Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([NH:8][S:9]([C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]#[N:29])[CH:23]=2)=[O:20])=[CH:14][CH:13]=1)(=[O:11])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30]([N:34]1[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]1)[CH2:31][CH2:32][CH3:33]>>[CH2:1]([NH:8][S:9]([C:12]1[CH:13]=[CH:14][C:15]([NH:18][C:19]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([C:28]([N:37]3[CH2:38][CH2:39][N:34]([CH2:30][CH2:31][CH2:32][CH3:33])[CH2:35][CH2:36]3)=[NH:29])[CH:23]=2)=[O:20])=[CH:16][CH:17]=1)(=[O:10])=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1cccc(NC(=O)Nc2ccc(S(=O)(=O)NCc3ccccc3)cc2)c1
Reactant: CCCCN1CCNCC1
Product: CCCCN1CCN(C(=N)c2cccc(NC(=O)Nc3ccc(S(=O)(=O)NCc4ccccc4)cc3)c2)CC1
Yield: 6 %

Procedure:
The title compound was prepared from N-benzyl-4-(3-(3-cyanophenyl)ureido)benzenesulfonamide following procedure C and using 3 equivalents of n-butylpiperazine as secondary amine. The product was purified by preparative HPLC.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1.[O:13]1[CH:18]=[CH:17][CH2:16][CH2:15][CH2:14]1.[NH+]1C=CC=CC=1>ClCCl.C1(C)C(S([O-])(=O)=O)=CC=CC=1>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH:14]2[CH2:15][CH2:16][CH2:17][CH2:18][O:13]2)=[C:4]([N+:10]([O-:12])=[O:11])[CH:3]=1
Reactant: C1=COCCC1
Reactant: O=[N+]([O-])c1cc(Cl)ccc1CO
Agent: Cc1ccccc1S(=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Cl)ccc1COC1CCCCO1
Reaction time: 12 h
Yield: 62.3 %

Procedure:
A magnetically stirred solution of 4-chloro-2-nitrobenzyl alcohol (25.0 g, 133 mmol) and 3,4-dihydro-2H-pyran (118.2 mL, 16.8 g, 200 mol) in anhydrous dichloromethane (250 mL) was treated at 25° C. with pyridinium (toluenesulfonate (PPTS, 50 mg). The solution was stirred for 12 h, washed with 1 N NaOH (250 mL), brine (250 mL), dried (K2CO3), filtered, and concentrated in vacuo. Silica gel chromatography (4:1 hexane:ethyl acetate) of the concentrate gave 22.5 g (62%) of the title compound as an oil.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>C(O)C.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][C:7]([S:10]([CH2:13][CH2:14][CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])(=[O:12])=[O:11])=[CH:6][CH:5]=1
Reactant: CCOC(=O)CCCS(=O)(=O)c1ccc([N+](=O)[O-])cc1
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)CCCS(=O)(=O)c1ccc(N)cc1
Reaction time: 18 h
Yield: 98.9 %

Procedure:
A solution of ethyl 4-(4-nitrophenylsulfonyl)butanoate (Intermediate 47, 4.5 g; 14.9 mmol) in ethanol (200 ml) was treated with palladium (450 mg, 5% on C). The mixture was stirred under hydrogen for 18 hours, filtered and the solvent removed in vacuo to give the title compound as an off-white solid (4.0 g, quant).
Reaction SMILES: [NH2:1][C:2]1[C:7]([N+:8]([O-])=O)=[C:6]([CH3:11])[C:5]([Cl:12])=[CH:4][N:3]=1>[Ni]>[Cl:12][C:5]1[C:6]([CH3:11])=[C:7]([NH2:8])[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Cc1c(Cl)cnc(N)c1[N+](=O)[O-]
Agent: [Ni]
Product: Cc1c(Cl)cnc(N)c1N

Procedure:
The title compound was prepared by reduction of 2-amino-5-chloro-4-methyl-3-nitropyridine (prepared according to the route described in Example 206) using Raney Nickel as described above.
Reaction SMILES: C(OC([NH:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1)=O)(C)(C)C.C(OC(NC1C=C(C2C(C3C=CC=CC=3)=NN(C3C=CC4N(C=NN=4)N=3)C=2)C=CN=1)=O)(C)(C)C>>[NH2:8][C:9]1[CH:14]=[C:13]([C:15]2[C:16]([C:29]3[CH:34]=[CH:33][C:32]([Cl:35])=[CH:31][CH:30]=3)=[N:17][N:18]([C:20]3[CH:21]=[CH:22][C:23]4[N:24]([CH:26]=[N:27][N:28]=4)[N:25]=3)[CH:19]=2)[CH:12]=[CH:11][N:10]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(Cl)cc2)ccn1
Agent: CC(C)(C)OC(=O)Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccccc2)ccn1
Product: Nc1cc(-c2cn(-c3ccc4nncn4n3)nc2-c2ccc(Cl)cc2)ccn1
Yield: 76.7 %

