Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[NH:12][CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1.[CH:20]1([CH2:23]Cl)[CH2:22][CH2:21]1>>[CH:1]1([CH2:4][N:5]2[C:14](=[O:15])[C:13]3[N:12]([CH2:23][CH:20]4[CH2:22][CH2:21]4)[CH:11]=[N:10][C:9]=3[N:8]([CH2:16][CH:17]3[CH2:19][CH2:18]3)[C:6]2=[O:7])[CH2:3][CH2:2]1
Reactant: O=c1c2[nH]cnc2n(CC2CC2)c(=O)n1CC1CC1
Reactant: ClCC1CC1
Product: O=c1c2c(ncn2CC2CC2)n(CC2CC2)c(=O)n1CC1CC1

Procedure:
1,3-Tri-cyclopropylmethyl-xanthine was prepared from 1,3-di-cyclopropylmethyl xanthine and cyclopropylchloromethane using an analogous procedure to that described in Example 5. The title compound was isolated as a crystalline solid, m.p. 78° C.
Reaction SMILES: [C:1]([O:5][C:6]([C:8](=[C:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[CH2:9][C:10]([O:12]C)=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].Cl>O1CCCC1.O>[C:1]([O:5][C:6]([C:8](=[C:14]([OH:54])[C:15](=[O:53])[N:16]([C@H:26]([CH3:52])[C@@H:27]([C:43]1[CH:48]=[CH:47][C:46]2[O:49][CH2:50][O:51][C:45]=2[CH:44]=1)[CH2:28][C:29]1[O:30][C:31]([C:34](=[O:42])[NH:35][C:36]2[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=2)=[CH:32][CH:33]=1)[CH2:17]/[CH:18]=[CH:19]/[C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[CH2:9][C:10]([OH:12])=[O:11])=[O:7])([CH3:3])([CH3:2])[CH3:4]
Reactant: COC(=O)CC(C(=O)OC(C)(C)C)=C(O)C(=O)N(C/C=C/c1ccccc1)[C@H](C)[C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: C[C@H]([C@H](Cc1ccc(C(=O)Nc2ccccc2)o1)c1ccc2c(c1)OCO2)N(C/C=C/c1ccccc1)C(=O)C(O)=C(CC(=O)O)C(=O)OC(C)(C)C
Yield: 76.2 %

Procedure:
285 mg of methyl 3-(tert-butoxycarbonyl)-4-hydroxy-4-[N-[(1R,2R)-1-methyl-2-(3,4-methylenedioxyphenyl)-3-{5-(phenylcarbamoyl)-2-furyl}propyl]-N-{(E)-3-phenyl-2-propenyl}carbamoyl]-3-butenoate was dissolved in a mixture of 15 ml of tetrahydrofuran and 10 ml of water and stirred together with 4 ml of 1N aqueous sodium hydroxide at room temperature for 2.5 days. The reaction solution was acidified with 1N hydrochloric acid and then extracted with ethyl acetate. The organic layer was dried over anhydrous magnesium sulfate, the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography [chloroform/methanol=100/1→10/1] to give 213 mg (yield: 76%) of the title compound as a colorless foamy substance.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17]OS(C4C=CC(C)=CC=4)(=O)=O)[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1.[CH3:35][NH2:36]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:16]3[O:15][CH:14]([CH2:17][NH:36][CH3:35])[CH2:13][C:12]=3[CH:11]=[C:10]([C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:9]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: CN
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(-c4ccccc4)cc(-c4cccc(Cl)c4)c3O2)cc1
Product: CNCC1Cc2cc(-c3ccccc3)cc(-c3cccc(Cl)c3)c2O1

