Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([CH:32]=4)[C:29](O)=[O:30])=[CH:17][C:11]=3[C:12]=2[C:13](=[O:16])[NH:14][CH3:15])=[CH:4][CH:3]=1.Cl.[N:36]1[CH:41]=[CH:40][CH:39]=[N:38][C:37]=1[C:42]1([NH2:46])[CH2:45][O:44][CH2:43]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]3[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[C:18]([C:24]4[CH:25]=[CH:26][C:27]([O:33][CH3:34])=[C:28]([C:29](=[O:30])[NH:46][C:42]5([C:37]6[N:36]=[CH:41][CH:40]=[CH:39][N:38]=6)[CH2:45][O:44][CH2:43]5)[CH:32]=4)=[CH:17][C:11]=3[C:12]=2[C:13]([NH:14][CH3:15])=[O:16])=[CH:4][CH:3]=1
Reactant: NC1(c2ncccn2)COC1
Reactant: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)O)c3)cc12
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Solvent: O
Product: CNC(=O)c1c(-c2ccc(F)cc2)oc2cc([N+](=O)[O-])c(-c3ccc(OC)c(C(=O)NC4(c5ncccn5)COC4)c3)cc12
Temperature: 0 °C
Reaction time: 8 h

Procedure:
To a mixture of 5-(2-(4-fluorophenyl)-3-(methylcarbamoyl)-6-nitrobenzofuran-5-yl)-2-methoxy-benzoic acid (150 mg, 0.323 mmol) and 3-(pyrimidin-2-yl)oxetan-3-amine hydrochloride (77 mg, 0.42 mmol) in DMF at room temperature under a nitrogen atmosphere (7.5 mL) was added triethylamine (0.225 mL, 1.615 mmol). The mixture was cooled to 0° C. and then added with BOP (214 mg, 0.484 mmol) at the same temperature. The reaction mixture was warmed to rt and stirred at rt overnight. The reaction mixture was then diluted with water and stirred for 5 min. The solid obtained was filtered and dried under suction. Yield: 0.180 g (93%).
Reaction SMILES: [CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[NH:20][C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Na+].I[CH2:32][CH:33]([CH3:35])[CH3:34]>CN(C=O)C.O.C(OCC)(=O)C>[CH2:1]([N:8]([CH3:28])[C:9]([CH:11]1[CH2:16][CH2:15][N:14]([C:17]([C:19]2[N:20]([CH2:32][CH:33]([CH3:35])[CH3:34])[C:21]3[C:26]([CH:27]=2)=[CH:25][CH:24]=[CH:23][CH:22]=3)=[O:18])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(Cc1ccccc1)C(=O)C1CCN(C(=O)c2cc3ccccc3[nH]2)CC1
Reactant: CC(C)CI
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CC(C)Cn1c(C(=O)N2CCC(C(=O)N(C)Cc3ccccc3)CC2)cc2ccccc21
Temperature: 80 °C
Reaction time: 0.17 h

Procedure:
N-benzyl-1-(1H-indole-2-carbonyl)-N-methylpiperidine-4-carboxamide (100 mg, 0.266 mmol) was dissolved in 1.0 mL of DMF and added to a suspension of sodium hydride (12.78 mg, 0.320 mmol) in 2.0 mL of DMF. The reaction was stirred at 80° C. for 10 minutes before adding 1-iodo-2-methylpropane (0.061 mL, 0.533 mmol). The reaction was allowed to stir overnight. After 18 hours, the reaction was cooled to room temperature before diluting with water and ethyl acetate. The organic phase was washed with water followed by saturated sodium chloride, dried over magnesium sulfate, filtered and concentrated. The crude material was purified via column chromatography using 50% ethyl acetate/hexanes to 100% ethyl acetate. The purification provided product as a white solid. (Yield: 28 mg, white solid) 1H-NMR (400 MHz, DMSO-d6) 7.64-7.51, 7.43-7.16, 7.11-7.03, 6.71-6.61, 4.67, 4.51, 4.19-4.07, 3.13-2.91, 2.79, 2.06-1.93, 1.88-1.50, 0.84-0.73
Reaction SMILES: [CH2:1]1[CH:9]2[N:4]([CH2:5][CH2:6][C:7]3[NH:12][C:11]4[N:13]=[CH:14][CH:15]=[CH:16][C:10]=4[C:8]=32)[CH2:3][CH2:2]1.[H-].[Na+].Cl[CH2:20][C:21]([N:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1)=[O:22]>CN(C=O)C>[N:23]1([C:21](=[O:22])[CH2:20][N:12]2[C:7]3[CH2:6][CH2:5][N:4]4[CH:9]([C:8]=3[C:10]3[CH:16]=[CH:15][CH:14]=[N:13][C:11]2=3)[CH2:1][CH2:2][CH2:3]4)[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1
Reactant: O=C(CCl)N1CCCCC1
Reactant: c1cnc2[nH]c3c(c2c1)C1CCCN1CC3
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Cn1c2c(c3cccnc31)C1CCCN1CC2)N1CCCCC1
Temperature: 25 °C
Reaction time: 0.08 h

