Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]12[CH2:11][CH:6]3[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]3)[CH2:3]1)[CH2:9]2.[Al+3].[Cl-:16].[Cl-].[Cl-]>ClC1C=CC=CC=1>[Cl:16][C:2]1[CH:11]=[CH:6][C:5]([C:2]23[CH2:11][CH:6]4[CH2:7][CH:8]([CH2:10][C:4]([C:12]([OH:14])=[O:13])([CH2:5]4)[CH2:3]2)[CH2:9]3)=[CH:4][CH:3]=1
Reactant: [Cl-]
Reactant: O=C(O)C12CC3CC(CC(Br)(C3)C1)C2
Agent: [Al+3]
Solvent: Clc1ccccc1
Product: O=C(O)C12CC3CC(C1)CC(c1ccc(Cl)cc1)(C3)C2
Temperature: 25 °C
Yield: 79.3 %

Procedure:
More specifically, adamantane-1-carboxylic acid (1) (45 g, 0.25 mol) was added to a mixture of AlCl3 (45 g, 0.34 mol) and Br2 (450 g) at 0° C. and stirred at 0-10° C. for 48 hrs, and then kept for 5 hrs at about 20° C. The mixture was then poured onto 500 g crushed ice, diluted with 300 mL of CHCl3 and decolorized with solid Na2S2O5. The aqueous phase was extracted twice with Et2O (50 mL each), and the combined organic phases were washed with H2O and extracted with 10% NaOH. The alkaline extraction was acidified with 2NH2SO4 and kept overnight to provide 49 g (yield=75.7%) of 3-bromoadamantane-1-carboxylic acid (2). Over a course of 0.5 hr, intermediate 2 (16.0 g, 61.7 mmol) in 50 mL of dry chlorobenzene was added at −10° C. to 100 mL of dry chlorobenzene containing 9.3 g (70 mmol) of AlCl3. The mixture was then warmed to room temperature for 1 hr, and then heated to 90° C. for 10 hr. The mixture was then poured onto 200 g of crushed ice and filtered to provide 14.2 g (yield=79.3%) of 3-(4-chlorophenyl)adamantane-1-carboxylic acid (3). Intermediate 3 (1 mmol) was added to a 50 mL round-bottom flask containing HPLC-grade toluene (20 mL), fitted with reflux condenser, and dry N2 was introduced. The mixture was stirred while thionyl chloride (SOCl2) (10 mmol) was added, and refluxed for 1 hr. The sample was then evaporated under a vacuum to produce intermediate 4,3-(4-chlorophenyl)adamantane-1-carbonyl chloride. Without further purification, intermediate 4 was added to 5 mL of a mixture containing 3-hydroxytyramine hydrochloride (5, 1 mmol), NaOH (1 mmol) and Na2CO3 (1 mmol) in 5 mL DMF under N2, and the mixture was stirred at 60° C. for 24 hr and then cool to room temperature. The mixture was evaporated under a vacuum, and 10% HCL was slowly added to the mixture until it reached a pH value of 1. The mixture was then extracted with 20 mL CHCl3, washed three times with water (10 mL each), dried with anhydrous Na2SO4, filtered and concentrated to give Compound 1 as white crystals (yield=83%) with a melting point of 146-148° C. 1H NMR (500 MHz, DMSO) δ 1.63-1.68 (m, 2H, Admant-H), 1.71-1.83 (m, 10H, Admant-H), 2.14 (s, 2H, Admant-H), 2.50-2.53 (m, 2H, CH2), 3.15-3.18 (t, J=7.5 Hz, 2H, NCH2), 3.40 (s, 1H, NH), 6.40-6.42 (d, J=10 Hz, 1H, Ar—H), 6.56 (s, 1H, Ar—H), 6.62-6.63 (d, J=5 Hz, 1H, Ar—H), 7.36-7.41 (m, 4H, Ar—H), 8.68 (s(br), 2H, OH). 13C NMR (500 MHz, DMSO) δ 28.8, 31.3, 35.0, 35.5, 36.3, 36.6, 38.3, 41.0, 41.3, 42.0, 44.3, 115.8, 116.4, 119.8, 127.4, 128.5, 130.7, 131.0, 149.6, 162.9, 176.8. Mass spectroscopy m/z (relative intensity) 426.18 (MH+, 100), 427.18 (68), 428.18 (75).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][C:6]([CH2:7][NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.CC(C)([O-])C.[K+].Br[C:24]1[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=[C:28]([Cl:30])[CH:29]=1>C1COCC1>[Cl:30][C:28]1[CH:29]=[C:24]([N:8]([CH2:7][C:6]2[CH:15]=[CH:16][C:3]([O:2][CH3:1])=[CH:4][CH:5]=2)[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:25]2[N:26]([CH:31]=[CH:32][N:33]=2)[N:27]=1
Reactant: COc1ccc(CNc2ccccc2)cc1
Reactant: Clc1cc(Br)c2nccn2n1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: COc1ccc(CN(c2ccccc2)c2cc(Cl)nn3ccnc23)cc1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 82.8 %

