Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[C:28]([N:35]1[CH2:40][CH2:39][CH:38]([CH2:41]O)[CH2:37][CH2:36]1)([O:30][C:31]([CH3:34])([CH3:33])[CH3:32])=[O:29].CCOC(/N=N/C(OCC)=O)=O>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH2:41][CH:38]2[CH2:39][CH2:40][N:35]([C:28]([O:30][C:31]([CH3:32])([CH3:34])[CH3:33])=[O:29])[CH2:36][CH2:37]2)=[CH:4][CH:3]=1
Reactant: Oc1ccc(F)cc1
Reactant: CC(C)(C)OC(=O)N1CCC(CO)CC1
Agent: CCOC(=O)/N=N/C(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(COc2ccc(F)cc2)CC1
Temperature: 0 °C
Reaction time: 8 h
Yield: 75 %

Procedure:
4-Fluorophenol (0.52 g, 4.64 mmol) and triphenylphosphine (1.22 g, 4.64 mmol) were added to a solution of N-boc-piperidine-4-methanol (500 mg, 2.32 mmol) in anhydrous THF (12 mL) under nitrogen. The reaction mixture was cooled to 0° C. and DEAD (670 μL, 3.69 mmol) was added dropwise. The solution was allowed to warm to room temperature and stirred overnight. The reaction mixture was concentrated under reduced pressure then diluted with dichloromethane and filtered. The filtrate was washed three times with NaOH 0.2N, dried over Na2SO4 and concentrated. The residue was purified on column chromatography (eluent: pentane/EtOAc 95/5) to give the title compound (538 mg, 75%) as a yellow oil.
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:18])[C@@H:5]1[CH2:9][C@@H:8]([NH2:10])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12].[Cl:19][C:20]1[S:24][C:23]([C:25](O)=[O:26])=[CH:22][CH:21]=1>>[CH3:2][O:3][C:4]([C@@H:5]1[CH2:9][C@@H:8]([NH:10][C:25]([C:23]2[S:24][C:20]([Cl:19])=[CH:21][CH:22]=2)=[O:26])[CH2:7][N:6]1[C:11]([O:13][C:14]([CH3:15])([CH3:17])[CH3:16])=[O:12])=[O:18]
Reactant: COC(=O)[C@@H]1C[C@@H](N)CN1C(=O)OC(C)(C)C
Reactant: O=C(O)c1ccc(Cl)s1
Agent: Cl
Product: COC(=O)[C@@H]1C[C@@H](NC(=O)c2ccc(Cl)s2)CN1C(=O)OC(C)(C)C

Procedure:
11.1 Using general procedure D N-Boc-trans-4-amino-L-proline methyl ester hydrochloride was coupled with 5-chlorothiophene-2-carboxylic acid to give (2S,4R)-4-[(5-chloro-thiophene-2-carbonyl)-amino]-pyrrolidine-1,2-dicarboxylic acid 1-tert-butyl ester 2-methyl ester. White solid. MS 389.4 ([M+H]+)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4](OS(C(F)(F)F)(=O)=O)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19].[NH:29]1[CH2:34][CH2:33][O:32][CH2:31][CH2:30]1.[Li+].[OH-]>C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([N:29]2[CH2:34][CH2:33][O:32][CH2:31][CH2:30]2)[CH:5]=[C:6]([Cl:20])[C:7]=1[CH2:8][N:9]1[CH2:13][CH2:12][C:11]2([CH2:18][CH2:17][CH2:16][CH2:15][CH2:14]2)[C:10]1=[O:19]
Reactant: C1COCCN1
Reactant: O=C1N(Cc2c(Cl)cc(OS(=O)(=O)C(F)(F)F)cc2Cl)CCC12CCCCC2
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C1N(Cc2c(Cl)cc(N3CCOCC3)cc2Cl)CCC12CCCCC2
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
Heat a solution of trifluoro-methanesulfonic acid 3,5-dichloro-4-(1-oxo-2-aza-spiro[4.5]dec-2-ylmethyl)-phenyl ester (0.15 g, 0.32 mmol) and morpholine (0.099 g, 1.13 mmol) in 1-methyl-2-pyrrolidine (2.5 mL) to 201° C. for 1.5 hours in a microwave reactor. Cool the reaction to room temperature and treat with 2M LiOH (1 mL) and stir 16 hours at room temperature. Dilute the reaction with ethyl acetate and wash with water. Dry the organic layer with Na2SO4 and remove the solvent in vacuo to afford crude product. Purify on silica isocratically using 5% methyl t-butyl ether in chloroform to afford 0.064 g (50%) of the titled product. Rf=0.22 (9:1 chloroform:methyl t-butyl ether). MS (m/z): 397 (M+).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([OH:20])=[CH:16][CH:15]=1)[CH3:13])[N:6]=[CH:5]2.Br[CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24].C(=O)([O-])[O-].[K+].[K+].C(C(C)=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([N:12]([C:14]1[CH:19]=[CH:18][C:17]([O:20][CH:22]([CH3:28])[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[CH:16][CH:15]=1)[CH3:13])[N:6]=[CH:5]2
Reactant: CN(c1ccc(O)cc1)c1ncc2cc(Cl)ccc2n1
Reactant: CCOC(=O)C(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: CCOC(=O)C(C)Oc1ccc(N(C)c2ncc3cc(Cl)ccc3n2)cc1

