Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:3]1[C:16](=O)[C:15]2[C:10](=[CH:11][C:12]([N+:18]([O-])=O)=[CH:13][CH:14]=2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-]>C1COCC1>[CH2:1]([N:3]1[CH2:16][C:15]2[C:10](=[CH:11][C:12]([NH2:18])=[CH:13][CH:14]=2)[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]1=2)[CH3:2]
Reactant: CCn1c(=O)c2ccc([N+](=O)[O-])cc2c2ccccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCN1Cc2ccc(N)cc2-c2ccccc21
Temperature: 23 °C

Procedure:
A solution of 5-ethyl-9-nitro-5H-phenanthridin-6-one I-1d (250 mg, 0.93 mmol) in THF (1 ml) was added to a suspension of lithium aluminum hydride (99 mg, 2.6 mmol) in THF (5 ml). The reaction mixture was heated to reflux for 2 h and cooled to 23° C. Excess hydride was quenched by careful sequential addition of water (5 drops from a Pasteur pipet), 1N aqueous sodium hydroxide (5 drops from a Pasteur pipet), and water (15 drops from a Pasteur pipet). Insolubles were removed by filtration, and the filter cake was washed with ethyl acetate (2 5-ml portions). The combined filtrates were washed with water (10 ml) and saturated aqueous sodium chloride (10 ml). The organics were dried over anhydrous sodium sulfate and were concentrated. The residue was purified by flash column chromatography (2% ethyl acetate in dichloromethane) to provide 5-ethyl-5,6-dihydro-phenanthridin-9-ylamine I-13a (52 mg, 25%).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([NH2:13])(=[O:12])=[O:11])=[C:6]([NH2:14])[CH:5]=1)(=[O:3])[CH3:2].[CH:15]([N:18]=[C:19]=S)([CH3:17])[CH3:16]>C(OCC)(=O)C>[C:1]([C:4]1[CH:9]=[CH:8][C:7]2[S:10](=[O:11])(=[O:12])[N:13]=[C:19]([NH:18][CH:15]([CH3:17])[CH3:16])[NH:14][C:6]=2[CH:5]=1)(=[O:3])[CH3:2]
Reactant: CC(C)N=C=S
Reactant: CC(=O)c1ccc(S(N)(=O)=O)c(N)c1
Solvent: CCOC(C)=O
Product: CC(=O)c1ccc2c(c1)NC(NC(C)C)=NS2(=O)=O

Procedure:
The title compound was prepared from 4-acetyl-2-aminobenzenesulfonamide and isopropyl isothiocyanate by a method analogous to the one described in Example 4; m.p. 305-308° C. (ethyl acetate); 1H-NMR (DMSO-d6): δ 1.19 (d, 6H, CH(CH3)2), 3.95 (m, 1H, CH(CH3)2), 7.25 (br., 1H, NH), 7.70-7.85 (m, 3H, ArH), 10.5 (br.s, 1H, NH); MS: m/e 281 (M+; 39%); (C12H15N3O3S1) calc. C, 51.23; H, 5.37; N, 14.94, found C, 51.15; H, 5.50; N, 14.69.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6].[C:8](Cl)(=[O:26])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](Cl)=[O:20]>>[C:5]([CH2:4][CH2:3][CH2:2][NH:1][C:8]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[S:15][S:16][C:17]1[CH:25]=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([NH:1][CH2:2][CH2:3][CH2:4][C:5]([OH:7])=[O:6])=[O:20])=[O:26])([OH:7])=[O:6]
Reactant: O=C(Cl)c1ccccc1SSc1ccccc1C(=O)Cl
Reactant: NCCCC(=O)O
Product: O=C(O)CCCNC(=O)c1ccccc1SSc1ccccc1C(=O)NCCCC(=O)O
Yield: 49.9 %