Procedure:
A solution of N-(4-methoxybenzyl)aniline (6.42 g, 30.10 mmol) in THF (10 mL) was stirred at 25° C., and potassium tert-butoxide (1M in THF, 90.30 mL, 90.30 mmol) was added. After 30 minutes, 8-bromo-6-chloroimidazo[1,2-b]pyridazine (7.00 g, 30.10 mmol, Example 1 from WO 2007/038314) was added, and the reaction solution stirred at room temperature for 2 hours. The reaction was quenched with water (50 mL) and extracted with ethyl acetate (2×200 mL). The organic layer was washed with saturated aqueous NaHCO3 (100 mL) and saturated aqueous at NaCl (100 mL). The organic phase was dried Na2SO4, filtered and concentrated in vacuo. The residue was purified via ISCO (5% EtOAC/DCM; 120 g column) to give 6-chloro-N-(4-methoxybenzyl)-N-phenylimidazo[1,2-b]pyridazin-8-amine (9.09 g, 83% yield) as a tan solid. LC/MS (Phenomenex Luna 5 micron C18 4.6×30 mm, 0 to 100 B in 2 min with 1 min hold time, Flow rate=5 mL/min, detection at 254 nm, Solvent A: 10% methanol/90% water/0.1% TFA; Solvent B: 10% water/90% methanol/0.1% TFA). Rt=3.918 minutes [M+H]=365.07.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([OH:11])(=[O:10])=[O:9])=[C:4]([NH2:12])[CH:3]=1.[OH-].[Na+].S(OC)(O[CH3:19])(=O)=O.S(=O)(=O)(O)O>C(O)=O.O>[CH3:19][NH:12][C:4]1[CH:3]=[C:2]([CH:7]=[CH:6][C:5]=1[S:8]([OH:11])(=[O:9])=[O:10])[NH2:1]
Reactant: COS(=O)(=O)OC
Reactant: Nc1ccc(S(=O)(=O)O)c(N)c1
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: O=CO
Product: CNc1cc(N)ccc1S(=O)(=O)O
Temperature: 30 °C
Reaction time: 0.5 h

