Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=1.Cl.[O:13]1[CH2:18][CH2:17][CH:16]([NH2:19])[CH2:15][CH2:14]1.C([O-])([O-])=O.[Cs+].[Cs+].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[O:13]1[CH2:18][CH2:17][CH:16]([NH:19][C:2]2[CH:7]=[CH:6][N:5]=[C:4]([C:8]([O:10][CH3:11])=[O:9])[CH:3]=2)[CH2:15][CH2:14]1
Reactant: NC1CCOCC1
Reactant: COC(=O)c1cc(Cl)ccn1
Agent: [Pd]
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: Cl
Solvent: Cc1ccccc1
Product: COC(=O)c1cc(NC2CCOCC2)ccn1
Temperature: 110 °C
Yield: 35.9 %

Procedure:
To a solution of compound methyl 4-chloropicolinate (100 mg, 0.59 mmol), tetrahydro-2H-pyran-4-amine hydrochloride (121 mg, 0.88 mmol), Cs2CO3 (762 mg, 2.34 mmol), Pd2(dba)3 (54 mg, 0.059 mmol) and XPhos (28 mg, 0.06 mmol) in toluene (10 mL) was stirred and heated at 110° C. under N2 for 16 h. The catalyst was filtered and the filtrate was washed with EA, concentrated in vacuo and the residue was purified by prep-TLC to give the title product (50 mg, Yield 36.2%). LCMS (m/z): 237.2 (M+1).
Reaction SMILES: Cl.Cl.Cl.N1C=C(C[N:10]2[C:16]3[CH:17]=CC(C4C=NC=CC=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)N=C1.CS(Cl)(=O)=O.[OH-].[Na+]>C(Cl)Cl>[C:11]([C:12]1[CH:33]=[CH:17][C:16]2[NH:10][CH2:11][C@@H:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:13]([C:27](=[O:32])[CH2:28][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:15]=2[CH:20]=1)#[N:10]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: CS(=O)(=O)Cl
Agent: Cl
Agent: [Na+]
Solvent: ClCCl
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of Compound B (28.5 mmol, 9.0 g) in CH2Cl2 (200 mL) was added TEA (142.5 mmol, 20 mL) and methanesulfonyl chloride (37.5 mmol, 2.9 mL). The mixture was stirred at rt for 1 hr, poured over 2N NaOH (500 mL) and extracted with 10%IPA-CH2Cl2 (3×250 mL). The combined organic layers were dried over Na2SO4, concentrated, and azeotroped with toluene to afford Compound C.
Reaction SMILES: [OH-].[K+].[O:3]=[CH:4][C:5]([Cl:8])([Cl:7])[Cl:6].C([C:11]1[N:15]([CH3:16])[C:14](CC(OC)=O)=[CH:13][CH:12]=1)#N>O>[CH3:16][N:15]1[CH:11]=[CH:12][CH:13]=[C:14]1[CH:4]([OH:3])[C:5]([Cl:8])([Cl:7])[Cl:6]
Reactant: O=CC(Cl)(Cl)Cl
Reactant: COC(=O)Cc1ccc(C#N)n1C
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: Cn1cccc1C(O)C(Cl)(Cl)Cl
Temperature: 45 °C