Procedure:
Following the procedure in Preparation 30, 16 g (0.15 mol) of 4-amino-butanoic acid was reacted with 10.8 g (0.03 mol) of 2,2'-dithiobisbenzoyl chloride to afford 7.14 g of the title compound.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([CH:7]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]1)=[O:6].[CH3:19]I.CO>O1CCCC1.O>[CH3:3][O:4][C:5]([C:7]1([CH3:19])[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH3:18])([CH3:17])[CH2:9][CH2:8]1)=[O:6]
Reactant: CI
Reactant: COC(=O)C1CCC(C)(C)c2ccccc21
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)C1(C)CCC(C)(C)c2ccccc21

Procedure:
5.7 g of sodium hydride are placed in 80 ml of absolute tetrahydrofuran in a 500 ml flask provided with a thermometer, stirrer, reflux condenser and dropping funnel and 43.6 g of 1,1-dimethyl-tetralin-4-carboxylic acid methyl ester are added dropwise thereto. The mixture is then heated at reflux temperature for 1 hour. After cooling, 34 g of methyl iodide in 80 ml of absolute tetrahydrofuran are added dropwise and the mixture is held at reflux temperature for a further 1 hour. After cooling, a small amount of methanol is added, the mixture is poured into water and extracted with ether. The ether extracts are washed neutral, dried and evaporated. Distillation gives a quantitative yield of 1,1,4-trimethyl-tetralin-4-carboxylic acid methyl ester of boiling point 102° C./1.5 mmHg; nD20 =1.5219. Odour: tobacco, similar to (3).
Reaction SMILES: [K+].[Br-].CC1[S:8]C=C(/C=C/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)N=1.[CH3:36][C:37]1O[CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:45]2[O:62][C:60](=[O:61])[CH2:59][C@H:58]([OH:63])[C:57]([CH3:65])([CH3:64])[C:55](=[O:56])[C@H:54]([CH3:66])[C@@H:53]([OH:67])[C@@H:52]([CH3:68])[CH2:51][CH2:50][CH2:49][C:48]([CH3:69])=[CH:47][CH2:46]2)\[CH3:44])[N:38]=1.CC1OC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC[C@H]3O[C@H]3C2)\C)N=1.CC1SC=C(/C=C(/[C@H]2OC(=O)C[C@H](O)C(C)(C)C(=O)C[C@@H](O)[C@@H](C)CCCC=CC2)\C)N=1>CO>[CH3:36][C:37]1[S:8][CH:40]=[C:39](/[CH:42]=[C:43](/[C@H:45]2[O:62][C:60](=[O:61])[CH2:59][C@H:58]([OH:63])[C:57]([CH3:65])([CH3:64])[C:55](=[O:56])[C@H:54]([CH3:66])[C@@H:53]([OH:67])[C:52]([CH3:68])=[CH:51][CH2:50][CH2:49][C:48]([CH3:69])=[CH:47][CH2:46]2)\[CH3:44])[N:38]=1
Reactant: CC1=CC[C@@H](/C(C)=C/c2coc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)[C@@H](C)CCC1
Reactant: Cc1nc(/C=C/[C@@H]2C[C@@H]3O[C@@H]3CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O2)cs1
Agent: C/C(=C\c1coc(C)n1)[C@@H]1C[C@@H]2O[C@@H]2CCC[C@H](C)[C@H](O)[C@@H](C)C(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1C/C=C\CCC[C@H](C)[C@H](O)CC(=O)C(C)(C)[C@@H](O)CC(=O)O1
Agent: C/C(=C\c1csc(C)n1)[C@@H]1CC=CCCC[C@H](C)[C@H](O)CC(=O)C(C)(C)[C@@H](O)CC(=O)O1
Solvent: CO
Product: CC1=CC[C@@H](/C(C)=C/c2csc(C)n2)OC(=O)C[C@H](O)C(C)(C)C(=O)[C@H](C)[C@@H](O)C(C)=CCC1

