Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][S:2][C:3]1[N:8]=[C:7]([C:9]2[C:10]([O:15][C:16]3[CH:21]=[CH:20][C:19]([NH2:22])=[CH:18][CH:17]=3)=[N:11][CH:12]=[CH:13][CH:14]=2)[CH:6]=[CH:5][N:4]=1.[C:23](=[S:38])(OC1C=CC=CN=1)OC1C=CC=CN=1>C(Cl)Cl>[N:22]([C:19]1[CH:18]=[CH:17][C:16]([O:15][C:10]2[C:9]([C:7]3[CH:6]=[CH:5][N:4]=[C:3]([S:2][CH3:1])[N:8]=3)=[CH:14][CH:13]=[CH:12][N:11]=2)=[CH:21][CH:20]=1)=[C:23]=[S:38]
Reactant: S=C(Oc1ccccn1)Oc1ccccn1
Reactant: CSc1nccc(-c2cccnc2Oc2ccc(N)cc2)n1
Solvent: ClCCl
Product: CSc1nccc(-c2cccnc2Oc2ccc(N=C=S)cc2)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
A dry 100 ml round bottom flask, under nitrogen, was charged with 4-(3-(2-(methylthio)pyrimidin-4-yl)pyridin-2-yloxy) benzenamine (1.72 g, 5.54 mmol), O,O-dipyridin-2-yl carbonothioate (1.35 g, 5.82 mmol), and DCM (37 ml, 0.15 M). The vessel was closed, kept under nitrogen, and mixture stirred at RT for 18 h. The reaction was diluted with 20 ml DCM and washed with water. The organic layer was collected, dried with Na2SO4, filtered, and concentrated to give 4-(2-(4-isothiocyanatophenoxy)pyridin-3-yl)-2-(methylthio)pyrimidine as a yellow solid. MS m/z=353.0 [M+H]+. Calc'd for C17H12N4OS2: 352.43.
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)(=[O:3])[CH3:2].BrCC(C1C=CC=CC=1)=O.[N-:20]=[N+:21]=[N-:22].[Na+]>>[N:20]([CH2:2][C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)=[O:3])=[N+:21]=[N-:22]
Reactant: CC(=O)c1ccccc1
Reactant: [N-]=[N+]=[N-]
Agent: O=C(CBr)c1ccccc1
Agent: [Na+]
Product: [N-]=[N+]=NCC(=O)c1ccccc1

Procedure:
The synthesis of 2,5-substituted thiazoles is described in Scheme 9. Reaction of the desired alcohol para-methoxybenzyl alcohol (PMB-OH) with substituted 4-fluoroacetophenone 1 afforded the acetophenone intermediate 2. Acetophenone intermediate 2 was then converted to the corresponding bromo-acetophenone using Bu4NBr3 which, upon reaction with NaN3, provided the azido-acetophenone intermediate. Hydrogenation of the azido-acetophenone intermediate afforded amine 3, followed by coupling with orthogonally protected amino acid 4 gave amide 5. Removal of PMB group under hydrogenation gave phenol 6. Mitsunobu reaction of the phenol 6 with the desired alcohol followed by thiazole formation under Lawesson's reagent conditions afforded intermediate 7 in good yield. Removal of the protecting group from intermediate 7 afforded the final amino-alcohol 8.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][C@@H:8]1[CH2:25][C:24]2[CH:23]=[C:22]([OH:26])[CH:21]=[CH:20][C:19]=2[C@@H:18]2[C@@H:9]1[C@H:10]1[C@@:14]([CH2:16][C@@H:17]2[F:27])([CH3:15])[C:13](=[O:28])[CH2:12][CH2:11]1.[I-:29].[Na+].O>C(C(C)=O)C>[F:27][C@H:17]1[CH2:16][C@@:14]2([CH3:15])[C@@H:10]([CH2:11][CH2:12][C:13]2=[O:28])[C@H:9]2[C@H:18]1[C:19]1[CH:20]=[CH:21][C:22]([OH:26])=[CH:23][C:24]=1[CH2:25][C@H:8]2[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][I:29]
Reactant: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCCl)[C@H]3[C@@H]1CCC2=O
Reactant: [I-]
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: C[C@]12C[C@H](F)[C@@H]3c4ccc(O)cc4C[C@@H](CCCCCCI)[C@H]3[C@@H]1CCC2=O
Temperature: 90 °C
Reaction time: 8 h
Yield: 102.8 %

