Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:6]=[CH:7][CH:8]=[C:9]2[C:14]=1[N:13]=[CH:12][N:11]=[C:10]2[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[C:19]([NH:23][C:24]([C:26]2[CH:27]=[N:28][CH:29]=[C:30]([N:32]3[CH2:37][CH2:36][O:35][CH2:34][CH2:33]3)[CH:31]=2)=[O:25])[CH:18]=1)=O.C1COCC1.CC(O)C.[OH-].[NH4+:48]>O>[N:32]1([C:30]2[CH:31]=[C:26]([C:24]([NH:23][C:19]3[CH:18]=[C:17]([CH:22]=[CH:21][CH:20]=3)[CH2:16][NH:15][C:10]3[C:9]4[C:14](=[C:5]([C:3]([NH2:48])=[O:2])[CH:6]=[CH:7][CH:8]=4)[N:13]=[CH:12][N:11]=3)=[O:25])[CH:27]=[N:28][CH:29]=2)[CH2:33][CH2:34][O:35][CH2:36][CH2:37]1
Reactant: COC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cncc(N5CCOCC5)c4)c3)ncnc12
Reactant: [NH4+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)O
Product: NC(=O)c1cccc2c(NCc3cccc(NC(=O)c4cncc(N5CCOCC5)c4)c3)ncnc12
Temperature: 50 °C
Yield: 45 %

Procedure:
To a 40-mL vial with magnetic stirbar at 25° C. was added 4-{3-[(5-Morpholin-4-yl-pyridine-3-carbonyl)-amino]-benzylamino}-quinazoline-8-carboxylic acid methyl ester (0.12 g, 0.24 mmol, 1 eq.) and THF (2 mL) and 2-propanol (2 mL). An approx. equal volume (i.e.; 2 mL) of concentrated aqueous ammonium hydroxide solution (28-30% soln.) was then added and stirring continued over the weekend (×96 hours). Water (15 mL) was added to the reaction mixture and a precipitate immediately began to form. The precipitate was collected and dried thoroughly in vacuo. The material required further purification via preparative HPLC. The isolated material was re-dissolved in THF (1 mL), iPrOH (1 mL), and DMSO (1 mL) to which concentrated aqueous ammonium hydroxide solution (28-30%) (1 mL) was added and heated at 50° C.×36 hours. H2O (10 mL) was added to the reaction mixture and the resulting white precipitate collected and dried thoroughly in vacuo to afford 50.2 mg (45% yield). LCMS (ESI) 484.2 (M+H).
Reaction SMILES: O1CCC(C[N:8]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][C:15]=3[Cl:17])[C:10]([C:18]([NH2:20])=[O:19])=[CH:9]2)CC1.Cl[C:22]([S:24]Cl)=[O:23]>O1CCCC1>[O:23]1[CH2:22][CH2:9][CH:10]([CH2:18][C:13]2[CH:12]=[C:11]3[C:16](=[C:15]([Cl:17])[CH:14]=2)[NH:8][CH:9]=[CH:10]3)[CH2:11][CH2:12]1.[O:19]1[CH:18]=[N:20][S:24][C:22]1=[O:23]
Reactant: NC(=O)c1cn(CC2CCOCC2)c2c(Cl)cccc12
Reactant: O=C(Cl)SCl
Solvent: C1CCOC1
Product: Clc1cc(CC2CCOCC2)cc2cc[nH]c12
Product: O=c1ocns1
Yield: 111.1 %

