Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH2:4].ClC(Cl)(O[C:28](=[O:34])OC(Cl)(Cl)Cl)Cl.Cl.[CH3:37][NH:38][CH3:39].CO>C(Cl)(Cl)Cl.C(N(CC)CC)C>[Cl:1][C:2]1[CH:8]=[C:7]([O:9][C:10]2[C:19]3[C:14](=[CH:15][C:16]([O:22][CH3:23])=[C:17]([O:20][CH3:21])[CH:18]=3)[N:13]=[CH:12][N:11]=2)[CH:6]=[CH:5][C:3]=1[NH:4][C:28](=[O:34])[N:38]([CH3:39])[CH3:37]
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1cc2ncnc(Oc3ccc(N)c(Cl)c3)c2cc1OC
Reactant: CNC
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COc1cc2ncnc(Oc3ccc(NC(=O)N(C)C)c(Cl)c3)c2cc1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 54.4 %

Procedure:
2-Chloro-4-[(6,7-dimethoxy-4-quinazolinyl)oxy]-aniline 50 mg) was dissolved in chloroform (2 ml) and triethylamine (0.5 ml), and a solution of triphosgene (48 mg) in chloroform was then added to the solution. The mixture was stirred at room temperature for 30 min. Next, the reaction solution was cooled to −78° C., and dimethylamine hydrochloride (250 mg) was added to the cooled reaction solution. The temperature of the mixture was spontaneously raised, and the mixture was further stirred at room temperature overnight. Methanol was added to the reaction solution, and the mixture was purified by HPLC by development with chloroform/methanol to give 33 mg (yield 53%) of the title compound.
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.C(N(C(C)C)CC)(C)C.[Cl:20][C:21]1[CH:26]=[C:25](Cl)[N:24]=[CH:23][N:22]=1>C(O)C>[Cl:20][C:21]1[N:22]=[CH:23][N:24]=[C:25]([N:8]2[CH2:9][CH2:10][C:5]3([O:4][CH2:3][CH2:2][O:1]3)[CH2:6][CH2:7]2)[CH:26]=1
Reactant: C1CC2(CCN1)OCCO2
Reactant: Clc1cc(Cl)ncn1
Solvent: CCO
Solvent: CCN(C(C)C)C(C)C
Product: Clc1cc(N2CCC3(CC2)OCCO3)ncn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.3 %

Procedure:
To a solution of 1,4-dioxa-8-azaspiro[4,5]decane (9.02 g) and diisopropylethylamine (9.77 g) in ethanol (30 ml) was added 4,6-dichloropyrimidine (9.88 g), and the mixture was stirred at room temperature for 1 hour. The reaction solution was concentrated, and the residue was diluted with dichloromethane (150 ml). The mixture was washed with 0.3N sodium hydroxide solution and saturated brine, dried and concentrated, and the residue was crystallized from diethylether to give colorless crystals of 8-(6-chloropyrimidine-4-yl)-1,4-dioxa-8-azaspiro[4,5]decane (15.84 g).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18]O)=[O:12])([CH3:9])([CH3:8])[CH3:7].C(N(CC)CC)C.[NH:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1>C(Cl)Cl.C1(C)C=CC=CC=1>[C:6]([O:10][C:11]([N:13]1[CH2:17][CH2:16][CH2:15][C@H:14]1[CH2:18][N:27]1[CH2:32][CH2:31][O:30][CH2:29][CH2:28]1)=[O:12])([CH3:7])([CH3:8])[CH3:9]
Reactant: CC(C)(C)OC(=O)N1CCC[C@H]1CO
Reactant: C1COCCN1
Agent: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N1CCC[C@H]1CN1CCOCC1
Temperature: 110 °C
Yield: 39.7 %

