Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([CH3:14])([CH3:13])[CH3:12])[C:5](O)=[O:6].[H-].[Al+3].[Li+].[H-].[H-].[H-]>O1CCCC1.[OH-].[Na+]>[NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[C:11]([CH3:14])([CH3:13])[CH3:12])[CH2:5][OH:6]
Reactant: CC(C)(C)c1ccc(C(=O)O)cc1N
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC(C)(C)c1ccc(CO)cc1N
Temperature: 25 °C
Reaction time: 3 h

Procedure:
A solution of 3-amino-4-t-butylbenzoic acid (10 g) in anhydrous tetrahydrofuran (150 ml) was added dropwise to a suspension of lithium aluminium hydride (4.0 g) in anhydrous tetrahydrofuran (150 ml) over a period of 45 minutes. The mixture was stirred at room temperature for 3 hours. The reaction mixture was diluted with tetrahydrofuran (150 ml) and aqueous sodium hydroxide solution (15%) was added to the mixture while cooling in an ice bath in order to decompose the excess lithium aluminium hydride. The insoluble material was filtered off through Celite (trademark) and the solvent of the filtrate was evaporated under reduced pressure to afford the desired compound (8.41 g, Rf=0.55: thin layer chromatography on a silica gel plate using n-hexane:ethyl acetate=1:3 as the eluant).
Reaction SMILES: [CH3:1][C:2]1C=CC(S(OCCC#C)(=O)=O)=[CH:4][CH:3]=1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(C(C)C)CC)(C)C>ClCCCl>[CH2:4]([N:25]1[CH2:24][CH2:23][N:22]([C:17]2[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=2)[CH2:27][CH2:26]1)[CH2:3][C:2]#[CH:1]
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Product: C#CCCN1CCN(c2ccccn2)CC1
Yield: 48.4 %

Procedure:
A solution of but-3-ynyl 4-methylbenzenesulfonate (1.27 g), 1-(pyridin-2-yl)piperazine (1.17 g) and diisoproylethylamine (1.37 mL) in 1,2-dichloroethane (7 mL) was heated to reflux overnight. The mixture was concentrated, diluted with sat. aq. NaHCO3 (5 mL) and extracted with DCM (2×50 mL). Drying (Na2SO4) and silica gel flash chromatography (EtOAc/hexane 1:1→1:0) afforded 1-(but-3-ynyl)-4-(pyridin-2-yl)piperazine (0.59 g)
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Br:8])[C:3]=1[O:9][CH3:10].[CH:11](=[O:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17].Cl>C1COCC1>[Br:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([CH:11]([OH:18])[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH3:17])[C:3]=1[O:9][CH3:10]
Reactant: COc1c(Br)cccc1Br
Reactant: CCCCCCC=O
Agent: Cl
Solvent: C1CCOC1
Product: CCCCCCC(O)c1cccc(Br)c1OC
Temperature: 40 °C
Yield: 79 %

Procedure:
To a THF solution of 2,6-dibromoanisole (10 g, 37.6 mmol) was added Mg (0.90 g, 37.6 mmol), and the mixture was heated and stirred at 40° C. Under ice-cooling, n-heptanal (47.2 g, 41.3 mmol) was added dropwise. Aqueous hydrochloric acid solution was added to the reaction mixture, this was extracted with ethyl acetate, and the solvent was distilled off to obtain 8.95 g of a compound (1).
Reaction SMILES: [H-].[Na+].[NH2:3][C:4]1[S:5][C:6]([C:10](=[O:12])[CH3:11])=[C:7]([CH3:9])[N:8]=1.[C:13](=O)([O:21]C1C=CC=CC=1)[O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>CCCCCC.CN(C=O)C.C(Cl)(Cl)Cl>[C:15]1([O:14][C:13](=[O:21])[NH:3][C:4]2[S:5][C:6]([C:10](=[O:12])[CH3:11])=[C:7]([CH3:9])[N:8]=2)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1
Reactant: CC(=O)c1sc(N)nc1C
Reactant: O=C(Oc1ccccc1)Oc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: CCCCCC
Solvent: ClC(Cl)Cl
Product: CC(=O)c1sc(NC(=O)Oc2ccccc2)nc1C
Yield: 84.8 %

