Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1.[S:12](Cl)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]>C(N(CC)CC)C>[S:12]([N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH:10]=[O:11])=[CH:2]1)([C:15]1[CH:21]=[CH:20][C:18]([CH3:19])=[CH:17][CH:16]=1)(=[O:14])=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=Cc1c[nH]c2ccccc12
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)n2cc(C=O)c3ccccc32)cc1
Temperature: 95 °C
Yield: 85 %

Procedure:
To a 25 mL round bottom flask containing a solution of crude indole-3-carboxaldehyde (4.5 mmol) in 10 mL of triethylamine was added 1.3 g (6.7 mmol) of tosyl chloride. The reaction mixture was heated to 95° C. for 4 h. The reaction mixture was quenched by pouring into 10 mL of ice water and filtered. The solid was washed with water (3×10 mL), triterated with ether (25 mL), and dried in vacuo to give N-tosyl-indole-3-carboxaldehyde (85-90% yield).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[OH:9].[Br:10]Br.C(N)(C)(C)C>C1(C)C=CC=CC=1>[Br:10][C:4]1[CH:5]=[C:6]([Cl:8])[CH:7]=[C:2]([Cl:1])[C:3]=1[OH:9]
Reactant: BrBr
Reactant: Oc1ccc(Cl)cc1Cl
Solvent: Cc1ccccc1
Solvent: CC(C)(C)N
Product: Oc1c(Cl)cc(Cl)cc1Br
Temperature: -50 °C
Reaction time: 0.5 h
Yield: 467.3 %

Procedure:
To a solution of 2,4-dichloro-phenol (15 g, 19.02 mmol) in toluene (200 ml) was added bromine (5.1 ml, 184.04 mmol) dropwise at −50° C. Then tert.-butylamine (19.4 ml, 99.02 mmol) was added dropwise and the reaction mixture was stirred at −50° C. for 30 minutes. The reaction was quenched by addition of 38% aqueous NaHSO3 solution, the organic layer was separated and the aqueous layer was extracted two times with EtOAc. The combined organic extracts were dried with Na2SO4, filtered and evaporated to obtain the title compound as white solid (21.5 g, 96%).
Reaction SMILES: Cl.[NH2:2][NH:3][C:4]([NH2:6])=[O:5].C(N(CC)CC)C.[CH:14]1([C:19](Cl)=O)[CH2:18][CH2:17][CH2:16][CH2:15]1.[OH-].[Na+].Cl>C(Cl)Cl.O>[CH:14]1([C:19]2[NH:6][C:4](=[O:5])[NH:3][N:2]=2)[CH2:18][CH2:17][CH2:16][CH2:15]1
Reactant: O=C(Cl)C1CCCC1
Reactant: NNC(N)=O
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=c1[nH]nc(C2CCCC2)[nH]1
Temperature: -10 °C
Reaction time: 0.5 h
Yield: 38.8 %

Procedure:
To a suspension of semicarbazide hydrochloride (5.00 g, 44.8 mmol) in DCM (100 mL) was added triethylamine (10.00 g, 99 mmol) and the mixture was stirred at −10° C. for 30 min. Cyclopentane carbonylchloride (5.00 g, 37.7 mmol) was added at the same temp and the mixture was allowed to warm to RT over night. The solvent from the reaction mixture was completely removed and the residue stirred in MeCN (200 mL) for 1 h. The solids were collected by filtration, washed and dried. The solid was treated with sodium hydroxide (7.00 g, 175 mmol) and water (20 mL). The resulting reaction mixture was heated at 100° C. for 3 h. The reaction mixture was cooled and acidified with conc. HCl. The solids were collected, washed and dried to provide 3-cyclopentyl-1H-1,2,4-triazol-5(4H)-one (2.24 g, 38.8% yield) as white solid. 1H NMR (400 MHz, DMSO-d6): δ 11.17 (s, 1H), 11.03 (s, 1H), 2.80 (m, 1H), 1.86 (m, 2H), 1.58 (m, 6H); MS (ESI) m/z: 154.1 (M+H+).
Reaction SMILES: [NH2:1][C:2]1[C:7]([Br:8])=[CH:6][C:5]([Br:9])=[CH:4][C:3]=1[S:10]([NH2:13])(=[O:12])=[O:11].[CH3:14]COC=O>C(N(CC)CC)C>[Br:8][C:7]1[C:2]2[N:1]=[CH:14][NH:13][S:10](=[O:12])(=[O:11])[C:3]=2[CH:4]=[C:5]([Br:9])[CH:6]=1
Reactant: Nc1c(Br)cc(Br)cc1S(N)(=O)=O
Reactant: CCOC=O
Solvent: CCN(CC)CC
Product: O=S1(=O)NC=Nc2c(Br)cc(Br)cc21

