Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11]Br.[C:20]1(=[O:30])[NH:24][C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]12.[K].CN(C)C=O>O>[Cl:1][C:2]1[CH:3]=[C:4]([O:14][CH2:15][CH:16]=[C:17]([Cl:19])[Cl:18])[CH:5]=[C:6]([Cl:13])[C:7]=1[O:8][CH2:9][CH2:10][CH2:11][N:24]1[C:23](=[O:25])[C:22]2=[CH:26][CH:27]=[CH:28][CH:29]=[C:21]2[C:20]1=[O:30]
Reactant: ClC(Cl)=CCOc1cc(Cl)c(OCCCBr)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=C1c2ccccc2C(=O)N1CCCOc1c(Cl)cc(OCC=C(Cl)Cl)cc1Cl
Temperature: 25 °C
Reaction time: 24 h
Yield: 98 %

Procedure:
A reaction vessel was charged with 4.09 g of 3,5-dichloro-4-(3-bromopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene, 2.41 of potassium phthalimide and 30 ml of N,N-dimethylformamide. After stirring at room temperature for 24 hours, the reaction mixture was poured into water and extracted twice with 150 ml of chloroform. The chloroform layers were combined, washed with diluted hydrochloric acid and diluted aqueous sodium hydroxide, dried over anhydrous magnesium sulfate, and then concen- trated, which afforded 4.67 g of crude 3,5-dichloro-4-(3-phthalimidopropyloxy)-1-(3,3-dichloro-2-propenyloxy)benzene (98% yield).
Reaction SMILES: [Cl-].[Cl-].[Cl-].[Al+3].[F:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[F:12].[Cl:13][CH2:14][C:15](Cl)=[O:16].Cl>O>[Cl:13][CH2:14][C:15]([C:9]1[CH:10]=[CH:11][C:6]([F:5])=[C:7]([F:12])[CH:8]=1)=[O:16]
Reactant: Fc1ccccc1F
Reactant: O=C(Cl)CCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O
Product: O=C(CCl)c1ccc(F)c(F)c1
Temperature: 50 °C
Reaction time: 1 h
Yield: 80.9 %

Procedure:
Aluminium trichloride (210.2 g) was added to 1,2-difluorobenzene (200.0 g) at room temperature. The obtained slurry was heated to 50° C., then chloroacetyl chloride (198.0 g) was added over 50 minutes. The reaction mixture was stirred for an additional 60 minutes, then added slowly to a mixture of ice (786.0 g), water (196.0 g) and 37 wt % hydrochloric acid (297.0 g), during the addition the temperature was kept below 60° C. After the addition, the reaction mixture was heated to 60° C. and the layers separated. The organic layer was washed twice with a 20 w/v % sodium chloride solution (200.0 mL). 2-Chloro-1-(3,4-difluorophenyl)ethanone (270.2 g) was obtained by vacuum distillation of the organic layer.
Reaction SMILES: C=CC=C.[CH:5]1[CH:6]=[CH:7][C:8]2[C:15](=O)[CH:14]=[CH:13][C:11](=O)[C:9]=2[CH:10]=1>CC1C=CC=CC=1C>[CH:10]1[C:9]2[C:8](=[CH:15][CH:14]=[CH:13][CH:11]=2)[CH:7]=[CH:6][CH:5]=1
Reactant: O=C1C=CC(=O)c2ccccc21
Agent: C=CC=C
Solvent: Cc1ccccc1C
Product: c1ccc2ccccc2c1

