Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[CH:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([Cl:20])=[CH:16][CH:15]=3)[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=2)[CH:5]=[CH:6][CH:7]=1.[NH2:25][C:26]1[CH:31]=[CH:30][C:29](B2OC(C)(C)C(C)(C)O2)=[CH:28][N:27]=1>>[Cl:20][C:17]1[CH:18]=[CH:19][C:14]([C:12]2[CH:11]=[C:10]([C:21]([F:24])([F:23])[F:22])[N:9]=[C:8]([C:4]3[CH:3]=[C:2]([C:29]4[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=4)[CH:7]=[CH:6][CH:5]=3)[CH:13]=2)=[CH:15][CH:16]=1
Reactant: FC(F)(F)c1cc(-c2ccc(Cl)cc2)cc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Nc1ccc(-c2cccc(-c3cc(-c4ccc(Cl)cc4)cc(C(F)(F)F)n3)c2)cn1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-chloro-phenyl)-6-trifluoromethyl-pyridine (example E.82) (0.30 g, 0.727 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.192 g, 0.873 mmol) according to the general procedure VI. Obtained as a light grey solid (0.200 g, 65%). MS (ISP) 426.0 [(M+H)+] and 428 [(M+2+H)+]; mp 172° C.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6](Cl)[CH:5]=[CH:4][N:3]=1.[NH:9]1[CH:13]=[CH:12][N:11]=[CH:10]1>O1CCCC1>[N:9]1([C:2]2[N:7]=[C:6]([N:9]3[CH:13]=[CH:12][N:11]=[CH:10]3)[CH:5]=[CH:4][N:3]=2)[CH:13]=[CH:12][N:11]=[CH:10]1
Reactant: c1c[nH]cn1
Reactant: Clc1ccnc(Cl)n1
Solvent: C1CCOC1
Product: c1cn(-c2ccnc(-n3ccnc3)n2)cn1
Yield: 76.9 %

Procedure:
In anhydrous tetrahydrofuran, 149 mg of 2,4-dichloropyrimidine was substituted with 136 mg of imidazole. The reaction mixture was treated according to the procedure of Example 1 to yield 163 mg of 2,4-bis(1-imidazolyl)pyrimidine, recrystallized from a mixture of n-hexane and ethyl acetate, the compound had a melting point of 131°-132° C.
Reaction SMILES: Cl.[Cl:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7]Cl.[CH2:9]([C:11]1[CH:12]=[C:13]([CH:15]=[CH:16][CH:17]=1)[NH2:14])[CH3:10].C(=O)([O-])[O-].[K+].[K+]>C(O)C>[ClH:2].[CH2:9]([C:11]1[CH:12]=[C:13]([N:14]2[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]2)[CH:15]=[CH:16][CH:17]=1)[CH3:10]
Reactant: ClCCNCCCl
Reactant: CCc1cccc(N)c1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCO
Product: CCc1cccc(N2CCNCC2)c1
Reaction time: 16 h
Yield: 70.5 %

Procedure:
A solution of 73.3 g (0.411 mol) of bis(2-chloroethyl)amine hydrochloride and 49.7 g (0.411 mol) of 3-ethylaniline in 500 mL of absolute ethanol was heated at reflux for 16 h under a nitrogen atmosphere. The mixture was cooled and 85.2 g (0.617 mol) of anhydrous potassium carbonate was added and heating was continued for 16 h. The hot mixture was filtered and the filtrate was concentrated under reduced pressure. The residue was triturated with ethyl acetate to yield 65.7 g (71%) of solid. A portion of this crude product was recrystallized from 2-propanol to yield a white crystalline solid, mp 194°-195° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([O:17]C)=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1.CO.[OH-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[C:12](=[O:19])[NH:13][C:14]([C:15]([OH:17])=[O:16])=[C:10]3[CH2:9][N:8]=[C:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:26])[C:6]=2[CH:27]=1
Reactant: COC(=O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2
Agent: [K+]
Agent: [OH-]
Solvent: CO
Solvent: O
Product: O=C(O)c1[nH]c(=O)n2c1CN=C(c1ccccc1Cl)c1cc(Cl)ccc1-2

