Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([O:25][CH3:26])=[C:6]([C:8]2[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])=[CH:11][NH:10][N:9]=2)[CH:7]=1.I[CH:28]1[CH2:31][N:30](C(OC(C)(C)C)=O)[CH2:29]1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[NH:30]1[CH2:31][CH:28]([N:10]2[CH:11]=[C:12]([NH:13][C:14]([C:16]3[CH:17]=[N:18][N:19]4[CH:24]=[CH:23][CH:22]=[N:21][C:20]=34)=[O:15])[C:8]([C:6]3[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=3[O:25][CH3:26])=[N:9]2)[CH2:29]1
Reactant: CC(C)(C)OC(=O)N1CC(I)C1
Reactant: COc1ccc(Cl)cc1-c1n[nH]cc1NC(=O)c1cnn2cccnc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: COc1ccc(Cl)cc1-c1nn(C2CNC2)cc1NC(=O)c1cnn2cccnc12
Temperature: 50 °C
Reaction time: 5 h
Yield: 22 %

Procedure:
A suspension of N-(3-(5-chloro-2-methoxyphenyl)-1H-pyrazol-4-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (50.0 mg, 0.136 mmol, 1 equiv), tert-butyl 3-iodoazetidine-1-carboxylate (230.3 mg, 0.813 mmol, 6.00 equiv), and cesium carbonate (177 mg, 0.542 mmol, 4.00 equiv) in N,N-dimethylformamide (1 mL) was heated at 50° C. After 5 h, the reaction mixture was partitioned between saturated aqueous sodium chloride solution (5 mL) and ethyl acetate (5 mL). The aqueous layer was extracted with ethyl acetate (2×5 mL). The combined organic was dried over anhydrous sodium sulfate, filtered, and concentrated. The crude residue was dissolved in dichloromethane (2 mL) and trifluoroacetic acid (2 mL) at 24° C. After 5 h, the reaction mixture was concentrated in vacuo and purified by preparative HPLC to afford product (12.7 mg, 22% yield). 1H NMR (400 MHz, DMSO-d6), δ: 9.75 (s, 1H), 9.36 (m, 1H), 8.79 (m, 1H), 8.67 (s, 1H), 8.46 (s, 1H), 7.53-7.56 (m, 2H), 7.29-7.34 (m, 2H), 5.45 (m, 1H), 4.33 (m, 2H), 4.23 (m, 2H), 3.86 (s, 3H). LCMS (ESI): M+H=424.1.
Reaction SMILES: Br[C:2]1[C:10]2[S:9][C:8]([NH:11][C:12](=[O:16])[NH:13][CH2:14][CH3:15])=[N:7][C:6]=2[CH:5]=[C:4]([C:17]2[CH:18]=[N:19][C:20]([N:23]3[CH2:28][CH2:27][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:25][CH2:24]3)=[N:21][CH:22]=2)[CH:3]=1.[C:35]([C:37]1[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=1)#[CH:36]>C(N(CC)CC)C.CCOC(C)=O.[Cu]I.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>[CH2:14]([NH:13][C:12]([NH:11][C:8]1[S:9][C:10]2[C:2]([C:36]#[C:35][C:37]3[N:41]([CH3:42])[CH:40]=[N:39][CH:38]=3)=[CH:3][C:4]([C:17]3[CH:22]=[N:21][C:20]([N:23]4[CH2:24][CH2:25][C:26]([CH3:34])([C:29]([O:31][CH2:32][CH3:33])=[O:30])[CH2:27][CH2:28]4)=[N:19][CH:18]=3)=[CH:5][C:6]=2[N:7]=1)=[O:16])[CH3:15]
Reactant: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(Br)c2s1
Reactant: C#Cc1cncn1C
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CCNC(=O)Nc1nc2cc(-c3cnc(N4CCC(C)(C(=O)OCC)CC4)nc3)cc(C#Cc3cncn3C)c2s1
Temperature: 80 °C

