Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]1[O:16][C:4]2([CH2:9][CH2:8][C:7](N3CCOCC3)=[CH:6][CH2:5]2)[O:3][CH2:2]1.B1C2CCCC1CCC2>O1CCCC1>[CH2:1]1[O:16][C:4]2([CH2:9][CH2:8][CH:7]=[CH:6][CH2:5]2)[O:3][CH2:2]1
Reactant: C1=C(N2CCOCC2)CCC2(C1)OCCO2
Agent: B1C2CCCC1CCC2
Solvent: C1CCOC1
Product: C1=CCC2(CC1)OCCO2
Temperature: 25 °C
Reaction time: 6 h
Yield: 74.9 %

Procedure:
A solution of 4.50 g (20 mmoles) of 4-morpholino-3-cyclohexene-1-one ethylene ketal in 10 ml of tetrahydrofuran (THF) is added to 2.44 g (20 mmoles) of solid 9-BBN. A suspension results which becomes clear after stirring for 6 hours at room temperature. The THF is removed under reduced pressure (20 Torr) and 2 ml of methanol is added to the remaining solid. An exothermic reaction is initiated by gentle warming and results in a clear solution which is stirred. The stirring is stopped and the mixture is cooled slowly to room temperature to crystallize the by-product, B-(morpholino)-9-BBN methanol complex. The solid is triturated with n-pentane (3×30 ml) and the combined pentane layers are washed successively with water (3×10 ml), 3N sodium hydroxide (3×6 ml) and water (2×10 ml). The pentane solution is dried and the pentane is evaporated under reduced pressure (20 Torr). The residue is purified by distillation to give 2.10 g (75 percent yield based on 4-morpholino-3-cyclohexene-1-one ethylene ketal) of 3-cyclohexene-1-one ethylene ketal, boiling point, 82° C.-84° C. at 20 Torr.
Reaction SMILES: C([O:8][C:9](=[O:22])[C:10]1[CH:15]=[CH:14][C:13]([N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)=[CH:12][CH:11]=1)C1C=CC=CC=1.Cl[C:24]1[CH:41]=[CH:40][C:27]([C:28]([NH:30][C:31]2[CH:36]=[CH:35][C:34]([O:37][CH3:38])=[CH:33][C:32]=2[CH3:39])=[O:29])=[CH:26][N:25]=1.C1(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=NC=2)=O)C=CC=CC=1>>[CH3:38][O:37][C:34]1[CH:35]=[CH:36][C:31]([NH:30][C:28]([C:27]2[CH:40]=[CH:41][C:24]([N:19]3[CH2:18][CH2:17][N:16]([C:13]4[CH:12]=[CH:11][C:10]([C:9]([OH:8])=[O:22])=[CH:15][CH:14]=4)[CH2:21][CH2:20]3)=[N:25][CH:26]=2)=[O:29])=[C:32]([CH3:39])[CH:33]=1
Reactant: O=C(OCc1ccccc1)c1ccc(N2CCNCC2)cc1
Reactant: COc1ccc(NC(=O)c2ccc(Cl)nc2)c(C)c1
Agent: O=C(O)c1ccc(N2CCN(c3ccc(C(=O)Nc4ccccc4)cn3)CC2)cc1
Product: COc1ccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)nc2)c(C)c1

Procedure:
4-{4-[5-(4-Methoxy-2-methyl-phenylcarbamoyl)-pyridin-2-yl}-piperazin-1-yl]-benzoic acid was prepared from 4-piperazin-1-yl-benzoic acid benzyl ester and 6-chloro-N-(4-methoxy-2-methyl-phenyl)-nicotinamide with a method similar to the one described in the synthesis of 4-[4-(5-phenylcarbamoyl-pyridin-2-yl)-piperazin-1-yl]-benzoic acid above. HRMS m/z calcd for C25H26N4O4 [M+H]+: 447.2027. Found: 447.2027.
Reaction SMILES: N.[NH2-].[Na+].Cl[C:5]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:6]=1[CH2:12][CH2:13][C:14]#[N:15].[N+]([O-])([O-])=O.[NH4+]>>[Cl:11][C:7]1[C:6]2[CH2:12][CH:13]([C:14]#[N:15])[C:5]=2[CH:10]=[CH:9][CH:8]=1
Reactant: N#CCCc1c(Cl)cccc1Cl
Agent: N
Agent: O=[N+]([O-])[O-]
Agent: [NH2-]
Product: N#CC1Cc2c(Cl)cccc21
Temperature: -78 °C
Reaction time: 8 h

