Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:11][C:12]1[CH:21]=[CH:20][C:15]([C:16]([O:18]C)=O)=[CH:14][CH:13]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].C([O-])([O-])=O.[K+].[K+].OC1C=CC(C=O)=CC=1.[Br:37][CH2:38][CH2:39]CCCCCCCC(Br)CC>>[Br:37][CH2:38][CH2:39][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2][CH2:1][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH:16]=[O:18])=[CH:20][CH:21]=1
Reactant: CCCCCCCCCCOc1ccc(C(=O)OC)cc1
Reactant: CCC(Br)CCCCCCCCCBr
Agent: O=C([O-])[O-]
Agent: O=Cc1ccc(O)cc1
Agent: [K+]
Product: O=Cc1ccc(OCCCCCCCCCCCCBr)cc1

Procedure:
Synthesized as described above for compound 1. Quantities: K2CO3 (4.6 g, 33 mmol), p-hydroxybenzaldehye (3.27 g, 27 mmol), 1,10-dibromododecane (11.56 g, 35 mmol). Yield 7.0 g (70%). 1H NMR: δH (CDCl3; 300 MHz): 1.24-1.52 (16 H, m, CH2), 1.84 (4 H, m, O—CH2—CH2/Br—CH2—CH2), 3.40 (2 H, t, 3J=6.9 Hz, Br—CH2), 4.06 (2 H, t, 3J=6.5 Hz, O—CH2), 6.98 (2 H, d, 3J=8.7 Hz, Ar—H), 7.82 (2 H, d, 3J=8.8 Hz, Ar—H), 9.88 (1 H, s, COH). 13C NMR: δC (CDCl3; 75 MHz): 26.3, 28.6, 29.1, 29.4, 29.7, 29.8, 29.9, 33.2, 34.4, 68.8, 115.1, 130.1, 132.3, 164.6, 191.1.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5](Cl)=[N:6][CH:7]=1.[C:9]([C:13]1[CH:18]=[CH:17][C:16]([S:19]([NH:22][C:23]2[N:27]([CH3:28])[N:26]=[C:25]([O:29][CH2:30][CH2:31][OH:32])[C:24]=2[C:33]2[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=2)(=[O:21])=[O:20])=[CH:15][CH:14]=1)([CH3:12])([CH3:11])[CH3:10]>>[Br:1][C:2]1[CH:3]=[N:4][C:5]([O:32][CH2:31][CH2:30][O:29][C:25]2[C:24]([C:33]3[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=3)=[C:23]([NH:22][S:19]([C:16]3[CH:15]=[CH:14][C:13]([C:9]([CH3:11])([CH3:10])[CH3:12])=[CH:18][CH:17]=3)(=[O:20])=[O:21])[N:27]([CH3:28])[N:26]=2)=[N:6][CH:7]=1
Reactant: Cn1nc(OCCO)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1
Reactant: Clc1ncc(Br)cn1
Product: Cn1nc(OCCOc2ncc(Br)cn2)c(-c2ccc(Cl)cc2)c1NS(=O)(=O)c1ccc(C(C)(C)C)cc1

