Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([N:8]2[CH2:13][CH2:12][N:11]([C:14]([O:16][Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[CH:18]([CH3:20])[CH3:19])=[O:15])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([O:30][B:31](OC(C)C)[O:32]C(C)C)(C)C.P(=O)(O)(O)O>C1(C)C=CC=CC=1.O1CCCC1>[CH:18]([Si:17]([CH:24]([CH3:26])[CH3:25])([CH:21]([CH3:23])[CH3:22])[O:16][C:14]([N:11]1[CH2:12][CH2:13][N:8]([C:5]2[CH:6]=[CH:7][C:2]([B:31]([OH:32])[OH:30])=[CH:3][CH:4]=2)[CH2:9][CH2:10]1)=[O:15])([CH3:20])[CH3:19]
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: CC(C)[Si](OC(=O)N1CCN(c2ccc(Br)cc2)CC1)(C(C)C)C(C)C
Agent: O=P(O)(O)O
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)[Si](OC(=O)N1CCN(c2ccc(B(O)O)cc2)CC1)(C(C)C)C(C)C
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
A solution of triisopropylsilyl 4-(4-bromophenyl)-1-piperazinecarboxylate (4.5 g, 10.2 mmoles) in toluene (17 mL) and tetrahydrofuran (17 mL) was degassed by bubbling nitrogen at room temperature via a fritted gas dispenser for 10 minutes and then cooled to −78° C. for the addition of butyllithium (4.9 mL as a 2.5 M solution in hexanes, 12.3 mmoles). The solution turned yellow and after 30 minutes, triisopropylborate (3 mL, 13.3 mmoles) was added and the solution was warmed to 0° C. over 2.5 h prior to quenching with sat. aq. ammonium chloride (22 mL). To the flask was added 0.825 mL of phosphoric acid (14.8 M, 12.3 mmoles). The solution was stirred for 30 minutes. The phases were separated and the organic phase was dried over sodium sulfate. Right after filtering off the drying agent, the organic phase was washed with wet tetrahydrofuran (approx 2% water). The solution was concentrated to approx 15 mL. While concentrating, three 0.5 mL-portions of water were added to prevent boroxine formation. At this point, hexane was added and the resulting precipitate was filtered to yield 4-(4-{[(triisopropylsilyl)oxy]carbonyl}-1-piperazinyl)phenylboronic acid.
Reaction SMILES: [Cl-].[Al+3].[Cl-].[Cl-].[C:5]([N:8]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])[CH3:6].[Cl:19][CH2:20][CH2:21][C:22](Cl)=[O:23].O>ClC(Cl)C>[C:5]([N:8]1[C:14]2[CH:15]=[C:16]([C:22](=[O:23])[CH2:21][CH2:20][Cl:19])[CH:17]=[CH:18][C:13]=2[CH2:12][CH2:11][CH2:10][CH2:9]1)(=[O:7])[CH3:6]
Reactant: O=C(Cl)CCCl
Reactant: CC(=O)N1CCCCc2ccccc21
Agent: [Al+3]
Agent: [Cl-]
Solvent: CC(Cl)Cl
Solvent: O
Product: CC(=O)N1CCCCc2ccc(C(=O)CCCl)cc21
Temperature: 50 °C
Reaction time: 24 h

