Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[C:10]1[N:15]=[C:14]([NH:16][C:17]2[CH:22]=[CH:21][C:20]([N:23]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]3)=[C:19]([O:29][CH3:30])[CH:18]=2)[CH:13]=[CH:12][CH:11]=1>>[CH3:30][O:29][C:19]1[CH:18]=[C:17]([NH:16][C:14]2[CH:13]=[CH:12][CH:11]=[C:10]([N:2]([CH3:1])[C:3]3[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=3)[N:15]=2)[CH:22]=[CH:21][C:20]=1[N:23]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24]1
Reactant: CNc1ccccc1
Reactant: COc1cc(Nc2cccc(Cl)n2)ccc1-n1cnc(C)c1
Product: COc1cc(Nc2cccc(N(C)c3ccccc3)n2)ccc1-n1cnc(C)c1

Procedure:
Prepared in analogy to example 62 from N-methylaniline and (6-chloro-pyridin-2-yl)-[3-methoxy-4-(4-methyl-imidazol-1-yl)-phenyl]-amine. The title compound was obtained as a brownish solid (Yield=16%). MS ISP (m/e): 386.2 (100) [(M+H)+]. 1H NMR (DMSO-D6, 300 MHz): δ (ppm)=9.06 (s, 1H), 7.68 (d, 1H), 7.61 (s, 1H), 7.50-7.35 (m, 3H), 7.35-7.15 (m, 4H), 7.09 (, 1H), 6.99 (s, 1H), 6.19 (d, 1H), 5.95 (d, 1H), 3.70 (s, 3H), 3.44 (s, 3H), 2.14 (s, 3H).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[NH2:12][CH:13]([CH2:21][CH3:22])[C:14]([O:16][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:15]>>[CH2:17]([O:16][C:14](=[O:15])[CH:13]([NH:12][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)[CH2:21][CH3:22])[CH:18]([CH3:19])[CH3:20]
Reactant: CCC(N)C(=O)OCC(C)C
Reactant: O=C(O)Cc1ccc(Br)cc1
Product: CCC(NC(=O)Cc1ccc(Br)cc1)C(=O)OCC(C)C

Procedure:
Following General Procedure BI above and using 4-bromophenylacetic acid (Aldrich) and iso-butyl 2-aminobutyrate (prepared following General Procedure BJ above), the title compound was prepared. The reaction was monitored by tlc on silica gel and purification was by filtration as described in the general procedure.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][N:9]=[C:8]([CH3:29])[C:7]=1[OH:30].Br[CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1>>[CH3:1][O:2][C:3](=[O:31])[CH2:4][CH2:5][C:6]1[C:11]([CH2:12][N:13]([C:22]([O:24][C:25]([CH3:26])([CH3:27])[CH3:28])=[O:23])[C:14]2[CH:19]=[CH:18][C:17]([C:20]#[N:21])=[CH:16][CH:15]=2)=[CH:10][N:9]=[C:8]([CH3:29])[C:7]=1[O:30][CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[C:36]([C:40]#[N:41])[CH:35]=1
Reactant: COC(=O)CCc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C)c1O
Reactant: N#Cc1cccc(CBr)c1
Product: COC(=O)CCc1c(CN(C(=O)OC(C)(C)C)c2ccc(C#N)cc2)cnc(C)c1OCc1cccc(C#N)c1
Yield: 68 %

