Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:12]([O:14]C)=[O:13])=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8].[OH-].[Na+]>CO>[NH2:1][C:2]1[C:3]([C:12]([OH:14])=[O:13])=[N:4][C:5]([O:9][CH2:10][CH3:11])=[CH:6][C:7]=1[Cl:8]
Reactant: CCOc1cc(Cl)c(N)c(C(=O)OC)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCOc1cc(Cl)c(N)c(C(=O)O)n1
Yield: 12.8 %

Procedure:
A solution of the compound prepared in Example 427 (0.025 g) in methanol (1 mL) was treated with sodium hydroxide (0.11 mL) and refluxed for 18 hours. This material was evaporated in vacuo and residue dissolved in water and acidified with 1N hydrochloric acid. The product was extracted with ethyl acetate, dried, and evaporated in vacuo to provide the title compound (0.003 g) having the following physical data.
Reaction SMILES: Cl.Cl.[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[CH:17]=[C:18]([Cl:30])[C:19]([C:28]#[N:29])=[C:20]4[C:26]=3[O:25][CH:24]([CH3:27])[CH2:23][NH:22][CH2:21]4)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12.O=[C:32]1[CH2:35][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:42])([CH3:41])[CH3:40])[CH2:33]1.C([BH3-])#N.[Na+]>CO.O>[NH2:3][C:4]1[N:9]=[CH:8][N:7]=[C:6]2[N:10]([CH:14]([C:16]3[C:26]4[O:25][CH:24]([CH3:27])[CH2:23][N:22]([CH:32]5[CH2:35][CH:34]([NH:36][C:37](=[O:43])[O:38][C:39]([CH3:41])([CH3:40])[CH3:42])[CH2:33]5)[CH2:21][C:20]=4[C:19]([C:28]#[N:29])=[C:18]([Cl:30])[CH:17]=3)[CH3:15])[N:11]=[C:12]([CH3:13])[C:5]=12
Reactant: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CNC3)c2ncnc(N)c12
Reactant: CC(C)(C)OC(=O)NC1CC(=O)C1
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: O
Product: Cc1nn(C(C)c2cc(Cl)c(C#N)c3c2OC(C)CN(C2CC(NC(=O)OC(C)(C)C)C2)C3)c2ncnc(N)c12
Temperature: 60 °C

Procedure:
9-[1-(4-Amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-2-methyl-2,3,4,5-tetrahydro-1,4-benzoxazepine-6-carbonitrile bishydrochloride (20 mg, 0.05 mmol) from Example 59, step 1, was dissolved in methanol (1.1 mL), and the tert-butyl (3-oxocyclobutyl)carbamate (0.019 g, 0.10 mmol) was added, followed by the sodium cyanoborohydride (0.0063 g, 0.10 mmol). The reaction was heated to 60° C. for 2 h, allowed to cool, diluted with water, and extracted with ethyl acetate. The combined organic layer was washed with brine, dried over magnesium sulfate, filtered, and concentrated to give tert-butyl {3-[9-[1-(4-amino-3-methyl-1H-pyrazolo[3,4-d]pyrimidin-1-yl)ethyl]-7-chloro-6-cyano-2-methyl-2,3-dihydro-1,4-benzoxazepin-4(5H)-yl]cyclobutyl}carbamate. LCMS calculated for C28H36ClN8O3 (M+H)+: m/z=567.2; found: 567.3.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13](B2OC(C)(C)C(C)(C)O2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1.Br[C:28]1[CH:33]=[CH:32][C:31]([S:34][C:35]2[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=2)=[CH:30][CH:29]=1.C(=O)(O)[O-].[Na+].O>C(COC)OC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH3:1][O:2][C:3](=[O:26])[CH2:4][C:5]1[C:14]([CH3:15])=[C:13]([C:28]2[CH:29]=[CH:30][C:31]([S:34][C:35]3[CH:40]=[C:39]([Cl:41])[CH:38]=[C:37]([Cl:42])[CH:36]=3)=[CH:32][CH:33]=2)[C:12]2[C:7](=[CH:8][CH:9]=[C:10]([F:25])[CH:11]=2)[CH:6]=1
Reactant: COC(=O)Cc1cc2ccc(F)cc2c(B2OC(C)(C)C(C)(C)O2)c1C
Reactant: Clc1cc(Cl)cc(Sc2ccc(Br)cc2)c1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: COCCOC
Product: COC(=O)Cc1cc2ccc(F)cc2c(-c2ccc(Sc3cc(Cl)cc(Cl)c3)cc2)c1C
Yield: 31.1 %

