Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2]([NH:5][CH2:6][C:7]1[C:15]2[S:14](=[O:17])(=[O:16])[N:13]=[C:12]([CH2:18][C:19]([OH:21])=O)[NH:11][C:10]=2[S:9][CH:8]=1)(=[O:4])=[O:3].F[P-](F)(F)(F)(F)F.N1([O:38][C:39](N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CN1CCOCC1.C(OC(=O)[C:57]([CH2:64][NH:65][CH:66]1[CH2:70][CH2:69][CH2:68][CH2:67]1)([CH3:63])[CH2:58][CH2:59][CH:60]([CH3:62])[CH3:61])C.[O-]CC.[Na+].C(O)C>CN(C)C=O>[CH:66]1([N:65]2[CH2:64][C:57]([CH3:63])([CH2:58][CH2:59][CH:60]([CH3:61])[CH3:62])[C:19]([OH:21])=[C:18]([C:12]3[NH:11][C:10]4[S:9][CH:8]=[C:7]([CH2:6][NH:5][S:2]([CH3:1])(=[O:3])=[O:4])[C:15]=4[S:14](=[O:16])(=[O:17])[N:13]=3)[C:39]2=[O:38])[CH2:67][CH2:68][CH2:69][CH2:70]1
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: CS(=O)(=O)NCc1csc2c1S(=O)(=O)N=C(CC(=O)O)N2
Reactant: CCOC(=O)C(C)(CCC(C)C)CNC1CCCC1
Agent: CC[O-]
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CN1CCOCC1
Solvent: CCO
Solvent: CN(C)C=O
Product: CC(C)CCC1(C)CN(C2CCCC2)C(=O)C(C2=NS(=O)(=O)c3c(CNS(C)(=O)=O)csc3N2)=C1O
Temperature: 25 °C
Reaction time: 22 h
Yield: 7.4 %

Procedure:
[7-(Methanesulfonylamino-methyl)-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-3-yl]-acetic acid (prepared as described in Example 2c; 0.274 g, 0.775 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (0.324 g, 0.853 mmol) and 4-methylmorpholine (0.171 mL, 1.55 mmol) were added sequentially to a solution of rac-2-cyclopentylaminomethyl-2,5-dimethyl-hexanoic acid ethyl ester (0.209 g, 0.776 mmol) in N,N-dimethylformamide (8 mL) at 25° C. The reaction mixture was stirred at 25° C. for 22 h, and then was concentrated in vacuo. The residue was partitioned between 1.0 M aqueous hydrochloric acid solution (100 mL) and ethyl acetate (2×100 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was dissolved in ethanol (15 mL) at 25° C. A 21 wt. % solution of sodium ethoxide in ethanol (1.51 mL, 4.66 mmol) was added and the reaction mixture was heated to 70° C. for 24 h. After cooling to 25° C., the reaction mixture was partitioned between 1.0 M aqueous hydrochloric acid solution (150 mL) and ethyl acetate (2×150 mL). The organic layers were dried over sodium sulfate and were concentrated in vacuo. The residue was purified by flash chromatography (Teledyne Isco RediSep column; 40-100% ethyl acetate in hexanes) to afford rac-N-{3-[1-cyclopentyl-4-hydroxy-5-methyl-5-(3-methyl-butyl)-2-oxo-1,2,5,6-tetrahydro-pyridin-3-yl]-1,1-dioxo-1,4-dihydro-1λ6-thieno[2,3-e][1,2,4]thiadiazin-7-ylmethyl}-methanesulfonamide (0.032 g, 0.057 mmol, 7%) as an orange oil. 1H NMR (400 MHz, DMSO-d6) δ: 0.83-0.86 (6H, m), 0.88-0.91 (1H, m), 1.01 (3H, s), 1.08-1.17 (6H, m), 1.23-1.30 (2H, m), 1.41-1.51 (3H, m), 1.95-2.01 (1H, m), 2.95 (3H, s), 3.17-3.21 (1H, m), 3.46-3.51 (1H, m), 3.99-4.05 (1H, m), 4.23 (2H, d, J=5.4 Hz), 7.24 (1H, s), 7.64 (1H, bs). LC-MS (ESI) calculated for C23H34N4O6S3 558.16. found 559.1 [M+H+].
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([NH:23][C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH3:31][Si](C)(C)[N-][Si](C)(C)C.[Na+].CI>C1COCC1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([NH:14][C:15]([C:17]2[CH:18]=[N:19][C:20]([N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH3:31])=[CH:21][CH:22]=2)=[O:16])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: CC(C)(C)OC(=O)Nc1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Product: CN(C(=O)OC(C)(C)C)c1ccc(C(=O)NC2CCN(C(=O)OC(C)(C)C)CC2)cn1

