Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]([Br:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15]C)=[C:11]([CH2:17][C:18]2[CH:23]=[CH:22][C:21]([F:24])=[CH:20][CH:19]=2)[CH:10]=1.ClCCl.B(Br)(Br)Br>C(OCC)(=O)C>[Br:1][C:2]1[CH:3]=[C:4]([OH:26])[CH:5]=[C:6]([Br:25])[C:7]=1[O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[C:11]([CH2:17][C:18]2[CH:19]=[CH:20][C:21]([F:24])=[CH:22][CH:23]=2)[CH:10]=1
Reactant: COc1ccc(Oc2c(Br)cc(O)cc2Br)cc1Cc1ccc(F)cc1
Agent: BrB(Br)Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: Oc1cc(Br)c(Oc2ccc(O)c(Cc3ccc(F)cc3)c2)c(Br)c1
Reaction time: 8 h
Yield: 65.8 %

Procedure:
To a stirred solution of 3,5-dibromo-4-[3′-(4-fluorobenzyl)-4′-methoxyphenoxy]phenol (1.66 gm, 3.44 mmol), dichloromethane 100 mL, was added boron tribromide (8.6 mL, 8.60 mmol) in an ice/water bath. The reaction was stirred overnight under a nitrogen atmosphere. The reaction was diluted with ethyl acetate 60 mL, filtered and washed with water 2× with 10 mL and brine 3×10 mL. The ethyl acetate was dried over Na2SO4, filtered and concentrated under reduced pressure. 3,5-Dibromo-4-[3′-(4-fluorobenzyl)-4′-hydroxyphenoxy]phenol (1.06 gm, 66%) was obtained by flash chromatography using SiO2 eluted with a step gradient of hexane-ethyl acetate[3:1] 2L and hexane-ethyl acetate [3:2]; 1H NMR (300 MHz, DMSO-d6): δ 10.24 (s, 1H), 9.14 (s, 1H), 7.22 (m, 2H), 7.08 (m, 4H), 6.69 (td, J=8.7 Hz, 1H), 6.54 (d, J=3.3 Hz, 1H), 6.55 (dd, J=8.4, 3.3 Hz, 1H), 6.35 (dd, J=9, 3 Hz, 1H), 3.80 (s, 2H); TLC conditions: Uniplate silica gel, 250 microns; Mobile phase=methylene chloride-hexanes (1:1); Rf=0.55.
Reaction SMILES: [C:1]([N:9]1[CH2:14][CH2:13][N:12]([C:15]([O:17]C(C)(C)C)=[O:16])[CH2:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CO.C(Cl)(Cl)[Cl:25]>O1CCOCC1>[ClH:25].[C:1]([N:9]1[CH2:10][CH2:11][N:12]([C:15]([O-:17])=[O:16])[CH2:13][CH2:14]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: ClC(Cl)Cl
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccccc2)CC1
Solvent: C1COCCO1
Solvent: CO
Product: Cl
Product: O=C([O-])N1CCN(C(=O)c2ccccc2)CC1
Yield: 96 %

Procedure:
General procedure B was followed using tert-butyl 4-benzoylpiperazine-1-carboxylate 9 (75 mg, 0.26 mmol), MeOH (2 mL) and a 4 M solution of hydrogen chloride in 1,4-dioxane (2 mL) to furnish the title compound as a colourless oil (47 mg, 96%), umax (CHCl3)/cm−1 3015, 2954, 1622, 1435, 1290, 1136, 1018; m/z (ESI) C11H15N2O requires 191.1179, found [M+H]+ 191.1179.
Reaction SMILES: [C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[CH2:14]3)(=[O:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[N:21]1([CH2:26][CH2:27][O:28][C:29]2[CH:30]=[C:31]3[C:35](=[CH:36][CH:37]=2)[NH:34][C:33]([CH:38]=O)=[CH:32]3)[CH2:25][CH2:24][CH2:23][CH2:22]1>>[C:1]1([NH:7][S:8]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][C:15](=[O:20])[C:14]3=[CH:38][C:33]2[NH:34][C:35]3[C:31]([CH:32]=2)=[CH:30][C:29]([O:28][CH2:27][CH2:26][N:21]2[CH2:25][CH2:24][CH2:23][CH2:22]2)=[CH:37][CH:36]=3)(=[O:10])=[O:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1
Reactant: O=C1Cc2cc(S(=O)(=O)Nc3ccccc3)ccc2N1
Product: O=C1Nc2ccc(S(=O)(=O)Nc3ccccc3)cc2C1=Cc1cc2cc(OCCN3CCCC3)ccc2[nH]1