Procedure:
The coupling of 3-(5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-hydroxy-2-methyl-pyridin-4-yl)-propionic acid methyl ester (121) and α-bromo-m-tolunitrile (102 mg, 0.5 mmol), as described in Example 1, gave 3-[5-{[tert-butoxycarbonyl-(4-cyano-phenyl)-amino]-methyl}-3-(3-cyano-benzyloxy)-2-methyl-pyridin-4-yl]-propionic acid methyl ester (122) (162 mg, 68% yield for 2 steps).
Reaction SMILES: CS(O[C@H:6]([C:16]1[CH:17]=[N:18][C:19]([CH:22]([F:24])[F:23])=[CH:20][CH:21]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])(=O)=O.[N-:25]=[N+:26]=[N-:27].[Na+]>CN(C=O)C>[N:25]([C@@H:6]([C:16]1[CH:21]=[CH:20][C:19]([CH:22]([F:24])[F:23])=[N:18][CH:17]=1)[CH2:7][O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10])=[N+:26]=[N-:27]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H](OS(C)(=O)=O)c1ccc(C(F)F)nc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OC[C@@H](N=[N+]=[N-])c1ccc(C(F)F)nc1
Temperature: 60 °C
Yield: 84.5 %

Procedure:
To a stirred solution of (R)-2-(tert-Butyldimethylsilyloxy)-1-(6-(difluoromethyl)pyridin-3-yl)ethyl methanesulfonate (2.24 g, 5.87 mmol) in dry DMF (15 mL) was added NaN3 (0.45 g, 7.05 mmol) and the resulting reaction mixture was heated at 60° C. for 2 h. After completion of the reaction the reaction mixture was treated with ice-cold water and extracted with Et2O. The organic layer was dried over anhydrous Na2SO4 and the solvents were evaporated in vacuo to afford the title compound (1.63 g, 85% yield). MS: 328 [M+1]+; 1H-NMR (300 MHz, CDCl3): 8.60 (s, 1H), 7.82 (d, 1H, J=8.3 Hz), 7.64 (d, 1H, J=8.3 Hz), 6.64 (t, 1H, J=55.7 Hz), 4.65-4.70 (m 1H), 3.80-3.86 (m, 2H), 0.89 (s, 9H), 0.04-0.06 (m, 61-1).
Reaction SMILES: [CH2:1]([N:3]([CH2:21][CH3:22])[CH2:4][CH2:5][NH:6][C:7]([C:9]1[NH:10][C:11]2[C:16]([C:17](=O)[CH:18]=1)=[CH:15][C:14]([I:20])=[CH:13][CH:12]=2)=[O:8])[CH3:2].[Cl:23]C1C2C(=CC=C(I)C=2)N=CC=1C(NCCN(CC)CC)=O>>[Cl:23][C:17]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([I:20])[CH:15]=2)[N:10]=[C:9]([C:7]([NH:6][CH2:5][CH2:4][N:3]([CH2:21][CH3:22])[CH2:1][CH3:2])=[O:8])[CH:18]=1
Reactant: CCN(CC)CCNC(=O)c1cnc2ccc(I)cc2c1Cl
Reactant: CCN(CC)CCNC(=O)c1cc(=O)c2cc(I)ccc2[nH]1
Product: CCN(CC)CCNC(=O)c1cc(Cl)c2cc(I)ccc2n1
Yield: 91 %

Procedure:
This compound was prepared, starting from compound 104 (0.34 g, 0.82 mmol), according to the procedure developed for compound 95. Reaction time at 100° C.: 15 min; the purification was performed using column chromatography (Al2O3, CH2Cl2/EtOH, 99/1, v/v) to give compound 105 (323 mg, 0.75 mmol) as a beige solid. Yield 91%; Rf (Al2O3, CH2Cl2/EtOH, 99/1, v/v) 0.42; mp 64-66° C.: IR (KBr) ν 1182, 1297, 1386, 1479, 1518, 1691, 2811, 2965, 3354 cm−1; 1H NMR (200 MHz, CDCl3) δ 1.11 (t, 6H, J=7.1 Hz), 2.66 (q, 4H, J=7.1 Hz), 2.75 (t, 2H, J=6.2 Hz), 3.60 (q, 2H, J=6.1 Hz), 7.82 (d, 1H, J=8.9 Hz), 8.03 (dd, 1H, J=1.8, 8.9 Hz), 8.36 (s, 1H), 8.56 (m, 1H), 8.64 (d, 1H, J=1.8 Hz); ESI-MS m/z 431.8 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5](=[O:13])(=[O:12])[NH:4][CH:3]1[C:14]([NH:16][C:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[O:19][CH:18]=1)=[O:15].[H-].[Na+].[CH2:30](I)[CH3:31]>CN(C)C=O>[CH2:30]([N:4]1[CH:3]([C:14]([NH:16][C:17]2[C:22](=[O:23])[C:21]3[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=3[O:19][CH:18]=2)=[O:15])[C:2](=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[S:5]1(=[O:13])=[O:12])[CH3:31]
Reactant: CCI
Reactant: O=C(Nc1coc2ccccc2c1=O)C1NS(=O)(=O)c2ccccc2C1=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN1C(C(=O)Nc2coc3ccccc3c2=O)C(=O)c2ccccc2S1(=O)=O

