Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[CH2:5]O.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O.[C:41]1([C:47]2[CH:48]=[C:49]3[CH:55]=[C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[NH:53][C:50]3=[CH:51][N:52]=2)[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=1>O1CCCC1>[C:41]1([C:47]2[CH:48]=[C:49]3[CH:55]=[C:54]([C:56]([O:58][CH2:59][CH3:60])=[O:57])[N:53]([CH2:5][C:4]4[CH:7]=[CH:8][CH:9]=[C:2]([F:1])[CH:3]=4)[C:50]3=[CH:51][N:52]=2)[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=1
Reactant: CCOC(=O)c1cc2cc(-c3ccccc3)ncc2[nH]1
Reactant: OCc1cccc(F)c1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Product: CCOC(=O)c1cc2cc(-c3ccccc3)ncc2n1Cc1cccc(F)c1
Temperature: 20 °C
Reaction time: 20 h
Yield: 78.1 %

Procedure:
0.72 g (5.63 mmol) of 3-fluorobenzyl alcohol, 1.47 g (5.63 mmol) of triphenylphosphine and then 1.01 g (5.63 mmol) of diethyl azodicarboxylate are successively added to a solution, stirred at 0° C. under argon, of 1 g (3.76 mmol) of ethyl 5-phenyl-1H-pyrrolo[2,3-c]pyridine-2-carboxylate, obtained in step 18.3, in 30 ml of dry tetrahydrofuran. The mixture is then stirred for 20 hours at 20° C., concentrated under reduced pressure and then purified by chromatography on a column of silica (eluents: heptane/ethyl acetate). 1.1 g of the expected product are thus isolated in the form of a white powder.
Reaction SMILES: C([O:3][C:4]([C:6]1[NH:7][C:8]2[C:13]([CH:14]=1)=[C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:18]([CH3:21])([CH3:20])[CH3:19])[CH:11]=[CH:10][C:9]=2[O:30][CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1)=[O:5])C.O1CCCC1.[OH-].[Na+].[ClH:45]>CO>[ClH:45].[CH2:31]([O:30][C:9]1[CH:10]=[CH:11][C:12]([C:15](=[O:29])[CH2:16][N:17]([CH2:22][C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=2)[C:18]([CH3:21])([CH3:20])[CH3:19])=[C:13]2[C:8]=1[NH:7][C:6]([C:4]([OH:5])=[O:3])=[CH:14]2)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: CCOC(=O)c1cc2c(C(=O)CN(Cc3ccccc3)C(C)(C)C)ccc(OCc3ccccc3)c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC(C)(C)N(CC(=O)c1ccc(OCc2ccccc2)c2[nH]c(C(=O)O)cc12)Cc1ccccc1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
10 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)-2-indolecarboxylic acid ethyl ester is combined with 300 ml of tetrahydrofuran, 300 ml of methanol, and 100 ml of 2N sodium hydroxide solution and stirred for 4 hours at room temperature. Then 120 ml of 2N hydrochloric acid is added and the mixture concentrated until the onset of crystallization. The crystallized product is vacuum-filtered and the mother liquor once more concentrated. The resultant secondary crystallization product is combined with the first-obtained crystallized product, dried, and recrystallized from methanol/ethyl acetate, thus obtaining 8.8 g of 7-benzyloxy-4-(N-benzyl-N-tert-butylaminoacetyl)indole-2-carboxylic acid hydrochloride, decomposition point 158° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[CH3:24][O:25][CH2:26][CH2:27][CH2:28][OH:29]>CN(C=O)C.CCOC(C)=O>[CH3:24][O:25][CH2:26][CH2:27][CH2:28][O:29][C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[C:5]([N+:15]([O-:17])=[O:16])=[CH:4][CH:3]=1
Reactant: COCCCO
Reactant: O=[N+]([O-])c1ccc(Cl)nc1OC1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COCCCOc1ccc([N+](=O)[O-])c(OC2CCOCC2)n1
Temperature: 60 °C
Reaction time: 24 h
Yield: 54.4 %

