Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N:1]1([C:7](=[O:26])[CH2:8][O:9][CH:10]2[CH2:15][CH2:14][N:13]([C:16]3[O:17][C:18]4[CH:24]=[C:23]([OH:25])[CH:22]=[CH:21][C:19]=4[N:20]=3)[CH2:12][CH2:11]2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:34][CH:35]1[CH2:37][CH2:36]1>CN(C=O)C.C(OCC)(=O)C>[CH:35]1([CH2:34][O:25][C:23]2[CH:22]=[CH:21][C:19]3[N:20]=[C:16]([N:13]4[CH2:12][CH2:11][CH:10]([O:9][CH2:8][C:7]([N:1]5[CH2:2][CH2:3][O:4][CH2:5][CH2:6]5)=[O:26])[CH2:15][CH2:14]4)[O:17][C:18]=3[CH:24]=2)[CH2:37][CH2:36]1
Reactant: BrCC1CC1
Reactant: O=C(COC1CCN(c2nc3ccc(O)cc3o2)CC1)N1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=C(COC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Temperature: 80 °C
Reaction time: 8 h

Procedure:
To a solution of 2-{4-[2-(morpholin-4-yl)-2-oxoethoxy]piperidin-1-yl}-1,3-benzoxazol-6-ol (2.81 g) in DMF (26 mL) were added potassium carbonate (3.22 g) and (bromomethyl)cyclopropane (1.51 mL), and the mixture was stirred at 80° C. overnight. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The diluted solution was washed with distilled water and saturated brine, and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (NH, hexane/ethyl acetate) to give the title compound (2.10 g).
Reaction SMILES: [C:1]([NH2:6])(=[O:5])[C:2]([CH3:4])=[CH2:3].[C:7]([C:9]1[CH:14]=[CH:13][C:12](F)=[CH:11][C:10]=1[C:16]([F:19])([F:18])[F:17])#[N:8].[H-].[Na+].Cl>CN(C)C=O.CCCCCC.O>[C:7]([C:9]1[CH:14]=[CH:13][C:12]([NH:6][C:1](=[O:5])[C:2]([CH3:4])=[CH2:3])=[CH:11][C:10]=1[C:16]([F:17])([F:18])[F:19])#[N:8]
Reactant: N#Cc1ccc(F)cc1C(F)(F)F
Reactant: C=C(C)C(N)=O
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CN(C)C=O
Solvent: O
Product: C=C(C)C(=O)Nc1ccc(C#N)c(C(F)(F)F)c1
Temperature: -20 °C
Reaction time: 4 h

Procedure:
To a solution of methacrylamide (153.00 g, 1797.88 mmol) in 800 mL of N,N-dimethylformamide was added 4-cyano-3-(trifluoromethyl)phenyl fluoride (200 g, 1057.58 mmol) at room temperature. The solution was cooled in a methanol/dry ice bath to −20° C. To this cooled solution was added sodium hydride (102 g, 2696.84 mmol), portion-wise, while keeping the reaction mixture temperature below 70° C. The reaction mixture was allowed to cool to room temperature and stirred for 4 hours under nitrogen atmosphere. Water (915 mL) was added followed by 18% HCl (250 mL) and hexane (970 mL). The resultant slurry was allowed to stir overnight. The solid was filtered, washed sequentially with water (3×150 mL) and hexane (100 mL), and dried at 60° C. to give the title product as an off white solid (260 g, 97%).
Reaction SMILES: Cl.[CH3:2][C:3]1[CH:7]=[C:6]([C:8]2[N:13]=[N:12][C:11]([NH:14][NH2:15])=[CH:10][CH:9]=2)[O:5][N:4]=1.[F:16][C:17]([F:32])([C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2)[C:18](OC)=O>Cl.CO>[F:32][C:17]([F:16])([C:18]1[N:12]2[N:13]=[C:8]([C:6]3[O:5][N:4]=[C:3]([CH3:2])[CH:7]=3)[CH:9]=[CH:10][C:11]2=[N:14][N:15]=1)[C:22]1[CH:23]=[C:24]2[C:29](=[CH:30][CH:31]=1)[N:28]=[CH:27][CH:26]=[CH:25]2
Reactant: COC(=O)C(F)(F)c1ccc2ncccc2c1
Reactant: Cc1cc(-c2ccc(NN)nn2)on1
Agent: Cl
Solvent: CO
Product: Cc1cc(-c2ccc3nnc(C(F)(F)c4ccc5ncccc5c4)n3n2)on1
Temperature: 150 °C

