Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [K].[C:2]([NH:6][S:7]([C:10]1[CH:18]=[C:17]([C:19](=[O:23])[N:20]([CH3:22])[CH3:21])[CH:16]=[CH:15][C:11]=1[C:12]([OH:14])=[O:13])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3].Br[CH2:25][CH3:26]>C(#N)C.C(OCC)(=O)C>[C:2]([NH:6][S:7]([C:10]1[CH:18]=[C:17]([C:19](=[O:23])[N:20]([CH3:21])[CH3:22])[CH:16]=[CH:15][C:11]=1[C:12]([O:14][CH2:25][CH3:26])=[O:13])(=[O:9])=[O:8])([CH3:5])([CH3:4])[CH3:3]
Reactant: CN(C)C(=O)c1ccc(C(=O)O)c(S(=O)(=O)NC(C)(C)C)c1
Reactant: CCBr
Agent: [K]
Solvent: CCOC(C)=O
Solvent: CC#N
Product: CCOC(=O)c1ccc(C(=O)N(C)C)cc1S(=O)(=O)NC(C)(C)C
Temperature: 25 °C

Procedure:
A suspension of 3.0 g (8.2 mmol) of the potassium salt of 2-tert-butylsulfamoyl-4-dimethylcarbamoylbenzoic acid, and 0.21 g (0.79 mmol) of 1,4,7,10,13,16-hexaoxacyclooctane in 25 ml of acetonitrile was stirred at room temperature for half an hour, and 890 mg (8.2 mmol) of bromoethane were then added. The mixture was subsequently heated under reflux for 6 h and then allowed to cool to room temperature. For work-up, the reaction mixture was diluted with ethyl acetate and extracted with 1 M aqueous hydrochloric acid solution, saturated aqueous sodium bicarbonate solution and water. The organic phase was dried over sodium sulfate, filtered off and concentrated. This gave 2.31 g (79% of theory) of ethyl 2-tert-butylsulfamoyl-4-dimethylcarbamoylbenzoate as a colorless solid of m.p. 101 to 102.5° C.
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:8]([N+]([O-])=O)=[CH:7][C:3]=1[C:4](Cl)=[O:5].[Al+3].[Cl-].[Cl-].[Cl-].Cl>ClCCl>[C:4]([C:2]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:3]=1)(=[O:5])[C:3]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:2]=1
Reactant: O=C(Cl)c1cc([N+](=O)[O-])ccc1Cl
Agent: Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Reaction time: 24 h

Procedure:
[13C6]-Benzene (0.6 g, 7.1 mmol) was added to a solution of 2-chloro-5-nitrobenzoic acid chloride (3.13 g, 14.3 mmol) in 50 mL of dichloromethane. The mixture was cooled to 0-5° C. before AlCl3 (2.29 g, 17.2 mmol) was added in slowly. Upon completion of the addition, the mixture was allowed to reach room temperature, and stirring was continued for 24 h. The deep-red solution was treated with HCl and ice, and the resulting aqueous phase was extracted with ether. The combined organic extracts were washed with 2% aqueous NaOH and then water and dried over sodium sulphate. The solvent was removed in vacuo to give crude benzophenone, which was recrystallized from toluene/isopropyl ether to yield 1.52 g (80%) of pure [13C6]-2-chloro-5-nitrobenzophenone.
Reaction SMILES: [Br:1][C:2]1[C:7]([N+:8]([O-])=O)=[CH:6][CH:5]=[CH:4][C:3]=1[CH3:11].[Cl-].[NH4+]>[Fe]>[Br:1][C:2]1[C:3]([CH3:11])=[CH:4][CH:5]=[CH:6][C:7]=1[NH2:8]
Reactant: Cc1cccc([N+](=O)[O-])c1Br
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Product: Cc1cccc(N)c1Br

