Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([O:22]C(C4C=CC=CC=4)C4C=CC=CC=4)=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1.C1(OC)C=CC=CC=1.FC(F)(F)C(O)=O.C(OC(C)C)(C)C>C(Cl)Cl>[NH2:1][C:2]1[S:3][CH:4]=[C:5]([C:7](=[N:38][O:39][CH3:40])[C:8]([NH:10][CH:11]2[C:36](=[O:37])[N:13]3[C:14]([C:20]([OH:22])=[O:21])=[C:15]([CH:18]=[CH2:19])[CH2:16][S:17][C@H:12]23)=[O:9])[N:6]=1
Reactant: C=CC1=C(C(=O)OC(c2ccccc2)c2ccccc2)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Solvent: ClCCl
Solvent: CC(C)OC(C)C
Solvent: O=C(O)C(F)(F)F
Product: C=CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NOC)c3csc(N)n3)[C@H]2SC1
Temperature: 25 °C

Procedure:
To a suspension of benzhydryl 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylate (syn isomer)(0.9 g) in methylene chloride (10 ml) and anisole (0.66 g) was added trifluoroacetic acid (2.5 g) under ice-cooling, followed by stirring at ambient temperature for an hour. The reaction mixture was added dropwise to diisopropyl ether (100 ml), and the precipitates were collected by filtration and suspended in a mixture of ethyl acetate and water, followed by adjusting to pH 7 with a saturated aqueous sodium bicarbonate. The separated aqueous solution was saturated with sodium chloride, and thereto was added a mixed solvent of ethyl acetate and tetrahydrofuran (8:2 by volume). After adjusting to pH 3.2 with 10% hydrochloric acid, the organic layer was separated out, washed with a saturated aqueous sodium chloride and then dried over magnesium sulfate. Removal of the solvent gave a residue, which was washed with diisopropyl ether to obtain 7-[2-(2-aminothiazol-4-yl)-2-methoxyiminoacetamido]-3-vinyl-3-cephem-4-carboxylic acid (syn isomer (0.4 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([O:11][CH3:12])[CH:8]=[C:7]([O:13][CH3:14])[C:3]=1[C:4]([NH2:6])=[O:5].[C:15]([C:19]1[CH:20]=[C:21]([CH:24]=[C:25]([C:28]([CH3:31])([CH3:30])[CH3:29])[C:26]=1[OH:27])[CH:22]=O)([CH3:18])([CH3:17])[CH3:16].COC1C=C(OC)C=C2C=1C(=O)NC(C1C=CC=CN=1)=N2>>[C:28]([C:25]1[CH:24]=[C:21]([C:22]2[NH:6][C:4](=[O:5])[C:3]3[C:2](=[CH:10][C:9]([O:11][CH3:12])=[CH:8][C:7]=3[O:13][CH3:14])[N:1]=2)[CH:20]=[C:19]([C:15]([CH3:18])([CH3:17])[CH3:16])[C:26]=1[OH:27])([CH3:31])([CH3:30])[CH3:29]
Reactant: COc1cc(N)c(C(N)=O)c(OC)c1
Reactant: CC(C)(C)c1cc(C=O)cc(C(C)(C)C)c1O
Agent: COc1cc(OC)c2c(=O)[nH]c(-c3ccccn3)nc2c1
Product: COc1cc(OC)c2c(=O)[nH]c(-c3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)nc2c1
Yield: 41 %

Procedure:
2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one was synthesized from 2-amino-4,6-dimethoxybenzamide and 3,5-di-tert-butyl-4-hydroxybenzaldehyde, using the method described for 5,7-dimethoxy-2-(pyridin-2-yl)quinazolin-4(3H)-one. 2-(3,5-di-tert-butyl-4-hydroxyphenyl)-5,7-dimethoxyquinazolin-4(3H)-one (130 mg, 41%) was isolated as a light yellow solid. Selected data: MS (m/z): 411.17; MP 229.7-230.5° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:11])[CH2:7][CH:6]([OH:8])[CH2:5][C:4]([CH3:10])([CH3:9])[NH:3]1.Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]>C(#N)C>[CH2:13]([N:3]1[C:4]([CH3:10])([CH3:9])[CH2:5][CH:6]([OH:8])[CH2:7][C:2]1([CH3:11])[CH3:1])[CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: CCCCCCBr
Solvent: CC#N
Product: CCCCCCN1C(C)(C)CC(O)CC1(C)C

