Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH2:11].FC(F)(F)C(O)=O.COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](CC1C=CC(OCC2C=CC=CC=2)=CC=1)N.[C:76]([O:80][C:81]([NH:83][C@H:84]([C:94](O)=[O:95])[CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)=[O:82])([CH3:79])([CH3:78])[CH3:77].C1(N=C=NC2CCCCC2)CCCCC1>C(N(CC)CC)C>[CH3:1][O:2][C:3](=[O:34])[C@H:4]([CH2:30][CH:31]([CH3:33])[CH3:32])[NH:5][C:6](=[O:29])[C@@H:7]([CH3:28])[NH:8][C:9](=[O:27])[C@H:10]([CH2:12][C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[CH:15][CH:14]=1)[NH:11][C:94](=[O:95])[C@H:84]([CH2:85][O:86][CH2:87][C:88]1[CH:93]=[CH:92][CH:91]=[CH:90][CH:89]=1)[NH:83][C:81]([O:80][C:76]([CH3:79])([CH3:77])[CH3:78])=[O:82]
Reactant: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@@H](N)Cc1ccc(OCc2ccccc2)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](COCc1ccccc1)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](C)NC(=O)[C@H](Cc1ccc(OCc2ccccc2)cc1)NC(=O)[C@H](COCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: -5 °C
Reaction time: 8 h

Procedure:
Nα -t-Butoxycarbonyl-O-benzyl-L-seryl-O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester is prepared from 10 mmoles of O-benzyl-L-tyrosyl-D-alanyl-L-leucine methyl ester trifluoroacetic acid salt by neutralizing to litmus with triethylamine in the cold and then adding 1.4 ml. (10 mmol) of additional triethylamine (pH 8.5). The cold solution is treated with 2.95 g. (10 mmol) of Nα -t-butoxycarbonyl-O-benzyl-L-serine, 1.35 g. of 1-hydroxybentriazole and 2.2 g. of dicyclohexylcarbodiimide. The mixture is stirred for two and one-half hours at -5° C. and overnight at room temperature. The mixture is filtered, the solid rinsed with dimethylformamide and the filtrate evaporated at 40° C. under reduced pressure. The residue is dissolved in 50 ml. of ethyl acetate and 200 ml. of ether and washed three times with 5% sodium bicarbonate solution and with saturated salt solution, dried over magnesium sulfate and evaporated. The residue is crystallized from a minimum of methanol by adding ether; 6.6 g. The product is recrystallized from methanol-ether; 6 g.; m.p. 67°-71° C.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[N:12]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:13]3[C:18]([CH:19]=2)=[CH:17][C:16]([CH2:20][N:21]2[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:15][CH:14]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:34].C(N(CC)CC)C.[CH:42]1([C:45](Cl)=[O:46])[CH2:44][CH2:43]1.O>C(OCC)(=O)C>[CH:42]1([C:45]([NH:1][C:2]2[CH:10]=[CH:9][C:8]([C:11]3[N:12]([C:27]([O:29][C:30]([CH3:31])([CH3:33])[CH3:32])=[O:28])[C:13]4[C:18]([CH:19]=3)=[CH:17][C:16]([CH2:20][N:21]3[CH2:26][CH2:25][CH2:24][CH2:23][CH2:22]3)=[CH:15][CH:14]=4)=[C:7]3[C:3]=2[CH2:4][NH:5][C:6]3=[O:34])=[O:46])[CH2:44][CH2:43]1
Reactant: CC(C)(C)OC(=O)n1c(-c2ccc(N)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Reactant: O=C(Cl)C1CC1
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)n1c(-c2ccc(NC(=O)C3CC3)c3c2C(=O)NC3)cc2cc(CN3CCCCC3)ccc21
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 26 %

Procedure:
4-Amino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0940 g, 0.204 mmol) was dissolved in ethyl acetate (4.0 mL), and the solution was added with triethylamine (0.0570 mL, 0.408 mmol) and cyclopropanecarbonyl chloride (0.0280 mL, 0.306 mmol), followed by stirring at room temperature for 1.5 hours. The reaction mixture was added with water and extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by flash column chromatography (chloroform/methanol=85/15) to obtain 4-cyclopropylcarbonylamino-7-[1-(tert-butoxycarbonyl)-5-(piperidinomethyl)indol-2-yl]isoindolinone (0.0280 g, yield 26%).
Reaction SMILES: [OH:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C([O-])([O-])=O.[K+].[K+].[I-].[K+]>CN(C=O)C>[CH2:17]([O:1][C:2]1[C:3]([O:15][CH3:16])=[CH:4][C:5]([N+:12]([O-:14])=[O:13])=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: COC(=O)c1cc(O)c(OC)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1cc(OCc2ccccc2)c(OC)cc1[N+](=O)[O-]
Temperature: 92.5 °C
Yield: 77.1 %

