Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: ClC(OCC(C)C)=O.[CH2:9]([N:11]1[CH2:16][CH2:15][N:14]([CH2:17][C:18]#[C:19][C:20]([OH:22])=O)[CH2:13][CH2:12]1)[CH3:10].CN1CCOCC1.N#N.[NH2:32][C:33]1[CH:34]=[C:35]2[C:40](=[CH:41][CH:42]=1)[N:39]=[CH:38][C:37]([C:43]#[N:44])=[C:36]2[NH:45][C:46]1[CH:51]=[CH:50][CH:49]=[C:48]([Br:52])[CH:47]=1>N1C=CC=CC=1>[Br:52][C:48]1[CH:47]=[C:46]([NH:45][C:36]2[C:35]3[C:40](=[CH:41][CH:42]=[C:33]([NH:32][C:20](=[O:22])[C:19]#[C:18][CH2:17][N:14]4[CH2:13][CH2:12][N:11]([CH2:9][CH3:10])[CH2:16][CH2:15]4)[CH:34]=3)[N:39]=[CH:38][C:37]=2[C:43]#[N:44])[CH:51]=[CH:50][CH:49]=1
Reactant: N#Cc1cnc2ccc(N)cc2c1Nc1cccc(Br)c1
Reactant: CCN1CCN(CC#CC(=O)O)CC1
Agent: CC(C)COC(=O)Cl
Agent: N#N
Solvent: c1ccncc1
Solvent: CN1CCOCC1
Product: CCN1CCN(CC#CC(=O)Nc2ccc3ncc(C#N)c(Nc4cccc(Br)c4)c3c2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Isobutyl chloroformate (0.785 g, 5.75 mmol) was dropwise added into an ice cold solution of 4-(N-ethylpiperazino)-2-butynoic acid (1.75 g, 8.85 mmol) and N-methylmorpholine (1.3453 g, 13.3 mmol) in 50 mL of tetrahydrofuan under N2. After stirring for 30 min, a solution of 1.5 g (4.42 mmol) of 6-amino-4-[(3-bromophenyl)amino]-3-quinolinecarbonitrile in 10 mL of pyridine was added dropwise and the mixture was stirred at 0° C. for 2 hr. The reaction was quenched with ice water, poured into saturated sodium bicarbonate and brine, and extracted with ethyl acetate. The ethyl acetate layer was concentrated and purified by flash column chromatography. The product fractions were collected, and dried in vacuo to give 1.07 g (46%) of light brown solid; ESMS m/z 517.1, 519.1 (M+H+); mp 161° C. (dec).
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:30])[CH2:15][O:16][C:17]1[CH:22]=[C:21]([CH:23]2[CH2:28][CH2:27][CH2:26][NH:25][CH2:24]2)[CH:20]=[CH:19][C:18]=1[CH3:29])[CH3:12].[F:31][C:32]([F:49])([F:48])[C:33]1[CH:47]=[CH:46][C:36]([CH2:37][O:38][C:39](N2C=CN=C2)=[O:40])=[CH:35][CH:34]=1>C(OCC)(=O)C>[F:31][C:32]([F:48])([F:49])[C:33]1[CH:47]=[CH:46][C:36]([CH2:37][O:38][C:39]([N:25]2[CH2:26][CH2:27][CH2:28][CH:23]([C:21]3[CH:20]=[CH:19][C:18]([CH3:29])=[C:17]([O:16][CH2:15][C:14]([O:13][CH2:11][CH3:12])=[O:30])[CH:22]=3)[CH2:24]2)=[O:40])=[CH:35][CH:34]=1
Reactant: O=C(OCc1ccc(C(F)(F)F)cc1)n1ccnc1
Reactant: CCOC(=O)COc1cc(C2CCCNC2)ccc1C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Product: CCOC(=O)COc1cc(C2CCCN(C(=O)OCc3ccc(C(F)(F)F)cc3)C2)ccc1C
Temperature: 25 °C
Reaction time: 18 h
Yield: 72.4 %