Procedure:
258.9 Parts of 2,2,6,6-tetramethylpiperidin-4-ol, 540 parts of bromohexane and 1000 parts of acetonitrile were heated at reflux for 72 hours. After cooling the solid was filtered off and the filtrate evaporated in vacuo to yield a semi-solid material. Addition of petroleum ether of boiling range 40° to 60°C gave further precipitation and the solution was filtered once more. Evaporation in vacuo of the filtrate gave a liquid which was distilled at 116°C/0.1 mm to give 106.1 parts of 1-n-hexyl-2,2,6,6-tetramethylpiperidin-4-ol. This material gave the following elemental analysis by weight:
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5]([O:10]C2C=CC(OC)=CC=2)=[N:4][CH:3]=1.[N+]([O-])([O-])=O.[Ce+3].[NH4+].[NH4+].[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.[N+]([O-])([O-])=O.C1(C)C=CC=CC=1.S([O-])([O-])(=O)=S.[Na+].[Na+]>C(#N)C.O>[F:1][C:2]1[N:7]=[C:6]([C:8]#[N:9])[C:5](=[O:10])[NH:4][CH:3]=1
Reactant: COc1ccc(Oc2ncc(F)nc2C#N)cc1
Agent: O=S([O-])([O-])=S
Agent: O=[N+]([O-])[O-]
Agent: [Ce+3]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: O
Product: N#Cc1nc(F)c[nH]c1=O

Procedure:
In a mixture of 30 mL of acetonitrile and 20 mL of water was dissolved 1.0 g of 6-fluoro-3-(4-methoxyphenoxy)-2-pyrazinecarbonitrile. After adding 11.2 g of diammonium cerium nitrate, the mixture was heated under reflux for 3 hours. The reaction mixture was returned to room temperature, a mixture consisting of 50 mL of toluene, 50 mL of water and 10 mL of 5% aqueous solution of sodium thiosulfate was added to the reaction mixture, and the aqueous layer was separated. Ethyl acetate (50 mL) was added to the aqueous layer thus obtained, and the organic layer was separated. The organic layer thus obtained was washed with saturated aqueous solution of sodium chloride, treated with active charcoal, and dried on anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. Thus, 6-fluoro-3-oxo-3,4-dihydro-2-pyrazinecarbonitrile was obtained as a yellow-colored solid product.
Reaction SMILES: [NH:1]([C:8](=[O:30])[CH2:9][N:10]([CH2:20][C:21](=[O:29])[NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:11]1[CH:19]=[CH:18][C:14]([C:15](O)=[O:16])=[CH:13][CH:12]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.[CH:35]1[CH:36]=[CH:37][C:38]2[N:43](O)N=[N:41][C:39]=2[CH:40]=1.C1(N)C=CC=CC=1N>CN(C=O)C.CCOC(C)=O>[NH2:41][C:39]1[CH:40]=[CH:35][CH:36]=[CH:37][C:38]=1[NH:43][C:15](=[O:16])[C:14]1[CH:18]=[CH:19][C:11]([N:10]([CH2:9][C:8]([NH:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:30])[CH2:20][C:21](=[O:29])[NH:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)=[CH:12][CH:13]=1
Reactant: On1nnc2ccccc21
Reactant: O=C(CN(CC(=O)Nc1ccccc1)c1ccc(C(=O)O)cc1)Nc1ccccc1
Agent: Nc1ccccc1N
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: Nc1ccccc1NC(=O)c1ccc(N(CC(=O)Nc2ccccc2)CC(=O)Nc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of 4-[bis(2-anilino-2-oxoethyl)amino]benzoic acid (20 mg, 0.050 mmol) in DMF was added EDC (28 mg, 0.149 mmol), HOBt (20 mg, 0.149 mmol) and phenylenediamine (27 mg, 0.248 mmol) and the reaction was allowed to stir at room temperature for 12 hours. The crude reaction mixture was diluted with EtOAc (25 mL) and then washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude residue was purified by reverse-phase chromatography (30-100% MeCN/H2O with 0.05% TFA). The appropriate fractions were combined, diluted with EtOAc (20 mL) and washed with sat.'d aq. NaHCO3 (1×10 mL). The organic layer was dried over MgSO4, filtered, and concentrated in vacuo and gave the desired N-(2-aminophenyl)-4-[bis(2-anilino-2-oxoethyl)amino]benzamide: 1H NMR (600 MHz, DMSO-d6) δ 10.90 (s, 2H), 9.31 (s, 1H), 7.83 (d, J=9.0 Hz, 2H), 7.64 (dd, J=8.6, 1.0 Hz, 4H), 7.33 (m, 4H), 7.07 (m, 3H), 6.89 (t, J=7.8 Hz, 1H), 6.70 (d, J=7.8 Hz, 1H), 6.60 (d, 9.1 Hz, 1H), 6.53 (t, J=7.2 Hz, 1H), 4.79 (s, 2H), 4.42 (s, 4H); MS: cal'd 494.2 (MH+), exp 494.2 (MH+).
Reaction SMILES: [NH2:1][C@H:2]([C:35]([O:37][CH3:38])=[O:36])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-:20])=[O:19])=[CH:14][CH:13]=1)=[O:9].[CH3:39]I>C(#N)C.C(OCC)(=O)C>[CH3:38][O:37][C:35]([C@@H:2]([NH:1][CH3:39])[CH2:3][S:4][CH2:5][C:6]1[C:24]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:27])[CH3:28])=[CH:23][C:22]([O:33][CH3:34])=[CH:21][C:7]=1[C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][C:15]([N+:18]([O-:20])=[O:19])=[CH:16][CH:17]=1)=[O:9])=[O:36]
Reactant: COC(=O)[C@@H](N)CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1
Reactant: CI
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CN[C@@H](CSCc1c(O[Si](C)(C)C(C)(C)C)cc(OC)cc1C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)OC
Yield: 26.7 %

