Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:5]([C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[O:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:23][CH2:24][CH2:25][C:26](Cl)=[O:27]>C(C(C)=O)C>[C:6]([C:5]1[CH:4]=[CH:3][C:2]([O:1][C:26](=[O:27])[CH2:25][CH2:24][Cl:23])=[CH:15][CH:14]=1)(=[O:7])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: O=C(c1ccccc1)c1ccc(O)cc1
Reactant: O=C(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: CCC(C)=O
Product: O=C(CCCl)Oc1ccc(C(=O)c2ccccc2)cc1
Temperature: -10 °C
Reaction time: 3 h

Procedure:
6.7 g (35 mmol) of 4-hydroxy-benzophenone was dissolved in 100 ml methyl ethyl ketone. 4.2 g (42 mmol) triethyl amine was added and the mixture was cooled to −10° C. 5.3 g (42 mmol) 3-chloro-propionyl chloride was added drop wise, while the temperature was kept below −5° C. The reaction was allowed to continue for 30 minutes at 0° C. and 3 hours at room temperature. The precipitated salts were removed by filtration and the solvent was evaporated under reduced pressure. 3-Chloro-propionic acid 4-benzoylphenyl ester was isolated by preparative column chromatography on a Prochrom LC80 column, using n-hexane/ethylacetate 75/25 as eluent at a flow rate of 150 ml/min and Kromasil 60A 10 micron as silica. 1.2 g of 3-chloro-propionic acid 4-benzoylphenyl ester was isolated.
Reaction SMILES: [CH2:1]([NH:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4].C(=O)([O-])[O-].[K+].[K+].Br[CH:19]([CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[CH3:20].CN(C=O)C>O>[CH2:1]([N:5]([CH:19]([CH3:20])[CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[CH2:2][CH2:3][CH3:4]
Reactant: CCCCNc1ccccc1
Reactant: CCCCCC(C)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCCCC(C)N(CCCC)c1ccccc1
Temperature: 130 °C
Reaction time: 86 h
Yield: 60 %

Procedure:
A mixture of N-butylaniline (7.45 parts) anhydrous potassium carbonate (7.5 parts), 2-bromoheptane (13.5 parts) and DMF (25 parts) was stirred at 130° C. for 86 hours. The reaction mixture was poured into water, saturated with salt and extracted with ethyl acetate. The organic phase was washed with water, dried (MgSO4) and evaporated to leave N-butyl-N-(1-methylhexyl)aniline (11.8 parts, approximately 60% strength). This material had acetic anhydride (10 parts) added to it prior to further use.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([OH:18])=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8].[OH-].[K+].Br[C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1>CN(C)C(=O)C.[Cu]>[F:1][C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][C:31]=1[F:32])[CH2:5][NH:6][C:7]([C:9]1[C:17]2[C:12](=[CH:13][C:14]([O:18][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)=[CH:15][CH:16]=2)[N:11]([CH2:19][C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=2)[C:10]=1[CH:26]([CH3:28])[CH3:27])=[O:8]
Reactant: Brc1cccnc1
Reactant: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(O)cc2n1Cc1ccccn1
Agent: [Cu]
Agent: [K+]
Agent: [OH-]
Solvent: CC(=O)N(C)C
Product: CC(C)c1c(C(=O)NCc2ccc(F)c(F)c2)c2ccc(Oc3cccnc3)cc2n1Cc1ccccn1
Temperature: 130 °C
Reaction time: 0.08 h
Yield: 6.5 %