Procedure:
A mixture of 4-[N-(6-chloro-2-quinazolinyl)-N-methylamino]phenol (0.52 g), ethyl 2-bromopropionate (0.40 g), potassium carbonate (0.28 g) and methyl ethyl ketone (25 ml) was heated under reflux for a period of 18 hours. After cooling, the mixture was diluted with water and the aqueous mixture was extracted with dichloromethane. The dichloromethane extract was dried (anhydrous sodium sulfate) and the solvent was removed under reduced pressure. The residue was purified by chromatography over silica gel (eluant dichloromethane) to give ethyl 2-{4-[N-(6-chloro-2-quinazolinyl)-N-methylamino]phenoxy}propionate as a yellow oil. The assigned structure was confirmed by proton magnetic resonance (pmr) spectroscopy and mass spectrometry. Pmr spectrum (CDCl3 ; δ in ppm): 8.93 (1H, s, quinazoline hetero ring proton); 7.60 (3H, s, quinazoline benzo-ring protons); 7.13 (4H, d of d, phenoxy protons); 4.80 (1H, q, CH--CH3); 4.27 (2H, q, CH2 --CH3); 1.60 (3H, d, CH--CH3); 1.27 (3H, t, CH2 --cH3).
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2=[O:11])=[CH:4][CH:3]=1.Br[CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15].II>C(OCC)C.C1C=CC=CC=1.[Zn]>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH2:6][CH2:7][C:8]2([CH2:13][C:14]([O:16][CH2:17][CH3:18])=[O:15])[OH:11])=[CH:4][CH:3]=1
Reactant: CCOC(=O)CBr
Reactant: O=C1CCc2ccc(F)cc21
Agent: II
Agent: [Zn]
Solvent: CCOCC
Solvent: c1ccccc1
Product: CCOC(=O)CC1(O)CCc2ccc(F)cc21
Yield: 95.8 %

Procedure:
A mixture of 6-fluoro-1-indanone (5.0 g, 33.3 mmol), ethyl bromoacetate (8.3 g, 50.0 mmol, Aldrich), activated zinc powder (3.2 g, 50.0 mmol, Mallinckrodt; Org. Synth., Coll. Vol. 6, 290, 1988) and a few crystals of iodine in diethyl ether-benzene (1:1, 100 mL) was heated at reflux under nitrogen for 24 h. The mixture was filtered and the filtrate was concentrated in vacuo. The residue in diethyl ether was vigorously stirred with excess dilute ammonium hydroxide, dried and concentrated to give ethyl 2-(6-fluoro-1-hydroxy-1-indanyl)acetate as an amber oil (7.6 g, 97%);
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:14][CH2:13][N:12]([C:15]2SC(C(OC)=O)=CN=2)[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[N:28]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=1>>[C:1]([O:5][C:6]([NH:8][CH:9]1[CH2:10][CH2:11][N:12]([C:15]2[C:34]3[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:28]=[C:27]([C:35]([O:37][CH3:38])=[O:36])[CH:26]=2)[CH2:13][CH2:14]1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)c1cnc(N2CCC(NC(=O)OC(C)(C)C)CC2)s1
Reactant: COC(=O)c1cc(Cl)c2ccccc2n1
Product: COC(=O)c1cc(N2CCC(NC(=O)OC(C)(C)C)CC2)c2ccccc2n1

