Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O[C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1)C.O.[OH-].[Li+].[Cl-].[NH4+].C1C=CC2N(O)N=[N:56]C=2C=1.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C1COCC1.O.CO>[NH2:56][C:4](=[O:44])[CH2:5][C:6]1[C:7]([CH2:12][CH2:13][C:14]2[C:19]([C:20]([F:21])([F:23])[F:22])=[CH:18][N:17]=[C:16]([NH:24][C:25]3[CH:30]=[CH:29][C:28]([CH:31]4[CH2:32][CH2:33][N:34]([C:37]([O:39][C:40]([CH3:42])([CH3:43])[CH3:41])=[O:38])[CH2:35][CH2:36]4)=[CH:27][CH:26]=3)[N:15]=2)=[N:8][CH:9]=[CH:10][N:11]=1
Reactant: On1nnc2ccccc21
Reactant: CCOC(=O)Cc1nccnc1CCc1nc(Nc2ccc(C3CCN(C(=O)OC(C)(C)C)CC3)cc2)ncc1C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Agent: [Cl-]
Agent: [Li+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCC(c2ccc(Nc3ncc(C(F)(F)F)c(CCc4nccnc4CC(N)=O)n3)cc2)CC1
Temperature: 25 °C
Reaction time: 17 h
Yield: 49 %

Procedure:
tert-Butyl 4-(4-((4-(2-(3-(2-ethoxy-2-oxoethyl)pyrazin-2-yl)ethyl)-5-(trifluoromethyl)pyrimidin-2-yl)amino)phenyl)piperidine-1-carboxylate (I103) (142 mg, 0.231 mmol) was dissolved in THF (10 mL) and methanol (5 mL) then a solution of lithium hydroxide monohydrate (48.0 mg, 1.16 mmol) in water (2.5 mL) was added. The mixture was stirred at room temperature for 17 hours, and then concentrated. The residue was evaporated twice from toluene then dissolved in DMF (20 mL) and ammonium chloride (62 mg, 1.2 mmol), HOBt (47 mg, 0.35 mmol), PyBOP (181 mg, 0.347 mmol) and DIPEA (0.161 mL, 0.924 mmol) were added. After two hours the mixture was quenched with water (1 mL), concentrated and the residue partitioned between 1:3 saturated brine:water (30 mL) and ethyl acetate (20 mL). The aqueous phase was washed with ethyl acetate (3×20 mL) then the combined ethyl acetate phases were washed with brine (50 mL), dried (sodium sulfate) and evaporated. The residue was chromatographed (12 g silica cartridge, 20-100% ethyl acetate/petroleum benzine 40-60° C. then 100% ethyl acetate for 10 column volumes) to give the title compound (I104) (66.2 mg, 49% yield) as a colourless syrup; 1H NMR (400 MHz, d4-MeOD) δ 8.40 (d, J=0.6 Hz, 1H), 8.29 (d, J=2.6 Hz, 1H), 8.24 (d, J=2.5 Hz, 1H), 7.40 (d, J=8.3 Hz, 2H), 7.09-7.01 (m, 2H), 4.10 (d, J=13.3 Hz, 2H), 3.81-3.75 (m, 2H), 3.34-3.23 (m, 4H), 2.76 (br s), 2.58 (tt, J=12.0, 3.4 Hz, 1H), 1.71 (d, J=12.2 Hz, 2H), 1.47 (ddd, J=25.5, 12.8, 4.3 Hz, 2H), 1.38 (s, 9H). LCMS Method C: 6.17 min; m/z 586.1 [M+H]+, 530.1 [M-tBu+2H]+, 486.1 [M-Boc+2H]+; m/z 584.2 [M−H]−.
