Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:17])[F:16])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1.ClC1C=C(C=CC=1)C(OO)=[O:26].O>C(O)(=O)C>[NH2:1][C:2]1[N+:3]([O-:26])=[N:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([O:14][CH:15]([F:16])[F:17])=[C:10]([O:18][CH2:19][CH3:20])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CCOc1cc(-c2ccc(N)nn2)ccc1OC(F)F
Solvent: O
Solvent: CC(=O)O
Product: CCOc1cc(-c2ccc(N)[n+]([O-])n2)ccc1OC(F)F
Temperature: 60 °C
Reaction time: 2 h
Yield: 60.7 %

Procedure:
8.9 g (31.6 mmol) of 3-amino-6-(4-difluoromethoxy-3-ethoxyphenyl)pyridazine in 60 ml of glacial acetic acid are heated with 10.9 g (63.2 mmol) of m-chloroperoxybenzoic acid with stirring at 60° C. for 2 h. After cooling, the solution is stirred into 100 ml of water, the solution is exhaustively extracted with ethyl acetate, and the organic extract is dried over magnesium sulfate, concentrated in vacuo and chromatographed on neutral silica gel first with ethyl acetate and then with ethyl acetate/methanol 8:2. The appropriate fractions are concentrated, the residue is taken up in a little ethyl acetate, petroleum ether (b.p. 40°-70° C.) is added to incipient opalescence, and the product is crystallized by cooling. The crystals are filtered off with suction, washed with petroleum ether and dried at 80° C. in vacuo. 5.7 g (60.7%) of the title compound of m.p. 202°-3° C. are obtained.
Reaction SMILES: [C:1]1([C@H:7]2[CH2:11][CH2:10][C@@H:9]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[N:8]2[C:18](=[O:37])[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([O:33]CC)=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH-].[K+]>CO.O>[C:12]1([C@H:9]2[CH2:10][CH2:11][C@@H:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]2[C:18](=[O:37])[CH2:19][NH:20][C:21](=[O:36])[NH:22][C:23]2[CH:24]=[C:25]([CH2:29][CH2:30][C:31]([OH:33])=[O:32])[CH:26]=[CH:27][CH:28]=2)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: CCOC(=O)CCc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)CCc1cccc(NC(=O)NCC(=O)N2[C@@H](c3ccccc3)CC[C@H]2c2ccccc2)c1
Yield: 19.9 %

Procedure:
By proceeding in a fashion similar to that described in Example 9, but starting from 4.8 g of ethyl cis-3-{3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}-phenyl}propionate in solution in 25 cm3 of methanol and 0.25 g of potassium hydroxide dissolved in 5 cm3 of water and after treatment, 0.9 g of cis-3-{3-{3-[2-(2,5-diphenyl-1-pyrrolidinyl)-2-oxoethyl]ureido}phenyl}propionic acid, melting at 170° C., is obtained.
Reaction SMILES: [CH2:1]([C:3]1[CH:17]=[CH:16][C:6]([CH2:7][C:8]2[CH:13]=[CH:12][N:11]=[N:10][C:9]=2[O:14]C)=[CH:5][CH:4]=1)[CH3:2].C(Cl)(Cl)Cl>CO>[CH2:1]([C:3]1[CH:4]=[CH:5][C:6]([CH2:7][C:8]2[C:9](=[O:14])[NH:10][N:11]=[CH:12][CH:13]=2)=[CH:16][CH:17]=1)[CH3:2]
Reactant: CCc1ccc(Cc2ccnnc2OC)cc1
Solvent: ClC(Cl)Cl
Solvent: CO
Product: CCc1ccc(Cc2ccn[nH]c2=O)cc1
Temperature: 60 °C
Reaction time: 25 h
Yield: 68.7 %