Procedure:
The reaction was carried out in the same manner as in Example 37-2) except for using 3.00 g (6.14 mmol) of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-(4-chlorophenyl)-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole obtained in Example 39-1) in place of 4-(2-t-butoxycarbonylaminopyridin-4-yl)-3-phenyl-1-([1,2,4]triazolo[4,3-b]pyridazin-6-yl)-1H-pyrazole to obtain 1.83 g of the title compound as a white powder. (Yield: 77%)
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([C:12]2[O:13][CH2:14][C:15]([CH3:18])([CH3:17])[N:16]=2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.[B:19]([O:28]C(C)C)([O:24]C(C)C)[O:20]C(C)C.C([Li])CCC>O1CCCC1>[CH3:17][C:15]1([CH3:18])[CH2:14][O:13][C:12]([C:4]2[CH:3]=[C:2]([O:20][B:19]([OH:28])[OH:24])[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=2)=[N:16]1
Reactant: CC1(C)COC(c2cc(I)cc(C(F)(F)F)c2)=N1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CC1(C)COC(c2cc(OB(O)O)cc(C(F)(F)F)c2)=N1
Reaction time: 4 h
Yield: 95.3 %

Procedure:
To a solution of 2-[3-iodo-5-(trifluromethyl)phenyl]-4,4-dimethyl-4,5-dihydrooxazole (2.11 g) and triisopropyl borate (1.26 g) in tetrahydrofuran (21 ml) was added dropwise butyllithium (1.6 M in hexane) at −70° C. After stirring for 4 hours, the mixture was quenched with 2N hydrochloric acid and extracted with ethyl acetate. The combined extracts were washed with brine, dried over magnesium sulfate, and evaporated in vacuo to give 3-(4,4-dimethyl-4,5-dihydrooxazol-2-yl)-5-(trifluoromethyl)phenylboroic acid (1.65 g) as a yellow oil. This oil was used immediately in the next reaction without further purification because of its instability.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1.C([Sn](CCCC)(CCCC)[C:21]1[O:22][CH:23]=[CH:24][CH:25]=1)CCC>C1(C)C=CC=CC=1.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>[O:22]1[CH:23]=[CH:24][CH:25]=[C:21]1[C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[CH2:15][CH2:14][CH2:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: O=c1[nH]c2cc(Br)ccc2c2c1CCC2
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccco1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: O=c1[nH]c2cc(-c3ccco3)ccc2c2c1CCC2
Temperature: 25 °C
Reaction time: 15 h
Yield: 105.9 %

Procedure:
A suspension of 7-bromo-1,2,3,5-tetrahydrocyclopenta[c]quinolin-4-one (1.32 g, 5.0 mmol) in toluene (200 ml) is mixed with 2-(tributylstannyl)furan (1.7 ml, 5.5 mmol) and tetrakis(triphenylphosphine)palladium (0.29 g, 0.25 mmol). The reaction mixture is degassed, aerated with nitrogen, stirred for 15 hours at room temperature and heated for 4.5 hours to 110° C. The batch is mixed with silica gel and concentrated by evaporation in a vacuum. Column chromatography of the residue on silica gel with hexane-ethyl acetate yields 1.33 g of product.
Reaction SMILES: [C:1]1([C:7]2([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH:11]3[CH2:12][NH:13][CH2:14][CH2:15][N:10]3[C:9](=[O:16])[O:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:23]1([N:29]=[C:30]=[O:31])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C1(C)C=CC=CC=1>[O:16]=[C:9]1[N:10]2[CH2:15][CH2:14][N:13]([C:30]([NH:29][C:23]3[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=3)=[O:31])[CH2:12][CH:11]2[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=2)[O:8]1
Reactant: O=C=Nc1ccccc1
Reactant: O=C1OC(c2ccccc2)(c2ccccc2)C2CNCCN12
Solvent: Cc1ccccc1
Product: O=C(Nc1ccccc1)N1CCN2C(=O)OC(c3ccccc3)(c3ccccc3)C2C1
Temperature: 60 °C
Reaction time: 4 h
Yield: 100.1 %

