Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([OH:15])=O)[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:10])=[O:9].C(Cl)(=O)C(Cl)=O.[O:28]1[CH2:32][CH2:31][O:30][CH:29]1[C:33]1[N:34]=[CH:35][C:36]([NH2:39])=[N:37][CH:38]=1.N1C=CC=CC=1>C(Cl)Cl.CN(C)C=O>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:12]([CH2:16][CH:17]2[CH2:21][CH2:20][CH2:19][CH2:18]2)[C:13]([NH:39][C:36]2[CH:35]=[N:34][C:33]([CH:29]3[O:30][CH2:31][CH2:32][O:28]3)=[CH:38][N:37]=2)=[O:15])[CH:5]=[CH:6][C:7]=1[S:8]([CH3:11])(=[O:9])=[O:10]
Reactant: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)O)cc1Cl
Reactant: Nc1cnc(C2OCCO2)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CS(=O)(=O)c1ccc([C@@H](CC2CCCC2)C(=O)Nc2cnc(C3OCCO3)cn2)cc1Cl
Temperature: 5 °C
Reaction time: 0.08 h
Yield: 51.1 %

Procedure:
A solution of 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (prepared as in Example 1, 200 mg, 0.604 mmol) in methylene chloride (5 mL) and N,N-dimethylformamide (2 drops) was cooled to 5° C. and then treated with oxalyl chloride (105 μL, 1.2 mmol). The solution was stirred at 5° C. for 5 min, the cooling bath was removed, and the stirring was continued for 10 min. At this time, the reaction mixture was concentrated in vacuo, the residue was dissolved in benzene (10 mL), and the solvent was concentrated in vacuo again. The resulting acid chloride was dissolved in methylene chloride (5 mL), cooled to 5° C., and then treated with a solution of 5-[1,3]dioxolan-2-yl-pyrazin-2-ylamine (105 μL, 0.628 mmol), pyridine (100 μL, 1.23 mmol) in methylene chloride (5 mL). After 5 min, the cooling bath was removed, and the stirring was continued for 18 h. The reaction mixture was then diluted with methylene chloride (50 mL), and the solution was washed with a saturated aqueous sodium bicarbonate solution (25 mL), a 0.5M aqueous hydrochloric acid solution (25 mL), and a saturated aqueous sodium chloride solution (25 mL). Each aqueous wash was extracted with a small portion of methylene chloride. The combined organic layers were dried over sodium sulfate, filtered, and concentrated in vacuo to afford a yellow oil. Flash chromatography (Merck Silica gel 60, 230–400 mesh, various concentrations of ethyl acetate/hexanes) afforded the 2(R)-(3-chloro-4-methanesulfonyl-phenyl)-3-cyclopentyl-N-(5-[1,3]dioxolan-2-yl-pyrazin-2-yl)-propionamide (148 mg, 51%) as a colorless foam: (ES)+-HRMS m/e calcd for C22H26ClN3O5S (M+H)+ 480.1355, found 480.1357.
Reaction SMILES: [CH2:1]1[CH2:13][O:12][C:3]([CH3:11])([CH2:4][CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][OH:9])[O:2]1.C([Li])CCC.CO[CH2:21][CH2:22][O:23][CH2:24]Cl.[Cl-].[O:27]1CCC[CH2:28]1>>[CH2:13]1[CH2:1][O:2][C:3]([CH3:11])([CH2:4][CH2:5][CH2:6][CH:7]([CH3:10])[CH2:8][O:9][CH2:28][O:27][CH:22]([O:23][CH3:24])[CH3:21])[O:12]1
Reactant: C1CCOC1
Reactant: CC(CO)CCCC1(C)OCCO1
Reactant: COCCOCCl
Agent: [Cl-]
Agent: [Li]CCCC
Product: COC(C)OCOCC(C)CCCC1(C)OCCO1
Temperature: -78 °C
Reaction time: 1.5 h

Procedure:
6,6-Ethylenedioxy-2-methyl-heptanol (2.0 g) is dissolved in anhydrous tetrahydrofuran (35 ml) and cooled to -78° C. under nitrogen. n-Butyllithium (0.68 g) is added and the solution is warmed to 0° C. Methoxyethoxymethyl chloride (1.59 g) is added and the reaction stirred at 0° C. for 1.5 hours. An additional 1.59 g of the chloride is added and stirring is continued at 0° C. for 2 hours. The tetrahydrofuran is evaporated in vacuo and the residue is partitioned between ether and brine. The ether extract is dried (Na2SO4) and the solvent is evaporated in vacuo to give 6,6-ethylenedioxy-1-methoxyethoxymethoxy-2-methylheptane. The compound is dissolved in acetone (40 ml) and 10% hydrochloric acid (2.0 ml) is added and the resulting solution is stirred for two hours. A saturated sodium bicarbonate solution (50 ml) is added, and the resulting precipitate filtered and the filtrate evaporated in vacuo. The residue is partitioned between ether and brine and the ether extract is dried (Na2SO4) and evporated in vacuo. The residue is chromatographed on silica (solvent: ethyl acetate/hexane) to give 1-methoxyethoxymethoxy-2-methyl-6-oxo-heptane as a colorless liquid, nmr (CDCl3,δ) 0.9 (d, CH3CH), 2.12 (s, CH3C=O), 2.4 (t, --CH2C=O, 3.3-3.8 (m, --OCH3, ##STR44## --OCH2CH2O), 4.66 (s, 2H, --OCH2O--).
