Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[O:2][C:3](=[O:37])[C@@H:4]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[N:22][C:21]=1[CH3:36])=[O:19])[CH2:5][NH:6][C:7](=[O:16])[C:8]1[CH:13]=[C:12]([F:14])[CH:11]=[C:10]([F:15])[CH:9]=1.O.[OH-].[Li+].Cl>C1COCC1.O>[F:15][C:10]1[CH:9]=[C:8]([CH:13]=[C:12]([F:14])[CH:11]=1)[C:7]([NH:6][CH2:5][C@H:4]([NH:17][C:18]([C:20]1[S:24][C:23]([NH:25][C:26](=[O:35])[CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[C:30]([OH:34])[CH:29]=2)=[N:22][C:21]=1[CH3:36])=[O:19])[C:3]([OH:37])=[O:2])=[O:16]
Reactant: COC(=O)[C@H](CNC(=O)c1cc(F)cc(F)c1)NC(=O)c1sc(NC(=O)Cc2cccc(O)c2)nc1C
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1nc(NC(=O)Cc2cccc(O)c2)sc1C(=O)N[C@@H](CNC(=O)c1cc(F)cc(F)c1)C(=O)O
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 59 %

Procedure:
To a mixture of (S)-3-(3,5-Difluoro-benzoylamino)-2-({2-[2-(3-hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid methyl ester (89.9 mg, 0.169 mmol) in THF (4 mL) and water (2 mL) was added lithium hydroxide monohydrate (80 mg, 1.91 mmol) The reaction was stirred at 25° C. for 1.5 h. The reaction mixture was acidified with concentrated HCl and concentrated under reduced pressure. The resulting crude compound was purified by HPLC to give (S)-3-(3,5-Difluoro-benzoylamino)-2-({2-[2-(3-hydroxy-phenyl)-acetylamino]-4-methyl-thiazole-5-carbonyl}-amino)-propionic acid (51.7 mg, 59%) as a white solid. MS m/e 519.5 (M+H+)
Reaction SMILES: [NH:1]([C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[C@H:2]([C:7]([OH:9])=O)[C@H:3]([CH2:5][CH3:6])[CH3:4].Cl.[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH2:47])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH2:21]([O:28][P:29]([CH2:38][C@H:39]([OH:49])[CH2:40][NH:41][C:42](=[O:48])[C@@H:43]([NH:47][C:7](=[O:9])[C@@H:2]([NH:1][C:10]([O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)=[O:11])[CH:3]([CH3:4])[CH2:5][CH3:6])[CH:44]([CH3:46])[CH3:45])([CH2:31][CH:32]1[CH2:37][CH2:36][CH2:35][CH2:34][CH2:33]1)=[O:30])[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1
Reactant: CC(C)[C@H](N)C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Product: CCC(C)[C@H](NC(=O)OCc1ccccc1)C(=O)N[C@H](C(=O)NC[C@@H](O)CP(=O)(CC1CCCCC1)OCc1ccccc1)C(C)C

Procedure:
The title compound was prepared substantially in a similar manner as Step 1, Example 10 using N—Z-Ile-OH and [(R)-3-((S)-2-amino-3-methyl-butyrylamino)-2-hydroxy-propyl]-cyclohexylmethyl-phosphinic acid benzyl ester hydrochloride as the starting materials. The title compound was purified by SiO2 chromatography using 0-4% MeOH/CH2Cl2 as the eluent. 1H NMR (CD3OD, 300 MHz): δ 7.3 (m, 10H), 5.2-4.95 (m, 4H), 4.17 (d, 1H), 4.12 (m, 1H), 3.95 (d, 1H), 3.20 (m, 2H), 2.12-2.01 (m, 1H), 1.90-1.76 (m, 3H), 1.70-1.61 (m, 6H), 1.55-1.47 (m, 3H), 1.36-1.14 (m, 4H), 1.11-0.95 (m, 14H). 31P NMR (CD3OD, 300 MHz): δ 59.06, 58.33. LCMS m/z: [M+H]+=672.
Reaction SMILES: S([O:8][S:9]([C:12]([F:15])([F:14])[F:13])(=[O:11])=[O:10])(C(F)(F)F)(=O)=O.[F:16][C:17]([F:26])([F:25])[C:18]1[N:23]=[CH:22][C:21](O)=[CH:20][N:19]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C1(C)C=CC=CC=1>[F:15][C:12]([F:13])([F:14])[S:9]([O:8][C:21]1[CH:20]=[N:19][C:18]([C:17]([F:26])([F:25])[F:16])=[N:23][CH:22]=1)(=[O:10])=[O:11]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: Oc1cnc(C(F)(F)F)nc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: O=S(=O)(Oc1cnc(C(F)(F)F)nc1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 93 %

