Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[NH:3][CH2:2]1.NC1C=CC=CC=1S.C=O.[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:37])=[O:36])[C:32]=1[O:33][CH3:34])[C:27](Cl)=[O:28])([CH3:23])([CH3:22])[CH3:21]>C(Cl)(Cl)Cl.C(N(CC)CC)C>[C:20]([C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([S:35]([CH3:38])(=[O:36])=[O:37])[C:32]=1[O:33][CH3:34])[C:27]([N:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[S:1][CH2:2]1)=[O:28])([CH3:23])([CH3:21])[CH3:22]
Reactant: c1ccc2c(c1)NCS2
Reactant: COc1c(C(C)(C)C)cc(C(=O)Cl)cc1S(C)(=O)=O
Agent: C=O
Agent: Nc1ccccc1S
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1c(C(C)(C)C)cc(C(=O)N2CSc3ccccc32)cc1S(C)(=O)=O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2,3-dihydro-1,3-benzothiazole synthesized from 2-aminobenzenethiol (182 mg) and 37% formalin (87 μL) in the same manner as in Example 1 was dissolved in chloroform (4 mL), and triethylamine (0.29 mL) and 3-t-butyl-4-methoxy-5-methanesulfonylbenzoyl chloride were added to the solution, and then the mixture was stirred at room temperature for 1 hour. The solvent was distilled off under reduced pressure, water was added and then the mixture was extracted with ethyl acetate. The organic layer was washed with 1N hydrochloric acid, 1N sodium hydroxide and saturated brine, and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure and the obtained residue was purified by silica gel column chromatography (n-hexane:ethyl acetate=4:1) to obtain the title compound (246 mg) as a pale yellow amorphous product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH3:11][O:12][Na]>CN(C=O)C.[Cu]Br>[CH3:11][O:12][C:2]1[CH:3]=[C:4]2[CH:5]=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: Brc1cnc2[nH]ccc2c1
Reactant: CO[Na]
Agent: [Cu]Br
Solvent: CN(C)C=O
Product: COc1cnc2[nH]ccc2c1
Temperature: 140 °C
Yield: 78.3 %

Procedure:
To 5-bromo-7-azaindole 1 (0.98 g, 5.0 mmol) in DMF (32 mL) was added 25% (w/w) MeONa (48 mL, 210 mmol) followed by copper (1) bromide (1.43 g, 10.0 mmol), and the reaction mixture was heated at 140° C. for 2.5. It was then cooled and concentrated to remove DMF. Water (100 mL) was added followed by saturated aqueous NaHCO3 (20 mL). The mixture was extracted with AcOEt (3×), the combined organic extracts dried (MgSO4) and concentrated. The solid residue was purified by SGC using AcOEt:hexane (gradient elution up to 30:70) to give 30 as a green solid (0.58 g, 78%); 1H NMR (400 MHz, CDCl3) δ 3.90 (s, 3H), 6.45 (d, J=2.3 Hz, 1H), 7.33 (d, J=2.8 Hz, 1H), 7.48 (d, J=2.2 Hz, 1H), 8.00-8.20 (bs, 1H); 10.60-10.80 (bs, NH).
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(C(C)C)C(C)C.[CH3:22][C:23]1[C:28]2[O:29][CH2:30][C:31]3([CH2:33][CH2:32]3)[C:27]=2[C:26]([O:34][C:35]2[N:40]=[CH:39][C:38]([NH2:41])=[CH:37][CH:36]=2)=[CH:25][CH:24]=1.Cl.[NH2:43][C:44]([CH3:50])([CH3:49])[C:45](OC)=[O:46]>C(Cl)Cl>[CH3:50][C:44]1([CH3:49])[NH:43][C:2](=[O:4])[N:41]([C:38]2[CH:39]=[N:40][C:35]([O:34][C:26]3[C:27]4[C:31]5([CH2:30][O:29][C:28]=4[C:23]([CH3:22])=[CH:24][CH:25]=3)[CH2:33][CH2:32]5)=[CH:36][CH:37]=2)[C:45]1=[O:46]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COC(=O)C(C)(C)N
Reactant: Cc1ccc(Oc2ccc(N)cn2)c2c1OCC21CC1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(Oc2ccc(N3C(=O)NC(C)(C)C3=O)cn2)c2c1OCC21CC1
Reaction time: 0.25 h

