Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]([OH:10])=O)#[N:2].C(Cl)Cl.C(Cl)(=O)C(Cl)=O.[F:20][C:21]([F:33])([F:32])[C:22]1[CH:23]=[CH:24][C:25]([C:28](=[N:30]O)[NH2:29])=[N:26][CH:27]=1>CN(C)C=O.N1C=CC=CC=1>[C:1]([C:3]1[CH:7]=[CH:6][S:5][C:4]=1[C:8]1[O:10][N:30]=[C:28]([C:25]2[CH:24]=[CH:23][C:22]([C:21]([F:33])([F:20])[F:32])=[CH:27][N:26]=2)[N:29]=1)#[N:2]
Reactant: N#Cc1ccsc1C(=O)O
Reactant: NC(=NO)c1ccc(C(F)(F)F)cn1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN(C)C=O
Solvent: c1ccncc1
Solvent: ClCCl
Product: N#Cc1ccsc1-c1nc(-c2ccc(C(F)(F)F)cn2)no1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 43.2 %

Procedure:
To a stirred solution of 3-cyano-thiophene-2-carboxylic acid (42.5 mg, 0.278 mmol) and methylene chloride (1.5 mL) in an ice bath under argon, was added oxalyl chloride (205 μL, 0.410 mmol) over 2 min and then 2 drops of dimethylformamide. The solution was stirred for 5 min, the ice bath was removed, and the solution was stirred for 1 h. The solution was concentrated to dryness to yield a white solid. To the solid was added 5-trifluoromethyl-pyridine-2-amidoxime (56.4 mg, 0.275 mmol) and pyridine (1.6 mL), and the resultant solution was stirred for 10 min at ambient temperature. The solution was then refluxed for 21 h. The solution was cooled to room temperature and the product was precipitated by addition of 5 mL of deionized water. The precipitate was filtered, washed with deionized water, and dried under vacuum to yield 38.3 mg (43%) of the title compound as a pink solid. 1H NMR (CDCl3): 9.09 (m, 1H), 8.40 (d, J=8.25 Hz, 1H), 8.16 (dd, J=8.24, 2.20 Hz, 1H), 7.80 (d, J=5.22 Hz, 1H), 7.52 (d, J=5.22 Hz, 1H).
Reaction SMILES: [C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[N:9]=[CH:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31].C(=O)([O-])[O-:36].[K+].[K+]>CC(=O)CC>[C:1]1([N:7]2[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)[N:9]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][C:30]([O:32][CH2:33][CH3:34])=[O:31])[C:8]2=[O:36])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: c1ccc(-c2ncn(-c3ccccc3)c2-c2ccccc2)cc1
Reactant: CCOC(=O)CCCCCBr
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Product: CCOC(=O)CCCCCn1c(-c2ccccc2)c(-c2ccccc2)n(-c2ccccc2)c1=O
Yield: 58.6 %

Procedure:
A mixture of 1,4,5 triphenylimidazole (6.24 g), ethyl 6-bromohexanoate (13.38 g), potassium carbonate (13.2 g) and 2-butanone was stirred at reflux for 6 hours. The mixture was filtered, and the filtrate was evaporated. The residue was chromatographed on silica gel eluted with ethanol-hexane to give the title compound (5.61 g) m.p. 104°-106° C. Found: C, 76.35; H, 6.58; N, 6.07%; (C29H30N2O2O3) Requires: C, 76.63; H, 6.65; N, 6.16%
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[N:8]=[CH:7][C:6]([C@H:9]([NH:11][C:12](=[O:18])[O:13][C:14]([CH3:17])(C)C)[CH3:10])=[CH:5][CH:4]=1.[C:21](C1C=C(C)C=C(C(C)(C)C)C=1O)(C)(C)[CH3:22].ClC1C=CC=C(C(OO)=[O:45])C=1.S([O-])([O-])(=O)=S.[Na+].[Na+].C(=O)(O)[O-].[Na+]>C(Cl)(Cl)Cl>[CH2:14]([O:13][C:12](=[O:18])[NH:11][C@@H:9]([C:6]1[CH:7]=[N+:8]([O-:45])[C:3]([C:2]([F:1])([F:19])[F:20])=[CH:4][CH:5]=1)[CH3:10])[CH2:17][CH2:21][CH3:22]
Reactant: Cc1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Reactant: C[C@@H](NC(=O)OC(C)(C)C)c1ccc(C(F)(F)F)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CCCCOC(=O)N[C@H](C)c1ccc(C(F)(F)F)[n+]([O-])c1
Temperature: 50 °C
Reaction time: 48 h
Yield: 423.2 %