Procedure:
A stirred solution of [6-fluoro-3-methyl-4-(4,4,5,5-tetra methyl-[1,3,2]-dioxaborolan-2-yl)-naphthalen-2-yl]-acetic acid methyl ester (0.2 g, 0.55 mmol) in dimethoxyethane (5 mL) was purged with argon for 5 minutes at room temperature. Tetrakis(triphenylphosphine)palladium(0) (0.032 g, 0.028 mmol), impure 1-(4-bromo-phenylsulfanyl)-3,5-dichlorobenzene (0.2 g) and 1.0 M aqueous sodium bicarbonate (5 mL, 5 mmol) were added simultaneously to the reaction mixture under argon. The reaction mixture was refluxed for 2 hours and then brought to room temperature. Water was added and the resulting mixture was extracted twice with ethyl acetate. The combined organic extracts were washed with water and brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure to give the crude product, which was finally purified using flash chromatography (0-3% ethyl acetate in hexanes) to give {4-[4-(3,5-dichloro-phenylsulfanyl)-phenyl]-6-fluoro-3-methyl-naphthalen-2-yl}-acetic acid methyl ester (0.083 g, 31%) as a solid.
Reaction SMILES: C12NC(COC1)CC1O[N:4]=[CH:3]C2=1.[OH:13][CH:14]1[C:21](=[O:22])[CH2:20][CH:19]2[N:23]([C:24]([O:26][C:27]([CH3:30])([CH3:29])[CH3:28])=[O:25])[CH:15]1[CH2:16][O:17][CH2:18]2>>[C:27]([O:26][C:24]([N:23]1[CH:15]2[CH2:16][O:17][CH2:18][CH:19]1[C:20]1[CH:3]=[N:4][O:22][C:21]=1[CH:14]2[OH:13])=[O:25])([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N1C2COCC1C(O)C(=O)C2
Reactant: c1noc2c1C1COCC(C2)N1
Product: CC(C)(C)OC(=O)N1C2COCC1C(O)c1oncc12

Procedure:
7-Hydroxy-5,10-dioxa-4,12-diaza-tricyclo[6.3.1.0*2,6*]dodeca-2(6),3-diene-12-carboxylic acid tert-butyl ester 106d was prepared in analogy to compound 105a in Example 105, starting with 106c (260 mg). 141 mg of 106d was obtained as a colorless oil. MS: calc'd (MH+) 283, measured (MH+) 283.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[NH:4][N:3]=1.[C:14](=O)([O:20]C(C)(C)C)[O:15][C:16]([CH3:19])([CH3:18])[CH3:17].O.Cl>CN(C)C1C=CN=CC=1.O1CCCC1>[Br:1][C:2]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([N+:11]([O-:13])=[O:12])[CH:9]=2)[N:4]([C:14]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:20])[N:3]=1
Reactant: CC(C)(C)OC(=O)OC(C)(C)C
Reactant: O=[N+]([O-])c1ccc2[nH]nc(Br)c2c1
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)n1nc(Br)c2cc([N+](=O)[O-])ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 24.0 g of 3-bromo-5-nitro-1H-indazole and 12.2 g of 4-(dimethylamino)pyridine in 50 ml tetrahydrofuran was added dropwise 23 ml of di-tert-butyl carbonate at room temperature. After stirring at room temperature for 30 minutes, the mixture was added with water, acidified by adding diluted hydrochloric acid and extracted with ethyl acetate. The organic layer was washed with water, dried over anhydrous magnesium sulfate and the solvent was evaporated. The residue was purified and separated by silica gel column chromatography (ethyl acetate:hexane=1:10), to give 20.5 g of the title compound as colorless needles.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH2:23])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1.[CH3:25][S:26](Cl)(=[O:28])=[O:27].Cl>N1C=CC=CC=1.O>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]2[C:13]([O:14][CH3:15])=[CH:12][CH:11]=[C:10]([CH2:16][C:17]3[CH:18]=[CH:19][C:20]([NH:23][S:26]([CH3:25])(=[O:28])=[O:27])=[N:21][CH:22]=3)[C:9]=2[F:24])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(Cc2ccc(N)nc2)c(F)c1-c1cccc(Cl)c1
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(Cc2ccc(NS(C)(=O)=O)nc2)c(F)c1-c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 20 h
Yield: 32 %

