Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][NH:12][C:11](=[O:15])[CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:23][C:24]([C:26]1[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][C:27]=1[CH3:34])=[O:25].O>CS(C)=O>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH2:23][C:24]([C:26]2[CH:31]=[CH:30][C:29]([CH2:32][OH:33])=[CH:28][C:27]=2[CH3:34])=[O:25])[C:11](=[O:15])[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Cc1cc(CO)ccc1C(=O)CBr
Reactant: O=c1cc(OCc2ccccc2)cc[nH]1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CS(C)=O
Product: Cc1cc(CO)ccc1C(=O)Cn1ccc(OCc2ccccc2)cc1=O
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a solution of 4-benzyloxy-1H-pyridin-2-one (728 mg, 3.62 mmol) in DMSO (4.00 mL) is added cesium carbonate (2.95 g, 9.05 mmol) and the mixture is stirred 15 min at room temperature. 2-Bromo-1-(4-hydroxymethyl-2-methyl-phenyl)-ethanone (preparation 1b, 880 mg, 3.62 mmol) is added in portions and the mixture and is stirred 2 h at room temperature. After addition of water, the precipitate is collected, washed with water and dried.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:31][CH2:32][OH:33])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Reactant: OCCBr
Product: OCCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21

Procedure:
Following a similar procedure to that described in examples 22 and 23, but using 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 1) instead of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and 2-bromoethanol instead of iodomethane, the title compound was obtained.
Reaction SMILES: [C:1]([O-:4])(=[S:3])[CH3:2].[K+].[Br:6][C:7]1[CH:27]=[CH:26][C:10]([C:11]([CH:13](Br)[CH2:14][C:15]([N:17]2[CH2:24][CH2:23][CH2:22][C@H:18]2[C:19]([OH:21])=[O:20])=[O:16])=[O:12])=[CH:9][CH:8]=1>C(O)C>[C:1]([S:3][CH:13]([C:11](=[O:12])[C:10]1[CH:26]=[CH:27][C:7]([Br:6])=[CH:8][CH:9]=1)[CH2:14][C:15]([N:17]1[CH2:24][CH2:23][CH2:22][C@H:18]1[C:19]([OH:21])=[O:20])=[O:16])(=[O:4])[CH3:2]
Reactant: CC([O-])=S
Reactant: O=C(c1ccc(Br)cc1)C(Br)CC(=O)N1CCC[C@H]1C(=O)O
Agent: [K+]
Solvent: CCO
Product: CC(=O)SC(CC(=O)N1CCC[C@H]1C(=O)O)C(=O)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a stirred suspension of 469 mg. of potassium thioacetate in 10 ml. of ethanol is added 1.76 g. of 1-[3-(4-bromobenzoyl)-3-bromopropionyl]-L-proline (Example 37). The mixture is stirred at room temperature for 18 hours, filtered and the filtrate evaporated to dryness. The residue is dissolved in dichloromethane, washed with water and saturated sodium chloride solution, dried over magnesium sulfate and evaporated to dryness in vacuo giving the desired product as 1.68 g. of a white glass.
Reaction SMILES: FC(F)(F)C(O)=O.[NH2:8][CH2:9][CH2:10][C:11]1[CH:16]=[CH:15][N:14]=[C:13]([C:17]2[S:18][C:19]3[CH:27]=[CH:26][CH:25]=[CH:24][C:20]=3[C:21](=[O:23])[N:22]=2)[CH:12]=1.[C:28](Cl)(=[O:35])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C(=O)([O-])[O-].[K+].[K+].C(OCC)(=O)C>CN(C)C(=O)C.O>[O:23]=[C:21]1[C:20]2[CH:24]=[CH:25][CH:26]=[CH:27][C:19]=2[S:18][C:17]([C:13]2[CH:12]=[C:11]([CH2:10][CH2:9][NH:8][C:28](=[O:35])[C:29]3[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=3)[CH:16]=[CH:15][N:14]=2)=[N:22]1
Reactant: O=C(Cl)c1ccccc1
Reactant: NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CC(=O)N(C)C
Solvent: O=C(O)C(F)(F)F
Product: O=C(NCCc1ccnc(-c2nc(=O)c3ccccc3s2)c1)c1ccccc1
Temperature: 60 °C
Reaction time: 5 h
Yield: 36.6 %

