Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:7]=1[F:22])[CH3:2].C(N(CC)CC)C.[CH2:40]([O:42][C:43](=[O:46])[CH2:44]Br)[CH3:41]>C1COCC1>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:44][C:43]([O:42][CH2:40][CH3:41])=[O:46])[CH2:20][CH2:21]2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Reactant: CCOC(=O)CBr
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)CN1CCC(Oc2cc(OCC)cc(C(Nc3ccc(C#N)cc3)C(=O)OCC)c2F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 300 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester in 10 ml THF was cooled to 0° C. and treated with 0.14 ml triethylamine and 0.90 ml bromoacetic acid ethyl ester. The reaction mixture was stirred at r.t. overnight, then evaporated. The residue was taken up in water and extracted with EtOAc. The organic layer was dried over MgSO4. The crude product was purified by chromatography on silica with cyclohexane/EtOAc 1:2 to give 215 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-3-(1-ethoxycarbonylmethyl-piperidin-4-yloxy)-2-fluoro-phenyl]-acetic acid ethyl ester as a colorless foam. MS: 528.3 ([M+H]+).
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)[CH2:23][C:24]1[CH:25]=[N:26][NH:27][CH:28]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.C(N(CC)CC)C.[CH:45]1([C:51](Cl)=[O:52])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1>CN(C)C=O>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][CH:17]=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:20]([N:22]([CH2:23][C:24]1[CH:25]=[N:26][N:27]([C:51]([CH:45]2[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]2)=[O:52])[CH:28]=1)[C:29]1[CH:30]=[N:31][C:32]([CH:35]([CH3:37])[CH3:36])=[CH:33][CH:34]=1)=[O:21])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Reactant: O=C(Cl)C1CCCCC1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)c1ccc(N(Cc2cnn(C(=O)C3CCCCC3)c2)C(=O)C2CCCc3c(OCc4ccccc4)cccc32)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 5-benzyloxy-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.72 g) in dimethylformamide (5 mL) were added triethylamine (0.23 mL) and cyclohexanecarbonyl chloride (0.22 mL), and the mixture was stirred at room temperature for one day. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was washed with saturated brine and dried over magnesium sulfate. The solvent was evaporated, and the residue was purified by silica gel column chromatography to give 5-benzyloxy-N-{[1-(cyclohexylcarbonyl)pyrazol-4-yl]methyl}-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.67 g). By the reaction and treatment of this compound in the same manner as in Example 139, N-{[1-(cyclohexanecarbonyl)pyrazol-4-yl]methyl}-5-hydroxy-N-(6-isopropylpyridin-3-yl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.23 g) was obtained.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:20])[C:16]([F:19])([F:18])[F:17])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:21][Mg]Cl.[Cl-].[NH4+]>C(OCC)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([OH:20])([CH3:21])[C:16]([F:17])([F:18])[F:19])=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C[Mg]Cl
Reactant: O=C(c1ccc(OCc2ccccc2)cc1)C(F)(F)F
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Product: CC(O)(c1ccc(OCc2ccccc2)cc1)C(F)(F)F

Procedure:
A solution of 30.0 g (0.107 mol) of 4-(trifluoroacetyl)phenyl benzyl ether in 50 ml of diethyl ether was added dropwise at 0° C. to a solution of 12.0 g (0.161 mol) of methylmagnesium chloride in 150 ml of diethyl ether. After 2 hours at reflux, the mixture was poured into saturated ammonium chloride solution. 31.3 g (99% of theory) were obtained of colorless product.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][CH:4]=1.[CH3:23][O:24]C(Cl)Cl>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][C:8]2[C:16]([CH3:17])=[CH:15][C:14]([N+:18]([O-:20])=[O:19])=[C:13]3[C:9]=2[CH2:10][CH2:11][CH2:12]3)=[CH:5][C:4]=1[CH:23]=[O:24]
Reactant: COC(Cl)Cl
Reactant: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(Oc2c(C)cc([N+](=O)[O-])c3c2CCC3)cc1C=O
Temperature: 0 °C