Procedure:
A mixture of 6-chloro-3-nitro-2-(tetrahydro-2H-pyran-4-yloxy)pyridine (0.259 g, 1.00 mmol), K2CO3 (0.276 g, 2.00 mmol) and 3-methoxy-1-propanol (0.191 mL, 2.00 mmol) in DMF (3.0 mL) was heated at 60° C. for 6 hours and then at 100° C. for 24 hours. The reaction mixture was diluted with EtOAc, washed with water and brine (×2). The organic phase was dried (MgSO4), filtered and the solvent removed in vacuo. The residue was purified by flash column chromatography (100% iso-hexane 75% iso-hexane/EtOAc) to afford an oil (0.17 g, 54%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:16](COCC[Si](C)(C)C)[C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl>C(O)C>[OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:16][C:15]3[C:14](=[O:25])[N:13]([CH2:26][CH2:27][CH3:28])[CH:12]=[N:11][C:10]=3[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCn1cnc2nc(-c3ccc(O)cc3)n(COCC[Si](C)(C)C)c2c1=O
Agent: Cl
Solvent: CCO
Product: CCCn1cnc2nc(-c3ccc(O)cc3)[nH]c2c1=O
Temperature: 85 °C
Yield: 93.7 %

Procedure:
A mixture of 8-(4-hydroxy-phenyl)-1-propyl-7-(2-trimethylsilanyl-ethoxymethyl)-1,7-dihydro-purin-6-one (0.03 g, 0.075 mmol), 2N HCl (1 ml), ethanol (2 ml) was heated at 85° C. for 2 hours. The mixture was cooled and the solvent was evaporated. The residue was washed with n-pentane to obtain 8-(4-Hydroxy-phenyl)-1-propyl-1,7-dihydro-purin-6-one (0.019 g, 95%) as a yellow solid.
Reaction SMILES: [CH3:1][N:2]1[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3]1.C([Li])CCC.[CH2:13]([O:17][C:18]1[C:22](S(C)(=O)=O)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]>C1COCC1.CCCCCC>[CH2:13]([O:17][C:18]1[C:22]([O:7][CH:4]2[CH2:5][CH2:6][N:2]([CH3:1])[CH2:3]2)=[N:21][S:20][N:19]=1)[CH2:14][CH2:15][CH3:16]
Reactant: CN1CCC(O)C1
Reactant: CCCCOc1nsnc1S(C)(=O)=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCCOc1nsnc1OC1CCN(C)C1

Procedure:
A solution of 1-methyl-3-pyrrolidinol (0.6 g, 0.0059 mol) in THF (20 mL) was treated with 1.6 M n-butyllithium in hexane (3.1 mL), 0.005 mol). To the solution was added 3-butyloxy-4-methanesulfonyl-1,2,5-thiadiazole (1.0 g, 0.0042 mol) and the reaction heated to reflux overnight. The solvent was evaporated, the residue acidified with cold 1N HCl, and the mixture extracted with ether. The aqueous fraction was made basic, extracted with EtOAc, and the extracts washed with water. The extracts were dried and the solvent evaporated to give a liquid. The HCl salt (0.7 g) crystallized from EtOAc, m.p. 157°-158° C. (Compound 28).
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH:34]=O)=[CH:30][C:29]=4[O:36][CH3:37])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:38])[N:15]=1)=[O:13])[CH3:2].[CH3:39][N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].CC(O)=O>C(Cl)Cl>[CH2:1]([C:3]1[CH:8]=[CH:7][CH:6]=[C:5]([CH2:9][CH3:10])[C:4]=1[NH:11][C:12]([C:14]1[C:18]2[CH2:19][CH2:20][C:21]3[CH:22]=[N:23][C:24]([NH:27][C:28]4[CH:33]=[CH:32][C:31]([CH2:34][N:43]5[CH2:44][CH2:45][N:40]([CH3:39])[CH2:41][CH2:42]5)=[CH:30][C:29]=4[O:36][CH3:37])=[N:25][C:26]=3[C:17]=2[N:16]([CH3:38])[N:15]=1)=[O:13])[CH3:2]
Reactant: CN1CCNCC1
Reactant: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(C=O)cc3OC)nc1-2
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCc1cccc(CC)c1NC(=O)c1nn(C)c2c1CCc1cnc(Nc3ccc(CN4CCN(C)CC4)cc3OC)nc1-2
Temperature: 25 °C
Reaction time: 3 h
Yield: 75 %

