Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([CH3:12])=[N:10][CH:9]=[CH:8][N:7]3[C:13]=2[CH:14](O)[C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:3][CH2:2]1.FC(F)(F)C(O)=O.C([SiH](CC)CC)C>>[CH:1]1([C:4]2[N:5]=[C:6]3[C:11]([CH3:12])=[N:10][CH:9]=[CH:8][N:7]3[C:13]=2[CH2:14][C:15]2[CH:34]=[CH:33][C:18]3/[C:19](=[C:29](/[CH3:32])\[C:30]#[N:31])/[C:20]4[CH:27]=[CH:26][C:25]([F:28])=[CH:24][C:21]=4[O:22][CH2:23][C:17]=3[CH:16]=2)[CH2:3][CH2:2]1
Reactant: C/C(C#N)=C1/c2ccc(C(O)c3c(C4CC4)nc4c(C)nccn34)cc2COc2cc(F)ccc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Product: C/C(C#N)=C1/c2ccc(Cc3c(C4CC4)nc4c(C)nccn34)cc2COc2cc(F)ccc21
Temperature: 60 °C
Yield: 72 %

Procedure:
[step 4] (E)-2-{8-[(2-cyclopropyl-8-methylimidazo[1,2-a]pyrazin-3-yl)(hydroxy)methyl]-3-fluorodibenzo[b,e]oxepin-11(6H)-ylidene}propanenitrile (18 g, 39 mmol) obtained in step 3 was dissolved in trifluoroacetic acid (181 mL, 2.3 mol), triethylsilane (31 mL, 0.19 mol) was added, and the mixture was stirred with heating at 60° C. for 1 hr. The mixture was concentrated under reduced pressure, saturated aqueous sodium hydrogen carbonate solution (100 mL) was added to the obtained residue, and the mixture was extracted 3 times with a mixed solvent of chloroform-methanol. The combined organic layers were dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. To the obtained residue was added isopropylalcohol (133 mL), and the mixture was stirred at room temperature for 4 hr and further for 1 hr under ice-cooling. The precipitated crystals were collected by suction filtration to give the title compound (13g, 72%).
Reaction SMILES: [N+:1]([C:4]1[CH:16]=[CH:15][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:6][CH:5]=1)([O-])=O>CO.[Pd]>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([O:8][C:9]([CH3:14])([CH3:13])[C:10]([NH2:12])=[O:11])=[CH:15][CH:16]=1
Reactant: CC(C)(Oc1ccc([N+](=O)[O-])cc1)C(N)=O
Agent: [Pd]
Solvent: CO
Product: CC(C)(Oc1ccc(N)cc1)C(N)=O

Procedure:
2-(4-Nitrophenoxy)-2-methylpropanamide (51) was dissolved in methanol (50 mL) and to the solution was added 10% Pd—C (500 mg). The reaction mixture was reacted under hydrogen atmosphere (40 psi) for 1 hour. The catalyst was then filtered off over Celite. The filtrate was evaporated under reduced pressure to give 2-(4-aminophenoxy)-2-methylpropanamide as a white solid (52).
Reaction SMILES: [C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:19]=[CH:18][C:17]([CH2:20][OH:21])=[CH:16][CH:15]=3)[N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=1[CH2:32][C:33]([O:35][CH3:36])=[O:34].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1(C)C=CC=CC=1.C(OCC)(=O)C.O1CCCC1>[C:1]1([C:7]2[O:8][C:9]([CH2:22][CH2:23][CH3:24])=[C:10]([CH2:12][O:13][C:14]3[CH:15]=[CH:16][C:17]([CH2:20][O:21][C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[CH2:32][C:33]([O:35][CH3:36])=[O:34])=[CH:18][CH:19]=3)[N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COC(=O)Cc1ccccc1O
Reactant: CCCc1oc(-c2ccccc2)nc1COc1ccc(CO)cc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCCc1oc(-c2ccccc2)nc1COc1ccc(COc2ccccc2CC(=O)OC)cc1
Reaction time: 15 h
Yield: 54.9 %