Reaction SMILES: Cl.[F:2][C:3]1[CH:14]=[CH:13][C:6]([C:7](N2CCC2)=[O:8])=[CH:5][CH:4]=1.[CH2:15]([N:17]([CH2:20][CH3:21])[CH2:18][CH3:19])C.[C:22]([O:26][C:27](=[O:52])[NH:28][C@H:29]([C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[O:34][SiH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])CCI)([CH3:25])([CH3:24])[CH3:23]>CN(C)C=O>[C:22]([O:26][C:27](=[O:52])[NH:28][C@H:29]([C:33]([C:46]1[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=1)([C:40]1[CH:41]=[CH:42][CH:43]=[CH:44][CH:45]=1)[O:34][SiH2:35][C:36]([CH3:39])([CH3:38])[CH3:37])[CH2:21][CH2:20][N:17]1[CH2:15][CH:19]([C:7](=[O:8])[C:6]2[CH:5]=[CH:4][C:3]([F:2])=[CH:14][CH:13]=2)[CH2:18]1)([CH3:23])([CH3:24])[CH3:25]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCI)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1
Reactant: O=C(c1ccc(F)cc1)N1CCC1
Reactant: CCN(CC)CC
Agent: Cl
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CCN1CC(C(=O)c2ccc(F)cc2)C1)C(O[SiH2]C(C)(C)C)(c1ccccc1)c1ccccc1

Procedure:
A solution of 4-fluorobenzoyl-azetidine hydrochloride (0.192 g, 0.892 mmol), triethylamine (0.252 ml, 3.24 mmol) and [(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-iodo-propyl]-carbamic acid tert-butyl ester (0.448 g, 0.811 mmol) in dimethylformamide (3 ml) is stirred at ambient temperature for 18 hours, then partitioned between ethylacetate and water. The ethylacetate phase is dried over MgSO4 and evaporated. The crude product is purified by flash silica chromatography (elution with a 1:99 methanol/dichloromethane) to afford {(S)-1-(tert-butyl-diphenyl-silanyloxymethyl)-3-[3-(4-fluoro-benzoyl)-azetidin-1-yl]-propyl}carbamic acid tert-butyl ester. [MH]+ 605.2.
