Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([C:14]2[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:16][CH:15]=2)=[O:13])=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6].[C:29]1([Mg]Br)[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C1COCC1>[CH2:1]([O:7][C:8]1[CH:28]=[CH:27][C:11]([C:12]([OH:13])([C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[C:14]2[CH:15]=[CH:16][C:17]([O:20][CH2:21][CH2:22][CH:23]=[CH:24][CH:25]=[CH2:26])=[CH:18][CH:19]=2)=[CH:10][CH:9]=1)[CH2:2][CH:3]=[CH:4][CH:5]=[CH2:6]
Reactant: C=CC=CCCOc1ccc(C(=O)c2ccc(OCCC=CC=C)cc2)cc1
Reactant: Br[Mg]c1ccccc1
Solvent: C1CCOC1
Product: C=CC=CCCOc1ccc(C(O)(c2ccccc2)c2ccc(OCCC=CC=C)cc2)cc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 62 %

Procedure:
Compound 29 (5.96 g, 15.91 mmol) was dissolved in anhydrous THF (133 mL) with slight heating. Phenylmagnesium bromide (32 mL of a 1.0 M solution in THF, 32 mmol) was added to the solution and the mixture was stirred at room temperature under argon for 5 hours and evaporated to dryness under vacuum. The residue was redissolved in dichloromethane and washed with a saturated solution of ammonium chloride, followed by water. The organic phase was dried (MgSO4), concentrated in vacuo, and purified by column chromatography (silica gel; hexane/CH2Cl2, 1/9) to yield 4.45 grams (62%) of compound 30 as a yellow oil. 1H NMR (300 MHz, DMSO-d6)δ 2.45-2.56 (m, 4H), 3.98 (t, J=6.6 Hz, 4H), 5.01 (dd, J=1.5, 9.9 Hz, 2H), 5.14 (dd, J=1.5, 16.5 Hz, 2H), 5.73-5.87 (m, 2H), 6.12-6.41 (m, 4H), 6.25 (s, 1H), 6.84 (d, J=6.9 Hz, 4H), 7.06 (d, J=7.8 Hz, 4H), 7.15-7.33 (m, 5H).
Reaction SMILES: [NH2:1][C:2]1[N:12]=[C:5]2[N:6]=[C:7]([CH3:11])[CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=1.[S:13]1[CH:17]=[CH:16][CH:15]=[C:14]1[S:18](Cl)(=[O:20])=[O:19]>CN(C)C1C=CN=CC=1.N1C=CC=CC=1>[CH3:11][C:7]1[CH:8]=[C:9]([CH3:10])[N:4]2[N:3]=[C:2]([NH:1][S:18]([C:14]3[S:13][CH:17]=[CH:16][CH:15]=3)(=[O:20])=[O:19])[N:12]=[C:5]2[N:6]=1
Reactant: O=S(=O)(Cl)c1cccs1
Reactant: Cc1cc(C)n2nc(N)nc2n1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: Cc1cc(C)n2nc(NS(=O)(=O)c3cccs3)nc2n1
Yield: 6.2 %

Procedure:
A mixture of 4.24 g (26.0 mmol) of 2-amino-5,7-dimethyl-1,2,4-triazolo(1,5-a)pyrimidine, 5.08 g (27.8 mmol) of 2-thiophene sulfonyl chloride and 0.16 g (1.3 mmol) of 4-dimethylaminopyridine in 30 ml of dry pyridine was heated at reflux for 47 hours. The majority of the pyridine was removed by evaporation at reduced pressure and the residue was taken up in 1N NaOH, treated with charcoal and filtered through celite. The filtrated was treated with charcoal and filtered through celite. The yellow filtrate was cooled in an ice bath and acidified with concentrated HCl to precipitate a yellow solid. Drying in vacuo gave 0.50 g (6 percent) of the desired sulfonamide as a yellow powder, m.p. 236°-237.5° C.: IR (KBr) 3390 (broad), 1493, 1375 and 1156 cm-1 ; 'H NMR (DMSO-d6) δ12.3 (1H, broad, --SO2NH--), 7.7-8.1 (2H, m, thiophene H's at 3- and 5-positions), 6.9-7.3 (2H, m including S at 7.03, thiophene H at 4-position and pyrimidine H), 2.62 (3H, s, --CH3) and 2.49 (3H, s, --CH3).
Reaction SMILES: [C:1]([N:5]1[CH2:22][CH:21]([CH2:23][OH:24])[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].[CH3:27]I>CN(C)C=O>[C:1]([N:5]1[CH2:22][CH:21]([CH2:23][O:24][CH3:27])[O:20][C:7]2([CH2:12][CH2:11][N:10]([C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[CH2:9][CH2:8]2)[CH2:6]1)([CH3:2])([CH3:3])[CH3:4]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N1CCC2(CC1)CN(C(C)(C)C)CC(CO)O2
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCC1CN(C(C)(C)C)CC2(CCN(C(=O)OC(C)(C)C)CC2)O1
Reaction time: 0.17 h
Yield: 97.6 %

