Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH2:23])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1.C(N(CC)CC)C.[F:35][C:36]([F:41])([F:40])[C:37](O)=[O:38]>ClCCl>[CH3:1][S:2][C:3]1[N:4]=[CH:5][C:6]2[C:15](=[O:16])[N:14]([C:17]3[CH:18]=[C:19]([CH:24]=[CH:25][CH:26]=3)[C:20]([NH:22][NH:23][C:37](=[O:38])[C:36]([F:41])([F:40])[F:35])=[O:21])[CH2:13][C@H:12]3[N:8]([CH2:9][CH2:10][CH2:11]3)[C:7]=2[N:27]=1
Reactant: O=C(O)C(F)(F)F
Reactant: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NN)c1)C2=O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CSc1ncc2c(n1)N1CCC[C@H]1CN(c1cccc(C(=O)NNC(=O)C(F)(F)F)c1)C2=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 93.2 %

Procedure:
(S)-3-(9-Methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)benzoic hydrazide (257 mg, 0.67 mmol) obtained in Step 2 of Example 56 was dissolved in dichloromethane (8.0 mL), and the mixture was cooled to 0° C. after adding triethylamine (0.19 mL, 1.34 mmol). Thereafter, anhydrous trifluoroacetic acid (0.19 mL, 1.34 mmol) was added dropwise to the mixture, and the mixture was stirred at room temperature for 30 minutes. The mixture was concentrated under reduced pressure, and a 3 mol/L aqueous sodium hydroxide solution was added to the resulting residue to adjust the pH at 4. The precipitated white solid was then filtered off to obtain (S)-3-(9-methylthio-6-oxo-2,3,3a,4-tetrahydro-1H,6H-5,8,10,10b-tetraazabenzo[e]azulen-5-yl)-N′-(2,2,2-trifluoroacetyl)benzoic hydrazide (300 mg, 93%).
Reaction SMILES: [CH:1]12[O:8][CH:5]([CH2:6][CH2:7]1)[CH2:4][N:3]([C:9]1[N:14]=[C:13]([C:15]3[CH:21]=[CH:20][C:18]([NH2:19])=[CH:17][CH:16]=3)[N:12]=[C:11]3[N:22]([CH:25]4[CH2:30][CH2:29][N:28]([CH2:31][C:32]([F:35])([F:34])[F:33])[CH2:27][CH2:26]4)[N:23]=[CH:24][C:10]=13)[CH2:2]2.ClC(Cl)(O[C:40](=[O:46])[O:41][C:42](Cl)(Cl)Cl)Cl.C(N(CC)CC)C.C(O)[CH2:56][OH:57]>O1CCCC1>[OH:57][CH2:56][CH2:42][O:41][C:40](=[O:46])[NH:19][C:18]1[CH:20]=[CH:21][C:15]([C:13]2[N:12]=[C:11]3[N:22]([CH:25]4[CH2:26][CH2:27][N:28]([CH2:31][C:32]([F:34])([F:35])[F:33])[CH2:29][CH2:30]4)[N:23]=[CH:24][C:10]3=[C:9]([N:3]3[CH2:4][CH:5]4[O:8][CH:1]([CH2:7][CH2:6]4)[CH2:2]3)[N:14]=2)=[CH:16][CH:17]=1
Reactant: Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: OCCO
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: O=C(Nc1ccc(-c2nc(N3CC4CCC(C3)O4)c3cnn(C4CCN(CC(F)(F)F)CC4)c3n2)cc1)OCCO
Yield: 56 %

