Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6](Cl)[C:5]([F:9])=[CH:4][N:3]=1.C(N(CC)CC)C.[NH2:17][CH2:18][CH:19]1[CH2:24][CH2:23][N:22]([C:25]([O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)=[O:26])[CH2:21][CH2:20]1>CN(C=O)C>[CH2:28]([O:27][C:25]([N:22]1[CH2:23][CH2:24][CH:19]([CH2:18][NH:17][C:6]2[C:5]([F:9])=[CH:4][N:3]=[C:2]([Cl:1])[N:7]=2)[CH2:20][CH2:21]1)=[O:26])[C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1
Reactant: NCC1CCN(C(=O)OCc2ccccc2)CC1
Reactant: Fc1cnc(Cl)nc1Cl
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C(OCc1ccccc1)N1CCC(CNc2nc(Cl)ncc2F)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of 2,4-dichloro-5-fluoro-pyrimidine (0.67 g, 4.03 mmol) and triethylamine (0.84 mL, 6.04 mmol) in DMF (5 mL) was added benzyl 4-(aminomethyl)piperidine-1-carboxylate (EXAMPLE 13, Step 1) (1.00 g, 4.03 mmol). The resulting reaction solution was stirred at rt for 1 h, and concentrated in vacuo. The residue was purified by silica gel chromatography (CH2Cl2/IPA/hexanes) to give 4-[(2-chloro-5-fluoro-pyrimidin-4-ylamino)-methyl]-piperidine-1-carboxylic acid benzyl ester. M.S. (M+1): 379.25
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.C(N(CC)CC)C.[NH:17]1[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]1>C1COCC1>[Br:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:17]2[CH2:22][CH2:21][CH:20]([C:23]#[N:24])[CH2:19][CH2:18]2)=[CH:4][CH:3]=1
Reactant: N#CC1CCNCC1
Reactant: BrCc1ccc(Br)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: N#CC1CCN(Cc2ccc(Br)cc2)CC1
Temperature: 25 °C
Reaction time: 18 h
Yield: 98.5 %

Procedure:
A mixture of 4-bromobenzyl bromide (1.0 g, 4.0 mmol), triethylamine (0.84 mL, 6.0 mmol) and piperidine-4-carbonitrile (880 mg, 8.0 mmol) in THF (20 mL) was stirred at ambient temperature for 18 h. The reaction mixture was evaporated in vacuo and the residue partitioned between saturated sodium bicarbonate solution (100 mL) and dichloromethane (100 mL). The organic phase was separated, dried over sodium sulfate, filtered and evaporated in vacuo. The resultant residue was purified by flash chromatography (silica, Biotage 50 g column, 0-100% ethyl acetate in cyclohexane) to afford the title compound (1.10 g, 99%). 1H NMR (CDCl3, 300 MHz): 7.46-7.41 (m, 2H); 7.21-7.15 (m, 2H); 3.44 (s, 2H); 2.70-2.57 (m, 3H); 2.38-2.22 (m, 2H); 1.99-1.74 (m, 4H). LCMS (Method B): RT=1.82 min, M+H+=280.
Reaction SMILES: Br.[NH2:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:5][CH:4]=1.[C:16](Cl)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1>[OH-].[Na+]>[C:16]([NH:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[N:10]=[CH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][CH:8]=1)(=[O:23])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1
Reactant: Nc1ccc(-c2c[nH]c(=O)cn2)cc1
Reactant: O=C(Cl)c1ccccc1
Agent: Br
Agent: [Na+]
Agent: [OH-]
Product: O=C(Nc1ccc(-c2c[nH]c(=O)cn2)cc1)c1ccccc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A solution of 5-(4-aminophenyl)-2(1H)-pyrazinone hydrobromide (2.0 g) in aqueous sodium hydroxide (46 ml, 10%) was treated with benzoyl chloride (1.9 ml) and the mixture was agitated for 2 hours at room temperature. The pale yellow precipitate was collected, washed with water and dried. Recrystallisation from glacial acetic acid gave the title compound (0.9 g), m.p.>300° C.; ν(Nujol mull) 1660 (C=0), 1705 (C=0), 3330 (NH)cm-1.