Procedure:
2-Oxo-2,3-dihydro-1H-indole-5-sulfonic acid phenylamide was condensed with 5-(2-pyrrolidin-1-yl-ethoxy)-1H-indole-2-carbaldehyde to give the title compound.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([N:7]2[CH2:12][CH2:11][NH:10][CH2:9][CH2:8]2)=[CH:5][CH:6]=1.Cl.C=O.[C:16]([O-])(=O)C.[Na+].[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[CH:24]=[C:23]1[CH2:31][O:32][C:33]1[CH:38]=[CH:37][C:36]([Cl:39])=[CH:35][CH:34]=1>ClC(Cl)C>[CH3:21][N:22]1[C:30]2[C:25](=[CH:26][CH:27]=[CH:28][CH:29]=2)[C:24]([CH2:16][N:10]2[CH2:9][CH2:8][N:7]([C:4]3[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=3)[CH2:12][CH2:11]2)=[C:23]1[CH2:31][O:32][C:33]1[CH:34]=[CH:35][C:36]([Cl:39])=[CH:37][CH:38]=1
Reactant: c1ccc(N2CCNCC2)cc1
Reactant: Cn1c(COc2ccc(Cl)cc2)cc2ccccc21
Reactant: CC(=O)[O-]
Agent: C=O
Agent: Cl
Agent: [Na+]
Solvent: CC(Cl)Cl
Product: Cn1c(COc2ccc(Cl)cc2)c(CN2CCN(c3ccccc3)CC2)c2ccccc21
Temperature: 25 °C
Reaction time: 72 h

Procedure:
Under a nitrogen atmosphere in a round bottom flask, phenylpiperazine (0.149 g, 0.920 mmol) was dissolved in 2.0 ml of dichloroethane. The reaction vessel was placed in an ice bath. Concentrated hydrochloric acid (0.084 ml, 1.01 mmol) was added and the reaction vessel was removed from the ice bath. Paraformaldehyde (0.304 g, 1.01 mmol) and sodium acetate (0.113 g, 0.920 mmol) were then added, followed by the addition of 1-methyl-2-(4-chlorophenoxymethyl)-1H-indole (0.250 g, 0.920 mmol). The reaction mixture was then heated to reflux and maintained at this temperature for about six hours. The progress of the reaction was monitored by thin layer chromatography. The reaction mixture was then stirred at room temperature for about three days.
Reaction SMILES: [Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5](Cl)=[N:6][CH:7]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([CH2:26][OH:27])=[CH:22][CH:21]=1>CN(C=O)C>[Br:1][C:2]1[C:3]([O:9][CH2:10][CH3:11])=[CH:4][C:5]([O:27][CH2:26][C:23]2[CH:24]=[CH:25][C:20]([O:19][CH3:18])=[CH:21][CH:22]=2)=[N:6][CH:7]=1
Reactant: COc1ccc(CO)cc1
Reactant: CCOc1cc(Cl)ncc1Br
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOc1cc(OCc2ccc(OC)cc2)ncc1Br
Temperature: 120 °C
Reaction time: 12 h
Yield: 37.2 %