Procedure:
Triflic anhydride (1.01 mL, 6.0 mmol) was added dropwise to a stirred mixture of 2-(trifluoromethyl)pyrimidin-5-ol (prepared according to U.S. Pat. No. 4,558,039) (0.82 g, 5.0 mmol), toluene (10 mL) and aqueous tripotassium phosphate (30% by weight, 10 mL) at ice-bath temperature (Frantz et al., Organic Letters, 2002, 4(26), 4717-4718). When the addition was complete the ice-bath was taken away and the solution was stirred at ambient temperature for 30 minutes. The clear phases were separated and the organic layer was washed with water, then brine. Drying of the organic phase over anhydrous sodium sulfate, filtration and concentration by rotary evaporation at room temperature afforded 2-(trifluoromethyl)-pyrimidine-5-yl trifluoromethanesulfonate as a colourless oil (1.38 g, 93%). B.p. 75-77° C. (10 mbar).
Reaction SMILES: [C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:34](=[O:35])[C:33]4=[CH:36][CH:37]=[CH:38][CH:39]=[C:32]4[C:31]3=[O:40])=[C:28]([C:41]([O:43]C(C)(C)C)=[O:42])[N:27]=[CH:26]2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>FC(F)(F)C(O)=O.ClCCl>[C:1]([O:9][C@@H:10]1[C@@H:14]([CH2:15][O:16][C:17](=[O:24])[C:18]2[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=2)[O:13][C@@H:12]([N:25]2[C:29]([N:30]3[C:31](=[O:40])[C:32]4=[CH:39][CH:38]=[CH:37][CH:36]=[C:33]4[C:34]3=[O:35])=[C:28]([C:41]([OH:43])=[O:42])[N:27]=[CH:26]2)[C@H:11]1[F:48])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)c1ncn([C@@H]2O[C@H](COC(=O)c3ccccc3)[C@@H](OC(=O)c3ccccc3)[C@@H]2F)c1N1C(=O)c2ccccc2C1=O
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(OC[C@H]1O[C@@H](n2cnc(C(=O)O)c2N2C(=O)c3ccccc3C2=O)[C@@H](F)[C@@H]1OC(=O)c1ccccc1)c1ccccc1
Reaction time: 8 h
Yield: 97 %

Procedure:
Compound (11) obtained in step (2) above (2.00 g) was dissolved in a mixture (30 ml) of trifluoroacetic acid-dichloromethane (1:4) and the resulting solution was kept overnight at room temperature, when the deesterification of compound (11) occurred. The reaction solution was concentrated and the solid obtained was washed with diethyl ether to yield the titled compound (12) (1.77 g) which was insoluble in diethyl ether. Yield: 97%.
Reaction SMILES: [CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:12][CH:11]([C:23]([OH:25])=O)[CH2:10]2)=[CH:5][CH:4]=1)[CH3:2].[F:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[C:33](=[N:35]O)[NH2:34]>>[CH2:1]([C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:10][CH:11]([C:23]3[O:25][N:35]=[C:33]([C:28]4[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=4[F:26])[N:34]=3)[CH2:12][N:13]([C:15]([N:17]3[CH2:22][CH2:21][O:20][CH2:19][CH2:18]3)=[O:16])[CH2:14]2)=[CH:5][CH:4]=1)[CH3:2]
Reactant: CCc1ccc(C2CC(C(=O)O)CN(C(=O)N3CCOCC3)C2)cc1
Reactant: NC(=NO)c1ccccc1F
Product: CCc1ccc(C2CC(c3nc(-c4ccccc4F)no3)CN(C(=O)N3CCOCC3)C2)cc1

