Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: O.NN.[OH:4][CH:5]1[CH2:10][CH2:9][N:8]([CH2:11][CH2:12][CH2:13][N:14]2[C:22](=[O:23])C3C(=CC=CC=3)C2=O)[CH2:7][CH2:6]1.[CH2:25]([OH:27])[CH3:26]>>[OH:4][CH:5]1[CH2:6][CH2:7][N:8]([CH2:11][CH2:12][CH2:13][NH:14][C:22](=[O:23])[O:27][CH2:25][C:26]2[CH:9]=[CH:10][CH:5]=[CH:6][CH:7]=2)[CH2:9][CH2:10]1
Reactant: CCO
Reactant: O=C1c2ccccc2C(=O)N1CCCN1CCC(O)CC1
Agent: NN
Solvent: O
Product: O=C(NCCCN1CCC(O)CC1)OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Ethanol (100 ml) and hydrazine hydrate (1.5 g) were added to 2-(3-(4-hydroxypiperidino)propyl)isoindolin-1,3-dione (4.5 g); the reaction mixture was heated to reflux for 2.5 hours; and the produced crystals were filtered off. N-Methylmorpholine (2.5 ml) and N-(benzyloxycarbonyloxy)succinimide (5.2 g) were added to the filtrate; and the reaction mixture was stirred at room temperature overnight. Aqueous solution of sodium hydrogencarbonate was added to the reaction mixture; extraction was performed with ethyl acetate; and the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to yield the title compound (2.96 g).
Reaction SMILES: [F:1][C:2]([F:21])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([OH:13])=O.F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.CN1CCOCC1.[F:51][C:52]1[CH:59]=[CH:58][C:55]([CH2:56][NH2:57])=[CH:54][CH:53]=1>CN(C=O)C>[F:21][C:2]([F:1])([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][CH:15]=1)[CH2:3][CH2:4][S:5][C:6]1[N:7]=[CH:8][S:9][C:10]=1[C:11]([NH:57][CH2:56][C:55]1[CH:58]=[CH:59][C:52]([F:51])=[CH:53][CH:54]=1)=[O:13]
Reactant: NCc1ccc(F)cc1
Reactant: O=C(O)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: O=C(NCc1ccc(F)cc1)c1scnc1SCCC(F)(F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
To a solution of 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-thiazole-5-carboxylic acid (0.15 g, 0.45 mmol) in DMF (3 ml) are added O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium tetrafluoroborate (216 mg, 0.68 mmol) and N-methylmorpholine (0.01 ml, 0.9 mmol) at 0° C. followed by the addition of 4-fluorobenzyl amine (67 mg, 0.54 mmol). The reaction mixture is stirred at RT for 3 h. After completion of the reaction, the mixture is poured onto ice-water, extracted with EtOAc (3×50 ml). The combined organic layers are washed with brine (50 ml), dried over sodium sulfate and evaporated to dryness to yield the crude product, which is purified by column chromatography (silica gel, 15% acetone/hexane) affording 4-[[3,3-difluoro-3-(4-fluorophenyl)-propyl]sulfanyl]-N-[(4-fluorophenyl)-methyl]-thiazole-5-carboxylic acid amide (example 14) (93 mg, 0.21 mmol, 47%). [M+H]+ 441.1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[S:13][C:12]3[CH:14]=[CH:15][C:16]4[C:21]([C:11]=3[N:10]([CH2:22][CH2:23][CH2:24][NH:25][CH3:26])[C:9]2=[O:27])=[CH:20][CH:19]=[CH:18][CH:17]=4)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].[CH2:34](Br)[CH:35]=[CH2:36]>CC(C)=O>[CH2:34]([N:25]([CH2:24][CH2:23][CH2:22][N:10]1[C:9](=[O:27])[CH:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[S:13][C:12]2[CH:14]=[CH:15][C:16]3[C:21]([C:11]1=2)=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH3:26])[CH:35]=[CH2:36]
Reactant: C=CCBr
Reactant: CNCCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C=CCN(C)CCCN1C(=O)C(c2ccc(Cl)cc2)Sc2ccc3ccccc3c21
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a mixture of 3-(4-chlorophenyl)-1-[3-(methylamino)propyl]-1H-naphtho[2,1-b][1,4]thiazin-2(3H)-one (1.79 g), potassium carbonate (2.18 g) and acetone (50 ml) is added allyl bromide (0.65 g) under ice cooling, and the mixture is stirred at room temperature overnight. The insoluble materials are filtered off and acetone is distilled off, and the oily residue is purified by silica gel column chromatography (eluent, chloroform: methanol=20:1) to give 1-[3-(N-allyl-N-methylamino)propyl]-3-(4-chlorophenyl)-1H-naphtho-[2,1-b][1,4]thiazin-2(3H)-one as oil.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[C:9]1[CH:15]=[O:16])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:17]([Mg]Cl)#[CH:18]>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH:12]=[C:11]([CH3:13])[C:10]([CH3:14])=[C:9]1[CH:15]([OH:16])[C:17]#[CH:18])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C#C[Mg]Cl
Reactant: Cc1cn(C(=O)OC(C)(C)C)c(C=O)c1C
Solvent: C1CCOC1
Product: C#CC(O)c1c(C)c(C)cn1C(=O)OC(C)(C)C
Reaction time: 0.5 h

