Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([CH:3]([C:6]1[C:7]2[N:8]([CH:13]=[C:14]([CH3:16])[N:15]=2)[N:9]=[C:10]([CH3:12])[CH:11]=1)[CH2:4][CH3:5])[CH3:2].Br[C:18]1[C:19]([CH3:29])=[N:20][O:21][C:22]=1[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:29][C:19]1[C:18]([C:13]2[N:8]3[N:9]=[C:10]([CH3:12])[CH:11]=[C:6]([CH:3]([CH2:4][CH3:5])[CH2:1][CH3:2])[C:7]3=[N:15][C:14]=2[CH3:16])=[C:22]([C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[O:21][N:20]=1
Reactant: CCC(CC)c1cc(C)nn2cc(C)nc12
Reactant: Cc1noc(-c2ccccc2)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)noc3-c3ccccc3)c(C)nc12
Temperature: 130 °C
Yield: 19.3 %

Procedure:
Using the procedure analogous to Example 257, 8-(1-ethyl-propyl)-2,6-dimethyl-imidazo[1,2-b]pyridazine (200 mg, 0.90 mmol), 4-bromo-3-methyl-5-phenyl isoxazole (430 mg, 1.8 mmol), cesium carbonate (880 mg, 2.70 mmol) and PdCl2(PPh3)2 (25 mg) in DMF (5 ml) are combined and heated at 130° C. for 5 hrs to give the title compound (65 mg, 23% yield). ES-MS (m/z): calc'd for C23H26N4O: 374.5. found 375.1 (M+H)+. 1H NMR (400 mHz, CDCl3): δ 7.50 (d, 2H), 7.31 (m, 3H), 6.69 (s, 1H), 3.39 (m, 1H), 2.48 (s, 3H), 2.20 (s, 6H), 2.33 (s, 3H), 1.84 (m, 4H), 0.88 (m, 6H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8](C(OC)=O)[C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1.[Na+].[Cl-]>CS(C)=O.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][C:9]([O:11][CH3:12])=[O:10])=[N:6][CH:7]=1
Reactant: COC(=O)C(C(=O)OC)c1ccc(F)cn1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: COC(=O)Cc1ccc(F)cn1
Temperature: 25 °C

Procedure:
The solution of dimethyl 2-(5-fluoropyridin-2-yl)malonate (400 mg 1.76 mmol), NaCl (109.2 mg, 1.87 mmol) and H2O (56.3 g, 3.13 mmol) in DMSO (3 mL) was stirred at 130 degree for 6 h. After cooling to room temperature, the reaction mixture was diluted with H2O and extracted with ethyl acetate. The organic layer was dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by a standard method to get desired product. LC-MS: m/z (M+H)=170.1
Reaction SMILES: [CH2:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([OH:39])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[Cs+].[Cs+].[C:47]([O:51][C:52](=[O:55])[CH2:53]Br)([CH3:50])([CH3:49])[CH3:48]>CN(C=O)C.O>[CH2:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:40])[C@@H:15]([NH:26][C:27]([C:29]2[CH:38]=[C:37]([O:39][CH2:53][C:52]([O:51][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:55])[C:36]3[C:31](=[CH:32][CH:33]=[CH:34][CH:35]=3)[N:30]=2)=[O:28])[CH2:16][CH2:17][O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:12][CH2:13]1)=[O:7])[CH2:2][CH2:3][CH3:4]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(O)c3ccccc3n2)CC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N1CCN(C(=O)[C@H](CCOCc2ccccc2)NC(=O)c2cc(OCC(=O)OC(C)(C)C)c3ccccc3n2)CC1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To a solution of 900 mg 4-{(S)-4-Benzyloxy-2-[(4-hydroxy-quinoline-2-carbonyl)-amino]-butyryl}-piperazine-1-carboxylic acid butyl ester in 6.7 ml of DMF, 587 mg of cesium carbonate and 351 mg of Bromo-acetic acid tert-butyl ester was added and the reaction mixture was stirred for 5 h at RT. Then, the reaction mixture was diluted with water and extracted with ethyl acetate. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The isolated crude product was pure enough for the next reaction step. Yield: 1.1 g.
Reaction SMILES: [F:1][C@:2]12[CH:22]([OH:23])[CH2:21][C@@:20]3([CH3:24])[C@@H:12]([CH2:13][C@H:14]([CH3:26])[C@:15]3([OH:25])[C:16](=[O:19])[CH2:17][SH:18])[C@@H:11]1[CH2:10][CH2:9][C:8]1[C@:3]2([CH3:28])[CH:4]=[CH:5][C:6](=[O:27])[CH:7]=1.[C:29]([NH:32][C@H:33]([C:38](O)=[O:39])[CH2:34][S:35][CH2:36][CH3:37])(=[O:31])[CH3:30]>>[C:29]([NH:32][CH:33]([CH2:34][S:35][CH2:36][CH3:37])[C:38](=[O:39])[S:18][CH2:17][C:16](=[O:19])[C@:15]1([OH:25])[C@:20]2([CH3:24])[C@H:12]([C@H:11]3[C@:2]([F:1])([C@@H:22]([OH:23])[CH2:21]2)[C@:3]2([CH3:28])[C:8](=[CH:7][C:6](=[O:27])[CH:5]=[CH:4]2)[CH2:9][CH2:10]3)[CH2:13][C@@H:14]1[CH3:26])(=[O:31])[CH3:30]
Reactant: C[C@H]1C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)C(O)C[C@]2(C)[C@@]1(O)C(=O)CS
Reactant: CCSC[C@H](NC(C)=O)C(=O)O
Product: CCSCC(NC(C)=O)C(=O)SCC(=O)[C@@]1(O)[C@@H](C)C[C@H]2[C@@H]3CCC4=CC(=O)C=C[C@]4(C)[C@@]3(F)[C@@H](O)C[C@@]21C
Yield: 29.5 %

