Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:15]=[CH:14][C:12]([NH2:13])=[CH:11][CH:10]=2)O1.C(=O)([O-])[O-].[K+].[K+].Br[C:24]1[C:25]([NH2:46])=[N:26][CH:27]=[C:28]([C:30]2[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]3[CH2:43][CH2:42][CH2:41][CH2:40]3)=[C:32]([O:44][CH3:45])[CH:31]=2)[CH:29]=1>O1CCOCC1.O.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>[NH2:13][C:12]1[CH:11]=[CH:10][C:9]([C:24]2[C:25]([NH2:46])=[N:26][CH:27]=[C:28]([C:30]3[CH:35]=[CH:34][C:33]([O:36][CH2:37][CH2:38][N:39]4[CH2:43][CH2:42][CH2:41][CH2:40]4)=[C:32]([O:44][CH3:45])[CH:31]=3)[CH:29]=2)=[CH:15][CH:14]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: COc1cc(-c2cnc(N)c(Br)c2)ccc1OCCN1CCCC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(-c2cnc(N)c(-c3ccc(N)cc3)c2)ccc1OCCN1CCCC1
Temperature: 100 °C
Reaction time: 5 h
Yield: 105.3 %

Procedure:
4-(4,4,5,5-Tetramethyl-1,3,2-dioxaborolan-2-yl)aniline (285 mg), tetrakis(triphenylphosphine)palladium (110 mg) and potassium carbonate (396 mg) were added to a solution of the compound obtained in Step 1 of Example 39 (375 mg) in dioxane (10 ml) and water (1 ml) at room temperature. The reaction mixture was stirred at 100° C. for five hours. The reaction mixture was returned to room temperature, followed by extraction with chloroform. The organic layer was dried over magnesium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by column chromatography [chloroform:methanol=19:1 (v/v)] to give 407 mg of the title compound as an oily substance.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[N:4][CH:5]=[CH:6][C:7]=1[NH2:8].[C:9](O)(=[O:13])[C:10](O)=[O:11]>Cl>[NH:8]1[C:10](=[O:11])[C:9](=[O:13])[NH:1][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][C:7]1=2
Reactant: Nc1ccncc1N
Reactant: O=C(O)C(=O)O
Agent: Cl
Product: O=c1[nH]c2ccncc2[nH]c1=O
Yield: 81.1 %

Procedure:
To a suspension of 3,4-diaminopyridine (10 g, 0.068 mol) in 4N aqueous HCl (100 ml) is added oxalic acid (10.4 g, 0.082 mol) and the reaction mixture is refluxed for 20 h. The reaction mixture is cooled down and the solid precipitated is filtered, washed with water then dried under vacuum to afford 9 g (80%) of the title compound as a solid. HPLC (max plot) 98%. LC/MS: (ES+):164.3.
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[CH:6]=[CH:5]1.[CH2:28]([O:30][CH2:31][C:32](O)=[O:33])[CH3:29]>>[CH2:28]([O:30][CH2:31][C:32]([NH:27][C@H:24]1[CH2:25][CH2:26][C@H:21]([CH2:20][CH2:19][N:16]2[CH2:17][CH2:18][N:13]([C:8]3[C:7]4[CH:6]=[CH:5][O:4][C:12]=4[CH:11]=[CH:10][N:9]=3)[CH2:14][CH2:15]2)[CH2:22][CH2:23]1)=[O:33])[CH3:29]
Reactant: CCOCC(=O)O
Reactant: N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1
Agent: Cl
Product: CCOCC(=O)N[C@H]1CC[C@H](CCN2CCN(c3nccc4occc34)CC2)CC1

Procedure:
The title compound, white crystals (86 mg, 60%), MS (ISP) m/z=415.3 [(M+H)+], was prepared in analogy to example 4 starting from trans-4-[2-(4-furo[3,2-c]pyridin-4-yl-piperazin-1-yl)-ethyl]-cyclohexylamine trihydrochloride (intermediate A) (150 mg, 0.34 mmol) and ethoxyacetic acid (43 mg, 0.41 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:9][CH2:10][CH2:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[OH:19].[H-].[Na+].Cl.[CH3:23][N:24]([CH3:29])[CH2:25][CH2:26][CH2:27]Cl>CC(N(C)C)=O>[CH3:23][N:24]([CH2:25][CH2:26][CH2:27][O:19][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=1[CH2:12][CH2:11][CH2:10][CH2:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[CH3:29]
Reactant: COc1ccccc1CCCCc1ccccc1O
Reactant: CN(C)CCCCl
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COc1ccccc1CCCCc1ccccc1OCCCN(C)C
Yield: 85.2 %

