Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[CH:14][CH:13]=[CH:12][C:10]=2[N:11]=1.S(Cl)(Cl)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(OCC)(=O)C>[NH2:6][C:7]1[O:8][C:9]2[CH:15]=[C:14]([S:2]([Cl:1])(=[O:5])=[O:3])[CH:13]=[CH:12][C:10]=2[N:11]=1
Reactant: Nc1nc2ccccc2o1
Reactant: O=S(=O)(O)Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O=S(Cl)Cl
Solvent: CCOC(C)=O
Product: Nc1nc2ccc(S(=O)(=O)Cl)cc2o1
Temperature: 80 °C
Reaction time: 2 h
Yield: 90 %

Procedure:
A mixture of 2.5 g 2-aminophenol (7-1) and 20 ml ethyl acetate was heated to 45° C. 3 g of cyanogen bromide was added to the mixture. The mixture was stirred at 45-50° C. for 12 hours. After cooling to room temperature, 1.5 g of sodium hydroxide in 15 ml of water was added. The organic layer was separated and washed with brine until neutral pH. Toluene (5 ml) was added and the solvent was removed to yield 2.71 g (88%) 2-aminobenzoxazol (7-2). 7.5 ml of chlorosulfonic acid was stirred at room temperature under an inert atmosphere (nitrogen). 5 g of 2-aminobenzoxazol (7-2) was added in small portions. The temperature was kept between 30-60° C. during the addition of 7-2. The mixture was heated to 80° C. for 2 hours. 5.3 g of thionyl chloride was added drop wise, keeping the temperature at 65° C. The mixture was stirred during 2 hours. After cooling to 0° C. 10 ml of ethyl acetate and 10 ml of a solution of sodium carbonate (1N) were added. The organic layer was separated from the water layer and this latter was extracted with ethyl acetate. The combined organic layers were dried over calcium chloride, yielding 7.8 g (90%) of 2-amino-6-chlorosulfonylbenzoxazole (7-3).
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][NH2:13])=[O:9].[NH:28]1[CH:32]=[CH:31][N:30]=[C:29]1[CH2:33][C:34]1[CH:41]=[CH:40][C:37]([CH:38]=O)=[CH:36][CH:35]=1>>[CH3:1][C:2]1[NH:3][C:4]([CH3:27])=[C:5]([C:23]([O:25][CH3:26])=[O:24])[CH:6]([C:14]2[CH:19]=[CH:18][CH:17]=[C:16]([N+:20]([O-:22])=[O:21])[CH:15]=2)[C:7]=1[C:8]([O:10][CH2:11][CH2:12][N:13]=[CH:38][C:37]1[CH:36]=[CH:35][C:34]([CH2:33][C:29]2[NH:30][CH:31]=[CH:32][N:28]=2)=[CH:41][CH:40]=1)=[O:9]
Reactant: O=Cc1ccc(Cc2ncc[nH]2)cc1
Reactant: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN)C1c1cccc([N+](=O)[O-])c1
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN=Cc2ccc(Cc3ncc[nH]3)cc2)C1c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
506 mg (1.35 mM) of 2-aminoethyl methyl 1,4-dihydro-2,6-dimethyl-4-(3-nitrophenyl)pyridine -3,5-dicarboxylate was mixed with 251 mg (1.35 mM) of 4-(1-imidazolylmethyl)benzaldehyde and the mixture was stirred for 15 hours at room temperature, whereby the captioned compound was obtained. The yield was 544 mg (100%).
