Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([B:7]([OH:9])[OH:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N+:10]([O-])([OH:12])=[O:11].C(Cl)Cl.CCO>C(OC(=O)C)(=O)C>[N+:10]([C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=1[B:7]([OH:9])[OH:8])([O-:12])=[O:11]
Reactant: OB(O)c1ccccc1
Reactant: O=[N+]([O-])O
Solvent: CCO
Solvent: CC(=O)OC(C)=O
Solvent: ClCCl
Product: O=[N+]([O-])c1ccccc1B(O)O
Temperature: 25 °C
Yield: 35.1 %

Procedure:
A solution of phenylboronic acid (10 g; 82 mmol) in acetic acid anhydride (100 ml) at −15° C. was added fuming HNO3 (5 ml; 120 mmol) over 30 min such that reaction temperature was kept below −10° C. The reaction mixture was allowed to warm up to rt. and left with stirring over night. The reaction mixture was poured onto ice and concentrated to 50 ml. The remanense was then re-evaporated 5 times from additional H2O (100 ml) and finally filtered to give 7.1 g crude product as a mixture of isomers. Column chromatography (CH2Cl2/EtOH=10/0.5) gave 4.8 g (35%) pure product as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10](I)=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1.C([Sn](CCCC)(CCCC)[CH:31]=[CH:32][O:33]CC)CCC.O.CCOC(C)=O>O1CCOCC1.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>[Cl:1][C:2]1[N:3]=[C:4]([NH:22][CH:23]2[CH2:25][CH2:24]2)[C:5]2[C:10]([C:32](=[O:33])[CH3:31])=[CH:9][N:8]([S:12]([C:15]3[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=3)(=[O:14])=[O:13])[C:6]=2[N:7]=1
Reactant: CCCC[Sn](C=COCC)(CCCC)CCCC
Reactant: Cc1ccc(S(=O)(=O)n2cc(I)c3c(NC4CC4)nc(Cl)nc32)cc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1COCCO1
Solvent: CCOC(C)=O
Product: CC(=O)c1cn(S(=O)(=O)c2ccc(C)cc2)c2nc(Cl)nc(NC3CC3)c12
Temperature: 100 °C
Reaction time: 18 h
Yield: 45.7 %

Procedure:
A solution of 2-chloro-N-cyclopropyl-5-iodo-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-4-amine (489 mg, 1.00 mmol) in dioxane (6 mL) was degassed with Ar before being charged with tributyl(ethoxyvinyl)tin (0.371 mL, 1.10 mmol) and Pd(Ph3P)4 (90 mg, 0.078 mmol). The mixture was stirred at 100° C. for 18 h. Water and EtOAc were added. The organic phase was separated, dried over Na2SO4, concentrated in vacuo. The residue was purified by HPLC to give 1-(2-chloro-4-(cyclopropylamino)-7-tosyl-7H-pyrrolo[2,3-d]pyrimidin-5-yl)ethanone (185 mg).
Reaction SMILES: [NH2:1][CH:2]([C:8]#[N:9])[C:3]([O:5][CH2:6][CH3:7])=[O:4].C([O-])([O-])O[CH2:12][CH3:13].[NH2:16][C:17]1[S:18]C=[CH:20][N:21]=1>>[NH2:9][C:8]1[N:21]([C:17]2[S:18][CH:12]=[CH:13][N:16]=2)[CH:20]=[N:1][C:2]=1[C:3]([O:5][CH2:6][CH3:7])=[O:4]
Reactant: CCOC(=O)C(N)C#N
Reactant: CCOC([O-])[O-]
Reactant: Nc1nccs1
Product: CCOC(=O)c1ncn(-c2nccs2)c1N

