Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][C:11]2[NH:10][CH:9]=[C:8]3[C:14](=[O:23])[N:15]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=4)[N:16]=[C:7]3[C:6]=2[CH:5]=1)([O-:3])=[O:2].[Cl:24]C1C=CC(NN)=CC=1>>[Cl:24][C:20]1[CH:21]=[CH:22][C:17]([N:15]2[C:14](=[O:23])[C:8]3=[CH:9][NH:10][C:11]4[CH:12]=[CH:13][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][C:6]=4[C:7]3=[N:16]2)=[CH:18][CH:19]=1
Reactant: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccccc1
Reactant: NNc1ccc(Cl)cc1
Product: O=c1c2c[nH]c3ccc([N+](=O)[O-])cc3c-2nn1-c1ccc(Cl)cc1

Procedure:
The title compound was prepared following the procedure described for 5a using 4-chlorophenylhydrazine instead of phenylhydrazine. 1H-NMR (DMSO-d6) δ (ppm): 7.50 (2H, d, J=8.91 Hz), 7.90 (1H, d, J=8.91 Hz), 8.29 (2H, d, J=8.91 Hz), 8.48 (1H, dd, J=8.91, 2.38 Hz), 8.88 (1H, s), 8.91 (1H, d, J=2.67 Hz). m/z 341.8 (MH+).
Reaction SMILES: [CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]=[O:12])([CH3:3])[CH3:2].[CH2:13]([Mg]Br)[C:14]#[CH:15]>C1COCC1>[CH:1]([C@@H:4]1[CH2:9][CH2:8][C@@H:7]([CH3:10])[CH2:6][C@H:5]1[CH:11]([OH:12])[CH2:15][C:14]#[CH:13])([CH3:3])[CH3:2]
Reactant: CC(C)[C@@H]1CC[C@@H](C)C[C@H]1C=O
Reactant: C#CC[Mg]Br
Solvent: C1CCOC1
Product: C#CCC(O)[C@@H]1C[C@H](C)CC[C@H]1C(C)C
Temperature: 0 °C
Yield: 37.6 %

Procedure:
To a solution of (1R,2S,5R)-2-isopropyl-5-methylcyclohexanecarbaldehyde (1.0 g, 6.0 mmol) in THF (10 mL) at 0° C. was slowly added propargyl magnesium bromide (1 M, 8.9 mmol). After the reaction was allowed to warm to room temperature overnight 1.5 equivalents of additional propargyl magnesium bromide were added and the reaction was allowed to stir for 6 additional h. The reaction was again cooled to 0° C. and then quenched with 1 N HCl and partitioned between brine and MTBE. The organic layer was dried (MgSO4) and concentrated. The residue was purified by silica chromatography to give the desired alcohol (0.47 g).
Reaction SMILES: [CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=O)(=[O:5])=[O:4].O.[NH2:23][NH2:24]>C(O)C>[CH3:1][N:2]([CH3:21])[S:3]([NH:6][C:7]1[CH:8]=[C:9]([CH:18]=[CH:19][CH:20]=1)[C:10](=[N:23][NH2:24])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)Nc1cccc(C(=O)c2ccccc2)c1
Reactant: NN
Solvent: O
Solvent: CCO
Product: CN(C)S(=O)(=O)Nc1cccc(C(=NN)c2ccccc2)c1
Yield: 109 %

Procedure:
A solution of 3-[N-(dimethylaminosulfonyl)amino]-benzophenone (200 mg) and hydrazine hydrate (100 mg) in ethanol (4 ml) is refluxed for 17.5 hours. The reaction mixture is concentrated in vacuum and the residue is basified with aqueous sodium hydrogencarbonate and shaken with methylene chloride. The organic layer is washed with water, dried over anhydrous sodium sulfate and concentrated in vacuum. The residue is chromatographed on a column of silica gel, which is eluted with 3% methanol and methylene chloride. The eluate is concentrated in vacuum to give 3-[N-(dimethylaminosulfonyl)-amino]benzophenone hydrazone(228 mg) as an oil.
Reaction SMILES: Cl.[NH2:2][CH2:3][CH2:4][SH:5].[H-].[Na+].Cl[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11]N=1.O.O1CCOC[CH2:17]1>C(Cl)Cl>[C:11]1([S:5][CH2:4][CH2:3][NH2:2])[CH:17]=[CH:9][CH:14]=[CH:13][CH:12]=1
Reactant: NCCS
Reactant: C1COCCO1
Reactant: Clc1ccccn1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Product: NCCSc1ccccc1
Temperature: 25 °C

