Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[C:9]([O:10]CC2C=CC=CC=2)=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:6]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>CO.[Pd]>[NH2:1][C:2](=[O:36])[CH2:3][O:4][C:5]1[C:9]([OH:10])=[C:8]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[N:7]([C:23]2[CH:28]=[CH:27][C:26]([O:29][CH3:30])=[CH:25][CH:24]=2)[C:6]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]
Reactant: CCOC(=O)c1c(OCC(N)=O)c(OCc2ccccc2)c(C(=O)OCC)n1-c1ccc(OC)cc1
Agent: [Pd]
Solvent: CO
Product: CCOC(=O)c1c(O)c(OCC(N)=O)c(C(=O)OCC)n1-c1ccc(OC)cc1
Yield: 46.3 %

Procedure:
Diethyl 3-(2-amino-2-oxoethoxy)-4-(benzyloxy)-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (25) (66 mg, 0.133 mmol) in MeOH (66 mL) was passed through a Thales ‘H-cube’ cartridge (10% Pd/C) at a flow rate of 1 mL/min at 20° C. under H2 (full H2 mode). The output was concentrated in vacuo to afford a yellow oil. The residue was purified by silica gel chromatography (4 g, 0-100% EtOAc in isohexane) to afford diethyl 3-(2-amino-2-oxoethoxy)-4-hydroxy-1-(4-methoxyphenyl)-1H-pyrrole-2,5-dicarboxylate (UL2-031) (25 mg, 46%) as a white solid: m/z 407 (M+H)+ (ES+); 405 (M−H)− (ES−). 1H NMR (400 MHz, DMSO-d6) δ: 9.61 (s, 1H), 7.82-7.63 (m, 2H), 7.10-7.06 (m, 2H), 6.93-6.84 (m, 2H), 4.49 (s, 2H), 4.03-3.93 (m, 4H), 3.79 (s, 3H), 1.05-0.94 (m, 6H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][N:17](COCC[Si](C)(C)C)[C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([OH:7])=O.[CH3:37][NH:38][CH3:39].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.C(N(CC)C(C)C)(C)C.Cl>CN(C=O)C.C(OCC)(=O)C>[Cl:1][C:2]1[C:3]([OH:36])=[C:4]([CH:8]=[C:9]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)[CH:10]=1)[C:5]([N:38]([CH3:39])[CH3:37])=[O:7]
Reactant: COc1ccccc1-c1nn(COCC[Si](C)(C)C)c2ncc(-c3cc(Cl)c(O)c(C(=O)O)c3)cc12
Reactant: CNC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: COc1ccccc1-c1n[nH]c2ncc(-c3cc(Cl)c(O)c(C(=O)N(C)C)c3)cc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 21 %

Procedure:
3-Chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1-(2-trimethylsilanyl-ethoxymethyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid (143 mg, 0.3 mmol), dimethylamine (2M in THF, 0.4 ml, 0.6 mmol), O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (208 mg, 0.6 mmol), and N,N-di-iso-propylethylamine (0.1 ml, 0.6 mmol) were dissolved in DMF (2 ml). The reaction mixture was stirred at room temperature overnight. The mixture was distributed between ethyl acetate and 1 N aqueous hydrochloric acid. The organic layer was washed with saturated aqueous sodium bicarbonate and brine, dried over sodium sulfate and concentrated to dryness. The crude was purified by flash chromatography on silica gel. The resulting material was dissolved in 1 ml of a 5% v/v solution of 70% perchloric acid in acetic acid and stirred overnight at room temperature. The crude was filtered and purified by mass-triggered reverse phase HPLC to afford 11 mg (63 μmol, 21%) of 3-chloro-2-hydroxy-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-N,N-dimethylbenzamide. 1H-NMR (DMSO-d6): δ 2.94 (s, 6H), 3.82 (s, 3H), 7.09 (m, 1H), 7.21 (d, 1H), 7.47 (m, 2H), 7.63 (d, 1H), 7.81 (s, 1H), 8.29 (s, 1H), 8.81 (s, 1H). MS: m/z 423.0 (M+H+).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21](OS(C(F)(F)F)(=O)=O)[C:15]=3[O:14]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[Cl:31][C:32]1[CH:33]=[C:34](B(O)O)[CH:35]=[CH:36][CH:37]=1.C(=O)([O-])[O-].[K+].[K+]>C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C1C=CC([PH+]([C]2[CH][CH][CH][CH]2)C2C=CC=CC=2)=CC=1.C(Cl)Cl.Cl[Pd]Cl.[Fe]>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([O:11][CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:36]4[CH:35]=[CH:34][CH:33]=[C:32]([Cl:31])[CH:37]=4)[C:15]=3[O:14]2)(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(OS(=O)(=O)C(F)(F)F)c3O2)cc1
Reactant: OB(O)c1cccc(Cl)c1
Agent: Cl[Pd]Cl
Agent: [Fe]
Agent: O=C([O-])[O-]
Solvent: ClCCl
Product: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cccc(Cl)c4)c3O2)cc1
Yield: 79 %