Procedure:
To a suspension of 1-(tetrahydropyran-4-yl)methyl-7-chloro-1H-indole-3-carboxylic acid amide (8.0 g, 27.0 mmol) in tetrahydrofuran (100 ml) was added chlorocarbonylsulfenyl chloride (4.7 ml, 55.0 mmol) and the reaction mixture was heated at reflux for 3 h and allowed to cool. The precipitate was filtered off and dried to give 5-(1-tetrahydropyran-4-yl) methyl-7-chloro-1H-indole)-[1,3,4]-oxathiazol-2-one (5.3 g, 15.0 mmol) as a white solid. The filtrate was concentrated in vacuo, and the resulting solid was washed with 5% ethylacetate in n-heptane then dried to leave 7-chloro-3-([1,3,4]-oxathiazol-2-on-5-yl)-1-(tetrahydropyran-4-yl)methyl-1H-indole (2.6 g, 7.0 mmol) as a pink solid.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]([OH:17])=[CH:4][CH:3]=1.[CH2:18]([NH:20][CH2:21][CH3:22])[CH3:19].[CH2:23]=O>C(O)CCC>[CH2:18]([N:20]([CH2:23][C:4]1[CH:3]=[C:2]([CH3:1])[CH:7]=[C:6]([C:8]2[C:16]3[N:15]=[N:14][NH:13][C:12]=3[CH:11]=[CH:10][CH:9]=2)[C:5]=1[OH:17])[CH2:21][CH3:22])[CH3:19]
Reactant: C=O
Reactant: CCNCC
Reactant: Cc1ccc(O)c(-c2cccc3[nH]nnc23)c1
Solvent: CCCCO
Product: CCN(CC)Cc1cc(C)cc(-c2cccc3[nH]nnc23)c1O
Yield: 96.8 %

Procedure:
22.5 g of 4-methyl-6-benzotriazolylphenol, 11.0 g of diethylamine and 5.2 g of paraformaldehyde were dissolved in 25 ml of butanol, and heated to a temperature of 95° to 105° C. at which the solution was allowed to undergo reaction under reflux for about 24 hours. After the reaction, the solvent was removed from the reaction product under reduced pressure to obtain 30 g of 2-diethylaminomethyl-4-methyl-6-benzotriazolylphenol (a Mannich base compound).
Reaction SMILES: [C:1]([C:3]1[N:4]=[C:5]([CH3:15])[N:6]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[CH:7]=1)#[CH:2].[F:16][C:17]1[CH:22]=[C:21](I)[CH:20]=[CH:19][N:18]=1>>[F:16][C:17]1[CH:22]=[C:21]([C:2]#[C:1][C:3]2[N:4]=[C:5]([CH3:15])[N:6]([C:8]3[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=3)[CH:7]=2)[CH:20]=[CH:19][N:18]=1
Reactant: C#Cc1cn(-c2ccc(F)cc2)c(C)n1
Reactant: Fc1cc(I)ccn1
Product: Cc1nc(C#Cc2ccnc(F)c2)cn1-c1ccc(F)cc1

Procedure:
The title compound, MS: m/e=296.1 (M+H+), was prepared in accordance with the general method of example 1 from 4-ethynyl-1-(4-fluoro-phenyl)-2-methyl-1H-imidazole and 2-fluoro-4-iodopyridine.
Reaction SMILES: [OH-].[Na+].[CH2:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:16]3[CH:17]=[C:18]([C:21]([O:23]C)=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])=[CH:8][CH:7]=1)[CH:4]=[CH2:5].Cl>CO.O1CCOCC1.O>[CH2:3]([C:6]1[CH:30]=[CH:29][C:9]([C:10]([C:12]2[C:16]3[CH:17]=[C:18]([C:21]([OH:23])=[O:22])[CH:19]=[CH:20][C:15]=3[O:14][C:13]=2[CH2:25][CH2:26][CH2:27][CH3:28])=[O:11])=[CH:8][CH:7]=1)[CH:4]=[CH2:5]
Reactant: C=CCc1ccc(C(=O)c2c(CCCC)oc3ccc(C(=O)OC)cc23)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1COCCO1
Solvent: O
Product: C=CCc1ccc(C(=O)c2c(CCCC)oc3ccc(C(=O)O)cc23)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
1.7 g of NaOH pellets are added to 8.1 g of methyl 3-(4-allylbenzoyl)-2-butylbenzofuran-5-carboxylate in 40 ml of methanol, 200 ml of dioxane and 40 ml of water. The mixture is stirred at ambient temperature for 24 hours. It is neutralized to pH 7 with concentrated hydrochloric acid and then evaporated. Water is added and the acid is regenerated with concentrated hydrochloric acid. Extraction is carried out three times with ether and the extracts are washed with water and then with an aqueous NaCl solution. They are dried over Na2SO4 and then concentrated.
Reaction SMILES: [C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][Cl:16])=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[Cl-:16].[C:1]1([C:7]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:8][CH2:9][O:10][C:11]2[CH:18]=[CH:17][C:14]([CH2:15][N+:31]3[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=3)=[CH:13][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCc1ccc(OCCC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: c1ccncc1
Product: [Cl-]
Product: c1ccc(C(CCOc2ccc(C[n+]3ccccc3)cc2)(c2ccccc2)c2ccccc2)cc1

