Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [ClH:1].O1CCOCC1.[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][N:20](C(OC(C)(C)C)=O)[CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1>CO>[ClH:1].[ClH:1].[N:8]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14][CH2:15][CH:16]2[CH2:21][NH:20][CH2:19][CH2:18][N:17]2[C:29]([O:31][CH:32]2[CH2:37][CH2:36][N:35]([C:38](=[O:40])[CH3:39])[CH2:34][CH2:33]2)=[O:30])[CH:9]=1
Reactant: CC(=O)N1CCC(OC(=O)N2CCN(C(=O)OC(C)(C)C)CC2COc2cccnc2)CC1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: CC(=O)N1CCC(OC(=O)N2CCNCC2COc2cccnc2)CC1
Reaction time: 1 h
Yield: 97 %

Procedure:
4 M HCl in 1,4-dioxane (6 mL, 24 mmol) was added to a solution of 1-(1-acetylpiperidin-4-yl) 4-tert-butyl 2-((pyridin-3-yloxy)methyl)piperazine-1,4-dicarboxylate (112.5 mg, 0.195 mmol) in MeOH (1 mL). After 1 h, the reaction mixture was concentrated under reduced pressure, yielding 82.4 mg (97%) of the desired product as a white solid. LC-MS: RT=1.66 min, [M+H]+=363.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][N:22]4C(=O)C5=CC=CC=C5C4=O)[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:4][CH:3]=1.O.NN>C(O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:9]=[C:10]([CH2:13][O:14][C:15]3[CH:16]=[C:17]([CH2:21][NH2:22])[CH:18]=[CH:19][CH:20]=3)[S:11][CH:12]=2)=[CH:6][CH:7]=1
Reactant: O=C1c2ccccc2C(=O)N1Cc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Agent: NN
Solvent: O
Solvent: CCO
Product: NCc1cccc(OCc2nc(-c3ccc(Cl)cc3)cs2)c1
Temperature: 25 °C

Procedure:
The phthalimide compound (1.65 grams) (Scheme C, Compound C2) was suspended in ethanol (100 mL). Hydrazine hydrate (1 mL) was added and the reaction was stirred at reflux for 2 hours before being cooled to ambient temperature. The mix was then filtered and the filtrate was evaporated. The crude solid was dissolved in dichloromethane, then sequentially washed with 1 N potassium hydroxide and water. The organic layer was then evaporated to give 3-[[4-(4-chlorophenyl)-2-thiazolyl]methoxy]benzenemethanamine Compound 11. Mp 117–118.5° C.; MS 331 (MH+); 1HNMR (CDCl3) δ 7.85 (d, 2H), 7.50 (s, 1H), 7.40 (d, 2H), 5.43 (s, 2H), 3.86 (s, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[O:7][C:8]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:9]=2[CH:10]=1)=[O:5])[CH3:2]>C(Cl)Cl.O=[Mn]=O>[CH:15]([C:12]1[CH:13]=[CH:14][C:8]2[O:7][C:6]([C:4]([O:3][CH2:1][CH3:2])=[O:5])=[CH:10][C:9]=2[CH:11]=1)=[O:16]
Reactant: CCOC(=O)c1cc2cc(CO)ccc2o1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CCOC(=O)c1cc2cc(C=O)ccc2o1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.3 %

Procedure:
To a solution of the compound 26 (2.53 g, 11.49 mmol) in DCM (70 ml) was added MnO2 (9.99 g, 114.9 mmol). The reaction mixture was stirred at room temperature for 16 h and then filtered through a celite pad. The filtrate was concentrated in vacuum to give the title compound 27 (2.19 g, 87%) as a white solid. 1H-NMR (DMSO) δ: 10.07 (s, 1H), 8.40-8.39 (m, 1H), 8.03 (dd, J=8.6, 1.6 Hz, 1H), 7.93-7.92 (m, 2H), 4.38 (q, J=7.1 Hz, 2H); 1.35 (t, J=7.0, 3H).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH:14]=[CH:15][C:16]([NH:18][C@H:19]([C:30]([O:32]C)=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[OH-].[Na+]>CO>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH:14]=[CH:15][C:16]([NH:18][C@H:19]([C:30]([OH:32])=[O:31])[CH2:20][C:21]2[C:29]3[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=3)[NH:23][CH:22]=2)=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)[C@H](Cc1c[nH]c2ccccc12)NC(=O)C=Cc1ccc(Oc2ccccc2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: O=C(C=Cc1ccc(Oc2ccccc2)cc1)N[C@@H](Cc1c[nH]c2ccccc12)C(=O)O
Yield: 88.5 %

