Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH3:10])=[O:8].OC1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1>CCCCO.CCCCO.CCCCO.CCCCO.[Ti].CO>[CH3:1][C:2]1[O:3][C:4]([CH3:11])=[CH:5][C:6]=1[C:7]([O:9][CH:10]1[CH2:18][C:17]([CH3:20])([CH3:19])[NH:16][C:15]([CH3:22])([CH3:21])[CH2:14]1)=[O:8]
Reactant: CC1(C)CC(O)CC(C)(C)N1
Reactant: COC(=O)c1cc(C)oc1C
Agent: [Ti]
Solvent: CO
Solvent: CCCCO
Product: Cc1cc(C(=O)OC2CC(C)(C)NC(C)(C)C2)c(C)o1

Procedure:
154 g (1 mole) of methyl 2,5-dimethylfuran-3-carboxylate and 157 g (1 mole) of 4-hydroxy-2,2,6,6-tetramethylpiperidine were heated together with 10 g of tetrabutyl orthotitanate for 10 hours at about 190° C., the methanol formed being distilled off. When the reaction is complete, the mixture is cooled and the reaction mass is dissolved in ethyl acetate. The solution is extracted by shaking, first with 10% strength sodium carbonate solution and then with water, after which it is dried and evaporated down, and the residue is distilled under reduced pressure. The desired product distils at 142° C./2 mm as a virtually colorless oil which soon solidifies to a solid of melting point 59°-61° C.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=[O:6].[Cl:12][C:13]1[C:18]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[C:15]([CH3:24])[N:14]=1.[O-]S([O-])(=S)=O.[Na+].[Na+]>ClCCl>[Cl:12][C:13]1[C:18]([C:19]2([F:23])[CH2:22][CH2:21][CH2:20]2)=[CH:17][CH:16]=[C:15]([CH3:24])[N+:14]=1[O-:6]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: Cc1ccc(C2(F)CCC2)c(Cl)n1
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(C2(F)CCC2)c(Cl)[n+]1[O-]
Temperature: 25 °C
Reaction time: 72 h
Yield: 75 %

