Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[C@@H:9]1[N:13]([C:14]2[CH:19]=[CH:18][N:17]3[N:20]=[CH:21][C:22]([C:23]([OH:25])=O)=[C:16]3[N:15]=2)[C:12]([CH3:27])([CH3:26])[CH2:11][CH2:10]1.[CH:28]1([NH2:31])[CH2:30][CH2:29]1>>[CH:28]1([NH:31][C:23]([C:22]2[CH:21]=[N:20][N:17]3[CH:18]=[CH:19][C:14]([N:13]4[C@@H:9]([C:3]5[CH:4]=[C:5]([F:8])[CH:6]=[CH:7][C:2]=5[F:1])[CH2:10][CH2:11][C:12]4([CH3:27])[CH3:26])=[N:15][C:16]=23)=[O:25])[CH2:30][CH2:29]1
Reactant: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)O)c2n1
Reactant: NC1CC1
Product: CC1(C)CC[C@H](c2cc(F)ccc2F)N1c1ccn2ncc(C(=O)NC3CC3)c2n1
Yield: 39 %

Procedure:
Prepared by the method described in Example 1 using (R)-5-(5-(2,5-difluorophenyl)-2,2-dimethylpyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid and cyclopropylamine in Step D. The crude material was purified by reverse phase HPLC (0-75% acetonitrile/water) to provide the title compound (11 mg, 39% yield). MS (apci) m/z=412.1 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:12])=[C:5]([CH:9]=[CH:10][CH:11]=1)[C:6]([OH:8])=O.[F:13][C:14]1([F:32])[CH2:19][CH2:18][C:17]([CH2:30][NH2:31])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:25]=2)[CH2:16][CH2:15]1>>[F:32][C:14]1([F:13])[CH2:15][CH2:16][C:17]([CH2:30][NH:31][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][CH:11]=[C:3]([O:2][CH3:1])[C:4]=2[CH3:12])([C:20]2[CH:21]=[N:22][C:23]([C:26]([F:27])([F:28])[F:29])=[CH:24][CH:25]=2)[CH2:18][CH2:19]1
Reactant: COc1cccc(C(=O)O)c1C
Reactant: NCC1(c2ccc(C(F)(F)F)nc2)CCC(F)(F)CC1
Product: COc1cccc(C(=O)NCC2(c3ccc(C(F)(F)F)nc3)CCC(F)(F)CC2)c1C

Procedure:
From 3-methoxy-2-methylbenzoic acid and C-[4,4-difluoro-1-(6-trifluoromethyl-pyridin-3-yl)-cyclohexyl]-methylamine. LCMS (MH+): m/z=443.2, tR (minutes, Method D)=0.78
Reaction SMILES: [CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)([C:37]4[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=4)[C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)[N:28]=[N:27][N:26]=3)=[CH:15][CH:14]=2)[CH:6]=[C:7]([CH2:9][CH2:10][NH2:11])[N:8]=1)[CH2:2][CH3:3].O.[C:50]([O:54][CH2:55][CH3:56])(=[O:53])[CH:51]=O>O1CCCC1>[CH2:1]([C:4]1[N:5]([CH2:12][C:13]2[CH:14]=[CH:15][C:16]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=3[C:25]3[N:29]([C:30]([C:37]4[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=4)([C:31]4[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=4)[C:43]4[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=4)[N:28]=[N:27][N:26]=3)=[CH:17][CH:18]=2)[C:6]2[CH:51]([C:50]([O:54][CH2:55][CH3:56])=[O:53])[NH:11][CH2:10][CH2:9][C:7]=2[N:8]=1)[CH2:2][CH3:3]
Reactant: CCOC(=O)C=O
Reactant: CCCc1nc(CCN)cn1Cc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: CCCc1nc2c(n1Cc1ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc1)C(C(=O)OCC)NCC2
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A mixture of 2-n-propyl-4-(2-aminoethyl)-1-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methylimidazole (6.92 g), ethyl glyoxylate hydrate (1.30 g) and tetrahydrofuran (70 ml) is stirred overnight at room temperature. The mixture is evaporated, and the residue is purified by silica gel column chromatography (solvent; chloroform/ethanol) to give ethyl 2-n-propyl-3-[2'-(1-trityl-1H-tetrazol-5-yl)biphenyl-4-yl]methyl-4,5,6,7-tetrahydroimidazo[4,5-c]pyridine-4-carboxylate (5.32 g) as a foam.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][NH:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18]#[CH:19])[CH:13]=1)(C(C)(C)C)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-].C1COCC1>>[C:18]([C:14]1[CH:13]=[C:12]([NH:11][CH2:10][CH2:9][OH:8])[CH:17]=[CH:16][CH:15]=1)#[CH:19]
Reactant: C#Cc1cccc(NCCO[Si](C)(C)C(C)(C)C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1cccc(NCCO)c1