Procedure:
Ethyl 1-[5-[7-bromo-2-(ethylcarbamoylamino)-1,3-benzothiazol-5-yl]pyrimidin-2-yl]-4-methyl-piperidine-4-carboxylate (150 mg, 0.27 mmol), copper(I) iodide (5 mg, 0.027 mmol) and 5-ethynyl-1-methyl-1H-imidazole (56 μl, 0.54 mmol) were dissolved in triethylamine (2 mL) and DMF (1 mL) and the mixture deoxygenated by bubbling N2 through the solution for 20 min. Pd(PPh3)2Cl2, (19 mg, 0.027 mmol) was added and the reaction heated to 80° C. for 4 h under a N2 atmosphere, at the end of which time LCMS indicated product formation. The reaction was diluted with EtOAc, washed with water then brine and the organic layer dried (MgSO4), filtered and the solvent removed in vacuo to give the desired compound.
Reaction SMILES: CS(O[CH2:6][C@@H:7]1[O:12][C:11]2[CH:13]=[CH:14][CH:15]=[C:16]([C:17]([NH2:19])=[O:18])[C:10]=2[O:9][C@H:8]1[CH2:20]OS(C)(=O)=O)(=O)=O>C(N)C1C=CC=CC=1>[C:16]1([CH2:17][N:19]2[CH2:20][C@@H:8]3[O:9][C:10]4[C:16]([C:17]([NH2:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:11]=4[O:12][C@H:7]3[CH2:6]2)[CH:10]=[CH:11][CH:13]=[CH:14][CH:15]=1
Reactant: CS(=O)(=O)OC[C@@H]1Oc2cccc(C(N)=O)c2O[C@H]1COS(C)(=O)=O
Solvent: NCc1ccccc1
Product: NC(=O)c1cccc2c1O[C@H]1CN(Cc3ccccc3)C[C@@H]1O2
Reaction time: 1 h
Yield: 189.6 %

Procedure:
A solution of Compound D (6.76 g) in benzylamine (10 ml) was heated to 120° for 10 minutes. The warm (85°) solution was poured into stirred, distilled water (300 ml) at room temperature. An oil deposited which quickly solidified. After 1 hour's brisk stirring, the buff coloured particulate solid was collected, washed with water and dried to give the title compound 5.03 g, m.pt 155°-165°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[N:9][C:10]2[CH:15]=[CH:14][C:13]([S:16]([F:19])(=[O:18])=[O:17])=[CH:12][CH:11]=2)[CH:5]=[CH:4][C:3]=1[OH:20].[N+:21]([O-])([OH:23])=[O:22].S(=O)(=O)(O)O>>[Cl:1][C:2]1[CH:7]=[C:6]([N:8]=[N:9][C:10]2[CH:11]=[CH:12][C:13]([S:16]([F:19])(=[O:17])=[O:18])=[CH:14][CH:15]=2)[CH:5]=[C:4]([N+:21]([O-:23])=[O:22])[C:3]=1[OH:20]
Reactant: O=[N+]([O-])O
Reactant: O=S(=O)(F)c1ccc(N=Nc2ccc(O)c(Cl)c2)cc1
Agent: O=S(=O)(O)O
Product: O=[N+]([O-])c1cc(N=Nc2ccc(S(=O)(=O)F)cc2)cc(Cl)c1O
Temperature: -30 °C
Reaction time: 0.22 h

