Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]1[CH:5]=[CH:4][C:3]([C:6]2[CH:11]=[CH:10]N=[CH:8][CH:7]=2)=[CH:2]1.I[C:13]1[CH:18]=CC(CCC)=[CH:15][CH:14]=1.O1C=CC(B(O)O)=C1>>[CH2:13]([C:18]1[CH:10]=[CH:11][C:6]([C:3]2[CH:4]=[CH:5][O:1][CH:2]=2)=[CH:7][CH:8]=1)[CH2:14][CH3:15]
Reactant: c1cc(-c2ccoc2)ccn1
Reactant: CCCc1ccc(I)cc1
Agent: OB(O)c1ccoc1
Product: CCCc1ccc(-c2ccoc2)cc1

Procedure:
As described in Example 1(d) for the preparation of 4-furan-3-yl-pyridine, 1-iodo-4-propylbenzene (500 mg, 2.03 mmol) was coupled to 3-furanboronic acid to furnish in high yield 3-(4-propylphenyl)-furan as a light brown oil that was unstable and used immediately without further purification. 1H NMR (CDCl3): ∂ 7.69 (t, 1H, J=0.9 Hz), 7.46 (t, 1H, J=1.7 Hz), 7.40 (d, 2H, J=8.1 Hz), 7.18 (d, 2H, J=7.8 Hz), 6.68 (t, 1H, J=0.9 Hz), 2.59 (t, 2H, J=7.5 Hz), 1.66-1.60 (m, 2H), 0.95 (t, 3H, J=7.5 Hz). ##STR91##
Reaction SMILES: [OH:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([OH:17])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1.[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][Cl:25])[CH3:20].[OH-].[Na+].CS(C)=O>O>[ClH:25].[ClH:25].[CH2:19]([N:21]([CH2:26][CH3:27])[CH2:22][CH2:23][CH2:24][O:1][C:2]1[CH:15]=[CH:14][C:13]2[C:12](=[O:16])[C:11]3[C:6](=[CH:7][CH:8]=[C:9]([O:17][CH2:24][CH2:23][CH2:22][N:21]([CH2:26][CH3:27])[CH2:19][CH3:20])[CH:10]=3)[C:5](=[O:18])[C:4]=2[CH:3]=1)[CH3:20]
Reactant: O=C1c2ccc(O)cc2C(=O)c2ccc(O)cc21
Reactant: CCN(CC)CCCCl
Agent: [Na+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: CCN(CC)CCCOc1ccc2c(c1)C(=O)c1ccc(OCCCN(CC)CC)cc1C2=O
Product: Cl

Procedure:
A mixture of 12 g. (0.05 mole) of 2,6-dihydroxyanthraquinone, 16.5 g (0.11 mole) of 3-diethylaminopropyl chloride, 48 ml. of 10% sodium hydroxide solution, and 100 ml. of dimethylsulfoxide was stirred and heated on a steam bath for two hours. When cool, the mixture was poured into about 500 ml. of water. The solid which precipitated was filtered with suction and washed with water. The crude wet solid was dissolved in chloroform. This solution was dried over anhydrous magnesium sulfate, filtered, and the filtrate acidified to Congo Red with ethereal hydrogen chloride. After dilution with anhydrous ether, the yellow solid was filtered and dried. After two recrystallizations from 95% ethanol, the dihydrochloride (a hydrate) melted with decomposition at 273.5°-274.5°C; γmax (H2O) 274, E1cm1% 761.
Reaction SMILES: [NH:1]([C:8](=[O:42])[CH:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:38])([CH3:37])[CH3:36])=[O:24])=[CH:21][CH:20]=1)[C:10]([NH:12][C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1)=[O:11])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:43]C(C)([O-])C.[K+].CI>C1COCC1.C(OCC)(=O)C>[NH:1]([C:8](=[O:42])[C:9]([C:19]1[CH:41]=[CH:40][C:22]([C:23]([NH:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[NH:32][C:33](=[O:39])[O:34][C:35]([CH3:36])([CH3:37])[CH3:38])=[O:24])=[CH:21][CH:20]=1)([C:10]([NH:12][C:13]1[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=1)=[O:11])[CH3:43])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)[O-]
Reactant: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CI
Product: CC(C)(C)OC(=O)Nc1ccccc1NC(=O)c1ccc(C(C)(C(=O)Nc2ccccc2)C(=O)Nc2ccccc2)cc1
Reaction time: 0.5 h
Yield: 33.1 %

