Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([O:17][C:18]([F:21])([F:20])[F:19])=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)[CH:7]=1.[C:22]([O:26][C:27]([N:29]1[CH2:32][CH2:31][C@H:30]1[C:33]([OH:35])=O)=[O:28])([CH3:25])([CH3:24])[CH3:23].CN(C(ON1N=N[C:46]2C=CC=C[C:45]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CN1CCOCC1>CN(C=O)C>[C:22]([O:26][C:27]([N:29]1[CH2:32][CH2:31][C@H:30]1[C:33](=[O:35])[NH:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([O:16][CH2:45][CH3:46])=[O:15])=[CH:12][CH:13]=2)[C:5]([O:17][C:18]([F:19])([F:20])[F:21])=[CH:4][CH:3]=1)=[O:28])([CH3:23])([CH3:24])[CH3:25]
Reactant: Nc1ccc(OC(F)(F)F)c(-c2ccc(C(=O)O)cc2)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@H]1C(=O)O
Reactant: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CCOC(=O)c1ccc(-c2cc(NC(=O)[C@@H]3CCN3C(=O)OC(C)(C)C)ccc2OC(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 78.7 %

Procedure:
A mixture of 5′-amino-2′-trifluoromethoxy-biphenyl-4-carboxylic acid (150 mg), (S)-azetidine-1,2-dicarboxylic acid 1-tert-butyl ester (93 mg), HBTU (262 mg) and N-methyl morpholine (0.14 ml) in dry DMF (3 ml) was stirred at room temp for 18 h. The mixture was then partitioned between water and DCM. The dried organic layer was evaporated and the residue purified on silica gel. Elution with ethyl acetate:petrol 1:1 gave a pale orange oil (185 mg).
Reaction SMILES: [C:1](O)(=O)[CH2:2][C:3]([OH:5])=[O:4].C(=O)/[CH:9]=[CH:10]/[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.N1CCCCC1.Cl>N1C=CC=CC=1>[CH:1](=[CH:2][C:3]([OH:5])=[O:4])[CH:9]=[CH:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(O)CC(=O)O
Reactant: O=C/C=C/c1ccccc1
Agent: Cl
Solvent: c1ccncc1
Solvent: C1CCNCC1
Product: O=C(O)C=CC=Cc1ccccc1
Temperature: 115 °C
Reaction time: 26 h

Procedure:
Cinnamylidene acetic acid was synthesized according to the method described in U.S. Pat. No. 3,257,664, the disclosure of which is incorporated herein by reference. In general, 104 gms of malonic acid (Aldrich), 126 ml of trans-cinnamaldehyde and 90 ml of pyridine were mixed and exposed to slight heating for complete solubilization of the reaction mixture. Piperidine (0.25 ml) was then added, and the mixture was allowed to stand at room temperature for approximately 26 hours. The reaction mixture was then refluxed at 115° C. for 18 hours. When the reaction was completed, the reaction mixture was allowed to cool to room temperature. In turn, the solution was poured into cold dilute (5 w/v %) hydrochloric acid. The resulting yellowish solid cake was washed repeatedly with deionized water, and the wet product was crystallized from ethyl alcohol to give cinnamylidene acetic acid (65.22 gms). The purity of cinnamylidene acetic acid was determined by 1HNMR and UV spectroscopy. 1HNMR (CDCl3 -TMS): δ=6.1 ppm (d, 2H), δ=6.9 ppm (t, 2H), δ=7.5 ppm (m, 5H). The --COOH proton could not be detected in the NMR spectrum, but the product of the esterification reaction between cinnamylidene acetic chloride and polyethylene glycol established its existence. UV (in dichloromethane): λmax =313 nm, ε=37,390 L3 mol-1 cm-1, λmax =250 nm, ε=1985 L3 mol-1 cm-1.
Reaction SMILES: [C:1]1([C:7]#[C:8]/[CH:9]=[CH:10]/[CH2:11]O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.P(Br)(Br)[Br:14]>C1(C)C=CC=CC=1.C(OCC)(=O)C>[Br:14][CH2:11]/[CH:10]=[CH:9]/[C:8]#[C:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrP(Br)Br
Reactant: OC/C=C/C#Cc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: BrC/C=C/C#Cc1ccccc1
Yield: 65.7 %