Procedure:
To a solution of 3,4-dimethyl-2-formyl-pyrrole-1-carboxylic acid tert-butyl ester (3.18 g, 14.2 mmol) (prepared as described in Tietze et al., supra,) in dry THF(40 mL) was added ethynylmagnesium chloride (Aldrich, 0.5 M solution in THF, 57 mL, 28.5 mmol) dropwise at −65° C. and the reaction mixture was stirred at the same temperature for 0.5 hour. The cooling bath was then removed and the reaction mixture was stirred for another 2 hours to give a clear solution. The reaction was quenched by slowly adding EtOH (8 mL) and a saturated aqueous NH4Cl solution (26 mL) at 5° C. The mixture was extracted several times with ethyl acetate. The combined organic extract was washed with brine, dried over anhydrous magnesium sulfate, filtered, and concentrated in vacuo. Flash chromatography (silica gel, 95:5 hexanes/ethyl acetate) purification of the crude oil afforded 3,4-dimethyl-2-(1-hydroxy-prop-2-ynyl)-pyrrole-1-carboxylic acid tert-butyl ester as a yellow oil. (Yield 3.54 g, 100.0%).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([OH:12])=O)=[CH:9][C:4]=2[N:3]=[CH:2]1.[CH3:13][O:14][C:15]1[CH:16]=[CH:17][C:18]2[CH2:27][CH2:26][C@H:25]3[C@H:20]([CH2:21][CH2:22][CH2:23][NH:24]3)[C:19]=2[CH:28]=1>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:24]3[C@@H:25]4[C@@H:20]([C:19]5[CH:28]=[C:15]([O:14][CH3:13])[CH:16]=[CH:17][C:18]=5[CH2:27][CH2:26]4)[CH2:21][CH2:22][CH2:23]3)=[O:12])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COc1ccc2c(c1)[C@H]1CCCN[C@H]1CC2
Reactant: O=C(O)c1ccc2[nH]cnc2c1
Product: COc1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1CC2
Yield: 69 %

Procedure:
The title compound is prepared from 1H-benzoimidazole-5-carboxylic acid and cis-9-methoxy-1,2,3,4,4a,5,6,10b-octahydro-benzo[f]quinoline following a procedure analogous to that described in Example 1. Yield: 69% of theory; LC (method 1): tR=2.55 min; Mass spectrum (ESI+): m/z=362 [M+H]+.
Reaction SMILES: N1(C(OC(C)(C)C)=O)CCC[C@H]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])CC(C)C)=[O:43])[CH2:32][C:33]1C2C(=CC=CC=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=CC=CC=2)[NH:10][CH:9]=1)=[O:4].F[C:73](F)(F)[C:74](O)=O>CSC.C(S)(S)C>[NH:30]1[CH2:74][CH2:73][CH2:21][CH2:20][C@H:28]1[C:3]([NH:5][C@@H:6]([C:17]([NH:19][C@H:20]([C:28]([NH:30][C@@H:31]([C:42]([NH:44][C@H:45]([C:50]([N:52]([CH3:61])[C@H:53]([C:58]([NH2:60])=[O:59])[CH2:54][CH2:55][S:56][CH3:57])=[O:51])[CH2:16][CH:8]([CH3:9])[CH3:7])=[O:43])[CH2:32][C:33]1[C:22]2[C:27](=[CH:26][CH:25]=[CH:24][CH:23]=2)[NH:35][CH:34]=1)=[O:29])[CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:18])[CH2:7][C:8]1[C:16]2[C:11](=[CH:33][CH:32]=[CH:31][CH:42]=2)[NH:10][CH:9]=1)=[O:4]
Reactant: O=C(O)C(F)(F)F
Reactant: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Agent: CC(S)S
Solvent: CSC
Product: CSCC[C@@H](C(N)=O)N(C)C(=O)[C@H](CC(C)C)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@H](Cc1ccccc1)NC(=O)[C@@H](Cc1c[nH]c2ccccc12)NC(=O)[C@@H]1CCCCN1

