Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:19])([O:6][C:7]1[CH:12]=[CH:11][C:10]([N:13]2[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]2)=[CH:9][CH:8]=1)[CH:3]([F:5])[F:4].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([N:16]1[CH2:17][CH2:18][N:13]([C:10]2[CH:11]=[CH:12][C:7]([O:6][C:2]([F:1])([F:19])[CH:3]([F:4])[F:5])=[CH:8][CH:9]=2)[CH2:14][CH2:15]1)(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: FC(F)C(F)(F)Oc1ccc(N2CCNCC2)cc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(OC(F)(F)C(F)F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h

Procedure:
1-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine (10.95 g, 0.04) was dissolved in DCM (500 ml) and triethylamine (18.5 ml, 0.13 mol) was added. The mixture was cooled to 0° C. and methane sulphonyl chloride (7.4 ml, 0.048 mol) added. Allowed to reach ambient temperature and stirred overnight. The reaction mixture washed with water and the organic phase collected, dried over MgSO4, filtered and evaporated to dryness. The residual solid was crystallised from ethanol to yield 1-(methylsulfonyl)-4-[4-(1,1,2,2-tetrafluoroethoxy)phenyl]piperazine as a white solid. Yield 12.3 g (78.5%)
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4](Cl)=[O:5].[F:13][C:14]1[CH:15]=[N:16][CH:17]=[C:18]([F:21])[C:19]=1[NH2:20].O1CCOCC1>C1COCC1.N1C=CC=CC=1.[OH-].[Na+].CO>[Cl:1][C:2]1[CH:10]=[C:9]([I:11])[CH:8]=[C:7]([Cl:12])[C:3]=1[C:4]([NH:20][C:19]1[C:18]([F:21])=[CH:17][N:16]=[CH:15][C:14]=1[F:13])=[O:5]
Reactant: O=C(Cl)c1c(Cl)cc(I)cc1Cl
Reactant: Nc1c(F)cncc1F
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: C1COCCO1
Solvent: CO
Product: O=C(Nc1c(F)cncc1F)c1c(Cl)cc(I)cc1Cl
Temperature: 25 °C
Reaction time: 8 h
Yield: 68.9 %

Procedure:
A suspension of 2,6-dichloro-4-iodobenzoyl chloride (24.2 g, 72.1 mmol) in THF (25 mL), was added drop-wise over 10 minutes, to a solution of 3,5-difluoropyridin-4-ylamine (10.37 g, 79.7 mmol) in pyridine (100 mL) at a temperature of between 3 and 5° C., under nitrogen. The reaction mixture was allowed to warm to room temperature over 1 hour and then stirred overnight. The volatiles were removed under reduced pressure and the resultant residue was treated with HCl (1 N, 90 mL). The resultant suspension was stirred at room temperature for 45 minutes and the precipitate obtained was collected by filtration, washing with water before drying. The resultant solid obtained was suspended in 1N NaOH (124 mL) and MeOH (124 mL), and heated at 65° C. for 5 hours then slowly cooled to room temperature. Further MeOH (50 mL) and dioxane (100 mL) were added and the reaction mixture was heated at 75° C. overnight. The resultant mixture was cooled to room temperature and the organic solvents removed under reduced pressure. The pH of the aqueous mixture was adjusted to 4-5 by drop-wise addition of 12 N HCl, controlling the exotherm by the use of an ice-bath. The residue was left standing at room temperature for 18 hours and then the resultant solid was collected by filtration, washing with water and dried under vacuum to afford the title compound as an off-white solid (21.3 g, 83% yield). LCMS (Method D): RT=3.46 min, m/z: 429 [M+H+].
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([C:9]2[C:10](=[O:16])[CH2:11][CH2:12][C:13]=2[O:14][CH3:15])=[C:4]([CH3:17])[CH:3]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.[CH2:28]1[CH2:33][CH2:32][CH:31]([CH:34]=[O:35])[CH2:30][CH2:29]1>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH3:17])[C:5]([C:9]2[C:10](=[O:16])[CH:11]([CH:34]([CH:31]3[CH2:32][CH2:33][CH2:28][CH2:29][CH2:30]3)[OH:35])[CH2:12][C:13]=2[O:14][CH3:15])=[C:6]([CH3:8])[CH:7]=1
Reactant: COC1=C(c2c(C)cc(Br)cc2C)C(=O)CC1
Reactant: O=CC1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: COC1=C(c2c(C)cc(Br)cc2C)C(=O)C(C(O)C2CCCCC2)C1
Temperature: -78 °C
Reaction time: 0.67 h