Reaction SMILES: [NH2:1][C@H:2](CO)CCC1C=CC([NH-])=CC=1.[NH2:14][C@H:15]([CH2:35][OH:36])[CH2:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([N:24]([CH3:34])[C:25](=[O:33])[C:26]2[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=2)=[CH:20][CH:19]=1.C([O-])(=O)C.[Na+].N#CBr.N>CO>[NH2:1][C:2]1[O:36][CH2:35][C@H:15]([CH2:16][CH2:17][C:18]2[CH:19]=[CH:20][C:21]([N:24]([CH3:34])[C:25](=[O:33])[C:26]3[CH:31]=[CH:30][C:29]([Cl:32])=[CH:28][CH:27]=3)=[CH:22][CH:23]=2)[N:14]=1
Reactant: CN(C(=O)c1ccc(Cl)cc1)c1ccc(CC[C@H](N)CO)cc1
Reactant: [NH-]c1ccc(CC[C@H](N)CO)cc1
Agent: CC(=O)[O-]
Agent: N
Agent: N#CBr
Solvent: CO
Product: CN(C(=O)c1ccc(Cl)cc1)c1ccc(CC[C@H]2COC(N)=N2)cc1
Temperature: 25 °C
Reaction time: 36 h
Yield: 15.1 %

Procedure:
N-[4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-4-chloro-N-methyl-benzamide [4-((S)-3-amino-4-hydroxy-butyl)-phenyl]-amide (95 mg) was dissolved in methanol (3 ml) at room temperature before addition of sodium acetate (69.9 mg) and a solution of cyanogen bromide (39.1 mg) in methanol (1 ml) dropwise. The reaction mixture was stirred at room temperature for 36 hours, then aqueous ammonia 25% was added (214.5 μl) and stirring was continued for an another hour. The solvent was evaporated in vacuo and the residue purified by preparative HPLC to give N-{4-[2-((S)-2-amino-4,5-dihydro-oxazol-4-yl)-ethyl]-phenyl}-4-chloro-N-methyl-benzamide (10 mg) as a light yellow foam. Description. MS (ISP): 316.2 ([M+H]+).
Reaction SMILES: [C:1]1([CH3:9])[CH:6]=[CH:5][C:4]([S:7][CH3:8])=[CH:3][CH:2]=1.[Cl:10]N1C(=O)CCC1=O>ClC1C=CC=CC=1>[Cl:10][CH2:8][S:7][C:4]1[CH:5]=[CH:6][C:1]([CH3:9])=[CH:2][CH:3]=1
Reactant: CSc1ccc(C)cc1
Reactant: O=C1CCC(=O)N1Cl
Solvent: Clc1ccccc1
Product: Cc1ccc(SCCl)cc1
Yield: 109.7 %

Procedure:
Methyl p-tolyl sulfide (75 g, 542.27 mmol) was diluted in chorobenzene (452 mL). N-Chloro Succinimide (NCS) (76.07 g, 1.05 eq) was added in small portions maintaining the temperature between 35° C. and 45° C., under an argon atmosphere. The reaction mixture was stirred within the same temperature range until the reaction was complete. Thereafter, a solid separated out from the solution. The suspension was filtered, and the solid washed with chlorobenzene (50 ml). The filtrate was washed with water (3×225 mL). The resulting organic phase was dried with anhydrous magnesium sulfate and concentrated. The crude product was purified by distillation to give 102.68 g (100%) of the desired product as yellow oil (bp: 96° C. at 40 Pa).
Reaction SMILES: Cl.Cl.[N:3]12[CH2:10][CH2:9][CH:6]([CH2:7][CH2:8]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH2:23])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2.C(N(CC)CC)C.[O:31]1[CH:35]=[CH:34][CH:33]=[C:32]1[C:36]([Cl:38])=[O:37]>CN(C=O)C>[ClH:38].[N:3]12[CH2:8][CH2:7][CH:6]([CH2:9][CH2:10]1)[C@@H:5]([NH:11][C:12]([C:14]1[S:15][C:16]3[CH:22]=[CH:21][C:20]([NH:23][C:36]([C:32]4[O:31][CH:35]=[CH:34][CH:33]=4)=[O:37])=[CH:19][C:17]=3[CH:18]=1)=[O:13])[CH2:4]2
Reactant: O=C(Cl)c1ccco1
Reactant: Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc2sc(C(=O)N[C@H]3CN4CCC3CC4)cc2c1)c1ccco1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
30 mg (0.08 mmol) of N-[(3R)-1-azabicyclo[2.2.2]oct-3-yl]-5-amino-1-benzo-thiophene-2-carboxamide dihydrochloride are dissolved in 1 ml of DMF, and 33.5 μl (0.24 mmol) of triethylamine are added. At 0° C., 15.7 mg (0.12 mmol) of furan-2-carbonyl chloride are added. After 3 h of stirring at RT, the reaction mixture is separated by preparative HPLC. The product fraction is concentrated under reduced pressure and codistilled with 4M HCl in dioxane. 12 mg (34.7% of theory) of the title compound are obtained.