Procedure:
A dried 2 L 3-neck flask was fitted with a card-ice condenser, sealed under nitrogen and cooled to −78° C. Ammonia gas was condensed into the flask from a cylinder until approximately required volume was present (˜300 mL). Commercial sodium amide (800 mmol, 31.2 g) was added to the ammonia at −78° C. and after stirring for 10 minutes 3-(2,6-dichlorophenyl)propanenitrile (200 mmol, 40 g) was added over a 5 minute period. The mixture was allowed to warm such that the resultant mixture was stirred at reflux for 4 h before being neutralised with solid ammonium nitrate (800 mmol, 64.0 g) and allowed to stand overnight under a flow of nitrogen. The ammonia was evaporated and water was added to the solid residue and the products were extracted with dichloromethane (×3). The combined organics were washed with dilute hydrochloric acid (5%), followed by water. The organics were dried with sodium sulfate and concentrated to afford crude 3-chloro-1,2-dihydrocyclobutabenzene-1-carbonitrile as a brown residue (98% yield, 32 g).
Reaction SMILES: [CH:1]1([NH2:9])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C([O-])(=O)C.C([O-])(=O)C.C([O-])(=O)C.[CH3:22][O:23][C:24]1[CH:29]=[C:28]([CH3:30])[CH:27]=[C:26]([O:31][CH3:32])[C:25]=1[Pb+3]>ClCCl>[CH:1]1([NH:9][C:25]2[C:26]([O:31][CH3:32])=[CH:27][C:28]([CH3:30])=[CH:29][C:24]=2[O:23][CH3:22])[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: COc1cc(C)cc(OC)c1[Pb+3]
Reactant: NC1CCCCCCC1
Agent: CC(=O)[O-]
Solvent: ClCCl
Product: COc1cc(C)cc(OC)c1NC1CCCCCCC1
Reaction time: 18 h
Yield: 52 %

Procedure:
10.56 g of cyclooctylamine are dissolved in 500 ml of anhydrous dichloromethane and 1.5 g of cupric acetate are added thereto. A solution of 44.2 g of 2,6-dimethoxy-4-methylphenyllead triacetate, prepared above, in 250 ml of anhydrous dichloromethane is added dropwise to the reaction mixture under an inert atmosphere. The reaction mixture is left at room temperature for 18 hours, the heterogeneous mixture is then filtered over a bed of celite and the filtrate is concentrated to 450 ml. The organic phase is washed with water (3 times). The organic phase is extracted with 3×300 ml of 1N hydrochloric acid. The acidic aqeuous phase is basified with a 2N aqueous sodium hydroxide solution (pH=11). The alkaline aqeuous phase is extracted with dichloromethane and the organic extracts are dried over anhydrous sodium sulphate. Evaporation leaves an oil which is purified by flash chromatography on a column of silica gel, eluent:dichloromethane/methanol:99/1 (v/v) in order to obtain N-cyclooctyl-2,6-dimethoxy-4-methylaniline in the form of an oil. Yield 52%.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[N:8]2[C:9]3[CH:34]=[CH:33][CH:32]=[CH:31][C:10]=3[O:11][C:12]3([CH2:17][CH2:16][N:15]([C:18]([C:20]4[CH:25]=[CH:24][C:23]([O:26][CH:27]([CH3:29])[CH3:28])=[C:22]([CH3:30])[CH:21]=4)=[O:19])[CH2:14][CH2:13]3)[C:7]2=[CH:6][CH:5]=1.[CH:35](OCC)=[O:36]>>[CH:27]([O:26][C:23]1[CH:24]=[CH:25][C:20]([C:18]([N:15]2[CH2:16][CH2:17][C:12]3([O:11][C:10]4[CH:31]=[CH:32][CH:33]=[CH:34][C:9]=4[N:8]4[C:4]([CH2:3][NH:2][CH:35]=[O:36])=[CH:5][CH:6]=[C:7]34)[CH2:13][CH2:14]2)=[O:19])=[CH:21][C:22]=1[CH3:30])([CH3:28])[CH3:29]
Reactant: CCOC=O
Reactant: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CN)ccc23)ccc1OC(C)C
Agent: Cl
Product: Cc1cc(C(=O)N2CCC3(CC2)Oc2ccccc2-n2c(CNC=O)ccc23)ccc1OC(C)C

