Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14]Br)=[CH:12][CH:11]=1.[C-:18]#[N:19].[K+]>C1COCC1.CS(C)=O.C(Cl)Cl>[O:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]1[CH:17]=[CH:16][C:13]([CH2:14][C:18]#[N:19])=[CH:12][CH:11]=1
Reactant: BrCc1ccc(-c2nc3ccccc3o2)cc1
Reactant: [C-]#N
Agent: [K+]
Solvent: C1CCOC1
Solvent: CS(C)=O
Solvent: ClCCl
Product: N#CCc1ccc(-c2nc3ccccc3o2)cc1
Reaction time: 72 h

Procedure:
To a solution of 4-(benzoxazol-2-yl)benzyl bromide (0.5 g; 1.7 mmol) in THF (3 ml) and DMSO (3 ml) is added potassium cyanide (0.22 g; 3.4 mmol) and the reaction is stirred for 72 hours. The reaction is diluted with CH2Cl2, washed with H2O 3x, dried (MgSO4) and concentrated to dryness. The residue is purified by column chromatography using methylene chloride to yield 4-(benzoxazol-2-yl)-benzyl cyanide which is used directly in Step D.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.[Br:26][C:27]1[C:28](=[O:40])[N:29]([CH2:37][CH:38]=O)[C:30]2[C:35]([CH:36]=1)=[CH:34][CH:33]=[CH:32][CH:31]=2.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[O:1]1[C:6]2[CH:7]=[CH:8][C:9]([CH2:11][N:12]([CH:20]3[CH2:25][CH2:24][N:23]([CH2:38][CH2:37][N:29]4[C:30]5[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=5)[CH:36]=[C:27]([Br:26])[C:28]4=[O:40])[CH2:22][CH2:21]3)[C:13](=[O:19])[O:14][C:15]([CH3:18])([CH3:16])[CH3:17])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1
Reactant: O=CCn1c(=O)c(Br)cc2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCN(CCn2c(=O)c(Br)cc3ccccc32)CC1
Temperature: 25 °C
Yield: 66.9 %

Procedure:
To 3 mL of a chloroform solution containing 0.47 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 0.36 g of (3-bromo-2-oxoquinolin-1(2H)-yl)acetaldehyde, 30 μL of acetic acid and 0.43 g of sodium triacetoxyborohydride were added and stirred at room temperature for 2 nights. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated, and the aqueous layer was extracted with chloroform. The organic layer and extracts were combined, washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; ethyl acetate], to give 0.54 g of tert-butyl (2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(3-bromo-2-oxoquinolin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a white foam.
Reaction SMILES: Cl[C:2](Cl)=[CH:3][C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5].[NH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[CH:23]([NH2:26])([CH3:25])[CH3:24]>C(Cl)Cl.O1CCOCC1>[NH:16](/[C:2](/[NH:26][CH:23]([CH3:25])[CH3:24])=[CH:3]\[C:4]([C:6]1[C:7]([Cl:14])=[N:8][C:9]([Cl:13])=[C:10]([F:12])[CH:11]=1)=[O:5])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: O=C(C=C(Cl)Cl)c1cc(F)c(Cl)nc1Cl
Reactant: Nc1ccccc1
Reactant: CC(C)N
Solvent: C1COCCO1
Solvent: ClCCl
Product: CC(C)N/C(=C/C(=O)c1cc(F)c(Cl)nc1Cl)Nc1ccccc1
Temperature: 10 °C
Reaction time: 2 h
Yield: 9.5 %

