Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[NH:15][CH2:16][C:17]([F:20])([F:19])[F:18])=[C:4]([O:21][CH3:22])[CH:3]=1.[F:23][C:24]1[CH:25]=[C:26]([CH:30]=[C:31]([C:33]([F:36])([F:35])[F:34])[CH:32]=1)[C:27](Cl)=[O:28]>CCCCCCC.CCOC(C)=O>[F:1][C:2]1[C:7]([F:8])=[CH:6][C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][C:10]=2[N:15]([CH2:16][C:17]([F:18])([F:19])[F:20])[C:27](=[O:28])[C:26]2[CH:30]=[C:31]([C:33]([F:34])([F:35])[F:36])[CH:32]=[C:24]([F:23])[CH:25]=2)=[C:4]([O:21][CH3:22])[CH:3]=1
Reactant: O=C(Cl)c1cc(F)cc(C(F)(F)F)c1
Reactant: COc1cc(F)c(F)cc1-c1ccncc1NCC(F)(F)F
Solvent: CCCCCCC
Solvent: CCOC(C)=O
Product: COc1cc(F)c(F)cc1-c1ccncc1N(CC(F)(F)F)C(=O)c1cc(F)cc(C(F)(F)F)c1

Procedure:
The title compound was prepared in analogy to example 72, intermediate, from [4-(4,5-difluoro-2-methoxy-phenyl)-pyridin-3-yl]-(2,2,2-trifluoro-ethyl)-amine and 3-fluoro-5-(trifluoromethyl)benzoic acid chloride (CAS RN 171243-30-4) and using a gradient of n-heptane:EtOAc (100:0 to 50:50) for the chromatographic purification. Light yellow foam (39%). MS (ESI): m/z=509.091 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([OH:24])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.S(=O)(=O)(O)O.[CH2:32](O)[CH3:33]>>[Cl:1][C:2]1[CH:3]=[C:4]([C@@H:8]([OH:26])[CH2:9][NH:10][C@H:11]([CH3:25])[CH2:12][C:13]2[C:21]3[C:16](=[C:17]([C:22]([O:24][CH2:32][CH3:33])=[O:23])[CH:18]=[CH:19][CH:20]=3)[NH:15][CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: C[C@H](Cc1c[nH]c2c(C(=O)O)cccc12)NC[C@H](O)c1cccc(Cl)c1
Reactant: CCO
Agent: O=S(=O)(O)O
Product: CCOC(=O)c1cccc2c(C[C@@H](C)NC[C@H](O)c3cccc(Cl)c3)c[nH]c12
Temperature: 150 °C
Yield: 93 %

Procedure:
3-{(2R)-2-[2-(3-Chlorophenyl)-(2R)-2-hydroxyethylamino]propyl}-1H-indole-7-carboxylic acid (50 mg, 0.134 mmol) is dissolved in ethanol (5 mL), and thereto are added conc. sulfuric acid (0.05 mL) and Molecular Sieves 4A powder (trade name, 0.3 g), and the mixture is heated at 150° C. for 16 hours. After cooling, the insoluble materials are removed by filtration, and a saturated aqueous sodium hydrogen carbonate solution is added to the filtrate. The mixture is evaporated under reduced pressure to remove ethanol, and the resultant is extracted with ethyl acetate. The organic layer is washed with a saturated brine, dried over sodium sulfate, and concentrated. The residue is purified by silica gel column chromatography (chloroform/ethanol=4/1) to give the title compound (50 mg, yield: 93%).
Reaction SMILES: COC1C=C(OC)C=CC=1C[O:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:30])[CH3:29])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:13])=[O:12].FC(F)(F)C(O)=O>ClCCl>[OH:6][NH:7][C:8](=[O:31])[CH:9]([CH2:27][CH:28]([CH3:29])[CH3:30])[CH2:10][S:11]([N:14]1[CH2:19][CH2:18][N:17]([C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH2:16][CH2:15]1)(=[O:12])=[O:13]
Reactant: COc1ccc(CONC(=O)C(CC(C)C)CS(=O)(=O)N2CCN(c3ccc(F)cc3)CC2)c(OC)c1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)CC(CS(=O)(=O)N1CCN(c2ccc(F)cc2)CC1)C(=O)NO
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 55.5 %

