Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[C:9](#[N:11])[CH3:10].[C:12]([O:16][C:17]([NH:19][C@@H:20]([CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH:21]=[O:22])=[O:18])([CH3:15])([CH3:14])[CH3:13]>O1CCCC1>[OH:22][C@H:21]([C@@H:20]([NH:19][C:17]([O:16][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:18])[CH2:23][CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1)[CH2:10][C:9]#[N:11]
Reactant: CC#N
Reactant: CC(C)(C)OC(=O)N[C@H](C=O)CC1CCCCC1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@@H](CC1CCCCC1)[C@@H](O)CC#N
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 40.8 %

Procedure:
To a solution of lithium diisopropylamide (4.40 mmol) in dry tetrahydrofuran (4 mL) at -78° C. was added acetonitrile (0.25 mL, 4.4 mmol). To this enolate suspension was added 2(S)-t-butyloxycarbonylamino-3-cyclohexylpropanal (0.76 g, 2.98 mmol) in tetrahydrofuran (5 mL) pre-cooled to -78° C. After stirring for 15 minutes, the mixture was quenched with 2M HCl (5.0 mL), and extracted with ether which was dried over MgSO4 and evaporated. Flash chromatography on silica gel with ethyl acetate/hexane mixtures afforded 0.360 g (41%) of the desired compound as an oil.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl[C:22]([O:24][C:25]1[CH:30]=[CH:29][C:28]([N+:31]([O-:33])=[O:32])=[CH:27][CH:26]=1)=[O:23]>C1COCC1>[N+:31]([C:28]1[CH:27]=[CH:26][C:25]([O:24][C:22]([N:11]2[CH2:12][CH2:13][N:8]([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10]2)=[O:23])=[CH:30][CH:29]=1)([O-:33])=[O:32]
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Reactant: Fc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 67.6 %

Procedure:
1-(4-Fluoro-phenyl)-piperazine (12.2 g, 67.7 mmol) and triethylamine (4.63 mL, 67.7 mmol) were dissolved in anhydrous THF (150 mL) under nitrogen and the reaction mixture was cooled to 0° C. 4-Nitrophenyl chloroformate (13.4 g, 67.7 mmol) dissolved in anhydrous THF (150 mL) at 0° C. was added and the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo and the residue suspended between water and EtOAc. The aqueous layer was extracted with two further portions of EtOAc, the organic layers were combined, dried (MgSO4), dried in vacuo and then recrystallised from toluene (50 mL)/hexane (60 mL) to give 4-(4-fluorophenyl)-piperazine-1-carboxylic acid 4-nitrophenyl ester (15.8 g, 67%) as fine yellow needles.
Reaction SMILES: [Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH3:10])[CH:3]=1.C1C(=O)N([Br:18])C(=O)C1.CC(N=NC(C#N)(C)C)(C#N)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl.CCOC(C)=O>[Br:1][C:2]1[C:7]([O:8][CH3:9])=[CH:6][N:5]=[C:4]([CH2:10][Br:18])[CH:3]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: COc1cnc(C)cc1Br
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CCOC(C)=O
Product: COc1cnc(CBr)cc1Br

