Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26](=[O:29])[NH:27][CH3:28])[C:15]=3[CH:30]=2)[CH:10]=1)[C:5]([OH:7])=O.Cl.Cl.[N:33]1[CH:38]=[CH:37][CH:36]=[CH:35][C:34]=1[C:39]1([NH2:42])[CH2:41][CH2:40]1>O>[F:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][C:14]3[O:18][C:17]([C:19]4[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=4)=[C:16]([C:26]([NH:27][CH3:28])=[O:29])[C:15]=3[CH:30]=2)[CH:8]=[C:4]([C:5](=[O:7])[NH:42][C:39]2([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][N:33]=3)[CH2:41][CH2:40]2)[CH:3]=1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(F)cc(C(=O)O)c3)cc12
Reactant: NC1(c2ccccn2)CC1
Agent: Cl
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2ccc(-c3cc(F)cc(C(=O)NC4(c5ccccn5)CC4)c3)cc12

Procedure:
The product precipitated from the reaction mixture during the coupling of 3-fluoro-5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)benzofuran-5-yl)benzoic acid (0.068 mmol scale) with 1-(pyridin-2-yl)cyclopropanamine dihydrochloride (TBTU, iPr2NET, DMF, r.t.). The mixture was diluted with 4 ml H2O, the off white solid filtered and washed with 3×2 ml H2O. The solid was further washed with 3×1 ml MeOH and dried. 1H NMR (500 MHz, DMSO-d6) δ 9.50 (s, 1H), 8.52 (d, J=4.58, 1H), 8.47 (d, J=3.97, 1H), 8.17 (s, 1H), 8.03-8.00 (overlapping m, 3H), 7.83 (overlapping m, 3H), 7.73 (d, 1H), 7.70 (dt overlapping with d, 1H), 7.43-7.40 (overlapping m, 3H), 7.17 (dd, J=6.87, 5.34, 1H), 2.88 (d, J=4.27, 3H), 1.59 (m, 2H), 1.32 (m, 2H). LC/MS were performed by using Shimadzu-VP instrument with UV detection at 220 nm and Waters MICROMASS®. HPLC method: Solvent A=10% MeOH-90% H2O-0.1% TFA, Solvent B=90% MeOH-10% H2O-0.1% TFA, Start % B=0, Final % B=100, Gradient time=2 min, Stop time=3 min, Flow Rate=5 ml/min, Column: PHENOMENEX® Luna, 3.0×50 mm, S10; (ES+) m/z (M+H)+=524.25, HPLC Rt=1.512 min.
Reaction SMILES: [C:1]([O:11][CH3:12])(=[O:10])[C:2]1[C:3](=[CH:5][CH:6]=[C:7]([CH:9]=1)[OH:8])[OH:4].C(=O)([O-])[O-].[K+].[K+].Cl[CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24].O>CN(C=O)C>[OH:4][C:3]1[CH:5]=[CH:6][C:7]([O:8][CH2:20][CH2:21][CH2:22][Si:23]([CH3:26])([CH3:25])[CH3:24])=[CH:9][C:2]=1[C:1]([O:11][CH3:12])=[O:10]
Reactant: C[Si](C)(C)CCCCl
Reactant: COC(=O)c1cc(O)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCCC[Si](C)(C)C)ccc1O
Temperature: 90 °C

Procedure:
To a mixture of methyl gentisate (16.8 g, 0.1 mol) and potassium carbonate (15.2 g, 0.11 mol) in 80 ml of DMF, under a nitrogen atmosphere at 80° C., was added chloropropyltrimethylsilane (16.6 g, 0.11 mol) dropwise over 20 minutes. The mixture was heated at 90° C. for 8 hours. It was cooled and poured into 200 ml of water. The mixture was extracted with diisopropyl ether. The organic phase was washed with water, dried over sodium sulphate and then concentrated. After chromatography on silica of the yellow oil obtained (eluent: 90/10 heptane/CH2Cl2), 3.3 g of a clean fraction of methyl 2-hydroxy-5-(3-trimethylsilanylpropyloxy)benzoate were recovered.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH2:20][C:21]([O:23]C2C(F)=C(F)C(F)=C(F)C=2F)=O)[CH:6]=[CH:7][C:8]=1[NH:9][C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH3:19])=[O:11].[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][NH:49]1)[C:39]([O:41][CH3:42])=[O:40]>CN(C=O)C.CCOC(C)=O>[F:35][C:36]1[CH:37]=[C:38]([CH:43]=[CH:44][C:45]=1[O:46][CH2:47][CH:48]1[CH2:52][CH2:51][CH2:50][N:49]1[C:21](=[O:23])[CH2:20][C:5]1[CH:6]=[CH:7][C:8]([NH:9][C:10]([NH:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH3:19])=[O:11])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:39]([O:41][CH3:42])=[O:40]
Reactant: COC(=O)c1ccc(OCC2CCCN2)c(F)c1
Reactant: COc1cc(CC(=O)Oc2c(F)c(F)c(F)c(F)c2F)ccc1NC(=O)Nc1ccccc1C
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(OCC2CCCN2C(=O)Cc2ccc(NC(=O)Nc3ccccc3C)c(OC)c2)c(F)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 98.2 %

