Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH-].[K+].[O:3]1[C:7]2=[N:8][C:9]([C:17]([O:19]CC)=[O:18])=[C:10]([C:12]([O:14]CC)=[O:13])[CH:11]=[C:6]2[CH:5]=[CH:4]1.CC(C)=O>O.C(O)C>[O:3]1[C:7]2=[N:8][C:9]([C:17]([OH:19])=[O:18])=[C:10]([C:12]([OH:14])=[O:13])[CH:11]=[C:6]2[CH:5]=[CH:4]1
Reactant: CCOC(=O)c1cc2ccoc2nc1C(=O)OCC
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: CC(C)=O
Solvent: O
Product: O=C(O)c1cc2ccoc2nc1C(=O)O
Temperature: 60 °C

Procedure:
Potassium hydroxide (5.60 g, 85%, 0.087 mol) in water (5 mL) is added to a stirred suspension of diethyl furo[2,3-b]pyridine-5,6-dicarboxylate (9.3 g, 0.035 mol) in absolute ethanol (100 mL). The reaction mixture is heated at 60° C. for one hour, then cooled and anhydrous acetone added. The precipitate is filtered off, dried, suspended in dry acetone and treated with hydrogen chloride to adjust to a pH of 2. Crystallization of the isolated solids from an ethyl acetate-acetone mixture affords furo[2,3-b]pyridine-5,6-dicarboxylic acid mp 189°-192° C.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:18])[CH:5]([CH2:11][CH:12]1[CH2:17][CH2:16][CH2:15][CH2:14][CH2:13]1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH3:2].[O-]CC.[Na+].[CH2:23](Br)[CH2:24][CH2:25][CH3:26].C(OCC)(=O)C>CCCCCC>[CH2:23]([C:5]([CH2:11][CH:12]1[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17]1)([C:4]([O:3][CH2:1][CH3:2])=[O:18])[C:6]([O:8][CH2:9][CH3:10])=[O:7])[CH2:24][CH2:25][CH3:26]
Reactant: CCCCBr
Reactant: CCOC(=O)C(CC1CCCCC1)C(=O)OCC
Agent: CC[O-]
Agent: [Na+]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Product: CCCCC(CC1CCCCC1)(C(=O)OCC)C(=O)OCC

Procedure:
Diethyl(cyclohexylmethyl)malonate (5.12 g) was added to a solution of sodium ethoxide (from 0.5 g of sodium in ethanol (50 ml)) and the mixture warmed to 60° C. n-Butyl bromide (4.0 g) was then added and the mixture heated overnight under reflux, and the crude product isolated as in Part A above. Chromatography on silica gel eluting with 0-7.5% ethyl acetate in hexane gave pure diethyl 2-n-butyl-2-(cyclohexylmethyl)malonate.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5].[Si:13](Cl)([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14].C(N(CC)C(C)C)(C)C>CN(C1C=CN=CC=1)C.C(Cl)Cl>[Si:13]([O:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]([CH3:12])[C:3]=1[C:4]([O:6][CH3:7])=[O:5])([C:16]([CH3:19])([CH3:18])[CH3:17])([CH3:15])[CH3:14]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1c(C)cccc1O
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)c1c(C)cccc1O[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h
Yield: 70.5 %

Procedure:
A mixture of methyl 2-hydroxy-6-methylbenzoate (prepared according to Doehner et al, WO 01/05739, 10.0 g), tert-butyldimethylsilyl chloride (11.0 g), N,N-di-isopropylethylamine (32 mL) and DMAP (0.75 g) in DCM (400 mL) was stirred at room temperature overnight. The mixture was washed with water and brine, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was purified by chromatography on silica eluting with a mixture of ethyl acetate and pentane with a gradient of 0-10% to give methyl 2-(tert-butyldimethylsilyloxy)-6-methylbenzoate (11.9 g) as an oil.
Reaction SMILES: [Cl:1][S:2]([OH:5])(=O)=[O:3].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14].Cl>>[Cl:6][C:7]1[CH:12]=[CH:11][C:10]([S:2]([Cl:1])(=[O:5])=[O:3])=[CH:9][C:8]=1[N+:13]([O-:15])=[O:14]
Reactant: O=S(=O)(O)Cl
Reactant: O=[N+]([O-])c1ccccc1Cl
Agent: Cl
Product: O=[N+]([O-])c1cc(S(=O)(=O)Cl)ccc1Cl
Temperature: 80 °C
Reaction time: 0.33 h