Procedure:
3,3-dichloro-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-2-propen-1-one (374.0 mg, 1.29 mmol) was dissolved in CH2Cl2 (5 mL) and cooled to 10° C. Aniline (120.0 mg, 1.29 mmol) and isopropylamine (76.5 mg, 1.29 mmol) were added dropwise as a mixture in 3 mL of 1,4-dioxane. TEA (0.897 mL, 6.45 mmol) was added and the reaction mixture was warmed to room temperature and left to stir for 2 h. The dioxane was removed in vacuo and the brown residue was partitioned between EtOAc and saturated aqueous NaHCO3. The aqueous layer was extracted with EtOAc. The combined organic extracts were washed with brine, dried over MgSO4 and concentrated in vacuo. Purification of the residue using Biotage silica gel chromatography eluting with 6:1 to 7:3 Hex:EtOAc provided (2Z)-3-anilino-1-(2,6-dichloro-5-fluoro-3-pyridinyl)-3-(isopropylamino)-2-propen-1-one (45 mg, 10%) as an off-white solid: LCMS RT: 3.63 min, MH+: 368.2.
Reaction SMILES: [CH3:1][O:2][C:3]([NH:5][CH:6]([CH2:10][CH3:11])[C:7](O)=[O:8])=[O:4].C1C=CC2N(O)N=NC=2C=1.Cl.Cl.Cl.[CH3:25][O:26][C:27](=[O:75])[NH:28][CH:29]([C:33]([N:35]1[CH:41]([C:42]2[NH:43][C:44]([C:47]3[CH:52]=[CH:51][C:50]([C:53]4[CH:62]=[CH:61][C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:63]6[NH:64][C:65]([CH:68]7[CH2:72][CH:71]([C:73]#[N:74])[CH2:70][NH:69]7)=[N:66][CH:67]=6)[CH:59]=5)[CH:54]=4)=[CH:49][CH:48]=3)=[CH:45][N:46]=2)[CH2:40][C:37]2([CH2:39][CH2:38]2)[CH2:36]1)=[O:34])[CH:30]([CH3:32])[CH3:31].CN1CCOCC1>CN(C=O)C.CCOC(C)=O>[CH3:25][O:26][C:27](=[O:75])[NH:28][CH:29]([C:33]([N:35]1[CH:41]([C:42]2[NH:43][C:44]([C:47]3[CH:48]=[CH:49][C:50]([C:53]4[CH:62]=[CH:61][C:60]5[C:55](=[CH:56][CH:57]=[C:58]([C:63]6[NH:64][C:65]([CH:68]7[CH2:72][CH:71]([C:73]#[N:74])[CH2:70][N:69]7[C:7](=[O:8])[CH:6]([NH:5][C:3]([O:2][CH3:1])=[O:4])[CH2:10][CH3:11])=[N:66][CH:67]=6)[CH:59]=5)[CH:54]=4)=[CH:51][CH:52]=3)=[CH:45][N:46]=2)[CH2:40][C:37]2([CH2:38][CH2:39]2)[CH2:36]1)=[O:34])[CH:30]([CH3:32])[CH3:31]
Reactant: COC(=O)NC(C(=O)N1CC2(CC2)CC1c1ncc(-c2ccc(-c3ccc4cc(-c5cnc(C6CC(C#N)CN6)[nH]5)ccc4c3)cc2)[nH]1)C(C)C
Reactant: CCC(NC(=O)OC)C(=O)O
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: CN1CCOCC1
Product: CCC(NC(=O)OC)C(=O)N1CC(C#N)CC1c1ncc(-c2ccc3cc(-c4ccc(-c5cnc(C6CC7(CC7)CN6C(=O)C(NC(=O)OC)C(C)C)[nH]5)cc4)ccc3c2)[nH]1
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 54.4 %

