Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][C@H:2]1[CH2:6][OH:7].Cl[C:9]([O:11][CH2:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:10].[OH-].[Na+]>C(OCC)C>[C:13]1([CH2:12][O:11][C:9]([N:1]2[CH2:5][CH2:4][CH2:3][C@H:2]2[CH2:6][OH:7])=[O:10])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: O=C(Cl)OCc1ccccc1
Reactant: OC[C@@H]1CCCN1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Product: O=C(OCc1ccccc1)N1CCC[C@H]1CO
Temperature: 0 °C
Reaction time: 2 h
Yield: 101.6 %

Procedure:
To a 0° C. solution of 25 g of (S)-2-pyrrolidinemethanol in 150 ml of diethyl ether is added 54.8 g of benzyl chloroformate. At mid point of addition, 49.4 ml of 5N sodium hydroxide is added, simultaneously, and the reaction stirred at 0° C. for 2 hours. Diethyl ether is added, the layers are separated and the aqueous layer reextracted with diethyl ether. The combined organic layers are dried, filtered and concentrated in vacuo. The residue is purified by chromatography (silica gel, 0-10% methyl alcohol/methylene chloride) to give 59.1 g of (S)-2-hydroxymethyl-1-pyrrolidine carboxylic acid phenylmethyl ester.
Reaction SMILES: CN(C)[CH:3]=[O:4].P(Cl)(Cl)(Cl)=O.[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][C:25]=3[CH3:26])[CH:20]=[C:16]2[CH:15]=[CH:14][CH:13]=1.O>ClCCl>[Cl:11][C:12]1[N:17]2[N:18]=[C:19]([C:21]3[O:22][CH:23]=[CH:24][C:25]=3[CH3:26])[C:20]([CH:3]=[O:4])=[C:16]2[CH:15]=[CH:14][CH:13]=1
Reactant: CN(C)C=O
Reactant: Cc1ccoc1-c1cc2cccc(Cl)n2n1
Solvent: ClCCl
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1ccoc1-c1nn2c(Cl)cccc2c1C=O
Reaction time: 2.5 h
Yield: 760 %

Procedure:
A dry flask charged with dry N,N-dimethylformamide (100 mL) was treated with phosphorous oxychloride (8.8 mL, 94 mmol). The resultant solution was stirred at room temperature for 1 hour. 7-Chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine (14.6 g, 63 mmol) was added and the reaction mixture was stirred for 2.5 hours. Water and dichloromethane were added to quench the reaction. The aqueous phase and organic phase were separated. The aqueous phase was extracted with dichloromethane. The organics were combined and washed with water, dried over magnesium sulfate, filtered and the filtrate was concentrated. Crystallization from a small amount of methanol gave 7-chloro-2-(3-methyl-2-furyl)pyrazolo[1,5-a]pyridine-3-carbaldehyde (12.4 g, 760%) as a peach color crystalline compound. 1H NMR (CDCl3): δ 10.58 (s, 1H), 8.43 (d, 1H), 7.58 (d, 1H), 7.48 (t, 1H), 7.21 (d, 1H), 6.51 (d, 1H), 2.56 (s, 3H). MS m/261 (M+1).
Reaction SMILES: [CH3:1][C:2]1[S:6][C:5]([CH:7](O)[CH2:8][CH3:9])=[CH:4][CH:3]=1.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:12].[NH+]1C=CC=CC=1.[NH+]1C=CC=CC=1>C(Cl)Cl>[CH3:1][C:2]1[S:6][C:5]([CH2:7][C:8](=[O:12])[CH3:9])=[CH:4][CH:3]=1
Reactant: CCC(O)c1ccc(C)s1
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: CC(=O)Cc1ccc(C)s1