Procedure:
To a mixture of [4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]phenyl]methanol (0.50 g), methyl 2-(2-hydroxyphenyl)acetate (0.30 g), triphenylphosphine (0.60 g) and tetrahydrofuran (30 mL) was dropwise added a solution (40%, 1.00 g) of diethyl azodicarboxylate in toluene at room temperature, and the mixture was stirred for 15 hrs. To the reaction mixture was added ethyl acetate, and washed successively with water, a 2N aqueous sodium hydroxide solution and saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give methyl 2-[2-[4-[(2-phenyl-5-propyl-4-oxazolyl)methoxy]benzyloxy]phenyl]acetate as an oil (0.40 g, 56%) from a fraction eluted with ethyl acetate-hexane (1:4, v/v).
Reaction SMILES: [C:1](=[O:8])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])[NH2:2].[Li]CCCC.[C:14](Cl)(=[O:18])[CH:15]=[CH:16][CH3:17].[Li]CCCC.C(Cl)(=O)C=CC.C([O-])(O)=O.[Na+]>C1COCC1>[C:14]([NH:2][C:1](=[O:8])[O:3][C:4]([CH3:7])([CH3:6])[CH3:5])(=[O:18])/[CH:15]=[CH:16]/[CH3:17]
Reactant: CC=CC(=O)Cl
Reactant: CC(C)(C)OC(N)=O
Agent: O=C([O-])O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Product: C/C=C/C(=O)NC(=O)OC(C)(C)C
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 81 %

