Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:4][C:5](=[O:27])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH2:14])=[CH:10][C:9]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH:2]=[CH2:3].N1C=CC=CC=1.[C:34](OC(=O)C)(=[O:36])[CH3:35].C(OCC)(=O)C>O1CCCC1>[CH2:1]([O:4][C:5](=[O:27])[CH2:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:34](=[O:36])[CH3:35])=[CH:10][C:9]=1[C:15](=[O:26])[NH:16][CH2:17][C:18]1[CH:23]=[CH:22][C:21]([Br:24])=[CH:20][C:19]=1[F:25])[CH:2]=[CH2:3]
Reactant: CC(=O)OC(C)=O
Reactant: C=CCOC(=O)COc1ccc(N)cc1C(=O)NCc1ccc(Br)cc1F
Solvent: c1ccncc1
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: C=CCOC(=O)COc1ccc(NC(C)=O)cc1C(=O)NCc1ccc(Br)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 86.9 %

Procedure:
A solution of [4-amino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester (0.13 g, 0.30 mmol) was dissolved in tetrahydrofuran (2 mL, 0.2 M) along with pyridine (0.05 mL, 0.05 g, 0.61 mmol). This mixture was cooled to 0° C. before treatment with acetic anhydride (0.10 mL, 0.098 g, 0.95 mmol). After stirring at room temperature for 24 h, the reaction mixture was diluted ethyl acetate and sucessively washed with 2 N HCl, saturated aq NaHCO3 and saturated aq NaCl. The organic layer was dried over Na2SO4, filtered and concentrated to give [4-acetylamino-2-(4-bromo-2-fluoro-benzylcarbamoyl)-phenoxy]-acetic acid allyl ester (0.125 g, 87%): 1H NMR (DMSO-d6, 300 MHz) δ 89.95 (br s, 1 H), 8.94 (br t, J=5.7 Hz, 1 H), 7.98 (d, J=2.7 Hz, 1 H), 7.74 (dd, J1=9.0 Hz, J2=3.0 Hz, 1 H), 7.42–7.24 (m, 2 H), 7.22–7.02 (m, 2 H), 5.88 (m, 1 H), 5.30 (dd, J1=17.1 Hz, J2=1.8 Hz, 1 H), 5.21 (dd, J1=9.0 Hz, J2=1.8 hz, 1 H), 4.97 (s, 2 H), 4.64 (br d, J=5.4 Hz, 2 H), 4.55 (br d, J=6.0 Hz, 2 H), 2.00 (s, 3H).
Reaction SMILES: [CH3:1][C:2]([CH3:6])([CH3:5])[CH2:3][NH2:4].CC(C[AlH]CC(C)C)C.[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][C:27]2[C:30]([NH:35][CH2:36][C:37]3[CH:42]=[CH:41][C:40]([S:43][CH2:44][C:45](OC)=[O:46])=[CH:39][CH:38]=3)=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]>C1COCC1.CCOC(C)=O>[C:16]([O:20][C:21]([N:23]1[CH2:29][CH2:28][C:27]2[C:30]([NH:35][CH2:36][C:37]3[CH:38]=[CH:39][C:40]([S:43][CH2:44][C:45](=[O:46])[NH:4][CH2:3][C:2]([CH3:6])([CH3:5])[CH3:1])=[CH:41][CH:42]=3)=[C:31]([Cl:34])[CH:32]=[CH:33][C:26]=2[CH2:25][CH2:24]1)=[O:22])([CH3:19])([CH3:18])[CH3:17]
Reactant: CC(C)(C)CN
Reactant: COC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Agent: CC(C)C[AlH]CC(C)C
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)CNC(=O)CSc1ccc(CNc2c(Cl)ccc3c2CCN(C(=O)OC(C)(C)C)CC3)cc1
Temperature: 0 °C
Reaction time: 2 h
Yield: 66.7 %