Procedure:
A mixture of 4.02 g (0.01 mole) of 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid, methyl ester, 150 ml of methanol, 15 ml of water and 2 g (0.035 mole) of potassium hydroxide was heated to reflux for 5 hours under a nitrogen atmosphere. The solution was then concentrated down to 40 ml, acidified by addition of 4 ml of glacial acetic acid and crystallized by diluting with water. The precipitate was collected, dried and recrystallized from tetrahydrofuran/methanol/ethyl acetate to yield 8-chloro-6-(2-chlorophenyl)-1,2-dihydro-1-oxo-4H-imidazo[1,5-a][1,4]benzodiazepine-3-carboxylic acid which was decarboxylated as follows: A solution of 1 g of this acid in 5 ml of ethylene glycol was heated to reflux for 45 min and then partitioned between methylene chloride and saturated sodium bicarbonate solution. The organic layer was washed with bicarbonate solution and water, dried and evaporated. Crystallization of the residue from ethyl acetate/ether gave end product which was further purified by chromatography over 20 g silica gel using methylene chloride/ethyl acetate 1:3. Crystallization from ethyl acetate/ether yielded the pure colorless product with mp 236°-238°. nmr (CDCl3) δ 4.15 ppm (broad d, 1) and 4.86 (broad d, 1) (AB-system, J= 13 Hz, C4 -H) 6.25 (d, 1, J=2 Hz, C3 -H) 6.98 (d, 1, J=2.5 Hz, C7 -H) 7.1-7.7 (m, 5, aromatic H) 8.0 (d, 1, J=8 Hz, C10 -H) 10.4 (broad s, 1, NH).
Reaction SMILES: C1(C)C=CC(S(O)(=O)=O)=CC=1.[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH2:23])[CH:16]=1.[N+:25]([C:28]1[CH:35]=[CH:34][C:31]([C:32]#[N:33])=[CH:30][CH:29]=1)([O-:27])=[O:26].C([O-])(O)=O.[Na+]>C1C=CC=CC=1>[CH3:12][O:13][C:14](=[O:24])[C:15]1[CH:20]=[CH:19][C:18]([O:21][CH3:22])=[C:17]([NH:23][C:32](=[NH:33])[C:31]2[CH:30]=[CH:29][C:28]([N+:25]([O-:27])=[O:26])=[CH:35][CH:34]=2)[CH:16]=1
Reactant: COC(=O)c1ccc(OC)c(N)c1
Reactant: N#Cc1ccc([N+](=O)[O-])cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: COC(=O)c1ccc(OC)c(NC(=N)c2ccc([N+](=O)[O-])cc2)c1
Temperature: 160 °C
Reaction time: 8 h
Yield: 51.7 %

Procedure:
Anhydrous p-toluenesulfonic acid (6.30 g, 33.1 mmol) was added to 50 ml of benzene and the resulting mixture was refluxed while removing water using a dean-stock trap. Added thereto were 3-amino-4-methoxy benzoic acid methyl ester (3 g, 16.6 mmol) obtained in step 1 of Preparation Example 1 and 4-nitrobenzonitrile (2.94 g, 19.9 mol), followed by stirring at 160° C. for 8 hours. The resulting solution was cooled to room temperature, the reaction was stopped by adding NaHCO3 thereto, extracted with ethyl acetate, the extract was dried over MgSO4 and concentrated under a reduced pressure. The resulting residue was purified by silica gel column chromatography to obtain the title compound (2.83 g, 8.59 mmol) in a yield of 52%.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=O)[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8].P12(SP3(SP(SP(S3)(S1)=S)(=S)S2)=S)=[S:18]>N1C=CC=CC=1>[Cl:1][C:2]1[CH:3]=[C:4]([C:10]2[CH:11]=[CH:12][C:13](=[S:18])[NH:14][N:15]=2)[CH:5]=[C:6]([Cl:9])[C:7]=1[CH3:8]
Reactant: Cc1c(Cl)cc(-c2ccc(=O)[nH]n2)cc1Cl
Reactant: S=P12SP3(=S)SP(=S)(S1)SP(=S)(S2)S3
Solvent: c1ccncc1
Product: Cc1c(Cl)cc(-c2ccc(=S)[nH]n2)cc1Cl
Temperature: 25 °C
Yield: 55.9 %

