Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C@@H:2]1[C:6]2[NH:7][C:8](B3OC(C)(C)C(C)(C)O3)=[CH:9][C:5]=2[C:4](=[O:19])[NH:3]1.[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28](I)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21].[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O1CCOCC1.CC(C1C=C(C(C)C)C(C2C(P(C3CCCCC3)C3CCCCC3)=CC=CC=2)=C(C(C)C)C=1)C.C1C=[C-]C(CCN)=CC=1.Cl[Pd+].CCOC(C)=O.O>[C:20]([NH:24][C:25]1[N:34]([CH3:35])[C:33](=[O:36])[C:32]2[C:27](=[C:28]([C:8]3[NH:7][C:6]4[C@@H:2]([CH3:1])[NH:3][C:4](=[O:19])[C:5]=4[CH:9]=3)[CH:29]=[CH:30][CH:31]=2)[N:26]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: Cn1c(NC(C)(C)C)nc2c(I)cccc2c1=O
Reactant: C[C@H]1NC(=O)c2cc(B3OC(C)(C)C(C)(C)O3)[nH]c21
Agent: Cl[Pd+]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: NCCc1[c-]cccc1
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H]1NC(=O)c2cc(-c3cccc4c(=O)n(C)c(NC(C)(C)C)nc34)[nH]c21
Temperature: 45 °C
Yield: 73.7 %

Procedure:
A sealable tube (75 mL) was charged with (R)-6-methyl-2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyrrolo[3,4-b]pyrrol-4(1H)-one (705) (2.00 g, 6.26 mmol), 2-(tert-butylamino)-8-iodo-3-methylquinazolin-4(3H)-one (701) (1.78 g, 5.01 mmol) and K3PO4 (3.98 g, 18.77 mmol) in 1,4-dioxane (16 mL)/water (4 mL). The mixture was bubbled with Argon for 3 min, then XPhos precatalyst II (Sigma-Aldrich; 0.24 g, 0.31 mmol) was added and the tube was sealed and heated in an oil bath at 45° C. for 90 min. The mixture was diluted with EtOAc (80 mL) and water (30 mL) and the layers were separated. The aqueous layer was extracted with EtOAc (100 mL×2). The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified on a silica gel column (1-10% MeOH in DCM) to give (R)-2-(tert-butylamino)-3-methyl-8-(6-methyl-4-oxo-1,4,5,6-tetrahydropyrrolo[3,4-b]pyrrol-2-yl)quinazolin-4(3H)-one (1.35 g, 3.69 mmol, 59% yield) as a light brown crystalline solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 11.95 (1H, br.), 7.91 (2H, m), 7.62 (1H, s), 7.19 (1H, t, J=7.6 Hz), 6.73 (1H, m), 5.96 (1H, s), 4.54 (1H, q, J=6.4 Hz), 3.49 (3H, s), 1.52 (9H, s), 1.38 (3H, d, J=6.7 Hz). m/z (ESI, +ve ion) 366.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([O:11]CC)=[O:10])=[CH:4][C:3]=1[OH:14].[C:15]1([CH3:24])[C:16]([N:21]=[C:22]=S)=[CH:17][CH:18]=[CH:19][CH:20]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(O)C>[C:15]1([CH3:24])[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][C:22]1[O:14][C:3]2[CH:4]=[C:5]([CH2:8][C:9]([OH:11])=[O:10])[CH:6]=[CH:7][C:2]=2[N:1]=1
Reactant: CCOC(=O)Cc1ccc(N)c(O)c1
Reactant: Cc1ccccc1N=C=S
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCO
Product: Cc1ccccc1Nc1nc2ccc(CC(=O)O)cc2o1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of ethyl 4-amino-3-hydroxy-phenylacetate (3.3 g, Reference Example 2) and o-tolylisothiocyanate (2.5 mL) in ethanol (150 mL) was stirred at room temperature for about 2 hours. After standing at room temperature overnight the mixture was evaporated and the residue was subjected to flash chromatography on silica eluting with a mixture of pentane and ethyl acetate (7:3, v/v) to give a yellow foam. A solution of this material in ethanol (150 mL was treated with dicyclohexylcarbodiimide (3.0 g) and the mixture was heated at reflux temperature for 2 hours. The mixture was evaporated and the residue subjected to short column chromatography on silica eluting with a mixture of 5-10% tert-butyl methyl ether in dichloromethane to remove dicyclohexylurea. The resulting light yellow oil was dissolved in ethanol (100 mL) and the solution was treated with sodium hydroxide solution (15 mL, 1M) then heated at reflux temperature for 2 hours. The reaction mixture was evaporated and the residue was dissolved in water. The solution was washed with ethyl acetate and the aqueous layer was acidified to pH 1 by addition of concentrated hydrochloric acid. The resulting white precipitate was collected by filtration, then washed thoroughly with water, and then dried to give the title compound (1.8 g) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[C:9]([CH3:11])=[N:8][C:7]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:14][CH:13]=3)=[N:6][C:5]=2[S:4][C:3]=1[C:22]([NH2:24])=[O:23].[O:25]=[C:26](Cl)OC(Cl)(Cl)Cl.O>O1CCOCC1>[CH3:11][C:9]1[C:10]2[C:2]3[NH:1][C:26](=[O:25])[NH:24][C:22](=[O:23])[C:3]=3[S:4][C:5]=2[N:6]=[C:7]([C:12]2[CH:13]=[CH:14][C:15]([O:18][CH:19]([CH3:21])[CH3:20])=[CH:16][CH:17]=2)[N:8]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc(C(N)=O)c(N)c12
Solvent: C1COCCO1
Solvent: O
Product: Cc1nc(-c2ccc(OC(C)C)cc2)nc2sc3c(=O)[nH]c(=O)[nH]c3c12
Temperature: 25 °C
Yield: 72.4 %

