Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O[CH2:2][C:3]1[CH:19]=[CH:18][CH:17]=[CH:16][C:4]=1[CH2:5][CH:6]1[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7]1=[O:15].CCN(CC)CC.S([Cl:31])(C)(=O)=O.[Li+].[Cl-]>CN(C=O)C>[CH3:12][N:11]1[C:10](=[O:13])[CH2:9][N:8]([CH3:14])[C:7](=[O:15])[CH:6]1[CH2:5][C:4]1[CH:16]=[CH:17][CH:18]=[CH:19][C:3]=1[CH2:2][Cl:31]
Reactant: CN1CC(=O)N(C)C(Cc2ccccc2CO)C1=O
Reactant: CS(=O)(=O)Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CC(=O)N(C)C(Cc2ccccc2CCl)C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 3-[2-(hydroxymethyl)benzyl]-1,4-dimethylpiperazine-2,5-dione (1.48 g, 5.64 mmol) and Et3N (1.57 ml, 11.28 mmol) in DMF was cooled to 0° C. Mesyl chloride was added via syringe at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting overnight. More Et3N (2 equivalents) and mesyl chloride (1.1 equivalents) was added at 0° C. and the stirring reaction allowed to warm to ambient temperature via bath melting for 6 hours. LiCl (478 mg, 11.28 mmol) was added and the reaction stirred at ambient temperature for 1.5 hours. The mixture was partitioned between NH4Cl and EtOAc and extracted with EtOAc (3×). The combined organic solutions were washed with brine, dried over Na2SO4 and concentrated. The crude product was purified by normal phase chromatography (0-3% MeOH(NH3)/CH2Cl2) to give a yellow oil (1.47 g).
Reaction SMILES: C(OC([N:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][C:13]23[CH2:27][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=42)[C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1)=O)C>C(O)C.[OH-].[Na+].O>[NH:6]1[CH2:11][CH2:10][O:9][CH:8]([CH2:12][C:13]23[CH2:27][CH:20]([C:21]4[CH:22]=[CH:23][CH:24]=[CH:25][C:26]=42)[C:19]2[C:14]3=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:7]1
Reactant: CCOC(=O)N1CCOC(CC23CC(c4ccccc42)c2ccccc23)C1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: c1ccc2c(c1)C1CC2(CC2CNCCO2)c2ccccc21

Procedure:
A mixture of 9-(4-ethoxycarbonyl-2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene (400 mg) in ethanol (6 ml) and 25% aqueous sodium hydroxide solution (6 ml) was refluxed for 6 hours. The reaction mixture was diluted with water and extracted with ethyl acetate. The ethyl acetate layer was washed with water, dried over anhydrous sodium sulfate and evaporated to dryness to give 9-(2-morpholinylmethyl)-9,10-dihydro-9,10-methanoanthracene, M.P. 189° - 190° C.
Reaction SMILES: N1(C[C:8]2[C:9]([C:19]3[CH:20]=[C:21]4[C:25](=[CH:26][CH:27]=3)[C:24](=O)[CH2:23][CH2:22]4)=[C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)[O:11][CH:12]=2)CCOCC1.[NH2:29][OH:30].[CH2:31]([OH:33])[CH3:32]>>[N:16]1([CH2:17][C:12]2[O:11][C:10]([C:13]3[CH:18]=[CH:17][N:16]=[CH:15][CH:14]=3)=[C:9]([C:19]3[CH:27]=[C:26]4[C:23](=[CH:24][CH:20]=3)[C:22](=[N:29][OH:30])[CH2:21][CH2:25]4)[CH:8]=2)[CH2:15][CH2:14][O:33][CH2:31][CH2:32]1
Reactant: CCO
Reactant: NO
Reactant: O=C1CCc2cc(-c3c(CN4CCOCC4)coc3-c3ccncc3)ccc21
Product: ON=C1CCc2cc(-c3cc(CN4CCOCC4)oc3-c3ccncc3)ccc21
Temperature: 25 °C
Yield: 64 %

