Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16]OS(C2C=CC(C)=CC=2)(=O)=O)=[CH:9][CH:8]=1>CN(C=O)C>[CH3:5][O:6][C:7]1[CH:12]=[CH:11][C:10]([CH2:13][CH2:14][CH2:15][CH2:16][N:1]=[N+:2]=[N-:3])=[CH:9][CH:8]=1
Reactant: COc1ccc(CCCCOS(=O)(=O)c2ccc(C)cc2)cc1
Reactant: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COc1ccc(CCCCN=[N+]=[N-])cc1
Temperature: 80 °C
Reaction time: 12 h
Yield: 92.6 %

Procedure:
Sodium azide (3.07 g, 0.047 mol) was added to a solution of 1 (12.9 g, 0.04 mol) in anhydrous DMF (70 mL) and the reaction mixture was stirred 12 h at 80° C. (oil bath). Then solvent was removed at reduced pressure and the residual oil was treated with a mixture of CH2Cl2/ether 3:1 (100 mL). The resulting solution was washed with water (2×100 mL), brine and dried over magnesium sulfate. The solvent was removed under reduced pressure and 7.6 g (95%) of 2 was obtained. The purity of 2 (99%) was determined by GC and TLC (eluent:hexane/ethyl acetate 1:1), Rf=0.84.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[O:11][CH3:12])=[O:4].[CH3:13][N:14]1[C:22]2[N:21]=[C:20]([Cl:23])[N:19]([CH2:24][CH:25]=[C:26]([CH3:28])[CH3:27])[C:18]=2[C:17](=[O:29])[NH:16][C:15]1=[O:30].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH3:12][O:11][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=1[C:3](=[O:4])[CH2:2][N:16]1[C:17](=[O:29])[C:18]2[N:19]([CH2:24][CH:25]=[C:26]([CH3:27])[CH3:28])[C:20]([Cl:23])=[N:21][C:22]=2[N:14]([CH3:13])[C:15]1=[O:30]
Reactant: CC(C)=CCn1c(Cl)nc2c1c(=O)[nH]c(=O)n2C
Reactant: COc1ccccc1C(=O)CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1ccccc1C(=O)Cn1c(=O)c2c(nc(Cl)n2CC=C(C)C)n(C)c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
1.71 g of 2-bromo-1-(2-methoxy-phenyl)-ethanone are added to a mixture of 2.00 g of 3-methyl-7-(3-methyl-2-buten-1-yl)-8-chloro-xanthine and 1.38 mg of potassium carbonate in 15 ml of N,N-dimethylformamide. The reaction mixture is stirred for eight hours at ambient temperature. After aqueous working up the crude product is purified by chromatography through a silica gel column with cyclohexane/ethyl acetate (8:1 to 8:1) as eluant.
Reaction SMILES: C([O:3][C:4](=[O:44])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:25]=[C:24]([O:34][CH2:35][CH3:36])[CH:23]=2)[C:10]=1[CH2:37][CH2:38][C:39]([O:41]CC)=[O:40])C.[OH-].[Na+]>>[C:39]([CH2:38][CH2:37][C:10]1[C:11]([CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][O:21][C:22]2[CH:27]=[C:26]([C:28]3[CH:29]=[N:30][CH:31]=[N:32][CH:33]=3)[CH:25]=[C:24]([O:34][CH2:35][CH3:36])[CH:23]=2)=[CH:12][CH:13]=[CH:14][C:9]=1[O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:44])=[O:3])([OH:41])=[O:40]
Reactant: CCOC(=O)CCCOc1cccc(CCCCCCOc2cc(OCC)cc(-c3cncnc3)c2)c1CCC(=O)OCC
Agent: [Na+]
Agent: [OH-]
Product: CCOc1cc(OCCCCCCc2cccc(OCCCC(=O)O)c2CCC(=O)O)cc(-c2cncnc2)c1
Yield: 88 %