Procedure:
The title compound was prepared (0.055 g, 69%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-{[7-(3-chlorophenyl)-5-phenyl-2,3-dihydro-1-benzofuran-2-yl]methyl}4-methylbenzenesulfonate (0.10 g, 0.20 mmol) and methylamine (0.30 g, 9.8 mmol). mp 211-214° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:18]([O:20][CH2:21][CH2:22][N:23]1[C:27]2[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=2[N:25]=[C:24]1[N:32]1[CH2:38][CH2:37][CH2:36][N:35]([CH2:39][CH2:40][C:41]2([C:46]3[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=3)[CH2:45][CH2:44][NH:43][CH2:42]2)[CH2:34][CH2:33]1)[CH3:19]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([NH:12][S:13]([CH3:16])(=[O:15])=[O:14])=[CH:8][C:4]=1[C:5]([N:43]1[CH2:44][CH2:45][C:41]([CH2:40][CH2:39][N:35]2[CH2:36][CH2:37][CH2:38][N:32]([C:24]3[N:23]([CH2:22][CH2:21][O:20][CH2:18][CH3:19])[C:27]4[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=4[N:25]=3)[CH2:33][CH2:34]2)([C:46]2[CH:51]=[CH:50][CH:49]=[CH:48][CH:47]=2)[CH2:42]1)=[O:7]
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Reactant: COc1ccc(NS(C)(=O)=O)cc1C(=O)O
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(NS(C)(=O)=O)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-methylsulfonamidobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl[C:10]1[C:11]2[C:23]([Cl:24])=[C:22]([CH3:25])[S:21][C:12]=2[N:13]=[C:14]([C:16]2[O:20][N:19]=[CH:18][CH:17]=2)[N:15]=1>>[O:20]1[C:16]([C:14]2[N:15]=[C:10]([NH:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[C:11]3[C:23]([Cl:24])=[C:22]([CH3:25])[S:21][C:12]=3[N:13]=2)=[CH:17][CH:18]=[N:19]1
Reactant: NCc1ccccc1
Reactant: Cc1sc2nc(-c3ccno3)nc(Cl)c2c1Cl
Product: Cc1sc2nc(-c3ccno3)nc(NCc3ccccc3)c2c1Cl

Procedure:
With the procedure of Example 1, the reaction of benzylamine with 4-chloro-2-(isoxazol-5-yl)-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine yields 2-(isoxazol-5-yl)-4-benzylamino-5-chloro-6-methyl-thieno-[2,3-d]-pyrimidine.
Reaction SMILES: [Br:1]N1C(=O)CCC1=O.[CH3:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15])=[CH:12][CH:11]=1.C(O)(C)(C)C.C(OOC(=O)C1C=CC=CC=1)(=O)C1C=CC=CC=1>C(Cl)(Cl)(Cl)Cl>[Br:1][CH2:9][C:10]1[CH:22]=[CH:21][C:13]([C:14]([O:16][C:17]([CH3:19])([CH3:18])[CH3:20])=[O:15])=[CH:12][CH:11]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cc1ccc(C(=O)OC(C)(C)C)cc1
Agent: O=C(OOC(=O)c1ccccc1)c1ccccc1
Solvent: ClC(Cl)(Cl)Cl
Solvent: CC(C)(C)O
Product: CC(C)(C)OC(=O)c1ccc(CBr)cc1
Temperature: 25 °C
Yield: 40 %

Procedure:
N-Bromosuccinimide (NBS) (35.8 g, 0.20 mol) was added in several portions to a solution of 1,1-dimethylethyl 4-methylbenzoate (prepared by the reaction of the respective acid chloride with t-butanol.) (38.0 g, 0.20 mol) and benzoyl peroxide (0.36 g, 1.5 mmol) in carbon tetrachloride (1200 mL) at vigorous reflux. Another portion of benzoyl peroxide (0.36 g, 1.5 mmol) was added just before the final addition of NBS. After the foaming subsided, the reaction mixture was cooled to room temperature, washed with water (2×60 mL) and dried over magnesium sulfate. Filtration and concentration provided an oil that was purified by HPLC on silica gel eluting with a mixture of hexanes and ethyl acetate to give 1,1-dimethylethyl 4-bromomethylbenzoate (21.4 g) in 40% yield.
Reaction SMILES: [CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](OC(C)(C)C)=[O:41])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2].FC(F)(F)S(O[Si](C)(C)C)(=O)=O.C(N(CC)C(C)C)(C)C.[CH2:73]([O:75][C@H:76]([CH2:82][CH2:83][CH:84]=[CH2:85])[C@@H:77](C)[C:78](O)=O)[CH3:74].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>ClCCl>[CH:1]([C:3]1[CH:4]=[C:5]([CH:49]=[CH:50][CH:51]=1)[CH2:6][O:7][C:8]([C@@H:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16](=[O:48])[C@@H:17]([NH:33][C:34](=[O:47])[C@@H:35]([NH:39][C:40](=[O:41])[C@H:77]([CH3:78])[C@H:76]([O:75][CH2:73][CH3:74])[CH2:82][CH2:83][CH:84]=[CH2:85])[CH:36]([CH3:38])[CH3:37])[CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[C:21]([O:25][Si:26]([C:29]([CH3:32])([CH3:30])[CH3:31])([CH3:28])[CH3:27])[CH:20]=2)[NH:11]1)=[O:9])=[CH2:2]
Reactant: C=CCC[C@@H](OCC)[C@@H](C)C(=O)O
Reactant: C=Cc1cccc(COC(=O)[C@@H]2CCCN(C(=O)[C@H](Cc3cccc(O[Si](C)(C)C(C)(C)C)c3)NC(=O)[C@@H](NC(=O)OC(C)(C)C)C(C)C)N2)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: C=CCC[C@@H](OCC)[C@@H](C)C(=O)N[C@H](C(=O)N[C@@H](Cc1cccc(O[Si](C)(C)C(C)(C)C)c1)C(=O)N1CCC[C@@H](C(=O)OCc2cccc(C=C)c2)N1)C(C)C
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 60.2 %