Procedure:
Methanesulfonyl chloride (1.7 g, 14.9 mmol) was added dropwise to a solution of (S)-2-hydroxymethyl-pyrrolidine-1-carboxylic acid tert-butyl ester (1.5 g, 7.45 mmol) and triethylamine (753 mg mg, 7.45 mmol) in CH2Cl2 at 0° C. After 3 h reaction mixture was concentrated to give a white solid. The resulting solid was suspended in toluene, morpholine (1.3 g, 14.9 mmol) was added, and the resulting mixture was heated to 110° C. in a sealed tube. After 12 h the reaction mixture was concentrated, the resulting residue was dissolved in EtOAc and water, the layers were separated, and the aqueous was further extracted with EtOAc. The combined organic extracts were dried over Na2SO4, and the material was purified on silica gel by flash column chromatography CH2Cl2/MeOH/NH4OH (98.5/1/0.5) to afford the title compound as a white solid (800 mg, 40%). MS: 271.2 (MH+); HPLC Rf: n.d.; HPLC purity: n.d.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([O:12][C:13]3[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]4[C:23](=[O:35])[N:24]([C:29]5[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=5)[N:25]([CH3:28])[C:26]=4[CH3:27])=[O:21])=[CH:15][C:14]=3[F:36])=[CH:7][CH:8]=[N:9]2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].CS(O[CH2:48][C@H:49]1[CH2:55][CH2:54][C:51]2([CH2:53][CH2:52]2)[O:50]1)(=O)=O>CN(C)C(=O)C>[CH2:52]1[C:51]2([CH2:54][CH2:55][C@H:49]([CH2:48][O:1][C:2]3[CH:11]=[C:10]4[C:5]([C:6]([O:12][C:13]5[CH:18]=[CH:17][C:16]([NH:19][C:20]([C:22]6[C:23](=[O:35])[N:24]([C:29]7[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=7)[N:25]([CH3:28])[C:26]=6[CH3:27])=[O:21])=[CH:15][C:14]=5[F:36])=[CH:7][CH:8]=[N:9]4)=[CH:4][CH:3]=3)[O:50]2)[CH2:53]1
Reactant: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(O)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Reactant: CS(=O)(=O)OC[C@H]1CCC2(CC2)O1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC(=O)N(C)C
Product: Cc1c(C(=O)Nc2ccc(Oc3ccnc4cc(OC[C@H]5CCC6(CC6)O5)ccc34)c(F)c2)c(=O)n(-c2ccccc2)n1C
Temperature: 40 °C
Reaction time: 72 h
Yield: 59.7 %

Procedure:
To a mixture of N-(4-(7-hydroxyquinolin-4-yloxy)-3-fluorophenyl)-2,3-dihydro-1,5-dimethyl-3-oxo-2-phenyl-1H-pyrazole-4-carboxamide (300 mg, 0.62 mmol) and cesium carbonate (1.0 g, 3.1 mmol, Aladdin) in N,N-dimethylacetamide (1 mL) was added ((5R)-4-oxaspiro[2.4]heptane-5-yl)methyl methanesulfonate (187.5 mg, 0.91 mmol) in 3 mL of N,N-dimethylacetamide. After stirring at 40° C. for 3 days, the reaction mixture was concentrated in vacuo and was chromatographed with a silica gel column (1:6 (v/v) n-hexane/EtOAc) to afford the title compound as a colorless solid (220 mg, 60%).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([C:13]([OH:23])=[C:14]([C:20](O)=[O:21])[N:15]=[C:16]2[Cl:19])=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:25][O:26][C:27](=[O:31])[C@H:28]([CH3:30])[NH2:29]>>[CH3:25][O:26][C:27](=[O:31])[C@@H:28]([NH:29][C:20]([C:14]1[N:15]=[C:16]([Cl:19])[C:17]2[C:12]([C:13]=1[OH:23])=[CH:11][CH:10]=[C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)[CH:18]=2)=[O:21])[CH3:30]
Reactant: COC(=O)[C@H](C)N
Reactant: O=C(O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O
Agent: Cl
Product: COC(=O)[C@H](C)NC(=O)c1nc(Cl)c2cc(OCc3ccccc3)ccc2c1O