Procedure:
12.75 g of 6-(3,5-dichloro-4-methylphenyl)-3-pyridazone and 22 g of phosphorus pentasulphide in 80 ml of pyridine were heated under reflux on an oil bath for 7 hours. The reaction mixture was then cooled to room temperature and its volume was reduced by one-half by distilling off the pyridine under reduced pressure. 300 ml of ethyl acetate were added to the residue and the mixture was poured into ice-water. After stirring the mixture for a short time, the resulting yellow solid was collected by filtration, washed with water and dried to give 7.5 g (56%) of the desired compound. After recrystallizing the compound from a 10:1 by volume mixture of ethanol and dioxan, the compound melted at 255°-258° C.
Reaction SMILES: [NH2:1][C:2]1[CH:6]=[CH:5][NH:4][N:3]=1.[C:7]([CH:10]1[CH2:15][CH2:14][O:13][C:11]1=[O:12])(=O)[CH3:8]>C(O)C>[O:12]=[C:11]1[CH:10]([C:7](=[N:1][C:2]2[CH:6]=[CH:5][NH:4][N:3]=2)[CH3:8])[CH2:15][CH2:14][O:13]1
Reactant: CC(=O)C1CCOC1=O
Reactant: Nc1cc[nH]n1
Solvent: CCO
Product: CC(=Nc1cc[nH]n1)C1CCOC1=O
Temperature: 25 °C
Yield: 69.4 %

Procedure:
In 12 ml of anhydrous ethanol were added 0.83 g (10.00 mmol) of 3-aminopyrazole and 1.92 g (15.00 mmol) of 2-acetyl-γ-butyrolactone. While stirring at room temperature, 0.1 ml of a boron trifluoride methanol complex were added to the resultant solution, and the mixture was then stirred for 4 hours under the same conditions. Solids deposited were collected by filtration, washed with ethanol and air-dried to obtain 1.34 g (yield: 69.4%) of the intended product.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([CH:9]=1)[CH:7]=[O:8].[CH3:11][S-:12].[Na+].Cl>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([S:12][CH3:11])=[C:6]([CH:9]=1)[CH:7]=[O:8]
Reactant: C[S-]
Reactant: O=Cc1cc(Br)ccc1F
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CSc1ccc(Br)cc1C=O
Yield: 63.3 %

Procedure:
(Step 1) 5-Bromo-2-fluorobenzaldehyde (15.4 g) and sodium methanethiolate (5.85 g) were stirred in N,N-dimethylformamide (30 ml) at 60° C. for 30 min. The reaction solution was treated with 1N hydrochloric acid, and extracted with ethyl acetate. The extract was washed successively with aqueous sodium hydrogen carbonate solution and saturated brine, and dried over magnesium sulfate. The solvent was evaporated under reduced pressure. The residue was crystallized from ethyl acetate-hexane to give 5-bromo-2-(methylsulfanyl)benzaldehyde (11.1 g).
Reaction SMILES: [CH2:1]([S:8][CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:27].C([O-])(O)=O.[Na+]>C(OCC)(=O)C>[CH2:1]([S:8]([CH2:9][C@@H:10]1[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11]1)=[O:27])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: CC(C)(C)OC(=O)N1CC[C@@H](CSCc2ccccc2)C1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CC[C@@H](CS(=O)Cc2ccccc2)C1
Temperature: 0 °C
Yield: 88.7 %

Procedure:
To a stirred solution of (3R)-3-(benzylthio)methyl-1-(tert-butoxycarbonyl)pyrrolidine (0.2553 g, 0.830 mmol) in ethyl acetate (15 ml), under argon, cooled in a bath at ca. -40° C., was added portionwise 57-86% 3-chloroperoxybenzoic acid (0.2094 g). The mixture was then allowed to warm to 0° C. over 1.5 h, before pouring into 5% NaHCO3 solution (15 ml). The organic layer was separated and washed with more 5% NaHCO3 solution (15 ml), then saturated NaCl solution (10 ml), dried (MgSO4) and evaporated in vacuo. The residue was purified by flash chromatography (silica gel, 3% MeOH/CH2Cl2) to give 0.2381 g (89%) of the title compound as a colourless oil. δH (250 MHz, CDCl3) 1.44 (9H, s), 1.61 (1H, m), 2.15 (1H, m), 2.52 (1H, m), 2.66 (2H, m), 3.00 (1H, m), 3.29 (1H, m), 3.43 (1H, m), 3.63 (1H, m), 3.96 (1H, d, J=12.9 Hz), 4.07 (1H, d, J=12.9 Hz), 7.28-7.30 (2H, m), 7.35-7.39 (3H, m). m/e (ES+) 324 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH2:15]Cl)=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:18]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)(=O)C>CN(C)C=O>[CH2:1]([O:8][C:9]1[C:10](=[O:17])[CH2:11][C:12]([CH:15]=[CH2:18])=[N:13][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: O=C1CC(CCl)=NC=C1OCc1ccccc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: C=CC1=NC=C(OCc2ccccc2)C(=O)C1
Reaction time: 3 h
Yield: 66.2 %