Procedure:
The above prepared 4-[(6-tert-butoxycarbonylamino-pyridine-3-carbonyl)-amino]-piperidine-1-carboxylic acid tert-butyl ester (0.720 g, 1.71 mmol) was dissolved in 30 ml of abs. THF and treated at 0° C. with sodium hexamethyldisilazide-solution (1M in THF, 1.05 eq.) and, after 15 Min., 50 eq. of methyl iodide (5.33 ml). The mixture was allowed to react for six days! Pouring onto crashed ice/NH4Cl, twofold extraction with AcOEt, washing with water and brine, drying over magnesium sulfate, and evaporation of the solvents, followed by flash chromatography (silica gel, hexane/AcOEt=55/45) yielded eventually 0.497 g of the title compound as white foam.
Reaction SMILES: [CH:1]1[C:5]2=[CH:6][S:7][C:8]3[CH:15]=[CH:14][CH:13]=[CH:12][C:9]=3[C:10](=[O:11])[N:4]2[CH2:3][CH:2]=1.[CH3:16][N:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[Na+].[Na+].[Na+].[I-]>CC#N>[CH3:16][N:17]1[CH2:22][CH2:21][N:20]([C@H:6]2[C@@H:5]3[CH2:1][CH2:2][CH2:3][N:4]3[C:10](=[O:11])[C:9]3[CH:12]=[CH:13][CH:14]=[CH:15][C:8]=3[S:7]2)[CH2:19][CH2:18]1
Reactant: CN1CCNCC1
Reactant: O=C1c2ccccc2SC=C2C=CCN12
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [Na+]
Solvent: CC#N
Product: CN1CCN([C@@H]2Sc3ccccc3C(=O)N3CCC[C@@H]23)CC1

Procedure:
A mixture of (+)-11-chloro-2,3,11,11a-tetrahydro-1H,5H,-pyrrolo[2,1-c][1,4]benzothiazepin-5-one (38)15 (0.6 g, 2.4 mmol), freshly distilled 1-methylpiperazine (0.34 mL, 3.1 mmol), Na2CO3(1.06 g, 10.0 mmol), NaI (0.36 g, 2.4 mmol) in dry CH3CN (30 mL) was gently refluxed for 20 hours. The solvent was evaporated and the residue was partitioned between CH2Cl2 and water. The organic phase was successively washed with a 2% solution of Na2S2O3, water and brine. The residue obtained after evaporation was chromatographed on silica gel eluting with 5% methanol in CH2Cl2. The title compound 27 was obtained as a white solid (0.55 g, 73% yield): mp 188–190° C. (2-propanol-isopropyl ether); IR (KBr) 1630 cm−1; 1H NMR (CDCl3) δ7.71 (m, 1H), 7.50 (m, 2H), 7.61 (m, 1H), 7.33 (m, 2H), 4.36 (d, 1H, J=11.2 Hz), 3.70 (m, 3H), 2.58 (m, 4H), 2.38 (m, 4H), 2.27 (s, 3H), 2.02 (m, 4H). MS m/z 317 (100, M+), 217, 180, 139, 99, 70. Anal. (C17H23N3OS)C, H, N.
Reaction SMILES: [NH:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6].S(=O)(=O)(O)O.C(=O)([O-])O.[Na+].[CH2:17]([O:24][C:25](Cl)=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[CH2:17]([O:24][C:25]([N:1]1[CH2:4][CH2:3][C@H:2]1[CH2:5][OH:6])=[O:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: OC[C@@H]1CCN1
Reactant: O=C(Cl)OCc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: O=C(OCc1ccccc1)N1CC[C@H]1CO
Reaction time: 14 h
Yield: 85 %