Procedure:
To solution of methyl 5-hydroxy-4-methoxy-2-nitrobenzoate (13.0 g, 0.0572 mol) in DMF (120 mL) and benzyl chloride (7.23 ml, 0.0629 mol), K2CO3 (8.69 g, 0.0629 mol) and potassium iodide (0.949 g, 0.0057 mol) were added. The reaction mixture was heated at 90-95° C. overnight. The solvent was evaporated under vacuum and the residue was taken in ethyl acetate and washed with water and brine. After drying over MgSO4, the solution was concentrated ad purified on silica gel column to yield methyl 5-(benzyloxy)-4-methoxy-2-nitrobenzoate (13.99 g, 77% yield). 1HNMR (DMSO-d6): δ 7.66 (1H, s), 7.40 (6H, m), 5.27 (2H, s), 3.83 (3H, s), 3.80 (3H, s). LC-MS (ESI) m/z 318 (M+H)+.
Reaction SMILES: C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].[Cl:15][C:16]1[CH:35]=[CH:34][C:19]2[O:20][C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=3[C@@H:23]3[C@H:28]([NH2:29])[CH2:27][CH2:26][CH2:25][N:24]3[C:18]=2[CH:17]=1.[CH:36](=O)[CH:37]([CH3:39])[CH3:38]>C(Cl)Cl>[CH3:36][CH:37]([CH3:39])[CH2:38][NH:29][C@H:28]1[C@@H:23]2[N:24]([C:18]3[CH:17]=[C:16]([Cl:15])[CH:35]=[CH:34][C:19]=3[O:20][C:21]3[CH:33]=[CH:32][CH:31]=[CH:30][C:22]=32)[CH2:25][CH2:26][CH2:27]1
Reactant: N[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Reactant: CC(C)C=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: CC(C)CN[C@@H]1CCCN2c3cc(Cl)ccc3Oc3ccccc3[C@H]12
Temperature: 25 °C
Reaction time: 18 h
Yield: 121.4 %

Procedure:
After 10 min. stirring sodium triacetoxyborohydride (11 mg, 0.05 mmol) was added to trans-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (10 mg, 0.03 mmol) and isobutyraldehyde (3.45 mg, 0.03 mmol) in 1 mL of CH2Cl2 (pH=4). The resulting mixture was stirred at room temperature for 18 h. The mixture was evaporated and chromatographed on silica. Elution with CH2Cl2/methanol 8:2 gave trans-N-(2-methylpropyl)-7-chloro-2,3,4,14b-tetrahydro-1H-dibenzo[b,f]pyrido[1,2-d][1,4]oxazepine-1-amine (13 mg, 100%). Data: (m/z)=357 (M+H)+.
Reaction SMILES: C([O-])(O)=O.[Na+].[NH2:6][C@@H:7]([C:11]([OH:13])=[O:12])[C@H:8]([CH3:10])[OH:9].[C:14](Cl)(=[O:27])[O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>C1COCC1.O.[Br-].C([N+](CCCC)(CCCC)CCCC)CCC>[OH:9][C@@H:8]([CH3:10])[C@@H:7]([NH:6][C:14]([O:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:27])[C:11]([OH:13])=[O:12]
Reactant: O=C(Cl)OCCCCCc1ccccc1
Reactant: C[C@H](O)[C@@H](N)C(=O)O
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=C([O-])O
Agent: [Br-]
Solvent: O
Solvent: C1CCOC1
Product: C[C@H](O)[C@@H](NC(=O)OCCCCCc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 18 h
Yield: 17.9 %