Procedure:
Mix 2-aminoethanethiol hydrochloride (4.07 g, 35.6 mmol) in dioxane (75 mL) at 50° C. Add sodium hydride (60% in mineral oil, 2.84 g, 71.0 mmol) at room temperature under nitrogen. Stir the reaction for 5 minutes. Add 2-chloropyridine (3.5 mL, 37 mmol) to the mixture. Reflux the mixture for 24 hours, and then cool to room temperature. Add water (100 mL), and methylene chloride (300 mL) to this mixture. Extract the aqueous layer with methylene chloride (3×50 mL). Wash the combined organic phase with brine (200 mL), dry (magnesium sulfate), filter and concentrate to an orange oil. Perform flash chromatography on silica gel eluting with 50% (80:18:12 CHCl3/MeOH/concentrated NH4OH)/methylene chloride to afford the title compound as a yellow oil (1.67 g) m/e=155 (MH+).
Reaction SMILES: Cl[C:2]1[C:7]([C:8](=[O:16])[C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)=[CH:6][N:5]=[C:4]2[N:17]([CH2:20][CH3:21])[N:18]=[CH:19][C:3]=12.Cl.[NH2:23]O.Cl>C(O)(=O)C>[CH2:20]([N:17]1[C:4]2[N:5]=[CH:6][C:7]3[C:2](=[N:23][O:16][C:8]=3[C:9]3[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=3)[C:3]=2[CH:19]=[N:18]1)[CH3:21]
Reactant: NO
Reactant: CCn1ncc2c(Cl)c(C(=O)c3ccc(F)cc3)cnc21
Agent: Cl
Solvent: CC(=O)O
Product: CCn1ncc2c3noc(-c4ccc(F)cc4)c3cnc21
Yield: 52.6 %

Procedure:
4-Chloro-1-ethyl-5-(4-fluorobenzoyl)-1H-pyrazolo[3,4-b]pyridine (4.5 g) and hydroxylamine hydrochloride (14.0 g) were refluxed in a solution of 250 ml of acetic acid and 4 ml of concentrated hydrochloric acid. After two hours the solvent was evaporated and the residue distributed between dichloromethane and an aqueous sodium bicarbonate solution. The organic phase was evaporated and the residue chromatographed over 230-400 mesh silica gel (10% ethyl acetate/dichloromethane). Evaporation of the appropriate fractions gave 2.2 g of product after trituration with pentane, mp 222°-223° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][N+:13]([O-:15])=[O:14])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[CH3:16][O:17][C:18]1[CH:19]=[C:20]([C:26]([CH2:32][CH2:33][CH:34]=[O:35])(C(C)C)[C:27]#[N:28])[CH:21]=[CH:22][C:23]=1[O:24][CH3:25].[F-].[K+].[CH3:38][CH:39](O)[CH3:40]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]([CH:39]([CH3:40])[CH3:38])[CH:12]([N+:13]([O-:15])=[O:14])[CH:34]([OH:35])[CH2:33][CH2:32][CH:26]([C:27]#[N:28])[C:20]2[CH:21]=[CH:22][C:23]([O:24][CH3:25])=[C:18]([O:17][CH3:16])[CH:19]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)O
Reactant: COc1ccc(CC[N+](=O)[O-])cc1OC
Reactant: COc1ccc(C(C#N)(CCC=O)C(C)C)cc1OC
Agent: [F-]
Agent: [K+]
Product: COc1ccc(C(C#N)CCC(O)C(C(c2ccc(OC)c(OC)c2)C(C)C)[N+](=O)[O-])cc1OC
Temperature: 25 °C

