Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:14]=[N:13][C:12]([CH2:15][OH:16])=[CH:11][CH:10]=2)=[CH:5][CH:4]=1.[CH2:19]([O:21][C:22](=[O:35])[C:23]([O:26][C:27]1[CH:32]=[CH:31][C:30](O)=[CH:29][C:28]=1[CH3:34])([CH3:25])[CH3:24])[CH3:20].C(P(CCCC)CCCC)CCC.CN(C)C(N=NC(N(C)C)=O)=O>C1COCC1>[CH2:19]([O:21][C:22](=[O:35])[C:23]([CH3:25])([O:26][C:27]1[CH:32]=[CH:31][C:30]([O:16][CH2:15][C:12]2[N:13]=[N:14][C:9]([C:6]3[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:17])[F:18])=[CH:8][CH:7]=3)=[CH:10][CH:11]=2)=[CH:29][C:28]=1[CH3:34])[CH3:24])[CH3:20]
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Reactant: OCc1ccc(-c2ccc(C(F)(F)F)cc2)nn1
Agent: CCCCP(CCCC)CCCC
Agent: CN(C)C(=O)N=NC(=O)N(C)C
Solvent: C1CCOC1
Product: CCOC(=O)C(C)(C)Oc1ccc(OCc2ccc(-c3ccc(C(F)(F)F)cc3)nn2)cc1C

Procedure:
0.170 g (0.669 mmol) of the above prepared [6-(4-trifluoromethyl-phenyl)-pyridazin-3-yl]-methanol and 0.163 g (0.684 mmol) of 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) were dissolved in 8 ml of abs. THF and treated successively at 0° C. with 0.162 g (0.800 mmol) of tributylphosphine and 0.139 g (0.804 mmol) of N,N,N′,N′-tetramethylazodicarboxamide. The cooling bath was then removed and stirring continued for one night. The reaction mixture was then poured onto crashed ice, extracted twice with AcOEt, washed with water, and dried over sodium sulfate. Evaporation of the solvents i. V., followed by flash chromatography (SiO2, hexane/AcOEt=7/3) yielded, after recrystallisation from hexane/AcOEt, 0.208 g of a colorless solid.
Reaction SMILES: Cl.Cl.Cl.N1C=C(C[N:10]2[C:16]3[CH:17]=CC(C4C=NC=CC=4)=[CH:20][C:15]=3[CH2:14][N:13]([C:27](=[O:32])[C:28](F)(F)F)[CH:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:11]2)N=C1>C(O)(C(F)(F)F)=O.C(Cl)Cl>[C:11]([C:12]1[CH:33]=[CH:17][C:16]2[NH:10][CH2:11][C@@H:12]([CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[N:13]([C:27](=[O:32])[CH2:28][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[CH2:14][C:15]=2[CH:20]=1)#[N:10]
Reactant: O=C(N1Cc2cc(-c3cccnc3)ccc2N(Cc2c[nH]cn2)CC1Cc1ccccc1)C(F)(F)F
Agent: Cl
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: N#Cc1ccc2c(c1)CN(C(=O)Cc1ccccc1)[C@H](Cc1ccccc1)CN2
Yield: 131.1 %

Procedure:
A solution of Compound B ( 1.1 g, 2.8 mmol) in TFA (8 mL) and methylene chloride (8 mL) was stirred for 3 h and concentrated. Trituration with ethyl ether and drying under vacuum afforded 700 mg (74%) of Compound C as a white solid. MS (M+H)+ 337.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[C:9]([F:11])[C:5]([C:6]([OH:8])=O)=[C:4]([F:12])[CH:3]=1.O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[CH3:32][C:33]1[CH:38]=[C:37]([CH3:39])[CH:36]=[CH:35][C:34]=1[N:40]1[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>C(Cl)(Cl)Cl.CO>[Br:1][C:2]1[CH:3]=[C:4]([F:12])[C:5]([C:6]([N:43]2[CH2:44][CH2:45][N:40]([C:34]3[CH:35]=[CH:36][C:37]([CH3:39])=[CH:38][C:33]=3[CH3:32])[CH2:41][CH2:42]2)=[O:8])=[C:9]([F:11])[CH:10]=1
Reactant: O=C(O)c1c(F)cc(Br)cc1F
Reactant: Cc1ccc(N2CCNCC2)c(C)c1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: [Cl-]
Solvent: CO
Solvent: ClC(Cl)Cl
Solvent: O
Product: Cc1ccc(N2CCN(C(=O)c3c(F)cc(Br)cc3F)CC2)c(C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.4 %