Procedure:
2-Amino-3,5-dibromobenzenesulfonamide (see compound 125) was transformed by Method G (using ethylformiat and a catalytic amount of triethylamine). M.p. 289–292° C.
Reaction SMILES: [C:1]([OH:7])(=O)[CH2:2][CH2:3][C:4]#[CH:5].CN1CCOCC1.ClC(OCC(C)C)=O.[NH:23]([CH2:27][CH2:28][OH:29])[CH2:24][CH2:25][OH:26]>C(Cl)Cl.CN(C=O)C>[OH:26][CH2:25][CH2:24][N:23]([CH2:27][CH2:28][OH:29])[C:1](=[O:7])[CH2:2][CH2:3][C:4]#[CH:5]
Reactant: C#CCCC(=O)O
Reactant: OCCNCCO
Agent: CC(C)COC(=O)Cl
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CN1CCOCC1
Product: C#CCCC(=O)N(CCO)CCO
Temperature: -5 °C
Reaction time: 8 h

Procedure:
A mixture of 4-pentynoic acid (2.00 g; 20.4 mmol) and 4-methylmorpholine (2.24 ml; 20.4 mmol) in DCM (20 ml) is cooled to −5° C. Isobutyl chloroformate (2.68 ml; 20.4 mmol) is added, followed by DMF (10 ml). The resulting mixture is added in portions to a solution of diethanolamine (2.25 g; 21.4 mmol) in DCM (10 ml). The resulting mixture is stirred overnight and evaporated. The residue is purified by silica gel column chromatography (gradient: DCM/methanol 100:0→82:18 to yield N,N-bis(2-hydroxyethyl)pent-4-ynamide.
Reaction SMILES: [NH2:1][C@H](C(O)=O)CCCC.ON1C2C=CC=CC=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.Cl.Cl.N[C@@H:38]([CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1)[C@@H:39]([OH:49])[CH:40]([OH:48])[CH2:41][N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1>CN(C=O)C.C(N(CC)CC)C>[NH2:1][CH:41]([N:42]1[CH2:47][CH2:46][O:45][CH2:44][CH2:43]1)[CH:40]([OH:48])[CH:39]([OH:49])[CH2:38][CH2:50][CH:51]1[CH2:56][CH2:55][CH2:54][CH2:53][CH2:52]1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)C(O)CN1CCOCC1
Reactant: CCCC[C@H](N)C(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: NC(C(O)C(O)CCC1CCCCC1)N1CCOCC1
Temperature: 0 °C

Procedure:
50 mg of L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucine was dissolved in 0.2 ml of dry DMF, and 28.2 mg of 1-hydroxybenzotriazole and 33.2 mg of DCC were added thereto at 0° C. under stirring. Then, 55.2 mg of (2RS,3R,4S)-4-amino-5-cyclohexyl-1-morpholino-2,3-pentanediol dihydrochloride was dissolved in 0.2 ml of dry DMF, and 31.1 mg of triethylamine was added thereto for neutralization. This mixture was added to the previous reaction solution, and the mixture was stirred at 0° C. for two hours and at room temperature overnight. The precipitated dicyclohexyl urea was removed by filtration, and the filtrate was diluted with 10 ml of ethyl acetate. The ethyl acetate layer was washed sequentially with a 4% sodium hydrogencarbonate aqueous solution, with water and with a saturated sodium chloride aqueous solution and dried over anhydrous sodium sulfate. Then, the solvent was distilled off. The residue was purified by silica gel column chromatography (chloroform/methanol= 20/1) to obtain 20.1 mg of (2S,3R,4S)-4-{L-N-[(2S or R)-3-(2-hydroxyethyl)sulfonyl-2-(1-naphthylmethyl)propionyl]norleucyl}amino-5-cyclohexyl-1-morpholino-2,3-pentanediol as colorless
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21]Cl)=[CH:17][CH:16]=1.[CH3:24][N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[C:5]2[CH2:11][CH2:12][NH:13][C:14](=[O:23])[C:15]1[CH:20]=[CH:19][C:18]([CH2:21][N:28]2[CH2:29][CH2:30][N:25]([CH3:24])[CH2:26][CH2:27]2)=[CH:17][CH:16]=1
Reactant: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1ccc(CCl)cc1
Reactant: CN1CCNCC1
Solvent: C1CCOC1
Product: CN1CCN(Cc2ccc(C(=O)NCCc3c[nH]c4ccc(Cl)cc34)cc2)CC1
Temperature: 80 °C
Yield: 44.5 %

