccc([N+](=O)[O-])c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)NC(=O)NC(=O)c1cccc([N+](=O)[O-])c1
Reaction time: 0.25 h

Procedure:
A solution of 3-nitrophenylcarboxamide (2 g) in 25 ml of dry tetrahydrofuran was cooled to 0° C. and treated with 648 mg of sodium hydride (60% oil dispersion). The reaction mixture was stirred for 15 minutes and then 2-propylisocyanate (1.48 ml) was introduced dropwise via syringe. The reaction mixture was then stirred at 0° C. overnight. The reaction mixture was diluted with 300 ml of ethyl acetate. The reaction mixture was washed with 10% citric acid solution and brine. The organic extracts were dried and then concentrated in vacuo to yield 3.9 g of the title compound in sufficient purity to be used in the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]3[N:18]=[CH:19][C:20]([C:21]([OH:23])=O)=[C:10]3[N:9]=2)=[CH:4][CH:3]=1.[NH2:24][C:25]1[CH:26]=[C:27]([S:31]([NH:34][CH:35]2[CH2:37][CH2:36]2)(=[O:33])=[O:32])[CH:28]=[CH:29][CH:30]=1>>[CH:35]1([NH:34][S:31]([C:27]2[CH:26]=[C:25]([NH:24][C:21]([C:20]3[CH:19]=[N:18][N:11]4[C:12]([C:14]([F:17])([F:16])[F:15])=[CH:13][C:8]([C:5]5[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=5)=[N:9][C:10]=34)=[O:23])[CH:30]=[CH:29][CH:28]=2)(=[O:33])=[O:32])[CH2:37][CH2:36]1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12
Reactant: Nc1cccc(S(=O)(=O)NC2CC2)c1
Product: O=C(Nc1cccc(S(=O)(=O)NC2CC2)c1)c1cnn2c(C(F)(F)F)cc(-c3ccc(Cl)cc3)nc12

Procedure:
The title compound was prepared from 5-(4-chloro-phenyl)-7-trifluoromethyl-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.4) and 3-amino-N-cyclopropyl-benzenesulfonamide [CAS 459434-39-0] according to general procedure II. Yellow solid. MS (ISP) 534.1 [(M−H)−]; mp 257° C.
Reaction SMILES: [NH:1]([C:3]([C@@H:5]1[CH2:9][C:8](=[N:10][O:11][CH3:12])[CH2:7][N:6]1[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=[O:4])[NH2:2].[C:20](=S)=[S:21].[OH-].[K+]>C(O)C>[CH3:12][O:11][N:10]=[C:8]1[CH2:7][N:6]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C@H:5]([C:3]2[O:4][C:20](=[S:21])[NH:2][N:1]=2)[CH2:9]1
Reactant: CON=C1C[C@@H](C(=O)NN)N(C(=O)OC(C)(C)C)C1
Reactant: S=C=S
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Product: CON=C1C[C@@H](c2n[nH]c(=S)o2)N(C(=O)OC(C)(C)C)C1

Procedure:
To a solution of tert-butyl (2S,4EZ)-2-(hydrazinocarbonyl)-4-(methoxyimino)-1-pyrrolidinecarboxylate (Intermediate 9, 2.86 mmoles; 780 mg) in ethanol (25 mL) at 0° C. was added carbon disulfide (6.86 mmoles; 522 mg) and potassium hydroxide (3 mmoles; 168 mg). The mixture was refluxed for 7 h. The solvent was evaporated and the residue re-dissolved in EtOAc and washed with NH4Cl sat and 10% NaHCO3 and brine. The organic layer was dried over Na2SO4 and evaporated to give the desired N-protected intermediate, tert-butyl (2S,4EZ)-4-(methoxyimino)-2-(5-thioxo-4,5-dihydro-1,3,4-oxadiazol-2-yl)-1-pyrrolidine-carboxylate, as a yellowish oil (200 mg, 23%).
Reaction SMILES: C1(C[N:8]2[CH2:13][CH2:12][C@@H:11]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[C@H:10]([OH:20])[CH2:9]2)C=CC=CC=1.Cl>C(O)C.[Pd]>[C:14]1([C@@H:11]2[CH2:12][CH2:13][NH:8][CH2:9][C@H:10]2[OH:20])[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O[C@@H]1CN(Cc2ccccc2)CC[C@H]1c1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: CCO
Product: O[C@@H]1CNCC[C@H]1c1ccccc1
Reaction time: 8 h

