Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[NH:7][C:6]=2[CH:12]=1.C([O-])([O-])=O.[Cs+].[Cs+].[Cl:20][CH2:21][CH2:22][CH2:23]I>CCCCCCC.CCOC(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([F:13])[C:5]2[O:10][CH2:9][C:8](=[O:11])[N:7]([CH2:23][CH2:22][CH2:21][Cl:20])[C:6]=2[CH:12]=1
Reactant: ClCCCI
Reactant: O=C1COc2c(F)cc(Br)cc2N1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: O=C1COc2c(F)cc(Br)cc2N1CCCCl
Yield: 72.1 %

Procedure:
6-Bromo-8-fluoro-4H-benzo[1,4]oxazin-3-one (95MF44) (0.091 g, 0.37 mmol), Cs2CO3 (0.180 g, 0.55 mmol) and 3-chloro-1-iodopropane (0.083 g, 0.41 mmol) were mixed according to GP5. CC (SiO2; Heptane/EtOAc 9:1-4) gave the title compound (95MF50(2084)) (0.086 g, 72%). 1H NMR (CDCl3) δ 7.02-6.96 (m, 1H), 6.85 (d, J=5.2 Hz, 1H), 4.65 (s, 2H), 4.04-4.11 (m, 2H), 3.62 (t, J=6.2 Hz, 2H), 2.10-2.18 (m, 2H); 13C NMR (CDCl3) δ 163.8, 151.7 (d, J=250.9 Hz), 133.1 (d, J=14.6 Hz), 131.5 (d, J=3.8 Hz), 115.1 (d, J=21.5 Hz), 114.2 (d, J=10.0 Hz), 113.4 (d, J=3.4 Hz), 67.6, 42.2, 39.5, 30.0.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[N:22](S(C2C=CC(C)=CC=2)(=O)=O)[C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1.[OH-].[K+]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[CH3:12])[N:8]([CH3:13])[CH:7]=[C:6]2[C:14]1[NH:22][C:17]2=[N:18][CH:19]=[CH:20][CH:21]=[C:16]2[CH:15]=1
Reactant: COc1cc2c(-c3cc4cccnc4n3S(=O)(=O)c3ccc(C)cc3)cn(C)c2cc1C
Agent: [K+]
Agent: [OH-]
Product: COc1cc2c(-c3cc4cccnc4[nH]3)cn(C)c2cc1C
Yield: 54.6 %

Procedure:
2-(5-Methoxy-1,6-dimethyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]-pyridine is prepared by following the procedure described in example 89a, but using 0.028 g of 2-(5-methoxy-1,6-dimethyl-1H-indol-3-yl)-1-(toluene-4-sulfonyl)-1H-pyrrolo[2,3-b]pyridine and 0.283 ml of a 5N aqueous potassium hydroxide solution. 0.01 g of 2-(5-methoxy-1,6-dimethyl-1H-indol-3-yl)-1H-pyrrolo[2,3-b]-pyridine is obtained, the characteristics of which are as follows:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[C:4]([F:14])[CH:3]=1.[Mg].[C:16]([O-:21])(=[O:20])[C:17]([CH3:19])=[O:18].[Na+].Cl>O1CCCC1>[F:14][C:4]1[CH:3]=[C:2]([C:17]([OH:18])([CH3:19])[C:16]([OH:21])=[O:20])[CH:7]=[CH:6][C:5]=1[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: CC(=O)C(=O)[O-]
Reactant: Fc1cc(Br)ccc1-c1ccccc1
Agent: Cl
Agent: [Mg]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(O)(C(=O)O)c1ccc(-c2ccccc2)c(F)c1
Yield: 71 %

Procedure:
A solution of 4-bromo-2-fluorobiphenyl (5 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added dropwise, with stirring, to magnesium turnings (0.49 g.) in dry tetrahydrofuran (13 ml.). When the addition was complete, the mixture was stirred and boiled under reflux for one hour. A suspension of sodium pyruvate (2.2 g., 0.02 mole) in dry tetrahydrofuran (20 ml.) was added rapidly to the refluxing solution. Frothing occurred and when this had subsided the mixture was boiled under reflux with stirring for a further hour. The mixture was then cooled in an ice-bath and dilute hydrochloric acid (5N; 50 ml.) was added. The mixture was stirred and extracted with ether. The extract was then extracted with aqueous potassium carbonate (1N) and this extract acidified with dilute hydrochloric acid. The precipitate which separated, was collected and dried to give 2-(2-fluoro-4-biphenylyl)-2-hydroxypropionic acid, m.p. 166°-9° C. in 71% yield.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10](OC)=[O:11])[CH:2]=1.[NH2:17][NH2:18].C(OCC)C>CO>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]2[CH:8]=[C:9]([CH:14]=[CH:15][CH:16]=2)[C:10]([NH:17][NH2:18])=[O:11])[CH:2]=1
Reactant: NN
Reactant: COC(=O)c1cccc(-c2cccnc2)c1
Solvent: CCOCC
Solvent: CO
Product: NNC(=O)c1cccc(-c2cccnc2)c1
Yield: 35 %