Procedure:
To a mixture of 4-(4-ethylbenzyl)-3-methoxy-pyridazine (2.11 g, 9.24 mmol) and chloroform (20 ml), trimethylsilyliodo (1.45 ml, 10.2 mmol) was added and this reaction mixture was stirred at 60° C. for 25 hours. After cooling to room temperature, the reaction mixture was diluted with methanol and concentrated. The resulting residue was purified by silica gel column chromatography (chloroform:methanol=20:1) to give the titled compound (1.36 g, 69%) as a yellow powder.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:9](=[O:11])[CH3:10])[CH:5]=[CH:6][C:7]=1[F:8].[C:12]([Cu])#[N:13]>CN(C=O)C>[C:9]([C:4]1[CH:5]=[CH:6][C:7]([F:8])=[C:2]([CH:3]=1)[C:12]#[N:13])(=[O:11])[CH3:10]
Reactant: CC(=O)c1ccc(F)c(Br)c1
Reactant: N#C[Cu]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc(F)c(C#N)c1
Reaction time: 10 h

Procedure:
A solution of 1-(3-bromo-4-fluorophenyl)ethanone (81.3 g, 0.344 mol) in 300 mL of DMF was added CuCN (67.4 g, 0.749 mol) and the mixture was heated to reflux, and stirred under N2 for 10 h. The reaction mixture was quenched with water and extracted with ether. The organic layer was washed with brine dried over Na2SO4 and concentrated in vacuum. The residue was purified with silica gel column chromatography to give the product 5-acetyl-2-fluorobenzonitrile.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]#[N:10])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:17]=1Cl.Cl>C1COCC1.[Cl-].C([N+](CC)(CC)CC1C=CC=CC=1)C.[OH-].[Na+]>[Cl:15][C:16]1[CH:21]=[C:20]([N+:22]([O-:24])=[O:23])[CH:19]=[C:18]([Cl:25])[C:17]=1[CH:8]([C:5]1[CH:6]=[CH:7][C:2]([Cl:1])=[C:3]([C:11]([F:12])([F:13])[F:14])[CH:4]=1)[C:9]#[N:10]
Reactant: O=[N+]([O-])c1cc(Cl)c(Cl)c(Cl)c1
Reactant: N#CCc1ccc(Cl)c(C(F)(F)F)c1
Agent: CC[N+](CC)(CC)Cc1ccccc1
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Product: N#CC(c1ccc(Cl)c(C(F)(F)F)c1)c1c(Cl)cc([N+](=O)[O-])cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 86.5 %

Procedure:
A solution of 4-chloro-3-(trifluoromethyl)benzeneacetonitrile (0.114 mol) in THF (100 ml) was added dropwise at RT to a solution of 1,2,3-trichloro-5-nitrobenzene (0.114 mol) and N,N,N-triethylbenzenemethanaminium chloride (3 g) in NaOH 150 ml) and THF (100 ml). The mixture was stirred at RT for 2 hours, then poured out on ice, acidified with a concentrated HCl solution and extracted with CH2Cl2. The organic layer was separated, dried, filtered and the solvent was evaporated. The residue was crystallized from DIPE. The precipitate was filtered off and dried, yielding 40.4 g (86.5%) of (±)-2,6-dichloro-α-[4-chloro-3-(trifluoromethyl)phenyl]-4-nitrobenzeneacetonitrile (interm. 1).
Reaction SMILES: C([O:3][C:4]([C:6]1([CH2:9][O:10][C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)=[C:13]([CH3:25])[C:12]=2[CH3:26])[CH2:8][CH2:7]1)=[O:5])C.[OH-].[Na+].O.Cl>CO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([O:10][CH2:9][C:6]2([C:4]([OH:5])=[O:3])[CH2:7][CH2:8]2)=[C:12]([CH3:26])[C:13]=1[CH3:25])[C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1
Reactant: CCOC(=O)C1(COc2ccc(OCc3ccccc3)c(C)c2C)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: Cc1c(OCc2ccccc2)ccc(OCC2(C(=O)O)CC2)c1C
Temperature: 50 °C
Reaction time: 4 h