Procedure:
N-(2-(5-Chloro-1H-indol-3-yl)ethyl)-4-((4-methylpiperazin-1-yl)methyl)benzamide was prepared following Method C starting from N-(2-(5-chloro-1H-indol-3-yl)ethyl)-4-(chloromethyl)benzamide (0.053 g; 0.153 mmol) and N-methylpiperazine (0.0684 mL; 0.610 mmol) in THF (3 mL). The mixture was heated at 80° C. for 5 hours. Flash chromatography on silica gel (eluent 1 to 15% methanol in dichloromethane) furnished 0.028 g (44%) of the title compound as a white solid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12](Cl)=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:20]([NH:22][CH2:23][CH3:24])[CH3:21]>C(Cl)Cl>[CH2:1]([O:8][C:9]1[CH:10]=[C:11]([CH:15]=[CH:16][C:17]=1[O:18][CH3:19])[C:12]([N:22]([CH2:23][CH3:24])[CH2:20][CH3:21])=[O:13])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(C(=O)Cl)cc1OCc1ccccc1
Reactant: CCNCC
Solvent: ClCCl
Product: CCN(CC)C(=O)c1ccc(OC)c(OCc2ccccc2)c1
Yield: 94.6 %

Procedure:
A solution of 3-benzyloxy-4-methoxy-benzoyl chloride (35.01 g, 0.127 mole), prepared as described in example 54, in CH2Cl2 (200 ml) was dropwise added at 5-10° C. with diethylamine (131 ml, 92.54 g, 1.27 mole) in CH2Cl2 (130 ml). The mixture was evaporated to dryness, dissolved in ethyl acetate, washed with water, 2% KHSO4, water again and NaHCO3, anhydrified over Na2SO4 and brought to dryness. The residue was taken up in petrolatum (250 ml) to give 37.65 g of the title compound (yield: 95%)
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[C:14]#N.[H][H].[OH-:18].[Na+]>[Ni].O.C(O)(=O)C>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[N:5]=[CH:4][C:3]=1[CH:14]=[O:18]
Reactant: [OH-]
Reactant: [H][H]
Reactant: N#Cc1cnn(-c2ccc(F)cc2)c1N
Agent: [Ni]
Agent: [Na+]
Solvent: CC(=O)O
Solvent: O
Product: Nc1c(C=O)cnn1-c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
5-Amino-1-(4-fluorophenyl)-1H-pyrazole-4-carbonitrile (110, R1=4-Fluorophenyl) (56.2 g, 278 mmol), acetic acid (270 mL), water (75 mL) and Raney 2400 Nickel slurry in water (15 g, 278 mmol) was shaken under about 30 psi hydrogen at about 20°-25° C. for about 8 h. The mixture was filtered through a pad of Celite®. The contents of the reaction vessel were transferred with acetic acid (150 mL) and the pad was washed with an additional portion of acetic acid (200 mL). The filtrate was concentrated under reduced pressure to give a slurry. Water (300 mL) was added then the mixture was stirred for about 15 min. The mixture was cooled in an ice/water bath then basified with 5 N aq. NaOH. After stirring for about 20 min in the ice/water bath the solids were collected by filtration and washed with water (100 mL).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:18]3[CH:23]=[CH:22][C:21]([OH:24])=[CH:20][CH:19]=3)[C:9]3[C:14]([C:15]=2[C:16]#[N:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1.Cl.[NH2:27][OH:28].C(N(CC)CC)C>CCO.CO>[CH3:1][C:2]1[C:6]([C:7]2[N:8]([C:18]3[CH:19]=[CH:20][C:21]([OH:24])=[CH:22][CH:23]=3)[C:9]3[C:14]([C:15]=2/[C:16](=[N:27]/[OH:28])/[NH2:17])=[CH:13][CH:12]=[CH:11][CH:10]=3)=[C:5]([CH3:25])[O:4][N:3]=1
Reactant: Cc1noc(C)c1-c1c(C#N)c2ccccc2n1-c1ccc(O)cc1
Reactant: NO
Agent: Cl
Solvent: CCO
Solvent: CO
Solvent: CCN(CC)CC
Product: Cc1noc(C)c1-c1c(/C(N)=N/O)c2ccccc2n1-c1ccc(O)cc1
Temperature: 25 °C