Procedure:
Dissolve 2,2-dimethyl-propylamine (0.1 mL, 0.84 mmol) in anhydrous THF (0.6 mL) under nitrogen. Cool the solution at 0° C. and add DIBAL-H (0.79 mL, 0.79 mmol, 1M solution in toluene). Allow the mixture warm up to room temperature and stir for 2 h. Add this complex to a solution of 3-(tert-butoxycarbonyl)-7-chloro-6-(4-methoxycarbonylmethylthio-benzylamino)-2,3,4,5-tetrahydro-1H-benzo[d]azepine (70 mg, 0.14 mmol) in THF (0.3 mL) and stir at room temperature overnight. Dilute with EtOAc and quench with 5% aqueous KHSO4. Dry the organic phase over MgSO4, filter and concentrate in vacuo. Purify the crude mixture by chromatography on silica gel eluting with hexane/EtOAc (4:1) to obtain the desired intermediate as an oil (51 mg, 65%).
Reaction SMILES: [CH2:1]1[O:3][CH:2]1[CH2:4][OH:5].P([O-])([O-])(OCCCCCCCCCCCC)=O.[P:23]([O-:44])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]>>[P:23]([O:44][CH2:1][CH:2]([CH2:4][OH:5])[OH:3])([O:38][CH2:39][CH:40]([CH2:42][OH:43])[OH:41])([O:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH3:37])=[O:24]
Reactant: CCCCCCCCCCCCOP(=O)([O-])OCC(O)CO
Reactant: OCC1CO1
Agent: CCCCCCCCCCCCOP(=O)([O-])[O-]
Product: CCCCCCCCCCCCOP(=O)(OCC(O)CO)OCC(O)CO

Procedure:
While keeping the reaction system at 60° C., 150 g of glycidol (oxirane value=683.7) was gradually added, followed by their reaction at 70° C. for 2 hours. The acid value of the reaction system was AV1=4.4, AV2=6.0, revealing that the reaction system contained about 4.5 mole % of unreacted monododecyl phosphate and about 8.1 mole % of the corresponding phosphoric diester, i.e., dodecyl glyceryl phosphate and about 87.4 mole % of the corresponding phosphoric triester, i.e., dodecyl diglyceryl phosphate were formed.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[C:4]([OH:11])[CH:3]=1.[C:12]([O-])(=O)[CH3:13].[Na+].C(I)C.CN(C)C=O>O>[CH2:12]([O:7][C:6](=[O:8])[C:5]1[CH:9]=[CH:10][C:2]([F:1])=[CH:3][C:4]=1[OH:11])[CH3:13]
Reactant: CC(=O)[O-]
Reactant: O=C(O)c1ccc(F)cc1O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCI
Product: CCOC(=O)c1ccc(F)cc1O

Procedure:
4-Fluoro-2-hydroxy-benzoic acid (10.8 g, 0.07 mol), sodium acetate (6.9 g, 0.084 mol), ethyl iodide (55 g, 0.35 mol) and dimethylformamide was stirred at ambient temperature for 48 h. The mixture was poured into water and extracted with n-hexane. The solution was filtered through a plug of silica gel and evaporated. The residue was almost pure product and was used directly in the next step. Yield 10.2 g, 80%.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](Br)=[CH:11][C:10]=1[C@@H:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:32]([O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])[CH2:33][CH:34]=[CH2:35].C(N(C(C)C)CC)(C)C.C1(C)C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[NH3:19].[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12](/[CH:35]=[CH:34]/[CH2:33][CH2:32][O:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][C:42]#[N:43])=[CH:11][C:10]=1[C@@H:16]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH2:17][CH2:18][N:19]([CH:23]([CH3:25])[CH3:24])[CH:20]([CH3:22])[CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)N(CC[C@H](c1ccccc1)c1cc(Br)ccc1OCc1ccccc1)C(C)C
Reactant: C=CCCOCCCCCC#N
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)N(CC[C@H](c1ccccc1)c1cc(/C=C/CCOCCCCCC#N)ccc1OCc1ccccc1)C(C)C
Product: N
Temperature: 90 °C