Procedure:
A solution of 4-(4-(8-oxa-3-azabicyclo[3.2.1]octan-3-yl)-1-(1-(2,2,2-trifluoroethyl)piperidin-4-yl)-1H-pyrazolo[3,4-d]pyrimidin-6-yl)aniline (85 mg, 0.17 mmol) in tetrahydrofuran (6 mL) was treated with triphosgene (26 mg, 0.09 mmol), followed by triethylamine (0.11 mL). After the passage of five minutes, ethylene glycol (0.14 mL) was added. The mixture was concentrated to dryness under reduced pressure. The resultant residue was purified via reverse-phase high performance liquid chromatography using a Phenomenex Gemini 21 mm×100 mm column, running a gradient elution of 10% acetonitrile/90% of 0.1% aqueous trifluoroacetic acid to 70% acetonitrile over 20 minutes. After the concentration of fractions under reduced pressure, 2-hydroxyethyl(4-{4-(8-oxa-3-azabicyclo[3.2.1]oct-3-yl)-1-[1-(2,2,2-trifluoroethyl)piperidin-4-yl]-1H-pyrazolo[3,4-d]pyrimidin-6-yl}phenyl)carbamate (55 mg, 56%) was obtained as clear blond semi-solid. MS (ES+): 576.1, 577.1 (M+H)+
Reaction SMILES: I[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][N:3]=1.[CH2:8]([N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21])[CH2:9][C:10]#[CH:11]>>[N:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[C:11]#[C:10][CH2:9][CH2:8][N:12]1[CH2:20][C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:13]1=[O:21]
Reactant: Ic1ccccn1
Reactant: C#CCCN1Cc2ccccc2C1=O
Product: O=C1c2ccccc2CN1CCC#Cc1ccccn1
Yield: 37 %

Procedure:
The title compound was prepared in accordance with the general method of Example 1, from 2-iodopyridine (94 mg, 0.46 mmol) and 2-(but-3-ynyl)isoindolin-1-one (85 mg, 0.46 mmol). Reaction conditions: 14 hours at room temperature. The crude residue was purified by flash chromatography (cyclohexane/AcOEt 1:1 to 0:1) to yield 45 mg (0.17 mmol, 37%) of 2-(4-(pyridin-2-yl)but-3-ynyl)isoindolin-1-one as a white solid (M.P.=94-98° C.).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][C:9]1[C:14]([CH3:15])=[C:13]([O:16][CH3:17])[C:12]([O:18][CH3:19])=[C:11]([O:20][CH3:21])[C:10]=1[O:22][CH3:23])(=O)=O.[C:24]1([P:30]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.[Na+].[I-:44]>C(Cl)Cl>[I-:44].[CH3:23][O:22][C:10]1[C:11]([O:20][CH3:21])=[C:12]([O:18][CH3:19])[C:13]([O:16][CH3:17])=[C:14]([CH3:15])[C:9]=1[CH2:8][CH2:7][CH2:6][P+:30]([C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1)([C:37]1[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=1)[C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: COc1c(C)c(CCCOS(C)(=O)=O)c(OC)c(OC)c1OC
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: [I-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1c(C)c(CCC[P+](c2ccccc2)(c2ccccc2)c2ccccc2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 3 h
Yield: 90.4 %

Procedure:
The methanesulfonate 3 (3.30 g, 9.8 mmol) was mixed with a freshly ground mixture of triphenylphosphine (4.08 g, 15.6 mmol) and NaI (7.78 g, 51.9 mmol) in a KIMAX tube and sealed under argon. The mixture was then held at 70-74° C. with magnetic stirring for 3 hrs during which time the mixture changed from a molten thick liquid into a glassy solid. The tube was cooled to room temperature and the residue stirred with CH2Cl2 (30 mL). The suspension was then filtered and the filtrate evaporated in vacuo. The residue was dissolved in a minimum amount of CH2Cl2 and triturated with excess ether (250 mL) to precipitate the white solid. The solid was filtered and washed with ether, dried in vacuo to give pure 10 (5.69 g, 90%).
Reaction SMILES: CC1CCCC(C)(C)C=1C(O)CC=C.[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:23])([CH3:22])[C:17]=1[CH:24]([OH:29])[CH2:25][C:26]([CH3:28])=[CH2:27]>>[CH3:15][C:16]1[CH2:21][CH2:20][CH2:19][C:18]([CH3:22])([CH3:23])[C:17]=1[C:24](=[O:29])[CH2:25][C:26]([CH3:28])=[CH2:27]
Reactant: C=C(C)CC(O)C1=C(C)CCCC1(C)C
Agent: C=CCC(O)C1=C(C)CCCC1(C)C
Product: C=C(C)CC(=O)C1=C(C)CCCC1(C)C

