Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([CH:15]=O)[CH:10]=2)=[C:4]([CH3:17])[CH:3]=1.[NH2:18][C:19]1[CH:24]=[CH:23][C:22]([CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28])=[C:21]([F:32])[CH:20]=1.C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCCl>[F:32][C:21]1[CH:20]=[C:19]([NH:18][CH2:15][C:11]2[CH:10]=[C:9]([C:5]3[C:6]([CH3:8])=[CH:7][C:2]([OH:1])=[CH:3][C:4]=3[CH3:17])[CH:14]=[CH:13][CH:12]=2)[CH:24]=[CH:23][C:22]=1[CH2:25][CH2:26][C:27]([O:29][CH2:30][CH3:31])=[O:28]
Reactant: Cc1cc(O)cc(C)c1-c1cccc(C=O)c1
Reactant: CCOC(=O)CCc1ccc(N)cc1F
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCOC(=O)CCc1ccc(NCc2cccc(-c3c(C)cc(O)cc3C)c2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 66 %

Procedure:
A mixture of 4′-hydroxy-2′,6′-dimethylbiphenyl-3-carbaldehyde (1.05 g, 4.64 mmol), ethyl 3-(4-amino-2-fluorophenyl)propanoate. (1.00 g, 4.73 mol), acetic acid (0.80 mL, 14 mmol) and 1,2-dichloroethane (20 mL) was stirred at room temperature for 2 hr, and sodium triacetoxyborohydride (3.00 g, 14.2 mmol) was added. The mixture was stirred overnight at room temperature and concentrated. Ethyl acetate was added to the residue, and the mixture was washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The mixture was purified by silica gel column chromatography (30% ethyl acetate/hexane) to give the title compound (1.29 g, yield 66%) as a yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([NH2:24])[CH:22]=2)[CH2:17][CH2:16]1.Br[CH2:26][CH2:27][CH2:28][CH2:29]Br.N1C=CC=CC=1>CN(C=O)C.C([O-])(O)=O.[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[N:9]=[CH:8][N:7]=[C:6]2[N:15]1[C:23]2[C:18](=[CH:19][CH:20]=[C:21]([N:24]3[CH2:29][CH2:28][CH2:27][CH2:26]3)[CH:22]=2)[CH2:17][CH2:16]1
Reactant: BrCCCCBr
Reactant: COc1cc2ncnc(N3CCc4ccc(N)cc43)c2cc1OC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: COc1cc2ncnc(N3CCc4ccc(N5CCCC5)cc43)c2cc1OC
Temperature: 110 °C
Yield: 16.6 %

Procedure:
To 1-(6,7-dimethoxy-quinazolin-4-yl)-2,3-dihydro-1H-indol-6-ylamine (103 mg, 0.320 mmol; from Example 30) in DMF (4 mL) was added 1,4-dibromo-butane (42 μL, 0.352 mmol) and pyridine (34 μL, 0.64 mmol) and the mixture was heated to 110° C. for 36 hours under N2(g). The mixture was diluted with saturated aqueous NaHCO3 and extracted with EtOAc/Et2O (1:1) and the organic phase was washed with water and brine, dried over Na2SO4(s), filtered and concentrated in vacuo. The residue was chromatographed on silica (4% MeOH/CHCl3) to afford 20 mg of product. (M.P. 198°-205° C. (dec); GC-MS: 376 (M+); anal. RP18-HPLC RT: 5.05 min.).
Reaction SMILES: [CH3:1][CH:2]([CH3:19])[CH2:3][CH2:4][N:5]1[C:12](=[O:13])[CH2:11][C:9](=[O:10])[N:8]([CH2:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:6]1=[O:7].N1C=CC=CC=1.[C:26](Cl)(=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29]>ClCCl>[CH3:17][CH:16]([CH3:18])[CH2:15][CH2:14][N:8]1[C:9](=[O:10])[CH:11]([C:26](=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])[C:12](=[O:13])[N:5]([CH2:4][CH2:3][CH:2]([CH3:19])[CH3:1])[C:6]1=[O:7]
Reactant: CC(C)CCN1C(=O)CC(=O)N(CCC(C)C)C1=O
Reactant: CC(C)CC(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(C)CCN1C(=O)C(C(=O)CC(C)C)C(=O)N(CCC(C)C)C1=O
Temperature: 0 °C
Yield: 78.9 %

