Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C@:4]([N:9]=[C:10]=[O:11])([CH:6]([CH3:8])[CH3:7])N.[OH:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1>C(Cl)(Cl)Cl>[CH3:1][O:2][C:3](=[O:12])[C@H:4]([CH:6]([CH3:8])[CH3:7])[NH:9][C:10]([O:13][CH2:14][C:15]1[S:16][CH:17]=[C:18]([CH:20]([CH3:22])[CH3:21])[N:19]=1)=[O:11]
Reactant: CC(C)c1csc(CO)n1
Reactant: COC(=O)[C@](N)(N=C=O)C(C)C
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@@H](NC(=O)OCc1nc(C(C)C)cs1)C(C)C
Yield: 52.3 %

Procedure:
A solution of 1.4 mmol of α-isocyanato-valine methyl ester and 0.22 g (1.4 mmol) of 2-(hydroxymethyl)-4-isopropylthiazole in 10 ml of chloroform was heated at reflux for 3 h. After being allowed to cool, the solvent was removed in vacuo, and the residue was purified by silica gel chromatography using 2% methanol in chloroform to provide 0.23 g (52%) of the desired compound (Rf 0.54, 5% methanol in dichloromethane). NMR 1H NMR (DMSO-d6) δ0.87 (d, J=7 Hz, 3H), 0.88 (d, J=7 Hz, 3H), 1.23 (d, J=7 Hz, 6H), 2.04 (octet, J=7 Hz, 1H), 3.01 (heptet, J=7 Hz, 1H), 3.73 (s, 3H), 3.94 (dd, J=8, 6 Hz, 1H), 5.26 (AA', 2H), 7.28 (s, 1H), 7.92 (d, J=8 Hz, 1H). Mass spectrum: (M+H)+ =315.
Reaction SMILES: Cl.[O:2]=[C:3]1[NH:11][C:6]2=[N:7][CH:8]=[CH:9][CH:10]=[C:5]2[C:4]21[CH2:19][C:18]1[C:13](=[CH:14][CH:15]=[C:16]([NH:20][C:21]3[N:26]=[CH:25][N:24]=[C:23]([C:27]([OH:29])=O)[CH:22]=3)[CH:17]=1)[CH2:12]2.[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32]1.C(N(CC)CC)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[CH3:30][C:31]1([CH3:37])[CH2:36][CH2:35][CH2:34][N:33]([C:27]([C:23]2[N:24]=[CH:25][N:26]=[C:21]([NH:20][C:16]3[CH:17]=[C:18]4[C:13](=[CH:14][CH:15]=3)[CH2:12][C:4]3([C:5]5[C:6](=[N:7][CH:8]=[CH:9][CH:10]=5)[NH:11][C:3]3=[O:2])[CH2:19]4)[CH:22]=2)=[O:29])[CH2:32]1
Reactant: CC1(C)CCCNC1
Reactant: O=C(O)c1cc(Nc2ccc3c(c2)CC2(C3)C(=O)Nc3ncccc32)ncn1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC1(C)CCCN(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)C1

Procedure:
82 mg (0.20 mmol) 6-(2′-oxo-1,1′,2′,3-tetrahydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-5-ylamino)pyrimidine-4-carboxylic acid hydrochloride, 32 mg (0.27 mmol) 3,3-dimethyl-piperidine, 80 μL (0.57 mmol) triethylamine and 70 mg (0.22 mmol) TBTU in 0.80 mL DMF were stirred overnight at RT. The purification was carried out by preparative HPLC-MS. The product-containing fractions were combined and lyophilised.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([NH2:8])=[CH:6][CH:7]=1.[F:10][CH2:11][C:12](O)=O.Cl[C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]2[N:8]([C:16]([O:18][CH2:19][CH:20]([CH3:22])[CH3:21])=[O:17])[C:12]([CH2:11][F:10])=[N:9][C:4]=2[CH:3]=1
Reactant: Nc1ccc(Br)cc1N
Reactant: CC(C)COC(=O)Cl
Reactant: O=C(O)CF
Product: CC(C)COC(=O)n1c(CF)nc2cc(Br)ccc21