Procedure:
The title compound was made according to the procedure used for Example 13 except that (21 mg) of 5-bromo-2-chloropyrimidine was used and 4-(tert-butyl)-N-[4-(4-chlorophenyl)-3-(2-hydroxyethoxy)-1-methyl-1H-pyrazol-5-yl]benzenesulfonamide (Example 19) (30 mg) was used in place of 4-(tert-butyl)-N-{3-(2-hydroxyethoxy)-1-methyl-4-[4-(trifluoromethyl)phenyl]-1H-pyrazol-5-yl}benzenesulfonamide (Example 12). The crude material was purified by HPLC on a 5μ ODS Phenomenex Magellen column with a gradient elution of acetonitrile (5% to 95%) and 0.1M NH4OAc (95% to 5%) to yield the desired product as an off white solid (3 mg).
Reaction SMILES: [C:1](OC(=O)C)(=[O:3])[CH3:2].Cl.[NH2:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:36][CH2:35][CH2:34][CH2:33][CH2:32]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1.N1C=CC=CC=1.Cl>ClCCl>[C:1]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([C:16]2[N:20]([CH:21]([CH:31]3[CH2:32][CH2:33][CH2:34][CH2:35][CH2:36]3)[C:22]([NH:24][CH:25]3[CH2:30][CH2:29][CH2:28][CH2:27][CH2:26]3)=[O:23])[C:19]3[CH:37]=[CH:38][CH:39]=[CH:40][C:18]=3[N:17]=2)=[CH:12][CH:11]=1)(=[O:3])[CH3:2]
Reactant: Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Reactant: CC(=O)OC(C)=O
Agent: Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CC(=O)Nc1ccc(-c2nc3ccccc3n2C(C(=O)NC2CCCCC2)C2CCCCC2)cc1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
Acetic anhydride (175 mg, 1.71 mmol, 1.0 equiv.) was added to a solution of 2-[2-(4-amino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide hydrogen chloride (example 34) (74 mg, 1.71 mmol, 1.0 equiv.) and pyridine (13 mg, 1.71 mmol, 1.0 equiv.) in dichloromethane (2 mL). The reaction was stirred at room temperature for 16 hours then retreated with pyridine (13 mg, 1.71 mmol, 1.0 equiv.) and acetic anhydride (17 mg, 0.17 mmol, 0.1 equiv.) and stirred at room temperature for a further 24 hours. The reaction mixture was added to 1 N HCl (2 mL) and the resultant precipitate was filtered and washed with dichloromethane. The solid was dissolved in hot ethyl acetate (3 mL) and filtered, the filtrate was concentrated in vacuo to afford 2-[2-(4-acetylamino-phenyl)-benzoimidazol-1-yl]-2,N-dicyclohexyl-acetamide as a cream solid, 26 mg (32%), MS (ES+): 473 (M+H).
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]1[C:7]([O:9][CH3:10])=[O:8].[F:11][C:12]1[CH:13]=[C:14]([CH:19]=[C:20]([F:22])[CH:21]=1)[C:15](=[O:18])[CH2:16]Br.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:11][C:12]1[CH:13]=[C:14]([C:15](=[O:18])[CH2:16][N:1]2[CH2:6][CH2:5][O:4][CH2:3][C@@H:2]2[C:7]([O:9][CH3:10])=[O:8])[CH:19]=[C:20]([F:22])[CH:21]=1
Reactant: O=C(CBr)c1cc(F)cc(F)c1
Reactant: COC(=O)[C@H]1COCCN1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H]1COCCN1CC(=O)c1cc(F)cc(F)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a mixture of methyl (3R)-morpholine-3-carboxylate from Step A (556 mg, 3.83 mmol) and 3,5-difluorophenacyl bromide (450 mg, 1.92 mmol) in CH2Cl2 (2 mL) was added DIPEA (0.669 mL, 3.83 mmol). The reaction mixture was stirred at ambient temperature for 1 h, then concentrated in vacuo. The crude product was purified on silica gel, eluting with hexane:EtOAc—75:25, to yield the title compound. MS: m/z=300 (M+1).
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([C:8]2[CH:13]=[CH:12][C:11]([F:14])=[CH:10][CH:9]=2)[N:3]=1.[NH2:15][NH2:16]>O1CCOCC1.O>[F:14][C:11]1[CH:12]=[CH:13][C:8]([C:4]2[NH:3]/[C:2](=[N:15]\[NH2:16])/[CH:7]=[N:6][CH:5]=2)=[CH:9][CH:10]=1
Reactant: Fc1ccc(-c2cncc(Cl)n2)cc1
Reactant: NN
Solvent: O
Solvent: C1COCCO1
Product: N/N=c1/cncc(-c2ccc(F)cc2)[nH]1
Yield: 88.6 %