Procedure:
To a stirred solution of methyl 3-(pyridin-3-yl)benzoate (190 mg, 0.89 mmol) in anhydrous methanol (1 mL) was added hydrazine (0.07 mL,). The solution was stirred at RT overnight before ethyl ether was added. The solid was filtered and washed with ethyl ether to give 67 mg (35% yield) of 3-(pyridin-3-yl)benzohydrazide as a white solid. An additional 120 mg of the product was recovered from the filtrate. (M+H)+=214.13
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[CH2:15]([NH:22][CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.[CH:41](=O)[C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1.C(O)(=O)C.[OH-].[Na+]>ClCCCl>[CH2:15]([N:22]([CH2:41][C:42]1[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=1)[CH2:23][CH2:24][C:25]1[CH:40]=[CH:39][C:28]([O:29][C:30]2[CH:38]=[CH:37][C:33]([C:34]([NH2:36])=[O:35])=[CH:32][N:31]=2)=[CH:27][CH:26]=1)[C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: O=Cc1ccccc1
Reactant: NC(=O)c1ccc(Oc2ccc(CCNCc3ccccc3)cc2)nc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: ClCCCl
Product: NC(=O)c1ccc(Oc2ccc(CCN(Cc3ccccc3)Cc3ccccc3)cc2)nc1
Temperature: 25 °C
Reaction time: 18 h
Yield: 64.9 %

Procedure:
Add sodium triacetoxyborohydride (0.2600 g, 1.227 mmol) to a stirred solution of 6-[4-(2-benzylamino-ethyl)-phenoxy]-nicotinamide (0.3058 g, 0.8802 mmol), benzaldehyde (0.092 mL, 0.905 mmol), glacial acetic acid (0.052 mL, 0.908 mmol) and 1,2-dichloroethane (8 mL). Stir for 18 h at room temperature under nitrogen. Pour the reaction into 1N sodium hydroxide (50 mL) and extract with diethyl ether (3×50 mL). Wash the diethyl ether extracts with brine, dry over magnesium sulfate, filter, and concentrate on a rotary evaporator to give the crude product. The crude product is purified by flash chromatography on silica gel eluting with 75% ethyl acetate/hexanes to yield 0.2501 g (65%) of 6-[4-(2-dibenzylamino-ethyl)-phenoxy]-nicotinamide: HPLC (30/70 to 90/10 ACN/(0.1% TFA in water) Zorbax SB-Phenyl Column 4.6 mm×15 cm×5 micron: Retention time: 8.14 minutes, Purity: 99.7%; mass spectrum (ion spray): m/z=438.0 (M+1).
Reaction SMILES: [C:1]([CH:3]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)[C:4]([OH:6])=[O:5])#[N:2].[Cl:13][C:14]1[C:19](O)=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24].O=P(Cl)(Cl)Cl.Cl>C(Cl)(Cl)(Cl)Cl>[Cl:13][C:14]1[C:19]([O:5][C:4](=[O:6])[CH:3]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:1]#[N:2])=[C:18]([Cl:21])[C:17]([Cl:22])=[C:16]([Cl:23])[C:15]=1[Cl:24]
Reactant: N#CC(C(=O)O)c1ccccc1
Reactant: Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl
Agent: Cl
Solvent: ClC(Cl)(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CC(C(=O)Oc1c(Cl)c(Cl)c(Cl)c(Cl)c1Cl)c1ccccc1
Temperature: 25 °C