Procedure:
97 g of 1,3-diaminobenzene-4-sulfonic acid were stirred with 250 ml of water and, after the addition of 38 ml of 98% w/w formic acid, boiled at 95°-100° C. The mixture was then cooled to 30° C., and 65 g of ice were added, the pH being adjusted to 6.5 to 7.0 with 60.5 ml of 50% w/w caustic soda solution. There were then added 45 ml of 50% w/w caustic soda solution and 70 ml of dimethyl sulfate, and stirring was continued for 30 minutes. The mixture was then acidified with 43 ml of 96% w/w sulfuric acid and stirred at 100° C. for 3 hours. The mixture was then cooled, and the precipitated 3-(N-methylamino)aniline-4-sulfonic acid was isolated by filtration.
Reaction SMILES: [SH:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([CH3:11])[CH:8]=[CH:7][C:5]=2[N:6]=1.Cl.Cl[CH2:14][C:15]1[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=1[NH2:17]>C(O)(C)C>[CH3:11][C:9]1[CH:8]=[CH:7][C:5]2[NH:6][C:2]([S:1][CH2:14][C:15]3[CH:21]=[CH:20][CH:19]=[CH:18][C:16]=3[NH2:17])=[N:3][C:4]=2[CH:10]=1
Reactant: Nc1ccccc1CCl
Reactant: Cc1ccc2nc(S)[nH]c2c1
Agent: Cl
Solvent: CC(C)O
Product: Cc1ccc2[nH]c(SCc3ccccc3N)nc2c1
Yield: 40.2 %

Procedure:
The title compound was prepared by the method of Example 1 using 2.50 g of 2-mercapto-5-methylbenzimidazole instead of 2-mercaptobenzimidazole and 2.71 g of 2-(chloromethyl)aniline hydrochloride instead of 2-(chloromethyl)-N,N-dimethylaniline in isopropyl alcohol. The basic extraction used 5% sodium hydroxide instead of sodium carbonate. Washing the solid residue from the dichloromethane extract with additional dichloromethane gave 1.65 g of the title compound. Analysis. Calc'd. for C15H15N3S: C, 66.89; H, 5.61; N, 15.60; S, 11.90. Found: C, 65.78; H, 5.48; N, 15.54; S, 11.94.
Reaction SMILES: [CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH:17]=O)[N:12]=2)[CH:4]=1)[CH3:2].[N:19]1[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=1[CH2:25][NH2:26]>>[CH2:1]([C:3]1[C:8](=[O:9])[NH:7][C:6]([CH3:10])=[C:5]([C:11]2[CH:16]=[CH:15][CH:14]=[C:13]([CH2:17][NH:26][CH2:25][C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][N:19]=3)[N:12]=2)[CH:4]=1)[CH3:2]
Reactant: CCc1cc(-c2cccc(C=O)n2)c(C)[nH]c1=O
Reactant: NCc1ccccn1
Product: CCc1cc(-c2cccc(CNCc3ccccn3)n2)c(C)[nH]c1=O

Procedure:
5′-Ethyl-2′-methyl-6′-oxo-1′,6′-dihydro-[2,3′]bipyridinyl-6-carbaldehyde prepared in accordance with PREPARATION 11 is reacted with pyridin-2-ylmethylamine as described in Method A, Example 123 to give the title compound. MS: m/e=335 (M+H).
Reaction SMILES: Br[C:2]1[N:3]([CH3:8])[CH:4]=[C:5]([Br:7])[N:6]=1.[NH:9]1[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1>ClCCl>[Br:7][C:5]1[N:6]=[C:2]([N:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]2)[N:3]([CH3:8])[CH:4]=1
Reactant: Cn1cc(Br)nc1Br
Reactant: C1CNCCN1
Solvent: ClCCl
Product: Cn1cc(Br)nc1N1CCNCC1
Temperature: 130 °C
Reaction time: 3 h
Yield: 61.2 %