Procedure:
A 60% solution of THAQ was obtained by adding butadiene to a 50% o-xylene solution of naphthoquinone obtained by the catalytic vapor phase oxidation reaction of naphthalene, followed by the Diels-Alder reaction. Ten kg of such a solution was subjected to distillation under reduced pressure at 95° C. under 100 Torr to reduce the content of the solvent to 2.5%. Then, while maintaining the melt at 120° C., 6 kg of the melt thus obtained was droped in an amount of about 0.2 g per drop with an interval of every about 0.4 second onto a stainless belt flaker of 60° C. The belt was moved at a cooling time of about 30 seconds, and the solidified product was peeled off by a scraper at the end. The releasability was extremely good.
Reaction SMILES: [CH3:1][N:2]1[C:6]2[NH:7][C:8](=O)[CH:9]=[C:10]([C:11]([F:14])([F:13])[F:12])[C:5]=2[C:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:3]1.P(Br)(Br)([Br:24])=O>>[Br:24][C:8]1[N:7]=[C:6]2[N:2]([CH3:1])[N:3]=[C:4]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:5]2=[C:10]([C:11]([F:14])([F:13])[F:12])[CH:9]=1
Reactant: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(=O)[nH]c21
Reactant: O=P(Br)(Br)Br
Product: Cn1nc(-c2ccccc2)c2c(C(F)(F)F)cc(Br)nc21
Temperature: 120 °C
Yield: 99.1 %

Procedure:
A mixture of 1-methyl-3-phenyl-4-(trifluoromethyl)-1H-pyrazolo[3,4-b]pyridin-6(7H)-one (1.0 g, 3.4 mmol) and POBr3 (0.962 g, 3.4 mmol) was heated at 120° C. for 3 h. The reaction mixture was cooled to it and poured into rapidly stirred ice cold water to obtain a solid product. The product was collected by filtration and dried under vacuum to yield an off-white solid (1.20 g, 99%). [1H-NMR (CDCl3, 300 MHz) δ 7.58 (s, 1H), 7.54-7.41 (m, 5H), 4.22 (s, 3H); LCMS RtA=1.943 min; [M+H]+=355.9]
Reaction SMILES: [ClH:1].CC[O:4]CC.[NH:7]1[CH2:12][CH2:11][CH:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[CH2:9][CH2:8]1>C(Cl)(Cl)Cl.CO>[OH2:4].[ClH:1].[ClH:1].[NH:7]1[CH2:8][CH2:9][CH:10]([NH:13][C:14]2[CH:15]=[C:16]3[C:20](=[CH:21][CH:22]=2)[NH:19][N:18]=[CH:17]3)[CH2:11][CH2:12]1
Reactant: CCOCC
Agent: Cl
Agent: c1cc2[nH]ncc2cc1NC1CCNCC1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A 1N-hydrochloric acid/ether solution (5 ml) was added to a solution of N-(4-piperidinyl)-1H-indazol-5-amine (433 mg, 2.00 mmol) in a mixture of chloroform (4 ml) and methanol (4 ml) at room temperature and stirred at room temperature for 30 minutes. The solid precipitated was collected by filtration and recrystallized from a mixture of chloroform and methanol to obtain N-(4-piperidinyl)-1H-indazol-5-amine dihydrochloride monohydrate (2.86 g, 72%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:41]=[C:40]([CH3:42])[N:39]=[C:38]([CH3:43])[CH:37]=2)[CH:31]=1)=[O:29])(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28]([C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([C:36]2[CH:37]=[C:38]([CH3:43])[N:39]=[C:40]([CH3:42])[CH:41]=2)[CH:31]=1)=[O:29])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1ccc(OC(F)(F)F)cc1N
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)OC(C)(C)C)c2)cc(C)n1
Product: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(OC(F)(F)F)ccc3NC(=O)OC(C)(C)C)c2)cc(C)n1

Procedure:
The title compound was prepared from (2-amino-4-trifluoromethoxy-phenyl)-carbamic acid tert-butyl ester (Example J26) (219 mg, 0.75 mmol) and 3-[3-(2,6-dimethyl-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K15) (244 mg, 0.75 mmol) according to the general procedure M. Obtained as a light yellow foam (240 mg, 59%).
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4]Br.O.Cl.[NH:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1.C(N(CC)CC)C>ClCCl>[F:1][C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[CH2:4][N:13]1[CH2:18][CH2:17][C:16](=[O:19])[CH2:15][CH2:14]1
Reactant: O=C1CCNCC1
Reactant: Fc1ccc(CBr)c(F)c1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: O=C1CCN(Cc2ccc(F)cc2F)CC1
Yield: 217 %