Procedure:
Synthesized according to the method of reagent preparation 19 using 4-bromobenzene-1,2-diamine and fluoroacetic acid in step 1 then treatment with isobutyl chloroformate in step 3. MS (EI) for C13H14BrFN2O2: 330 (MH+).
Reaction SMILES: C[O:2][C:3](=[O:23])[CH:4]([C:11]1[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([C:21]#[N:22])[CH:12]=1)[CH2:5][CH:6]1[CH2:10][CH2:9][CH2:8][CH2:7]1.[OH-].[Li+].C(OCC)(=O)C>O1CCCC1>[C:21]([C:13]1[CH:12]=[C:11]([CH:4]([CH2:5][CH:6]2[CH2:7][CH2:8][CH2:9][CH2:10]2)[C:3]([OH:23])=[O:2])[CH:16]=[CH:15][C:14]=1[S:17]([CH3:20])(=[O:18])=[O:19])#[N:22]
Reactant: COC(=O)C(CC1CCCC1)c1ccc(S(C)(=O)=O)c(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1C#N
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid methyl ester (4.84 g, 14.4 mol) in tetrahydrofuran (25 mL) was treated with a 0.8M aqueous lithium hydroxide solution (27 mL, 21.6 mmol). The reaction mixture was stirred at 25° C. for 2.5 h. The reaction mixture was partitioned between water and ethyl acetate and then acidified to pH=2 with a 10% aqueous hydrochloric acid solution. The layers were shaken and separated. The resulting organic layer was washed with a saturated aqueous sodium chloride solution, dried over magnesium sulfate, filtered, and concentrated in vacuo to afford crude 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid (3.80 g, 82%) as a pale yellow oil that solidified to a pale yellow solid. An analytical sample was obtained by recrystallization from ethyl acetate to afford 2-(3-cyano-4-methanesulfonyl-phenyl)-3-cyclopentyl-propionic acid as a white solid: mp 180-181° C.; EI-HRMS m/e calcd for C16H19NO4S (M+) 321.1034, found 321.1039.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([OH:18])=O)=[N:14][CH:15]=1.[OH:30][N:31]1[C:35]2C=CC=CC=2N=N1.Cl.[CH2:41](N=C=NCCCN(C)C)C.CN1CCOCC1>C(Cl)Cl>[F:1][C:2]1[CH:7]=[CH:6][C:5]([F:8])=[CH:4][C:3]=1[CH:9]([S:20]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)(=[O:22])=[O:21])[C:10]1[C:11]([CH3:19])=[CH:12][C:13]([C:16]([N:31]([O:30][CH3:41])[CH3:35])=[O:18])=[N:14][CH:15]=1
Reactant: Cc1cc(C(=O)O)ncc1C(c1cc(F)ccc1F)S(=O)(=O)c1ccc(F)cc1
Reactant: On1nnc2ccccc21
Reactant: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: CON(C)C(=O)c1cc(C)c(C(c2cc(F)ccc2F)S(=O)(=O)c2ccc(F)cc2)cn1
Temperature: 25 °C
Reaction time: 120 h
Yield: 67 %

Procedure:
To a solution of 5-[(2,5-difluorophenyl) [(4-fluorophenyl)sulfonyl]methyl]-4-methylpyridine-2-carboxylic acid (99 mg, 0.235 mmol) obtained in Example 12 in methylene chloride (3 ml), N, O-dimethylhydroxyamine hydrochloride (28 mg, 0.282 mmol), 1-hydroxybenzotriazole (32 mg, 0.235 mmol), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride mg, 0.382 mmol) and 4-methylmorpholine (61 μl, 0.564 mmol) were added. The reaction solution was stirred for 5 days at room temperature, and was concentrated under reduced pressure. The resulting concentration residue was subjected to silica gel column chromatography, and the fraction obtained from an elution with hexane:ethylacetate (=1:1) was concentrated under reduced pressure. Ethyl acetate-hexane was added to the resulting concentration residue, and the solid thus precipitated was collected by filtration, to obtain the title compound (73 mg, 0.157 mmol, 67%) as a white powder.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][CH:12]=1)([CH3:7])[CH3:6])[CH3:2].[Cl:15]NC(=O)CCC(N)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:14])[C:5]([C:8]1[N:9]=[C:10]([NH2:13])[S:11][C:12]=1[Cl:15])([CH3:7])[CH3:6])[CH3:2]
Reactant: CCOC(=O)C(C)(C)c1csc(N)n1
Reactant: NC(=O)CCC(=O)NCl
Solvent: CC#N
Product: CCOC(=O)C(C)(C)c1nc(N)sc1Cl
Reaction time: 1 h
Yield: 86.2 %