Procedure:
2.7 g of 7α-(6-chlorohexyl)-11β-fluoro-3-hydroxy-estra-1,3,5(10)-trien-17-one is dissolved in 40 ml of ethylmethylketone, mixed with 3.0 g of sodium iodide and stirred overnight at a bath temperature of 90° C. For working-up, the reaction mixture is cooled to room temperature, stirred into water, extracted 3 times with ethyl acetate, washed with common salt solution, dried on magnesium sulfate and concentrated by evaporation in a vacuum. 3.4 g of 11β-fluoro-3-hydroxy-7α-(6-iodohexyl)-estra-1,3,5(10)-trien-17-one is obtained as a crude product, which is used without further purification in the next stage.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]2[C:6]([CH2:7][CH2:8][C:9]2=[O:12])=[CH:5][CH:4]=1.[CH3:13][CH:14](O)[CH:15]=[CH2:16].COC(OC)(C)C.C1(C)C=CC(S(O)(=O)=O)=CC=1>C1(C)C=CC=CC=1>[CH2:13]([CH:8]1[CH2:7][C:6]2[C:10](=[CH:11][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]1=[O:12])[CH:14]=[CH:15][CH3:16]
Reactant: COc1ccc2c(c1)C(=O)CC2
Reactant: C=CC(C)O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: COC(C)(C)OC
Solvent: Cc1ccccc1
Product: CC=CCC1Cc2ccc(OC)cc2C1=O
Yield: 55 %

Procedure:
A solution of 20.0 g of 6-methoxy-1-indanone, 31.3 ml of 3-buten-2-ol, 53.5 ml of 2,2-dimethoxypropane and 200 mg of p-toluenesulfonic acid in 200 ml of toluene was brought to boiling. The resulting methanol/acetone mixture was distilled off and the reaction solution was subsequently boiled under reflux overnight. After cooling, the solution was washed with 50 ml of saturated sodium hydrogen carbonate solution. The aqueous washing was extracted with 50 ml of ethyl acetate, the organic phases were combined, dried with magnesium sulfate and evaporated in a vacuum. Purification on silica gel (hexane/diethyl ether 5:1) yielded 13.6 g (55%) of (RS)-2-(2-buten-1-yl)-6-methoxy-1-indanone as a pale yellow oil.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:30]=[CH:29][C:6]([CH2:7][N:8]([C:19]2[CH:27]=[CH:26]C=C3[C:20]=2[CH2:21][O:22]C3=O)[C:9](=[O:18])[C:10](=O)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH:5][CH:4]=1.[O-]S([O-])(=O)=O.[Na+].[Na+].[O-]CC.[Na+].C(O)C.[C:45]([O:49][CH2:50][CH3:51])(=[O:48])[CH2:46][CH3:47]>>[OH:22][C:21]1[C:20]2[C:46]([C:45]([O:49][CH2:50][CH3:51])=[O:48])=[CH:47][CH:26]=[CH:27][C:19]=2[N:8]([CH2:7][C:6]2[CH:29]=[CH:30][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9](=[O:18])[C:10]=1[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: CCOC(=O)CC
Reactant: COc1ccc(CN(C(=O)C(=O)c2ccccc2)c2cccc3c2COC3=O)cc1
Agent: CC[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cccc2c1c(O)c(-c1ccccc1)c(=O)n2Cc1ccc(OC)cc1
Temperature: 0 °C
Reaction time: 18 h
Yield: 80 %