Procedure:
A solution of 1.90 g of p-nitrobenzyl (R)-2-[[[2-amino-2-methoxycarbonyl-ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate and 0.91 g of methyl iodide in 5 ml of acetonitrile was stirred at room temperature for 3 hours. The solution was diluted with ethyl acetate and washed successively with saturated sodium bicarbonate solution and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residual oil was chromatographed on silica gel using ethyl acetate/hexane (1:1, v/v) as eluent to yield 0.52 g of p-nitrobenzyl (R)-2-[[[2-methoxycarbonyl-2-(methylamino)ethyl]thio]methyl]-3-(tert-butyldimethylsilyloxy)-5-methoxybenzoate as an oil.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([CH2:11][CH3:12])[CH2:9][CH3:10])=[CH:4][C:3]=1[C:13]1[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=1)[C:16]([NH:18][CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:29])([F:28])[F:27])[CH:21]=1)=[O:17].[I:33][C:34]1[CH:35]=[C:36]([CH:40]=[CH:41][CH:42]=1)[C:37](O)=[O:38].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C.CCOC(C)=O>[CH2:9]([N:8]([CH2:11][CH3:12])[C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:37](=[O:38])[C:36]2[CH:40]=[CH:41][CH:42]=[C:34]([I:33])[CH:35]=2)=[C:3]([C:13]2[CH:14]=[C:15]([CH:30]=[CH:31][N:32]=2)[C:16]([NH:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([F:27])([F:28])[F:29])[CH:21]=2)=[O:17])[CH:4]=1)[CH3:10]
Reactant: O=C(O)c1cccc(I)c1
Reactant: CCN(CC)c1ccc(N)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Product: CCN(CC)c1ccc(NC(=O)c2cccc(I)c2)c(-c2cc(C(=O)NCc3cccc(C(F)(F)F)c3)ccn2)c1
Reaction time: 1 h
Yield: 106.8 %