Procedure:
A solution of 4-(3,3,3-triphenylpropoxy)benzyl chloride, prepared in example 28, (210 mg, 0.51 mmol) in pyridine (1.0 mL) was refluxed for two minutes, and concentrated. The residue was recrystallized from acetonitrile-ethyl acetate and dried at 90° under high vacuum for 18 hours, providing the title compound as a monohydrate, a white powder, mp 155°-159° C. (212 mg, 86%). 1H NMR (CDCl3) δ 9.56 (d, J=7.5 Hz, 2H), 8.31 (t, J=7.5 Hz, 1H), 7.94 (t, J=7.5 Hz, 2H), 7.54 (d, J=8.6 Hz, 2H) 7.15-7.35 (m, 15H), 6.68 (d, J=8.6 Hz, 2H), 3.68 (t, J=7.7 Hz, 2H), 3.09 (t, J=7.7 Hz, 2H). Anal. calcd. for C33H30NO·Cl·H2O: C, 77.71; H, 6.32; N, 2.75; Cl, 6.95. Found: C, 77.47; H, 6.27; N, 2.63; Cl, 6.65.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[C:5]([C:8]([OH:10])=O)[CH:4]=[N:3]1.S(Cl)(Cl)=O.[NH2:15][C:16]1[CH:17]=[C:18]([CH:31]=[CH:32][CH:33]=1)[C:19]([C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)=[O:20]>C1COCC1>[O:30]=[C:26]1[CH2:25][C:24]2[C:28](=[CH:29][C:21]([C:19]([C:18]3[CH:17]=[C:16]([NH:15][C:8]([C:5]4[CH:4]=[N:3][N:2]([CH3:1])[C:6]=4[CH3:7])=[O:10])[CH:33]=[CH:32][CH:31]=3)=[O:20])=[CH:22][CH:23]=2)[NH:27]1
Reactant: Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3)c1
Reactant: Cc1c(C(=O)O)cnn1C
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1c(C(=O)Nc2cccc(C(=O)c3ccc4c(c3)NC(=O)C4)c2)cnn1C
Temperature: 79 °C
Reaction time: 3 h
Yield: 45.6 %

Procedure:
A dry flask was charged with 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid (0.144 g, 1.03 mmol) and thionyl chloride (5 mL) and allowed to stir at 79° C. for 3 h. The thionyl chloride was then removed by concentration in vacuo. The crude acid chloride was cooled to room temperature, and then dissolved in THF (10 mL). 6-(3-Amino-benzoyl)-1,3-dihydro-indol-2-one (as prepared in Example 40, 0.260 g, 1.03 mmol) was added to the THF solution of the acid chloride, and the mixture was allowed to reflux overnight. The reaction mixture was then allowed to cool to room temperature and filtered. The solid residue was washed with 0° C. THF and collected to afford the 1,5-Dimethyl-1H-pyrazole-4-carboxylic acid [3-(2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide as a solid (0.177 g, 0.47 mmol, 46%).
Reaction SMILES: S(Cl)([Cl:3])=O.[CH3:5][CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([OH:28])=O)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]>>[CH3:5][CH:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C:26]([Cl:3])=[O:28])=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH3:12]
Reactant: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)O)cc2)cc1
Reactant: O=S(Cl)Cl
Product: CCCCCCC(C)Oc1ccc(-c2ccc(C(=O)Cl)cc2)cc1
Yield: 96.7 %

