Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([NH:7]N)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:9][N:10]1[CH2:15][CH2:14][C:13](=O)[CH2:12][CH2:11]1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+].[OH-].[Na+]>O1CCOCC1>[CH3:9][N:10]1[CH2:15][CH2:14][C:13]2[NH:7][C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=3[C:12]=2[CH2:11]1
Reactant: CN1CCC(=O)CC1
Reactant: NNc1ccccc1
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: C1COCCO1
Product: CN1CCc2[nH]c3ccccc3c2C1
Temperature: 0 °C
Yield: 92.4 %

Procedure:
Phenyl hydrazine (1.0 g, 9.3 mmols) and 1-methyl-piperidin-4-one (1.1 g, 9.3 mmols) were dissolved in 1,4-dioxane (35 mL) and cooled to 0° C. Concentrated sulfuric acid (5 mL) was added dropwise to the reaction at 0° C. with stirring upon which a precipitate formed. The reaction was then heated to 60° C. for one hour after which the precipitate was fully dissolved. The reaction was stirred for an additional hour at 60° C. The reaction was then cooled to room temperature and the pH was adjusted to approximately 12 by the addition of saturated aqueous sodium bicarbonate solution followed by small portions of solid sodium hydroxide. The organic products were extracted with chloroform (3×20 mL) and the combined organic extracts were washed with brine (15 mL), dried (Na2SO4) and concentrated in vacuo. Purification by column chromatography (0-80% gradient of ethyl acetate in hexane) afforded the final product (1.6 g, 93% yield) as a beige solid. 1H NMR (400 MHz, DMSO): δ 10.80 (s, 1H), 7.30 (m, 2H), 6.98 (m, 2H), 3.53 (s, 2H), 2.79 (t, J=5.2 Hz, 2H), 2.71 (t, 2H, J=5.4 Hz), 2.43 (s, 3H). 13C NMR APT (100 MHz, CDCl3): δ 136.2 (up), 132.0 (up), 126.0 (up), 121.0 (down), 119.1 (down), 117.4 (down), 110.7 (down), 108.3 (up), 52.5 (up), 51.8 (up), 45.8 (down), 23.5 (up). ESI-HRMS (m/z): [M+H]+ calcd. for C12H14N2, 187.1230. found, 187.1228
Reaction SMILES: [CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6]([CH:7]=O)=[C:5]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:4]=1.[C:24]([C:27]1[CH:32]=[CH:31][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:29][CH:28]=1)(=[O:26])[CH3:25].C[O-].[Li+]>CN(C)C=O.CO.O>[CH3:1][O:2][C:3]1[C:10]([C:11]2[S:12][CH:13]=[CH:14][CH:15]=2)=[CH:9][C:6](/[CH:7]=[CH:25]/[C:24]([C:27]2[CH:28]=[CH:29][C:30]([S:33]([NH2:36])(=[O:35])=[O:34])=[CH:31][CH:32]=2)=[O:26])=[C:5]([O:16][C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[N:18]=2)[CH:4]=1
Reactant: COc1cc(Oc2cccc(C)n2)c(C=O)cc1-c1cccs1
Reactant: CC(=O)c1ccc(S(N)(=O)=O)cc1
Agent: C[O-]
Agent: [Li+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CO
Product: COc1cc(Oc2cccc(C)n2)c(/C=C/C(=O)c2ccc(S(N)(=O)=O)cc2)cc1-c1cccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 79.6 %