Procedure:
The product of Step 2 (180 mg, 0.4 mmol) in ethanol (4 ml) containing aqueous hydroxylamine (2 ml, 50% in water) was heated under reflux for 1 hour. After cooling to room temperature, the mixture was concentrated in vacuo and the residue co-evaporated with ethanol (3×5 ml). The residue was purified by silica gel chromatography eluting with a 0.1:1:20 mixture of 0.880 ammonia solution:ethanol:chloroform to give the title compound (100 mg, 64%); MS(ES+) m/e 390 [M+H]+.
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=O)[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1.CCOCC>[Br-].C[P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C1(C)C=CC=CC=1>[CH3:7][N:8]1[CH2:15][CH:14]2[C:16](=[CH2:1])[CH:10]([CH2:11][CH2:12][CH2:13]2)[CH2:9]1
Reactant: CN1CC2CCCC(C1)C2=O
Reactant: CC(C)(C)[O-]
Agent: C[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [K+]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: C=C1C2CCCC1CN(C)C2
Reaction time: 0.5 h
Yield: 104.7 %

Procedure:
To a solution of 6.9 g of methyltriphenyl phosphonium bromide in toluene (30 ml) was added 2.2 g of potassium tert-butoxide at 0° C. and the resulting mixture was stirred for 30 minutes. Next, 3.0 g of 3-methyl-3-azabicyclo[3.3.1]nonan-9-one was added thereto and the mixture was reacted for 1 hour. After adding ether, the reaction mixture was washed with a saturated aqueous solution of sodium chloride and dried over anhydrous magnesium sulfate. After filtering and concentrating, the residue was purified by silica gel column chromatography (eluted with ether/n-hexane) to thereby give 3.1 g of the title compound as a yellow oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:21]=[CH:20][C:5]([C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[C:22]1([N:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[N:34]=[C:33](Cl)[N:32]=[C:31](Cl)[N:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:43](=[O:46])([O-:45])[O-].[K+].[K+]>CN1C(=O)CCC1>[C:22]1([N:28]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:29]2[N:34]=[C:33]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]4[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=4)=[CH:20][CH:21]=3)[N:32]=[C:31]([NH:1][C:2]3[CH:3]=[CH:4][C:5]([C:6](=[O:7])[C:8]4[CH:13]=[CH:12][C:11]([C:43]([OH:45])=[O:46])=[C:10]([C:17]([OH:19])=[O:18])[CH:9]=4)=[CH:20][CH:21]=3)[N:30]=2)[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: O=C([O-])[O-]
Reactant: Nc1ccc(C(=O)c2ccc(C(=O)O)c(C(=O)O)c2)cc1
Reactant: Clc1nc(Cl)nc(N(c2ccccc2)c2ccccc2)n1
Agent: [K+]
Solvent: CN1CCCC1=O
Product: O=C(c1ccc(Nc2nc(Nc3ccc(C(=O)c4ccc(C(=O)O)c(C(=O)O)c4)cc3)nc(N(c3ccccc3)c3ccccc3)n2)cc1)c1ccc(C(=O)O)c(C(=O)O)c1
Temperature: 100 °C

Procedure:
To a solution of 0.20 mole of 4-amino-3',4'-dicarboxybenzophenone and 0.10 mole of 2-diphenylamino-4,6-dichloro-s-triazine in 300 ml of NMP is added 0.60 mole of potassium carbonate. The reaction mixture is heated at 100°C for 24 hours and then treated essentially as in Example 1 to give 2-diphenylamino-4,6-bis-{4'-(3",4"-dicarboxybenzoyl)-anilino}-s-triazine. The tetraacid is heated in refluxing nitrobenzene essentially as in Example 1 to yield the corresponding dianhydride.
Reaction SMILES: Br[CH:2]([C:4]1[C:13]([Cl:14])=[N:12][CH:11]=[CH:10][C:5]=1[C:6]([O:8]C)=O)[CH3:3].Cl.[F:16][CH:17]([F:29])[CH2:18][O:19][C:20]1[N:25]=[CH:24][C:23]([CH2:26][NH2:27])=[CH:22][C:21]=1[CH3:28]>>[Cl:14][C:13]1[C:4]2[CH:2]([CH3:3])[N:27]([CH2:26][C:23]3[CH:24]=[N:25][C:20]([O:19][CH2:18][CH:17]([F:29])[F:16])=[C:21]([CH3:28])[CH:22]=3)[C:6](=[O:8])[C:5]=2[CH:10]=[CH:11][N:12]=1
Reactant: COC(=O)c1ccnc(Cl)c1C(C)Br
Reactant: Cc1cc(CN)cnc1OCC(F)F
Agent: Cl
Product: Cc1cc(CN2C(=O)c3ccnc(Cl)c3C2C)cnc1OCC(F)F
Yield: 24 %