Procedure:
Following the procedure described in Reference Example 7, the desired compound was synthesized using ethyl α-aminocyanoacetate, ethyl orthoformate and 2-aminothiazole as raw materials. m.p.: 120° to 123° C.
Reaction SMILES: [C:1]([O:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])(=[O:6])[CH2:2][C:3]([CH3:5])=O.[CH3:21][O:22][C:23](=[O:28])/[CH:24]=[C:25](\[NH2:27])/[CH3:26].[CH3:29][CH:30](O)[CH3:31]>>[CH3:5][C:3]1[NH:27][C:25]([CH3:26])=[C:24]([C:23]([O:22][CH3:21])=[O:28])[CH:29]([C:30]2[CH:31]=[CH:18][CH:19]=[C:12]([CH3:13])[CH:11]=2)[C:2]=1[C:1]([O:7][CH2:8][CH2:9][N:10]1[C:14](=[O:15])[C:13]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:12]2[C:11]1=[O:20])=[O:6]
Reactant: CC(C)O
Reactant: CC(=O)CC(=O)OCCN1C(=O)c2ccccc2C1=O
Reactant: COC(=O)/C=C(/C)N
Product: COC(=O)C1=C(C)NC(C)=C(C(=O)OCCN2C(=O)c3ccccc3C2=O)C1c1cccc(C)c1
Yield: 50 %

Procedure:
A solution of 7.0 g (0.25 mol) of 2-phthalimidoethyl acetoacetate and 3.1 g (0.025 mol) of methyl3-aminocrotonate in 150 ml of 2-propanol was refluxed for 15 hours under nitrogen. The solvent was removed in vacuo and the residue was subjected to flash chromatography (silica gel, 1:1 petroleum ether/ethyl acetate). The isolated product was recrystallized in dichloromethane/hexane to give 3.5 g (50%) of a pale yellow solid; m.p. 188°-190° C. NMR: (CDCl3) δ 2.1 (9H,d), 3.5 (3M,s), 3.7 (2H,m), 4.2 (2H,m), 4.6 (1H,s), 5.8 (1H,s), 7.2 (8H,m).
Reaction SMILES: C([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)C.[OH-].[Li+]>C1COCC1.O>[OH:11][B:9]1[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]=2[CH:6]([CH2:5][C:4]([OH:18])=[O:3])[O:10]1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1C(CC(=O)O)OB2O
Temperature: 0 °C
Reaction time: 1 h
Yield: 87.7 %

Procedure:
A solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (0.835 g, 3.34 mmol) in THF (10 mL) was treated with lithium hydroxide (0.383 g, 16.70 mmol) in water (10 mL) at 0° C. The solution was stirred at 0° C. for 1 hour then quenched with 2N HCl to pH 2. The mixture was concentrated to approximately half of the entire volume. The solid that precipitated was collected by vacuum filtration, then rinsed with cold water and dried to give (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid as a light yellow solid (0.65 g, 88%). mp 165-166° C. 1H NMR (400 MHz, DMSO-d6) δ 12.31 (s, 1H), 9.30 (s, 1H), 9.08 (s, 1H), 6.88 (s, 1H), 6.66 (s, 1H), 5.38 (d, J=9.38 Hz, 1H), 3.00 (d, J=15.24 Hz, 1H), 2.20 (s, 3H), 2.00 (dd, J=15.24, 10.16 Hz, 1H). MS (ESI) m/z: 221 [M−1].
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([OH:9])=[CH:5][CH:4]=1)#[N:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]1[CH:20]=[C:19]([CH3:21])[O:18][N:17]=1.C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>C(#N)C>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([O:9][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]2[CH:20]=[C:19]([CH3:21])[O:18][N:17]=2)=[CH:5][CH:4]=1)#[N:2]
Reactant: Cc1cc(CCCCCBr)no1
Reactant: N#Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC#N
Product: Cc1cc(CCCCCOc2ccc(C#N)cc2)no1
Yield: 53.6 %

Procedure:
A mixture of 5.1 g of 4-cyanophenol, 10 g of 3-(5-bromopentyl)-5-methylisoxazole, 8 g of potassium carbonate, 1 g of potassium iodide and 75 ml of acetonitrile was heated at reflux for 24 hours. The product was isolated and distilled, first at 115°-200° C.(0.1 mm) and then at 160°-190° C.(0.05 mm) to yield a yellow oil which crystallized upon cooling. Recrystallization from hexane-ether afforded 6.2 g of 3-[5-(4-cyanophenoxy)pentyl]-5-methylisoxazole, m.p. 61°-62° C.
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[CH:11]=[CH:10][CH:9]=[CH:8][C:4]=1[C:5]([Cl:7])=[O:6].[Cl:14][C:15]1[CH:28]=[CH:27][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]2)=[CH:17][CH:16]=1>C(Cl)Cl>[ClH:7].[Cl:14][C:15]1[CH:16]=[CH:17][C:18]([CH2:19][CH2:20][N:21]2[CH2:26][CH2:25][N:24]([C:5](=[O:6])[C:4]3[CH:8]=[CH:9][CH:10]=[CH:11][C:3]=3[C:2]([F:13])([F:12])[F:1])[CH2:23][CH2:22]2)=[CH:27][CH:28]=1
Reactant: Clc1ccc(CCN2CCNCC2)cc1
Reactant: O=C(Cl)c1ccccc1C(F)(F)F
Solvent: ClCCl
Product: Cl
Product: O=C(c1ccccc1C(F)(F)F)N1CCN(CCc2ccc(Cl)cc2)CC1
Reaction time: 1 h

