Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH2:9])([CH3:4])([CH3:3])[CH3:2].C[O:15][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH:22]=2)=O.C1CCN2C(=NCCC2)CC1>CC(N(C)C)=O>[C:1]([O:5][C:6](=[O:13])[CH:7]([CH:10]1[CH2:12][CH2:11]1)[CH2:8][NH:9][C:16]([C:18]1[N:19]=[CH:20][C:21]2[C:26]([C:27]=1[OH:28])=[CH:25][CH:24]=[C:23]([O:29][C:30]1[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=1)[CH:22]=2)=[O:15])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)C(CN)C1CC1
Reactant: COC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O
Solvent: CC(=O)N(C)C
Solvent: C1CCC2=NCCCN2CC1
Product: CC(C)(C)OC(=O)C(CNC(=O)c1ncc2cc(Oc3ccccc3)ccc2c1O)C1CC1
Temperature: 150 °C
Yield: 97.8 %

Procedure:
A mixture of 3-amino-2-cyclopropyl-propionic acid tert-butyl ester (66 mg), 4-hydroxy-7-phenoxy-isoquinoline-3-carboxylic acid methyl ester (35 mg) and DBU (0.027 mL) in DMA (1 mL) was heated in an oil bath (150° C.) for 1 h. The reaction mixture was then partitioned between EtOAc and diluted HCl solution, EtOAc phase was separated and washed with water, diluted NaCl solution and dried over anhydrous sodium sulfate solution, filtered, concentrated and silica gel column purified to give desired product as brown solid (52 mg). LC-MS ESI+: 449 (M+1)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=3)[CH:11]=[C:10]([CH3:24])[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>>[CH3:24][C:10]1[CH:11]=[C:12]([C:14]2[CH:19]=[CH:18][C:17]([C:20]([F:23])([F:22])[F:21])=[CH:16][CH:15]=2)[N:13]=[C:8]([C:4]2[CH:3]=[C:2]([C:29]3[CH:30]=[CH:31][C:26]([NH2:25])=[N:27][CH:28]=3)[CH:7]=[CH:6][CH:5]=2)[N:9]=1
Reactant: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(Br)c2)n1
Reactant: CC1(C)OB(c2ccc(N)nc2)OC1(C)C
Product: Cc1cc(-c2ccc(C(F)(F)F)cc2)nc(-c2cccc(-c3ccc(N)nc3)c2)n1

Procedure:
The title compound was prepared from 2-(3-bromo-phenyl)-4-(4-trifluoromethyl-phenyl)-6-methyl-pyrimidine (example E.47) (0.197 g, 0.5 mmol) and commercially available 2-amino-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (0.14 g, 0.65 mmol) according to the general procedure VI. Obtained as an off-white solid (0.097 g, 48%). MS (ISP) 407.3 [(M+H)+]; mp 224° C.
Reaction SMILES: [CH3:1][C:2]1([CH3:12])[O:6][C@@H:5]([CH:7]=[N:8][OH:9])[C:4]([CH3:11])([CH3:10])[O:3]1.[Cl:13]N1C(=O)CCC1=O.O>CN(C=O)C>[OH:9][N:8]=[C:7]([Cl:13])[C@H:5]1[C:4]([CH3:11])([CH3:10])[O:3][C:2]([CH3:12])([CH3:1])[O:6]1
Reactant: CC1(C)O[C@@H](C=NO)C(C)(C)O1
Reactant: O=C1CCC(=O)N1Cl
Solvent: CN(C)C=O
Solvent: O
Product: CC1(C)O[C@@H](C(Cl)=NO)C(C)(C)O1
Temperature: 25 °C
Reaction time: 8 h
Yield: 79.5 %