Procedure:
4-Methoxy-2-(6-methyl-pyridin-2-yloxy)-5-thiophen-2-yl-benzaldehyde (Ex-122A, 0.20 g, 0.62 mmol) and 4-acetylbenzenesulfonamide (Ex-26A, 0.12 g, 0.62 mmol) were dissolved in a dimethylformamide-methanol solution (4.2 mL, 7:3). After complete dissolution, lithium methoxide (0.093 g, 2.5 mmol) was added and the resulting orange slurry was stirred in the dark at room temperature for 3 h. Upon completion, as determined by HPLC, the mixture was diluted with water (10 mL) and extracted with ethyl acetate (3×20 mL). The combined organic extracts were dried over sodium sulfate and evaporated to dryness. The crude oil was taken up in ethanol (2 mL) and warmed to 60° C. to obtain complete dissolution and allowed to cool to room temperature. The resulting precipitate was collected on filter paper and dried in vacuo to yield 0.25 g (82%) of the title compound as a yellow solid, mp 164–165° C. 1H-NMR (300 MHz, DMSO-d6) δ 8.47 (s, 1H), 8.24 (d, 2H, J=8.1 Hz), 7.98 (d, 1H, J=15.3 Hz), 7.96 (d, 2H, J=8.1 Hz), 7.78–7.85 (m, 2H), 7.77 (d, 1H, J=15.3 Hz), 7.62 (d, 1H, J=5.1 Hz), 7.57 (s, 2H), 7.19 (dd, 1H, J=5.1, 3.6 Hz), 7.04 (d, 1H, J=7.5 Hz), 6.99 (s, 1H), 6.91 (d, 1H, J=8.4 Hz), 3.90 (s, 3H), 2.33 (s, 3H). Anal. Calcd. C26H22N2O5S2: C, 61.64; H, 4.38; N, 5.53; S, 12.66. Found: C, 61.88; H, 4.47; N, 5.59; S, 12.62.
Reaction SMILES: [CH3:1][C:2]([CH3:28])([CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([O:5]C)=[O:4].[OH-].[K+]>C(O)CO.C(OCC)(=O)C>[CH3:1][C:2]([CH3:28])([CH2:7][O:8][C:9]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)([C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[C:3]([OH:5])=[O:4]
Reactant: COC(=O)C(C)(C)COC(c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: OCCO
Product: CC(C)(COC(c1ccccc1)(c1ccccc1)c1ccccc1)C(=O)O
Yield: 14.6 %

Procedure:
A solution of 53.5 g of raw methyl 2,2-dimethyl-3-trityloxy-propionate and 16.8 g of potassium hydroxide in 100 ml of ethylene glycol was heated to 160° C. for 4 hours. The mixture was cooled, diluted with 400 ml of ethyl acetate, and then washed successively with ice-cold 1N hydrochloric acid and with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. The residue was triturated with diethylether, unsoluble material was filtered off, and the filtrate was evaporated. Crystallization of the residue from diethylether/hexane provided 7.5 g of 2,2-dimethyl-3-trityloxy-propanoic acid, m.p. 153°-158° C.
Reaction SMILES: [Cl:1][C:2]1[C:7](Cl)=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:5]=[CH:4][N:3]=1.[NH:17]1[CH2:22][CH2:21][O:20][CH2:19][CH2:18]1>>[Cl:1][C:2]1[N:3]=[C:4]([N:17]2[CH2:22][CH2:21][O:20][CH2:19][CH2:18]2)[CH:5]=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([F:15])=[C:11]([Cl:16])[CH:10]=2)[CH:7]=1
Reactant: C1COCCN1
Reactant: Fc1ccc(-c2ccnc(Cl)c2Cl)cc1Cl
Product: Fc1ccc(-c2cc(Cl)nc(N3CCOCC3)c2)cc1Cl

Procedure:
Stir the solution of 2,3-dichloro-4-(3-chloro-4-fluoro-phenyl)-pyridine (100 mg) in morpholine (2 mL) 3 hours at 80° C., concentrate, partition between H2O and EtOAc, dry over Na2SO4, and concentrate under vacuum. Purify by preparative TLC (3:1 hexanes/EtOAc) to give 4-[6-chloro-4-(3-chloro-4-fluoro-phenyl)-pyridin-2-yl]-morpholine.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[N:3]=1.[OH-].[Na+].Cl[CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[CH2:19][C:20]([O:22][CH3:23])=[O:21].O>C1OCCOCCOCCOCCOC1.C1(C)C=CC=CC=1.CN(C=O)C.[I-].[Na+]>[Br:8][C:4]1[N:3]=[C:2]([O:1][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=2[CH2:19][C:20]([O:22][CH3:23])=[O:21])[CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)Cc1ccccc1CCl
Reactant: Oc1cccc(Br)n1
Agent: C1COCCOCCOCCOCCO1
Agent: [I-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: Cc1ccccc1
Solvent: O
Product: COC(=O)Cc1ccccc1COc1cccc(Br)n1
Yield: 51.2 %