Procedure:
5,0 g of 3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide and 0,68 g of a sodium hydride suspension (50% in petroleum) are dissolved, with rigorous stirring, in 100 ml of dimethylformamide of 4°. 2,5 g of ethyl iodide are added and allowed to react for 2 hours. The reaction mixture is concentrated to one-third of its original volume, and ethanol is slowly added until crystals begin to precipitate. After some standing at room temperature, the crystals are filtered off, washed with ice-cold ethanol and recrystallised from ethanol/chloroform. After filtration and drying, 2-ethyl-3,4-dihydro-4-oxo-N-(4-oxo-4H-1-benzopyran-3-yl)-2H-1,2-benzothiazine-3-carboxamide 1,1-dioxide, of m.p. 235°-237°, is obtained.
Reaction SMILES: [F:1][C:2]([F:37])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:27])[CH2:25][CH2:26][C@H:20]3[C@@H:19]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[C:48](Cl)(=[O:51])[O:49][CH3:50]>C1COCC1>[F:37][C:2]([F:1])([F:36])[C:3]1[CH:4]=[C:5]([C@H:13]([N:15]([CH3:35])[C:16]([N:18]2[CH2:23][CH2:22][N:21]3[C:24](=[O:27])[C:25]([C:48]([O:49][CH3:50])=[O:51])([C:48]([O:49][CH3:50])=[O:51])[CH2:26][C@H:20]3[C@@H:19]2[C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[CH3:34])=[O:17])[CH3:14])[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: COC(=O)Cl
Reactant: Cc1ccccc1[C@H]1[C@@H]2CCC(=O)N2CCN1C(=O)N(C)[C@H](C)c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC(=O)C1(C(=O)OC)C[C@H]2[C@H](c3ccccc3C)N(C(=O)N(C)[C@H](C)c3cc(C(F)(F)F)cc(C(F)(F)F)c3)CCN2C1=O
Reaction time: 0.5 h
Yield: 45.3 %

Procedure:
To a solution of (1S,8aS)-N-((R)-1-(3,5-bis(trifluoromethyl)phenyl)ethyl)-N-methyl-6-oxo-1-o-tolylhexahydropyrrolo[1,2-a]pyrazine-2(1H)-carboxamide (300 mg, 0.57 mmol) in anhydrous THF (20 mL) under N2 atmosphere was added LiHMDS (2.3 mL, 1 M in THF, 2.3 mmol) at −60° C. The reaction was stirred for 30 min followed by addition of methyl carbonochloridate (134 mg, 1.43 mmol). After stirring for another 3 h at room temperature. The reaction was quenched with water at 0° C. and then extracted with EA (2×50 mL). The combined organic layers were dried over anhydrous Na2SO4 and then concentrated in high vacuum. The residue was purified by silica gel chromatography (DCM/MeOH=20/1 to 10/1) to give the title compound (166 mg, yield: 45.3%); m/z (ES+): 644 [M+H]+.
Reaction SMILES: [CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9](/[CH:13]=[CH:14]/[C:15]([C:17]3[CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=3)=[O:16])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1.[N:25]1[CH:30]=[CH:29][C:28]([CH:31]=[O:32])=[CH:27][CH:26]=1>>[CH3:1][O:2][N:3]=[C:4]1[C:12]2[C:7](=[CH:8][C:9]([CH:13]([CH2:14][C:15]([C:17]3[CH:18]=[N:19][C:20]([S:23][CH3:24])=[N:21][CH:22]=3)=[O:16])[C:31]([C:28]3[CH:29]=[CH:30][N:25]=[CH:26][CH:27]=3)=[O:32])=[CH:10][CH:11]=2)[CH2:6][CH2:5]1
Reactant: O=Cc1ccncc1
Reactant: CON=C1CCc2cc(/C=C/C(=O)c3cnc(SC)nc3)ccc21
Product: CON=C1CCc2cc(C(CC(=O)c3cnc(SC)nc3)C(=O)c3ccncc3)ccc21
Yield: 74 %

