Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C[C:2]([Si:5](Cl)([CH3:7])[CH3:6])(C)C.C1CCN2C(=NCCC2)CC1.[OH:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]>C1COCC1>[CH3:2][Si:5]([CH3:7])([CH3:6])[O:20][CH:21]([C:27]1[S:28][CH:29]=[CH:30][N:31]=1)[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: CCCCCC(O)c1nccs1
Solvent: C1CCC2=NCCCN2CC1
Solvent: C1CCOC1
Product: CCCCCC(O[Si](C)(C)C)c1nccs1
Temperature: 25 °C
Reaction time: 3 h
Yield: 105.3 %

Procedure:
TBDMSCl (1.37 g, 9.07 mmol) and DBU (1.4 mL, 9.07 mmol) were added to a solution of 2-(1-hydroxyhexyl)thiazole (0.7 g, 3.8 mmol) in dry THF (8 mL). The mixture was stirred at rt for 3 h, then quenched with water and the layers separated. The aqueous portion was extracted with EtOAc, the combined extracts dried (MgSO4) and concentrated. The material was purified by flash chromatography to give 1.03 g (91%) of 2-(1-trimethylsiloxyhexyl)thiazole as a pale yellow oil.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[CH:22][C:3]=1[CH2:4][O:5][C:6](=[O:21])[NH:7][C:8]1[C:9]([CH3:20])=[N:10][O:11][C:12]=1[C:13]1[CH:18]=[CH:17][C:16](Br)=[CH:15][CH:14]=1.[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34](B2OC(C)(C)C(C)(C)O2)=[CH:33][CH:32]=1)[CH3:27]>>[CH2:26]([O:28][C:29](=[O:46])[CH2:30][C:31]1[CH:36]=[CH:35][C:34]([C:16]2[CH:17]=[CH:18][C:13]([C:12]3[O:11][N:10]=[C:9]([CH3:20])[C:8]=3[NH:7][C:6]([O:5][CH2:4][C:3]3[CH:22]=[CH:23][CH:24]=[CH:25][C:2]=3[Cl:1])=[O:21])=[CH:14][CH:15]=2)=[CH:33][CH:32]=1)[CH3:27]
Reactant: CCOC(=O)Cc1ccc(B2OC(C)(C)C(C)(C)O2)cc1
Reactant: Cc1noc(-c2ccc(Br)cc2)c1NC(=O)OCc1ccccc1Cl
Product: CCOC(=O)Cc1ccc(-c2ccc(-c3onc(C)c3NC(=O)OCc3ccccc3Cl)cc2)cc1

Procedure:
Following the procedure described in Example 36, Step 6, [5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-carbamic acid 2-chloro-benzyl ester and [4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-acetic acid ethyl ester were reacted to provide {4′-[4-(2-chloro-benzyloxycarbonylamino)-3-methyl-isoxazol-5-yl]-biphenyl-4-yl}-acetic acid ethyl ester, which was hydrolyzed to the acid as described in Example 36, Step 7.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:18][CH3:19])[CH2:16][OH:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.[H-].[Na+].Br[CH2:23][C:24]([O:26][CH3:27])=[O:25]>CN(C)C=O>[NH2:1][C:2]1[C:11]2[N:12]=[CH:13][N:14]([CH:15]([CH2:18][CH3:19])[CH2:16][O:17][CH2:23][C:24]([O:26][CH3:27])=[O:25])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCC(CO)n1cnc2c(N)nc3ccccc3c21
Reactant: COC(=O)CBr
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(COCC(=O)OC)n1cnc2c(N)nc3ccccc3c21
Reaction time: 0.25 h