Procedure:
1.0 g (3 mmol) 5-amino-4-methyl-2-(4-iso-propoxy-phenyl)-thieno[2,3-d]pyrimidine-6-carboxamide was suspended in 200 ml dioxane, and following the addition of 0.73 ml (6 mmol) diphosgene the suspension is refluxed for 2 h. Having cooled down to room temperature, 20 ml water was carefully added and the precipitate was subsequently sucked off. 0.8 g (68%) 9-methyl-7-(4-iso-propoxy-phenyl)-thieno[2,3-d:4,5-d′]-dipyrimidine-2,4(1H,3H)-dione is obtained.
Reaction SMILES: [CH3:1][C:2]1(C)[C@@H](/C=C\C(=O)OC2C=CC=CC=2)[C@H:3]1C(O)=O.[CH3:20][C:21]1([CH3:54])[C@@H:23](/[CH:24]=[CH:25]\[C:26](=[O:34])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:22]1[C:35]([O:37][C@H:38](C#N)[C:39]1[CH:44]=C[CH:42]=[C:41]([O:45]C2C=CC=CC=2)[CH:40]=1)=[O:36].CC1(C)C(/C=C\C(=O)OC2C=CC=CC=2)C1C([O-])=O>>[CH3:20][C:21]1([CH3:54])[C@@H:23](/[CH:24]=[CH:25]\[C:26](=[O:34])[O:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[C@H:22]1[C:35]([O:37][CH:38]1[CH2:42][C:41](=[O:45])[C:40]([CH2:3][CH:2]=[CH2:1])=[C:39]1[CH3:44])=[O:36]
Reactant: CC1(C)[C@H](C(=O)O)[C@@H]1/C=C\C(=O)Oc1ccccc1
Reactant: CC1(C)[C@H](C(=O)O[C@H](C#N)c2cccc(Oc3ccccc3)c2)[C@@H]1/C=C\C(=O)Oc1ccccc1
Agent: CC1(C)C(/C=C\C(=O)Oc2ccccc2)C1C(=O)[O-]
Product: C=CCC1=C(C)C(OC(=O)[C@@H]2[C@H](/C=C\C(=O)Oc3ccccc3)C2(C)C)CC1=O
Yield: 189.6 %

