Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH2:2][C@@H:3]([C:5]([O:7][C@@H:8]1[C@@H:13]2[C@@H:14]([CH2:19][CH2:20][C@H:21]3[O:27][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22]3)[C@@H:15]([CH3:18])[CH:16]=[CH:17][C:12]2=[CH:11][C@H:10]([CH3:29])[CH2:9]1)=[O:6])[CH3:4].[CH3:30][O:31][CH2:32][CH2:33][NH2:34]>O1CCCC1>[CH3:30][O:31][CH2:32][CH2:33][NH:34][C:25](=[O:26])[CH2:24][C@H:23]([OH:28])[CH2:22][C@H:21]([OH:27])[CH2:20][CH2:19][C@@H:14]1[C@@H:13]2[C:12](=[CH:11][C@H:10]([CH3:29])[CH2:9][C@@H:8]2[O:7][C:5](=[O:6])[C@@H:3]([CH3:4])[CH2:2][CH3:1])[CH:17]=[CH:16][C@@H:15]1[CH3:18]
Reactant: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O)CC(=O)O3)[C@H]21
Reactant: COCCN
Solvent: C1CCOC1
Product: CC[C@H](C)C(=O)O[C@H]1C[C@@H](C)C=C2C=C[C@H](C)[C@H](CC[C@@H](O)C[C@@H](O)CC(=O)NCCOC)[C@H]21
Temperature: 50 °C
Reaction time: 4 h

Procedure:
Lovastatin (50 gm) is mixed with tetrahydrofuran (100 ml) and methoxy ethylamine (140 ml) to obtain a clear solution, the solution is heated to 50° C. and stirred for 4 hours at the same temperature. Then the solvent is distilled off at reduced pressure not allowing the temperature to raise above 50° C., tetrahydrofuran (200 ml) is added to the residue thus obtained, stirred for 30 minutes and distilled off the solvent to give 58 gm of N-methoxyethyl-7-[1,2,6,7,8,8a(R)-hexahydro-2(S),6(R)-dimethyl-8(S)-[[2(S)-methylbutanoyl]oxy]-1(S)-naphthyl]-3(R),5(R)-dihydroxyheptanamide as residue (HPLC Purity 97.3%).
Reaction SMILES: [OH:1][C@H:2]([CH3:6])[C:3]([NH2:5])=O.F[B-](F)(F)F.C([O+](CC)CC)C.N[C:20]1[C:21]([NH:29][C@H:30]2[CH2:35][CH2:34][C@H:33]([CH2:36][C:37]#[N:38])[CH2:32][CH2:31]2)=[C:22]2[S:28][CH:27]=[CH:26][C:23]2=[N:24][CH:25]=1>O1CCCC1.C(O)C>[OH:1][C@@H:2]([C:3]1[N:29]([C@H:30]2[CH2:31][CH2:32][C@H:33]([CH2:36][C:37]#[N:38])[CH2:34][CH2:35]2)[C:21]2=[C:22]3[S:28][CH:27]=[CH:26][C:23]3=[N:24][CH:25]=[C:20]2[N:5]=1)[CH3:6]
Reactant: C[C@@H](O)C(N)=O
Reactant: N#CC[C@H]1CC[C@H](Nc2c(N)cnc3ccsc23)CC1
Agent: CC[O+](CC)CC
Agent: F[B-](F)(F)F
Solvent: C1CCOC1
Solvent: CCO
Product: C[C@@H](O)c1nc2cnc3ccsc3c2n1[C@H]1CC[C@H](CC#N)CC1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of (2R)-2-hydroxypropanamide (0.630 g, 7.07 mmol) and triethyloxonium tetrafluoroborate (1.26 g, 6.66 mmol) in tetrahydrofuran (9.7 mL) was stirred at room temperature for 2 h. The solvent was removed, and the residue dissolved in ethanol (4.1 mL) and added to a suspension of {trans-4-[(6-aminothieno[3,2-b]pyridin-7-yl)amino]cyclohexyl}acetonitrile (0.63 g, 2.2 mmol) in ethanol (15 mL). The reaction was stirred at 80° C. for 2 h. The solvent