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-ethynylaniline (335 mg, 1.22 mmol) was treated with 1M TBAF in THF (1.5 mL, 1.5 mmol) at room temperature for 5 min. The volatiles were removed and the crude was dissolved in EtOAc (30 mL). The organic phase was washed with water (20 mL) and finally with brine, dried over sodium sulfate and evaporated to give the corresponding alcohol as brownish oil.
Reaction SMILES: Cl[CH:2]([C:5]1[CH:10]=[CH:9][C:8]([O:11][CH2:12][CH3:13])=[C:7]([O:14][CH2:15][CH3:16])[CH:6]=1)[C:3]#[N:4].[NH2:17][C:18]([NH2:20])=[S:19].C(=O)([O-])O.[Na+]>C(O)C.O>[CH2:15]([O:14][C:7]1[CH:6]=[C:5]([CH:2]2[S:19][C:18](=[NH:20])[NH:17][C:3]2=[NH:4])[CH:10]=[CH:9][C:8]=1[O:11][CH2:12][CH3:13])[CH3:16]
Reactant: NC(N)=S
Reactant: CCOc1ccc(C(Cl)C#N)cc1OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: CCOc1ccc(C2SC(=N)NC2=N)cc1OCC
Yield: 69.7 %

Procedure:
4.8 g of α-chloro-α-(3,4-diethoxyphenyl)acetonitrile and 2.3 g of thiourea, in 70 ml of ethanol, are stirred under reflux for 1 hour. After cooling, the solution is poured in 200 ml of water, neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with chloroform. The extract is washed with water, dried (MgSO4) and distilled to remove the chloroform. The above procedure provides 3.9 g (69.6%) of 5-(3,4-diethoxyphenyl)-2,4-diiminothiazolidine, m.p. 185°-190° C.
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[N+:6]([C:9]1[CH:10]=[N:11][N:12]([CH2:14][C:15]([OH:17])=O)[CH:13]=1)([O-:8])=[O:7].[F:18][C:19]1[CH:20]=[C:21]([CH:23]=[CH:24][CH:25]=1)[NH2:22].N1C=CC=CC=1.C(=O)(O)[O-].[Na+]>O1CCCC1.O>[F:18][C:19]1[CH:20]=[C:21]([NH:22][C:15](=[O:17])[CH2:14][N:12]2[CH:13]=[C:9]([N+:6]([O-:8])=[O:7])[CH:10]=[N:11]2)[CH:23]=[CH:24][CH:25]=1
Reactant: O=C(O)Cn1cc([N+](=O)[O-])cn1
Reactant: Nc1cccc(F)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: O=C(Cn1cc([N+](=O)[O-])cn1)Nc1cccc(F)c1
Reaction time: 1 h
Yield: 65.8 %

Procedure:
A solution of phosphorus oxychloride (668 mg, 4.40 mmol) in tetrahydrofuran (4 ml) was added to a mixture of (4-nitro-1H-pyrazol-1-yl)acetic acid (684 mg, 4.00 mmol), 3-fluoroaniline (500 mg, 4.5 mmol) and pyridine (1.26 g, 16 mmol) in tetrahydrofuran (20 ml) at 0° C. under argon. The resulting mixture was stirred for 1 hour and an aqueous solution of sodium bicarbonate (20 ml) added. The mixture was further diluted with water and extracted with ethyl acetate (3×50 ml). The organic phase was recovered, dried and concentrated to give an oil which was triturated with diethyl ether:petroleum ether (1:1) to yield N-(3-fluorophenyl)-2-(4-nitro-1H-pyrazol-1-yl)acetamide (695 mg, 65% yield):
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8](B2OC(C)(C)C(C)(C)O2)[CH:7]=1)[CH3:2].Br[C:25]1[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:26]=1[CH:27]=[O:28].C(=O)([O-])[O-].[K+].[K+].N#N>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.O.COCCOC>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][C:6]1[CH:7]=[C:8]([C:25]2[CH:32]=[CH:31][C:30]([C:33]([F:36])([F:35])[F:34])=[CH:29][C:26]=2[CH:27]=[O:28])[C:9]([O:12][CH3:13])=[CH:10][CH:11]=1)[CH3:2]
Reactant: O=Cc1cc(C(F)(F)F)ccc1Br
Reactant: CCOC(=O)Cc1ccc(OC)c(B2OC(C)(C)C(C)(C)O2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: N#N
Agent: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: CCOC(=O)Cc1ccc(OC)c(-c2ccc(C(F)(F)F)cc2C=O)c1
Temperature: 85 °C
Reaction time: 8 h