Procedure:
2-(2-Amino-thiazol-4-yl)-2-methyl-propionic acid ethyl ester (0.3 g, 1.40 mmol) was taken in 10 mL of acetonitrile and N-Chlorosuccinamide (0.224 g, 1.68 mmol) was added the reaction was stirred for 1 hr. at room temperature. After completion of reaction acetonitrile was evaporated under reduced pressure and the residue was partitioned between water (25 mL) and ethyl acetate (25 mL). The layers were separated and the aqueous layer was extracted with ethyl acetate (2×25 mL). The combined organic layer was washed with brine and dried over anhydrous sodium sulphate and the solvent was removed in vacuo. The residue was purified by preparative TLC plate (mobile phase 40% ethyl acetate in hexane) to afford pure compound (0.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([O:14]C(C)(C)C)=[CH:12][CH:13]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]>C1COCC1.FC(F)(F)C(O)=O>[NH2:1][C:2]1[CH:7]=[C:6]([C:8]2[CH:9]=[N:10][C:11]([OH:14])=[CH:12][CH:13]=2)[N:5]=[C:4]([C:19]([O:21][CH3:22])=[O:20])[C:3]=1[Cl:23]
Reactant: COC(=O)c1nc(-c2ccc(OC(C)(C)C)nc2)cc(N)c1Cl
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1nc(-c2ccc(O)nc2)cc(N)c1Cl
Yield: 83.9 %

Procedure:
Methyl 4-amino-3-chloro-6-(6-t-butoxy-3-pyridinyl)pyridine-2-carboxylate (0.50 g, 1.49 mmol) was dissolved in a 1:1 mixture of THF and trifluoroacetic acid (5 mL) and heated to reflux for 30 minutes. The volatiles were removed in vacuo and the crude material was purified by HPLC (linear gradient, 100% water to 100% acetonitrile) to give of methyl 4-amino-3-chloro-6-(6-hydroxy-3-pyridinyl)pyridine-2-carboxylate (0.35 g, 1.25 mmol): Mp 251-52° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][CH2:16][N:17]1[CH2:21][CH2:20][CH2:19][CH2:18]1)[NH:9][CH:8]=[CH:7][C:6]2=O.O=P(Cl)(Cl)[Cl:25].[OH-].[K+]>C(#N)C>[Cl:25][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:14][CH2:15][CH2:16][N:17]3[CH2:21][CH2:20][CH2:19][CH2:18]3)=[C:3]([O:2][CH3:1])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: COc1cc2c(=O)cc[nH]c2cc1OCCCN1CCCC1
Reactant: O=P(Cl)(Cl)Cl
Agent: [K+]
Agent: [OH-]
Solvent: CC#N
Product: COc1cc2c(Cl)ccnc2cc1OCCCN1CCCC1
Temperature: 85 °C
Yield: 87.3 %

Procedure:
Intermediate VI (63 g, 0.198 mol) and POCl3 (5 v/w, 315 in L) were added to acetonitrile (5 v/w, 315 mL). The mixture was warmed up to 85° C. to react under reflux for 6 h. After completion of the reaction, the reaction solution was cooled. POCl3 and acetonitrile were evaporated off to produce a grey viscous solid. This solid was added to a great deal of ice-water mixture, adjusted with a 10% KOH solution to a pH of 10, and extracted with CH2Cl2 (200 mL×3). The organic layer was collected, dried over anhydrous sodium sulfate, and cooled after evaporating off the solvate to produce an off-white solid (58 g) in a yield of 87.3%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]2[C@@H:13]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[NH:12][C:11](=[O:21])[CH2:10][CH2:9]2)[CH:5]=[CH:6][CH:7]=1.[Li][CH2:23][CH2:24][CH2:25]C.C(Br)C=C>C1COCC1>[CH2:25]([C@@H:10]1[CH2:9][C@H:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[C@@H:13]([C:14]2[CH:15]=[CH:16][C:17]([Cl:20])=[CH:18][CH:19]=2)[NH:12][C:11]1=[O:21])[CH:24]=[CH2:23]
Reactant: O=C1CC[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)N1
Reactant: [Li]CCCC
Solvent: C=CCBr
Solvent: C1CCOC1
Product: C=CC[C@@H]1C[C@H](c2cccc(Cl)c2)[C@@H](c2ccc(Cl)cc2)NC1=O
Temperature: 0 °C