Procedure:
To a solution of tert-butyl {(1R)-1-[6-(trifluoromethyl)-3-pyridinyl]ethyl}carbamate (0.626 g, 2.157 mmol) in chloroform (10.0 mL) were added 2,6-di-tert-butyl-4-methylphenol (24 mg, 0.108 mmol) and 3-chloroperbenzoic acid (0.665 g, 2.70 mmol). The reaction mixture was stirred at 50° C. for 48 h. The reaction mixture was cooled to ambient temperature. Saturated aqueous sodium thiosulfate and saturated aqueous sodium bicarbonate were added. The mixture was extracted with dichloromethane (3×). The combined organics extracts were washed with brine, dried over magnesium sulfate, filtered and concentrated. Purification by silica gel chromatography (75% hexanes/ethyl acetate→100% ethyl acetate) gave the title compound (140 mg). MS 307.0 (M+1).
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1.ClC1C=CC=C(C(OO)=[O:28])C=1>C(Cl)(Cl)Cl>[CH3:1][S:2]([C:3]1[N:8]=[CH:7][CH:6]=[C:5]([C:9]2[S:10][C:11]3[CH:19]=[CH:18][CH:17]=[CH:16][C:12]=3[C:13](=[O:15])[N:14]=2)[N:4]=1)=[O:28]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CSc1nccc(-c2nc(=O)c3ccccc3s2)n1
Solvent: ClC(Cl)Cl
Product: CS(=O)c1nccc(-c2nc(=O)c3ccccc3s2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 39.6 %

Procedure:
2-[2-(Methylthio)-6-pyrimidinyl]-4H-1,3-benzothiazine-4-one (0.30 g, 1.50 mmol) was dissolved in chloroform (100 ml), and a solution of 3-chloroperbenzoic acid (ca. 77%, 0.23 g, 1.50 mmol) in chloroform (10 ml) was added dropwise thereto. The mixture was stirred at room temperature for 1 hr. The solvent was evaporated, and the residue was recrystallized from ethanol to give the titled compound (0.18 g, 55%) as pale yellow crystals.
Reaction SMILES: [F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:9][C:8]([C:10]#[N:11])=[CH:7][C:6]=2[CH:12]=1.Cl.[NH2:15][OH:16].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[F:1][C:2]1[C:3]([F:13])=[CH:4][C:5]2[O:9][C:8]([C:10](=[N:15][OH:16])[NH2:11])=[CH:7][C:6]=2[CH:12]=1
Reactant: N#Cc1cc2cc(F)c(F)cc2o1
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: NC(=NO)c1cc2cc(F)c(F)cc2o1
Yield: 61.9 %

Procedure:
A mixture of 1.2 g (6.7 mmol) of 5,6-difluorobenzofuran-2-carbonitrile, 0.93 g (13.4 mmol) of hydroxylamine hydrochloride, 2.78 g (20.1 mmol) of potassium carbonate and 50 ml of anhydrous ethanol was heated under reflux over 16 hours while stirring. Subsequently, the solid was filtered off and the filtrate was concentrated in a vacuum. The crude product obtained was purified by column chromatography on silica gel (ethyl acetate/hexane 3:2). There was obtained 0.88 g (61%) of 5,6-difluorobenzofuran-2-carboxamidoxime as a light yellow solid with m.p. 184°.
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5]([C:7]1[CH:26]=[CH:25][C:10]([CH2:11][CH:12]([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:9][CH:8]=1)=[O:6].Br[CH2:28][CH2:29][C:30]1[CH:42]=[CH:41][C:33]([C:34]([O:36][C:37]([CH3:40])([CH3:39])[CH3:38])=[O:35])=[CH:32][CH:31]=1>CN(C=O)C>[C:37]([O:36][C:34]([C:33]1[CH:41]=[CH:42][C:30]([CH2:29][CH2:28][C:12]([CH2:11][C:10]2[CH:9]=[CH:8][C:7]([C:5]([O:4][CH3:3])=[O:6])=[CH:26][CH:25]=2)([C:19]([O:21][CH2:22][CH:23]=[CH2:24])=[O:20])[C:13]([O:15][CH2:16][CH:17]=[CH2:18])=[O:14])=[CH:31][CH:32]=1)=[O:35])([CH3:40])([CH3:39])[CH3:38]
Reactant: CC(C)(C)OC(=O)c1ccc(CCBr)cc1
Reactant: C=CCOC(=O)C(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCOC(=O)C(CCc1ccc(C(=O)OC(C)(C)C)cc1)(Cc1ccc(C(=O)OC)cc1)C(=O)OCC=C
Temperature: 0 °C
Reaction time: 1 h
Yield: 13.7 %