Procedure:
A mixture of N-(4-methoxybenzyl)-2-oxo-N-(1-oxo-1,3-dihydroisobenzofuran-4-yl)-2-phenylacetamide (4.7 g, 11.7 mmol) and anhydrous Na2SO4 (16.6 g, 117 mmol) in anhydrous ethyl propionate (120 mL) was cooled to 0° C. Then a solution of sodium ethoxide in ethanol (sodium (673 mg, 29.2 mmol) in anhydrous ethanol (70 mL)) was added dropwise. After the addition, the mixture was stirred at room temperature for 18 hr. The mixture was quenched with water (100 mL) and solvent was removed in vacuum. The residue was dissolved in water, and then extracted with ethyl acetate (250 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate, and concentrated to give product (4.02 g, yield 80%). LC-MS (ESI) m/z: 430 (M+1)+. 1H-NMR (400 MHz, DMSO-d6) δ (ppm): 1.23-1.26 (t, J=6.8 Hz, 3H), 3.69 (s, 3H), 4.21-4.23 (m, 2H), 5.46 (s, 1H), 6.86-6.88 (d, J=7.6 Hz, 2H), 7.11-7.18 (m, 3H), 7.36-7.55 (m, 7H), 10.59 (s, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1.C([Li])CCC.CCCCCC.[B:25](OC(C)C)([O:30]C(C)C)[O:26]C(C)C>C1COCC1>[B:25]([C:2]1[CH:7]=[CH:6][C:5]([C:8]([CH3:13])([CH3:12])[C:9]([OH:11])=[O:10])=[CH:4][CH:3]=1)([OH:30])[OH:26]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)(C(=O)O)c1ccc(Br)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CC(C)(C(=O)O)c1ccc(B(O)O)cc1
Temperature: -50 °C
Reaction time: 2 h
Yield: 101.3 %

Procedure:
To a solution of 2-(4-bromophenyl)-2-methylpropanoic acid (15 g, 61.7 mmol) in anhydrous THF (150 mL) was added at −78° C. under argon a 2.5 M solution of n-butyllithium in hexane (37 ml, 92.6 mmol) dropwise, followed by triisopropyl borate (43 ml, 185.1 mmol). After the addition, the reaction mixture was stirred at −50° C. for 2 hrs and allowed to warm up to room temperature and stirred over night. The reaction mixture was quenched with 1 N HCl then extracted with EtOAc and washed successively with water and brine, dried over MgSO4, filtered and evaporated to give 13 g of product as a white solid in 99% yield. 1H NMR (400 MHz, DMSO): δ 1.41 (s, 6H), 7.25-7.27 (d, 2H), 7.29-7.47 (dd, 1H), 7.68-7.70 (d, 1H), 12.31 (s, 1H).
Reaction SMILES: [NH2:1][C@@H:2]([CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[C:3]([NH:5][C@H:6]([B:12]1[O:16][C@@H:15]2[CH2:17][C@@H:18]3[CH2:21][C@H:20]([C@:14]2([CH3:24])[O:13]1)[C:19]3([CH3:23])[CH3:22])[CH2:7][CH:8]1[CH2:11][CH2:10][CH2:9]1)=[O:4].Cl.C(N(CC)C(C)C)(C)C.[O:42]([C:49]1[N:54]=[CH:53][C:52]([S:55](Cl)(=[O:57])=[O:56])=[CH:51][CH:50]=1)[C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=1>C1COCC1>[CH:8]1([CH2:7][C@H:6]([NH:5][C:3](=[O:4])[C@@H:2]([NH:1][S:55]([C:52]2[CH:53]=[N:54][C:49]([O:42][C:43]3[CH:48]=[CH:47][CH:46]=[CH:45][CH:44]=3)=[CH:50][CH:51]=2)(=[O:56])=[O:57])[CH2:25][C:26]2[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=2)[B:12]2[O:16][C@@H:15]3[CH2:17][C@@H:18]4[CH2:21][C@H:20]([C@:14]3([CH3:24])[O:13]2)[C:19]4([CH3:23])[CH3:22])[CH2:11][CH2:10][CH2:9]1
Reactant: O=S(=O)(Cl)c1ccc(Oc2ccccc2)nc1
Reactant: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@@H](N)Cc4ccccc4)O[C@@]3(C)[C@H]1C2
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CC1(C)[C@@H]2C[C@H]3OB([C@H](CC4CCC4)NC(=O)[C@H](Cc4ccccc4)NS(=O)(=O)c4ccc(Oc5ccccc5)nc4)O[C@@]3(C)[C@H]1C2
Temperature: 25 °C
Reaction time: 8 h