Procedure:
A solution of (1-(aminomethyl)spiro[benzo[b]pyrrolo[1,2-d][1,4]oxazine-4,4′-piperidine]-1′-yl)(4-isopropoxy-3-methylphenyl)methanone hydrochloride (60 mg, 0.13 mmol) in ethyl formate (109 μL, 1.35 mmol) was heated at 50° C. overnight. The solvent was removed under reduced pressure and the product was purified by reverse phase HPLC 10-99% acetonitrile in water (HCl modifier) to give N-((1′-(4-isopropoxy-3-methylbenzoyl)spiro[benzo[b]pyrrolo-[1,2-d][1,4]oxazine-4,4′-piperidine]-1-yl)methyl)formamide. 1H NMR (400 MHz, CDCl3) δ 8.23 (s, 1H), 7.40 (d, J=7.8 Hz, 1H), 7.30-7.22 (m, 1H), 7.20-7.01 (m, 3H), 6.83 (d, J=8.1 Hz, 1H), 6.28 (d, J=3.5 Hz, 1H), 5.99 (d, J=3.6 Hz, 1H), 5.89 (s, 1H), 4.77 (d, J=5.0 Hz, 2H), 4.62-4.52 (m, 1H), 3.50 (s, 2H), 2.21 (s, 3H), 2.17-1.78 (m, 4H), 1.70 (s, 2H), 1.36 (d, J=6.0 Hz, 6H). ESI-MS m/z talc. 473.6, found 474.5 (M+1)+; Retention time: 1.80 minutes (3 min run).
Reaction SMILES: [CH3:1][N:2]([CH3:20])[CH:3]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[C:4](=[O:8])[CH2:5][CH2:6][CH3:7].O.Cl>O1CCCC1>[CH3:20][N:2]([CH3:1])[CH:3]([C:9]1([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)[CH2:12][CH2:11][CH2:10]1)[CH:4]([OH:8])[CH2:5][CH2:6][CH3:7]
Reactant: CCCC(=O)C(N(C)C)C1(c2ccc(C)cc2)CCC1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CCCC(O)C(N(C)C)C1(c2ccc(C)cc2)CCC1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Boranedimethylsulphide complex (3 ml) was added dropwise under nitrogen over a period of 20 minutes to a solution of 1-dimethylamino-1-[1-(4-tolyl)cyclobutyl]pentan-2-one (1.85 g preprared as described in Example 16) in tetrahydrofuran (20 ml) and the resulting mixture stirred for 3 days at ambient temperature. The mixture was cooled to 0° C. and water (25 ml) and then 5N hydrochloric acid (25 ml) added. The mixture was basified and the tetrahydrofuran removed by evaporation. The residue was extracted with ether and the extracts washed with water, dried, filtered and evaporated to give an oil which was dissolved in petroleum ether (b.p. 80°-100° C.) and purified on a column packed with magnesia-silica gel sold under the trade name Florisil using petroleum ether (b.p. 80° to 100° C.) as eluant. The eluate was evaporated to give an oil which was distilled (215° C./1.5 mm Hg) to give 1-dimethylamino-1-[ 1-(4-tolyl)cyclobutyl]pentan-2-ol.
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[CH:6][C:5]([NH:9][CH2:10][C:11]([N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[O:12])=[C:4]([O:26][CH3:27])[CH:3]=1.[Cl:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:22]([O:21][C:19]([N:16]1[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][NH:9][C:5]2[CH:6]=[C:7]([C:30]3[CH:31]=[CH:32][CH:33]=[CH:34][C:29]=3[Cl:28])[C:2]([Cl:1])=[CH:3][C:4]=2[O:26][CH3:27])[CH2:14][CH2:15]1)=[O:20])([CH3:25])([CH3:24])[CH3:23]
Reactant: COc1cc(Cl)c(I)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Reactant: OB(O)c1ccccc1Cl
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: COc1cc(Cl)c(-c2ccccc2Cl)cc1NCC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 75.8 %