Reaction SMILES: [C:1]([OH:11])(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[CH:12]1[CH:17]=[C:16](O)[C:15]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1.[Na+:23].C(O)(C(F)(F)F)=O.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>>[C:1]([O:11][C:12]1[CH:17]=[CH:16][C:15]([S:19]([O-:22])(=[O:21])=[O:20])=[CH:14][CH:13]=1)(=[O:10])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].[Na+:23]
Reactant: O=S(=O)([O-])c1ccccc1O
Reactant: CCCCCCCCC(=O)O
Agent: [Na+]
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCCC(=O)Oc1ccc(S(=O)(=O)[O-])cc1
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
A 300 ml, round-bottom flask with a nitrogen inlet and a magnetic stir bar was flushed with nitrogen for ten minutes. Nonanoic acid (4.45 g, 28.0 millimoles—mmol), sodium phenolsulfonate (5.00 g, 25.0 mmol) and TFA were placed in the flask which was sealed with a septum cap and the resulting slurry was stirred while being cooled by an ice-water bath. A single rapid addition of TFAA (6.5 ml) was made via syringe. Within one minute the slurry is dissolved to yield a homogeneous solution. The stirring was continued for five minutes. The volatiles were removed by rotary evaporation yielding a white solid that was washed with 100 ml of acetone and collected on a Buchner funnel. The resulting white solid was dried under reduced pressure yielding 7.90 g (94% yield) of sodium 4-(nonanoyloxy)benzene-sulfonate (NOBS). 1H and 13C NMR show complete conversion of the SPS to NOBS.
Reaction SMILES: [CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[NH:12][N:13]=3)[C:4]=2[CH:3]=1.[H-].[Na+].[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38]Cl>CN(C)C=O.C1(C)C(C)=CC=CC=1>[CH3:1][C:2]1[C:30]([CH3:31])=[CH:29][C:5]2[N:6]([C:19](=[O:28])[CH2:20][N:21]([CH2:25][CH2:26][CH3:27])[CH2:22][CH2:23][CH3:24])[C:7]3[N:18]=[CH:17][CH:16]=[CH:15][C:8]=3[C:9]3[N:10]([C:11](=[O:14])[N:12]([CH2:38][CH2:37][CH2:36][N:35]([CH3:40])[CH3:34])[N:13]=3)[C:4]=2[CH:3]=1
Reactant: CN(C)CCCCl
Reactant: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(n[nH]c2=O)-c2cccnc21
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1C
Solvent: CN(C)C=O
Product: CCCN(CCC)CC(=O)N1c2cc(C)c(C)cc2-n2c(nn(CCCN(C)C)c2=O)-c2cccnc21
Reaction time: 22 h

Procedure:
In the manner given in Example 25, to 6,7-dimethyl-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a]-[1,5]benzodiazepin-3-one in dimethylformamide is added a solution of sodium hydride in mineral oil. The mixture is allowed to react at about 95° C. for 40 minutes and after cooling 3-(dimethylamino)propylchloride in xylene is added. The mixture is kept at 95°-100° C. for a period of 22 hours, evaporated and worked up as in example 21 to give 6,7-dimethyl-2,9-dihydro-2-[3-(dimethylamino)-propyl]-9-[(dipropylamino)acetyl]-3H-pyrido[3,2-c]-s-triazolo[4,3-a][1,5]benzodiazepine-3-one.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([OH:16])=O)=[C:12]([F:19])[CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:20][N:21]1[C:30]2[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]=3[NH:26][CH2:25][C:24]=2[CH:23]=[N:22]1.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>ClCCl>[C:1]([O:5][C:6](=[O:7])[NH:8][CH2:9][C:10]1[CH:18]=[CH:17][C:13]([C:14]([N:26]2[CH2:25][C:24]3[CH:23]=[N:22][N:21]([CH3:20])[C:30]=3[NH:29][C:28]3[CH:31]=[CH:32][CH:33]=[CH:34][C:27]2=3)=[O:16])=[C:12]([F:19])[CH:11]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cn1ncc2c1Nc1ccccc1NC2
Reactant: CC(C)(C)OC(=O)NCc1ccc(C(=O)O)c(F)c1
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc2c1Nc1ccccc1N(C(=O)c1ccc(CNC(=O)OC(C)(C)C)cc1F)C2
Temperature: 25 °C
Yield: 56 %

Procedure:
A mixture of 4-(tert-butoxycarbonylamino-methyl)-2-fluoro-benzoic acid from Example E2 (1.35 g, 5.0 mmol), 3-methyl-3,4,9,10-tetrahydro-2,3,4,9-tetraaza-benzo[f]azulene from Example E11 (11.0 g, 5.0 mmol) and PyBroP (3.03 g, 6.5 mmol) in dichloromethane (25 ml) and DIEA (1.31 ml, 7.5 mmol) was heated at reflux for 18 h. After cooling to room temperature, the mixture was washed with 5% KHCO3, 1M HCl then brine, dried and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (eluant; EtOAc) to yield the title compound (1.25 g, 56%).