Procedure:
69 mg (0.20 mmol) of 5-(4-ethylphenyl)-1-(morpholin-4-ylcarbonyl)piperidine-3-carboxylic acid (Example 38A) and 34 mg (0.22 mmol, 1.1 eq.) of 2-fluoro-N′-hydroxybenzenecarboximidamide were reacted according to the General Method 1. Yield: 39 mg (42% of theory)
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36]O[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18].ClC1C=C(NC2C=CC(F)=CC=2F)C=CC=1C(C1C=[C:46]([N:51]2C=C(CCOS(C3C=CC(C)=CC=3)(=O)=O)N=N2)C=CC=1C)=O.CN1CCNCC1>>[Cl:1][C:2]1[CH:7]=[C:6]([NH:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][C:10]=2[F:16])[CH:5]=[CH:4][C:3]=1[C:17]([C:19]1[CH:24]=[C:23]([N:25]2[CH:29]=[C:28]([CH2:30][CH2:31][N:32]3[CH2:37][CH2:36][N:51]([CH3:46])[CH2:34][CH2:33]3)[N:27]=[N:26]2)[CH:22]=[CH:21][C:20]=1[CH3:38])=[O:18]
Reactant: Cc1ccc(-n2cc(CCN3CCOCC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl
Reactant: Cc1ccc(S(=O)(=O)OCCc2cn(-c3ccc(C)c(C(=O)c4ccc(Nc5ccc(F)cc5F)cc4Cl)c3)nn2)cc1
Agent: CN1CCNCC1
Product: Cc1ccc(-n2cc(CCN3CCN(C)CC3)nn2)cc1C(=O)c1ccc(Nc2ccc(F)cc2F)cc1Cl

Procedure:
The reaction was carried out similarly as described in the preparation of compound 138, using compound 435 (0.24 mmol) and 1-methyl-piperazine (0.5 mL). The crude product was purified by continuous gradient flash chromatography using MeOH/DCM 0:100 to 15:85 as the eluent to afford the title compound as yellow foam.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15].[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[NH:20]1.C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>C(OCC)(=O)C>[CH3:18][CH:19]1[CH2:28][CH2:27][C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[N:20]1[CH2:2][C:3]1[CH:12]=[CH:11][C:6]([C:7]([O:9][CH3:10])=[O:8])=[CH:5][C:4]=1[O:13][S:14]([CH3:17])(=[O:16])=[O:15]
Reactant: COC(=O)c1ccc(CBr)c(OS(C)(=O)=O)c1
Reactant: CC1CCc2ccccc2N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(CN2c3ccccc3CCC2C)c(OS(C)(=O)=O)c1
Temperature: 70 °C
Reaction time: 23 h
Yield: 73.5 %

Procedure:
A mixture of methyl 4-(bromomethyl)-3-[(methylsulfonyl)oxy]benzoate (0.70 g, 2.2 mmol), 2-methyl-1,2,3,4-tetrahydroquinoline (0.39 g, 2.6 mmol), potassium carbonate (0.60 g, 4.3 mmol) and N,N-dimethylformamide (14 mL) was stirred at 70° C. for 23 hr. The reaction mixture was diluted with ethyl acetate, washed with water and saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate=10/1-2/1) to give the title compound (0.63 g, yield 75%) as a pale-yellow oil.
Reaction SMILES: [F:1][C:2]1([F:27])[CH2:6][N:5]([C:7]2[CH:12]=[CH:11][N:10]3[N:13]=[CH:14][C:15]([C:16](O)=[O:17])=[C:9]3[N:8]=2)[CH:4]([C:19]2[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=2[OH:26])[CH2:3]1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.Cl.[NH2:50][CH2:51][C@H:52]([OH:55])[CH2:53][Cl:54].CCN(C(C)C)C(C)C>CN(C=O)C.CCOC(C)=O>[Cl:54][CH2:53][C@@H:52]([OH:55])[CH2:51][NH:50][C:16]([C:15]1[CH:14]=[N:13][N:10]2[CH:11]=[CH:12][C:7]([N:5]3[CH2:6][C:2]([F:1])([F:27])[CH2:3][CH:4]3[C:19]3[CH:24]=[C:23]([F:25])[CH:22]=[CH:21][C:20]=3[OH:26])=[N:8][C:9]=12)=[O:17]
Reactant: NC[C@H](O)CCl
Reactant: O=C(O)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3O)nc12
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NC[C@H](O)CCl)c1cnn2ccc(N3CC(F)(F)CC3c3cc(F)ccc3O)nc12
Reaction time: 1 h
Yield: 104.7 %