Procedure:
A solution of 4.65 g of 2-trifluoromethylbenzoyl chloride in 50 ml of methylene chloride is added dropwise, over a period of 10 minutes, to a solution, stirred at room temperature, of 5 g of 1-(4-chlorophenethyl)-piperazine in 75 ml of methylene chloride. The reaction mixture is heated under reflux for 5 minutes, allowed to stand at room temperature for 1 hour and then concentrated by evaporation. The residue is made into a slurry with hot acetone and, after the addition of hexane, the whole is filtered. 1-(4-chlorophenethyl)-4-(2-trifluoromethylbenzoyl)piperazine hydrochloride having a melting point of 212°-214° is obtained.
Reaction SMILES: O[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[NH:32][C:33](=[O:47])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=1[C:40]1[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=1)[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]([N:21]2[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]2)=[O:20])[C:10](=O)[CH2:9][CH2:8]1)=[O:6].Cl.[CH3:49][N:50]([CH3:55])[CH2:51][CH2:52][CH2:53]Cl.C(=O)([O-])[O-:57].[K+].[K+]>CN(C)C=O.C(OCC)(=O)C>[CH3:49][N:50]([CH3:55])[CH2:51][CH2:52][CH2:53][O:57][C:29]1[CH:30]=[C:31]([NH:32][C:33](=[O:47])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[C:40]2[CH:45]=[CH:44][C:43]([CH3:46])=[CH:42][CH:41]=2)[CH:2]=[CH:3][C:4]=1[C:5]([N:7]1[C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=2[N:11]([CH2:18][C:19]([N:21]2[CH2:22][CH2:23][N:24]([CH3:27])[CH2:25][CH2:26]2)=[O:20])[CH2:10][CH2:9][CH2:8]1)=[O:6]
Reactant: CN(C)CCCCl
Reactant: O=C([O-])[O-]
Reactant: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCC(=O)N(CC(=O)N4CCN(C)CC4)c4ccccc43)cc2O)cc1
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: Cc1ccc(-c2ccccc2C(=O)Nc2ccc(C(=O)N3CCCN(CC(=O)N4CCN(C)CC4)c4ccccc43)c(OCCCN(C)C)c2)cc1
Yield: 38.5 %

Procedure:
A solution of 5-{3-hydroxy-4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-[(4-methyl-1-piperazinyl)carbonylmethyl]-1,3,4,5-tetrahydro-1,5-benzodiazepin-2(2H)-one (350 mg), 3-dimethylaminopropyl chloride hydrochloride (96.4 mg) and potassium carbonate (230 mg) in N,N-dimethylformamide (15 ml) were stirred for 4 hours at 80° C. The mixture was diluted with ethyl acetate and washed with water, saturated aqueous sodium bicarbonate and brine. The organic solution was dried over sodium sulfate, concentrated, and purified by silica gel column chromatography (SiO2 10 g, 15% methanol in chloroform) to give 5-{3-dimethylaminopropoxy-4-[2-(4-methylphenyl)benzoylamino]benzoyl}-1-[(4-methyl-1-piperazinyl)carbonylmethyl]-1,3,4,5-tetrahydro-1,5-benzodiazepin -(2H)-one (150 mg).
Reaction SMILES: [CH2:1]([O:3][N:4]=[C:5]([C:30]1[N:34]=[C:33]([NH2:35])[S:32][N:31]=1)[C:6]([NH:8][CH:9]1[C:28](=[O:29])[N:11]2[C:12]([C:25]([OH:27])=[O:26])=[C:13]([CH:16]=[CH:17][S:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2].[CH3:36]N(C)C=O.C[I:42]>C(OCC)(=O)C>[IH:42].[CH2:1]([O:3][N:4]=[C:5]([C:30]1[N:34]=[C:33]([NH2:35])[S:32][N:31]=1)[C:6]([NH:8][CH:9]1[C:28](=[O:29])[N:11]2[C:12]([C:25]([O-:27])=[O:26])=[C:13]([CH:16]=[CH:17][S:18][CH2+:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]3[CH3:36])[CH2:14][S:15][C@H:10]12)=[O:7])[CH3:2]
Reactant: CI
Reactant: CN(C)C=O
Reactant: CCON=C(C(=O)NC1C(=O)N2C(C(=O)O)=C(C=CSc3ccccn3)CS[C@H]12)c1nsc(N)n1
Solvent: CCOC(C)=O
Product: CCON=C(C(=O)NC1C(=O)N2C(C(=O)[O-])=C(C=CS[CH2+]3C=CC=CN3C)CS[C@H]12)c1nsc(N)n1
Product: I
Reaction time: 144 h