Reaction SMILES: [CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]3[O:17][CH2:16]3)=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1.[NH2:20][CH2:21][CH2:22][CH2:23][O:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]2[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=2)=[CH:27][C:26]=1[Cl:38]>>[CH:1]1([CH2:5][O:6][CH2:7][CH2:8][C:9]2[CH:19]=[CH:18][C:12]([O:13][CH2:14][CH:15]([OH:17])[CH2:16][NH:20][CH2:21][CH2:22][CH2:23][O:24][C:25]3[CH:30]=[CH:29][C:28]([C:31]4[CH2:32][CH2:33][C:34](=[O:37])[NH:35][N:36]=4)=[CH:27][C:26]=3[Cl:38])=[CH:11][CH:10]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: c1cc(OCC2CO2)ccc1CCOCC1CCC1
Reactant: NCCCOc1ccc(C2=NNC(=O)CC2)cc1Cl
Product: O=C1CCC(c2ccc(OCCCNCC(O)COc3ccc(CCOCC4CCC4)cc3)c(Cl)c2)=NN1

Procedure:
Prepared analogously to Example 1 from 1-[4-(2-cyclobutylmethoxy-ethyl)phenoxy]-2,3-epoxypropane and 6-[4-(3-aminopropoxy)-3-chloro-phenyl]-4,5-dihydro-3(2H)-pyridazinone.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[C:15](=[O:16])[C:14]([CH3:18])([CH3:17])[N:13]([CH2:19][C:20]3[CH:25]=[CH:24][N:23]=[C:22]([NH:26]C(=O)C)[CH:21]=3)[C:12]2=[O:30])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[ClH:31]>O1CCOCC1>[ClH:31].[NH2:26][C:22]1[CH:21]=[C:20]([CH2:19][N:13]2[C:14]([CH3:18])([CH3:17])[C:15](=[O:16])[N:11]([C:8]3[CH:7]=[CH:6][C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])=[CH:10][CH:9]=3)[C:12]2=[O:30])[CH:25]=[CH:24][N:23]=1
Reactant: CC(=O)Nc1cc(CN2C(=O)N(c3ccc(C(C)(C)C)cc3)C(=O)C2(C)C)ccn1
Agent: Cl
Solvent: C1COCCO1
Product: CC(C)(C)c1ccc(N2C(=O)N(Cc3ccnc(N)c3)C(C)(C)C2=O)cc1
Temperature: 75 °C
Reaction time: 36 h

Procedure:
To a solution of 1.8 g of N-(4-{[3-(4-tert-butylphenyl)-5,5-dimethyl-2,4-dioxoimidazolidin-1-yl]methyl}pyridin-2-yl)acetamide obtained in stage b) below in 40 mL of dioxane are added 20.8 mL of 1N hydrochloric acid solution. The mixture is heated at 75° C. for six hours, 42 mL of 1N hydrochloric acid solution are then added and stirring is continued for 36 hours at the same temperature. The solution is then concentrated under reduced pressure to give 1.4 g of 1-[(2-aminopyridin-4-yl)methyl]-3-(4-tert-butylphenyl)-5,5-dimethylimidazolidine-2,4-dione hydrochloride in the form of a white powder, the characteristics of which are as follows:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]/OC.[NH:17]1[CH:21]=[C:20]([C:22]2[CH:28]=[CH:27][C:25]([NH2:26])=[CH:24][CH:23]=2)[N:19]=[CH:18]1>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])[C:5]2=[CH:14][NH:26][C:25]1[CH:24]=[CH:23][C:22]([C:20]2[N:19]=[CH:18][NH:17][CH:21]=2)=[CH:28][CH:27]=1
Reactant: Nc1ccc(-c2c[nH]cn2)cc1
Reactant: CO/C=C1/C(=O)NC(=O)c2ccc(Br)cc21
Solvent: CN(C)C=O
Product: O=C1NC(=O)c2ccc(Br)cc2C1=CNc1ccc(-c2c[nH]cn2)cc1
Temperature: 120 °C

Procedure:
