Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CC1(C)CCCC(C)(C)N1.C([Li])CCC.[F:16][C:17]([F:29])([F:28])[C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=1.CN(C)[CH:32]=[O:33].Cl>O1CCCC1.CCCCCC>[F:16][C:17]([F:28])([F:29])[C:18]1[CH:19]=[C:20]([C:24]([F:25])([F:26])[F:27])[CH:21]=[CH:22][C:23]=1[CH:32]=[O:33]
Reactant: CN(C)C=O
Reactant: FC(F)(F)c1cccc(C(F)(F)F)c1
Agent: CC1(C)CCCC(C)(C)N1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCCCCC
Product: O=Cc1ccc(C(F)(F)F)cc1C(F)(F)F

Procedure:
A solution of y mol of 2,2,6,6-tetramethylpiperidine in 400 ml of anhydrous tetrahydrofuran is cooled under a stream of argon to to and there is added dropwise thereto at this temperature within 30 minutes 100·y/0.16 ml of a 1.6M solution of n-butyllithium in hexane. Subsequently, 20.2 ml (0.13 mol) of 1,3-bis(trifluoromethyl)benzene are added dropwise thereto at to within 15 minutes, the wine-red solution obtained is stirred for a further×minutes at to and then at this temperature 20 ml (0.26 mol) of N,N-dimethylformamide are allowed to flow in rapidly from a dropping funnel. The internal temperature t rises by about 15° as a consequence of the exothermic reaction. The dark red solution obtained is then slowly added dropwise and while stirring and cooling to 500 ml of cold 3M hydrochloric acid (strongly exothermic). The emulsion obtained is diluted with 300 ml of hexane, the aqueous phase is separated, the organic phase is extracted with 500 ml of cold 3M hydrochloric acid, washed neutral twice with 250 ml of saturated sodium chloride solution each time, dried over sodium sulphate and the organic solvent is largely distilled off at 40° bath temperature/20 kPa. The residue is distilled over a column having a length of 20 cm, whereby firstly residual solvent is removed at 50° bath temperature/20 kPa and then the bath temperature is increased to 80° and the vacuum is increased to 1.4 kPa. During the increase in the internal temperature a forerun of about 1 g is removed and then the 2,4-bis(trifluoromethyl)benzaldehyde obtained distils over at 56°./1.4 kPa as a colourless liquid.
Reaction SMILES: C(N(CC)CC)C.[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13](Cl)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1.[N:21]1[CH:26]=[CH:25][C:24]([CH2:27][O:28][CH2:29][CH2:30][NH2:31])=[CH:23][CH:22]=1.O>CN(C=O)C>[Cl:8][C:9]1[C:14]([N+:15]([O-:17])=[O:16])=[C:13]([NH:31][CH2:30][CH2:29][O:28][CH2:27][C:24]2[CH:23]=[CH:22][N:21]=[CH:26][CH:25]=2)[C:12]([CH3:19])=[C:11]([CH3:20])[N:10]=1
Reactant: NCCOCc1ccncc1
Reactant: Cc1nc(Cl)c([N+](=O)[O-])c(Cl)c1C
Solvent: CCN(CC)CC
Solvent: O
Solvent: CN(C)C=O
Product: Cc1nc(Cl)c([N+](=O)[O-])c(NCCOCc2ccncc2)c1C
Temperature: 25 °C
Reaction time: 17.5 h
Yield: 68.2 %