Procedure:
Under a nitrogen atmosphere, 350 ml. of chlorosulfonic acid was added to 236 g. (1.50 mole) of 2-chloronitrobenzene. The resulting green colored solution was heated for 18 hours at 80° C., then the temperature was increased to 140° C. and held at this temperature until HCl gas evolution ceased (about 90 minutes). The reaction mixture was then cooled to 25° C. and slowly poured onto 4 liters of ice. After stirring for 20 minutes the mixture was filtered to obtain a pale yellow solid. The filter cake was sucked dry then allowed to dry in a vacuum oven at 25° C. overnight, m.p. 37°-38° C., yield 362.3 g. (94%).
Reaction SMILES: [CH2:1]([P:3](=[O:9])([O-:8])[S:4][CH2:5][CH2:6][CH3:7])[CH3:2].C(N(CC)CC)C.O[C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21]>C(Cl)Cl>[CH2:1]([P:3](=[O:8])([O:9][C:18]1[CH:25]=[CH:24][CH:23]=[CH:22][C:19]=1[CH:20]=[O:21])[S:4][CH2:5][CH2:6][CH3:7])[CH3:2]
Reactant: CCCSP(=O)([O-])CC
Reactant: O=Cc1ccccc1O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCCSP(=O)(CC)Oc1ccccc1C=O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of S-propyl ethylthiophosphonate (0.03 mole) in methylene chloride (50 ml) is charged into a glass reaction vessel equipped with a mechanical stirrer. Triethylamine (0.03 mole) is added and the mixture is cooled to a temperature of about 0° C. A solution of 2-hydroxybenzaldehyde (0.03 mole) in methylene chloride (15 ml) is slowly added with stirring while maintaining the temperature of the reaction mixture at about 0° C. After the addition is completed the reaction mixture is allowed to warm to room temperature and stirring is continued for a period of about 1 hour. After this time the reaction mixture is transferred to a separatory funnel and methylene chloride (100 ml) is added. The resulting solution is then washed with water, dilute aqueous sodium hydroxide and again with water. The washed solution is dried over anhydrous magnesium sulfate, is filtered and stripped of solvent under vacuum to yield the desired product S-propyl O-(2-formylphenyl) ethylthiophosphate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH:9]2C(=O)O[C:12](C)([CH3:16])[O:11][C:10]2=[O:18])=[CH:4][CH:3]=1>N1C=CC=CC=1.C(O)C.[Cu]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([C:19]2[C:27]3[C:22](=[C:23]([CH2:29][S:30][CH3:31])[C:24]([F:28])=[CH:25][CH:26]=3)[NH:21][CH:20]=2)[CH2:9][C:10]([O:11][CH2:12][CH3:16])=[O:18])=[CH:6][CH:7]=1
Reactant: CSCc1c(F)ccc2c(C(c3ccc(Cl)cc3)C3C(=O)OC(C)(C)OC3=O)c[nH]c12
Agent: [Cu]
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)CC(c1ccc(Cl)cc1)c1c[nH]c2c(CSC)c(F)ccc12

Procedure:
23 mg (0.36 mmol) of copper powder were added to 3.31 g (7.16 mmol) of the compound from Example 21A in 13 ml of pyridine and 3 ml of ethanol. The reaction mixture was heated under reflux for 4 h and then the pyridine was removed in vacuo. The residue was taken up in ethyl acetate, silica gel was added, and the mixture was concentrated. The crude product-silica gel mixture was initially prepurified by flash chromatography (mobile phase: cyclohexane/ethyl acetate 5/1→3/1), and the product was again purified by preparative HPLC (acetonitrile/water gradient). 2.38 g (82% of theory) of the title compound were obtained.
Reaction SMILES: CC(C)([O-])C.[K+].[Cl-].[CH3:8][O:9][CH2:10][P+](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[CH3:30][C:31]1[CH:32]=[C:33]([C:40]2[CH:45]=[CH:44][C:43]([C:46]([F:49])([F:48])[F:47])=[CH:42][CH:41]=2)[CH:34]=[CH:35][C:36]=1[C:37](=O)[CH3:38].CCOC(C)=O.CCCCCC>C1COCC1>[CH3:8][O:9][CH:10]=[C:37]([C:36]1[CH:35]=[CH:34][C:33]([C:40]2[CH:41]=[CH:42][C:43]([C:46]([F:47])([F:48])[F:49])=[CH:44][CH:45]=2)=[CH:32][C:31]=1[CH3:30])[CH3:38]
Reactant: CC(=O)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Reactant: COC[P+](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: CC(C)(C)[O-]
Agent: [Cl-]
Agent: [K+]
Solvent: CCCCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC=C(C)c1ccc(-c2ccc(C(F)(F)F)cc2)cc1C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100.8 %

