Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1](C(OCC1C2C(=CC=CC=2)C2C1=CC=CC=2)=O)([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:16]=[CH:15][C:14]([O:17]CC2C=CC=CC=2)=[CH:13][CH:12]=1)=[O:7])[CH:3]([CH3:5])[CH3:4].[H][H]>CO.C(OCC)(=O)C.[OH-].[Pd+2].[OH-].[C]>[NH:1]([CH3:29])[C@H:2]([C:6]([N:8]([CH3:28])[C@H:9]([C:25]([NH2:27])=[O:26])[CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)=[O:7])[CH:3]([CH3:5])[CH3:4]
Reactant: CC(C)[C@@H](C(=O)N(C)[C@@H](Cc1ccc(OCc2ccccc2)cc1)C(N)=O)N(C)C(=O)OCC1c2ccccc2-c2ccccc21
Reactant: [H][H]
Agent: [Pd+2]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CO
Product: CN[C@H](C(=O)N(C)[C@@H](Cc1ccc(O)cc1)C(N)=O)C(C)C
Yield: 54.5 %

Procedure:
Fmoc-N-Me-Val-N-Me-Tyr(Bzl)-NH2(802 mg, 1.29 mmol) was dissolved in a mixed solution of MeOH (6 ml) and ethyl acetate (6 ml), mixed with 20% palladium hydroxide-carbon (150 mg), followed by stirring in a hydrogen atmosphere at room temperature for 2 days. The mixture was filtered and the filtrate was concentrated under reduced pressure; the thus obtained residue was subjected to silica gel column chromatography (developing solvent: chloroform:methanol 10:1) to give the titled compound (216 mg, 55%).
Reaction SMILES: P(Cl)(Cl)(Cl)=O.CN(C)[CH:8]=[O:9].[CH3:11][S:12][C:13]1[N:18]=[CH:17][C:16]2=[CH:19][CH:20]=[CH:21][N:15]2[N:14]=1.BrC1N2C(C=NC(SC)=N2)=CC=1>>[CH3:11][S:12][C:13]1[N:18]=[CH:17][C:16]2=[CH:19][CH:20]=[C:21]([CH:8]=[O:9])[N:15]2[N:14]=1
Reactant: CSc1ncc2cccn2n1
Reactant: CN(C)C=O
Agent: CSc1ncc2ccc(Br)n2n1
Solvent: O=P(Cl)(Cl)Cl
Product: CSc1ncc2ccc(C=O)n2n1
Temperature: 80 °C
Yield: 78.6 %

Procedure:
To a cooled (0° C.) mixture of Phosphoryl chloride (55 mL, 0.59 mol) and N,N-Dimethylformamide (27 mL, 0.35 mol) was added 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine (3.70 g, 0.0224 mol) in N,N-Dimethylformamide (55 mL, 0.71 mol). The addition was added to ensure that the temperature of the reaction stayed below 20° C. After complete addition of 7-Bromo-2-methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine, the mixture was heated at 80° C. and was allowed to stir until HPLC showed consumption of starting material (−1 hour). The reaction was then poured over ice water and was neutralized with saturated sodium bicarbonate. Organics were then extracted with ethyl acetate and combined extracts were dried over magnesium sulfate, filtered and reduced to afford 3.40 g of 2-Methylsulfanyl-pyrrolo[2,1-f][1,2,4]triazine-7-carbaldehyde which was used without further purification. 1H NMR (400 MHz, DMSO, d6) δ 10.41 (s, 1H), 9.25 (s, 1H), 7.43 (d, 1H, J=4.96 Hz), 7.05 (d, 1H, J=5.00 Hz), 2.59 (s, 3H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:23])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[NH:17][C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:14])([F:13])[F:12])[CH:10]=1.Br[CH2:25][C:26]1[CH:31]=[C:30]([C:32]([F:35])([F:34])[F:33])[CH:29]=[CH:28][C:27]=1[I:36]>C1COCC1>[F:23][C:4]([F:3])([F:22])[C:5]1[CH:6]=[C:7]([C@H:15]2[O:19][C:18](=[O:20])[N:17]([CH2:25][C:26]3[CH:31]=[C:30]([C:32]([F:33])([F:35])[F:34])[CH:29]=[CH:28][C:27]=3[I:36])[C@H:16]2[CH3:21])[CH:8]=[C:9]([C:11]([F:12])([F:13])[F:14])[CH:10]=1
Reactant: C[C@@H]1NC(=O)O[C@@H]1c1cc(C(F)(F)F)cc(C(F)(F)F)c1
Reactant: FC(F)(F)c1ccc(I)c(CBr)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: C[C@H]1[C@@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)OC(=O)N1Cc1cc(C(F)(F)F)ccc1I
Temperature: 25 °C
Reaction time: 14 h
Yield: 82.4 %