Procedure:
To a solution of 2,3,5,6,7,11c-hexahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizine (120 mg, 0.565 mmol) in DMF (1 mL) was added a suspension of NaH (68.0 mg, 1.69 mmol) in DMF (1 mL). After stirring for 5 min at RT, a solution of 2-chloro-1-(piperidin-1-yl)ethanone (272 mg, 1.69 mmol) in DMF (1 mL) was added dropwise into the reaction mixture and stirring continued for another 3 h. The progress of reaction was monitored by TLC and NMR. The reaction mixture was diluted with ice-water (20 mL) and extracted with EtOAc (3×25 mL). The organic layer was washed with water (3×20 mL), dried over anhydrous sodium sulfate and concentrated under reduced pressure to afford crude material, which was purified by silica gel flash chromatography (10% MeOH-DCM) to yield 1-(piperidin-1-yl)-2-(2,3,5,6-tetrahydro-1H-pyrido[3′,2′:4,5]pyrrolo[2,3-g]indolizin-7(11cH)-yl)ethanone;
Reaction SMILES: Cl[CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1.[O:23]=[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][C:32]([OH:34])=[O:33].N12CCCN=C1CCCCC2.O>CN(C)C=O>[O:23]=[C:24]1[CH2:29][CH2:28][CH2:27][CH2:26][N:25]1[CH2:30][CH2:31][C:32]([O:34][CH:2]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4](=[O:11])[N:3]1[C:12]1[CH:21]=[CH:20][C:19]2[C:14](=[N:15][C:16]([Cl:22])=[CH:17][CH:18]=2)[N:13]=1)=[O:33]
Reactant: O=C(O)CCN1CCCCC1=O
Reactant: O=C1c2ccccc2C(Cl)N1c1ccc2ccc(Cl)nc2n1
Solvent: C1CCC2=NCCCN2CC1
Solvent: O
Solvent: CN(C)C=O
Product: O=C(CCN1CCCCC1=O)OC1c2ccccc2C(=O)N1c1ccc2ccc(Cl)nc2n1
Yield: 46.9 %

Procedure:
The procedure is as in Example 1, but starting with 3-chloro-2-(7-chloro-1,8-naphthyridin-2-yl)-1-isoindolinone (4,3 g) in anhydrous dimethylformamide (40 cc), 3-(2-oxopiperidino)propionic acid (2.2 g) and 1,8-diazabicyclo [5.4.0]undec-7-ene (2 g). After the reaction mixture has been taken up with water, the resulting mixture extracted with methylene chloride and the solvent evaporated, the residue obtained is recrystallized in acetonitrile. The product thereby obtained is purified by chromatography on silica (0.063-0.2 mm; 100 g) contained in a column 2.3 cm in diameter (eluant: methylene chloride), collecting 50-cc fractions. Fractions 56 to 64 are combined and concentrated to dryness under reduced pressure (2.7 kPa) at 20° C. The residue obtained is recrystallized in acetonitrile. 2-(7-Chloro-1,8-naphthridin-2-yl)-3-oxo-1-isoindolinyl 3-(2-oxopiperidino)propionate (2.8 g), m.p. 175° C., is thereby obtained.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1.N1C=CC=CC=1.[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37](Cl)(=[O:39])=[O:38]>C(Cl)Cl>[F:30][C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[S:37]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([C:13]([NH:15][C@H:16]([CH:21]([CH3:23])[CH3:22])[C:17]([O:19][CH3:20])=[O:18])=[O:14])[O:10][N:9]=2)=[CH:4][CH:3]=1)(=[O:39])=[O:38]
Reactant: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(N)cc2)no1)C(C)C
Reactant: O=S(=O)(Cl)c1ccccc1F
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)[C@H](NC(=O)c1cc(-c2ccc(NS(=O)(=O)c3ccccc3F)cc2)no1)C(C)C
Reaction time: 0.17 h
Yield: 54.9 %