Procedure:
4-Bromo-2,6-difluorobenzoic acid (5 g) and 4-(4,6-dimethoxy[1.3.5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (DMT-MM) (6.9 g) were dissolved in a mixture of chloroform (50 mL) and methanol (50 mL), 1-(2,4-dimethylphenyl)piperazine (4 g) was added, and the mixture was stirred at room temperature overnight. After evaporation of the solvent, ethyl acetate was added, and insoluble materials were filtered off. The solvent in the filtrate was evaporated to give the title compound (7 g).
Reaction SMILES: [NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:16])[F:15])=[CH:9][CH:8]=2)[C:3]=1[C:18]([OH:20])=O.Cl.C(N=C=NCCCN(C)C)C.[CH3:33][O:34][C:35]1[CH:36]=[C:37]([N:41]2[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]2)[CH:38]=[CH:39][CH:40]=1>ClCCl>[NH2:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][C:14]([F:17])([F:15])[F:16])=[CH:9][CH:8]=2)[C:3]=1[C:18]([N:44]1[CH2:43][CH2:42][N:41]([C:37]2[CH:38]=[CH:39][CH:40]=[C:35]([O:34][CH3:33])[CH:36]=2)[CH2:46][CH2:45]1)=[O:20]
Reactant: COc1cccc(N2CCNCC2)c1
Reactant: Nc1onc(-c2ccc(OC(F)(F)F)cc2)c1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: COc1cccc(N2CCN(C(=O)c3c(-c4ccc(OC(F)(F)F)cc4)noc3N)CC2)c1
Yield: 69 %

Procedure:
In a similar manner as described in Example 1, by using dichloromethane (30 mL), 5-amino-3-(4-(trifluoromethoxy)phenyl)isoxazol-4-carboxylic acid (530 mg, 1.84 mmol), 1-ethyl-3-(dimethylaminopropyl)carbodiimide hydrochloride (388 mg, 2.02 mmol) and 1-(3-methoxyphenyl)piperazine (354 mg, 1.84 mmol), a white solid required compound (588 mg, 1.27 mmol, 69%) was obtained.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[N:9]=2)[CH:5]=[CH:4][N:3]=1.[NH2:25][S:26]([C:29]1[CH:34]=[CH:33][C:32](B(O)O)=[CH:31][CH:30]=1)(=[O:28])=[O:27]>>[CH3:24][C:10]1[N:9]=[C:8]([C:6]2[CH:5]=[CH:4][N:3]=[C:2]([C:32]3[CH:33]=[CH:34][C:29]([S:26]([NH2:25])(=[O:28])=[O:27])=[CH:30][CH:31]=3)[N:7]=2)[CH:13]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[CH:11]=1
Reactant: NS(=O)(=O)c1ccc(B(O)O)cc1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(Cl)n2)n1
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)cc(-c2ccnc(-c3ccc(S(N)(=O)=O)cc3)n2)n1