Procedure:
To a solution of tert-butyl [2-({-4-[2-anilino-1-(anilinocarbonyl)-2-oxoethyl]benzoyl}amino)phenyl]carbamate (41 mg, 0.073 mmol) in THF (1 mL) at room temperature was added potassium tert-butoxide (85 μL, 1 M in THF, 0.085 mmol). The solution was stirred for 30 min and methyl iodide (6 μL, 0.096 mmol) was added. The reaction mixture was stirred at room temperature for 4 h, diluted with ethyl acetate, washed with water (1×), brine (1×), dried over MgSO4, filtered, and concentrated. Purification by flash column chromatography on silica gel (20% to 65% ethyl acetate in hexanes) gave tert-butyl [2-({4-[2-anilino-1-(anilinocarbonyl)-1-methyl-2-oxoethyl]benzoyl}amino)phenyl]carbamate (14 mg, 33%) as a white solid: 1H NMR (600 MHz, CDCl3) δ 9.29 (s br, 1H), 8.93 (s br, 2H), 7.98 (d, J=8.2 Hz, 2H), 7.75 (d, J=7.6 Hz, 1H), 7.52-7.50 (m, 6H), 7.34 (t, J=8.2 Hz, 4H), 7.27 (d, J=7.0 Hz, 1H), 7.21 (td, J=7.9, 1.5 Hz, 1H), 7.17-7.14 (m, 3H), 6.92 (s br, 1H), 2.07 (s, 3H), 1.49 (s, 913); ESIMS calcd 579.3 (M++H), found 579.2 (M++H).
Reaction SMILES: Br[C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1.CN(C=O)C.C(Cl)[Cl:17]>[Cu](Cl)Cl>[Cl:17][C:2]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[S:4][CH:3]=1
Reactant: Brc1csc2ncccc12
Reactant: ClCCl
Agent: Cl[Cu]Cl
Solvent: CN(C)C=O
Product: Clc1csc2ncccc12
Temperature: 130 °C
Yield: 71 %

Procedure:
500 mg of 3-Bromo-thieno[2,3-b]pyridine (2.3 mmol) and 136 mg of copper chloride (I) (2.78 mmol) are placed into reaction vial with 3.0 ml of dry DMF. The vial is capped with a Teflon cap and heated at 130° C. overnight. The reaction mixture is poured into CH2Cl2 and washed with NaHCO3, brine and dried over Na2SO4. The solvents are removed and the residue applied onto a chromatography silica-gel column (Hexane:AcOEt=10:1) to give 280 mg of the title compound (71%); mass spectrum (m/e): 170; 1H-NMR (CDCl3): 8.53 (m, 1H), 8.11 (m, 1H), 7.41 (m, 2H) ppm.
Reaction SMILES: FC(F)(F)S(O[CH2:7][C:8]([F:21])([F:20])[CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)(=O)=O.[C:24]1(=[O:34])[NH:28][C:27](=[O:29])[C:26]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:25]12.[K].CN1CCCC1=O.C(=O)([O-])O.[Na+]>C(OCC)(=O)C>[F:20][C:8]([F:21])([CH:9]([F:19])[C:10]1[CH:15]=[CH:14][CH:13]=[C:12]([N+:16]([O-:18])=[O:17])[CH:11]=1)[CH2:7][N:28]1[C:24](=[O:34])[C:25]2[C:26](=[CH:30][CH:31]=[CH:32][CH:33]=2)[C:27]1=[O:29]
Reactant: O=C1NC(=O)c2ccccc21
Reactant: O=[N+]([O-])c1cccc(C(F)C(F)(F)COS(=O)(=O)C(F)(F)F)c1
Agent: O=C([O-])O
Agent: [K]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN1CCCC1=O
Product: O=C1c2ccccc2C(=O)N1CC(F)(F)C(F)c1cccc([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 3 h
Yield: 75.5 %