Procedure:
Under nitrogen atmosphere, a solution of 2-(3,5-dimethyl-isoxazol-4-yl)-1-(4-hydroxy-phenyl)-1H-indole-3-carbonitrile (Example 51), 12 eq hydroxylamine hydrochloride and 12 eq triethylamine in EtOH was heated at 100° C. for 24 hours. The reaction mixture was cooled to rt, diluted with methanol, precipitation filtered off and subjected to reversed phase preparative HPLC. Appropriate fractions were combined and evaporated, and identified by 1H-NMR and LC/MS. Purity was determined by analytical HPLC. ES/MS m/z: 363.5 (M+H), 361.6 (M−H); 1H NMR (acetone-d6, 500 MHz): 8.14-8.13 (s, OH), 8.08-8.04 (m, 1H), 7.23-7.14 (m, 3H), 7.15-7.06 (m, 2H), 6.96-6.91 (m, 2H), 5.18-5.07 (m, 2H), 2.16 (s, 3H), 2.00 (s, 3H).
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[C:7]([C:14]([F:17])([F:16])[F:15])=[CH:8][C:9]([NH2:13])=[C:10]([NH2:12])[CH:11]=1.O=[C:19]([C:25](OCC)=[O:26])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>C(O)C>[NH:1]1[CH:5]=[CH:4][N:3]=[C:2]1[C:6]1[CH:11]=[C:10]2[C:9]([NH:13][C:25](=[O:26])[C:19]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[N:12]2)=[CH:8][C:7]=1[C:14]([F:15])([F:16])[F:17]
Reactant: CCOC(=O)C(=O)C(=O)OCC
Reactant: Nc1cc(-c2ncc[nH]2)c(C(F)(F)F)cc1N
Solvent: CCO
Product: CCOC(=O)c1nc2cc(-c3ncc[nH]3)c(C(F)(F)F)cc2[nH]c1=O
Yield: 33.6 %

Procedure:
To a solution of 5-imidazolyl-4-trifluoromethyl-1,2-phenylenediamine (303 mg, 1.25 mmol) in ethanol (50 ml) was added diethyl ketomalonate (210 μl, 1.38 mmol) at room temperature, and the mixture was refluxed for 6 hours. The reaction mixture. was concentrated to around half volume under reduced pressure, then the precipitate was collected by filtration and washed with cold ethanol. The filtrate was distilled off under reduced pressure, small quantity of mixed solution of ethyl acetate-diisopropyl ether was added to the residue obtained and the precipitate was collected by filtration to obtain 148 mg of the title compound as pale yellowish brown powder. Yield 34%.
Reaction SMILES: [C:1]1([C:11]([CH3:13])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1.C(Cl)(Cl)Cl.[BrH:18]>[Cu](Br)Br.C(OCC)(=O)C>[C:1]1([C:11]([CH2:13][Br:18])=[O:12])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][CH:2]=1
Reactant: Br
Reactant: CC(=O)c1cccc2ccccc12
Agent: Br[Cu]Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: O=C(CBr)c1cccc2ccccc12

Procedure:
Methyl 1-naphthyl ketone (10.1 g.), in 50 ml of a 1:1 mixture of chloroform and ethyl acetate is treated with 26.5 g. of copper (II) bromide. The resulting reaction mixture is heated under reflux with vigorous stirring until the evolution of hydrogen bromide ceases. When the reaction is complete the solvent is removed, ether is added and the copper (I) bromide is removed by filtration. Evaporation of the filtrate under reduced pressure yields crude bromomethyl 1-naphthyl ketone.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[NH:14][C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2].C([O-])([O-])=O.[K+].[K+].Br[CH2:32][C:33]([NH:35][C:36]1[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=1[O:45][CH3:46])=[O:34].CN(C=O)C>O>[CH2:1]([O:3][C:4](=[O:24])[CH2:5][C:6]1[CH:11]=[CH:10][C:9]([N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[N:14]([CH2:32][C:33](=[O:34])[NH:35][C:36]3[CH:41]=[C:40]([Cl:42])[C:39]([O:43][CH3:44])=[CH:38][C:37]=3[O:45][CH3:46])[C:13]2=[O:23])=[CH:8][CH:7]=1)[CH3:2]
Reactant: CCOC(=O)Cc1ccc(-n2c(=O)[nH]c3ccccc3c2=O)cc1
Reactant: COc1cc(OC)c(NC(=O)CBr)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1ccc(-n2c(=O)c3ccccc3n(CC(=O)Nc3cc(Cl)c(OC)cc3OC)c2=O)cc1
Temperature: 25 °C
Reaction time: 72 h