Procedure:
In a round-bottom flask, NaH 60% dispersion in mineral oil (3.07 g, 77 mmol) was washed 2× with hexane and suspended in DMF. Then 2-amino-5-acetyl-4-methyl-thiazole (10.0 g , 64 mmol) was added and stirred while cooling in an ice bath. Stirring continued until the NaH was consumed. Diphenyl carbonate (34 g, 160 mmol) was added while cooling and after the addition was complete the reaction mixture was stirred for an additional ˜30 minutes at room temperature. The dimethylformamide was removed on a rotary evaporator (high vacuum, 40° C.) to yield a brown residue. This residue was dissolved in 1 L of chloroform and washed successively with 2 L of 0.5N aqueous hydrochloric acid, twice with 1 L of water, and finally by 1 L of brine. The aqueous portions were back extracted twice with 300 mL of chloroform. The combined organic fractions were dried over anhydrous sodium sulfate, filtered and concentrated on a rotary evaporator to give a white solid. This was chromatographed on silica (15%-70% EtOAc/hexane) to give 15 g of the desired carbamate as a white solid. 1H NMR (300 MHz, CDCl3) δ: 11.42 (bs, 1H), 7.47-7.40 (m, 2H), 7.33-7.27 (m, 1H), 7.22-7.18 (m, 2H), 2.72 (s, 3H), 2.50 (s, 3H). ESI MS: (M+H)+=277.1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[NH:17][N:18]=[CH:19][CH:20]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1.Br[CH2:23][CH:24]([C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1)[CH3:25]>>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([CH2:7][NH:8][C:9]([C:11]2[S:15][C:14]([C:16]3[CH:20]=[CH:19][N:18]([CH2:23][CH:24]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=4)[CH3:25])[N:17]=3)=[N:13][C:12]=2[CH3:21])=[O:10])[CH:2]=1
Reactant: Cc1nc(-c2ccn[nH]2)sc1C(=O)NCc1cccnc1
Reactant: CC(CBr)c1ccccc1
Product: Cc1nc(-c2ccn(CC(C)c3ccccc3)n2)sc1C(=O)NCc1cccnc1

Procedure:
The title compound was prepared from 4-methyl-2-(2H-pyrazol-3-yl)-thiazole-5-carboxylic acid (pyridin-3-ylmethyl)-amide and (2-bromo-1-methyl-ethyl)benzene as described in Example 49 and isolated as a white solid (0.120 mg, 45% yield). 1H NMR (400 MHz, CDCl3) δ 8.60 (s, 1H), 8.55 (d, J=4 Hz, 1H), 7.71 (d, J=8 Hz, 1H), 7.18-7.33 (m, 4H), 7.12 (d, J=8 Hz, 2H), 7.03 (d, J=2 Hz, 1H), 6.67 (d, J=2 Hz, 1H), 6.16-6.24 (m, 1H), 4.63 (d, J=4 Hz, 2H), 4.18-4.31 (m, 2H), 3.34-3.44 (m, 1H), 2.74 (s, 3H), 1.29 (d, J=4 Hz, 3H); MS (M+H)+=418.2; Rt=1.31 min; HRMS (M+H)+=418.17.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[C:4]([N+:9]([O-])=O)[CH:3]=1>CO.[C].[Pd]>[NH2:9][C:4]1[CH:3]=[C:2]([F:1])[CH:7]=[CH:6][C:5]=1[OH:8]
Reactant: O=[N+]([O-])c1cc(F)ccc1O
Agent: [Pd]
Solvent: CO
Product: Nc1cc(F)ccc1O
Reaction time: 48 h
Yield: 105 %