Procedure:
By replacing hereabove 2,6,6-trimethyl-1-[1-hydroxy-3-butenyl]-1-cyclohexene with 2,6,6-trimethyl-1-[1-hydroxy-3-methyl-3-butenyl]-1-cyclohexene (nD20 = 1.4939; d420 = 0.9270), 2,6,6-trimethyl-1-[3-methyl-3-butenoyl]-1-cyclohexene was obtained; nD20 = 1.4862; d420 = 0.9307.
Reaction SMILES: [CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=O)[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1.Cl.[NH2:26][OH:27].[OH-].[Na+]>C(O)C.O>[CH3:1][N:2]([CH3:24])[C:3]1[N:7]=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([C:16](=[N:26][OH:27])[C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]=2)[CH3:9])[O:5][N:4]=1
Reactant: CC(c1cccc(C(=O)c2ccccc2)c1)c1nc(N(C)C)no1
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(c1cccc(C(=NO)c2ccccc2)c1)c1nc(N(C)C)no1
Temperature: 0 °C
Reaction time: 24 h
Yield: 83.4 %

Procedure:
To 3-dimethylamino-5-(1-(3-benzoylphenyl)ethyl)-1,2,4-oxadiazole (1.0 g, 3.11 mmol) in ethanol (10 ml) were added hydroxylamine hydrochloride (0.25 g, 3.45 mmol) in water (2 ml) and sodium hydroxide (0.40 g, 9.5 mmol) in water (2 ml). After reflux with stirring for 24 h, the mixture was poured upon ice water and extracted with ethyl acetate. The ethyl acetate extracts were washed with saturated NaCl aq. dried with anhydrous magnesium salfate, and evaporated under redused pressure to a residue, which was chromatographed to afford 3-dimethylamino-5-(1-(3-(α-hydroxyiminobenzyl)phenyl)ethyl)-1,2,4-oxadiazole (0.873 g, 84% yield) as oily substance: NMR(CDCl3)δ1.66(d)+1.77(d) (3H), 2.98(s, 6H), 4.20(m, 1H), 7.22-7.55(m, 9H) ppm; IR(neat) 3700-3100, 1600, 1405 cm-1.
Reaction SMILES: Cl.[CH2:2]([C@H:5]1[CH2:9][NH:8][CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4].[C:25]([O:29][C:30]([N:32]1[CH:41]([C:42](O)=[O:43])[CH2:40][C:39]2[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=2)[CH2:33]1)=[O:31])([CH3:28])([CH3:27])[CH3:26].CCN(CC)CC.F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1>C(Cl)Cl>[CH2:2]([C@H:5]1[CH2:9][N:8]([C:42]([CH:41]2[CH2:40][C:39]3[C:34](=[CH:35][C:36]([Cl:45])=[CH:37][CH:38]=3)[CH2:33][N:32]2[C:30]([O:29][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:31])=[O:43])[CH2:7][C@@:6]1([N:22]=[N+:23]=[N-:24])[C:10]([O:12][CH2:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11])[CH:3]=[CH2:4]
Reactant: C=CC[C@H]1CNC[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Reactant: CC(C)(C)OC(=O)N1Cc2cc(Cl)ccc2CC1C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC[C@H]1CN(C(=O)C2Cc3ccc(Cl)cc3CN2C(=O)OC(C)(C)C)C[C@@]1(N=[N+]=[N-])C(=O)OCC(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 54.1 %

