Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16]O)=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.C(Cl)[Cl:26].CS(Cl)(=O)=O>O.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[N:12][C:13]([CH2:16][Cl:26])=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: ClCCl
Reactant: CC(C)(C)OC(=O)NCc1ccc(CO)nc1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: O
Product: CC(C)(C)OC(=O)NCc1ccc(CCl)nc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
Add 3-(tert-butoxycarbonylamino-methyl)-6-hydroxymethyl-pyridine (2.3 g, 9.65 mmol) and triethylamine (2.05 mL, 14.5 mmol) to DCM (30 mL). Cool the mixture to 0° C. and add methanesulfonyl chloride (0.83 mL, 10.6 mmol) to the mixture. Allow the mixture to warm to room temperature and stir overnight. Dilute the mixture with water (10 mL) and saturated aqueous NaHCO3 (10 mL). Separate the layers, and extract the aqueous layer with DCM (3×20 mL). Dry the combined organic extracts over Na2SO4, filter and concentrate in vacuo. Purify by chromatography on silica gel (80 g) eluting with hexane/EtOAc (1:0 to 1:1 gradient over 60 min, 80 mL/min) to obtain the desired intermediate as a colorless oil (1.14 g, 46%). MS (APCI+) m/z: 257 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[CH2:4][NH:5][NH2:6].[C:11](/[CH:13]=[C:14](/[O-])\[C:15]([O:17][CH2:18][CH3:19])=[O:16])#[N:12].[Na+].FC(F)(F)C(O)=O>O1CCOCC1>[NH2:12][C:11]1[N:5]([CH2:4][C:3]2[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=2[Cl:1])[N:6]=[C:14]([C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH:13]=1
Reactant: NNCc1ccccc1Cl
Reactant: CCOC(=O)/C([O-])=C\C#N
Agent: [Na+]
Solvent: O=C(O)C(F)(F)F
Solvent: C1COCCO1
Product: CCOC(=O)c1cc(N)n(Cc2ccccc2Cl)n1

Procedure:
2.29 g (14.60 mmol) of 1-(2-chlorobenzyl)hydrazine from Example 1 A are dissolved in 60 ml of dioxane under argon. To this are added 2.38 g 814.60 mmol) of sodium (1E)-1-cyano-3-ethoxy-3-oxo-1-propen-2-olate from Example 6 A and 2.66 g (1.80 ml; 23.36 mmol) of trifluoroacetic acid. The mixture is boiled under reflux overnight and reacted further without further workup. LC/MS (Method 2): Rt=2.45 min MS (EI): m/z=280 (M+H)+
Reaction SMILES: COC1C=C(C(C2C=CC=C(OC)C=2)=O)C=CC=1.C(OP(CC#N)(=O)OCC)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH3:40][O:41][C:42]1[CH:43]=[C:44]([C:50]([C:54]2[CH:59]=[CH:58][CH:57]=[C:56]([O:60][CH3:61])[CH:55]=2)=[CH:51][C:52]#[N:53])[CH:45]=[C:46](OC)[CH:47]=1>C1COCC1>[CH3:61][O:60][C:56]1[CH:55]=[C:54]([C:50]([C:44]2[CH:45]=[CH:46][CH:47]=[C:42]([O:41][CH3:40])[CH:43]=2)=[CH:51][C:52]#[N:53])[CH:59]=[CH:58][CH:57]=1
Reactant: COc1cccc(C(=CC#N)c2cc(OC)cc(OC)c2)c1
Agent: CCOP(=O)(CC#N)OCC
Agent: COc1cccc(C(=O)c2cccc(OC)c2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: C1CCOC1
Product: COc1cccc(C(=CC#N)c2cccc(OC)c2)c1
Yield: 56 %

