Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:10][C:11](=[O:27])[C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[N:14][C:13]=2[O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH3:9])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)CCCP(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(N(CC)CC)C.CN(C)[CH:66]=[O:67].C[CH2:70][O:71]CC>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.CO>[F:18][C:16]1[CH:17]=[C:12]([C:11]([NH:10][CH:8]([C:5]2[CH:6]=[CH:7][C:2]([C:70]([O:67][CH3:66])=[O:71])=[CH:3][CH:4]=2)[CH3:9])=[O:27])[C:13]([O:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)=[N:14][CH:15]=1
Reactant: CCOCC
Reactant: CC(NC(=O)c1cc(F)cnc1Oc1ccc(F)cc1)c1ccc(Br)cc1
Reactant: CN(C)C=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: c1ccc(P(CCCP(c2ccccc2)c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: CO
Product: COC(=O)c1ccc(C(C)NC(=O)c2cc(F)cnc2Oc2ccc(F)cc2)cc1
Temperature: 80 °C
Reaction time: 16 h
Yield: 78 %

Procedure:
A mixture of N-[1-(4-bromophenyl)ethyl]-5-fluoro-2-(4-fluorophenoxy)nicotinamide (step 1, 398 mg, 0.92 mmol), 1,3-bis(diphenylphosphino)-propane (38 mg, 0.09 mmol), palladium (II) acetate (21 mg, 0.09 mmol), triethylamine (0.38 mL, 2.76 mmol), N,N-dimethylforamide (6 mL) and methanol (4 mL) was stirred at 80° C. for 16 h under carbon monoxide atmosphere. After cooling to room temperature, the mixture was diluted with ether (100 mL) and washed with water (60 mL×3). The organic layer was dried over magnesium sulfate and evaporated. The residue was purified by flush column chromatography on silica gel eluting with hexane/ethyl acetate (2:1) to afford 296 mg (78%) of the title compounds as white solids: 1H-NMR (CDCl3) δ 8.32 (1H, dd, J=8.1, 3.1 Hz), 8.21 (1H, d, J=7.3 Hz), 8.04–7.99 (3H, m), 7.43 (2H, d, J=8.2 Hz), 7.27–7.13 (4H, m), 5.38 (1H, dq, J=7.3, 6.9 Hz), 3.90 (3H, s), 1.60 (3H, d, J=6.9 Hz); MS (ESI) m/z 413 (M+H)+, 411 (M−H)−.
Reaction SMILES: [CH3:1][C:2]([C:5]([OH:7])=[O:6])([CH3:4])[NH2:3].[OH-].[Na+].[C:10](#[N:13])[CH:11]=[CH2:12].C(O)(=O)C>O>[C:10]([CH2:11][CH2:12][NH:3][C:2]([CH3:4])([C:5]([OH:7])=[O:6])[CH3:1])#[N:13]
Reactant: CC(C)(N)C(=O)O
Reactant: C=CC#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: CC(C)(NCCC#N)C(=O)O
Reaction time: 8 h
Yield: 96 %

Procedure:
50 g (0.48 mol) of 2-methylalanine were added to a cooled solution (water/ice) of NaOH (19.6 g) in water (100 ml). Once the solution had turned clear, 34 ml (0.50 mol) of acrylonitrile were dropped on cooling. The mixture was left overnight. After 18 hours, 28 ml of acetic acid were added on cooling (water/ice); a white solid precipitated; 200 ml of 95% ethanol were dropped in the flask, stirring was continued for 1 hour, then the mixture was allowed to stand in a fridge for 2-3 hours. After filtration, the solid was collected and dried in an oven at 80° C. The filtrates were evaporated and taken up with ethanol (160 ml). On cooling a further amount of product was obtained, which was filtered and dried. 72 g of the title compound were obtained from the first filtration. Total yield: 95%.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][NH:8][CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.Cl[C:12]1[N:17]=[CH:16][C:15]([CH2:18][CH3:19])=[CH:14][N:13]=1.CN(C)C=O.O1CCOCC1>C(N(CC)CC)C>[CH2:18]([C:15]1[CH:14]=[N:13][C:12]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)=[N:17][CH:16]=1)[CH3:19]
Reactant: CCc1cnc(Cl)nc1
Reactant: C1CC2(CCN1)OCCO2
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: C1COCCO1
Product: CCc1cnc(N2CCC3(CC2)OCCO3)nc1
Reaction time: 22 h