Procedure:
General Procedure G. To a solution of N-(3,4-difluorobenzyl)-2-isopropyl-6-hydroxy-1-(pyridin-2-ylmethyl)-1H-indole-3-carboxamide (Compound 220, 30 mg, 0.069 mmol) in N,N-dimethylacetamide (1.50 ml) stirring at room temperature, was added potassium hydroxide (80 mg, 1.43 mmol) and the reaction stirred for 5 minutes. 3-bromopyridine (0.05 mL, 0.08 g, 0.51 mmol) and then Copper powder (9.0 mg, 0.14 mmol) was then directly added and the resulting mixture heated at 120-140° C. for 18 h. The reaction was cooled to room temperature, quenched with water, extracted with EtOAc, washed with brine, dried over Na2SO4, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (50% EtOAc-hexanes, 100 % EtOAc) to yield N-(3,4-difluorobenzyl)-2-isopropyl-1-(pyridin-2-ylmethyl)-6-(pyridin-3-yloxy)-1H-indole-3-carboxamide (Compound 222) as a yellow solid (2.3 mg). 1H NMR (300 MHz, METHANOL-d4) δ ppm 1.34 (d, J=7.0 Hz, 6 H), 4.59 (s, 2 H), 5.55 (s, 2 H), 6.72 (d, J=8.2 Hz, 1 H), 6.92 (dd, J=8.6, 2.2 Hz, 1 H), 7.02 (d, J=2.0 Hz, 1 H), 7.19-7.42 (m, 6 H), 7.62-7.74 (m, 2 H), 8.14-8.24 (m, 2 H), 8.49 (d, J=5.0 Hz, 1 H).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:17][CH2:16][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:14][CH2:13]1)=[O:11].Br[CH2:26][CH2:27][CH2:28][CH2:29][C:30]#[N:31].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[C:30]([CH2:29][CH2:28][CH2:27][CH2:26][N:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[C:10]([CH:12]1[CH2:13][CH2:14][N:15]([C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])[CH2:16][CH2:17]1)=[O:11])#[N:31]
Reactant: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3[nH]2)CC1
Reactant: N#CCCCCBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC(C(=O)c2nc3ccccc3n2CCCCC#N)CC1
Temperature: 90 °C

Procedure:
Mix [1H-benzimidazol-2-yl][1-(t-butyloxycarbonyl)-4-piperidinyl]methanone (4.25 g, 12.91 mmol), 5-bromovaleronitrile (2.5 g, 15.3 mmol), potassium carbonate (5.29 g, 38.25 mmol) and dimethylformamide (100 mL). Stir and heat and at 90° C. overnight. Allow to cool to room temperature, dilute with water and extract with ethyl acetate (2×). Wash the combined organic phases with water (3×), then brine and dry (MgSO4). Evaporate the solvent in vacuo and purify by chromatography to give the title compound.
Reaction SMILES: [Cl-].[OH:2][NH3+:3].C([O-])(=O)C.[Na+].[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=O>O.C(O)C>[F:9][C:10]([F:23])([F:22])[CH2:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([S:20][CH3:21])=[CH:16][CH:15]=1)=[N:3][OH:2]
Reactant: CSc1ccc(C(=O)CC(F)(F)F)cc1
Reactant: [NH3+]O
Agent: CC(=O)[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: CSc1ccc(C(CC(F)(F)F)=NO)cc1
Yield: 59.4 %