Procedure:
1-Methyl-2-(2',2',2'-trichloro-1'-hydroxyethyl)pyrrole (1.14 g, 5 mmol), which was prepared by the procedure of Example 2, was dissolved in the solvent (15 ml) shown in the next table. After water (15 ml) and alkali metal cyanide (MCN: amount is shown in the table) were added to the solution, a solution of potassium hydroxide in water (10 ml) was added during a period of 6 hours under vigorous stirring at 45° C. After confirmation of the disappearance of starting chloral adduct (overnight), the reaction mixture was diluted with water (100 ml) and extracted twice with ethyl acetate. The combined organic extracts were washed with brine and dried over anhydrous magnesium sulfate. Most of the solvent was removed under reduced pressure and the residue was dissolved again in the 50 ml exact amount of ethyl acetate. A portion of the solution was taken up and treated with diazomethane dissolved in ether. After removal of the excess diazomethane under reduced pressure, trans-stilbene was added as the internal standard and the yield of methyl 5-cyano-1-methylpyrrole-2-acetate (theoretical yield; 5 mmol) was determined by GC (2% EGA column, 1 m, 160° C.).
Reaction SMILES: [CH3:1][N:2]([C:4](=[O:28])[C:5]([N:7]([CH3:27])[CH:8]1[CH2:14][N:13]([CH2:15][CH3:16])[CH2:12][CH2:11][N:10]2[C:17](=[O:26])[C:18]([OH:25])=[C:19]([C:21]([O:23]C)=O)[N:20]=[C:9]12)=[O:6])[CH3:3].C(N(CC)CC)C.[F:36][C:37]1[CH:44]=[CH:43][C:40]([CH2:41][NH2:42])=[CH:39][C:38]=1[CH3:45]>CO>[CH2:15]([N:13]1[CH2:14][CH:8]([N:7]([CH3:27])[C:5](=[O:6])[C:4]([N:2]([CH3:3])[CH3:1])=[O:28])[C:9]2=[N:20][C:19]([C:21]([NH:42][CH2:41][C:40]3[CH:43]=[CH:44][C:37]([F:36])=[C:38]([CH3:45])[CH:39]=3)=[O:23])=[C:18]([OH:25])[C:17](=[O:26])[N:10]2[CH2:11][CH2:12]1)[CH3:16]
Reactant: CCN1CCn2c(nc(C(=O)OC)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Reactant: Cc1cc(CN)ccc1F
Solvent: CO
Solvent: CCN(CC)CC
Product: CCN1CCn2c(nc(C(=O)NCc3ccc(F)c(C)c3)c(O)c2=O)C(N(C)C(=O)C(=O)N(C)C)C1
Temperature: 25 °C

Procedure:
Crude methyl 10-[[(dimethylamino)(oxo)acetyl](methyl)amino]-8-ethyl-3-hydroxy-4-oxo-4,6,7,8,9,10-hexahydropyrimido[1,2-d][1,4]diazepine-2-carboxylate was dissolved in methanol and treated with 1.2 eq. of triethylamine and 1.2 eq. of 4-fluoro-3-methylbenzylamine. The reaction mixture was refluxed overnight, then cooled to room temperature and purified by RP HPLC (C18, 5 μM, H2O/MeCN with 1% of TFA as eluant) affording desired compound as a white solid. 1H NMR (300 MHz, CD3CN) δ 12.4 (bs, 1H), 9.74 (bs, 1H), 7.26-7.16 (m, 2H), 6.96 (t, J=8.62 Hz, 1H), 5.40-5.22 (m, 2H), 4.51 (dd, J=14.6 Hz, J=6.86 Hz, 1H), 4.42 (dd, J=14.6 Hz, J=6.41 Hz, 1H), 4.18-3.92 (m, 3H), 3.78-3.73 (ms, 1H), 3.28-3.18 (m, 3H), 3.01 (s, 3H), 2.95 (s, 3H), 2.93 (s, 3H), 2.21 (s, 3H), 1.30 (t, J=5.97 Hz, 3H). MS (ES) C24H31FN6O5 requires 502. Found: 503 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](Cl)=[N:9]2)=[CH:4][N:3]=1.[CH3:13][C:14]([OH:31])([CH3:30])[CH2:15][N:16]1[CH:20]=[C:19](B2OC(C)(C)C(C)(C)O2)[CH:18]=[N:17]1>>[Br:1][C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8]([C:19]3[CH:18]=[N:17][N:16]([CH2:15][C:14]([CH3:30])([OH:31])[CH3:13])[CH:20]=3)=[N:9]2)=[CH:4][N:3]=1
Reactant: Clc1ccc2cnc(Br)cc2n1
Reactant: CC(C)(O)Cn1cc(B2OC(C)(C)C(C)(C)O2)cn1
Product: CC(C)(O)Cn1cc(-c2ccc3cnc(Br)cc3n2)cn1