Procedure:
Following a procedure similar to that described in Example 2(a), 200 mg of 2-[4-(2-methoxyphenyl)butyl]phenol (prepared as described in Preparation 4), 75 mg of sodium hydride (as a 55% w/w dispersion in mineral oil) and 0.14 g of 3-dimethylaminopropyl chloride hydrochloride were reacted in 20 ml of dimethylacetamide. The crude product, extracted as described in Example 2(a), was purified by column chromatography through silica gel, using a 10:1 by volume mixture of methylene chloride and methanol as the eluent, to give 227 mg (yield 85%) of the title compound as pale yellow solid.
Reaction SMILES: [CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[CH:7][CH:8]=2)[O:3]1.[C:16](Cl)(=[O:18])[CH3:17].[Cl-].[Al+3].[Cl-].[Cl-]>[N+](C)([O-])=O.CCOCC.O>[CH3:1][C:2]1([CH3:15])[CH2:11][C:10]([CH3:13])([CH3:12])[C:9]2[C:4](=[CH:5][C:6]([CH3:14])=[C:7]([C:16](=[O:18])[CH3:17])[CH:8]=2)[O:3]1
Reactant: Cc1ccc2c(c1)OC(C)(C)CC2(C)C
Reactant: CC(=O)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Solvent: C[N+](=O)[O-]
Solvent: CCOCC
Product: CC(=O)c1cc2c(cc1C)OC(C)(C)CC2(C)C
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To an ice-bath cooled solution of 1.96 g (9.6 mmol) of 2,2,4,4,7-pentamethyl-chroman (Compound 52) in 30 ml of nitromethane was added under argon 1.059 g (13.5 mmol) of acetyl chloride followed by 1.9 g (14.3 mmol) of aluminum chloride. The reaction mixture was stirred at room temperature for 14 h and then cooled in an ice-bath and treated with 25 ml of conc. HC1. The mixture was warmed to room temperature and diluted with ether and water. The organic layer was separated and the aqueous layer extracted with ether. The organic extracts were combined and washed successively with water, saturated NaHCO3 solution, water again, and saturated NaCl solution, and then dried (MgSO4). The solvent was removed in vacuo and the residue was purified by flash chromatography (silica; 5% ethyl acetate in hexanes) to give the title compound as a pale yellow oil. PMR (CDCl3): 1.36 (6H, s), 1.37 (6H, s), 1.86 (2H, s), 2.49 (3H, s), 2.56 (3H, s), 6.65 (1H, s), 7.74 (1H, s).
Reaction SMILES: Br[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[O:4][C:3]=1[C:13]([CH3:21])([CH3:20])[O:14][SiH2:15][C:16]([CH3:19])([CH3:18])[CH3:17].[F:22][C:23]1[CH:24]=[C:25](B(O)O)[CH:26]=[CH:27][C:28]=1[F:29].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:16]([SiH2:15][O:14][C:13]([CH3:21])([CH3:20])[C:3]1[O:4][C:5](=[O:12])[C:6]2[C:11]([C:2]=1[C:27]1[CH:26]=[CH:25][CH:24]=[C:23]([F:22])[C:28]=1[F:29])=[CH:10][CH:9]=[CH:8][CH:7]=2)([CH3:19])([CH3:18])[CH3:17]
Reactant: OB(O)c1ccc(F)c(F)c1
Reactant: CC(C)(C)[SiH2]OC(C)(C)c1oc(=O)c2ccccc2c1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: CC(C)(C)[SiH2]OC(C)(C)c1oc(=O)c2ccccc2c1-c1cccc(F)c1F
Temperature: 25 °C
Yield: 85 %

