Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15]O)[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].[CH3:18][C@H:19]1[CH2:24][CH2:23][CH2:22][CH2:21][NH:20]1.CCN(C(C)C)C(C)C.[I-].C(C[P+](C)(C)C)#N>>[C:1]([O:5][C:6](=[O:17])[NH:7][CH:8]1[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][N:20]2[CH2:21][CH2:22][CH2:23][CH2:24][C@@H:19]2[CH3:18])[CH2:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)NC1CCN(CCO)CC1
Reactant: C[C@H]1CCCCN1
Agent: C[P+](C)(C)CC#N
Agent: [I-]
Solvent: CCN(C(C)C)C(C)C
Product: C[C@H]1CCCCN1CCN1CCC(NC(=O)OC(C)(C)C)CC1

Procedure:
It is prepared analogously to 9 starting from tert-butyl ester 8 (2 g, 8.19 mmol), (S)-2-methyl-piperidine (0.985 ml, 8.19 mmol), DIEA (1.8 ml, 10.65 mmol) and cyanomethyl-trimethyl-phosphonium iodide (2.39 g, 9.83 mmol).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][C@H:14]([CH2:16][OH:17])[O:13][C:12]3=[O:18])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[CH2:19]([Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH3:31])[CH:24]=[CH:25][CH2:26]Cl)[CH2:20][CH2:21][CH3:22].[H-].[Na+].[CH3:38]N(C=O)C>>[CH2:19]([Sn:23]([CH2:32][CH2:33][CH2:34][CH3:35])([CH2:28][CH2:29][CH2:30][CH2:31][CH3:38])[CH:24]=[CH:25][CH2:26][O:17][CH2:16][CH:14]1[O:13][C:12](=[O:18])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:20][CH2:21][CH3:22]
Reactant: O=C1O[C@@H](CO)CN1c1ccc2c(c1)OCCO2
Reactant: CN(C)C=O
Reactant: CCCC[Sn](C=CCCl)(CCCC)CCCC
Agent: [H-]
Agent: [Na+]
Product: CCCCC[Sn](C=CCOCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1)(CCCC)CCCC
Temperature: 0 °C
Reaction time: 8 h
Yield: 53 %

Procedure:
A solution of rac-3-(2,3-dihydro-benzo[1,4]dioxin-6-yl)-5-hydroxymethyl-oxazolidin-2-one (prepared in analogy to Example 1, step 1.i; 0.852 g, 3.4 mmol) and tributyl-(3-chloro-propenyl)-stannane (prepared according to J. Org. Chem. (2000), 65, 7070; 1.2 g, 3.4 mmol) in DMF (20 mL) was cooled to 0° C. and a NaH dispersion (50% in mineral oil, 325 mg, 2 eq.) was added. The mixture was stirred at 0° C. for 30 min and at rt overnight. The volatiles were removed under reduced pressure and the residue partitioned between EA and water. The org. phase was washed with water, dried over MgSO4 and concentrated. The product was purified by FC (Hept/EA 2:1) to give a yellow oil (1.06 g, 53% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[S:9][C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])=[N:7][C:6]=1[CH3:24])=[O:4].O.[OH-].[Li+].CO>C1COCC1.O>[CH3:24][C:6]1[N:7]=[C:8]([CH2:10][CH2:11][C:12]2[C:13]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][N:19]=3)=[N:14][O:15][C:16]=2[CH3:17])[S:9][C:5]=1[C:3]([OH:4])=[O:2]
Reactant: COC(=O)c1sc(CCc2c(-c3ccccn3)noc2C)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: Cc1nc(CCc2c(-c3ccccn3)noc2C)sc1C(=O)O
Temperature: 25 °C
Reaction time: 4 h
Yield: 88 %