Procedure:
Bis-(3-methoxyphenyl)methanone (1.23 g, 5.08 mmol), cyanomethylphosphonic acid diethyl ester (1.60 ml, 10.15 mmol) in anhydrous THF (10 ml), and lithium bis(trimethylsilyl)amide (1.0 M solution in THF, 10.15 ml, 10.15 mmol) were treated in the same manner as described above for the synthesis of 3-(3,5-dimethoxy-phenyl)-3-(3-methoxy-phenyl)-acrylonitrile. The crude was purified via flash column chromatography (10% EtOAc in hexane gradient to 25% EtOAc in hexane) to give 3,3-bis-(3-methoxy-phenyl)-acrylonitrile as a clear colorless oil (0.76 g, 56%): 1HNMR (DMSO-d6) δ 7.47-7.30 (two triplets, 2H, Ar), 7.12-7.04 (m, 2H, Ar), 6.98-6.82 (m, 4H, Ar), 6.38(s, 1H, double bond proton), 3.78 (s, 3H, OCH3), 3.76 (s, 3H, OCH3); 13C NMR (CDCl3) δ 163.0, 159.8, 159.6, 140.3, 138.3, 129.8, 129.7, 122.1, 121.1, 117.9, 116.1, 115.9, 115.0, 114.4, 95.3, 55.5; Anal. Calcd. For C17H15NO2: C, 76.96; H, 5.70; N, 5.28. Found: C, 76.65; H, 5.72; N, 5.15.
Reaction SMILES: [C:1]1([C:7]2[C:15]3[C:10](=[CH:11][CH:12]=[C:13]([CH3:16])[CH:14]=3)[NH:9][N:8]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]=[O:18]>>[OH:18][CH2:17][N:9]1[C:10]2[C:15](=[CH:14][C:13]([CH3:16])=[CH:12][CH:11]=2)[C:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[N:8]1
Reactant: C=O
Reactant: Cc1ccc2[nH]nc(-c3ccccc3)c2c1
Product: Cc1ccc2c(c1)c(-c1ccccc1)nn2CO
Yield: 83.6 %

Procedure:
By the procedure similar to that described in Example 19, 3-phenyl-5-methylindazole (13.7 g) and paraformaldehyde (2.4 g) were treated to obtain 13.1 g of 1-hydroxymethyl-3-phenyl-5-methylindazole (m.p. 109°-111° C).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][O:5][C@H:4]([CH2:8][OH:9])[CH2:3]1.[H-].[Na+].[C:12]1([N:18]2[CH2:23][CH2:22][N:21]([C:24](OC3C=CC([N+]([O-])=O)=CC=3)=[O:25])[CH2:20][CH2:19]2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([N:18]2[CH2:19][CH2:20][N:21]([C:24]([O:9][CH2:8][C@H:4]3[O:5][CH2:6][CH2:7][N:2]([CH3:1])[CH2:3]3)=[O:25])[CH2:22][CH2:23]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CCN(c2ccccc2)CC1
Reactant: CN1CCO[C@H](CO)C1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1CCO[C@H](COC(=O)N2CCN(c3ccccc3)CC2)C1
Reaction time: 0.5 h
Yield: 20.6 %

Procedure:
(S)-(4-Methyl-morpholin-2-yl)-methanol (Intermediate 10; 100 mg, 0.76 mmol) was added to a suspension of NaH (60% dispersion in oil; 90.0 mg, 2.28 mmol,) in anhydrous THF (7 mL) and stirred under nitrogen for 30 min. 4-Nitrophenyl 4-phenylpiperazine-1-carboxylate (Intermediate 2; 300 mg, 0.92 mmol) was added and the reaction mixture was stirred at room temperature for 48 h. The reaction mixture was filtered through celite and the solid washed with THF (10 mL). The filtrates were combined and the solvent removed in vacuo. The residue was purified by column chromatography (normal phase silica, 5 g Isolute-Si column, gradient 1-5% MeOH in DCM) then by reverse phase HPLC(YMC ODS-A 100×20 mm, 5 μm, 25 mL/min, gradient 20% to 100% (over 7 min) then 100% (3 min) MeOH in 10% MeOH/water). The pure product was taken up in DCM (5 mL), filtered, and dried in vacuo to give [(2S)-4-methylmorpholin-2-yl]methyl 4-phenyl-piperazine-1-carboxylate (50 mg, 20%) as a colourless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Cl)=[CH:4][CH:3]=1.[OH:10][C:11]1[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=1[O:19][CH2:20][C:21]1[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=1)[CH:14]=[O:15].C(=O)([O-])[O-].[K+].[K+]>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.CC(C)=O>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:10][C:11]2[CH:12]=[C:13]([CH:16]=[CH:17][C:18]=2[O:19][CH2:20][C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[CH:23][CH:22]=2)[CH:14]=[O:15])=[CH:4][CH:3]=1
Reactant: ClCc1ccc(Cl)cc1
Reactant: COc1ccc(COc2ccc(C=O)cc2O)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CC(C)=O
Product: COc1ccc(COc2ccc(C=O)cc2OCc2ccc(Cl)cc2)cc1
Yield: 73.6 %