Procedure:
4-(4-methoxyphenoxy)-5-methyl-7-nitroindane (5.0 g) and dichloromethyl methyl ether (3.02 mL) were dissolved in dichloromethane (50 mL). To the solution was added dropwise titanium tetrachloride (3.67 mL) under ice-cooling with stirring. The reaction mixture was stirred at room temperature under an argon atmosphere for 20 hours. After adding ice water (300 mL), the reaction mixture was extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of sodium hydrogen carbonate and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure. The residue was triturated with hexane (50 mL) and diethyl ether (5 mL), and the insoluble material was collected by filtration and washed with hexane to give the title compound (4.37 g).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[NH2:10][C:11]1[CH:19]=[C:18]([O:20][CH3:21])[CH:17]=[C:16]([O:22][CH3:23])[C:12]=1[C:13]([NH2:15])=[O:14].OS([O-])=O.[Na+].CC1C=CC(S(O)(=O)=O)=CC=1.O>CC(N(C)C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[C:4]1[NH:15][C:13](=[O:14])[C:12]2[C:11](=[CH:19][C:18]([O:20][CH3:21])=[CH:17][C:16]=2[O:22][CH3:23])[N:10]=1
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: O=Cc1ccccc1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=S([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: COc1cc(OC)c2c(=O)[nH]c(-c3ccccc3Cl)nc2c1
Temperature: 140 °C
Yield: 38.9 %

Procedure:
A mixture of 2-chlorobenzaldehyde (0.0430 g, 306 mmol), 2-amino-4,6-dimethoxybenzamide (0.0600 g, 0.306 mmol), NaHSO3 (94%, 0.0474 g, 0.428 mmol), and p-TsOH.H2O (0.0175 g, 0.0918 mmol) in DMA (3.06 mL) was heated at 140° C. for 16 h. The mixture was cooled and chromatographed on silica gel, fractions containing the product were combined, concentrated under vacuum, diluted with EtOAc (300 mL), washed with water (3×75 mL), brine (75 mL), dried over sodium sulfate, filtered and concentrated under vacuum to provide 2-(2-chlorophenyl)-5,7-dimethoxyquinazolin-4(3H)-one (0.0377 g, 39%) as a yellow solid. Selected data: 1H NMR (300 MHz, DMSO-d6) δ 12.14 (s, 1H), 7.65-7.40 (m, 4H), 6.72 (d, J=2.29 Hz, 1H), 6.59 (d, J=2.30 Hz, 1H), 3.87 (s, 3H), 3.85 (s, 3H); MS (APCI) m/z 317 [M+H]+.
Reaction SMILES: C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@H:22]([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12].C(Cl)(Cl)(Cl)Cl.C(=O)=O.[CH3:36][C:37]([CH3:39])=[O:38]>O1CCCC1>[C:11]([O:15][C:16]([NH:18][C@H:19]1[CH2:23][C@@:22]([C:37]([OH:38])([CH3:39])[CH3:36])([C:24]([O:26][CH3:27])=[O:25])[CH:21]=[CH:20]1)=[O:17])([CH3:14])([CH3:13])[CH3:12]
Reactant: CC(C)=O
Reactant: COC(=O)[C@H]1C=C[C@@H](NC(=O)OC(C)(C)C)C1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: O=C=O
Agent: [Li+]
Solvent: C1CCOC1
Solvent: ClC(Cl)(Cl)Cl
Product: COC(=O)[C@@]1(C(C)(C)O)C=C[C@@H](NC(=O)OC(C)(C)C)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 22.3 %