Procedure:
To a an ambient temperature suspension of potassium tert-butoxide (2.42 g, 21.56 mmol) in THF (70 mL) is added (methoxymethyl)triphenylphosphonium chloride (7.39 g, 21.56 mmol) and is stirred at room temperature for 30 min. 1-(3-methyl-4′-trifluoromethyl-biphenyl-4-yl)-ethanone (2.0 g, 7.19 mmol) is added and the reaction mixture continues to stir at room temperature. After 2 h TLC (20% EtOAc/hexane) indicates complete consumption of starting material. The reaction is quenched with saturated aqueous NH4Cl and concentrated. The residue is partitioned between EtOAc (100 mL) and water (30 mL). The aqueous layer is extracted with EtOAc (100 mL) and The combined organic layers are washed with brine, dried (MgSO4), filtered, concentrated and chromatographed (120 g SiO2, 10% EtOAc/Hexanes) to yield the title compound (2.22 g, quant.).
Reaction SMILES: [CH2:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([O:24]C)=[O:23])=[C:16]([C:29]3[CH:34]=[CH:33][C:32]([CH3:35])=[CH:31][CH:30]=3)[N:15]=2)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+]>CO>[CH2:1]([NH:5][C:6]([CH:8]1[CH2:13][CH2:12][CH2:11][N:10]([C:14]2[N:19]=[C:18]([CH3:20])[C:17]([CH:21]([CH2:26][CH2:27][CH3:28])[C:22]([OH:24])=[O:23])=[C:16]([C:29]3[CH:30]=[CH:31][C:32]([CH3:35])=[CH:33][CH:34]=3)[N:15]=2)[CH2:9]1)=[O:7])[CH:2]([CH3:4])[CH3:3]
Reactant: CCCC(C(=O)OC)c1c(C)nc(N2CCCC(C(=O)NCC(C)C)C2)nc1-c1ccc(C)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc(N2CCCC(C(=O)NCC(C)C)C2)nc1-c1ccc(C)cc1
Temperature: 50 °C
Yield: 112.2 %

Procedure:
To a solution of methyl 2-(2-(3-(isobutylcarbamoyl)piperidin-1-yl)-4-methyl-6-p-tolylpyrimidin-5-yl)pentanoate (0.150 g; 0.191 mmol) in methanol (4.60 mL) was added a solution sodium hydroxide 5% (4.60 mL, 5.75 mmol) and the reaction mixturestirred at room temperature for 4 days, then heated for 18 h at 50° C. The volatiles were removed under reduced pressure, the residue was dissolved in water and the aqueous solution was washed with diethylether (3 times). The pH of the aqueous solution was adjusted between 2 and 3 by addition of a solution of hydrochloric acid 6N and the formed precipitate was collected by filtration. Purification by preparative HPLC (HPLC method 4) furnished 0.10 g (11%) of the title compound as a white solid.
Reaction SMILES: [C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][NH:14][CH3:15])[C:8]([NH2:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[OH:22][C:23]1[CH:31]=[CH:30][C:26]([CH2:27][CH2:28]Br)=[CH:25][CH:24]=1.C(=O)(O)[O-].[Na+]>C(#N)C>[C:1]1([C:7]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)([CH2:11][CH2:12][CH2:13][N:14]([CH2:28][CH2:27][C:26]2[CH:30]=[CH:31][C:23]([OH:22])=[CH:24][CH:25]=2)[CH3:15])[C:8]([NH2:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(CCBr)cc1
Reactant: CNCCCC(C(N)=O)(c1ccccc1)c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC#N
Product: CN(CCCC(C(N)=O)(c1ccccc1)c1ccccc1)CCc1ccc(O)cc1