Procedure:
A stirred mixture of racemic 2-oxo-2-phenylethyl (3R,4S)-4-allyl-3-azidopyrrolidine-3-carboxylate hydrochloride (228 mg, 0.650 mmol) and 2-(tert-butoxycarbonyl)-7-chloro-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid (258 mg, 0.826 mmol) in methylene chloride (6 mL) was treated with Et3N (0.272 mL, 1.95 mmol) followed by N,N,N′,N′-tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (HATU, 321 mg, 0.845 mmol), and the resulting nearly homogeneous mixture was stirred at room temperature. After 1 h, the reaction was diluted with methylene chloride (20 mL), washed successively with water (20 mL), 1 N aqueous HCl (20 mL), saturated aqueous NaHCO3 (20 mL) and saturated aqueous sodium chloride (10 mL), dried over Na2SO4, and concentrated. Purification by silica gel chromatography (40 g column, 15-25% ethyl acetate in hexanes) gave tert-butyl 3-({(3R,4S)-4-allyl-3-azido-3-[(2-oxo-2-phenylethoxy)carbonyl]pyrrolidin-1-yl}carbonyl)-7-chloro-3,4-dihydroisoquinoline-2(1H)-carboxylate (214 mg, 54%) as a pale amber film which was used without further purification. LC-MS ESI+MS found for C31H34ClN5O6 m/z 608.2 (M+H), 630.3 (M+Na); ESI−MS m/z 606.3 (M−H).
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[S:11]1[CH2:17][C:15](=[O:16])[NH:14][C:12]1=[S:13].C([O-])(=O)C.[Na+]>C(O)(=O)C>[Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=[C:17]1[S:11][C:12](=[S:13])[NH:14][C:15]1=[O:16]
Reactant: O=C1CSC(=S)N1
Reactant: O=Cc1c(Cl)cccc1Cl
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CC(=O)O
Product: O=C1NC(=S)SC1=Cc1c(Cl)cccc1Cl
Temperature: 25 °C

Procedure:
2,6-Dichlorobenzaldehyde (77.0 g), rhodanine (58.6 g), and acetic acid (539 ml) were suspended with stirring at room temperature. Anhydrous sodium acetate (116 g) was added to the suspension, and the resulting mixture was heated under reflux for 3 hours. The reaction mixture was cooled to 45° C., and ice water (700 ml) was added. After the mixture was stirred for 0.2 hours, the precipitated crystals were collected by filtration, washed with water, and then dried to obtain 2,6-dichlorobenzylidenerhodanine. Even in non-dried form, this product could be subjected to the subsequent step.
Reaction SMILES: [CH3:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2.C([Li])CCC.[CH3:16][C:17]([CH3:20])([O-])[CH3:18].[K+].BrCC(C)=C>C(OCC)C.CCCCCC>[CH3:18][C:17]([CH2:20][CH2:1][C:2]1[NH:3][C:4]2[C:9]([CH:10]=1)=[CH:8][CH:7]=[CH:6][CH:5]=2)=[CH2:16]
Reactant: Cc1cc2ccccc2[nH]1
Reactant: CC(C)(C)[O-]
Agent: C=C(C)CBr
Agent: [K+]
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: CCCCCC
Product: C=C(C)CCc1cc2ccccc2[nH]1
Temperature: 25 °C
Reaction time: 0.83 h
Yield: 47 %

