Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[N:6]2[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]2=[N:4][CH:3]=1.[I:22][C:23]1[N:28]=[C:27](I)[CH:26]=[CH:25][N:24]=1>>[I:22][C:23]1[N:28]=[C:27]([C:2]2[N:6]3[CH:7]=[CH:8][C:9]([C:11]([CH3:21])([O:13][Si:14]([CH2:19][CH3:20])([CH2:17][CH3:18])[CH2:15][CH3:16])[CH3:12])=[N:10][C:5]3=[N:4][CH:3]=2)[CH:26]=[CH:25][N:24]=1
Reactant: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(Br)cnc2n1
Reactant: Ic1ccnc(I)n1
Product: CC[Si](CC)(CC)OC(C)(C)c1ccn2c(-c3ccnc(I)n3)cnc2n1
Yield: 74.3 %

Procedure:
3-Bromo-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (5.0 g, 13.5 mmol) and 2,4-diiodopyrimidine (prepared according to Leprete et al. in Tetrahedron, 2000, 56, 265-273) (5.6 g, 16.9 mmol) were reacted together as described in Example 39, Step 1. Purification by column chromatography on silica using 2.5% MeOH/CH2Cl2 gave 3-(2-iodopyrimidin-4-yl)-7-(1-methyl-1-triethylsilanyloxyethyl)imidazo[1,2-α]pyrimidine (4.97 g, 74%): 1H NMR (400 MHz, CDCl3) δ 9.95 (1H, d, J 7.3), 8.47 (1H, s), 8.35 (1H, d, J 5.4), 7.66 (1H, d, J 7.3), 7.59 (1H, d, J 5.4), 1.66 (6H, s), 1.00 (9H, t, J 8.0), 0.67 (6H, q, J 8.0).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[S:12][C:11]([CH3:13])=[N:10][C:9]=2[C:14]([N:16]2[CH2:21][CH2:20][CH2:19][CH:18]3[CH2:22][NH:23][CH2:24][CH:17]23)=[O:15])=[CH:4][CH:3]=1.Cl[C:26]1[O:27][C:28]2[CH:34]=[C:33]([Cl:35])[CH:32]=[CH:31][C:29]=2[N:30]=1>>[Cl:35][C:33]1[CH:32]=[CH:31][C:29]2[N:30]=[C:26]([N:23]3[CH2:22][CH:18]4[CH:17]([N:16]([C:14]([C:9]5[N:10]=[C:11]([CH3:13])[S:12][C:8]=5[C:5]5[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=5)=[O:15])[CH2:21][CH2:20][CH2:19]4)[CH2:24]3)[O:27][C:28]=2[CH:34]=1
Reactant: Clc1ccc2nc(Cl)oc2c1
Reactant: Cc1nc(C(=O)N2CCCC3CNCC32)c(-c2ccc(F)cc2)s1
Product: Cc1nc(C(=O)N2CCCC3CN(c4nc5ccc(Cl)cc5o4)CC32)c(-c2ccc(F)cc2)s1

Procedure:
The title compound was prepared following the same general protocol as described for Example A2 using (5-(4-fluorophenyl)-2-methylthiazol-4-yl)(octahydro-1H-pyrrolo[3,4-b]pyridin-1-yl)methanone and 2,6-dichlorobenzoxazole. MS (ESI) 497 (M+H).
Reaction SMILES: C([NH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:21][CH2:20][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:18][CH2:17]2)=[O:15])=[CH:7][C:6]=1[Br:34])(=O)C.Cl>O>[NH2:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:33])[CH2:12][CH2:13][C:14]([N:16]2[CH2:17][CH2:18][CH:19]([N:22]3[CH2:31][C:30]4[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=4)[NH:24][C:23]3=[O:32])[CH2:20][CH2:21]2)=[O:15])=[CH:7][C:6]=1[Br:34]
Reactant: CC(=O)Nc1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Br
Agent: Cl
Solvent: O
Product: Nc1ccc(C(=O)CCC(=O)N2CCC(N3Cc4ccccc4NC3=O)CC2)cc1Br

