Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC(C)([O-])C.[K+].[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12](=O)[NH:13]2.C(OP(Cl)(OCC)=O)C.[N+:35]([CH2:37][C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])#[C-:36]>C1COCC1>[F:7][C:8]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:9]=1[N:10]([C:19]([N:21]1[CH2:25][CH2:24][CH2:23][CH2:22]1)=[O:20])[CH2:11][C:12]1[N:13]2[CH:36]=[N:35][C:37]=1[C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39]
Reactant: [C-]#[N+]CC(=O)OC(C)(C)C
Reactant: O=C1CN(C(=O)N2CCCC2)c2c(F)cccc2N1
Agent: CC(C)(C)[O-]
Agent: CCOP(=O)(Cl)OCC
Agent: [K+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1c(F)cccc1-2
Reaction time: 0.5 h

Procedure:
Potassium tert-butoxide (1M, 3.8 ml) is added to 5-fluoro-1,2,3,4-tetrahydro-4-[(pyrrolidino)carbonyl]quinoxalin-2-one (XXXII, EXAMPLE 29, 0.908 g) at 0° in THF (20 ml). The mixture is stirred for 30 min and then diethylchlorophosphate (0.55 ml) is added. The reaction is stirred for 1 hr at 0°, then cooled at -78°. tert-butyl isocyanoacetate (0.58 g) is added, followed by potassium tert-butoxide (1M, 4.14 ml). The reaction is stirred at -78° for 4 hr, then allowed to warm to 20°-25° over 1 hr. The mixture is then partitioned between ethyl acetate, water, and saline. The organic layers are dried over magnesium sulfate and concentrated. The crude product is chromatographed on silica gel (250 ml) eluting with a gradient of ethyl acetate/dichloromethane (20/80 to 40/60). The appropriate fractions are pooled, concentrated and crystallized from dichloromethane/hexane to give the title compound; mp 213.5°-214.5°; MS (m/z) at 386; IR (mineral oil) 1689, 1677, 1217, 1363 and 1157 cm-1 ; NMR (CDCl3) 1.63, 1.88, 3.36, 5.08, 7.08, 7.20, 7.33 and 8.00 δ.
Reaction SMILES: [CH3:1][C:2]1[NH:3][CH:4]=[CH:5][N:6]=1.[N+:7]([O-])([OH:9])=[O:8].S(=O)(=O)(O)O>O>[CH3:1][C:2]1[NH:3][C:4]([N+:7]([O-:9])=[O:8])=[CH:5][N:6]=1
Reactant: O=[N+]([O-])O
Reactant: Cc1ncc[nH]1
Agent: O=S(=O)(O)O
Solvent: O
Product: Cc1ncc([N+](=O)[O-])[nH]1
Reaction time: 0.17 h

