Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13].[CH2:15]([SH:17])[CH3:16].[OH-].[K+]>C(O)C.C(OCC)(=O)C>[CH2:15]([S:17][CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][C:12]([OH:14])=[O:13])[CH3:16]
Reactant: O=C(O)CCCCCCCCCCBr
Reactant: CCS
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCSCCCCCCCCCCC(=O)O
Yield: 8.2 %

Procedure:
11-Bromoundecanoic acid (1 g, 3.77 mmol, Aldrich) was added to a solution of ethanethiol (0.279 mL, 3.77 mmol, Aldrich) and potassium hydroxide (0.486 g, 8.66 mmol) in absolute ethanol (40 mL) and refluxed for 5 hr under a nitrogen atmosphere. After cooling and acidification with HCl, solvent was removed under reduced pressure to give a white solid. The solid was dissolved in ethyl acetate and extracted with water. The organic phase was dried over sodium sulfate, filtered and the solvent removed under reduced pressure. The product was purified by silica column chromatography using increasing concentrations of ethyl acetate in hexane for elution. The product eluted at 25% ethyl acetate/hexane. Solvent was removed under reduced pressure to yield 11-(ethylthio)-undecanoic acid (76 mg, 8%), mp 58°-61° C.; 1H NMR (300 MHz, CDCl3) δ 1.24 (t, 3H, J=7.4, CH3), 1.20-1.40 (bm, 12H, methylene envelope), 1.48-1.67 (bm, 4H, S--CH2 --CH2COO--CH2 --CH2), 2.33 (t, 2H, J=7.5, CH2 --COOH), 2.49 (t, 2H, J=7.4, S--CH2 --CH2), 2.51 (q, 2H, J=7.4, S--CH2 --CH3), 10.5 (br, 1H, COOH); 13C NMR (75.4 MHz, CDCl3) δ 14.88, 24.70, 25.98, 28.97, 29.08, 29.24*, 29.38, 29.48, 29.69, 31.73, 34.11, 180.05; MS, m/z 246 (M+, 50), 217 (COOH(CH2)10S+, 7), 199 (100), 181 (7), 167 (7), 149 (6), 117 (7), 101 (9), 97 (9), 87 (14), 83 (18), 75 (54), 69 (29), 62 (18), 55 (37).
Reaction SMILES: O.[OH-].[Li+].[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([O:23]C(C)(C)C)=[O:22])[N:20]=3)=[CH:12][N:11]=2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1>C(O)C.O.CN(C=O)C>[C:4]1([C:10]2[N:15]=[CH:14][C:13]([C:16]3[S:17][CH:18]=[C:19]([C:21]([OH:23])=[O:22])[N:20]=3)=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: CC(C)(C)OC(=O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CN(C)C=O
Solvent: O
Solvent: CCO
Product: O=C(O)c1csc(-c2cnc(-c3ccccc3)nc2)n1
Temperature: 25 °C
Reaction time: 18 h
Yield: 43.7 %

Procedure:
To a solution consisting of lithium hydroxide monohydrate (0.38 g, 9.0 mmol) dissolved in ethanol (20 mL)/water (10 mL) was added tert-butyl 2-(2-phenylpyrimidin-5-yl)thiazole-4-carboxylate (Example 62, 705 mg, 3.0 mmol) in dry DMF (11 mL) and the mixture stirred at room temperature for 18 hours. Ethanol was removed under reduced pressure and the solution diluted with water and subsequently extracted with diethyl ether (2×30 mL). The aqueous phase was acidified with 2 N hydrochloric acid to pH2. The solid precipitate was filtered, washed with water and dried under high vacuum to give the title compound as an off-white solid (371 mg, 87% yield); Rf 0.15 with 9:1 v/v dichloromethane-methanol; 1H-NMR (300 MHz; DMSO-d6) δ 9.39 (s, 2H), 8.63 (s, 1H), 8.44 (dd, 2H), 7.55 (m, 3H); MS (ESI+) m/z 284 (M+1); H-PGDS FPBA IC50: 1.1 μM.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]1.[CH2:12]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20](Cl)[C:19]2[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:13]1.[I-].[Na+].C(N(CC)CC)C>O1CCOCC1>[CH:15]1[C:14]2[CH2:13][CH2:12][C:26]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[CH:20]([N:2]3[CH2:7][CH2:6][CH:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH2:3]3)[C:19]=2[CH:18]=[CH:17][CH:16]=1
Reactant: COC(=O)C1=CCCNC1
Reactant: ClC1c2ccccc2CCc2ccccc21
Agent: Cl
Agent: [I-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: CCN(CC)CC
Product: COC(=O)C1=CCCN(C2c3ccccc3CCc3ccccc32)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 54 %

