Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: F[C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1.[CH3:9][OH:10].C[O-].[Na+]>O>[CH3:9][O:10][C:2]1[C:7]([CH3:8])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: CO
Reactant: Cc1cccnc1F
Agent: C[O-]
Agent: [Na+]
Solvent: O
Product: COc1ncccc1C
Yield: 62.1 %

Procedure:
A mixture of 2-fluoro-3-methylpyridine (2.34 g, 21.1 mmol) and a 28% sodium methoxide methanol solution (7.72 g, 40 mmol) was stirred for 15 minutes under reflux. After the reaction was completed, water was poured into the reaction mixture, and after neutralized, the reaction mixture was extracted with ethyl acetate, dried over magnesium sulfate, and the solvent was evaporated, thereby yielding the title compound (1.62 g, 13.1 mmol, 62%) as a colorless liquid.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1.[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16](Cl)=[O:17]>CC(C)=O>[Br:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][C:16]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([CH3:9])[CH:3]=1)=[O:17]
Reactant: Cc1cc(N)ccc1O
Reactant: O=C(Cl)CCCCCBr
Solvent: CC(C)=O
Product: Cc1cc(NC(=O)CCCCCBr)ccc1O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 25 g (0.20 mol) of 4-amino-2-methylphenol in about 450 mL of acetone was stirred at room temperature and 20.6 g (0.09 mol) of 6-bromohexanoyl chloride was dripped in over 20 minutes. The reaction was stirred at room temperature for 3 hours then ice-cooled and filtered. The filtrate was stripped in vacuo to a residual oil which was triturated once in 225 mL of 1N HCl and then several times in cold water. The resulting gum was dissolved in absolute ethanol and 28 g of product (95%) were crystallized out by the addition of water, mp 111°-112° C. The product, which contained a small amount of 4-amino-2-methylphenol, was used as is in the following reaction.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1.B(Br)(Br)Br>C(Cl)Cl>[OH:2][C:3]1[CH:8]=[CH:7][C:6]([CH3:9])=[CH:5][C:4]=1[C:10]1[N:15]=[C:14]([N:16]2[C:20]([C:21]([F:24])([F:23])[F:22])=[C:19]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:18]=[N:17]2)[CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3OC)n2)c1C(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: CCOC(=O)c1cnn(-c2cccc(-c3cc(C)ccc3O)n2)c1C(F)(F)F
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a cooled (0° C.) solution of the title compound from Example 12 Step A (1.58 g, 3.90 mmol) in DCM (20 mL) was added boron tribromide (11.7 mL, 1.0 M in DCM, 11.7 mmol). After 15 min, the reaction mixture was allowed to warm to ambient temperature. After an additional 2 h, the reaction mixture was cooled to 0° C., then was quenched by dropwise addition of sat. aq. NaHCO3 (gas evolution) and was extracted with DCM. The organic phase was separated and concentrated in vacuo. Purification by flash chromatography on silica gel (0 to 30% EtOAc in hexanes, then 30 to 100% EtOAc in hexanes) provided the title compound: LCMS m/z 392.6 [M+H]+; 1H NMR (500 MHz, CDCl3) δ 11.78 (s, 1H), 8.17 (s, 1H), 8.07-8.03 (m, 2H), 7.60 (d, J=1.5 Hz, 1H), 7.48 (dd, J=7.0, 1.5 Hz, 1H), 7.17 (dd, J=8.0, 2.0 Hz, 1H), 6.94 (d, J=8.0 Hz, 1H), 4.39 (q, J=7.0 Hz, 2H), 2.36 (s, 3H), 1.40 (t, J=7.0 Hz, 3H).
Reaction SMILES: Br[C:2]1[C:11]([CH3:12])=[C:10]2[C:5]([CH2:6][CH2:7][CH2:8][C:9]32[S:16][CH2:15][CH2:14][S:13]3)=[C:4]([CH3:17])[CH:3]=1.C([Li])CCC.[C:23](=[O:25])=[O:24]>O1CCCC1.CCCCCC>[CH3:17][C:4]1[CH:3]=[C:2]([C:23]([OH:25])=[O:24])[C:11]([CH3:12])=[C:10]2[C:5]=1[CH2:6][CH2:7][CH2:8][C:9]12[S:16][CH2:15][CH2:14][S:13]1
Reactant: Cc1cc(Br)c(C)c2c1CCCC21SCCS1
Reactant: O=C=O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(C(=O)O)c(C)c2c1CCCC21SCCS1
Temperature: -78 °C
Reaction time: 0.5 h
Yield: 28.2 %