Procedure:
The title compound was prepared by a procedure analogous to Intermediate 133 starting with methyl 4-chloroquinoline-2-carboxylate (WO 9505378). The product was purified on a silica gel flash column (0→5% MeOH in DCM) followed by recrystallization from EtOAc.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([N:8]2[CH:12]=[C:11]([NH2:13])[CH:10]=[N:9]2)[CH2:4][CH2:3]1.Cl[C:15]1[N:20]=[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])[C:18]([Cl:34])=[CH:17][N:16]=1.O>CO>[Cl:34][C:18]1[C:19]([CH2:21][CH2:22][C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=2[CH:29]([CH3:33])[C:30]([NH2:32])=[O:31])=[N:20][C:15]([NH:13][C:11]2[CH:10]=[N:9][N:8]([CH:5]3[CH2:4][CH2:3][N:2]([CH3:1])[CH2:7][CH2:6]3)[CH:12]=2)=[N:16][CH:17]=1
Reactant: CC(C(N)=O)c1ccccc1CCc1nc(Cl)ncc1Cl
Reactant: CN1CCC(n2cc(N)cn2)CC1
Solvent: CO
Solvent: O
Product: CC(C(N)=O)c1ccccc1CCc1nc(Nc2cnn(C3CCN(C)CC3)c2)ncc1Cl
Temperature: 70 °C
Reaction time: 16 h
Yield: 2 %

Procedure:
A stirred solution of 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.117 g, 0.648 mmol), 2-(2-(2-(2,5-dichloropyrimidin-4-yl)ethyl)phenyl)propanamide A30 (0.060 g, 0.185 mmol) in MeOH (10 mL) and water (1.0 mL) was stirred at 70° C. for 16 hours. Additional 1-(1-methylpiperidin-4-yl)-1H-pyrazol-4-amine (0.052 g, 0.29 mmol) was added and the reaction was stirred for 16 hours at 70° C. After cooling the solvent was removed to afford an oil which was purified by HPLC (Gradient: 30-100%, acetonitrile 0.1% formic acid in water 0.1% formic acid, 12 min) to give the title compound 44 as a red gum (0.0018 g, 2% yield). LCMS-C: rt 4.28 min; m/z 468 [M+H]+.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[CH3:29][C:30]1([OH:37])[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]1>>[CH3:29][C:30]1([OH:37])[CH2:36][CH2:35][CH2:34][N:33]([CH2:2][C:3]2[N:4]([CH3:28])[C:5]3[C:10]([N:11]=2)=[C:9]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[N:8]=[C:7]([N:18]2[C:22]4[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=4[N:20]=[C:19]2[CH3:27])[N:6]=3)[CH2:32][CH2:31]1
Reactant: CC1(O)CCCNCC1
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CN3CCCC(C)(O)CC3)n(C)c2n1

Procedure:
Following General Procedure E for Displacement of alkyl bromide with amines, 4-(8-(bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine and 4-methylazepan-4-ol were reacted to give 429. [M+H]+ 491.6
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1.C(N(CC)CC)C.[O:18](C(OC(C)(C)C)=O)[C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=O>C(Cl)Cl.CN(C)C1C=CN=CC=1>[O:1]=[C:2]1[N:6]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[C@H:5]([C:7]([O:9][CH3:10])=[O:8])[CH2:4][CH2:3]1
Reactant: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)[C@@H]1CCC(=O)N1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 2 h
Yield: 95.1 %

Procedure:
To a solution of commercially available (Aldrich) methyl 5-oxo-L-prolinate (20 g, 140 mmol) in DCM (200 ml) were added triethylamine (19.6 ml, 140 mmol), 4-(dimethylamino)pyridine (17.2 g, 140 mmol) and finally, dropwise, a solution of BOC2O (61 g, 280 mmol) in DCM (100 ml). The resulting red mixture was stirred at room temperature for 2 hours. Then the solvent was removed in vacuo and the crude material was purified by chromatography on silica gel eluting with cyclohexane/ethyl acetate (7:3 to 4:6) to afford (after trituration in hexane/diethylether 1:1) the title compound as a white solid (32.4 g, 96%); Rf (cyclohexanes:ethyl acetate=65:35): 0.21; 1H NMR (300 MHz, CDCl3) δ (ppm): 4.62 (dd, 1H), 3.78 (s, 3H), 2.68-2.58 (m, 1H), 2.52-2.45 (m, 1H), 2.37-2.27 (m, 1H), 2.08-1.97 (m, 1H), 1.48 (s, 9H).
Reaction SMILES: [N+:1]([C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1)([O-])=O.[Cl-].[NH4+]>C(O)C.O.[Fe]>[NH2:1][C:4]1[CH:15]=[CH:14][C:7]2[CH2:8][CH2:9][CH2:10][CH2:11][C:12](=[O:13])[C:6]=2[CH:5]=1
Reactant: O=C1CCCCc2ccc([N+](=O)[O-])cc21
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1ccc2c(c1)C(=O)CCCC2
Yield: 101.3 %

