Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(O)(C(F)(F)F)=O.C([O:12][C:13]([C:15]1[CH:16]=[N:17][N:18]([CH2:24][C:25]2[CH:30]=[CH:29][C:28]([C:31]([O:33][CH3:34])=[O:32])=[CH:27][CH:26]=2)[C:19]=1[S:20][CH2:21][CH2:22][CH3:23])=[O:14])(C)(C)C>C(Cl)Cl>[CH3:34][O:33][C:31]([C:28]1[CH:29]=[CH:30][C:25]([CH2:24][N:18]2[C:19]([S:20][CH2:21][CH2:22][CH3:23])=[C:15]([C:13]([OH:14])=[O:12])[CH:16]=[N:17]2)=[CH:26][CH:27]=1)=[O:32]
Reactant: CCCSc1c(C(=O)OC(C)(C)C)cnn1Cc1ccc(C(=O)OC)cc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCSc1c(C(=O)O)cnn1Cc1ccc(C(=O)OC)cc1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
TFA (1.5 ml) was added to a stirred solution of 1-(4-Methoxycarbonyl-benzyl)-5-propylsulfanyl-1H-pyrazole-4-carboxylic acid tert-butyl ester (Intermediate #46) (274 mg, 0.70 mmol) in DCM (6 ml). The reaction was stirred at ambient temperature for 3 hours then evaporated in vacuo. The resulting gum was sonicated with isohexane to yield a solid. The solvent was removed then the white solid was dissolved in EtOAc and evaporated in vacuo to yield the title compound as an off white solid (236 mg, 100%).
Reaction SMILES: [OH:1][B:2]1[C:6]2[CH:7]=[C:8]([O:12]C3CCCCO3)[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:3]1.Cl>C1COCC1>[OH:1][B:2]1[C:6]2[CH:7]=[C:8]([OH:12])[CH:9]=[C:10]([CH3:11])[C:5]=2[CH:4]([CH2:19][C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[O:3]1
Reactant: Cc1cc(OC2CCCCO2)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Agent: Cl
Solvent: C1CCOC1
Product: Cc1cc(O)cc2c1C(CC(=O)OC(C)(C)C)OB2O
Temperature: 25 °C
Reaction time: 8 h
Yield: 71.1 %

Procedure:
To a solution of tert-butyl 2-(1-hydroxy-4-methyl-6-(tetrahydro-2H-pyran-2-yloxy)-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (2.2 g, 6.07 mmol) in 15 mL THF was added 2N HCl (6 mL) at 0° C. The mixture was stirred overnight at room temperature and concentrated in vacuo. The residue was purified by column to give the desired product (1.2 g, yield: 71%).
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([C:9]2[CH:10]=[C:11]([CH:20]=[CH:21][C:22]=2[CH3:23])[C:12]([NH:14][CH2:15][C:16]([NH:18]C)=[O:17])=[O:13])[C:5]([CH3:24])=[N:4][C:3]=1[O:25][CH2:26][C:27]1[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=1[F:34].Cl.[CH3:36]NC(=O)CN>>[NH2:18][C:16]([C@@H:15]([NH:14][C:12](=[O:13])[C:11]1[CH:20]=[CH:21][C:22]([CH3:23])=[C:9]([N:6]2[C:7](=[O:8])[C:2]([Br:1])=[C:3]([O:25][CH2:26][C:27]3[CH:32]=[CH:31][C:30]([F:33])=[CH:29][C:28]=3[F:34])[N:4]=[C:5]2[CH3:24])[CH:10]=1)[CH3:36])=[O:17]
Reactant: CNC(=O)CNC(=O)c1ccc(C)c(-n2c(C)nc(OCc3ccc(F)cc3F)c(Br)c2=O)c1
Reactant: CNC(=O)CN
Agent: Cl
Product: Cc1ccc(C(=O)N[C@@H](C)C(N)=O)cc1-n1c(C)nc(OCc2ccc(F)cc2F)c(Br)c1=O
Yield: 45 %