Reaction SMILES: [CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([OH:51])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:18]=[CH:17][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:15][CH:14]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:58][O:59][CH2:60][CH2:61]Br>CN(C=O)C.CCOC(C)=O>[CH:1]1([N:4]([CH2:39][C:40]2[CH:45]=[C:44]([CH2:46][CH2:47][CH2:48][O:49][CH3:50])[CH:43]=[C:42]([O:51][CH2:61][CH2:60][O:59][CH3:58])[CH:41]=2)[C:5]([C@@H:7]2[C@@H:12]([C:13]3[CH:14]=[CH:15][C:16]([O:19][CH2:20][CH2:21][O:22][C:23]4[C:28]([Cl:29])=[CH:27][C:26]([CH3:30])=[CH:25][C:24]=4[Cl:31])=[CH:17][CH:18]=3)[CH2:11][CH2:10][N:9]([C:32]([O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:33])[CH2:8]2)=[O:6])[CH2:3][CH2:2]1
Reactant: COCCBr
Reactant: COCCCc1cc(O)cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCc1cc(CN(C(=O)[C@H]2CN(C(=O)OC(C)(C)C)CC[C@@H]2c2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C2CC2)cc(OCCOC)c1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
To a solution of tert-butyl (3R,4S)-3-({cyclopropyl[3-hydroxy-5-(3-methoxy-propyl)benzyl]amino}carbonyl)-4-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]-phenyl}piperidine-1-carboxylate (1 eq.) from the previous step in DMF (0.2 M) was added cesium carbonate (1.3 eq.) and 2-bromoethyl methyl ether (1.6 eq.). The reaction was heated to 80° C. and stirred for 3 h. After cooling to rt, the reaction was diluted with EtOAc. The organic extract was washed with water, brine, dried over MgSO4, and concentrated in vacuo. The crude product was purified by flash column chromatography (SiO2, 50%→65% EtOAc in Hex) to afford the title compound as an oil.
Reaction SMILES: [N:1]1[C:6]([CH3:7])=[CH:5][C:4]([CH3:8])=[CH:3][C:2]=1[CH3:9].C([Li])(C)(C)C.[CH:15]1([CH2:21][C:22](=[O:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1>C1COCC1>[CH:15]1([CH2:21][C:22]([CH2:9][C:2]2[CH:3]=[C:4]([CH3:8])[CH:5]=[C:6]([CH3:7])[N:1]=2)([OH:36])[CH2:23][C:24]([C:27]2[CH:32]=[C:31]([F:33])[CH:30]=[CH:29][C:28]=2[O:34][CH3:35])([CH3:26])[CH3:25])[CH2:16][CH2:17][CH2:18][CH2:19][CH2:20]1
Reactant: Cc1cc(C)nc(C)c1
Reactant: COc1ccc(F)cc1C(C)(C)CC(=O)CC1CCCCC1
Agent: [Li]C(C)(C)C
Solvent: C1CCOC1
Product: COc1ccc(F)cc1C(C)(C)CC(O)(Cc1cc(C)cc(C)n1)CC1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 55.1 %

Procedure:
To a solution of collidine (0.113 g) in THF (1 mL) cooled to −70° C. was added dropwise over 3 minutes tert-butyl lithium (1.7 M in pentane, 0.55 mL). The mixture was stirred for 5 minutes and then 1-cyclohexyl-4-(5-fluoro-2-methoxyphenyl)-4-methylpentan-2-one (Example 15) (0.095 g) in THF (0.5 mL) was added dropwise. After 10 minutes at −70° C., the reaction was quenched by addition of EtOH (0.2 mL) and warmed to room temperature. The mixture was diluted with EtOAc, washed with water, dried over sodium sulfate, filtered, and evaporated. The residue was fractionated by preparative layer chromatography (developer: methylene chloride-EtOAc (99:1)) followed by preparative layer chromatography (developer: hexanes-methylene chloride-EtOH (1:1:0.01)) to give the title compound as an oil (73 mg).
