Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][N:14]=[CH:13][N:12]=2)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=1.C([O:20][CH2:21][C:22]1[C:27](B2OC(C)(C)C(C)(C)O2)=[CH:26][CH:25]=[CH:24][C:23]=1[N:37]1[CH2:45][C:44]2[C:39](=[CH:40][CH:41]=[C:42]([C:46]([CH3:49])([CH3:48])[CH3:47])[CH:43]=2)[C:38]1=[O:50])(=O)C>>[C:46]([C:42]1[CH:43]=[C:44]2[C:39](=[CH:40][CH:41]=1)[C:38](=[O:50])[N:37]([C:23]1[CH:24]=[CH:25][CH:26]=[C:27]([C:2]3[CH:3]=[C:4]([NH:10][C:11]4[CH:16]=[CH:15][N:14]=[CH:13][N:12]=4)[C:5](=[O:9])[N:6]([CH3:8])[CH:7]=3)[C:22]=1[CH2:21][OH:20])[CH2:45]2)([CH3:49])([CH3:47])[CH3:48]
Reactant: Cn1cc(Br)cc(Nc2ccncn2)c1=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1Cc2cc(C(C)(C)C)ccc2C1=O
Product: Cn1cc(-c2cccc(N3Cc4cc(C(C)(C)C)ccc4C3=O)c2CO)cc(Nc2ccncn2)c1=O
Yield: 38 %

Procedure:
Using the same general procedure as in Example 105, reaction of 107a (250 mg, 0.889 mmol) with 103f (495 mg, 1.07 mmol) afforded 107 in 38% yield (166 mg) as an amorphous off-white solid: mp 216-218° C.; 1H NMR (500 MHz, DMSO-d6) δ 9.18 (s, 1H), 8.72 (d, J=2.0 Hz, 1H), 8.65 (s, 1H), 8.30 (d, J=5.5 Hz, 1H), 7.73 (d, J=8.5 Hz, 2H), 7.62 (dd, J=8.0, 1.5 Hz, 1H), 7.54 (d, J=2.0 Hz, 1H), 7.51 (t, J=7.5 Hz, 1H), 7.46 (dd, J=7.5, 1.0 Hz, 1H), 7.40 (dd, J=7.5, 1.5 Hz, 1H), 7.32 (dd, J=6.0, 1.0 Hz, 1H), 4.95 (s, 2H), 4.92 (t, J=4.5 Hz, 1H), 4.34 (d, J=5.0 Hz, 2H), 3.61 (s, 3H), 1.37 (s, 9H); MS (ESI+) m/z 496.2 (M+H).
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9](=O)[C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[N+:16]([O-:18])=[O:17])=[CH:6][C:5]([CH3:20])=[CH:4][N:3]=1.P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:22].C1(C)C(C)=CC=CC=1>N1C=CC=CC=1>[CH3:20][C:5]1[CH:6]=[C:7]2[N:8]=[C:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[N+:16]([O-:18])=[O:17])[S:22][C:2]2=[N:3][CH:4]=1
Reactant: Cc1cnc(Cl)c(NC(=O)c2ccccc2[N+](=O)[O-])c1
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Solvent: Cc1ccccc1C
Product: Cc1cnc2sc(-c3ccccc3[N+](=O)[O-])nc2c1
Temperature: 140 °C
Reaction time: 20 h
Yield: 75.4 %

Procedure:
A mixture of N-(2-chloro-5-methylpyridin-3-yl)-2-nitrobenzamide (5.0 g, 17.1 mmol) and P2S5 (7.6 g, 34.2 mmol) in pyridine (50 mL) and p -xylene (200 mL) was stirred at 140° C. for 20 h. The hot solution was transferred to another flask and the solvent was removed in vacuo. The residue was purified by recrystallization from EtOH to afford 6-methyl-2-(2-nitrophenyl)thiazolo[5,4-b]pyridine as a yellow solid (3.5 g, yield: 75%).
Reaction SMILES: [CH3:1][N:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[NH:5][C:4](=O)[C:3]1=[O:13].CN(C=O)C.S(Cl)([Cl:21])=O>C1(C)C=CC=CC=1>[Cl:21][C:4]1[C:3](=[O:13])[N:2]([CH3:1])[C:11]2[C:6]([N:5]=1)=[CH:7][CH:8]=[CH:9][CH:10]=2
Reactant: Cn1c(=O)c(=O)[nH]c2ccccc21
Reactant: O=S(Cl)Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cn1c(=O)c(Cl)nc2ccccc21