Procedure:
To a solution of N-(2,4-dimethoxybenzyloxy)-3-[4-(4-fluorophenyl)piperazine-1-sulfonyl]-2-isobutylpropionamide (220 mg) in dichioromethane (4 ml) was added trifluoroacetic acid (200 μl) andtriethylsilane (145 μl). The mixture was stirred at room temperature for 15 minutes, evaporated in vacuo and the residue was purified on silica gel (eluant: dichloromethane-ether-methanol (80:20:0.5) to dichloromethane-methanol (80:20) to give the title compound (88 mg, 56%).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=1.Cl.[N:17]1([C:23]2[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=3[S:25][N:24]=2)[CH2:22][CH2:21][NH:20][CH2:19][CH2:18]1>>[S:25]1[C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:23]([N:17]2[CH2:18][CH2:19][N:20]([CH2:2][CH2:3][C:4]3[CH:9]=[CH:8][C:7]([N:10]([CH3:14])[C:11](=[O:13])[CH3:12])=[C:6]([CH3:15])[CH:5]=3)[CH2:21][CH2:22]2)=[N:24]1
Reactant: CC(=O)N(C)c1ccc(CCCl)cc1C
Reactant: c1ccc2c(N3CCNCC3)nsc2c1
Agent: Cl
Product: CC(=O)N(C)c1ccc(CCN2CCN(c3nsc4ccccc34)CC2)cc1C
Yield: 71 %

Procedure:
Starting with N-[4-(2-chloro-ethyl)-2-methyl-phenyl]-N-methyl-acetamide (0.226 g, 1.00 mmol) and 3-piperazin-1-yl-benzo[d]isothiazole hydrochloride (0.384 g, 1.50 mmol), and following the procedure outlined in Example 501, N-{4-[2-(4-benzo[d]isothiazol-3-yl-piperazin-1-yl)-ethyl]-2-methyl-phenyl}-N-methyl-acetamide was obtained as its hydrochloride salt (0.341 g, 0.41 mmol). Yield=71%;100% purity at 254 nm; LCMS (APCI): 409.2 [M+H]+, 1H NMR (400 MHz, DMSO-d6) δ 8.12 (d, J=7.51 Hz, 1H), 8.08 (d, J=7.51 Hz, 1H), 7.57 (t, J=7.51 Hz, 1H), 7.44 (t, J=7.51 Hz, 1H), 7.26 (s, 1H), 7.24–7.19 (m, 2H), 4.07 (d, J=13.23 Hz, 2H), 3.65 (d, J=13.23 Hz, 2H), 3.53 (apparent t, J=12.21 Hz, 2H), 3.44–3.22 (m, 4H), 3.19–3.07 (m, 2H), 3.00 (s, 3H), 2.14 (s, 3H), 1.60 (s, 3H); Anal. Calcd for C23H29N4O1S1Cl1: C, 60.88; H, 6.49; N, 12.35. Found: C, 60.48; H, 6.59; N, 11.98.
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[C:4](F)[CH:3]=1.[CH2:12]([NH2:15])[CH2:13][NH2:14].F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.[OH-].[Na+]>C(Cl)Cl.CN(C=O)C>[Br:1][C:2]1[CH:10]=[CH:9][C:5]2[C:6](=[O:8])[NH:15][CH2:12][CH2:13][NH:14][C:4]=2[CH:3]=1
Reactant: NCCN
Reactant: O=C(O)c1ccc(Br)cc1F
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C1NCCNc2cc(Br)ccc21
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 4-Bromo-2-fluoro-benzoic acid (500 mg, 2.28 mmol) and 5 mL Ethane-1,2-diamine was reacted in a sealed tube under argon with microwave irradiation at 150 C for 30 min. The reaction was cooled, diluted with methylene chloride (200 mL), and DMF (10 mL) to give a homogeneous solution. 2-(7-Aza-1H-benzotriazole-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate (HATU), (1 g, 2.63 mmol, 1.1 eq.) was added, and the reaction stirred at room temperature for 2 hours. The reaction was then heated to 95 C for 15 hours, cooled, and 3 mL 5 N NaOH was added. The mixture was stirred at room temperature for 1 hour, the reaction was concentrated in vacuo, extracted with ethyl acetate 3×, the organic layers were dried and concentrated. The residue was purified by flash chromatography to give 150 mg of 8-Bromo-1,2,3,4-tetrahydro-benzo[e][1,4]diazepin-5-one, 27%.
Reaction SMILES: [Cl:1][C:2]1[CH:38]=[CH:37][C:36]([CH2:39][CH2:40][O:41][CH3:42])=[CH:35][C:3]=1[CH2:4][N:5]([CH:32]1[CH2:34][CH2:33]1)[C:6](=[O:31])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:27]([Cl:28])=[CH:26][C:25]([CH3:29])=[CH:24][C:23]=2[Cl:30])=[CH:14][CH:13]=1)[C:8](=O)[CH3:9].C([O-])(=O)C.[NH4+:47].C([BH3-])#N.[Na+]>CO>[NH2:47][CH:8]([CH3:9])[CH:7]([CH2:11][C:12]1[CH:17]=[CH:16][C:15]([O:18][CH2:19][CH2:20][O:21][C:22]2[C:23]([Cl:30])=[CH:24][C:25]([CH3:29])=[CH:26][C:27]=2[Cl:28])=[CH:14][CH:13]=1)[C:6]([N:5]([CH2:4][C:3]1[CH:35]=[C:36]([CH2:39][CH2:40][O:41][CH3:42])[CH:37]=[CH:38][C:2]=1[Cl:1])[CH:32]1[CH2:34][CH2:33]1)=[O:31]
Reactant: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)=O)C2CC2)c1
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: COCCc1ccc(Cl)c(CN(C(=O)C(Cc2ccc(OCCOc3c(Cl)cc(C)cc3Cl)cc2)C(C)N)C2CC2)c1