Procedure:
A mixture of 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(2-pyridyl)thiovinyl]-3-cephem-4-carboxylic acid (syn isomer) (trans isomer) (1.5 g), dimetylformamide (15 ml) and methyliodide (1.5 ml) was shaked for six days at ambient temperature in a stainless-steel bomb. The reaction mixture was poured into ethyl acetate. The resultant, precipitate was collected by filtration and washed with ethyl acetate and dr d to give 7-[2-ethoxyimino-2-(5-amino-1,2,4-thiadiazol-3-yl)acetamido]-3-[2-(1-methyl-2-pyridinio)thiovinyl]-3-cephem-4-carboxylate hydriodide (syn isomer) (trans isomer) (2.0 g).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6](I)[CH:7]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.[O-]P([O-])([O-])=O.[K+].[K+].[K+].C(O)CO>C(O)(C)C.[Cu]I>[Br:1][C:2]1[CH:7]=[C:6]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)[CH:5]=[N:4][CH:3]=1
Reactant: Brc1cncc(I)c1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)N1CCN(c2cncc(Br)c2)CC1
Temperature: 25 °C
Yield: 36.7 %

Procedure:
A solution of 3-bromo-5-iodopyridine (13.0 g, 45.8 mmol) , tert-butyl piperazine-1-carboxylate (8.53 g, 45.8 mmol) , copper(I) iodide (0.871 g, 4.57 mmol), K3PO4 (19.46 g, 91.68 mmol), 1,2-ethanediol (5.1 mL, 91 mmol) in isopropyl alcohol (80 mL) in a sealed tube was heated at 80° C. in an oil bath for 2 days. After cooling to room temperature, the reaction mixture was filtered through celite. The filtrate was concentrated in vacuo. The residue was taken up in EtOAc and the solution was washed with saturated NaHCO3, dried (MgSO4) and concentrated. Purification by flash chromatography on silica gel (20% EtOAc/hexanes to 30% EtOAc/hexanes) afforded 5.75 g (37%) of desired product. MS calculated for C14H20BrN3O2: (M+H) 343; found 342.0, 344.0.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[N:9]1[C:14]2[N:15]=[C:16](S(C)(=O)=O)[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]=2[CH:12]=[CH:11][C:10]1=[O:41].[NH:42]1[CH2:47][CH2:46][CH:45]([NH:48]C(=O)OC(C)(C)C)[CH2:44][CH2:43]1>>[NH2:48][CH:45]1[CH2:46][CH2:47][N:42]([C:16]2[N:17]=[C:18]([C:19]3[CH:20]=[C:21]([NH:26][C:27](=[O:36])[C:28]4[CH:33]=[CH:32][C:31]([F:34])=[C:30]([CH3:35])[CH:29]=4)[CH:22]=[CH:23][C:24]=3[CH3:25])[C:13]3[CH:12]=[CH:11][C:10](=[O:41])[N:9]([C:3]4[C:2]([F:1])=[CH:7][CH:6]=[CH:5][C:4]=4[F:8])[C:14]=3[N:15]=2)[CH2:43][CH2:44]1
Reactant: CC(C)(C)OC(=O)NC1CCNCC1
Reactant: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(S(C)(=O)=O)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F
Product: Cc1cc(C(=O)Nc2ccc(C)c(-c3nc(N4CCC(N)CC4)nc4c3ccc(=O)n4-c3c(F)cccc3F)c2)ccc1F