Procedure:
28.20 g (0.125 mol) of 2,4-difluorobenzyl bromide was weighed, to which 200 mL of dichloromethane was added and then 62.00 g (0.404 mol) of 4-piperidone hydrochloride monohydrate was added under stirring. And then 86.00 g (0.850 mol) of triethylamine was added dropwise at a bath temperature of 30-40° C. under stirring. After the addition, the reaction was heated, refluxed and reacted overnight. On the next day, the reaction was cooled, filtered to removed solid, washed in sequence with dichloromethane and ethyl ether, combined, washed with water and dried, and the solvent was recovered to obtain 61.10 g of crude product (73.3%), 1H-NMR (CDCl3, ppm) δ: 7.31-7.33 (5H, m), 3.56 (2H, s), 2.64 (2H, s), 2.53-2.62 (4H, m), 1.52-1.86 (4H, m); which was used directly in the next step of reaction.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[S:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=O>CS(O)(=O)=O>[CH3:1][O:2][C:3]1[C:4]2[S:9][C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][C:17](=[O:19])[C:5]=2[CH:6]=[CH:7][CH:8]=1
Reactant: COc1ccccc1Sc1ccccc1CC(=O)O
Agent: CS(=O)(=O)O
Product: COc1cccc2c1Sc1ccccc1CC2=O
Temperature: 90 °C