Procedure:
0.6 g (14.92 mmol) of sodium hydride is added in portions to a solution of 4.13 g (12.43 mmol) of diallyl 2-(4-methoxycarbonylbenzyl)malonate in 40 ml of DMF at 0° C. The reaction solution is then allowed to reach room temperature and is stirred for 1 hour. The reaction solution is then cooled again to 0° C., 3.9 g (13.68 mmol) of tert-butyl 4-(2-bromoethyl)benzoate in 10 ml of DMF are added, and the mixture is stirred at this temperature for 30 min. The mixture is then stirred at room temperature overnight. The reaction mixture is added to ice-water and extracted three times with ethyl acetate, and the combined organic phases are washed with saturated brine and dried over sodium sulphate. After filtration, the solvent is evaporated to dryness in vacuo, and the resulting crude product is purified by preparative HPLC. 933 mg (1.7 mmol, 14% yield) of a colourless solid are obtained.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2/[CH:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]/2)[CH:6]=1.C[Si](C)(C)[Cl:32].O>CC(C)=O>[ClH:32].[CH3:2][O:3][C:4](=[O:29])[C:5]1[CH:10]=[CH:9][CH:8]=[C:7](/[CH:11]=[C:12]2\[CH:13]=[C:14]([C:22]3[CH:27]=[CH:26][CH:25]=[C:24]([OH:28])[CH:23]=3)[CH:15]([CH2:18][N:19]([CH3:21])[CH3:20])[CH2:16][CH2:17]\2)[CH:6]=1
Reactant: COC(=O)c1cccc(/C=C2/C=C(c3cccc(O)c3)C(CN(C)C)CC2)c1
Reactant: C[Si](C)(C)Cl
Agent: Cl
Solvent: O
Solvent: CC(C)=O
Product: COC(=O)c1cccc(/C=C2\C=C(c3cccc(O)c3)C(CN(C)C)CC2)c1
Yield: 27.6 %

Procedure:
8.1 g potassium tert-butylate and 35.4 g 3-(benzoic acid methyl ester)-methyltriphenylphosphonium chloride were suspended in 800 ml analytical grade toluene under a nitrogen atmosphere at room temperature and the suspension was then stirred at 70° C. for one hour. 7 g 3-(3-(tert-butyl-diphenyl-silanyloxy)-cyclohex-2-enone in 100 ml analytical grade toluene were added at this temperature and the mixture was stirred at 70° C. for 3 days. The mixture was quenched with 500 ml water. The phases were separated and the aqueous phase was washed 3 times with 200 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from solvent in vacuo. The residue obtained in this way was taken up in a mixture of 150 ml ethyl acetate and 150 ml diiso-ether. The solid which had precipitated out was filtered off and washed with diiso-ether. The combined organic phases were freed from the solvent in vacuo. The residue (16.7 g) was dissolved in 70 ml tetrahydrofuran, and 16.7 ml tetrabutylammonium fluoride were added. After a reaction time of 10 minutes the reaction solution was quenched with 50 ml water and extracted three times with 50 ml ethyl acetate each time. The combined organic phases were dried over magnesium sulfate and then freed from the solvent in vacuo. The residue was purified by column chromatography on silica gel with ethyl acetate/methanol=9/1. 2.5 g E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester base were obtained as the first product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 2 g (36.8% of theory) E-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester hydrochloride (37) were obtained in this way. 1.8 g (27.6% of theory) Z-3 [4-Dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester were obtained as the second product fraction. To liberate the hydrochloride, the base was dissolved in 50 ml acetone, and an equimolar amount of trimethylchlorosilane and water was added. 1.5 g (27.6% of theory) Z-3-[4-dimethylaminomethyl-3-(3-hydroxy-phenyl)-cyclohex-2-enylidenemethyl]-benzoic acid methyl ester hydrochloride (38) were obtained in this way.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH:20]([O:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[OH-:35].[Na+].[OH2:37]>CO>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[CH:10]([O:27][CH:28]1[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]1)[C:11]1[CH:12]=[C:13]([N:17]2[CH2:22][CH2:21][CH:20]([OH:23])[CH2:19][CH2:18]2)[CH:14]=[CH:15][CH:16]=1.[C:25]([O-:37])(=[O:35])[C:24]([O-:23])=[O:26]
Reactant: [OH-]
Reactant: CC(=O)OC1CCN(c2cccc(C(OC3CCN(C)CC3)c3nc4ccccc4s3)c2)CC1
Reactant: O
Agent: [Na+]
Solvent: CO
Product: CN1CCC(OC(c2cccc(N3CCC(O)CC3)c2)c2nc3ccccc3s2)CC1
Product: O=C([O-])C(=O)[O-]