Procedure:
(2-methyl-5-piperidin-3-yl-phenoxy)-acetic acid ethyl ester L-tartaric acid salt (Example 12; 147 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 3 mL toluene and imidazole-1-carboxylic acid 4-trifluoromethyl-benzyl ester (93 mg, 0.34 mmol) was added. The reaction was stirred for 18 h at room temperature under nitrogen. The reaction was flash chromatographed with 15% ethyl acetate/hexanes to yield 118 mg (74%) of the desired 3-(3-ethoxycarbonylmethoxy-4-methyl-phenyl)-piperidine-1-carboxylic acid 4-trifluoromethyl-benzyl ester as a clear oil.
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([C:25]([OH:27])=O)[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1.[NH3:28]>>[NH:1]1[C:5]2[CH:6]=[CH:7][C:8]([C:10]([N:12]3[CH2:17][CH2:16][CH2:15][C@@H:14]4[C:18]5[CH:19]=[C:20]([C:25]([NH2:28])=[O:27])[CH:21]=[CH:22][C:23]=5[CH2:24][C@H:13]34)=[O:11])=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: O=C(O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Reactant: N
Product: NC(=O)c1ccc2c(c1)[C@H]1CCCN(C(=O)c3ccc4[nH]cnc4c3)[C@H]1C2
Yield: 64 %

Procedure:
The title compound is prepared from cis-1-(1H-benzoimidazole-5-carbonyl)-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine-6-carboxylic acid and ammonia (0.5 mol/L in 1,4-dioxane) following a procedure analogous to that described in Example 1. Yield: 64% of theory; LC (method 1): tR=1.64 min; Mass spectrum (ESI+): m/z=361 [M+H]+.
Reaction SMILES: O=[C:2]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][O:5][C:4]2[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=2.[NH2:17][CH:18]1[CH:23]2[CH2:24][CH2:25][N:20]([CH2:21][CH2:22]2)[CH2:19]1>C1C=CC=CC=1.[Ti](Cl)(Cl)(Cl)Cl>[N:20]12[CH2:25][CH2:24][CH:23]([CH2:22][CH2:21]1)[CH:18]([N:17]=[C:2]1[C:12]3[C:7](=[N:8][CH:9]=[CH:10][CH:11]=3)[CH2:6][O:5][C:4]3[CH:13]=[CH:14][CH:15]=[CH:16][C:3]1=3)[CH2:19]2
Reactant: O=C1c2ccccc2OCc2ncccc21
Reactant: NC1CN2CCC1CC2
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: c1ccccc1
Product: c1ccc2c(c1)OCc1ncccc1C2=NC1CN2CCC1CC2
Temperature: 25 °C
Reaction time: 48 h
Yield: 42.5 %