Procedure:
(S)-2,2,5,5-Tetramethyl-1,3-dioxolane-4-carbaldehyde oxime (13 g, 75.1 mmol) was dissolved in DMF (200 mL) and cooled in an ice bath. 1-Chloropyrrolidine-2,5-dione (10.0 g, 75.1 mmol) was added and the reaction was stirred overnight while slowly warming to ambient temperature. The pale yellow solution was poured into water (1.5 L) and extracted with EtOAc. The organic layers were washed with water and brine, dried, filtered and concentrated. The residue was purified over silica gel (40% EtOAc in hexanes) to afford (R)—N-hydroxy-2,2,5,5-tetramethyl-1,3-dioxolane-4-carbimidoyl chloride (12.4 g, 59.7 mmol, 79.6% yield).
Reaction SMILES: S(Cl)(Cl)=O.[CH:5](N(C(C)C)CC)(C)C.[CH3:14][O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20]>C(O)C>[CH2:14]([O:15][C:16](=[O:31])[C@H:17]([CH2:29][OH:30])[NH:18][C:19]([O:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH3:5]
Reactant: CCN(C(C)C)C(C)C
Reactant: COC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Solvent: O=S(Cl)Cl
Solvent: CCO
Product: CCOC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Reaction time: 16 h

Procedure:
Thionyl chloride (5.25 mL, 72 mmol, 3.6 equiv.) is added dropwise to a 0° C. solution of absolute ethyl alcohol (20 ml). Diisopropyl ethylamine (3.45 ml, 19. mmol, 1 equiv.) was added and then 4.8 g of N-CBZ-L-serine methyl ester was added as a solid. Stirring is continued for 16 hours at room temperature. The ethanol and thionyl chloride are then removed by rotary evaporation and the residue is dissolved in ethyl acetate (200 ml). The organic phase is washed with 1N hydrochloric acid (50 ml) and saturated sodium bicarbonate (50 ml) and brine (20 ml). The organic layer is dried with magnesium sulfate. Rotary evaporation of the product gives an oil which is chromatographed on silica gel with hexane/ethyl acetate (3:1) to give N-CBZ-L-serine ethyl ester.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[C:6](=[CH:7][C:8](F)=[CH:9][CH:10]=2)[C:5]([Br:13])=[CH:4][N:3]=1.[NH2:14][NH2:15].C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:5]1[C:6]2[C:11](=[CH:10][CH:9]=[C:8]([NH:14][NH2:15])[CH:7]=2)[C:2]([NH2:1])=[N:3][CH:4]=1
Reactant: Nc1ncc(Br)c2cc(F)ccc12
Reactant: NN
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: NNc1ccc2c(N)ncc(Br)c2c1
Temperature: 100 °C
Reaction time: 16 h
Yield: 64 %

Procedure:
A solution of 1-amino-4-bromo-6-fluoro-isoquinoline (0.1179 g, 0.49 mmol), and hydrazine (0.5 mL) in THF (5 mL) is microwaved at 100° C. for 40 min. Then it is placed in an oil bath and is stirred at 100° C. for 16 h. The reaction mixture is cooled to RT. It is treated with NaHCO3 (satd. aq, 10 mL). The aqueous phase is extracted with EtOAc (2×). The combined organic layers are washed with brine, and dried over MgSO4. The solvent is evaporated and the residue is dried under vacuum to afford 0.079 g (64%) of 4-Bromo-6-hydrazino-isoquinolin-1-ylamine. LC/MS m/z=254 [M+H]+.
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([OH:22])=O)[NH:12][C:13]([O:15][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:14])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:24]([NH2:28])[CH2:25][CH2:26][CH3:27].CCN=C=NCCCN(C)C.Cl.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C.O>[CH2:1]([O:8][C:9](=[O:23])[CH2:10][C@@H:11]([C:20]([NH:28][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22])[NH:12][C:13]([O:15][C:16]([CH3:17])([CH3:18])[CH3:19])=[O:14])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N[C@@H](CC(=O)OCc1ccccc1)C(=O)O
Reactant: CCCCN
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Product: CCCCNC(=O)[C@H](CC(=O)OCc1ccccc1)NC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
4.27 g of N-(tert-butoxycarbonyl)aspartic acid-4-benzyl ester and 1.31 mL of n-butyl amine were dissolved in 25 mL of DMF, and then 2.93 g of WSC hydrochloride and 1.93 g of HOBt were added thereto, and the reaction solution was stirred at room temperature overnight. The reaction solution was added with water, and extracted with ethyl acetate. The organic layer was washed with a saturated aqueous solution of ammonium chloride and a saturated aqueous solution of sodium hydrogen carbonate, dried with magnesium sulfate, and then distilled under reduced pressure to remove ethyl acetate, and then dried under vacuum, thereby to give 5.12 g of Compound 6.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH2:8][CH2:9][OH:10])[CH:5]=[CH:6][CH:7]=1.C(=O)([O-])O.[Na+].[C:16](OC(=O)C)(=[O:18])[CH3:17]>O1CCOCC1.O>[OH:10][CH2:9][CH2:8][C:4]1[CH:3]=[C:2]([O:1][C:16](=[O:18])[CH3:17])[CH:7]=[CH:6][CH:5]=1
Reactant: CC(=O)OC(C)=O
Reactant: OCCc1cccc(O)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)Oc1cccc(CCO)c1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
2-(3-Hydroxyphenyl)ethanol (400 mg, 2.90 mmol) was dissolved in a mixture of 4 ml of dioxane and 4 ml of water, and sodium hydrogencarbonate (2.43 g, 29 mmol) was added followed by acetic anhydride (2.96 g, 29 mmol) with ice cooling. The mixture was stirred overnight at room temperature and then partitioned between 2 N hydrochloric acid and EA. The aqueous phase was extracted with EA, the combined organic phases were dried over sodium sulfate and evaporated to dryness to yield the crude title compound which was used without further purification.
Reaction SMILES: [CH2:1]([NH:4][P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8])[CH2:2][CH3:3].[S:13](Cl)[Cl:14].Cl.C(N(CC)CC)C>CCCCCC.C(N(CC)CC)C>[Cl:14][S:13][N:4]([CH2:1][CH2:2][CH3:3])[P:5](=[S:12])([O:9][CH2:10][CH3:11])[O:6][CH2:7][CH3:8]
Reactant: ClSCl
Reactant: CCCNP(=S)(OCC)OCC
Agent: Cl
Solvent: CCCCCC
Solvent: CCN(CC)CC
Product: CCCN(SCl)P(=S)(OCC)OCC
Reaction time: 0.5 h