Procedure:
To a solution of tert-butyl carbamate (1.0 g, 8.54 mmol) in THF (20 mL) at −78° C., were added nBuLi and 2-butenoyl chloride successively, in the following quantities (nBuLi/2-butenoyl chloride): 5.34/0.41, 2.67/0.21, 1.34/0.10, 0.67/0.05, 0.34/0.03 mL. Stirring was continued for 30 min, before the reaction mixture was poured into an ice-cooled solution of saturated aq. NaHCO3 (50 mL) and extracted with EtOAc. The combined organic layers were washed with brine, dried over MgSO4, and evaporated. The crude product was purified by flash chromatography (Et2O:pet. ether, 1:3, Rf 0.4) to give the product as a white solid. Yield 81% (1.28 g). m.pt. 138–139° C. 1H NMR: δ 1.49 (s, 9H, tBu); 1.92 (dd, 1H, CH3CH, 2JHH=6.8 Hz, 3JHH=1.5 Hz); 6.82 (dd, 1H, COCH, 2JHH=15.2 Hz, 3JHH=1.5 Hz); 7.05–7.15 (m, 1H, CH3CH); 7.31 (s, br, 1H, NH). 13C NMR: δ 15.9 (CH3CH), 27.9 (C(CH3)3), 82.3 (C(CH3)3), 121.2 (COCH), 145.5 (CH3CH), 150.5(CO2), 166.3 (COCH). m/z (HR-ESMS): Expected 185.1052 (M+), observed 185.1046. Anal. calcd for C9H15NO3: C, 58.36; H, 8.16; N, 7.56%. Found: C, 58.08; H, 8.05; N, 7.63%.
Reaction SMILES: C(NC(C)C)(C)C.C([Li])CCC.[N:13]1[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=1.[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](OC)=[O:35])=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:24][CH2:23][CH2:22][CH2:21]1>O1CCCC1>[CH:20]1([C:25]2[NH:26][C:27]3[C:33]([C:34](=[O:35])[CH2:19][C:16]4[CH:17]=[CH:18][N:13]=[CH:14][CH:15]=4)=[CH:32][CH:31]=[C:30]([O:38][CH3:39])[C:28]=3[N:29]=2)[CH2:21][CH2:22][CH2:23][CH2:24]1
Reactant: COC(=O)c1ccc(OC)c2nc(C3CCCC3)[nH]c12
Reactant: Cc1ccncc1
Agent: [Li]CCCC
Solvent: CC(C)NC(C)C
Solvent: C1CCOC1
Product: COc1ccc(C(=O)Cc2ccncc2)c2[nH]c(C3CCCC3)nc12
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
A solution of diisopropylamine (0.47 ml) in tetrahydrofuran (6 ml), cooled to −10° C., was treated dropwise, with a solution of butyl lithium in hexanes (1.2 ml, 2.5 M). The resulting solution was stirred for 10 minutes, then cooled to −78° C. and then treated dropwise with a solution of 4-picoline (0.29 ml) in tetrahydrofuran (1 ml). This solution was stirred for 30 minutes then treated with a solution of methyl 2-cyclopentyl-7-methoxy-3H-benzimidazole-4-carboxylate [0.274 g, Reference Example 3(t)] in tetrahydrofuran (2 ml). The cold bath was removed and the reaction mixture stirred for 15 minutes at ambient temperature. The mixture was quenched with water, then diluted with ethyl acetate. The organic phase was separated then washed with brine, then dried over magnesium sulphate and then evaporated. The residue was subjected to flash chromatography on silica, eluting with a mixture of methanol and dichloromethane (8:92, v/v), to give the title compound (0.126 g) as a white solid. [Elemental analysis:—C, 71.7; H, 6.40; N, 12.5%. Calculated:—C, 71.6; H, 6.31; N, 12.5%]. NMR (CDCl3): δ 1.63-2.05(m, 6H), 2.2(m, 2H), 3.33(m, 1H), 4.11(s, 3H), 4.35(s, 2H), 6.72(d, J=8 Hz, 1H), 7.23(m, 2H), 7.82(d, J=8 Hz, 1H), 8.6(m, 2H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C@@H:8]([N:10]2[CH2:15][CH2:14][C@@:13]([C:21]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][CH:22]=3)([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11]2=[O:28])[CH3:9])=[CH:4][CH:3]=1.[CH3:29][C:30]1[CH:35]=[C:34](B(O)O)[CH:33]=[CH:32][N:31]=1>>[F:27][C:24]1[CH:25]=[CH:26][C:21]([C@:13]2([CH2:16][C:17]([OH:20])([CH3:19])[CH3:18])[O:12][C:11](=[O:28])[N:10]([C@H:8]([C:5]3[CH:6]=[CH:7][C:2]([C:34]4[CH:33]=[CH:32][N:31]=[C:30]([CH3:29])[CH:35]=4)=[CH:3][CH:4]=3)[CH3:9])[CH2:15][CH2:14]2)=[CH:22][CH:23]=1
Reactant: Cc1cc(B(O)O)ccn1
Reactant: C[C@@H](c1ccc(Br)cc1)N1CC[C@](CC(C)(C)O)(c2ccc(F)cc2)OC1=O
Product: Cc1cc(-c2ccc([C@H](C)N3CC[C@](CC(C)(C)O)(c4ccc(F)cc4)OC3=O)cc2)ccn1

Procedure:
The title compound was prepared from (S)-3-((S)-1-(4-bromophenyl)ethyl)-6-(4-fluorophenyl)-6-(2-hydroxy-2-methylpropyl)-1,3-oxazinan-2-one and 2-methylpyridine-4-boronic acid following a procedure analogous to that described in Example 1 Step 2. LC-MS Method 2 tR=0.976 min, m/z=463.8; 1H NMR (CDCl3) 1.09 (d, 6H), 1.49 (d, 3H), 2.16 (m, 4H), 2.35 (m, 1H), 2.56 (d, 3H), 2.85 (m, 1H), 5.65 (m, 1H), 6.94-7.05 (m, 4H), 7.17-7.26 (m, 4H), 7.34 (d, 2H), 8.47 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9](=[O:35])[NH:10][C:11]2[CH:16]=[CH:15][C:14]([C:17]3[CH:18]=[C:19]4[C:23](=[CH:24][CH:25]=3)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:34])[CH3:33])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]4)=[CH:13][CH:12]=2)=[CH:4][CH:3]=1.NC1C=CC(C2C=C3C(=CC=2)C(=O)N([C@@H](C(C)C)C(OC)=O)C3)=CC=1.[F:61]C1C=C(F)C=CC=1N=C=O>>[F:61][C:6]1[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=1[NH:8][C:9](=[O:35])[NH:10][C:11]1[CH:16]=[CH:15][C:14]([C:17]2[CH:18]=[C:19]3[C:23](=[CH:24][CH:25]=2)[C:22](=[O:26])[N:21]([C@@H:27]([CH:32]([CH3:33])[CH3:34])[C:28]([O:30][CH3:31])=[O:29])[CH2:20]3)=[CH:13][CH:12]=1
Reactant: O=C=Nc1ccc(F)cc1F
Reactant: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4)cc3)ccc2C1=O
Agent: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(N)cc3)ccc2C1=O
Product: COC(=O)[C@H](C(C)C)N1Cc2cc(-c3ccc(NC(=O)Nc4ccc(F)cc4F)cc3)ccc2C1=O