Procedure:
To a solution of 5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-ylamine (P-252) synthesized above (70 mg, 0.18 mmol) in pyridine (2 ml) was added methanesulfonyl chloride (23 mg, 0.20 mmol) at 0 C under nitrogen, and stirred at room temperature for 20 h. The reaction mixture was diluted with water, neutralized with 6N HCl, extracted with ethyl acetate, washed with water and brine, and dried over Na2SO4. After it was concentrated in vacuo, the residue was purified by a chromatography on silica gel to yield N-[5-(3′-chloro-2-fluoro-6-methoxy-biphenyl-3-ylmethyl)-pyridin-2-yl]-methanesulfonamide (P-258) (25 mg, 32%). 1H NMR (400 MHz, CDCl3) 8.15 (s, 1H), 7.58 (dd, J=8.8, 2.1 Hz, 1H), 7.38 (s, 1H), 7.34 (t, J=6.6 Hz, 3H), 7.24-7.31 (m, 2H), 7.11 (t, J=8.5 Hz, 1H), 6.73 (d, J=8.5 Hz, 1H), 3.89 (s, 2H), 3.77 (s, 3H), 3.09 (s, 3H) ppm.
Reaction SMILES: Cl[C:2]1[N:28]=[CH:27][C:5]2[C:6]3[N:10]([CH2:11][CH2:12][O:13][C:4]=2[CH:3]=1)[CH:9]=[C:8]([C:14]1[N:15]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=2[F:26])[N:16]=[CH:17][N:18]=1)[N:7]=3.[NH:29]1[CH2:36][CH2:35][CH2:34][C@H:30]1[C:31]([NH2:33])=[O:32].C(N(CC)CC)C.[NH4+].[Cl-]>CN1CCCC1=O.ClCCl>[F:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[N:15]1[C:14]([C:8]2[N:7]=[C:6]3[C:5]4[CH:27]=[N:28][C:2]([N:29]5[CH2:36][CH2:35][CH2:34][C@H:30]5[C:31]([NH2:33])=[O:32])=[CH:3][C:4]=4[O:13][CH2:12][CH2:11][N:10]3[CH:9]=2)=[N:18][CH:17]=[N:16]1
Reactant: NC(=O)[C@@H]1CCCN1
Reactant: Fc1ccc(-n2ncnc2-c2cn3c(n2)-c2cnc(Cl)cc2OCC3)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: ClCCl
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: NC(=O)[C@@H]1CCCN1c1cc2c(cn1)-c1nc(-c3ncnn3-c3ccc(F)cc3F)cn1CCO2
Yield: 39.4 %