Procedure:
2-(4-Amino-1H-imidazo[4,5-c]quinolin-1-yl)butan-1-ol (25 mg, 0.0975 mmol) was placed in a 2 dram (7.4 mL) vial. Sodium hydride (5 mg of a 60% dispersion in mineral oil, 0.117 mmol) and N,N-dimethylformamide (1 mL) were added. The vial was placed on a sonicator for 15 minutes at ambient temperature to allow the alkoxide to form. Methyl bromoacetate (11 μL, 0.117 mmol) was added. The reaction was sonicated at ambient temperature for 1.5 hours. The reaction mixture was analyzed by LC/MS to confirm the formation of the desired product. The reaction mixture was purified by semi-preparative HPLC using Method A Mass Measurement (Da.): Theoretical mass=328.1535, Measured mass=328.1534.
Reaction SMILES: [I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6]Br)=[CH:4][CH:3]=1.[C:10]1(=[O:20])[NH:14][C:13](=[O:15])[C:12]2=[CH:16][CH:17]=[CH:18][CH:19]=[C:11]12.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C>[I:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][N:14]2[C:10](=[O:20])[C:11]3[C:12](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:13]2=[O:15])=[CH:4][CH:3]=1
Reactant: BrCc1ccc(I)cc1
Reactant: O=C1NC(=O)c2ccccc21
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: O=C1c2ccccc2C(=O)N1Cc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 86.1 %

Procedure:
To a solution of 4-iodo-benzyl bromide (9.04 g, 30.4 mmol) in DMF (316 mL) was added phthalimide (4.47 g, 30.4 mmol) and cesium carbonate (14.86 g, 45.6 mmol). The reaction stirred at room temperature overnight under nitrogen atmosphere. The next day, the reaction mixture was quenched with water. The product precipitated from the quenched reaction mixture and was filtered off, washed with water, and collected as a white solid (9.5 g, 86% yield). 1H NMR (600 MHz, CDCl3): δ 7.84 (m, 2H), 7.71 (m, 2H), 7.63 (d, 2H, J=8.4 Hz), 7.17 (d, 2H, J=8.4 Hz), 4.77 (s, 2H). 13C NMR (150 MHz, CDCl3): δ 168.1, 138.0, 136.2, 134.3, 132.2, 130.8, 123.6, 93.7, 41.3.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45.O1CCCC1.[CH3:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH2:34][CH2:35][CH2:36][CH2:37][CH2:38][CH2:39][CH2:40][CH2:41][CH2:42][CH2:43][CH2:44][CH2:45][N:46]=[C:47]=[O:48].[N-]=C=O>CCOCC>[CH2:45]([NH:46][C:47](=[O:48])[NH:1][C:2]1[CH:3]=[CH:4][C:5]2[N:22]=[C:9]3[C:10]4[CH:11]=[CH:12][CH:13]=[C:14]5[CH:21]=[CH:20][CH:19]=[C:16]([C:17](=[O:18])[N:8]3[C:6]=2[CH:7]=1)[C:15]=45)[CH2:44][CH2:43][CH2:42][CH2:41][CH2:40][CH2:39][CH2:38][CH2:37][CH2:36][CH2:35][CH2:34][CH2:33][CH2:32][CH2:31][CH2:30][CH2:29][CH3:28]
Reactant: CCCCCCCCCCCCCCCCCCN=C=O
Reactant: Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54
Agent: [N-]=C=O
Solvent: CCOCC
Solvent: C1CCOC1
Product: CCCCCCCCCCCCCCCCCCNC(=O)Nc1ccc2nc3c4cccc5cccc(c(=O)n3c2c1)c54