Procedure:
Thionyl chloride (11.3 g, 0.095 mol) was added to the above optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid (20 g, 0.063 mol), followed by heating under reflux for one hour and distilling off excess thionyl chloride to obtain optically active 4'-(1-methyl-heptyloxy)-4-biphenylcarboxylic acid chloride (21 g).
Reaction SMILES: [O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]=[O:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:17][C:18]1([CH3:38])[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[CH:19]1[C:35](Cl)=[O:36].[C-:39]#[N:40].[Na+].O>[Br-].C([N+](CCCC)(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.CCCCCC>[O:1]([C:8]1[CH:9]=[C:10]([CH:13]=[CH:14][C:15]=1[F:16])[CH:11]([O:12][C:35]([CH:19]1[CH:20]([CH:21]=[C:22]([Cl:34])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=2)[C:18]1([CH3:38])[CH3:17])=[O:36])[C:39]#[N:40])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: [C-]#N
Reactant: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)Cl
Reactant: O=Cc1ccc(F)c(Oc2ccccc2)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [Br-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: O
Solvent: Cc1ccccc1
Product: CC1(C)C(C=C(Cl)c2ccc(OC(F)(F)F)cc2)C1C(=O)OC(C#N)c1ccc(F)c(Oc2ccccc2)c1
Yield: 62.5 %

Procedure:
4.32 g (0.02 mol) of 3-phenoxy-4-fluoro-benzaldehyde and 7.1 g (0.02 mol) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid chloride were together added dropwise to a mixture of 1.6 g of sodium cyanide, 2.5 ml of water, 100 ml of n-hexane and 0.5 g of tetrabutylammonium bromide at 20°-25° C., while stirring, and the mixture was then stirred at 20°-25° C. for 4 hours. 300 ml of toluene were subsequently added, and the reaction mixture was extracted by shaking twice with 300 ml of water each time. The organic phase was separated off and dried over magnesium sulphate and the solvent was distilled off under a waterpump vacuum. Last residues of solvent were removed by brief incipient distillation at a bath temperature of 60° C./1 mm Hg. 7 g (62.6% of theory) of 2,2-dimethyl-3-(2-chloro-2-(4-trifluoromethoxy-phenyl)-vinyl)-cyclopropanecarboxylic acid 3-phenoxy-4 -fluoro-α-cyano-benzyl ester were obtained as a viscous oil. The structure was confirmed by the 1H-NMR spectrum.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH2:8][CH3:9])[CH:5]=[CH:4][C:3]=1[OH:10].[Br:11][C:12]1[CH:17]=[CH:16][C:15]([N:18]=[C:19]=S)=[CH:14][CH:13]=1.C(N(CC)CC)C>O1CCCC1.S([O-])([O-])(=O)=O.[Cu+2]>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([NH:18][C:19]2[O:10][C:3]3[CH:4]=[CH:5][C:6]([CH2:8][CH3:9])=[CH:7][C:2]=3[N:1]=2)=[CH:14][CH:13]=1
Reactant: CCc1ccc(O)c(N)c1
Reactant: S=C=Nc1ccc(Br)cc1
Agent: [Cu+2]
Agent: O=S(=O)([O-])[O-]
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCc1ccc2oc(Nc3ccc(Br)cc3)nc2c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 46.2 %

Procedure:
To a mixture of 2-amino-4-ethylphenol (0.89 g, 0.0065 mol) in tetrahydrofuran (80 mL) was added 4-bromophenyl isothiocyanate (1.4 g, 0.0065 mol) at room temperature. The mixture was stirred for 2 hours at room temperature. Anhydrous copper sulfate (6.2 g, 0.039 mol), triethylamine (0.9 mL, 0.0065 mol) and silica gel (11.7 g) were added to the reaction mixture. The mixture was stirred for 4 hours at room temperature. The solvent was removed under reduced pressure. The mixture was filtered through silica gel pad using 25% ethyl acetate/n-heptane as a mobile phase to give brown colored solid. The solid was purified by flash column chromatography on silica using 0%-25% ethyl acetate/n-heptane as a mobile phase. The solvent was removed, and the residue was triturated with n-heptane to give N2-(4-bromophenyl)-5-ethyl-1,3-benzoxazol-2-amine (0.96 g, 0.003 mol). RP-HPLC (Delta Pak C18, 5 μm, 300A, 15 cm; 5%-95% acetonitrile—0.1M ammonium acetate over 10 min, 1 mL/min) Rt 12.1 min. MS: MH+: 318
Reaction SMILES: [NH2:1][CH2:2][C:3]([N:5]1[C@@H:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])[C@@H:8]([C:17]([O:19][CH3:20])=[O:18])[S:7][C@H:6]1[C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])=[O:4].O1[CH2:32][CH2:31][CH2:30][CH2:29]1>CC1C=C(N=C=O)C=CC=1>[CH3:20][O:19][C:17]([C@H:8]1[S:7][C@@H:6]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[N:5]([C:3](=[O:4])[CH2:2][NH:1][C:3]([NH:5][C:9]2[CH:10]=[CH:32][CH:31]=[C:30]([CH3:29])[CH:8]=2)=[O:4])[C@H:9]1[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[F:16])=[O:18]
Reactant: C1CCOC1
Reactant: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CN)[C@H]1c1ccccc1F
Agent: Cc1cccc(N=C=O)c1
Product: COC(=O)[C@H]1S[C@@H](C(=O)OC(C)(C)C)N(C(=O)CNC(=O)Nc2cccc(C)c2)[C@H]1c1ccccc1F