Procedure:
A solution of 8-Chloro-2-[2-(2,4-difluoro-phenyl)-2H-[1,2,4]triazol-3-yl]-4,5-dihydro-6-oxa-1,3a,9-triaza-benzo[e]azulene (0.200 g, 0.499 mmol), L-prolinamide (0.171 g, 0.00150 mol) and Triethylamine (0.417 mL, 0.00299 mol) in N-Methylpyrrolidinone (5 mL) under N2 was heated to 150° C. overnight. The mixture was diluted with dichloromethane. Saturated NH4Cl was added and the mixture was extracted 3 times with dichloromethane. The organic phases were combined, dried with Na2SO4 and concentrated. The crude was purified by reverse-phase HPLC to obtain 94 mg (39% yield) of 378 as a light pink solid. MS (ESI+) 479.2. 1H NMR (400 MHz, DMSO) δ 8.35 (s, 1H), 8.18 (s, 1H), 7.86 (s, 1H), 7.69 (td, J=8.7, 6.0 Hz, 1H), 7.62-7.53 (m, 1H), 7.35-7.26 (m, 2H), 6.92 (br, 1H), 5.84 (s, 1H), 4.47-4.36 (m, 4H), 4.24 (d, J=7.4 Hz, 1H), 3.62-3.53 (m, 1H), 3.42-3.32 (m, 1H), 2.24-2.08 (m, 1H), 2.02-1.83 (m, 3H)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1B(O)O.[CH3:14][C:15]1[CH:19]=[C:18]([CH3:20])[NH:17][N:16]=1.N1C=CC=CC=1.O>C(Cl)Cl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:8]=[C:7]([O:9][CH3:10])[CH:6]=[CH:5][C:4]=1[N:16]1[C:15]([CH3:14])=[CH:19][C:18]([CH3:20])=[N:17]1
Reactant: COc1ccc(B(O)O)c(OC)c1
Reactant: Cc1cc(C)[nH]n1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: COc1ccc(-n2nc(C)cc2C)c(OC)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 10.5 %

Procedure:
610.2 mg of 2,4-dimethoxyphenylboronic acid was dissolved in 6 ml of methylene chloride, to the mixture were added 387 mg of 3,5-dimethylpyrazol, 730 mg of copper(II) acetate and 948 μl of pyridine, and the mixture was stirred overnight at room temperature. To the reaction mixture was added 60 ml of water and extracted with 60 ml of ethyl acetate. After the organic layer was dried over anhydrous magnesium sulfate, the solvent was distilled off under reduced pressure, and purified by silica gel column chromatography (hexane:ethyl acetate=3:2) to yield 81.7 mg of the title compound.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[CH:2]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[C:24]1([C:30]([C:38]2[CH:43]=[CH:42][CH:41]=[CH:40][CH:39]=2)=[N:31][S:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>C1COCC1>[C:24]1([C:30]([NH:31][S@:32]([C:34]([CH3:37])([CH3:36])[CH3:35])=[O:33])([C:38]2[CH:39]=[CH:40][CH:41]=[CH:42][CH:43]=2)[CH:7]([C:8]2[CH:9]=[N:10][CH:11]=[CH:12][CH:13]=2)[C:3]2[CH:2]=[N:1][CH:6]=[CH:5][CH:4]=2)[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=1
Reactant: CC(C)(C)S(=O)N=C(c1ccccc1)c1ccccc1
Reactant: c1cncc(Cc2cccnc2)c1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)[S@](=O)NC(c1ccccc1)(c1ccccc1)C(c1cccnc1)c1cccnc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
In a flame dried flask under N2, 3-(pyridin-3-ylmethyl)pyridine (0.072 g, 0.42 mmol) was dissolved in THF (3 mL). The solution was cooled to 0° C. Lithium bis(trimethylsilyl)-amide (1 M solution in THF, 0.465 mL, 0.47 mmol) was slowly added and the reaction was stirred at 0° C. for 15 min. The reaction became dark red. A solution of N-(diphenylmethylene)-2-methylpropane-2-sulfinamide (0.121 g, 0.42 mmol) in THF (1 mL) was slowly added drop-wise. The reaction was stirred at 0° C. for 1 hr then removed from the ice bath. Sat. aq. NH4Cl (20 mL) was added and the reaction was stirred vigorously. The product was extracted with EtOAc (3×50 mL). The combined organics were dried over Na2SO4, filtered and concentrated to afford an oil which was purified by flash column chromatography (0-5% MeOH/CH2Cl2). The fractions were combined and concentrated in vacuo to afford the title compound as a white solid. (S) Enantiomer at Sulfur: 1H NMR (CD3OD) δ 8.49 (d, 1H, J=2.20 Hz), 8.46 (dd, 1H, J=1.46 Hz), 8.36 (dd, 1H, J=5.37 Hz), 8.30 (d, 1H, J=2.20 Hz), 7.49-7.33 (m, 11H), 7.25-7.23 (m, 3H), 5.78 (s, 1H), 1.08 (s, 1H ). HRMS m/z (M+H) found: 478.1920 (M+Na).
Reaction SMILES: C[O:2][C:3](=[O:30])[C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([NH:10][C:11]2[N:19]=[C:18]([NH:20][C@H:21]3[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]3)[N:17]=[C:16]3[C:12]=2[N:13]=[CH:14][N:15]3[CH2:28][CH3:29])[CH:5]=1.O.[Li+].[OH-]>CO>[CH2:28]([N:15]1[CH:14]=[N:13][C:12]2[C:16]1=[N:17][C:18]([NH:20][C@H:21]1[CH2:26][CH2:25][C@H:24]([OH:27])[CH2:23][CH2:22]1)=[N:19][C:11]=2[NH:10][C:6]1[CH:5]=[C:4]([CH:9]=[CH:8][CH:7]=1)[C:3]([OH:30])=[O:2])[CH3:29]
Reactant: CCn1cnc2c(Nc3cccc(C(=O)OC)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCn1cnc2c(Nc3cccc(C(=O)O)c3)nc(N[C@H]3CC[C@H](O)CC3)nc21