Procedure:
In this example, 2.1 g of 5-oxo-5,11-dihydro[1]benzoxepino[3,4-b]pyridine and 8.8 g of 3-aminoquinuclidine were dissolved in 50 ml of anhydrous benzene. Then, a solution of 1.1 g of titanium tetrachloride in 20 ml of anhydrous benzene was added dropwise thereto under ice cooling. The mixture was stirred under ice cooling for 3 hours and at room temperature for an additional two days. After completion of the reaction, the precipitate formed was filtered away, and the filtrate was concentrated under the reduced pressure. Then, 150 ml of ethyl acetate and 30 ml of water were added thereto and the mixture was shaken. The separated aqueous layer was removed, and the ethyl acetate layer was dried and concentrated. Purification of the residue by chromatography on silica gel, followed by concentration of the main fraction, gave 1.35 g of 5-(3-quinuclidinyl)imino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine as crystals. This product was dissolved in 20 ml of methanol and pH of the solution was adjusted to 5 with hydrochloric acid. Then, 1.0 g of sodium borocyanohydride was added thereto, and the mixture was heated at 40°-50° C. for 8 hours. After addition of 30 ml water, pH was adjusted to 12 with 1N aqueous sodium hydroxide solution, and the alkaline solution was extracted twice with 100 ml ethyl acetate. The ethyl acetate layer was dried and concentrated under reduced pressure, and the residue was purified by chromatography on silica gel. The main fraction was concentrated, whereby 1.0 g of 5-(3-quinuclidinyl)amino-5,11-dihydro[1]benzoxepino[3,4-b]pyridine (compound 25) as a diastereomeric mixture was obtained.
Reaction SMILES: C(OC1N=NC(C#CC2C=CC(C(F)(F)F)=CN=2)=CC=1OCC1C=CC=CC=1)C1C=CC=CC=1.[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[CH:58])=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][CH:37]=1.[F:59][CH:60]([F:69])[O:61][C:62]1[CH:67]=[CH:66][CH:65]=[C:64](I)[CH:63]=1>>[CH2:35]([O:42][C:43]1[N:44]=[N:45][C:46]([C:57]#[C:58][C:64]2[CH:65]=[CH:66][CH:67]=[C:62]([O:61][CH:60]([F:69])[F:59])[CH:63]=2)=[CH:47][C:48]=1[O:49][CH2:50][C:51]1[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=1)[C:36]1[CH:37]=[CH:38][CH:39]=[CH:40][CH:41]=1
Reactant: FC(F)Oc1cccc(I)c1
Reactant: C#Cc1cc(OCc2ccccc2)c(OCc2ccccc2)nn1
Agent: FC(F)(F)c1ccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)nc1
Product: FC(F)Oc1cccc(C#Cc2cc(OCc3ccccc3)c(OCc3ccccc3)nn2)c1
Yield: 87 %

Procedure:
Prepared as described for 3,4-bis(benzyloxy)-6-{[5-(trifluoromethyl)pyridin-2-yl]ethynyl}pyridazine (Intermediate 6) from 3,4-bis(benzyloxy)-6-ethynylpyridazine (Intermediate 5) and 1-(difluoromethoxy)-3-iodobenzene in 87% yield.
Reaction SMILES: C(N(CC)C(C)C)(C)C.[CH3:10][C:11]1[C:15]([CH3:16])=[C:14]([NH:17][S:18]([C:21]2[CH:25]=[CH:24][S:23][CH:22]=2)(=[O:20])=[O:19])[O:13][N:12]=1.[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31]Cl>C(Cl)Cl>[CH3:26][Si:27]([CH3:34])([CH3:33])[CH2:28][CH2:29][O:30][CH2:31][C:22]1[S:23][CH:24]=[CH:25][C:21]=1[S:18]([NH:17][C:14]1[O:13][N:12]=[C:11]([CH3:10])[C:15]=1[CH3:16])(=[O:19])=[O:20]
Reactant: C[Si](C)(C)CCOCCl
Reactant: Cc1noc(NS(=O)(=O)c2ccsc2)c1C
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1noc(NS(=O)(=O)c2ccsc2COCC[Si](C)(C)C)c1C
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 71.2 %

Procedure:
N,N-diisoproplyethylamine (222 μl, 128 mmol) was added to a solution of N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide (300 mg, 1.16 mmol) in methylene chloride (5 ml), and the mixture was stirred at room temperature for 15 min. The mixture was then cooled to 0° C. and 2-(trimethysilyl)ethoxy methyl chloride (SEM chloride) (226 μl, 1.28 mmol) was added dropwise via syringe, and the resultant yellow solution was stirred at room temperature for 5 hours. Evaporation of solvents left an oil which was extracted into ethyl acetate, washed with water and brine solution and dried over magnesium sulfate. Flash chromatography of the residue using 10% ethyl acetate/hexanes yielded 321 mg 2-[2-(trimethylsilyl)ethoxymethyl]-N-(3,4-dimethyl-5-isoxazolyl)thiophene-3-sulfonamide as a clear colorless oil which solidified into a white solid upon standing (71% yield).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7](Br)=[CH:6][C:5]=1[CH3:11].[C:13](B1OC(C)(C)C(C)(C)O1)([CH3:15])=[CH2:14].C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1>[CH3:1][O:2][C:3](=[O:12])[C:4]1[CH:9]=[CH:8][C:7]([C:13]([CH3:15])=[CH2:14])=[CH:6][C:5]=1[CH3:11]
Reactant: C=C(C)B1OC(C)(C)C(C)(C)O1
Reactant: COC(=O)c1ccc(Br)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: C1COCCO1
Product: C=C(C)c1ccc(C(=O)OC)c(C)c1
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 88.5 %