Procedure:
To a solution of 2-(2-amino-5-(diethylamino)phenyl)-N-(3-(trifluoromethyl)benzyl)isonicotinamide (440 mg, 1.0 mmol), 3-iodobenzoic acid (248 mg, 1.0 mmol) and DIPEA (387 mg, 3.0 mmol) in DMF (5 mL) was added HATU (418 mg, 1.1 mmol). After one hour, the reaction mixture was added to EtOAc (150 mL) washed with water (5×50 mL) and saturated aqueous NaCl (25 mL), dried (Na2SO4) and concentrated. The residue was triturated with DCM (3 mL) to give a solid (718 mg) which was dried under vacuum.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=1)=[O:3].C(N(C(C)C)CC)(C)C.[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([NH:45][CH3:46])[N:40]=2)=[CH:35][CH:34]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24].O>ClCCl>[CH2:23]([O:25]/[C:26](=[CH:32]\[C:33]1[CH:38]=[CH:37][C:36]([C:39]2[CH:44]=[CH:43][CH:42]=[C:41]([N:45]([CH3:46])[C:2]([O:4][C:5]3[CH:10]=[CH:9][C:8]([N+:11]([O-:13])=[O:12])=[CH:7][CH:6]=3)=[O:3])[N:40]=2)=[CH:35][CH:34]=1)/[C:27]([O:29][CH2:30][CH3:31])=[O:28])[CH3:24]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: CCOC(=O)/C(=C/c1ccc(-c2cccc(NC)n2)cc1)OCC
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOC(=O)/C(=C/c1ccc(-c2cccc(N(C)C(=O)Oc3ccc([N+](=O)[O-])cc3)n2)cc1)OCC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 110.6 %

Procedure:
0.55 g (2.75 mmol) of 4-nitrophenyl chloroformate and then 0.48 mL (2.75 mmol) of diisopropylethylamine are added to a solution of 0.6 g (1.84 mmol) of ethyl (Z)-2-ethoxy-3-[4-(6-methylaminopyrid-2-yl)phenyl]acrylate in 15 mL of dichloromethane. The reaction mixture is stirred for 1 hour 30 minutes at room temperature. The reaction is worked up by addition of 10 mL of water and extraction with dichloromethane. The organic phases are combined and then dried over magnesium sulfate, filtered and the solvent is evaporated off. 1 g (100%) of ethyl (Z)-2-ethoxy-3-(4-{6-[methyl-(4-nitrophenoxycarbonyl)amino]pyrid-2-yl}phenyl)acrylate is obtained in the form of a yellow oil.
Reaction SMILES: [NH2:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C(N(C(C)C)CC)(C)C.Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl>C1COCC1.ClCCl>[CH3:11][C:10]1[C:2]2[NH:1][C:22](=[O:24])[O:5][C:4](=[O:6])[C:3]=2[CH:7]=[CH:8][CH:9]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: Cc1cccc(C(=O)O)c1N
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: ClCCl
Product: Cc1cccc2c(=O)oc(=O)[nH]c12
Temperature: 25 °C
Reaction time: 16 h
Yield: 282.8 %

Procedure:
To a solution of 2-amino-3-methylbenzoic acid (9.07 g, 60 mmol) in THF (60 mL) was added simultaneously diisopropylethylamine (20.9 mL) and a solution of triphosgene (5.94 g, 20 mmol) in dichloromethane (60 mL) over 30 minutes period. After the addition was completed, the mixture stirred at ambient temperature for 16 hours. Solid was filtered and washed with ether (2×100 mL) and H2O (3×50 mL), and dried in high vacuum to afford the title compound (10.02 g, 94% yield) as a white solid. 1H NMR (DMSO) δ 11.02 (s, 1H), 7.76 (d, 1H, J=7.7 Hz), 7.57 (d, 1H, J=7.5 Hz), 7.17–7.13 (m, 1H), 2.32 (s, 3H).
Reaction SMILES: [OH:1][CH:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][O:4][CH2:5][O:6][CH3:7].[CH3:13][C:14]([Si:17](Cl)([CH3:19])[CH3:18])([CH3:16])[CH3:15].C1CCN2C(=NCCC2)CC1>C1COCC1.O>[O:1]([CH:2]([C:8]1[S:9][CH:10]=[CH:11][N:12]=1)[CH2:3][O:4][CH2:5][O:6][CH3:7])[Si:17]([C:14]([CH3:16])([CH3:15])[CH3:13])([CH3:19])[CH3:18]
Reactant: COCOCC(O)c1nccs1
Reactant: CC(C)(C)[Si](C)(C)Cl
Solvent: C1CCOC1
Solvent: O
Solvent: C1CCC2=NCCCN2CC1
Product: COCOCC(O[Si](C)(C)C(C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.9 %