Procedure:
A suspension of 1-(6-(3-methylisoxazol-5-yl)pyridazin-3-yl)hydrazine hydrochloride (200 mg, 879 μmol) and methyl 2,2-difluoro-2-(quinolin-6-yl)acetate (208 mg, 879 μmol) in 5 M HCl (1 mL) was appropriately sealed and heated to 150° C. with microwaves for 4 h. The reaction was then quenched by a dropwise into cold 5 M NaOH (2 mL) and aqueous extracted with CHCl3/IPA (25 mL). The organic phase was then dried over MgSO4, concentrated, and purified with silica (40 g) eluting with 1>5% 2 M NH3 in MeOH/DCM. The product was then further purified on RP-HPLC eluting with water/ACN (0.1% TFA). Combined fractions concentrated, dissolved in DCM (5 mL) and MeOH (5 mL), then stirred with Si-Carbonate (0.5 g; 35 mmol) for 1 h. Si-Carbonate removed by filtration and filtrated concentrated with <0.5 mL remaining with product isolated by trituration. MS (ESI pos. ion) m/z: 379 (MH+). Calc'd exact mass for C19H12F2N6O: 378.
Reaction SMILES: [CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[CH:22][C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3].[CH2:31]([O:33]C1C2C=CC=CC=2C2C(=C3C(=C(C=O)C=2)C=CC=C3)C=1)[CH3:32].NC(C)(CO)CO>>[CH3:1][S:2]([O:5][CH2:6][C:7]([NH:11][CH2:12][C:13]1[CH:14]=[C:15]2[C:24](=[C:25]3[C:30]=1[CH:29]=[CH:28][CH:27]=[CH:26]3)[CH:23]=[C:22]([O:33][CH2:31][CH3:32])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]2=1)([CH3:10])[CH2:8][OH:9])(=[O:4])=[O:3]
Reactant: CC(CO)(COS(C)(=O)=O)NCc1cc2c3ccccc3ccc2c2ccccc12
Reactant: CCOc1cc2c3ccccc3c(C=O)cc2c2ccccc12
Agent: CC(N)(CO)CO
Product: CCOc1cc2c3ccccc3c(CNC(C)(CO)COS(C)(=O)=O)cc2c2ccccc12

Procedure:
Using the reductive amination procedure described in 1C, 12-ethoxy-6-chrysenecarbaldehyde (17A) and 2-amino-2-methyl-1,3-propanediol (Aldrich) gave 2-(((12-ethoxy-6-chrysenyl)methyl)amino)-2-methyl-1,3-propanediol methanesulfonate mp 202°-204° (dec) (EtOH/Et2O), (C,H,N,S).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[CH:17][C:5]([O:6][C:7]2[CH:12]=[CH:11][N:10]=[C:9]([NH2:13])[C:8]=2[N+:14]([O-:16])=[O:15])=[CH:4][C:3]=1[F:19].[F:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][C:22]=1[N:31]=[C:32]=[O:33]>>[NH2:13][C:9]1[C:8]([N+:14]([O-:16])=[O:15])=[C:7]([O:6][C:5]2[CH:17]=[CH:18][C:2]([NH:1][C:32]([NH:31][C:22]3[CH:23]=[C:24]([C:27]([F:28])([F:30])[F:29])[CH:25]=[CH:26][C:21]=3[F:20])=[O:33])=[C:3]([F:19])[CH:4]=2)[CH:12]=[CH:11][N:10]=1
Reactant: O=C=Nc1cc(C(F)(F)F)ccc1F
Reactant: Nc1ccc(Oc2ccnc(N)c2[N+](=O)[O-])cc1F
Product: Nc1nccc(Oc2ccc(NC(=O)Nc3cc(C(F)(F)F)ccc3F)c(F)c2)c1[N+](=O)[O-]
Yield: 85 %

