Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:8]2[O:12][CH2:11][CH2:10][O:9]2)[CH:5]=[CH:6][CH:7]=1.C([Li])CCC.[CH3:18][C:19]([CH3:39])([CH3:38])[CH2:20][C:21]([NH:23][C:24]1[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]2[O:31][C:30]([CH3:33])([CH3:32])[C:29](=[O:34])[C:28]=2[CH:35]=1)=[O:22].O>C1COCC1>[O:9]1[CH2:10][CH2:11][O:12][CH:8]1[C:4]1[CH:3]=[C:2]([C:29]2([OH:34])[C:28]3[CH:35]=[C:24]([NH:23][C:21](=[O:22])[CH2:20][C:19]([CH3:18])([CH3:38])[CH3:39])[C:25]([CH3:37])=[C:26]([CH3:36])[C:27]=3[O:31][C:30]2([CH3:33])[CH3:32])[CH:7]=[CH:6][CH:5]=1
Reactant: Brc1cccc(C2OCCO2)c1
Reactant: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2=O
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: Cc1c(NC(=O)CC(C)(C)C)cc2c(c1C)OC(C)(C)C2(O)c1cccc(C2OCCO2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.2 %

Procedure:
To a solution of 2-(3-bromophenyl)-1,3-dioxolane (1.65 mL, 10.9 mmol) in THF (20 mL) was added dropwise at −78° C. under an argon atmosphere n-butyllithium (1.59 M hexane solution, 6.4 mL, 10.2 mmol), and the resulting mixture was stirred for 30 minutes. To the reaction solution was added dropwise at −78° C. a solution of 3,3-dimethyl-N-(2,2,6,7-tetramethyl-3-oxo-2,3-dihydro-1-benzofuran-5-yl)butanamide (1.0 g, 3.30 mmol) obtained in Reference Example 65 in THF (10 mL), and the resulting mixture was stirred for 30 minutes. The reaction solution was warmed to room temperature and stirred for 1 hour, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel column chromatography (ethyl acetate:hexane=2:3) to obtain 1.38 g (yield: 92%) of N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide as an amorphous powder. To a mixed solution of the obtained N-(3-(3-(1,3-dioxolan-2-yl)phenyl)-3-hydroxy-2,2,6,7-tetramethyl-2,3-dihydro-1-benzofuran-5-yl)-3,3-dimethylbutanamide (300 mg, 0.66 mmol) in acetone (4 mL)-water (0.3 mL) was added pyridinium p-toluenesulfonate (5 mg, 0.03 mmol), and the mixture was stirred for 30 minutes. The reaction solution was cooled to room temperature, and water was added to the reaction solution and the product was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The obtained residue was recrystallized from THF-diisopropyl ether to obtain 194 mg (yield: 72%) of the title compound. Melting point: 189-190° C.
Reaction SMILES: [CH3:1][Si:2]([CH3:5])([CH3:4])Cl.C(N(CC)CC)C.[Cl:13][CH:14]([Cl:31])[C:15]([NH:17][CH:18]1[C:29](=[O:30])[N:20]2[C:21]([C:26]([OH:28])=[O:27])=[C:22]([CH3:25])[CH2:23][S:24][C@H:19]12)=[O:16]>C(Cl)(Cl)Cl>[CH3:1][Si:2]([O:28][C:26]([C:21]1[N:20]2[C:29](=[O:30])[CH:18]([NH:17][C:15](=[O:16])[CH:14]([Cl:31])[Cl:13])[C@H:19]2[S:24][CH2:23][C:22]=1[CH3:25])=[O:27])([CH3:5])[CH3:4]
Reactant: C[Si](C)(C)Cl
Reactant: CC1=C(C(=O)O)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: CC1=C(C(=O)O[Si](C)(C)C)N2C(=O)C(NC(=O)C(Cl)Cl)[C@H]2SC1
Temperature: 10 °C
Reaction time: 8 h