Procedure:
Under a nitrogen atmosphere, triethylamine (7.4 mL, 53 mmol) was added to a solution of 2,4-dichloro-5,6-dimethyl-3-nitropyridine (9.78 g, 44.2 mmol) in anhydrous DMF (200 mL). 2-(Pyridin-4-ylmethoxy)ethylamine (6.8 g, 45 mmol) was added, and the reaction was stirred at room temperature for 17.5 hours. The reaction solution was slowly added to water (1.8 L) and stirred for two hours to form a precipitate, which was isolated by filtration and washed with cold hexane (200 mL). The solid was dried under reduced pressure for one hour to provide 10.15 g of (2-chloro-5,6-dimethyl-3-nitropyridin-4-yl)-[2-(pyridin-4-ylmethoxy)ethyl]amine as a yellow solid. An analysis by HPLC indicated that starting material and an isomer were present as impurities.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:18][C:19]([O:21][CH2:22]C)=[O:20].O>CC(C)=O.C(Cl)Cl>[NH:7]1[C:8]2[C:4](=[CH:3][C:2]([O:1][CH2:18][C:19]([O:21][CH3:22])=[O:20])=[CH:10][CH:9]=2)[CH:5]=[CH:6]1
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CCOC(=O)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CC(C)=O
Solvent: ClCCl
Product: COC(=O)COc1ccc2[nH]ccc2c1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A suspension of 5-hydroxyindole (5.00 g; 37.6 mmol), caesium carbonate (26.9 g, 82.6 mmol) and ethyl bromoacetate (4.60 g, 30.0 mmol) in 100 ml acetone is stirred for 18 hours at ambient temperature. Then the reaction mixture is combined with water and DCM. The phases are separated and the aqueous phase is extracted with DCM. The combined phases are dried on sodium sulphate and freed from the solvent in vacuo.
Reaction SMILES: C[O:2][C:3](=[O:19])[CH2:4][C@@:5]([OH:18])([CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=1)[CH:6]([CH3:8])[CH3:7].[OH-].[Li+]>CO.O>[OH:18][C@:5]([CH2:9][CH2:10][C:11]1[CH:12]=[CH:13][C:14]([OH:17])=[CH:15][CH:16]=1)([CH:6]([CH3:7])[CH3:8])[CH2:4][C:3]([OH:19])=[O:2]
Reactant: COC(=O)C[C@@](O)(CCc1ccc(O)cc1)C(C)C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CC(C)[C@](O)(CCc1ccc(O)cc1)CC(=O)O

Procedure:
The title compound was prepared by dissolving (S)-3-hydroxy-3-[2-(4-hydroxy-phenyl)-ethyl]-4-methyl-pentanoic acid methyl ester (0.57 g, 2.15 mmol) from Example TTTT in MeOH (30 mL). Lithium hydroxide (0.18 g, 4.29 mmol) in water (10 mL) was added and the reaction heated to reflux for 1 hour, cooled and pumped to dryness under vacuum. The product was partitioned between water and Et2O. The aqueous layer was decanted, acidified with 1N HCl and extracted with Et2O. The solution was dried (MgSO4) and concentrated to give the title compound (m.p. 137-140° C.).
Reaction SMILES: [NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.CN(C(O[N:20]1N=N[C:22]2C=CC=N[C:21]1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N)C.CO>O.CN(C=O)C>[NH2:1][C:2]1[C:10]([Br:11])=[CH:9][CH:8]=[CH:7][C:3]=1[C:4]([NH:20][CH2:21][CH3:22])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: Nc1c(Br)cccc1C(=O)O
Agent: CCN
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: O
Solvent: CO
Product: CCNC(=O)c1cccc(Br)c1N
Temperature: 25 °C
Reaction time: 18 h
Yield: 111.1 %