Procedure:
A mixture of 5-bromo-2-chloro-4-ethoxypyridine (8 g, 33.8 mmol), Cs2CO3 (33.1 g, 101 mmol) and (4-methoxyphenyl)methanol (5.37 g, 38.9 mmol) in DMF (100 mL) was stirred at 120° C. for 12 h. The mixture was then concentrated. The residue was added to DCM (150 mL). The mixture was filtered and the filtrate was concentrated. The crude material was purified by silica column chromatography (PE/EA=8:1). All fractions found to contain product by TLC (PE/EA=5:1, Rf=0.4) were combined and concentrated to yield a yellow solid of 5-bromo-4-ethoxy-2-((4-methoxybenzyl)oxy)pyridine (5 g, 12.57 mmol, 37% yield): 1H NMR (400 MHz, CDCl3) δ: 8.05 (s, 1H), 7.32 (d, J=8.8 Hz, 1H), 6.84 (d, J=8.4 Hz, 1H), 6.17 (s, 1H), 5.18 (s, 2H), 4.02 (q, J=6.8 Hz, 2H), 3.74 (s, 3H), 1.40 (t, J=7.2 Hz, 3H); ES-LCMS m/z 338 (M+H).
Reaction SMILES: [CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([O:22]C)=O)[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2].O.[NH2:25][NH2:26]>CCO>[CH:1]([O:4][C:5]1[N:10]=[C:9]([C:11]2[CH:12]=[C:13]3[C:17](=[CH:18][CH:19]=2)[NH:16][CH:15]=[C:14]3[C:20]([NH:25][NH2:26])=[O:22])[CH:8]=[N:7][CH:6]=1)([CH3:3])[CH3:2]
Reactant: COC(=O)c1c[nH]c2ccc(-c3cncc(OC(C)C)n3)cc12
Reactant: NN
Solvent: CCO
Solvent: O
Product: CC(C)Oc1cncc(-c2ccc3[nH]cc(C(=O)NN)c3c2)n1
Temperature: 25 °C
Yield: 90.9 %

Procedure:
To a stirred solution of methyl 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carboxylate (10 g, 30 mmol) in EtOH (50 mL) was added hydrazine hydrate (30 mL) and the reaction was heated at reflux for 48 h. The reaction was cooled to RT and a white precipitate was formed. The suspension was filtered and dried to afford 5-(6-isopropoxypyrazin-2-yl)-1H-indole-3-carbohydrazide (9.0 g, 90.9%) as a white solid. MS (ESI, pos. ion) m/z: 312 (M+1); 1H-NMR (DMSO-d6) δ ppm; 11.71 (s, 1H), 9.2 (s, 1H), 8.8 (d, J=1.6 Hz, 1H), 8.71 (s, 1H), 8.1 (s, 1H), 8.0 (s, 1H), 7.90 (dd, J=8.4, 1.6 Hz, 1H), 7.55 (d, J=8.4 Hz, 1H), 5.4 (m, 1H), 4.35 (d, J=2 Hz, 1H), 1.4 (d, J=6.0 Hz, 6H).
Reaction SMILES: [Cl:1][CH2:2][C:3](Cl)=[O:4].[NH2:6][CH:7]([C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1)[C:8]1[CH:13]=[CH:12][C:11]([NH:14][C:15]([CH:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18]2)=[O:16])=[CH:10][CH:9]=1.C(N(C(C)C)C(C)C)C.O>C(Cl)Cl>[Cl:1][CH2:2][C:3]([NH:6][CH:7]([C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1)[C:8]1[CH:9]=[CH:10][C:11]([NH:14][C:15]([CH:17]2[O:21][N:20]=[C:19]([C:22]3[CH:23]=[N:24][CH:25]=[CH:26][CH:27]=3)[CH2:18]2)=[O:16])=[CH:12][CH:13]=1)=[O:4]
Reactant: NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: ClCCl
Product: O=C(CCl)NC(c1ccccc1)c1ccc(NC(=O)C2CC(c3cccnc3)=NO2)cc1
Temperature: 0 °C
Reaction time: 1 h
Yield: 67.9 %