Procedure:
A similar procedure as described in Example 43, step 5 was used, starting from 4-[2-(2-ethoxycarbonyl-ethyl)-3-[6-(3-ethoxy-5-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy]-butyric acid ethyl ester (76 mg, 0.13 mmol) and 1.0 N aqueous sodium hydroxide (1.3 mL) to afford 4-[2-(2-carboxy-ethyl)-3-[6-(3-ethoxy-5-pyrimidin-5-yl-phenoxy)-hexyl]-phenoxy]-butyric acid (63 mg, 92%) as a light brown solid: ES(+)-HRMS m/e calcd for C31H38N2O7 (M+H)+ 551.2752. found 551.2750.
Reaction SMILES: [N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH2:11])[CH2:2]1)[CH2:8]2.[OH:12][C:13]1[CH:14]=[C:15]([CH:19]=[CH:20][CH:21]=1)[C:16](O)=[O:17].N>>[N:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([C@@H:4]3[NH:11][C:16](=[O:17])[C:15]3[CH:19]=[CH:20][CH:21]=[C:13]([OH:12])[CH:14]=3)[CH2:2]1)[CH2:8]2
Reactant: O=C(O)c1cccc(O)c1
Reactant: NC1C2CC3CC1CN(C3)C2
Agent: N
Product: O=C(NC1C2CC3CC1CN(C3)C2)c1cccc(O)c1

Procedure:
Prepared from (4s)-1-azatricyclo[3.3.1.13,7]dec-4-ylamine and 3-hydroxybenzoic acid (Aldrich) according to method B; 1H NMR (500 MHz, methanol-d4) δ 1.96 (s, 3H), 2.12 (s, 1H), 2.29 (d, J=14 Hz, 2H), 2.38 (s, 2H), 3.49 (s, 2H), 3.59 (s, 3H), 3.74-3.91 (m, 1H), 4.36 (s, 1H), 6.90-7.06 (m, 1H), 7.18-7.25 (m, J=2 Hz, 1H), 7.24-7.31 (m, 2H); MS (APCI/NH3) m/z 273 (M+H)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(OC)[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1.C([SiH](CC)CC)C.B(F)(F)F>C(#N)C.ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C@H:13]([OH:14])[C@@H:12]([OH:15])[C@H:11]([OH:16])[C@@H:10]([CH2:17][OH:18])[O:9]2)=[CH:4][C:3]=1[CH2:21][C:22]1[CH:31]=[CH:30][C:25]2[O:26][CH2:27][CH2:28][O:29][C:24]=2[CH:23]=1
Reactant: COC1(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)O[C@H](CO)[C@@H](O)[C@H](O)[C@H]1O
Agent: CC[SiH](CC)CC
Agent: FB(F)F
Solvent: CC#N
Solvent: ClCCl
Product: OC[C@H]1OC(c2ccc(Br)c(Cc3ccc4c(c3)OCCO4)c2)[C@H](O)[C@@H](O)[C@@H]1O
Temperature: 10 °C
Reaction time: 4 h
Yield: 106.4 %

Procedure:
To a stirred solution of (3R,4S,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-2-methoxy-tetrahydro-pyran-3,4,5-triol (28.4 g, 57.1 mmol) in acetonitrile-dichloromethane 1:1 (250 mL) was added triethylsilane (36.5 mL, 228.4 mmol) and boron trifluoride diethyletharate complex (14.1 mL, 114.2 mmol) at 10° C. After stirring for 4 h at 10° C., the reaction was quenched with saturated aqueous sodium bicarbonate (˜100 mL). The organic layer was separated, and the aqueous layer was extracted with ethyl acetate (3×150 mL). The organic layers were combined and dried over sodium sulfate, concentrated to furnish (3R,4R,5S,6R)-2-[4-bromo-3-(2,3-dihydro-benzo[1,4]dioxin-6-ylmethyl)-phenyl]-6-hydroxymethyl-tetrahydro-pyran-3,4,5-triol (28.4 g). Crude product was used for next reaction without purification.
Reaction SMILES: O=[C:2]1[NH:7][C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])=[N:5][C:4]2[NH:18][C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:20][C:3]1=2.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:38]>CC#N>[Cl:38][C:2]1[C:3]2[CH:20]=[C:19]([CH2:21][N:22]3[CH2:26][CH2:25][CH2:24][CH2:23]3)[NH:18][C:4]=2[N:5]=[C:6]([NH:8][C:9](=[O:17])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH3:16])[N:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CCCCCCCC(=O)Nc1nc2[nH]c(CN3CCCC3)cc2c(=O)[nH]1
Solvent: CC#N
Solvent: CN(C)c1ccccc1
Product: CCCCCCCC(=O)Nc1nc(Cl)c2cc(CN3CCCC3)[nH]c2n1