Reaction SMILES: [C:1]([N:5]1[C:9](=[O:10])[C:8](Cl)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2].[N:20]1([C:26]2[CH:32]=[CH:31][C:29]([NH2:30])=[CH:28][CH:27]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.CCOC(C)=O>CN(C=O)C>[C:1]([N:5]1[C:9](=[O:10])[C:8]([NH:30][C:29]2[CH:28]=[CH:27][C:26]([N:20]3[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]3)=[CH:32][CH:31]=2)=[C:7]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[S:6]1(=[O:19])=[O:18])([CH3:4])([CH3:3])[CH3:2]
Reactant: Nc1ccc(N2CCCCC2)cc1
Reactant: CC(C)(C)N1C(=O)C(Cl)=C(c2ccccc2)S1(=O)=O
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(C)(C)N1C(=O)C(Nc2ccc(N3CCCCC3)cc2)=C(c2ccccc2)S1(=O)=O
Yield: 50 %

Procedure:
A solution of 2-tert-butyl-4-chloro-5-phenylisothiazol-3(2H)-one 1,1-dioxide (0.150 g, 0.50 mmol) and 4-piperidinoaniline (0.176 g, 1.00 mmol) in DMF (2 mL) was heated at 120° C. for 15 mins in a microwave reactor. EtOAc was then added and the resulting mixture was washed with brine and evaporated. The residue was purified by silica gel column chromatography using a 9:1 mixture of petroleum ether and EtOAc as eluant, to give the title compound (0.110 g, 50%) as a solid; 1H NMR (500 MHz, CDCl3): δ 7.22-7.18 (m, 1H), 7.16-7.05 (m, 5H), 6.58 (d, 2H), 6.54 (d, 2H), 3.02 (t, 4H), 1.80 (s, 9H), 1.70-1.62 (m, 4H), 1.58-1.54 (m, 2H); 13C NMR (125 MHz, CDCl3): δ 160.3, 149.9, 131.3, 129.6, 128.8, 128.1, 127.8, 125.3, 123.5, 116.3, 109.4, 61.9, 51.1, 27.9, 25.7, 24.4; Mass Spectrum: M+H+ 440.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([OH:7])=[O:6].[C:12](Cl)(=O)C>>[Br:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[CH3:11])[C:5]([O:7][CH3:12])=[O:6]
Reactant: Cc1ccc(C(=O)O)cc1Br
Reactant: CC(=O)Cl
Product: COC(=O)c1ccc(C)c(Br)c1

Procedure:
n.m.r. δ values include 2.40 (s, 3 H), 3.90 (s, 3 H), 7.25 (d, 1 H), 7.80 (d, 1 H), 8.15 (s, 1 H), from 3-bromo4-methylbenzoic acid (2.63 g) and acetyl chloride(1.8 mL).
Reaction SMILES: [NH2:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17].[NH:19]([C:24]([O:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)=[O:25])[CH2:20][C:21](O)=[O:22].CN1CCOCC1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C>[CH2:27]([O:26][C:24]([NH:19][CH2:20][C:21]([NH:1][C@H:2]1[CH2:7][CH2:6][C@@H:5]([NH:8][C:9](=[O:15])[O:10][C:11]([CH3:12])([CH3:13])[CH3:14])[CH2:4][C@H:3]1[CH:16]([CH3:18])[CH3:17])=[O:22])=[O:25])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1N
Reactant: O=C(O)CNC(=O)OCc1ccccc1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CC(C)[C@@H]1C[C@H](NC(=O)OC(C)(C)C)CC[C@@H]1NC(=O)CNC(=O)OCc1ccccc1
Temperature: 0 °C
Reaction time: 12 h
Yield: 58 %

Procedure:
Tert-butyl(1R,3S,4S)-4-amino-3-isopropylcyclohexylcarbamate (780 mg) dissolved in DMF (10 mL) and cooled to 0° C. prior to the addition of N-Cbz-Gly-OH (1.14 g), 4-methylmorpholine (1.2 mL), and BOP (2.42 g). The reaction was stirred for 12 h at rt and then partitioned between EtOAc and 1N HCl solution. The organic phases were combined, washed with saturated NaHCO3 and brine, dried (MgSO4), filtered, and concentrated in vacuo. The residue was purified by flash chromatography to afford tert-butyl (1R,3S,4S)-4-(2-benzyloxycarbonylaminoacetamido)-3-isopropylcyclohexylcarbamate (790 mg). MS found: (M+H)+=448.4.
Reaction SMILES: [CH:1]([Mg]Br)=[CH2:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[C:13]([O:15][CH3:16])[CH:14]=1)[CH2:10]Br>C1COCC1.[Cu]I>[CH2:10]([C:9]1[CH:8]=[C:7]([O:6][CH3:5])[CH:14]=[C:13]([O:15][CH3:16])[CH:12]=1)[CH:1]=[CH2:2]
Reactant: C=C[Mg]Br
Reactant: COc1cc(CBr)cc(OC)c1
Agent: [Cu]I
Solvent: C1CCOC1
Product: C=CCc1cc(OC)cc(OC)c1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 100 %

Procedure:
To a suspension of 308 mg (1.62 mmol, 25 mol %) of copper (I) iodide in 30 mL of THF was added dropwise vinylmagnesium bromide as a 1 M solution in THF at −50° C. After stirring for 10 min, a solution of 1.5 g (6.49 mmol) of 3,5-dimethoxybenzyl bromide in 8 mL of THF was added, and the resulting solution was stirred at −30° C. for 1 h and then was warmed to room temperature. The reaction mixture was quenched by the slow addition of 20 mL of water. After stirring for 5 min, the layers were separated and the aqueous layer was extracted twice with 20-mL portions of ethyl acetate. The combined organic fractions were dried (Na2SO4), filtered through a plug of silica gel (eluted with ethyl acetate) and concentrated in vacuo to afford 1.2 g (100%) of product as a yellow oil.