Procedure:
1,4-Dioxa-8-azaspiro[4.5]decane (1.76 g), 2-chloro-5-ethylpyrimidine (1.7 g), N,N-dimethylformamide (50 mL), 1,4-dioxane (75 mL) and triethylamine (5.07 ml) are heated in a sealed vessel at 120° C. with stirring for 22 h. After cooling the mixture is concentrated and partitioned between ethyl acetate (100 mL) and water (100 mL). The water layer is extracted with ethyl acetate (100 mL) and the combined ethyl acetate layers are dried over Na2SO4, filtered and concentrated to give the title compound. LC (method 20): tR=1.73 min; Mass spectrum (APCI): m/z=250 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][OH:8])=[CH:5][CH:4]=1.[H-].[Na+].F[C:14]1[CH:19]=[CH:18][C:17]([I:20])=[CH:16][N:15]=1>CN(C=O)C>[I:20][C:17]1[CH:18]=[CH:19][C:14]([O:8][CH2:7][C:6]2[CH:9]=[CH:10][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)=[N:15][CH:16]=1
Reactant: COc1ccc(CO)cc1
Reactant: Fc1ccc(I)cn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(COc2ccc(I)cn2)cc1
Reaction time: 18 h

Procedure:
4-Methoxybenzyl alcohol (6.51 g, 47.1 mole) in 15 mL DMF was added to a stirring suspension of sodium hydride (1.973 g, 49.3 mmol) in DMF at 0° C. After 10 minutes a solution of 2-fluoro-5-iodopyridine (10 g, 44.8 mmol) in 15 mL DMF was added dropwise using an addition funnel. The reaction slowly reached room temperature, and was allowed to stir for 18 hours. The homogenous yellow solution was cooled again and quenched with about 50 ml of water. The suspension was then partitioned between ethyl acetate (200 mL) and water (150 mL). The aqueous was extracted a second time with ethyl acetate and the combined organic layers were washed with water three times and with brine twice. The organic layer was dried over sodium sulfate, filtered and evaporated. When the evaporation neared completion a white solid precipitated. Triturated with the addition of hexanes. The solid was filtered and dried on the filter. Repeated partial evaporation trituration and filtration of the resulting white solids gave the title compound.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]=[O:17])[C:14]=1[CH3:15])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F:22][C:23]1[CH:28]=[CH:27][C:26]([Mg]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-]>O1CCCC1>[CH2:1]([O:8][C:9]1[C:10]([C:18]([O:20][CH3:21])=[O:19])=[N:11][CH:12]=[C:13]([CH:16]([C:26]2[CH:27]=[CH:28][C:23]([F:22])=[CH:24][CH:25]=2)[OH:17])[C:14]=1[CH3:15])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccc([Mg]Br)cc1
Reactant: COC(=O)c1ncc(C=O)c(C)c1OCc1ccccc1
Agent: O=C([O-])O
Solvent: C1CCOC1
Product: COC(=O)c1ncc(C(O)c2ccc(F)cc2)c(C)c1OCc1ccccc1
Yield: 52.4 %