Procedure:
Aluminum chloride (30.8 g, 231 mmol) was added to a solution of 1-acetyl-2,3,4,5-tetrahydro-1H-1-benzazepine (17.5 g, 92.5 mmol) and 3-chloropropionyl chloride (13.2 ml, 139 mmol) in dichloroethane under cooling with water-bath, and then the mixture was stirred at 50° C. for 1 day. The reaction solution was poured into iced water and extracted with dichloromethane. The extract was washed with a saturated saline solution and dried over anhydrous sodium sulfate, and the solvent was distilled away under reduced pressure. The resultant residues were purified by silica gel column chromatography (developing solvent; hexane:ethyl acetate=1:1) and crystallized from hexane, whereby the title compound (8.47 g) was obtained as colorless powder with a mp. of 106 to 107° C.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[N:12][N:11]3[C:14](=[O:17])[NH:15][N:16]=[C:10]3[C:9]=2[C:18]2[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:31][C:32]1[CH:37]=[CH:36][C:35]([C:38]2[CH:42]=[CH:41][O:40][N:39]=2)=[CH:34][CH:33]=1>CN(C=O)C.CCOC(C)=O>[O:40]1[CH:41]=[CH:42][C:38]([C:35]2[CH:36]=[CH:37][C:32]([CH2:31][N:15]3[C:14](=[O:17])[N:11]4[N:12]=[CH:13][C:8]([C:5]5[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=5)=[C:9]([C:18]5[CH:23]=[CH:22][N:21]=[CH:20][CH:19]=5)[C:10]4=[N:16]3)=[CH:33][CH:34]=2)=[N:39]1
Reactant: O=c1[nH]nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Reactant: BrCc1ccc(-c2ccon2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: O=c1n(Cc2ccc(-c3ccon3)cc2)nc2c(-c3ccncc3)c(-c3ccc(Cl)cc3)cnn12
Temperature: 65 °C
Reaction time: 2 h

Procedure:
To a solution of 7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one (0.27 g, 0.834 mmol), prepared as described in Example 244, in DMF (4 mL), potassium carbonate (0.23 g, 1.67 mmol) and 3-(4-(bromomethyl)phenyl)isoxazole (0.248 g, 1.04 mmol) were added. The resulting mixture was heated to 65° C. After 2 h, the reaction mixture was then cooled to RT and diluted with EtOAc (200 mL). The resultant solution was then washed with water and saturated aqueous NaCl. The organic layer was dried over magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography eluting with hexanes/EtOAc to give the title compound, 2-(4-(isoxazol-3-yl)benzyl)-7-(4-chlorophenyl)-8-(pyridin-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one, as a light yellow solid. HPLC RT: 2.60 min; 1H NMR (CDCl3): δ 8.64 (d, J=1.1 Hz, 1H), 8.63 (d, J=1.7 Hz, 1H), 8.45 (d, J=1.7 Hz, 1H), 8.20 (s, 1H), 7.80 (d, J=8.2 Hz, 2H), 7.50 (d, J=8.2 Hz, 2H), 7.34 (m, 2H), 7.23 (m, 2H), 7.10 (m, 2H), 6.65 (d, J=2.2 Hz, 1H), 5.26 (s, 2H).
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[CH:8][C:5]([C:6]#[N:7])=[CH:4][CH:3]=1.Cl[CH2:11][C:12]([O-:14])=[O:13].[Na+]>O>[C:6]([C:5]1[CH:8]=[CH:9][C:2]([NH:1][CH2:11][C:12]([OH:14])=[O:13])=[CH:3][CH:4]=1)#[N:7]
Reactant: O=C([O-])CCl
Reactant: N#Cc1ccc(N)cc1
Agent: [Na+]
Solvent: O
Product: N#Cc1ccc(NCC(=O)O)cc1
Temperature: 0 °C
Yield: 72.7 %