Reaction SMILES: [NH:1]([C:3]1[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=1)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[NH2:2].[CH3:14][CH:15]([CH3:21])[C:16](=O)[CH2:17][C:18]#[N:19].Cl>C(O)C>[NH2:19][C:18]1[N:1]([C:3]2[CH:4]=[C:5]([CH:11]=[CH:12][CH:13]=2)[C:6]([O:8][CH2:9][CH3:10])=[O:7])[N:2]=[C:16]([CH:15]([CH3:21])[CH3:14])[CH:17]=1
Reactant: CCOC(=O)c1cccc(NN)c1
Reactant: CC(C)C(=O)CC#N
Agent: Cl
Solvent: CCO
Product: CCOC(=O)c1cccc(-n2nc(C(C)C)cc2N)c1
Yield: 88.2 %

Procedure:
To a mixture of ethyl 3-hydrazinobenzoate (from Example A81, 3 g, 16.6 mmol) and 4-methyl-3-oxopentanenitrile (2.7 g, 24.9 mmol) in ethanol (50 mL) was added conc. HCl (5 mL). The resulting mixture was heated to reflux for 3 h. After removal of the solvent, the residue was washed with Et2O to afford ethyl 3-(5-amino-3-isopropyl-1H-pyrazol-1-yl)benzoate (4 g), which was used in the next reaction without further purification.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OC(C)C)=O)=NC(OC(C)C)=O.[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46]O)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35].[F:49][C:50]1[CH:55]=[CH:54][C:53]([SH:56])=[CH:52][CH:51]=1>CN(C)C=O>[C:34]([CH2:36][NH:37][C:38]([CH:40]1[CH:45]([CH2:46][S:56][C:53]2[CH:54]=[CH:55][C:50]([F:49])=[CH:51][CH:52]=2)[CH:44]2[CH2:48][CH:41]1[CH:42]=[CH:43]2)=[O:39])#[N:35]
Reactant: N#CCNC(=O)C1C2C=CC(C2)C1CO
Reactant: Fc1ccc(S)cc1
Agent: CC(C)OC(=O)N=NC(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: N#CCNC(=O)C1C2C=CC(C2)C1CSc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
A solution of triphenylphosphine (120 mg, 460 μmol) in dimethylformamide (1.0 mL) was cooled to 0° C. Diisopropyl azodicarboxylate (83 μL, 420 μmol) was added and the reaction mixture was stirred for 2 min. (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-(hydroxymethyl)-bicyclo[2.2.1]hept-5-ene-2-carboxamide (79 mg, 380 μmol) and 4-fluorothiophenol (45 μl, 420 μmol) were added and the reaction mixture was stirred at ambient temperature for 2.5 h. The reaction mixture was partitioned between ethyl acetate (10 mL) and 1:1 water:saturated aqueous sodium chloride (10 mL). The product was extracted into ethyl acetate, dried with anhydrous sodium sulfate and concentrated. Chromatography of the residue on silica gel eluting with 4:96 methanol:dichloromethane provided (1R/S,2R/S,3R/S,4S/R)-N-(cyanomethyl)-3-{[(4-fluorophenyl)sulfanyl]methyl}bicyclo[2.2.1]hept-5-ene-2-carboxamide as a colorless syrup.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@H:16]([C:41]([OH:43])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:35])=[O:34])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:44]1CCC(N=C=NC2CCCCC2)CC1>CO>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([S:8]([N:11]([C@H:16]([C:41]([O:43][CH3:44])=[O:42])[CH2:17][CH2:18][CH2:19][CH2:20][NH:21][C:22]([C@@H:24]([NH:32][S:33]([C:36]2[S:40][CH:39]=[CH:38][CH:37]=2)(=[O:34])=[O:35])[CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)=[O:23])[CH2:12][CH:13]([CH3:15])[CH3:14])(=[O:9])=[O:10])=[CH:6][CH:7]=1
Reactant: C(=NC1CCCCC1)=NC1CCCCC1
Reactant: Cc1ccc(S(=O)(=O)N(CC(C)C)[C@@H](CCCCNC(=O)[C@H](Cc2ccccc2)NS(=O)(=O)c2cccs2)C(=O)O)cc1
Solvent: CO
Product: COC(=O)[C@H](CCCCNC(=O)[C@H](Cc1ccccc1)NS(=O)(=O)c1cccs1)N(CC(C)C)S(=O)(=O)c1ccc(C)cc1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
The title compound was prepared by treating Nα-isobutyl-Nα-(4-methylbenzenesulfonyl)-Nε-[N′α-(2-thiophenesulfonyl)-L-phenylalanyl]-L-lysine (60 mg, 0.1 mmol, example 24) dissolved in MeOH (2 mL) with DCC (1 eq.). The reaction mixture was stirred at room temperature for a period of 2 h. Filtration and evaporation of the solvent followed by HPLC purification gave the desired methyl ester (15 mg, 22%).
