Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:20]=[CH:19][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:17][CH:16]=1)[C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].B(C1C=CC(C[C@H](NC(OC(C)(C)C)=O)C(O)=O)=CC=1)(O)O>>[C:1]([O:5][C:6]([NH:8][C@@H:9]([CH2:14][C:15]1[CH:16]=[CH:17][C:18]([B:21]2[O:25][C:24]([CH3:27])([CH3:26])[C:23]([CH3:29])([CH3:28])[O:22]2)=[CH:19][CH:20]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: COC(=O)[C@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)NC(=O)OC(C)(C)C
Agent: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Product: CC(C)(C)OC(=O)N[C@@H](Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1)C(=O)O

Procedure:
The above organic layer of the ester was stirred with aqueous lithium hydroxide solution (23 g in 500 mL water) at room temperature for 30 minutes. The pH of the resulting slurry was adjusted to about 10 with 6 N hydrochloric acid and filtered. The cake was washed with water (200 mL). Acetonitrile was removed from the filtrate under reduced pressure to give an aqueous slurry (950 mL, additional water was added during distillation). The slurry was filtered through a pad of cellulose and washed with water (200 mL). The filtrate was washed with MTBE (500 mL) and rediluted with 700 mL MTBE. The mixture was acidified to pH about 4.5 with 6 N hydrochloric acid. The organic layer was washed with water (500 mL) and concentrated under reduced pressure to the acid compound as a brown oil (206 g, 95% yield based on estimated purity by NMR). The crude product can be used directly in the following step. Alternatively, the compound can be purified by crystallization from MTBE/heptane to give a white solid, which contains a small amount of the corresponding boronic acid, (S)-3-(4-boronophenyl)-2-(tert-butoxycarbonylamino)propanoic acid. MS (ESI): MH+=392.2, MNH4+=409.2, M2H+=783.4, M2NH4+=800.4. 1H NMR (CDCl3) δ 7.95 (br s, 1H), 7.76 (d, J=7.8 Hz, 2H), 7.21 (d, J=7.6 Hz, 2H), 5.03 (d, J=7.8 Hz, 1H), 4.62 (m, 1H), 3.18 (m, 2H), 1.43 (s, 9H), 1.35 (s, 12H). 13C NMR (CDCl3) δ 175.8, 155.7, 139.7, 135.4, 129.2, 84.2, 80.5, 54.5, 38.3, 28.7, 25.2.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[CH:11]=[C:10]([CH:12]2[CH2:17][CH2:16][N:15](C(OC(C)(C)C)=O)[CH2:14][CH2:13]2)[NH:9][N:8]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[NH:15]1[CH2:14][CH2:13][CH:12]([C:10]2[CH:11]=[C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[NH:8][N:9]=2)[CH2:17][CH2:16]1
Reactant: CC(C)(C)OC(=O)N1CCC(c2cc(-c3ccccn3)n[nH]2)CC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: c1ccc(-c2cc(C3CCNCC3)n[nH]2)nc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108.3 %

Procedure:
tert-Butyl 4-(3-pyridin-2-yl-1H-pyrazol-5-yl)piperidine-1-carboxylate (1.46 g, 4.45 mmol) was dissolved in 15 ml DCM. Trifluoroacetic acid (5 ml) was added gradually and the resulting solution was stirred at ambient temperature for 3 h and was then concentrated in vacuo. The residue was dissolved in 4:1 MeOH/water and treated with MP-carbonate resin (5 g, 2.55 mmol/g). After stirring overnight the reaction was filtered and the filtrate was concentrated in vacuo to provide 1.1 g of 2-(3-piperidin-4-yl-1H-pyrazol-5-yl)pyridine (1-4) as a tan solid. δ 8.56 (d, J=3.9 Hz, 1H), 7.84 (m, 2H), 7.21 (m, 1H), 6.65 (s, 1H), 3.22 (m, 3H), 2.87 (m, 2H), 2.03 (d, J=12.8 Hz, 2H), 1.71 (d, J=10.3 Hz, 2H). m/z (m+1): 229.3,
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([O:14]CC)=[O:13])=[CH:4][C:3]=1[O:37][CH3:38].[OH-].[K+].Cl>O1CCOCC1.O>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH2:6][CH2:7][N:8]([C:17](=[O:36])[C:18]([N:20]([C:32]([CH3:33])([CH3:35])[CH3:34])[CH2:21][CH2:22][O:23][CH2:24][C:25]#[C:26][C:27]3[S:31][CH:30]=[N:29][CH:28]=3)=[O:19])[CH:9]2[C:12]([OH:14])=[O:13])=[CH:4][C:3]=1[O:37][CH3:38]
Reactant: CCOC(=O)C1c2cc(Br)c(OC)cc2CCN1C(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: COc1cc2c(cc1Br)C(C(=O)O)N(C(=O)C(=O)N(CCOCC#Cc1cncs1)C(C)(C)C)CC2
Temperature: 50 °C
Yield: 100.7 %