Procedure:
Into a 20 mL vial was added (2S)-2-amino-N-{(1R)-2-cyclobutyl-1-[(3aS,4S,6S,7aR)-3a,5,5-trimethylhexahydro-4,6-methano-1,3,2-benzodioxaborol-2-yl]ethyl}-3-phenylpropanamide.HCl (46.3 mg, 0.109 mmol) (prepared as described in Example, THF (1.47 mL), N,N diisopropylethylamine (47.5 μL), and 6-phenoxy-3-pyridine sulfonyl chloride (32.4 mg.) The mixture was stirred at room temperature overnight. The product was purified by preparative TLC on silica plates using 50% ethyl acetate in hexanes to give 35 mg desired product as a white solid.
Reaction SMILES: COC(=O)N[C@@H](C(C)C)C(N1[C@H](C2NC(C3C=CC(C4C=CC5C(=CC=C(C6NC([C@@H]7CCCN7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=NC=6)C=5)C=4)=CC=3)=CN=2)CC2(OCCO2)C1)=O.Cl.Cl.Cl.[F:69][C:70]1([F:121])[C:82]2[CH:81]=[C:80]([C:83]3[CH:84]=[CH:85][C:86]4[N:90]=[C:89]([C@@H:91]5[CH2:95][CH2:94][CH2:93][N:92]5[C:96](=[O:109])[C@@H:97]([NH:104][C:105](=[O:108])[O:106][CH3:107])[CH:98]5[CH2:103][CH2:102][O:101][CH2:100][CH2:99]5)[NH:88][C:87]=4[CH:110]=3)[CH:79]=[CH:78][C:77]=2[C:76]2[C:71]1=[CH:72][C:73]([C:111]1[NH:115][C:114]([C@@H:116]3[CH2:120][CH2:119][CH2:118][NH:117]3)=[N:113][CH:112]=1)=[CH:74][CH:75]=2>>[CH3:107][O:106][C:105](=[O:108])[NH:104][C@@H:97]([CH:98]1[CH2:103][CH2:102][O:101][CH2:100][CH2:99]1)[C:96]([N:92]1[CH2:93][CH2:94][CH2:95][C@H:91]1[C:89]1[NH:88][C:87]2[CH:110]=[C:83]([C:80]3[CH:79]=[CH:78][C:77]4[C:76]5[C:71](=[CH:72][C:73]([C:111]6[NH:115][C:114]([C@@H:116]7[CH2:120][CH2:119][CH2:118][N:117]7[C:48](=[O:61])[C@H:49]([NH:56][C:57]([O:59][CH3:60])=[O:58])[C:50]7[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=7)=[N:113][CH:112]=6)=[CH:74][CH:75]=5)[C:70]([F:69])([F:121])[C:82]=4[CH:81]=3)[CH:84]=[CH:85][C:86]=2[N:90]=1)=[O:109]
Reactant: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1
Reactant: COC(=O)N[C@H](C(=O)N1CC2(C[C@H]1c1ncc(-c3ccc(-c4ccc5cc(-c6cnc([C@@H]7CCCN7C(=O)[C@H](NC(=O)OC)c7ccccc7)[nH]6)ccc5c4)cc3)[nH]1)OCCO2)C(C)C
Agent: Cl
Product: COC(=O)N[C@H](C(=O)N1CCC[C@H]1c1nc2ccc(-c3ccc4c(c3)C(F)(F)c3cc(-c5cnc([C@@H]6CCCN6C(=O)[C@H](NC(=O)OC)c6ccccc6)[nH]5)ccc3-4)cc2[nH]1)C1CCOCC1