Procedure:
A solution of trans-1-phenylmethyl-4-phenyl-3-piperidinol (11.00 g, 51.5 mmoles, described in Example 11) in anhydrous ethanol (150 ml) containing concentrated hydrochloric acid (5 ml) is hydrogenated over 10% palladium on charcoal under 50 p.s.i. at 50° C. for 8 hours. The catalyst is removed by filtration over diatomaceous earth and the filtrate is evaporated. The residue is triturated with isopropanol and crystallized from methanol-ether to give the title compound, isolated as the hydrochloride salt, mp 233°-235° C.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][OH:5].[Br:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:10]([N:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[OH:21])[CH3:13])=[O:11].C([O-])([O-])=O.[K+].[K+].Cl>CN(C=O)C>[Br:6][C:7]1[CH:8]=[C:9]([CH:22]=[CH:23][C:24]=1[Cl:25])[C:10]([N:12]([C:14]1[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][C:15]=1[O:21][CH2:2][CH2:3][CH2:4][OH:5])[CH3:13])=[O:11]
Reactant: Cc1cccc(O)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Reactant: OCCCBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cccc(OCCCO)c1N(C)C(=O)c1ccc(Cl)c(Br)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 75.5 %

Procedure:
3-Bromo-1-propanol (2.48 mL, 27.3 mmol) was added to a solution of 3-bromo-4-chloro-N-(2-hydroxy-6-methyl-phenyl)-N-methyl-benzamide (6.47 g, 18.3 mmol, Step 3B) in DMF (80 mL). To this was added K2CO3 (3.3 g, 24 mmol) and the mixture was stirred at room temperature for approximately 16 hrs. At this time the reaction was neutralized with 1N hydrochloric acid and the mixture was extracted with ethyl acetate. The organic layer was washed with first water and then brine solution. The organic filtrate was evaporated and the residue purified using column chromatography in a gradient of 50% ethyl acetate to 60% ethyl acetate in hexanes giving 3-bromo-4-chloro-N-[2-(3-hydroxy-propoxy)-6-methyl-phenyl]-N-methyl-benzamide (5.7 g, 76%). MS [M+H]+: 413.9; tR=2.29 min. (method 1)
Reaction SMILES: [O:1]=[C:2]1[N:6]([C:7]2[CH:8]=[C:9]([CH:13]=[CH:14][N:15]=2)[C:10]([OH:12])=[O:11])[NH:5][CH:4]=[C:3]1[C:16]1[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=1.S(=O)(=O)(O)O.[CH3:27]O>>[CH3:27][O:11][C:10](=[O:12])[C:9]1[CH:13]=[CH:14][N:15]=[C:7]([N:6]2[C:2](=[O:1])[C:3]([C:16]3[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=3)=[CH:4][NH:5]2)[CH:8]=1
Reactant: CO
Reactant: O=C(O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1
Agent: O=S(=O)(O)O
Product: COC(=O)c1ccnc(-n2[nH]cc(-c3cccnc3)c2=O)c1

Procedure:
150 mg (531 μmol) of the compound from Example 41 are dissolved in 20 ml methanol, 1 ml concentrated sulfuric acid are added and the mixture is heated under reflux overnight. After cooling, the precipitate formed is filtered off with suction, washed with methanol and dried.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[C:12]([Cl:20])[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>>[C:1]([O:5][C:6](=[O:21])[CH2:7][CH2:8][N:9]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:18])([F:19])[F:17])=[C:12]([Cl:20])[CH:11]=1)[CH2:23][C:24]([O:26][CH3:27])=[O:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)CCNc1ccc(C(F)(F)F)c(Cl)c1
Product: COC(=O)CN(CCC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)c(Cl)c1
Yield: 34 %

Procedure:
In analogy to the procedure described for intermediate 40B, 3-(3-chloro-4-trifluoromethyl-phenylamino)-propionic acid tert-butyl ester and methyl bromoacetate gave the title compound in 34% yield as yellow oil. MS: 396.12 (MH+, Cl).
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8](B(O)O)=[CH:7][CH:6]=1)([O-:4])=[O:3].Br[C:15]1[S:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:19]=1.C(=O)(O)[O-].[Na+]>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.C(OCC)(=O)C.O1CCOCC1>[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([C:15]2[S:16][C:17]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:18][N:19]=2)=[CH:7][CH:6]=1)([O-:4])=[O:3]
Reactant: CCOC(=O)c1cnc(Br)s1
Reactant: O=[N+]([O-])c1ccc(B(O)O)cc1
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
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1cnc(-c2ccc([N+](=O)[O-])cc2)s1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 53.9 %