Procedure:
colorless amorphous solid; [α]22D −150 (c 0.2, MeOH); UV (MeOH) λmax nm (ε) 205 (23300), 248 (13600); IR (KBr) νmax 3439, 2967, 2927, 1736, 1690, 1451, 1254, 1181, 987 cm−1; 1H NMR (CDCl3, 400 MHz) 5; 6.94 (1H, s, H-19), 6.51 (1H, bs, H-17), 5.34 (1H, bs, H-9), 5.29 (1H, dd, J=8.0, 2.4 Hz, H-15), 5.16 (1H, dd, J=8.2, 6.2 Hz, H-13), 4.30 (1H, bd, J=4.9 Hz, H-7), 4.19 (1H, ddd, J=10.8, 7.6, 3.0 Hz, H-3), 3.68 (1H, d, J=7.6 Hz, 3-OH), 3.17 (1H, dq, J=4.9, 7.0 Hz, H-6), 2.69 (3H, s, H-21), 2.65 (1H, d, J=2.1 Hz, 7-OH), 2.56 (1H, ddd, J=16.2, 8.2, 8.0 Hz, H-14a), 2.40 (1H, dd, J=15.0, 3.0 Hz, H-2a), 2.39 (1H, bd, J=16.2 Hz, H-14b), 2.34 (1H, dd, J=15.0, 10.8 Hz, H-2b), 2.25 (2H, m, H-10a and H-11a), 2.20 (1H, m, H-10b), 2.17 (1H, m, H-11b), 2.05 (3H, d, J=1.0 Hz, H-27),1.69 (3H, bs, H-25), 1.68 (3H, bs, H-26),1.29 (3H, s, H-23), 1.23 (3H, d, J=7.0 Hz, H-24), 1.16 (3H, s, H-22); 13C NMR, see Table 1; EIMS m/z 489 [M]+ (4), 406 (4), 338 (7), 302 (13), 218 (35), 171 (10), 168 (100), 153 (20), 125 (10); HREIMS m/z 489.2536 (calcd. for C27H39NO5S, 489.2549).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[CH2:14](Br)[C:15]#[CH:16]>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:16][C:15]#[CH:14])[CH2:3]1
Reactant: O[C@@H]1CCNC1
Reactant: C#CCBr
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C#CCN1CC[C@@H](O)C1

Procedure:
To a solution of (R)-3-hydroxy-pyrrolidine (2.00 g, 22.95 mmol) (Aldrich) and Et3N (9.00 g, 88.93 mmol) in 45 mL of CH2Cl2 at 0° C. it was added propargyl bromide (3.00 g, 25.21 mmol) in a dropwise manner. Upon completion of the addition, the reaction mixture was filtered and the filtrate was washed with brine, dried over Na2SO4 and concentrated. (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine was obtained after Krugerhor distilation (Yield 700 mg, 24%).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[NH2:8][C:9]1[N:14]=[CH:13][N:12]=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26](O)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[C:10]=1[C:36]#[N:37].C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>CN(C=O)C>[NH2:8][C:9]1[C:10]([C:36]#[N:37])=[C:11]([NH:15][C@H:16]([C:18]2[N:19]=[C:20]3[CH:25]=[CH:24][CH:23]=[C:22]([C:26]([N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[O:27])[N:21]3[C:29]=2[C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH3:17])[N:12]=[CH:13][N:14]=1
Reactant: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)O)n2c1-c1ccccc1
Reactant: CN1CCNCC1
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: C[C@H](Nc1ncnc(N)c1C#N)c1nc2cccc(C(=O)N3CCN(C)CC3)n2c1-c1ccccc1