Procedure:
The process is performed in a similar manner to that described in Example 1, but starting with 0.30 g of tert-butyl (2S,4S,5S)-3-(2-aminoacetyl)-5-methoxycarbonyl-4-(2-fluorophenyl)-2-thiazolidinecarboxylate dissolved in 10 ml of tetrahydrofuran and 100 μl of 3-methylphenyl isocyanate. The crude product is purified by chromatography on silica [eluent: ethyl acetate/cyclohexane (30/70 by volume)]. The fractions containing the expected product are combined and concentrated to dryness under reduced pressure at 40° C. 0.08 g of tert-butyl (2S,4S,5S)-5-methoxycarbonyl-3-{2-[3-(3-methylphenyl)ureido]acetyl}-4-(2-fluorophenyl)-2-thiazolidinecarboxylate is thus obtained in the form of a yellow foam, Rf=0.43 [ethyl acetate/cyclohexane (40/60 by volume); 1 H NMR (200 MHz, (CD3)2SO with addition of a few drops of CD3COOD, at a temperature of 393 K, δ in ppm): 1.52 (s, 9H: CH3 of the tert-butyl); 2.25 (s, 3H: ArCH3); 3.34 (s, 3H: COOCH3); 3.70 and 4.05 (broad d and d respectively, J=17 Hz, 1H each: COCH2N); 4.95 (d, J=7.5 Hz, 1H: H at C5 of the ring); 5.75 (s, 1H: H at C2 of the ring); 6.05 (d, J=7.5 Hz: 1H: H at C4 of the ring); 6.76 (broad d, J=7.5 Hz, 1H: aromatic H (H ortho to the CH3)); 7.09 (t, J=7.5 Hz, 1H: aromatic H (H meta to the CH3)); from 7.10 to 7.50 (mt, 5H: aromatic H); 8.00 (mt, 1H: aromatic H (H meta to the F)).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[C:7]1[C:16]([OH:18])=[O:17].[CH2:23](Br)[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:19]=[CH:20][C:21]=1[Cl:22])[CH2:5][N:6]1[C:14]2[CH2:13][CH2:12][CH2:11][C:10](=[O:15])[C:9]=2[CH:8]=[C:7]1[C:16]([O:18][CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)=[O:17]
Reactant: O=C1CCCc2c1cc(C(=O)O)n2Cc1ccc(Cl)c(Cl)c1
Reactant: BrCc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: O=C1CCCc2c1cc(C(=O)OCc1ccccc1)n2Cc1ccc(Cl)c(Cl)c1
Yield: 97.5 %