Procedure:
Treatment of (±)-(5-chloro-7-{[(trifluoromethyl)sulfonyl]oxy}-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (1.50 g, 3.10 mmol) with 3-chlorophenylboronic acid (0.72 g, 4.60 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II) dichloromethane adduct (0.252 g, 0.30 mmol), and potassium carbonate (0.829 g, 6.0 mmol) generally according to the procedure described for Intermediate 35 gave 1.1 g (80%) of (±)-[5-chloro-7-(3-chlorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate as a white solid. mp 80-82° C. Anal. calcd. for C22H18Cl2O4S: C, 58.8; H, 4.04. Found: C, 56.91; H, 3.82.
Reaction SMILES: [F:1][C:2]1[C:9](F)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1.Cl.[F:15][C:16]([F:24])([F:23])[CH:17]1[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1.C([O-])([O-])=O.[K+].[K+].N>CN(C=O)C>[F:1][C:2]1[C:9]([N:20]2[CH2:21][CH2:22][CH:17]([C:16]([F:24])([F:23])[F:15])[CH2:18][CH2:19]2)=[CH:8][C:5]([NH:6][CH3:7])=[C:4]([N+:11]([O-:13])=[O:12])[CH:3]=1
Reactant: FC(F)(F)C1CCNCC1
Reactant: CNc1cc(F)c(F)cc1[N+](=O)[O-]
Agent: Cl
Agent: N
Agent: O=C([O-])[O-]
Solvent: CN(C)C=O
Product: CNc1cc(N2CCC(C(F)(F)F)CC2)c(F)cc1[N+](=O)[O-]
Temperature: 40 °C
Reaction time: 8 h

Procedure:
A mixture of 4,5-difluoro-N-methyl-2-nitroaniline (1.0 g, 5.3 mmol), 4-trifluoromethylpiperidine hydrochloride (2.02 g, 10.6 mmol), K2CO3 (1.47 g, 10.6 mmol) and DMF (7 mL) was stirred at 40° C. overnight under Ar atmosphere. The mixture was poured into aqueous ammonia and extracted with EtOAc. The organic layer was dried over Na2SO4, filtered and concentrated. The residue was washed with Et2O/PE to give the sub-title compound.
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][NH:14]C(=O)C>Cl>[N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[NH:11][CH2:12][CH2:13][NH2:14]
Reactant: CC(=O)NCCNc1ccc2ccccc2n1
Agent: Cl
Product: NCCNc1ccc2ccccc2n1
Yield: 69.3 %