Reaction SMILES: [OH:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2.[H-].[Na+].[CH3:18][O:19][CH2:20]Cl.O>C1COCC1>[CH3:18][O:19][CH2:20][O:1][C:2]1[C:3]([C:12]([O:14][CH3:15])=[O:13])=[CH:4][C:5]2[C:10]([CH:11]=1)=[CH:9][CH:8]=[CH:7][CH:6]=2
Reactant: COC(=O)c1cc2ccccc2cc1O
Reactant: COCCl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: COCOc1cc2ccccc2cc1C(=O)OC
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of methyl 3-hydroxy-2-naphthoate (7.01 g) in THF (200 ml) was cooled to 0° C., to which was added 60% sodium hydride (1.58 g) during 10 minutes. Then, the mixture was stirred for one hour at room temperature, to which was added dropwise chloromethyl methyl ether (2.8 ml). The mixture was then stirred for two hours, to which was added water to quench the reaction, followed by extraction with ethyl acetate. The organic layer was dried (anhydrous magnesium sulfate), and distilled off the solvent under reduced pressure. The residue was purified by means of a silica gel column chromatography (eluted with ethyl acetate/hexane) to give methyl 3-methoxymethoxy-2-naphthoate (7.11 g) (Compound B-19). The physical properties are shown in Table 7.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[C:8]([N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1)=[N:7][N:6]=[CH:5]2.[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25](B3OC(C)(C)C(C)(C)O3)[CH:24]=2)[CH2:20][CH2:19]1.C(=O)([O-])[O-].[K+].[K+]>COCCOC.CCO.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH:18]1([NH:21][C:22](=[O:39])[C:23]2[CH:28]=[CH:27][C:26]([CH3:29])=[C:25]([C:2]3[CH:3]=[C:4]4[C:9](=[CH:10][CH:11]=3)[C:8]([N:12]3[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]3)=[N:7][N:6]=[CH:5]4)[CH:24]=2)[CH2:19][CH2:20]1
Reactant: Brc1ccc2c(N3CCNCC3)nncc2c1
Reactant: Cc1ccc(C(=O)NC2CC2)cc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: COCCOC
Solvent: CCO
Product: Cc1ccc(C(=O)NC2CC2)cc1-c1ccc2c(N3CCNCC3)nncc2c1
Temperature: 90 °C
Reaction time: 2 h
Yield: 88.1 %

Procedure:
A mixture of 6-bromo-1-(piperazin-1-yl)phthalazine (0.12g, 0.41 mmol), N-cyclopropyl-4-methyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzamide (0.12g, 0.41 mmol), tetrakis(triphenylphosphine)palladium (24mg, 0.0205 mmol) and 2 M potassium carbonate (0.7 mL, 1.4 mmol) in 5 mL DME/EtOH (4:1) was stirred at 90° C. for 2 h. The mixture was directly purified via flash chromatography (silica gel) with a gradient of 2% 2 M ammonia in MeOH/DCM to 10% 2 M ammonia in MeOH/DCM to give the title compound (0.14g) as a yellow solid. Found MS (ES+): 388(M+H)+.