Procedure:
2-[4-(2-Aminoethyl)-2-pyridyl]-4H-1,3-benzothiazine-4-one trifluoroacetic acid salt (0.50 g, 1.2 mmol) was dissolved in N,N-dimethylacetamide (10 ml), and benzoyl chloride (0.36 g, 2.6 mmol) and potassium carbonate (0.17 g, 1.2 mmol) were added thereto. The reaction mixture was stirred at 60° C. for 5 hrs, combined with ethyl acetate and water. The organic layer was successively washed with saturated aqueous sodium hydrogen carbonate solution and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated, and the residue was subjected to a silica gel column chromatography. The fractions eluted with methanol-ethyl acetate (1:20, v/v) were collected, concentrated and recrystallized from hexane-chloroform to give the titled compound (0.17 g, 36%) as white crystals.
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:30]=[CH:29][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:19][CH:18]=1)([CH3:14])[CH2:6][C:5]2=O.Cl.[NH2:34][OH:35].CO.C(=O)([O-])[O-].[K+].[K+]>C(OCC)(=O)C.N1C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:32])=[C:4]2[C:9](=[C:10]([CH3:13])[C:11]=1[CH3:12])[O:8][C:7]([CH2:15][O:16][C:17]1[CH:18]=[CH:19][C:20]([CH2:21][CH:22]3[S:26][C:25](=[O:27])[NH:24][C:23]3=[O:28])=[CH:29][CH:30]=1)([CH3:14])[CH2:6]/[C:5]/2=[N:34]\[OH:35]
Reactant: Cc1c(C)c2c(c(C)c1O)C(=O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: c1ccncc1
Product: Cc1c(C)c2c(c(C)c1O)/C(=N/O)CC(C)(COc1ccc(CC3SC(=O)NC3=O)cc1)O2

Procedure:
A mixture of 5 g of 5-[4-(6hydroxy-2,5,7,8-tetramethyl-4-oxochroman-2-ylmethoxy)benzyl]thiazolidine-2,4-dione (prepared as described in Example 22 of copending U.S. Ser. No. 644,996), 3 g of hydroxylamine hydrochloride, 50 g of methanol and 3 g of pyridine was stirred for 1 week at room temperature. At the end of this time, ethyl acetate and an aqueous solution of potassium carbonate were added. The organic layer was separated and dried over anhydrous sodium sulfate. The solvent was distilled off and the residue was purified by silica gel column chromatography, eluted with a 1:1 by volume mixture of hexane and ethyl acetate, to give the title compound, softening at 84°-100° C.
Reaction SMILES: C([O:4][C@@H:5]1[O:22][C@@H:21]([CH3:23])[C@@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@@H:6]1[O:7][C:8](=[O:10])[CH3:9])(=O)C.C(O)(=O)C.NN.C(OCC)(=O)C>CN(C)C=O>[C:8]([O:7][C@H:6]1[C@H:11]([O:12][C:13](=[O:15])[CH3:14])[C@H:16]([O:17][C:18](=[O:20])[CH3:19])[C@H:21]([CH3:23])[O:22][CH:5]1[OH:4])(=[O:10])[CH3:9]
Reactant: CC(=O)O[C@@H]1O[C@@H](C)[C@@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: NN
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@H](C)OC(O)[C@H]1OC(C)=O
Yield: 80 %