Procedure:
A solution of N-[2-[(quinolin-2-yl)amino]ethyl]acetamide (6.8 g, 0.030 mol) in 2N HCl (45 ml, 0.090 ml) was heated under reflux for 20 hours. The solution was cooled and extracted with EtOAc. The aqueous phase was made basic (pH9) with solid KOH, saturated with NaCl, and extracted with EtOAc. The combined extracts were dried (MgSO4) and concentrated to give 3.89 g (68%) of an off-white solid m.p. 124°-125° C.
Reaction SMILES: [H-].[Al+3].[Li+].[H-].[H-].[H-].[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:19])([CH3:18])[C:9]1=O.S([O-])([O-])(=O)=O.[Na+].[Na+]>C1COCC1>[CH3:7][N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][C:15]=2[CH3:17])[C:10]([CH3:19])([CH3:18])[CH2:9]1
Reactant: Cc1cccc2c1N(C)C(=O)C2(C)C
Agent: O=S(=O)([O-])[O-]
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: Cc1cccc2c1N(C)CC2(C)C
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
Under an argon atmosphere 5.71 mL of a 1 molar lithium aluminium hydride solution in THF were added dropwise to 600 mg (2.85 mmol) 1,3,3,7-tetramethyl-1,3-dihydro-indol-2-one in 20 mL THF. The reaction mixture was stirred for 2.5 h at 60° C. and then cooled to RT. While cooling with the ice bath, saturated, aqueous sodium sulphate solution was slowly added dropwise and the resulting suspension was filtered through Celite. The filtrate was combined with EtOAc and saturated sodium chloride solution. The organic phase was dried on sodium sulphate, filtered and the filtrate was evaporated down.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][NH2:11])[CH:5]=[CH:6][CH:7]=1.C[O:13][C:14](=O)[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH2:21]Br.C([O-])([O-])=O.[K+].[K+].C(OCC)(=O)C>C1(C)C=CC=CC=1>[F:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][CH2:10][N:11]2[CH2:21][C:16]3[C:15](=[CH:20][CH:19]=[CH:18][CH:17]=3)[C:14]2=[O:13])[CH:5]=[CH:6][CH:7]=1
Reactant: NCCCc1cccc(F)c1
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: O=C1c2ccccc2CN1CCCc1cccc(F)c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 72.6 %

Procedure:
A mixture of 3-(3-fluorophenyl)-propylamine (306 mg, 2 mmol), 2-bromomethyl-benzoic acid methyl ester (458 mg, 2 mmol), and K2CO3 (200 mg, 1.45 mmol) in toluene (10 mL) was heated with stirring at 100° C. for 16 h. Workup and silica gel column chromatography using a gradient of hexanes to 50% ethyl acetate in hexanes afforded 2-[3-(3-fluorophenyl)-propyl]-2,3-dihydroisoindol-1-one (391 mg, 73%). GC/MS gave: m/z (rel.int.) 269 (M+, 32), 147 (100), 146 (100), 119 (37), 109 (26) and 91 (45).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1.[CH2:12]([CH:14]([CH2:17][CH2:18][CH2:19][CH3:20])[CH2:15]Cl)[CH3:13].C[O-].[Na+]>CN(C)C=O>[CH3:1][O:2][C:3](=[O:11])[C:4]1[CH:9]=[CH:8][C:7]([O:10][CH2:15][CH:14]([CH2:12][CH3:13])[CH2:17][CH2:18][CH2:19][CH3:20])=[CH:6][CH:5]=1
Reactant: CCCCC(CC)CCl
Reactant: COC(=O)c1ccc(O)cc1
Agent: C[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCCCC(CC)COc1ccc(C(=O)OC)cc1

Procedure:
A mixture of 51.7 g (0.34 mol) of 4-hydroxybenzoic acid methylester, 500 ml of dimethyl formamide, 60 g (0.40 mol) of 2-ethylhexylchloride and 21.8 g (0.40 mol) of sodium methylate was heated for 7 hours to boiling temperature and, after cooling and removal of the sodium chloride by filtration, was evaporated to dryness under reduced pressure. The residue was dissolved in methylene chloride and chromatographed (eluent: methylene chloride) on silica gel (Merck) to yield 43 g (48% of the theoretical) of 4-(2-ethylhexyloxy)benzoic acid methylester. A refractive index of
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:10]=[CH:9][CH:8]=[CH:7][C:4]=1[CH:5]=O.[CH2:11]([O:13][C:14](=[O:19])[CH2:15][C:16](=[NH:18])[NH2:17])[CH3:12]>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[CH:5]([C:4]2[CH:7]=[CH:8][CH:9]=[CH:10][C:3]=2[O:2][CH3:1])[C:15]([C:14]([O:13][CH2:11][CH3:12])=[O:19])=[C:16]([NH2:17])[NH:18][C:16]=1[NH2:17])=[O:19])[CH3:12]
Reactant: CCOC(=O)CC(=N)N
Reactant: COc1ccccc1C=O
Solvent: CCO
Product: CCOC(=O)C1=C(N)NC(N)=C(C(=O)OCC)C1c1ccccc1OC
Yield: 72 %