Procedure:
A mixture of methyl 1,2,5,6-tetrahydropyridine-3-carboxylate hydrochloride (crude, 150 mmol), 5-chlorodibenzosuberane (41 g, 180 mmol, 1.2 eq), sodium iodide (2.2 g, 15 mmol, 0.1 eq) and triethylamine (63 mL, 450 mmol, 3.0 eq) in dioxane (300 mL) was stirred at 90° C. overnight. The reaction mixture was concentrated in vacuo and the residue was partitioned between ethyl acetate and water. The organic phase was washed with brine, dried over MgSO4, and concentrated. The crude product was passed through a silica gel plug, eluting with CH2Cl2. After concentration, the resulting solid was triturated with ether to yield 27 g (55%) of methyl 1-(10,11-dihydro5H-dibenzo[a,d][7]annulen-5-yl)-1,2,5,6-tetrahydropyridine-3-carboxylate.
Reaction SMILES: [NH2:1][C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8].[C:17](O)(=[O:19])[CH3:18].O.CC(=O)OCC.C(OCC)C>CN(C=O)C>[NH:1]([C:17]([CH3:18])=[O:19])[C@H:2]([C:14]([OH:16])=[O:15])[CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:9][C:10]([CH3:11])([CH3:12])[CH3:13])=[O:8]
Reactant: CC(=O)O
Reactant: CC(C)(C)OC(=O)NCCC[C@H](N)C(=O)O
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(=O)N[C@@H](CCCNC(=O)OC(C)(C)C)C(=O)O
Yield: 88 %

Procedure:
9.3 g of H-Orn(Boc)-OH, 5.0 g of the N-hydroxysuccinimide ester of acetic acid and 4.1 ml of NEM in 50 ml of DMF and 10 ml of H2O are allowed to react at room temperature for 3 days. The solvent is evaporated off in vacuo, and the residue is chromatographed on silica gel (system 4). 9.6 g of Ac-Orn(Boc)-OH (yield: 88%) readily crystallize from EA/diethyl ether. MS (FAB): 275 (M+1).
Reaction SMILES: O.O.O.O.O.O.O.O.O.O.B([O-])([O-])[O-].[Na+].[Na+].[Na+].[C:18]([O:29][CH3:30])(=[O:28])[C:19]1[CH:27]=[C:25]([OH:26])[C:23]([OH:24])=[C:21]([OH:22])[CH:20]=1.S(OC)(O[CH3:35])(=O)=O.[OH-].[Na+]>O>[OH:26][C:25]1[CH:27]=[C:19]([CH:20]=[C:21]([O:22][CH3:35])[C:23]=1[OH:24])[C:18]([O:29][CH3:30])=[O:28]
Reactant: COS(=O)(=O)OC
Reactant: COC(=O)c1cc(O)c(O)c(O)c1
Agent: [Na+]
Agent: [O-]B([O-])[O-]
Agent: [OH-]
Solvent: O
Product: COC(=O)c1cc(O)c(O)c(OC)c1
Reaction time: 1 h
Yield: 84.3 %

Procedure:
To a stirred mixture of sodium borate decahydrate (borax, 80 g) in H2O (1 L) was added methyl gallate (3, 15.0 g, 82 mmol) at rt. After stirring for 1 h, dimethyl sulfate (30 ml, 317 mmol) and NaOH (50 ml, 6.5 M) were added dropwise simultaneously via separate addition funnels over the course of 1 h. After stirring an additional 12 h, the methylation was terminated with H2SO4, (65 ml, conc.) and stirring continued an additional h. The product was removed by extraction with DCM (5×500 ml, each time stirring the solution for 20 min). The combined DCM extracts were washed with brine (300 ml), dried, concentrated in vacuo, and the residue crystallized from methanol-benzene to afford methyl ether 4 (13.7 g, 85%) as a light tan solid, mp 110–111° C., (lit. mp 110–111° C., Pettit and Singh, 1987); 1H-NMR (300 MHz): 3.89 (3H, s, —OCH3), 3.94 (3H, s, —OCH3), 5.40 (2H, bs, —OH), 5.80 (2H, bs, —OH), 7.22 (1H, d, J=1.8 Hz, ArH), 7.35 (1H, d, J=1.8 Hz, ArH).
Reaction SMILES: ClC(O[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=O.[Br-:11].[Na+].CO.O.[CH3:16][N:17]([CH3:20])[CH:18]=[O:19]>>[Br-:11].[C:5]1([C:18]([N:17]([CH3:20])[CH3:16])=[O:19])[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CN(C)C=O
Agent: [Br-]
Agent: [Na+]
Solvent: O
Solvent: CO
Product: CN(C)C(=O)c1ccccc1
Temperature: 0 °C
Reaction time: 4 h