Procedure:
The title compound was prepared according to the method described for Preparation 58 using 7-Bromo-2-chloro-1,6-naphthyridine (Preparation 61) and 2-methyl-1-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazol-1-yl)propan-2-ol (Preparation 124).
Reaction SMILES: [CH2:1]([N:3]1[C:11]2[C:6](=[CH:7][CH:8]=[C:9]([NH:12][C:13](=[O:26])[C:14]3[CH:19]=[CH:18][C:17]([N:20]4[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]4)=[N:16][CH:15]=3)[CH:10]=2)[CH:5]=[CH:4]1)[CH3:2].Br[C:28]1[CH:36]=[CH:35][C:31]([C:32]([OH:34])=[O:33])=[C:30]([CH3:37])[CH:29]=1.C(C1C=C(NC(C2C=CC(N3CCN(C4C=CC(C(O)=O)=CC=4)CC3)=C(F)C=2)=O)C=CC=1)(C)(C)C>>[CH3:37][C:30]1[CH:29]=[C:28]([N:23]2[CH2:24][CH2:25][N:20]([C:17]3[CH:18]=[CH:19][C:14]([C:13](=[O:26])[NH:12][C:9]4[CH:10]=[C:11]5[C:6]([CH:5]=[CH:4][N:3]5[CH2:1][CH3:2])=[CH:7][CH:8]=4)=[CH:15][N:16]=3)[CH2:21][CH2:22]2)[CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33]
Reactant: Cc1cc(Br)ccc1C(=O)O
Reactant: CCn1ccc2ccc(NC(=O)c3ccc(N4CCNCC4)nc3)cc21
Agent: CC(C)(C)c1cccc(NC(=O)c2ccc(N3CCN(c4ccc(C(=O)O)cc4)CC3)c(F)c2)c1
Product: CCn1ccc2ccc(NC(=O)c3ccc(N4CCN(c5ccc(C(=O)O)c(C)c5)CC4)nc3)cc21

Procedure:
2-methyl-4-{4-[5-(1-ethyl-1H-indol-6-ylcarbamoyl)-pyridin-2-yl]-piperazin-1-yl}-benzoic acid was synthesized from N-(1-ethyl-1H-indol-6-yl)-6-piperazin-1-yl-nicotinamide and 4-bromo-2-methyl-benzoic acid in a manner similar to the one described in the synthesis of 4-{4-[4-(3-tert-butyl-phenylcarbamoyl)-2-fluoro-phenyl]-piperazin-1-yl}-benzoic acid above. LCMS calcd for C28H29N5O3 (m/e) 483, obsd 484 (M+H).
Reaction SMILES: Cl.[NH4+].[Cl-].Cl.[F:5][C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-])=O)=[CH:8][C:7]=1[C@:15]12[CH2:23][O:22][C@H:21]([C:24]([F:27])([F:26])[F:25])[C@H:20]1[CH2:19][S:18][C:17]([NH2:28])=[N:16]2.[OH-].[Na+]>[Fe].C(O)C>[NH2:12][C:9]1[CH:10]=[CH:11][C:6]([F:5])=[C:7]([C@:15]23[CH2:23][O:22][C@H:21]([C:24]([F:26])([F:25])[F:27])[C@H:20]2[CH2:19][S:18][C:17]([NH2:28])=[N:16]3)[CH:8]=1
Reactant: NC1=N[C@@]2(c3cc([N+](=O)[O-])ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Agent: [Fe]
Agent: Cl
Agent: [Cl-]
Solvent: CCO
Product: NC1=N[C@@]2(c3cc(N)ccc3F)CO[C@H](C(F)(F)F)[C@H]2CS1
Temperature: 65 °C
Reaction time: 0.5 h
Yield: 0.1 %