Procedure:
8 g. (0.05 moles) of α-cyanophenylacetic acid, 13 g. (0.05 moles) of pentachlorophenol are mixed together. 4.3 g. (0.05 moles) of phosphoroxychloride are added dropwise. The obtained mixture is heated slowly to 85°-90° C. on an oil-bath and the mixture is kept at this temperature until the HCl evolution ceases. When the reaction is completed, the mixture is cooled to room temperature, and the melt is taken up in 100 ml. of carbon tetrachloride. The solution is washed three times with 30 ml. of water, treated with decolorizing charcoal, dried and evaporated. The product is recrystalized from diisopropyl ether, and crystalline pentachlorophenyl ester is precipitated.
Reaction SMILES: [CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:28][CH2:27]3)[CH:18]=[C:17]4[CH:29]=O)[CH:7]=2)[CH2:3][CH2:2]1.[CH3:32][N:33]([CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)C(=O)OC(C)(C)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>ClCCl>[CH:1]1([NH:4][C:5](=[O:31])[C:6]2[CH:11]=[C:10]([F:12])[C:9]([CH3:13])=[C:8]([C:14]3[CH:15]=[C:16]4[C:21](=[CH:22][CH:23]=3)[C:20](=[O:24])[N:19]([CH2:25][CH:26]3[CH2:27][CH2:28]3)[CH:18]=[C:17]4[CH2:29][N:44]3[CH2:45][CH2:46][CH:41]([NH:33][CH3:32])[CH2:42][CH2:43]3)[CH:7]=2)[CH2:3][CH2:2]1
Reactant: CN(C(=O)OC(C)(C)C)C1CCNCC1
Reactant: Cc1c(F)cc(C(=O)NC2CC2)cc1-c1ccc2c(=O)n(CC3CC3)cc(C=O)c2c1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CNC1CCN(Cc2cn(CC3CC3)c(=O)c3ccc(-c4cc(C(=O)NC5CC5)cc(F)c4C)cc23)CC1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of the product of Example 75 step i) (320 mg) in dichloromethane (15 mL) was added methylpiperidine-4-yl-carbamic acid, tert-butyl ester (490 mg) and the reaction was stirred at room temperature for 10 minutes before the addition of sodium triacetoxyborohydride (490 mg). The reaction was then stirred at room temperature for 24 hours. The reaction mixture was diluted with dichloromethane (50 mL), washed with water (50 mL), dried over magnesium sulfate, filtered and evaporated in vacuo. The residue was then dissolved in methanol (5 mL) and treated with hydrogen chloride (4N in 1,4-dioxane, 10 mL) and stirred at room temperature for 1 hour. The reaction mixture was evaporated in vacuo and the residue was purified (SiO2, chromatography eluting with 5% methanol in dichloromethane to 5% 7N ammonia/methanol in dichloromethane) to afford the title compound as a solid (250 mg).
Reaction SMILES: [O:1]=[C:2]([C:6]1[N:14]2[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]2)=[CH:8][C:7]=1[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:3](Cl)=[O:4].[O:21]=[S:22]1(=[O:35])[CH2:27][CH2:26][N:25]([C:28]2[CH:33]=[CH:32][C:31]([NH2:34])=[CH:30][CH:29]=2)[CH2:24][CH2:23]1.C(N(CC)CC)C>C1COCC1>[O:35]=[S:22]1(=[O:21])[CH2:23][CH2:24][N:25]([C:28]2[CH:29]=[CH:30][C:31]([NH:34][C:3](=[O:4])[C:2](=[O:1])[C:6]3[N:14]4[C:9]([CH:10]=[CH:11][CH:12]=[CH:13]4)=[CH:8][C:7]=3[C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:32][CH:33]=2)[CH2:26][CH2:27]1
Reactant: O=C(Cl)C(=O)c1c(-c2ccccc2)cc2ccccn12
Reactant: Nc1ccc(N2CCS(=O)(=O)CC2)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(Nc1ccc(N2CCS(=O)(=O)CC2)cc1)C(=O)c1c(-c2ccccc2)cc2ccccn12
Temperature: 25 °C
Reaction time: 8 h
Yield: 47.7 %