Procedure:
Condensation of BocPro-DTrp-PheOH (Example 33, 1.49 g.) and HDTrp-Leu-MeMetNH2 trifluoroacetate salt (1.25 g.) using dicyclohexylcarbodiimide and 1-hydroxybenzotriazole gave BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 in 60% yield. De-t-butoxycarbonylation of BocPro-DTrp-Phe-DTrp-Leu-MeMetNH2 (1.50 g.) using trifluoroacetic acid in dimethyl sulfide and ethanedithiol gave HPro-DTrp-Phe-DTrp-Leu-MeMetNH2, which was isolated as the amorphous white solid phosphate (1:2) salt dihydrate in 57% yield.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH3:10])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12].C1C(=O)N([Br:22])C(=O)C1.COC(C)(C)C>C(#N)C>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][Br:22])=[CH:6][C:5]=1[N+:11]([O-:13])=[O:12]
Reactant: COC(=O)c1ccc(C)cc1[N+](=O)[O-]
Reactant: O=C1CCC(=O)N1Br
Solvent: COC(C)(C)C
Solvent: CC#N
Product: COC(=O)c1ccc(CBr)cc1[N+](=O)[O-]
Temperature: 70 °C
Yield: 43.8 %

Procedure:
To a stirred solution of 4-methyl-2-nitro-benzoic acid methyl ester (108.5 g, 555.7 mmol) in acetonitrile (750 mL), was added NBS (97.9 g, 550.1 mmol). The mixture was heated to a gentle reflex with a 200 W light bulb on for 5.5 hours. The solvent was evaporated, and the residue was dissolved in ethyl acetate (1500 mL). The solution was washed with water (2×600 mL) and brine (300 mL), dried over magnesium sulfate, and concentrated to give a brown oil. To the oil, was added t-butyl methyl ether (300 mL). The mixture was heated at 70° C. for 15 minutes. The mixture was allowed to cool to about 53° C. over one hour, then to 45° C., and then at 20-25° C., while blowing nitrogen with a glass pipette overnight. The suspension was filtered via a medium pore-sized funnel. The solid was washed with a pre-cooled 10° C. mixed solvent of heptane/MTBE (1/2 vol/vol) and suction dried in hood overnight to give 4-bromomethyl-2-nitro-benzoic acid methyl ester as an off-white solid (66 g, 43% yield). The solid was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=O)=[N:4][CH:5]=[C:6]([C:8]#[N:9])[CH:7]=1.[NH2:13][C:14]1[CH:15]=[CH:16][C:17]([F:51])=[C:18]([C@:20]2([CH3:50])[CH2:25][O:24][CH2:23][C:22]([NH:26][C:27]([C:42]3[CH:47]=[CH:46][C:45]([O:48][CH3:49])=[CH:44][CH:43]=3)([C:34]3[CH:39]=[CH:38][C:37]([O:40][CH3:41])=[CH:36][CH:35]=3)[C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)=[N:21]2)[CH:19]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1>>[CH3:49][O:48][C:45]1[CH:46]=[CH:47][C:42]([C:27]([NH:26][C:22]2[CH2:23][O:24][CH2:25][C@:20]([C:18]3[CH:19]=[C:14]([NH:13][C:10]([C:3]4[C:2]([Cl:1])=[CH:7][C:6]([C:8]#[N:9])=[CH:5][N:4]=4)=[O:12])[CH:15]=[CH:16][C:17]=3[F:51])([CH3:50])[N:21]=2)([C:34]2[CH:35]=[CH:36][C:37]([O:40][CH3:41])=[CH:38][CH:39]=2)[C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)=[CH:43][CH:44]=1
Reactant: COc1ccc(C(NC2=N[C@](C)(c3cc(N)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Reactant: N#Cc1cnc(C(=O)O)c(Cl)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: O
Product: COc1ccc(C(NC2=N[C@](C)(c3cc(NC(=O)c4ncc(C#N)cc4Cl)ccc3F)COC2)(c2ccccc2)c2ccc(OC)cc2)cc1
Yield: 44 %