Procedure:
The title compound (2.9 g, 74%) was prepared from the product of Step 2 and 4-pyridinecarboxaldehyde using the method of Example 1 Step 4; MS(ES+) m/e 447 [M+H]+.
Reaction SMILES: [C:1]1(=[O:7])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(C)([O-])C.[K+].O.[C:15]1(C)[CH:20]=CC=[CH:17][CH:16]=1>>[CH2:20]1[C:2]2([CH2:3][CH2:4][CH2:5][CH2:6][C:1]2=[O:7])[CH2:17][CH2:16][CH2:15]1
Reactant: O=C1CCCCC1
Reactant: Cc1ccccc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: O
Product: O=C1CCCCC12CCCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Cyclohexanone (3.0 mL) was dissolved in toluene (60 mL), and cooled to 0° C. in nitrogen atmosphere. Potassium tert-butoxide (6.86 g) was added to the reaction mixture at 0° C. and stirred for 30 minutes. To the resulting suspension, 1,4-dibromomethane (3.65 mL) was added, and then the reaction mixture was stirred at 150° C. for 6 hours. Cooling the reaction mixture to room temperature, water was added thereto, followed by extraction with ethyl acetate. The extract was dried over anhydrous magnesium sulfate, the solvent was removed by distillation, and the resulting residue was purified on silica gel column chromatography (hexane/ethyl acetate=50/1) to provide 690.0 mg of the title compound as a colorless, oily substance.
Reaction SMILES: [Na].C([C:4](CC)(C([O-])=O)[C:5]([O-])=[O:6])C.[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]=[CH:22][C:23](=[O:25])[CH3:24]>C(O)C>[Cl:13][C:14]1[CH:19]=[C:18]([Cl:20])[CH:17]=[CH:16][C:15]=1[CH:21]1[CH2:4][C:5](=[O:6])[CH2:24][C:23](=[O:25])[CH2:22]1
Reactant: CCC(CC)(C(=O)[O-])C(=O)[O-]
Reactant: CC(=O)C=Cc1ccc(Cl)cc1Cl
Agent: [Na]
Solvent: CCO
Product: O=C1CC(=O)CC(c2ccc(Cl)cc2Cl)C1
Temperature: 0 °C

Procedure:
To a solution of 2.3 g of sodium in 200 ml of ethanol is added 15.7 g of diethylmalonate followed by a suspension of 20 g of 1-(2,4-dichlorophenyl)-1-butene-3-one in 100 ml ethanol. The mixture is heated under reflux for 2 hrs and then concentrated to dryness in vacuo. The solid is partitioned between 200 ml water and 200 ml ether. The ether layer is discarded and 20 ml 50% NaOH is added to the aqueous layer which is heated under reflux for 2 hrs. The mixture is filtered and the filtrate is made strongly acidic pH <2 with concentrated sulfuric acid. The mixture is heated on a steam bath for 2 hrs. The resulting solid is collected, pulverized and suspended in 500 ml of 10N sulfuric acid and heated on a steam bath for 2 hrs and cooled to 0° C. The solid is collected, washed with water and recrystallized from a mixture of dimethylformamide and ethyl acetate. Drying in vacuo at 80° C. for 6 hrs gives 5-(2,4-dichlorophenyl)cyclohexane-1,3dione; mp 192°-196° C.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[CH:5]=[C:4]([O:10][CH3:11])[N:3]=1.[CH2:12]([O:14][C:15]([N:17]=[C:18]=[S:19])=[O:16])[CH3:13]>O1CCCC1>[CH3:9][O:8][C:6]1[CH:5]=[C:4]([O:10][CH3:11])[N:3]=[C:2]([NH:1][C:18]([NH:17][C:15](=[O:16])[O:14][CH2:12][CH3:13])=[S:19])[N:7]=1
Reactant: COc1cc(OC)nc(N)n1
Reactant: CCOC(=O)N=C=S
Solvent: C1CCOC1
Product: CCOC(=O)NC(=S)Nc1nc(OC)cc(OC)n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.3 %