Procedure:
N-[2-Chloro-5-(2-methoxyethyl)benzyl]-N-cyclopropyl-2-{4-[2-(2,6-dichloro-4-methylphenoxy)ethoxy]benzyl}-3-oxobutanamide from the previous step (1 eq.) and ammonium acetate (10 eq.) were combined in MeOH (0.06 M). After the addition of sodium cyanoborohydride (1.2 eq.), the resulting reaction mixture was heated at reflux for 2 h. The volatiles were then removed in vacuo and the resulting residue partitioned between EtOAc and 1 N aq. NaOH. The aqueous wash was separated and back extracted with EtOAc. The combined organic extracts were then washed further with water and brine, dried over MgSO4, filtered and the filtrate concentrated in vacuo. The crude product thus obtained was purified further by way of flash chromatography (SiO2, 96:4 (v/v) CH2Cl2: 2.0 M NH3 in MeOH) to reveal the title compound as a white froth. MS (ESI+): 635.3.
Reaction SMILES: [C:1]([N:9]1[C:13]2=[N:14][C:15](Br)=[CH:16][CH:17]=[C:12]2[CH:11]=[CH:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:19][Si:20]([C:23]#[CH:24])([CH3:22])[CH3:21]>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:19][Si:20]([C:23]#[C:24][C:15]1[N:14]=[C:13]2[N:9]([C:1](=[O:8])[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:10]=[CH:11][C:12]2=[CH:17][CH:16]=1)([CH3:22])[CH3:21]
Reactant: C#C[Si](C)(C)C
Reactant: O=C(c1ccccc1)n1ccc2ccc(Br)nc21
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C[Si](C)(C)C#Cc1ccc2ccn(C(=O)c3ccccc3)c2n1
Temperature: 25 °C
Reaction time: 24 h
Yield: 14.1 %

