Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=O)[C:4]1[CH:9]=[CH:8][C:7]([C:10]#[N:11])=[C:6]([OH:12])[CH:5]=1.[Li+].[BH4-]>C1COCC1>[OH:12][C:6]1[CH:5]=[C:4]([CH2:3][OH:2])[CH:9]=[CH:8][C:7]=1[C:10]#[N:11]
Reactant: COC(=O)c1ccc(C#N)c(O)c1
Agent: [BH4-]
Agent: [Li+]
Solvent: C1CCOC1
Product: N#Cc1ccc(CO)cc1O
Temperature: 70 °C

Procedure:
4-cyano-3-hydroxybenzoic acid methyl ester, Example 34, Step 3 (2.5 g, 14 mmol) was dissolved in THF (70 ml). LiBH4 in THF (2 M, 14 ml, 28 mmol) was added. The reaction mixture was heated to 70° C. for 60 hrs. The reaction mixture was quenched carefully with 3N HCl. The solvent was removed in vacuo and the crude material was purified by flash chromatography [10% MeOH(5% NH4OH)/CH2Cl2 ] to yield the desired product.
Reaction SMILES: [CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][N:16](S(C5C=CC(C)=CC=5)(=O)=O)[C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>O1CCOCC1.CCOC(C)=O.[NH4+].[Cl-]>[CH:1]1([C:7]2[N:11]3[C:12]4[CH:18]=[CH:17][NH:16][C:13]=4[N:14]=[CH:15][C:10]3=[CH:9][CH:8]=2)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ccc(C4CCCCC4)n23)cc1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: c1cc2c(ncc3ccc(C4CCCCC4)n32)[nH]1
Temperature: 90 °C
Reaction time: 15 h
Yield: 55 %

Procedure:
To a solution of 8-cyclohexyl-3-tosyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine (0.015 g, 0.038 mmol) in 1,4-dioxane (3 mL) was added aqueous NaOH (2 N, 0.29 mL, 0.57 mmol). The reaction mixture was heated to about 90° C. After about 15 h, the reaction mixture was cooled to ambient temperature and diluted with EtOAc (5 mL) and saturated aqueous NH4Cl (5 mL). The organic layer was separated, washed with water (5 mL) followed by brine (5 mL), dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure. The residue was triturated with EtOAc/heptane (1:1, 1 mL). The resulting solid was collected by filtration and dried in vacuo to provide 8-cyclohexyl-3H-dipyrrolo[1,2-a:2′,3′-e]pyrazine as a tan solid (0.005 g, 55%). LC/MS (Table 2, Method a) Rt=2.78 min; MS m/z: 240 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[NH:9][N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19].[H-].[Na+].I[CH:23]([CH3:25])[CH3:24]>>[Cl:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[N:9]([CH2:24][CH2:23][CH3:25])[N:8]=[C:7]2[C:11]1[CH:16]=[CH:15][C:14]([O:17][CH3:18])=[CH:13][C:12]=1[CH3:19]
Reactant: CC(C)I
Reactant: COc1ccc(-c2n[nH]c3c(Cl)cccc23)c(C)c1
Agent: [H-]
Agent: [Na+]
Product: CCCn1nc(-c2ccc(OC)cc2C)c2cccc(Cl)c21
Yield: 61.1 %

Procedure:
Prepared according to Method D step B from 7-chloro-3-(4-methoxy-2-methylphenyl)-1H-indazole (0.150 g, 0.52 mmol), sodium hydride (60% in oil, 0.025 g, 1.04 mmol) and 2-iodopropane (0.07 mL, 0.7 mmol) to give the title compound (0.100 g) as a white solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14]Br)[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1.[C-:16]#[N:17].[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][C:16]#[N:17])[C:5](=[O:13])[N:6]([CH2:8][C:9]([F:12])([F:11])[F:10])[CH:7]=1
Reactant: O=c1c(CBr)cc(Br)cn1CC(F)(F)F
Reactant: [C-]#N
Agent: [Na+]
Solvent: CO
Product: N#CCc1cc(Br)cn(CC(F)(F)F)c1=O
Reaction time: 1 h
Yield: 62.5 %