Procedure:
To 2,2,3-trifluoro-3-(3-nitrophenyl)propyl trifluoromethanesulfonate (C32, 709 mg) and potassium phthalimide (1.07 g), N-methylpyrrolidone (4 mL) was added at room temperature, and the mixture was stirred at 80° C. for 3 hours. The reaction mixture was cooled to room temperature, and then ethyl acetate and saturated aqueous sodium hydrogencarbonate were added to the mixture. The organic layer was separated, washed successively with water and saturated aqueous sodium chloride, and then dried over anhydrous sodium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography (eluent, 100 to 30% hexane in ethyl acetate) to obtain 2-(2,2,3-trifluoro-3-(3-nitrophenyl)propyl)isoindoline-1,3-dione (C33, 531 mg).
Reaction SMILES: [N:1]1[CH:2]=[C:3]2[N:12]3[C:7](=[CH:8][CH:9]=[CH:10][C:11]=13)[S:6][C:5]([C:13]([OH:15])=O)=[CH:4]2.ON1C(=O)CCC1=O.Cl.C(N=C=NCCCN(C)C)C.Cl.Cl.[NH2:38][CH2:39][CH2:40][CH2:41][CH2:42][N:43]1[CH2:52][CH2:51][C:50]2[C:45](=[CH:46][CH:47]=[CH:48][CH:49]=2)[CH2:44]1>C(#N)C.C(O)C.C(N(CC)CC)C>[CH2:44]1[C:45]2[C:50](=[CH:49][CH:48]=[CH:47][CH:46]=2)[CH2:51][CH2:52][N:43]1[CH2:42][CH2:41][CH2:40][CH2:39][NH:38][C:13]([C:5]1[S:6][C:7]2[N:12]3[C:3](=[CH:2][N:1]=[C:11]3[CH:10]=[CH:9][CH:8]=2)[CH:4]=1)=[O:15]
Reactant: O=C(O)C1=Cc2cnc3cccc(n23)S1
Reactant: NCCCCN1CCc2ccccc2C1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: O=C1CCC(=O)N1O
Solvent: CCN(CC)CC
Solvent: CCO
Solvent: CC#N
Product: O=C(NCCCCN1CCc2ccccc2C1)C1=Cc2cnc3cccc(n23)S1
Reaction time: 2 h

Procedure:
To a suspension of 1.0 g (4.58 mM) of 5-thia-1,8b-diazaacenaphthylene-4-carboxylic acid and 1.05 g (9.12 mM) of N-hydroxysuccinimide in acetonitrile (10 ml) was added 1.76 g (9.18 mM) of N-ethyl-N′-3-(N,N-dimethylamino)propylcarbodiimide hydrochloride at room temperature and the mixture was stirred at the prevailing temperature for 2 hours. To this reaction mixture was added a solution of 1.90 g (6.85 mM) of 2-(4-aminobutan-1-yl)-1,2,3,4-tetrahydroisoquinoline dihydrochloride and 4.0 ml (28.7 mM) of triethylamine in ethanol (10 ml) and the mixture was further stirred for one hour. The solvent was then distilled off under reduced pressure and the residue was diluted with water and extracted with methylene chloride. The organic layer was washed with saturated aqueous solution of sodium chloride, dried over MgSO4, and purified by column chromatography (methanol/ethyl acetate 30%) to provide the title compound as red-purple amorphous substance.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[N:20]=[C:19]([O:21][CH3:22])[N:18]=[C:17]([C:23]2[CH:24]=[C:25]([OH:29])[CH:26]=[CH:27][CH:28]=2)[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].[CH2:36]([CH:38]1[O:40][CH2:39]1)Cl>CN(C=O)C.O>[F:1][C:2]1[CH:7]=[C:6]([C:8]([F:9])([F:10])[F:11])[CH:5]=[CH:4][C:3]=1[CH2:12][CH2:13][NH:14][C:15]1[CH:16]=[C:17]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25]([O:29][CH2:36][CH:38]3[CH2:39][O:40]3)[CH:24]=2)[N:18]=[C:19]([O:21][CH3:22])[N:20]=1
Reactant: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(O)c2)n1
Reactant: ClCC1CO1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: COc1nc(NCCc2ccc(C(F)(F)F)cc2F)cc(-c2cccc(OCC3CO3)c2)n1
Reaction time: 4 h
Yield: 50.8 %