Procedure:
To a solution of the ester prepared as above (0.78 g) in MeOH (20 mL), was added NaOH solution (10% wt, 3 mL) and water (2 mL). After stirring the solution at 50° C. for 4 h it was poured into water, and diluted HCl solution was added to adjust pH to 3. The mixture was partitioned between EtOAc and water, and the organic layer was washed with water, dried over MgSO4 and evaporated. The residue was purified by silica gel column eluting with 40% EtOAc in hexane to give 0.6 g of 1-(4-benzyloxy-2,3-dimethyl-phenoxymethyl)-cyclopropanecarboxylic acid as a pale solid.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1>>[C:10]1([NH:9][C:4]2[C:5]([Br:8])=[CH:6][CH:7]=[CH:2][N:3]=2)[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: Brc1ccc(Br)nc1
Reactant: Nc1ccccc1
Product: Brc1cccnc1Nc1ccccc1
Yield: 67 %

Procedure:
A mixture of 2,5-dibromopyridine (10.2 g, 43 mmole) in aniline (25 mL) was stirred and heated at reflux for 3 h. The reaction was cooled to RT and most of the aniline was distilled off under vacuum. The remaining residue was taken up in ethyl acetate and the solution was washed with 1.0 N Na2CO3 then with brine, dried (Na2SO4), and concentrated under vacuum. Trituration with petroleum ether, filtration and drying under vacuum gave the title compound (7.20 g, 67%) as a tan solid: 1H NMR (400 MHz, CDCl3) δ 8.25 (d, J=2.4 Hz, 1 H), 7.58 (dd, 1 H), 7.31-7.39 (m, 4 H), 7.11 (m, 1 H), 6.79 (br s, 1 H); MS (ES) m/e 249.0 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(C(C)(C)C)C1C=CC=CC=1C1C=CC=CC=1)(C)(C)C.CC(C)([O-])C.[Na+].[CH3:45][N:46]1[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]1>CCOCC.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].C1(C)C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([N:49]3[CH2:50][CH2:51][N:46]([CH3:45])[CH2:47][CH2:48]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(Br)cc2C1
Agent: [Pd]
Agent: CC(C)(C)P(c1ccccc1-c1ccccc1)C(C)(C)C
Agent: CC(C)(C)[O-]
Solvent: CCOCC
Solvent: Cc1ccccc1
Product: CN1CCN(c2ccc3c(c2)CN(C(=O)OC(C)(C)C)C3)CC1
Temperature: 80 °C
Yield: 45.7 %

Procedure:
5-Bromo-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester (2.97 g, 10 mmol) was azeotropically dried by evaporation from toluene. Tris(dibenzylideneacetone)dipalladium (0) (228 mg, 0.25 mmol), 2-(di-tert-butylphosphino)biphenyl (149 mg, 0.50 mmol) and sodium tert-butoxide (1.34 g, 13.9 mmol) were added and the flask was purged with nitrogen. Toluene (25 mL) then N-methylpiperazine (1.33 mL, 12 mmol) were added and the mixture was heated to 80° C. for 2 hours. After allowing to cool to r.t. the mixture was diluted with ether, filtered through Celite and concentrated to give a residue that was purified by flash chromatography on silica (2M methanolic ammonia/dichloromethane, 1% to 3% gradient). This afforded the title compound as a brown solid (1.45 g, 46%). 1H NMR (MeOH-d4) 7.15 (1H, m), 6.94-6.88 (2H, m), 4.60-4.54 (4H, m), 3.20-3.17 (4H, m), 2.63-2.60 (4H, m), 2.34 (3H, s), 1.52 (9H, s). MS: [M+H]+ 318.
Reaction SMILES: C(C(O)=O)(F)(F)F.[O:8]=[C:9]1[N:13](C(OC(C)(C)C)=O)[C:12]2[CH:21]=[CH:22][CH:23]=[CH:24][C:11]=2[N:10]1[CH:25]1[CH2:30][CH2:29][S:28][CH2:27][CH2:26]1>C(Cl)Cl>[S:28]1[CH2:27][CH2:26][CH:25]([N:10]2[C:11]3[CH:24]=[CH:23][CH:22]=[CH:21][C:12]=3[NH:13][C:9]2=[O:8])[CH2:30][CH2:29]1
Reactant: CC(C)(C)OC(=O)n1c(=O)n(C2CCSCC2)c2ccccc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2ccccc2n1C1CCSCC1
Reaction time: 2 h