Procedure:
To a 1.00 M solution of lithium hexamethyldisilazide in tetrahydrofuran (45 mL) stirring at −78° C. was added a solution of methyl (1R,4S)-4-[(tert-butoxycarbonyl)amino]cyclopent-2-ene-1-carboxylate (5.0 g, 21 mmol) in tetrahydrofuran (40 mL). The resulting golden mixture was warmed to −28° C. to −23° C. (CCl4/dry ice) and stirred for 30 min. The reaction solution was cooled down to −78° C. and anhydrous acetone (1.8 mL, 25 mmol) was added. After the addition, the reaction mixture was kept in a CCl4/dry ice bath and allowed to warm to room temperature overnight. The dark solution was quenched with saturated NH4Cl and extracted with ether three times. The combined extracts were dried, filtered, concentrated. The crude residue was purified by flash column chromatography (EtOAc/Hexane) to yield the desired product (1.4 g, 22.6%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].C([NH+:22]([CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33])[CH2:23][CH2:24][CH2:25][NH+:26]([CH3:28])[CH3:27])C1C=CC=CC=1>C(O)C.[OH-].[Pd+2].[OH-]>[F:1][C:2]([F:7])([F:6])[C:3]([O-:5])=[O:4].[F:8][C:9]([F:14])([F:13])[C:10]([O-:12])=[O:11].[CH3:28][NH+:26]([CH3:27])[CH2:25][CH2:24][CH2:23][NH2+:22][CH2:29][CH:30]1[CH2:32][CH:31]1[CH3:33]
Reactant: CC1CC1C[NH+](CCC[NH+](C)C)Cc1ccccc1
Agent: [Pd+2]
Agent: O=C([O-])C(F)(F)F
Agent: [OH-]
Solvent: CCO
Product: CC1CC1C[NH2+]CCC[NH+](C)C
Reaction time: 1 h

Procedure:
Coupling In a 100-mL flask acrylic acid (0.17 g, 2.4 mmol), N-benzyl-1-(2-trans-methylcyclopropyl)methanamine (0.5 g, 2.4 mmol) and DIPEA (0.64 g, 4.9 mmol) were dissolved in 20 mL of dichloromethane. To this solution at room temperature EDC (0.68 g, 3.5 mmol) was added as a solid portionwise and stirred 15 hours. The reaction was partitioned between 1M HCl and methylene chloride. The organics were dried over sodium sulfate, filtered, concentrated in vacuo and carried into next reaction crude. Step B: Michael Addition. In a 50-mL flask acrylamide (crude from step A) in methanol (10 mL) was treated with dimethylamine (4.5 mmol, 2.2 mL of a 2M solution in methanol). The reaction was stirred for 1 hour at ambient temperature then concentrated in vacuo. The residue was purified by flash column chromatography (2.5-15% MeOH/methylene chloride) to provide N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)-methyl]-β-alaninamide as a clear oil: 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 5H), 4.68 (m, 2H), 3.21 (m, 2H), 2.67 (m, 4H), 2.34 (s, 3H), 2.24 (s, 3H), 0.97 (m, 3H), 0.58 (m, 2H), 0.29 m, 2H). LCMS [M+H]+=275.4. Step C: Reduction In a round-bottom flask N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)-methyl]-β-alaninamide (0.47 g, 1.7 mmol) was dissolved in 10 mL anhydrous THF. To this solution was added BH3-THF (5.1 mmol, 5.1 mL of a 1M solution in THF). The reaction was equipped with a reflux condenser and heated to reflux for 16 hours. The reaction was cooled to 0° C. and quenched with methanol followed by concentrated HCl (5 mL). The resulting mixture was heated to reflux for 16 hours. The crude mixture was then concentrated in vacuo and partitioned between 10% NaOH/ethyl acetate. The organics were dried over sodium sulfate, filtered and evaporated in vacuo. Purification by reverse phase chromatography gave N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) as a clear oil: LCMS [M+H]+=261.5. Step D: Hydrogenation A solution of N1-benzyl-N3,N3-dimethyl-N1-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) (0.42 g, 0.86 mmol) in ethanol (50 mL) was degassed with nitrogen and treated with palladium hydroxide (75 mg). The reaction was placed under a hydrogen atmosphere and stirred vigorously for 1 hour. The reaction was filtered through celite, washed with methanol and concentrated in vacuo to give N,N-dimethyl-N′-[(2-methylcyclopropyl)methyl]propane-1,3-diaminium bis(trifluoroacetate) as a pale yellow oil.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]3=[C:7]([CH3:16])[C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[Cl:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([Cl:26])[CH:25]=1>>[Cl:19][C:20]1[CH:21]=[C:22]([C:2]2[C:10]3[N:9]4[CH2:11][CH2:12][NH:13][C:14](=[O:15])[C:8]4=[C:7]([CH3:16])[C:6]=3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=2)[CH:23]=[C:24]([Cl:26])[CH:25]=1
Reactant: Cc1c2n(c3c(Br)cc(C#N)cc13)CCNC2=O
Reactant: OB(O)c1cc(Cl)cc(Cl)c1
Product: Cc1c2n(c3c(-c4cc(Cl)cc(Cl)c4)cc(C#N)cc13)CCNC2=O