Procedure:
A solution of (S)-1-{(S)-2-((S)-2-tert-butoxycarbonylamino-3-methyl-butyrylamino)-3-[3-(tert-butyl-dimethyl-silanyloxy)-phenyl]-propionyl}-hexahydro-pyridazine-3-carboxylic acid 3-vinyl-benzyl ester (300 mg, 0.42 mmol) in anhydrous dichloromethane (9 mL) was treated with trimethylsilyl trifluoromethanesulfonate (114 μL, 0.63 mmol). The reaction mixture was stirred at room temperature for 1.5 hours then N,N-diisopropylethylamine (293 μL, 1.68 mmol) was added. The reaction mixture was evaporated to give the crude amine as a colourless solid. A solution of (2R,3R)-3-ethoxy-2-methyl-hept-6-enoic acid (78 mg, 0.42 mmol) in anhydrous dichloromethane (8 mL) was cooled to 0° C. before adding N,N-diisopropylethylamine (293 μL, 1.68 mmol) and 2-(7-aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (160 mg, 0.42 mmol). The mixture was stirred at 0° C. for 20 minutes before adding a solution of the crude amine in dichloromethane (8 mL). The reaction mixture was allowed to warm to room temperature and was stirred under a nitrogen atmosphere for 16 hours. The reaction mixture was evaporated and purified by silica gel chromatography using iso-hexanes/ethyl acetate 1:1 to yield the title compound (200 mg, 60%) as a colourless solid. 1H NMR (300 MHz, CDCl3) δ0.17 (s, 6H), 0.88-0.99 (m, 6H), 0.97 (s, 9H), 1.08-1.30 (m, 8H), 1.34-1.60 (m, 3H), 1.61-1.87 (m, 4H), 2.09-2.26 (m, 3H), 2.38-2.55 (m, 2H), 3.39-3.72 (m, 4H), 4.24-4.36 (m, 2H), 4.91-5.19 (m, 4H), 5.30 (d, J=10.9 Hz, 1H), 5.70-5.90 (m, 3H), 6.53-6.84 (m, 6H), 6.97-7.50 (m, 1H), 7.21-7.44 (m, 4H). LCMS (m/z) 791.4 [M+H] Tr=6.01 min.
Reaction SMILES: Br[C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1.CN([CH:14]=[O:15])C.O>C1COCC1.C([Li])CCC>[CH:14]([C:2]1[N:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:5]2=[N:4][CH:3]=1)=[O:15]
Reactant: Brc1cnc2n1CCCC2
Reactant: CN(C)C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Product: O=Cc1cnc2n1CCCC2
Temperature: -78 °C
Reaction time: 1 h

Procedure:
To a solution of 3-bromo-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (2.84 g) in THF (50 ml), n-butyllithium (1.6M hexane solution, 28 ml) was added dropwise at −78° C. The mixture was stirred for 1 hour at −78° C., DMF (5 ml) was added to the mixture, and the mixture was stirred for 0.5 hour at room temperature. To the reaction solution was added water, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The obtained residue was separated and purified by column chromatography (ethyl acetate:hexane 1:1→ethyl acetate), to give 3-formyl-5,6,7,8-tetrahydroimidazo[1,2-a]pyridine (1.48 g) as colorless oil.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:34][CH3:35])[CH2:9][C:10]2[N:11](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:12]=[CH:13][N:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.[OH-].[Na+]>C(O)C.O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([O:34][CH3:35])[CH2:9][C:10]2[NH:14][CH:13]=[CH:12][N:11]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: COC(Cc1nccn1C(c1ccccc1)(c1ccccc1)c1ccccc1)c1cccc(Cl)c1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: COC(Cc1ncc[nH]1)c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 3 h
Yield: 0.1 %