Procedure:
The same procedures as in Example 64 were carried out from the compound obtained in Example 17 (4.9 g), 1 mol/L of an aqueous sodium hydroxide solution (17 mL), and methanol (170 mL), to give the captioned compound (4.2 g, 89%) as crystals.
Reaction SMILES: [C:1]([N:4]([C:8]1[C:9]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][CH2:27][CH2:28]3)=[CH:23][C:10]=2[O:11][C:12]=1[C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][C:15]=1[Cl:21])C(=O)C)(=[O:3])[CH3:2].[OH-].[Na+].C(OCC)(=O)C.CCCCCC>C1COCC1.C(OCC)(=O)C>[Cl:21][C:15]1[CH:16]=[C:17]([Cl:20])[CH:18]=[CH:19][C:14]=1[C:13]([C:12]1[O:11][C:10]2[CH:23]=[C:24]3[C:29](=[CH:30][C:9]=2[C:8]=1[NH:4][C:1](=[O:3])[CH3:2])[CH2:28][CH2:27][CH2:26][CH2:25]3)=[O:22]
Reactant: CC(=O)N(C(C)=O)c1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)Nc1c(C(=O)c2ccc(Cl)cc2Cl)oc2cc3c(cc12)CCCC3
Temperature: 100 °C
Reaction time: 1 h

Procedure:
To a solution of N-acetyl-N-[2-(2,4-dichlorobenzoyl)-5,6,7,8-tetrahydronaphtho[2,3-b]furan-3-yl]-acetamide (40 mg, 0.09 mmol) in anhydrous THF (1.8 mL) was added 2N sodium hydroxide solution (1.8 mL), and the reaction mixture was stirred at 100° C. for 1 h. The reaction was diluted with ethyl acetate, washed with saturated aqueous ammonium chloride solution, water, and brine. The organic layer was then dried over sodium sulfate, filtered, and evaporated under reduced pressure. The crude product was purified on the MPLC (Biotage) eluted with 5% ethyl acetate-hexane to afford 24.5 mg (67.6%) as yellow foam. 1H-NMR (DMSO-d6) δ 10.22 (s, 1H), 7.79 (t, J=1.2 Hz, 1H), 7.62 (s, 1H), 7.58 (d, J=0.9 Hz, 2H), 7.30 (s, 1H), 2.84 to 2.79 (m, 4H), 2.06 (s, 3H), 1.74 to 1.72 (m, 4H); LC-MS (ES MH+=402); Rf=0.68 (25% ethyl acetate-hexane).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:4]([CH2:13][NH2:14])=[N:5][CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]=[C:23]=[S:24]>O1CCCC1.C(N(CC)CC)C>[Cl:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[NH:22][C:23]([NH:14][CH2:13][C:4]1[C:3]([Cl:2])=[CH:8][C:7]([C:9]([F:12])([F:10])[F:11])=[CH:6][N:5]=1)=[S:24]
Reactant: S=C=Nc1ccccc1Cl
Reactant: NCc1ncc(C(F)(F)F)cc1Cl
Agent: Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: FC(F)(F)c1cnc(CNC(=S)Nc2ccccc2Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a suspension of (3-chloro-5-trifluoromethyl-2-pyridyl)methylamine hydrochloride (0.12 g) and 2-chlorophenylisothiocyanate (0.09 g) in dry tetrahydrofuran (10 ml) was added 10 drops of triethylamine. The mixture was stirred at room temperature overnight. The solvent was removed by evaporation in vacuo and the residue extracted with ethyl acetate and washed with 2M hydrochloric acid. The layers were separated and the organic phase was evaporated to dryness to give the title product, m.p. 126° C.
Reaction SMILES: [N-:1]=[C:2]=[O:3].[K+].O.[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]3[NH:32][CH2:31][CH2:30][S:29]3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1.C(=O)(O)[O-].[Na+]>C(O)C.C(O)(=O)C>[F:6][C:7]1[CH:8]=[C:9]([N:13]2[CH2:18][CH2:17][N:16]([CH2:19][CH2:20][O:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=3[CH:28]3[N:32]([C:2]([NH2:1])=[O:3])[CH2:31][CH2:30][S:29]3)[CH2:15][CH2:14]2)[CH:10]=[CH:11][CH:12]=1
Reactant: Fc1cccc(N2CCN(CCOc3ccccc3C3NCCS3)CC2)c1
Reactant: [N-]=C=O
Agent: O=C([O-])O
Agent: [K+]
Agent: [Na+]
Solvent: CCO
Solvent: O
Solvent: CC(=O)O
Product: NC(=O)N1CCSC1c1ccccc1OCCN1CCN(c2cccc(F)c2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 87.3 %