Procedure:
In a manner analogous to that described in example E1 (method E), the reaction of 3-chloro-5-cyano-pyridine-2-carboxylic acid with Building block J, [(R)-5-(5-amino-2-fluoro-phenyl)-5-methyl-5,6-dihydro-2H-[1,4]oxazin-3-yl]-[bis-(4-methoxy-phenyl)-phenyl-methyl]-amine, using the 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMTMM) as the condensating agent, yielded the title compound as a yellow solid (44% of theory). Mass (calculated) C39H33ClFN5O4 [690.160]; (found) [M]+=690.
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([CH:8]=[C:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)=[CH:6][CH:5]=1)([O-:3])=[O:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:24][C:25]1[CH:30]=[CH:29][C:28]([C:31]([OH:40])([C:36]([F:39])([F:38])[F:37])[C:32]([F:35])([F:34])[F:33])=[CH:27][CH:26]=1>C(#N)C>[F:33][C:32]([F:34])([F:35])[C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:12]2[CH2:11][CH2:10][C:9](=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:16][CH:15]=3)[CH2:14][CH2:13]2)=[CH:26][CH:27]=1)([OH:40])[C:36]([F:37])([F:39])[F:38]
Reactant: OC(c1ccc(CBr)cc1)(C(F)(F)F)C(F)(F)F
Reactant: O=[N+]([O-])c1ccc(C=C2CCNCC2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: O=[N+]([O-])c1ccc(C=C2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reaction time: 5 h
Yield: 64.6 %

Procedure:
To a stirred mixture of 4-(4-nitrobenzylidene)piperidine (23.83 mmol, 5.2 g) and potassium carbonate (31.0 mmol, 4.28 g) in acetonitrile was added a solution of 2-(4-(bromomethyl)phenyl)-1,1,1,3,3,3-hexafluoropropan-2-ol (23.83 mmol, 8.03 g) in acetonitrile. The reaction was stirred for 5 hours then was concentrated under reduced pressure. Dichloromethane was added and the reaction was filtered. The filtrate was chromatographed on silica (eluting with a gradient of dichloromethane to dichloromethane/ethyl acetate) to give the title compound (7.3 g).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[C:4]([Cl:9])[C:3]=1[N:10]1[C:14](=[O:15])[CH2:13][C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1.C(=O)([O-])[O-].[K+].[K+].Cl.[CH2:47]([S:54]SC(=N)N)[C:48]1[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=1.O>C(O)C>[Cl:9][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[N:10]1[C:14](=[O:15])[CH:13]([S:54][CH2:47][C:48]2[CH:53]=[CH:52][CH:51]=[CH:50][CH:49]=2)[C:12]([NH:16][C:17]2[CH:22]=[C:21]([NH:23][C:24](=[O:38])[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])[CH:20]=[CH:19][C:18]=2[Cl:39])=[N:11]1
Reactant: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2)c1
Reactant: N=C(N)SSCc1ccccc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCC(=O)Nc1ccc(Cl)c(NC2=NN(c3c(Cl)cc(Cl)cc3Cl)C(=O)C2SCc2ccccc2)c1
Reaction time: 3 h