Reaction SMILES: [F:1][C:2]1[C:3]([N:11]2[CH2:15][C:14]([CH3:17])([CH3:16])[CH:13]([N:18]([CH3:20])[CH3:19])[CH2:12]2)=[N:4][C:5]([CH3:10])=[N:6][C:7]=1[NH:8][NH2:9].[CH:21]1([CH2:26][C@H:27]([CH2:31][N:32]([CH:41]=[O:42])[O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[C:28](O)=[O:29])[CH2:25][CH2:24][CH2:23][CH2:22]1.CN1CCOCC1.ON1C2N=CC=CC=2N=N1.C(Cl)CCl>CN(C=O)C>[CH:21]1([CH2:26][C@@H:27]([C:28]([NH:9][NH:8][C:7]2[C:2]([F:1])=[C:3]([N:11]3[CH2:12][CH:13]([N:18]([CH3:20])[CH3:19])[C:14]([CH3:17])([CH3:16])[CH2:15]3)[N:4]=[C:5]([CH3:10])[N:6]=2)=[O:29])[CH2:31][N:32]([O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:41]=[O:42])[CH2:25][CH2:24][CH2:23][CH2:22]1
Reactant: O=CN(C[C@@H](CC1CCCC1)C(=O)O)OCc1ccccc1
Reactant: Cc1nc(NN)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Agent: On1nnc2cccnc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Solvent: ClCCCl
Product: Cc1nc(NNC(=O)[C@H](CC2CCCC2)CN(C=O)OCc2ccccc2)c(F)c(N2CC(N(C)C)C(C)(C)C2)n1
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of racemic 1-(5-fluoro-6-hydrazino-2-methyl-4-pyrimidinyl)-N,N,4,4-tetramethyl-3-pyrrolidinamine (0.0617 g, 0.219 mmol) in DMF (3 mL) was added (2R)-3-cyclopentyl-2-({formyl[(phenylmethyl)oxy]amino}methyl)propanoic acid (0.0637 g, 0.209 mmol), N-methylmorpholine (0.120 mL, 1.091 mmol), 1-hydroxy-7-azabenzotriazole (34 mg, 0.250 mmol), and EDC (48 mg, 0.250 mmol). The solution was stirred overnight and then purified directly by Gilson RPLC to give [(2R)-2-(cyclopentylmethyl)-3-(2-{6-[4-(dimethylamino)-3,3-dimethyl-1-pyrrolidinyl]-5-fluoro-2-methyl-4-pyrimidinyl}hydrazino)-3-oxopropyl][(phenylmethyl)oxy]formamide (0.0775 g, 65% yield, mixture of diastereomers) as a pale yellow oil. LCMS: (M+H)+: 570.3.