was removed and the residue was partitioned between EtOAc and sat. NaHCO3 solution. The organic phase was washed with brine, dried over MgSO4, and concentrated. The residue was purified on silica gel (eluting with 0 to 10% MeOH in dichloromethane), then further purified on RP-HPLC (XBridge C18 column, eluting with a gradient of acetonitrile/water containing 0.1% ammonium hydroxide, at flow rate of 30 mL/min) to give the desired product (0.55 g, 73%). LCMS calculated for C18H21N4OS (M+H)+: m/z=341.1. Found: 341.1.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]([OH:8])=O.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:43]=[C:44]([NH2:57])[C:45]4[C:49]([CH:50]=3)=[N:48][N:47](C3CCCCO3)[CH:46]=4)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1.CCN(C(C)C)C(C)C.N>CN(C=O)C.CO>[NH:33]1[C:41]2[C:36](=[C:37]([C:42]3[CH:50]=[C:49]4[C:45]([CH:46]=[N:47][NH:48]4)=[C:44]([NH:57][C:6]([C:2]4[NH:1][CH:5]=[CH:4][N:3]=4)=[O:8])[CH:43]=3)[CH:38]=[CH:39][CH:40]=2)[CH:35]=[CH:34]1
Reactant: Nc1cc(-c2cccc3[nH]ccc23)cc2nn(C3CCCCO3)cc12
Reactant: O=C(O)c1ncc[nH]1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: N
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: O=C(Nc1cc(-c2cccc3[nH]ccc23)cc2[nH]ncc12)c1ncc[nH]1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
1H-Imidazole-2-carboxylic acid (17 mg) (available from Maybridge), HATU (63 mg) and 6-(1H-indol-4-yl)-2-(tetrahydro-2H-pyran-2-yl)-2H-indazol-4-amine (50 mg) were dissolved in anhydrous DMF (3 ml) and then treated with DIPEA (0.052 ml) and stirred at RT for 15 h. The mixture was treated with methanol (3 ml) and then macroporous-tosic acid resin (170 mg; 4.4 mmol/g) then stirred for 15 h. The mixture was then treated with 0.88 ammonia solution (0.600 ml), stirred for 10 min, then filtered and solvent blown off under a stream of nitrogen. The crude residue was purified by mass directed preparative HPLC (Method A) to give the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[NH:16][NH:17]C(OC(C)(C)C)=O.[F:25][C:26]([F:39])([F:38])[C:27]1[CH:37]=[CH:36][C:30]([C:31]([N:33]=[C:34]=[O:35])=O)=[CH:29][CH:28]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][NH:9][C:10](=[O:15])[C:11]([CH3:14])([CH3:13])[CH3:12])=[CH:4][C:3]=1[N:16]1[C:34](=[O:35])[NH:33][C:31]([C:30]2[CH:36]=[CH:37][C:27]([C:26]([F:39])([F:38])[F:25])=[CH:28][CH:29]=2)=[N:17]1
Reactant: O=C=NC(=O)c1ccc(C(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NNc1cc(CNC(=O)C(C)(C)C)ccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)C(=O)NCc1ccc(Cl)c(-n2nc(-c3ccc(C(F)(F)F)cc3)[nH]c2=O)c1
Yield: 36.8 %

Procedure:
The title compound was prepared according to the procedure described in Example-83 by using tert-butyl 2-(2-chloro-5-{[(2,2-dimethylpropanoyl)amino]methyl}phenyl)hydrazinecarboxylate (Intermediate-94, 0.150 g, 0.420 mmol), 4-(trifluoromethyl)benzoyl isocyanate (Intermediate-59, 0.181 g, 0.84 mmol), DCM (15 mL), and trifluoro acetic acid (3.0 mL) to afford 0.070 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 1.13 (s; 9H), 4.29 (d, J=5.4 Hz, 2H), 7.36 (d, J=8.7 Hz, 1H), 7.45 (s, 1H), 7.62 (d, J=8.4 Hz, 1H), 7.92 (d, J=8.4 Hz, 2H), 8.06 (d, J=8.4 Hz, 2H), 8.19 (m, 1H), 12.79 (s, 1H); MS (m/z): 456.59 (M+H)+.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([NH:14][C:15](=[O:19])OCC)=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2.[F:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]2[CH2:32][CH2:31][NH:30][CH2:29][CH2:28]2)=[CH:23][CH:22]=1>>[CH3:1][O:2][C:3]1[C:4]([NH:14][C:15]([N:30]2[CH2:29][CH2:28][N:27]([C:24]3[CH:23]=[CH:22][C:21]([F:20])=[CH:26][CH:25]=3)[CH2:32][CH2:31]2)=[O:19])=[N:5][C:6]2[C:11]([N:12]=1)=[CH:10][C:9]([CH3:13])=[CH:8][CH:7]=2
Reactant: CCOC(=O)Nc1nc2ccc(C)cc2nc1OC
Reactant: Fc1ccc(N2CCNCC2)cc1
Product: COc1nc2cc(C)ccc2nc1NC(=O)N1CCN(c2ccc(F)cc2)CC1
Yield: 90 %

Procedure:
Ethyl N-(3-methoxy-6-methylquinoxalin-2-yl)carbamate and 1-(4-fluorophenyl)piperazine were reacted by the same way with the example 127 to obtain the titled compound (yield, 90%). 1H NMR (300 MHz, CDCl3): δ 2.47 (s, 3H), 3.07-3.17 (m, 4H), 3.77-3.87 (m, 4H), 4.13 (s, 3H), 6.87-8.01 (m, 8H).
Reaction SMILES: [Br:1]P(Br)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:22][O:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[O:30][CH:29]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1)[C:28]([CH2:40]O)=[CH:27]2.CCOCC.CCCCCC>C(#N)C>[Br:1][CH2:40][C:28]1[CH:29]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:30][C:31]2[C:26]([CH:27]=1)=[CH:25][C:24]([O:23][CH3:22])=[CH:33][CH:32]=2
Reactant: BrP(Br)(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1ccc2c(c1)C=C(CO)C(c1ccccc1)O2
Solvent: CC#N
Solvent: CCOCC
Solvent: CCCCCC
Product: COc1ccc2c(c1)C=C(CBr)C(c1ccccc1)O2
Reaction time: 0.25 h

Procedure:
4.79 g (8.95 mmol) of dibromotriphenylphosphorane are added to a solution of 2.4 g (8.95 mmol) of the alcohol obtained in Step A in 80 ml of acetonitrile. After 15 minutes of stirring under argon, the solvent is evaporated in vacuo; the residue obtained is then taken up in an ether/hexane mixture (1/1). The solid formed is filtered off; the filtrate is then concentrated under reduced pressure to yield the brominated compound of the title in the form of a chestnut-brown syrup.