Procedure:
To a solution of 4-Bromo-3-(tert-butyl-dimethyl-silanyloxymethyl)-isochromen-1-one (1.3 g, 3.53 mmol) in 15 ml of dioxane/H2O (5:1) was added 3,4-Difluorophenylboronic acid (0.83 g, 5.3 mmol) and Na2CO3(0.75 g, 7.06 mmol), then Pd(dppf)Cl2 (0.26 g, 0.35 mmol). Then the resultant mixture was stirred for 2 hours at 90° C. under N2. TLC showed SM was consumed, the reaction mixture was cooled to RT, removed the solvent, the residue was purified by column chromatography on silica gel eluted with (PE:EA=50:1) to afford title product. (m=1.3 g, yield=85%). 1HNMR: (400 MHz, CDCl3) δ 0.00 (s, 6 H), 0.83 (s, 9 H), 4.30 (tt, J=12 Hz, 2H), 7.00 (d, J=8.4 Hz, 1H), 7.11 (t, J=6.0 Hz, 1H), 7.20 (m, 1H), 7.31 (tt, J=6.8 Hz, 1H), 7.54 (t, J=6.8 Hz, 1H), 7.64 (t, J=6.8 Hz, 1H), 8.36 (d, J=8.0 Hz, 1H).
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([C:11]#[C:12][Si](C)(C)C)=[CH:7][CH:6]=1)(=[O:4])=[O:3].O.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(OCC)(=O)C>O1CCCC1.CCCCCC>[C:11]([C:8]1[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=1)#[CH:12]
Reactant: C[Si](C)(C)C#Cc1ccc(S(C)(=O)=O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: O
Product: C#Cc1ccc(S(C)(=O)=O)cc1
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
To a solution of (4-methanesulfonyl-phenylethynyl)-trimethyl-silane (20.7 g , 82.0 mmol) in tetrahydrofuran (450 mL) was added tetrabutylammonium fluoride hydrate (8.80 g, 27.3 mmol). An immediate color change from yellow to red was observed. After 5 minutes, the reaction was complete, and the solvent was removed in vacuo. Water was added, and the resulting mixture was then extracted three times with ethyl acetate. The combined organic layers were washed with water and brine, dried over magnesium sulfate, filtered, and concentrated. The residue was suspended in dichloromethane, and the insoluble material was filtered off. The filtrate was concentrated to give the crude product. Flash chromatography (RediSep® Flash column, 230-400 mesh, 0-25% ethyl acetate in hexane) afforded 1-ethynyl-4-methanesulfonyl-benzene (10.7 g, 72% yield) as a yellow solid.
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[NH:6][CH:7]=[N:8]2.Br[CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:20])[OH:19]>CN(C)C=O>[Cl:3][C:4]1[N:12]=[CH:11][N:10]=[C:9]2[C:5]=1[N:6]=[CH:7][N:8]2[CH2:14][CH2:15][CH2:16][CH2:17][B:18]([OH:20])[OH:19]
Reactant: OB(O)CCCCBr
Reactant: Clc1ncnc2nc[nH]c12
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: OB(O)CCCCn1cnc2c(Cl)ncnc21
Reaction time: 0.17 h
Yield: 51.1 %

Procedure:
Sodium hydride (0.22 g, 7.2 mmol) was added to a solution of 6-chloropurine (0.93 g, 6.0 mmol) in dimethylformamide (20 mL) and stirred for 10 minutes. 4-Bromobutyl boronic acid (1.1 g, 6.0 mmol) in dimethylformamide (5 mL) was added to the reaction mixture and stirred at room temperature for 16 hours. After the removal of the dimethylformamide under high vacuum, the residue was purified by column chromatography (chloroform/methanol discontinuous gradient 95:5, 9:1) to yield 0.78 g of pure product. Yield 51%; mp 135°-138° C.; 1H NMR (DMSO-d6) 0.55-0.68 (t, B CH2), 1.22-1.35 (m, B CH2 CH2), 1.78-1.91 (m, B CH2 CH2 CH2), 4.26-4.32 (t, CH2 CH2 N), 7.40-7.42 (s, (HO)2 B), 8.68-8.70 (s, H C8 purine), 8.80-8.81 (s, H C2 purine). Elemental Analysis. (C9H12BO2N4Cl); Calcd. C, 42.47%; H, 4.75%; N, 22.02%; Found C, 42.48%; H, 4.80%; N, 22.06%.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3](B(O)O)[CH:2]=1.Br[C:11]1[C:12]([O:21][CH3:22])=[CH:13][C:14]([O:19][CH3:20])=[C:15]([CH:18]=1)[CH:16]=[O:17]>>[CH3:20][O:19][C:14]1[CH:13]=[C:12]([O:21][CH3:22])[C:11]([C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)=[CH:18][C:15]=1[CH:16]=[O:17]
Reactant: OB(O)c1cccnc1
Reactant: COc1cc(OC)c(C=O)cc1Br
Product: COc1cc(OC)c(-c2cccnc2)cc1C=O
Yield: 68 %

