Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][C:11](=[O:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:21])([CH3:20])[C:17]([OH:19])=[O:18])[CH2:6][CH2:5]1)([OH:3])=[O:2].[OH-].[Na+].[BH4-].[Na+].Cl>CC(O)C.O>[C:1]([C:4]1([CH2:7][CH2:8][CH2:9][CH2:10][CH:11]([OH:22])[CH2:12][CH2:13][CH2:14][CH2:15][C:16]([CH3:20])([CH3:21])[C:17]([OH:19])=[O:18])[CH2:5][CH2:6]1)([OH:3])=[O:2]
Reactant: CC(C)(CCCCC(=O)CCCCC1(C(=O)O)CC1)C(=O)O
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CC(C)O
Product: CC(C)(CCCCC(O)CCCCC1(C(=O)O)CC1)C(=O)O
Reaction time: 0.08 h
Yield: 93.9 %

Procedure:
To a mixture of 11-(1-carboxycyclopropyl)-2,2-dimethyl-7-oxoundecanoic acid (3.63 g, >90% pure by NMR, 10.4 mmol) in iPrOH (20 mL) and H2O (20 mL) was added NaOH (0.94 g, 23.5 mmol). After 5 min of stirring, NaBH4 (0.24 g, 6.3 mmol) was added to the resulting clear solution. After 19 h, the mixture was acidified to pH-1 with aqueous HCl (2M) and extracted with Et2O (3×50 mL). The combined organic phases were washed with brine (1×50 mL), dried (Na2SO4) and evaporated in vacuo. The remaining residue was coevaporated in vacuo from EtOAc to give 11-(1-carboxycyclopropyl)-7-hydroxy-2,2-dimethylundecanoic acid (3.43 g, 93%, contains 8% (%) EtOAc and 3% (w/w) iPrOH) as a viscous colorless oil. 1H NMR (CD3OD): δ=3.5 (br s, 1H), 1.56-1.27 (m, 16H), 1.16 (s, 6H), 1.16-1.14 (m, 2H), 0.72 (dd, J=3.4, 6.6 Hz, 2H). 13C NMR (CD3OD): δ=181.6, 179.1, 72.3, 43.1, 42.0, 38.5, 38.4, 35.2, 29.0, 27.5, 27.1, 26.4, 26.0, 25.9, 24.4, 16.43, 16.38. HRMS calcd for C12H31O5 (M+H+): 315.2171, found 315.2175.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:27]=[CH:26][C:25]([C:28]4[CH:33]=[CH:32][C:31](B5OC(C)(C)C(C)(C)O5)=[CH:30][CH:29]=4)=[CH:24][CH:23]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:43]([O:47][C:48]([N:50]1[CH2:54][CH2:53][CH2:52][CH:51]1[C:55]1[N:56]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[C:57](Br)=[CH:58][N:59]=1)=[O:49])([CH3:46])([CH3:45])[CH3:44].C(=O)([O-])[O-].[K+].[K+]>COCCOC.O.C(OCC)(=O)C.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.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][CH2:10][CH:9]1[C:13]1[NH:17][C:16]2[CH:18]=[C:19]([C:22]3[CH:23]=[CH:24][C:25]([C:28]4[CH:29]=[CH:30][C:31]([C:57]5[N:56]([CH2:61][O:62][CH2:63][CH2:64][Si:65]([CH3:68])([CH3:67])[CH3:66])[C:55]([CH:51]6[CH2:52][CH2:53][CH2:54][N:50]6[C:48]([O:47][C:43]([CH3:46])([CH3:45])[CH3:44])=[O:49])=[N:59][CH:58]=5)=[CH:32][CH:33]=4)=[CH:26][CH:27]=3)[CH:20]=[CH:21][C:15]=2[N:14]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)cc3)cc2[nH]1
Reactant: CC(C)(C)OC(=O)N1CCCC1c1ncc(Br)n1COCC[Si](C)(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: O
Solvent: COCCOC
Product: CC(C)(C)OC(=O)N1CCCC1c1nc2ccc(-c3ccc(-c4ccc(-c5cnc(C6CCCN6C(=O)OC(C)(C)C)n5COCC[Si](C)(C)C)cc4)cc3)cc2[nH]1
Temperature: 90 °C
Yield: 24.8 %

