Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:10])[CH2:5][NH:6][C:7](=[O:9])[CH3:8])[CH3:2].CN1C=CN=C1.[C:17](Cl)(=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32].C(N(CC)CC)C>[Ti](Cl)(Cl)(Cl)Cl.O.C1(C)C=CC=CC=1>[C:7]([NH:6][CH:5]([C:17](=[O:33])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])[C:4]([O:3][CH2:1][CH3:2])=[O:10])(=[O:9])[CH3:8]
Reactant: CCOC(=O)CNC(C)=O
Reactant: CCCCCCCCCCCCCCCC(=O)Cl
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: Cn1ccnc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Solvent: O
Product: CCCCCCCCCCCCCCCC(=O)C(NC(C)=O)C(=O)OCC
Temperature: -20 °C
Reaction time: 2 h
Yield: 66.2 %

Procedure:
A toluene solution (33.0 ml) of N-acetylglycine ethyl ester (1.00 g, 6.89 mmol) and N-methylimidazole (679 mg, 8.27 mmol) was cooled to −20° C., and palmitoyl chloride (1.89 g, 6.89 mmol) was added thereto in nitrogen atmosphere. After the mixture was stirred for 30 minutes at the same temperature, titanium tetrachloride (4.57 mg, 24.12 mmol) and triethylamine (2.79 g, 27.56 mmol) were added thereto. The resulting mixture was stirred for 2 hours at −20° C. Water (20 mL) was added thereto, and the mixture was heated to room temperature, and the organic layer was separated. It was confirmed by comparative analysis with sample product using HPLC that the organic layer contained 1.75 g of the title compound (yield: 66%).
Reaction SMILES: [Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([OH:16])=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:25])([CH3:24])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1.Br[CH2:29][C:30]1[S:31][C:32]2[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=2[N:34]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CC#N.CN(C=O)C>[Cl:1][C:2]1[CH:27]=[CH:26][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][C:12]([O:16][CH2:29][C:30]4[S:31][C:32]5[CH:38]=[CH:37][CH:36]=[CH:35][C:33]=5[N:34]=4)=[CH:13][CH:14]=3)[C:9]([CH3:17])=[C:8]2[CH2:18][C:19]([CH3:24])([CH3:25])[C:20]([O:22][CH3:23])=[O:21])=[CH:4][CH:3]=1
Reactant: COC(=O)C(C)(C)Cc1c(C)c2cc(O)ccc2n1Cc1ccc(Cl)cc1
Reactant: BrCc1nc2ccccc2s1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)C(C)(C)Cc1c(C)c2cc(OCc3nc4ccccc4s3)ccc2n1Cc1ccc(Cl)cc1

Procedure:
A solution of methyl 3-[1-(4-chlorobenzyl)-3-methyl-5-hydroxyindol-2-yl]-2,2-dimethylpropanoate (Preparation 1) (200 mg), 2-bromomethylbenzothiazole (147 mg), Cs2CO3 (263 mg) in 3 mL CH3CN and 3 mL DMF was stirred at 60° C. for 4 hours. The mixture was poured onto water, extracted with EtOAc, washed twice with brine, dried (MgSO4), and evaporated. Chromatography of the residue on silica gel eluting with hexane/EtOAc 4:1 provided the title compound as a solid.
Reaction SMILES: [ClH:1].[CH3:2][O:3][C:4]1[CH:9]=[CH:8][C:7]([NH:10][NH2:11])=[CH:6][CH:5]=1.C1(C)C=CC=CC=1.[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Br)=[CH:22][CH:21]=1.C(N(CC)CC)C>C(OCC)(=O)C>[ClH:1].[Br:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:10]([C:7]2[CH:8]=[CH:9][C:4]([O:3][CH3:2])=[CH:5][CH:6]=2)[NH2:11])=[CH:22][CH:21]=1
Reactant: COc1ccc(NN)cc1
Reactant: BrCc1ccc(Br)cc1
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: COc1ccc(N(N)Cc2ccc(Br)cc2)cc1
Temperature: 102.5 °C
Reaction time: 3 h