Procedure:
A solution of [4-methoxy-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester (1.38 g, 4.32 mmol), 2-bromo-5-(trifluoromethyl)benzaldehyde (1.09 g, 4.32 mmol), and potassium carbonate (1.49 g, 10.8 mmol) in 2:1 DME:H2O was purged with N2 for 15 minutes. Tetrakis(triphenylphosphine)palladium(0) (0.499 g, 0.43 mmol) was added, and the reaction was purged with N2 for another 10 minutes, and then stirred at 85° C. overnight. The mixture was partitioned between EtOAc and H2O, and the aqueous layer was extracted with EtOAc. The combined organic layers were dried over MgSO4, filtered, and concentrated, and the residue was purified by silica gel chromatography to give the title compound.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH2:6][C:7]1([O:12][CH2:11][CH2:10][O:9]1)[CH3:8])([O-])=O>CO>[NH2:1][CH2:4][CH2:5][CH2:6][C:7]1([O:12][CH2:11][CH2:10][O:9]1)[CH3:8]
Reactant: CC1(CCC[N+](=O)[O-])OCCO1
Solvent: CO
Product: CC1(CCCN)OCCO1
Yield: 99.6 %

Procedure:
5-Nitro-2,2-ethylenedioxypentane (103 g) is dissolved in methanol (2.0 l) and initially introduced into a hydrogenation flask. After the thorough flushing of the apparatus with N2, 10% Pd/C (10 g) is added. Hydrogenation is then carried out at RT under normal conditions in a stream of H2 for a total of 11 h with vigorous stirring. After the reaction is complete (TLC dichloromethane/methanol=9:1, staining reagent 1.0% strength ethanolic ninhydrin solution), the flask is flushed with N2 and the mixture is filtered off with suction through kieselguhr. The colorless filtrate is concentrated to dryness at T≦40° C. and p≧30 mbar, the title compound (85 g, quant.) first being obtained as a colorless oil, which solidifies to give a wax. TLC (dichloromethane/methanol=9:1), Rf=0.0-0.22.
Reaction SMILES: [C:1]([O:5][CH3:6])(=[O:4])[CH2:2][OH:3].C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:17]1([NH:20][C:21]([C:23]2[S:36][C:26]3=[N:27][C:28](S(C)=O)=[C:29]([Cl:32])[C:30]([CH3:31])=[C:25]3[C:24]=2[NH2:37])=[O:22])[CH2:19][CH2:18]1>C1COCC1>[CH3:6][O:5][C:1](=[O:4])[CH2:2][O:3][C:28]1[N:27]=[C:26]2[S:36][C:23]([C:21](=[O:22])[NH:20][CH:17]3[CH2:18][CH2:19]3)=[C:24]([NH2:37])[C:25]2=[C:30]([CH3:31])[C:29]=1[Cl:32]
Reactant: COC(=O)CO
Reactant: Cc1c(Cl)c(S(C)=O)nc2sc(C(=O)NC3CC3)c(N)c12
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)COc1nc2sc(C(=O)NC3CC3)c(N)c2c(C)c1Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 57.7 %