Procedure:
A solution of 2.98 gm. (0.014 mole) O,O-diethyl n-propylphosphoramidothioate in 10 ml. hexane and 2 ml. triethylamine is added to a cold (0° C.) solution of 1.0 ml. (0.016 mole) sulfur dichloride in 10 ml. hexane slowly and with stirring. There is vigorous reaction and heavy precipitation of triethylamine hydrochloride. An additional 20 ml. hexane is added. The reaction mixture is kept at 0° to 5° C. and stirred for 30 minutes, then it is filtered. The filtrate is concentrated to a pale yellow oil by evaporating the hexane under reduced pressure. The oil comprises the desired O,O-diethyl N-(chlorothio)-n-propylphosphoramidothioate which can be used for further reactions with N-methylcarbamates.
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:10]=[CH:9][C:8]([S:11](Cl)(=[O:13])=[O:12])=[CH:7][CH:6]=1)(=[O:3])[CH3:2].[NH2:15][C:16]1[S:17][C:18]([CH2:21][OH:22])=[N:19][N:20]=1.Cl>N1C=CC=CC=1>[OH:22][CH2:21][C:18]1[S:17][C:16]([NH:15][S:11]([C:8]2[CH:9]=[CH:10][C:5]([NH:4][C:1](=[O:3])[CH3:2])=[CH:6][CH:7]=2)(=[O:13])=[O:12])=[N:20][N:19]=1
Reactant: Nc1nnc(CO)s1
Reactant: CC(=O)Nc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: c1ccncc1
Product: CC(=O)Nc1ccc(S(=O)(=O)Nc2nnc(CO)s2)cc1
Temperature: 25 °C
Reaction time: 4.5 h
Yield: 82 %