Procedure:
A solution of 1,2,3,4-tetra-O-acetyl-α-L-fucopyranose (6.00 g, 18 mmol), prepared, for example, according to Nunez et al., supra., and hydrazine acetate (1.99 g, 21.6 mmol) in 20 ml of dry dimethylformamide is stirred at 50° C. for 4.5 h. After addition of ethyl acetate, the mixture is extracted about twice with aqueous sodium chloride solution and the concentrated organic extract is chromatographed (petroleum ether (40°-60°)/ethyl acetate 1:1). 2,3,4-Tri-O-acetyl-L-fucopyranose (1) is obtained in an anomer ratio of α:β of 3:1 with a yield of 80%. TLC analysis (petroleum ether (40°-60°)/ethyl acetate 1:1) gives Rf =0.47.
Reaction SMILES: S(O)(O)(=O)=O.[NH2:6][OH:7].[OH-].[Na+].[O:10]1[CH2:19][C:11]1([CH3:20])[CH2:12][CH2:13][C:14](OCC)=[O:15].C(O)C>O>[OH:7][N:6]1[CH2:19][C:11]([OH:10])([CH3:20])[CH2:12][CH2:13][C:14]1=[O:15]
Reactant: CCOC(=O)CCC1(C)CO1
Reactant: NO
Agent: O=S(=O)(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CC1(O)CCC(=O)N(O)C1
Reaction time: 17 h
Yield: 4.2 %

Procedure:
To a mixture of 28.27 g (0.172 m) of hydroxylamine sulfate in 25 ml of water was added slowly a 25 ml aqueous solution of 13.80 g (0.344 m) of sodium hydroxide. To the resulting solution was added 5.45 g (0.034 m) of ethyl 4,5-epoxy-4-methylpentanoate with the aid of 2 ml of ethanol. The mixture was heated to reflux and stirred for 17 hours. The reaction mixture was cooled and concentrated under reduced pressure to yield a yellow moist solid. The solid was washed with methanol several times and the methanol solution was then concentrated. Triuration with acetone yielded 3.72 g (74.4% yield) of a nicely crystalline white solid. A second crop of 0.21 g of solid was obtained. The total yield was 78.5%; mp 98°-100° C.
Reaction SMILES: [CH3:1]/[C:2](/[CH2:7][CH2:8][CH3:9])=[CH:3]\[C:4]([OH:6])=O.ClC(OCC)=O.C(N(CC)CC)C.[CH:23]([NH:26][CH:27]([CH3:29])[CH3:28])([CH3:25])[CH3:24].Cl>>[CH:23]([N:26]([CH:27]([CH3:29])[CH3:28])[C:4](=[O:6])/[CH:3]=[C:2](\[CH3:1])/[CH2:7][CH2:8][CH3:9])([CH3:25])[CH3:24]
Reactant: CCC/C(C)=C/C(=O)O
Reactant: CC(C)NC(C)C
Agent: CCOC(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CCC/C(C)=C/C(=O)N(C(C)C)C(C)C
Yield: 34 %

Procedure:
3-Methyl-2E-hexenoic acid 1 eq, ethyl chloroformate 1.5 eq, triethylamine 1.6 eq, diisopropylamine 3.0 eq, quench with 10% hydrogen chloride solution, yield=34%.
Reaction SMILES: [N:1]([CH2:4][CH:5]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:17]2=[N:16][C:15]=1[CH3:33])=[O:13])[CH2:6][C:7]([F:10])([F:9])[F:8])=[N+]=[N-].[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][CH:5]([NH:11][C:12]([C:14]1[N:18]2[CH:19]=[CH:20][CH:21]=[C:22]([O:23][CH2:24][C:25]3[C:30]([F:31])=[CH:29][CH:28]=[CH:27][C:26]=3[F:32])[C:17]2=[N:16][C:15]=1[CH3:33])=[O:13])[CH2:6][C:7]([F:8])([F:10])[F:9]
Reactant: [H][H]
Reactant: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN=[N+]=[N-])CC(F)(F)F
Agent: [Pd]
Solvent: CCO
Product: Cc1nc2c(OCc3c(F)cccc3F)cccn2c1C(=O)NC(CN)CC(F)(F)F