Procedure:
15.8 g (38.5 mmol) of 3-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-benzoic acid methyl ester is suspended in 400 ml of MeOH, 77 ml of H2O and 77 ml of LiOH solution (1M), and stirred for 75 min at 80° C. After completion, the MeOH is removed under reduced pressure and the aqueous layer is washed with EtOAc (2 fold). The aqueous layer is then slowly treated with 1N HCl solution to pH 4-4.5. The precipitate is filtered off and washed to neutral pH to obtain 13.2 g (87% yield) of 3-[9-ethyl-2-(trans-4-hydroxy-cyclohexylamino)-9H-purin-6-yl-amino]-benzoic acid; Rf=0.34; (CH3Cl/MeOH/H2O/CH3COOH 85/13/1.5/0.5); m.p. 317° C.; ESI-MS: 397 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13]OS(CC1C=CC(C)=CC=1)(=O)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:33].C([N+](CCCC)(CCCC)CCCC)CCC>C1COCC1>[CH2:1]([O:8][C:9](=[O:10])[N:11]([C:26]1[CH:31]=[CH:30][C:29]([Br:32])=[CH:28][CH:27]=1)[CH2:12][CH2:13][F:33])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: [F-]
Reactant: Cc1ccc(CS(=O)(=O)OCCN(C(=O)OCc2ccccc2)c2ccc(Br)cc2)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: C1CCOC1
Product: O=C(OCc1ccccc1)N(CCF)c1ccc(Br)cc1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
2.9 g (6 mmol) toluene-4-methanesulfonic acid 2-[benzyloxycarbonyl-(4-bromo-phenyl)-amino]-ethyl ester are dissolved in 100 mL THF and stirred for 18 hours at room temperature after addition of a 1 M solution of tetrabutyl-ammonium fluoride in THF. The reaction mixture is poured onto ice and extracted with tertbutyl-methyl ether and a saturated aqueous solution of sodium bicarbonate. The combined organic phases are washed with brine, dried with sodium sulfate and evaporated to dryness. The crude product is column chromatographed (petroleum ether/ethyl acetate 4:1) to yield 920 mg desired product as a yellow resin. MS(ES+): 352 (M+1).
Reaction SMILES: [C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][O:44]C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[O:32][C@H:10]2[CH2:11][O:12]C(C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)(=O)C>CC(C)=O>[C:1]1([CH2:7][O:8][C@H:9]2[C@H:34]([O:35][CH2:36][C:37]3[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=3)[C@@H:33]([CH2:43][OH:44])[O:32][C@H:10]2[CH2:11][OH:12])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: c1ccc(CO[C@H]2[C@H](OCc3ccccc3)[C@@H](COC(c3ccccc3)(c3ccccc3)c3ccccc3)O[C@H]2COC(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: CC(=O)O
Product: OC[C@@H]1O[C@H](CO)[C@@H](OCc2ccccc2)[C@@H]1OCc1ccccc1
Temperature: 80 °C
Reaction time: 20 h
Yield: 73.9 %