Procedure:
1-(2,4,6-trichlorophenyl)-3-(2-chloro-5-tetradecanamidoanilino)-5-oxo-2-pyrazoline (21.4 g) was dissolved in 80% ethanol (ratio by volume of water:20%), and 2.42 g of anhydrous potassium carbonate was added thereto. The solution was refluxed with heating. 8.2 g of S-benzylthioisothiourea hydrochloride was added to the solution and the solution was vigorously stirred for 3 hours. After confirming the conclusion of the reaction by thin film chromatography, the reaction container was cooled with water. The formed crystals were separated by filtration and dissolved in 100 ml of hot ethanol. Insoluble materials were separated by filtration, and the filtrate was cooled. The resulting colorless crystals were Compound (1). The melting point was 182° to 185° C. and the yield was 12 g.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Cl:11][C:12]1[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:14][C:15]2[S:16]C3C(O[C:24]=2[CH:25]=1)=CC(Cl)=C(Cl)C=3>>[Cl:11][C:12]1[C:13]([O:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][C:34]([OH:36])=[O:35])=[CH:14][C:15]2[S:16][C:4]3[C:3]([O:10][C:24]=2[CH:25]=1)=[C:2]([Cl:1])[C:7]([Cl:8])=[C:6]([Cl:9])[CH:5]=3
Reactant: O=C(O)CCCCCOc1cc2c(cc1Cl)Oc1cc(Cl)c(Cl)cc1S2
Reactant: Oc1ccc(Cl)c(Cl)c1Cl
Product: O=C(O)CCCCCOc1cc2c(cc1Cl)Oc1c(cc(Cl)c(Cl)c1Cl)S2
Yield: 4.3 %

Procedure:
Similar procedures were carried out using 2,3,4-trichlorophenol instead of 3,4-dichlorophenol used in the above (1) to obtain 6-(3,6,7,8-tetrachlorophenoxathiin-2-yloxy)hexanoic acid in an overall yield of 4.3%.
Reaction SMILES: ClC(Cl)(OC(=O)[O:6][C:7]([Cl:10])(Cl)Cl)Cl.[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([C@H:26]2[C@H:30]([C:31]3[CH:36]=[CH:35][C:34]([F:37])=[CH:33][CH:32]=3)[CH2:29][NH:28][CH2:27]2)[CH3:25])=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1.N1C=CC=CC=1>C(Cl)Cl>[Cl:13][C:14]1[CH:15]=[C:16]([C:21]([CH3:39])([CH3:38])[C:22]([N:24]([CH3:25])[CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([F:37])=[CH:35][CH:36]=3)[CH2:29][N:28]([C:7]([Cl:10])=[O:6])[CH2:27]2)=[O:23])[CH:17]=[C:18]([Cl:20])[CH:19]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)[C@@H]1CNC[C@H]1c1ccc(F)cc1
Solvent: ClCCl
Solvent: c1ccncc1
Product: CN(C(=O)C(C)(C)c1cc(Cl)cc(Cl)c1)C1CN(C(=O)Cl)CC1c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 196.1 %

Procedure:
To a stirred solution of carbonic acid ditrichloromethyl ester (triphosgene) (12 mg, 0.040 mmol) in CH2Cl2 (3 ml) at −78° C., was added a solution of rac-2-(3,5-dichloro-phenyl)-N-[(3S,4R)-4-(4-fluoro-phenyl)-pyrrolidin-3-yl]-N-methyl-isobutyramide (Intermediate VII-5), (41 mg, 0.10 mmol) and pyridine (0.02 ml, 0.22 mmol) in CH2Cl2 (2 ml) over 30 minutes. The temperature was raised to RT, and stirring was continued for 2 hours. The organic phase was washed with H2O, dried over Na2SO4. Purification by flash chromatography (SiO2, EtOAc/Hx 1:1) yielded 37 mg (79%) of the title compound as_colorless oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][C:6]([C:12]([CH:14]1[CH2:16][CH2:15]1)=[O:13])=[C:5]2[NH:17][C:18]1[CH:19]=[CH:20][C:21]([NH:24][CH:25]2[CH2:30][CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[CH2:26]2)=[N:22][CH:23]=1.[Cl:38][C:39]1[CH:44]=[C:43](B2OC(C)(C)C(C)(C)O2)[CH:42]=[C:41]([Cl:54])[C:40]=1[OH:55]>>[CH:14]1([C:12]([C:6]2[CH:7]=[N:8][C:9]3[C:4]([C:5]=2[NH:17][C:18]2[CH:23]=[N:22][C:21]([NH:24][CH:25]4[CH2:30][CH2:29][CH2:28][NH:27][CH2:26]4)=[CH:20][CH:19]=2)=[CH:3][C:2]([C:43]2[CH:44]=[C:39]([Cl:38])[C:40]([OH:55])=[C:41]([Cl:54])[CH:42]=2)=[CH:11][CH:10]=3)=[O:13])[CH2:16][CH2:15]1
Reactant: CC(C)(C)OC(=O)N1CCCC(Nc2ccc(Nc3c(C(=O)C4CC4)cnc4ccc(Br)cc34)cn2)C1
Reactant: CC1(C)OB(c2cc(Cl)c(O)c(Cl)c2)OC1(C)C
Product: O=C(c1cnc2ccc(-c3cc(Cl)c(O)c(Cl)c3)cc2c1Nc1ccc(NC2CCCNC2)nc1)C1CC1
Yield: 11.1 %