Procedure:
To a mixture of 5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (0.047 g, 0.124 mmol) and HOBT (0.0252 g, 0.186 mmol) in DMF (1 mL) at ambient temperature was added EDCI (0.0357 g, 0.186 mmol). The resulting mixture was stirred for 1 hour. To this mixture was added (S)-1-amino-3-chloropropan-2-ol hydrochloride (Example 19, Step A; 0.0218 g, 0.149 mmol) followed by DIEA (0.0656 mL, 0.373 mmol) at ambient temperature. The resulting mixture was stirred for 48 hours. The reaction mixture was diluted with EtOAc (10 mL), and the organic layer was washed with a 1:1 mixture of brine and water. The aqueous layer was separated and extracted with EtOAc (2×10 mL). The combined organic layers were washed with a 1:1 mixture of brine and water (15 mL) and combined with the organic layer obtained previously. The organic layer was dried over MgSO4, filtered, and concentrated under reduced pressure to afford N-((S)-3-chloro-2-hydroxypropyl)-5-(4,4-difluoro-2-(5-fluoro-2-hydroxyphenyl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxamide (0.061 g, 105% yield). LC/MS (ES+APCI) m/z=468.1 (M−H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N+:10]([O-:12])=[O:11])=[CH:6][C:5]=1[OH:13])([O-:3])=[O:2].[CH2:14](Br)[CH:15]=[CH2:16].CC(C)=O.C(=O)([O-])[O-].[K+].[K+]>CN1CCCC1=O>[CH2:16]([O:13][C:5]1[CH:6]=[C:7]([N+:10]([O-:12])=[O:11])[CH:8]=[CH:9][C:4]=1[N+:1]([O-:3])=[O:2])[CH:15]=[CH2:14]
Reactant: O=[N+]([O-])c1ccc([N+](=O)[O-])c(O)c1
Reactant: C=CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CN1CCCC1=O
Product: C=CCOc1cc([N+](=O)[O-])ccc1[N+](=O)[O-]
Temperature: 55 °C
Yield: 93.2 %

Procedure:
A mixture of 2,5-dinitrophenol (7.36 g, 40 mmol), allyl bromide (4.84 g, 40 mmol), acetone (75 mL), 1-methylpyrrolidinone (3 mL) and potassium carbonate (11.0 g, 80 mmol) was heated to 50-60° C. for 22 h. The mixture was cooled to room temperature and filtered and the solid rinsed with ethyl acetate. The filtrate was concentrated and recrystallized from isopropanol-hexane (1:1) to give 2-allyloxy-1,4-dinitrobenzene as yellow crystals (8.36 g, mp 66.5-68° C.).
Reaction SMILES: N1C=CC=CC=1.[F:7][C:8]([F:32])([F:31])[C:9]1[C:13]([CH:14]([C:16]2[CH:21]=[CH:20][C:19]([Cl:22])=[CH:18][C:17]=2[N+:23]([O-:25])=[O:24])[OH:15])=[C:12]([C:26]([O:28][CH2:29][CH3:30])=[O:27])[NH:11][N:10]=1>ClCCl.[O-2].[Cr+6].[O-2].[O-2]>[Cl:22][C:19]1[CH:20]=[CH:21][C:16]([C:14]([C:13]2[C:9]([C:8]([F:31])([F:7])[F:32])=[N:10][NH:11][C:12]=2[C:26]([O:28][CH2:29][CH3:30])=[O:27])=[O:15])=[C:17]([N+:23]([O-:25])=[O:24])[CH:18]=1
Reactant: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(O)c1ccc(Cl)cc1[N+](=O)[O-]
Agent: [Cr+6]
Agent: [O-2]
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)c1[nH]nc(C(F)(F)F)c1C(=O)c1ccc(Cl)cc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 81.4 %