Procedure:
A mixture of 1.5 g (2.84 mmol) of 3-{1-[4-(4-acetylamino-3-bromophenyl)-1,4-dioxobutyl]-4-piperidinyl}-3,4-dihydro-2(1H)-quinazolinone and 150 ml of conc. hydrochloric acid was refluxed for 1 hour. The residue was digested with water, the solid precipitated was suction filtered, recrystallised from acetonitrile and dried in vacuo. Yield: 0.88 g (64% of theoretical). Rf 0.34 (El A). IR (KBr): 3471.7, 3342.4 (NH, NH2); 1666.4 (C═O) MS: M+484/486 (Br)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[C:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)#[N:13].C([O-])([O-])=O.[K+].[K+].O>CN(C=O)C>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]([O:20][C:17]2[CH:18]=[CH:19][C:14]([C:12]#[N:13])=[CH:15][CH:16]=2)=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1
Reactant: N#Cc1ccc(O)cc1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1ccc(Oc2ccc(Cl)cc2[N+](=O)[O-])cc1
Temperature: 80 °C
Yield: 77.5 %

Procedure:
1-Bromo-4-chloro-2-nitrobenzene (10 g, 42.3 mmol) was added to a solution of 4-cyanophenol (5.0 g, 42.3 mmol), and K2CO3 (14.6 g, 0.10 mol) in DMF (50 mL). The mixture was heated at 80° C. for 15 hr. The reaction was poured into water. The aqueous phase was extracted with ethyl acetate and the combined organic phases were washed with water, brine, and dried over sodium sulfate. The organic phase was filtered and concentrated under vacuum. The residue was purified by flash chromatography eluting with (hexanes/ethyl acetate 4:1) to give the product (9.0 g, 77.8%).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([SH:9])=[CH:5][CH:4]=1)[CH3:2].Br[CH2:11][CH:12]([O:15][CH3:16])[O:13][CH3:14].CO.C[O-].[Na+]>>[CH3:14][O:13][CH:12]([O:15][CH3:16])[CH2:11][S:9][C:6]1[CH:7]=[CH:8][C:3]([CH2:1][CH3:2])=[CH:4][CH:5]=1
Reactant: CCc1ccc(S)cc1
Reactant: COC(CBr)OC
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: CCc1ccc(SCC(OC)OC)cc1
Reaction time: 0.17 h
Yield: 92.4 %

Procedure:
Under a nitrogen atmosphere, 4-ethylbenzenethiol (3.50 ml, 25.4 mmol) and 2-bromo-1,1-dimethoxyethane (3.3 ml, 27.9 mmol) were added to a sodium methoxide methanol solution (0.5 M, 81.4 ml, 40.7 mmol) under cooling with ice. The reaction mixture was stirred at the same temperature for 10 minutes, and then heated to reflux for five hours. The reaction mixture was concentrated under reduced pressure, and cold water was added. The resulting mixture was extracted with ether and the organic layer was washed with a saturated sodium chloride aqueous solution and dried with sodium sulfate. After filtration, the solvent was distilled under reduced pressure and the obtained residue was purified by silica gel column chromatography [developing solution=ethyl acetate:n-hexane (1:20)] to obtain the title compound (5.31 g, 93%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@@H:6]([CH:33]=[CH2:34])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]2[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21][CH2:20]2)[CH2:11]1)=[O:9])[CH3:2]>C(O)C.O=[Pt]=O>[CH2:1]([O:3][C:4](=[O:35])[CH2:5][C@H:6]([CH2:33][CH3:34])[NH:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:32])[CH2:17][CH2:18][CH:19]2[CH2:20][CH2:21][N:22]([C:25]([O:27][C:28]([CH3:29])([CH3:31])[CH3:30])=[O:26])[CH2:23][CH2:24]2)[CH2:11]1)=[O:9])[CH3:2]
Reactant: C=C[C@H](CC(=O)OCC)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Agent: O=[Pt]=O
Solvent: CCO
Product: CCOC(=O)C[C@H](CC)NC(=O)[C@@H]1CCCN(C(=O)CCC2CCN(C(=O)OC(C)(C)C)CC2)C1
Reaction time: 2 h
Yield: 90.9 %