A mixture of 2.00 g (7.09 mmol) of (4E)-6-bromo-4-(methoxymethylene)isoquinoline-1,3(2H,4H)-dione and 1.24 g (7.80 mmol) of 4-(1H-Imidazol-4-yl)aniline in 22 mL of N,N-dimethylformamide (DMF) is heated at 120° C. for 1.25 h. The chilled reaction mixture is filtered and the insoluble material is washed with N,N-dimethylformamide (DMF) and Et2O. In order to remove residual N,N-dimethylformamide (DMF), the solid is boiled with MeOH (2×), washed with Et2O and dried in vacuo. The yield is 2.10 g (72%) of yellow-brown crystals: mp >300° C. (dec); 1H NMR (DMSO-d6) δ 12.6 (d, 1H, J=12.7 Hz), 12.2 (s, 1H), 11.4 (s, 1H), 8.98 (d, 1H, J=12.7 Hz), 8.49 (s, 1H), 7.86 (m, 3H), 7.67 (m, 4H), 7.41 (d, 1H, J=8.34 Hz); HRMS (ESI) m/e calcd for C19H13BrN4O2 409.02947. found 409.02902 (M+H)+1.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].CC(C)=O.FC(F)(F)C([O:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:26]=[CH:25][C:24]([S:27](Cl)(=[O:29])=[O:28])=[CH:23][CH:22]=2)[CH2:16]1)=O.C(#N)C>O>[OH:13][CH2:14][CH:15]1[O:19][C:18](=[O:20])[N:17]([C:21]2[CH:22]=[CH:23][C:24]([S:27]([N:1]=[N+:2]=[N-:3])(=[O:28])=[O:29])=[CH:25][CH:26]=2)[CH2:16]1
Reactant: O=C1OC(COC(=O)C(F)(F)F)CN1c1ccc(S(=O)(=O)Cl)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CC#N
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc(N2CC(CO)OC2=O)cc1
Temperature: -5 °C
Reaction time: 1 h

Procedure:
A solution of 10 g sodium azide in 20 ml water was added to 200 ml reagent grade acetone and then cooled to -5° C. A 19 g portion of dl-4-[5-(trifluoroacetoxymethyl)-2-oxooxazolidin-3-yl]benzenesulfonyl chloride (prepared as in Example 1) was added to the solution while maintaining the temperature of the mixture below 0° C. After stirring the mixture for one hour, it was allowed to stand overnight. The acetone was removed under reduced pressure, water was added and the product was filtered and washed with water to yield 12.8 g, m.p. 108°-110° C. This product was stirred with 250 ml acetonitrile at 25° C. and filtered to remove some insoluble material. The acetonitrile was concentrated and the crystallized product filtered to yield 12.3 g. This product was recrystallized from ethyl acetae to yield 6.0 g of the title compound, m.p. 112°-113° C.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([P:15]([CH3:18])([CH3:17])=[O:16])=[CH:11][CH:10]=2)[CH:3]=1.C(N(CC)CC)C.[NH2:26][CH2:27][CH2:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([NH2:38])(=[O:37])=[O:36])=[CH:31][CH:30]=1>C(O)C>[CH3:17][P:15]([C:12]1[CH:13]=[CH:14][C:9]([NH:8][C:4]2[N:5]=[CH:6][N:7]=[C:2]([NH:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][C:32]([S:35]([NH2:38])(=[O:36])=[O:37])=[CH:33][CH:34]=3)[CH:3]=2)=[CH:10][CH:11]=1)([CH3:18])=[O:16]
Reactant: CP(C)(=O)c1ccc(Nc2cc(Cl)ncn2)cc1
Reactant: NCCc1ccc(S(N)(=O)=O)cc1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CP(C)(=O)c1ccc(Nc2cc(NCCc3ccc(S(N)(=O)=O)cc3)ncn2)cc1

Procedure:
To a solution of 6-chloro-N-[4-(dimethylphosphoryl)phenyl]pyrimidin-4-amine (prepared as in Example 59: 0.12 mmol) in 2 mL of ethanol is added 50 μL of triethylamine and 4-(2-aminoethyl)benzene-sulfonamide (23 mg, 0.12 mmol). The mixture can be microwaved at 120 degrees until formation of the desired compound. The reaction mixture can be filtered through a syringe filter and purified by prep-HPLC.