Procedure:
To a solution of hexahydro-1,1-diphenyl-3H-oxazolo[3,4-a]pyrazin-3-one (85 mg, 0.29 mmol) in toluene (3 mL) was added phenyl isocyanate (70 mg, 0.59 mmol), and the mixture was stirred at 60° C. for 4 hours. The reaction solution was concentrated. Then, the residue was purified with silica gel column chromatography (hexane:ethyl acetate=2:1) and crystallized from diisopropyl ether to obtain the title compound (0.12 g, yield 99%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10]O)([CH3:4])([CH3:3])[CH3:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:45]I>C1COCC1>[C:1]([O:5][C:6](=[O:20])[C@H:7]([NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:8][CH2:9][CH2:10][I:45])([CH3:4])([CH3:3])[CH3:2]
Reactant: II
Reactant: CC(C)(C)OC(=O)N[C@H](CCCO)C(=O)OC(C)(C)C
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N[C@H](CCCI)C(=O)OC(C)(C)C
Reaction time: 2 h
Yield: 72 %

Procedure:
A solution of the title E compound, (2R)-(t-butyloxycarbonylamino)-5-hydroxypentanoic acid t-butyl ester (9.12 g, 31.5 mmol), imidazole (3.22 g, 47.3 mmol) and triphenylphosphine (12.40 g, 47.3 mmol) in 300 mL of THF is treated portionwise over 5 min with iodine (9.60 g, 37.8 mmol) at RT. After 2 h, the mixture is filtered and concentrated. The residue is first filtrated though silica gel (eluant; ethyl acetate) then purified by chomatography on silica gel (eluant; 10% ethyl acetate in hexane) affording 9.05 g (72%) of (2R)-(t-butyloxycarbonylamino)-5-iodopentanoic acid t-butyl ester as a colorless oil: NMR(CDCl3)) 1.42 (s, 9H), 1.46 (s, 9H), 1.65-1.95 (m, 4H), 3.14-3.28 (m, 2H), 4.19-4.26 (m, 1H), 5.06 (br d, 1H, J=7.4); IR 1712, 1500, 1155; ESI-MS 400 (M++1).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1.[N+:11]([O-])([OH:13])=[O:12]>>[OH:1][C:2]1[C:10]([N+:11]([O-:13])=[O:12])=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][N:3]=1
Reactant: O=[N+]([O-])O
Reactant: O=C(O)c1ccc(O)nc1
Product: O=C(O)c1cnc(O)c([N+](=O)[O-])c1
Temperature: 50 °C
Yield: 23 %

Procedure:
A mixture of 6-hydroxynicotinic acid (16.60 g, 0.119 mol) and fuming nitric acid (166 mL) was heated at 50° C. for 4 hours. The resulting reaction solution was cooled to room temperature, and then carefully added to ice (300 g). The resultant mixture was then stored at 10° C. overnight, and the precipitated solid was filtered and dried in vacu to afford the title compound (5.50 g, 0.027 mol, 23%) as a yellow solid: 1H NMR (DMSO-d6) δ 13.4 (br s, 2H), 8.64 (d, J=2.2 Hz, 1H), 8.37 (d, J=2.2 Hz, 1H); 13C NMR (DMSO-d6) δ 164.1, 154.4, 146.1, 138.5, 137.2, 107.9. HRMS calculated for C6H4N2O5 184.0120, found 184.0134. Anal. calcd for C6H4N2O5 : C, 39.14; H, 2.19; N, 15.21. Found: C, 39.21; H, 2.33; N, 15.56.
Reaction SMILES: [F:1][CH:2]([F:24])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[CH:13])=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1.Br[C:26]1[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=1>>[F:24][CH:2]([F:1])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12]#[C:13][C:26]3[CH:27]=[C:28]([S:32]([NH2:35])(=[O:34])=[O:33])[CH:29]=[N:30][CH:31]=3)=[C:7]2[N:6]=[C:5]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:4]=1
Reactant: C#Cc1cnn2c(C(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Reactant: NS(=O)(=O)c1cncc(Br)c1
Product: NS(=O)(=O)c1cncc(C#Cc2cnn3c(C(F)F)cc(-c4ccc(C(F)(F)F)cc4)nc23)c1