Procedure:
Hydroxylammonium chloride (1.07 g, 15.4 mmol) and sodium acetate (1.85 g, 22.5 mmol) are dissolved in 10 ml of water. To this solution are added 2.35 g (10.0 mmol) of 3,3,3-trifluoro-1-(4-methylsulfanyl-phenyl)-propan-1-one in 30 ml of ethanol. The reaction mixture is heated to reflux for 6.5 hr. The reaction mixture was concentrated by rotary evaporation and poured into water. The product is extracted with CH2Cl2, and the organic layer is washed with water, followed by drying over anhydrous MgSO4. After evaporation of the solvent, the product is purified by column chromatography on silica gel with CH2Cl2-Hexane (2:1) as eluent. 1.48 g of white solid melting at 106-107° C. are obtained (59%). 1H NMR (CDCl3), δ[ppm]: d 2.51 (s, 3H), 3.73 (q, 2H), 7.26 (d, 2H), 7.57 (d, 2H), 8.23 (s, 1H).
Reaction SMILES: C(O)(=[O:3])C.[BH4-].[Na+].[C:7]([C:11]1[CH:16]=[CH:15][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[CH2:27])[CH:24]=3)[N:19]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:18]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:13][CH:12]=1)([CH3:10])([CH3:9])[CH3:8]>O1CCCC1>[C:7]([C:11]1[CH:12]=[CH:13][C:14]([C:17]2[C:25]3[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][CH2:27][OH:3])[CH:24]=3)[N:19]([CH2:28][C:29]3[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[CH:30]=3)[C:18]=2[C:37]([O:39][CH2:40][CH3:41])=[O:38])=[CH:15][CH:16]=1)([CH3:8])([CH3:9])[CH3:10]
Reactant: C=Cc1ccc2c(c1)c(-c1ccc(C(C)(C)C)cc1)c(C(=O)OCC)n2Cc1cccc(OC)c1
Reactant: CC(=O)O
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)c1c(-c2ccc(C(C)(C)C)cc2)c2cc(CCO)ccc2n1Cc1cccc(OC)c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 72.7 %

Procedure:
Acetic acid (63 μL, 66 mg, 1.1 mmol) was added slowly to a cooled (0° C.) and stirred slurry of sodium borohydride (41.6 mg, 1.10 mmol) in tetrahydrofuran (2 mL). The mixture was stirred for 1 h and then a solution of ethyl 3-(4-tert-butylphenyl)-1-(3-methoxybenzyl)-5-vinyl-1H-indole-2-carboxylate (Example 129, 430 mg, 0.920 mmol) in tetrahydrofuran (5+2 mL rinse) was added. The reaction was stirred overnight and then cooled (0° C.). The reaction was quenched by successive addition of EtOH (6 mL), 6 M aqueous sodium acetate (5 mL) and 27% aqueous hydrogen peroxide (5 mL). The mixture was heated (50° C.) for 1 h and then cooled. The reaction was diluted with water (100 mL) and then extracted with ethyl acetate (3×50 mL). The combined organic extracts were washed with brine, dried over anhydrous magnesium sulfate, and concentrated in vacuo. Flash chromatography of the residue over silica gel using 30% ethyl acetate/hexane afforded 325 mg (75%) of desired product. The product had: 1H NMR (300 MHz, CDCl3) δ 7.28-7.48 (m, 6 H), 7.15-7.22 (m, 2 H), 6.75 (dd, 1 H), 6.64-6.72 (m, 2 H), 7.76(s, 2 H), 4.08 (q, 2 H), 3.78-4.00 (m, 3 H), 3.73 (s, 3 H), 2.91 (t, 2 H), 1.39 (s, 9 H), 0.95 (t, 3 H).
Reaction SMILES: [CH:1]1[C:6]([CH2:7][CH2:8][CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=[C:3]([N:13]([CH2:17][CH2:18][Cl:19])[CH2:14][CH2:15][Cl:16])[CH:2]=1.[CH:20](N(CC)C(C)C)(C)C>CO>[Cl:19][CH2:18][CH2:17][N:13]([CH2:14][CH2:15][Cl:16])[C:3]1[CH:2]=[CH:1][C:6]([CH2:7][CH2:8][CH2:9][C:10]([O:12][CH3:20])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(O)CCCc1ccc(N(CCCl)CCCl)cc1
Reactant: CCN(C(C)C)C(C)C
Solvent: CO
Product: COC(=O)CCCc1ccc(N(CCCl)CCCl)cc1
Temperature: 25 °C
Yield: 55 %