Procedure:
Chromium(VI) oxide (CrO3, 2.828 g, 28.28 mmol) was added to a solution of pyridine (4.58 mL, 56.63 mmol) in dichloromethane (70 mL) and the mixture was stirred at room temperature for 15 minutes. To the resulting burgundy-colored solution was added a solution of ethyl 3-trifluoromethyl-4-[(4-chloro-2-nitro-phenyl)(hydroxy)methyl]-1H-pyrazole-5-carboxylate (1.64 g, 4.17 mmol) in dichloromethane (15 mL). The resulting mixture was stirred at room temperature for 4 days. The dichloromethane solution was decanted from the dark viscous residue, which was washed with diethyl ether (3×100 mL). The dichloromethane and diethyl ether extracts were combined, washed successively with 1 N aqueous hydrochloric acid (2×100 mL) and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate, filtered, and concentrated by rotary evaporation to afford 1.33 g (82%) of the title compound as a yellow solid.
Reaction SMILES: [C:1]([C:3]([C:14](=[O:30])[N:15]([CH2:26][CH2:27][CH2:28][CH3:29])[C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=1)=[CH:4][NH:5][C:6](=[NH:13])[N:7]1[CH2:11][CH2:10][NH:9][C:8]1=[O:12])#[N:2].F[C:32](F)(F)[C:33](O)=O.[C:38](O)(=O)C>>[CH2:26]([N:15]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:23])([F:24])[F:25])[CH:17]=1)[C:14]([C:3]1[C:1]([NH2:2])=[N:13][C:6]([N:7]2[CH2:11][CH:10]([CH:32]=[CH2:33])[NH:9][C:8]2=[O:12])=[N:5][CH:4]=1)=[O:30])[CH2:27][CH2:28][CH2:29][CH3:38]
Reactant: O=C(O)C(F)(F)F
Reactant: CCCCN(C(=O)C(C#N)=CNC(=N)N1CCNC1=O)c1cccc(C(F)(F)F)c1
Reactant: CC(=O)O
Product: C=CC1CN(c2ncc(C(=O)N(CCCCC)c3cccc(C(F)(F)F)c3)c(N)n2)C(=O)N1
Reaction time: 2 h
Yield: 65.8 %

Procedure:
A mixture of 3.04 g (7 mmol) of a compound II (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH2CH=CH2), 0.45 ml (~5.8 mmol) of trifluoroacetic acid and 5.0 ml of glacial acetic acid was stirred at 70° for 2 hours and worked up as described in Example 5. 2.00 g (=65.8% yield) of the compound I (R1, R2 =CH3 ; R3, R5, R6 =H; R4 =CH2CH=CH2) were obtained, melting point 189°.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10](Cl)[N:11]=1)[C:8](=[O:13])[N:7]([CH3:14])[CH:6]=[CH:5]2.[CH3:15][NH2:16]>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([NH:16][CH3:15])[N:11]=1)[C:8](=[O:13])[N:7]([CH3:14])[CH:6]=[CH:5]2
Reactant: Cn1ccc2cc(Cl)nc(Cl)c2c1=O
Reactant: CN
Solvent: C1CCOC1
Product: CNc1nc(Cl)cc2ccn(C)c(=O)c12
Temperature: 95 °C