Procedure:
Water (5 mL) and 1,4-dioxane (5 mL) were added to 4-nitrophenylboronic acid (667 mg, 4 mmol), ethyl 2-bromo-1,3-thiazole-5-carboxylate (448 μL, 4 mmol), sodium bicarbonate (1.01 g, 12 mmol) and tetrakis(triphenylphosphine)palladium (462 mg, 0.4 mmol), and the mixture was stirred in a nitrogen atmosphere at 100° C. for 1.5 hours. Ethyl acetate was added to the reaction solution, and the organic layer was washed with water and brine, and dried over anhydrous magnesium sulfate. Following concentration under reduced pressure, the residue was purified by silica gel column chromatography (elution solvent: hexane/ethyl acetate=10/1, 4/1, 2/1) to obtain 0.6 g of the title compound as a colorless solid (54%).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([C:31]([OH:33])=O)[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][C@H:25]([CH3:29])[CH2:24]2)=[CH:19][C:18]3=[O:30])[CH:5]=[CH:6][CH:7]=1.[CH3:34][NH:35][CH3:36]>>[F:1][C:2]1[CH:3]=[C:4]([N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([C:31]([N:35]([CH3:36])[CH3:34])=[O:33])[CH:16]=[C:17]3[C:22]=2[O:21][C:20]([N:23]2[CH2:28][CH2:27][O:26][C@H:25]([CH3:29])[CH2:24]2)=[CH:19][C:18]3=[O:30])[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)O)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Reactant: CNC
Product: C[C@@H]1CN(c2cc(=O)c3cc(C(=O)N(C)C)cc(C4CCCN4c4cccc(F)c4)c3o2)CCO1
Yield: 46.2 %

Procedure:
8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxylic acid (102 mg, 0.23 mmol) was reacted with dimethylamine (2N in THF) (0.169 ml, 0.34 mmol) as described in Example 3.02 to give 8-(1-(3-fluorophenyl)pyrrolidin-2-yl)-N,N-dimethyl-2-((R)-2-methylmorpholino)-4-oxo-4H-chromene-6-carboxamide (51 mg, 47%) as a pale yellow foam.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:4][CH:3]=1.[OH-:24].[Na+].Cl>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([C:17]3[CH:18]=[CH:19][C:20]([O:23][C:4](=[O:24])[CH2:3][CH2:2][CH2:7][CH3:6])=[CH:21][CH:22]=3)[S:11][C:12]=2[CH2:13][C:14]([OH:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C(O)Cc1sc(-c2ccc(O)cc2)nc1-c1ccc(Cl)cc1
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Product: CCCCC(=O)Oc1ccc(-c2nc(-c3ccc(Cl)cc3)c(CC(=O)O)s2)cc1
Temperature: 0 °C
Reaction time: 0.07 h
Yield: 31.7 %

Procedure:
4-[4-Chlorophenyl]-2-[4-hydroxyphenyl]thiazole-5-acetic acid (3.81 g, 0.11 moles) was dissolved in 0.2 N sodium hydroxide (55 ml, 0.027 moles) and cooled to 0° C. Valeryl anhydride (2.0 g, 0.011 moles) was added and the reaction flask shaken vigorously for 4 minutes. Dilute hydrochloric acid was added, and the resulting gum extracted into chloroform. The chloroform layer was washed with water, separated, dried over magnesium sulphate to give a white solid. The solid was stirred with water at about 50° C. for 1/4 hour, filtered and dried to give the title compound as a colourless solid (3.68 g), m.p. 197°-9° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1.C(N(CC)CC)C.C(O)(=O)C.[O-:43][C:44]#[N:45].[K+]>C(OCC)(=O)C.O>[NH2:45][C:44]([NH:2][CH2:3][C:4]1[CH:5]=[C:6]([CH2:10][N:11]2[C:19]3[C:14](=[C:15]([O:20][CH3:21])[CH:16]=[CH:17][CH:18]=3)[C:13]([NH:22][S:23]([C:26]3[S:27][C:28]([Cl:31])=[CH:29][CH:30]=3)(=[O:25])=[O:24])=[N:12]2)[CH:7]=[CH:8][CH:9]=1)=[O:43]
Reactant: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CN)c1
Reactant: N#C[O-]
Agent: Cl
Agent: [K+]
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: COc1cccc2c1c(NS(=O)(=O)c1ccc(Cl)s1)nn2Cc1cccc(CNC(N)=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 5 %