Procedure:
To a solution of 1,3-bis(3-methylbutyl)barbituric acid 268 mg (1.00 mmol) in dry dichloromethane 3.0 mL under a nitrogen atmosphere, added was pyridine 0.81 mL (0.79 g, 10 mmol, 10 equivalents) and stirred at 0° C. Added was isovaleryl chloride 121 mg (1.00 mmol, 1.00 equivalent) in dichloromethane 1.5 mL to the solution slowly during a period of 20 minutes, then stirred at room temperature for 4 hours. Added was dichloromethane 40 mL and washed the organic layer with 2 M hydrochloric acid and saturated brine, and dried over sodium sulfate. Purified was the crude product 383 mg, after removal of the solvent under the reduced pressure, by column chromatography (silica gel, eluted with dichloromethane). It obtained 1,3-bis(3-methylbutyl)-5-(3-methyl-1-oxobutyl)barbituric acid 278 mg as white plates (79.0% yield).
Reaction SMILES: Cl.[C:2]12([NH2:12])[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][CH:4]([CH2:5]3)[CH2:3]1)[CH2:9]2.C(N(CC)CC)C.[C:20]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([S:30](Cl)(=[O:32])=[O:31])=[CH:26][CH:25]=1)(=[O:22])[CH3:21]>O1CCOCC1>[C:2]12([NH:12][S:30]([C:27]3[CH:26]=[CH:25][C:24]([NH:23][C:20](=[O:22])[CH3:21])=[CH:29][CH:28]=3)(=[O:32])=[O:31])[CH2:9][CH:8]3[CH2:7][CH:6]([CH2:5][CH:4]([CH2:10]3)[CH2:3]1)[CH2:11]2
Reactant: NC12CC3CC(CC(C3)C1)C2
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: C1COCCO1
Product: CC(=O)Nc1ccc(S(=O)(=O)NC23CC4CC(CC(C4)C2)C3)cc1
Temperature: 80 °C
Yield: 30.3 %

Procedure:
1-Adamantanamine hydrochloride (0.0114 mol) and triethylamine (0.0114 mol) are added to a solution of 4-acetamidophenylsulfonyl chloride (1.34 g, 0.0057 mol) in dioxane (5 mL). The mixture is heated for 1 hour at 80° C., then part of the solvent is removed by evaporation at reduced pressure, and water is added until precipitation of the resulting sulfonamide. The product is collected by filtration as a pink solid in 30.3% yield and used without further purification.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([CH:9]=1)C=O.OO.S(=O)(=O)(O)[OH:15]>CO>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:10][CH3:11])=[C:6]([OH:15])[CH:9]=1
Reactant: O=S(=O)(O)O
Reactant: COc1ccc(Br)cc1C=O
Agent: OO
Solvent: CO
Product: COc1ccc(Br)cc1O
Temperature: 70 °C
Reaction time: 60 h
Yield: 115.9 %

Procedure:
To a solution of 5-bromo-2 methoxybenzaldehyde (32.25 g, 0.15 mol) in methanol (300 ml) was added hydrogen peroxide (38 ml of 30% aqueous solution, 0.34 mol) and concentrated sulfuric acid (7 ml, 0.13 mol). The resulting solution was heated at 70° C. for 3 hr. and allowed to cool to room temperature. Stirring was continued for 60 hr. and the reaction mixture was concentrated under reduce pressure. The residue was partitioned between ether and water and the organic extract was washed with slightly acidic water (three times) and dried (magnesium sulfate). The solvent was removed in vacuo to provide an orange solid (30.6 g) which was used without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH2:4].[F:9][C:10]1[N:25]=[CH:24][CH:23]=[CH:22][C:11]=1[C:12](NC1C=CC=CC=1C)=[O:13]>>[Cl:1][C:2]1[CH:8]=[CH:7][CH:6]=[CH:5][C:3]=1[NH:4][C:12](=[O:13])[C:11]1[CH:22]=[CH:23][CH:24]=[N:25][C:10]=1[F:9]
Reactant: Nc1ccccc1Cl
Reactant: Cc1ccccc1NC(=O)c1cccnc1F
Product: O=C(Nc1ccccc1Cl)c1cccnc1F
Yield: 84 %