Procedure:
A mixture of 2-(3,4-dimethoxyphenyl)-1-nitroethane (4, 135 g, 0.64 mol), 2-(3,4-dimethoxyphenyl)-2-(3-oxopropyl)-2-isopropylacetonitrile (7, 156 g, 0.57 mol) and KF (19.3 g, anhydrous, Aldrich) in 2-propanol (2.0 L) was heated to 50°-55° C. for about 40 hours. The mixture was then cooled to room temperature and the isopropanol removed in vacuo. The residue was dissolved in CH2Cl2 (1.6 L) and filtered through Celite (50 g). The filtrate was extracted with saturated aqueous NaHCO3 (2×500 mL), the organic layer evaporated, and the product recrystallized from ethyl acetate-hexane (1:1) to yield 1-(3,4-dimethoxyphenyl)-2-nitro-6-cyano-(i-propyl)-6-(3,4-dimethoxyphenyl)hexan-3-ol (8, 205 g, m.p. 171°-173° C., MS m/e 486 (M+)).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][CH:3]=[C:2]1[C:6]1[O:7][C:8]([CH3:38])=[C:9]([CH2:11][O:12][C:13]2[CH:35]=[CH:34][C:16]([CH2:17][O:18][C:19]3[C:23]([CH2:24][C:25]([OH:27])=O)=[CH:22][N:21]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=4)[N:20]=3)=[CH:15][C:14]=2[O:36][CH3:37])[N:10]=1.C(Cl)(=O)OCC.Cl.[NH2:46][CH2:47][CH2:48]Cl>O.O1CCCC1.C(N(CC)CC)C>[O:27]1[CH2:48][CH2:47][N:46]=[C:25]1[CH2:24][C:23]1[C:19]([O:18][CH2:17][C:16]2[CH:34]=[CH:35][C:13]([O:12][CH2:11][C:9]3[N:10]=[C:6]([C:2]4[O:1][CH:5]=[CH:4][CH:3]=4)[O:7][C:8]=3[CH3:38])=[C:14]([O:36][CH3:37])[CH:15]=2)=[N:20][N:21]([C:28]2[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:22]=1
Reactant: COc1cc(COc2nn(-c3ccccc3)cc2CC(=O)O)ccc1OCc1nc(-c2ccco2)oc1C
Reactant: NCCCl
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: O
Solvent: CCN(CC)CC
Product: COc1cc(COc2nn(-c3ccccc3)cc2CC2=NCCO2)ccc1OCc1nc(-c2ccco2)oc1C
Reaction time: 0.67 h
Yield: 19.1 %

Procedure:
To a mixture of {3-[(4-{[2-(2-furyl)-5-methyl-1,3-oxazol-4-yl]methoxy}-3-methoxybenzyl)oxy]-1-phenyl-1H-pyrazol-4-yl}acetic acid (0.70 g), triethylamine (0.17 g) and tetrahydrofuran (30 mL) was added ethyl chlorocarbonate (0.18 g) at −30° C., and the mixture was stirred at the same temperature for 40 min. The reaction mixture was added to a mixture of 1-amino-2-chloroethane hydrochloride (0.81 g), triethylamine (0.71 g) and tetrahydrofuran (20 mL) at −30° C., and the mixture was stirred at room temperature for 1 hr. 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. A mixture of the obtained residue, potassium carbonate (0.24 g) and N,N-dimethylformamide (20 mL) was stirred at 90° C. for 2 hrs. Water was poured into 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. The residue was subjected to silica gel column chromatography to give 4-{[4-({[4-(4,5-dihydro-1,3-oxazol-2-ylmethyl)-1-phenyl-1H-pyrazol-3-yl]oxy}methyl)-2-methoxyphenoxy]methyl}-2-(2-furyl)-5-methyl-1,3-oxazole as colorless crystals (0.14 g, yield 18%) from a fraction eluted with ethyl acetate-methanol (50:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 95-96° C.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:14])[F:13])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=3)[N:17]=2)[CH:9]=[N:8]1.C(O)(=O)C.[NH:33]1[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[N:7]1[C:11]([C:12]([F:15])([F:13])[F:14])=[C:10]([C:16]2[O:20][N:19]=[C:18]([C:21]3[CH:22]=[CH:23][C:24]([CH2:25][N:33]4[CH2:36][CH:35]([C:37]([OH:39])=[O:38])[CH2:34]4)=[CH:27][CH:28]=3)[N:17]=2)[CH:9]=[N:8]1
Reactant: O=Cc1ccc(-c2noc(-c3cnn(-c4ccccn4)c3C(F)(F)F)n2)cc1
Reactant: O=C(O)C1CNC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: O=C(O)C1CN(Cc2ccc(-c3noc(-c4cnn(-c5ccccn5)c4C(F)(F)F)n3)cc2)C1
Temperature: 25 °C
Reaction time: 0.67 h
Yield: 63.5 %