Procedure:
Following general procedure D, tert-butyl 3-(5-(6-bromo-3-(cyclopropanecarbonyl)quinolin-4-ylamino)pyridin-2-ylamino)piperidine-1-carboxylate (100 mg, 0.18 mmol) was reacted with 2,6-dichloro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenol (78 mg, 0.27 mmol) to obtain the protected intermediate which was subjected to general procedure A-2 to afford the desired product (11 mg, 11% over 2 steps) as a yellow-brown solid: 1H NMR (500 MHz, CD3OD+TFA-d) δ 9.40 (s, 1H), 8.23 (dd, J=8.8, 1.9 Hz, 1H), 8.15 (s, 1H), 8.12 (d, J=2.6 Hz, 1H), 8.00 (d, J=8.7 Hz, 1H), 7.58 (dd, J=9.0, 2.7 Hz, 1H), 7.36 (s, 2H), 6.82 (d, J=9.2 Hz, 1H), 4.22 (ddd, J=14.0, 10.0, 3.8 Hz, 1H), 3.63 (dd, J=12.1, 3.5 Hz, 1H), 3.02 (td, J=11.9, 3.4 Hz, 1H), 2.89 (m, 2H), 2.12 (m, 1H), 1.86 (dtt, J=14.9, 11.2, 3.7 Hz, 1H), 1.71 (q, J=10.1 Hz, 1H), 1.21 (m, 4H); ESI MS m/z 548 [C29H27Cl2N5O2+H]+; HPLC 99.5% (AUC), tR=10.58 min.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([NH2:8])[N:3]=1.[F:9][C:10]1[CH:18]=[CH:17][C:13]([C:14](Cl)=[O:15])=[CH:12][CH:11]=1>O1CCOCC1>[NH2:8][C:4]1[N:3]=[C:2]([NH:1][C:14](=[O:15])[C:13]2[CH:17]=[CH:18][C:10]([F:9])=[CH:11][CH:12]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: Nc1cccc(N)n1
Reactant: O=C(Cl)c1ccc(F)cc1
Solvent: C1COCCO1
Product: Nc1cccc(NC(=O)c2ccc(F)cc2)n1
Temperature: 0 °C
Reaction time: 0.67 h

Procedure:
Dissolve 2,6-diaminopyridine (1.637 g, 15 mmol) in dioxane (15 mL) and cool to 0° C. for 10 min. Add 4-fluorobenzoyl chloride (793 mg, 0.59 mL, 5.0 mmol) slowly. After 40 min, remove ice bath and stir the reaction at room temperature. Use the work-up and purification procedures described in Preparation 43 to provide N-(6-Amino-pyridin-2-yl)-4-fluoro-benzamide as a slightly yellow solid (1.170 g, 100%): mass spectrum (ion spray): m/z=232.0 (M+1).
Reaction SMILES: N[CH2:2][CH:3]([C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=1)[OH:4].O=[C:13]([CH3:27])[CH2:14][O:15][C:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]([O:25][CH3:26])=[O:24])=[CH:18][CH:17]=1.C1C=CC=CC=1.C([BH3-])#N.[Na+]>CO>[CH3:26][O:25][C:23]([CH2:22][C:19]1[CH:18]=[CH:17][C:16]([O:15][CH2:14][CH:13]([CH2:2][CH:3]([C:5]2[CH:10]=[CH:9][CH:8]=[C:7]([CH3:11])[CH:6]=2)[OH:4])[CH3:27])=[CH:21][CH:20]=1)=[O:24]
Reactant: Cc1cccc(C(O)CN)c1
Reactant: COC(=O)Cc1ccc(OCC(C)=O)cc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: c1ccccc1
Product: COC(=O)Cc1ccc(OCC(C)CC(O)c2cccc(C)c2)cc1
Yield: 56.5 %