Procedure:
To a suspension of 4-methyl-2-[2-(5-methyl-3-pyridin-2-yl-isoxazol-4-yl)-ethyl]-thiazole-5-carboxylic acid methyl ester (1.62 g, 5.0 mmol) in THF (16 mL) was added a solution of lithium hydroxide monohydrate (396 mg, 9.0 mmol) in water (16 mL) followed by methanol (6 mL) and the resulting mixture stirred at room temperature for 4 h. The mixture was then evaporated to half volume and then acidified to pH 4 with HCl (1N) and cooled to 0° C. for 30 min. A solid precipitated and was filtered off and dried to afford the title compound (1.45 g, 93%) which was obtained as an off white solid. MS: m/e=328.3 [M−H]−.
Reaction SMILES: [C:1](Cl)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[NH2:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1>ClCCl>[C:1]([NH:9][C:10]1[CH:11]=[CH:12][C:13]2[O:18][CH2:17][CH2:16][N:15]([CH2:19][C:20]3[CH:29]=[CH:28][C:23]([C:24]([O:26][CH3:27])=[O:25])=[CH:22][C:21]=3[O:30][CH3:31])[C:14]=2[CH:32]=1)(=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCC(=O)Cl
Reactant: COC(=O)c1ccc(CN2CCOc3ccc(N)cc32)c(OC)c1
Solvent: ClCCl
Product: CCCCCC(=O)Nc1ccc2c(c1)N(Cc1ccc(C(=O)OC)cc1OC)CCO2
Reaction time: 1 h
Yield: 81.6 %

Procedure:
Hexanoyl chloride (0.084 g.) was added to a stirred solution of methyl 4-(6-amino-2,3-dihydrobenz-1,4-oxazin-4-ylmethyl)-3-methoxybenzoate (L) (0.2 g.) in dichloromethane (20 ml.), under an atmosphere of nitrogen. The mixture was stirred for one hour and then diluted with dichloromethane (40 ml.). This mixture was washed with water, dried (MgSO4) and evaporated. The residual oil was dissolved in 3:7 v/v ethyl acetate:hexane, and the solution obtained was allowed to filter through a short column of silica gel, washing with one column volume of the same solvent mixture. Evaporation of the column eluate gave the title compound (0.212 g., 82%), as a foam; NMR (250 MHz, CDCl3): 0.9(t,3H, CH2CH3), 1.3(m,4H, CH3.CH2.CH2), 1.6(m,2H, CH2.CH2.CON), 2.2(t,2H, CH2.CON), 3.35(t,2H, OCH2.CH2N), 3.9(br s,6H, OCH3 +CO.OCH3), 4.2 (t,2H, OCH2.CH2N), 4.5(s,2H, CH2 --Ar), 6.8(m,3H), 6.9(br s,1H, NH), 7.2(m,1H), 7.5(m, 2H).
Reaction SMILES: [CH3:1][NH:2][C:3](=[O:27])[C:4]1[CH:9]=[C:8]([O:10][C:11]2[CH:26]=[CH:25][C:14]3[N:15]=[C:16]([NH:18][C@H:19]4[CH2:24][CH2:23][CH2:22][NH:21][CH2:20]4)[S:17][C:13]=3[CH:12]=2)[CH:7]=[CH:6][N:5]=1.CCN(C(C)C)C(C)C.[N:37]([CH:40]([CH3:42])[CH3:41])=[C:38]=[O:39]>CN1C(=O)CCC1>[CH:40]([NH:37][C:38]([N:21]1[CH2:22][CH2:23][CH2:24][C@H:19]([NH:18][C:16]2[S:17][C:13]3[CH:12]=[C:11]([O:10][C:8]4[CH:7]=[CH:6][N:5]=[C:4]([C:3]([NH:2][CH3:1])=[O:27])[CH:9]=4)[CH:26]=[CH:25][C:14]=3[N:15]=2)[CH2:20]1)=[O:39])([CH3:42])[CH3:41]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCNC4)sc3c2)ccn1
Reactant: CC(C)N=C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN1CCCC1=O
Product: CNC(=O)c1cc(Oc2ccc3nc(N[C@H]4CCCN(C(=O)NC(C)C)C4)sc3c2)ccn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 40 %