Procedure:
The title compound (0.21 gm) was prepared from 9-fluoro-11 ,17-dihydroxy-16β-methylpregna-1,4-diene-3,20-dione-21-thiol (0.5 gm) and N-acetyl-S-ethylcysteine (0.70 gm) in the same manner as in Synthetic Example 1.
Reaction SMILES: [C:1](Cl)(=O)[C:2]([Cl:4])=[O:3].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14]C=1C([O-])=O>C(Cl)Cl.CN(C=O)C>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][C:12]1[S:16][C:15]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[N:14][C:1]=1[C:2]([Cl:4])=[O:3]
Reactant: COCCCc1sc(-c2ccccc2)nc1C(=O)[O-]
Reactant: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COCCCc1sc(-c2ccccc2)nc1C(=O)Cl
Reaction time: 0.33 h
Yield: 99.6 %

Procedure:
Oxalyl chloride (67.2 mmol, 5.9 mL) was slowly added to a room temperature solution of 5-(3-methoxypropyl)-2-phenylthiazole-4-carboxylate (22.4 mmol, 6.2 g) in CH2Cl2 (100 mL). 3 drops of DMF were added and the reaction became homogeneous over ˜20 min. The reaction was stirred for 3 h, then concentrated under reduced pressure. The crude product was dissolved in CH2Cl2 (150 mL) and concentrated under reduced pressure. The crude product was dissolved in EtOAc (150 mL), washed with brine (2×100 mL), dried (MgSO4), and concentrated under reduced pressure to give 5-(3-methoxypropyl)-2-phenylthiazole-4-carbonyl chloride as a tan solid (6.6 g, 99% yield).
Reaction SMILES: [CH3:1][S:2]([N:5]1[CH2:10][CH2:9][N:8]([CH2:11][C:12]2[S:20][C:19]3[C:18]([N:21]4[CH2:26][CH2:25][O:24][CH2:23][CH2:22]4)=[N:17][C:16]([C:27]4[CH:28]=[C:29]([CH:33]=[O:34])[CH:30]=[N:31][CH:32]=4)=[N:15][C:14]=3[CH:13]=2)[CH2:7][CH2:6]1)(=[O:4])=[O:3].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>CN(C=O)C>[O:24]1[CH2:23][CH2:22][N:21]([C:18]2[C:19]3[S:20][C:12]([CH2:11][N:8]4[CH2:7][CH2:6][N:5]([S:2]([CH3:1])(=[O:4])=[O:3])[CH2:10][CH2:9]4)=[CH:13][C:14]=3[N:15]=[C:16]([C:27]3[CH:28]=[C:29]([CH2:33][OH:34])[CH:30]=[N:31][CH:32]=3)[N:17]=2)[CH2:26][CH2:25]1
Reactant: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(C=O)c4)nc(N4CCOCC4)c3s2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CS(=O)(=O)N1CCN(Cc2cc3nc(-c4cncc(CO)c4)nc(N4CCOCC4)c3s2)CC1
Temperature: 40 °C
Yield: 74.7 %