Procedure:
In a nitrator made of acid-resistant stainless steel of 75 liters capacity, provided with a reflux condenser, a mixer and a thermometer as well as a cooling mantle, there were dissolved 8 kg of 2-methylimidazole into a solution already nitrated as in example IV, and then 24 liters of nitric acid of 1.40 density were added in such a manner, that the temperature was maintained at 70°. Thereafter sulphuric acid of 1.84 density was added such that, by simultaneous stirring and cooling, a constant temperature was maintained. After addition of 10 liters of sulphuric acid, the introduction was interrupted and after 10 minutes the sulphuric acid was gradually introduced until a total quantity of 24 liters was used. The reaction proceeded progressively more intensively and the flow of cooling water was correspondingly increased. A supplementary reservoir in the form of a tank with a conduit enabled the introduction of 10 liters of already reacted nitrated solution to the nitrator--a similar device was used in all reactions which have begun at a low temperature. During and after addition of the entire quantity of sulphuric acid, the solution was continually stirred and cooled for 15 minutes, and then, after a clear diminution of the reaction and diminishing of the exothermic effect, a slow increase of temperature, degree by degree in one minute, was allowed until a temperature of 110° has been reached. The mixture was maintained at this temperature for 15 minutes more. Then the reflux condenser was disengaged, while simultaneously leading the liberated vapors and gases directly to the absorption device, and the flow of the cooling water was terminated. The temperature of the reacting mixture raised by itself, reaching at the end a temperature of 138°. At this temperature the reaction was completed in 20 minutes, whereby the solution was condensed by distilling off about 3 liters, mainly water and nitric acid (i.e. diluted nitric acid), whereby after this treatment the cooling of the mixture was reinstituted. In the nitrator, 20% of the volume of the solution was retained for the treatment of the following charge, and from the remaining quantity there was obtained in known manner 8.700 kg of 2-methyl-5-nitroimidazole corresponding to 70% of theoretical.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1)#[N:2].N[CH2:22][CH2:23][SH:24].[Cl-].[Na+]>C(O)C>[S:24]1[CH2:23][CH2:22][N:2]=[C:1]1[C:3]1[CH:4]=[CH:5][C:6]([CH2:7][NH:8][S:9]([C:12]2[CH:17]=[CH:16][C:15]([F:18])=[CH:14][CH:13]=2)(=[O:11])=[O:10])=[CH:19][CH:20]=1
Reactant: NCCS
Reactant: N#Cc1ccc(CNS(=O)(=O)c2ccc(F)cc2)cc1
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Product: O=S(=O)(NCc1ccc(C2=NCCS2)cc1)c1ccc(F)cc1
Yield: 88.8 %

Procedure:
To a solution of N-(4-cyanobenzyl)-4-fluorobenzenesulfonamide (1.23 g, 4.24 mmol) obtained in Reference Example 7-(a) in ethanol (5 ml) was added 2-aminoethanethiol (0.426 g, 5.52 mmol), which was deaerated under reduced pressure, followed by argon substitution. This reaction mixture was then heated to reflux for 6 hours. After completion of the reaction, a saturated aqueous sodium chloride solution was added to the reaction solution, followed by extraction with ethyl acetate. The separated organic layer was dried over anhydrous magnesium sulfate, and then concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; chloroform:ethyl acetate=7:3 (V/V)), and fractions containing the desired compound were concentrated under reduced pressure to afford the title compound (1.32 g) as a white solid. (Yield: 89%)
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([N+:32]([O-])=O)[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:17])([F:16])[F:15])[C:5]#[N:6]>C(O)C.C(O)(=O)C.C(OCC)(=O)C.[Fe]>[NH2:32][C:8]1[CH:7]=[C:4]([CH:3]=[C:2]([CH3:1])[C:9]=1[C:10]#[C:11][CH2:12][C:13]([CH2:19][C:20]1([CH3:31])[C:29]2[C:24](=[CH:25][CH:26]=[C:27]([F:30])[CH:28]=2)[O:23][CH2:22][CH2:21]1)([OH:18])[C:14]([F:15])([F:16])[F:17])[C:5]#[N:6]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Agent: [Fe]
Solvent: CCO
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: Cc1cc(C#N)cc(N)c1C#CCC(O)(CC1(C)CCOc2ccc(F)cc21)C(F)(F)F
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 93.3 %

