Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[C:13]([O:17][CH2:18][CH3:19])(=[O:16])[CH2:14][CH3:15].Br[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][Br:28]>C1COCC1>[Br:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][CH2:21][CH:14]([CH3:15])[C:13]([O:17][CH2:18][CH3:19])=[O:16]
Reactant: BrCCCCCCCBr
Reactant: CCOC(=O)CC
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCOC(=O)C(C)CCCCCCCBr
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a solution of diisopropylamine (5.42 mL) in dry THF (30 mL) under argon at 0° C. was added 2.5M n-butyl lithium (15.5 mL) slowly, keeping the temperature below 10° C. The solution was stirred at 0° C. for 30 minutes before cooling to −78° C. Ethyl propionate (4.01 mL) was added dropwise and the solution stirred at −78° C. for 1 hour. 1,7-dibromoheptane (6.63 mL) was added and stirring continued at −78° C. for 1 hour then the cooling bath was removed and the reaction mixture was stirred at room temperature overnight. Saturated aqueous ammonium chloride (30 mL) was added to the reaction followed by ethyl acetate (30 mL). The layers were separated and the aqueous phase was extracted with ethyl acetate (2×30 mL). The organics were combined, washed with saturated aqueous sodium bicarbonate solution (50 mL), brine (50 mL), dried over sodium sulfate and evaporated. Purification was by silica gel chromatography eluting with 1-5% ethyl acetate in petroleum ether (40-60° C.) to give ethyl 9-bromo-2-methylnonanoate, which was used without further purification. This material (0.84 g) was dissolved in dry ether (27 mL) and cooled to 0° C. under argon. Diisobutylaluminium hydride (1M in toluene, 6.7 mL) was added dropwise and the reaction was stirred at 0° C. for 1 h 15 minutes. The reaction was quenched by addition of saturated aqueous potassium sodium tartrate and the resulting mixture was stirred for 15 minutes. Ethyl acetate (60 mL) and water (20 mL) were added and the phases separated. The aqueous layer was extracted with ethyl acetate (3×30 mL) then the combined organics were washed with brine, dried over sodium sulfate, filtered and evaporated. Purification was by silica gel chromatography eluting with 0 to 10% ethyl acetate in cyclohexane to afford the subtitled compound as a colourless oil. Yield 0.23 g.
Reaction SMILES: C([O:8][C:9]1[C:25]([O:26][CH3:27])=[CH:24][C:12]([CH2:13][C:14]2[C:22]3[C:17](=[N:18][CH:19]=[C:20]([Cl:23])[CH:21]=3)[NH:16][CH:15]=2)=[C:11]([F:28])[CH:10]=1)C1C=CC=CC=1.C(O)(=O)C>O1CCCC1.[Pd]>[Cl:23][C:20]1[CH:21]=[C:22]2[C:14]([CH2:13][C:12]3[C:11]([F:28])=[CH:10][C:9]([OH:8])=[C:25]([O:26][CH3:27])[CH:24]=3)=[CH:15][NH:16][C:17]2=[N:18][CH:19]=1
Reactant: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1OCc1ccccc1
Agent: [Pd]
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1cc(Cc2c[nH]c3ncc(Cl)cc23)c(F)cc1O

Procedure:
3-(4-Benzyloxy-2-fluoro-5-methoxy-benzyl)-5-chloro-1H-pyrrolo[2,3-b]pyridine (224, 48 mmol) was dissolved in tetrahydrofuran (300 mL) and 20% palladium on carbon (50% water wet, 2.3 g) was added. The mixture was stirred under an atmosphere of hydrogen at 50 psi in the presence of acetic acid (100 mL). The reaction mixture was filtered through Celite and evaporated to dryness to give the desired compound 225. MS (ESI) [M+H+]+=307.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:9]=[N:10][N:11]([CH3:21])[C:12]=2[C:13]2[CH:18]=[CH:17][C:16]([Cl:19])=[CH:15][C:14]=2[Cl:20])[CH:5]=[CH:4][N:3]=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]([NH2:32])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]>>[Cl:20][C:14]1[CH:15]=[C:16]([Cl:19])[CH:17]=[CH:18][C:13]=1[C:12]1[N:11]([CH3:21])[N:10]=[CH:9][C:8]=1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:32][C:26]2[CH:27]=[CH:28][C:29]([O:30][CH3:31])=[C:24]([O:23][CH3:22])[CH:25]=2)[N:7]=1
Reactant: COc1ccc(N)cc1OC
Reactant: Cn1ncc(-c2ccnc(Cl)n2)c1-c1ccc(Cl)cc1Cl
Product: COc1ccc(Nc2nccc(-c3cnn(C)c3-c3ccc(Cl)cc3Cl)n2)cc1OC

Procedure:
The title compound is prepared as described in Example 1 but using 2-chloro[5-(2,4-dichloro-phenyl)-1-methyl-1H-pyrazol-4-yl]-pyrimidine and 3,4-dimethoxy-phenylamine.