Procedure:
A solution of 4-chlorobenzyl chloride (67.9 g), 3-hydroxy-4-(4-methoxy-benzyloxy)-benzaldehyde (40) (99 g) and tetrabutylammonium iodide (14.1 g) was heated at reflux in acetone (0.4 L) over solid potassium carbonate (39.1 g) for 3 hours. Excess acetone was removed by rotary evaporation under reduced pressure and the resulting residue partitioned between ethyl acetate and dilute hydrochloric acid (0.5 N). The organic layer was washed with water and brine and then dried over magnesium sulphate. Ethyl acetate was removed by rotary evaporation under reduced pressure to afford the crude product. The crude oil was triturated with a 50/50 mixture of diethyl ether and hexane accompanied by vigorous stirring to afford the product as a colourless solid (108 g, 73% yield, retention time 3.70 mins, poor ionization, ES− m/z 538.05). 1H NMR (400 MHz, CDCl3) δ 9.84 (s, 1H), 7.51-7.43 (m, 2H), 7.42-7.32 (m, 6H), 7.07 (d, J=8.1 Hz, 1H), 6.97-6.89 (m, 2H), 5.19 (s, 2H), 5.17 (s, 2H), 3.85 (s, 3H).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C@H:3]([CH3:22])[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.Br[C:26]1[C:27](=[O:33])[N:28]([CH3:32])[CH:29]=[CH:30][CH:31]=1>>[CH3:32][N:28]1[CH:29]=[CH:30][CH:31]=[C:26]([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][C@@H:3]([CH3:22])[C:2]([F:1])([F:23])[F:24])=[CH:6][CH:7]=4)[CH2:15][CH2:14]3)[CH2:20][CH2:19]2)[C:27]1=[O:33]
Reactant: Cn1cccc(Br)c1=O
Reactant: C[C@H](Oc1ccc(N2CCC3(CCNCC3)C2=O)cc1)C(F)(F)F
Product: C[C@H](Oc1ccc(N2CCC3(CCN(c4cccn(C)c4=O)CC3)C2=O)cc1)C(F)(F)F

Procedure:
The title compound was prepared in analogy to example 1 step D from a mixture of 2-[4-((S)-2,2,2-trifluoro-1-methylethoxy)-phenyl]-2,8-diaza-spiro[4.5]decan-1-one (prepared in analogy to example 1 step B-C from 1-benzyl-4-(2-methoxyethyl)-piperidine-4-carboxylic acid ethyl ester and 4-((S)-2,2,2-trifluoro-1-methyl-ethoxy)-phenylamine) and 3-bromo-1-methyl-1H-pyridin-2-one. Light green solid. MS (ESI): 450.1 (MH+)
Reaction SMILES: [NH:1]([C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:22])[CH3:21])[CH:14]=2)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1)N.[H][H]>CO.C1COCC1.[Ni]>[NH2:1][C:3]1[N:12]([C:13]2[CH:18]=[CH:17][CH:16]=[C:15]([O:19][CH:20]([CH3:21])[CH3:22])[CH:14]=2)[C:11](=[O:23])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: [H][H]
Reactant: CC(C)Oc1cccc(-n2c(NN)nc3ccccc3c2=O)c1
Agent: [Ni]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)Oc1cccc(-n2c(N)nc3ccccc3c2=O)c1
Reaction time: 40 h

Procedure:
A solution of 2-Hydrazino-3-(3-isopropoxy-phenyl)-3H-quinazolin-4-one (2.5g, 8.0 mmol) in 100 mL methanol-THF (1:1) was treated with Raney Ni (2.0), and resulting suspension was subjected to atmosphere of hydrogen at 52.0 psi for 30 hours with agitation at temperature of 50° C. An additional 1.0 g of Raney Ni was added and reaction was continued for additional 40 hours at 50° C. The mixture was then filtered through celite, and the solvent was removed in vacuo to give the title compound as a reddish yellow solid. This crude product was then titurated with ethyl acetate and hexane to isolate 1.85 g (78%) product as a light yellow solid, mp 130°-133° C.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]1=[O:11].[Br:12]Br.O>C(O)(=O)C>[Br:12][C:8]1[CH:9]=[C:10]2[C:5]([N:4]=[CH:3][C:2](=[O:11])[NH:1]2)=[CH:6][CH:7]=1
Reactant: BrBr
Reactant: O=c1cnc2ccccc2[nH]1
Solvent: CC(=O)O
Solvent: O
Product: O=c1cnc2ccc(Br)cc2[nH]1
Reaction time: 18 h
Yield: 66.2 %