Procedure:
To a solution of tert-butyl 8-tert-butyl-10-(hydroxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (720 mg, 2.10 mmol) in N,N-dimethylformamide (7.0 mL) was added sodium hydride (588 mg, 14.7 mmol) and the reaction stirred for 10 min. Methyl iodide (916 μL, 14.7 mmol) was added and the reaction mixture stirred for 20 min. The reaction was quenched with saturated aqueous NH4Cl and extracted with ethyl acetate (2×25 mL). The combined organic layers were dried over Na2SO4, filtered and concentrated to provide tert-butyl 8-tert-butyl-10-(methoxymethyl)-11-oxa-3,8-diazaspiro[5.5]undecane-3-carboxylate (732 mg, 2.05 mmol, 98%). ESI-MS m/z calc. 356.3. found 357.3 (M+1)+; Retention time: 0.97 minutes (3 min run).
Reaction SMILES: O[CH:2]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)[CH2:3][NH:4][CH2:5][CH2:6][C:7]1[CH:11]=[CH:10][N:9]([S:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)(=[O:14])=[O:13])[CH:8]=1.CS(O)(=O)=O>FC(F)(F)C(O)=O>[C:15]1([S:12]([N:9]2[C:8]3[CH:2]([C:21]4[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=4)[CH2:3][NH:4][CH2:5][CH2:6][C:7]=3[CH:11]=[CH:10]2)(=[O:14])=[O:13])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: O=S(=O)(c1ccccc1)n1ccc(CCNCC(O)c2ccccc2)c1
Agent: CS(=O)(=O)O
Solvent: O=C(O)C(F)(F)F
Product: O=S(=O)(c1ccccc1)n1ccc2c1C(c1ccccc1)CNCC2

Procedure:
N-(2-Hydroxy-2-phenylethyl)-2-(1-phenylsulphonyl-3-pyrrolyl)ethylamine (1.67 g), trifluoroacetic acid (60 ml) and methanesulphonic acid (0.65 g, 6.68 mmole) were refluxed for 1.5 hours. After evaporating to dryness, water then 0.88 ammonia were added and the product was extracted into dichloromethane. The extracts were washed with water, dried and evaporated to give an oil. The oil was purified by chromatography on silica, eluting with chloroform then increasing amounts of methanol (1-15%) in chloroform to give the title product as an oily solid.
Reaction SMILES: [NH2:1][C:2]1[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9][C:8](=[O:12])[C:7]=12.C(N(CC)CC)C.[C:21](OC(=O)C)(=[O:23])[CH3:22]>C(#N)C>[O:12]=[C:8]1[C:7]2=[C:2]([NH:1][C:21](=[O:23])[CH3:22])[N:3]=[C:4]([CH3:13])[CH:5]=[C:6]2[CH2:11][CH2:10][O:9]1
Reactant: CC(=O)OC(C)=O
Reactant: Cc1cc2c(c(N)n1)C(=O)OCC2
Solvent: CCN(CC)CC
Solvent: CC#N
Product: CC(=O)Nc1nc(C)cc2c1C(=O)OCC2
Yield: 88.6 %

