Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4](O)=[O:5].C(N1C=CN=C1)([N:22]1C=CN=C1)=O.N>CN(C=O)C>[F:1][C:2]1[CH:10]=[N:9][CH:8]=[C:7]([NH:11][C:12]2[CH:17]=[CH:16][C:15]([I:18])=[CH:14][C:13]=2[F:19])[C:3]=1[C:4]([NH2:22])=[O:5]
Reactant: O=C(O)c1c(F)cncc1Nc1ccc(I)cc1F
Reactant: O=C(n1ccnc1)n1ccnc1
Agent: N
Solvent: CN(C)C=O
Product: NC(=O)c1c(F)cncc1Nc1ccc(I)cc1F
Temperature: 60 °C
Reaction time: 1.5 h

Procedure:
5.000 g of 3-fluoro-5-[(2-fluoro-4-iodophenyl)amino]isonicotinic acid (13.294 mmol, 1. eq.) and 4.980 g of 1,1′-carbonyldiimidazol (30.710 mmol. 2.31 eq) were weighed into a round-bottom flask. 650 mL of dry DMF were added under a nitrogen atmosphere and the resulting mixture was stirred at 60° C. for 1.5 hours. The mixture was cooled to 3° C. in an ice bath, then ammonia (25 weight % in water) was added dropwise and the mixture stirred at room temperature for 18 hours. The resulting slurry was filtered off, the precipitate was rinsed with water and then dried in vacuo to yield 2.54 g (6.36 mmol, 48%) of the analytically pure target compound.
Reaction SMILES: [Cl:1][C:2]1[N:11]=[C:10]([N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH:13]2[CH2:22][CH3:23])[C:9]2[C:4](=[C:5]([O:24][CH3:25])[CH:6]=[CH:7][CH:8]=2)[N:3]=1.[CH3:26][C:27]1[CH:33]=[C:32]([F:34])[CH:31]=[CH:30][C:28]=1[NH2:29]>CN(C)C=O>[ClH:1].[CH3:25][O:24][C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:4]=1[N:3]=[C:2]([NH:29][C:28]1[CH:30]=[CH:31][C:32]([F:34])=[CH:33][C:27]=1[CH3:26])[N:11]=[C:10]2[N:12]1[CH2:21][CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:13]1[CH2:22][CH3:23]
Reactant: CCC1c2ccccc2CCN1c1nc(Cl)nc2c(OC)cccc12
Reactant: Cc1cc(F)ccc1N
Solvent: CN(C)C=O
Product: CCC1c2ccccc2CCN1c1nc(Nc2ccc(F)cc2C)nc2c(OC)cccc12
Product: Cl
Yield: 32 %

Procedure:
In accordance with the same procedures as in Example 18, except that to a mixture of 1.5 g of the compound (4.63 mM) prepared in Example 10 and 15 ml of dimethyl-formamide, 0.80 ml of 2-methyl-4-fluoroaniline(9.73 mM) was added, 0.70 g of the title compound was prepared.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[Cl:7].[OH-:8].[K+].[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=[O:17]>C(#N)C>[Br-:10].[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][N:3]1[C:2]([Cl:1])=[C:6]([Cl:7])[N+:5]([CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([OH:17])=[O:8])=[CH:4]1)([OH:18])=[O:17]
Reactant: Clc1nc[nH]c1Cl
Reactant: O=C(O)CCCCCBr
Reactant: [OH-]
Agent: [K+]
Solvent: CC#N
Product: O=C(O)CCCCCn1c[n+](CCCCCC(=O)O)c(Cl)c1Cl
Product: [Br-]

Procedure:
4,5-dichloroimidazole (1.00 g, 7.36 mmol) was dissolved in acetonitrile. Potassium hydroxide (0.828 g, 14.72 mmol) was added to the solution and allowed to reflux for 30 min. 2 equivalents of 6-bromohexanoic acid (2.87 g, 14.72 mmol) was added to the solution and refluxed for 5 h. Solution was filtered to remove the KBr precipitate and neutralized with 6M HBr. Volatiles were removed in vacuo and the resulting product will be collected and analyzed.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][C:7]#[C:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18].[H][H]>[Pd].CO>[CH3:1][O:2][C:3](=[O:19])[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][N:10]1[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH:11]1[CH2:17][OH:18]
Reactant: [H][H]
Reactant: COC(=O)CCCC#CCN1C(=O)CCCC1CO
Agent: [Pd]
Solvent: CO
Product: COC(=O)CCCCCCN1C(=O)CCCC1CO
Reaction time: 23 h
Yield: 101.2 %