Procedure:
A mixture of 580 mg (1.2 mmol) of 3-methyl-5-nitro-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile and 1.4 g (24 mmol) of iron powder in 15 mL of ethanol and 10 mL of acetic acid was warmed to 80° C. After 30 minutes, the mixture was cooled and diluted with 50 mL of ethyl acetate and filtered through CELITE® filter aid. The filtrate was washed with three portions of saturated aqueous sodium bicarbonate, then washed with brine, dried over magnesium sulfate, and concentrated in vacuo to afford 500 mg (92%) of 3-amino-5-methyl-4-[5,5,5-trifluoro-4-(6-fluoro-4-methylchroman-4-ylmethyl)-4-hydroxypent-1-ynyl]benzonitrile as a brown oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([SH:8])=[CH:4][C:3]=1[N+:9]([O-:11])=[O:10].[CH2:12](Br)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH2:12]([S:8][C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([N+:9]([O-:11])=[O:10])[CH:4]=1)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: BrCc1ccccc1
Reactant: O=[N+]([O-])c1cc(S)ccc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1cc(SCc2ccccc2)ccc1Cl
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-chloro-3-nitrothiophenol (0.4 g) and benzyl bromide (0.3 mL) in N,N-dimethylformamide (6 mL) was added potassium carbonate (0.44 g), and the mixture was stirred at room temperature for 15 minutes. To the reaction mixture was added water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane −n-hexane/ethyl acetate=9/1) to give 1-benzylthio-4-chloro -3-nitrobenzene (0.54 g). This material was dissolved in methanol (5 mL)-tetrahydrofuran (5 mL). To the solution were added nickel (II) bromide (21 mg) and sodium borohydride (0.22 g) under ice-cooling, and the mixture was stirred at the same temperature for 30 minutes. The mixture was stirred at room temperature for 1 hour. The reaction mixture was diluted with ethyl acetate, and the resulting mixture was washed with a saturated aqueous sodium hydrogen carbonate solution, water and brine successively, and dried over anhydrous magnesium sulfate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:11][CH2:12][C:13]2[N:14]=[C:15]3[CH:21]=[C:20]([C:22]4[CH:27]=[CH:26][N:25]=[C:24]([C:28](O)=[O:29])[CH:23]=4)[NH:19][C:16]3=[N:17][CH:18]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[CH3:31][NH:32][CH3:33]>>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1)[CH2:11][CH2:12][C:13]1[N:14]=[C:15]2[CH:21]=[C:20]([C:22]3[CH:27]=[CH:26][N:25]=[C:24]([C:28]([N:32]([CH3:33])[CH3:31])=[O:29])[CH:23]=3)[NH:19][C:16]2=[N:17][CH:18]=1
Reactant: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)O)c4)cc3n2)cc(OC)c1
Reactant: CNC
Product: COc1cc(CCc2cnc3[nH]c(-c4ccnc(C(=O)N(C)C)c4)cc3n2)cc(OC)c1

Procedure:
The compound was prepared by using procedures analogous to those described for the synthesis of Example 73, Step 3 starting from 4-{2-[2-(3,5-dimethoxyphenyl)ethyl]-5H-pyrrolo[2,3-b]pyrazin-6-yl}pyridine-2-carboxylic acid and N,N-dimethyl amine (2.0 M in THF). LCMS calculated for C24H26N5O3 (M+H)+: m/z=432.2. Found 432.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.Cl.C(N=C=NCCCN(C)C)C.[NH2:22][C:23]1[CH:34]=[CH:33][C:26]([C:27]([N:29]([O:31][CH3:32])[CH3:30])=[O:28])=[C:25]([F:35])[CH:24]=1>N1C=CC=CC=1>[F:35][C:25]1[CH:24]=[C:23]([NH:22][C:7]([C:2]2[CH:3]=[N:4][CH:5]=[CH:6][N:1]=2)=[O:9])[CH:34]=[CH:33][C:26]=1[C:27]([N:29]([O:31][CH3:32])[CH3:30])=[O:28]
Reactant: CON(C)C(=O)c1ccc(N)cc1F
Reactant: O=C(O)c1cnccn1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CON(C)C(=O)c1ccc(NC(=O)c2cnccn2)cc1F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
2.56 g of pyrazine-2-carboxylic acid and 4.66 g of 1-ethyl-3-(3′-dimethylaminopropyl)-carbodiimide hydrochloride were added to a pyridine (20 ml) solution of 3.7 g of 4-amino-2-fluoro-N-methoxy-N-methylbenzamide, and the reaction liquid was stirred at room temperature for 1 hour. Pyridine was evaporated away under reduced pressure, and the residue was diluted with ethyl acetate, washed with water, and dried with anhydrous magnesium sulfate. The solvent was evaporated away under reduced pressure, and the resulting solid was washed with a mixed solvent of ethyl acetate and hexane to obtain the entitled compound as a pale yellow solid.
Reaction SMILES: [NH2:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1.[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15]>C1C(Cl)=CC=C(Cl)C=1>[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14]([NH:1][C:2]1[S:6][N:5]=[C:4]([C:7]([Cl:10])([Cl:9])[Cl:8])[N:3]=1)=[O:15]
Reactant: Nc1nc(C(Cl)(Cl)Cl)ns1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Solvent: Clc1ccc(Cl)cc1
Product: O=C(Nc1nc(C(Cl)(Cl)Cl)ns1)c1c(Cl)cccc1Cl
Yield: 22 %