Procedure:
The title compound was prepared by employing a similar procedure as described for (±) 3-[5-bromo-4-[(2,4-difluorobenzyl)oxy]-2-methyl-6-oxopyrimidin-1(6H)-yl]-4-methyl-N-{1-[(methylamino)carbonyl]methyl}benzamide, substituting S-alanineamide hydrochloride for N-methylglycineamide hydrochloride. Yield 45%: 1H NMR (CD3OD/400 MHz) δ 7.96 (m,1H), 7.73 (dd, 1H, J=2.0 Hz), 7.62 (m, 1H), 7.55 (d, 1H, J=8.0 Hz), 7.01 (m, 2H), 5.56 (abq, 2H), 4.55 (abq, 1H), 2.18 (s, 3H), 2.14 (s, 3H), and 1.45 (d, 3H, J=7.2 Hz); ES-HRMS m/z 535.0757 (M+H calcd for C23H22N4O4F2 Br requires 535.0787). 19F NMR (CD3OD/400 MHz) −111.86 (m) and −115.90 (m).
Reaction SMILES: C[O:2][CH:3](OC)[C:4]1[CH:9]=[C:8]([CH:10]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:22][C:23](=[O:25])[CH3:24].C(O)(=O)C>O>[CH:3]([C:4]1[CH:9]=[C:8]([CH:10]([N:17]2[CH:21]=[CH:20][N:19]=[CH:18]2)[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH:7]=[CH:6][C:5]=1[NH:22][C:23](=[O:25])[CH3:24])=[O:2]
Reactant: COC(OC)c1cc(C(c2ccccc2)n2ccnc2)ccc1NC(C)=O
Solvent: O
Solvent: CC(=O)O
Product: CC(=O)Nc1ccc(C(c2ccccc2)n2ccnc2)cc1C=O
Yield: 100 %

Procedure:
A solution of 2.5 parts of intermediate 67, namely N-[2-(dimethoxymethyl)-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide, 52.5 parts of acetic acid and 10 parts of water was stirred for 1/2 hour at reflux temperature. The reaction mixture was evaporated and the residue was co-evaporated with methylbenzene, yielding 2.2 parts (100%) of N-[2-formyl-4-[(1H-imidazol-1-yl)phenylmethyl]phenyl]acetamide (interm. 68).
Reaction SMILES: [CH2:1]([N:3]([CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1)[C:4]1[CH:5]=[C:6]([C:15]#[C:16][CH:17]2[CH2:22][CH2:21][N:20]([C:23]([O:25][C:26]([CH3:29])([CH3:28])[CH3:27])=[O:24])[CH2:19][CH2:18]2)[CH:7]=[C:8]([C:11]([O:13]C)=[O:12])[C:9]=1[CH3:10])[CH3:2].[OH-].[Na+]>C(O)C.O>[C:26]([O:25][C:23]([N:20]1[CH2:21][CH2:22][CH:17]([C:16]#[C:15][C:6]2[CH:5]=[C:4]([N:3]([CH2:1][CH3:2])[CH:30]3[CH2:35][CH2:34][O:33][CH2:32][CH2:31]3)[C:9]([CH3:10])=[C:8]([CH:7]=2)[C:11]([OH:13])=[O:12])[CH2:18][CH2:19]1)=[O:24])([CH3:28])([CH3:29])[CH3:27]
Reactant: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)OC)c1C)C1CCOCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CCN(c1cc(C#CC2CCN(C(=O)OC(C)(C)C)CC2)cc(C(=O)O)c1C)C1CCOCC1
Temperature: 60 °C
Yield: 98.7 %