Procedure:
A mixture of 56.1 g. (0.32 m.) of 1,4-dihydro-1-methylquinoxalin-2,3-dione, 10 ml. of DMF, 50 ml. (0.67 m.) of thionyl chloride and 1 l. of toluene was refluxed for 1 hour, cooled, and stripped, finally under high vacuum to a crude dark solid, m.p. 124°-130° C. of sufficient purity to use in the next step.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C@H:10]([NH:14][C:15]([O:17][CH2:18][CH2:19][CH2:20][CH3:21])=[O:16])[C:11]([OH:13])=O)=[CH:5][CH:4]=1)#[N:2].Cl.CN(C)CCCN=C=NCC.O.ON1C2C=CC=CC=2N=N1.[CH3:45][S:46]([N:49]1[CH2:54][CH2:53][NH:52][CH2:51][CH2:50]1)(=[O:48])=[O:47].CN1CCOCC1>CN(C)C=O>[CH2:18]([O:17][C:15]([NH:14][C@H:10]([C:11]([N:52]1[CH2:53][CH2:54][N:49]([S:46]([CH3:45])(=[O:48])=[O:47])[CH2:50][CH2:51]1)=[O:13])[CH2:9][C:6]1[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:8][CH:7]=1)=[O:16])[CH2:19][CH2:20][CH3:21]
Reactant: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)O
Reactant: CS(=O)(=O)N1CCNCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Solvent: O
Product: CCCCOC(=O)N[C@@H](Cc1ccc(C#N)cc1)C(=O)N1CCN(S(C)(=O)=O)CC1
Temperature: 0 °C
Yield: 94.3 %

Procedure:
(S)-3-(4-cyanophenyl)-2-(butyloxycarbonylamino)propionic acid (0.5 g, 1.7 mmole) was dissolved in dimethylformamide (DMF, 20 ml) and then cooled to 0° C. Then, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 0.5 g) and 1-hydroxybenzotriazole hydrate (HOBT, 0.3 g) were added to this solution and stirred until they are completely dissolved therein. To this reaction mixture were added 1-methanesulfonyl-piperazine (0.3 g) and N-methylmorpholine (0.2 ml), and then the temperature was slowly elevated to room temperature. The reaction solution was stirred for 3.5 hours. After the reaction is completed, the reaction solution was distilled under reduced pressure to remove the volatile substance and the remaining solution was diluted with ethyl acetate, washed successively with aqueous saturated sodium hydrogen carbonate solution, dilute hydrochloric acid and saturated saline, dried over anhydrous sodium sulfate, filtered and then concentrated. The residue was purified with column chromatography using ethyl acetate/hexane (6/4, by volume) as an eluent to obtain the purified title compound (0.7 g, Yield: 93%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[CH2:7][NH:8][CH2:9][CH2:10][NH2:11])([CH3:4])([CH3:3])[CH3:2].[C:13]([O:17][C:18](=[O:21])[CH:19]=[CH2:20])([CH3:16])([CH3:15])[CH3:14]>CC(O)C>[C:13]([O:17][C:18](=[O:21])[CH2:19][CH2:20][NH:11][CH2:10][CH2:9][NH:8][CH2:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)OC(=O)CNCCN
Reactant: C=CC(=O)OC(C)(C)C
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)CCNCCNCC(=O)OC(C)(C)C
Temperature: 60 °C
Yield: 0.1 %

Procedure:
To the solution of (2-amino-ethylamino)-acetic acid tert-butyl ester (1.0 mL, 6.32 mmol) in i-PrOH (50 mL) was added acrylic acid tert-butyl ester (309.1 μL, 2.11 mmol). The suspension was heated for 48 hours at 60° C. The solvent was evaporated and product was purificated by column chromatography (DCM-MeOH—NH3=90:3:0.5) yielded the title product as colorless oil (0.45 mg).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2([C:14]([OH:16])=O)[CH2:13][CH2:12]2)=[O:10])=[CH:4][CH:3]=1.C(N(CC)CC)C.S(Cl)(Cl)=O.[NH2:28][C:29]1[C:44]([F:45])=[CH:43][C:32]([O:33][C:34]2[CH:39]=[CH:38][N:37]=[C:36]([C:40]([NH2:42])=[O:41])[CH:35]=2)=[C:31]([F:46])[CH:30]=1>O1CCCC1>[NH2:42][C:40]([C:36]1[CH:35]=[C:34]([O:33][C:32]2[C:31]([F:46])=[CH:30][C:29]([NH:28][C:14]([C:11]3([C:9]([NH:8][C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=4)=[O:10])[CH2:12][CH2:13]3)=[O:16])=[C:44]([F:45])[CH:43]=2)[CH:39]=[CH:38][N:37]=1)=[O:41]
Reactant: NC(=O)c1cc(Oc2cc(F)c(N)cc2F)ccn1
Reactant: O=C(O)C1(C(=O)Nc2ccc(F)cc2)CC1
Solvent: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: NC(=O)c1cc(Oc2cc(F)c(NC(=O)C3(C(=O)Nc4ccc(F)cc4)CC3)cc2F)ccn1
Reaction time: 0.25 h
Yield: 21 %