Procedure:
To a stirred solution of 1H-quinoxalin-2-one (50 g, 342.5 mmol) in glacial acetic acid (2500 mL) was added bromine (54.7 g, 342.5 mmol in 120 mL acetic acid) over a period of 1.5 h at rt. After 18 h stirring, the mixture was slowly poured into 2000 mL water and stirred for 1 h at rt. The precipitate was filtered and the residue was washed with water and dried to give 7-bromo-1H-quinoxalin-2-one as an off-white solid (51 g, 66%): 1H-NMR (300 MHz, d6-DMSO): δ=12.42 (1H, s), 8.19 (1H, s), 7.75 (1H, d), 7.44 (2H, m) ppm.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[N+](C)([O-])=O.[Cl:9][CH2:10][CH2:11][C:12](Cl)=[O:13].Cl.[C:16]1([CH3:22])[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>C(Cl)Cl.O>[CH3:22][C:16]1[CH:21]=[CH:20][C:19]([C:12](=[O:13])[CH2:11][CH2:10][Cl:9])=[CH:18][CH:17]=1
Reactant: Cc1ccccc1
Reactant: O=C(Cl)CCCl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: C[N+](=O)[O-]
Solvent: O
Solvent: ClCCl
Product: Cc1ccc(C(=O)CCCl)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Aluminum chloride (480 g) was suspended in methylene chloride (1125 mL). Nitromethane (195 mL) was added dropwise to the suspension and the resulting mixture was stirred for one hour at room temperature. Subsequently, toluene (321 mL) was added dropwise thereto and the mixture was stirred for one hour at room temperature. Further, to the mixture was added dropwise 3-chloropropionylchloride (289 mL) at 10-15° C. and the resultant mixture was stirred for 2 hours at room temperature. After the reaction mixture was cooled in an ice bath, ice, then methylene chloride, water, and concentrated hydrochloric acid were added to the mixture with stirring. The layers were separated, and the organic layer was washed sequentially with 1N hydrochloric acid, saturated sodium bicarbonate, and saturated brine, and dried over anhydrous sodium sulfate, after which the solvent was evaporated under reduced pressure. The residue was recrystallized from a solvent mixture of hexane and ethyl acetate, to thereby obtain 457.9 g of the target compound as white crystals. Melting point: 77.5-78.5° C.
Reaction SMILES: [F:1][C:2]([F:27])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[CH2:23][C:22](=[O:25])[CH2:21][CH2:20]4)=[N:11][CH:10]=2)=[CH:5][CH:4]=1.[BH4-].[Na+].O>C(O)C>[F:27][C:2]([F:1])([F:26])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[O:13][C:12]([NH:14][C:15]3[CH:16]=[CH:17][CH:18]=[C:19]4[C:24]=3[CH2:23][CH:22]([OH:25])[CH2:21][CH2:20]4)=[N:11][CH:10]=2)=[CH:5][CH:4]=1
Reactant: O=C1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OC1CCc2cccc(Nc3ncc(-c4ccc(C(F)(F)F)cc4)o3)c2C1
Temperature: 0 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
The product of Example 1I (60 mg, 0.161 mmol) in ethanol (6 mL) was treated at 0° C. with NaBH4 (7 mg, 0.184 mmol). The reaction was stirred at 0° C. for 1 hour and was then poured into H2O and extracted with ethyl acetate. The extracts were dried over Na2SO4, and concentrated in vacuo. The residue was chromatographed on silica gel eluting with 70%-85% ethyl acetate-hexane to afford the title compound as a tan solid (34 mg, 56%). 1H NMR (DMSO-d6) δ 9.33 (s, 1H), 7.78 (m, 4H), 7.62 (s, 1H), 7.55 (d, 1H, J=7.4 Hz), 7.11 (m, 1H), 6.88 (d, 1H, J=7.2 Hz), 4.83 (d, 1H, J=4.1 Hz), 3.92 (m, 1H), 2.69-2.98 (m, 4H), 1.86 (m, 1H), 1.62 (m, 1H); MS (ESI+) m/z 375 (M+H).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1([CH:13]=O)[CH2:8][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:6]1)=[O:4].C([O-])(=O)C.[Na+].Cl.[CH2:21]([O:28][NH2:29])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>CO>[CH3:1][O:2][C:3]([C:5]1([CH:13]=[N:29][O:28][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:6][CH:7]([CH2:9][CH2:10][CH2:11][CH3:12])[CH2:8]1)=[O:4]
Reactant: CCCCC1CC(C=O)(C(=O)OC)C1
Reactant: NOCc1ccccc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CCCCC1CC(C=NOCc2ccccc2)(C(=O)OC)C1
Yield: 64.9 %