Procedure:
The procedure as in Example 20: step c was followed using 2-bromo-1-methyl-3-nitro-benzene (1 g, 4.6 mmol dissolved in 12 mL EtOH, Aldrich Chemical Company), ammonium chloride (2.5 g, 46 mmol dissolved in 6 mL H2O) and iron (1.3 g, 23 mmol). The title compound was obtained (1.0 g, quantitative yield) which was used without further purification. 1H-NMR (CDCl3): δ 6.95–7.00 (t, 1H, J=7.6 Hz), 6.60–6.65 (dd, 2H, J=8.1, 4.4 Hz), 4.10 (br s, 2H), 2.35 (s, 3H).
Reaction SMILES: [F:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[C:7](Cl)[C:3]=1[C:4](O)=[O:5].S(Cl)([Cl:17])=O>>[F:1][C:2]1[C:10]([Cl:11])=[C:9]([F:12])[C:8]([F:13])=[CH:7][C:3]=1[C:4]([Cl:17])=[O:5]
Reactant: O=C(O)c1c(F)c(Cl)c(F)c(F)c1Cl
Reactant: O=S(Cl)Cl
Product: O=C(Cl)c1cc(F)c(F)c(Cl)c1F

Procedure:
The chlorination of the 2,4,5-trifluorobenzoic acid is carried out in the melt, under pressure and/or in a solvent, for example chlorosulphonic acid or oleum, in the presence of halogen transfer agents, for example iodine. 2,4,5-Trifluoro-3-chlorobenzoic acid is obtained in this reaction. However, since the reaction mixture still contains unchanged starting material and some 2,4,5,-trifluoro-3,6-dichlorobenzoic acid, the crude mixture is treated, without intermediate isolation, with thionyl chloride. The desired 2,4,5-trifluoro-3-chlorobenzoyl chloride is then obtained by fractional distillation. However, it is more favorable to carry out the separation by distillation of the acid fluorides.
Reaction SMILES: [CH3:1][C:2]1[O:3][CH:4]=[C:5]([C:7]([OH:9])=O)[N:6]=1.O1CCCC1.C(Cl)(=O)C(Cl)=O.[NH2:21][C:22]1[CH:23]=[C:24]([CH:41]=[CH:42][C:43]=1[CH3:44])[O:25][C:26]1[CH:27]=[CH:28][C:29]2[N:30]([CH:32]=[C:33]([NH:35][C:36]([CH:38]3[CH2:40][CH2:39]3)=[O:37])[N:34]=2)[N:31]=1>CN(C)C=O.CN(C)C(=O)C>[CH:38]1([C:36]([NH:35][C:33]2[N:34]=[C:29]3[CH:28]=[CH:27][C:26]([O:25][C:24]4[CH:41]=[CH:42][C:43]([CH3:44])=[C:22]([NH:21][C:7]([C:5]5[N:6]=[C:2]([CH3:1])[O:3][CH:4]=5)=[O:9])[CH:23]=4)=[N:31][N:30]3[CH:32]=2)=[O:37])[CH2:39][CH2:40]1
Reactant: Cc1ccc(Oc2ccc3nc(NC(=O)C4CC4)cn3n2)cc1N
Reactant: Cc1nc(C(=O)O)co1
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: CC(=O)N(C)C
Solvent: CN(C)C=O
Product: Cc1nc(C(=O)Nc2cc(Oc3ccc4nc(NC(=O)C5CC5)cn4n3)ccc2C)co1
Yield: 75.4 %

Procedure:
In the same manner as in Example 259 and using 2-methyl-1,3-oxazole-4-carboxylic acid (77 mg, 0.60 mmol), tetrahydrofuran (10 mL), N,N-dimethylformamide (1 drop), oxalyl chloride (62 μL, 0.72 mmol), N-[6-(3-amino-4-methylphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (150 mg, 0.46 mmol) and N,N-dimethylacetamide (7 mL) as starting materials, the title compound (150 mg, 74%) was obtained as a white solid.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([OH:18])=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:20][C:21]([C:23]1[CH:28]=[CH:27][C:26]([O:29][C:30]([F:33])([F:32])[F:31])=[CH:25][CH:24]=1)=[O:22]>>[C:1]([O:5][C:6]([NH:8][C:9]1([CH2:15][C:16]([O:18][CH2:20][C:21](=[O:22])[C:23]2[CH:28]=[CH:27][C:26]([O:29][C:30]([F:31])([F:32])[F:33])=[CH:25][CH:24]=2)=[O:17])[CH2:14][CH2:13][O:12][CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(CBr)c1ccc(OC(F)(F)F)cc1
Reactant: CC(C)(C)OC(=O)NC1(CC(=O)O)CCOCC1
Product: CC(C)(C)OC(=O)NC1(CC(=O)OCC(=O)c2ccc(OC(F)(F)F)cc2)CCOCC1
Temperature: 50 °C
Reaction time: 0.83 h
Yield: 105.1 %