Procedure:
A mixture of pentafluorophenyl 3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetate (324.5 mg, 0.676 mmol), methyl 3-fluoro4-(2-pyrrolidinyl)methoxybenzoate (171.1 mg, 0.676 mmol), Et3 N (113 ul, 0.811 mmol) in DMF (5 mL) was stirred for 2 hr at room temp. The mixture was diluted with EtOAc, washed with brine, and dried over Na2SO4. The solvent was removed under a reduced pressure and the residue was chromatographed on silica-gel with n-hexane:EtOAc (1:2, v/v) as eluent to afford methyl 3-fluoro-4-[[1-[3-methoxy-4-[N′-(2-methylphenyl)ureido]phenylacetyl]-2-pyrrolidinyl]methoxy]benzoate (365.1 mg, 0.664 mmol) as an oil. To a stirred solution of this compound in THF (4.4 mL) and H2O (1.1 mL) was added LiOH (46.3 mg, 1.932 mmol), and the reaction mixture was stirred at room temp overnight. The mixture was diluted with CHCl3 and acidified by the addition of 1 N HCl. The separated organic layer was washed with brine and dried over Na2SO4. The solvent was removed under a reduced pressure, and the obtained crude solid was recrystallized from n-hexane-EtOAc—CHCl3 to afford 102 mg (30%) 38 as a white crystalline powder. mp 123–126; IR (KBr) 1616, 1537, 1282, 756 cm−1; 1H-NMR (400 MHz, DMSO-d6) δ 1.87–2.09 (m, 4H), 2.25 (s, 3H), 3.48–3.57 (m, 2H), 3.60 (s, 2H), 3.83 (s, 3H), 4.11–4.16 (m, 1H), 4.24 (dd, J=2.9, 9.8 Hz, 1H), 4.28–4.34 (br s, 1H), 6.74 (dd, J=1.5, 8.3 Hz, 1H), 6.87 (s, 1H), 6.94 (t, J=7.3 Hz, l), 7.12 (d, J=7.8 Hz, 1H), 7.15 (t, J=8.3 Hz, 1H), 7.34 (t, J=8.8 Hz, 1H), 7.66 (dd, J=2.0, 12.2 Hz, 1H), 7.73 (d, J=9.3 Hz, 1H), 7.79 (d, J=8.3 Hz, 1H), 7.99 (d, J=7.8 Hz, 1H), 8.46 (s, 1H), 8.55 (s, 1H); MS (FAB) m/z 536 (M++1); Anal. Calcd for C29H30N3O6.0.5H2O: C, 63.96; H. 5.74; N, 7.72; F; 3.49. Found: C, 64.11; H, 5.80; N, 7.39; F, 3.54.