Procedure:
To a solution of N-(2,6-diethylphenyl)-8-[(4-formyl-2-methoxyphenyl)amino]-1-methyl-4,5-dihydro-1H-pyrazolo[4,3-h]quinazoline-3-carboxamide (50 mg, 0.097 mmol) and N-methyl-piperazine (49 mg, 0.49 mmol) in 1 ml of dry DCM, NaBH(AcO)3 (123 mg, 0.58 mmol) and AcOH (25 μl) were added. The mixture was stirred at room temperature for 3 h, washed with aqueous NaHCO3, dried over Na2SO4 and evaporated to dryness. The crude was purified by flash column chromatography (DCM/MeOH 9:1) affording the title compound in 75% yield.
Reaction SMILES: [OH-].[Li+].C([O:5][C:6](=[O:25])[C:7]([C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([Br:24])[N:19]=1)([CH2:13][O:14][CH2:15][O:16][CH3:17])[CH2:8][O:9][CH2:10][O:11][CH3:12])C>C(O)C.O>[Br:24][C:20]1[N:19]=[C:18]([C:7]([CH2:8][O:9][CH2:10][O:11][CH3:12])([CH2:13][O:14][CH2:15][O:16][CH3:17])[C:6]([OH:25])=[O:5])[CH:23]=[CH:22][CH:21]=1
Reactant: CCOC(=O)C(COCOC)(COCOC)c1cccc(Br)n1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: COCOCC(COCOC)(C(=O)O)c1cccc(Br)n1
Reaction time: 8 h

Procedure:
Lithium hydroxide (10.69 g, 254.95 mmol) was added to a solution of 2-(6-bromo-pyridin-2-yl)-3-methoxymethoxy-2-methoxymethoxymethyl-propionic acid ethyl ester (20.0 g, 50.99 mmol) in ethanol (100 ml) and water (100 ml) at rt and the reaction mixture was allowed to stir overnight. The reaction mass was concentrated under reduced pressure and acidified with dilute HCl and at 0° C. The product was extracted with ethyl acetate, washed with minimum amount of brine. Organic layer was concentrated under reduced pressure to obtain title compound as a brown liquid. Yield=18.0 g. TLC (50% ethyl acetate in hexane) Rf=0.05; LCMS: RtH8=1.383, [M+1]=364.0 and 366.0; HPLC: RtH9=3.844 min (49%) and 3.885 min. (22%).
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[C:11](=[N:13][OH:14])[CH3:12].[H-].[Na+].Br[CH2:18][C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[N:25]1[C:29]([O:30][CH3:31])=[N:28][N:27]([CH3:32])[C:26]1=[O:33]>CN(C=O)C>[CH3:31][O:30][C:29]1[N:25]([C:20]2[CH:21]=[CH:22][CH:23]=[CH:24][C:19]=2[CH2:18][O:14][N:13]=[C:11]([C:2]2[CH:3]=[CH:4][C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[CH:1]=2)[CH3:12])[C:26](=[O:33])[N:27]([CH3:32])[N:28]=1
Reactant: COc1nn(C)c(=O)n1-c1ccccc1CBr
Reactant: CC(=NO)c1ccc2ccccc2c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1nn(C)c(=O)n1-c1ccccc1CON=C(C)c1ccc2ccccc2c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79 %