Procedure:
Using the procedure of Example 2, 1.5 g of (1R,cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-phenoxy-1-propenyl]-cyclopropane-carboxylic acid and 1 g of (S) 3-(2-propenyl)-1-hydroxy-2-methyl-4-oxo-cyclopent-2-en-1-yl were reacted to obtain 1.6 g of (1S) 2-methyl-4-oxo-3-(2-propenyl)-2-cyclopenten-1-yl (1R, cis) 2,2-dimethyl-3-[(Z) 3-oxo-3-phenoxy-1-propenyl]-cyclopropane-carboxylate with a specific rotation of [α]D20 =+66°±2.5 (c=0.5% in benzene).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([N+:11]([O-:13])=[O:12])[CH:10]=1)[NH:7][C:6]([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[CH:5]2.[O:20](C(OC(C)(C)C)=O)[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=O>CN(C1C=CN=CC=1)C>[C:21]([N:7]1[C:8]2[C:4](=[CH:3][C:2]([CH3:1])=[CH:10][C:9]=2[N+:11]([O-:13])=[O:12])[CH:5]=[C:6]1[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:20]
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: Cc1cc([N+](=O)[O-])c2[nH]c(-c3ccccc3)cc2c1
Agent: CN(C)c1ccncc1
Product: Cc1cc([N+](=O)[O-])c2c(c1)cc(-c1ccccc1)n2C(=O)OC(C)(C)C

Procedure:
5-Methyl-7-nitro-2-phenyl-1H-indole prepared in Preparation 24, (BOC)2O and DMAP were reacted according to the same procedure as Preparation 23 to give the title compound.
Reaction SMILES: Br[CH:2](Br)[C:3]([C:5]([F:8])([F:7])[F:6])=[O:4].C([O-])(=O)C.[Na+].[Cl:15][C:16]1[C:21]([O:22][C:23]2[N:28]=[CH:27][CH:26]=[CH:25][N:24]=2)=[CH:20][C:19]([NH:29][NH2:30])=[C:18]([F:31])[CH:17]=1>O>[Cl:15][C:16]1[C:21]([O:22][C:23]2[N:24]=[CH:25][CH:26]=[CH:27][N:28]=2)=[CH:20][C:19]([NH:29][N:30]=[CH:2][C:3](=[O:4])[C:5]([F:8])([F:7])[F:6])=[C:18]([F:31])[CH:17]=1
Reactant: O=C(C(Br)Br)C(F)(F)F
Reactant: NNc1cc(Oc2ncccn2)c(Cl)cc1F
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Product: O=C(C=NNc1cc(Oc2ncccn2)c(Cl)cc1F)C(F)(F)F
Temperature: 80 °C
Reaction time: 2 h

Procedure:
1,1-Dibromo-3,3,3-trifluoroacetone (0.162 g) was added to a solution of sodium acetate (0.162 g) in water (0.5 ml) and the solution heated at 80° C. for 20 minutes. It was cooled to 0° C. and 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazine hydrachloride (0.15 g) was added. After stirring at room temperature for 2 hour the reaction mixture was processed to give 3,3,3-trifluoro-2-oxopropanal 4-chloro-2-fluoro-5-(pyrimidyloxy)-phenylhydrazone (0.122 g) mp=188-90° C.
Reaction SMILES: C(OC(=O)[NH:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[NH:10][CH2:9]1)(C)(C)C.[CH:21](=O)[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[NH2:7][CH:8]1[CH2:17][C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:18]#[N:19])[CH:15]=2)[N:10]([CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:9]1
Reactant: CC(C)(C)OC(=O)NC1CNc2ccc(C#N)cc2C1
Reactant: O=Cc1ccccc1
Product: N#Cc1ccc2c(c1)CC(N)CN2Cc1ccccc1

Procedure:
157A was prepared from 1C and benzaldehyde by procedures analogous to those described in Example 22A, followed by removal of N-Boc protecting group according to the procedures described in Example 22B.
Reaction SMILES: Cl.[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][NH:17][CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl.[NH:35]1[CH:39]=[C:38]([CH2:40][C:41](O)=[O:42])[N:37]=[CH:36]1>>[CH:2]([C@H:15]1[C@@H:20]([O:21][CH2:22][C:23]2[CH:28]=[C:27]([C:29]([F:32])([F:30])[F:31])[CH:26]=[C:25]([F:33])[CH:24]=2)[CH2:19][CH2:18][N:17]([C:41](=[O:42])[CH2:40][C:38]2[N:37]=[CH:36][NH:35][CH:39]=2)[CH2:16]1)([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: O=C(O)Cc1c[nH]cn1
Reactant: Fc1cc(CO[C@H]2CCNC[C@H]2C(c2ccccc2)c2ccccc2)cc(C(F)(F)F)c1
Agent: Cl
Product: O=C(Cc1c[nH]cn1)N1CC[C@H](OCc2cc(F)cc(C(F)(F)F)c2)[C@H](C(c2ccccc2)c2ccccc2)C1