Procedure:
A solution of 4-bromo-5-methoxy-2-methyl-pyridine (Step AL3) (1.9 g, 9.4 mmol), NBS (1.8 g, 9.9 mmol), AIBN (15 mg, 0.094 mmol) and benzoyl peroxide (23 mg, 0.094 mmol) in CCl4 (2 mL) was stirred at rt for 18 h. The reaction mixture was dissolved in EtOAc and extracted with a saturated aqueous solution of NaHCO3, washed with brine, dried (Na2SO4), filtered and concentrated. The crude product was purified by silica gel column chromatography (hexane/EtOAc, 100:0→70:30). ESI-MS: tR=0.90 min, [M+H]+ 281.9 (LC-MS 1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([S:9]([NH:12][C:13]2[CH:14]=[C:15]3[C:19](=[CH:20][CH:21]=2)[NH:18][CH:17]=[CH:16]3)(=[O:11])=[O:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.CN(C1C=CC=CN=1)C.[CH2:31]([N:38]=[C:39]=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.Cl>ClCCl.C(OCC)(=O)C>[CH2:31]([NH:38][C:39]([N:18]1[C:19]2[C:15](=[CH:14][C:13]([NH:12][S:9]([C:4]3[CH:3]=[C:2]([Cl:1])[CH:7]=[C:6]([Cl:8])[CH:5]=3)(=[O:11])=[O:10])=[CH:21][CH:20]=2)[CH:16]=[CH:17]1)=[O:40])[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C=NCc1ccccc1
Reactant: O=S(=O)(Nc1ccc2[nH]ccc2c1)c1cc(Cl)cc(Cl)c1
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: O=C(NCc1ccccc1)n1ccc2cc(NS(=O)(=O)c3cc(Cl)cc(Cl)c3)ccc21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
130 mg 3,5-dichloro-N-(1H-indol-5-yl)-phenylsulphonamide are dissolved in 5 ml dichloromethane and 14 mg dimethylaminopyridine and 56 μl benzylisocyanate are added. The mixture is stirred overnight at ambient temperature, divided between 1 N HCl and ethyl acetate, the aqueous phase is extracted with ethyl acetate and the combined organic phases are dried with magnesium sulphate. The solvents are eliminated in vacuo and the residue is chromatographed on silica gel (cyclohexane/ethyl acetate 10:1 to 1:3).
Reaction SMILES: [CH3:1][C:2]([CH3:12])([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3](O)=[O:4].C1C=CC2N(O)N=[N:19][C:17]=2C=1.C(Cl)CCl.C(N(CC)CC)C.CN>ClCCl>[CH3:1][C:2]([CH3:12])([CH2:6][C:7]1[S:8][CH:9]=[CH:10][CH:11]=1)[C:3]([NH:19][CH3:17])=[O:4]
Reactant: On1nnc2ccccc21
Reactant: CC(C)(Cc1cccs1)C(=O)O
Agent: CN
Solvent: ClCCl
Solvent: ClCCCl
Solvent: CCN(CC)CC
Product: CNC(=O)C(C)(C)Cc1cccs1
Reaction time: 0.33 h

Procedure:
A solution of 2,2-dimethyl-3-thiophen-2-yl-propionic acid (315 mg, 1.589 mmol) in 10 ml of dichloromethane was treated successively with HOBt (257 mg, 1.9 mmol), EDC (364 mg, 1.9 mmol) and triethylamine (0.223 ml, 1.6 mmol). The mixture was stirred for 20 minutes, then methylamine (0.621 ml, 8 mmol) was added and stirring was continued for 18 hours. The solvent was then evaporated and the crude was redissolved in ether, washed with 2N-HCl, saturated sodium bicarbonate and brine. Drying over sodium sulfate and evaporation gave a yellow-brown oil which was used without further purification. Yield: 244 mg (78%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([N:14]([CH2:17][CH3:18])[CH2:15][CH3:16])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29](=[O:49])[C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([N:36]2[C:40]([CH2:41][O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)=[CH:39][N:38]=[N:37]2)[CH:31]=1)([CH3:3])([CH3:2])[CH3:4]
Reactant: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(N)cc1Cl
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: CCN(CC)c1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1Cl