Procedure:
A mixture of 2-hydroxy-6-bromopyridine (1.3 g, 7.5 mmol), sodium hydroxide (0.36 g, 9.0 mmol) and 15-crown-5 (1 drop) in dry toluene (20 ml) were stirred at reflux for 1.5 hours. The toluene was removed under reduced pressure and the white salt residue was dissolved in dry DMF (10 ml). Methyl 2-chloromethylphenylacetate (1.0 g, 5 mmol) in dry DMF (10 ml) was added dropwise along with sodium iodide (10 mg). The mixture was stirred at 80° C. for 2 hours, poured into water and extracted with diethyl ether. The ether extracts were washed with water, dried and the ether removed in vacuo leaving an orange oil which was purified by column chromatography (silica eluted with 10% ethyl acetate in hexane) to give methyl 2-(6-bromopyrid-2-yloxymethyl)phenylacetate (0.86 g, 51%) (Compound No. 2 in Table 1) as an orange oil; 1H NMR (270 MHz)δ: 3.68(3H,s), 3.73(2H,s), 5.38(2H,s), 6.68(1H,d), 7.06(1H,d), 7.25-7.50(5H,m) ppm.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1.[Na+].[I-:16]>CC(=O)CC.CCOCC>[I:16][CH2:2][CH2:3][CH2:4][CH2:5][C:6]1([C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH2:9][CH2:8][CH2:7]1
Reactant: [I-]
Reactant: CCOC(=O)C1(CCCCCl)CCC1
Agent: [Na+]
Solvent: CCC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C1(CCCCI)CCC1
Yield: 99.4 %

Procedure:
To a solution of ethyl 1-(4-chlorobutyl)-1-cyclobutanecarboxylate (21.21 g, 97.0 mmol) in 2-butanone (125 mL) was added NaI (19.07 g, 127 mmol). The reaction mixture was stirred under reflux for 20 h and diluted with Et2O (500 mL). The resulting mixture was washed with aqueous Na2S2O3 (10% (W/W), 250 mL), brine (250 mL), dried (Na2SO4) and evaporated in vacuo to give ethyl 1-(4-iodobutyl)-1-cyclobutanecarboxylate (29.91 g, 99%) as a slightly yellow oil. 1H NMR (CDCl3): δ=4.14 (q, J=7.1 Hz, 2H), 3.17 (t, J=6.9 Hz, 2H), 2.49-2.32 (m, 2H), 1.98-1.69 (m, 8H), 1.37-1.19 (m, 2H), 1.27 (t, J=7.1 Hz, 3H). 13C NMR (CDCl3): δ=176.5, 60.3, 47.5, 36.9, 33.7, 30.1 (2×), 26.0, 15.7, 14.5, 6.8. HRMS calcd for C11H20IO2 (MH+): 311.0508. found: 311.0511.
Reaction SMILES: IC.[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([OH:15])=[O:14])=[O:9])([CH3:6])([CH3:5])[CH3:4].[C:23](=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[C:3]([O:7][C:8]([NH:10][C@H:11]([C:16]1[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][CH:17]=1)[CH2:12][C:13]([O:15][CH3:23])=[O:14])=[O:9])([CH3:6])([CH3:4])[CH3:5]
Reactant: O=C([O-])[O-]
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)O)c1ccc(Cl)cc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CI
Product: COC(=O)C[C@H](NC(=O)OC(C)(C)C)c1ccc(Cl)cc1
Temperature: 80 °C
Reaction time: 24 h
Yield: 127.9 %

Procedure:
Iodomethane (1.038 mL, 16.68 mmol) was added in one portion to (S)-3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoic acid (1 g, 3.34 mmol) and potassium carbonate (0.922 g, 6.67 mmol) in DMF (15 mL). The resulting suspension was stirred at 80° C. for 24 hours. The reaction mixture was concentrated and diluted with EtOAc (50 mL) with water (50 mL). The organic layer was dried over MgSO4, filtered and evaporated to afford (S)-methyl 3-(tert-butoxycarbonylamino)-3-(4-chlorophenyl)propanoate (1.340 g, 128%) as a orange solid. 1H NMR (399.9 MHz, DMSO-d6) δ 1.36 (9H, s), 2.71-2.74 (1H, m), 2.74-2.80 (1H, m), 3.57 (3H, s), 4.91 (1H, d), 7.33 (2H, d), 7.39 (2H, d), 7.49 (1H, d). m/z (ESI−) (M−H)−=312; HPLC tR=2.57 min.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[C:11]([F:14])([F:13])[F:12].O=S(Cl)Cl.[CH3:19]O>>[F:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH3:19])=[O:7])=[CH:4][C:3]=1[C:11]([F:12])([F:13])[F:14]
Reactant: O=C(O)c1ccc(F)c(C(F)(F)F)c1
Reactant: CO
Solvent: O=S(Cl)Cl
Product: COC(=O)c1ccc(F)c(C(F)(F)F)c1