Procedure:
A mixture of 6,8-dichloro-2-methyl-2,7-naphthyridin-1(2H)-one (46 mg, 0.2 mmol) and CH3NH2 solution in THF (2.0 M, 2.5 mL) was heated at 95° C. for 5 hours and evaporated to afford the crude title compound. ESI-MS m/z 224.0 (MH+).
Reaction SMILES: [CH2:1]([N:3]([CH2:7][CH3:8])[CH2:4][CH2:5][NH2:6])[CH3:2].[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH:12]=O>CO.[Pd]>[CH3:9][O:10][CH:11]([O:14][CH3:15])[CH2:12][NH:6][CH2:5][CH2:4][N:3]([CH2:7][CH3:8])[CH2:1][CH3:2]
Reactant: CCN(CC)CCN
Reactant: COC(C=O)OC
Agent: [Pd]
Solvent: CO
Product: CCN(CC)CCNCC(OC)OC
Temperature: 15 °C
Reaction time: 16 h
Yield: 74.4 %

Procedure:
A solution of N,N-diethyl-ethylenediamine (150 g) in methanol (500 mL) was treated dropwise rapidly with glyoxal dimethylacetal (60 wt % soln. in water, 225 g) at 10-15° C. After the addition was complete the solution was warmed to 15° C., then to 22° C. and left at this temperature for 16 hours. The reaction mixture was treated with 5% palladium on carbon (Johnson-Matthey type 38H paste, 15 g) and hydrogenated at 6 bar until the reaction was complete as judged by GC/MS. The catalyst was removed by filtration and the filtrate evaporated to dryness (toluene azeotrope, 2.5 L), affording 196.2 g of the sub-titled compound.
Reaction SMILES: [CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12](Br)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[S:26]1[CH:30]=[CH:29][C:28](B(O)O)=[CH:27]1.C1(C)C=CC=CC=1.C(=O)([O-])[O-].[Na+].[Na+]>CO>[CH2:1]([C:8]1[C:9]([C:15]#[C:16][C:17]2([OH:25])[CH:22]3[CH2:23][CH2:24][N:19]([CH2:20][CH2:21]3)[CH2:18]2)=[N:10][CH:11]=[C:12]([C:28]2[CH:29]=[CH:30][S:26][CH:27]=2)[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1(C#Cc2ncc(Br)cc2Cc2ccccc2)CN2CCC1CC2
Reactant: OB(O)c1ccsc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Solvent: Cc1ccccc1
Product: OC1(C#Cc2ncc(-c3ccsc3)cc2Cc2ccccc2)CN2CCC1CC2
Temperature: 80 °C
Reaction time: 2 h
Yield: 65.5 %

Procedure:
A mixture of 127 mg of 3-(3-benzyl-5-bromo-2-pyridyl)ethynyl-3-quinuclidinol (Example 22-a), 61.4 mg of 3-thiopheneboronic acid, 55.4 mg of tetrakis (triphenylphosphine)palladium(0), 2 ml of toluene, 0.5 ml of methanol and 1 ml of aqueous 2 mol sodium carbonate solution was stirred at 80° C. for 2 hours in a nitrogen atmosphere. NH-silica gel was added to the reaction solution and the solvent was removed. The residue was subjected to NH-silica gel column chromatography using 3% methanol/ethyl acetate, to give 83.9 mg of the target compound.
Reaction SMILES: [CH3:1][CH2:2][O:3][C:4]([CH2:6][CH2:7][CH2:8][P:9]([O:14][CH2:15][CH3:16])([O:11][CH2:12][CH3:13])=[O:10])=[O:5].C[Si]([N-][Si](C)(C)C)(C)C.[K+].I[CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH3:39]>C1COCC1>[C:4]([CH:6]([CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28])[CH2:7][CH2:8][P:9](=[O:10])([O:14][CH2:15][CH3:16])[O:11][CH2:12][CH3:13])([O:3][CH2:2][CH3:1])=[O:5]
Reactant: CCCCCCCCCCCCI
Reactant: CCOC(=O)CCCP(=O)(OCC)OCC
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: C1CCOC1
Product: CCCCCCCCCCCCC(CCP(=O)(OCC)OCC)C(=O)OCC
Temperature: -78 °C
Reaction time: 1 h
Yield: 36.6 %