Procedure:
The title compound, light grey solid (58 mg, 62%), MS (ISN) m/z=368.4 [(M−H)+], mp 347° C., was prepared in accordance with the general method of example 1 from 6-bromo-10-methyl-1-oxo-1,2,3,4-tetrahydro-pyrazino[1,2-a]indole-8-carbonitrile (intermediate 16) (76 mg, 0.25 mmol) and commercially available 3,5-dichloro-phenylboronic acid (62.0 mg, 0.325 mmol).
Reaction SMILES: C(OC(=O)[NH:7][CH2:8][CH2:9][C:10](=[O:13])[NH:11][CH3:12])(C)(C)C.[F:15][C:16]([F:21])([F:20])[C:17]([OH:19])=[O:18]>ClCCl>[NH2:7][CH2:8][CH2:9][C:10]([NH:11][CH3:12])=[O:13].[C:17]([OH:19])([C:16]([F:21])([F:20])[F:15])=[O:18]
Reactant: CNC(=O)CCNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNC(=O)CCN
Temperature: 25 °C
Reaction time: 8 h

Procedure:
(2-Methylcarbamoyl-ethyl)-carbamic acid tert-butyl ester (534 mg, 2.64 mmol) was dissolved in dichloromethane (10 mL) and the solution was treated with trifluoroacetic acid (3 mL). The reaction was allowed to stir overnight at room temperature. The solvent and excess TFA was then concentrated to afford 3-Amino-N-methyl-propionamide as a crude TFA salt. The crude material (270 mg) was used without further purification.
Reaction SMILES: N(OCCC(C)C)=O.N[C:10]1[S:11][CH:12]=[C:13]([C:15](=[N:19][O:20][CH2:21][C:22]([O:24][CH:25]([C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=2)[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[C:16]([OH:18])=[O:17])[N:14]=1>O1CCCC1>[CH:25]([O:24][C:22]([CH2:21][O:20][N:19]=[C:15]([C:13]1[N:14]=[CH:10][S:11][CH:12]=1)[C:16]([OH:18])=[O:17])=[O:23])([C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: Nc1nc(C(=NOCC(=O)OC(c2ccccc2)c2ccccc2)C(=O)O)cs1
Agent: CC(C)CCON=O
Solvent: C1CCOC1
Product: O=C(CON=C(C(=O)O)c1cscn1)OC(c1ccccc1)c1ccccc1
Yield: 48 %