Procedure:
A solution of 847 mg of 2,5-anhydro-3,4-bis-O-(phenylmethyl)-1,6-bis-O-(triphenylmethyl)-D-glucitol in 5 ml of acetone was treated with 16 ml of 80% aqueous acetic acid with stirring for 1 hour at 80° C., for 20 hours at room temperature and then evaporated in vacuo. The residue was taken up in ether, washed with brine, dried and evaporated to an oil. Chromatography of the oil, eluting with ether, gave 260 mg of the desired compound.
Reaction SMILES: [CH:1]([C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:13])=O.O1CCCC1.C(N(CC)CC)C.ClC(OCC)=O.[BH4-].[Na+].Cl>O>[CH3:1][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]=1[OH:13]
Reactant: O=Cc1ccc2ccccc2c1O
Agent: CCOC(=O)Cl
Agent: Cl
Agent: [BH4-]
Solvent: CCN(CC)CC
Solvent: O
Solvent: C1CCOC1
Product: Cc1ccc2ccccc2c1O
Temperature: 0 °C
Reaction time: 0.75 h

Procedure:
To a solution of 2-formyl-1-naphtol in tetrahydrofuran (1.0 eq, 1 mmol·mL−1) was added triethylamine (1.2 eq). The solution was cooled to 0° C. and then ethyl chloroformate (1.2 eq) was added over a period of 30 min. The solution was left under stirring during 30-60 min (white precipitates formation). The precipitates (triethylamine hydrochloride) were removed by filtration and washed with tetrahydrofuran (twice less than the amount used for the reaction). To the combined filtrates were added, at 5-15° C., an aqueous solution of NaBH4 (4.0 eq, 2.6 M). When the addition was completed, the reaction mixture was stirred at room temperature for 1-2 h, then diluted with water. The solution was cooled to 0° C. and made acidic by the slow addition of aqueous HCl (10%) (FROZING!). The aqueous solution was extracted with Et2O. The organic phases were washed with dilute solution of NaOH (10%), dried (brine, MgSO4) and concentrated in vacuo to yield methylnaphtol (usually as a solid or an oil which crystallized on standing).
Reaction SMILES: C(=O)/C=C/C1C=CC=CC=1.[OH:11][CH2:12][CH:13]([CH2:15][OH:16])[OH:14].C1(CCC[CH2:26][CH:27]([OH:30])[CH2:28][OH:29])C=CC=CC=1.C1(CCCCC(O)CO)CCCCC1>[Pd]>[CH2:12]([O:11][CH2:26][CH:27]([CH2:28][OH:29])[OH:30])[CH:13]([CH2:15][OH:16])[OH:14]
Reactant: OCC(O)CCCCc1ccccc1
Reactant: OCC(O)CO
Agent: [Pd]
Agent: O=C/C=C/c1ccccc1
Agent: OCC(O)CCCCC1CCCCC1
Product: OCC(O)COCC(O)CO
Temperature: 200 °C