Procedure:
A solution of (E)-5-phenyl-pent-2-en-4-yn-1-ol (Method 1b) (980 mg, 6.2 mmol) in dry toluene (20 mL) was cooled on ice and phosphorus tribromide (0.59 mL, 6.2 mmol) added slowly. After 16 h at 5° C. the mixture was diluted with ethyl acetate and washed with water (×3). The organic phase was concentrated in vacuo and the residue extracted with heptane (×3). The combined heptane phases were concentrated in vacuo to give 900 mg of crude (E)-(5-bromo-pent-3-en-1-ynyl)-benzene. (According to NMR the product contained ˜5% of the (Z)-isomer).
Reaction SMILES: [N:1]1([C:7]([N:9]2[CH2:14][CH:13]([C:15]3[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=3)[CH2:12][CH:11]([C:25](=[S:27])[NH2:26])[CH2:10]2)=[O:8])[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.Br[CH2:29][C:30]([C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([O:38][CH3:39])[CH:33]=1)=O>>[CH3:39][O:38][C:34]1[CH:33]=[C:32]([C:30]2[N:26]=[C:25]([CH:11]3[CH2:12][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([C:21]([F:22])([F:23])[F:24])=[CH:17][CH:16]=4)[CH2:14][N:9]([C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[O:8])[CH2:10]3)[S:27][CH:29]=2)[CH:37]=[CH:36][CH:35]=1
Reactant: NC(=S)C1CC(c2ccc(C(F)(F)F)cc2)CN(C(=O)N2CCOCC2)C1
Reactant: COc1cccc(C(=O)CBr)c1
Product: COc1cccc(-c2csc(C3CC(c4ccc(C(F)(F)F)cc4)CN(C(=O)N4CCOCC4)C3)n2)c1

Procedure:
100 mg (0.152 mmol) of 1-(morpholin-4-ylcarbonyl)-5-[4-(trifluoromethyl)phenyl]piperidine-3-carbothioamide (Example 53A) and 42 mg (0.182 mmol) of 2-bromo-1-(3-methoxyphenyl)ethanone were reacted according to the General Method 3. Yield: 29 mg (35% of theory)
Reaction SMILES: [C:1]1([C:7]2[O:8][CH:9]=[CH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20](O)=[O:21])[CH:16]=[CH:17][CH:18]=1.O=P12OP3(OP(OP(O3)(O1)=O)(=O)O2)=O>ClC1C=CC=CC=1Cl>[Br:12][C:13]1[CH:14]=[C:15]([CH2:19][C:20]([C:9]2[O:8][C:7]([C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[CH:11][CH:10]=2)=[O:21])[CH:16]=[CH:17][CH:18]=1
Reactant: c1ccc(-c2ccco2)cc1
Reactant: O=C(O)Cc1cccc(Br)c1
Agent: O=P12OP3(=O)OP(=O)(O1)OP(=O)(O2)O3
Solvent: Clc1ccccc1Cl
Product: O=C(Cc1cccc(Br)c1)c1ccc(-c2ccccc2)o1
Temperature: 80 °C
Reaction time: 3 h

Procedure:
2-Phenyl-furan (119) (50 mg, 0.28 mmol) and (3-bromo-phenyl)-acetic acid (134 mg, 0.63 mmol) were dissolved in ortho-dichlorobenzene (4 ml). P2O5 (202 mg, 1.42 mmol) was added as a suspension in ortho-dichlorobenzene (2 ml). The reaction mixture was heated to 80° C. for 2 h and cooled to room temperature overnight. After the addition of further P2O5 (202 mg, 1.42 mmol), heating was resumed at 90° C. for 3 h. The reaction mixture was cooled to 0° C. and quenched with H2O (15 ml). The organic layer was separated and the aqueous layer was washed with DCM (3×10 ml). The combined organic layers were dried (MgSO4), filtered and the DCM removed in vacuo. The ortho-dichlorobenzene solution was loaded to a silica-gel column and flushed with heptane (100 ml). The title compound was then eluted with 10% EtOAc in heptane.
Reaction SMILES: [CH2:1]=[C:2]=[CH2:3].C=C1CCC1=C.[CH2:10]=[C:11]1[CH2:14][C:13](=[CH2:15])[CH2:12]1>>[CH2:1]=[C:2]1[CH2:3][CH2:12][C:13](=[CH2:15])[CH2:14][C:11]1=[CH2:10]
Reactant: C=C1CC(=C)C1
Reactant: C=C=C
Agent: C=C1CCC1=C
Product: C=C1CCC(=C)C(=C)C1