Procedure:
Upon boiling a solution of 6.8 g 2-methoxybenzaldehyde and 13.0 g amidinoacetic acid ethyl ester in 150 ml ethanol for 2 hours, 2,6-diamino-4-(2-methoxyphenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid diethyl ester of m.p. 147°C (ethanol) is obtained. Yield: 72% of theory.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:33]([CH3:34])=[CH:32][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:26][C:25]=3[CH3:35])=[O:22])[C:18]([CH3:36])=[CH:17][CH:16]=2)[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[OH:8][CH2:9][CH:10]1[CH2:14][CH2:13][N:12]([C:15]2[N:20]=[C:19]([C:21]([NH:23][C:24]3[C:25]([CH3:35])=[CH:26][C:27]([C:28]([O:30][CH3:31])=[O:29])=[CH:32][C:33]=3[CH3:34])=[O:22])[C:18]([CH3:36])=[CH:17][CH:16]=2)[CH2:11]1
Reactant: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2C)c(C)c1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1cc(C)c(NC(=O)c2nc(N3CCC(CO)C3)ccc2C)c(C)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 42.1 %

Procedure:
To a solution of methyl 4-[[6-[3-[[tert-butyl(dimethyl) silyl]oxymethyl]pyrrolidin-1-yl]-3-methyl-pyridine-2-carbonyl]amino]-3,5-dimethyl-benzoate (1.1 g, 2.15 mmol) in THF (7 ml) is added Bu4NF 1.0 M in THF (5.00 ml) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 6 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure. The resulting residue is purified by flash chromatography (silica gel) over a gradient using 0-50% ethyl acetate in hexanes to afford the title compound as an off-white solid (0.36 g, 42%). Mass spectrum (m/z): 398.2 (M+1).
Reaction SMILES: Br[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1.[S:25]1(=[O:32])(=[O:31])[CH2:30][CH2:29][CH2:28][CH2:27][NH:26]1>>[O:31]=[S:25]1(=[O:32])[CH2:30][CH2:29][CH2:28][CH2:27][N:26]1[C:2]1[N:7]=[CH:6][C:5]([C:8]([N:10]2[CH2:15][CH2:14][N:13]([C:16]3[C:21]([CH3:22])=[CH:20][C:19]([CH2:23][CH3:24])=[CH:18][N:17]=3)[CH2:12][CH2:11]2)=[O:9])=[CH:4][CH:3]=1
Reactant: CCc1cnc(N2CCN(C(=O)c3ccc(Br)nc3)CC2)c(C)c1
Reactant: O=S1(=O)CCCCN1
Product: CCc1cnc(N2CCN(C(=O)c3ccc(N4CCCCS4(=O)=O)nc3)CC2)c(C)c1
Yield: 79.6 %

Procedure:
Using (6-bromopyridin-3-yl)[4-(5-ethyl-3-methylpyridin-2-yl)piperazin-1-yl]methanone (389 mg) described in Preparation Example 145 and [1,2]thiazinane 1,1-dioxide (176 mg) and by the reaction and treatment in the same manner as in Example 20262, the title compound (353 mg) was obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([OH:21])=[O:20])(=[O:14])=[O:13])=[C:8]([CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:26]O>>[CH3:1][O:2][C:3]1[C:11]2[S:10][C:9]([S:12]([NH:15][C:16]3[CH:17]=[C:18]([CH:22]=[CH:23][CH:24]=3)[C:19]([O:21][CH3:26])=[O:20])(=[O:13])=[O:14])=[C:8]([CH3:25])[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c(C)c(S(=O)(=O)Nc3cccc(C(=O)O)c3)sc12
Reactant: CO
Product: COC(=O)c1cccc(NS(=O)(=O)c2sc3c(OC)cccc3c2C)c1
Yield: 71 %