Reaction SMILES: [N:1]([CH2:4][C:5]1[N:6]=[C:7]([N:10]2[CH2:13][CH:12]([O:14][Si:15]([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[CH2:11]2)[S:8][CH:9]=1)=[N+]=[N-].[C:32]1([S:38](Cl)(=[O:40])=[O:39])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1.C(N(CC)CC)C>CO.[OH-].[Pd+2].[OH-]>[Si:15]([O:14][CH:12]1[CH2:13][N:10]([C:7]2[S:8][CH:9]=[C:5]([CH2:4][NH:1][S:38]([C:32]3[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=3)(=[O:40])=[O:39])[N:6]=2)[CH2:11]1)([C:28]([CH3:31])([CH3:30])[CH3:29])([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)[Si](OC1CN(c2nc(CN=[N+]=[N-])cs2)C1)(c1ccccc1)c1ccccc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCN(CC)CC
Solvent: CO
Product: CC(C)(C)[Si](OC1CN(c2nc(CNS(=O)(=O)c3ccccc3)cs2)C1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 28.4 %

Procedure:
1-(4-Azidomethyl-1,3-thiazol-2-yl)-3-t-butyldiphenylsilyloxyazetidine (2.12 g, 4.71 mmol) (obtained as described in Reference Example 62(1)) in methanol (106 ml) was subjected to catalytic hydrogenation in the presence of 20% palladium hydroxide (2.12 g) at room temperature. After checking the completion of the reaction, the reaction mixture was filtered in order to remove the catalyst and the filtrate concentrated under reduced pressure. The residue was dissolved in methylene chloride (100 ml). To the mixture were added benzenesulfonyl chloride (0.90 g, 7.07 mmol) and triethylamine (0.98 ml, 7.07 mmol) in an ice bath, and the mixture was stirred at room temperature for 2 hours. After checking the completion of the reaction, the mixture was distilled under reduced pressure. The residue was partitioned between ethyl acetate and saturated aqueous sodium hydrogencarbonate solution. The organic layer was washed with saturated aqueous sodium chloride solution, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by chromatography on a silica gel column using ethyl acetate as the eluant to afford 3-t-butyldiphenylsilyloxy-1-[4-(benzenesulfonylamino)methyl-1,3-thiazol-2-yl]azetidine (755 mg, yield 28%) as pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([O:27]COC)=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([OH:27])=[C:7]([C:9]2[O:10][C:11]3[CH:17]=[CH:16][CH:15]=[C:14]([CH2:18][NH:19][CH2:20][C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=4)[C:12]=3[N:13]=2)[CH:8]=1
Reactant: COCOc1ccc(OC)cc1-c1nc2c(CNCc3ccccn3)cccc2o1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CO
Solvent: O
Product: COc1ccc(O)c(-c2nc3c(CNCc4ccccn4)cccc3o2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 96.5 %

Procedure:
A mixture of 2-(5-methoxy-2-methoxymethoxyphenyl)-4-(2-pyridylmethyl)aminomethyl-benzoxazole (F16) (283 mg, 0.70 mmol) and p-toluenesulfonic acid monohydrate (532 mg, 2.8 mmol) in methanol (20 mL) was stirred overnight at room temperature. After the solvent was removed by evaporation, ethyl acetate (20 mL) was added to the resulting residue, neutralized by Na2CO3, washed with brine and water, dried over MgSO4, and concentrated in vacuo. The residue was recrystallized from hot ethanol/hexane to afford the objective compound as a pale yellow crystal (244 mg, 96%); 1H-NMR (500 MHz, CDCl3) δ3.86 (s, 3H), 4.01 (s, 2H), 4.21 (s, 2H), 7.05 (br s, 2H), 7.17 (dd, 1H, J=7.5, 4.5 Hz), 7.33-7.37 (m, 2H), 7.41 (d, 1H, J=7.5 Hz), 7.48-7.51 (m, 2H), 7.66 (t, 1H, J=7.5 Hz), 8.59 (d, 1H, J=4.5 Hz), 11.00 (s, 1H).