Procedure:
To 60 mg of 5-[6-(4-methanesulfonyl-piperazin-1-ylmethyl)-4-morpholin-4-yl-thieno[3,2-d]pyrimidin-2-yl]-pyridine-3-carbaldehyde 241 (Example 158) in dry DMF was added sodium triacetoxyborohydride (66 mg) and the reaction mixture was heated at 40° C. overnight. After the SCX-2 cartridge work-up, purification on silica and recrystallization from DCM/hexane gave 235 (45 mg). NMR (CDCl3): 1.80-1.90 (1H, br, OH), 2.67-2.71 (4H, m), 2.81 (3H, s), 3.29-3.33 (4H, m), 3.89 (2H, s), 3.89-3.93 (4H, m), 4.08-4.12 (4H, m), 4.86 (2H, s), 7.35 (1H, s), 8.70 (1H, s), 8.71 (1H, s), 9.56 (1H, s). MS (ESI+): MH+505.17 (100%)
Reaction SMILES: C([O:3][C:4](=[O:26])[CH2:5][O:6][C:7]1[CH:12]=[C:11](Cl)[CH:10]=[CH:9][C:8]=1[C:14](=[O:25])[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([Br:23])=[CH:19][C:18]=1[F:24])C.[OH-].[Na+].Cl.[CH2:30]([OH:32])C>C(OCC)(=O)C>[Br:23][C:20]1[CH:21]=[CH:22][C:17]([CH2:16][NH:15][C:14]([C:8]2[CH:9]=[CH:10][C:11]([O:32][CH3:30])=[CH:12][C:7]=2[O:6][CH2:5][C:4]([OH:3])=[O:26])=[O:25])=[C:18]([F:24])[CH:19]=1
Reactant: CCOC(=O)COc1cc(Cl)ccc1C(=O)NCc1ccc(Br)cc1F
Reactant: CCO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: COc1ccc(C(=O)NCc2ccc(Br)cc2F)c(OCC(=O)O)c1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 89 %

Procedure:
A solution of [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-chloro-phenoxy]-acetic acid ethyl ester (1.23 g, 2.8 mmol) in ethanol (16 mL, 0.18 M) was cooled to 0° C. and treated with aq NaOH (1.25 M, 7.0 mL, 8.7 mmol). After stirring for 2.5 h, the solution was warmed to room temperature and stirred an additional 24 h. Next, the solution was acidified to pH 1-2 with 2 N HCl, diluted with ethyl acetate and washed with saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give [2-(4-bromo-2-fluoro-benzylcarbamoyl)-5-methoxy-phenoxy]-acetic acid as a white solid (1.03 g, 89%): mp 203-204° C.; Rf 0.10 (10% methanol in dichloromethane); 1H NMR (DMSO-d6, 300 MHz) δ 9.02 (br t, J=5.9 Hz, 1H), 7.84, (d, J=8.2 Hz, 1H), 7.50, (br d, J=8.7 Hz, 1H), 7.48-7.29 (m, 2H), 6.69-6.8 0 (m, 2H), 4.87 (s, 2H), 4.49 (d, J=5.8 Hz, 2H), 3.79 (s, 3H). ESI-LC/MS m/z calcd for C17H15BrFNO5: 411.0; found 412.0 (M+1)−. Anal. calcd for C17H15BrFNO5: C, 49.53; H, 3.67; N, 3.40. Found C, 49.48; H, 3.68; N, 3.39.
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][CH2:9][N:8]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][CH3:19])[CH:12]=2)[CH2:7][CH2:6]1)=[O:4].[C:20]1([CH:26]2[CH2:30][O:29][C:28](=[O:31])[NH:27]2)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([N:8]2[CH2:9][CH2:10][N:5]([C:3](=[O:4])[CH2:2][N:27]3[CH:26]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)[CH2:30][O:29][C:28]3=[O:31])[CH2:6][CH2:7]2)=[CH:12][C:13]=1[O:18][CH3:19]
Reactant: COc1cc(N2CCN(C(=O)CCl)CC2)ccc1Cl
Reactant: O=C1NC(c2ccccc2)CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1cc(N2CCN(C(=O)CN3C(=O)OCC3c3ccccc3)CC2)ccc1Cl