Procedure:
Prepared by Method F using {4-[(tert-butoxycarbonyl)amino]tetrahydro-2H-pyran-4-yl}acetic acid (0.259 g, 1.00 mmol) and 2-bromo-1-[4-(trifluoromethoxy)phenyl]-ethanone (0.283 g, 1.00 mmol). The reaction was stirred at 50° C. for 50 minutes. The residue was isolated as a crude oil that crystallised to afford the title compound as a solid (0.485 g, 105% yield).
Reaction SMILES: Cl.[NH2:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:11]=1[OH:12])[NH:8][C:7](=[O:13])[C:6]2([CH3:15])[CH3:14].[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23](O)=O)=[CH:18][CH:17]=1.N>>[N:16]1[CH:21]=[CH:20][C:19]([CH2:22][C:23]2[O:12][C:11]3[CH:10]=[C:9]4[NH:8][C:7](=[O:13])[C:6]([CH3:15])([CH3:14])[C:5]4=[CH:4][C:3]=3[N:2]=2)=[CH:18][CH:17]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: CC1(C)C(=O)Nc2cc(O)c(N)cc21
Agent: Cl
Agent: N
Product: CC1(C)C(=O)Nc2cc3oc(Cc4ccncc4)nc3cc21

Procedure:
4.52 g. 5-Amino-1,3-dihydro-3,3-dimethyl-6-hydroxy-2H-indol-2-one hydrochloride and 3.65 g. 4-pyridylacetic acid were heated in 20 g. polyphosphoric acid for 30 minutes to 170° C. and the reaction mixture subsequently poured on to ice. A concentrated aqueous solution of ammonia was added thereto to give a pH of 10, the precipitate obtained was filtered off with suction, successively washed with water, methanol and diethyl ether and then dried to constant weight to give 3.20 g. (55% of theory) of the title compound; m.p. 208°-211° C.
Reaction SMILES: [CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:14]1([CH3:24])[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=1>O>[CH2:1]([N:8]1[CH2:12][CH2:11][C@@H:10]([OH:13])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1.[S:20]([C:17]1[CH:18]=[CH:19][C:14]([CH3:24])=[CH:15][CH:16]=1)([O-:13])(=[O:22])=[O:21]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: O[C@@H]1CCN(Cc2ccccc2)C1
Solvent: O
Product: Cc1ccc(S(=O)(=O)[O-])cc1
Temperature: 25 °C
Reaction time: 90 h
Yield: 175.6 %

Procedure:
To a stirred solution of (R)1-benzyl-3-pyrrolidinol (1.77 g, 10 mmol) pyridine(30 ml) was added p-toluenesulfonyl chloride (9.53 g, 50 mmol) by portions at 0° C. After 90 h stirring at room temperature, water was added to the reaction mixture and the mixture was extracted with ether (150 ml). The extract was washed with water brine, dried (Na2SO4), and concentrated to give 3.06 g (92%) of brown oil.
Reaction SMILES: I[C:2]1[N:6]=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=2)[N:4]([CH3:17])[C:3]=1[C:18]([N:20]1[CH2:25][CH2:24][CH:23]([N:26]2[CH2:30][CH2:29][CH2:28][CH2:27]2)[CH2:22][CH2:21]1)=[O:19].[N:31]1[CH:36]=[C:35](B(O)O)[CH:34]=[N:33][CH:32]=1>>[CH3:17][N:4]1[C:3]([C:18]([N:20]2[CH2:25][CH2:24][CH:23]([N:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:22][CH2:21]2)=[O:19])=[C:2]([C:35]2[CH:36]=[N:31][CH:32]=[N:33][CH:34]=2)[N:6]=[C:5]1[C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([C:13]([F:16])([F:15])[F:14])[CH:8]=1
Reactant: Cn1c(-c2cccc(C(F)(F)F)c2)nc(I)c1C(=O)N1CCC(N2CCCC2)CC1
Reactant: OB(O)c1cncnc1
Product: Cn1c(-c2cccc(C(F)(F)F)c2)nc(-c2cncnc2)c1C(=O)N1CCC(N2CCCC2)CC1