Procedure:
This solution of (S)-azetidine-2-methanol was adjusted to pH 10 by adding 10% sulfuric acid, sodium hydrogen carbonate (2.00 g, 24.0 mmol) was then added, and benzyloxycarbonyl chloride (4.00 g, 24.0 mmol) was added thereto at room temperature. The mixture was then stirred for 14 hours. The solution was adjusted to pH 7, and extracted with ethyl acetate (50 mL×2). The extract was washed with water (50 mL×1), dried over magnesium sulfate and filtered, and the filtrate was concentrated. The concentrate was subjected to column chromatography (Wakogel C-200) using toluene/ethyl acetate (1/1) as a mobile phase. This separation/purification gave (S)-N-benzyloxycarbonylazetidine-2-methanol (1.88 g, yield 85.0%). The yield was improved as compared with that obtained in Example 1 (69.1%). The formation of the byproduct (S)-2-N-benzyloxycarbonyl-1,4-butanediol decreased to a yield of 3.0% (0.07 g).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([S:10](Cl)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2].[NH2:14][C:15]1[S:16][CH:17]=[CH:18][N:19]=1.N1C=CC=CC=1>ClCCl>[C:1]([C:3]1[CH:4]=[C:5]([S:10]([NH:14][C:15]2[S:16][CH:17]=[CH:18][N:19]=2)(=[O:12])=[O:11])[CH:6]=[CH:7][C:8]=1[F:9])#[N:2]
Reactant: N#Cc1cc(S(=O)(=O)Cl)ccc1F
Reactant: Nc1nccs1
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1cc(S(=O)(=O)Nc2nccs2)ccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 60.5 %

Procedure:
3-Cyano-4-fluorobenzenesulfonyl chloride (10 g, 45.53 mmol) was added portion wise to a solution of 2-aminothiazole (5 g, 50.13 mmol) in dichloromethane (50 mL) and pyridine (18.4 mL, 228 mmol) at 0° C. The reaction mixture was allowed to warm to room temperature. After 1 hour a precipitate was observed. The mixture was stirred for 18 hours at room temperature. The mixture was sonicated for 2.5 hours until the solid had dissolved, then left to stir at room temperature for 18 hours. The reaction mixture was then concentrated in vacuo and azeotropically dried with toluene (2×100 mL). The residue was diluted carefully with a 1M aqueous solution of hydrogen chloride and stirred for 1 hour at room temperature whereupon a precipitate formed. The brown solid was collected by filtration and triturated with dichloromethane to afford the title compound as a brown solid (7.8 g, 60%).
Reaction SMILES: Cl.C[O:3][C:4](=[O:34])[C@H:5]([CH2:27][C:28]1[N:29]=[C:30]([NH2:33])[S:31][CH:32]=1)[NH:6][C:7](=[O:26])[C@H:8]([CH2:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[NH:9][S:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)(=[O:12])=[O:11].O1CCCC1.[OH-].[Na+].Cl>O>[N:13]1([S:10]([NH:9][C@H:8]([C:7]([NH:6][C@H:5]([C:4]([OH:34])=[O:3])[CH2:27][C:28]2[N:29]=[C:30]([NH2:33])[S:31][CH:32]=2)=[O:26])[CH2:19][C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)(=[O:11])=[O:12])[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1
Reactant: COC(=O)[C@H](Cc1csc(N)n1)NC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)N1CCOCC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Nc1nc(C[C@H](NC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)N2CCOCC2)C(=O)O)cs1

