Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]([O:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15]C)=[O:3].[CH3:17]C(O)CCCCCCCCCC.C(Cl)(Cl)=O>>[Cl:1][C:2]([O:4][CH:5]([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH3:15])[CH3:17])=[O:3]
Reactant: CCCCCCCCCCCCOC(=O)Cl
Reactant: CCCCCCCCCCC(C)O
Agent: O=C(Cl)Cl
Product: CCCCCCCCCCC(C)OC(=O)Cl

Procedure:
The procedure is the same as for preparing n-dodecyl chloroformate except freshly distilled 2-dodecanol (41.3 g, 0.222 moles) is added to the phosgene mixture. 99% yields of 2-dodecyl chloroformate are obtained. The product is purified via distillation (90° C. at 0.1 mm Hg). 1H MNR (60 MHz, neat) δ 4.6-4.98 (1H,m), δ 1.5-1.8 (21H,m), δ0.89 (3H, t). IR (neat) 1780 cm-1 (carbonyl).
Reaction SMILES: [C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:16]=[CH:15][C:14](B2OC(C)(C)C(C)(C)O2)=[CH:13][CH:12]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[C:33]1[C:34]([NH:39][C:40](=[O:46])[O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[N:35][N:36]([CH3:38])[CH:37]=1>CN(C)C=O.O>[C:1]([NH:4][CH:5]([CH2:10][C:11]1[CH:12]=[CH:13][C:14]([C:33]2[C:34]([NH:39][C:40]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:46])=[N:35][N:36]([CH3:38])[CH:37]=2)=[CH:15][CH:16]=1)[C:6]([O:8][CH3:9])=[O:7])(=[O:3])[CH3:2]
Reactant: Cn1cc(Br)c(NC(=O)OC(C)(C)C)n1
Reactant: COC(=O)C(Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1)NC(C)=O
Temperature: 85 °C
Reaction time: 8 h

Procedure:
1,1′-bis(diphenylphosphino)ferrocene-palladium(II)dichloride dichloromethane complex (353 mg, 0.43 mmol) was added to a degassed, ambient temperature solution of methyl 2-(acetylamino)-3-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]propanoate (1.5 g, 4.3 mmol), potassium carbonate (2.39 g, 17.3 mmol) and tert-butyl (4-bromo-1-methyl-1H-pyrazol-3-yl)carbamate (1.19 g, 4.3 mmol) in wet N,N-dimethylformamide (40 mL). After stirring at 85° C. overnight, the reaction mixture was cooled, diluted with water and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo. Chromatography over silica eluting with 0-100% acetone/methylene chloride afforded methyl 2-(acetylamino)-3-(4-{3-[(tert-butoxycarbonyl)amino]-1-methyl-1H-pyrazol-4-yl}phenyl)propanoate.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][C@H:9]1[C:13]([NH:15][C:16]1[CH:17]=[C:18]([CH:32]2[N:36]([C:37]3[CH:42]=[CH:41][C:40]([C:43]([CH3:46])([CH3:45])[CH3:44])=[CH:39][CH:38]=3)[CH:35]([C:47]3[CH:52]=[CH:51][C:50]([NH:53][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:55])=[CH:49][CH:48]=3)[CH2:34][CH2:33]2)[CH:19]=[CH:20][C:21]=1[NH:22]CC1C=CC(OC)=CC=1)=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1C(=O)C(C#N)=C(C#N)C(=O)C=1Cl>C(Cl)Cl.O>[NH2:22][C:21]1[CH:20]=[CH:19][C:18]([CH:32]2[N:36]([C:37]3[CH:38]=[CH:39][C:40]([C:43]([CH3:45])([CH3:44])[CH3:46])=[CH:41][CH:42]=3)[CH:35]([C:47]3[CH:48]=[CH:49][C:50]([NH:53][C:54]([C@@H:56]4[CH2:60][CH2:59][CH2:58][N:57]4[C:61]([O:63][C:64]([CH3:67])([CH3:66])[CH3:65])=[O:62])=[O:55])=[CH:51][CH:52]=3)[CH2:34][CH2:33]2)=[CH:17][C:16]=1[NH:15][C:13]([C@@H:9]1[CH2:10][CH2:11][CH2:12][N:8]1[C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])=[O:14]
Reactant: COc1ccc(CNc2ccc(C3CCC(c4ccc(NC(=O)[C@@H]5CCCN5C(=O)OC(C)(C)C)cc4)N3c3ccc(C(C)(C)C)cc3)cc2NC(=O)[C@@H]2CCCN2C(=O)OC(C)(C)C)cc1
Agent: N#CC1=C(C#N)C(=O)C(Cl)=C(Cl)C1=O
Solvent: O
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N1CCC[C@H]1C(=O)Nc1ccc(C2CCC(c3ccc(N)c(NC(=O)[C@@H]4CCCN4C(=O)OC(C)(C)C)c3)N2c2ccc(C(C)(C)C)cc2)cc1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 57.5 %