Procedure:
The synthesis was performed with reference to the known literature (Bulletin of the Chemical Society of Japan, Vol. 65, p. 2992, 1992). A solution of 1-benzoyl-6-bromo-1H-pyrrolo[2,3-b]pyridine (0.30 g, 1.0 mmol) in triethylamine (25 mL) was added with dichlorobis(triphenylphosphine)palladium(II) (0.036 g, 0.050 mmol), and copper(I) iodide (0.016 g, 0.085 mmol) under an argon atmosphere. Then, the mixture was slowly added with trimethylsilylacetylene (0.20 g, 2.0 mmol), and then the mixture was stirred at room temperature for 24 hours. Triethylamine was evaporated under reduced pressure, the residue was dissolved in ethyl acetate, and then the organic layer was washed successively with water and saturated brine, and dried over anhydrous magnesium sulfate. The solvent was evaporated under reduced pressure, and the residue was subjected to silica gel column chromatography (eluted with hexane/ethyl acetate (100:0→90:10)) to obtain 6-[(trimethylsilyl)ethynyl]-1-benzoyl-1H-pyrrolo[2,3-b]pyridine (0.045 g, 14%).
Reaction SMILES: [O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][CH:8]=[CH:9][N:10]=1.CCCCCC.C([Li])CCC.CN(C)[CH:24]=[O:25].C(O)(=O)CC(CC(O)=O)(C(O)=O)O>O1CCCC1>[O:1]1[CH2:5][CH2:4][O:3][CH:2]1[C:6]1[S:7][C:8]([CH:24]=[O:25])=[CH:9][N:10]=1
Reactant: CN(C)C=O
Reactant: c1csc(C2OCCO2)n1
Agent: O=C(O)CC(O)(CC(=O)O)C(=O)O
Agent: [Li]CCCC
Solvent: CCCCCC
Solvent: C1CCOC1
Product: O=Cc1cnc(C2OCCO2)s1
Temperature: -70 °C
Reaction time: 1 h
Yield: 56.4 %

Procedure:
To a solution of 2-(1,3-dioxolan-2-yl)-1,3-thiazole (10.00 g) in tetrahydrofuran (150 mL) was slowly added a 1.6M n-butyllithium hexane solution (44 mL) at −70° C. under a nitrogen atmosphere. The reaction mixture was stirred at −70° C. for 1 hr and N,N-dimethylformamide (14 g) was added. The reaction mixture was warmed to room temperature, 10% aqueous citric acid solution was added, and the mixture was extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried (MgSO4) and concentrated. The obtained residue was subjected to silica gel column chromatography, and the title compound (6.64 g, yield 56%) was obtained as a colorless oil from a fraction eluted with ethyl acetate-hexane (3:2, volume ratio). MS: 186 (MH+).
Reaction SMILES: Br[C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[CH:4]=[C:5]([CH3:11])[NH:6]2.[CH3:12][N:13]1C(=O)CCC1>[C-]#N.[C-]#N.[Zn+2].[Zn].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.[Fe+2].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]>[CH3:11][C:5]1[NH:6][C:7]2[CH:8]=[CH:9][CH:10]=[C:2]([C:12]#[N:13])[C:3]=2[CH:4]=1
Reactant: CN1CCCC1=O
Reactant: Cc1cc2c(Br)cccc2[nH]1
Agent: [Fe+2]
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: Cc1cc2c(C#N)cccc2[nH]1
Temperature: 120 °C
Yield: 96 %

Procedure:
A mixture of 4-bromo-2-methyl-1H-indole (572 mg, 2.72 mmol), Zn(CN)2 (351 mg, 3.0 mmol), Zn (35 mg, 0.54 mmol), dppf (606 mg, 1.09 mmol), and Pd2(dba)3 (498 mg, 0.54 mmol) in NMP (10 mL) under argon atmosphere was heated at 120° C. for 18 h. After cooling to RT, the reaction mixture was partitioned between EtOAc (300 mL) and water (50 mL). The organic layer was washed with brine, dried (MgSO4), filtered and concentrated in vacuo. The residue was purified by SiO2 chromatography eluting with petroleum ether/EtOAc (3:1) to afford 2-methyl-1H-indole-4-carbonitrile as a yellow oil (408 mg, 96%). MS (ESI): m/z=157.2 [M+1]+.
Reaction SMILES: [CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH2:23])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1.[N:24]1([S:30](Cl)(=[O:32])=[O:31])[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1>N1C=CC=CC=1>[CH3:1][N:2]1[CH:6]=[C:5]([C:7]2[CH:8]=[N:9][C:10]3[C:15]([N:16]=2)=[CH:14][C:13]([C:17]2[CH:18]=[C:19]([NH:23][S:30]([N:24]4[CH2:29][CH2:28][O:27][CH2:26][CH2:25]4)(=[O:32])=[O:31])[CH:20]=[N:21][CH:22]=2)=[CH:12][CH:11]=3)[CH:4]=[N:3]1
Reactant: O=S(=O)(Cl)N1CCOCC1
Reactant: Cn1cc(-c2cnc3ccc(-c4cncc(N)c4)cc3n2)cn1
Solvent: c1ccncc1
Product: Cn1cc(-c2cnc3ccc(-c4cncc(NS(=O)(=O)N5CCOCC5)c4)cc3n2)cn1
Temperature: 25 °C
Reaction time: 16.5 h