Procedure:
A mixture of chlorambucil (600 mg, 2 mmol), HBTO (625 mg, 2 mmol), and N,N-diisopropylethylamine (300 uL, 2 mmol) was stirred in methanol at 55° C. for 18 hrs. After cooling to room temperature, the solvent was evaporated and the residue was quenched with 50 mL water. The mixture was then extracted with EtOAc and the combined organic layer was washed with water, then brine, and dried over Na2SO4. The solvent was evaporated and the residue was purified by silica gel column chromatography with hexane/CH2Cl2 (10:1) to provide the compound 27a (350 mg, 1.1 mmol, 55% yield) as a yellow oil. 1H NMR (400 MHz, Chloroform-d) δ 7.20-7.05 (dd, 2H), 6.71-6.62 (dd, 2H), 3.75-3.70 (m, 4H), 3.69 (s, 3H), 3.64 (m, 4H), 2.58 (t, J=7.6 Hz, 2H), 2.35 (t, J=7.5 Hz, 2H), 1.93 (p, J=7.6 Hz, 2H). HRMS (ESI, positive) m/z calcd. for C15H22Cl2NO2 [M+H]+: 318.10221, found: 318.10216.
Reaction SMILES: C(O)(C(F)(F)F)=O.[Cl:8][C:9]1[N:17]=[C:16]2[C:12]([NH:13][CH:14]=[N:15]2)=[C:11](Cl)[N:10]=1.C([N:22](CC)C(C)C)(C)C>C(O)(C)C>[Cl:8][C:9]1[NH:10][C:11]([NH2:22])=[C:12]2[C:16]([N:17]=1)=[N:15][CH:14]=[N:13]2
Reactant: Clc1nc(Cl)c2[nH]cnc2n1
Reactant: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CC(C)O
Product: Nc1[nH]c(Cl)nc2ncnc1-2
Temperature: 100 °C
Reaction time: 17 h
Yield: 70 %

Procedure:
A glass tube was charged with the above amount of TFA salt 13, commercially available 2,6-dichloropurine (1.02 g, 5.43 mmol), N,N-diisopropylethylamine (DIPEA, 3.14 mL, 4.96 mmol) and isopropyl alcohol (IPA, 6 mL). The glass tube was sealed and then shaken at 100° C. for 17 hours. The volatiles were evaporated and the resulting residue was purified by flash chromatography eluting with ethyl acetate-methanol (100:5, including 1% triethylamine) to afford 1.25 g of mono-SNAR product 14, racemic-(2-exo,3-exo-)-N6[3-(dimethylamino)carbonylbicyclo-[2.2.1]hept-5-en-2-yl)]-2-chloro-1H-purine-6-amine, in 70% yield. 1H NMR (300 MHz, CD3OD) δ: 8.05 (s, 1H), 6.35 (m, 2H), 4.68 (m, 1H), 3.00 (s, 1H), 3.04 (s, 1H), 3.00 (s, 3H), 2.95 (s, 1H), 2.83 (s, 1H), 2.68 (s, 3H), 2.39 (d, J=8.7 Hz, 1H), 1.69 (d, J=9.0 Hz, 1H), 1.33 (m, 1H); LC-MS: purity: 90.51%; MS (m/e): 333.43 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]([NH2:9])[C:5]([NH2:8])=[N:6][CH:7]=1.[OH:12][CH2:13][CH2:14][O:15][C:16]1[CH:23]=[CH:22][C:19]([CH:20]=O)=[CH:18][CH:17]=1>CN(C=O)C.O.O.O.O.O.O.[Fe](Cl)(Cl)Cl>[Cl:1][C:2]1[C:3]([O:10][CH3:11])=[C:4]2[N:9]=[C:20]([C:19]3[CH:22]=[CH:23][C:16]([O:15][CH2:14][CH2:13][OH:12])=[CH:17][CH:18]=3)[NH:8][C:5]2=[N:6][CH:7]=1
Reactant: COc1c(Cl)cnc(N)c1N
Reactant: O=Cc1ccc(OCCO)cc1
Agent: Cl[Fe](Cl)Cl
Solvent: O
Solvent: CN(C)C=O
Product: COc1c(Cl)cnc2[nH]c(-c3ccc(OCCO)cc3)nc12
Temperature: 110 °C