Procedure:
To a solution of 2-(4-bromo-2,6-dimethyl-phenyl)-3-methoxy-cyclopent-2-enone (1 g, 3.4 mmol) in 10 ml of dry tetrahydrofuran under nitrogen atmosphere at −78° C. LiHMDS (4.42 ml, 4.42 mmol) is added slowly and it is stirred at −78° C. for 40 minutes. A solution of cyclohexyl carboxaldehyde (761 mg, 6.8 mmol) in dry tetrahydrofuran (10 ml) is added to the reaction mixture at −78° C. The reaction mixture is stirred at this temperature for 2 hours and then at room temperature for 3 hours. The reaction mixture is quenched with water (50 ml) and the aqueous layer is extracted with ethyl acetate (3*100 ml). The combined organic layers are dried with sodium sulfate and concentrated under vacuum to obtain crude product which is directly taken to the next step without further purification.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][C@@H:7]([CH2:11][C:12]1[N:13]=[CH:14][NH:15][CH:16]=1)[C:8]([OH:10])=[O:9])=[O:5])#[N:2]>N.CO.[Co]>[CH:16]1[N:15]=[CH:14][NH:13][C:12]=1[CH2:11][C@H:7]([NH:6][C:4]([CH2:3][CH2:1][NH2:2])=[O:5])[C:8]([OH:10])=[O:9]
Reactant: N#CCC(=O)N[C@@H](Cc1c[nH]cn1)C(=O)O
Agent: [Co]
Agent: N
Solvent: CO
Product: NCCC(=O)N[C@@H](Cc1cnc[nH]1)C(=O)O
Temperature: 100 °C

Procedure:
A 1-litre pressure autoclave was initial charged with 4.50 g of Raney cobalt (doped with 0.3% iron) in a mixture of 285 of conc. ammonia/methanol (m/m=1.9:1) The autoclave was closed and flushed twice with 40 bar of nitrogen and then pressurized with 45 bar of hydrogen, and the mixture was then heated to 100° C. This was followed by metering in a solution of 30.0 g (0.135 mol) of (S)-2-(cyanoacetylamino)-3-(1H-imidazol-4-yl)propionic acid (prepared according to Example 3) in a mixture of 285 g of conc. ammonia/methanol (m/m=1.9:1) over the course of one hour. After further reaction at 100° C. for one hour, the reaction mixture was cooled to room temperature. The autoclave was depressurized and the catalyst was filtered off. An in-process HPLC analysis showed that the reddish-brow-n reaction solution (310.5 g) contained 9.57% (m/m) carnosine, corresponding to a selectivity of 97% for complete conversion.
Reaction SMILES: [N:1]#[C:2][NH2:3].[Na].[C:5]1([CH2:11][O:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]=[C:20]=[S:21])=[CH:15][CH:14]=2)[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1>C(O)C>[C:2]([NH:3][C:20]([NH:19][C:16]1[CH:15]=[CH:14][C:13]([O:12][CH2:11][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=2)=[CH:18][CH:17]=1)=[S:21])#[N:1]
Reactant: N#CN
Reactant: S=C=Nc1ccc(OCc2ccccc2)cc1
Agent: [Na]
Solvent: CCO
Product: N#CNC(=S)Nc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 68.2 %

Procedure:
The suspension of monosodium cyanamide (1.33 g, 20.7 mmol) in absolute ethanol (50 mL) was slowly treated with 4-phenylmethoxyphenylisothiocyanate (5.0 g, 20.7 mmol). The reaction was allowed to stir at room temperature for 1 hour and then heated at 75° C. for 4 hours. The reaction was cooled to room temperature and the colorless solid was filtered and washed with ethanol to give the title A compound (4.0 g), m.p. >270° C.
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15]Br)[C:6]=1[F:17])(=[O:4])=[O:3].[CH3:18][S-:19].[Na+]>C1COCC1>[CH3:1][S:2]([C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:15][S:19][CH3:18])[C:6]=1[F:17])(=[O:4])=[O:3]
Reactant: C[S-]
Reactant: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CBr
Agent: [Na+]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(S(C)(=O)=O)c(F)c1CSC