Procedure:
A solution of acetic acid 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-yl ester (example 413, 100 mg) and aqueous 1N sodium hydroxide in methanol (1 mL) is stirred at room temperature for 30 min. The mixture is diluted water and extracted with dichloromethane. The pooled organic extracts are dried over magnesium sulfate and concentrated under reduced pressure. The residue is purified by chromatography (gradient dichloromethane/methanol/ammonia from 95/5/0.5 to 90/10/0.5). The base is converted into its oxalate salt in acetone to give 1-{3-[benzothiazol-2-yl(1-methylpiperidin-4-yloxy)methyl]phenyl}piperidin-4-ol, oxalate melting at 110° C.
Reaction SMILES: [CH3:1][S:2][CH2:3][CH2:4][OH:5].[C:6](Cl)(Cl)=[O:7].C1(C)C=CC=CC=1.[CH3:17][NH:18][C:19]1[S:20][C:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:22][N:23]=1>CN(C)C1C=CN=CC=1.ClCCCl.C(=O)(O)[O-].[Na+]>[CH3:17][N:18]([C:19]1[S:20][C:21]([C:24]2[CH:25]=[N:26][CH:27]=[CH:28][CH:29]=2)=[N:22][N:23]=1)[C:6](=[O:7])[O:5][CH2:4][CH2:3][S:2][CH3:1]
Reactant: CSCCO
Reactant: CNc1nnc(-c2cccnc2)s1
Reactant: O=C(Cl)Cl
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: Cc1ccccc1
Product: CSCCOC(=O)N(C)c1nnc(-c2cccnc2)s1
Temperature: 23 °C
Reaction time: 1.5 h
Yield: 79 %

Procedure:
2-Methylthioethanol (100 μL, 1.2 mmol, 1.5 equiv) was added to a stirred 20% solution of phosgene in toluene (1.2 mL, 2.3 mmol, 3.0 equiv) at 0° C. The resulting colorless solution was allowed to warm to 23° C. and stirred for 1.5 h. The reaction mixture was concentrated by rotary evaporation. The residue was added to a stirred suspension of N-methyl-5-(pyridin-3-yl)-1,3,4-thiadiazol-2-amine (150 mg, 0.78 mmol, 1.0 equiv) and 4-dimethylaminopyridine (190 mg, 1.6 mmol, 2.0 equiv) in 1,2-dichloroethane (7.8 mL) at 23° C. The resulting yellow solution was heated to 75° C. for 18 h. The cooled reaction mixture was diluted with a saturated solution of sodium bicarbonate (50 mL) and extracted with ethyl acetate (3×40 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation. The residue was purified by silica gel column chromatography (ethyl acetate) to afford the title compound as a white powder (190 mg, 79%): mp 126-128° C.; IR (KBr thin film) 3044 (w), 2958 (w), 2910 (w), 1700 (s), 1572 (w) cm−1; 1H NMR (300 MHz, CDCl3) δ 9.12 (br s, 1H), 8.70 (d, J=5 Hz, 1H), 8.27 (dt, J=8, 2 Hz, 1H), 7.42 (dd, J=8, 5 Hz, 1H), 4.51 (t, J=7 Hz, 2H), 3.75 (s, 3H), 2.87 (t, J=7 Hz, 2H), 2.21 (s, 3H); ESIMS m/z 311 ([M+H]+). Compounds 14, 15, and 16 were prepared as described in Example 12.
Reaction SMILES: [Cl-].[In+3].[Cl-].[Cl-].FC(F)(F)C(O)=O.[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])O)=[CH:15][CH:14]=1.[F:26][C:27]1[CH:28]=[C:29]2[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:39])=[O:38])[CH:35]=1)[NH:32][CH:31]=[CH:30]2>ClCCCl>[Cl:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH:21]2[CH2:23][C:22]2([F:25])[F:24])[C:30]2[C:29]3[C:33](=[C:34]([CH2:36][S:37]([CH3:40])(=[O:38])=[O:39])[CH:35]=[C:27]([F:26])[CH:28]=3)[NH:32][CH:31]=2)=[CH:15][CH:14]=1
Reactant: CS(=O)(=O)Cc1cc(F)cc2cc[nH]c12
Reactant: OC(c1ccc(Cl)cc1)C1CC1(F)F
Agent: [Cl-]
Agent: [In+3]
Solvent: ClCCCl
Solvent: O=C(O)C(F)(F)F
Product: CS(=O)(=O)Cc1cc(F)cc2c(C(c3ccc(Cl)cc3)C3CC3(F)F)c[nH]c12