Procedure:
A solution of 22.0 g (0.1 mole) 5-amino-3-trichloromethyl-1,2,4-thiadiazole and 20.1 g (0.1 mole) 2,6-dichlorobenzoyl chloride was refluxed for 8 hours in 200 ml dichlorobenzene. After filtration, the crude product precipitated from the filtrate upon standing. Recrystallization from toluene gave 8.6 g (22% yield) of pure product; m.p. 209° C.
Reaction SMILES: [NH2:1][C:2]1[C:10]2[S:9][C:8]([S:11][CH3:12])=[N:7][C:6]=2[C:5]([Cl:13])=[CH:4][C:3]=1[F:14].[O:15]=[C:16](Cl)OC(Cl)(Cl)Cl.C(Cl)(Cl)=O>C1(C)C=CC=CC=1>[Cl:13][C:5]1[C:6]2[N:7]=[C:8]([S:11][CH3:12])[S:9][C:10]=2[C:2]([N:1]=[C:16]=[O:15])=[C:3]([F:14])[CH:4]=1
Reactant: O=C(Cl)OC(Cl)(Cl)Cl
Reactant: CSc1nc2c(Cl)cc(F)c(N)c2s1
Agent: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: CSc1nc2c(Cl)cc(F)c(N=C=O)c2s1

Procedure:
First, 4-chloro-6-fluoro-7-isocyanato-2-(methylthio)benzothiazole was prepared by refluxing a solution of 7 g (28 mmol) of 7-amino-4-chloro-6-fluoro-2-(methylthio)benzothiazole and 55 g (0.28 mol) of diphosgene (200 ml of toluene for 7 hours, then adding 20 g (0.1 mol) of phosgene, refluxing for a further 8 hours and finally evaporating down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([O:7]C)=[O:6].[OH-].[Li+]>O1CCCC1.CO.O>[F:1][C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[CH:12]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[CH3:13])[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2)c(F)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(Oc1ccccc1)c1ccc(C(=O)O)cc1F
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.8 %