Procedure:
To a solution of triphosgene (30 mg, 0.1 mmol) in dry DCM (1 ml) at 0° C., under nitrogen atmosphere, DIPEA (0.175 ml, 1.0 mmol) was added followed by the addition (slowly added) of a solution of 6-(7-methylspiro[2H-benzofuran-3,1′-cyclopropane]-4-yl)oxypyridin-3-amine (Intermediate 15, 27 mg, 0.1 mmol) in dry DCM (2 ml) and the reaction mixture was stirred for 15 minutes at the same temperature. After that a solution of Methyl 2-amino-2-methylpropanoate hydrochloride (30 mg, 0.2 mmol) in dry DCM (2 ml) was added and the reaction mixture was stirred for 30 minutes at 0° C. The reaction was quenched with a 1M aqueous solution of HCl (5 ml), diluted with DCM (10 ml) and two phases were separated. The organic layer was washed with brine (10 ml), dried (Na2SO4), filtered and evaporated affording the urea intermediate as yellow foam.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:19]([O:25][CH2:26][CH3:27])(=[O:24])[CH2:20][C:21]([CH3:23])=[O:22].C(O)(=O)C.N1CCCCC1>C1(C)C=CC=CC=1>[CH2:1]([O:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:20]([C:21](=[O:22])[CH3:23])[C:19]([O:25][CH2:26][CH3:27])=[O:24])=[C:11]([O:17][CH3:18])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)CC(C)=O
Reactant: COc1cc(OCc2ccccc2)ccc1C=O
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Solvent: CC(=O)O
Product: CCOC(=O)C(=Cc1ccc(OCc2ccccc2)cc1OC)C(C)=O

Procedure:
A solution of 4-(benzyloxy)-2-methoxybenzaldehyde (28.3 g), ethyl acetoacetate (18 ml), acetic acid (1.74 ml) and piperidine (0.56 ml) in toluene (400 ml) was heated under reflux for 48 h. A solution of acetic acid (1.74 ml) and piperidine (0.56 ml) in toluene (10 ml) was added and the solution heated under reflux for a further 48 h. The solvent was evaporated under reduced pressure and the residue partitioned between EtOAc and brine. The organics were separated, washed with aq NaHCO3 soln, 1M HCl, brine, dried and evaporated under reduced pressure to give the subtitle compound, 40 g (used crude in next step).
Reaction SMILES: C([O-])(=O)C.[NH4+].[CH2:6]([O:13][C:14]1[C:19]([O:20][CH3:21])=[CH:18][C:17]([C:22](=[O:24])[CH3:23])=[C:16]([N+:25]([O-])=O)[CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C1(C)C=CC=CC=1>[Fe].O>[NH2:25][C:16]1[CH:15]=[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:19]([O:20][CH3:21])=[CH:18][C:17]=1[C:22](=[O:24])[CH3:23]
Reactant: COc1cc(C(C)=O)c([N+](=O)[O-])cc1OCc1ccccc1
Agent: [Fe]
Agent: CC(=O)[O-]
Agent: [NH4+]
Solvent: O
Solvent: Cc1ccccc1
Product: COc1cc(C(C)=O)c(N)cc1OCc1ccccc1