Procedure:
A solution of octanoic acid (4-oxo-6-pyrrolidin-1-ylmethyl-4,7-dihydro-3H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide (0.36 g 1 mmol; J. Chem. Soc. Perkin Trans. 1 1998, 1637), BnNEt3Cl (0.70 g, 2 mmol), PhNMe2 (0.25 mL) and POCl3 (0.86 mL, 6 mmol) in CH3CN (5 mL) was heated to 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (50 mL×3), and evaporated to give octanoic acid (4-chloro-6-pyrrolidin-1-ylmethyl-7H-pyrrolo[2,3-d]pyrimidin-2-yl)-amide as a crude (0.33 g) which was used without purification. HPLC Rt: 6.737 min. 1H-NMR (CDCl3): δ 11.60 (br s, 1H), 10.20 (br s, 1H), 6.38 (s, 1H), 3.86 (s, 2H), 2.90 (m, 2H), 2.70 9s, 4H), 1.86 (s, 4H), 1.78 (t, 2H), 1.32–1.29 (m, 8H), 0.90 (t, 3H).
Reaction SMILES: Br[C:2]1[CH:22]=[CH:21][C:5]2[N:6]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)=[N:8][C:4]=2[CH:3]=1.C([Li])CCC.C[O:29][B:30](OC)[O:31]C.Cl>C1COCC1>[C:15]1([N:6]2[C:5]3[CH:21]=[CH:22][C:2]([B:30]([OH:31])[OH:29])=[CH:3][C:4]=3[N:8]=[C:7]2[C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: COB(OC)OC
Reactant: Brc1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Agent: Cl
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OB(O)c1ccc2c(c1)nc(-c1ccccc1)n2-c1ccccc1
Temperature: -78 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
In an argon atmosphere, 10 g (29 mmol) of 5-bromo-1,2-diphenyl-1H-benzimidazole were dissolved into 100 mL of dehydrated THF, and the temperature of the solution was cooled to −78° C. Then, 20 mL of n-butyllithium (in hexane, 1.6 mol/L) were dropped. After the mixture had been stirred at −78° C. for 1 hour, the temperature of the mixture was increased to 0° C. The temperature of the mixture was cooled to −78° C. again, and 9.7 mL (87 mmol) of trimethoxyborane were dropped. The mixture was stirred at −78° C. for 1 hour, and was then stirred at room temperature for 2 hours. 100 mL of 10-mass % hydrochloric acid were added, and the whole was stirred for 1 hour, followed by filtration. The organic layer of the filtrate was washed with a saturated sodium chloride solution and dried with magnesium sulfate. The solvent was distilled off under reduced pressure, and the residue was purified by means of silica gel column chromatography to obtain 3.2 g of 1,2-diphenyl-1H-benzimidazole-5-boronic acid (35% yield).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24]Br)[CH:7]=1)[CH3:2].[CH2:27]([SH:34])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:1]([O:3][C:4](=[O:26])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-:23])=[O:22])=[CH:17][C:16]=2[CH2:24][S:34][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)[CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CBr)c1
Reactant: SCc1ccccc1
Product: CCOC(=O)Cc1ccc(OC)c(Oc2ccc([N+](=O)[O-])cc2CSCc2ccccc2)c1

Procedure:
As described for Example 10, [3-(2-bromomethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and benzyl mercaptan were reacted to provide [3-(2-benzylsulfanylmethyl-4-nitro-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester, which was reduced to [3-(4-amino-2-benzylsulfanylmethyl-phenoxy)-4-methoxy-phenyl]-acetic acid ethyl ester and then treated with 4-chlorobenzoyl chloride to provide {3-[2-benzylsulfanylmethyl-4-(4-chloro-benzoylamino)-phenoxy]-4-methoxy-phenyl}-acetic acid ethyl ester. Hydrolysis of the ester provided Compound 18.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11](Cl)(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCOCC1.[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([S:11]([NH:15][CH2:16][CH2:17][C:18]([OH:20])=[O:19])(=[O:13])=[O:12])[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: NCCC(=O)O
Reactant: COc1ccc(S(=O)(=O)Cl)cc1OC
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ccc(S(=O)(=O)NCCC(=O)O)cc1OC