Procedure:
To a solution of 4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzaldehyde (1.0 g, 2.60 mmol) in DCM (10 mL) was added acetic acid (15 mL) and azetidine-3-carboxylic acid (1.5 eq, 3.90 mmol). The mixture was stirred at RT for 40 min., then a suspension of sodium triacetoxyborohydride (1 eq, 2.60 mmol) in DCM (30 mL) was added dropwise over 1.5 h. The volatiles were removed in vacuo, water (200 mL) was added and the resulting solid was collected by filtration. Ethyl acetate (40 mL) was added to the crude product and after sonication for 30 min, the solids were collected by filtration and washed additional ethyl acetate to afford 1-(4-(5-(1-(pyridin-2-yl)-5-(trifluoromethyl)-1H-pyrazol-4-yl)-1,2,4-oxadiazol-3-yl)benzyl) azetidine-3-carboxylic acid (777 mg, 1.65 mmol) as a white solid. The compound had an HPLC retention time=2.55 min. Column: CHROMOLITH® SpeedROD 4.6×50 mm (4 min.); Solvent A=10% MeOH, 90% H2O, 0.2% H3PO4; Solvent B=90% MeOH, 10% H2O, 0.2% H3PO4. LC/MS M+1=471.05. 1H NMR (400 MHz, DMSO-d6) δ ppm 3.21-3.25 (m, 3H), 3.40-3.44 (m, 2H), 3.64 (s, 2H), 7.51 (d, J=8.3 Hz, 2H), 7.69 (ddd, J=0.8 Hz, 4.7 Hz, 8.3 Hz, 1H), 7.90 (d, J=8.0 Hz, 1H), 8.03 (d, J=8.3 Hz, 2H), 8.20 (dt, J=1.9 Hz, 7.7 Hz, 1H), 8.66 (dd, J=1.1 Hz, 4.1 Hz, 1 H) 8.73 (s, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][NH:11][CH2:12][C:13]([F:16])([F:15])[F:14])=[CH:4][CH:3]=1.[CH2:17]([N:24]([CH2:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1)[C@@H:25]([C@H:27]1[CH2:29][O:28]1)[CH3:26])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C(O)C>[CH2:30]([N:24]([CH2:17][C:18]1[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1)[C@H:25]([CH3:26])[C@@H:27]([OH:28])[CH2:29][N:11]([CH2:10][CH2:9][CH2:8][C:5]1[CH:6]=[CH:7][C:2]([F:1])=[CH:3][CH:4]=1)[CH2:12][C:13]([F:14])([F:15])[F:16])[C:31]1[CH:32]=[CH:33][CH:34]=[CH:35][CH:36]=1
Reactant: Fc1ccc(CCCNCC(F)(F)F)cc1
Reactant: C[C@H]([C@H]1CO1)N(Cc1ccccc1)Cc1ccccc1
Solvent: CCO
Product: C[C@H]([C@@H](O)CN(CCCc1ccc(F)cc1)CC(F)(F)F)N(Cc1ccccc1)Cc1ccccc1