Procedure:
4-Methoxyphenylhydrazine hydrochloride (1.0 eq) was added to a reaction flask containing toluene (16.5-fold, V/W of starting material) under N2. 4-Bromobenzyl bromide (1.05 eq) and triethylamine (2.1 eq) were added, and the mixture was heated to 100-105° C. and stirred for 3 hours. The reaction was then cooled to room temperature and checked by analytical thin layer chromatography (tlc) for completion. Since no starting material was seen by tlc analysis, the reaction was diluted with ethyl acetate (10.0-fold, V/W of starting material) and agitated for 1.5 hours. The mixture was filtered to collect the solid product, which was subsequently washed with toluene and dried under vacuum at 60-65° C. Ethyl acetate (10.0-fold, V/W of starting material) was then added to the product and the mixture was agitated well. The pH of the solution was adjusted to pH 2 with saturated hydrochloric acid/ethyl acetate solution and further agitated for 1 hour. The solid was then collected by filtration, washed with cold ethyl acetate, and air dried. The product was taken on to the next step without further purification.
Reaction SMILES: [O:1]=[C:2]1[C@:6]2([CH:10]=[CH:9][C@@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:16])[CH3:15])[CH2:7]2)[CH2:5][CH2:4][O:3]1.CO.[BH4-].[Na+]>O.CCOC(C)=O>[OH:3][CH2:4][CH2:5][C@@:6]1([CH2:2][OH:1])[CH2:7][C@H:8]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])([CH3:15])[CH3:16])[CH:9]=[CH:10]1
Reactant: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@]2(CCOC2=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CO
Product: CC(C)(C)OC(=O)N[C@@H]1C=C[C@@](CO)(CCO)C1
Temperature: 2 °C
Reaction time: 2.5 h

Procedure:
To a 5-L three-neck round bottom flask equipped with a mechanical stirrer, Claisen adapter with temperature probe and nitrogen inlet, and N2 outlet was purged with nitrogen for 2 h before use. The product of Step A (255.9 g, 1.01 mol, 1 eq) and MeOH (2 L) were added and the solution was chilled to 2° C. in an ice bath. NaBH4 (75 g, 1.98 mol, 2 eq) was added in ˜5 equal portions; the temperature exothermed to 17° C. before coming back to 6° C., when the next portion was added. The addition took ˜2.5 h and the reaction was judged complete by HPLC after the last addition. The reaction was quenched at 7° C. by addition of aqueous NH4Cl (saturated, 1 L), wherein the temperature rose to about 10° C. The white hazy mixture was concentrated on a rotary evaporate to about 1 L (45° C. bath) when a white solid with some liquid resulted. The mixture was diluted with water and EtOAc (1 L each), transferred to a separatory funnel and the layers were separated. The aqueous layer was extracted with EtOAc (3×250 mL). The combined organics were washed with brine (125 mL), dried over MgSO4, filtered through Celite and evaporated at a bath temperature of 55° C. and provided the product of Step B as a thick oil. 1H NMR (CHLOROFORM-d) δ: 5.74 (s, 2H), 4.65-4.95 (m, 2H), 3.70 (t, J=5.7 Hz, 2H), 3.40-3.57 (m, 2H), 2.76 (br. s., 1H), 2.28 (br. s., 1H), 2.19 (dd, J=13.4, 8.8 Hz, 1H), 1.70 (t, J=5.7 Hz, 2H), 1.55 (dd, J=13.8, 4.0 Hz, 1H), 1.44 (s, 9H). Calculated for C13H23NO4: 280.2 (M+23). found: 280.2.
Reaction SMILES: CN(C)[CH:3]=[O:4].[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[CH:22]=[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1.P(Cl)(Cl)(Cl)=O.O>ClCCl>[Br:6][C:7]1[CH:8]=[C:9]([C:13]2[C:22]([CH:3]=[O:4])=[C:16]3[CH:17]=[CH:18][CH:19]=[C:20]([Cl:21])[N:15]3[N:14]=2)[CH:10]=[CH:11][CH:12]=1
Reactant: Clc1cccc2cc(-c3cccc(Br)c3)nn12
Reactant: CN(C)C=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: ClCCl
Product: O=Cc1c(-c2cccc(Br)c2)nn2c(Cl)cccc12
Temperature: 25 °C
Yield: 96 %