Procedure:
To a solution of 0.56 g (3.02 mmol) of 1-(2-naphthalenyl)ethanone oxime in 10 mL of DMF was added 0.13 g (3.28 mmol) of NaH. 0.75 (2.52 mmol) of the title compound of Step D was then added to the reaction and the mixture was stirred at room temperature for 3 h. The reaction mixture was washed successively with water and saturated NaCl and then extracted with ethyl acetate. The combined organic extracts were dried over magnesium sulfate, filtered, and concentrated. The crude product was purified by flash chromatography on silica gel using 60% ethyl acetate/hexane as eluent to give 0.80 g (79% yield) of the title compound of Step E, a compound of the invention, as a solid melting at 91-94° C.
Reaction SMILES: Cl.[NH2:2][CH2:3][C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[N:10]=[C:9]([CH3:14])[N:8]([CH:15]1[CH2:20][CH2:19][C:18](=[O:21])[NH:17][C:16]1=[O:22])[C:7]2=[O:23].C(N(CC)CC)C.[CH2:31]([N:37]=[C:38]=[O:39])[CH2:32][CH2:33][CH2:34][CH2:35][CH3:36]>C1COCC1>[O:22]=[C:16]1[CH:15]([N:8]2[C:7](=[O:23])[C:6]3[C:11](=[CH:12][CH:13]=[C:4]([CH2:3][NH:2][C:38]([NH:37][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH3:36])=[O:39])[CH:5]=3)[N:10]=[C:9]2[CH3:14])[CH2:20][CH2:19][C:18](=[O:21])[NH:17]1
Reactant: Cc1nc2ccc(CN)cc2c(=O)n1C1CCC(=O)NC1=O
Reactant: CCCCCCN=C=O
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCCCCNC(=O)NCc1ccc2nc(C)n(C3CCC(=O)NC3=O)c(=O)c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 63.9 %

Procedure:
To a stirred suspension of 3-(6-aminomethyl-2-methyl-4-oxo-4H-quinazolin-3-yl)-piperidine-2,6-dione hydrogen chloride (0.50 g, 1.5 mmol) and triethylamine (0.29 mL, 2.1 mmol) in THF (12 mL) at 510° C., was added hexyl isocyanate (0.25 g, 1.9 mmol), and the mixture was stirred at room temperature overnight. The mixture was quenched with methanol (1 mL), and the solvent was evaporated. The residue was purified by flash column chromatography (Silica gel, methanol/methylene chloride 4%/96%) to give 1-[3-(2,6-dioxo-piperidin-3-yl)-2-methyl-4-oxo-3,4-dihydro-quinazolin-6-ylmethyl]-3-hexyl-urea as an off-white solid (410 mg, 65% yield); HPLC, Waters Symmetry C18, 5 μm, 3.9×150 mm, 1 mL/min, 240 nm, 10/90 CH3CN/0.1% H3PO4, grad. to 95/5 in 5 min, kept 5 min, 6.05 min (99.0%); mp, 220-222° C.; 1HNMR (DMSO-d6) 0.85 (t, J=6 Hz, 3H, CH3CH2CH2), 1.24-1.38 (m, 8H, CH2CH2CH2CH2), 2.15-2.20 (m, 1H, CHH), 2.56-3.03 (m, 6H, CHCH2, CH3), 4.30 (d, J=6 Hz, 2H, ArCH2NH), 5.26 (dd, J=6, 11 Hz, 1H, Ch), 5.97 (t, J=5 Hz, 1H, CH2NH), 6.40 (t, J=6 Hz, 1H, ArCH2NH), 7.55-7.89 (m, 3H, Ar), 11.02 (s, 1H, NH); 13C NMR (DMSO-d6) δ 13.88, 20.93, 22.05, 23.38, 26.03, 29.94, 30.63, 31.02, 39.35, 42.44, 56.51, 119.96, 123.46, 126.40, 133.81, 139.87, 145.64, 154.36, 157.99, 160.46, 169.47, 172.60. LCMS MH=428; Anal Calcd For C22H29N5O4: C, 61.81; H, 6.84; N, 16.38. Found: C, 61.50; H, 6.82; N, 16.23.
Reaction SMILES: Cl.[NH2:2][C@H:3]1[CH2:7][CH2:6][CH2:5][C:4]1([CH3:9])[OH:8].[Cl:10][C:11]1[C:18]([CH2:19][CH3:20])=[C:17](F)[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]>>[Cl:10][C:11]1[C:18]([CH2:19][CH3:20])=[C:17]([NH:2][C@H:3]2[CH2:7][CH2:6][CH2:5][C:4]2([OH:8])[CH3:9])[CH:16]=[CH:15][C:12]=1[C:13]#[N:14]
Reactant: CCc1c(F)ccc(C#N)c1Cl
Reactant: CC1(O)CCC[C@@H]1N
Agent: Cl
Product: CCc1c(N[C@H]2CCCC2(C)O)ccc(C#N)c1Cl