Procedure:
In a round bottom flask, NaHCO3 (12.0 g, 143.2 mmol) was suspended in THF (30 mL) and water (60 mL), then D-threonine (6.8 g, 56.8 mmol) was added followed by 5-phenylpentyl chlorocarbonate (14.3 g, 63.1 mmol) and a catalytic amount (0.67 g) of tetrabutylamonium bromide. After stirring 18 h at rt, the mixture was diluted with water, washed twice with Et2O and pH adjusted to 2 with 2M HCl solution. The aqueous phase was extracted with AcOEt (4×150 mL), the collected organic phases were washed with brine, dried over Na2SO4, filtered and the solvent removed under vacuum. The crude was purified by typical silica gel column chromatography, eluting with Cy/AcOEt (20:80+1% CH3COOH), yielding the title compound (3.15 g, 18%), as pale yellow oil. Rf=0.38 (Cy/AcOEt 2:8+1% CH3COOH). FTIR (cm−1): 3332 (br), 3027, 2935, 2859, 1714, 1530, 1454, 1415, 1257, 1072, 1007, 963, 870, 779, 748, 700. 1H NMR (CDCl3): δ 1.26 (d, 3H); 1.39 (m, 2H); 1.62-1.68 (m, 4H); 2.61 (t, 2H); 4.08 (t, 2H); 4.34 (d, 1H); 4.42 (d, 1H); 5.68 (d, 1H); 7.16-7.78 (m, 3H); 7.26-7.28 (m, 2H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][N:8]=2)[CH:3]=[CH:2]1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Br[C:21]1[C:25](=[O:26])[N:24]([CH3:27])[C:23](=[O:28])[C:22]=1[C:29]1[C:37]2[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=2)[N:31]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])[CH:30]=1.[Cl-].[NH4+]>C1(C)C=CC=CC=1>[CH3:27][N:24]1[C:25](=[O:26])[C:21]([C:3]2[C:4]3[C:9](=[N:8][CH:7]=[CH:6][CH:5]=3)[NH:1][CH:2]=2)=[C:22]([C:29]2[C:37]3[C:32](=[CH:33][CH:34]=[CH:35][CH:36]=3)[N:31]([C:38]([O:40][C:41]([CH3:43])([CH3:42])[CH3:44])=[O:39])[CH:30]=2)[C:23]1=[O:28]
Reactant: c1cnc2[nH]ccc2c1
Reactant: CN1C(=O)C(Br)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [Li+]
Solvent: Cc1ccccc1
Product: CN1C(=O)C(c2c[nH]c3ncccc23)=C(c2cn(C(=O)OC(C)(C)C)c3ccccc23)C1=O
Temperature: -10 °C
Reaction time: 1 h

Procedure:
To a solution, maintained at −10° C., of 7-azaindole (1.78 mmol), dissolved in 10 ml of dry toluene, there is added, dropwise, a solution of commercial LiHMDS (1M in hexane) (4.6 mmol). After stirring for 1 hour at −10° C., a solution of the product obtained in Step B (0.85 mmol), dissolved in 10 ml of dry toluene, is added dropwise at ambient temperature. After stirring for 24 hours at ambient temperature, the reaction mixture is hydrolysed with saturated aqueous ammonium chloride solution and the pH is then adjusted to 7. The mixture is extracted with ethyl acetate. The organic phases are combined, washed with aqueous sodium chloride solution and dried over magnesium sulphate. After purification by chromatography on silica gel (cyclohexane/ethyl acetate/triethylamine: 7/3/1%), the expected product is isolated.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:21][CH2:20][N:19]([CH2:22][C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=4)[CH2:18][CH2:17]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([OH:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([OH:34])=[O:33]>CC(C)=O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[CH2:14][CH:13]([CH2:15][CH:16]3[CH2:17][CH2:18][N:19]([CH2:22][C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[CH2:20][CH2:21]3)[C:11](=[O:12])[C:6]2=[CH:7][C:8]=1[O:9][CH3:10].[C:29]([O-:36])(=[O:35])/[CH:30]=[CH:31]/[C:32]([O-:34])=[O:33]
Reactant: O=C(O)/C=C/C(=O)O
Agent: COc1cc2c(cc1OC)C(=O)C(CC1CCN(Cc3ccccc3)CC1)C2
Solvent: CC(C)=O
Product: O=C([O-])/C=C/C(=O)[O-]
Temperature: 25 °C

