Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([OH:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1.[H-].[Na+].O>CS(C)=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1CCC(O)CC1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 85.4 %

Procedure:
To a solution of 4-hydroxypiperidine-1-carboxylic acid tert-butyl ester (38.28 g) and 4-fluoronitrobenzene (26.84 g) in dimethyl sulfoxide (326 ml) was added 60% sodium hydride (7.99 g) under nitrogen atmosphere and with ice-cooling, and the mixture was stirred at room temperature for 1 hour. After completion of the reaction, water was added and the mixture was extracted with ethyl acetate and washed with water. The organic layer was dried over anhydrous sodium sulfate and the solvent was evaporated. The obtained residue was purified by silica gel column chromatography (hexane:ethyl acetate=10:1) to give the title compound (52.384 g).
Reaction SMILES: [O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13](Cl)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]#[N:24])=[N:21][CH:22]=1>N1C=CC=CC=1>[O:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]3([C:13]([NH:16][C:17]4[CH:22]=[N:21][C:20]([C:23]#[N:24])=[CH:19][CH:18]=4)=[O:14])[CH2:12][CH2:11]3)=[CH:9][C:4]=2[O:3][CH2:2]1
Reactant: N#Cc1ccc(N)cn1
Reactant: O=C(Cl)C1(c2ccc3c(c2)OCO3)CC1
Solvent: c1ccncc1
Product: N#Cc1ccc(NC(=O)C2(c3ccc4c(c3)OCO4)CC2)cn1
Temperature: 115 °C
Reaction time: 15 h

Procedure:
To 1-(benzo[d][1,3]dioxol-5-yl)cyclopropanecarbonyl chloride (45 mg, 0.2 mmol) in pyridine (2 mL) was added 5-aminopicolinonitrile (24 mg, 0.2 mmol) and the reaction mixture was stirred at 115° C. for 15 hours. The solvent was evaporated to dryness and the residue redissolved in DMF, filtered and purified by reverse-phase preparative liquid chromatography utilizing a gradient of 0-99% acetonitrile in water containing 0.05% trifluoracetic acid to yield the pure product. ESI-MS m/z calc. 307.3. Found 308.3 (M+1)+. Retention time 2.87 minutes.
Reaction SMILES: [N:1]1([C:18]([O:20]C(C)(C)C)=O)[CH2:17][CH2:16][CH2:15][C@H:2]1[C:3]([N:5]([CH2:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)[CH2:6][CH3:7])=[O:4].[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26](C(O)=O)[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34].CS(O)(=O)=O.C(=O)([O-])[O-].[Na+].[Na+]>ClC1C=CC=CC=1>[NH:25]([C:47]([O:49][C:50]([CH3:53])([CH3:52])[CH3:51])=[O:48])[C@H:26]([C:18]([N:1]1[CH2:17][CH2:16][CH2:15][C@H:2]1[C:3]([N:5]([CH2:8][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=1)[CH2:6][CH3:7])=[O:4])=[O:20])[CH2:27][CH2:28][CH2:29][NH:30][C:31](=[NH:43])[NH:32][S:33]([C:36]1[CH:42]=[CH:41][C:39]([CH3:40])=[CH:38][CH:37]=1)(=[O:35])=[O:34]
Reactant: CCN(Cc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)OC(C)(C)C
Reactant: Cc1ccc(S(=O)(=O)NC(=N)NCCC[C@H](NC(=O)OC(C)(C)C)C(=O)O)cc1
Agent: CS(=O)(=O)O
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: Clc1ccccc1
Product: CCN(Cc1ccccc1)C(=O)[C@@H]1CCCN1C(=O)[C@H](CCCNC(=N)NS(=O)(=O)c1ccc(C)cc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 24 h

Procedure:
Boc-Arg(Ts)-Pro-NEtBn was prepared by a similar procedure to Example 1 from Boc-Pro-NEtBn and Boc-Arg(Ts). To the solution composed of the compound (1.00 g), chlorobenzene (5.8 ml) and DBF (1.5 ml), methanesulfonic acid (1.41 g, 9.8 equivalents) was added at room temperature, and the resulting mixture was stirred at room temperature for 24 hours, thereby the Boc group was removed (reaction conversion ratio: 100.0%). After the reaction, 10% aqueous sodium carbonate solution (12 ml) was added thereto, and the resulting mixture was stirred for 15 minutes for neutralization. Then, the aqueous layer was separated off, thereby a solution containing Arg(Ts)-Pro-NEtBn (8.58 g) was obtained.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[NH:11][C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(=O)([O-])[O-].[K+].[K+].Br[CH2:23][CH2:24][CH2:25][C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1.O>CN(C)C=O>[C:1]([O:5][C:6]([N:8]1[CH2:13][C@H:12]([CH3:14])[N:11]([CH2:23][CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@H:10]([CH3:15])[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrCCCc1ccccc1
Reactant: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: C[C@@H]1CN(C(=O)OC(C)(C)C)C[C@H](C)N1CCCc1ccccc1
Temperature: 120 °C
Reaction time: 40 h