Procedure:
A solution of N,N-Dimethylformamide (150 mL) and 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine (10.3 g, 33 mmol) was cooled to 0° C. and treated with phosphorous oxychloride (4.7 mL, 50 mmol). After the addition was complete, the mixture was warmed to room temperature and the resultant solution was stirred over the weekend. Water was added, followed by dichloromethane. The aqueous layer was extracted with dichloromethane. The combined organics were washed with brine, dried over magnesium sulfate, filtered and concentrated. The residue was washed with diethyl ether and hexanes to give 2-(3-bromophenyl)-7-chloropyrazolo[1,5-a]pyridine-3-carbaldehyde (10.6 g, 96%) as a fluffy white solid. 1H NMR (DMSO-d6): δ 10.09 (s, 1 H), 8.37 (d, 1 H), 8.11 (d, 1H), 7.95 (d, 1H), 7.80 (m, 2 H), 7.65 (d, 1 H), 7.55 (m, 1 H).
Reaction SMILES: C([O:8][CH2:9][C@@:10]12[CH2:19][C:18]([F:21])([F:20])[CH2:17][C@@H:11]1[C:12]([CH2:15][OH:16])=[N:13][O:14]2)C1C=CC=CC=1.B(Cl)(Cl)Cl.CO>ClCCl>[F:21][C:18]1([F:20])[CH2:17][C@@H:11]2[C:12]([CH2:15][OH:16])=[N:13][O:14][C@:10]2([CH2:9][OH:8])[CH2:19]1
Reactant: OCC1=NO[C@]2(COCc3ccccc3)CC(F)(F)C[C@H]12
Agent: ClB(Cl)Cl
Solvent: CO
Solvent: ClCCl
Product: OCC1=NO[C@]2(CO)CC(F)(F)C[C@H]12
Temperature: -70 °C
Reaction time: 1 h
Yield: 83.1 %

Procedure:
To a solution of rac-((3aR,6aR)-6a-(benzyloxymethyl)-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazol-3-yl)methanol (1.52 g, 5.11 mmol) in dichloromethane (23 ml) was added dropwise at −70° C. boron trichloride (1 M in dichloromethane) (15.3 ml, 15.3 mmol). The reaction mixture was stirred at −70° C. for 1 hour, then allowed to warm to 0° C. within another hour. The reaction mixture was quenched with methanol (10 ml) at −70° C., stirred for 30 minutes at room temperature and evaporated to dryness. The residue was purified by chromatography with a 9:1-mixture of dichloromethane and methanol to give rac-((3aR,6aR)-5,5-difluoro-4,5,6,6a-tetrahydro-3aH-cyclopenta[d]isoxazole-3,6a-diyl)dimethanol (880 mg, 83% yield) as a light brown solid. MS: m/z=208.1 [M+H]+.
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([P:17](=O)([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:8]=[C:9]([C:13]([CH3:16])([CH3:15])[CH3:14])[C:10]=1[O:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].Cl[SiH](Cl)Cl.[OH-].[Na+]>C1(C)C=CC=CC=1>[C:13]([C:9]1[CH:8]=[C:7]([P:17]([C:25]2[CH:30]=[C:29]([C:31]([CH3:34])([CH3:33])[CH3:32])[C:28]([O:35][CH3:36])=[C:27]([C:37]([CH3:40])([CH3:39])[CH3:38])[CH:26]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Br:24])[CH:6]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[C:10]=1[O:11][CH3:12])([CH3:14])([CH3:15])[CH3:16]
Reactant: COc1c(C(C)(C)C)cc(P(=O)(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Agent: Cl[SiH](Cl)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: Cc1ccccc1
Product: COc1c(C(C)(C)C)cc(P(c2cc(C(C)(C)C)c(OC)c(C(C)(C)C)c2)c2ccccc2Br)cc1C(C)(C)C
Temperature: 25 °C
Reaction time: 15 h
Yield: 86.5 %