Procedure:
A solution of 5-benzyloxy-2-chloromethyl-4-pyridone (10.0 g) and triphenylphosphine (10.5 g) in N,N-dimethylformamide (50 ml) was stirred for 5 hours at 90°-100° C. The resulting mixture was poured into ethyl acetate (800 ml). The precipitate was collected by filtration, washed with ethyl acetate and dissolved in dichloromethane (500 ml). To the solution were added water (300 ml) and 38% aqueous formaldehyde (100 ml). The mixture was adjusted to pH 10-10.5 with potassium carbonate. After being stirred for 3 hours at 35°-40° C., the organic layer was separated, washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The product was isolated by column chromatography on silica gel with ethyl acetate as an eluent to give 5-benzyloxy-2-vinyl-4-pyridone (6.02 g).
Reaction SMILES: Cl.[N:2]1([CH:7]2[CH2:11][CH2:10][NH:9][CH2:8]2)[CH:6]=[CH:5][N:4]=[N:3]1.C1CCN2C(=NCCC2)CC1.[NH2:23][C:24]1[C:33]([F:34])=[C:32](F)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1>N1C=CC=CC=1>[NH2:23][C:24]1[C:33]([F:34])=[C:32]([N:9]2[CH2:10][CH2:11][CH:7]([N:2]3[CH:6]=[CH:5][N:4]=[N:3]3)[CH2:8]2)[C:31]([O:36][CH3:37])=[C:30]2[C:25]=1[C:26](=[O:44])[C:27]([C:41]([OH:43])=[O:42])=[CH:28][N:29]2[CH:38]1[CH2:40][CH2:39]1
Reactant: COc1c(F)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Reactant: c1cn(C2CCNC2)nn1
Agent: Cl
Solvent: C1CCC2=NCCCN2CC1
Solvent: c1ccncc1
Product: COc1c(N2CCC(n3ccnn3)C2)c(F)c(N)c2c(=O)c(C(=O)O)cn(C3CC3)c12
Temperature: 120 °C

Procedure:
3-(1,2,3-triazol-1-yl)pyrrolidinehydrochloride (147 mg, 0.84 mmol) and DBU (128 mg, 0.84 mmol) were added to a suspension of 5-Amino-1-cyclopropyl-6,7-difluoro-8-methoxy-1,4-dihydro-4-oxoquinoline-3-carboxylic acid (100 mg, 0.33 mmol) in pyridine (5 ml). The reaction mixture was heated at 120° C. for 30 hrs, concentrated and the residue was triturated with water. The separated solid was filtered, washed with water and recrystallized from chloroform-hexane. Yield 40 mg; m.p. 208° C.; 1H NMR (TFA) δ: 9.39 (s, 1H), 8.70 (s, 1H), 8.57 (s, 1H), 5.88 (s, 1H), 4.43-4.73 (m, 4H), 4.10 (m, 1H), 3.79 (s, 3H), 2.92 (m, 2H), 1.12-1.58 (m, 4H).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[C:13](=[CH:14][C:15]3[CH:16]=[C:17]([NH2:21])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1.[CH3:26][S:27](Cl)(=[O:29])=[O:28]>C1(C)C=CC=CC=1>[CH3:1][O:2][C:3]1[C:8]2[O:9][CH2:10][C:11]3[CH:25]=[CH:24][CH:23]=[CH:22][C:12]=3[C:13](=[CH:14][C:15]3[CH:16]=[C:17]([NH:21][S:27]([CH3:26])(=[O:29])=[O:28])[CH:18]=[CH:19][CH:20]=3)[C:7]=2[CH:6]=[CH:5][CH:4]=1
Reactant: COc1cccc2c1OCc1ccccc1C2=Cc1cccc(N)c1
Reactant: CS(=O)(=O)Cl
Solvent: Cc1ccccc1
Product: COc1cccc2c1OCc1ccccc1C2=Cc1cccc(NS(C)(=O)=O)c1