Procedure:
Palladium on carbon (10 wt. %, 20 mg) was added to a solution of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-hept-5-ynoic acid methyl ester (180 mg, 0.67 mmol) in MeOH (6.0 mL). A hydrogen atmosphere was established by evacuating and refilling with hydrogen (3×) and the reaction mixture was stirred under a balloon of hydrogen for 23 h. The reaction mixture was filtered through celite, washing with MeOH, and the filtrate was concentrated in vacuo to afford 184 mg (quant.) of 7-(2-hydroxymethyl-6-oxo-piperidin-1-yl)-heptanoic acid methyl ester.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24][CH3:25])[CH:3]=1.ClC1C=CC=C(C(OO)=[O:34])C=1>C(Cl)(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][S:9]([C:12]2[S:16][C:15]3[CH:17]=[CH:18][C:19]([F:21])=[CH:20][C:14]=3[C:13]=2[CH3:22])(=[O:11])=[O:10])=[C:4]([CH2:23][S:24]([CH3:25])=[O:34])[CH:3]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSCc1cc(Br)ccc1NS(=O)(=O)c1sc2ccc(F)cc2c1C
Solvent: ClC(Cl)Cl
Product: Cc1c(S(=O)(=O)Nc2ccc(Br)cc2CS(C)=O)sc2ccc(F)cc12
Temperature: 25 °C
Reaction time: 18 h
Yield: 65.1 %

Procedure:
To a solution of 5-fluoro-3-methyl-benzo[b]thiophene-2-sulfonic acid(4-bromo-2-methylsulfanylmethyl-phenyl)-amide (0.46 g) (cf. example 13a) in chloroform (25 ml) was added m-chloroperbenzoic acid 85% (0.272 g). The reaction mixture was stirred at rt for 18 h, concentrated, and the crude residue was chromatographed on silica gel using heptane/ethyl acetate as eluent to obtain the desired compound (0.31 g) as an off-white solid. MS (ISN): 473.9, 476.0 (M−H)−
Reaction SMILES: C([O:5][C:6]([CH:8]1[CH2:12][CH:11]([O:13][C:14]2[C:23]3[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=3)[N:17]=[C:16]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[N:15]=2)[CH2:10][CH:9]1[C:32](=[O:44])[NH:33][C:34]1([C:39]([O:41][CH2:42][CH3:43])=[O:40])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:7])(C)(C)C.FC(F)(F)S(O)(=O)=O>ClCCl.C([SiH](CC)CC)C>[CH2:42]([O:41][C:39]([C:34]1([NH:33][C:32]([CH:9]2[CH2:10][CH:11]([O:13][C:14]3[C:23]4[C:18](=[CH:19][C:20]([O:24][CH3:25])=[CH:21][CH:22]=4)[N:17]=[C:16]([C:26]4[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=4)[N:15]=3)[CH2:12][CH:8]2[C:6]([OH:7])=[O:5])=[O:44])[CH2:36][CH:35]1[CH:37]=[CH2:38])=[O:40])[CH3:43]
Reactant: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)OC(C)(C)C)C(=O)OCC
Agent: CC[SiH](CC)CC
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClCCl
Product: C=CC1CC1(NC(=O)C1CC(Oc2nc(-c3ccccc3)nc3cc(OC)ccc23)CC1C(=O)O)C(=O)OCC
Reaction time: 2 h
Yield: 99.5 %