Reaction SMILES: Cl.[NH2:2][C@@H:3]1[CH2:8][CH2:7][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1.CCN(C(C)C)C(C)C.[Cl:24][C:25]1[CH:30]=[C:29](Cl)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1>C(#N)C.O>[Cl:24][C:25]1[CH:30]=[C:29]([NH:2][C@@H:3]2[CH2:4][CH2:5][C@H:6]([C:9]([NH:11][CH:12]([CH3:14])[CH3:13])=[O:10])[CH2:7][CH2:8]2)[C:28]([N+:32]([O-:34])=[O:33])=[CH:27][N:26]=1
Reactant: CC(C)NC(=O)[C@H]1CC[C@@H](N)CC1
Reactant: O=[N+]([O-])c1cnc(Cl)cc1Cl
Agent: Cl
Solvent: O
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)NC(=O)[C@H]1CC[C@@H](Nc2cc(Cl)ncc2[N+](=O)[O-])CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of cis-4-amino-N-isopropylcyclohexanecarboxamide hydrochloride (12.58 g, 57.0 mmol) and DIPEA (29.0 mL, 166 mmol) in ACN (104 mL) was added 2,4-dichloro-5-nitropyridine (10.00 g, 51.8 mmol). The resulting mixture was stirred at RT for 24 hours. The reaction mixture was diluted with water and washed with DCM (×2). The combined organic layers were washed with a minimal volume of brine, dried over sodium sulfate, filtered and concentrated in vacuo. After almost complete concentration of solvent, EtOAc was added, and the solid precipitate was collected yielding cis-4-(2-chloro-5-nitropyridin-4-ylamino)-N-isopropylcyclohexanecarboxamide as a yellow solid (12.97 g, 73.4% yield).
Reaction SMILES: Cl.[CH3:2][C:3]1[N:7]([C:8]2[CH:26]=[CH:25][C:11]([O:12][C@H:13]3[CH2:17][CH2:16][N:15]([CH:18]4[CH2:23][CH2:22][NH:21][CH2:20][CH2:19]4)[C:14]3=[O:24])=[CH:10][CH:9]=2)[N:6]=[N:5][N:4]=1.CCN(C(C)C)C(C)C.Cl[C:37]1[N:42]=[CH:41][C:40]([CH2:43][CH3:44])=[CH:39][N:38]=1.O>CN(C=O)C.CCOC(C)=O>[CH2:43]([C:40]1[CH:39]=[N:38][C:37]([N:21]2[CH2:20][CH2:19][CH:18]([N:15]3[CH2:16][CH2:17][C@H:13]([O:12][C:11]4[CH:10]=[CH:9][C:8]([N:7]5[C:3]([CH3:2])=[N:4][N:5]=[N:6]5)=[CH:26][CH:25]=4)[C:14]3=[O:24])[CH2:23][CH2:22]2)=[N:42][CH:41]=1)[CH3:44]
Reactant: Cc1nnnn1-c1ccc(O[C@H]2CCN(C3CCNCC3)C2=O)cc1
Reactant: CCc1cnc(Cl)nc1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: CCc1cnc(N2CCC(N3CC[C@H](Oc4ccc(-n5nnnc5C)cc4)C3=O)CC2)nc1
Temperature: 100 °C
Yield: 16.9 %

Procedure:
To a solution of (S)-3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)-1-(piperidin-4-yl)pyrrolidin-2-one hydrochloride salt (128 mg, 0.198 mmol) and DIEA (0.173 mL, 0.99 mmol) in DMF (3 mL) was added 2-chloro-5-ethylpyrimidine (85 mg, 0.532 mmol). The reaction was heated to 100° C. for 4 hours and then poured into water (10 mL) and EtOAc (10 mL). The organic layer was separated and the aqueous layer extracted with EtOAc (2×5 mL). The combined organic layers were dried with MgSO4 and concentrated in vacuo. The resulting material was purified by silica gel chromatography eluting with a gradient of 1:1 hexanes/EtOAc to EtOAc to yield (S)-1-(1-(5-ethylpyrimidin-2-yl)piperidin-4-yl)-3-(4-(5-methyl-1H-tetrazol-1-yl)phenoxy)pyrrolidin-2-one (15 mg, 17%) as an off white solid. Mass spectrum (apci) m/z=449.2 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([NH:13][C:14](=[O:26])[C:15]2[CH:20]=[CH:19][C:18]([N:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:17][CH:16]=2)[CH:7]=[CH:8][C:9]=1[N+:10]([O-])=O)([O-])=O.