Procedure:
555 mg of rac-N-(1-azido-4,4,4-trifluorobutan-2-yl)-8-[(2,6-difluorobenzyl)oxy]-2-methylimidazo[1,2-a]pyridine-3-carboxamide (Example 41A, 1.19 mmol) were initially charged in 74 ml of ethanol, 126 mg of palladium on activated carbon (10%) were added and the mixture was hydrogenated at hydrogen standard pressure and RT for 60 min. The reaction solution was filtered and concentrated. The crude product was purified by preparative HPLC (RP18 column, mobile phase: acetonitrile/water gradient with addition of 0.1% TFA). The product-containing fractions were taken up in ethyl acetate and washed with saturated aqueous sodium bicarbonate solution. The organic phase was dried over sodium sulphate, filtered and concentrated. This gave 473 mg of the title compound (88% of theory).
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O-:8])=[O:7])=[CH:4][CH:3]=1.[Na+].[CH2:12](Cl)[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>CN(C)C=O>[OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([O:8][CH2:12][C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)=[O:7])=[CH:4][CH:3]=1
Reactant: ClCc1ccccc1
Reactant: O=C([O-])c1ccc(O)cc1
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(OCc1ccccc1)c1ccc(O)cc1
Yield: 74 %

Procedure:
Sodium p-hydroxybenzoate (64 g) and 51 g of benzyl chloride were added to 150 g of dimethylformamide, and reacted at 100° C. for 3 hours. Benzyl p-hydroxybenzoate was obtained in a yield of 74%. The ratio of benzyl p-benzyloxybenzoate, a by-product, formed was 10%.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][NH:9]2)=[CH:4][CH:3]=1.[C:13]([C:15]1[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1)#[N:14]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[CH2:12][CH2:11][CH2:10][N:9]2[S:21]([C:18]2[CH:17]=[CH:16][C:15]([C:13]#[N:14])=[CH:20][CH:19]=2)(=[O:23])=[O:22])=[CH:6][CH:7]=1
Reactant: Fc1ccc(C2CCCN2)cc1
Reactant: N#Cc1ccc(S(=O)(=O)Cl)cc1
Product: N#Cc1ccc(S(=O)(=O)N2CCCC2c2ccc(F)cc2)cc1

Procedure:
The title compound, off-white solid, m.p. 147° C. and MS: m/e=330 (M+) was prepared in accordance with the general method of example 1e from (RS)-2-(4-fluoro-phenyl)-pyrrolidine and 4-cyano-benzenesulfonyl chloride.
Reaction SMILES: Br[C:2]1[CH:11]=[N:10][C:9]2[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=3)[C:7](=[O:21])[N:6]3[N:22]=[CH:23][N:24]=[C:5]3[C:4]=2[CH:3]=1.[B-](F)(F)(F)[CH:26]=[CH2:27].[K+].C(N(CC)CC)C>C(O)CCC>[CH3:20][O:19][C:16]1[CH:17]=[CH:18][C:13]([CH2:12][N:8]2[C:9]3[N:10]=[CH:11][C:2]([CH:26]=[CH2:27])=[CH:3][C:4]=3[C:5]3=[N:24][CH:23]=[N:22][N:6]3[C:7]2=[O:21])=[CH:14][CH:15]=1
Reactant: C=C[B-](F)(F)F
Reactant: COc1ccc(Cn2c(=O)n3ncnc3c3cc(Br)cnc32)cc1
Agent: [K+]
Solvent: CCCCO
Solvent: CCN(CC)CC
Product: C=Cc1cnc2c(c1)c1ncnn1c(=O)n2Cc1ccc(OC)cc1
Temperature: 100 °C
Yield: 63.1 %