Procedure:
The title compound was prepared from [2-amino-4-chloro-5-(diethyl-amino)-phenyl]-carbamic acid tert-butyl ester (Example J9) (310 mg, 1.0 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (402 mg, 1.0 mmol) according to the general procedure M. Obtained as a yellow foam (530 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1.Cl[C:22]1[N:27]=[CH:26][N:25]=[C:24]([C:28]([C:30]2[CH:31]=[C:32]([CH3:39])[C:33]3[O:37][CH2:36][CH2:35][C:34]=3[CH:38]=2)=[O:29])[CH:23]=1.CCN(C(C)C)C(C)C>CN(C=O)C.Cl>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[NH:12][C:11](=[O:13])[N:10]([CH:14]3[CH2:19][CH2:18][N:17]([C:22]4[CH:23]=[C:24]([C:28]([C:30]5[CH:31]=[C:32]([CH3:39])[C:33]6[O:37][CH2:36][CH2:35][C:34]=6[CH:38]=5)=[O:29])[N:25]=[CH:26][N:27]=4)[CH2:16][CH2:15]3)[CH2:9][CH2:8][C:7]=2[CH:20]=1
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Reactant: COc1ccc2c(c1)CCN(C1CCNCC1)C(=O)N2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COc1ccc2c(c1)CCN(C1CCN(c3cc(C(=O)c4cc(C)c5c(c4)CCO5)ncn3)CC1)C(=O)N2
Temperature: 25 °C
Reaction time: 48 h

Procedure:
100 mg (0.363 mmol) 7-methoxy-3-piperidin-4-yl-1,3,4,5-tetrahydro-1,3-benzodiazepin-2-one, 90.0 mg (0.229 mmol) (6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone and 0.200 mL (1.16 mmol) DIPEA were combined in 1.5 mL DMF and stirred for 48 h at RT. Then the reaction mixture was combined with a few drops of hydrochloric acid and purified by preparative HPLC-MS. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27]S(C)(=O)=O)[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35].[CH3:36][O-].[Na+].O>CO>[Br:1][C:2]1[N:6]2[CH:7]=[CH:8][CH:9]=[C:10]([O:11][CH2:12][C:13]3[C:18]([Cl:19])=[CH:17][CH:16]=[C:15]([N:20]([C:22](=[O:33])[CH2:23][NH:24][C:25](=[O:32])[CH2:26][O:27][CH3:36])[CH3:21])[C:14]=3[Cl:34])[C:5]2=[N:4][C:3]=1[CH3:35]
Reactant: Cc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)COS(C)(=O)=O)c3Cl)cccn2c1Br
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Solvent: O
Product: COCC(=O)NCC(=O)N(C)c1ccc(Cl)c(COc2cccn3c(Br)c(C)nc23)c1Cl
Reaction time: 1 h
Yield: 67.1 %

Procedure:
To a solution of 3-bromo-8-[2,6-dichloro-3-[N-(N-mesyloxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (100 mg) in methanol (2 ml) was added sodium methoxide (317 mg), and the mixture was stirred for 1 hour. Sodium methoxide (200 mg) was added thereto, and the mixture was stirred for 3 hours. To the reaction mixture was added water, and the mixture was extracted with methylene chloride 3 times. The extracts were combined, washed with brine, dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative thin-layer chromatography (methylene chloride:methanol=10:1, V/V) to give 3-bromo-8-[2,6-dichloro-3-[N-(methoxyacetylglycyl)-N-methylamino]benzyloxy]-2-methylimidazo[1,2-a]pyridine (60 mg).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1.[C:12](Cl)(=[O:15])[CH:13]=[CH2:14].C(N(CC)CC)C.[O:24]1C[CH2:27][CH2:26][CH2:25]1>>[C:12]([NH:1][C:2]1[N:7]=[C:6]([NH:8][C:25](=[O:24])[CH:26]=[CH2:27])[CH:5]=[C:4]([O:9][CH2:10][CH3:11])[N:3]=1)(=[O:15])[CH:13]=[CH2:14]
Reactant: CCOc1cc(N)nc(N)n1
Reactant: C1CCOC1
Reactant: C=CC(=O)Cl
Solvent: CCN(CC)CC
Product: C=CC(=O)Nc1cc(OCC)nc(NC(=O)C=C)n1
Temperature: 25 °C