Procedure:
2-Methoxycarbonylamino-butyric acid (37 mg, 0.227 mmol) EDC-HCl (44 mg, 0.227 mmol) and HOBt (32 mg, 0.237 mmol) were combined in DMF (2 mL) and stirred for 20 min at RT. (1-{6-[5-(4-{6-[2-(4-Cyano-pyrrolidin-2-yl)-3H-imidazol-4-yl]-naphthalen-2-yl}-phenyl)-1H-imidazol-2-yl]-5-aza-spiro[2.4]heptane-5-carbonyl}-2-methyl-propyl)-carbamic acid methyl ester-tris-hydrochloride (150 mg, 0.189 mg) was added, the reaction mixture was cooled to 0° C. and NMM (0.104 mL, 0.947 mmol) was added dropwise. After 1.5 h, the reaction mixture was warmed to RT. 30 min later, the mixture was diluted with EtOAc and washed with NaHCO3, then 1:1 brine/5M NaOH. The organic phase was dried over MgSO4, then filtered and concentrated. The resulting residue was purified by HPLC to afford the title compound (85 mg, 54%). MS (ESI) m/z 826 [M+H]+.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[NH:7][C:8]([NH2:10])=[S:9].[Cl:11][CH:12]([C:16](=O)[CH3:17])[C:13](=[O:15])[CH3:14]>C(O)C>[ClH:11].[CH3:17][C:16]1[N:10]=[C:8]([NH:7][C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)[S:9][C:12]=1[C:13](=[O:15])[CH3:14]
Reactant: CC(=O)C(Cl)C(C)=O
Reactant: NC(=S)Nc1cnccn1
Solvent: CCO
Product: CC(=O)c1sc(Nc2cnccn2)nc1C
Product: Cl
Temperature: 25 °C

Procedure:
To a solution of N-pyrazin-2-ylthiourea (5 g, 0.032 mol) in absolute ethanol (50 ml) is added 3-chloro-2,4-pentanedione (4.4 g, 0.032 mol). The mixture is refluxed for 20 h under nitrogen. The reaction mixture is cooled down to rt and the resulting precipitate is filtered, washed with ethanol (25 ml) and dried under suction to afford 1-[4-Methyl-2-(pyrazin-2-ylamino)-1,3-thiazol-5-yl]ethanone, hydrochloride salt as white-off solid (7 g; 92%). 1H NMR (DMSO-d6, 300 MHz): δ 2.47 (s, 3H), 2.57 (s, 3H), 8.21 (s, 1H), 8.41 (s, 1H), 8.48 (s, 1H), 12.2 (br s, 1H). M+ (ESI): 234.9. HPLC (Method B), Rt: 1.56 min (purity: 97.75%). TLC: Chloroform/methanol (9/1): Rf−0.25. Mp: 224° C.-229° C.
Reaction SMILES: FC(F)(F)C(O[Si](C)(C)C)=O.[NH2:12][C:13]1[CH:14]=[CH:15][C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])=[N:17][C:18]=1[CH3:19].[CH:26](OCC)(OCC)OCC.[N:36]([Si](C)(C)C)=[N+:37]=[N-:38]>C(OCC)(=O)C.[Cl-].[Na+].O>[CH3:19][C:18]1[N:17]=[C:16]([CH2:20][C:21]([O:23][CH2:24][CH3:25])=[O:22])[CH:15]=[CH:14][C:13]=1[N:12]1[CH:26]=[N:36][N:37]=[N:38]1
Reactant: CCOC(OCC)OCC
Reactant: C[Si](C)(C)N=[N+]=[N-]
Reactant: CCOC(=O)Cc1ccc(N)c(C)n1
Agent: C[Si](C)(C)OC(=O)C(F)(F)F
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)Cc1ccc(-n2cnnn2)c(C)n1
Reaction time: 0.08 h

Procedure:
Trimethylsilyl trifluoroacetate (1.010 ml, 5.85 mmol) was added to a suspension of ethyl 2-(5-amino-6-methylpyridin-2-yl)acetate (710 mg, 3.66 mmol) in ethyl acetate (20 ml). The mixture was stirred for 5 mins then added triethyl orthoformate (1.096 ml, 6.58 mmol). Stirred for another 5 mins then added azidotrimethylsilane (0.817 ml, 6.21 mmol). The reaction was stirred overnight. The reaction was poured into brine and extracted with ethyl acetate. The ethyl acetate was separated, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography through 120 g ISCO Redi-Sep column and eluted with 5% MeOH/DCM to yield ethyl 2-(6-methyl-5-(1H-tetrazol-1-yl)pyridin-2-yl)acetate.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2)#[N:2].[H][H]>CO.[Ni]>[NH2:2][CH2:1][C:3]1[CH:4]=[CH:5][CH:6]=[C:7]2[C:11]=1[N:10]([CH2:12][C:13]([OH:15])=[O:14])[CH:9]=[CH:8]2
Reactant: N#Cc1cccc2ccn(CC(=O)O)c12
Reactant: [H][H]
Agent: [Ni]
Solvent: CO
Product: NCc1cccc2ccn(CC(=O)O)c12
Reaction time: 6 h
Yield: 96 %