Procedure:
A mixture of 3-butyl-1-formyl-cyclobutanecarboxylic acid methyl ester (7.2 g, 36.7 mmol), sodium acetate (6.1 g, 73.4 mmol) and O-benzylhydroxylamine hydrochloride (11.9 g, 73.4 mmol) were stirred in methanol (90 mL) for 18 h. The methanol was removed in vacuo, water (100 mL) was added and the aqueous phase was extracted with EtOAc (75 mL×5). The combined organic extracts were dried (MgSO4) and were evaporated in vacuo. The residue was purified by flash column chromatography using an eluting system of hexane/EtOAc (9:1) to yield the title compound as a clear colorless oil (7.23 g, 64%). MH+304.
Reaction SMILES: FC(F)(F)S(O[C:7]1[CH:11]=[CH:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[N:8]=1)(=O)=O.F[C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=1)[C:24]#[N:25].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.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>[N:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[N:9]1[CH:10]=[CH:11][C:7]([C:21]2[CH:22]=[C:23]([CH:26]=[CH:27][CH:28]=2)[C:24]#[N:25])=[N:8]1
Reactant: N#Cc1cccc(F)c1
Reactant: O=S(=O)(Oc1ccn(-c2ccccn2)n1)C(F)(F)F
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: COCCOC
Product: N#Cc1cccc(-c2ccn(-c3ccccn3)n2)c1
Temperature: 65 °C
Reaction time: 12 h

Procedure:
1-Pyridin-2-yl-1H-pyrazol-3-yl trifluoromethanesulfonate (0.211 g, 0.72 mmol), 3-fluorobenzonitrile (0.111 g, 0.76 mmol) and potassium carbonate (0.209 g, 1.51 mmol) in a mixture of ethyleneglycol dimethyl ether (20 mL) and water (4 mL) was degassed by argon bubbling for 15 min., then tetrakis(triphenylphosphine)palladium(0) (20 mg, 0.017 mmol) was added the resulting solution degassed for a further 15 min. The solution was stirred at 65° C. for 12 h. The reaction mixture was quenched with water (30 mL), then extracted with EtOAc (3×30 mL) and washed with brine. The combined organic phase was dried over Na2SO4 and concentrated in vacuo. The crude residue was chromagraphed on silica gel eluting with EtOAc:hexane (2:3) to afford a white solid which was recrystallized from EtOAc-hexane to give 3-(1-pyridin-2-yl-1H-pyrazol-3-yl)benzonitrile as a white solid. 1H NMR (CD3Cl, 300 MHz) δ 8.64 (d, 1H), 8.44 (d, 1H), 8.25 (s, 1H), 8.14 (d, 1H), 8.10 (d, 1H), 7.87 (t, 1H), 7.64 (d, 1H), 7.55 (t, 1H), 7.24 (dd, 1H), 6.80 (d, 1H). MS (ESI) 247 (M++H).
Reaction SMILES: [Cl:1][C:2]([Cl:18])([CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]#[N:17])[C:3]([OH:5])=[O:4].S(=O)(=O)(O)[OH:20]>>[C:16]([CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][C:2]([Cl:18])([Cl:1])[C:3]([OH:5])=[O:4])(=[O:20])[NH2:17]
Reactant: N#CCCCCCCCCCCC(Cl)(Cl)C(=O)O
Reactant: O=S(=O)(O)O
Product: NC(=O)CCCCCCCCCCC(Cl)(Cl)C(=O)O
Temperature: 0 °C
Reaction time: 6 h