Procedure:
A Mixture of iron powder (477 mmol, 27 g), ammonium acetate (500 mmol, 31 g), 1-(4-Benzyloxy-5-methoxy-2-nitro-phenyl)-ethanone (120 mmol, 36 g), toluene (500 ml) and water (500 ml) was refluxed overnight until completion. The mixture was filtered through celite and washed with EtOAc. The organic layer was washed with water and Sat. NaCl, dried over Na2SO4, and concentrated to afford the product, 90%. 1H NMR (CDCl3): 7.408-7.298 (5H, m), 7.130 (1H, s), 6.155 (2H, br), 6.104 (1H, s), 5.134 (2H, s), 3.834 (3H, s), 2.507 (3H, s). LC/MS (M+1=272).
Reaction SMILES: [Cl:1][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1.[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH2:21].C(O)(C)C>CC(C)=O>[ClH:1].[Cl:17][C:18]1[CH:19]=[C:20]([CH:22]=[CH:23][C:24]=1[F:25])[NH:21][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[CH:10]=2)[N:5]=[CH:4][N:3]=1
Reactant: Clc1ncnc2ccc(-n3cncn3)cc12
Reactant: Nc1ccc(F)c(Cl)c1
Solvent: CC(C)=O
Solvent: CC(C)O
Product: Cl
Product: Fc1ccc(Nc2ncnc3ccc(-n4cncn4)cc23)cc1Cl
Temperature: 25 °C
Yield: 69.4 %

Procedure:
A mixture of 4-chloro-6-(1,2,4-triazol-1-yl)quinazoline (0.54 g), 3-chloro-4-fluoroaniline (0.34 g) and isopropanol (25 ml) was stirred and heated to reflux for 2 hours. The mixture was cooled to ambient temperature, acetone (20 ml) was added and the mixture was filtered. The solid so obtained was washed with acetone and dried to give 4-(3-chloro-4-fluoroanilino)-6-(1,2,4-triazol-1-yl)quinazoline hydrochloride salt (0.61 g), m.p. >250° C.; NMR Spectrum: (CD3SOCD3) 7.49 (t, 1H), 7.8 (m, 1H), 8.03-8.08 (m, 2H), 8.33 (s, 1H), 8.52 (m, 1H), 8.93 (s, 1H), 9.62 (m, 2H);
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH2:25])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[CH2:26]([S:29](Cl)(=[O:31])=[O:30])[CH2:27][CH3:28]>ClCCl.CN(C)C1C=CN=CC=1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]3[C:21]4[C:16](=[CH:17][CH:18]=[C:19]([O:22][CH2:23][CH2:24][NH:25][S:29]([CH2:26][CH2:27][CH3:28])(=[O:31])=[O:30])[CH:20]=4)[CH2:15][CH2:14][N:13]=3)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: CCCS(=O)(=O)Cl
Reactant: NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CCCS(=O)(=O)NCCOc1ccc2c(c1)C(C1(c3ccc(F)cc3)CCC1)=NCC2

Procedure:
2-({1-[1-(4-Fluorophenyl)cyclobutyl]-3,4-dihydroisoquinolin-7-yl}oxy)ethanamine (298 mg, 0.88 mmol) was dissolved in dichloromethane (10 mL) and N,N-dimethylpyridin-4-amine (118 mg, 0.97 mmol) was added. After dropwise addition of a solution of propane-1-sulfonyl chloride (138 mg, 0.97 mmol) in dichloromethane (2 mL) stirring was continued over night. The reaction mixture was diluted with dichloromethane (20 mL), washed with an aqueous ammonium chloride solution (30 mL). The organic layer was dried (MgSO4) and concentrated in vacuo. The crude product was purified by flash chromatography (silica, ethyl acetate:dichloromethane=1:10). Yield: 200 mg (0.45 mmol, 51%).
Reaction SMILES: O=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[NH2:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16].CO>[Ni].[Pd].O>[OH:4][CH:3]([CH:5]([OH:6])[CH:7]([OH:8])[CH:9]([OH:10])[CH2:11][OH:12])[CH2:2][NH:13][CH:14]([C:18]([OH:20])=[O:19])[CH:15]([CH3:17])[OH:16]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Reactant: CC(O)C(N)C(=O)O
Agent: [Ni]
Agent: [Pd]
Solvent: O
Solvent: CO
Product: CC(O)C(NCC(O)C(O)C(O)C(O)CO)C(=O)O