Reaction SMILES: C[O:2][C:3]([C@@H:5]1[CH2:16][C@:8]2([C:13]([CH3:15])([CH3:14])[C:9]32[CH2:12][CH2:11][CH2:10]3)[CH2:7][N:6]1[C:17](=[O:45])[C@@H:18]([NH:23][C:24](=[O:44])[C@H:25]([CH:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH2:39]1)[NH:26][C:27]([C@@H:29]1[CH2:34][CH2:33][CH2:32][CH2:31][N:30]1[CH:35]([CH3:37])[CH3:36])=[O:28])[C:19]([CH3:22])([CH3:21])[CH3:20])=[O:4]>C1COCC1.CO.O>[CH:38]1([C@H:25]([NH:26][C:27]([C@@H:29]2[CH2:34][CH2:33][CH2:32][CH2:31][N:30]2[CH:35]([CH3:37])[CH3:36])=[O:28])[C:24]([NH:23][C@@H:18]([C:19]([CH3:20])([CH3:21])[CH3:22])[C:17]([N:6]2[C@H:5]([C:3]([OH:4])=[O:2])[CH2:16][C@:8]3([C:13]([CH3:14])([CH3:15])[C:9]43[CH2:12][CH2:11][CH2:10]4)[CH2:7]2)=[O:45])=[O:44])[CH2:39][CH2:40][CH2:41][CH2:42][CH2:43]1
Reactant: COC(=O)[C@@H]1C[C@@]2(CN1C(=O)[C@@H](NC(=O)[C@@H](NC(=O)[C@@H]1CCCCN1C(C)C)C1CCCCC1)C(C)(C)C)C(C)(C)C21CCC1
Solvent: O
Solvent: C1CCOC1
Solvent: CO
Product: CC(C)N1CCCC[C@H]1C(=O)N[C@H](C(=O)N[C@H](C(=O)N1C[C@]2(C[C@H]1C(=O)O)C(C)(C)C21CCC1)C(C)(C)C)C1CCCCC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5R,8S)-7-((S)-2-{(S)-2-Cyclohexyl-2-[((S)-1-isopropyl-piperidine-2-carbonyl)-amino]-acetylamino}-3,3-dimethyl-butyryl)-10,10-dimethyl-7-aza-dispiro[3.0.4.1]decane-8-carboxylic acid methyl ester (0.69 g; 1.10 mmol) in THF/Methanol/water (2:1:1; 20 mL) was added LiOH monohydrate (0.138 g; 3.3 mmol) and the reaction was stirred overnight at room temperature. The solvent was removed in vacuo, water was added, the product was frozen in liquid nitrogen and lyophilized overnight to yield the title compound. LC-MS (method E): Rt=1.50 min; M/z=615 [M+]; HPLC (method A3): Rt=4.38 min
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:7][C:6]=1[F:22])(=O)C.C(N)C1C=CC=CC=1>C(O)C.CCOCC>[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]([O:13][CH:14]([CH3:21])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])=[O:12])=[CH:7][C:6]=1[F:22]
Reactant: CCCCCCC(C)OC(=O)c1ccc(OC(C)=O)c(F)c1
Solvent: CCOCC
Solvent: CCO
Solvent: NCc1ccccc1
Product: CCCCCCC(C)OC(=O)c1ccc(O)c(F)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 63.1 %