Procedure:
The title compound was prepared from 7-Difluoromethyl-3-ethynyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.2)(340 mg, 1.0 mmol) and 5-Bromo-pyridine-3-sulfonic acid amide (example B.1) (215 mg, 1.0 mmol) according to general procedure II. Obtained as a yellow solid (330 mg, 66%). MS (ISP) 494.3 [(M+H)+]; mp 238° C.
Reaction SMILES: N#N.[F:3][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:11]=1[NH:12][CH:13]([CH2:16][OH:17])[CH2:14][CH3:15])[C:7]#[N:8].C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O[CH:32](O)[C:33]([F:36])([F:35])[F:34])C>C1(C)C=CC=CC=1>[CH2:14]([CH:13]1[CH2:16][O:17][CH:32]([C:33]([F:36])([F:35])[F:34])[N:12]1[C:11]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][C:4]=1[F:3])[CH3:15]
Reactant: CCC(CO)Nc1ccc(C#N)cc1F
Reactant: CCOC(O)C(F)(F)F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: N#N
Solvent: Cc1ccccc1
Product: CCC1COC(C(F)(F)F)N1c1ccc(C#N)cc1F
Temperature: 125 °C
Yield: 82.4 %

Procedure:
A 25 mL round bottom flask fitted with a Dean-Stark trap, reflux condenser, and N2 line was charged with 245.3 mg (1.17 mmol) of 3-Fluoro-4-(1-hydroxymethyl-propylamino)-benzonitrile. p-Toluenesulfonic acid (27.4 mg, 0.144 mmol) was then added, along with trifluoroacetaldehyde ethyl hemiacetal (859.2 mg, 5.96 mmol) in 4 mL toluene. Toluene was then added to the Dean-Stark trap and the reaction was heated in an oil bath at 125° C. overnight. The reaction was cooled to room temperature, poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (10% EtOAc/Hexanes) to afford 277.8 mg (82%) of 4-(4-Ethyl-2-trifluoromethyl-oxazolidin-3-yl)-3-fluoro-benzonitrile as a mixture of diastereomers. This was dissolved in 8 mL CHCl3 (8 mL) and Et3SiH (0.62 mL, 3.88 mmol) was then added via syringe and the resulting solution was cooled to −78° C. TiCl4 (1M in dichloromethane, 1.95 mL) was then added dropwise via syringe. The reaction was slowly warmed to room temperature and stirred for 18 hours. The reaction mixture was poured onto water, and the water extracted with EtOAc (2×). The organic layers were combined, washed with brine, dried (MgSO4), and concentrated. The resulting residue was purified via silica gel chromatography (gradient from 5% EtOAc/Hexanes to 15% EtOAc/Hexanes followed by 50% EtOAc/Hexanes) to afford 99.8 mg (36% yield) of 4-(N-(2,2,2-trifluoroethyl)-N-(1-hydroxybut-2-yl)amino)-3-fluorobenzonitrile. 1H NMR (CDCl3, 500 MHz) δ: 7.39-7.34 (m, 2H), 7.32 (m, 1H), 4.05 (m, 1H), 3.83 (m, 1H), 3.73 (m, 1H), 3.65 (m, 1H), 3.46 (m, 1H), 1.96 (m, 1H), 1.55 (m, 2H), 0.94 (t, J=7.4 Hz, 3H).
Reaction SMILES: [CH3:1][O:2][CH2:3][N:4]1[C:9]2[CH:10]=[C:11]([CH2:14][N:15]3C(=O)C4=CC=CC=C4C3=O)[CH:12]=[CH:13][C:8]=2[S:7][C:6]2[N:26]=[CH:27][CH:28]=[N:29][C:5]1=2.O.NN>C(O)C>[NH2:15][CH2:14][C:11]1[CH:12]=[CH:13][C:8]2[S:7][C:6]3[N:26]=[CH:27][CH:28]=[N:29][C:5]=3[N:4]([CH2:3][O:2][CH3:1])[C:9]=2[CH:10]=1
Reactant: COCN1c2cc(CN3C(=O)c4ccccc4C3=O)ccc2Sc2nccnc21
Agent: NN
Solvent: CCO
Solvent: O
Product: COCN1c2cc(CN)ccc2Sc2nccnc21
Temperature: 60 °C
Yield: 100.9 %