Procedure:
To a solution of the product from Example 179F (1.06 g, 1.16 mmol) in CH2Cl2 (40 mL) and H2O (2 mL) was added 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) (0.316 g, 1.393 mmol) in several portions. The mixture was stirred at rt for 20 min and was washed with saturated. aq. NaHCO3. The organic layer was dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by column chromatography on silica gel using a solvent gradient of 0-25% EtOAc in hexane to give the title compound (0.53 g, 57%).
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([O:9]C)=[O:8].[O:14](C(OC(C)(C)C)=O)[C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=O.Cl.[Na+].[Cl-]>[OH-].[Na+].O1CCOCC1>[C:18]([O:17][C:15]([NH:1][CH2:2][CH2:3][C:4]1[CH:5]=[C:6]([CH:11]=[CH:12][CH:13]=1)[C:7]([OH:9])=[O:8])=[O:14])([CH3:21])([CH3:20])[CH3:19]
Reactant: COC(=O)c1cccc(CCN)c1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NCCc1cccc(C(=O)O)c1
Temperature: 22 °C
Reaction time: 2 h

Procedure:
To a solution of 1.90 g (10.6 mmol) of methyl 3-(2-aminoethyl)benzoate in 106 mL of 1 N NaOH and 50 mL of dioxane was added 3.47 g (15.9 mmol) of BOC2O in 10 mL of dioxane at 22° C. The solution was stirred for 2 h at 22° C. and then acidified to pH 2 by addition of 1 N HCl. The aqueous/organic mixture was saturated by stirring with solid NaCl and then extracted with DCM (5×100 mL). The combined organic extracts were dried (Na2SO4) and evaporated to give 3-(2-(tert-butoxycarbonylamino)ethyl)benzoic acid as a foamy white solid which was used subsequently without purification.
Reaction SMILES: [S:1]1[CH2:6][CH2:5][CH2:4][S:3][CH:2]1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1.C([Li])CCC.[CH:18]([CH:20]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:23]([C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)[CH2:22][CH2:21]1)=[O:19]>C1COCC1>[OH:19][CH:18]([C:2]1([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=2)[S:3][CH2:4][CH2:5][CH2:6][S:1]1)[CH:20]1[CH2:25][N:24]([C:26]([O:28][C:29]([CH3:31])([CH3:32])[CH3:30])=[O:27])[CH:23]([C:33]2[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=2)[CH2:22][CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CC(C=O)CCC1c1ccccc1
Reactant: c1ccc(C2SCCCS2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CC(C(O)C2(c3ccccn3)SCCCS2)CCC1c1ccccc1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(1,3-dithian-2-yl)pyridine (2.86 g, 14.51 mmol) in THF (80 ml) was added n-butyllithium (6.77 ml, 2.5 M, 16.93 mmol) by syringe at −78° C. The mixture was stirred at −78° C. for 0.5 h, then tert-Butyl 5-formyl-2-phenylpiperidine-1-carboxylate (3.5 g, 12.10 mmol) in THF (15 ml) was added via syringe. The mixture was stirred at −78° C. for 1 h, then quenched with aqueous NH4Cl, and diluted with EtOAc. The organic layer was separated, washed with brine, dried over MgSO4, filtered and concentrated in vacuo. LC-MS m/e 487.03 [M+1]+.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH:8]=O)=[CH:6][CH:5]=[CH:4][N:3]=1.[C:10]1([C:16]([CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=O)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.N1CCCCC1>>[C:10]1([C:16]2[C:18]([C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=3)=[CH:8][C:7]3[C:2](=[N:3][CH:4]=[CH:5][CH:6]=3)[N:1]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Nc1ncccc1C=O
Reactant: O=C(Cc1ccccc1)c1ccccc1
Solvent: C1CCNCC1
Product: c1ccc(-c2cc3cccnc3nc2-c2ccccc2)cc1
Temperature: 120 °C