Procedure:
A solution of N-methylpiperazine (0.040 mL, 0.356 mmol), (S)-2-(1-(6-amino-5-cyanopyrimidin-4-ylamino)ethyl)-3-phenylimidazo[1,2-a]pyridine-5-carboxylic acid (0.071 g, 0.178 mmol), PyBOP (0.185 g, 0.356 mmol) and DIEA (0.062 mL, 0.356 mmol) in DMF (1.78 mL) was stirred at rt for 1 h. The solution was loaded onto silica gel and purified by MPLC (eluted with a gradient of 0-10% MeOH in DCM) to afford an off-white solid that was repurified by MPLC (eluted with a gradient of 0-80% (1:10:90 NH4OH:MeOH:DCM) solution in DCM) to afford 4-amino-6-(((1S)-1-(5-((4-methyl-1-piperazinyl)carbonyl)-3-phenylimidazo[1,2-a]pyridin-2-yl)ethyl)amino)-5-pyrimidinecarbonitrile as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 1.43 (dd, J=14.18, 6.75 Hz, 3H) 1.88-2.01 (m, 1H) 2.03-2.10 (m, 1H) 2.12-2.44 (m, 6H) 3.00-3.14 (m, 1H) 3.22 (m, J=9.19 Hz, 1H) 3.40 (d, J=4.30 Hz, 1H) 5.13-5.34 (m, 1H) 6.75-6.98 (m, 2H) 7.16-7.53 (m, 8H) 7.75 (m, J=9.00, 5.09 Hz, 1H) 7.94 (d, J=6.85 Hz, 1H). LC-MS (ESI) m/z 482.1 [M+H]+.
Reaction SMILES: [CH2:1]([CH:8]([CH2:13][Br:14])[CH2:9][C:10](O)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:17])=O>>[CH2:1]([CH:8]([CH2:13][Br:14])[CH2:9][C:10]([Cl:17])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CC(CBr)Cc1ccccc1
Product: O=C(Cl)CC(CBr)Cc1ccccc1
Temperature: 80 °C
Yield: 127 %

Procedure:
A mixture of 3-benzyl-4-bromo-butyric acid (2.0 g, 7.78 mmol) and thionyl chloride (6.0 mmol) is heated to 80° C. for 2 h. The thionyl chloride is evaporated to yield 3-benzyl-4-bromo-butyryl chloride 2.1 g (99%), as a colorless liquid.
Reaction SMILES: [C:1]1([C:7]2([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[O:28])=[CH:26][C:20]=5[N:19]=4)=[CH:14][CH:13]=3)[O:11][CH2:10][CH2:9][O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Cl:30]C1C=CC(C2(C3C=CC(C4NC5C=CC(C(O)=O)=CC=5N=4)=CC=3)OCCO2)=CC=1.C(N1C=CN=C1)(N1C=CN=C1)=O.C(=O)(O)[O-].[NH4+].[NH4+].[Cl-]>CN(C=O)C>[Cl:30][C:4]1[CH:3]=[CH:2][C:1]([C:7]2([C:12]3[CH:17]=[CH:16][C:15]([C:18]4[NH:22][C:21]5[CH:23]=[CH:24][C:25]([C:27]([NH2:29])=[O:28])=[CH:26][C:20]=5[N:19]=4)=[CH:14][CH:13]=3)[O:8][CH2:9][CH2:10][O:11]2)=[CH:6][CH:5]=1
Reactant: O=C(O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1
Reactant: NC(=O)c1ccc2[nH]c(-c3ccc(C4(c5ccccc5)OCCO4)cc3)nc2c1
Agent: O=C([O-])O
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc2[nH]c(-c3ccc(C4(c5ccc(Cl)cc5)OCCO4)cc3)nc2c1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 76 %

Procedure:
2-[4-(2-Phenyl-[1,3]dioxolan-2-yl)-phenyl]-1H-benzoimidazole-5-carboxylic acid amide. To a solution of 2-{4-[2-(4-chloro-phenyl)-[1,3]dioxolan-2-yl]-phenyl}-1H-benzoimidazole-5-carboxylic acid (135 mg, 0.32 mmol) in anhydrous DMF was added carbonyldiimidazole (118 mg, 0.73 mmol). The reaction mixture was stirred under N2 for 30 min and then cooled to 0° C., and ammonium bicarbonate (140 mg, 1.4 mmol) was added. The resulting mixture was allowed to warm to RT and was stirred for 16 h. The mixture was added dropwise to saturated aqueous NH4Cl. The resulting precipitate was collected by filtration and washed with H2O (100 mL) then hexanes (100 mL). The product was dried under vacuum overnight to give the title compound (1.02 mg, 76%). TLC (silica, 1% methanol saturated with ammonia/9% methanol/CH2Cl2): Rf=0.33. HPLC (Method A): Rt=7.42. MS (ESI+): mass calculated for C23H18ClN3O3, 419.1; m/z found, 420.1 [M+H]+. 1H NMR (400 MHz, CD3OD): δ 8.09 (s, 1H), 8.00 (d, J=8.4 Hz, 2H), 7.75-7.72 (dd, J=8.5, 1.5 Hz, 1H), 7.59 (d, J=8.4 Hz, 2H), 7.56 (br d, J=8.7 Hz, 1H), 7.43 (d, J=8.5 Hz, 2H), 7.27 (d, J=8.6 Hz, 2H), 3.99 (s, 4H).
Reaction SMILES: [Li+].[OH-].C[O:4][C:5](=[O:27])[C@@H:6]([NH:14][C:15]([C:17]1[NH:18][C:19]2[C:24]([CH:25]=1)=[CH:23][C:22]([Cl:26])=[CH:21][CH:20]=2)=[O:16])[CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1COCC1>[Cl:26][C:22]1[CH:23]=[C:24]2[C:19](=[CH:20][CH:21]=1)[NH:18][C:17]([C:15]([NH:14][CH:6]([CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)[C:5]([OH:27])=[O:4])=[O:16])=[CH:25]2
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)c1cc2cc(Cl)ccc2[nH]1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: O=C(NC(Cc1ccccc1)C(=O)O)c1cc2cc(Cl)ccc2[nH]1
Reaction time: 0.5 h
Yield: 91.3 %