Procedure:
Raney Ni (7.0 g) was added to a solution of 2-(7-cyano-1H-indol-1-yl)acetic acid (700 mg, 3.5 mmol) in MeOH (15 ml), and the mixture was hydrogenated for 6 h at RT and 60 psi hydrogen in a Parr apparatus. The reaction mixture was filtered over celite and the filtrate was concentrated under vacuum. The crude product so obtained was used directly in the following stage without being purified further. Yield: 96% (692 mg, 3.36 mmol)
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:23])([CH3:22])[CH:11]([O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:12]=C)(=[O:7])=[O:6].O=O.[O:26]=[O+][O-].CSC>ClCCl>[Cl:1][CH2:2][CH2:3][CH2:4][S:5]([O:8][CH2:9][C:10]([CH3:22])([CH3:23])[CH:11]([O:14][CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[CH:12]=[O:26])(=[O:6])=[O:7]
Reactant: C=CC(OCc1ccccc1)C(C)(C)COS(=O)(=O)CCCCl
Reactant: O=[O+][O-]
Agent: O=O
Solvent: ClCCl
Solvent: CSC
Product: CC(C)(COS(=O)(=O)CCCCl)C(C=O)OCc1ccccc1
Yield: 76 %

Procedure:
Following the general procedure for the preparation of aldehydes from alkenes of Description 11, (3R/S)-2,2-dimethyl-3-(phenylmethoxy)pent-4-enyl (3-chloropropyl]sulfonate (12a) (10.0 g, 27.7 mmol) dissolved in 150 mL of dichloromethane (DCM) was treated with a mixture of oxygen and ozone (O2/O3). Upon completion of the reaction, 4.0 mL (3.4 g, 55 mmol) of dimethyl sulfide (DMS) was added. After work-up, the crude material was purified by silica gel column chromatography using a mixture of ethyl acetate (EtOAc) and hexane (Hxn) (EtOAc/Hxn=1:2) as eluent to provide 7.6 g (76% yield) of the title compound (12b) as a colorless oil. The analytical data was consistent with the proposed structure and the data obtained for the enantiopure compound (11b).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:10][S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1.[CH2:14](Br)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C(OCC)(=O)C>CCCC[N+](CCCC)(CCCC)CCCC.[Br-].CN(C=O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:10]([CH2:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[S:9](=[O:12])(=[O:11])[CH2:8][O:7][C:6]=2[CH:13]=1
Reactant: BrCc1ccccc1
Reactant: O=S1(=O)COc2cc(F)ccc2N1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=S1(=O)COc2cc(F)ccc2N1Cc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 105.3 %

Procedure:
A mixture of the title compound of Step D (0.5 g, 2.46 mmol), K2 CO3 (1.02 g, 7.38 mmol), benzyl bromide (0.463 g, 2.71 mmol) and TBAB (79 mg) in DMF (5 mL) was stirred at room temperature for 48 h. After the reaction was complete, the reaction mixture was poured into an H2 O/ethyl acetate mixture (10/100 mL). The organic phase was separated, dried and concentrated to give the title compound of Step E as a brown solid (0.76 g). 1H NMR (CDCl3, 300 MHz): δ7.32 (m,6H, aromatic) 6.72 (d,1H, 11 Hz), 6.34 (d, 1H, 8 Hz), 4.82 (s,2H), 4.69 (s,2H).
Reaction SMILES: S(=O)(=O)(O)[OH:2].[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[CH:9][C:8]=1[NH:14][C:15](=[O:19])[CH:16]=NO>CCOC(C)=O>[Br:6][C:7]1[C:12]([F:13])=[CH:11][CH:10]=[C:9]2[C:8]=1[NH:14][C:15](=[O:19])[C:16]2=[O:2]
Reactant: O=S(=O)(O)O
Reactant: O=C(C=NO)Nc1cccc(F)c1Br
Solvent: CCOC(C)=O
Product: O=C1Nc2c(ccc(F)c2Br)C1=O
Temperature: 70 °C
Reaction time: 0.75 h
Yield: 100 %