Procedure:
Solid 2-Chloro-4-(4-fluorosulfonylphenylazo)phenol (7.5 g. 23 mmol) was added rapidly to a vigorously stirred mixture of 15 ml concentrated nitric acid and 15 ml concentrated sulfuric acid, cooled to -30° C. After 13 minutes of stirring, the reaction mixture was poured into 400 ml ice water with vigorous stirring. The resulting precipitate was filtered off and washed with water. During drying on the funnel the solid softened and became tarry. When the tar was dissolved in acetic acid and then carefully and slowly diluted with water, a fine precipitate separated and was filtered off. This process was repeated with the filtrate until the resulting precipitate no longer separated as a solid. The collected solids were combined and air dried. Yield: 3.1 g, (37%) m.p. 129°-133° C.
Reaction SMILES: [BH4-].[Na+].[F:3][CH:4]([F:33])[CH2:5][O:6][C:7]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]([B:22]3[O:26]C(C)(C)C(C)(C)[O:23]3)=[C:18]([CH:31]=O)[CH:17]=2)[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]>CO.C(Cl)Cl>[F:33][CH:4]([F:3])[CH2:5][O:6][C:7]1[N:14]=[C:13]([O:15][C:16]2[CH:21]=[CH:20][C:19]3[B:22]([OH:26])[O:23][CH2:31][C:18]=3[CH:17]=2)[CH:12]=[CH:11][C:8]=1[C:9]#[N:10]
Reactant: CC1(C)OB(c2ccc(Oc3ccc(C#N)c(OCC(F)F)n3)cc2C=O)OC1(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: N#Cc1ccc(Oc2ccc3c(c2)COB3O)nc1OCC(F)F
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
A solution of NaBH4 (0.100 g, 2.6 mmol) in anhydrous methanol (20 mL) was added to a solution of 2-(2,2-difluoro-ethoxy)-6-[3-formyl-4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenoxy]-nicotinonitrile (5.20 g, 12.1 mmol) in CH2Cl2 (80 mL) and stirred at room temperature for 5 minutes. Solid NaBH4 (0.815 g, 21.5 mmol) was then added portionwise over 30 minutes to the reaction at room temperature and the reaction stirred for an additional 30 minutes. The reaction was quenched by the addition of 60% aqueous acetic acid (5 mL), stirred for 30 minutes at room temperature then concentrated in vacuo. The residue was purified by silica gel flash column chromatography (AcOH/MeOH/CH2Cl2 1:1:100 v/v/v) to give the title compound as a viscous oil which was lyophilized to give a white solid (1.92 g, 48% yield).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:6]=1[OH:12])([CH3:4])([CH3:3])[CH3:2].[C:13](O)(=[O:16])[CH:14]=[O:15]>ClCCCl.C1(C)C=CC(S(O)(=O)=O)=CC=1>[C:1]([C:5]1[C:6]2[O:12][C:14](=[O:15])[CH:13]([OH:16])[C:7]=2[CH:8]=[C:9]([Cl:11])[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=CC(=O)O
Reactant: CC(C)(C)c1cc(Cl)ccc1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: ClCCCl
Product: CC(C)(C)c1cc(Cl)cc2c1OC(=O)C2O
Yield: 31.5 %

Procedure:
2.8 g of 2-tert-butyl-4-chlorophenol [J. Amer. Chem. Soc. 78, 4604 (1956)] are refluxed for 3¼ h with 2.45 g of 50% aqueous glyoxylic acid and 50 mg of p-toluenesulfonic acid in 20 ml of 1,2-dichloroethane. Thereafter a further 2.45 g of 50% aqueous glyoxylic acid are added to continue refluxing for 18 h. The reaction mixture is then washed with water, dried over MgSO4 and evaporated in a rotary evaporator. Crystallization of the residue from hexane leaves 1.15 g of 7-tert-butyl-5-chloro-3-hydroxy-3H-benzofuran-2-one (melting point: 150-154° C.).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([O:13]CC)=O)=[N:9][N:10]=2)[CH:7]=1.Cl.Cl.[F:18][C:19]1[CH:20]=[CH:21][C:22]([C:31]([F:34])([F:33])[F:32])=[C:23]([CH:25]2[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]2)[CH:24]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C1COCC1.O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([C:11]([N:28]3[CH2:29][CH2:30][CH:25]([C:23]4[CH:24]=[C:19]([F:18])[CH:20]=[CH:21][C:22]=4[C:31]([F:34])([F:32])[F:33])[CH2:26][CH2:27]3)=[O:13])=[N:9][N:10]=2)[CH:7]=1
Reactant: Fc1ccc(C(F)(F)F)c(C2CCNCC2)c1
Reactant: CCOC(=O)c1nnc2ccc(Br)cn12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(c1nnc2ccc(Br)cn12)N1CCC(c2cc(F)ccc2C(F)(F)F)CC1
Reaction time: 0.33 h
Yield: 64.3 %