Procedure:
To a solution of 500 mg (1.57 mmol) of (R)-methyl 2-(3-(4-aminophenyl)isoxazole-5-carboxamido)-3-methylbutanoate (example 151, step 3) in DCM, 1.2 eq of pyridine was added and stirred for 10 minutes, then 368 mg (1.89 mmol) 2-fluorobenzene-1-sulfonyl chloride was added and the reaction mixture was stirred for 3 hours. DCM was removed under vacuum, the reaction mixture was washed with 1NHCl and extracted with EtOAc. The organic layer was concentrated and purified by precipitation using DCM and petroleum ether to yield 410 mg (86%) of title compound. MS (ESI): m/z 476(M+H)+; 1HNMR (DMSO-d6, 300 MHz): δ 11.039 (s, 1H), 9.215 (d, 1H), 7.942 (m, 1H), 7.805 (d, 2H), 7.718 (m, 1H), 7.625 (s, 1H), 7.465 (m, 2H), 7.271(d, 2H), 4.314 (t, 1H), 3.690 (s, 3H), 2.228 (m, 1H), 0.971 (d, 6H).
Reaction SMILES: [Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C@H:18]([OH:23])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1.Cl(O)(=O)(=O)=O.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OC(C)(C)C)(=O)C>[Br:1][C:2]1[CH:25]=[C:5]2[N:6]=[C:7]([CH3:24])[C:8]([C@H:18]([O:23][C:8]([CH3:18])([CH3:9])[CH3:7])[C:19]([O:21][CH3:22])=[O:20])=[C:9]([N:10]3[CH2:15][CH2:14][C:13]([CH3:17])([CH3:16])[CH2:12][CH2:11]3)[N:4]2[N:3]=1
Reactant: COC(=O)[C@@H](O)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Agent: O=C([O-])O
Agent: [Na+]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: ClCCl
Solvent: CC(=O)OC(C)(C)C
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)nc2cc(Br)nn2c1N1CCC(C)(C)CC1
Reaction time: 3 h
Yield: 86.8 %

Procedure:
To a solution of (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-hydroxyacetate (5.68 g, 13.81 mmol, 1 equiv) in DCM (92 mL) and t-butyl acetate (184 mL) was added 70% perchloric acid (3.3 mL, 55.2 mmol, 4 equiv). The reaction turned pale yellow. After 3 h, the reaction was added very cautiously to a saturated aqueous solution of NaHCO3 and extracted with CHCl3 (×3). Combined organic extracts dried over Na2SO4 and concentrated in vacuo. The crude product was purified by silica gel flash chromatography (0-70% EtOAc/hexane) to provide (S)-methyl 2-(2-bromo-7-(4,4-dimethylpiperidin-1-yl)-5-methylpyrazolo[1,5-a]pyrimidin-6-yl)-2-(tert-butoxy)acetate as a pale yellow solid (2.8 g, 43%) and recovered starting material (3.0 g, 53%). 1H NMR (400 MHz, CDCl3) δ 6.54 (s, 1H), 5.92 (s, 1H), 3.74 (s, 3H), 2.59 (s, 3H), 1.58 (s, 8H), 1.24 (s, 9H), 1.11 (s, 6H); LCMS (ESI, M+1):467.3.
Reaction SMILES: [C:1]([C@H:4]([CH2:31][CH2:32][O:33][CH3:34])[CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:15][C:16]([O:18]CC)=[O:17])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2].[OH-].[Na+]>O1CCOCC1>[C:1]([C@H:4]([CH2:31][CH2:32][O:33][CH3:34])[CH2:5][C:6]1([C:11]([NH:13][C@@H:14]([CH2:21][CH2:22][O:23][C:24]2[CH:29]=[CH:28][C:27]([Cl:30])=[CH:26][CH:25]=2)[CH2:15][C:16]([OH:18])=[O:17])=[O:12])[CH2:10][CH2:9][CH2:8][CH2:7]1)([OH:3])=[O:2]
Reactant: CCOC(=O)C[C@H](CCOc1ccc(Cl)cc1)NC(=O)C1(C[C@@H](CCOC)C(=O)O)CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COCC[C@H](CC1(C(=O)N[C@@H](CCOc2ccc(Cl)cc2)CC(=O)O)CCCC1)C(=O)O