Procedure:
To a suspension of N-[1-{[3-(aminomethyl)phenyl]methyl}-4-(methyloxy)-1H-indazol-3-yl]-5-chloro-2-thiophenesulfonamide hydrochloride ((for a preparation see Intermediate 4) 47 mg, 0.094 mmol) in ethyl acetate (0.4 mL) and triethylamine (0.013 mL, 0.094 mmol) was added acetic acid (1.5 mL). A solution of potassium cyanate (11 mg, 0.14 mmol) in water (0.2 mL) was added portionwise. The resultant clear solution was stirred at room temperature overnight. LCMS showed incomplete reaction and a higher percentage of product to SM. The reaction mixture was concentrated in vacuo and the resultant oil was divided into 2 equal portions. Each was dissolved in 1:1 MeOH:DMSO (1 mL) and purified by MDAP on Xbridge column using Acetonitrile Water with an ammonium carbonate modifier. The appropriate fractions were combined and concentrated in vacuo to give two respective batches, which were not clean, so these were combined and re-purified by MDAP to give the title compound (2.4 mg, 5%). LCMS (System A) RT=0.95 min, ES+ve m/z 506/508 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[S:15][C:14]([C:16]3[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=3)=[N:13][C:12]=2[CH2:26]O)=[CH:5][C:4]=1[CH3:28].C(Br)(Br)(Br)[Br:30].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[Br:30][CH2:26][C:12]1[N:13]=[C:14]([C:16]2[CH:21]=[CH:20][C:19]([C:22]([F:25])([F:24])[F:23])=[CH:18][CH:17]=2)[S:15][C:11]=1[CH2:10][CH2:9][C:6]1[CH:7]=[CH:8][C:3]([O:2][CH3:1])=[C:4]([CH3:28])[CH:5]=1
Reactant: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CO)cc1C
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(CCc2sc(-c3ccc(C(F)(F)F)cc3)nc2CBr)cc1C
Reaction time: 8 h
Yield: 70 %

Procedure:
To a 100 ml round-bottom flask equipped with a magnetic stir-bar and N2 inlet was added {5-[2-(4-Methoxy-3-methyl phenyl)ethyl]-2-[4-(trifluoromethyl)phenyl]-1,3-thiazol-4-yl}methanol (0.708 g, 1.74 mmoles, 1 eq), CH2Cl2 (20 ml), carbon tetrabromide (0.634 g, 1.91 mmoles, 1.1 eq) and triphenylphosphine (0.501 g, 1.91 mmoles, 1.1 eq) in that order. The reaction was stirred overnight at which time it was diluted with CH2Cl2 and washed with H2O, brine, dried over Na2SO4, concentrated in vacuo and purified via silica gel chromatography to yield 573 mg (70%) of product.
Reaction SMILES: Cl[C:2]1[CH:14]=[CH:13][C:5]([C:6]([NH:8][CH2:9][CH:10]2[CH2:12][CH2:11]2)=[O:7])=[CH:4][N:3]=1.[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1.C(=O)([O-])[O-].[Na+].[Na+]>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>[CH:10]1([CH2:9][NH:8][C:6](=[O:7])[C:5]2[CH:13]=[CH:14][C:2]([C:17]3[CH:18]=[C:19]([C:20](=[O:21])[NH:22][C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][N:30]=5)[CH:24]=4)[CH:35]=[CH:36][C:16]=3[CH3:15])=[N:3][CH:4]=2)[CH2:12][CH2:11]1
Reactant: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: O=C(NCC1CC1)c1ccc(Cl)nc1
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: CN(C)C=O
Product: Cc1ccc(C(=O)Nc2cccc(-c3ccccn3)c2)cc1-c1ccc(C(=O)NCC2CC2)cn1
Yield: 60.1 %

Procedure:
6-Chloro-N-cyclopropylmethylnicotinamide (Intermediate 1) (18.5 mg, 0.073 mmol) and 4-methyl-N-(3-pyridin-2-yl-phenyl)-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 6) (30 mg, 0.072 mmol), aqueous sodium carbonate (2N, 0.5 ml) and tetrakis(triphenylphosphine)palladium (4 mg) were heated at 90° C. in DMF (1 ml) for 4 hours. The reaction was absorbed onto silica, applied to a bond-elut (5 g, silica) and eluted with an ethylacetate/cyclohexane (0 to 100%) and then acetone. The solvent was evaporated from the product fractions under vacuum and the residue triturated with ether to give N-cyclopropylmethyl-6-[2-methyl-5-(3-pyridin-2-yl-phenylcarbamoyl)-phenyl]-nicotinamide as a white solid (20 mg). LCMS: retention time 3.18 min, MH− 463. NMR: δH [2H6]-DMSO 10.43, (1H, s), 9.14, (1H, s), 8.86, (1H, t), 8.69, (1H, s), 8.53, (1H, s), 8.34, (1H, d), 8.11, (1H, s), 8.01, (1H, d), 7.95-7.89, (3H, m), 7.81-7.78, (2H, m), 7.53-7.46, (2H, m), 7.38, (1H, t), 3.21, (2H, t), 2.44, (3H, s), 1.07, (1H, m), 0.47, (2H, m), 0.27, (2H, m).