Procedure:
1-(4-Fluorophenylaminocarbonyl)cyclopropanecarboxylic acid (1.35 g) was dissolved in tetrahydrofuran (25.0 ml) under a nitrogen atmosphere, and triethylamine (1.06 ml) was added dropwise while cooling in an ice water bath, followed by stirring for 15 min. Then thionyl chloride (0.439 ml) was added at the same temperature, followed by stirring for 1.5 hr. To the reaction mixture was added dropwise at the same temperature a mixture of 4-(4-amino-2,5-difluorophenoxy)pyridine-2-carboxamide (1.0 g), tetrahydrofuran (12 ml) and triethylamine (1.06 ml), followed by stirring at 0° C. for 24 hr and 45 min. The reaction mixture was partitioned between ethyl acetate (70 ml) and a 2N aqueous solution of sodium hydroxide (15 ml). The organic layer was washed with a 2N aqueous solution of sodium hydroxide (15 ml) twice, 1N hydrochloric acid (15 ml) three times and a saturated aqueous solution of sodium hydrogencarbonate (10 ml) in this order, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure. The resultant residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; heptane:ethyl acetate=1:1, 1:2, then ethyl acetate), and fractions containing the target compound were concentrated under reduced pressure. The residue was dried under reduced pressure to provide the titled compound as a white solid (372.8 mg, 21%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([CH:9]([NH:17]S(C(C)(C)C)=O)[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14])=[C:7]([O:24][CH3:25])[CH:6]=[CH:5][N:4]=1.Cl.O1CCOCC1>CO>[NH2:17][CH:9]([C:8]1[C:3]([O:2][CH3:1])=[N:4][CH:5]=[CH:6][C:7]=1[O:24][CH3:25])[CH2:10][CH2:11][CH2:12][C:13]([O:15][CH3:16])=[O:14]
Reactant: COC(=O)CCCC(NS(=O)C(C)(C)C)c1c(OC)ccnc1OC
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: COC(=O)CCCC(N)c1c(OC)ccnc1OC
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) yellow solution of methyl 5-(2,4-dimethoxypyridin-3-yl)-5-(1,1-dimethylethylsulfinamido)pentanoate (653 mg; 1.75 mmol) in MeOH (14 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.90 ml; 3.60 mmol). The resulting yellow mixture was further stirred at 0° C., under nitrogen, for 10 min., and then at rt for 1 h. The reaction mixture was then concentrated to dryness under reduced pressure and the yellow oily residue was further dried under HV to give the chlorhydrate salt of methyl 5-amino-5-(2,4-dimethoxypyridin-3-yl)pentanoate as a beige solid. LC-MS (conditions B): tR=0.51 min.; [M+H]+: 269.03 g/mol.
Reaction SMILES: [CH3:1][C:2]1([CH3:16])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([OH:15])=[O:14].[CH2:17]([N:20]1[CH2:24][C:23](=[O:25])[N:22]([CH2:26]O)[C:21]1=[O:28])[C:18]#[CH:19]>C(Cl)(Cl)Cl>[CH3:16][C:2]1([CH3:1])[C@@H:4](/[CH:5]=[C:6](/[F:12])\[C:7](=[O:11])[O:8][CH2:9][CH3:10])[C@H:3]1[C:13]([O:15][CH2:26][N:22]1[C:23](=[O:25])[CH2:24][N:20]([CH2:17][C:18]#[CH:19])[C:21]1=[O:28])=[O:14]
Reactant: CCOC(=O)/C(F)=C\[C@H]1[C@@H](C(=O)O)C1(C)C
Reactant: C#CCN1CC(=O)N(CO)C1=O
Solvent: ClC(Cl)Cl
Product: C#CCN1CC(=O)N(COC(=O)[C@@H]2[C@H](/C=C(/F)C(=O)OCC)C2(C)C)C1=O