Procedure:
A 2 L 3-neck flask with a temperature probe adapter was fixed with a mechanical stirrer, condenser, and temperature probe. The flask was charged with conc. sulfuric acid (79 mL, 1418 mmol) and was heated to 70° C.; solid N-(2-bromo-3-fluorophenyl)-2-(hydroxyimino)acetamide (719a; 12.34 g, 47.3 mmol) was then slowly added (exotherm) and the temperature raised to 100° C. The brown solution was stirred at 90° C. for 45 min. The heating mantle was replaced with an ice bath to cool the reaction mixture to RT; the brown solution was poured into a beaker containing ice (500 mL), diluted with EtOAc (200 mL), added to a separatory funnel, and extracted with EtOAc (2×150 mL); the combined organics were dried over Na2SO4 and concentrated to give 7-bromo-6-fluoroindoline-2,3-dione (11.53 g, 47.3 mmol, 100% yield) as a reddish solid. 1H NMR (400 MHz, CDCl3) δ ppm 6.91 (t, J=8.51 Hz, 1H) 7.63 (dd, J=8.22, 4.89 Hz, 1H) 7.99 (br. s., 1H). 19F NMR (377 MHz, CDCl3) δ ppm −90.65 (s, 1F). MS (ESI, pos. ion) m/z: 243.9/245.9 (M+1).
Reaction SMILES: CS[C:3]([S:13][CH3:14])=[C:4]([C:10](=O)[CH3:11])[C:5]([O:7][CH2:8][CH3:9])=[O:6].[Cl:15][C:16]1[CH:21]=[C:20]([Cl:22])[CH:19]=[C:18]([Cl:23])[C:17]=1[NH:24][NH2:25].O>C(O)C>[CH2:8]([O:7][C:5]([C:4]1[C:3]([S:13][CH3:14])=[N:25][N:24]([C:17]2[C:18]([Cl:23])=[CH:19][C:20]([Cl:22])=[CH:21][C:16]=2[Cl:15])[C:10]=1[CH3:11])=[O:6])[CH3:9]
Reactant: NNc1c(Cl)cc(Cl)cc1Cl
Reactant: CCOC(=O)C(C(C)=O)=C(SC)SC
Solvent: CCO
Solvent: O
Product: CCOC(=O)c1c(SC)nn(-c2c(Cl)cc(Cl)cc2Cl)c1C
Yield: 56.4 %

Procedure:
A mixture of 1.22 g (5.23 mmol) of ethyl 3,3-bismethylthio-2-acetylacrylate and 1.11 g (5.23 mmol) of 2,4,6-trichlorophenylhydrazine in 12 mL of ethanol was heated at reflux for 2 hours. The cooled reaction mixture was then poured into cold water and the product was extracted into ether. The ethereal extracts were dried and evaporated and the residues were chromatographed on silica gel using 6:1 hexane/ethyl acetate as eluent to give 1.12 g (56%) of the desired product as a crystalline solid, m.p. 95°-98° C. 1H-NMR (CDCl3) δ1.38 (3H, t, J=7), 2.30 (3H, s), 2.49 (3H, s.), 4.31 (2H, q, J=7), 7.47 m(2H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH:7]1S(O)(=O)=O.[CH2:19]([NH2:22])[CH:20]=[CH2:21]>O>[ClH:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]=[CH:16][C:17]=1[Cl:18])[NH:5][C@@H:6]1[CH2:10][CH2:9][CH2:8][C@H:7]1[NH:22][CH2:19][CH:20]=[CH2:21]
Reactant: C=CCN
Reactant: O=S(=O)(O)C1CCCC1Nc1ccc(Cl)c(Cl)c1
Solvent: O
Product: C=CCN[C@@H]1CCC[C@H]1Nc1ccc(Cl)c(Cl)c1
Product: Cl
Temperature: 125 °C
Yield: 77 %