Procedure:
A solution of 500 mg of 11g in 6 ml of dioxane was mixed with a solution of 300 mg of KOH in 3 ml of water and heated to 50° C. for 2 h. The reaction mixture was cooled and diluted with water and then acidified to pH3 by addition of 0.5N HCl. The product was extracted with ethyl acetate and the organic extract was washed once with water, dried and concentrated, to provide 480 mg of 11h as colorless amorphous material;
Reaction SMILES: [CH3:1][C:2]([CH3:25])([CH3:24])[C:3]([O:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH3:16])[CH:12]=[CH:11]2)=[O:4].[Se](=O)=[O:27]>O1CCOCC1>[CH3:1][C:2]([CH3:24])([CH3:25])[C:3]([O:5][C:6]1[C:7]([C:17]([O:19][CH2:20][CH2:21][CH2:22][CH3:23])=[O:18])=[CH:8][CH:9]=[C:10]2[C:15]=1[N:14]=[C:13]([CH:16]=[O:27])[CH:12]=[CH:11]2)=[O:4]
Reactant: O=[Se]=O
Reactant: CCCCOC(=O)c1ccc2ccc(C)nc2c1OC(=O)C(C)(C)C
Solvent: C1COCCO1
Product: CCCCOC(=O)c1ccc2ccc(C=O)nc2c1OC(=O)C(C)(C)C
Temperature: 20 °C
Yield: 70.8 %

Procedure:
A mixture of the preceding diester 3 (step 2) (11.5 g, 34 mmol) and selenium dioxide (6.7 g, 60 mmol) in 50 ml of 1,4-dioxane is heated under reflux for 12 hours. After cooling to 20° C., the reaction mixture is filtered on Celite® and concentrated under reduced pressure. The residue is chromatographed on a silica column, eluting a 4/1 cyclohexane/ethyl acetate mixture so as to give 8.6 g (71%) of n-butyl 8-(2,2-dimethylpropionyloxy)-2-formylquinoline-7-carboxylate 4. White solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[C:5]([F:12])=[CH:4][CH:3]=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH:23]([C:25]3[C:30]([O:31][CH3:32])=[CH:29][CH:28]=[C:27](F)[C:26]=3[Cl:34])[CH3:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.ClC1C(F)=CC=C(OC)C=1C=O.ClC1C(C=O)=C(F)C(F)=CC=1.C[O-].[Na+]>CO>[Br:13][C:14]1[CH:15]=[C:16]2[C:22]([CH:23]([C:25]3[C:26]([Cl:34])=[CH:27][CH:28]=[C:29]([F:12])[C:30]=3[O:31][CH3:32])[CH3:24])=[CH:21][NH:20][C:17]2=[N:18][CH:19]=1.[Cl:1][C:2]1[C:7]([CH:8]=[O:9])=[C:6]([O:10][CH3:11])[C:5]([F:12])=[CH:4][CH:3]=1
Reactant: COc1ccc(F)c(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12
Agent: COc1c(F)ccc(Cl)c1C=O
Agent: COc1ccc(F)c(Cl)c1C=O
Agent: C[O-]
Solvent: CO
Product: COc1c(F)ccc(Cl)c1C(C)c1c[nH]c2ncc(Br)cc12