Reaction SMILES: [F:1][C:2]1[CH:9]=[C:8](F)[C:7]([F:11])=[CH:6][C:3]=1[C:4]#[N:5].[NH3:12]>O1CCCC1>[C:4]([C:3]1[C:2]([F:1])=[CH:9][C:8]([NH2:12])=[C:7]([F:11])[CH:6]=1)#[N:5]
Reactant: N#Cc1cc(F)c(F)cc1F
Reactant: N
Solvent: C1CCOC1
Product: N#Cc1cc(F)c(N)cc1F
Temperature: 100 °C
Reaction time: 8 h
Yield: 95.4 %

Procedure:
515 g of 2,4,5-trifluorobenzonitrile in 2000 ml of tetrahydrofuran are introduced into an autoclave and heated to 100° C. 250 ml of liquid ammonia are then pumped in at such a rate that the temperature remains in the range from 100 to 105° C. The mixture is then stirred at this temperature for 8 h and then cooled. The pressure reaches a maximum of 22 bar gauge. After the ammonia has been blown off, the solvent is removed using a rotary evaporator. The residue is stirred into 500 ml of water and placed on a suction filter. After filtering with suction, the residue is again slurried with 200 ml of water and filtered with suction. Drying in a vacuum at 40° C. gives 482 g (95.4% of theory) of 4-cyano-2,5-difluoroaniline having a melting point of from 99 to 100° C.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:35])[CH:4]=[CH:5][C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH3:32])[C:11]([CH2:13][NH:14]C(OCC3C4C(=CC=CC=4)C4C3=CC=CC=4)=O)=[N:12][C:8]=2[CH:7]=1.N1CCCCC1>ClCCl>[CH3:1][O:2][C:3](=[O:35])[CH:4]=[CH:5][C:6]1[CH:34]=[CH:33][C:9]2[N:10]([CH3:32])[C:11]([CH2:13][NH2:14])=[N:12][C:8]=2[CH:7]=1
Reactant: COC(=O)C=Cc1ccc2c(c1)nc(CNC(=O)OCC1c3ccccc3-c3ccccc31)n2C
Solvent: ClCCl
Solvent: C1CCNCC1
Product: COC(=O)C=Cc1ccc2c(c1)nc(CN)n2C

Procedure:
3-[2-(N-Fmoc-aminomethyl)-1-methyl-1H-benzimidazol-5-yl]-acrylic acid methyl ester (43 mg, 0.176 mmol, prepared according to Example 42, step 1-3 by using appropriate starting materials) was dissolved in 10 mL of dichloromethane. The resulting solution was treated with 2.0 mL of piperidine. Removed all the solvent and piperidine under vacuum gave 3-(2-aminomethyl-1-methyl-1H-benzimidazol-5-yl)-acrylic acid methyl ester. MS(m/z): 246 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[CH:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])[CH2:7][CH2:6]2.[H-].[Na+].[CH3:22]I>CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[C:9](=[O:13])[C:8]([CH2:14][C:15]([O:17][CH2:18][CH3:19])=[O:16])([CH3:22])[CH2:7][CH2:6]2
Reactant: CCOC(=O)CC1CCc2cc(OC)ccc2C1=O
Reactant: CI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)CC1(C)CCc2cc(OC)ccc2C1=O
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 95.2 %

Procedure:
A solution of 1C (30 g, 114 mmol) in DMF (100 mL) was added over a period of 30 min to an ice cold solution of NaH (11.44 g, 286 mmol) in DMF (100 mL), and the mixture was stirred for 10 min. Methyl iodide (21.36 mL, 343 mmol) was then added, and the mixture was stirred for 6 h at room temperature. The reaction was then brought to 0° C., excess NaH was quenched with ice water, and the aqueous layer was extracted with ethyl acetate (2×200 mL). The combined organic layers were dried over sodium sulfate and filtered, and the filtrate was concentrated under vacuum to give the title compound (30 g, 81%) as a solid. 1H NMR (400 MHz, DMSO-d6): δ 7.96 (d, J=8.4 Hz, 2H), 6.72 (dd, J1=2.4 Hz, J2=8.4 Hz, 1H), 6.62 (s, 1H), 4.09 (q, J=7.2 Hz, 2H), 3.08-2.80 (m, 3H), 2.46 (d, J=15.6 Hz, 1H), 2.39 (dd, J1=4.4 Hz, J2=12.0 Hz, 1H), 1.90 (dt, J1=14 Hz, J2=4.4 Hz, 1H), 1.26 (s, 3H), 1.21 (t, J=7.2 Hz, 1H). ESI-MS m/z: 277 (M+H)+.