Procedure:
The title compound was prepared from 2-chloro-4-[6-methyl-4-(4-trifluoromethylphenyl)-pyridin-2-yl]-pyrimidine (example E.83) (0.150 g, 0.381 mmol) and commercially available (4-aminosulfonylphenyl)boronic acid [CAS-No. 613660-87-0] (0.130 g, 0.457 mmol) according to the general procedure VI. Obtained as a white solid (0.045 g, 25%). MS (ISP) 471.1 [(M+H)+].
Reaction SMILES: CN1CCCC1=O.[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[C:22](C(O)=O)=[CH:21][N:20]=1.N>O>[CH3:8][C:9]1[CH:14]=[CH:13][C:12]([N+:15]([O-:17])=[O:16])=[CH:11][C:10]=1[NH:18][C:19]1[N:24]=[C:23]([C:25]2[CH:26]=[N:27][CH:28]=[CH:29][CH:30]=2)[CH:22]=[CH:21][N:20]=1
Reactant: Cc1ccc([N+](=O)[O-])cc1Nc1ncc(C(=O)O)c(-c2cccnc2)n1
Agent: N
Solvent: CN1CCCC1=O
Solvent: O
Product: Cc1ccc([N+](=O)[O-])cc1Nc1nccc(-c2cccnc2)n1
Temperature: 180 °C

Procedure:
To 25 mL N-methylpyrrolidone, 5.0 g 2-[(2-methyl-5-nitrophenyl)amino]-4-(3-pyridinyl)pyrimidine-5-carboxylic acid and 0.2 g cupric oxide is added. The mixture is heated to 180° C. for 2 hours, then cooled to 60° C., and 30% aqueous ammonia 1 mL and 50 mL water is added. It is cooled to 25° C., and the precipitate is filtrated, yielding, upon drying, 4.3 g of product with HPLC purity of 97% (A %), which is identified through GC-MS.
Reaction SMILES: [BrH:1].[N:2]([CH2:5][C@H:6]1[O:15][CH:10](OC(=O)C)[C@H:9]([O:16][C:17](=[O:19])[CH3:18])[C@@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@H:7]1[O:24][C:25](=[O:27])[CH3:26])=[N+:3]=[N-:4].C(OCC)(=O)C>C(O)(=O)C.C(Cl)Cl>[C:17]([O:16][C@@H:9]1[C@@H:8]([O:20][C:21](=[O:23])[CH3:22])[C@@H:7]([O:24][C:25](=[O:27])[CH3:26])[C@@H:6]([CH2:5][N:2]=[N+:3]=[N-:4])[O:15][C@@H:10]1[Br:1])(=[O:19])[CH3:18]
Reactant: CC(=O)OC1O[C@H](CN=[N+]=[N-])[C@H](OC(C)=O)[C@H](OC(C)=O)[C@H]1OC(C)=O
Reactant: Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@@H](OC(C)=O)[C@@H](Br)O[C@H](CN=[N+]=[N-])[C@@H]1OC(C)=O
Temperature: 0 °C

Procedure:
Hydrogen bromide (2 mL of a 30% solution in acetic acid) was added to a solution of 6-azido-6-deoxy-1,2,3,4-tetra-O-acetyl-galactopyranose 36 (α:β, 0.8:1) (320 mg, 0.86 mmol) in anhydrous DCM (10 mL). The mixture was stirred under argon at 0° C. After 1¾h, t.1.c. (petrol:ethyl acetate, 2:1) indicated the formation of two products (Rf 0.5, 0.2) with some remaining starting material (Rf 0.3). The reaction mixture was quenched with ice/water (30 mL), diluted with DCM (40 mL), neutralized with sodium bicarbonate (2×40 mL), washed with brine (40 mL), dried (MgSO4), filtered and concentrated in vacuo to yield 350 mg of crude product, which was used without further purification, but a small portion was retained and purified by flash column chromatography (DCM:ether, 60:1) to afford 2,3,4-tri-O-acetyl-6-azido-6-deoxy-α-D-galactopyranosylbromide 37 as a white solid Rf 0.5 (60:1, DCM:ether); m.p. 81.5-82.2C (ether/petrol) [Lit. 82-83° C. (ether/petrol) Jezo, I. and Zemek, J., Chemicke Zvesti, 33, 533-541 (1979)]; [α]D25+70.8 (c, 1.7 in CHCl3) [Lit. [α]D22 +133.8 (c, 1 in CHCl3)], νmax (thin film) 2107 (sh, N3), 1750 (st, C═O)cm−1; δH (400 MHz, CDCl3) 2.03, 2.12, 2,18 (9H, 3 x s, 3 x CH3), 3.30-3.40 (2H, m, H-6, H-6′), 4.47 (1H, t, H-5), 5.04 (1H, dd, J1,2 4.0, J2,3 10.7, H-2), 5.43 (1H, dd, J3,4 3.2, H-3), 5.69 (1H, m, H-4), 6.69 (1H, d, H-1).
Reaction SMILES: CS(C)=O.[Cl:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]([CH3:17])([CH3:16])[CH2:14][OH:15])=[CH:8][CH:7]=1.C(N(CC)CC)C>C(Cl)Cl>[Cl:5][C:6]1[N:11]=[CH:10][C:9]([O:12][C:13]([CH3:17])([CH3:16])[CH:14]=[O:15])=[CH:8][CH:7]=1
Reactant: CC(C)(CO)Oc1ccc(Cl)nc1
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(C)(C=O)Oc1ccc(Cl)nc1
Temperature: -78 °C
Reaction time: 0.17 h
Yield: 98.9 %