Procedure:
(3R)-3-[2-(Benzyloxy)-5-bromophenyl]-N,N-diisopropyl-3-phenylpropan-1-amine (WO9411337, 1.21 g, 2.50 mmol) was dissolved in acetonitrile (8 ml) and 6-(but-3-en-1-yloxy)hexanenitrile (Preparation 23, 708 mg, 4.20 mmol), diisopropylethylamine (0.64 ml, 3.75 mmol), palladium acetate (54 mg, 0.25 mmol) and tri(o-tolyl)phosphine (145 mg, 0.25 mmol) were added. The stirred reaction was heated at 90° C., under a nitrogen atmosphere, for 12 hours, cooled to room temperature and the solvent removed in vacuo. The residue was dissolved in ethyl acetate (50 ml) and washed with saturated aqueous sodium hydrogen carbonate (50 ml), brine (50 ml), dried (magnesium sulphate) and the solvent removed in vacuo. The residue was purified by column chromatography on silica gel eluting with dichloromethane:methanol:880 ammonia (95/5/0.5 by volume) to furnish the title compound as an oil, 960 mg.
Reaction SMILES: CC(C)([O-])C.[Na+].[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH2:22][O:23][CH:24]3[CH:29]([C:30]4[CH:35]=[CH:34][C:33]([O:36][C@H:37]5[CH2:41][CH2:40][NH:39][CH2:38]5)=[CH:32][CH:31]=4)[CH2:28][CH2:27][N:26]([C:42]([O:44][CH2:45][C:46]4[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=4)=[O:43])[CH2:25]3)[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:52].I[C:54]1[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=1.CC1(C)C2C=CC=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=2OC2C1=CC=CC=2P(C1C=CC=CC=1)C1C=CC=CC=1>O1CCOCC1>[CH3:7][O:8][CH2:9][CH2:10][CH2:11][N:12]1[C:17]2[CH:18]=[C:19]([CH2:22][O:23][CH:24]3[CH:29]([C:30]4[CH:31]=[CH:32][C:33]([O:36][C@H:37]5[CH2:41][CH2:40][N:39]([C:54]6[CH:59]=[CH:58][CH:57]=[CH:56][CH:55]=6)[CH2:38]5)=[CH:34][CH:35]=4)[CH2:28][CH2:27][N:26]([C:42]([O:44][CH2:45][C:46]4[CH:47]=[CH:48][CH:49]=[CH:50][CH:51]=4)=[O:43])[CH2:25]3)[CH:20]=[CH:21][C:16]=2[O:15][CH2:14][C:13]1=[O:52]
Reactant: Ic1ccccc1
Reactant: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCNC4)cc3)cc21
Agent: CC(C)(C)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: [Na+]
Solvent: C1COCCO1
Product: COCCCN1C(=O)COc2ccc(COC3CN(C(=O)OCc4ccccc4)CCC3c3ccc(O[C@H]4CCN(c5ccccc5)C4)cc3)cc21