Procedure:
The above compound (3) (1.1 g) was dissolved in 30 ml of ethanol, and 3 g of benzylamine was added dropwise. The mixture was stirred at room temperature for 24 hours, then diluted with 300 ml of ether, washed with dilute hydrochloric acid and water in this sequence, and dried over magnesium sulfate. After the solvent was evaporated, the solid was purified by silica gel column chromatograhy to afford 0.6 g of a final product (4).
Reaction SMILES: [Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9](Cl)=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15].[CH2:17]([NH2:21])[CH:18]([CH3:20])[CH3:19]>ClCCl.C([O-])(O)=O.[Na+]>[Cl:1][CH2:2][CH2:3][S:4][C:5]1[CH:13]=[CH:12][C:8]([C:9]([NH:21][CH2:17][CH:18]([CH3:20])[CH3:19])=[O:10])=[CH:7][C:6]=1[N+:14]([O-:16])=[O:15]
Reactant: CC(C)CN
Reactant: O=C(Cl)c1ccc(SCCCl)c([N+](=O)[O-])c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CNC(=O)c1ccc(SCCCl)c([N+](=O)[O-])c1
Reaction time: 16 h

Procedure:
To a biphasic solution of 4-(2-chloroethylthio)-3-nitrobenzoyl chloride (2.331 g, 8.32 mmol) in dichloromethane (75 mL) and saturated aqueous NaHCO3 (75 mL) was added isobutylamine (1.043 mL, 10.40 mmol). The reaction was allowed to stir for 16 hours. TLC and LCMS analysis of the reaction mixture indicated consumption of starting material. The reaction mixture was diluted with H2O (100 mL) and extracted with DCM (4×50 mL). The combined organics were dried over Na2SO4 and concentrated in vacuo. The product, 4-(2-chloroethylthio)-N-isobutyl-3-nitrobenzamide, was used without further purification. Product yield was assumed to be 100% (2.64 g, 8.32 mmol) for future calculations. LCMS (+ESI) m/z=317.13 [M+H]+.
Reaction SMILES: [O:1]=[C:2]1[CH2:16][CH2:15][C@H:14]([CH:17]=[CH:18][CH:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:25])[CH3:24])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([O:12]C)=[O:11].[OH-].[Na+]>O.CO>[O:1]=[C:2]1[CH2:16][CH2:15][C@H:14]([CH:17]=[CH:18][CH:19]([OH:26])[CH2:20][CH2:21][CH:22]=[C:23]([CH3:24])[CH3:25])[C@H:3]1[CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11]
Reactant: COC(=O)CCCCCC[C@H]1C(=O)CC[C@@H]1C=CC(O)CCC=C(C)C
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: CC(C)=CCCC(O)C=C[C@H]1CCC(=O)[C@@H]1CCCCCCC(=O)O
Yield: 91.5 %

Procedure:
The solution of 0.5 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid, methyl ester, 0.170 g of NaOH in water (1.5 ml), methanol (4.5 ml) is left for two hours at room temperature under nitrogen, then diluted with water (22 ml) and extracted with diethyl ether (10 ml). The aqueous layer is acidified (congo red) with HCl (5%), then extracted with diethyl ether (3×15 ml). The ethereal solution is washed with water to neutrality, dried over sodium sulphate and the solvent evaporated in vacuo to yield 0.44 g of 9-keto-15-hydroxy-19-methyl-prosta-13,18-dienoic acid (oil).
Reaction SMILES: [C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](Cl)=[O:9])[CH2:6][CH2:5]1)(=[O:3])[CH3:2].[Cl-].[Al+3].[Cl-].[Cl-].[F:17][C:18]1[CH:19]=[C:20]([CH3:24])[CH:21]=[CH:22][CH:23]=1>C(Cl)CCl>[C:1]([N:4]1[CH2:12][CH2:11][CH:7]([C:8](=[O:9])[C:23]2[CH:22]=[CH:21][C:20]([CH3:24])=[CH:19][C:18]=2[F:17])[CH2:6][CH2:5]1)(=[O:3])[CH3:2]
Reactant: Cc1cccc(F)c1
Reactant: CC(=O)N1CCC(C(=O)Cl)CC1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCCl
Product: CC(=O)N1CCC(C(=O)c2ccc(C)cc2F)CC1

Procedure:
By following the manipulative procedure described above in Example 4(a), 25 g of 1-acetylisonipecotoyl chloride are added to stirred suspension of 25 g of aluminum chloride and 14 g of m-fluorotoluene in 220 ml of ethylene dichloride to produce the oil, 1-acetyl-4-(2-fluoro-4-methylbenzoyl)piperidine.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[C:9]1[CH:14]=[CH:13][C:12]([CH:15]=O)=[CH:11][CH:10]=1)#[N:2].Cl.[CH3:18][O:19][C:20](=[O:27])[C@H:21]([C@H:23]([CH2:25][CH3:26])[CH3:24])[NH2:22].C([BH3-])#N.[Na+]>C(OCC)(=O)C.CCCCCC>[CH3:18][O:19][C:20](=[O:27])[C@H:21]([C@H:23]([CH2:25][CH3:26])[CH3:24])[NH:22][CH2:15][C:12]1[CH:11]=[CH:10][C:9]([C:4]2[CH:5]=[CH:6][CH:7]=[CH:8][C:3]=2[C:1]#[N:2])=[CH:14][CH:13]=1
Reactant: CC[C@H](C)[C@H](N)C(=O)OC
Reactant: N#Cc1ccccc1-c1ccc(C=O)cc1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CC[C@H](C)[C@H](NCc1ccc(-c2ccccc2C#N)cc1)C(=O)OC