Procedure:
Into a four-neck flask were weighed 28.81 g (44.9 mmol) of the bis(3,5-di-t-butyl-4-methoxyphenyl)(2-bromophenyl)phosphine oxide (6). The atmosphere of the reaction vessel which was fitted with a thermometer, a condenser tube, and a dropping funnel with a pressure-equalizing tube was completely replaced with nitrogen. Thereto were added 300 mL of toluene, 29.92 g (247.0 mmol) of N,N′-dimethylaniline, and 30.41 g (224.5 mmol) of trichlorosilane, followed by 15 hours of heating at reflux. After the completion of the reaction, the reaction mixture was poured into 180 mL of 25% sodium hydroxide aqueous solution at 0° C. to 10° C. After 30 minutes of stirring at room temperature, the layers were separated from each other. The water layer was extracted with toluene (100 mL). The combined organic layer was washed with 1N hydrochloric acid aqueous solution, water and brine and dried over anhydrous magnesium sulfate. Toluene was removed by evaporation and the residue was recrystallized from toluene-methanol to obtain the title compound (24.30 g, a white solid).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22](Cl)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:14])[CH3:13]>>[C:12]([C:16]1[CH:21]=[CH:20][C:19]([S:22]([NH:1][C:2]2[CH:3]=[CH:4][C:5]([NH:8][C:9](=[O:11])[CH3:10])=[N:6][CH:7]=2)(=[O:24])=[O:23])=[CH:18][CH:17]=1)([CH3:15])([CH3:13])[CH3:14]
Reactant: CC(=O)Nc1ccc(N)cn1
Reactant: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Product: CC(=O)Nc1ccc(NS(=O)(=O)c2ccc(C(C)(C)C)cc2)cn1

Procedure:
prepared by reaction of N-(5-amino-pyridin-2-yl)-acetamide with 4-tert-butyl-benzene-sulfonyl chloride
Reaction SMILES: [NH2:1][N:2]1[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1.C(N(CC)CC)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([CH:22]2[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=[C:24]([C:35](Cl)=[O:36])[CH2:23]2)=[CH:18][CH:17]=1>C(Cl)Cl>[N:2]1([NH:1][C:35]([C:24]2[CH2:23][CH:22]([C:19]3[CH:20]=[CH:21][C:16]([Cl:15])=[CH:17][CH:18]=3)[N:26]([C:27]3[CH:32]=[CH:31][C:30]([Cl:33])=[CH:29][C:28]=3[Cl:34])[N:25]=2)=[O:36])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3]1
Reactant: O=C(Cl)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Reactant: NN1CCCCC1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(NN1CCCCC1)C1=NN(c2ccc(Cl)cc2Cl)C(c2ccc(Cl)cc2)C1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
N-Aminopiperidine (0.6 mL, 5.6 mmol) and triethylamine (4 mL) were dissolved in methylene chloride (25 mL) under nitrogen atmosphere. The resulting mixture was cooled to 0° C. and a solution of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4,5-dihydro-pyrazole-3-carboxylic acid chloride in methylene chloride (15 mL) was added drop wise. The resulting reaction mixture was stirred at room temperature (approximately 25° C.) overnight. The reaction mixture was washed with water, followed by a saturated aqueous solution of sodium bicarbonate, again with water, dried over sodium sulfate, filtered and evaporated to dryness in a rotavapor. The resulting crude solid was crystallised from ethanol. The crystallised solid was removed via filtration and the mother liquors were concentrated to yield a second fraction of crystallised product. The two fractions were combined to give a total amount of 1.7 g (57% of theoretical yield) of the title compound having a melting point of 183-186° C.
Reaction SMILES: [H-].[Na+].[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6](F)[N:5]1[O:12][CH:13]([F:15])[F:14].[CH2:16]([OH:18])[CH3:17]>>[NH2:3][CH:4]1[N:9]=[C:8]([Cl:10])[N:7]=[C:6]([O:18][CH2:16][CH3:17])[N:5]1[O:12][CH:13]([F:15])[F:14]
Reactant: CCO
Reactant: NC1N=C(Cl)N=C(F)N1OC(F)F
Agent: [H-]
Agent: [Na+]
Product: CCOC1=NC(Cl)=NC(N)N1OC(F)F
Reaction time: 0.25 h