Procedure:
7-Benzyloxy-1-chloro-4-hydroxy-isoquinoline-3-carboxylic acid, 0.33 g, was coupled with L-Alanine methyl ester hydrochloride, 0.150 g, analogously to Example A-1 a). 0.264 G of white solid were obtained: MS-(+)-ion, M+1=415. amu.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]2[CH2:21][CH2:20]2)[CH2:10][C:11]([O:13]C(C)(C)C)=[O:12])=[CH:5][C:4]=1[C:22]([F:25])([F:24])[F:23])#[N:2].C(O)(C(F)(F)F)=O.C([SiH](CC)CC)C>C(Cl)Cl>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]([CH2:18][CH:19]2[CH2:20][CH2:21]2)[CH2:10][C:11]([OH:13])=[O:12])=[CH:5][C:4]=1[C:22]([F:23])([F:25])[F:24])#[N:2]
Reactant: CC(C)(C)OC(=O)CN(CC1CC1)c1ccc(C#N)c(C(F)(F)F)c1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc(N(CC(=O)O)CC2CC2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 3 h
Yield: 69 %

Procedure:
A mixture of 1,1-dimethylethyl N-[4-cyano-3-(trifluoromethyl)phenyl]-N-(cyclopropylmethyl)glycinate (5.01 g, 14.1 mmol), TFA (50 mL), and triethylsilane (5 mL) in CH2Cl2 (50 mL) was stirred at ambient temperature for 3 h. When the TLC indicated no remaining starting material, the solvents were removed under reduced pressure, and the residue was stirred in hexane (50 mL) for 12 hours. The solid precipitate was filtered and dried to obtain 2.9 g (71%) of the title compound as a white solid: 1H NMR (400 MHz, CDCl3) δ 7.61 (d, J=8.8 Hz, 1H), 6.97 (d, J=2.8 Hz, 1H), 6.78 (dd, J=8.8, 2.8 Hz, 1H), 4.29 (s, 2H), 3.34 (d, J=6.4 Hz, 2H), 1.37 (m, 1H), 0.64 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[C:18]([B:23]2[O:27]C(C)(C)C(C)(C)[O:24]2)[CH:17]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:51]([O:56]C(C)(C)C)(=[O:55])[C@@H:52]([CH3:54])O>C1COCC1>[B:23]([C:18]1[CH:17]=[C:16]([Cl:15])[CH:21]=[CH:20][C:19]=1[O:22][C@@H:52]([CH3:54])[C:51]([OH:56])=[O:55])([OH:24])[OH:27]
Reactant: C[C@@H](O)C(=O)OC(C)(C)C
Reactant: CC1(C)OB(c2cc(Cl)ccc2O)OC1(C)C
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: C[C@H](Oc1ccc(Cl)cc1B(O)O)C(=O)O

Procedure:
DIAD (3 ml) was added to a mixture of the product from step b) (3.51 g), triphenyl phosphine (3.98 g), tert-butyl (R)-(+) lactate (2.02 g) and THF (80 ml) at 0° C. overnight. The mixture was concentrated in vacuo. The residue was purified by flash column chromatography eluting with isohexane:ethyl acetate (7:3) to give the sub-title compound (4 g). The intermediate obtained was dissolved in acetone and 1M HCl (15 ml) was added, stirred for 20 min, then concentrated in vacuo. Redissolved in dichloromethane (10 ml) and added TFA (5 ml). Stirred for 2 h, then added water (1 ml), stirred for 1 h. The reaction mixture was then diluted (water) and made alkaline by adding dilute NaOH. The organic layer was separated and discarded. The aqueous phase was acidified with concentrated HCl to pH1, then washed with dichloromethane (×2). These organic extracts were dried (MgSO4) then concentrated in vacuo to give the sub-title compound. Yield 1.4 g
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].C[Li].FC([I:19])(F)F.O>C1COCC1.C(OCC)C>[Cl:1][C:2]1[N:10]=[C:9]([Cl:11])[C:8]([F:12])=[C:7]([I:19])[C:3]=1[C:4]([OH:6])=[O:5]
Reactant: FC(F)(F)I
Reactant: O=C(O)c1cc(F)c(Cl)nc1Cl
Agent: [Li]C
Solvent: C1CCOC1
Solvent: O
Solvent: CCOCC
Product: O=C(O)c1c(Cl)nc(Cl)c(F)c1I
Temperature: -25 °C
Reaction time: 1.5 h