Procedure:
To a solution of ethyl 6-bromo-[1,2,4]triazolo[4,3-a]pyridine-3-carboxylate (85 mg, 0.32 mmol) in THF (2.6 mL) was added a solution of LiOH monohydrate (15 mg, 0.35 mmol) in H2O (1.8 mL). The mixture stirred for 20 min and was neutralized with 2 N HCl. The mixture was concentrated under reduced pressure. The obtained residue was diluted in DMF (3.0 mL) under an atmosphere of N2. To this mixture was added 4-(5-fluoro-2-trifluoromethyl)phenylpiperidine hydrochloride (11, 89 mg, 0.32 mmol), benzotriazole-1-yl-oxy-tris-(dimethylamino)-phosphonium hexafluorophosphate (280 mg, 0.63 mmol), and diisopropylethylamine (0.17 mL, 0.95 mmol). The mixture was stirred at ambient temperature for 18 h. The resulting mixture was diluted with H2O (20 mL). The solution was extracted with EtOAc (3×20 mL). The combined organic layers were washed with a saturated brine solution (3×20 mL) and concentrated under reduced pressure. The resulting residue was chromatographed over silica gel (Isco CombiFlash Rf unit, 12 g Redisep column, 0% to 50% EtOAc in hexanes) to provide to provide (6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)(4-(5-fluoro-2-(trifluoromethyl)phenyl)piperidin-1-yl)methanone as a white solid (97 mg, 65%): 1H NMR (500 MHz, DMSO-d6) δ 9.16-9.14 (m, 1H), 7.98 (dd, J=10.0, 1.0 Hz, 1H), 7.77 (dd, J=8.5, 5.5 Hz, 1H), 7.72 (dd, J=9.5, 1.5 Hz, 1H), 7.52 (dd, J=11.0, 3.5 Hz, 1H), 7.29-7.23 (m, 1H), 5.31-5.24 (m, 1H), 4.76-4.70 (m, 1H), 3.42-3.32 (m, 1H), 3.27-3.19 (m, 1H), 3.06-2.96 (m, 1H), 1.98-1.75 (m, 4H).
Reaction SMILES: [CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][NH:29][CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[CH3:60][N:61]1[CH2:66]C[O:64][CH2:63][CH2:62]1.Cl.CN(C)CC(O)=O.C[O-].[Na+].N>C1COCC1.CO.C(Cl)Cl>[CH2:1]([N:8]1[CH:16]=[C:15]2[C:10]([CH:11]=[C:12]([C:17]3[CH:18]=[C:19]([CH:27]4[O:32][CH2:31][CH2:30][N:29]([C:63](=[O:64])[CH2:62][N:61]([CH3:66])[CH3:60])[CH2:28]4)[N:20]4[C:25]=3[C:24]([NH2:26])=[N:23][CH:22]=[N:21]4)[CH:13]=[CH:14]2)=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Nc1ncnn2c(C3CNCCO3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CN1CCOCC1
Agent: CN(C)CC(=O)O
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: C[O-]
Solvent: ClCCl
Solvent: CO
Solvent: C1CCOC1
Product: CN(C)CC(=O)N1CCOC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 70.9 %