Procedure:
A mixture of 2-{6-[4′-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-biphenyl-4-yl]-1H-benzoimidazol-2-yl}-pyrrolidine-1-carboxylic acid tert-butyl ester (147 mg, 0.26 mmol), 2-[5-bromo-1-(2-trimethylsilanyl-ethoxymethyl)-1H-imidazol-2-yl]-pyrrolidine-1-carboxylic acid tert-butyl ester (116 mg, 0.26 mmol), tetrakis(triphenylphosphine)palladium (30 mg, 0.026 mmol), Pd(dppf)Cl2 (21 mg, 0.026 mmol) and potassium carbonate (72 mg, 0.52 mmol) in 3 ml 1,2-dimethoxyethane and 1 mL water was heated to 90° C. for 2.5 hours. The reaction mixture was cooled and dissolved in ethyl acetate and washed with 5% lithium chloride aqueous solution. The organic layer was dried (MgSO4), concentrated and purified by preparative reverse phase HPLC (GEMINI, 5 to 100% ACN/H2O+0.1% TFA). Product was lyophilized to give 2-(6-{4′-[2-(1-Boc-pyrrolidin-2-yl)-3-(2-trimethylsilanyl-ethoxymethyl)-3H-imidazol-4-yl]-biphenyl-4-yl}-1H-benzoimidazol-2-yl)-pyrrolidine-1-carboxylic acid tert-butyl ester (52 mg, yield 25%); LCMS-ESI+: calc'd for C46H60N6O5Si: 805.09. Found: 805.1 (M+H+).
Reaction SMILES: [CH3:1][C:2]1([CH3:29])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([OH:18])=O)[C:5]=2[C@@H:4]2[CH2:24][C:25]([CH3:28])=[CH:26][CH2:27][C@@H:3]12.C(Cl)(=O)C(Cl)=O.[NH2:36][CH2:37][CH2:38][C:39]1[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=1.Cl.O>C1C=CC=CC=1.[OH-].[Na+]>[CH3:29][C:2]1([CH3:1])[O:7][C:6]2[CH:8]=[C:9]([CH2:19][CH2:20][CH2:21][CH2:22][CH3:23])[CH:10]=[C:11]([O:12][CH2:13][CH2:14][CH2:15][C:16]([NH:36][CH2:37][CH2:38][C:39]3[CH:44]=[CH:43][C:42]([OH:45])=[CH:41][CH:40]=3)=[O:18])[C:5]=2[C@@H:4]2[CH2:24][C:25]([CH3:28])=[CH:26][CH2:27][C@@H:3]12
Reactant: NCCc1ccc(O)cc1
Reactant: CCCCCc1cc(OCCCC(=O)O)c2c(c1)OC(C)(C)[C@@H]1CC=C(C)C[C@@H]21
Agent: Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: O
Solvent: c1ccccc1
Product: CCCCCc1cc(OCCCC(=O)NCCc2ccc(O)cc2)c2c(c1)OC(C)(C)[C@@H]1CC=C(C)C[C@@H]21
Temperature: 0 °C
Reaction time: 1 h
Yield: 27.1 %