Procedure:
The title compound is prepared in 24% yield (63 mg, colorless oil) from methyl 3-(1-bromoethyl)-2-chloroisonicotinate (200 mg, 0.72 mmol, Step-1 of Intermediate-6, racemate) and (6-(2,2-difluoroethoxy)-5-methylpyridin-3-yl)methanamine hydrochloride (206 mg, 0.86 mmol, Amine-4) in a similar manner to Intermediate-2.
Reaction SMILES: C(N=[CH:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[N:13]=[CH:12][CH:11]=[C:10]2Cl)CCC.[CH3:18][O:19][CH2:20][CH2:21][O-:22].[Na+].C[O:25]CCO>[Cl-].[NH4+]>[CH3:18][O:19][CH2:20][CH2:21][O:22][C:10]1[C:9]2[C:14](=[CH:15][CH:16]=[C:7]([CH:6]=[O:25])[CH:8]=2)[N:13]=[CH:12][CH:11]=1
Reactant: CCCCN=Cc1ccc2nccc(Cl)c2c1
Reactant: COCC[O-]
Reactant: COCCO
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Product: COCCOc1ccnc2ccc(C=O)cc12
Temperature: 120 °C
Reaction time: 1 h
Yield: 68.3 %

Procedure:
A mixture of butyl (4-chloro-quinolin-6-ylmethylene)-amine (preparation was described in example 27b) (250 mg, 1.01 mmol) and a solution of sodium (2-methoxy)-ethoxide in 2-methoxy-ethanol (2.5 mL, 10.0 mmol, 4.0M) were placed in a microwave tube and the mixture was heated to 120° C. for 30 min in a closed microwave. Then, the suspension was diluted with saturated ammonium chloride solution and the organic compound was extracted into ethyl acetate (3×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under the vacuum and the brown residue was dissolved in THF (2 mL) and 1 mL of HCl solution (3.0N) was added. The resulting solution was stirred for 1 h at room temperature. Then, it was neutralized with potassium carbonate solution and extracted with ethyl acetate (2×50 mL). The combined extracts were washed with brine solution and dried over anhydrous magnesium sulfate. After filtration of the drying agent, the solvent was removed under the vacuum and the brown residue was purified by using a Biotage silica gel column chromatography to obtain 160 mg (68.3% yield) of 4-(2-methoxy-ethoxy)-quinoline-6-carbaldehyde as a brown solid: EI-LRMS m/e calcd for C13H13NO3 (M+) 232.1, found 232.1.
Reaction SMILES: [CH:1]1([C:4]2[C:16]3[C:15]4[CH2:14][CH2:13][N:12](C(OCC5C=CC=CC=5)=O)[CH2:11][C:10]=4[C:9](=[O:27])[NH:8][C:7]=3[N:6]([CH3:28])[N:5]=2)[CH2:3][CH2:2]1.C(#N)C.[F:32][C:33]([F:38])([F:37])[C:34]([OH:36])=[O:35]>>[CH:1]1([C:4]2[C:16]3[C:15]4[CH2:14][CH2:13][NH:12][CH2:11][C:10]=4[C:9](=[O:27])[NH:8][C:7]=3[N:6]([CH3:28])[N:5]=2)[CH2:3][CH2:2]1.[F:32][C:33]([F:38])([F:37])[C:34]([O-:36])=[O:35]
Reactant: Cn1nc(C2CC2)c2c3c(c(=O)[nH]c21)CN(C(=O)OCc1ccccc1)CC3
Reactant: O=C(O)C(F)(F)F
Solvent: CC#N
Product: Cn1nc(C2CC2)c2c3c(c(=O)[nH]c21)CNCC3
Product: O=C([O-])C(F)(F)F