Procedure:
A 100 mL flame-dried round-bottomed flask equipped with a magnetic stir bar was charged with (5R,6S)-5-(3-chlorophenyl)-6-(4-chlorophenyl)piperidin-2-one (1.32 g, 4.12 mmol) (Example 1, Step E) and anhydrous THF (41.2 mL). This solution was cooled to 0° C. under argon and BuLi (3.30 mL, 8.24 mmol) was added. After 10 minutes allyl bromide (0.357 mL, 4.12 mmol) was added. After an additional 45 minutes the reaction was quenched by the addition of sat. aq. NH4Cl and the layers were separated. The aqueous layer was extracted with EtOAc twice and the organics were pooled, washed with sat. aq. NaCl solution, dried (MgSO4), filtered and concentrated in vacuo to provide a colorless oil. Purification using a Combiflash Companion (flash column chromatography, Teledyne Isco, Lincoln, Nebr.) with a 120 g SiO2 column and eluting with 10 to 100% EtOAc/hexanes provided the title compound.
Reaction SMILES: O.[N+:2]([C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:16][CH2:15][N:14]([C:17]3[CH:24]=[CH:23][C:20]([CH:21]=O)=[CH:19][CH:18]=3)[CH2:13][CH2:12]2)=[CH:7][CH:6]=1)([O-:4])=[O:3].[NH:25]1[CH2:30][CH2:29][O:28][CH2:27][CH2:26]1.C([BH3-])#N.[Na+]>O1CCCC1.C(O)(=O)C>[N+:2]([C:5]1[CH:6]=[CH:7][C:8]([N:11]2[CH2:12][CH2:13][N:14]([C:17]3[CH:24]=[CH:23][C:20]([CH2:21][N:25]4[CH2:30][CH2:29][O:28][CH2:27][CH2:26]4)=[CH:19][CH:18]=3)[CH2:15][CH2:16]2)=[CH:9][CH:10]=1)([O-:4])=[O:3]
Reactant: O=Cc1ccc(N2CCN(c3ccc([N+](=O)[O-])cc3)CC2)cc1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CC(=O)O
Product: O=[N+]([O-])c1ccc(N2CCN(c3ccc(CN4CCOCC4)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 52.3 %

Procedure:
A mixture of water (1 mL), acetic acid (1 mL), 4-[4-(4-nitro-phenyl)-piperazin-1-yl]-benzaldehyde (700 mg, 2.25 mmol) and morpholine (215 mg, 2.47 mmol) in tetrahydrofuran (10 mL) was stirred at room temperature for 1 h. Sodium cyanoborohydride (212 mg, 3.37 mmol) was added at room temperature then the mixture was heated at reflux for 10 h. The tetrahydrofuran was removed in vacuo and the residue was partitioned between water and ethyl acetate. The organic layer was washed with saturated sodium bicarbonate solution, dried over anhydrous sodium sulfate and evaporated in vacuo to afford a residue which was purified by column chromatography on silica gel (60-120 mesh) using 1% methanol in chloroform as eluent to afford 4-{4-[4-(4-nitro-phenyl)-piperazin-1-yl]-benzyl}-morpholine (450 mg, 52%) as a brownish yellow solid.
Reaction SMILES: [CH2:1]([N:4]([CH2:9][CH2:10][CH3:11])[CH2:5][CH2:6][CH2:7]O)[CH2:2][CH3:3].S(Cl)([Cl:14])=O>C(O)C>[ClH:14].[Cl:14][CH2:7][CH2:6][CH2:5][N:4]([CH2:1][CH2:2][CH3:3])[CH2:9][CH2:10][CH3:11]
Reactant: O=S(Cl)Cl
Reactant: CCCN(CCC)CCCO
Solvent: CCO
Product: CCCN(CCC)CCCCl
Product: Cl
Temperature: 25 °C
Reaction time: 2 h