Procedure:
To a solution of 2.10 g (5.24 mmol) of (6aR-trans)-4-[(6a,7,10,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6H-dibenzo[b,d]pyran-1-yl)oxy]butanoic acid in 6 ml of benzene was added 2.1 ml (3.06 g, 24 mmol) of oxalyl chloride. When the spontaneous bubbling ceased, the mixture was heated with an 85° oil bath for 30 min. The excess oxalyl chloride and the benzene were evaporated under vacuum, 2×2 ml of benzene was added, and this was also evaporated. The residue was dissolved in 2 ml of ether and added with stirring to an ice cold solution of 0.93 g (6.78 mmol) of tyramine in 6.8 ml of 1 N sodium hydroxide, while also adding, at the same rate, 5.3 ml of ice cold 1 N sodium hydroxide. The resulting thick suspension was stirred at ice temperature for one hour, acidified with hydrochloric acid and extracted with ether. The extracts were dried and concentrated. The residue was subjected to chromatography over silica gel. Elution with 2% methanol in chloroform and concentration of the fractions containing product gave 738 mg (27%) of (6aR-trans)-4-[(6a,7,10,10a-Tetrahydro-6,6,9-trimethyl-3-pentyl-6Hdibenzo[b,d]pyran-1-yl)oxy]-N-[2-(4-hydroxyphenyl)ethyl]-butanamide as a pale yellow gum occluding 0.5 mol of water: ir (CHCl3) 1665 cm-1 ; uv max (C2H5OH) 225 (infl) (ε20,400), 280 (3030), and 305 (infl) (830); nmr (CDCl3) 6.47 and 6.73 (two d, 1,4-disubstituted benzene), 6.31 and 6.21 (two sharp d, H-2 and H-4), 5.54 (m, NH), 5.42 (m, H-8) , 3.94 (t, OCH2C), 3.46 (t, NCH2C), 3.12 (m, H-10a), 1.65 (s, 9-CH3), 1.36 and 1.08 (two s, 6,6-diCH3), and 0.87 (t, ω-CH3); mass mol wt 519; [α]D25 -154.6° (c 1.015, CHCl3).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([O:16]C)[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2].B(Br)(Br)Br>[I-].C([N+](CCCC)(CCCC)CCCC)CCC.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:19])[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[C:13]([OH:16])[CH:14]=2)[CH:9]=[CH:8][C:7]=1[Cl:18])[CH3:2]
Reactant: CCOC(=O)Cc1c(Cl)ccc2ccc(OC)cc12
Agent: BrB(Br)Br
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [I-]
Solvent: ClCCl
Product: CCOC(=O)Cc1c(Cl)ccc2ccc(O)cc12
Temperature: -78 °C
Reaction time: 1 h

Procedure:
(2-Chloro-7-methoxy-naphthalen-1-yl)-acetic acid ethyl ester (12.0 g, 43.10 mmol) and tetrabutylammonium iodide (20.7 g, 56.04 mmol) are dissolved under an atmosphere of argon in CH2Cl2 (240 ml). The reaction mixture is cooled to −78° C. and a 1 M solution of BBr3 in CH2Cl2 (108 ml, 107.77 mmol) is added during 30 minutes. After stirring at −78° C. for 15 minutes and at RT for 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NaHCO3 (8 ml) is carefully added. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc4:1 to 3:2) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 1.51 (t, J=9.9 Hz, 3H), 4.43 (q, J=9.9 Hz, 2H), 4.48 (s, 2H), 6.28-6.36 (br, 1H), 7.29-7.32 (m, 1H), 7.48-7.49 (m, 1H), 7.58 (d, J=10 Hz, 1H), 7.89 (d, J=10 Hz, 1H), 7.96 (d, J=10 Hz, 1H). ES+-MS: 265.2, 267.2 [M+H]+.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=[S:16])[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=1.Cl[CH2:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20].C[O-].[Na+]>CO>[CH2:22]([O:21][C:19](=[O:20])[CH2:18][S:16][C:4]1[C:5]([C:14]#[N:15])=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:7]=[C:2]([NH2:1])[N:3]=1)[C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: O=C(CCl)OCc1ccccc1
Reactant: N#Cc1c(-c2ccccc2)nc(N)[nH]c1=S
Agent: C[O-]
Agent: [Na+]
Solvent: CO
Product: N#Cc1c(SCC(=O)OCc2ccccc2)nc(N)nc1-c1ccccc1

Procedure:
From 2-amino-4-phenyl-6-thioxo-1,6-dihydro-pyrimidine-5-carbonitrile, benzyl chloroacetate and sodium methylate in methanol. ES-MS m/e (%): 399 (M+Na+, 40), 377 (M+H+, 100).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[S:20][C:19]([CH2:21][CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([O:30]CC)=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:17]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=1.[OH-].[Na+].Cl>CO>[CH3:1][C:2]1[CH:3]=[C:4]([C:16]2[S:20][C:19]([CH2:21][CH:22]3[CH2:27][CH2:26][CH:25]([C:28]([OH:30])=[O:29])[CH2:24][CH2:23]3)=[N:18][CH:17]=2)[CH:5]=[C:6]([NH:8][C:9]2[N:14]=[C:13]([CH3:15])[CH:12]=[CH:11][N:10]=2)[CH:7]=1
Reactant: CCOC(=O)C1CCC(Cc2ncc(-c3cc(C)cc(Nc4nccc(C)n4)c3)s2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1cc(Nc2nccc(C)n2)cc(-c2cnc(CC3CCC(C(=O)O)CC3)s2)c1
Temperature: 110 °C