Procedure:
Following procedures essentially as described in Example 90, the title compound is prepared from 3-(4-Methoxy-6H-dibenzo[b,e]oxepin-11-ylidenemethyl)-phenylamine and methanesulfonyl chloride. Flash chromatography eluting with 5 to 10 to 20% ethyl acetate:toluene provides 198 mg product (60% yield) of the title final product.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH2:11][C:12]3[C:13]([F:22])=[C:14]4[C:19](=[CH:20][CH:21]=3)[N:18]=[CH:17][CH:16]=[CH:15]4)=[CH:9][N:10]=2)[N:7]=1.[NH:23]1[CH2:28][CH2:27][NH:26][CH2:25][C:24]1=[O:29]>>[F:22][C:13]1[C:12]([CH2:11][C:8]2[N:6]3[N:7]=[C:2]([N:26]4[CH2:27][CH2:28][NH:23][C:24](=[O:29])[CH2:25]4)[CH:3]=[CH:4][C:5]3=[N:10][CH:9]=2)=[CH:21][CH:20]=[C:19]2[C:14]=1[CH:15]=[CH:16][CH:17]=[N:18]2
Reactant: Fc1c(Cc2cnc3ccc(Cl)nn23)ccc2ncccc12
Reactant: O=C1CNCCN1
Product: O=C1CN(c2ccc3ncc(Cc4ccc5ncccc5c4F)n3n2)CCN1

Procedure:
The title compound was prepared in analogy to Example 38 6-(6-chloro-imidazo[1,2-b]pyridazin-3-ylmethyl)-5-fluoro-quinoline (Intermediate N, 100 mg, 0.320 mmol), piperazin-2-one (96 mg, 0.959 mmol) (tR 3.16 min (conditions 5), MH+=377, 1H-NMR in DMSO-d6: 8.91 (m, 1H); 8.47 (d, 1H); 8.07 (s, 1H); 7.84 (d, 1H); 7.78 (d, 1H); 7.69 (m, 1H); 7.60 (m, 1H); 7.47 (s, 1H); 7.12 (d, 1H); 4.42 (s, 2H); 3.98 (s, 2H); 3.66 (m, 2H); 3.25 (m, 4H)).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:4]=[C:5]([NH:9][NH2:10])[CH:6]=[CH:7][CH:8]=1.[CH2:11]([O:13][C:14](=[O:22])[CH:15]([C:19](=O)[CH3:20])[C:16](=O)[CH3:17])[CH3:12].N1C=CC=CC=1>C(O)C>[CH2:11]([O:13][C:14]([C:15]1[C:16]([CH3:17])=[N:10][N:9]([C:5]2[CH:6]=[CH:7][CH:8]=[C:3]([Br:2])[CH:4]=2)[C:19]=1[CH3:20])=[O:22])[CH3:12]
Reactant: CCOC(=O)C(C(C)=O)C(C)=O
Reactant: NNc1cccc(Br)c1
Agent: Cl
Solvent: CCO
Solvent: c1ccncc1
Product: CCOC(=O)c1c(C)nn(-c2cccc(Br)c2)c1C

Procedure:
Similar to Example 1, equimolar amounts of 3-bromophenylhydrazine hydrochloride and 2-acetyl-3-oxo-butyric acid ethyl ester were combined in a solution of 50% pyridine in ethanol. Analysis showed that the resulting solid was the named product (m.p. 34° C.–35° C.).
Reaction SMILES: [NH2:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1.CCN(CC)CC.[C:32](OC(=O)C)(=[O:34])[CH3:33]>C(Cl)Cl>[C:32]([NH:1][C:2]1[S:6][C:5]([O:7][C:8]2[CH:9]=[C:10]([CH3:24])[C:11]3[CH:15]([CH2:16][C:17]([O:19][CH2:20][CH3:21])=[O:18])[O:14][B:13]([OH:22])[C:12]=3[CH:23]=2)=[N:4][N:3]=1)(=[O:34])[CH3:33]
Reactant: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(N)s3)cc(C)c21
Reactant: CC(=O)OC(C)=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCOC(=O)CC1OB(O)c2cc(Oc3nnc(NC(C)=O)s3)cc(C)c21
Reaction time: 8 h