Procedure:
44.6 g (0.14 mol) of methyl 4-methylsulfonyl-3-fluoro-2-bromomethylbenzoate were dissolved in THF. 10.58 g (0.15 mol) of sodium thiomethoxide were added at RT and the mixture was then heated under reflux for 5 h. It was then poured onto ice-water and extracted with EE. The combined organic phases were dried over MgSO4 and concentrated to completion.
Reaction SMILES: [CH3:1][C:2]1([CH3:8])[O:6][C:5](=[O:7])[CH2:4][CH2:3]1.C[Al](C)C.[NH2:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]([N:22]2[CH2:27][CH2:26][N:25]([CH2:28][C:29]3[CH:34]=[CH:33][C:32]([C:35]([OH:44])([C:40]([F:43])([F:42])[F:41])[C:36]([F:39])([F:38])[F:37])=[CH:31][CH:30]=3)[CH2:24][CH2:23]2)=[O:21])=[CH:16][CH:15]=1.CN(C)C=O>C1(C)C=CC=CC=1>[F:42][C:40]([F:41])([F:43])[C:35]([C:32]1[CH:31]=[CH:30][C:29]([CH2:28][N:25]2[CH2:24][CH2:23][N:22]([C:20]([C:17]3[CH:18]=[CH:19][C:14]([NH:13][C:5](=[O:7])[CH2:4][CH2:3][C:2]([OH:6])([CH3:8])[CH3:1])=[CH:15][CH:16]=3)=[O:21])[CH2:27][CH2:26]2)=[CH:34][CH:33]=1)([OH:44])[C:36]([F:39])([F:38])[F:37]
Reactant: Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Reactant: CC1(C)CCC(=O)O1
Agent: C[Al](C)C
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Product: CC(C)(O)CCC(=O)Nc1ccc(C(=O)N2CCN(Cc3ccc(C(O)(C(F)(F)F)C(F)(F)F)cc3)CC2)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 0.4 %

Procedure:
5,5-Dimethyldihydrofuran-2(3H)-one (0.433 mmol, 0.049 g) was stirred in toluene (5 mL). Trimethylaluminium (0.867 mmol, 0.867 mL, 1 M in heptane) was added and the reaction stirred for 10 minutes at room temperature. (4-Aminophenyl)(4-(4-(1,1,1,3,3,3-hexafluoro-2-hydroxypropan-2-yl)benzyl)piperazin-1-yl)methanone (0.433 mmol, 0.2 g) was added and the reaction heated to reflux for 1 hour then a drop of N,N-dimethylformamide was added. The reaction mixture was heated to reflux for 1 hour. The reaction mixture was quenched with water. Ethyl acetate was added and the layers separated. The organic phase was concentrated under vacuum and the resulting residue purified by acidic preparative HPLC to afford the desired compound (1 mg).
Reaction SMILES: C(OC(=O)[N:7]([CH:25]([CH3:27])[CH3:26])[C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19](SC)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)(C)(C)C.[NH2:29][C@H:30]1[CH2:35][CH2:34][C@H:33]([OH:36])[CH2:32][CH2:31]1>>[CH:25]([NH:7][C:8]1[C:9]2[N:10]([C:14]([C:17]3[CH:22]=[CH:21][N:20]=[C:19]([NH:29][CH:30]4[CH2:35][CH2:34][CH:33]([OH:36])[CH2:32][CH2:31]4)[N:18]=3)=[CH:15][N:16]=2)[CH:11]=[CH:12][N:13]=1)([CH3:26])[CH3:27]
Reactant: N[C@H]1CC[C@H](O)CC1
Reactant: CSc1nccc(-c2cnc3c(N(C(=O)OC(C)(C)C)C(C)C)nccn23)n1
Product: CC(C)Nc1nccn2c(-c3ccnc(NC4CCC(O)CC4)n3)cnc12