Procedure:
The compound of example 236 was prepared analogous to compound of example 224 by reaction of compound of example 223 with 2,4-difluorophenyl isocyanate. The compound of example 236 was used directly without isolation for the preparation of compound of example 237.
Reaction SMILES: [CH2:1]([N:3]([CH2:16][CH3:17])[C:4]1[O:5][C:6]2[C:7](=[C:9]([C:13]([O-:15])=O)[CH:10]=[CH:11][CH:12]=2)[N:8]=1)[CH3:2].[Li+].Cl.Cl.[NH2:21][C@H:22]1[CH:27]2[CH2:28][CH2:29][N:24]([CH2:25][CH2:26]2)[CH2:23]1>>[N:24]12[CH2:23][C@@H:22]([NH:21][C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:6]4[O:5][C:4]([N:3]([CH2:1][CH3:2])[CH2:16][CH3:17])=[N:8][C:7]=34)=[O:15])[CH:27]([CH2:28][CH2:29]1)[CH2:26][CH2:25]2
Reactant: N[C@@H]1CN2CCC1CC2
Reactant: CCN(CC)c1nc2c(C(=O)[O-])cccc2o1
Agent: Cl
Agent: [Li+]
Product: CCN(CC)c1nc2c(C(=O)N[C@@H]3CN4CCC3CC4)cccc2o1

Procedure:
Following general procedure GP-C2, lithium 2-(diethylamino)benzoxazole-4-carboxylate and (S)-(−)-3-aminoquinuclidine dihydrochloride were coupled to provide (S)—N-(quinuclidine-8-yl)-2-diethylaminobenzoxazole-4-carboxamide, which was converted to the hydrochloride salt following general procedure GP-D1. 1H NMR and MS consistent.
Reaction SMILES: [Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23](Cl)(=[O:25])=[O:24])[CH:3]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1.O>C(OCC)(=O)C>[Cl:1][C:2]1[C:7]2[O:8][C:9]3[C:18]([CH3:19])=[CH:17][C:16]([C:20]([OH:22])=[O:21])=[CH:15][C:10]=3[S:11](=[O:14])(=[O:13])[CH2:12][C:6]=2[CH:5]=[C:4]([S:23]([N:31]2[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]2)(=[O:25])=[O:24])[CH:3]=1
Reactant: CN1CCNCC1
Reactant: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)Cl)cc1CS2(=O)=O
Solvent: CCOC(C)=O
Solvent: O
Product: Cc1cc(C(=O)O)cc2c1Oc1c(Cl)cc(S(=O)(=O)N3CCN(C)CC3)cc1CS2(=O)=O