Procedure:
A mixture of 65.2 g (0.20 mole) of 3,4-dichloro-N-(2-sulfocyclopentyl)aniline and 250 ml of a 50 percent allylamine in water solution was heated at 125° C. in autoclave for 48 hours. The resulting reaction mixture was washed from the autoclave 1500 ml solution of methanol. This solution was evaporated until material therefrom oiled out as a separate layer. The oil was extracted with 500 ml of methylene chloride. The organic layer was washed with saturated sodium chloride solution, dried over magnesium sulfate and evaporated to an orange oil. The oil was chromatographed on 600 ml of silica gel eluting with 2 liters of chloroform and 4 liters of ethyl acetate. The ethyl acetate fraction was separated and evaporated to a yellow oil; the trans-3,4-dichloro-N-[2-(N-allylamino)cyclopentyl]aniline. This amine oil was converted to its hydrochloride salt with excess ether-hydrogen chloride mixture and recrystallized from a mixture of 450 ml of methanol and about 2000 ml of ethyl ether to obtain 54.8 g (77 percent yield) of trans-3,4-dichloro-N-[2-(N-allylamino)cyclopentyl]-aniline hydrochloride, m.p. 131°-132° C.
Reaction SMILES: [CH3:1][NH:2][C:3]1=[N:4][C:5](=[O:22])[S:6]/[C:7]/1=[CH:8]\[CH:9]1[CH2:14][CH2:13][N:12](C(OC(C)(C)C)=O)[CH2:11][CH2:10]1.[ClH:23].C(OCC)(=O)C>O1CCCC1.CO>[ClH:23].[ClH:23].[CH3:1][NH:2][C:3]1=[N:4][C:5](=[O:22])[S:6]/[C:7]/1=[CH:8]\[CH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1
Reactant: CNC1=NC(=O)S/C1=C\C1CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CNC1=NC(=O)S/C1=C\C1CCNCC1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of tert-butyl 4-{(Z)-[4-(methylamino)-2-oxo-1,3-thiazol-5(2H)-ylidene]methyl}piperidine-1-carboxylate (1.27 g) in tetrahydrofuran/methanol (6 mL/6 mL) was added 4M hydrogen chloride/ethyl acetate solution (5.85 mL), and the reaction mixture was stirred at 80° C. for 2 hr. The solvent was evaporated under reduced pressure, and the residue was washed with ethyl acetate to give the title compound (1.02 g).
Reaction SMILES: C[O:2][C:3](=[O:25])[CH2:4][C:5]1[C:13]2[C:8](=[N:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][C:15]2[CH:20]=[CH:19][C:18]([S:21]([CH3:23])=[O:22])=[CH:17][CH:16]=2)[C:6]=1[CH3:24].[OH-].[Na+]>C1COCC1.CO>[CH3:23][S:21]([C:18]1[CH:19]=[CH:20][C:15]([CH2:14][N:7]2[C:8]3=[N:9][CH:10]=[CH:11][CH:12]=[C:13]3[C:5]([CH2:4][C:3]([OH:25])=[O:2])=[C:6]2[CH3:24])=[CH:16][CH:17]=1)=[O:22]
Reactant: COC(=O)Cc1c(C)n(Cc2ccc(S(C)=O)cc2)c2ncccc12
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: Cc1c(CC(=O)O)c2cccnc2n1Cc1ccc(S(C)=O)cc1
Reaction time: 2 h