Reaction SMILES: [CH3:1][NH:2][C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2.[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([OH:38])=O.C1CN([P+](ON2N=NC3C=CC=CC2=3)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>CN(C=O)C>[O:21]=[C:22]1[N:26]2[CH2:27][C:28](=[O:34])[NH:29][C:30]3[CH:31]=[CH:32][CH:33]=[C:24]([C:25]=32)[N:23]1[CH2:35][C:36]([N:2]([CH3:1])[C:3]1[CH:4]=[C:5]2[C:18](=[CH:19][CH:20]=1)[CH2:17][C:7]1([C:15]3[C:10](=[N:11][CH:12]=[CH:13][CH:14]=3)[NH:9][C:8]1=[O:16])[CH2:6]2)=[O:38]
Reactant: CNc1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21
Reactant: O=C(O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2
Agent: F[P-](F)(F)(F)(F)F
Agent: c1ccc2c(c1)nnn2O[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CN(C(=O)Cn1c(=O)n2c3c(cccc31)NC(=O)C2)c1ccc2c(c1)CC1(C2)C(=O)Nc2ncccc21

Procedure:
A mixture of 5-(methylamino)-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one, enantiomer B (14 mg, 0.053 mmol, described in Intermediate 19), (2,5-dioxo-5,6-dihydro-4H-imidazo[1,5,4-de]quinoxalin-1(2H)-yl)acetic acid (14 mg, 0.058 mmol, described in Intermediate 9), PyBOP (41 mg, 0.079 mmol), and N,N-diisopropylethylamine (0.028 mL, 0.158 mmol) was stirred in DMF (1 mL) at 50° C. for 20 h. The reaction mixture was purified directly by HPLC using a reversed phase C18 column and eluting with a gradient of H2O:CH3CN:CF3CO2H—90:10:0.1 to 5:95:0.1. The pure, product-containing fractions were combined and lyophilized to give the title compound. MS: m/z=495 (M+1). HRMS: m/z=495.1778; calculated m/z=495.1776 for C27H23N5O4.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH2:5][OH:6].C[N+]1([O-])CCOCC1>C(Cl)Cl.[Ru]([O-])(=O)(=O)=O.C([N+](CCC)(CCC)CCC)CC>[CH3:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[N+:10]([O-:12])=[O:11])[CH:5]=[O:6]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: O=[Ru](=O)(=O)[O-]
Agent: CCC[N+](CCC)(CCC)CCC
Agent: C[N+]1([O-])CCOCC1
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 25 °C
Yield: 74 %

Procedure:
To a solution of 3-methyl-4-nitrobenzyl alcohol (3.0 g, 18 mmol), N-methylmorpholine-N-oxide (3.2 g, 27 mmol), and powdered 4A molecular sieves (8.98 g) in methylene chloride (40 mL) was added in one portion tetrapropylammonium perruthenate (0.315 g, 0.898 mmol), and the reaction stirred at room temperature. The reaction was filtered through silica gel, eluting with methylene chloride, solvent evaporated and the residue purified by flash chromatography to provide 2.2 g of the title compound. Examp~le 219B 5 9-(3-methyl-4-nitrophenyl)-2,3,5.6,7,9-hexahydrothieno[3.2-b]quinolin-8(4H)-one 1,1-dioxide 3-Methyl-4-nitrobenzaldehyde (0.99 g, 6.0 mmol) was processed according to the method of Example 11 5C to provide the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([Cl:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:20](=[O:40])[CH2:21][C:22](=O)[C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]2[CH:34]=[CH:33][N:32]=C(C(F)(F)F)[CH:30]=2)[CH:24]=1)(C)(C)C.[C:42](O)([C:44]([F:47])([F:46])[F:45])=O>C(Cl)Cl>[Cl:14][C:12]1[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]2[NH:19][C:20](=[O:40])[CH2:21][C:22]([C:23]3[CH:28]=[CH:27][CH:26]=[C:25]([C:29]4[CH:34]=[CH:33][N:32]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:30]=4)[CH:24]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)c(C(F)(F)F)cc1NC(=O)CC(=O)c1cccc(-c2ccnc(C(F)(F)F)c2)c1