Procedure:
1.2 g (0.047 mol) of 97% strength sodium hydride were added a little at a time to 150 ml of ethanol at from 20° to 35° C., and stirring was carried out until a solution was obtained, which took 15 minutes. 10.0 g (0.047 mol) of 2-amino-4-chlorodifluoromethoxy-6-fluoro-1,3,5-triazine were then added at 0° C. while stirring, and stirring was continued for one hour at 0° C. and overnight at 22° C. The mixture was evaporated down under reduced pressure, after which the residue was taken up in methylene chloride and the solution was extracted with water and dried. Evaporating down gave 10.6 g (94.6% of theory) of the title compound of melting point 63°-65° C.
Reaction SMILES: COC1C=CC(OC)=CC=1C(=O)CN1C(C(OCC)=O)=CC(C2C=NC=CC=2)=N1.[CH3:30][Si:31]([CH3:43])([CH3:42])[C:32]1[CH:36]=[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])[NH:34][N:33]=1.Br[CH2:45][C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)=[O:47].Br>>[O:47]=[C:46]([C:48]1[CH:49]=[N:50][CH:51]=[CH:52][CH:53]=1)[CH2:45][N:34]1[C:35]([C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:36][C:32]([Si:31]([CH3:42])([CH3:43])[CH3:30])=[N:33]1
Reactant: CCOC(=O)c1cc([Si](C)(C)C)n[nH]1
Reactant: O=C(CBr)c1cccnc1
Agent: Br
Agent: CCOC(=O)c1cc(-c2cccnc2)nn1CC(=O)c1cc(OC)ccc1OC
Product: CCOC(=O)c1cc([Si](C)(C)C)nn1CC(=O)c1cccnc1

Procedure:
This compound was made in an analogous fashion to ethyl 1-(2-(2,5-dimethoxyphenyl)-2-oxoethyl)-3-(pyridin-3-yl)-1H-pyrazole-5-carboxylate using ethyl 3-(trimethylsilyl)-1H-pyrazole-5-carboxylate and 2-bromo-1-(pyridin-3-yl)ethanone.HBr (purchased from Aldrich). 1H-NMR δ 9.20 (d, 1H), 8.84 (dd, 1H), 8.25 (dt, 1H), 7.46 (dd, 1H), 7.07 (s, 1H), 6.05 (s, 2H), 4.26 (q, 2H), 1.31 (t, 3H), 0.32 (s, 9H). Calculated mass for C16H21N3O3Si, 331.14, observed, 332.0 (M+1).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:5][CH:4]=1.[OH:20][C:21]1[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=1>>[O:20]=[C:21]1[CH:26]=[CH:25][N:24]([CH2:2][C:3]2[CH:8]=[CH:7][C:6]([O:9][C:10](=[O:19])[N:11]([CH3:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[CH:5][CH:4]=2)[CH:23]=[CH:22]1
Reactant: CN(C(=O)Oc1ccc(CO)cc1)c1ccccc1
Reactant: Oc1ccncc1
Product: CN(C(=O)Oc1ccc(Cn2ccc(=O)cc2)cc1)c1ccccc1
Yield: 33 %

Procedure:
The title compound was prepared in 33% yield as colorless crystals using methyl-phenyl-carbamic acid 4-hydroxymethyl-phenyl ester and 4-hydroxypyridine. 1H NMR (400 MHz; CDCl3): δ 3.43 (br s, 3H), 4.92 (s, 2H), 6.43 (d, 2H), 7.17 (br s, 4H), 7.22–7.42 (m, 9H), HPLC-MS: m/z=335.0 (M+1); Rt=2.55 min.
Reaction SMILES: [C:1]([O:9][CH2:10][CH2:11][N:12]([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:15]([Cl:22])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(#N)C>[Cl-:22].[C:1]([O:9][CH2:10][CH2:11][N+:12]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)([CH3:14])[CH3:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(C)CCOC(=O)c1ccccc1
Reactant: ClCc1ccccc1
Solvent: CC#N
Product: C[N+](C)(CCOC(=O)c1ccccc1)Cc1ccccc1
Product: [Cl-]