Procedure:
3-Chlorobenzoperoxoic acid (173 mg, 1.00 mmol) was added in 2 portions to a solution of 2-chloro-3-(1-fluorocyclobutyl)-6-methylpyridine (Example 130 b, 100 mg, 501 μmol) in dichloromethane (2 mL). The reaction mixture was stirred at ambient temperature for 72 h, poured onto a 10% aqueous Na2S2O3 solution (30 mL) and extracted with dichloromethane (2×40 mL). The combined organic layers were washed with ice water/brine (30 mL), dried over Na2SO4 and concentrated in vacuo. The residue was dissolved in dichloromethane, washed with sat. NaHCO3 solution (30 mL) and ice water (30 mL), dried over Na2SO4 and concentrated in vacuo to give the title compound (81 mg, 74%) as yellow oil, MS (ESI): m/e=216.3 [MH+].
Reaction SMILES: Br.Br[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2.[CH3:31][S:32]([N:35]1[CH2:40][C@@H:39]([CH3:41])[NH:38][C@@H:37]([CH3:42])[CH2:36]1)(=[O:34])=[O:33].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[CH3:42][C@@H:37]1[CH2:36][N:35]([S:32]([CH3:31])(=[O:34])=[O:33])[CH2:40][C@H:39]([CH3:41])[N:38]1[CH2:3][C:4]1[N:5]([CH3:30])[C:6]2[C:11]([N:12]=1)=[C:10]([N:13]1[CH2:18][CH2:17][O:16][CH2:15][CH2:14]1)[N:9]=[C:8]([N:19]1[C:23]3[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=3[N:21]=[C:20]1[CH2:28][CH3:29])[N:7]=2
Reactant: C[C@@H]1CN(S(C)(=O)=O)C[C@H](C)N1
Reactant: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Agent: Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3[C@H](C)CN(S(C)(=O)=O)C[C@@H]3C)n(C)c2n1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture of 8-bromomethyl-2-(2-ethylbenzoimidazol-1-yl)-9-methyl-6-morpholin-4-yl-9H-purine hydrobromide (200 mg, 0.37 mmol), (3S,5R)-1-methanesulfonyl-3,5-dimethylpiperazine (88 mg, 0.46 mmol) and K2CO3 (150 mg, 1.09 mmol) in DMF (1 mL) was allowed to stir at r.t. for 24 h. The reaction mixture was partitioned between EtOAc and H2O, the organic phase dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography (Si-PCC, MeOH:EtOAc, 0-10%) followed by recrystallisation from EtOAc affording 737 (57 mg, 28%). LCMS (method I): RT 3.05 min, [M+H]+ 568.2. 1H NMR (CDCl3, 400 MHz): δ 8.02-7.98 (1 H, m), 7.76-7.75 (1 H, m), 7.26-7.25 (2 H, m), 4.34 (4 H, s), 4.18 (2 H, s), 3.87 (4 H, t, J=4.70 Hz), 3.84 (3 H, s), 3.54-3.51 (2 H, m), 3.35 (2 H, q, J=7.48 Hz), 3.29-3.23 (2 H, m), 2.80 (3 H, s), 2.68-2.66 (2 H, m), 1.45 (3 H, dd, J=7.69, 7.26 Hz), 1.17 (6 H, d, J=6.36 Hz)
Reaction SMILES: [NH2:1][C:2]1[N:7]=[CH:6][C:5](/[CH:8]=[CH:9]/[C:10]([NH:12][CH2:13][C:14]([N:16]([C:18]2[C:19]([Cl:39])=[C:20]([C:35]([Cl:38])=[CH:36][CH:37]=2)[CH2:21][O:22][C:23]2[C:31]3[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=3[CH:26]=[CH:25][CH:24]=2)[CH3:17])=[O:15])=[O:11])=[CH:4][CH:3]=1.C(N(CC)CC)C.Cl.[CH3:48][C:49]1[C:54]([C:55](Cl)=[O:56])=[CH:53][CH:52]=[CH:51][N:50]=1>ClCCl>[Cl:39][C:19]1[C:18]([N:16]([CH3:17])[C:14](=[O:15])[CH2:13][NH:12][C:10](=[O:11])/[CH:9]=[CH:8]/[C:5]2[CH:6]=[N:7][C:2]([NH:1][C:55]([C:54]3[C:49]([CH3:48])=[N:50][CH:51]=[CH:52][CH:53]=3)=[O:56])=[CH:3][CH:4]=2)=[CH:37][CH:36]=[C:35]([Cl:38])[C:20]=1[CH2:21][O:22][C:23]1[C:31]2[N:30]=[C:29]([O:32][CH3:33])[N:28]([CH3:34])[C:27]=2[CH:26]=[CH:25][CH:24]=1
Reactant: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(N)nc4)c3Cl)cccc2n1C
Reactant: Cc1ncccc1C(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1nc2c(OCc3c(Cl)ccc(N(C)C(=O)CNC(=O)/C=C/c4ccc(NC(=O)c5cccnc5C)nc4)c3Cl)cccc2n1C
Reaction time: 0.25 h
Yield: 81.9 %

Procedure:
To a solution of 4-[3-[N-[(E)-3-(6-aminopyridin-3-yl)acryloylglycyl]-N-methylamino]-2,6-dichlorobenzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (100 mg) and triethylamine (53.3 mg) in dichloromethane (2 ml) was added 2-methyl-3-pyridinecarbonyl chloride hydrochloride (74.2 mg) under ice-cooling, and the mixture was stirred for 15 minutes at the same temperature and then for 3 hours at ambient temperature. The reaction mixture was concentrated, and the residue was dissolved in methanol (3 ml). To the solution was added 1N sodium hydroxide solution (0.5 ml), and the mixture was stirred for 1 hour. Chloroform was added to the reaction mixture, and the solution was washed with water and brine, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (chloroform:methanol, 10:1, v/v) to give 4-[2,6-dichloro-3-[N-methyl-N-[(E)-3-[6-(2-methylpyridin-3-carboxamido)pyridin-3-yl]acryloylglycyl]amino]benzyloxy]-2-methoxy-1-methyl-1H-benzimidazole (99 mg).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[O:5][C:4](=[O:10])[CH:3]=1.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17].O>CN(C)C=O>[Si:16]([O:9][CH2:8][C:6]1[O:5][C:4](=[O:10])[CH:3]=[C:2]([OH:1])[CH:7]=1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: O=c1cc(O)cc(CO)o1
Agent: c1c[nH]cn1
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)[Si](C)(C)OCc1cc(O)cc(=O)o1
Yield: 47 %

