Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([S:15]([CH3:18])(=[O:17])=[O:16])[CH2:10][CH2:9]1)=O)(C)(C)C.[ClH:19]>CO.CCOCC>[ClH:19].[CH3:18][S:15]([N:11]1[CH2:12][CH2:13][CH2:14][NH:8][CH2:9][CH2:10]1)(=[O:16])=[O:17]
Reactant: CC(C)(C)OC(=O)N1CCCN(S(C)(=O)=O)CC1
Agent: Cl
Solvent: CO
Solvent: CCOCC
Product: CS(=O)(=O)N1CCCNCC1
Temperature: 25 °C

Procedure:
Crude 4-Methanesulfonyl-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.23 g) was stirred in anhydrous methanol (10 ml). 2M hydrogen chloride in ether (22 ml) was added. The reaction mixture was stirred at room temperature. After 5 minutes a precipitate formed, addition of anhydrous methanol (5 ml) caused this to dissolve. The reaction mixture was stirred overnight at room temperature. The solvents were removed in vacuo to yield 1.06 g of 1-methanesulfonyl-[1,4]diazepane hydrochloride salt.
Reaction SMILES: C([Al:5]([CH2:10][CH:11]([CH3:13])[CH3:12])[CH2:6][CH:7]([CH3:9])[CH3:8])C(C)C.[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[OH:23]>C1(C)C=CC=CC=1>[Cl:14][C:15]1[CH:20]=[C:19]([Cl:21])[CH:18]=[C:17]([Cl:22])[C:16]=1[O:23][Al:5]([CH2:6][CH:7]([CH3:8])[CH3:9])[CH2:10][CH:11]([CH3:12])[CH3:13]
Reactant: CC(C)C[Al](CC(C)C)CC(C)C
Reactant: Oc1c(Cl)cc(Cl)cc1Cl
Solvent: Cc1ccccc1
Product: CC(C)C[Al](CC(C)C)Oc1c(Cl)cc(Cl)cc1Cl

Procedure:
In a manner analogous to that described in Example 1, 17.5 g of triisobutylaluminum and 17.4 g of 2,4,6-trichlorophenol are reacted in absolute toluene to give (2,4,6-trichlorophenoxy)diisobutylaluminum and this is then reacted with 22.4 g of pyridine-N-oxide-2-thiol to afford the title compound. The isolation of the product is carried out in analogous manner. The yield of (2,4,6-trichlorophenoxy)bis(2-pyridinethiolato)-aluminum N,N'-dioxide, a fine white powder with a melting point of 207°-208° C., is 28.6 g, about 68% of theory.
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]2[N:14]([CH2:23][C:24]3[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=3)[CH:15]=[C:16]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:10]=2[CH2:9]1)=O)(C)(C)C.C(OC(N1CCC(=O)CC1)=O)(C)(C)C.[N+](C=CC1C=CC=CC=1)([O-])=O>C(N)C1C=CC=CC=1>[CH2:23]([N:14]1[C:11]2[CH2:12][CH2:13][NH:8][CH2:9][C:10]=2[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15]1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)OC(=O)N1CCc2c(c(-c3ccccc3)cn2Cc2ccccc2)C1
Agent: CC(C)(C)OC(=O)N1CCC(=O)CC1
Agent: O=[N+]([O-])C=Cc1ccccc1
Solvent: NCc1ccccc1
Product: c1ccc(Cn2cc(-c3ccccc3)c3c2CCNC3)cc1

Procedure:
1-Benzyl-3-phenyl-1,4,6,7-tetrahydro-pyrrolo[3,2-c]pyridine-5-carboxylic acid tert-butyl ester. The desired compound (380.7 mg) was prepared from 0.51 g of 4-oxo-piperidine-1-carboxylic acid tert-butyl ester, 280 μL of benzylamine, and 0.39 g of (2-nitro-vinyl)-benzene as in Example 1, Step A. MS (ESI): exact mass calculated for C25H28N2O2, 388.22. found, m/z 389.2 [M+H]+.
Reaction SMILES: [CH:1]1[C:6]([OH:7])=[CH:5][CH:4]=[C:3]([Br:8])[CH:2]=1.N1C=CN=C1.[Si:14](Cl)([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15].[NH4+].[Cl-]>ClCCCl>[Br:8][C:3]1[CH:4]=[CH:5][C:6]([O:7][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])=[CH:1][CH:2]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(Br)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: c1c[nH]cn1
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 99.6 %