Procedure:
4-Bromo-2-methyl-benzoic acid methyl ester (4 g, 17.46 mmol), isopropenylboronic acid pinacol ester (3.228 g, 19.21 mmol) and cesium carbonate (19.913 g, 61.11 mmol) were treated with a degassed solution of 15 ml dioxane/5 ml water. After 5 min stirring [1,1′-bis(diphenylphosphino)ferrocene]dichloropalladium(II) complex (0.718 g, 0.873 mmol) was added and heated to 120° C. for 40 min in the microwave. The reaction mixture was filtered over cellulose; washed with 20 ml dioxane and concentrated in vacuo. The residue was purified by 120 g silica gel chromatography (gradient elution 0-50% ethyl acetate in hexane during 50 min) to yield 4-Isopropenyl-2-methyl-benzoic acid methyl ester (2.94 g, 15.45 mmol). MS (ESI) 191.3 (M+H)+
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:26])=[C:4]([CH2:12][N:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)[C:5]2[O:9][CH2:8][C:7](=[O:10])[C:6]=2[CH:11]=1.[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29]([CH:36]=O)=[CH:28]1>CO.N1CCCCC1>[NH:27]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[C:29](/[CH:36]=[C:8]2\[O:9][C:5]3[C:4]([CH2:12][N:13]4[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:23])([CH3:25])[CH3:24])=[O:20])[CH2:15][CH2:14]4)=[C:3]([OH:26])[C:2]([Cl:1])=[CH:11][C:6]=3[C:7]\2=[O:10])=[CH:28]1
Reactant: O=Cc1c[nH]c2ccccc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)c(Cl)cc3c2O/C(=C\c2c[nH]c4ccccc24)C3=O)CC1
Temperature: 40 °C
Reaction time: 2 h
Yield: 84.8 %

Procedure:
A solution of tert-butyl 4-[(5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.014 g, 0.037 mmol) in methanol (2.0 mL) was added with 1H-indole-3-carboxaldehyde (0.013 g, 0.090 mmol). Then, the mixture was added with 5 drops of piperidine, and then the mixture was stirred at 40° C. for 2 hours. The reaction mixture was cooled to room temperature, and then the solid was collected by filtration, and washed with methanol to obtain tert-butyl (Z)-4-({2-[(1H-indol-3-yl)methylene]-5-chloro-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.016 g, 85%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[C:8](=[O:10])[CH3:9].Br[CH2:12][C:13]([O:15][CH3:16])=[O:14].C(=O)([O-])[O-].[K+].[K+]>CC(C)=O.CCOC(C)=O>[C:8]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=1[O:1][CH2:12][C:13]([O:15][CH3:16])=[O:14])(=[O:10])[CH3:9]
Reactant: COC(=O)CBr
Reactant: CC(=O)c1ccccc1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: COC(=O)COc1ccccc1C(C)=O
Temperature: 25 °C
Yield: 98.7 %

Procedure:
1-(2-Hydroxyphenyl)ethanone (1.0 g, 7.3 mmol) and methyl bromoacetate (0.70 mL, 7.3 mmol) were combined in acetone (20.0 mL) with potassium carbonate (2.0 g, 15 mmol) and was stirred at room temperature. The reaction mixture was stirred for 18 h, diluted with EtOAc and filtered to remove the solids. The organic layer was concentrated to give the sub-title compound as a clear oil (1.5 g, 100%). LCMS calc. for C11H13O4 (M+H)+: m/z=209.1. found: 209.1.
Reaction SMILES: [P:1](=[O:7])([NH2:6])([S:4][CH3:5])[O:2][CH3:3].[C:8](OC(=O)C)(=[O:10])[CH3:9]>S(OC)(OC)(=O)=O>[C:8]([NH:6][P:1](=[O:7])([S:4][CH3:5])[O:2][CH3:3])(=[O:10])[CH3:9]
Reactant: COP(N)(=O)SC
Reactant: CC(=O)OC(C)=O
Solvent: COS(=O)(=O)OC
Product: COP(=O)(NC(C)=O)SC
Yield: 138.1 %