Procedure:
4-Hydroxy-6-hydroxymethylpyran-2-one (14.6 parts) was dissolved in dimethyl formamide (30 parts) at 20° C., imidazole (17.2 parts) was added and the temperature of the mixture cooled to 13° C. t-Butyldimethylsilyl chloride (17.1 parts) was then added in portions, the temperature was allowed to rise to 25° C. and maintained at 25°-30° C. by external cooling. The mixture was stirred for a further hour at 25°-30° C., before pouring into water (1100 parts) and stirring for 30 minutes until the product crystallised. The product was filtered off, washed with water (2×200 parts) and dried at 40° C./20 mm to give 6-t-butyldimethylsilyloxymethyl-4-hydroxy pyran-2-one (12.1 parts, 47%) m.pt 139°-141° C. Extraction of the filtrates with dichlorometane gave a further 7.0 parts, 27% of the product.
Reaction SMILES: [CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[CH:18]=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Cl:28]N1C(=O)CCC1=O>O1CCOCC1>[CH2:1]([N:8]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH:9]1[CH2:15][CH2:14][CH2:13][C:12]2[CH:16]=[C:17]([OH:20])[C:18]([Cl:28])=[CH:19][C:11]=2[CH2:10]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)ccc2C1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1ccccc1)C1CCCc2cc(O)c(Cl)cc2C1
Temperature: 25 °C
Yield: 76.6 %

Procedure:
A solution of N-benzyl-N-(6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (166 mg) and N-chlorosuccinimide (66.4 mg) in 1,4-dioxane (2 ml) was refluxed for 28 hours, cooled to room temperature, and partitioned between ethyl acetate and brine. The organic layer was separated, washed with brine, dried over sodium sulfate, and evaporated in vacuo. The residue was chromatographed (toluene -ethyl acetate) over silica gel (3.6 g) to afford N-benzyl-N-(3-chloro-6,7,8,9-tetrahydro-2-hydroxy-5H-benzocyclohepten-6-yl)-tert-butoxycarbonylamine (139 mg) as a colorless gum.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH3:41])[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21](Cl)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:37][CH2:36][CH2:35][CH2:34]4)(=[O:32])=[O:31])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:4][CH:3]=1.Cl.Cl.[N:44]1([CH2:50][CH2:51][NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]1>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C@@:8]2([CH3:41])[C@:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)([CH3:13])[N:11]([C:21]([N:47]3[CH2:48][CH2:49][N:44]([CH2:50][CH2:51][NH:52][S:53]([CH3:56])(=[O:55])=[O:54])[CH2:45][CH2:46]3)=[O:22])[C:10]([C:24]3[CH:29]=[CH:28][C:27]([S:30]([N:33]4[CH2:34][CH2:35][CH2:36][CH2:37]4)(=[O:31])=[O:32])=[CH:26][C:25]=3[O:38][CH2:39][CH3:40])=[N:9]2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)NCCN1CCNCC1
Reactant: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=NC(C)(c2ccc(Cl)cc2)C(C)(c2ccc(Cl)cc2)N1C(=O)Cl
Agent: Cl
Product: CCOc1cc(S(=O)(=O)N2CCCC2)ccc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCN(CCNS(C)(=O)=O)CC1