Procedure:
3-(Dipropylamino)propanol (32.9 g) was added dropwise at 0° C. over 1.5 hours to stirred thionyl chloride (15.7 ml). When the addition was complete, the mixture was stirred at ambient temperature for 2 hours then poured into ethanol (250 ml). The stirred mixture was heated under reflux for 10 minutes, then the solvent was removed in vacuo to leave 1-chloro-3-(dipropylamino)-propane hydrochloride as an off-white solid (42 g) which was used without purification.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH2:18][OH:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(C)=O.I(C1C=CC=CC=1C(O)=O)(=O)=O>C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:14]([N:15]([CH3:17])[CH3:16])=[CH:13][CH:12]=[CH:11][C:10]=1[CH:18]=[O:19])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CN(C)c1cccc(CO)c1OCc1ccccc1
Agent: O=C(O)c1ccccc1I(=O)=O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: CN(C)c1cccc(C=O)c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Into a 250-mL 3-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed [2-(benzyloxy)-3-(dimethylamino)phenyl]methanol (3.6 g, 13.99 mmol, 1.00 equiv) and DMSO (50 mL). This was followed by the addition of 2-iodoxybenzoic acid (4.31 g, 15.39 mmol, 1.10 equiv) in several batches. The resulting solution was stirred for 2 h at 25° C. The resulting solution was diluted with 200 mL of ethyl acetate. The resulting mixture was washed with 4×50 mL of water. The solids were filtered out. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 3.4 g (95%) of 2-(benzyloxy)-3-(dimethylamino)benzaldehyde as yellow oil. MS (ESI) m/z 256 ([M+H]+).
Reaction SMILES: O.O.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([O-:12])=[O:11])=[CH:6][CH:5]=1.[Na+].[C:14](#[N:17])[CH:15]=[CH2:16].C(O)(=O)C>O>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:16][CH2:15][C:14]#[N:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: C=CC#N
Reactant: O=S([O-])c1ccc(Br)cc1
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: N#CCCS(=O)(=O)c1ccc(Br)cc1
Temperature: 100 °C
Reaction time: 1.5 h
Yield: 86 %

Procedure:
To a suspension of sodium 4-bromophenylsulfinate dihydrate (130 g, 0.53 mol) in water (600 mL) was added acrylonitrile (70 mL, 1.07 mol) and acetic acid (62 mL, 1.07 mol). The reaction was stirred for 1.5 h at 100° C. then cooled to room temperature. The solid was filtered off, washed thoroughly with water and dried over P2O5 to give 3-[(4-bromophenyl)sulfonyl]propanenitrile (125 g). δH (400 MHz, CDCl3): 7.27–7.22 (4H, m), 2.85 (2H, t, J 7.6), 2.30 (2H, t, J 7.6).
Reaction SMILES: [CH2:1]([OH:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12].[C:14]([OH:23])(=[O:22])[CH:15]([CH:17]([C:19]([OH:21])=O)[OH:18])[OH:16].[C:24]1([CH3:34])[CH:29]=[CH:28][C:27](S(O)(=O)=O)=[CH:26][CH:25]=1>C1(C)C=CC=CC=1>[C:14]([O:23][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:24][CH3:34])(=[O:22])[CH:15]([CH:17]([C:19]([O:13][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12])=[O:21])[OH:18])[OH:16]
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Reactant: CCCCCCCCCCCCO
Reactant: O=C(O)C(O)C(O)C(=O)O
Solvent: Cc1ccccc1
Product: CCCCCCCCCCCCOC(=O)C(O)C(O)C(=O)OCCCCCCCCCCCC
Temperature: 150 °C
Yield: 776 %