Procedure:
A 20-mL resealable tube was charged with 2,4-dibromo-1-methyl-1H-imidazole (0.480 g, 2.00 mmol) and piperazine (3.4 g, 39.5 mmol), and the resulting mixture was stirred for 3 h at 130° C. The reaction mixture was cooled to room temperature, diluted with dichloromethane (20 mL), washed with water (2×10 mL), dried over anhydrous sodium sulfate, filtered, and concentrated under vacuum. The residue was purified via column chromatography on silica gel (eluting with 10:1, dichloromethane/methanol) to afford 1-(4-bromo-1-methyl-1H-imidazol-2-yl)piperazine (0.300 g, 61%) as a light yellow solid. MS (ESI, pos. ion) m/z 245, 247 [M+H]+.
Reaction SMILES: C[O-].[Na+].[CH3:4][O:5][C:6]1[CH:7]=[C:8]2[C:12](=[CH:13][CH:14]=1)[NH:11][CH:10]=[C:9]2[CH2:15][C:16]#[N:17].[CH3:18][O:19][C:20]1[CH:27]=[C:26]([O:28][CH3:29])[CH:25]=[CH:24][C:21]=1C=O.[CH2:30](OCC)C>C(O)C.O.C(Cl)Cl>[CH3:29][O:28][C:26]1[CH:25]=[C:24](/[CH:30]=[C:15](/[C:9]2[C:8]3[C:12](=[CH:13][CH:14]=[C:6]([O:5][CH3:4])[CH:7]=3)[NH:11][CH:10]=2)\[C:16]#[N:17])[CH:21]=[C:20]([O:19][CH3:18])[CH:27]=1
Reactant: CCOCC
Reactant: COc1ccc2[nH]cc(CC#N)c2c1
Reactant: COc1ccc(C=O)c(OC)c1
Agent: C[O-]
Agent: [Na+]
Solvent: CCO
Solvent: ClCCl
Solvent: O
Product: COc1cc(/C=C(\C#N)c2c[nH]c3ccc(OC)cc23)cc(OC)c1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
To a solution of sodium methanolate (61 mg, 1.1 mmol, 1.4 eq.) in anhydrous ethanol (10 mL) were added, under an argon atmosphere, (5-methoxy-1H-indol-3-yl)-acetonitrile (150 mg, 0.8 mmol, 1.0 eq.) and, after 30 minutes stirring, 2,4-dimethoxy-benzaldehyde (200 mg, 1.2 mmol, 1.5 eq.). The reaction apparatus was protected from light and the mixture stirred at room temperature for 3 days. The solvent was removed under reduced pressure and the residue purified by silica gel flash-column chromatography (eluent: CH2Cl2/EtOH, 100:0 to 98:2) to afford, after trituration with diethyl ether, the compound (14) as a yellow powder (85 mg, 32%). TLC: Rf=0.55 (CH2Cl2 96/EtOH 4); mp: 141° C.; IR νmax (cm-1): 2212 (νCN), 3400 (νN—H); 1H NMR (DMSO, 300 MHz): δ (ppm): 3.81 (6H, s, 3″-methoxy and 5″-methoxy), 3.82 (3H, s, 5′-methoxy), 6.58 (1H, s, H4″), 6.89 (1H, dd, J6′-7′=8.9 Hz, J6′-4′=2.1 Hz, H6′), 7.11 and 7.12 (2H, m, H2″ and H6″), 7.39 (1H, d, J7′-6′=8.9 Hz, H7′), 7.44 (1H, d, J4′-6′=2.1 Hz, H4′), 7.64 (1H, s, H2′), 7.74 (1H, s, H3), 11.60 (1H, s, H indolic H); 13C NMR (DMSO, 75.5 MHz): δ (ppm): 55.8 (3″-methoxy and 5″-methoxy), 56.0 (5′-methoxy), 101.8 (C4′), 102.3 (C4″), 106.7 (C2), 107.0 (C2″ and C6″), 110.7 (C3′), 112.7 (C6′), 113.6 (C7′), 118.9 (C1), 124.5 (C3a′), 127.6 (C2′), 132.7 (C7a′), 136.5 (C3), 136.9 (C1″), 154.9 (C5′), 161.0 (C3″ and C5″); ESI-MS: m/z 357.1 ([M+Na]+); HRESI-MS: m/z 357.1219 (calcd for C20H18N2O3Na, 357.1205); Anal. Calcd for C20H18N2O2, 0.2 H2O: C, 71.08; H, 5.49; N, 8.29; O, 15.15. Found: C, 70.89; H, 5.23; N, 8.34.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25](OCC)=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1.[NH2:31][CH:32]([CH3:35])[CH2:33][OH:34]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]2[CH:18]=[C:17]3[C:12]([C:13]([OH:30])=[C:14]([C:25]([NH:31][CH:32]([CH3:35])[CH2:33][OH:34])=[O:26])[C:15](=[O:24])[N:16]3[CH2:19][C:20]([F:23])([F:22])[F:21])=[N:11][CH:10]=2)=[CH:4][CH:3]=1
Reactant: CC(N)CO
Reactant: CCOC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Product: CC(CO)NC(=O)c1c(O)c2ncc(Cc3ccc(F)cc3)cc2n(CC(F)(F)F)c1=O
Yield: 65 %