Procedure:
The compound (28.8 mg) obtained in Example 26 and 4-imidazoleacetic acid hydrochloride (19.5 mg) were reacted and treated in the same manner as in the method described in Example 32 to obtain the title compound.
Reaction SMILES: N[C:2]1[NH:3][C:4](=[O:20])[C:5]2[N:6]([CH2:11][C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=3[C:18]#[N:19])[CH:7]=[N:8][C:9]=2[N:10]=1.N([O-])=[O:22].[Na+].O.Cl>C(O)(=O)C>[C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[CH2:11][N:6]1[C:5]2[C:4](=[O:20])[NH:3][C:2](=[O:22])[NH:10][C:9]=2[N:8]=[CH:7]1)#[N:19]
Reactant: O=N[O-]
Reactant: N#Cc1ccccc1Cn1cnc2nc(N)[nH]c(=O)c21
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#Cc1ccccc1Cn1cnc2[nH]c(=O)[nH]c(=O)c21

Procedure:
Prepared by treating 16.68 g of 2-amino-7-(2-cyano-benzyl)-1,7-dihydro-purin-6-one with 17.00 g of sodium nitrite in a mixture of 375 ml of conc. acetic acid, 84 ml of water and 5.2 ml of conc. hydrochloric acid at 50° C.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]#[C:9][C:10]2[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=2)[CH:5]=[CH:4][N:3]=1.OC1O[N:20]=[N+:21]2[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[O:28])[CH2:23][C:22]=12>C1(C)C=C(C)C=C(C)C=1>[Cl:1][C:2]1[N:7]=[C:6]([C:8]2[C:9]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[N:20][N:21]3[CH2:26][CH2:25][N:24]([C:27]([O:29][CH2:30][C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:28])[CH2:23][C:22]=23)[CH:5]=[CH:4][N:3]=1
Reactant: Fc1ccc(C#Cc2ccnc(Cl)n2)cc1
Reactant: O=C(OCc1ccccc1)N1CC[n+]2noc(O)c2C1
Solvent: Cc1cc(C)cc(C)c1
Product: O=C(OCc1ccccc1)N1CCn2nc(-c3ccc(F)cc3)c(-c3ccnc(Cl)n3)c2C1
Temperature: 165 °C
Reaction time: 18 h

Procedure:
A mixture of 2-chloro-4-[2-(4-fluorophenyl)ethynyl]pyrimidine (i.e. the product of Example 2, Step A) (2.51 g, 10.8 mmol) and 4,5,6,7-tetrahydro-3-hydroxy-5-[(phenylmethoxy)carbonyl][1,2,3]oxadiazolo[3,4-a]pyrazin-8-ium inner salt (i.e. the product of Step B) (3.00 g, 10.8 mmol) in mesitylene (100 mL) was stirred at 165° C. for 18 h. The reaction mixture was cooled and concentrated under reduced pressure. The residue was diluted with dichloromethane (50 mL) and treated with silica gel (10.0 g). The silica gel suspension was concentrated under reduced pressure to leave a mixture of silica gel and crude product, which was purified by silica gel chromatography using a gradient of ethyl acetate/hexanes (0:1 to 1:1) as eluant to give 1.5 g of the title compound as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](O)=[O:7])=[CH:4][CH:3]=1.S(Cl)([Cl:13])=O>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([Cl:13])=[O:7])=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)c1ccc(O)cc1
Solvent: CN(C)C=O
Product: O=C(Cl)c1ccc(O)cc1