Procedure:
In a 2 l three-necked flask equipped with a condenser and a stirring device, 372.7 g (2 mol) of dodecanol, 150.1 g (1 mol) of tartaric acid, 500 ml of toluene and 17.2 g (0.1 mol) of p-toluenesulfonic acid were placed, heated to 150° C. and reacted for 12 hours as azeotropic dehydration was run under refluxing toluene. The reaction solution was cooled to room temperature, and the toluene was distilled away under reduced pressure. The thus obtained oily material was submitted to chromatographic separation and purification on a column of silica gel (eluent: ethylacetate/hexane=1/1) to give 377.7 g of the intended compound as a colorless transparent liquid (yield: 77.6%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[NH:8][CH2:9][C:10]([SH:13])([CH3:12])[CH3:11].[CH2:14]([S:19][C:20]([CH3:24])([CH3:23])[CH:21]=O)[CH2:15][CH2:16][CH:17]=[CH2:18].C(O)(=O)C.C([BH3-])#N.[Na+].Cl>CO>[SH:13][C:10]([CH3:11])([CH3:12])[CH2:9][NH:8][C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[NH:1][CH2:21][C:20]([S:19][CH2:14][CH2:15][CH2:16][CH:17]=[CH2:18])([CH3:24])[CH3:23]
Reactant: CC(C)(S)CNc1ccccc1N
Reactant: C=CCCCSC(C)(C)C=O
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: C=CCCCSC(C)(C)CNc1ccccc1NCC(C)(C)S
Temperature: 25 °C
Reaction time: 17 h
Yield: 85.1 %

Procedure:
2-Amino-1-(2-mercapto-2-methylpropylamino)benzene (0.155 g, 7/9×10-4 mol) and 0.30 g (1.74×10-3 mol, 220 M%) of 2-(4-pentenylthio)-2-methylpropanal were dissolved in 40 ml methanol. Acetic acid (0.09 ml, 1.59×10-3 mol, 200 M%) was added followed by 0.155 g (2.3×10-3 mol, 300 M%) sodium cyanoborohydride. The reaction was stirred at room temperature under nitrogen for 17 hr, then 20 ml 0.5 M HCl was added and the mixture was extracted with 2×40 ml diethyl ether. The ether layer was washed with 30 ml saturated NaCl solution and dried (Na2SO4), and the solvent was removed on the rotary evaporator. The product was purified by radial chromatography on a 2 mm silica plate eluting with 50 ml 100% hexane and 100 ml 90% hexane/ether to give 0.27 g (97% yield) of 2-(2-mercapto-2-methylpropylamino)-1-[2-(4-pentenylthio)-2-methylpropylamino]-benzene as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7]2[CH:8]=[CH:9][C:10]([N:12]3[CH2:16][C@H:15]([C:17]([NH2:19])=[O:18])[O:14][C:13]3=[O:20])=[CH:11][C:6]=2[O:5][CH2:4][C:3]1=[O:21].[CH3:22]N>CO>[CH3:22][NH:19][C:17]([C@@H:15]1[O:14][C:13](=[O:20])[N:12]([C:10]2[CH:9]=[CH:8][C:7]3[N:2]([CH3:1])[C:3](=[O:21])[CH2:4][O:5][C:6]=3[CH:11]=2)[CH2:16]1)=[O:18]
Reactant: CN
Reactant: CN1C(=O)COc2cc(N3C[C@H](C(N)=O)OC3=O)ccc21
Solvent: CO
Product: CNC(=O)[C@H]1CN(c2ccc3c(c2)OCC(=O)N3C)C(=O)O1
Temperature: 25 °C
Reaction time: 3 h
Yield: 77.1 %