Procedure:
[2-(2-Methoxy-phenylsulfanyl)-phenyl]-acetic acid (5.40 g, 20 mmol) was dissolved in methanesulfonic acid (50 ml) and the mixture was heated for 2 hours at 90° C. under stirring and a nitrogen atmosphere. The reaction mixture was cooled to room temperature and poured onto ice with stirring. The black precipitate was filtered and dried over night in a vacuum oven (50° C.). The compound was used without any further purification (4.60 g, 91%).
Reaction SMILES: FC(F)(F)C(O)=O.[O:8]=[C:9]1[C:14]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:27][C:28]([N:30]([CH:41]1[CH2:46][CH2:45][N:44](C(OC(C)(C)C)=O)[CH2:43][CH2:42]1)[C:31]1[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=1)=[O:29]>C(Cl)Cl>[O:8]=[C:9]1[C:14]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[CH2:13][CH2:12][CH2:11][N:10]1[CH2:27][C:28]([N:30]([CH:41]1[CH2:42][CH2:43][NH:44][CH2:45][CH2:46]1)[C:31]1[CH:32]=[CH:33][C:34]([C:37]([F:38])([F:39])[F:40])=[CH:35][CH:36]=1)=[O:29]
Reactant: CC(C)(C)OC(=O)N1CCC(N(C(=O)CN2CCCC(c3ccccc3)(c3ccccc3)C2=O)c2ccc(C(F)(F)F)cc2)CC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(CN1CCCC(c2ccccc2)(c2ccccc2)C1=O)N(c1ccc(C(F)(F)F)cc1)C1CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Trifluoroacetic acid (3.0 mL, 39 mmol) was added to a solution of the product of Example 166C (279 mg, 0.439 mmol) in CH2Cl2 (3 mL), and the reaction mixture was stirred at ambient temperature for 1 hour. The reaction was then cooled to 0° C., diluted with CH2Cl2 (25 mL) and quenched by slow addition of 2 N aqueous NaOH solution (25 mL). The mixture was separated and the aqueous phase was extracted with CH2Cl2. The combined organic layer was washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. Ether was added to the residue which caused a solid to form, which was collected by vacuum filtration and washed with minimal ether and air-dried. The material was then chromatographed on silica gel (Analogix® Intelliflash™ 280; SF10-8 g column; 10% methanol/CH2Cl2) to afford the title compound. 1H NMR (300 MHz, CDCl3) δ ppm 7.68 (d, J=8.3, 2H), 7.36 (d, J=8.2, 2H), 7.32-7.15 (m, 10H), 4.85-4.69 (m, 1H), 3.68 (s, 2H), 3.45 (t, J=6.4, 2H), 3.17-3.06 (m, 2H), 2.76 (td, J=12.4, 1.9, 2H), 2.66-2.56 (m, 2H), 2.00-1.65 (m, 5H), 1.40-1.21 (m, 2H); MS (DCI+) m/z 536 (M+H)+.
Reaction SMILES: [C:1]([C:3]1([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:8][CH2:7][N:6]([S:9]([NH:12][CH2:13][CH3:14])(=[O:11])=[O:10])[CH2:5][CH2:4]1)#[N:2].[OH-].[Na+]>C(O)C.C(O)C.O>[NH2:2][CH2:1][C:3]1([CH2:15][CH:16]2[CH2:18][CH2:17]2)[CH2:4][CH2:5][N:6]([S:9]([NH:12][CH2:13][CH3:14])(=[O:10])=[O:11])[CH2:7][CH2:8]1
Reactant: CCNS(=O)(=O)N1CCC(C#N)(CC2CC2)CC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCNS(=O)(=O)N1CCC(CN)(CC2CC2)CC1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A solution of 4-cyano-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-9) (83 mg, 0.306 mmol) in ethanol (1 mL) was added to 1M sodium hydroxide in 95% ethanol-water (15 mL) and the solution degassed with nitrogen. Raney Nickel (50% slurry in water) (220 mg) was added and the black suspension shaken under hydrogen pressure (40 psi) at room temperature for 12 h. The catalyst was filtered off and wahed with 95% ethanol-water. The filtrate was evaporated in vacuo then partitioned between water and DCM. The organic phase was separated and the aqueous phase re-extracted with DCM twice. The combined organic phase was dried (MgSO4) and the solvent removed in vacuo to leave 4-aminomethyl-4-(cyclopropylmethyl)-N-ethylpiperidine-1-sulfonamide (I-10) that was used in the next step without further purification. 1H NMR (500 MHz, CD3OD): δ 3.21-3.11 (m, 4 H), 3.02 (q, J=7.2 Hz, 2 H), 2.69 (s, 2 H), 1.63-1.53 (m, 4 H), 1.31 (m, 2 H), 1.15 (t, J=7.2 Hz, 3 H), 0.65 (m, 1 H), 0.48 (t, J=6.4 Hz, 2 H), 0.07 (m, 2 H).
Reaction SMILES: [C:1]([C:3]([C:14]1[CH:19]=[CH:18][C:17]([S:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:16][CH:15]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)#[N:2].ClC1C=C(C=CC=1)C(OO)=[O:32].[N+]([O-])(O)=O.CCOCC>C(Cl)Cl>[C:1]([C:3]([C:14]1[CH:15]=[CH:16][C:17]([S:20]([C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[O:32])=[CH:18][CH:19]=1)([CH2:10][CH2:11][CH2:12][CH3:13])[CH2:4][N:5]1[CH:9]=[CH:8][N:7]=[CH:6]1)#[N:2]
Reactant: CCCCC(C#N)(Cn1ccnc1)c1ccc(Sc2ccccc2)cc1
Reactant: O=C(OO)c1cccc(Cl)c1
Solvent: CCOCC
Solvent: ClCCl
Solvent: O=[N+]([O-])O
Product: CCCCC(C#N)(Cn1ccnc1)c1ccc(S(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 92.7 %

Procedure:
To a solution of 4 g (0.01 mole) of 1-[2-cyano-2-(4-phenylthiophenyl) hexyl]imidazole in 25 ml of methylene chloride is added 2.5 g (0.012 mole) of 85% m-chloroperoxybenzoic acid in small portions at 0°. The mixture is stirred at room temperature overnight. To the reaction mixture is added conc. nitric acid until it is strongly acidic. To this solution is added 150 ml of anhydrous ether. The gummy solid precipitates are washed with ether and back neutralized with dilute NH4OH solution. The free base (3.5 g) thus obtained is a yellow solid, mp 55°-61°.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH:6]=O)=[CH:4][CH:3]=1.[CH:10](I)(I)[I:11]>O1CCCC1.[Cl-].[Cr+2].[Cl-]>[I:11]/[CH:10]=[CH:6]/[C:5]1[CH:8]=[CH:9][C:2]([Br:1])=[CH:3][CH:4]=1
Reactant: O=Cc1ccc(Br)cc1
Reactant: IC(I)I
Agent: [Cr+2]
Agent: [Cl-]
Solvent: C1CCOC1
Product: Brc1ccc(/C=C/I)cc1
Reaction time: 1 h