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]1[CH:21]=[CH:20][C:19]2[O:18][C:17]3[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26]Cl)=[CH:15][CH:16]=3)[S:11][C:10]=2[CH:9]=1)=[O:7].[I-].[K+].[NH:31]1[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1>O1CCCC1>[N:31]1([CH2:2][CH2:3][CH2:4][CH2:5][C:6]([C:8]2[CH:21]=[CH:20][C:19]3[O:18][C:17]4[C:12](=[CH:13][C:14]([C:22](=[O:28])[CH2:23][CH2:24][CH2:25][CH2:26][N:31]5[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]5)=[CH:15][CH:16]=4)[S:11][C:10]=3[CH:9]=2)=[O:7])[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCCl)c1ccc2c(c1)Sc1cc(C(=O)CCCCCl)ccc1O2
Agent: [I-]
Agent: [K+]
Solvent: C1CCOC1
Product: O=C(CCCCN1CCCCC1)c1ccc2c(c1)Sc1cc(C(=O)CCCCN3CCCCC3)ccc1O2
Temperature: 110 °C

Procedure:
A mixture of 35 g (0.08 mole) of 2,8-bis(5-chlorovaleryl)phenoxathiin, 2 g potassium iodide, 100 ml piperidine and 100 ml tetrahydrofuran is heated for 24 hours with stirring in a Parr bomb at 110° C. After cooling the mixture is filtered and washed with tetrahydrofuran, and the filtrate is evaporated to dryness. The residue is cooled and diluted with water. The mixture is extracted twice with ether, the ether extracts combined and filtered. The filtrate is evaporated to dryness, cooled and diluted with pentane followed by filtering off of the solid, washing with pentane and drying. The residue is recrystallized from isopropanol to yield 2,8-bis(5-piperidinovaleryl)phenoxathiin, M.P. 128.5°-129.5° C.
Reaction SMILES: Br[C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[CH:9][N:8]=2)=[CH:4][CH:3]=1.C([Li])CCC.[CH:24](N1CCOCC1)=[O:25]>O1CCCC1>[CH:14]([O:13][C:10]1[CH:11]=[CH:12][C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([CH:24]=[O:25])=[CH:3][CH:4]=2)=[N:8][CH:9]=1)([CH3:16])[CH3:15]
Reactant: O=CN1CCOCC1
Reactant: CC(C)Oc1ccc(Oc2ccc(Br)cc2)nc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC(C)Oc1ccc(Oc2ccc(C=O)cc2)nc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of Example 69B (1.00 g, 3.25 mmol) in tetrahydrofuran (10 mL) was added n-butyl lithium (2.5 M in hexanes, 1.35 mL, 3.38 mmol) at −78° C. The mixture was stirred for 30 minutes, and then 4-formylmorpholine (380 μL) 3.80 mmol) was added. The mixture was stirred for 30 minutes and warmed to room temperature before quenching with water. The aqueous layer was extracted with ether (1×). The ether layer was washed with brine (1×), dried over MgSO4 and concentrated to give the title compound as colorless viscous oil.