Procedure:
CF3CO2H (1 mL) was added to a solution of tert-butyl 2-oxo-3-tetrahydro-2H-thiopyran-4-yl-2,3-dihydro-1H-benzimidazole-1-carboxylate from Step A (210 mg, 0.628 mmol) in CH2Cl2 (3 mL). After 2 h, the mixture was concentrated in vacuo to give the title compound. MS: m/z=235 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:37]=[CH:36][C:35]([CH:38]=[O:39])=[CH:34][CH:33]=2)=[CH:4][N:3]=1.[BH4-].[Na+].CO>CN(C)C=O.C(=O)([O-])[O-].[Na+].[Na+]>[NH2:1][C:2]1[C:7]2[C:8]([C:11]3[CH:16]=[CH:15][C:14]([NH:17][C:18]([C:20]4[N:21]([CH3:29])[C:22]5[C:27]([CH:28]=4)=[CH:26][CH:25]=[CH:24][CH:23]=5)=[O:19])=[C:13]([O:30][CH3:31])[CH:12]=3)=[CH:9][S:10][C:6]=2[C:5]([C:32]2[CH:33]=[CH:34][C:35]([CH2:38][OH:39])=[CH:36][CH:37]=2)=[CH:4][N:3]=1
Reactant: COc1cc(-c2csc3c(-c4ccc(C=O)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Agent: O=C([O-])[O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: COc1cc(-c2csc3c(-c4ccc(CO)cc4)cnc(N)c23)ccc1NC(=O)c1cc2ccccc2n1C
Temperature: 25 °C
Reaction time: 16 h
Yield: 35.7 %

Procedure:
N-{4-[4-amino-7-(4-formylphenyl)thieno[3,2-c]pyridin-3-yl]-2-methoxyphenyl}-1-methyl-1H-indole-2-carboxamide (Example 2, 0.030 g, 0.056 mmol) was dissolved in N,N-dimethylformamide (0.5 mL). Sodium borohydride (0.006 g, 0.167 mmol) and methanol (0.5 mL) were added, and the reaction mixture was stirred at ambient temperature for 16 h. The mixture was diluted with aqueous sodium carbonate (1 M, 10 mL) and the product was extracted with methanol/dichloromethane (1:33, 3×20 mL). The organic fractions were combined, dried over magnesium sulfate, filtered, and concentrated. The residue was purified by flash column chromatography on silica gel, using ethyl acetate-heptane (3:1) as the mobile phase, to afford the title compound (0.011 g, 0.020 mmol) as a white powder. 1H NMR (DMSO-d6, 400 MHz) δ 9.53 (s, 1H), 8.00 (d, 1H), 7.92 (s, 1H), 7.71 (s, 1H), 7.62 (m, 1H), 7.59 (s, 1H), 7.56 (m, 2H), 7.49 (t, 1H), 7.36 (s, 1H), 7.32 (m, 3H), 7.16 (d, 1H), 7.12 (m, 1H), 5.61 (br, 2H), 5.31 (t, 1H), 4.61 (d, 2H), 4.05 (s, 3H), 3.92 (s, 3H); MS: (M−H)− 533.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.[CH3:13][O:14][C:15]([CH:17]1[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16].C1C=CC(S(N(S(C2C=CC=CC=2)(=O)=O)[F:39])(=O)=O)=CC=1>C1COCC1>[CH3:13][O:14][C:15]([C:17]1([F:39])[CH2:21][CH2:20][N:19]([C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[CH2:18]1)=[O:16]
Reactant: O=S(=O)(c1ccccc1)N(F)S(=O)(=O)c1ccccc1
Reactant: COC(=O)C1CCN(C(=O)OC(C)(C)C)C1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COC(=O)C1(F)CCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 64 %