Procedure:
The product was prepared from 3-{[(7-methoxy-3-methyl-1-benzothien-2-yl)sulfonyl]amino}benzoic acid (6.8 mg, 0.018 mmol) (Example 42) and MeOH (50 μL, 1.23 mmol) according to the General Procedure 8, described in Example 119. The title compound was obtained in 71% yield (5.0 mg). 1H NMR (500 MHz, CDCl3:DMSO-d6 6:1) δ ppm 2.23 (s, 3 H) 3.56 (s, 3 H) 3.68 (s, 3 H) 6.60 (dd, J=7.54, 1.10 Hz, 1 H) 6.98 (dd, J=8.13, 7.73 Hz, 1H) 7.05 (dd, J=8.17, 1.10 Hz, 1 H) 7.09 (dd, J=8.17, 7.54 Hz, 1 H) 7.14 (ddd, J=8.13, 2.32, 1.09 Hz, 1 H) 7.38 (ddd, J=7.73, 1.63, 1.09 Hz, 1 H) 7.57 (dd, J=2.32, 1.63 Hz, 1 H) 10.18 (s, 1 H). MS (ESI+) m/z 392 [M+H]+.
Reaction SMILES: Cl.[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:21]([N:23]([C:30]1[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=1)[CH2:24][C:25]1[CH:26]=[N:27][NH:28][CH:29]=1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl[CH2:40][C:41]1[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=1>>[CH2:2]([O:9][C:10]1[CH:19]=[CH:18][C:17]([F:20])=[C:16]2[C:11]=1[CH2:12][CH2:13][CH2:14][CH:15]2[C:21]([N:23]([C:30]1[CH:31]=[N:32][C:33]([CH:36]([CH3:38])[CH3:37])=[CH:34][CH:35]=1)[CH2:24][C:25]1[CH:29]=[N:28][N:27]([CH2:40][C:41]2[CH:46]=[C:45]([CH3:47])[CH:44]=[CH:43][N:42]=2)[CH:26]=1)=[O:22])[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: Cc1ccnc(CCl)c1
Reactant: CC(C)c1ccc(N(Cc2cn[nH]c2)C(=O)C2CCCc3c(OCc4ccccc4)ccc(F)c32)cn1
Agent: Cl
Product: Cc1ccnc(Cn2cc(CN(C(=O)C3CCCc4c(OCc5ccccc5)ccc(F)c43)c3ccc(C(C)C)nc3)cn2)c1
Yield: 84.2 %

Procedure:
By the reaction and treatment in the same manner as in Example 271 using 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-[(pyrazol-4-yl)methyl]-1,2,3,4-tetrahydronaphthalene-1-carboxamide hydrochloride (0.81 g) and 2-chloromethyl-4-methylpyridine (0.54 g) as starting materials, 5-benzyloxy-8-fluoro-N-(6-isopropylpyridin-3-yl)-N-({1-[(4-methylpyridin-2-yl)methyl]pyrazol-4-yl}methyl)-1,2,3,4-tetrahydronaphthalene-1-carboxamide (0.77 g) was obtained.
Reaction SMILES: [CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.[H-].[Na+].Br[C:13]1[N:21]=[CH:20][CH:19]=[CH:18][C:14]=1[C:15]([OH:17])=[O:16].Cl>C1COCC1.[Cl-].[Na+].O>[CH3:1][C:2]1([CH3:9])[O:6][C@H:5]([CH2:7][O:8][C:13]2[N:21]=[CH:20][CH:19]=[CH:18][C:14]=2[C:15]([OH:17])=[O:16])[CH2:4][O:3]1
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: O=C(O)c1cccnc1Br
Agent: Cl
Agent: [Cl-]
Agent: [H-]
Solvent: C1CCOC1
Solvent: O
Product: CC1(C)OC[C@@H](COc2ncccc2C(=O)O)O1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 95.7 %

Procedure:
(R)-(2,2-dimethyl-1,3-dioxolan-4-yl)methanol 54 (1.8 mL, 14.9 mmol) was added to a room temperature suspension of NaH (392 mg, 16.3 mmol) in THF (30 mL). The reaction mixture was stirred at room temperature for 30 min and 2-bromo-nicotinic acid 53 (1 g, 4.95 mmol) was added. The reaction mixture was heated at reflux for 12 h. After cooling to room temperature, the pH was adjusted to 3 by the addition of 3 N HCl. The mixture was poured into brine and extracted with EtOAc. The combined organics were dried and concentrated. The crude product was recrystallized from pentane/EtOAc to give 55 (1.2 g, 92% yield). The acetonide protecting group could be removed after coupling with the appropriate aniline by treatment with EtOH/3 N HCl (4:1) at reflux for 12 h.
Reaction SMILES: C([O:3][C:4]([C:6]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)=O)C.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[OH:3][CH2:4][C:6]1([C:11]#[N:12])[CH2:10][CH2:9][CH2:8][CH2:7]1
Reactant: CCOC(=O)C1(C#N)CCCC1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC1(CO)CCCC1
Yield: 5 %