Procedure:
2-Chloroaniline (Aldrich, 0.17 mL, 1.6 mmol) was converted to the desired compound (0.084 g, 84%) in a manner similar to the preparation of 2-fluoro-N-o-tolylnicotinamide (Step A of Example 8). MS(ESI+) m/z 251 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[C:3]2[N:11]=[C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])[S:9][C:4]=2[CH:5]=[N+:6]([O-])[CH:7]=1.P(Br)(Br)([Br:22])=O.C([O-])(O)=O.[Na+]>ClCCCl>[Br:22][C:5]1[C:4]2[S:9][C:10]([C:12]3[C:17]([F:18])=[CH:16][CH:15]=[CH:14][C:13]=3[Cl:19])=[N:11][C:3]=2[C:2]([Br:1])=[CH:7][N:6]=1
Reactant: O=P(Br)(Br)Br
Reactant: [O-][n+]1cc(Br)c2nc(-c3c(F)cccc3Cl)sc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Product: Fc1cccc(Cl)c1-c1nc2c(Br)cnc(Br)c2s1
Temperature: 70 °C
Yield: 71 %

Procedure:
To a suspension of 7-bromo-2-(2-chloro-6-fluoro-phenyl)-5-oxido-thiazolo[5,4-c]pyridin-5-ium (2.0 mmol, 720 mg) in 1,2-dichloroethane (30 mL) was added POBr3 (8.0 mmol, 2.3 g). The mixture was heated at 70° C. for 3 hours. The mixture was cooled to room temperature, and sat. NaHCO3 solution was added. The aqueous layer was extracted with DCM. The combined organics were dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel chromatography (0-15% EtOAc/hexane) to give the title compound as a white solid (600 mg, 71% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 7.49 (dd, J=14.2, 8.0 Hz, 1H), 7.39 (d, J=8.2 Hz, 1H), 7.19 (t, J=8.7 Hz, 1H). LCMS (ESI) m/z 422.9 [M+H+].
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]([CH3:11])([CH3:10])[C:5](=[O:9])[CH2:6][C:7]#[N:8].[OH-].[Na+].Cl.[NH2:15]O.Cl>C(O)C.O>[CH3:1][O:2][CH2:3][C:4]([C:5]1[O:9][N:8]=[C:7]([NH2:15])[CH:6]=1)([CH3:11])[CH3:10]
Reactant: NO
Reactant: COCC(C)(C)C(=O)CC#N
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCC(C)(C)c1cc(N)no1
Temperature: 25 °C
Yield: 31.6 %

Procedure:
To a mixture of 5-methoxy-4,4-dimethyl-3-oxopentanenitrile (1 g, 6.5 mmol) in ethanol (100 mL), was added 96% sodium hydroxide (308 mg, 7.70 mmol). To this was added a solution of hydroxylamine hydrochloride (537 mg, 7.70 mmol) in water (100 mL). The resulting solution (pH 7.8) was stirred at 60° C. for 22 h, then cooled to room temperature. To this was added concentrated hydrochloric acid (3 mL, 36 mmol) and the mixture refluxed (80° C.) for 1 h. The reaction mixture was concentrated under reduced pressure to remove ethanol and the residue was mixed with 30% sodium hydroxide (2.1 g). The mixture was shaken with chloroform. The chloroform layer was washed with water, dried over anhydrous sodium sulfate and concentrated under reduced pressure to give an oil. Purification via silica gel chromatography afforded 5-(1-methoxy-2-methylpropan-2-yl)isoxazol-3-amine as a colorless solid (350 mg, 32%). 1H NMR (300 MHz, CDCl3) δ 5.60 (s, 1H), 3.39 (s, 2H), 3.32 (s, 3H), 2.94 (brs, 2H), 1.28 (s, 6H); LC-MS (ESI) m/z 171 (M+H)+.
Reaction SMILES: [F:1][C:2]1([F:35])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29](O)=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:13][CH2:12]3)=[CH:10][C:4]=2[O:3]1.[CH3:36][NH:37][CH3:38].C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[F:35][C:2]1([F:1])[O:6][C:5]2[CH:7]=[CH:8][C:9]([C:11]3([C:14]([NH:16][C:17]4[N:22]=[C:21]([C:23]5[CH:24]=[N:25][C:26]([O:32][CH3:33])=[C:27]([C:29]([N:37]([CH3:38])[CH3:36])=[O:30])[CH:28]=5)[C:20]([CH3:34])=[CH:19][CH:18]=4)=[O:15])[CH2:12][CH2:13]3)=[CH:10][C:4]=2[O:3]1
Reactant: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)O
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ncc(-c2nc(NC(=O)C3(c4ccc5c(c4)OC(F)(F)O5)CC3)ccc2C)cc1C(=O)N(C)C
Temperature: 80 °C
Reaction time: 8 h
Yield: 66.6 %