Procedure:
In methanol (20 ml) was dissolved 4-fluoro-2-nitrophenol (1.00 g, 6.37 mmol). To the resulting solution was added 10% palladium-carbon (0.20 g, 20 wt %). The resulting mixture was subjected to catalytic hydrogenation under stirring for 2 days. After the reaction mixture was filtered through Celite to remove the catalyst, the filtrate was distilled under reduced pressure to remove the solvent, whereby 2-amino-4-fluorophenol (850 mg, 100%) was obtained as a reddish brown solid.
Reaction SMILES: [CH:1]([N-]C(C)C)(C)C.[Li+].C(C1C=CC=CC=1)C.CCCCCCC.[CH3:24][O:25][C:26](=[O:41])[CH2:27][C:28]1[CH:29]=[CH:30][C:31]2[S:35][C:34]([CH2:36][CH:37]([CH3:39])[CH3:38])=[N:33][C:32]=2[CH:40]=1.CI>O1CCCC1>[CH3:39][CH:37]([CH3:38])[CH2:36][C:34]1[S:35][C:31]2[CH:30]=[CH:29][C:28]([CH:27]([CH3:1])[C:26]([O:25][CH3:24])=[O:41])=[CH:40][C:32]=2[N:33]=1
Reactant: COC(=O)Cc1ccc2sc(CC(C)C)nc2c1
Reactant: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: CCCCCCC
Solvent: CI
Solvent: C1CCOC1
Product: COC(=O)C(C)c1ccc2sc(CC(C)C)nc2c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.7 %

Procedure:
A solution of lithium diisopropylamide (2.0M solution in tetrahydrofran/ethylbenzene/heptane, 2.09 ml, 0.0042 mol) was added, dropwise, to a solution of methyl[2-(2-methylpropyl)benzothiazol-5-yl]acetate (1.1 g, 0.0042 mol) in tetrahydrofuran (27 ml) at −78° C. under a nitrogen atmosphere and the mixture was stirred at below −60° C. for 1 hour. Methyl iodide (2.29 ml, 0.037 mol) was added, dropwise, and the mixture was stirred at below −60° C. for a further 1 hour. The cooling bath was removed and the mixture was allowed to warm to room temperature over a period of 1 hour. The mixture was diluted with water, acidified with 2M aqueous hydrochloric acid and extracted with ethyl acetate. The organic extract was dried over anhydrous magnesium sulfate, filtered and the filtrate evaporated in vacuo to give methyl 2-[2-(2-methylpropyl)benzothiazol-5-yl]propionate (1.15 g) which was used without further purification in the next step.
Reaction SMILES: [CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C:17](=[O:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3].C(N(CC)CC)C>C(=O)(O)[O-].[Na+].O.Cl.Cl.Cl[Ir](Cl)(Cl)Cl>[CH2:1]([N:4]([CH2:8][C:9]([O:11][C@H:12]1[CH2:31][C@@:30]2([CH3:32])[C@@H:23]([CH2:24][CH2:25][C@@H:26]2[C:27](=[O:29])[CH3:28])[C@H:22]2[C@H:13]1[C@:14]1([CH3:34])[C@@H:19]([CH2:20][CH2:21]2)[CH2:18][C@H:17]([OH:33])[CH2:16][CH2:15]1)=[O:10])[CH2:5][CH2:6][CH3:7])[CH2:2][CH3:3]
Reactant: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3CC(=O)CC[C@]3(C)[C@H]21
Agent: Cl[Ir](Cl)(Cl)Cl
Agent: Cl
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: O
Product: CCCN(CCC)CC(=O)O[C@H]1C[C@]2(C)[C@@H](C(C)=O)CC[C@H]2[C@@H]2CC[C@H]3C[C@H](O)CC[C@]3(C)[C@H]21
Reaction time: 0.33 h