Procedure:
A solution of the ethyl ester from example 47 (100 mg, 0.20 mmol) and 2N sodium hydroxide solution (2 ml) in dioxan (4 ml) was stirred at 50° C. for 3 hours, then concentrated under reduced pressure. The residue was suspended in 2N hydrochloric acid (2 ml), extracted with ethyl acetate (3×20 ml), and the combined organic solutions dried (MgSO4) and evaporated under reduced pressure. The crude product was purified by column chromatography on silica gel using an elution gradient of ethyl acetate:methanol:acetic acid (90:10:0 to 90:10:1) to afford the title compound as a colourless oil, 50 mg; 1H NMR (CDCl3, 400 MHz) δ: 1.45–1.78 (m, 8H), 1.85–2.19 (m, 6H), 2.56 (m, 1H), 2.62 (m, 2H), 3.37 (m, 4H), 3.46 (m, 1H), 4.00 (t, 2H), 4.62 (m, 1H), 6.64 (d, 1H), 6.81 (d, 2H), 7.22 (d, 2H); LRMS: m/z (ES−) 468 [M-H]−.
Reaction SMILES: ClC(Cl)(O[C:5](=[O:11])OC(Cl)(Cl)Cl)Cl.[C:13]1([CH:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:20][NH2:21])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>C(Cl)Cl>[C:22]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][N:21]=[C:5]=[O:11])[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: NCC(c1ccccc1)c1ccccc1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C=NCC(c1ccccc1)c1ccccc1
Reaction time: 0.5 h

Procedure:
A suspension of triphosgene (0.78 g, 2.6 mmol) in 15 ml of CH2Cl2 was treated in small portions with 2,2-diphenylethylamine (1.54 g, 7.8 mmol) at 0° C., under N2. The reaction mixture was stirred for 30 minutes and filtered. The filtrate was then concentrated in vacuo to provide a yellow oil.
Reaction SMILES: C([O:5][C:6](=[O:24])[CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])[NH:8][C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])CCC.CO.C(=O)(O)[O-].[Na+]>O>[C:12]([O:11][C:9]([NH:8][CH:7]([C:16]1[CH:21]=[CH:20][C:19]([OH:22])=[CH:18][C:17]=1[OH:23])[C:6]([OH:24])=[O:5])=[O:10])([CH3:15])([CH3:13])[CH3:14]
Reactant: CCCCOC(=O)C(NC(=O)OC(C)(C)C)c1ccc(O)cc1O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: O
Product: CC(C)(C)OC(=O)NC(C(=O)O)c1ccc(O)cc1O

Procedure:
To a boiling solution of 23 g. (0.067 mol.) of N-t-butoxycarbonyl-2-(2,4-dihydroxyphenyl)glycine n-butyl ester in 300 ml. of methanol was slowly added a solution of 23 g. of sodium bicarbonate in 300 ml. of water. During addition, the reaction mixture was kept under a nitrogen atmosphere and the methanol was allowed to distill from the mixture. When all the methanol had been distilled the mixture was cooled, adjusted to pH 7.0 with phosphoric acid and extracted with ethyl acetate. The aqueous phase was acidified to pH 4.0 and again extracted with ethyl acetate. The extract was dried (Na2SO4) and concentrated in vacuo to give the title compound.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7](Cl)[CH:6]=1)=[O:4].[F-:16].[K+]>CS(C)(=O)=O.ClCCl.O>[CH3:1][O:2][C:3]([C:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[N:8]=[C:7]([F:16])[CH:6]=1)=[O:4]
Reactant: COC(=O)c1cc(Cl)nc2ccccc12
Reactant: [F-]
Agent: CS(C)(=O)=O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: COC(=O)c1cc(F)nc2ccccc12
Temperature: 180 °C
Yield: 66.3 %