Procedure:
A mixture of 2-chloro-6-(4-fluoro-phenyl)-pyrazine (1.0 g, 4.7 mmol) and anhydrous hydrazine (1.5 mL, 47 mmol) in dioxane (20 mL) was heated to reflux for two hours, then cooled and diluted with cold water. The resulting precipitate was collected by filtration, washed with cold water, and dried to give 0.85 g of [6-(4-fluoro-phenyl)-1H-pyrazin-(2Z)-ylidene]-hydrazine.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]3[C:17]4[C:22]([CH:23]=[CH:24][C:9]2=3)=[CH:21][CH:20]=[CH:19][CH:18]=4)=[CH:4][CH:3]=1.[CH3:25][C:26]1[S:30][C:29]([C:31](O)=[O:32])=[CH:28][CH:27]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.C(N(CC)CC)C>CN(C=O)C>[CH3:25][C:26]1[S:30][C:29]([C:31]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([N:8]3[C:14](=[O:15])[CH2:13][C:12](=[O:16])[NH:11][C:10]4[C:17]5[C:22]([CH:23]=[CH:24][C:9]3=4)=[CH:21][CH:20]=[CH:19][CH:18]=5)=[CH:4][CH:3]=2)=[O:32])=[CH:28][CH:27]=1
Reactant: Nc1ccc(N2C(=O)CC(=O)Nc3c2ccc2ccccc32)cc1
Reactant: Cc1ccc(C(=O)O)s1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: Cc1ccc(C(=O)Nc2ccc(N3C(=O)CC(=O)Nc4c3ccc3ccccc43)cc2)s1
Yield: 45.3 %

Procedure:
5-(4-Aminophenyl)-1H-naphtho[1,2-b][1,4]diazepine-2,4(3H,5H)-dione (16 mg, 0.050 mmol) obtained in Example 1, (3), 5-methylthiophene-2-carboxylic acid (14 mg, 0.101 mmol), and O-(benzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (21 mg, 0.055 mmol) were dissolved in DMF (2.0 mL), then the solution was added with triethylamine (10 mg, 0.101 mmol), and the mixture was stirred over night. The reaction mixture was treated in a conventional manner to give the title compound (10 mg, yield 45%) as white crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([OH:24])=O)=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1.[CH3:25][O:26][NH2:27]>>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[CH2:12][CH2:11][CH2:10][N:9]2[C:13]2[CH:18]=[CH:17][N:16]3[N:19]=[CH:20][C:21]([C:22]([NH:27][O:26][CH3:25])=[O:24])=[C:15]3[N:14]=2)[CH:5]=[N:6][CH:7]=1
Reactant: CON
Reactant: O=C(O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Product: CONC(=O)c1cnn2ccc(N3CCC[C@@H]3c3cncc(F)c3)nc12
Yield: 35 %

Procedure:
Prepared by the method as described in Example 1 using (R)-5-(2-(5-fluoropyridin-3-yl)pyrrolidin-1-yl)pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (Preparation I) and O-methylhydroxylamine to yield the title compound as a white solid (15 mg, 35% yield). MS (apci) m/z=357.0 (M+H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH:5]=O.[CH3:11][N:12]1[CH2:17][CH2:16][NH:15][CH2:14][CH2:13]1.CC(O)=O.[BH3-]C#N.[Na+]>CO>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([F:10])[CH:9]=1)[CH2:5][N:15]1[CH2:16][CH2:17][N:12]([CH3:11])[CH2:13][CH2:14]1
Reactant: O=Cc1cc(F)cc(Br)c1
Reactant: CN1CCNCC1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CN1CCN(Cc2cc(F)cc(Br)c2)CC1
Reaction time: 1 h
Yield: 51 %