Procedure:
Compound 42 was prepared according to the procedure described in Example 2 using 2-Chloro-1-[4-(4-chloro-3-methoxy-phenyl)-piperazin-1-yl]-ethanone (1) (0.1 mmol), 4-phenyl-oxazolidin-2-one and Cs2CO3 in DMF: HPLC retention time, 2.30 minutes (Agilent Zorbax SB-C18, 2.1×50 mm, 5μ, 35° C.) using 1 ml/min flow rate, a 2.5 minute gradient of 20% to 100% B with a 1.1 minute wash at 100% B (A=0.1% formic acid/5% acetonitrile/94.9% water, B=0.1% formic acid/5% water/94.9% acetonitrile); MS (ES) M+H expected, 430.2, found, 430.3.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1.[CH:13]1([NH2:17])[CH2:16][CH2:15][CH2:14]1>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:17][CH:13]2[CH2:16][CH2:15][CH2:14]2)(=[O:10])=[O:9])=[C:4]([F:12])[CH:3]=1
Reactant: NC1CCC1
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1F
Solvent: ClCCl
Product: O=S(=O)(NC1CCC1)c1ccc(Br)cc1F
Yield: 42.7 %

Procedure:
According to general procedure C, 4-Bromo-2-fluoro-benzenesulfonyl chloride (0.40 g, 1.46 mmol) and cyclobutylamine (0.31 mL, 3.65 mmol) were stirred together with dry dichloromethane (5 mL) for 16 hours. 4-bromo-N-cyclobutyl-2-fluorobenzenesulfonamide (192 mg, 43%) was provided after purification. MS (ESI) m/z 308. HPLC purity 90.7% at 210-370 nm, 11.2 min.; the Xterra® RP18 column, 3.5μ, 150×4.6 mm column, 1.2 mL/min., 85/15-5/95 (ammonium formate buffer pH=3.5/ACN+MeOH) for 10 min., hold 4 min.
Reaction SMILES: [CH:1]1([C:5](Cl)=[O:6])[CH2:4][CH2:3][CH2:2]1.[NH2:8][CH:9]1[C:14](=[O:15])[N:13]2[CH:16]([CH2:24][C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)[C:17](=[O:23])[N:18]([CH:20]([CH3:22])[CH3:21])[CH2:19][CH:12]2[N:11]([S:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=2[Cl:42])(=[O:34])=[O:33])[CH2:10]1>>[Cl:31][C:28]1[CH:29]=[CH:30][C:25]([CH2:24][CH:16]2[N:13]3[C:14](=[O:15])[CH:9]([NH:8][C:5]([CH:1]4[CH2:4][CH2:3][CH2:2]4)=[O:6])[CH2:10][N:11]([S:32]([C:35]4[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][C:36]=4[Cl:42])(=[O:34])=[O:33])[CH:12]3[CH2:19][N:18]([CH:20]([CH3:22])[CH3:21])[C:17]2=[O:23])=[CH:26][CH:27]=1
Reactant: CC(C)N1CC2N(C(=O)C(N)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O
Reactant: O=C(Cl)C1CCC1
Product: CC(C)N1CC2N(C(=O)C(NC(=O)C3CCC3)CN2S(=O)(=O)c2ccc(Cl)cc2Cl)C(Cc2ccc(Cl)cc2)C1=O