Procedure:
2-Chloroquinoline-4-carboxylic acid methyl ester (1.14 g) in dimethylsulfone (4.0 g) was treated with potassium fluoride (2.5 g) and heated at 180° C. for 1 h. The reaction mixture was cooled to room temperature, diluted with dichloromethane:water (1:1, 200 ml), the organic phase separated, solvent removed at reduced pressure and the residue column chromatographed (silica gel, dichloromethane eluant) to give 2-fluoroquinoline-4-carboxylic acid methyl ester (0.7 g). 1H NMR (CDCl3) δ: 3.99 (3H, s), 7.57 (2H, m), 7.72 (1H, m), 7.95 (1H, d, J=8.5 Hz), 8.67 (1H, d, J=8.4 Hz). m/z (API+): 205 (MH+).
Reaction SMILES: [C:1]([NH:9][NH:10][C:11]([CH3:14])([CH3:13])[CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:15]1([S:21](Cl)(=[O:23])=[O:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>N1C=CC=CC=1.C(OCC)C>[C:11]([N:10]([S:21]([C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)(=[O:23])=[O:22])[NH:9][C:1](=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)([CH3:14])([CH3:13])[CH3:12]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)NNC(=O)c1ccccc1
Solvent: c1ccncc1
Solvent: CCOCC
Product: CC(C)(C)N(NC(=O)c1ccccc1)S(=O)(=O)c1ccccc1
Reaction time: 1 h

Procedure:
N-benzoyl-N'-t-butyl hydrazine (0.8 g) was stirred in pyridine (2 ml) at room temperature. Benzenesulfonyl chloride (0.8 g) was added slowly dropwise, stirred about 1 hour, diluted with diethyl ether (10 ml) and washed several times with a 10% HCl solution and then water. The organic layer was dried over magnesium sulfate. The mixture was filtered and the solvent rotavapped off to afford a white solid in good yield.
Reaction SMILES: [C:1]1([C:7]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1>C(O)C.[Pd]>[C:18]1([CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:8][CH:9]2[C:14](=[O:15])[CH:13]3[CH2:16][CH2:17][N:10]2[CH2:11][CH2:12]3)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=C1C2CCN(CC2)C1C=C(c1ccccc1)c1ccccc1
Agent: [Pd]
Solvent: CCO
Product: O=C1C2CCN(CC2)C1CC(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
18.9 Parts of a mixture of the two isomers (cis and trans) of 2-(2,2-diphenylethylidenyl)-1-azabicyclo[2.2.2]-octan -3-one, and 2-(2,2-diphenylethenyl)-1-azabicyclo[2.2.2]-octan-3-one is dissolved in approximately 790 parts ethanol. Then, 4 parts of a 5% palladium-on-carbon catalyst is added and the mixture shaken in a Parr Shaker at room temperature and a pressure of 36-60 psi for 3 hours. The catalyst is removed by filtration and the solvents removed in vacuo. The residual white solid is dissolved in 560 parts of hot n-pentane. The solution is filtered and then concentrated on a steam bath to a volume of about 190 ml. Standing at room temperature affords a precipitate which is filtered, washed with n-pentane and dried in vacuo to provide a white solid. This solid is recrystallized from ethyl ether to afford 2-(2,2-diphenylethyl)-1-azabicyclo[2.2.2]octan-3-one. This compound begins to shrink at 103° C., clouds at 104°-105° C. and melts at about 107° C. and is represented by the following structural formula. ##STR9##
Reaction SMILES: [CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([C:16]([C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]5)=[O:17])[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2.[BH4-].[Na+]>CO.O1CCCC1>[CH3:1][C:2]12[CH2:33][CH:5]([C:6]3([CH3:32])[C:10]1([CH3:11])[C:9]1[CH:12]=[C:13]([CH:16]([OH:17])[C:18]4[CH:19]=[C:20]5[C:25](=[CH:26][CH:27]=4)[CH:24]=[C:23]([C:28]([O:30][CH3:31])=[O:29])[CH:22]=[CH:21]5)[CH:14]=[CH:15][C:8]=1[O:7]3)[CH2:4][CH2:3]2
Reactant: COC(=O)c1ccc2cc(C(=O)c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)ccc2c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CO
Product: COC(=O)c1ccc2cc(C(O)c3ccc4c(c3)C3(C)C5(C)CCC(C5)C3(C)O4)ccc2c1
Temperature: 25 °C
Reaction time: 5 h
Yield: 95.6 %