Procedure:
A solution of 1-(5-methylthien-2-yl)propanol from above (20 mmol) and pyridinium dichromate (9.03 g, 24 mmol) in 100 mL CH2Cl2 was stirred for 18 h. The reaction was then filtered through Celite and the filtrate was concentrated. The resulting residue was purified by chromatography (silica gel, etherhexanes, 1:9) to afford 1.86 g (60% over the two steps) of the desired product.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2].C(N(CC)CC)C.Br[CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34]>C1COCC1>[C:1]([C:3]1[CH:4]=[CH:5][C:6]2[C:16](=[C:17]3[CH2:22][CH2:21][N:20]([CH2:32][C:33]([O:35][CH2:36][CH3:37])=[O:34])[CH2:19][CH2:18]3)[C:11]3=[N:12][CH:13]=[CH:14][CH:15]=[C:10]3[CH2:9][CH2:8][C:7]=2[CH:23]=1)#[N:2]
Reactant: CCOC(=O)CBr
Reactant: N#Cc1ccc2c(c1)CCc1cccnc1C2=C1CCNCC1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: CCOC(=O)CN1CCC(=C2c3ccc(C#N)cc3CCc3cccnc32)CC1
Yield: 97.2 %

Procedure:
Dry THF (20 ml) was added to 0.4 g of 8-cyano-11-(4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine to dissolve the latter, followed by the addition of 0.2 g of triethylamine and 0.27 g of ethyl bromoacetate. The resultant mixture was stirred at room temperature for 24 hours. After the completion of the reaction, THF was distilled off under reduced pressure, the residue was dissolved in chloroform, and the resultant solution was washed with water. The chloroform layer was dried over anhydrous Na2SO4 and then filtered. The chloroform was distilled off under reduced pressure. The residue was purified by chromatography on a silica gel column and, from relevant fractions eluted with chloroform:methanol (20:1), 0.5 g of 8-cyano-11-(1-ethoxycarbonylmethyl-4-piperidylidene)-6,11-dihydro-5H-benzo[5,6]cyclohepta[1,2-b]pyridine was obtained (yield: 97%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8]O)=[C:4]([CH3:10])[CH:3]=1.S(Cl)([Cl:13])=O>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][Cl:13])=[C:4]([CH3:10])[CH:3]=1
Reactant: Cc1cc(Br)ccc1CO
Reactant: O=S(Cl)Cl
Product: Cc1cc(Br)ccc1CCl
Temperature: 25 °C
Yield: 78.9 %

Procedure:
(4-Bromo-2-methyl-phenyl)-methanol (40.0 g, 199 mmol) was added to thionyl chloride (106.6 g, 0.896 mole, 65.3 mL). The mixture was heated to reflux, for 1.5 hours. After cooling to room temperature the mixture was concentrated under reduced pressure. The residue was dissolved in EtOAc (300 mL) and added carefully to saturated aqueous NaHCO3 (500 mL). The EtOAc layer was separated, and the aqueous layer was extracted with EtOAc (250 mL). The combined organic layers were dried (Na2SO4), filtered and concentrated in vacuo yielding the title compound (34.19 g, 157 mmol, 79%) as a slightly colored oil that solidified to a white solid upon standing. 1H NMR (CDCl3, 300 MHz) δ ppm 2.38 (s, 3H); 4.57 (s, 2H); 7.12 (d, 1H); 7.28 (s, 1H); 7.55 (d, 1H)
Reaction SMILES: [CH3:1][O:2][C:3](=[O:21])[CH:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:20])[CH3:19])[CH:13]=1)[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1.[Br:22]Br>>[CH3:1][O:2][C:3](=[O:21])[CH:4]([O:11][C:12]1[CH:17]=[CH:16][CH:15]=[C:14]([C:18](=[O:20])[CH2:19][Br:22])[CH:13]=1)[C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1
Reactant: BrBr
Reactant: COC(=O)C(Oc1cccc(C(C)=O)c1)c1ccccc1
Product: COC(=O)C(Oc1cccc(C(=O)CBr)c1)c1ccccc1

Procedure:
[3-(2-Bromo-acetyl)-phenoxy]-phenyl-acetic acid methyl ester was synthesized from (3-acetyl-phenoxy)-phenyl-acetic acid methyl ester and bromine as described in example 31.
Reaction SMILES: [Si]([O:8][CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][N:12]([C:16]2[CH:17]=[CH:18][C:19]([F:37])=[C:20]([CH:36]=2)[C:21]([NH:23][C:24]2[C:25]([CH3:35])=[C:26]([CH:31]=[CH:32][C:33]=2[CH3:34])[C:27]([O:29][CH3:30])=[O:28])=[O:22])[CH2:11]1)(C(C)(C)C)(C)C.[N+](CCCC)(CCCC)(CCCC)CCCC.[F-]>C1COCC1>[F:37][C:19]1[CH:18]=[CH:17][C:16]([N:12]2[CH2:13][CH2:14][CH2:15][CH:10]([CH2:9][OH:8])[CH2:11]2)=[CH:36][C:20]=1[C:21]([NH:23][C:24]1[C:25]([CH3:35])=[C:26]([CH:31]=[CH:32][C:33]=1[CH3:34])[C:27]([O:29][CH3:30])=[O:28])=[O:22]
Reactant: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO[Si](C)(C)C(C)(C)C)C3)ccc2F)c1C
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: COC(=O)c1ccc(C)c(NC(=O)c2cc(N3CCCC(CO)C3)ccc2F)c1C
Temperature: 25 °C
Reaction time: 4 h
Yield: 16.7 %