Procedure:
To a solution of tert-butyl 4-(2-(4-chloro-5-iodo-2-methoxyphenylamino)acetyl)piperazine-1-carboxylate (200 mg, 0.4 mmol) and 2-chlorophenylboronic acid (69 mg, 0.44 mmol) in 1,4-dioxane (10 mL) and water (2 mL), Pd(PPh3)4 (40 mg, 0.035 mmol) and Na2CO3 (212 mg, 2 mmol) were added. The mixture was stirred at 80° C. for 16 h. The mixture was allowed to cool to room temperature and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (petroleum ether/ethyl acetate=4:1) to afford the desire product (150 mg, 76% yield).
Reaction SMILES: [Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4](I)[CH:3]=1.[F:10][C:11]1[C:16](B(O)O)=[CH:15][CH:14]=[CH:13][N:12]=1>C(#N)C.[F-].[K+]>[Br:1][C:2]1[N:7]=[CH:6][C:5]([NH2:8])=[C:4]([C:16]2[C:11]([F:10])=[N:12][CH:13]=[CH:14][CH:15]=2)[CH:3]=1
Reactant: Nc1cnc(Br)cc1I
Reactant: OB(O)c1cccnc1F
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: Nc1cnc(Br)cc1-c1cccnc1F
Temperature: 70 °C
Yield: 39.1 %

Procedure:
A mixture of 6-bromo-4-iodo-pyridin-3-ylamine (10.0 g, 33.4 mmol), 2-fluoropyridine-3-boronic acid (5.2 g, 36.8 mmol) and 1,1′-[bis(diphenylphosphino)ferrocene]dichloropalladium(II) dichloromethane complex (2.73 g, 3.34 mmol) in acetonitrile (150 mL) and 1N aqueous potassium fluoride solution (150 mL) was degassed with nitrogen for 20 minutes. The reaction mixture was heated at 70° C. for 2.5 h, allowed to cool to ambient temperature and then partitioned between ethyl acetate (400 mL) and water (150 mL). The organic layer was separated, dried over anhydrous sodium sulfate, filtered and evaporated in vacuo. The resultant solid residue was triturated with dichloromethane: methanol (1:1, 100 mL), collected by filtration and washed with diethyl ether (50 mL) to furnish the title compound as a brown solid (3.5 g, 39%). The filtrate was evaporated and purified by passing the resultant residue through a pad of silica eluting with ethyl acetate:cyclohexane (1:1). Collection of the appropriate fractions and evaporation to dryness afforded a solid that was then triturated with diethyl ether to afford the title compound as a brown solid (3.7 g, 42%) (combined yield—7.22 g, 81%). 1H NMR (CDCl3, 300 MHz): 8.34 (ddd, J=4.9, 2.0, 1.2 Hz, 1H), 7.99 (s, 1H), 7.85 (ddd, J=9.4, 7.4, 2.0 Hz, 1H), 7.37 (ddd, J=7.4, 4.9, 2.0 Hz, 1H), 7.22 (s, 1H), 3.75 (s, 2H). LCMS (Method B): RT=2.78 min, M+H+=268/270.
Reaction SMILES: [NH2:1][C:2]1[N:6]=[C:5]([CH3:7])[NH:4][N:3]=1.O=[C:9]([CH2:15][CH2:16][C:17](OC)=[O:18])[CH2:10][C:11]([O:13][CH3:14])=[O:12]>>[CH3:7][C:5]1[N:6]=[C:2]2[NH:1][C:15]([CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])=[CH:16][C:17](=[O:18])[N:3]2[N:4]=1
Reactant: COC(=O)CCC(=O)CC(=O)OC
Reactant: Cc1nc(N)n[nH]1
Product: COC(=O)CCc1cc(=O)n2nc(C)nc2[nH]1
Temperature: 160 °C
Reaction time: 1 h
Yield: 70.6 %