Procedure:
To a suspension of 3-{6-[2-(2-fluoro-4-trifluoromethyl-phenyl)-ethylamino]-2-methoxy-pyrimidin-4-yl}-phenol (280 mg, 0.68 mmol), and Cs2CO3 (0.44 g, 1.36 mmol) in DMF (2 mL) is added epichlorohydrin (80 μL, 1.02 mmol) at room temperature. After 4 h at 20° C., the mixture is diluted with water (10 mL), and extracted with EtOAc (2×10 mL). The extracts are washed with water (2×20 mL), dried (MgSO4), filtered, and concentrated. The residue is chromatographed on SiO2 eluting with 50% EtOAc in heptane to afford [2-(2-fluoro-4-trifluoromethyl-phenyl)-ethyl]-[2-methoxy-6-(3-oxiranylmethoxy-phenyl)-pyrimidin-4-yl]-amine [0.16 g, Example 66]. LCMS: RT=2.62 minutes; MS: 464 (M+H).
Reaction SMILES: Cl.[CH3:2][N:3](C)[CH2:4]CCN=C=NCC.[NH2:13][C:14]1[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:19]=1[NH2:20].Cl[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44](O)=O)=[CH:31][N:30]=1>CO.O>[CH3:2][N:3]([CH3:4])[C:29]1[C:38]2[C:33](=[CH:34][C:35]([O:41][CH3:42])=[C:36]([O:39][CH3:40])[CH:37]=2)[C:32]([CH2:43][C:44]2[NH:13][C:14]3[C:15](=[O:27])[N:16]([CH3:26])[C:17](=[O:25])[N:18]([CH2:21][CH:22]([CH3:23])[CH3:24])[C:19]=3[N:20]=2)=[CH:31][N:30]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: COc1cc2c(CC(=O)O)cnc(Cl)c2cc1OC
Reactant: CC(C)Cn1c(N)c(N)c(=O)n(C)c1=O
Agent: Cl
Solvent: O
Solvent: CO
Product: COc1cc2c(Cc3nc4c([nH]3)c(=O)n(C)c(=O)n4CC(C)C)cnc(N(C)C)c2cc1OC
Temperature: 25 °C
Reaction time: 2 h

Procedure:
1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.29 g, 1.9 mmol) is added to 5,6-diamino-1-isobutyl-3-methyl-1H-pyrimidine-2,4-dione (0.40 g, 1.9 mmol)) and (1-chloro-6,7-dimethoxy-isoquinolin-4-yl)-acetic acid (0.39 g, 1.78 mmol) in methanol and water and the mixture is stirred at ambient temperature for 2 hours. The methanol is evaporated and the resultant solid collected by filtration and recrystalised from ethylacetate/methanol. The resulting solid is heated in a sealed tube (100° C., 8 h) with 40% aqueous dimethylamine. The mixture is evaporated and extracted with ethylacetate. The ethylacetate solution is then washed with water and brine, dried over sodium sulphate, filtered and concentrated. Further purification by flash silica column chromatography (eluant: ethylacetate/methanol) yields 8-(1-dimethylamino-6,7-dimethoxy-isoquinolin-4-ylmethyl)-3-isobutyl-1-methyl-3,7-dihydro-purine-2,6-dione, MH+ 467.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Cl:8])=[CH:4][C:3]=1[C:9](=[O:14])[C:10]([F:13])([F:12])[F:11].[CH3:15][Mg]Br.[C:18](N1C=CN=C1)(N1C=CN=C1)=[O:19]>CO>[Cl:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][C:18](=[O:19])[O:14][C:9]([CH3:15])([C:10]([F:13])([F:11])[F:12])[C:3]=2[CH:4]=1
Reactant: Nc1ccc(Cl)cc1C(=O)C(F)(F)F
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: C[Mg]Br
Solvent: CO
Product: CC1(C(F)(F)F)OC(=O)Nc2ccc(Cl)cc21