Procedure:
The starting materials were D-glucose and DL-threonine. The reductive amination was carried out using Raney nickel or palladium/activated carbon (10%) and yielded a product having a melting point of 219° C. (decomposition) and a RF -value of 0.67 (determined on DC-finished plates of silica gel G (Merck) with a transporting fluid made up of 75 parts by volume of methanol and 25 parts by volume of water).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[CH:5]=[C:6]2[C:11]=1[N:10]=[CH:9][CH:8]=[CH:7]2.Cl[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]Cl.C(O)CCCCC.[OH-].[Na+].[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36]>C(OC(C)C)(=O)C>[C:30]([OH:39])(=[O:38])[CH2:31][CH2:32][CH2:33][CH2:34][C:35]([OH:37])=[O:36].[CH3:13][O:12][C:4]1[CH:5]=[C:6]2[C:11](=[C:2]([N:1]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH:3]=1)[N:10]=[CH:9][CH:8]=[CH:7]2
Reactant: ClCCNCCCl
Reactant: COc1cc(N)c2ncccc2c1
Agent: O=C(O)CCCCC(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)OC(C)C
Solvent: CCCCCCO
Product: COc1cc(N2CCNCC2)c2ncccc2c1
Temperature: 145 °C
Reaction time: 21 h

Procedure:
A mixture of 8-amino-6-methoxyquinoline (150.0 g, 0.862 mol) and bis(2-chloroethyl)amine (219 g, 1.23 mol,) in 6 parts (volume of hexanol vs weight of 8-amino-6-methoxyquinoline) of 1-hexanol (900 mL) was heated to 145° C. and stirred for 21 hours. Upon completion, the reaction mixture is cooled 50-60° C., and 507 g of aqueous NaOH solution was added slowly. The reaction mixture was cooled to 25-30° C. and isopropyl acetate (750 mL) was added. The mixture was clarified through a celite pad. The aqueous phase was then split off. The organic solution was treated with a slurry of adipic acid (126 g, 0.862 mol) in isopropyl acetate (250 ml). The resulting mixture was stirred for 16 hours to form 6-methoxy-8-(1-piperazinyl)quinoline adipate salt. The adipate salt was filtered and washed with isopropyl acetate (2×150 ml) and dried by nitrogen flow to give adipate of 6-Methoxy-8-piperazin-1-yl-quinoline (186 g, 55% yield) with ˜97% HPLC area, 88% strength purity in 51% yield.
Reaction SMILES: [OH-].[Na+].[CH2:3]([NH:7][C:8](=[O:31])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:22]=[CH:21][C:20](/[CH:23]=[C:24](\[O:29][CH3:30])/[C:25]([O:27]C)=[O:26])=[CH:19][CH:18]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6].C(O)(=O)C>O1CCCC1>[CH2:3]([NH:7][C:8](=[O:31])[N:9]([C:11]1[CH:12]=[C:13]([C:17]2[CH:18]=[CH:19][C:20](/[CH:23]=[C:24](\[O:29][CH3:30])/[C:25]([OH:27])=[O:26])=[CH:21][CH:22]=2)[CH:14]=[CH:15][CH:16]=1)[CH3:10])[CH2:4][CH2:5][CH3:6]
Reactant: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)OC)cc2)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: C1CCOC1
Product: CCCCNC(=O)N(C)c1cccc(-c2ccc(/C=C(\OC)C(=O)O)cc2)c1
Temperature: 68 °C
Reaction time: 2 h
Yield: 77 %