Procedure:
4-[4-(8-Isopropylamino-imidazo[1,2-a]pyrazin-3-yl)-pyrimidin-2-ylamino]-cyclohexanol was prepared by a process analogous to that described in Example 12 starting from isopropyl-[3-(2-methylsulfanyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-carbamic acid tert-butyl ester (from Example 11 supra), and trans-4-amino-cyclohexanol. LC-MS: [M+H]+ 368.3.
Reaction SMILES: C([O:4][C:5](=[O:40])[C@@H:6]([NH:25][C:26]([C:28]1([CH2:33][CH2:34][CH2:35][CH2:36][N:37]=[N+:38]=[N-:39])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[O:27])[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)CC.[OH-].[Na+]>>[N:37]([CH2:36][CH2:35][CH2:34][CH2:33][C:28]1([C:26]([NH:25][C@@H:6]([CH2:7][C:8]2[CH:9]=[CH:10][C:11]([C:14]3[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=3[CH3:20])=[CH:12][CH:13]=2)[C:5]([OH:40])=[O:4])=[O:27])[CH2:32][CH2:31][CH2:30][CH2:29]1)=[N+:38]=[N-:39]
Reactant: CCCOC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)C1(CCCCN=[N+]=[N-])CCCC1
Agent: [Na+]
Agent: [OH-]
Product: Cc1c(-c2ccc(C[C@H](NC(=O)C3(CCCCN=[N+]=[N-])CCCC3)C(=O)O)cc2)c(=O)n(C)c(=O)n1C

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 9, starting from (S)-2-[[1-(4-azidobutyl)cyclopentanecarbonyl]amino]-3-[4-(1,3,6-trimethyl-2,4-dioxo-1,2,3,4-tetrahydropyrimidin-5-yl)phenyl]propionic acid propyl ester (4.1 g, 7.42 mmol) and NaOH (35 mL, 35 mmol, 1M) which resulted in a white solid (3.75 g, 99%). ES(+)-HRMS m/e calcd. for C26H34N6O5 (M+H)+ 511.2664, obsd. 511.2664.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[O:13]([C:20]1[CH:25]=[CH:24][C:23]([CH2:26][C:27]([OH:29])=[O:28])=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.I[CH2:31][CH:32]1[CH2:36][CH2:35][CH2:34][CH2:33]1.Cl>O1CCCC1.CN1CCCN(C)C1=O>[CH:32]1([CH2:31][CH:26]([C:23]2[CH:22]=[CH:21][C:20]([O:13][C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=3)=[CH:25][CH:24]=2)[C:27]([OH:29])=[O:28])[CH2:36][CH2:35][CH2:34][CH2:33]1
Reactant: ICC1CCCC1
Reactant: O=C(O)Cc1ccc(Oc2ccccc2)cc1
Agent: Cl
Agent: [Li]CCCC
Solvent: CN1CCCN(C)C1=O
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: O=C(O)C(CC1CCCC1)c1ccc(Oc2ccccc2)cc1
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 91.2 %

Procedure:
A solution of diisopropylamine (2.52 mL, 19.3 mmol) in tetrahydrofuran (50 mL) was cooled to −78° C. under a nitrogen atmosphere and then treated with a 2.5M solution of n-butyllithium in hexanes (7.7 mL, 19.3 mmol). The reaction mixture was stirred at −78° C. for 15 min and then slowly treated with a solution of 4-phenoxyphenylacetic acid (2.00 g, 8.8 mmol) in tetrahydrofuran (12 mL) and 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (4 mL) via cannulation. The resulting bright yellow solution was allowed to stir for 1 h at −78° C. After this time, the reaction mixture was treated with a solution of iodomethylcyclopentane (2.02 g, 9.6 mmol) in 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone (1 mL) via cannulation. The resulting reaction mixture was stirred for 1 h at −78° C. and then allowed to warm to 25° C. where it was stirred for 14 h. The reaction was then acidified to pH=2 by the dropwise addition of a 1N aqueous hydrochloric acid solution and then extracted with ethyl acetate (3×25 mL). The combined organic extracts were dried over sodium sulfate, filtered and concentrated in vacuo. Flash chromatography (Merck Silica gel 60, 230-400 mesh, 50/50 hexanes/ethyl acetate plus 1% acetic acid) afforded 3-cyclopentyl-2-(4-phenoxy-phenyl)propionic acid (2.49 g, 91%) as a white foam: EI-HRMS m/e calcd for C20H22O3 (M+) 310.1568, found 310.1568.
Reaction SMILES: C[O:2][C:3](=[O:27])[CH2:4][O:5][C:6]1[C:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:10][C:9]([N+:18]([O-:20])=[O:19])=[CH:8][C:7]=1[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.[K+].[Br-]>>[N+:18]([C:9]1[CH:8]=[C:7]([C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[C:6]([O:5][CH2:4][C:3]([OH:27])=[O:2])=[C:11]([C:12]2[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=2)[CH:10]=1)([O-:20])=[O:19]
Reactant: COC(=O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1
Agent: [Br-]
Agent: [K+]
Product: O=C(O)COc1c(-c2ccccc2)cc([N+](=O)[O-])cc1-c1ccccc1