Procedure:
3-Amino-5-methyl-1H-s-triazole (19.8 g) (about 0.12 mol) (about 70%) and 30 g (0.16 mol) of dimethyl 3-oxo-adipate are melted together while gassing with argon for 1 hour in a bath heated at 160° C. In so doing, the volatile products are removed in a water-jet vacuum. After cooling the solid residue is dissolved in dichloromethane/methanol (1:1 v/v). The turbid yellowish solution is filtered and concentrated. The crystals which thereby result are filtered off under suction and washed with ethanol, subsequently with diethyl ether. There are obtained 20 g of methyl 4,7-dihydro-2-methyl-7-oxo-s-triazolo[1,5-a]pyrimidine-5-propionate as a white crystals of melting point 222°-225° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6](I)[CH:5]=1.C([Mg]Cl)(C)C.C1COCC1.[Cl:24][C:25]1[CH:33]=[C:32]([N+:34]([O-:36])=[O:35])[CH:31]=[CH:30][C:26]=1[C:27](Cl)=[O:28]>[Cl-].[Cl-].[Zn+2].CC([O-])=O.CC([O-])=O.[Cu+2].CCOC(C)=O.O>[CH3:1][O:2][C:3](=[O:13])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH3:11])=[C:6]([C:27](=[O:28])[C:26]2[CH:30]=[CH:31][C:32]([N+:34]([O-:36])=[O:35])=[CH:33][C:25]=2[Cl:24])[CH:5]=1
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1Cl
Reactant: COC(=O)c1ccc(OC)c(I)c1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COC(=O)c1ccc(OC)c(C(=O)c2ccc([N+](=O)[O-])cc2Cl)c1
Temperature: -50 °C
Reaction time: 0.75 h

Procedure:
A dry flask was charged with 3-iodo-4-methoxy-benzoic acid methyl ester (8.9 g, 30.5 mmol) and the flask was evaporated and then filled with argon and this process repeated twice. Dry THF (50 mL) was added, and the solution cooled to −50° C.; then isopropylmagnesium chloride (15.2 mL, 2.0 M in diethyl ether, 30.5 mmol) was added slowly over 20 min keeping the temperature below −40° C. On completion of the addition the reaction mixture was stirred at −40° C. for 45 min. A THF solution of ZnCl2 (5.19 g, 38.1 mmol, 1.0 M) was added dropwise over 20 min. The reaction mixture was stirred at 0° C. for 20 min; then 2-chloro-4-nitro-benzoyl chloride (7.04 g, 32.0 mmol) and Cu(OAc)2 (122 mg, 0.61 mmol) were added and the reaction mixture was allowed to warm to room temperature. After 16 h the reaction mixture was poured into a mixture of EtOAc/water, then shaken and separated. The aqueous phase was extracted with more EtOAc. The organic phases were combined, dried (MgSO4), filtered, and concentrated in vacuo to afford the crude product. The crude product was purified by flash chromatography using EtOAc/petroleum ether (40-60) 1:6 followed by 1:3 as the eluent to give the title compound as yellow solid.
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)[C@@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[O:12][C@H:11]1SCCNC(=O)OCC1C=CC=CC=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH:58][CH2:59][CH:60]([NH:65][C:66](=[O:84])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83])[C:61]([O:63][CH3:64])=[O:62].IN1C(=O)CCC1=O.FC(F)(F)S(O)(=O)=O>C(Cl)(Cl)Cl>[C:66]([NH:65][CH:60]([CH2:59][O:58][C@@H:11]1[O:12][C@H:13]([CH2:34][O:35][C:36](=[O:43])[C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)[C@H:14]([O:25][C:26](=[O:33])[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=2)[C@H:15]([O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[C@H:10]1[O:9][C:1](=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[C:61]([O:63][CH3:64])=[O:62])(=[O:84])[CH2:67][CH2:68][CH2:69][CH2:70][CH2:71][CH2:72][CH2:73][CH2:74][CH2:75][CH2:76][CH2:77][CH2:78][CH2:79][CH2:80][CH2:81][CH2:82][CH3:83]
Reactant: O=C(NCCS[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)OCc1ccccc1
Reactant: CCCCCCCCCCCCCCCCCC(=O)NC(CO)C(=O)OC
Agent: O=C1CCC(=O)N1I
Agent: O=S(=O)(O)C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CCCCCCCCCCCCCCCCCC(=O)NC(CO[C@@H]1O[C@H](COC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H](OC(=O)c2ccccc2)[C@H]1OC(=O)c1ccccc1)C(=O)OC
Temperature: 0 °C
Reaction time: 3 h
Yield: 56 %