Reaction SMILES: [Br:1][C:2]1[C:3]([N:22]2[CH2:27][CH2:26][CH2:25][C@@H:24]([NH:28]C(=O)OC(C)(C)C)[CH2:23]2)=[C:4]2[C:10]([NH:11][C:12](=[O:21])[C:13]3[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[ClH:20].[NH2:28][C@@H:24]1[CH2:25][CH2:26][CH2:27][N:22]([C:3]2[C:2]([Br:1])=[CH:7][N:6]=[C:5]3[NH:8][CH:9]=[C:10]([NH:11][C:12](=[O:21])[C:13]4[CH:18]=[CH:17][C:16]([F:19])=[C:15]([Cl:20])[CH:14]=4)[C:4]=23)[CH2:23]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cl
Product: N[C@@H]1CCCN(c2c(Br)cnc3[nH]cc(NC(=O)c4ccc(F)c(Cl)c4)c23)C1
Yield: 163.9 %

Procedure:
A solution of (R)-tert-butyl 1-(5-bromo-3-(3-chloro-4-fluorobenzamido)-1H-pyrrolo[2,3-b]pyridin-4-yl)piperidin-3-ylcarbamate (110 mg, 0.194 mmol) in DCM (3 mL) was treated with TFA (1 mL) at room temperature for 1 hour. The mixture was then concentrated in vacuo. The resulting residue was dissolved in a minimal amount of DCM and added to a stirring solution of 1M HCl in ether. The solid obtained was filtered, washed with ether and dried to provide (R)-N-(4-(3-aminopiperidin-1-yl)-5-bromo-1H-pyrrolo[2,3-b]pyridin-3-yl)-3-chloro-4-fluorobenzamide hydrochloride (80 mg, 76% yield). 1H NMR (400 MHz, D2O) δ 8.22 (s, 1H), 7.97-7.94 (m, 1H), 7.80-7.77 (m, 1H), 7.38 (s, 1H), 7.32-7.28 (m, 1H), 3.54-3.52 (m, 1H), 3.32-3.30 (m, 1H), 3.25-3.21 (m, 1H), 3.18-3.10 (m, 2H), 1.88-1.80 (m, 1H), 1.68-1.63 (m, 1H), 1.50-1.33 (m, 2H); LCMS (APCI+) m/z 466, 486 (M+H)+.
Reaction SMILES: [H-].[Na+].[N:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[NH:9][CH2:10][CH2:11][CH2:12][NH2:13].[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19]Br)=[CH:17][CH:16]=1>CS(C)=O>[Br:14][C:15]1[CH:22]=[CH:21][C:18]([CH2:19][N:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][N:3]=2)[CH2:10][CH2:11][CH2:12][NH2:13])=[CH:17][CH:16]=1
Reactant: BrCc1ccc(Br)cc1
Reactant: NCCCNc1ccccn1
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: NCCCN(Cc1ccc(Br)cc1)c1ccccn1
Yield: 86.8 %

Procedure:
To a mixture of sodium hydride (5.86 g, 60 % dispersion in mineral oil, 0.1415 mol) in dry dimethylsulfoxide (250 ml) was slowly added a solution of N-(pyridin-2-yl)propane-1,3-diamine (20 g, 0.1323 mol) in dry dimethylsulfoxide (50 ml) at room temperature under an atmosphere of nitrogen. The reaction mixture was stirred until gas evolution was ceased. A solution of 4-bromobenzylbromide (36.09 g, 0.1415 mol) in dry dimethylsulfoxide (100 ml) was slowly added at room temperature. The reaction mixture was stirred for 48 h at room temperature. The reaction mixture was poured onto ice water (500 ml) and extracted with ethyl acetate (3×250 ml). The combined organic extracts were washed with water (3×150 ml), dried (MgSO4), filtered and the solvent evaporated in vacuo. The residue (40.56 g) was washed with n-heptane (30 ml) which afforded 36.77 g of crude N-(4-bromobenzyl)-N-(pyridin-2-yl)propane-1,3-diamine. 20 g crude product was purified by column chromatography on silica gel (900 ml) using dichloremethane/methanol/triethylamine 9:0.5:0.5 as eluent affording 13.75 g (70%) of N-(4-bromobenzyl)-N-(pyridin-2-yl)propane-1,3-diamine as an oil.