Procedure:
2-Amino-4,6-dimethoxypyrimidine (5.0 g, 36 mmol) was dissolved in dry tetrahydrofuran (THF, 35 mL), ethoxycarbonylisothiocyanate (6.4 mL, 54 mmol) was added and the solution was allowed to stir at room temperature. After 24 hours, the solvent is removed in vacuo and the residue was mixed with ether to form a crystalline solid. The solids were removed by vacuum filtration and dried to afford ethyl [(4,6-dimethoxypyrimidin-2-yl)amino]carbono thioylcarbamate as a tan solid (8.9 g, 87%). mp 196-197° C. 1H NMR (CDCl3): δ 13.2 (bs, 1H); 8.8 (bs, 1H); 5.80 (s, 1H); 4.32-4.25 (q, 2H, J=7.2); 3.93 (s, 3H); 1.30 (t, 3H, J=7.2).
Reaction SMILES: C([O:8][C:9]1[CH:16]=[CH:15][C:14]([C:17]([F:20])([F:19])[F:18])=[CH:13][C:10]=1[C:11]#[N:12])C1C=CC=CC=1.C(O)C.Cl[Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27].N1C=CN=C1>[Pd].C(OCC)C>[F:20][C:17]([F:18])([F:19])[C:14]1[CH:15]=[CH:16][C:9]([O:8][Si:25]([CH:32]([CH3:34])[CH3:33])([CH:29]([CH3:31])[CH3:30])[CH:26]([CH3:28])[CH3:27])=[C:10]([CH:13]=1)[C:11]#[N:12]
Reactant: N#Cc1cc(C(F)(F)F)ccc1OCc1ccccc1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Agent: [Pd]
Agent: c1c[nH]cn1
Solvent: CCO
Solvent: CCOCC
Product: CC(C)[Si](Oc1ccc(C(F)(F)F)cc1C#N)(C(C)C)C(C)C
Reaction time: 3 h
Yield: 97.3 %

Procedure:
Intermediate B, Step 2: A 250-mL round bottom flask containing a magnetic stir bar was charged successively with 2-(benzyloxy)-5-(trifluoromethyl)benzonitrile (7.30 g, 26.3 mmol), ethanol (76 mL) and 10 wt % palladium on carbon (560 mg, 5.27 mmol). The resulting solution was put under a hydrogen atmosphere and stirred for 3 h. The solution was then filtered and evaporated until all ethanol was removed. The residue was redissolved in DMF (38 mL), and chlorotriisopropylsilane (9.02 mL, 42.1 mmol) and imidazole (2.87 g, 42.1 mmol) were added and stirred for 4 h. At this time the solution was diluted with diethyl ether (300 mL) and washed with brine (5×100 mL). The organic layer was dried (MgSO4) and concentrated on a rotary evaporator. The residue was purified using a 120 g silica gel cartridge and 20:1 Hex/EtOAc to 4:1 Hex/EtOAc to elute 5-(trifluoromethyl)-2-(triisopropylsilyloxy)benzonitrile (8.80 g, 25.6 mmol, 97% yield) as a colorless oil. LC/MS [M+H]-=344.19. 1H-NMR (400 MHz, CDCl3) δ=7.83 (s, 1H), 7.70 (dd, J=8.0, 3.6 Hz, 1H), 7.03 (d, J=8.0 Hz, 1H), 1.15-1.0 (m, 21H).
Reaction SMILES: Cl.Cl.Cl.[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH2:27])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1.[O:28]1[CH2:33][CH2:32][CH2:31][CH:30]([C:34](O)=[O:35])[CH2:29]1>>[O:4]1[C:12]2[CH:11]=[CH:10][N:9]=[C:8]([N:13]3[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][C@H:21]4[CH2:26][CH2:25][C@H:24]([NH:27][C:34]([CH:30]5[CH2:31][CH2:32][CH2:33][O:28][CH2:29]5)=[O:35])[CH2:23][CH2:22]4)[CH2:15][CH2:14]3)[C:7]=2[CH2:6][CH2:5]1
Reactant: O=C(O)C1CCCOC1
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1
Agent: Cl
Product: O=C(N[C@H]1CC[C@H](CCN2CCN(c3nccc4c3CCO4)CC2)CC1)C1CCCOC1