Procedure:
The system was first purged with nitrogen. The power to the fluidized bed was turned on and its temperature was brought to 450°-470° C. Allene was introduced into the system from the allene cylinder at a rate of 80-100 grams/hour. The allene supply from the cylinder was shut off two to three hours before the end of a dimerization run in order that the allene present in the system could be used up, with little allene remaining in the reservoir a the end. At the end of the day, the power to the fluidized bed was turned off, the system was allowed to cool, and the accumulated crude liquid product was poured into a bottle and weighed. Approximately 3 grams of phenothiazine was added per kilogram of crude liquid product to inhibit polymerization and oxidation of the dimers and trimers. The crude product was then analyzed by gas chromatography for peaks corresponding to two allene dimers, 1,2-dimethylenecyclobutane (1,2-DMCB) and 1,3-dimethylenecyclobutane (1,3-DMCB), and the allene trimer 1,2,4-trimethylenecyclohexane (TMCH). Data from seven hot tube reaction runs are shown in Table 1.
Reaction SMILES: [CH2:1]([NH2:4])[CH:2]=[CH2:3].[Cl:5][C:6]1[N:7]=[C:8]([NH:16][CH:17]2[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]2)[C:9]2[S:14][CH:13]=[C:12]([CH3:15])[C:10]=2[N:11]=1>O>[ClH:5].[CH2:1]([NH:4][C:6]1[N:7]=[C:8]([NH:16][CH:17]2[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]2)[C:9]2[S:14][CH:13]=[C:12]([CH3:15])[C:10]=2[N:11]=1)[CH:2]=[CH2:3]
Reactant: Cc1csc2c(NC3CCCCC3)nc(Cl)nc12
Reactant: C=CCN
Solvent: O
Product: C=CCNc1nc(NC2CCCCC2)c2scc(C)c2n1
Product: Cl
Temperature: 140 °C
Yield: 65.6 %

Procedure:
In 2.28 g (40.0 mmol) of allylamine was dissolved 250 mg (0.9 mmol) of 2-chloro-4-cyclohexylamino-7-methylthieno[3,2-d]pyrimidine, and the resulting solution was heated in a sealed tube at 140° C. for 24 hours. After the reaction mixture was cooled, 100 ml of water was added thereto, followed by extraction with ethyl acetate (20 ml×3). The organic layer was washed with 20 ml of water and dried over anhydrous sodium sulfate, and then the solvent was distilled off. The residue was purified by silica gel column chromatography and an eluate of hexane/ethyl acetate=4/1 was concentrated. To the concentrate was added a 4N hydrochloric acid-ethyl acetate solution (1 ml), and crystals thus precipitated were filtered to give 200 mg (yield: 66.7%) of the title compound.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][CH:5]=1)=O.COC(OC)[N:16]([CH3:18])C.[NH2:21]N>O.C1(C)C=CC(S(O)(=O)=O)=CC=1>[N+:10]([C:7]1[CH:8]=[CH:9][C:4]([C:2]2[NH:21][N:16]=[CH:18][CH:1]=2)=[CH:5][CH:6]=1)([O-:12])=[O:11]
Reactant: COC(OC)N(C)C
Reactant: NN
Reactant: CC(=O)c1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=[N+]([O-])c1ccc(-c2ccn[nH]2)cc1
Yield: 58.8 %

Procedure:
4-Nitroacetophenone(15 g) and N,N-dimethylformamide dimethylacetal(54 g) were refluxed for 1 hour. The reaction mixture was cooled, then crystals precipitate were filtered. To a solution of the crystals obtained (13.5 g) in ethanol (150 ml) was added hydrazine (4.52 g) and p-toluene sulfonic acid monohydrate (0.15 g) and the mixture was refluxed for 1 hours. The solvent was evaporated to dryness and the residue was crystallized from ether to obtain thr title compound (10.1 g).
Reaction SMILES: CO.[CH2:3]([Br:6])[CH:4]=[CH2:5].[CH2:7]([N:9]([CH2:12][CH3:13])[CH2:10][CH3:11])[CH3:8]>>[Br-:6].[CH2:3]([N+:9]([CH2:12][CH3:13])([CH2:10][CH3:11])[CH2:7][CH3:8])[CH:4]=[CH2:5]
Reactant: C=CCBr
Reactant: CCN(CC)CC
Solvent: CO
Product: C=CC[N+](CC)(CC)CC
Product: [Br-]
Reaction time: 0.08 h