Procedure:
To a solution of ethyl 2-(6-(5-amino-1,3,4-thiadiazol-2-yloxy)-1-hydroxy-4-methyl-1,3-dihydrobenzo[c][1,2]oxaborol-3-yl)acetate (70 mg, 0.2 mmol) in DCM (10 mL) was added Et3N (0.11 ml) and acetic anhydride (0.08 mL). The mixture was stirred at room overnight. The mixture was concentrated and precipitate was filtered and washed with a mixture of hexane and ethyl acetate to afford the product as a light yellow solid (59 mg). 1H NMR (DMSO-d6) δ 12.44 (s, 1H), 9.28 (s, 1H), 7.4 (s, 1H), 7.26 (s, 1H), 5.54 (d, 1H), 4.03 (q, H) 3.14 (dd, 1H), 2.48 (d, 1H), 2.35 (s, 3H), 2.13 (s, 3H), 1.11 (t, 3H); MS found: (M+H)+=392.1.
Reaction SMILES: [CH3:1][N:2]1[C:6]([C:7]([NH2:9])=[O:8])=[C:5]([N+:10]([O-])=O)[C:4]([CH3:13])=[N:3]1>C(O)C.C(OCC)(=O)C.[Pd]>[NH2:10][C:5]1[C:4]([CH3:13])=[N:3][N:2]([CH3:1])[C:6]=1[C:7]([NH2:9])=[O:8]
Reactant: Cc1nn(C)c(C(N)=O)c1[N+](=O)[O-]
Agent: [Pd]
Solvent: CCO
Solvent: CCOC(C)=O
Product: Cc1nn(C)c(C(N)=O)c1N
Reaction time: 5 h
Yield: 97.8 %

Procedure:
To a solution of 1,3-dimethyl-4-nitro-1H-pyrazole-5-carboxamide (730 mg, 3.96 mmol) in anhydrous ethanol (100 mL) and ethyl acetate (100 mL) was added 10 wt % Pd on carbon (100.0 mg). The reaction mixture was evacuated with vacuum and purged with H2 (3×), then stirred under H2 at 50 psi for 5 hours. The reaction mixture was then filtered through a pad of Celite®. The filtrate was concentrated in vacuo and the crude was purified by column chromotagraphy (Si-PPC, gradient 0 to 30% methanol in dichloromethane) to get the desired product (597.0 mg, 97.7%) as a solid. 1H NMR (DMSO-d6, 400 MHz) δ ppm 7.26 (br s, 2H), 4.03 (br s, 2H), 3.84 (s, 3H), 2.02 (s, 3H); LC-MS m/z (method A)=155.2 [M+H]+, RT=0.35 min.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1.CC(O)=O.N[C@@H:15]([CH2:17][OH:18])[CH3:16]>O>[OH:18][CH2:17][C@H:15]([NH:1][C:2]1[N:7]=[C:6]([SH:8])[N:5]=[C:4]([OH:9])[CH:3]=1)[CH3:16]
Reactant: Nc1cc(O)nc(S)n1
Reactant: C[C@@H](N)CO
Solvent: CC(=O)O
Solvent: O
Product: C[C@H](CO)Nc1cc(O)nc(S)n1
Temperature: 50 °C

Procedure:
6-Amino-2-mercapto-4-pyrimidinol (16.1 g), AcOH (14.3 ml) and (R)-Alaninol (39 ml) were heated at 170° C. for 5 h. The mixture was cooled to approximately 50° C., diluted with water (500 ml) and cooled at 0° C. for 20 h. The resulting solid was filtered, washed with water and dried in vacuo to yield a mixture of subtitle product and starting material (2:1) as a cream coloured solid. Yield 7.2 g.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([O:11]C)[C:9]=1[OH:10])[CH:5]=[O:6].B(Br)(Br)Br>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([OH:11])[C:9]=1[OH:10])[CH:5]=[O:6]
Reactant: COc1cc(C=O)cc(Br)c1O
Agent: BrB(Br)Br
Solvent: ClCCl
Product: O=Cc1cc(O)c(O)c(Br)c1
Reaction time: 0.33 h
Yield: 10.2 %