Procedure:
) A solution of chloroacetylchloride (0.0089 mol) in CH2Cl2 (20 ml, dried over MgSO4) was added to a cooled solution of (±)-N-[4-(aminophenylmethyl)phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide (0.0081 mol) and N-ethyl-N-(1-methylethyl)-2-propanamine (0.0093 mol) in CH2Cl2 (100 ml). The reaction mixture was stirred for one hour at 0° C. Water was added. The organic layer was separated, dried (MgSO4), filtered and the solvent was evaporated under reduced pressure. The residue (crude oil) was purified by short column chromatography over silica gel (eluent: CH2Cl2/CH3OH 98/2). The pure fractions were collected and the solvent was evaporated under reduced pressure. The residue was stirred in EtOAc. The precipitate was filtered off, washed with EtOAc, and dried, yielding 2.47 g (68%) of (±)-N-[4-[[(chloroacetyl)amino]phenylmethyl]phenyl]-4,5-dihydro-3-(3-pyridinyl)-5-isoxazolecarboxamide. (compound 127)
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12](Cl)(=O)=O)[CH:11]=1)[O:8][CH:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2.II.[C:27]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CCN(CC)CC.CI>C1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([S:12][CH3:27])[CH:11]=1)[O:8][CH:7]([C:16]([F:19])([F:18])[F:17])[C:6]([C:20]([O:22][CH2:23][CH3:24])=[O:21])=[CH:5]2
Reactant: CCOC(=O)C1=Cc2cc(Cl)cc(S(=O)(=O)Cl)c2OC1C(F)(F)F
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Agent: II
Solvent: c1ccccc1
Solvent: CCN(CC)CC
Solvent: CI
Product: CCOC(=O)C1=Cc2cc(Cl)cc(SC)c2OC1C(F)(F)F
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To benzene (solvent) was added ethyl 6-chloro-8-(chlorosulfonyl)-2-(trifluoromethyl)-2H-chromene-3-carboxylate (Step 2, 0.68 g, 1.68 mmol), iodine (0.11 g, 0.84 mmol), and triphenyl phosphine (4.41 g, 16.8 mmol) amd the resulting mixture heated to reflux for 4 h and allowed to cool to RT and stand for 48 h. To this crude reaction was added Et3N (0.58 mL, 0.424 g, 4.20 mmol) and methyl iodide (0.06 mL, 0.13 g, 0.92 mmol). After extractive workup and silica chromatography the title compound was obtained as a yellow, crystalline mass (0.215 g, 36%). 1HNMR (CDCl3-d6/300 MHz) 7.59 (s, 1H), 7.07 (d, J=2.4 Hz, 1H), 6.98 (d, J=2.4 Hz, 1H), 5.78 (q, 1H, J=6.8 Hz), 4.20-4.40 (m, 3H), 2.42 (s, 3H), 1.33 (t, 3H, J=7.3 Hz).
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH:5]=[CH:6]1)[C:3](=[O:8])[NH:2]2.[CH2:9](O)[CH3:10].[ClH:12].CC[O:15]CC>>[ClH:12].[NH2:2][C@@H:1]1[CH2:7][C@H:4]([C:3]([O:8][CH2:9][CH3:10])=[O:15])[CH:5]=[CH:6]1
Reactant: CCOCC
Reactant: CCO
Reactant: O=C1NC2C=CC1C2
Agent: Cl
Product: CCOC(=O)[C@@H]1C=C[C@H](N)C1
Yield: 100 %