Procedure:
To a stirred solution of 2-methylindole (1 g) in diethylether (76 ml) under nitrogen was added a 1.6 M solution of n-butyllithium in hexane (14.3 ml) slowly dropwise via syringe. Potassium tert-butoxide (1.711 g) was then added, producing a bright yellow mixture. After stirring at room temperature under nitrogen for 50 minutes, the mixture was cooled to −78° C., whereupon 3-bromo-2-methylpropene (1.54 ml) was added dropwise via syringe, giving a red-orange solution. The reaction mixture was stirred at −78° C. for 2 hours, then quenched with water (10 ml). After warming to room temperature, water (150 ml) and 1 N hydrochloric acid (1 ml) was added to neutralize the reaction mixture. The mixture was extracted with ethyl acetate (250 ml), and the organic layer was washed with brine (100 ml) and dried with sodium sulfate. The solvent was removed under reduced pressure, and the crude residue was purified by flash chromatography (4% ethyl acetate/hexane) to afford 2-(2-methyl-1-butene-4-yl)indole (664 mg. 47%) as a waxy yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([O:23]C2CCCCO2)[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([O:30]C2CCCCO2)[CH2:12][C:11]1=[O:37].C(O)(=O)C>O1CCCC1.O>[CH3:1][O:2][C:3](=[O:39])[CH2:4][CH2:5][CH2:6][CH2:7][C:8](=[O:38])[CH2:9][C@@H:10]1[C@@H:14](/[CH:15]=[CH:16]/[C@@H:17]([OH:23])[CH2:18][CH2:19][CH2:20][CH2:21][CH3:22])[C@H:13]([OH:30])[CH2:12][C:11]1=[O:37]
Reactant: CCCCC[C@@H](/C=C/[C@H]1[C@H](OC2CCCCO2)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC)OC1CCCCO1
Solvent: C1CCOC1
Solvent: CC(=O)O
Solvent: O
Product: CCCCC[C@H](O)/C=C/[C@H]1[C@H](O)CC(=O)[C@@H]1CC(=O)CCCCC(=O)OC
Temperature: 45 °C
Reaction time: 3 h
Yield: 53.1 %

Procedure:
To a solution of 480 mg of (13E)-(11α,15S)-6,9-dioxo-11,15-bis(tetrahydropyran-2-yloxy)prost-13-enoic acid methyl ester (prepared as described in Example 1) in 1 ml of tetrahydrofuran was added 3 ml of 65% (v/v) aqueous acetic acid and the mixture was stirred at 45° C. for 3 hours. The reaction mixture was diluted with 16 ml of water and extracted with a mixture of ethyl acetate and n-hexane (1:1). The extract was washed with water, an aqueous solution of sodium bicarbonate and an aqueous solution of sodium chloride, dried over magnesium sulphate and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel using a mixture of ethyl acetate and n-hexane (1:1) as eluent to give 177 mg of the title compound having the following physical characteristics:
Reaction SMILES: [CH3:1][C:2]1([CH2:6][O:7][C:8](=[O:26])[C@@H:9]([NH:15][C:16]([O:18][CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[O:17])[CH2:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][O:4][CH2:3]1.C(N(CC)CC)C>C(Cl)Cl.B(F)(F)F.CCOCC>[CH2:19]([O:18][C:16](=[O:17])[NH:15][C@H:9]([C:8]12[O:4][CH2:5][C:2]([CH3:1])([CH2:3][O:26]1)[CH2:6][O:7]2)[CH2:10][C:11]([CH3:12])([CH3:14])[CH3:13])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C(=O)OCC1(C)COC1
Agent: FB(F)F
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)C[C@H](NC(=O)OCc1ccccc1)C12OCC(C)(CO1)CO2
Reaction time: 5 h
Yield: 72.3 %

Procedure:
To a solution of 2(S)-benzyloxycarbonylamino-4,4-dimethylpentanoic acid 3-methyl-oxetan-3-ylmethyl ester (21.5 g, 59 mmol) in dry DCM (50 ml) was added BF3.Et2O (0.4 ml, 3.2 mmol). After 5 h, triethylamine (0.9 ml, 6.4 mmol) was added and stirring was continued for 30 min at room temperature. The solvent was evaporated using a rotavap and the resulting oil was redissolved in ethyl acetate and was washed with 50 ml of 3% NH4Cl solution followed by brine. The ethyl acetate layer was dried over MgSO4, the solvent was evaporated and the residue was purified with column chromatography using silica gel and 20:80 EtOAc:Hexane as eluent to give [3,3-dimethyl-1(S)-(4-methyl-2,6,7-trioxabicyclo[2.2.2]oct-1-yl)butyl]carbamic acid benzyl ester (15.5 g).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[CH2:5][NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=1)[CH3:2].[CH2:18]=O.[CH:20]([S:22]([C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]([F:34])([F:33])[F:32])(=[O:24])=[O:23])=[CH2:21]>>[CH2:1]([O:3][C:4]([CH:5]1[CH2:18][CH:20]([S:22]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]([F:32])([F:34])[F:33])(=[O:23])=[O:24])[CH2:21][N:6]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([S:13]([CH3:16])(=[O:15])=[O:14])[CH:8]=1)=[O:17])[CH3:2]
Reactant: CCOC(=O)CNc1cccc(S(C)(=O)=O)c1
Reactant: C=CS(=O)(=O)c1ccccc1C(F)(F)F
Reactant: C=O
Product: CCOC(=O)C1CC(S(=O)(=O)c2ccccc2C(F)(F)F)CN1c1cccc(S(C)(=O)=O)c1