Procedure:
A solution of Example 66A (180 mg, 0.48 mmol) in trifluoroacetic acid (5 mL) was heated at 50° C. for 16 h. After cooling, acetonitrile was added and the mixture concentrated on a rotary evaporator. The residue was separated by HPLC (Zorbax C-18, 0.1% TFA/CH3CN/H2O) to provide the title product as trifluoroacetate salt. This product was treated with 1.0 M solution of HCl in ether to yield the HCl salt. Yield: 92 mg (60%). MS (DCI/NH3) m/z 245 (M+H)+; 1H NMR (500 MHz, DMSO-d6): δ 0.77-0.85 (m, 2H), 0.86-0.92 (m, 2H), 2.04-2.17 (m, 1H), 3.24-3.32 (m, 2H), 3.33-3.41 (m, 2H), 3.74 (s, 3H), 3.84-3.96 (m, 2H), 5.27 (br s, 1H), 9.64 (br s, 1H). Anal. Calcd for C13H16N4O.2.1HCl: C, 48.91; H, 5.69; N, 17.46. Found: C, 48.91; H, 5.88; N, 17.11.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5](B2OC(C)(C)C(C)(C)O2)=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2.Br[C:36]1[C:49]([CH3:50])=[CH:48][C:39]([O:40][CH:41]2[CH2:45][CH2:44][C:43]([CH3:47])([OH:46])[CH2:42]2)=[CH:38][C:37]=1[CH3:51].BrC1C=CC(F)=C2C=1CC[C@H]2OC1C=CC2[C@H](CC(OC)=O)COC=2C=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:36]2[C:37]([CH3:51])=[CH:38][C:39]([O:40][CH:41]3[CH2:45][CH2:44][C:43]([OH:46])([CH3:47])[CH2:42]3)=[CH:48][C:49]=2[CH3:50])=[C:6]2[C:10]=1[C@H:9]([O:11][C:12]1[CH:25]=[CH:24][C:15]3[C@H:16]([CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH2:17][O:18][C:14]=3[CH:13]=1)[CH2:8][CH2:7]2
Reactant: Cc1cc(OC2CCC(C)(O)C2)cc(C)c1Br
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(B5OC(C)(C)C(C)(C)O5)ccc(F)c43)ccc21
Agent: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Br)ccc(F)c43)ccc21
Product: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(-c5c(C)cc(OC6CCC(C)(O)C6)cc5C)ccc(F)c43)ccc21

Procedure:
The title compound is prepared from methyl 2-((S)-6-((R)-7-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,3-dihydro-1H-inden-1-yloxy)-2,3-dihydrobenzofuran-3-yl)acetate and 3-(4-bromo-3,5-dimethylphenoxy)-1-methylcyclopentanol (enantiomer 1) following a procedure analogous to that described in Step 5 of Intermediate 1. LC (method 8): tR=0.81 min.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:4][CH:3]=1.C1C(=O)N([Br:24])C(=O)C1>C(Cl)(Cl)(Cl)Cl>[Br:24][CH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[N+:14]([O-:16])=[O:15])=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(-c2ccccc2[N+](=O)[O-])cc1
Solvent: ClC(Cl)(Cl)Cl
Product: O=[N+]([O-])c1ccccc1-c1ccc(CBr)cc1
Temperature: 0 °C
Yield: 101.2 %