Procedure:
5-Chloro-4-methoxypyridin-2,3-diamine (0.498 g, 2.9 mmol) was dissolved in DMF (7 ml). Iron(III)chloride hexahydrate (0.06 g, 0.2 mmol) was added and the mixture heated to is 80° C. 4-(2-Hydroxyethoxy)benzaldehyde (0.48 g, 2.9 mmol) dissolved in DMF (4 ml) was added dropwise, and the reaction mixture was heated at 110° C. for 11 h with air bubbling through the solution. The solvent was removed by evaporation, the solid residue was dissolved in warm methanol and filtered through a short plug of silica gel. Following evaporation and recrystallization (methanol), the title compound was isolated (0.26 g, 28%).
Reaction SMILES: [F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19](I)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.[C:26]1([C:32]#[CH:33])[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>>[F:1][C:2]([F:25])([F:24])[C:3]1[CH:4]=[C:5]([NH:13][C:14](=[O:23])[C:15]2[CH:20]=[C:19]([C:33]#[C:32][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[CH:18]=[CH:17][C:16]=2[OH:22])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1
Reactant: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(I)ccc1O
Reactant: C#Cc1ccccc1
Product: O=C(Nc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1cc(C#Cc2ccccc2)ccc1O

Procedure:
Using N-[3,5-bis(trifluoromethyl)phenyl]-2-hydroxy-5-iodobenzamide and phenylacetylene as the raw materials, the same operation as the example 66 gave the title compound.
Reaction SMILES: [CH2:1]([C:4]1[CH:11]=[CH:10][C:7]([CH:8]=[O:9])=[CH:6][CH:5]=1)[C:2]#[CH:3].O.Cl([O-])=[O:14].[Na+]>C1COCC1>[CH2:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([OH:14])=[O:9])=[CH:10][CH:11]=1)[C:2]#[CH:3]
Reactant: [O-][Cl+][O-]
Reactant: C#CCc1ccc(C=O)cc1
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Product: C#CCc1ccc(C(=O)O)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 62 %

Procedure:
To a solution of 4-prop-2-ynyl-benzaldehyde (10 mmol) in THF (30 ml), amidosurfulic acid (16 mmol) and water (15 ml) solution of sodium chlorite (30 mmol) are added. The reaction mixture is stirred at room temperature for 2 h. Water is added and then aqueous layer is extracted with two 50 ml portions of CH2Cl2. The combined extracts are washed with brine, dried over sodium sulfate and concentrated under vacuum to give crude product which is purified by silica gel column chromatography. Yield: 62%. Rf=0.44 (n-hexane:AcOEt=7:3)
Reaction SMILES: [SH:1][CH2:2][CH:3]([CH3:14])[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5].Cl.C(=O)(O)[O-].[Na+].Cl[C:22]1[C:27]2=[N:28][O:29][N:30]=[C:26]2[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1>C(C(C)=O)C.O>[CH3:14][CH:3]([CH2:2][S:1][C:22]1[C:27]2[C:26](=[N:30][O:29][N:28]=2)[C:25]([N+:31]([O-:33])=[O:32])=[CH:24][CH:23]=1)[C:4]([N:6]1[CH2:13][CH2:12][CH2:11][C@H:7]1[C:8]([OH:10])=[O:9])=[O:5]
Reactant: O=[N+]([O-])c1ccc(Cl)c2nonc12
Reactant: CC(CS)C(=O)N1CCC[C@H]1C(=O)O
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCC(C)=O
Product: CC(CSc1ccc([N+](=O)[O-])c2nonc12)C(=O)N1CCC[C@H]1C(=O)O
Reaction time: 0.03 h