Procedure:
To a stirred suspension of sodium hydride (60% dispersion in mineral oil; 1.3 g; 0.0325 mol) in THF (60 mL) at 0° C. under N2 was added dropwise a solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-4-methyl-1,3-oxazolidin-2-one (Example 17) (4.077 g; 0.013 mol) in THF (50 mL). Gas evolution was observed. The resultant mixture stirred at 0° C. for 30 min prior to addition of a solution of 2-(bromomethyl)-1-iodo-4-(trifluoromethyl)benzene (4.754 g; 0.013 mol) in THF (20 mL). The reaction was allowed to warm to room temperature and stirred for 14 h. The reaction was carefully quenched with H2O (15 mL) and partitioned between EtOAc (250 mL) and H2O (75 mL). The aqueous layer was extracted with EtOAc (3×100 mL). Combined organic layers were washed with brine (100 mL), dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by flash chromatography (0-20% EtOAc/hexanes gradient) to afford 6.4 g (82.5%) of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-[2-iodo-5-(trifluoromethyl)benzyl]4-methyl-1,3-oxazolidin-2-one as a white solid. LCMS=598.1 (M+1)+. 1H NMR (CDCl3, 500 MHz): δ 8.03 (d, J=8.2 Hz, 1H), 7.90 (s, 1H), 7.79 (s, 2H), 7.58 (s, 1H), 7.30 (dd, J=8.2 Hz, J=2.0 Hz, 1H), 5.76 (d, J=8 Hz, 1H), 4.88 (d, J=15.8 Hz, 1H), 4.37 (d, J=15.8 Hz, 1H), 4.09-4.02 (m, 1H), 0.8 (d, J=6.6 Hz, 3H).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:43])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[CH:17][C:16]=3[F:38])[C:10]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:9]2)[CH:7]=1.[C:44](Cl)(=[O:46])[CH3:45]>>[C:44]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:43])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([C:21]4[CH:26]=[C:25]([CH2:27][CH2:28][CH3:29])[CH:24]=[CH:23][C:22]=4[S:30](=[O:37])(=[O:36])[NH:31][C:32]([CH3:35])([CH3:33])[CH3:34])=[CH:17][C:16]=3[F:38])[C:10]([CH2:39][CH2:40][CH2:41][CH3:42])=[N:9]2)[CH:7]=1)(=[O:46])[CH3:45]
Reactant: CC(=O)Cl
Reactant: CCCCc1nn(-c2cc(N)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Product: CCCCc1nn(-c2cc(NC(C)=O)ccc2Cl)c(=O)n1Cc1ccc(-c2cc(CCC)ccc2S(=O)(=O)NC(C)(C)C)cc1F
Yield: 88 %

Procedure:
The reaction of 2-(5-amino-2-chlorophenyl)-5-n-butyl-4-[[2'-(N-t-butylsulfamoyl)-3-fluoro-5'-n-propylbiphenyl-4-yl]methyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (from Step C) with acetyl chloride was carried out according to the procedure of Example 69, affording an 88% yield of the title compound as a cream-colored solid, mp 125°-128° C.; satisfactory purity by TLC in 95:5 CH2Cl2 --MeOH; mass spectrum (FAB) m/e 676 (M+Li)+.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:11]=[C:10]([Cl:12])[S:9][C:8]=1[Cl:13].C([O:17][B:18](OC(C)C)[O:19]C(C)C)(C)C.Cl>CCCCCC.CCOCC>[Cl:13][C:8]1[S:9][C:10]([Cl:12])=[CH:11][C:7]=1[B:18]([OH:19])[OH:17]
Reactant: Clc1cc(Br)c(Cl)s1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: OB(O)c1cc(Cl)sc1Cl
Reaction time: 1 h