Procedure:
A mixture of 3-nitro-6,7,8,9-tetrahydrobenzocyclohepten-5-one (14.87 g), iron (14.87 g) and ammonium chloride (2.0 g) in ethanol (200 ml) and water (40 ml) was refluxed for 5 hours, and filtered. The filtrate was evaporated in vacuo to afford 3-amino-6,7,8,9-tetrahydrobenzocyclohepten-5-one (12.86 g).
Reaction SMILES: [Cl:1][C:2]1[C:7](I)=[C:6]([CH3:9])[N:5]=[C:4]([NH2:10])[N:3]=1.[C:11]([C:13]1[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=1)#[CH:12].C(N(CC)CC)C>CN(C=O)C.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>[NH2:10][C:4]1[N:3]=[C:2]([Cl:1])[C:7]([C:12]#[C:11][C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)=[C:6]([CH3:9])[N:5]=1
Reactant: C#Cc1cccc(O)c1
Reactant: Cc1nc(N)nc(Cl)c1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(Cl)c1C#Cc1cccc(O)c1

Procedure:
The title compound is synthesized according to general procedure GP2 starting from 1.5 g (5.7 mmol) 4-chloro-5-iodo-6-methyl-pyrimidin-2-ylamine (GP3) and 986 mg (8.4 mmol) 3-ethynyl-phenol using 106 mg (0.56 mmol) CuI, 390 mg (0.56 mmol) PdCl2(PPh3)2 and 8 mL (55 mmol) triethylamine in 12 mL dry DMF. For the work-up the solvent is removed in vacuo and the product is purified by chromatography on silica gel (DCM/MeOH gradient) and subsequently RP-HPLC (ACN/H2O gradient). Yield: 419 mg (29%).
Reaction SMILES: [N:1]1[C:2]([C:10]([OH:12])=O)=[CH:3][N:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=12.[NH2:13][C@@H:14]([CH3:31])[CH2:15][N:16]1[CH:20]=[CH:19][C:18]([C:21]2[CH:28]=[C:27]([F:29])[C:24]([C:25]#[N:26])=[C:23]([Cl:30])[CH:22]=2)=[N:17]1>>[Cl:30][C:23]1[CH:22]=[C:21]([C:18]2[CH:19]=[CH:20][N:16]([CH2:15][C@@H:14]([NH:13][C:10]([C:2]3[N:1]=[C:5]4[CH:6]=[CH:7][CH:8]=[CH:9][N:4]4[CH:3]=3)=[O:12])[CH3:31])[N:17]=2)[CH:28]=[C:27]([F:29])[C:24]=1[C:25]#[N:26]
Reactant: C[C@H](N)Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1
Reactant: O=C(O)c1cn2ccccc2n1
Product: C[C@@H](Cn1ccc(-c2cc(F)c(C#N)c(Cl)c2)n1)NC(=O)c1cn2ccccc2n1
Yield: 39 %