Procedure:
In analogy to the procedure described in example 343d, (3-methanesulfonyl-phenylamino)-acetic acid ethyl ester was reacted with paraformaldehyde and 1-ethenesulfonyl-2-trifluoromethyl-benzene (example 243c) to give the title compound as yellow oil. MS (ESI): m/z=506.1 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([CH:24]=O)=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1.C1COCC1.O.[NH2:33]OS(O)(=O)=O>CCOC(C)=O>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:9]2[C:10]([C:24]#[N:33])=[CH:11][C:12]([O:14][CH2:15][C:16]3[C:17]([CH3:23])=[N:18][C:19]([CH3:22])=[CH:20][CH:21]=3)=[CH:13][C:8]=2[S:7][CH:6]=1
Reactant: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C=O)c12
Reactant: NOS(=O)(=O)O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)Cc1csc2cc(OCc3ccc(C)nc3C)cc(C#N)c12
Yield: 96.8 %

Procedure:
To a mixture of methyl(6-((2,6-dimethylpyridin-3-yl)methoxy)-4-formyl-1-benzothiophen-3-yl)acetate (100 mg), THF (5 mL) and water (5 mL) was added hydroxylamine-O-sulfonic acid (45.9 mg) at room temperature, and the mixture was refluxed for 48 h. The suspension was diluted with EtOAc, and TEA (1 mL) was added to the mixture. The mixture was refluxed for 1 h. The mixture was poured into water at room temperature and extracted with EtOAc. The organic layer was separated, washed successively with water and brine, dried over MgSO4 and concentrated in vacuo. The residue was purified by silica gel column chromatography (EtOAc/hexane) to give the title compound (96 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[OH:9].C(=O)([O-])[O-].[K+].[K+].[CH3:16][O:17][C:18](=[O:25])[CH:19](Cl)[C:20]([O:22][CH3:23])=[O:21]>CC(C)=O>[CH3:16][O:17][C:18](=[O:25])[CH:19]([O:9][C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=1[O:2][CH3:1])[C:20]([O:22][CH3:23])=[O:21]
Reactant: COc1ccccc1O
Reactant: COC(=O)C(Cl)C(=O)OC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: COC(=O)C(Oc1ccccc1OC)C(=O)OC
Temperature: 45 °C