Procedure:
An oven dried flask containing 350 ml dry CH2Cl2 was cooled to −78° C. under argon. The oxalyl chloride (31.0 g, 20.7 mL, 244 mmol, Eq: 1.30) was added followed by the addition of DMSO (28 mL, 394 mmol, 2.1 equiv) via dropwise addition. The mixture is stirred for 10 minutes and then a solution of 2-(6-chloropyridin-3-yloxy)-2-methylpropan-1-ol (41.17 g of 92% pure material, 188 mmol, Eq: 1.00), dissolved in 60 ml CH2Cl2, was added via slow dropwise addition. The mixture is stirred for 30 minutes at −78° C. Triethylamine (105 mL, 751 mmol, 4 equiv) was added and the cooling bath was removed and the reaction mixture was allowed to stir for 1 hour with warming to ambient temperature. The reaction mixture was diluted with saturated NaHCO3 (275 mL), shaken and the organic phase collected and washed with an equal volume of brine. The aqueous phase was back-extracted with DCM (2×150 ml). The combined organics phase was dried (MgSO4), filtered and concentrated in vacuo. This resulting residue was purified by Analogix MPLC (SF40-240G column) eluting with 2% to 30% EtOAC/Hex gradient over 60 minutes to afford the desired product (37.1 g) as a light yellow oil. (M+H)+=200 m/e. 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.44 (s, 6 H) 7.07-7.34 (m, 2 H) 8.05 (d, J=3.02 Hz, 1 H) 9.79 (s, 1 H).
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][C:11]1[CH:15]=[C:14]([C:16]2[C:17]([NH:30][CH2:31][CH2:32][CH3:33])=[N:18][C:19]([NH:22][C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[CH:24]=3)=[N:20][CH:21]=2)[O:13][N:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.C(=O)([O-])O.[Na+].C(OCC)(=O)C>O1CCCC1>[F:29][C:25]1[CH:24]=[C:23]([NH:22][C:19]2[N:18]=[C:17]([NH:30][CH2:31][CH2:32][CH3:33])[C:16]([C:14]3[O:13][N:12]=[C:11]([CH2:10][CH2:9][OH:8])[CH:15]=3)=[CH:21][N:20]=2)[CH:28]=[CH:27][CH:26]=1
Reactant: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO[Si](C)(C)C(C)(C)C)no1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [F-]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCNc1nc(Nc2cccc(F)c2)ncc1-c1cc(CCO)no1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of 5-(3-(2-((tert-butyldimethylsilyl)oxy)ethyl)isoxazol-5-yl)-N2-(3-fluorophenyl)-N4-propylpyrimidine-2,4-diamine (S4, 22 mg) in tetrahydrofuran (1 mL), a 1.0 mol/L solution of tetrabutylammonium fluoride in tetrahydrofuran (69 μL) was added under ice cooling, and the mixture was stirred at room temperature for 3 hours. To the reaction mixture, saturated aqueous sodium hydrogencarbonate and ethyl acetate were added. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 70 to 5% hexane in ethyl acetate) to obtain 2-(5-(2-((3-fluorophenyl)amino)-4-(propylamino)pyrimidin-5-yl)isoxazol-3-yl)ethanol (S5, 5.3 mg) as white solid.
Reaction SMILES: [CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][OH:10])[CH3:2].[CH2:11]([N:14]=[C:15]=[O:16])[CH:12]=[CH2:13]>C(Cl)(Cl)Cl.C(#N)C.C(N(CC)CC)C>[CH2:1]([N:3]1[C:7](=[O:8])[CH2:6][S:5][C:4]1=[N:9][O:10][C:15](=[O:16])[NH:14][CH2:11][CH:12]=[CH2:13])[CH3:2]
Reactant: C=CCN=C=O
Reactant: CCN1C(=O)CSC1=NO
Solvent: CC#N
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: C=CCNC(=O)ON=C1SCC(=O)N1CC
Reaction time: 8 h
Yield: 85.6 %