Procedure:
The title compound was prepared as a white solid (0.229 g, 86%) from (5′-nitro-[1,1′;3′,1″]terphenyl-2′-yloxy)acetic acid methyl ester using a procedure similar to step 2 of Example 36, mp 153.5–156° C.; 1H NMR (DMSO-d6) δ 3.92 (s, 2H), 7.42–7.52 (m, 6H), 7.61–7.65 (m, 4H), 8.13 (s, 2H), 12.15–13.20 (bs, 1H); IR (KBr) 3410, 3070, 2910, 2570, 1750, 1705, 1590, 1525, 1500, 1450, 1410, 1395, 1350, 1305, 1290, 1250, 1220, 1110, 1070, 910, 745, 725, and 710 cm−1; mass spectrum [EI], m/z 349 (M)+; Anal. Calcd. for C20H15NO5: C, 68.76; H, 4.33; N, 4.01. Found: C, 68.66; H, 4.33; N, 3.89.
Reaction SMILES: C([O:5][C:6]([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14]1[CH:19]=[CH:18][C:17]([CH2:20][N:21]2[C:25]([C:26](ON3C(=O)CCC3=O)=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=[C:22]2[CH2:38][CH2:39][CH2:40][CH3:41])=[CH:16][CH:15]=1)=[O:7])(C)(C)C.Cl.[NH:43]1[CH2:51][CH2:50][CH2:49][C@H:44]1[C:45]([O:47][CH3:48])=[O:46].Cl>C(N(CC)CC)C>[CH2:38]([C:22]1[N:21]([CH2:20][C:17]2[CH:16]=[CH:15][C:14]([C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=3[C:6]([OH:7])=[O:5])=[CH:19][CH:18]=2)[C:25]([C:26]([N:43]2[CH2:51][CH2:50][CH2:49][C@H:44]2[C:45]([O:47][CH3:48])=[O:46])=[O:27])=[C:24]([CH2:36][OH:37])[N:23]=1)[CH2:39][CH2:40][CH3:41]
Reactant: COC(=O)[C@@H]1CCCN1
Reactant: CCCCc1nc(CO)c(C(=O)ON2C(=O)CCC2=O)n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Agent: Cl
Solvent: CCN(CC)CC
Product: CCCCc1nc(CO)c(C(=O)N2CCC[C@H]2C(=O)OC)n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Following a procedure similar to that described in Example 53, but using 529 mg of succinimido 1-[(2'-t-butoxycarbonylbiphenyl-4-yl)methyl]-2-butyl-4-hydroxymethylimidazole-5-carboxylate [prepared as described in Example 52(a)], 180 mg of methyl (S)-prolinate hydrochloride and 0.2 ml of triethylamine, 0.39 g of the hydrochloride of the title compound was obtained as an amorphous powder, melting at above 120° C. (with softening).
Reaction SMILES: [C:1]([NH:3][C:4](=[O:25])[CH:5]([O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:10][CH:9]=1)[CH3:6])#[N:2].[C:26](=O)([O-])[O-].[K+].[K+].CI>CC(CC)=O>[C:1]([N:3]([CH3:26])[C:4](=[O:25])[CH:5]([O:7][C:8]1[CH:9]=[CH:10][C:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)=[CH:12][CH:13]=1)[CH3:6])#[N:2]
Reactant: O=C([O-])[O-]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)NC#N
Agent: [K+]
Solvent: CI
Solvent: CCC(C)=O
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)N(C)C#N
Reaction time: 2 h
Yield: 59.8 %