Procedure:
To a stirred suspension of (5R)-3-(3,4-dihydro-4-methyl-3-oxo-2H-1,4-benzoxazin-7-yl)-2-oxo-oxazolidine-5-carboxylic acid methyl ester (EXAMPLE 59, Step 3, 200 mg, 0.65 mmol) in MeOH (5 mL) is added MeNH2 (5 mL, 10 mmol, 2 M solution in MeOH). The resulting solution is stirred for 3 h at room temperature at which time the resulting white precipitate is filtered, washed with additional MeOH (5 mL), and dried under high vacuum to give the title compound (153 mg, 77%); 1H NMR (300 MHz, DMSO) δ 8.56 (br t, 1H), 7.50 (d, 1H), 7.41-7.33 (m, 2H), 5.23 (dd, 1H), 4.85 (s, 2H), 4.45 (dd, 1H), 4.15 (dd, 1H), 3.45 (s, 3H), 2.84 (d, 2H); MS for C14H15N3O5 m/z 306.5 (M+H)+.
Reaction SMILES: [CH:1]1[C:6](Cl)=[CH:5][CH:4]=[C:3]([Cl:8])[CH:2]=1.[NH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]1.CC[O-].[Na+]>C(O)C.O1CCOCC1>[Cl:8][C:3]1[CH:2]=[CH:1][C:6]([N:9]2[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10]2)=[CH:5][CH:4]=1
Reactant: C1CCNCC1
Reactant: Clc1ccc(Cl)cc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Solvent: C1COCCO1
Product: Clc1ccc(N2CCCCC2)cc1
Yield: 59 %

Procedure:
15 mmol of p-dichlorobenzene (2.2 g), 15.5 mmol of piperidine (1.3 g), 15.5 mmol of NaOEt solution in ethanol (10% by weight) and 50 mg of trans-di-μ-chlorobis[2-[bis(1,1-dimethylethyl)phosphino]-2-methylpropyl-C,P]dipallium(II) are suspended in 75 ml of dioxane and refluxed for 15 hours. After aqueous work-up, extraction with petroleum ether and drying over sodium sulfate, the solvents are removed under reduced pressure. This gives crude N-(4-chlorophenyl)piperidine as a light brown liquid which can be purified by distillation (boiling point: 50° C./0.08 torr); melting point: 69° C.; yield: 59%.
Reaction SMILES: Br[C:2]1[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([C:26]([F:30])=[C:27]([F:29])[CH:28]=1)[CH:24]=[O:25])([CH3:18])([CH3:17])[CH3:16].[Cl-].[NH4+]>O1CCCC1.O.C(OCC)(=O)C>[C:15]([Si:19]([CH3:34])([CH3:33])[O:20][C:21]1[C:22]([O:31][CH3:32])=[C:23]([CH:24]([C:2]2[C:3]([Cl:9])=[N:4][C:5]([Cl:8])=[N:6][CH:7]=2)[OH:25])[C:26]([F:30])=[C:27]([F:29])[CH:28]=1)([CH3:18])([CH3:17])[CH3:16]
Reactant: Clc1ncc(Br)c(Cl)n1
Reactant: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C=O
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Solvent: O
Product: COc1c(O[Si](C)(C)C(C)(C)C)cc(F)c(F)c1C(O)c1cnc(Cl)nc1Cl
Temperature: -30 °C
Reaction time: 0.33 h
Yield: 64.6 %

Procedure:
To a solution of 5-bromo-2,4-dichloropyrimidine (753.6 mg, 3.307 mmol, Matrix Chemicals) in tetrahydrofuran (20 mL) cooled to −30° C. was added dropwise isopropylmagnesium chloride. The temperature was maintained below −25° C. throughout the addition. At the end of addition, the reaction mixture was stirred at −30° C. for 20 minutes and a solution of 3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-benzaldehyde (1 g, 3.307 mmol, Example 266) in tetrahydrofuran was added dropwise. The temperature was maintained below −25° C. throughout the addition. The reaction mixture was allowed to warm up to 0° C. after the addition was completed. After being stirred at 0° C. for 45 minutes, saturated solution of ammonium chloride (˜3 mL) was added. The mixture was taken up in water and ethyl acetate. The aqueous layer was extracted with ethyl acetate. The combined organic layers were washed with brine and dried over anhydrous magnesium sulfate. The solids were filtered off and the filtrate was concentrated in vacuo. Purification of the crude residue by flash chromatography (Biotage system, 60 Å silica gel, eluting with 5-10% ethyl acetate in hexanes) yielded [3-(tert-butyl-dimethyl-silanyloxy)-5,6-difluoro-2-methoxy-phenyl]-(2,4-dichloro-pyrimidin-5-yl)-methanol as white solids (965 mg, 65%). LR-MS (M+) 451.1.