Procedure:
19.1 Grams of dimethyl sulfate were gradually added to 296 g (purity 86.3%) of O,O-dimethylphosphoramidothioate at 40° C. in 30 min and to the resultant were further added 1180 g of O,O-dimethyl phosphoramidothioate and 76.1 g of dimethyl sulfate at the same temperature over 2 hours separately. The resultant reaction mixture was further maintained at the temperature for 8 hours to obtain 1562 g of O,S-dimethyl phosphoramidothioate(purity: 79.1%). To 1562 g of obtained O,S-dimethyl phosphoramidothioate was added 1218 g of acetic anhydride and 41 g of dimethyl sulfate at 40° C. over an hour. The resultant was maintained at the temperature for an hour to complete the reaction to give 2799 g of crude O,S-dimethyl N-acetylphosphoramidothioate (purity: 49.13%).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][N+:8]([O-])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+].P(Br)(Br)([Br:16])=O>ClCCCl>[Br:16][C:9]1[CH:10]=[C:5]([C:1]([CH3:4])([CH3:3])[CH3:2])[CH:6]=[CH:7][N:8]=1
Reactant: O=P(Br)(Br)Br
Reactant: CC(C)(C)c1cc[n+]([O-])cc1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCCl
Product: CC(C)(C)c1ccnc(Br)c1
Temperature: 70 °C
Reaction time: 8 h
Yield: 14 %

Procedure:
In a round-bottomed flask, phosphorous oxybromide (5.0 g, 17.4 mmol and 4-tert-butylpyridine N-oxide (0.85 g, 5.34 mmol) were dissolved in 1,2-dichloroethane (35 mL). The reaction mixture was stirred at 70° C. overnight then cooled to room temperature and slowly poured onto ice. Sodium hydroxide (50% solution in water) was added slowly until pH˜10. The mixture was then extracted three times with ˜100 mL dichloromethane. The organic layers were combined, dried over sodium sulfate, filtered and concentrated. The residue was absorbed on 4 g SiO2 and chromatographed over 24 g SiO2 with EtOAc/Hexanes (gradient: 0-10% EtOAc). All fractions containing product were combined and concentrated to give 157 mg (14%) of 2-bromo-4-tert-butyl pyridine as a colorless oil.
Reaction SMILES: P(OP(O)=O)(O)=O.C(C(C(C)C)(C(C)C)C(C)C)(C)C.[CH2:21]1[C:29]2[C:25](=[CH:26][C:27]([P:40]([O:46]C(C)C)(=[O:45])[O:41]C(C)C)([P:30]([O:36]C(C)C)(=[O:35])[O:31]C(C)C)[CH:28]=2)[CH:24]=[CH:23][NH:22]1.ClCC1C=NC=CC=1CCl>>[CH2:21]1[C:29]2[C:25](=[CH:26][C:27]([P:30]([OH:35])(=[O:31])[OH:36])([P:40]([OH:46])(=[O:41])[OH:45])[CH:28]=2)[CH:24]=[CH:23][NH:22]1
Reactant: CC(C)OP(=O)(OC(C)C)C1(P(=O)(OC(C)C)OC(C)C)C=C2C=CNCC2=C1
Agent: CC(C)C(C(C)C)(C(C)C)C(C)C
Agent: ClCc1ccncc1CCl
Agent: O=[PH](O)O[PH](=O)O
Product: O=P(O)(O)C1(P(=O)(O)O)C=C2C=CNCC2=C1