Procedure:
A mixture of (−)-2-azabicyclo[2.2.1]hept-5-en-3-one (10 g, 91.7 mmol), ethanol (200 mL) and conc. HCl (10 mL) was heated at reflux for 2 h. The mixture was concentrated and the residue dried under vacuum. A white solid was obtained which was suspended in ether to give 17.5 g (100%) of (−)-ethyl cis-4-amino-2-cyclopentene-1-carboxylate hydrochloride.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9](S(C)=O)[N:8]=1.C[N:32]1[CH2:35][C:34]2([CH2:40][CH2:39][NH:38][CH2:37][CH2:36]2)[CH2:33]1.[CH2:41](N(CC)CC)C>C1COCC1>[Cl:1][C:2]1[CH:3]=[C:4]([CH:26]=[CH:27][C:28]=1[O:29][CH3:30])[CH2:5][NH:6][C:7]1[C:12]([C:13]([NH:15][CH2:16][C:17]2[N:22]=[CH:21][CH:20]=[CH:19][N:18]=2)=[O:14])=[CH:11][N:10]=[C:9]([N:32]2[CH2:33][C:34]3([CH2:36][CH2:37][N:38]([CH3:41])[CH2:39][CH2:40]3)[CH2:35]2)[N:8]=1
Reactant: CCN(CC)CC
Reactant: COc1ccc(CNc2nc(S(C)=O)ncc2C(=O)NCc2ncccn2)cc1Cl
Reactant: CN1CC2(CCNCC2)C1
Solvent: C1CCOC1
Product: COc1ccc(CNc2nc(N3CC4(CCN(C)CC4)C3)ncc2C(=O)NCc2ncccn2)cc1Cl
Reaction time: 4 h
Yield: 9 %

Procedure:
In THF (10 mL) were dissolved 4-((3-chloro-4-methoxybenzyl)amino)-2-(methyl sulfinyl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide (152 mg, 0.34 mmol) and 2-methyl-2,7-diazaspiro[3.5]nonane (70 mg, 0.50 mmol). Then triethylamine (68 mg, 0.67 mmol) was added dropwisely. The reaction was conducted at ambient temperature for 4 h. The solvent was removed by rotary evaporation, followed by addition of water and extraction with DCM. The organic phase was dried over sodium sulfate and purified by silica gel column chromatography (DCM/methanol=20/1) to give 4-((3-chloro-4-methoxybenzyl)amino)-2-(7-methyl-2,7-diazaspiro[3.5]nonan-2-yl)-N-(pyrimidin-2-ylmethyl)pyrimidine-5-formamide as a white solid (16 mg, 9% yield).
Reaction SMILES: [C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:17][CH2:16][N:15]([C:18]3[S:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:14][CH2:13]2)=[O:11])=[CH:5][CH:4]=1)#[N:2].[OH-:29].[Na+].O>CO.O1CCCC1>[NH2:2][C:1]([C:3]1[N:8]=[CH:7][C:6]([NH:9][C:10]([N:12]2[CH2:13][CH2:14][N:15]([C:18]3[S:22][N:21]=[C:20]([C:23]4[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=4)[N:19]=3)[CH2:16][CH2:17]2)=[O:11])=[CH:5][CH:4]=1)=[O:29]
Reactant: [OH-]
Reactant: N#Cc1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: NC(=O)c1ccc(NC(=O)N2CCN(c3nc(-c4ccccc4)ns3)CC2)cn1
Temperature: 60 °C
Reaction time: 48 h
Yield: 12.3 %