Procedure:
Prepared from 1-(2-amino-5-chloro-phenyl)-2,2,2-trifluoro-ethanone by addition of methylmagnesium bromide followed by treatment of the resultant carbinol with 1,1′-carbonyldiimidazole according to the procedure of Example 2. White solid: mp 216-216° C.; 1H-NMR (DMSO-d6) δ10.91 (bs, 1H, D2O exchangeable), 7.64 (d, 1H, J=1.6 Hz), 7.49 (dd, 1H, J=8.6, 2.3 Hz), 6.95 (d, 1H, J=8.6 Hz), 1.91 (s, 3H); 19F-NMR (DMSO-d6) δ−82.0 (s, 1F); MS (EI) m/z 264 ([M−H]−, 100%), 266 ([M−H]31 , 33%). Anal. Calc. For C10H7ClF3NO2: C, 45.22, H, 2.66, N, 5.27. Found: C, 45.32, H, 2.77, N, 4.83.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][C:5]([NH2:8])=[CH:4][C:3]=1[CH2:9][CH3:10].ClC1C(CC)=C(N)N=NC=1.C([O-])(O)=O.[Na+].[Br:26]Br>CO.CCOC(C)=O>[Br:26][C:4]1[C:3]([CH2:9][CH3:10])=[C:2]([Cl:1])[N:7]=[N:6][C:5]=1[NH2:8]
Reactant: BrBr
Reactant: CCc1cc(N)nnc1Cl
Agent: CCc1c(Cl)cnnc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CO
Product: CCc1c(Cl)nnc(N)c1Br
Temperature: 25 °C
Reaction time: 24 h

Procedure:
The mixture of 6-Chloro-5-ethylpyridazin-3-amine and chloro-4-ethylpyridazin-3-amine (3.50 g, 0.022 mol) from 1b and NaHCO3 (3.73 g, 0.044 mol, 2 eq) were suspended in MeOH (20 mL) and treated with Br2 (1.25 mL, 0.024 mol). The mixture was stirred at room temperature for 24 h, then filtered. The filtrate was condensed in vacuo. The resulting residue was resuspended in EtOAc (100 mL) and washed sequentially with sat. aqueous NaHCO3 solution (2×20 mL) and aqueous NaCl solution (1×20 mL). The solution was dried over sodium sulfate. The solvent was removed in vacuo to give crude 4-bromo-6-chloro-5-ethylpyridazin-3-amine. LC/MS, m/e 236 (M+1). HPLC Rt, 2.15 min. Waters Sunfire C18 column (4.6×50 mm). 0%-100% B. Solvent B: (90% MeOH, 10% H2O, 0.1% TFA). Solvent A: (10% MeOH, 90% H2O, 0.1% TFA). Gradient, start % B=0, final % B=100, gradient time 4 min, hold at 100% B 1 min, flow rate 4 mL/min.
Reaction SMILES: [C:1]([O:7][CH2:8][CH3:9])(=[O:6])[CH2:2][C:3]([CH3:5])=[O:4].[H-].[Na+].Br[CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16]>C1(C)C=CC=CC=1>[C:3]([CH:2]([CH2:13][C:14](=[O:19])[C:15]([CH3:18])([CH3:17])[CH3:16])[C:1]([O:7][CH2:8][CH3:9])=[O:6])(=[O:4])[CH3:5]
Reactant: CC(C)(C)C(=O)CBr
Reactant: CCOC(=O)CC(C)=O
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: CCOC(=O)C(CC(=O)C(C)(C)C)C(C)=O
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 87.4 %