Procedure:
n-Butyl lithium (2.5M/Hexanes, 3.83 ml; 9.575 mmol) added dropwise to solution of diisopropylamine (1.36 ml; 9.62 mmol) at −78° C. Solution was allowed warm to room temperature and stirred for 30 minutes, then cooled to −78° C. A solution of Pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester 3-methyl ester (2 g, 8.72 mmol) in THF (10 ml) was added dropwise, warmed to −40° C. for 1 hour, then cooled to −70° C.A solution of N-fluorobenzene-sulfonimide (3.02 g, 9.57 mmol) in THF (15 ml) was added dropwise, stirred at −78° C. for 1 hour, then stirred at room temperature overnight. Precipitated solid was filtered, washed with EtOAc (2×150 ml). Organic layer was washed with 1N HCl (30 ml), brine (100 ml), dried (MgSO4), filtered and solvent evaporated. The residue was chromatographed on silica gel eluting with 10% v/v EtOAc/hexanes yielding product as colorless oil (1.38 g: 64% yield). MS (ESMS, MH 249).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:16]=[CH:15][CH:14]=[C:13]3[C:9]=2[CH2:10][C:11](=[O:17])[NH:12]3)=[CH:4][CH:3]=1.[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=O)[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]>C(O)C.N1CCCCC1>[CH2:18]([O:20][C:21]([C:23]1[C:27]([CH2:28][CH2:29][CH2:30][N:31]2[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]2)=[C:26]([CH:38]=[C:10]2[C:9]3[C:13](=[CH:14][CH:15]=[CH:16][C:8]=3[C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[NH:12][C:11]2=[O:17])[NH:25][C:24]=1[CH3:40])=[O:22])[CH3:19]
Reactant: CCOC(=O)c1c(C)[nH]c(C=O)c1CCCN1CCN(C)CC1
Reactant: O=C1Cc2c(cccc2-c2ccc(Cl)cc2)N1
Solvent: CCO
Solvent: C1CCNCC1
Product: CCOC(=O)c1c(C)[nH]c(C=C2C(=O)Nc3cccc(-c4ccc(Cl)cc4)c32)c1CCCN1CCN(C)CC1
Temperature: 25 °C
Reaction time: 72 h
Yield: 28.4 %

Procedure:
To a solution of 4-(4-chloro-phenyl)-1,3-dihydro-indol-2-one (60.9 mg, 0.25 mmol) and 5-formyl-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester (80.3 mg, 0.26 mmol) in ethanol (2 mL) was added piperidine (3 drops). The reaction mixture was stirred at room temperature for three days. A yellow solid product was precipitated out, filtered, washed by ethanol for three times, and dried under high vacuum to provide pure product 5-[4-(4-chloro-phenyl)-2-oxo-1,2-dihydro-indol-3-ylidenemethyl]-2-methyl-4-[3-(4-methyl-piperazin-1-yl)-propyl]-1H-pyrrole-3-carboxylic acid ethyl ester as a yellow solid (38.8 mg, 28%).
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18](Cl)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:21]1[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]1>C(O)(C)(C)C>[C:1]1([S:7]([N:10]2[C:14]3[N:15]=[CH:16][N:17]=[C:18]([N:21]4[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]4)[C:13]=3[C:12]([Br:20])=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: C1CCNCC1
Reactant: O=S(=O)(c1ccccc1)n1cc(Br)c2c(Cl)ncnc21
Solvent: CC(C)(C)O
Product: O=S(=O)(c1ccccc1)n1cc(Br)c2c(N3CCCCC3)ncnc21
Temperature: 60 °C
Reaction time: 2 h
Yield: 97.2 %