Procedure:
To the solution of (S)—N-methyl-4-(2-(piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)picolinamide (13 mg, 30 μmol) and DIPEA (17 μL, 100 μmol) in 300 μL of NMP was added 2-isocyanatopropane (5 μL, 50 μmol). The reaction solution was stirred at room temperature for 18 hours. The crude reaction solution was purified on prep HPLC and evaporated in vacuo to give (S)-4-(2-(1-(isopropylcarbamoyl)piperidin-3-ylamino)benzo[d]thiazol-6-yloxy)-N-methylpicolinamide (5.9 mg, 12 μmol) as white powder. ES/MS m/z 469.2 (MH+).
Reaction SMILES: C([Si](C)(C)[O:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][C:25]=1[O:26][CH3:27])[C:10]([C:12]1[CH:13]=[CH:14][C:15]([Cl:22])=[C:16]([S:18]([NH2:21])(=[O:20])=[O:19])[CH:17]=1)=[O:11])(C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1>[Cl:22][C:15]1[CH:14]=[CH:13][C:12]([C:10](=[O:11])[C:9]2[CH:23]=[CH:24][C:25]([O:26][CH3:27])=[C:7]([OH:6])[CH:8]=2)=[CH:17][C:16]=1[S:18]([NH2:21])(=[O:20])=[O:19]
Reactant: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O[Si](C)(C)C(C)(C)C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COc1ccc(C(=O)c2ccc(Cl)c(S(N)(=O)=O)c2)cc1O
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 52.8 %

Procedure:
To a solution of 5-[3-(tert-butyl-dimethyl-silanyloxy)-4-methoxy-benzoyl]-2-chloro-benzenesulfonamide (0.28 g, 0.61 mmol) dissolved in tetrahydrofuran (20 mL) is added 1 M tetrabutylammonium fluoride (1.23 mL, 1.22 mmol) in tetrahydrofuran. The reaction mixture is stirred at room temperature for 30 minutes. The reaction is quenched with 1 N of HCl, and extracted with ethyl acetate three times. The combined organic extracts are washed with a saturated sodium chloride solution, dried with magnesium sulfate, and concentrated in vacuo. Recrystallization from ethyl acetate/methylene chloride provides 0.11 g (49%) of the title compound as a brown solid. 1H NMR (DMSO): δ 9.60 (s, 1H), 8.20 (d, J=2 Hz, 1H), 7.80 (m, 4H), 7.20 (m, 2H), 7.10 (d, J=8 Hz, 1H), 3.90 (s, 3H). Analytics calculated for C14H12ClNO5S: C, 49.20; H, 3.54; N, 4.10. Found: C, 49.90; H, 3.30; N, 5.06. MS (m/z): 342 (M+1).
Reaction SMILES: [CH:1]1([NH:7][CH:8]2[CH2:12][CH:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[CH:10]([CH2:19][N:20]3[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[CH2:22][CH2:21]3)[CH2:9]2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[C:36](OC(=O)C)(=[O:38])[CH3:37].N1C=CC=CC=1>C(Cl)Cl>[C:36]([N:7]([CH:8]1[CH2:12][CH:11]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:10]([CH2:19][N:20]2[CH2:25][CH2:24][C:23]([OH:35])([CH2:26][CH2:27][CH2:28][C:29]3[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=3)[CH2:22][CH2:21]2)[CH2:9]1)[CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)(=[O:38])[CH3:37]
Reactant: OC1(CCCc2ccccc2)CCN(CC2CC(NC3CCCCC3)CC2c2ccccc2)CC1
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)N(C1CCCCC1)C1CC(CN2CCC(O)(CCCc3ccccc3)CC2)C(c2ccccc2)C1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-(RS and SR)-(cyclohexylamino)-3-(SR)-((4-hydroxy-4-(3-phenylprop-1-yl)piperidin-1-yl)methyl)-4-(SR)-phenylcyclopentane (prepared as in Example 43A) in methylene chloride (2 mL) was added acetic anhydride (0.17 mL, 1.67 mmol) and pyridine (0.17 mL, 2 mmol). The reaction was stirred at rt for 16 h. It was then diluted with methylene chloride and quenched with 1N NaOH. The mixture was washed with 1N NaOH and brine, dried over sodium sulfate and evaporated to dryness. The sample was purified by HPLC and the fractions containing the title compound by HPLC/MS were combined and evaporated.
Reaction SMILES: [NH2:1][C:2]1[C:6]([C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[N:4]([CH3:20])[N:3]=1.C(N(CC)CC)C.[C:28]1([CH2:34][C:35](Cl)=[O:36])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1.O>O1CCCC1>[F:19][C:16]1[CH:17]=[CH:18][C:13]([C:5]2[N:4]([CH3:20])[N:3]=[C:2]([NH:1][C:35](=[O:36])[CH2:34][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[C:6]=2[C:7]2[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=2)=[CH:14][CH:15]=1
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cn1nc(N)c(-c2ccncc2)c1-c1ccc(F)cc1
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: Cn1nc(NC(=O)Cc2ccccc2)c(-c2ccncc2)c1-c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.7 %