Procedure:
To a solution of methyl 3-fluoro-4-(1-phenoxyethyl)benzoate (400 mg, 1.5 mmol) in mixed solution of tetrahydrofuran/methanol/water=3:1:1 (4 mL) was added lithium hydroxide (200 mg, 8.4 mmol). The mixture was stirred at room temperature for 2 hours. The suspension was concentrated in vacuo and quenched with hydrochloride acid aqueous (1N, 5 mL). To the residue, water (50 mL) was added and extracted with dichloromethane (2*50 mL). The combined organic phase was separated, dried over sodium sulfate, filtered and concentrated to give a residue. The residue was purified by column chromatography (silica gel, petroleum ether/ethyl acetate=5:1) to give 3-fluoro-4-(1-phenoxyethyl)benzoic acid as pale solid (300 mg, 82%).
Reaction SMILES: C[Si](C)(C)[NH:3][Si](C)(C)C.[Li]CCCC.[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1.Cl>CCOCC>[F:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([NH2:3])=[NH:21])=[CH:18][CH:17]=1
Reactant: N#Cc1ccc(F)cc1
Reactant: C[Si](C)(C)N[Si](C)(C)C
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Product: N=C(N)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
To an ice-cold solution of hexamethyldisilazane (7 ml) in Et2O (40 ml) was added n-BuLi (1.6M in hexanes, 20.6 ml), followed by a solution of 4-fluorobenzonitrile (2 g) in Et2O (10 ml). After stirring at 0° C. for 10 min, the mixture was allowed to warm to RT and was stirred at RT for 20 h. The mixture was acidified to pH 1 by adding a 1M HCl solution and was washed with CHCl3. The aqueous layer was then basified to pH 14 by adding Na2CO3 and NaOH and was extracted twice with CHCl3. The org. layers were dried (Na2SO4) and evaporated off to afford the desired compound (1.59 g).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([C:13]3[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=3)[N:11]=[C:10]([C:23]([F:26])([F:25])[F:24])[C:9]=2[Cl:27])=[CH:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:33]1[N:34]=[CH:35][S:36][CH:37]=1)CCC.[Cl-].[Li+]>O1CCOCC1.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>[Cl:27][C:9]1[C:10]([C:23]([F:26])([F:25])[F:24])=[N:11][N:12]([C:13]2[CH:14]=[CH:15][C:16]([S:19]([NH2:22])(=[O:21])=[O:20])=[N:17][CH:18]=2)[C:8]=1[C:5]1[CH:6]=[CH:7][C:2]([C:33]2[N:34]=[CH:35][S:36][CH:37]=2)=[CH:3][CH:4]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cscn1
Reactant: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(Br)cc2)cn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cl-]
Agent: [Li+]
Solvent: C1COCCO1
Product: NS(=O)(=O)c1ccc(-n2nc(C(F)(F)F)c(Cl)c2-c2ccc(-c3cscn3)cc2)cn1
Yield: 84.2 %

Procedure:
A mixture of 5-[5-(4-bromophenyl)-4-chloro-3-(trifluoromethyl)-1H-pyrazol-1-yl]-2-pyridinesulfonamide (236 mg, 0.489 mmol), 4-(tributylstannyl)-1,3-thiazole (238 mg, 0.636 mmol), lithium chloride (27 mg, 0.636 mmol) and tetrakis(triphenylphosphine)palladium (57 mg, 0.0489 mmol) in 1,4-dioxane (10 ml) was refluxed for 5 hr under nitrogen atmosphere. After evaporation, the residue obtained was chromatographed on a column of silica gel (50 g) eluting with ethyl acetate/hexane (3:4) to afford 200 mg (84%) of the title compound as a pale brown gum.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[S:10](Cl)(=[O:12])=[O:11])([O-:3])=[O:2].Cl.[CH3:15][NH:16][O:17][CH3:18].C(N(CC)CC)C>>[CH3:15][N:16]([O:17][CH3:18])[S:10]([C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])(=[O:12])=[O:11]
Reactant: CNOC
Reactant: O=[N+]([O-])c1ccccc1S(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CON(C)S(=O)(=O)c1ccccc1[N+](=O)[O-]
Yield: 1793.6 %

Procedure:
2-Nitrobenzenesulfonyl chloride (5 g, 22.5 mmol) was allowed to react with N-methyl-N-methoxyamine hydrochloride (2.42 g, 22.5×1.2 mmol) in the presence of triethylamine (5.47 g, 22.5×2.4 mmol) to obtain 5.3 g (percent yield: 95.3%) of N-methyl-N-methoxy-2-nitrophenylsulfonamide.
Reaction SMILES: CC[O-].[Na+].[C:5]([CH2:7][C:8](OCC)=[O:9])#[N:6].[C:13]1([CH:19]=[C:20]2[C:25](=[O:26])[C:24](=[CH:27][C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[CH2:23][S:22][CH2:21]2)[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[O:9]=[C:8]1[O:26][C:25]2[C:24](=[CH:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[CH2:23][S:22][CH2:21][C:20]=2[CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH:7]1[C:5]#[N:6]
Reactant: CCOC(=O)CC#N
Reactant: O=C1C(=Cc2ccccc2)CSCC1=Cc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: N#CC1C(=O)OC2=C(CSCC2=Cc2ccccc2)C1c1ccccc1
Reaction time: 0.17 h