Procedure:
A solution of triethyl 4-phosphonobutyrate (1.00 g, 3.96 mmol) in 1 mL of THF was added to potassium bis(trimethylsilyl)amide (0.5 M in THF, 8.70 ml, 4.36 mmol) at −78° C. After stirring for 1 h at −78° C., 1-iodododecane (1.2 mL, 4.75 mmol) was added dropwise. The reaction was removed from the bath, warmed to rt and stirred for 2 h. The reaction was diluted with ethyl acetate (50 ml), washed with 2 N HCl (50 mL), sat'd NaCl (50 mL), dried and concentrated. Flash chromatography using 3:1 v/v hexane/acetone afforded 610 mg of the title compound: ESI-MS 421.3 (M+H).
Reaction SMILES: [CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[NH:18][C:19]3[CH:25]=[C:24]([C:26]#[N:27])[C:23]([C:28]#[N:29])=[CH:22][C:20]=3[N:21]=2)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3].[CH2:30]1[CH2:40]CN2C(=NCCC2)C[CH2:31]1.ICCC>CN1C(=O)CCC1.C(OCC)(=O)C>[CH2:1]([C:4]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[N:21]([CH2:31][CH2:30][CH3:40])[C:20]3[CH:22]=[C:23]([C:28]#[N:29])[C:24]([C:26]#[N:27])=[CH:25][C:19]=3[N:18]=2)=[CH:13][CH:12]=1)([CH2:8][CH:9]=[CH2:10])[CH2:5][CH:6]=[CH2:7])[CH:2]=[CH2:3]
Reactant: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3[nH]2)cc1
Reactant: C1CCC2=NCCCN2CC1
Solvent: CN1CCCC1=O
Solvent: CCCI
Solvent: CCOC(C)=O
Product: C=CCC(CC=C)(CC=C)c1ccc(-c2nc3cc(C#N)c(C#N)cc3n2CCC)cc1
Reaction time: 0.03 h
Yield: 62.2 %

Procedure:
Following a reported procedure, a sample of 3 (265 mg, 0.70 mmol) in NMP (2.5 mL) was heated to 120° C. and treated with DBU (105 μL, 0.70 mmol). After stirring for 2 min, iodopropane (105 μL, 0.70 mmol) was added and the mixture was stirred for 15 min. A second dose of DBU (68 μL, 0.70 mmol), followed by iodopropane (68 μL, 0.70 mmol), was added, and 15 min later, a third identical round of DBU and iodopropane was again added. After the mixture was stirred for 15 min, the reaction mixture was allowed to cool and was diluted with ethyl acetate. The organic solution was washed with water and brine. The organic layer was dried (Na2SO4), filtered, concentrated, and chromatographed (silica, CH2Cl2 w/ethyl acetate gradient of 0-5%). Some starting material was recovered (83 mg, 31%), and fractions containing the product were concentrated to give a colorless solid (183 mg, 62%): mp 132-134° C.; 1H NMR δ 0.92 (t, J=8.0 Hz, 3H), 1.82-1.93 (m, 2H), 2.52 (d, J=8.8 Hz, 6H), 4.31 (t, J=7.6 Hz, 2H), 4.98-5.09 (m, 6H), 5.50-5.63 (3H), 7.53 (d, J=8.4 Hz, 2H), 7.70 (d, J=8.4 Hz, 2H), 7.88 (s, 1H), 8.19 (s, 1H); 13C NMR δ 11.4, 23.5, 41.9, 44.1, 47.3, 108.5, 109.0, 116.7, 116.8, 118.5, 126.1, 126.4, 127.9, 129.2, 134.0, 137.9, 145.4, 149.9, 159.4; Anal. Calcd for C28H28N4: C, 79.97; H, 6.71; N, 13.32. Found: C, 79.93; H, 6.73; N, 13.35.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:18]3[CH2:24][CH:23]4[N:25]([C:26](=[O:31])[C:27]([F:30])([F:29])[F:28])[CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.FC(F)(F)C(N1C2CCC1CC(C1C3C=CC(C4NN=NN=4)=CC=3OC3C1=CC=CC=3)C2)=[O:35]>>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([CH:18]3[CH2:24][CH:23]4[NH:25][CH:20]([CH2:21][CH2:22]4)[CH2:19]3)[C:7]3[C:12]([O:13][C:14]=2[CH:15]=1)=[C:11]([O:16][CH3:17])[CH:10]=[CH:9][CH:8]=3.[C:26]([OH:31])([C:27]([F:30])([F:29])[F:28])=[O:35]
Reactant: O=C(N1C2CCC1CC(C1c3ccccc3Oc3cc(-c4nnn[nH]4)ccc31)C2)C(F)(F)F
Reactant: COc1cccc2c1Oc1cc(Br)ccc1C2C1CC2CCC(C1)N2C(=O)C(F)(F)F
Product: COc1cccc2c1Oc1cc(Br)ccc1C2C1CC2CCC(C1)N2
Product: O=C(O)C(F)(F)F