Procedure:
The product of Step c (3.48 g, 15.0 mmol, 1 eq.), (1R)-N,N-dibenzyl-1-[(2S)-oxiran-2-yl]ethanamine (the synthesis of which is described in Example 100) (3.96 g, 15.0 mmol, 1 eq.) and ethanol (20 mL) were mixed at 25° C. under N2 then refluxed for 4 days. Worked up by stripping off the ethanol then purifying the residue by flash chromatography in 3:1 Hexanes/EtOAc. Obtained to 3.78 g of a yellow oil. By NMR, the oil is product and some minor impurities and was carried on to the next step. MS (ESI) detects (M+H)+=503.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH2:9])[C:5]([CH3:8])=[N:6][CH:7]=1.[CH3:10][Si]([N-][Si](C)(C)C)(C)C.IC>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][CH3:10])[C:5]([CH3:8])=[N:6][CH:7]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: Cc1ncc(Br)cc1N
Solvent: CI
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CNc1cc(Br)cnc1C
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 5-bromo-2-methyl-pyridin-3-ylamine (Stage 75.1.4, 3.81 mmol) in THF (25 ml) cooled with an ice-bath was added 1 M bis(trimethylsilyl)amide in THF (4.38 mmol). The RM was stirred for 1 h at rt then was added iodomethane (4.38 mmol). The RM was stirred for 1 h at rt. The RM was cooled with an ice-bath and was added 1 M bis(trimethylsilyl)amide in THF (1.9 mmol). The RM was stirred for 30 min at it then was added iodomethane (1.9 mmol). The RM was stirred for 1 h at it then was diluted with EtOAc and washed with aqueous Na2CO3, with brine, dried over Na2SO4, filtered and evaporated. The residue was taken in MeOH and separated by preparative HPLC. The first eluting pure fractions containing product were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (HPLC: tR 1.88 min (Method A); M+H=201, 203 MS-ES). The second eluting pure fractions, that contained (5-bromo-2-methyl-pyridin-3-yl)-dimethyl-amine side product, were basified with NaHCO3, concentrated and extracted with dichloromethane (2×). The combined fractions were washed with brine, dried over Na2SO4, filtered and evaporated to give the title compound as a brown oil (HPLC: tR 2.01 min (Method A); M+H=215, 217 MS-ES).
Reaction SMILES: [CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20](Br)[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:56][Si:57]([C:60]#[CH:61])([CH3:59])[CH3:58]>[Cu]I.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.CN(C)C=O>[CH:1]1([C@H:5]([NH:13][C:14]([C:16]2[C:21]([CH3:22])=[C:20]([C:61]#[C:60][Si:57]([CH3:59])([CH3:58])[CH3:56])[C:19](=[O:24])[N:18]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[C:17]=2[CH3:31])=[O:15])[C:6]2[CH:11]=[CH:10][CH:9]=[C:8]([F:12])[CH:7]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: C#C[Si](C)(C)C
Reactant: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1Br
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1c(C(=O)N[C@H](c2cccc(F)c2)C2CCC2)c(C)n(-c2ccccc2)c(=O)c1C#C[Si](C)(C)C
Temperature: 120 °C
Yield: 53.2 %

Procedure:
A mixture of 5-bromo-2,4-dimethyl-6-oxo-1-phenyl-1,6-dihydro-pyridine-3-carboxylic acid [(S)-cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (2a, 60.0 mg, 0.124 mmol), N,N-dimethylformamide (0.6 mL), copper(I) iodide (4.5 mg, 0.024 mmol), bis(triphenylphosphine)palladium(II) chloride (9.1 mg, 0.013 mmol), triphenylphosphine (20.0 mg, 0.0762 mmol), N-ethylethanamine (0.6 mL, 6 mmol) and (trimethylsilyl)acetylene (0.052.6 mL, 0.372 mmol) was flushed with Argon and heated under microwave irradiation for 30 min at 120° C. It was evaporated in vacuo, transferred to 20 g silica gel column with 1,2-dichloroethane and separated by flash chromatography with gradient heptane-ethyl acetate to give 2,4-dimethyl-6-oxo-1-phenyl-5-trimethylsilanylethynyl-1,6-dihydro-pyridine-3-carboxylic acid [(S) -cyclobutyl-(3-fluoro-phenyl)-methyl]-amide (33 mg; yield=53%) as a pale yellow-brown solid. LC-MS (m/z) 501.7 (MH+); tR=1.94 (method C).
Reaction SMILES: C(OP([CH2:9][C:10]1[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][CH:11]=1)(OCC)=O)C.[C:20]1([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[CH:34]=[C:33]([C:36](=O)[CH3:37])[CH:32]=[CH:31]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.[O-][CH2:40]C.[Na+].C(O)C>CS(C)=O.C(=O)(O)[O-].[Na+]>[C:20]1([C:26]2[CH:27]=[CH:28][CH:29]=[C:30]3[C:35]=2[CH:34]=[C:33]([C:36]([CH3:37])=[CH:9][C:10]2[CH:11]=[CH:12][C:13]([C:14]([O:16][CH2:17][CH3:40])=[O:15])=[CH:18][CH:19]=2)[CH:32]=[CH:31]3)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: CC(=O)c1ccc2cccc(-c3ccccc3)c2c1
Reactant: CC[O-]
Reactant: CCOP(=O)(Cc1ccc(C(=O)OC)cc1)OCC
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCO
Product: CCOC(=O)c1ccc(C=C(C)c2ccc3cccc(-c4ccccc4)c3c2)cc1
Reaction time: 0.5 h
Yield: 64 %