Procedure:
11β-Dipropylaminoacetoxy-5α-pregnane-3,20-dione (300 mg) was added to a solution of chloroiridic acid reagent (10 ml) containing triethylamine (1.1 ml). The mixture was boiled for about 20 minutes, cooled and diluted with sodium bicarbonate solution and the precipitated solid collected by filtration to afford title compound, m.p. 107°-115°, [α]D +91.3° (230 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([OH:17])=O)[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:13][CH2:12][CH2:11][CH2:10]1.C(=O)([O-])[O-].[K+].[K+].CC(C)(C)C(Cl)=O.[CH3:31][C@@H:32]([NH:41][CH3:42])[C@H:33]([OH:40])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>CC(C)=O>[Cl:1][C:2]1[CH:3]=[C:4]([CH2:14][C:15]([N:41]([C@H:32]([CH3:31])[C@H:33]([OH:40])[C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[CH3:42])=[O:17])[CH:5]=[CH:6][C:7]=1[S:8][CH:9]1[CH2:10][CH2:11][CH2:12][CH2:13]1
Reactant: CN[C@H](C)[C@H](O)c1ccccc1
Reactant: O=C(O)Cc1ccc(SC2CCCC2)c(Cl)c1
Agent: CC(C)(C)C(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: C[C@H]([C@H](O)c1ccccc1)N(C)C(=O)Cc1ccc(SC2CCCC2)c(Cl)c1
Temperature: -10 °C
Reaction time: 0.25 h

Procedure:
To a three neck round bottom flask is added a stir bar, dropping funnel, argon inlet and thermometer. It is then charged (3-chloro-4-cyclopentylsulfanyl-phenyl)-acetic acid (5.00 mmol), acetone (15 mL) and potassium carbonate (3.0 equiv.) and cooled to −10° C. To this cooled solution is then added trimethylacetyl chloride (1.05 equiv.) dropwise slowly to keep the temperature below −10° C. throughout the addition. It is then stirred at −10° C. for 15 min, then warmed to 0° C. and stirred for an additional 10 min and then recooled to −10° C. To the reaction is then added (1R,2R)-(−)-pseudoephedrine (1.5 equiv.) in one portion. It is then stirred at −10° C. for 10 min and then warmed to 25° C. and stirred for 1 h. After such time, the reaction is quenched with water (10 mL) and poured into a separatory funnel and added ethyl acetate (25 mL). The layers are separated and the organic layer is washed with water (2×10 mL) and the organic layers are then back extracted with ethyl acetate (3×25 mL) dried over magnesium sulfate, filtered and concentrated in vacuo. Purification on an AnaLogix Intelliflash system (silica gel cartridge) will afford 2-(3-chloro-4-cyclopentylsulfanyl-phenyl)-N-((1R,2R)-2-hydroxy-1-methyl-2-phenyl-ethyl)-N-methyl-acetamide.
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([OH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Br[CH2:14][C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.O>CN(C)C=O>[S:16]1[C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=[C:15]1[CH2:14][C:10]1[CH:11]=[C:6]([N+:3]([O-:5])=[O:4])[CH:7]=[CH:8][C:9]=1[OH:12]
Reactant: BrCc1nc2ccccc2s1
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: O=[N+]([O-])c1ccc(O)c(Cc2nc3ccccc3s2)c1
Reaction time: 0.08 h
Yield: 85.7 %

Procedure:
855.5 mg of sodium hydride (as a 60% w/w dispersion in mineral oil) were added to a solution of 2.83 g of 4-nitrophenol in 30 ml of dimethylformamide cooled in an ice-water bath. The resulting mixture was stirred at the same temperature for 5 minutes, after which a solution of 4.88 g of 2-bromomethylbenzothiazole in 25 ml of dimethylformamide was added thereto. The temperature of the resulting mixture was elevated to room temperature, and the mixture was then stirred at this temperature for 4 hours. At the end of this time the reaction mixture was cooled in an ice-water bath and 100 ml of water was added to said reaction mixture resulting in the precipitation of a crystalline solid which was filtered off, washed with water and then further washed with hexane. The resulting crude crystalline solid was purified by column chromatography through silica gel using a 10:1 by volume mixture of hexane and ethyl acetate, to give 4.99 g (yield 86%) of the title compound having a melting point of 189° to 191° C.
Reaction SMILES: [C:1]([NH:11][C@H:12]([C:20]([OH:22])=O)[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([O:3][CH2:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)=[O:2].OC1C2N=NNC=2C=CC=1.Cl.CN(C)CCCN=C=NCC.[NH2:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51].C(N(CC)C(C)C)(C)C>O1CCCC1>[CH2:13]([C@H:12]([NH:11][C:1](=[O:2])[O:3][CH2:4][C:5]1[CH:6]=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:20]([NH:45][CH2:46][CH2:47][CH:48]([O:52][CH2:53][CH3:54])[O:49][CH2:50][CH3:51])=[O:22])[C:14]1[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=1
Reactant: O=C(N[C@@H](Cc1ccccc1)C(=O)O)OCc1ccccc1
Reactant: CCOC(CCN)OCC
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: Oc1cccc2[nH]nnc12
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(CCNC(=O)[C@H](Cc1ccccc1)NC(=O)OCc1ccccc1)OCC
Yield: 91.7 %