Procedure:
200 mg (0.70 mmol) 8 was fed into 10 ml 80% sulfuric acid and kept at room temperature for 6 h. The solution that was obtained was poured into 150 ml ice water, the beige-coloured precipitate was suction filtered and washed with petroleum ether. 180 mg (85%) 35, melting point 93-94° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)[Br:2].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(Cl)(Cl)(Cl)Cl.[CH2:30]([C:32]1[CH:39]=[CH:38][C:35]([CH:36]=O)=[CH:34][CH:33]=1)[CH3:31]>[Zn].C(Cl)Cl>[Br:2][C:1]([Br:5])=[CH:36][C:35]1[CH:38]=[CH:39][C:32]([CH2:30][CH3:31])=[CH:33][CH:34]=1
Reactant: CCc1ccc(C=O)cc1
Reactant: BrC(Br)(Br)Br
Agent: [Zn]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: ClCCl
Product: CCc1ccc(C=C(Br)Br)cc1
Reaction time: 2 h

Procedure:
A mixture of 4.94 g. (0.015 mol.) of carbon tetrabromide, 3.90 g. (0.015 mol.) of triphenylphosphine and 0.975 g. (0.015 g.-atom) of zinc in 25 ml. of carbon tetrachloride is stirred at 25° for 24 hours. A solution of 1.0 g. (7.45 mmol.) of p-ethylbenzaldehyde in 10 ml. of methylene chloride is added and the reaction mixture is stirred an additional two hours. Petroleum ether (140 ml.) is added to the mixture, the organic layer is decanted and the residue is extracted with 1:4 methylene chloride-petroleum ether. The combined organic solutions are concentrated under reduced pressure to give 1,1-dibromo-2-(4-ethylphenyl)ethylene.
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:21])([F:20])[F:19])[C:5]1[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:16])([F:15])[F:14])[CH:6]=1.O[C:23]1[N:24]=[N:25][CH:26]=[CH:27][CH:28]=1>COCCOC>[N:24]1[CH:23]=[CH:28][CH:27]=[C:26]([O:1][CH2:2][CH2:3][N:4]([CH2:17][C:18]([F:19])([F:20])[F:21])[C:5]2[CH:12]=[CH:11][C:8]([C:9]#[N:10])=[C:7]([C:13]([F:15])([F:16])[F:14])[CH:6]=2)[N:25]=1
Reactant: N#Cc1ccc(N(CCO)CC(F)(F)F)cc1C(F)(F)F
Reactant: Oc1cccnn1
Solvent: COCCOC
Product: N#Cc1ccc(N(CCOc2cccnn2)CC(F)(F)F)cc1C(F)(F)F

Procedure:
Synthesized as described in Example 27B from 4-[(2-hydroxyethyl)(2,2,2-trifluoroethyl)amino]-2-(trifluoromethyl)benzonitrile (Example 15B) and 3-hydroxypyridazine, using dry DME as the reaction solvent: MS (ESI) m/z 391 (M+1).
Reaction SMILES: C[O:2][C:3](=[O:12])[C:4]1[CH:9]=[C:8]([Br:10])[C:7](Cl)=[N:6][CH:5]=1.[CH3:13][O:14][CH2:15][CH2:16][OH:17].C1CCN2C(=NCCC2)CC1.[OH-].[K+].Cl>O>[Br:10][C:8]1[C:7]([O:17][CH2:16][CH2:15][O:14][CH3:13])=[N:6][CH:5]=[C:4]([CH:9]=1)[C:3]([OH:2])=[O:12]
Reactant: COCCO
Reactant: COC(=O)c1cnc(Cl)c(Br)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Product: COCCOc1ncc(C(=O)O)cc1Br
Yield: 66 %