Procedure:
In 35 mL of chloroform were dissolved 2.4 g of benzyl 2-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosylthio)ethylcarbamate and 1 g of methyl 3-hydroxy-2-(octadecanoylamino)propionate, and after cooling the solution to 0° C., 1.4 g of N-iodosuccinimide and 0.13 mL of trifluoromethanesulfonic acid were added to the solution and the resulting mixture was stirred at room temperature for 3 hours. Then, chloroform was added to the reaction mixture, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution and 10% aqueous sodium thiosulfate solution. The chloroform layer was dried over anhydrous magnesium sulfate, magnesium sulfate was filtered off, and the filtrate was concentrated under reduced pressure. The residue was purified by silica gel chromatography (Eluent; n-hexane:ethyl acetate=3:1) to obtain 1.4 g of methyl 2-(octadecanoylamino)-3-(2,3,4,6-tetra-O-benzoyl-β-D-galactopyranosyloxy)propionate.
Reaction SMILES: [C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9](O)=[O:10])=[CH:3][CH:2]=1.O=S(Cl)[Cl:20]>>[C:1]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH:6]=[CH:5][C:4]([CH2:7][CH2:8][C:9]([Cl:20])=[O:10])=[CH:3][CH:2]=1
Reactant: O=S(Cl)Cl
Reactant: O=C(O)CCc1ccc(-c2ccccc2)cc1
Product: O=C(Cl)CCc1ccc(-c2ccccc2)cc1
Temperature: 85 °C
Yield: 101 %

Procedure:
A mixture of 3-(4-biphenylyl)propionic acid (5 g, 22.10 mmol) and SOCl2 (4.03 ml, 55.2 mmol) is refluxed under nitrogen at 85° C. for 1.5 hour. The reaction mixture is concentrated under reduced pressure to give 3-(biphenyl-4-yl)propanoyl chloride (5.46 g). The material is used in the next step without further purification.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[O:11]1[CH2:15][CH2:14][NH:13][C:12]1=[O:16].N1CCC[C@H]1C(O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.[Cu]I>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:13]2[CH2:14][CH2:15][O:11][C:12]2=[O:16])=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: O=C1NCCO1
Reactant: O=[N+]([O-])c1ccc(Br)cc1
Agent: [Cu]I
Agent: O=C(O)[C@@H]1CCCN1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Product: O=C1OCCN1c1ccc([N+](=O)[O-])cc1
Yield: 26.9 %

Procedure:
To a mixture of 1-bromo-4-nitrobenzene (5.00 g, 25 mmol) and oxazolidin-2-one (3.23 g, 37 mmol) in dioxane (25 mL) were added L-proline (285 mg, 2.5 mmol), CuI (238 mg, 1.2 mmol) and K2CO3 (6.90 g, 50 mmol). The resultant mixture was stirred under N2 at 110° C. for 63 h and then evaporated. The residue was diluted with EA/water (40 mL/40 mL). The mixture was filtered and the resultant aqueous layer was extracted with EA (30 mL×5). The combined organic layers were washed with brine, dried over NaSO4, concentrated and purified by silica gel column chromatography (DCM to DCM:MeOH=50:1) to afford desired as a yellow solid (1.40 g, yield 27%).
Reaction SMILES: [CH3:1][S-:2].[Na+].Cl[C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1>CN(C)C=O>[CH3:1][S:2][C:5]1[CH:10]=[CH:9][N:8]=[C:7]([C:11]#[N:12])[CH:6]=1
Reactant: N#Cc1cc(Cl)ccn1
Reactant: C[S-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccnc(C#N)c1
Reaction time: 2 h
Yield: 90.6 %