Procedure:
To a solution of tert-butyl 4-((3-(ethyl(tetrahydro-2H-pyran-4-yl)amino)-5-(methoxycarbonyl)-4-methylphenyl)ethynyl)piperidine-1-carboxylate (2.4 g, 4.95 mmol) in ethanol (20.0 mL) was added a solution of sodium hydroxide (0.565 g, 14.1 mmol) in water (3.0 ml) at rt. The reaction mixture was heated at 60° C. for 6 h. The reaction was quenched with 1M HCl (5 mL) and then excess citric acid solution to adjust to the pH to 5. The mixture was concentrated to remove EtOH and the remaining aqueous phase was extracted with AcOEt (2×40 mL). The organic layers were combined, dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (10%-100% AcOEt/Heptane) to give the titled compound (2.30 g, 99% yield). 1H-NMR (500 MHz) δ ppm; 7.82 (s, 1H), 7.35 (s, 1H), 3.98 (brd, J=11.3 Hz, 2H), 3.77 (m, 2H), 3.35 (dt, J=1.5, 11.3 Hz, 2H), 3.25 (ddd, J=3.4, 8.3, 12.2 Hz, 2H), 3.11 (brs, 2H), 3.00 (brs, 1H), 2.81 (dddd, J=3.9, 3.9, 3.9, 3.9 Hz, 1H), 2.60 (s, 3H), 1.88 (m, 2H), 1.60-1.78 (m, 6H), 1.48 (s, 9H), 0.90 (t, J=6.8 Hz, 3H); MS (ESI) [M+H]+471.4.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]2[C:14](=[CH:15][CH:16]=1)[NH:13][C:12]([CH3:18])([CH3:17])[CH:11]=[C:10]2[CH3:19]>N1C=CC=CC=1>[C:1]([N:13]1[C:14]2[C:9](=[CH:8][C:7]([O:6][CH3:5])=[CH:16][CH:15]=2)[C:10]([CH3:19])=[CH:11][C:12]1([CH3:18])[CH3:17])(=[O:3])[CH3:2]
Reactant: COc1ccc2c(c1)C(C)=CC(C)(C)N2
Reactant: CC(=O)Cl
Solvent: c1ccncc1
Product: COc1ccc2c(c1)C(C)=CC(C)(C)N2C(C)=O
Reaction time: 18 h

Procedure:
Acetyl chloride (8 ml) was added dropwise to a cooled (0° C.) solution of 1,2-dihydro-6-methoxy-2,2,4-trimethylquinoline (1.7 g) and a catalytic amount of N,N-dimethylaminopyridine in pyridine (60 ml). After stirring for 18 h, the reaction mixture was concentrated in vacuo. The residue was dissolved in dichloromethane and washed with 1 M HCl, water, 5% aq. NaHCO3, water and brine. The organic layer was dried (MgSO4) and concentrated in vacuo. The residue was chromatographed on silicagel in dichloromethane as eluent.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]([OH:23])=[C:19]([OH:24])[CH:18]=1.C(=O)([O-])[O-].[K+].[K+].Br[C:32](Br)([C:38]([O:40][CH2:41][CH3:42])=[O:39])[C:33]([O:35][CH2:36][CH3:37])=[O:34]>CN(C)C=O>[Br:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8](=[O:12])[NH:7][C:6](=[O:13])/[C:5]/2=[CH:14]\[NH:15][CH2:16][C:17]1[CH:22]=[CH:21][C:20]2[O:23][C:32]([C:33]([O:35][CH2:36][CH3:37])=[O:34])([C:38]([O:40][CH2:41][CH3:42])=[O:39])[O:24][C:19]=2[CH:18]=1
Reactant: O=C1NC(=O)c2ccc(Br)cc2/C1=C/NCc1ccc(O)c(O)c1
Reactant: CCOC(=O)C(Br)(Br)C(=O)OCC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C1(C(=O)OCC)Oc2ccc(CN/C=C3\C(=O)NC(=O)c4ccc(Br)cc43)cc2O1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of (Z)-6-bromo-4-((3,4-dihydroxybenzylamino)methylene)isoquinoline-1,3(2H,4H)-dione (195 mg, 0.50 mmole), dimethylformamide (5 mL), potassium carbonate (415 mg, 3.0 mmole) and diethyl 2,2-dibromomalonate (159 mg, 0.50 mmole) is stirred at room temperature overnight. The reaction mixture is filtered and washed with dimethylformamide, the filtrate is evaporated dissolved in 2% methanol in chloroform and passed through a pad of Florisil. The eluate is evaporated to give a beige solid, 114 mg, (41%), mp 222-3° C.; MS (ES+): m/z 545.1 (M+H).
Reaction SMILES: [OH-].[Na+].[OH:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1.Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>C(O)C>[CH2:14]([O:3][C:4]1[CH:12]=[CH:11][C:7]([C:8]([OH:10])=[O:9])=[CH:6][CH:5]=1)[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23]
Reactant: CCCCCCCCCCBr
Reactant: O=C(O)c1ccc(O)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCCCOc1ccc(C(=O)O)cc1
Yield: 73 %