Procedure:
944 mg (2.14 mmol) of the ester obtained in Example 3, dissolved in 30 ml of a methanol/tetrahydrofuran (1/1) mixture, were treated with 81 mg of sodium borohydride. The reaction mixture was stirred for 5 hours at room temperature. Evaporation was carried out to dryness, the residue was taken up in ether and this phase was washed to neutral pH. After drying and evaporating, 905 mg (96%) of the expected compound, melting at 140°-141° C., were isolated.
Reaction SMILES: [C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([OH:23])=O)[C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N1CCOCC1)C.O.OC1C2N=NNC=2C=CC=1.Cl.C(N=C=NCCCN(C)C)C.[CH2:59]([NH:63][NH2:64])[CH:60]([CH3:62])[CH3:61]>ClCCl>[C:1]([NH:9][CH2:10][CH2:11][C@@H:12]([C@@H:20]([CH2:24][CH:25]([CH3:27])[CH3:26])[C:21]([NH:64][NH:63][CH2:59][CH:60]([CH3:62])[CH3:61])=[O:23])[C:13]([O:15][C:16]([CH3:17])([CH3:19])[CH3:18])=[O:14])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)C[C@@H](C(=O)O)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Reactant: CC(C)CNN
Agent: CCN1CCOCC1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: CC(C)CNNC(=O)[C@H](CC(C)C)[C@H](CCNC(=O)c1ccccc1)C(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 82.5 %

Procedure:
A solution of 0.78 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-4-methylvaleric acid in 10 ml of dichloromethane was cooled to 0° C. under nitrogen and treated sequentially with 0.80 ml of N-ethylmorpholine, 0.437 g of hydroxybenzotriazole hydrate, and 0.50 g of 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride. The mixture was stirred for 5 minutes at 0° C. and then 1.1 g of isobutyl hydrazine was added. Stirring was continued overnight at room temperature and then the solvent was evaporated. The residue was dissolved in ethyl acetate and washed with 5% aqueous sodium hydrogen carbonate, water, 2M aqueous hydrogen chloride, and saturated aqueous sodium chloride. Drying over anhydrous magnesium sulfate, filtration and evaporation of the solvent gave 0.763 g of 2(R)-[3-benzamido-1(S)-(tert-butoxycarbonyl)propyl]-2′-isobutyl-4-methylvalerohydrazide in the form of an off-white foam.
Reaction SMILES: C(OC([NH:8][C@@H:9]([CH2:13][O:14][CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[CH:10]([CH3:12])[CH3:11])=O)(C)(C)C>C(O)=O>[CH2:15]([O:14][CH2:13][C@@H:9]([CH:10]([CH3:12])[CH3:11])[NH2:8])[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CC(C)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Solvent: O=CO
Product: CC(C)[C@@H](N)COCc1ccccc1

Procedure:
A solution of N-tert-butoxycarbonyl-O-benzyl-D-valinol (9.95 g, 34 mmol) in formic acid (50 mL) is stirred for 4 hours at room temperature. After removal of the formic acid under vacuum, the sticky residue is dissolved in water (100 mL), neutralized with a saturated solution of sodium bicarbonate (100 mL) and the organic material is extracted twice with ethyl acetate (2×200 mL). The organic phases are washed until neutral with water (2×200 mL) and the combined organic layers are dried over anhydrous sodium sulfate. Filtration and concentration under vacuum provides O-benzyl-D-valinol as a slightly yellowish oil (5.20 g, 79%).
Reaction SMILES: Br[C:2]1[S:6][C:5]2=[N:7][C:8]([C:10]3[CH:15]=[CH:14][C:13]([F:16])=[CH:12][CH:11]=3)=[CH:9][N:4]2[CH:3]=1.C([Li])CCC.[C:22](=[O:24])=[O:23]>C1COCC1.CCCCCC>[F:16][C:13]1[CH:14]=[CH:15][C:10]([C:8]2[N:7]=[C:5]3[N:4]([CH:9]=2)[CH:3]=[C:2]([C:22]([OH:24])=[O:23])[S:6]3)=[CH:11][CH:12]=1
Reactant: O=C=O
Reactant: Fc1ccc(-c2cn3cc(Br)sc3n2)cc1
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=C(O)c1cn2cc(-c3ccc(F)cc3)nc2s1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 10 %