Procedure:
The title compound was prepared from 6-chloro-3-fluoro-2-methoxybenzaldehyde following the procedures for the synthesis of 5-bromo-3-[1-(2-chloro-3-fluoro-6-methoxyphenyl)ethyl]-1H-pyrrolo[2,3-b]pyridine from 2-chloro-3-fluoro-6-methoxybenzaldehyde, vide supra. 6-Chloro-3-fluoro-2-methoxybenzaldehyde was prepared from the known 6-chloro-2,3-difluorobenzaldehyde by reaction with sodium methoxide in methanol. 1H NMR (300 MHz, CDCl3): δ=1.78 (d, J=7.2 Hz, 3H), 3.44 (brs, 3H), 4.94 (q, J=7.2 Hz, 1H), 6.93 (dd, J=9.0, 9.0 Hz, 1H), 7.09 (dd, J=8.7, 4.5 Hz, 1H), 7.30 (s, 1H), 7.71 (d, J=1.5 Hz, 1H), 8.28 (d, J=1.5 Hz, 1H), 9.68 (brs, 1H).
Reaction SMILES: [Cl-].[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][Zn+])=[CH:5][CH:4]=1.[CH3:11][O:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[C:19]([C:23](=[O:39])[C:24]1[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=1)=[C:18](OS(C(F)(F)F)(=O)=O)[CH:17]=[CH:16]2>[N+](CCCC)(CCCC)(CCCC)CCCC.[I-].C1COCC1.CN1C(=O)CCC1.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].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.[Fe+2]>[F:2][C:3]1[CH:10]=[CH:9][C:6]([CH2:7][C:18]2[CH:17]=[CH:16][C:15]3[C:20](=[CH:21][CH:22]=[C:13]([O:12][CH3:11])[CH:14]=3)[C:19]=2[C:23]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][CH2:32][N:33]3[CH2:38][CH2:37][CH2:36][CH2:35][CH2:34]3)=[CH:26][CH:25]=2)=[O:39])=[CH:5][CH:4]=1
Reactant: Fc1ccc(C[Zn+])cc1
Reactant: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(OS(=O)(=O)C(F)(F)F)ccc2c1
Agent: [Fe+2]
Agent: [Pd]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Product: COc1ccc2c(C(=O)c3ccc(OCCN4CCCCC4)cc3)c(Cc3ccc(F)cc3)ccc2c1
Yield: 78 %

Procedure:
Add 4-fluorobenzylzinc chloride (4 mL of 0.5 M/THF) to a stirred solution of trifluoro-methanesulfonic acid 6-methoxy-1-[4-(2-piperidin-1-yl-ethoxy)-benzoyl]-naphthalen-2-yl ester (525 mg), Pd(dba)2 (68 mg), dppf (66 mg) and Bu4NI (1.1 g) in THF/NMP (2 mL/1.5 mL) at room temperature. Heat the mixture to reflux for 2 h and quench with water. Dilute the mixture with CH2Cl2 and wash with water and brine, dry over MgSO4, filter and concentrate. Load the crude product on an SCX cartridge, wash with MeOH and elute the product with 2M NH3/MeOH. Purify the product by flash chromatography (0–5% (2M NH3 in MeOH/CH2Cl2) to afford [2-(4-fluoro-benzyl)-6-methoxy-naphthalen-1-yl]-[4-(2-piperidin-1-yl-ethoxy)-phenyl]-methanone (380 mg, 78%)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][O:15][C:16]1[N:21]=[C:20]([O:22][CH3:23])[C:19]([C:24]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:25]=2[CH2:26][CH2:27][NH:28][CH:29]3[CH3:34])=[CH:18][N:17]=1>>[Cl:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:28]3[CH2:27][CH2:26][C:25]4[C:30](=[CH:31][CH:32]=[CH:33][C:24]=4[C:19]4[C:20]([O:22][CH3:23])=[N:21][C:16]([O:15][CH3:14])=[N:17][CH:18]=4)[CH:29]3[CH3:34])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: O=C(O)c1cc2ncc(Cl)cn2n1
Reactant: COc1ncc(-c2cccc3c2CCNC3C)c(OC)n1
Product: COc1ncc(-c2cccc3c2CCN(C(=O)c2cc4ncc(Cl)cn4n2)C3C)c(OC)n1

Procedure:
In close analogy to the procedure described in Example 1, 6-chloro-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 5-(2,4-Dimethoxy-pyrimidin-5-yl)-1-methyl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: [C:1]([N:3]=[C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)OC)#[N:2].[CH3:13][CH:14]([NH2:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>CO>[C:1]([NH:3][C:4]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][N:8]=1)=[N:19][CH:14]([CH3:13])[C:15]([CH3:18])([CH3:17])[CH3:16])#[N:2]
Reactant: COC(=NC#N)c1ccccn1
Reactant: CC(N)C(C)(C)C
Solvent: CO
Product: CC(N=C(NC#N)c1ccccn1)C(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93.5 %