Procedure:
Donepezil (3.79 g, dissolved in 70 ml of ethyl acetate) is slowly added to a solution of fumaric acid (0.58 g) in acetone (35 ml) with stirring at room temperature. The solid precipitated is filtered and dried at 55° C. under vacuum to give the title compound. Melting point: 167.4° C.
Reaction SMILES: [Cl:1][C:2]1[N:10]=[C:9]2[C:5]([N:6]=[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])[NH:8]2)=[C:4]([N:15]2[CH2:20][CH2:19][O:18][CH2:17][CH2:16]2)[N:3]=1.Br[CH2:22][CH2:23][CH2:24][CH3:25]>>[CH2:22]([N:8]1[C:7]([C:11]([OH:14])([CH3:13])[CH3:12])=[N:6][C:5]2[C:9]1=[N:10][C:2]([Cl:1])=[N:3][C:4]=2[N:15]1[CH2:16][CH2:17][O:18][CH2:19][CH2:20]1)[CH2:23][CH2:24][CH3:25]
Reactant: CCCCBr
Reactant: CC(C)(O)c1nc2c(N3CCOCC3)nc(Cl)nc2[nH]1
Product: CCCCn1c(C(C)(C)O)nc2c(N3CCOCC3)nc(Cl)nc21

Procedure:
2-(2-Chloro-6-morpholino-9H-purin-8-yl)propan-2-ol 100 mg was treated with bromobutane via General Procedure C to give crude intermediate 2-(9-butyl-2-chloro-6-morpholino-9H-purin-8-yl)propan-2-ol which was treated with 2-aminopyrimidine-5-boronic acid, pinacol ester via General Procedure A and was purified via reverse phase HPLC to give 55 mg of 103 as a white solid. MS (Q1) 413.3 (M)+.
Reaction SMILES: [F:1][C:2]([F:14])([F:13])[O:3][C:4]1[CH:11]=[C:8]([CH:9]=O)[C:7]([OH:12])=[CH:6][CH:5]=1.C(=O)(OC(C)(C)C)[NH2:16].C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[NH2:16][CH2:9][C:8]1[CH:11]=[C:4]([O:3][C:2]([F:14])([F:13])[F:1])[CH:5]=[CH:6][C:7]=1[OH:12]
Reactant: O=Cc1cc(OC(F)(F)F)ccc1O
Reactant: CC(C)(C)OC(N)=O
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: CC#N
Product: NCc1cc(OC(F)(F)F)ccc1O
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(trifluoromethoxy)salicylaldehyde (4.85 mmol, 1.0 g), tert-butyl carbamate (14.55 mmol, 1.70 g), triethylsilane (14.55 mmol, 2.3 mL), trifluoroacetic acid (9.7 mmol, 0.72 mL) in acetonitrile was stirred at room temperature overnight. The reaction was quenched with saturated NaHCO3 and extracted with EtOAc. The combined organic layers were dried over Na2SO4 and purified by silica gel chromatography (15%-100% EtOAc/hexane). The resulting yellow solid was then dissolved in a mixture of TFA (10 mL) and dichloromethane (20 mL) and stirred for 2 hours at room temperature. The volatile solvents were then removed by rotovap to afford 2-(aminomethyl)-4-(trifluoromethoxy)phenol as a yellow oil. 1H NMR (CD3OD) 7.28 (s, 1H), 7.22 (m, 1H), 6.97 (m, 1H), 4.13 (s, 2H), 1.59 (s, 1H).
Reaction SMILES: [Cl:1][C:2]1[C:20]([Cl:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([CH:6](C(OCC)=O)[C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5].C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[Cl:1][C:2]1[C:20]([Cl:21])=[C:19]([F:22])[C:18]([F:23])=[CH:17][C:3]=1[C:4]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[O:5]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)c1cc(F)c(F)c(Cl)c1Cl
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: CCOC(=O)CC(=O)c1cc(F)c(F)c(Cl)c1Cl
Yield: 54.3 %

Procedure:
To an emulsion of diethyl 2-(2,3-dichloro-4,5-difluorobenzoyl)malonate (9.71 g) in water (11.2 ml) was added p-toluenesulfonic acid (11.2 mg) and refluxed for 3 hours with stirring vigorously. After cooling, the reaction mixture was extracted with dichloromethane. The organic layer was washed with 7% aqueous sodium carbonate solution and then with water successively, dried over anhydrous sodium sulfate and concentrated. The residue was recrystallized from n-hexane to give the title compound (4.24 g) as powdery crystals. mp 52°-53° C.
Reaction SMILES: [C:1]([C@@:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)([CH2:12][NH2:13])C(O)=O)([O:3]C(C)(C)C)=[O:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]>C(Cl)Cl>[NH2:13][CH2:12][C@H:8]([CH2:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)[C:1]([OH:3])=[O:2].[C:21]([OH:27])([C:23]([F:26])([F:25])[F:24])=[O:22]
Reactant: CC(C)(C)OC(=O)[C@](CN)(Cc1ccccc1)C(=O)O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NC[C@H](Cc1ccccc1)C(=O)O
Temperature: 25 °C
Reaction time: 3 h