Procedure:
A mixture of N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-vinyl-β-alanine ethyl ester (0.8 g) and PtO2 (0.2 g) in ethanol (10 ml) was hydrogenated at atmospheric pressure for 2 hours. After the catalyst was removed by filtration, the filtrate was concentrated in vacuo to give N-[(R)-1-{3-(1-tert-butoxycarbonyl-4-piperidyl)propionyl}-3-piperidylcarbonyl]-3(S)-ethyl-β-alanine ethyl ester (0.73 g) as a colorless oil.
Reaction SMILES: [NH2:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:14]1=[O:29].C(N(CC)CC)C.[C:37](OC(=O)C)(=[O:39])[CH3:38]>ClCCl>[C:37]([NH:1][C@@H:2]1[CH2:7][C@H:6]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])[CH2:5][CH2:4][C@@H:3]1[N:13]1[CH2:17][CH2:16][C@H:15]([NH:18][C:19](=[O:28])[O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)[C:14]1=[O:29])(=[O:39])[CH3:38]
Reactant: CC(C)(C)N[C@@H]1CC[C@H](N2CC[C@H](NC(=O)OCc3ccccc3)C2=O)[C@H](N)C1
Reactant: CC(=O)OC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(=O)N[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1N1CC[C@H](NC(=O)OCc2ccccc2)C1=O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 90 %

Procedure:
A solution of benzyl (S)-1-((1S,2R,4R)-2-amino-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 0.055 mmol) in dichloromethane (2 mL) was charged sequentially with triethylamine (11.1 mg, 2 eq) and acetic anhydride (6.1 mg, 1.1 eq). The reaction was stirred for 1.5 h at room temperature, diluted with dichloromethane (50 mL) and washed with saturated NaHCO3 (20 mL). The organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give benzyl (S)-1-((1S,2R,4R)-2-acetamido-4-(tert-butylamino)cyclohexyl)-2-oxopyrrolidin-3-ylcarbamate (22 mg, 90%). LC/MS found [M+H]=445.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][NH:12][CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1.[CH:24](O)=[O:25].Cl.C(N=C=NCCCN(C)C)C>CN(C=O)C.O>[Br:1][C:2]1[CH:3]=[C:4]2[C:10]3([CH2:14][CH2:13][N:12]([CH:24]=[O:25])[CH2:11]3)[CH2:9][N:8]([C:15]([NH:17][C:18]3[S:19][C:20]([Cl:23])=[CH:21][N:22]=3)=[O:16])[C:5]2=[CH:6][CH:7]=1
Reactant: O=CO
Reactant: O=C(Nc1ncc(Cl)s1)N1CC2(CCNC2)c2cc(Br)ccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Product: O=CN1CCC2(C1)CN(C(=O)Nc1ncc(Cl)s1)c1ccc(Br)cc12
Reaction time: 18 h
Yield: 54.3 %

Procedure:
The 5-bromo-N-(5-chlorothiazol-2-yl)spiro[indoline-3,3′-pyrrolidine]-1-carboxamide (160 mg, 0.387 mmol) obtained in Example 2 was dissolved in N,N′-dimethylformamide (4.0 mL). Thereafter, formic acid (22.0 μL, 0.581 mmol) and 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (148 mg, 0.774 mmol) were added to the above obtained solution, and the thus obtained mixture was then stirred for 18 hours. Thereafter, the reaction solution was diluted with water, and was then extracted with ethyl acetate. The organic layer was washed with brine, and was then dried over anhydrous sodium sulfate, followed by concentration in vacuo. The obtained residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to obtain the captioned compound (92.8 mg, 54%) in the form of a white solid.
Reaction SMILES: [OH:1][C@:2]12[C:19]([CH3:21])([CH3:20])[C:18](=O)[CH2:17][CH2:16][C@:15]1([CH3:23])[C@@H:14]1[C@H:5]([C@H:6]3[C@@:10]([CH2:12][CH2:13]1)([CH3:11])[C@@H:9]([OH:24])[CH2:8][CH2:7]3)[CH2:4][C@@H:3]2[OH:25].[ClH:26].Cl.[NH:28]1[CH2:32][CH2:31][C@@H:30]([O:33][NH2:34])[CH2:29]1>>[ClH:26].[NH:28]1[CH2:32][CH2:31][C@@H:30]([O:33]/[N:34]=[C:18]2/[C:19]([CH3:21])([CH3:20])[C@@:2]3([OH:1])[C@:15]([CH3:23])([CH2:16][CH2:17]/2)[C@@H:14]2[C@H:5]([C@H:6]4[C@@:10]([CH2:12][CH2:13]2)([CH3:11])[C@@H:9]([OH:24])[CH2:8][CH2:7]4)[CH2:4][C@@H:3]3[OH:25])[CH2:29]1
Reactant: CC1(C)C(=O)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Reactant: NO[C@@H]1CCNC1
Agent: Cl
Product: CC1(C)/C(=N/O[C@@H]2CCNC2)CC[C@]2(C)[C@H]3CC[C@]4(C)[C@@H](O)CC[C@H]4[C@@H]3C[C@H](O)[C@@]12O
Yield: 90 %