Procedure:
A solution of 12.7 g of the title compound of Step B in 300 mL of tetrahydrofuran under a nitrogen atmosphere was cooled to -78° C. To this solution was slowly added 19.2 mL of a 2.5M solution of n-butyllithium in hexane (purchased from Aldrich Chemical Co.). The reaction mixture was maintained below -60° C. during the addition of n-butyllithium and stirring 30 min after addition was complete. The mixture was then cooled to -78° C. and 35.0 g of crushed dry ice was added. The resulting mixture was stirred and allowed to warm to room over 1.5 h. The mixture was then concentrated under reduced pressure, and to the resulting residue was added 300 mL of water. The mixture was then cooled to 0° C., acidified to pH 2 with concentrated hydrochloric acid, and extracted with ethyl acetate. The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The resulting solid was crystallized from 1-chlorobutane to gave 3.2 g of the title compound of Step C as a white solid melting at 215° C. (dec.). 1H NMR ((CD3)2SO): δ 1.90 (m, 2H), 2.16 (s, 3H), 2.34 (m, 2H), 2.61 (t, 2H), 2.75 (s, 3H), 3.40-3.70 (m, 4H), 7.29 (s, 1H), 12.75 (br s, 1 H).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29]OS(C3C=CC(C)=CC=3)(=O)=O)[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[Br-:48].[Li+].CN(P(N(C)C)(N(C)C)=O)C>C(OCC)(=O)C>[C:1]1([CH2:7][CH2:8][C:9]([NH:11][C@H:12]([C:20]([NH:22][C@H:23]2[C@@H:26]([O:27][CH:28]([C:41]3[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=3)[CH2:29][Br:48])[NH:25][C:24]2=[O:47])=[O:21])[CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[O:10])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: [Br-]
Reactant: Cc1ccc(S(=O)(=O)OCC(O[C@H]2NC(=O)[C@H]2NC(=O)[C@H](Cc2ccccc2)NC(=O)CCc2ccccc2)c2ccccc2)cc1
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: O=C(CCc1ccccc1)N[C@@H](Cc1ccccc1)C(=O)N[C@@H]1C(=O)N[C@@H]1OC(CBr)c1ccccc1
Temperature: 60 °C
Reaction time: 1.5 h
Yield: 72.6 %

Procedure:
A mixture of (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-{2-(p-toluenesulfonyl)oxy-1 -phenylethoxy}azetidin-2-one (160 mg, 0.244 mmol), lithium bromide (133 mg, 1.525 mmol) and HMPA (4 ml) was stirred at 60° C. for 1.5 hrs. The resulting mixture was diluted with ethyl acetate, washed with water, brine, and dried over sodium sulfate. After removal of solvent, the residue was purified by silica gel column chromatography using hexane-ethyl acetate (1:2) as eluent and 100 mg (3S,4R)-3-{N-(3-phenylpropionoyl)-L-phenylalanyl}amino-4-(2-bromo-1-phenylethoxy)-azetidin-2-one as white foam was obtained in 72% yield.
Reaction SMILES: [CH3:1][N:2]1[CH2:8][CH:7]([OH:9])[CH2:6][N:5]([CH3:10])[CH2:4][CH2:3]1.C([Li])CCC.[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25](O)=[O:26])=[N:17]1>O1CCCC1.CCCCCC.CN(C)C=O>[NH:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]([C:25]([O:9][CH:7]2[CH2:6][N:5]([CH3:10])[CH2:4][CH2:3][N:2]([CH3:1])[CH2:8]2)=[O:26])=[N:17]1
Reactant: CN1CCN(C)CC(O)C1
Reactant: O=C(O)c1n[nH]c2ccccc12
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CN(C)C=O
Solvent: CCCCCC
Product: CN1CCN(C)CC(OC(=O)c2n[nH]c3ccccc23)C1
Temperature: 80 °C
Reaction time: 0.5 h
Yield: 67.5 %