Reaction SMILES: [CH3:1][C@:2]1([CH2:24][NH:25][C:26]2[CH:27]=[C:28]([CH:31]=[CH:32][C:33]=2[N+:34]([O-])=O)[C:29]#[N:30])[CH2:23][CH2:22][CH2:21][C:4]2([O:8][C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:5]2)[CH2:3]1.CO.[CH:39](OC)(OC)OC.C(O)=O>[Fe].CCOC(C)=O>[CH3:1][C@:2]1([CH2:24][N:25]2[C:26]3[CH:27]=[C:28]([C:29]#[N:30])[CH:31]=[CH:32][C:33]=3[N:34]=[CH:39]2)[CH2:23][CH2:22][CH2:21][C:4]2([O:8][C@H:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C@@H:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:5]2)[CH2:3]1
Reactant: C[C@]1(CNc2cc(C#N)ccc2[N+](=O)[O-])CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Reactant: COC(OC)OC
Agent: [Fe]
Solvent: O=CO
Solvent: CO
Solvent: CCOC(C)=O
Product: C[C@]1(Cn2cnc3ccc(C#N)cc32)CCCC2(C1)O[C@H](c1ccccc1)[C@@H](c1ccccc1)O2
Temperature: 64 °C
Yield: 100 %

Procedure:
A 5 L three neck flask was fitted with a mechanical stirrer and condenser. To the flask was added 3-({[(2R,3R,7S)-7-methyl-2,3-diphenyl-1,4-dioxaspiro[4.5]dec-7-yl]methyl}amino)-4-nitrobenzonitrile (245.5 g, 508 mmol), MeOH (891 mL) and EtOAc (891 mL). Next, trimethyl orthoformate (561 mL, 5077 mmol) and formic acid (195 mL, 5077 mmol) were added. The resulting mixture was heated at 64° C. Next, (2-3 eq) of formic acid, trimethylorthoformate and iron were added every 15 min until the reaction was finished (3.5 h). Next, the mixture was filtered to remove excess iron, and the iron was washed with EtOAc. The filtrate was concentrated and the resulting thick purple residue (residue contained formic acid) was used without further purification (235 g, 100% yield).
Reaction SMILES: CO[C:3]([N:5]([CH2:16][CH2:17][CH3:18])[CH:6](NCCC)[C:7]([O:9]CC)=[O:8])=O.[CH2:19](NC(NCCC)C(OCC)=O)[CH2:20]C.[ClH:33]>>[ClH:33].[CH2:16]([N:5]([CH2:3][CH2:19][CH3:20])[CH2:6][C:7]([OH:9])=[O:8])[CH2:17][CH3:18]
Reactant: CCCNC(C(=O)OCC)N(CCC)C(=O)OC
Reactant: CCCNC(NCCC)C(=O)OCC
Agent: Cl
Product: CCCN(CCC)CC(=O)O
Yield: 80 %

Procedure:
The amino acid di-n-propylglycine can be obtained in the form of its hydrochloride by combining the ethyl N-methoxycarbonyl-2,2-di-n-propylaminoacetate and the ethyl 2,2-di-n-propylaminoacetate and refluxing the mixture with concentrated hydrochloric acid for 12 hours. After cooling, the solution is extracted with MTBE, and the aqueous solution is evaporated to dryness. The residue is taken up again in water, and the solution is evaporated under reduced pressure in order to remove excess hydrochloric acid to leave 43.8 g (80%) of di-n-propylglycine hydrochloride. This can be used to obtain the free amino acid in accordance with known methods.