Procedure:
Compound 52 (780 mg, 1.29 mmol) was dissolved in dichloromethane (20 mL) and triethyl silane (0.4 mL). Trifluoromethane sulfonic acid was added dropwise at room temperature. The mixture was then left for 2 h at room temperature. Removal of the solvent gave pure title product (700 mg, 99%) MS (M+H+) 546.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([N:9]2[CH2:14][CH2:13][CH:12]([OH:15])[CH2:11][CH2:10]2)[O:6][N:5]=1)([CH3:3])[CH3:2].[H-].[Na+].[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24](Cl)[S:25][C:21]=2[CH:20]=1>C1COCC1.O>[Br:18][C:19]1[CH:28]=[CH:27][C:22]2[N:23]=[C:24]([O:15][CH:12]3[CH2:11][CH2:10][N:9]([C:7]4[O:6][N:5]=[C:4]([CH:1]([CH3:3])[CH3:2])[N:8]=4)[CH2:14][CH2:13]3)[S:25][C:21]=2[CH:20]=1
Reactant: Clc1nc2ccc(Br)cc2s1
Reactant: CC(C)c1noc(N2CCC(O)CC2)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)c1noc(N2CCC(Oc3nc4ccc(Br)cc4s3)CC2)n1
Temperature: 60 °C
Reaction time: 4 h
Yield: 64.8 %

Procedure:
To a solution of 1-(3-isopropyl-1,2,4-oxadiazol-5-yl)piperidin-4-ol (590 mg, 2.79 mmol) in THF (20 mL) was added NaH (60% in mineral oil, 142 mg, 3.55 mmol) followed by 6-bromo-2-chlorobenzo[d]thiazole (631 mg, 2.54 mmol). The reaction mixture was stirred at 60° C. for 4 h. The mixture was cooled to rt, diluted with water (40 mL), and extracted with EtOAc (3×30 mL). The combined organic layers were dried (Na2SO4), filtered, and concentrated. The residue was purified by column chromatography (silica gel, hexanes-EtOAc gradient 0 to 50% EtOAc) to afford 5-(4-(6-bromobenzo[d]thiazol-2-yloxy)piperidin-1-yl)-3-isopropyl-1,2,4-oxadiazole (697 mg, 1.646 mmol, 65% yield) as a white solid.
Reaction SMILES: [OH:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7](OC(=O)C)(=[O:9])[CH3:8]>N1C=CC=CC=1>[C:7]([N:4]1[CH:5]=[CH:6][C:2]([OH:1])=[N:3]1)(=[O:9])[CH3:8]
Reactant: Oc1cc[nH]n1
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)n1ccc(O)n1
Temperature: 95 °C
Reaction time: 1 h
Yield: 83.8 %

Procedure:
A solution of 3-hydroxy-1H-pyrazole (8.2 g, 97.5 mmol) in pyridine (40 mL) was heated to 95° C. A mixture consisting of acetic anhydride (9.4 mL, 102 mmol) and pyridine (20 mL) was added over 15 min; then stirring at 95° C. was continued for 60 min. All volatiles were then removed under reduced pressure and to the residue was added 200 mL of diethyl ether. The slurry was stirred overnight at room temperature, then the solid was filtered off and rinsed with diethyl ether. The product was obtained as an off-white solid (10.3 g, 81.7 mmol, 84% yield).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([N+:11]([O-])=O)[C:6]=1[CH2:14][S:15]([C:18]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[CH:21]=[CH:20][CH:19]=1)(=[O:17])=[O:16].C(O)=O>C1COCC1.CO.[Pd]>[Cl:1][CH2:2][CH2:3][O:4][C:5]1[C:6]([CH2:14][S:15]([C:18]2[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[CH:21]=[CH:20][CH:19]=2)(=[O:17])=[O:16])=[C:7]([NH2:11])[CH:8]=[CH:9][CH:10]=1
Reactant: O=[N+]([O-])c1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Agent: [Pd]
Solvent: CO
Solvent: C1CCOC1
Solvent: O=CO
Product: Nc1cccc(OCCCl)c1CS(=O)(=O)c1cccc2ccccc12
Reaction time: 20 h
Yield: 93.8 %