Procedure:
A round bottomed flask charged with [4-(2,4-dioxo-1,4-dihydro-2H-quinazolin-3-yl)-phenyl]-acetic acid ethyl ester (Intermediate H) (2.0 g, 6.17 mmol), K2CO3 (2.5 eq, 2.14 g, 15.52 mmol), and 2-bromo-N-(5-chloro-2,4-dimethoxy-phenyl)-acetamide (Intermediate C) (1.02 eq, 1.99 g, 6.49 mmol) is treated with dry DMF (20 ml). The reaction is stirred at RT for 72 hours. The reaction mixture is diluted with distilled water and stirred for 15 minutes. The precipitate formed was filtered, washed with water and dried under vacuum to give the title compound; [M+H]+ 552
Reaction SMILES: [NH2:1][C:2]1[N:6]([CH3:7])[NH:5][C:4](=[O:8])[CH:3]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][C:17]=1[F:18])[CH:13]=O.[CH3:19][C:20]1([CH3:28])[CH2:25][CH2:24][C:23](=O)[CH2:22][C:21]1=[O:27]>C(O)C>[Br:9][C:10]1[CH:11]=[C:12]([CH:13]2[C:22]3[C:21](=[O:27])[C:20]([CH3:28])([CH3:19])[CH2:25][CH2:24][C:23]=3[NH:1][C:2]3[N:6]([CH3:7])[NH:5][C:4](=[O:8])[C:3]2=3)[CH:15]=[CH:16][C:17]=1[F:18]
Reactant: O=Cc1ccc(F)c(Br)c1
Reactant: Cn1[nH]c(=O)cc1N
Reactant: CC1(C)CCC(=O)CC1=O
Solvent: CCO
Product: Cn1[nH]c(=O)c2c1NC1=C(C(=O)C(C)(C)CC1)C2c1ccc(F)c(Br)c1
Yield: 65.4 %

Procedure:
5-Amino-1-methyl-1,2-dihydropyrazol-3-one (0.23 g, 2 mmol), 3-bromo-4-fluorobenzaldehyde (0.4 g, 2 mmol), and 4,4-dimethyl-1,3-cyclohexanedione (0.28 g, 2 mmol) in ethyl alcohol (3 mL) were heated at 80° C. in a sealed tube for 2 days. The reaction mixture was cooled and the resulting precipitate was filtered off and washed with ethyl acetate to provide 0.55 g of the title compound as a tan solid. 1H NMR (300 MHz, DMSO-d6) δ 0.92 (s, 3H), 0.98 (s, 3H), 1.78 (t, 2H), 2.63 (m, 2H), 3.43 (s, 3H), 4.83 (s, 1H), 7.11 (m, 1H), 7.17 (t, 1H), 7.33 (dd, 1H), 9.53 (s, 1H), 9.66 (s, 1H); MS (ESI−) m/z 420 (M−H)−; Anal. calcd for C19H19N3BrFO2: C, 54.30; H, 4.56; N, 10.00. Found: C, 54.29; H, 4.61; N, 9.97.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][CH:4]([C:6]1[CH:11]=[CH:10][C:9]([O:12][CH3:13])=[C:8]([O:14][CH3:15])[CH:7]=1)[OH:5].C(N(CC)CC)C.Cl[C:24]([O:26][CH3:27])=[O:25]>O1CCCC1>[CH3:15][O:14][C:8]1[CH:7]=[C:6]([CH:4]([OH:5])[CH2:3][CH2:2][NH:1][C:24]([O:26][CH3:27])=[O:25])[CH:11]=[CH:10][C:9]=1[O:12][CH3:13]
Reactant: COC(=O)Cl
Reactant: COc1ccc(C(O)CCN)cc1OC
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)NCCC(O)c1ccc(OC)c(OC)c1
Temperature: 25 °C
Reaction time: 5.5 h