Procedure:
Trimethylchlorosilane(0.5 ml) and triethylamine (0.17 ml) were added to a solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid(325 mg) in chloroform (12 ml). The reaction mixture was stirred at 10°C. overnight to afford a chloroform solution of 7-dichloroacetamido-3-methyl-3-cephem-4-carboxylic acid trimethylsilyl ester. The resulting solution was added dropwise at -50°C. to a mixture prepared from phosphorus pentachloride(220 mg), quinoline(0.15 ml) and chloroform (15 ml). The reaction mixture was stirred at -50°C. for 3 hours and diluted with dry tetrahydrofuran(20 ml). To this solution was added a methanol solution of lithium methoxide prepared from lithium(150 mg) and methanol(15 ml) a -78°C. The mixture was stirred at -78°C. for 30 minutes and treated with acetic acid(1.5 ml). The solution was poured into water and extracted with chloroform. The extracts were washed with water, dried(Na2SO4) and evaporated under reduced pressure. The residue was dissolved in a small amount of chloroform, to which was added excess hexane to precipitate the desired substance. This process was repeated three times to give 240 mg of 7β-(2'-chloro-1'-methoxyethylidenimino)-7α-methoxy-3-methyl-3-cephem-4-carboxylic acid. NMR(CDCl3) δ ppm: 2.05(3H, singlet), 3.03 and 3.43(2H, AB-quartet, J=18 Hz), 3.40(3H, singlet), 3.75(3H, singlet), 4.18 and 4.53(2H, AB-quartet, J=12 Hz), 5.00(1H, singlet).
Reaction SMILES: C[O:2][C:3]([C:5]1[C:22]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([Br:30])=[CH:26][C:25]=2[Cl:31])=[C:21]([F:32])[C:8]2[N:9]=[CH:10][N:11]([CH2:12][CH2:13][C:14](=[O:20])[N:15]3[CH2:19][CH2:18][CH2:17][CH2:16]3)[C:7]=2[CH:6]=1)=[O:4].[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[Br:30][C:27]1[CH:28]=[CH:29][C:24]([NH:23][C:22]2[C:5]([C:3]([OH:4])=[O:2])=[CH:6][C:7]3[N:11]([CH2:12][CH2:13][C:14](=[O:20])[N:15]4[CH2:19][CH2:18][CH2:17][CH2:16]4)[CH:10]=[N:9][C:8]=3[C:21]=2[F:32])=[C:25]([Cl:31])[CH:26]=1
Reactant: COC(=O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: O=C(O)c1cc2c(ncn2CCC(=O)N2CCCC2)c(F)c1Nc1ccc(Br)cc1Cl
Reaction time: 16 h
Yield: 104.3 %

Procedure:
To a solution of 6-(4-bromo-2-chloro-phenylamino)-7-fluoro-3-(3-oxo-3-pyrrolidin-1-yl-propyl)-3H-benzoimidazole-5-carboxylic acid methyl ester (41 mg, 0.079 mmol) in THF/H2O (1.5 mL/0.75 mL) is added 0.20 mL (0.20 mmol) of 1 N aqueous LiOH at room temperature. The resulting solution is stirred 16 hours. The reaction mixture is acidified with 1 N aqueous HCl (pH ˜2 to 3) and diluted with EtOAc. The organic layer is dried over MgSO4, filtered, and concentrated in vacuo to give a crude product (42 mg) which is directly used without further purification.
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([NH2:13])[C:6]=1[CH3:14])=[O:4].[CH:15](=O)[CH2:16][CH3:17].[BH4-].[Na+]>CO>[CH3:1][O:2][C:3]([C:5]1[C:10]([CH3:11])=[CH:9][C:8](=[O:12])[N:7]([NH:13][CH2:15][CH2:16][CH3:17])[C:6]=1[CH3:14])=[O:4]
Reactant: CCC=O
Reactant: COC(=O)c1c(C)cc(=O)n(N)c1C
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CCCNn1c(C)c(C(=O)OC)c(C)cc1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A mixture of 1-amino-2,4-dimethyl-6-oxo-1,6-dihydro-pyridine-3-carboxylic acid methyl ester (2.8 g, 14 mmol), propionaldehyde (5.1 mL, 71 mmol) and molecular sieves (size 4 Å, 5 g) in methanol (50 mL) was stirred overnight at room temperature. The solution was cooled to 5° C. and sodium tetrahydroborate (2.2 g, 57 mmol) was added in small portions. It was stirred for 1 hour at 5° C., then filtered and evaporated. The residue was partitioned between water (100 mL) and ethyl acetate (3×100 mL). The combined organic solution was dried (MgSO4) and evaporated. The residue was treated with hot n-heptane, cooled to 10° C. and the unreacted starting material was removed by filtration. The heptane solution was purified by flash chromatography to give the title compound. LC-MS (m/z) 239.1 (MH+); tR=1.20 (method C). 1H NMR (600 MHz, CDCl3): 1.01 (t, J=7.4 Hz, 3H, Me of Pr), 1.61 (sextet, J=7.3 Hz, 2H, CH2 of Pr), 2.19 (d, J=0.9 Hz, 3H, Me), 2.53 (s, 3H, Me), 2.56-3.1 (very br. coalescing d, 2H, CH2N), 3.87 (s, 3H, OMe), 5.92 (t, J=7.3 Hz, 1H, NH), 6.35 (s, 1H, C5-H).
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:12][CH3:13])=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:14][C:15]2[CH:19]=[CH:18][NH:17][N:16]=2)[N:3]=1.B(O)(O)[C:21]1[CH:22]=[CH:23][C:24]([CH3:27])=[CH:25][CH:26]=1>>[CH3:13][O:12][C:8]1[CH:7]=[C:6]2[C:11](=[CH:10][CH:9]=1)[C:2]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][CH:22]=1)=[N:3][C:4]([NH:14][C:15]1[CH:19]=[CH:18][NH:17][N:16]=1)=[CH:5]2
Reactant: Cc1ccc(B(O)O)cc1
Reactant: COc1ccc2c(Cl)nc(Nc3cc[nH]n3)cc2c1
Product: COc1ccc2c(-c3ccc(C)cc3)nc(Nc3cc[nH]n3)cc2c1