Procedure:
To a solution of p-acetamidobenzenesulfonyl chloride (510 mg, 2.18 mmol) in pyridine (6 mL) was added 2-amino-5-hydroxymethyl-1,3,4-thiadiazole (260 mg, 1.98 mmol). The reaction mixture was stirred at room temperature for 4.5 h, then 2 M HCl (20 mL) was added to quench the reaction. The mixture was extracted with ethyl acetate (4×50 mL). The organic extracts were washed with water (40 mL), brine (40 mL), dried over Na2SO4, filtered, and concentrated. The residue was purified by chromatography on silica gel (70-230 mesh) eluted with CH2Cl2:methanol 9:1 to give the product as a solid, mp 101-102° C., in 82% yield (533 mg, 1.62 mmol); 1H NMR (300 MHz, DMSO-d6) δ 2.07 (s, 3H), 4.56 (d, 2H, J=5.1 Hz), 6.09 (t, 1H, J=4.8 Hz), 7.73 (m, 4H); 13C NMR (75 MHz, DMSO-d6) δ 24.8, 59.1, 119.3, 127.7, 136.2, 143.5, 161.7, 168.1, 169.6; MS (LCQ, ESI+) Calcd for C11H13N4O4S2 329.0. found 329.1 (M+H)+; HRMS (ESI+, m/z) Calcd for C11H13N4O4S2 329.0378. found 329.0376 (M+H)+.
Reaction SMILES: [OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][NH:10][CH2:11][C@@H:6]2[CH2:5][CH2:4]1.Cl[C:14]1[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=1.C(=O)([O-])[O-].[Na+].[Na+]>O>[OH:1][CH2:2][C@@H:3]1[CH2:12][N:7]2[CH2:8][CH2:9][N:10]([C:14]3[N:19]=[CH:18][C:17]([F:20])=[CH:16][N:15]=3)[CH2:11][C@@H:6]2[CH2:5][CH2:4]1
Reactant: OC[C@H]1CC[C@H]2CNCCN2C1
Reactant: Fc1cnc(Cl)nc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: O
Product: OC[C@H]1CC[C@H]2CN(c3ncc(F)cn3)CCN2C1
Temperature: 25 °C
Yield: 74.5 %

Procedure:
A mixture of 2.31 g (13.6 mmol) of (7S,9aS)-7-hydroxymethyl-2,3,4,6,7,8,9,9a-octahydro-1H-pyrido[1,2-a]pyrazine (Preparation 2), 1.98 g (15.0 mmol) of 2-chloro-5-fluoropyrimidine (B. Baasner, E. Klauke, J. Fluorine Chem., 1989, 45, 417), 4.32 g (40.8 mmol) of sodium carbonate and 50 mL of water was heated at reflux for 16 h. The mixture was cooled to room temperature and extracted with chloroform (3×). The combined organic layers were dried (magnesium sulfate), filtered and evaporated. Purification by flash silica gel chromatography with 95:5 chloroform:methanol gave 2.7 g (75%) of the title compound. mp (base) 111-112° C. 13C NMR (base, CDCl3): δ26.5, 27.3, 34.2, 44.3, 49.8, 54.8, 58.8, 60.7, 68.2, 145.0, 145.3, 149.9, 153.2, 158.6. HRMS calcd for C13H19FN4O: 266.1543, found: 266.1530.
Reaction SMILES: O=[C:2]1[CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[CH2:6][CH2:5][CH2:4][NH:3]1.F[B-](F)(F)F.C[O+](C)C.[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]([NH:32][NH2:33])=O)[CH:27]=[CH:26][C:25]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1>C(#N)C>[CH3:22][O:23][C:24]1[N:29]=[C:28]([C:30]2[N:3]3[CH2:4][CH2:5][CH2:6][CH:7]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[C:2]3=[N:33][N:32]=2)[CH:27]=[CH:26][C:25]=1[N:34]1[CH:38]=[C:37]([CH3:39])[N:36]=[CH:35]1
Reactant: COc1nc(C(=O)NN)ccc1-n1cnc(C)c1
Reactant: CCOC(=O)C1CCCNC1=O
Agent: C[O+](C)C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CCOC(=O)C1CCCn2c(-c3ccc(-n4cnc(C)c4)c(OC)n3)nnc21
Temperature: 25 °C
Reaction time: 2 h
Yield: 40.1 %