Procedure:
To a solution of N-(6-cyanopyridin-3-yl)-4-(3-phenyl-1,2,4-thiadiazol-5-yl)piperazine-1-carboxamide (100 mg, 0.255 mmol) in methanol/tetrahydrofuran (1:4) (15 ml) was added a 1N aqueous sodium hydroxide solution (2.56 ml, 2.55 mmol) at room temperature, and the mixture was stirred at 60° C. for 2 days. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate) and recrystallized from a mixed solvent of hexane and tetrahydrofuran to give 12.8 mg (12.2%) of the desired product as a solid.
Reaction SMILES: [C:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1CC(OCCCCNC(=O)C=C)=O)(=[O:4])[CH:2]=[CH2:3].C(NCCCCO[C:40]1[CH:41]=[C:42]([CH2:46]C(OCCCCNC(=O)C=C)=O)[CH:43]=[CH:44][CH:45]=1)(=O)C=C.C(NCCCCOC1C=CC(C[C:76]([O:78]CCCCNC(=O)C=C)=[O:77])=CC=1)(=O)C=C.C(NCCCCOC(C1C=CC=CC=1)C(OCCCCNC(=O)C=C)=O)(=O)C=C>>[C:1]([NH:5][CH2:6][CH2:7][CH2:8][CH2:9][O:10][C:11]1[CH:12]=[CH:13][C:14]([C:76]([O:78][CH2:46][C:42]2[CH:41]=[CH:40][CH:45]=[CH:44][CH:43]=2)=[O:77])=[CH:15][CH:16]=1)(=[O:4])[CH:2]=[CH2:3]
Reactant: C=CC(=O)NCCCCOC(=O)Cc1ccc(OCCCCNC(=O)C=C)cc1
Reactant: C=CC(=O)NCCCCOC(=O)Cc1cccc(OCCCCNC(=O)C=C)c1
Reactant: C=CC(=O)NCCCCOC(=O)Cc1ccccc1OCCCCNC(=O)C=C
Agent: C=CC(=O)NCCCCOC(=O)C(OCCCCNC(=O)C=C)c1ccccc1
Product: C=CC(=O)NCCCCOc1ccc(C(=O)OCc2ccccc2)cc1

Procedure:
4-Acrylamidobutyl 2-(4-acrylamidobutoxy)phenylacetate; 4-Acrylamidobutyl 3-(4-acrylamidobutoxy)phenylacetate; 4-Acrylamidobutyl 4-(4-acrylamidobutoxy)phenylacetate; 4-Acrylamidobutyl α-(4-acrylamidobutoxy)phenylacetate;
Reaction SMILES: [CH3:1][S:2]([C:5]1[CH:10]=[CH:9][C:8]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[NH:13])=[CH:7][CH:6]=1)(=[O:4])=[O:3].C(=O)(O)[O-].[Na+].Br[CH2:26][C:27](=[O:32])[C:28]([F:31])([F:30])[F:29]>C(O)(C)C>[OH:32][C:27]1([C:28]([F:31])([F:30])[F:29])[CH2:26][N:11]([C:8]2[CH:7]=[CH:6][C:5]([S:2]([CH3:1])(=[O:3])=[O:4])=[CH:10][CH:9]=2)[C:12]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:13]1
Reactant: CS(=O)(=O)c1ccc(NC(=N)c2ccccc2)cc1
Reactant: O=C(CBr)C(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(C)O
Product: CS(=O)(=O)c1ccc(N2CC(O)(C(F)(F)F)N=C2c2ccccc2)cc1
Yield: 58.9 %

Procedure:
To a mixture of N-[4-(methylsulfonyl)phenyl]benzenecarboximidamide (Step 1) (16.5 g, 60.1 mmol) and sodium bicarbonate (10.1 g, 0.12 mol) in isopropanol (900 mL), 3-bromo-1,1,1-trifluoroacetone (8.7 ml, 84 mmol) was added. After heating the reaction mixture at 75–80° C. for 20 hours, the solvent was removed. The residue was redissolved in methylene chloride and washed with water. The organic fractions were combined, dried over sodium sulfate, filtered and concentrated in vacuo. The crude mixture was purified by chromatography (silica gel, hexane/ethyl acetate, 45/55) to give 4-hydroxy-1-[4-(methylsulfonyl)phenyl]-2-phenyl-4-trifluoromethyl-4,5-dihydro-1H-imidazole (13.6 g, 59%) as awhite solid: mp 189–190° C. Anal. Calc'd for C17H15N2F3SO3: C, 53.12; H, 3.93; N, 7.29; S, 8.34. Found: C, 53.05; H, 3.90; N, 7.14; S, 8.38.
Reaction SMILES: [OH:1][C:2]1[CH2:7][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[CH2:5][C:4](=[O:16])[C:3]=1[C:17](=O)[CH2:18][CH3:19].[CH2:21]([O:23][NH2:24])[CH3:22]>C(O)C>[CH2:21]([O:23][N:24]=[C:17]([C:3]1[C:4](=[O:16])[CH2:5][CH:6]([C:8]2[CH:13]=[CH:12][C:11]([S:14][CH3:15])=[CH:10][CH:9]=2)[CH2:7][C:2]=1[OH:1])[CH2:18][CH3:19])[CH3:22]
Reactant: CCC(=O)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Reactant: CCON
Solvent: CCO
Product: CCON=C(CC)C1=C(O)CC(c2ccc(SC)cc2)CC1=O
Temperature: 0 °C
Reaction time: 15 h