Procedure:
Synthesis took place in analogy to Example 22 using cyclobutanecarbonyl chloride and 3-amino-6-(4-chlorobenzyl)-1-(2,4-dichlorobenzenesulfonyl)-8-isopropylhexahydropyrazino[1,2-a]pyrimidine-4,7-dione. The desired product is obtained with MW=640.11 (calculated, monoisotopic); measured value (M+H)+: 641.09
Reaction SMILES: [NH:1]1[C:5]2[CH2:6][CH2:7][CH:8]([C:10]([OH:12])=O)[CH2:9][C:4]=2[N:3]=[CH:2]1.[C:13]1([CH2:19][CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>>[C:13]1([CH2:19][CH2:20][CH2:21][NH:22][C:10]([CH:8]2[CH2:7][CH2:6][C:5]3[NH:1][CH:2]=[N:3][C:4]=3[CH2:9]2)=[O:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(O)C1CCc2[nH]cnc2C1
Reactant: NCCCc1ccccc1
Product: O=C(NCCCc1ccccc1)C1CCc2[nH]cnc2C1

Procedure:
The title compound was prepared by a similar procedure as described in Example 4 from 100 mg of 2-formyl-5-methoxyphenoxyethylpolystyrene (0.55 mmol/g) resin, 4,5,6,7-tetrahydro-1H-benzimidazole-5-carboxylic acid (111 mg, 0.55 mmol) and 3-phenylpropylamine (74.4 mg, 0.55 mmol).
Reaction SMILES: [CH2:1]([NH:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:16]([CH2:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:15]([C:25]([OH:27])=O)[N:14]=[N:13]2)=[CH:8][CH:7]=1)=[O:5])[CH3:2].C1C=C[C:31]2N(O)N=[N:34][C:32]=2[CH:33]=1.C1(N)CC1.CCN=C=NCCCN(C)C>C(#N)C.CN(C=O)C>[CH:32]1([NH:34][C:25]([C:15]2[N:14]=[N:13][N:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([NH:3][CH2:1][CH3:2])=[O:5])=[CH:7][CH:8]=3)[C:16]=2[CH2:17][CH2:18][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:27])[CH2:33][CH2:31]1
Reactant: On1nnc2ccccc21
Reactant: CCNC(=O)c1ccc(-n2nnc(C(=O)O)c2CCc2ccccc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: NC1CC1
Solvent: CN(C)C=O
Solvent: CC#N
Product: CCNC(=O)c1ccc(-n2nnc(C(=O)NC3CC3)c2CCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 189.2 %

Procedure:
1-{4-[(Ethylamino)carbonyl]phenyl}-5-(2-phenylethyl)-1H-1,2,3-triazole-4-carboxylic acid (501 mg, 1.37 mmol) obtained in Example 98b), HOBt (93.8 mg, 0.687 mmol, 0.5 eq.) and cyclopropylamine (0.128 ml, 1.79 mmol, 1.3 eq.) were dissolved in acetonitrile-DMF (2:1, 7.5 ml), WSC (323 mg, 1.65 mmol, 1.2 eq.) was added, and the mixture was stirred at room temperature for 1.5 hr. The reaction mixture was concentrated, and the residue was diluted with ethyl acetate (40 ml) and washed with 2% aqueous sodium carbonate solution (×2), 10% aqueous ammonium chloride solution and saturated brine. The aqueous layer was each extracted with ethyl acetate-hexane (2:1, 30 ml). The organic layers were combined, dried over anhydrous sodium sulfate and concentrated, and diethyl ether was added to the residue. The precipitate was collected by filtration, washed with diethyl ether and dried to give the title compound as a white powder (526 mg, 1.30 mmol, 95.2%).
Reaction SMILES: [CH:1]1([N:4]([CH:20]([C:22]2[CH:23]=[N:24][C:25]([O:36][CH3:37])=[C:26]([C:28]#[C:29][CH2:30][NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.O1CCCC1>C(OCC)(=O)C.[Pd]>[CH:1]1([N:4]([CH:20]([C:22]2[CH:23]=[N:24][C:25]([O:36][CH3:37])=[C:26]([CH2:28][CH2:29][CH2:30][NH:31][C:32]([O:34][CH3:35])=[O:33])[CH:27]=2)[CH3:21])[C:5]([C@@H:7]2[O:12][CH2:11][CH2:10][N:9]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:8]2)=[O:6])[CH2:2][CH2:3]1
Reactant: COC(=O)NCC#Cc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)NCCCc1cc(C(C)N(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CCO2)C2CC2)cnc1OC
Reaction time: 0.75 h
Yield: 105.2 %