Procedure:
338 mg of 3-amino-5-(4-fluorophenyl)-1-methyl-4-(4-pyridyl)pyrazole was dissolved in 20 ml of a tetrahydrofuran, followed by the addition of 140 mg of triethylamine. Then, 5 ml of a tetrahydrofuran solution containing 214 mg of phenylacetyl chloride was added dropwise thereto, followed by stirring at room temperature overnight. After the addition of water, the reaction mixture was extracted with chloroform. After the organic layer was washed with water and dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography using 80 g of silica gel [with an elution solvent comprising chloroform-methanol (40:1)]. Thus, 310 mg (64% yield) of the title compound was obtained as pale-yellow crystals.
Reaction SMILES: O1CCCC1.O1CCCC1.C([N-]C(C)C)(C)C.[Li+].[C:19]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])(=[O:21])[CH3:20].[O:27]1[CH2:31][CH:30]=[CH:29][C:28]1=[O:32]>O>[C:23]([O:22][C:19](=[O:21])[CH2:20][CH:30]1[CH2:29][C:28](=[O:32])[O:27][CH2:31]1)([CH3:26])([CH3:25])[CH3:24]
Reactant: O=C1C=CCO1
Reactant: CC(=O)OC(C)(C)C
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)CC1COC(=O)C1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 72 %

Procedure:
Tetrahydrofuran (50 mL) and Lithium diisopropylamide mono tetrahydrofuran complex (20 mL of 1.5 M in cyclohexane) was cooled in a dry ice/Isopropanol bath for 10 min. Tert-butyl acetate (3.5 mL 26 mmoles) was added via syringe and stirred at −78° C. for 30 min. 2(5H)-Furanone (1.59 g, 19 mmoles) was added dropwise and the reaction was stirred for 1 h at −78° C. The reaction was poured into water and extracted with ether 2×150 mL The ether extracts were combined and washed with water 100 mL then brine 3×100 mL, dried and the ether removed under reduced pressure to give 2.74 g of product (72%). MS (ESI+) for C10H16O4 m/z 223 (M+Na)+.
Reaction SMILES: [NH2:1][CH:2]([C:8]([O:10]CC)=O)[C:3]([O:5]CC)=O.[NH2:13][CH2:14][CH2:15][NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20].[OH2:24]>C(Cl)(Cl)Cl>[NH2:1][CH:2]([C:3](=[O:5])[NH:13][CH2:14][CH2:15][NH:16][C:17]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:24])[C:8](=[O:10])[NH:13][CH2:14][CH2:15][NH:16][C:17]([O:18][C:19]([CH3:20])([CH3:22])[CH3:21])=[O:23]
Reactant: CCOC(=O)C(N)C(=O)OCC
Reactant: CC(C)(C)OC(=O)NCCN
Reactant: O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)NCCNC(=O)C(N)C(=O)NCCNC(=O)OC(C)(C)C
Reaction time: 7 h