Procedure:
5-Bromo-3-(bromomethyl)-1-(2,2,2-trifluoroethyl)pyridin-2(1H)-one (1.40 g, 4.01 mmol) was added in portions over 15 min to a solution of sodium cyanide (1.48 g, 30.1 mmol) in methanol (15 mL). After 1 h, the reaction was concentrated to dryness, diluted with water, extracted with dichloromethane (3×), and the combined organic extracts were dried over sodium sulfate, filtered and concentrated. Purification by silica gel chromatography (100% dichloromethane >5% methanol/dichloromethane) gave the title compound (0.740 g). MS 296.9 (M+1).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14](Cl)(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1([NH2:25])[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=1[NH2:24]>CCCCCC>[O:1]([C:8]1[CH:13]=[CH:12][C:11]([S:14]([NH:24][C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=2[NH2:25])(=[O:16])=[O:15])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)cc1
Reactant: Nc1ccccc1N
Solvent: CCCCCC
Product: Nc1ccccc1NS(=O)(=O)c1ccc(Oc2ccccc2)cc1

Procedure:
The title compound was prepared according to General Method C using 4-phenoxyphenylsulfonyl chloride (969 mg, 3.6 mmol) and o-phenylenediamine (300 mg, 2.77 mmol). The reaction mixture was partitioned between water (200 ml) and toluene:methylene chloride (1:3). The organic phase collected and the methylene chloride evaporated leaving the toluene. Hexane added and the product precipatated from solution. (317 mg, 34%) EI-MS m/z 341 (M+H)+
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH2:8])[CH:2]=1.[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[S:22][C:23]([C:27](O)=[O:28])=[C:24]([CH3:26])[N:25]=3)[C:17](=[O:30])[CH:16]=2)[CH2:11][CH2:10]1>>[CH:9]1([CH2:12][CH2:13][O:14][C:15]2[CH:20]=[CH:19][N:18]([C:21]3[S:22][C:23]([C:27]([NH:8][CH2:7][C:3]4[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=4)=[O:28])=[C:24]([CH3:26])[N:25]=3)[C:17](=[O:30])[CH:16]=2)[CH2:11][CH2:10]1
Reactant: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)O
Reactant: NCc1cccnc1
Product: Cc1nc(-n2ccc(OCCC3CC3)cc2=O)sc1C(=O)NCc1cccnc1
Yield: 47 %

Procedure:
Following the procedure as described in Example 1, making variations only as required to use pyridin-3-ylmethanamine in place of benzylamine to react with 2-(4-(2-cyclopropylethoxy)-2-oxopyridin-1(2H)-yl)-4-methylthiazole-5-carboxylic acid, the title compound was obtained as a colorless solid in 47% yield: mp 170-172° C. (ethyl acetate); 1H NMR (300 MHz, CDCl3) δ 8.63 (d, J=8.1 Hz, 2H), 8.55 (s, 1H), 7.77 (d, J=7.8 Hz, 1H), 7.37-7.27 (m, 1H), 6.43 (t, J=5.7 Hz, 1H), 6.16 (dd, J=8.1, 2.6 Hz, 1H), 5.96 (d, J=2.6 Hz, 1H), 4.62 (d, J=5.7 Hz, 2H), 4.03 (t, J=6.6 Hz, 2H), 2.67 (s, 3H), 1.68 (q, J=6.6 Hz, 2H), 0.86-0.74 (m, 1H), 0.52-0.46 (m, 2H), 0.13-0.08 (m, 2H); 13C NMR (75 MHz, CDCl3) δ 167.9, 162.5, 162.1, 153.7, 152.6, 148.6, 148.3, 136.3, 131.3, 121.7, 104.2, 96.6, 69.1, 41.4, 33.6, 17.3, 7.56, 4.2; MS (ES+) m/z 411.2 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[C:9]([C:10]#[N:11])=[C:8]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=2)[C:7]([C:22]#[N:23])=[C:6]([SH:24])[N:5]=1)[CH3:2].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[S:30][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([C:29]2[S:30][CH:31]=[C:27]([CH2:26][S:24][C:6]3[C:7]([C:22]#[N:23])=[C:8]([C:12]4[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][OH:21])=[CH:14][CH:13]=4)[C:9]([C:10]#[N:11])=[C:4]([O:3][CH2:1][CH3:2])[N:5]=3)[N:28]=2)=[CH:37][CH:36]=1
Reactant: CCOc1nc(S)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOc1nc(SCc2csc(-c3ccc(Cl)cc3)n2)c(C#N)c(-c2ccc(OCCO)cc2)c1C#N