Procedure:
n-Butyllithium in hexane (1.66M solution, 5.2 ml) was added dropwise to a solution of 3-bromo-2,5-dichlorothiophene (2.0 g) and triisopropoxyborane (2.4 ml) in ether (20.0 ml) at -75-65° C. for 10 minutes and the mixture was stirred at same temperature for 1 hour. The reaction mixture was poured onto 1N-hydrochloric acid (30 ml) and the mixture was extracted with ether. The separated extract layer was washed with brine, dried over magnesium sulfate and evaporated in vacuo to give (2,5-dichlorothiophen-3-yl)-dihydroxyborane (1.13 g).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]([CH:17]([C:24]2[CH:29]=[CH:28][C:27]([OH:30])=[CH:26][CH:25]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.[OH-].[K+].[CH2:33](Br)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46].O>C(O)C>[CH2:33]([O:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:15]([CH:17]([C:24]2[CH:25]=[CH:26][C:27]([O:30][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:15][CH2:8][CH2:5][CH2:4][CH2:3][CH2:2][CH2:7][CH3:6])=[CH:28][CH:29]=2)[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:16])[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:4][CH:3]=1)[CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][CH3:46]
Reactant: O=C(C(c1ccccc1)c1ccc(O)cc1)C(c1ccccc1)c1ccc(O)cc1
Reactant: CCCCCCCCCCCCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCCCCCCCCCCCCCOc1ccc(C(C(=O)C(c2ccccc2)c2ccc(OCCCCCCCCCCCCCC)cc2)c2ccccc2)cc1
Reaction time: 12 h
Yield: 167 %

Procedure:
To a solution of 4-hydroxyphenyl-benzyl ketone (10.5 g) in a solution of potassium hydroxide (3.0 g) in ethanol (100 ml) was added tetradecylbromide (16 g). The reaction mixture was stirred at gentle reflux temperature for 12 hours, cooled and poured into water. The product was extracted into chloroform, washed further with water, dried over MgSO4, filtered and evaporated. Recrystallisation of the residue from methanol gave the above compound as a colourless crystalline solid (17.5 g, 86%) m.p. 72°-74° C.
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26](O)=[O:27])=[CH:22][N:21]([C:29]4[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1.CN1CCOCC1.Cl.C(N=C=NCCCN(C)C)C.O.ON1C2C=CC=CC=2N=N1.O[N:71]=[C:72]([NH2:76])[CH2:73][CH2:74][CH3:75]>O.CN(C)C=O>[O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:39])=[C:9]([CH2:11][O:12][C:13]2[CH:36]=[CH:35][C:16]([CH2:17][O:18][C:19]3[C:23](/[CH:24]=[CH:25]/[C:26]4[O:27][N:76]=[C:72]([CH2:73][CH2:74][CH3:75])[N:71]=4)=[CH:22][N:21]([C:29]4[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=4)[N:20]=3)=[CH:15][C:14]=2[O:37][CH3:38])[N:10]=1
Reactant: CCCC(N)=NO
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2/C=C/C(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CCCc1noc(/C=C/c2cn(-c3ccccc3)nc2OCc2ccc(OCc3nc(-c4ccco4)oc3C)c(OC)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 17.8 %