Procedure:
In analogy to the procedure described for example 7, [5-iodo-3-methyl-2-(3-trifluoromethyl-phenyl)-3H-imidazol-4-yl]-(4-pyrrolidin-1-yl-piperidin-1-yl)-methanone (example 36) was reacted with pyrimidine-5-yl-boronic acid to give the title compound as yellow solid. MS: 485.3 (MH+).
Reaction SMILES: FC(F)(F)C(O)=O.[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[C:16]2[O:18][C:19]([C:21]3[CH:35]=[C:34]([CH3:36])[C:24]([O:25][CH2:26][C:27]([O:29]C(C)(C)C)=[O:28])=[C:23]([CH3:37])[CH:22]=3)=[N:20][C:15]2=[CH:14][CH:13]=1>ClCCl>[F:8][C:9]1[CH:41]=[CH:40][CH:39]=[CH:38][C:10]=1[O:11][C:12]1[N:17]=[C:16]2[O:18][C:19]([C:21]3[CH:22]=[C:23]([CH3:37])[C:24]([O:25][CH2:26][C:27]([OH:29])=[O:28])=[C:34]([CH3:36])[CH:35]=3)=[N:20][C:15]2=[CH:14][CH:13]=1
Reactant: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2nc3ccc(Oc4ccccc4F)nc3o2)cc(C)c1OCC(=O)O
Temperature: 25 °C
Reaction time: 16 h

Procedure:
1 ml of trifluoroacetic acid was added to a solution of 170 mg of tert-butyl {4-[5-(2-fluorophenoxy)oxazolo[5,4-b]pyridin-2-yl]-2,6-dimethylphenoxy}acetate in 3 ml of dichloromethane, and the mixture was stirred at room temperature for 16 h. The reaction was then concentrated under reduced pressure, purified by preparative HPLC and freeze-dried. This gave 85 mg (57%) of the title compound.
Reaction SMILES: [NH2:1][C:2]1[C:7]([O:8][CH2:9][C:10]2[C:15]([F:16])=[CH:14][CH:13]=[CH:12][C:11]=2[F:17])=[CH:6][CH:5]=[CH:4][N:3]=1.[C:18]1([N:24]=[C:25]=[S:26])[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.C1(C)C=CC=CC=1>CCOCC>[F:17][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]([F:16])[C:10]=1[CH2:9][O:8][C:7]1[C:2]([NH:1][C:25]([NH:24][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[S:26])=[N:3][CH:4]=[CH:5][CH:6]=1
Reactant: Nc1ncccc1OCc1c(F)cccc1F
Reactant: S=C=Nc1ccccc1
Solvent: Cc1ccccc1
Solvent: CCOCC
Product: Fc1cccc(F)c1COc1cccnc1NC(=S)Nc1ccccc1

Procedure:
A mixture of 2-amino-3-(2,6-difluorobenzyloxy)pyridine (2.1 g, 0.09 mol), phenyl isothiocyanate (1.43 g, 0.011 mol) and toluene (10 ml) was heated under reflux for 3 hours, then cooled and diluted with ether to induce crystallisation of the product, which was recrystallised from ethanol/ether. Yield 2.0 g (82%), m.p. 132°-133 ° C.
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:13][C:14]2[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=2)=[N:4][C:5]([C:11]#[N:12])=[N:6][C:7]=1[NH:8][CH2:9][CH3:10].[CH:21]([N:24]=C=NC(C)C)(C)C.N1CCNCC1>C(#N)C>[NH2:24][C:21]1[N:8]([CH2:9][CH3:10])[C:7]2[C:2]([N:1]=1)=[C:3]([NH:13][C:14]1[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=1)[N:4]=[C:5]([C:11]#[N:12])[N:6]=2
Reactant: CC(C)N=C=NC(C)C
Reactant: CCNc1nc(C#N)nc(Nc2ccc(Cl)cc2)c1N
Agent: C1CNCCN1
Solvent: CC#N
Product: CCn1c(N)nc2c(Nc3ccc(Cl)cc3)nc(C#N)nc21
Temperature: 25 °C
Reaction time: 1 h