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(O[C:11](=[O:24])[CH2:12][NH:13][C:14]([O:16][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)=[O:15])C.[H-].[Na+].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>C(OCC)(=O)C.C1(C)C=CC=CC=1>[CH2:17]([O:16][C:14]([N:13]1[CH2:3][CH:2]([C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:11](=[O:24])[CH2:12]1)=[O:15])[C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)CNC(=O)OCc1ccccc1
Reactant: C=CC(=O)OCC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)C1CN(C(=O)OCc2ccccc2)CC1=O
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
Ethyl acrylate (65.01 ml, 600.0 mmol) was added to a toluene (1,200 ml) solution containing N-benzyloxycarbonylglycine ethyl ester (156.3 g, 600.0 mmol) and then, under ice-cooling, sodium hydride (60% oil; 26.40 g, 660.0 mmol) was added thereto. After 10 minutes of stirring at the same temperature, the ice bath was taken off, and the mixture was stirred at room temperature for 20 minutes and then at 50° C. for 3 hours. After completion of the reaction, and under ice-cooling, the reaction solution was adjusted to about pH 3 by adding 10% citric acid aqueous solution and mixed with ethyl acetate, and the mixture was shaken and then subjected to separation of layers. The organic layer was separated and washed with saturated brine, and the water layer was further extracted with ethyl acetate. The organic layers were dried over anhydrous sodium sulfate and then filtered, and the solvent was evaporated under a reduced pressure to obtain 196.7 g (600.0 mmol, quantitative) of the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:22]([OH:24])=O)=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1.[NH2:25][CH2:26][C:27]1([C:40]2[CH:45]=[CH:44][C:43]([F:46])=[CH:42][CH:41]=2)[CH2:32][CH2:31][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:29][CH2:28]1>>[F:1][C:2]1[C:3]([C:22]([NH:25][CH2:26][C:27]2([C:40]3[CH:41]=[CH:42][C:43]([F:46])=[CH:44][CH:45]=3)[CH2:28][CH2:29][N:30]([C:33]([O:35][C:36]([CH3:39])([CH3:38])[CH3:37])=[O:34])[CH2:31][CH2:32]2)=[O:24])=[N:4][CH:5]=[CH:6][C:7]=1[S:8][C:9]1[S:13][C:12]([NH:14][C:15]2[CH:20]=[C:19]([CH3:21])[CH:18]=[CH:17][N:16]=2)=[N:11][CH:10]=1
Reactant: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)O)c3F)s2)c1
Reactant: CC(C)(C)OC(=O)N1CCC(CN)(c2ccc(F)cc2)CC1
Product: Cc1ccnc(Nc2ncc(Sc3ccnc(C(=O)NCC4(c5ccc(F)cc5)CCN(C(=O)OC(C)(C)C)CC4)c3F)s2)c1

Procedure:
Following the amide bond forming procedure given in example 37, 3-fluoro-4-(2-(4-methylpyridin-2-ylamino)thiazol-5-ylthio)picolinic acid (intermediate B in example 1) and tert-butyl 4-(aminomethyl)-4-(4-fluorophenyl)piperidine-1-carboxylate (amine intermediate “P”) were reacted to give the title compound. LC/MS (M+H)+: 653. Ret. time: 2.06 min. (Condition L).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[NH:6]1)=[O:4].[C:14]([O:18][C:19]([NH:21][CH:22]([CH2:26][CH:27]=[CH2:28])[C:23](O)=[O:24])=[O:20])([CH3:17])([CH3:16])[CH3:15].CC(COC1N(C(OCC(C)C)=O)C2C(=CC=CC=2)C=C1)C>C1COCC1.CCOC(C)=O>[CH3:1][O:2][C:3]([CH:5]1[CH2:10][CH2:9][CH2:8][CH:7]([CH2:11][CH:12]=[CH2:13])[N:6]1[C:23](=[O:24])[CH:22]([NH:21][C:19]([O:18][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:20])[CH2:26][CH:27]=[CH2:28])=[O:4]
Reactant: C=CCC1CCCC(C(=O)OC)N1
Reactant: C=CCC(NC(=O)OC(C)(C)C)C(=O)O