Procedure:
In an oven-dried flask under nitrogen, a solution of 5-[3-(1-methyl-1H-pyrazol-4-yl)-6-quinoxalinyl]-3-pyridinamine (99 mg, 0.327 mmol) in pyridine (3 mL) at room temperature was treated with morpholine-4-sulfonyl chloride (96 mg, 0.491 mmol) by syringe. The reaction was stirred at room temperature for 16.5 hours. The reaction was very sluggish so the reaction was placed in an oil bath at 50° C. and stirred at that temperature for 23 hours. The reaction was progressing to the desired product as determined by LCMS but was not yet complete. The reaction mixture was stirred for an additional 4 days at 50° C. The reaction did not progress to completion. The reaction was cooled to room temperature and concentrated in vacuo. The residue was taken up into 200 mL ethyl acetate and 50 mL water. The organic layer was washed with saturated aqueous sodium bicarbonate solution (100 mL) followed by brine (100 mL), dried over magnesium sulfate and concentrated in vacuo. Purification by silica gel chromatography eluting with 0-10% methanol in dichloromethane provided the desired product as a residue which was not pure. Addition of dichloromethane/ether resulted in precipitate formation. The precipitate was collected by filtration. Recrystallization of the precipitate from ethanol provided the title compound (26 mg, 18%) as a rust-coloured solid. MS(ES)+ m/e 452.0 [M+H]+.
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([OH:12])=[O:11])=[CH:5][CH:4]=1.[Si](C=[N+]=[N-])(C)(C)[CH3:14]>CO>[OH:1][CH2:2][C:3]1[CH:8]=[CH:7][C:6]([CH2:9][C:10]([O:12][CH3:14])=[O:11])=[CH:5][CH:4]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: O=C(O)Cc1ccc(CO)cc1
Solvent: CO
Product: COC(=O)Cc1ccc(CO)cc1
Reaction time: 3 h

Procedure:
To 2-(4-(hydroxymethyl)phenyl)acetic acid in MeOH at 0° C. was added TMS-CHN2. The solution was stirred for 3 h then quenched with a few drops of AcOH. The solvents were evaporated. Column chromatography (SiO2, 3-15% EtOAc/Hex) gave pure methyl 2-(4-(hydroxymethyl)phenyl)acetate (E132).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[CH:6][CH:5]=1)([O-])=O.[CH2:16](Br)[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.CI>>[CH:8]1[C:9]2[C:4](=[N:1][C:22]3[C:17]([C:16]=2[NH:1][C:4]2[CH:9]=[CH:8][C:7]([N:10]4[CH2:15][CH2:14][N:13]([CH2:16][C:17]5[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=5)[CH2:12][CH2:11]4)=[CH:6][CH:5]=2)=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:5]=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(N2CCNCC2)cc1
Reactant: BrCc1ccccc1
Solvent: CI
Product: c1ccc(CN2CCN(c3ccc(Nc4c5ccccc5nc5ccccc45)cc3)CC2)cc1
Yield: 2 %