Procedure:
N-(4-Morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine methyl ester monohydrochloride, 2057.6 g, and 6 L of tetrahydrofuran are charged into a 50 L reactor and stirred to a thick slurry at 0° to 5° C. A solution of 456 g of sodium hydroxide in 11.4 L of water is added over 2 hours at 0° to 5° C. After stirring the reaction mixture for 30 minutes, a solution of 630.8 mL of concentrated hydrochloric acid in 7.6 L of water is added over 2 hours at 0° to 5° C. The product precipitates as a thick slurry, which is filtered and the cake washed with water (2×500 mL). The solid is dried under vacuum at 40° C. to give 1700 g of N-(4-morpholinylsulfonyl)-L-phenylalanyl-3-(2-amino-4-thiazolyl)-L-alanine as a white solid, 99.5% pure. A second crop of 108 g is obtained of 99.7% purity by HPLC; mp 149°-151° C.
Reaction SMILES: [Na].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24].O.O.C([O-])(=O)C.[Zn+2:52].C([O-])(=O)C.O>CC(C)=O>[Zn:52].[CH3:2][CH2:3][C@@H:4]([C:25]([C@H:27]([C@@H:29]([OH:45])[C@H:30]([C@H:32]1[O:37][C@@H:36]([CH2:38][C:39]([O:41][OH:42])=[O:40])[C@H:35]([CH3:43])[CH2:34][C@@H:33]1[CH3:44])[CH3:31])[CH3:28])=[O:26])[C@H:5]1[O:9][C@@:8]([C@:11]2([OH:23])[O:15][C@@:14]([C@@H:18]([OH:21])[CH2:19][CH3:20])([CH2:16][CH3:17])[CH2:13][C@H:12]2[CH3:22])([CH3:10])[CH2:7][C@@H:6]1[CH3:24]
Reactant: [Zn+2]
Agent: CC(=O)[O-]
Agent: CC[C@@H](C(=O)[C@@H](C)[C@@H](O)[C@@H](C)[C@H]1O[C@@H](CC(=O)OO)[C@H](C)C[C@@H]1C)[C@H]1O[C@](C)([C@]2(O)O[C@](CC)([C@@H](O)CC)C[C@H]2C)C[C@@H]1C
Agent: [Na]
Solvent: O
Solvent: CC(C)=O
Product: [Zn]
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A mixture of 13.0 g of sodium lysocellin and 5.0 g zinc acetate dihydrate in 150 ml of acetone was stirred at ambient temperature for approximately 18 hours. Stirring was continued and two volumes of water were added slowly to precipitate the zinc salt. The product was isolated and dried (14.0 g). The zinc salt was recrystallized from acetone. The resulting solid product had a melting point of 102.0° C. Analysis: % Zn calculated (4.95); Found (4.37).
Reaction SMILES: Br[C:2]1[C:11]([NH2:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([O:6]C)=O.O=C1CC(=O)CN(C(OCC2C=CC=CC=2)=O)C1.[CH3:32][N:33]([CH3:53])[CH2:34][CH2:35][N:36]1[CH2:48][C:47]2NC3C=CC=C4C(=O)[NH:50][N:51]=[C:38]([C:39]=2C=34)[CH2:37]1>>[CH3:32][N:33]([CH3:53])[CH2:34][CH2:35][N:36]1[CH2:48][C:47]2[NH:12][C:11]3[CH:10]=[C:9]([F:13])[CH:8]=[C:3]4[C:4](=[O:6])[NH:50][N:51]=[C:38]([C:39]=2[C:2]=34)[CH2:37]1
Reactant: CN(C)CCN1CC2=NNC(=O)c3cccc4[nH]c(c2c34)C1
Reactant: COC(=O)c1cc(F)cc(N)c1Br
Agent: O=C1CC(=O)CN(C(=O)OCc2ccccc2)C1
Product: CN(C)CCN1CC2=NNC(=O)c3cc(F)cc4[nH]c(c2c34)C1

Procedure:
Compound 61 was prepared from methyl 2-bromo-5-fluoro-3-aminobenzoate and benzyl 3,5-dioxopiperidine-1-carboxylate according to the procedures similar to those for Compound 60. 1H NMR δ 10.1 (s, 1H), 7.58 (dd, 1H, J=1.8, 10.2 Hz), 7.21 (dd, 1H, J=1.8, 10.2 Hz), 4.20-4.22 (m, 2H), 4.03 (s, 2H), 3.42 (s, 2H), 2.51-2.54 (m, 2H), and 2.19 (s, 6H). MS (ESI) m/e [M+1]+316.
Reaction SMILES: [NH2:1][C:2]1[C:35]([NH2:36])=[CH:34][CH:33]=[CH:32][C:3]=1[O:4][CH2:5][CH:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]2[O:23][N:22]=[C:21]([C:24]3[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][CH:25]=3)[N:20]=2)=[CH:13][CH:12]=1.[N:37]([O-])=O.[Na+]>C(O)(=O)C.O>[NH:36]1[C:35]2[CH:34]=[CH:33][CH:32]=[C:3]([O:4][CH2:5][C@@H:6]([OH:31])[CH2:7][NH:8][CH2:9][CH2:10][C:11]3[CH:16]=[CH:15][C:14]([S:17][CH2:18][C:19]4[O:23][N:22]=[C:21]([C:24]5[CH:25]=[CH:26][C:27]([CH3:30])=[CH:28][CH:29]=5)[N:20]=4)=[CH:13][CH:12]=3)[C:2]=2[N:1]=[N:37]1
Reactant: O=N[O-]
Reactant: Cc1ccc(-c2noc(CSc3ccc(CCNCC(O)COc4cccc(N)c4N)cc3)n2)cc1
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Cc1ccc(-c2noc(CSc3ccc(CCNC[C@H](O)COc4cccc5[nH]nnc45)cc3)n2)cc1
Reaction time: 0.5 h
Yield: 88.9 %