Procedure:
To a stirred suspension of 2-[2-(3-chloro-phenyl)-2-methoxy-ethyl]-1-trityl-1H-imidazole (0.24 g) at room temperature in ethanol (2 ml) under an argon atmosphere was added 2 N HCl (3 ml). The mixture was heated to reflux. Stirring was continued for 3 hours. The mixture was cooled to room temperature and concentrated to leave a light yellow solid. This was taken up in H2O and brought to pH=12 by the addition of 4 N NaOH. The product was extracted with CH2Cl2/methanol 4:1. The combined organics were dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient:CH2Cl2→CH2Cl2/methanol 9:1) to give 2-[2-(3-chloro-phenyl)-2-methoxy-ethyl]-1H-imidazole (0.11 mg) as light yellow gum. MS 237.1 ([M+H]+)
Reaction SMILES: [OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3](OC)=[O:4].[CH3:25][NH2:26]>>[OH:1][CH:2]([CH:7]([N:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[CH:18]=[CH:17]1)[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][CH:9]=1)[C:3]([NH:26][CH3:25])=[O:4]
Reactant: COC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Reactant: CN
Product: CNC(=O)C(O)C(c1ccc(OC)cc1)n1ccc2ccccc21
Yield: 80 %

Procedure:
A solution of methyl (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)propanoate (2.43 g, 7.5 mmol) in methylamine solution (33% wt. in absolute ethanol, 40 mL) was heated to 75° C. in a sealed tube for 1 hour . The cooled reaction mixture was then concentrated under reduced pressure to afford a yellow syrup. Purification by crystallization from 80% chloroform/hexane (50 mL) afforded 1.93 g (80%) of (2SR,3SR)-2-hydroxy-3-(1H-indol-1-yl)-3-(4-methoxyphenyl)-N-methylpropanamide as a white crystalline solid. MS (ES) m/z 323.2 ([M−H]−); HRMS: calcd for C19H20N2O3+H+, 325.15467; found (ESI, [M+H]+), 325.1562.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:10]=[N:11][CH:12]=1)(C)C.CO.C(=O)([O-])[O-].[K+].[K+]>O>[C:6]([C:7]1[CH:8]=[C:9]([NH:13][C:14](=[O:20])[O:15][C:16]([CH3:18])([CH3:17])[CH3:19])[CH:10]=[N:11][CH:12]=1)#[CH:5]
Reactant: CC(C)(C)OC(=O)Nc1cncc(C#C[Si](C)(C)C)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: C#Cc1cncc(NC(=O)OC(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 66.4 %

Procedure:
Into a reaction flask were added tert-butyl {5-[(trimethylsilyl)ethynyl]pyridin-3-yl}carbamate (2.0 g, 6.9 mmol), methanol (25 mL), and a solution of potassium carbonate (7.1 g, 52 mmol) in water (25 mL). The reaction mixture was stirred at rt overnight. The solvent was removed under vacuum and the residue was diluted with EtOAc and water. After separation, the organic layer was dried over Na2SO4 and concentrated under vacuum. The crude product was purified by silica gel column chromatography to give the desired product as a white powder (1.0 g, 67%). LCMS for C12H15N2O2 (M+H)+: m/z=219.0.
Reaction SMILES: C(O[C:4](=[C:6]([C:9]#[N:10])[C:7]#[N:8])[CH3:5])C.[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([NH:19][NH2:20])=[CH:15][CH:14]=1.NN.Cl>CCO>[NH2:10][C:9]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)[N:20]=[C:4]([CH3:5])[C:6]=1[C:7]#[N:8]
Reactant: COc1ccc(NN)cc1
Reactant: CCOC(C)=C(C#N)C#N
Agent: Cl
Agent: NN
Solvent: CCO
Product: COc1ccc(-n2nc(C)c(C#N)c2N)cc1
Temperature: 105 °C
Yield: 90.8 %