Procedure:
To a solution of NaOEt (from 555 mg, 92 mg atom Na in absolute EtOH) in 100 ml of absolute EtOH is added ethyl cyanoacetate (2.44 g, 22 mmole) dissolved in 50 ml of absolute EtOH. This is heated at reflux temperature for 2 hours, cooled slightly and tetrahydro-3,5-bis(phenylmethylene)-4H-thiopyran-4-one (5.84 g, 20 mmole) is added at once. The mixture quickly turns orange-red for ca. 10 minutes, changing to yellow (yellow solids in orange-red solution) as heating is continued for 2 hours.
Reaction SMILES: CC(C)([O-])C.[K+].CCOCC.[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][CH2:20][C:21]2=[O:24])=[CH:16][CH:15]=1.[N:25](OCCC(C)C)=[O:26]>C(O)C.C(O)(C)(C)C>[CH3:12][O:13][C:14]1[CH:23]=[C:22]2[C:17]([CH2:18][CH2:19][C:20](=[N:25][OH:26])[C:21]2=[O:24])=[CH:16][CH:15]=1
Reactant: CC(C)CCON=O
Reactant: COc1ccc2c(c1)C(=O)CCC2
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CC(C)(C)O
Solvent: CCO
Product: COc1ccc2c(c1)C(=O)C(=NO)CC2
Reaction time: 0.5 h
Yield: 50 %

Procedure:
A mixture of potassium tert-butoxide (11.5 gm, 0.1 m), ether (400 ml), tert-butanol (15 ml) and absolute ethanol (15 ml) was refluxed for 1/2 hour to insure complete solution of the potassium tert-butoxide. To the hot solution was added 7-methoxy-1-tetralone (17.6 gms, 0.1 m) and the reaction mixture turned from yellow to dark brown. To this refluxing solution was added isopentyl nitrite (19 ml). During this addition external heating was not necessary because of the exothermic nature of the reaction. The reaction mixture was refluxed for 1/2 hour during which time the walls of the flask became coated with a brown solid. After cooling in an ice-bath, the solvent was removed by decantation. To the solid was added aqueous hydrogen chloride (1 N, 200 ml). After stirring 1/2 hour, the brown solid was filtered to yield 10 gms (50%) of product.
Reaction SMILES: [C:1]([N:8]1[C@H:12]([C:13]#[CH:14])[C@@H:11]([CH3:15])[O:10]C1(C)C)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[C:1]([NH:8][C@H:12]([C:13]#[CH:14])[C@H:11]([OH:10])[CH3:15])([O:3][C:4]([CH3:6])([CH3:7])[CH3:5])=[O:2]
Reactant: C#C[C@@H]1[C@@H](C)OC(C)(C)N1C(=O)OC(C)(C)C
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C#C[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O
Reaction time: 8 h
Yield: 82.5 %