Procedure:
A solution of 57.96 g (0.30 mol) of 2-(N,N-dimethylamino)ethyl benzoate (prepared as described in Example 2), 37.98 g (0.30 mol) of benzyl chloride and 500 ml of acetonitrile was heated at reflux for 2 hours. The reaction mixture was concentrated to a white solid which was then washed with ether and recrystallized from acetonitrile. The yield of product was 69.0 g; mp=164°-6° C.
Reaction SMILES: [Cl:1][C:2]1[CH:26]=[CH:25][C:5]([C:6]([C:8]2[CH:24]=[CH:23][C:11]([C:12]([N:14]3[CH2:19][CH2:18][C:17]4[CH:20]=[CH:21][O:22][C:16]=4[CH2:15]3)=[O:13])=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.[CH2:27]([NH:29][CH2:30][CH3:31])[CH3:28].[CH2:32]=O>C(O)(=O)C>[CH2:27]([N:29]([CH2:32][C:21]1[O:22][C:16]2[CH2:15][N:14]([C:12](=[O:13])[C:11]3[CH:23]=[CH:24][C:8]([C:6](=[O:7])[C:5]4[CH:4]=[CH:3][C:2]([Cl:1])=[CH:26][CH:25]=4)=[CH:9][CH:10]=3)[CH2:19][CH2:18][C:17]=2[CH:20]=1)[CH2:30][CH3:31])[CH3:28]
Reactant: CCNCC
Reactant: C=O
Reactant: O=C(c1ccc(Cl)cc1)c1ccc(C(=O)N2CCc3ccoc3C2)cc1
Solvent: CC(=O)O
Product: CCN(CC)Cc1cc2c(o1)CN(C(=O)c1ccc(C(=O)c3ccc(Cl)cc3)cc1)CC2
Temperature: 100 °C
Reaction time: 2 h

Procedure:
To a solution of 1.647 g (4.502 mmol) of 6-[4-(4-chlorobenzoyl)benzoyl]-4,5,6,7-tetrahydrofuro[2,3-c]pyridine in 30 ml of acetic acid, 0.56 ml (5.40 mmol) of diethylamine and 0.44 g (5.40 mmol) of 37% aqueous formaldehyde were added, followed by stirring at 100° C. for 2 hours. After the solvent was distilled off under reduced pressure, the residual solution was alkalified with aqueous sodium hydroxide and extracted with dichloromethane 3 times. The combined organic layer was dried over anhydrous magnesium sulfate; the solvent was distilled off under reduced pressure. The resulting crude product was purified by silica gel column chromatography (ethyl acetate to ethyl acetate/methanol=9/1) to yield the desired product.
Reaction SMILES: [C:1]([O-:9])(=[O:8])[C:2]1C=CC=C[CH:3]=1.[NH2+:10]1[CH2:15][CH2:14][O:13][CH2:12][CH2:11]1.O.[CH:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>>[CH3:3][CH:2]1[C:18]2[CH:19]=[CH:20][C:21]([N:10]3[CH2:15][CH2:14][O:13][CH2:12][CH2:11]3)=[CH:22][C:17]=2[O:9][C:1]1=[O:8]
Reactant: O=C([O-])c1ccccc1
Reactant: c1ccccc1
Reactant: C1COCC[NH2+]1
Solvent: O
Product: CC1C(=O)Oc2cc(N3CCOCC3)ccc21