Procedure:
1-Cyano-cyclopentanecarboxylic acid ethyl ester (2.00 g, 12.0 mmol) was dissolved in anhydrous tetrahydrofuran (5 ml) under nitrogen and lithium aluminium hydride (36 ml, 36 mmoles, 1.0M in THF) was added dropwise at 0° C. After stirring at room temperature for 24 h water was carefully added to the reaction and the product mixture extracted with ethyl acetate (3×50 ml). The organic layers were combined and washed with water (40 ml) and saturated sodium chloride solution (25 ml). The combined organic phases were dried over magnesium sulphate, filtered and evaporated under reduced pressure to give 1-hydroxymethyl-cyclopentanecarbonitrile (75 mg, 28%) as an oil which solidified on standing to give a waxy yellow solid.
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=1.[C:12]([C:14]1[CH:15]=[N:16][C:17]2[C:22]([CH:23]=1)=[CH:21][CH:20]=[CH:19][CH:18]=2)#[CH:13].C(N(C(C)C)CC)(C)C>CN(C=O)C.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.[Cu]I>[N:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[C:14]([C:12]#[C:13][C:2]2[N:7]=[C:6]([C:8]([O:10][CH3:11])=[O:9])[CH:5]=[CH:4][CH:3]=2)[CH:15]=1
Reactant: C#Cc1cnc2ccccc2c1
Reactant: COC(=O)c1cccc(Br)n1
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1cccc(C#Cc2cnc3ccccc3c2)n1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
A mixture of methyl 6-bromo-2-pyridinecarboxylate (0.3 g, 1.3 mmol), 3-ethynylquinoline (0.3 g, 1.3 mmol), Pd(PPh3)4 (0.11 g, 0.01 mmol), CuI (0.179 g, 0.1 mmol) and diisopropylethylamine (0.5 ml, 3 mmol) in DMF (15 ml) was stirred at ambient temperature for 12 hrs under an atmosphere of nitrogen. The reaction mixture was concentrated and the crude product was purified by flash chromatography on silica gel (elution with 10% ethyl acetate in n-hexane) to provide methyl 6-[(quinolin-3-yl)ethynyl]pyridine-2-carboxylate.
Reaction SMILES: [CH2:1]([CH:3]1[O:5][CH2:4]1)Cl.[CH2:6]([NH:10][CH2:11][CH:12]([CH3:14])[CH3:13])[CH:7]([CH3:9])[CH3:8]>>[CH2:6]([N:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:1][CH:3]1[O:5][CH2:4]1)[CH:7]([CH3:9])[CH3:8]
Reactant: CC(C)CNCC(C)C
Reactant: ClCC1CO1
Product: CC(C)CN(CC(C)C)CC1CO1
Temperature: 25 °C
Reaction time: 8 h
Yield: 37.1 %