Procedure:
Methyl N-cyano-2-pyridinecarboximidate (0.50 g, 3.1 mmol) was dissolved in methanol (10 ml), 1,2,2-trimethylpropylamine (0.34 g, 3.4 mmol) was added, and the resulting mixture was stirred at room temperature for 30 minutes. After the reaction was completed, the reaction solution was concentrated under reduced pressure, and the residue thus obtained was crystallized from dichloromethane-diethyl ether to give the title compound (0.67 g, 2.9 mmol, yield: 92%) as colorless needles.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5][OH:6].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(Cl)Cl>[O:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH:11]1[O:6][CH2:5][C:4]1[CH:7]=[CH:8][CH:9]=[C:2]([Br:1])[CH:3]=1
Reactant: OCc1cccc(Br)c1
Reactant: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCl
Product: Brc1cccc(COC2CCCCO2)c1

Procedure:
A solution of 3-bromobenzyl alcohol (84.9 g; Aldrich), 3,4-dihydro-2H-pyran (44 g) and anhydrous p-toluene sulfonic acid (1 g) in CH2Cl2 (800 mL) was stirred at 5° C. for 1 hr. then at r.t. overnight. The mixture was concentrated and the residue chromatographed (5% EtOAc/hexane) to afford the title compound as an oil.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH3:12])[CH:6]=[CH:5]2.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(NCC)C.[CH3:37][Si:38]([C:41]#[CH:42])([CH3:40])[CH3:39]>[Cu](I)I.CN(C=O)C>[CH3:12][C:7]1[CH:6]=[CH:5][C:4]2[C:9](=[CH:10][CH:11]=[C:2]([C:42]#[C:41][Si:38]([CH3:40])([CH3:39])[CH3:37])[CH:3]=2)[N:8]=1
Reactant: Cc1ccc2cc(Br)ccc2n1
Reactant: C#C[Si](C)(C)C
Agent: I[Cu]I
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCNCC
Solvent: CN(C)C=O
Product: Cc1ccc2cc(C#C[Si](C)(C)C)ccc2n1
Yield: 83.5 %

Procedure:
In a sealed tube were introduced 6-bromo-2-methyl-quinoline (4.6 g, 21 mmol, 1 eq), PdCl2(PPh3)3 (727 mg, 1 mmol, 5% mol), copper iodide (197 mg, 1 mmol, 5% mol), and triphenylphosphine (1.1 g, 4.1 mmol, 20% mol). Then, DMF (35 mL) was added followed by diethylamine (6 mL, 62 mmol, 5 eq) and trimethylsilylacetylene (3.2 mL, 23 mmol, 1.1 eq). The mixture was refluxed overnight. After cooling down the solvent was evaporated and the crude product was purified by column chromatography (Florisil, Cyclohexane-AcOEt 95/5) and obtained as a white solid (4.2 g, 83%).
Reaction SMILES: C1(C)C=CC(S(Cl)(=O)=O)=CC=1.[C:12](O)(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29].C(N(CC)CC)C.S(O)(O)(=O)=O.[OH:44][CH2:45][C@@H:46]([C@@H:48]([C@@H:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[OH:51])[OH:49])[NH2:47]>C(OCC)(=O)C>[C:12]([NH:47][C@H:46]([C@@H:48]([C@@H:50]([CH2:52][CH2:53][CH2:54][CH2:55][CH2:56][CH2:57][CH2:58][CH2:59][CH2:60][CH2:61][CH2:62][CH2:63][CH2:64][CH3:65])[OH:51])[OH:49])[CH2:45][OH:44])(=[O:30])[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][CH3:29]
Reactant: CCCCCCCC/C=C\CCCCCCCC(=O)O
Reactant: CCCCCCCCCCCCCC[C@@H](O)[C@@H](O)[C@@H](N)CO
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O=S(=O)(O)O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCCCCCCC/C=C\CCCCCCCC(=O)N[C@@H](CO)[C@H](O)[C@H](O)CCCCCCCCCCCCCC
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 74.8 %