Procedure:
3-amino-1-(3,4-dimethoxyphenyl)-1-propanol (1.27 g, 6.02 mM), triethylamine (0.84 g, 8.30 mM), and methyl chloroformate (0.59 g, 6.25 mM) were dissolved in dried tetrahydrofuran (80 ml) and stirred at room temperature for 5.5 hours. The solution obtained was poured into ice water and extracted with methylene chloride. The organic layer was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product of 1-(3,4-dimethoxyphenyl)-3-(methoxycarbonylamino)-1-propanol as a yellow oil. Next, the crude product was dissolved in dried benzene (5 ml). The mixture was dropped into a solution of sodium hydride (60%) (0.24 g, 6.04 mM) in dried benzene (40 ml) at room temperature, water was added into the reaction solution and the mixture stirred at that temperature for 24 hours, which was then extracted with methylene chloride. The extract was dried over anhydrous sodium sulfate, then the solvent was removed in vacuo to obtain a crude product as a brown solid. The crude product was washed with ether to obtain the above-described compound 0.86 g (yield 63.1%) as a light brown solid.
Reaction SMILES: N1C=CC=C[C:2]=1C(O)=O.[NH2:10][C:11]1[C:16]([C:17]2[CH:22]=[CH:21][C:20]([OH:23])=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][N:12]=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+].Br[C:33]1[CH:38]=[CH:37][CH:36]=[C:35]([C:39]([F:42])([F:41])[CH3:40])[CH:34]=1>[Cu]I.CS(C)=O>[F:41][C:39]([C:35]1[CH:34]=[C:33]([CH:38]=[CH:37][CH:36]=1)[O:23][C:20]1[CH:21]=[CH:22][C:17]([C:16]2[C:11]([NH2:10])=[N:12][CH:13]=[C:14]([CH3:2])[CH:15]=2)=[CH:18][CH:19]=1)([F:42])[CH3:40]
Reactant: O=C(O)c1ccccn1
Reactant: CC(F)(F)c1cccc(Br)c1
Reactant: Nc1ncccc1-c1ccc(O)cc1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: Cc1cnc(N)c(-c2ccc(Oc3cccc(C(C)(F)F)c3)cc2)c1
Temperature: 130 °C
Reaction time: 10 h
Yield: 235 %

Procedure:
Copper(I) iodide (39.2 mg) was added to a mixture of picolinic acid (25.4 mg), 4-(2-aminopyridin-3-yl)phenol (206 mg), tripotassium phosphate (656 mg), 1-bromo-3-(1,1-difluoroethyl)benzene (239 mg) and DMSO (3 ml). The mixture was stirred at 130° C. under nitrogen for 10 hr. The insoluble solid was removed by filtration through silica gel/Celite pad (eluted with EtOAc). Silica-gel was added to the filtrate and the volatiles were removed in vacuo. The mixture supported on silica-gel was purified by column chromatography (NH-silica gel, eluted with EtOAc in hexane) to give the title compound (165 mg) as a yellow amorphous solid.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:8]=[CH:9][C:10]=1[O:11][CH3:12])[C:5]([OH:7])=O.[C:13](Cl)(=[O:16])[CH2:14][CH3:15].[N+:18]([C:21]1[CH:27]=[CH:26][C:24]([NH2:25])=[CH:23][CH:22]=1)([O-:20])=[O:19]>>[N+:18]([C:21]1[CH:27]=[CH:26][C:24]([NH:25][C:5](=[O:7])[C:4]2[CH:8]=[CH:9][C:10]([O:11][CH3:12])=[C:2]([NH:1][C:13](=[O:16])[CH2:14][CH3:15])[CH:3]=2)=[CH:23][CH:22]=1)([O-:20])=[O:19]
Reactant: Nc1ccc([N+](=O)[O-])cc1
Reactant: COc1ccc(C(=O)O)cc1N
Reactant: CCC(=O)Cl
Product: CCC(=O)Nc1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)ccc1OC

