Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C1(P(C2CCCCC2)C2C=CC=CC=2C2C=CC=CC=2N(C)C)CCCCC1.C(=O)([O-])[O-].[Cs+].[Cs+].[F:35][C:36]([F:49])([F:48])[C:37]1[CH:42]=[CH:41][C:40]([CH:43]2[CH2:47][CH2:46][CH2:45][NH:44]2)=[CH:39][CH:38]=1.Br[C:51]1[CH:56]=[C:55]([CH3:57])[C:54]([NH:58][C:59](=[O:66])[CH2:60][CH:61]2[CH2:65][CH2:64][CH2:63][CH2:62]2)=[C:53]([CH3:67])[CH:52]=1.C(=O)(O)[O-].[Na+]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd]>[CH:61]1([CH2:60][C:59]([NH:58][C:54]2[C:53]([CH3:67])=[CH:52][C:51]([N:44]3[CH2:45][CH2:46][CH2:47][CH:43]3[C:40]3[CH:41]=[CH:42][C:37]([C:36]([F:35])([F:48])[F:49])=[CH:38][CH:39]=3)=[CH:56][C:55]=2[CH3:57])=[O:66])[CH2:65][CH2:64][CH2:63][CH2:62]1
Reactant: FC(F)(F)c1ccc(C2CCCN2)cc1
Reactant: Cc1cc(Br)cc(C)c1NC(=O)CC1CCCC1
Agent: [Pd]
Agent: CN(C)c1ccccc1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: Cc1ccccc1
Product: Cc1cc(N2CCCC2c2ccc(C(F)(F)F)cc2)cc(C)c1NC(=O)CC1CCCC1
Temperature: 110 °C
Yield: 26.5 %

Procedure:
Bis(dibenzylideneacetone)palladium (3.6 mg) and (2′-dicyclohexylphosphanyl-biphenyl-2-yl)-dimethyl-amine (3.7 mg) were mixed in dry toluene (2 mL) under argon for 5 minutes. To this mixture were added cesium carbonate (41 mg), 2-[4-(trifluoromethyl)phenyl]pyrrolidine (15 mg) and N-(4-bromo-2,6-dimethyl-phenyl)-2-cyclopentyl-acetamide (1p, 20 mg) and the reaction was heated to 110° C. in a sealed 4 mL vial under argon for 48 hours. Aqueous sodium bicarbonate (5 mL) was added and the mixture was extracted with ethyl acetate (3×3 mL). The combined organic phases were dried over magnesium sulfate and concentrated in vacuo. The crude product was purified by vacuum liquid chromatography to furnish 7.6 mg (27% yield) of the title compound as an oil. LC-MS-TOF (m/z) 445 (MH+); tR=3.91, (UV, ELSD) 98%, 99%.
Reaction SMILES: [O:1]=[C:2]1[NH:7][C:6]2[CH:8]=[C:9]([C:12](OC)=[O:13])[CH:10]=[N:11][C:5]=2[N:4]2[CH2:16][CH2:17][CH2:18][C@@H:3]12.[H-].[Na+].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[OH:13][CH2:12][C:9]1[CH:10]=[N:11][C:5]2[N:4]3[CH2:16][CH2:17][CH2:18][C@H:3]3[C:2](=[O:1])[NH:7][C:6]=2[CH:8]=1
Reactant: COC(=O)c1cnc2c(c1)NC(=O)[C@@H]1CCCN21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C1Nc2cc(CO)cnc2N2CCC[C@@H]12
Temperature: 25 °C
Reaction time: 1 h
Yield: 112.9 %