Procedure:
Using Method F2 with 4-(4-amino-3-fluorophenoxy)-3-nitropyridin-2-amine and 2-fluoro-5-trifluoromethylphenyl isocyanate, the title compound was obtained (yield 85%).
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=3[O:21][CH3:22])=[C:10]([C:23]([F:26])([F:25])[F:24])[CH:9]=2)[CH:5]=[CH:4][N:3]=1.OC1CCNC1.[CH2:33]([N:36]1[CH2:41][CH2:40][NH:39][CH2:38][CH2:37]1)[CH2:34][CH3:35]>>[CH3:22][O:21][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=1[S:14][C:11]1[CH:12]=[CH:13][C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([N:39]3[CH2:40][CH2:41][N:36]([CH2:33][CH2:34][CH3:35])[CH2:37][CH2:38]3)[CH:7]=2)=[CH:9][C:10]=1[C:23]([F:26])([F:25])[F:24]
Reactant: COc1ccccc1Sc1ccc(-c2ccnc(Cl)c2)cc1C(F)(F)F
Reactant: CCCN1CCNCC1
Agent: OC1CCNC1
Product: CCCN1CCN(c2cc(-c3ccc(Sc4ccccc4OC)c(C(F)(F)F)c3)ccn2)CC1

Procedure:
The title compound was prepared according to the procedures of Example 38E, substituting compound 76 with compound 96 (0.039 g, 0.0985 mmol) and 3-hydroxypyrrolidine with 1-propylpiperazine. A yellow solid 114 was obtained (0.033 g, 69%). 1H-NMR (CDCl3, 400 MHz) δ 1.03 (t, J=7.3 Hz, 3H), 1.83-1.92 (m, 2H), 2.65-3.10 (br, 8H), 2.98-3.04 (m, 2H), 3.83 (s, 3H), 6.89 (s, 1H), 6.99-7.06 (m, 3H), 7.09 (d, J=8.1 Hz, 1H), 7.43-7.52 (m, 3H), 7.85 (s, 1H), 8.26 (d, J=5.9 Hz, 1H); MS (APCI) m/z 488 (M+H)+.
Reaction SMILES: [C:1]([S:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:19][CH3:20])([O:17][CH3:18])[CH2:14][C@H:10]1[C:11]([OH:13])=[O:12])=[O:8])(=[O:3])[CH3:2].[N+](=[CH2:24])=[N-]>CCOCC>[C:1]([S:4][CH2:5][CH:6]([CH3:21])[C:7]([N:9]1[CH2:16][C:15]([O:17][CH3:18])([O:19][CH3:20])[CH2:14][C@H:10]1[C:11]([O:13][CH3:24])=[O:12])=[O:8])(=[O:3])[CH3:2]
Reactant: C=[N+]=[N-]
Reactant: COC1(OC)C[C@@H](C(=O)O)N(C(=O)C(C)CSC(C)=O)C1
Solvent: CCOCC
Product: COC(=O)[C@@H]1CC(OC)(OC)CN1C(=O)C(C)CSC(C)=O

Procedure:
A solution of the product from Example 3 in ether is treated with a slight excess of diazomethane. After standing at room temperature, the solvent is evaporated to give (S)-1-[3-(acetylthio)-2-methyl-1-oxopropyl]-4,4-dimethoxy-L-proline, methyl ester.
Reaction SMILES: [H-].C([Al+]CC(C)C)C(C)C.C1(C)C=CC=CC=1.[CH2:18]([N:25]([CH:35]1[CH2:39][CH2:38][O:37][C:36]1=[O:40])[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][C:30](C)=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1.CO.C(C(C(C([O-])=O)O)O)([O-])=O.[Na+].[K+]>C1(C)C=CC=CC=1.C(Cl)Cl>[CH2:18]([N:25]([CH:35]1[CH2:39][CH2:38][O:37][CH:36]1[OH:40])[C:26](=[O:34])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1
Reactant: Cc1ccc(C(=O)N(Cc2ccccc2)C2CCOC2=O)cc1
Agent: CC(C)C[Al+]CC(C)C
Agent: O=C([O-])C(O)C(O)C(=O)[O-]
Agent: [H-]
Solvent: ClCCl
Solvent: CO
Solvent: Cc1ccccc1
Product: O=C(c1ccccc1)N(Cc1ccccc1)C1CCOC1O
Temperature: 15 °C
Reaction time: 0.5 h
Yield: 46.3 %