Procedure:
A mixture of 18.2 g (0.1 mole) of 4-methyl-3-(3-oxobutyl)-maleic acid anhydride and 22 g (0.105 mole) of morpholinium benzoate in 400 ml of benzene is heated under reflux for 48 hours using a water separator. The benzene is removed in vacuo, the residue is taken up in methylene chloride and the organic phase is extracted twice with saturated sodium bicarbonate solution. The crude product remaining after drying and after removal of the methylene chloride is chromatographed over silica gel with petroleum ether/ether. Pale-yellow crystals are obtained, which are recrystallised from methylene chloride/ether. In this manner 3-methyl-6-morpholino-benzofuran-2(3H)-one having a melting point of 118°-121° C. is obtained.
Reaction SMILES: Br[C:2]1[CH:13]=[CH:12][C:5]([CH2:6][N:7]2[CH2:11][CH2:10][CH2:9][CH2:8]2)=[C:4]([F:14])[CH:3]=1.[Li]CCCC.[O:20]=[C:21]1[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]1>C1COCC1>[F:14][C:4]1[CH:3]=[C:2]([C:21]2([OH:20])[CH2:24][CH:23]([C:25]([OH:27])=[O:26])[CH2:22]2)[CH:13]=[CH:12][C:5]=1[CH2:6][N:7]1[CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: Fc1cc(Br)ccc1CN1CCCC1
Reactant: O=C1CC(C(=O)O)C1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)C1CC(O)(c2ccc(CN3CCCC3)c(F)c2)C1
Temperature: -85 °C
Reaction time: 0.25 h

Procedure:
A 2-L 3-neck RB flask, equipped a mechanical stirrer, addition funnel, thermometer and nitrogen gas inlet was charged with Intermediate 8, 1-(4-bromo-2-fluorobenzyl)pyrrolidine (69.86 g, 0.27 mol) and 700 mL of anhydrous THF. The system was flushed with nitrogen and cooled to −85° C. with liquid nitrogen with an ether/MeOH (1:1) bath. Then n-BuLi (10M in hexane, 30 mL, 0.298 mol) was added dropwise through an addition funnel at T<−80° C. The mixture was stirred at this temperature for an additional 15 min, then a solution of 3-oxocyclobutanecarboxylic acid (dried under vacuum for 2 days, 15.4 g, 0.135 mol) in 300 mL of anhydrous THF was added dropwise through an addition funnel keeping T<−80° C. The mixture was allowed to warm to RT and evaporated. The residue was mixed with 500 mL of water and washed with ether (2×300 mL). Then the aqueous solution was acidified to pH 1 with conc. HCl and washed with ether (2×300 mL). Then the aqueous solution was neutralized to pH 6-5 with NaOH and coevaporated three times with iPrOH (300 mL each time). Then the mixture was coevaporated with THF (200 mL) and dried to give gummy residue containing the product with inorganic salts LCMS (M+H): 294.4
Reaction SMILES: Br[CH2:2][C:3]1[CH:4]=[C:5]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])[CH:6]=[CH:7][C:8]=1/[CH:9]=[CH:10]/[C:11]1[CH:16]=[C:15]([C:17]2[C:18](=[O:24])[NH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:14]=[C:13]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:12]=1[O:29][CH3:30].[CH3:36][O-:37].[Na+]>CO>[C:25]([C:13]1[C:12]([O:29][CH3:30])=[C:11](/[CH:10]=[CH:9]/[C:8]2[CH:7]=[CH:6][C:5]([NH:31][S:32]([CH3:35])(=[O:34])=[O:33])=[CH:4][C:3]=2[CH2:2][O:37][CH3:36])[CH:16]=[C:15]([C:17]2[C:18](=[O:24])[NH:19][C:20]([CH3:23])=[CH:21][CH:22]=2)[CH:14]=1)([CH3:28])([CH3:27])[CH3:26]
Reactant: C[O-]
Reactant: COc1c(/C=C/c2ccc(NS(C)(=O)=O)cc2CBr)cc(-c2ccc(C)[nH]c2=O)cc1C(C)(C)C
Agent: [Na+]
Solvent: CO
Product: COCc1cc(NS(C)(=O)=O)ccc1/C=C/c1cc(-c2ccc(C)[nH]c2=O)cc(C(C)(C)C)c1OC
Temperature: 25 °C
Reaction time: 8 h

Procedure:
step 3—To a solution of 320 (70 mg, 0.125 mmol) in MeOH (10 mL) was added sodium methoxide (10 mL, 5 mmol, 0.5 M MeOH solution). The reaction was stirred at RT overnight. The reaction mixture was concentrated, diluted with EtOAc and acidified with 6N HCl (1 mL). The organic extract was dried (Na2SO4), filtered and concentrated. The crude product was purified on a preparative SiO2 TLC plate developed with 2:1 EtOAc/hexane to afford 28 mg of I-208 as an off-white solid.