Procedure:
To a mixture of ethyl 2-oxopiperidine-3-carboxylate (3.5 g) in acetonitrile (100 mL) was added trimethyloxonium tetrafluoroborate (3.0 g) at room temperature, and the mixture was stirred at room temperature for 2 hr. 6-Methoxy-5-(4-methyl-1H-imidazol-1-yl)pyridine-2-carbohydrazide (5.0 g) was added to the reaction mixture at room temperature, and the solvent was evaporated under reduced pressure. Methanol (100 mL) was added to the residue at room temperature, and the mixture was stirred for 2 hr under reflux. The solvent in the reaction mixture was evaporated under reduced pressure, acetonitrile (100 mL) was added to the residue at room temperature, and the mixture was stirred at 80° C. overnight. The solvent in the reaction mixture was evaporated under reduced pressure, the residue was diluted with ethyl acetate and saturated aqueous sodium hydrogen carbonate solution, the mixture was washed with saturated brine and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue of another lot synthesized similarly was combined, and the mixture was purified by silica gel column chromatography (methanol/ethyl acetate) to give the title compound (3.1 g).
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.[OH-].[Na+].[CH2:12](Br)[CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH3:23].Cl>CN(C)P(N(C)C)(N(C)C)=O>[C:1]([O:9][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH3:12])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: CCCCCCCCCCCCBr
Reactant: O=C(O)c1cccnc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: CCCCCCCCCCCCOC(=O)c1cccnc1
Reaction time: 24 h
Yield: 77.2 %

Procedure:
In 100 ml of hexamethylphosphoramide was dissolved 4.9 g (0.04 mol) of nicotinic acid, and a 25% aqueous solution of sodium hydroxide (0.06 mol) was added thereto, followed by stirring using a magnetic stirrer at room temperature for 1 hour. To the mixture was further added 29.8 g (0.12 mol) of lauryl bromide, and the stirring was continued for an additional 24 hours. The reaction mixture was added to 200 ml of a 5% aqueous solution of hydrochloric acid and extracted with diethyl ether. The extract was washed with water, dried over sodium sulfate and distilled to remove the solvent. The residue was purified by column chromatography (Wakogel C-300, benzene:ethyl acetate=6:1 v/v) and recrystallized from methyl alcohol at 1° C. to obtain 9 g of n-dodecyl nicotinate as a colorless liquid in a yield of 77%, based on the nicotinic acid.
Reaction SMILES: [NH2:1][CH2:2][C:3]([CH3:6])([OH:5])[CH3:4].S=[C:8]1[CH2:12][S:11][C:10](=[O:13])[NH:9]1>C(O)C>[OH:5][C:3]([CH3:6])([CH3:4])[CH2:2][NH:1][C:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]=1
Reactant: O=C1NC(=S)CS1
Reactant: CC(C)(O)CN
Solvent: CCO
Product: CC(C)(O)CNC1=NC(=O)SC1
Temperature: 25 °C
Reaction time: 6 h
Yield: 92 %

Procedure:
To a solution of 1-amino-2-methylpropan-2-ol (2.61 g) in ethanol (30 mL) was added 4-thioxo-1,3-thiazolidin-2-one (3 g), and the mixture was stirred at room temperature for 6 hr. The reaction mixture was concentrated, and the residue was washed with ethanol to give the title compound (3.90 g).
Reaction SMILES: C(=O)(O)O.[NH:5]([C:7](=[NH:9])[NH2:8])[NH2:6].[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14](Cl)=[O:15].[OH-].[Na+]>N1C=CC=CC=1.O>[Cl:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][C:19]=1[Cl:20])[C:14]([NH:6][NH:5][C:7](=[NH:8])[NH2:9])=[O:15]
Reactant: N=C(N)NN
Reactant: O=C(Cl)c1ccc(Cl)c(Cl)c1
Agent: O=C(O)O
Agent: [Na+]
Agent: [OH-]
Solvent: c1ccncc1
Solvent: O
Product: N=C(N)NNC(=O)c1ccc(Cl)c(Cl)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 40.3 %