Procedure:
5 g of 4-fluoro-3-trifluoromethylbenzoic acid and 9 ml of SOCl2 are stirred at 60° C. for 8 h in 50 ml of MeOH. The volatile constituents are then removed in vacuo and 5.1 g of a colorless oil are obtained, which is further employed without purification. Rf (EA/MeOH 10:1)=0.74 MS (DCl) 223 (M+H)+
Reaction SMILES: [C:1]12[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[NH:6]C(=O)[O:4][C:2]2=O.C(N(CC)CC)C.Cl.[F:21][C:22]([F:26])([F:25])[CH2:23][NH2:24]>O>[NH2:6][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:1]=1[C:2]([NH:24][CH2:23][C:22]([F:26])([F:25])[F:21])=[O:4]
Reactant: O=c1[nH]c2ccccc2c(=O)o1
Reactant: NCC(F)(F)F
Agent: Cl
Solvent: O
Solvent: CCN(CC)CC
Product: Nc1ccccc1C(=O)NCC(F)(F)F
Reaction time: 16 h
Yield: 52.3 %

Procedure:
A round-bottomed flask was charged with isatoic anhydride (5.0 g, 0.030 mol), 15 mL water, and triethylamine (4.69 mL, 0.033 mol). (2,2,2-trifluoroethyl)amine hydrochloride (4.98 g, 0.036 mol) was added slowly to the reaction mixture. After 16 h, the reaction mixture was concentrated to dryness. The crude product was purified silica gel column (EtOAc/Hexanes) to afford the title compound as a white solid (3.42 g, 51%): Mass (M+H)+=120, 219.
Reaction SMILES: [NH:1]1[CH2:7][C:5](=[O:6])[NH:4][C:2]1=[O:3].S(Cl)(Cl)(=O)=O.[C:13]1([OH:19])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CC(N=NC(C#N)(C)C)(C#N)C.O1CCOCC1>[OH:19][C:13]1[CH:18]=[CH:17][C:16]([CH:7]2[NH:1][C:2](=[O:3])[NH:4][C:5]2=[O:6])=[CH:15][CH:14]=1
Reactant: O=C1CNC(=O)N1
Reactant: Oc1ccccc1
Agent: CC(C)(C#N)N=NC(C)(C)C#N
Solvent: C1COCCO1
Solvent: O=S(=O)(Cl)Cl
Product: O=C1NC(=O)C(c2ccc(O)cc2)N1
Temperature: 90 °C
Reaction time: 5 h
Yield: 5.3 %

Procedure:
4.0 g (40 mmol) of hydantoin, 50 ml of dioxane, 5.4 g (40 mmol) of sulfuryl chloride, and 0.01 g of azobisiso-butylonitrile were mixed. The reaction mixture was then stirred at a temperature of 90° C. for 5 hours. The reaction system was then allowed to cool to room temperature. To the reaction system was then added 7.6 g (80 mmol) of phenol. The reaction mixture was then allowed to undergo reaction at a temperature of 80° C. for 5 hours. The resulting precipitate was recovered by filtration, washed with water, recrystallized from water and then dried to obtain 0.41 g (yield: 5.3%) of 5-(p-hydroxyphenyl)hydantoin.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1.[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22](Cl)=[O:23]>>[F:18][C:19]1[CH:20]=[C:21]([CH:25]=[CH:26][C:27]=1[F:28])[C:22]([NH:1][C:2]1[CH:3]=[C:4]2[C:12](=[CH:13][CH:14]=1)[NH:11][C:10]1[CH2:9][CH2:8][CH:7]([N:15]([CH3:17])[CH3:16])[CH2:6][C:5]2=1)=[O:23]
Reactant: CN(C)C1CCc2[nH]c3ccc(N)cc3c2C1
Reactant: O=C(Cl)c1ccc(F)c(F)c1
Product: CN(C)C1CCc2[nH]c3ccc(NC(=O)c4ccc(F)c(F)c4)cc3c2C1
Yield: 42.4 %