Procedure:
A suspension comprising 2-amino-pyridine-3-carbaldehyde (5 g, 40.9 mmol) and deoxybenzoin (8.03 g, 40.9 mmol) in piperidine (4.46 ml, 45.0 mmol) was heated at 120° C. overnight. The resulting solution was partitioned between DCM (200 ml) and water (200 ml). The organic layer was separated and washed with water (2×150 ml), brine, dried over MgSO4, filtered and concentrated in vacuo. The crude product was purified by chromatography on silica eluting with 0-50% EtOAc in iso-hexane to afford the title product as a yellow solid;
Reaction SMILES: [C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH:17]=C)[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:4])([CH3:3])[CH3:2].[O:25]1CCCC1.C([O-])([O-])=O.[K+].[K+].I([O-])(=O)(=O)=O.[Na+]>C(OCC)(=O)C.O>[C:1]([O:5][C:6](=[O:24])[NH:7][C:8]1[CH:9]=[C:10]2[C:22](=[O:23])[NH:21][N:20]=[CH:19][C:12]3=[C:13]([CH:17]=[O:25])[NH:14][C:15]([CH:16]=1)=[C:11]23)([CH3:2])([CH3:3])[CH3:4]
Reactant: C=Cc1[nH]c2cc(NC(=O)OC(C)(C)C)cc3c2c1C=NNC3=O
Reactant: C1CCOC1
Agent: O=C([O-])[O-]
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Nc1cc2c3c(c(C=O)[nH]c3c1)C=NNC2=O
Yield: 22 %

Procedure:
To a solution of the title compound of Example 164 (48 mg, 0.146 mmol) in 1:1 tetrahydrofuran:H2O (4 mL) was added K2CO3 (30 mg, 0.219 mmol), K2OSO2(OH)4 (7 mg) and K3Fe(CN)6 (72 mg, 0.219 mmol). The mixture was stirred at room temperature for 2 hours whereupon water and ethyl acetate were added. Following extractive work-up, the organic layer was then dried, filtered, and concentrated. The residue was dissolved in 1:1 tetrahydrofuran:H2O (2 mL) and sodium periodate (156 mg, 50.73 mmol) was added. The mixture was stirred at room temperature for 30 min whereupon water and ethyl acetate were added. Following extractive work-up, the organic layer was then dried, filtered, and concentrated. Silica gel chromatography of the residue, eluting with 30% ethyl acetate in hexane gave Intermediate 230(a) as a pale yellow solid (11 mg, 0.034 mmol) in 22% yield.
Reaction SMILES: C([NH:3][C:4]1[S:5][C:6]([Br:36])=[C:7]([C:9](=[N:33][O:34][CH3:35])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH:20]([S:22][C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1)=O.[ClH:37]>>[ClH:37].[NH2:3][C:4]1[S:5][C:6]([Br:36])=[C:7]([C:9](=[N:33][O:34][CH3:35])[C:10]([NH:12][CH:13]2[C:31](=[O:32])[N:15]3[C:16]([C:28]([OH:30])=[O:29])=[C:17]([CH:20]([S:22][C:23]4[NH:27][N:26]=[N:25][N:24]=4)[CH3:21])[CH2:18][S:19][C@H:14]23)=[O:11])[N:8]=1
Reactant: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nc(NC=O)sc1Br
Agent: Cl
Product: CON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C(C)Sc3nnn[nH]3)CS[C@H]12)c1nc(N)sc1Br

Procedure:
7-[2-(2-Formamido-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid (syn isomer, 700 mg.) was treated with conc. hydrochloric acid (1 ml.) in a similar manner to that of Example 1-(2) to give 7-[2-(2-amino-5-bromothiazol-4-yl)-2-methoxyiminoacetamido]-3-(1-methyl-1H-tetrazol-5-ylthiomethyl)-3-cephem-4-carboxylic acid hydrochloride (syn isomer, 660 mg.).
Reaction SMILES: [Br:1]C1CC2C(=CC=CC=2F)C1=O.[Cl:13][C:14]1[CH:22]=[C:21]([Cl:23])[CH:20]=[C:19]2[C:15]=1[CH2:16][CH2:17][C:18]2=[O:24]>[Cu](Br)Br.O1CCOCC1>[Br:1][CH:17]1[CH2:16][C:15]2[C:19](=[CH:20][C:21]([Cl:23])=[CH:22][C:14]=2[Cl:13])[C:18]1=[O:24]
Reactant: O=C1c2cccc(F)c2CC1Br
Reactant: O=C1CCc2c(Cl)cc(Cl)cc21
Agent: Br[Cu]Br
Solvent: C1COCCO1
Product: O=C1c2cc(Cl)cc(Cl)c2CC1Br