Procedure:
To a solution of hydrazinecarboximidamide carbonic acid salt (15.6 g, 114.61 mmol) in pyridine (100 ml) was added 3,4-dichlorobenzoyl chloride (20 g, 95.48 mmol), and the resulting mixture was stirred overnight at room temperature, then concentrated under vacuum to give a residue, which was dissolved in water (30 ml) and adjusted to pH 12 with sodium hydroxide (aq., sat). The product precipitated and was collected by filtration and dried in an oven under reduced pressure to afford 2-(3,4-dichlorobenzoyl)hydrazinecarboximidamide as a light yellow solid (9.5 g, 40%).
Reaction SMILES: [C:1]([N:20]1[CH:24]=[C:23](I)[N:22]=[CH:21]1)([C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CC[Mg+].[Br-].[CH3:30][C:31]1[C:32]([CH:36]=[O:37])=[CH:33][S:34][CH:35]=1>C(Cl)Cl>[CH3:30][C:31]1[C:32]([CH:36]([C:23]2[N:22]=[CH:21][N:20]([C:1]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)([C:8]3[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=3)[C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)[CH:24]=2)[OH:37])=[CH:33][S:34][CH:35]=1
Reactant: Ic1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reactant: Cc1cscc1C=O
Agent: CC[Mg+]
Agent: [Br-]
Solvent: ClCCl
Product: Cc1cscc1C(O)c1cn(C(c2ccccc2)(c2ccccc2)c2ccccc2)cn1
Reaction time: 3 h

Procedure:
To a solution of N-trityl-4-iodo-imidazole (11.8 g, 27 mmol) in dry CH2Cl2 (75 mL) was added EtMgBr (10.0 mL, 3.0M in Et2O), and the solution was stirred for 3 hrs. Then a solution of 4-methylthiophene-3-carboxaldehyde (3.3 g, 27 mmol) in CH2Cl2 (25 mL) was added. The reaction mixture was stirred at room temperature overnight and then was quenched with aqueous NH4Cl. The mixture was transferred to a separatory funnel, and the aqueous layer was extracted with a second portion of CH2Cl2. The combined extracts were washed with a small portion of water, dried (Na2SO4), and filtered. The solvent was evaporated in vacuo to give a thick syrup which was triturated with Et2O to give a solid which was recrystallized with charcoal treatment from EtOAc to give (4-methylthien-3-yl)-1-trityl-imidazol-4-yl-methanol, B2. 1H NMR (CDCl3) supported the assigned structure. ##STR39##
Reaction SMILES: [NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10](I)=[CH:9][CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1.C[Sn](C)(C)[C:20]1[O:21][CH:22]=[CH:23][CH:24]=1>>[NH2:1][C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([C:20]3[O:21][CH:22]=[CH:23][CH:24]=3)=[CH:9][CH:8]=2)[C:5]2[CH:14]=[CH:15][CH:16]=[CH:17][C:4]=2[N:3]=1
Reactant: Nc1nc2ccccc2n1-c1ccc(I)cc1
Reactant: C[Sn](C)(C)c1ccco1
Product: Nc1nc2ccccc2n1-c1ccc(-c2ccco2)cc1

Procedure:
2-Amino-1-[4-(2-furyl)phenyl]benzimidazole was prepared from 1 -(2-amino-1-benzimidazolyl)-4-iodobenzene and 2-trimethylstannylfuran according to method C, mp 210°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:23]=[C:22]([O:24]C)[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19].B(Br)(Br)Br.C(Cl)Cl>ClC(Cl)C>[Cl:1][C:2]1[CH:23]=[C:22]([OH:24])[CH:21]=[CH:20][C:3]=1[CH2:4][CH:5]1[CH2:9][CH2:8][N:7]([CH:10]2[CH2:18][CH2:17][C:16]3[C:12](=[CH:13][NH:14][N:15]=3)[CH2:11]2)[C:6]1=[O:19]
Reactant: COc1ccc(CC2CCN(C3CCc4n[nH]cc4C3)C2=O)c(Cl)c1
Agent: BrB(Br)Br
Solvent: CC(Cl)Cl
Solvent: ClCCl
Product: O=C1C(Cc2ccc(O)cc2Cl)CCN1C1CCc2n[nH]cc2C1
Temperature: 25 °C
Reaction time: 4 h
Yield: 78 %