Procedure:
A solution of 2,6-dichloro-5-fluoronicotinic acid (10 g) in THF (100 mL) at −78° C. was treated with 1.6M methyllithium in diethyl ether (62.5 mL), stirred at −25° C. for 1.5 hours, cooled to −78° C., treated with trifluoromethyl iodide (22.6 g) over 30 minutes, stirred at −78° C. for 1.5 hours, −25° C. for 1.5 hours, and 0° C. for two hours, treated with water, concentrated to remove the organic solvents, washed with diethyl ether, acidified with 1M HCl, and extracted with diethyl ether; and the extract was dried (Na2SO4), filtered, and concentrated.
Reaction SMILES: [C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH2:20])=[C:8]([CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])=[O:10])(=[O:3])[CH3:2].[CH3:21][S:22](Cl)(=[O:24])=[O:23].N1C=CC=CC=1>C1C=CC=CC=1>[C:1]([C:4]1[CH:5]=[CH:6][C:7]([NH:20][S:22]([CH3:21])(=[O:24])=[O:23])=[C:8]([C:9](=[O:10])[C:11]2[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=2[F:18])[CH:19]=1)(=[O:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)c1ccc(N)c(C(=O)c2ccc(F)cc2F)c1
Solvent: c1ccccc1
Solvent: c1ccncc1
Product: CC(=O)c1ccc(NS(C)(=O)=O)c(C(=O)c2ccc(F)cc2F)c1
Temperature: 0 °C

Procedure:
A mixture of 5-acetyl-2-amino-2',4'-difluorobenzophenone (3.3 g), methanesulfonyl chloride (5.5 ml) and pyridine (1 ml) in benzene (30 ml) was refluxed for 4 hours. The reaction mixture was poured into ice-water (100 ml ) and extracted with ethyl acetate (100 ml). The extract was washed with an aqueous solution of sodium bicarbonate, dried and concentrated. The residue (5 g) was purified by column chromatography on silica gel (120 g) eluting with a mixture of toluene and ethyl acetate (20:1), and recrystallized from ethanol to afford yellow crystals of 4'-acetyl-2'-(2,4-difluorobenzoyl)methanesulfonanilide (1.5 g).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][C:14]([OH:16])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(Cl)CCl.C1C=CC2N(O)N=NC=2C=1.[O:32]([CH2:43][CH2:44][NH:45][CH2:46][CH2:47][O:48][C@@H:49]1[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51])[C@@H:33]1[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]1[OH:35]>CN(C=O)C>[C@@H:49]1([O:48][CH2:47][CH2:46][N:45]([CH2:44][CH2:43][O:32][C@@H:33]2[O:41][C@@H:40]([CH3:42])[C@@H:38]([OH:39])[C@@H:36]([OH:37])[C@@H:34]2[OH:35])[C:14](=[O:16])[CH2:13][CH2:12][CH2:11][CH2:10][C:9]([O:8][CH2:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[O:17])[O:57][C@@H:56]([CH3:58])[C@@H:54]([OH:55])[C@@H:52]([OH:53])[C@@H:50]1[OH:51]
Reactant: O=C(O)CCCCC(=O)OCc1ccccc1
Reactant: C[C@@H]1O[C@@H](OCCNCCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)[C@@H](O)[C@H](O)[C@@H]1O
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: ClCCCl
Product: C[C@@H]1O[C@@H](OCCN(CCO[C@@H]2O[C@@H](C)[C@@H](O)[C@@H](O)[C@@H]2O)C(=O)CCCCC(=O)OCc2ccccc2)[C@@H](O)[C@H](O)[C@@H]1O
Reaction time: 16 h

Procedure:
To a solution of 6-(benzyloxy)-6-oxohexanoic acid (40 mg, 0.169 mmol), EDC (114 mg, 0.593 mmol) and HOBt (2.59 mg, 0.017 mmol) in DMF (5 mL) at rt was added 2-({2-[(α-L-fucopyranosyl)oxy]ethyl}amino)ethyl α-L-fucopyranoside (190 mg, 0.478 mmol). After stirring for 16 hr, the reaction mixture was concentrated and the residue was purified by flash chromatography on C18 reverse phase silica gel (50 g), eluting with 5-40% AcCN in water to give the title compound. UPLC Method B: m/e=616.2923 [M+1]; Rt=3.114 min. 1H NMR (CD3OD) δ 1.24 (6H, d, J=6.58), 1.72-1.64 (4H, m), 2.45 (2H, t, J=7.11), 2.53 (2H, t, J=7.32), 3.91-3.55 (17H, m), 4.78-4.75 (2H, m), 5.14 (2H, s), 7.38-7.37 (5H, m).
Reaction SMILES: O[CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16].C(N(CC)CC)C.S(Cl)([Cl:26])=O>C(Cl)(Cl)Cl>[Cl:26][CH2:2][N:3]1[C:8]2[CH:9]=[C:10]([N+:13]([O-:15])=[O:14])[CH:11]=[CH:12][C:7]=2[O:6][CH2:5][C:4]1=[O:16]
Reactant: O=C1COc2ccc([N+](=O)[O-])cc2N1CO
Reactant: O=S(Cl)Cl
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: O=C1COc2ccc([N+](=O)[O-])cc2N1CCl
Temperature: 25 °C