Procedure:
A mixture of 1-[2-(2-Chloro-ethoxy)-6-nitro-phenylmethanesulfonyl]-naphthalene (0.9 g, 2.24 mmoles) and 10% Pd/C in THF (10 mL), methanol (10 mL), and formic acid (2 mL) was hydrogenated in a Parr hydrogenation bottle (250 mL) at 40 lb/in2 for 20 hours. The mixture was filtered through Celite, and the filtrate was diluted with EtOAc, washed with water, dried over Na2SO4, and concentrated under vacuum to afford the title compound as an off-white solid (0.78 g, 2.1 mmoles).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:8]([O-])=O.[Na+].C([O-])(=O)C.[Na+].[C:17]([CH2:20][C:21](=[O:23])[CH3:22])(=[O:19])[CH3:18]>C(O)(=O)C.Cl.O.C(O)C>[C:2]1([NH:1][N:8]=[C:20]([C:21](=[O:23])[CH3:22])[C:17](=[O:19])[CH3:18])[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(=O)CC(C)=O
Reactant: O=N[O-]
Reactant: Nc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Solvent: CC(=O)O
Product: CC(=O)C(=NNc1ccccc1)C(C)=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.3 %

Procedure:
To a solution of aniline (2000 mg, 21.50 mmol) in 30 mL of acetic acid and 5 mL of concentrated hydrochloride solution, sodium nitrite (1780 mg, 25.80 mmol) in 8 mL of water was added dropwise at 0° C., and the mixture was stirred at 0° C. for 1 h. Then to the reaction mixture was added dropwise a solution of sodium acetate (5290 mg, 64.50 mmol) and acetylacetone (2795 mg, 27.95 mmol) in 20 mL of ethanol and 12 mL of water. The mixture was stirred at room temperature overnight, filtered, washed with water, EtOH/H2O (1:1) and hexane, and dried to give 3-(phenylhydrazono)pentane-2,4-dione (2955 mg, 67%).
Reaction SMILES: C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.[CH3:19][C@H:20]1[CH2:25][O:24][CH2:23][CH2:22][NH:21]1.[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48](O)=[O:49])[CH:46]=3)[C:41]([S:51]([CH3:53])=[O:52])=[CH:40]2)=[N:37][CH:38]=1.C(=O)([O-])[O-].[Na+].[Na+]>ClCCl>[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33]1[CH:34]=[N:35][C:36]([N:39]2[C:47]3[C:42](=[CH:43][CH:44]=[C:45]([C:48]([N:21]4[CH2:22][CH2:23][O:24][CH2:25][C@@H:20]4[CH3:19])=[O:49])[CH:46]=3)[C:41]([S:51]([CH3:53])=[O:52])=[CH:40]2)=[N:37][CH:38]=1
Reactant: C[C@H]1COCCN1
Reactant: CS(=O)c1cn(-c2ncc(-c3ccccc3F)cn2)c2cc(C(=O)O)ccc12
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: C[C@H]1COCCN1C(=O)c1ccc2c(S(C)=O)cn(-c3ncc(-c4ccccc4F)cn3)c2c1
Reaction time: 8 h

Procedure:
T3P (50 wt % solution in ethyl acetate, 179 μl, 0.304 mmol) was added to a solution of (S)-3-methylmorpholine (46 mg, 0.456 mmol) and 1-(5-(2-fluorophenyl)pyrimidin-2-yl)-3-(methylsulfinyl)-1H-indole-6-carboxylic acid (60 mg, 0.152 mmol) in dichloromethane (3 mL) at room temperature and the mixture was stirred overnight. 1 M sodium carbonate solution (20 mL) was poured into the reaction mixture and stirring was continued for 1 h. The mixture was extracted with dichloromethane (3×) and the combined organic layers were dried over magnesium sulfate and concentrated. The residue was purified by flash chromatography [dichloromethane with 0-5% ethanol]. White foam. Yield: 68 mg (93% of theory).
Reaction SMILES: [NH2:1][C:2]([CH3:7])([CH3:6])[C:3]([OH:5])=[O:4].S(Cl)([Cl:10])=O.[CH2:12](O)[CH3:13]>>[ClH:10].[CH2:12]([O:4][C:3](=[O:5])[C:2]([NH2:1])([CH3:7])[CH3:6])[CH3:13]
Reactant: CCO
Reactant: O=S(Cl)Cl
Reactant: CC(C)(N)C(=O)O
Product: CCOC(=O)C(C)(C)N
Product: Cl
Yield: 86.3 %