Procedure:
3 Mg of 1-(3-mercapto-2-methyl-1-oxopropyl)-L-proline was placed in a vial and dilute hydrochloric acid (0.1N, 2 ml) added to dissolve same. 3 Ml of 0.1M sodium bicarbonate solution was next added and the mixture was mixed in a vortex mixer. Thereafter, 3 ml of 1% (w/v) 4-chloro-7-nitrobenzofurazan in methyl ethyl ketone was added to the mixture, the vial was then closed and mixing was continued. The vial was held under running hot tap water, while shaking the vial, for about 2 minutes. The vial was then allowed to stand for 3 minutes, the organic (upper) layer was removed and was found to contain the title compound. The title compound was found to be fluorescent.
Reaction SMILES: [C:1](OC(=O)C)(=O)C.[CH3:8][O:9][C:10]1[CH:25]=[CH:24][C:13]([CH2:14][NH:15][C:16]2[CH:21]=[C:20]([Br:22])[N:19]=[CH:18][C:17]=2[NH2:23])=[CH:12][CH:11]=1>C(OC(OCC)OCC)C>[CH3:8][O:9][C:10]1[CH:11]=[CH:12][C:13]([CH2:14][N:15]2[C:16]3[CH:21]=[C:20]([Br:22])[N:19]=[CH:18][C:17]=3[N:23]=[CH:1]2)=[CH:24][CH:25]=1
Reactant: COc1ccc(CNc2cc(Br)ncc2N)cc1
Reactant: CC(=O)OC(C)=O
Solvent: CCOC(OCC)OCC
Product: COc1ccc(Cn2cnc3cnc(Br)cc32)cc1
Temperature: 100 °C
Yield: 108.8 %

Procedure:
Acetic anhydride (1.28 mL, 13.6 mmol) was added to a solution of N4-(4-methoxybenzyl)-6-bromopyridine-3,4-diamine (1.05 g, 3.41 mmol) in triethylorthoformate (13 mL). The mixture was heated at 100° C. for 18 hours and then concentrated to give the title compound as a brown oil (1.18 g, quantitative). 1H NMR (d6-DMSO, 400 MHz) δ 8.75 (s, 1H), 8.60 (s, 1H), 8.00 (s, 1H), 7.35 (d, 2H, J=8.8 Hz), 6.90 (d, 2H, J=8.8 Hz), 5.45 (s, 2H), 3.70 (s, 3H). LCMS (2) Rt=2.27 min; m/z (ESI+) 318, 320 (MH+).
Reaction SMILES: [Cl:1][C:2]1[C:7]([O:8][CH2:9][CH3:10])=[CH:6][C:5]([I:11])=[CH:4][C:3]=1[OH:12].Br[CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16]>>[Cl:1][C:2]1[C:3]([O:12][CH:14]([CH2:17][CH3:18])[CH2:15][CH3:16])=[CH:4][C:5]([I:11])=[CH:6][C:7]=1[O:8][CH2:9][CH3:10]
Reactant: CCOc1cc(I)cc(O)c1Cl
Reactant: CCC(Br)CC
Product: CCOc1cc(I)cc(OC(CC)CC)c1Cl
Yield: 79 %

Procedure:
2-Chloro-1-ethoxy-5-iodo-3-(pentan-3-yloxy)benzene (8) (1.2 g, 79%) was prepared from 2-chloro-3-ethoxy-5-iodophenol (7) (1.1 g, 3.7 mmol) using a procedure essentially the same as in step (i) for AAA-001 except that 3-bromopentane was used instead of cyclopentyl bromide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][CH:16]=[C:10]2[CH:9]1[CH2:19][O:20][C:21]1[CH:26]=[CH:25][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:23][CH:22]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Cl)[Cl:32].CO>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]2[C:14]([CH2:17][CH3:18])=[N:15][C:16]([Cl:32])=[C:10]2[CH:9]1[CH2:19][O:20][C:21]1[CH:22]=[CH:23][C:24]([C:27]([F:28])([F:29])[F:30])=[CH:25][CH:26]=1)=[O:7])([CH3:2])([CH3:3])[CH3:4]
Reactant: ClCCl
Reactant: CCc1ncc2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(C(F)(F)F)cc1
Solvent: CO
Product: CCc1nc(Cl)c2n1CCN(C(=O)OC(C)(C)C)C2COc1ccc(C(F)(F)F)cc1