Agent: CC(C)COC(=O)N1c2ccccc2C=CC1OCC(C)C
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C=CCC(NC(=O)OC(C)(C)C)C(=O)N1C(CC=C)CCCC1C(=O)OC

Procedure:
A solution of 6-allyl-piperidine-2-carboxylic acid methyl ester, 39, (2.1 g, 11.5 mmol), 2-tert-butoxycarbonylamino-pent-4-enoic acid (9.9 g, 46 mmol), and IIDQ (13.9 g, 46 mmol) in THF (50 mL) is stirred at rt for 24 h. The reaction is diluted with EtOAc and washed with 1N HCl, saturated NaHCO3, and brine. The solution is then dried (MgSO4), concentrated, and purified by flash chromatography over silica (hexanes/ethyl acetate) to afford 1.1 g of the desired product. 1H NMR (CDCl3) δ 5.76 (m, 2H), 5.60–4.20 (series of m, 8H), 3.71 (s, 3H), 2.60–1.50 (series of m, 10H), 1.44 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[NH:7][C@H:8]1[CH2:11][C@H:10]([OH:12])[CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1.N1C=CC=CC=1>ClCCl.CN(C)C1C=CN=CC=1>[CH3:24][C:14]1[CH:19]=[CH:18][C:17]([S:20]([O:12][C@H:10]2[CH2:11][C@H:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:13])[CH2:9]2)(=[O:22])=[O:21])=[CH:16][CH:15]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@H]1C[C@H](O)C1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)O[C@H]2C[C@H](NC(=O)OC(C)(C)C)C2)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Trans-tert-butyl-3-hydroxycyclobutylcarbamate (440 mg), p-toluenesulfonyl chloride (498 mg) and pyridine (0.74 mL) are dissolved in dichloromethane (7 mL) and a catalytic amount of 4-(dimethylamino)pyridine is added. The reaction mixture is stirred at ambient temperature overnight, concentrated, partitioned between ethyl acetate and water. The organic phase is washed with a 20% aqueous solution of citric acid, dried (MgSO4) and concentrated to give the title compound. Yield: 806 mg.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=1[C:12]([C:14]1[CH:19]=[CH:18][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:16][CH:15]=1)=[O:13].C(=O)([O-])[O-].[K+].[K+].Br[CH2:30][C:31]1[CH:32]=[C:33]2[C:38](=[CH:39][CH:40]=1)[N:37]=[C:36]([O:41][CH3:42])[C:35]([O:43][CH3:44])=[N:34]2>O1CCOCC1.O>[CH3:42][O:41][C:36]1[C:35]([O:43][CH3:44])=[N:34][C:33]2[C:38](=[CH:39][CH:40]=[C:31]([CH2:30][NH:1][C:2]3[CH:7]=[CH:6][C:5]([O:8][CH2:9][C:10]#[CH:11])=[CH:4][C:3]=3[C:12]([C:14]3[CH:15]=[CH:16][C:17]([CH:20]([CH3:22])[CH3:21])=[CH:18][CH:19]=3)=[O:13])[CH:32]=2)[N:37]=1
Reactant: C#CCOc1ccc(N)c(C(=O)c2ccc(C(C)C)cc2)c1
Reactant: COc1nc2ccc(CBr)cc2nc1OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: C#CCOc1ccc(NCc2ccc3nc(OC)c(OC)nc3c2)c(C(=O)c2ccc(C(C)C)cc2)c1
Temperature: 80 °C
Reaction time: 48 h

Procedure:
To a solution of 82 mg (0.280 mmol) (2-amino-5-propargyloxy-phenyl)-(4-isopropyl-phenyl)-methanone in 3 ml dioxane is added 193 mg (1.40 mmol) potassium carbonate and 119 mg (0.419 mmol) 6-Bromomethyl-2,3-dimethoxy-quinoxalin. The mixture is stirred at 80° C. for two days, diluted with water and extracted with CH2Cl2. Purification of the crude product by chromatography (ethyl acetate/hexanes 1:1) affords a yellow oil.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1.CC1(C)C(C)(C)OB([C:33]2[CH:38]=[CH:37][N:36]=[CH:35][C:34]=2[NH2:39])O1>COCCOC.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2].C(Cl)Cl>[NH2:39][C:34]1[CH:35]=[N:36][CH:37]=[CH:38][C:33]=1[C:2]1[N:7]=[C:6]([S:8][CH3:9])[N:5]=[C:4]([N:10]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:3]=1