Procedure:
A mixture containing 6.5 g of 4-methyl-2'-nitrobiphenyl and 5.42 g of NBS in 50 ml of carbon tetrachloride is refluxed for 5 hours. It is cooled to 0° C. and filtered and the filtrate is concentrated to give 9 g of an oily product, which is used as such in the next step.
Reaction SMILES: [CH3:1][C:2]([CH3:13])([CH3:12])[C:3]([NH:5][C:6]1[CH:11]=[CH:10][N:9]=[CH:8][CH:7]=1)=[O:4].[Li]CCCC.CN([CH:22]=[O:23])C>C1COCC1.[Cl-].[Na+].O>[CH:22]([C:7]1[CH:8]=[N:9][CH:10]=[CH:11][C:6]=1[NH:5][C:3](=[O:4])[C:2]([CH3:13])([CH3:12])[CH3:1])=[O:23]
Reactant: CC(C)(C)C(=O)Nc1ccncc1
Reactant: CN(C)C=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)Nc1ccncc1C=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 68.9 %

Procedure:
A mixture of Example 25A (11.4 g, 64 mmol) in 200 mL THF was cooled to −78° C., treated with 1.6 M nBuLi in hexanes (100 mL, 160 mmol), warmed to 0° C., stirred for 1 hour, treated with a solution of DMF (22 g, 215 mmol) in 100 mL THF, warmed to room temperature, stirred for 1 hour, diluted with brine, and extracted three times with ethyl acetate. The combined extracts were washed with water, washed twice with brine, dried (MgSO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 3% methanol/dichloromethane to provide the desired product (9.1 g, 69%).
Reaction SMILES: [CH:1]1([C:4]([NH2:6])=O)[CH2:3][CH2:2]1.[CH:7](N)([CH3:9])[CH3:8].C1(C2N(C)[C:17]([CH:20]=[O:21])=[CH:16][N:15]=2)CC1>>[CH:1]1([C:4]2[N:6]([CH:7]([CH3:9])[CH3:8])[C:17]([CH:20]=[O:21])=[CH:16][N:15]=2)[CH2:3][CH2:2]1
Reactant: CC(C)N
Reactant: Cn1c(C=O)cnc1C1CC1
Reactant: NC(=O)C1CC1
Product: CC(C)n1c(C=O)cnc1C1CC1

Procedure:
2-Cyclopropyl-3-isopropyl-3H-imidazole-4-carbaldehyde was prepared from cyclopropane carboxamide and isopropylamine in the same manner as 2-cyclopropyl-3-methyl-3H-imidazole-4-carbaldehyde (Example 46).
Reaction SMILES: [Si:1]([O:8][CH:9]1[CH2:12][N:11]([C:13]([C:15]2[S:23][C:22]3[C:17](=[N:18][CH:19]=[CH:20][C:21]=3[O:24][C:25]3[CH:30]=[CH:29][C:28]([N+:31]([O-])=O)=[CH:27][C:26]=3[F:34])[CH:16]=2)=[O:14])[CH2:10]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[BH4-].[Na+].C(N(CC(O)=O)CC(O)=O)CN(CC(O)=O)CC(O)=O>CO.C1COCC1>[NH2:31][C:28]1[CH:29]=[CH:30][C:25]([O:24][C:21]2[CH:20]=[CH:19][N:18]=[C:17]3[CH:16]=[C:15]([C:13]([N:11]4[CH2:12][CH:9]([O:8][Si:1]([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2])[CH2:10]4)=[O:14])[S:23][C:22]=23)=[C:26]([F:34])[CH:27]=1
Reactant: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)C1
Agent: O=C(O)CN(CCN(CC(=O)O)CC(=O)O)CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)[Si](C)(C)OC1CN(C(=O)c2cc3nccc(Oc4ccc(N)cc4F)c3s2)C1
Reaction time: 1 h
Yield: 45.8 %