Procedure:
To a solution of methyl 3-[[5-[3-[[tert-butyl(dimethyl)silyl]oxymethyl]-1-piperidyl]-2-fluoro-benzoyl]amino]-2,4-dimethyl-benzoate (2.9 g, 5.48 mmol) in THF (20 ml) is added Bu4NF 1.0 M in THF (5.73 g, 0.0219 mol) at 0° C. The reaction mixture is gradually warmed to ambient temperature. After 4 hours, the reaction mixture is diluted with ice-water and extracted with ethyl acetate. The organic layers are combined, dried over sodium sulfate, filtered, and concentrated under reduced pressure to give a residue. The residue is purified by flash chromatography (silica gel) over a gradient using 35-45% ethyl acetate in hexane to afford the title compound as a white solid (0.38 g, 16.8%). Mass spectrum (m/z): 415.2 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([O:18]CC)=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1.[OH-].[Na+].[Na].C(O)(=O)C>O>[Cl:1][C:2]1[CH:3]=[C:4]([CH:14]=[CH:15][C:16]([OH:18])=[O:17])[CH:5]=[CH:6][C:7]=1[CH2:8][N:9]1[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: CCOC(=O)C=Cc1ccc(Cn2ccnc2)c(Cl)c1
Agent: [Na+]
Agent: [Na]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: O
Product: O=C(O)C=Cc1ccc(Cn2ccnc2)c(Cl)c1

Procedure:
A mixture of ethyl 3-[3-chloro-4-(imidazol-1-yl-methyl)phenyl]prop-2-enoate (0.5 g) and sodium hydroxide (0.25 g) in water (10 ml) was stirred and heated under reflux for 3 h. The resulting solution of the sodium salt of the acid was acidified to pH 6 with glacial acetic acid, and the mixture was evaporated to dryness. Ethanol (10 ml) was added to the residue, and the mixture was boiled and filtered. Concentration of the filtrate gave a residue which was recrystallised from ethanol/ether, to give 3-[3-chloro-4-(imidazol-1-ylmethyl)phenyl]prop-2-enoic acid, m.p. 227°-229°.
Reaction SMILES: [N:1]1([C:7]2[CH:14]=[CH:13][C:10]([CH2:11]O)=[CH:9][CH:8]=2)[CH2:6][CH2:5][O:4][CH2:3][CH2:2]1.C(Cl)(Cl)=O.[CH3:19][O:20][C:21]1[CH:36]=[CH:35][C:24]([C:25]([NH:27][C:28]2[C:29]([NH2:34])=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:23][CH:22]=1.N1C=CC=CC=1>C1(C)C=CC=CC=1.C(Cl)Cl>[CH3:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:25]([NH:27][C:28]2[C:29]([NH:34][CH2:11][C:10]3[CH:13]=[CH:14][C:7]([N:1]4[CH2:6][CH2:5][O:4][CH2:3][CH2:2]4)=[CH:8][CH:9]=3)=[CH:30][CH:31]=[CH:32][CH:33]=2)=[O:26])=[CH:35][CH:36]=1
Reactant: OCc1ccc(N2CCOCC2)cc1
Reactant: COc1ccc(C(=O)Nc2ccccc2N)cc1
Agent: O=C(Cl)Cl
Solvent: ClCCl
Solvent: Cc1ccccc1
Solvent: c1ccncc1
Product: COc1ccc(C(=O)Nc2ccccc2NCc2ccc(N3CCOCC3)cc2)cc1
Reaction time: 4 h
Yield: 13.8 %