Procedure:
A solution of diethyl 2-aminomalonate (1.68 g) and tert-butyl (2-aminoethyl)carbamate (3.20 g) in dehydrated chloroform (5 ml) was stirred under reflux. After 7 hours, additional tert-butyl (2-aminoethyl)carbamate (3.20 g) was added to the reaction mixture, and the mixture was stirred under reflux for 2 days. To the reaction mixture was added water, and the solution was washed with a mixed solvent of hexane and diisopropyl ether (1:1). The aqueous layer was extracted with methylene chloride. The organic layer was washed with water and extracted with 5% aqueous citric acid solution. The aqueous layer was washed with diethyl ether and basified with sodium hydroxide. The aqueous solution was extracted with methylene chloride. The organic layer was washed with brine, dried over anhydrous sodium sulfate, filtered and concentrated in vacuo. The residue was triturated with a mixed solvent of diisopropyl ether and diethyl ether to give di-tert-butyl 7-amino-6,8-dioxo-2,5,9,12-tetraazatridecanedioate (1.87 g) as a solid.
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]1[CH2:11][CH:10]2[N:12]([CH3:13])[CH:6]([CH2:7][CH2:8][CH2:9]2)[CH2:5]1.[C:14]1([C:20]2[O:21][C:22]3[C:23](=[C:25]([C:29](O)=[O:30])[CH:26]=[CH:27][CH:28]=3)[N:24]=2)[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>>[CH3:13][N:12]1[CH:6]2[CH2:7][CH2:8][CH2:9][CH:10]1[CH2:11][CH:4]([NH:3][C:29]([C:25]1[CH:26]=[CH:27][CH:28]=[C:22]3[O:21][C:20]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)=[N:24][C:23]=13)=[O:30])[CH2:5]2
Reactant: O=C(O)c1cccc2oc(-c3ccccc3)nc12
Reactant: CN1C2CCCC1CC(N)C2
Agent: Cl
Product: CN1C2CCCC1CC(NC(=O)c1cccc3oc(-c4ccccc4)nc13)C2
Yield: 40 %

Procedure:
N-(9-Methyl-9-azabicyclo[3.3.1]non-3-yl)-2-phenylbenzoxazole-4-carboxamide was prepared from 3-amino-9-methyl-9-azabicyclo[3.3.1]nonane dihydrochloride and 2-phenylbenzoxazole-4-carboxylic acid using conditions similar to those described for Step C in Example 1. This compound was obtained in 40% yield as a white solid; mp 182-185° C.; 1H NMR (300 MHz, CDCl3) δ 9.18 (d, J=6.5 Hz, 1H), 8.25 (m, 2H), 8.19 (dd, J=7.8, 0.9 Hz, 1H), 7.72 (dd, J=8.1, 1.0 Hz, 1H), 7.55-7.65 (m, 3H), 7.47 (t, J=8.0 Hz, 1H), 4.71-4.58 (m, 1H), 3.30 (m, 2H), 2.76 (m, 2H), 2.69 (s, 3H), 2.38-1.33 (m, 8H); MS (APCI) m/z 376 [M+H]+
Reaction SMILES: [C:1]1(=O)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH2:8]([NH:11][CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]>ClCCl>[CH2:8]([N:11]([CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[CH2:12][CH2:13][CH3:14])[CH2:9][CH3:10]
Reactant: O=C1CCCCC1
Reactant: CCCNCCC
Solvent: ClCCl
Product: CCCN(CCC)C1CCCCC1