Procedure:
The mixture of 0.106 g of sodium tert-butoxide, 0.500 g of benzyl 3-[4-(3-methoxypropyl)-3-oxo-3,4-dihydro-2H-benzo[1,4]oxazin-6-ylmethoxy]-4-[4-(pyrrolidin-3(S)-yloxy)phenyl]piperidine-1-carboxylate, 0.106 ml iodobenzene and 8.5 ml of dioxane is initially charged under argon in a Schlenk apparatus with stirring. The mixture is admixed with the solution of 0.028 g of 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene and tris(dibenzylidenacetone)dipalladium(0) in 2.5 ml of dioxane (prepared in a Schlenk apparatus under argon) and stirred at 60° C. for 3 hours. The reaction mixture is cooled, poured onto ice-water (70 ml) and extracted with tert-butyl methyl ether (2×70 ml). The organic phases are washed with brine (70 ml), dried over sodium sulphate and concentrated by evaporation. The title compound is obtained as a brown foam from the residue by means of flash chromatography (SiO2 60F). Rf=0.20 (1:1 EtOAc-heptane). Rt=5.88.
Reaction SMILES: O=[C:2]1[C:10](=[CH:11][C:12]2[NH:13][C:14]3[CH2:15][CH2:16][CH2:17][CH2:18][C:19]=3[C:20]=2[CH2:21][CH2:22][C:23](O)=[O:24])[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3]1.C(N1C=CN=C1)(N1C=CN=C1)=O.[CH3:38][NH2:39].[OH2:40]>CN(C)C=O>[CH3:38][NH:39][C:23](=[O:24])[CH2:22][CH2:21][C:20]1[C:19]2[CH2:18][CH2:17][CH2:16][CH2:15][C:14]=2[NH:13][C:12]=1[CH:11]=[C:10]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[NH:3][C:2]1=[O:40]
Reactant: O=C(O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Reactant: CN
Reactant: O
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CN(C)C=O
Product: CNC(=O)CCc1c(C=C2C(=O)Nc3ccccc32)[nH]c2c1CCCC2
Temperature: 25 °C
Reaction time: 1 h
Yield: 80 %

Procedure:
3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionic acid (10 g) was dissolved in 100 mL of dimethylformamide. Carbonyldiimidazole (6.3 g) was added and the mixture stirred at ambient temperature for 1 hour. Methyl amine (1.8 g) in 30 mL of dimethylformamide was added and the stirring continued overnight. Fifty mL of water was added to the mixture and stirring was continued for 10 minutes. The precipitate was collected by vacuum filtration, washed with 20 mL of water and then 20 mL of ethanol. The solid was slurry-washed in 30 mL of refluxing ethanol for 5 minutes and cooled to room temperature. The solid was collected by vacuum filtration, washed with 20 mL of ethanol and vacuum dried to give 8.3 g (80% yield) of N-methyl-3-[2-(2-oxo-1,2-dihydroindol-3-ylidenemethyl)-4,5,6,7-tetrahydro-1H-indol-3-yl]-propionamide as an orange solid.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]2[S:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH2:15])[C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[N:4]=[CH:3]1.[CH3:23][C:24](N(C)C)=[O:25].CCN(C(C)C)C(C)C.C(OC(=O)C)(=O)C>O>[CH3:1][N:2]1[C:6]([C:7]2[S:16][C:10]3[N:11]=[CH:12][N:13]=[C:14]([NH:15][C:24](=[O:25])[CH3:23])[C:9]=3[CH:8]=2)=[C:5]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[N:4]=[CH:3]1
Reactant: Cn1cnc(-c2ccccc2)c1-c1cc2c(N)ncnc2s1
Reactant: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC(=O)OC(C)=O
Product: CC(=O)Nc1ncnc2sc(-c3c(-c4ccccc4)ncn3C)cc12
Temperature: 25 °C
Yield: 76 %

Procedure:
6-(1-Methyl-4-phenyl-1H-imidazol-5-yl)thieno[2,3-d]pyrimidine-4-amine (Example 8) (29 mg), DMA (2 mL), DIPEA (0.05 mL) and acetic anhydride (0.01 mL) were heated at 82° C. for 1 day. The reaction mixture was cooled to ambient temperature, water (2 mL) added and then preparative RPHPLC (eluting with a gradient of MeCN and water containing 0.1% TFA) afforded the title compound as a colourless solid (25 mg, 76%);
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][CH2:10][N:11]2C(=O)C3C(=CC=CC=3)C2=O)[N:5]=[CH:4][C:3]=1[NH:22][C@@H:23]1[CH2:28][C@@H:27]2[CH2:29][C@@H:25]([C:26]2([CH3:31])[CH3:30])[C@H:24]1[CH3:32].O.NN>CO>[NH2:11][CH2:10][CH2:9][N:6]1[C:7](=[O:8])[C:2]([Br:1])=[C:3]([NH:22][C@@H:23]2[CH2:28][C@@H:27]3[CH2:29][C@@H:25]([C:26]3([CH3:31])[CH3:30])[C@H:24]2[CH3:32])[CH:4]=[N:5]1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN3C(=O)c4ccccc4C3=O)c(=O)c1Br)C2(C)C
Agent: NN
Solvent: O
Solvent: CO
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CCN)c(=O)c1Br)C2(C)C
Yield: 28 %