Procedure:
to a solution of tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)-amino]prop-1-yn-1-yl}pyridin-3-yl)ethyl]amino}carbonyl)morpholin-4-carboxylate (150 mg) in ethyl acetate (2.5 mL)-tetrahydrofuran (2.5 mL) was added 10% palladium on carbon (30 mg), and the mixture was stirred under hydrogen for 45 minutes. An insoluble was filtered off, and then the filtrate was concentrated under reduced pressure, and the resulting residue was purified by NH-silica gel column chromatography (eluent: ethyl acetate) to give tert-butyl (2R)-2-({cyclopropyl[1-(6-methoxy-5-{3-[(methoxycarbonyl)amino]propyl}pyridin-3-yl)ethyl]amino}carbonyl)morpholine-4-carboxylate [Ex(296-5)] (159 mg) as a colorless oil.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[OH:9][CH:10]1[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]1.C([O-])([O-])=O.[K+].[K+]>C(O)C>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][CH:10]([OH:9])[CH2:11][CH2:12]2)=[N:3][CH:4]=1
Reactant: OC1CCNCC1
Reactant: Brc1ccc(Br)nc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: OC1CCN(c2ccc(Br)cn2)CC1
Temperature: 110 °C
Yield: 493.5 %

Procedure:
A mixture of 2,5-dibromopyridine (100 mg, 0.42 mmol), 4-hydroxypiperidine (49 mg, 0.46 mmol) and K2CO3 (64 mg, 0.46 mmol) in ethanol (4 mL) was heated to 110° C. for 52 h. The crude reaction mixture was concentrated under reduced pressure to dryness and the residue was treated with water. Crude product was collected by vacuum filtration and purified by flash chromatography using EtOAc/hexanes (1:4 to 2:3) to give the title compound as a white solid (533 mg, 41%). 1H NMR (400 MHz, CDCl3) δ 8.18 (d, J=2.2 Hz, 1H), 7.53 (dd, J=9.0, 2.3 Hz, 1H), 6.59 (d, J=9.0 Hz, 1H), 4.04-3.94 (m, 3H), 3.18 (t, J=11 Hz, 2H), 2.00-1.95 (m, 2H), 1.63-1.54 (m, 2H); MS ESI 256.9 [M+H]+, calcd for [C10H13BrN2O+H]+ 257.02.
Reaction SMILES: ClC(Cl)(Cl)[C:3]([C:5]1[N:14]2[C:8]([CH2:9][N:10]([C:19](=[O:29])[CH2:20][O:21][C:22]3[CH:27]=[CH:26][C:25]([Cl:28])=[CH:24][CH:23]=3)[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13]2)=[CH:7][CH:6]=1)=[O:4].[NH2:32][CH2:33][CH:34]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[OH:35]>>[Cl:28][C:25]1[CH:26]=[CH:27][C:22]([O:21][CH2:20][C:19]([N:10]2[C:11]3[CH:18]=[CH:17][CH:16]=[CH:15][C:12]=3[CH2:13][N:14]3[C:5]([C:3]([NH:32][CH2:33][CH:34]([OH:35])[C:36]4[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=4)=[O:4])=[CH:6][CH:7]=[C:8]3[CH2:9]2)=[O:29])=[CH:23][CH:24]=1
Reactant: NCC(O)c1ccccc1
Reactant: O=C(COc1ccc(Cl)cc1)N1Cc2ccc(C(=O)C(Cl)(Cl)Cl)n2Cc2ccccc21
Product: O=C(NCC(O)c1ccccc1)c1ccc2n1Cc1ccccc1N(C(=O)COc1ccc(Cl)cc1)C2