Procedure:
Ethanol (0.975 L) was added to iron powder (62.5 g, 1.12 mol) under nitrogen atmosphere. Concentrated HCl (9.03 mL) was added at ambient temperature and the suspension was heated to 65° C. for 1.5 h. The suspension was then cooled to 50° C., and sat. aq. NH4Cl (299 g) were added. The temperature of the reaction mixture was allowed to reach 50° C., and (4aS,5S,7aS)-7a-(2-fluoro-5-nitrophenyl)-5-(trifluoromethyl)-4a,5,7,7a-tetrahydro-4H-furo[3,4-d][1,3]thiazin-2-amine hydrochloride (75.0 g, 187.0 mol) was added in portions while maintaining temperature below 68° C. After 30 min, ethanol (0.45 L) was added, and the reaction mixture was cooled to 20−25° C. over 1 h. The suspension was stirred for 2 h and filtered over Celite (75 g) rinsing with ethanol (0.972 L). The solution was concentrated under vacuum to a brown solid. Water (0.9 L) was added followed by 3.0 N NaOH (0.187 L, 560 mmol) while maintaining temperature below 35° C. The resulting suspension was stirred for 1 h at 20−25° C. The suspension was filtered, and the solid was rinsed with cold water (0.38 L). The solid was dried under vacuum at 40−45° C. over 24 h to obtain the title compound (57.7 g, 95.5%). 1H NMR (500 MHz, DMSO) δ ppm 6.81 (dd, J=12.5, 8.6 Hz, 1H), 6.62 (dd, J=7.0, 2.9 Hz, 1H), 6.50-6.42 (m, 1H), 6.16 (s, 2H), 4.96 (s, 2H), 4.72-4.54 (m, 1H), 4.35 (d, J=7.8 Hz, 1H), 3.74 (dd, J=7.8, 2.5 Hz, 1H), 3.18-3.08 (m, 1H), 3.01 (dd, J=13.9, 3.0 Hz, 1H). 2.84 (dd, J=13.8, 3.8 Hz, 1H); 13C NMR (125 MHz, DMSO) δ ppm 156.20 (d, JCF=243.0 Hz), 148.73, 145.49, 127.86 (d, JCF=11.0 Hz), 116.79 (d, JCF=24.8 Hz), 116.10 (d, JCF=3.3 Hz), 114.10 (d, JCF=8.0 Hz), 78.89, 76.57 (q, JCF=31.0 Hz), 66.35, 36.35, 23.11.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[NH:19][CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[C:26](=O)([O-])[O-].[K+].[K+].CI>CN(C)C=O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[CH2:24][CH2:23][CH2:22][CH2:21][C:20]=4[N:19]([CH3:26])[CH:18]=3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc(N2CCN(CCCc3c[nH]c4c3CCCC4)CC2)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: Cn1cc(CCCN2CCN(c3ccc(Cl)cc3)CC2)c2c1CCCC2

Procedure:
3-(3-(4-(4-Chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydroindole (0.5 g) obtained in Example 161 and potassium carbonate (0.6 g) were dissolved in dimethylformamide (10 ml) and methyl iodide (0.3 g) was added under ice-cooling with stirring. The reaction mixture was stirred at room temperature for 2 hours and the solvent was evaporated under reduced pressure. Chloroform and an aqueous potassium carbonate solution were added and the chloroform layer was separated. The layer was dried over magnesium sulfate and the solvent was evaporated under reduced pressure. The residue was subjected to silica gel column chromatography to give 3-(3-(4-(4-chlorophenyl)piperazin-1-yl)propyl)-4,5,6,7-tetrahydro-1-methylindole.
Reaction SMILES: [NH2:1][C:2]([NH2:4])=[O:3].N[C:6]1[CH:7]=[C:8]([CH3:13])[CH:9]=[CH:10][C:11]=1N>C(O)CCCC>[CH3:13][C:8]1[CH:7]=[CH:6][C:11]2=[N:1][C:2](=[O:3])[N:4]=[C:10]2[CH:9]=1
Reactant: Cc1ccc(N)c(N)c1
Reactant: NC(N)=O
Solvent: CCCCCO
Product: Cc1ccc2c(c1)=NC(=O)N=2
Temperature: 25 °C
Reaction time: 2 h
Yield: 56 %