Procedure:
To a solution of 6-(1-(2,2-difluorobenzo[d][1,3]dioxol-5-yl)cyclopropanecarboxamido)-6′-methoxy-3-methyl-2,3′-bipyridine-5′-carboxylic acid (72 mg, 0.15 mmol), dimethyl amine (10 mg, 0.23 mmol), and triethylamine (42 μL, 0.30 mmol) in N,N-dimethylformamide (1 mL) was added O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (68 mg, 0.18 mmol) and the reaction mixture was stirred at 80° C. overnight. The crude reaction mixture was purified by silica gel chromatography (eluting with 0-100% ethyl acetate in hexanes) to yield the product (51 mg, 67%). ESI-MS m/z calc. 510.49. found 511.5 (M+1)+. Retention time 1.81 minutes.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([O:25]CC)=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8].[OH-].[Li+].CO>C1COCC1>[Cl:1][C:2]1[N:3]=[C:4]([C:9]([NH:11][C@H:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:19][C:20]([C:23]([OH:25])=[O:24])=[CH:21][N:22]=3)[CH2:14][C@H:13]2[O:28][CH2:29][CH2:30][F:31])=[O:10])[NH:5][C:6]=1[CH2:7][CH3:8]
Reactant: CCOC(=O)c1cnc(N2CC[C@H](NC(=O)c3nc(Cl)c(CC)[nH]3)[C@H](OCCF)C2)s1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CCc1[nH]c(C(=O)N[C@H]2CCN(c3ncc(C(=O)O)s3)C[C@H]2OCCF)nc1Cl
Yield: 47.7 %

Procedure:
The same operation as in Example (91d) was performed using ethyl cis(±)-2-(4-{[(4-chloro-5-ethyl-1H-imidazol-2-yl)carbonyl]amino}-3-(2-fluoroethoxy)piperidin-1-yl)-1,3-thiazole-5-carboxylate obtained in Example (123f) (0.25 g, 0.8 mmol), 2 N lithium hydroxide (3 mL, 6 mmol), methanol (8 mL) and THF (8 mL), to obtain 0.17 g of the title compound as a light brown solid (72%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[CH:11]([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1.[CH3:22][C:23](C)([O-])C.[K+].ICC>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[C:6]([C:8]2[NH:9][CH:10]([CH2:19][CH3:20])[C:11]([CH2:22][CH3:23])([C:15]([O:17][CH3:18])=[O:16])[C:12](=[O:14])[N:13]=2)[CH:5]=[C:4]([Cl:21])[N:3]=1
Reactant: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1C(=O)OC
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCI
Solvent: CN(C)C=O
Product: CCC1NC(c2cc(Cl)nc(Cl)c2)=NC(=O)C1(CC)C(=O)OC
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.3 %