Procedure:
A solution of 3-bromo-5-fluorobenzaldehyde (CI) (2.12 g, 10.42 mmol) in MeOH (200 mL) was added 1-methylpiperazine (2.3 mL, 20.84 mL). The pH was adjusted to 6 using HOAc and stirred for 1 h. NaCNBH3 (917 mg, 14.59 mmol) was added and stirred at room temperature overnight. The MeOH was removed under vacuum and the residue was partitioned between CHCl3 and saturated aqueous NaHCO3. The organic layer was dried over MgSO4 and evaporated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH[7N NH3]:CHCl3) to produce 1-(3-bromo-5-fluorobenzyl)-4-methylpiperazine (CII) as a yellow oil (1.52 g, 5.29 mmol, 51% yield). 1H NMR (DMSO-d6, 500 MHz) δ ppm 2.14 (s, 3H), 2.28-2.40 (m, 8H), 3.46 (s, 2H), 7.15-7.17 (m, 1H), 7.35 (s, 1H), 7.40-7.42 (m, 1H); ESIMS found C12H16BrFN2 m/z 287 (M+H).
Reaction SMILES: [C:1]([C:4]1[C:8]([O:9][CH3:10])=[C:7]([C:11]2[CH:16]=[CH:15][C:14]([Cl:17])=[CH:13][CH:12]=2)[N:6]([C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=2[Cl:24])[N:5]=1)([OH:3])=O.C[Li].[CH:27]([Mg]Br)=[CH2:28].Cl>O1CCCC1.O>[Cl:24][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][C:18]=1[N:6]1[C:7]([C:11]2[CH:12]=[CH:13][C:14]([Cl:17])=[CH:15][CH:16]=2)=[C:8]([O:9][CH3:10])[C:4]([C:1]([CH:27]=[CH2:28])=[O:3])=[N:5]1
Reactant: COc1c(C(=O)O)nn(-c2ccccc2Cl)c1-c1ccc(Cl)cc1
Reactant: C=C[Mg]Br
Agent: Cl
Agent: [Li]C
Solvent: O
Solvent: C1CCOC1
Product: C=CC(=O)c1nn(-c2ccccc2Cl)c(-c2ccc(Cl)cc2)c1OC
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 70 %

Procedure:
To a solution of 3-carboxy-1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-1H-pyrazole (1.09 g) in tetrahydrofuran (30 mL) was added dropwise methyl lithium (2.9 mL, 1.04 M diethylether solution) at −78° C. under nitrogen-gas atmosphere and the mixture was stirred at the same temperature for 30 minutes After warming to room temperature, to the reaction mixture was added dropwise vinylmagnesium bromide (7.7 mL, 0.97 M tetrahydrofuran solution) and the mixture was stirred at room temperature for 3 hours. To the reaction mixture was added water and an aqueous 1N HCl solution. After stirring, the mixture was extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and filtered. The filtrate was concentrated in vacuo and the resultant crude product was purified by column chromatography on silica gel (solvent: hexane/ethyl acetate=90/10 to 85/15) to obtain 1-(2-chlorophenyl)-5-(4-chlorophenyl)-4-methoxy-3-vinylcarbonyl-1H-pyrazole (780 mg, yield: 70%) as a colorless solid.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([OH:18])=O)[C:13](=[O:19])[C:12]([CH3:21])([CH3:20])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1.[NH2:23][C:24]1[CH:25]=[C:26]2[C:39](=[CH:40][CH:41]=1)[CH2:38][C@:28]1([C:36]3[C:31](=[N:32][CH:33]=[CH:34][CH:35]=3)[NH:30][C:29]1=[O:37])[CH2:27]2.C1C=CC2N(O)N=NC=2C=1.C(Cl)CCl>CN(C=O)C>[F:1][C:2]1[CH:3]=[C:4]([C@H:9]2[N:14]([CH2:15][C:16]([NH:23][C:24]3[CH:25]=[C:26]4[C:39](=[CH:40][CH:41]=3)[CH2:38][C@:28]3([C:36]5[C:31](=[N:32][CH:33]=[CH:34][CH:35]=5)[NH:30][C:29]3=[O:37])[CH2:27]4)=[O:18])[C:13](=[O:19])[C:12]([CH3:20])([CH3:21])[C:11](=[O:22])[CH2:10]2)[CH:5]=[C:6]([F:8])[CH:7]=1
Reactant: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)O)C1=O
Reactant: Nc1ccc2c(c1)C[C@@]1(C2)C(=O)Nc2ncccc21
Agent: On1nnc2ccccc21
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: CC1(C)C(=O)C[C@@H](c2cc(F)cc(F)c2)N(CC(=O)Nc2ccc3c(c2)C[C@@]2(C3)C(=O)Nc3ncccc32)C1=O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
A mixture of [(6S)-6-(3,5-difluorophenyl)-3,3-dimethyl-2,4-dioxopiperidin-1-yl]acetic acid (156 mg, 0.501 mmol, described in Intermediate 22), (R)-5-amino-1,3-dihydrospiro[indene-2,3′-pyrrolo[2,3-b]pyridin]-2′(1′H)-one (145 mg, 0.577 mmol, described in Intermediate 9), HOBT (95 mg, 0.620 mmol), and EDC (123 mg, 0.642 mmol) in DMF (2 mL) was stirred at ambient temperature for 16 h. The reaction mixture was partitioned between H2O (60 mL) and EtOAc (100 mL). The organic layer was dried over Na2SO4, filtered, and concentrated in vacuo. The crude product was purified by silica gel chromatography, eluting with a gradient of CH2Cl2:CH3OH—100:0 to 90:10, to give the title compound. MS: m/z=545 (M+1). HRMS: m/z=545.2025; calculated m/z=545.1995 for C30H27F2N4O4.
Reaction SMILES: [C:1]1([C:7]2[N:8]=[CH:9][NH:10][CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[H-].[Na+].[C:14](Cl)(=[O:16])[CH3:15]>O1CCCC1>[C:14]([N:10]1[CH:11]=[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)[N:8]=[CH:9]1)(=[O:16])[CH3:15]
Reactant: CC(=O)Cl
Reactant: c1ccc(-c2c[nH]cn2)cc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CC(=O)n1cnc(-c2ccccc2)c1
Reaction time: 0.33 h