Procedure:
To a solution of 2-bromo-6-(4-fluoro-phenyl)-imidazo[2,1-b]thiazole (example 22, 100 mg, 0.336 mmol) in 5 ml THF were added 200 μl butyllithium (2.5 M) in hexane at −60° C. The mixture was stirred for 10 min, solid carbon dioxide was added and the mixture was allowed to warm at RT. The solution was quenched with methanol and water, acidified and extracted with ethyl acetate. The organic layer was separated, washed with water, dried and evaporated. The crude product was purified by preparative HPLC (RP18, acetonitrile/water 0.1% TFA) to yield 9 mg (10%) of the desired product. MS: M+H+=263.03.
Reaction SMILES: [C:1]([C:4]1[NH:5][CH:6]=[NH+:7][C:8]=1[O-:9])(=[O:3])[NH2:2].[CH2:10]([O:17][C:18]1[CH:26]=[CH:25][C:21]([C:22](Cl)=[O:23])=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>>[CH2:10]([O:17][C:18]1[CH:19]=[CH:20][C:21]([C:22]([O:9][C:8]2[N:7]=[CH:6][NH:5][C:4]=2[C:1](=[O:3])[NH2:2])=[O:23])=[CH:25][CH:26]=1)[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: O=C(Cl)c1ccc(OCc2ccccc2)cc1
Reactant: NC(=O)c1[nH]c[nH+]c1[O-]
Product: NC(=O)c1[nH]cnc1OC(=O)c1ccc(OCc2ccccc2)cc1

Procedure:
Following a procedure similar to that of Example 1 but using 2.544 g of 4-carbamoylimidazolium-5-olate and 5.922 g of p-benzyloxybenzoyl chloride, there was obtained 5-carbamoyl-1H-imidazole-4-yl p-benzyloxybenzoate.
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][C:13]([NH:17][C:18]3[N:23]=[C:22]([Cl:24])[N:21]=[CH:20][N:19]=3)=[CH:14][CH:15]=2)[CH:10]=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25]I.[H-].[Na+]>CN(C=O)C>[CH3:25][N:17]([C:13]1[CH:12]=[C:11]2[C:16](=[CH:15][CH:14]=1)[N:8]([CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[N:9]=[CH:10]2)[C:18]1[N:23]=[C:22]([Cl:24])[N:21]=[CH:20][N:19]=1
Reactant: CI
Reactant: Clc1ncnc(Nc2ccc3c(cnn3Cc3ccccc3)c2)n1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CN(c1ccc2c(cnn2Cc2ccccc2)c1)c1ncnc(Cl)n1
Temperature: 0 °C
Reaction time: 4.25 h

Procedure:
To (1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine (473 mg, 1.40 mmol) in DMF (7.5 ml) at 0° C. was added MeI (0.262 mL, 4.21 mmol), followed by NaH (60% dispersion in oil)(67.4 mg, 1.69 mmol). The resulting mixture was stirred at 0° C. for 4.25 h. An additional 10 mg NaH was added after 3.1 h as TLC indicated remaining starting material. At this point, the reaction mixture was quenched with sat'd aq NH4Cl and diluted with water and EtOAc. The organic layer was washed with water and brine. The aqueous layer and washings were extracted once with EtOAc. The combined organics were dried, concentrated and purified by chromatography (SiO2, elution with 1:1 EtOAc-hexanes) to give N-methyl-(1-benzyl-1H-indazol-5-yl)-(4-chloro-[1,3,5]triazin-2-yl)amine as a pale oil: MS m/z=351 [M+H]+. Calc'd for C18H15ClN6: 350.10.