Procedure:
2.7 mL (2.7 mmol) of aqueous 1 N sodium hydroxide solution are added to a solution of 0.7 g (1.8 mmol) of methyl (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylate in 12 mL of tetrahydrofuran. The reaction medium is heated at 68° C. and stirred for 2 hours. The reaction medium is acidified with 2.8 mL of 1 N acetic acid solution and extracted with ethyl acetate. The organic phase is washed with water, dried over magnesium sulfate, filtered and evaporated. The residue obtained is recrystallized from hot ethyl acetate. 530 mg (77%) of (Z)-3-[3′-(3-butyl-1-methylureido)biphenyl-4-yl]-2-methoxyacrylic acid are obtained in the form of a white solid with a melting point of 146° C.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:19]([C:20]4([C:23]([F:26])([F:25])[F:24])[CH2:22][CH2:21]4)=[CH:18][N:17]=[C:13]3[C@H:14]([NH2:16])[CH2:15][C:4]=2[CH:3]=1.C(N(CC)CC)C.Cl[C:35](OC1C=CC([N+]([O-])=O)=CC=1)=[O:36].Cl.Cl.[NH:49]1[CH2:54][CH2:53][CH:52]([N:55]2[C:63]3[C:58](=[N:59][CH:60]=[CH:61][CH:62]=3)[NH:57][C:56]2=[O:64])[CH2:51][CH2:50]1>C(=O)([O-])[O-].[Na+].[Na+]>[Cl:1][C:2]1[C:10]2[NH:9][N:8]=[CH:7][C:6]=2[C:5]2[CH2:11][N:12]3[C:19]([C:20]4([C:23]([F:24])([F:25])[F:26])[CH2:21][CH2:22]4)=[CH:18][N:17]=[C:13]3[C@H:14]([NH:16][C:35]([N:49]3[CH2:50][CH2:51][CH:52]([N:55]4[C:63]5[C:58](=[N:59][CH:60]=[CH:61][CH:62]=5)[NH:57][C:56]4=[O:64])[CH2:53][CH2:54]3)=[O:36])[CH2:15][C:4]=2[CH:3]=1
Reactant: O=c1[nH]c2ncccc2n1C1CCNCC1
Reactant: N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2Cn2c(C3(C(F)(F)F)CC3)cnc21
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCN(CC)CC
Product: O=C(N[C@@H]1Cc2cc(Cl)c3[nH]ncc3c2Cn2c(C3(C(F)(F)F)CC3)cnc21)N1CCC(n2c(=O)[nH]c3ncccc32)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To solution of (7R)-4-chloro-10-[1-(trifluoromethyl)cyclopropyl]-3,6,7,12-tetrahydroimidazo[1′,2′:1,7]azepino[3,4-e]indazol-7-amine (100 mg, 0.3 mmol) and triethyl amine (120 uL, 0.9 mmole) is added 4-nitrophenyl chloroformate (60 mg, 0.3 mmol) and stirred at 0° C. for 1 hr. 1-Piperidin-4-yl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one dihydrochloride [Burgey et al. WO 2006/044504], (87 mg, 0.3 mmol), is added along with triethylamine (120 uL, 0.9 mmol) and the reaction mixture is stirred at ambient temperature for 18 h. Saturated aqueous sodium carbonate (50 mL) is added and the mixture is extracted with dichloromethane (3×25 mL) The combined organic layers are washed with saturated aqueous sodium bicarbonate, brine, dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography [100% dichloromethane→93% dichloromethane/methanol] provides the title compound.
Reaction SMILES: [Cl:1][C:2]1[C:10]([OH:11])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35].C(N(CC)CC)C.[F:43][C:44]([F:50])([F:49])[S:45](Cl)(=[O:47])=[O:46]>ClCCl>[Cl:1][C:2]1[C:10]([O:11][S:45]([C:44]([F:50])([F:49])[F:43])(=[O:47])=[O:46])=[CH:9][C:8]([C:12]2[N:13]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:35]
Reactant: CC(C)(C)OC(=O)n1c(-c2cc(O)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=S(=O)(Cl)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)n1c(-c2cc(OS(=O)(=O)C(F)(F)F)c(Cl)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Yield: 69.8 %