Procedure:
The title compound was prepared in 90% yield (121 mg) as described in Example 2 starting from 5α,6α,17β-trihydroxy-4,4-dimethylandrostan-3-one, (Preparation 5, 100 mg) and 3-(R)-pyrrolidinyloxyamine dihydrochloride (Preparation 12, 200 mg).
Reaction SMILES: [CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13](Cl)[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:22]([NH2:29])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28].C(O)CCCC>>[CH2:1]([NH:8][C:9]1[C:10]2[NH:18][N:17]=[C:16]([CH:19]([CH3:21])[CH3:20])[C:11]=2[N:12]=[C:13]([NH:29][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[N:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)c1n[nH]c2c(NCc3ccccc3)nc(Cl)nc12
Reactant: CCCCCCCN
Solvent: CCCCCO
Product: CCCCCCCNc1nc(NCc2ccccc2)c2[nH]nc(C(C)C)c2n1
Yield: 60 %

Procedure:
The mixture 85.6 mg of 7-benzylamino-5-chloro-3-isopropylpyrazolo[4,3-d]pyrimidine XVI, 0.21 mL of heptyl amine and 1 mL of pentanol was heated at 125° C. for 12 hours. The reaction mixture was evaporated to dryness in vacuo and then chromatographed on silica gel. The mixture of chloroform/acetone/heptane (1:1:1) was used as a mobile phase. Yield=60%; white syrupy; MS (ES+): 381.0 (100%, M+H+). 1H-NMR (300 MHz, CDCl3): 0.86 t (3H, J=6.6 Hz), 1.22-1.36 m (12H), 1.56 m (2H), 1.64 m (2H), 3.12 sept (1H, J=7.1 Hz), 3.41 d (2H, J=5.2 Hz), 4.79 bs (2H), 7.19-7.35 m (5H), 7.60 s (1H).
Reaction SMILES: Br[CH2:2][C:3]1[C:12]([C:13]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=2[Cl:20])=[N:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][C:9]=2[Cl:21])[N:4]=1.I([O-])(=O)(=O)=[O:23].[Na+].CN(C=O)C>CCOC(C)=O>[Cl:21][C:9]1[CH:8]=[CH:7][CH:6]=[C:5]2[C:10]=1[N:11]=[C:12]([C:13]1[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:14]=1[Cl:20])[C:3]([CH:2]=[O:23])=[N:4]2
Reactant: Fc1ccc(Cl)c(-c2nc3c(Cl)cccc3nc2CBr)c1
Reactant: [O-][I+3]([O-])([O-])[O-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=Cc1nc2cccc(Cl)c2nc1-c1cc(F)ccc1Cl
Temperature: 150 °C
Reaction time: 3 h