Procedure:
To a stirred solution of [1-(4-methanesulfinyl-benzyl)-2-methyl-1H-pyrrolo[2,3-b]pyridin-3-yl]-acetic acid methyl ester (0.340 g, 0.95 mmol) in THF/MeOH (8 ml of a 1:1 mixture) is added 1M NaOH (2 ml) and the reaction mixture is stirred for 2 hours. The solvent is removed in vacuo and the resulting oil is dissolved in water and acidified to pH2 using concentrated HCl. A precipitate forms which is filtered, washed with water and dried in vacuo to yield the titled product. (MH+ 343)
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([OH:10])=[CH:4][C:3]=2[O:2]1.[CH2:11]([O:14][C:15]1[C:22]([O:23][CH3:24])=[CH:21][C:18]([CH:19]=O)=[CH:17][C:16]=1[Br:25])[CH:12]=[CH2:13].[C:26]([CH2:28][C:29]([O:31][CH2:32][CH3:33])=[O:30])#[N:27].N1CCCCC1>C(O)C.O>[CH2:32]([O:31][C:29]([C:28]1[CH:19]([C:18]2[CH:21]=[C:22]([O:23][CH3:24])[C:15]([O:14][CH2:11][CH:12]=[CH2:13])=[C:16]([Br:25])[CH:17]=2)[C:6]2[CH:7]=[C:8]3[O:9][CH2:1][O:2][C:3]3=[CH:4][C:5]=2[O:10][C:26]=1[NH2:27])=[O:30])[CH3:33]
Reactant: CCOC(=O)CC#N
Reactant: Oc1ccc2c(c1)OCO2
Reactant: C=CCOc1c(Br)cc(C=O)cc1OC
Solvent: CCO
Solvent: C1CCNCC1
Solvent: O
Product: C=CCOc1c(Br)cc(C2C(C(=O)OCC)=C(N)Oc3cc4c(cc32)OCO4)cc1OC
Temperature: 80 °C

Procedure:
3,4-Methylenedioxyphenol (166 mg, 1.2 mmol), 4-allyloxy-3-bromo-5-methoxy-benzaldehyde (271 g, 1 mmol) and ethyl cyanoacetate (113 mg, 1 mmol) were taken in 7 ml ethanol at room temperature, charged with piperidine (50 μL) and then stirred at 80° C. under LC-MS control till the reaction was complete. The reaction mixture was cooled down to room temperature, diluted with 10 ml water, stirred for 2 h at room temperature, solids were collected by filtration, washed with 1:1 mixture of ethanol/water and dried (239 mg, 0.47 mmol, 47%).
Reaction SMILES: [C:1]([CH2:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])(=O)[CH:2]([CH3:4])[CH3:3].[NH3:14]>CO>[NH2:14][C:1]([CH:2]([CH3:4])[CH3:3])=[CH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8]
Reactant: N
Reactant: CC(C)C(=O)CC(=O)OC(C)(C)C
Solvent: CO
Product: CC(C)C(N)=CC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 75.4 %

Procedure:
To a solution of 240 g of t-butyl isobutyrylacetate in 500 mL of methanol was passed 70 g of ammonia in 2 hours, maintaining the temperature at below 25° C. The resulting solution was stirred at room temperature for 18 hours, after which methanol was removed in vacuo. Methylene chloride was added and the suspension was filtered. The filtrate was concentrated on a rotary evaporator to give 180 g of t-butyl 3-amino-4-methyl-2-pentenoate as an oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][N:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[N+:24]([O-])=O)[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[Sn]Cl.O>C(O)C>[CH2:1]([O:8][C:9]([N:11]1[CH2:12][CH2:13][N:14]([C:17]2[CH:22]=[C:21]([CH3:23])[CH:20]=[CH:19][C:18]=2[NH2:24])[CH2:15][CH2:16]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc([N+](=O)[O-])c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Agent: Cl[Sn]Cl
Solvent: CCO
Solvent: O
Product: Cc1ccc(N)c(N2CCN(C(=O)OCc3ccccc3)CC2)c1
Yield: 92.4 %