Procedure:
(S)-methyl 6-oxo-5,6,6a,7,8,9-hexahydropyrido[3,2-e]pyrrolo[1,2-a]pyrazine-3-carboxylate (3.00 g, 10.5 mmol) was suspended in THF and sodium hydride (60% suspension in mineral oil, 0.712 g, 17.8 mmol) was added under nitrogen atmosphere. The reaction mixture was stirred at room temperature for 1 h and cooled to −78° C. LiAlH4 (2M in THF, 12.5 mL, 25 mmol) was added dropwise over 5 min and the reaction mixture was allowed to warm to −40° C. and kept at −40-(−20)° C. for 3 h. The reaction mixture was cooled to −60° C. and quenched with MeOH, water and TFA until a clear mixture resulted. This was purified using HPLC (1-30% acetnitrile in water, TFA buffered). The fractions containing product were concentrated in vacuo and crystallized with ethyl ether. The solid was filtered and dried in vacuum to afford the title compound as a grey solid (2.60 g, 74%, TFA salt). [M+H] calc'd for C11H13N3O2, 220; found, 220.
Reaction SMILES: C(O)(=O)C(C)(C)C.[CH3:8][C:9]1([CH3:29])[C:21]2[CH:20]=[C:19]([NH:22][C:23]3[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=3)[CH:18]=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2.C(=O)([O-])[O-].[K+].[K+].C([O-])([O-])=O.[Na+].[Na+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.ClCCl>[CH3:8][C:9]1([CH3:29])[C:21]2[CH:20]=[C:19]3[NH:22][C:23]4[C:28]([C:18]3=[CH:17][C:16]=2[C:15]2[C:10]1=[CH:11][CH:12]=[CH:13][CH:14]=2)=[CH:27][N:26]=[CH:25][CH:24]=4
Reactant: CC1(C)c2ccccc2-c2ccc(Nc3ccncc3)cc21
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC(C)(C)C(=O)O
Solvent: ClCCl
Product: CC1(C)c2ccccc2-c2cc3c(cc21)[nH]c1ccncc13
Temperature: 120 °C
Reaction time: 9 h

Procedure:
70 ml of pivalic acid are added to 30 g of (9,9-dimethyl-9H-fluoren-2-yl)pyridin-4-ylamine (105 mmol), 2.35 g of palladium(II)acetate (10.5 mmol) and 1.44 g of potassium carbonate (10.5 mmol), and the mixture is stirred at 120° C. for 9 h. After this time, 2.35 g of palladium(II)acetate (10.5 mmol) are added, and the mixture is stirred at 120° C. for a further 9 h. 200 ml of dichloromethane and 0.1 M Na2CO3 solution are then added. The mixture is partitioned between water and dichloromethane, the aqueous phase is extracted three times with dichloromethane, the combined organic phases are dried over Na2SO4 and evaporated in a rotary evaporator. The residue is recrystallised from toluene/heptane. The yield is 13.4 g (13.5 mmol, 45%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1)[C:12]#[N:13].[H-].[Al+3].[Li+].[H-].[H-].[H-]>>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH:11]([CH2:14][N:15]1[CH2:20][CH2:19][N:18]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH2:17][CH2:16]1)[CH2:12][NH2:13]
Reactant: CCCCCN1CCN(CC(C#N)c2ccc3ccccc3c2)CC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Product: CCCCCN1CCN(CC(CN)c2ccc3ccccc3c2)CC1

Procedure:
In a manner similar to Preparation 2 react α-(2-naphthalenyl)-4-pentylpiperazinepropanenitrile with lithium aluminum hydride to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[Li]CCCC.[CH:14]([C:16]1[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]2[C:25]=1[CH:24]=[CH:23][CH:22]=[CH:21]2)=[O:15].[Cl-].[NH4+]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([CH:14]([OH:15])[C:16]2[CH:17]=[C:18]([C:27]([O:29][CH2:30][CH3:31])=[O:28])[C:19](=[O:26])[N:20]3[C:25]=2[CH:24]=[CH:23][CH:22]=[CH:21]3)=[N:3][CH:4]=1
Reactant: Brc1ccc(Br)nc1
Reactant: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Agent: [Cl-]
Agent: [Li]CCCC
Agent: [NH4+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc(C(O)c2ccc(Br)cn2)c2ccccn2c1=O
Temperature: -78 °C
Reaction time: 2 h