Procedure:
The 2-bromo-4,6-dichloro-1-indanone is prepared as in Example 14 for the preparation of 2-bromo-4-fluoro-1-indanone but starting with 21.6 g of 4,6-dichloro-1-indanone, 63.56 g of copper bromide and 690 ml of dioxane. 14.5 g of 2-bromo-4,6-dichloro-1-indanone are obtained which melt at 80° C.
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[NH2:7][CH2:8][C:9]1[CH:17]=[CH:16][C:12]([C:13]([OH:15])=[O:14])=[CH:11][CH:10]=1.[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])N1C(OCC)=O.Cl>O>[O:18]=[C:19]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21](=[O:28])[N:7]1[CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:13]([OH:15])=[O:14])=[CH:16][CH:17]=1
Reactant: NCc1ccc(C(=O)O)cc1
Reactant: CCOC(=O)N1C(=O)c2ccccc2C1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: O=C(O)c1ccc(CN2C(=O)c3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Into a 250-mL 3-necked round-bottom flask, was placed sodium carbonate (3.7 g, 34.91 mmol, 0.54 equiv), water (66 mL), 4-(aminomethyl)benzoic acid (9.7 g, 64.17 mmol, 1.00 equiv) and ethyl 1,3-dioxo-2,3-dihydro-1H-isoindole-2-carboxylate (14.6 g, 66.61 mmol, 1.04 equiv). The resulting solution was stirred for 3 h at 25° C. The pH value of the solution was adjusted to 4 with hydrogen chloride (1 mol/L). The solids were collected by filtration. The filter cake was washed with 1×100 mL of water. This resulted in 15.7 g (87%) of 4-[(1,3-dioxo-2,3-dihydro-1H-isoindol-2-yl)methyl]benzoic acid as a white solid. MS (ESI) m/z 282 ([M+H]+).
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:17][C@H:18]([C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([O:26]C)[CH:21]=2)[CH3:19])=[N:4][C:5]([NH:8][C:9]2[CH:10]=[C:11]([CH2:15]O)[CH:12]=[CH:13][CH:14]=2)=[N:6][CH:7]=1.B(Br)(Br)[Br:29].O.CCOC(C)=O>C(Cl)Cl>[Br:29][CH2:15][C:11]1[CH:10]=[C:9]([NH:8][C:5]2[N:4]=[C:3]([NH:17][C@H:18]([C:20]3[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=3)[CH3:19])[C:2]([Cl:1])=[CH:7][N:6]=2)[CH:14]=[CH:13][CH:12]=1
Reactant: COc1cccc([C@H](C)Nc2nc(Nc3cccc(CO)c3)ncc2Cl)c1
Reactant: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: O
Product: C[C@H](Nc1nc(Nc2cccc(CBr)c2)ncc1Cl)c1cccc(O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
To a solution of {3-[(5-chloro-4-{[(1S)-1-(3-methoxyphenyl)ethyl]amino}pyrimidin-2-yl)amino]phenyl}methanol (0.30 g, 0.78 mmol) in methylene chloride (5.0 mL) was added slowly a solution of boron tribromide in methylene chloride (3.9 mL, 3.9 mmol, 1.0 M) at 0° C. The mixture was allowed to warm up to rt and stirred overnight. The resultant mixture was cooled in a dry ice bath when water was added. The mixture was allowed to warm up to rt. Water and EtOAc were added. The aqueous layer was extracted with EtOAc twice. The combined organic layers were dried over Na2SO4, filtered, and concentrated (then triturated with cold EtOAc) to give the desired product as a white powder (0.255 g, 75%). LCMS for C19H19BrClN4O (M+H)+: m/z=433.0, 435.0.
Reaction SMILES: Br[CH2:2][C:3]1[C:7]([CH3:8])=[CH:6][O:5][N:4]=1.[CH2:9]([NH2:11])[CH3:10]>C1COCC1>[CH3:8][C:7]1[C:3]([CH2:2][NH:11][CH2:9][CH3:10])=[N:4][O:5][CH:6]=1
Reactant: Cc1conc1CBr
Reactant: CCN
Solvent: C1CCOC1
Product: CCNCc1nocc1C