Procedure:
A solution of isopentyl nitrite (5.9 ml) in tetrahydrofuran (50 ml) was dropwise added to a mixture of 2-(2-aminothiazol-4-yl)-2-(benzhydryloxycarbonylmethoxyimino)acetic acid (syn isomer) (10.6 g) in tetrahydrofuran (100 ml) at 50 to 55° C. under stirring and the mixture was stirred at 55 to 60° C. for 30 minutes. Tetrahydrofuran was evaporated in vacuo. The residue was dissolved in a mixture of ethyl acetate and water and the mixture was adjusted to pH 7.5 with 20% aqueous solution of potassium carbonate. The separated aqueous layer was adjusted to pH 2.0 with 10% hydrochloric acid and extracted with ethyl acetate. The extract layer was washed with saturated aqueous solution of sodium chloride, dried over magnesium sulfate and evaporated to give 2-(benzhydryloxycarbonylmethoxyimino)-2-(4-thiazolyl)acetic acid (syn isomer) (4.9 g).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[CH:5]=1)=[O:3].[N+:12]([O-])([OH:14])=[O:13]>O>[CH3:1][C:2]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([O:10][CH3:11])[C:5]=1[N+:12]([O-:14])=[O:13])=[O:3]
Reactant: O=[N+]([O-])O
Reactant: COc1cccc(C(C)=O)c1
Solvent: O
Product: COc1cccc(C(C)=O)c1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 17 h

Procedure:
50.0 g of 3-methoxyacetophenone was slowly added drop-by-drop to 250 ml of 70% nitric acid at room temperature. After 17 hours, the resulting solution was warmed to 40° C. and held for one hour. The mixture was cooled, diluted with three times its volume of water and extracted with ethyl acetate. The extract was washed with water, then brine, dried (NaSO4), and the solvent was evaporated. The residue was dissolved in ethyl acetate. Hexane was added and the mixture was set in dry ice. The solid material that formed was separated and dried under reduced pressure, to give 3-methoxy-2-nitroacetophenone (5A), as a cream colored solid, m.p.: 125°-127° C.
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([OH:9])=O)[CH2:4][CH2:3]1.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.[NH2:43][C@@H:44]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([CH:71]2[S:75](=[O:77])(=[O:76])[NH:74][C:73](=[O:78])[CH2:72]2)=[CH:67][CH:66]=1)[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]1[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=1[C:55]([O:57][CH3:58])=[O:56])=[O:46]>CN(C=O)C>[O:76]=[S:75]1(=[O:77])[CH:71]([C:68]2[CH:67]=[CH:66][C:65]([CH2:64][C@H:44]([NH:43][C:7]([C@@H:5]3[CH2:4][CH2:3][C:2](=[O:1])[NH:6]3)=[O:9])[C:45]([NH:47][CH2:48][CH2:49][CH2:50][CH2:51][O:52][C:53]3[CH:62]=[CH:61][CH:60]=[C:59]([OH:63])[C:54]=3[C:55]([O:57][CH3:58])=[O:56])=[O:46])=[CH:70][CH:69]=2)[CH2:72][C:73](=[O:78])[NH:74]1
Reactant: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@@H](N)Cc1ccc(C2CC(=O)NS2(=O)=O)cc1
Reactant: O=C1CC[C@@H](C(=O)O)N1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1c(O)cccc1OCCCCNC(=O)[C@H](Cc1ccc(C2CC(=O)NS2(=O)=O)cc1)NC(=O)[C@@H]1CCC(=O)N1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14.8 %