Procedure:
77.4 g (0.66 mol) of 4-aminobenzonitrile and 150 g (1.31 mol) of sodium chloroacetate were suspended in 1.1 L of water, and the resulting mixture was stirred at reflux temperature for 6.5 hours. After cooling to 0° C., the resulting suspension was stirred at this temperature overnight. The solid was filtered and washed with 200 mL of water. The resulting solid was suspended in 200 mL of ethyl acetate and stirred at room temperature for 1 hour. The solid was filtered, washed with 400 mL of ethyl acetate and dried at 60° C. under vacuum for 5 hours to yield 84.5 g of 2-(4-cyanophenylamino)acetic acid as an off-white solid. Yield: 73.2%. Purity (HPLC, method 3): 98.4%.
Reaction SMILES: [O:1]=[C:2]1[NH:10][C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[N:3]1[CH:11]1[CH2:16][CH2:15][N:14]([C:17]2[N:22]=[CH:21][N:20]=[C:19]([C:23]([OH:25])=O)[CH:18]=2)[CH2:13][CH2:12]1.[NH:26]1[C:34]2[C:29](=[C:30]([NH2:35])[CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27]1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F>CN(C=O)C>[NH:26]1[C:34]2[C:29](=[C:30]([NH:35][C:23]([C:19]3[CH:18]=[C:17]([N:14]4[CH2:15][CH2:16][CH:11]([N:3]5[C:4]6[C:5](=[N:6][CH:7]=[CH:8][CH:9]=6)[NH:10][C:2]5=[O:1])[CH2:12][CH2:13]4)[N:22]=[CH:21][N:20]=3)=[O:25])[CH:31]=[CH:32][CH:33]=2)[CH:28]=[N:27]1
Reactant: O=C(O)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Reactant: Nc1cccc2[nH]ncc12
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: CN(C)C=O
Product: O=C(Nc1cccc2[nH]ncc12)c1cc(N2CCC(n3c(=O)[nH]c4ncccc43)CC2)ncn1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.29 mmol) 6-[4-(2-oxo-2,3-dihydroimidazo[4,5-b]pyridin-1-yl)-piperidin-1-yl]-pyrimidine-4-carboxylic acid and 39 mg (0.29 mmol) 1H-indazole-4-ylamine in 87 mL (0.62 mmol) TEA and 1.5 mL DMF were combined with 104 mg (0.32 mmol) TBTU and stirred overnight at RT. Then the reaction mixture was purified by preparative HPLC-MS. The product-containing fractions were combined and freeze-dried.
Reaction SMILES: [C:1]([Si:5](Cl)([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)([CH3:4])([CH3:3])[CH3:2].[F:19][C:20]1[C:25]([F:26])=[C:24]([F:27])[CH:23]=[CH:22][C:21]=1[CH2:28][OH:29].N1C=CN=C1>C(Cl)Cl>[C:1]([Si:5]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)[O:29][CH2:28][C:21]1[CH:22]=[CH:23][C:24]([F:27])=[C:25]([F:26])[C:20]=1[F:19])([CH3:4])([CH3:3])[CH3:2]
Reactant: OCc1ccc(F)c(F)c1F
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](OCc1ccc(F)c(F)c1F)(c1ccccc1)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 95.8 %

Procedure:
tert-Butylchlorodiphenylsilane (8.86 ml, 34 mmol) was added slowly via syringe to a solution of (2,3,4-trifluorophenyl)methanol (5.0 g, 31 mmol) and imidazole (2.53 g, 37.2 mmol) in CH2Cl2 (30 ml) cooled in an ice water bath. The mixture warmed to room temperature and stir overnight. Solvent was removed and the residue was partitioned between Et2O and water. The Et2O was separated and washed with brine, and the combined aqueous layers were twice more extracted with Et2O, which was washed with brine. Drying (MgSO4) and removal of solvent gave an oil that was chromatographed on silica gel (50% CH2Cl2 in hexanes followed by gradient elution to 100% CH2Cl2) to isolate an oil that slowly solidified to afford 11.9 g (96%) of a white solid.
Reaction SMILES: [Cl:1][C:2]1[CH:8]=[C:7]([Cl:9])[CH:6]=[CH:5][C:3]=1[NH2:4].C[Al](C)C.Br.[NH2:15][CH:16]1[CH2:21][CH2:20][O:19][C:17]1=[O:18].Cl>C(Cl)Cl.CCCCCC>[NH2:15][CH:16]([CH2:21][CH2:20][OH:19])[C:17]([NH:4][C:3]1[CH:5]=[CH:6][C:7]([Cl:9])=[CH:8][C:2]=1[Cl:1])=[O:18]
Reactant: Nc1ccc(Cl)cc1Cl
Reactant: NC1CCOC1=O
Agent: Br
Agent: C[Al](C)C
Agent: Cl
Solvent: CCCCCC
Solvent: ClCCl
Product: NC(CCO)C(=O)Nc1ccc(Cl)cc1Cl
Temperature: 25 °C
Reaction time: 48 h
Yield: 33.1 %