Procedure:
4-(4-Morpholinyl)benzyl alcohol (150 mg, 0.78 mmol) was added to a solution of phosgene in toluene (1.93 M, 1.2 mL). After 4 h, the mixture was treated with a solution of N1-(4-methoxybenzoyl)-1,2-benzenediamine (188 mg, 0.78 mmol) and pyridine (2 mL) in methylene chloride (3 mL). After 16 h, the mixture was concentrated and the residue was dissolved in EtOAc. The organic layer was washed with water (4×), brine (1×), dried with potassium carbonate, and concentrated. The residue was purified by chromatography (SiO2, 5 to 15% EtOAc in CH2Cl2), yielding 45 mg (14%) of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][OH:7])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18]>>[Cl:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][O:7][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][Cl:18])=[CH:4][CH:3]=1
Reactant: ClCCCCCBr
Reactant: OCc1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Product: ClCCCCCOCc1ccc(Cl)cc1
Yield: 48.3 %

Procedure:
4-Chlorobenzyl alcohol (4.3 g), 60% sodium hydride (1.8 g) and 1-bromo-5-chloropentane (6.0 g) were reacted and treated in the same manner as in Example 96 to give 3.6 g of 5-(4-chlorobenzyloxy)pentyl chloride.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:17]=[N:16][N:15]4[C:18]([C:21]5[CH:22]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:35])([F:34])[F:33])=[O:29])[CH:24]=[CH:25][CH:26]=5)=[CH:19][N:20]=[C:14]4[CH:13]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.[N:36]([C:39]1[CH:40]=[N:41][CH:42]=[CH:43][CH:44]=1)=[C:37]=[O:38]>>[N:41]1[CH:42]=[CH:43][CH:44]=[C:39]([NH:36][C:37]([N:1]2[CH2:6][CH2:5][CH:4]([N:7]3[CH:11]=[C:10]([C:12]4[CH:17]=[N:16][N:15]5[C:18]([C:21]6[CH:26]=[CH:25][CH:24]=[C:23]([NH:27][C:28]([NH:30][CH2:31][C:32]([F:33])([F:35])[F:34])=[O:29])[CH:22]=6)=[CH:19][N:20]=[C:14]5[CH:13]=4)[CH:9]=[N:8]3)[CH2:3][CH2:2]2)=[O:38])[CH:40]=1
Reactant: O=C=Nc1cccnc1
Reactant: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCNCC5)c4)cnn23)c1
Product: O=C(NCC(F)(F)F)Nc1cccc(-c2cnc3cc(-c4cnn(C5CCN(C(=O)Nc6cccnc6)CC5)c4)cnn23)c1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 30 (Step 6) starting from N-{3-[7-(1-piperidin-4-yl-1H-pyrazol-4-yl)imidazo[1,2-b]pyridazin-3-yl]phenyl}-N′-(2,2,2-trifluoroethyl)urea and 3-isocyanatopyridine (Oakwood, Cat. No. 022077). LCMS (M+H)+: m/z=605.3.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([CH3:8])[C:5]([Br:9])=[CH:4][N:3]=1.[Cu](C#N)[C:11]#[N:12].[C-]#N.[Na+]>CN(C)C=O>[Br:9][C:5]1[C:6]([CH3:8])=[CH:7][C:2]([C:11]#[N:12])=[N:3][CH:4]=1
Reactant: N#C[Cu]C#N
Reactant: Cc1cc(Br)ncc1Br
Agent: [C-]#N
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1cc(C#N)ncc1Br
Temperature: 158 °C
Yield: 73 %

Procedure:
2,5-Dibromo-4-methylpyridine (5.0 g, 19.9 mmol), copper cyanide (1.43 g, 15.9 mmol), sodium cyanide (0.801 g, 16.3 mmol) and dimethylformamide (30 mL) were combined in a sealed reaction vessel and heated at 158° C. for 3 h. The reaction mixture was purified by silica gel column chromatography (0-80% ethyl acetate in hexanes). The resulting material was subjected to a second silica gel column (0-20% methanol in dichloromethane). Clean fractions were combined and concentrated to afford the title compound as a white solid (2.30 g, 11.6 mmol, 58% yield). MS (ESI) m/z 198.0 [M+1]+.
Reaction SMILES: [C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][CH:16]([CH2:20][NH:21][C:22]([C@H:24]([O:26]C(=O)C)[CH3:25])=[O:23])[O:17]3)=[CH:12][CH:11]=2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O.[Li+].[OH-]>CO>[C:1]1([S:7]([C:10]2[CH:19]=[C:18]3[C:13]([CH2:14][CH2:15][C@H:16]([CH2:20][NH:21][C:22](=[O:23])[C@H:24]([OH:26])[CH3:25])[O:17]3)=[CH:12][CH:11]=2)(=[O:8])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)O[C@H](C)C(=O)NCC1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C[C@@H](O)C(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3ccccc3)cc2O1
Temperature: 25 °C
Reaction time: 2 h
Yield: 542.1 %