Procedure:
A solution of 2.0 g of 3-ethyl-2-oximino-4-thiazolidinone in 100 ml chloroform and 50 ml of acetonitrile, 1.04 g allylisocyanate and 2 drops of triethylamine was taken in a pressure bottle and left standing overnight at ambient temperature. Concentration yielded 2.6 g of product, m.p. 103°-104°.
Reaction SMILES: [I-:1].C([N:9]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[C:18]([CH2:45][CH3:46])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:44])[CH:23]=[C:24]([N:30]4[CH2:36][CH2:35][CH2:34][N:33](C(OC(C)(C)C)=O)[CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:11][CH2:10]1)(OC(C)(C)C)=O>ClCCl.FC(F)(F)C(O)=O>[I-:1].[N:12]1([C:16]2[CH:17]=[C:18]([CH2:45][CH3:46])[C:19]3[C:28]([CH:29]=2)=[S+:27][C:26]2[C:21](=[C:22]([CH3:44])[CH:23]=[C:24]([N:30]4[CH2:36][CH2:35][CH2:34][NH:33][CH2:32][CH2:31]4)[CH:25]=2)[N:20]=3)[CH2:13][CH2:14][CH2:15][NH:9][CH2:10][CH2:11]1
Reactant: CCc1cc(N2CCCN(C(=O)OC(C)(C)C)CC2)cc2[s+]c3cc(N4CCCN(C(=O)OC(C)(C)C)CC4)cc(C)c3nc12
Agent: [I-]
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCc1cc(N2CCCNCC2)cc2[s+]c3cc(N4CCCNCC4)cc(C)c3nc12

Procedure:
a solution of 3,7-bis(4-Boc-1,4-diazepan-1-yl)-1-ethyl-9-methyl-phenothiazin-5-ium iodide (75 mg, 0.01 mmol) in dichloromethane (10 mL) and trifluoroacetic acid (1.0 mL) was stirred for 3 h at 50° C. The resulting mixture was washed by toluene (2×5 mL), pentane (2×5 mL) and concentrated to dryness.
Reaction SMILES: [CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([OH:24])=O)=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.CN1CCOCC1.ClC1N=C(OC)N=C(OC)N=1.[NH2:45][CH:46]1[CH2:51][CH2:50][O:49][CH2:48][CH2:47]1.Cl>C1COCC1.C(Cl)Cl>[CH:1]1([C:6]2[C:14]3[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:8]([S:15]([C:18]3[CH:26]=[CH:25][C:21]([C:22]([NH:45][CH:46]4[CH2:51][CH2:50][O:49][CH2:48][CH2:47]4)=[O:24])=[CH:20][CH:19]=3)(=[O:17])=[O:16])[CH:7]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: O=C(O)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Reactant: NC1CCOCC1
Agent: COc1nc(Cl)nc(OC)n1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: O=C(NC1CCOCC1)c1ccc(S(=O)(=O)n2cc(C3CCCC3)c3ccccc32)cc1
Temperature: 5 °C
Reaction time: 1 h