Procedure:
2.11 g of sodium hydroxide was dissolved in 50 ml of ethyl alcohol and to the solution were added 2.6 g of para-hydroxy benzoic acid and 5.8 ml of 1-bromodecane. After the mixture was refluxed for 15 hours, 25 ml of 10% aqueous sodium hydroxide solution was added and refluxed for another two hours. After cooling, concentrated HCl was dropped into the solution until it was acidic. Filtration and recrystallization from ethyl alcohol gave 3.8 g of pure product (yield 73%).
Reaction SMILES: O[CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1.C(Br)(Br)(Br)[Br:21].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:21][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][CH2:10][C:11]2[N:12]=[C:13]([NH:16][C:17](=[O:19])[CH3:18])[S:14][CH:15]=2)=[CH:5][CH:4]=1
Reactant: CC(=O)Nc1nc(CCc2ccc(CO)cc2)cs1
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: CC(=O)Nc1nc(CCc2ccc(CBr)cc2)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 78.2 %

Procedure:
To a mixture of N-(4-(2-[4-(hydroxymethyl)phenyl]ethyl)-1,3-thiazol-2-yl)acetamide (50 mg) prepared in a similar manner according to Step 3 of the following Production Example 16, carbon tetrabromide (72 mg) and dichloromethane (1 ml) was added triphenylphosphine (71 mg), and the mixture was stirred at ambient temperature for 1 hour. The reaction mixture was purified by flash column chromatography on silica gel with 1% methanol/chloroform as an eluent. The crystalline residue was collected and washed with diisopropyl ether to give N-(4-{2-[4-(bromomethyl)phenyl]ethyl}-1,3-thiazol-2-yl)acetamide (48 mg).
Reaction SMILES: [CH2:1]([S:4][C:5]1[N:10]=[C:9]([OH:11])[CH:8]=[C:7]([OH:12])[N:6]=1)[CH2:2][CH3:3].[N+:13]([O-])([OH:15])=[O:14]>>[N+:13]([C:8]1[C:7]([OH:12])=[N:6][C:5]([S:4][CH2:1][CH2:2][CH3:3])=[N:10][C:9]=1[OH:11])([O-:15])=[O:14]
Reactant: O=[N+]([O-])O
Reactant: CCCSc1nc(O)cc(O)n1
Product: CCCSc1nc(O)c([N+](=O)[O-])c(O)n1