Procedure:
The title compound, white solid (91 mg, 82%), MS (ISP) m/z=443.5 [(M+H)+], mp 216° C., was prepared in accordance with the general method of example 32 from trans-4-{2-[4-(2,3-dihydrofuro[3,2-c]pyridin-4-yl)-piperazin-1-yl]-ethyl}-cyclohexanamine trihydrochloride (intermediate C) (110 mg, 0.25 mmol) and rac-tetrahydro-pyran-3-carboxylic acid.
Reaction SMILES: [Br:1][CH:2]1[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]2[C:5]([NH:7][C:8](=[O:9])[CH:3]12)=[O:6].N1C=CC=CC=1.[Cl:20][C:21]1[C:26]([C:27](Cl)=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]>C1C=CC=CC=1>[Cl:20][C:21]1[C:26]([C:27]([N:7]2[C:8](=[O:9])[CH:3]3[CH:2]([Br:1])[CH:12]([Br:13])[CH2:11][CH2:10][CH:4]3[C:5]2=[O:6])=[O:28])=[C:25]([Cl:30])[C:24]([Cl:31])=[C:23]([Cl:32])[C:22]=1[Cl:33]
Reactant: O=C(Cl)c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Reactant: O=C1NC(=O)C2C1CCC(Br)C2Br
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: O=C(c1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)N1C(=O)C2CCC(Br)C(Br)C2C1=O
Temperature: 25 °C

Procedure:
3,4-Dibromohexahydrophthalimide (0.10 mole), benzene (300 ml) and pyridine (0.11 mole) are charged into a glass reaction vessel equipped with a mechanical stirrer, thermometer and reflux condenser. Pentachlorobenzoyl chloride (0.10 mole) is then added dropwise to the flask with stirring at room temperature. After the addition is completed the reaction mixture is heated at reflux with continued stirring for a period of about 1 hour. After this time the reaction mixture is filtered and the filtrate is washed with water. The washed filtrate is then dried over anhydrous magnesium sulfate, filtered and stripped of solvent under reduced pressure to yield the desired product N-(pentachlorobenzoyl)-3,4-dibromohexahydrophthalimide.
Reaction SMILES: [CH2:1]([O:3][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]2[CH:14]([O:15]C(C)(C)[O:17]2)[CH:13]([N:21]2[C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]=3[N:23]=[N:22]2)[O:12]1)(=[O:8])[O:5][CH2:6][CH3:7])[CH3:2]>C(O)(C(F)(F)F)=O.O>[CH2:6]([O:5][P:4]([CH:9]=[CH:10][CH:11]1[CH:18]([OH:17])[CH:14]([OH:15])[CH:13]([N:21]2[C:25]3[N:26]=[CH:27][N:28]=[C:29]([NH:30][C:31](=[O:38])[C:32]4[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=4)[C:24]=3[N:23]=[N:22]2)[O:12]1)(=[O:8])[O:3][CH2:1][CH3:2])[CH3:7]
Reactant: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C2OC(C)(C)OC12)OCC
Solvent: O
Solvent: O=C(O)C(F)(F)F
Product: CCOP(=O)(C=CC1OC(n2nnc3c(NC(=O)c4ccccc4)ncnc32)C(O)C1O)OCC
Reaction time: 0.5 h
Yield: 70.3 %