Procedure:
A solution of urea (6.00 g, 0.1000 mol) and 3,4-diaminotoluene (1) (12.20 g, 0.0999 mol) in pentan-1-ol (40 mL) was vigorously stirred and heated to reflux under a nitrogen atmosphere. After 2 hours the heating was discontinued and on cooling to room temperature a pink solid settled out. This was filtered off and recrystallised from boiling ethanol (17.98 g. in 400 mL) to give 2 crops of 5-methylbenzimidazol-2-one (2) as a pink powder. The total mass was recovered was 8.21 g (56% yield);
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][C:10]([C:12]2[CH:17]=[CH:16][C:15](F)=[CH:14][CH:13]=2)=[O:11])=[CH:4][CH:3]=1.[CH2:19]([O:21][C:22]([N:24]1[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]1)=[O:23])[CH3:20].C(NC(C)C)(C)C>CS(C)=O.C(OCC)(=O)C>[CH2:19]([O:21][C:22]([N:24]1[CH2:25][CH2:26][N:27]([C:15]2[CH:16]=[CH:17][C:12]([C:10](=[O:11])[CH2:9][CH2:8][C:5]3[CH:6]=[CH:7][C:2]([NH2:1])=[CH:3][CH:4]=3)=[CH:13][CH:14]=2)[CH2:28][CH2:29]1)=[O:23])[CH3:20]
Reactant: Nc1ccc(CCC(=O)c2ccc(F)cc2)cc1
Reactant: CCOC(=O)N1CCNCC1
Solvent: CC(C)NC(C)C
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CCOC(=O)N1CCN(c2ccc(C(=O)CCc3ccc(N)cc3)cc2)CC1
Temperature: 105 °C

Procedure:
A mixture of 3-(4-aminophenyl)-1-(4-fluorophenyl)propan-1-one (1.1 g, 4.52 mmol) (prepared as described in Example 1b),1-ethoxycarbonylpiperazine (2.15 g, 13.57 mmol), and diisopropylamine (6.5 g, 4.98 mmol) in dimethylsulfoxide (10 mL) was heated at 100-110° C. for about 12 hours. The reaction mixture was cooled, diluted with ethyl acetate (150 mL), washed with cold water and brine. The organic layer was separated, dried, and evaporated in vacua. Purification by silica gel chromatography, eluting with 60% ethyl acetate/hexane, gave the title compound, m.p. 106.3-106.7° C. Analysis for C22H27N3O3: Calcd.: C, 69.27; H, 7.13; N, 11.02. Found: C, 69.13; H, 7.04; N, 11.03.
Reaction SMILES: [F:1][C:2]1[C:20]([F:21])=[C:19](F)[C:18]([F:23])=[CH:17][C:3]=1[C:4]([CH:6]([C:12]([O:14][CH2:15][CH3:16])=[O:13])C(OCC)=O)=[O:5].[CH2:24]([O:26][C:27]([N:29]([CH2:31][CH:32]1[O:37][CH2:36][CH2:35][NH:34][CH2:33]1)[CH3:30])=[O:28])[CH3:25].C(=O)([O-])O.[Na+]>C(#N)C>[CH2:24]([O:26][C:27]([N:29]([CH2:31][CH:32]1[CH2:33][N:34]([C:19]2[C:18]([F:23])=[CH:17][C:3]([C:4]([CH2:6][C:12]([O:14][CH2:15][CH3:16])=[O:13])=[O:5])=[C:2]([F:1])[C:20]=2[F:21])[CH2:35][CH2:36][O:37]1)[CH3:30])=[O:28])[CH3:25]
Reactant: CCOC(=O)N(C)CC1CNCCO1
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(F)c1F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CCOC(=O)CC(=O)c1cc(F)c(N2CCOC(CN(C)C(=O)OCC)C2)c(F)c1F