Procedure:
A mixture of (2E)-3-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}-2-propenoic acid (0.60 g), 4-methylmorpholine (0.28 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.21 g), 1-hydroxybenzotriazole monohydrate (0.17 g) and N,N-dimethylformamide (30 mL) was stirred at room temperature for 30 min, N′-hydroxybutanimidamide (0.14 g) was added, and the mixture was further stirred at room temperature for 15 hrs. Water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. Xylene (50 mL) was added to the residue, and the mixture was heated under reflux for 24 hrs. The reaction mixture was concentrated, and the obtained residue was subjected to silica gel column chromatography to give 5-((E)-2-{3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}ethenyl)-3-propyl-1,2,4-oxadiazole as colorless crystals (0.12 g, yield 18%) from a fraction eluted with ethyl acetate-hexane (1:2, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 192-193° C.
Reaction SMILES: [Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH3:11][O:12][C:13]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[CH:22][C:14]=1[CH2:15][NH:16][C:17]1[S:21][N:20]=[CH:19][N:18]=1.[Br:28][C:29]1[C:30]([S:39](Cl)(=[O:41])=[O:40])=[CH:31][C:32]2[O:36][C:35](=[O:37])[NH:34][C:33]=2[CH:38]=1>C1COCC1>[Br:28][C:29]1[C:30]([S:39]([N:16]([CH2:15][C:14]2[CH:22]=[CH:23][C:24]([O:26][CH3:27])=[CH:25][C:13]=2[O:12][CH3:11])[C:17]2[S:21][N:20]=[CH:19][N:18]=2)(=[O:40])=[O:41])=[CH:31][C:32]2[O:36][C:35](=[O:37])[NH:34][C:33]=2[CH:38]=1
Reactant: COc1ccc(CNc2ncns2)c(OC)c1
Reactant: O=c1[nH]c2cc(Br)c(S(=O)(=O)Cl)cc2o1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ncns2)S(=O)(=O)c2cc3oc(=O)[nH]c3cc2Br)c(OC)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Added LHMDS (1603 μl, 1.603 mmol, 1M in THF) to 1-3 (422 mg, 1.679 mmol) in THF (1908 μl) at −78° C. Removed cooling bath and stirred at RT for 30 min. Cooled back to −78 C and slowly added the 35-2 (159 mg, 0.509 mmol) in THF (636 μl). The resulting reaction mixture was allowed to slowly warm to RT while remaining in bath. After 2 h, quenched with 5 mL saturated NH4Cl and diluted with 10 mL EtOAc. Separated layers, back-extracted aqueous with 3×5 mL EtOAc. Dried over Na2SO4, filtered, concentrated to give a clear, orange oil. Purified by normal-phase HPLC (40 g ISCO column, 0-50% EtOAc:Hex) to give 35-3 as a white solid.
Reaction SMILES: [CH3:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([CH3:10])[C:3]=1[CH2:4][OH:5].[C:11](OC(=O)C)(=[O:13])[CH3:12]>CN(C)C1C=CN=CC=1>[C:11]([O:5][CH2:4][C:3]1[C:6]([CH3:10])=[CH:7][CH:8]=[CH:9][C:2]=1[CH3:1])(=[O:13])[CH3:12]
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cccc(C)c1CO
Agent: CN(C)c1ccncc1
Product: CC(=O)OCc1c(C)cccc1C
Temperature: 70 °C
Reaction time: 5 h

Procedure:
To a mixture of 2,6-dimethylbenzyl alcohol (17.1 g) and acetic anhydride (14.2 ml) was added 4-dimethylaminopyridine (17 mg), and the mixture was stirred at 70° C. for 5 hours. After cooling, the mixture was concentrated in vacuo, and ethyl acetate was added to the residue. The solution was washed with water, dried over magnesium sulfate and evaporated in vacuo to give 2,6-dimethylbenzyl acetate (22.5 g) as colorless oil.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[N:5][N:4]=[N:3]1.C([Mg]Cl)(C)C.[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16]([CH:23]=[CH:24][CH:25]=1)[C:17](N(OC)C)=[O:18].Cl>C1COCC1>[CH3:12][N:13]([CH3:26])[C:14]1[CH:15]=[C:16]([C:17]([C:6]2[N:2]([CH3:1])[N:3]=[N:4][N:5]=2)=[O:18])[CH:23]=[CH:24][CH:25]=1
Reactant: CON(C)C(=O)c1cccc(N(C)C)c1
Reactant: Cn1cnnn1
Agent: CC(C)[Mg]Cl
Agent: Cl
Solvent: C1CCOC1
Product: CN(C)c1cccc(C(=O)c2nnnn2C)c1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 25 %