Procedure:
Similar procedure as described in example 131 was used, starting from (1-chloro-6-methoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and p-tolylboronic acid to give (6-methoxy-1-p-tolyl-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 331 (MH+).
Reaction SMILES: [Br:1][C:2]1[C:11]2[C:6](=[C:7]([O:14]C)[CH:8]=[CH:9][C:10]=2[O:12]C)[N:5]=[CH:4][CH:3]=1.O.[N+]([O-])([O-])=O.[NH4+].[Ce]>CC#N>[Br:1][C:2]1[C:11]2[C:10](=[O:12])[CH:9]=[CH:8][C:7](=[O:14])[C:6]=2[N:5]=[CH:4][CH:3]=1
Reactant: COc1ccc(OC)c2c(Br)ccnc12
Agent: O=[N+]([O-])[O-]
Agent: [Ce]
Agent: [NH4+]
Solvent: O
Solvent: CC#N
Product: O=C1C=CC(=O)c2c(Br)ccnc21
Reaction time: 0.5 h

Procedure:
100 mg (0.373 mmol) of 4-bromo-5,8-dimethoxyquinoline are dissolved in 8 mL of CH3CN and 4 mL of water at room temperature. 0.6 g (1.11 mmol) of cerium ammonium nitrate (CAN) is added and the mixture is stirred for 30 min. After evaporating off the CH3CN on a rotary evaporator, 100 mL of water are added and the medium is extracted with CHCl3 (3 times 100 mL). After drying the organic phases over MgSO4 and evaporating off the solvent on a rotary evaporator, 83 mg of quinone are obtained in the form of a pinkish powder.
Reaction SMILES: Cl.[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH:13]C(OC(C)(C)C)=O)[CH2:6][CH2:5][CH2:4]1>CO>[CH3:2][N:3]1[C:12]2[C:7](=[CH:8][CH:9]=[CH:10][C:11]=2[NH2:13])[CH2:6][CH2:5][CH2:4]1
Reactant: CN1CCCc2cccc(NC(=O)OC(C)(C)C)c21
Agent: Cl
Solvent: CO
Product: CN1CCCc2cccc(N)c21
Yield: 91.3 %