Procedure:
A solution of 3.8 g of 3,4-dimethoxybenzenesulfonyl chloride in 5 ml of dioxane is added dropwise to a solution of 1.5 g of 3-aminopropionic acid in 20 ml of 1N NaOH solution. The mixture is left to stir while controlling the pH (pH>7) for 12 h, the pH is reduced below 7 by adding citric acid, and the reaction solution is then extracted with methylene chloride. The organic phase is dried over magnesium sulfate, concentrated under reduced pressure and employed without further purification in the next reaction step. The desired product is obtained with MW=289.31 (calculated); measured value (M+H)+: 290.1
Reaction SMILES: BrC[C:3]1[C:12]2[C:7](=[CH:8][C:9](OC)=[CH:10][CH:11]=2)OC(=O)C=1.[C:16]([O-:19])(=[O:18])[CH3:17].[Ca+2].[C:21]([O-])(=[O:23])C.Cl>C(O)(=O)C.C(O)C>[OH:23][C:21]1[C:9]2[C:10](=[CH:11][C:12]([CH3:3])=[CH:7][CH:8]=2)[O:18][C:16](=[O:19])[CH:17]=1
Reactant: CC(=O)[O-]
Reactant: COc1ccc2c(CBr)cc(=O)oc2c1
Agent: Cl
Agent: [Ca+2]
Solvent: CC(=O)O
Solvent: CCO
Product: Cc1ccc2c(O)cc(=O)oc2c1
Reaction time: 2.5 h

Procedure:
10 g of 4-bromomethyl-7-methoxycoumarin [produced according to Secrist et al., Biochem. Biophys. Res. Commun., 45, 1262 (1971)] are heated to boiling for 2.5 hours under reflux in 40 ml of glacial acetic acid together with 6 g of calcium acetate (free of water). The solution is brought to dryness in vacuo. The residue is heated to boiling in 50 ml of ethanol and 50 ml of concentrated hydrochloric acid for 1.5 hours under reflux. The volatile components are removed under reduced pressure. The residue is dissolved in chloroform. The resulting solution is made free of acids by extraction with diluted aqueous ammoniac and water and dried over annealed potassium carbonate. After removing the chloroform in vacuo, the residue is recrystallized from ethylacetate. In this manner 1.9 g (24.8 percent of the theoretically-calculated amount) of the title compound with a melting point of 179° to 182° C. are obtained.
Reaction SMILES: C([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19])C1C=CC=CC=1.[H][H]>CO.[Pd]>[OH:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:20][N:21]1[CH2:26][CH2:25][N:24]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[CH2:23][CH2:22]1)=[O:19]
Reactant: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3OCc2ccccc2)CC1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(NC(=O)[C@@H]2CC[C@@H]3CN2C(=O)N3O)CC1
Yield: 99.5 %

Procedure:
To a solution of tert-butyl 4-({[(2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 206 (0.25 g, 0.54 mml) in methanol (15 mL) was added 10% Pd/C (0.3 g). The mixture was hydrogenated under 35 psi hydrogen atmosphere at room temperature for 2 h. The catalyst was filtered out through Celite, and the filtrate was evaporated to give tert-butyl 4-({[(2S,5R)-6-hydroxy-7-oxo-1,6-diazabicyclo[3.2.1]oct-2-yl]carbonyl}amino)piperazine-1-carboxylate 207 (0.20 g, 99%) as a colorless foam.
Reaction SMILES: O[C:2]1([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH3:31])=[CH:26][CH:25]=2)[C:6]2[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=2[O:4][C:3]1([CH3:23])[CH3:22]>C(OCC)(=O)C.CCCCCC>[CH3:31][O:30][C:27]1[CH:26]=[CH:25][C:24]([CH:2]2[C:6]3[C:7]([CH3:21])=[C:8]([NH:13][C:14](=[O:20])[CH2:15][C:16]([CH3:17])([CH3:18])[CH3:19])[C:9]([CH3:12])=[C:10]([CH3:11])[C:5]=3[O:4][C:3]2([CH3:23])[CH3:22])=[CH:29][CH:28]=1
Reactant: COc1ccc(C2(O)c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: COc1ccc(C2c3c(C)c(NC(=O)CC(C)(C)C)c(C)c(C)c3OC2(C)C)cc1
Yield: 40 %