Procedure:
4-(5-Methyl-2-nitro-phenyl)-piperazine-1-carboxylic acid benzyl ester (5.60 g; 15.7 mmol) and SnCl2.H2O (17.5 g; 77.6 mmol) were refluxed in 100 mL ethanol for 2½ hours. Ethanol was removed in vacuo. The residue was poured into 300 mL saturated NaHCO3. The mixture was extracted with ethyl acetate (2×250 mL). The organic phase was washed with brine (2×100 mL), dried with MgSO4, filtered through a pad of silica and concentrated in vacuo to give 4.71 g (14.5 mmol; 91.6%) 4-(2-amino-5-methyl-phenyl)-piperazine-1-carboxylic acid benzyl ester.
Reaction SMILES: [CH:1]1[N:2]=[CH:3][N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12.[Li]CCCC.CN([CH:18]=[O:19])C>C1COCC1>[CH:1]1[N:2]=[C:3]([CH:18]=[O:19])[N:4]2[CH2:9][CH2:8][CH2:7][CH2:6][C:5]=12
Reactant: c1ncn2c1CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=Cc1ncc2n1CCCC2
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 40 %

Procedure:
To a solution of 5,6,7,8-tetrahydro-imidazo[1,5-a]pyridine (prepared as described by Lattrell, R. et al. The J. of Antibiotics 1988, 41, 1395-1408) in THF (7 mL) at −78° C. was added a solution of n-BuLi (2.5 M in hexanes, 0.70 mL, 1.75 mmol) and the reaction stirred at −78° C. for 10 min. DMF (1.0 mL) was added to the mixture at −78° C. and the reaction warmed to room temperature and stirred for 2 h before quenching with saturated aqueous NH4Cl (5 mL). The mixture was diluted with EtOAc (30 mL) and brine and the organic phase washed with brine (1×30 mL), dried (Na2SO4) and concentrated in vacuo. The resultant brown oil (191 mg) was purified by column chromatography on silica gel (CH2Cl2/MeOH, 96:4) to afford the desired aldehyde (105 mg, 40%) as an orange oil. 1H NMR (CDCl3) δ 1.83-1.89 (m, 2H), 1.94-2.02 (m, 2H), 2.85 (t, 2H, J=6 Hz), 4.39 (t, 2H, J=6 Hz), 7.05 (s, 1H), 9.71 (s, 1H).
Reaction SMILES: [CH2:1]=[C:2]([CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].Cl.[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][SH:25].N1CCCCC1.[OH-].C([N+](C)(C)C)C1C=CC=CC=1>CO>[CH3:21][N:22]([CH3:26])[CH2:23][CH2:24][S:25][CH2:1][CH:2]([CH2:13][C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1)[C:3]([O:5][CH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=1)=[O:4]
Reactant: CN(C)CCS
Reactant: C=C(Cc1ccccc1)C(=O)OCc1ccccc1
Agent: C[N+](C)(C)Cc1ccccc1
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: C1CCNCC1
Product: CN(C)CCSCC(Cc1ccccc1)C(=O)OCc1ccccc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 23.5 %

Procedure:
The oil prepared in Step 9 (1.5 g, 5.95 mmol) was dissolved under argon in methanol (22 mL). To this solution was added 2-dimethylaminoethanethiol hydrochloride (843 mg, 5.95 mmol), piperidine (0.78 mL, 7.85 mmol) and benzyltrimethylammonium hydroxide (0.25 mL, 0.6 mmol), and the mixture was stirred at room temperature for 16 hours. The solvent was removed on a rotary evaporator and then the residue was purified by flash chromatography on silica gel, eluting with 20:1 CH2Cl2 :MeOH to give the pure title compound (0.5 g, 24% yield). 1H NMR: 300 MHz spectrum consistent with proposed structure. Anal: calcd. for C21H27NO2S+0.2H2O: C, 69.85; H, 7.65; N, 3.88. Found: C, 69.58; H, 7.60; N, 3.98.