Procedure:
By using an analogous procedure to that described for Reference Example 13, N-(carbobenzyloxy)-L-phenylalanine (2 g, 6.68 mmol), hydroxybenzotriazole (903 mg, 6.68 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride 1.28 g, 6.68 mmol), 1-amino-3,3-diethoxypropane (935 mg, 6.36 mmol) and N,N-diisopropylethylamine (1.16 mL, 6.68 mmol) were reacted in anhydrous tetrahydrofuran (32 mL) at room temperature for 16 h, to provide benzyl (1S)-1-benzyl-2-[(3,3-diethoxypropyl)amino]-2-oxoethylcarbamate (2.5 g, 92%) as a white solid.
Reaction SMILES: [CH2:1]([NH:6][NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.[OH-].[Na+]>C1(C)C=CC=CC=1.CCCCCC>[CH2:1]([N:6]([C:16](=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)[NH:7][C:8](=[O:15])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)CNNC(=O)c1ccccc1
Reactant: O=C(Cl)c1ccccc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCCCCC
Solvent: Cc1ccccc1
Product: CC(C)(C)CN(NC(=O)c1ccccc1)C(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of the 2-neopentyl-1-benzoylhydrazine in toluene (40 ml) at 5° C., were added dropwise and simultaneously solutions of benzoyl chloride (1.4 g, 10 mmoles) in toluene (5 ml) and aqueous 50% sodium hydroxide solution (0.8 g) while maintaining the temperature below 10° C. After the addition, the reaction mixture was warmed to room temperature and stirred for 1 hour. The reaction mixture was diluted with hexane and the precipitated product isolated by filtration. The product was washed with water and hexane and dried. The crude product was recrystallized from methanol to afford N'-neopentyl-N,N'-dibenzoylhydrazine as a white powder: m.p. 237-239° C.
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:13])[CH3:12])=[CH:4][CH:3]=1.[N+:17]([O-])([OH:19])=[O:18].OS(O)(=O)=O>C(O)(=O)C>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:16])([CH3:15])[C:7](=[O:14])[N:8]2[CH:11]([CH3:12])[CH3:13])=[CH:4][C:3]=1[N+:17]([O-:19])=[O:18]
Reactant: O=[N+]([O-])O
Reactant: CC(C)N1C(=O)C(C)(C)c2ccc(F)cc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CC(C)N1C(=O)C(C)(C)c2cc([N+](=O)[O-])c(F)cc21
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
To a stirred solution of 6-Fluoro-1-isopropyl-3,3-dimethyl-1,3-dihydro-indol-2-one E-1.2′″ (17.0 g; 76.9 mmol) in acetic acid (550 ml) was added fuming HNO3 (8.5 g; 134.9 mmol) at 25° C. The reaction mixture is stirred for 15 min at 25° C. and then concentrate H2SO4 (17.0 g; 173.5 mmol) is added and the mixture is stirred for 30 min at 25° C. After completion of the reaction the reaction mixture was poured in to ice cold water. The obtained solid was filtered and dried. The solid was recrystallized with ethyl acetate to obtain pure compound.
Reaction SMILES: [NH2:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12].[C:13](=[O:16])([O-])[OH:14].[Na+]>O1CCCC1.O.ClC(OCC1C=CC=CC=1)=O>[CH2:6]([O:14][C:13]([NH:1][C:2]1[CH:11]=[CH:10][C:5]([C:6]([O:8][CH3:9])=[O:7])=[CH:4][C:3]=1[Cl:12])=[O:16])[C:5]1[CH:10]=[CH:11][CH:2]=[CH:3][CH:4]=1
Reactant: O=C([O-])O
Reactant: COC(=O)c1ccc(N)c(Cl)c1
Agent: O=C(Cl)OCc1ccccc1
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: COC(=O)c1ccc(NC(=O)OCc2ccccc2)c(Cl)c1
Temperature: 25 °C
Reaction time: 22.5 h
Yield: 154.3 %