Procedure:
Aqueous 2M LiOH (33.10 ml) was added to a solution of (2S)-[(5-chloro-1H-indole-2-carbonyl)-amino]-3-phenyl-propionic acid methyl ester (21.47 g, 60 mmol) in THF (140 ml) at 0-5° C. After 0.5 hour, the mixture was partially concentrated, acidified to pH 1-2 with 6N HCl, concentrated to dryness, and the solids washed with water and then etherto yield a colorless solid (18.78g,91%): mp 248-255° C.; HPLC (60/40) 5.21 minutes (98%); TSPMS 343/345 (MH+, 100%).
Reaction SMILES: [CH2:1]([O:3][PH:4](=[O:8])[O:5][CH2:6][CH3:7])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].[CH2:15]1[CH2:19]O[CH2:17][CH2:16]1>>[C:1]1([O:3][PH:4](=[O:8])[O:5][C:6]2[CH:17]=[CH:16][CH:15]=[CH:19][CH:7]=2)[CH:19]=[CH:15][CH:16]=[CH:17][CH:2]=1
Reactant: C1CCOC1
Reactant: CCO[PH](=O)OCC
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=[PH](Oc1ccccc1)Oc1ccccc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
and triflate 13 isomer A (70 mg, 0.167 mmol) in THF (2 mL) was added Cs2CO3 (72 mg, 0.222 mmol). After the reaction mixture was stirred for 30 min at room temperature, the mixture was partitioned between EtOAc and water. The organic phase was dried over Na2SO4, filtered, and evaporated under reduced pressure. The crude product was chromatographed on silica gel (eluting 60-80% EtOAc/hexane) to give a mixture. The mixture was further purified by HPLC on C18 reverse phase chromatography (eluting 55% CH3CN/water) to give phosphonate 14 isomer A (30 mg, 32%) as a colorless solid. 1H NMR (300 MHz, CDCl3) δ 7.71 (d, 2H), 7.26 (m, 6H), 7.00 (m, 5H), 5.65 (d, 1H), 5.14 (m, 1H), 5.00 (m, 2H), 4.54 (dd, 1H), 4.44 (dd, 1H), 4.17 (m, 2H), 3.96 (dd, 1H), 3.86 (m, 5H), 3.72 (m, 3H), 3.14 (m, 1H), 2.97 (m, 4H), 2.79 (m, 2H), 1.83 (m, 1H), 1.62 (m, 3H), 1.50 (d, 3H), 1.25 (m, 3H), 0.93 (d, 3H), 0.88 (d, 3H). 31P NMR (300 MHz, CDCl3) δ 17.4.
Reaction SMILES: C(OC([N:8]1[C:16]2[C:11](=[CH:12][C:13]([C:17]#[N:18])=[CH:14][CH:15]=2)[C:10]([N:19]2[CH2:28][C@H:27]3[N:23]([CH2:24][CH2:25][CH2:26]3)[C:22]3[N:29]=[C:30]([NH:33][CH2:34][CH3:35])[N:31]=[CH:32][C:21]=3[C:20]2=[O:36])=[CH:9]1)=O)(C)(C)C.[OH-].[Na+].Cl>C(O)C>[C:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[NH:8][CH:9]=[C:10]2[N:19]1[CH2:28][C@H:27]2[N:23]([CH2:24][CH2:25][CH2:26]2)[C:22]2[N:29]=[C:30]([NH:33][CH2:34][CH3:35])[N:31]=[CH:32][C:21]=2[C:20]1=[O:36])#[N:18]
Reactant: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1cn(C(=O)OC(C)(C)C)c3ccc(C#N)cc13)C2=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCNc1ncc2c(n1)N1CCC[C@H]1CN(c1c[nH]c3ccc(C#N)cc13)C2=O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 96.6 %