Procedure:
To a solution of (3-(tert-butyldimethylsilyloxy)azetidin-1-yl)(7-(2-fluoro-4-nitrophenoxy)thieno[3,2-b]pyridin-2-yl)methanone 273 (336 mg, 0.67 mmol) and NiCl20.6H2O (318 g, 1.34 mmol) in MeOH/THF (4.7 mL/4.7 mL) was added NaBH4 (101 g, 2.68 mmol) at 0° C. and the mixture stirred for 1 hr. The reaction mixture was added to an EDTA. 4Na (1.1 g/100 mL) solution and extracted with EtOAc. The aqueous layer was filtered and extracted again with EtOAc. The combined organic phase was dried over anhydrous Na2SO4 and concentrated under reduced pressure. The residue was purified by flash chromatography (pure EtOAc) giving 274 as creamy foam (145.2 mg, 46% yield). MS (m/z): (M+1) 474.1 (100%).
Reaction SMILES: C(C1C=CC=CC=1CCN)#C.Cl.[C:13]1([CH:19]([CH2:48][CH:49](C)C)[CH2:20][N:21]([CH2:34][CH2:35][CH2:36][O:37][C:38]2[CH2:39][C:40](=[CH:44][C:45]([OH:47])=[O:46])[CH:41]=[CH:42][CH:43]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:32])([F:31])[F:30])[C:24]=2[Cl:33])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH:19]([C:48]#[CH:49])[CH2:20][N:21]([CH2:34][CH2:35][CH2:36][O:37][C:38]2[CH2:39][C:40](=[CH:44][C:45]([OH:47])=[O:46])[CH:41]=[CH:42][CH:43]=2)[CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([C:29]([F:30])([F:32])[F:31])[C:24]=2[Cl:33])[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1
Reactant: CC(C)CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1
Agent: C#Cc1ccccc1CCN
Agent: Cl
Product: C#CC(CN(CCCOC1=CC=CC(=CC(=O)O)C1)Cc1cccc(C(F)(F)F)c1Cl)c1ccccc1

Procedure:
The titled compound was prepared from 2-ethynylphenethylamine (J. Med. Chem. (1988), 31(4), 704-6) in the same manner as the preparation of N-(2-Phenyl-4-methylpentyl)-N-(2-chloro-3-trifluoromethylbenzyl)-3-(3-carboxymethylenephenoxy)propylamine, hydrochloride, Example 189e-h. MS (ESI) 530 (MH+)
Reaction SMILES: ClC1C=C(C=CC=1Cl)C(CCC(O)=O)=O.N1CCC[C@H]1C(O)=O.[Cl:24][C:25]1[CH:26]=[C:27]([CH:42]=[CH:43][C:44]=1[Cl:45])[C:28]([CH2:30][CH2:31][C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33])=[O:29].[Br:46]Br>C(O)(=O)C>[Br:46][CH:30]([C:28](=[O:29])[C:27]1[CH:42]=[CH:43][C:44]([Cl:45])=[C:25]([Cl:24])[CH:26]=1)[CH2:31][C:32]([N:34]1[CH2:41][CH2:40][CH2:39][C@H:35]1[C:36]([OH:38])=[O:37])=[O:33]
Reactant: BrBr
Reactant: O=C(CCC(=O)N1CCC[C@H]1C(=O)O)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)CCC(=O)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)[C@@H]1CCCN1
Solvent: CC(=O)O
Product: O=C(c1ccc(Cl)c(Cl)c1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O