Procedure:
(R)-Acetic acid 1-[(7-benzenesulfonyl-chroman-2-ylmethyl)-carbamoyl]-ethyl ester (7.59 mg) was dissolved in 1 mL MeOH, and water (0.25 mL) and LiOH (200 mg) were added. The reaction was stirred at room temperature for two hours, then quenched by addition of water. Crystals formed and were collected by filtration, washed with water and dried under vacuum to give 37 mg of (R)—N-(7-Benzenesulfonyl-chroman-2-ylmethyl)-2-(R)-hydroxy-propionamide. MP=129.5-131.5° C.; MS (M−H)=374.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:9]=[CH:10][C:11]=1[O:12][CH3:13])[C:5]([O:7][CH3:8])=[O:6].C([O-])([O-])=O.[Na+].[Na+].[C:20]1(B(O)O)[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1>COCCOC>[CH3:13][O:12][C:11]1[C:2]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)=[CH:3][C:4]([C:5]([O:7][CH3:8])=[O:6])=[CH:9][CH:10]=1
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(OC)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: COC(=O)c1ccc(OC)c(-c2ccccc2)c1
Temperature: 80 °C

Procedure:
Methyl 3-bromo-4-(methyloxy)benzoate (245 mg, 1 mmol, commercially available) was dissolved in DME: 2N Na2CO3 (2:1, 18 ml) and then phenyl boronic acid (244 mg) and tetrakistriphenylphosphine palladium(0) (58 mg) were added. The reaction was heated to 80° C. and then left to cool over the weekend. Added EtOAc and water, the organics were separated, dried and evaporated to give a black gum. Purification by flash chromatography afforded the title compound (194 mg) as a gum. δH (d6-DMSO, 400 MHz) 3.83 (3H, s), 3.85 (3H, s), 7.24 (1H, d), 7.33-7.50 (5H, m), 7.83 (1H, d), 7.97 (1H, dd). MS (ES): C15H14O3 requires 242; found 243 (MH+).
Reaction SMILES: [N:1]1([S:7]([C:10]2[CH:11]=[C:12]([CH:16]=[CH:17][CH:18]=2)[C:13]([OH:15])=O)(=[O:9])=[O:8])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[NH2:19][C:20]1[C:25]([OH:26])=[CH:24][CH:23]=[CH:22][N:21]=1>>[OH:26][C:25]1[C:20]([NH:19][C:13](=[O:15])[C:12]2[CH:16]=[CH:17][CH:18]=[C:10]([S:7]([N:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)(=[O:8])=[O:9])[CH:11]=2)=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: O=C(O)c1cccc(S(=O)(=O)N2CCCCC2)c1
Reactant: Nc1ncccc1O
Product: O=C(Nc1ncccc1O)c1cccc(S(=O)(=O)N2CCCCC2)c1