Procedure:
To a stirred solution of p-bromophenol (30 g, 0.1734 mol) in 1, 2-dichloroethane (300 mL) at 23° C. was added imidazole (29.45 g, 0.433 mol). After 15 min, tert-butyldimethylsilylchloride (28.75 g, 0.190 mol) was added, and the resulting solution heated at reflux for 3 h. The mixture was cooled to room temperature and poured onto saturated aqueous NH4Cl and extracted with CH2Cl2 (3×200 mL). The combined extracts were washed with brine (200 mL), dried (NaSO4), filtered and evaporated in vacuo. The crude product was distilled via short-path distillation (0.5 mm Hg, 130° C.) to give (4-bromo-phenoxy)-tert-butyl-dimethylsilane (49.6 g, 99.5% yield) as a colorless oil. Rf=0.80 (1:3 EtOAc/hexanes). IR (thin film) 3390, 2951, 2928, 1584, 1479, 1250 cm−1. 1H NMR (300 MHz, CDCl3) δ 7.34 (1H, d, J=9 Hz), 6.74 (1H, d, J=9 Hz), 1.00 (12H, s), 0.21 (6H, s). 13C NMR (75 MHz, CDCl3) δ 154.76, 132.22, 121.83, 113.55, 25.58, 18.12, −4.54. HRMS calcd. for C12H20BrOSi (MH+) 287.0461. found 287.0463.
Reaction SMILES: C(OC([NH:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:32]=[CH:31][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)=[CH:29][N:28]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])=O)C1C=CC=CC=1>CC(=O)OCC.[Pd]>[NH2:11][C@@H:12]([CH2:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]2[N:28]=[CH:29][C:30]([C:33]3[CH:38]=[CH:37][C:36]([C:39]([CH3:42])([CH3:41])[CH3:40])=[CH:35][CH:34]=3)=[CH:31][N:32]=2)=[CH:23][CH:22]=1)[C:13]([O:15][C:16]([CH3:18])([CH3:17])[CH3:19])=[O:14]
Reactant: CC(C)(C)OC(=O)[C@H](Cc1ccc(-c2ncc(-c3ccc(C(C)(C)C)cc3)cn2)cc1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)[C@@H](N)Cc1ccc(-c2ncc(-c3ccc(C(C)(C)C)cc3)cn2)cc1
Reaction time: 8 h
Yield: 88 %

Procedure:
To a stirred solution of (S)-tert-butyl 2-(((benzyloxy)carbonyl)amino)-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-10 (757 mg, 1.34 mmol) in EA (100 ml) was added Pd/C (142 mg, 0.13 mmol) and the suspension degassed with H2. The mixture was stirred vigorously under an atmosphere of H2 overnight then filtered through celite and the filtrate was concentrated to give 532 mg (88%) of (S)-tert-butyl 2-amino-3-(4-(5-(4-(tert-butyl)phenyl)pyrimidin-2-yl)phenyl)propanoate INT-11. LCMS-ESI (m/z) calculated for C27H33N3O2: 431.3; found: 432.0 [M+H]+, tR=2.01 min (Method 4).
Reaction SMILES: [C:1]([O:5][CH2:6][CH3:7])(=[O:4])[CH:2]=[CH2:3].C(=O)([O-])[O-].[K+].[K+].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([NH:27][C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[N:32]=2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43]>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C(OC(C)C)(C)C.CC(C)=O.O>[C:41]([OH:46])(=[O:45])[C:42]([OH:44])=[O:43].[CH2:14]([N:21]1[CH2:26][CH2:25][CH:24]([N:27]([CH2:3][CH2:2][C:1]([O:5][CH2:6][CH3:7])=[O:4])[C:28]2[S:29][CH:30]=[C:31]([C:33]3[CH:40]=[CH:39][C:36]([C:37]#[N:38])=[CH:35][CH:34]=3)[N:32]=2)[CH2:23][CH2:22]1)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: N#Cc1ccc(-c2csc(NC3CCN(Cc4ccccc4)CC3)n2)cc1
Reactant: C=CC(=O)OCC
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C(O)C(=O)O
Agent: O=C([O-])[O-]
Solvent: CC(C)=O
Solvent: O
Solvent: Cc1ccccc1
Product: CCOC(=O)CCN(c1nc(-c2ccc(C#N)cc2)cs1)C1CCN(Cc2ccccc2)CC1
Yield: 84 %