Procedure:
4.4 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to a solution of 2.0 g of N-benzyl-4-methyl-N-(2-oxooxolan-3-yl)benzamide in 30 mL of toluene and 10 mL of methylene chloride at −60° C., and the obtained mixture was then stirred for 30 minutes. Thereafter, the reaction mixture was heated to 15° C., and 6.6 mL of a 1.5 mol/L diisobutylaluminum hydride/toluene solution was added dropwise to the mixture at −60° C. The obtained mixture was stirred for 25 minutes. Thereafter, 1 mL of methanol was added to the reaction mixture, and 80 mL of a 20% potassium sodium tartrate aqueous solution was then added thereto at room temperature. The water layer was removed, and the solvent was then distilled away under reduced pressure. The obtained residue was purified by silica gel column chromatography (hexane/ethyl acetate=−60/40 to 35/65), so as to obtain 0.89 g of N-benzyl-N-(2-hydroxyoxolan-3-yl)benzamide in the form of a colorless oily product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1I.[CH3:9][C:10]1[S:11][CH:12]=[CH:13][N:14]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.Cl.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:12]1[S:11][C:10]([CH3:9])=[N:14][CH:13]=1
Reactant: Cc1nccs1
Reactant: Clc1ccccc1I
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cl
Solvent: CN(C)C=O
Product: Cc1ncc(-c2ccccc2Cl)s1
Temperature: 140 °C
Reaction time: 24 h

Procedure:
1-chloro-2-iodobenzene (500 μL, 4.1 mmol) is dissolved in DMF (10 mL), then 2-methylthiazole (406 mg, 4.1 mmol), triphenylphosphine (54 mg, 0.20 mmol), cesium carbonate (1.33 g, 4.1 mmol), palladium(II) acetate (92 mg, 0.41 mmol) are added and the mixture is stirred at 140° C. for 24 h. The reaction mixture is diluted with 1 M HCl (10 mL) and extracted into EtOAc (3×10 mL). The organic layers are combined and washed with H2O (2×20 mL) and brine (10 mL), then dried (MgSO4), filtered, concentrated and purified by silica gel chromatography (EtOAc/hexane, gradient) to give 5-(2-chlorophenyl)-2-methylthiazole 6. 1H-NMR (400 MHz, CDCl3) δ=7.80 (s, 1H), 7.48 (m, 2H), 7.28 (m, 2H), 2.75 (s, 3H). MS calcd. for C10H9ClNS (M+H+) 210.0. found 210.1.
Reaction SMILES: C[O:2][C:3](=[O:34])[CH2:4][C@H:5]1[C:9]2[CH:10]=[CH:11][C:12]([O:14][C@H:15]3[C:23]4[C:18](=[C:19]([CH2:25][C:26]5[CH:31]=[CH:30][C:29]([O:32][CH3:33])=[CH:28][CH:27]=5)[CH:20]=[CH:21][C:22]=4[F:24])[CH2:17][CH2:16]3)=[CH:13][C:8]=2[O:7][CH2:6]1.[OH-].[Na+].Cl.CC#N.O>O1CCCC1>[F:24][C:22]1[CH:21]=[CH:20][C:19]([CH2:25][C:26]2[CH:27]=[CH:28][C:29]([O:32][CH3:33])=[CH:30][CH:31]=2)=[C:18]2[C:23]=1[C@H:15]([O:14][C:12]1[CH:11]=[CH:10][C:9]3[C@H:5]([CH2:4][C:3]([OH:34])=[O:2])[CH2:6][O:7][C:8]=3[CH:13]=1)[CH2:16][CH2:17]2
Reactant: COC(=O)C[C@@H]1COc2cc(O[C@@H]3CCc4c(Cc5ccc(OC)cc5)ccc(F)c43)ccc21
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CC#N
Product: COc1ccc(Cc2ccc(F)c3c2CC[C@H]3Oc2ccc3c(c2)OC[C@H]3CC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
{(S)-6-[(R)-7-Fluoro-4-(4-methoxybenzyl)-indan-1-yloxy]-2,3-dihydrobenzofuran-3-yl}acetic acid methyl ester (40.9 mg) is dissolved in tetrahydrofuran (4 mL) and 1N aqueous sodium hydroxide solution (0.4 mL) is added. The mixture is stirred at room temperature overnight and then acidified with aqueous 1 N hydrochloric acid (0.4 mL). The solution is submitted to HPLC on reversed phase (MeCN/water) to give the title compound. LC (method 6): tR=0.71 min; Mass spectrum (ESI−): m/z=447 [M−H]−.
Reaction SMILES: [CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25](OCC)=[O:26])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:31][O:32][CH2:33][CH2:34][NH2:35]>>[CH2:1]([C:8]1[CH:17]=[C:16]2[C:11]([C:12]([OH:30])=[C:13]([C:25]([NH:35][CH2:34][CH2:33][O:32][CH3:31])=[O:26])[C:14](=[O:24])[N:15]2[CH2:18][C:19]2[S:20][CH:21]=[CH:22][N:23]=2)=[N:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COCCN
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O
Product: COCCNC(=O)c1c(O)c2ncc(Cc3ccccc3)cc2n(Cc2nccs2)c1=O