Procedure:
To a solution of (2S)-5-oxopyrrolidine-2-carboxylic acid (2.0 mg, 0.015 mmol) in DMF (0.5 mL) was added N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (5.8 mg, 0.015 mmol) and N,N-diisopropylethylamine (0.008 mL, 0.045 mmol) and premixed for 5 minutes. To the solution was added methyl 2-[4-({(2S)-2-amino-3-[4-(1,1-dioxido-3-oxoisothiazolidin-5-yl)phenyl]propanoyl}amino)-butoxy]-6-hydroxybenzoate (8.0 mg, 0.015 mmol) and stirred overnight at room temperature. The product was purified by preparative LCMS to afford the desired product (1.4 mg). LCMS found for C29H35N4O10S (M+H)+: m/z=631.0
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[N:14]=[C:13]([NH:15][C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=3)[C:12]([F:23])=[CH:11][N:10]=2)[CH:5]=[CH:6][CH:7]=1.Br[CH2:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27]>>[NH2:22][C:18]1[CH:17]=[C:16]([NH:15][C:13]2[C:12]([F:23])=[CH:11][N:10]=[C:9]([NH:8][C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([N:1]=[CH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])[CH:3]=3)[N:14]=2)[CH:21]=[CH:20][CH:19]=1
Reactant: CC(C)(C)OC(=O)CBr
Reactant: Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1
Product: CC(C)(C)OC(=O)C=Nc1cccc(Nc2ncc(F)c(Nc3cccc(N)c3)n2)c1

Procedure:
In like manner to the preparation of N2,N4-bis(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine, N2,N4-bis(3-aminophenyl)-5-fluoro-2,4-pyrimidinediamine and tert-butyl bromoacetate were reacted together to give N4-(3-aminophenyl)-N2-(3-tert-butoxycarbonylmethyleneaminophenyl)-5-fluoro-2,4-pyrimidinediamine. LCMS: ret. time: 18.33 min.; purity: 94.5%; MS (m/e): 369.09 (MH+).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)[CH3:2].[Br:14]N1C(=O)CCC1=O.N(C(C)(C)C#N)=NC(C)(C)C#N>C(OCC)(=O)C>[Br:14][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([O:3][CH2:1][CH3:2])=[CH:5][C:6]=1[N+:11]([O-:13])=[O:12]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOc1ccc(C)c([N+](=O)[O-])c1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: CCOC(C)=O
Product: CCOc1ccc(CBr)c([N+](=O)[O-])c1
Temperature: 90 °C
Reaction time: 8 h
Yield: 66.7 %

Procedure:
A mixture of 4-ethoxy-1-methyl-2-nitrobenzene (11.8 g), N-bromosuccinimide (17.4 g), 2,2′-azobisisobutyronitrile (1.07 g) and ethyl acetate (300 mL) was stirred under an argon atmosphere at 90° C. overnight. The solvent was evaporated under reduced pressure, and the residue was diluted with diethyl ether, and the mixture was washed three times with water. The separated organic layer was washed with saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound as a yellow oil (11.3 g).
Reaction SMILES: [C:1]([C:5]1[N:6]=[C:7]([N:16]2[CH2:20][CH2:19][C:18]([F:22])([F:21])[CH2:17]2)[C:8]2[N:13]=[N:12][N:11]([CH2:14][CH3:15])[C:9]=2[N:10]=1)([CH3:4])([CH3:3])[CH3:2].C(C1N=C(N2CCC(F)(F)C2)C2N=NNC=2N=1)(C)(C)C.[Br:43][C:44]1C=[CH:48][CH:47]=[CH:46][C:45]=1CBr>>[Br:43][C:44]1[CH:45]=[CH:46][CH:47]=[CH:48][C:15]=1[CH2:14][N:11]1[C:9]2[N:10]=[C:5]([C:1]([CH3:2])([CH3:3])[CH3:4])[N:6]=[C:7]([N:16]3[CH2:20][CH2:19][C:18]([F:21])([F:22])[CH2:17]3)[C:8]=2[N:13]=[N:12]1
Reactant: BrCc1ccccc1Br
Reactant: CCn1nnc2c(N3CCC(F)(F)C3)nc(C(C)(C)C)nc21
Agent: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nn[nH]c2n1
Product: CC(C)(C)c1nc(N2CCC(F)(F)C2)c2nnn(Cc3ccccc3Br)c2n1