Procedure:
The title compound was prepared according to the method employed to prepare (S)-1-((S)-8-(5-(4-(6-(2-((S)-1-((R)-2-(methoxycarbonylamino)-2-phenylacetyl)pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)-3-methyl-1-oxobutan-2-ylcarbamic acid methyl ester, except that methyl (S)-2-((S)-2-(6-(9,9-difluoro-7-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)-9H-fluoren-2-yl)-1H-benzo[d]imidazol-2-yl)pyrrolidin-1-yl)-2-oxo-1-(tetrahydro-2H-pyran-4-yl)ethylcarbamate 3HCl salt was used instead of methyl (S)-3-methyl-1-oxo-1-((S)-8-(5-(4-(6-(2-((S)-pyrrolidin-2-yl)-1H-imidazol-5-yl)naphthalen-2-yl)phenyl)-1H-imidazol-2-yl)-1,4-dioxa-7-azaspiro[4.4]nonan-7-yl)butan-2-ylcarbamate 3HCl salt. MS (ESI) m/z 913.94 [M+H]+. (77.4 mg, 24%).
Reaction SMILES: [F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:18][CH2:17][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][CH2:36][C@@H:37]5CCCO5)[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:15][CH2:14]1)(=[O:12])=[O:11])[CH3:9].O1[CH2:50][CH2:49][CH2:48][C@H]1CN>>[F:1][C:2]([F:7])([F:6])[C:3]([OH:5])=[O:4].[CH2:8]([S:10]([N:13]1[CH2:14][CH2:15][CH:16]([C:19]2[C:27]3[C:22](=[C:23]([C:43]([NH2:45])=[O:44])[CH:24]=[C:25]([C:28]4[CH:33]=[C:32]([CH2:34][NH:35][C@H:36]([CH3:37])[C:49]([CH3:48])([CH3:50])[CH3:2])[CH:31]=[C:30]([F:42])[CH:29]=4)[CH:26]=3)[NH:21][CH:20]=2)[CH2:17][CH2:18]1)(=[O:11])=[O:12])[CH3:9]
Reactant: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CNC[C@@H]5CCCO5)c4)cc23)CC1
Reactant: NC[C@@H]1CCCO1
Solvent: O=C(O)C(F)(F)F
Product: CCS(=O)(=O)N1CCC(c2c[nH]c3c(C(N)=O)cc(-c4cc(F)cc(CN[C@H](C)C(C)(C)C)c4)cc23)CC1
Yield: 43.6 %

Procedure:
The title compound was prepared according to the general procedure of 3-[1-(ethylsulfonyl)-4-piperidinyl]-5-[3-fluoro-5-({[(2S)-tetrahydro-2-furanylmethyl]amino}methyl)phenyl]-1H-indole-7-carboxamide trifluoroacetate, substituting (2R)-3,3-dimethyl-2-butanamine (52 mg, 0.525 mmol) for 1-[(2S)-tetrahydro-2-furanyl]methanamine to afford 24.9 mg of the title compound (43.6%).
Reaction SMILES: [I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH2:15])(=[O:14])=[O:13])[CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH2:22]([N:26]=[C:27]=[O:28])[CH2:23][CH2:24][CH3:25].Cl>ClC1C=CC=CC=1.O>[I:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[C:4]([S:12]([NH:15][C:27]([NH:26][CH2:22][CH2:23][CH2:24][CH3:25])=[O:28])(=[O:13])=[O:14])[CH:3]=1
Reactant: COC(=O)c1ccc(I)cc1S(N)(=O)=O
Reactant: CCCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Clc1ccccc1
Solvent: O
Product: CCCCNC(=O)NS(=O)(=O)c1cc(I)ccc1C(=O)OC
Temperature: 90 °C
Reaction time: 2 h