Procedure:
Ethyl acetoacetate (1 g, 7.68 mmol) was added dropwise to a suspension of NaH (60% in mineral oil, 338 mg, 8.45 mmol) in toluene (20 mL). The resulting suspension was stirred at rt for 10 min, then treated with 1-bromopinacolone (1.3 g, 7.32 mmol). The mixture was immersed in a 75° C. oil bath, and stirred under Ar for 1 h. The reaction was cooled to rt, diluted with toluene and washed with H2O (2×50 mL). The organic layer was dried over Na2SO4, filtered and concentrated in vacuo to afford crude ethyl 2-acetyl-5,5-dimethyl-4-oxo-hexanoate (1.46 g) which was not purified: 1H NMR (CDCl3, chemical shifts in ppm relative to TMS): 1.166 (s, 9H), 1.277 (t, 3H, J=7.1 Hz), 2.368 (s, 3H), 3.000 (dd, 1H, J=5.8 Hz, J=18.4 Hz), 3.231 (dd, 1H, J=8.2 Hz, J=18.4 Hz), 4.010 (dd, 1H, J=5.8 Hz, J=8.2 Hz), 4.191 (q, 2H, J=7.1 Hz); Field Desorption Mass Spectrometry: m/z 229 (M+1).
Reaction SMILES: [C:1]([NH2:10])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)([CH3:3])[CH3:2].F[B-](F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1.Cl.[CH2:34]([O:36][C:37]([N:39]1[C:43]2[S:44][C:45]([C:47](O)=[O:48])=[CH:46][C:42]=2[C:41]([NH:50][C:51](=[O:64])[C:52]2[CH:57]=[CH:56][C:55]([N:58]3[CH2:63][CH2:62][O:61][CH2:60][CH2:59]3)=[CH:54][CH:53]=2)=[N:40]1)=[O:38])[CH3:35].CCN(C(C)C)C(C)C>CN(C)C=O.O>[CH3:2][C:1]([NH:10][C:47]([C:45]1[S:44][C:43]2[N:39]([C:37]([O:36][CH2:34][CH3:35])=[O:38])[N:40]=[C:41]([NH:50][C:51](=[O:64])[C:52]3[CH:57]=[CH:56][C:55]([N:58]4[CH2:63][CH2:62][O:61][CH2:60][CH2:59]4)=[CH:54][CH:53]=3)[C:42]=2[CH:46]=1)=[O:48])([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[CH3:3]
Reactant: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)O)sc21
Reactant: CC(C)(N)c1ccccc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[B-](F)(F)F
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CCOC(=O)n1nc(NC(=O)c2ccc(N3CCOCC3)cc2)c2cc(C(=O)NC(C)(C)c3ccccc3)sc21
Temperature: 25 °C
Reaction time: 20 h
Yield: 93.2 %

Procedure:
A mixture of cumylamine (1.43 g, 10.6 mmol), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate (TBTU, 3.40 g, 10.6 mmol), 1-(ethoxycarbonyl)-3-[(4-morpholin-4-ylbenzoyl)amino]-1H-thieno[2,3-c]pyrazole-5-carboxylic acid hydrochloride (3.40 mg, 7.07 mmol) and N,N′-diisopropylethylamine (12.1 mL, 7.07 mmol) in 80 mL of dimethylformamide was stirred at room temperature for 20 hours. Afterward the reaction mixture was diluted with water and extracted with dichloromethane. Volatiles were removed by evaporation under reduced pressure and the residue was triturated with ethyl acetate, filtered, extensively washed with diethyl ether and dried under vacuum at 40° C., to give 3.7 g of the title compound, used in the next step without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:9]=[C:10]([C:11](O)=[O:12])[C:4]=2[O:3]1.CN1CCOCC1.C(OC(Cl)=O)C(C)C.[BH4-].[Na+]>O.O1CCCC1>[CH3:1][C:2]1([CH3:19])[CH2:6][C:5]2[CH:7]=[C:8]([N:14]3[CH:18]=[N:17][N:16]=[N:15]3)[CH:9]=[C:10]([CH2:11][OH:12])[C:4]=2[O:3]1
Reactant: CC1(C)Cc2cc(-n3cnnn3)cc(C(=O)O)c2O1
Agent: CC(C)COC(=O)Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CN1CCOCC1
Product: CC1(C)Cc2cc(-n3cnnn3)cc(CO)c2O1
Reaction time: 2 h
Yield: 60.9 %