Procedure:
Anhydrous HCl (gas) was bubbled through a stirred solution of 1-methyl-8-(N-tert-butoxycarbonylamino)-1,2,3,4-tetrahydroquinoline (0.83 g, 3.16 mmol) in methanol (30 mL), at room temperature, for 10 minutes. The resultant solution was stirred at room temperature for 1 hour then concentrated under reduced pressure. The residue was partitioned between CH2Cl2 (50 mL) and aqueous NaOH (10 N, 10 mL). The phases were separated and the aqueous phase was extracted with CH2Cl2 (3×10 mL). The combined organic extracts were dried (Na2SO4) and concentrated to afford 0.468 g (88%) of 1-methyl-8-amino-1,2,3,4-tetrahydroquinoline as a white solid. 1H NMR (CDCl3) δ 1.83-1.91 (m, 2H), 2.69 (s, 3H), 2.78 (t, 2H, J=6.6 Hz), 3.07-3.11 (m, 2H), 3.84 (br s, 2H, NH2), 6.52 (d, 1H, J=7.5 Hz), 6.56 (d, 1H, J=7.5 Hz), 6.81 (dd, 1H, J=7.5, 7.5 Hz).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]([OH:12])[C:9]([NH2:11])=[O:10])=[CH:4][CH:3]=1.Cl[C:14](OCC)=[O:15].O>[OH-].[Na+]>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:9](=[O:10])[NH:11][C:14](=[O:15])[O:12]2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: NC(=O)N(O)c1ccc(F)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=c1[nH]c(=O)n(-c2ccc(F)cc2)o1
Reaction time: 1 h

Procedure:
1-(4-Fluorophenyl)-1-hydroxyurea (0.2 mole) dissolved in aqueous sodium hydroxide (200 ml; 2 N) is charged into a glass reaction vessel equipped with a mechanical stirrer and thermometer. The solution is cooled to a temperature of about 10°C and ethyl chloroformate (0.21 mole) is slowly added with stirring. After the addition is completed stirring is continued for a period of about one hour. The reaction mixture is then poured into 2 liters of water. The resulting aqueous solution is then filtered and the filtrate is cooled and acidified with concentrated hydrochloric acid to form a precipitate. The precipitate is recovered by filtration and is dried. The dried product is then dissolved in a methylene chloridetetrahydrofuran mixture and the resulting solution is dried over anhydrous magnesium sulfate, filtered and stripped of solvent to yield the desired product 2-(4-fluorophenyl)-1,2,4-oxadiazolidin-3,5-dione as the residue.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:26](=[CH:27][CH:28]=1)[C:12]1[NH:13][C:14]([C:16]3[C:23]([C:24]#[N:25])=[CH:22][CH:21]=[CH:20][C:17]=3[C:18]#[N:19])=[N:15][C:11]=1[C:10]1[CH:9]=[CH:8][C:7]([C:29]#[C:30][C:31](O)([CH3:33])[CH3:32])=[CH:6][C:5]2=1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1C=CC=CC=1.CCOC(C)=O>[Cl:1][C:2]1[CH:28]=[CH:27][C:26]2[C:12]3[N:13]=[C:14]([C:16]4[C:17]([C:18]#[N:19])=[CH:20][CH:21]=[CH:22][C:23]=4[C:24]#[N:25])[NH:15][C:11]=3[C:10]3[C:5](=[CH:6][C:7]([C:29]#[C:30][C:31]([CH3:33])=[CH2:32])=[CH:8][CH:9]=3)[C:4]=2[CH:3]=1
Reactant: CC(C)(O)C#Cc1ccc2c(c1)c1cc(Cl)ccc1c1[nH]c(-c3c(C#N)cccc3C#N)nc21
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: c1ccccc1
Solvent: CCOC(C)=O
Product: C=C(C)C#Cc1ccc2c(c1)c1cc(Cl)ccc1c1nc(-c3c(C#N)cccc3C#N)[nH]c21
Yield: 78.2 %

Procedure:
To a stirred suspension of 2-[9-chloro-6-(3-hydroxy-3-methylbut-1-yn-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile from Example 40 (120 mg, 0.26 mmol) in benzene (4 mL) was added Burgess Reagent (70 mg, 0.29 mmol) and refluxed for 2 hours under N2. The resulting reaction mixture was diluted with EtOAc (20 mL). This EtOAc solution washed with water, brine and dried over MgSO4. After removing the drying agent via filtration, the organic solution was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (eluted with 50/50 EtOAc/hexane) to yield 90 mg of 2-[6-chloro-9-(3-methylbut-3-en-1-yn-1-yl)-1H-phenanthro[9,10-d]imidazol-2-yl]isophthalonitrile as a yellow solid.
Reaction SMILES: ClCC([Si](C)(C)C)[CH2:4][O:5][CH2:6][CH:7]([Si:10]([CH3:13])([CH3:12])[CH3:11])CCl.[Cl:18][C:19]1[N:24]=[C:23]([CH2:25][OH:26])[CH:22]=[CH:21][CH:20]=1.C(N(C(C)C)CC)(C)C>ClCCl>[Cl:18][C:19]1[CH:20]=[CH:21][CH:22]=[C:23]([CH2:25][O:26][CH2:4][O:5][CH2:6][CH2:7][Si:10]([CH3:11])([CH3:12])[CH3:13])[N:24]=1
Reactant: C[Si](C)(C)C(CCl)COCC(CCl)[Si](C)(C)C
Reactant: OCc1cccc(Cl)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[Si](C)(C)CCOCOCc1cccc(Cl)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 76.6 %