Procedure:
The title compound was prepared as described in Example 2 from N-{3-[8-(2,6-difluorophenyl)-2-(methylsulfonyl)-7-oxo-7,8-dihydropyrido[2,3-d]pyrimidin-4-yl]-4-methylphenyl}-4-fluoro-3-methylbenzamide and 1,1-dimethylethyl 4-piperidinylcarbamate: LC-MS m/z 599 (M+H)+, 1.99 min (ret time).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([OH:5])=[O:4].S(Cl)([Cl:10])=O.[CH3:12]O>>[ClH:10].[NH2:1][C@@H:2]([CH2:6][CH3:7])[C:3]([O:5][CH3:12])=[O:4]
Reactant: CO
Reactant: O=S(Cl)Cl
Reactant: CC[C@H](N)C(=O)O
Product: CC[C@H](N)C(=O)OC
Product: Cl
Temperature: 2.5 °C

Procedure:
5.0 g of (S)-amino butyric acid (23) was suspended in 50 ml of methanol and stirred at 0-5° C. 6.35 g of thionyl chloride was added dropwise over 45 min to form a clear solution. After stirring for 20 hours at room temperature, the reaction was concentrated under reduced pressure to dryness and the almost colourless residue solidified to give the required product which was dried in an oven at 50° C. under vacuum (7.6 g; 102% crude yield). The same reaction was scaled-up from 200 g of the amino acid and provided 296 g (99.5% yield) of product (24).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[SH:8].[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22]O)[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:11])[CH3:10].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>O1CCCC1>[C:9]([O:13][C:14]([N:16]1[CH2:21][CH2:20][CH:19]([CH2:22][S:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[F:1])[CH2:18][CH2:17]1)=[O:15])([CH3:12])([CH3:10])[CH3:11]
Reactant: Fc1ccccc1S
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(CSc2ccccc2F)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 4.8 %

Procedure:
After dissolving 1.97 g of 2-fluorothiophenol in 50 ml of tetrahydrofuran, 3.0 g of 1-(tert-butoxycarbonyl)piperidine-4-methanol and 4.03 g of triphenylphosphine were added, and then 3.3 ml of diethyl azodicarboxylate was added dropwise while cooling on ice and the mixture was stirred overnight at room temperature. The reaction solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (solvent: n-hexane/ethyl acetate) to obtain the title compound (216 mg, 5% yield).
Reaction SMILES: [C:1]([CH:3]([C:14]1[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][C:15]=1[N+:21]([O-])=O)C(OCC1C=CC=CC=1)=O)#N.O>[Pd].C(O)C>[CH3:20][C:17]1[CH:16]=[C:15]2[C:14]([CH:3]=[CH:1][NH:21]2)=[CH:19][CH:18]=1
Reactant: Cc1ccc(C(C#N)C(=O)OCc2ccccc2)c([N+](=O)[O-])c1
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: Cc1ccc2cc[nH]c2c1
Reaction time: 18 h
Yield: 74 %

Procedure:
a mixture of benzyl 2-cyano-2-(2-nitro-4-methylphenyl)ethanoate (13 mmol), 5% palladium (0.84 g), water (4 mL) and ethanol (40 mL) is hydrogenated under 50 psi for 18 hours at 25° C. The catalyst is eliminated by filtration on celite and the solid is washed with ethanol. The filtrate obtained is evaporated under vacuum and the residue is purified by chromatography on silica gel (eluent: CH2Cl2/pentane, 2/1) in order to produce 6-methylindole with a yield of 74%.
Reaction SMILES: C(O[C:4]([C:6]1[NH:10][C:9]2[CH:11]=[C:12]([Cl:14])[S:13][C:8]=2[CH:7]=1)=[O:5])C.[CH2:15]1[NH:20][CH2:19][CH2:18][N:17]2[CH2:21][CH2:22][CH2:23][CH:16]12>>[Cl:14][C:12]1[S:13][C:8]2[CH:7]=[C:6]([C:4]([N:20]3[CH2:19][CH2:18][N:17]4[CH2:21][CH2:22][CH2:23][CH:16]4[CH2:15]3)=[O:5])[NH:10][C:9]=2[CH:11]=1
Reactant: CCOC(=O)c1cc2sc(Cl)cc2[nH]1
Reactant: C1CC2CNCCN2C1
Product: O=C(c1cc2sc(Cl)cc2[nH]1)N1CCN2CCCC2C1
Yield: 30 %