Procedure:
To a suspension of 10 g (46.66 mmol.) of cis-1-tert-butoxycarbonyl-3,5-dimethyl piperazine and 12.90 g (93.3 mmol.) of potassium carbonate in N,N-dimethylformamide (50 ml) was added, at room temperature, 11.15 g (56 mmol.) of 1-bromo-3-phenylpropane. The mixture was stirred for 40 hours at 120° C., which was then cooled to room temperature. To the reaction system was added water, which was subjected to extraction with ethyl acetate. The organic layer was washed with a saturated aqueous saline solution and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by means of a column chromatography (ethyl acetate/hexane 20-30%) to give the object compound as a yellow oily product. The yield was 12.21 g (79%).
Reaction SMILES: [CH:1]1([C:5]2[C:6]([C:12]3[CH:17]=[CH:16][C:15]([O:18][CH:19]4[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]4)=[CH:14][CH:13]=3)=[CH:7][C:8](=O)[NH:9][N:10]=2)[CH2:4][CH2:3][CH2:2]1.P(Cl)(Cl)([Cl:27])=O>>[Cl:27][C:8]1[N:9]=[N:10][C:5]([CH:1]2[CH2:4][CH2:3][CH2:2]2)=[C:6]([C:12]2[CH:17]=[CH:16][C:15]([O:18][CH:19]3[CH2:24][CH2:23][CH2:22][CH2:21][CH2:20]3)=[CH:14][CH:13]=2)[CH:7]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: O=c1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)n[nH]1
Product: Clc1cc(-c2ccc(OC3CCCCC3)cc2)c(C2CCC2)nn1
Temperature: 80 °C
Yield: 59.1 %

Procedure:
A suspension of 6-cyclobutyl-5-(4-cyclohexyloxy-phenyl)-2H-pyridazin-3-one (0.74 mmol, 0.24 g) in phosphorous oxychloride (7.41 mmol, 0.68 mL) was heated at 80° C. for 20 minutes. The reaction mixture was cooled to room temperature and the volatiles were removed under reduced pressure. The residue was partitioned between ethyl acetate (5 mL) and saturated NaHCO3. The layers were separated and the organic layer was washed with saturated NaHCO3 (5 mL), brine (5 mL) and dried (Na2SO4). The residue was purified on a 12 g SiO2 cartridge eluting with an ethyl acetate/hexanes gradient to give 6-chloro-3-cyclobutyl-4-(4-cyclohexyloxy-phenyl)-pyridazine (0.15 g).
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)[C:13](=[O:30])[NH:12]2)[CH:7]=[C:8]([F:10])[CH:9]=1.Br[CH2:32][C:33]([O:35][CH3:36])=[O:34]>CN(C=O)C>[F:3][C:4]1[CH:5]=[C:6]([CH:11]2[CH2:16][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:14]([CH:24]3[CH2:25][CH2:26][O:27][CH2:28][CH2:29]3)[C:13](=[O:30])[N:12]2[CH2:32][C:33]([O:35][CH3:36])=[O:34])[CH:7]=[C:8]([F:10])[CH:9]=1
Reactant: COC(=O)CBr
Reactant: CC(C)(C)OC(=O)N1CC(c2cc(F)cc(F)c2)NC(=O)C1C1CCOCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)CN1C(=O)C(C2CCOCC2)N(C(=O)OC(C)(C)C)CC1c1cc(F)cc(F)c1
Temperature: 0 °C
Reaction time: 0.33 h