Procedure:
A mixture of 60 grams of methanol, 60.23 grams of triethylamine and 60.72 grams of allyl bromide was prepared. The mixture was stirred for 5 minutes before refluxing. The mixture was allowed to reflux for 30 minutes before 12.0 grams of allyl bromide was added.
Reaction SMILES: C1(CN(C2C=CC(S(C)(=O)=O)=CC=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][CH:12]=[C:13](CC(O)=O)[N:14]=2)CCCC1.[CH:30]1([CH2:35][NH:36][C:37]2[CH:42]=[C:41]([C:43]([F:46])([F:45])[F:44])[CH:40]=[C:39]([O:47][CH3:48])[CH:38]=2)[CH2:34][CH2:33][CH2:32][CH2:31]1.C([O:51][C:52](=[O:61])[CH2:53][S:54]C1SC(N)=NC=1)C>>[CH:30]1([CH2:35][N:36]([C:37]2[CH:42]=[C:41]([C:43]([F:45])([F:46])[F:44])[CH:40]=[C:39]([O:47][CH3:48])[CH:38]=2)[C:8](=[O:19])[NH:9][C:10]2[S:11][C:12]([S:54][CH2:53][C:52]([OH:61])=[O:51])=[CH:13][N:14]=2)[CH2:31][CH2:32][CH2:33][CH2:34]1
Reactant: COc1cc(NCC2CCCC2)cc(C(F)(F)F)c1
Reactant: CCOC(=O)CSc1cnc(N)s1
Reactant: CS(=O)(=O)c1ccc(N(CC2CCCC2)C(=O)Nc2nc(CC(=O)O)cs2)cc1
Product: COc1cc(N(CC2CCCC2)C(=O)Nc2ncc(SCC(=O)O)s2)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared via {2-[3-(3-methoxy-5-trifluoromethyl-phenyl)-3-cyclopentylmethyl-ureido]-thiazol-5-ylsulfanyl}-acetic acid ethyl esterin a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(4-methanesulfonyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using cyclopentylmethyl-(3-methoxy-5-trifluoromethyl-phenyl)-amine and (2-amino-thiazol-5-ylsulfanyl)acetic acid ethyl ester
Reaction SMILES: [NH:1]1[CH2:11][CH2:10][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:3][CH2:2]1.C(N(CC)CC)C.[C:19](Cl)(=[O:21])[CH3:20]>C1COCC1.CN(C1C=CC=CN=1)C>[C:19]([N:1]1[CH2:2][CH2:3][CH:4]([C:5]([O:7][CH2:8][CH3:9])=[O:6])[CH2:10][CH2:11]1)(=[O:21])[CH3:20]
Reactant: CCOC(=O)C1CCNCC1
Reactant: CC(=O)Cl
Agent: CN(C)c1ccccn1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)C1CCN(C(C)=O)CC1
Yield: 98.6 %

Procedure:
To a solution of ethyl isonipecotate (8.0 g) in THF (100 mL) was added triethylamine (5.7 g), dimethylaminopyridine (0.6 g) and acetyl chloride (4.4 g) at 0° C. and the mixture was stirred for an hour. The mixture was extracted with ethyl acetate and the solvent was evaporated under reduced pressure to give ethyl 1-acetylpiperidine-4-carboxylate (10 g) as a colorless oil. To a solution of acetonitrile (2.5 g) in THF (300 mL) was added n-BuLi (57 mmol) at −78° C. Further, ethyl 1-acetylpiperidine-4-carboxylate (10 g) was added and the mixture was stirred for an hour. After acidification with hydrochloric acid, the mixture was extracted with ethyl acetate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel column chromatography (eluent:hexane-ethyl acetate (10:1)) to give 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (7.5 g) as a colorless oil. A solution of 2,1,3-benzoxadiazole-4-aldehyde (0.3 g), 3-aminopyrazole (0.17 g) and 1-(1-acetylpiperidin-4-yl)-2-cyanoethan-1-one (0.4 g) in acetonitrile (10 mL) was heated under reflux overnight. The reaction mixture was cooled to room temperature, and the precipitated crystals were collected by filtration to give the title compound (0.49 g) as yellow crystals.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[O:11][CH3:12].[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:49]=[CH:48][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([NH:35][C:36]4[N:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:39]=[CH:38][N:37]=4)[CH:29]=3)=[O:26])=[CH:23][CH:22]=2)[CH2:16][CH2:15]1>C(O)C>[CH3:13][N:14]1[CH2:19][CH2:18][N:17]([CH2:20][C:21]2[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]3[CH:33]=[CH:32][C:31]([CH3:34])=[C:30]([NH:35][C:36]4[N:41]=[C:40]([C:42]5[CH:43]=[N:44][CH:45]=[CH:46][CH:47]=5)[CH:39]=[CH:38][N:37]=4)[CH:29]=3)=[O:26])=[CH:48][CH:49]=2)[CH2:16][CH2:15]1.[C:6]([O-:8])(=[O:7])[C:5]1[CH:9]=[CH:10][C:2]([OH:1])=[C:3]([O:11][CH3:12])[CH:4]=1
Reactant: COc1cc(C(=O)O)ccc1O
Agent: Cc1ccc(NC(=O)c2ccc(CN3CCN(C)CC3)cc2)cc1Nc1nccc(-c2cccnc2)n1
Solvent: CCO
Product: COc1cc(C(=O)[O-])ccc1O