Procedure:
A suspension of 3.36 g of diethyl 2,3,4,5-tetrafluorobenzoylmalonate, 2.22 g of 2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholine and 0.84 g of sodium hydrogen carbonate in 13 ml of acetonitrile is refluxed for 5 hours., The reaction mixture is concentrated under reduced pressure, to the obtained residue is added 20 ml of chloroform and it is washed with water. After drying over anhydrous magnesium sulfate, the chloroform is distilled off under reduced pressure and to the residue are added 20 mg of p-toluenesulfonic acid and 20 ml of water. After refluxing for 16 hours, the resultant mixture is extracted with chloroform. The extract is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure to give ethyl 4-[2-(N-ethoxycarbonyl-N-methylaminomethyl)morpholino]-2,3,5-trifluorobenzoylacetate as an oily substance. The NMR values of this compound are identical with those of the compound obtained by Reference example 15(1).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1.[NH2:29][C:30]1[CH:38]=[CH:37][C:33]([C:34](O)=[O:35])=[CH:32][N:31]=1>CCO>[NH2:29][C:30]1[N:31]=[CH:32][C:33]([C:34]([N:1]2[CH2:6][CH2:5][O:4][CH2:3][CH2:2]2)=[O:35])=[CH:37][CH:38]=1
Reactant: Nc1ccc(C(=O)O)cn1
Reactant: C1COCCN1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cn1
Reaction time: 18 h
Yield: 30 %

Procedure:
To a solution of morpholine (9.00 g, 103 mmol) in EtOH (400 mL) was added EDCl (10.0 g, 52.2 mmol), HOBt (7.00 g 51.8 mmol), and 6-aminonicotinic acid (6.00 g, 43.4 mmol). After stirring for 18 h, the resulting suspension was filtered. The solid was triturated with a mixture of MeOH (100 mL) and methylene chloride (100 mL) to afford 170a as a white solid (2.7 g, 30%). LCMS: (M+H)+ 208
Reaction SMILES: C[O:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[S:11]([NH:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:16]=1[C:25]([O:27][CH3:28])=[O:26])(=[O:13])=[O:12])=[O:4].O.O.[OH-].[Li+].Cl>CO>[CH3:28][O:27][C:25]([C:16]1[C:17]2[C:22](=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:23]=[CH:24][C:15]=1[NH:14][S:11]([C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3]([OH:4])=[O:2])(=[O:12])=[O:13])=[O:26]
Reactant: COC(=O)c1ccccc1S(=O)(=O)Nc1ccc2ccccc2c1C(=O)OC
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: COC(=O)c1c(NS(=O)(=O)c2ccccc2C(=O)O)ccc2ccccc12
Temperature: 60 °C

Procedure:
A solution of Example 149A (0.60 g, 1.50 mmol) in methanol (16 mL) and distilled water (1.8 mL) was treated with lithium hydroxide monohydrate (0.19 g, 4.50 mmol), heated to 60° C. for four days, cooled to room temperature treated with 1N HCl, and extracted with ethyl acetate (2×). The combined extracts were washed with brine, dried (MgSO4), filtered, and concentrated to provide the desired product. MS (ESI(−)) m/e 384 (M−H)−; 1H NMR (300 MHz, DMSO-d6) δ 14.25 (br s, 1H), 9.38 (br s, 1H), 8.06 (d, 1H), 7.94 (dd, 1H), 7.80 (m, 3H), 7.72 (dt, 1H), 7.66 (d, 1H), 7.62 (dd, 1H), 7.54 (dt, 2H), 3.81 (s, 3H).
Reaction SMILES: [CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][CH:13]([C:19](=O)[C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[C:12](=O)[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:30][NH:31][NH2:32]>C(O)C>[CH2:1]([S:8][C:9]1[N:18]=[CH:17][C:16]2[CH2:15][CH2:14][C:13]3[C:19]([C:20]([C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=4)=[O:21])=[N:32][N:31]([CH3:30])[C:12]=3[C:11]=2[N:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CNN
Reactant: O=C(C(=O)C1CCc2cnc(SCc3ccccc3)nc2C1=O)c1ccccc1
Solvent: CCO
Product: Cn1nc(C(=O)c2ccccc2)c2c1-c1nc(SCc3ccccc3)ncc1CC2
Yield: 70.5 %