Procedure:
A mixture of 2-(1-hydroxy-2-(methoxymethoxy)ethyl)thiazole (0.93 mmol, 0.18 g), TBSCl (1.1 mmol, 0.17 g) and DBU (1.1 mmol, 0.16 mL) in THF (1 mL) was stirred at rt overnight. The reaction was diluted with water and extracted with ethyl ether, dried (MgSO4), filtered and concentrated. The residue was subjected to flash chromatography (10% ethyl acetate/hexane) to afford 0.20 g (70%) of 2-(1-(t-butyldimethylsiloxy)-2-(methoxymethoxy)ethyl)thiazole.
Reaction SMILES: Cl.[CH:2]1([C:11]([OH:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][NH:3]1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.C([O-])([O-])=O.[Na+].[Na+]>O>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([N:3]2[CH2:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:2]2[C:11]([OH:13])=[O:12])(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: O=C(O)C1NCc2ccccc21
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: Cc1ccc(S(=O)(=O)N2Cc3ccccc3C2C(=O)O)cc1
Temperature: 25 °C
Reaction time: 20 h
Yield: 7.8 %

Procedure:
1,3-Dihydro-2H-isoindole-1-carboxylic acid, hydrochloride (0.31 g, 1.9 mmol), p-toluenesulfonyl chloride (0.4 g, 2.09 mmol), and Na2CO3 (0.403 g, 3,8 mmol) were dissolved in water (4 mL). The reaction mixture was stirred at rt for 20 hr. The residue was dissolved in water and washed with EtOAc. The aqueous layer was acidified with concentrated HCl and extracted with CH2Cl2 (2X). The organic layers were dried over anhydrous MgSO4 and concentrated in vacuo. The crude product was purified by HPLC to give N-[4-methylbenzenesulfonyl]-1,3-dihydro-2H-isoindole-1-carboxylic acid (0.047 g). MS m/e 318.1 (M+)
Reaction SMILES: [CH3:1][NH:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[N:6]([CH3:13])[CH:5]=1.CNCC1C=CC2C(=CC=CC=2)C=1CCC.Cl.[CH2:31]([O:38][C:39]([N:41]1[CH2:47][C:46]2[CH:48]=[C:49](/[CH:52]=[CH:53]/[C:54]([OH:56])=O)[CH:50]=[N:51][C:45]=2[NH:44][C:43](=[O:57])[CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl.CN1CC2C=C(/C=C/C(O)=O)C=NC=2NC(=O)C1>>[CH2:31]([O:38][C:39]([N:41]1[CH2:47][C:46]2[CH:48]=[C:49](/[CH:52]=[CH:53]/[C:54](=[O:56])[N:2]([CH3:1])[CH2:3][C:4]3[C:12]4[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=4)[N:6]([CH3:13])[CH:5]=3)[CH:50]=[N:51][C:45]=2[NH:44][C:43](=[O:57])[CH2:42]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Reactant: CNCc1cn(C)c2ccccc12
Agent: CCCc1c(CNC)ccc2ccccc12
Agent: CN1CC(=O)Nc2ncc(/C=C/C(=O)O)cc2C1
Agent: Cl
Product: CN(Cc1cn(C)c2ccccc12)C(=O)/C=C/c1cnc2c(c1)CN(C(=O)OCc1ccccc1)CC(=O)N2
Yield: 73 %