Procedure:
According to U.S. Pat. No. 5,747,496, the 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine of formula II is prepared by adding propyl iodide to a suspension of 4,6-dihydroxy-2-mercaptopyrimidine in water containing sodium hydroxide; the reaction mixture is stirred for 2 weeks and then the reaction mass is concentrated to half volume; followed by the addition of hydrochloric acid and isolating the product by filtration to produce 2-propylthio-pyrimidine-4,6-diol. The 2-propylthio-pyrimidine-4,6-diol is then reacted with excess fuming nitric acid to produce 5-nitro-2-propylthiopyrimidine-4,6-diol. The 5-nitro-2-propylthiopyrimidine-4,6-diol is reacted with phosphoryl chloride in the presence of N,N-dimethylaniline at reflux to produce a reaction mass. The cooled reaction mass is poured onto ice followed by extracting with diethyl ether to afford a solution; then the combined extracts are dried and concentrated. The residue is chromatographed (SiO2, light petrol) to produce 4,6-dichloro-5-nitro-2-(propylthio)pyrimidine.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][C:11]([OH:13])=[O:12])=[CH:4][CH:3]=1.[CH3:14][C:15](=[CH2:17])[CH3:16]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH2:8][CH2:9][CH2:10][C:11]([O:13][C:15]([CH3:17])([CH3:16])[CH3:14])=[O:12])=[CH:6][CH:7]=1
Reactant: C=C(C)C
Reactant: O=C(O)CCCc1ccc(F)cc1
Product: CC(C)(C)OC(=O)CCCc1ccc(F)cc1

Procedure:
In Scheme A, step 1, 4-(p-fluorophenyl)butyric acid is contacted with isobutylene to give t-butyl 4-(p-fluorophenyl)butyrate.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=[CH:4][C:3]=1[NH:12][C:13](=O)[C:14]([CH3:17])([CH3:16])[CH3:15].Cl.[CH:20]([O:23][NH2:24])([CH3:22])[CH3:21]>C(O)(C)C>[C:14]([C:13]1[N:24]([O:23][CH:20]([CH3:22])[CH3:21])[C:2]2[C:11]3[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=3[N:5]=[CH:4][C:3]=2[N:12]=1)([CH3:17])([CH3:16])[CH3:15]
Reactant: CC(C)ON
Reactant: CC(C)(C)C(=O)Nc1cnc2ccccc2c1Cl
Agent: Cl
Solvent: CC(C)O
Product: CC(C)On1c(C(C)(C)C)nc2cnc3ccccc3c21
Temperature: 80 °C
Yield: 43.3 %

Procedure:
Under a nitrogen atmosphere, a mixture of N-(4-chloroquinolin-3-yl)trimethylacetamide (6.00 g, 1 eq), O-isopropylhydroxylamine hydrochloride (7.6 g, 3 eq), and anhydrous isopropanol (80 mL) was heated at 80° C. for 19 hours. The reaction mixture was concentrated under reduced pressure. The residue was dissolved in dichloromethane, washed sequentially with saturated aqueous potassium carbonate, water, and brine, dried over sodium sulfate, filtered, and then concentrated under reduced pressure. The residue was purified by column chromatography (150 g of silica gel eluted with a gradient of 20-55% ethyl acetate in dichloromethane) to provide 2.8 g of 2-tert-butyl-1-isopropoxy-1H-imidazo[4,5-c]quinoline as a brown oil.
Reaction SMILES: [NH2:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][OH:11].[C:19]([N:27]=[C:28]=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>ClCCl>[C:19]([NH:27][C:28]([NH:1][C@@:2]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[F:18])[CH2:7][CH2:6][CH:5]([O:8][CH3:9])[CH2:4][C@H:3]1[CH2:10][OH:11])=[S:29])(=[O:26])[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1
Reactant: COC1CC[C@@](N)(c2ccccc2F)[C@H](CO)C1
Reactant: O=C(N=C=S)c1ccccc1
Solvent: ClCCl
Product: COC1CC[C@@](NC(=S)NC(=O)c2ccccc2)(c2ccccc2F)[C@H](CO)C1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
(±)-[(1R*,2S*)-2-Amino-2-(2-fluorophenyl)-5-methoxycyclohexyl]methanol obtained in Preparation Example 59-(6) (5.49 g) was dissolved in dichloromethane (22 mL). Then, benzoyl isothiocyanate (3.04 mL, specific gravity: 1.21 g/cm3) was added and the mixture was stirred at room temperature for 16 hours and 30 minutes. The reaction solution was concentrated under reduced pressure and then purified by silica gel column chromatography to obtain the title compound (7.16 g).
Reaction SMILES: [O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([OH:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].C(=O)([O-])O.[Na+:28]>O>[O:1]=[C:2]1[C:10]2[C:5](=[CH:6][C:7]([O:13][CH2:14][C:15]([O-:17])=[O:16])=[C:8]([Cl:12])[C:9]=2[Cl:11])[CH2:4][C:3]1([CH:19]1[CH2:23][CH2:22][CH2:21][CH2:20]1)[CH3:18].[Na+:28]
Reactant: CC1(C2CCCC2)Cc2cc(OCC(=O)O)c(Cl)c(Cl)c2C1=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C2CCCC2)Cc2cc(OCC(=O)[O-])c(Cl)c(Cl)c2C1=O