Procedure:
Ethyl 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methyl]cyclohexanecarboxylate (147 mg, 0.326 mmol) was suspended in methanol (2.0 mL) in a microwave vial, and sodium hydroxide (1M in water, 0.652 mL, 0.652 mmol) was added. The reaction was heated to 110° C. for 30 min via microwave irradiation. The reaction was acidified to pH=3-4 with aqueous 1M HCl and extracted with 15% isopropyl alcohol in chloroform (2×). The combined organic layers were dried over magnesium sulfate and concentrated under reduced pressure to afford 4-[(5-{3-methyl-5-[(4-methylpyrimidin-2-yl)amino]phenyl}-1,3-thiazol-2-yl)methyl]cyclohexanecarboxylic acid as an off-white solid in a 2.5:1 mixture of diastereomers.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])O[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1.Cl.[NH2:25][OH:26].C([O-])(=O)C.[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:23]=[CH:22][C:5]([O:6][C:7]2[CH:12]=[CH:11][C:10]([C:13]3[C:18](=[O:19])[CH:17]=[C:16]([CH3:20])[N:25]([OH:26])[C:14]=3[CH3:21])=[CH:9][CH:8]=2)=[CH:4][CH:3]=1
Reactant: NO
Reactant: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)o1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: Cc1cc(=O)c(-c2ccc(Oc3ccc(Cl)cc3)cc2)c(C)n1O
Temperature: 25 °C
Yield: 19.1 %

Procedure:
A mixture of 3-(4-(4-chlorophenoxy)phenyl)-2,6-dimethylpyran-4-one (1.0 g), hydroxylamine hydrochloride (1.06 g), sodium acetate (1.25 g) and water (5 ml) in ethanol (10 ml) was heated at reflux for 3 days. After cooling to rt the mixture was diluted with water (20 ml) and the precipitate filtered off and washed with ethyl acetate. Recrystallisation from DMF afforded the title compound (0.2 g), m.p. 232°-236°, NMR δH (d6-DMSO)7.5-7.4 (2H, d, a 8 Hz), 7.3-7.2 (2H, d, J 8 Hz), 7.15-7.0 (4H, m), 6.75 (1H, s), 2.35 (3H, s), 2.15 (3H, s).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([OH:17])[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2].[H-].[Na+].Br[C:22]1[N:23]=[CH:24][C:25]([C:28]#[N:29])=[N:26][CH:27]=1>C1COCC1>[CH2:1]([O:3][C:4](=[O:18])[CH2:5][CH:6]1[O:10][B:9]([OH:11])[C:8]2[CH:12]=[C:13]([O:17][C:22]3[CH:27]=[N:26][C:25]([C:28]#[N:29])=[CH:24][N:23]=3)[CH:14]=[C:15]([CH3:16])[C:7]1=2)[CH3:2]
Reactant: N#Cc1cnc(Br)cn1
Reactant: CCOC(=O)CC1OB(O)c2cc(O)cc(C)c21
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)CC1OB(O)c2cc(Oc3cnc(C#N)cn3)cc(C)c21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of (1,6-dihydroxy-4-methyl-1,3-dihydro-benzo[c][1,2]oxaborol-3-yl)-acetic acid ethyl ester (3.68 g, 20.0 mmol) in THF (60 mL) was treated with NaH (1.20 g, 30.0 mmol) at 0° C. The resulting suspension was stirred at room temperature 15 min and 5-bromo-pyrazine-2-carbonitrile was added. The reaction was stirred at room temperature for 3 h. The suspension was quenched with 1N HCl and extracted with ethyl acetate. The organic phase was separated, dried (Na2SO4), and concentrated. The residue was purified by the flash column chromatography (silica, hexanes/ethyl acetate=1:1) to afford the title compound (1.63 g). 1H NMR (300 MHz, CD3OD) δ 8.58 (s, 1H), 8.55 (s, 1H), 7.29 (s, 1H), 7.16 (s, 1H), 5.73-5.69 (m, 1H), 4.16 (q, 2H), 3.27-3.18 (m, 1H), 2.56-2.48 (m, 1H), 2.41 (s, 3H), 1.23 (t, 3H). MS found: (M+H)+=354.1.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH:9]=[CH2:10])([CH3:4])[CH3:3].C12BC(CCC1)CCC2.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Cl[C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([Cl:50])[C:36]=2[NH:40][C:41](=[O:49])[CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[N:31]=1>O.CN(C)C=O.[Cl-].[Na+].O.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>[CH3:4][C:2]([O:5][C:6](=[O:11])[NH:7][CH2:8][CH2:9][CH2:10][C:30]1[CH:39]=[CH:38][C:37]2[C:32](=[CH:33][CH:34]=[C:35]([Cl:50])[C:36]=2[NH:40][C:41](=[O:49])[CH2:42][CH:43]2[CH2:48][CH2:47][CH2:46][CH2:45][CH2:44]2)[N:31]=1)([CH3:1])[CH3:3]
Reactant: C=CCNC(=O)OC(C)(C)C
Reactant: O=C(CC1CCCCC1)Nc1c(Cl)ccc2nc(Cl)ccc12
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: B1C2CCCC1CCC2
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NCCCc1ccc2c(NC(=O)CC3CCCCC3)c(Cl)ccc2n1
Temperature: 25 °C