[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34]([C:36]2[CH:43]=[CH:42][C:39]([CH:40]=O)=[CH:38][CH:37]=2)=[O:35])[CH:28]=1>>[N:27]1[CH:32]=[CH:31][CH:30]=[C:29]([NH:33][C:34](=[O:35])[C:36]2[CH:37]=[CH:38][C:39]([C:40]3[NH:10][C:9]4[CH:8]=[CH:7][C:6]([NH:13][C:14](=[O:26])[C:15]5[CH:20]=[CH:19][C:18]([N:21]6[CH2:25][CH2:24][CH2:23][CH2:22]6)=[CH:17][CH:16]=5)=[CH:5][C:4]=4[N:1]=3)=[CH:42][CH:43]=2)[CH:28]=1
Reactant: O=Cc1ccc(C(=O)Nc2cccnc2)cc1
Reactant: O=C(Nc1ccc([N+](=O)[O-])c([N+](=O)[O-])c1)c1ccc(N2CCCC2)cc1
Product: O=C(Nc1cccnc1)c1ccc(-c2nc3cc(NC(=O)c4ccc(N5CCCC5)cc4)ccc3[nH]2)cc1

Procedure:
Compound 241 was prepared according to the procedure similar to that described in Scheme III from N-(3,4-dinitrophenyl)-4-pyrrolidinylbenzamide and 4-(3-pyridinylaminocarbonyl)benzaldehyde. [M+H]+ calcd for C30H26N6O2: 503.22; found: 502.97.
Reaction SMILES: C[Si]([N-][Si](C)(C)C)(C)C.[Na+].O1CCCC1.Cl[C:17]1[C:26]2[C:21](=[CH:22][C:23]([O:29][CH2:30][CH2:31][CH2:32][CH2:33][Cl:34])=[C:24]([O:27][CH3:28])[CH:25]=2)[N:20]=[CH:19][N:18]=1.[Cl:35][C:36]1[CH:44]=[C:43]([C:45]#[C:46][CH2:47][O:48][CH3:49])[C:39]2[O:40][CH2:41][O:42][C:38]=2[C:37]=1[NH2:50].[Cl-].[NH4+]>CN(C)C=O>[Cl:34][CH2:33][CH2:32][CH2:31][CH2:30][O:29][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([NH:50][C:37]3[C:38]4[O:42][CH2:41][O:40][C:39]=4[C:43]([C:45]#[C:46][CH2:47][O:48][CH3:49])=[CH:44][C:36]=3[Cl:35])=[N:18][CH:19]=[N:20]2)=[CH:25][C:24]=1[O:27][CH3:28]
Reactant: COc1cc2c(Cl)ncnc2cc1OCCCCCl
Reactant: COCC#Cc1cc(Cl)c(N)c2c1OCO2
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCCl)c(OC)cc23)c2c1OCO2
Temperature: 25 °C
Yield: 73.5 %

Procedure:
A solution of sodium bis(trimethylsilyl)amide (2.66 ml) in tetrahydrofuran (1.0M, 2.66 mmol) was added dropwise to an ice-cold solution of 4-chloro-7-(4-chlorobutoxy)-6-methoxyquinazoline (0.4 g, 1.33 mmol) and 5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-amine (0.35 g, 1.47 mmol) in dimethylformamide (4 ml). The mixture was allowed to warm to room temperature over 1 hour. A saturated solution of ammonium chloride was added and the mixture was partitioned between water and dichloromethane. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure to give 7-(4-chlorobutoxy)-N-[5-chloro-7-(3-methoxyprop-1-yn-1-yl)-1,3-benzodioxol-4-yl]-6-methoxyquinazolin-4-amine as a gum (0.493 g, 73%). NMR Spectrum: (CDCl3) 2.05 (m, 4H), 3.48 (s, 3H), 3.65 (t, 2H), 3.98 (s, 3H), 4.23 (t, 2H), 4.37 (s, 2H), 6.08 (s, 2H), 6.88 (s, 1H), 7.07 (s, 1H), 7.09 (s, 1H), 7.25 (s, 1H), 8.63 (s, 1H). Mass Spectrum: M+H+ 504 and M+H− 502.