Procedure:
prepared by reaction of the commercially available 3-bromomethyl-4-methyl-isoxazole with 2M ethylamine in THF.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[CH3:12].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1.CN(C)C1C=CN=CC=1>[C:13]([O:1][C:2]1[C:3]([CH3:12])=[CH:4][C:5]([C:6]([OH:8])=[O:7])=[CH:9][C:10]=1[CH3:11])(=[O:15])[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 4-hydroxy-3,5-dimethyl-benzoic acid (1) (5.41 g, 32.5 mmol) in anhydrous pyridine (50 mL) were added acetic anhydride and 4-dimethylaminopyridine (0.1 g, 0.8 mmol). The reaction mixture was stirred at room temperature for 16 hours. Pyridine was evaporated under reduced pressure. The residue was taken in ethyl acetate (300 mL). The organic phase was washed with 2 N aq. HCl (100 mL), water (2×100 mL), brine (100 mL) and dried over anhydrous Na2SO4. Solvent was evaporated to give 4-acetoxy-3,5-dimethylbenzoic acid (2) as an off-white solid. Yield: 6.65 g (98%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]1[CH2:13][CH2:12][C@:11]([CH2:17][CH2:18][O:19][CH3:20])([C:14]([OH:16])=O)[CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.Cl.[F:23][C:24]([F:38])([F:37])[C:25]1[CH:30]=[CH:29][N:28]=[C:27]([N:31]2[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]2)[CH:26]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>CN(C=O)C.C(Cl)Cl>[CH3:20][O:19][CH2:18][CH2:17][C@:11]1([C:14]([N:34]2[CH2:35][CH2:36][N:31]([C:27]3[CH:26]=[C:25]([C:24]([F:38])([F:23])[F:37])[CH:30]=[CH:29][N:28]=3)[CH2:32][CH2:33]2)=[O:16])[CH2:12][CH2:13][C@@H:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:2])([CH3:3])[CH3:4])[CH2:10]1
Reactant: COCC[C@]1(C(=O)O)CC[C@@H](NC(=O)OC(C)(C)C)C1
Reactant: FC(F)(F)c1ccnc(N2CCNCC2)c1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COCC[C@]1(C(=O)N2CCN(c3cc(C(F)(F)F)ccn3)CC2)CC[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 72 h
Yield: 52.4 %

Procedure:
(1S,3R)-3-[(tert-Butoxycarbonyl)amino]- 1 -(2-methoxyethyl)cyclopentanecarboxylic acid (276.6 mg, 0.96 mmol) , 1-[4-(trifluoromethyl)pyridin-2-yl]piperazine dihydrochloride (322.0 mg, 1.06 mmol) , triethylamine (0.54 mL, 3.85 mmol) and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (547.6 mg, 1.44 mmol) (HBTU) were mixed in dry DMF (6.6 mL) and the resultanting brown solution was stirred at room temperature under N2 for three days. The reaction mixture was diluted with CH2Cl2, and washed with saturated Na2CO3. The aqueous layer was extracted with CH2Cl2 four times. The combined organic layers were dried (MgSO4), filtered, concentrated and purified by flash chromatography (EtOAc/Hexane) to provide the desired product (252 mg, 52%). MS calculated for C24H36F3N4O4(M+H) 501.3; found 401.3 (M+H-Boc).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14](S(C)(=O)=O)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29].[CH:30]1([NH2:36])[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]1>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[CH2:18][C:17]2[C:12](=[N:13][C:14]([NH:36][CH:30]3[CH2:35][CH2:34][CH2:33][CH2:32][CH2:31]3)=[N:15][CH:16]=2)[N:11]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[C:10]1=[O:29]
Reactant: NC1CCCCC1
Reactant: CS(=O)(=O)c1ncc2c(n1)N(c1ccccc1)C(=O)N(c1c(Cl)cccc1Cl)C2
Solvent: ClCCl
Product: O=C1N(c2c(Cl)cccc2Cl)Cc2cnc(NC3CCCCC3)nc2N1c1ccccc1
Yield: 96.1 %