Procedure:
Using an adaptation of the method described in Procedure 23, substituting 1-[3-(3-bromo-5-methoxy-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]oct-8-yl]-2,2,2-trifluoro-ethanone, 5k for 2,2,2-trifluoro-1-{3-[3-(1H-tetrazol-5-yl)-9H-xanthen-9-yl]-8-aza-bicyclo[3.2.1]oct-8-yl}-ethanone, 4j, the title compound 3-(3-bromo-5-methoxy-9H-xanthen-9-yl)-8-aza-bicyclo[3.2.1]octane, 14k was obtained as a TFA salt. MS m/z (MH+) 400.2.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9](Cl)=[O:10])[CH3:2].C(OC1C=CSC=1C(O)=O)C.C(Cl)(=O)C(Cl)=O.[NH2:29][C:30]1[C:31]([CH2:39][CH2:40][CH3:41])=[N:32][N:33]([CH3:38])[C:34]=1[C:35]([NH2:37])=[O:36].CCN(CC)CC>CN(C1C=CN=CC=1)C.C(Cl)Cl>[CH2:1]([O:3][C:4]1[CH:8]=[CH:7][S:6][C:5]=1[C:9]([NH:29][C:30]1[C:31]([CH2:39][CH2:40][CH3:41])=[N:32][N:33]([CH3:38])[C:34]=1[C:35]([NH2:37])=[O:36])=[O:10])[CH3:2]
Reactant: CCOc1ccsc1C(=O)Cl
Reactant: CCCc1nn(C)c(C(N)=O)c1N
Agent: CCOc1ccsc1C(=O)O
Agent: CN(C)c1ccncc1
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCc1nn(C)c(C(N)=O)c1NC(=O)c1sccc1OCC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
3-Ethoxythiophene-2-carbonyl chloride 2, prepared from the reaction of 3-ethoxythiophene-2-carboxylic acid (2.79 g, 16.2 mmol) with oxalyl chloride, was added to a solution of 4-amino-1-methyl-3-n-propylpyrazole-5-carboxamide 1 (2.08 g, 11.4 mmol), DMAP (28 mg, 0.23 mmol) and Et3N (1.64 g, 16.2 mmol) in anhydrous CH2Cl2 (30 mL) at 0° C., and stirred at r.t. for 24 h. The mixture was washed with 1 N HCl and dried with MgSO4. Chromatography (silica gel, hexane:ethyl acetate=3:1) gave a white solid; mp: 103-104° C.; 1H NMR (DMSO-d6) δ 0.87 (t, J=7 Hz, 3 H), 1.39 (t, J=7 Hz, 3 H), 1.56 (sxt, J=7 Hz, 2 H), 2.43 (t, J=7 Hz, 2 H), 3.88 (s, 3 H), 4.32 (q, J=7 Hz, 2 H), 7.18 (d, J=6 Hz, 1 H), 7.66 (s, br. 1 H), 7.75 (s, br. 1 H), 7.81 (d, J=6 Hz, 1 H), 8.87 (s, 1 H); MS (m/z): 337 (MH+).