Procedure:
17.5 g (0.05 mole) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyanamide are dissolved in 60 ml of methylethyl ketone and with 7.6 g (0.055 mole) of potassium carbonate heated for 30 minutes to reflux. Then 3.6 ml (0.057 mole) of methyl iodide are added at 30° C. to the colourless suspension and the mixture is stirred for two hours at the same temperature. The reaction mixture is then filtered and the filtrate is concentrated by evaporation. The oily residue is chromatographed through silica gel eluted with petroleum ether/ethyl acetate (3:1) and the main fraction is concentrated by evaporation, affording 10.9 g (59.9% of theory) of 2-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid N-cyano-N-methylamide as a clear, colourless oil with a refractive index of nD23 =1.5228.
Reaction SMILES: [C:1]1([NH:7][N:8]=[C:9]([C:12]#[N:13])[C:10]#[N:11])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.NC1C=CC=CC=1.C(#N)CC#N.Cl.[Br:27][C:28]1[CH:33]=[CH:32][C:31]([NH:34][NH2:35])=[CH:30][CH:29]=1.[OH-].[Na+]>>[Br:27][C:28]1[CH:33]=[CH:32][C:31]([N:34]2[C:10]([NH2:11])=[C:9]([N:8]=[N:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[C:12]([NH2:13])=[N:35]2)=[CH:30][CH:29]=1
Reactant: N#CC(C#N)=NNc1ccccc1
Reactant: NNc1ccc(Br)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: N#CCC#N
Solvent: Nc1ccccc1
Product: Nc1nn(-c2ccc(Br)cc2)c(N)c1N=Nc1ccccc1
Temperature: 25 °C

Procedure:
1-(4-bromophenyl)-4-phenylazo-1H-pyrazole-3,5-diamine was prepared using 85 mg (0.5 mmol) of 2-(phenylhydrazono)malononitrile, which was derived from aniline (10 mL, 107 mmol) and malononitrile (161 mmol), and 4-bromophenylhydrazine hydrochloride (112 mg, 0.5 mmol) with the addition of 0.5 mL of 5% sodium hydroxide solution. Solids had not formed after heating the reaction at 75° C. for 3 hrs, however, analysis of the reaction solution by TLC indicated that no starting material remained. The solution was allowed to cool to ambient temperature and the solvent was evaporated. The residue was dissolved in methanol and then precipitated by the addition of water. The resulting solid was isolated by filtration and dried to yield 49 mg (27%) of the compound as a brown solid.
Reaction SMILES: Br[C:2]1[CH:9]=[C:8]([F:10])[CH:7]=[CH:6][C:3]=1[C:4]#[N:5].[O:11]1[CH:15]=[CH:14][CH:13]=[C:12]1B(O)O.C([O-])([O-])=O.[Na+].[Na+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].COCCOC>[F:10][C:8]1[CH:7]=[CH:6][C:3]([C:4]#[N:5])=[C:2]([C:12]2[O:11][CH:15]=[CH:14][CH:13]=2)[CH:9]=1
Reactant: OB(O)c1ccco1
Reactant: N#Cc1ccc(F)cc1Br
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: COCCOC
Product: N#Cc1ccc(F)cc1-c1ccco1
Yield: 35 %

Procedure:
Following the same procedure used for AUP01158-1, AUP01160-1 was prepared from 2-bromo-4-fluorobenzonitrile (5.0 g, 25.0 mmol), furan-2-ylboronic acid (3.36 g, 30.0 mmol), Pd2(dba)3 (100 mg), 1,2-dimethoxyethane (25 mL) and 2M Na2CO3 (40 mL). The crude was purified by Combiflash chromatography (24 g column, 8 g silica., gradient of eluent from PE to PE/EtOac 9/1) to give the title compound as a light yellow solid. This solid had to be purified an ultimate time by drying under vacuum at 40° C. for 5 days. Finally, pure expected compound was obtained as a white off solid in 35% yield (1.65 g); mp 55-56° C.; 1H NMR (270 MHz, CDCl3) δ 6.58-6.59 (1H, m, ArH), 7.02 (1H, td, J=2.7 and 8.0 Hz, ArH), 7.40 (1H, d, J=3.6 Hz, ArH), 7.57 (1H, s, ArH), 7.62 (1H, d, J=2.7 Hz, ArH), 7.70 (1H, dd, J=5.5 and 7.7 Hz, ArH); HRMS (ESI) calcd. for C11H7FNO (M+H)+188.0506. found 188.0513.
Reaction SMILES: [Br:1][C:2]1[CH:6]=[C:5]([CH2:7][OH:8])[S:4][CH:3]=1.C(N(CC)CC)C.CS(Cl)(=O)=O.[I-].[Na+].C(=O)([O-])[O-].[K+].[K+].O[C:30]1[CH:31]=[C:32]([C:40]([O:42][CH3:43])=[O:41])[C:33](=[CH:38][CH:39]=1)[C:34]([O:36][CH3:37])=[O:35]>>[Br:1][C:2]1[CH:6]=[C:5]([CH2:7][O:8][C:38]2[CH:39]=[CH:30][CH:31]=[C:32]([C:40]([O:42][CH3:43])=[O:41])[C:33]=2[C:34]([O:36][CH3:37])=[O:35])[S:4][CH:3]=1
Reactant: COC(=O)c1ccc(O)cc1C(=O)OC
Reactant: OCc1cc(Br)cs1
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [I-]
Solvent: CCN(CC)CC
Product: COC(=O)c1cccc(OCc2cc(Br)cs2)c1C(=O)OC