Procedure:
2-{2-[5-Bromo-6-oxo-4-{[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-yl]amino}pyridazin-1(6H)-yl]ethyl}-1H-isoindole-1,3(2H)-dione prepared above in methanol (6 mL) was stirred with hydrazine monohydrate (50 μL, 1.6 mmol) at 80° C. for 6 hours. After completion of the reaction, the solvent was removed by vacuum distillation, and the resulting residue was purified by silica gel column chromatography (ethyl acetate/methanol=4/1) to give the desired product (32 mg, 28% yield).
Reaction SMILES: [OH:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4].C(N(CC)CC)C.[CH3:16][S:17](Cl)(=[O:19])=[O:18]>C(Cl)Cl>[CH3:16][S:17]([O:1][CH:2]([CH2:5][CH2:6][C:7]#[CH:8])[C:3]#[N:4])(=[O:19])=[O:18]
Reactant: CS(=O)(=O)Cl
Reactant: C#CCCC(O)C#N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCCC(C#N)OS(C)(=O)=O
Yield: 87.4 %

Procedure:
A mixture of 2-hydroxy-5-hexynenitrile (8.0 g, 73.3 mmol) and dry triethylamine (10.1 g, 0.1 mol) in 50 ml of dry CH2Cl2 was treated with a solution of methanesulfonyl chloride (10.3 g, 90 mmol) in 50 ml of CH2Cl2, at 0° C. for 11/2 h. The reaction mixture was diluted with CH2Cl2, washed twice with cold 1.0 N H2SO4, twice with water, and dried over MgSO4. The filtered CH2Cl2 solution was concentrated at 40° C./30 mm to give 12 g of pale yellow liquid. Purification of this material on 220 g of silica gel and eluted with ether-petroleum ether (1:1 parts by volume) gave 8.7 g (56% by weight yield from pentynal) of 2-[(methylsulfonyl)]-5-hexynenitrile as a colorless liquid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:23]([OH:25])=O.Cl.Cl.[C:39]1([CH2:49][NH2:50])[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:32]=[CH:33][C:34]=1[O:35][CH3:36])[CH2:6][CH:7]1[C:13]2[CH:14]=[C:15]([O:20][CH3:21])[C:16]([O:18][CH3:19])=[CH:17][C:12]=2[CH2:11][CH2:10][CH2:9][N:8]1[CH:22]([C:26]1[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1)[C:23]([NH:50][CH2:49][C:39]1[C:48]2[C:43](=[CH:44][CH:45]=[CH:46][CH:47]=2)[CH:42]=[CH:41][N:40]=1)=[O:25]
Reactant: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)O)c2ccccc2)cc1OC
Reactant: NCc1nccc2ccccc12
Agent: Cl
Product: COc1ccc(CC2c3cc(OC)c(OC)cc3CCCN2C(C(=O)NCc2nccc3ccccc23)c2ccccc2)cc1OC