Procedure:
Trans-Cinnamaldehyde (13.2 g, 12.6 ml, 0.1 mol) of, glycerol (92.09 g, 73.7 ml, 1 mol) and 10% Pd/C (0.66 g, 5 wt % relative to the aldehyde) are charged to a Parr reactor, purged three times with nitrogen, heated to 200° C. with stirring and reacted at 1000 psi of hydrogen for 20 h. GC analysis shows complete consumption of the aldehyde. The mixture is filtered, the product extracted with ether (50 ml×5), and the combined ether solution is dried with sodium sulfate. The solvent is evaporated and the residue chromatographed on silica gel using hexane-ethyl acetate from 5:1 to 1:1 to give 4.6 g of the monoether (95% purity). This product is approximately a 2:1 mixture of 3-(3-phenylpropyl)-1,2-propanediol and 3-(3-cyclohexylpropyl)-1,2-propanediol. The individual components of this mixture are separated by second column chromatography and characterized by 1H and 13C NMR.
Reaction SMILES: [H-].[Na+].[CH3:3][C:4]([CH3:18])([CH2:9][O:10][C:11]1[C:12]([NH2:17])=[N:13][CH:14]=[CH:15][CH:16]=1)[C:5](OC)=[O:6]>CS(C)=O.O>[CH3:3][C:4]1([CH3:18])[CH2:9][O:10][C:11]2[CH:16]=[CH:15][CH:14]=[N:13][C:12]=2[NH:17][C:5]1=[O:6]
Reactant: COC(=O)C(C)(C)COc1cccnc1N
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Solvent: O
Product: CC1(C)COc2cccnc2NC1=O
Temperature: 25 °C
Reaction time: 8 h
Yield: 91.4 %

Procedure:
NaH (60% in oil 533 mg) was added to a solution of methyl 2,2-dimethyl-3-(2-aminopyridin-3-yloxy)propanoate (8.04, 37 mmol) in DMSO (400 mL) and the mixture stirred overnight at rt. The mixture was diluted with water and separated. The aqueous layer was washed with ethyl acetate and the combined organic phases were dried over magnesium sulfate and evaporated in vacuo to afford the title compound (6.5 g, 94%). 1H NMR (300 MHz, DMSO-d6) δ 9.83 (s, 1H), 7.96 (d, J=4.0 Hz, 1H), 7.37 (d, J=8.0 Hz, 1H), 6.98 (m, 1H), 4.02 (s, 2H), 1.47 (s, 6H)
Reaction SMILES: F[C:2]1[CH:3]=[CH:4][C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=1)[C:7]([OH:9])=[O:8].[F:16]C1C(I)=C(C=CC=1)C(O)=O.FC1C=CC(I)=C(C=1)C(O)=O>>[F:16][C:4]1[C:5]([N:11]2[N:15]=[CH:14][CH:13]=[N:12]2)=[C:6]([CH:10]=[CH:2][CH:3]=1)[C:7]([OH:9])=[O:8]
Reactant: O=C(O)c1cc(F)ccc1-n1nccn1
Reactant: O=C(O)c1cccc(F)c1I
Agent: O=C(O)c1cc(F)ccc1I
Product: O=C(O)c1cccc(F)c1-n1nccn1