Procedure:
Using the procedure of Example 1, (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl]-cyclopropane-1-carboxylic acid and 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methanol were reacted to obtain 3-(2-propynyl)-2,5-dioxoimidazolidinyl-methyl (1R,cis) 2,2-dimethyl-3(E)-[2-fluoro-3-oxo-3-ethoxy-propenyl)-cyclopropane-1-carboxylate with a specific rotation of [α]D20 =+12°±2° (c=0.5% in chloroform).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:21][OH:22])[CH2:13][CH2:12][N:11]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:23][C:24]1[CH:32]=[C:31]([C:33](=[N+]=[N-])[C:34]([O:36][CH3:37])=[O:35])[C:30]2[C:26](=[CH:27][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:47])([CH3:46])[CH3:45])[N:29]=2)[CH:25]=1>C1C=CC=CC=1.C(OCC)(=O)C.CCCCCC.CC([O-])=O.CC([O-])=O.CC([O-])=O.CC([O-])=O.[Rh+2].[Rh+2]>[Cl:23][C:24]1[CH:32]=[C:31]([CH:33]([O:22][CH2:21][C:8]2([C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:7][CH:6]=3)[CH2:9][CH2:10][N:11]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:12][CH2:13]2)[C:34]([O:36][CH3:37])=[O:35])[C:30]2[C:26](=[CH:27][N:28]([CH2:40][O:41][CH2:42][CH2:43][Si:44]([CH3:46])([CH3:45])[CH3:47])[N:29]=2)[CH:25]=1
Reactant: COC(=O)C(=[N+]=[N-])c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12
Reactant: CC(C)(C)OC(=O)N1CCC(CO)(c2ccc(F)cc2)CC1
Agent: [Rh+2]
Agent: CC(=O)[O-]
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COC(=O)C(OCC1(c2ccc(F)cc2)CCN(C(=O)OC(C)(C)C)CC1)c1cc(Cl)cc2cn(COCC[Si](C)(C)C)nc12

Procedure:
To a suspension of tert-butyl 4-(4-fluorophenyl)-4-(hydroxymethyl)piperidine-1-carboxylate (2.26 g, 7.30 mmol) and rhodium(II) acetate dimer (4.84 mg, 11 μmol) in benzene (4 mL) at reflux was added a solution of methyl 2-(5-chloro-2-((2-(trimethylsilyl)ethoxy)methyl)-2H-indazol-7-yl)-2-diazoacetate (1.39 g, 3.65 mmol) in benzene (3 mL) via syringe pump over 60 h. After addition was complete, the reaction was cooled. It became a very viscous solution. The reaction mixture was diluted with 20% ethyl acetate/n-hexane and loaded onto a column. Column chromatography (20% ethyl acetate/n-hexane→25% ethyl acetate/n-hexane) gave 1.88 g (78%) as a yellow foam solid. 1H-NMR (CDCl3, 500 MHz) δ 8.03 (s, 1H), 7.58 (d, J=1.8 Hz, 1H), 7.29 (dd, J=8.5, 5.2 Hz, 2H), 7.06 (s, 1H), 6.97 (dd, J=8.9, 8.5 Hz, 2H), 5.68 (d, J=10.7 Hz, 1H), 5.65 (d, J=10.7 Hz, 1H), 5.42 (s, 1H), 3.71 (bs, 2H), 3.61 (s, 3H), 3.60 (t, J=8.6 Hz, 2H), 3.39 (d, J=8.9 Hz, 1H), 3.03 (m, 2H), 2.16 (m, 1H), 2.08 (m, 1H), 1.93 (m, 2H), 1.42 (s, 9H), 0.91 (t, J=8.2 Hz, 2H), −0.05 (s, 9H); 13C NMR (126 MHz, CDCl3) δ ppm 170.5, 161.5 (d, J=246 Hz), 155.0, 145.6, 138.3, 128.9 (d, J=7.7 Hz), 127.9, 125.5, 122.8, 122.5, 119.5, 115.2 (d, J=21 Hz), 82.1, 79.4, 78.6, 76.4, 67.7, 52.3, 41.4, 40.0 (br), 32.1, 31.9, 28.6, 17.9, −1.4. Mass spec.: 662.53 (MH)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](Cl)(=[O:13])=[O:12].C(N(CC)CC)C.O1CCOCC1.[NH2:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[CH:4][C:3]=1[S:11](=[O:13])(=[O:12])[NH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: Nc1ccccc1
Reactant: CC(=O)c1ccc(Cl)c(S(=O)(=O)Cl)c1
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Cl)c(S(=O)(=O)Nc2ccccc2)c1
Temperature: 60 °C