Procedure:
Using N-(3-hydroxy-3-(4-methoxyphenyl)-2,2,4,6,7-pentamethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide obtained in Example 258, the title compound was synthesized in the same manner as in Example 271. Yield: 40%. Melting point: 175-176° C. (ethyl acetate-hexane).
Reaction SMILES: [OH-].[Li+].[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:10]([C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=[O:17])=[CH:14][CH:13]=1)[CH3:11]>CO.O>[C:3]1([CH3:22])[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[O:9][CH:10]([C:12]1[CH:13]=[CH:14][C:15]([C:16]([OH:18])=[O:17])=[CH:20][CH:21]=1)[CH3:11]
Reactant: COC(=O)c1ccc(C(C)Oc2ccccc2C)cc1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: Cc1ccccc1OC(C)c1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 88.5 %

Procedure:
Lithium hydroxide (54 mg, 2.24 mmol) was added to a solution of methyl 4-(1-(o-tolyloxy)ethyl)benzoate (151 mg, 0.56 mmol) in methanol (100 mL) and water (10 mL). The reaction mixture was stirred at room temperature for 3 hours. After the reaction, the solvent was removed in vacuo. 3 mol/L aqueous hydrogen chloride was added to make pH 2˜3, and the product was extracted with dichloromethane (100 mL*3) The combined organic phase was washed with Sodium Chloride (20 mL*3), dried over anhydrous sodium sulfate, and the solvent was evaporated to dryness to give 4-(1-(o-tolyloxy)ethyl)benzoic acid (127 mg, 88%).
Reaction SMILES: [OH:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].C([O-])([O-])=O.[K+].[K+].I[CH2:19][CH:20]([CH3:22])[CH3:21]>CN(C=O)C>[CH2:19]([O:1][C:2]1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:3]=1[CH:4]=[O:5])[CH:20]([CH3:22])[CH3:21]
Reactant: CC(C)CI
Reactant: COc1cccc(C=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COc1cccc(C=O)c1OCC(C)C
Temperature: 25 °C
Reaction time: 18 h
Yield: 45.1 %

Procedure:
A solution of 2-hydroxy-3-methoxybenzaldehyde (4.00 g, 26.2 mmol) in DMF (50 mL) was treated with K2CO3 (8.00 g, 57.9 mmol) followed by iodoisobutane (4.53 mL, 39.4 mmol). The resulting slurry was stirred for at ambient temperature for 18 h. Additional DMF (70 mL) was added to help aid stirring, and the mixture was heated to 40° C. for 18 h. Additional iodoisobutane (2.26 mL, 19.7 mmol) was added and the mixture was stirred at ambient temperature for 48 h. The reaction was quenched with H2O (100 mL) and the mixture was extracted with EtOAc (3×100 mL). The combined organics were washed with H2O (2×100 mL) and brine (2×100 mL), dried (Na2SO4) and concentrated to an orange oil. Purification by column chromatography (silica gel, hexanes/EtOAc, 90:10) gave the title compound (2.46 g, 62%) as a clear oil: 1H NMR (300 MHz, DMSO-d6) δ 10.34 (s, 1H), 7.36 (dd, J=7.9, 1.7 Hz, 1H), 7.27 (dd, J=7.8, 1.7 Hz, 1H), 7.19 (dt, J=7.8, 0.6 Hz, 1H), 3.85 (m, 5H), 2.09-2.00 (m, 1H), 0.99 (d, J=6.7 Hz, 6H).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[CH:21][CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1.BrC1C=NC=C([F:31])C=1>>[CH3:1][C:2]1[N:3]=[C:4]([NH:7][C:8]([C:10]2[C:15]([NH:16][C:17]3[CH:18]=[N:19][CH:20]=[C:21]([F:31])[CH:22]=3)=[CH:14][CH:13]=[C:12]([CH3:23])[N:11]=2)=[O:9])[S:5][CH:6]=1
Reactant: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cccnc2)n1
Reactant: Fc1cncc(Br)c1
Product: Cc1csc(NC(=O)c2nc(C)ccc2Nc2cncc(F)c2)n1

Procedure:
The title compound, was prepared from 3-Amino-6-methyl-pyridine-2-carboxylic acid (4-methyl-thiazol-2-yl)-amide (example 14) in accordance with the general method of example 20 using 3-Bromo-5-fluoropyridine (CAS [407-20-5]) instead of 3-Bromo-4-methylpyridine to yield the final compound as a yellow solid, MS (ISP): m/e=344.0 (M+H+).
Reaction SMILES: [F:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N:8]2[CH:12]=[C:11]([N+:13]([O-])=O)[C:10]([CH3:16])=[N:9]2)[CH:7]=1.C(OCC)(=O)C>C(O)C.[Pd]>[F:1][C:2]1[CH:7]=[C:6]([N:8]2[CH:12]=[C:11]([NH2:13])[C:10]([CH3:16])=[N:9]2)[CH:5]=[N:4][CH:3]=1
Reactant: Cc1nn(-c2cncc(F)c2)cc1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn(-c2cncc(F)c2)cc1N
Reaction time: 3 h
Yield: 73.8 %