Procedure:
To a solution of 1-(2,3-diaminophenoxy)-3-[[2-[4-[[[3-(4-methylphenyl)-1,2,4-oxadiazol-5-yl]methyl]thio]phenyl]ethyl]amino]-2-propanol (0.077 g, 0.172 mmol.) in acetic acid (1.2 mL) at 5° C. was added a solution of sodium nitrite (0.013 g, 0.189 mmol) in water (0.5 mL). The mixture was stirred for 30 minutes and evaporated to dryness. The residue was purified by flash chromatography (silica gel; CH2Cl2/MeOH (3/1) to afford 0.079 g of the pure title compound. MP=110° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1)#[CH:2].[CH3:9][CH:10]1[CH2:14][CH2:13][C:12](=O)[CH2:11]1>>[CH3:9][CH:10]1[CH2:14][C:13]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:12][CH2:11]1.[CH3:9][CH:10]1[CH2:14][CH2:13][C:12]([C:2]#[C:1][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=2)=[CH:11]1
Reactant: CC1CCC(=O)C1
Reactant: C#Cc1ccccn1
Product: CC1C=C(C#Cc2ccccn2)CC1
Product: CC1CC=C(C#Cc2ccccn2)C1

Procedure:
Reactants: 2-ethynylpyridine (620 mg, 6.0 mmol), 3-methylcyclopentanone (0.64 mL, 6.0 mmol); yields 2-[(4-methyl-1-cyclopenten-1-yl)ethynyl]pyridine and 2-[(3-methyl-1-cyclopenten-1-yl)ethynyl]pyridine (1:1) as a transparent oil (200 mg, 18% overall yield), as mixture of regio- and stereoisomers. 1H NMR (CDCl3, 300 MHz) Δ8.56 (m, 1H), 7.64 (m, 1H), 7.44 (m, 1H), 7.20 (m, 1H), 6.19 (m, 0.5H), 6.18 (m, 0.5H), 2.90 (m, 0.5H), 2.70 (m, 2.5H), 2.21 (m, 2H), 1.48 (m, 0.5H), 1.08 (app d, J=7.5 Hz, 3H). Two peaks: 182 (M+), 167 (M+−Me).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[CH:6]2.C(O)(=O)C.C([BH3-])#N.[Na+].[CH:20](=O)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>O1CCCC1.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:7][CH2:6]2
Reactant: O=Cc1ccccc1
Reactant: COc1ccc2[nH]ccc2c1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: COc1ccc2c(c1)CCN2Cc1ccccc1
Reaction time: 0.33 h
Yield: 66 %

Procedure:
To a solution of 5-methoxyindole (147 mg, 1.00 mmol) in 2.5 mL of tetrahydrofuran was added acetic acid (2.5 mL) and sodium cyanoborohydride (220 mg, 3.50 mmol) at room temperature. After the reaction mixture was stirred at the same temperature for 20 min, benzaldehyde (0.20 mL, 2.0 mmol) was added with additional stirring for 1 h. After the reaction mixture was diluted with water (20 mL) and a 1:1 solution (20 mL) of hexane and ethyl acetate, the aqueous layer was extracted with a 1:1 solution (20 mL) of hexane and ethyl acetate. The combined extracts were washed with saturated NaHCO3 aqueous solution, brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=90/10 to 80/20) to obtain 5-methoxy-1-benzylindoline (158 mg, 66%) as a sticky oil. To 5-methoxy-1-benzylindoline (4.30 g, 18.0 mmol) was added a solution of 50% hydrogen bromide-acetic acid solution (90 mL) at room temperature. After the reaction mixture was stirred at 115° C. for 22 h, the reaction mixture was neutralized by saturated NaHCO3 aqueous solution (200 mL) and the solution was extracted with ethyl acetate (200 mL) twice. The combined extracts were washed with brine, and dried over MgSO4. After filtration, the filtrate was concentrated in vacuo, and the residue was purified by silica gel column chromatography (hexane/ethyl acetate=80/20 to 70/30) to obtain the title compound (3.78 g, 93%) as a sticky oil.
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])=[CH:6][C:5]([Cl:23])=[CH:4][N:3]=1.[Cl:24][C:25]1[CH:26]=[C:27]([OH:32])[CH:28]=[C:29]([Cl:31])[CH:30]=1>>[Cl:23][C:5]1[CH:6]=[C:7]([C:8]([NH:10][C@H:11]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][CH:14]=2)[CH3:12])=[O:9])[C:2]([O:32][C:27]2[CH:26]=[C:25]([Cl:24])[CH:30]=[C:29]([Cl:31])[CH:28]=2)=[N:3][CH:4]=1
Reactant: Oc1cc(Cl)cc(Cl)c1
Reactant: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Cl)cc1
Product: COC(=O)c1ccc([C@H](C)NC(=O)c2cc(Cl)cnc2Oc2cc(Cl)cc(Cl)c2)cc1