Procedure:
This compound was prepared from ethyl 7-benzyl-4-hydroxy-2-oxo-1-(1,3-thiazol-2-ylmethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate and 2-methoxyethylamine employing methods similar to those described in Example 5 and was obtained as a white solid: 1H NMR (d6-DMSO) δ 10.21 (1H, t, J=5 Hz), 8.56 (1H, s), 8.12 (1H, s), 7.69 (1H, d, J=3.2 Hz), 7.67 (1H, d, J=3.2 Hz) 7.28-7.22 (4H, m), 7.18 (1H, t, J=7 Hz), 5.78 (2H, s), 4.09 (2H, s), 3.56-3.48 (4H, m), 3.28 (3H, s); HRMS calcd for C23H22N4O4S+H+: 451.1440. Found: 451.1428.
Reaction SMILES: [CH3:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1)=O.C[SiH](C)O[SiH](C)C>C1(C)C=CC=CC=1>[CH3:1][CH:2]([CH3:13])[CH2:3][CH:4]=[CH:5][N:7]1[CH2:12][CH2:11][CH2:10][CH2:9][CH2:8]1
Reactant: CC(C)CCC(=O)N1CCCCC1
Agent: C[SiH](C)O[SiH](C)C
Solvent: Cc1ccccc1
Product: CC(C)CC=CN1CCCCC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 248.3 %

Procedure:
4-Methyl-1-piperidin-1-ylpentan-1-one (372.4 g) and toluene (1000 mL) were mixed. To the mixture was added (Ph3P)IrCl(CO) (633 mg). In a water-bath, 1,1,3,3-tetramethyldisiloxane (627 mL) was added dropwise to the mixture. The resulting mixture was stirred at RT for 2 hr. The reaction mixture was concentrated in vacuo to give the title compound (844 g) as a crude product.
Reaction SMILES: ClC1N=CC=C2C=1NC=CC2=O.C(C1C=CC(B2OC(C)(C)C(C)(C)O2)=CC=1NCC)#N.Cl[C:34]1[C:43]2[C:38](=[C:39]([C:44]3[CH:51]=[CH:50][C:47]([C:48]#[N:49])=[C:46]([NH:52][CH2:53][CH3:54])[CH:45]=3)[N:40]=[CH:41][CH:42]=2)[N:37]=[CH:36][CH:35]=1.Cl.[NH:56]1[CH:60]=[C:59]([C:61]2[CH:62]=[N:63][N:64]([CH3:66])[CH:65]=2)[N:58]=[CH:57]1.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.[Cu]=O>[CH2:53]([NH:52][C:46]1[CH:45]=[C:44]([C:39]2[N:40]=[CH:41][CH:42]=[C:43]3[C:38]=2[N:37]=[CH:36][CH:35]=[C:34]3[N:56]2[CH:60]=[C:59]([C:61]3[CH:62]=[N:63][N:64]([CH3:66])[CH:65]=3)[N:58]=[CH:57]2)[CH:51]=[CH:50][C:47]=1[C:48]#[N:49])[CH3:54]
Reactant: CCNc1cc(-c2nccc3c(Cl)ccnc23)ccc1C#N
Reactant: Cn1cc(-c2c[nH]cn2)cn1
Agent: O=[Cu]
Agent: CCNc1cc(B2OC(C)(C)C(C)(C)O2)ccc1C#N
Agent: Cl
Solvent: CN(C)C=O
Product: CCNc1cc(-c2nccc3c(-n4cnc(-c5cnn(C)c5)c4)ccnc23)ccc1C#N
Temperature: 125 °C
Reaction time: 8 h