Procedure:
A mixture containing 2,2-diphenyl-5-methylaminopentanamide (0.36 g--see Preparation 3), 4-hydroxyphenethyl bromide (0.26 g), sodium bicarbonate (0.5 g) and acetonitrile (20 ml) was heated under reflux for 16 hours. The mixture was partitioned between dichloromethane (40 ml) and aqueous sodium bicarbonate (30 ml), the layers separated and the aqueous layer extracted with dichloromethane (2×30 ml). The combined dichloromethane extracts were concentrated in vacuo to give an oil which was purified by column chromatography on silica eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give a foam which was further purified by column chromatography on alumina eluting with dichloromethane containing methanol (0% up to 10%). The product-containing fractions were combined and concentrated in vacuo to give the title compound as a foam, yield 0.09 g.
Reaction SMILES: [C:1]([CH2:4][C:5]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:6]=1[C:7]([OH:9])=[O:8])(O)=[O:2].C(Cl)(=O)C>CC(C)=O>[CH3:15][O:14][C:11]1[CH:10]=[C:6]2[C:5]([CH2:4][C:1](=[O:2])[O:8][C:7]2=[O:9])=[CH:13][CH:12]=1
Reactant: COc1ccc(CC(=O)O)c(C(=O)O)c1
Solvent: CC(C)=O
Solvent: CC(=O)Cl
Product: COc1ccc2c(c1)C(=O)OC(=O)C2
Temperature: 25 °C
Reaction time: 18 h
Yield: 91.4 %

Procedure:
To a suspension of 2-(carboxymethyl)-5-methoxybenzoic acid (5.22 g) (synthesised using the procedure in Tetrahedron 1975, 31, 2607-19) in acetone (50 ml) was added acetyl chloride (7.06 ml) and the reaction mixture was stirred at room temperature for 18 hours. The solvent was evaporated and azeotroped with toluene (×3). The resultant solid was triturated with diethyl ether to yield 7-methoxy-1H-isochromene-1,3(4H)-dione as a brown solid (4.36 g); NMR Spectrum: (DMSOd6) 3.84 (s, 3H), 4.20 (s, 2H), 7.36 (m, 2H), 7.50 (s, 1H).
Reaction SMILES: Cl.FC1C=C(C=CC=1)CN1C=C(C2C3C(=NC=C(C4C=CC(C5CCNCC5)=CC=4)C=3)N(S(C3C=CC(C)=CC=3)(=O)=O)C=2)C=N1.[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:72]=[CH:71][C:70]([N:73]5[CH2:78][CH2:77][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:75][CH2:74]5)=[CH:69][CH:68]=4)[CH:65]=3)[N:60](S(C3C=CC(C)=CC=3)(=O)=O)[CH:59]=2)[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1.[OH-].[Li+]>C1COCC1.CO.O>[CH2:46]([N:53]1[CH:57]=[C:56]([C:58]2[C:66]3[C:61](=[N:62][CH:63]=[C:64]([C:67]4[CH:68]=[CH:69][C:70]([N:73]5[CH2:74][CH2:75][N:76]([CH2:79][C@@H:80]([OH:82])[CH3:81])[CH2:77][CH2:78]5)=[CH:71][CH:72]=4)[CH:65]=3)[NH:60][CH:59]=2)[CH:55]=[N:54]1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4ccccc4)c3)c3cc(-c4ccc(N5CCN(C[C@H](C)O)CC5)cc4)cnc32)cc1
Agent: Cc1ccc(S(=O)(=O)n2cc(-c3cnn(Cc4cccc(F)c4)c3)c3cc(-c4ccc(C5CCNCC5)cc4)cnc32)cc1
Agent: Cl
Agent: [Li+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: C[C@H](O)CN1CCN(c2ccc(-c3cnc4[nH]cc(-c5cnn(Cc6ccccc6)c5)c4c3)cc2)CC1
Yield: 40.9 %