Procedure:
A solution in THF (1 mL) containing 5-(2-benzyl-2H-indazol-6-yl)-7-morpholin-2-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine (170 mg, 0.315 mmol), (1H-benzotriazol-1-yloxy)[tris(dimethylamino)]phosphonium hexafluorophosphate (209 mg, 0.47 mmol), N-methylmorpholine (111 mg, 1.1 mmol) and N,N-dimethylglycine hydrochloride (65.9 mg, 0.47 mmol) was stirred at rt for one hour. The reaction was diluted with 1 mL MeOH and treated with 25% sodium methoxide solution in MeOH (100 uL, 2 mmol). After an additional 30 min stirring at rt, the reaction was partitioned between EtOAc and 2N sodium carbonate solution. The organic phase was separated, dried with sodium sulfate and concentrated in vacuo to provide a dark orange solid. This material was taken up in 9.5 mL CH2Cl2 and 0.5 mL 7N NH3 in MeOH. The resulting solution was filtered through a silica plug (pretreated with NH3) and the volatiles removed in vacuo. Trituration of the resulting solid with ether provided 114 mg (71%) of the desired product as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 8.55 (s, 1 H), 7.98 (d, 1 H, J=4 Hz)), 7.60 (s, 1 H), 7.50-7.60 (m, 2H), 7.14 (d, 1H, J=7 Hz), 6.80 (s, 1H), 7.27-7.41 (m, 5H), 5.65 (s, 2H), 4.89-5.06 (m, 1H), 4.18-4.52 (m, 2H), 3.86-4.04 (m, 2H), 3.21-3.65 (m, 2H), 3.30 (s, 2H), 2.19 (s, 3H), 2.15 (s, 3H); ES-MS m/z 511.3 [M+H]+, HPLC RT (min) 2.12 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH:11]3[CH2:16][CH2:15][N:14]([CH2:17][CH2:18][NH2:19])[CH2:13][CH2:12]3)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[F:20][C:21]1[CH:22]=[C:23]2[C:28](=O)[O:27][C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1.C(Cl)Cl.CO>CN(C=O)C>[F:20][C:21]1[CH:22]=[C:23]2[C:28](=[O:27])[N:19]([CH2:18][CH2:17][N:14]3[CH2:13][CH2:12][CH:11]([C:6]4[C:5]5[C:9](=[CH:10][C:2]([F:1])=[CH:3][CH:4]=5)[NH:8][N:7]=4)[CH2:16][CH2:15]3)[C:25](=[O:26])[C:24]2=[CH:30][CH:31]=1
Reactant: O=C1OC(=O)c2cc(F)ccc21
Reactant: NCCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CO
Product: O=C1c2ccc(F)cc2C(=O)N1CCN1CCC(c2n[nH]c3cc(F)ccc23)CC1
Temperature: 80 °C
Yield: 37.8 %

Procedure:
To a solution consisting of 2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethylamine (6.1 g, 23.2 mmol) in DMF (230 ml) was added 4-fluorophthalic anhydride (4.2 g, 25.5 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to 80° C. for 2.5 hours at which time it was allowed to cool to room temperature. The DMF was removed under reduced pressure (<0.5 mmHg, 55° C.) to give a brown oil which was dissolved into DCM/MeOH. Purification via flash column chromatography (silica gel, 2% MeOH/DCM) afforded 3.6 g of 4-fluoro-N-[2-[4-(6-fluoro-1H-indazol-3-yl)-1-piperidinyl]ethyl]phthalimide. To a solution of the latter compound (3.6 g 8.8 mmol) in anhydrous THF (100 ml) was added LAH (18.4 ml of a 1.0M solution in THF, 18.4 mmol) at room temperature, under nitrogen. The reaction mixture was warmed to reflux for 4 hours. Upon cooling to room temperature, the reaction was quenched with water (1.5 ml, dropwise). The precipitated salts were removed via filtration and washed with DCM. The combined filtrates were concentrated to give a solid which was purified via flash column chromatography (silica gel, 0-8% MeOH/DCM). The product containing fractions were concentrated to give 2.4 g product as an off-white solid. The dimaleate salt was prepared in methanol using 2.4 eq. of maleic acid. The white precipitate was collected via filtration and washed with methanol, m.p. 186°-188° C.
Reaction SMILES: [C:1]([S:9][CH2:10][CH2:11][C:12]([N:14]1[C@H:18]([C:19]([OH:21])=O)[CH2:17][S:16][C@@H:15]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=1[OH:28])=[O:13])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN1CCOCC1.C(Cl)(=O)OCC(C)C.Cl.[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH2:50])[CH3:46]>C1COCC1.O>[CH2:45]([O:47][C:48](=[O:51])[CH2:49][NH:50][C:19]([C@@H:18]1[CH2:17][S:16][C@H:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[OH:28])[N:14]1[C:12](=[O:13])[CH2:11][CH2:10][S:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:21])[CH3:46]
Reactant: O=C(SCCC(=O)N1[C@@H](c2ccccc2O)SC[C@H]1C(=O)O)c1ccccc1
Reactant: CCOC(=O)CN
Agent: CC(C)COC(=O)Cl
Agent: Cl
Solvent: O
Solvent: CN1CCOCC1
Solvent: C1CCOC1
Product: CCOC(=O)CNC(=O)[C@@H]1CS[C@H](c2ccccc2O)N1C(=O)CCSC(=O)c1ccccc1
Reaction time: 0.25 h
Yield: 96.6 %