Procedure:
The preceding compound is heated with 6 N hydrochloric acid to give 3-(3,4-dichlorobenzoyl)propionic acid. As described in Example 15, 3-(3,4-dichlorobenzoyl)propionic acid, hydroxysuccinimide ester is prepared and coupled to L-proline as in Example 16. The 1-[3-(3,4-dichlorobenzoyl)propionyl]-L-proline in acetic acid is reacted with bromine as in Example 20 to give 1-[3-bromo-3-(3,4-dichlorobenzoyl)propionyl]-L-proline.
Reaction SMILES: [CH2:1]([N:3](CC)CC)C.[CH2:8]([OH:10])[CH3:9].[CH3:11][C:12]1[C:16]([C:17]2[C:26]3[O:25][CH2:24][C@H:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[N:22]4[C:33]([N:35]5[CH2:39][CH2:38][C@@H:37]([NH:40][CH3:41])[CH2:36]5)=[N:34][C:20]([C:21]=34)=[CH:19][CH:18]=2)=[C:15]([CH3:42])[O:14][N:13]=1.O=C1CCC(=O)N1OC(=O)CC#N>C(Cl)Cl.CO>[C:1]([CH2:9][C:8]([N:40]([C@@H:37]1[CH2:38][CH2:39][N:35]([C:33]2[N:22]3[C@@H:23]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][N:28]=4)[CH2:24][O:25][C:26]4=[C:21]3[C:20](=[CH:19][CH:18]=[C:17]4[C:16]3[C:12]([CH3:11])=[N:13][O:14][C:15]=3[CH3:42])[N:34]=2)[CH2:36]1)[CH3:41])=[O:10])#[N:3]
Reactant: CN[C@@H]1CCN(c2nc3ccc(-c4c(C)noc4C)c4c3n2[C@@H](c2ccccn2)CO4)C1
Reactant: CCN(CC)CC
Reactant: CCO
Agent: N#CCC(=O)ON1C(=O)CCC1=O
Solvent: ClCCl
Solvent: CO
Product: Cc1noc(C)c1-c1ccc2nc(N3CC[C@@H](N(C)C(=O)CC#N)C3)n3c2c1OC[C@@H]3c1ccccn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
Triethylamine (8.2 μL, 0.059 mmol) and ethanol (1.0 mL) were added to a solution of (3R)-1-[(4S)-7-(3,5-dimethylisoxazol-4-yl)-4-pyridin-2-yl-4,5-dihydroimidazo[1,5,4-de][1,4]benzoxazin-2-yl]-N-methylpyrrolidin-3-amine (8.5 mg, 0.020 mmol) in methylene chloride (0.50 mL), followed by addition of 3-[(2,5-dioxopyrrolidin-1-yl)oxy]-3-oxopropanenitrile (7.2 mg, 0.039 mmol) and the mixture was stirred overnight at room temperature. The mixture was then diluted with methanol and purified by preparative LCMS using pH 10 buffer to give the title compound (1.4 mg, 14%). LCMS calc. for C27H28N7O3 (M+H)+: m/z=498.2. found: 498.3.
Reaction SMILES: [Na].[CH2:2]([OH:6])[CH2:3][CH2:4][CH3:5].[CH2:7]([N:11]1[C:15]2=[N:16][C:17]([CH3:26])=[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])[C:19](Cl)=[C:14]2[N:13]=[CH:12]1)[CH2:8][CH2:9][CH3:10]>C1C=CC=CC=1>[CH2:2]([O:6][C:19]1[C:18]([C:21]([O:23][CH2:24][CH3:25])=[O:22])=[C:17]([CH3:26])[N:16]=[C:15]2[N:11]([CH2:7][CH2:8][CH2:9][CH3:10])[CH:12]=[N:13][C:14]=12)[CH2:3][CH2:4][CH3:5]
Reactant: CCCCn1cnc2c(Cl)c(C(=O)OCC)c(C)nc21
Reactant: CCCCO
Agent: [Na]
Solvent: c1ccccc1
Product: CCCCOc1c(C(=O)OCC)c(C)nc2c1ncn2CCCC

Procedure:
0.03 g. of sodium and 0.8 g. of n-butyl alcohol are refluxed for 5 hours in 50 ml. of dry benzene. After this time, 3 g. of 3-butyl-7-chloro-5-methyl-3H-imidazo[4,5-b]-pyridine-6-carboxylic acid, ethyl ester obtained in Example 3 c are added and the mixture is refluxed for 12 hours. After the inorganic precipitate has been filtered off, the solvent is removed in vacuo and the residue distilled to obtain 7-butoxy-3-butyl-5-methyl-3H-imidazo[4,5-b]pyridine-6-carboxylic acid, ethyl ester, b.p. 210°-220°/0.01. Yield 2.1 g. (66%).
Reaction SMILES: [NH2:1][C:2]1[CH:19]=[CH:18][C:5]([C:6]([N:8]2[CH2:14][CH2:13][CH2:12][CH2:11][C:10]3[S:15][CH:16]=[CH:17][C:9]2=3)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:27][C:28]1[CH:29]=[C:30]([CH:34]=[CH:35][C:36]=1[Cl:37])[C:31](Cl)=[O:32]>ClCCl>[S:15]1[C:10]2[CH2:11][CH2:12][CH2:13][CH2:14][N:8]([C:6]([C:5]3[CH:4]=[CH:3][C:2]([NH:1][C:31](=[O:32])[C:30]4[CH:34]=[CH:35][C:36]([Cl:37])=[C:28]([Cl:27])[CH:29]=4)=[CH:19][CH:18]=3)=[O:7])[C:9]=2[CH:17]=[CH:16]1
Reactant: Nc1ccc(C(=O)N2CCCCc3sccc32)cc1
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(C(=O)N2CCCCc3sccc32)cc1)c1ccc(Cl)c(Cl)c1
Reaction time: 8 h
Yield: 51.8 %