Procedure:
A suspension of 3-amino-2-chloropyridine (17.6 g) and 5-(methoxymethylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (25.5 g) in isopropanol (274 ml) was heated to reflux for 5 minutes. After cooling, the deposit was filtrated to obtain 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-dione (34.8 g). The obtained 5-((2-chloropyridin-3-ylamino)methylene)-2,2-dimethyl-1,3-dioxane-4,6-di one (8.2 g) was gradually added to Dowtherm heated to 220° C., and the mixture was heated at 220° C. for 30 minutes. After cooling, hexane (300 ml) was added to the reaction solution, and the deposit was filtrated to obtain 8-chloro-1,7-naphthyridin-4(1H)-one (2.02 g). 4-(4-Chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.107 g) was obtained according to Example 5(1) using the obtained 8-chloro-1,7-naphthyridin-4(1H)-one (0.295 g) instead of compound (3a) and 4-cyano-3-(ethylamino)phenylboronic acid pinacol ester instead of 3-quinolineboronic acid. A suspension of the obtained 4-(4-chloro-1,7-naphthyridin-8-yl)-2-(ethylamino)benzonitrile (0.0491 g), 4-(1H-imidazol-4-yl)-1-methyl-1H-pyrazole hydrochloride (0.035 g), copper(II) oxide nanoparticles (0.06 g), and potassium carbonate (0.0883 g) in DMF (1.5 ml) was stirred overnight at 125° C. The reaction solution was partitioned between ethyl acetate and water. The organic layer was washed with brine. The organic layer thus washed was dried over anhydrous sodium sulfate. Then, the solvent was distilled off, and the residue was purified by neutral silica gel column chromatography (chloroform/methanol) to obtain 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile. An aqueous sodium hydroxide solution (4 M, 0.093 mL) and a 30% aqueous hydrogen peroxide solution (0.045 mL) were added to a solution of the obtained 2-(ethylamino)-4-(4-(4-(1-methyl-1H-pyrazol-4-yl)-1H-imidazol-1-yl)-1,7-naphthyridin-8yl)benzonitrile in DMSO (3 mL) at room temperature, and the mixture was stirred for 30 minutes. Water was added to the reaction solution, and the deposit was collected by filtration, then washed with water and ether by sprinkling, and then dried under reduced pressure to obtain compound (72) (0.040 g, yield based on 6 steps: 4%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([NH:14][C:15](=[O:21])[O:16][C:17]([CH3:20])([CH3:19])[CH3:18])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23].[H-].[Na+].I[CH3:27]>CN(C=O)C.CCOC(C)=O>[Cl:1][C:2]1[N:7]=[C:6]([N:8]2[CH2:13][CH2:12][CH2:11][C@@H:10]([N:14]([CH3:27])[C:15](=[O:21])[O:16][C:17]([CH3:18])([CH3:19])[CH3:20])[CH2:9]2)[CH:5]=[N:4][C:3]=1[C:22]#[N:23]
Reactant: CI
Reactant: CC(C)(C)OC(=O)N[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN(C(=O)OC(C)(C)C)[C@@H]1CCCN(c2cnc(C#N)c(Cl)n2)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(R)-tert-Butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-ylcarbamate (87, 550 mg, 1.63 mmol) was dissolved in 20 mL DMF. To it was added NaH (60% in mineral oil, 98 mg, 2.45 mmol). The mixture was stirred at RT for 30 min, and then iodomethane (305 μL, 4.89 mmol) was added. It was stirred for 1.5 hour, diluted with 120 mL EtOAc, washed with water ×3, dried, concentrated, and subjected to flash column using 0 to 50% EtOAc in hexane to isolate (R)-tert-butyl 1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl(methyl)carbamate (293). It was treated with 20 mL commercial 4N HCl in dioxane at RT for 1 hour, and the mixture was concentrated in vacuo to dryness. It was dissolved in 5 mL DMF and 15 mL dioxane. To it were added DIEA (1.45 mL, 8.15 mmol) and then dimethylcarbamoyl chloride (300 μL, 3.26 mmol). The mixture was stirred at RT for overnight, diluted with 120 mL EtOAc, washed with water ×2, dried, concentrated, and subjected to silica flash column using 0 to 5% MeOH in DCM to isolate (R)-1-(1-(6-chloro-5-cyanopyrazin-2-yl)piperidin-3-yl)-1,3,3-trimethylurea (294, 490 mg, 93% overall) as a white solid.
Reaction SMILES: CC1C=CC=CC=1P(C1C=CC=CC=1C)C1C=CC=CC=1C.Br[C:24]1[CH:25]=[C:26]2[C:30](=[C:31]([CH:33]([CH3:35])[CH3:34])[CH:32]=1)[NH:29][C:28]1[C:36]([CH2:42][CH2:43][OH:44])([CH2:40][CH3:41])[O:37][CH2:38][CH2:39][C:27]2=1.C(N(CC)CC)C.[C:52]([O:56][CH2:57][CH3:58])(=[O:55])[CH:53]=[CH2:54]>C(#N)C.CC([O-])=O.CC([O-])=O.[Pd+2]>[CH2:40]([C:36]1([CH2:42][CH2:43][OH:44])[C:28]2[NH:29][C:30]3[C:26]([C:27]=2[CH2:39][CH2:38][O:37]1)=[CH:25][C:24](/[CH:54]=[CH:53]/[C:52]([O:56][CH2:57][CH3:58])=[O:55])=[CH:32][C:31]=3[CH:33]([CH3:35])[CH3:34])[CH3:41]
Reactant: CCC1(CCO)OCCc2c1[nH]c1c(C(C)C)cc(Br)cc21
Reactant: C=CC(=O)OCC
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: Cc1ccccc1P(c1ccccc1C)c1ccccc1C
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCOC(=O)/C=C/c1cc(C(C)C)c2[nH]c3c(c2c1)CCOC3(CC)CCO
Temperature: 100 °C
Reaction time: 24 h
Yield: 56.9 %