Procedure:
Subsequent chlorination (70° C.; 3 h) of 3-ethyl-8-(4-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester (0.664 g; 1.561 mmol), and purification by FC (DCM/MeOH=80/1) afforded 1-chloro-3-ethyl-8-(4-trifluoromethyl-phenoxymethyl)-5,6-dihydro-8H-imidazo[1,5-a]pyrazine-7-carboxylic acid tert-butyl ester as a yellow solid (0.381 g; 53%). LC-MS: tR=1.04 min.; [M+H]+=460.23 g/mol.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15]OS(C)(=O)=O)[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[F-:22].C([N+](CCCC)(CCCC)CCCC)CCC>C(#N)C.C(OCC)(=O)C>[CH2:1]([O:8][C:9]1[C:10](=[O:21])[CH:11]=[C:12]([CH2:15][F:22])[O:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)OCc1cc(=O)c(OCc2ccccc2)co1
Reactant: [F-]
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Solvent: CCOC(C)=O
Solvent: CC#N
Product: O=c1cc(CF)occ1OCc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To an ice/salt cooled solution of the sulfonate ester obtained in step 1 above ester (20.0 g, 64.4 mmol) in acetonitrile (120 mL) was added a mixture of a 75 wt % solution of tetrabutylammonium fluoride (35 g, 96.6 mmol) and 40 mL of acetonitrile. Additional tetrabutylammonium fluoride solution (35 g, 96.6 mmol) was added after 2.5 hrs and the reaction mixture was allowed to stir at room temperature for overnight. The reaction was concentrated in vacuo to give a dark red oil. The residue was diluted with 700 mL of ethyl acetate and washed 5 times with 120 mL of a 10% sodium hydrogen carbonate solution and twice with 120 mL of brine. The organic layer was dried over sodium sulfate, and concentrated to give a dark red oil. The crude product was purified by column chromatography on silica gel using a mixture of ethyl acetate and hexanes (1/1, v/v) as the eluant to give 5-benzyloxy-2-fluoromethyl-pyran-4-one as a waxy-like solid (10.0 g, 66% yield). 1H NMR (400 MHz, DMSO-D6) δ (ppm): 7.69 (s, 1H), 7.42-7.37 (m, 5H, H—Ar)), 6.57 (s, 1H), 5.36 (d, J=46.5 Hz, 2H, CFH2), 4.97 (m, 2H, OCH2).
Reaction SMILES: [Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11](Cl)=[O:12])[C:4]=2[CH:3]=1.[CH2:21]([N:23]([CH2:34][CH3:35])[CH2:24][CH2:25][CH2:26][CH2:27][CH:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1)[CH3:22]>>[Cl:1][C:2]1[CH:20]=[CH:19][C:5]2[C:6](=[O:18])[NH:7][C:8]3[CH:17]=[CH:16][CH:15]=[N:14][C:9]=3[N:10]([C:11]([N:31]3[CH2:32][CH2:33][CH:28]([CH2:27][CH2:26][CH2:25][CH2:24][N:23]([CH2:34][CH3:35])[CH2:21][CH3:22])[CH2:29][CH2:30]3)=[O:12])[C:4]=2[CH:3]=1
Reactant: CCN(CC)CCCCC1CCNCC1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2cc(Cl)ccc21
Product: CCN(CC)CCCCC1CCN(C(=O)N2c3cc(Cl)ccc3C(=O)Nc3cccnc32)CC1
Yield: 38 %