Procedure:
100 mg (0.293 mmol) of 2-ethoxy-4-[4-(2-hydroxyethoxy)phenyl]-6-sulphanylpyridine-3,5-dicarbonitrile together with 78 mg (0.322 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 98 mg (1.172 mmol) of sodium bicarbonate are stirred in 2 ml of DMF at room temperature overnight. The reaction mixture is purified by preparative HPLC (acetonitrile/water: 10:90→95:5). This gives 77 mg (47% of theory) of the target compound.
Reaction SMILES: [CH3:1][C:2]([CH3:9])([CH3:8])[C:3](=O)[C:4](O)=[O:5].[NH2:10][NH:11][C:12]([NH:14][NH2:15])=[S:13]>>[NH2:15][N:14]1[C:4](=[O:5])[C:3]([C:2]([CH3:9])([CH3:8])[CH3:1])=[N:10][N:11]=[C:12]1[SH:13]
Reactant: NNC(=S)NN
Reactant: CC(C)(C)C(=O)C(=O)O
Product: CC(C)(C)c1nnc(S)n(N)c1=O

Procedure:
which is formed in step (1) and which was hitherto unknown, is reacted, in a second stage, either directly in the solution obtained or after intermediate isolation and if appropriate after prior saponification to give free trimethylpyruvic acid (VI), with thiocarbohydrazide (H2N--NH--CS--NH--NH2) in an aqueous solution containing a hydrogen halide acid, at a temperature from about 20° to 100° C. in a manner which is in itself known to give 4-amino-6-tert.-butyl-3-mercapto-1,2,4-triazin-5(4H)-one (VII), and this compound is alkylated in alkaline solution, in a third stage, by means of methyl iodide or methyl bromide or other alkylating agents (especially ethyl iodide or ethyl bromide) in a known manner.
Reaction SMILES: [CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([Li])CCC.O1CCNC1=O.[C:25](Cl)(=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29]>O1CCCC1.Cl.C(OCC)C>[CH2:1]([C@@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:25](=[O:30])[CH2:26][CH2:27][CH:28]=[CH2:29])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C=CCCC(=O)Cl
Reactant: O=C1N[C@H](Cc2ccccc2)CO1
Agent: Cl
Agent: O=C1NCCO1
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: C1CCOC1
Product: C=CCCC(=O)N1C(=O)OC[C@H]1Cc1ccccc1
Reaction time: 0.5 h