Reaction SMILES: [CH3:1][O-:2].[Na+].[F:4][C:5]1[C:10](F)=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]>CO>[F:4][C:5]1[C:10]([O:2][CH3:1])=[C:9]([CH:12]=[O:13])[CH:8]=[CH:7][C:6]=1[C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21]
Reactant: O=Cc1ccc(-c2ccc(F)cc2F)c(F)c1F
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: COc1c(C=O)ccc(-c2ccc(F)cc2F)c1F
Yield: 99.1 %

Procedure:
Sodium methoxide (28% methanol solution, 5.64 g) was added at room temperature to a methanol (120 mL) solution of 2,2′,3,4′-tetrafluorobiphenyl-4-carbaldehyde (4.95 g), and the mixture was heated to reflux for 16 hours in a nitrogen atmosphere. Then, the solvent was distilled off under reduced pressure. The residue was diluted with ethyl acetate and water, followed by extraction with ethyl acetate. The organic layer was separated, washed with water and saturated saline in this order, and dried over anhydrous magnesium sulfate, and then, the solvent was distilled off under reduced pressure to obtain the title compound (5.14 g).
Reaction SMILES: [CH:1]([C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1)=[O:2].[CH2:11](O)[CH2:12][OH:13].C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C1(C)C=CC(S(O)(=O)=O)=CC=1>[O:2]1[CH2:11][CH2:12][O:13][CH:1]1[C:3]1[CH:10]=[CH:9][C:6]([C:7]#[N:8])=[CH:5][CH:4]=1
Reactant: N#Cc1ccc(C=O)cc1
Reactant: OCCO
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: N#Cc1ccc(C2OCCO2)cc1
Yield: 89.1 %

Procedure:
A solution of 4-formylbenzonitrile (10 g, 76.3 mmol), ethylene glycol (18.95 g, 305 mmol) and p-toluene sulfonic acid (7 mg, 0.003 mmol) in toluene (100 mL) was heated to reflux for 9 hours. During this time a Dean-Stark trap was used to remove water formed during the reaction. To the reaction was added aq. Na2CO3 (150 mL). The organic layer was washed twice with water (100 mL), then dried over Na2SO4. The solvent was removed under vacuum to provide 4-(1,3-dioxolan-2-yl)benzonitrile (12 g, 68 mmol). The compound had an HPLC retention time=4.24 min. −Column: HYPERSIL® BDS C18 (4.6×50 mm) Flow rate=0.8 mL/min. Solvent A=, 0.1% TFA in water; Solvent B=acetonitrile. 5%-100% B (0-6 min), 100% B (6-9 min), 100%-5% B (9-11 min).
Reaction SMILES: [CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[O:8][C:4]=2[N:5]=[CH:6][N:7]=1.[C:12]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[S:22]([N:25]=[C:26]=[O:27])(=[O:24])=[O:23])([O:14][CH3:15])=[O:13].C(#[N:30])C>>[CH3:1][C:2]1[C:3]2[CH:10]=[C:9]([CH3:11])[O:8][C:4]=2[N:5]=[C:6]([NH:30][C:26]([NH:25][S:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=2[C:12]([O:14][CH3:15])=[O:13])(=[O:23])=[O:24])=[O:27])[N:7]=1
Reactant: COC(=O)c1ccccc1S(=O)(=O)N=C=O
Reactant: CC#N
Reactant: Cc1cc2c(C)ncnc2o1
Product: COC(=O)c1ccccc1S(=O)(=O)NC(=O)Nc1nc(C)c2cc(C)oc2n1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a dry stirred solution of 0.5 g of 4,6-dimethylfuro[2,3-d]pyrimidin in 10 ml of acetonitrile at ambient temperature and pressure was added 1.6 g of 2-carbomethoxybenzenesulfonyl isocyanate. The resulting mixture was warmed on the steam bath for several minutes then stirred at ambient temperature for 4 hours. The suspended solid was collected by filtration and rinsed with acetonitrile to yield 0.87 g of methyl 2-{[(4,6-dimethylfuro[2,3-d]pyrimidin-2-yl)aminocarbonyl]aminosulfonyl}benzoate, m.p. 197°-198°. The product showed characteristic absorption bands at 1690 and 1735 cm-1 in the infrared spectrum and at 2.45, 2.75, 3.95, 6.6, 7.7, 8.3, 10.4 and 13.0 ppm in the nuclear magnetic resonance (60 MHz) spectrum indicating the title compound.