Procedure:
A mixture of 325 mg (1.3 mmol) 5-Bromo-6-chloro-nicotinic acid methyl ester, 233 mg (3.24 mmol) 2-methoxyethanol and 493 mg (3.24 mmol) DBU was heated under microwave radiation for 2 min to 180° C. 0.65 mL water and 0.49 mL 5N KOH aq. was added and the mixture was heated under microwave radiation for 2 min to 160° C. The mixture was acidified with 1N HCl aq. and extracted with ethyl acetate. After evaporation the residue was purified by preparative HPLC on reversed phase eluting with a gradient formed from acetonitrile/water/HCOOH. The combined product fractions were evaporated to yield 237 mg (66%) of the title compound as white solid. MS (m/e): 274 (M−H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([OH:9])=O.C(Cl)(=O)C([Cl:13])=O>ClCCl.CN(C=O)C>[N:1]1[CH:6]=[CH:5][N:4]=[CH:3][C:2]=1[C:7]([Cl:13])=[O:9]
Reactant: O=C(O)c1cnccn1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)c1cnccn1
Temperature: 25 °C

Procedure:
A suspension of pyrazine 2-carboxylic acid (2.52 g, 20.3 mmol) in dichloromethane (30 mL) at 0° C. was treated with oxalyl chloride (1.95 mL, 22.3 mmol) followed by the addition of catalytic DMF (1 drop). The reaction mixture was allowed to warm to room temperature overnight, then concentrated in vacuo to give pyrazine 2-carbonyl chloride as a violet-colored solid.
Reaction SMILES: [H-].[Na+].[I:3][C:4]1[CH:5]=[N:6][NH:7][CH:8]=1.CS(O[CH:14]1[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)(=O)=O.O>CN(C=O)C>[O:17]1[CH2:18][CH2:19][CH:14]([N:6]2[CH:5]=[C:4]([I:3])[CH:8]=[N:7]2)[CH2:15][CH2:16]1
Reactant: Ic1cn[nH]c1
Reactant: CS(=O)(=O)OC1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Ic1cnn(C2CCOCC2)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 34.5 %

Procedure:
As shown in step 2-ii of Scheme 2, sodium hydride (6.101 mL of 60% NaH/mineral oil, 137.3 mmol) was added slowly to a solution of 4-iodopyrazole (24.21 g, 124.8 mmol) in 200 mL of anhydrous DMF at 0° C. The solution was stirred for 1 hour at 0° C. and tetrahydro-2H-pyran-4-yl methanesulfonate (Compound 1010, 22.5 g, 124.8 mmol) in 100 mL of anhydrous DMF was added dropwise. The reaction mixture was heated at 100° C. for 18 hours, at which time an additional 8.0 g of (Compound 1010) in 25 mL of anhydrous DMF was added dropwise. The reaction mixture was heated at 100° C. for an additional 24 hours. The mixture was cooled to room temperature and 100 mL of water was added. The mixture was extracted with EtOAc (3×100 mL) and the combined organics were washed with water, washed with brine, dried over sodium sulfate, filtered, and concentrated under reduced pressure to afford a semi-solid. Recrystallization from DCM yielded 1-(tetrahydro-2H-pyran-4-yl)-4-iodo-1H-pyrazole (Compound 1011, 11.96 g). A second crop of crystals was obtained upon trituration of the mother liquor with hexanes (5.26 g, 49.6% total yield): ESMS (M+H)=279.0.
Reaction SMILES: [C:1]([CH2:3][C:4]([O:6][CH3:7])=[O:5])#[N:2].[CH3:8][C:9]1([CH3:16])[O:13][CH:12](CO)[CH2:11][O:10]1>CN(C1C=CN=CC=1)C>[C:1]([CH2:3][C:4]([O:6][CH2:7][CH:11]1[CH2:12][O:13][C:9]([CH3:16])([CH3:8])[O:10]1)=[O:5])#[N:2]
Reactant: CC1(C)OCC(CO)O1
Reactant: COC(=O)CC#N
Agent: CN(C)c1ccncc1
Product: CC1(C)OCC(COC(=O)CC#N)O1
Reaction time: 30 h
Yield: 23 %

Procedure:
A mixture of methyl cyanoacetate (1.3 ml, 15×10−3 mol), of solketal (1.25 ml, 10×10−3 mol) and of DMAP (2.7 mg, 0.03 equiv.) is heated at reflux with stirring for 30 hours in a reactor rendered inert with nitrogen. After cooling, the solvent is evaporated under vacuum and the brown oil obtained is chromatographed on a silica column (gradient of eluents: heptane/EtOAc from 90:10 to 80:20). 423 mg (yield: 23%) of the pure fractions of (2,2-dimethyl-1,3-dioxolan-4-yl)methyl cyanoacetate are thus obtained in the form of a yellow oil used as is in the following stage.