Procedure:
To a solution of 1,4-dimethy-6-hydroxy- hexahydro-1H-1,4-diazepine (1.9 g) in anhydrous tetrahydrofuran (10 ml), a solution of n-butyllithium in hexane (9.4 g) is added dropwise under nitrogen stream at 25° C., and the mixture is stirred for 30 minutes at the same temperature. To the reaction mixture is added dropwise, the reaction mixture prepared by the following method; to a solution of 1H-indazole-3-carboxylic acid (2.0 g) in anhydrous N,N-dimethylformamide (20 ml), N,N'-carbonyldiimidazole (2.0 g) is added at 25° C., and the mixture is heated at 80° C. for 4.5 hours and cooled to 25° C. The resulting reaction mixture is refluxed with stirring for 1 hour. Tetrahydrofuran is evaporated under reduced pressure, and the residue is diluted with water, extracted with diethyl ether. The organic layer is washed with saturated sodium chloride solution and dried over magnesium sulfate. The solvent is evaporated under reduced pressure, and the residue is chromatographed on silica gel with elution of chloroform-methanol (9:1). Fractions containing the title compound are pooled and evaporated under reduced pressure to give the title compound (2.4 g) as an oil. The free base is converted to 5/2 fumarate 1/4 ethanol of the title compound in a usual manner, m.p. 184-185° C. (recrystallized from ethanol).
Reaction SMILES: [NH2:1][C:2]1[C:7]([NH2:8])=[C:6]([O:9][CH3:10])[CH:5]=[CH:4][C:3]=1[CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16].[O:20]1CCC[CH2:21]1>>[CH3:10][O:9][C:6]1[C:7]2[NH:8][C:21](=[O:20])[NH:1][C:2]=2[C:3]([CH2:11][CH2:12][N:13]([CH2:17][CH2:18][CH3:19])[CH2:14][CH2:15][CH3:16])=[CH:4][CH:5]=1
Reactant: CCCN(CCC)CCc1ccc(OC)c(N)c1N
Reactant: C1CCOC1
Product: CCCN(CCC)CCc1ccc(OC)c2[nH]c(=O)[nH]c12

Procedure:
530 mg of N-[2-(2,3-diamino-4-methoxyphenyl)ethyl]-N,N-dipropylamine is heated under reflux for one hour with 30 ml of tetrahydrofuran and 500 mg of N,N'-carbonyldiimidazole. After concentration, the residue is combined with methanol and water, again concentrated, and dried over phosphorus pentoxide, yielding 530 mg of 7-methoxy-4-[2-(N,N-dipropylamino)ethyl]-2,3-dihydro-2-benzimidazolone, mp 35° C.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]23[CH2:15][N:12]([CH2:13][CH2:14]2)[CH2:11][CH:10]=[CH:9]3)=[CH:4][N:3]=1.[C:16]1([C:22]([C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)([C:41]2[CH:46]=[CH:45][CH:44]=[CH:43][CH:42]=2)[N:23]2[CH:27]=[C:26]([Sn](CCCC)(CCCC)CCCC)[N:25]=[CH:24]2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1>O1CCCC1.C(Cl)(Cl)Cl.C(=O)([O-])[O-].[Na+].[Na+].Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:47]1([C:22]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)([C:41]2[CH:42]=[CH:43][CH:44]=[CH:45][CH:46]=2)[N:23]2[CH:27]=[C:26]([C:2]3[CH:7]=[CH:6][C:5]([C:8]45[CH2:15][N:12]([CH2:13][CH2:14]4)[CH2:11][CH:10]=[CH:9]5)=[CH:4][N:3]=3)[N:25]=[CH:24]2)[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Brc1ccc(C23C=CCN(CC2)C3)cn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Solvent: C1CCOC1
Product: C1=CC2(c3ccc(-c4cn(C(c5ccccc5)(c5ccccc5)c5ccccc5)cn4)nc3)CCN(C1)C2
Temperature: 85 °C