Procedure:
prepared by reaction of [1-(3,4-dimethoxy-benzyl)-7,8-dimethoxy-1,3,4,5-tetrahydro-benzo[c]azepin-2-yl]-phenyl-acetic acid with C-isoquinolin-1-yl-methylamine dihydrochloride.
Reaction SMILES: COC(=O)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1C.BrN1[C:17](=[O:18])CCC1=O.COC(C)(C)C.[C:26]([O-:29])(O)=[O:27].[Na+]>C(Cl)(Cl)(Cl)Cl>[CH3:17][O:18][C:8]1[CH:7]=[CH:6][C:5]2[O:27][CH2:26][O:29][C:4]=2[CH:9]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccccc1C
Reactant: O=C1CCC(=O)N1Br
Agent: [Na+]
Solvent: ClC(Cl)(Cl)Cl
Solvent: COC(C)(C)C
Product: COc1ccc2c(c1)OCO2

Procedure:
To a solution of methyl-2-methylbenzoate (3.00 g, 20.0 mmol) in carbon tetrachloride (15 ml) was added N-bromosuccinimide (3.55 g. 20.00 mmol). The reaction was allowed to stir at reflux for 3 h. The mixture was cooled and then partioned between t-butyl methyl ether and 5% NaHCO3. The combined organic extracts (×3) were washed with water, brine, and dried (MgSO4). Removal of the solvent under reduced pressure afforded the title compound as a white solid (4.60 g, quantitative yield). 1H NMR (400 MHz. CDCl13) δ 7.98 (d, 1H), 7.54-7.35 (mm, 3H), 4.98 (s, 2H), 3.98 (s. 3H)
Reaction SMILES: [C:1]1([C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[C:14]([CH3:17])([CH3:16])[CH3:15])[C@H:9]([C:27]([O:29]C)=[O:28])[CH2:8]2)=[CH:3][CH:2]=1.O.[OH-].[Li+]>C1COCC1.CO.O>[C:1]1([C:36]2[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=2)[CH:6]=[CH:5][C:4]([C@@:7]2([S:31][CH2:32][CH2:33][CH2:34][CH3:35])[CH2:11][N:10]([C:12](=[O:26])[C@@H:13]([NH:18][C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[C:14]([CH3:15])([CH3:16])[CH3:17])[C@H:9]([C:27]([OH:29])=[O:28])[CH2:8]2)=[CH:3][CH:2]=1
Reactant: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)OC)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: CCCCS[C@@]1(c2ccc(-c3ccccc3)cc2)C[C@@H](C(=O)O)N(C(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)(C)C)C1
Temperature: 25 °C
Reaction time: 5 h
Yield: 82.8 %

Procedure:
To a solution of (2S,4R)-methyl 4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylate (430 mg, 0.738 mmol) in THF (4 mL) and MeOH (4.00 mL) was added pre-made solution of lithium hydroxide monohydrate (61.9 mg, 1.476 mmol) in water (4 mL). The formed cloudy solution was stirred at room temperature for 5 h. Quenched with 5% citric acid, extracted with EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered, evaporated, to afford the desired product (2S,4R)-4-(biphenyl-4-yl)-1-((S)-2-(tert-butoxycarbonylamino)-3,3-dimethylbutanoyl)-4-(butylthio)pyrrolidine-2-carboxylic acid (409 mg, 0.611 mmol, 83% yield) as a white foam. LC-MS (retention time: 3.49 min, method B), MS m/z 569 (M+H).
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:16][CH3:17])=[CH:4][C:5]([F:15])=[C:6]([CH:14]=1)[C:7]([NH:9][CH2:10][CH2:11][O:12][CH3:13])=[O:8].[NH2:18][C:19]1[S:20][C:21]2[CH:27]=[C:26]([O:28][C:29]([F:32])([F:31])[F:30])[CH:25]=[CH:24][C:22]=2[N:23]=1.[C:33](N1C=CN=C1)(N1C=CN=C1)=S>C(Cl)CCl>[CH3:13][O:12][CH2:11][CH2:10][NH:9][C:7]([C:6]1[C:5]([F:15])=[CH:4][C:3]2[N:16]([CH3:33])[C:17]([NH:18][C:19]3[S:20][C:21]4[CH:27]=[C:26]([O:28][C:29]([F:32])([F:30])[F:31])[CH:25]=[CH:24][C:22]=4[N:23]=3)=[N:1][C:2]=2[CH:14]=1)=[O:8]
Reactant: S=C(n1ccnc1)n1ccnc1
Reactant: CNc1cc(F)c(C(=O)NCCOC)cc1N
Reactant: Nc1nc2ccc(OC(F)(F)F)cc2s1
Solvent: ClCCCl
Product: COCCNC(=O)c1cc2nc(Nc3nc4ccc(OC(F)(F)F)cc4s3)n(C)c2cc1F
Yield: 33.7 %