Procedure:
A solution of 2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-carboxylic acid (677) (135 mg, 0.519 mmol), N-methylmorpholine (57 μL, 0.519 mmol), and tetrahydrofuran (10 mL) at 0° C. was added isobutylchloroformate (68 μL, 0.519 mmol) and stirred for 2 hours. Sodium borohydride (58.9 mg, 1.56 mmol) in water (3 mL) was added and stirred for 1 hour and at room temperature for an additional 1 hour. The reaction was concentrated in vacuo and water was added. The aqueous phase was extracted with ethyl acetate and the combined organic layers dried over sodium sulfate, filtered and concentrated in vacuo. The crude compound was purified by flash column chromatography on silica gel with hexanes and EtOAc (60%) to afford (2,2-dimethyl-5-(1H-tetrazol-1-yl)-2,3-dihydrobenzofuran-7-yl)methanol (678) (77.8 mg, 61%).
Reaction SMILES: [Br:1][C:2]1[S:6][C:5]([C:7]2[S:11][C:10]([C:12]3[S:13][C:14]([C:17]4[S:18][C:19]([C:27]5[S:28][C:29]([Br:32])=[CH:30][CH:31]=5)=[CH:20][C:21]=4[CH2:22][C:23]([O:25]C)=[O:24])=[CH:15][CH:16]=3)=[C:9]([CH2:33][C:34]([O:36]C)=[O:35])[CH:8]=2)=[CH:4][CH:3]=1.[OH-].[Na+].O.Cl>O1CCOCC1>[Br:32][C:29]1[S:28][C:27]([C:19]2[S:18][C:17]([C:14]3[S:13][C:12]([C:10]4[S:11][C:7]([C:5]5[S:6][C:2]([Br:1])=[CH:3][CH:4]=5)=[CH:8][C:9]=4[CH2:33][C:34]([OH:36])=[O:35])=[CH:16][CH:15]=3)=[C:21]([CH2:22][C:23]([OH:25])=[O:24])[CH:20]=2)=[CH:31][CH:30]=1
Reactant: COC(=O)Cc1cc(-c2ccc(Br)s2)sc1-c1ccc(-c2sc(-c3ccc(Br)s3)cc2CC(=O)OC)s1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: O=C(O)Cc1cc(-c2ccc(Br)s2)sc1-c1ccc(-c2sc(-c3ccc(Br)s3)cc2CC(=O)O)s1
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Intermediate O (707 mg, 0.989 mmol) was dissolved in dioxane (5 ml) and 2 M NaOH (5 ml) was added. The mixture was heated at 80° C. for 1 h and dioxane (10 ml) and 2 M NaOH (10 ml) was added. The mixture was stirred for 1 h at 80° C. Water was added and the mixture acidified using 6 M HCl. The precipitated material was isolated by centrifugation, washed with water and dried at high vacuum overnight. Yield: 679 mg (100%); orange solid. 1H NMR (400 MHz, DMSO-d6): δ 3.75 (s, 4H), 7.21 (d, J 3.8 Hz, 2H), 7.25 (d, J 3.8 Hz, 2H), 7.29 (s, 2H), 7.31 (s, 2H),
Reaction SMILES: [CH2:1]([N:7]1[CH2:12][CH:11]2[CH:9]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH2:20])[CH3:13])[CH2:8]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].[CH3:21][S:22](Cl)(=[O:24])=[O:23].ClCCl>N1C=CC=CC=1>[NH3:7].[CH2:1]([N:7]1[CH2:8][CH:9]2[CH:11]([C:10]2([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=2[NH:20][S:22]([CH3:21])(=[O:24])=[O:23])[CH3:13])[CH2:12]1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: CCCCCCN1CC2C(C1)C2(C)c1ccccc1N
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCCCCCN1CC2C(C1)C2(C)c1ccccc1NS(C)(=O)=O
Product: N
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 2-[3-hexyl-6-methyl-3-azabicyclo[3.1.0]hex-6-yl]phenylamine (Preparation 140, 30 mg, 0.11 mmol) in pyridine (1.0 ml) under a nitrogen atmosphere at room temperature was added dropwise methane sulfonyl chloride (13 μl, 0.16 mmol), and the reaction mixture was stirred at room temperature for 2 d. Ice (2 g) and dichloromethane (5 ml) were added, the layers were separated and the aqueous layer was further extracted with dichloromethane (5 ml). The combined extracts were dried (Na2SO4), filtered and concentrated in vacuo. This was purified by chromatography using silica gel (1.5 g) eluting with dichloromethane:ethanol:0.880 ammonia (200:8:1) to afford the title compound as a very pale yellow oil (5.2 mg, 14%).
Reaction SMILES: [Cl:1]N1C(=O)CCC1=O.[F:9][C:10]1[C:25]([F:26])=[CH:24][C:13]2[NH:14][C:15]([NH:17][C:18]3[C:22]([CH3:23])=[CH:21][S:20][CH:19]=3)=[N:16][C:12]=2[CH:11]=1>C(O)(=O)C>[ClH:1].[Cl:1][C:19]1[S:20][CH:21]=[C:22]([CH3:23])[C:18]=1[NH:17][C:15]1[NH:14][C:13]2[CH:24]=[C:25]([F:26])[C:10]([F:9])=[CH:11][C:12]=2[N:16]=1
Reactant: Cc1cscc1Nc1nc2cc(F)c(F)cc2[nH]1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CC(=O)O
Product: Cc1csc(Cl)c1Nc1nc2cc(F)c(F)cc2[nH]1
Product: Cl
Temperature: 25 °C
Reaction time: 3.5 h