Procedure:
To a stirring solution of 2,4-dichloroaniline (4.27 g, 26.37 mmol), in anhydrous methylene chloride (100 mL) under N2 at 0° C. (ice-water bath), was added dropwise, trimethylaluminum (39.56 mL of a 2M solution in hexane, 79.11 mmol). The resultant mixture was stirred under N2 at room temperature for 24 h. The mixture was cooled and (±)-α-amino-γ-butyrolactone hydrobromide (39.56 mL, 74.11 mmol, Aldrich Chemical Co., Milwaukee, Wis.) was then added portionwise and the reaction mixture then allowed to stir at room temperature for 48 h. The reaction mixture was cooled to 0° C., treated with 6N hydrochloric acid until the pH of the mixture was 2 to 3. The resultant solid was filtered and suspended in 100 mL of water. The suspension was made basic with 50% aqueous NaOH (pH=13) and 300 mL of methylene chloride was added. The organic layer was separated, dried over magnesium sulfate and evaporated under reduced pressure. The residue obtained was chromatographed on silica gel eluting with 50% ethyl acetate in hexane. The desired fractions were combined and evaporated under reduced pressure to give the title compound as a white solid (2.3 g, 36%), mp 89°-91° C. IR (Nujol, cm-1), C=O (1658), N--H (3323.9), OH (3265.9). 1H NMR (400 MHz, CDCl3) spectrum was consistent with the title product. Analysis calculated for C10H12Cl2N2O: C, 45.65; H, 4.60; N, 10.68; Cl, 26.90; Found: C, 45.69; H, 4.60; N, 10.53; Cl, 26.70.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=2)[N:5]=[CH:4][C:3]=1[C:17]#[N:18].[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH2:24])=[C:22]([F:27])[CH:21]=1>C(O)C>[Cl:19][C:20]1[CH:26]=[CH:25][C:23]([NH:24][C:2]2[C:11]3[C:6](=[CH:7][C:8]([O:15][CH3:16])=[C:9]([N+:12]([O-:14])=[O:13])[CH:10]=3)[N:5]=[CH:4][C:3]=2[C:17]#[N:18])=[C:22]([F:27])[CH:21]=1
Reactant: Nc1ccc(Cl)cc1F
Reactant: COc1cc2ncc(C#N)c(Cl)c2cc1[N+](=O)[O-]
Solvent: CCO
Product: COc1cc2ncc(C#N)c(Nc3ccc(Cl)cc3F)c2cc1[N+](=O)[O-]
Reaction time: 3.5 h

Procedure:
A mixture of 5.017 g (19.0 mmol) 4-chloro-7-methoxy-6-nitro-3-quinolinecarbonitrile, 250 ml ethanol, and .2.55 ml 22.8 mmol) 4-chloro-2-fluoroaniline was heated to reflux under N2. At 3.5 hours, removed heat and made basic with saturated sodium bicarbonate. Stripped solvents and azeotroped with ethanol. Slurried residue with hexane, collected solids, and washed with water. Dissolved in ethyl acetate, stirred with Darco, filtered, stripped solvent, and dried in vacuo, giving 6.54 g of yellow solid: mass spectrum (electrospray m/e): M+H=372.8, 374.8.
Reaction SMILES: O=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9].Cl.[CH3:17][O:18][NH2:19]>>[CH3:17][O:18][N:19]=[C:2]([C:10]1[CH:11]=[N:12][CH:13]=[CH:14][CH:15]=1)[CH2:3][N:4]1[CH2:8][CH2:7][CH2:6][C:5]1=[O:9]
Reactant: O=C(CN1CCCC1=O)c1cccnc1
Reactant: CON
Agent: Cl
Product: CON=C(CN1CCCC1=O)c1cccnc1
Yield: 70 %