Procedure:
To a solution of 2,5-dibromopyridine (1.00 g, 4.22 mmol) in 50 mL of toluene at −78° C. was added n-BuLi (2.0 mL, 5.0 mol, 2.5 M in THF) dropwise. After 2 h, ethyl 1-formyl-4-oxo-4H-quinolizine-3-carboxylate (1.35 g, 5.5 mmol) was added. The reaction was stirred at −78° C. for another 1 h, then transferred to a 0° C. ice water bath. After an additional 1 h at 0° C., saturated aqueous ammonium chloride (10 mL) was added. The mixture was warmed to rt and filtered to remove an insoluble brown solid. The filtrate was separated, and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo. The resultant residue was subjected to purification via silica gel chromatography from 0-5% MeOH in CH2Cl2 to yield crude ethyl 1-[(5-bromopyridin-2-yl)(hydroxy)methyl]-4-oxo-4H-quinolizine-3-carboxylate that gave a mass ion (ES+) of 402.9 (79Br) for M+H+.
Reaction SMILES: CON(C)[C:4]([C:6]1[CH:7]=[C:8]2[CH2:13][CH2:12][CH2:11][N:9]2[N:10]=1)=[O:5].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.ClCCl>[N:10]1[N:9]2[CH2:11][CH2:12][CH2:13][C:8]2=[CH:7][C:6]=1[CH:4]=[O:5]
Reactant: CON(C)C(=O)c1cc2n(n1)CCC2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: ClCCl
Solvent: C1CCOC1
Product: O=Cc1cc2n(n1)CCC2
Temperature: 2.5 °C
Reaction time: 5 h
Yield: 67 %

Procedure:
To a stirred, cold (0-5° C.) solution of N-methoxy-N-methyl-5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carboxamide (300 g, 1.54 mol, in anhydrous tetrahydrofuran (3.0 L) under a nitrogen atmosphere is added slowly, in portions, lithium aluminum hydride (pellets, 30 g, 0.79 mol) over a period of 0.5 hours. After stirring for 5 hours at 0-5° C. the reaction is quenched by slowly adding saturated sodium sulfate solution (75 mL) to the stirred reaction mixture maintained at 5-15° C. Magnesium sulfate (70 g) is added and the mixture is stirred for 15 minutes. The mixture is then filtered and the filter pad is washed with tetrahydrofuran (1.0 L). The solvent is removed by evaporation at 20-70° C. under diminished pressure to provide a tan-colored oil. The oil is diluted with dichloromethane (1.0 L) and the solution is washed with 1.5 N hydrochloric acid (350 mL). The organic layer is separated and concentrated under aspirator vacuum at 20-70° C. to an oil. Fresh dichloromethane (1.00 L) and water (1.50 L) containing dissolved sodium hydrogensulfite (220 g) are added to the oil. The mixture is stirred for 15 minutes and the phases are separated. The aqueous phase is washed with dichloromethane (2×300 mL). Dichloromethane (1.0 L) and 10 N sodium hydroxide (220 mL) are added (with cooling) to the aqueous phase and the mixture is stirred for 10 minutes The lower organic phase is separated and washed with water (500 mL). The dichloromethane extract is evaporated under diminished pressure at 20-70° C. to give an oil, which crystallizes on cooling, to provide 140.1 g (67%) of 5,6-dihydro-4H-pyrrolo-[1,2-b]pyrazole-2-carbaldehyde, as a white, crystalline solid having, m.p 40-42° C., 1H NMR (300 MHz, CDCl3) 2.67-2.75 (m, 2H), 2.95 (t, 2H, J=7.3 Hz), 4.22 (t, 2H, J=7.3 Hz), 6.52 (s, 1H), 9.89 (s, 1H) and HPLC-MS purity, 99.86% at 12.9 minutes:
Reaction SMILES: [NH2:1][C@@H:2]([CH2:33][C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[CH2:3][C@H:4]([OH:32])[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1.[CH3:40][C@@H:41]([CH2:60][CH3:61])[C@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[C:43](O)=[O:44].CCOP(ON1N=NC2C=CC=CC=2C1=O)(OCC)=O.C(N(CC)C(C)C)(C)C>C1COCC1>[OH:32][C@@H:4]([CH2:3][C@@H:2]([NH:1][C:43](=[O:44])[C@@H:42]([N:46]1[CH2:50][CH2:49][N:48]([CH2:51][C:52]2[CH:57]=[CH:56][CH:55]=[C:54]([CH3:58])[N:53]=2)[C:47]1=[O:59])[CH:41]([CH3:40])[CH2:60][CH3:61])[CH2:33][C:34]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=1)[C@@H:5]([NH:19][C:20]([C@@H:22]([NH:27][C:28](=[O:31])[O:29][CH3:30])[C:23]([CH3:25])([CH3:26])[CH3:24])=[O:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)=[CH:9][CH:8]=1
Reactant: CC[C@H](C)[C@@H](C(=O)O)N1CCN(Cc2cccc(C)n2)C1=O
Reactant: COC(=O)N[C@H](C(=O)N[C@@H](Cc1ccc(-c2ccccn2)cc1)[C@@H](O)C[C@@H](N)Cc1ccccc1)C(C)(C)C
Agent: CCOP(=O)(OCC)On1nnc2ccccc2c1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCC(C)[C@@H](C(=O)N[C@@H](Cc1ccccc1)C[C@H](O)[C@H](Cc1ccc(-c2ccccn2)cc1)NC(=O)[C@@H](NC(=O)OC)C(C)(C)C)N1CCN(Cc2cccc(C)n2)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 54.5 %