Procedure:
4-Hydroxybenzoic acid (11.04 g.) was heated under reflux with thionyl chloride (80 ml.) containing dimethylformamide (0.1 ml.) for 2 hours. The solution obtained was evaporated. The residue was dissolved in toluene and the subsequent solution was evaporated. The residue obtained (which contained 4-hydroxybenzoyl chloride) was dissolved in methylene chloride (80 ml.). The solution obtained was treated dropwise with 1,2,3,6-tetrahydropyridine to pH7 with stirring and ice-cooling. The mixture was further stirred at 25° C. after the addition was complete for 2 hours and then evaporated. The residue was stirred with water and the solid was collected by filtration and then washed with water and acetone. After recrystallisation from a mixture of ethanol and ethyl acetate, there was obtained 1-(4-hydroxybenzoyl)-1,2,3,6-tetrahydropyridine (11.3 g.), m.p. 202°-206° C.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[O:17][CH3:18].Cl[C:20]1[N:25]=[C:24]([NH:26][C:27]2[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][N:36]([C:39](=[O:41])[CH3:40])[CH2:35][CH2:34]3)=[CH:29][C:28]=2[O:42][CH2:43][CH3:44])[C:23]([Cl:45])=[CH:22][N:21]=1>C(OC(O)C)C.Cl>[C:39]([N:36]1[CH2:35][CH2:34][N:33]([C:30]2[CH:31]=[CH:32][C:27]([NH:26][C:24]3[C:23]([Cl:45])=[CH:22][N:21]=[C:20]([NH:1][C:2]4[CH:7]=[CH:6][C:5]([N:8]5[CH2:13][CH2:12][N:11]([C:14](=[O:16])[CH3:15])[CH2:10][CH2:9]5)=[CH:4][C:3]=4[O:17][CH3:18])[N:25]=3)=[C:28]([O:42][CH2:43][CH3:44])[CH:29]=2)[CH2:38][CH2:37]1)(=[O:41])[CH3:40]
Reactant: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Cl)ncc1Cl
Reactant: COc1cc(N2CCN(C(C)=O)CC2)ccc1N
Agent: CCOC(C)O
Agent: Cl
Product: CCOc1cc(N2CCN(C(C)=O)CC2)ccc1Nc1nc(Nc2ccc(N3CCN(C(C)=O)CC3)cc2OC)ncc1Cl

Procedure:
1-(4-(4-amino-3-methoxyphenyl)piperazin-1-yl)ethanone (40 mg) prepared in Preparation Example 1 and 1-(4-(4-(2,5-dichloropyrimidine-4-ylamino)-3-ethoxyphenyl)piperazin-1-yl)ethanone (50 mg) prepared in Preparation Example 15 were dissolved in 0.08M HCl ethoxyethanol solution (1.2 mL), and allowed to react at 115° C. overnight. Upon completion of the reaction, the solvent of the mixture was removed under reduced pressure, diluted with ethyl acetate, neutralized with an aqueous saturated sodium carbonate solution, water was removed from the organic layer with sodium sulfate, and the solvent was removed under reduced pressure. The mixture was purified by column chromatography to obtain a target compound.
Reaction SMILES: C(OC(=O)C)(=O)C.[CH:8]([OH:10])=O.[F:11][C:12]1[CH:13]=[CH:14][C:15]([NH:21][CH3:22])=[C:16]([C:18](=[O:20])[CH3:19])[CH:17]=1.[OH-].[Na+]>O>[C:18]([C:16]1[CH:17]=[C:12]([F:11])[CH:13]=[CH:14][C:15]=1[N:21]([CH3:22])[CH:8]=[O:10])(=[O:20])[CH3:19]
Reactant: O=CO
Reactant: CNc1ccc(F)cc1C(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1cc(F)ccc1N(C)C=O
Reaction time: 2 h

Procedure:
A mixture of acetic anhydride (4.6 ml) and formic acid (3.1 3 ml) was stirred at 60° for 2 hours and then cooled to 10°. 5'-Fluoro-2'-(methylamino)acetophenone (3.0 g) was then added and the mixture stirred overnight. The solution was cooled in an ice-bath and water (20 ml) added followed by aqueous sodium hydroxide (specific gravity 1.5) added dropwise to pH 10. The mixture was extracted with dichloromethane (3×30 ml) and the combined extracts dried over magnesium sulphate to give a solution of 2'-acetyl-4'-fluoro-N-methylformanilide.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1[CH:9]=[C:8]([Cl:10])[CH:7]=[CH:6][C:5]=1[C:11]1[C:16]([C:17]2C=CN[N:18]=2)=[CH:15][N:14]=[C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)[N:12]=1.[N:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[CH:43][C:38]=2NC=1C(=CN(C)C)C(C1C=CC([Cl:53])=CC=1Cl)=O>>[ClH:3].[ClH:53].[N:18]1[C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][C:39]=2[NH:35][C:17]=1[C:16]1[C:11]([C:5]2[CH:6]=[CH:7][C:8]([Cl:10])=[CH:9][C:4]=2[Cl:3])=[N:12][C:13]([NH:22][CH2:23][CH2:24][NH:25][C:26]2[CH:31]=[CH:30][C:29]([N+:32]([O-:34])=[O:33])=[CH:28][N:27]=2)=[N:14][CH:15]=1
Reactant: CN(C)C=C(C(=O)c1ccc(Cl)cc1Cl)c1nc2ccccc2[nH]1
Reactant: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3cc[nH]n3)c(-c3ccc(Cl)cc3Cl)n2)nc1
Agent: Cl
Product: O=[N+]([O-])c1ccc(NCCNc2ncc(-c3nc4ccccc4[nH]3)c(-c3ccc(Cl)cc3Cl)n2)nc1