Procedure:
0.3 g (1.47 mmol) of 1-(2-oxo-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one prepared from Example 20 and 0.18 g (2.21 mmol) of methoxyamine hydrochloride salt were treated as described in Example 22 to obtain 0.24 g (70% yield) of 1-(2-methoxyimino-2-pyridin-3-yl-ethyl)-pyrrolidin-2-one as E/Z mixture (2.38:1).
Reaction SMILES: [C:1](Cl)(=[O:11])[C:2]1[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=1)[C:4](Cl)=[O:5].[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH2:19])=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[F:13][C:14]1[CH:21]=[CH:20][C:17]([CH2:18][NH:19][C:1](=[O:11])[C:2]2[C:3](=[CH:7][CH:8]=[CH:9][CH:10]=2)[C:4]([NH:19][CH2:18][C:17]2[CH:20]=[CH:21][C:14]([F:13])=[CH:15][CH:16]=2)=[O:5])=[CH:16][CH:15]=1
Reactant: NCc1ccc(F)cc1
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: Cc1ccccc1
Product: O=C(NCc1ccc(F)cc1)c1ccccc1C(=O)NCc1ccc(F)cc1
Temperature: 0 °C
Reaction time: 24 h
Yield: 80.6 %

Procedure:
To a mixture of phthaloyl dichloride (3 g, 15 mmol, 1 eq) in toluene (HPLC grade, 20 mL), cooled to 0° C., was added slowly a solution of 4-fluorobenzylamine (4.62 g, 37 mmol, 2.2 eq) in toluene (5 mL). After stirring at ambient temperature for 24 h, the reaction mixture was concentrated in vacuo to remove toluene. The resultant residue was dissolved in DCM, washed with brine and dried over Na2SO4. The organic layer was evaporated under reduced pressure. Recrystallization from DCM:hexane afforded the desired compound (4.6 g, 82%). 1H NMR (400 MHz, DMSO-d6) δ 9.3 (s, 2H), 9.1 (s, 2H), 8.64 (s, 1H), 7.39-7.34 (m, 4H), 7.17-7.12 (m, 4H), 4.48-4.46 (d, 4H). MS (ESI): 381.2 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19](Cl)=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:22][C:23]1[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=1[O:32][CH3:33].C(O)C>Cl.O>[CH2:1]([N:8]1[CH2:14][CH2:13][C:12](=[O:15])[N:11]([CH3:16])[C:10]2[CH:17]=[N:18][C:19]([NH:22][C:23]3[CH:31]=[CH:30][C:26]([C:27]([OH:29])=[O:28])=[CH:25][C:24]=3[O:32][CH3:33])=[N:20][C:9]1=2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COc1cc(C(=O)O)ccc1N
Reactant: CN1C(=O)CCN(Cc2ccccc2)c2nc(Cl)ncc21
Agent: Cl
Solvent: CCO
Solvent: O
Product: COc1cc(C(=O)O)ccc1Nc1ncc2c(n1)N(Cc1ccccc1)CCC(=O)N2C
Yield: 64.6 %