Procedure:
To a solution of methyl glycolate (6.55 g, 72.7 mmol) in THF (35 ml) at room temperature is added dropwise a solution of lithium bis(trimethylsilyl)amide (1.0 M in hexanes) (36.35 ml, 36.35 mmol). The resulting mixture is stirred for 20 minutes, then treated with 3-amino-5-chloro-6-methanesulfinyl-4-methyl-thieno[2,3-b]pyridine-2-carboxylic acid cyclopropylamide (5.0 g, 14.54 mmol). The reaction vessel is sealed and heated at 90° C. for 3 hours. The reaction is cooled to room temperature and quenched by the addition of water (50 ml). The mixture is partitioned between water and EtOAc (250 ml each), and the layers are shaken and separated. The aqueous layer is extracted with 2×100 ml of EtOAc. The combined organic layers are dried (anhydrous magnesium sulfate), filtered, concentrated, and flashed (1:1 hexane:EtOAc) to give the title compound as a yellow solid (3.1 g, 58%). Mass (m/z): 370.1 (M++1), 368.0 (M+−1).
Reaction SMILES: [C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[OH:13])=[CH:5][C:4]=1[C:16]([F:19])([F:18])[F:17])#[N:2].P([O-])([O-])([O-])=O.I[CH3:26]>C(O)C>[C:1]([C:3]1[CH:12]=[C:11]2[C:6]([NH:7][C:8](=[O:15])[C:9](=[O:14])[N:10]2[O:13][CH3:26])=[CH:5][C:4]=1[C:16]([F:19])([F:17])[F:18])#[N:2]
Reactant: N#Cc1cc2c(cc1C(F)(F)F)[nH]c(=O)c(=O)n2O
Reactant: CI
Agent: O=P([O-])([O-])[O-]
Solvent: CCO
Product: COn1c(=O)c(=O)[nH]c2cc(C(F)(F)F)c(C#N)cc21
Reaction time: 8 h
Yield: 63.4 %

Procedure:
To a solution of 0.3 g (1.1- mmol) 7-cyano-1-hydroxy-6-trifluoromethylquinoxaline 2,3(1H,4H)-dione in 30 ml ethanol was added 15 ml 0.5M phosphate buffer pH 7.4. The mixture was added 1 ml (16 mmol) iodomethane, and then stirred overnight. The reaction mixture was evaporated, and the residue was stirred with water to give a precipitate. Recrystallization (dimethylformamide-water) gave 0.2 g (63%) of 7-cyano-1-methoxy-6-trifluoromethylquinoxaline-2,3(1H,4H)-dione. M.p. 250° C. decomp. 1H-NMR (DMSO-d6): 7.9 (1H, s), 7.6 (1H, s), 4.07 (3H, s).
Reaction SMILES: [S:1]([NH:17][C@@H:18]([CH2:23][NH:24]C(OC(C)(C)C)=O)[C:19]([O:21][CH3:22])=[O:20])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2]>CCOC(C)=O>[S:1]([NH:17][C@@H:18]([CH2:23][NH2:24])[C:19]([O:21][CH3:22])=[O:20])([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:2])=[O:3]
Reactant: COC(=O)[C@H](CNC(=O)OC(C)(C)C)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Solvent: CCOC(C)=O
Product: COC(=O)[C@H](CN)NS(=O)(=O)c1cccc2c(N(C)C)cccc12
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of 2-4 (0.43 g, 0.95 mmol) was suspended in EtOAc (15 mL) and cooled to -78° C. HCl gas was bubbled through the solution and the solution became homogenous. The solution was placed in an ice bath for 0.5 h, then concentrated to give 2-5 as an amorphous yellow solid. 1H NMR (300 MHz, CD3OD) δ8.97 (d, 1H), 8.62 (d, 1H), 8.44 (d, 1H), 8.18 (d, 1H), 7.95 (t, 2H), 4.25 (dd, 1H), 3.52 (s, 6H), 3.35 (dd, 1H), 3.12 (dd, 1H), 3.06 (s, 3H).
Reaction SMILES: [C:1]1([CH3:15])[CH:6]=[CH:5][C:4](S(N=S(C)(C)=O)(=O)=O)=[CH:3][CH:2]=1.[H-].[Na+].C=C1CC[C:22](=[O:25])[CH2:21]C1>CS(C)=O.[Na+].[Cl-]>[CH2:15]=[C:1]1[CH2:6][CH2:5][C:4]2([O:25][CH2:22][CH2:21]2)[CH2:3][CH2:2]1
Reactant: Cc1ccc(S(=O)(=O)N=S(C)(C)=O)cc1
Reactant: C=C1CCC(=O)CC1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: C=C1CCC2(CCO2)CC1
Yield: 100.2 %