Procedure:
Phenyl N,N-dimethylformamide bromide was prepared by dropwise addition of phenyl chloroformate (6.5 ml; 50 mmol) to a stirred solution of sodium bromide (5.14 g; 50 mmol) in dimethylformamide at 0°-5° C. Sodium chloride precipitated, and the resulting suspension was stirred at 0°-5° C. for 4 hours and then at room temperature overnight. The mixture was cooled to 0° C. and 16-deacetoxy-16β-(acetylthio)fusidic acid acetoxymethyl ester (6.07 g; 10 mmol) was added with stirring. After stirring at 0°-5° C. for 4 hours, the mixture was left at room temperature for a further 4 days. On dilution of the stirred reaction mixture with methanol-water 1:1 (75 ml) an oily product precipitated, which was washed repeatedly by decantation with methanol-water 1:1 and finally taken up in ether, dried, and evaporated in vacuo. The amorphous residue thus obtained was purified by dry column chromatography on silica gel (petroleum ether-ethyl acetate 85:15) to give the desired compound as a colourless foam.
Reaction SMILES: Br[CH2:2][C:3]([CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1.C(N(CC)CC)C.[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH2:42]>C(#N)C>[CH3:34][N:35]1[CH2:39][CH2:38][CH2:37][CH:36]1[CH2:40][CH2:41][NH:42][CH2:2]/[C:3](/[CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[CH:20]=[CH:19][CH:18]=1)=[CH:4]/[C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[CH:7][CH:6]=1
Reactant: CN1CCCC1CCN
Reactant: COC(=O)c1ccc(C=C(CBr)COc2cccc3ccccc23)cc1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COC(=O)c1ccc(/C=C(/CNCCC2CCCN2C)COc2cccc3ccccc23)cc1
Yield: 48 %

Procedure:
Methyl 4-[2-bromomethyl-3-(naphthalen-1-yloxy)-propenyl]-benzoate (412 mg, 1 mmol) was dissolved acetonitrile (5 ml) in a 100 ml vessel at 0° C., and thereto triethylamine (0.21 ml, 1.5 mmol, 1.5 eq.) and 2-(1-methylpyrrolidin-2-yl)ethylamine (R1′″NH2; 0.22 ml, 1.5 mmol, 1.5 eq.) were added while stirring. The resulting mixture was heated from 0° C. to room temperature, and then reacted for 4 hours. After the completion of reaction, the solvent was distilled off, and the residue thus obtained was extracted with ethyl ester. The organic layer was separated, washed with an aqueous saturated sodium bicarbonate solution and brine in order, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue thus obtained was subjected to a silica gel column chromatography to obtain 220 mg of the title compound as pale yellow oil (yield 48%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH2:14][CH2:15][N:16]1[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]1)[N:9]=[CH:8][N:7]=[C:6]2[O:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[NH:28][C:27]([CH3:32])=[CH:26]2.Cl[CH2:34][C:35](=[O:37])[CH3:36].C(=O)([O-])[O-].[K+].[K+]>CC(N(C)C)=O>[C:35]([CH2:36][N:19]1[CH2:20][CH2:21][N:16]([CH2:15][CH2:14][O:13][C:12]2[CH:11]=[C:10]3[C:5]([C:6]([O:22][C:23]4[CH:24]=[C:25]5[C:29](=[CH:30][CH:31]=4)[NH:28][C:27]([CH3:32])=[CH:26]5)=[N:7][CH:8]=[N:9]3)=[CH:4][C:3]=2[O:2][CH3:1])[CH2:17][CH2:18]1)(=[O:37])[CH3:34]
Reactant: CC(=O)CCl
Reactant: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Product: COc1cc2c(Oc3ccc4[nH]c(C)cc4c3)ncnc2cc1OCCN1CCN(CC(C)=O)CC1
Temperature: 70 °C