Procedure:
Compound 6.4 (170 mg, 0.31 mmol) was dissolved in 90% TFA in H2O (10 mL). The mixture was stirred for 30 min and concentrated down under reduced pressure. The residue was subjected to a silica gel column chromatography eluting with 10% MeOH in CH2Cl2 to yield compound 6.5 (110 mg, 70% yield). 1HNMR (300 MHz, CD3OD) δ 1.24-1.28 (m, 6H), 3.96-4.06 (m, 4H), 4.63 (t, 1H, J=5.1), 4.73 (s, 1H), 4.97 (t, 1H, J=4.2), 5.92-6.04 (m, 1H), 6.5 (d, 1H, J=3.9), 6.81-6.96 (m, 1H), 7.55-8.12 (m, 5H), 8.77 (s, 1H). LRMS (ESI) MH+ C21H25N6O7P requires 505.2. Found 504.9.
Reaction SMILES: [C:1](Cl)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)Cl.[NH2:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17]>C(N(CC)CC)C>[C:1]([NH:13][C:14]1[CH:23]=[C:22]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)[CH:21]=[CH:20][C:15]=1[C:16]([O:18][CH3:19])=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.28 mL of benzoyl chloride was added to 10 mL of methylene chloride solution containing 0.50 g of methyl 2-amino-4-phenylbenzoate and 0.36 mL of triethylamine and stirred at room temperature overnight. The solvent was evaporated under reduced pressure and water and ethyl acetate were added. The organic layer was separated and dried over anhydrous magnesium sulfate after washed with 1.0 mol/L hydrochloric acid and a saturated sodium chloride aqueous solution sequentially, and the solvent was evaporated under reduced pressure. Hexane and diisopropyl ether were added to the obtained residue and a solid substance was separated by filtration to obtain 0.52 g of methyl 2-(benzamido)-4-phenylbenzoate as white solid.
Reaction SMILES: [CH:1]1([C:4]2[CH:5]=[CH:6][C:7]([C:15]([NH:17][C:18]([CH2:24][CH3:25])([CH2:22][CH3:23])[C:19](O)=[O:20])=[O:16])=[N:8][C:9]=2[O:10][CH2:11][CH:12]2[CH2:14][CH2:13]2)[CH2:3][CH2:2]1.[NH:26]1[CH2:29][CH2:28][CH2:27]1>>[N:26]1([C:19]([C:18]([NH:17][C:15]([C:7]2[CH:6]=[CH:5][C:4]([CH:1]3[CH2:3][CH2:2]3)=[C:9]([O:10][CH2:11][CH:12]3[CH2:13][CH2:14]3)[N:8]=2)=[O:16])([CH2:22][CH3:23])[CH2:24][CH3:25])=[O:20])[CH2:29][CH2:28][CH2:27]1
Reactant: C1CNC1
Reactant: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)O
Product: CCC(CC)(NC(=O)c1ccc(C2CC2)c(OCC2CC2)n1)C(=O)N1CCC1