Procedure:
At 0° C. 38 mg (0.86 mmol) sodium hydride were added to 0.30 g (0.76 mmol) tert-butyl 5-(3,5-difluorophenyl)-3-oxo-2-(tetrahydro-2H-pyran-4-yl)piperazine-1-carboxylate (isomer mixture 1) in 10 ml DMF. After 20 min, while cooling with an ice bath, 84 μl (0.86 mmol) methyl bromoacetate were added dropwise. Then the mixture was stirred for 30 min in the ice bath and for 5 h at RT. The reaction mixture was poured onto water and extracted with ethyl acetate. The organic phase was washed with water, dried and evaporated down.
Reaction SMILES: [Cl:1][C:2]1[NH:12][C:5]2[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=2[C:3]=1[Cl:13].[H-].[Na+].[Cl:16][C:17]1[CH:32]=[CH:31][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26]Br)=[O:22])=[CH:19][CH:18]=1.O>CN(C=O)C>[Cl:16][C:17]1[CH:18]=[CH:19][C:20]([C:21]([C:23]2[CH:24]=[C:25]([CH:28]=[CH:29][CH:30]=2)[CH2:26][N:12]2[C:5]3[CH:6]=[N:7][N:8]([CH3:11])[C:9](=[O:10])[C:4]=3[C:3]([Cl:13])=[C:2]2[Cl:1])=[O:22])=[CH:31][CH:32]=1
Reactant: O=C(c1ccc(Cl)cc1)c1cccc(CBr)c1
Reactant: Cn1ncc2[nH]c(Cl)c(Cl)c2c1=O
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: Cn1ncc2c(c(Cl)c(Cl)n2Cc2cccc(C(=O)c3ccc(Cl)cc3)c2)c1=O
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 16.8 %

Procedure:
A solution of 2,3-dichloro-5-methyl-1H-pyrrolo [2,3-d]pyridazin-4(5H)-one (303 mg) in DMF (50 ml) was dripped into a suspension of 60% sodium hydride-oil (72 mg) in DMF (10 ml) on an ice-water bath. The mixture was stirred at room temperature for 2.5 hours, after which a solution of 3-(4-chlorobenzoyl) benzyl bromide (511 mg) in DMF (10 ml) was added and the mixture was further stirred at room temperature for 17 hours. The reaction was stopped by adding water and the reaction mixture was extracted with ethyl acetate. The extract was dried over anhydrous magnesium sulfate and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (developer; n-hexane: ethyl acetate=1:1) to provide the title compound as white powder (104 mg, yield 16%).
Reaction SMILES: Cl.[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][NH:14]1.CCN(C(C)C)C(C)C.[C:32](Cl)(=[O:35])[O:33][CH3:34]>C(Cl)Cl>[F:2][C:3]1[CH:8]=[C:7]([C:9]([F:12])([F:10])[F:11])[CH:6]=[CH:5][C:4]=1[CH:13]1[CH2:18][CH:17]([C:19]([O:21][CH3:22])=[O:20])[CH2:16][CH2:15][N:14]1[C:32]([O:33][CH3:34])=[O:35]
Reactant: COC(=O)C1CCNC(c2ccc(C(F)(F)F)cc2F)C1
Reactant: COC(=O)Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)C1CCN(C(=O)OC)C(c2ccc(C(F)(F)F)cc2F)C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 91.2 %

Procedure:
Methyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-4-carboxylate hydrochloride (5.50 g, 16.09 mmol) was dissolved in DCM (100 mL), then DIPEA (7.03 mL, 40.23 mmol) was added. Methyl carbonochloridate (1.774 mL, 22.53 mmol) was added dropwise to the solution. The mixture was stirred at room temperature for 4 h. The mixture was washed with 0.1 M HCl (100 mL) and satd NaHCO3 (100 mL), then dried through a phase-separator and evaporated yielding dimethyl 2-(2-fluoro-4-(trifluoromethyl)phenyl)piperidine-1,4-dicarboxylate (5.33 g, 91%) as a brown oil.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]([CH3:23])[CH2:12][CH2:13][N:14]1[CH2:19][CH2:18][CH2:17][CH2:16][C@H:15]1[C:20]([OH:22])=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH2:49].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>CN(C=O)C>[CH3:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][O:31][CH2:32][CH2:33][O:34][CH2:35][CH2:36][O:37][CH2:38][CH2:39][O:40][CH2:41][CH2:42][O:43][CH2:44][CH2:45][O:46][CH2:47][CH2:48][NH:49][C:20]([C@@H:15]1[CH2:16][CH2:17][CH2:18][CH2:19][N:14]1[CH2:13][CH2:12][N:11]([CH3:23])[C:9](=[O:10])[O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:22]
Reactant: COCCOCCOCCOCCOCCOCCOCCOCCN
Reactant: CN(CCN1CCCC[C@H]1C(=O)O)C(=O)OCc1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COCCOCCOCCOCCOCCOCCOCCOCCNC(=O)[C@@H]1CCCCN1CCN(C)C(=O)OCc1ccccc1
Temperature: 60 °C
Reaction time: 1 h