Procedure:
To a mixture of p-toluenesulfonyl chloride (54.43 g; 286 mmoles) and ethyl acetate (425 ml) stirred at 40° C. a solution of oleic acid (86.1 g; purity 90%; 305 mmoles) and triethyl amine (100 ml) in ethyl acetate (160 ml) was added during 30 minutes. After stirring was continued at 43° C. for another 30 minutes this reaction mixture, containing the mixed anhydride of oleic acid, was added to a stirred mixture of phytosphingosine sulphate (84.03 g), triethyl amine (40 ml) and ethyl acetate (275 ml) during 30 minutes at 43° C. The flask that contained the mixed anhydride was rinsed with 50 ml ethyl acetate. After stirring for about 1 hour at 43° C. 400 ml of water was added to the reaction mixture and the pH was adjusted at 6.8 with 18 ml of a HCl solution (37%). The the layers were separated and the organic layer was washed again with 400 ml of water of which the pH was adjusted to 6.4 with 2 ml of a HCl solution (37%). After washing the ethyl acetate layer with 150 ml of a NaCl solution (10% in water) 500 ml of ethyl acetate was removed by distillation. More ethyl acetate (500 ml) was added and another 200 ml of ethyl acetate was removed by distillation. After cooling the ethyl acetate solution to 20° C. the crystalline product was filtered off, washed with ethyl acetate (2×200 ml) and dried in vacuo giving 87.99 g of N-oleoyl-phytosphingosine.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5](/[C:8](=[C:19](/[CH2:23][C:24](O)=[O:25])\[C:20](O)=[O:21])/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:4][CH:3]=1.C(O)C>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5](/[C:8](=[C:19](/[CH2:23][CH2:24][OH:25])\[CH2:20][OH:21])/[C:9]2[CH:14]=[CH:13][C:12]([S:15]([CH3:18])(=[O:17])=[O:16])=[CH:11][CH:10]=2)=[CH:6][CH:7]=1
Reactant: CS(=O)(=O)c1ccc(/C(=C(\CC(=O)O)C(=O)O)c2ccc(Cl)cc2)cc1
Solvent: CCO
Solvent: C1CCOC1
Product: CS(=O)(=O)c1ccc(/C(=C(/CO)CCO)c2ccc(Cl)cc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 94.8 %

Procedure:
To a solution of 7.85 g (0.0199 mole) of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)methylene]succinic acid, prepared in example 28, in 40 ml of tetrahydrofuran are added dropwise 5.65 ml (0.0596 mole) of borane/dimethyl sulphide complex. The mixture is then stirred for 3 hours at ambient temperature and then 1 hour at 50° C. After returning to ambient temperature, 5 ml of ethanol are added dropwise. The mixture is then concentrated to half its volume and then taken up into water. The crystals obtained are filtered off under suction and washed with pentane and dried giving 6.92 g of (Z)-2-[1-(4-chlorophenyl)-1-(4-methanesulphonylphenyl)-methylene]-1,4-butanediol in the form of crystals with a melting point of 159-160° C.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][N:11]2[CH2:16][CH2:15][C:14]([CH2:18][N:19]([CH3:33])[C:20]3[CH:32]=[CH:31][C:23]([C:24]([O:26]C(C)(C)C)=[O:25])=[CH:22][CH:21]=3)([OH:17])[CH2:13][CH2:12]2)=[CH:5][CH:4]=1)#[N:2].O.C(=O)([O-])[O-].[K+].[K+].[ClH:41]>>[ClH:41].[C:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:9][CH2:10][N:11]2[CH2:12][CH2:13][C:14]([CH2:18][N:19]([CH3:33])[C:20]3[CH:21]=[CH:22][C:23]([C:24]([OH:26])=[O:25])=[CH:31][CH:32]=3)([OH:17])[CH2:15][CH2:16]2)=[CH:7][CH:8]=1)#[N:2]
Reactant: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)OC(C)(C)C)cc1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: CN(CC1(O)CCN(CCc2ccc(C#N)cc2)CC1)c1ccc(C(=O)O)cc1
Reaction time: 5 h