Procedure:
A mixture of Example 49j (0.2 g, 0.45 mmol) and 1-methyl-piperazine (0.08 mL, 0.9 mmol) in dry ethyl acetate was stirred overnight at 25° C., treated with water and extracted with ethyl acetate. The organic layer was washed with dil aqueous HCl (10%, 50 mL), water, brine, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound. Yield: 0.180 g, (80%) 1H NMR (DMSO-d6): δ 2.20 (s, 3H, CH3), 2.30 (s, 4H, CH2), 2.80 (s, 3H, CH3), 3.00 (s, 4H, CH2), 5.40 (s, 2H, CH2), 8.00 (s, 1H, Ar), 8.10 (s, 1H, Ar), 8.20 (s, 2H, Ar). MS: m/e (ES+) 501 (M+).
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[C:5]([C:7]([CH3:10])([CH3:9])[CH3:8])[NH:4][N:3]=1.C(=O)(O)[O-].[Na+].[C:16](Cl)(=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20].O>CC(C)=O>[C:7]([C:5]1[NH:4][N:3]=[C:2]([NH:1][C:16](=[O:21])[CH2:17][CH2:18][CH2:19][CH3:20])[CH:6]=1)([CH3:10])([CH3:9])[CH3:8]
Reactant: CC(C)(C)c1cc(N)n[nH]1
Reactant: CCCCC(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: CCCCC(=O)Nc1cc(C(C)(C)C)[nH]n1
Yield: 33.6 %

Procedure:
5.6 g (0.04 mole) of 3-amino-5-t-butylpyrazole prepared in Example 1 was dissolved in 50 ml of acetone, and 4 g of sodium bicarbonate was suspended thereinto. To the suspension was added dropwise 3.7 g of valeryl chloride with stirring. After completion of the dropwise addition, the mixture was further allowed to react at 40° C. for 3 hours. Water was added to the reaction mixture, from which the reaction product was extracted with methylene chloride, followed by the concentration of methylene chloride solution. Thereafter, hexane was added thereto whereby crystals were precipitated. The crystals were collected by filtration and washed with water and benzene to obtain 2.3 g of 5-t-butyl-3-valerylaminopyrazole.
Reaction SMILES: [N+:1]([O-:4])([O-])=[O:2].[K+].C[Si](Cl)(C)C.[C:11](=[O:27])([O:25][CH3:26])[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH2:19][CH3:20])=[CH:15][C:14]=1[C:21]([CH3:24])([CH3:23])[CH3:22].[Al+3].[Cl-].[Cl-].[Cl-]>C(Cl)Cl>[C:11](=[O:27])([O:25][CH3:26])[O:12][C:13]1[CH:18]=[C:17]([N+:1]([O-:4])=[O:2])[C:16]([CH2:19][CH3:20])=[CH:15][C:14]=1[C:21]([CH3:22])([CH3:23])[CH3:24]
Reactant: CCc1ccc(OC(=O)OC)c(C(C)(C)C)c1
Reactant: O=[N+]([O-])[O-]
Agent: C[Si](C)(C)Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: CCc1cc(C(C)(C)C)c(OC(=O)OC)cc1[N+](=O)[O-]
Reaction time: 0.25 h
Yield: 70 %

Procedure:
To a solution of KNO3 (3.9 g, 38.57 mmol) in DCM (50 mL) was added TMSCl (5.5 g, 50.62 mmol) and 2-tert-butyl-4-ethylphenyl methyl carbonate (6 g, 25.39 mmol) at 0° C. After stirring for 15 minutes, AlCl3 (10 g, 0.08 mol) was added and then the reaction mixture was stirred for 2 h. The reaction mixture was poured onto ice water and extracted with EtOAc (50 mL×3). The combined organic layers were dried over anhydrous Na2SO4, filtered and evaporated under vacuum to give the crude compound, which was purified by silica gel column chromatography (10-15% EtOAc in petroleum ether as eluant) to yield 2-tert-butyl-4-ethyl-5-nitrophenyl methyl carbonate (5 g, 70%). 1H NMR (400 MHz, CDCl3) 7.69 (s, 1H), 7.25 (s, 1H), 3.82 (s, 3H), 2.54 (q, J=7.6 Hz, 2H), 1.26 (s, 9H), 1.15 (d, J=7.6 Hz, 3H).
Reaction SMILES: [F:1][C:2]([F:13])([F:12])[C:3]1[N:4]=[C:5]2[CH2:10][NH:9][CH2:8][CH2:7][N:6]2[CH:11]=1.C(N(CC)CC)C.[Cl:21][C:22]1[C:30]([C:31]([F:34])([F:33])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25]>ClCCl>[Cl:21][C:22]1[C:30]([C:31]([F:33])([F:34])[F:32])=[CH:29][CH:28]=[CH:27][C:23]=1[C:24]([N:9]1[CH2:8][CH2:7][N:6]2[CH:11]=[C:3]([C:2]([F:12])([F:1])[F:13])[N:4]=[C:5]2[CH2:10]1)=[O:25]
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1Cl
Reactant: FC(F)(F)c1cn2c(n1)CNCC2
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCn2cc(C(F)(F)F)nc2C1
Temperature: 25 °C
Reaction time: 24 h
Yield: 100.5 %