Procedure:
Following the procedure outlined in Step 1 of Example 1, but substituting 9-[4-(piperazin-1-yl)phenyl]aminoacridine (Example 16) for N-(4-nitrophenyl)piperazine, and benzyl bromide for methyl iodide, afforded the title compound (15%, overall yield 2%)
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:14]=[CH:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH2:27])=[CH:17][CH:16]=3)=[CH:11][CH:10]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2].Br[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=1>>[CH2:1]([O:3][C:4]([C:6]1([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:20]=[CH:19][C:18]([C:21]4[O:25][N:24]=[C:23]([CH3:26])[C:22]=4[NH:27][C:29]4[CH:34]=[CH:33][CH:32]=[C:31]([O:35][CH3:36])[N:30]=4)=[CH:17][CH:16]=3)=[CH:13][CH:14]=2)[CH2:8][CH2:7]1)=[O:5])[CH3:2]
Reactant: COc1cccc(Br)n1
Reactant: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4N)cc3)cc2)CC1
Product: CCOC(=O)C1(c2ccc(-c3ccc(-c4onc(C)c4Nc4cccc(OC)n4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 290, Step 1, using 1-[4′-(4-amino-3-methyl-isoxazol-5-yl)-biphenyl-4-yl]-cyclopropanecarboxylic acid ethyl ester and 2-bromo-6-methoxy-pyridine.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[CH:34])=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:35]([O:42][C:43]([N:45]1[CH2:50][CH2:49][CH2:48][CH2:47][C@H:46]1[C:51]1[NH:55][C:54]2[CH:56]=[CH:57][C:58](I)=[CH:59][C:53]=2[N:52]=1)=[O:44])[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>CN(C=O)C.CCOC(C)=O.O.[Cu]I.C1(C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)[Pd][P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[O:15])[C@H:10]([C:24]2[NH:28][C:27]3[CH:29]=[CH:30][C:31]([C:33]#[C:34][C:57]4[CH:58]=[CH:59][C:53]5[NH:52][C:51]([C@@H:46]6[CH2:47][CH2:48][CH2:49][CH2:50][N:45]6[C:43]([O:42][CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=6)=[O:44])=[N:55][C:54]=5[CH:56]=4)=[CH:32][C:26]=3[N:25]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(OCc1ccccc1)N1CCCC[C@H]1c1nc2cc(I)ccc2[nH]1
Reactant: C#Cc1ccc2[nH]c([C@@H]3CN(C(=O)OC(C)(C)C)CCN3C(=O)OCc3ccccc3)nc2c1
Agent: [Cu]I
Agent: c1ccc([P]([Pd][P](c2ccccc2)(c2ccccc2)c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCN(C(=O)OCc2ccccc2)[C@H](c2nc3cc(C#Cc4ccc5[nH]c([C@@H]6CCCCN6C(=O)OCc6ccccc6)nc5c4)ccc3[nH]2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 7893.4 %

Procedure:
To a stirring solution of (S)-2-(5-ethynyl-1H-benzoimidazol-2-yl)-piperazine-1,4-dicarboxylic acid 1-benzyl ester 4-tert-butyl ester (77 mg, 0.16 mmol), (S)-2-(5-iodo-1H-benzoimidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester (70 mg, 0.15 mmol), CuI (3 mg, 0.015 mmol) and bis(triphenylphosphine)palladium (II) dichloride (10.6 mg, 0.015 mmol) in DMF (2 mL) is added TEA (0.1 mL, 0.76 mmol). The reaction mixture is stirred at room temperature for 2 hours, diluted with EtOAc and water. The mixture is filtered to remove insoluble material and the layers of the filtrate are separated. The organic layer is dried over sodium sulfate and concentrated in vacuum to dryness. The residue is purified by flash column chromatography on silica gel (MeOH/DCM 0% to 20%) and repurified by reverse phase HPLC using a gradient of CH3CN/water to give the title compound (9.4 g, 7%).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6](I)=[N:7][NH:8]2)=[CH:4][CH:3]=1.[H-].[Na+].C([Mg]Cl)(C)C.[CH2:19]([Sn:23](Cl)([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH3:22]>C1COCC1.O.C(OCC)(=O)C>[Cl:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([Sn:23]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:28][CH2:29][CH2:30][CH3:31])[CH2:19][CH2:20][CH2:21][CH3:22])=[N:7][NH:8]2)=[CH:4][CH:3]=1
Reactant: Clc1ccc2c(I)n[nH]c2c1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Agent: CC(C)[Mg]Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: CCCC[Sn](CCCC)(CCCC)c1n[nH]c2cc(Cl)ccc12
Temperature: -16 °C
Reaction time: 2 h