Procedure:
To a stirred solution of 2-(1-ethoxyethylidene)malononitrile (1.00 g, 6.66 mmol) in EtOH (8 mL) was added (4-methoxyphenyl)hydrazine (1.29 g, 9.32 mmol). (Prior to use the hydrazine its HCl salt was washed with NaHCO3/CH2Cl2. The organic phase was concentrated and used directly.) The solution was heated to 105° C. in the microwave for 20 min. CH2Cl2 was added and the organic phase was washed with 1M HCl and the organic extract was washed with aqueous NaHCO3. The solution was dried using a phase separator and concentrated under reduced pressure to give 5-amino-1-(4-methoxyphenyl)-3-methyl-1H-pyrazole-4-carbonitrile (1.38 g, 85%) which was used as such in the next step. The procedure was adapted from J. Med. Chem. 2004, 47, 5894-5911.
Reaction SMILES: [F:1][CH2:2][C:3]([C:7]1[O:11][N:10]=[C:9]([NH2:12])[CH:8]=1)([CH3:6])[CH2:4][F:5].Cl[C:14]([O:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:15].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:5][CH2:4][C:3]([C:7]1[O:11][N:10]=[C:9]([NH:12][C:14](=[O:15])[O:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[CH:8]=1)([CH3:6])[CH2:2][F:1]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: CC(CF)(CF)c1cc(N)no1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CC(CF)(CF)c1cc(NC(=O)Oc2ccccc2)no1
Yield: 75.5 %

Procedure:
Using the procedure described in Example 161C, using 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-amine (0.287 g, 1.6 mmol), phenyl chloroformate (0.313 g, 2 mmol) were reacted in the presence of K2CO3 (0.345 g, 2.5 mmol) in THF (15 mL), and purified by silica gel chromatography (using 5-25% EtOAc/hexane as eluants) to afford phenyl 5-(1,3-difluoro-2-methylpropan-2-yl)isoxazol-3-ylcarbamate as a solid (0.358 g, 76%). 1H NMR (300 MHz, CDCl3) δ 8.17 (br, 1H), 7.42 (m, 2H), 7.26 (m, 1H), 7.20 (m, 2H), 6.81 (s, 1H), 4.67 (q, 2H), 4.51 (q, 2H), 1.42 (s, 3H); LC-MS (ESI) m/z 297 (M+H)+.
Reaction SMILES: [CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20]O)[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].C(Br)(Br)(Br)[Br:24].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>C(Cl)Cl>[CH2:1]([N:7]1[C:16]2[C:11](=[CH:12][C:13]([CH3:17])=[CH:14][CH:15]=2)[C:10]([O:18][CH3:19])=[C:9]([CH2:20][Br:24])[C:8]1=[O:22])[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCn1c(=O)c(CO)c(OC)c2cc(C)ccc21
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CCCCCCn1c(=O)c(CBr)c(OC)c2cc(C)ccc21
Reaction time: 0.08 h

Procedure:
A solution of 1 -hexyl-3-hydroxymethyl-4-methoxy-6-methyl-2(1H)-quinolinone (Example 12, 0.6 g) in methylene chloride (12 ml) containing carbon tetrabromide (1 g) was treated with triphenylphosphine (0.87 g) and stirred at ice bath temperature for 5mins and then at room temperature for hr. The reaction mixture was then evaporated under reduced pressure and the crude product was chromatographed on silica-gel (25 g). Elution with ether-hexane gave 1-hexyl-3-bromomethyl-4-methoxy-6-methyl-2(1H)-quinolinone as a white crystralline solid. That the expected product was obtained was confirmed by the spectral data: MS: m/e 365,367 (M+); NMR (CDCl3): δ4.12 (s, 3H, OCH3) 4.68 (s, 2H, CH2Br).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[C:10]([NH2:12])[C:9]([N+:13]([O-:15])=[O:14])=[CH:8][C:4]=1[C:5]([OH:7])=O.C(N(CC)CC)C.ClC(OCC)=O.[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH2:42])[CH2:38][CH2:37]1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>CN(C)C=O>[CH2:29]([N:36]1[CH2:41][CH2:40][CH:39]([NH:42][C:5](=[O:7])[C:4]2[CH:8]=[C:9]([N+:13]([O-:15])=[O:14])[C:10]([NH2:12])=[CH:11][C:3]=2[O:2][CH3:1])[CH2:38][CH2:37]1)[C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1
Reactant: NC1CCN(Cc2ccccc2)CC1
Reactant: COc1cc(N)c([N+](=O)[O-])cc1C(=O)O
Agent: CCOC(=O)Cl
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: COc1cc(N)c([N+](=O)[O-])cc1C(=O)NC1CCN(Cc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 80.6 %