Procedure:
Stir a solution of 4-(3-cyclopentyl-indole-1-sulfonyl)-benzoic acid (19.0 g, 51.43 mmol) in anhydrous THF (250 mL), cool to 5° C., add N-methylmorpholine (5.8 mL, 52.72 mmol) and 2-chloro-4,6-dimethoxy-1,3,5-triazine (CDMT) (9.0 g, 51.34 mmol). Stir the mixture at 0-5° C. for 1 h, add a solution of 4-aminotetrahydro-pyran (5.8 g, 57.36 mmol) in dry THF (75 mL) via dropping funnel. Bring the mixture to room temperature, stir for 3 h, and cool back down to 5° C. Stir the mixture and add 1N HCl (250 mL), add the resulting solution to a separatory funnel, and extract with ethyl acetate (250 mL). Separate the layers, wash the organic layer with brine (250 mL), and combine the aqueous layers and extract with ethyl acetate (250 mL). Combine the organics and wash with saturated aqueous sodium bicarbonate (400 mL) and dry the organic layer over sodium sulfate. Concentrate to give a foam, dissolve in minimum methylene chloride, and add to a biotage flash 65M cartridge. Elute with 3:2 hexanes/ethyl acetate to provide the major product as a foam, and dry (20 mm Hg, 40° C.) to give a white powder of pure product (20.3 g, 87%); MS (ESI) m/z 453 (m+H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][C:15](=O)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2.[N:19]1([C:25]2[CH:33]=[CH:32][CH:31]=[C:30]3[C:26]=2[CH:27]=[CH:28][NH:29]3)[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C>C(Cl)Cl.ClC(Cl)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([N:12]3[CH2:17][CH2:16][CH:15]([N:22]4[CH2:23][CH2:24][N:19]([C:25]5[CH:33]=[CH:32][CH:31]=[C:30]6[C:26]=5[CH:27]=[CH:28][NH:29]6)[CH2:20][CH2:21]4)[CH2:14][CH2:13]3)[CH:11]=1)[N:8]=[CH:7][CH:6]=[CH:5]2
Reactant: O=C1CCN(c2cc(Cl)cc3cccnc23)CC1
Reactant: c1cc(N2CCNCC2)c2cc[nH]c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(Cl)Cl
Solvent: ClCCl
Solvent: CC(=O)O
Product: Clc1cc(N2CCC(N3CCN(c4cccc5[nH]ccc45)CC3)CC2)c2ncccc2c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 1-(6-chloro-quinolin-8-yl)-piperidin-4-one (Step 1, 0.13 g) and of 4-piperazino-indole (commercially available, 0.100 g) in 15 mL CH2Cl2 in 10 mL of dichloroethane, was added 0.137 g of sodium triacetoxyborohydride and 0.1 mL acetic acid. The reaction was stirred at room temperature overnight. It was quenched with 1N NaOH, and the product was extracted with CH2Cl2. The organic phase was washed with water and dried over magnesium sulfate. The product was filtered through 100 ml of silica gel using 100% Ethyl acetate, to give 0.070 g of the desired product. Mp: 224° C.; MS (ES) m/z (relative intensity): 447 (M++−H, 100).
Reaction SMILES: [OH:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1>C(OCC)C>[C:28]([O:1][C@H:2]1[C@@H:11]([O:12][CH2:13][CH2:14][O:15][CH3:16])[C:10]2[CH:9]=[CH:8][N:7]3[C:17]([CH3:21])=[C:18]([CH3:20])[N:19]=[C:6]3[C:5]=2[NH:4][C@@H:3]1[C:22]1[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=1)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1O
Solvent: CCOCC
Product: COCCO[C@H]1c2ccn3c(C)c(C)nc3c2N[C@H](c2ccccc2)[C@H]1OC(=O)c1ccccc1