Procedure:
0.22 g (0.55 mmol) of 1-[2-(benzylthio)-8-oxo-5,6,7,8-tetrahydroquinazolin-7-yl]-2-phenylethane-1,2-dione were dissolved in 6 mL of ethanol and 0.03 g (0.66 mmol) of methyl hydrazine were added. The reaction mixture was maintained under stirring at refluxing temperature for 5 hours. After that time the solvent was removed under reduced pressure, the residue redissolved with dichloromethane and washed with water. The organic layer was dried over Na2SO4 and concentrated, giving 0.16 g of the title compound (70% yield).
Reaction SMILES: C1C=CC(P([N:15]=[N+:16]=[N-:17])(C2C=CC=CC=2)=O)=CC=1.C1COCC1.CN(C=O)C.[CH3:28][O:29][C:30]([C:32]1[CH:33]=[N:34][CH:35]=[C:36]([CH:40]=1)[C:37]([O-])=[O:38])=[O:31].[K+].C(N(CC)CC)C>C(OCC)(=O)C>[N:15]([C:37]([C:36]1[CH:35]=[N:34][CH:33]=[C:32]([CH:40]=1)[C:30]([O:29][CH3:28])=[O:31])=[O:38])=[N+:16]=[N-:17]
Reactant: COC(=O)c1cncc(C(=O)[O-])c1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1cncc(C(=O)N=[N+]=[N-])c1
Temperature: 25 °C

Procedure:
A 3.29 ml portion of DPPA was added under ice-cooling to 24 ml of a THF-DMF (1:1) mixed solution of 3.04 g of potassium 5-(methoxycarbonyl)nicotinate and 2.32 ml of triethylamine and stirred at room temperature for 3Hours. The reaction solution was mixed with ethyl acetate, washed with water, saturated sodium bicarbonate aqueous solution and saturated brine in that order and dried with anhydrous magnesium sulfate. By concentrating this under a reduced pressure, methyl 5-(azidocarbonyl)nicotinate was obtained as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:15](=O)[CH3:16])[CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12].[CH3:18][C:19]([S@:22]([NH2:24])=[O:23])([CH3:21])[CH3:20]>>[Cl:1][C:2]1[CH:3]=[C:4]([CH:15]([NH:24][S@@:22]([C:19]([CH3:21])([CH3:20])[CH3:18])=[O:23])[CH3:16])[CH:5]=[N:6][C:7]=1[CH2:8][O:9][CH2:10][C:11]([F:14])([F:13])[F:12]
Reactant: CC(=O)c1cnc(COCC(F)(F)F)c(Cl)c1
Reactant: CC(C)(C)[S@](N)=O
Product: CC(N[S@](=O)C(C)(C)C)c1cnc(COCC(F)(F)F)c(Cl)c1
Yield: 82 %

Procedure:
The title compound is prepared in 82% yield (827 mg, yellows oil) from 1-(5-chloro-6-((2,2,2-trifluoroethoxy)methyl)pyridin-3-yl)ethanone (720 mg, 2.69 mmol, Step-6) and (R)-2-methylpropane-2-sulfinamide (489 mg, 4.04 mmol) in a similar manner to Step-4 of Amine-1.
Reaction SMILES: [NH2:1][C@@H:2]([C:6]1[O:7][C:8]2[C:13]([C:14](=[O:23])[C:15]=1[CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[CH:12][CH:11]=[C:10]([Cl:24])[CH:9]=2)[CH:3]([CH3:5])[CH3:4].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33](=[O:46])[CH2:34][N:35]1[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]2[C:36]1=[O:45]>CN(C=O)C>[C:36]1(=[O:45])[N:35]([CH2:34][C:33](=[O:46])[CH2:32][NH:1][C@@H:2]([C:6]2[O:7][C:8]3[C:13]([C:14](=[O:23])[C:15]=2[CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:12][CH:11]=[C:10]([Cl:24])[CH:9]=3)[CH:3]([CH3:4])[CH3:5])[C:39](=[O:40])[C:38]2=[CH:41][CH:42]=[CH:43][CH:44]=[C:37]12
Reactant: O=C(CBr)CN1C(=O)c2ccccc2C1=O
Reactant: CC(C)[C@@H](N)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)[C@@H](NCC(=O)CN1C(=O)c2ccccc2C1=O)c1oc2cc(Cl)ccc2c(=O)c1Cc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 108 %