Procedure:
A solution of 5-amino-4-[(4-chlorophenyl)amino]-6-(ethylamino)pyrimidine-2-carbonitrile (0.41 g, prepared using the method of example 20) in acetonitrile (5 ml) was added to a stirred solution of FMOC-NCS (0.44 g) in acetonitrile (10 ml) at 0° C. After 1 h, diisopropylcarbodiimide (0.252 g) was added, the mixture heated under reflux for 4 h, cooled, piperazine (0.1 g) added and stirred at room temperature for 3 h. The solvent was removed under reduced pressure and the residue partitioned between ethyl acetate and brine, the organics dried (MgSO4) and evaporated under reduced pressure. The solid was purified by chromatography on silica eluting with 2-4% methanol in dichloromethane. Yield 0.12 g
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1.[CH2:24]([NH:26][CH2:27][CH3:28])[CH3:25].Cl>>[CH2:24]([N:26]([CH2:27][CH3:28])[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][C:8]=1/[CH:13]=[CH:14]/[C:15]1[S:16][C:17]2[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=2[N:19]=1)[CH3:25]
Reactant: ClCCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Reactant: CCNCC
Agent: Cl
Product: CCN(CC)CCCCOc1ccccc1/C=C/c1nc2ccccc2s1
Yield: 31 %

Procedure:
The procedure of Example 38 was followed starting with (H) of Example 38 (3.0 g, 8.7 mmol) and using diethylamine in place of dipropylamine to produce 1.2 g (31% yield) of the title compound as the HCl salt, mp 205°-207° C. IR(KBr): 3400, 1605 cm-1. MS: 381(MH+). 1H NMR (CD3OD): δ 8.14-7.04 (m, 10H), 4.14 (t, J=5.2 Hz, 2H), 3.25 (m, 6H), 1.98 (m, 4H), 1.34 (m, 6H).
Reaction SMILES: C([N:8]1[CH:12]=[C:11]([C:13]2([OH:17])[CH2:16][O:15][CH2:14]2)[N:10]=[CH:9]1)C1C=CC=CC=1.C(N1C=C(I)N=C1)C1C=CC=CC=1.CC[Mg+].[Br-].[NH4+].[Cl-]>C(Cl)Cl>[NH:8]1[CH:12]=[C:11]([C:13]2([OH:17])[CH2:16][O:15][CH2:14]2)[N:10]=[CH:9]1
Reactant: OC1(c2cn(Cc3ccccc3)cn2)COC1
Agent: CC[Mg+]
Agent: Ic1cn(Cc2ccccc2)cn1
Agent: [Br-]
Solvent: ClCCl
Product: OC1(c2c[nH]cn2)COC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
3-(1-benzyl-1H-imidazol-4-yl)oxetan-3-ol. A solution of 1-benzyl-4-iodo-1H-imidazole (6.0 g, 21.12 mmol) in DCM (80 mL) was treated with EtMgBr (3M in ether, 7.74 mL, 23.23 mmol) at rt and the mixture was stirred at RT overnight. The mixture was then poured onto saturated aqueous NH4Cl solution and extracted with DCM. The combined org. layers were dried over Na2SO4, filtered and concentrated in vacuo. The crude product was purified by flash-column chromatography over silicagel (Biotage Isolera Four, eluent: 1% MeOH in DCM for 3 min, then from 1% MeOH in DCM to 5% MeOH in DCM in 25 min, followed by 5% MeOH in DCM for 6 min). The residue was crystallized from EtOAc to yield the title compound as white crystals (2.35 g). UPLC-MS: MS 231.1 (M+H+); UPLC rt 0.43 min.
Reaction SMILES: N([O-])=O.[Na+].O.O.S([O-])(=O)(C1C=CC([NH2:15])=CC=1)=O.[Na+].Cl.[OH-].[Na+].[CH3:22][C:23]1[CH:24]=[C:25]([OH:30])[CH:26]=[C:27]([CH3:29])[CH:28]=1.S(S([O-])(=O)=O)([O-])(=O)=O.[Na+].[Na+]>>[NH2:15][C:28]1[C:27]([CH3:29])=[CH:26][C:25]([OH:30])=[CH:24][C:23]=1[CH3:22]
Reactant: Nc1ccc(S(=O)(=O)[O-])cc1
Reactant: Cc1cc(C)cc(O)c1
Agent: Cl
Agent: O=N[O-]
Agent: O=S(=O)([O-])S(=O)(=O)[O-]
Solvent: O
Product: Cc1cc(O)cc(C)c1N
Temperature: 25 °C
Reaction time: 0.33 h
Yield: 71.7 %