Procedure:
9-Bromo-6-(4-methoxybenzyl)pyrido[3,2-e][1,2,4]triazolo[1,5-c]pyrimidin-5(6H)-one (2.00 g, 5.18 mmol), potassium trifluoro(vinyl)borate (1.51 g, 11.3 mmol), butan-1-ol (20 ml), triethylamine (1.05 ml, 7.53 mmol) and [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II)-dichloromethane complex (0.31 g, 0.38 mmol) were combined and heated at 100° C. for 20 hours. The mixture was cooled, concentrated under vacuum and taken up in dichloromethane (120 mL). It was washed with water (50 mL) and brine (50 mL), dried (MgSO4) and concentrated under vacuum. The residue was triturated with ethyl acetate (15 mL) for 20 hours, filtered, washed with cold ethyl acetate and suction dried to afford 1.09 g (63%) of the title compound as a yellow powder. 1H NMR (400 MHz, CDCl3) δ 3.76 (s, 3H), 5.52 (d, J=10.92 Hz, 1H), 5.75 (s, 2H), 5.98 (d, J=17.57 Hz, 1H), 6.75-6.88 (m, 3H), 7.60 (d, J=8.66 Hz, 2H), 8.36 (s, 1H), 8.66 (d, J=2.13 Hz, 1H), 8.79 (d, J=2.26 Hz, 1H). LCMS (MH+, 334.1).
Reaction SMILES: [I:1]I.[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:18])=[C:13]([CH2:15][CH2:16]O)[N:14]=2)=[CH:6][CH:5]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.O.C(OCC)(=O)C>[Br:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[O:11][C:12]([CH3:18])=[C:13]([CH2:15][CH2:16][I:1])[N:14]=2)=[CH:6][CH:5]=1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCO
Reactant: II
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: Cc1oc(-c2ccc(Br)cc2)nc1CCI
Temperature: 100 °C

Procedure:
Add iodine (1.90 g, 7.49 mmol) to a stirred mixture of 2-[2-(4-bromo-phenyl)-5-methyl-oxazol-4-yl]-ethanol (1.503 g, 5.33 mmol), triphenylphosphine (2.101 g, 8.01 mmol), and pyridine (1.4 mL, 17 mmol) in toluene (48 mL) and heat at 100° C. for 45 min. Cool to room temperature, add ethyl acetate and water, and separate the layers. Extract the aqueous layer twice with ethyl acetate, wash the organic layer with 0.1N HCl, dry over anhydrous magnesium sulfate, and concentrate under reduced pressure. Purify the residue by flash chromatography (SiO2, elute 0% to 10% EtOAc/hexanes) to-yield 1.804 g of the title compound as a colorless solid. 1H NMR (400 MHz, CDCl3) δ 7.89 (d, J=8.4 Hz, 2H), 7.60 (d, J=8.8 Hz, 2H), 3.49 (dd, J=7.2, 7.2 Hz, 2H), 3.11 (dd, J=7.2, 7.2 Hz, 2H), 2.39 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10](I)=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1.C([Mg]Cl)(C)C.[F:27][C:28]1[CH:35]=[C:34]([O:36][CH2:37][C:38]2[N:42]([CH3:43])[C:41]3[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=3[N:39]=2)[C:33]([O:48][CH3:49])=[CH:32][C:29]=1[CH:30]=[O:31]>O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:30]([C:29]3[CH:32]=[C:33]([O:48][CH3:49])[C:34]([O:36][CH2:37][C:38]4[N:42]([CH3:43])[C:41]5[CH:44]=[CH:45][CH:46]=[CH:47][C:40]=5[N:39]=4)=[CH:35][C:28]=3[F:27])[OH:31])=[CH:9][N:8]([Si:12]([CH:19]([CH3:21])[CH3:20])([CH:16]([CH3:18])[CH3:17])[CH:13]([CH3:15])[CH3:14])[C:5]2=[N:6][CH:7]=1
Reactant: CC(C)[Si](C(C)C)(C(C)C)n1cc(I)c2cc(Cl)cnc21
Reactant: COc1cc(C=O)c(F)cc1OCc1nc2ccccc2n1C
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: COc1cc(C(O)c2cn([Si](C(C)C)(C(C)C)C(C)C)c3ncc(Cl)cc23)c(F)cc1OCc1nc2ccccc2n1C
Temperature: -25 °C