Procedure:
A mixture of 2-amino-3-bromo-benzoic acid (2 g, 9.26 mmol), HATU (3.84 g, 10.10 mmol, Sigma Aldrich), DMF (42.1 mL), 2.0 M ethylamine in MeOH (4.21 mL, 8.42 mmol, Sigma Aldrich), and TEA (1.8 mL, 12.62 mmol) was set stirring at RT for 18 h. It was diluted with water and extracted with EtOAc. The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure. It was diluted with DCM, adsorbed onto silica, and purified on 40 g SiO2 (eluent: 0-100% EtOAc/hexanes over 25 min, RediSep Gold). The product fractions were combined and concentrated to give the product as a yellow oil (2.5 g, 122%). 1H NMR (400 MHz, DMSO-d6) δ ppm 8.39 (1H, br. s.) 7.47-7.54 (2H, m) 6.52 (1H, t, J=7.82 Hz) 6.44 (2H, br. s.) 3.19-3.29 (2H, m) 1.11 (3H, t, J=7.24 Hz). m/z (ESI, +ve) 242.9 (M+H)+.
Reaction SMILES: [C:1]([OH:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([OH:6])=[O:5].[CH3:9][N:10]([CH3:32])[CH:11]1[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]([O:14]2)[CH:12]1[OH:31].CC(C)=O>>[C:1]([O-:8])(=[O:7])/[CH:2]=[CH:3]/[C:4]([O-:6])=[O:5].[OH:31][CH:12]1[CH:11]([NH+:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2.[OH:31][CH:12]1[CH:11]([NH+:10]([CH3:9])[CH3:32])[C:25]2=[CH:26][CH:22]([O:23][C:24]2=[O:27])[CH:21]2[CH:17]([O:18][C:19](=[O:29])[CH:20]2[CH3:28])[CH2:16][C:15]2([CH3:30])[CH:13]1[O:14]2
Reactant: O=C(O)/C=C/C(=O)O
Reactant: CC1C(=O)OC2CC3(C)OC3C(O)C(N(C)C)C3=CC(OC3=O)C21
Solvent: CC(C)=O
Product: CC1C(=O)OC2CC3(C)OC3C(O)C([NH+](C)C)C3=CC(OC3=O)C21
Product: O=C([O-])/C=C/C(=O)[O-]
Yield: 37.9 %

Procedure:
A solution of fumaric acid (0.1 mmol; 11.6 mg) in acetone (3 ml) is added to a solution of the compound of Example 5 (0.1 mmol; 34 mg) in acetone (0.5 ml). The precipitate is filtered, washed with acetone and dried under reduced pressure. 15 mg of the expected product is obtained in the form of a white powder. Melting point: 159° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1.[CH:9](/B(O)O)=[CH:10]/[CH3:11].ClC1C=CC(CC2C=C(C=O)SC=2)=CC=1>CN(C=O)C>[CH:9](/[C:2]1[CH:3]=[C:4]([CH:7]=[O:8])[O:5][CH:6]=1)=[CH:10]/[CH3:11]
Reactant: O=Cc1cc(Br)co1
Reactant: C/C=C\B(O)O
Agent: O=Cc1cc(Cc2ccc(Cl)cc2)cs1
Solvent: CN(C)C=O
Product: C/C=C\c1coc(C=O)c1
Yield: 48.2 %

Procedure:
The title compound was synthesized from 4-bromo-furan-2-carboxaldehyde (1.1 g, 6.3 mmol, 1 equiv) and cis-propene boronic acid (0.65 g, 7.5 mmol, 1.2 equiv) using the conditions to synthesize 4-(4-chlorobenzyl)thiophene-2-carbaldehyde, with the exception that the reaction was run in DMF (20 mL). The resulting residue was purified via ISCO Companion (0-25% EtOAc/heptane over 30 min, retention time of product: 23-26 min) to give (Z)-4-(prop-1-enyl)furan-2-carbaldehyde (0.4130 g, 48% yield). LC/MS m/e 136.8 (M+H). 1H NMR (400 MHz, CD3CN) δ (ppm): 9.59 (d, J=0.63 Hz, 1H), 7.83 (s, 1H), 7.42 (s, 1H), 6.23 (dd, J=11.40, 1.68 Hz, 1H), 5.79-5.89 (m, 1H), 1.87 (dd, J=7.10, 1.78 Hz, 3H).
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[N:9][CH:10]=[CH:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[CH2:14](O)CCCCCCCCCCC>[Ni]>[C:1]1([C:7]2[CH:12]=[CH:11][C:10]([CH3:14])=[N:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCO
Reactant: c1ccc(-c2cccnc2)cc1
Agent: [Ni]
Solvent: O
Product: Cc1ccc(-c2ccccc2)cn1
Temperature: 25 °C