Procedure:
Using similar reaction conditions as described in step-iii of example-1, (S)-1-(4-(4-(3-(1-benzyl-1H-pyrazol-4-yl)-1-tosyl-1H-pyrrolo[2,3-b]pyridin-5-yl)phenyl)piperazin-1-yl)propan-2-ol (100 mg, 0.154 mmol) was hydrolyzed with lithium hydroxide (13 mg, 0.309 mmol) in THF/methanol/water (5./1/1 mL) to yield 31 mg (32.9% yield) of desired product. 1H NMR (CD3OD, 400 MHz): δ 8.605-8.601 (d, 1H), 8.537-8.533 (d, 1H), 8.22 (s, 1H), 7.95 (s, 1H), 7.75 (s, 1H), 7.69-7.67 (d, 2H), 7.38-7.29 (m, 5H), 7.17-7.15 (d, 2H), 5.42 (s, 2H), 4.29-4.25 (m, 1H), 4.00-3.80 (m, 2H), 3.35-3.20 (m, 2H), 3.35 (s, 2H), 3.25-3.20 (m, 2H), 3.19-3.10 (m, 2H), 1.30-1.27 (m, 3H). MS: m/z=493.2 (M+1), HPLC: 90.54% in method A.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10]O)=[N:8][CH:9]=1)=[O:4].[ClH:13].S(Cl)([Cl:16])=O>C(OCC)(=O)C.CO>[ClH:16].[CH3:1][O:2][C:3]([C:5]1[N:6]([CH3:12])[C:7]([CH2:10][Cl:13])=[N:8][CH:9]=1)=[O:4]
Reactant: O=S(Cl)Cl
Reactant: COC(=O)c1cnc(CO)n1C
Agent: Cl
Solvent: CO
Solvent: CCOC(C)=O
Product: COC(=O)c1cnc(CCl)n1C
Reaction time: 0.5 h

Procedure:
A solution of 2-hydroxymethyl-3-methyl-3H-imidazole-4-carboxylic acid methyl ester (250 mg, 1.5 mmol) in ethyl acetate/methanol 6 ml, 1:1) was converted to the hydrochloride by usage of an excess of an etheral solution of hydrogen chloride. After evaporation, the light brown residue was treated with thionyl chloride (1.1 ml, 15 mmol) and stirred for 0.5 h. After evaporation, the title compound was obtained as brown solid (100% yield). MS: m/e=189(M+H+), mp 106-108° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([O:15][C:16]2[CH:17]=[C:18]([CH:24]=[CH:25][C:26]=2[Cl:27])[C:19]([O:21][CH2:22][CH3:23])=[O:20])[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=1.[C:28]1([SH:34])[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[Cl:27][C:26]1[CH:25]=[CH:24][C:18]([C:19]([O:21][CH2:22][CH3:23])=[O:20])=[CH:17][C:16]=1[O:15][C:4]1[C:5]([NH:8][C:9]2[S:10][CH:11]=[C:12]([CH3:14])[N:13]=2)=[N:6][CH:7]=[C:2]([S:34][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:3]=1
Reactant: CCOC(=O)c1ccc(Cl)c(Oc2cc(Br)cnc2Nc2nc(C)cs2)c1
Reactant: Sc1ccccc1
Product: CCOC(=O)c1ccc(Cl)c(Oc2cc(Sc3ccccc3)cnc2Nc2nc(C)cs2)c1

Procedure:
Prepared according to the method of Example 13, using Ethyl 3-(5-bromo-2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)-4-chlorobenzoate and benzenethiol.
Reaction SMILES: [N+]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])([O-])=O.[CH3:13][P:14]([O:18]CC)[O:15][CH2:16][CH3:17]>C(#N)C>[CH3:13][P:14]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[N+:10]([O-:12])=[O:11])(=[O:18])[O:15][CH2:16][CH3:17]
Reactant: O=[N+]([O-])c1ccccc1[N+](=O)[O-]
Reactant: CCOP(C)OCC
Solvent: CC#N
Product: CCOP(C)(=O)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1,2-dinitrobenzene (2.48 mmol), diethyl methylphosphonite (3.72 mmol) and acetonitrile (3 ml) is stirred at RT overnight. The reaction is concentrated to dryness, and the residue is purified by preparative thin layer chromatography (TLC) to yield ethyl P-methyl-2-nitrophenyl-phosphinate.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=O)=[CH:5][CH:4]=1.COC1C=C[C:17]([C:20]2[C:24]([C:25]([OH:27])=[O:26])=[C:23](C)[N:22](C)[N:21]=2)=CC=1>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[N:22]([CH3:23])[N:21]=[C:20]([CH3:17])[C:24]=2[C:25]([OH:27])=[O:26])=[CH:5][CH:4]=1
Reactant: COc1ccc(-c2nn(C)c(C)c2C(=O)O)cc1
Reactant: COc1ccc(C(=O)Cl)cc1
Product: COc1ccc(-c2c(C(=O)O)c(C)nn2C)cc1