Procedure:
2-(Trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (1.06 g, 5.55 mmol, Intermediate 4) and triethylamine (0.850 ml, 6.10 mmol) were dissolved in dichloromethane (DCM) (25 ml). 2-chloro-3-(trifluoromethyl)benzoyl chloride (1.348 g, 5.55 mmol) was added and the mixture stirred at room temperature for 24 h. The solvents were removed in vacuo and the solid partitioned between dichloromethane (100 ml) and saturated sodium bicarbonate solution (50 ml). The aqueous phase was extracted with dichloromethane (3×50 ml), the combine organic extracts were dried over anhydrous sodium sulfate and then concentrated to afford 7-{[2-chloro-3-(trifluoromethyl)phenyl]carbonyl}-2-(trifluoromethyl)-5,6,7,8-tetrahydroimidazo[1,2-a]pyrazine (2.22 g, 5.58 mmol, 101% yield).
Reaction SMILES: [CH:1]1([N:5]2[CH2:10][CH:9]3[CH:7]([CH:8]3[C:11]([OH:13])=O)[CH2:6]2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)(Cl)=O.[NH2:19][C:20]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([NH:33][NH2:34])=O)=[C:26]2[C:21]=1[CH2:22][CH2:23][CH2:24][O:25]2>>[Cl:30][C:29]1[C:20]([NH2:19])=[C:21]2[C:26](=[C:27]([C:31]3[O:13][C:11]([CH:8]4[CH:7]5[CH:9]4[CH2:10][N:5]([CH:1]4[CH2:2][CH2:3][CH2:4]4)[CH2:6]5)=[N:34][N:33]=3)[CH:28]=1)[O:25][CH2:24][CH2:23][CH2:22]2
Reactant: O=C(O)C1C2CN(C3CCC3)CC21
Reactant: NNC(=O)c1cc(Cl)c(N)c2c1OCCC2
Solvent: O=P(Cl)(Cl)Cl
Product: Nc1c(Cl)cc(-c2nnc(C3C4CN(C5CCC5)CC43)o2)c2c1CCCO2
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 14.1 %

Procedure:
To 3-cyclobutyl-3-aza bicyclo[3.1.0]hexane-6-carboxylic acid (74 mg, 0.40 mmol, obtained in preparation 8) was added phosphoryl chloride (1 mL). The mixture was stirred for 15 minutes and 5-amino-6-chloro chroman-8-carboxylic acid hydrazide (80 mg, 0.33 mmol) was added. The reaction mixture was gradually heated to reflux for 1 hour. The reaction mixture was cooled to room temperature, triturated with hexanes (2×20 mL) and the crude mass was basified with aqueous sodium bicarbonate solution. The basified mixture was extracted with 10% methanol in dichloromethane The organic layer was dried over anhydrous sodium sulphate and the solvent was removed under reduced pressure and was purified by silica gel column to obtain 6-chloro-8-[5-(3-cyclobutyl-3-aza bicyclo[3.1.0]hex-6-yl)-[1,3,4]oxadiazol-2-yl]chroman-5-yl amine (18 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:26][CH2:25][C:20]5(OCC[O:21]5)[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1.FC(F)(F)C(O)=O>ClCCl>[F:1][C:2]1[CH:3]=[CH:4][C:5]([O:27][CH3:28])=[C:6]([C:8]2[C:9]3[CH:16]=[C:15]([C:17]4[CH2:26][CH2:25][C:20](=[O:21])[CH2:19][CH:18]=4)[NH:14][C:10]=3[N:11]=[CH:12][N:13]=2)[CH:7]=1
Reactant: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC4(CC3)OCCO4)cc12
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COc1ccc(F)cc1-c1ncnc2[nH]c(C3=CCC(=O)CC3)cc12
Reaction time: 8 h