Procedure:
Cyclohexanone (0.415 cm3, 4.0 mmol), di-n-propylamine (0.548 cm3, 4.0 mmol) and [Ir(COD)(dppb)][PF6] (0.070 g, 2 mol %) were reacted in dichloromethane at 20° C. for 24 hrs, at approx. 1 bar H2. The yield of N,N-di-n-propylcyclohexylamine obtained was 43.5%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=O)[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].[C:18]1([S:24]([O-:26])=[O:25])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.[C:27](=[O:34])([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[NH2:28].C(O)=O>C1COCC1.O>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]([NH:28][C:27](=[O:34])[O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[S:24]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)(=[O:26])=[O:25])[CH:12]=[N:13][CH:14]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(N)=O
Reactant: O=S([O-])c1ccccc1
Reactant: O=Cc1cncc(OCc2ccccc2)c1
Agent: [Na+]
Solvent: O=CO
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(c1cncc(OCc2ccccc2)c1)S(=O)(=O)c1ccccc1
Reaction time: 96 h

Procedure:
To 5-(Benzyloxy)pyridine-3-carbaldehyde (3.61 g, 16.9 mmol, Harrowven, D. C. et all Tetrahedron, 2001 57 p. 4447-4454) and benzenesulfinic acid sodium salt (2.7 g, 16.6 mmol) in THF (16.3 mL) was added water (36.3 mL), tert-butyl carbamate (1.94 g, 16.6 mmol) and formic acid (1.9 mL, 49 mmol). The mixture was stirred for 4 day and filtrated. The filtrate was stirred for 2 additional days and filtrated again. The formed precipitates were washed with water and triturated in hexane containing 9% dichloromethane. After filtration the solids were dried in vacuum to yield 3.17 g of tert-butyl {[5-(benzyloxy)pyridin-3-yl](phenylsulfonyl)methyl}carbamate.
Reaction SMILES: [NH2:1][CH:2]([C:10]1[C:15]([O:16][CH3:17])=[CH:14][CH:13]=[CH:12][C:11]=1[O:18][CH3:19])[CH2:3][CH2:4][CH2:5][C:6]([O:8]C)=O.[CH3:20][C:21]1[S:22][C:23]2[CH:29]=[C:28]([CH:30]=O)[CH:27]=[CH:26][C:24]=2[N:25]=1>>[CH3:19][O:18][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([O:16][CH3:17])[C:10]=1[CH:2]1[N:1]([CH2:30][C:28]2[CH:27]=[CH:26][C:24]3[N:25]=[C:21]([CH3:20])[S:22][C:23]=3[CH:29]=2)[C:6](=[O:8])[CH2:5][CH2:4][CH2:3]1
Reactant: Cc1nc2ccc(C=O)cc2s1
Reactant: COC(=O)CCCC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CCCC(=O)N1Cc1ccc2nc(C)sc2c1

Procedure:
Prepared according to the described general procedure 1 (GP1) by reaction of methyl 5-amino-5-(2,6-dimethoxyphenyl)pentanoate with 2-methylbenzo[d]thiazole-6-carbaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.77 min.; [M+H]+: 397.01 g/mol.
Reaction SMILES: [NH2:1][CH2:2][CH:3]1[CH2:15][CH2:14][C:13]2[C:12]3[C:7](=[C:8]([C:17]([NH2:19])=[O:18])[CH:9]=[CH:10][C:11]=3[Br:16])[NH:6][C:5]=2[CH2:4]1.[Br:20][CH2:21][CH2:22][CH2:23][C:24](Cl)=[O:25]>C1COCC1.C(Cl)Cl>[Br:16][C:11]1[CH:10]=[CH:9][C:8]([C:17]([NH2:19])=[O:18])=[C:7]2[C:12]=1[C:13]1[CH2:14][CH2:15][CH:3]([CH2:2][NH:1][C:24](=[O:25])[CH2:23][CH2:22][CH2:21][Br:20])[CH2:4][C:5]=1[NH:6]2
Reactant: NCC1CCc2c([nH]c3c(C(N)=O)ccc(Br)c23)C1
Reactant: O=C(Cl)CCCBr
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1ccc(Br)c2c3c([nH]c12)CC(CNC(=O)CCCBr)CC3
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 42.1 %