Reaction SMILES: C[O:2][C:3](=[O:24])[CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[N:11]([CH3:23])[S:12]([C:15]1[CH:20]=[CH:19][C:18]([Cl:21])=[C:17]([Cl:22])[CH:16]=1)(=[O:14])=[O:13].CO.O1CCOCC1.[OH-].[Na+]>>[Cl:22][C:17]1[CH:16]=[C:15]([S:12]([N:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[CH2:4][C:3]([OH:24])=[O:2])[CH3:23])(=[O:13])=[O:14])[CH:20]=[CH:19][C:18]=1[Cl:21]
Reactant: COC(=O)Cc1ccccc1N(C)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Product: CN(c1ccccc1CC(=O)O)S(=O)(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(2-(3,4-Dichloro-N-methylphenylsulfonamido)phenyl)acetic acid methyl ester (13.7 g, 34.26 mmol) was dissolved in a mixture of methanol/dioxane/4 M NaOH (15/4/1) (266 ml, 52.92 mmol NaOH), and then further 4 M NaOH (39.7 ml, 158.76 mmol) was added. The resulting clear solution was stirred overnight at room temperature and then concentrated in vacuo. The residue was taken up in ethyl acetate and washed with 0.5 M KHSO4. The aqueous phase was then extracted several times with ethyl acetate. The combined organic phases were washed with saturated NaCl solution, dried over sodium sulfate and concentrated.
Reaction SMILES: [CH2:1]([CH:8]1[C:17]2[C:12](=[C:13](Br)[N:14]=[CH:15][CH:16]=2)[CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC([O-])(C)C.[Na+].[F:25][C:26]([F:35])([F:34])[C:27]1[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=1>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC(P([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.Cl[Pd]Cl.[Fe]>[CH2:1]([CH:8]1[CH2:17][C:16]2[C:15]([NH:31][C:30]3[CH:32]=[CH:33][C:27]([C:26]([F:25])([F:34])[F:35])=[CH:28][CH:29]=3)=[N:14][CH:13]=[CH:12][C:11]=2[CH2:10][NH:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Nc1ccc(C(F)(F)F)cc1
Reactant: Brc1nccc2c1CCNC2Cc1ccccc1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: [Pd]
Solvent: Cc1ccccc1
Product: FC(F)(F)c1ccc(Nc2nccc3c2CC(Cc2ccccc2)NC3)cc1
Yield: 91.6 %

Procedure:
Benzyl-5-bromo-1,2,3,4-tetrahydro-2,6-naphthyridine (see WO03/076427) (250 mg, 0.82 mmol) was dissolved in 1 mL of anhydrous toluene. To the mixture was added Pd2 (dba)3 (10 mol %, 85 mg) and PdCl2(DPPF) (33 mg, 5 mol %), followed by NaOtBu (118 mg, 1.23 mmol). After mixing for 5 min, 4-(trifluoromethyl)aniline (0.153 mL, 1.23 mmol) was added and the mixture was heated at 160° C. for 1200s in a Personal Chemistry microwave. The reaction mixture was filtered and the solvent was evaporated and the residue was dissolved in ethyl acetate and washed with saturated aqueous sodium bicarbonate and brine. The organic layer was dried over Na2SO4, filtered and evaporated to give a brown-purple residue. The residue was purified by flash chromatography over silica gel using a gradient of ethyl acetate:hexane (0-100%) to give the desired compound as an off-white powder (288 mg, 92%).