Procedure:
This was synthesised according to Standard Procedure 1, using 2-amino-isobutyric acid (5.102 g, 48.49 mmol) with thionyl chloride (11.772 g, 98.95 mmol, 7.2 mL) and anhydrous ethanol (29 mL). The product was isolated as a white solid (7.159 g, yield 86.3%).
Reaction SMILES: Cl[C:2]1[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][N:16]2[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]2)=[O:7])=[CH:4][N:3]=1.[CH:25]1([NH:28][C:29](=[O:46])[C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32](B3OC(C)(C)C(C)(C)O3)[CH:31]=2)[CH2:27][CH2:26]1>>[CH:25]1([NH:28][C:29]([C:30]2[CH:35]=[CH:34][C:33]([CH3:36])=[C:32]([C:2]3[CH:24]=[CH:23][C:5]([C:6]([NH:8][C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=4[CH2:15][N:16]4[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]4)=[O:7])=[CH:4][N:3]=3)[CH:31]=2)=[O:46])[CH2:26][CH2:27]1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: CN1CCN(Cc2ccccc2NC(=O)c2ccc(Cl)nc2)CC1
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc(C(=O)Nc2ccccc2CN2CCN(C)CC2)cn1

Procedure:
6-(5-Cyclopropylcarbamoyl-2-methyl-phenyl)-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]-nicotinamide was prepared from 6-chloro-N-[2-(4-methylpiperazin-1-ylmethyl)phenyl]nicotinamide (Intermediate 5) and N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-benzamide (Intermediate 8) using General Method B. LCMS: retention time 2.36 min, MH+ 484. NMR: δH [2H6]-DMSO 11.70,(1H, b), 9.23,(1H, s), 8.50,(1H, d), 8.38,(1H, d), 8.33,(1H, d), 7.92,(1H, s), 7.83,(2H, m), 7.43,(1H, d), 7.36,(1H, t), 7.29,(1H, d), 7.11,(1H, t), 3.77,(2H, s), 2.87,(1H, m), 2.67–2.24,(11H, m), 2.13,(3H, s), 0.70,(2H, m), 0.58,(2H, m).
Reaction SMILES: CN([CH:4]=[C:5]([C:15]1[CH:20]=[CH:19][C:18]([S:21][CH3:22])=[CH:17][CH:16]=1)[C:6]([C:8]1[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=1)=O)C.[C:23]([CH2:25][C:26]([NH2:28])=[O:27])#[N:24].CO.[H-].[Na+]>CN(C=O)C>[F:14][C:11]1[CH:10]=[CH:9][C:8]([C:6]2[NH:28][C:26](=[O:27])[C:25]([C:23]#[N:24])=[CH:4][C:5]=2[C:15]2[CH:16]=[CH:17][C:18]([S:21][CH3:22])=[CH:19][CH:20]=2)=[CH:13][CH:12]=1
Reactant: CSc1ccc(C(=CN(C)C)C(=O)c2ccc(F)cc2)cc1
Reactant: N#CCC(N)=O
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CO
Product: CSc1ccc(-c2cc(C#N)c(=O)[nH]c2-c2ccc(F)cc2)cc1
Temperature: 80 °C
Yield: 846.9 %

Procedure:
A solution of 26.1 g of 1-(N,N-dimethylamino)-3-(4-fluorophenyl)-2-[4-(methylthio)phenyl]prop-1-en-3-one (Step 1), 200 ml of dry DMF, 7.2 g (8.6 mMol) of the cyanoacetamide and 8 ml methanol was transferred to a dropping funnel. This solution was added dropwise to a slurry of 4.0 g of sodium hydride in 100 ml of DMF in a 3-necked round bottom flask with a magnetic stirrer and cooled with an ice bath. The temperature reached to 25° C. After complete addition of the reactants the mixture was heated to 80° C. for 4 hours, cooled and poured into one liter of 1M NaH2PO4 to give an insoluble yellow solid which was washed with water and air dried to yield 24.5 g of a yellow powder (95%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH2:15])=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl[C:17]1[CH:26]=[N:25][C:24]2[C:19](=[CH:20][C:21]([F:28])=[C:22]([F:27])[CH:23]=2)[N:18]=1>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][C@H:9]1[CH2:14][NH:15][C:26]1[CH:17]=[N:18][C:19]2[C:24](=[CH:23][C:22]([F:27])=[C:21]([F:28])[CH:20]=2)[N:25]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Fc1cc2ncc(Cl)nc2cc1F
Reactant: CC(C)(C)OC(=O)N1CCCC[C@H]1CN
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CCCC[C@H]1CNc1cnc2cc(F)c(F)cc2n1
Temperature: 90 °C