Procedure:
Methyl p-[(diethoxyphosphoryl)methyl]benzoate (4.00 g, 13.97 mmoles, prepared as in Liebigs Ann. Chem. 1985, 929) was added to a 1M dimsyl anion solution in dimethylsulfoxide (12.71 mL,12.71 mmoles, prepared by warming sodium hydride in dimethylsulfoxide for 1 hour at 65° C.). After 30 minutes, the mixture was added to a solution of 1-(8-phenyl-2-naphthyl)ethanone (XIVa) (0.540 g, 2.19 mmoles) in dimethylsulfoxide (10.0 mL) at room temperature. After 2 hours at room temperature, a 1M solution of sodium ethoxide in ethanol (1.31 mL, 2.63 mmoles) was added. After 2 hours at room temperature, the mixture was diluted with saturated sodium bicarbonate (100 mL) and extracted with diethyl ether (100 mL×3). The solution was evaporated and the residue chromatographed (eluted with 5% ethyl acetate in hexane) over silica to give 0.500 g (yield: 64%) of 4-[2-(8-phenyl-2-naphthalenyl)-propenyl]benzoic acid, ethyl ester as a white solid. NMR indicated the ratio of E to Z isomers as 2:1.
Reaction SMILES: [C:1]1([O:7][CH3:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[B:9](OC)([O:12]C)[O:10]C.Cl>C1COCC1>[CH3:8][O:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[B:9]([OH:12])[OH:10]
Reactant: COc1ccccc1
Reactant: COB(OC)OC
Agent: Cl
Solvent: C1CCOC1
Product: COc1ccccc1B(O)O
Temperature: 0 °C
Yield: 94.8 %

Procedure:
Anisole (2.16 g, 20.0 mmol) was dissolved in dry THF (50 ml) in a dry 100 ml flask flushed with nitrogen. The mixture was chilled in a dry ice/2-propanol bath, n-butyl lithium (10.9 ml of a 2.3M solution in hexanes, 25 mmol) was added, then the cooling bath was exchanged for an ice-water bath. The reaction was stirred for an hour at 0° C., then trimethyl borate (2.3 ml, 20 mmol) was added and the mixture was stirred at room temperature overnight. The reaction mixture was treated with 2N aqueous HCl to pH 3 and mixed well for 30 minutes, then extracted with ether (3×15 ml). The organic materials were combined, dried (MgSO4), then concentrated under reduced pressure which gave 2.88 g (95%) of 2-methoxybenzene boronic acid as a clear oil which was used in the next step without further purification.
Reaction SMILES: [Cl:1][C:2]([Cl:11])([Cl:10])[C:3]([C:5]1[NH:6][CH:7]=[CH:8][CH:9]=1)=[O:4].C(OC(=O)C)(=O)C.[N+:19]([O-])([OH:21])=[O:20].C(=O)(O)[O-].[Na+]>C(O)(=O)C>[N+:19]([C:7]1[NH:6][C:5]([C:3](=[O:4])[C:2]([Cl:1])([Cl:10])[Cl:11])=[CH:9][CH:8]=1)([O-:21])=[O:20]
Reactant: O=[N+]([O-])O
Reactant: O=C(c1ccc[nH]1)C(Cl)(Cl)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: O=C(c1ccc([N+](=O)[O-])[nH]1)C(Cl)(Cl)Cl
Temperature: 25 °C

Procedure:
21.3 g (0.1 mol) of 2-trichloroacetylpyrrole and 100 ml of acetic anhydride were introduced into a round-bottomed flask. At 0° C., a solution of 4.2 ml of fuming nitric acid, 8 ml of acetic acid and 8 ml of acetic anhydride was added dropwise and the temperature was permitted to increase to room temperature. The reaction medium was poured into ice, the pH adjusted to 8 with sodium bicarbonate, extracted with dichloromethane, the organic phase decanted off, dried over magnesium sulfate and evaporated. The residue obtained was purified by chromatography on a silica column eluted with a mixture of dichloromethane and hexane (60-40). There were recovered 5.5 g (21%) of 5-nitro-2-trichloroacetylpyrrole in the form of a dark green oil and 11.2 g of 4-nitro-2-trichloroacetylpyrrole of melting point 160°-163° C.
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[NH:7][C:8](=[S:12])[NH:9][C:10]=1[CH3:11])=[O:5])[CH3:2].Cl[CH2:14][C:15](=O)[CH3:16].O=P(Cl)(Cl)Cl>CCO.CC#N>[CH2:1]([O:3][C:4]([C:6]1[N:7]=[C:8]2[N:9]([C:10]=1[CH3:11])[C:15]([CH3:16])=[CH:14][S:12]2)=[O:5])[CH3:2]
Reactant: CCOC(=O)c1[nH]c(=S)[nH]c1C
Reactant: CC(=O)CCl
Solvent: CC#N
Solvent: CCO
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1nc2scc(C)n2c1C