Procedure:
8-amino-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-1-on (200 g, 1.122 mmol) was dissolved in 6 mL of anhydrous acetonitrile, and then dropwisely added with triethylamine (0.63 mL, 4.490 mmol) and actic anhydride (0.42 mL, 4.490 mmol) in this order and then heated to reflux for about 20 hours under the nitrogen atmosphere. The mixture was concentrated under reduced pressure, added with 15 mL of a saturated solution of sodium carbonate and 15 mL of distilled water and then extracted twice with 40 mL of methylene chloride. The resulting organic layer was dried with anhydrous sodium sulfate, and filtered. A silica gel column chromatography (5% MeOH/MC) was performed on the resulting residue and 219 mg (89%) of N-(1-oxo-6-methyl-3,4-dihydro-pyrano[3,4-c]pyridine-8-yl)-acetamide was obtained in white solid.
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][CH:5]=[CH:4][N:3]=1.C([Li])CCC.[O:13]1[C:17]2([CH2:22][CH2:21][C:20](=[O:23])[CH2:19][CH2:18]2)[O:16][CH2:15][CH2:14]1>C(Cl)Cl.CCCCCC>[N:3]1[CH:4]=[CH:5][CH:6]=[N:7][C:2]=1[C:20]1([OH:23])[CH2:21][CH2:22][C:17]2([O:16][CH2:15][CH2:14][O:13]2)[CH2:18][CH2:19]1
Reactant: O=C1CCC2(CC1)OCCO2
Reactant: Brc1ncccn1
Agent: [Li]CCCC
Solvent: ClCCl
Solvent: CCCCCC
Product: OC1(c2ncccn2)CCC2(CC1)OCCO2
Temperature: -78 °C
Reaction time: 0.48 h
Yield: 53.5 %

Procedure:
To a solution of 2-bromopyrimidine (0.20 g, 1.258 mmol) in dry methylene chloride (3.0 mL) was dropwise added 1.6 M of n-butyllithium in hexane (0.86 mL) at −78° C. The reaction mixture was stirred for 29 min at −78° C. and 1,4-dioxa-spiro[4.5]decan-8-one (0.196 g, 1.26 mmol) in CH2Cl2(3 mL) was added dropwise. The reaction was stirred at −78° C. for 50 min and quenched with an aqueous solution of NH4Cl. After being warmed to room temperature, the mixture was extracted with CH2Cl2 three times. The combined extracts were dried over MgSO4, filtered and concentrated in vacuo to provide 0.50 g of crude product. Purification by column chromatography on silica gel eluting with 0->50% EtOAc in hexanes provided 0.159 g (54%) of desired product as a light brown-yellow solid. MS (M+H)+237.2.
Reaction SMILES: C([Li])CCC.Cl.Br[C:8]1[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=1.CCOCC.[O:19]=[C:20]1[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1>CCCCCC>[OH:19][C:20]1([C:8]2[CH:13]=[CH:12][N:11]=[CH:10][CH:9]=2)[CH2:24][CH2:23][N:22]([C:25]([O:27][C:28]([CH3:31])([CH3:30])[CH3:29])=[O:26])[CH2:21]1
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Brc1ccncc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1CCC(O)(c2ccncc2)C1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
1.600 M of n-Butyllithium in hexane (0.810 mL) was added to a solution of 4-bromopyridine hydrochloride (210 mg, 1.1 mmol) in ether (5 mL, 0.05 mol) at −78° C. The solution was stirred at −78° C. for 30 min. and then tert-butyl 3-oxopyrrolidine-1-carboxylate (200 mg, 0.001 mol) was added and the temperature was maintained at −78° C. for 3 hours. The reaction mixture was quenched with water, extracted with AcOEt. The organic layer was dried with MgSO4, and concentrated to afford the desired product.
Reaction SMILES: [OH:1][CH:2]1[CH2:7][CH2:6][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:4][CH2:3]1.[H-].[Na+].[Cl:17][C:18]1[N:23]=[C:22](Cl)[CH:21]=[CH:20][N:19]=1>C1COCC1.C(OCC)(=O)C>[Cl:17][C:18]1[N:23]=[C:22]([O:1][CH:2]2[CH2:3][CH2:4][N:5]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:6][CH2:7]2)[CH:21]=[CH:20][N:19]=1
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: Clc1ccnc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
tert-Butyl 4-hydroxypiperidine-1-carboxylate (500 mg, 2.48 mmol) was added to a suspension of sodium hydride (60%, 149 mg, 3.73 mmol) in THF (8.28 mL) and the mixture was stirred for 30 minutes at room temperature. 2,4-Dichloropyrimidine (333 mg, 2.24 mmol) was added to the reaction mixture at 0° C. and warmed to room temperature over 3 days. The mixture was diluted with ethyl acetate (20.0 mL), and then washed with water:brine 1:1 (3×40 mL). The organic extracts were dried (Na2SO4) and concentrated in vacuo. The residue was purified by silica gel chromatography (10-60% ethyl acetate in hexanes) to yield tert-butyl 4-[(2-chloropyrimidin-4-yl)oxy]piperidine-1-carboxylate. MS APCI calc'd for C14H21ClN3O3 [M+H]+ 314. found 314.
Reaction SMILES: [F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4]Cl.[C-:12]#[N:13].[Na+].O>CS(C)=O>[F:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][C:12]#[N:13]
Reactant: [C-]#N
Reactant: COc1cccc(CCl)c1F
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: COc1cccc(CC#N)c1F