Procedure:
12.6 g of 4'-chloro-3'-chlorosulfonylacetophenone were introduced, while stirring, in a mixture of 5.6 g of aniline, 7.5 g of triethyl amine and 100 ml of dioxane. The mixture was allowed to dwell over night at 20° C, it was heated to 60° C during 30 minutes while stirring and the separated triethylamine-hydrochloride was separated. The filtrate was concentrated under reduced pressure and the residue was crystallized under water. Colorless crystals (from isopropanol/active charcoal, melting point: 142° C.
Reaction SMILES: [CH2:1]([C:6]1([CH2:21][CH2:22][CH2:23][CH:24]=[CH2:25])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([OH:20])=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)[CH2:2][CH2:3][CH:4]=[CH2:5].[C:26]1([O:36][CH2:37][CH2:38][CH2:39]Br)[C:35]2[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=2[CH:29]=[CH:28][CH:27]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:21]([C:6]1([CH2:1][CH2:2][CH2:3][CH:4]=[CH2:5])[CH2:11][C:10](=[O:12])[C:9]2[CH:13]=[CH:14][C:15]([O:20][CH2:39][CH2:38][CH2:37][O:36][C:26]3[C:35]4[CH2:34][CH2:33][CH2:32][CH2:31][C:30]=4[CH:29]=[CH:28][CH:27]=3)=[C:16]([CH2:17][CH2:18][CH3:19])[C:8]=2[O:7]1)[CH2:22][CH2:23][CH:24]=[CH2:25]
Reactant: BrCCCOc1cccc2c1CCCC2
Reactant: C=CCCCC1(CCCC=C)CC(=O)c2ccc(O)c(CCC)c2O1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCCC1(CCCC=C)CC(=O)c2ccc(OCCCOc3cccc4c3CCCC4)c(CCC)c2O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 82.7 %

Procedure:
To a solution of 3.0 g (9.55 mmol) of the title product of Example 69 and 4.01 g (11 mmol) of the title product of Example 12 in 56 ml of dry dimethylformamide (DMF) was added 2.77 g (20.1 mmol) of anhydrous potassium carbonate. The resulting mixture was stirred overnight at room temperature. The solvent was removed in vacuo, and the residue was partitioned between ethyl acetate and 3N hydrochloric acid. The aqueous layer was further extracted with two portions of ethyl acetate. The combined organic extracts were washed with water and with brine, dried over magnesium sulfate, filtered, and the solvent removed under reduced pressure. Chromatography of the residue over silica gel, using 10% ethyl acetate/hexane as eluent, gave the title compound (4.19 g) as an oil.
Reaction SMILES: [OH-].[K+].[C:3]([OH:6])(=[S:5])[CH3:4].Br[CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10]>O.CC(C)=O>[C:3]([S:5][CH2:8][C:9]([O:11][CH2:12][CH2:13][O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:10])(=[O:6])[CH3:4]
Reactant: O=C(CBr)OCCOc1ccccc1
Reactant: CC(O)=S
Agent: [K+]
Agent: [OH-]
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)SCC(=O)OCCOc1ccccc1
Yield: 98.1 %