Procedure:
The title compound was prepared according to the procedure described in step 2 of Example 45 from methyl 4-((1S)-1-{[(2,5-dichloropyridin-3-yl)carbonyl]amino}ethyl)benzoate (step 1 of Example 48) and 3,5-dichlorophenol: 1H-NMR (CDCl3) δ 8.54 (1H, d, J=2.6 Hz), 8.16 (1H, d, J=2.8 Hz), 8.02 (2H, dd, J=6.6, 1.8 Hz), 7.84 (1H, d, J=7.3 Hz), 7.42 (2H, d, J=8.6 Hz), 7.31 (1H, t, J=1.8 Hz), 7.08 (2H, d, J=1.8 Hz), 5.41–5.31 (1H, m), 3.91 (3H, s), 1.60 (3H, d, J=6.9 Hz).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:24])[CH:4]=[P:5]([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Br[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]>C(Cl)Cl>[CH3:1][O:2][C:3](=[O:24])[C:4](=[P:5]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:26][C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28]
Reactant: COC(=O)C=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)(C)OC(=O)CBr
Solvent: ClCCl
Product: COC(=O)C(CC(=O)OC(C)(C)C)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of (triphenylphosphanylidene)-acetic acid methyl ester (2.26 g, 6.77 mmol) in methylene chloride (25 mL) is added t-butyl bromoacetate (1.32 g, 6.77 mmol) and the mixture is stirred at room temperature for 48 hours. The solvent is removed under reduced pressure and the residue is purified by column chromatography using a gradient of 80-100% heptane/EtOAc to afford 2-(triphenylphosphanylidene)-succinic acid 4-tert-butyl ester 1-methyl ester. MS 449.3 (M+1).
Reaction SMILES: [C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([N:17]=[N+]=[N-])[CH3:16])[C:9]=1[C:21]([O:23]CC1C=CC([N+]([O-])=O)=CC=1)=[O:22])(=[O:3])[CH3:2].O.C(O)C.P([O-])([O-])([O-])=O>O1CCOCC1.[Pd]>[C:1]([NH:4]/[CH:5]=[CH:6]/[S:7][C:8]1[CH2:14][C@H:13]2[N:10]([C:11](=[O:20])[C@@H:12]2[C@H:15]([NH2:17])[CH3:16])[C:9]=1[C:21]([OH:23])=[O:22])(=[O:3])[CH3:2]
Reactant: CC(=O)N/C=C/SC1=C(C(=O)OCc2ccc([N+](=O)[O-])cc2)N2C(=O)[C@H]([C@@H](C)N=[N+]=[N-])[C@H]2C1
Agent: [Pd]
Agent: O=P([O-])([O-])[O-]
Solvent: C1COCCO1
Solvent: CCO
Solvent: O
Product: CC(=O)N/C=C/SC1=C(C(=O)O)N2C(=O)[C@H]([C@@H](C)N)[C@H]2C1
Yield: 19.2 %