Procedure:
The entitled compound was produced according to the method of Example 92 but using 3-(piperidin-1-ylsulfonyl)benzoic acid and 2-aminopyridin-3-ol as the starting materials.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([OH:17])=O)[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14].C(Cl)(=O)C([Cl:21])=O>C(Cl)Cl.CN(C=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]([Cl:21])=[O:17])[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[C:12]=1[O:13][CH3:14]
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1cc(C(=O)O)c2c(c1OC)CCCC2
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COc1cc(C(=O)Cl)c2c(c1OC)CCCC2
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarboxylic acid (0.20 g, 0.85 mmol) in DCM (5 mL) was added oxalyl chloride (0.09 mL, 1.06 mmol) and 1 drop of DMF. The mixture was stirred at room temperature for 2 h. The solvent was removed in vacuo and the 3,4-dimethoxy-5,6,7,8-tetrahydro-1-naphthalenecarbonyl chloride was used without purification.
Reaction SMILES: [O:1]=[S:2]1(=[O:31])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([N:23]=[C:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1.CO.[BH4-].[Li+].Cl>O1CCCC1.O>[O:31]=[S:2]1(=[O:1])[C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=2[NH:5][C:4]([C:12]2[C:13](=[O:30])[N:14]([NH:23][CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:15]3[C:20]([C:21]=2[OH:22])=[CH:19][CH:18]=[CH:17][CH:16]=3)=[N:3]1
Reactant: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1N=C1CCOCC1
Agent: Cl
Agent: [BH4-]
Agent: [Li+]
Solvent: CO
Solvent: O
Solvent: C1CCOC1
Product: O=c1c(C2=NS(=O)(=O)c3ccccc3N2)c(O)c2ccccc2n1NC1CCOCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
The product of Example 237A (0.082 g, 0.19 mmol) in tetrahydrofuran (2.0 mL) and methanol (0.015 mL, 0.42 mmol) at 0° C. was treated with dropwise addition of a 2.0M solution of lithium borohydride in tetrahydrofuran (0.140 mL, 0.28 mmol). The reaction was stirred at 25° C. for 1 hour, acidified with 1 M hydrochloric acid to a pH of approximately 2-4, diluted with water, and , and the resulting precipitate was collected by filtration and dried. The crude product was chromatographed on silica gel with dichloromethaneto give the title compound. The sodium salt of the title compound was prepared according to the procedure of Example 1D. 1H NMR (300 MHz, DMSO-d6) δ ppm 0.86 (m, 1 H) 1.24 (m, 2 H) 1.48 (m, 2 H) 3.20 (m, J=18.02, 10.66 Hz, 2 H) 3.81 (m, 2 H) 5.82 (d, J=4.04 Hz, 1 H) 7.04 (m, J=7.72 Hz, 1 H) 7.27 (m, J=8.46, 8.46 Hz, 2 H) 7.52 (m, 2 H) 7.66 (d, J=7.72 Hz, 1 H) 7.76 (d, J=8.09 Hz, 1 H) 8.04 (d, J=1.47 Hz, 1 H). MS (ESI−) m/z 439 (M−H)−.
Reaction SMILES: Cl[C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1.[CH3:17][NH2:18].O>O1CCCC1>[CH3:17][NH:18][C:2]1[C:7]([NH:8][C:9]([CH3:12])([CH3:11])[CH3:10])=[N:6][C:5]([C:13]#[N:14])=[C:4]([C:15]#[N:16])[N:3]=1
Reactant: CC(C)(C)Nc1nc(C#N)c(C#N)nc1Cl
Reactant: CN
Solvent: C1CCOC1
Solvent: O
Product: CNc1nc(C#N)c(C#N)nc1NC(C)(C)C
Reaction time: 1 h
Yield: 76.1 %

Procedure:
2.0 g (0.008 mol) of 2-chloro-3-tert-butylamino-5,6-dicyanopyrazine was dissolved in 50 ml of tetrahydrofuran., and 1.3 g (0.017 mol) of a 40% methylamine aqueous solution was dropwise added thereto at room temperature. The mixture was stirred for 1 hour, and then the reaction solution was poured into 500 ml of water. The precipitated solid was collected by filtration and recrystallized from isobutyl alcohol to obtain 1.4 g of slightly yellow crystals (yield: 76.1%, melting point: at least 250° C.).
Reaction SMILES: [Br:1]Br.[CH3:3][CH:4]([CH3:25])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6].S([O-])([O-])(=O)=S.[Na+].[Na+]>C(Cl)Cl>[Br:1][C:4]([CH3:25])([CH3:3])[C:5]([C:7]1[CH:12]=[CH:11][C:10]([CH:13]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH2:14][C:15]([O:17][CH3:18])=[O:16])=[CH:9][CH:8]=1)=[O:6]
Reactant: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)C)cc1
Reactant: BrBr
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)CC(c1ccccc1)c1ccc(C(=O)C(C)(C)Br)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 97.9 %