Procedure:
0.25 g (0.94 mmol) of 5-(2-bromopyrid-5-yl)-1-azabicyclo[3.2.1]oct-3-ene (WO 03/057 697) dissolved in 3 ml of tetrahydrofuran, 1.24 g (2.07 mmol) of 1-triphenylmethyl-4-tributylstannylimidazole and 0.06 g (0.08 mmol) of bis(triphenylphosphine)dichloropalladium are successively introduced into a 10 ml three-necked round-bottomed flask. The mixture is then heated at 85° C. for 15 hours and then diluted in 10 ml of chloroform and 10 ml of saturated aqueous sodium carbonate solution.
Reaction SMILES: C[O:2][C:3]([C@H:5]1[CH2:10][CH2:9][C@H:8]([O:11][C:12]2[CH:17]=[C:16]([CH3:18])[N:15]=[C:14]([CH3:19])[N:13]=2)[CH2:7][CH2:6]1)=O.O.[NH2:21][NH2:22]>C(O)CCC>[CH3:19][C:14]1[N:13]=[C:12]([O:11][C@H:8]2[CH2:9][CH2:10][C@H:5]([C:3]([NH:21][NH2:22])=[O:2])[CH2:6][CH2:7]2)[CH:17]=[C:16]([CH3:18])[N:15]=1
Reactant: COC(=O)[C@H]1CC[C@H](Oc2cc(C)nc(C)n2)CC1
Reactant: NN
Solvent: O
Solvent: CCCCO
Product: Cc1cc(O[C@H]2CC[C@H](C(=O)NN)CC2)nc(C)n1

Procedure:
A mixture of trans-4-(2,6-dimethyl-pyrimidin-4-yloxy)-cyclohexanecarboxylic acid methyl ester (0.20 g, 0.76 mmol) and hydrazine hydrate (0.15 ml, 3.0 mmol) in n-butanol (0.5 ml) was heated at reflux over night. The reaction mixture was evaporated and dried in high vacuo (ca. 1-2 mbar) to give the crude title compound (0.19 g, 95%) as white solid, which was used in the next step without further purification. MS m/e: 265 (M+H+)
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([OH:9])=[C:7]([O:10][CH3:11])[CH:6]=[C:5]([CH:12]=[O:13])[CH:4]=1.S(OC)(O[CH3:18])(=O)=O.C(=O)([O-])[O-].[K+].[K+].C(=O)=O>C1C=CC=CC=1.O>[CH3:11][O:10][C:7]1[CH:6]=[C:5]([CH:4]=[C:3]([O:2][CH3:1])[C:8]=1[O:9][CH3:18])[CH:12]=[O:13]
Reactant: COc1cc(C=O)cc(OC)c1O
Reactant: COS(=O)(=O)OC
Agent: O=C([O-])[O-]
Agent: O=C=O
Agent: [K+]
Solvent: O
Solvent: c1ccccc1
Product: COc1cc(C=O)cc(OC)c1OC
Temperature: 75 °C
Reaction time: 1 h

Procedure:
25.0g syringealdehyde (0.137 mol), 26.6g of dimethyl sulfate (0.211 mol), and 27.7 g. of potassium carbonate (0.201 mol) were heated with stirring as in Example 1. When the temperature reached 45° C the mixture became fluid and carbon dioxide was given off. The temperature was slowly increased to 75° C and held at this value for 1 hour. Addition of water, acidification, and benzene extraction gave a quantitative yield of 3,4,5-trimethoxybenzaldehyde which contained no detectable syringealdehyde or other impurities as determined by g.l.c. analysis.
Reaction SMILES: Cl.[NH:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1.[CH2:25]([S:27](Cl)(=[O:29])=[O:28])[CH3:26].C(N(CC)CC)C>C(Cl)Cl>[CH2:25]([S:27]([N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[C:16]3[C:11](=[C:12]([C:22]([NH2:24])=[O:23])[CH:13]=[C:14]([C:17]4[CH:21]=[CH:20][S:19][CH:18]=4)[CH:15]=3)[NH:10][N:9]=2)[CH2:4][CH2:3]1)(=[O:29])=[O:28])[CH3:26]
Reactant: CCS(=O)(=O)Cl
Reactant: NC(=O)c1cc(-c2ccsc2)cc2c(C3CCNCC3)n[nH]c12
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCS(=O)(=O)N1CCC(c2n[nH]c3c(C(N)=O)cc(-c4ccsc4)cc23)CC1