Procedure:
34.1 g (0.1 mol) of the sulfonamide of the formula (IV) from Example 1 and 14.7 g of K2CO3 (0.105 mol) are admixed with 10.6 g of n-butyl isocyanate (98% pure) (0.105 mol) in 250 ml of chlorobenzene, and the mixture is kept at 55 to 60° C. for 2 hours. The mixture is then stirred at 90° C. for 8.5 h. The mixture is cooled to room temperature and initially 200 ml of water and then 2n of hydrochloric acid are added until the pH has reached 1-2. The organic phase is separated off and washed free of acid using four times 50 ml of water. The solvent is removed under reduced pressure, and 43.8 g of the desired compound of the formula (I) (99.3% of theory) of melting point 128 to 130° C. remain.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([Sn](CCCC)(CCCC)CCCC)=[CH:26][CH:25]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:21])[CH3:20])=[O:17]>CN(C=O)C.ClCCl.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[CH3:11][O:12][C:13](=[O:43])[C@H:14]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([C:2]2[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=2)=[CH:28][CH:29]=1)[NH:15][C:16]([O:18][C:19]([CH3:22])([CH3:20])[CH3:21])=[O:17]
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CCCC[Sn](CCCC)(CCCC)c1ccc(C[C@H](NC(=O)OC(C)(C)C)C(=O)OC)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)[C@H](Cc1ccc(-c2cc(Br)cn(C)c2=O)cc1)NC(=O)OC(C)(C)C
Temperature: 90 °C
Reaction time: 4 h
Yield: 30.1 %

Procedure:
solution of 3,5-dibromo-1-methyl-2-pyridone (267 mg, 1.0 mmol) and N-[(1,1-dimethylethoxy)carbonyl]-4-[(tributyl)stannyl]-L-phenylalanine methyl ester (568 mg, 1.0 mmol) in DMF (7 mL) was deoxygenated by alternately freezing the mixture in a liquid nitrogen bath under vacuum and thawing under argon (3×). bis(triphenylphosphine)palladium dichloride (80 mg, 0.11 mmol) was added and the mixture was heated to 90° C. for 3 hr as the mixture turned dark. TLC indicated that the reaction was not complete and an additional 40 mg portion of the catalyst was added and heating continued for 4 hr. The mixture was allowed to cool and was diluted with dichloromethane (40 mL) and was filtered through a pad of celite. The filtrate was evaporated to dryness and the residue was dissolved in ethyl acetate (30 mL). The solution was washed with water (1×10 mL), 5% potassium fluoride (2×10 mL) and brine (1×5 mL) and was dried (MgSO4). The residue obtained upon concentration was chromatographed over 45 g of silica gel eluting with 3:7 ethyl acetate:hexane to give 4-(5-bromo-1-methyl-2-oxo-3-pyridinyl)-N-[(1,1-dimethylethoxyl)carbonyl]-L-phenylalanine methyl ester (140 mg, 30%). FAB MS: 465 (M+H (1 Br)).
Reaction SMILES: [F:1][C:2]([F:36])([F:35])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][CH2:29]CS([O-])(=O)=O)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1.Cl.[C:38]1([C:44]2([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>>[F:1][C:2]([F:35])([F:36])[C:3]1[CH:4]=[C:5]([C:9]2([CH2:28][CH2:29][N:47]3[CH2:46][CH2:45][C:44]([C:38]4[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=4)([C:50]([NH2:52])=[O:51])[CH2:49][CH2:48]3)[CH2:13][CH2:12][N:11]([C:14](=[O:27])[C:15]3[CH:20]=[C:19]([O:21][CH3:22])[C:18]([O:23][CH3:24])=[C:17]([O:25][CH3:26])[CH:16]=3)[CH2:10]2)[CH:6]=[CH:7][CH:8]=1
Reactant: NC(=O)C1(c2ccccc2)CCNCC1
Reactant: COc1cc(C(=O)N2CCC(CCCS(=O)(=O)[O-])(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC
Agent: Cl
Product: COc1cc(C(=O)N2CCC(CCN3CCC(C(N)=O)(c4ccccc4)CC3)(c3cccc(C(F)(F)F)c3)C2)cc(OC)c1OC