Reactant: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C1CC(c2cccc(-c3ccnc(C(F)(F)F)c3)c2)=Nc2cc(Cl)c(C(F)(F)F)cc2N1

Procedure:
The title compound was prepared from (5-chloro-2-{3-oxo-3-[3-(2-trifluoromethyl-pyridin-4-yl)-phenyl]-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M246) (0.24 g, 0.40 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light brown solid (150 mg, 78%).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[CH:11].[CH2:13]([O:15][C:16](=[O:20])/[CH:17]=[CH:18]\I)[CH3:14]>>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[C:10]#[C:11][CH:18]=[CH:17][C:16]([O:15][CH2:13][CH3:14])=[O:20]
Reactant: C#Cc1ccccc1C(=O)OC
Reactant: CCOC(=O)/C=C\I
Product: CCOC(=O)C=CC#Cc1ccccc1C(=O)OC

Procedure:
The general procedure was used to convert 2-Ethynyl-benzoic acid methyl ester and (Z)-ethyl-3-iodoacrylate to the title product. Purification by flash chromatography (20% ethyl acetate in hexane as the eluent) gave the analytically pure product as a light yellow oil (410 mg, 77% yield). 1H NMR (400 MHz, CDCl3) δ 7.96-7.95 (d, J=7.8, 1H), 7.70-7.68 (d, J=8.2, 1H), 7.50-7.46 (t, J=7.5, 1H), 7.37-7.41 (t, J=7.7, 1H), 6.46-6.43 (d, J=11.4, 1H), 6.18-6.15 (d, J=11.4, 1H), 4.27-4.21 (q, J=7.1, 2H), 3.92 (s, 3H), 1.31-1.27 (t, J=7.1, 3H). 13C NMR (100 MHz, CDCl3) δ 166.31, 164.65, 134.69, 131.79, 131.74, 130.42, 128.73, 128.70, 123.23, 122.91, 99.64, 90.93, 60.40, 52.23, 14.27. Anal. Calcd. for C15H14O4: C, 69.76; H, 5.46; Found C, 69.93; H, 5.59.
Reaction SMILES: [H-].[Na+].[C:3](=[O:10])([O:7][CH2:8][CH3:9])OCC.[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH3:19])=[CH:14][CH:13]=1>C(OCC)C.C(OCC)C.CCO>[Br:11][C:12]1[CH:17]=[CH:16][C:15]([C:18](=[O:20])[CH2:19][C:3]([O:7][CH2:8][CH3:9])=[O:10])=[CH:14][CH:13]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: CCOC(=O)OCC
Agent: [H-]
Agent: [Na+]
Solvent: CCO
Solvent: CCOCC
Product: CCOC(=O)CC(=O)c1ccc(Br)cc1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
Into a 1000 mL 4-necked round-bottom flask purged and maintained with an inert atmosphere of nitrogen, was placed a solution of sodium hydride (10.1 g, 420.83 mmol, 2.10 equiv) in diethyl ether (400 mL). To the resulting mixture was then added diethyl carbonate (35.6 g, 301.69 mmol, 1.50 equiv) in 10 min at 0° C., followed by addition of a solution of 1-(4-bromophenyl)ethanone (40 g, 202.02 mmol, 1.00 equiv) in diethyl ether/EtOH (100 mL/1 mL) dropwise with stirring at 0° C. in 20 min. The resulting solution was heated to reflux for 3 hr. The reaction was then quenched by the addition of water/ice. The pH value of the solution was adjusted to about 5-6 with HCl (1 mol/L). The resulting solution was extracted with diethyl ether (3×200 mL), the organic layers combined and dried over anhydrous magnesium sulfate, then concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate/petroleum ether (1:100) to yield ethyl 3-(4-bromophenyl)-3-oxopropanoate as yellow oil.