Procedure:
In a manner analogous to the method described in example 5, rac-(4S*,5R*)-4,5-bis-(4-chloro-phenyl)-2-[2-ethoxy-4-(pyrrolidine-1-sulfonyl)-phenyl]-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl chloride was reacted with N-(2-piperazin-1-yl-ethyl)-methanesulfonamide dihydrochloride (prepared as described in Fotouhi, N. et al. WO 2005110996) to give the title compound as a racemic mixture. The enantiomers were then separated by supercritical fluid chromatography (Berger Instrument Multi-Gram II, Daicel ChiralPak OD-H 3×25 cm, 35° C. at 100 bar, eluting with 35% methanol in carbon dioxide). HR-MS (ES, m/z) calculated for C37H46N6O6S2Cl2 [(M+H)+] 805.2370, observed 805.2372.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1.C(N(CC)CC)C.[O:22](S(C(F)(F)F)(=O)=O)[S:23]([C:26]([F:29])([F:28])[F:27])(=O)=[O:24].C([O-])(O)=O.[Na+]>C(Cl)Cl>[F:27][C:26]([F:29])([F:28])[S:23]([O:1][C:2]1[CH:7]=[N:6][N:5]([CH:8]2[CH2:13][CH2:12][CH2:11][CH2:10][O:9]2)[C:4](=[O:14])[CH:3]=1)(=[O:24])=[O:22]
Reactant: O=c1cc(O)cnn1C1CCCCO1
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=c1cc(OS(=O)(=O)C(F)(F)F)cnn1C1CCCCO1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 57.9 %

Procedure:
5-Hydroxy-2-(tetrahydro-2H-pyran-2-yl)pyridazin-3(2H)-one (2.4 g, 13 mmol) dissolved in methylene chloride (75 mL) and cooled to 0° C. Triethylamine (3.5 mL, 25 mmol) and Tf2O (2.3 mL, 14 mmol) were added and the mixture stirred for a further 2.5 h. Saturated NaHCO3 solution was added and the organic phase removed, dried over Na2SO4 and concentrated. Purification by flash column chromatography (silica gel, EtOAc/hexanes) provided the title compound (2.47 g, 60%) as a yellow oil: 1H NMR (500 MHz, CDCl3) δ 7.85 (d, J=2.8 Hz, 1H), 6.86 (d, J=2.7 Hz, 1H), 6.01 (dd, J=10.2, 2.2 Hz, 1H), 4.15-4.12 (m, 1H), 3.75 (dt, J=11.6, 2.5 Hz, 1H), 2.18-2.02 (m, 2H), 1.78-1.66 (m, 3H), 1.62-1.55 (m, 1H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[N+:13]([O-:15])=[O:14])[NH:9][CH2:8][CH2:7][CH2:6]2.C(N(CC)CC)C.[C:23](Cl)(=[O:26])[CH:24]=[CH2:25]>ClCCl.CN(C)C1C=CN=CC=1.[Cl-].[NH4+]>[C:23]([N:9]1[C:10]2[C:5](=[CH:4][C:3]([O:2][CH3:1])=[C:12]([N+:13]([O-:15])=[O:14])[CH:11]=2)[CH2:6][CH2:7][CH2:8]1)(=[O:26])[CH:24]=[CH2:25]
Reactant: C=CC(=O)Cl
Reactant: COc1cc2c(cc1[N+](=O)[O-])NCCC2
Agent: CN(C)c1ccncc1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CC(=O)N1CCCc2cc(OC)c([N+](=O)[O-])cc21
Reaction time: 8 h