Procedure:
A solution of 4-hydroxy-3-methoxybenzoic acid (vanillic acid; Fluka, Buchs, Switzerland; 694 mg, 4 mmol) in ethanol (50 mL) is added to a solution of 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide (1.975 g, 4 mmol) in hot ethanol (150 mL at 90° C.). The solution is evaporated to dryness under reduced pressure and the resulting residue is re-crystallized from ethanol-acetone. The product is filtered-off and dried to afford 4-[(4-methyl-1-piperazinyl)methyl]-N-[4-methyl-3-[[4-(3-pyridinyl)-2-pyrimidinyl]amino]phenyl]-benzamide, vanillate as a crystalline solid, having the following analytical properties: Analysis found: C, 66.61; H, 6.18; N, 14.74; 0, 12.86%. H2O, 0.84%. Calculated for C37H39N7O5-0.31 H2O: C, 66.59; H, 5.98; N, 14.69; O, 12.73%. H2O, 0.84%.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[CH:3]=1.[Br:9]NC(=O)CCC(N)=O>C(O)(=O)C>[NH2:1][C:2]1[CH:7]=[CH:6][N:5]=[C:4]([Cl:8])[C:3]=1[Br:9]
Reactant: Nc1ccnc(Cl)c1
Reactant: NC(=O)CCC(=O)NBr
Solvent: CC(=O)O
Product: Nc1ccnc(Cl)c1Br
Temperature: 25 °C
Reaction time: 1 h

Procedure:
4-amino-2-chloropyridine (50 g, 388 mmol) was dissolved in glacial acetic acid (500 mL). To this solution was added N-bromosuccinamide (75 g, 426 mmol), portionwise at room temperature (water bath cooling was provided to control the exothermicity). The reaction mixture was stirred at RT for 1 h at which point the reaction was found complete (as monitored by TLC). Solvent was removed under reduced pressure followed by azeotropic distillation with ethanol. The crude product was purified by column chromatography on silica gel (230-400 mesh) eluting with ethyl acetate hexane mixture.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([C:11]3[N:12](COCC[Si](C)(C)C)[CH:13]=[CH:14][N:15]=3)[CH:9]=2)[CH:4]=[CH:3]1.Cl.C([O:28][C:29](=[NH:41])[CH2:30][C:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[N:33]([CH3:40])[CH:32]=1)(C)C.Cl.[CH3:43][CH2:44][OH:45]>>[NH:12]1[CH:13]=[CH:14][N:15]=[C:11]1[C:8]1[CH:9]=[C:10]2[C:5]([C:4]([C:43]3[C:44](=[O:45])[NH:28][C:29](=[O:41])[C:30]=3[C:31]3[C:39]4[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=4)[N:33]([CH3:40])[CH:32]=3)=[CH:3][N:2]2[CH3:1])=[CH:6][CH:7]=1
Reactant: CCO
Reactant: CC(C)OC(=N)Cc1cn(C)c2ccccc12
Reactant: Cn1ccc2ccc(-c3nccn3COCC[Si](C)(C)C)cc21
Agent: Cl
Product: Cn1cc(C2=C(c3cn(C)c4cc(-c5ncc[nH]5)ccc34)C(=O)NC2=O)c2ccccc21
Yield: 14 %