Procedure:
In analogy to the procedure described for the synthesis of 5-tert-butyl-7-(3,3-difluoro-pyrrolidin-1-yl)-3-ethyl-3H-[1,2,3]triazolo[4,5-d]pyrimidine (example 61), the title compound was prepared from 5-tert-butyl-7-(3,3-difluoropyrrolidin-1-yl)-3H-[1,2,3]triazolo[4,5-d]pyrimidine and 1-bromo-2-(bromomethyl)benzene and isolated as colorless gum (6.6 mg, 35%). MS(m/e): 451.3 (MH+).
Reaction SMILES: [Br:1][C:2]1[S:3][C:4]([C:15]([O:17]CC)=[O:16])=[C:5]([CH2:7][C:8]2[CH:13]=[CH:12][C:11]([Cl:14])=[CH:10][CH:9]=2)[N:6]=1.O1CC[CH2:22][CH2:21]1.[OH-].[Li+].O.Cl>CO>[CH2:21]([SH:3]1[C:4]([C:15]([OH:17])=[O:16])=[C:5]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([Cl:14])=[CH:12][CH:13]=2)[N:6]=[C:2]1[Br:1])[CH3:22]
Reactant: CCOC(=O)c1sc(Br)nc1Cc1ccc(Cl)cc1
Reactant: C1CCOC1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC[SH]1C(Br)=NC(Cc2ccc(Cl)cc2)=C1C(=O)O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
In a 100 mL round bottomed flask were placed ethyl 2-bromo-4-(4-chlorobenzyl)-1,3-thiazole-5-carboxylate (955 mg, 2.65 mmol) and tetrahydrofuran (50 mL, 600 mmol). To this solution was added a freshly prepared aqueous solution of lithium hydroxide [(lithium hydroxide.H2O (177 mg, 4.22 mmol) and water (15 mL, 830 mmol)). The mixture was stirred for 4 h at rt then MeOH (20 mL) was added and the mixture was refluxed for 3 h. The mixture was allowed to cool to rt and then acidified by the addition of 1.0N HCl aq (4.5 mL). The mixture was stirred for 1 h at rt. The mixture was then concentrated under reduced pressure until reduced to ca 5 mL volume. EtOAc (50 mL) was added and the mixture was washed with water (50 mL), then brine (50 mL), then was dried over anhydrous MgSO4. Insoluble materials were removed by filtration and the filtrate was concentrated under reduced pressure. The residual yellow crystalline solid was used in the next step without further purification. LC/MS (FA) ES+ 332.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH2:9][N+:10]([O-])=O)[CH:5]=[CH:6][CH:7]=1>[Ni].CO>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:13][Si:14]([CH2:15][CH3:16])([CH2:19][CH3:20])[CH2:17][CH3:18])[CH2:9][NH2:10])[CH:5]=[CH:6][CH:7]=1
Reactant: CC[Si](CC)(CC)OC(C[N+](=O)[O-])c1cccc(Cl)c1
Agent: [Ni]
Solvent: CO
Product: CC[Si](CC)(CC)OC(CN)c1cccc(Cl)c1
Yield: 61.2 %

Procedure:
Raney nickel (1 g) was washed with distilled water five times and methanol three times. [1-(3-Chloro-phenyl)-2-nitro-ethoxy]-triethyl-silane (10 g, 0.032 mol) and Raney nickel in methanol (100 mL) was hydrogenated (35 psi) at room temperature for 14 h. The reaction mixture was filtered through a pad of celite and rinsed with methanol. Concentration of the filtrate to dryness gave the title compound (5.6 g, 62%) as a colorless oil which was used for the next step without purification. 1H NMR (300 MHz, CDCl3) δ 7.32 (1H, s), 7.18-7.26 (3H, m), 4.70 (1H, t, J=5.8 Hz), 2.86 (2H, m), 0.89 (9H, t, J=7.9 Hz), 0.56 (6H, q, J=7.8 Hz). LRMS (M+H)+ m/z 286.