Procedure:
In a similar manner to Step 1 of Example 299, 4-chloro-5-hydroxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]Isoindolinone (550 mg, 1.12 mmol) was dissolved in dichloromethane (22 mL), and the solution was treated with triethylamine (0.78 ml, 5.56 mmol) and trifluoromethanesulfonyl chloride (0.356 mL, 3.34 mmol), followed by purification by flash chromatography (chloroform, chloroform/methanol=99/1, 95/1) to obtain 4-chloro-5-trifluoromethanesulfonyloxy-7-[1-(tert-butoxycarbonyl)-5-(piperidin-1-ylmethyl)indol-2-yl]isoindolinone (491 mg, yield 71%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20](Cl)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:25][CH:26]1[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]1>CN1C(=O)CCC1.O>[CH2:1]([O:8][C:9]1[C:10]2[N:11]([C:15]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([NH:25][CH:26]4[CH2:31][CH2:30][CH:29]([NH:32][S:33]([CH3:36])(=[O:35])=[O:34])[CH2:28][CH2:27]4)[N:19]=3)=[CH:16][N:17]=2)[CH:12]=[CH:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Clc1nccc(-c2cnc3c(OCc4ccccc4)cccn23)n1
Reactant: CS(=O)(=O)NC1CCC(N)CC1
Solvent: CN1CCCC1=O
Solvent: O
Product: CS(=O)(=O)NC1CCC(Nc2nccc(-c3cnc4c(OCc5ccccc5)cccn34)n2)CC1
Temperature: 100 °C
Reaction time: 8 h
Yield: 9.6 %

Procedure:
A mixture of 8-benzyloxy-3-(2-chloropyrimidin-4-yl)-imidazo[1,2-a]pyridine (0.1 g), N-(4-amino-cyclohexyl)-methanesulfonamide (0.2 g), and TEA (0.21 mL) in NMP (2 mL) was stirred at 100° C. overnight. The reaction mixture was cooled to RT, diluted with water, and the resulting solid filtered, washed with water, and dried. The product was purified by ISCO 2× using 100% DCM to 15% MeOH/DCM. Pure fractions were collected, concentrated, and titurated with EtOAc. The resulting solid was filtered and dried at 50° C. under vacuum overnight to provide N-{4-[4-(8-benzyloxy-imidazo[1,2-a]pyridin-3-yl)-pyrimidin-2-ylamino]-cyclohexyl}-methanesulfonamide (compound 7, 14 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].C[C:11]1[CH:16]=[CH:15][CH:14]=[C:13](C)[C:12]=1[C:18]([O:20]C)=O.[CH3:22][O-].[Na+]>C1(C)C(C)=CC=CC=1>[C:1]([CH2:2][C:18](=[O:20])[C:12]1[CH:11]=[CH:16][CH:15]=[C:14]([CH3:22])[CH:13]=1)(=[O:3])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)c1ccccc1
Reactant: COC(=O)c1c(C)cccc1C
Reactant: C[O-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Product: Cc1cccc(C(=O)CC(=O)c2ccccc2)c1

Procedure:
Acetophenone (30 grams; 0.25 mol) methyl m-methyltoluate (136 grams; 1.0 mol), xylene (300 ml) and sodium methoxide (17.3 grams; 0.3 mol) were placed into a four-necked round bottom one liter flask equipped as in Example 1. The mixture was heated with stirring to 135°-140° C. and maintained there for 6 hours under a blanket of nitrogen. The procedure set forth in Example 1 was used to recover the desired product, benzoyl m-methylbenzoylmethane (48 grams; 90% weight percent yield).
Reaction SMILES: [Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[OH:6][C:7]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N+:10]([CH3:18])[N:9]([CH3:19])[C:8]=1[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[OH-].[Na+].[CH3:28]I.O>CS(C)=O>[Cl:1]([O-:5])(=[O:4])(=[O:3])=[O:2].[CH3:28][O:6][C:7]1[C:8]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)=[N+:9]([CH3:19])[N:10]([CH3:18])[C:11]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CI
Reactant: Cn1c(-c2ccccc2)c(O)c(-c2ccccc2)[n+]1C
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])[O-]
Agent: [OH-]
Solvent: O
Solvent: CS(C)=O
Product: COc1c(-c2ccccc2)n(C)[n+](C)c1-c1ccccc1
Temperature: 60 °C
Yield: 53 %