Procedure:
2-Chloro-3-ethyl-4-[[(1S)-2-hydroxy-2-methyl-cyclopentyl]amino]benzonitrile is prepared essentially as described in Example 1 using (2S)-2-amino-1-methyl-cyclopentanol hydrochloride (Preparation 18) and 2-chloro-3-ethyl-4-fluoro-benzonitrile. The crude material (350 mg) is purified using silica gel chromatography (20-60% EtOAc/hexane) to obtain Diastereomer 1 (cis) (82 mg) and Diastereomer 2 (trans) (29 mg).
Reaction SMILES: Br[C:2]1[C:10]2[NH:9][C:8]3[CH:11]4[CH2:17][CH2:16][N:14]([CH2:15][C:7]=3[C:6]=2[CH:5]=[CH:4][CH:3]=1)[CH2:13][CH2:12]4.[C:18]1([CH2:24][CH2:25][CH2:26][CH:27]=[CH:28]B2OC(C)(C)C(C)(C)O2)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>>[C:18]1([CH2:24][CH2:25][CH2:26]/[CH:27]=[CH:28]/[C:2]2[C:10]3[NH:9][C:8]4[CH:11]5[CH2:17][CH2:16][N:14]([CH2:15][C:7]=4[C:6]=3[CH:5]=[CH:4][CH:3]=2)[CH2:13][CH2:12]5)[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: CC1(C)OB(C=CCCCc2ccccc2)OC1(C)C
Reactant: Brc1cccc2c3c([nH]c12)C1CCN(CC1)C3
Product: C(=C/c1cccc2c3c([nH]c12)C1CCN(CC1)C3)\CCCc1ccccc1

Procedure:
A suspension of the product of Example 1B (110 mg, 0.38 mmol) and 5-phenyl-1-pentenylboronic acid pinacol ester (123 mg, 0.45 mmol; Alfa) was processed as described in Example 4 to provide the title compound: 1H NMR (500 MHz, methanol-d4) δ ppm 1.79-1.90 (m, 2 H), 2.00-2.14 (m, 4 H), 2.28-2.37 (m, 2 H), 2.69 (t, J=7.0 Hz, 2 H), 3.00-3.08 (m, 2 H), 3.08-3.11 (m, 1 H), 3.22 (ddd, J=14.1, 8.5, 5.8 Hz, 2 H), 4.20 (s, 2 H), 6.33 (dt, J=15.9, 7.0 Hz, 1 H), 6.77 (d, J=15.9 Hz, 1 H), 6.93 (t, J=7.6 Hz, 1 H), 7.12-7.17 (m, 3 H), 7.18-7.22 (m, 2 H), 7.22-7.28 (m, 2 H); MS (APCI) m/z 357 (M+H)+. Anal. Calcd. for C25H28N2.0.2H2O: C, 83.38; H, 7.95; N, 7.78. Found: C, 83.29; H, 7.66; N, 7.68.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=1[C:16]1[CH:21]=[CH:20][C:19]([S:22]([C:25]2[CH:30]=[CH:29][C:28]([O:31][CH3:32])=[CH:27][CH:26]=2)(=[O:24])=[O:23])=[C:18]([F:33])[CH:17]=1)C1C=CC=CC=1.[H][H]>C(O)(=O)C.[Pd]>[F:33][C:18]1[CH:17]=[C:16]([C:10]2[C:9]([OH:8])=[CH:14][CH:13]=[C:12]([F:15])[CH:11]=2)[CH:21]=[CH:20][C:19]=1[S:22]([C:25]1[CH:26]=[CH:27][C:28]([O:31][CH3:32])=[CH:29][CH:30]=1)(=[O:23])=[O:24]
Reactant: [H][H]
Reactant: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3OCc3ccccc3)cc2F)cc1
Agent: [Pd]
Solvent: CC(=O)O
Product: COc1ccc(S(=O)(=O)c2ccc(-c3cc(F)ccc3O)cc2F)cc1