Procedure:
A 5.7 g portion of the 10-amino-benzimidazo[2,1-a]benz[de]isoquinoline-7-one was added to 200 ml of distilled tetrahydrofuran in a 500 ml flask. To this mixture was added 5.9 g of Mondur O (octadecyl isocyanate) and 0.3 g of 1,4-diazobicyclo-octane. The mixture was stirred with a magnetic stirring bar and brought to reflux. The mixture was refluxed until no isocyanate peak was visible at 2240 cm-1 on infrared spectraphotometric analysis (~48-72 hours). It was then cooled and the solvent removed on the rotary evaporator. The solid thus obtained was ground to a fine powder, stirred in ether, filtered and dried in the vaccuum oven. The yield was 10.7 g of 10 octadecylureido benzimidazo [2,1-a]benz[de]isoquinoline-7-one.
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[NH:7]2.[H-].[Na+].I[CH3:16]>C1COCC1.[Cl-].[Na+].O>[F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[NH:4][CH2:5][C:6](=[O:12])[N:7]2[CH3:16]
Reactant: CI
Reactant: O=C1CNc2c(F)cccc2N1
Agent: [Cl-]
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: CN1C(=O)CNc2c(F)cccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of 5-fluoro-3,4-dihydro-1H-quinoxalin-2-one from Example B (415 mg, 2.5 mmol) in THF (10 ml) was added sodium hydride (60%, 100 mg, 2.5 mmol) while cooling in an ice/water bath. The mixture was allowed to warm to room temperature and stirred for 0.5 h. The mixture was cooled again in an ice/water bath and iodomethane (156 μl, 2.5 mmol) was added. The mixture was allowed to warm slowly to room temperature and stirred for 3 days. Brine was added and the mixture was evaporated in vacuo. The residue was partitioned between EtOAc and brine and separated. The organic phase was washed with brine, dried and evaporated in vacuo. The residue was purified by flash chromatography on silica (eluant EtOAc:pet ether 45:55) to give a white solid; yield 210 mg, 47%.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:32])[CH:5]([N:8]([CH2:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH2:31])(=[O:30])=[O:29])=[CH:18][CH:17]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[C:6]#[N:7])[CH3:2].C(=O)([O-])[O-].[K+].[K+].[CH2:39]([N:42]=[C:43]=[O:44])[CH2:40][CH3:41].Cl>CC(C)=O.ClCCl>[CH2:1]([O:3][C:4](=[O:32])[CH:5]([C:6]#[N:7])[N:8]([CH2:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[S:28]([NH:31][C:43]([NH:42][CH2:39][CH2:40][CH3:41])=[O:44])(=[O:29])=[O:30])=[CH:20][CH:21]=1)[C:9](=[O:14])[CH2:10][CH2:11][CH2:12][CH3:13])[CH3:2]
Reactant: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(N)(=O)=O)cc1)C(C#N)C(=O)OCC
Reactant: CCCN=C=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Solvent: CC(C)=O
Product: CCCCC(=O)N(Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)NCCC)cc1)C(C#N)C(=O)OCC

Procedure:
7.2 g of the product of Stage A, 6.5 g of anhydrous potassium carbonate and 1.48 ml of n-propyl isocyanate were stirred in 180 ml of acetone at reflux for 2 hours 30 minutes. After cooling, the solution was treated with 2N hydrochloric acid and the residue obtained was dissolved in an aqueous mixture of dichloromethane. After extraction with methylene chloride, the extracts were dried and the solvents were eliminated under reduced pressure and the product was crystallized from ethyl acetate to obtain 6.5 g of the expected product as a white solid with a Rf (SiO2, ethyl acetate)=0.48 and melting at 131°-133° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31](O)[C:19]=4[CH2:18]3)[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Na+].[C:36]1([S:42]([N:45]=[C:46]=[O:47])(=[O:44])=[O:43])[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:33])[CH2:9][CH2:10][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:27]4[C:22](=[N:23][CH:24]=[CH:25][CH:26]=4)[O:21][C:20]4[CH:28]=[CH:29][CH:30]=[C:31]([C:46](=[O:47])[NH:45][S:42]([C:36]5[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=5)(=[O:43])=[O:44])[C:19]=4[CH2:18]3)[CH2:12][CH2:13]2)=[CH:4][CH:3]=1
Reactant: Oc1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Reactant: O=C=NS(=O)(=O)c1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C(NS(=O)(=O)c1ccccc1)c1cccc2c1CC(=CCCN1CCC(O)(c3ccc(Cl)cc3)CC1)c1cccnc1O2
Temperature: 40 °C
Reaction time: 0.33 h
Yield: 39.5 %