Procedure:
The title compound was prepared using the method of Example 34(d) starting from imidazo[1,2-a]pyridine-2-carboxylic acid (0.853 g, 5.26 mmol) and (S)-4-(1-(2-aminopropyl)-1H-pyrazol-3-yl)-2-chloro-6-fluorobenzonitrile (1.0 g, 3.59 mmol). The product was purified by flash chromatography and recrystallization from acetonitrile/water, respectively. Yield 39.0%. 1H-NMR (400 MHz; DMSO-d6): δ 1.13 (d, 3H), 4.35 (dd, 1H), 4.43 (dd, 1H), 4.47-4.57 (m, 1H), 6.96-7.01 (m, 1H), 7.02 (d, 1H), 7.34-7.40 (m, 1H), 7.60 (dd, 1H), 7.89 (d, 1H), 7.93 (dd, 1H), 7.97 (s, 1H), 8.32 (d, 1H), 8.55-8.58 (m, 1H), 8.61 (d, 1H).
Reaction SMILES: [CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][NH:15][CH2:14]2)=[CH:9][CH:8]=1)=[O:5].Cl[C:21]1[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]2[CH:34]=[CH:33][N:32]=[CH:31][C:30]=2[F:35])[N:22]=1.C(N(CC)CC)C>O1CCCC1>[CH3:1][N:2]([CH3:19])[CH2:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C@@H:13]2[O:18][CH2:17][CH2:16][N:15]([C:21]3[N:26]([CH3:27])[C:25](=[O:28])[CH:24]=[C:23]([C:29]4[CH:34]=[CH:33][N:32]=[CH:31][C:30]=4[F:35])[N:22]=3)[CH2:14]2)=[CH:11][CH:12]=1)=[O:5]
Reactant: CN(C)CC(=O)Nc1ccc([C@H]2CNCCO2)cc1
Reactant: Cn1c(Cl)nc(-c2ccncc2F)cc1=O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CN(C)CC(=O)Nc1ccc([C@H]2CN(c3nc(-c4ccncc4F)cc(=O)n3C)CCO2)cc1
Temperature: 95 °C
Reaction time: 1 h
Yield: 50 %

Procedure:
A solution of N2,N2-dimethyl-N1-(4-((2S)-morpholin-2-yl)phenyl)glycinamide obtained in Reference Example 13 (0.21 g, 0.8 mmol), 2-chloro-6-(3-fluoropyridin-4-yl)-3-methyl-3H-pyrimidin-4-one (0.15 g, 0.64 mmol), and triethylamine (0.40 g, 4 mmol) in tetrahydrofuran (10 ml) was stirred at 95° C. for one hour. The solvent was removed in vacuo and the residue was partitioned between water and dichloromethane. The organic layer was dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. The resulting residue was purified by silica gel column chromatography (chloroform/methanol=10/1) to afford N2,N2-dimethyl-N1-(4-((2S)-4-(3-methyl-4-oxo-3,4-dihydro-6-(3-fluoropyridin-4-yl)pyrimidin-2-yl)-morpholin-2-yl)phenyl)glycinamide (0.15 g, 50%) as colorless crystals.
Reaction SMILES: [C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]([CH3:39])[CH3:38])([CH3:4])([CH3:3])[CH3:2].N1(CCN)C[CH2:45][O:44][CH2:43]C1>>[C:1]([O:5][C:6](=[O:40])[CH2:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[C:14]([C:17]([O:19][CH3:20])=[O:18])[CH:15]=2)[C:10]([CH:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[C:9]1[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[CH2:33][NH:34][CH2:35][CH2:36][N:37]1[CH2:39][CH2:45][O:44][CH2:43][CH2:38]1)([CH3:2])([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN(C)C)n(CC(=O)OC(C)(C)C)c2c1
Reactant: NCCN1CCOCC1
Product: COC(=O)c1ccc2c(C3CCCCC3)c(-c3ccccc3CNCCN3CCOCC3)n(CC(=O)OC(C)(C)C)c2c1
Yield: 92 %

Procedure:
The title compound was obtained following the same procedure described in Example 1, Step 3 for the synthesis of methyl 1-(2-tert-butoxy-2-oxoethyl)-3-cyclohexyl-2-[2-({[2-(dimethylamino)ethyl]amino}methyl)phenyl]-1H-indole-6-carboxylate, using 2-morpholin-4-ylethyl amine instead of N,N-dimethylethane-1,2-diamine. The title compound was obtained in a 92% yield; MS (ES+) m/z 590 (M+H)+
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH:17]([C:18]3[N:19]([CH3:27])[C:20]4[CH:25]=[CH:24][N:23]=[CH:22][C:21]=4[N:26]=3)[C:16](=O)[C:15]3[C:14]([C:29]([O:31]CC)=O)=[CH:13][CH:12]=[CH:11][C:10]=3[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:35][NH2:36]>CO>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[NH:9][C:10]3[C:15]4[C:16](=[N:35][NH:36][C:29](=[O:31])[C:14]=4[CH:13]=[CH:12][CH:11]=3)[CH:17]2[C:18]2[N:19]([CH3:27])[C:20]3[CH:25]=[CH:24][N:23]=[CH:22][C:21]=3[N:26]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc2c1C(=O)C(c1nc3cnccc3n1C)C(c1ccc(F)cc1)N2
Reactant: NN
Solvent: O
Solvent: CO
Product: Cn1c(C2c3n[nH]c(=O)c4cccc(c34)NC2c2ccc(F)cc2)nc2cnccc21
Temperature: 25 °C
Reaction time: 4 h
Yield: 5 %