Procedure:
2-Methoxy-phenol (guaiacol) (48 ml) was slowly added to a stirred suspension of potassium carbonate (70.8 g) in acetone (480 ml) followed by heating to 45° C. Then, dimethylchloromalonate (63.2 ml) in acetone (50 ml) was added within 20 min. The reaction mixture was heated to reflux for 16 h. The solvent was evaporated under reduced pressure, the residue taken into water and extracted with DCM. The combined organic layers were dried over sodium sulfate and evaporated. The oily product was crystallized from tert.-butyl-methyl-ether. Dimethyl-(o-methoxyphenoxy)malonate (86 g) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CN=C1.[I:37]I>C(Cl)Cl>[I:37][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: II
Reactant: OCCCCCc1ccccc1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: ICCCCCc1ccccc1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of 5-phenyl-pentane-1-ol (1.0 gm, 6.09 mmol) in CH2Cl2 (20 ml), triphenyl phosphine (2.35 gm, 8.52 mmol), imidazole (0.58 gm, 8.52 mmol) and elemental iodine (2.16 gm, 8.52 mmol) was stirred at room temperature for 12 h. The solvent was evaporated under reduced pressure. The residue was diluted with EtOAc (30 ml), H2O (20 ml) was added, separated and the organic phase was washed with brine (30 ml). The organic layer was dried over anhydrous Na2SO4; solvent was evaporated under reduced pressure and the crude product was purified by column chromatography using hexane as eluent. The crude product was purified by column chromatography using hexane as eluent. The pure product was an oily liquid (750 mg).
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([O:15]CC)=[O:14].[OH-].[Na+]>C(O)C.O>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[S:3][C:2]1=[N:10][CH2:11][CH2:12][C:13]([OH:15])=[O:14]
Reactant: CCOC(=O)CCN=c1sc2ccccc2s1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)CCN=c1sc2ccccc2s1
Yield: 70.8 %

Procedure:
A solution of 3-[(1,3-benzodithiol-2ylidene)amino]-propanoic acid, ethyl ester (3.0g, prepared as described in Example 2) and sodium hydroxide (499 mg) in 120 ml of absolute ethanol is stirred at room temperature for 120 hours. The reaction mixture is concentrated in vacuo, and the resultant solid residue is washed with diethyl ether to remove unreacted starting material. The crude reaction product is dissolved in 50 ml of water, filtered through Celite, and the aqueous solution is then treated with 10% hydrochloric acid until the pH is 5. The resultant precipitate is collected by filtration and dried in vacuo at 60° C overnight. Recrystallization of the dried product from n-pentyl alcohol yields 1.9g of the title compound, melting point 203-204° C.
Reaction SMILES: Br[CH2:2][CH2:3][C:4]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[NH:6][CH:5]=1.Cl.[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1)=[O:18].C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[F:14][C:15]1[CH:28]=[CH:27][CH:26]=[CH:25][C:16]=1[C:17]([CH:19]1[CH2:24][CH2:23][N:22]([CH2:2][CH2:3][C:4]2[C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[NH:6][CH:5]=2)[CH2:21][CH2:20]1)=[O:18]
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: O=C(c1ccccc1F)C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: O=C(c1ccccc1F)C1CCN(CCc2c[nH]c3ccccc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A solution of 9.1 g of 3-(2-bromoethyl)indole in 100 ml of dimethyl formamide is added to a stirring solution of 11.2 g of 4-(2-fluorobenzoyl)piperidine hydrochloride and 13 g of potassium carbonate in 400 ml of dimethylformamide. The reaction mixture is stirred at ambient temperature for 24 hours, and then 800 ml of water are added dropwise, yielding a dark precipitate. This mixture is again stirred at ambient temperature for 24 hours and filtered to give a yellow crystalline material which is recrystallized thrice from an ehtanol-water mixture to give an off-white crystalline material, mp 106°-108° C. , 3-{2-[4-(2-fluorobenzoyl)piperidyl]-ethyl}indole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([OH:8])[CH:7]=1.BrC[C:14]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[CH2:15].[C:22](=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N+:9]([O-:11])=[O:10])=[C:6]([O:8][CH2:22][CH:15]=[CH:14][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:7]=1
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1ccc(Cl)cc1O
Reactant: C=C(CBr)c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(Cl)cc1OCC=Cc1ccccc1

Procedure:
A solution of 5-chloro-2-nitrophenol (7 g) in dimethylformamide (40 ml) was stirred at room temperature with 1-bromo-2-phenyl-2-propene (8 ml) and potassium carbonate (5.5 g) for 18 h. The reaction mixture was diluted with water (200 ml) was extracted with ether (100 ml). The ether was washed with water (3×100 ml). The solvent was removed under reduced pressure and the residue was crystallized from hexanes. The yellow solid (8.6 g) was the desired product. m.p. 74.5°-75.5° C.