Procedure:
Into 20 ml of ethanol was dissolved 2.9 g of 3-hydroxy-5-(4-methylthiophenyl)-2-propionyl-2-cyclohexen-1-one and to the solution was added 0.8 g of ethoxyamine. The mixture was kept for 15 hours at room temperature and it was poured into ice water. The crystal sedimented was collected with a filtering step and recrystallized with methanol. Thus, 3.1 g of colorless objective crystals having a melting point of 83°-84° C. was obtained.
Reaction SMILES: [F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=O)=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35].C([N:39](C(C)C)C(C)C)C.[Cl-].[NH4+]>CN(C)C=O>[F:1][C:2]1([F:36])[CH2:8][N:7]([C@@H:9]2[CH2:11][C@H:10]2[C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:6]2[N:18]=[C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([NH2:39])=[O:29])=[CH:25][C:24]=3[O:32][CH3:33])[N:20]=[CH:21][C:5]=2[N:4]([CH3:34])[C:3]1=[O:35]
Reactant: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Reactant: CCN(C(C)C)C(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: CN(C)C=O
Product: COc1cc(C(N)=O)ccc1Nc1ncc2c(n1)N([C@@H]1C[C@H]1c1ccccc1)CC(F)(F)C(=O)N2C
Temperature: 25 °C
Reaction time: 1 h
Yield: 97.1 %

Procedure:
To a mixture of 0.074 g (0.15 mmole) of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzoic acid (I-287), 0.11 mL (0.6 mmole) of ethyldiisopropyl amine and 0.016 g (0.30 mmole) of ammonium chloride in 2.0 mL of dimethylformamide was added 0.071 g (0.17 mmole) of 1-(di-1-pyrrolidinylmethylene)-1H-benzotriazolium 3-oxide hexafluorophosphate. The mixture was stirred at room temperature for 1 hour, then diluted with 10 mL of ice water. The mixture was extracted three times with dichloromethane. The combined organic layers were washed three times with sodium carbonate, three times with brine, dried over anhydrous sodium sulfate, filtered and concentrated under reduced pressure. Purification by silica gel chromatography, eluting with dichloromethane-methanol (gradient, 100:0-90:10) gave 0.072 g of 4-[7,7-difluoro-5-methyl-6-oxo-9-(trans-2-phenyl-cyclopropyl)-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-ylamino]-3-methoxy-benzamide (I-289) as a white solid.
Reaction SMILES: [C:1]1([CH3:25])[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[CH:7]1[CH2:12][CH2:11][N:10]([CH2:13][CH:14]2[CH:18]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[CH2:17][NH:16][CH2:15]2)[CH2:9][CH2:8]1.CCN(C(C)C)C(C)C.C1N(P(Cl)(N2C(=O)OCC2)=O)C(=O)OC1.[C:50](O)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1>C(Cl)Cl>[C:50]([N:16]1[CH2:17][CH:18]([C:19]2[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=2)[CH:14]([CH2:13][N:10]2[CH2:11][CH2:12][CH:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][C:1]=3[CH3:25])[CH2:8][CH2:9]2)[CH2:15]1)(=[O:57])[C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1
Reactant: O=C(O)c1ccccc1
Reactant: Cc1ccccc1C1CCN(CC2CNCC2c2ccccc2)CC1
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccccc1C1CCN(CC2CN(C(=O)c3ccccc3)CC2c2ccccc2)CC1