Procedure:
To a suspension of 4-hydroxymethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (22.42 g) in chloroform (50 ml) is added a catalytic amount of triethylamine. The mixture is stirred at ambient temperature, treated dropwise with thionyl chloride, and stirred at 60° C. for 6 hours. The reaction mixture is made free form insoluble materials by filtration and the filtrate is poured into water. The separated chloroform layer is washed with water, saturated sodium bicarbonate solution and saturated sodium chloride solution successively, dried, and evaporated to obtain 4-chloromethyl-6-nitro-2H-1,4-benzoxazin-3(4H)-one (17.23 g).
Reaction SMILES: C(OC(=O)C)(=O)C.[N+]([O-])(O)=O.C(=O)(O)[O-].[Na+].[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH2:34]S(CCO)=O)=[O:31])[CH:23]=[CH:22]2>C(OCC)(=O)C>[CH3:17][O:18][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[CH:25]=[C:24]([C@H:29]([CH3:40])[C:30]([O:32][CH2:33][CH3:34])=[O:31])[CH:23]=[CH:22]2
Reactant: COc1ccc2cc([C@H](C)C(=O)OCCS(=O)CCO)ccc2c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)OC(C)=O
Solvent: O=[N+]([O-])O
Solvent: CCOC(C)=O
Product: CCOC(=O)[C@@H](C)c1ccc2cc(OC)ccc2c1
Temperature: 25 °C
Yield: 22 %

Procedure:
To acetic anhydride (9.1 mL, 98.1 mmol) at 0° C. was added fuming nitric acid (90%, 2.86 mL, 61.3 mmol) with stirring. After addition was complete, the mixture was stirred at 0° C. for 5 minutes, then added drop-wise to a solution of the product of Example 1a (4.10 g, 12.3 mmol) in ethyl acetate (20 mL) at 0° C. The reaction mixture was stirred at 0° C. for 10 minutes, then poured into a pre-cooled (0° C.) mixture of 25 mL of ethyl acetate and 50 mL of sodium bicarbonate. The mixture was stirred cold for 20 minutes, and then warmed to room temperature for 1 hour. The reaction mixture was partitioned between ethyl acetate and water, washed with sodium bicarbonate, water, and brine, and dried over sodium sulfate. The solvent was evaporated and the residue was purified by column chromatography on silica, eluting with methanol/ethyl acetate (gradient, 0% to 20%), gave 2-((2-nitrooxy)ethyl)sulfinyl)ethyl (2S)-2-(6-methoxy(2-naphthyl))propanoate as a pale yellow solid (1.07 g, 22% yield) and 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate as a white solid. 2-((2-hydroxyethyl)sulfinyl)ethyl(2S)-2-(6-methoxy(2-naphthyl))propanoate (1.87 g, 44% yield). Mp 74–86° C. 1H NM (300 MHz, CDCl3) δ 7.70 (d, J=8.6 Hz, 2H), 7.65 (d, J=1.0 Hz, 1H), 7.37 (dt, J 1.9, 8.5 Hz, 1H), 7.15 (dd, J=2.5, 8.8 Hz, 1H), 7.11 (d, J=2.3 Hz, 1H), 4.52 (m, 2H), 3.91 (s, 3H), 3.87 (q, J=7.2 Hz, 1H), 2.97 (m, 2H), 2.84 (br.s, 1H), 2.62 (m, 2H), 1.59 (d, J=7.2 Hz, 3H) Mass spectrum (API-TIS) m/z 351 (MH+).
Reaction SMILES: [CH2:1]([OH:7])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH2:8]=[O:9].C1N2CN3[CH2:19][N:13](C2)CN1C3>>[CH2:1]([O:7][C:19]([O:7][CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])([O:9][CH2:8][CH2:1][CH2:2][CH2:3][CH2:4][CH3:5])[NH2:13])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1N2CN3CN1CN(C2)C3
Reactant: C=O
Reactant: CCCCCCO
Product: CCCCCCOC(N)(OCCCCCC)OCCCCCC