Procedure:
A mixture of 2-(bromomethyl)-5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline (Prepared in Example 100, 0.5625 g, 1.457 mmol) and sodium metaperiodate (0.1613 mL, 2.914 mmol) in DMF (9.714 mL, 1.457 mmol) was heated at 150° C. with stirring. After 3 h, the mixture was cooled to room temperature, diluted with EtOAc (100 mL), washed with brine (50 mL×2), dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography on a 80 g of Redi-Sep™ column using 0 to 10% gradient of EtOAc in hexane over 10 min, then 10% isocratic of EtOAc for 20 min, then 10 to 20% gradient of EtOAc in hexane over 20 min, then 20% isocratic of EtOAc for 3 min as eluent to give 5-chloro-3-(2-chloro-5-fluorophenyl)quinoxaline-2-carbaldehyde as an off-white solid: 1H NMR (400 MHz, DMSO-d6) δ ppm 10.16 (1 H, s), 8.35-8.41 (1 H, m), 8.29-8.34 (1 H, m), 8.07 (1 H, dd, J=8.4, 7.6 Hz), 7.68 (1 H, dd, J=8.8, 4.9 Hz), 7.44-7.58 (2 H, m); LC-MS (ESI) m/z 321.0 [M+H]+.
Reaction SMILES: [CH3:1][N:2]([CH3:49])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[N:17]=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[C:19]4[CH:24]=[CH:23][N:22](S(C5C=CC(C)=CC=5)(=O)=O)[C:20]=4[N:21]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5].[OH-].[K+]>O1CCOCC1.CCOC(C)=O>[CH3:49][N:2]([CH3:1])[CH2:3][C:4]([N:6]1[C:14]2[C:9](=[CH:10][C:11]([O:47][CH3:48])=[C:12]([NH:15][C:16]3[NH:21][C:20]4=[N:22][CH:23]=[CH:24][C:19]4=[C:18]([NH:35][C:36]4[CH:45]=[CH:44][CH:43]=[C:42]([F:46])[C:37]=4[C:38]([NH:40][CH3:41])=[O:39])[N:17]=3)[CH:13]=2)[CH2:8][CH2:7]1)=[O:5]
Reactant: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)nc2c1ccn2S(=O)(=O)c1ccc(C)cc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CNC(=O)c1c(F)cccc1Nc1nc(Nc2cc3c(cc2OC)CCN3C(=O)CN(C)C)[nH]c2nccc1-2
Temperature: 90 °C

Procedure:
A light brown solution of 2-({2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-7-[(4-methylphenyl)sulfonyl]-7H-pyrrolo[2,3-d]pyrimidin-4-yl}amino)-6-fluoro-N-methylbenzamide (26 g, 37.9 mmol) prepared in multiple batches as described in Step C above, in dioxane (900 mL) was treated with a 1N aqueous KOH solution (379 mL, 379 mmol). The resulting mixture was heated in a 90° C. bath for 3 hours. The resulting mixture was allowed to cool to room temperature, then was diluted with EtOAc (500 mL). The organic layer was separated and sequentially washed with a 2N aqueous NaOH solution (2×200 mL) and a saturated NaCl solution (300 mL), then concentrated to a thick slurry. The resulting slurry was filtered and the solid washed with Et2O. The filtrate was concentrated to a slurry, filtered, and combined with the previous residue to obtain 2-[(2-{[1-(N,N-dimethylglycyl)-5-(methyloxy)-2,3-dihydro-1H-indol-6-yl]amino}-1H-pyrrolo[2,3-d]pyrimidin-4-yl)amino]-6-fluoro-N-methylbenzamide as a light brown solid. (16.9 g, 84%, Yield). The remaining filtrate was concentrated and purified by flash silica gel chromatography using 1-10% MeOH (0.2% NH3)/CH2Cl2 affording an additional 1 g (5%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.28 (s, 6H), 2.82 (d, J=4.40 Hz, 3H), 3.08-3.15 (m, 2H), 3.22 (s, 2H), 3.79 (s, 3H), 4.16 (t, J=8.25 Hz, 2H), 6.27 (d, J=1.83 Hz, 1H), 6.80-6.89 (m, 1H), 6.92 (d, J=2.20 Hz, 1H), 6.93 (s, 1H), 7.26-7.35 (m, 1H), 7.38 (s, 1H), 8.28 (s, 1H), 8.36 (d, J=8.43 Hz, 1H), 8.65 (s, 1H), 10.10 (s, 1H), 11.06 (s, 1H). ESIMS (M+H)=533.
Reaction SMILES: [Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][NH:14]3)=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Br[CH2:23][CH2:24][CH2:25][N:26]1[C:30](=[O:31])[C:29]2=[CH:32][CH:33]=[CH:34][CH:35]=[C:28]2[C:27]1=[O:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:21]=[CH:20][C:5]([O:6][C:7]2[CH:19]=[CH:18][C:10]([O:11][CH2:12][C@@H:13]3[CH2:17][CH2:16][CH2:15][N:14]3[CH2:23][CH2:24][CH2:25][N:26]3[C:30](=[O:31])[C:29]4[C:28](=[CH:35][CH:34]=[CH:33][CH:32]=4)[C:27]3=[O:36])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(Oc2ccc(OC[C@@H]3CCCN3)cc2)cc1
Reactant: O=C1c2ccccc2C(=O)N1CCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1CCCN1CCC[C@H]1COc1ccc(Oc2ccc(Cl)cc2)cc1
Temperature: 60 °C
Yield: 61246.2 %