Procedure:
A mixture of 6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline (0.19 g, 0.91 mmol) and triethylamine (0.5 mL, 3.6 mmol, Aldrich) in dichloromethane was treated with dropwise addition of acryloyl chloride (0.3 mL, 3.7 mmol, Pfaltz and Bauer). A catalytic amount of 4-dimethylaminopyridine was added and the reaction stirred overnight. The mixture was diluted with saturated aqueous ammonium chloride and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered, and concentrated to give 1-acryloyl-6-(methyloxy)-7-nitro-1,2,3,4-tetrahydroquinoline which was taken directly to the next step without determination of yield. ESIMS (M+H)+=263.
Reaction SMILES: [CH3:1][C:2]1[C:3]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[N:4][C:5]([NH:8][C:9]2[CH:24]=[CH:23][C:12]([C:13]([NH:15][CH:16]3[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]3)=[O:14])=[CH:11][C:10]=2[N+:25]([O-:27])=[O:26])=[N:6][CH:7]=1.[N:34]([C:37]1[CH:44]=[CH:43][C:40]([C:41]#[N:42])=[CH:39][CH:38]=1)=[C:35]=[O:36].C(N(CC)CC)C>C(Cl)Cl>[C:41]([C:40]1[CH:39]=[CH:38][C:37]([NH:34][C:35]([N:31]2[CH2:32][CH2:33][N:28]([C:3]3[C:2]([CH3:1])=[CH:7][N:6]=[C:5]([NH:8][C:9]4[CH:24]=[CH:23][C:12]([C:13](=[O:14])[NH:15][CH:16]5[CH2:21][CH2:20][N:19]([CH3:22])[CH2:18][CH2:17]5)=[CH:11][C:10]=4[N+:25]([O-:27])=[O:26])[N:4]=3)[CH2:29][CH2:30]2)=[O:36])=[CH:44][CH:43]=1)#[N:42]
Reactant: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCNCC1
Reactant: N#Cc1ccc(N=C=O)cc1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cnc(Nc2ccc(C(=O)NC3CCN(C)CC3)cc2[N+](=O)[O-])nc1N1CCN(C(=O)Nc2ccc(C#N)cc2)CC1
Temperature: 23 °C
Reaction time: 16 h
Yield: 222 %

Procedure:
To a solution of 4-((5-methyl-4-(piperazin-1-yl)pyrimidin-2-yl)amino)-N-(1-methylpiperidin-4-yl)-3-nitrobenzamide (0.073 mmol) in DCM (1.5 mL) was added 4-isocyanatobenzonitrile (23 mg, 0.16 mmol) and triethylamine (0.055 mL, 0.39 mmol) and the mixture was stirred at 23° C. for 16 h. reaction. The crude reaction mixture was filtered and washed with minimal volume of DCM and then hexanes to give the title compound (97 mg, 100%). MS (ES+) C30H34N10O4 requires: 598. found: 599 [M+H]+.
Reaction SMILES: [F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([O:23]CC)=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1.[OH-].[Na+].Cl>C(O)C.O>[F:1][C:2]1[CH:29]=[CH:28][C:5]([CH2:6][NH:7][C:8](=[O:27])[CH2:9][N:10]2[CH2:14][CH2:13][N:12]([C:15]3[S:16][C:17]([C:21]([OH:23])=[O:22])=[C:18]([CH3:20])[N:19]=3)[C:11]2=[O:26])=[CH:4][CH:3]=1
Reactant: CCOC(=O)c1sc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)nc1C
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: Cc1nc(N2CCN(CC(=O)NCc3ccc(F)cc3)C2=O)sc1C(=O)O
Temperature: 0 °C
Yield: 95.6 %

Procedure:
A mixture of ethyl 2-(3-(2-(4-fluorobenzylamino)-2-oxoethyl)-2-oxoimidazolidin-1-yl)-4-methylthiazole-5-carboxylate (0.20 g, 0.48 mmol) and 1 N aqueous sodium hydroxide solution (1.0 mL, 1.0 mmol) in ethanol (2 mL) was stirred at reflux for 1 h, cooled to 0° C. and acidified with 10% aqueous hydrochloric acid to pH˜2. The mixture was diluted with water (25 mL), and the aqueous layer was extracted with dichloromethane (2×50 mL). The aqueous layer was concentrated to dryness in vacuo to afford the crude title compound as an off-white foamy solid (0.18 g): MS (ES+) m/z 393.2 (M+1).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6](B(O)O)[CH:7]=1.Cl[C:13]1[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.O1CCOCC1.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([C:13]2[CH:22]=[CH:21][C:16]([C:17]([O:19][CH3:20])=[O:18])=[CH:15][N:14]=2)[CH:7]=1
Reactant: OB(O)c1cc(F)ccc1O
Reactant: COC(=O)c1ccc(Cl)nc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Solvent: O
Product: COC(=O)c1ccc(-c2cc(F)ccc2O)nc1
Temperature: 80 °C
Reaction time: 2 h
Yield: 57.4 %