Procedure:
A mixture of 0.06 g (0.0002 mole) of 9-benzyl-2-chloro-5-methyl-5,7,8,9-tetrahydro-pyrimido[4,5-b][1,4]diazepin-6-one (VII-22), 0.04 g (0.00024 mole) of 4-amino-3-methoxy-benzoic acid, 0.5 mL of ethanol, 2 mL of water, and 2 drops of hydrochloric acid was heated at 100 degrees overnight. Upon cooling, a precipitate formed which was collected by filtration to give 0.056 g of 4-(9-benzyl-5-methyl-6-oxo-6,7,8,9-tetrahydro-5H-pyrimido[4,5-b][1,4]diazepin-2-yl amino)-3-methoxy-benzoic acid (I-22a) as an off-white solid.
Reaction SMILES: O[C:2]([C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[C:12]([CH3:36])=[CH:13][C:14]([OH:35])=[CH:15][C:16]=3[CH:17]=[C:18]2[C:21]2[CH:26]=[CH:25][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:23][CH:22]=2)=[CH:9][CH:8]=1)([CH3:6])[CH:3]([CH3:5])[CH3:4].[C:37]([O-])(O)=O.[Na+]>C(O)(=O)C.OS(O)(=O)=O>[CH3:6][C:2]([C:7]1[CH:20]=[C:19]2[C:10]([C:11]3[C:12]([CH3:36])=[CH:13][C:14]([OH:35])=[CH:15][C:16]=3[CH:17]=[C:18]2[C:21]2[CH:22]=[CH:23][C:24]([O:27][CH2:28][CH2:29][N:30]3[CH2:37][CH2:34][CH2:33][CH2:32][CH2:31]3)=[CH:25][CH:26]=2)=[CH:9][CH:8]=1)=[C:3]([CH3:4])[CH3:5]
Reactant: Cc1cc(O)cc2cc(-c3ccc(OCCN4CCCC4)cc3)c3cc(C(C)(O)C(C)C)ccc3c12
Reactant: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(C)=C(C)c1ccc2c(c1)c(-c1ccc(OCCN3CCCCC3)cc1)cc1cc(O)cc(C)c12
Temperature: 75 °C
Yield: 70.7 %

Procedure:
The compound from Step A (0.587 g, 1.2 mmol) was dissolved in glacial acetic acid (7.0 ml) and concentrated H2SO4 (1 drop) was added. The mixture was heated for 20 min at 75° C. with stirring. The reaction was neutralized with NaHCO3 (10.5 g in 25 ml of water) and extracted with methyl t-butyl ether (3×25 ml), evaporated and dried under high vacuum. The residue was chromatographed on silica gel with acetone/hexane (1:2) to give 0.407 g (85%) of the title compound. 1H-NMR (400 MHz, CDCl3) δH 0.77 (3H, d, CH3), 0.83 (3H, d, CH3), 1.47 (3H, s, CH3), 1.55 (2H, m, NCH2CH2CH2), 1.76 (4H, m, NCH2CH2CH2), 2.72 (4H, br, NCH2CH2CH2), 2.95 (2H, t, OCH2CH2N), 3.11 (3H, s, CH3), 4.24 (2H, t, OCH2CH2N), 6.87-8.78 (10H, ArH).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]3[CH:10]([CH2:24][CH2:25][C:26](O)=[O:27])[N:9]=2)=[CH:4][CH:3]=1.O[N:30]1[C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][C:33]=2N=N1.Cl.C(N=C=NCCCN(C)C)C.NC1C=CC=CC=1>O.C(N(CC)CC)C.CN(C)C=O>[C:34]1([NH:30][C:26](=[O:27])[CH2:25][CH2:24][CH:10]2[N:9]=[C:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)[C:14]3[CH:15]=[C:16]([CH2:18][CH3:19])[S:17][C:13]=3[N:12]3[C:20]([CH3:23])=[N:21][N:22]=[C:11]23)[CH:35]=[CH:36][CH:37]=[CH:38][CH:33]=1
Reactant: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)O)N=C2c1ccc(Cl)cc1
Reactant: On1nnc2ccccc21
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CN(C)C=O
Solvent: O
Solvent: Nc1ccccc1
Product: CCc1cc2c(s1)-n1c(C)nnc1C(CCC(=O)Nc1ccccc1)N=C2c1ccc(Cl)cc1
Yield: 7.7 %