Procedure:
100 mg of (1-oxo-2-cyclopentyl-2-methyl-6,7-dichloro-5-indanyloxy)acetic acid are dissolved in 3 ml. of 0.1 N-sodium hydrogen carbonate solution. The solution is made up to 10 ml with water and sterilized.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]([OH:12])[C:5]2[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=2)[CH:7]=1.[C:13]([N:17]1[CH:21]=[C:20](B2OC(C)(C)C(C)(C)O2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14].C([O-])([O-])=O.[Cs+].[Cs+].COCCOC>O>[C:13]([N:17]1[CH:21]=[C:20]([C:2]2[CH:3]=[C:4]([OH:12])[C:5]3[N:6]([N:8]=[C:9]([CH3:11])[CH:10]=3)[CH:7]=2)[CH:19]=[N:18]1)([CH3:16])([CH3:15])[CH3:14]
Reactant: CC(C)(C)n1cc(B2OC(C)(C)C(C)(C)O2)cn1
Reactant: Cc1cc2c(O)cc(Cl)cn2n1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: COCCOC
Product: Cc1cc2c(O)cc(-c3cnn(C(C)(C)C)c3)cn2n1
Temperature: 80 °C
Yield: 48.7 %

Procedure:
To a mixture 6-chloro-2-methylpyrazolo[1,5-a]pyridin-4-ol 6.59 (17 mg), 1-(tert-butyl)-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-pyrazole (19 mg), Cs2CO3 (76 mg) and PEPPSI-IPr (6 mg) was added DME and water (2:1, 3 mL) and the reaction mixture was heated to 80° C. for 2 h. The mixture was then extracted with ethyl acetate. Combined organics were washed with brine, dried, filtered, and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography to provide 10 mg of 6-(1-(tert-butyl)-1H-pyrazol-4-yl)-2-methylpyrazolo[1,5-a]pyridin-4-ol. LCMS [M+H]+: 271.12.
Reaction SMILES: [CH:1]1[C:6]([CH:7]=[O:8])=[CH:5][C:4]2[O:9][CH2:10][O:11][C:3]=2[CH:2]=1.[CH2:12]1[O:20][C:19]2[C:14](=[CH:15][CH:16]=[C-:17][CH:18]=2)[O:13]1.[Mg+2].[Br-]>ClCCl>[CH2:10]1[O:11][C:3]2[CH:2]=[CH:1][C:6]([CH:7]([C:17]3[CH:16]=[CH:15][C:14]4[O:13][CH2:12][O:20][C:19]=4[CH:18]=3)[OH:8])=[CH:5][C:4]=2[O:9]1
Reactant: [c-]1ccc2c(c1)OCO2
Reactant: O=Cc1ccc2c(c1)OCO2
Agent: [Br-]
Agent: [Mg+2]
Solvent: ClCCl
Product: OC(c1ccc2c(c1)OCO2)c1ccc2c(c1)OCO2
Temperature: 25 °C
Reaction time: 8 h
Yield: 87 %