Reactant: CSc1nc(Cl)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Reactant: CC1(C)OB(c2ccncc2N)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: ClCCl
Solvent: COCCOC
Product: CSc1nc(-c2ccncc2N)cc(N(C(=O)OC(C)(C)C)C(=O)OC(C)(C)C)n1
Yield: 32 %

Procedure:
Method 26 was followed using 6-chloro-N,N-di-BOC-2-(methyl-thio)pyrimidin-4-amine (1.0 equiv.), 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-3-amine (3.0 equiv.), Pd(dppf)Cl2-DCM (0.10 equiv.) in DME/2M Na2CO3 (0.07M) at 90° C. for 30 min. Purification via SiO2 column chromatography eluting with EtOAc and hexanes (1:1) afforded 6-(3-aminopyridin-4-yl)-N,N-di-BOC-2-(methyl-thio)pyrimidin-4-amine in 32% yield. LCMS (m/z): 434.2 (MH+); LC Rt=3.56 min.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH2:5].[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=S.CCN(C(C)C)C(C)C>C(#N)C>[Cl:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][NH:5][C:12]1[S:11][CH2:17][C:15](=[O:16])[N:14]=1
Reactant: O=C1CSC(=S)N1
Reactant: NCc1ccc(F)cc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: O=C1CSC(NCc2ccc(F)cc2Cl)=N1
Temperature: 0 °C
Reaction time: 72 h
Yield: 16.5 %

Procedure:
To a solution of 2-chloro-4-fluoro-benzylamine (4.5 g, 28.19 mmol) and Rhodanine (3.75 g, 28.2 mmol) in acetonitrile (170 mL) was added DIPEA (9.82 mL, 56.4 mmol) at room temperature. Then, this solution was cooled to 0° C. and mercuric chloride (8.42 g, 31.02 mmol) was added in two portions within 10 min. After addition, the suspension was allowed to warm to room temperature and stirred for 3 days. The resulting black solids were filtered through a plug of celite and washed with acetonitrile (1.0 L) and ethyl acetate (500 mL). The combined solvents were removed under the vacuum and the crude residue was dissolved in ethyl acetate (150 mL) and washed with water (100 mL) and brine solution (100 mL). After drying over magnesium sulfate, the filtrate was removed under the vacuum and the residue was dissolved in ethyl acetate (50 mL). After cooling in the refrigerator overnight, the solids were collected by filtration and washed with hexanes. After drying in air, 1.2 g (16.5% yield) of 2-(2-chloro-4-fluoro-benzylamino)-thiazol-4-one was isolated as a white amorphous solid: EI-HRMS m/e calcd for C10H8FN2OS2 (M+) 258.0030. found 258.0027.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[N:7]=[C:6]2[C:19]1[CH:24]=[CH:23][CH:22]=[C:21]([F:25])[CH:20]=1.[I-:26].[Na+]>CC(C)=O>[F:25][C:21]1[CH:20]=[C:19]([C:6]2[C:5]3[C:9](=[CH:10][CH:11]=[C:3]([CH2:2][I:26])[CH:4]=3)[N:8]([C:12]([O:14][C:15]([CH3:17])([CH3:16])[CH3:18])=[O:13])[N:7]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CCl)ccc21
Reactant: [I-]
Agent: [Na+]
Solvent: CC(C)=O
Product: CC(C)(C)OC(=O)n1nc(-c2cccc(F)c2)c2cc(CI)ccc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 101.8 %

Procedure:
To a solution of 500 mg of tert-butyl 5-(chloromethyl)-3-(3-fluorophenyl)-1H-1-indazolecarboxylate produced in Production Example I-24-b in 2.5 ml acetone was added 218 mg of sodium iodide, and the mixture was stirred at room temperature for 2 hours. After filtering off the resulting sodium chloride through Celite, the solvent was evaporated, to give 638 mg of the title compound as bright yellow crystals.