Procedure:
The title compound was prepared from 3-(SR)-(4-(2-tolyl)-piperidin-1-ylmethyl)-4-(SR)-phenylpyrrolidine (Step A), 0.014 mL of DIEA, 12.5 mg of BOP-Cl and 5 mg of benzoic acid in 0.5 mL of CH2Cl2 using a procedure analogous to that described in Example 63 to provide the title compound. RF : 0.45 (5% MeOH in CH2Cl2). 1H NMR (300 MHz, CDCl3): δ 1.4-4.5 (m, 20H), 7.05-7.6 (m, 14H). Mass Spectrum (CI): 439.4 (M+H).
Reaction SMILES: Br[CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9].[Br:10][C:11]1[CH:12]=[CH:13][C:14]([OH:20])=[C:15]([CH:19]=1)[C:16]([OH:18])=[O:17].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O>[Br:10][C:11]1[CH:12]=[CH:13][C:14]([O:20][CH2:2][C:3]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[F:9])=[C:15]([CH:19]=1)[C:16]([O:18][CH2:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=1[F:9])=[O:17]
Reactant: Fc1ccccc1CBr
Reactant: O=C(O)c1cc(Br)ccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: O=C(OCc1ccccc1F)c1cc(Br)ccc1OCc1ccccc1F
Temperature: 70 °C
Reaction time: 8 h

Procedure:
Neat 1-(bromomethyl)-2-fluorobenzene (1533 mg, 8.11 mmol) was added over 1 min to a stirred suspension of 5-bromo-2-hydroxybenzoic acid (800 mg, 3.69 mmol) and potassium carbonate (1274 mg, 9.22 mmol) in acetone (60 ml) in air at room temperature. The reaction mixture was stirred at 70° C. overnight. The reaction mixture was filtered. The filtrate was evaporated and the residue was dissolved in diethyl ether (30 ml) and evaporated again. The residue was dried in vacuo to yield the title compound as a white solid. 1.74 g.
Reaction SMILES: [CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8](O)=[O:9])[CH2:5][CH2:4][CH2:3][CH2:2]1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.[NH2:58][C:59]1[CH:64]=[CH:63][N:62]=[CH:61][N:60]=1>C(Cl)Cl>[CH:1]1([CH2:6][CH:7]([C:11]2[CH:16]=[CH:15][C:14]([S:17]([CH3:20])(=[O:19])=[O:18])=[C:13]([N+:21]([O-:23])=[O:22])[CH:12]=2)[C:8]([NH:58][C:59]2[CH:64]=[CH:63][N:62]=[CH:61][N:60]=2)=[O:9])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)O)cc1[N+](=O)[O-]
Reactant: Nc1ccncn1
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)c1ccc(C(CC2CCCC2)C(=O)Nc2ccncn2)cc1[N+](=O)[O-]
Yield: 30.5 %

Procedure:
A solution of 3-cyclopentyl-2-(4-methanesulfonyl-3-nitrophenyl)-propionic acid (prepared as in Example 14, 150 mg, 0.439 mmol), triethylamine (0.184 mL, 1.32 mmol), benzotriazol-1-yloxy-tris(dimethylamino)phosphonium hexafluorophosphate (291 mg, 0.659 mmol), and 4-aminopyrimidine (63 mg, 0.659 mmol) in methylene chloride (4 mL) was stirred at 25° C. overnight. The crude reaction mixture was directly purified by Biotage chromatography (FLASH 40M, Silica, 1/2 hexanes/ethyl acetate) to afford 3-cyclopentyl-2-(4-methanesulfonyl-3-nitro-phenyl)-N-pyrimidin-4-yl-propionamide (56 mg, 30%) as a pale yellow foam: mp 91-95° C. (foam to gel); EI-HRMS m/e calcd for C19H22N4O5S (M+) 418.1311, found 418.1310.