Procedure:
A mixture of 6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]-7-[2-(piperazin-1-yl)ethoxy]quinazoline (0.15 g), chloroacetone (0.036 ml), potassium carbonate (0.05 g) and DMA (1.3 ml) was stirred and heated to 70° C. for 1.5 hours. The mixture was cooled to ambient temperature, the precipitate was filtered off and the residue was purified by preparative LCMS (Hypersil C18-β-Basic column using a solvent gradient consisting of acetonitrile and water buffered with a 5% ammonium carbonate solution (100 g/L, pH 8.9). Evaporation of the solvents gave 7-{2-[4-(acetylmethyl)piperazin-1-yl]ethoxy}-6-methoxy-4-[(2-methyl-1H-indol-5-yl)oxy]quinazoline as a pale yellow solid (0.10 g), which was dried under vacuum.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9](Cl)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1.[NH:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:9]([N:13]2[CH2:18][CH2:17][O:16][CH2:15][CH2:14]2)(=[O:11])=[O:10])[CH:6]=[CH:7][CH:8]=1
Reactant: C1COCCN1
Reactant: COc1cccc(S(=O)(=O)Cl)c1
Solvent: CC(C)=O
Product: COc1cccc(S(=O)(=O)N2CCOCC2)c1

Procedure:
3-Methoxybenzenesulfonyl chloride (0.20 g, 0.968 mmol) in acetone (2 mL) at 0° C. was treated with excess morpholine (0.253 mL, 2.9 mmol) with stirring. After 0.5 hr the reaction mixture was partitioned between CH2Cl2 (1 mL) and 1N HCl, the organic layer separated, washed with brine, dried (Na2SO4), filtered and concentrated to dryness to give the title compound.
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:31])[C:7]1[CH:12]=[CH:11][C:10]([C:13](=[N:28][OH:29])[CH:14]=[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)[C:16]([F:19])([F:18])[F:17])=[CH:9][C:8]=1[CH3:30])[CH2:2][CH2:3][CH3:4].[Br:32]N1C(=O)CCC1=O>CN(C)C=O>[Br:32][CH:14]1[C:15]([C:20]2[CH:25]=[C:24]([Cl:26])[CH:23]=[C:22]([Cl:27])[CH:21]=2)([C:16]([F:18])([F:17])[F:19])[O:29][N:28]=[C:13]1[C:10]1[CH:11]=[CH:12][C:7]([C:6]([NH:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:31])=[C:8]([CH3:30])[CH:9]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CCCCNC(=O)c1ccc(C(C=C(c2cc(Cl)cc(Cl)c2)C(F)(F)F)=NO)cc1C
Solvent: CN(C)C=O
Product: CCCCNC(=O)c1ccc(C2=NOC(c3cc(Cl)cc(Cl)c3)(C(F)(F)F)C2Br)cc1C
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Butyl-4-[3-(3,5-dichloro-phenyl)-4,4,4-trifluoro-1-hydroxyimino-but-2-enyl]-2-methyl-benzamide (Example 3.1) (380 mg, 0.94 mmol) and N-bromosuccinimide (200 mg, 1.12 mmol) were heated in N,N-dimethylformamide (2 ml) at 120° C. for 7 minutes. The reaction mixture was allowed to cool to ambient temperature and then extracted with diethyl ether. The combined organic extracts were dried over magnesium sulfate and concentrated. The residue was purified by chromatography on silica gel (eluent: hexane/ethyl acetate 4:1) to give Compound No. A1 of Table A (210 mg, 40% yield) as a solid foam.
Reaction SMILES: C(OC([N:8]1[CH2:17][CH2:16][C:15]2[C:11](=[C:12](OS(C(F)(F)F)(=O)=O)[N:13]([CH:18]3[CH2:22][CH2:21][CH2:20][CH2:19]3)[N:14]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.[S:31]1[CH:35]=[CH:34][C:33](B(O)O)=[CH:32]1>>[CH:18]1([N:13]2[C:12]([C:33]3[CH:34]=[CH:35][S:31][CH:32]=3)=[C:11]3[C:15]([CH2:16][CH2:17][NH:8][CH2:9][CH2:10]3)=[N:14]2)[CH2:19][CH2:20][CH2:21][CH2:22]1
Reactant: CC(C)(C)OC(=O)N1CCc2nn(C3CCCC3)c(OS(=O)(=O)C(F)(F)F)c2CC1
Reactant: OB(O)c1ccsc1
Product: c1cc(-c2c3c(nn2C2CCCC2)CCNCC3)cs1
Yield: 89.9 %