Procedure:
1.54 g (10 mmols) of the product obtained by the procedure described in (1b) are reacted with 1.8 mL of acryloyl chloride, in the presence of 4.2 mL of triethylamine in 100 mL of tetrahydrofuran. The addition is performed dropwise and under cooling in an ice bath. After the addition is complete, the reaction mixture is stirred at room temperature for several hours. The solvent is evaporated under vacuum and then 100 mL of water are added to the solid residue to dissolve the TEA.HCl salt. The mixture is then extracted with 3×100 mL CHCl3, the organic phases are combined, dried over MgSO4 and the solvent is finally evaporated in vacuo. A white solid is finally obtained and there is no need for further purification.
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[CH:5][C:6]([Cl:17])=[C:7]([CH:16]=1)[O:8][Si:9]([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(=O)([O-])[O-].[K+].[K+].[Cl:24][C:25]1[CH:26]=[C:27]([C@H:31]([NH2:33])[CH3:32])[CH:28]=[CH:29][CH:30]=1>CN(C=O)C.O.CCOCC>[Si:9]([O:8][C:7]1[CH:16]=[C:3]([CH:4]=[CH:5][C:6]=1[Cl:17])[CH2:2][NH:33][C@@H:31]([C:27]1[CH:28]=[CH:29][CH:30]=[C:25]([Cl:24])[CH:26]=1)[CH3:32])([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10]
Reactant: C[C@@H](N)c1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)Oc1cc(CBr)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)C=O
Product: C[C@@H](NCc1ccc(Cl)c(O[Si](C)(C)C(C)(C)C)c1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 50 %

Procedure:
A solution of (5-(bromomethyl)-2-chlorophenoxy)(tert-butyl)dimethylsilane 81 (1.00 g, 2.98 mmol) and potassium carbonate (0.453 g, 3.28 mmol) in DMF was stirred at room temp under N2. (R)-1-(3-Chlorophenyl)ethanamine (0.464 g, 2.98 mmol) was added to the solution and the reaction was stirred at room temperature for 8 h. The reaction was checked by TLC for completion. The reaction mixture was diluted with water and ether. The ether solution was washed with water (2×) and brine. The organic layer was dried over MgSO4, filtered, and concentrated in vacuo. The crude material was purified by silica gel chromatography using a 5% to 30% gradient of EtOAc in hexanes as the eluant. The desired fractions were combined and concentrated to give (R)—N-(3-(tert-butyldimethylsilyloxy)-4-chlorobenzyl)-1-(3-chlorophenyl)ethanamine 82 (0.612 g, 50.1% yield) as a colorless oil. The product was carried forth to the next step without further purification.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1.[CH3:12][NH:13][CH3:14].CO>>[CH3:12][N:13]([CH3:14])[C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][N:3]=1
Reactant: COC(=O)c1ccc(Cl)nc1
Reactant: CNC
Solvent: CO
Product: COC(=O)c1ccc(N(C)C)nc1
Temperature: 25 °C
Yield: 98.9 %

Procedure:
A solution of methyl 6-chloronicotinate (4.0 g, 23 mmol) in dimethylamine/MeOH (2 M, 80 mL, 160 mmol) in a pressure vessel was stirred at 95° C. for 2 h, cooled to rt and concentrated. The residue was dissolved in EtOAc (250 mL), washed with water (2×150 mL), dried over Na2SO4, and concentrated to afford the title compound as a tan solid (4.1 g, 98%). MS (ESI), (M+H)+ 181.24; 1H NMR (CDCl3) δ 8.79 (s, 1H), 7.99 (d, 1H, J=9.2), 6.45 (d, 1H, J=9.2), 3.85 (s, 3H), 3.15 (s, 6H).
Reaction SMILES: [NH2-].[Na+].[O:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH:4]1[O:9][CH2:10][CH2:11][CH2:12][C:13]1(C#N)[C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[CH2:17][CH2:16][C:15]2[CH:24]=[CH:25][CH:26]=[CH:27][C:14]1=2.O>C1(C)C=CC=CC=1>[CH:24]1[C:15]2[CH2:16][CH2:17][C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[CH:13]([CH2:12][CH2:11][CH2:10][O:9][CH:4]3[CH2:5][CH2:6][CH2:7][CH2:8][O:3]3)[C:14]=2[CH:27]=[CH:26][CH:25]=1
Reactant: N#CC1(CCCOC2CCCCO2)c2ccccc2CCc2ccccc21
Agent: [NH2-]
Agent: [Na+]
Solvent: O
Solvent: Cc1ccccc1
Product: c1ccc2c(c1)CCc1ccccc1C2CCCOC1CCCCO1
Temperature: 25 °C
Yield: 81.1 %