Procedure:
A suspension of Pd(OAc)2 (0.2 g, 0.8 Mmol), P(o-tolyl)3 (0.25 g, 0.8 mmol), 2-(6-bromo-1-ethyl-1,3,4,9-tetrahydro-8-isopropylpyrano[3,4-b]indol-1-yl)ethanol (1.5 g, 4.1 mmol), triethylamine (1.5 ml, 11 mmol), and ethyl acrylate (1.8 ml, 16 mmol) in acetonitrile (45 ml) and stirred under a nitrogen atmosphere at 100° C. for 24 hr. The mixture was allowed to cool, quenched with water, worked-up with dichloromethane, and washed with brine. The organic layers were dried over MgSO4 and concentrated under reduced pressure. The crude product was chromatographed on silica hexane/EtOAc (6:4) to give the product (0.9 g, 56%). %). 1H NMR (300 MHz, CDCl3) δ 8.07 (br, NH), 7.83 (d, 1H), 7.53 (d, 1H), 7.28 (d, 1H), 6.43 (d, 1H), 4.27 (m, 2H), 4.04 (m, 2H), 3.73 (m, 2H), 3.19 (m, 1H), 2.84 (m, 1), 2.77 (d, 1H), 2.52 (br, 1H), 2.20 (m, 1H), 2.09 (m, 1H), 1.92 (m, 1H), 1.38 (d, 6H), 1.35 (t, 3H), 0.95 (t, 3H); ESI (+) MS m/e=386 (MH+), ESI (−) MS m/e=384 (MH−).
Reaction SMILES: [CH:1]([C:11]([O:13]C)=O)([C:7](OC)=[O:8])[CH2:2][C:3]([O:5][CH3:6])=[O:4].C(O)(=O)C.[CH:19]([NH2:21])=[NH:20].C[O-].[Na+].Cl>CO.C(OC)(C)(C)C.O>[OH:13][C:11]1[C:1]([CH2:2][C:3]([O:5][CH3:6])=[O:4])=[C:7]([OH:8])[N:21]=[CH:19][N:20]=1
Reactant: COC(=O)CC(C(=O)OC)C(=O)OC
Reactant: N=CN
Agent: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Solvent: O
Product: COC(=O)Cc1c(O)ncnc1O
Reaction time: 12 h