Procedure:
A mixture of 1.12 g of potassium isocyanate, 10 ml of water and 2 ml of acetic acid is added to a solution of 2.68 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine in 20 ml of ethanol, and the mixture is stirred at room temperature for 2 hours. A mixture of 0.56 g of potassium isocyanate and 0.5 ml of acetic acid is added to said mixture, and the mixture is stirred at the same temperature for 2 hours. The mixture is made alkaline with sodium bicarbonate and concentrated under reduced pressure to remove solvent. The residue is extracted with ethyl acetate. The extract is washed with a saturated sodium chloride solution, dried and then concentrated under reduced pressure to remove solvent. The residue is purified by silica gel chromatograph (solvent, ethyl acetate), and the resultant product is recrystallized from a mixture of ethyl acetate and ether. 2.6 g of 2-{2-[2-(4-(3-fluorophenyl)piperazin-1-yl)ethyloxy]phenyl}thiazolidine-3-carboxamide are obtained.
Reaction SMILES: [C:1]1([CH3:13])[CH:6]=[CH:5][C:4]([C:7]2([C:10]([OH:12])=O)[CH2:9][CH2:8]2)=[CH:3][CH:2]=1.S(Cl)(Cl)=O.[CH2:18]([NH2:25])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24].C(N(CC)C(C)C)(C)C.Cl>C(Cl)(Cl)Cl.ClCCl>[CH2:18]([NH:25][C:10]([C:7]1([C:4]2[CH:3]=[CH:2][C:1]([CH3:13])=[CH:6][CH:5]=2)[CH2:8][CH2:9]1)=[O:12])[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH3:24]
Reactant: CCCCCCCN
Reactant: Cc1ccc(C2(C(=O)O)CC2)cc1
Agent: Cl
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Solvent: CCN(C(C)C)C(C)C
Product: CCCCCCCNC(=O)C1(c2ccc(C)cc2)CC1
Temperature: 25 °C
Reaction time: 3 h
Yield: 53.6 %

Procedure:
To a solution of 1-p-tolylcyclopropanecarboxylic acid (5.68 grams) in chloroform (10 mL) was added thionyl chloride (17.0 mmol, 1.26 mL). The resulting mixture was brought to reflux and was allowed to stir for 3 h. The mixture was cooled to room temperature and concentrated to give a yellow oil. The oil was dissolved in dichloromethane (5 mL) and added dropwise to a solution of 1-heptylamine (6.82 mmol, 1.01 mL) and N,N-diisopropylethylamine (6.82 mmol, 1.19 mL) dissolved in dichloromethane (10 mL) cooled to 0° C. The mixture was warmed to room temperature and was allowed to stir for 30 minutes. The solution was poured over 1 N HCl, and the aqueous layer was isolated and extracted with dichloromethane (3×). The organic layers were combined, washed with 2N HCl (1×), brine (1×), dried over anhydrous sodium sulfate and concentrated to a yellow oil which solidified under high vacuum. The solid was crystallized from hexanes to give 1-p-tolyl-cyclopropanecarboxylic acid heptylamide as a white solid (1.0 g, 64%).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:17])([F:16])[F:15])[NH:10][C:9]=2[C:18]([N:20]2[CH2:25][CH2:24][O:23][CH2:22][CH2:21]2)=[O:19])=[CH:4][CH:3]=1.C([O-])([O-])=O.[K+].[K+].[Cl:32][C:33]1[CH:34]=[C:35]([CH:38]=[CH:39][CH:40]=1)[CH2:36]Br.CCOCC>CC#N.O>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:12]([CH3:13])=[C:11]([C:14]([F:15])([F:16])[F:17])[N:10]([CH2:36][C:35]3[CH:38]=[CH:39][CH:40]=[C:33]([Cl:32])[CH:34]=3)[C:9]=2[C:18]([N:20]2[CH2:21][CH2:22][O:23][CH2:24][CH2:25]2)=[O:19])=[CH:4][CH:3]=1
Reactant: Clc1cccc(CBr)c1
Reactant: Cc1c(C(F)(F)F)[nH]c(C(=O)N2CCOCC2)c1-c1ccc(Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Solvent: CCOCC
Product: Cc1c(-c2ccc(Cl)cc2)c(C(=O)N2CCOCC2)n(Cc2cccc(Cl)c2)c1C(F)(F)F
Temperature: 80 °C
Reaction time: 8 h