Procedure:
To 2-propenyl-carbamic acid 1,1-dimethylethyl ester under nitrogen was added 9-borabicyclo[3.3.1]nonane (0.5M in tetrahydrofuran, 7.1 mL) and the mixture refluxed for 2 hours. The reaction was allowed to cool to room temperature and potassium phosphate (1.02 g) in water (1.8 mL) added. The resultant mixture was stirred for 15 minutes. N-(2,6-Dichloro-5-quinolinyl)-cyclohexaneacetamide (prepared as described in Example 1a) (0.5 g) was added followed by tetrakis(triphenylphosphine)palladium(0) (17 mg) in dimethylformamide (2.8 mL). The reaction was heated at 70° C. under nitrogen for 4 hours. To the cooled solution was added brine (30 mL) and the mixture extracted with ethyl acetate (3×30 mL). The combined organics were dried, filtered and concentrated to give the sub-title compound (0.9 g).
Reaction SMILES: [CH3:1][C:2](=[CH:4][CH2:5][CH2:6][CH:7]([CH2:9][CH:10]=[O:11])[CH3:8])[CH3:3]>C1(C)C=CC=CC=1>[CH3:8][C@H:7]1[CH2:9][C@@H:10]([OH:11])[C@H:4]([C:2]([CH3:3])=[CH2:1])[CH2:5][CH2:6]1
Reactant: CC(C)=CCCC(C)CC=O
Solvent: Cc1ccccc1
Product: C=C(C)[C@@H]1CC[C@@H](C)C[C@H]1O
Temperature: -10 °C

Procedure:
The reaction solution from 3.1 is diluted with 50 ml toluene and cooled to −10° C. 50 mmol of racemic citronellal are added dropwise to the cold reaction solution over a period of 5 minutes.
Reaction SMILES: C(OS([C:9]1[CH:14]=[CH:13][C:12](C)=[CH:11][CH:10]=1)(=O)=O)CC#C.[C:16]1([N:22]2[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]2)C=C[CH:19]=[CH:18][CH:17]=1.C(=O)(O)[O-].[Na+]>CN(C)C=O>[CH2:16]([N:22]1[CH2:27][CH2:26][N:25]([C:9]2[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:24][CH2:23]1)[CH2:17][C:18]#[CH:19]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: c1ccc(N2CCNCC2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: C#CCCN1CCN(c2ccccc2)CC1
Temperature: 80 °C
Reaction time: 14 h
Yield: 78.9 %