Procedure:
25.92 ml of ethyl acrylate, 32.98 g of potassium carbonate and 7.7 g of tetrabutylammonium bromide are added to 44.8 g of 4-{2-[N-(1-benzylpiperid-4-yl)amino]-1,3-thiazol-4-yl}benzonitrile in 900 ml of toluene, and then the reaction mixture is heated under reflux for 24 hours. The reaction mixture is cooled, then water is added and the mixture is separated after settling has taken place. The organic phase is dried over sodium sulphate and then evaporated to dryness. The oil obtained is taken up in isopropyl ether and filtered on a silica bed, entraining with isopropyl ether. The evaporation of the filtrate leads to a resin which is then salified by addition of one equivalent of oxalic acid in acetone in order to provide white crystals which melt at 225° C.; yield 84%.
Reaction SMILES: [NH2:1][C:2]1([C:6]2[S:7][C:8]([C:11]3[CH:12]=[C:13]([NH:18][C:19]4[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=4)[CH:14]=[C:15]([CH3:17])[CH:16]=3)=[CH:9][N:10]=2)[CH2:5][O:4][CH2:3]1.CCN(CC)CC.[CH3:36][S:37](Cl)(=[O:39])=[O:38]>ClCCl.C(OCC)(=O)C>[CH3:17][C:15]1[CH:16]=[C:11]([C:8]2[S:7][C:6]([C:2]3([NH:1][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:3][O:4][CH2:5]3)=[N:10][CH:9]=2)[CH:12]=[C:13]([NH:18][C:19]2[N:24]=[C:23]([C:25]([F:28])([F:27])[F:26])[CH:22]=[CH:21][N:20]=2)[CH:14]=1
Reactant: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(N)COC3)s2)c1
Reactant: CS(=O)(=O)Cl
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1cc(Nc2nccc(C(F)(F)F)n2)cc(-c2cnc(C3(NS(C)(=O)=O)COC3)s2)c1
Temperature: 25 °C
Reaction time: 1.58 h
Yield: 47.5 %

Procedure:
To a solution of N-{3-[2-(3-aminooxetan-3-yl)-1,3-thiazol-5-yl]-5-methylphenyl}-4-(trifluoromethyl)pyrimidin-2-amine (200 mg, 0.491 mmol) and Et3N (82 μL, 0.589 mmol) in dichloromethane (3.9 mL), methanesulfonyl chloride (57 μL, 0.736 mmol) was added. The reaction mixture was stirred at room temperature for 95 minutes. The mixture was then diluted with ethyl acetate, washed with saturated NaHCO3, followed by brine, dried (Na2SO4), filtered and concentrated. The residue was purified by column chromatography on silica (10-100% ethyl acetate in hexanes) and lyophilized to afford N-{3-[5-(3-methyl-5-{[4-(trifluoromethyl)-pyrimidin-2-yl]amino}phenyl)-1,3-thiazol-2-yl]oxetan-3-yl}methanesulfonamide (113 mg, 0.233 mmol, 47.4% yield) as a white powder. MS ESI: [M+H]+ m/z 486.0. 1H NMR (500 MHz, DMSO-d6) δ 10.28 (s, 1H), 8.83 (m, 2H), 8.11 (s, 1H), 7.99 (s, 1H), 7.50 (s, 1H), 7.29 (m, 1H), 7.21 (s, 1H), 4.91 (dd, J=6.6, 16.1, 4H), 2.98 (s, 3H), 2.33 (s, 3H). rhSYK activity=+++
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]#[N:5].FC1C=C(C2SC(N)=NC=2C)C=CC=1S(C)(=O)=O.[N:24]1([C:29]2[CH:30]=[C:31]([C:39]3[S:43][C:42]([NH:44][C:45](N4C=CN=C4)=[O:46])=[N:41][C:40]=3[CH3:52])[CH:32]=[CH:33][C:34]=2[S:35]([CH3:38])(=[O:37])=[O:36])[CH:28]=[CH:27][N:26]=[CH:25]1>>[C:4]([CH2:3][CH2:2][NH:1][C:45]([NH:44][C:42]1[S:43][C:39]([C:31]2[CH:32]=[CH:33][C:34]([S:35]([CH3:38])(=[O:37])=[O:36])=[C:29]([N:24]3[CH:28]=[CH:27][N:26]=[CH:25]3)[CH:30]=2)=[C:40]([CH3:52])[N:41]=1)=[O:46])#[N:5]
Reactant: Cc1nc(NC(=O)n2ccnc2)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1
Reactant: N#CCCN
Agent: Cc1nc(N)sc1-c1ccc(S(C)(=O)=O)c(F)c1
Product: Cc1nc(NC(=O)NCCC#N)sc1-c1ccc(S(C)(=O)=O)c(-n2ccnc2)c1