Procedure:
To a solution of 4-phenylimidazole in 40 ml of tetrahydrofuran was added portionwise 1.66 g of 50% sodium hydride. After stirring for 20 minutes, 2.46 ml of acetyl chloride was added over 10 minutes and the reaction mixture allowed to stir overnight at room temperature. The reaction was filtered and the filtrate concentrated to give 4 g of crude product which was purified by chromatographing on 150 g of silica gel using 5% methanol in chloroform as eluent, 2.88 g.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([N+:12]([O-:14])=[O:13])[CH:3]=1.CCN(C(C)C)C(C)C.[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>CN(C=O)C>[N+:12]([C:4]1[CH:3]=[C:2]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=1)([O-:14])=[O:13]
Reactant: C1COCCN1
Reactant: O=[N+]([O-])c1cc(Br)cc(C(F)(F)F)c1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(N2CCOCC2)cc(C(F)(F)F)c1
Temperature: 25 °C
Yield: 50 %

Procedure:
Dissolve 1-bromo-3-nitro-5-(trifluoromethyl)benzene (270 mg, 1 mmol) and DIEA (258 mg, 2 mmol) in DMF (5 mL), add morpholine (174 mg, 2 mmol). Stir the reaction at 120° C. overnight. Cool to room temperature; remove the volatiles under reduced pressure to give a crude residue. Purification of the residue by chromatography (silica gel, EtOAc:PE=1:5) affords the product (138 mg, 50%).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12](Cl)[N:11]=1>C(O)CCCC.C(O)(C)C>[Cl:9][C:10]1[N:18]=[C:17]2[C:13]([NH:14][CH:15]=[N:16]2)=[C:12]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[N:11]=1
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: Nc1cccc(Cl)c1
Solvent: CC(C)O
Solvent: CCCCCO
Product: Clc1cccc(Nc2nc(Cl)nc3nc[nH]c23)c1
Temperature: 100 °C
Reaction time: 3 h

Procedure:
1.4 ml (13 mmol) of 3-chloro-aniline are added to a suspension of 650 mg (3.44 mmol) of 2,6-dichloro-purine in 5 ml of 1-pentanol. The reaction mixture is stirred at 100° C. (oil bath temperature) for 3 hours. After cooling to room temperature, the mixture is diluted with isopropanol and stirred at 10° C. for 90 minutes. The precipitate is filtered off and rinsed with isopropanol and diethyl ether. The crystals are partitioned between 50 ml of 2 N (two normal) sodium hydroxide solution, 100 ml of water and 700 ml of ethyl acetate. The aqueous phase is subsequently extracted twice with ethyl acetate. The combined organic extracts are washed twice with water and once with saturated sodium chloride solution and dried over sodium sulfate. After filtration, the filtrate is concentrated under reduced pressure. The crude product is stirred with diethyl ether and the crystals are dried at 50° C. under an HV. 2-Chloro-6-(3-chloro-phenyl-amino)-purine is obtained; Rf=0.47 (ethyl acetate:hexane=3:1); APCI-MS: (M+H)+=280; HPLC: tret(grad 20/1)=10.26 minutes.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[N:15]2[CH:16]=[CH:17][N:18]=[C:14]2[CH:13]=[CH:12][CH:11]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].ClC(Cl)(Cl)[C:21](Cl)=[O:22].C(=O)([O-])O.[Na+]>CN(C1C=CN=CC=1)C.C(Cl)(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[N:15]3[C:16](=[CH:17][N:18]=[C:14]3[CH:13]=[CH:12][CH:11]=2)[C:21]1=[O:22])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)C(Cl)(Cl)Cl
Reactant: CC(C)(C)OC(=O)NCc1cccc2nccn12
Agent: CN(C)c1ccncc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: CC(C)(C)OC(=O)N1Cc2cccc3ncc(n23)C1=O
Temperature: 0 °C
Yield: 45 %