Procedure:
To the solution of 2.09 g of (2R,4R)-3-(S-benzoyl-3-mercaptopropanoyl)-2-(2-hydroxyphenyl)-4-thiazolidinecarboxylic acid dissolved in 30 ml of dry THF, 0.51 g of N-methylmorpholine is added. To the mixture 0.68 g of isobutyl chlorocarbonate is added at a temperature of -15° to -10° C. After stirring it for 15 minutes, the solution of 0.7 g of glycine ethyl ester hydrochloride and 0.51 g of N-methylmorpholine dissolved in 5 ml of THF and 15 ml of water is added to it. After stirring it for 1 hour while being back to the room temperature gradually, and then removing THF in vacuo, the mixture is extracted with ethyl acetate. The organic layer is washed with N--HCl, water, saturated aqueous sodium chloride solution, in order, dried over anhydrous magnesium sulfate, and concentrated in vacuo. The residue is crystallized from ethyl acetate-benzene to give 2.43 g (82%) of the titled compound.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][C:3]=1[N:11]1[CH:15]=[C:14]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)[N:13]=[N:12]1.[NH2:22][C:23]1[C:24]([O:38][CH3:39])=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[CH:26]=[C:27]([C:29]([CH3:32])([CH3:31])[CH3:30])[CH:28]=1>>[C:29]([C:27]1[CH:26]=[C:25]([NH:33][S:34]([CH3:37])(=[O:36])=[O:35])[C:24]([O:38][CH3:39])=[C:23]([NH:22][C:6](=[O:8])[C:5]2[CH:9]=[CH:10][C:2]([F:1])=[C:3]([N:11]3[CH:15]=[C:14]([C:16]4[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=4)[N:13]=[N:12]3)[CH:4]=2)[CH:28]=1)([CH3:32])([CH3:30])[CH3:31]
Reactant: COc1c(N)cc(C(C)(C)C)cc1NS(C)(=O)=O
Reactant: O=C(O)c1ccc(F)c(-n2cc(-c3cccnc3)nn2)c1
Product: COc1c(NC(=O)c2ccc(F)c(-n3cc(-c4cccnc4)nn3)c2)cc(C(C)(C)C)cc1NS(C)(=O)=O