Procedure:
The titled compound is prepared by the same procedure as example 88, replacing 2-aminoethanol (part 88b) in this example with 3-aminopropionitrile and replacing 5-(3-fluoro-4-methanesulfonyl-phenyl)-2-isocyanato-4-methyl-thiazole (88a) with Imidazole-1-carboxylic acid [5-(3-imidazol-1-yl-4-methanesulfonyl-phenyl)-4-methyl-thiazol-2-yl]-amide (150a)
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][O:5][C:6]1[CH:7]=[C:8]([C:12]2[C:16]3[S:17][CH:18]=[CH:19][C:15]=3[O:14][N:13]=2)[CH:9]=[CH:10][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH2:32])=[CH:29][CH:28]=1.C(#N)C>C(OCC)(=O)C.ClCCl>[CH3:26][C:27]1[CH:34]=[CH:33][C:30]([CH2:31][NH:32][CH2:2][CH2:3][CH2:4][O:5][C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([C:12]3[C:16]4[S:17][CH:18]=[CH:19][C:15]=4[O:14][N:13]=3)[CH:7]=2)=[CH:29][CH:28]=1
Reactant: Cc1ccc(CN)cc1
Reactant: BrCCCOc1cccc(-c2noc3ccsc23)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CC#N
Product: Cc1ccc(CNCCCOc2cccc(-c3noc4ccsc34)c2)cc1
Temperature: 75 °C
Yield: 79.7 %

Procedure:
Mix 3-[3-(3-bromo-propoxy)-phenyl]-thieno[2,3-d]isoxazole (0.400 g, 1.18 mmol), potassium carbonate (0.326 g, 2.36 mmol), 4-methylbenzylamine (0.606, 5.00 mmol) and acetonitrile (5.0 mL) and heat (75° C.), overnight. Cool the reaction mixture and filter through a Waters Sep-Pak 1 g silica cartridge (ethyl acetate). Combine the appropriate fractions and concentrate to give a residue. Dissolved residue in 50% ethyl acetate in dichloromethane and chromatograph on silica (10 g) using ethyl acetate to give the title compound (356 mg, 80% yield). Purity by LC/MS (APCI)=98, [M+H]+=379.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5](Br)=[CH:4][N:3]=1.[F:12][C:13]1[CH:14]=[C:15](B(O)O)[CH:16]=[C:17]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:18]=1.C(=O)([O-])[O-].[K+].[K+]>C1(C)C=CC=CC=1.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([CH3:10])[C:5]([C:15]2[CH:16]=[C:17]([O:19][C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[CH:18]=[C:13]([F:12])[CH:14]=2)=[CH:4][N:3]=1
Reactant: Cc1c(Br)cnc(N)c1C#N
Reactant: OB(O)c1cc(F)cc(Oc2ccc(F)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: Cc1c(-c2cc(F)cc(Oc3ccc(F)cc3)c2)cnc(N)c1C#N