Procedure:
According to the procedure of Example 1 (a), except substituting methyl-(1-methyl-1H-indol-3-ylmethyl)amine for the methyl-(1-propyl-naphthalen-2-ylmethyl)amine, and substituting (E)-7-(2-carboxy-vinyl)-2-oxo-1,2,3,5-tetrahydro-pyrido[2,3-e][1,4]diazepine-4-carboxylic acid benzyl ester hydrochloride for the (E)-3-(4-methyl-2-oxo-2,3,4,5-tetrahydro-1H-pyrido[2,3-e][1,4]diazepin-7-yl)acrylic acid hydrochloride, the title compound (0.29 g, 73%) was prepared as an off-white powder and as a mixture of amide rotamers: 1H NMR (300 MHz, DMSO-d6) δ 10.43 (s, 1H), 8.51 (s, 1H), 8.11-8.25 (m, 1H), 7.53-7.64 (m, 2H), 7.30-7.42 (m, 5H), 7.12-7.20 (m, 4H), 6.98-7.03 (m, 1H), 5.03-5.08 (m, 2H), 4.75-4.93 (m, 2H), 4.62 (s, 2H), 4.41 (s, 2H), 3.73-3.77 (m, 3H), 2.91-3.06 (m, 3H); MS (ESI) m/e 524 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C@@H:3]([C@@H:21]1[CH2:25][CH2:24][CH2:23][N:22]1[C:26](=[O:45])[CH2:27][C@@H:28]([O:43][CH3:44])[C@@H:29]([N:34]([CH3:42])[C:35](=[O:41])[C@H:36]([CH:38]([CH3:40])[CH3:39])[NH2:37])[C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@@H:4]([CH3:20])[C:5]([NH:7][C@H:8]([C:16]([O:18][CH3:19])=[O:17])[CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)=[O:6].C1C2C(COC([NH:63][C@@:64]([C:69](O)=[O:70])([CH3:68])[CH:65]([CH3:67])[CH3:66])=O)C3C(=CC=CC=3)C=2C=CC=1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(NCC)C>ClCCl>[CH3:66][CH:65]([CH3:67])[C@:64]([C:69]([NH:37][C@H:36]([C:35]([N:34]([C@@H:29]([C@@H:30]([CH3:33])[CH2:31][CH3:32])[C@H:28]([O:43][CH3:44])[CH2:27][C:26]([N:22]1[CH2:23][CH2:24][CH2:25][C@H:21]1[C@H:3]([O:2][CH3:1])[C@@H:4]([CH3:20])[C:5]([NH:7][C@@H:8]([CH2:9][C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[C:16]([O:18][CH3:19])=[O:17])=[O:6])=[O:45])[CH3:42])=[O:41])[CH:38]([CH3:39])[CH3:40])=[O:70])([CH3:68])[NH2:63]
Reactant: CC(C)[C@](C)(NC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Reactant: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](N)C(C)C
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: ClCCl
Solvent: CCNCC
Product: CC[C@H](C)[C@@H]([C@@H](CC(=O)N1CCC[C@H]1[C@H](OC)[C@@H](C)C(=O)N[C@@H](Cc1ccccc1)C(=O)OC)OC)N(C)C(=O)[C@@H](NC(=O)[C@@](C)(N)C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 12 h
Yield: 68.9 %

Procedure:
A solution of #114 (225 mg, 0.356 mmol, 1.0 eq.) in 2 mL of dichloromethane was added to a solution of N-[(9H-fluoren-9-ylmethoxy)carbonyl]-3-methyl-D-isovaline (126 mg, 0.356 mmol, 1.0 eq.) in 4 mL of dichloromethane. Hunig's base (0.188 mL, 1.07 mmol, 3.0 eq.) was added followed by HATU (167 mg, 0.427 mmol, 1.2 eq). The reaction was allowed to stir at room temperature for 12 hours. The reaction was concentrated in vacuo and then taken up in ethyl acetate before being washed two times with 1M HCl and once with brine. The organic layer was dried over sodium sulfate and decanted. The organic solvent was removed in a genevac. THF (4 mL) was added followed diethylamine (2 mL, 19 mmol, 53.4 eq.). The reaction was allowed to stir for ˜12 hours. Reaction was concentrated using a genevac followed by silica chromatography (Gradient: 0%-30% methanol in ethyl acetate) producing #146 (183 mg, 69%) as a solid. LC-MS (Protocol Q): m/z 746.4 [M+H+] retention time=1.37 minutes. 1H NMR (400 MHz, DMSO-d6), δ 8.55 (d), 8.26-8.36 (m), 7.88-8.03 (m), 7.81 (d), 7.41-7.53 (m), 7.13-7.30 (m), 7.01 (s), 4.71-4.79 (m), 4.44-4.70 (m), 3.96-4.04 (m), 3.70-3.80 (m), 3.62-3.69 (m), 3.40-3.61 (m), 2.76-3.35 (m), 2.67-2.71 (m), 2.56-2.58 (m), 2.06-2.46 (m), 1.61-1.90 (m), 1.14-1.54 (m), 0.72-1.12 (m).
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[CH2:7][C:6]([CH2:9][NH2:10])([CH3:8])[CH2:5][CH:4]([NH2:11])[CH2:3]1.[C:13](=[O:20])([O:15][CH2:16][CH2:17][CH2:18][CH3:19])N>C(O)CCC>[CH2:16]([O:15][C:13]([NH:11][CH:4]1[CH2:5][C:6]([CH3:8])([CH2:9][NH:10][C:13]([O:15][CH2:16][CH2:17][CH2:18][CH3:19])=[O:20])[CH2:7][C:2]([CH3:12])([CH3:1])[CH2:3]1)=[O:20])[CH2:17][CH2:18][CH3:19]
Reactant: CCCCOC(N)=O
Reactant: CC1(C)CC(N)CC(C)(CN)C1
Solvent: CCCCO
Product: CCCCOC(=O)NCC1(C)CC(NC(=O)OCCCC)CC(C)(C)C1
Reaction time: 4 h