Procedure:
The compound (100 mg) obtained in Step 2 of Example 21 was dissolved in 6N hydrochloric acid (0.5 mL) at room temperature and stirred at the same temperature for five hours. To the mixture was added water (3 mL) and adjusted to pH 9 to 10 by potassium carbonate, and the aqueous layer was washed with ethyl acetate. Insoluble matter of the aqueous layer was removed by filtration and the filtrate was adjusted to pH 3 with 6N hydrochloric acid. The precipitate was collected by filtration and dried to obtain the titled compound (71 mg) as crystals. The physical data of the obtained compound accord with those of the compound of Example 29.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:14]=[CH:13][N:12]([CH2:15][C@@H:16]([NH:18][C:19]([C:21]3[CH:25]=[C:24]([C:26]([OH:29])([CH3:28])[CH3:27])[O:23][N:22]=3)=[O:20])[CH3:17])[N:11]=2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[C:30](OC(=O)C)(=[O:32])[CH3:31]>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[C:30]([O:29][C:26]([C:24]1[O:23][N:22]=[C:21]([C:19](=[O:20])[NH:18][C@@H:16]([CH3:17])[CH2:15][N:12]2[CH:13]=[CH:14][C:10]([C:4]3[CH:5]=[CH:6][C:7]([C:8]#[N:9])=[C:2]([Cl:1])[CH:3]=3)=[N:11]2)[CH:25]=1)([CH3:28])[CH3:27])(=[O:32])[CH3:31]
Reactant: CC(=O)OC(C)=O
Reactant: C[C@@H](Cn1ccc(-c2ccc(C#N)c(Cl)c2)n1)NC(=O)c1cc(C(C)(C)O)on1
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Product: CC(=O)OC(C)(C)c1cc(C(=O)N[C@@H](C)Cn2ccc(-c3ccc(C#N)c(Cl)c3)n2)no1
Temperature: 0 °C
Reaction time: 2 h
Yield: 99 %