Procedure:
The azido derivative (e2) (15 mg) was dissolved in 1,4-dioxan (4 ml), water (0.6 ml), ethanol (0.15 ml) and 0.05 M pH 7.0 phosphate buffer (0.75 ml) and hydrogenated in the presence of 5% palladium on carbon (25 mg) catalyst for 2 hours. The suspension was filtered over Celite, washing well with water (25 ml). The filtrate was concentrated to about 20 ml and washed with ethyl acetate (3×50 ml). The aqueous solution was further concentrated to approximately 5 ml and chromatographed over Biogel P2, eluting with water. Fractions containing the title compound (e3) were identified by the chromophore at λmax (H2O) 307 nm in the uv spectrum and were combined to yield an aqueous solution of the product (1.9 mg), λmax (H2O) 307 nm, 230 nm.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]([OH:12])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2.C(=O)([O-])[O-].[K+].[K+].[CH:21](I)([CH3:23])[CH3:22]>CN(C=O)C>[OH:1][C:2]1[CH:11]=[C:10]([O:12][CH:21]([CH3:23])[CH3:22])[CH:9]=[C:8]2[C:3]=1[C:4](=[S:14])[CH:5]=[C:6]([CH3:13])[O:7]2
Reactant: Cc1cc(=S)c2c(O)cc(O)cc2o1
Reactant: CC(C)I
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(=S)c2c(O)cc(OC(C)C)cc2o1
Temperature: 60 °C
Reaction time: 0.5 h
Yield: 88.3 %

Procedure:
A mixture consisting of 6.88 g (30.35 mmol) 5,7-dihydroxy-2-methylthiochromone, 12.56 g (91.05 mmol) potassium carbonate, 6.07 ml (60.70 mmol) isopropyl iodide, and 150 ml DMF was stirred at 60° C. for 30 min. Subsequently, 5 added to the solution thus reacted. The product was extracted twice with ethyl acetate. organic layer was washed with saturated salt water and dried over sodium sulfate anhydride. The solvent was distilled out under reduced pressure. The resulting crude product was purified by flash column cliromatography (hexane ethyl acetate =4:1), whereby 6.71 g of 5-hydroxy-7-isopropoxy-2-methylthiochromone was obtained (yield: 83%).
Reaction SMILES: [C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH:16]S(C(C)(C)C)=O)[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11].Cl.O1CCOCC1>CO>[C:1]1([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]([NH2:16])[CH2:8][CH:9]([CH3:15])[C:10]([O:12][CH2:13][CH3:14])=[O:11]
Reactant: CCOC(=O)C(C)CC(NS(=O)C(C)(C)C)c1ccccc1-c1ccccc1
Agent: Cl
Solvent: CO
Solvent: C1COCCO1
Product: CCOC(=O)C(C)CC(N)c1ccccc1-c1ccccc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A cooled (0° C.) slightly yellow solution of ethyl 4-([1,1′-biphenyl]-2-yl)-4-(1,1-dimethylethylsulfinamido)-2-methylbutanoate (220 mg; 0.54 mmol) in MeOH (3 ml) was treated dropwise with a solution of 4 M HCl in 1,4-dioxane (0.27 ml; 1.08 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 oily residue was further dried under HV to give the chlorhydrate salt of ethyl 4-([1,1′-biphenyl]-2-yl)-4-amino-2-methylbutanoate. LC-MS (conditions A): tR=0.63 min.; [M+H]+: 298.22 g/mol.
Reaction SMILES: S(=O)(=O)(O)O.C=O.[CH:8]1([CH2:14][CH:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1.[CH2:17](NCC)C>>[CH:8]1([C:14](=[CH2:17])[CH:15]=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][CH2:9]1
Reactant: O=CCC1CCCCC1
Reactant: CCNCC
Agent: C=O
Agent: O=S(=O)(O)O
Product: C=C(C=O)C1CCCCC1
Temperature: 80 °C
Reaction time: 8 h
Yield: 80.9 %

Procedure:
Successively, sulfuric acid 62% (79.4 g, 0.5 mol), aqueous formaldehyde 35% (82 g, 1.0 mol) and cyclohexyl acetaldehyde (100.8 g, 0.8 mol) were added slowly to diethylamine (73 g, 1.0 mol) at 0° C. After stirring at 80° C. overnight, the reaction mixture was extracted with MTBE. The combined organic phases were washed with H2O until neutral pH was achieved, dried (MgSO4) and concentrated in vacuo. The crude product was distilled under reduced pressure using a Widmer column (10 Torr, 80° C.) yielding 89.5 g (81%) of pure product as colorless oil.