Procedure:
Beginning with 10.4 mg (0.046 mMol) 6-amino-3-(dimethyl)amino-1,2,3,4-tetrahydro-9H-carbazole and 8.6 μL (0.051 mMol) 3,4-difluorobenzoyl chloride, 7.2 mg (42%) of the title compound were recovered as a beige solid.
Reaction SMILES: F[C:2]1[C:7](/[CH:8]=[CH:9]\[C:10]2[C:11](F)=[N:12][CH:13]=[CH:14][CH:15]=2)=[CH:6][CH:5]=[CH:4][N:3]=1.[CH:17]1([NH2:20])[CH2:19][CH2:18]1>>[CH:17]1([N:20]2[C:2]3[N:3]=[CH:4][CH:5]=[CH:6][C:7]=3[CH:8]=[CH:9][C:10]3[CH:15]=[CH:14][CH:13]=[N:12][C:11]2=3)[CH2:19][CH2:18]1
Reactant: Fc1ncccc1/C=C\c1cccnc1F
Reactant: NC1CC1
Product: C1=Cc2cccnc2N(C2CC2)c2ncccc21
Temperature: 125 °C
Yield: 54.9 %

Procedure:
A mixture of Z-1,2-di-(2-fluoropyridinyl)ethylene (0.436 g) and cyclopropylamine (2 g) was heated at 125° C. in a sealed tube for 12 hours. The mixture was cooled and fractionated directly over silica gel to give 11-cyclopropyl-dipyrido[2,3-b:3',2'-f]azepine (0.258 g), mp 184°-185° C.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][O:10][CH2:11][CH2:12][NH:13][S:14]([CH2:17][CH2:18][C:19](OC)=O)(=[O:16])=[O:15])=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.[ClH:33].[NH2:34][CH2:35][CH2:36][C:37]1[C:45]2[S:44][C:43](=[O:46])[NH:42][C:41]=2[C:40]([OH:47])=[CH:39][CH:38]=1.C([BH3-])#N.[Na+]>>[ClH:33].[OH:47][C:40]1[C:41]2[NH:42][C:43](=[O:46])[S:44][C:45]=2[C:37]([CH2:36][CH2:35][NH:34][CH2:19][CH2:18][CH2:17][S:14]([NH:13][CH2:12][CH2:11][O:10][CH2:9][CH2:8][C:5]2[CH:4]=[CH:3][C:2]([CH3:1])=[CH:7][CH:6]=2)(=[O:15])=[O:16])=[CH:38][CH:39]=1
Reactant: COC(=O)CCS(=O)(=O)NCCOCCc1ccc(C)cc1
Reactant: NCCc1ccc(O)c2[nH]c(=O)sc12
Agent: CC(C)C[Al+]CC(C)C
Agent: Cl
Agent: [BH3-]C#N
Product: Cc1ccc(CCOCCNS(=O)(=O)CCCNCCc2ccc(O)c3[nH]c(=O)sc23)cc1
Yield: 5 %

Procedure:
The title compound (0.2 g) was prepared according to the procedure in example 5 part e using methyl 3-[2-[2-(4-methylphenyl)ethoxy]ethylaminosulphonyl]propanoate (2.49 g), diisobutylaluminiumhydride (1.5M in toluene, 7.5 ml), 7-(2-aminoethyl)-4-hydroxy-1,3-benzothiazol-2(3H)-one hydrochloride (2.2 g) and sodium cyanoborohydride (0.48 g).
Reaction SMILES: [NH2:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1.[C:24]([N:32]=[C:33]=[S:34])(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>ClCCl>[C:24]([NH:32][C:33](=[S:34])[NH:1][C:2]1[CH:22]=[CH:21][CH:20]=[C:19]([CH3:23])[C:3]=1[CH2:4][O:5][C:6]1[C:7]2[N:8]([C:12]([CH2:16][C:17]#[CH:18])=[C:13]([CH3:15])[N:14]=2)[CH:9]=[CH:10][CH:11]=1)(=[O:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: C#CCc1c(C)nc2c(OCc3c(C)cccc3N)cccn12
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: C#CCc1c(C)nc2c(OCc3c(C)cccc3NC(=S)NC(=O)c3ccccc3)cccn12
Reaction time: 1 h