Procedure:
The title compound (114 mg) was prepared as in Example 177, Steps C and D, using 200 mg of 2-cyclopentyl-3-trifluoromethanesulfonyloxy-4,5,7,8-tetrahydro-2H-1,2,6-triaza-azulene-6-carboxylic acid tert-butyl ester (Example 180, Step A) and 169 mg of 3-thiopheneboronic acid. MS (ESI): exact mass calculated for C16H21N3S, 287.15; found, m/z 288.4 [M+H]+. 1H NMR (500 MHz, CDCl3): 7.68-7.63 (m, 1H), 7.56-7.51 (m, 1H), 7.17-7.12 (m, 1H), 4.58 (m, 1H), 3.43-3.37 (m, 2H), 3.34-3.28 (m, 2H), 3.19-3.14 (m, 2H), 2.86-2.80 (m, 2H), 2.04-1.85 (m, 6H), 1.67-1.57 (m, 2H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH2:15])[CH2:8][CH2:7][CH2:6][C:5]2=1.Cl[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH:9]([NH:15][C:17]3[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[CH:19][N:18]=3)[CH2:8][CH2:7][CH2:6][C:5]2=1
Reactant: NC1CCCc2c1[nH]c1ccc(Br)cc21
Reactant: N#Cc1ccc(Cl)nc1
Product: N#Cc1ccc(NC2CCCc3c2[nH]c2ccc(Br)cc32)nc1

Procedure:
6-[(6-Bromo-2,3,4,9-tetrahydro-1H-carbazol-1-yl)amino]nicotinonitrile was prepared from 6-bromo-2,3,4,9-tetrahydro-1H-carbazol-1-amine (75 mg, 0.28 mmol) and 6-chloronicotinonitrile (118 mg, 0.85 mmol) in a similar manner as described in Example 22 to give 6.5 mg (6%) of a light brown solid. 1H-NMR (DMSO-d6): δ 10.95 (s, 1H), 8.36 (s, 1H), 7.79 (d, 1H), 7.64 (dd, 1H), 7.57 (d, 1H), 7.23 (d, 1H), 7.13 (dd, 1H), 6.62 (d, 1H), 5.40-5.35 (m, 1H), 2.70-2.55 (m, 2H), 2.07-1.78 (m, 4H); MS m/z (M−1) 365, 367.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C[Si]([C:11]#[C:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:21][CH:22]2[CH2:24][CH2:23]2)[CH3:20])=[CH:15][CH:14]=1)(C)C>CO>[C:12]([C:13]1[CH:18]=[CH:17][C:16]([CH:19]([NH:21][CH:22]2[CH2:23][CH2:24]2)[CH3:20])=[CH:15][CH:14]=1)#[CH:11]
Reactant: CC(NC1CC1)c1ccc(C#C[Si](C)(C)C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#Cc1ccc(C(C)NC2CC2)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98.4 %

Procedure:
Potassium carbonate (96 mg) was added to a methanol (3.0 mL) solution of N-(1-{4-[(trimethylsilyl)ethynyl]phenyl}ethyl)cyclopropylamine (0.12 g) as obtained in Example 14-(2), and the mixture was stirred in a nitrogen atmosphere for 30 minutes at room temperature. After the solid was filtered out, the reaction mixture was concentrated. The resulting residue was purified by OH type silica gel chromatography (hexane/ethyl acetate=95/5) to obtain N-[1-(4-ethynylphenyl)ethyl]cyclopropylamine (colorless oil) (85 mg, 100%).
Reaction SMILES: [NH4+].[Cl-].[Br:3][C:4]1[CH:9]=[C:8]([N+:10]([O-])=O)[C:7]([CH3:13])=[CH:6][C:5]=1[F:14]>O.[Fe]>[Br:3][C:4]1[C:5]([F:14])=[CH:6][C:7]([CH3:13])=[C:8]([CH:9]=1)[NH2:10]
Reactant: Cc1cc(F)c(Br)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Product: Cc1cc(F)c(Br)cc1N
Temperature: 25 °C
Yield: 72.1 %