Procedure:
Following a procedure similar to that described in Example 3, but using 2.5 g of 2-amino-1-(3-methylphenyl)ethanol (prepared as described in Preparation 44), 4.4 g of methyl 4-(2-oxopropoxy)phenylacetate (prepared as described in Preparation 3), 80 ml of benzene, 60 ml of absolute methanol and 4.5 g of sodium cyanoborohydride, and then purifying the reaction product by column chromatography through silica gel, using ethyl acetate as the eluent, 3.2 g of the title compound were obtained having an Rf=0.24 (thin layer chromatography over silica gel, using ethyl acetate as the developing solvent).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:13][C:12](=[O:14])[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]=2[C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)=[CH:4][CH:3]=1.[CH2:25](Br)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH2:25]([O:14][C:12]1[C:11]([C:15]([O:17][CH3:18])=[O:16])=[CH:10][C:9]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)=[C:8]([C:5]2[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=2)[N:13]=1)[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1
Reactant: BrCc1ccccc1
Reactant: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)[nH]c1=O
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(-c2ccccc2)c(-c2ccc(Cl)cc2)nc1OCc1ccccc1
Temperature: 55 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 6-(4-chlorophenyl)-5-(phenyl)-2-oxo-1,2-dihydropyridine-3-carboxylate (500 mg, 1.47 mmol) from Step D in DMF (6 mL) was added benzyl bromide (0.22 mL, 1.91 mmol) and then cesium carbonate (622 mg, 1.91 mmol). The reaction was stirred at 55° C. for 4 h and was then diluted with water and extracted twice with methylene chloride. The organic layers were washed with a portion of brine and the combined organic layers were dried over anhydrous sodium sulfate and concentrated in vacuo to give a 4:1 mixture of the crude products. The products were separated by flash column chromatography on silica gel eluted with a gradient of 5 to 10% ethyl acetate in hexanes to first yield the desired higher Rf O-alkylation title product. HPLC/MS: 430 (M+1); Rt=4.9 min;
Reaction SMILES: C(N(CC)CC)C.[CH3:8][N:9]1[CH2:14][CH2:13][N:12]([C:15]2[CH:16]=[C:17]([NH2:22])[C:18]([NH2:21])=[CH:19][CH:20]=2)[CH2:11][CH2:10]1.CC([N:27]([C:31]1[CH:36]=[CH:35][C:34]([C:37]2[CH:41]=[C:40]([CH:42]=O)[NH:39][N:38]=2)=[CH:33][CH:32]=1)C(=O)[O-])(C)C>CN(C=O)C>[CH3:8][N:9]1[CH2:10][CH2:11][N:12]([C:15]2[CH:20]=[CH:19][C:18]3[N:21]=[C:42]([C:40]4[NH:39][N:38]=[C:37]([C:34]5[CH:35]=[CH:36][C:31]([NH2:27])=[CH:32][CH:33]=5)[CH:41]=4)[NH:22][C:17]=3[CH:16]=2)[CH2:13][CH2:14]1
Reactant: CN1CCN(c2ccc(N)c(N)c2)CC1
Reactant: CC(C)(C)N(C(=O)[O-])c1ccc(-c2cc(C=O)[nH]n2)cc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CN1CCN(c2ccc3nc(-c4cc(-c5ccc(N)cc5)n[nH]4)[nH]c3c2)CC1
Temperature: 65 °C
Yield: 70 %

Procedure:
Triethylamine (2.32 g, 23 mmol) was added to a solution of 4-(4-methylpiperazin-1-yl)-benzene-1,2-diamine as the tetra-hydrochloride salt in anhydrous DMF (11 mL) after five minutes, a solution of 1,1-dimethylethyl[4-(5-formyl-1H-pyrazol-3-yl)phenyl]carbamate in anhydrous DMF (2 mL) was added to the diamine. The reaction flask was left open to the air and heated to 65° C. After twelve hours the reaction was concentrated in vacuo and the residue purified on reverse phase HPLC using water-acetonitrile gradient (0.1% TFA) to provide the product (0.60 g, 70% yield). (Note that the BOC group was removed under the purification conditions.)