Procedure:
To a solution of the compound of Example (a) (12.1 g, 0.52 mol) in CH2Cl2 (200 mL) was added 1.0 M boron tribromide in CH2Cl2 (2.2 eq, 115 mL) at 0°. The reaction was stirred at 0° for 20 min, then at ambient temperature for 2.5 h. The reaction was then cooled to 0°, and quenched by the slow addition of methanol. The solvents were removed under reduced pressure and the trimethyl borate was removed by azeotropation with added methanol. Vacuum drying yielded a dark green-brown solid (11.51 g, 100%) which was used without further purification: MS (ES) m/z 217.2. (M+H)+.
Reaction SMILES: [F:1][C:2]1[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])=[CH:10][C:9]([N+:18]([O-])=O)=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5]>CCO.O.[Pd]>[NH2:18][C:9]1[CH:10]=[C:11]([N:12]2[CH2:16][CH2:15][CH2:14][C:13]2=[O:17])[C:2]([F:1])=[C:3]([CH:8]=1)[C:4]([O:6][CH3:7])=[O:5]
Reactant: COC(=O)c1cc([N+](=O)[O-])cc(N2CCCC2=O)c1F
Agent: [Pd]
Solvent: CCO
Solvent: O
Product: COC(=O)c1cc(N)cc(N2CCCC2=O)c1F
Temperature: 25 °C
Yield: 62.7 %

Procedure:
To a solution of methyl 2-fluoro-5-nitro-3-(2-oxo-1-pyrrolidinyl)benzoate (D140) (3.3 g, 11.7 mmol, 1 equiv) in EtOH (100 ml) and H2O (10 ml) were added NH4COOH (7.4 g, 117 mmol, 10 equiv) and 10% palladium on charcoal (50% wet, 660 mg, 10% w/w) and the resulting mixture was refluxed for 2 h then cooled to room temperature. The catalyst was removed by filtration through a pad of celite and most of the solvent removed in vacuo. The residue was partitioned between AcOEt and H2O and the two layers were separated. The organic phase was dried over MgSO4 and concentrated in vacuo to give methyl 5-amino-2-fluoro-3-(2-oxo-1-pyrrolidinyl)benzoate (D150) (1.85 g, 63%) as a pale yellow solid which was used in the next step without further purification. [M+H]+=253.0, RT=2.12 min.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1)=[O:11].C([O-])([O-])=O.[Na+].[Na+].[F:31][C:32]1[CH:37]=[CH:36][C:35](B(O)O)=[CH:34][CH:33]=1>COCCOC>[F:31][C:32]1[CH:37]=[CH:36][C:35]([C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=2[CH2:8][CH2:9][C:10]([N:12]([CH:22]([CH3:24])[CH3:23])[NH:13][C:14](=[O:21])[C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)=[O:11])=[CH:34][CH:33]=1
Reactant: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1Br
Reactant: OB(O)c1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Product: CC(C)N(NC(=O)c1ccccc1)C(=O)CCc1ccccc1-c1ccc(F)cc1
Yield: 78 %

Procedure:
A solution of benzoic acid N′-[3-(2-bromo-phenyl)-propionyl]-N′-isopropyl-hydrazide (50 mg, 0.13 mmol) in DME (4 ml)/2M Na2CO3 (225 μL, 0.45 mmol) was treated with 4-fluoro-phenylboronic acid (29 mg, 0.19 mmol) and Pd[PPh3]4 (15 mg, 0.013 mmol) for 18 hours at 90° C. The reaction mixture was partitioned between water and dichloromethane. The organic layer was washed with brine, dried over sodium sulfate, filtered, and concentrated. The crude was absorbed on silica and purified on a silica gel column with a 20-50% ethyl acetate/hexanes gradient to afford the product as a solid (41 mg, 79%). LC-MS m/e 405.25 (M+H+)
Reaction SMILES: [CH3:1][OH:2].[Na].Cl[C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1>C(O)(=O)C>[CH3:1][O:2][C:5]1[N:14]2[CH:15]=[C:16]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][C:19]=3[F:24])[N:17]=[C:13]2[C:12]2[CH2:11][CH2:10][CH2:9][CH2:8][C:7]=2[N:6]=1
Reactant: Fc1ccccc1-c1cn2c(Cl)nc3c(c2n1)CCCC3
Reactant: CO
Agent: [Na]
Solvent: CC(=O)O
Product: COc1nc2c(c3nc(-c4ccccc4F)cn13)CCCC2

Procedure:
To 10 mL anhydrous methanol was added 100 mg of sodium, and the mixture was stirred to ensure all the sodium had dissolved. Next, 5-Chloro-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (200 mg) was added and the mixture refluxed for 1 h. To this mixture was added 2 mL of acetic acid and the solvent was then removed under reduced pressure. The resulting solid was recrystallized from ethanol and collected to yield 5-Methoxy-2-(2-fluorophenyl)-7,8,9,10-tetrahydro-imidazo[1,2-c]-quinazoline (Compound 37), m.p. 160-161° C.