Reaction SMILES: [F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[C:20]2([CH:25]=[O:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1.O=[O+][O-].[BH4-].[Na+].CCOC(C)=O>C(Cl)Cl.CO>[F:1][C:2]1[C:3]([C:10]2[CH:19]=[CH:18][C:13]([C:14]([O:16][CH3:17])=[O:15])=[CH:12][C:11]=2[C:20]2([CH2:25][OH:26])[CH2:24][CH2:23][CH2:22][CH2:21]2)=[CH:4][C:5]([O:8][CH3:9])=[N:6][CH:7]=1
Reactant: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(C=O)CCCC2)c1
Agent: O=[O+][O-]
Agent: [BH4-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)c1ccc(-c2cc(OC)ncc2F)c(C2(CO)CCCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The mixture of methyl 4-(5-fluoro-2-methoxypyridin-4-yl)-3-(1-formylcyclopentyl)benzoate (0.13 g, 0.36 mmol) in DCM (6.0 mL) and MeOH (1.5 mL) was reacted with ozone gas at −78° C. for 10 minutes. The excess ozone was removed by flushing with nitrogen, and dimethylsulfide (0.3 mL) was added. The resulting reaction mixture was stirred at room temperature for 30 minutes. Sodium borohydride (0.13 mL, 3.6 mmol) was added to the reaction mixture, and the reaction was stirred at room temperature overnight. EtOAc (50 mL) was added, and the organic layer was washed with brine (20×2 mL) and dried over Na2SO4. After filtration, the solvent was removed. The product thus obtained was used in the next step without further purification. MS ESI (pos.) m/e: 360.2 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13](Br)[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:7]2)[N:6]=1.[C:25]([C:27]1[CH:28]=[C:29](B(O)O)[CH:30]=[CH:31][CH:32]=1)#[N:26].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[NH2:1][C:2]1[N:3]([CH3:24])[C:4](=[O:23])[C:5]2([C:15]3[C:10](=[CH:11][CH:12]=[C:13]([C:31]4[CH:32]=[C:27]([CH:28]=[CH:29][CH:30]=4)[C:25]#[N:26])[CH:14]=3)[O:9][CH:8]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[CH2:7]2)[N:6]=1
Reactant: CN1C(=O)C2(CC(C3CCCCC3)Oc3ccc(Br)cc32)N=C1N
Reactant: N#Cc1cccc(B(O)O)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: CN1C(=O)C2(CC(C3CCCCC3)Oc3ccc(-c4cccc(C#N)c4)cc32)N=C1N
Temperature: 120 °C
Yield: 54.9 %

Procedure:
A mixture of 2′-amino-6-bromo-2-cyclohexy-1′-methylspiro[chroman-4,4′-imidazol]-5′(1′H)-one (30 mg, 0.08 mmol), 3-cyanophenylboronic acid (23 mg, 0.15 mmol), Pd(PPh3)2Cl2 (20 mg), aqueous cesium carbonate solution (2 M, 0.5 mL) in dry 1,4-dioxane (1 mL) was heated at 120° C. under microwave for 35 minutes. The reaction mixture was concentrated to give the residue, which was purified by preparative TLC and preparative HPLC to give 3-(2′-amino-2-cyclohexy-1′-methyl-5′-oxo-1′,5′-dihydrospiro[chroman-4,4′-imidazole]-6-yl)benzonitrile (18.2 mg, 56%). 1H-NMR (MeOD): 1.22-1.39 (m, 4H), 1.69-1.86 (m, 4H), 2.01 (s, 1H), 2.13-2.24 (m, 1H), 2.28-2.46 (m, 1H), 3.12 (s, 1H), 3.27-3.36 (m, 3H), 4.63 (m, 1H), 7.06 (m, 1H), 7.49 (s, 1H), 7.57-7.76 (m, 3H), 7.86 (t, 1H), 7.94 (d, 1H).