Procedure:
N-(para-Toluenesulfonyl)dimethylsulfoximine (1.49 g, 6.01 mmol) and anhydrous DMSO (5 mL) were added to NaH 60% oil dispersion (0.22 g, 5.46 mmol) kept under stirring under anhydrous inert gas atmosphere in a flamed 3 necks flask. The mixture became greenish, and then changed to yellow. After stirring at 35° C. for 10 h, a solution of 4-methylidenecylohexanone (0.2 g, 1.82 mmol) in 5 mL of DMSO was added and the reaction mixture was stirred at 50° C. for 20 h. Afterwards, the reaction mixture was diluted with a saturated solution of NaCl and extracted with Et2O (3 times). After drying on Na2SO4 and evaporation to dryness, the residue from evaporation was purified by means of automated flash chromatography (Isolera®TM-Biotage; isocratic Petroleum Ether-EtOAc 9:1) to give 0.252 g of the title compound as a colorless oil. Yield: 27.8%.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:11]=2)[C:6](=[C:17](OCC)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:5]1=[O:27])(=O)C.[CH2:28]([N:35]1[CH2:40][CH2:39][N:38]([CH2:41][C:42]([N:44]([CH3:52])[C:45]2[CH:50]=[CH:49][C:48]([NH2:51])=[CH:47][CH:46]=2)=[O:43])[CH2:37][CH2:36]1)[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[CH2:28]([N:35]1[CH2:36][CH2:37][N:38]([CH2:41][C:42]([N:44]([C:45]2[CH:46]=[CH:47][C:48]([NH:51]/[C:17](=[C:6]3\[C:5](=[O:27])[NH:4][C:8]4[C:7]\3=[CH:12][CH:11]=[C:10]([C:13]([O:15][CH3:16])=[O:14])[CH:9]=4)/[C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[CH:49][CH:50]=2)[CH3:52])=[O:43])[CH2:39][CH2:40]1)[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: CN(C(=O)CN1CCN(Cc2ccccc2)CC1)c1ccc(N)cc1
Reactant: CCOC(=C1C(=O)N(C(C)=O)c2cc(C(=O)OC)ccc21)c1ccccc1
Product: COC(=O)c1ccc2c(c1)NC(=O)/C2=C(\Nc1ccc(N(C)C(=O)CN2CCN(Cc3ccccc3)CC2)cc1)c1ccccc1

Procedure:
Prepared from 1-acetyl-3-(1-ethoxy-1-phenylmethylene)-6-methoxycarbonyl-2-indolinone and N-((4-benzyl-piperazin-1-yl)-methylcarbonyl)-N-methyl-p-phenylenediamine Rf value: 0.5 (silica gel, methylene chloride/methanol=9:1) C37H37N5O4
Reaction SMILES: [CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]([NH:14][C:15]2[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=2[CH3:23])[C:8]=1[NH2:24])[CH2:4][CH3:5])[CH3:2].Cl[C:26](Cl)([O:28]C(=O)OC(Cl)(Cl)Cl)Cl.CCN(CC)CC>C1COCC1>[CH2:1]([CH:3]([O:6][C:7]1[CH:12]=[C:11]([CH3:13])[N:10]=[C:9]2[N:14]([C:15]3[C:20]([CH3:21])=[CH:19][C:18]([CH3:22])=[CH:17][C:16]=3[CH3:23])[C:26](=[O:28])[NH:24][C:8]=12)[CH2:4][CH3:5])[CH3:2]
Reactant: CCC(CC)Oc1cc(C)nc(Nc2c(C)cc(C)cc2C)c1N
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCC(CC)Oc1cc(C)nc2c1[nH]c(=O)n2-c1c(C)cc(C)cc1C

Procedure:
The title compound was prepared by reacting 4-(1-ethyl-propoxy)-6-methyl-N2-(2,4,6-trimethyl-phenyl)-pyridine-2,3-diamine with triphosgene, NEt3 in THF at room temperature. A white solid was isolated, mp. 184-186° C. Anal. For C21H27N3O2 calc. C, 71.36; H, 7.70; N, 11.89; found: C, 71.09; H, 7.75; N, 11.63.
Reaction SMILES: Br[C:2]1[C:3]([F:22])=[CH:4][C:5]2[O:11][CH2:10][CH2:9][N:8]3[C:12]([CH:18]4[CH2:20][CH2:19]4)=[C:13]([C:15]([NH2:17])=[O:16])[N:14]=[C:7]3[C:6]=2[CH:21]=1.[CH3:23][C:24]1[O:28][N:27]=[C:26]([C@:29]([OH:33])([C:31]#[CH:32])[CH3:30])[N:25]=1>>[CH:18]1([C:12]2[N:8]3[CH2:9][CH2:10][O:11][C:5]4[CH:4]=[C:3]([F:22])[C:2]([C:32]#[C:31][C@@:29]([OH:33])([C:26]5[N:25]=[C:24]([CH3:23])[O:28][N:27]=5)[CH3:30])=[CH:21][C:6]=4[C:7]3=[N:14][C:13]=2[C:15]([NH2:17])=[O:16])[CH2:20][CH2:19]1
Reactant: C#C[C@@](C)(O)c1noc(C)n1
Reactant: NC(=O)c1nc2n(c1C1CC1)CCOc1cc(F)c(Br)cc1-2
Product: Cc1nc([C@](C)(O)C#Cc2cc3c(cc2F)OCCn2c-3nc(C(N)=O)c2C2CC2)no1
Yield: 14 %