Procedure:
1.0 g of methyl 3-(benzyloxy)-5-formyl-4-methylpicolinate (3.50 mmol, 1 eq) was dissolved in 20.0 mL of tetrahydrofuran and 4.2 mL of a 4-fluorophenyl magnesium bromide solution (1M in tetrahydrofuran, 4.20 mmol, 1.2 eq) was added at −78° C. over a period of 1 hr. The reaction mixture was then stirred for 20 min. −78° C. A saturated bicarbonate solution was added and reaction mixture was extracted with ethyl acetate. The resulting organic phases were combined, dried over magnesium sulphate and concentrated under reduced pressure. The crude product was purified by silica gel (50% ethyl acetate/hexane) yielding 0.70 g of colourless oil containing the desired product 7a (53% yield).
Reaction SMILES: C([O:4][C@H:5]1[CH2:9][C@H:8]([N:10]2C=N[C:16]3[C:11]2=[N:12][CH:13]=[N:14][C:15]=3[NH:19][C@@H:20]2[C:28]3[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=3)[CH2:22][CH2:21]2)[O:7][C@@H:6]1[CH2:29][O:30][S:31]([NH2:34])(=[O:33])=[O:32])(=O)C.O1CC[CH2:37][CH2:36]1.N.C[OH:42]>>[S:31](=[O:33])(=[O:32])([O:30][CH2:29][C@@H:6]1[C@@H:5]([OH:4])[C@@H:9]([OH:42])[C@H:8]([N:10]2[C:11]3[N:12]=[CH:13][N:14]=[C:15]([NH:19][C@@H:20]4[C:28]5[C:23](=[CH:24][CH:25]=[CH:26][CH:27]=5)[CH2:22][CH2:21]4)[C:16]=3[CH:37]=[CH:36]2)[O:7]1)[NH2:34]
Reactant: CC(=O)O[C@H]1C[C@H](n2cnc3c(N[C@H]4CCc5ccccc54)ncnc32)O[C@@H]1COS(N)(=O)=O
Reactant: C1CCOC1
Reactant: CO
Agent: N
Product: NS(=O)(=O)OC[C@H]1O[C@@H](n2ccc3c(N[C@H]4CCc5ccccc54)ncnc32)[C@H](O)[C@@H]1O
Reaction time: 1 h
Yield: 66 %

Procedure:
(2R,3S,5R)-2-{[(Aminosulfonyl)oxy]methyl}-5-{6-[(1S)-2,3-dihydro-1H-inden-1-ylamino]-9H-purin-9-yl}tetrahydrofuran-3-yl acetate (96 mg, 0.20 mmol) was dissolved in 2.6 mL of 7M NH3/MeOH and stirred for one hour. Approximately 1 mL tetrahydrofuran was added, and the resulting solution was stirred for 3 hours. The solvent was removed in vacuo and the residue purified by silica gel chromatography (0% to 10% MeOH/CH2Cl2) to afford 59 mg (66%) of the title compound.
Reaction SMILES: Cl[CH2:2][C:3]#[N:4].[Na+].[C:6]1([CH3:15])[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([O-:14])=[O:13])[CH:7]=1>CN(C=O)C>[C:6]1([CH3:15])[CH:11]=[CH:10][CH:9]=[C:8]([S:12]([CH2:2][C:3]#[N:4])(=[O:14])=[O:13])[CH:7]=1
Reactant: N#CCCl
Reactant: Cc1cccc(S(=O)[O-])c1
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cccc(S(=O)(=O)CC#N)c1
Reaction time: 1 h
Yield: 25.1 %

Procedure:
2.65 ml (42 mmol) of chloroacetonitrile were added to a suspension of 7.5 g (42 mmol) of toluene-3-sulphinic acid sodium salt in 80 ml of DMF and stirred at 100° for 1 hr. The reaction solution was evaporated, the residue was partitioned between H2O and CH2Cl2. The aqueous phase was washed three times with CH2Cl2. The combined organic phases were washed once with H2O, dried (MgSO4). filtered and evaporated. Chromatography (SiO2, CH2Cl2) yielded 2.06 g (25%) of (toluene-3-sulphonyl)-acetonitrile as a colorless oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][NH2:10])=[CH:5][CH:4]=1.C([O-])(=O)C.[Na+].[C:16](OCC)(=[O:21])[CH2:17][C:18]([CH3:20])=O>C(O)C.O>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:16](=[O:21])[CH2:17][C:18]([CH3:20])=[N:10]2)=[CH:5][CH:4]=1
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(=O)CC(C)=O
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc(N2N=C(C)CC2=O)cc1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
The starting material is obtained as follows: To the suspension of 2,700 g of p-methoxyphenylhydrazine in 24,600 ml of 50% aqueous ethanol, the solution of 1,411 g of sodium acetate in 3,000 ml of water is added while stirring under nitrogen at room temperature for 15 minutes, followed by 2,148 g of ethyl acetoacetate during 30 minutes at 25°-30°. The mixture is refluxed for 45 minutes, slowly cooled to 10° and stirred overnight. The precipitate formed is filtered off, washed twice with 2,000 ml of cold 50% aqueous ethanol each, and dissolved in 2,000 ml of boiling anhydrous ethanol. The solution is stirred at room temperature overnight, the precipitate formed filtered off and washed twice with 500 ml of cold ethanol, to yield the 1-(p-methoxyphenyl)-3-methyl-2-pyrazolin-5-one melting at 125°-128°.
Reaction SMILES: C[Mg]Cl.[C:4]1(C)C=CC=CC=1.[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH:23]=[CH:24][C:25]1[CH:26]=[C:27]([C@@H:31]([OH:45])[CH2:32][CH2:33][C:34]3[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=3C(OCC)=O)[CH:28]=[CH:29][CH:30]=1)[CH:16]=[CH:15]2.[CH3:46][C:47]([OH:49])=O>C1COCC1>[F:11][C:12]1[CH:13]=[C:14]2[C:19](=[CH:20][C:21]=1[F:22])[N:18]=[C:17]([CH:23]=[CH:24][C:25]1[CH:26]=[C:27]([C@@H:31]([OH:45])[CH2:32][CH2:33][C:34]3[CH:44]=[CH:43][CH:42]=[CH:41][C:35]=3[C:47]([OH:49])([CH3:46])[CH3:4])[CH:28]=[CH:29][CH:30]=1)[CH:16]=[CH:15]2
Reactant: Cc1ccccc1
Reactant: CCOC(=O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Reactant: CC(=O)O
Agent: C[Mg]Cl
Solvent: C1CCOC1
Product: CC(C)(O)c1ccccc1CC[C@H](O)c1cccc(C=Cc2ccc3cc(F)c(F)cc3n2)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 91 %