Procedure:
A mixture of but-3-ynyl-p-toluenesulfonate (8.97 g), 1-phenylpiperazine (6.49 g) and sodium bicarbonate (3.7 g) in dimethylformamide (100 mL) is stirred at 80° C. for 14 hours. The solvent is evaporated and the residue dissolved in dichloromethane, washed with water and dried over MgSO4. The solution is filtered through silica gel and the product eluted with 10% ethyl acetate/hexanes to give 6.76 g of the title compound as a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([OH:30])=O)[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:27])([F:26])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1.C1N=CN(C(N2C=NC=C2)=O)C=1.[NH2:44][CH2:45][CH2:46][OH:47].[Cl-].[Na+]>CN(C=O)C.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([NH:11][C:12]2[N:13]=[C:14]([C:28]([NH:44][CH2:45][CH2:46][OH:47])=[O:30])[N:15]([CH2:17][C:18]3[CH:23]=[CH:22][C:21]([C:24]([F:26])([F:27])[F:25])=[CH:20][CH:19]=3)[CH:16]=2)=[O:10])=[C:4]([CH3:31])[CH:3]=1
Reactant: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)O)n1
Reactant: NCCO
Agent: O=C(n1ccnc1)n1ccnc1
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(Cl)ccc1NC(=O)Nc1cn(Cc2ccc(C(F)(F)F)cc2)c(C(=O)NCCO)n1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
1.81 g (4 mmol) of 4-({[(4-chloro-2-methylphenyl)amino]carbonyl}amino)-1-[4-(trifluoromethyl)benzyl]-1H-imidazole-2-carboxylic acid (Example 20A) are dissolved in 16 ml of absolute DMF, and 1.94 g (12 mmol) of N,N-carbonyldiimidazole are added. The reaction mixture is stirred at RT for 1.5 h and, after addition of 144 μl of water, stirred at RT for 10 min. Then 366 mg (6 mmol) of 2-aminoethanol are added, and the mixture is stirred at RT for 1 h. The reaction mixture is mixed with saturated sodium chloride solution and extracted twice with ethyl acetate. The combined extracts are washed once each with 10% strength citric acid, saturated sodium bicarbonate solution, water and saturated sodium chloride solution, dried with magnesium sulphate and concentrated in vacuo. The residue from evaporation is purified by chromatography on silica gel with dichloromethane/methanol as eluent.
Reaction SMILES: Br[CH:2]1[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1.[Mg].[CH:11](=[O:13])[CH3:12].Cl>C(OCC)C>[CH:2]1([C:11](=[O:13])[CH3:12])[CH2:9][CH2:8][CH2:7][CH:6]=[CH:5][CH2:4][CH2:3]1
Reactant: BrC1CCC=CCCC1
Reactant: CC=O
Agent: Cl
Agent: [Mg]
Solvent: CCOCC
Product: CC(=O)C1CCC=CCCC1
Temperature: 5 °C
Reaction time: 3 h
Yield: 30.3 %

Procedure:
A solution of 5-bromo-cyclooctene (5 g, 26 mmol; prepared by treatment of 1,5-cyclooctadiene with HBr in AcOH) in diethyl ether was added to magnesium (0.7 g, 29 mmol, 1.1 eq.). The resulting solution was cooled to 5° C. and treated dropwise with a solution of acetaldehyde (5 ml, 89 mmol, 3.4 eq.) in diethyl ether (10 ml). The resulting mixture was stirred 3 h at 20° C., treated with 2M HCl, and extracted with diethyl ether. The organic phases were washed successively with NaHCO3, NH4Cl and NaCl solutions, and dried (Na2SO4) and the solvent evaporated under vacuum. The crude product was purified by flash chromatography (hexane/Et2O 10:1) to give 1.2 g of 1-cyclooct-4-enylethanone (30%).
Reaction SMILES: CC([O-])(C)C.[K+].Br[C:8]1[C:17]2[CH2:16][CH2:15][CH2:14][CH2:13][C:12]=2[C:11]([O:18][CH3:19])=[N:10][CH:9]=1.[NH2:20][C:21]1[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=1)[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(P(C1C=CC=CC=1C1C=CC=CC=1)C(C)(C)C)(C)(C)C>C1(C)C=CC=CC=1>[CH3:19][O:18][C:11]1[C:12]2[CH2:13][CH2:14][CH2:15][CH2:16][C:17]=2[C:8]([NH:20][C:21]2[CH:22]=[C:23]([CH:29]=[CH:30][CH:31]=2)[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[CH:9][N:10]=1
Reactant: CCOC(=O)c1cccc(N)c1
Reactant: COc1ncc(Br)c2c1CCCC2
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cccc(Nc2cnc(OC)c3c2CCCC3)c1
Temperature: 100 °C
Yield: 56 %