Procedure:
If the preferred raw materials are used in the process described above, in first step of the process n-hexanol was reacted with paraformaldehyde and hexamethylenetetramine to produce tris-hexoxymethanamine. In the second step of the process, phosphorus trichloride was reacted with neopentyl glycol in a mixture of neopentyl glycol and water to produce 5,5-dimethyl 1,3,2-dioxaphosphorinane-2-oxide. In the final step of the process the tris-hexoxymethanamine was reacted with the 5,5-dimethyl 1,3,2-dioxaphosphorinane-2-oxide to produce 5,5,5',5',5",5"-hexamethyl tris(1,3,2-dioxaphosphorinanemethan) amine 2,2',2"-trioxide.
Reaction SMILES: [C:1]1([NH:7][C:8]2[C:9]([NH2:14])=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18](Cl)=[O:19].C(N(CC)CC)C.O>ClCCl>[Br:15][C:16]1[CH:24]=[CH:23][CH:22]=[CH:21][C:17]=1[C:18]([NH:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[NH:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)=[O:19]
Reactant: O=C(Cl)c1ccccc1Br
Reactant: Nc1ccccc1Nc1ccccc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccccc1Nc1ccccc1)c1ccccc1Br
Temperature: 25 °C
Reaction time: 8 h
Yield: 92 %

Procedure:
To a solution of N-phenylbenzene-1,2-diamine (6.08 g, 30 mmol) in anhydrous dichloromethane (˜100 mL), was added 2-bromobenzoylchloride (6.585 g, 33 mmol), followed by triethylamine (7.0 mL, 50 mmol) slowly with water bath cooling. After the additions, the whole was stirred at room temperature overnight. The resulting mixture was poured into water (˜150 mL) and extracted with dichloromethane (˜100 mL) twice. The organic phase was collected, dried over Na2SO4, concentrated and recrystallized in dichloromethane/hexanes to give a white solid (10.7 g, in 92% yield).
Reaction SMILES: [CH3:1][S:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=[C:5]([CH:17]=O)[CH:4]=1.Cl.[NH2:20][OH:21].[OH-].[Na+]>C(O)C.O>[CH3:1][S:2][C:3]1[C:16]2[C:7](=[C:8]3[C:13](=[CH:14][CH:15]=2)[CH:12]=[CH:11][CH:10]=[N:9]3)[N:6]=[C:5]([CH:17]=[N:20][OH:21])[CH:4]=1
Reactant: CSc1cc(C=O)nc2c1ccc1cccnc12
Reactant: NO
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CSc1cc(C=NO)nc2c1ccc1cccnc12
Temperature: 25 °C
Yield: 81 %

Procedure:
To a 25 mL round-bottomed flask containing a solution of 4-methylsulfanyl-[1,10]phenanthroline-2-carbaldehyde (228.0 mg, 1.1 mmol) in ethanol (3.2 mL), a solution of hydroxylamine hydrochloride (707.0 mg, 10.2 mmol) in water (5.0 mL) was added followed by the addition of 10% NaOH until a precipitate was formed. The reaction mixture was heated to 90° for about 30 minutes, cooled to room temperature and the white precipitate was filtered, washed with cold water and dried. White solid (240.0 mg, 100%) was obtained.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]#[CH:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)C=C.[OH-].[K+].C[N+]1([O-])CC[O:21][CH2:20][CH2:19]1>O=[Os](=O)(=O)=O.O.C(Cl)Cl>[C:1]1([CH2:7][CH2:8][C:9]#[C:10][CH2:19][CH:20]=[O:21])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C[N+]1([O-])CCOCC1
Reactant: C#CCCc1ccccc1
Agent: O=[Os](=O)(=O)=O
Agent: [K+]
Agent: [OH-]
Solvent: C=CCBr
Solvent: ClCCl
Solvent: O
Product: O=CCC#CCCc1ccccc1