Procedure:
An aqueous solution (4 ml) of sodium nitrite (1.90 g, 27.5 mmol) was added to an aqueous solution (20 ml) of sodium sulfanilate dihydrate (5.78 g, 25.0 mmol). The resulting solution was dropped into a beaker containing concentrated hydrochloric acid (5.1 ml) and ice (30 g), and the resulting mixture was kept cold in an ice bath for 20 minutes to prepare solution A. An aqueous solution (30 ml) of sodium hydroxide (5.50 g, 138 mmol) and ice (20 g) were added to 3,5-dimethylphenol (3.05 g, 250 mmol) to effect dissolution, and then solution A was added dropwise thereto in an ice bath. The resulting solution was stirred in the ice bath for 1 hour and then heated to 65° C. to 75° C., and sodium dithionate (16.8 g, 96.5 mmol) was added thereto until the solution lost its color. The solution was cooled to room temperature and stirred for 30 minutes, and the solid formed was collected by filtration and dried to obtain 4-amino-3,5-dimethylphenol (2.46 g, 72%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].ClC1N=C(OC)N=C(OC)N=1.CN1CCOCC1.[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][NH:46][CH2:45]1)[CH3:42]>CC#N>[CH2:41]([N:43]([CH2:49][CH3:50])[CH:44]1[CH2:48][CH2:47][N:46]([C:19]([C:16]2[N:17]([CH3:18])[C:13]([C:9]3[CH:10]=[CH:11][CH:12]=[C:7]([CH2:1][CH2:2][CH2:3][CH2:4][CH2:5][CH3:6])[CH:8]=3)=[N:14][C:15]=2[I:22])=[O:21])[CH2:45]1)[CH3:42]
Reactant: CCN(CC)C1CCNC1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
Agent: COc1nc(Cl)nc(OC)n1
Solvent: CC#N
Solvent: CN1CCOCC1
Product: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N(CC)CC)C3)n2C)c1
Temperature: 0 °C
Reaction time: 2 h
Yield: 72.7 %

Procedure:
A solution of 0.41 g (1.0 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazol-4-carboxylic acid (intermediate 1) in 10 ml of MeCN was treated with 0.192 g (1.1 mmol) of 2-chloro-4,6-dimethoxy-[1,3,5]triazine and cooled down to 0° C. 0.33 ml=0.30 g (3.0 mmol) of N-methylmorpholine was added and stirring continued at 0° C. for another 2 hours. Then, a solution of 0.159 g (1.1 mmol) of (rac)-diethyl-pyrrolidin-3-yl-amine in 5 ml of MeCN was added and the reaction mixture was allowed the reach RT. After stirring at RT for 18 hours, it was poured into crashed ice and extracted twice with EtOAc; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 4:1) to give 0.39 g (73%) of the title compound as light brown oil. MS: 537.3 (MH+).
Reaction SMILES: C(O)C.[OH:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:7][CH:6]=1.[OH-].[K+].Br[CH2:23][CH2:24][CH2:25][CH:26]=[CH2:27]>O>[CH2:27]([O:4][C:5]1[CH:6]=[CH:7][C:8]([C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][CH:12]=2)=[CH:9][CH:10]=1)[CH2:26][CH2:25][CH:24]=[CH2:23]
Reactant: O=[N+]([O-])c1ccc(-c2ccc(O)cc2)cc1
Reactant: C=CCCCBr
Agent: [K+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: C=CCCCOc1ccc(-c2ccc([N+](=O)[O-])cc2)cc1