Procedure:
24.89 g (142.56 mmol) of 2-fluoro-3-methoxybenzyl chloride is stirred in 200 ml of DMSO with 8.38 g (171.07 mmol) of sodium cyanide for three hours at 90° C. The reaction mixture is poured into water and extracted four times with methyl tert-butyl ether. The combined organic phases are washed with brine, dried, the desiccant is suctioned off, and the solvent is spun off. First, only a portion of the residue (21.43 g) is incorporated in crude form into the next stage.
Reaction SMILES: [O:1]([CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][C:13]1([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:18][CH2:17][CH2:16][CH2:15][C:14]1=[O:19])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:37])[CH3:36])[C:30]=1[N:38]=[C:39]=[O:40])([CH3:28])[CH3:27].C([N-]C(C)C)(C)C.[Li+]>>[CH3:28][CH:26]([C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([CH:35]([CH3:36])[CH3:37])[C:30]=1[NH:38][C:39]([CH:15]1[CH2:16][CH2:17][CH2:18][C:13]([CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][O:1][C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:14]1=[O:19])=[O:40])[CH3:27]
Reactant: CC(C)c1cccc(C(C)C)c1N=C=O
Reactant: O=C1CCCCC1(CCCCCOc1ccccc1)c1ccccc1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Product: CC(C)c1cccc(C(C)C)c1NC(=O)C1CCCC(CCCCCOc2ccccc2)(c2ccccc2)C1=O

Procedure:
The title compound, mp 150°-153° C., was prepared from 2-(5-phenoxypentyl)-2-phenylcyclohexanone (2.50 g, 0.007 mol), 2,6 diisopropylphenyl isocyanate (1.42 g, 0.007 mol), and lithium diisopropylamide (0.007 mol) using the procedure described in Example 1.
Reaction SMILES: C(#N)C.[CH3:4][O:5][C:6]1[C:11]([CH2:12]Cl)=[CH:10][CH:9]=[CH:8][N:7]=1.[CH2:14]1[CH2:19][CH2:18][CH2:17][CH2:16][CH:15]1[CH2:20][O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1/[CH:28]=[CH:29]/[CH:30]1[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C>[CH3:4][O:5][C:6]1[C:11]([CH2:12][N:33]2[CH2:34][CH2:35][CH:30](/[CH:29]=[CH:28]/[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[O:21][CH2:20][CH:15]3[CH2:14][CH2:19][CH2:18][CH2:17][CH2:16]3)[CH2:31][CH2:32]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: COc1ncccc1CCl
Reactant: C(=C/C1CCNCC1)\c1ccccc1OCC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: COc1ncccc1CN1CCC(/C=C/c2ccccc2OCC2CCCCC2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To acetonitrile (10 ml) were added 500 mg of 2-methoxy-3-(chloromethyl)pyridine, 1.04 g of 4-[(E)-2-[(2-cyclohexylmethyloxy)phenyl]-1-ethenyl]piperidine and 531 mg of potassium carbonate, followed by stirring at room temperature overnight. Ethyl acetate was added to the reaction solution, and the mixture was filtered through alumina-silica gel. Then, the solvent was evaporated, and the crude product was purified by silica gel column chromatography (hexane:ethyl acetate=8:1), to give 961 mg of the title compound as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH:11]=[O:12].C([O-])([O-])=O.[K+].[K+].Br[CH2:20][C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22]>CCOC(C)=O.O>[C:24]([O:23][C:21](=[O:22])[CH2:20][N:7]1[C:8]2[C:4](=[CH:3][C:2]([Cl:1])=[CH:10][CH:9]=2)[C:5]([CH:11]=[O:12])=[CH:6]1)([CH3:27])([CH3:26])[CH3:25]
Reactant: CC(C)(C)OC(=O)CBr
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)Cn1cc(C=O)c2cc(Cl)ccc21
Temperature: 25 °C