Procedure:
To a solution of 1.3 g of N-(10-methoxymethyl-10H-pyrazino[2,3-b][1,4]benzothiazin-8-ylmethyl)phthalimide in 20 ml of ethanol was added 5 ml of hydrazine monohydrate and the resulting mixture was heated to 60° C. for 10 minutes. After distilling off the solvent under reduced pressure, the residue was distributed into a 5% aqueous solution of sodium hydroxide and ethyl acetate. The organic layer was extracted and the extract was dried over potassium carbonate. After distilling off the solvent under reduced pressure, the obtained residue was purified by silica gel column chromatography (eluted with dichloromethane/methanol/aqueous ammonia) to thereby give 890 mg of the title compound as a yellow oily substance.
Reaction SMILES: [ClH:1].C(OC([N:9]1[CH2:14][CH2:13][C@@H:12]([NH:15][C:16]2[CH:21]=[CH:20][C:19]([Br:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[C@H:11]([OH:26])[CH2:10]1)=O)(C)(C)C>O1CCOCC1.ClCCl>[ClH:1].[Br:22][C:19]1[CH:20]=[CH:21][C:16]([NH:15][C@@H:12]2[CH2:13][CH2:14][NH:9][CH2:10][C@H:11]2[OH:26])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](Nc2ccc(Br)cc2[N+](=O)[O-])[C@H](O)C1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=[N+]([O-])c1cc(Br)ccc1N[C@@H]1CCNC[C@H]1O
Reaction time: 16 h
Yield: 89 %

Procedure:
Add 4.0 M hydrogen chloride in dioxane (70 mL) slowly to a solution of (3R,4R)-4-(4-bromo-2-nitro-phenylamino)-3-hydroxy-piperidine-1-carboxylic acid tert-butyl ester (0.027 mol, 11.5 g) in dry dichloromethane (40 mL) at room temperature and stir for 16 h. Filter the precipitate and dry under vacuum to obtain the title compound (8.68 g, 89%) as a yellow solid. 1H NMR (400 MHz, CD3OD) δ 1.81-1.86 (m, 1H), 2.39-2.44 (m, 1H), 3.02-3.07 (m, 1H), 3.18-3.26 (m, 1H), 3.34-3.40 (m, 1H), 3.45 (dd, 1H), 3.87-3.91 (m, 2H), 7.17 (d, 1H), 7.61 (dd, 1H), 8.28 (d, 1H).
Reaction SMILES: [CH2:1]1[O:4][CH:2]1[CH3:3].[CH3:5][CH:6]1[CH2:10][O:9][C:8](=[O:11])[O:7]1>>[CH3:5][CH:6]1[CH2:10][O:9][C:8]2([O:4][CH2:1][CH:2]([CH3:3])[O:11]2)[O:7]1
Reactant: CC1COC(=O)O1
Reactant: CC1CO1
Product: CC1COC2(OCC(C)O2)O1
Yield: 70 %