Procedure:
(S)-2-[4-(4-Chloro-phenoxy)-phenoxymethyl]-pyrrolidine (200 mg, 0.658 mmol) was taken into anhydrous DMF (2 mL) in a nitrogen flushed 20 mL vial. N-(3-Bromopropyl)phthalimide (194 mg, 0.724 mmol) was added to the mixture followed by potassium carbonate (364 mg, 2.43 mmol). The reaction was sealed and heated at 60° C. for 24 h. The mixture was then cooled to room temperature and partitioned between ethyl acetate and water. The water layer was washed with ethyl acetate (3×). The combined ethyl acetate layers were then washed with brine, dried over anhydrous sodium sulfate, filtered, and concentrated to dryness. The resulting residue was then purified by silica gel flash chromatography (20:1 silica ratio, eluted with 40% Methanol in dichloromethane). The overlap from the purification was repurified by silica gel flash chromatography (20:1 silica ratio, eluted with 1% methanol in dichloromethane followed by 5% methanol in dichloromethane) to obtain the title product (198 mg, 403 mmol, 61%); MS; m/z 491 (M); 1H NMR (400 MHz, DMSO-d6) δ 1.5-1.67 (m, 3H), 1.75-1.82 (m, 2H), 1.86-1.91 (m, 1H), 2.13-2.14 (m, 1H), 2.34-2.37 (m, 1H), 2.72-2.73 (m, 1H), 2.89-2.94 (m, 1H), 3.02-3.06 (m, 1H), 3.60-3.70 (m, 3H), 3.88-3.91 (m, 1H), 6.89-6.98 (m, 6H), 7.38 (d, J=9.2, 2H), 7.82-7.85 (m, 4H).
Reaction SMILES: [CH3:1][C:2]1[S:3][C:4]([C:13]([N:15]2[CH2:20][C:19](=O)[CH2:18][CH2:17][CH:16]2[CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])=[O:14])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[CH2:36]([NH2:38])[CH3:37]>>[CH2:36]([NH:38][CH:19]1[CH2:20][N:15]([C:13]([C:4]2[S:3][C:2]([CH3:1])=[N:6][C:5]=2[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[O:14])[CH:16]([CH2:22][NH:23][C:24]([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[N:34]=[CH:33][CH:32]=[CH:31]3)=[O:25])[CH2:17][CH2:18]1)[CH3:37]
Reactant: Cc1nc(-c2ccccc2)c(C(=O)N2CC(=O)CCC2CNC(=O)c2cccc3cccnc23)s1
Reactant: CCN
Product: CCNC1CCC(CNC(=O)c2cccc3cccnc23)N(C(=O)c2sc(C)nc2-c2ccccc2)C1