Procedure:
766 g of isophorone diamine (3-aminomethyl-3,5,5-trimethyl-cyclohexylamine), 1054 g of n-butyl carbamate and 1000 g n-butanol were reacted in the apparatus described in Example 1 for 4.0 hours at 180° C. After the apparatus had cooled and the pressure had been reduced, the reaction mixture was removed, filtered and analyzed by high pressure liquid chromatography. A yield of 1350 g (81% of the theoretical yield) of 1-(n-butoxy-carbonylamino)-3,3,5-trimethyl-5-(n-butoxy carbonylamino-methyl)-cyclohexane was obtained.
Reaction SMILES: [I-].[CH3:2][S+](C)(C)=O.[H-].[Na+].[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=[C:19]([C:27]([N:29]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:30]2[CH2:35][C@@H:34]([CH:36]=[O:37])[CH2:33][N:32]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH2:31]2)=[O:28])[N:18]=[N:17]1>CS(C)=O.C(=O)([O-])O.[Na+]>[F:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[N:16]1[C:20]([CH2:21][CH2:22][CH2:23][CH2:24][O:25][CH3:26])=[C:19]([C:27]([N:29]([CH2:45][CH:46]([CH3:48])[CH3:47])[C@H:30]2[CH2:35][C@@H:34]([CH:36]3[CH2:2][O:37]3)[CH2:33][N:32]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])[CH2:31]2)=[O:28])[N:18]=[N:17]1
Reactant: C[S+](C)(C)=O
Reactant: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C=O)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Agent: O=C([O-])O
Agent: [H-]
Agent: [I-]
Solvent: CS(C)=O
Product: COCCCCc1c(C(=O)N(CC(C)C)[C@H]2C[C@@H](C3CO3)CN(C(=O)OC(C)(C)C)C2)nnn1-c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.3 %

Procedure:
Trimethylsulfoxonium iodide (390 mg) was dissolved in DMSO (5 ml), sodium hydride (50% in oil, 85 mg) was added, and the mixture was stirred at room temperature for 1 hr. A solution (10 ml) of tert-butyl (3S,5R)-3-[{[1-(2-fluorophenyl)-5-(4-methoxybutyl)-1H-1,2,3-triazol-4-yl]carbonyl}(2-methylpropyl)amino]-5-formylpiperidine-1-carboxylate (656 mg) in DMSO was added to the reaction mixture, and the mixture was further stirred at room temperature for 1 hr. The reaction mixture was diluted with saturated aqueous sodium hydrogen carbonate solution and extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography, and a fraction eluted with ethyl acetate-hexane (10:90-100:0) was concentrated under reduced pressure to give the object product (372 mg).
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7](I)=[N:6]1.[Cu][C:20]#[N:21]>CS(C)=O>[F:1][C:2]1[CH:18]=[CH:17][CH:16]=[CH:15][C:3]=1[CH2:4][N:5]1[C:9]2=[N:10][CH:11]=[N:12][CH:13]=[C:8]2[C:7]([C:20]#[N:21])=[N:6]1
Reactant: Fc1ccccc1Cn1nc(I)c2cncnc21
Reactant: N#C[Cu]
Solvent: CS(C)=O
Product: N#Cc1nn(Cc2ccccc2F)c2ncncc12
Temperature: 150 °C

Procedure:
950 mg (purity 85%, approx. 2.281 mmol) of 1-(2-fluorobenzyl)-3-iodo-1H-pyrazolo[3,4-d]pyrimidine and 225 mg (2.509 mmol) of copper(I) cyanide were initially charged in 6 ml of absolute DMSO and the mixture was heated at 150° C. for 2 h. After cooling, the mixture was filtered through Celite and washed through with ethyl acetate and THF. The organic phase was washed with 25% aqueous ammonia solution, saturated aqueous ammonium chloride solution and saturated aqueous sodium chloride solution, dried over sodium sulphate and concentrated on a rotary evaporator. 685 mg (purity 84%, 99% of theory) of the target compound were obtained.