Procedure:
2-Chloro-4H-thieno[3,2-b]pyrrole-5-carboxylic acid ethyl ester (230 mg, 1.0 mmol) was hydrolyzed (Procedure B) and then coupled with octahydro-pyrrolo[1,2-a]pyrazine (Procedure C) to provide the title compound (93 mg, 30% for two steps) as an off-white solid. TLC (silica, 10% MeOH/CH2Cl2): Rf=0.4. MS (electrospray): exact mass calculated for C14H16ClN3OS, 309.07; m/z found, 310.1 [M+H]+. 1H NMR (CDCl3, 400 MHz): 10.9 (br s, 1H), 6.86 (s, 1H), 6.64 (d, J=1.4 Hz, 1H), 4.77 (d, J=12.2 Hz, 1H), 4.65 (d, J=12.7 Hz, 1H), 3.30-2.90 (m, 4H), 2.30-1.40 (m, 7H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10](Br)[CH:9]=2)=[O:4].[N:18]1[CH:23]=[CH:22][CH:21]=[C:20](B(O)O)[CH:19]=1>>[CH3:1][O:2][C:3]([C:5]1[C:6](=[O:17])[S:7][C:8]2[C:13]([C:14]=1[OH:15])=[CH:12][CH:11]=[C:10]([C:20]1[CH:19]=[N:18][CH:23]=[CH:22][CH:21]=1)[CH:9]=2)=[O:4]
Reactant: OB(O)c1cccnc1
Reactant: COC(=O)c1c(O)c2ccc(Br)cc2sc1=O
Product: COC(=O)c1c(O)c2ccc(-c3cccnc3)cc2sc1=O

Procedure:
4-Hydroxy-2-oxo-7-pyridin-3-yl-2H-thiochromene-3-carboxylic acid methyl ester was prepared from 7-bromo-4-hydroxy-2-oxo-2H-thiochromene-3-carboxylic acid methyl ester (Example 5e) and 3-pyridyl-boronic acid under conditions analogous to Example 14(a). MS ESI(+) m/e: 314.12 (M+1).
Reaction SMILES: C([N-]C(C)C)(C)C.[Li+].[CH3:9][O:10][C:11]1[CH:12]=[C:13]([S:17][C:18]2[C:26](CC)=[C:25](CC)[CH:24]=[CH:23][C:19]=2[C:20](N)=[O:21])[CH:14]=[CH:15][CH:16]=1.CO>CCCCCCC.C1COCC1.O1CCCC1>[CH3:9][O:10][C:11]1[C:12]2[C:20](=[O:21])[C:19]3[C:18](=[CH:26][CH:25]=[CH:24][CH:23]=3)[S:17][C:13]=2[CH:14]=[CH:15][CH:16]=1
Reactant: CCc1ccc(C(N)=O)c(Sc2cccc(OC)c2)c1CC
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCCCCC
Product: COc1cccc2sc3ccccc3c(=O)c12
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Finally, 1-methoxythioxanthen-9-one (S-12) was prepared. A stirred mixture of 2.05 mL of a 2.0 M solution in heptane/THF of lithium diisopropylamide (4.1 mmol) diluted with 15 mL of anhydrous tetrahydrofuran was cooled to 0° C. and treated dropwise with a solution of 2-[(3-methoxyphenyl)thio]diethylbenzamide (0.4 g, 1.4 mmol) in 3 mL of anhydrous tetrahydrofuran. The reaction mixture was warmed to ambient and stirred for 2 h. Methanol (1 mL) was added, and the resulting solution was washed twice with water, and then with brine. The solution was dried (Na2SO4) and the solvent was removed at reduced pressure to deposit a yellow solid. This crude product was recrystallized from methanol to provide 0.15 g (45% of theory) of a yellow solid. 1H NMR (CDCl3): δ 4.00 (s, 3H), 7.92 (d, 1H), 7.12 (d, 1H), 7.50 (m, 4H), 8.45 (d, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[N:8][N:9]([C@H:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH3:12])[CH:10]=1)=[O:5])C.[OH-].[Li+]>O1CCCC1.O>[C:13]1([C@@H:11]([N:9]2[CH:10]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[N:8]2)[CH3:12])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCOC(=O)c1cnn([C@@H](C)c2ccccc2)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@@H](c1ccccc1)n1cc(C(=O)O)cn1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Intermediate (6f), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid ethyl ester (1.525 g, 6.2 mmol) was stirred in a mixture of tetrahydrofuran (20 mL) and water (20 mL). Lithium hydroxide (0.524 g, 12.5 mmol) was added and the reaction stirred at ambient temperature for 24 hours. The reaction mixture was reduced in volume and extracted with diethyl ether (3×20 mL). The aqueous layer was carefully acidified using an aqueous 6N hydrochloric acid solution. The resulting precipitate was filtered, washed with copious amounts of water and dried in vacuo to afford intermediate (6g), 1-((S)-1-Phenyl-ethyl)-1H-pyrazole-4-carboxylic acid as a white solid, 0.664 g, 49%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[Cl:8].C(C1NC=CN=1)(C1NC=CN=1)=O.[CH3:25][NH:26][CH:27]1[CH2:35][C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]1[N:36]1[CH2:40][CH2:39][CH2:38][CH2:37]1>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([N:26]([CH:27]2[CH2:35][C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH:28]2[N:36]2[CH2:40][CH2:39][CH2:38][CH2:37]2)[CH3:25])=[O:12])[CH:5]=[CH:6][C:7]=1[Cl:8]
Reactant: CNC1Cc2ccccc2C1N1CCCC1
Reactant: O=C(O)Cc1ccc(Cl)c(Cl)c1
Agent: O=C(c1ncc[nH]1)c1ncc[nH]1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1ccc(Cl)c(Cl)c1)C1Cc2ccccc2C1N1CCCC1
Temperature: 22.5 °C
Reaction time: 1 h