Procedure:
To a mixture of (S)-1-(2-(((benzyloxy)carbonyl)(methyl)amino)ethyl)piperidine-2-carboxylic acid (0.145 mmol, 46.4 mg), 2,5,8,11,14,17,20,23-octaoxapentacosan-25-amine (0.145 mmol, 55.6 mg), DIEA (0.725 mmol, 94 mg) in DMF (0.3 mL) was added HATU (0.16 mmol, 61 mg). The mixture was stirred at 60° C. for 1 h. The crude mixture was used in next step without purification.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1.Cl[C:23]([O:25][CH2:26][CH3:27])=[O:24]>N1C=CC=CC=1>[CH2:26]([O:25][C:23]([NH:1][C:2]1[CH:3]=[CH:4][C:5]([N:9]2[CH2:13][CH2:12][C@H:11]([NH:14][C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:10]2)=[C:6]([F:8])[CH:7]=1)=[O:24])[CH3:27]
Reactant: CC(C)(C)OC(=O)N[C@H]1CCN(c2ccc(N)cc2F)C1
Reactant: CCOC(=O)Cl
Solvent: c1ccncc1
Product: CCOC(=O)Nc1ccc(N2CC[C@H](NC(=O)OC(C)(C)C)C2)c(F)c1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
5-Amino-2-(3(S)-(t-butoxycarbonyl)aminopyrrolidin-1-yl)fluorobenzene (30.4 g, 0.103 M) was dissolved in dry pyridine (150 ml) and cooled under nitrogen with stirring to 0°. Ethyl chloroformate (12.3, 0.113 M) was added dropwise, and the mixture stirred 1 hour at the same temperature. Ice-water (250 ml) was added, and stirring continued for 1 hour. The resulting precipitate was collected, washed thoroughly with water, and air dried. The residue was treated with toluene, azeotroped to half volume, then treated with isohexane (500 ml), to precipitate the desired product (35.3 g).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8](Cl)[N:7]=[CH:6][N:5]=2.[O:13]=[C:14]1[N:18]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[C:17]2[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=2[NH:15]1>C(O)C>[Br:1][C:2]1[N:3]([CH3:12])[C:4]2[C:9]([N:10]=1)=[C:8]([N:22]1[CH2:21][CH2:20][CH:19]([N:18]3[C:17]4[CH:25]=[CH:26][CH:27]=[CH:28][C:16]=4[NH:15][C:14]3=[O:13])[CH2:24][CH2:23]1)[N:7]=[CH:6][N:5]=2
Reactant: O=c1[nH]c2ccccc2n1C1CCNCC1
Reactant: Cn1c(Br)nc2c(Cl)ncnc21
Solvent: CCO
Product: Cn1c(Br)nc2c(N3CCC(n4c(=O)[nH]c5ccccc54)CC3)ncnc21
Temperature: 100 °C
Yield: 74 %