Procedure:
To a stirred solution of 1-methyl-1H-tetrazole (4.54 g, 54 mmol) in anhydrous THF (200 mL), cooled to 0° C. with a brine/ice bath, was added dropwise a solution of isopropylmagnesium chloride (2 M in THF, 27 mL, 54 mmol). After the addition was over, the resulting cloudy suspension was stirred for 15 min at 0° C. A solution of 3-(dimethylamino)-N-methoxy-N-methylbenzamide (9.37 g, 45 mmol) in THF (80 mL) was then added dropwise while keeping the internal temperature below 5° C. The reaction mixture was then allowed to warm up and stirred at room temperature for 1 h. A mixture of ice-cold water (50 mL) and aq. HCl (1 M, 55 mL) was added to the reaction mixture, the layers were separated, the water phase was extracted with ethyl acetate (3×50 mL) and the combined organic layers were dried. Purification on silica gel followed by recrystallization from diethyl ether afforded [3-(dimethylamino)phenyl](1-methyl-1H-tetrazol-5-yl)methanone as a bright yellow solid [3.06 g, yield 25%; HPLC/MS m/z=232 (M+H); logP(HCOOH)=2.21].
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([C:11]2[CH:16]=[C:15]([S:17]([NH:20][CH3:21])(=O)=[O:18])[C:14]([Cl:22])=[CH:13][C:12]=2[O:23][CH3:24])[N:8]=[C:7]2[C:3]=1[NH:4][CH:5]=[N:6]2.[OH-:25].[K+]>>[Cl:22][C:14]1[C:15]([S:17]([NH:20][CH3:21])=[O:18])=[CH:16][C:11]([C:9]2[N:10]=[C:2]3[C:7](=[N:6][CH:5]=[N:4][C:3]3=[O:25])[N:8]=2)=[C:12]([O:23][CH3:24])[CH:13]=1
Reactant: [OH-]
Reactant: CNS(=O)(=O)c1cc(-c2nc(Cl)c3[nH]cnc3n2)c(OC)cc1Cl
Agent: [K+]
Product: CNS(=O)c1cc(C2=NC3=NC=NC(=O)C3=N2)c(OC)cc1Cl

Procedure:
Prepared analogously to Example 16 from 6-chloro-(4-chloro-2-methoxy-5-methylaminosulfonyl-phenyl)-purine with 20% potassium hydroxide solution.
Reaction SMILES: [C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([N+:26]([O-])=O)=[CH:22][C:21]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:19])=[O:18])[CH:9]([O:13][CH2:14][CH3:15])[O:10][CH2:11][CH3:12])([CH3:4])([CH3:3])[CH3:2].[H][H]>[Ni].O1CCCC1>[C:1]([O:5][C:6](=[O:37])[CH2:7][C@H:8]([NH:16][S:17]([C:20]1[CH:25]=[CH:24][C:23]([NH2:26])=[CH:22][C:21]=1[O:29][CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)(=[O:19])=[O:18])[CH:9]([O:10][CH2:11][CH3:12])[O:13][CH2:14][CH3:15])([CH3:3])([CH3:4])[CH3:2]
Reactant: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc([N+](=O)[O-])cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Ni]
Solvent: C1CCOC1
Product: CCOC(OCC)[C@H](CC(=O)OC(C)(C)C)NS(=O)(=O)c1ccc(N)cc1OCc1ccccc1
Yield: 100 %

Procedure:
A mixture of 11.7 g (21.72 mmol) of (S)-3-(2-benzyloxy-4-nitro-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester, 2 g Raney Ni, and 200 mL tetrahydrofuran was shaken under a 50 psi hydrogen atomosphere for 16 h at room temperature. TLC analysis indicated complete reaction. The catalyst was filtered and the resulting solution was concentrated to give 11.2 g (21.72 mmol, 100%) of (S)-3-(4-amino-2-benzyloxy-benzenesulfonylamino)-4,4-diethoxy-butyric acid tert-butyl ester as a brown oil. MS (APCI) m/z 507 (M−1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:9]2[O:15][CH2:14][CH2:13][N:12]([C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17])[CH2:11][C@H:10]2[CH:23]=[O:24])[CH:5]=[CH:6][C:7]=1[Cl:8].Cl([O-])=[O:26].[Na+].P([O-])(O)(O)=O.[K+]>CC(=CC)C.C(O)(C)(C)C.C1COCC1.O.C(OCC)(=O)C>[C:19]([O:18][C:16]([N:12]1[CH2:11][C@@H:10]([C:23]([OH:26])=[O:24])[C@H:9]([C:4]2[CH:5]=[CH:6][C:7]([Cl:8])=[C:2]([Cl:1])[CH:3]=2)[O:15][CH2:14][CH2:13]1)=[O:17])([CH3:20])([CH3:21])[CH3:22]
Reactant: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C=O)C1
Reactant: [O-][Cl+][O-]
Agent: CC=C(C)C
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCO[C@@H](c2ccc(Cl)c(Cl)c2)[C@H](C(=O)O)C1
Yield: 92 %