Procedure:
3.20 ml of chloromethyl-2-(trimethylsilyl)ethyl ether (18.2 mmol) are added dropwise to a solution containing 2.50 g of (6-chloropyridin-2-yl)methanol (17.4 mmol), 3.30 ml of diisopropylethylamine (19.1 mmol) and 20 ml of dichloromethane cooled to 0° C. maintained under a nitrogen atmosphere. The mixture is stirred for 3 hours at room temperature and then the dichloromethane is evaporated off, the residue is taken up in water, the mixture is extracted with diethyl ether, the organic phase is washed with water and then dried over sodium sulfate. After filtration and evaporation of the solvent, the title product is isolated by chromatography on a silica column (eluent: dichloromethane).
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH2:10]([Mg]Br)[CH3:11].C1COCC1>Cl>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]2([NH2:7])[CH2:11][CH2:10]2)=[CH:8][CH:9]=1
Reactant: CC[Mg]Br
Reactant: N#Cc1ccc(Br)nc1
Agent: Cl
Solvent: C1CCOC1
Product: NC1(c2ccc(Br)nc2)CC1
Temperature: 50 °C
Reaction time: 3 h

Procedure:
An oven dried 2 L round-bottom flask equipped with a mechanical stirrer is charged with anhydrous THF (750 mL) followed by Ti(Oi-Pr)4 (72.8 mL, 246 mmol) under Ar atmosphere. The solution is purged under Ar and heated to 50° C. 6-Bromo-nicotinonitrile (30.0 g, 164 mmol) is added to the mixture followed by dropwise addition (over 40 minutes) of 1M solution of ethylmagnesium bromide in THF (410 mL, 410 mmol). The reaction is allowed to stir at 50° C. After 3 hours, the reaction mixture is cooled to room temperature and a 3M aqueous solution of HCl (approx 350 mL) is added. The mixture is transfered to a separatory funnel and is washed with ethyl ether (3×500 mL). The aqueous layer is allowed to stand overnight. The aqueous layer is then basified to pH 10 with 2M aqueous solution of NaOH. The solution is diluted with EtOAc (500 mL) and the resulting solution is vigorously stirred for 5 minutes. The solution is allowed to stand while the layers slowly separated. The organic layer is decanted and the same extraction process is repeated twice. The organic layers are combined, washed with brine (50 mL), dried over MgSO4 and concentrated in vacuo to yield an oil. The crude oil is purified by silica gel chromatography using a gradient of 0-10% MeOH in CH2Cl2 to afford 1-(6-bromo-pyridin-3-yl)-cyclopropylamine as an oil, which slowly crystallizes (ES+ m/z 213.3, 215.3).
Reaction SMILES: [CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21](B5OC(C)(C)C(C)(C)O5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:3][CH2:2]1.Br[C:35]1[CH:36]=[CH:37][C:38]2[O:42][CH2:41][CH2:40][C:39]=2[CH:43]=1.C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1.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.Cl[Pd]Cl.[Fe+2].ClCCl>[CH:1]1([C:4]([N:6]2[CH2:10][CH2:9][C@@H:8]([CH2:11][C:12]3[N:13]([C:18]4[CH:23]=[CH:22][C:21]([C:35]5[CH:36]=[CH:37][C:38]6[O:42][CH2:41][CH2:40][C:39]=6[CH:43]=5)=[CH:20][C:19]=4[F:33])[C:14](=[O:17])[NH:15][N:16]=3)[CH2:7]2)=[O:5])[CH2:2][CH2:3]1
Reactant: Brc1ccc2c(c1)CCO2
Reactant: CC1(C)OB(c2ccc(-n3c(C[C@@H]4CCN(C(=O)C5CC5)C4)n[nH]c3=O)c(F)c2)OC1(C)C
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: ClCCl
Product: O=C(C1CC1)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(-c3ccc4c(c3)CCO4)cc2F)C1
Temperature: 100 °C
Reaction time: 8 h
Yield: 29 %