Procedure:
5-Chloro-3-iodo-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridine (144, 0.235 g, 0.541 mmol, prepared as described in Example 49) was dissolved in tetrahydrofuran (5 mL, 60 mmol). The solution was cooled to −25° C. After the addition of 2 M of isopropylmagnesium chloride in tetrahydrofuran (400 μL) the reaction was warmed to −10° C. with stirring. The reaction was cooled to −30° C. and 2-fluoro-5-methoxy-4-(1-methyl-1H-benzimidazol-2-ylmethoxy)-benzaldehyde (143, 0.170 g, 0.541 mmol) in 4 mL of tetrahydrofuran was added at once to the mixture. The reaction warmed to −10° C. and then evaporated to dryness. Ethyl acetate was added and the organic portion was washed with saturated sodium bicarbonate solution and brine, dried over anhydrous sodium sulfate and concentrated. Purification with silica gel flash chromatography with a gradient of ethyl acetate (5 to 80%) in hexanes gave the desired compound 145.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1.[CH3:23][O:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1>>[CH3:1][O:2][C:3]1[C:8]([NH:9][C:10]([N:34]2[CH2:33][CH2:32][N:31]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[O:24][CH3:23])[CH2:36][CH2:35]2)=[O:18])=[CH:7][C:6]([CH2:19][CH2:20][CH3:21])=[C:5]([CH3:22])[N:4]=1
Reactant: CCCc1cc(NC(=O)Oc2ccccc2)c(OC)nc1C
Reactant: COc1ccccc1N1CCNCC1
Product: CCCc1cc(NC(=O)N2CCN(c3ccccc3OC)CC2)c(OC)nc1C
Yield: 71 %

Procedure:
Phenyl N-(2-methoxy-6-methyl-5-propylpyridin-3-yl)carbamate and 1-(2-methoxyphenyl)piperazine were reacted by the same way with the example 1 to obtain the titled compound.
Reaction SMILES: [Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][N:9](C)[C:10](=O)OC(C)(C)C)=[C:4]([CH:20]=[O:21])[CH:3]=1.[C:22]([OH:28])([C:24]([F:27])([F:26])[F:25])=[O:23]>C(Cl)Cl>[F:25][C:24]([F:27])([F:26])[C:22]([OH:28])=[O:23].[Br:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][CH2:8][NH:9][CH3:10])=[C:4]([CH:3]=1)[CH:20]=[O:21]
Reactant: CN(CCOc1ccc(Br)cc1C=O)C(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CNCCOc1ccc(Br)cc1C=O
Reaction time: 9 h