Procedure:
This compound was prepared in a fashion analogous to the procedure described in Example 3. Thus, 3-(4-piperidinyl)-5-(3-thienyl)-1H-indazole-7-carboxamide hydrochloride (Intermediate 19) (0.117 mmol) was reacted with ethane sulfonyl chloride (0.02 mL, 0.234 mmol) in the presence of triethylamine (0.04 mL, 0.468 mmol) in methylene chloride (10 mL) to give the title compound (9.4 mg, 19% for the last two steps)
Reaction SMILES: [C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:9]([O:15][C:16](=[O:18])[CH3:17])[C@@H:8]([CH2:19][O:20][C:21](=[O:23])[CH3:22])[O:7][C@H:6]1[O:24][C:25]1[CH:30]=[C:29]([CH3:31])[CH:28]=[C:27]([O:32][CH2:33][C:34](OC)=O)[C:26]=1C(=O)C)(=[O:3])[CH3:2].[C:41]1([CH3:49])[CH:46]=[CH:45][C:44]([CH:47]=O)=[CH:43][CH:42]=1.[OH-].[K+].Cl.[CH2:53](O)C>O>[C:1]([O:4][C@@H:5]1[C@@H:10]([O:11][C:12](=[O:14])[CH3:13])[C@H:19]([O:20][C:21](=[O:23])[CH3:22])[C@@H:8]([CH2:9][O:15][C:16](=[O:18])[CH3:17])[O:7][C@H:6]1[O:24][C:25]1[C:26]2[C:34]([CH2:53][CH2:47][C:44]3[CH:45]=[CH:46][C:41]([CH3:49])=[CH:42][CH:43]=3)=[CH:33][O:32][C:27]=2[CH:28]=[C:29]([CH3:31])[CH:30]=1)(=[O:3])[CH3:2]
Reactant: Cc1ccc(C=O)cc1
Reactant: COC(=O)COc1cc(C)cc(O[C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@H]2OC(C)=O)c1C(C)=O
Reactant: CCO
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(=O)OC[C@H]1O[C@@H](Oc2cc(C)cc3occ(CCc4ccc(C)cc4)c23)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a suspension of 2′-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6′-methoxycarbonylmethoxy-4′-methylacetophenone (0.35 g) and p-tolualdehyde (81 mg) in ethanol (10 mL) were added water (1.7 mL) and potassium hydroxide (0.41 g), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was poured into 1 mol/L hydrochloric acid (7.5 mL), and the resulting mixture was extracted with ethyl acetate twice. The extracts were combined and washed with brine, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (6 mL)-tetrahydrofuran (1 mL). To the solution was added 10% palladium-carbon powder (0.11 g), and the mixture was stirred at room temperature under a hydrogen atmosphere for 2 hours. The insoluble material was removed by filtration, and the filtrate was concentrated under reduced pressure. To the residue were added sodium acetate (1.15 g), acetic acid (6 mL) and acetic anhydride (1.16 mL), and the mixture was stirred at 115° C. overnight. The reaction mixture was cooled to room temperature and poured into water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with a saturated aqueous sodium hydrogen carbonate solution twice, water and brine successively, and dried over anhydrous magnesium sulfate. The solvent was removed under reduced pressure, and the residue was purified by column chromatography on silica gel (eluent: n-hexane/ethyl acetate=2/1) to give 4-(2,3,4,6-tetra-O-acetyl-β-D-glucopyranosyloxy)-6-methyl-3-[2-(4-methylphenyl)ethyl]benzofuran (0.11 g). This material was dissolved in methanol (5 mL). To the solution was added sodium methoxide (28% methanol solution, 0.036 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was purified by VARIAN BOND ELUT-SCX (eluent: methanol) to give the title compound (74 mg).
Reaction SMILES: [F:1][C:2]([F:35])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:26][CH2:25][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[NH:13][C:12]2=[O:24])[CH2:10][CH2:9]1)=[O:7].Cl[CH2:37][CH2:38][N:39]1[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]1>>[F:35][C:2]([F:1])([F:34])[C:3]1[CH:4]=[C:5]([CH:27]=[C:28]([C:30]([F:33])([F:32])[F:31])[CH:29]=1)[C:6]([N:8]1[CH2:9][CH2:10][C:11]2([N:15]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=3[CH3:22])[CH:14]([CH3:23])[N:13]([CH2:37][CH2:38][N:39]3[CH2:44][CH2:43][NH:42][CH2:41][CH2:40]3)[C:12]2=[O:24])[CH2:25][CH2:26]1)=[O:7]
Reactant: Cc1ccccc1N1C(C)NC(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2
Reactant: ClCCN1CCNCC1
Product: Cc1ccccc1N1C(C)N(CCN2CCNCC2)C(=O)C12CCN(C(=O)c1cc(C(F)(F)F)cc(C(F)(F)F)c1)CC2