Procedure:
To a suspension of 5-chloro-1H-indole-3-carbaldehyde [827-01-0] (500 mg, 2.78 mmol) and K2CO3 (885 mg, 6.40 mmol) in (14 mL) was added tert-butyl 2-bromoacetate (0.576 mL, 3.90 mmol) dropwise at RT. The resulting mixture was then heated to reflux for 18 h. After cooling to RT, the mixture was diluted with EtOAc and water. The organic layer was separated, subsequently washed with water (1×) and brine (1×), dried (Phase separator) and concentrated in vacuo to give the crude title compound. MS (LC/MS): 294 [M+H]+; tR (HPLC conditions b): 5.45 min. The product was used in the next reaction step without further purification.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[OH:10])[CH:5]=[O:6].[H-].[Na+].I[CH2:14][CH2:15][CH3:16]>CN(C=O)C.C(OCC)(=O)C>[OH:10][C:9]1[CH:8]=[CH:7][C:4]([CH:5]=[O:6])=[CH:3][C:2]=1[O:1][CH2:14][CH2:15][CH3:16]
Reactant: CCCI
Reactant: O=Cc1ccc(O)c(O)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCCOc1cc(C=O)ccc1O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 143.2 %

Procedure:
3,4-Dihydroxybenzaldehyde (0.5 g, 3.62 mmol) was dissolved in DMF (10 mL) and sodium hydride (0.087 g, 3.62 mmol) was added. The reaction mixture was stirred at rt for 10 min. Iodopropane (0.35 mL, 0.62 mmol) was added and the reaction was stirred at 80° C. for 2.5 h. The reaction was diluted with ethyl acetate and washed with 2N HCl and water. Silica gel chromatography eluting with 35% ethyl acetate/hexane yielded 0.16 g of desired product: ESI-MS 181 (M+H).
Reaction SMILES: [N+:1]([C:4]1[CH:28]=[CH:27][C:7]([CH:8]=[CH:9][C:10]2[N:11]=[N:12][C:13]([CH:16]=[CH:17][C:18]3[CH:23]=[CH:22][C:21]([N+:24]([O-:26])=[O:25])=[CH:20][CH:19]=3)=[CH:14][CH:15]=2)=[CH:6][CH:5]=1)([O-:3])=[O:2].ClC1C=CC=C(C(OO)=[O:37])C=1>ClCCCl>[N+:24]([C:21]1[CH:22]=[CH:23][C:18]([CH:17]=[CH:16][C:13]2[N:12]=[N+:11]([O-:37])[C:10]([CH:9]=[CH:8][C:7]3[CH:6]=[CH:5][C:4]([N+:1]([O-:3])=[O:2])=[CH:28][CH:27]=3)=[CH:15][CH:14]=2)=[CH:19][CH:20]=1)([O-:26])=[O:25]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)nn2)cc1
Solvent: ClCCCl
Product: O=[N+]([O-])c1ccc(C=Cc2ccc(C=Cc3ccc([N+](=O)[O-])cc3)[n+]([O-])n2)cc1