Procedure:
Analogously to example 6, 1.1 g of the title compound of melting point 78–80° C. (diethyl ether) are obtained by reaction of (7S,8R,9R)-8-hydroxy-7-(2-methoxyethoxy)-2,3-dimethyl-9-phenyl-7,8,9,10-tetrahydroimidazo[1,2-h][1,7]naphthyridine with benzoyl chloride.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]2[C:11](=[O:12])[CH:10]=[CH:9][C:7](=[O:8])[C:5]=2[CH:6]=1.[O:13]=[C:14]([CH3:20])[CH2:15][CH2:16]C(O)=O.S(OOS([O-])(=O)=O)([O-])(=O)=O.[NH4+].[NH4+]>C(#N)C.[N+]([O-])([O-])=O.[Ag+]>[O:8]=[C:7]([CH3:9])[CH2:5][CH2:4][C:9]1[C:7](=[O:8])[C:5]2[C:4]([C:11](=[O:12])[C:10]=1[CH2:16][CH2:15][C:14](=[O:13])[CH3:20])=[CH:3][CH:2]=[CH:1][CH:6]=2
Reactant: O=C1C=CC(=O)c2ccccc21
Reactant: CC(=O)CCC(=O)O
Agent: [Ag+]
Agent: O=S(=O)([O-])OOS(=O)(=O)[O-]
Agent: O=[N+]([O-])[O-]
Solvent: CC#N
Product: CC(=O)CCC1=C(CCC(C)=O)C(=O)c2ccccc2C1=O

Procedure:
Naphthoquinone (3.12 g, 20 mmol), 4-oxopentanoic acid (13.9 g, 120 mmol) and silver nitrate (2.0 g, 11.8 mmole) are combined in 30% aqueous acetonitrile at 65° C. A solution of ammonium peroxydisulfate (12.0 g, 52.6 mmole) is added dropwise over 30 minutes while the stirred mixture is maintained at 65°-75° C. On cooling, the mixture is extracted with diethyl ether (300 ml). The extract is then washed with water (3×50 ml), 5% NaHCO3 (2×50 ml) and brine (50 ml) and dried over MgSO4. After filtration through active carbon, the ether solution is evaporated to give crude 2,3-bis(3-oxobutyl)-1,4-naphthoquinone which is recrystallized from aqueous ethanol to give 1.45 g product, mp 110°-112° C. This 2,3-bis(3-oxobutyl)-1,4-naphthoquinone (0.456 g, 1.53 mmole), aminoguanidine hydrochloride (0.46 g, 4.3 mmole) and a drop of concentrated HCl are combined in 5 ml of 90% ethanol and heated at reflux for 3 hours. On cooling, 2,3-bis(3-(2-amidinohydrazono)butyl)-1,4-naphthoquinone crystallizes from the reaction mixture, and recrystallization from ethanol gives 400 mg product, mp 181°-183° C.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:12]=[CH:11][C:10]([Si:13]([CH3:16])([CH3:15])[CH3:14])=[C:9]([F:17])[CH:8]=1.C(O[B:22]1[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]1)(C)C.C(=O)=O.CC(C)=O.Cl>C1COCC1.O>[F:17][C:9]1[CH:8]=[C:7]([B:22]2[O:26][C:25]([CH3:28])([CH3:27])[C:24]([CH3:30])([CH3:29])[O:23]2)[CH:12]=[CH:11][C:10]=1[Si:13]([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)OB1OC(C)(C)C(C)(C)O1
Reactant: C[Si](C)(C)c1ccc(Br)cc1F
Agent: Cl
Agent: O=C=O
Agent: [Li]CCCC
Solvent: O
Solvent: C1CCOC1
Solvent: CC(C)=O
Product: CC1(C)OB(c2ccc([Si](C)(C)C)c(F)c2)OC1(C)C
Temperature: -78 °C
Reaction time: 0.25 h