Reaction SMILES: [CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH3:10])[C:5](O)=[O:6])[CH2:3][CH2:2]1.CSC.B>C1COCC1>[CH:1]1([C@H:4]([NH:8][C@H:9]([C:11]2[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=2)[CH3:10])[CH2:5][OH:6])[CH2:3][CH2:2]1
Reactant: C[C@H](N[C@H](C(=O)O)C1CC1)c1ccccc1
Agent: B
Solvent: C1CCOC1
Solvent: CSC
Product: C[C@H](N[C@H](CO)C1CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 44.4 %

Procedure:
To a solution of (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]acetic acid (400 g, 1.82 mol) in dry THF (5.2 L) at 0° C. was added borane dimethylsulfide (neat) (485 g, 6.39 mol) with vigorous stirring. The reaction mixture was stirred overnight at room temperature. Reaction progress was monitored by HPLC. Stirring was continued until the acid was consumed completely (18-20 h). Upon completion the reaction mixture was cooled to 0° C. and methanol (6 L) was added dropwise. The mixture was concentrated under vacuum and the residue was dissolved in chloroform (5 L). The organic layer was washed with 10% aqueous NaHCO3 solution (2×1 L) followed by brine, dried over Na2SO4, filtered and concentrated to afford a tan-yellow oil. The oil was distilled under reduced pressure to afford (S)-2-cyclopropyl-2-[(S)-1-phenylethylamino]ethanol (166 g, 44% yield) as a colorless oil: bp 175-184° C., 0.1 mm Hg; [α]25D−52.1 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 1H NMR (400 MHz, CDCl3) δ 7.33-7.20 (m, 5H), 3.91-3.86 (m, 1H), 3.67 (dd, JAB=10.6, JAX=3.8 Hz, 1H), 3.39 (dd, JBA=10.6, JBX=4.3 Hz, 1H), 2.40 (s br, 2H), 1.70-1.65 (m, 1H), 1.35 (d, J=6.6 Hz, 3H), 0.88-0.82 (m, 1H), 0.47-0.37 (m, 2H), 0.05-0.06 (m, 2H); 13C NMR (100 MHz, DMSO-d6) δ 146.8, 127.6, 126.2, 125.9, 63.0, 60.5, 54.4, 24.4, 13.3, 3.0, 1.5; LRMS (ESI) m/e 206.3 [(M+H)+, calcd for C13H20NO 206.2].
Reaction SMILES: Cl[S:2]([CH2:5][CH2:6][CH2:7][NH:8][C:9](=[O:11])[CH3:10])(=[O:4])=[O:3].C(N(CC)CC)C.[OH:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:34])([CH3:33])[CH3:32])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26]>ClCCl.CN(C1C=CN=CC=1)C>[C:9]([NH:8][CH2:7][CH2:6][CH2:5][S:2]([O:19][CH2:20][C:21]([CH3:38])([CH3:37])[C@@H:22]([O:29][Si:30]([CH3:36])([CH3:35])[C:31]([CH3:32])([CH3:34])[CH3:33])/[CH:23]=[CH:24]/[C:25]([O:27][CH3:28])=[O:26])(=[O:4])=[O:3])(=[O:11])[CH3:10]
Reactant: CC(=O)NCCCS(=O)(=O)Cl
Reactant: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)CO
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)/C=C/[C@H](O[Si](C)(C)C(C)(C)C)C(C)(C)COS(=O)(=O)CCCNC(C)=O
Yield: 54.2 %

Procedure:
Following the general procedure for the preparation of neopentyl sulfonylester intermediates of Description 10, N-[3-(chlorosulfonyl)propyl]acetamide (9) (4.0 g, 19.8 mmol) in 40 mL of dichloromethane (DCM) in the presence of 1.2 g (9.8 mmol) of 4-(N,N-dimethylamino)pyridine (DMAP) and 2.8 mL (2.0 g, 19.8 mmol) of triethylamine (Et3N, TEA) was reacted at ca. 0° C. with 3.0 g (9.9 mmol) of methyl (2E)(4S)-6-hydroxy-5,5-dimethyl-4-(1,1,2,2-tetramethyl-1-silapropoxy)hex-2-enoate (4). After work-up and isolation, the crude material was purified by silica gel column chromatography using ethyl acetate (EtOAc) and methanol (MeOH) mixtures (EtOAc/MeOH=9:1) as eluent to provide 2.5 g (55% yield) the title compound (19a) as a colorless oil. Rf=0.46 (EtOAc). 1H NMR (400 MHz, CDCl3): δ=0.01 (s, 3H), 0.08 (s, 3H), 0.93 (s, 9H), 0.97 (s, 6H), 2.06 (s, 3H) 2.07-2.11 (m, 2H), 3.14-3.18 (m, 2H), 3.40-3.45 (m, 2H), 3.77 (s, 3H), 3.98 (d, J=9.6 Hz, 1H), 4.06 (d, J=9.2 Hz, 1H), 4.09 (dd, superimposed, J=6.4, 1.6 Hz, 1H), 5.93 (br., 1H), 5.96 (dd, J=15.6, 1H), 6.90 (dd, J=15.6, 6.4 Hz, 1H) ppm. MS (ESI) m/z 466.10 (M+H)+. The analytical data was consistent with the proposed structure.