Procedure:
To a heterogeneous mixture of chromium (II) chloride (3.98 g, 32.4 mmol) in tetrahydrofuran (40 mL) at 0° C. was added via syringe pump over 1 hour (in the total absence of light) 4-bromo-benzaldehyde (1.00 g, 5.40 imol) and iodoform (4.25 g, 10.8 mmol) combined as a homogeneous solution in tetrahydrofuran (20 mL). The cold bath was removed, whereupon a quantitative reaction as indicated occurred within 1 hour. The reaction mixture was diluted with 1:1 ether-hexanes (200 mL) then filtered through a short pad of silica gel, concentrated to a solid tainted with residual iodoform.
Reaction SMILES: [H-].[Na+].[Br-].[OH:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][C:31](=O)[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH3:40]>CS(C)=O>[CH3:40][CH:39]([CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH3:30])[CH2:10][CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][OH:4]
Reactant: CCCCCCCCCC(C)=O
Reactant: OCCCCCC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Br-]
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: CCCCCCCCCC(C)CCCCC=CO
Temperature: 70 °C
Reaction time: 18 h

Procedure:
Into a dried 5L, 3 neck round bottom flask fitted with mechanical stirring, nitrogen inlet, dropping fimnel, thermometer and nitrogen outlet is added 70.2 g of 60% sodium hydride (1.76 mol) in mineral oil. The mineral oil is removed by washing with hexanes. Anhydrous dimethyl sulfoxide (500 ml) is added to the flask and the mixture is heated to 70° C. until evolution of hydrogen stops. The reaction mixture is cooled to room temperature followed by addition of 1L of anhydrous tetrahydrofuran. (6-hydroxyhexyl) triphenylphosphonium bromide (443.4 g, 1 mol) is slurried with warm anhydrous dimethyl sulfoxide (50° C., 500 ml) and slowly added to the reaction mixture through the dropping funnel while keeping it at 25-30° C. The mixture is stirred for 30 minutes at room temperature at which time 2-undecanone (187 g, 1.1 mol) is slowly added through a dropping funnel. Reaction is slightly exothermic and cooling is needed to maintain 25-30° C. The mixture is stirred for 18 hr. and then poured into a 5L beaker containing 1L purified water with stirring. The oil phase (top) is allowed to separate out in a separatory funnel and the water phase is removed. The water phase is washed with hexanes (500 ml) and the organic phase is separated and combined with the oil phase from the water wash. The organic mixture is then extracted with water 3 times (500 ml each) followed by vacuum distillation to collect the clear, oily product (132 g) at 140C and 1 mm Hg.
Reaction SMILES: [CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][OH:6].[N+:7]([C:10]1[CH:17]=[CH:16][CH:15]=[C:14]([N+]([O-])=O)[C:11]=1[C:12]#[N:13])([O-:9])=[O:8]>>[CH3:1][CH:2]1[CH2:4][CH:3]1[CH2:5][O:6][C:14]1[CH:15]=[CH:16][CH:17]=[C:10]([N+:7]([O-:9])=[O:8])[C:11]=1[C:12]#[N:13]
Reactant: CC1CC1CO
Reactant: N#Cc1c([N+](=O)[O-])cccc1[N+](=O)[O-]
Product: CC1CC1COc1cccc([N+](=O)[O-])c1C#N
Yield: 81 %