Procedure:
In a similar manner to that described in example 196, from ethyl 7-[(4-fluorophenyl)methyl]-4-hydroxy-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxylate (20 mg, 0.050mmol) and 2-amino-1-propanol (0.05 mL) was prepared 7-[(4-fluorophenyl)methyl]-4-hydroxy-N-(2-hydroxy-1-methylethyl)-2-oxo-1-(2,2,2-trifluoroethyl)-1,2-dihydro-1,5-naphthyridine-3-carboxamide(15 mg, 65% yield) as a white solid after purification by reverse phase HPLC. 1H NMR (CDCl3) δ 9.98 (d, J=7.6 Hz, 1 H), 8.58 (s, 1 H), 7.37 (s, 1 H), 7.15-7.12 (m, 2 H), 7.04-6.99 (m, 2 H), 4.82 (br s, 2 H), 4.26 (m, 1 H), 4.13 (s, 2 H), 3.78 (dd, J=10.8, 4 Hz, 1 H), 3.67 (dd, J=10.8, 6, 1 H), 1.30 (d, J=6.8 Hz, 3 H); MS m/z 454 M+1).
Reaction SMILES: C([O:4][CH:5]([C:9]1[CH:14]=C[C:12](C)=[CH:11][CH:10]=1)C(C)=C)C=C.[C:16]1([C:18](=[CH:20][C:21](=[CH:23][CH:24]=1)[CH3:22])C)[CH3:17]>>[CH3:14][CH:9]([CH2:10]/[C:11](/[CH3:12])=[CH:17]/[C:16]1[CH:24]=[CH:23][C:21]([CH3:22])=[CH:20][CH:18]=1)[CH:5]=[O:4]
Reactant: C=CCOC(C(=C)C)c1ccc(C)cc1
Reactant: Cc1ccc(C)c(C)c1
Product: C/C(=C\c1ccc(C)cc1)CC(C)C=O

Procedure:
The 1-[1-(allyloxy)-2-methyl-2-propenyl]-4-methylbenzene (24 g, 0.116 mol) and [RuCl2(PPh3)3] (200 mg) were heated in the presence of BHT (50 mg) in pseudo-cumene (50 ml) at 170-180° C. (reflux) for 4 hours.
Reaction SMILES: C1(S(O)(=O)=O)C=CC=CC=1.[NH2:11][C:12]1[CH:13]=[C:14]2[C:27](=[CH:28][CH:29]=1)[CH2:26][C:16]1([C:24]3[C:19](=[N:20][CH:21]=[CH:22][CH:23]=3)[NH:18][C:17]1=[O:25])[CH2:15]2.Cl[C:31]1[N:36]=[CH:35][N:34]=[C:33]([C:37]([C:39]2[CH:40]=[C:41]([CH3:48])[C:42]3[O:46][CH2:45][CH2:44][C:43]=3[CH:47]=2)=[O:38])[CH:32]=1>C(O)CCCC>[CH3:48][C:41]1[C:42]2[O:46][CH2:45][CH2:44][C:43]=2[CH:47]=[C:39]([C:37]([C:33]2[N:34]=[CH:35][N:36]=[C:31]([NH:11][C:12]3[CH:13]=[C:14]4[C:27](=[CH:28][CH:29]=3)[CH2:26][C:16]3([C:24]5[C:19](=[N:20][CH:21]=[CH:22][CH:23]=5)[NH:18][C:17]3=[O:25])[CH2:15]4)[CH:32]=2)=[O:38])[CH:40]=1
Reactant: Nc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: Cc1cc(C(=O)c2cc(Cl)ncn2)cc2c1OCC2
Agent: O=S(=O)(O)c1ccccc1
Solvent: CCCCCO
Product: Cc1cc(C(=O)c2cc(Nc3ccc4c(c3)CC3(C4)C(=O)Nc4ncccc43)ncn2)cc2c1OCC2
Temperature: 85 °C
Reaction time: 1 h