Procedure:
Step 4 A suspension of 2-(aminomethyl)-5-bromo-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide (130 mg, 0.403 mmol) and TEA (0.067 mL, 0.484 mmol) in THF (2 mL) was treated with 4-bromobutanoyl chloride (74.8 mg, 0.403 mmol). The mixture was stirred at rt for 20 min, diluted with DCM, washed with NaHCO3 (aq), dried and concentrated. The residue was purified by column chromatography (eluting with EtOAc) to provide 5-bromo-2-((4-bromobutanamido)methyl)-2,3,4,9-tetrahydro-1H-carbazole-8-carboxamide as a white solid (80 mg, 42%). Mass spectrum m/z 470, 472, 474 (M+H)+.
Reaction SMILES: [CH:1]([C:4]1[CH:9]=[CH:8][C:7](B(O)O)=[CH:6][CH:5]=1)([CH3:3])[CH3:2].Br[C:14]1[S:18][C:17]([S:19]([N:22]2[CH:26]=[CH:25][CH:24]=[CH:23]2)(=[O:21])=[O:20])=[CH:16][CH:15]=1>>[CH:1]([C:4]1[CH:9]=[CH:8][C:7]([C:14]2[S:18][C:17]([S:19]([N:22]3[CH:26]=[CH:25][CH:24]=[CH:23]3)(=[O:20])=[O:21])=[CH:16][CH:15]=2)=[CH:6][CH:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1ccc(B(O)O)cc1
Reactant: O=S(=O)(c1ccc(Br)s1)n1cccc1
Product: CC(C)c1ccc(-c2ccc(S(=O)(=O)n3cccc3)s2)cc1
Yield: 84 %

Procedure:
N-[5-(4-isopropylphenyl)thiophene-2-sulfonyl]pyrrole was prepared in the same manner as described in Example 33C, from 4-isopropylphenyl boronic acid and N-(5-bromothiophene sulfonyl)-pyrrole. Purification by column chromatography using 10% ethyl acetate/hexanes gave the pure sulfonamide as an off white colored solid in 84% yield, m.p. 112-114° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH:9][C@@H:10]2[C:18](=[O:19])[N:17]3[C@H:12]([CH2:13][CH2:14][C@@H:15]([NH:20][C:21]4[C:22]5[CH:29]=[CH:28][N:27](S(C6C=CC(C)=CC=6)(=O)=O)[C:23]=5[N:24]=[CH:25][N:26]=4)[CH2:16]3)[CH2:11]2)[CH:5]=[C:6]([F:8])[CH:7]=1.C([O-])([O-])=O.[K+].[K+]>CO.O>[N:24]1[C:23]2[NH:27][CH:28]=[CH:29][C:22]=2[C:21]([NH:20][C@@H:15]2[CH2:14][CH2:13][C@H:12]3[N:17]([C:18](=[O:19])[C@@H:10]([NH:9][C:4]4[CH:5]=[C:6]([F:8])[CH:7]=[C:2]([Cl:1])[CH:3]=4)[CH2:11]3)[CH2:16]2)=[N:26][CH:25]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(N[C@@H]4CC[C@@H]5C[C@H](Nc6cc(F)cc(Cl)c6)C(=O)N5C4)ncnc32)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: O=C1[C@@H](Nc2cc(F)cc(Cl)c2)C[C@H]2CC[C@@H](Nc3ncnc4[nH]ccc34)CN12
Temperature: 70 °C
Yield: 50.5 %