Procedure:
A suspension of the product of step (ii) (838 mg) in acetic acid (30 ml) and 10% Pd/C (200 mg) was stirred under 2 bar pressure of hydrogen for 30 min. The catalyst was removed by filtration and the filtrate was evaporated to give the subtitle compound, yield 630 mg.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[Br:10]Br>C(O)C>[NH2:1][C:2]1[N:3]=[CH:4][C:5]([Br:10])=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: BrBr
Reactant: N#Cc1cccnc1N
Solvent: CCO
Product: N#Cc1cc(Br)cnc1N
Temperature: 0 °C
Reaction time: 2 h
Yield: 94.2 %

Procedure:
To a solution of commercially available 2-amino-3-cyanopyridine (15 g, 126 mmol) in ethanol (250 mL) at 0° C. was dropwise added bromine (6.7 mL, 130 mmol) and the mixture was stirred at 0° C. for 2 h, then at 23° C. for 16 h. The solvent was totally evaporated, water (200 mL) was added, then sat. NaHCO3-solution until neutral. Extracted with AcOEt (3×300 mL), the organic layer was dried over Na2SO4, filtered and totally evaporated. The residue was triturated with ether to give the title compound as a light yellow solid (23.5 g, 94%). MS (ISP) 198.1 [(M+H)+], 200.2 [(M+2+H)+].
Reaction SMILES: [CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20]I)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3].CCN(C(C)C)C(C)C.[CH2:44]([C:48]1[CH:58]=[C:57]([F:59])[CH:56]=[CH:55][C:49]=1[CH2:50][NH:51][CH:52]1[CH2:54][CH2:53]1)[CH2:45][CH:46]=[CH2:47]>C(#N)C>[CH2:1]([O:4][C:5]1([CH3:34])[CH2:10][CH2:9][N:8]([C:11]2[N:16]3[N:17]=[C:18]([CH2:20][N:51]([CH2:50][C:49]4[CH:55]=[CH:56][C:57]([F:59])=[CH:58][C:48]=4[CH2:44][CH2:45][CH:46]=[CH2:47])[CH:52]4[CH2:54][CH2:53]4)[CH:19]=[C:15]3[N:14]=[C:13]([CH3:22])[C:12]=2[C@H:23]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])[C:24]([O:26][CH2:27][CH3:28])=[O:25])[CH2:7][CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OCC)c(C)nc3cc(CI)nn23)CC1
Reactant: C=CCCc1cc(F)ccc1CNC1CC1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: C=CCCc1cc(F)ccc1CN(Cc1cc2nc(C)c([C@H](OC(C)(C)C)C(=O)OCC)c(N3CCC(C)(OCC=C)CC3)n2n1)C1CC1
Temperature: 0 °C
Reaction time: 2 h
Yield: 73.6 %