Procedure:
Trimethyl ethane-1,1,2-tricarboxylate (600 g, 3.0 mol) and formamidine acetate (312 g, 3.0 mol) are added sequentially to a vigourously stirred solution of sodium methylate (324 g, 6.0 mol) in methanol (1800 ml) at 0° C. The reaction mixture is stirred for 12 hours, diluted with t-butylmethyl ether (300 ml) and filtered with suction. The mixture of salts obtained is suspended in water (1000 ml) and acidified with concentrated hydrochloric acid (600 ml). Filtration and drying gives the methyl 4,6-dihydroxy-pyrimidin-5-yl-acetate or the tautomeric forms thereof as a white solid (420 g), m.p. >200° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N+:8]([O-])=[C:7]([CH3:13])[CH:6]=[CH:5]2.C1(C)C=CC(S([Cl:23])(=O)=O)=CC=1.CCCCCC.C(OCC)(=O)C>ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([CH2:13][Cl:23])[CH:6]=[CH:5]2
Reactant: Cc1ccc2cc(Cl)ccc2[n+]1[O-]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: CC(Cl)Cl
Product: ClCc1ccc2cc(Cl)ccc2n1
Temperature: 100 °C
Yield: 54.1 %

Procedure:
6-Chloro-2-methylquinoline N-oxide (1.73 g, 8.1 mmol) was added to a stirring solution of p-toluenesulfonyl chloride (1.7 g, 8.96 mmol) in dichloroethane (80 mL). The reaction mixture was heated to 100° C. overnight under N2, cooled and concentrated, partitioned between 10% K2CO3 /ethyl acetate, dried over MgSO4, and evaporated under reduced pressure to afford a solid. The crude solid was purifed by flash chromatography (4:1 hexane/ethyl acetate) to afford 0.93 g (52%) of pure product as an off white solid.
Reaction SMILES: [CH3:1][CH:2]([NH:4][C:5]([CH:7]1[CH:9]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=2)[O:8]1)=[O:6])[CH3:3].[C:17]1([OH:23])[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[H-].[Na+].C1OCCOCCOCCOCCOCCOC1>C(#N)C>[OH:8][CH:7]([CH:9]([O:23][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([Cl:16])[CH:11]=1)[C:5]([NH:4][CH:2]([CH3:1])[CH3:3])=[O:6]
Reactant: CC(C)NC(=O)C1OC1c1cccc(Cl)c1
Reactant: Oc1ccccc1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: [H-]
Agent: [Na+]
Solvent: CC#N
Product: CC(C)NC(=O)C(O)C(Oc1ccccc1)c1cccc(Cl)c1

Procedure:
This compound was prepared from N-(1-methylethyl)-3-(3-chlorophenyl)-2-oxiranecarboxamide (7.2 g.), phenol (3.0 g.), sodium hydride (50% oil dispersion, 1.6 g.), 18-crown-6 (0.9 g.) and acetonitrile (250 ml.) as described in Example 12. The crude product was recrystallized from ether. The compound melted at 160°-162°, and weighed 1.7 g.