Procedure:
To a solution of piperonal (0.75 g) in solution in dichloromethane (25 ml) was added dropwise 3,4-(methylenedioxy)phenylmagnesium bromide (5 ml, 1M solution in toluene/THF). The mixture was stirred at room temperature overnight, then poured onto water, extracted with dichloromethane, dried and evaporated in vacuo to give the crude alcohol as a brown gum. Purification by column chromatography over silica gel eluting with ethyl acetate in CH2Cl2 (10 to 20%) gave the pure alcohol as a white gum (1.18 g, 87%).
Reaction SMILES: Cl[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[NH2:9][C:10]1[CH:11]=[C:12]([OH:16])[CH:13]=[CH:14][CH:15]=1.N1C=CN=C1>ClCCl>[Si:2]([O:16][C:12]1[CH:11]=[C:10]([CH:15]=[CH:14][CH:13]=1)[NH2:9])([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3]
Reactant: Nc1cccc(O)c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1cccc(N)c1
Temperature: 25 °C
Reaction time: 15 h
Yield: 99.4 %

Procedure:
Chloro t-butyldimethylsilane (11 g, 72.98 mmol), 3-aminophenol (6.64 g, 60.81 mmol) and imidazole (5.38 g, 79.10 mmol) were added into 200 ml of dichloromethane. The mixture was stirred at room temperature for 15 hours. The reaction mixture was extracted using 200 ml of saturated ammonium chloride and 200 m of dichloromethane and the organic layer was washed twice using 200 ml of water. After concentrated under vacuum, the title compound (13.5 g, 99%) was obtained.
Reaction SMILES: [Li]CCCC.Br[C:7]1[CH:8]=[CH:9][C:10]([C:18]([OH:20])=[O:19])=[N:11][C:12]=1[O:13][CH2:14][CH:15]1[CH2:17][CH2:16]1.[C:21]1(=[O:25])[CH2:24][CH2:23][CH2:22]1>C1COCC1>[CH:15]1([CH2:14][O:13][C:12]2[N:11]=[C:10]([C:18]([OH:20])=[O:19])[CH:9]=[CH:8][C:7]=2[C:21]2([OH:25])[CH2:24][CH2:23][CH2:22]2)[CH2:17][CH2:16]1
Reactant: O=C1CCC1
Reactant: O=C(O)c1ccc(Br)c(OCC2CC2)n1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1ccc(C2(O)CCC2)c(OCC2CC2)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
Under nitrogen atmosphere, BuLi (0.58 mL, 0.89 mmol) was added dropwise to a solution of 5-bromo-6-cyclopropylmethoxy-pyridine-2-carboxylic acid (Example 9 d, 0.2 g, 0.74 mmol) in THF (20 mL) at −78° C. The reaction mixture was stirred for 1 h at −78° C. then cyclobutanone (CAN 1191-95-3, 1.11 mL, 1.47 mmol) in THF (3 mL) was added to the above solution at −78° C. The reaction mixture was allowed to warm to ambient temperature and stirred for 1 h. The reaction mixture was then quenched with NH4Cl and the pH was adjusted to 2 by addition of 1 N HCl. The mixture was extracted with ethyl acetate (3×10 mL); the organic layers were combined, washed with brine (2×10 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was used for the next step without further purification; MS (EI): m/e=264.1 [M+H]+.
Reaction SMILES: [C:1]([Mg]Br)#[CH:2].[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11](=[O:13])[CH3:12])[CH:7]=1>O1CCCC1>[CH3:5][C:6]1[O:10][N:9]=[C:8]([C:11]([OH:13])([C:1]#[CH:2])[CH3:12])[CH:7]=1
Reactant: C#C[Mg]Br
Reactant: CC(=O)c1cc(C)on1
Solvent: C1CCOC1
Product: C#CC(C)(O)c1cc(C)on1
Temperature: 25 °C
Reaction time: 3 h
Yield: 76.2 %