Procedure:
To a solution of the compound of Example 44 (0.511 g, 1.1 mmol) in dry THF (20 ml) was added sodium hydride (60% in mineral oil, 48 mg, 1.2 mmol), and the slurry heated at 40° C. under argon with stirring for 20 minutes. Phenylsulfonylisocyanate (160 μl, 1.2 mmol) was added and the mixture was stirred for 14 hours. The solvent was then removed by rotary evaporation to give the crude product. The solid material was washed twice with 20 ml CH2Cl2, and then twice with 20 ml MeOH: CH2Cl2 (1:1) to give the title compound (274 mg).
Reaction SMILES: [CH3:1][C:2]1[N:3]=[CH:4][C:5]([NH2:8])=[N:6][CH:7]=1.C(=O)([O-])[O-].[Cs+].[Cs+].[Br:15][CH2:16][C:17](Br)=[O:18].O>CN(C=O)C>[Br:15][CH2:16][C:17]([NH:8][C:5]1[CH:4]=[N:3][C:2]([CH3:1])=[CH:7][N:6]=1)=[O:18]
Reactant: Cc1cnc(N)cn1
Reactant: O=C(Br)CBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1cnc(NC(=O)CBr)cn1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-methyl-pyrazin-2-ylamine and cesium carbonate (11.2 g) dissolved in dry DMF (30 mL) was added by dropwise addition bromoacetylbromide (2.89 g) and the mixture stirred at rt for 2 hours. Water (200 mL) was added and the mixture extracted with ethyl acetate (2×100 mL) and dried over magnesium sulfate. Concentration of the extract to ˜50 mL and addition of isohexane (100 mL) gave the sub-titled compound as a solid (1.64 g).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18](F)[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Cl.[CH3:34][NH:35][CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38].CCN(C(C)C)C(C)C>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH2:11][C@@H:10]([NH:13][C:14]2[N:19]=[C:18]([N:35]([CH2:36][C:37]([CH3:40])([CH3:39])[CH3:38])[CH3:34])[CH:17]=[C:16]([NH:21][C:22]3[CH:27]=[C:26]([C:28](=[O:31])[NH:29][CH3:30])[CH:25]=[CH:24][C:23]=3[CH3:32])[N:15]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CNC(=O)c1ccc(C)c(Nc2cc(F)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Reactant: CNCC(C)(C)C
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: C1COCCO1
Product: CNC(=O)c1ccc(C)c(Nc2cc(N(C)CC(C)(C)C)nc(N[C@@H]3CCN(C(=O)OC(C)(C)C)C3)n2)c1
Temperature: 90 °C
Reaction time: 8 h

Procedure:
A mixture of 3-(R)-[4-fluoro-6-(2-methyl-5-methylcarbamoyl-phenylamino)-pyrimidin-2-ylamino]-pyrrolidine-1-carboxylic acid tert-butyl ester (0.36 g, 0.81 mmol), N-methyl-neopentylamine hydrochloride (411 mg, 3 mmol) and DIEA(0.4 mL) in 1,4-dioxane (0.5 mL) was stirred at 90° C. overnight. After removing the solvent under reduced pressure the desired product (81 mg) was purified by silica gel chromatography. C28H43N7O3 MS m/e=526 (M+H).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH3:29])(=[O:4])[CH2:2][CH3:3].C(=O)(O)[O-:31].[Na+].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl.O>[C:1]([C:5]1[CH:6]=[N:7][C:8]2[C:13]([C:14]=1[NH:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[CH3:22])=[CH:12][CH:11]=[CH:10][C:9]=2[O:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH3:29])=[O:31])(=[O:4])[CH2:2][CH3:3]
Reactant: CCCSCCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Reactant: O=C([O-])O
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Solvent: O
Solvent: ClCCl
Product: CCCS(=O)CCOc1cccc2c(Nc3ccccc3C)c(C(=O)CC)cnc12
Reaction time: 0.5 h
Yield: 73.4 %