Procedure:
33 g of this nitro compound (K') is reacted, with 15g of m-chloroperbenzoic acid in halogen-containing solvent (such as 1,2-dichloroethane) to obtain 27 g of 3,6-di(p-nitrostyryl)pyridazine-N-oxide (L'). The nitro group in the N-oxide compound (L') is selectively reduced under a neutral or basic condition to obtain 20 g of vermilion crystals of 3,6-di(p-aminostyryl)pyridazine-N-oxide (M').
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:28]([F:31])([F:30])[F:29])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][NH:25][CH2:24]4)=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1.C(N(CC)CC)C.[S:39](Cl)([CH3:42])(=[O:41])=[O:40]>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:3]=[C:4]([C:12]2([C:28]([F:31])([F:29])[F:30])[O:16][N:15]=[C:14]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4([F:27])[CH2:26][N:25]([S:39]([CH3:42])(=[O:41])=[O:40])[CH2:24]4)=[CH:19][CH:18]=3)[CH2:13]2)[CH:5]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:7]=1
Reactant: FC(F)(F)c1cc(Cl)cc(C2(C(F)(F)F)CC(c3ccc(C4(F)CNC4)cc3)=NO2)c1
Reactant: CS(=O)(=O)Cl
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CC(F)(c2ccc(C3=NOC(c4cc(Cl)cc(C(F)(F)F)c4)(C(F)(F)F)C3)cc2)C1
Temperature: 25 °C
Reaction time: 18 h
Yield: 87.2 %

Procedure:
To a solution of 5-(3-chloro-5-(trifluoromethyl)phenyl)-3-(4-(3-fluoroazetidin-3-yl)phenyl)-5-(trifluoromethyl)-4,5-dihydroisoxazole (Preparation 22, 95 mg, 0.2 mmol) in CH2Cl2 (5 mL) was added triethylamine (0.15 mL, 1.1 mmol) and DMAP (5 mg, 0.04 mmol). Contents were stirred for 30 minutes at which time mesyl chloride (25 mg, 0.2 mmol) was added and the reaction was stirred for 18 hours at room temperature. Next, the reaction was concentrated to ˜3 mL under nitrogen purge and injected directly onto a 24 g Redi-Sep column. The crude material was chromatographed eluting from 100% heptane to 30:70 EtOAc:heptane to afford the final product (95 mg, 94%) as a solid. 1HNMR (CDCl3) δ ppm: 7.85 (1H), 7.79-7.77 (3H), 7.72 (1H), 7.64 (2H), 4.50-4.42, (2H), 4.34-4.27 (2H), 4.18 (1H), 3.76 (1H), 3.03 (3H); m/z (Cl) 545 ([M+H]+.
Reaction SMILES: [NH2:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1.[C:15]([O:19][C:20](O)=[O:21])([CH3:18])([CH3:17])[CH3:16]>CO>[C:15]([O:19][C:20]([NH:1][CH:2]1[CH:6]([CH3:7])[CH2:5][N:4]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH2:3]1)=[O:21])([CH3:18])([CH3:17])[CH3:16]
Reactant: CC1CN(Cc2ccccc2)CC1N
Reactant: CC(C)(C)OC(=O)O
Solvent: CO
Product: CC1CN(Cc2ccccc2)CC1NC(=O)OC(C)(C)C
Reaction time: 1 h

Procedure:
To a solution of 3-amino-1-benzyl-4-methylpyrrolidine (9.5 g) in methanol (190 ml) is added anhydrous t-butoxycarboxylic acid (13.0 g) at room temperature, and the mixture is stirred for one hour. Methanol is distilled off under reduced pressure, and to the resulting residue is added water. The mixture is extracted with dichloromethane, and the extract is dried over magnesium sulfate and then dichloromethane is distilled off. The residue is purified by silica gel column chromatography (solvent, dichloromethane:methanol=19:1) to give 3-(t-butoxycarbonylamino)-1-benzyl-4-methylpyrrolidine (isomer A) (4.4 g), as colorless prisms, m.p. 131.5°-132.7° C.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10](=[O:16])[C@H:11]1[CH2:15][CH2:14][CH2:13][NH:12]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[N:17]1[C:22]([C:23]([OH:25])=O)=[CH:21][CH:20]=[CH:19][C:18]=1[C:26]([OH:28])=O>CCOC(C)=O>[CH2:2]([O:9][C:10]([C@H:11]1[CH2:15][CH2:14][CH2:13][N:12]1[C:23]([C:22]1[CH:21]=[CH:20][CH:19]=[C:18]([C:26]([N:12]2[CH2:13][CH2:14][CH2:15][C@@H:11]2[C:10]([O:9][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=2)=[O:16])=[O:28])[N:17]=1)=[O:25])=[O:16])[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: O=C(O)c1cccc(C(=O)O)n1
Reactant: O=C(OCc1ccccc1)[C@H]1CCCN1
Agent: Cl
Solvent: CCOC(C)=O
Product: O=C(OCc1ccccc1)[C@H]1CCCN1C(=O)c1cccc(C(=O)N2CCC[C@@H]2C(=O)OCc2ccccc2)n1
Yield: 76.9 %