Procedure:
A mixture of anhydrous CeCl3 (40.5 g, 164 mmol) in THF (500 mL) was refluxed overnight using a Dean Stark trap filled with activated 3 Å molecular sieves. Methyl magnesium chloride (263 mL, 3.0 Molar in THF, 790 mmol) was added dropwise over 30 minutes to the CeCl3 slurry at 0° C. After stirring 2 hours at 0° C., the mixture was cooled to -5° C. and a toluene (600 mL) solution of the hydroxyester (71.8 g, 152 mmol) from Step 5 was added dropwise over 1 hour. The reaction mixture was stirred another hour before the addition of 2M HOAc (600 mL) and toluene (600 mL). The organic layer was washed with saturated aq. NaHCO3 and with brine. Concentration in vacuo and purification of the residue by flash chromatography (30% EtOAc in toluene) gave 63.48 g (91%) of the title compound.
Reaction SMILES: F[B-](F)(F)F.[F:6][S:7]([F:19])([F:18])([F:17])([F:16])[C:8]1[CH:13]=[CH:12][C:11]([N+:14]#[N:15])=[CH:10][CH:9]=1.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C(O)C>[NH2:20][C:21]1[CH:26]=[CH:25][C:24](/[N:15]=[N:14]/[C:11]2[CH:12]=[CH:13][C:8]([S:7]([F:16])([F:17])([F:18])([F:19])[F:6])=[CH:9][CH:10]=2)=[CH:23][CH:22]=1
Reactant: Nc1ccccc1
Reactant: N#[N+]c1ccc(S(F)(F)(F)(F)F)cc1
Agent: F[B-](F)(F)F
Solvent: CCO
Product: Nc1ccc(/N=N/c2ccc(S(F)(F)(F)(F)F)cc2)cc1
Reaction time: 480 h
Yield: 22.2 %