Procedure:
To 27.0 g (81.8 mmol) of 2-(2,6-dichloro-4-pyridyl)-6-ethyl-5-methoxycarbonyl5,6-dihydropyrimidin-4-one in 500 mL of dimethylformamide was added at 0° C. over 30 min via a solid addition funnel 19.3 g (172 mmol) of potassium-t-butoxide followed by the dropwise addition over 15 min of 13.3 g (85.2 mmol) of iodoethane. The reaction was stirred at 0° C. for one hour before quenching onto 700 mL of ice water. The aqueous was acidified to pH=1 (conc. HCl) and extracted with EtOAc (3×400 mL). The organics were combined before washing with water (2×500 mL), and saturated NaCl (1×300 mL) drying over MgSO4, filtering and evaporating to dryness in vacuo to give 27.32 g (76.3 mmol, 93%) of the desired product as a pale yellow solid with mp=202°-203° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12](COCC[Si](C)(C)C)[N:11]=[CH:10][C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:4][CH:3]=1.BrC1C(C2C=CN=CC=2)=C(C2C=CC(F)=CC=2)NN=1.[CH2:46]1[C@@H:54]2[N:49]([CH2:50][CH2:51][C:52](=O)[CH2:53]2)[CH2:48][CH2:47]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][N:11]=[C:10]([C:52]3[CH2:53][C@H:54]4[N:49]([CH2:48][CH2:47][CH2:46]4)[CH2:50][CH:51]=3)[C:9]=2[C:21]2[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=2)=[CH:6][CH:7]=1
Reactant: C[Si](C)(C)CCOCn1ncc(-c2ccncc2)c1-c1ccc(Cl)cc1
Reactant: O=C1CCN2CCC[C@H]2C1
Agent: Fc1ccc(-c2[nH]nc(Br)c2-c2ccncc2)cc1
Product: Clc1ccc(-c2[nH]nc(C3=CCN4CCC[C@H]4C3)c2-c2ccncc2)cc1
Yield: 4 %

Procedure:
Following a procedure similar to that described in Example 2-2), but using 5-(4-chlorophenyl)-4-(pyridin-4-yl)-1-(2-trimethylsilylethoxy)methylpyrazole prepared as described in 1) instead of 3-bromo-5-(4-fluorophenyl)-4-(pyridin-4-yl)pyrazole, and using (S)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one instead of (±)-1,2,3,5,6,7,8,8a-octahydroindolizin-7-one, the resulting product was subjected to a dehydration reaction as described in Example 3 and then treated by column chromatography through silica gel (eluent, ethyl acetate:methanol:isopropylamine=10:1:1), to give the title compound (Rf=0.50, 357 mg) as a pale brown powder (yield 4%).
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH:19][C:20]4[S:21][CH:22]=[CH:23][N:24]=4)=[O:18])[C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[N:25]1([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>CS(C)=O.O>[S:21]1[CH:22]=[CH:23][N:24]=[C:20]1[NH:19][C:17]([C:16]1[C:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([N:28]4[CH2:27][CH2:26][N:25]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[CH2:30][CH2:29]4)=[N:7][CH:6]=3)[NH:12][C:11]=2[CH:13]=[CH:14][CH:15]=1)=[O:18]
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Reactant: O=C(Nc1nccs1)c1cccc2[nH]c(-c3ccc(Cl)nc3)nc12
Solvent: CS(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(c2ccc(-c3nc4c(C(=O)Nc5nccs5)cccc4[nH]3)cn2)CC1
Temperature: 140 °C
Reaction time: 0.42 h
Yield: 47.1 %

Procedure:
A mixture containing 2-(6-chloropyridin-3-yl)-N-(thiazol-2-yl)-1H-benzo[d]imidazole-4-carboxamide (7; 30 mg, 0.084 mmol) and tert-butyl piperazine-1-carboxylate (170; 156.5 mg, 0.84 mmol) in DMSO (1.2 mL) was stirred at 140° C. in a microwave reactor for 25 min. The reaction mixture was cooled to room temperature and diluted with water. The resulting solids were collected by filtration, washed with water and dried under vacuum to afford tert-butyl 4-(5-(4-(thiazol-2-ylcarbamoyl)-1H-benzo[d]imidazol-2-yl)pyridin-2-yl)piperazine-1-carboxylate 8 as a pale yellow solid (20 mg, 71%). MS (ESI) calcd for C25H27N7O3S: 505.19; found: 506 [M+H].
Reaction SMILES: ClC(N(C)C)=C(C)C.[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([OH:27])=O)=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1.[NH2:37][C:38]1[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=1.N1C=CC=CC=1>C(Cl)Cl>[N:9]1([C:13]([C:15]2[N:16]=[CH:17][C:18]([O:21][C:22]3[CH:23]=[C:24]([CH:28]=[C:29]([O:31][C@H:32]([CH3:36])[CH2:33][O:34][CH3:35])[CH:30]=3)[C:25]([NH:37][C:38]3[CH:43]=[N:42][C:41]([CH3:44])=[CH:40][N:39]=3)=[O:27])=[N:19][CH:20]=2)=[O:14])[CH2:12][CH2:11][CH2:10]1
Reactant: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)O)c1
Reactant: Cc1cnc(N)cn1
Agent: CC(C)=C(Cl)N(C)C
Solvent: c1ccncc1
Solvent: ClCCl
Product: COC[C@@H](C)Oc1cc(Oc2cnc(C(=O)N3CCC3)cn2)cc(C(=O)Nc2cnc(C)cn2)c1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 68.3 %