Procedure:
(3-(4-Chlorophenyl)-4-methyl-5-(trifluoromethyl)-1H-pyrrol-2-yl)(morpholino)methanone (80 mg, 0.215 mmol) was dissolved in dry MeCN (5 mL). The solution was mixed with K2CO3 (59 mg, 0.429 mmol), followed by addition of 3-chlorobenzyl bromide (31 μL, 0.236 mmol). The reaction mixture was stirred vigorously at 80° C. overnight. The temperature was lowered to room temperature; the reaction mixture was combined with a few lumps of ice, Et2O (50 mL) and H2O (10 mL) to result in a clear two phase system. The phases were separated; the organic phase was washed with brine. Drying (Na2SO4) was followed by concentration in vacuo. The residue was dissolved in MeCN (30 mL), concentrated in vacuo and used for preparative TLC (silica, heptane/EtOAc, 5:1), providing 96 mg (90%) of SC-25 as a fluffy white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11](=[O:26])[NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)[C:5](O)=[O:6].[CH3:27][S:28]([C:31]1[CH:36]=[CH:35][C:34]([CH2:37][NH2:38])=[CH:33][CH:32]=1)(=[O:30])=[O:29]>>[Cl:1][C:2]1[CH:3]=[C:4]([C:5]([NH:38][CH2:37][C:34]2[CH:33]=[CH:32][C:31]([S:28]([CH3:27])(=[O:30])=[O:29])=[CH:36][CH:35]=2)=[O:6])[CH:8]=[CH:9][C:10]=1[C:11]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([Cl:19])=[C:15]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[CH:14]=1)=[O:26]
Reactant: O=C(O)c1ccc(C(=O)Nc2ccc(Cl)c(-c3ccccn3)c2)c(Cl)c1
Reactant: CS(=O)(=O)c1ccc(CN)cc1
Product: CS(=O)(=O)c1ccc(CNC(=O)c2ccc(C(=O)Nc3ccc(Cl)c(-c4ccccn4)c3)c(Cl)c2)cc1

Procedure:
62 mg of 3-chloro-4-(4-chloro-3-(pyridin-2-yl)phenylcarbamoyl)benzoic acid was coupled to (4-(methylsulfonyl)phenyl)methanamine via Procedure G. The crude product was purified on reverse phase HPLC to yield 2-chloro-N1-(4-chloro-3-(pyridin-2-yl)phenyl)-N4-(4-(methylsulfonyl)benzyl)terephthalamide. MS (Q1) 554 (M)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([NH:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1)=[O:6].[H-].[Na+]>CN(C=O)C>[O:6]=[C:5]1[CH2:4][CH2:3][CH2:2][N:7]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2[CH:15]([CH3:21])[NH:16][C:17](=[O:20])[NH:18][N:19]=2)=[CH:10][CH:9]=1
Reactant: CC1NC(=O)NN=C1c1ccc(NC(=O)CCCCl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1NC(=O)NN=C1c1ccc(N2CCCC2=O)cc1
Reaction time: 0.5 h
Yield: 51.7 %