Procedure:
The starting material can be obtained, for example, analogously to Example 1b): The reaction of 2.0 g of 2'-cyanobiphenyl-4-carbaldehyde, 9.6 g of molecular sieve 5 A, 1.76 g of (L)-isoleucine methyl ester hydrochloride and 680 mg of sodium cyanoborohydride yields N-[(2'-cyanobiphenyl-4-yl)methyl]-(L)-isoleucine methyl ester after flash chromatography (ethyl acetate/hexane 1:3). 1H-NMR (DMSO): 1.21 ppm (d, 3H), 3.63 ppm (s, 3H), 3.75 (dd, 1H), 4.56 ppm (d, 2H), 4.58 ppm (d, 2H), 5.31 ppm (t, 1H), 7.4-8 ppm aromatics.
Reaction SMILES: O=[C:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1.[NH2:15][CH:16]([CH3:18])[CH3:17].[BH4-].[Na+].O>CO.C(Cl)Cl>[CH:16]([NH:15][CH:2]1[CH2:7][CH2:6][CH2:5][N:4]([C:8]([O:10][C:11]([CH3:14])([CH3:13])[CH3:12])=[O:9])[CH2:3]1)([CH3:18])[CH3:17]
Reactant: CC(C)N
Reactant: CC(C)(C)OC(=O)N1CCCC(=O)C1
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: CO
Solvent: ClCCl
Product: CC(C)NC1CCCN(C(=O)OC(C)(C)C)C1
Temperature: 25 °C
Reaction time: 12 h
Yield: 82.3 %

Procedure:
A solution of tert-butyl 3-oxopiperidine-1-carboxylate (2 g, 10.03 mmol) and 2-aminopropane (710 mg, 12.04 mmol) in MeOH (40 mL) was stirred at rt for 1 h. To the solution was added NaBH4 (758 mg, 20.06 mmol) at 0° C. and the reaction mixture was stirred at rt for 12 h. The reaction mixture was diluted with ice-cooled water and the solvent was reduced to afford a residue which was dissolved in CH2Cl2 and washed with water. The organic layer was dried over Na2SO4, concentrated in vacuo and purified by column chromatography (silica gel, gradient MeOH in CH2Cl2) to afford the titled compound (2 g, 82%). 1H NMR (400 MHz, CDCl3): δ 4.01-3.90 (m, 1H), 3.78 (dt, J=3.6, 9.2 Hz, 1H), 3.48 (s, 1H), 2.96 (heptate, 0.1=6.4 Hz, 1H), 2.92-2.79 (m, 1H), 2.69-2.55 (m, 1H), 1.90-1.87 (m, 1H), 1.68-1.61 (m, 1H), 1.46 (s, 9H), 1.29-1.18 (m, 2H), 1.05 (d, J=6.0 Hz, 6H). ES-MS: m/z [M+1]=243.
Reaction SMILES: [NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:23]=[CH:22][C:16]([C:17]([O:19]CC)=[O:18])=[CH:15][CH:14]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1.[ClH:24]>>[ClH:24].[NH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([OH:19])=[O:18])=[CH:22][CH:23]=3)[N:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: CCOC(=O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1
Agent: Cl
Product: O=C(O)c1ccc(CCc2ccc3c(n2)NCCC3)cc1

Procedure:
Ester 37-5 (680 mg, 2.11 mmol) in 10 mL 6N HCl was heated to 50° C. for 18 hours. Concentration provided 34-7 as a yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9](N)[CH:10]=1)=[O:4].N(OCCC(C)C)=O.[I:27]CI>N1CCCCC1.CC#N>[CH3:1][O:2][C:3]([C:5]1[CH:6]=[C:7]([C:12]2[CH:17]=[CH:16][C:15]([CH3:18])=[CH:14][CH:13]=2)[CH:8]=[C:9]([I:27])[CH:10]=1)=[O:4]
Reactant: ICI
Reactant: COC(=O)c1cc(N)cc(-c2ccc(C)cc2)c1
Agent: CC(C)CCON=O
Solvent: CC#N
Solvent: C1CCNCC1
Product: COC(=O)c1cc(I)cc(-c2ccc(C)cc2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 66 %