Procedure:
A suspension of 100 g of wet Raney Nickel in 1.5L of dodecanol in a three neck round bottom flask equipped with a Dean Stark apparatus was heated until the temperature reached 130° C., then 3-phenylpyridine (Aldrich) was added and the reaction was heated at 190°-200° C. for 6 hours. During the reaction, water was constantly eliminated. When the reaction was over, half of the dodecanol was removed by distillation. After cooling the reaction mixture to room temperature, 200 mL of H2O and 400 mL of hexane were added, the mixture was shaken and the hexane layer decanted. This process was repeated several times. The combined hexane fractions were washed with 1N HCl until the disappearance of 5-phenyl-2-picoline from the organic phase. The combined aqueous layers were filtered, washed with hexane, basified with 10N NaOH, and extracted with CH2Cl2. The organic layer was washed with NH4OAc (25%), dried over MgSO4 and evaporated to dryness. The crude residue was then distilled under vacuum (100° C. at 0.1 mm of Hg) to afford the pure title product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[NH:5][C:6]1[C:7]2[N:15]=[C:14](F)[CH:13]=[CH:12][C:8]=2[N:9]=[CH:10][N:11]=1.[NH3:20]>C(O)C>[NH2:20][C:14]1[CH:13]=[CH:12][C:8]2[N:9]=[CH:10][N:11]=[C:6]([NH:5][C:4]3[CH:17]=[CH:18][CH:19]=[C:2]([Br:1])[CH:3]=3)[C:7]=2[N:15]=1
Reactant: Fc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Reactant: N
Solvent: CCO
Product: Nc1ccc2ncnc(Nc3cccc(Br)c3)c2n1
Yield: 72 %

Procedure:
Reaction of 4-(3-bromoanilino)-6-fluoropyrido[3,2-d]pyrimidine (0.12 g, 0.38 mmol)(described in a previous experimental) with a saturated solution of ammonia in ethanol in a pressure vessel at 100° C. for 18 h gives 6-amino-4-(3-bromoanilino)pyrido[3,2-d]pyrimidine, (87 mg, 72%). 1H NMR (CDCl3) δ 8.76 (1H, brs), 8.64 (1H, s), 8.23 (1H, brs), 7.93 (1H, d, J=9.0 Hz), 7.81 (1H, dt, Jd =7.7 Hz, Jt =1.8 Hz), 7.28-7.22 (2H, m), 7.00 (1H, d, J=9.0 Hz), 4.90 (2H, brs).
Reaction SMILES: [N:1]1([CH2:6][C:7]2[CH:8]=[C:9]3[N:15]=[C:14]([C:16]4[CH:22]=[CH:21][CH:20]=[CH:19][C:17]=4[NH2:18])[S:13][C:10]3=[N:11][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[C:23]1([C:29]2[N:30]=[C:31]([C:34](O)=[O:35])[S:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>O>[C:23]1([C:29]2[N:30]=[C:31]([C:34]([NH:18][C:17]3[CH:19]=[CH:20][CH:21]=[CH:22][C:16]=3[C:14]3[S:13][C:10]4[C:9]([N:15]=3)=[CH:8][C:7]([CH2:6][N:1]3[CH2:2][CH2:3][CH2:4][CH2:5]3)=[CH:12][N:11]=4)=[O:35])[S:32][CH:33]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)c1nc(-c2ccccc2)cs1
Reactant: Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1
Solvent: O
Product: O=C(Nc1ccccc1-c1nc2cc(CN3CCCC3)cnc2s1)c1nc(-c2ccccc2)cs1

Procedure:
The title compound was prepared according to amide synthesis general method A, utilizing 2-(6-(pyrrolidin-1-ylmethyl)thiazolo[5,4-b]pyridin-2-yl)aniline and 4-phenylthiazole-2-carboxylic acid. The product was isolated by precipitation by the addition of water, triturated with hot methanol and purified by silica gel chromatography (gradient 0 to 10% methanol in CH2Cl2). MS Calcd for C27H23N5OS2: 497.13. Found (M+H)+ m/z=498.
Reaction SMILES: P(Br)(Br)[Br:2].[CH:5]1([CH:8]([CH:12]2[CH2:14][CH2:13]2)[CH2:9][CH2:10]O)[CH2:7][CH2:6]1.[H-].[Al+3].[Li+].[H-].[H-].[H-]>CCOCC>[Br:2][CH2:10][CH2:9][CH:8]([CH:12]1[CH2:14][CH2:13]1)[CH:5]1[CH2:7][CH2:6]1
Reactant: OCCC(C1CC1)C1CC1
Reactant: BrP(Br)Br
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Product: BrCCC(C1CC1)C1CC1
Temperature: 0 °C
Yield: 60 %