Procedure:
To a mixture of (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(iodomethyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (53.3 mg, 0.091 mmol) in acetonitrile (2 mL) at 0° C. was added Hunig's Base (0.016 mL, 0.091 mmol) and N-(2-(but-3-en-1-yl)-4-fluorobenzyl)cyclopropanamine (20 mg, 0.091 mmol). It was stirred at 0° C. for 2 h and then quenched with water, extracted with EtOAc. The organic layer was dried over MgSO4, filtered and concentrated. The residue was purified by biotage, eluting with 20% EtOAc/hexane to obtain (S)-ethyl 2-(7-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(((2-(but-3-en-1-yl)-4-fluorobenzyl)(cyclopropyl)amino)methyl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate (45 mg, 0.067 mmol, 73.0% yield) as an oil. 1H NMR (400 MHz, CDCl3) δ 7.36 (dd, J=8.3, 6.1 Hz, 1H), 6.89-6.78 (m, 2H), 6.41 (s, 1H), 6.06-5.95 (m, 2H), 5.80 (ddt, J=17.1, 10.3, 6.6 Hz, 1H), 5.41 (d, J=17.1 Hz, 1H), 5.17 (d, J=11.0 Hz, 1H), 5.03-4.92 (m, 2H), 4.30-4.13 (m, 2H), 4.01 (d, J=4.9 Hz, 2H), 3.88 (s, 2H), 3.80 (s, 2H), 2.76-2.69 (m, 2H), 2.63 (s, 3H), 2.33-2.22 (m, 2H), 2.10-1.87 (m, 4H), 1.72 (br. s., 1H), 1.36 (br. s., 3H), 1.27-1.21 (m, 12H), 0.48-0.31 (m, 4H), 4 protons from piperidine were missing. LCMS (M+1)=676.5.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10](F)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2].[F:17][C:18]([F:27])([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1)[CH2:19][NH2:20].C([O-])([O-])=O.[Ca+2]>CN(C=O)C>[CH2:1]([O:3][C:4](=[O:16])[CH2:5][C:6]1[C:11]([F:12])=[C:10]([NH:20][CH2:19][C:18]([F:27])([F:17])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=2)[N:9]=[C:8]([F:14])[C:7]=1[Cl:15])[CH3:2]
Reactant: NCC(F)(F)c1ccccn1
Reactant: CCOC(=O)Cc1c(F)c(F)nc(F)c1Cl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1c(F)c(NCC(F)(F)c2ccccn2)nc(F)c1Cl
Temperature: 70 °C

Procedure:
To a solution of 5.5 g (22 mmol) ethyl(3-chloro-2,5,6-trifluoro-4-pyridinyl)acetate 1-1 in 75 mL DMF was added 3 g (19 mmol) 2,2-difluoro-2-(2-pyridinyl)ethylamine and 4 g (40 mmol) CaCO3 and the reaction mixture was heated to 70° C. for 18 hours. The reaction mixture was then cooled, diluted w. 400 mL ether, washed 2×300 mL water, and 1×300 mL brine, dried over MgSO4, filtered, and concentrated. Purification by automated flash chromatography (90 g silica cartridge, linear gradient 5-50% EtOAc/hex over 30 min, 70 mL/min flow rate.) afforded ethyl (3-chloro-6-{[2,2-difluoro-2-(2-pyridinyl)ethyl]amino}-2,5-difluoro-4-pyridinyl)acetate 1-2 as a white solid. 1H NMR (400 mHz, CDCl3) δ8.66 (br d, 1H, J=4.94 Hz); 7.84 (ddd, 1H, J=7.7, 7.7, and 1.64 Hz); 7.70 (d, 1H, J=7.88 Hz); 7.41 (dd, 1H, J=4.95, 7.14 Hz); 5.40 (br m, 1H); 4.36 (dt, 2H, J=13.9, 6.22 Hz); 4.19 (q, 2H, J=7.14 Hz); 3.77 (d, 2H, J=1.83 Hz); 1.27 (t, 3H, J=7.14 Hz). Mass Spectrum (electrospray) M+H=392.0.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[C:10]1(=[O:17])[O:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[C:15](=[O:16])[CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][OH:17]
Reactant: COCCNCCOC
Reactant: O=C1CCCCCO1
Solvent: Cc1ccccc1
Product: COCCN(CCOC)C(=O)CCCCCO
Temperature: 65 °C
Reaction time: 20 h
Yield: 108.5 %