Procedure:
A solution of 5-{[(3S)-1-(cyclopropylcarbonyl)-3-pyrrolidinyl]methyl}-4-[2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl]-2,4-dihydro-3H-1,2,4-triazol-3-one (0.351 mmol) in dioxane (1.5 mL) was treated with 5-bromo-2,3-dihydro-1-benzofuran (0.319 mmol), dichloro[1,1′-bis(diphenylphosphino)ferrocene]palladium(II)-dichloromethane adduct (18 mg), and 2M aq potassium carbonate (0.956 mmol). The reaction mixture was purged with nitrogen, sealed, and stirred at 100° C. overnight. The reaction mixture was cooled to room temperature and was diluted with water (50 mL). The aqueous layer was acidified to pH˜4 using 1N aq HCl and was extracted with dichloromethane. The organic layer was dried over magnesium sulfate, filtered, and concentrated in vacuo. The crude residue was purified by reverse phase HPLC (20-50% acetonitrile/water+0.1% NH4OH) to afford the title compound (29%). MS(ES)+ m/e 449.0 [M+H]+.
Reaction SMILES: [ClH:1].[CH3:2][N:3](C)CCCN=C=NCC.ON1C2C=CC=CC=2N=N1.[CH3:23][CH:24]([CH3:65])[CH2:25][CH2:26][N:27]([CH2:60][CH2:61][CH:62]([CH3:64])[CH3:63])[C:28]([C:30]1[CH:31]=[CH:32][C:33]2[N:37]=[C:36]([NH:38][C:39]3[CH:47]=[CH:46][C:42]([C:43](O)=[O:44])=[CH:41][CH:40]=3)[N:35]([CH2:48][CH2:49][CH2:50][NH:51]C(OC(C)(C)C)=O)[C:34]=2[CH:59]=1)=[O:29].CN.Cl>C(Cl)(Cl)Cl.O1CCCC1.ClCCl.C(OCC)(=O)C>[ClH:1].[ClH:1].[NH2:51][CH2:50][CH2:49][CH2:48][N:35]1[C:34]2[CH:59]=[C:30]([C:28]([N:27]([CH2:26][CH2:25][CH:24]([CH3:23])[CH3:65])[CH2:60][CH2:61][CH:62]([CH3:64])[CH3:63])=[O:29])[CH:31]=[CH:32][C:33]=2[N:37]=[C:36]1[NH:38][C:39]1[CH:40]=[CH:41][C:42]([C:43]([NH:3][CH3:2])=[O:44])=[CH:46][CH:47]=1
Reactant: CCN=C=NCCCN(C)C
Reactant: CC(C)CCN(CCC(C)C)C(=O)c1ccc2nc(Nc3ccc(C(=O)O)cc3)n(CCCNC(=O)OC(C)(C)C)c2c1
Agent: CN
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CNC(=O)c1ccc(Nc2nc3ccc(C(=O)N(CCC(C)C)CCC(C)C)cc3n2CCCN)cc1
Temperature: 20 °C
Reaction time: 1 h
Yield: 106.6 %

Procedure:
A solution of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC) (18 mg, 1.1 eq) in chloroform (1 ml) and a solution of 1-hydroxybenzotriazole (HOBt) (13 mg, 1.1 eq) in tetrahydrofuran (1 ml) are successively added to 4-[(6-{[bis(3-methylbutyl)amino]carbonyl}-1-{3-[(tert-butoxycarbonyl)amino]propyl}-1H-benzimidazol-2-yl)amino]benzoic acid (50 mg, 1 eq) in anhydrous tetrahydrofuran (1 ml). The mixture is stirred for 1 hour at a temperature of approximately 20° C. then the methylamine is added (2M in THF; 0.86 ml, 2 eq). After stirring for 17 hours at a temperature of approximately 20° C., the mixture is diluted with dichloromethane (3 ml) followed by the addition of aminomethylpolystyrene resin (2 eq), TBD-methyl polystyrene resin (2 eq) and methylisothiocyanate-polystyrene resin (4 eq). After stirring for 6 hours at approximately 20° C., the mixture is filtered and the filtrate is concentrated under reduced pressure at 40° C. The residue obtained is dissolved in dichloromethane (3 ml) and washed with a saturated aqueous solution of sodium hydrogen carbonate. The organic phase is dried over sodium sulphate and concentrated at a temperature of approximately 40° C. The residue obtained is dissolved in ethyl acetate (0.5 ml) and a solution of hydrochloric acid (4N in dioxane, 2 ml) is added. After stirring for 1 hour a temperature of approximately 20° C., the precipitate obtained is filtered and dried in order to produce the expected compound (29 mg; 60% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[B:10]([OH:12])[OH:11])([O-])=O>CCO.[Pd]>[NH2:1][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=1[B:10]([OH:12])[OH:11]
Reactant: O=[N+]([O-])c1ccccc1B(O)O
Agent: [Pd]
Solvent: CCO
Product: Nc1ccccc1B(O)O
Yield: 54.8 %