Procedure:
A solution of oxo-(2-phenyl-indolizin-3-yl)-acetyl chloride (0.12 g, 0.42 mmol) in THF was added to a solution of 4-(1,1-dioxo-1λ6-thiomorpholin-4-yl)-phenylamine (70 mg, 0.31 mmol) and triethylamine (85 mg, 0.85 mmol) in THF (10 mL) at 0° C., then the mixture was stirred for 8 h at r.t. The mixture was concentrated to dryness and washed with water to give a crude product which was triturated with methanol to afford the title compound (70 mg, 48%) as a solid.
Reaction SMILES: [Cl:1][C:2]1[C:7]([C:8](Cl)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1.[F:11][C:12]([F:21])([F:20])[C:13]1[CH:14]=[C:15]([CH:17]=[CH:18][CH:19]=1)[NH2:16].CCN(C(C)C)C(C)C>C(Cl)Cl>[Cl:1][C:2]1[C:7]([C:8]([NH:16][C:15]2[CH:17]=[CH:18][CH:19]=[C:13]([C:12]([F:11])([F:20])[F:21])[CH:14]=2)=[O:9])=[CH:6][CH:5]=[CH:4][N:3]=1
Reactant: Nc1cccc(C(F)(F)F)c1
Reactant: O=C(Cl)c1cccnc1Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(Nc1cccc(C(F)(F)F)c1)c1cccnc1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 93.3 %

Procedure:
2-Chloropyridine-3-carbonyl chloride (18.02 g, 0.102 mol) in CH2Cl2 (100 ml) was added dropwise (via an addition funnel) to a stirred solution of 3-(trifluoromethyl)-aniline (15.00 g, 0.093 mol) and DIEA (24.39 ml, 0.14 mol) in CH2Cl2 (500 ml) at 0° C. The mixture gradually was warmed to RT. The reaction continued for 18 h before washing several times with saturated NaHCO3 aqueous solution and brine, respectively. The organic layer was dried over Na2SO4 and evaporated. The resulting oil was purified over silica gel with EtOAc/hexane (2:1) as eluant to leave the amide as a white solid (26.08 g). MS: (ES+) 301 (M+1)+; (ES−): 299 (M−1)−. Calc'd for C13H8ClF3N2O: 300.03.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:6]([C:7]([OH:9])=O)[C:5]([OH:11])=[CH:4][CH:3]=1.[F:12][C:13]1[C:19]([C:20]([F:23])([F:22])[F:21])=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15]>>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([OH:11])=[C:6]([CH:10]=1)[C:7]([NH:15][C:14]1[CH:16]=[CH:17][CH:18]=[C:19]([C:20]([F:21])([F:22])[F:23])[C:13]=1[F:12])=[O:9]
Reactant: O=C(O)c1cc(Cl)ccc1O
Reactant: Nc1cccc(C(F)(F)F)c1F
Product: O=C(Nc1cccc(C(F)(F)F)c1F)c1cc(Cl)ccc1O
Yield: 71.7 %

Procedure:
Using 5-chlorosalicylic acid and 2-fluoro-3-(trifluoromethyl)aniline as the raw materials, the same operation as the example 16 gave the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6](Cl)=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1.[CH2:19]([N:21]([CH2:30][CH3:31])[CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH2:28][NH2:29])[CH3:20].C1(O)C=CC=CC=1.[ClH:39]>CC(C)=O>[ClH:1].[ClH:39].[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]([NH:29][CH2:28][CH2:27][CH2:26][CH2:25][CH2:24][CH2:23][CH2:22][N:21]([CH2:30][CH3:31])[CH2:19][CH3:20])=[C:7]3[N:15]=[C:14]([O:16][CH3:17])[CH:13]=[CH:12][C:8]3=[N:9][C:10]=2[CH:11]=1
Reactant: CCN(CC)CCCCCCCN
Reactant: COc1ccc2nc3cc(Cl)ccc3c(Cl)c2n1
Agent: Cl
Solvent: CC(C)=O
Solvent: Oc1ccccc1
Product: CCN(CC)CCCCCCCNc1c2ccc(Cl)cc2nc2ccc(OC)nc12