Procedure:
Boc-(S)-3-amino-2-benzylpropionic acid (105 mg, 0.38 mmol, PepTech) was dissolved in TFA (4 mL) and CH2Cl2 (4 mL). The resulting mixture was stirred at room temperature for 3 hours. The volatiles were removed in vacuo and the residue was dissolved again in CH2Cl2 (4 mL). The volatiles were removed again in vacuo to give the title compound as its TFA salt, which was used in the subsequent step without further purification.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][CH:3]=[C:2]1B(O)O.Br[C:10]1[CH:15]=[CH:14][C:13]([C:16]([N:18]2[CH2:22][CH2:21][CH2:20][C@H:19]2[CH2:23][N:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:17])=[C:12]([F:29])[CH:11]=1>>[F:29][C:12]1[CH:11]=[C:10]([C:2]2[S:1][CH:5]=[CH:4][CH:3]=2)[CH:15]=[CH:14][C:13]=1[C:16]([N:18]1[CH2:22][CH2:21][CH2:20][C@H:19]1[CH2:23][N:24]1[CH2:28][CH2:27][CH2:26][CH2:25]1)=[O:17]
Reactant: O=C(c1ccc(Br)cc1F)N1CCC[C@H]1CN1CCCC1
Reactant: OB(O)c1cccs1
Product: O=C(c1ccc(-c2cccs2)cc1F)N1CCC[C@H]1CN1CCCC1

Procedure:
The title compound is prepared in a manner substantially analogous to Procedure Q starting from 2-thiophene boronic acid and (4-Bromo-2-fluoro-phenyl)-((S)-2-pyrrolidin-1-ylmethyl-pyrrolidin-1-yl)-methanone to give 29 mg (58%). MS (ES+) 359.1
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH2:8])=[C:4]([F:9])[CH:3]=1.N1C=CC=CC=1.[C:16](Cl)(=[O:18])[CH3:17]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:16](=[O:18])[CH3:17])=[C:4]([F:9])[CH:3]=1
Reactant: Nc1ccc(Br)cc1F
Reactant: CC(=O)Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(Br)cc1F
Reaction time: 0.17 h
Yield: 96.8 %

Procedure:
A solution of 4-bromo-2-fluorophenylamine (10.9 g, 57.4 mmol) and pyridine (9.4 mL, 115 mmol) in 50 mL of anhydrous dichloromethane was treated with acetyl chloride (3.33 mL, 63.1 mmol) at 0° C. After 10 minutes at 0° C. and 10 minutes at room temperature, the mixture was concentrated in vacuo and the residue was treated with 300 mL of 1 N aqueous sulfuric acid. The organic layer was concentrated in vacuo to give 12.9 g of N-(4-bromo-2-fluorophenyl)acetamide as a light greyish solid (97% yield).
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([N:8]2[C@@H:12]([CH:13]([CH3:15])[CH3:14])[CH2:11][O:10][C:9]2=[O:16])[CH:5]=[CH:4][N:3]=1.[N:17]1([C:23]2[CH:28]=[CH:27][C:26]([CH:29]([NH2:31])[CH3:30])=[CH:25][CH:24]=2)[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]1>CS(C)=O.CCOC(C)=O>[CH:13]([C@H:12]1[CH2:11][O:10][C:9](=[O:16])[N:8]1[C:6]1[CH:5]=[CH:4][N:3]=[C:2]([NH:31][CH:29]([C:26]2[CH:27]=[CH:28][C:23]([N:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)=[CH:24][CH:25]=2)[CH3:30])[N:7]=1)([CH3:15])[CH3:14]
Reactant: CC(C)[C@H]1COC(=O)N1c1ccnc(Cl)n1
Reactant: CC(N)c1ccc(N2CCCCC2)cc1
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: CC(Nc1nccc(N2C(=O)OC[C@@H]2C(C)C)n1)c1ccc(N2CCCCC2)cc1
Yield: 36.6 %