Procedure:
To a solution of t-butyl 2-(4-bromo-2-formylphenoxy)ethylmethylcarbamate (1.26 g, 3.52 mmol) in CH2Cl2 (50 ml) was added TFA (4.01 g, 2.71 mmol 35.17 mmol) at 0° C., followed by stirring for 9 hours. Thereafter, the reaction solution was concentrated in a vacuum and completely dried to afford the object compound (dark brown oil, suitable amount).
Reaction SMILES: [CH2:1]([C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1)C=C.I([O-])(=O)(=O)=O.[Na+].[CH3:28][OH:29]>O.[Os](=O)(=O)(=O)=O>[O:29]=[CH:28][CH2:1][C:4]1([C:18]([O:20][CH3:21])=[O:19])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([C:14]([O:16][CH3:17])=[O:15])[CH:10]=2)[CH2:5]1
Reactant: CO
Reactant: C=CCC1(C(=O)OC)CCc2cc(C(=O)OC)ccc2C1
Agent: O=[Os](=O)(=O)=O
Agent: [Na+]
Agent: [O-][I+3]([O-])([O-])[O-]
Solvent: O
Product: COC(=O)c1ccc2c(c1)CCC(CC=O)(C(=O)OC)C2
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of (±)-dimethyl 2-allyl-1,2,3,4-tetrahydronaphthalene-2,6-dicarboxylate from Step B (433 mg, 1.50 mmol) in MeOH (20 mL) and H2O (7 mL) was added osmium tetroxide (2.5 wt. % in t-BuOH, 1.07 mL, 0.105 mmol) and sodium periodate (964 mg, 4.51 mmol). The resulting mixture was stirred for 1 h at ambient temperature and a thick white precipitate quickly formed. After 70 min, the mixture was partitioned between dilute aqueous NaCl (100 mL) and EtOAc (200 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo to give the title compound in sufficient purity for use in the next step. MS: m/z=291 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[CH:6][C:7]2[C:12]([NH:13][C:14]3[CH:19]=[C:18]([C:20](=[O:33])[NH:21][C@H:22]([C:27]4[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=4)[C:23]([F:26])([F:25])[F:24])[CH:17]=[CH:16][C:15]=3[S:34][C:35]3[CH:40]=[CH:39][C:38]([NH:41]C(=O)OC(C)(C)C)=[CH:37][CH:36]=3)=[N:11][CH:10]=[N:9][C:8]=2[N:49]=1)([CH3:3])[CH3:2].C(OC(=O)NC1C=CC(SC2C=CC(C(=O)N[C@H](C3C=CC=CC=3)C)=CC=2NC2C3C=CC(C(C)C)=NC=3N=CN=2)=CC=1)(C)(C)C>>[NH2:41][C:38]1[CH:39]=[CH:40][C:35]([S:34][C:15]2[CH:16]=[CH:17][C:18]([C:20]([NH:21][C@H:22]([C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[C:23]([F:24])([F:25])[F:26])=[O:33])=[CH:19][C:14]=2[NH:13][C:12]2[C:7]3[CH:6]=[CH:5][C:4]([CH:1]([CH3:3])[CH3:2])=[N:49][C:8]=3[N:9]=[CH:10][N:11]=2)=[CH:36][CH:37]=1
Reactant: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](c4ccccc4)C(F)(F)F)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Agent: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@@H](C)c4ccccc4)ccc3Sc3ccc(NC(=O)OC(C)(C)C)cc3)ncnc2n1
Product: CC(C)c1ccc2c(Nc3cc(C(=O)N[C@H](c4ccccc4)C(F)(F)F)ccc3Sc3ccc(N)cc3)ncnc2n1
Yield: 88 %

Procedure:
The title compound was prepared (yield 88%) by the procedure in Example 385G substituting the product of Example 447D for the product of Example 385F.
Reaction SMILES: Cl[C:2]1[C:6]2[CH:7]=[CH:8][C:9]([O:11][CH3:12])=[CH:10][C:5]=2[O:4][N:3]=1.[N:13]1[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=1[N:19]1[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]1>CO>[CH3:12][O:11][C:9]1[CH:8]=[CH:7][C:6]2[C:2]([CH:20]3[CH2:21][NH:22][CH2:23][CH2:24][N:19]3[C:14]3[CH:15]=[CH:16][CH:17]=[CH:18][N:13]=3)=[N:3][O:4][C:5]=2[CH:10]=1
Reactant: COc1ccc2c(Cl)noc2c1
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: CO
Product: COc1ccc2c(C3CNCCN3c3ccccn3)noc2c1
Temperature: 140 °C
Yield: 34.5 %

Procedure:
A sealed tube was charged with 3-chloro-6-methoxy-1,2-benzisoxazole (0.25 g, 1.4 mmol) and 1-(2-pyridyl)piperazine (0.67 g, 4 mmol) and heated to 140° C. overnight. The reaction was cooled to room temperature, diluted with methanol, and concentrated in vacuo. The material was flash chromatographed (silica gel) eluting with CH2Cl2. The material was further purified through recrystallization from 1,2-dichloroethane/pet. ether to afford 0.15 g of the product, m.p.=123°-124° C.