Procedure:
(±)-3-(4-(4-Chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo[4,3-a][1,4]diazepin-6-yl)propionic acid (0.33 g) and 1-hydroxybenzotriazole (0.12 g) are added to dry dimethylformamide (20 ml) and the mixture is stirred under ice-cooling. Thereto is added 1-ethyl-3-(3-dimethylaminopropyl)-carbodiimide hydrochloride (0.17 g), and then triethylamine (0.16 g) and aniline (72 mg) are added. The mixture is stirred at room temperature for 24 hours. After the completion of the reaction, water (100 ml) is added and the mixture is extracted with ethyl acetate. The organic layer is washed with 6N hydrochloric acid, a saturated aqueous solution of sodium hydrogencarbonate and saturated brine, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The residue is purified by silica gel column chromatography (ethyl acetate:methanol=10:1) and crystallized from ethyl acetate and isopropyl ether to give 0.03 g of (±)-N-phenyl-3-(4-(4-chlorophenyl)-2-ethyl-9-methyl-6H-thieno[3,2-f][1,2,4]triazolo-[4,3-a][1,4]diazepin-6-yl)propaneamide as white powdery crystals, melting point 183°-185° C.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]([CH3:17])=[CH:5]2.[OH:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.P([O-])([O-])([O-])=O.[K+].[K+].[K+]>C([O-])(=O)C.[Pd+2].C([O-])(=O)C.C(OCC)(=O)C.O.O1CCOCC1>[OH:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[CH:3]=[C:4]3[C:9](=[CH:10][CH:11]=2)[N:8]=[C:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:6]([CH3:17])=[CH:5]3)=[CH:21][CH:20]=1
Reactant: CCOC(=O)c1nc2ccc(Br)cc2cc1C
Reactant: OB(O)c1ccc(O)cc1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCOC(C)=O
Solvent: C1COCCO1
Product: CCOC(=O)c1nc2ccc(-c3ccc(O)cc3)cc2cc1C
Temperature: 60 °C
Yield: 49 %

Procedure:
Palladium(II)acetate (4.9 mg, 22.0 μmol) was added to ethyl 6-bromo-3-methyl-2-quinolinecarboxylate (129.6 mg, 440.6 μmol), 4-hydroxy-phenyl-boronic acid (91.2 mg, 660.9 μmol), triphenylphosphine (11.6 mg, 44.0 μmol), and potassium phosphate (327.3 mg, 1.54 mmol). Then, dioxane (4.4 mL) was added to the mixture, followed by water (44.1 μL), and the reaction mixture was heated open to the atmosphere at 60° C. in an oil bath for 17 hours, then allowed to cool to room temperature. Water was added followed by ethyl acetate and the mixture was filtered through Celite®. The filtrate was extracted with ethyl acetate and the organic layer was dried over anhydrous magnesium sulfate, then filtered and concentrated. The residue was purified by silica gel chromatography eluting with 2:3 ethyl acetate:hexanes to give 66.4 mg (49%) of ethyl 6-(4-hydroxyphenyl)-3-methyl-2-quinolinecarboxylate as a solid. 1H NMR (400 MHz, d6-DMSO): δ 9.71 (s, 1H), 8.31 (s, 1H), 8.13 (s, 1H), 8.07-8.02 (m, 2H), 7.68 (d, J=9 Hz, 2H), 6.90 (d, J=9 Hz, 2H), 4.41 (q, J=7 Hz, 2H), 2.55 (s, 3H), 1.36 (t, J=7 Hz, 3H). ESI-LCMS m/z 308 (M+H)+.
Reaction SMILES: [C:1]1([CH:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][C:16]#[N:17])[CH2:9][CH2:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Cl.[OH-].[Na+]>C1COCC1>[NH2:17][CH2:16][CH2:15][CH2:14][CH2:13][N:10]1[CH2:9][CH2:8][CH:7]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH2:12][CH2:11]1
Reactant: N#CCCCN1CCC(c2ccccc2)CC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: NCCCCN1CCC(c2ccccc2)CC1
Temperature: 25 °C
Reaction time: 2 h
Yield: 91.2 %