Procedure:
To a degassed mixture of 1,4-dioxane:water (4:1, 15 mls) was added (5-fluoro-2-hydroxyphenyl)boronic acid (0.781 g, 5.0 mmol), methyl 6-chloronicotinate (0.86 g, 5.0 mmol), potassium carbonate (2.08 g, 15.0 mmol) and tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) and the resulting mixture stirred at 80° C. for 2 h. After this time additional tetrakis(triphenylphosphine)palladium(0) (0.29 g, 0.05 mmol) was added and then heating continued at 80° C. for 3 h. The mixture was then stirred at room temperature overnight. The solvent was evaporated in vacuo and the residue suspended in ethyl acetate (50 ml). The suspension was filtered through a plug of arbocel and the filtrate concentrated in vacuo. The resulting residue was dissolved in ethyl acetate (100 ml) and washed with saturated aqueous sodium carbonate (3×100 ml). The aqueous washings were combined and extracted with ethyl acetate (3×50 ml). The ethyl acetate layers were combined, dried with anhydrous MgSO4 and concentrated in vacuo to afford a solid which was recrystallised from dichloromethane/heptane to afford the title compound as a yellow solid (0.71 g) (57%). 1H NMR (400 MHz, CDCl3) □ ppm 9.14 (1H, s), 8.46-8.40 (1H, m), 7.91-7.86 (1H, m) 7.53-7.46 (1H, m), 7.11-7.03 (1H, m), 7.02-6.96 (1H, m), 3.99 (3H, s). LRMS: AP m/z 248 [M+H]+.
Reaction SMILES: C(OP([CH:9]([CH:12]([CH3:14])[CH3:13])[C:10]#[N:11])(OCC)=O)C.C[Si]([N-][Si](C)(C)C)(C)C.[K+].O[CH2:26][CH:27]=[C:28]([CH2:30][CH2:31][CH:32]=[C:33]([CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[CH3:34])[CH3:29].O>C1(C)C=CC=CC=1>[CH3:14][CH:12]([C:9](=[CH:26][CH:27]=[C:28]([CH3:29])[CH2:30][CH2:31][CH:32]=[C:33]([CH3:34])[CH2:35][CH2:36][CH:37]=[C:38]([CH3:40])[CH3:39])[C:10]#[N:11])[CH3:13]
Reactant: CCOP(=O)(OCC)C(C#N)C(C)C
Reactant: CC(C)=CCCC(C)=CCCC(C)=CCO
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: O
Product: CC(C)=CCCC(C)=CCCC(C)=CC=C(C#N)C(C)C
Temperature: -70 °C
Yield: 94.9 %

Procedure:
To a solution of 2-(diethylphosphono)isovaleronitrile (8.72 g, 40 mmol) in toluene (75 ml) was gradually added a 0.5 M solution of potassium bis(trimethylsilyl)amide in toluene (75 ml) with stirring at -70° C. under argon atmosphere. The cooling bath was removed, and the reaction mixture was stirred at room temperature for 30 minutes. The reaction mixture was cooled to -70° C. again, and farnesol (5.88 g, 26.7 mmol) was added thereto with stirring, and the mixture was allowed to warm to room temperature. After addition of water, the organic layer was separated, washed with saturated aqueous sodium bicarbonate and then saturated aqueous sodium chloride, and dried over MgSO4. The organic layer was separated from MgSO4 by filtration and concentrated to give a residue, which was purified with silica gel column chromatography (solvent: n-hexane/ethyl acetate=100:1) to obtain the aimed 2 -(1-methylethyl)-5,9,13-trimethyl-2,4,8,12-tetradecatetraenenitrile (7.23 g, 96%; 2Z:2E=25.6:1).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]2)=[C:8]([Cl:18])[CH:7]=1)[CH3:2].[CH2:20]([O:22][C:23](=[O:26])[CH:24]=[CH2:25])[CH3:21].[Na].C(O)(=O)C>C(O)C>[CH2:1]([O:3][C:4](=[O:19])[CH:5]([C:6]1[CH:11]=[CH:10][C:9]([CH:12]2[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]2)=[C:8]([Cl:18])[CH:7]=1)[CH2:25][CH2:24][C:23]([O:22][CH2:20][CH3:21])=[O:26])[CH3:2]
Reactant: C=CC(=O)OCC
Reactant: CCOC(=O)Cc1ccc(C2CCCCC2)c(Cl)c1
Agent: [Na]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)CCC(C(=O)OCC)c1ccc(C2CCCCC2)c(Cl)c1
Temperature: 0 °C
Yield: 44.2 %