Procedure:
To a solution of 3-fluoro-5-(3-methyl-4-nitro-1H-pyrazol-1-yl)pyridine (3.133 g, 14.10 mmol) in ethanol (28.2 ml) was added ethyl acetate until all of the starting material went into solution. The solution was degassed and 10% palladium on carbon (0.750 g, 0.705 mmol) was added and the reaction was stirred in a parr hydrogenator at 40 psi for 3 hours. The solution was filtered through celite with ethyl acetate and concentrated to give 1-(5-fluoropyridin-3-yl)-3-methyl-1H-pyrazol-4-amine (2.000 g, 10.41 mmol, 73.8%) as a brown solid: mp 136.0-138.0° C.; 1H NMR (400 MHz, CDCl3) δ 8.67-8.59 (m, 1H), 8.27 (d, J=2.5 Hz, 1H), 7.73 (dt, J=9.9, 2.3 Hz, 1H), 7.45 (s, 1H), 3.01 (s, 2H), 2.28 (s, 3H); EIMS m/z 192.
Reaction SMILES: [F:1][C:2]([F:18])([F:17])[O:3][C:4]1[CH:9]=[CH:8][C:7]([CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][C:11]2=[O:16])=[CH:6][CH:5]=1.[Br:19]Br>C(Cl)(Cl)Cl>[Br:19][CH:12]1[C:11](=[O:16])[CH:10]([C:7]2[CH:6]=[CH:5][C:4]([O:3][C:2]([F:17])([F:18])[F:1])=[CH:9][CH:8]=2)[CH2:15][CH2:14][CH2:13]1
Reactant: O=C1CCCCC1c1ccc(OC(F)(F)F)cc1
Reactant: BrBr
Solvent: ClC(Cl)Cl
Product: O=C1C(Br)CCCC1c1ccc(OC(F)(F)F)cc1
Temperature: 25 °C
Yield: 91.8 %

Procedure:
2-(4-Trifluoromethoxyl-phenyl)-cyclohexanone (53 mg, 0.21 mmol) was dissolved in chloroform (1 mL). To this solution bromine (34.4 mg, 0.22 mmol) in chloroform (0.5 mL) was added drop wise at room temperature. The reaction was stirred for 1½ hours at room temperature. The solvent was removed under reduced pressure to yield the crude title compound (65 mg) which was used directly in the next step without further purification.
Reaction SMILES: [NH2:1][C:2]1[C:7]([Cl:8])=[CH:6][C:5]([Cl:9])=[CH:4][N:3]=1.[OH-].[K+].[N+:12]([C:15]1[CH:20]=[C:19]([N+:21]([O-:23])=[O:22])[CH:18]=[C:17]([C:24]([F:27])([F:26])[F:25])[C:16]=1Cl)([O-:14])=[O:13].Cl>CN(C)C=O>[Cl:8][C:7]1[C:2]([NH:1][C:16]2[C:17]([C:24]([F:26])([F:27])[F:25])=[CH:18][C:19]([N+:21]([O-:23])=[O:22])=[CH:20][C:15]=2[N+:12]([O-:14])=[O:13])=[N:3][CH:4]=[C:5]([Cl:9])[CH:6]=1
Reactant: Nc1ncc(Cl)cc1Cl
Reactant: O=[N+]([O-])c1cc([N+](=O)[O-])c(Cl)c(C(F)(F)F)c1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1cc([N+](=O)[O-])c(Nc2ncc(Cl)cc2Cl)c(C(F)(F)F)c1