Procedure:
1-(3,4-Dichlorobenzyl)-4-oxo-4,5,6,7-tetrahydroindole-2-carboxylic acid (1.32 g) and benzyl bromide (0.68 g) was stirred in DMF (10 mL) over potassium carbonate (0.48 g) for 18 hours. The DMF was removed in vacuo and the residue was dissolved in ethyl acetate (50 mL). The organic solution was washed with 2M HCl and dried over MgSO4. The solvents were removed in vacuo to afford the title compound as a pale solid (1.63 g, 97%), NMR d(CDCl3) 2.20 (2H, di), 2.50 (2H, t), 2.70 (2H, t), 5.21 (2H, m), 5.55 (2H, s), 6.80 (1H, d), 7.10 (1H,s), 7.35(6H, s), 7.50(1H, s); M/z(+)430, 428 (M+).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23]Br)=[CH:11][CH:12]=2)[CH:7]=1.[OH:29][C:30]1[C:35]([CH2:36][CH2:37][CH3:38])=[C:34]([OH:39])[CH:33]=[CH:32][C:31]=1[C:40](=[O:42])[CH3:41].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CN(C)C=O>[CH3:1][O:2][C:3](=[O:28])[CH2:4][O:5][C:6]1[CH:15]=[CH:14][C:13]2[C:8](=[C:9]([C:25](=[O:27])[CH3:26])[C:10]([O:16][CH2:17][CH2:18][CH2:19][O:20][CH2:21][CH2:22][CH2:23][O:39][C:34]3[CH:33]=[CH:32][C:31]([C:40](=[O:42])[CH3:41])=[C:30]([OH:29])[C:35]=3[CH2:36][CH2:37][CH3:38])=[CH:11][CH:12]=2)[CH:7]=1
Reactant: CCCc1c(O)ccc(C(C)=O)c1O
Reactant: COC(=O)COc1ccc2ccc(OCCCOCCCBr)c(C(C)=O)c2c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CC(C)=O
Product: CCCc1c(OCCCOCCCOc2ccc3ccc(OCC(=O)OC)cc3c2C(C)=O)ccc(C(C)=O)c1O
Yield: 55.5 %

Procedure:
A mixture of 1.73 g of [[8-acetyl-7-[3-(3-bromopropoxy)propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester, 0.89 g of 1-(2,4-dihydroxy-3-propylphenyl)ethanone and 0.79 g of anhydrous potassium carbonate in 33 ml of anhydrous acetone and 11 ml of anhydrous dimethylformamide was stirred at reflux for 18 hours. The mixture was filtered and filtrate was concentrated in vacuo to an oil. Purification by high pressure liquid chromatography (10% ethyl acetate-toluene) gave 1.2 g (56%) of [[8-acetyl-7-[3-[3-(4-acetyl-3-hydroxy-2-propylphenoxy)propoxy]propoxy]-2-naphthalenyl]oxy]acetic acid methyl ester.
Reaction SMILES: [CH2:1]([C:3]1[NH:7][N:6]=[C:5]([CH:8]([OH:10])[CH3:9])[C:4]=1[O:11][C:12]1[CH:13]=[C:14]([C:20]#[N:21])[CH:15]=[C:16]([CH:19]=1)[C:17]#[N:18])[CH3:2].Br[CH2:23][CH2:24][O:25][CH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][O:27]1.[H-].[Na+]>CN(C)C=O>[CH2:1]([C:3]1[N:7]([CH2:23][CH2:24][O:25][CH:26]2[CH2:31][CH2:30][CH2:29][CH2:28][O:27]2)[N:6]=[C:5]([CH:8]([OH:10])[CH3:9])[C:4]=1[O:11][C:12]1[CH:19]=[C:16]([C:17]#[N:18])[CH:15]=[C:14]([CH:13]=1)[C:20]#[N:21])[CH3:2]
Reactant: BrCCOC1CCCCO1
Reactant: CCc1[nH]nc(C(C)O)c1Oc1cc(C#N)cc(C#N)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCc1c(Oc2cc(C#N)cc(C#N)c2)c(C(C)O)nn1CCOC1CCCCO1
Temperature: 25 °C
Reaction time: 60 h
Yield: 29.2 %

Procedure:
To a stirred solution of the pyrazole from Example 263 (197 mg, 0.70 mmol) in dimethylformamide (3 ml) at 0° C. was added 2-(2-bromoethoxy)tetrahydro-2H-pyran (105 μl, 0.70 mmol) followed by sodium hydride (31 mg, 0.77 mmol). After 15 minutes the cooling bath was removed and the mixture was stirred at room temperature for 60 hours. The reaction mixture was quenched by addition of saturated aqueous ammonium chloride solution (0.5 ml) and then concentrated under reduced pressure. The crude product mixture was purified by flash chromatography on silica gel eluting with dichloromethane:methanol (a gradient from 100:0 to 95:5, by volume) to provide the title compound (84 mg) as a white foam which reverts to an oil on standing.
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([OH:15])=O)=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1.[F:24][C:25]([F:29])([F:28])[CH2:26][NH2:27]>>[CH3:1][N:2]1[C:6]([CH2:7][O:8][C:9]2[CH:17]=[CH:16][C:12]([C:13]([NH:27][CH2:26][C:25]([F:29])([F:28])[F:24])=[O:15])=[CH:11][N:10]=2)=[C:5]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[N:4]=[N:3]1
Reactant: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)O)cn1
Reactant: NCC(F)(F)F
Product: Cn1nnc(-c2ccccc2)c1COc1ccc(C(=O)NCC(F)(F)F)cn1
Yield: 58 %