Procedure:
Example 5 was prepared by coupling 4-fluoro-3-(4-pyridin-3-yl-[1,2,3]triazol-1-yl)-benzoic acid with N-(3-amino-5-tert-butyl-2-methoxy-phenyl)-methane-sulfonamide in the same manner as Example 1. ESI MS m/z 539 [C26H27FN6O4S+H]+.
Reaction SMILES: FC1C=CC(S(CCC)(=O)=O)=CC=1C#C[Si](C)(C)C.[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[CH:36])([CH3:23])([CH3:22])[CH3:21].Br[C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:50]=[CH:49][C:48]([C:51]([F:54])([F:53])[F:52])=[CH:47][CH:46]=2)=[C:41]([S:55]([CH3:58])(=[O:57])=[O:56])[CH:40]=1>>[C:20]([O:24][C:25](=[O:37])[CH2:26][O:27][C:28]1[CH:33]=[CH:32][C:31]([Cl:34])=[CH:30][C:29]=1[C:35]#[C:36][C:39]1[CH:44]=[CH:43][C:42]([C:45]2[CH:46]=[CH:47][C:48]([C:51]([F:54])([F:52])[F:53])=[CH:49][CH:50]=2)=[C:41]([S:55]([CH3:58])(=[O:56])=[O:57])[CH:40]=1)([CH3:23])([CH3:22])[CH3:21]
Reactant: CS(=O)(=O)c1cc(Br)ccc1-c1ccc(C(F)(F)F)cc1
Reactant: C#Cc1cc(Cl)ccc1OCC(=O)OC(C)(C)C
Agent: CCCS(=O)(=O)c1ccc(F)c(C#C[Si](C)(C)C)c1
Product: CC(C)(C)OC(=O)COc1ccc(Cl)cc1C#Cc1ccc(-c2ccc(C(F)(F)F)cc2)c(S(C)(=O)=O)c1

Procedure:
Following the general method as outlined in Intermediate 107, starting from (4-chloro-2-ethynyl-phenoxy)-acetic acid tert-butyl ester (Intermediate 3) and 4-bromo-2-(methylsulfonyl)-4′-(trifluoromethyl)biphenyl (Intermediate 209), the title compound was obtained as a brown sticky solid after purification by flash column chromatography (silica), eluting with cyclohexane containing increasing amounts of EtOAc.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:8]([CH:18]=[O:19])=[CH:7]2.[CH3:20][Li]>C1COCC1>[CH3:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:8]([CH:18]([OH:19])[CH3:20])=[CH:7]2
Reactant: Cc1cccc2cc(C=O)c(-c3ccccc3)nc12
Reactant: [Li]C
Solvent: C1CCOC1
Product: Cc1cccc2cc(C(C)O)c(-c3ccccc3)nc12
Temperature: 25 °C
Yield: 64.8 %

Procedure:
To a solution of 8-methyl-2-phenylquinoline-3-carboxaldehyde (211 mg, 0.85 mmol) in THF (6 mL) cooled to −78° C. was added methyllithium (1.6N solution in ether, 0.6 mL, 0.93 mmol). After 1 h a further portion of methyllithium (0.2 mL, 0.32 mmol) was added. The reaction was allowed to warm to r.t. before being quenched with water (10 mL). The THF was removed in vacuo and the residue partitioned between DCM (100 mL) and water (30 mL). The organic layer was separated, dried (MgSO4) and concentrated in vacuo. Purification by column chromatography (SiO2, 5-25% EtOAc in heptane) gave the title compound as a white solid (145 mg, 65%). δH (CDCl3) 8.42 (s, 1H), 7.70 (d, J 12 Hz, 1H), 7.60-7.63 (m, 2H), 7.42-7.55 (m, 5H), 5.23-5.31 (m, 1H), 2.80 (s, 3H), 1.87 (d, J 3.6 Hz, 1H), 1.47 (d, J 6.4 Hz, 3H). LCMS (ES+) 264.16 (M+H)+, RT 4.03 minutes (Method 4).
Reaction SMILES: [CH:1]([Mg]Br)=[CH:2][CH3:3].[Cl:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][C:10]([I:16])=[CH:9][N:8]=1>O1CCCC1>[Cl:6][C:7]1[N:8]=[CH:9][C:10]([I:16])=[C:11]2[C:2]([CH3:3])=[CH:1][NH:13][C:12]=12
Reactant: CC=C[Mg]Br
Reactant: O=[N+]([O-])c1cc(I)cnc1Cl
Solvent: C1CCOC1
Product: Cc1c[nH]c2c(Cl)ncc(I)c12
Reaction time: 0.75 h