Procedure:
Prepare by the method of example 3.3 using 2-[3-(3-trifluoromethyl-phenyl)-1-(3,4,5-trimethoxy-benzoyl)-pyrrolidin-3-yl]-ethyl-methanesulfonate (8 mmol) and 4-phenyl-piperidine-4-carboxylic acid amide hydrochloride (12 mmol). Chromatograph on silica gel to give the title compound.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2.C(N(CC)C(C)C)(C)C.[CH2:37](Cl)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1>C(#N)C>[CH2:37]([NH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH2:11][C:12]([C:20]1[CH:25]=[CH:24][C:23]([F:26])=[CH:22][C:21]=1[F:27])([OH:19])[CH2:13][N:14]1[CH:18]=[N:17][CH:16]=[N:15]1)[NH:6][CH2:5]2)[C:38]1[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=1
Reactant: ClCc1ccccc1
Reactant: Nc1ccc2c(c1)CNN2CC(O)(Cn1cncn1)c1ccc(F)cc1F
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: OC(CN1NCc2cc(NCc3ccccc3)ccc21)(Cn1cncn1)c1ccc(F)cc1F
Reaction time: 0.5 h
Yield: 84 %

Procedure:
To a solution of (5-Amino-2H-indazol-1-yl)-2-(2,4-difluorophenyl)-3-(1H-1,2,4-triazol-1-yl)propan-2-ol (0.065 g, 0.17 mmol) in acetonitrile (1 ml) was slowly added N,N-Diisopropylethylamine (0.033 ml, 0.19 mmol) at 0° C. and the solution was stirred for 30 min in the same condition. Benzylchloride (0.024 g, 0.19 mmol) was added to the solution, which was then stirred at room temperature for 2 hours and concentrated using vacuum evaporation. The crude product was purified by chromatography on silica gel to give the title compound. (Yield 84%).
Reaction SMILES: [N:1]1[CH:2]=[CH:3][N:4]2[C:9]([CH2:10][CH2:11][N:12]3[C:16](=[O:17])[CH2:15][S:14][C:13]3=[O:18])=[CH:8][CH:7]=[CH:6][C:5]=12.[CH:19](=O)[CH2:20][CH2:21][CH3:22].N1CCCCC1>C(O)C>[CH:19](=[C:15]1[S:14][C:13](=[O:18])[N:12]([CH2:11][CH2:10][C:9]2[N:4]3[CH:3]=[CH:2][N:1]=[C:5]3[CH:6]=[CH:7][CH:8]=2)[C:16]1=[O:17])[CH2:20][CH2:21][CH3:22]
Reactant: CCCC=O
Reactant: O=C1CSC(=O)N1CCc1cccc2nccn12
Solvent: C1CCNCC1
Solvent: CCO
Product: CCCC=C1SC(=O)N(CCc2cccc3nccn23)C1=O

Procedure:
To a solution of 1.18 g (4.5 mmol) of 3-[2-(imidazo[1,2-a]pyridin-5-yl)ethyl]thiazolidine-2,4-dione and 0.41 ml (4.5 mmol) of n-butyraldehyde in 20 ml of ethanol, 0.05 ml (0.5 mmol) of piperidine was added, followed by refluxing for 2 hours. After the reaction mixture was cooled, the solvent was distilled off. The residue was dissolved in chloroform, washed with water and dried, after which the solvent was distilled off. The residue was purified by column chromatography (eluent, hexane/ethyl acetate=1/2) to yield 1.15 g (81.0%, light yellow oily substance) of the desired product.
Reaction SMILES: [CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([NH2:6])=[CH:4][C:3]=2[O:2]1.[C:11](Cl)(Cl)=[O:12]>C1(C)C=CC=CC=1>[CH2:1]1[O:10][C:9]2[CH:8]=[CH:7][C:5]([N:6]=[C:11]=[O:12])=[CH:4][C:3]=2[O:2]1
Reactant: Nc1ccc2c(c1)OCO2
Reactant: O=C(Cl)Cl
Solvent: Cc1ccccc1
Product: O=C=Nc1ccc2c(c1)OCO2