Procedure:
A mixture of 5-amino-4′-methyl-biphenyl-3-carboxylic acid methyl ester (10.9 g, 45.2 mmol), iso-amyl nitrite (36.5 ml, 271.4 mmol) and diiodomethane (23 ml, 271.4 mmol) was stirred at room temperature for 1 hour. The mixture was then heated to 65° C. and kept at this temperature for 8 hours. The reaction mixture to room temperature and then added to a stirred solution of piperidine/CH3CN (V:V=90 ml:90 ml). A vigorous exothermic reaction ensued. The excess volatile reagents were removed by rotary evaporation. The residue was diluted with ethyl acetate, washed with 10% hydrochloric acid, water, brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography, eluting with n-hexane, followed by n-hexane/ethyl acetate (20:1), giving 5-Iodo-4′-methyl-biphenyl-3-carboxylic acid methyl ester as white yellow solid (10.5 g, 66%).
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH2:20])([CH3:4])([CH3:3])[CH3:2].C([O:26][C:27](=O)[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)[CH:32]=1)=[O:30])(C)(C)C>>[C:1]([O:5][C:6](=[O:21])[NH:7][C:8]1[CH:13]=[C:12]([CH2:14][CH3:15])[C:11]([C:16]([F:19])([F:18])[F:17])=[CH:10][C:9]=1[NH:20][C:27](=[O:26])[CH2:28][C:29]([C:31]1[CH:36]=[CH:35][CH:34]=[C:33]([C:37]2[CH:42]=[CH:41][N:40]=[C:39]([C:43]#[N:44])[CH:38]=2)[CH:32]=1)=[O:30])([CH3:2])([CH3:3])[CH3:4]
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-c2ccnc(C#N)c2)c1
Reactant: CCc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Product: CCc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3ccnc(C#N)c3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-ethyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J33) (228 mg, 0.75 mmol) and 3-[3-(2-cyano-pyridin-4-yl)-phenyl]-3-oxo-propionic acid tert-butyl ester (Example K24) (242 mg, 0.75 mmol) according to the general procedure M. Obtained as a light brown solid (308 mg, 74%).
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].Cl.[CH3:21][CH:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[NH:24][CH2:23]1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:10][CH2:11][O:12][CH2:13][CH2:14]2)[N:4]=[C:3]1[CH2:15][C:16]([N:24]1[C:25]2[C:30](=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH:22]([CH3:21])[CH2:23]1)=[O:18]
Reactant: CC1CNc2ccccc21
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: CC1CN(C(=O)Cc2nc(N3CCOCC3)cc(=O)n2C)c2ccccc21
Yield: 26.1 %

Procedure:
The product is prepared according to the procedure described in example 68, using 275 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate, 254 mg of 3-methylindoline hydrochloride and 254 mg of N-[3-(dimethylamino)propyl]-N′-ethylcarbodiimide hydrochloride in a mixture of 161 μl of pyridine and 4.0 ml of N,N-dimethylformamide. 96 mg of 3-methyl-2-[2-(3-methyl-2,3-dihydro-1H-indol-1-yl)-2-oxoethyl]-6-(morpholin-4-yl)pyrimidin-4(3H)-one are obtained in the form of a pink powder, the characteristics of which are the following:
Reaction SMILES: [C:1]([OH:14])(=O)/[CH:2]=[CH:3]/[C:4]1[CH:12]=[CH:11][C:9]([OH:10])=[C:6]([O:7][CH3:8])[CH:5]=1.C(N(CC)CC)C.[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:26][CH2:27][NH2:28]>CN(C=O)C.ClCCl>[CH3:8][O:7][C:6]1[CH:5]=[C:4](/[CH:3]=[CH:2]/[C:1]([NH:28][CH2:27][CH2:26][C:25]2[CH:29]=[CH:30][C:31]([OH:32])=[C:23]([OH:22])[CH:24]=2)=[O:14])[CH:12]=[CH:11][C:9]=1[OH:10]
Reactant: COc1cc(/C=C/C(=O)O)ccc1O
Reactant: NCCc1ccc(O)c(O)c1
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1cc(/C=C/C(=O)NCCc2ccc(O)c(O)c2)ccc1O
Temperature: 0 °C
Reaction time: 20 h