Procedure:
(S)-5-(1-Tert-butoxycarbonyl-5-cyanoindole-3-yl)-9-ethylamino-1,2,3,3a,4,5-hexahydro-5,8,10,10b-tetraazabenzo[e]azulen-6-one (25.0 mg, 0.0513 mmol) obtained in Step 4 was dissolved in ethanol (2 mL), and the mixture was stirred at room temperature for 30 minutes after adding a 2 mol/L aqueous sodium hydroxide solution (0.256 mL, 0.513 mmol). The mixture was neutralized with 1 mol/L hydrochloric acid, and extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The resulting residue was then purified by preparative TLC to give the title compound (Compound 140) (19.2 mg, 96%).
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]2[C:6]([C:9]3[CH:14]=[CH:13][C:12]([O:15][CH2:16][C@H:17]4[CH2:19][O:18]4)=[CH:11][CH:10]=3)=[N:7][O:8][C:4]=2[CH:3]=1.[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH2:27]>C(O)C>[Cl:22][C:23]1[CH:24]=[C:25]([CH:28]=[CH:29][C:30]=1[Cl:31])[CH2:26][NH:27][CH2:19][C@@H:17]([OH:18])[CH2:16][O:15][C:12]1[CH:13]=[CH:14][C:9]([C:6]2[C:5]3[CH:20]=[CH:21][C:2]([F:1])=[CH:3][C:4]=3[O:8][N:7]=2)=[CH:10][CH:11]=1
Reactant: NCc1ccc(Cl)c(Cl)c1
Reactant: Fc1ccc2c(-c3ccc(OC[C@H]4CO4)cc3)noc2c1
Solvent: CCO
Product: O[C@H](CNCc1ccc(Cl)c(Cl)c1)COc1ccc(-c2noc3cc(F)ccc23)cc1
Yield: 78.9 %

Procedure:
Combine (R)-6-fluoro-3-(4-oxiranylmethoxy-phenyl)-benzo[d]isoxazole (29) (250 mg, 0.86 mmol), 3,4-dichlorobenzylamine (617 mg, 3.50 mmol), ethanol (4.0 ml) and heat (˜80° C.) for 16 hours. Cool reaction at 0° C. for 1 h. Collect the solid product and wash with cold ethanol several times. Dry the solid at (50° C./0.5 mm Hg) overnight to give 313 mg (77% yield) of the title compound. Purity by LC/MS=96%, [M+H]+=461.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:18][CH2:17]2)[C@H:10]([C:12]([OH:14])=O)[CH3:11])=[CH:5][C:4]=1[C:19]([F:22])([F:21])[F:20])#[N:2].[NH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:15][CH:16]2[CH2:17][CH2:18]2)[C@H:10]([C:12]([NH:23][C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[O:14])[CH3:11])=[CH:5][C:4]=1[C:19]([F:21])([F:22])[F:20])#[N:2]
Reactant: C[C@@H](C(=O)O)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: Nc1ccccc1
Product: C[C@@H](C(=O)Nc1ccccc1)N(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1