Reaction SMILES: N(C(OCC)=O)=NC(OCC)=O.[OH:13][C:14]1[CH:23]=[C:22]2[C:17]([C:18](=[O:32])[N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH:20]=[N:21]2)=[CH:16][C:15]=1[O:33][CH3:34].O[CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH3:34][O:33][C:15]1[CH:16]=[C:17]2[C:22](=[CH:23][C:14]=1[O:13][CH2:36][CH2:37][N:38]1[CH2:42][CH2:41][CH2:40][CH2:39]1)[N:21]=[CH:20][N:19]([CH2:24][O:25][C:26](=[O:31])[C:27]([CH3:28])([CH3:29])[CH3:30])[C:18]2=[O:32]
Reactant: OCCN1CCCC1
Reactant: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1cc2c(=O)n(COC(=O)C(C)(C)C)cnc2cc1OCCN1CCCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.5 %

Procedure:
Diethyl azodicarboxylate (566 mg, 3.25 mmol) was added dropwise to a solution of 7-hydroxy-6-methoxy-3-((pivaloyloxy)methyl)-3,4-dihydroquinazolin-4-one (765 mg, 2.5 mmol), (prepared as described for the starting material in Example 22), 1-(2-hydroxyethyl)pyrrolidine (374 mg, 3.25 mmol) and triphenylphosphine (851 mg, 3.25 mmol) in methylene chloride (15 ml). The mixture was stirred for 1 hour at ambient temperature and further triphenylphosphine (861 mg, 3.25 mmol) followed by diethyl azodicarboxylate (566 mg, 3.25 mmol) was added. The mixture was stirred for 1 hour at ambient temperature and the solvent was removed by evaporation. The residue was dissolved in ethyl acetate/ether and extracted with 2M hydrochloric acid. The aqueous layer was basified by addition of solid sodium hydrogen carbonate and extracted with methylene chloride. The combined extracts were dried (MgSO4), and the solvent removed by evaporation. The resulting oil was purified by column chromatography on neutral aluminium oxide eluting with methylene chloride/methanol (90/10 followed by 80/20) to give 6-methoxy-3-((pivaloyloxy)methyl)-7-(2-(pyrrolidin-1-yl)ethoxy)-3,4-dihydroquinazolin-4-one (550 mg, 55%).
Reaction SMILES: Br.[Br-].[N:3]1([CH2:8][CH2:9][CH2:10][P+](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH2:7][CH2:6][CH2:5][CH2:4]1.C([Li])CCC.[Br:35][C:36]1[CH:52]=[CH:51][C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][C:43]=3[C:44](=O)[C:38]=2[CH:37]=1.CS(C)=O>CCCCCC.O1CCCC1>[Br:35][C:36]1[CH:52]=[CH:51][C:39]2[O:40][CH2:41][C:42]3[CH:49]=[CH:48][C:47]([Br:50])=[CH:46][C:43]=3/[C:44](=[CH:10]/[CH2:9][CH2:8][N:3]3[CH2:4][CH2:5][CH2:6][CH2:7]3)/[C:38]=2[CH:37]=1
Reactant: O=C1c2cc(Br)ccc2COc2ccc(Br)cc21
Reactant: c1ccc([P+](CCCN2CCCC2)(c2ccccc2)c2ccccc2)cc1
Agent: Br
Agent: [Br-]
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Solvent: CS(C)=O
Product: Brc1ccc2c(c1)/C(=C/CCN1CCCC1)c1cc(Br)ccc1OC2

Procedure:
Anhydrous 3-(N-pyrrolidinyl)propyltriphenylphosphonium bromide hydrobromide (47 g, 0.08 mole), 0.20 mole of n-butyl lithium in hexane (1.6 M), and 2,9-dibromo-6,11-dihydrodibenz[b,e]oxepin-11-one (25 g, 0.07 mole) in one liter of dry tetrahydrofuran by the procedure of Example 1, Step a. The crude product was chromatographed on a silica gel column (Waters Associates - Prep 500) with ethyl acetate/methanol (95:5) to give the product as 98% pure Z-isomer (0.30 g), mp 102°-103° C. pmr (DMSO-d6) δ: 7.31-7.54 (m, 5H, aromatic H), 6.79 (d, J=7.8 Hz, H4 of 98% Z), 6.67 (d, J=7.8 Hz, H of 2% E), 6.11 (t, CH= of 2% E), 5.78 (t, CH= of 98% Z), 2.34-2.56 (m, 8H, CH2 and 3NHCH2), 1.63 (m, 4H, 2CH2). And it gave another batch of the product as 90% pure E-isomer (0.18 g), mp 115°-116° C., pmr (DMSO) δ: 7.71-7.68 (m, 5H, aromatic H), 6.80 (d, J=7.8 Hz, H4 of 10% Z), 6.70 (d, J=7.8 Hz, H4 of 90% E), 6.10 (t, CH= of 90% E), 5.81 (t, CH= of 10% Z), 2.26-2.40 (m, 8H, CH2 and 3NCH2), 1.60 (m, 4H, 2CH2).