Procedure:
A solution of 100 mg (0.22 mmol) of 3-(2,6-dichlorophenyl)-7-methanesulfonyl-1-phenyl-3,4-dihydro-1H-pyrimido[4,5-d]pyrimidin-2-one and 300 μl (2.4 mmol) of cyclohexylamine in 2 ml of dichloromethane was stirred at room temperature overnight. The mixture was diluted with 10 ml of dichloromethane, washed with 10 ml of 2M hydrochloric acid and with 10 ml of saturated aqueous sodium bicarbonate solution, dried over magnesium sulfate, filtered and evaporated. 99 mg (96%) of 3-(2,6-dichlorophenyl)-7-cyclohexylamino-3,4-dihydro-1-phenylpyrimido[4,5-d]pyrimidin-2(1H)-one were isolated as a white foam of melting point 258-259° C.
Reaction SMILES: N#N.Cl[C:4]1[N:9]=[N:8][C:7]([N:10]2[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]2)=[C:6]([CH3:25])[C:5]=1[CH3:26].[F:27][C:28]1[CH:33]=[CH:32][C:31](B(O)O)=[CH:30][CH:29]=1.[F-].[Cs+]>O1CCOCC1>[F:27][C:28]1[CH:33]=[CH:32][C:31]([C:4]2[N:9]=[N:8][C:7]([N:10]3[CH2:15][CH2:14][CH:13]([N:16]([CH3:24])[C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH2:12][CH2:11]3)=[C:6]([CH3:25])[C:5]=2[CH3:26])=[CH:30][CH:29]=1
Reactant: Cc1c(Cl)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Reactant: OB(O)c1ccc(F)cc1
Agent: N#N
Agent: [Cs+]
Agent: [F-]
Solvent: C1COCCO1
Product: Cc1c(-c2ccc(F)cc2)nnc(N2CCC(N(C)C(=O)OC(C)(C)C)CC2)c1C
Temperature: 95 °C
Yield: 86.8 %

Procedure:
Treat a N2 degassed mixture of tert-butyl 1-(6-chloro-4,5-dimethylpyridazin-3-yl)piperidin-4-yl(methyl)carbamate (3.01 g, 8.48 mmol), 4-fluorophenylboronic acid (1.23 g, 8.80 mmol) and CsF (4.08 g, 26.8 mmol) in 1,4-dioxane (80 mL) with (1,1′-bis(diphenylphosphino)ferrocene)palladium(II) chloride (1.10 g, 1.35 mmol). Heat the resulting mixture under N2 at 95° C. overnight. Partition the reaction mixture between H2O and EtOAc. Separate the layers, and wash the organic layer with brine. Dry the organic layer over Na2SO4, filter, and concentrate under reduced pressure. Purify the residue by flash silica gel chromatography (gradient of 20 to 80% EtOAc in hexanes) to provide the title compound (3.05 g, 87%). ES/MS m/z 415.2 (M+1).
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]=[CH:13][CH:14]=[CH:15][CH3:16])=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].[C:17](#[N:22])/[CH:18]=[CH:19]/[C:20]#[N:21]>>[CH2:1]([O:5][C:6]1[CH:7]=[CH:8][C:9]([C:12]2[CH:13]=[CH:14][C:15]([CH3:16])=[C:19]([C:20]#[N:21])[C:18]=2[C:17]#[N:22])=[CH:10][CH:11]=1)[CH2:2][CH2:3][CH3:4]
Reactant: N#C/C=C/C#N
Reactant: CC=CC=Cc1ccc(OCCCC)cc1
Product: CCCCOc1ccc(-c2ccc(C)c(C#N)c2C#N)cc1