Procedure:
To a solution of 0.30 g of 4-(4-aminobenzoyl)-5,6,7,8-tetrahydro-4H-thieno[3,2-b]azepine and 0.208 ml of triethylamine in 10 ml of dichloromethane is added, under argon, 0.251 g of 3,4-dichlorobenzoyl chloride. The mixture is stirred overnight and concentrated to dryness under vacuum. The residue is dissolved in ethyl acetate and the solution washed with H2O, 2N citric acid, NaHCO3 solution, brine and dried (Na2SO4). The solvent is removed and the residual yellow solid crystallized from ethyl acetate-hexane to give 0.254 g of crystals, m.p. 154°-160° C.
Reaction SMILES: [N:1]1([C:7]2[N:12]=[CH:11][C:10]([C:13](=[O:15])[CH3:14])=[CH:9][N:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([Mg]Br)=[CH:19][CH:18]=1>C1COCC1>[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:13]([C:10]2[CH:11]=[N:12][C:7]([N:1]3[CH2:2][CH2:3][NH:4][CH2:5][CH2:6]3)=[N:8][CH:9]=2)([OH:15])[CH3:14])=[CH:19][CH:18]=1
Reactant: CC(=O)c1cnc(N2CCNCC2)nc1
Reactant: Fc1ccc([Mg]Br)cc1
Solvent: C1CCOC1
Product: CC(O)(c1ccc(F)cc1)c1cnc(N2CCNCC2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
To a solution of 1-(2-(piperazin-1-yl)pyrimidin-5-yl)ethanone (1.8 g, 8.73 mmol) in dry THF (100 mL) was added (4-fluorophenyl)magnesium bromide (1 M in THF, 87.3 mL) at 0° C. under N2. The mixture was stirred at RT for 3 h, then quenched with ammonium chloride solution and extracted with dichloromethane (300 mL). The organic layer was dried over sodium sulfate, filtered and concentrated. The residue was purified by Combi-flash (dicholomethane:methanol=10:1) to give the title compound (1.02 g, 38%) as a yellow solid.
Reaction SMILES: F[C:2](F)(F)[C:3]([OH:5])=[O:4].[C:8]1(C)[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>O>[CH3:11][C:10]1[CH:9]=[CH:8][CH:13]=[CH:12][C:2]=1[C:3]([OH:5])=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: Cc1ccccc1
Solvent: O
Product: Cc1ccccc1C(=O)O
Temperature: 53 °C
Reaction time: 16 h

Procedure:
A mixture of K2S2O8 (1.35 g), trifluoroacetic acid (5 mL), 0.083 mL of a catalyst solution as prepared in Example 3(a) above, and toluene (5 mL) was stirred under CO (1 atm) at 53° C. (oil bath) for 16 hours. After the reaction was quenched with water, the unreacted toluene was removed with an air flow over the liquid phase. Ether (20 mL) and chlorobenzene (internal standard; 0.15 mL) were added. After vigorously stirring the mixture for 5-10 minutes, the ethereal phase was analyzed by GC-MS. The GC yield of toluic acid was 260 mg (TON=58, assuming that the Rh oxide used to prepare the catalyst contained 5 molecules of water per each Rh2O3 unit). The ether layer was separated, and the aqueous layer was extracted with ether. The combined ether solutions were evaporated to dryness to give solid toluic acid which was purified by vacuum sublimation. The yield of the purified toluic acid (1H NMR: 95% p-isomer) was 222 mg.