Procedure:
A solution of 6-[4-(4-chlorobutyrylamino)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (3.879 g) in DMF (38 ml) was added dropwise to a stirred mixture of sodium hydride (1.055 g) in DMF (13 ml) under ice cooling and stirring was continued for 30 minutes. The mixture was evaporated in vacuo after addition of acetic acid (1.85 ml) thereto. Water was added to the residue and the resultant precipitates were collected by filtration and recrystallized 70% aqueous ethanol to give 6-[4-(2oxo-1-pyrrolidinyl)phenyl]-5-methyl-4,5-dihydro-1,2,4-triazin-3(2H)-one (1.77 g).
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[Cl:5][CH2:6][CH2:7][CH2:8][C:9](Cl)=[O:10].[CH:12]1[C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=[CH:14][CH:13]=1>[N+](C1C=CC=CC=1)([O-])=O>[Cl:5][CH2:6][CH2:7][CH2:8][C:9]([C:14]1[CH:13]=[CH:12][C:21]2[C:16](=[CH:17][CH:18]=[CH:19][CH:20]=2)[CH:15]=1)=[O:10]
Reactant: c1ccc2ccccc2c1
Reactant: O=C(Cl)CCCCl
Agent: [Al+3]
Agent: [Cl-]
Solvent: O=[N+]([O-])c1ccccc1
Product: O=C(CCCCl)c1ccc2ccccc2c1
Reaction time: 0.5 h
Yield: 18.1 %

Procedure:
Aluminum chloride (26.7 g) is added to nitrobenzene (20 ml) and 4-chlorobutyric acid chloride (15.5 g) is added dropwise to the mixture with ice-cooling. Naphthalene (12.8 g) is slowly added to the mixture with ice-cooling and stirring is continued at the same temperature for 30 minutes. After stirring at room temperature for additional 2 hours, the reaction mixture is poured into ice-hydrochloric acid and extracted with chloroform. The chloroform extract is washed with water, saturated aqueous sodium bicarbonate, water and then saturated aqueous sodium chloride and dried over anhydrous sodium sulfate. The dried solution is distilled. A fraction having b.p. 187°-191° C./1.6 mmHg is separated and purified by silica gel column chromatography. The product thus obtained is crystallized from hexane and then further recrystallized from hexane-petroleum ether to obtain 2-(4-chlorobutyryl)naphthalene (4.2 g) as colorless flakes, m.p. 43°-44° C.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1.C(=O)([O-])[O-].[K+].[K+].[Br:19][C:20]1[CH:21]=[C:22]([OH:26])[CH:23]=[CH:24][CH:25]=1.O>CN(C=O)C>[Br:19][C:20]1[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=1)[O:26][CH2:2][C:3]1[CH:12]=[CH:11][C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=1
Reactant: BrCc1ccc2ccccc2c1
Reactant: Oc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Brc1cccc(OCc2ccc3ccccc3c2)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 87.2 %

Procedure:
2-Bromomethylnaphthalene (5.00 g, 22.6 mmol) was dissolved in N,N'-dimethylformamide (100 ml) and potassium carbonate (9.4 g, 68 mmol) and 3-bromophenol (3.91 g, 22.6 mmol) were added. The mixture was stirred vigorously for 16 h at room temperature and then poured into water (700 ml). The precipitate was filtered off, washed with water and dried in vacuo at 50° C. for 16 h to give 6.17 g (87%) of 2-(3-bromophenoxymethyl)naphthalene as a solid.
Reaction SMILES: [CH3:1][N:2]([CH3:7])[CH2:3][CH2:4][NH:5][CH3:6].Cl[C:9]1[N:14]=[C:13]([Cl:15])[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]=12>>[Cl:15][C:13]1[N:12]=[C:11]2[N:16]([CH3:19])[N:17]=[CH:18][C:10]2=[C:9]([N:5]([CH3:6])[CH2:4][CH2:3][N:2]([CH3:7])[CH3:1])[N:14]=1
Reactant: Cn1ncc2c(Cl)nc(Cl)nc21
Reactant: CNCCN(C)C
Product: CN(C)CCN(C)c1nc(Cl)nc2c1cnn2C