Procedure:
(S)-2-Aminomethyl-piperidine-1-carboxylic acid tert-butyl ester (0.607 g), and 2-chloro-6,7-difluoroquinoxaline McQuaid et. al. J. Med. Chem. (1992), 35(18), 3319-24 (0.569 g) were dissolved in dimethylformamide (1 ml) and heated to 90° C. for 5 days under an atmosphere of argon. After cooling, the reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with water, saturated brine, dried and evaporated. The residue was chromatographed over silica gel, eluting with a gradient of 10 to 50% ethyl acetate in hexane. The title compound was obtained as a pale yellow solid (0.460 g), MH+ 379.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C@@H:17]([O:38][Si](C(C)(C)C)(C)C)[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:26]=CN=[CH:23][CH:22]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C[OH:47]>ClCCl>[C:1]([NH:8][C@H:9]([C@@H:17]([OH:38])[CH2:18][C@@H:19]([NH:27][C:28]([O:30][CH2:31][C:32]1[CH:33]=[N:34][CH:35]=[CH:36][CH:37]=1)=[O:29])[CH2:20][C:21]1[CH:22]=[CH:23][O:47][CH:26]=1)[CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: CO
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@H](C[C@H](Cc1ccncc1)NC(=O)OCc1cccnc1)O[Si](C)(C)C(C)(C)C
Solvent: ClCCl
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccccc1)[C@@H](O)C[C@H](Cc1ccoc1)NC(=O)OCc1cccnc1
Yield: 60 %

Procedure:
Using the procedure of Example 4G but replacing (2S,3S,5S)-2-(Boc-amino)-5-(N-((3-pyridinyl)methoxy-carbonyl)amino)-1-phenyl-6-(4-pyridinyl)-3-(tert-butyl-dimethylsilyloxy)hexane with the resultant compound of Example 5D provided, after silica gel chromatography using 5% methanol in dichloromethane, 334.5 mg (60%) of the desired compound as a white solid. 1H NMR (CDCl3) δ 1.38 (s, 9H), 1.66 (t, 2H), 2.61 (d, 2H), 2.85 (t, 3H), 3.70 (m, 2H), 3.89 (m, 1H), 4.84 (br d, 1H), 5.07 (br, 1H), 5.12 (s, 2H), 7.14-7.31 (m, 7H), 7.40 (m, 1H), 7.76 (br d, 1H), 8.57 (dd, 1H), 8.64 (br s, 1H). Mass spectrum: (M+H)+ =510.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[N:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.[F:11][C:12]1[C:17]([CH:18]=[O:19])=[CH:16][CH:15]=[CH:14][C:13]=1[NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22].[OH-].[K+].O>CO>[Br:1][C:2]1[CH:3]=[C:4]2[C:5]([CH:18]([OH:19])[C:17]3[C:12]([F:11])=[C:13]([NH:20][S:21]([CH2:24][CH2:25][CH3:26])(=[O:23])=[O:22])[CH:14]=[CH:15][CH:16]=3)=[CH:6][NH:7][C:8]2=[N:9][CH:10]=1
Reactant: CCCS(=O)(=O)Nc1cccc(C=O)c1F
Reactant: Brc1cnc2[nH]ccc2c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CCCS(=O)(=O)Nc1cccc(C(O)c2c[nH]c3ncc(Br)cc23)c1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.2 %