Procedure:
To 400 ml ethanol is added 21.5 g of 4-hydroxy-4'-nitrobiphenyl, and the mixture is heated to reflux. A solution of 7.1 g KOH in 30 ml of water is added dropwise at reflux temperatures. After complete addition, 18 g of 5-bromo-1-pentene is added and the reaction medium is heated at reflux temperarure for about 15 hours. Ethanol is removed under vacuum from the cooled mixture, and the solid residue is slurried with water in a blender,filtered, washed with water, and air dried. The product then is recrystallized from 90/10 hexane/toluene, mp 74°-76° C.
Reaction SMILES: CON(C)[C:4]([C:6]1[N:7]=[CH:8][N:9]([C:11]2[CH:12]=[C:13]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=3[O:23][C:24]([F:27])([F:26])[F:25])[CH:14]=[CH:15][CH:16]=2)[CH:10]=1)=[O:5].Br[C:30]1[CH:35]=[C:34]([CH3:36])[CH:33]=[CH:32][N:31]=1>>[CH3:36][C:34]1[CH:33]=[CH:32][N:31]=[C:30]([C:4]([C:6]2[N:7]=[CH:8][N:9]([C:11]3[CH:12]=[C:13]([C:17]4[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=4[O:23][C:24]([F:25])([F:27])[F:26])[CH:14]=[CH:15][CH:16]=3)[CH:10]=2)=[O:5])[CH:35]=1
Reactant: Cc1ccnc(Br)c1
Reactant: CON(C)C(=O)c1cn(-c2cccc(-c3ccccc3OC(F)(F)F)c2)cn1
Product: Cc1ccnc(C(=O)c2cn(-c3cccc(-c4ccccc4OC(F)(F)F)c3)cn2)c1

Procedure:
This compound is prepared by method C using compound 12f and 2-bromo-4-methylpyridine
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C=CC(P(C2C(C3C(P(C4C=CC=CC=4)C4C=CC=CC=4)=CC=C4C=3C=CC=C4)=C3C(C=CC=C3)=CC=2)C2C=CC=CC=2)=CC=1.C(=O)([O-])[O-].[Cs+].[Cs+].[CH2:66]([O:68][C:69]([C:71]1[O:72][C:73]2[C:79](Br)=[CH:78][C:77]([F:81])=[CH:76][C:74]=2[CH:75]=1)=[O:70])[CH3:67]>C1(C)C=CC=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[CH2:66]([O:68][C:69]([C:71]1[O:72][C:73]2[C:79]([N:11]3[CH2:12][CH2:13][N:8]([CH2:1][C:2]4[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=4)[CH2:9][CH2:10]3)=[CH:78][C:77]([F:81])=[CH:76][C:74]=2[CH:75]=1)=[O:70])[CH3:67]
Reactant: c1ccc(CN2CCNCC2)cc1
Reactant: CCOC(=O)c1cc2cc(F)cc(Br)c2o1
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: Cc1ccccc1
Product: CCOC(=O)c1cc2cc(F)cc(N3CCN(Cc4ccccc4)CC3)c2o1