Procedure:
Diazonium salt 1 (11.1 mg, 0.0349 mmol) and aniline (32.0 mg, 0.344 mmol) were dissolved in 0.19 g of 95% ethanol. After 20 d, the solution was filtered through Celite 545. Evaporation of the solvent gave an orange oil, which was purified by SiO2 column chromatography (8:2 hexane/ethyl acetate) and following preparative TLC (SiO2, CH2Cl2) afforded 27e as orange crystals (2.5 mg, 22%); m.p. 153.0-154.5° C. IR (ATR): {tilde over (v)}=3417, 2915, 1666, 1628, 1603, 1507, 1398, 1302, 1148, 1092, 834 cm−1. MS (GC, EI): m/z=323 [M+], 197, 120, 94, 65. 1H NMR (500 MHz, CDCl3): δ=7.88-7.82 (m, 6H), 6.76 (d, J=8.8 Hz, 2H), 2.20 (br. s, 1H) ppm. 13C NMR (125 MHz, CDCl3): δ=154.1 (C), 150.5 (C), 145.3 (C), 126.9 (2CH), 125.8 (2CH), 122.2 (2CH), 114.5 (2CH) ppm. 19F NMR (470 MHz, CDCl3): δ=84.4 (quint, J=150 Hz, 1 F), 63.2 (d, J=150 Hz, 4 F) ppm.
Reaction SMILES: F[C@H:2]1CCNC1.C(N1CCN(C(=O)CC2C[C@@H]([C:22](N3CCSC3)=[O:23])NC2)CC1)C.CO[CH:32]([C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)[C:33]([NH:35][CH2:36][CH:37]1[CH2:41][CH:40]([C:42]([N:44]2[CH2:48][CH2:47][S:46][CH2:45]2)=[O:43])[NH:39][CH2:38]1)=[O:34]>>[CH3:22][O:23][C:51]1[CH:52]=[CH:53][C:54]([CH2:49][CH2:32][C:33]([NH:35][CH2:36][C@H:37]2[CH2:41][C@@H:40]([C:42]([N:44]3[CH2:48][CH2:47][S:46][CH2:45]3)=[O:43])[NH:39][CH2:38]2)=[O:34])=[CH:2][CH:50]=1
Reactant: F[C@H]1CCNC1
Reactant: COC(C(=O)NCC1CNC(C(=O)N2CCSC2)C1)c1ccccc1
Reactant: CCN1CCN(C(=O)CC2CN[C@H](C(=O)N3CCSC3)C2)CC1
Product: COc1ccc(CCC(=O)NC[C@@H]2CN[C@H](C(=O)N3CCSC3)C2)cc1

Procedure:
(2′R, 3S, 5S)-2-Methoxy-2-phenyl-N-[5-(thiazolidine-3-carbonyl)-pyrrolidin-3-ylmethyl]-acetamide;
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[Cl:23])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].[CH3:25][C:26]1[S:30][CH:29]=[N:28][CH:27]=1>>[Cl:23][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][C:17]=1[C:13]1[CH:14]=[CH:15][CH:16]=[C:11]([N:9]2[CH:10]=[C:6]([C:4]([C:29]3[S:30][C:26]([CH3:25])=[CH:27][N:28]=3)=[O:5])[N:7]=[CH:8]2)[CH:12]=1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3Cl)c2)cn1
Reactant: Cc1cncs1
Product: Cc1cnc(C(=O)c2cn(-c3cccc(-c4ccccc4Cl)c3)cn2)s1

Procedure:
This compound is prepared by method C using compound 12e and 5-methylthiazole
Reaction SMILES: [Cl:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([CH2:17][CH3:18])[C:14]2[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=2)[NH:8][C:7]1=[O:16].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1>>[ClH:1].[Cl:19][C:20]1[CH:21]=[C:22]([N:26]2[CH2:31][CH2:30][N:29]([CH2:2][CH2:3][CH2:4][CH2:5][C:6]3([CH2:17][CH3:18])[C:14]4[C:9](=[CH:10][CH:11]=[C:12]([F:15])[CH:13]=4)[NH:8][C:7]3=[O:16])[CH2:28][CH2:27]2)[CH:23]=[CH:24][CH:25]=1
Reactant: CCC1(CCCCCl)C(=O)Nc2ccc(F)cc21
Reactant: Clc1cccc(N2CCNCC2)c1
Product: CCC1(CCCCN2CCN(c3cccc(Cl)c3)CC2)C(=O)Nc2ccc(F)cc21
Product: Cl

Procedure:
The title compound is prepared according to process H by applying processing method 2 starting from 3-(4-chlorobutyl)-3-ethyl-5-fluoro-1,3-dihydro-2H-indol-2-one and 1-(3-chloro-phenyl)-piperazine.
Reaction SMILES: [C:1]([O:24]CC)(=[O:23])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[OH-].[Na+].O.Cl>CO>[C:1]([OH:24])(=[O:23])/[CH:2]=[CH:3]\[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=[CH:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)OCC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCCCCCCCC=CC=CC=CC=CC=C/C=C\C(=O)O
Reaction time: 1.5 h
Yield: 91.3 %