Procedure:
Using the same procedure as in Example VII, tetraisopropyl methane diphosphonate is converted to tetraisopropyl dihydro-2-pyrindine-6,6-diphosphonate by reaction with 3,4-bis(chloromethyl)pyridine. The resulting ester is hydrolyzed as in Example VII to yield the dihydro-2-pyrindine-6,6-diphosphonic acid.
Reaction SMILES: [C:1]1([NH:7][C:8]([NH2:10])=[S:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CO[CH:13](OC)[N:14]([CH3:16])[CH3:15]>>[CH3:13][N:14]([CH3:16])[CH:15]=[N:10][C:8](=[S:9])[NH:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: COC(OC)N(C)C
Reactant: NC(=S)Nc1ccccc1
Product: CN(C)C=NC(=S)Nc1ccccc1

Procedure:
6.1 G. PHENYLTHIOUREA AND 4.3 G. DIMETHYL FORMAMIDE DIMETHYLACETAL WERE SUSPENDED IN 100 ML. OF BENZENE WITH ~ 100 MG OF P-TOLUENE SULFURIC ACID AND THE MIXTURE DISTILLED THROUGH A 6 PLATE DISTILLING COLUMN. The methanol-benzene azeotrope, bp 57°C, came off rapidly. After the bp rose to 80°C, the mixture was cooled and the product crystallized from the benzene. The yield was 6.3 g of solid m.p. 131°-138°C which was triturated with ether to give 6 g m.p. 139°-143°C.
Reaction SMILES: C(OC([N:11]1[CH2:15][C:14](=[O:16])[N:13]=[C:12]1[NH:17][CH2:18][C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][C:20]=1[Cl:26])=O)C1C=CC=CC=1.[N:27]1[C:36]2[C:31](=[N:32][C:33]([CH:37]=O)=[CH:34][CH:35]=2)[CH:30]=[CH:29][CH:28]=1.N1CCCCC1>CC(O)C>[Cl:26][C:20]1[CH:21]=[C:22]([F:25])[CH:23]=[CH:24][C:19]=1[CH2:18][NH:17][C:12]1[NH:11][C:15](=[CH:37][C:33]2[CH:34]=[CH:35][C:36]3[C:31](=[CH:30][CH:29]=[CH:28][N:27]=3)[N:32]=2)[C:14](=[O:16])[N:13]=1
Reactant: O=C1CN(C(=O)OCc2ccccc2)C(NCc2ccc(F)cc2Cl)=N1
Reactant: O=Cc1ccc2ncccc2n1
Solvent: C1CCNCC1
Solvent: CC(C)O
Product: O=C1N=C(NCc2ccc(F)cc2Cl)NC1=Cc1ccc2ncccc2n1
Temperature: 25 °C

Procedure:
To a mixture of 2-(2-chloro-4-fluoro-benzylamino)-4-oxo-4,5-dihydro-imidazole-1-carboxylic acid benzyl ester (70.1 mg, 0.19 mmol), 1,5-naphthyridine-6-carboxaldehyde (28.7 mg, 0.18 mmol) and iPrOH (5.0 mL) in a 25-mL round bottom flask was added piperidine (0.05 mL) and the suspension was then heated under refluxing for 4 hrs to give a suspension. The reaction mixture was cooled to r.t. and the solid was collected by filtration, washed with MeOH, and ether to give 2-(2-chloro-4-fluoro-benzylamino)-5-[1,5]naphthyridin-2-ylmethylene-1,5-dihydro-imidazol-4-one as a light yellow solid, 30.6 mg (43.0%). HR-ES (+) m/e calcd. for C19H13FClN5O: (M+H)+ 382.0866. Found: 382.0866.
Reaction SMILES: [CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[CH:4]=[CH:3][CH:2]=1.C([Li:18])CCC.CCCCCC>CCOCC>[CH:1]1[C:9]2[C:8]3[CH:10]=[CH:11][CH:12]=[CH:13][C:7]=3[O:6][C:5]=2[C:4]([Li:18])=[CH:3][CH:2]=1
Reactant: c1ccc2c(c1)oc1ccccc12
Reactant: [Li]CCCC
Solvent: CCCCCC
Solvent: CCOCC
Product: [Li]c1cccc2c1oc1ccccc12
Temperature: 25 °C
Reaction time: 20 h