Procedure:
8-bromo-6-chloro-9-methyl-9H-purine (175 mg, 0.71 mmol) was combined with 4-(2-keto-1-benzimidazolinyl)piperidine (185 mg, 0.85 mmol) and dissolved in ethanol (2 mL). The resulting solution was warmed to 100° C. in a sealed tube for 15 minutes. A precipitate formed which was collected and washed with ethanol. An amount of 225 mg of a tan solid was isolated, which was 80% pure an indicated by LCMS analysis. A portion of this material was purified by prep HPLC to provide 6 mg of a white solid. 1H NMR (400 MHz, DMSO-d6): δ 10.80 (s, 1H), 8.21 (s, 1H), 7.14-7.00 (m, 1H), 6.88 (m, 3H), 5.38 (s, 2H), 4.48 (m, 1H), 3.62 (s, 3H), 3.13 (s, 2H), 2.25 (m, 2H), 1.78 (m, 2H). EI (MS) for C18H18BrN7O, found 428.
Reaction SMILES: [Si]([O:8][CH2:9][C@@H:10]([N:19]1[CH:24]=[CH:23][C:22]([C:25]2[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=3)[N:26]=2)=[CH:21][C:20]1=[O:39])[C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([F:18])[CH:12]=1)(C(C)(C)C)(C)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC.O>C1COCC1>[Cl:17][C:14]1[CH:15]=[CH:16][C:11]([C@H:10]([N:19]2[CH:24]=[CH:23][C:22]([C:25]3[CH:30]=[CH:29][N:28]=[C:27]([NH:31][C:32]4[CH:37]=[CH:36][N:35]=[C:34]([CH3:38])[N:33]=4)[N:26]=3)=[CH:21][C:20]2=[O:39])[CH2:9][OH:8])=[CH:12][C:13]=1[F:18]
Reactant: Cc1nccc(Nc2nccc(-c3ccn([C@H](CO[Si](C)(C)C(C)(C)C)c4ccc(Cl)c(F)c4)c(=O)c3)n2)n1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nccc(Nc2nccc(-c3ccn([C@H](CO)c4ccc(Cl)c(F)c4)c(=O)c3)n2)n1
Reaction time: 1 h
Yield: 18.4 %

Procedure:
(S)-1-(2-(tert-Butyldimethylsilyloxy)-1-(4-chloro-3-fluorophenyl)ethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.034 g, 0.060 mmol) was placed in THF (5 mL) at room temperature. Tetra-n-butylammonium fluoride (“TBAF”) (0.18 mL, 0.18 mmol) was added to the mixture. The mixture was stirred for 1 hour, then poured into water, and extracted with DCM. The combined organic fractions were dried (MgSO4), filtered, and concentrated to give the crude product, which was purified by column chromatography (0-5.5% MeOH in DCM) to give the product (S)-1-(1-(4-chloro-3-fluorophenyl)-2-hydroxyethyl)-4-(2-((2-methylpyrimidin-4-yl)amino)pyrimidin-4-yl)pyridin-2(1H)-one (0.005 g, 18% yield). m/z (APCI-pos) M+1=453.
Reaction SMILES: C([O:3][C:4]([C:6]1([S:21]([C:24]2[CH:29]=[CH:28][C:27]([O:30][CH2:31][C:32]#[C:33][CH3:34])=[CH:26][CH:25]=2)(=[O:23])=[O:22])[CH2:11][CH2:10][N:9]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([C:19]#[N:20])=[CH:15][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])C.CO.[OH-].[Na+]>C1COCC1>[CH2:31]([O:30][C:27]1[CH:28]=[CH:29][C:24]([S:21]([C:6]2([C:4]([OH:5])=[O:3])[CH2:11][CH2:10][N:9]([CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:19]#[N:20])=[CH:17][CH:18]=3)[CH2:8][CH2:7]2)(=[O:22])=[O:23])=[CH:25][CH:26]=1)[C:32]#[C:33][CH3:34]
Reactant: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)OCC)CCN(Cc3ccc(C#N)cc3)CC2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: CC#CCOc1ccc(S(=O)(=O)C2(C(=O)O)CCN(Cc3ccc(C#N)cc3)CC2)cc1

Procedure:
4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid was prepared starting from 4-(4-But-2-ynyloxy-benzenesulfonyl)-1-(4-cyano-benzyl)-piperidine-4-carboxylic acid ethyl ester (4 g, 8.3 mmol) dissolved in THF:Methanol (60:30 ml) and 10 N NaOH (10 ml). The resulting reaction mixture was worked up as outlined in Example 1 (Step 7). Yield 1.8 g (48%); off white solid; MS: 441.9 (M+H)+.
Reaction SMILES: Br[C:2]1[C:3]([C:13]2[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=2)=[CH:4][C:5]2[O:9][C:8]([CH3:11])([CH3:10])[CH2:7][C:6]=2[CH:12]=1.[CH3:20][O:21][C:22]1[CH:27]=[CH:26][C:25]([N:28]2[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]2)=[CH:24][CH:23]=1>>[CH3:10][C:8]1([CH3:11])[CH2:7][C:6]2[CH:12]=[C:2]([N:31]3[CH2:30][CH2:29][N:28]([C:25]4[CH:24]=[CH:23][C:22]([O:21][CH3:20])=[CH:27][CH:26]=4)[CH2:33][CH2:32]3)[C:3]([C:13]3[CH:18]=[CH:17][C:16]([CH3:19])=[CH:15][CH:14]=3)=[CH:4][C:5]=2[O:9]1
Reactant: COc1ccc(N2CCNCC2)cc1
Reactant: Cc1ccc(-c2cc3c(cc2Br)CC(C)(C)O3)cc1
Product: COc1ccc(N2CCN(c3cc4c(cc3-c3ccc(C)cc3)OC(C)(C)C4)CC2)cc1
Yield: 16.3 %