Procedure:
Methyl 4-amino-3-chlorobenzoate (5.65 g; synthesized in accordance with Synthesis, 1985, 669) was dissolved in tetrahydrofuran (112 ml) and admixed with a solution of sodium hydrogen carbonate (7.67 g) in water (84.8 ml) and benzyl chloroformate (39.1 ml) and the mixture was stirred under a nitrogen atmosphere at room temperature for 22.5 hours. The reaction mixture was extracted with ethyl acetate and the ethyl acetate layer was washed three times with water and then twice with saturated brine. The ethyl acetate layer was dried over magnesium sulfate and then the solvent was distilled off under reduced pressure, and then the residue was purified by column chromatography on silica gel (ethyl acetate/hexane=1:7). A desired fraction was concentrated under reduced pressure and the residue was crystallized from a mixture of ethyl acetate and diisopropyl ether to yield methyl 4-benzyloxycarbonylamino-3-chlorobenzoate (7.51 g) as white crystals.
Reaction SMILES: Cl[C:2]1[C:10]2[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]3[CH2:19][CH2:18][O:17][CH2:16][CH2:15]3)=[N:8][CH:9]=2)[N:4]([CH3:20])[N:3]=1.CC1(C)C(C)(C)OB([C:29]2[CH:35]=[CH:34][C:32]([NH2:33])=[CH:31][CH:30]=2)O1>>[NH2:33][C:32]1[CH:34]=[CH:35][C:29]([C:2]2[C:10]3[C:5](=[N:6][C:7]([NH:11][CH2:12][CH2:13][N:14]4[CH2:19][CH2:18][O:17][CH2:16][CH2:15]4)=[N:8][CH:9]=3)[N:4]([CH3:20])[N:3]=2)=[CH:30][CH:31]=1
Reactant: CC1(C)OB(c2ccc(N)cc2)OC1(C)C
Reactant: Cn1nc(Cl)c2cnc(NCCN3CCOCC3)nc21
Product: Cn1nc(-c2ccc(N)cc2)c2cnc(NCCN3CCOCC3)nc21

Procedure:
Prepared as described above in Example 15 starting from (3-chloro-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl)-(2-morpholin-4-yl-ethyl)-amine and 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)aniline to give the title compound [3-(4-amino-phenyl)-1-methyl-1H-pyrazolo[3,4-d]pyrimidin-6-yl]-(2-morpholin-4-yl-ethyl)-amine; LC/MS (m/e)=354.4 (MH+), Rt=1.12 min.
Reaction SMILES: [C:1]1([P:7]([Cl:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=O.[CH4:17]>C1(C)C=CC=CC=1>[CH:4]1[CH:5]=[CH:6][C:1]([P:7]([P:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:17]2[CH:10]=[CH:9][CH:8]=[CH:13][CH:12]=2)[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:2][CH:3]=1.[C:1]1([P:7]([Cl:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: C
Agent: ClP(c1ccccc1)c1ccccc1
Agent: O=O
Solvent: Cc1ccccc1
Product: c1ccc(P(c2ccccc2)P(c2ccccc2)c2ccccc2)cc1
Temperature: 160 °C
Reaction time: 22 h