Procedure:
15.5 g Of phosphorus tribromide are slowly added to a solution, cooled to -30° C., of 22 g of 3,3-dicyclopropylpropanol (obtained by reduction of the compound described in preparation A in the presence of lithium aluminum hydride) in 85 ml of anhydrous ether, and the mixture is poured, after returning to room temperature, into 7 ml of ice cold water. The organic phase is then washed with a saturated solution of sodium bicarbonate and then with water until neutral and finally dried and evaporated. The expected product obtained after distillation under vacuum.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.C(N(CC)CC)C.[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.[OH-].[Na+]>O1CCCC1.O>[F:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([NH:1][C:2]2[CH:3]=[C:4]3[C:8](=[CH:9][CH:10]=2)[NH:7][CH:6]=[CH:5]3)=[O:24])=[CH:21][CH:20]=1
Reactant: Nc1ccc2[nH]ccc2c1
Reactant: O=C(Cl)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Solvent: O
Product: O=C(Nc1ccc2[nH]ccc2c1)c1ccc(F)cc1
Yield: 83.5 %

Procedure:
To a solution of 3.96 gm (30.0 mMol) 5-amino-1H-indole in 150 mL tetrahydrofuran were added 5.6 mL triethylamine followed by a solution of 5.2 gm (33.0 mMol) 4-fluorobenzoyl chloride in 30 mL tetrahydrofuran. After 18 hours the reaction mixture was poured into water, made basic with sodium hydroxide solution, and extracted with dichloromethane. The organic extracts were combined, dried over sodium sulfate and concentrated under reduced pressure to give a purple solid. This residue was recrystallized from ethyl acetate/hexane to give 6.37 gm (84%) 5-(4-fluoro-benzoyl)amino-1H-indole as brown crystals in two crops.
Reaction SMILES: [CH2-:1][C:2]([CH3:4])=[O:3].[O:5]=[CH:6][C@@H:7]([CH2:9][OH:10])[OH:8].C(N(CC)CC)C.[S:18](Cl)([CH3:21])(=[O:20])=[O:19]>ClCCl>[CH2-:1][C:2]([CH3:4])=[O:3].[S:18]([O:5][CH2:6][C@H:7]([OH:8])[CH2:9][OH:10])([CH3:21])(=[O:20])=[O:19]
Reactant: O=C[C@H](O)CO
Reactant: CS(=O)(=O)Cl
Agent: [CH2-]C(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OC[C@H](O)CO

Procedure:
A solution of 2(S)-glycerol-2,3-acetonide (109 g), obtained from mannitol-1,2:5,6-diacetonide via D-glyceraldehyde acetonide using the method described by LeCocq et al., Biochem., 3, 976 (1964), in 1 L dry dichloromethane was cooled to -35° with stirring. Triethylamine (140 ml) was added followed by the dropwise addition of mesyl chloride (71 ml) over 10 minutes while maintaining the reaction between -35° and -25°. The cooling bath was removed and after 45 minutes, 250 ml 1N hydrochloric acid was added. The layers were separated and the dichloromethane solution was washed in turn with 250 ml portions of water (1×), 1N sodium hydroxide (1×) and water (1×). The aqueous layers were dried over sodium sulfate and evaporated to give 172.1 g of (2R)-3-mesyloxy-1,2-propanediol acetonide as a pale yellow oil.
Reaction SMILES: [C:1]([N:8]1[CH2:12][CH2:11][C:10](=[O:13])[CH2:9]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].[C:14]1([CH3:22])[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[Mg]Br>>[C:4]([O:3][C:1]([N:8]1[CH2:12][CH2:11][C:10]([OH:13])([C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=2[CH3:22])[CH2:9]1)=[O:2])([CH3:7])([CH3:6])[CH3:5]
Reactant: CC(C)(C)OC(=O)N1CCC(=O)C1
Reactant: Cc1ccccc1[Mg]Br
Product: Cc1ccccc1C1(O)CCN(C(=O)OC(C)(C)C)C1