Procedure:
The title compound was synthesized from 2,2,2-trichloro-1-{10-[(4-chlorophenoxy)acetyl]-10,11-dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepin-3-yl}ethanone of Example 67 (0.3 mmol) and 2-amino-1-phenylethanol (2.2 eq.) in the manner of Example 68, m.p. 157-158° C. MS [(−)ESI, m/z]: 514.3 [M−H]−
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4]Br.CC[N:14](CC)CC>N.CO.C(Cl)Cl>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:7]([Br:11])=[CH:6][C:3]=1[CH2:4][NH2:14]
Reactant: Fc1cc(Br)c(CBr)cc1Br
Reactant: CCN(CC)CC
Agent: N
Solvent: ClCCl
Solvent: CO
Product: NCc1cc(Br)c(F)cc1Br

Procedure:
A solution of 2,5-dibromo-4-fluorobenzyl bromide (0.350 g, 1 mmol) in 7M NH3/MeOH was heated in a sealed tube at 100° C. for 2 h. The reaction mixture was cooled and concentrated to give a white solid which was dissolved in CH2Cl2 and treated with Et3N (1 mL) then concentrated. The resulting residue was triturated with ethyl acetate (25 mL), filtered and concentrated to give the title compound (0.291 g) as a pale yellow oil. HRMS (M+H) calcd for C7H7Br2FN: 283.94; found: 283.93.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Cl)=[O:4].[NH:7]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][C:14]=2[CH2:16][NH:17][CH2:18][C:19]2[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][C:20]=2[O:27][CH3:28])[CH:9]=[CH:8]1.C(N(CC)CC)C>O1CCCC1>[CH3:28][O:27][C:20]1[CH:21]=[C:22]([O:25][CH3:26])[CH:23]=[CH:24][C:19]=1[CH2:18][N:17]([CH2:16][C:14]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:15]=1[NH:7][CH:8]=[CH:9]2)[C:3](=[O:4])[CH:2]([Br:1])[CH3:6]
Reactant: CC(Br)C(=O)Cl
Reactant: COc1ccc(CNCc2cccc3cc[nH]c23)c(OC)c1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COc1ccc(CN(Cc2cccc3cc[nH]c23)C(=O)C(C)Br)c(OC)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.5 %

Procedure:
Add 2-bromopropionyl chloride (3.25 g, 18.96 mmol) to a solution of N-[(indol-7-yl)methyl]-2,4-dimethoxybenzylamine (5.0 g, 17.24 mmol) and triethylamine (3.49 g, 64.48 mmol) in tetrahydrofuran (100 ml). Stir for 1 hour at room temperature and quench with saturated aqueous sodium bicarbonate. Extract with ethyl acetate, concentrate under reduced pressure, and subject the residue to silica gel chromatography eluting with 1:1 ethyl acetate:hexanes to provide the desired compound (4.72 g, 63%).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:5](=[O:12])[NH:4][N:3]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1.C(O)CO>CCOC(C)=O>[O:16]1[CH2:17][CH2:18][N:13]([C:2]2[C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5](=[O:12])[NH:4][N:3]=2)[CH2:14][CH2:15]1
Reactant: C1COCCN1
Reactant: O=c1[nH]nc(Cl)c2ccccc12
Solvent: OCCO
Solvent: CCOC(C)=O
Product: O=c1[nH]nc(N2CCOCC2)c2ccccc12
Reaction time: 0.5 h
Yield: 48 %