Procedure:
A spatula tip of benzenesulphonic acid was added to 70 mg (0.28 mmol) 5-amino-1,3-dihydrospiro[inden-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one and 0.10 g (0.26 mmol) (6-chloro-pyrimidin-4-yl)-(7-methyl-2,3-dihydro-benzofuran-5-yl)-methanone in 2 mL 1-pentanol and the mixture was stirred at 85° C. for 1 h. The reaction mixture was evaporated down, taken up in DMF, acidified with a few drops of hydrochloric acid and purified by preparative HPLC. The fractions containing the product were combined and freeze-dried.
Reaction SMILES: [C:1]([CH2:3][C:4]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[NH:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2].[CH2:19]([Br:28])[C:20]([C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:21]>C(#N)C>[BrH:28].[C:1]([CH2:3][C:4]1[C:12]2[C:7]([N:8]([CH2:19][C:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)=[O:21])[CH:9]=[CH:10][CH:11]=2)=[N:6][C:5]=1[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)#[N:2]
Reactant: N#CCc1c(-c2ccccc2)[nH]c2ncccc12
Reactant: O=C(CBr)c1ccccc1
Solvent: CC#N
Product: Br
Product: N#CCc1c2cccn(CC(=O)c3ccccc3)c-2nc1-c1ccccc1
Yield: 70.9 %

Procedure:
3-(Cyanomethyl)-2-phenylpyrrolo[2,3-b]pyridine (0.35 g, 1.5 mmol) and phenacyl bromide (0.36 g) in acetonitrile (5 ml) was refluxed for 18 h. The resulting solid product was isolated by filtration and washed with diethyl ether to give pure 3-(cyanomethyl)-7-phenacyl-2-phenylpyrrolo[2,3-b]pyridine hydrobromide (0.46 g, 70%).
Reaction SMILES: [C:1]1(=[O:8])[O:7][C:5](=[O:6])[CH2:4][CH2:3][CH2:2]1.[CH2:9]([NH2:16])[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(OCC)C>ClCCl>[O:6]=[C:5]([NH:16][CH2:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1)[CH2:4][CH2:3][CH2:2][C:1]([OH:7])=[O:8]
Reactant: O=C1CCCC(=O)O1
Reactant: NCc1ccccc1
Solvent: ClCCl
Solvent: CCOCC
Product: O=C(O)CCCC(=O)NCc1ccccc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 50.9 %

Procedure:
To a solution of 25 gm (220 mMol) glutaric anhydride in dichloromethane (250 ml) was added a solution of 26.4 ml (242 mMol) benzylamine in dichloromethane (50 ml) dropwise. The reaction mixture was stirred for 3 hours at room temperature. The reaction mixture was then poured into diethyl ether (500 ml) and the resulting solid was filtered. The filter cake was washed with diethyl ether, dried under vacuum and then recrystallized from ethyl acetate to give 24.8 gm (51%) 5-oxo-5-(phenylmethylamino)pentanoic acid as a crystalline solid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26].[Cl:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31](Cl)(=[O:33])=[O:32]>>[Cl:27][C:28]1[CH:38]=[CH:37][CH:36]=[CH:35][C:29]=1[CH2:30][S:31]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][C:3]=1[O:25][CH3:26])(=[O:33])=[O:32]
Reactant: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1N
Reactant: O=S(=O)(Cl)Cc1ccccc1Cl
Product: COc1cc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)ccc1NS(=O)(=O)Cc1ccccc1Cl