Procedure:
To a solution of ethyl cis-docosahexaenoate (5 g, 14.0 mmol) in methanol (100 mL) was added an aqueous solution of NaOH (6 g, 150 mmol, in 20 mL of water) at rt and stirred for 1.5 h. The reaction mixture was poured into ice cooled water and acidified with dil. HCl. The solution was extracted with DCM (3×50 mL) and the combined layer was washed with water, brine and dried over sodium sulfate. The solution was filtered and the solvent evaporated to give the acid (4.2 g, 91%) as an oil; LCMS (ESI, negative ion mode): m/z 327 (M-H)−.
Reaction SMILES: [S:1]1(=O)[CH2:5][CH2:4][S:3][CH2:2]1.[F:7][C:8]([F:19])([F:18])[C:9]([O:11]C(=O)C(F)(F)F)=[O:10]>C1COCC1>[F:7][C:8]([F:19])([F:18])[C:9]([O-:11])=[O:10].[S:1]1[CH2:5][CH2:4][S:3][CH+:2]1
Reactant: O=S1CCSC1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: C1CCOC1
Product: O=C([O-])C(F)(F)F
Product: [CH+]1SCCS1
Yield: 100 %

Procedure:
To a stirred of solution of 1,3-dithiolane (4.8 g, 45 mmol) in methanol (225 mL) at 0° C. was added dropwise a solution of (9.6 g, 45 mmol) sodium periodate in water (70 mL). After stirring overnight the precipitated solids were removed by filtration and the filtrate was evaporated. The residue was dissolved in dichloromethane, dried over MgSO4 and the solvent was evaporated to dryness. The product was purified by column chromatography over silica gel and eluted with 2:1 EtOAc/n-heptane to obtain 1,3-dithiolane-1-oxide (4 g) in 73% yield. A THF (40 mL) solution of the above prepared 1,3-dithiolane-1-oxide (2.8 g, 23 mmol) was treated with trifluoroacetic anhydride (3.2 mL, 23 mmol) furnishing 1,3-dithiolan-2-ylium trifluoroacetate salt (BIa) (23 mmol).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]N.N1C=C[C:14](CCN)=[CH:13][CH:12]=1.[CH3:20][O:21]C1C=C(CCN)C=CC=1OC.C(C1C=C(C=CC=1)CN)(C)C>>[CH3:20][O:21][CH:3]([O:2][CH3:1])[CH2:4][C@H:5]([CH3:6])[CH2:8][CH2:9][CH:10]=[C:13]([CH3:14])[CH3:12]
Reactant: NCCc1ccncc1
Reactant: COc1ccc(CCN)cc1OC
Reactant: COc1cccc(CN)c1
Agent: CC(C)c1cccc(CN)c1
Product: COC(C[C@H](C)CCC=C(C)C)OC