Procedure:
A solution of (4R,5R)-N-boc-4-ethynyl-2,2,5-trimethyl-oxazolidine (1.60 g 6.69 mmol) (Example 102B) and ρ-toluenesulfonic acid monohydrate (130 mg 0.67 mmol) in MeOH (70 mL) was heated at refluxed. After stirring overnight the solvent was concentrated and the residue was chromatographed directly on a silica gel column with a 0-40% EtOAc in hexanes gradient. This afforded the product (Yield 1.10 g, 83%) as well as recovered starting material (220 mg, 14%).
Reaction SMILES: [H-].[Na+].[Cl:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[NH:14][N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:6][CH:5]=1.[CH3:21][Si:22]([CH3:29])([CH3:28])[CH2:23][CH2:24][O:25][CH2:26]Cl.O>O1CCCC1>[Cl:3][C:4]1[CH:5]=[CH:6][C:7]([C:10]2[N:14]([CH2:26][O:25][CH2:24][CH2:23][Si:22]([CH3:29])([CH3:28])[CH3:21])[N:13]=[CH:12][C:11]=2[C:15]2[CH:20]=[CH:19][N:18]=[CH:17][CH:16]=2)=[CH:8][CH:9]=1
Reactant: Clc1ccc(-c2[nH]ncc2-c2ccncc2)cc1
Reactant: C[Si](C)(C)CCOCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C[Si](C)(C)CCOCn1ncc(-c2ccncc2)c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 89.8 %

Procedure:
55% Sodium hydride (1.41 g, 32.1 mmol) was suspended in tetrahydrofuran (300 ml). To the suspension was added 5-(4-chlorophenyl)-4-(pyridin-4-yl)pyrazole (8.21 g, 32.1 mmol), and the resulting mixture was stirred at room temperature for 1 hour. To the resulting mixture was added (2-trimethylsilylethoxy)methyl chloride (5.68 ml, 32.1 mmol) dropwise under ice cooling, and the mixture was stirred at room temperature overnight. At the end of this time, water was added to the mixture and the mixture was extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous sodium sulfate and the solvent was removed by distillation under reduced pressure. The residue was purified by column chromatography through silica gel (eluent, hexane:ethyl acetate=3:1), to give the title compound (11.12 g) as a pale brown oil (yield 90%).
Reaction SMILES: [NH2:1][N:2]1[CH:6]=[N:5][N:4]=[CH:3]1.[CH:7](=O)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10]>C1(C)C(C)=CC=CC=1>[CH:7](=[C:6]1[N:2]([NH2:1])[CH:3]=[N:4][NH:5]1)[C:8]1[C:9](=[CH:11][CH:12]=[CH:13][CH:14]=1)[OH:10]
Reactant: O=Cc1ccccc1O
Reactant: Nn1cnnc1
Solvent: Cc1ccccc1C
Product: NN1C=NNC1=Cc1ccccc1O
Yield: 94.7 %

Procedure:
4-amino-1,2,4-triazole (4.2 g.), salicylaldehyde (6.1g.) and xylene 140 ml. were heated at reflux for 3 hr. The reaction mixture was cooled and filtered to afford 9 grams of product, m.p. 210°-12°.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH2:15][CH2:14][C:13]3([CH2:20][CH2:19][NH:18][CH2:17][CH2:16]3)[C:12]2=[O:21])=[CH:7][CH:6]=1.[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30](Cl)(=[O:32])=[O:31])[CH:25]=1.Cl>>[N:24]1[CH:29]=[CH:28][CH:27]=[C:26]([S:30]([N:18]2[CH2:17][CH2:16][C:13]3([C:12](=[O:21])[N:11]([C:8]4[CH:9]=[CH:10][C:5]([O:4][CH2:3][C:2]([F:1])([F:22])[F:23])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)(=[O:32])=[O:31])[CH:25]=1
Reactant: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCNCC2
Reactant: O=S(=O)(Cl)c1cccnc1
Agent: Cl
Product: O=C1N(c2ccc(OCC(F)(F)F)cc2)CCC12CCN(S(=O)(=O)c1cccnc1)CC2

Procedure:
The title compound was prepared in analogy to example 180 step D from 2-[4-(2,2,2-trifluoro-ethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 180 step B-D using 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-(2,2,2-trifluoro-ethoxy)aniline) and pyridine-3-sulfonyl chloride; hydrochloride. White solid. MS (ESI): 470.1 (MH+).