Procedure:
6-Fluoro-1-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-1H-benzoimidazole-5-carboxylic acid (2-methoxy-ethyl)-amide (41 mg) was prepared by following General Procedure D starting from 5-amino-2-fluoro-N-(2-methoxy-ethyl)-4-methylamino-benzamide (72 mg), 2-amino-6-(trifluoromethoxy)-benzothiazole (59 mg), 1,1′-thiocarbonyldiimidazole (64 mg), and EDC (77 mg). LC/MS: m/z 484.8. 1H NMR (DMSO-d6, 400 MHz): δ 12.35 (bs, 1H), 8.16 (s, 1H), 7.91 (d, 1H), 7.88 (s, 1H), 7.73 (d, 1H), 7.50 (d, 1H), 7.36 (d, 1H), 3.61 (bs, 3H), 3.51-3.40 (m, 4H), 3.30 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:31])([F:30])[C:3]1[CH:4]=[C:5]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:29]=[CH:28][CH:27]=[C:26]4[C:22]=3[CH2:23][CH2:24][NH:25]4)[N:17]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH:10]([CH3:15])[C:11]([F:14])([F:13])[F:12].[H-].[Na+].[C:34](Cl)(=[O:36])[CH3:35].O>CN(C=O)C>[C:34]([N:25]1[C:26]2[C:22](=[C:21]([C:18]3[N:17]=[C:16]([C:5]4[CH:6]=[CH:7][C:8]([O:9][CH:10]([CH3:15])[C:11]([F:12])([F:13])[F:14])=[C:3]([C:2]([F:1])([F:30])[F:31])[CH:4]=4)[O:20][N:19]=3)[CH:29]=[CH:28][CH:27]=2)[CH2:23][CH2:24]1)(=[O:36])[CH3:35]
Reactant: CC(=O)Cl
Reactant: CC(Oc1ccc(-c2nc(-c3cccc4c3CCN4)no2)cc1C(F)(F)F)C(F)(F)F
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)N1CCc2c(-c3noc(-c4ccc(OC(C)C(F)(F)F)c(C(F)(F)F)c4)n3)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (100 mg) in DMF (1.0 ml) was added 60% NaH (10.9 mg) at 0° C., followed by stirring at room temperature for 0.5 hour. Acetyl chloride (24.1 μl) was added thereto at 0° C., followed by stirring at room temperature for 3 hours. To the reaction solution was added water (30 ml), followed by extraction three times with EtOAc (20 ml). The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and then filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography (automatic purifier, n-hexane:EtOAc=90:10 to 60:40) to obtain 1-acetyl-4-{5-[3-(trifluoromethyl)-4-(2,2,2-trifluoro-1-methylethoxy)phenyl]-1,2,4-oxadiazol-3-yl}indoline (56.8 mg) as a white crystal.