Procedure:
A mixture of 40.5 g of 3-chloro-4-cyclohexylphenylacetic acid ethyl ester and 16 g of acrylic acid ethyl ester is added dropwise to a solution of 3.6 g of sodium in 60 ml of ethanol. The solution is refluxed overnight and then poured into a mixture of 10 ml of glacial acetic acid and 170 ml of ice water. The ethanol is distilled off and the residue extracted with ethyl acetate and evaporated; the residue is distilled under a high vacuum, to yield 24.3 g of 2-(3-chloro-4-cyclohexylphenyl)-glutaric acid diethyl ester boiling at 203°-205°C under 0.4 mm Hg pressure.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:29]=[CH:28][C:27]([C:30]#[N:31])=[CH:26][CH:25]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[C:7]=1[F:22])[CH3:2].C(N(CC)CC)C.Br[CH2:41][CH2:42][OH:43]>C1COCC1.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([NH:23][C:24]1[CH:25]=[CH:26][C:27]([C:30]#[N:31])=[CH:28][CH:29]=1)[C:6]1[CH:11]=[C:10]([O:12][CH2:13][CH3:14])[CH:9]=[C:8]([O:15][CH:16]2[CH2:17][CH2:18][N:19]([CH2:41][CH2:42][OH:43])[CH2:20][CH2:21]2)[C:7]=1[F:22])[CH3:2]
Reactant: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCNCC2)c1F
Reactant: OCCBr
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCOC(=O)C(Nc1ccc(C#N)cc1)c1cc(OCC)cc(OC2CCN(CCO)CC2)c1F
Temperature: 50 °C

Procedure:
A solution of 300 mg (RS)-(4-cyano-phenylamino)-[5-ethoxy-2-fluoro-3-(piperidin-4-yloxy)-phenyl]-acetic acid ethyl ester described in example 11.2 in 10 ml THF was treated with 0.19 ml triethylamine, 0.82 ml 2-bromoethanol and 25 mg tetrabutylammonium iodide. The reaction mixture was heated to 50° C. for 6 hrs, then evaporated. The residue was taken up in water and extracted with EtOAc. The crude product was purified by chromatography on silica with dichloromethane/MeOH 9:1 to give 175 mg (RS)-(4-cyano-phenylamino)-{5-ethoxy-2-fluoro-3-[1-(2-hydroxy-ethyl)-piperidin-4-yloxy]-phenyl}acetic acid ethyl ester. MS: 486.4 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12]OS(C)(=O)=O)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:3][CH2:2]1.[CH3:26][N:27]1[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]1>>[CH:1]1([CH2:4][N:5]2[C:10](=[O:11])[C:9]([CH2:12][N:30]3[CH2:31][CH2:32][N:27]([CH3:26])[CH2:28][CH2:29]3)=[CH:8][C:7]([C:18]3[CH:23]=[CH:22][C:21]([S:24][CH3:25])=[CH:20][CH:19]=3)=[N:6]2)[CH2:2][CH2:3]1
Reactant: CN1CCNCC1
Reactant: CSc1ccc(-c2cc(COS(C)(=O)=O)c(=O)n(CC3CC3)n2)cc1
Product: CSc1ccc(-c2cc(CN3CCN(C)CC3)c(=O)n(CC3CC3)n2)cc1
Yield: 85.7 %

Procedure:
Following the procedure of Example 1(10), 2-cyclopropylmethyl-4-methanesulfonyloxymethyl-6-[4-(methylthio)phenyl]-2H-pyridazin-3-one and 1-methylpiperazine were reacted to yield the title compound as a yellow oil (yield: 85.7%).