Procedure:
A mixture of 2.8 g. of 7,10-dichloro-2-methoxypyrido [3,2-b]quinoline, 2.0 g. of 7-diethylaminoheptylamine and 6.5 g. of phenol is stirred on a steam bath for 3 hours. The reaction is cooled, 20 ml. of 95% alcohol is added and this mixture is poured into a mixture of 200 ml. of acetone and 2.5 ml. of concentrated hydrochloric acid. The resulting solution is cooled in ice. The solid is collected and recrystallized from n-propanol:ethyl acetate (50:50), giving the desired product as yellow crystals, mp. 170°-174° C. (dec.).
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4][CH:3]1[CH:18]([CH3:20])[CH3:19].[NH:21]1[C:29]2[C:24](=[CH:25][CH:26]=[CH:27][CH:28]=2)[CH:23]=[C:22]1[C:30](ON1C(=O)CCC1=O)=[O:31]>CN(C)C=O>[CH:18]([CH:3]1[CH:2]([NH:1][C:30]([C:22]2[NH:21][C:29]3[C:24]([CH:23]=2)=[CH:25][CH:26]=[CH:27][CH:28]=3)=[O:31])[C:8](=[O:9])[N:7]([CH2:10][C:11]([NH2:13])=[O:12])[C:6]2[CH:14]=[CH:15][CH:16]=[CH:17][C:5]=2[S:4]1)([CH3:20])[CH3:19]
Reactant: CC(C)C1Sc2ccccc2N(CC(N)=O)C(=O)C1N
Reactant: O=C(ON1C(=O)CCC1=O)c1cc2ccccc2[nH]1
Solvent: CN(C)C=O
Product: CC(C)C1Sc2ccccc2N(CC(N)=O)C(=O)C1NC(=O)c1cc2ccccc2[nH]1
Temperature: 70 °C
Yield: 61.8 %

Procedure:
A solution of 1 g of 3-amino-2-isopropyl-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5-acetamide and 1 g of succinimido 2-indolecarboxylate in 35 ml of dimethylformamide is stirred with heating at 70° C. Twenty-four hours later, the reaction mixture is concentrated under reduced pressure, whereto 50 ml of saturated sodium hydrogencarbonate and 50 ml of ethyl acetate are added. The mixture is stirred for a while. The resulting crystals are collected by filtration and recrystallized from a mixed solvent of dimethylformamidemethanol to give 0.92 g of 2-isopropyl 3-(2-indolecarboxamido)-4-oxo-2,3,4,5-tetrahydro-1,5-benzothiazepine-5 acetamide, the decomposition temperature being not less than 300° C.
Reaction SMILES: C([O:4][CH2:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7])(=O)C.C(=O)([O-])[O-].[K+].[K+].O>CO>[OH:4][CH2:5][C:6]([N:8]([CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[O:29][CH3:30])[C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[O:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)=[O:7]
Reactant: COc1ccccc1CN(C(=O)COC(C)=O)c1ccccc1Oc1ccccc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: COc1ccccc1CN(C(=O)CO)c1ccccc1Oc1ccccc1
Temperature: 50 °C
Reaction time: 7 h
Yield: 95.6 %

Procedure:
In 6 ml of methanol was dissolved 525 mg of N-acetoxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline, and then 537 mg of potassium carbonate was added, followed by stirring at 50° C. for 7 hours. The reaction mixture was poured into water and extracted with ethyl acetate. The extract was washed with 5% hydrochloric acid, a saturated aqueous sodium bicarbonate solution and a saturated aqueous sodium chloride solution, successively, and dried over anhydrous sodium sulfate. After removal of the drying agent by filtration, the solvent was concentrated under reduced pressure, and the residue was purified by silica gel column chromatography (eluent; ethyl acetate-hexane=1:3) and allowed to stand at room temperature to give 450 mg of N-hydroxyacetyl-N-(2-methoxybenzyl)-2-phenoxyaniline as crystals.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][C:10]2[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]3[CH2:23][CH2:22][CH2:21][CH2:20]3)[CH:11]=2)[CH:3]=1.B([C:27]1[CH:38]=[CH:37][C:30]([CH2:31][C@@H:32]([C:34]([OH:36])=[O:35])[NH2:33])=[CH:29][CH:28]=1)(O)O.C(=O)([O-])[O-].[Na+].[Na+]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C(#N)C>[NH2:33][CH:32]([CH2:31][C:30]1[CH:37]=[CH:38][C:27]([C:2]2[CH:3]=[C:4]([NH:8][CH2:9][C:10]3[CH:15]=[CH:14][C:13]([O:16][CH3:17])=[C:12]([O:18][CH:19]4[CH2:23][CH2:22][CH2:21][CH2:20]4)[CH:11]=3)[N:5]=[CH:6][N:7]=2)=[CH:28][CH:29]=1)[C:34]([OH:36])=[O:35]
Reactant: N[C@@H](Cc1ccc(B(O)O)cc1)C(=O)O
Reactant: COc1ccc(CNc2cc(Cl)ncn2)cc1OC1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CC#N
Product: COc1ccc(CNc2cc(-c3ccc(CC(N)C(=O)O)cc3)ncn2)cc1OC1CCCC1
Temperature: 150 °C
Yield: 6 %