Procedure:
10-bromo-3-cyclopropyl-9-fluoro-5,6-dihydrobenzo[f]imidazo[1,2-d][1,4]oxazepine-2-carboxamide was reacted with (R)-2-(5-methyl-1,2,4-oxadiazol-3-yl)but-3-yn-2-ol via General Procedure E to yield 8.2 mg (14%) of 3-cyclopropyl-9-fluoro-10-[(3R)-3-hydroxy-3-(5-methyl-1,2,4-oxadiazol-3-yl)but-1-ynyl]-5,6-dihydroimidazo[1,2-d][1,4]benzoxazepine-2-carboxamide.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8]([OH:10])=[O:9])=[CH:6][N:5]=[CH:4][CH:3]=1.[H-].[Na+].[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1)#[N:14]>CN(C=O)C.O>[C:13]([C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:5]2[CH:4]=[CH:3][C:2](=[O:1])[C:7]([C:8]([OH:10])=[O:9])=[CH:6]2)=[CH:17][CH:16]=1)#[N:14]
Reactant: N#Cc1ccc(CBr)cc1
Reactant: O=C(O)c1cnccc1O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Cn2ccc(=O)c(C(=O)O)c2)cc1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
To a solution of 4-hydroxynicotinic acid (2.00 g, 14.4 mmol) in DMF (30 mL) is added sodium hydride (0.62 g, 55% dispersion in mineral oil, 14.2 mmol). After stirring for 10 min at room temperature, 4-cyanobenzyl bromide (2.88 g, 14.7 mmol) is added. After stirring for 2 h at room temperature, DMF (15 mL) is added and the reaction mixture is diluted with water. The formed precipitate is filtered off and dried. Yield: 2.57 g (56% of theory); ESI mass spectrum: [M+H]+=255; Retention time HPLC: 0.68 min (Z002—002).
Reaction SMILES: Cl[N:2]1[CH:11]=[C:10]([Cl:12])[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3]1.[CH:15]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)([CH3:17])[CH3:16].C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O>[Cl:12][C:10]1[C:9]2[C:4](=[CH:5][C:6]([O:13][CH3:14])=[CH:7][CH:8]=2)[CH2:3][N:2]([C:22]2[CH:23]=[CH:24][C:19]([O:18][CH:15]([CH3:17])[CH3:16])=[CH:20][CH:21]=2)[CH:11]=1
Reactant: COc1ccc2c(c1)CN(Cl)C=C2Cl
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc2c(c1)CN(c1ccc(OC(C)C)cc1)C=C2Cl
Temperature: 90 °C
Reaction time: 0.33 h
Yield: 83.9 %

Procedure:
To a solution of 2,4-dichloro-7-methoxyisoquinolin (0.7 g, 3.07 mmol), 4-isopropoxyphenylboronic acid (0.60 g, 3.38 mmol) in 1,4-Dioxane (15 ml) and water (10 ml) was added K2CO3 (0.84 g, 6.14 mmol). The reaction mass was degasified for 20 min. Pd (Ph3P)4 (0.17 g, 0.15 mmol) was added to the above reaction mass and degasified again for 5 min at room temperature. The reaction vessel (Pressure tube) was sealed and heated at 90° C. for 18 h. The reaction mass was evaporated under reduced pressure. The residue was diluted with water and extracted with ethyl acetate. The combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to get crude compound. The crude compound was purified by silica gel chromatography to get desired compound (0.85 g, 84%) as white solid. 1HNMR (400 MHz, CDCl3): δ ppm 8.25-8.22 (d, J=8 Hz, 1H), 8.13 (s, 1H), 8.07-8.05 (d, J=8 Hz, 1H), 7.48-7.47 (d, J=4 Hz, 1H), 7.34-7.32 (d, J=8 Hz, 1H), 7.07-7.05 (m, 2H), 4.77-4.71 (m, 1H), 4.15 (s, 3H), 1.32-1.31 (d, J=4 Hz, 6H); MS: MS m/z 328.20 (M++1).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([O:23]CC)=[O:22])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10].[OH-].[K+].S(S([O-])=O)([O-])=O.[Na+].[Na+].Cl>C(OCC)C>[CH3:1][O:2][C:3]1[C:4](=[O:26])[C:5]([CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]([OH:23])=[O:22])=[C:6]([CH3:12])[C:7](=[O:11])[C:8]=1[O:9][CH3:10]
Reactant: CCOC(=O)CCCCCCCCC1=C(C)C(=O)C(OC)=C(OC)C1=O
Agent: Cl
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CCOCC
Product: COC1=C(OC)C(=O)C(CCCCCCCCC(=O)O)=C(C)C1=O