Procedure:
This compound is prepared in a manner analogous to that of Step D of Example 4, using 1.7 grams (0.008 mole) of 2-amino-5-bromo-3-cyano-4-methylpyridine, 3.0 grams (0.012 mole) of 3-fluoro-5-(4-fluorophenoxy)-phenylboronic acid, 4.3 grams (0.031 mole) of potassium carbonate and 0.3 gram of tetrakis(triphenylphosphine)palladium(0) in 150 mL of toluene, yielding 2-amino-3-cyano-4-methyl-5-[3-fluoro-5-(4-fluorophenoxy)phenyl]-pyridine.
Reaction SMILES: [CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26](OC)=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:30]#N.N>C1COCC1>[CH2:1]([N:8]1[C:20]2[CH:19]=[C:18]3[CH2:21][CH2:22][CH2:23][CH2:24][C:17]3=[C:16]([OH:25])[C:15]=2[C:14]2[C:13]([C:26]([NH2:30])=[O:27])=[CH:12][CH:11]=[CH:10][C:9]1=2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: N#N
Reactant: COC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Agent: N
Solvent: C1CCOC1
Product: NC(=O)c1cccc2c1c1c(O)c3c(cc1n2Cc1ccccc1)CCCC3
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazol-1-carboxylic acid, methyl ester, (0.097 g, 0.25 mM) in 8 mL THF was placed in an Ace Glass pressure tube (203 mm×38 mm) with a small stirring bar. A N2(g) stream was installed over the solution surface. The pressure tube and reaction solution were cooled to −78° C., and ˜8 mL NH3(l) was condensed into the reaction vessel by introduction of an NH3(g) stream. The pressure tube was sealed with a teflon O-ring screw cap, the resultant brown solution stirred at −78° C. for 10 minutes, then the cooling bath was removed and the reaction solution allowed to warm to ambient temperature behind a blast shield. After 24 h, the pressure tube was re-cooled to −78° C. and the internal NH3(g) pressure was released by careful removal of the Teflon cap. The reaction solution was allowed to slowly warm to room temperature while NH3(g) bubbled off, then the solution was concentrated in vacuo to afford 0.92 g (quantitative) of the title compound 5-benzyl-11-hydroxy-7,8,9,10-tetrahydro-5H-benzo[b]carbazole-1-carboxylic acid amide as a tan solid (MP 225° C. dec, MW 370.46).
Reaction SMILES: [CH2:1]([NH:4][C:5](=[O:11])[O:6][C:7]([CH3:10])([CH3:9])[CH3:8])[CH:2]=[CH2:3].[Cl:12][CH2:13][SiH:14]([CH3:16])[CH3:15]>C1(C)C=CC=CC=1>[C:5]([NH:4][CH2:1][CH2:2][CH2:3][Si:14]([CH2:13][Cl:12])([CH3:16])[CH3:15])([O:6][C:7]([CH3:10])([CH3:9])[CH3:8])=[O:11]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: C[SiH](C)CCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)NCCC[Si](C)(C)CCl
Temperature: 70 °C

Procedure:
A 250 mL 3-necked round bottom flask equipped with reflux condenser nitrogen inlet, thermometer heating mantle, pressure equalizing addition funnel and magnetic stirrer was charged with 14.36 g (91.3 mmol) of t-butyl N-allylcarbamate and 150 mL of toluene. The olefin and solvent were stirred and heated to about 70° C., then 10 microliters of Karstedt's catalyst (5% Pt solution, about 30 ppm Pt based on olefin) was added. A solution containing 12 g (110.5 mmol) of chloromethyldimethylsilane in 20 mL toluene was added cautiously over about 30 minutes at a rate sufficient to maintain the reaction temperature between about 80 and about 100° C. After addition was completed, the temperature was stirred and heated at about 85° for about 1 hour. GC-MS indicated complete reaction of the olefin to form the silylated compound, N-Boc-3-aminopropylchloromethyldimethylsilane. The solution was transferred to a 500 ml single neck round bottom flask and the solvent and excess silane were stripped via rotary evaporation to yield 25 g of crude product (quantitative yield based on olefin).
Reaction SMILES: [Cl:1][C:2]1[C:9]([Cl:10])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=O.[C:11]([O:17][CH3:18])(=[O:16])[CH2:12][C:13]([CH3:15])=[O:14].O.N1CCCCC1>C(Cl)Cl.CC(O)=O>[C:13]([C:12](=[CH:4][C:3]1[CH:6]=[CH:7][CH:8]=[C:9]([Cl:10])[C:2]=1[Cl:1])[C:11]([O:17][CH3:18])=[O:16])(=[O:14])[CH3:15]
Reactant: O=Cc1cccc(Cl)c1Cl
Reactant: COC(=O)CC(C)=O
Solvent: CC(=O)O
Solvent: C1CCNCC1
Solvent: O
Product: COC(=O)C(=Cc1cccc(Cl)c1Cl)C(C)=O