Procedure:
Prepared analogously to Example 4 from 9-chloro-11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]-benzodiazepin-6-one and 4-[4-(diethylamino)butyl]piperidine in a yield of 38% of theory. Colourless crystals, m.p. 126°-127° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][NH:16][CH2:17][C:18]2[CH:23]=[CH:22][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:20][CH:19]=2)[CH:10]=1)([CH3:4])([CH3:3])[CH3:2].[C:31]1([S:37](Cl)(=[O:39])=[O:38])[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>>[C:1]([O:5][C:6](=[O:30])[CH2:7][O:8][C:9]1[CH:14]=[CH:13][CH:12]=[C:11]([CH2:15][N:16]([S:37]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)(=[O:39])=[O:38])[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([C:24]3[N:29]=[CH:28][CH:27]=[CH:26][N:25]=3)=[CH:22][CH:23]=2)[CH:10]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: CC(C)(C)OC(=O)COc1cccc(CNCc2ccc(-c3ncccn3)cc2)c1
Product: CC(C)(C)OC(=O)COc1cccc(CN(Cc2ccc(-c3ncccn3)cc2)S(=O)(=O)c2ccccc2)c1

Procedure:
The title compound of Step B was prepared from {3-[(4-pyrimidin-2-yl-benzylamino)-methyl]-phenoxy}-acetic acid tert-butyl ester, of Step A, and benzenesulfonyl chloride following the method described in Example 3, Step B. 1H NMR (400 MHz, CDCl3) δ 8.78 (dd, 2H), 8.27 (d, 2H), 7.87 (m, 2H), 7.59-7.50 (m, 3H), 7.18 (m, 1H), 7.11 (m, 3H), 6.75 (d, 1H), 6.64 (d, 1H), 6.59 (s, 1H), 4.39 (s, 2H), 4.35 (s, 2H), 4.31 (s, 2H), 1.48 (s, 9H); MS 546 (M+1).
Reaction SMILES: FC(F)(F)C(OI(C1C=CC=CC=1)OC(=O)C(F)(F)F)=[O:4].[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37]2([C:43]3[CH:48]=[CH:47][C:46]([C:49]4[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=4)=[CH:45][CH:44]=3)SCCCS2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1>C(#N)C.O>[CH3:22][C:23]([CH3:58])([CH2:56][CH3:57])[CH2:24][C:25]1[N:26]=[C:27]([CH:36]([OH:55])[C:37](=[O:4])[C:43]2[CH:48]=[CH:47][C:46]([C:49]3[CH:54]=[CH:53][CH:52]=[CH:51][N:50]=3)=[CH:45][CH:44]=2)[N:28]([S:30]([N:33]([CH3:35])[CH3:34])(=[O:32])=[O:31])[CH:29]=1
Reactant: O=C(OI(OC(=O)C(F)(F)F)c1ccccc1)C(F)(F)F
Reactant: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C2(c3ccc(-c4ccccn4)cc3)SCCCS2)n1
Solvent: O
Solvent: CC#N
Product: CCC(C)(C)Cc1cn(S(=O)(=O)N(C)C)c(C(O)C(=O)c2ccc(-c3ccccn3)cc2)n1
Temperature: 0 °C

Procedure:
[Bis(trifluoroacetoxy)iodo]benzene (184 mg, 0.48 mmol) was added to a 0° C. solution of 4-(2,2-dimethylbutyl)-2-{hydroxy[2-(4-pyridin-2-ylphenyl)-1,3-dithian-2-yl]methyl}-N,N-dimethyl-1H-imidazole-1-sulfonamide (110 mg, 0.20 mmol) in acetonitrile/water (3:1) (4 mL). After stirring at 0° C. until no further reaction (LCMS), the reaction mixture was quenched with saturated aqueous sodium thiosulfate/saturated aqueous sodium bicarbonate (1:1) and extracted with methylene chloride. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford 4-(2,2-dimethylbutyl)-2-[1-hydroxy-2-oxo-2-(4-pyridin-2-ylphenyl)ethyl]-N,N-dimethyl-1H-imidazole-1-sulfonamide which was used in the next step without further purification.