Procedure:
Prepared as in Example 166d from (2-methylcyclopropyl)methanol and 2,6-dinitrobenzonitrile in 81% yield. MS 233 (MH+).
Reaction SMILES: [C:1](Cl)(=[O:5])[C:2]([CH3:4])=[CH2:3].Cl.[NH2:8][C@H:9]([C:14]([NH2:16])=[O:15])[CH2:10][C:11](=[O:13])[NH2:12].C(OCC)C.C(=O)([O-])[O-].[K+].[K+]>CO.O>[C:1]([NH:16][C:14](=[O:15])[C@H:9]([CH2:10][C:11](=[O:13])[NH2:12])[NH2:8])(=[O:5])[C:2]([CH3:4])=[CH2:3]
Reactant: C=C(C)C(=O)Cl
Reactant: NC(=O)C[C@H](N)C(N)=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Solvent: CCOCC
Product: C=C(C)C(=O)NC(=O)[C@@H](N)CC(N)=O
Reaction time: 12 h

Procedure:
A 11.3 ml portion of methacrylic acid chloride, 1 g of asparagineamide hydrochloride (mfd. by Kokusan Kagaku) and 50 ml of diethyl ether were put into a 300 ml capacity eggplant type flask and stirred on an ice bath. Next, 20 ml of saturated potassium carbonate aqueous solution was added dropwise thereto. Thereafter, this was stirred on an ice bath for 30 minutes and then at room temperature for 12 hours. Diethyl ether layer in the thus obtained reaction liquid was discarded, and the water layer was dissolved in 100 ml of methanol. After filtration, the filtrate was concentrated under a reduced pressure and fractionated by a silica gel column using methanol as the developing solvent. The thus obtained amide compound fraction was purified using an ion exchange resin (“Dynaion (trade name) PA 412” mfd. by Mitsubishi Kagaku) After concentration under a reduced pressure and subsequent drying under a reduced pressure, 0.43 g of colorless crystals were obtained.
Reaction SMILES: [C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3](Cl)[CH3:4].[C:9]([OH:14])(=[O:13])[CH:10]([CH3:12])[CH3:11].C(N(C(C)C)CC)(C)C>CCOCC>[C:1](=[O:8])([S:6][CH3:7])[O:2][CH:3]([O:14][C:9](=[O:13])[CH:10]([CH3:12])[CH3:11])[CH3:4]
Reactant: CSC(=O)OC(C)Cl
Reactant: CC(C)C(=O)O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOCC
Product: CSC(=O)OC(C)OC(=O)C(C)C
Temperature: 55 °C
Yield: 97 %

Procedure:
Compound (3) (308 g, 2 mol) was dissolved in isobutyric acid (264 g, 3 mol). This mixture was slowly added to a pre-mixed solution of isobutyric acid (264 g, 3 mol) and diisopropylethylamine (387 g, 3 mol), and the reaction mixture heated to 55° C. for 16 h, diluted with ether (10 L), washed with water (4×5 L), saturated bicarbonate solution (2×5 L), and brine (5 L), then dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give the title compound (2) as a colorless liquid (400 g, 97% yield). The product was optionally further purified by vacuum distillation (135° C./20 Torr). 1H NMR (CDCl3, 400 MHz): δ 1.17 (d, J=6.8 Hz, 6H), 1.49 (d, J=5.6 Hz, 3H), 2.33 (s, 3H), 2.54 (m, 1H), 6.91 (q, J=5.2 Hz, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=O)[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C([O-])(=O)C.[Na+].O>C(#N)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[N:20][OH:21])[CH2:9][C:10]2[CH:15]=[CH:14][N:13]=[C:12]([S:16][CH3:17])[N:11]=2)=[CH:4][CH:3]=1
Reactant: CSc1nccc(CC(=O)c2ccc(F)cc2)n1
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC#N
Solvent: O
Product: CSc1nccc(CC(=NO)c2ccc(F)cc2)n1
Reaction time: 24 h
Yield: 498.8 %