Procedure:
A solution containing the product from Example 23S (0.025 g, 0.047 mmol) in THF (0.5 mL) was treated with the product from Example 7B (0.025 g, 0.060 mmol), DEPBT (0.025 g, 0.084 mmol), and N,N-diisopropylethylamine (0.040 mL, 0.230 mmol), stirred at 25° C. for 2 hours, and partitioned between ethyl acetate and 10% Na2CO3 solution. The organic phase was washed with additional 10% Na2CO3 solution and brine, dried over MgSO4, filtered and concentrated. The residue was chromatographed on silica gel eluting with 0-100% ethyl acetate/dichloromethane, followed by eluting with 0-10% methanol in ethyl acetate to give the title compound (0.021 g, 54% yield). 1H NMR (300 MHz, DMSO-d6), δ ppm 0.60 (d, J=6.62 Hz, 3 H), 0.73 (t, J=7.17 Hz, 3 H), 0.87(m, 10 H), 1.27 (m, 1 H), 1.54 (m, 2 H), 1.75 (m, 1 H), 2.43 (m, 4 H), 2.66 (m, 1 H), 2.77 (d, J=6.99 Hz, 2 H), 2.91 (m, 1 H), 3.12 (m, 3 H), 3.51 (s, 3 H), 3.59 (m, 1 H), 3.85 (d, J=11.03 Hz, 1 H), 3.94 (d, J=9.56 Hz, 1 H), 4.14 (m, 2 H), 4.33 (s, 2 H), 4.81 (d, J=5.15 Hz, 1 H), 6.80 (d, J=9.56 Hz, 1 H), 7.07 (m, 7 H), 7.30 (d, J=7.72 Hz, 3 H), 7.58 (d, J=8.82 Hz, 1 H), 7.65 (t, J=7.54 Hz, 1 H), 7.87 (m, 5 H), 8.63 (d, J=4.04 Hz, 1 H).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1.[CH:43]([NH2:46])([CH3:45])[CH3:44]>>[CH:43]([NH:46][C:2]1[CH:3]=[C:4]([CH:40]=[CH:41][CH:42]=1)[CH2:5][O:6][CH:7]1[CH:12]([C:13]2[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][CH2:22][O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[O:31][CH3:32])=[CH:15][CH:14]=2)[CH2:11][CH2:10][N:9]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:8]1)([CH3:45])[CH3:44]
Reactant: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(Br)c2)cc1
Reactant: CC(C)N
Product: COc1ccccc1COCCCOc1ccc(C2CCN(C(=O)OC(C)(C)C)CC2OCc2cccc(NC(C)C)c2)cc1

Procedure:
Analogously to Example 125a, 0.510 g of tert-butyl 3-(3-bromobenzyloxy)-4-{4-[3-(2-methoxybenzyloxy)propoxy]phenyl}piperidine-1-carboxylate and 0.086 ml of isopropylamine are reacted. The title compound is obtained as a yellowish oil. Rf=0.30 (1:2 EtOAc-heptane); Rt=5.18.
Reaction SMILES: [CH:1](=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S([O-])([O-])(=O)=O.[Mg+2].[NH2:15][C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:26]>C(#N)C>[CH:1](=[N:15]/[C:16]1[CH:24]=[C:23]([F:25])[CH:22]=[C:21]2[C:17]=1[CH2:18][O:19][C:20]2=[O:26])\[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccccc1
Reactant: Nc1cc(F)cc2c1COC2=O
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: CC#N
Product: O=C1OCc2c(/N=C/c3ccccc3)cc(F)cc21
Temperature: 25 °C
Reaction time: 144 h
Yield: 65.5 %