Procedure:
To a solution of 8-(2-amino-6-methylbenzyloxy)-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (9.3 g) in dichloromethane (140 ml) was added dropwise benzoyl isothiocyanate and the mixture was stirred for 1 hour. The solvent was evaporated under reduced pressure and the residue was triturated with ether (50 ml) to give a crystalline product. The crystals were recrystallized from ethanol to give 8-{2-[3-(benzoyl)thioureido]-6-methylbenzyloxy}-2-methyl-3-(2-propynyl)imidazo[1,2-a]pyridine (11.7 g).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@H:9]([CH2:29][C:30]1[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=1[F:38])[CH2:10][C:11]([N:13]1[CH2:18][CH2:17][N:16]2[C:19]([C:25]([F:28])([F:27])[F:26])=[N:20][C:21]([C:22]([OH:24])=[O:23])=[C:15]2[CH2:14]1)=[O:12])=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:39](=[O:51])([O:44][CH:45]1[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1)[O:40][CH:41](Cl)[CH3:42].[I-].[K+].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH:45]1([O:44][C:39]([O:40][CH2:41][CH2:42][O:23][C:22]([C:21]2[N:20]=[C:19]([C:25]([F:27])([F:28])[F:26])[N:16]3[CH2:17][CH2:18][N:13]([C:11](=[O:12])[CH2:10][C@H:9]([NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:29][C:30]4[CH:35]=[C:34]([F:36])[C:33]([F:37])=[CH:32][C:31]=4[F:38])[CH2:14][C:15]=23)=[O:24])=[O:51])[CH2:50][CH2:49][CH2:48][CH2:47][CH2:46]1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)O)c2C1)Cc1cc(F)c(F)cc1F
Reactant: CC(Cl)OC(=O)OC1CCCCC1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N[C@@H](CC(=O)N1CCn2c(C(F)(F)F)nc(C(=O)OCCOC(=O)OC3CCCCC3)c2C1)Cc1cc(F)c(F)cc1F
Temperature: 25 °C
Yield: 69.4 %

Procedure:
(R)-7-[3-tert-Butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid 2a (0.275 g, 0.5 mmol) and 4 mL of N,N-dimethylformamide were added to the reaction tube. After stirring until 2a was dissolved, 1-chloroethyl cyclohexyl carbonate (0.124 g, 0.6 mmol), potassium iodide (0.0415 g, 0.25 mmol) and potassium carbonate (0.083 g, 0.6 mmol) were then added to the solution successively. Upon completion of the addition, the reaction tube was sealed up. The reaction mixture was reacted at 65° C. in an oil bath for 2 hours and monitored by thin layer chromatography until the disappearance of the starting materials, and then the oil bath was removed. After cooling to room temperature, 40 mL of water was added to the reaction tube. The reaction mixture was extracted with ethyl acetate (30 mL×3). The combined organic phase was washed with 30 mL of water and 30 mL of saturated brine successively. The combined organic phase was dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (R)-7-[3-tert-butoxycarbonylamino-4-(2,4,5-trifluoro-phenyl)-butyryl]-3-trifluoromethyl-5,6,7,8-tetrahydro-imidazo[1,5-a]pyrazine-1-carboxylic acid (1-cyclohexyloxycarbonyloxy)-ethyl ester 38a (0.25 g, yield 69.4%) as a white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2].Br[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]Br.C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1>[CH2:1]([N:3]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][N:3]([CH2:1][CH3:2])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:2]
Reactant: BrCCCCCCBr
Reactant: CCNc1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCN(CCCCCCN(CC)c1ccccc1)c1ccccc1
Temperature: 115 °C
Reaction time: 8 h
Yield: 69.9 %