Procedure:
In 20 ml. of dimethylformamide, 1.65 g. of 2-amino-3,5-dichloropyridine was dissolved and 1.0 g. of powdery potassium hydroxide was gradually added with stirring. After the addition, 2.7 g. of 2,4-dinitro-6-trifluoromethylchlorobenzene was added at 30° C. during 5 minutes to react them for about 3 hours. The reaction mixture was acidified with conc. HCl and the product was extracted with methylenechloride. The extracted layer was washed with water and dehydrated and the solvent was distilled. The product was separated by a silica gel column with an eluent of toluene and the solvent was distilled off to obtain 2.5 g. of the object compound having the melting point of 98° to 101° C.
Reaction SMILES: [CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([O:24]CC)=[O:23])[CH:19]=[N:18]1)[NH:10][C:9]2=O.[NH:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1>>[CH3:1][C:2]1[CH:31]=[CH:30][CH:29]=[C:28]([CH3:32])[C:3]=1[CH2:4][NH:5][C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][C:15]=1[Cl:16])[N:12]=[C:11]([N:17]1[CH:21]=[C:20]([C:22]([OH:24])=[O:23])[CH:19]=[N:18]1)[N:10]=[C:9]2[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CCOC(=O)c1cnn(-c2nc3cc(Cl)c(NCc4c(C)cccc4C)cc3c(=O)[nH]2)c1
Reactant: C1COCCN1
Product: Cc1cccc(C)c1CNc1cc2c(N3CCOCC3)nc(-n3cc(C(=O)O)cn3)nc2cc1Cl

Procedure:
The above compound may be made analogous to Example 1 using ethyl 1-(6-((2,6-dimethylbenzyl)amino)-7-chloro-4-oxo-3,4-dihydroquinazolin-2-yl)-1H-pyrazole-4-carboxylate in step D and morpholine in step E. MS (ESI): predicted mass calcd. for C25H25ClN6O3, 492.9
Reaction SMILES: [Cl-].[C:2]([C:4]1[C:16]([N+:17]([O-:19])=[O:18])=[CH:15][CH:14]=[CH:13][C:5]=1[O:6][CH2:7][C@H:8]1[CH2:12][CH2:11][CH2:10][NH2+:9]1)#[N:3].[C:20](Cl)(=[O:22])[CH3:21]>>[C:20]([N:9]1[CH2:10][CH2:11][CH2:12][C@@H:8]1[CH2:7][O:6][C:5]1[CH:13]=[CH:14][CH:15]=[C:16]([N+:17]([O-:19])=[O:18])[C:4]=1[C:2]#[N:3])(=[O:22])[CH3:21]
Reactant: CC(=O)Cl
Reactant: N#Cc1c(OC[C@H]2CCC[NH2+]2)cccc1[N+](=O)[O-]
Agent: [Cl-]
Product: CC(=O)N1CCC[C@@H]1COc1cccc([N+](=O)[O-])c1C#N
Yield: 100 %

Procedure:
Prepared as in Example 165b from (R)-2-((2-cyano-3-nitrophenoxy)methyl)pyrrolidinium chloride and acetyl chloride in 100% yield as a yellow syrup. MS 290 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]([O:9][CH3:10])=[C:7]([O:11][CH3:12])[C:6]([O:13][CH3:14])=[C:5]([CH3:15])[C:4]=1[CH2:16][CH2:17][CH2:18][OH:19].C(N(CC)CC)C.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>C(Cl)Cl>[CH3:27][S:28]([O:19][CH2:18][CH2:17][CH2:16][C:4]1[C:5]([CH3:15])=[C:6]([O:13][CH3:14])[C:7]([O:11][CH3:12])=[C:8]([O:9][CH3:10])[C:3]=1[O:2][CH3:1])(=[O:30])=[O:29]
Reactant: CS(=O)(=O)Cl
Reactant: COc1c(C)c(CCCO)c(OC)c(OC)c1OC
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1c(C)c(CCCOS(C)(=O)=O)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91.8 %

Procedure:
A solution of 9 (3.88 g, 15 mmol) and triethylamine (3.0 g, 30 mmol, 4.2 mL) in CH2Cl2 (50 mL) was stirred at room temperature for 10 mins. Methane sulfonyl chloride (1.8 g, 1.20 mL, 15.75 mmol) in CH2Cl2 (50 mL) was added dropwise over 20 mins and the reaction mixture stirred at room temperature for 1 hr. The mixture was then diluted with CH2Cl2 (50 mL) and the organic layer washed with H2O (5×100 mL), 10% aqueous NaHCO3 (100 mL), dried (MgSO4), filtered and the solvent removed in vacuo by rotary evaporation to afford pure 3 as a liquid (4.8 g, 95%).