Procedure:
The following compounds can be obtained by a similar procedure, using 3-methoxy-benzylamine, 2-pyridin-4-yl-ethylamine, 2-(3,4-dimethoxy-phenyl)-ethylamine or 3-isopropyl-benzylamine instead of 3-methyl-benzylamine:
Reaction SMILES: [CH:1]([N-]C(C)C)(C)[CH3:2].[Li+].C(NC(C)C)(C)C.C([Li])CCC.[F:21][C:22]1[CH:27]=[CH:26][C:25]([C:28]2[CH2:32][N:31]([C:33]3[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=3)[C:30](=[O:41])[CH:29]=2)=[CH:24][CH:23]=1.C(I)C.Cl>O1CCCC1>[CH2:1]([C:29]1[C:30](=[O:41])[N:31]([C:33]2[CH:38]=[CH:37][C:36]([O:39][CH3:40])=[CH:35][CH:34]=2)[CH2:32][C:28]=1[C:25]1[CH:24]=[CH:23][C:22]([F:21])=[CH:27][CH:26]=1)[CH3:2]
Reactant: COc1ccc(N2CC(c3ccc(F)cc3)=CC2=O)cc1
Reactant: CC(C)[N-]C(C)C
Agent: Cl
Agent: [Li+]
Agent: [Li]CCCC
Solvent: CCI
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: CCC1=C(c2ccc(F)cc2)CN(c2ccc(OC)cc2)C1=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
Lithium diisopropylamide is generated from diisopropylamine (122 mL, 0.87 mol) and n-butyllithium (2.5 M in hexane, 348 mL, 0.87 mol) in tetrahydrofuran (1.5 L) under a nitrogen atmosphere at -60° C., and 4-(4-fluorophenyl)-1,5-dihydro-1-(4-methoxyphenyl)-2H-pyrrol-2-one (235 g, 0.83 mol) is added to this mixture. The mixture is stirred for 30 minutes at -50° C., 1 hr at 0° C., and then re-cooled to -60° C. Ethyl iodide (73 mL, 0.91 mol) is added, and the reaction is allowed to warm slowly to 25° C., and stirred at this temperature for 18 hr. The mixture is poured into 1.5 L of 4 N HCl and stirred for 1 hr. The mixture is then extracted with methylene chloride, and the extracts are dried with magnesium sulfate and evaporated. Recrystallization of the residue from ethanol followed by drying under vacuum at 60° C. for 18 hr gives the title compound.
Reaction SMILES: [C:1]([N:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[N:7]([CH2:14][CH:15]=O)[C:6](=[O:17])[CH2:5]1)(=[O:3])[CH3:2].[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1)([CH3:21])([CH3:20])[CH3:19].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)([O-])O.[Na+]>C(O)(=O)C.C(Cl)(Cl)Cl>[C:18]([O:22][C:23](=[O:42])[N:24]([CH2:31][C:32]1[CH:41]=[CH:40][C:35]2[O:36][CH2:37][CH2:38][O:39][C:34]=2[CH:33]=1)[CH:25]1[CH2:30][CH2:29][N:28]([CH2:15][CH2:14][N:7]2[C:8]3[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=3)[N:4]([C:1](=[O:3])[CH3:2])[CH2:5][C:6]2=[O:17])[CH2:27][CH2:26]1)([CH3:21])([CH3:19])[CH3:20]
Reactant: CC(=O)N1CC(=O)N(CC=O)c2ccccc21
Reactant: CC(C)(C)OC(=O)N(Cc1ccc2c(c1)OCCO2)C1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClC(Cl)Cl
Product: CC(=O)N1CC(=O)N(CCN2CCC(N(Cc3ccc4c(c3)OCCO4)C(=O)OC(C)(C)C)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 1 h
Yield: 84.6 %

Procedure:
To 15 mL of a chloroform solution containing 337 mg of (4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)acetaldehyde and 504 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(piperidin-4-yl)carbamate, 83 μL of acetic acid was added, and stirred at room temperature for 1 hour. To the reaction mixture, 477 mg of sodium triacetoxyborohydride was added, and stirred for 1.5 hours. Aqueous saturated sodium hydrogen carbonate solution was added, the organic layer was separated. The organic layer was washed with aqueous saturated sodium chloride solution, dried over anhydrous magnesium sulfate, and the solvent was removed under reduced pressure. The residue thus obtained was purified by silica gel column chromatography [Silica Gel; Kanto Chemical Co., Inc., Silica Gel 60, eluent; chloroform:methanol=20:1] to give 691 mg of tert-butyl(2,3-dihydro-1,4-benzodioxin-6-ylmethyl)(1-(2-(4-acetyl-2-oxo-3,4-dihydroquinoxalin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a pale yellow foam.
Reaction SMILES: C[O:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9].Cl.N1C=CC=CC=1>O>[OH:2][C:3]1[CH:18]=[CH:17][CH:16]=[CH:15][C:4]=1[O:5][C:6]1[CH:14]=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=[O:9]
Reactant: COc1ccccc1Oc1ccccc1C(=O)O
Agent: Cl
Solvent: O
Solvent: c1ccncc1
Product: O=C(O)c1ccccc1Oc1ccccc1O
Temperature: 25 °C
Reaction time: 8 h
Yield: 48.7 %

Procedure:
Fifteen grams of 2-(2-methoxyphenoxy)benzoic acid were heated at 180°-185° C. together with 150 g of pyridine hydrochloride for 3 hours. After cooling to room temperature, water was added and the mixture was stirred overnight at room temperature. The reaction was filtered and the water extracted several times with ethyl acetate. The combined ethyl acetate layers were dried and concentrated in vacuo. The crystallization of the residue from ethyl acetate/hexane provided 6.88 g of the desired subtitled intermediate, m.p. 147°-149° C.