Procedure:
To a stirred mixture of benzaldehyde (4.125 g, 29.9 mmol) and anhydrous magnesium sulfate (36 g, 299 mmol) in anhydrous acetonitrile (200 mL) was added 4-amino-6-fluoroisobenzofuran-1(3H)-one (5 g, 29.9 mmol) at 0° C. After the addition, the mixture was stirred at room temperature for 6 days. The mixture was filtered and the cake was washed with ethyl acetate (50 mL×3). The filtrate was concentrated to give crude product. The crude product was washed with petroleum ether to give (E)-4-(benzylideneamino)-6-fluoroisobenzofuran-1(3H)-one (5 g, yield: 66%). 1H-NMR (400 MHz, CDCl3) δ (ppm): 5.40 (s, 2); 7.11-7.14 (dd, 1H), 7.44-7.46 (dd, 2H), 7.53-7.59 (m, 3H), 7.93-7.95 (m, 2H), 8.54 (s, 1H); LC-MS (ESI) m/z: 256 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[Cl:11])[C:5]([OH:7])=O.[NH2:12][C:13]1[CH:18]=[C:17]([NH2:19])[CH:16]=[CH:15][C:14]=1[CH3:20].C(Cl)CCl>C(Cl)Cl>[NH2:12][C:13]1[CH:18]=[C:17]([NH:19][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([Cl:11])=[C:2]([Cl:1])[CH:3]=2)[CH:16]=[CH:15][C:14]=1[CH3:20]
Reactant: Cc1ccc(N)cc1N
Reactant: O=C(O)c1ccc(Cl)c(Cl)c1
Solvent: ClCCCl
Solvent: ClCCl
Product: Cc1ccc(NC(=O)c2ccc(Cl)c(Cl)c2)cc1N
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 3,4-dichlorobenzoic acid (200 mg, 1.05 mmol), 2,4-diaminotoluene (513 mg, 4.20 mmol), and EDC (403 mg, 2.10 mmol) was added CH2Cl2 (40 mL). The mixture was stirred overnight at RT, concentrated, diluted with EtOAc and extracted with water. The organic layer was dried over Na2SO4, filtered, concentrated, and purified by flash chromatography (n-Hexanes→50% EtOAc/n-Hexanes) yielding N-(3-amino-4-methyl-phenyl)-3,4-dichloro-benzamide. MS m/z=295, 297 [M]+ and [M+2]+. Calc'd for C14H12Cl2N2O: 295.17.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][NH2:17])[CH2:11][CH2:10]1.[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH:41]=O)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:23][CH2:22][CH2:21][CH2:20][CH2:19]1>>[CH:18]1([C:24]2[CH:29]=[CH:28][C:27]([C:30]3[N:34]([C:35]4[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=4)[N:33]=[C:32]([CH2:41][NH:17][CH2:16][CH2:15][N:12]4[CH2:13][CH2:14][N:9]([C:3]5[CH:4]=[CH:5][C:6]([CH3:8])=[CH:7][C:2]=5[CH3:1])[CH2:10][CH2:11]4)[CH:31]=3)=[CH:26][CH:25]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23]1
Reactant: O=Cc1cc(-c2ccc(C3CCCCC3)cc2)n(-c2ccccc2)n1
Reactant: Cc1ccc(N2CCN(CCN)CC2)c(C)c1
Product: Cc1ccc(N2CCN(CCNCc3cc(-c4ccc(C5CCCCC5)cc4)n(-c4ccccc4)n3)CC2)c(C)c1
Yield: 52.8 %

Procedure:
Compound 34 was prepared using the same method as that of Example 1 except that 4-(2,4-dimethylphenyl)piperazin-1-ylethylamine and 5-(4-cyclohexyl phenyl)-1-phenyl pyrazole-3-carbaldehyde were used.
Reaction SMILES: C([O:3][C:4]([C:6]1[S:10][C:9]([NH:11][C:12](=[O:28])[CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[CH2:14][CH:15]2[CH2:19][CH2:18][CH2:17][CH2:16]2)=[N:8][CH:7]=1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-]>C(OCC)C>[CH:15]1([CH2:14][CH:13]([C:20]2[CH:25]=[CH:24][C:23]([Cl:26])=[C:22]([Cl:27])[CH:21]=2)[C:12]([NH:11][C:9]2[S:10][C:6]([CH2:4][OH:3])=[CH:7][N:8]=2)=[O:28])[CH2:16][CH2:17][CH2:18][CH2:19]1
Reactant: CCOC(=O)c1cnc(NC(=O)C(CC2CCCC2)c2ccc(Cl)c(Cl)c2)s1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: O=C(Nc1ncc(CO)s1)C(CC1CCCC1)c1ccc(Cl)c(Cl)c1
Temperature: 0 °C
Yield: 53 %