Procedure:
1-Chloro-N,N,2-trimethyl-1-propenylamine (0.042 mL, 0.31 mmol) was added to a solution of 3-{[5-(azetidin-1-ylcarbonyl)pyrazin-2-yl]oxy}-5-{[(1R)-1-methyl-2-(methyloxy)ethyl]oxy}benzoic acid (0.102 g, 0.0.31 mmol) in DCM (3 mL) under argon and stirred at RT for 40 minutes. 2-Amino-5-methylpyrazine (57 mg, 0.52 mmol) and pyridine (0.043 mL, 0.52 mmol) were added and the reaction stirred for a further 3 hours. The solvent was removed in vacuo and the residue taken up in ethyl acetate (30 mL), washed with water (2×10 mL), a saturated aqueous solution of sodium bicarbonate (10 mL), brine (10 mL), dried (MgSO4), filtered, and evaporated in vacuo. The crude material was chromatographed on silica, eluting with a gradient of 60-100% ethyl acetate in isohexane, to give the desired compound as a white foam (86 mg).
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1.[N+:12]([O-])([OH:14])=[O:13]>S(=O)(=O)(O)O>[F:1][C:2]1[C:11]([N+:12]([O-:14])=[O:13])=[CH:10][C:5]2[NH:6][C:7](=[O:9])[O:8][C:4]=2[CH:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=c1[nH]c2ccc(F)cc2o1
Agent: O=S(=O)(O)O
Product: O=c1[nH]c2cc([N+](=O)[O-])c(F)cc2o1
Yield: 85 %

Procedure:
A solution cf 6-fluoro-2(3H)-benzoxazolone (1.0 g) in 80% aqueous sulfuric acid (6.5 g) was cooled to 0° to 5° C., and 60% nitric acid (0.8 g) was gradually added thereto at 0° to 5° C. The resultant mixture was stirred at the same temperature for 30 minutes and poured onto ice water. The precipitated crystals were collected by filtration, washed with water and dried to give 6-fluoro-5-nitro-2(3H)-benzoxazolone (1.1 g). m.p., 175.4° C. 1H-NMR (CDCl3 +DMSO-D6) δ ppm: 4.0 (1H, broad), 6.8-7.9 (3H, m).
Reaction SMILES: Br[C:2]1[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.[Cl:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[CH:17][C:18]=1[C:19]([F:22])([F:21])[F:20].C([O-])([O-])=O.[Na+].[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>[Cl:12][C:13]1[CH:14]=[C:15]([C:2]2[CH:8]=[CH:7][C:5]([NH2:6])=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=2)[CH:16]=[CH:17][C:18]=1[C:19]([F:20])([F:21])[F:22]
Reactant: OB(O)c1ccc(C(F)(F)F)c(Cl)c1
Reactant: Nc1ccc(Br)cc1[N+](=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+]
Product: Nc1ccc(-c2ccc(C(F)(F)F)c(Cl)c2)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 4 h
Yield: 101.1 %