Procedure:
4-methyl-1,3-dioxolan-2-one and propylene oxide were reacted in a similar manner to the procedure of Example 2, whereby 2,7-dimethyl-1,4,6,9-tetraoxaspiro[4.4]nonane was obtained in yield of about 70%.
Reaction SMILES: [CH2:1]([C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]23[C:57](=[O:58])[N:56]([CH3:59])[C:51]([CH2:60][O:61]CC4C=CC=CC=4)([C:52](=[O:55])[N:53]2[CH3:54])[S:50][CH:49]([C:69]2[CH:74]=[CH:73][C:72]([O:75][CH3:76])=[CH:71][CH:70]=2)[S:48]3)=[CH:42][CH:41]=1)[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]23[C:20](=[O:21])[N:19]([CH3:22])[C:14]([CH2:23][O:24]CC4C=CC=CC=4)([C:15](=[O:18])[N:16]2[CH3:17])[S:13][CH:12]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[S:11]3)=[CH:5][CH:4]=1.B(Cl)(Cl)Cl>ClCCl>[CH2:2]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]23[C:20](=[O:21])[N:19]([CH3:22])[C:14]([CH2:23][OH:24])([C:15](=[O:18])[N:16]2[CH3:17])[S:13][CH:12]([C:32]2[CH:37]=[CH:36][C:35]([O:38][CH3:39])=[CH:34][CH:33]=2)[S:11]3)=[CH:5][CH:4]=1)[CH2:1][C:40]1[CH:45]=[CH:44][C:43]([CH2:46][C:47]23[C:57](=[O:58])[N:56]([CH3:59])[C:51]([CH2:60][OH:61])([C:52](=[O:55])[N:53]2[CH3:54])[S:50][CH:49]([C:69]2[CH:70]=[CH:71][C:72]([O:75][CH3:76])=[CH:73][CH:74]=2)[S:48]3)=[CH:42][CH:41]=1
Reactant: COc1ccc(C2SC3(COCc4ccccc4)C(=O)N(C)C(Cc4ccc(CCc5ccc(CC67SC(c8ccc(OC)cc8)SC(COCc8ccccc8)(C(=O)N6C)N(C)C7=O)cc5)cc4)(S2)C(=O)N3C)cc1
Agent: ClB(Cl)Cl
Solvent: ClCCl
Product: COc1ccc(C2SC3(CO)C(=O)N(C)C(Cc4ccc(CCc5ccc(CC67SC(c8ccc(OC)cc8)SC(CO)(C(=O)N6C)N(C)C7=O)cc5)cc4)(S2)C(=O)N3C)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
To an ice-cooled solution of 21 (125 mg, 0.126 mmol, 1 eq.) in dichloromethane, a 1 M solution of boron trichloride in dichloromethane (320 μL, 0.32 mmol, 2.5 eq) was added dropwise while stirring. The mixture was allowed to stand at 0° C. for 15 min and then was poured into the ice-cold water. The aqueous layer was extracted. with dichloromethane (3×50 mL). The combined organic extracts were dried over anhydrous magnesium sulfate, filtered and evaporated under reduced pressure. The crude reaction mixture was purified by flash column chromatography to give 78 mg of product mixture of meso-22 and (±)-22 as a white solid (75% combined yield). The mixture of meso-22 and (±)-22 was further purified on silica gel column using gradient of EtOAC in dichloromethane from 10% to 50% in order to separate meso-22 and (±)-22. Analytical data for (±)-22: 1H NMR (CDCl3, ppm) δ: 7.32 (d, 4H), 6.93 (d, 4H) 6.89 (d, 4H), 6.86 (d, 4H), 5.08 (s, 2H), 4.47 (dd, J=6 Hz, 13 Hz, 2H), 4.37 (d, 2H), 4.26 (m, 2H), 3.98 (dd, J 10 Hz, 13 Hz, 2H), 3.80 (s, 6H), 3.41 (s, 6H), 2.98 (d, 2H), 2.84 (s, 6H), 2.69 (d, 2H). 13C NMR (DMSO-d6, ppm) δ:165.42, 165.19, 160.06, 140.00, 132.93, 130.52, 128.53, 128.42, 126.82, 114.38, 73.47, 71.51, 60.79, 55.29, 49.91, 40.14, 36.36, 29.60, 27.96. FABMS: Calcd. for C46H50N4O8S4: 914.3. Found [M+Na]+: 936.9. Analytical data for meso-7: 1H NMR (CDCl3, ppm) δ: 7.33 (d, 4H), 7.02 (d, 4H) 6.99 (d, 4H), 6.86 (d, 4H), 5.09 (s, 2H), 4.35 (dd, J=10 Hz, 13 Hz, 2H), 4.37 (d, 2H), 3.11 (m, 2H), 4.04 (dd, J=10 Hz, 13 Hz, 2H), 3.81 (s, 6H), 3.41 (s, 6H), 2.91 (s, 6H), 2.85 (s, 4H). 13C NMR (DMSO-d6, ppm) δ:165.47, 165.24, 160.10, 140.04, 132.96, 130.56, 128.55, 128.48, 126.85, 114.42, 73.50, 71.55, 60.83, 55.34, 49.96, 40.14, 36.42, 29.63, 28.00. FABMS: Calcd. for C46H50N4O8S4: 914.3. Found [M+Na]+: 936.9.
Reaction SMILES: [NH:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7].[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10](Cl)=[O:11]>C1C=CC=CC=1>[CH3:8][N:9]([C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)[C:10]([N:1]=[C:2]1[CH2:6][CH2:5][CH2:4][N:3]1[CH3:7])=[O:11]
Reactant: CN(C(=O)Cl)c1ccccc1
Reactant: CN1CCCC1=N
Solvent: c1ccccc1
Product: CN1CCCC1=NC(=O)N(C)c1ccccc1
Temperature: 25 °C