Procedure:
To a stirred solution of ethynylmagnesium bromide (0.5 M in THF, 50 mL, 25 mmol) maintained under nitrogen below 0° C. was added a solution of 1-(5-methyl-1,2-oxazol-3-yl)ethan-1-one (2.5 g, 19.98 mmol) in tetrahydrofuran (20 mL) dropwise over 5 min. The resulting solution was warmed to room temperature and then stirred for a further 3 hr. The reaction was quenched by the addition of saturated ammonium chloride solution (100 mL) then extracted with ethyl acetate (2×100 mL). The combined organic layers was washed with brine (200 mL), dried with anhydrous sodium sulphate and concentrated in vacuo. The residue was purified on a silica gel column, elution with ethyl acetate/petroleum ether (0:1-1:4) afforded the title compound (2.3 g, 75%) as a colorless oil: 1H NMR (300 MHz, CDCl3) delta 6.12 (s, 1H), 3.47 (s, 1H), 2.63 (s, 1H), 2.42 (s, 3H), 1.86 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][NH:8]2)=[CH:4][CH:3]=1.Cl[CH2:28][CH2:29][N:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([C:11]([N:13]3[CH2:18][CH2:17][C:16]4([C:22]5[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=5[CH2:20][O:19]4)[CH2:15][CH2:14]3)=[O:12])=[CH:7][N:8]2[CH2:28][CH2:29][N:30]2[CH2:35][CH2:34][O:33][CH2:32][CH2:31]2)=[CH:4][CH:3]=1
Reactant: ClCCN1CCOCC1
Reactant: O=C(c1c[nH]c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Product: O=C(c1cn(CCN2CCOCC2)c2cc(Cl)ccc12)N1CCC2(CC1)OCc1ccccc12
Yield: 50 %

Procedure:
Following the general procedure III as described above, the alkylation of 1′-[(6-chloro-1H-indol-3-yl)carbonyl]-3H-spiro[2-benzofuran-1,4′-piperidine] (prepared according to example 69) with commercially available 4-(2-chloro-ethyl)-morpholine gave the title compound in 50% yield. ES-MS m/e (%): 480.5(M+H+).
Reaction SMILES: [CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][C:12](OC)=[O:13])[CH:2]=[CH2:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH2:1]([O:4][CH2:5][CH2:6][O:7][CH2:8][CH2:9][O:10][CH2:11][CH2:12][OH:13])[CH:2]=[CH2:3]
Reactant: C=CCOCCOCCOCC(=O)OC
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCOCCOCCOCCO
Reaction time: 0.5 h

Procedure:
To a stirred solution of ester (14) (4.60 g, 21.1 mmol, 1.0 equiv.) in THF (60 mL) was carefully added one portion of LAH (0.50 g, 12.5 mmol, 0.5 equiv.) at 0° C. After 30 min, another portion of LAH was carefully added and the reaction was stirred for an additional 30 min. The reaction was then carefully quenched with a Na2SO4-saturated aqueous solution. The resulting white aluminum salts were then filtered off over a short plug of Celite (EtOAc washings) and the filtrate was finally evaporated under reduced pressure to afford pure alcohol (15) (no purification required) as a pale yellow oil (3.89 g, 97%). Spectroscopic data were consistent with those reported in the literature:26a 1H NMR (400 MHz, CDCl3) δ 5.93 (ddt, J=17.2, 10.3, 5.7 Hz, 1H), 5.28 (dq, J=17.2, 1.5 Hz, 1H), 5.19 (dq, J=10.3, 1.5 Hz, 1H), 4.04 (dt, J=5.7, 1.5 Hz, 2H), 3.78-3.58 (m, 12H); 13C NMR (75 MHz, CDCl3) δ 134.8, 117.3, 72.7, 72.4, 70.8, 70.7, 70.5, 69.5, 61.8.