Procedure:
To a solution of 989 mg (4.0 mmol) of 5-(tert-butoxycarbonylamino)methylimidazo[1,2-a]pyridine and 2200 mg (18.0 mmol) of 4-(N,N-dimethylamino)pyridine in 25 ml of chloroform was added dropwise 1.34 ml (12.0 mmol) of trichloroacetyl chloride at room temperature. The reaction mixture was heated for 5 hours under reflux. The reaction mixture was poured into ice-water. The mixture was neutralized with a saturated aqueous solution of sodium hydrogencarbonate. To the mixture was added 100 ml of chloroform for extraction of the desired compound. The organic layer was washed with 100 ml of a saturated saline, and dried over magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (eluent: chloroform:methanol=20:1) to give 492 mg of the desired compound (45.0%, pale yellow solid).
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[NH:4][C:3](=O)[C:2]1=[O:12].S(Cl)([Cl:15])=O>C1(C)C=CC=CC=1.CN(C)C=O>[Cl:15][CH:3]1[NH:4][C:5]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[O:1][C:2]1=[O:12]
Reactant: O=S(Cl)Cl
Reactant: O=c1[nH]c2ccccc2oc1=O
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: O=C1Oc2ccccc2NC1Cl
Temperature: 130 °C

Procedure:
A mixture of 25 g of 4H-1,4-benzoxazin-2,3-dione and 14.3 ml of thionylchloride in 500 ml of toluene and 5 ml dimethylformamide was heated at about 130° C. until all solids dissolved (about 2-3 hours). The solution was decanted hot (if the solution was deeply colored, charcoal was added and following stirring, the solution was filtered) and the organic solution was evaporated to dryness to give 29 g of 3-chloro-4H-1,4-benzoxazin-2-one, m.p. 133°-136° C.
Reaction SMILES: [C:1]([Br:5])(Br)(Br)Br.[Br:6][C:7]1[C:12]2[CH:13]=[C:14](CO)[O:15][C:11]=2[C:10]([O:18][CH3:19])=[CH:9][CH:8]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl>[Br:6][C:7]1[C:12]2[CH:13]=[C:14]([CH2:1][Br:5])[O:15][C:11]=2[C:10]([O:18][CH3:19])=[CH:9][CH:8]=1
Reactant: COc1ccc(Br)c2cc(CO)oc12
Reactant: BrC(Br)(Br)Br
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Product: COc1ccc(Br)c2cc(CBr)oc12
Reaction time: 1 h
Yield: 62.7 %

Procedure:
Carbon tetrabromide (1.52 g) was added to a stirred solution of (4-bromo-7-methoxybenzofuran-2-yl)-methanol (1 g) in dichloromethane (10 ml) at 0° C. under an inert atmosphere. Triphenylphosphine (1.53 g) was then added and the reaction stirred for 1 h. The reaction mixture was preadsorbed onto silica and purified by column chromatography eluting with 25% ethyl acetate in hexane to afford the title compound as a yellow solid (0.78 g).
Reaction SMILES: [CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18](I)[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3].C(N(CC)CC)C.[CH2:28]([NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:29]#[CH:30]>CN(C=O)C.[Cu]I.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>[CH2:1]([O:4][C@@H:5]1[C@@H:9]([CH2:10][OH:11])[O:8][C@@H:7]([N:12]2[CH:19]=[C:18]([C:30]#[C:29][CH2:28][NH:31][C:32](=[O:37])[C:33]([F:36])([F:35])[F:34])[C:16](=[O:17])[NH:15][C:13]2=[O:14])[CH2:6]1)[CH:2]=[CH2:3]
Reactant: C=CCO[C@H]1C[C@H](n2cc(I)c(=O)[nH]c2=O)O[C@@H]1CO
Reactant: C#CCNC(=O)C(F)(F)F
Agent: [Cu]I
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C=CCO[C@H]1C[C@H](n2cc(C#CCNC(=O)C(F)(F)F)c(=O)[nH]c2=O)O[C@@H]1CO
Reaction time: 16 h
Yield: 95.4 %