Procedure:
17.5 g (100 mmol) of 2,3-dichlorobenzaldehyde and 11.6 g (100 mmol) of methyl acetoacetate are boiled in a water separator for 3 h with 1 ml of piperidine and 0.5 ml of HOAc in 350 ml of CH2Cl2. The mixture is then washed twice with water, dried over MgSO4 and concentrated. The residue crystallizes from petroleum ether/ether. Yield: 15.0 g (55%)
Reaction SMILES: CO[C:3](=[O:25])[CH:4]([CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[NH:5][C:6]([NH:8][C:9]1[S:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:13]=1)=[S:7].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[F:16][C:14]([F:15])([F:17])[C:12]1[N:13]=[C:9]([N:8]2[C:3](=[O:25])[CH:4]([CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[NH:5][C:6]2=[S:7])[S:10][CH:11]=1
Reactant: COC(=O)C(Cc1ccccc1)NC(=S)Nc1nc(C(F)(F)F)cs1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: Cc1ccccc1
Product: O=C1C(Cc2ccccc2)NC(=S)N1c1nc(C(F)(F)F)cs1
Temperature: 25 °C
Yield: 52.5 %

Procedure:
A solution of N-[[(4-trifluoromethyl-2-thiazolyl)amino]thioxomethyl]-DL-phenylalanine methyl ester (2.09 g, 5.38 mmol) and p-toluene sulfonic acid hydrate (0.20 g 1.05 mmol) in toluene (80 mL) was refluxed with a Dean-Stark trap for 48 h. The reaction was cooled to room temperature, solvent removed under reduced pressure, residue taken up in ethyl acetate, washed with saturated sodium bicarbonate and saturated sodium chloride, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting product was recrystallized from ethyl ether-hexanes to provide 1.01 g (53%) of the titled product: mp 187°-189° C.; IR (CHCl3, cm-1) 3431, 3008, 1782, 1495, 1369, 1328, 1242, 1178, 1149, 1085; 1H NMR (300 MHz, DMSO-d6) δ 11.02 (s, 1H), 8.59 (s, 1H), 7.22-7.80 (m, 3H), 7.20-7.22 (m, 2H), 4.83 (t, 1H), 3.17 (d, 2H); MS (FD) m/e 357 (M+); UV (EtOH) 263 nm (ε=13898), 202 nm (ε=19355). Anal. Calcd. for C14H10F3N3OS2 : C, 47.05; H,2.82; N,11.76. Found: C,47.33; H, 2.86; N, 11.67.
Reaction SMILES: [CH:1]([C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH2:15][OH:16])[O:6][N:5]=1)([CH3:3])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH:1]([C:4]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[CH:15]=[O:16])[O:6][N:5]=1)([CH3:3])[CH3:2]
Reactant: CC(C)c1noc(-c2ccccc2CO)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC(C)c1noc(-c2ccccc2C=O)n1
Temperature: 25 °C
Reaction time: 48 h
Yield: 37.6 %

Procedure:
To a solution of [2-(3-isopropyl-1,2,4-oxadiazol-5-yl)-phenyl]methanol (373 mg, 1.71 mmol) in CH2Cl2 (5.0 mL) is added MnO2 (300 mg, 3.45 mmol). The reaction mixture is stirred at room temperature for 48 hours and is filtered through diatomaceous earth. The filtrate is concentrated under reduced pressure and the residue is purified by silica gel flash column chromatography with 30% EtOAc in heptanes as the eluent to afford 2-(3-isopropyl-1,2,4-oxadiazol-5-yl)-benzaldehyde (139 mg, 37%).
Reaction SMILES: O[CH2:2][C@@H:3]([NH:5]C(=O)OC(C)(C)C)[CH3:4].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl:32][C:33]1[CH:40]=[C:39]([C:41]2[CH:45]=[CH:44][NH:43][N:42]=2)[CH:38]=[C:37]([F:46])[C:34]=1[C:35]#[N:36].CC(OC(/N=N/C(OC(C)C)=O)=O)C.Cl>CCOC(C)=O.C(Cl)Cl.O>[NH2:5][C@@H:3]([CH3:4])[CH2:2][N:43]1[CH:44]=[CH:45][C:41]([C:39]2[CH:38]=[C:37]([F:46])[C:34]([C:35]#[N:36])=[C:33]([Cl:32])[CH:40]=2)=[N:42]1
Reactant: C[C@@H](CO)NC(=O)OC(C)(C)C
Reactant: N#Cc1c(F)cc(-c2cc[nH]n2)cc1Cl
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: Cl
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: ClCCl
Product: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 66.2 %