Procedure:
To a mixed solution of tert-butyl (6R,7R)-7-(3,4-dichlorophenyl)-6-formyl-1,4-oxazepane-4-carboxylate (7.3 g) in 2-methyl-2-butene (45 mL), tert-butanol (100 ml) and THF (100 ml) was added dropwise a solution of sodium chlorite (10.58 g) and potassium dihydrogenphosphate (16.38 g) in water (160 ml) under ice-cooling, and the mixture was stirred under ice-cooling for 2 hr. The reaction mixture was diluted with ethyl acetate. The diluted solution was washed with distilled water and brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (7.0 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH2:10])[CH3:9])[CH:5]=[CH:6][CH:7]=1.F[C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[N+:19]([O-:21])=[O:20].C(N(CC)C(C)C)(C)C>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([NH:10][C:12]2[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=2[N+:19]([O-:21])=[O:20])[CH3:9])[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(F)cc1F
Reactant: CC(N)c1cccc(Cl)c1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: CC(Nc1cc(F)ccc1[N+](=O)[O-])c1cccc(Cl)c1
Yield: 57.3 %

Procedure:
1-(3-Chlorophenyl)ethanamine (553 mg, 3.55 mmol), 2,4-difluoronitrobenzene (565 mg, 3.55 mmol) and N,N-diisopropylethylamine (918 mg, 7.10 mmol) were stirred at room temperature in dry acetonitrile (20 mL) for 6 h. The solvent was evaporated and the residue was dissolved in dichloromethane and washed with water. The dichloromethane was evaporated to collect the title compound (600 mg, 57% yield). 1H NMR (400 MHz, CDCl3): δ 8.49 (s, 1H), 8.23 (m, 1H), 7.04 (m, 4H), 6.36 (t, 1H), 6.22 (d, 1H), 4.56 (m, 1H), 1.64 (d, 3H); MS (ESI) m/z: Calculated for C14H13ClFN2O2: 295.06; Observed: 295.0 (M++1).
Reaction SMILES: [CH2:1]1[N:6]([CH2:7][CH2:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][C:15]3[CH:18]=[CH:19][C:20]([NH:22][C:14]=3[CH:13]=2)=[O:21])[CH2:5][CH2:4][N:3]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=2[Cl:30])[CH2:2]1.C(N(CC)CC)C.[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](Cl)=[O:42])[CH3:39]>O1CCCC1>[CH2:38]([N:40]([CH2:44][CH3:45])[C:41](=[O:42])[O:21][C:20]1[CH:19]=[CH:18][C:15]2[C:14](=[CH:13][C:12]([O:11][CH2:10][CH2:9][CH2:8][CH2:7][N:6]3[CH2:5][CH2:4][N:3]([C:23]4[CH:28]=[CH:27][CH:26]=[C:25]([Cl:29])[C:24]=4[Cl:30])[CH2:2][CH2:1]3)=[CH:17][CH:16]=2)[N:22]=1)[CH3:39]
Reactant: CCN(CC)C(=O)Cl
Reactant: O=c1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2[nH]1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCN(CC)C(=O)Oc1ccc2ccc(OCCCCN3CCN(c4cccc(Cl)c4Cl)CC3)cc2n1
Temperature: 100 °C

Procedure:
A mixture of dehydro-aripiprazole (1.50 g, 3.36 mmol), triethylamine (1.03 mL, 7.39 mmol), diethyl carbamoyl chloride (1.02 mL) were combined in tetrahydrofuran (30 mL). This was then heated to 100° C. for 6 hours by microwave. The reaction was quenched with water (50 mL) and extracted with dichloromethane (2×100 mL). The combined organics were dried (MgSO4) and concentrated. The crude product was purified by column chromatrography on silica eluting with ethyl acetate to 20% tetrahydrofuran/ethyl acetate to give the product. The product was then triturated with heptane to remove aliphatic impurities and then dried to give Compound-334 (1.54 g) as a light brown oil.
Reaction SMILES: [NH:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[S:12]([NH:15][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([CH:20]4[CH2:30][CH:21]4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:14])=[O:13])[CH2:2]1.I[CH2:32][CH3:33].C(=O)([O-])[O-].[K+].[K+]>C(#N)C>[CH2:32]([N:1]1[CH2:4][CH:3]([C:5]2[CH:10]=[C:9]([F:11])[CH:8]=[CH:7][C:6]=2[S:12]([NH:15][C:16]2[C:25]([C:26]([O:28][CH3:29])=[O:27])=[C:24]3[C:19]([CH:20]4[CH2:30][CH:21]4[CH2:22][O:23]3)=[CH:18][CH:17]=2)(=[O:13])=[O:14])[CH2:2]1)[CH3:33]
Reactant: CCI
Reactant: COC(=O)c1c(NS(=O)(=O)c2ccc(F)cc2C2CNC2)ccc2c1OCC1CC21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: CCN1CC(c2cc(F)ccc2S(=O)(=O)Nc2ccc3c(c2C(=O)OC)OCC2CC32)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 22.2 %