Procedure:
The title compound, MS: m/e=626.1 (M+H+), was prepared in accordance with the general method of example 99 from (rac)-8-(3,5-bis-trifluoromethyl-benzoyl)-2-methyl-1-o-tolyl-1,3,8-triaza-spiro[4.5]decan-4-one and 1-(2-chloroethyl)-piperazine.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]([O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])=[C:6](B(O)O)[CH:7]=1.[CH2:17]([O:20][C:21]1([CH3:54])[CH2:26][CH2:25][N:24]([C:27]2[N:32]3[CH:33]=[C:34]([C:36]4[CH:41]=[CH:40][CH:39]=[C:38](Br)[CH:37]=4)[N:35]=[C:31]3[CH:30]=[C:29]([CH3:43])[C:28]=2[C@H:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:23][CH2:22]1)[CH:18]=[CH2:19].C(OC1(C)CCN(C2N3C=C(C4C=C(C5C=CC(F)=CC=5O[C@H](CC=C)C)C=CC=4)N=C3C=C(C)C=2[C@H](OC(C)(C)C)C(OC)=O)CC1)C=C>>[CH2:17]([O:20][C:21]1([CH3:54])[CH2:22][CH2:23][N:24]([C:27]2[N:32]3[CH:33]=[C:34]([C:36]4[CH:37]=[C:38]([C:6]5[CH:7]=[C:2]([F:1])[CH:3]=[CH:4][C:5]=5[O:11][C@H:12]([CH2:14][CH:15]=[CH2:16])[CH3:13])[CH:39]=[CH:40][CH:41]=4)[N:35]=[C:31]3[CH:30]=[C:29]([CH3:43])[C:28]=2[C@H:44]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])[C:45]([O:47][CH3:48])=[O:46])[CH2:25][CH2:26]1)[CH:18]=[CH2:19]
Reactant: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(Br)c4)cn23)CC1
Reactant: C=CC[C@H](C)Oc1ccc(F)cc1B(O)O
Agent: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5ccc(F)cc5O[C@@H](C)CC=C)c4)cn23)CC1
Product: C=CCOC1(C)CCN(c2c([C@H](OC(C)(C)C)C(=O)OC)c(C)cc3nc(-c4cccc(-c5cc(F)ccc5O[C@@H](C)CC=C)c4)cn23)CC1
Yield: 82 %

Procedure:
Prepared in 82% yield from (S)-(5-fluoro-2-(pent-4-en-2-yloxy)phenyl)boronic acid and (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(3-bromophenyl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate following the procedure for (S)-methyl 2-(5-(4-(allyloxy)-4-methylpiperidin-1-yl)-2-(4′-fluoro-2′-((S)-pent-4-en-2-yloxy)-[1,1′-biphenyl]-3-yl)-7-methylimidazo[1,2-a]pyridin-6-yl)-2-(tert-butoxy)acetate. LCMS (ESI, M+1): 684.4.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:7])[S:5][CH:6]=1.[B:8](OC(C)C)([O:13]C(C)C)[O:9]C(C)C.N#N.[Li]CCCC.CCCCCC.Cl>C1COCC1>[CH3:7][C:4]1[S:5][CH:6]=[C:2]([B:8]([OH:13])[OH:9])[CH:3]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Cc1cc(Br)cs1
Agent: Cl
Agent: N#N
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: Cc1cc(B(O)O)cs1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
4-Bromo-2-methylthiophene (300 mg, 1.69 mmol) and triisopropyl borate (486 μL, 2.12 mmol) were dissolved in THF (1 mL) and the solution was vacuumed and filled with N2 3 times. The solution was cooled to −70° C. using an acetone/dry ice bath. 2.5 M of n-BuLi in hexane (1.0 mL, 2.54 mmol) was added drop wise and the mixture was stirred for an additional 30 minutes while the temperature was held at −70° C. The reaction mixture was allowed to warm up to −20° C. and 2 mL of 3 N HCl was added. When the mixture was warmed up to room temperature, two layers were separated. The water layer was neutralized to about pH 7, using 5 N NaOH. Both layers were extracted with EtOAc and washed with brine. The organic layer was dried over anhydrous Na2SO4. The material was not further purified and was used directly in the next step. MS (ESI): 143.05 [M+H]+; HPLC tR=1.30 min (HPLC: Anayltical—2 min).
Reaction SMILES: Cl[C:2]1[N:7]2[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:10]=[C:6]2[CH:5]=[CH:4][CH:3]=1.[CH:20]1([NH2:26])[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1>>[CH:20]1([NH:26][C:2]2[N:7]3[N:8]=[C:9]([NH:11][C:12](=[O:19])[C:13]4[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=4)[N:10]=[C:6]3[CH:5]=[CH:4][CH:3]=2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: O=C(Nc1nc2cccc(Cl)n2n1)c1ccccc1
Reactant: NC1CCCCC1
Product: O=C(Nc1nc2cccc(NC3CCCCC3)n2n1)c1ccccc1