Procedure:
The mixture of ethyl 2-(4-fluorophenyl)-3-(1-methyl-1H-imidazo[4,5-c]pyridin-2-yl)-4-oxo-1,2,3,4-tetrahydroquinoline-5-carboxylate (150 mg, 0.34 mmol) and hydrazine monohydrate (2 mL) in methanol (5 mL) was stirred at room temperature for 4 h. Then methanol was evaporated under reduced pressure and the residue was extracted with ethyl acetate (20 mL×4). The combined organic layers were washed with brine, dried over anhydrous sodium sulfate and concentrated to give crude product, which was purified by chromatography (silica gel, DCM/MeOH=25:1 to 1:1) to give the title compound (6.7 mg, yield 5%). LC-MS (ESI) m/z: 413 (M+1)+. 1H-NMR (400 MHz, CD3OD) δ (ppm): 3.58 (s, 3H), 4.93-4.95 (d, J=11.6 Hz, 1H), 5.04-5.07 (d, J=11.6 Hz, 1H), 6.85-6.90 (t, J=8.8 Hz, 2H), 7.12-7.14 (d, J=8.0 Hz, 1H), 7.38-7.44 (m, 3H), 7.49-7.57 (m, 2H), 8.19-8.21 (d, J=5.6 Hz, 1H), 8.72 (s, 1H).
Reaction SMILES: [C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH2:21])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1.[CH3:22][O:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[N:30]=[C:31]=[O:32]>>[C@H:1]1([NH:10][C:11]2[CH:20]=[CH:19][C:18]3[C:13](=[CH:14][CH:15]=[C:16]([NH:21][C:31]([NH:30][C:25]4[CH:26]=[CH:27][CH:28]=[CH:29][C:24]=4[O:23][CH3:22])=[O:32])[CH:17]=3)[N:12]=2)[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH2:3][CH2:2]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: COc1ccccc1N=C=O
Product: COc1ccccc1NC(=O)Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1

Procedure:
The title compound, MS: m/e=425.7 (M+H+), was prepared in accordance with the general method 4 of example 16 from (R)—N2-indan-1-yl-quinoline-2,6-diamine and 2-methoxyphenyl-isocyanate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][NH:15][CH2:14]1.C(=O)(O)[O-].[Na+].Cl[CH2:25][CH2:26][CH2:27][C:28]1([C:33]2[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=2)OCC[O:29]1>CN(C)C=O.O1CCCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][CH:7]=[C:6]2[CH2:12][CH:13]1[CH2:18][CH2:17][CH2:16][N:15]([CH2:25][CH2:26][CH2:27][C:28]([C:33]2[CH:34]=[CH:35][C:36]([F:39])=[CH:37][CH:38]=2)=[O:29])[CH2:14]1
Reactant: COc1ccc2[nH]cc(CC3CCCNC3)c2c1
Reactant: Fc1ccc(C2(CCCCl)OCCO2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: C1CCOC1
Product: COc1ccc2[nH]cc(CC3CCCN(CCCC(=O)c4ccc(F)cc4)C3)c2c1