Procedure:
Using 1-(p-n-butoxyphenyl)-4-methyl-1,3-butadiene and fumaronitrile, 3-(p-n-butoxyphenyl)-6-methylphthalonitrile was obtained by the same method as in Example 1. m.p. was 151.5° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([CH3:36])([CH3:35])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([NH:16][C:17]2[C:22]([CH2:23][NH:24][C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:21][N:20]=[C:19]([S:33][CH3:34])[N:18]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[C:45](Cl)(Cl)=[O:46].C(OCC)(=O)C>C1(C)C=CC=CC=1.O>[C:1]([O:5][C:6](=[O:37])[NH:7][C:8]([CH3:36])([CH3:35])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N:16]2[C:17]3=[N:18][C:19]([S:33][CH3:34])=[N:20][CH:21]=[C:22]3[CH2:23][N:24]([C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])[C:45]2=[O:46])[CH:11]=1)([CH3:3])([CH3:4])[CH3:2]
Reactant: O=C(Cl)Cl
Reactant: CSc1ncc(CNc2c(Cl)cccc2Cl)c(Nc2cccc(CC(C)(C)NC(=O)OC(C)(C)C)c2)n1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CSc1ncc2c(n1)N(c1cccc(CC(C)(C)NC(=O)OC(C)(C)C)c1)C(=O)N(c1c(Cl)cccc1Cl)C2
Yield: 100 %

Procedure:
A solution of 320 mg (0.6 mmol) of (2-(3-[5-[(2,6-dichlorophenylamino)-methyl]-2-methylthiopyrimidin-4-yl-amino]-phenyl)-1,1-dimethyl-ethyl)-carbamic acid tert-butyl ester in 40 ml of toluene was treated with 0.25 ml (1.8 mmol) of triethylamine and the resulting solution was added dropwise to a solution of phosgene (0.6 ml of a 20% solution in toluene) in a further 40 ml of toluene. The mixture was heated at reflux for 1 hour and then cooled. 80 ml of ethyl acetate and 80 ml of water were added. The organic phase was dried over magnesium sulfate, filtered and evaporated to give 350 mg (100%) of (2-[3-[3-(2,6-dichlorophenyl)-7-methylthio-2-oxo-3,4-dihydro-2H-pyrimido[4,5-d]pyrimidin-1-yl]-phenyl]-1,1-dimethylethyl)-carbamic acid tert-butyl ester as a white solid. [Mass spectrum (ESI) MH+ =588].
Reaction SMILES: Br[CH:2]1[CH2:7][CH2:6][CH2:5][CH:4]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:3]1=O.[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH2:30])=[S:29])=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1>C(O)C.CCOC(C)=O>[Cl:15][C:16]1[N:17]=[CH:18][N:19]([C:21]2[CH:26]=[CH:25][C:24]([NH:27][C:28]3[S:29][C:2]4[CH2:7][CH2:6][CH2:5][CH:4]([C:8]5[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=5)[C:3]=4[N:30]=3)=[CH:23][C:22]=2[O:31][CH3:32])[CH:20]=1
Reactant: O=C1C(Br)CCCC1c1ccccc1
Reactant: COc1cc(NC(N)=S)ccc1-n1cnc(Cl)c1
Solvent: CCOC(C)=O
Solvent: CCO
Product: COc1cc(Nc2nc3c(s2)CCCC3c2ccccc2)ccc1-n1cnc(Cl)c1
Yield: 26 %

Procedure:
A mixture of 2-bromo-6-phenylcyclohexanone (89 mg, 0.352 mmol, from preparation AAA) and 1-(4-(4-chloro-1H-imidazol-1-yl)-3-methoxyphenyl)thiourea (99 mg, 0.352 mmol, from step 4 of preparation A) was heated in ethanol (0.60 mL) at 80° C. for 3 h. The crude reaction was diluted with EtOAc and washed with saturated sodium bicarbonate solution. The organic layer was concentrated in vacuo. The crude product was purified using preparatory TLC (60% acetone/hexanes) to give 42 mg (26% yield) of the titled compound as a white solid. LC-MS (M+H)+ 437.0. 1H NMR (400 MHz, chloroform-d) δ ppm 7.50 (d, J=1.51 Hz, 1 H) 7.45 (d, J=2.52 Hz, 1 H) 7.28-7.36 (m, 2 H) 7.14-7.23 (m, 3H) 7.08 (d, J=8.31 Hz, 1 H) 7.00 (d, J=1.51 Hz, 1 H) 6.60 (dd, J=8.44, 2.39 Hz, 1 H) 4.05 (t, J=6.30 Hz, 1H) 3.47 (s, 3 H) 2.68-2.89 (m, 2 H) 2.20-2.28 (m, 1 H) 1.98 (dd, J=7.30, 5.29 Hz, 1 H) 1.78-1.93 (m, 2 H).