Procedure:
N-((5-(Ethylamino)-1-(2-methyl-4-phenylthiazole-5-carbonyl)piperidin-2-yl)methyl)quinoline-8-carboxamide was prepared according to general procedure N using N-((1-(2-methyl-4-phenylthiazole-5-carbonyl)-5-oxopiperidin-2-yl)methyl)quinoline-8-carboxamide and ethyl amine. (ESI) 514 (M+H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[CH2:7][CH:8]([NH:23]C(OCC1C=CC=CC=1)=O)[CH:9]([OH:22])[CH2:10][O:11][C:12]1[C:17]([F:18])=[C:16]([F:19])[CH:15]=[C:14]([F:20])[C:13]=1[F:21])([CH3:4])([CH3:3])[CH3:2]>CO.[Pd]>[C:1]([O:5][C:6](=[O:34])[CH2:7][C@H:8]([NH2:23])[CH:9]([OH:22])[CH2:10][O:11][C:12]1[C:13]([F:21])=[C:14]([F:20])[CH:15]=[C:16]([F:19])[C:17]=1[F:18])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)CC(NC(=O)OCc1ccccc1)C(O)COc1c(F)c(F)cc(F)c1F
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)C[C@H](N)C(O)COc1c(F)c(F)cc(F)c1F
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 89.8 %

Procedure:
10% Pd on carbon (2.92 g) was added portionwise to a solution of 3-benzyloxycarbonylamino-4-hydroxy-5-(2,3,5,6-tetrafluoro-phenoxy)-pentanoic acid tert-butyl ester (14.6 g) in anhydrous MeOH (350 mL) which has been degassed under nitrogen (5×). The reaction was further degassed under nitrogen (3×) and hydrogen (5×) and stirred at room temperature for 20 minutes. The palladium residues were removed by filtration and the filtrate concentrated to give the sub-title compound as a white solid (9.5 g, 90%); 1H NMR (400 MHz, CDCl3) δ 1.49 (9H, s), 2.35-2.43 (1H, m), 5.67-5.64 (1H, m), 3.37-3.43 (1H, m), 3.77-3.87 (1H, m), 4.28-4.63 (2H, m), 6.77-6.86 (1H, m); 19F NMR (346 MHz, CDCl3) (proton decoupled) δ −139.95, −139.97, −140.00, −140.03, −140.05, −140.08, −140.11, −140.13, −157.15, −157.18, −157.21, −157.23, −157.27, −157.29.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:6]=[CH:7][C:8]([C:25]([F:28])([F:27])[F:26])=[C:9]([CH:24]=1)[O:10][CH2:11][C@H:12]1[CH2:16][CH2:15][CH2:14][N:13]1C(OC(C)(C)C)=O)(=[O:3])[CH3:2].C(O)(C(F)(F)F)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.[OH-].[Na+]>[NH:13]1[CH2:14][CH2:15][CH2:16][C@@H:12]1[CH2:11][O:10][C:9]1[CH:24]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[CH:6]=[CH:7][C:8]=1[C:25]([F:28])([F:27])[F:26]
Reactant: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2C(=O)OC(C)(C)C)c1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(=O)Nc1ccc(C(F)(F)F)c(OC[C@H]2CCCN2)c1
Reaction time: 0.83 h

Procedure:
To a solution of (R)-2-(5-acetylamino-2-trifluoromethyl-phenoxymethyl)-1-(tert-butoxycarbonyl)pyrrolidine (1.34 g, 3.33 mol) in 10 mL CH2Cl2 at RT was added 5 mL TFA. The reaction was stirred for 50 min, neutralized with saturated aqueous NaHCO3, and diluted with CH2Cl2 and 2N NaOH. The layers were separated, and the organic layer was brine-washed. The aqueous layers were back-extracted 4 times with CH2Cl2. The combined organic layers were dried over Na2SO4, filtered, and concentrated in vacuo to yield the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:4][C:3]=1[CH3:13].[I:14]Cl>>[NH2:1][C:2]1[C:3]([CH3:13])=[CH:4][C:5]([N:8]2[N:12]=[N:11][CH:10]=[N:9]2)=[CH:6][C:7]=1[I:14]
Reactant: Cc1cc(-n2ncnn2)ccc1N
Reactant: ClI
Product: Cc1cc(-n2ncnn2)cc(I)c1N

Procedure:
The following compound, m.p. 196°-199° was prepared similarly to the previous Preparation using 2-(4-amino-3-methylphenyl)tetrazole and iodine monochloride as the starting materials: ##STR141##