Procedure:
To a suspension of Example 83A (370 mg, 0.970 mmol) in 15 mL dichloromethane was added excess trifluoroacetic acid. The reaction was held at room temperature overnight. The volatiles were removed in vacuo, and the residue was dissolved in 30 mL ethyl acetate. The mixture was washed with saturated sodium bicarbonate and brine, dried over magnesium sulfate, and concentrated to give the title compound. MS (ESI+) m/z 338.2 (M+H)+.
Reaction SMILES: [CH3:1][CH:2]([CH3:38])[CH:3]([NH2:37])[CH:4]1[CH:9]([O:10]CC2C=CC=CC=2)[CH:8]([O:18]CC2C=CC=CC=2)[CH:7]([O:26]CC2C=CC=CC=2)[CH:6]([CH2:34][CH:35]=[CH2:36])[O:5]1.Cl>C1COCC1.[Pd]>[NH2:37][CH:3]([CH:4]1[CH:9]([OH:10])[CH:8]([OH:18])[CH:7]([OH:26])[CH:6]([CH2:34][CH2:35][CH3:36])[O:5]1)[CH:2]([CH3:38])[CH3:1]
Reactant: C=CCC1OC(C(N)C(C)C)C(OCc2ccccc2)C(OCc2ccccc2)C1OCc1ccccc1
Agent: [Pd]
Agent: Cl
Solvent: C1CCOC1
Product: CCCC1OC(C(N)C(C)C)C(O)C(O)C1O
Yield: 89 %

Procedure:
2-Methyl-1-(6-allyl-3,4,5-tris-benzyloxy-tetrahydro-pyran-2-yl)-propylamine, 15c 160 mg and 100 mg degussa 50% w/w wet 10% palladium/carbon under N2 was suspended in THF (5 mL) and 1 M aq. HCl (1 mL) the reaction mixture was stirred 24 h under 1 atm pressure H2. The reaction mixture was filtered through Celite evaporated to dryness to provide the product 2-(1-Amino-2-methyl-propyl)-6-propyl-tetrahydro-pyran-3,4,5-triol (60.8 mg 89%) as the HCl salt. TLC (CHCl3: MeOH: 32% aq. AcOH)Rf=0.35. MS (ESPOS): 248 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6](=[O:11])[C:5]2=[O:12].O1C2=CC3C(=O)C(=O)NC=3C=C2OCC1.Br[CH:29]([C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1.BrCC1OC(C(F)(F)F)=CC=1>>[Br:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[N:7]([CH:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1)[C:6](=[O:11])[C:5]2=[O:12]
Reactant: BrC(c1ccccc1)c1ccccc1
Reactant: O=C1Nc2ccc(Br)cc2C1=O
Agent: FC(F)(F)c1ccc(CBr)o1
Agent: O=C1Nc2cc3c(cc2C1=O)OCCO3
Product: O=C1C(=O)N(C(c2ccccc2)c2ccccc2)c2ccc(Br)cc21

Procedure:
Following the procedure as described in PREPARATION 26A and making non-critical variations using 5-bromoisatin to replace 2,3-dihydro-6H-[1,4]dioxino[2,3-f]indole-7,8-dione, and bromodiphenylmethane to replace 2-(bromomethyl)-5-(trifluoromethyl)furan, 5-bromo-1-(diphenylmethyl)-1H-indole-2,3-dione was obtained (76%): 1H NMR (300 MHz, CDCl3) δ 7.74-7.67 (m, 1H), 7.46-7.20 (m, 11H), 6.96 (s, 1H), 6.37 (d, J=8.5 Hz, 1H).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1)=O)C.[H-]>>[OH:3][CH2:4][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[N:12]=[CH:11][C:10]([C:16]#[N:17])=[C:9]2[C:18]1[CH:19]=[N:20][CH:21]=[CH:22][CH:23]=1
Reactant: CCOC(=O)c1ccc2ncc(C#N)c(-c3cccnc3)c2c1
Agent: [H-]
Product: N#Cc1cnc2ccc(CO)cc2c1-c1cccnc1