Procedure:
Reaction of N,N,N′-trimethylethylene diamine with 4,6-dichloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidine 5 by General Procedure B gave N-(6-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-4-yl)-N,N′,N′-trimethyl-ethane-1,2-diamine.
Reaction SMILES: C(O[C:4](=[O:15])[C:5]([N:10]1[CH:14]=[CH:13][N:12]=[CH:11]1)=[CH:6][N:7](C)C)C.[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([NH:26]N)=[N:24][CH:25]=1.O.C1(C)C=CC(S(O)(=O)=O)=CC=1>C(O)C>[CH3:16][C:17]([CH3:29])([CH3:28])[CH2:18][O:19][C:20]1[CH:21]=[CH:22][C:23]([N:26]2[C:4](=[O:15])[C:5]([N:10]3[CH:14]=[CH:13][N:12]=[CH:11]3)=[CH:6][NH:7]2)=[N:24][CH:25]=1
Reactant: CC(C)(C)COc1ccc(NN)nc1
Reactant: CCOC(=O)C(=CN(C)C)n1ccnc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CCO
Product: CC(C)(C)COc1ccc(-n2[nH]cc(-n3ccnc3)c2=O)nc1
Temperature: 25 °C

Procedure:
233 mg (1.0 mmol, purity 90%) of the compound from Example 42A are initially introduced into 4 ml ethanol. 260 mg (1.0 mmol, purity 75%) of the compound from Example 12A and 38 mg (0.2 mmol) p-toluenesulfonic acid monohydrate are added and the mixture is stirred under reflux for 16 h. The mixture is then allowed to cool to RT, the solid which has precipitated out is filtered off and washed with a little ethanol and the solid is dried under a high vacuum. A further amount of the target compound is obtained by purifying the mother liquor of the filtration via preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% TFA).
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][C:11]2([CH2:17][C:16]3[CH:18]=[CH:19][C:20]([Cl:22])=[CH:21][C:15]=3[O:14]2)[CH2:10][CH2:9]1)C1C=CC=CC=1.Cl.C(N1CCC2(CC3C=CC(Cl)=CC=3O2)CC1)C1C=CC=CC=1.[CH2:46]([O:48][C:49](Cl)=[O:50])[CH3:47]>C1C=CC=CC=1>[Cl:22][C:20]1[CH:19]=[CH:18][C:16]2[CH2:17][C:11]3([O:14][C:15]=2[CH:21]=1)[CH2:10][CH2:9][N:8]([C:49]([O:48][CH2:46][CH3:47])=[O:50])[CH2:13][CH2:12]3
Reactant: CCOC(=O)Cl
Reactant: Clc1ccc2c(c1)OC1(CCN(Cc3ccccc3)CC1)C2
Agent: Cl
Solvent: c1ccccc1
Product: CCOC(=O)N1CCC2(CC1)Cc1ccc(Cl)cc1O2
Temperature: 25 °C

Procedure:
A stirred solution of 6.1 g of 2,3-dihydro-1'-benzyl-6-chlorospiro[benzofuran-2,4'-piperidine], free base of Example 5, and 2.5 g of ethylchloroformate in 150 ml of benzene is refluxed for 18 hours. Thereafter, the solution is successively permitted to cool to ambient temperature, washed with water, washed with a saturated sodium bicarbonate solution, washed with a saturated sodium chloride solution, dried and concentrated to dryness, leaving 2,3-dihydro-6-chloro-1'-ethoxycarbonylspiro[benzofuran-2,4'-piperidine] as a dark oil. The oil is taken up in a mixture of 50 ml of a 50% potassium hydroxide solution and 100 ml of ethyl alcohol and this mixture is refluxed for 18 hours and then permitted to cool to room temperature before removal of the ethyl alcohol under reduced pressure. The remaining aqueous suspension is extracted with ether and the combined ether extracts are washed with 3 N hydrochloric acid, the acidic wash is basified with 6 N sodium hydroxide and the basified solution is extracted with ether. The combined ether extracts are dried before being concentrated to dryness, leaving on off-white solid. The solid is dissolved in ether where it is converted to its hydrogen chloride salt which is recrystallized twice from ethyl alcohol providing the product, 2,3-dihydro-6-chlorospiro[benzofuran-2,4'-piperidine]hydrochloride, mp 281°-288° C.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH:27]=O.CCOC(C)=O>ClCCCl>[CH3:23][O:24][C:25]1[CH:32]=[C:31]([O:33][CH3:34])[CH:30]=[CH:29][C:26]=1[CH2:27][NH:5][C:4]1[CH:6]=[CH:7][CH:8]=[C:2]([OH:1])[CH:3]=1
Reactant: COc1ccc(C=O)c(OC)c1
Reactant: Nc1cccc(O)c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: ClCCCl
Product: COc1ccc(CNc2cccc(O)c2)c(OC)c1
Temperature: 25 °C