Procedure:
4-Hydroxy-1,2-dimethyl-3,5-diphenylpyrazolium perchlorate (7 g, 0.02 mole) in DMSO (2.5 ml) is added to 5% sodium hydroxide (0.84 g, 0.02 mole) in DMSO (100 ml), dropwise with stirring. The mixture is warmed to 60°C for 5 minutes, then stirred at room temperature for 4 hours. The reaction mixture (75 ml) is treated with methyl iodide (0.43 g, 0.013 mole) and the mixture is stirred at room temperature for 16 hours, then heated at 40°C for 2 hours. On pouring into water, a solid precipitates with melting point 88°C. One crystallization from methanol gives the product with melting point 132°-132.5°C in 53% yield.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([OH:10])=[O:9].[NH:25]1[CH:29]=[CH:28][N:27]=[C:26]1[CH2:30][C:31]1[CH:36]=[CH:35][C:34](/[CH:37]=[CH:38]/[CH2:39]O)=[CH:33][CH:32]=1.[CH:41]1(N=C=NC2CCCCC2)CCCCC1>C1(C)C=CC=CC=1>[CH3:1][C:2]1[NH:3][C:4]([CH3:24])=[C:5]([C:20]([O:22][CH3:23])=[O:21])[CH:6]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([N+:17]([O-:19])=[O:18])[CH:12]=2)[C:7]=1[C:8]([O:10][CH2:41]/[C:38](/[CH3:39])=[CH:37]/[C:34]1[CH:35]=[CH:36][C:31]([CH2:30][C:26]2[NH:27][CH:28]=[CH:29][N:25]=2)=[CH:32][CH:33]=1)=[O:9]
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)O)C1c1cccc([N+](=O)[O-])c1
Reactant: OC/C=C/c1ccc(Cc2ncc[nH]2)cc1
Solvent: Cc1ccccc1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OC/C(C)=C/c2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C

Procedure:
332 mg (1 mM) of 1,4-dihydro-2,6-dimethyl-5-methoxycabonyl-4-(3-nitrophenyl)pyridine-3-carboxylic acid together with 228 mg (1 mM) of (E)-3-{4-(1-imidazolylmethyl)-phenyl}-2-propen-1-ol, 248 mg (1.2 mM) of dicyclohexylcarbodiimide and 134 mg (1.1 mM) of 4-N,N-dimethylaminopyridine were dissolved in 5 ml of toluene, while heating, and refluxed for six hours. The solution was cooled in room temperature, and the crystals produced were filtered off. The filtrate was washed with water and dried over anhydrous sodium sulfate. After the solvent was distilled away, the residue was purified by chromatography on a silica gel column, whereby the captioned compound was obtained. The yield was 523 mg (96.3%).
Reaction SMILES: [C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[CH:18]=[CH:17][C:16]([C:19]([S:21][CH2:22][CH3:23])=[O:20])=[CH:15][CH:14]=2)[CH2:10][C:11]=1[OH:12])(=O)[CH2:2][CH2:3][CH3:4].[CH2:25]([O:28][NH2:29])[CH:26]=[CH2:27]>O1CCCC1>[CH2:25]([O:28][N:29]=[C:1]([C:6]1[C:7](=[O:24])[CH2:8][CH:9]([C:13]2[CH:14]=[CH:15][C:16]([C:19]([S:21][CH2:22][CH3:23])=[O:20])=[CH:17][CH:18]=2)[CH2:10][C:11]=1[OH:12])[CH2:2][CH2:3][CH3:4])[CH:26]=[CH2:27]
Reactant: C=CCON
Reactant: CCCC(=O)C1=C(O)CC(c2ccc(C(=O)SCC)cc2)CC1=O
Solvent: C1CCOC1
Product: C=CCON=C(CCC)C1=C(O)CC(c2ccc(C(=O)SCC)cc2)CC1=O
Reaction time: 15 h

Procedure:
Into 20 ml og tetrahydrofuran was dissolved 2 g of 2-butyryl-5-[4-(ethylthio)carbonylphenyl]-3-hydroxy-2-cyclohexen-1-one and to the solution was added 0.8 g of allyloxyamine. The mixture was kept for 15 hours at room temperature and the solvent was distilled off from it under reduced pressure. Then, the residue was recrystallized with mixture of benzene-ligroin and 0.8 g of colorless objective crystals having a melting point of 72°-75° C. was obtained.