Procedure:
580 mg (4.9 mmol) of 95% pure KOtBu are introduced into 20 ml of abs. toluene. After evacuation and ventilation with argon three times, 847 mg (3.5 mmol) of 4-bromo-1-methoxy-5,6,7,8-tetrahydroisoquinoline, and 868 mg (5.25 mmol) of ethyl 3-aminobenzoate are added. Addition of 160 mg (0.175 mmol) of tris(dibenzylidene)dipalladium and 209 mg (0.7 mmol) of di-tert-butylphosphinobiphenyl is followed by heating at 100° C. for three hours. For workup, the mixture is concentrated and the residue is partitioned between H2O and ethyl acetate. The phases are separated and the aqueous phase is extracted three times more. The combined organic phases are washed once more with H2O, dried with Na2SO4 and concentrated. Further purification takes place by chromatography on silica gel (CH2Cl2/MeOH 99:1), resulting in 640 mg of the title compound. Yield: 55%.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)[N:10]=1.[CH2:33]([S:35](Cl)(=[O:37])=[O:36])[CH3:34]>>[NH2:8][C:9]1[C:14]([C:15]([C:17]2[CH:22]=[C:21]([F:23])[CH:20]=[CH:19][C:18]=2[O:24][CH3:25])=[O:16])=[CH:13][N:12]=[C:11]([NH:26][CH:27]2[CH2:28][CH2:29][N:30]([S:35]([CH2:33][CH3:34])(=[O:37])=[O:36])[CH2:31][CH2:32]2)[N:10]=1
Reactant: CCS(=O)(=O)Cl
Reactant: COc1ccc(F)cc1C(=O)c1cnc(NC2CCNCC2)nc1N
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(Nc2ncc(C(=O)c3cc(F)ccc3OC)c(N)n2)CC1

Procedure:
The same procedure as described in Example 60 was used, starting from [4-amino-2-(piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone trifluoroacetic acid salt, Example 59, and ethanesulfonyl chloride (Aldrich), to give [4-amino-2-( 1-ethanesulfonyl-piperidin-4-ylamino)-pyrimidin-5-yl]-(5-fluoro-2-methoxy-phenyl)-methanone. MS (M+H)+, 438.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([F:14])=[CH:5][C:6]([Cl:13])=[C:7]([CH:12]=1)[C:8]([O:10][CH3:11])=[O:9].CCN(C(C)C)C(C)C.[C:24](Cl)(=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26]>C(Cl)Cl>[Cl:13][C:6]1[CH:5]=[C:4]([F:14])[C:3]([CH2:2][NH:1][C:24](=[O:29])[C:25]([CH3:28])([CH3:27])[CH3:26])=[CH:12][C:7]=1[C:8]([O:10][CH3:11])=[O:9]
Reactant: COC(=O)c1cc(CN)c(F)cc1Cl
Reactant: CC(C)(C)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1cc(CNC(=O)C(C)(C)C)c(F)cc1Cl
Yield: 99.8 %

Procedure:
The title compound was prepared following the procedure described in step-2 of Intermediate-2 using methyl 5-(aminomethyl)-2-chloro-4-fluorobenzoate (180 mg, 0.83 mmol), DIPEA (321 mg, 2.49 mmol) and pivaloyl chloride (120 mg, 1.0 mmol) in CH2Cl2 (5 mL) to afford 250 mg of the title product. 1H NMR (300 MHz, DMSO-d6): δ 8.16 (t, 1H), 7.73 (d, J=6.9 Hz, 1H), 7.58-7.54 (d, J=10.2 Hz, 1H), 4.26-4.24 (d, J=5.7 Hz, 2H), 3.83 (s, 3H), 1.11 (s, 9H).