Procedure:
Flush with nitrogen a 12 L 3-neck round bottom flask equipped with a mechanical stirrer, internal temperature probe/N2 inlet, and 1 L addition funnel for 20 min and then add (R)-4-benzyl-2-oxazolidinone (250 g, 1.41 mol). Dilute with tetrahydrofuran (THF) (1.8 L) and cool in a dry ice/acetone bath until the internal temperature is −74° C. Transfer a 1.6M hexanes solution of n-butyllithium (970 mL, 1.552 mol) to the addition funnel via cannula, and add to the oxazolidinone solution at a rate such that the internal temperature does not reach above −65° C. After the addition is complete, allow the reaction to stir in the cooling bath 30 min. Transfer 4-pentenoyl chloride (175 mL, 1.585 mol) to the addition funnel and add dropwise to the anion solution over a 25 min period. Stir the reaction for 45 min in the cooling bath. Remove the cooling bath and stir the reaction 18 hr as it slowly reaches room temperature. Dilute the mixture with 1N aqueous hydrochloric acid (1.5 L) and diethyl ether (1 L). Separate the layers and wash the organic phase with water (2×1 L) then brine (1 L). Extract the combined aqueous washes with ether (1 L). Dry the combined organic phases over anhydrous magnesium sulfate, filter, and concentrate to 390 g of a light tan oil. Purify this material by silica gel chromatography using hexanes:ethyl acetate to obtain 345 g (94.5%) of a clear, yellow oil.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([CH:15]([OH:18])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Si:22](Cl)([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23].N1C=CN=C1>CN(C)C=O.CN(C)C1C=CN=CC=1>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][C:12]([C@@H:15]([O:18][Si:22]([C:25]([CH3:28])([CH3:27])[CH3:26])([CH3:24])[CH3:23])[CH2:16][Br:17])=[CH:11][C:10]=1[NH:19][CH:20]=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=CNc1cc(C(O)CBr)ccc1OCc1ccccc1
Agent: CN(C)c1ccncc1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)O[C@@H](CBr)c1ccc(OCc2ccccc2)c(NC=O)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 104 %

Procedure:
To a solution of N-[2-benzyloxy-5-(2-bromo-1-hydroxyethyl)phenyl]formamide (Organic Process Research and Development 1998, 2, 96-99) (4.12 g, 11.8 mmol) in N,N-dimethylformamide (25 mL) at RT under N2 was added tert-butyldimethylsilyl chloride (3.50 g, 23.2 mmol), imidazole (1.90 g, 27.9 mmol) and 4-(dimethylamino)pyridine (40 mg, 330 □mol). The resulting solution was stirred at RT overnight, the solvent was removed and the product taken up in ethyl acetate (70 mL). The organics were washed with water (100 mL), and the aqueous extracted with ethyl acetate (20 mlmL The combined organics were washed with hydrochloric acid (2M, 50 ml), brine (100 mL) and dried (MgSO4). The crude material was purified by chromatography (5-25% ethyl acetate in pentane) to yield a colourless oil (5.7 g). 1HNMR (CDCl3, 400 MHz) δ: −0.08 to −0.05 (3H, m), 0.09-0.11 (3H, s), 0.89-0.90 (9H, m), 3.38-3.55 (2H, m), 3.78-3.84 (1H, m), 5.06-5.11 (2H, m), 6.90-6.97 (1H, m), 7.03-7.12 (1H, m), 7.24 (m), 7.36-7.43 (5H, m), 7.67-7.78 (m), 7.88 (d), 8.74 (d); LRMS APCI m/z 464/466 [M+H]+
Reaction SMILES: [F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21](Br)=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.C([O-])(=[O:36])C.[K+].B1(B2OC(C)(C)C(C)(C)O2)OC(C)(C)C(C)(C)O1.O>CS(C)=O.C(OCC)(=O)C>[F:1][C:2]([F:33])([F:32])[C:3]1[CH:4]=[C:5]([CH:25]=[C:26]([C:28]([F:31])([F:30])[F:29])[CH:27]=1)[CH2:6][N:7]([C:18]1[N:23]=[CH:22][C:21]([OH:36])=[CH:20][N:19]=1)[C:8](=[O:17])[O:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(Br)cn1
Reactant: CC(=O)[O-]
Agent: CC1(C)OB(B2OC(C)(C)C(C)(C)O2)OC1(C)C
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CS(C)=O
Product: O=C(OCc1ccccc1)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(O)cn1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 95.6 %