Procedure:
By using 5-bromo-2,2-dimethyl-6-(4-methylphenyl)-2,3-dihydro-1-benzofuran (250 mg, 0.788 mmol) synthesized in Reference example 9 and 1-(4-methoxyphenyl)piperazine (455 mg, 2.36 mmol), the reaction was carried out in the same manner as Example 1 to synthesize the title compound 55 mg (yield 16%). Melting point was 187 to 190° C. (ethyl acetate-hexane).
Reaction SMILES: [CH:1]1[C:5]2[C:6]([Cl:10])=[N:7][CH:8]=[N:9][C:4]=2[NH:3][CH:2]=1.[I:11]N1C(=O)CCC1=O>C(Cl)Cl>[CH:2]1[NH:3][C:4]2[N:9]=[CH:8][N:7]=[C:6]([Cl:10])[C:5]=2[C:1]=1[I:11]
Reactant: Clc1ncnc2[nH]ccc12
Reactant: O=C1CCC(=O)N1I
Solvent: ClCCl
Product: Clc1ncnc2[nH]cc(I)c12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
Compound dA.23 was synthesized according to the procedure described by Ju et al. (2006, which is incorporated herein by reference). To a suspension of 6-chloro-7-deazapurine (1.00 g, 6.51 mmol) in anhydrous CH2Cl2 (55 mL) was added N-iodosuccinimide (1.70 g, 7.56 mmol). The reaction was protected from light while stirring at room temperature for two hours. The reaction was then concentrated down in vacuo. The material was re-crystallized from hot methanol to yield 6-chloro-7-iodo-7-deazapurine dA.23 (0.94 g, 52%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:9]([C:11]2[NH:12][CH:13]=[C:14]([C:16]3[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=3)[N:15]=2)=[O:10])[CH:6]=[CH:7][CH:8]=1.C(=O)([O-])[O-].[K+].[K+].C1OCCOCCOCCOCCOCCOC1.[CH2:46](Br)[CH2:47][CH:48]=[CH2:49]>CN(C=O)C.O>[CH2:49]([N:12]1[CH:13]=[C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[N:15]=[C:11]1[C:9]([C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([O:2][CH3:1])[CH:4]=1)=[O:10])[CH2:48][CH:47]=[CH2:46]
Reactant: C=CCCBr
Reactant: COc1cccc(C(=O)c2nc(-c3ccccc3)c[nH]2)c1
Agent: C1COCCOCCOCCOCCOCCO1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C=CCCn1cc(-c2ccccc2)nc1C(=O)c1cccc(OC)c1
Temperature: 80 °C
Reaction time: 5 h
Yield: 93 %