Procedure:
A solution of n-BuLi (2.5 M in hexanes; 8.5 mL, 21 mmol, 1.1 equiv) was added to a stirred solution of (4-bromo-2-fluorophenyl)trimethylsilane (4.8 g, 19 mmol, 1.0 equiv) in THF (80 mL) at −78° C. The resulting orange solution was stirred at −78° C. for 15 min. 2-Isopropoxy-4,4,5,5-tetramethyl-1,3,2-dioxaborolane (4.4 mL, 21 mmol, 1.1 equiv) was added, and the cloudy orange solution was allowed to slowly warm to 23° C., by allowing the dry ice/acetone bath to melt, and was stirred for 20 h. The reaction mixture was diluted with H2O (200 mL), adjusted to approximately pH=4 using 1 M hydrochloric acid (HCl), and extracted with CH2Cl2 (3×100 mL). The combined organic layers were dried (MgSO4), gravity filtered, and concentrated by rotary evaporation to afford the crude product, (2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)trimethylsilane, as a pale yellow semisolid (6.0 g, 99% crude yield): 1H NMR (400 MHz, CDCl3) δ 7.55 (dt, J=7.5, 1 Hz, 1H), 7.38-7.42 (m, 2H), 1.34 (s, 12H), 0.29 (d, J=1 Hz, 9H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:10]([OH:12])=[O:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=NC1CCCCC1)=NC1CCCCC1.N1(O)C2C=CC=CC=2N=N1.[N:45]12[CH2:52][CH2:51][CH:48]([CH2:49][CH2:50]1)[C@@H:47](O)[CH2:46]2>C1COCC1>[C:1]([O:5][C:6]([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][CH:16]=[C:15]([F:19])[CH:14]=1)[C:10]([O:12][C@@H:47]1[CH:48]2[CH2:51][CH2:52][N:45]([CH2:50][CH2:49]2)[CH2:46]1)=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O[C@H]1CN2CCC1CC2
Reactant: CC(C)(C)OC(=O)NC(C(=O)O)c1cccc(F)c1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: On1nnc2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NC(C(=O)O[C@H]1CN2CCC1CC2)c1cccc(F)c1
Temperature: 25 °C
Yield: 100.1 %

Procedure:
To a solution of 2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetic acid (I52) (1.10 g, 4.09 mmol) in THF (50 ml), were added N,N′-methanediylidenedicyclohexanamine (1.01 g, 4.90 mmol), 1H-benzo[d][1,2,3]triazol-1-ol (0.66 g, 4.90 mmol), and (R)-quinuclidin-3-ol (0.62 g, 4.90 mmol). The reaction was stirred at RT for hours, and the solvent was evaporated. The residue was taken up with DCM, the insoluble solid was filtered off, and the organic solution was washed twice with aq. Na2CO3 and then brine, dried over Na2SO4 and evaporated to obtain (R)-quinuclidin-3-yl 2-(tert-butoxycarbonylamino)-2-(3-fluorophenyl)acetate (1.55 g; quantitative yield).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)=[CH:4][C:3]=1[CH3:14].[CH3:15][C:16]1[CH:36]=[CH:35][C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])=[CH:18][C:17]=1B1OC(C)(C)C(C)(C)O1>>[CH3:14][C:3]1[CH:4]=[C:5]([C:8]2[O:9][C:10]([CH3:13])=[N:11][N:12]=2)[CH:6]=[CH:7][C:2]=1[C:17]1[C:16]([CH3:15])=[CH:36][CH:35]=[C:19]([C:20]([NH:22][C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([N:29]3[CH2:34][CH2:33][O:32][CH2:31][CH2:30]3)[CH:24]=2)=[O:21])[CH:18]=1
Reactant: Cc1ccc(C(=O)Nc2cccc(N3CCOCC3)c2)cc1B1OC(C)(C)C(C)(C)O1
Reactant: Cc1nnc(-c2ccc(Br)c(C)c2)o1
Product: Cc1nnc(-c2ccc(-c3cc(C(=O)Nc4cccc(N5CCOCC5)c4)ccc3C)c(C)c2)o1

Procedure:
Example 2 was prepared using 2-(4-bromo-3-methylphenyl)-5-methyl-1,3,4-oxadiazole and 4-methyl-N-[3-(4-morpholinyl)phenyl]-3-(4,4,5,5-tetramethyl-[1,3,2]-dioxaborolan-2-yl)benzamide (Intermediate 5).