Procedure:
3-Propanoyl-4-(2-methylphenylamino)-8-(2-propylthioethoxy)quinoline (0.5 g, 1.22 mmol) was dissolved in 10 ml methylene chloride. A solution of sodium bicarbonate (250 mg, 3.0 mmol) in 10 ml water was added. The mixture was cooled to 2°-4° C. A solution of 70% m-CPBA (295 mg, 1.20 mmol) in 10 ml methylene chloride was added dropwise during 10 min. The temperature was allowed to rise to room temperature and the mixture was stirred 30 min at this temperature. The organic layer was dried over Na2SO4 and evaporated. The residue was purified by column chromatography (methylene chloride:ethanol 90:10) to give 380 mg (73%) of the title compound.
Reaction SMILES: ClC1C=C(C=CC=1)C(OO)=O.[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])[CH:17]=[CH:16]2.[OH-:33].[Ca+2].[OH-:35]>ClCCl>[Br:12][C:13]1[CH:14]=[C:15]2[C:20](=[CH:21][CH:22]=1)[CH:19]=[C:18]([S:23]([C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][C:25]=1[C@@H:30]([OH:32])[CH3:31])(=[O:35])=[O:33])[CH:17]=[CH:16]2
Reactant: C[C@H](O)c1ccccc1Sc1ccc2cc(Br)ccc2c1
Reactant: [OH-]
Agent: O=C(OO)c1cccc(Cl)c1
Agent: [Ca+2]
Solvent: ClCCl
Product: C[C@H](O)c1ccccc1S(=O)(=O)c1ccc2cc(Br)ccc2c1
Reaction time: 1 h
Yield: 59.6 %

Procedure:
3-Chloroperoxybenzoic acid (2.85 g, 12.7 mmol) was added to a stirred solution of (1S)-1-{2-[(6-bromo-2-naphthyl)thio]phenyl}ethanol (2.28 g, 6.3 mmol) in dichloromethane (50 mL) at ambient temperature under nitrogen. Calcium hydroxide (1.50 g, 20.2 mmol) was added after 2 hours, stirred for a further 1 hour then filtered and concentrated in vacuo. Purification by flash column chromatography eluting with a 10-40% ethyl acetate/isohexane gradient followed by trituration using isohexane gave solid (1S)-1-{2-[(6-bromo-2-naphthyl)sulfonyl]phenyl}ethanol (1.47 g, 59%). 1H NMR (500 MHz, CDCl3) δ 8.50 (1H, s), 8.16 (1H, d, J 7.9 Hz), 8.08 (1H, s), 7.90-7.82 (2H, m), 7.77-7.70 (3H, m), 7.67 (1H, t, J 7.5 Hz), 7.50 (1H, t, J 7.7 Hz), 5.60 (1H, q, J 6.3 Hz), 2.46 (1H, s), 1.33 (3H, d, J 6.3 Hz); m/z (ES+) 373, 375 [(M-OH)+].
Reaction SMILES: CON(C)[C:4]([C:6]1[C:11]([NH2:12])=[N:10][C:9]([CH3:13])=[CH:8][N:7]=1)=[O:5].[C:15]1([Mg]Br)[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1.C([O-])(O)=O.[Na+].CCOC(C)=O>C1COCC1>[NH2:12][C:11]1[C:6]([C:4]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:5])=[N:7][CH:8]=[C:9]([CH3:13])[N:10]=1
Reactant: CON(C)C(=O)c1ncc(C)nc1N
Reactant: Br[Mg]c1ccccc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Cc1cnc(C(=O)c2ccccc2)c(N)n1
Temperature: -78 °C
Reaction time: 1 h