Reaction SMILES: [CH3:1][C@:2]12[C:9]([CH3:11])([CH3:10])[CH:6]([CH2:7][CH2:8]1)[C:5](=[O:12])[CH2:4][C:3]2=[O:13].C(N(CC)CC)C.[F:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]=[C:29]=[O:30])=[CH:24][C:23]=1[C:31]([F:34])([F:33])[F:32].Cl>CN(C)C1C=CN=CC=1.ClCCl>[F:33][C:31]([F:32])([F:34])[C:23]1[CH:24]=[C:25]([NH:28][C:29]([CH:4]2[C:5](=[O:12])[CH:6]3[C:9]([CH3:10])([CH3:11])[C@@:2]([CH3:1])([CH2:8][CH2:7]3)[C:3]2=[O:13])=[O:30])[CH:26]=[CH:27][C:22]=1[F:21]
Reactant: CC1(C)C2CC[C@@]1(C)C(=O)CC2=O
Reactant: O=C=Nc1ccc(F)c(C(F)(F)F)c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC1(C)C2CC[C@@]1(C)C(=O)C(C(=O)Nc1ccc(F)c(C(F)(F)F)c1)C2=O
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To an ice-cooled solution of (1R)-1,8,8-trimethylbicyclo[3.2.1]octane-2,4-dione (0.18 g, 1.0 mmole), triethylamine (0.10 g, 1.0 mmole) and 4-(dimethylamino)pyridine (0.12 g, 1.0 mmole) in dry dichloromethane (25 mL) was added a solution of 4-fluoro-3-(trifluoromethyl)phenyl isocyanate (0.21 g, 1.0 mmole) in dry dichloromethane (5 mL). The resulting reaction mixture was allowed to stir overnight under a nitrogen atmosphere, during which time it came up to room temperature. It was then stirred at 30° C. for twenty-four hours. The resulting mixture was treated with 2N aqueous HCl (30 mL) and the layers were separated. The aqueous layer was extracted with two additional portions of dichloromethane (50 mL). The combined organic layers were dried over anhydrous sodium sulfate and concentrated on a rotary evaporator. The desired product was isolated by chromatography on silica gel (10% ethyl acetate/hexane) and recrystallized from 95% ethanol to yield the title compound as a beige solid (0.18 g, 48% yield), mp=96–98° C.; MS (−) ESI m/z=384 (M−H)−; [α]D25=+22.1° (c=1, EtOH).
Reaction SMILES: [N+:1](C1C=CC(N)=CC=1)([O-:3])=[O:2].[N:11]([O-:13])=[O:12].[Na+].[C:15]1([P:21](C2C=CC=CC=2)C2C=CC=CC=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>Cl.O.C([O-])(=O)C.[Na+].C(OCC)(=O)C>[N+:1]([O-:3])([O-:12])=[O:2].[N+:11]([C:18]1[CH:19]=[CH:20][C:15]([PH3+:21])=[CH:16][CH:17]=1)([O-:13])=[O:12]
Reactant: O=N[O-]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])[O-]
Product: O=[N+]([O-])c1ccc([PH3+])cc1
Reaction time: 1 h

Procedure:
Non-radioactive standards and compounds used for radiolabeling were prepared by the method of Horner [Chem. Ber. 1958, 91, 45] and Rieke [J. Am. Chem. Soc. 1976, 98, 6872]. 4-Nitroaniline (2.8 g, 0.02 mol) and the molar equivalent of sodium nitrite were dissolved in 10 ml of concentrated HCl acid 10 ml of water at 0° C. Water (20 ml), in which was dissolved sodium acetate (5.6 g), was added. Triphenylphosphine (5.6 g) dissolved in ethyl acetate (80 ml) was added dropwise with stirring. After one hour, the resulting solution was acidified, the water layer separated from the ethyl acetate, and the aqueous portion extracted twice with ether. The ethyl acetate solution was extracted twice with water, the extracts were combined with the other aqueous fraction. Addition of an aqueous solution of sodium iodide precipitated the phosphonium iodide, mp 225-227° C. (Lit. 228.5° C.; Chem. Ber. 1958, 91, 45). 4-Nitrophenylphosphonium iodide was dissolved in 5 mL of ethanol treated with an aqueous solution of AgNO3. The silver iodide was removed by filtration and the solution was evaporated to dryness. Chromatography of the crude salt on silica gel (methylene chloride/methanol (90:10)) afforded pure 4-nitrophenylphosphonium nitrate; mp 215-127° C. Anal. calcd for C24H19N2O5P: C, 64.57. H, 4.29. Found: C, 64.49; H, 4.14.