Procedure:
Under nitrogen, sodium amide (3.5 g, 0.045 mol, 50% suspension in toluene) was added to a 100 ml three-necked roundbottom flask. The above nitrile (4.0 g, 0.011 mol) was dissolved in dry toluene (50 ml) and added. The reaction mixture was heated at reflux temperature for 16 h. After cooling to room temperature, water was added with caution (100 ml). More toluene was added and the organic phase was washed with dilute HCl. After drying (MgSO4), the organic phase was evaporated in vacuo affording 3.0 g (81%) of crude 2-(3-(10,11-dihydro-5H-dibenzo[a,d]cyclohepten-5-yl)-1-propyloxy)tetrahydropyran as an oil.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][C:22]([C:24]4[CH:33]=[CH:32][C:27]([C:28]([O:30]C)=[O:29])=[CH:26][CH:25]=4)=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:6][CH:5]=1)([CH3:3])[CH3:2].O1CCCC1.[OH-].[Na+]>CO>[CH:1]([C:4]1[CH:5]=[CH:6][C:7]([CH:10]2[C:14]3[C:15]([CH3:34])=[C:16]([NH:21][C:22]([C:24]4[CH:25]=[CH:26][C:27]([C:28]([OH:30])=[O:29])=[CH:32][CH:33]=4)=[O:23])[C:17]([CH3:20])=[C:18]([CH3:19])[C:13]=3[O:12][C:11]2([CH3:36])[CH3:35])=[CH:8][CH:9]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1ccc(C(=O)Nc2c(C)c(C)c3c(c2C)C(c2ccc(C(C)C)cc2)C(C)(C)O3)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: Cc1c(C)c2c(c(C)c1NC(=O)c1ccc(C(=O)O)cc1)C(c1ccc(C(C)C)cc1)C(C)(C)O2
Temperature: 25 °C
Reaction time: 3 h
Yield: 60 %

Procedure:
To a solution of methyl 4-[[3-(4-isopropylphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-ylamino]carbonyl]benzoate (341.7 mg, 0.70 mmol) in a mixed solvent of tetrahydrofuran (10 ml) and methanol (2.5 ml) was added a 1 N aqueous solution of sodium hydroxide (0.75 ml, 0.75 mmol) and the resulting mixture was stirred at room temperature for 3 hours. The reaction mixture was concentrated under reduced pressure and 1N hydrochloric acid was added into the residue. The product was extracted twice with ethyl acetate. The combined extracts were dried on magnesium sulfate, filtered, and concentrated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to obtain the title compound (60% yield) Melting point: 258-261° C.
Reaction SMILES: [CH3:1][C:2]1[Te:3][C:4]2[CH:14]=[CH:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[C:5]=2[N:6]=1.[F:15][C:16]([F:23])([F:22])[S:17]([O:20]C)(=[O:19])=[O:18]>ClCCl>[F:15][C:16]([F:23])([F:22])[S:17]([O-:20])(=[O:19])=[O:18].[CH3:16][N+:6]1[C:5]2[C:7]3[C:12]([CH:13]=[CH:14][C:4]=2[Te:3][C:2]=1[CH3:1])=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: Cc1nc2c(ccc3ccccc32)[te]1
Reactant: COS(=O)(=O)C(F)(F)F
Solvent: ClCCl
Product: Cc1[te]c2ccc3ccccc3c2[n+]1C
Product: O=S(=O)([O-])C(F)(F)F