Procedure:
Ex-104A: 2,4-Dimethoxy-5-pyridin-3-yl-benzaldehyde was prepared in a similar manner as described in Ex-3A from pyridine-3-boronic acid and 5-bromo-2,4-dimethoxybenzaldehyde, 68% yield. 1H-NMR (CDCl3) δ 10.33 (s, 1H), 8.71 (d, J=1 Hz, 1H), 8.51–8.53 (m, 1H), 7.81 (s, 1H), 7.74–7.78 (m, 1H), 7.27–7.31 (m, 1H), 6.52 (s, 1H), 3.99 (s, 3H), 3.91 (s, 3H). HMRS (EI) calcd. for C14H13NO3: 243.0895; found: 243.0888.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([OH:6])=O.O=S(Cl)Cl.[Cl:16][C:17]1[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=1[NH2:19].C(Cl)(Cl)Cl>C1C=CC=CC=1>[NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([NH:19][C:18]1[CH:20]=[CH:21][CH:22]=[CH:23][C:17]=1[Cl:16])=[O:6]
Reactant: Nc1ccccc1Cl
Reactant: Nc1cccc(Cl)c1C(=O)O
Solvent: c1ccccc1
Solvent: ClC(Cl)Cl
Solvent: O=S(Cl)Cl
Product: Nc1cccc(Cl)c1C(=O)Nc1ccccc1Cl
Yield: 25.6 %

Procedure:
Prepared according to Procedure A using 2-amino-6-chlorobenzoic acid (2.5 g, 14.6 mmol) and SOCl2 (2.7 mL, 36.4 mmol) in benzene (75 mL), followed by 2-chloroaniline (3.1 mL, 29.1 mmol) and CHCl3 (75 mL). The product chromatographed in CH2Cl2 to provide 1.05 g of a yellow orange solid (26%). 1H NMR (CDCl3) δ: 8.54 (d, J=8.1 Hz, 1H); 8.30 (br s, 1H); 7.41 (dd, J=1.5, 8.0 Hz, 1H); 7.33 (t, J=7.8 Hz, 1H); 7.10 (t, J=8.1 Hz, 1H); 7.09 (dt, J=1.6, 7.8 Hz, 1H); 6.78 (dd, J=0.4, 7.9 Hz, 1H); 6.63 (dd, J=0.9, 8.2 Hz, 1H); 4.69 (br s, 2H). MS (ES): m/z 303.0 (M+22), 281.0 (M+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][CH:3]=1.[O:13]1CCOCC1>Cl>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:13])[NH:9]2)=[CH:4][CH:3]=1
Reactant: C1COCCO1
Reactant: Clc1ccc2ccc(Br)cc2n1
Agent: Cl
Product: O=c1ccc2ccc(Br)cc2[nH]1

Procedure:
7-Bromo-2-chloroquinoline was heated in 5M HCl (100 mL) and dioxane (10 mL) for 1 hour at reflux. The Reaction mixture was cooled, filtered and washed with water to give the title compound, 2.89 g, as a colorless solid, mp 295° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14]Br)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[N:24]=[N:25][NH:26][N:27]=2)=[CH:19][CH:18]=1.C(=O)([O-])[O-].[K+].[K+].C(N(C(C)C)CC)(C)C>C1(C)C(C)=CC=CC=1>[CH2:1]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][N:25]1[N:26]=[N:27][C:23]([C:20]2[CH:21]=[CH:22][C:17]([F:16])=[CH:18][CH:19]=2)=[N:24]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: BrCC1CCCCN1Cc1ccccc1
Reactant: Fc1ccc(-c2nn[nH]n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1C
Product: Fc1ccc(-c2nnn(CC3CCCCN3Cc3ccccc3)n2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
N-Benzyl-2-bromomethylpiperidine (2.1 g), 5-(4-fluoro-phenyl)-2H-tetrazole (1.28 g) and potassium carbonate (6 g) were combined in xylene (100 ml) containing diisopropylethylamine (7 ml) and boiled for 16 h. The reaction mixture was cooled to room temperature, filtered, solvent removed at reduced pressure and the residue column chromatographed (silica gel; diethyl ether/petroleum ether 40:60 eluant) to give after combining appropriate fractions and removing solvent at reduced pressure the title compound 1.44 g.
Reaction SMILES: [CH:1]1([C:4](=[O:28])[CH:5](C(OC(C)(C)C)=O)[C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[C:11]([S:19][CH3:20])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH:1]1([C:4](=[O:28])[CH2:5][C:6]([C:8]2[C:16]3[O:15][C:14]([F:18])([F:17])[O:13][C:12]=3[C:11]([S:19][CH3:20])=[CH:10][CH:9]=2)=[O:7])[CH2:3][CH2:2]1
Reactant: CSc1ccc(C(=O)C(C(=O)OC(C)(C)C)C(=O)C2CC2)c2c1OC(F)(F)O2
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CSc1ccc(C(=O)CC(=O)C2CC2)c2c1OC(F)(F)O2
Yield: 84.6 %