Procedure:
The solution of potassium hydroxide (6.6g) in water (20 ml) was added under ice cooling to thioacetic acid (7.6g) and then the solution of β-phenoxyethyl bromoacetate (25.9g) in acetone (30ml) was added and treated for 6 hours at room temperature. Extracted twice with 200 ml of ethylether and the ether layer was washed with water, dried, and concentrated, giving colourless crystals (24.9g) which was then recrystallized from n-hexane. Thus colourless crystals (20.8g), m.p. 56.0°-57.0° C., of β-phenoxyethyl S-acetylthioglycolate was obtained.
Reaction SMILES: C[O:2][C:3](=O)[C:4]([N:13](N)[CH2:14][CH:15](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)[CH2:16][O:17]C(C)(C)C)([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8].C(=O)(O)[O-].[Na+].[C:46](Cl)([O:48][CH2:49][CH:50]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]2[C:51]1=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47].C([NH:66]CC)C>C(OCC)(=O)C.O>[C:46]([N:13]1[CH2:14][CH:15]([CH2:16][OH:17])[NH:66][C:3](=[O:2])[C:4]1([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:5][CH2:6][CH2:7][CH3:8])([O:48][CH2:49][CH:50]1[C:62]2[C:57](=[CH:58][CH:59]=[CH:60][CH:61]=2)[C:56]2[C:51]1=[CH:52][CH:53]=[CH:54][CH:55]=2)=[O:47]
Reactant: CCNCC
Reactant: O=C(Cl)OCC1c2ccccc2-c2ccccc21
Reactant: CCCCC(CCCC)(C(=O)OC)N(N)CC(COC(C)(C)C)C(=O)OCC1c2ccccc2-c2ccccc21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCCCC1(CCCC)C(=O)NC(CO)CN1C(=O)OCC1c2ccccc2-c2ccccc21
Reaction time: 3 h

Procedure:
A solution of 10 mmol of compound (88) in 30 mL of 30% diethyl amine in ethyl acetate is stirred at room temperature overnight, and then concentrated to dryness. The residue is dissolved in 20 mL of tetrahydrofuran and 10 mL of water, 2.52 g (30 mmol) of solid sodium bicarbonate is added, followed by 3.36 g (13 mmol) of Fmoc-Cl. The mixture is stirred for 3 hours, diluted with 50 mL of ethyl acetate, the layers separated, and the organic layer washed with 30 mL of water, dried over magnesium sulfate, and concentrated. The crude mixture is dissolved in a solution of 10 mL of 90% trifluoroacetic acid in dichloromethane, stirred for 2 hours, and then concentrated to dryness. The residue is dissolved in ethyl acetate and washed with 50 mL of a saturated solution of sodium bicarbonate, dried over magnesium sulfate, and concentrated. Compound (89) is purified by silica gel column chromatography.
Reaction SMILES: [NH2:1][C:2]1[CH:17]=[CH:16][CH:15]=[CH:14][C:3]=1[C:4]([NH:6][CH2:7][CH2:8][C:9]1[NH:10][CH:11]=[CH:12][N:13]=1)=[O:5].[CH:18]([C:21]1[CH:29]=[CH:28][C:24]([C:25]([Cl:27])=[O:26])=[CH:23][CH:22]=1)([CH3:20])[CH3:19]>>[ClH:27].[NH:13]1[CH:12]=[CH:11][N:10]=[C:9]1[CH2:8][CH2:7][NH:6][C:4](=[O:5])[C:3]1[CH:14]=[CH:15][CH:16]=[CH:17][C:2]=1[NH:1][C:25](=[O:26])[C:24]1[CH:28]=[CH:29][C:21]([CH:18]([CH3:19])[CH3:20])=[CH:22][CH:23]=1
Reactant: CC(C)c1ccc(C(=O)Cl)cc1
Reactant: Nc1ccccc1C(=O)NCCc1ncc[nH]1
Product: CC(C)c1ccc(C(=O)Nc2ccccc2C(=O)NCCc2ncc[nH]2)cc1
Product: Cl

Procedure:
The titled compound was prepared substantially in accordance with the method detailed in Example 11 using 2.50 g (0.0109 mol) of 2-amino-N-[2-(1H-imidazol-2-yl)-ethyl]benzamide, prepared as in Example 6A, and 4.0 g (0.0217 mol) of p-isopropylbenzoyl chloride with the exception that, after removing ethyl acetate the resulting solid was purified using column chromatography (8000 ml of a gradient eluent of 0-15% methanol in a 1% ammonia in dichloromethane solution). The fractions containing the desired product were combined and reduced to dryness under reduced pressure to provide 2.1 g of a solid. This solid was then dissolved in methanol containing diethyl ether and hydrochloric acid and the resulting solution was again reduced to dryness under reduced pressure. The final product was recrystallized from an ethanol/diethyl ether solution to provide 2.37 g of the desired titled compound (m.p. 188°-192° C.).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH3:12])[C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8].O[N:14]1[C:18](=[O:19])[C:17]2=[CH:20][CH:21]=[CH:22][CH:23]=[C:16]2[C:15]1=[O:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:7]([O:6][C:5](=[O:11])[N:4]([CH2:3][CH2:2][O:1][N:14]1[C:18](=[O:19])[C:17]2[C:16](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:15]1=[O:24])[CH3:12])([CH3:8])([CH3:9])[CH3:10]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: O=C1c2ccccc2C(=O)N1O
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CN(CCON1C(=O)c2ccccc2C1=O)C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 48 h
Yield: 79 %