Procedure:
Synthesized as described for Example 91C using N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)alanine and aniline: 1H NMR (400 MHz, CDCl3) δ 8.20 (s, 1H), 7.51 (d, J=8.9 Hz, 1H), 7.45 (d, J=7.9 Hz, 2H), 7.30 (t, J=7.7 Hz, 2H), 7.16 (d, J=2.4 Hz, 1H), 7.11 (t, J=7.5 Hz, 1H), 6.93 (dd, J=8.9, 2.7 Hz, 1H), 4.47 (q, J=7.0 Hz, 1H), 3.37 (m, 2H), 1.56 (d, J=6.9 Hz, 3H), 1.12 (m, 1H), 0.69 (m, 2H), 0.37 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([C:22]#[C:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].[H][H]>CO.[Pd]>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:28][CH:29]2[CH2:30][CH2:31][CH2:32][CH2:33]2)[C:13]([NH:15][C:16]2[CH:21]=[N:20][C:19]([CH2:22][CH2:23][CH2:24][N:25]([CH3:27])[CH3:26])=[CH:18][N:17]=2)=[O:14])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CN(C)CC#Cc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CN(C)CCCc1cnc(NC(=O)[C@H](CC2CCCC2)c2ccc(S(C)(=O)=O)c(Cl)c2)cn1
Yield: 62.6 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-prop-1-ynyl)-pyrazin-2-yl]-propionamide (prepared as in Example 11, 190 mg, 0.389 mmol) in methanol (20 ml) was treated with 10% palladium on activated carbon (65 mg). The resulting reaction mixture was stirred under a positive pressure of hydrogen gas (balloon) overnight. At this time, the catalyst was removed by filtration through a pad of celite, and the filtrate was concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230–400 mesh, 1/1 methylene chloride/methanol) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-[5-(3-dimethylamino-propyl)-pyrazin-2-yl]-propionamide (120 mg, 63%) as a solid: (ES)+-HRMS m/e calcd for C24H33ClN4O3S (M+H)+ 493.2035, found 493.2041.
Reaction SMILES: Br[C:2]1[C:10]2[N:9]3[CH2:11][CH2:12][CH2:13][NH:14][C:15](=[O:16])[C:8]3=[CH:7][C:6]=2[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=1.[F:19][C:20]1[CH:21]=[C:22](B(O)O)[CH:23]=[C:24]([F:27])[C:25]=1[F:26]>>[O:16]=[C:15]1[C:8]2=[CH:7][C:6]3[CH:5]=[C:4]([C:17]#[N:18])[CH:3]=[C:2]([C:22]4[CH:21]=[C:20]([F:19])[C:25]([F:26])=[C:24]([F:27])[CH:23]=4)[C:10]=3[N:9]2[CH2:11][CH2:12][CH2:13][NH:14]1
Reactant: OB(O)c1cc(F)c(F)c(F)c1
Reactant: N#Cc1cc(Br)c2c(c1)cc1n2CCCNC1=O
Product: N#Cc1cc(-c2cc(F)c(F)c(F)c2)c2c(c1)cc1n2CCCNC1=O

Procedure:
The title compound, light grey solid (72 mg, 81%), MS (ISP) m/z=356.4 [(M+H)+], mp 248.5° C., was prepared in accordance with the general method of example 1 from 7-bromo-1-oxo-2,3,4,5-tetrahydro-[1,4]diazepino[1,2-a]indole-9-carbonitrile (intermediate 20) (76.0 mg, 0.25 mmol) and commercially available 3,4,5-trifluoro-phenylboronic acid (57.2 mg, 0.325 mmol).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([F:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[CH2:12][C:13](=[O:15])[CH3:14]>C(O)(=O)C.[Fe]>[NH2:9][C:5]1[C:6]([F:8])=[CH:7][C:2]([Br:1])=[C:3]([CH2:12][C:13](=[O:15])[CH3:14])[CH:4]=1
Reactant: CC(=O)Cc1cc([N+](=O)[O-])c(F)cc1Br
Agent: [Fe]
Solvent: CC(=O)O
Product: CC(=O)Cc1cc(N)c(F)cc1Br
Temperature: 50 °C
Reaction time: 1 h
Yield: 95.1 %