Procedure:
3-[6-(1H-Imidazol-2-yl)-1-methyl-1H-indol-3-yl]-4-(1-methyl-1H-indol-3-yl)pyrrole-2,5-dione (37 mg, 14%) was prepared as an orange solid using 1-methyl-6-[1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-1H-indole (200 mg, 0.61 mmol) and 1-methyl-3-indoleacetimidic acid isopropyl ester hydrochloride (162 mg, 0.61 mmol) followed by deprotection using 20% HCl in refluxing EtOH.
Reaction SMILES: [C:1]1([CH:7]([OH:10])[C:8]#[CH:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>CC(C)=O.O.S(=O)(=O)(O)O.[O-2].[O-2].[O-2].[Cr+6]>[C:1]1([C:7]([C:8]#[CH:9])=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C#CC(O)c1ccccc1
Agent: [Cr+6]
Agent: O=S(=O)(O)O
Agent: [O-2]
Solvent: O
Solvent: CC(C)=O
Product: C#CC(=O)c1ccccc1

Procedure:
A solution of 1-phenyl-2-propyne-1-ol (34.2 g) in 50 ml acetone is cooled down to 0°, stirred under N2 and treated dropwise, over a period of 3 hours with a solution of chromium trioxide (17.5 g) in water (50 ml) and concentrated sulfuric acid (14.8 ml), keeping the temperature below 5° at all times. After the addition is complete, the mixture is stirred for another hour at 5°. The reaction mixture is then diluted with water (100 ml) and extracted with two 250-ml portions of ether. The organic extracts are combined, dried over anhydrous sodium sulfate, filtered and stripped to give a yellow product. A small amount dried on a porous plate gives a m.p. of 45°-47°.
Reaction SMILES: [CH2:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH2:4][CH:3]([C:14]([OH:16])=[O:15])[NH:2]1.[OH-].[Na+].[C:19](=[S:21])=[S:20].[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29]Br)=[CH:27][CH:26]=1)([O-:24])=[O:23]>CS(C)=O>[N+:22]([C:25]1[CH:32]=[CH:31][C:28]([CH2:29][S:20][C:19]([N:2]2[CH:3]([C:14]([OH:16])=[O:15])[CH2:4][C:5]3[C:6]4[C:11](=[CH:10][CH:9]=[CH:8][CH:7]=4)[NH:12][C:13]=3[CH2:1]2)=[S:21])=[CH:27][CH:26]=1)([O-:24])=[O:23]
Reactant: O=C(O)C1Cc2c([nH]c3ccccc23)CN1
Reactant: S=C=S
Reactant: O=[N+]([O-])c1ccc(CBr)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=C(O)C1Cc2c([nH]c3ccccc23)CN1C(=S)SCc1ccc([N+](=O)[O-])cc1
Yield: 54 %

Procedure:
In the same manner as described in Example 16, (3RS)-1,2,3,4-tetrahydro-β-carboline-3-carboxylic acid (4.22 g), 10N NaOH (3.9 ml), carbon disulfide (1.4 ml), dimethylsulfoxide (12 ml) and 4-nitrobenzyl bromide (4.63 g) are reacted and treated. The product is crystallized from ethanol to give the title compound (4.7 g, 54%) as yellow crystals, m.p. 194°-195° C.
Reaction SMILES: C([O:4][CH2:5][CH:6]=[CH:7][C:8]1[CH:13]=[CH:12][C:11]([Cl:14])=[C:10]([Cl:15])[CH:9]=1)(=O)C.Cl[Si]([CH2:22][CH3:23])(CC)CC.C[Si]([N-][Si](C)(C)C)(C)C.[K+].C1C[O:37]CC1>>[Cl:15][C:10]1[CH:9]=[C:8]([CH:7]([CH:22]=[CH2:23])[CH2:6][C:5]([OH:4])=[O:37])[CH:13]=[CH:12][C:11]=1[Cl:14]
Reactant: C1CCOC1
Reactant: CC(=O)OCC=Cc1ccc(Cl)c(Cl)c1
Reactant: CC[Si](Cl)(CC)CC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Product: C=CC(CC(=O)O)c1ccc(Cl)c(Cl)c1
Temperature: 23 °C
Yield: 89 %