Procedure:
A solution of 2-[3-cyclopentyl-2-(3,4-dichlorophenyl)-propionylamino]-thiazole-5-carboxylic acid ethyl ester (prepared in Example 1 (B)(g), 110 mg, 0.25 mmol) in diethyl ether (2 mL) at 0° C. was slowly treated with lithium aluminum hydride (12 mg, 0.31 mmol). The resulting reaction mixture continued to stir at 0° C. and was allowed to gradually warm to 25° C.. The reaction mixture was then stirred at 25° C. over a period of 14 h. The reaction mixture was slowly quenched by the dropwise addition of water (5 mL). The resulting reaction mixture was partitioned between water and ethyl acetate. A saturated aqueous sodium chloride solution was added to break up the emulsions. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 1/3 hexanes/ethyl acetate) afforded 3-cyclopentyl-2-(3,4-dichlorophenyl)-N-(5-hydroxymethyl-thiazol-2-yl)-propionamide (52.9 mg, 53%) as a light yellow solid: mp 128-130° C.; EI-HRMS m/e calcd for C18H20Cl2N2O2S (M) 398.0623, found 398.0623.
Reaction SMILES: Cl[C:2]([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:3].[NH2:11][C:12]1[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:15]([C:16]#[N:17])=[CH:14][N:13]=1.N1C=CC=CC=1>C1COCC1>[C:5]1([O:4][C:2](=[O:3])[NH:11][C:12]2[CH:19]=[C:18]([O:20][CH:21]([CH3:23])[CH3:22])[C:15]([C:16]#[N:17])=[CH:14][N:13]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: CC(C)Oc1cc(N)ncc1C#N
Reactant: O=C(Cl)Oc1ccccc1
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)Oc1cc(NC(=O)Oc2ccccc2)ncc1C#N
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Phenyl chloroformate (3.89 ml, 31.0 mmol) was added drop wise to a mixture of 6-amino-4-isopropoxynicotinonitrile (intermediate 97, 2.5 g, 14.11 mmol) and pyridine (2.51 ml, 31.0 mmol) in THF (100 ml) at room temperature. The reaction mixture was stirred for 12 h at room temperature, additional pyridine (2.51 ml, 31.0 mmol) added, before stirring for an additional 12 h and then partitioned between EtOAc and saturated aqueous NaHCO3 solution. The organic layer was washed with saturated brine, dried over MgSO4 and evaporated. The residue was triturated with Et2O and the product obtained by filtration as a beige solid. (UPLC-MS 7) tR 1.09; ESI-MS 298.2 [M+H]+.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:28]=[CH:27][N:26]=[CH:25][CH:24]=2)=[CH:19][CH:18]=1)=O)(C)(C)C.[ClH:30]>O1CCOCC1>[NH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[NH:15][C:16](=[O:29])[C:17]1[CH:22]=[CH:21][C:20]([C:23]2[CH:24]=[CH:25][N:26]=[CH:27][CH:28]=2)=[CH:19][CH:18]=1.[ClH:30]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(-c2ccncc2)cc1
Agent: Cl
Solvent: C1COCCO1
Product: Nc1ccccc1NC(=O)c1ccc(-c2ccncc2)cc1