Procedure:
A mixture of Bis(2-methoxyethyl)amine (11.85 g) and toluene (100 mL) was warmed to 65° C. under nitrogen. A solution of epsilon-Caprolactone (9.23 g) in toluene (35 mL) was added over several minutes. The mixture was stirred at this temperature until all the caprolactone was consumed, as determined by thin layer chromatography (silica gel plate), 4:1 ethanol/NH4OH). After 20 hours, an additional portion of bis(2-methoxyethyl)amine (3.1 g) was added and heating continued. After about 36 hours, all caprolactone had been consumed. The solvent was removed in vacuo on a rotary evaporator to afford the product as an oil (21.7 g).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:17]3[C:12](=[N:13][C:14]([CH3:18])=[CH:15][CH:16]=3)[N:11]([CH2:19][CH3:20])[C:10](=[O:21])[C:9]=2[NH:22]C(=O)OCC)[CH:5]=[CH:6][CH:7]=1>C(O)C.O>[NH2:22][C:9]1[C:10](=[O:21])[N:11]([CH2:19][CH3:20])[C:12]2[C:17]([C:8]=1[C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=1)=[CH:16][CH:15]=[C:14]([CH3:18])[N:13]=2
Reactant: CCOC(=O)Nc1c(-c2cccc(Cl)c2)c2ccc(C)nc2n(CC)c1=O
Solvent: O
Solvent: CCO
Product: CCn1c(=O)c(N)c(-c2cccc(Cl)c2)c2ccc(C)nc21
Temperature: 100 °C

Procedure:
A 720 mg portion of ethyl N-[4-(3-chlorophenyl)-1-ethyl-7-methyl-2-oxo-1,2-dihydro-1,8-naphthyridin-3-yl]carbamate was stirred in 40 ml of an ethanol-3M sodium hydroxide aqueous solution (1:1) under heating at an oil bath temperature of 100° C. for 4 hours. After cooling to room temperature, the reaction mixture was diluted with water and then extracted with ethyl acetate. The organic layer was washed with saturated brine and the solvent was evaporated. The resulting residue was purified by a silica gel column chromatography (toluene-ethyl acetate) and then recrystallized from diisopropyl ether-ethyl acetate to obtain 298 mg of 3-amino-4-(3-chlorophenyl)-1-ethyl-7-methyl-1,8-naphthyridin-2(1H)-one as colorless crystals.
Reaction SMILES: Br[C:2]1[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4][N:5]([CH3:13])[C:6]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.[C:20]1([SH:26])[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.N1C2C(=CC=CC=2)C=CC=1.Cl>N1C=CC=CC=1>[CH3:13][N:5]1[C:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[C:2]([S:26][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:3]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:4]1
Reactant: Sc1ccccc1
Reactant: Cn1nc(-c2ccccc2)c(Br)c1-c1ccccc1
Agent: Cl
Solvent: c1ccc2ncccc2c1
Solvent: c1ccncc1
Product: Cn1nc(-c2ccccc2)c(Sc2ccccc2)c1-c1ccccc1
Reaction time: 8 h

Procedure:
A mixture of 4-bromo-1-methyl-3,5-diphenylpyrazole (21.84 g, 0.07 mole), copper(1)salt of benzenethiol (14.67 g, 0.085 mole), pyridine (10 ml) and quinoline (100 ml) is stirred and heated at 175° C to 185° C (reflux) for 8 hours. The reaction mixture is allowed to stand overnight at room temperature. The mixture is poured into dilute hydrochloride acid and extracted with benzene. The benzene layer is separated and stripped in vacuo to give a brown syrup. The syrup is extracted with a hot mixture of n-hexane and n-heptane and filtered. The cooled filtrate yields a gray colored solid m.p. 109° C to 110° C. Recrystallization from n-hexane affords white crystals 17.35 g (74.5%), m.p. 109° C to 110° C.