Procedure:
97.1 mg (0.44 mmol) of indium(III) chloride and 0.05 ml (0.07 mmol) of trifluoroacetic acid were added to 80.0 mg (0.37 mmol) of the compound from Example 159A and 100 mg (0.44 mmol) of the compound from Example 87A in 4 ml of 1,2-dichloroethane, and the mixture was heated under reflux overnight. It was concentrated and the residue was taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over sodium sulfate, filtered and concentrated. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 6.0 mg (4% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: CC1(C)[O:6][C:5](=[CH:7][C:8]([N:10]([CH2:12][CH2:13][CH2:14][C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=2)[CH3:11])=[O:9])[C:4](=[O:22])O1.C=O.[CH3:26][NH2:27].[CH3:28]O>>[F:21][C:18]1[CH:17]=[CH:16][C:15]([CH2:14][CH2:13][CH2:12][N:10]([CH3:11])[C:8]([C:7]2[CH2:26][N:27]([CH3:28])[C:4](=[O:22])[C:5]=2[OH:6])=[O:9])=[CH:20][CH:19]=1
Reactant: CO
Reactant: CN(CCCc1ccc(F)cc1)C(=O)C=C1OC(C)(C)OC1=O
Reactant: CN
Agent: C=O
Product: CN1CC(C(=O)N(C)CCCc2ccc(F)cc2)=C(O)C1=O
Yield: 56 %

Procedure:
Reaction of 2-(2,2-dimethyl-5-oxo-[1,3]-dioxolan-4-ylidene)-N-[3-(4-fluorophenyl)-propyl]-N-methyl-acetamide (0.20 g, 0.62 mmol) with the paraformaldehyde-methylamine adduct in methanol using a procedure similar to the one described in the preparation of compound 44 (method 44B) gave 0.11 g (56% yield) of the title compound as white crystals; mp 129° C. (dec) (ethyl acetate-hexane). 1HNMR 400 MHz (CDCl3) δ (ppm); 1.91 (2H, m, CH2), 2.63 (2H, t, J=7.6 Hz, CH2), 3.04 (3H, s, NCH3), 3.05 (3H, s, NCH3), 3.40 (2H, broad t, J=7.5 Hz, NCH2), 3.90 (2H, broad s, NCH2), 6.99 (2H, m, aromatics), 7.14 (2H, m, aromatics). Anal. Calcd for C16H19FN2O3: C, 62.73; H, 6.25; N, 9.14. Found: C, 62.75; H, 6.23; N, 9.11.
Reaction SMILES: Cl[CH2:2][C:3]1[C:11]([O:12][CH3:13])=[CH:10][CH:9]=[C:8]2[C:4]=1[CH2:5][CH2:6][C:7]2=[O:14].CCN(CC)CC.CC(O[Na])=O>CO.[Pd]>[CH3:13][O:12][C:11]1[C:3]([CH3:2])=[C:4]2[C:8](=[CH:9][CH:10]=1)[C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: COc1ccc2c(c1CCl)CCC2=O
Agent: [Pd]
Agent: CC(=O)O[Na]
Solvent: CCN(CC)CC
Solvent: CO
Product: COc1ccc2c(c1C)CCC2=O
Temperature: 25 °C
Reaction time: 6 h