Procedure:
Prepared in analogy to Example A1 (a) from N-boc-3-pyrrolidinone and o-tolyl-magnesiumbromide to yield the title compound as an light yellow oil. MS (m/e): 278.2 (M+H+, 100%).
Reaction SMILES: F[C:2]1[CH:9]=[CH:8][C:7]([C:10]#[C:11][Si](C)(C)C)=[CH:6][C:3]=1[C:4]#[N:5].CO.[C:18](=O)([O-])[O-:19].[Cs+].[Cs+]>C(Cl)Cl.C(OCC)C>[C:10]([C:7]1[CH:8]=[CH:9][C:2]([O:19][CH3:18])=[C:3]([CH:6]=1)[C:4]#[N:5])#[CH:11]
Reactant: C[Si](C)(C)C#Cc1ccc(F)c(C#N)c1
Reactant: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CO
Solvent: ClCCl
Solvent: CCOCC
Product: C#Cc1ccc(OC)c(C#N)c1
Reaction time: 2 h
Yield: 69.2 %

Procedure:
To a stirred solution of 2-Fluoro-5-trimethylsilanylethynyl-benzonitrile (0.935 g, 4.3 mmol), in dry methylene chloride (10 mL) and methanol (10 mL) was added cesium carbonate (1.7 g, 5.2 mmol) and stirred for 2 h under a nitrogen atmosphere. The mixture was diluted with diethyl ether (100 mL), and partitioned between diethyl ether and H2O (100 mL), and the aqueous layer was extracted with diethyl ether (50 mL), washed with brine and dried over MgSO4, filtered and concentrated in vacuo. Purification by flash chromatography (20-30% ethyl acetate/petroleum ether) gave the title compound as a tan solid (0.468 g, 69%), identified by NMR and mass spectral analyses. Mp: 100-101° C. MS (EI+): 157 (M+).
Reaction SMILES: [OH-:1].[Na+].COC([NH:7][C:8](=[O:29])[C:9]([O:27][CH3:28])([O:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=2)=[CH:14][CH:13]=1)[CH3:10])=O.[CH3:30][OH:31]>>[OH:1][NH:7][C:8](=[O:29])[C:9]([O:27][CH:28]=[C:30]=[O:31])([O:11][C:12]1[CH:13]=[CH:14][C:15]([O:18][C:19]2[C:24]([Cl:25])=[CH:23][C:22]([Cl:26])=[CH:21][N:20]=2)=[CH:16][CH:17]=1)[CH3:10]
Reactant: COC(=O)NC(=O)C(C)(OC)Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1
Reactant: CO
Reactant: [OH-]
Agent: [Na+]
Product: CC(OC=C=O)(Oc1ccc(Oc2ncc(Cl)cc2Cl)cc1)C(=O)NO

Procedure:
Into a mixture of IN aqueous sodium hydroxide solution (48 ml) and methanol (300 ml), N-methoxycarbonyl-methoxy-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]propionamide (Compound No. 38 as obtained in Example 1) (9.4 g) was dissolved, and the resultant mixture was stirred at 50° C. for 1 hour. After removal of methanol by distillation, the aqueous layer was made acidic with conc. hydrochloric acid and extracted with ethyl acetate. Removal of the ethyl acetate from the extract by distillation gave N-hydroxy-carbonylmethoxy-2-[4-(3,5-dichloro-2-pyridyloxy)phenoxy]-propionamide (9.0 g). Yield, 98%.
Reaction SMILES: [C-:1]#[N:2].[Na+].Br[CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12].O.Cl>CS(C)=O>[C:1]([CH2:5][CH2:6][CH2:7][CH2:8][N:9]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][CH:17]=1)[C:10](=[O:15])[C:11]([F:14])([F:13])[F:12])#[N:2]
Reactant: [C-]#N
Reactant: O=C(N(CCCCBr)c1ccc(O)cc1)C(F)(F)F
Agent: Cl
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: N#CCCCCN(C(=O)C(F)(F)F)c1ccc(O)cc1
Temperature: 64 °C
Reaction time: 2 h
Yield: 46 %