Procedure:
At room temperature, a solution of N-chlorosuccinimide (124.6 mg) in glacial acetic acid (5 ml) was added dropwise to a solution of (5,6-difluoro-1H-benzimidazol-2-yl)-(4-methylthiophen-3-yl)amine (225 mg) in glacial acetic acid (5 ml). The mixture was then stirred at room temperature for 3.5 hours. The glacial acetic acid was then removed and the residue was taken up in water and adjusted to pH 10 using 2 M aqueous sodium hydroxide solution. The aqueous phase was extracted three times with ethyl acetate, the combined organic phases were dried over magnesium sulfate and the solvent was removed. The residue was purified by preparative chromatography and the product-containing fractions were combined, freed from acetonitrile, made basic and extracted three times with ethyl acetate. The organic phases were combined, dried (MgSO4), filtered and concentrated. The residue was taken up in water, acidified with 10% strength hydrochloric acid and freeze-dried. This gave 81 mg of the desired product as a solid.
Reaction SMILES: [Cl:1][C:2]1[CH:9]=[CH:8][CH:7]=[C:6]([Cl:10])[C:3]=1[CH:4]=O.[CH3:11][O:12][C:13](=[O:22])[C:14]1[CH:19]=[CH:18][C:17]([NH2:20])=[C:16]([NH2:21])[CH:15]=1>CS(C)=O.CCOC(C)=O>[CH3:11][O:12][C:13]([C:14]1[CH:19]=[CH:18][C:17]2[N:20]=[C:4]([C:3]3[C:2]([Cl:1])=[CH:9][CH:8]=[CH:7][C:6]=3[Cl:10])[NH:21][C:16]=2[CH:15]=1)=[O:22]
Reactant: COC(=O)c1ccc(N)c(N)c1
Reactant: O=Cc1c(Cl)cccc1Cl
Solvent: CS(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc2nc(-c3c(Cl)cccc3Cl)[nH]c2c1
Reaction time: 17 h

Procedure:
Slowly add a solution of FeCl3 (1.46 g, 9.02 mmol) in DMSO (10 mL) to a stirring solution of 2,6-dichloro-benzaldehyde (5.27 g, 30.1 mmol) and 3,4-diamino-benzoic acid methyl ester (5.00 g, 30.1 mmol) in DMSO (90 mL). Allow the reaction to stir open to the air for 17 hr. Add additional FeCl3 (0.73 g, 4.51 mmol). Stir for an additional 24 hr. Dilute with EtOAc (600 mL) and extract with water (3×50 mL). Dry the organic phase over Na2SO4 and evaporate the solvent. Triturate the residue with DCM to afford the desired product as a light tan solid: 1H NMR (400 MHz, MeOD) δ ppm 3.96 (s, 3H) 7.55-7.63 (m, 3H) 7.71 (d, J=8.21 Hz, 1H) 8.04 (dd, J=8.53, 1.58 Hz, 1H) 8.37 (br. s., 1H); (M+H)+ 320.9.