Procedure:
To a solution of 1-propenylmagnesium bromide (0.5M solution in tetrahydrofuran, 264 ml) at 0° C. under nitrogen was added a solution of 2-chloro-5-iodo-3-nitro-pyridine (11 g) in dry tetrahydrofuran (225 ml), dropwise over 45 minutes. After 10 minutes at 0° C. the reaction was quenched with saturated ammonium chloride (300 ml). The mixture was then extracted with ethyl acetate (300 ml) which was dried over magnesium sulphate, filtered and evaporated to give a red oily solid. The residue was triturated with diethyl ether and refrigerated over night. The solid was then filtered onto a sinter, sucked dry then dried at 60° C. under vacuum to afford the title compound (3.27 g). The filtrate was evaporated, dissolved in the minimum of diethyl ether and seeded with the above, refrigerated overnight, filtered and dried under vacuum at 60° C. to afford a further crop (345 mg).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][N:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11]([OH:13])=O.O.O[N:16]1[C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[N:18]=N1.NCC1C=CC=CN=1>CN(C=O)C>[N:18]1[CH:19]=[CH:24][CH:23]=[CH:22][C:21]=1[CH2:20][NH:16][C:11]([C:2]1[CH:3]=[CH:4][C:5]2[C:10](=[CH:9][CH:8]=[N:7][CH:6]=2)[N:1]=1)=[O:13]
Reactant: O=C(O)c1ccc2cnccc2n1
Reactant: On1nnc2ccccc21
Agent: NCc1ccccn1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(NCc1ccccn1)c1ccc2cnccc2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 103.8 %

Procedure:
To a stirring mixture of 2-[1,6]naphthyridinecarboxylic acid (50 mg, 0.287 mmol) in anhydrous DMF (1.0 mL) at room temperature was added sequentially 1-hydroxybenzotriazole hydrate (42.7 mg, 0.316 mmol), 2-(aminomethyl)pyridine (45.3 μL, 0.431 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarboiimide hydrochloride (61.8 mg, 0.316 mmol). The resulting mixture was allowed to stir at room temperature overnight and it was found to be clear. The solvent was removed under vacuum. Flash column chromatography of the residue (50% hexane/ethyl acetate to 5% methanol/ethyl acetate) afforded the desired product as a light brown solid (78.7 mg, 99%): m.p. 123-125° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([OH:17])[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:3])[CH3:2].CC(C)[CH:21]([C:23]1[S:27][C:26]([C:28]2[CH:33]=[CH:32][C:31]([C:34]([F:37])([F:36])[F:35])=[CH:30][CH:29]=2)=[N:25][C:24]=1C)O.C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>>[C:1]([O:5][C:6](=[O:18])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([O:17][CH2:21][C:23]3[S:27][C:26]([C:28]4[CH:29]=[CH:30][C:31]([C:34]([F:37])([F:35])[F:36])=[CH:32][CH:33]=4)=[N:25][CH:24]=3)[CH:15]=2)[CH:10]=[CH:9]1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(O)C(C)C
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(O)cc21
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Product: CC(C)(C)OC(=O)Cn1ccc2ccc(OCc3cnc(-c4ccc(C(F)(F)F)cc4)s3)cc21

Procedure:
In analogy to the procedure described in example 3 c], (6-hydroxy-indol-1-yl)-acetic acid tert-butyl ester was reacted with [2-(4-trifluoromethyl-phenyl)-thiazol-5-yl]-methanol [PCT Int. Appl. (2002), WO 02/062774 A1] in the presence of tributylphosphine and N,N,N′,N′-tetramethyl azodicarboxamide to yield {6-[2-(4-trifluoromethyl-phenyl)-thiazol-5-ylmethoxy]-indol-1-yl}-acetic acid tert-butyl ester as white solid.