Procedure:
To a solution of 3-hydroxyaniline (1 equiv) in 1,2-dichloroethane is added 4Å powdered molecular sieves, followed by sodium triacetoxyborohydride (1.5 equiv). 2,4-dimethoxybenzaldehyde (1.1 equiv) is added, and the reaction is stirred at room temperature. After completion, the reaction is poured into EtOAc, washed with sat. aq. NaHCO3 and brine, dried (Na2SO4), filtered, and concentrated in vacuo to provide the titled product.
Reaction SMILES: [OH-].[Na+].[CH2:3]([O:5][P:6]([O:23][CH2:24][CH3:25])([CH:8]([P:15]([O:20][CH2:21][CH3:22])([O:17][CH2:18][CH3:19])=[O:16])[CH2:9][C:10]([O:12]CC)=[O:11])=[O:7])[CH3:4]>O.CCO>[O:20]([P:15]([O:17][CH2:18][CH3:19])([CH:8]([P:6]([O:5][CH2:3][CH3:4])([O:23][CH2:24][CH3:25])=[O:7])[CH2:9][C:10]([OH:12])=[O:11])=[O:16])[CH2:21][CH3:22]
Reactant: CCOC(=O)CC(P(=O)(OCC)OCC)P(=O)(OCC)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CCOP(=O)(OCC)C(CC(=O)O)P(=O)(OCC)OCC
Temperature: 80 °C
Yield: 95.6 %

Procedure:
A solution of NaOH (4.00 g, 100 mmol) in water (50 ml) was added to a solution of ethyl 3,3-bis(diethoxyphosphinyl)propionate (32.6 g, 87 mmol) in EtOH (100 ml), and heated at 80° C. for 1 hour. After cooling, the EtOH was evaporated, and the residue was acidified to methyl orange with 12N HCl. The product was extracted into dichloromethane (5×50 ml). The organic layer was dried (Na2SO4) and concentrated to give the title compound (28.8 g, 96%) as a viscous oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[C:15]2[CH2:14][CH2:13][NH:12][CH2:11][C:10]=2[N:9]=[N:8]1.[Cl:16][C:17]1[C:25]([C:26]([F:29])([F:28])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19](O)=[O:20].CCN(CC)CC.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[Cl:16][C:17]1[C:25]([C:26]([F:28])([F:29])[F:27])=[CH:24][CH:23]=[CH:22][C:18]=1[C:19]([N:12]1[CH2:13][CH2:14][C:15]2[N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[N:8]=[N:9][C:10]=2[CH2:11]1)=[O:20]
Reactant: c1cnc(-n2nnc3c2CCNC3)nc1
Reactant: O=C(O)c1cccc(C(F)(F)F)c1Cl
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(c1cccc(C(F)(F)F)c1Cl)N1CCc2c(nnn2-c2ncccn2)C1
Reaction time: 3 h

Procedure:
A solution of 1-pyrimidin-2-yl-4,5,6,7-tetrahydro-1H-[1,2,3]triazolo[4,5-c]pyridine (97 mg, 0.48 mmol), 2-chloro-3-(trifluoromethyl)-benzoic acid (118 mg, 0.53 mmol) and Et3N (0.1 ml, 0.72 mmol) in DMF (2.5 ml), was treated with HATU (219 mg, 0.58 mmol) and stirred for 3 h.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4]2[C:8](=[C:9](Cl)[CH:10]=1)[CH:7]([NH2:12])[CH2:6][CH2:5]2.[Br:13]C1C=CC=C2C=1C(=O)CC2>>[Br:13][C:9]1[CH:10]=[CH:2][CH:3]=[C:4]2[C:8]=1[CH:7]([NH2:12])[CH2:6][CH2:5]2
Reactant: NC1CCc2cc(Cl)cc(Cl)c21
Reactant: O=C1CCc2cccc(Br)c21
Product: NC1CCc2cccc(Br)c21

Procedure:
This compound was prepared using a method analogous to that of 5,7-dichloro-2,3-dihydro-1H-inden-1-amine (A.2.13), 7-bromo-1-indanone replacing 5,7-dichloro-1-indanone.