Procedure:
Made using the same procedure as for [4-(2,4-dichlorophenyl)-5-pyrazolylpyrimidin-2-yl]{2-[(5-nitro(2-pyridyl))amino]ethyl}amine dihydrochloride except that 2-benzimidazolyl-1-(2,4-dichlorophenyl)-3(dimethylamino)prop-2-en-1-one (XIV, 468 mg, 1.3 mmol) was used and the crude product was purified by recrystallization (CH2Cl2/Et2O/hexanes).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:22][CH:23]2[CH2:27][CH2:26][CH2:25][CH2:24]2)[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[O:28]1[CH2:33][CH2:32][N:31]([CH2:34][C:35]2[CH:40]=[CH:39][C:38](B(O)O)=[CH:37][CH:36]=2)[CH2:30][CH2:29]1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>O1CCOCC1.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:23]1([NH:22][C:4]2[C:5]([CH3:21])=[C:6]([C:7]([NH:9][CH2:10][C:11]3[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=3[CH3:17])=[O:8])[CH:20]=[C:2]([C:38]3[CH:37]=[CH:36][C:35]([CH2:34][N:31]4[CH2:32][CH2:33][O:28][CH2:29][CH2:30]4)=[CH:40][CH:39]=3)[CH:3]=2)[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(NC3CCCC3)c2C)c(=O)[nH]1
Reactant: OB(O)c1ccc(CN2CCOCC2)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: ClCCl
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3ccc(CN4CCOCC4)cc3)cc(NC3CCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Reaction time: 2 h

Procedure:
A solution of 5-bromo-3-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.), (4-(morpholinomethyl)phenyl)boronic acid (1.2 equiv.) and Pd(PPh3)4 (0.1 equiv.) in 1,4-dioxane (4 mL) was purged with argon for 10 min. Then, 2 M Na2CO3 solution (3.6 equiv.) was added to it and argon was purged again for 10 min. The reaction mixture was stirred at 100° C. for 2 h. After completion of the reaction, water was added to it and extraction was carried out using DCM. The combined organic layers were washed with water, dried over anhydrous Na2SO4, filtered and concentrated under reduced pressure to afford crude material which was purified by column chromatography over silica gel (60-120 mesh size) to afford 5-(cyclopentylamino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-4-methyl-4′-(morpholinomethyl)-[1,1′-biphenyl]-3-carboxamide which was further purified using preparative HPLC which gave the TFA salt.
Reaction SMILES: N(C(OC(C)(C)C)=O)=NC([O-])=O.[OH:13][C:14]1[C:23]([O:24][CH3:25])=[CH:22][CH:21]=[C:20]2[C:15]=1[C:16](=[O:34])[N:17](COC(=O)C(C)(C)C)[CH:18]=[N:19]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.O[CH:55]1[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]1.N>C(Cl)Cl>[CH3:25][O:24][C:23]1[C:14]([O:13][CH:55]2[CH2:60][CH2:59][N:58]([CH3:61])[CH2:57][CH2:56]2)=[C:15]2[C:20](=[CH:21][CH:22]=1)[N:19]=[CH:18][NH:17][C:16]2=[O:34]
Reactant: CN1CCC(O)CC1
Reactant: COc1ccc2ncn(COC(=O)C(C)(C)C)c(=O)c2c1O
Agent: CC(C)(C)OC(=O)N=NC(=O)[O-]
Agent: N
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc2nc[nH]c(=O)c2c1OC1CCN(C)CC1
Temperature: 5 °C
Reaction time: 1 h
Yield: 62.8 %