Procedure:
A mixture of 3,4-methylenedioxyaniline (275 mg; 2.0 mmol) in toluene (15 ml) and phosgene (4.75 ml; 20% in toluene; 9 mmol) was refluxed for 6 h. The solvent was removed under reduced pressure to give crude 3,4-methylenedioxyphenylisocyanate. The crude product was added to 3-[4-(2-chlorophenyl) -1-piperazinyl]propanol (510 mg; 2.0 mmol) in toluene (30 ml) was refluxed for 16 h. The reaction mixture was then concentrated and submitted to flash chromatography on silica gel 60 eluting with toluene graduated to toluene/ethyl acetate (1:3). The product was taken up in ethanol which was treated with hydrogen chloride in ether. Recrystallization from methanol/ether afforded 550 mg of the title compound. M.p. 211°-213° C. MS (70 eV): m/z 37%, M+), 254 (28), 209 (100), 163 (75), 138 (32), 70 (42).
Reaction SMILES: C([CH:3]([C:14]([NH2:16])=[O:15])[C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)=[O:5])C.[CH2:17](N)[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].CN(C)C=O.Cl>C1(C)C=CC=CC=1>[CH2:17]([NH:16][C:14](=[O:15])[CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1)=[O:5])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCC(C(N)=O)C(=O)NCc1ccccc1
Reactant: CCCCCCCCN
Agent: Cl
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: CCCCCCCCNC(=O)CC(=O)NCc1ccccc1
Yield: 0.1 %

Procedure:
A solution of 1.1 g (5.0 mol) of ethyl N-benzylmalonamide in 30 mL of toluene was heated to reflux under nitrogen and 1.29 g (10.0 mol) of n-octylamine was added. The reaction was heated to reflux for 5 h and 5 mL of N,N-dimethylformamide was added. This mixture was kept at reflux for 12 h and poured into 5% aqueous hydrochloric acid. the organic layer was washed with saturated aqueous sodium bicarbonate, water, brine, and dried over magnesium sulfate. Filtration and removal of solvents afforded a crude solid which was recrystallized from 50% ethyl acetate/hexane to give 0.8 g (53% yield) of N-n-octyl-N'-benzylmalonamide.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1.[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1B(O)O.O>COCCOC.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[Cl:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][N:3]=1
Reactant: FC(F)(F)c1ccnc(Cl)c1
Reactant: OB(O)c1ccccc1Cl
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: O
Solvent: COCCOC
Product: FC(F)(F)c1ccnc(-c2ccccc2Cl)c1
Temperature: 110 °C
Yield: 89.1 %

Procedure:
A mixture of 2-chloro-4-(trifluoromethyl)pyridine (4 g, 22.0 mmol), 2-chlorophenylboronic acid (5.04 g, 24.2 mmol), Ba(OH)2 (12.5 g, 66.1 mmol) and Pd(PPh3)2Cl2 (464 mg, 0.66 mmol) in DME (140 mL)/water (35 mL) was heated at 110° C. for 1 h. The solids were filtered off and the mother liquor were concentrated to around 80 mL and extracted with EtOAc. The organic layer was washed with brine, then water, dried (MgSO4), filtered and concentrated. Purification by column chromatography (1/1 Petroleum ether/EtOAc) gave the Suzuki adduct (5.05 g, 89%) as a colourless oil.