Procedure:
3-Amino-5-methyl-pyrazin-2-carboxylic acid methoxy-methyl-amide (0.3 g, 1.53 mmol) is dissolved in anhydrous THF (30 ml) under N2. The clear yellow solution is cooled to −78° C., and a 1M solution of phenyl magnesium bromide in THF (7.6 ml, 7.6 mmol) is added. The resulting reaction mixture is stirred at −78° C. for 1 hour, and is then allowed to warm to room temperature and stirred for a further 2.5 hours. The reaction mixture is poured onto aq. NaHCO3 and EtOAc. The phases are separated and the aqueous layer is washed with EtOAc. The combined organic layers are washed with brine, dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography (SiO2, 0-7% MeOH in DCM) yields (3-amino-5-methyl-pyrazin-2-yl)-phenyl-methanone as a yellow solid. [M+H]+ 214.
Reaction SMILES: [CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][C:10](=O)[CH2:9][CH2:8]2)[S:4][N:3]=1.[F:14][C:15]([F:30])([F:29])[C:16]1[CH:17]=[C:18]([CH:26]=[CH:27][CH:28]=1)[CH2:19][N:20]1[CH:24]=[N:23][C:22]([NH2:25])=[N:21]1>>[CH3:1][C:2]1[N:6]=[C:5]([N:7]2[CH2:12][CH2:11][CH:10]([NH:25][C:22]3[N:23]=[CH:24][N:20]([CH2:19][C:18]4[CH:26]=[CH:27][CH:28]=[C:16]([C:15]([F:30])([F:14])[F:29])[CH:17]=4)[N:21]=3)[CH2:9][CH2:8]2)[S:4][N:3]=1
Reactant: Cc1nsc(N2CCC(=O)CC2)n1
Reactant: Nc1ncn(Cc2cccc(C(F)(F)F)c2)n1
Product: Cc1nsc(N2CCC(Nc3ncn(Cc4cccc(C(F)(F)F)c4)n3)CC2)n1

Procedure:
Prepared in analogy to example 1 step h) starting from 1-(3-methyl-[1,2,4]thiadiazol-5-yl)-piperidin-4-one (example 1c) and 1-(3-trifluoromethyl-benzyl)-1H-[1,2,4]triazol-3-ylamine. The title compound was obtained as a white solid.
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[CH2:11]([NH2:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>>[CH2:11]([NH:18][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: NCc1ccccc1
Reactant: O=[N+]([O-])c1ccc(F)cc1
Product: O=[N+]([O-])c1ccc(NCc2ccccc2)cc1