Procedure:
The title compound was prepared following procedure described for example 30 but starting from N-(5 chloro[1,2,4]triazolo[1,5-a]pyridin-2-yl)benzamide ((B3), 50 mg; 0.18 mmol; 1.0 eq.) and cyclohexylamine (1.0 mL) as an off-white powder (50 mg, 81%). HPLC, Rt: 3.33 min. (purity 94.3%). LC/MS, M+(ESI): 336.2, M−(ESI): 334.1.
Reaction SMILES: C1(CO[C:6]2[N:11]=[C:10]([C:12]([OH:14])=O)[CH:9]=[CH:8][C:7]=2[N:15]2[CH2:18][C:17]([F:20])([F:19])[CH2:16]2)CC1.C[C:22]1([CH2:26]N)[CH2:25][O:24][CH2:23]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.CC[N:52]([CH:56]([CH3:58])[CH3:57])[CH:53]([CH3:55])[CH3:54]>>[CH:53]([N:52]([CH:56]([CH3:58])[CH3:57])[C:12]([C:10]1[C:9]([O:24][CH2:25][CH:22]2[CH2:23][CH2:26]2)=[CH:8][C:7]([N:15]2[CH2:16][C:17]([F:19])([F:20])[CH2:18]2)=[CH:6][N:11]=1)=[O:14])([CH3:55])[CH3:54]
Reactant: O=C(O)c1ccc(N2CC(F)(F)C2)c(OCC2CC2)n1
Reactant: CC1(CN)COC1
Reactant: CCN(C(C)C)C(C)C
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Product: CC(C)N(C(=O)c1ncc(N2CC(F)(F)C2)cc1OCC1CC1)C(C)C

Procedure:
In analogy to the procedure described in Example 47 b), 6-cyclopropylmethoxy-5-(3,3-difluoro-azetidin-1-yl)-pyridine-2-carboxylic acid (Example 1 b)) was reacted with (3-methyloxetan-3-yl)methanamine (CAN 153209-97-3) in the presence of TBTU and DIEA to give the title compound as a byproduct as colorless oil; MS (EI): m/e=368.5 [MH+].
Reaction SMILES: [H-].[Na+].C(OP([CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13])(OCC)=O)C.[CH3:17][C:18]1[S:19][C:20]2[C:26]([CH:27]=O)=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1.O>O1CCCC1>[CH3:17][C:18]1[S:19][C:20]2[C:26](/[CH:27]=[CH:11]/[C:12]([O:14][CH2:15][CH3:16])=[O:13])=[CH:25][CH:24]=[CH:23][C:21]=2[N:22]=1
Reactant: Cc1nc2cccc(C=O)c2s1
Reactant: CCOC(=O)CP(=O)(OCC)OCC
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)/C=C/c1cccc2nc(C)sc12
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 101.1 %

Procedure:
Under nitrogen atmosphere, to a suspension of 60% sodium hydride (1.26 g, 31.5 mmol) in tetrahydrofuran (50 mL) was added a solution of ethyl diethylphosphonoacetate (7.06 g, 31.5 mmol) in tetrahydrofuran (50 mL) at 0° C. and the mixture was stirred for 20 min. To the reaction mixture was added a solution of 2-methyl-1,3-benzothiazole-7-carbaldehyde (4.60 g, 26.0 mmol) in tetrahydrofuran (100 mL), and the mixture was warmed to room temperature over 2 hr. Water was added and the mixture was extracted with ethyl acetate. The extract was washed with saturated brine, and dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane=1/1) to give the title compound (6.50 g, yield 98%).