Procedure:
(S)—N-(1-(3-(3-chloro-4-cyanophenyl)-1H-pyrazol-1-yl)propan-2-yl)-5-(2-hydroxypropan-2-yl)isoxazole-3-carboxamide (97 mg, 0.234 mmol) and DMAP (2.89 mg, 0.023 mmol) were dissolved in pyridine under nitrogen atmosphere. The reaction mixture was cooled to 0° C., acetic anhydride (25.1 mg, 0.246 mmol) was added and the reaction mixture stirred for 2 h in RT. The mixture was again cooled to 0° C. and 10 μA of acetic anhydride was added. The reaction mixture was stirred in RT overnight after which the solvent was evaporated. Yield 99%. 1H-NMR (400 MHz; CDCl3): δ 1.22 (d, 3H), 1.80 (s, 6H), 2.05 (s, 3H), 4.25 (dd, 1H), 4.42 (dd, 1H), 4.58 (m, 1H), 6.58 (s, 1H), 6.63 (d, 1H), 7.49 (d, 1H), 7.69 (d, 1H), 7.83 (dd, 1H), 7.89 (d, 1H), 8.09 (d, 1H).
Reaction SMILES: [CH2:1]([O:5][C:6]([C@H:8]1[CH2:13][CH2:12][C@H:11]([C:14]([OH:16])=O)[CH2:10][CH2:9]1)=[O:7])[CH2:2][CH2:3][CH3:4].[CH3:17]N(C=O)C.C(Cl)(=O)C(Cl)=O.C[Zn]C>C(Cl)Cl.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(Cl)Cl>[C:14]([C@H:11]1[CH2:10][CH2:9][C@H:8]([C:6]([O:5][CH2:1][CH2:2][CH2:3][CH3:4])=[O:7])[CH2:13][CH2:12]1)(=[O:16])[CH3:17]
Reactant: CCCCOC(=O)[C@H]1CC[C@H](C(=O)O)CC1
Reactant: CN(C)C=O
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: C[Zn]C
Solvent: ClCCl
Product: CCCCOC(=O)[C@H]1CC[C@H](C(C)=O)CC1
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a vented and cooled solution (0° C.) under nitrogen of trans-4-(butoxycarbonyl)cyclohexanecarboxylic acid (J. Chem. Soc., Perkin Trans. 1, 1999, 20, 3023) (18.9 g, 83 mmol) in CH2Cl2 (150 mL) was added a catalytic amount of DMF (30 μL) followed by oxalyl chloride (7.97 mL, 91 mmol). The reaction mixture was then allowed to slowly warm to room temperature where it was stirred for 14 h at which point it was concentrated to a yellow oil and dried under vacuum for 3 h. The residue consisting primarily of butyl trans-4-(chlorocarbonyl)cyclohexanecarboxylate was diluted with THF (200 mL) and cooled in an ice bath. To this solution was added PdCl2(dppf)-CH2Cl2 (3.38 g, 4.14 mmol) followed by dimethyl zinc (2 M in PhCH3, 29 mL, 58 mmol) at such a rate that the internal temperature did not exceed 15° C. The cooling bath was then removed and after 2 h of stirring at room temperature the reaction mixture was re-cooled to 0° C. where it was diluted carefully with H2O. After the initial exotherm had subsided, sufficient 1N HCl and EtOAc were introduced such that a homogenous biphasic mixture formed. The layers were separated, the organic washed a second time with H2O then dried with MgSO4, filtered and concentrated in vacuo. The crude residue was absorbed on silica and purified by flash chromatography to afford butyl trans-4-acetylcyclohexanecarboxylate as a non-viscous orange oil. MS ESI calc'd. for C13H23O3 [M+H]+ 227. found 227. 1H NMR (500 MHz, CDCl3) δ 4.06 (t, J=6.6 Hz, 2H), 2.37-2.29 (m, 1H), 2.28-2.20 (m, 1H), 2.14 (s, 3H), 2.11-2.02 (m, 2H), 1.99 (d, J=13.8 Hz, 2H), 1.66-1.55 (m, 2H), 1.51-1.40 (m, 2H), 1.39-1.29 (m, 4H), 0.93 (t, J=7.4 Hz, 3H).
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][NH:7][S:8]([C:11]1[S:15][C:14]([NH:16][C:17]([N:19]([CH2:28][CH:29]2[CH2:33][CH2:32][CH2:31][CH2:30]2)[C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)=[O:18])=[N:13][CH:12]=1)(=[O:10])=[O:9])C.C1(CN(C2C=CC(F)=C(F)C=2)C(=O)NC2SC=C(CC(O)=O)N=2)CCCC1.FC1C=C(C=CC=1F)N.C1(C=O)CCCC1.C(OC(=O)CCNS(C1SC(N)=NC=1)(=O)=O)C.COC([C@@H]1CCCN1S(C1SC(N)=NC=1)(=O)=O)=O>>[CH:29]1([CH2:28][N:19]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[C:22]([F:27])[CH:21]=2)[C:17](=[O:18])[NH:16][C:14]2[S:15][C:11]([S:8]([NH:7][CH2:6][CH2:5][C:4]([OH:34])=[O:3])(=[O:10])=[O:9])=[CH:12][N:13]=2)[CH2:33][CH2:32][CH2:31][CH2:30]1
Reactant: CCOC(=O)CCNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1
Agent: CCOC(=O)CCNS(=O)(=O)c1cnc(N)s1
Agent: COC(=O)[C@@H]1CCCN1S(=O)(=O)c1cnc(N)s1
Agent: Nc1ccc(F)c(F)c1
Product: O=C(O)CCNS(=O)(=O)c1cnc(NC(=O)N(CC2CCCC2)c2ccc(F)c(F)c2)s1

Procedure:
The title compound was prepared via 3-{2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)ureido]-thiazole-5-sulfonylamino}-propionic acid ethyl ester in a similar manner as described for the synthesis of {2-[3-cyclopentylmethyl-3-(3,4-difluoro-phenyl)-ureido]-thiazol-4-yl}-acetic acid, using 3,4-difluoroaniline, cyclopentanecarbaldehyde and 3-(2-amino-thiazole-5-sulfonylamino)-propionic acid ethyl ester the latter prepared in a similar manner as (S)-1-(2-amino-thiazole-5-sulfonyl)-pyrrolidine-2-carboxylic acid methyl ester.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18]([OH:20])=O)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[O:8][N:9]=2.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:17][C:18](=[O:20])[N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)[C:5]2[C:6]([CH:16]=1)=[C:7]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[O:8][N:9]=2
Reactant: O=C(O)Cc1cc(Cl)cc2c(-c3ccccc3)onc12
Reactant: C1CCNCC1
Product: O=C(Cc1cc(Cl)cc2c(-c3ccccc3)onc12)N1CCCCC1

Procedure:
The title compound is prepared by reacting the acid chloride of 5-chloro-3-phenyl-2,1-benzisoxazole-7-acetic acid with piperidine in an aprotic solvent and washing the reaction mixture with sodium bicarbonate solution.