Procedure:
From 3.59 g of 4-methoxybenzoyl chloride, 1.97 g (59%) of a mixture of the title compound (major) and 3-(4-methoxyphenyl)-1,5-dimethyl-1H-pyrazole-4-carboxylic acid (minor) was prepared. H1-NMR(CD3OD, 500 MHz) for the title compound: δ 7.27 (2H, d, J=9 Hz), 7.03 (2H,d, J=9 Hz), 3.84 (3H, s), 3.60 (3H, s), 2.43 (3H, s).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([N+]([O-])=O)[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1.N([O-])=O.[Na+].[I-:24].[K+]>>[NH2:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([C:9]2[CH:14]=[C:13]([I:24])[CH:12]=[CH:11][C:10]=2[Cl:18])=[C:4]([CH3:19])[N:3]=1
Reactant: Cc1nc(N)nc(N)c1-c1cc([N+](=O)[O-])ccc1Cl
Reactant: [I-]
Agent: O=N[O-]
Agent: [K+]
Agent: [Na+]
Product: Cc1nc(N)nc(N)c1-c1cc(I)ccc1Cl

Procedure:
This compound was prepared in a similar manner to the compound of Example 54 by reaction of the diazonium salt with potassium iodide, mp. 232°-234° C.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[C:11]([O:14][C@H:15]1[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@H:18]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][C:37]3[CH:42]=[CH:41][C:40]([O:43][CH2:44][CH2:45][OH:46])=[CH:39][CH:38]=3)[CH:30]=2)[O:17][C@@H:16]1[CH2:47][O:48][C:49](=[O:51])[CH3:50])(=[O:13])[CH3:12].CCN(CC)CC>C(Cl)Cl>[C:11]([O:14][C@H:15]1[C@H:20]([O:21][C:22](=[O:24])[CH3:23])[C@@H:19]([O:25][C:26](=[O:28])[CH3:27])[C@H:18]([C:29]2[CH:34]=[CH:33][C:32]([Cl:35])=[C:31]([CH2:36][C:37]3[CH:38]=[CH:39][C:40]([O:43][CH2:44][CH:45]=[O:46])=[CH:41][CH:42]=3)[CH:30]=2)[O:17][C@@H:16]1[CH2:47][O:48][C:49](=[O:51])[CH3:50])(=[O:13])[CH3:12]
Reactant: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCCO)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: O=C(Cl)C(=O)Cl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Solvent: ClCCl
Product: CC(=O)OC[C@H]1O[C@@H](c2ccc(Cl)c(Cc3ccc(OCC=O)cc3)c2)[C@H](OC(C)=O)[C@@H](OC(C)=O)[C@@H]1OC(C)=O
Reaction time: 0.08 h

Procedure:
Oxalyl chloride (0.042 mL, 0.51 mmol) was added to a solution of DMSO (0.071 mL, 1.01 mmol) in dry DCM (0.5 mL) at −78° C. under nitrogen atmosphere. The reaction mixture was stirred for 5 min. at the same temperature and then a solution of (2R,3R,4R,5S,6S)-2-(acetoxymethyl)-6-(4-chloro-3-(4-(2-hydroxyethoxy)benzyl)phenyl)tetrahydro-2H-pyran-3,4,5-triyl triacetate (150 mg, 0.25 mmol), in dry DCM (2 mL) was added. The reaction mixture was stirred at the same temperature for 1 h. NEt3 (0.211 mL, 1.518 mmol) was added and the reaction mixture was allowed to come to r.t. The crude compound was extracted with DCM (20 mL). The organic layer was separated, washed with water (15 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the title compound which was used as such in next step.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][N:12](C)[CH2:11][CH:10]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1.COC1C=C(C=CC=1)C=O.F[B-](F)(F)F.C[O+](C)C.[BH4-].[Na+]>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:9]2[CH2:14][CH2:13][NH:12][CH2:11][CH:10]2[C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH:6]=[CH:7][CH:8]=1
Reactant: CCOC(=O)C1CN(C)CCC1c1cccc(OC)c1
Agent: COc1cccc(C=O)c1
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CCO
Product: CCOC(=O)C1CNCCC1c1cccc(OC)c1