Procedure:
A mixture of 4-bromo-2-nitroaniline (2.17 g), 3-chloro-4-trifluoromethyl-phenylboronic acid (3.5 g), and Na2CO3 (3.5 g), tetrakis(triphenylphosphine)palladium(0) (0.5 g), in DME (60 mL) and water (60 mL) was degassed under vacuum and the vacuum was broken with N2 gas. The resultant reaction mixture was kept stirring at 90-100° C. for 4 h. The reaction mixture was cooled to room temperature, separated the organic layer and the aqueous layer was extracted with ethyl acetate (100 mL). The combined organic layer was dried over sodium sulfate, filtered off sodium sulfate, the filtrate was concentrated and the residue was purified by column chromatography using a silica gel stationary phase and ethyl acetate in hexanes (2:8) as an eluent to afford 3′-chloro-3-nitro-4′-trifluoromethyl-biphenyl-4-ylamine (3.2 g).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:10]([C:11]2([C:15]2[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>N1C=CC=CC=1>[CH2:1]([N:8]1[CH2:9][CH:10]2[CH:12]([C:11]2([C:15]2[CH:16]=[C:17]([NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[CH:18]=[CH:19][CH:20]=2)[CH3:14])[CH2:13]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1(c2cccc(N)c2)C2CN(Cc3ccccc3)CC21
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CC1(c2cccc(NS(C)(=O)=O)c2)C2CN(Cc3ccccc3)CC21
Temperature: 25 °C
Reaction time: 14 h
Yield: 49.4 %

Procedure:
To a solution of 3-(3-benzyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl)phenylamine (Preparation 30, 1.58 g, 5.68 mmol) in pyridine (10 ml) under nitrogen at 0° C. was added methanesulphonyl chloride (0.66 ml, 8.52 mmol) dropwise to the solution, and the mixture was stirred for 14 hours at room temperature. The pyridine was evaporated in vacuo and the residue was partitioned between dichloromethane (50 ml) and dilute aqueous sodium hydrogen carbonate solution (1 M, 50 ml). The layers were separated and the organic extract was dried (Na2SO4), filtered and concentrated in vacuo. The residue was purified by silica (60 g) column chromatography eluting with ethyl acetate:hexane (5:95) then ethyl iacetate:hexane:triethylamine (5:95:0.1 increasing to 80:20:0.1). Appropriate fractions were combined and concentrated in vacuo to give the title compound as an off-white solid (1 g, 50%).
Reaction SMILES: [CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:16])=[O:15])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:27]=[CH:26][C:25]([OH:28])=[CH:24][CH:23]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1.[C:33](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C>[CH:1]1([C:4]2[C:12]([N:13]([CH2:18][CH2:19][CH2:20][OH:21])[S:14]([CH3:17])(=[O:15])=[O:16])=[CH:11][C:10]3[C:6](=[C:7]([C:29]([NH:31][CH3:32])=[O:30])[N:8]([C:22]4[CH:23]=[CH:24][C:25]([O:28][CH3:33])=[CH:26][CH:27]=4)[N:9]=3)[CH:5]=2)[CH2:3][CH2:2]1
Reactant: O=C([O-])[O-]
Reactant: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(O)cc1
Agent: [K+]
Solvent: CI
Solvent: CN(C)C=O
Product: CNC(=O)c1c2cc(C3CC3)c(N(CCCO)S(C)(=O)=O)cc2nn1-c1ccc(OC)cc1
Temperature: 60 °C
Reaction time: 0.75 h
Yield: 60.5 %

Procedure:
To a suspension of compound (ii) (3 mg, 0.007 mmol) and potassium carbonate (3 mg, 0.022 mmol) in DMF (0.25 mL) was added iodomethane (3 μL, 0.048 mmol) and the reaction was stirred at 60° C. for 45 min. The mixture was concentrated to dryness and the residue was purified by reverse phase flash column chromatography eluting with ACN/water (5-100%) to afford Compound (55) as a white solid (2 mg, 65%). ESI-MS m/z calculated for [M+H]+: 473.2; found: 473.2; 1H NMR (400 MHz, Acetone) δ 7.86 (d, J=0.5 Hz, 1H), 7.64 (brs, 1H), 7.62-7.56 (m, 2H), 7.42 (s, 1H), 7.14-7.06 (m, 2H), 3.99-3.85 (m, 5H), 3.71-3.62 (m, 2H), 3.59 (t, J=5.2 Hz, 1H), 3.18 (s, 3H), 2.96 (d, J=4.7 Hz, 3H), 2.52-2.42 (m, 1H), 1.91-1.73 (m, 2H), 1.11-0.94 (m, 3H), 0.64-0.53 (m, 1H).