Reaction SMILES: [F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1.CS([C:21]1[N:22]=[CH:23][C:24]2[CH:30]=[CH:29][C:28](=[O:31])[N:27]([C:32]3[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=3)[C:25]=2[N:26]=1)=O.CCN(C(C)C)C(C)C>O1CCOCC1.CC(O)(C)C.CS(C)=O>[F:1][CH2:2][CH2:3][N:4]1[CH2:7][CH:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([NH:15][C:21]3[N:22]=[CH:23][C:24]4[CH:30]=[CH:29][C:28](=[O:31])[N:27]([C:32]5[CH:33]=[C:34]([NH:38][C:39](=[O:42])[CH:40]=[CH2:41])[CH:35]=[CH:36][CH:37]=5)[C:25]=4[N:26]=3)=[C:11]([O:16][CH3:17])[CH:10]=2)[CH2:5]1
Reactant: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(S(C)=O)nc32)c1
Reactant: COc1cc(NC2CN(CCF)C2)ccc1N
Solvent: CC(C)(C)O
Solvent: C1COCCO1
Solvent: CS(C)=O
Product: C=CC(=O)Nc1cccc(-n2c(=O)ccc3cnc(Nc4ccc(NC5CN(CCF)C5)cc4OC)nc32)c1
Temperature: 85 °C
Yield: 32 %

Procedure:
To a suspension of N1-(1-(2-fluoroethyl)azetidin-3-yl)-3-methoxybenzene-1,4-diamine (11c) (135 mg, 0.56 mmol) and N-(3-(2-(methylsulfinyl)-7-oxopyrido[2,3-d]pyrimidin-8(7H)-yl)phenyl)acrylamide (11b) (230 ing, 0.65 mmol) in 1 mL of dioxane and 1 mL of tBuOH at RT was added DIEA (0.29 mL, 1.69 mmol). The mixture was heated in an oil bath at 85° C. for 3 h. It was concentrated under reduced pressure. The residue was purified on a silica gel column (5% MeOH in DCM followed by 2-6% of 2 M NH3 in MeOH in DCM) to give a material that was about 95% pure. The material was dissolved in 10 mL of DMSO and purified on a reverse phase HPLC, using a gradient of 10-90% of (0.1% TFA in CH3CN) in (0.1% TFA in water). Desired fractions were collected, lyophilized and the powdery residue was dissolved in 2 mL of MeOH, passed through a Silicycle (5 G) carbonate cartridge, rinsed with MeOH (20 mL). The fractions were collected and concentrated to give the title compound (95 mg, 31% yield) as a brown crystalline solid. m/z (ESI, +ve ion) 530.0 (M+H)+. 1H NMR (400 MHz, DMSO-d6) δ ppm 10.40 (1H, br.), 8.73 (1H, br.), 8.10 (1H, br.), 7.90 (1H, d, J=9.4 Hz), 7.83 (1H, br.), 7.64 (1H, s), 7.51 (1H, t, J=8.0 Hz), 7.15 (1H, br.), 7.02 (1H, d, J=8.6 Hz), 6.44 (2H, m), 6.29 (1H, m), 6.16 (1H, d, J=2.0 Hz), 5.86 (1H, br.), 5.78 (1H, m), 5.57 (1H, br.), 4.49 (1H, t, J=4.8 Hz), 4.37 (1H, t, J=4.9 Hz), 3.90 (1H, br.), 3.72 (3H, s), 3.70 (2H, m), 2.83 (2H, m), 2.74 (1H, 1, J=4.8 Hz), 2.67 (1H, t, J=4.8 Hz).