Procedure:
A mixture of 2-nitrophenylboronic acid (2 g; 12 mmol) and 5% Pd/C (100 mg) in EtOH (100 ml) was hydrogenated at 1 bar until TLC indicated complete conversion of starting material. The reaction mixture was filtered through celite and the filtrate evaporated to dryness. The remanense was washed with hexane and filtered to give 900 mg of (55%) 2-aminophenylboronic acid.
Reaction SMILES: Br[C:2]1[S:3][C:4]([CH3:13])=[C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[N:6]=1.[N:14]1([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[CH3:13][C:4]1[S:3][C:2]([N:17]2[CH2:16][CH2:15][N:14]([C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:19][CH2:18]2)=[N:6][C:5]=1[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: Cc1sc(Br)nc1-c1ccccc1
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: Cc1sc(N2CCN(C(=O)OC(C)(C)C)CC2)nc1-c1ccccc1
Yield: 18.1 %

Procedure:
A solution of 2-bromo-5-methyl-4-phenyl-1,3-thiazole (9.56 g, 37.6 mmol), tert-butyl piperazine-1-carboxylate (14.8 g, 75.2 mmol) and potassium carbonate (5.20 g, 37.6 mmol) in dimethylformamide (125 ml) was stirred at 120° C. for 4 hours. Water was poured into the reaction solution, and the mixture was extracted with ethyl acetate. The extract was washed with water and dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was purified by silica gel column chromatography (hexane:ethyl acetate=9:1) to give 2.45 g (18.1%) of the desired product as a solid.
Reaction SMILES: [NH:1]([C:5]1[CH:11]=[CH:10][C:8]([OH:9])=[CH:7][CH:6]=1)[C:2]([CH3:4])=[O:3].[C:12]([O:15][C:16]1[CH:21]=[CH:20][C:19](/[CH:22]=[CH:23]/[C:24](Cl)=[O:25])=[CH:18][C:17]=1[O:27][CH3:28])(=[O:14])[CH3:13].O>N1C=CC=CC=1.CC(C)=O>[C:2]([NH:1][C:5]1[CH:11]=[CH:10][C:8]([O:9][C:24](=[O:25])/[CH:23]=[CH:22]/[C:19]2[CH:20]=[CH:21][C:16]([O:15][C:12](=[O:14])[CH3:13])=[C:17]([O:27][CH3:28])[CH:18]=2)=[CH:7][CH:6]=1)(=[O:3])[CH3:4]
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: COc1cc(/C=C/C(=O)Cl)ccc1OC(C)=O
Solvent: c1ccncc1
Solvent: O
Solvent: CC(C)=O
Product: COc1cc(/C=C/C(=O)Oc2ccc(NC(C)=O)cc2)ccc1OC(C)=O
Reaction time: 3 h
Yield: 70.1 %

Procedure:
To a solution of paracetamol (2.56 g, 16.92 mmoles) in pyridine (20 ml) cooled in an ice bath trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoyl chloride (4.31 g, 16.92 mmoles) dissolved in acetone (45 ml) is dropped. The mixture is maintained under stirring in ice for 3 hours then it is poured into water (300 ml) and the precipitate is filtered and triturated with hexane to give trans-3-[4-acetyloxy-3-methoxyphenyl]-2-propenoic acid 4-(acetylamino)phenyl ester (4.38 g) as an orange solid. M.p. 246-250° C. Yield 70%.