Procedure:
A flask was charged with 3.35 g 4-chloromethyl-5-methoxy-indan-1-one, 0.5 g Pd/C, 2.4 g Et3N and 2 g CH3COONa in 50 mL MeOH, and then evacuated and filled with H2 (1.2 bar) three cycles. The mixture was shaken at r.t. for 6 h. The mixture was concentrated to give the crude product without further purification.
Reaction SMILES: [CH:1]1([NH:4][C:5]([NH:7][C:8]2[CH:13]=[CH:12][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][NH:21][CH2:20][C:18]=4[N:19]=3)=[CH:10][CH:9]=2)=[O:6])[CH2:3][CH2:2]1.[CH3:31][O:32][C:33](Cl)=[O:34]>>[CH:1]1([NH:4][C:5](=[O:6])[NH:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[N:15]=[C:16]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][C@@H:25]4[CH3:30])[C:17]4[CH2:23][CH2:22][N:21]([C:33]([O:32][CH3:31])=[O:34])[CH2:20][C:18]=4[N:19]=3)=[CH:12][CH:13]=2)[CH2:2][CH2:3]1
Reactant: COC(=O)Cl
Reactant: C[C@H]1COCCN1c1nc(-c2ccc(NC(=O)NC3CC3)cc2)nc2c1CCNC2
Product: COC(=O)N1CCc2c(nc(-c3ccc(NC(=O)NC4CC4)cc3)nc2N2CCOC[C@@H]2C)C1

Procedure:
Method as example 34 using (S)-1-cyclopropyl-3-(4-(4-(3-methylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea (example 15) and methylchloroformate as starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[CH:13][N:14]=1)[N:11]([C@H:15]([C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[CH:8]2)=[O:4].[Br:31]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:1][O:2][C:3]([C:5]1[C:6]([OH:30])=[C:7]2[C:12](=[C:13]([Br:31])[N:14]=1)[N:11]([C@H:15]([C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1)[CH3:16])[C:10](=[O:23])[C:9]([C:24]1[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1)=[CH:8]2)=[O:4]
Reactant: COC(=O)c1ncc2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: COC(=O)c1nc(Br)c2c(cc(-c3ccccc3)c(=O)n2[C@@H](C)c2ccccc2)c1O
Yield: 65.1 %

Procedure:
A mixture of (5)-5-hydroxy-2-oxo-3-phenyl-1-(1-phenyl-ethyl)-1,2-dihydro-[1,7]naphthyridine-6-carboxylic acid methyl ester (100 mg, 0.25 mmol) and N-bromosuccinimide (49 mg, 0.275 mmol) in CH2Cl2 (1 mL) was refluxed for 3 h. Solvent was evaporated in vacuo, and the residue was purified by silica gel chromatography (5-20% EtOAc/hexanes+1% AcOH) to give 78 mg of the title compound. MS: (−) m/z 477.19, 479.21 (M−1, 79/81Br).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]2[CH:20]=[CH:19][C:16]([CH:17]=[O:18])=[CH:15][C:14]=2[C:21]2[S:22][CH:23]=[CH:24][CH:25]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:26][C:27]([C:30](O)([CH3:32])[CH3:31])([CH3:29])[CH3:28].C1(C)C=CC(S(O)(=O)=O)=CC=1.CCOC(C)=O>C1C=CC=CC=1.CCCCCC>[CH3:31][C:30]1([CH3:32])[C:27]([CH3:29])([CH3:28])[O:26][CH:17]([C:16]2[CH:19]=[CH:20][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)=[C:14]([C:21]3[S:22][CH:23]=[CH:24][CH:25]=3)[CH:15]=2)[O:18]1
Reactant: CC(C)(O)C(C)(C)O
Reactant: O=Cc1ccc(OCCCCCc2ccccc2)c(-c2cccs2)c1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC1(C)OC(c2ccc(OCCCCCc3ccccc3)c(-c3cccs3)c2)OC1(C)C
Temperature: 25 °C
Yield: 808.4 %