Procedure:
A mixture of 2.66 g of 3,4-dichlorophenyl-acetic acid, 2.10 g of carbonyl-diimidazole and 25 ml of tetrahydrofuran was stirred for 1 hour at 20 to 25° C. and then 2.16 g of the product of Step C was added in 10 ml of tetrahydrofuran with stirring for 3 hours 30 minutes at 20 to 25° C. after which the tetrahydrofuran was distilled off under reduced pressure. The residue was taken up in ether, washed with a saturated solution of sodium bicarbonate and then with water saturated with sodium chloride. After drying and concentrating to dryness under reduced pressure, 5.048 g of [Trans (±)] 3,4-dichloro-N-[2,3-dihydro-1-(pyrrolidinyl)-1H-inden-2-yl]-n-methyl-benzene-acetamide as a fluid resin.
Reaction SMILES: [F-].C([N+](CCCC)(CCCC)CCCC)CCC.[CH2:19]([C:21]12[CH2:28][O:27][C:24]([C:29]3[CH:34]=[CH:33][C:32]([C:35]#[C:36][Si](C)(C)C)=[CH:31][CH:30]=3)([O:25][CH2:26]1)[O:23][CH2:22]2)[CH3:20]>O1CCCC1>[CH2:19]([C:21]12[CH2:26][O:25][C:24]([C:29]3[CH:30]=[CH:31][C:32]([C:35]#[CH:36])=[CH:33][CH:34]=3)([O:23][CH2:22]1)[O:27][CH2:28]2)[CH3:20]
Reactant: CCC12COC(c3ccc(C#C[Si](C)(C)C)cc3)(OC1)OC2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#Cc1ccc(C23OCC(CC)(CO2)CO3)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.3 %

Procedure:
Tetrabutyl ammonium fluoride solution (3.3 ml, 1M in tetrahydroforan) was added to a stirred solution of 4-ethyl-1-[4-(2-trimethylsilylethynyl)phenyl]-2,6,7-trioxabicyclo[2,2,2]octane (0.87 gms) in tetrahydrofuran (15 ml). The mixture was stirred for 30 minutes at room temperature when the solvent was removed under vacuum. The residue was taken up in ether and washed with water and brine. The ethereal solution was dried over anhydrous magnesium sulphate and evaporated in vacuo. Recrystallisation from hexane gave 4-ethyl-1-(4-ethynylphenyl)-2,6,7-trioxabicyclo[2,2,2]octane as an off-white solid (0.66 gms).