Procedure:
Similar procedure as described in example 61h was used, starting from 3-cyano-4-pyridin-3-yl-quinoline-6-carboxylic acid ethyl ester (example 63a), and diisobutylaminum hydride to give 6-hydroxymethyl-4-pyridin-3-yl-quinoline-3-carbonitrile. LC-MS m/e 262 (MH+).
Reaction SMILES: [C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:20]1[CH:25]=[CH:24][CH:23]=[C:22]([CH2:26][CH2:27][CH2:28][C:29](O)=[O:30])[CH:21]=1>CN(C)C=O.C(N(CC)CC)C.ClCCl>[C:1]1([CH:7]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH:8]2[CH2:9][CH2:10][N:11]([C:29](=[O:30])[CH2:28][CH2:27][CH2:26][C:22]3[CH:21]=[N:20][CH:25]=[CH:24][CH:23]=3)[CH2:12][CH2:13]2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C(O)CCCc1cccnc1
Reactant: c1ccc(C(c2ccccc2)C2CCNCC2)cc1
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(CCCc1cccnc1)N1CCC(C(c2ccccc2)c2ccccc2)CC1
Yield: 88.3 %

Procedure:
A mixture of 2.0 g of 4-diphenylmethylpiperidine in 5 mL of dimethylformamide and 4.2 mL of triethylamine was treated at 0° C. with a solution composed of 5 mL of dimethylformamide and the acid chloride prepared from 2.0 g of 3-pyridine butanoic acid. After 15 minutes the mixture was diluted with dichloromethane, filtered and evaporated to dryness. The residue was partitioned between toluene and 1N sodium hydroxide and the organic layer was washed with brine, dried over sodium sulfate and evaporated to give 3.3 g of crude oil. Purification was accomplished by chromatography on a Waters Prep 500 HPLC using silica gel columns and eluting with 98:2 ethyl acetate-triethylamine. The product consisted of a colorless oil which was dried under vacuum at 70° C. to give 2.8 g (86%) of 4-diphenylmethyl-1-[1-oxo-4-(3-pyridinyl)butyl]piperidine, 0.1 molar ethylacetate solvate. Analysis Calculated for C27H30N2O.O.1C4H8O 2 : C, 80.79; H, 7.62; N, 6.88. Found: C, 80.91; H, 7.57; N, 6.81.
Reaction SMILES: [N:1]1([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.Cl[C:15]1[CH:20]=[N:19][CH:18]=[CH:17][N:16]=1.C([O-])([O-])=O.[Cs+].[Cs+]>CS(C)=O>[N:16]1[CH:17]=[CH:18][N:19]=[CH:20][C:15]=1[N:4]1[CH2:5][CH2:6][N:1]([C:7]([O:9][C:10]([CH3:13])([CH3:12])[CH3:11])=[O:8])[CH2:2][CH2:3]1
Reactant: Clc1cnccn1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCN(c2cnccn2)CC1
Temperature: 60 °C
Yield: 59.2 %

Procedure:
A 500-mL single-neck round-bottomed flask equipped with a magnetic stirrer and a reflux condenser was charged with DMSO (250 mL), tert-butyl piperazine-1-carboxylate (15.8 g, 85.0 mmol), 2-chloropyrazine (9.7 g, 85.0 mmol), and Cs2CO3 (55.3 g, 170 mmol). The mixture was heated at 60° C. for 3 days. After this time the reaction was cooled to room temperature. It was then filtered and the filtrate was evaporated under reduced pressure. The residue was purified by silica-gel column chromatography eluting with 5:1 petroleum ether/ethyl acetate to afford 189a (13.3 g, 60%) as a yellow solid. MS: [M+H]+ 265.3