Procedure:
To an ice-cold solution of tert-butyl (2-hydroxyethyl)methylcarbamate (3.0 g, 17 mmol), N-hydroxyphthalimide (2.8 g, 17 mmol) and triphenylphosphine (4.5 g, 17 mmol) in THF (90 mL) was added a solution of diethyl azodicarboxylate (3.0 mL, 19 mmol) in THF (15 mL) dropwise. The stirred reaction mixture was allowed to warm to ambient temperature. After 2 days, most of the THF was removed under reduced pressure. The residue was partitioned between CH2Cl2 (40 ml) and H2O (30 mL). The organic layer was separated and washed with saturated NaCl (20 ml), dried (Na2SO4) and concentrated under reduced pressure. Purification by column chromatography (silica gel, 50:50 hexanes/EtOAc) gave tert-butyl[2-[(1,3-dioxo-1,3-dihydro-2H-isoindol-2-yl)oxy]ethyl]methylcarbamate (4.3 g, 79%) as a yellow oil: 1H NMR (300 MHz, CDCl3) δ1.46 (9H, s), 3.03 (3H, br s), 3.62 (2H, br s), 4.34 (2H, br s), 7.74-7.85 (4H, m).
Reaction SMILES: [ClH:1].Cl.[NH2:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:15])[CH3:14])=[CH:6][C:5]=1[F:17].ClCl>>[NH2:3][C:4]1[C:5]([F:17])=[CH:6][C:7]([CH:10]([OH:16])[CH2:11][NH:12][CH:13]([CH3:14])[CH3:15])=[CH:8][C:9]=1[Cl:1]
Reactant: CC(C)NCC(O)c1ccc(N)c(F)c1
Reactant: Cl
Agent: ClCl
Product: CC(C)NCC(O)c1cc(F)c(N)c(Cl)c1

Procedure:
m.p. of the hydrochloride: 152°-154° C. (decomp.), was prepared from 1-(4'-amino-3'-fluoro-phenyl)-2-isopropylamino-ethanol hydrochloride and chlorine analogous to Example 98.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH3:10][C:11]([S@@:14]([NH2:16])=[O:15])([CH3:13])[CH3:12].CC([S@](N)=O)(C)C.C(Cl)Cl>O1CCCC1.CC(C)[O-].CC(C)[O-].CC(C)[O-].CC(C)[O-].[Ti+4].O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5](/[CH:6]=[N:16]/[S:14]([C:11]([CH3:13])([CH3:12])[CH3:10])=[O:15])=[CH:4][CH:3]=1
Reactant: CC(C)(C)[S@@](N)=O
Reactant: O=Cc1ccc(Cl)cc1
Agent: [Ti+4]
Agent: CC(C)(C)[S@](N)=O
Agent: CC(C)[O-]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CC(C)(C)S(=O)/N=C/c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 139 %

Procedure:
To a solution of 4-chlorobenzaldehyde (2.88 g, 20.5 mmol), (S)-(−)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol), and (R)-(+)-2-methyl-2-propanesulfinamide (1.40 g, 11.6 mmol) in anhydrous tetrahydrofuran (30.0 mL) under nitrogen atmosphere was added titanium tetraisopropoxide (6.00 mL, 20.3 mmol) dropwise. The clear solution was stirred at room temperature for 3 hours. Methylene chloride (200 mL) and water (2.0 mL) were added and the mixture was stirred at room temperature for 1 hour. The suspension was filtered through Celite and washed with DCM. The filtrate was concentrated in vacuo and purified by column chromatography (gradient elution: 0-20% EtOAc/hexane) to afford N—[(E)-(4-chlorophenyl)methylene]-2-methylpropane-2-sulfinamide (3.93 g, yield 78.7%). LCMS: (FA) ES+ 244; 1H NMR (400 MHz, CDCl3) δ 8.55 (s, 1H), 7.78-7.80 (d, 2H, J=8.53 Hz), 7.44-7.47 (d, 2H, J=8.53 Hz), 1.26 (s, 9H).