Procedure:
50.8 g of N-ethyl aniline together with 48.8 g of 1,6-dibromohexane and 25.2 g of sodium carbonate were dissolved in 500 ml of toluene. The mixture was stirred while refluxed at 115° C. Reflux was continued overnight. The precipitate was filtered and stirred in 1.25 l of ethyl acetate. The ethyl acetate phase was washed with 500 ml of water and 20 ml of acetic acid. The filtrate and the ethyl acetate phase were washed with a saturated sodium chloride solution and dried on sodium sulfate. The reaction product was isolated by concentration under reduced pressure. 45.4 g of N,N'-diethyl-N,N'-diphenyl-1,6-diaminohexane were obtained (yield: 70%).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([N+:10]([O-])=O)[CH:9]=1)=[O:4].[H][H]>C(OCC)(=O)C.C(O)(=O)C.[Pd]>[CH3:1][O:2][C:3]([C:5]1[N:6]([CH2:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])[N:7]=[C:8]([NH2:10])[CH:9]=1)=[O:4]
Reactant: COC(=O)c1cc([N+](=O)[O-])nn1CC(=O)OC(C)(C)C
Reactant: [H][H]
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: COC(=O)c1cc(N)nn1CC(=O)OC(C)(C)C
Yield: 97.6 %

Procedure:
A solution of 2-tert-Butoxycarbonylmethyl-5-nitro-2H-pyrazole-3-carboxylic acid methyl ester (3 gm) in ethyl acetate (60 ml) and acetic acid (4.5 ml) was hydrogenated at 50 psi hydrogen in the presence of 1.5 gm of 10% palladium/carbon for 3 hours. The mixture was then filtered and evaporated to obtain 2.62 gm of pure title product. ESI M+1=256.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[C:7]3[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=3[N:9]=[CH:10][N:11]=2)[CH:3]=[N:2]1.[CH:23]1(/[CH:28]=[CH:29]/[C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1.C1CCN2C(=NCCC2)CC1>C(#N)C>[CH:23]1([CH:28]([N:1]2[CH:5]=[C:4]([C:6]3[C:7]4[CH:14]=[CH:13][N:12]([CH2:15][O:16][CH2:17][CH2:18][Si:19]([CH3:22])([CH3:21])[CH3:20])[C:8]=4[N:9]=[CH:10][N:11]=3)[CH:3]=[N:2]2)[CH2:29][C:30]([O:32][CH3:33])=[O:31])[CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: C[Si](C)(C)CCOCn1ccc2c(-c3cn[nH]c3)ncnc21
Reactant: COC(=O)/C=C/C1CCCC1
Solvent: C1CCC2=NCCCN2CC1
Solvent: CC#N
Product: COC(=O)CC(C1CCCC1)n1cc(-c2ncnc3c2ccn3COCC[Si](C)(C)C)cn1
Reaction time: 96 h
Yield: 63.2 %

Procedure:
To a solution of 4-(1H-pyrazol-4-yl)-7-[2-(trimethylsilyl)ethoxy]methyl-7H-pyrrolo[2,3-d]pyrimidine (2.9 g, 9.2 mmol) and methyl (2E)-3-cyclopentylacrylate (1.70 g, 11.0 mmol) in ACN (100 mL), was added DBU (2.7 mL, 18 mmol). The resulting mixture was stirred for 96 hours. The ACN was removed in vacuo, and the resulting residue was dissolved in ethyl acetate. This solution was washed with 1.0 N HCl, followed by brine, and then dried over sodium sulfate, and the solvent removed in vacuo. Flash column chromatography (eluting with a gradient from 0-70% ethyl acetate in hexanes) afforded the product (2.73 g, 63%).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[NH:9]2.[CH3:15][O:16][CH2:17][CH2:18]Br.[I-].[Na+]>CN(C=O)C.[Cl-].[Na+].O>[F:3][C:4]1[CH:13]=[CH:12][CH:11]=[C:10]2[C:5]=1[NH:6][CH2:7][C:8](=[O:14])[N:9]2[CH2:18][CH2:17][O:16][CH3:15]
Reactant: O=C1CNc2c(F)cccc2N1
Reactant: COCCBr
Agent: [Cl-]
Agent: [H-]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: O
Product: COCCN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
Sodium hydride (60%, 72 mg, 1.8 mmol) was added to a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (300 mg, 1.8 mmol) in DMF (6.0 ml) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled in an ice/water bath and 2-bromoethyl methyl ether (170 μl, 1.8 mmol) and sodium iodide (140 mg, 0.9 mmol) were added. The mixture was allowed to warm to room temperature and stirred for 18 h. The mixture was diluted with brine and evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was dried and evaporated. The residue was purified by flash chromatography (eluant EtOAc:pet.ether 55:45) to give a pale yellow gum; yield 200 mg, 50%.