Procedure:
Sodium thiomethoxide (1.01 g) was added to 4-chloropyridine-2-carbonitrile (2.00 g) obtained from Referential Example 113 in N,N-dimethylformamide (20 mL) at 0° C., followed by stirring for 2 hours. The reaction mixture was partitioned between water and ethyl acetate. The organic layer was dried over sodium sulfate anhydrate, followed by filtration. The solvent was evaporated under reduced pressure. The residue was purified through silica gel column chromatography (hexane-ethyl acetate), to thereby give the title compound as a solid (1.96 g, 90%).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([OH:11])=O)[CH:2]=1.C(Cl)(=O)C([Cl:15])=O>C(Cl)Cl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][CH2:8][C:9]([Cl:15])=[O:11])[CH:2]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: O=C(O)CCc1cccnc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)CCc1cccnc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of 300 mg (1.99 mmol) 3-pyridine propionic acid in 10 mL CH2Cl2 was added one drop DMF and 2.3 mL (4.56 mmol) oxalyl chloride, and the mixture stirred at rt for 4 h. The volatiles were evaporated under reduced pressure and the material used crude in the following procedure.
Reaction SMILES: Cl[CH2:2][C:3]([O-:5])=[O:4].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([SH:17])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8].[OH-].[Na+].Cl>O>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([S:17][CH2:2][C:3]([OH:5])=[O:4])=[CH:15][CH:16]=1)([CH3:10])([CH3:8])[CH3:9]
Reactant: O=C([O-])CCl
Reactant: CC(C)(C)c1ccc(S)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)(C)c1ccc(SCC(=O)O)cc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 74.9 %

Procedure:
Sodium chloroacetate (6.29 g, 54 mmol) was added in portions to a solution of 4-t-butylbenzenethiol (9.0 g, 54 mmol) in a 30% (w/v) aqueous solution of sodium hydroxide (10.8 ml, 81 mmol) with stirring at 80° C. When the addition was complete, stirring was continued for an additional 2 hours at 80° C., during which time a thick white precipitate had formed. The reaction mixture was added to water (200 ml) and was acidified to pH 2 by the addition of 2M hydrochloric acid. The mixture was extracted with ethyl acetate. The combined extracts were then extracted with a 10% (w/v) aqueous solution of potassium carbonate. The aqueous extracts were acidified to pH 2 by the addition of 2M hydrochloric acid and again extracted with ethyl acetate. These combined extracts were dried (MgSO4) and the solvent was removed by evaporation to give 2-(4-t-butylphenylthio)acetic acid (B) as a straw coloured oil (9.07 g); which had a satisfactory NMR spectrum.
Reaction SMILES: [C:1]([NH:5][S:6]([C:9]1[S:10][CH:11]=[CH:12][CH:13]=1)(=[O:8])=[O:7])([CH3:4])([CH3:3])[CH3:2].[Li][CH2:15][CH2:16][CH2:17][CH3:18].C(I)CCC>C1COCC1>[CH2:15]([C:11]1[S:10][C:9]([S:6]([NH:5][C:1]([CH3:4])([CH3:2])[CH3:3])(=[O:7])=[O:8])=[CH:13][CH:12]=1)[CH2:16][CH2:17][CH3:18]
Reactant: CC(C)(C)NS(=O)(=O)c1cccs1
Reactant: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCI
Product: CCCCc1ccc(S(=O)(=O)NC(C)(C)C)s1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of 2-(N-t-butylaminosulfonyl)thiophene (2.01 g, 9.18 mmol) in anhydrous THF (17 mL) cooled to -78° C. under N2 was added 2.5 M n-BuLi (10 mL, 2.7 equiv). After stirring at -78° C. for 30 min the bath temperature was raised to -40° C. and the mixture was stirred for an additional 2 hrs. To this mixure was added n-butyliodide (2.0 mL, 2 equiv) and the reaction was allowed to warm to room temperature. After stirring overnight the darkened reaction mixture was quenched with NH4Cl soln and extracted with EtOAc. The organic was washed with brine and dried over anhydrous MgSO4 and concentrated in vacuo. The titled compound was purified by flash chromatography eluting with hex/EtOAc (15:1 to 7:1). Rf=0.32 (6:1 Hex/EtOAc).