Procedure:
A solution of 4-(3-cyclopropyl-2-t-butyloxycarbonyl-1,3-dioxoprop-1-yl)-2,2-difluoro-7-methylsulphenyl-1,3-benzodioxole (10.3 g) and para-toluenesulphonic acid (0.5 g) was heated under reflux with toluene for 3 hours. After cooling, the solvent was evaporated in vacuo, and ethyl acetate added. The solution was washed with water, dried over anhydrous magnesium sulphate and evaporated. The residue was purified by column chromatography, eluting with ethyl acetate/cyclohexane to yield 4-(3-cyclopropyl-1,3-dioxoprop-1-yl)-2,2-difluoro-7-methylsulphenyl-1,3-benzodioxole (6.61 g) m.p. 117.5°-118.5° C.
Reaction SMILES: S(C1C=CC(C)=CC=1)(O)(=O)=O.[CH2:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH2:15][C@@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[NH:13]1.CN1CCOCC1.C1(N=C=NC2CCCCC2)CCCCC1.[C:54](O)(=[O:58])[C:55]([CH3:57])=[O:56]>C(Cl)(Cl)Cl>[C:54]([N:13]1[C@H:14]([C:22]([O:24][CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)=[O:23])[CH2:15][C:16]2[C:21](=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH2:12]1)(=[O:58])[C:55]([CH3:57])=[O:56]
Reactant: CC(=O)C(=O)O
Reactant: O=C(OCc1ccccc1)[C@@H]1Cc2ccccc2CN1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClC(Cl)Cl
Solvent: CN1CCOCC1
Product: CC(=O)C(=O)N1Cc2ccccc2C[C@H]1C(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 48 h

Procedure:
13.17 g of benzyl (S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate tosylate (N. Yoneda, et al., Chem.Pharm.Bull., 31, 312 (1983)) was suspended in 30 mL CHCl3. N-methylmorpholine was added until the pH was 7, 6.8 g of dicyclohexylcarbodiimide and 3.17 g of pyruvic acid was added at -5° C. The reaction mixture was stirred at -50° C. for one hour and 0° C. for 48 hours. The reaction mixture was filtered, and the filtrate was concentrated to dryness to give a semi-solid, which was purified by passing through a silica gel column and eluting with ethyl acetate:hexane (1:1) to give benzyl N-pyruvoyl-(S)-1,2,3,4-tetrahydroisoquinoline-3-carboxylate as a yellow oil, [α]D25 -10.3°.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15](=[O:21])[CH:16](OCC)O)=[CH:11][C:10]=1[NH:22][S:23]([CH3:26])(=[O:25])=[O:24])C1C=CC=CC=1.[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]3[N:40]=[C:39]([CH3:41])[N:38]([CH2:42][CH2:43][C:44]([NH2:47])([CH3:46])[CH3:45])[N:37]=3)=[CH:35][C:30]=2[O:29][CH2:28]1>>[O:27]1[C:31]2[CH:32]=[CH:33][C:34]([C:36]3[N:40]=[C:39]([CH3:41])[N:38]([CH2:42][CH2:43][C:44]([NH:47][CH2:16][CH:15]([C:12]4[CH:13]=[CH:14][C:9]([OH:8])=[C:10]([NH:22][S:23]([CH3:26])(=[O:24])=[O:25])[CH:11]=4)[OH:21])([CH3:45])[CH3:46])[N:37]=3)=[CH:35][C:30]=2[O:29][CH2:28]1
Reactant: Cc1nc(-c2ccc3c(c2)OCO3)nn1CCC(C)(C)N
Reactant: CCOC(O)C(=O)c1ccc(OCc2ccccc2)c(NS(C)(=O)=O)c1
Product: Cc1nc(-c2ccc3c(c2)OCO3)nn1CCC(C)(C)NCC(O)c1ccc(O)c(NS(C)(=O)=O)c1