Reaction SMILES: CCCP(O)(O)=O.CCN(C(C)C)C(C)C.[CH2:17]([O:19][P:20]([CH2:25][C:26]1[CH:31]=[CH:30][C:29]([NH:32][C:33]2[N:38]=[C:37]([NH:39][C:40]3[CH:41]=[CH:42][C:43]([C@@H:51]4[CH2:56][CH2:55][C@H:54]([C:57]([OH:59])=O)[CH2:53][CH2:52]4)=[C:44]4[C:48]=3[C:47](=[O:49])[N:46]([CH3:50])[CH2:45]4)[C:36]([C:60]([F:63])([F:62])[F:61])=[CH:35][N:34]=2)=[C:28]([O:64][CH3:65])[CH:27]=1)([O:22][CH2:23][CH3:24])=[O:21])[CH3:18].Cl.[NH2:67][OH:68]>CN(C=O)C>[OH:68][NH:67][C:57]([C@@H:54]1[CH2:55][CH2:56][C@H:51]([C:43]2[CH:42]=[CH:41][C:40]([NH:39][C:37]3[C:36]([C:60]([F:63])([F:61])[F:62])=[CH:35][N:34]=[C:33]([NH:32][C:29]4[CH:30]=[CH:31][C:26]([CH2:25][P:20](=[O:21])([O:19][CH2:17][CH3:18])[O:22][CH2:23][CH3:24])=[CH:27][C:28]=4[O:64][CH3:65])[N:38]=3)=[C:48]3[C:44]=2[CH2:45][N:46]([CH3:50])[C:47]3=[O:49])[CH2:52][CH2:53]1)=[O:59]
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)O)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Reactant: NO
Agent: CCCP(=O)(O)O
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc([C@H]4CC[C@@H](C(=O)NO)CC4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To 50% 1-propylphosphonic acid cyclic anhydride in DMF (9.9 μL, 0.017 mmol) were added additional DMF (0.5 mL), DIPEA (9.9 μL, 0.0567 mmol) and cis-4-(7-{[2-({4-[(diethoxyphosphoryl)methyl]-2-methoxyphenyl}amino)-5-(trifluoromethyl) pyrimidin-4-yl]amino}-2-methyl-1-oxo-2,3-dihydro-1H-isoindol-4-yl)cyclohexanecarboxylic acid (10.0 mg, 0.0142 mmol). The mixture was stirred at room temperature for 30 minutes. Hydroxylamine hydrochloride (2.0 mg, 0.0283 mmol) was added and the mixture was stirred at room temperature overnight. The crude mixture was purified by MDP to obtain the title compound (5.2 mg, 51% yield). 1H NMR (400 MHz, methanol-d4) d ppm 1.29 (t, J=7.1 Hz, 6 H), 1.68-1.82 (m, 4 H), 2.00-2.16 (m, 4 H), 2.52 (br. s., 1 H), 2.73 (t, J=11.1 Hz, 1 H), 3.19 (s, 3 H), 3.38 (d, J=21.7 Hz, 2 H), 3.90 (s, 3 H), 4.11 (qd, J=7.3, 7.1 Hz, 4 H), 4.55 (s, 2 H), 6.95-7.04 (m, 1 H), 7.14 (s, 1 H), 7.39 (br. s., 1 H), 7.65 (d, J=8.1 Hz, 1 H), 8.33 (br. s., 2 H). MS (ES+): m/z 721.19 (100) [MH+]; HPLC: tR=0.97 min (UPLC, purity).
Reaction SMILES: [NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][SH:4].[CH2:8](Br)[CH:9]=[CH2:10].[OH:12]O>>[NH2:1][C@H:2]([C:5]([OH:7])=[O:6])[CH2:3][S:4]([CH2:8][CH:9]=[CH2:10])=[O:12]
Reactant: N[C@@H](CS)C(=O)O
Reactant: C=CCBr
Reactant: OO
Product: C=CCS(=O)C[C@H](N)C(=O)O
Yield: 15.7 %

Procedure:
Alliin was synthesized from L-cysteine and allyl bromide following oxidation by H2O2 by the procedure of Stoll and Seebeck, 1951. The stereospecific product obtained, (+)S-allyl-L-cysteine sulfoxide (M.P.=164°, [α]D in H2O+62.1°), was identical to the natural substrate, alliin (Yield: 15.7%).