Procedure:
Treat a solution of the product of step 3 (15 g, 61 mmol, dried by azeotropic distillation with toluene, 1×50 mL) in dry THF (250 mL) at -78° C. with chlorotriethylsilane (20.2 mL, 120 mmol, 2.0 eq) rapidly followed by the addition of potassium bis(trimethylsilyl)amide (183 mL, 91.5 mmol, 1.5 eq of 0.5M in toluene) via addition funnel over 50 min. Allow the mixture to warm to 23° C. and heat to reflux for 3 h. Gradually cool the solution overnight, then quench with saturated NH4Cl (150 mL). Stir the resultant mixture vigorously for 3h, treat with 1M HCl (150 mL) and then extract with Et2O (500 mL). Extract the aqueous layer with Et2O (400 mL), wash the combined organic layers with 5% NaOH (300 mL) and extract with 5% NaOH (8×150 mL). Cool the combined aqueous layers to 5° C. and, maintaining the temperature at 5°-10° C., acidify with conc. HCl (ca 175 mL) to pH 1. Extract the aqueous layer with CH2Cl2 (2×800 mL), dry (Na2SO4) and concentrate to give 13.4 g (54.5 mmol, 89%) of 3-(3,4-dichlorophenyl)-4-pentenoic acid as a faint yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH3:17])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1.C(C1C=C(C)C=C(C(C)(C)C)N=1)(C)(C)C.[Xe](F)[F:42]>ClCCl>[Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([Cl:25])[C:7]=1[NH:8][C:9](=[O:24])[C:10]1[CH:15]=[CH:14][C:13]([S:16][CH2:17][F:42])=[C:12]([O:18][CH:19]2[CH2:23][CH2:22][CH2:21][CH2:20]2)[CH:11]=1
Reactant: CSc1ccc(C(=O)Nc2c(Cl)cncc2Cl)cc1OC1CCCC1
Reactant: F[Xe]F
Agent: Cc1cc(C(C)(C)C)nc(C(C)(C)C)c1
Solvent: ClCCl
Product: O=C(Nc1c(Cl)cncc1Cl)c1ccc(SCF)c(OC2CCCC2)c1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A solution of N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(methylthio)benzamide (1 g; that is prepared as described in Example 20) in dichloromethane (100 mL), containing molecular sieve 4A, under nitrogen, is treated with 2,6-di-tert-butyl-4-methylpyridine (1.28 g). The resulting mixture is stirred at room temperature for 1.5 hours, and then it is cooled to 0° C. (in an ice/salt bath) and treated with xenon difluoride (0.51 g) in one portion. After stirring for a further 2 hours in the cold, the mixture is filtered, and the filtrate is washed with saturated aqueous ammonium chloride solution. The organic phase is dried over sodium sulfate and evaporated. The resulting residue is subjected to flash chromatography, eluting with a mixture of ethyl acetate and pentane (2:3 v/v), to give impure N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)-benzamide (600 mg). It is further purified by reversed phase HPLC on octadecylsilyl silica gel, eluting with a mixture of methanol and water (7:3 v/v). to give N-(3,5-dichloropyrid-4-yl)-3-cyclopentyloxy-4-(fluoromethylthio)benzamide (519 mg), in the form of a white solid, m.p. 111-113° C. [Elemental analysis: C,51.50; H,4.12; N,6.74%; calculated: C,52.05; H,4.12; N,6.74%].
Reaction SMILES: [NH:1]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20](OC)=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4].O.[NH2:32][NH2:33]>CO>[C:27]([O:26][C:24]([NH:1][CH2:2][C:3]([NH:5][CH2:6][C:7]([NH:9][CH2:10][C:11]([NH:13][C@H:14]([C:16]([NH:18][CH2:19][C:20]([NH:32][NH2:33])=[O:21])=[O:17])[CH3:15])=[O:12])=[O:8])=[O:4])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: COC(=O)CNC(=O)[C@H](C)NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C
Reactant: NN
Solvent: O
Solvent: CO
Product: C[C@H](NC(=O)CNC(=O)CNC(=O)CNC(=O)OC(C)(C)C)C(=O)NCC(=O)NN

Procedure:
A solution of Boc-Gly-Gly-Gly-Ala-Gly-OMe (1.0 g, 2.32 mmole, described in Example 16) and hydrazine hydrate (1 ml, 23.2 mmole) in methanol (30 ml) is stirred at 0° C for 4 hr. After evaporation the residue is triturated with diethyl ether and dried to give the title compound, mp 221° - 223° C.