Procedure:
A solution of (S)-3-(2-chloropyrimidin-4-yl)-4-isopropyloxazolidin-2-one (93 mg, 0.38 mmol) and 1-(4-(piperidin-1-yl)phenyl)ethanamine (410 mg, 2.01 mmol, 5.2 equiv) in DMSO (1 mL) was heated at 110° C. for 2 h. The reaction mixture was diluted with EtOAc (8 mL) and washed with water (30 mL). After separation, the aqueous phase was extracted with EtOAc (3×8 mL). Combined organics were dried over Na2SO4, filtered and concentrated. Silica gel column chromatography (EtOAc/Heptane 10 to 100%) provided (4S)-4-isopropyl-3-(2-((1-(4-(piperidin-1-yl)phenyl)ethyl)amino)pyrimidin-4-yl)oxazolidin-2-one (57 mg) in 36% yield. A mixture of (4S)-4-isopropyl-3-(2-(1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one was resolved on a column (AD-H 4.6×100 mm) using 5 to 55% MeOH with 0.2% Et2NH in CO2 to give (S)-4-isopropyl-3-(2-((R)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one and (S)-4-isopropyl-3-(2-((S)-1-(4-(piperidin-1-yl)phenyl)ethylamino)pyrimidin-4-yl)oxazolidin-2-one.
Reaction SMILES: [CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25](OCC)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:20][CH2:19][N:18]([CH3:21])[CH2:17][CH2:16]3)[CH:10]=2)=[N:6][CH:7]=1.[NH:34]1[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]1>>[CH3:1][C:2]1[C:3]([NH:22][C:23]2[CH:33]=[CH:32][CH:31]=[CH:30][C:24]=2[C:25]([N:34]2[CH2:38][CH2:37][C@@H:36]([OH:39])[CH2:35]2)=[O:26])=[N:4][C:5]([NH:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([N:15]3[CH2:16][CH2:17][N:18]([CH3:21])[CH2:19][CH2:20]3)[CH:10]=2)=[N:6][CH:7]=1
Reactant: O[C@@H]1CCNC1
Reactant: CCOC(=O)c1ccccc1Nc1nc(Nc2cccc(N3CCN(C)CC3)c2)ncc1C
Product: Cc1cnc(Nc2cccc(N3CCN(C)CC3)c2)nc1Nc1ccccc1C(=O)N1CC[C@@H](O)C1
Temperature: 125 °C
Reaction time: 18 h

Procedure:
Ethyl 2-[(5-methyl-2-{[3-(4-methyl-1-piperazinyl)phenyl]amino}-4-pyrimidinyl)amino]benzoate (120 mg, 0.27 mmol) and (R)-(+)-3-pyrrolidinol (0.65 mL, used as solvent) were combined in a vessel, which was sealed and heated with stirring at 125° C. for 18 h. The reaction was cooled to room temperature and evaporated. The residue was partitioned between ethyl acetate (10 mL) and water (10 mL). The organic layer was washed with brine, dried over magnesium sulfate, filtered and evaporated. The residue was purified using normal phase HPLC eluting with a gradient of dichloromethane/methanol/ammonium hydroxide (90:10:0-90:10:1) affording the title compound as an off-white solid; yield 63 mg. (48%). (MS: M(C27H33N7O2)=487.60, (M+H)+=488.2.
Reaction SMILES: CC1C=CC(S(O[CH2:12][CH:13]2[CH2:17][C:16]3[CH:18]=[C:19]([Cl:30])[CH:20]=[C:21]([C:22]4[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=4[F:29])[C:15]=3[O:14]2)(=O)=O)=CC=1.[CH3:31][NH2:32]>>[Cl:30][C:19]1[CH:20]=[C:21]([C:22]2[CH:27]=[C:26]([F:28])[CH:25]=[CH:24][C:23]=2[F:29])[C:15]2[O:14][CH:13]([CH2:12][NH:32][CH3:31])[CH2:17][C:16]=2[CH:18]=1
Reactant: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(-c4cc(F)ccc4F)c3O2)cc1
Reactant: CN
Product: CNCC1Cc2cc(Cl)cc(-c3cc(F)ccc3F)c2O1