Procedure:
In a manner similar to that of Example 9(i), by reaction of 20 g (103 mmol) of (3-bromo-5-thienyl)methanol with 21.6 mL (155 mmol) of triethylamine and 8.8 mL (114 mmol) of methanesulphonyl chloride, followed by 500 mg (3.5 mmol) of sodium iodide, 14.3 g (103 mmol) of potassium carbonate and 21.7 g (103 mmol) of dimethyl 4-hydroxyphthalate, the desired product is obtained in the form of orange-coloured crystals (m.p.=65° C.; m=27 g; Y=74%).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=1)#[N:2].[C:18](OC)(=[O:26])[C:19]1[C:20](=[CH:22][CH:23]=[CH:24][CH:25]=1)[SH:21].C(N(CC)CC)C>C1(C)C=CC=CC=1>[O:26]=[C:18]1[C:19]2[CH:25]=[CH:24][CH:23]=[CH:22][C:20]=2[S:21][C:1]([C:3]2[CH:8]=[C:7](/[CH:9]=[CH:10]/[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH:6]=[CH:5][N:4]=2)=[N:2]1
Reactant: COC(=O)c1ccccc1S
Reactant: CC(C)(C)OC(=O)/C=C/c1ccnc(C#N)c1
Solvent: CCN(CC)CC
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)/C=C/c1ccnc(-c2nc(=O)c3ccccc3s2)c1
Yield: 13.6 %

Procedure:
tert-Butyl (E)-3-(2-cyano-4-pyridyl)acrylate (0.84 g, 3.2 mmol) and methyl thiosalicylate (0.74 g, 4.4 mmol) were dissolved in toluene (3 ml), and triethylamine (0.77 ml, 5.5 mmol) was added thereto. The reaction mixture was refluxed for 7 hrs and subjected to a silica gel (50 g) column chromatography. The fractions eluted with hexane-ethyl acetate (3:1, v/v) were collected and concentrated. The residue was recrystallized from ethyl acetate-isopropyl ether to give the titled compound (0.16 g, 17%) as white crystals.
Reaction SMILES: [Cl-].[CH2:2]([P+:10]([CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:11][CH2:12][OH:13])[CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9].COC1C=CC(O)=CC=1.[C:39]([Cl:44])(=[O:43])[C:40]([CH3:42])=[CH2:41]>C(#N)C>[Cl-:44].[CH2:22]([P+:10]([CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH3:9])([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21])[CH2:11][CH2:12][O:13][C:39](=[O:43])[C:40]([CH3:42])=[CH2:41])[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: C=C(C)C(=O)Cl
Reactant: CCCCCCCC[P+](CCO)(CCCCCCCC)CCCCCCCC
Agent: COc1ccc(O)cc1
Agent: [Cl-]
Solvent: CC#N
Product: C=C(C)C(=O)OCC[P+](CCCCCCCC)(CCCCCCCC)CCCCCCCC
Reaction time: 2 h

Procedure:
Into a 1 L-four-necked flask equipped with a stirrer, a thermometer and a distillation line, was added the obtained tri-n-octyl(2-hydroxyethyl)phosphonium chloride dissolved in 500 ml of acetonitrile. The solution was heated under a normal pressure while stirring and about 200 ml of acetonitrile was distilled. A condenser having a calcium chloride tube was installed, 1.5 g of hydroquinone monomethyl ether was added as a polymerization inhibitor, and 42.3 g (0.405 mol) of methacryloyl chloride was added thereto dropwise at 50° C. over 2 hours through a dropping funnel, then the solution was maturated for 3 hours at the same temperature as above. The absence of an unreacted substance was confirmed by FT-IR, and the reaction solution was concentrated and dried with a vacuum pump to give 209.2 g of a slightly yellow viscous liquid. The titration purity was 97.1% and the yield was 96.6%.