Procedure:
Benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-bromo-pyrimidin-2-yl)-carbamate (11.5 g), [1,1′-bis(diphenylphosphino)ferrocene]-dichloropalladium dichloromethane complex (3.51 g), potassium acetate (6.33 g) and bis(pinacolato)diboron (10.9 g) are dissolved in dimethylsulfoxide (75 ml), and the mixture is heated to 80° C. under nitrogen atmosphere and stirred for 30 minutes. The reaction solution is cooled to room temperature and thereto are added water and ethyl acetate, and the insoluble materials are removed by filtration through Celite™, and the mixture is separated and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is dissolved in tetrahydrofuran (100 ml) and thereto is added dropwise a 30% aqueous hydrogen peroxide solution (50 ml) under ice-cooling and the mixture is stirred for 1 hour. Thereto is added a saturated aqueous sodium thiosulfate solution under ice-cooling to consume the excess hydrogen peroxide, followed by an addition of water and ethyl acetate, and the mixture is separated. The organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give benzyl (3,5-bis-trifluoromethyl-benzyl)-(5-hydroxy-pyrimidin-2-yl)-carbamate (9.70 g). MS (m/z): 472 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22].[Cl:23][CH2:24][CH2:25][N:26]=[C:27]=[O:28].C(N(CC)CC)C.C(O)C>O1CCCC1>[Cl:23][CH2:24][CH2:25][NH:26][C:27]([NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]([CH3:12])[C:10](=[O:13])[CH2:9][N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[C:21]=1[Cl:22])=[O:28]
Reactant: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(N)c2Cl
Reactant: O=C=NCCCl
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: C1CCOC1
Product: CN1C(=O)CN=C(c2ccccc2F)c2c1ccc(NC(=O)NCCCl)c2Cl
Temperature: 25 °C

Procedure:
5 g (0.016 M) of 7-amino-6-chloro-5-(o-fluorophenyl) -1,3-dihydro-1-methyl-2H-1,4-benzodiazepin-2-one in 85 ml of absolute tetrahydrofuran are treated with 11.1 ml of chloroethylisocyanate and 1 ml of triethylamine. The mixture is stirred at room temperature for 1 week and heated at reflux for 5 hours. The mixture is treated with 50 ml of ethanol and concentrated. The residue is treated with methylene chloride/water and extracted several times with methylene chloride. The organic phase is separated, dried with sodium sulphate, filtered and concentrated. The residue is purified on a 300 g silica gel column using methylene chloride/ethyl acetate (3:1) as the eluting agent, there being obtained 1-(2-chloroethyl)-3-[6-chloro-5-(o-fluorophenyl)-2,3-dihydro-1-methyl-2-oxo-1H-1,4-benzodiazepin-7-yl]urea which is further processed directly.
Reaction SMILES: [Cl:1]/[C:2](=[C:6](\[Cl:10])/[C:7](O)=[O:8])/[C:3](O)=[O:4].[F:11][C:12]1[CH:18]=[CH:17][C:15]([NH2:16])=[CH:14][CH:13]=1>O>[F:11][C:12]1[CH:18]=[CH:17][C:15]([N:16]2[C:3](=[O:4])[C:2]([Cl:1])=[C:6]([Cl:10])[C:7]2=[O:8])=[CH:14][CH:13]=1
Reactant: O=C(O)/C(Cl)=C(/Cl)C(=O)O
Reactant: Nc1ccc(F)cc1
Solvent: O
Product: O=C1C(Cl)=C(Cl)C(=O)N1c1ccc(F)cc1
Yield: 97.6 %