Procedure:
To a stirred solution of 4-(4-phenylpiperidin-1-yl)butyronitrile (3.81 g, 16.7 mmol, 1.0 equiv) in anhydrous THF (20 mL) under argon was added a solution of BH3 in THF (1.0 M, 58.5 mL, 58 mmol, 3.5 equiv) at room temperature. The mixture was refluxed for 4.5 hours and then cooled to room temperature. Aqueous HCl (6 N, 100 mL) was added and stirring was continued for 2 hours at 55-60° C. The mixture was basified to pH 9 by addition of 6 N aq. NaOH and extracted with CH2Cl2 (3×100 mL). The combined organic solutions were dried over MgSO4 and concentrated. The residue was dissolved in CH2Cl2 (20 mL) and treated with HCl in ether (1.0 M, 35 mL). The solvents were removed, ether (200 mL) was added, the mixture was filtered, and the filter cake was washed with ether. Water (50 mL) was added to the resulting white solid, the pH was adjusted to 10-11 with 1 M NaOH, and the aqueous phase was extracted with CH2Cl2 (3×100 mL). Drying over MgSO4 followed by removal of solvents gave 3.54 g of 1-(4-aminobutyl)-4-phenylpiperidine (light yellow solid, 91%) which was characterized spectroscopically.
Reaction SMILES: [C:1]([CH2:3][C:4]([OH:6])=O)#[N:2].[NH2:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1.C1(N=C=NC2CCCCC2)CCCCC1>C(#N)C.[OH-].[Na+]>[C:1]([CH2:3][C:4]([NH:7][C:8]1[S:9][CH:10]=[CH:11][N:12]=1)=[O:6])#[N:2]
Reactant: Nc1nccs1
Reactant: N#CCC(=O)O
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: CC#N
Product: N#CCC(=O)Nc1nccs1
Reaction time: 1 h

Procedure:
4.5 g of cyanoacetic acid and 5.3 g of 2-aminothiazole, each in acetonitrile were combined, and the suspension (60 ml) was treated with a solution of 12.0 g of dicyclohexylcarbodiimide in 30 ml of acetonitrile. After exothermic reaction (and solidification) additional acetonitrile (60 ml) was added and the mixture stirred 1 hr and let stand overnight. The collected solid (20 g) was stirred with dilute (ca. 2%) NaOH solution and filtered. The filtrate was acidified with 6 N HCl and the product collected, washed with water, dried (m.p. 229°-230°) and recrystallized from acetone to give 2-(cyanoacetylamino)thiazole, m.p. 231°-2° dec.
Reaction SMILES: [NH2:1][C:2]1[C:11]([N+:12]([O-])=O)=[CH:10][C:9]([CH3:15])=[C:8]([CH3:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]>ClCCl.[Pd]>[NH2:1][C:2]1[C:11]([NH2:12])=[CH:10][C:9]([CH3:15])=[C:8]([CH3:16])[C:3]=1[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1c(C)c(C)cc([N+](=O)[O-])c1N
Agent: [Pd]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(C)cc(N)c1N
Reaction time: 16 h
Yield: 82 %

Procedure:
A solution of methyl 2-amino-5,6-dimethyl-3-nitrobenzoate (11.78 g, 52.5 mmol) in dichloromethane (525 mL) was hydrogenated over 10% palladium on charcoal (1.2 g) at 50 psi (3.3 atm) and 50° C. for 16 hours. Another portion of catalyst (1.2 g) was added, and hydrogenation was allowed to proceed for a further 16 hours. The mixture was filtered through Arbocel filter aid, and the filtrate was concentrated under reduced pressure. The residue was purified by flash chromatography (gradient elution with dichloromethane/methanol) to give methyl 2,3-diamino-5,6-dimethylbenzoate (8.36 g, 82%) as an orange oil.