Procedure:
The hydrochloride salt of 2-imino-1-methylpyrrolidine (13.46 g.; 0.1 mole) is converted to free base by adding 10 ml. of 50% NaOH and extracting into benzene. After drying over K2CO3, the benzene layer is stirred at room temperature and 8.48 g. (0.05 mole) of N-methyl-phenylcarbamoyl chloride (prepared according to the method of J. A. Aeschlimann, U.S. Pat. No. 2,449,440), dissolved in anhydrous benzene, is added dropwise to this solution. Cloudiness occurs and then solid precipitates from solution. The mixture is stirred at room temperature overnight and then filtered. The filtrate is taken to dryness in vacuo to an oily residue which is dissolved in hot hexane and filtered hot. Cooling and scratching yields crystals which are collected and recrystallized from hexane to give the pure product, 1-methyl-3-(1-methyl-2-pyrrolidylidene)-1-phenylurea, 27.5°-30° C.
Reaction SMILES: [CH3:1][C:2]([O:5][OH:6])([CH3:4])[CH3:3].[CH3:7][C:8]([CH3:10])=[O:9].[CH3:11]O>[Pd].[Pt]>[CH3:1][C:2]([O:5][OH:6])([CH3:4])[CH3:3].[CH3:7][C:8]([O:9][O:5][C:2]([CH3:4])([CH3:3])[CH3:1])([CH3:11])[CH3:10]
Reactant: CC(C)=O
Reactant: CO
Agent: [Pd]
Agent: [Pt]
Agent: CC(C)(C)OO
Product: CC(C)(C)OOC(C)(C)C
Yield: 5 %

Procedure:
A 19.1% solution of TBHP in TBA decomposed over a commercial 0.15% Pd, 0.15% Pt on alumina gave (80° C., 0.5 space velocity) 74.2 TBHP conversion with selectivity to TBA of 84.1%, DTBP 5.0%, acetone 10.9%, and methanol 2.6%. Minor products including carboxylic acids were also formed.
Reaction SMILES: [C:1]([O:5][C:6](=[O:25])[CH:7]([NH:17][C:18](N1C=CN=C1)=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])([CH3:4])([CH3:3])[CH3:2].[CH3:26][O:27][C:28](=[O:39])[CH2:29][CH:30]([NH2:38])[C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1>ClCCCl.C(Cl)Cl>[C:1]([O:5][C:6](=[O:25])[C@@H:7]([NH:17][C:18]([NH:38][C@H:30]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([I:37])[CH:32]=1)[CH2:29][C:28]([O:27][CH3:26])=[O:39])=[O:19])[CH2:8][CH2:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)CC(N)c1cccc(I)c1
Reactant: CC(C)(C)OC(=O)CCC(NC(=O)n1ccnc1)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: ClCCCl
Product: COC(=O)C[C@H](NC(=O)N[C@@H](CCC(=O)OC(C)(C)C)C(=O)OC(C)(C)C)c1cccc(I)c1
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 48.8 %

Procedure:
2-[(Imidazole-1-carbonyl)-amino]-pentanedioic acid di-tert-butyl ester (370 mg, 1.05 mmol) was dissolved in DCE (10 mL) and cooled to 0° C. MeoTf (142 μL, 1.25 mmol) was added and the reaction was allowed to proceed for 20 min. (±)-3-Amino-3-(3-iodo-phenyl)-propionic acid methyl ester (356 mg, 1.045 mmol) was added and the reaction was allowed to warm to room temperature and then warmed to 55° C. and stirred overnight. The reaction was diluted with DCM (50 mL) and washed with water (30 mL), 5% aq. Citric acid (30 mL), sat. sodium bicarbonate (30 mL), water (30 mL) and brine (30 mL). The organic layer was dried over sodium sulfate and concentrated to afford the crude product. The product was puridied by column chromatography to afford the desired product (303 mg, 0.51 mmol, 49%) as a white foam. 1H NMR (400 MHz, CDCl3) δ 7.66 (s, 1H), 7.57 (d, J=7.6 Hz, 1H), 7.29 (s, 1H), 7.07-7.02 (m, 1H), 5.74 (br, 1H), 5.17 (br, 2H), 4.30 (m, 1H), 3.63 (s, 1.5H), 3.62 (s 1.5H), 2.88-2.76 (m, 2H), 2.38-2.24 (m, 2H), 2.10-2.00 (m, 1H), 1.90-1.80 (m, 1H), 1.46 (s, 9H), 1.44 (s, 9H).