Procedure:
A stirred solution of epichlorohydrin (21.0 g, 0.23 mole) is treated dropwise with diisobutylamine (31.14 g, 0.24 mole) over a 1 hour period followed by continuous stirring at room temperature overnight. The reaction mixture is washed with 20% K2CO3 (50 ml). The organic layer is then stirred with 40% NaOH for 1 hour and then extracted with 3×100 ml portions of ether. The etheral extracts are pooled with the organic layer and washed with H2O (100 ml). The organic layer is dried over anhydrous Na2SO4 and filtered. The filtrate is concentrated under reduced pressure to leave the crude product. The crude product is distilled at 68°/0.1 mmHg to yield 15.83 g (37.14%) pure product to oe used as an intermediate in Part B.
Reaction SMILES: CCN(C(C)C)C(C)C.C1C=CC2N(O)N=NC=2C=1.[O:20]=[C:21]1[O:25][C@H:24]([C:26]([OH:28])=O)[CH2:23][CH2:22]1.CCN=C=NCCCN(C)C.[NH2:40][C@@H:41]1[C:49]2[C:44](=[CH:45][CH:46]=[CH:47][CH:48]=2)[CH2:43][C@H:42]1[NH:50][C:51]([C:53]1[NH:57][C:56]2[S:58][C:59]([Cl:61])=[CH:60][C:55]=2[CH:54]=1)=[O:52]>C(Cl)Cl>[Cl:61][C:59]1[S:58][C:56]2[NH:57][C:53]([C:51]([NH:50][C@@H:42]3[CH2:43][C:44]4[C:49](=[CH:48][CH:47]=[CH:46][CH:45]=4)[C@H:41]3[NH:40][C:26]([C@@H:24]3[CH2:23][CH2:22][C:21](=[O:20])[O:25]3)=[O:28])=[O:52])=[CH:54][C:55]=2[CH:60]=1
Reactant: O=C1CC[C@@H](C(=O)O)O1
Reactant: N[C@@H]1c2ccccc2C[C@H]1NC(=O)c1cc2cc(Cl)sc2[nH]1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C1CC[C@@H](C(=O)N[C@@H]2c3ccccc3C[C@H]2NC(=O)c2cc3cc(Cl)sc3[nH]2)O1
Temperature: 25 °C
Reaction time: 16 h
Yield: 56 %

Procedure:
DIPEA (180 μL, 1.05 mmol), HOBT (68 mg, 0.5 mmol), (2S)-5-oxotetrahydrofuran-2-carboxylic acid (CAS Reg. No: [21461–84–7], 0.5 mmol, 65 mg) and EDAC (120 mg, 0.63 mmol) were added to a suspension of N-[(1R,2R)-1-amino-2,3-dihydro-1H-inden-2-yl]-2-chloro-6H-thieno[2,3-b]pyrrole-5-carboxamide (Method 21, 223 mg, 0.5 mmol) in anhydrous DCM (7 mL). The reaction was stirred at ambient temperature for approximately 16 h. The volatiles were removed by evaporation under reduced pressure, the residue dissolved in EtOAc (5 mL), washed with water (2×5 mL), brine (10 mL) and dried (MgSO4). The volatiles were removed by evaporation under reduced pressure and the residue triturated (EtOAc:hexane, 1:10), collected by filtration, washed with hexane (2×5 mL) and dried to give the title compound (112 mg, 56%) as a brown solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1.[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32](Cl)(=[O:34])=[O:33]>ClCCl>[CH:22]1[C:31]2[C:26](=[CH:27][CH:28]=[CH:29][CH:30]=2)[CH:25]=[CH:24][C:23]=1[S:32]([N:1]1[CH2:6][CH2:5][CH:4]([CH2:7][CH2:8][CH2:9][CH2:10][NH:11][C:12](=[O:21])[CH2:13][CH2:14][C:15]2[CH:16]=[N:17][CH:18]=[CH:19][CH:20]=2)[CH2:3][CH2:2]1)(=[O:33])=[O:34]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Reactant: O=C(CCc1cccnc1)NCCCCC1CCNCC1
Solvent: ClCCl
Product: O=C(CCc1cccnc1)NCCCCC1CCN(S(=O)(=O)c2ccc3ccccc3c2)CC1
Temperature: 25 °C

Procedure:
3.5 g (12 mmol) N-(4-piperidin-4-yl-butyl)-3-(pyridin-3-yl)-propionamide and 6.7 ml (48.1 mmol) TEA are placed in 100 ml absolute dichloromethane and cooled to ca 0° C. under moisture exclusion. 3.0 g (13.2 mmol) naphthalin-2-sulfonic acid chloride are dissolved in 40 ml absolute dichloromethane and added dropwise. The mixture is stirred without further cooling at RT overnight. Subsequently, the batch is washed twice, each with 80 ml water. The organic phase is dried over sodium sulfate and the solvent is removed under vacuum. The residue is chromatographically purified over silica gel with CHCl3/CH3OH (97/3) and crystallized from acetic acid ethyl ester after drawing off the solvent. Colorless crystals with an MP of 103-105° C.; yield 2.87 g (50%).