Procedure:
2-Methylnaphtho[1,2-d]tellurazole (Example 26) (14.8 g=0.05 mole) was dissolved in dry dichloromethane, and methyl trifluoromethanesulfonate (5.52 ml=0.05 mole) was added. The flask was sealed and kept over a weekend. Pale yellow plates (16.1 g, 70% of theory) formed. The product was recrystallized from 150 ml of acetone by addition of diethyl ether (m.p. 178°-183° C.). The mass and nuclear magnetic resonance spectra were in agreement with that expected for the structural formula.
Reaction SMILES: COC1C=CC=CC=1S(O[C:13]1[C:24]2=[C:25]3[N:20]([CH:21]([CH3:26])[CH2:22][CH2:23]2)[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[C:17](=[O:30])[C:16]3=[CH:15][CH:14]=1)(=O)=O.[NH:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>CS(C)=O>[N:31]1([C:13]2[C:24]3=[C:25]4[N:20]([CH:21]([CH3:26])[CH2:22][CH2:23]3)[CH:19]=[C:18]([C:27]([OH:29])=[O:28])[C:17](=[O:30])[C:16]4=[CH:15][CH:14]=2)[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1
Reactant: C1CNCCN1
Reactant: COc1ccccc1S(=O)(=O)Oc1ccc2c(=O)c(C(=O)O)cn3c2c1CCC3C
Solvent: CS(C)=O
Product: CC1CCc2c(N3CCNCC3)ccc3c(=O)c(C(=O)O)cn1c23
Yield: 15.8 %

Procedure:
20.7 g of 8-(o-methoxybenzenesulfonyloxy)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid and 12.9 g of piperazine were added to 200 ml of anhydrous dimethyl sulfoxide and the mixture was heated in autoclave under flow of nitrogen at 10 atm. at a temperature of 150° to 160° C. for 18 hours while stirring. Treatment in an analogous manner as in Example 17 gave 2.5 g of 8-(1-piperazinyl)-5-methyl-6,7-dihydro-1-oxo-1H,5H-benzo[ij]quinolizine-2-carboxylic acid as white amorphous crystals having a melting point of not lower than 300° C.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([NH:15][C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:28](=O)[CH3:29].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C([O-])(O)=O.[Na+]>ClCCCl.C(O)(=O)C>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([N:15]([CH2:28][CH3:29])[C:16]2[C:17]([CH3:27])=[C:18]([CH:23]=[C:24]([Cl:26])[CH:25]=2)[C:19]([O:21][CH3:22])=[O:20])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: COC(=O)c1cc(Cl)cc(N[C@H]2CC[C@H](NC(=O)OC(C)(C)C)CC2)c1C
Reactant: CC=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CCN(c1cc(Cl)cc(C(=O)OC)c1C)[C@H]1CC[C@H](NC(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)amino)-5-chloro-2-methylbenzoate (330 mg, 0.831 mmol) and acetaldehyde (200 μL, 3.56 mmol) in 1,2-dichloroethane (DCE) (5 mL) was added acetic acid (400 μL) and the mixture was stirred at room temperature for 1 h. The mixture was cooled to 0° C. in an ice bath and sodium triacetoxyborohydride (700 mg, 3.30 mmol) was added (very thick suspension that slowly dissolved). The reaction was allowed to warm to room temperature and stirred overnight. LCMS showed the reaction was mostly complete. The reaction was neutralized with sat. NaHCO3, extracted with CH2Cl2, dried (Na2SO4), filtered and concentrated under vacuum. The residue was purified by silica gel chromatography (Analogix, 5 to 20% EtOAc in hexanes) and the pure fractions were combined and evaporated to dryness to give the product methyl 3-(((trans)-4-((tert -butoxycarbonyl)amino)cyclohexyl)(ethyl)amino)-5-chloro-2-methylbenzoate (250 mg, 0.588 mmol, 70.8% yield) as a white solid. 1H NMR (400 MHz, DMSO-d6) 6=7.44 (d, J =2.3 Hz, 1 H), 7.38 (d, J=2.3 Hz, 1 H), 6.68 (d, J=7.8 Hz, 1 H), 3.83 (s, 3 H), 3.16 (br. s., 1 H), 3.05 (q, J=6.9 Hz, 2 H), 2.59 (t, J=11.1Hz, 1 H), 2.34 (s, 3 H), 1.82-1.64 (m, 4 H), 1.47-1.38 (m, 2 H), 1.36 (s, 9 H), 1.16-1.04 (m, 2 H), 0.78 (t, J=6.9 Hz, 3 H). MS(ES) [M+H]+ 425.2.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=O)[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl.[NH2:23][OH:24]>CCO>[CH2:1]([N:8]1[CH2:13][CH2:12][C:11](=[N:23][OH:24])[CH:10]([CH3:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NO
Reactant: CC1CN(Cc2ccccc2)CCC1=O
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CC1CN(Cc2ccccc2)CCC1=NO
Temperature: 90 °C
Reaction time: 8 h