Procedure:
The title compound was prepared (0.090 g, 67%) following the general procedure of Example 390 as a white solid, hydrochloride salt from (±)-[5-chloro-7-(2,5-difluorophenyl)-2,3-dihydro-1-benzofuran-2-yl]methyl 4-methylbenzenesulfonate (0.175 g, 0.39 mmol) and methylamine (0.120 g, 3.9 mmol). mp 189-191° C.
Reaction SMILES: O[CH:2]=[C:3]1[C:11]2[C:6](=[CH:7][C:8]([C:12]([C:14]3[CH:15]=[C:16]([NH:20][C:21]([C:23]4[O:24][CH:25]=[CH:26][C:27]=4[CH3:28])=[O:22])[CH:17]=[CH:18][CH:19]=3)=[O:13])=[CH:9][CH:10]=2)[NH:5][C:4]1=[O:29].[NH2:30][C:31]1[CH:36]=[CH:35][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:33][CH:32]=1>C1COCC1>[CH3:28][C:27]1[CH:26]=[CH:25][O:24][C:23]=1[C:21]([NH:20][C:16]1[CH:15]=[C:14]([CH:19]=[CH:18][CH:17]=1)[C:12]([C:8]1[CH:7]=[C:6]2[C:11]([C:3](=[CH:2][NH:30][C:31]3[CH:32]=[CH:33][C:34]([CH2:37][CH2:38][C:39]([OH:41])=[O:40])=[CH:35][CH:36]=3)[C:4](=[O:29])[NH:5]2)=[CH:10][CH:9]=1)=[O:13])=[O:22]
Reactant: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CO)c1
Reactant: Nc1ccc(CCC(=O)O)cc1
Solvent: C1CCOC1
Product: Cc1ccoc1C(=O)Nc1cccc(C(=O)c2ccc3c(c2)NC(=O)C3=CNc2ccc(CCC(=O)O)cc2)c1
Temperature: 65 °C
Reaction time: 24 h
Yield: 57 %

Procedure:
A small screw cap test tube was charged with 3-Methyl-furan-2-carboxylic acid [3-(3-hydroxymethylene-2-oxo-2,3-dihydro-1H-indole-6-carbonyl)-phenyl]-amide (as prepared in Example 354, 200 mg, 0.515 mmol) and THF (5.0 mL). To the resulting solution was added 3-(4-Amino-phenyl)-propionic acid (85.1 mg, 0.515 mmol), and the mixture was stirred for 24 h at 65° C. Subsequently, the reaction mixture was cooled to room temperature and concentrated in vacuo. The crude residue was purified by flash silica gel chromatography (EtOAc:MeOH mix eluant with gradient of 1% MeOH to 10% MeOH) to afford the title compound in 57% yield (0.157 g, 0.293 mmol).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([NH:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][C:13]=2[C:18]([OH:20])=O)[CH:8]=[C:7]([C:21]([CH3:24])([CH3:23])[CH3:22])[C:6]=1[OH:25])([CH3:4])([CH3:3])[CH3:2].[CH2:26]([NH2:33])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1.CCOC(OC(OCC)=O)=O.C(N(CC)CC)C>CN(C=O)C.O>[CH2:26]([NH:33][C:18]([C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][C:12]=1[NH:11][C:9]1[CH:10]=[C:5]([C:1]([CH3:2])([CH3:4])[CH3:3])[C:6]([OH:25])=[C:7]([C:21]([CH3:23])([CH3:22])[CH3:24])[CH:8]=1)=[O:20])[C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1
Reactant: NCc1ccccc1
Reactant: CC(C)(C)c1cc(Nc2ccccc2C(=O)O)cc(C(C)(C)C)c1O
Agent: CCOC(=O)OC(=O)OCC
Solvent: O
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CC(C)(C)c1cc(Nc2ccccc2C(=O)NCc2ccccc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 20 h

Procedure:
A 1 g quantity of 2,6-di-tert-butyl-4-(2-carboxyphenylamino)phenol (Compound 25) was dissolved in 20 ml of DMF. To the solution were added with ice-cooling 340 mg of benzylamine and 570 mg of DEPC and then added a solution of 330 mg of triethylamine in 5 ml of DMF over 20 minutes. Then the reaction mixture was stirred at room temperature for 20 hours, and then poured into water, and extracted with ethyl acetate. The organic layer was washed with water, dried over MgSO4 and concentrated to give a crude product which was purified by silica gel column chromatography (eluent: diethyl ether-hexane=1:10→1:5), giving 1.1 g of the title compound as white crystals.