Procedure:
A mixture of 5-methyl-2-thioxo-2,3-dihydro-1H-imidazole-4-carboxylic acid ethyl ester (5.37 mmol) and chloroacetone (6.44 mmol) in EtOH (10 mL) is heated at reflux for 150 min. The solvents are removed in vacuo and a solution of POCl3 (16.1 mmol) in MeCN (10 mL) is added. The mixture is stirred at reflux for 60 h, concentrated in vacuo and diluted with chloroform. Ice water is added and the mixture is neutralized by addition of Na2CO3. The layers are separated and the aq. layer is extracted with chloroform. The combined organic layers are dried over Na2SO4 and concentrated in vacuo to give a mixture of two regioisomers (see A.7.7) which are separated by FC (heptane to heptane/EtOAc 3/7). LC-MS: tR=0.71 min; [M+H]+=225.0.
Reaction SMILES: CS(O[CH2:6][C:7]1([CH2:27][O:28][CH2:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH2:26][CH2:25][CH2:24][C:9]2([O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:21]=[CH:20][C:19]([O:22][CH3:23])=[CH:18][CH:17]=3)[CH2:10]2)[CH2:8]1)(=O)=O.[N-:36]=[N+:37]=[N-:38].[Na+].CCOCC>CS(C)=O.CCOC(C)=O>[N:36]([CH2:6][C:7]1([CH2:27][O:28][CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH2:26][CH2:25][CH2:24][C:9]2([O:13][C:12](=[O:14])[N:11]([CH2:15][C:16]3[CH:17]=[CH:18][C:19]([O:22][CH3:23])=[CH:20][CH:21]=3)[CH2:10]2)[CH2:8]1)=[N+:37]=[N-:38]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(CN2CC3(CCCC(COCc4ccccc4)(COS(C)(=O)=O)C3)OC2=O)cc1
Agent: [Na+]
Solvent: CCOCC
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: COc1ccc(CN2CC3(CCCC(CN=[N+]=[N-])(COCc4ccccc4)C3)OC2=O)cc1
Temperature: 120 °C
Yield: 93.9 %

Procedure:
To a light orange solution of (7-((benzyloxy)methyl)-3-(4-methoxybenzyl)-2-oxo-1-oxa-3-azaspiro[4.5]decan-7-yl)methyl methanesulfonate (5.71 g, 11.3 mmol) in DMSO (45.4 mL) was added sodium azide (2.21 g, 34.0 mmol). The reaction was heated at 120° C. behind a blast shield. After 4 days the reaction was cooled to RT and diluted with 1:1 EtOAc:Et2O (150 mL). This mixture was washed with water (3×100 mL), and the resulting organic layer was dried over magnesium sulphate, filtered, and concentrated to provide 7-(azidomethyl)-3-{[4-(methyloxy)phenyl]methyl}-7-{[(phenylmethyl)oxy]methyl}-1-oxa-3-azaspiro[4.5]decan-2-one (4.78 g, 89% crude yield) which was used without further purification. MS (m/z) 451.0 (M+H+).
Reaction SMILES: [N+:1]([C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[CH:6]=[CH:7][C:8](Cl)=[N:9]2)([O-])=O.[F:15][C:16]1[CH:17]=[C:18]([S:23](Cl)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1.[NH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[C:30]([CH3:34])[CH:29]=1>>[F:15][C:16]1[CH:17]=[C:18]([S:23]([NH:1][C:4]2[CH:13]=[CH:12][CH:11]=[C:10]3[C:5]=2[CH:6]=[CH:7][C:8]([NH:27][C:28]2[CH:29]=[C:30]([CH3:34])[CH:31]=[CH:32][CH:33]=2)=[N:9]3)(=[O:25])=[O:24])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: Cc1cccc(N)c1
Reactant: O=[N+]([O-])c1cccc2nc(Cl)ccc12
Reactant: O=S(=O)(Cl)c1cc(F)cc(F)c1
Product: Cc1cccc(Nc2ccc3c(NS(=O)(=O)c4cc(F)cc(F)c4)cccc3n2)c1

Procedure:
The title compound, MS: m/e=426.0 (M+H+), was prepared in accordance with the general method of example 89 from 5-nitro-2-chloroquinoline, 3,5-difluorobenzenesulfonylchloride and m-toluidine.