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][CH2:8][CH2:9][N:10]1[C:18]2[C:17](Cl)=[N:16][CH:15]=[N:14][C:13]=2[CH:12]=[CH:11]1)([CH3:4])([CH3:3])[CH3:2].[Cl:21][C:22]1[CH:23]=[C:24]([CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:40])([F:39])[F:38])[CH:31]=1)[NH2:25].C(=O)([O-])O.[Na+]>C(O)(C)C>[Cl:21][C:22]1[CH:23]=[C:24]([NH:25][C:17]2[C:18]3[N:10]([CH2:9][CH2:8][NH:7][C:6](=[O:20])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:11]=[CH:12][C:13]=3[N:14]=[CH:15][N:16]=2)[CH:26]=[CH:27][C:28]=1[O:29][C:30]1[CH:35]=[CH:34][CH:33]=[C:32]([O:36][C:37]([F:39])([F:40])[F:38])[CH:31]=1
Reactant: Nc1ccc(Oc2cccc(OC(F)(F)F)c2)c(Cl)c1
Reactant: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Cl)c21
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CC(C)(C)OC(=O)NCCn1ccc2ncnc(Nc3ccc(Oc4cccc(OC(F)(F)F)c4)c(Cl)c3)c21
Yield: 91 %

Procedure:
A solution of tert-butyl[2-(4-chloro-5H-pyrrolo[3,2-d]pyrimidin-5-yl)ethyl]carbamate (100 mg), 3-chloro-4-[3-(trifluoromethoxy)phenoxy]aniline (153 mg) in isopropyl alcohol (1.5 mL) was stirred at 80° C. for 12 hrs. Aqueous sodium hydrogen carbonate was added to the reaction system and the mixture was extracted with ethyl acetate. The organic layer washed with saturated brine and dried over magnesium sulfate. After concentration under reduced pressure, the residue was separated and purified by silica gel column chromatography (eluent, hexane:ethyl acetate=1:1→ethyl acetate) to give the title compound (173 mg) as colorless crystals.
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[C:31](O)(=[O:33])[CH3:32]>C1COCC1.C(Cl)Cl>[F:9][C:7]1[CH:8]=[C:3]([CH2:2][NH:1][C:31](=[O:33])[CH3:32])[C:4]([NH:20][C@H:21]([C:24]2[CH:29]=[CH:28][C:27]([F:30])=[CH:26][CH:25]=2)[CH2:22][OH:23])=[N:5][C:6]=1[NH:10][C:11]1[CH:15]=[C:14]([O:16][CH:17]([CH3:19])[CH3:18])[NH:13][N:12]=1
Reactant: CC(=O)O
Reactant: CC(C)Oc1cc(Nc2nc(N[C@@H](CO)c3ccc(F)cc3)c(CN)cc2F)n[nH]1
Solvent: ClCCl
Solvent: C1CCOC1
Product: CC(=O)NCc1cc(F)c(Nc2cc(OC(C)C)[nH]n2)nc1N[C@@H](CO)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.75 h
Yield: 39 %

Procedure:
(R)-2-(3-(Aminomethyl)-5-fluoro-6-(5-isopropoxy-1H-pyrazol-3-ylamino)pyridin-2-ylamino)-2-(4-fluorophenyl)ethanol (Example 13; 0.175 g, 0.42 mmol) and acetic acid loaded TFP resin (1.4 mmol/g loading, 0.42 mmol) were placed in a THF-DCM solution (1:1, 5 ml) at 0° C. The resulting solution was shaken vigorously at 0° C. for 45 min and filtered. The resulting resin was washed with a THF-DCM solution (1:1, 3×5 ml for 30 min. each). The resulting organic layers were combined and concentrated. The resulting solid was purified by reverse-phase column chromatography (5-50% CH3CN in H2O over 400 ml) to give the title compound (0.075 g, 39%). 1H NMR (400 MHz, CD3OD) δ 7.42-7.39 (m, 2H), 7.17 (d, J=10.7 Hz, 1H), 7.05-7.01 (m, 2H), 5.26 (s, 1H), 5.02-4.95 (m, 1H), 4.55-4.53 (m, 1H), 4.36 (d, J=15.0 Hz, 1H), 4.22 (d, J=15.0 Hz, 1H), 3.84-3.72 (m, 2H), 2.01 (s, 3H), 1.31 (d, J=6.0 Hz, 6H). MS: Calcd.: 460. Found: [M+H]+ 461.