Procedure:
A mixture of 2.0 g (5.37 mmol) of the product from Method L and 1.1 grams (13.4 mmol) of piperidine in 10 mL of tert-butanol was heated with stirring at 60° C. for 2 hours. After cooling to room temperature, the reaction mixture was partitioned between dichloromethane (25 mL) and water (25 mL). The dichloromethane layer was dried over sodium sulfate (Na2SO4) and concentrated to dryness in vacuo affording 2.2 grams (97%) of the title compound. 1H NMR (400 MHz) (CDCl3)δ: 1.63-1.72 (m, 6H), 3.54-3.57 (m, 4H), 7.53 (t, 2H, J=2.0 Hz), 7.60 (s, 1H), 7.61 (t, 1H, J=2.0 Hz), 8.17-8.20 (m, 2H), 8.43 (s, 1H). LRMS: 422.7, 420.7 (M+1).
Reaction SMILES: Br[C:2]1[C:7]2[S:8][C:9]([C:11]3[C:18]([F:19])=[CH:17][C:14]([C:15]#[N:16])=[CH:13][C:12]=3[Cl:20])=[N:10][C:6]=2[CH:5]=[CH:4][N:3]=1.[NH2:21][C:22]1[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.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.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Cl:20][C:12]1[CH:13]=[C:14]([CH:17]=[C:18]([F:19])[C:11]=1[C:9]1[S:8][C:7]2[C:2]([NH:21][C:22]3[CH:27]=[C:26]([CH3:28])[N:25]=[CH:24][N:23]=3)=[N:3][CH:4]=[CH:5][C:6]=2[N:10]=1)[C:15]#[N:16]
Reactant: N#Cc1cc(F)c(-c2nc3ccnc(Br)c3s2)c(Cl)c1
Reactant: Cc1cc(N)ncn1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cc1cc(Nc2nccc3nc(-c4c(F)cc(C#N)cc4Cl)sc23)ncn1
Temperature: 70 °C
Yield: 37.8 %

Procedure:
A mixture of 4-(4-bromo-thiazolo[5,4-c]pyridin-2-yl)-3-chloro-5-fluoro-benzonitrile (0.087 g, 0.24 mmol), 4-amino-6-methylpyrimidine (0.024 g, 0.22 mmol), Pd2(dba)3 (0.011 g, 0.01 mmol), XantPhos (0.014 g, 0.02 mmol) and cesium carbonate (0.192 g, 0.59 mmol) in dioxane (2.4 mL) was degassed with nitrogen and heated to 70° C. for 16 hours. The reaction mixture was diluted with DCM and water, and then filtered through Celite®. The layers of the filtrate were separated and the organic layer dried over Na2SO4 and concentrated under reduced pressure. The residue was purified by silica gel flash chromatography eluting with 0-5% MeOH in DCM and triturated with acetonitrile to give the desired compound as a yellow solid (0.033 g, 35% yield). 1H NMR (300 MHz, DMSO-d6): δ 10.70 (s, 1H), 8.63 (d, J=1.2 Hz, 1H), 8.46 (d, J=5.6 Hz, 1H), 8.27 (t, J=1.3 Hz, 1H), 8.22 (dd, J=9.0, 1.4 Hz, 1H), 7.85 (d, J=5.6 Hz, 1H), 7.56 (s, 1H), 2.39 (s, 3H). LCMS (Method C): RT=3.30 min, m/z: 397 [M+H+].
Reaction SMILES: CCN=C=NCCCN(C)C.Cl.[CH2:13]([C:15]1[CH:27]=[C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[N:36]=[C:35]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:34]=3)[O:30][N:29]=2)[CH:25]=[C:24]([CH3:46])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:23])[CH2:20][NH:21][CH3:22])[CH3:14].[C:47]([OH:51])(=O)[CH2:48][OH:49].C1C=CC2N(O)N=NC=2C=1>C1COCC1>[CH2:13]([C:15]1[CH:27]=[C:26]([C:28]2[N:32]=[C:31]([C:33]3[CH:38]=[C:37]([O:39][CH3:40])[N:36]=[C:35]([CH:41]([CH2:44][CH3:45])[CH2:42][CH3:43])[CH:34]=3)[O:30][N:29]=2)[CH:25]=[C:24]([CH3:46])[C:16]=1[O:17][CH2:18][C@@H:19]([OH:23])[CH2:20][N:21]([CH3:22])[C:47](=[O:51])[CH2:48][OH:49])[CH3:14]
Reactant: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CNC
Reactant: O=C(O)CO
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CCc1cc(-c2noc(-c3cc(OC)nc(C(CC)CC)c3)n2)cc(C)c1OC[C@@H](O)CN(C)C(=O)CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.1 %