Procedure:
To 2-((R)-1-amino-2-methyl-propyl)-3-benzyl-7-chloro-chromen-4-one (0.5 g, 1.5 mMol) and K2CO3 (0.21 g, 1.5 mMol) in DMF (10 mL) was added N-(3-bromo-2-oxopropyl)-phthalimide (0.45 g, 1.5 mMol) (Nair et al.; J. Org. Chem.; 40; 1975; 1745). The reaction was stirred at RT for 3 h, concentrated under vacuum, taken up in EtOAc, washed with water, brine, dried (Na2SO4) and evaporated to give the title compound (0.88 g, 100%) as a yellow solid: MS (ES) m/e 543.2 (M+H)+.
Reaction SMILES: C([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[F:23])[CH2:10][CH2:9]1)=O)(C)(C)C.F[C:25]1C=C(C=CC=1OC1CCNCC1)C#N>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([C:21]#[N:22])=[CH:17][C:16]=2[F:23])[CH2:10][CH2:9]1)(=[O:5])[CH3:25]
Reactant: N#Cc1ccc(OC2CCNCC2)c(F)c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1
Solvent: c1ccncc1
Solvent: CC(=O)OC(C)=O
Product: CC(=O)N1CCC(Oc2ccc(C#N)cc2F)CC1

Procedure:
Synthesized from 4-(4-cyano-2-fluorophenoxy)piperidine-1-carboxylic acid tert-butyl ester (2.8 g) according to an analogous synthetic method to Example 215 described below, the total amount of 3-fluoro-4-(piperidin-4-yloxy)benzonitrile crude product was dissolved in acetic anhydride (30 ml) and pyridine (30 ml), and the solution was stirred overnight at room temperature. The solvent was evaporated in vacuo, the solution was extracted with ethyl acetate, then sequentially washed with a saturated aqueous solution of sodium bicarbonate, water and brine, dried over anhydrous magnesium sulfate, and then the solvent was evaporated in vacuo. The residue was purified by NH silica gel column chromatography (hexane-ethyl acetate system) to provide the title compound (2.2 g).
Reaction SMILES: [S:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]([C:11]([OH:13])=O)[CH2:3][CH2:2]1.[CH3:14][N:15]([CH3:33])[C:16]1[CH:21]=[CH:20][C:19]([CH2:22][NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:32])[CH3:31])=[CH:26][CH:25]=2)=[CH:18][CH:17]=1>>[CH3:14][N:15]([CH3:33])[C:16]1[CH:17]=[CH:18][C:19]([CH2:22][N:23]([C:24]2[CH:29]=[CH:28][C:27]([CH:30]([CH3:31])[CH3:32])=[CH:26][CH:25]=2)[C:11]([CH:4]2[C:5]3[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=3)[S:1][CH2:2][CH2:3]2)=[O:13])=[CH:20][CH:21]=1
Reactant: CC(C)c1ccc(NCc2ccc(N(C)C)cc2)cc1
Reactant: O=C(O)C1CCSc2ccccc21
Product: CC(C)c1ccc(N(Cc2ccc(N(C)C)cc2)C(=O)C2CCSc3ccccc32)cc1
Yield: 28.7 %

Procedure:
By the reaction and treatment in the same manner as in Example 1 using thiochroman-4-carboxylic acid (0.55 g) and [(4-dimethylaminophenyl)methyl](4-isopropylphenyl)amine (0.63 g) as starting materials, N-[(4-dimethylaminophenyl)methyl]-N-(4-isopropylphenyl)thiochroman-4-carboxamide (0.3 g) was obtained. melting point: 118° C.