Procedure:
To a solution of 1-benzyl-3-methyl-piperidin-4-one (2.04 g, 10 mmol) in EtOH (20 mL), was added pyridine (20 mL, 0.25 mol) and hydroxylamine hydrochloride (0.70 g, 10 mmol). After being stirred at 90° C. overnight, the resultant solution was concentrated in vacuo to give the crude product 1-benzyl-3-methyl-piperidin-4-one oxime. LCMS m/z: 219 (M+H)+. This material was used without further purification.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[N:20]3[C:14]([CH2:15][N:16]([C:25]([C:27]4[CH:32]=[CH:31][C:30]([C:33]5[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=5[CH2:39][C:40]([OH:42])=O)=[CH:29][CH:28]=4)=[O:26])[C:17]4[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=4[CH2:19]3)=[CH:13][CH:12]=2)=[O:10])[CH:2]=1.[CH3:43][NH:44]C.CN>>[CH3:43][NH:44][C:40](=[O:42])[CH2:39][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=1[C:30]1[CH:29]=[CH:28][C:27]([C:25]([N:16]2[C:17]3[CH:24]=[CH:23][CH:22]=[CH:21][C:18]=3[CH2:19][N:20]3[C:11]([C:9]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:10])=[CH:12][CH:13]=[C:14]3[CH2:15]2)=[O:26])=[CH:32][CH:31]=1
Reactant: O=C(O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Reactant: CNC
Agent: CN
Product: CNC(=O)Cc1ccccc1-c1ccc(C(=O)N2Cc3ccc(C(=O)NCc4cccnc4)n3Cc3ccccc32)cc1
Yield: 61 %

Procedure:
The title compound was prepared in essentially the same manner as Example 68, replacing 4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-carboxylic acid with (4′-{[3-{[(pyridin-3-ylmethyl)amino]carbonyl}-5H-pyrrolo[2,1-c][1,4]benzodiazepin-10(11H)-yl]carbonyl}-1,1′-biphenyl-2-yl)acetic acid, Example 36, and dimethylamine with methylamine. Purification by flash chromatography using a solvent gradient of 2 to 8% methanol in dichloromethane gave the title compound (0.149 g, 61%) as an off-white solid.
Reaction SMILES: Cl.[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([C:10](=[O:18])[CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:19]#[N:20]>>[NH2:2][C:3]1[C:8]([F:9])=[CH:7][C:6]([CH:10]([OH:18])[CH2:11][NH:12][CH:13]2[CH2:17][CH2:16][CH2:15][CH2:14]2)=[CH:5][C:4]=1[C:19]#[N:20]
Reactant: N#Cc1cc(C(=O)CNC2CCCC2)cc(F)c1N
Agent: Cl
Product: N#Cc1cc(C(O)CNC2CCCC2)cc(F)c1N

Procedure:
m.p. of the hydrochloride: 184°-186° C. (decomp.), was prepared from 4'-amino-3'-cyano-2-cyclopentylamino-5'-fluoroacetophenone analogous to Example 49.