Procedure:
EDC hydrochloride (144 mg, 753 μmol) is added to a stirred solution of (2S)-1-(2-ethyl-4-{5-[2-(1-ethyl-propyl)-6-methoxy-pyridin-4-yl]-[1,2,4]oxadiazol-3-yl}-6-methyl-phenoxy)-3-methylamino-propan-2-ol (294 mg, 627 μmol), glycolic acid (57 mg, 753 μmol) and HOBt (101 mg, 753 μmol) in THF (10 mL). The mixture is stirred at rt for 2 h before it is concentrated. The crude product is purified by prep. HPLC, then on prep. TLC plates using DCM containing 10% of 7 N NH3 in methanol to give the title compound (149 mg) as a white solid; LC-MS: tR=1.14 min, [M+H]+=527.17; 1H NMR (CDCl3): δ0.84 (t, J=7.5 Hz, 6H), 1.33 (t, J=7.5 Hz, 3H), 1.69-1.88 (m, 4H), 2.40 (s, 3H), 2.57-2.66 (m, 1H), 2.76 (q, J=7.5 Hz, 2H), 3.10 (s, 3H), 3.76 (d, J=5.3 Hz, 2H), 3.80-3.88 (m, 1H), 3.89-3.94 (m, 1H), 4.02 (s, 3H), 4.25 (s, 2H), 4.28-4.36 (m, 1H), 7.33 (s, 1H), 7.45 (s, 1H), 7.88 (s, 1H), 7.89 (s, 1H).
Reaction SMILES: [CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH:24]=[CH:25][C:26]([O:28]CC)=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7].[OH-].[Na+].C(NC(=O)N(C1N=C(C2C=CC(CCC(OCC)=O)=CC=2)C=CC=1)C)CCCCCC.O1CCCC1.CO>CO.[Pd].C(O)(=O)C.O>[CH2:1]([NH:8][C:9](=[O:31])[N:10]([C:12]1[N:17]=[C:16]([C:18]2[CH:23]=[CH:22][C:21]([CH2:24][CH2:25][C:26]([OH:28])=[O:27])=[CH:20][CH:19]=2)[CH:15]=[CH:14][CH:13]=1)[CH3:11])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH3:7]
Reactant: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(C=CC(=O)OCC)cc2)n1
Agent: [Pd]
Agent: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)OCC)cc2)n1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: CCCCCCCNC(=O)N(C)c1cccc(-c2ccc(CCC(=O)O)cc2)n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 69.2 %

Procedure:
170 mg (0.4 mmol) of ethyl 3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}acrylate are dissolved in 5 ml of methanol. 50 mg of 10% palladium-on-charcoal are added. The reaction mixture is stirred for 3 hours at room temperature under a hydrogen atmosphere. The catalyst is filtered off and the solvents are then evaporated off and the oil obtained is used directly in the following reaction. 170 mg of sodium hydroxide are added to the solution of ethyl 3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoate in 5 ml of 9/1 tetrahydrofuran/methanol. The reaction mixture is stirred for two hours at room temperature. The reaction is stopped by adding 20 mL of water and 3 mL of acetic acid and is then extracted with ethyl acetate. The organic phases are combined and dried over sodium sulfate. The solvents are evaporated off and the residue is then chromatographed on silica gel (7/3 to 1/1 heptane/EtOAc). 110 mg of 3-{4-[6-(3-heptyl-1-methylureido)pyrid-2-yl]phenyl}propanoic acid are obtained. Yield=69% over two steps. m.p.=108° C.