Procedure:
Compound 2612 is synthesized following a similar method as in Example 1 and using 3-amino-4-methoxybenzoic acid, propionyl chloride and 4-nitroaniline as materials. Total yield of the two steps: 53%.
Reaction SMILES: [NH2:1][C@H:2]([C:4]1[N:9]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[C:8](=[O:16])[C:7]2=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]2[N:5]=1)[CH3:3].[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26](Br)[N:25]=[CH:24][N:23]=1.CCN(C(C)C)C(C)C.[F-].[Cs+]>C(O)(C)(C)C.C(OCC)(=O)C>[NH2:21][C:22]1[C:27]([C:28]([NH:30][C:31]2[CH:36]=[C:35]([OH:37])[CH:34]=[C:33]([F:38])[CH:32]=2)=[O:29])=[C:26]([NH:1][C@H:2]([C:4]2[N:9]([C:10]3[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=3)[C:8](=[O:16])[C:7]3=[C:17]([CH3:20])[CH:18]=[CH:19][N:6]3[N:5]=2)[CH3:3])[N:25]=[CH:24][N:23]=1
Reactant: Cc1ccn2nc([C@H](C)N)n(-c3ccccc3)c(=O)c12
Reactant: Nc1ncnc(Br)c1C(=O)Nc1cc(O)cc(F)c1
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccn2nc([C@H](C)Nc3ncnc(N)c3C(=O)Nc3cc(O)cc(F)c3)n(-c3ccccc3)c(=O)c12
Temperature: 120 °C
Reaction time: 8 h
Yield: 8 %

Procedure:
(S)-2-(1-Aminoethyl)-5-methyl-3-phenylpyrrolo[2,1-f][1,2,4]triazin-4(3H)-one (100 mg, 0.37 mmol), 4-amino-6-bromo-N-(3-fluoro-5-hydroxyphenyl)pyrimidine-5-carboxamide (183 mg, 0.56 mmol), DIEA (325 μl, 1.87 mmol) and cesium fluoride (113 mg, 0.74 mmol) were suspended in tert-butanol (5 ml) and the mixture was stirred overnight at 120° C. in a sealed tube. The reaction mixture was diluted with ethyl acetate and washed with water and brine. After evaporation of the solvent, the residue was purified by reverse phase using SP1® Purification System to give 15 mg (8% yield) as a solid. Purity 97%.
Reaction SMILES: [Si]([O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]1[CH:18]=[CH:17][C:16](F)=[C:15]([Cl:20])[C:14]=1F)(C(C)(C)C)(C)C.[OH:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29].C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[Cl:20][C:15]1[C:14]2[O:8][CH2:9][CH2:10][N:11]([CH3:23])[C:12](=[O:22])[C:13]=2[CH:18]=[CH:17][C:16]=1[O:24][C:25]1[CH:26]=[C:27]([CH:37]=[C:38]([O:40][CH:41]([CH3:43])[CH3:42])[CH:39]=1)[C:28]([NH:30][C:31]1[CH:35]=[CH:34][N:33]([CH3:36])[N:32]=1)=[O:29]
Reactant: CC(C)Oc1cc(O)cc(C(=O)Nc2ccn(C)n2)c1
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1ccc(F)c(Cl)c1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)N(C)C
Product: CC(C)Oc1cc(Oc2ccc3c(c2Cl)OCCN(C)C3=O)cc(C(=O)Nc2ccn(C)n2)c1
Temperature: 135 °C
Yield: 33.3 %

Procedure:
N-(2-{[tert-Butyl(dimethyl)silyl]oxy}ethyl)-3-chloro-2,4-difluoro-N-methylbenzamide (705 mg, 1.94 mmol) was added to 3-hydroxy-5-[(1-methylethyl)oxy]-N-(1-methyl-1H-pyrazol-3-yl)benzamide (512 mg, 1.86 mmol) and potassium carbonate (536 mg, 3.88 mmol) in DMA (25 mL) and the mixture was heated at 135° C. for 5 hours. Water (100 mL) was added and the reaction mixture extracted with ethyl acetate (3×30 mL). The combined organic phases were washed with water (2×30 mL), brine (2×30 mL), dried (MgSO4), filtered and evaporated. Purification by column chromatography on silica, eluting with 40-100% ethyl acetate in hexanes, afforded the desired compound as a pale yellow oil (300 mg). 1H NMR δ (CDCl3): 1.28 (d, 6H), 3.17 (s, 3H), 3.53 (t, 2H), 3.73 (s, 3H), 4.48 (t, 2H), 4.48-4.55 (m, 1H), 6.63 (t, 1H), 6.71 (d, 1H), 6.73 (d, 1H), 6.95 (t, 1H), 7.12 (t, 1H), 7.22 (d, 1H), 7.61 (d, 1H), 8.52 (s, 1H), m/z 485 (M+H)+ 483 (M−H)−