Procedure:
Reaction of 4-phenyl-1-butyne (5; commercially available from Lancaster Synthesis, Windham, N.H.) with allyl bromide under phase-transfer conditions (CH2Cl2, n-BU4NCl, water, KOH), selective oxidation of the alkene moiety using catalytic OsO4/pyr and stoichiometric N-methylmorpholine-N-oxide, and oxidative cleavage of the resultant diol using NalO4 affords 6-phenyl-hex-3-ynal (6). Lithiation of phosphine oxide 7 [Katritzky, Alan R., Feng, Daming, Lang, Hengyuan J. Org. Chem., volume 62(12) page 4131 (1997)], Wittig condensation with 6, and heating of the intermediate dienyne (not shown) with p-toluenesulfonic acid in ethanol affords enyne 8. Asymmetric dihydroxylation of 8 with AD mix α (Aldrich Chemical Co., Milwaukee) and methanesulfonamide [Sharpless, K. B., Amberg, W., Bennani, Y. Crispino, G. A.; Hartung, J; Jeong, K. S.; Kwong, H.-L.; Morikawa, K.; Wang, Z.-M.; Xu, D. Zhang, X.-L. J. Org. Chem., volume 57, page 2768 (1992)], followed by selective reduction with H2 over Pd/BaSO4, affords β-hydroxy lactone 9. Sequential treatment of 9 with CH3SO2Cl/NEt3 and diisobutylaluminum hydride (DIBAL-H) provides lactol 10. Sodium borohydride reduction, K2CO3 treatment, and oxidation of the resulting β-hydroxyepoxide with the Dess-Martin reagent produces the epoxyaldehyde 11. Wittig olefination of 11 and known ylide 12 [Zamboni, R.; Milettee, S.; Rokach, J. Tetrahedron Lett., volume 24, page 4899 (1983)] followed by saponification of the resulting methyl ester with LiOH in dimethoxyethane (DME)/water yields 2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:21]=[CH:20][C:16]([C:17]([OH:19])=O)=[CH:15][CH:14]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23].C(Cl)(=O)C(Cl)=O.[Cl:33][C:34]1[CH:39]=[CH:38][C:37]([CH2:40][CH2:41][NH2:42])=[CH:36][CH:35]=1.C(N(C(C)C)CC)(C)C>ClCCl.CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][C:11]=1[O:12][C:13]1[CH:14]=[CH:15][C:16]([C:17](=[O:19])[NH:42][CH2:41][CH2:40][C:37]3[CH:38]=[CH:39][C:34]([Cl:33])=[CH:35][CH:36]=3)=[CH:20][CH:21]=1)[O:8][CH2:7][CH2:6][CH:5]2[C:22]([O:24][CH2:25][CH3:26])=[O:23]
Reactant: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)O)cc3)c(Cl)cc21
Reactant: NCCc1ccc(Cl)cc1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)C1CCOc2cc(Oc3ccc(C(=O)NCCc4ccc(Cl)cc4)cc3)c(Cl)cc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 105.1 %

Procedure:
4-(6-Chloro-4-(ethoxycarbonyl)chroman-7-yloxy)benzoic acid (Preparation 1) (100 g, 265.40 mmol) was dissolved in dry dichloromethane (750 ml) and few drops of DMF. Oxalyl Chloride (24.310 ml, 278.67 mmol) was slowly added to the mixture under nitrogen stream over a period of 0.5 hours at ambient temperature. Gas evolution was observed. The mixture was stirred for 5 hours at ambient temperature and cooled in an ice bath. 2-(4-Chlorophenyl)ethanamine (40.602 ml, 291.94 mmol) and diisopropylethylamine (55.624 ml, 318.48 mmol) were added. The mixture was warmed to ambient temperature and stirred for 16 hours. The crude mixture was transferred to a separatory funnel and washed with 1N HCl, water, and brine, dried over magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting crude solid was further dried under high vacuum to provide 143.5 g of a pink solid. This solid was recrystallized from hot EtOAc/hexanes to provide 130.0 g of the title compound as a light purple solid.