Procedure:
18.5g (0.1 mol) of 2,3-dichloromaleic acid was dissolved in 120 ml of water. To the resulting solution 8.9g (0.08mol) of 4-fluoroaniline was added dropwise over a period of 5 min. at reflux temperatures under agitation. The mixture was then allowed to react for 2 hours at reflux temperatures. Upon cooling the reaction mixture, precipitated crystal was separated by filtration to obtain 20.3g of N-(4-fluorophenyl)-2,3-dichloromaleimide melting at 239°-240° C (not corrected) at a yield of 98.1%. An analysis by gas chromatography showed the product had a purity of 95.5%.
Reaction SMILES: F[C:2]1[N:3]=[N:4][C:5]([F:8])=[CH:6][CH:7]=1.[F:9][C:10]([F:24])([F:23])[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.C(=O)([O-])[O-].[Na+].[Na+].CN(C)C=O>O>[F:8][C:5]1[N:4]=[N:3][C:2]([N:20]2[CH2:19][CH2:18][N:17]([C:13]3[CH:14]=[CH:15][CH:16]=[C:11]([C:10]([F:23])([F:24])[F:9])[CH:12]=3)[CH2:22][CH2:21]2)=[CH:7][CH:6]=1
Reactant: Fc1ccc(F)nn1
Reactant: FC(F)(F)c1cccc(N2CCNCC2)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: Fc1ccc(N2CCN(c3cccc(C(F)(F)F)c3)CC2)nn1
Temperature: 60 °C
Reaction time: 8 h
Yield: 46 %

Procedure:
A mixture of 2.7 parts of 3,6-difluoropyridazine, 4.6 parts of 1-[3-(trifluoromethyl)phenyl]piperazine, 3.2 parts of sodium carbonate and 90 parts of N,N-dimethylformamide was stirred overnight at 60° C. The reaction mixture was poured into water. The product was filtered off, washed with water and crystallized from 2-propanol, yielding 3 parts (46%) of 3-fluoro-6-[4-[3-(trifluoromethyl)phenyl]-1-piperazinyl]pyridazine; mp. 131.5° C. (compound 24).
Reaction SMILES: C(O)CC(O)C.C(C1C=CC(S(O)(=O)=O)=CC=1)C.[CH2:19]([O:21][C:22]([O:29][CH2:30][CH3:31])([O:26][CH2:27][CH3:28])[O:23][CH2:24][CH3:25])[CH3:20]>C1(C)C=CC=CC=1>[CH3:31][CH:30]1[CH2:28][CH2:27][O:26][C:22]2([O:23][CH2:24][CH2:25][CH:19]([CH3:20])[O:21]2)[O:29]1
Reactant: CCOC(OCC)(OCC)OCC
Agent: CC(O)CCO
Agent: CCc1ccc(S(=O)(=O)O)cc1
Solvent: Cc1ccccc1
Product: CC1CCOC2(OCCC(C)O2)O1
Temperature: 25 °C

Procedure:
See also U.S. Pat. No. 5,808,108. In a 500 mL RB flask equipped with a reflux condenser, a stirrer and a Dean Stark trap, 1,3-butanediol (20.0 g, 0.22 mol), and toluene (350 mL) were added. After placing under nitrogen the resulting solution was heated to reflux for two h to remove water from the mixture. The solution was cooled to RT and 4-ethylbenzenesulfonic acid (0.35 g) and tetraethylorthocarbonate (21.3 g, 0.11 mol) were added. The solution was heated to reflux and the azeotropic mixture collected; The reaction was refluxed until the temperature of the distillated reached 110° C. (boiling point of pure toluene). The collected azeotropic mixture was measured and weighed and then poured into brine and the organic phase was separated, which indicated ˜22 mL of ethanol was collected. TLC analysis indicated that the reaction was complete by the disappearance of the diol and the appearance of the product at Rf=0.59 (silica gel, EtOAc/hexanes (3/2). The reaction was cooled to RT and triethylamine (2.5 mL) added. The toluene was removed at reduced pressure (rotovap) and the resulting liquid dried under vacuum. Vacuum distillation afforded four fractions of the desired product as a water white clear liquid boiling, bp: 70–75° C. at 40 Pa. Fractions 1 and 2 were slightly impure and were combined to give 5.715 g and fractions 3 and 4 were very pure and were combined to give 10.046 g. Overall yield: 15.761 g (75.66%). 13C NMR indicated the product to be a mixture of isomers.
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1.[I:20]I>O1CCCC1>[F:1][C:2]1[C:7]([F:8])=[C:6]([I:20])[CH:5]=[CH:4][C:3]=1[C:9]1[CH:14]=[CH:13][C:12]([CH2:15][CH2:16][CH2:17][CH2:18][CH3:19])=[CH:11][CH:10]=1
Reactant: II
Reactant: CCCCCc1ccc(-c2cccc(F)c2F)cc1
Solvent: C1CCOC1
Product: CCCCCc1ccc(-c2ccc(I)c(F)c2F)cc1
Temperature: -78 °C
Reaction time: 2 h