Procedure:
The title compound was prepared in a manner analogous to Intermediate 13, substituting for 3-fluoro-2-iodo-benzoic acid for 5-fluoro-2-iodo-benzoic acid in Step A. 1H NMR (400 MHz, CD3OD): 7.93 (s, 2H), 7.81 (d, J=8.3 Hz, 1H), 7.63-7.58 (m, 1H), 7.29 (td, J=8.9, 0.9 Hz, 1H).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15](/[CH:17]=[CH:18]/[C:19]([OH:21])=O)=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[Cl:23][C:24]1[CH:25]=[C:26]2[C:31](=[CH:32][CH:33]=1)[CH:30]=[C:29]([S:34]([N:37]1[CH2:42][CH2:41][NH:40][CH2:39][CH2:38]1)(=[O:36])=[O:35])[CH:28]=[CH:27]2>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]2[S:14][C:15](/[CH:17]=[CH:18]/[C:19]([N:40]3[CH2:39][CH2:38][N:37]([S:34]([C:29]4[CH:28]=[CH:27][C:26]5[C:31](=[CH:32][CH:33]=[C:24]([Cl:23])[CH:25]=5)[CH:30]=4)(=[O:36])=[O:35])[CH2:42][CH2:41]3)=[O:21])=[CH:16][C:10]=2[CH2:9]1)=[O:7])([CH3:2])([CH3:4])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCc2sc(/C=C/C(=O)O)cc2C1
Reactant: O=S(=O)(c1ccc2cc(Cl)ccc2c1)N1CCNCC1
Agent: Cl
Product: CC(C)(C)OC(=O)N1CCc2sc(/C=C/C(=O)N3CCN(S(=O)(=O)c4ccc5cc(Cl)ccc5c4)CC3)cc2C1

Procedure:
In a similar manner to Referential Example 12 except for the use of (E)-3-(5-tert-butoxycarbonyl-4,5,6,7-tetrahydrothieno[3,2-c]pyridin-2-yl)acrylic acid and 1-[(6-chloronaphthalen-2-yl)sulfonyl]piperazine hydrochloride as the raw materials, the reaction was conducted, whereby the title compound was obtained.
Reaction SMILES: [CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:13])=[N:10][CH:11]=2)[N:6]([C@@H:14]2[O:26][C@H:25]([CH2:27][O:28]C(=O)C)[C@@H:20]([O:21]C(=O)C)[C@H:15]2[O:16]C(=O)C)[C:5]1=[O:32])[CH:2]=[CH2:3].C([O-])([O-])=O.[K+].[K+]>CO>[CH2:1]([N:4]1[C:12]2[C:7](=[N:8][C:9]([NH2:13])=[N:10][CH:11]=2)[N:6]([C@@H:14]2[O:26][C@H:25]([CH2:27][OH:28])[C@@H:20]([OH:21])[C@H:15]2[OH:16])[C:5]1=[O:32])[CH:2]=[CH2:3]
Reactant: C=CCn1c(=O)n([C@@H]2O[C@H](COC(C)=O)[C@@H](OC(C)=O)[C@H]2OC(C)=O)c2nc(N)ncc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C=CCn1c(=O)n([C@@H]2O[C@H](CO)[C@@H](O)[C@H]2O)c2nc(N)ncc21
Temperature: 25 °C
Reaction time: 18 h

Procedure:
To a solution of 42 (0.13 g, 0.29 mmol) in methanol (4 mL) was added solid K2CO3 (0.024 g, 0.17 mmol) and the reaction stirred at ambient temperature for 18 h. To the cloudy mixture was added Amberlite CG-50 (0.5 g) and stirred till neutral and filtered. The filtrate was concentrated to give an off-white solid, which was washed with water and dried under high vacuum to give 93.5 mg of pure 43 in quantitative yield as an off white solid: 1H NMR (400 MHz, d6-DMSO) δ 7.88 (s, 1H), 6.33 (br s, 2H), 5.85 (m, 1H), 5.66 (d, J=6.0 Hz, 1H), 5.30 (d, J=5.6 Hz, 1H), 5.20 (s, 1H), 5.16 (d, J=8.4 Hz, 1H), 5.01 (d, J=4.8 Hz, H), 4.89 (q, J=5.6 Hz, 1H), 4.75 (br s, 1H), 4.35 (d, J=5.2 Hz, 2H), 4.10 (t, J=8.4 Hz, 1) 3.80 (q, J=3.6 Hz, 1H), 3.57 (m, 1H), 3.44 (m, 1H). MS (+)-ES [M+H]+ 324.1 m/z.