Procedure:
As described for example 2b, 6-(3-methyl-5-phenyl-3H-[1,2,3]triazol-4-ylmethoxy)-nicotinic acid (155 mg, 0.5 mmol) was converted, using 2,2,2-trifluoroethylamine instead of 4-aminotetrahydropyran, to the title compound (127 mg, 58%) which was obtained as a white solid after a further recrystallisation from ethyl acetate. MS: m/e=392.1 [M+H]+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([N:22]([CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]2)[CH3:23])[C:5]([CH3:21])=[C:6]([CH:20]=1)[C:7]([NH:9][CH2:10][C:11]1[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=1[CH3:17])=[O:8].[CH3:30][N:31]1[CH:35]=[C:34](B2OC(C)(C)C(C)(C)O2)[CH:33]=[N:32]1.C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.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>[CH:24]1([N:22]([CH3:23])[C:4]2[C:5]([CH3:21])=[C:6]([CH:20]=[C:2]([C:34]3[CH:33]=[N:32][N:31]([CH3:30])[CH:35]=3)[CH:3]=2)[C:7]([NH:9][CH2:10][C:11]2[C:12](=[O:19])[NH:13][C:14]([CH3:18])=[CH:15][C:16]=2[CH3:17])=[O:8])[CH2:29][CH2:28][CH2:27][CH2:26][CH2:25]1
Reactant: Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc(C)c(CNC(=O)c2cc(Br)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1cc(C)c(CNC(=O)c2cc(-c3cnn(C)c3)cc(N(C)C3CCCCC3)c2C)c(=O)[nH]1
Temperature: 100 °C
Yield: 20 %

Procedure:
To a stirred solution of 5-bromo-3-(cyclohexyl(methyl)amino)-N-((4,6-dimethyl-2-oxo-1,2-dihydropyridin-3-yl)methyl)-2-methylbenzamide (1 equiv.) and 1-methyl-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (1.2 equiv.) in dioxane/water mixture (5 mL+1 mL), Na2CO3 (3.6 equiv.) was added and solution purged with argon for 15 min. Then Pd(PPh3)4 (0.1 equiv.) was added and argon was purged again for 10 min. The reaction was heated at 100° C. for 4 h. After cooling, the reaction mixture was diluted with water and extracted with 10% MeOH/DCM. The combined organic layers were dried over Na2SO4 and the solvent removed under reduced pressure to afford crude product. Purification by column chromatography over silica gel afforded the title compound (0.02 g, 20%).
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[Cl:7][C:8]1[CH:13]=[CH:12][C:11]([C@H:14]([NH2:16])[CH3:15])=[CH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22]Br>CC#N>[CH3:17][O:18][C:19](=[O:24])[CH2:20][CH2:21][CH2:22][NH:16][C@@H:14]([C:11]1[CH:12]=[CH:13][C:8]([Cl:7])=[CH:9][CH:10]=1)[CH3:15]
Reactant: COC(=O)CCCBr
Reactant: C[C@@H](N)c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COC(=O)CCCN[C@H](C)c1ccc(Cl)cc1
Temperature: 20 °C
Reaction time: 15 h

Procedure:
To a suspension of K2CO3 (1.5 eq.) and (R)-1-(4-chloro-phenyl)-ethylamine (0.9 eq.) in MeCN was added 4-bromo-butyric acid methyl ester (1 eq.) and KI (0.1 eq.). The reaction was stirred for 15 h at 20° C., then heated to reflux until completion. The crude was partitioned between water and EtOAc. The organic layer was washed with brine, dried over MgSO4, filtered and concentrated under reduced pressure. The crude was purified by chromatography on silica gel (elution with DCM/MeOH: 99/1 to 90/10) to afford 4-[(R)-1-(4-chloro-phenyl)-ethylamino]-butyric acid methyl ester.