Procedure:
The mixture of Iron powder (17.8 g, 318 mmol) and NH4Cl (5.10 g, 95.4 mmol) in water (100 mL) was refluxed for 30 minutes. To this hot mixture was added 4-bromo-3-fluoro-6-nitrotoluene (18.6 g, 79.5 mmol) slowly and then the reaction mixture was refluxed for 48 hours. The mixture was cooled to room temperature and extracted with EtOAc (3×200 mL). The organic solution was washed with H2O (3×300 mL) and brine (300 mL), dried (Na2SO4), and concentrated. The residue was purified by flash chromatography (silica, 20% EtOAc in hexanes) to give 11.7 g (72%) of title compound as a pale yellow solid. 1H NMR (CDCl3): 300 MHz δ 6.82 (m, 2H), 3.49 (bs, 2H), 2.11 (s, 3H).
Reaction SMILES: [OH:1][C@@H:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([OH:5])=[O:4].[Cl:13][CH2:14][CH2:15]O>>[OH:1][CH:2]([CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:3]([O:5][CH2:15][CH2:14][Cl:13])=[O:4]
Reactant: OCCCl
Reactant: O=C(O)[C@@H](O)Cc1ccccc1
Product: O=C(OCCCl)C(O)Cc1ccccc1

Procedure:
2-Chloroethyl 2-hydroxy-3-phenylpropionate was prepared from (S)-2-hydroxy-3-phenylpropionic acid and excess 2-chloroethanol essentially by the method described in Step 1 of Example 1; however, the distillate solidified after standing at 4° C.: b.p. 120° C./0.35 mm Hg; 1H NMR δ2.86 (bs, 1H), δ2.98 (dd, 1H, J=6.7 Hz and 14.0 Hz), δ3.13 (dd, 1H, J=4.6 Hz and 14.0 Hz), δ3.63 (t, 2H, J=5.6 Hz), δ4.35 (m, 2H), δ4.48 (dd, 1H, J=4.7 Hz and 6.6 Hz), δ7.2-7.3 (5H); 13C NMR 40.5, 41.0, 64.8, 71.3, 126.8, 128.3, 129.4, 136.2, 173.6 ppm; HRMS calcd for C10H9ClO3Tms (M-CH3) 285.0714, obsd 285.0756.
Reaction SMILES: COC1C=CC(C[N:8]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][N:16]=[C:15]([NH:19][CH3:20])[CH:14]=3)[C:10]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:39])[F:38])=[CH:33][CH:32]=4)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[N:9]2)=CC=1.FC(F)(F)C(O)=O>C(OCC)C>[CH3:20][NH:19][C:15]1[CH:14]=[C:13]([C:11]2[C:10]([C:21]3[CH:22]=[C:23]([NH:27][C:28]([NH:30][C:31]4[CH:36]=[CH:35][C:34]([C:37]([F:40])([F:38])[F:39])=[CH:33][CH:32]=4)=[O:29])[CH:24]=[CH:25][CH:26]=3)=[N:9][NH:8][CH:12]=2)[CH:18]=[CH:17][N:16]=1
Reactant: CNc1cc(-c2cn(Cc3ccc(OC)cc3)nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Solvent: CCOCC
Solvent: O=C(O)C(F)(F)F
Product: CNc1cc(-c2c[nH]nc2-c2cccc(NC(=O)Nc3ccc(C(F)(F)F)cc3)c2)ccn1
Temperature: 70 °C
Reaction time: 6 h
Yield: 63.2 %