Procedure:
2′,3′-Difluoro-4-pentylbiphenyl (612 g, 0.243 mol), and dry tetrahydrofurane (400 ml) were placed in 1 L flask equipped with mechanical stirrer, nitrogen inlet and outlet, pressure-equilibrated dropping funnel and thermometer. The reaction flask was flushed with nitrogen and minor flow was held during whole reaction time. The mixture was cooled down to −78° C. on the dry ice/acetone bath and then 2.5 mol/dm3 of n-butyllithium solution in hexane (100 ml 025 mol) was added dropwise, keeping the reaction temperature below −70° C. After addition of all n-butyllithium the mixture was stirred for additional 2 hours at −78° C. Next iodine solution in tetrahydrofurane (63.5 g, 0.25 mol) was added dropwise maintaining the temperature below −70° C. After addition of the iodine solution the cooling bath was removed and the mixture was stirred to reach the room temperature. Organic solvents were evaporated and the thick oily residue was diluted with hexane and treated with water solution of sodium sulfite to remove the remaining iodine. Phases were separated and hexane was evaporated. The residue was distilled under reduced pressure 1 mmHg collecting the fraction boiling at 174-175° C. The colourles liquid product 71 g was obtained with 78% of theor. yield.
Reaction SMILES: [O:1]([C:8]1[S:12][C:11]([CH:13]=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[O-:15]Cl=O.[Na+].[OH-].[Na+]>C1COCC1.CC(O)(C)C.O>[O:1]([C:8]1[S:12][C:11]([C:13]([OH:15])=[O:14])=[CH:10][CH:9]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1ccc(Oc2ccccc2)s1
Agent: [Na+]
Agent: [OH-]
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(Oc2ccccc2)s1
Temperature: 25 °C
Reaction time: 24 h
Yield: 54.5 %

Procedure:
5-Phenoxy-thiophene-2-carboxaldehyde (325 mg, 1.6 mmol) is dissolved in a mixture of THF (10 mL), t-BuOH (5 mL) and water (5 mL). NaH2PO4 (650 mg, 4.8 mmol) is added followed by NaClO2 (432 mg, 4.8 mmol). The resulting mixture is stirred for 24 hours at room temperature. Aqueous NaOH (2M, 5 mL) is added, and the organic solvents are removed in vacuo. The resulting aqueous suspension is poured into water (50 mL) and washed with ether (3×50 mL). The aqueous layer is acidified to pH<2 with 25% H2SO4 then washed with CH2Cl2 (3×50 mL). The combined organic washes are dried over Na2SO4, filtered and concentrated in vacuo. The crude product is dissolved in hot aqueous acetone and filtered. The solvents are gradually removed until a precipitate forms. The solid is collected by filtration and dried in vacuo to yield the desired product (192 mg, 55%). MS for C11H7O3S (ESI) (M−H)+ m/z 219.