Reaction SMILES: C([C:8]1[CH:19]=[C:18]([OH:20])[CH:17]=[CH:16][C:9]=1[CH2:10][C@@H:11]([C:13]([OH:15])=[O:14])[NH2:12])C1C=CC=CC=1.[CH:21]1([NH:27][CH:28]2[CH2:33][CH2:32][CH2:31][CH2:30][CH2:29]2)[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1.[C:34]([CH:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]1=O)(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1.[CH3:49]O>>[CH:28]1([NH:27][CH:21]2[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26]2)[CH2:29][CH2:30][CH2:31][CH2:32][CH2:33]1.[C:34]([C:42]1[CH2:47][CH2:46][CH2:45][CH2:44][C:43]=1[NH:12][C@@H:11]([CH2:10][C:9]1[CH:8]=[CH:19][C:18]([O:20][CH2:49][C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:17][CH:16]=1)[C:13]([OH:15])=[O:14])(=[O:41])[C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1
Reactant: N[C@@H](Cc1ccc(O)cc1Cc1ccccc1)C(=O)O
Reactant: O=C1CCCCC1C(=O)c1ccccc1
Reactant: CO
Agent: C1CCC(NC2CCCCC2)CC1
Product: O=C(C1=C(N[C@@H](Cc2ccc(OCc3ccccc3)cc2)C(=O)O)CCCC1)c1ccccc1
Temperature: 20 °C

Procedure:
A stirred mixture of 1.35 g (5 mmol) o-benzyl-L-tyrosine, 1.0 mL (5 mmol) dicyclohexylamine and 1.01 g (5 mmol) 2-benzoylcyclohexanone (Denny, William A.; Cain, Bruce F.; J. Med. Chem. (1978), 21(5), 430-7.) in 25 mL MeOH was refluxed for 24 h. The solution was then cooled to 20° C., and the solvent was evaporated under reduced pressure. Purification of the residue by flash chromatography using Hexane/EtOAc (1:1) then EtOAc (neat), finally CHCl3/MeOH (10:1) as eluents resulted in 1.4 g of the of the title compound. 1H NMR (DMSO-d6, 400 MHz) δ 12.00 (d, 1H, J=8.4) 7.3 (m, 10H), 7.13 (d, 2H, J=8.5), 6.85 (d, 2H, J=8.5), 5.01 (s, 2H), 4.02 (m, 1H), 3.05 (m, 1H), 2.89 (m, 2H), 2.73 (dd, 1H, J=8.5, 13.7), 2.25 (m, 1H), 2.03 (m, 3H) 1.93 (m, 3H), 1.66 (m, 3H), 1.53 (d, 2H, J=12.3), 1.30 (m, 2H), 1.20 (m, 12H), 1.03 m (2H); low resolution MS (ESP+) m/e 456 (MH+).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20](O)=[O:21])=[CH:9]1)[CH2:5][O:6][CH3:7].[N:23]1([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]1.OC1C2N=NNC=2C=CC=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C>ClCCl>[CH3:7][O:6][CH2:5][CH:4]([N:8]1[C:17]2[C:12](=[CH:13][C:14]([I:18])=[CH:15][CH:16]=2)[C:11](=[O:19])[C:10]([C:20]([N:26]2[CH2:27][CH2:28][N:23]([C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])[CH2:24][CH2:25]2)=[O:21])=[CH:9]1)[CH2:3][O:2][CH3:1]
Reactant: COCC(COC)n1cc(C(=O)O)c(=O)c2cc(I)ccc21
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: COCC(COC)n1cc(C(=O)N2CCN(C(=O)OC(C)(C)C)CC2)c(=O)c2cc(I)ccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
To a solution of 1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinoline-3-carboxylic acid (Intermediate 78, 500 mg, 1.12 mmol) and tert-butyl piperazine-1-carboxylate (312 mg, 1.67 mmol) in dichloromethane (50 mL) was added hydroxybenzotriazole (HOBT) (183 mg, 1.12 mmol) and N-methyl morpholine (484 mg, 4.79 mmol). The reaction mixture was stirred for 1 h at room temperature and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (EDCI HCl) (390. mg, 2.15 mmol) was added. The resulting reaction mixture was stirred for room temperature overnight. The reaction mixture was quenched with dilute hydrochloric acid (2N, 30 mL) and the layers were separated. The organic layer was washed with saturated sodium bicarbonate solution (40 mL), water (60 mL) and finally with brine successively and dried over anhydrous sodium sulphate, filtered, concentrated under vacuum to afford tert-butyl 4-{[1-(1,3-dimethoxypropan-2-yl)-6-iodo-4-oxo-1,4-dihydroquinolin-3-yl]carbonyl}piperazine-1-carboxylate 400 mg (57%) as thick oil.