Reaction SMILES: [CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13](Cl)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3]1.[S:16]1[CH:20]=[CH:19][N:18]=[C:17]1[NH2:21].O>C1COCC1.C(Cl)(Cl)Cl>[CH3:1][N:2]1[C:11](=[O:12])[C:10]2[C:5](=[CH:6][C:7]([C:13]([NH:21][C:17]3[S:16][CH:20]=[CH:19][N:18]=3)=[O:14])=[CH:8][CH:9]=2)[N:4]=[CH:3]1
Reactant: Nc1nccs1
Reactant: Cn1cnc2cc(C(=O)Cl)ccc2c1=O
Solvent: O
Solvent: C1CCOC1
Solvent: ClC(Cl)Cl
Product: Cn1cnc2cc(C(=O)Nc3nccs3)ccc2c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-methyl-4-oxo-3,4-dihydroquinazoline-7-carbonyl chloride prepared as described in Example 22.1a was dissolved in anhydrous THF and added to a solution of thiazol-2-amine (81 mg, 0.81 mmol) in CHCl3 (10 mL). The reaction was stirred at room temperature for 30 min and then poured into water. The mixture was extracted with ethyl acetate, and the organic layer was washed with brine, dried over anhydrous sodium sulfate. After filtration and concentration, the crude product was purified by silica gel chromatography purification to provide the desired product. MS (ESI): 287 (MH+); 1H NMR (300 MHz, DMSO-d6) δ 12.95 (s, 1H), 8.46 (s, 1H), 8.38-8.37 (d, J=1.44 Hz, 1H), 8.29-8.26 (m, 1H), 8.15-8.12 (dd, J=8.36, 1.60 Hz, 1H), 7.60-7.59 (d, J=3.57 Hz, 1H), 7.33-7.32 (d, J=3.45 Hz, 1H), 3.53 (s, 3H).
Reaction SMILES: [C:1]([NH:6][C:7]1[C:8]([CH3:13])=[CH:9][CH:10]=[CH:11][CH:12]=1)(=[O:5])[CH2:2][CH2:3][CH3:4].[Br:14]Br.O>C(O)(=O)C>[Br:14][C:10]1[CH:11]=[CH:12][C:7]([NH:6][C:1](=[O:5])[CH2:2][CH2:3][CH3:4])=[C:8]([CH3:13])[CH:9]=1
Reactant: CCCC(=O)Nc1ccccc1C
Reactant: BrBr
Solvent: CC(=O)O
Solvent: O
Product: CCCC(=O)Nc1ccc(Br)cc1C
Reaction time: 1 h
Yield: 98 %

Procedure:
30 g of N-butyryl-o-toluidine and 150 g of glacial acetic acid were initially charged at 30° C. A solution of 33 g of bromine in 66 g of glacial acetic acid was added with stirring and then stirring was continued at from 25 to 30° C. for 1 hour. 300 ml of water were then added to the reaction mixture which, after continued stirring for a short time, was filtered, the crystals were washed with water and dried under reduced pressure. 42.5 g (98% yield) of N-(4-bromo-2-methylphenyl)butanamide were obtained in 99.4% purity.