Procedure:
A mixture of compound of Description 6 [5-methoxy-3-(piperidin-3-ylmethyl)-1H-indole] (2 g; 0.0082 mol), sodium bicarbonate (0.68 g; 0.0082 mol), KI (0.087 g; 0.00053 mol) and 2-(3-chloropropyl)-2-(4-fluorophenyl)-1,3-dioxolane [2.2 g (1,8 ml); 0.009 mol] in dry dimethylformamide (25 ml) and tetrahydrofuran (25 ml), was heated under reflux for 5 hours. After evaporation under vacuum, the residue was flash chromatographed on silica gel using as eluent methylene chloride/methanol/ammonia (95/5/0.5) and the desired compound was obtained. A solution of the compound in ethanol was saturated with gaseous hydrogen chloride, a solid was precipitated. The title compound hydrochloride was collected by filtration.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[CH2:6]([O:13][C:14]1[CH:19]=[CH:18][C:17]([CH2:20][CH2:21][CH2:22][CH2:23][OH:24])=[CH:16][CH:15]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.C(N(CC)CC)C>C(OCC)(=O)C>[CH3:1][S:2]([O:24][CH2:23][CH2:22][CH2:21][CH2:20][C:17]1[CH:16]=[CH:15][C:14]([O:13][CH2:6][C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[CH:19][CH:18]=1)(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCCc1ccc(OCc2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCCc1ccc(OCc2ccccc2)cc1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
Methanesulfonyl chloride (17.9 g) was added to a solution of 4-(4-benzyloxyphenyl)butanol (20.0 g) and triethyl amine (15.8 g) in ethyl acetate (500 ml) at 0° C. and then stirred for 5 hours at room temperature. The reaction mixture was washed with water, dried (MgSo4) and concentrated under reduced pressure to give 4-(4-benzyloxyphenyl)butyl methanesulfonate (26.0 g, quantitatively). Oily substance.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([NH:15][C:16](=[O:32])[CH2:17][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[CH2:19]O)=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(P(CCCC)CCCC)CCC.C1(C)C=CC=CC=1.C1(C)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1>[C:1]([O:5][C:6]([NH:8][C:9]1[C:10]([N:15]2[C:16](=[O:32])[CH2:17][C@H:18]([NH:21][C:22](=[O:31])[O:23][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[CH2:19]2)=[N:11][N:12]([CH3:14])[CH:13]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: Cn1cc(NC(=O)OC(C)(C)C)c(NC(=O)C[C@@H](CO)NC(=O)OCc2ccccc2)n1
Agent: CCCCP(CCCC)CCCC
Agent: CCOC(=O)N=NC(=O)OCC
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: Cn1cc(NC(=O)OC(C)(C)C)c(N2C[C@@H](NC(=O)OCc3ccccc3)CC2=O)n1
Temperature: 60 °C
Reaction time: 1 h
Yield: 84.7 %

Procedure:
To a mixture of benzyl ((2S)-4-((4-((tert-butoxycarbonyl)amino)-1-methyl-1H-pyrazol-3-yl)amino)-1-hydroxy-4-oxobutan-2-yl)carbamate (1.6 g), tri-n-butylphosphine (1.3 mL), toluene (18 mL) and THF (6.0 mL) was added 40% diethyl azodicarboxylate toluene solution (1.8 mL) under ice-cooling, and the mixture was stirred at 60° C. for 1 hr. The reaction mixture was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (ethyl acetate/hexane) to give the title compound (1.3 g).
Reaction SMILES: [NH2:1][C:2]1[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=1[O:4][CH2:5][CH2:6][CH2:7][C:8]([O:10]CC)=[O:9].[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39](O)=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1>>[CH3:17][C:18]1[CH:46]=[CH:45][CH:44]=[CH:43][C:19]=1[CH:20]([N:28]1[C:36]2[C:31](=[CH:32][C:33](/[C:37](/[CH3:42])=[CH:38]/[C:39]([NH:1][C:2]3[CH:16]=[CH:15][CH:14]=[CH:13][C:3]=3[O:4][CH2:5][CH2:6][CH2:7][C:8]([OH:10])=[O:9])=[O:40])=[CH:34][CH:35]=2)[CH:30]=[CH:29]1)[C:21]1[CH:26]=[CH:25][CH:24]=[C:23]([CH3:27])[CH:22]=1
Reactant: CCOC(=O)CCCOc1ccccc1N
Reactant: C/C(=C\C(=O)O)c1ccc2c(ccn2C(c2cccc(C)c2)c2ccccc2C)c1
Product: C/C(=C\C(=O)Nc1ccccc1OCCCC(=O)O)c1ccc2c(ccn2C(c2cccc(C)c2)c2ccccc2C)c1

Procedure:
0.20 g of compound 73 was obtained in a similar manner to those described in the Examples 1 and 2 using 0.41 g of ethyl 4-(2-aminophenoxy)butyrate and 0.36 g of 3-[1-(2,3'-dimethylbenzhydryl)indol-5yl]isocrotonic acid obtained according to the procedures described in the Reference Examples 1-4.