Procedure:
Benzylpiperazine (1.3 mL, 8.4 mmol), BINAP (0.43 g, 0.69 mmol), Pd2 dba3 (0.32 g, 0.35 mmol), cesium carbonate (3.25 g, 9.76 mmol) were added to a degassed solution of 7-bromo-5-fluoro-benzofuran-2-carboxylic acid ethyl ester (2.0 g, 6.97 mmol) in toluene (50 mL). The mixture was heated at reflux over night. After cooling, the mixture was filtered through a pad of celite and washed with dichloromethane. The filtrate was concentrated under reduced pressure. The product was purified by flash chromatography (SiO2; hexane/EtOAc, 7/3). Yield: 1.6 g (60%).
Reaction SMILES: [C:1]([C:3]1[C:8]2[N:9]([CH:36]3[CH2:40][CH2:39][CH2:38][CH2:37]3)[C:10]3[N:11]=[C:12]([NH:16][C:17]4[N:22]=[CH:21][C:20]([N:23]5[CH2:28][CH2:27][N:26](C(OC(C)(C)C)=O)[CH2:25][CH2:24]5)=[CH:19][CH:18]=4)[N:13]=[CH:14][C:15]=3[C:7]=2[CH:6]=[CH:5][N:4]=1)#[N:2].Cl>CO>[CH:36]1([N:9]2[C:10]3[N:11]=[C:12]([NH:16][C:17]4[CH:18]=[CH:19][C:20]([N:23]5[CH2:24][CH2:25][NH:26][CH2:27][CH2:28]5)=[CH:21][N:22]=4)[N:13]=[CH:14][C:15]=3[C:7]3[CH:6]=[CH:5][N:4]=[C:3]([C:1]#[N:2])[C:8]2=3)[CH2:37][CH2:38][CH2:39][CH2:40]1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccc(Nc3ncc4c5ccnc(C#N)c5n(C5CCCC5)c4n3)nc2)CC1
Agent: Cl
Solvent: CO
Product: N#Cc1nccc2c3cnc(Nc4ccc(N5CCNCC5)cn4)nc3n(C3CCCC3)c12
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 103.3 %

Procedure:
Compound 288 (44.0 mg, 81.5 μmol) was suspended in 3 mL methanol. Mmethanol saturated at room temperature with HCl (1 mL) was added, and the reaction stirred at room temperature for 2.5 hours. The solvents were removed in vacuo. The residue was taken up in methanol (10 mL) and stripped again to give compound 286 as a yellow solid (37 mg, 91%). 1H NMR (500 MHz, DMSO-d6) δ 1.68-1.80 (m, 2 H) 2.01-2.20 (m, 4 H) 2.64 (none, 2 H) 3.25-3.34 (m, 4 H) 3.34-3.44 (m, 5 H) 5.62-5.73 (m, 1 H) 7.60-7.73 (m, 1 H) 7.98-8.07 (m, 1 H) 8.09-8.16 (m, 1 H) 8.39-8.48 (m, 1 H) 8.58-8.65 (m, 1 H) 8.67-8.80 (m, 2 H) 9.40-9.49 (m, 1 H) 10.32-10.51 (m, 1 H) ppm.
Reaction SMILES: [CH2:1]1[C:12]2[C:11]3[C:6](=[C:7]([C:13]([OH:15])=O)[CH:8]=[CH:9][CH:10]=3)[NH:5][C:4]=2[CH2:3][CH2:2]1.[CH2:16]([O:18][C:19](=[O:23])[C@H:20]([CH3:22])[NH2:21])[CH3:17].Cl.CN(C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C>C(Cl)Cl>[CH2:1]1[C:12]2[C:11]3[CH:10]=[CH:9][CH:8]=[C:7]([C:13]([NH:21][C@@H:20]([CH3:22])[C:19]([O:18][CH2:16][CH3:17])=[O:23])=[O:15])[C:6]=3[NH:5][C:4]=2[CH2:3][CH2:2]1
Reactant: O=C(O)c1cccc2c3c([nH]c12)CCC3
Reactant: CCOC(=O)[C@H](C)N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)[C@H](C)NC(=O)c1cccc2c3c([nH]c12)CCC3
Temperature: 25 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
To a stirred, cooled (0° C.) solution of crude 1,2,3,4-tetrahydrocyclopenta[b]indole-5-carboxylic acid (60 mmol, 12 g), L-alanine ethyl ester (72 mmol, 11 g), 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride (EDC) (72 mmol, 14 g), 1-hydroxybenzotriazole (HOBT) (72 mmol, 10 g) in CH2Cl2 (100 mL) was slowly added diisopropylethylamine (360 mmol, 46 g). The reaction mixture was stirred overnight while warming to room temperature. The reaction was concentrated in vacuo and the resulting oil was partitioned between water and ethyl acetate. The organic layer was washed with saturated aqueous NH4Cl, NaHCO3, and brine, dried over MgSO4, filtered and concentrated to a brown oil. The crude material was purified by chromatography through silica gel (Biotage) eluting with 15% ethyl acetate-hexanes to afford a yellow oil (8.4 mmol, 2.5 g, 16% yield over 2 steps).