Procedure:
An Emrys process vial (2-5 ml) for microwave was charged with (6-chloro-pyrimidin-4-yl)-(3-cyclopentyloxy-4-methoxy-benzyl)-amine (64 mg, 0.19 mmol), 4-borono-L-phenylalanine (40 mg, 0.19 mmol) and 2 ml of acetonitrile. Aqueous sodium carbonate (2 ml, 1M) was added to above solution followed by 5 mol percent of dichlorobis(triphenylphosphine)-palladium(II). The reaction vessel was sealed and heated to 150° C. for 5 minutes with microwave. After cooling, the reaction mixture was evaporated to dryness. The residue was dissolved in 2.5 ml of methanol and purified with Prep-LC to give 5.3 mg of 2-amino-3-{4-[6-(3-cyclopentyloxy-4-methoxy-benzylamino)-pyrimidin-4-yl]-phenyl}-propionic acid, yield 6%. 1H-NMR (400 MHz, DMSO-d6): δ 1.46 (m, 2H), 1.62 (m, 4H), 3.01 (m, 2H), 3.08 (m, 2H), 3.65 (s, 3H), 4.20 (m, 1H), 4.46 (d, 2H), 4.68 (m, 1H), 6.82 (t, 2H), 6.87 (d, 2H), 7.40 (d, 2H), 7.90 (s, 2H), 8.25 (s, 2H), 8.6 (s, 1H).
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11](=[O:28])[C:10]=1I)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:30](N(CC)CC)[CH3:31].ClCCl>[Pd](Cl)Cl.C1(P(C2C=CC=CC=2)[C-]2C=CC=C2)C=CC=CC=1.[C-]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C1.[Fe+2].C(O)C>[CH2:1]([O:8][C:9]1[CH:14]=[CH:13][N:12]([CH:15]2[CH2:20][CH2:19][N:18]([C:21]([O:23][C:24]([CH3:27])([CH3:26])[CH3:25])=[O:22])[CH2:17][CH2:16]2)[C:11](=[O:28])[C:10]=1[CH:30]=[CH2:31])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCN(CC)CC
Reactant: CC(C)(C)OC(=O)N1CCC(n2ccc(OCc3ccccc3)c(I)c2=O)CC1
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: c1ccc(P(c2ccccc2)[c-]2cccc2)cc1
Solvent: CCO
Solvent: ClCCl
Product: C=Cc1c(OCc2ccccc2)ccn(C2CCN(C(=O)OC(C)(C)C)CC2)c1=O
Temperature: 25 °C

Procedure:
A mixture of tert-butyl 4-(4-(benzyloxy)-3-iodo-2-oxopyridin-1(2H)-yl)piperidine-1-carboxylate (2.4 g), potassium vinyl trifluoroborate (0.945 g), triethylamine (1.3 mL), a dichloromethane adduct of 1,1′-bis(diphenylphosphino)ferrocene-palladium(II) dichloride (0.269 g), and ethanol (47 mL) was stirred overnight at 90 C in a nitrogen atmosphere. After cooling to room temperature, the solvent was distilled off under reduced pressure. Water and ethyl acetate were added to the obtained residue, and the organic layer was separated. The obtained organic layer was washed with saturated saline and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The obtained residue was purified by silica gel column chromatography (NH, hexane/ethyl acetate) to obtain the title compound (1.48 g).
Reaction SMILES: C([O:5][C@@H:6]([C@H:8]1[CH2:12][O:11][C:10](=[O:13])[N:9]1[C:14]1[CH:19]=[C:18]([Cl:20])[N:17]=[C:16]([Cl:21])[N:15]=1)[CH3:7])(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:21][C:16]1[N:15]=[C:14]([N:9]2[C@@H:8]([C@H:6]([OH:5])[CH3:7])[CH2:12][O:11][C:10]2=[O:13])[CH:19]=[C:18]([Cl:20])[N:17]=1
Reactant: C[C@@H](OC(C)(C)C)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: C[C@@H](O)[C@H]1COC(=O)N1c1cc(Cl)nc(Cl)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 88.6 %