Procedure:
By using 5-(4-amino-3-methoxyphenyl)-1H-naphtho[2,1-b][1,4]diazepine-2,4(3H,5H)-dione obtained in Example 63, (3), and 2-chlorobenzylsulfonyl chloride, the title compound was obtained in the same manner as that of Example 145.
Reaction SMILES: [CH:1]([C:3]1[N:8]=[CH:7][CH:6]=[CH:5][N:4]=1)=[CH2:2].CC(O)=O.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CCO>[C:23]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][NH:22][CH2:2][CH2:1][C:3]2[N:8]=[CH:7][CH:6]=[CH:5][N:4]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: NCCC(c1ccccc1)c1ccccc1
Reactant: C=Cc1ncccn1
Solvent: CC(=O)O
Solvent: CCO
Product: c1ccc(C(CCNCCc2ncccn2)c2ccccc2)cc1
Temperature: 0 °C

Procedure:
To a solution of 2-vinylpyrimidine (0.373 g, 3.51 mmol) in EtOH (6 mL) at room temperature was added AcOH (1 mL) and 3,3-diphenylpropan-1-amine (2.21 g, 10.5 mmol). The reaction mixture was heated to reflux for 1 d, cooled to 0° C., and the solids were removed by filtration. The filtrate was concentrated and diluted with 5 M NaOH, brine, and EtOAc. The aqueous phase was extracted with EtOAc (2×) and the combined organic extracts were washed with brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (eluted with 10% MeOH in DCM) gave 3,3-diphenyl-N-(2-(pyrimidin-2-yl)ethyl)propan-1-amine.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.[C:27]1([P:33]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1>C(#N)C>[Cl-:1].[C:24]([C:7]1[C:6]2[N:26]=[C:3]([CH2:2][P+:33]([C:34]3[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=3)([C:40]3[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[NH:4][C:5]=2[CH:10]=[C:9]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=2)[N:8]=1)#[N:25]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Solvent: CC#N
Product: CCOc1ccc(-c2cc3[nH]c(C[P+](c4ccccc4)(c4ccccc4)c4ccccc4)nc3c(C#N)n2)cc1C(F)(F)F
Product: [Cl-]
Reaction time: 8 h

Procedure:
2-Chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5,c]-pyridine-4-carbonitrile (100 mg, 0.26 mmol) and triphenylphosphine in acetonitrile were heated to 60° C. and stirred overnight. The reaction mixture was concentrated and triturated with ether to give a light yellow solid. MS m/z 607.5 (m).
Reaction SMILES: C(N(CC)CC)C.ClCCl.[CH:11]1([C:14](Cl)=[O:15])[CH2:13][CH2:12]1.C(OCC)(=O)C.[NH2:23][C:24]1[S:28][N:27]=[C:26]([Br:29])[C:25]=1[C:30](=[O:32])[CH3:31]>>[C:30]([C:25]1[C:26]([Br:29])=[N:27][S:28][C:24]=1[NH:23][C:14]([CH:11]1[CH2:13][CH2:12]1)=[O:15])(=[O:32])[CH3:31]
Reactant: CC(=O)c1c(Br)nsc1N
Reactant: O=C(Cl)C1CC1
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)c1c(Br)nsc1NC(=O)C1CC1
Temperature: 16 °C
Yield: 60 %