Procedure:
Analogously to the method described for Example 7, 379 mg (1 mmol) N-[2-benzyloxy-5-[2-ethoxy-2-hydroxy-acetyl)-phenyl]-methanesulphonamide and 288 mg (1 mmol) 3-(3-benzo[1,3]dioxol-5-yl-5-methyl-[1,2,4]triazol-1-yl)-1,1-dimethyl-propylamine are reacted with one another. The subsequent debenzylation yields the target compound.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:31][CH2:30]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:4][CH2:3]1.[C:32](Cl)(=[O:34])[CH3:33]>>[C:32]([N:2]1[CH2:3][CH2:4][CH:5]([NH:8][C:9]([C:11]2[C:15]3[N:16]=[CH:17][N:18]=[C:19]([C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=4[O:27][CH2:28][CH:29]4[CH2:30][CH2:31]4)[C:14]=3[NH:13][CH:12]=2)=[O:10])[CH2:6][CH2:7]1)(=[O:34])[CH3:33]
Reactant: O=C(NC1CCNCC1)c1c[nH]c2c(-c3ccc(F)cc3OCC3CC3)ncnc12
Reactant: CC(=O)Cl
Agent: Cl
Product: CC(=O)N1CCC(NC(=O)c2c[nH]c3c(-c4ccc(F)cc4OCC4CC4)ncnc23)CC1

Procedure:
Starting from 4-(2-Cyclopropylmethoxy-4-fluoro-phenyl)-5H-pyrrolo[3,2-d]pyrimidine-7-carboxylic acid piperidin-4-ylamide hydrochloride (example A158) and acetyl chloride the title compound is obtained as colorless solid.
Reaction SMILES: Cl[CH2:2][C@@H:3]([OH:21])[CH2:4][NH:5][CH2:6][CH2:7][NH:8][S:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=1[N+:18]([O-:20])=[O:19])(=[O:11])=[O:10].C([O-])([O-])=O.[Cs+].[Cs+]>C(#N)C>[N+:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[S:9]([N:8]1[CH2:2][C@@H:3]([OH:21])[CH2:4][NH:5][CH2:6][CH2:7]1)(=[O:11])=[O:10])([O-:20])=[O:19]
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)NCCNC[C@H](O)CCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccccc1S(=O)(=O)N1CCNC[C@H](O)C1
Temperature: 60 °C
Yield: 30.7 %

Procedure:
A suspension of N-[2-({2S}-3-chloro-2-hydroxy-propylamino)-ethyl]-2-nitro-benzenesulfonamide (20.73 gm, 61.4 mmole) and Cs2CO3 (73 gm, 3 equiv) in dry acetonitrile (600 mL) under a N2 atmosphere was heated at 60° C. for 6.5 hr. The solid was removed by filtration and then the solvent was removed from the filtrate. The residue was partitioned between DCM (400 mL) and water (100 mL). The organic phase was dried (Na2SO4) and the solvent was removed. Silica gel chromatography (step gradient elution with DCM containing: 0, 1, 2, 3, 4% MeOH) afforded the title compound as an oil (5.68 gm, 31%). 1H NMR (CDCl3+D2O) δ 2.3 (br. s, 2H), 2,85 (m, 4H), 3.09 (m, 4H), 7.68 (m, 3H), 8.00 (m, 1H); MS: 302 (M+H+); HPLC Ret Time: 0.56 min (YMC Xterra 3.0×50 mm S7 C18 column, 3 min gradient, 4 mL/min).
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[Br:12]Br.O.CO>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]([CH3:11])[C:2]([OH:1])=[C:3]([CH:7]=1)[C:4]([OH:6])=[O:5]
Reactant: Cc1cccc(C(=O)O)c1O
Reactant: BrBr
Solvent: O
Solvent: CO
Solvent: CC(=O)O
Product: Cc1cc(Br)cc(C(=O)O)c1O
Reaction time: 24 h