Procedure:
To a round bottom flask containing (R)-4-((R)-1-(tert-butoxy)ethyl)-3-(2,6-dichloropyrimidin-4-yl)oxazolidin-2-one (1 g, 2.99 mmol) was added DCM (7.5 mL) followed by the addition of TFA (7.5 mL). The resulting homogenous reaction mixture allowed to stir 1 hr at room temperature. The volatiles were then removed. Residue dissolved in DCM and neutralized with a saturated solution of NaHCO3. The phases were partioned, the aqueous phase extracted with DCM. Organic phases combined, washed with water, brine, dried (Na2SO4), filtered and concentrated to a white foam of (R)-3-(2,6-dichloropyrimidin-4-yl)-4-((R)-1-hydroxyethyl)oxazolidin-2-one (737 mg, 2.65 mmol, 89% yield). 1H NMR (400 MHz, CDCl3) δ 1.19 (d, J=6.46 Hz, 3H) 4.47 (dd, J=9.37, 8.53 Hz, 1H) 4.55 (quin, J=5.69 Hz, 1H) 4.63 (dd, J=9.49, 2.79 Hz, 1H) 4.89 (ddd, J=8.19, 4.96, 2.79 Hz, 1H) 8.24 (s, 1H). LCMS m/z 278.0 (M+H)+, Rt 0.66 min.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=1.[NH2:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17]>C(O)(C)C>[Cl:8][C:6]1[N:5]=[C:4]([NH:9][C:10]([CH3:13])([CH3:12])[CH3:11])[N:3]=[C:2]([NH:14][CH2:15][C:16]([CH3:19])([CH3:18])[CH3:17])[CH:7]=1
Reactant: CC(C)(C)CN
Reactant: CC(C)(C)Nc1nc(Cl)cc(Cl)n1
Solvent: CC(C)O
Product: CC(C)(C)CNc1cc(Cl)nc(NC(C)(C)C)n1

Procedure:
After dissolving 5.0 g of 4,6-dichloro-2-(1,1-dimethylethylamino)pyrimidine in 25 ml of isopropanol and adding 5 ml of 1-amino-2,2-dimethylpropane, the reaction mixture is boiled under reflux for 20 hours, then the reaction mixture is evaporated and the residue is distributed between 80 ml of chloroform and 15 ml of 10% sodium hydroxide solution. After separation the organic phase is washed 4 times with 20 ml of water each, then dried and evaporated. The residue is recrystallized from hexane to give the title compound in a yield of 4.49 g (73%), m.p.:109.5°-111° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1.[OH-].[NH4+:13]>C(O)(C)C>[NH2:13][C:2]1[CH:11]=[N:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]=1
Reactant: Clc1cnc2ncccc2n1
Reactant: [NH4+]
Agent: [OH-]
Solvent: CC(C)O
Product: Nc1cnc2ncccc2n1
Temperature: 115 °C

Procedure:
A mixture of 2-chloro-pyrazino[2,3-b]pyridine (3.35g), isopropanol (20 mL) and concentrated ammonium hydroxide (50 mL) was heated at 115° C. for 17 h in a sealed tube. The tube was cooled and the product was collected and recrystallized from ethanol to afford 2-amino-pyrazino[2,3-b]pyridine as a yellow solid.
Reaction SMILES: [OH-:1].[Na+].[CH2:3]([C:5]1[CH:17]=[C:8]2[C:9]([CH:15]=[O:16])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4]>[N+]([O-])([O-])=O.[Ag+]>[CH2:3]([C:5]1[CH:17]=[C:8]2[C:9]([C:15]([OH:1])=[O:16])=[CH:10][CH:11]=[C:12]([O:13][CH3:14])[N:7]2[N:6]=1)[CH3:4]
Reactant: [OH-]
Reactant: CCc1cc2c(C=O)ccc(OC)n2n1
Agent: [Ag+]
Agent: O=[N+]([O-])[O-]
Agent: [Na+]
Product: CCc1cc2c(C(=O)O)ccc(OC)n2n1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 95.9 %

Procedure:
An aqueous suspension (526 mL) of silver nitrate (22.28 g) and sodium hydroxide (10.86 g, 15.1) was added to the compound of Example 347 (10.76 g). The mixture was stirred at room temperature for 1.5 hours. Subsequently, the insoluble material in the mixture was removed by filtration through Celite. The filtrate was washed with diethyl ether. Diluted hydrochloric acid was then added to the aqueous layer to make it acidic. The mixture was then extracted with ethyl acetate and the organic layer was dried over anhydrous sodium sulfate. Evaporation of the solvent afforded the title compound as a yellow powder (11.13 g).