Procedure:
To a solution of 2,3-dimethoxy-5-methyl-6-(8'-ethoxycarbonyloctyl)-1,4-benzoquinone(formula I-2 wherein R=H3CO, n=7, in the form of ethylester) (0.8 part) in diethyl ether (10 volume parts), followed by the addition of a 30% solution (20 volume parts) of potassium hydroxide containing sodium hydrosulfite. The mixture was refluxed for 1 hour. After cooling, the reaction mixture was rendered acidic with hydrochloric acid and extracted with diethyl ether. The ethereal extract was washed with water and shaken together with a solution of ferric chloride. The ethereal layer was washed with water and dried over anhydrous sodium sulfate. The diethyl ether was distilled off under reduced pressure and the resulting residue was crystallized from diethyl ether-hexane. The procedure provided 2,3-dimethoxy-5-methyl-6-(8'-carboxyoctyl)-1,4-benzoquinone (formula I-2 wherein R=H3CO, n=7, in the free form) (0.53 part) as orange-colored needles melting at 39°-40.5° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([C:14]([OH:16])=[O:15])[CH2:10][C:11]([OH:13])=O)=[O:7])([CH3:4])([CH3:3])[CH3:2]>O1CCCC1>[C:1]([O:5][C:6]([NH:8][C@@H:9]1[C:14](=[O:15])[O:16][C:11](=[O:13])[CH2:10]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)C(=O)O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H]1CC(=O)OC1=O

Procedure:
To a solution of 23.3 g N-t-butyloxycarbonyl-L-aspartic acid in 150 mL of tetrahydrofuran was added portionwise 20.6 g of N,N-dicyclohexyl-carbodiimide at 0° C. and overnight at room temperature. The precipitated dicyclohexyl urea was filtered off and all solvent was evaporated under reduced pressure. The oily residue was crystallized from acetone/hexane to give 18.24 g of anydride as white needles.
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].[CH2:7]([O:14][C:15]([NH:17][CH:18]1[C:26]2[C:21](=[CH:22][C:23]([C:27](OC)=[O:28])=[CH:24][CH:25]=2)[CH2:20][CH2:19]1)=[O:16])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[OH:28][CH2:27][C:23]1[CH:22]=[C:21]2[C:26](=[CH:25][CH:24]=1)[CH:18]([NH:17][C:15](=[O:16])[O:14][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[CH2:19][CH2:20]2
Reactant: COC(=O)c1ccc2c(c1)CCC2NC(=O)OCc1ccccc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC1CCc2cc(CO)ccc21)OCc1ccccc1
Reaction time: 1.5 h

Procedure:
At 0° C., LiAlH4 (2.4 M, 5.2 mL, 12.5 mmol) was added gradually to a solution of methyl 1-(benzyloxycarbonylamino)-2,3-dihydro-1H-indene-5-carboxylate (3.87 g, 11.9 mmol) in anhydrous THF (50 mL). The reaction was stirred for 1.5 h before being quenched by sequentially adding of water (450 μL), of 1 N NaOH (450 μL), and water (900 μL). The mixture was stirred for 10 minutes. Sodium sulfate was added and the mixture was filtered to remove insoluble salts. The residue was washed with ethyl acetate. The combined organic filtrates were evaporated to dryness in vacuo. The off-white residue was triturated with diethyl ether to afford the title compound as an off white solid (2.53 g, 71.5%). MS (ESI): m/z [M+NH4]+ 315.0