Procedure:
Prepared from 1-fluoro-4-nitrobenzene and benzylamine
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[Cl:27][C:28]1[CH:29]=[C:30]2[C:34](=[CH:35][CH:36]=1)[NH:33][N:32]=[C:31]2[CH:37]=O.N1CCCCC1>CO>[Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9]/[C:8](=[CH:37]\[C:31]3[C:30]4[C:34](=[CH:35][CH:36]=[C:28]([Cl:27])[CH:29]=4)[NH:33][N:32]=3)/[C:7](=[O:10])[C:6]=2[CH:11]=1
Reactant: O=Cc1n[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: CO
Solvent: C1CCNCC1
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2n[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 1 h
Yield: 35.1 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.261 mmol) synthesized in Example B13, Step 2 in methanol (1 mL) was added with 5-chloro-1H-indazole-3-carbaldehyde (0.0471 g, 0.261 mmol) synthesized in Example B9, Step 3, and piperidine (0.00222 g, 0.0261 mmol) at room temperature, and the mixture was stirred at 60° C. for 1 hour. The reaction mixture was cooled to room temperature, then added with methanol (4 mL), and suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({5-chloro-2-[(5-chloro-1H-indazol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.050 g, 35%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([N:28]4[CH2:33][CH2:32][N:31](C(OC(C)(C)C)=O)[CH2:30][CH2:29]4)=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1.[ClH:42]>CO.O1CCOCC1>[ClH:42].[Br:1][C:2]1[CH:3]=[CH:4][C:5]([CH3:41])=[C:6]([NH:8][C:9]([C:11]2[N:12]=[CH:13][NH:14][C:15]=2[C:16]([NH:18][C:19]2[NH:23][C:22]3[CH:24]=[CH:25][C:26]([N:28]4[CH2:29][CH2:30][NH:31][CH2:32][CH2:33]4)=[CH:27][C:21]=3[N:20]=2)=[O:17])=[O:10])[CH:7]=1
Reactant: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCN(C(=O)OC(C)(C)C)CC3)ccc2[nH]1
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: Cc1ccc(Br)cc1NC(=O)c1nc[nH]c1C(=O)Nc1nc2cc(N3CCNCC3)ccc2[nH]1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
To a solution of 1,1-dimethylethyl 4-(2-{[(4-{[(5-bromo-2-methylphenyl)amino]carbonyl}-1H-imidazol-5-yl)carbonyl]amino}-1H-benzimidazol-5-yl)piperazine-1-carboxylate (2.5 g, 4 mmol) in methanol (100 mL) was added 4 N hydrogen chloride in 1,4-dioxane (20 mL). The solution was stirred at room temperature for 48 hours. The resulting suspension was filtered to give 2.0 g of N4-(5-bromo-2-methylphenyl)-N5-(5-piperazin-1-yl-1H-benzimidazol-2-yl)-1H-imidazole-4,5-dicarboxamide hydrochloride. 1H-NMR (400 MHz, DMSO-d6) δ 12.62 (br s, 1H), 12.50 (br s, 1H), 11.20 (br s, 1H), 9.28 (d, 1H), 9.00 (d, 1H), 8.39 (s, 1H), 7.86 (s, 1H), 7.60 (d, 1H), 7.42 (d, 1H), 7.31 (d, 1H), 7.21 (s, 1H), 7.03 (d, 1H), 4.23 (br s 2H), 3.94 (m, 2H), 3.33 (m, 2H), 2.91 (m, 2H), 2.29 (s, 3H), 2.11 (m, 1H), 1.94 (m, 2H), 1.54 (m, 2H). MS (EI): 553 (MH+).
Reaction SMILES: Br[C:2]1[S:3][C:4]2[CH2:5][C:6]3[C:12]([C:13]4[CH:18]=[CH:17][C:16]([O:19][CH3:20])=[CH:15][CH:14]=4)=[N:11][N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:28])([CH3:27])[CH3:26])[C:7]=3[C:8]=2[CH:9]=1.CC1(C)C(C)(C)OB([C:37]2[CH:38]=[C:39]([NH2:43])[CH:40]=[N:41][CH:42]=2)O1.C([O-])([O-])=O.[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)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>[CH3:20][O:19][C:16]1[CH:15]=[CH:14][C:13]([C:12]2[C:6]3[CH2:5][C:4]4[S:3][C:2]([C:37]5[CH:38]=[C:39]([NH2:43])[CH:40]=[N:41][CH:42]=5)=[CH:9][C:8]=4[C:7]=3[N:10]([CH2:21][O:22][CH2:23][CH2:24][Si:25]([CH3:26])([CH3:27])[CH3:28])[N:11]=2)=[CH:18][CH:17]=1
Reactant: CC1(C)OB(c2cncc(N)c2)OC1(C)C
Reactant: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(Br)cc2-3)cc1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: COc1ccc(-c2nn(COCC[Si](C)(C)C)c3c2Cc2sc(-c4cncc(N)c4)cc2-3)cc1
Temperature: 100 °C
Yield: 68 %

Procedure:
A mixture of the corresponding 2-Bromo-6-(4-methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalene (1.1 g, 2.3 mmol), 5-(4,4,5,5-Tetramethyl-[1,3,2]dioxaborolan-2-yl)-pyridin-3-ylamine (0.75 g, 3.4 mmol), Na2CO3 (2 M, 5.4 mL), and Pd(PPh3)2Cl2 (260 mg, 0.23 mmol) in toluene/ethanol (1:1, 15 mL) was heated at 100° C. for 8 hr. The solution was cooled to room temperature and extracted with ethyl acetate. The target product was purified by gravity column chromatography (30% EtOAc in hexane) to give 5-[6-(4-Methoxy-phenyl)-4-(2-trimethylsilanyl-ethoxymethyl)-4,7-dihydro-1-thia-4,5-diaza-cyclopenta[a]pentalen-2-yl]-pyridin-3-ylamine as brown solid in 68% yield.