Procedure:
A solution of (2S,6R,8aR)-2-(3-chloro-5-fluorophenylamino)-6-(7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)hexahydroindolizin-3(5H)-one (19 mg) 127.6 in MeOH (0.5 mL) & H2O (2 mL) was treated with of K2CO3 (5 mg, 0.033 mmol) and heated at 70° C. for 24 hours. The white suspension was cooled and diluted with H2O. The precipitate was collected on a Whatman 0.45 um nylon membrane filter and concentrated in vacuo to afford of (2S,6R,8aR)-6-(7H-pyrrolo[2,3-d]pyrimidin-4-ylamino)-2-(3-chloro-5-fluorophenylamino)hexahydroindolizin-3(5H)-one 127.7 (7 mg) as a white solid that exists as 3:1 mixture of diasteromers. LCMS (ESI) m/z: 415.2 [M+H]+.
Reaction SMILES: [CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[CH:4]([OH:8])[C:5]([OH:7])=[O:6].O=C(C([O-])=O)[C:16]([O:18][CH2:19][CH3:20])=[O:17].[C:24]1(C)C=CC(C)=C[CH:25]=1>>[CH3:1][C:2]1[CH:12]=[CH:11][C:10]([CH3:13])=[CH:9][C:3]=1[C:4]([OH:8])([C:16]([O:18][CH2:19][CH3:20])=[O:17])[C:5]([O:7][CH2:24][CH3:25])=[O:6]
Reactant: Cc1ccc(C)c(C(O)C(=O)O)c1
Reactant: CCOC(=O)C(=O)C(=O)[O-]
Reactant: Cc1ccc(C)cc1
Product: CCOC(=O)C(O)(C(=O)OCC)c1cc(C)ccc1C
Temperature: 25 °C
Reaction time: 3 h

Procedure:
The method used to prepare 2.5-dimethylmandelic acid was similar to that described by Riebsomer and Irvine (Org. Synth., Coll. Vol.3, p.327). Thus, ethyl oxomalonate (25 parts) in para-xylene (38 parts) was stirred at 0°-5° C. under a nitrogen atmosphere as anhydrous stannic chloride (46 parts) was charged over 20 minutes. The mixture was kept mobile by addition of further para-xylene (43 parts) and allowed to warm to ambient temperature. After 3 hours stirring, the mixture was quenched on a mixture of ice and 10M hydrochloric acid and extracted into diethyl ether. The separated organic phase was washed with water, dried over magnesium sulfate, filtered and the solvent was evaporated under reduced pressure. The crude brown oil (31 parts) was then distilled under vacuum to give diethyl (2,5-dimethylphenyl)-hydroxymalonate (26 parts). 1 Hnmr, 13Cnmr and mass spectra and micro-analysis were all consistent with the structure.
Reaction SMILES: C(NC(C)C)(C)C.[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]#[C:18][Si:19]([CH3:22])([CH3:21])[CH3:20])=[C:14]([OH:16])[CH:15]=1.[CH3:23][Si:24]([CH3:31])([CH3:30])[CH2:25][CH2:26][O:27][CH2:28]Cl.Cl>C(Cl)Cl.O>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([C:17]#[C:18][Si:19]([CH3:20])([CH3:22])[CH3:21])=[C:14]([O:16][CH2:28][O:27][CH2:26][CH2:25][Si:24]([CH3:31])([CH3:30])[CH3:23])[CH:15]=1
Reactant: C[Si](C)(C)CCOCCl
Reactant: COc1ccc(C#C[Si](C)(C)C)c(O)c1
Agent: Cl
Solvent: O
Solvent: ClCCl
Solvent: CC(C)NC(C)C
Product: COc1ccc(C#C[Si](C)(C)C)c(OCOCC[Si](C)(C)C)c1
Yield: 73.8 %

Procedure:
Add diisopropylamine (11.0 mL, 78.3 mmol) to a rapidly stirred solution of 5-methoxy-2-trimethylsilanylethynyl-phenol (11.5 g, 52.2 mmol) in CH2Cl2 at room temperature under N2. Add 2-(trimethylsilyl)ethoxymethyl chloride (13.9 mL, 78.3 mmol) dropwise over 5 minutes and stir at room temperature under N2 overnight Acidify with aqueous 1N HCl solution, add water, separate layers. Extract from aqueous layer with CH2Cl2 (×2), dry combined organic layers over MgSO4 and concentrate. Adsorb on SiO2 and purify the residue by flash chromatography on silica gel eluting with 0-5% EtOAc/hexanes to afford 4-methoxy-2-(2-trimethylsilanyl-ethoxymethoxy)-1-trimethylsilanylethynyl-benzene (13.5 g, 74%). MS (IS) 351 (M+1)+.