Procedure:
A mixture of methyl (1aRS,7bSR)-5-[2-(azetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa[c]chromene-4-carboxylate (Intermediate 87, 0.216 g), iodoethane (0.078 g) and potassium carbonate (0.138 g) in acetonitrile (5 mL) was stirred at room temperature for 18 hours. The mixture was evaporated to dryness and the residue was purified by chromatography on silica, eluting with a mixture of methanol and DCM with a gradient of 0-15% to give methyl (1aRS,7bSR)-5-[2-(1-ethylazetidin-3-yl)-4-fluorobenzenesulfonylamino]-1,1a,2,7b-tetrahydrocyclopropa-[c]chromene-4-carboxylate (0.051 g).
Reaction SMILES: Cl.[NH2:2][C@H:3]([CH3:15])[CH2:4][S:5][C:6]1[O:7][C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=1.C([O:19][C@@H:20]1[C@H:24]([O:25]C(=O)C)[C@@H:23]([CH2:29][O:30]C(=O)C)[O:22][C@H:21]1[N:34]1[CH:42]=[N:41][C:40]2[C:35]1=[N:36][C:37]([Cl:44])=[N:38][C:39]=2Cl)(=O)C.C[O-].[Na+]>CO>[O:7]1[C:8]2[CH:14]=[CH:13][CH:12]=[CH:11][C:9]=2[N:10]=[C:6]1[S:5][CH2:4][C@H:3]([NH:2][C:39]1[C:40]2[N:41]=[CH:42][N:34]([C:35]=2[N:36]=[C:37]([Cl:44])[N:38]=1)[C@@H:21]1[O:22][C@H:23]([CH2:29][OH:30])[C@@H:24]([OH:25])[C@H:20]1[OH:19])[CH3:15]
Reactant: C[C@@H](N)CSc1nc2ccccc2o1
Reactant: CC(=O)OC[C@H]1O[C@@H](n2cnc3c(Cl)nc(Cl)nc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: C[C@H](CSc1nc2ccccc2o1)Nc1nc(Cl)nc2c1ncn2[C@@H]1O[C@H](CO)[C@@H](O)[C@H]1O
Yield: 12.5 %

Procedure:
The title compound was prepared essentially according to method A as described above in Example 1 by reacting 2-[(R)-2-amino-1-propylthio]benzoxazole hydrochloride [prepared by alkylation of 2-mercaptobenzoxazole (3.5 g, 23 mmol) using methanesulphonic acid, 2-[(R)-N-tert-butyloxycarbonylamino]-1-propyl ester (7.2 g, 30 mmol) followed by acidic hydrolysis] (1.7 g, 6 mmol) with 9-(2,3,5-tri-O-acetyl-β-D-ribofuranosyl)-2,6-dichloro-9H-purine (2.7 g, 6.0 mmol), followed by deacylation of the purified product using sodium methoxide in methanol. This provided the title N-[(R)-1-(2-benzoxazolyl)thio2-propyl]-2-chloroadenosine (0.37 g, 28%) as a foam after column chromatography. 1H NMR (DMSO-d6) δ1.38 (3H, d, --CHCH3), 3.40-3.75 (4H, m, H-5'a and H-5'b and --CH2 --), 3.94 (1H, q, H-4), 4.12 (1H, q, H-3'), 4.52 (1H, m, H-2'), 5.06 (1H, t, 5'-OH), 5.22, 5.49 (2H, 2d, 2'- and 3'-OH), 5.82 (1H, d, H-1'), 7.26-7.35 (2H, m, Ar--H), 7.53-7.64 (2H, m, Ar--H), 8.39 (1H, s, H-8), 8.48 (1H, d, --NH).