Procedure:
A mixture of 4-chlorophthalazin-1-one (0.49 g, 2.7 mmol), morpholine (2.4 mL, 27 mmol), and ethylene glycol (1.5 mL) was microwaved at 190° C. for 1 hour, and 210° C. for 30 minutes, diluted with EtOAc, washed with sat NaHCO3 and water, concentrated, adsorbed onto silica, and chromatographed (30% EtOAc/DCM) to give 300.0 mg of product as a white solid: 1H NMR (300 MHz, DMSO-d6) δ 12.13 (s, 1H), 8.27-8.20 (m, 1H), 8.00-7.79 (m, 3H), 3.86-3.77 (m, 4H), 3.07 (dd, J=10.2, 5.6, 4H).
Reaction SMILES: [Cl:1][C:2]1[C:9]([CH3:10])=[C:8]([NH:11][C@@H:12]([C:16]2[O:17][C:18]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)=[N:19][N:20]=2)[C@@H:13]([OH:15])[CH3:14])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].N1C=CC=CC=1.[C:33](Cl)(=[O:36])[CH2:34][CH3:35]>C(Cl)Cl>[C:33]([O:15][C@@H:13]([CH3:14])[C@@H:12]([NH:11][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([Cl:1])[C:9]=1[CH3:10])[C:16]1[O:17][C:18]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[N:19][N:20]=1)(=[O:36])[CH2:34][CH3:35]
Reactant: Cc1c(N[C@@H](c2nnc(-c3ccccc3)o2)[C@H](C)O)ccc(C#N)c1Cl
Reactant: CCC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CCC(=O)O[C@@H](C)[C@@H](Nc1ccc(C#N)c(Cl)c1C)c1nnc(-c2ccccc2)o1
Temperature: 25 °C
Reaction time: 48 h
Yield: 98 %

Procedure:
To a 50 mL round bottomed flask was added 2-chloro-4-((1R,2S)-2-hydroxy-1-(5-phenyl-1,3,4-oxadiazol-2-yl)propylamino)-3-methylbenzonitrile (300 mg, 0.82 mmol, pyridine (1 mL, 12.41 mmol) and methylene chloride (15 mL). Propionyl chloride (0.358 mL, 4.1 mmol) was then added dropwise and the mixture was stirred at room temperature for 48 h. The reaction mixture was then quenched with 10% aq HCl (15 mL) and methylene chloride (30 mL) was added. The phases were partitioned and the aqueous phase extracted with methylene chloride (30 mL) (×2). The combined organics were washed with a saturated solution of sodium hydrogen carbonate, dried (Na2SO4) and concentrated to furnish a yellow oil (0.382 g, 98%). 1H NMR (Acetone d6, 400 MHz) δ 8.01 (d, J=8 Hz, 2H), 7.64-7.53 (m, 4H), 7.02 (d, J=9 Hz, 1H), 5.73 (d, J=9 Hz, 1H), 5.69-5.62 (m, 1H), 5.44 (dd, J=5 and 8 Hz, 1H), 2.37 (s, 3H), 2.35 (q, J=7 Hz, 1H), 2.34 (q, J=7 Hz, 1H), 1.46 (d, J=6 Hz, 3H) and 1.03 (t, J=8 Hz, 3H).
Reaction SMILES: N1C=CC=CC=1.[NH2:7][C:8]1[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=1[C:10]#[N:11].[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1>O1CCCC1>[Br:17][C:18]1[CH:26]=[CH:25][C:21]([C:22]([NH:7][C:8]2[CH:15]=[C:14]([Cl:16])[CH:13]=[CH:12][C:9]=2[C:10]#[N:11])=[O:23])=[CH:20][CH:19]=1
Reactant: O=C(Cl)c1ccc(Br)cc1
Reactant: N#Cc1ccc(Cl)cc1N
Solvent: c1ccncc1
Solvent: C1CCOC1
Product: N#Cc1ccc(Cl)cc1NC(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
Pyridine (0.144 mole) is given to a solution of 2-amino-4-chlorobenzonitrile (0,131 mole) in 100 ml tetrahydrofuran (THF) and a solution of 4-bromobenzoylchloride (31,6 g, 0,144 mole) in 50 ml THF is added under nitrogen. After addition of 100 ml THF, the mixture is stirred for 6 h at room temperature (rt). The crude reaction is then customary worked up for solution reactions affording 4-bromo-N-(5-chloro-2-cyano-phenyl)-benzamide as a solid; m.p. 151-152°.