Reaction SMILES: Cl[CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8].[N-:19]=[N+:20]=[N-:21].[Na+]>CO.O>[N:19]([CH2:2][C:3]1[N:4]=[C:5]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[O:6][C:7]=1[CH3:8])=[N+:20]=[N-:21]
Reactant: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CCl
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1oc(-c2ccc(C(F)(F)F)cc2)nc1CN=[N+]=[N-]
Temperature: 25 °C
Yield: 85.4 %

Procedure:
To a solution of 4-chloromethyl-5-methyl-2-(4-trifluoromethyl-phenyl)-oxazole (2.4 g, 8.71 mmol) in methanol (13 mL) is added sodium azide (1.13 g, 17.4 mmol) in water (10 mL). The mixture is heated to reflux for 3 hrs, cooled to room temperature, majority of the methanol is evaporated, the residue is extracted with ethyl acetate, dried, concentrated and column chromatography on silica gel yields the title compound (2.10 g).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)CC)C.[NH2:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53]>ClCCl>[Cl:1][C:2]1[CH:10]=[C:9]([CH:11]([CH3:13])[CH3:12])[CH:8]=[CH:7][C:3]=1[C:4]([NH:45][CH2:46][C:47]1[C:48]([OH:55])=[N:49][C:50]([CH3:54])=[CH:51][C:52]=1[CH3:53])=[O:6]
Reactant: CC(C)c1ccc(C(=O)O)c(Cl)c1
Reactant: Cc1cc(C)c(CN)c(O)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(C)c(CNC(=O)c2ccc(C(C)C)cc2Cl)c(O)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 24 %

Procedure:
To a solution of 2-chloro-4-isopropylbenzoic acid (100 mg, 0.50 mmol) in dichloromethane (50 mL) were added 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (190 mg, 0.50 mmol) and triethylamine (175 mg, 1.73 mmol). The resultant reaction mixture was stirred at room temperature for 30 minutes. Then 3-(aminomethyl)-4,6-dimethylpyridin-2-ol (152 mg, 1.0 mmol) was added and the mixture was stirred at ambient temperature overnight. The mixture was washed with brine (50 mL), dried over sodium sulfate, filtered, and concentrated. The residue was purified through pre-HPLC and the obtained solution was freeze-dried to afford 2-chloro-N-((2-hydroxy-4,6-dimethylpyridin-3-yl)methyl)-4-isopropylbenzamide (40 mg, 23.9%) as a white solid. LRMS (M+H+) m/z: calcd 333.13. found 333. HPLC purity (214 nm): 96.2% 1H NMR (300 MHz, DMSO) δ 7.37 (d, J=7.8 Hz, 1H), 7.30 (d, J=1.5 Hz, 1H), 7.23 (dd, J1=7.8 Hz, J2=1.5 Hz, 1H), 6.11 (s, 1H), 4.49 (s, 2H), 2.93 (m, 1H), 2.38 (s, 3H), 2.25 (s, 3H), 1.25 (d, J=6.9 Hz, 6H).
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([S:11](Cl)(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=1[O:31][CH3:32])[C:19]([NH:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>>[C:1]([NH:4][C:5]1[S:6][C:7]([S:11]([NH:15][C:16]2[CH:17]=[C:18]([CH:28]=[CH:29][C:30]=2[O:31][CH3:32])[C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[O:20])(=[O:13])=[O:12])=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2]
Reactant: COc1ccc(C(=O)Nc2ccccc2)cc1N
Reactant: CC(=O)Nc1nc(C)c(S(=O)(=O)Cl)s1
Product: COc1ccc(C(=O)Nc2ccccc2)cc1NS(=O)(=O)c1sc(NC(C)=O)nc1C
Yield: 50.7 %

Procedure:
Prepared according to the procedure described for Example 126 using 2-acetamido-4-methyl-5-thiazolesulfonyl chloride (0.76 g, 3.0 mmol) and 3-amino-4-methoxy-N-phenyl-benzamide (0.73 g, 3.0 mmol) to afford the product (0.7 g); m.p. 260-261° C. after trituration in diethyl ether.