Procedure:
To 5-bromo-7-azaindole 67 (312 mg, 1.58 mmol) in methanol (28 mL) were added propane-1-sulfonic acid (2-fluoro-3-formyl-phenyl)-amide (503, 370 mg, 1.5 mmol) and potassium hydroxide (422.8 mg, 7.5 mmol) under an atmosphere of nitrogen. The reaction was stirred at room temperature overnight, then poured into water and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate, and filtered. The filtrate was concentrated and purified by silica gel column chromatography eluting with 20% ethyl acetate in hexane to give the desired compound as white solid (504, 300 mg, 45.0%).
Reaction SMILES: [CH2:1]([C:8]1[C:9]([NH:21][CH:22]([CH2:26][CH2:27][CH2:28][CH3:29])[C:23](O)=[O:24])=[N:10][CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)[N:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.C1(N=C=NC2CCCCC2)CCCCC1>C(Cl)Cl>[CH2:1]([C:8]1[NH:13][C:12]([C:14]2[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=2)=[CH:11][N:10]2[C:23](=[O:24])[C:22]([CH2:26][CH2:27][CH2:28][CH3:29])=[N:21][C:9]=12)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCCCC(Nc1ncc(-c2ccc(O)cc2)nc1Cc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCc1nc2c(Cc3ccccc3)[nH]c(-c3ccc(O)cc3)cn-2c1=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.3 %

Procedure:
2-((3-benzyl-5-(4-hydroxyphenyl)pyrazin-2-yl)amino)hexanoic acid (130 mg, 0.33 mmol) was dissolved in DCM (10 mL). Pyridine (0.5 mL) was added followed by N,N′-Dicyclohexylcarbodiimide (137 mg, 0.67 mmol). The reaction mixture was slowly stirred at room temperature for 1 hr. The solvent was evaporated, and the residue purified by flash chromatography (eluting solvent: EtOAc to DCM to 10% methanol in DCM) to give the product as a yellow powder (110 mg, 89%). 1H NMR (300 MHz, CD3OD, δ): 7.30 (m, 8H), 6.88 (d, 2H), 4.40 (s, 2H), 2.84 (t, 2H), 1.77 (m, 2H), 1.51 (m, 2H), 0.89 (m, 3H); MS (ESI) m/z 374.3 (M+1).
Reaction SMILES: [C:1]([Mg]Br)([CH3:3])=[CH2:2].[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][C:22]([N+]([O-])=O)=[CH:21][CH:20]=2)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7].[Cl-].[NH4+:29]>C1COCC1>[C:6]([O:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]([C:19]2[CH:24]=[CH:23][CH:22]=[C:21]3[C:20]=2[NH:29][C:1]([CH3:3])=[CH:2]3)[CH2:15][CH2:14]1)=[O:12])([CH3:9])([CH3:8])[CH3:7]
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc([N+](=O)[O-])cc2)CC1
Reactant: C=C(C)[Mg]Br
Reactant: [NH4+]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Cc1cc2cccc(N3CCN(C(=O)OC(C)(C)C)CC3)c2[nH]1
Temperature: -40 °C
Reaction time: 0.33 h

Procedure:
Isopropenyl magnesium bromide (234 mL of a 0.5 M solution in THF, 117 mmol) was slowly added to a −40° C. solution of 4-(4-nitrophenyl)-piperazine-1-carboxylic acid tert-butyl ester (12 g, 39 mmol) in 200 mL of THF and the resulting mixture was stirred at −40° C. for 20 min. Saturated aqueous ammonium chloride was added and the mixture was extracted with ethyl acetate. The extract was washed with water and brine, dried (sodium sulfate) and evaporated. Silica gel chromatography (20% ethyl acetate-hexane) afforded 4.8 g of 4-(2-methyl-1H-indol-7-yl)-piperazine-1-carboxylic acid tert-butyl ester (21) as an oil, mass spec, M+ 315.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.C([O-])([O-])=O.[K+].[K+].[CH2:20](Br)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CC(C)=O>[CH2:20]([O:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([N:10]([O:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1
Reactant: CON(C)C(=O)c1ccc(O)cn1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CON(C)C(=O)c1ccc(OCc2ccccc2)cn1
Temperature: 50 °C
Reaction time: 14 h

Procedure:
A mixture of 5-hydroxy-N-methoxy-N-methylpicolinamide (7.51 g), K2CO3 (6.27 g) and benzyl bromide (2.83 mL) in acetone (70 mL) was stirred at 50° C. for 14 h, evaporated, treated with water and extracted with AcOEt. The organic layer was dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (AcOEt/hexane) to the title compound (4.87 g).