Procedure:
To a solution of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone (91.49 g,48 mmol) in acetonitrile (1.8 L) was added hydroxylamine hydrochloride (121 g, 91.7 mol) and sodium acetate (139 g, 1.7 mol). The reaction was stirred for 24 hours before 100 mL of water was added. The reaction was stirred for 24 hours. The mixture was filtered through a glass frit and the filtrate partitioned between dichloromethane and water. The layers were separated and the aqueous phase extracted with dichloromethane (2×500 mL). The organic layers were combined, washed with saturated aqueous sodium bicarbonate (300 mL), washed with brine (300 mL), dried over magnesium sulfate, filtered and concentrated. The residue was recrystalized from dichloromethane and hexanes to yield 66.4 g (69%) of 1-(4-fluorophenyl)-2-[2-(methylsulfanyl)pyrimidin-4-yl]ethanone oxime. 1H NMR (CDCl3): δ 8.75 (m, 1H), 8.42 (d, 1H), 7.75 (dd, 2H), 7.09 (t, 2H), 6.98 (d, 1H), 4.29 (s, 2H), 2.54 (s, 3H). MS m/z 278 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([OH:10])=O.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.CCN(C(C)C)C(C)C.[NH2:48][CH:49]1[CH:56]2[CH2:57][C:52]3([OH:59])[CH2:53][CH:54]([CH2:58][CH:50]1[CH2:51]3)[CH2:55]2>CN(C=O)C>[Cl:1][C:2]1[CH:16]=[C:15]([Cl:17])[CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][C:7]([CH3:12])([CH3:11])[C:8]([NH:48][CH:49]1[CH:50]2[CH2:58][CH:54]3[CH2:53][C:52]([OH:59])([CH2:57][CH:56]1[CH2:55]3)[CH2:51]2)=[O:10]
Reactant: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)O
Reactant: NC1C2CC3CC1CC(O)(C3)C2
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)(CCOc1ccc(Cl)cc1Cl)C(=O)NC1C2CC3CC1CC(O)(C3)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 40 %

Procedure:
To a stirred solution of 4-(2,4-dichloro-phenoxy)-2,2-dimethyl-butyric acid (250 g, 0.902 mmol, prepared in a similar way as described in J. Am. Chem. Soc. 89, 2500-1 (1967)) in dry DMF (3 mL) was added HOBt (180 mg, 1.173 mmol) and EDAC (225 mg, 1.173 mmol). After stirring for 1 hr at room temperature, DIPEA (306 μL) and 4-amino-adamantan-1-ol (181 mg, 1.082 mmol) were added and the resulting mixture was stirred for 16 hrs. at room temperature. The volatiles were removed in vacuo and the residue was purified using prep. HPLC/MS affording 153 mg (40%) of the title compound as a solid. 1H NMR (400 MHz, CDCl3) □ 1.34 (s, 6H), 1.52 (q, 4H), 1.69-1.79 (m, 4H), 1.87 (d, 2H), 2.02-2.16 (m, 5H), 2.57 (br.s., 1H), 3.95-4.02 (m, 1H), 4.05 (t, 2H), 6.02 (d, 1H), 6.83 (d, 1H), 7.17 (dd, 1H), 7.35 (d, 1H).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH:6]=O)=[C:4]([F:11])[CH:3]=1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:26]([NH:28][CH2:29][CH3:30])[CH3:27]>>[Br:1][C:2]1[CH:9]=[C:8]([F:10])[C:5]([CH2:6][N:28]([CH2:29][CH3:30])[CH2:26][CH3:27])=[C:4]([F:11])[CH:3]=1
Reactant: O=Cc1c(F)cc(Br)cc1F
Reactant: CCNCC
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Product: CCN(CC)Cc1c(F)cc(Br)cc1F
Yield: 86 %

Procedure:
According to procedure for the synthesis of Example A211A, by using 4-bromo-2,6-difluorobenzaldehyde (610 mg, 2.76 mmol), sodium triacetoxyborohydride (883.35 mg, 4.15 mmol) and diethylamine (425.21 mL, 4.15 mmol) to give the title compound as a colorless oil (660 mg, 86%). 1H NMR (400 MHz, CDCl3) δ 7.06 (d, J=6.4 Hz, 2H), 3.61 (s, 2H), 2.55-2.50 (m, 4H), 1.07 (t, J=6.8 Hz, 6H); MS ESI 279.9 [M+H]+, calcd for [C11H14BrF2N+H]+ 278.03.