Procedure:
Cool a solution of 3-(2-Chloro-4-methoxy-benzyl)-1-(4,5,6,7-tetrahydro-2H-indazol-5-yl)-pyrrolidin-2-one (3.0 g, 8.3 mmol) in dichloroethane (100 mL) to −78° C. Treat the solution with 1.0M Boron tribromide in CH2Cl2 (46 mL, 46 mmol) and allow the reaction to warm to room temp and stir for 4 hr. Then, cool the reaction to 0° C. and quench with water. Extract the organic with CHCl3, wash with brine, dry over MgSO4, filter, and remove the solvent. Purify the crude by silica gel column chromatography using 10% EtOH in CHCl3 to elute the pure product. Remove the solvent to afford 2.24 g (78%) of product. MS (m/e): 364 (M+1).
Reaction SMILES: [N+]([CH2:4][CH3:5])([O-])=O.ClCCl.[N+]([C:12]1[CH:20]=[CH:19][C:15]([C:16](Cl)=[O:17])=[CH:14][CH:13]=1)([O-])=O.[Cl-].[Al+3].[Cl-].[Cl-]>C(Cl)(Cl)Cl>[C:16]([C:5]1[CH:4]=[CH:14][CH:13]=[CH:12][CH:20]=1)(=[O:17])[C:15]1[CH:19]=[CH:20][CH:12]=[CH:13][CH:14]=1
Reactant: CC[N+](=O)[O-]
Reactant: O=C(Cl)c1ccc([N+](=O)[O-])cc1
Agent: [Al+3]
Agent: [Cl-]
Solvent: ClC(Cl)Cl
Solvent: ClCCl
Product: O=C(c1ccccc1)c1ccccc1
Temperature: 40 °C

Procedure:
A solution of polymer in a suitable solvent (nitroethane, dichloromethane, chloroform) was treated with 4-nitro benzoyl chloride (1 eq) and aluminium chloride (1.2 eq). The solution was stirred at room temperature or at 40° C. then quenched with water. The organic layer was collected and washed with 1M HCl and 1M NaOH solutions sequentially. Concentration of the organic layer yielded the product.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:19])([F:18])[F:17])[C:10](=[O:13])[NH:11][N:12]=2)=[CH:4][CH:3]=1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:28][C:29]1[CH:30]=[N:31][N:32]([C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=2[Cl:40])[CH:33]=1.O>C(#N)C>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]([CH2:14][C@H:15]([OH:20])[C:16]([F:18])([F:19])[F:17])[C:10](=[O:13])[N:11]([CH2:28][C:29]3[CH:30]=[N:31][N:32]([C:34]4[CH:39]=[CH:38][CH:37]=[CH:36][C:35]=4[Cl:40])[CH:33]=3)[N:12]=2)=[CH:4][CH:3]=1
Reactant: O=c1[nH]nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Reactant: Clc1ccccc1-n1cc(CBr)cn1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Solvent: O
Product: O=c1n(Cc2cnn(-c3ccccc3Cl)c2)nc(-c2ccc(Cl)cc2)n1C[C@H](O)C(F)(F)F
Temperature: 65 °C
Reaction time: 2 h

Procedure:
27 mg (0.09 mmol) of the compound from Example 5A were dissolved in 2 ml of acetonitrile, and 58 mg (0.18 mmol) of cesium carbonate and 24 mg (0.09 mmol) of the compound from Example 43A were added. The mixture was stirred at 65° C. for 2 h and then at RT for 20 h. For work-up, 5 ml of water were added and the mixture was extracted twice with in each case 10 ml of ethyl acetate. The organic phase was washed once with 5 ml of saturated sodium chloride solution, dried over sodium sulfate, filtered and concentrated under reduced pressure. The crude product was purified chromatographically [Method 19]. This gave 25 mg (56% of theory) of the target compound.
Reaction SMILES: [Br:1][C:2]1[NH:10][C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1.[Br:14][C:15]1[CH:22]=[CH:21][CH:20]=[CH:19][C:16]=1[CH2:17]Br>>[Br:1][C:2]1[N:10]([CH2:17][C:16]2[CH:19]=[CH:20][CH:21]=[CH:22][C:15]=2[Br:14])[C:9]2[C:8](=[O:11])[NH:7][C:6](=[O:12])[N:5]([CH3:13])[C:4]=2[N:3]=1
Reactant: BrCc1ccccc1Br
Reactant: Cn1c(=O)[nH]c(=O)c2[nH]c(Br)nc21
Product: Cn1c(=O)[nH]c(=O)c2c1nc(Br)n2Cc1ccccc1Br

Procedure:
8-Bromo-3-methyl-3,7-dihydropurine-2,6-dione and 2-bromobenzyl bromide were reacted and purified as described in the General procedure G, step A, to afford 80A.