Reaction SMILES: [NH:1]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4](=[O:5])[C:2]1=[O:3].[H-].[Na+].[CH3:14][OH:15]>CN(C=O)C.C(Cl)(Cl)Cl.[Cu]I>[O:15]1[CH:4]=[CH:2][O:3][CH:14]1[C:6]1[CH:11]=[CH:10][C:9]([N:1]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:4](=[O:5])[C:2]2=[O:3])=[CH:8][CH:7]=1
Reactant: O=C1Nc2ccccc2C1=O
Reactant: CO
Agent: [Cu]I
Agent: [H-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: CN(C)C=O
Product: O=C1C(=O)N(c2ccc(C3OC=CO3)cc2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Isatin (1.88 g, 0.0128 mol) in anhydrous DMF (100 mL) was cooled in an ice-bath under nitrogen and treated with sodium hydride (0.3 g, 1 equivalent). The reaction was warmed to room temperature and stirred for 1 hour. It was then treated with 2-(4-bromophenyl)-1,3-dioxalane (2.83 g, 0.0124 mol) followed by CuI (4.71 g, 2 equivalents). This suspension was heated in an oil-bath at 135° C. under nitrogen for 16 hours. It was then cooled to room temperature and diluted with an equal volume of chloroform. The resulting suspension was filtered and the filtrate was concentrated under reduced pressure. The residue was suspended in xylenes (100 mL) and evaporated to dryness. A thick, viscous oil was recovered which was used as such for the next reaction. TLC (5% methanol in chloroform) showed clean conversion, Rf (product)=0.91.
Reaction SMILES: [OH:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1.CCOCC.[CH2:16]([S:23](Cl)(=[O:25])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[CH2:16]([S:23]([O:1][N:2]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[N:4]=[N:3]1)(=[O:25])=[O:24])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=S(=O)(Cl)Cc1ccccc1
Reactant: On1nnc2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=S(=O)(Cc1ccccc1)On1nnc2ccccc21
Yield: 46.7 %

Procedure:
In 1 N aqueous sodium hydroxide (50 ml) is dissolved 1-hydroxy-1,2,3-benzotriazole (5 g) and thereto is added ether (25 ml). To the solution is added benzylsulfonyl chloride (8 g) with stirring under ice-cooling. The mixture is stirred at the same temperature for 3 hours. The reaction mixture is extracted with ethyl acetate. The extract is washed with a saturated aqueous sodium hydrogen carbonate and water in order and dried over anhydrous magnesium sulfate. After drying, the solvent is distilled off and the oily residue is allowed to stand. The resulting crystals are recrystallized from benzene-petroleum ether to give 1-benzylsulfonyloxy-1,2,3-benzotriazole (5.0 g), melting point: 65°-67° C.
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[C:12](O)=[O:13].B.C1COCC1>C1COCC1>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][CH2:5][O:6][CH:7]2[CH2:12][OH:13]
Reactant: O=C(O)C1OCCc2c(Br)cccc21
Agent: B
Solvent: C1CCOC1
Product: OCC1OCCc2c(Br)cccc21
Temperature: 0 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3,4-dihydro-1H-isochromene-1-carboxylic acid (0.500 g, 1.94 mmol) in 1 mL of THF was added BH3.THF (3.88 mL, 3.88 mmol) drop wise at 0° C. The mixture was stirred at 0° C. for 2 h. The reaction was quenched with water and aqueous sodium hydroxide (1 N, 2 mL). The contents were stirred for 3 h, and then extracted with EtOAc. The organic layer was dried and concentrated to give (5-bromo-3,4-dihydro-1H-isochromen-1-yl)methanol