Procedure:
Using General Procedure A with 5.8 g (24.0 mmol) D-Proline benzyl ester hydrochloride and 2.0 g (12.0 mmol) pyridine-2,6-dicarboxylic acid afforded, after flash chromatography (EtOAc), 5.0 g (77%) of the title compound as a yellow oil. MS m/e (%): 559 (M+NH4+, 60), 542 (M+H+, 100).
Reaction SMILES: [NH2:1][CH:2]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:21])[F:20])=[CH:15][CH:14]=1)[CH:3]([C:5]1[CH:10]=[CH:9][C:8]([F:11])=[CH:7][CH:6]=1)[OH:4].[C:23]1([CH2:29][CH2:30][C:31](Cl)=[O:32])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1.C(=O)([O-])O.[Na+]>C(OCC)(=O)C.O>[F:11][C:8]1[CH:9]=[CH:10][C:5]([CH:3]([OH:4])[CH:2]([NH:1][C:31](=[O:32])[CH2:30][CH2:29][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]([F:22])([F:20])[F:21])=[CH:15][CH:14]=2)=[CH:6][CH:7]=1
Reactant: NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Reactant: O=C(Cl)CCc1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=C(CCc1ccccc1)NC(Cc1ccc(C(F)(F)F)cc1)C(O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 87.3 %

Procedure:
To a solution of (1RS,2SR)-2-amino-1-(4-fluorophenyl)-3-(4-(trifluoromethyl)phenyl)-1-propanol (450 mg, 1.44 mmol) in ethyl acetate (20 ml) were added 3-phenylpropionyl chloride (320 ml, 2.15 mmol) and saturated aqueous sodium hydrogen carbonate (20 ml) and the mixture was stirred overnight at room temperature. The reaction solution was diluted with water (100 ml), and extracted with ethyl acetate (100 ml×2). The extract was washed with saturated brine, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The residue was recrystallized from ethyl acetate-hexane to give the title compound (560 mg, 88%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:25])[CH3:24])[N:5]([S:7]([NH:10]C(OCC1C=CC=CC=1)=O)(=[O:9])=[O:8])[CH3:6]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:26])[CH:4]([CH2:21][CH2:22][CH:23]([CH3:24])[CH3:25])[N:5]([S:7]([NH2:10])(=[O:8])=[O:9])[CH3:6]
Reactant: COC(=O)C(CCC(C)C)N(C)S(=O)(=O)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(CCC(C)C)N(C)S(N)(=O)=O
Reaction time: 3.5 h
Yield: 98.7 %

Procedure:
A solution of (N-carbobenzyloxyaminosulfonyl)-2-(3-methylbutyl)sarcosine methyl ester (20.6 g, 53.17 mmol) in 200 ml of methanol under nitrogen was cooled to 0° C. and 1.5 g of 10% Pd/C was added. The mixture was placed on a Parr Apparatus at 50 psi and hydrogenated for 3.5 hours. The catalyst was removed on a pad of CELITE® and the filtrate was concentrated in vacuo to afford 13.24 g (98.6%) of N-(aminosulfonyl)-2-(3-methylbutyl)sarcosine methyl ester (Formula V: R=CH3 ; R1 =(CH2)2CH(CH3)2 ; R2 =H; R3 =CH3) as an oil.