Procedure:
To a solution of 2-methoxy-4-amino-5-nitrobenzoic acid (6.4 g; 0.03 moles) in N,N-dimethylformamide (175 ml) a solution of triethylamine (3 g; 0.03 moles) in N,N-dimethylformamide (5 ml) was added. The mixture was cooled to -5° to -10° C. and a solution of ethyl chloroformate (3.3 g; 0.03 moles) in N,N-dimethylformamide (5 ml) was added. The reaction mixture was stirred at the same temperature for 0.5 hours and then a solution of 1-benzyl-4-aminopiperidine (5.7 g; 0.03 moles) in N,N-dimethylformamide (15 ml) was added. After stirring for 1 hour at -5° to -10° C., the temperature was allowed to reach room temperature overnight. The solvent was removed in vacuo and the residue was poured into an aqueous sodium bicarbonate solution. The resulting solid was exhaustively extracted with methylene chloride, the organic layers washed with an aqueous sodium bicarbonate solution and then with water, dried (Na2SO4 ) and the solvent removed in vacuo. N-(1-Benzylpiperid-4-yl)-2-methoxy-4-amino-5-nitrobenzamide (9.3 g) was obtained and converted into its hydrochloride by treatment with a saturated solution of ethanolic hydrogen chloride; the hydrochloride melted at 218°-220° C. (dec).
Reaction SMILES: Br[C:2]1[CH:7]=[N:6][C:5]([I:8])=[CH:4][N:3]=1.[N:9]1([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13][NH:12][CH2:11][CH2:10]1.CCN(C(C)C)C(C)C>CC(O)(C)C>[I:8][C:5]1[N:6]=[CH:7][C:2]([N:12]2[CH2:11][CH2:10][N:9]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:14][CH2:13]2)=[N:3][CH:4]=1
Reactant: Brc1cnc(I)cn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CCN(c2cnc(I)cn2)CC1
Temperature: 100 °C
Reaction time: 66 h

Procedure:
2-bromo-5-iodopyrazine (503 mg, 1.77 mmol) and tert-butyl piperazine-1-carboxylate (355 mg, 1.91 mmol) were taken up in tBuOH (8 mL). iPr2NEt (400 μL, 2.3 mmol) was added and the stirred reaction mixture was heated to 100° C. After 66 h, the reaction mixture was cooled and was partitioned between EtOAc, water and brine. The phases were separated, and the organic phase was dried over Na2SO4, filtered, and concentrated. The crude residue was purified by silica gel chromatography (10-30% EtOAc in hexanes) to afford tert-butyl 4-(5-iodopyrazin-2-yl)piperazine-1-carboxylate 7.11.
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:13][NH:12][CH2:11][CH2:10][NH:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH:14]1([C:19]2[S:28][C:27]3[NH:26][C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[NH:23][C:22](=S)[C:21]=3[N:20]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1>N1C=CC=CC=1>[CH:14]1([C:19]2[S:28][C:27]3[NH:26][C:25]4[CH:29]=[CH:30][CH:31]=[CH:32][C:24]=4[N:23]=[C:22]([N:12]4[CH2:11][CH2:10][NH:9][C@@H:8]([CH2:1][C:2]5[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=5)[CH2:13]4)[C:21]=3[N:20]=2)[CH2:15][CH2:16][CH2:17][CH2:18]1
Reactant: S=C1Nc2ccccc2Nc2sc(C3CCCC3)nc21
Reactant: c1ccc(C[C@H]2CNCCN2)cc1
Solvent: c1ccncc1
Product: c1ccc(C[C@H]2CN(C3=Nc4ccccc4Nc4sc(C5CCCC5)nc43)CCN2)cc1

Procedure:
Using a method similar to the method of Example 491, using (S)-2-benzyl-piperazine (1.23 g, 7.0 mmol), 2-cyclopentyl-4,9-dihydro-3-thia-1,4,9-triaza-benzo{f}azulene-10-thione (0.602 g, 2.0 mmol) in 8 ml of pyridine Obtain 240 mg light brown foam of title compound. Mass spectrum (electrospray) (m/e): C26H29N5S, Cacl. Mass: 443.36; Found: 444.1 (M+1); 1H NMR (400 MHz, CDCl3) δ ppm: 7.32–7.21 (m, 5H), 7.03–6.97 (m, 2H), 6.86 (dt, 1H, J=7.8 Hz, J=1.9 Hz), 6.61 (d, 1H, J=7.8 Hz), 5.00 (br, 1H), 3.21–2.90 (m, 4H), 2.78–2.72 (m, 1H), 2.62–2.56 (m, 1H), 2.03–1.95 (m, 2H), 1.77–1.62 (m, 10H).