Procedure:
Add triethylamine (234.5; mL, 1.68; mol) to a cooled suspension of 1-(5-amino-3-bromo-isothiazol-4-yl)-ethanone (310; g, 1.40; mol) in dichloromethane (2.79; L, 43.53 mol) at 0° C. under nitrogen and then add slowly a solution of cyclopropanecarbonyl chloride (137.5; mL, 1.47; mol) in dichloromethane (310; mL, 4.84; mol) at 0° C. over 1 hour. Warm to 16° C. over 2; hours and then cool to 10° C., add water (1; L) and separate the layers. Extract the aqueous layer once with dichloromethane (500; mL). Combine the organic layers, concentrate and purify by silica gel chromatography eluting with n-hexane:dichloromethane 30:70. Triturate the recovered solid with hexanes to give the title compound as a white solid (256.1; g, 60%). MS (m/z): 289, 291; (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12.[C:32](O)(=[O:34])[CH3:33].Cl.C(N=C=NCCCN(C)C)C.ON1C2C=CC=CC=2N=N1>CN(C)C=O.C(N(CC)CC)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([NH:24][CH2:25][CH:26]2[CH2:27][CH2:28][N:29]([C:32](=[O:34])[CH3:33])[CH2:30][CH2:31]2)=[N:6][C:7]=1[C:8]1[CH:13]=[CH:12][N:11]=[C:10]2[NH:14][C:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH3:23])[CH2:19][CH2:18]3)=[CH:16][C:9]=12
Reactant: CC(=O)O
Reactant: CN1CCC(c2cc3c(-c4nc(NCC5CCNCC5)ccc4Cl)ccnc3[nH]2)CC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(=O)N1CCC(CNc2ccc(Cl)c(-c3ccnc4[nH]c(C5CCN(C)CC5)cc34)n2)CC1
Reaction time: 8 h

Procedure:
To a solution of Example 165 (20 mg, 0.05 mmol) in N,N-dimethylformamide (1 mL) was added acetic acid (4 mg, 0.07 mmol) and triethylamine (0.1 mL) at room temperature. 1-Ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (11 mg, 0.07 mmol) and N-hydroxybenzotriazole (10 mg, 0.07 mmol) were added and the mixture was stirred overnight. Purification by HPLC (Zorbax XDB C-18 (32) using a gradient of 5-40% acetonitrile/water (containing 0.1% trifluoroacetic acid) afforded the title compound. 1H NMR (400 MHz, DMSO-d6): δ 1.57-1.93 (m, 5H), 1.96 (s, 3H), 2.28 (d, J=13.73 Hz, 2H), 2.80 (d, J=3.97 Hz, 3H), 2.87-3.01 (m, 2H), 3.02-3.22 (m, 5H), 3.52 (d, J=11.60 Hz, 2H), 3.77 (d, J=13.12 Hz, 2H), 4.34 (d, J=12.82 Hz, 2H), 6.10 (s, 1H), 6.61 (d, J=9.16 Hz, 1H), 7.11-7.18 (m, 1H), 7.56 (d, J=9.16 Hz, 1H), 8.23 (d, J=5.19 Hz, 1H). LCMS: 481 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7](S)[N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([OH:18])[N:3]=1>[OH-].[Na+].[Ni]>[OH:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[CH:7][N:8]2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:4]([OH:18])[N:3]=1
Reactant: Oc1nc(O)c2nc(S)n(-c3ccccc3)c2n1
Agent: [Ni]
Agent: [Na+]
Agent: [OH-]
Product: Oc1nc(O)c2ncn(-c3ccccc3)c2n1
Temperature: 4 °C
Yield: 515.5 %

Procedure:
2.5 g of 2,6-dihydroxy-9-phenyl-8-purinethiol was dissolved in 250 ml 1N sodium hydroxide and treated with 75 g Raney nickel. It was then heated to reflux for 2 hours and then filtered through Celite while hot. The filtrate was cooled to about 4° C., the white precipitate collected, dissolved in hot water, treated with charcoal, filtered, cooled in an ice bath and acidified with concentrated hydrochloric acid. The white product was collected and dried under vacuum at 70° C. for 2 days to yield 11.3 g of 2,6-dihydroxy-9-phenylpurine.