Procedure:
(3-Methoxyphenyl)(4-phenyl-1H-imidazol-2-yl)methanone (278 mg, 1.00 mmol) was dissolved in DMF (3 ml), and thereto were added potassium carbonate (207 mg, 1.50 mmol), 18-crown-6 (26.4 mg, 0.100 mmol), 3-butenyl bromide (162 mg, 1.20 mmol), and the mixture was stirred at 80° C. for 5 hours. The reaction solution was cooled to room temperature, and thereto was added water. The mixture was extracted with ethyl acetate, and the solvent was evaporated under reduced pressure. The resulting residue was subjected to azeotropic distillation with toluene to give the title compound (309 mg, 93%).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([NH:5][CH2:6]1)[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][CH:24]([C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH3:25])[CH:18]=2)[N:9]=1.Br[CH2:33][CH3:34].C([O-])([O-])=O.[K+].[K+]>CC#N.C(Cl)Cl>[CH2:33]([N:5]1[CH2:6][C@@H:1]2[CH2:7][C@H:4]1[CH2:3][N:2]2[C:8]1[N:13]2[CH:14]=[CH:15][N:16]=[C:12]2[CH:11]=[C:10]([C:17]2[CH:22]=[CH:21][N:20]=[C:19]([NH:23][C@H:24]([C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[CH3:25])[CH:18]=2)[N:9]=1)[CH3:34]
Reactant: CC(Nc1cc(-c2cc3nccn3c(N3CC4CC3CN4)n2)ccn1)c1ccccc1
Reactant: CCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: ClCCl
Product: CCN1C[C@@H]2C[C@H]1CN2c1nc(-c2ccnc(N[C@@H](C)c3ccccc3)c2)cc2nccn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
The mixture of 50 mg (0.12 mmol) {4-[5-(2,5-diaza-bicyclo[2.2.1]hept-2-yl)-imidazo [1,2-c]pyrimidin-7-yl]-pyridin-2-yl}-(1-phenyl-ethyl)-amine in 20 mL CH3CN was treated with 26 mg (0.24 mmol) bromoethane and 33 mg (0.24 mmol) K2CO3. The mixture was stirred at rt for 15 h. MS showed all starting materials were converted. The mixture was diluted with 50 mL DCM, washed with 20 mL sat. NaHCO3, dried over anhydrous Na2SO4. After purification by chromatography, obtained the title compound in 20 mg as a yellow solid. MS (ES+): 440 (M+H)+.
Reaction SMILES: [F:1][CH:2]([F:13])[O:3]C1C=C2C(C=CN2)=CC=1.[C:14]([C:17]1[C:25]2[C:20](=[CH:21][C:22](F)=[C:23](F)[CH:24]=2)[N:19]([CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)(=[O:16])[NH2:15]>>[C:14]([C:17]1[C:25]2[C:20](=[CH:21][C:22]([O:3][CH:2]([F:13])[F:1])=[CH:23][CH:24]=2)[N:19]([CH2:28][C:29]([OH:31])=[O:30])[CH:18]=1)(=[O:16])[NH2:15]
Reactant: NC(=O)c1cn(CC(=O)O)c2cc(F)c(F)cc12
Reactant: FC(F)Oc1ccc2cc[nH]c2c1
Product: NC(=O)c1cn(CC(=O)O)c2cc(OC(F)F)ccc12

Procedure:
was prepared from 6-difluoromethoxy-1H-indole [200207-21-2] in a similar manner as described for the preparation of (3-carbamoyl-5,6-difluoro-indol-1-yl)acetic acid. White solid. MS (LC/MS): 285 [M+H]+, 569 [2M+H]+; tR (HPLC conditions k): 2.64 min.
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]([C:12]2[O:13][C:14](=[O:30])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH2:19][CH2:18]3)[N:16]=2)[C:5]2[O:6][CH2:7][CH2:8][O:9][C:4]=2[C:3]=1[NH:31]C(=O)OCC1C=CC=CC=1.Br.C(OCC)C>C(O)(=O)C>[NH2:31][C:3]1[C:4]2[O:9][CH2:8][CH2:7][O:6][C:5]=2[C:10]([C:12]2[O:13][C:14](=[O:30])[N:15]([CH:17]3[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][CH2:25][C:26]([F:28])([F:27])[F:29])[CH2:19][CH2:18]3)[N:16]=2)=[CH:11][C:2]=1[Cl:1]
Reactant: O=C(Nc1c(Cl)cc(-c2nn(C3CCN(CCCC(F)(F)F)CC3)c(=O)o2)c2c1OCCO2)OCc1ccccc1
Agent: Br
Solvent: CCOCC
Solvent: CC(=O)O
Product: Nc1c(Cl)cc(-c2nn(C3CCN(CCCC(F)(F)F)CC3)c(=O)o2)c2c1OCCO2
Temperature: 25 °C
Reaction time: 7 h
Yield: 89.3 %

Procedure:
1.72 g (2.88 mmol) of phenylmethyl [6-chloro-8-[5-oxo-4-[1-(4,4,4-trifluorobutyl)piperidin-4-yl]-4,5-dihydro-1,3,4-oxadiazol-2-yl]-2,3-dihydro-1,4-benzodioxin-5-yl]carbamate and 17 ml of acetic acid are introduced into a 100 ml round-bottomed flask, 5 ml of 33% hydrobromic acid in acetic acid are added and the mixture is stirred at room temperature for 7 h. Diethyl ether is added to the precipitate which has formed and 1.8 g of hydrobromide are collected by filtration. It is taken up in water and chloroform, sodium hydroxide is added in order to release the base and, after the usual treatment of the organic phase, 1.19 g of compound are obtained. Melting point: 188° C.