Procedure:
The title compound was synthesized in analogy to Example 1, using 2-(5-cyclopropyl-6-(cyclopropylmethoxy)picolinamido)-2-ethylbutanoic acid and azetidine (CAN 503-29-7) as starting materials. MS (EI): m/e=386.0 [M+H]+.
Reaction SMILES: [CH:1]1([C:4]([OH:6])=O)[CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH2:57])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1>CN(C=O)C>[CH2:38]([O:45][C:46]([N:48]1[CH2:53][CH2:52][C:51]2[N:54]=[C:55]([NH:57][C:4]([CH:1]3[CH2:3][CH2:2]3)=[O:6])[S:56][C:50]=2[CH:49]1[C:58]1[CH:63]=[C:62]([Cl:64])[CH:61]=[CH:60][C:59]=1[O:65][CH2:66][C:67]([O:69][CH2:70][CH3:71])=[O:68])=[O:47])[C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1
Reactant: O=C(O)C1CC1
Reactant: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(N)nc2CCN1C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)COc1ccc(Cl)cc1C1c2sc(NC(=O)C3CC3)nc2CCN1C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of cyclopropanecarboxylic acid (5 μL, 60 μmol, 1 eq.) in DMF (5 mL), DIPEA (51 μL, 300 μmol, 5 eq.) and TBTU (19 mg, 60 μmol, 1 eq.) were added in sequence. The resulting solution was stirred at r.t. for 30 minutes. Then (±)-2-amino-4-(5-chloro-2-ethoxycarbonylmethoxy-phenyl)-6,7-dihydro-4H-thiazolo[5,4-c]pyridine-5-carboxylic acid benzyl ester (30 mg, 60 μmol, 1 eq.) was added and the resulting mixture was stirred at r.t. for 18 hours. The reaction mixture was concentrated in vacuo. The residue was purified by prep. HPLC (column: Atlantis, 30×75 mm, 10 um, UV/MS, acidic conditions) and concentrated in vacuo to give the title compound as a colorless oil.
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:8]=[C:7]([C:9]([N:11]2[C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=3[CH2:15][N:14]3[C:22]([C:25]([N:27]4[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]4)=[O:26])=[CH:23][CH:24]=[C:13]3[CH2:12]2)=[O:10])[CH:6]=[CH:5][C:4]=1[C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]([F:42])([F:41])[F:40].C(N(CC)C(C)C)(C)C.[CH3:52][O:53][CH2:54][C@@H:55]1[O:57][CH2:56]1>CO>[CH3:52][O:53][CH2:54][C@H:55]([OH:57])[CH2:56][N:30]1[CH2:29][CH2:28][N:27]([C:25]([C:22]2[N:14]3[C:13]([CH2:12][N:11]([C:9]([C:7]4[CH:6]=[CH:5][C:4]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[C:39]([F:40])([F:42])[F:41])=[C:3]([CH3:2])[CH:8]=4)=[O:10])[C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[CH2:15]3)=[CH:24][CH:23]=2)=[O:26])[CH2:32][CH2:31]1
Reactant: COC[C@H]1CO1
Reactant: Cc1cc(C(=O)N2Cc3ccc(C(=O)N4CCNCC4)n3Cc3ccccc32)ccc1-c1ccccc1C(F)(F)F
Agent: Cl
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: COC[C@H](O)CN1CCN(C(=O)c2ccc3n2Cc2ccccc2N(C(=O)c2ccc(-c4ccccc4C(F)(F)F)c(C)c2)C3)CC1
Temperature: 60 °C
Yield: 73.6 %

Procedure:
To a solution of 10,11-dihydro-10-[[2-methyl-2′-trifluoromethyl-[1,1′-biphenyl]-4-yl]carbonyl]-3-(1-piperazinylcarbonyl)-5H-pyrrolo[2,1-c][1,4]benzodiazepine hydrochloride salt of Example 5, Step B (0.50 g, 0.84 mmol) and N,N-diisopropylethyl amine (0.16 mL, 0.92 mmol) in methanol (5 mL) was added (R)-(−)-glycidyl methyl ether (0.11 mL, 1.22 mmol). The reaction mixture was heated to 60° C. overnight then cooled and concentrated in vacuo. The residue was partitioned between dichloromethane and water. The organic layer was dried over anhydrous sodium sulfate, filtered and concentrated in vacuo to give a white foam. Purification by flash chromatography on silica gel using a solvent system of 3% methanol in chloroform provided 0.40 g of title product as a white foam.