Procedure:
To a solution of (35) (400 mg, 1.0 mmol) in dry DMF (10 ml) was added CuI (38 mg, 20 μmol) and triethylamine (300 μl, 2.0 mmol). The propargyltrifluoroacetamide (453 mg, 3.0 mmol) was added drop wise, followed by Pd(PPh3)4 (110 mg, 9.5 μmol). The reaction was stirred for 16 h in the dark. The reaction was quenched by adding MeOH (10 ml), DCM (10 ml) and bicarbonate dowex. The mixture was stirred for 30 min and then filtered. The solvents were removed under vacuum and the crude product was purified by chromatography on silica (EtOAc:petrol 3:7 to 7:3). The product was isolated as slightly yellow crystals (398 mg, 95%). 1H NMR (d6 DMSO) δ 2.25-2.43 (m, 2H, H-2′), 3.65-3.76 (m, 2H, H-5′), 4.07-4.17 (m, 3H, H-4′, CH2), 4.21-4.23 (m, 1H, H-3′), 4.34 (d, J=5.5 Hz, 2H, CH2N), 5.25-5.27 (m, 2H, ═CH2, OH), 5.38 (dd, J=1.83, 17.3 Hz, 1H, ═CH2), 5.96-6.06 (m, 1H, ═CH), 6.17 (t, J=6.9 Hz, 1H, H-1′), 8.29 (8, 1H, H-6), 10.17 (t, J=5.5 Hz, 1H, NHTFA), 11.78 (s, 1H, NH). Mass (−ve electrospray) calcd for C17H18F3N3O6 417.11, found 416.
Reaction SMILES: [N+:1]([C:4]1[CH:10]=[CH:9][C:7]([NH2:8])=[CH:6][CH:5]=1)([O-:3])=[O:2].[C:11]([C:15]1[CH:16]=[C:17]([CH:21]=[C:22]([C:25]([CH3:28])([CH3:27])[CH3:26])[C:23]=1[OH:24])[C:18](O)=[O:19])([CH3:14])([CH3:13])[CH3:12].C1(N=C=NC2CCCCC2)CCCCC1>C1COCC1>[CH3:28][C:25]([C:22]1[CH:21]=[C:17]([CH:16]=[C:15]([C:11]([CH3:14])([CH3:13])[CH3:12])[C:23]=1[OH:24])[C:18]([NH:8][C:7]1[CH:9]=[CH:10][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)=[O:19])([CH3:26])[CH3:27]
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: Nc1ccc([N+](=O)[O-])cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: CC(C)(C)c1cc(C(=O)Nc2ccc([N+](=O)[O-])cc2)cc(C(C)(C)C)c1O
Temperature: 25 °C
Reaction time: 15 h
Yield: 65 %

Procedure:
1.38 g (10 mmoles) of 4-nitroaniline, 2.5 g (10 mmoles) of 3,5-di-tert-butyl-4-hydroxybenzoic acid and 2.26 g (11 mmoles) of dicyclohexylcarbodiimide are introduced into a 250 ml flask containing 20 ml of THF. The reaction medium is agitated for 15 hours at ambient temperature, and the precipitate which appears is filtered out and rinsed with ethyl acetate After the solution is concentrated under reduced pressure, the residue is diluted in 20 ml of ethyl acetate and the insoluble part is filtered out. The solvent is eliminated under vacuum and the residue is precipitated from diethyl ether. The solid is recovered by filtration, rinsed abundantly with diethyl ether in order to produce a white powder with a yield of 65%. Melting point: 277-278° C.