Reaction SMILES: C(N(CC)CC)C.[C:8]([C:10]1[CH:11]=[CH:12][C:13]([CH3:16])=[N:14][CH:15]=1)#[CH:9].Br[C:18]1[C:26]2[NH:25][C:24]3[CH:27]4[CH2:33][CH2:32][N:30]([CH2:31][C:23]=3[C:22]=2[CH:21]=[CH:20][CH:19]=1)[CH2:29][CH2:28]4>O1CCCC1.C(P([Pd]P(C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C)(C)C.[Cu]I>[CH3:16][C:13]1[N:14]=[CH:15][C:10]([C:8]#[C:9][C:18]2[C:26]3[NH:25][C:24]4[CH:27]5[CH2:33][CH2:32][N:30]([CH2:31][C:23]=4[C:22]=3[CH:21]=[CH:20][CH:19]=2)[CH2:29][CH2:28]5)=[CH:11][CH:12]=1
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Reactant: C#Cc1ccc(C)nc1
Agent: CC(C)(C)[PH]([Pd][PH](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Agent: [Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: Cc1ccc(C#Cc2cccc3c4c([nH]c23)C2CCN(CC2)C4)cn1
Temperature: 100 °C
Reaction time: 5 h

Procedure:
Triethylamine (2 mL) was added to a mixture of bis(tri-t-butylphosphino)palladium (8.8 mg, 0.017 mmol; Aldrich), 5-ethynyl-2-methylpyridine (60 mg, 0.52 mmol; International Publication No. WO2005090333), CuI (3.3 mg, 0.017 mmol; Aldrich) and the product of Example 1B (100 mg, 0.34 mmol) in anhydrous tetrahydrofuran (2 mL). The mixture was purged with a nitrogen stream for 2 minutes, then stirred under nitrogen at 100° C. for 5 hours in a sealed tube. The mixture was cooled to ambient temperature and concentrated under vacuum. The residue was taken up in dimethyl sulfoxide (5 mL), filtered through a glass microfiber frit and purified by reverse-phase HPLC [Waters XBridge™ RP18 column, 5 μm, 30×100 mm, flow rate 40 mL/minute, 20-99% gradient of methanol in buffer (0.1 M aqueous ammonium bicarbonate, adjusted to pH 10 with ammonium hydroxide)] to afford the title compound: 1H NMR (500 MHz, methanol-d4 ) δ ppm 2.05-2.16 (m, 4 H), 2.56 (s, 3 H), 3.02-3.12 (m, 2 H), 3.17-3.21 (m, 1 H), 3.21-3.29 (m, 2 H), 4.24 (s, 2 H), 7.00 (t, J=7.6 Hz, 1 H), 7.24 (dd, J=7.3, 0.9 Hz, 1 H), 7.34 (d, J=7.9 Hz, 1 H), 7.36 (dd, J=7.9, 0.9 Hz, 1 H), 7.94 (dd, J=8.1, 2.3 Hz, 1 H), 8.68 (d, J=1.8 Hz, 1H); MS (APCI) m/z 328 (M+H)+.