Procedure:
A mixture of diphenylphosphinous chloride, 7.0 grams, 0.03 moles, and calcium carbide, 2.0 grams, 0.038 moles is vigorously stirred for 22 hours under a nitrogen atmosphere and at a temperature of about 160° C., care being taken to avoid oxygen and moisture contamination. The hot mixture is cooled to room temperature and mixed with dry toluene, 60 ml, at 100° C. Charcoal is then added to the solution, which is filtered while hot. The toluene is removed by evaporation using a rotary evaporator, leaving crude tetraphenyldiphosphine and unreacted diphenylphosphinous chloride. Dry ether, 60 ml, is added to the mixture to precipitate the tetraphenyldiphosphine. The solids are isolated by filtration and washed with dry, cold ether three times in order to remove any unreacted diphenylphosphinous chloride, and the remaining solids are dried in vacuo at room temperature. The product is then treated with 1 percent aqueous KOH solution and washed three times with distilled water, three times with dry ether, and then vacuum dried at 35° C. for 24 hours. The yield is 7.4 grams, 63 percent. The product is characterized by its melting point, measured as 120° C., which is in good agreement with the melting point, 120.5° C., obtained from the literature. An infrared spectrum of the product is obtained which is found to be identical to an infrared spectrum of tetraphenylbiphosphine obtained from the literature, confirming the structure of the product obtained.
Reaction SMILES: [CH:1]([C:3]([Cl:11])(Cl)[CH2:4][C:5]([CH3:9])(Cl)[C:6]#[N:7])=O.[ClH:12]>>[Cl:12][C:6]1[C:5]([CH3:9])=[CH:4][C:3]([Cl:11])=[CH:1][N:7]=1
Reactant: Cl
Reactant: CC(Cl)(C#N)CC(Cl)(Cl)C=O
Product: Cc1cc(Cl)cnc1Cl
Temperature: 145 °C

Procedure:
21.4 g of the 4-formyl-2-methyl-2,4,4-trichlorobutyronitrile obtained in 1) are heated for 4 to 5 hours to 145° C. while introducing a weak stream of dry HCl gas. After it has cooled, the dark melt is subject to steam distillation, affording 9.9 g of 2,5-dichloro-3-methylpyridine in the form of colorless crystals (recrystallized from CH3OH/H2O in the volume ratio of 4:1).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:18]#[N:19].[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH:27]=[CH:28][C:29]=1[O:30][CH3:31])[CH2:25][NH2:26]>>[CH3:20][O:21][C:22]1[CH:23]=[C:24]([CH2:25][NH:26][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH2:16][CH3:17])=[C:9]([O:12][CH2:13][CH3:14])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:18]#[N:19])[CH:27]=[CH:28][C:29]=1[O:30][CH3:31]
Reactant: COc1ccc(CN)cc1OC
Reactant: CCOc1cc2ncc(C#N)c(Cl)c2cc1OCC
Product: CCOc1cc2ncc(C#N)c(NCc3ccc(OC)c(OC)c3)c2cc1OCC

Procedure:
In the manner of Example 61 reaction of 4-chloro-6,7-diethoxy-3-quinolinecarbonitrile with 3,4-dimethoxybenzylamine gave the title compound as a tan solid, mp 200-204° C.
Reaction SMILES: BrC1C=CC(S(O[CH2:12][CH2:13][O:14][C:15]2[CH:24]=[CH:23][C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=2)(=O)=O)=CC=1.[I-:25].[Na+]>CC(C)=O>[I:25][CH2:12][CH2:13][O:14][C:15]1[CH:24]=[CH:23][C:22]2[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=2)[CH:16]=1
Reactant: [I-]
Reactant: O=S(=O)(OCCOc1ccc2ccccc2c1)c1ccc(Br)cc1
Agent: [Na+]
Solvent: CC(C)=O
Product: ICCOc1ccc2ccccc2c1
Temperature: 35 °C
Yield: 72.1 %

Procedure:
To a solution of 2-(2-naphthyloxy)ethyl 4-bromobenzenesulfonate (Preparation 10, 380 mg, 0.93 mmol) in acetone (5 mL) at room temperature was added sodium iodide (1.0 g, 6.66 mmol). The mixture was heated at 35° C. for 16 hours and then cooled. The residual precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was partitioned between diethyl ether (20 mL) and water (20 mL). The two layers were separated and the organic layer was dried over sodium sulfate, filtered, and concentrated in vacuo to give the title compound (200 mg, 72%) as a pale yellow oil.