Procedure:
(S)-tert-Butyl (1-hydroxypropan-2-yl)carbamate (259 mmol, 45.4 g) and triphenylphosphine (259 mmol, 68.0 g) were mixed in dry EtOAc (380 ml) under nitrogen atmosphere. 2-Chloro-6-fluoro-4-(1H-pyrazol-3-yl)benzonitrile (130 mmol, 35.9 g) was added and the resulting mixture was stirred for 10 min. DIAD (259 mmol, 52.4 g) was added slowly while keeping the temperature between 15-25° C. with an ice bath. After the addition the mixture was allowed to warm to RT and stirred for 4 h. Water and concentrated HCl (1296 mmol, 106 ml) was added to the mixture and stirred for 6 days during which more HCl (107 ml in total) was added. Water and DCM was added and the mixture was stirred for a while before separating the phases. The organic phase was extracted twice with water. The water phases were combined and washed twice with DCM. DCM was added to the water phase and the pH of the water phase was adjusted to 12.5 with 50% NaOH. The phases were separated and the water phase was extracted once more with DCM. The DCM phases were combined and washed once with water. The separated DCM phase was evaporated and dried under vacuum. 24.0 g of the title compound was obtained. 1H-NMR (400 MHz, DMSO-d6): δ 0.96 (d, 3H), 1.18 (bs, 2H), 3.19-3.29 (m, 1H), 3.97-4.08 (m, 2H), 7.03 (d, 1H), 7.85-7.92 (m, 2H), 7.98-8.02 (m, 1H).
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][C:8](C(O)=O)=[CH:9][C:5]=2[CH:4]=1.N12CCCN=C1CCCCC2>CC(N(C)C)=O.Cl>[F:16][C:2]([F:1])([F:15])[C:3]1[CH:14]=[CH:13][C:6]2[S:7][CH:8]=[CH:9][C:5]=2[CH:4]=1
Reactant: O=C(O)c1cc2cc(C(F)(F)F)ccc2s1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC(=O)N(C)C
Product: FC(F)(F)c1ccc2sccc2c1
Temperature: 200 °C
Yield: 74.3 %

Procedure:
A mixture of 5-trifluoromethyl-benzo[b]thiophene-2-carboxylic acid (2.00 g, 8.12 mmol) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU) (5.0 mL, 34 mmol) in DMA (13 mL) was heated via microwave irradiation at 200° C. for 1 h. The reaction was cooled to rt, diluted with HCl (1 N aq., 20 mL) and extracted with EtOAc (20 mL). The organic layer was washed with water (10 mL), dried (Na2SO4) and concentrated. The residue was taken up in Et2O (25 mL) and washed with water (25 mL). The aqueous layer was extracted with Et2O (10 mL×2). The combined Et2O layers were dried (Na2SO4) and concentrated. The crude material was purified (FCC) to yield the title compound (1.22 g, 74%).
Reaction SMILES: [CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH2:44])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47].[C:48](OC(=O)C)(=[O:50])[CH3:49].O>CO>[CH3:1][C@H:2]1[O:7][C@H:6]([O:8][C@@H:9]2[C@:14]([OH:16])([CH3:15])[C@@H:13]([OH:17])[C@@H:12]([CH3:18])[O:11][C@H:10]2[O:19][C:20]2[C:25]3[C:26]4[O:36][C:34](=[O:35])[C:33]5[C:28]6=[C:29]([O:38][C:39]([C:41](=[C:42]([OH:43])[C:24]=3[CH:23]=[CH:22][CH:21]=2)[C:27]=46)=[O:40])[CH:30]=[CH:31][C:32]=5[CH3:37])[C@H:5]([NH:44][C:48]([CH3:49])=[O:50])[C@@H:4]([O:45][CH3:46])[C@H:3]1[OH:47]
Reactant: CO[C@@H]1[C@@H](N)[C@@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)O[C@H](C)[C@@H]1O
Reactant: CC(=O)OC(C)=O
Solvent: O
Solvent: CO
Product: CO[C@H]1[C@@H](O)[C@@H](C)O[C@H](O[C@H]2[C@H](Oc3cccc4c(O)c5c(=O)oc6ccc(C)c7c(=O)oc(c34)c5c67)O[C@H](C)[C@H](O)[C@]2(C)O)[C@@H]1NC(C)=O
Temperature: 25 °C
Reaction time: 1 h
Yield: 100 %

Procedure:
A mixture of elsamicin A (65.4 mg) and acetic anhydride (0.1 ml) in dry methanol (2 ml) was stirred at room temperature for 1 hour. Water (1 ml) was added and the mixture was evaporated in vacuo to give a yellow oil, which was purified by column chromatography on silica gel to give 70.5 mg (100%) of the desired product.