Procedure:
A solution of 29.4 g (0.184 mol) of bromine in 50 ml of methylene chloride is added drop wise at room temperature to a mixture of 52.0 g (0.168 mol) of methyl 3-[4-(2-methylpropionyl)phenyl]-3-phenylpropanoate in 250 ml of methylene chloride. A small exotherm is controlled using a water bath. The mixture is stirred for 16 hours at room temperature. The reaction mixture is poured into a 5% aqueous sodium thiosulfate solution and stirred for 10 minutes. The organic layer is washed twice with 5% aqueous sodium thiosulfate solution, once with 10% sodium bicarbonate solution, dried over sodium sulfate, and concentrated to give 64.0 grams (98% yield) of methyl 3-[4-(2-bromo-2-methylpropionyl)phenyl]-3-phenylpropanoate.
Reaction SMILES: [F:1][C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].[Cl:15][C:16]1[CH:21]=[C:20]([O:22][CH3:23])[CH:19]=[C:18]([O:24][CH3:25])[CH:17]=1.Cl>ClCCl>[Cl:15][C:16]1[CH:17]=[C:18]([O:24][CH3:25])[CH:19]=[C:20]([O:22][CH3:23])[C:21]=1[C:4]([C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][C:2]=1[F:1])=[O:5]
Reactant: O=C(Cl)c1ccccc1F
Reactant: COc1cc(Cl)cc(OC)c1
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: COc1cc(Cl)c(C(=O)c2ccccc2F)c(OC)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of o-fluorobenzoyl chloride (47.6 g) in 100 ml dichloromethane is added AlCl3 (40.0 g) portionwise, in about thirty minutes. To this resultant dark solution is added dropwise a solution of 1-chloro-3,5-dimethoxybenzene (52.0 g) in 120 ml dichloromethane, in fifteen minutes. After stirring at ambient temperature for four hours, the mixture is poured into one liter iced-dilute HCl solution and then stirred for 30 minutes. The organic layer is collected, evaporated to an oil, which is dissolved into ether, washed with water, dilute NaOH solution, water, then dried (saturated NaCl, anhydrous MgSO4). After filtering, the solvent is evaporated to a solid, which is purified by silica gel, eluted with dichloromethane to yield 2-chloro-4,6-dimethoxy-2'-fluorobenzophenone, mp 88°-92° C.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][CH:10]=2)[CH:7]=1.C(=O)(O)[O-].[Na+].[I:18]I>C(O)C.O>[F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][OH:12])=[N:9][C:10]=2[I:18])[CH:7]=1
Reactant: II
Reactant: OCc1ncc2ccc(F)cn12
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: OCc1nc(I)c2ccc(F)cn12
Temperature: 25 °C
Reaction time: 3 h
Yield: 46.7 %

Procedure:
In a round-bottomed flask, (6-fluoro-imidazo[1,5-a]pyridin-3-yl)-methanol (225 mg, 1.15 mmol) was dissolved in ethanol (2 ml) and water (1 ml). Sodium bicarbonate (341 mg, 4.06 mmol) was added followed by iodine (383 mg, 1.51 mmol). The dark brown suspension was stirred at room temperature for 3 h then quenched with 10% Na2S2O3-solution and extracted with EtOAc (2×). The organic layers were washed with water and brine then dried over sodium sulfate, filtered and concentrated. The residue was absorbed on silica gel and chromatographed with EtOAc/hexanes (gradient 0-40% EtOAc) to provide 157 mg (50%, 2 steps) of (6-fluoro-1-iodo-imidazo[1,5-a]pyridin-3-yl)-methanol as a light yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[CH:11]=[C:10]([NH2:12])[N:9]([CH3:13])[N:8]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[CH3:14][O:15][C:16](=[O:31])[C:17](=[CH:21][C:22]1[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=1)[C:18]([CH3:20])=O>>[CH3:14][O:15][C:16]([C:17]1[CH:21]([C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([N+:28]([O-:30])=[O:29])[CH:23]=2)[C:11]2[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[N:8][N:9]([CH3:13])[C:10]=2[NH:12][C:18]=1[CH3:20])=[O:31]
Reactant: Cn1nc(C2CCCCC2)cc1N
Reactant: COC(=O)C(=Cc1cccc([N+](=O)[O-])c1)C(C)=O
Product: COC(=O)C1=C(C)Nc2c(c(C3CCCCC3)nn2C)C1c1cccc([N+](=O)[O-])c1

Procedure:
Starting from 3-cyclohexyl-1-methyl-5-pyrazolamine and methyl-2-(3-nitrobenzyliden)acetoacetate in equimolar proportions.