Procedure:
A solution of ferulic acid (300 mg; 1.54 mmol) and of triethylamine (1.5 eq; 2.31 mmol) in DMF (3.5 mL) is cooled to 3 or 4° C. using an ice bath. An amine, 3-hydroxytyramine (dopamine) (1 eq; 1.54 mmol) is added to the medium, followed by addition of a solution of BOP (benzotriazol-1-yloxy)tris(dimethylamino)phosphonium hexafluorophosphate; (1 eq; 1.54 mmol) in dichloromethane (3.5 mL); the mixture is stirred for about thirty minutes in the ice bath and then for 20 hours at room temperature. Stirring is then stopped and the dichloromethane is evaporated off under vacuum. 30 mL of water are added to the remaining solution and the mixture obtained is extracted with ethyl acetate (3×75 mL). The organic phase is successively washed with 100 mL of 1N HCl solution, 100 mL of water and 100 mL of 1M sodium bicarbonate (NaHCO3) solution. It is then dried over sodium sulfate and evaporated to dryness. The product obtained is in the form of a white precipitate after chromatography on a column of silica gel.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH2:21][C:22]([O:24][CH3:25])=[O:23].[H-].[Na+].Br[CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1.[Cl-].[NH4+]>CN(C=O)C>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:14]2[CH:19]=[CH:18][C:17]([CH3:20])=[CH:16][CH:15]=2)[C:3]=1[CH:21]([CH:29]1[CH2:33][CH2:32][CH2:31][CH2:30]1)[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC(=O)Cc1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3
Reactant: BrC1CCCC1
Agent: [Cl-]
Agent: [H-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COC(=O)C(c1c(C)nc2sc3c(c2c1-c1ccc(C)cc1)CCC3)C1CCCC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 18 %

Procedure:
This compound was prepared according the following procedure: To a solution of methyl [2-Methyl-4-(4-methylphenyl)-6,7-dihydro-5H-cyclopenta[4,5]thieno[2,3-b]pyridin-3-yl]acetate in dry DMF (4 mL) at −10° C. was added sodium hydride (60% in mineral oil) (0.048 g; 1.2 mmol) and bromocyclopentane (0.120 mL; 1.5 mmol). The reaction mixture was allowed to warm up to room temperature and stirred for 18 h. The reaction mixture was then heated to 70° C. for 24 h. A saturated solution of ammonium chloride (10 ml) was added and the mixture was extracted with ethyl acetate. The organic layers were combined, washed with brine, dried over magnesium sulphatesulphate and concentrated under reduced pressure. The crude material was purified by flash-chromatography on silica gel column using a gradient of ethyl acetate (3 to 30%) in heptane to furnish 0.077 g (18%) of the title compound as a colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[O:17][C:18]2[C:19]([N:26]=1)=[N:20][CH:21]=[C:22]([CH:24]=[CH2:25])[CH:23]=2>CCOC(C)=O.ClCCl.[Pd]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C:11]2[O:12][CH:13]=[CH:14][CH:15]=2)=[O:10])=[CH:4][C:3]=1[C:16]1[O:17][C:18]2[C:19]([N:26]=1)=[N:20][CH:21]=[C:22]([CH2:24][CH3:25])[CH:23]=2
Reactant: C=Cc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Agent: [Pd]
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CCc1cnc2nc(-c3cc(NC(=O)c4ccco4)ccc3Cl)oc2c1
Reaction time: 0.5 h

Procedure:
N-(4-chloro-3-(6-vinyloxazolo[4,5-b]pyridin-2-yl)phenyl)-furan-2-carboxamide (I-22) was dissolved in EtOAc/dichloromethane (1:1; 12 ml). To the solution, catalytic amount of 5 wt % Pd—C was added. The reaction was stirred under hydrogen atmosphere for 30 minutes. LCMS indicated that the reaction was complete with a formation of new peak of desired mass 368.1 (M+1). The reaction was filtered to remove palladium on carbon and the filterate wasn concentrated under reduced pressure. The crude product was purified by column chromatography to yield the desired product N-(4-chloro-3-(6-ethyloxazolo[4,5-b]pyridin-2-yl)phenyl)furan-2-carboxamide (Example 419). 1H NMR (400 MHz, DMSO) δ 10.63 (s, 1H), 8.73 (d, J=2.6 Hz, 1H), 8.51 (d, J=1.8 Hz, 1H), 8.21 (d, J=1.5 Hz, 1H), 8.12-8.03 (m, 1H), 8.00 (dd, J=6.3, 7.0 Hz, 1H), 7.74 (t, J=10.6 Hz, 1H), 7.46-7.38 (m, 1H), 6.75 (dd, J=1.7, 3.5 Hz, 1H), 2.83 (q, J=7.6, 2H), 1.34-1.22 (m, 3H). LCMS M/Z=368.1 (M+1). RT=3.20: Method A.