Procedure:
To a mixture of 2-hydroxy-3-methylbenzoic acid (2.1 g, 13.5 mmol) in acetic acid (30 mL) was added bromine (0.7 mL, 13.7 mmol) slowly over 5 minutes. After 24 h, water was added slowly to the reaction mixture and the reaction stirred for 30 min. The resulting precipitate was collected by filtration and washed several times with water. The product was dried overnight under high vacuum to afford 2.8 g (90%). LC/MS: tR=2.86 min, 229.14 (MH)+. (Phenomenex C18 4.6×50 mm, 10% MeOH/90% H2O/0.1% TFA→90% MeOH/10% H2O/0.1% TFA, Gradient time=4 min., Flow rate=4 mL/min.).
Reaction SMILES: [NH2:1][CH:2]([CH2:6][CH:7]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)[C:3]([OH:5])=[O:4].[C:15](#N)[CH3:16]>>[CH:7]1([CH2:6][CH:2]([N:1]2[CH2:16][C:15]3[C:2](=[CH:6][CH:7]=[CH:8][CH:9]=3)[C:3]2=[O:4])[C:3]([OH:5])=[O:4])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC#N
Reactant: NC(CC1CCCCCCC1)C(=O)O
Product: O=C(O)C(CC1CCCCCCC1)N1Cc2ccccc2C1=O
Temperature: 25 °C
Yield: 62 %

Procedure:
A solution of phthalic dicarboxaldehyde (349 mg; 2.60 mmol) and 2-Amino-3-cyclooctyl-propionic acid (500 mg; 2.51 mmol) in acetonitrile (20 mL) was heated to reflux for 3 h. The mixture was then hot filtered to remove insoluble material and then allowed to cool to room temperature and then further cooled to 0° C. The solid was filtered off, rinsed with cold acetonitrile and air dried to give 480 mg (62%) of 3-Cyclooctyl-2-(1-oxo-1,3-dihydro-isoindol-2-yl)-propionic acid as a white solid: EI-HRMS m/e calcd for C19H25NO3 (M+) 315.1834, found 315.1840.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH2:13])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[Cl:14][C:15]1[CH:22]=[C:21]([Cl:23])[CH:20]=[CH:19][C:16]=1[CH:17]=O.[BH4-].[Na+]>CO>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@H:10]([NH:13][CH2:17][C:16]2[CH:19]=[CH:20][C:21]([Cl:23])=[CH:22][C:15]=2[Cl:14])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=Cc1ccc(Cl)cc1Cl
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CC[C@H](NCc2ccc(Cl)cc2Cl)C1

Procedure:
Stir a mixture of (S)-3-amino-pyrrolidine-1-carboxylic acid tert-butyl ester (15.07 g, 81.0 mmol) and 2,4-dichlorobenzaldehyde (13.46 g, 76.9 mmol) in dry methanol (250 mL) at room temperature under nitrogen overnight. Add slowly sodium borohydride (4.74 g, 125.4 mmol) and stir for 10 min. Concentrate and add 2 N NaOH (150 mL) and extract with diethyl ether. Combine the organic layers, wash with saturated aqueous sodium chloride, dry (magnesium sulfate) and concentrate to give (S)-3-(2,4-dichlorobenzylamino)-pyrrolidine-1-carboxylic acid tert-butyl ester which may be used without further purification (26.9 g, 100%).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[N:4]([CH3:19])[C:3]1=[O:20].[CH3:21][CH:22]([C:26]([NH:28][CH2:29][C:30]1[CH:35]=[C:34]([F:36])[CH:33]=[CH:32][C:31]=1[F:37])=[O:27])[C:23](O)=[O:24]>>[F:37][C:31]1[CH:32]=[CH:33][C:34]([F:36])=[CH:35][C:30]=1[CH2:29][NH:28][C:26](=[O:27])[CH:22]([CH3:21])[C:23]([NH:1][CH:2]1[C:3](=[O:20])[N:4]([CH3:19])[C:5]2[CH:18]=[CH:17][CH:16]=[CH:15][C:6]=2[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[N:8]1)=[O:24]
Reactant: CC(C(=O)O)C(=O)NCc1cc(F)ccc1F
Reactant: CN1C(=O)C(N)N=C(c2ccccc2)c2ccccc21
Product: CC(C(=O)NCc1cc(F)ccc1F)C(=O)NC1N=C(c2ccccc2)c2ccccc2N(C)C1=O

Procedure:
The title compound, MS: m/e=491.3 (M+H+), was prepared in analogy to example 16 from 3-amino-1,3-dihydro-1-methyl-5-phenyl-2H-1,4-benzodiazepin-2-one and 2-methyl-N-(2,5-difluoro-benzyl)-malonamic acid.