Procedure:
200 mg (0.35 mmol) of 1-(3-{1-(4-methoxybenzyl)-4-[2-(methylamino)pyridin-4-yl]-1H-pyrazol-3-yl}phenyl)-3-[4-(trifluoromethyl)phenyl]urea were dissolved with 10 ml of trifluoroacetic acid and the solution was stirred at 70° C. for 6 hours. The solvent was then evaporated and the residue taken up with dichloromethane and washed with aqueous sodium hydrogenocarbonate. The organic layer was dried over sodium sulphate and evaporated again, affording, after trituration with diethylether, 100 mg (63%) of the title compound.
Reaction SMILES: [CH3:1]C1C=CC(/C(=C\C(O)=O)/C(O)=S)=CC=1.C(O[C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[S:25][C:24]([C:29]([O-:31])=[O:30])=[CH:23][C:22]2=[O:32])C.[Na+].S(=O)(=O)(O)O>>[CH3:1][C:19]1[CH:20]=[C:21]2[C:26](=[CH:27][CH:28]=1)[S:25][C:24]([C:29]([OH:31])=[O:30])=[CH:23][C:22]2=[O:32]
Reactant: CCOc1ccc2sc(C(=O)[O-])cc(=O)c2c1
Reactant: Cc1ccc(/C(=C\C(=O)O)C(O)=S)cc1
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc2sc(C(=O)O)cc(=O)c2c1
Reaction time: 0.5 h

Procedure:
4.7 parts of 4-methylphenylthio fumaric acid, made in analogous manner to part (a) of Example 1, was added in small lots to 20 parts of stirred concentrated sulphuric acid. The solution was allowed to stand for 30 minutes and then it was cautiously poured on to ice. The resulting precipitate was filtered off, washed with water and crystallised from an ethanol/dioxan mixture to give 2.3 parts of 6-methyl-1-thiachromone-2-carboxylic acid, melting point 236°-7°C.
Reaction SMILES: Cl[CH2:2][C:3]1[CH:4]=[N:5][CH:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:8]=1.CC1C=NC=C(C2C=CC=CC=2)C=1.[C:28]1([N:34]2[CH2:39][CH2:38][NH:37][CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>C(#N)C>[C:28]1([N:34]2[CH2:39][CH2:38][N:37]([CH2:2][C:3]3[CH:4]=[N:5][CH:6]=[C:7]([C:9]4[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=4)[CH:8]=3)[CH2:36][CH2:35]2)[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1
Reactant: ClCc1cncc(-c2ccccc2)c1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: Cc1cncc(-c2ccccc2)c1
Solvent: CC#N
Product: c1ccc(-c2cncc(CN3CCN(c4ccccc4)CC3)c2)cc1
Temperature: 25 °C
Reaction time: 6 h

Procedure:
2.04 g of 3-chloromethyl-5-phenylpyridine (“A”) [obtainable for example by radical chlorination of 3-methyl-5-phenylpyridine] and 1.62 g of 1-phenylpiperazine are dissolved in 200 ml of acetonitrile and the mixture is stirred for six hours at room temperature. After customary work-up, 1-phenyl-4-[(5-phenyl-3-pyridyl)methyl]piperazine, m.p. 83-85°, is obtained.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:17])[C:6]2[CH:11]=[CH:10][C:9]([CH3:12])=[C:8]([NH:13][C:14]([NH2:16])=[S:15])[CH:7]=2)[CH2:3][CH2:2]1.Br[CH2:19][C:20](=O)[C:21]([O:23]CC)=O>C(O)C>[C:8]1([NH:13][C:21]([C:20]2[N:16]=[C:14]([NH:13][C:8]3[CH:7]=[C:6]([C:5](=[O:17])[NH:4][CH:1]4[CH2:3][CH2:2]4)[CH:11]=[CH:10][C:9]=3[CH3:12])[S:15][CH:19]=2)=[O:23])[CH:9]=[CH:10][CH:11]=[CH:6][CH:7]=1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1NC(N)=S
Reactant: CCOC(=O)C(=O)CBr
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1Nc1nc(C(=O)Nc2ccccc2)cs1
Temperature: 75 °C
Reaction time: 16 h
Yield: 79.6 %

Procedure:
To a stirred solution of N-Cyclopropyl-4-methyl-3-thioureido-benzamide 3A (100 mg, 0.48 mmol) in 10 mL of ethanol was added ethyl bromopyruvate (89 mg, 0.48 mmol) and the reaction was heated at 75° C. overnight. After 16 hours, the reaction was cooled and concentrated and the crude product was purified by flash chromatography on silica gel loaded with CH2Cl2 and eluted with 1:1 hexanes/ethyl acetate followed by 1:2 hexanes/ethyl acetate to provide the title compound as a solid (75 mg, 45%). HPLC, tR, 2.97 min. (4 minute method); MS, m/z 346.0 [M+1]+.