Reaction SMILES: [S-:1][C:2]#[N:3].[K+].[Br:5][C:6]1[N:11]=[CH:10][C:9]([NH2:12])=[CH:8][CH:7]=1.BrBr>C(O)(=O)C>[Br:5][C:6]1[N:11]=[C:10]2[S:1][C:2]([NH2:3])=[N:12][C:9]2=[CH:8][CH:7]=1
Reactant: Nc1ccc(Br)nc1
Reactant: N#C[S-]
Agent: BrBr
Agent: [K+]
Solvent: CC(=O)O
Product: Nc1nc2ccc(Br)nc2s1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 77.9 %

Procedure:
To a suspension of potassium thiocyanate (33.8 g, 348 mmol) in acetic acid (150 mL) was added 6-bromopyridin-3-amine (15.2 g, 88.1 mmol), and the mixture was stirred at room temperature for 15 min. A solution of bromine (18.4 g, 115 mmol) in acetic acid (200 mL) was added dropwise to the obtained solution at room temperature for 30 min or more. After the completion of the dropwise addition, the mixture was stirred at room temperature for 6 hr. The yielded yellow solid was filtered off, and the filtrate was concentrated under reduced pressure. The residue was suspended in tetrahydrofuran (200 mL) and ethyl acetate (200 mL), the suspension was washed with saturated aqueous sodium hydrogen carbonate solution (300 mL×2) and saturated brine (200 mL), dried over anhydrous magnesium sulfate, and decolorized with activated carbon. The insoluble material was filtered off, and the filtrate was concentrated under reduced pressure. The obtained crude product was recrystallized from tetrahydrofuran and diisopropyl ether to give the title compound (15.8 g, 78%) as a pale-brown solid.
Reaction SMILES: [CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=O)([CH3:3])[CH3:2].[C:17]([NH:20][C:21]1[CH:29]=[C:28]2[C:24]([CH2:25][C:26](=[O:30])[NH:27]2)=[CH:23][CH:22]=1)(=[O:19])[CH3:18]>>[CH:1]([C:4]1[CH:5]=[C:6]([CH:9]=[C:10]([CH:14]([CH3:16])[CH3:15])[C:11]=1[O:12][CH3:13])[CH:7]=[C:25]1[C:24]2[C:28](=[CH:29][C:21]([NH:20][C:17](=[O:19])[CH3:18])=[CH:22][CH:23]=2)[NH:27][C:26]1=[O:30])([CH3:3])[CH3:2]
Reactant: CC(=O)Nc1ccc2c(c1)NC(=O)C2
Reactant: COc1c(C(C)C)cc(C=O)cc1C(C)C
Product: COc1c(C(C)C)cc(C=C2C(=O)Nc3cc(NC(C)=O)ccc32)cc1C(C)C

Procedure:
3,5-Diisopropyl-4-methoxybenzaldehyde was condensed with 6-acetamido-2-oxindole to give 0.3 g of N-[3-(3,5-diisopropyl-4-methoxybenzylidene)-2-oxo-2,3-dihydro-1H-indol-6-yl]-acetamide as a yellow-orange solid.
Reaction SMILES: Br[CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2.[NH2:29][CH2:30][C:31]([CH3:34])([OH:33])[CH3:32]>>[CH3:32][C:31]([OH:33])([CH3:34])[CH2:30][NH:29][CH2:2][C:3]1[N:4]([CH3:28])[C:5]2[C:10]([N:11]=1)=[C:9]([N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[N:8]=[C:7]([N:18]1[C:22]3[CH:23]=[CH:24][CH:25]=[CH:26][C:21]=3[N:20]=[C:19]1[CH3:27])[N:6]=2
Reactant: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CBr)n(C)c2n1
Reactant: CC(C)(O)CN
Product: Cc1nc2ccccc2n1-c1nc(N2CCOCC2)c2nc(CNCC(C)(C)O)n(C)c2n1

Procedure:
4-(8-(Bromomethyl)-9-methyl-2-(2-methyl-1H-benzo[d]imidazol-1-yl)-9H-purin-6-yl)morpholine (50 mg) was reacted with 1-amino-2-methylpropan-2-ol via General Procedure E to give 8.1 mg of 292 following reverse phase purification. MS (Q1) 451.2 (M)+