Procedure:
Treat a mixture of 1-(2-bromo-4-fluoro-5-nitrophenyl)propan-2-one (12 g, 43.6 mmol) in acetic acid (200 mL) with iron powder (24 g, 0.436 mol) and stir at 50° C. for 1 h. Add water and EtOAc, filter to remove solids, and extract the filtrate with EtOAc (2×). Wash the combined organics with saturated. Na2CO3, then brine, dry over Na2SO4 and concentrate to dryness to afford the title compound (10.2 g, 94% yield). 1H NMR (400 MHz, DMSO-d6): δ 7.26 (d, J=10.8 Hz, 1H), 6.69 (d, J=9.6 Hz, 1H), 5.33 (s, 2H), 3.74 (s, 2H), 2.14 (s, 3H).
Reaction SMILES: [H-].[H-].[H-].[H-].[Li+].[Al+3].F[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1([C:20]#[N:21])[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1.[C@H](O)(C([O-])=O)[C@@H](O)C([O-])=O.[Na+].[K+]>C(COC)OC>[O:17]1[CH2:18][CH2:19][C:14]2([C:9]3[C:10](=[CH:11][CH:12]=[CH:13][CH:8]=3)[NH:21][CH2:20]2)[CH2:15][CH2:16]1
Reactant: N#CC1(c2ccccc2F)CCOCC1
Agent: O=C([O-])[C@H](O)[C@@H](O)C(=O)[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: COCCOC
Product: c1ccc2c(c1)NCC21CCOCC1
Yield: 45.3 %

Procedure:
Add LiAlH4 (398 mg, 10.5 mmol) to a solution of 4-(2-fluoro-phenyl)-tetrahydro-pyran-4-carbonitrile (1.39 g, 6.77 mmol) in dimethoxyethane (25 mL). Stir the solution at reflux overnight then add aq. Satd Rochelle's salt solution (30 mL) and stir for an additional 1 h at RT. Extract the mixture with CH2Cl2 (3×30 mL). Combine the organic extracts and wash with additional aq satd Rochelle's salt solution (30 mL) and brine (30 mL). Dry, filter and concentrate the organic solution then purify the crude material by flash chromatography, using a linear gradient of 100% hexanes and 50% EtOAc/hexanes, to give the title compound (581 mg, 45%) as a white solid. 1H NMR (400 MHz CDCl3): δ 7.09 (d, 1H, J=7.3), 7.06 (t, 1H, J=7.6), 6.77 (m, 1H), 6.67 (m, 1H), 3.97 (m, 2H), 3.94 (dt, 2H, J=1.7, 7.9), 3.56 (dt, 2H, J=2.1, 11.8), 3.55 (s, 2H), 1.99 (m, 2H), 1.67 (m, 2H).
Reaction SMILES: [O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][CH2:13][NH:12][C:11]1=O.[H-].[Al+3].[Li+].[H-].[H-].[H-].O.[OH-].[Na+]>O1CCCC1>[O:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH:2]1[O:7][CH2:8][CH2:9][C:10]1([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[C:18]([Cl:23])[CH:17]=2)[CH2:14][CH2:13][NH:12][CH2:11]1
Reactant: O=C1NCCC1(CCOC1CCCCO1)c1ccc(Cl)c(Cl)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: Clc1ccc(C2(CCOC3CCCCO3)CCNC2)cc1Cl
Temperature: 60 °C

Procedure:
The 3-(2-tetrahydropyranyloxyethyl)-3-(3,4-dichlorophenyl)-2-pyrrolidinone (3.9 grams prepared as described supra) is dissolved in 50 ml of tetrahydrofuran and the solution is added to a suspension of 0.9 grams of lithium aluminum hydride in 5 ml of tetrahydrofuran heated to 60° C. The reaction mixture is then heated for one hour at 60° C. and then cooled. To the resulting mixture 1 ml of water, 1 ml of 4N sodium hydroxide, and 3 ml of water are added sequentially. The insoluble portion is removed by filtration and the filtrate is concentrated in vacuo. The residue is taken up in diethyl ether, dried over magnesium sulfate, and concentrated under vacuum to give the desired intermediate.