Procedure:
Sodium cyanide (17.2 g, 0.35 mol) was stirred mechanically in 325 mL DMSO under nitrogen and heated to 64° C. The 29.7 g of N-(4-bromobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide in 125 mL of DMSO was dripped in over 13/4 hours. The reaction was stirred for two hours at 65°-72° C., cooled to -15° C., and poured into 3 L of ice and water. The cold mixture was immediately acidified with about 350 mL of 1N HCl and extracted three times with a total of 1.2 L of ethyl acetate. The ethyl acetate extracts were washed once with saturated sodium chloride solution and dried over magnesium sulfate. The solution was evaporated on a rotary evaporator to yield 11.5 g of N-(4-cyanobutyl)-N-(4-hydroxyphenyl)trifluoroacetamide.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.Cl[C:17]1[CH:18]=[CH:19][C:20]2[N:21]([C:23]([C:26]([F:29])([F:28])[F:27])=[N:24][N:25]=2)[N:22]=1>>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:17]2[CH:18]=[CH:19][C:20]3[N:21]([C:23]([C:26]([F:27])([F:29])[F:28])=[N:24][N:25]=3)[N:22]=2)[CH2:11][CH2:10]1
Reactant: FC(F)(F)c1nnc2ccc(Cl)nn12
Reactant: Clc1ccccc1CN1CCCNCC1
Product: FC(F)(F)c1nnc2ccc(N3CCCN(Cc4ccccc4Cl)CC3)nn12

Procedure:
A mixture of 1-[(2-chlorophenyl)methyl]-1,4-diazepane and 6-chloro-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine was allowed to react by General Synthetic Method 3. The crude product was purified by hplc using a Waters XTerra C18 column (5μ silica, 19 mm diameter, 100 mm length) eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give 6-[4-[(2-chlorophenyl)methyl]-1,4-diazepan-1-yl]-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine.
Reaction SMILES: [F:1][C:2]([C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=O)([F:4])[F:3].[C:13]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])#[N:14].N1C=CC=CC=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:19]([O:18][C:16](=[O:17])[C:15]([C:13]#[N:14])=[C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:2]([F:4])([F:3])[F:1])[CH3:20]
Reactant: O=C(c1ccccc1)C(F)(F)F
Reactant: CCOC(=O)CC#N
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)C(C#N)=C(c1ccccc1)C(F)(F)F
Temperature: 0 °C
Reaction time: 0.17 h

Procedure:
A mixture of trifluoromethylphenylketone [C.A.S. 434-45-7] (5 g, 28.71 mmol) and ethyl cyanoacetate [C.A.S. 105-56-6] (3.61 mL, 31.58 mmol) in DCM (100 mL) was flushed with nitrogen, then cooled to 0° C. and maintained under a nitrogen atmosphere. Neat titanium(IV) chloride (6.79 mL, 60.30 mmol) was added dropwise, the reaction mixture was stirred for 10 min at 0° C. and then pyridine (1.5 mL) was added dropwise. When the addition was complete, the ice bath was removed, the reaction reaction was stirred for 30 min at r.t., additional pyridine was added (5 mL) and the reaction mixture was stirred for a further 20 h at r.t. The mixture was then diluted in DCM (100 mL) and washed with HCl 2N (2×200 mL), water (300 mL) and brine (100 mL). The organic phase was evaporated to yield intermediate compound D42 (4.8 g, 61%) as a mixture of E/Z isomers, as a colourless oil which was used without further purification.