Procedure:
In a 500 mL 3-necked flask equipped with a stir-bar and condenser was placed 4-((5-phenylpentyl)oxy)-3-(thiophen-2-yl)benzaldehyde (Intermediate 7) (4.9 g, 1.4 mmol), pinacol (6.6 g, 5.6 mol) and p-toluenesulfonic acid (0.8 g, 4.2 mmol) in benzene (125 mL). The resulting mixture was refluxed for 1 h. TLC analysis (EtOAc:hexane; 1:1) showed the reaction was complete. The reaction was cooled to room temperature, washed with saturated NaHCO3 (2×75 mL), brine (1×75 mL), filtered through 1 PS filter paper and concentrated under reduced pressure to give a brown oil. The oil was flash chromatographed over silica gel (100 g) with anhydrous sodium sulfate (20 g) on top packed with hexane. The column was eluted with 12×50 mL of 15% EtOAc in hexane. The product was eluted to give 5.1 g (81%) 4,4,5,5-tetramethyl-2-(4-((5-phenylpentyl)oxy)-3-(thiophen-2-yl)phenyl)-1,3-dioxolane (Intermediate 8) as a yellow oil. HPLC analysis showed a purity of ˜97%. NMR (CDCl3) δ 7.8 (s, 1H), 7.55 (d, 1H), 7.1-7.4 (m, 8H), 6.95 (d, 1H), 6.0 (s, 1H), 4.1 (t, 2H), 2.7 (t, 2H), 1.95 (m, 2H), 1.7 (m, 2H), 1.6 (m, 2H), 1.35 (d, 12H).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][OH:13])=[CH:6][CH:5]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[CH3:1][O:2][C:3](=[O:14])[C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][O:13][S:23]([CH3:22])(=[O:25])=[O:24])=[CH:6][CH:5]=1
Reactant: CS(=O)(=O)Cl
Reactant: COC(=O)c1ccc(CCCO)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(CCCOS(C)(=O)=O)cc1
Temperature: -15 °C
Reaction time: 4 h

Procedure:
4-(3-Hydroxy-propyl)-benzoic acid methyl ester (1.27 g, 6.5 mmol) and triethylamine (1 ml, 7.1 mmol) are dissolved in dichloromethane (30 ml), cooled to −15° C., methanesulfonylchloride (510 μl, 6.5 mmol) is added and stirred at room temperature for 4 h. The reaction mixture is diluted with dichloromethane, washed with potassiumhydrogensulfoate solution and potassiumcarbonate solution, the organic phase is dried over Na2SO4 and concentrated in vacuo. LC (method F): tR=1.88 min; Mass spectrum (ESP): m/z=295 [M+Na]+.
Reaction SMILES: [FH:1].N[C:3]1[C:4]([Cl:10])=[N:5][CH:6]=[C:7]([Cl:9])[CH:8]=1.N([O-])=O.[Na+]>CC(N(C)C)=O>[Cl:10][C:4]1[C:3]([F:1])=[CH:8][C:7]([Cl:9])=[CH:6][N:5]=1
Reactant: F
Reactant: Nc1cc(Cl)cnc1Cl
Agent: O=N[O-]
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: Fc1cc(Cl)cnc1Cl
Yield: 87.7 %

Procedure:
A 500 ml polytetrafluoroethylene reactor equipped with stirrer, thermometer and reflux condenser is charged with 120 g of hydrogen fluoride. A solution of 40.7 g (0.25 mol) of 3-amino-2,5-dichloropyridine in 100 ml of dimethylacetamide is added dropwise at a temperature in the range from 0° to +10° C. Then 20.7 g (0.3 mol) of sodium nitrite are introduced into this solution at 55° C. The resultant nitrogen is removed from the reactor through the reflux condenser. Gas evolution ceases after 21/2 hours at 55° C. 150 ml of methylene chloride are added to the reaction mixture which is then poured into ice water. The two-phase mixture is neutralised with concentrated ammonia solution. The organic phase is separated and the aqueous phase is extracted several times with methylene chloride. The combined organic phases are dried over sodium sulfate and concentrated by evaporation. The crude product is purified by distillation, affording 36.4 g (87.8% of theory) of 2,5-dichloro-3 -fluoropyridine.