Procedure:
A solution of di-(tert-butyl azodicarboxylate (1.75 g) in methylene chloride (3 ml) was added to a stirred mixture of 5-hydroxy-6-methoxy-3-pivaloyloxymethyl-3,4-dihydroquinazolin-4-one (1.55 g), triphenylphosphine (1.99 g), 4-hydroxy-1-methylpiperidine (0.75 g) and methylene chloride (12 ml) which had been cooled to 5° C. The mixture was stirred at ambient temperature for 1 hour. The mixture was evaporated and the residue was purified by column chromatography on silica using a 9:10:1 mixture of methylene chloride, ethyl acetate and a saturated methanolic ammonia solution as eluent. The material so obtained was stirred in a saturated methanolic ammonia solution for 48 hours. The mixture was evaporated and the residue was triturated under diethyl ether. The resultant solid was washed with diethyl ether and dried under vacuum to give 6-methoxy-5-(N-methylpiperidin-4-yloxy)-3,4-dihydroquinazolin-4-one (0.92 g); NMR Spectrum: (DMSOd6) 1.7-1.9 (m, 4H), 1.95 (t, 2H), 2.15 (s, 3H), 2.7 (m, 2H), 3.85 (s, 3H), 4.08 (m, 1H), 7.4 (d, 1H), 7.6 (d, 1H), 7.85 (s, 1H), 11.8 (br s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)(=[O:11])=[O:10])=[CH:5][CH:4]=1.Cl>O1CCOCC1.O>[F:26][C:2]([F:1])([F:25])[C:3]1[CH:4]=[CH:5][C:6]([S:9]([N:12]2[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]2)(=[O:10])=[O:11])=[CH:7][CH:8]=1
Reactant: CC(C)(C)OC(=O)N1CCN(S(=O)(=O)c2ccc(C(F)(F)F)cc2)CC1
Agent: Cl
Solvent: O
Solvent: C1COCCO1
Product: O=S(=O)(c1ccc(C(F)(F)F)cc1)N1CCNCC1
Reaction time: 8 h

Procedure:
To a solution of 1,1-dimethylethyl 4-{[4-(trifluoromethyl)phenyl]sulfonyl}-1-piperazinecarboxylate in 1,4-dioxane (100 ml) was added 4M HCl in 1,4-dioxane (50 ml, 200 mmol) and 3 drops of distilled water. The reaction mixture was stirred overnight. Reaction mixture was then reduced to dryness in vacuo.
Reaction SMILES: C([Li])(C)(C)C.Br[C:7](Br)=[CH:8][CH2:9][C@@H:10]1[C@H:13]([N:14]([CH2:25][C:26]2[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12](=[O:34])[N:11]1[CH2:35][C:36]1[CH:41]=[CH:40][C:39]([O:42][CH3:43])=[CH:38][C:37]=1[O:44][CH3:45]>C1COCC1>[CH3:45][O:44][C:37]1[CH:38]=[C:39]([O:42][CH3:43])[CH:40]=[CH:41][C:36]=1[CH2:35][N:11]1[C@H:10]([CH2:9][C:8]#[CH:7])[C@H:13]([N:14]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)[C:15](=[O:24])[O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:12]1=[O:34]
Reactant: COc1ccc(CN(C(=O)OCc2ccccc2)[C@@H]2C(=O)N(Cc3ccc(OC)cc3OC)[C@@H]2CC=C(Br)Br)cc1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: C#CC[C@@H]1[C@H](N(Cc2ccc(OC)cc2)C(=O)OCc2ccccc2)C(=O)N1Cc1ccc(OC)cc1OC
Reaction time: 0.25 h
Yield: 78.9 %

Procedure:
tert-Butyllithium (0.291 mL, 0.494 mmol) was added to the solution of benzyl ((2R,3S)-2-(3,3-dibromoallyl)-1-(2,4-dimethoxybenzyl)-4-oxoazetidin-3-yl)(4-methoxybenzyl)carbamate (162 mg, 0.235 mmol) in THF (Volume: 3.4 mL) at −78° C. After 15 min, the reaction mixture was quenched with NH4Cl, and diluted with water and EtOAc. The layers were separated, and the organic layer was extracted with EtOAc (2×). Combined organic layers were washed with brine, dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc-Hept, 0-40%) to afford the title compound (98 mg, 79%). LCMS: Rt=1.08 min, m/z=529.3 (M+1) Method 2m_acidic.