Procedure:
To a stirred solution of 6-chloro-3-iodo-1H-indazole (1.11 g, 4.0 mmol) in THF (25 mL) was added sodium hydride (192 mg, 4.8 mmol). After 15 min the mixture was cooled to −16° C. Isopropylmagnesium chloride (3.00 mL, 6.00 mmol) was added dropwise and the mixture stirred at −16° C. for 2 h. Tributyltin chloride (1.56 g, 1.3 mL, 4.8 mmol) was then added and the reaction mixture warmed to room temperature. After 15 h the mixture was diluted with water and ethyl acetate. The organic layer was washed with brine, dried (sodium sulfate) filtered and concentrated in vacuo. The crude brown oil was used directly in the next step without further purification.
Reaction SMILES: [Br:1]Br.[F:3][C:4]([F:15])([F:14])[C:5]1[CH:6]=[C:7]([C:11](=[O:13])[CH3:12])[CH:8]=[CH:9][CH:10]=1>C(OCC)C>[Br:1][CH2:12][C:11]([C:7]1[CH:8]=[CH:9][CH:10]=[C:5]([C:4]([F:14])([F:15])[F:3])[CH:6]=1)=[O:13]
Reactant: CC(=O)c1cccc(C(F)(F)F)c1
Reactant: BrBr
Solvent: CCOCC
Product: O=C(CBr)c1cccc(C(F)(F)F)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
Bromine (4.25 g, 26.6 mmol) was slowly added dropwise to a solution of 1-[3-(trifluoromethyl)phenyl]ethanone (5.00 g, 26.6 mmol) in diethyl ether (100 ml), and the mixture was stirred at room temperature for 4 hours. The reaction mixture was distilled off under reduced pressure to give the desired product as an oil quantitatively.
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]3[C:12](=[CH:13][CH:14]=2)[C:11](=O)[CH:10]([N:16]2[CH:20]=[CH:19][N:18]=[C:17]2[C:21]([NH2:23])=[O:22])[CH2:9]3)[CH:5]=[CH:4][N:3]=[CH:2]1.[ClH:24]>CO>[ClH:24].[N:1]1([C:6]2[CH:14]=[CH:13][C:12]3[C:11]4[NH:23][C:21](=[O:22])[C:17]5[N:16]([CH:20]=[CH:19][N:18]=5)[C:10]=4[CH2:9][C:8]=3[CH:7]=2)[CH:5]=[CH:4][N:3]=[CH:2]1
Reactant: NC(=O)c1nccn1C1Cc2cc(-n3ccnc3)ccc2C1=O
Agent: Cl
Solvent: CO
Product: O=c1[nH]c2c(n3ccnc13)Cc1cc(-n3ccnc3)ccc1-2

Procedure:
The procedure is carried out as in Example 1 but starting with 0.46 g of 1-[5-(1-imidazolyl)-1-oxo-2-indanyl]imidazole-2-carboxamide, a total of 35 ml of methanol and 7 ml of a 12N aqueous hydrochloric acid solution. 0.23 of 8-(1-imidazolyl)-5H, 10H-imidazo[1,2-a]indeno[1,2-e]pyrazine-4-one hydrochloride is thus obtained which decomposes without melting above 300° C. [NMR spectrum: (200 MHz; DMSO-d6 ; δ in ppm): 4.18 (s, 2H: --CH2-- in position 10); 7.71 and from 8.00 to 8.15 (broad s and mt respectively, 1H for the s: --H of imidazole); 7.88 (dd, J=8 and 2 Hz 1H: --H7); 7.96 and 8.34 (2 mt, 1H each: --H4' and --H5' of imidazole in position 8); 8.08 (d, J=8 Hz: --H6); from 8.00 to 8.15 (mt: --H9); 9.73 (broad s, 1H: --H2' of imidazole in position 8); 12.65 (unresolved complex, 1H: --CONH--)].