Procedure:
In the preparation of ethyl 4-(3'-methoxyphenyl)-1-methylpiperidine-3-carboxylate (23), a synthesis of 4-aryl 2-unsubstituted nipecotic acids was developed. In this process modifying a known procedure [cf. C. F. Koelsch, J. of the Am. Chem. Soc., 65:2459 (1943)], 3-methoxybenzaldehyde (18) was converted to the amide ester, ethyl 4-(3'-methoxyphenyl)-2-piperidone-5-carboxylate (21), via standard procedures. Selective reduction of the amide function of 21 was achieved by reaction with trimethyloxonium fluoroborate followed immediately by treatment with NaBH4 in ethanol to yield amino ester, ethyl 4-(3'-methoxyphenyl)piperidine-3-carboxylate (22). Reductive methylation gave the required nipecotate 23 in 48% overall yield from 3-methoxybenzaldehyde (18).
Reaction SMILES: [C:1]1([CH2:7][CH2:8][C:9]2[NH:10][C:11]3[CH:17]=[CH:16][CH:15]=[CH:14][C:12]=3[N:13]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH:26]([CH3:28])[CH3:27]>CN(C=O)C>[CH2:25]([N:13]1[C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=[C:9]1[CH2:8][CH2:7][C:1]1[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1)[CH:26]([CH3:28])[CH3:27]
Reactant: c1ccc(CCc2nc3ccccc3[nH]2)cc1
Reactant: CC(C)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)Cn1c(CCc2ccccc2)nc2ccccc21
Temperature: 90 °C
Yield: 63.9 %

Procedure:
A 100 mL flask fitted with a stir-bar and septum with an Ar inlet was charged with benzimidazole 67 (2.00 g, 9.00 mmol) and K2CO3 (2.49 g, 18.0 mmol). DMF (25 mL) was added followed by 1-bromo-2-methylpropane (1.84 g, 1.47 mL, 13.5 mmol), and the mixture was heated in a 90° C. bath overnight. Another 1 mL of 1-bromo-2-methylpropane was added and the mixture was heated overnight again. Another addition of 1 mL of 1-bromo-2-methylpropane and 1 g K2CO3 was executed, and the mixture was heated overnight again. The suspension was cooled, and the solids were filtered off and rinsed with EtOAc (80 mL). The filtrate was washed with saturated NH4Cl (2×50 mL), H2O (2×50 mL), and brine (30 mL), filtered through phase separation paper, and concentrated in vacuo to an orange oil. The crude oil was filtered through a plug of silica gel with CH2Cl2 (100 mL). The filtrate was concentrated in vacuo to give 1.60 g of Compound #14 as a yellow oil (64%). 1H NMR (300 MHz, CDCl3): δ 7.80 (m, 1H), 7.35-7.21 (m, 8H), 3.81 (d, 2H), 3.35-3.26 (m, 2H), 3.22-3.13 (m, 2H), 2.16 (nonet, 1H), 0.95 (d, 6H) ppm. HPLC analysis (5:10:85 H2O:A1:MeOH) showed a purity of 96% with a retention time of 4.7 min.
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][N:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH3:15][O:16][CH2:17]Cl>C(#N)C.O1CCCC1>[F:1][C:2]1[C:7]([O:8][CH2:15][O:16][CH3:17])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Oc1cccnc1F
Reactant: COCCl
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1CCOC1
Solvent: CC#N
Product: COCOc1cccnc1F
Reaction time: 2 h
Yield: 70 %

Procedure:
2-Fluoropyridin-3-ol (55 g, 486 mmol) and cesium carbonate (158 g, 486 mmol) were suspended in ACN (400 mL). A solution of chloromethyl methyl ether (40 mL, 527 mmol) in dry tetrahydrofuran (50 mL) was added dropwise via an addition funnel. After 1 hour additional MOM-Cl (5 mL) was added and the reaction stirred for another 2 h. The reaction was evaporated to dryness under reduced pressure and the residue partitioned between diethyl ether (400 mL) and water (500 mL). The organic was washed with saturated sodium bicarbonate (100 mL) then dried with magnesium sulfate and evaporated to dryness under reduced pressure. The crude was purified using silica chromatography (hexane to 1:1 hexane:DCM gradient) to give the desired 2-fluoro-3-(methoxymethoxy)pyridine (53.5 g, 340 mmol, 70.0% yield).