Procedure:
N-(2-t-Butoxycarbonylaminophenyl)-4-pyridin-4-ylbenzamide (Method 1; 100 mg, 0.26 mmol), 1,4-dioxane (2 ml) and a 4M solution of hydrogen chloride in dioxane (2 ml) were stirred at ambient temperature for approximately 20 hours. The resultant precipitate was collected by filtration and washed with iso-hexane and diethyl ether and dried in vacuo to give the title compound as its hydrochloride (43 mg, 46%); NMR Spectrum: (DMSO-d6) 7.31 (m, 2H), 7.39 (t, 1H), 7.54 (t, 1H), 8.17 (d, 2H), 8.30 (d, 2H), 8.40 (d, 2H), 8.96 (d, 2H), 10.62 (s, 1H); Mass Spectrum: M+H+ 290.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:14])[CH2:13][CH2:12][NH:11][CH2:10]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.C(N(C(C)C)C(C)C)C.[CH3:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[C:57]([C:58](O)=[O:59])=[CH:56][O:55][N:54]=2)=[CH:49][CH:48]=1>CN(C=O)C>[Cl:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1([OH:14])[CH2:13][CH2:12][N:11]([C:58]([C:57]2[C:53]([C:50]3[CH:51]=[CH:52][C:47]([CH3:46])=[CH:48][CH:49]=3)=[N:54][O:55][CH:56]=2)=[O:59])[CH2:10]1
Reactant: Cc1ccc(-c2nocc2C(=O)O)cc1
Reactant: OC1(c2ccccc2Cl)CCNC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1ccc(-c2nocc2C(=O)N2CCC(O)(c3ccccc3Cl)C2)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.7 %

Procedure:
A solution of 3-(2-chlorophenyl)pyrrolidin-3-ol hydrochloride (9 mg, 0.039 mmol), TBTU (15 mg, 0.047 mmol, 1.2 equ.) and N-ethyl-N-isopropylpropan-2-amine (14 μL, 0.079 mmol, 2 equ.) in DMF (0.3 mL) was added to 3-(4-methylphenyl)isoxazole-4-carboxylic acid (8 mg, 0.039 mmol) and the reaction mixture was stirred at rt for 2 h. The solvent was evaporated and the crude product was purified by RP-HPLC. After evaporation of the solvents the product was dried in vacuum to yield the title compound (11 mg). MS (ESI, pos. ion) m/z: calcd for C21H19ClN2O3: 382.1084, found 382.1080.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])[C:6]=2[CH:5]=[CH:4][C:3]=1[OH:16].[N:17]1[CH:22]=[CH:21][N:20]=[CH:19][C:18]=1[CH2:23]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)(C)C)=O)=NC(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C1COCC1.C(Cl)Cl>[Br:1][C:2]1[C:10]2[N:9]=[N:8][N:7]([CH2:11][C:12]([CH3:13])([CH3:15])[CH3:14])[C:6]=2[CH:5]=[CH:4][C:3]=1[O:16][CH2:23][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][N:17]=1
Reactant: CC(C)(C)Cn1nnc2c(Br)c(O)ccc21
Reactant: OCc1cnccn1
Agent: CC(C)(C)OC(=O)N=NC(=O)OC(C)(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: C1CCOC1
Product: CC(C)(C)Cn1nnc2c(Br)c(OCc3cnccn3)ccc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a suspension of 4-bromo-1-(2,2-dimethylpropyl)-1H-1,2,3-benzotriazol-5-ol (Example 1-2) (1.5 g, 5.28 mmol, 1.0 equiv.), 2-pyrazinylmethanol (13) (0.581 g, 5.28 mmol, 1.0 equiv.) and polymer-supported triphenylphosphine (2.2 mmol/g, 5.75 g, 21.91 mmol, 2.5 equiv.) in THF (37.7 ml) and DCM (37.7 ml) was slowly added di-tert-butyl azodicarboxylate (2.431 g, 10.56 mmol, 2.0 equiv.). After stirring at room temperature for 1 hr, the reaction mixture was passed through a filter. The residue was washed with DCM and THF. The filtrate was concentrated to dryness to give a solid, which was taken up in DCM (12 mL) and treated with TFA (6 mL). The mixture was stirred at room temperature until LCMS showed only the desired product. The reaction mixture was neutralized to pH=7 with saturated aqueous NaHCO3, and then extracted with DCM. The combined organic layers were dried over Na2SO4, filtered and concentrated in vacuo. The residue was purified via silica gel chromatography (EtOAc/Hexane gradient from 0 to 100%) to obtain product Example 4-1. 1H NMR δ (CDCl3): 9.06 (s, 1H), 8.59-8.57 (m, 2H), 7.42 (d, 1H, J=9.5 Hz), 7.31 (d, 1H, J=9.0 Hz), 5.38 (s, 2H), 4.38 (s, 2H), 1.04 (s, 9H) ppm. LRMS m/z (M+H) 376.1 and 378.1 (intensity ratio ˜1:1) found, 376.1 and 378.1 required.