Procedure:
Into a solution of dibenzo[b,d]furan (4.98 g, 29.6 mmol) in ether (50 mL) at −78° C. was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise and the solution was allowed to warm to room temperature and stirred for 20 h to yield a dibenzo[b,d]furan-4-yl lithium solution. Into a solution of 1,3-dibromobenzene (2.56 mL, 21.20 mmol) in ether (50 mL) was added n-butyllithium solution in hexane (2.5 M, 9.48 mL, 23.70 mmol) dropwise at −78° C. The reaction solution was stirred at this temperature for 3.5 h before adding into a solution of dichlorodiphenylsilane (4.88 mL, 23.70 mmol) in ether (50.0 mL) at −78° C. The resultant reaction solution was stirred at this temperature for 2 h before the dibenzo[b,d]furan-4-yl lithium solution prepared above was introduced dropwise. The reaction mixture was allowed to slowly warm to room temperature overnight at which time it was quenched with water, extracted with ether, and dried over Na2SO4. Upon filtration and evaporation of the solvent, the residue was purified by column chromatography on silica gel with hexane/DCM (9/1, v/v) as eluent to yield (3-bromophenyl)(dibenzo[b,d]furan-4-yl)diphenylsilane (6.2 g, 52%) as a white powder.
Reaction SMILES: [CH3:1][C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1.CO[CH:17](OC)[N:18]([CH3:20])[CH3:19]>C(#N)C.CN(C=O)C>[CH3:17][N:18]([CH3:20])/[CH:19]=[CH:1]/[C:2]1[C:7]([N+:8]([O-:10])=[O:9])=[CH:6][N:5]=[C:4]([C:11]([O:13][CH3:14])=[O:12])[CH:3]=1
Reactant: COC(=O)c1cc(C)c([N+](=O)[O-])cn1
Reactant: COC(OC)N(C)C
Solvent: CN(C)C=O
Solvent: CC#N
Product: COC(=O)c1cc(/C=C/N(C)C)c([N+](=O)[O-])cn1
Temperature: 140 °C

Procedure:
Method 1. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (3.5 g, 17.8 mmol), dimethylformamide dimethylacetal (DMF-DMA) (3.6 ml, 1.5 eq) in acetonitrile (35 mL) was heated in a microwave at 140° C. for 20 min. The solvent was removed. The residue (5.1 g) was carried onto the next step without further purification. Method 2. A mixture of methyl 4-methyl-5-nitropyridine-2-carboxylate (39.5 g, 0.19 mol) and DMF-DMA (30.6 g, 0.26 mol, 1.35 eq) in DMF (470 mL) was heated to 90° C. for 30 min. The solvent was removed in vacuo. The residue (78 g) was used without further purification in the next step.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16].F[B-](F)(F)F.[O:22]=[N+:23]=[O:24]>C(#N)C>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([N+:23]([O-:24])=[O:22])=[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[CH:11][CH:10]=2)[N:4]=[C:3]1[S:15][CH3:16]
Reactant: O=[N+]=O
Reactant: CSc1nc(-c2ccncc2)cc(=O)n1C
Agent: F[B-](F)(F)F
Solvent: CC#N
Product: CSc1nc(-c2ccncc2)c([N+](=O)[O-])c(=O)n1C
Reaction time: 2 h

Procedure:
3-Methyl-2-methylsulfanyl-6-pyridin-4-yl-3H-pyrimidin-4-one (1.0 g, 4.3 mmol) in 10 mL dry acetonitrile at 0° C. under nitrogen was added nitronium tetrafluoroborate (0.5 M in sulfolane, Aldrich Chemical, 17.2 mL, 8.6 mmol) at such a rate as to not let the internal temperature rise above 5° C. The suspension slowly became a homogeneous solution. The reaction was monitored by mass spec and after 2 h, no remaining starting material was observed. The acetonitrile was removed under reduced pressure and the resulting solution was loaded directly onto 90 g of silica. The product was eluted with 0% to 5% methanol/dichloromethane. M+1=279; NMR (CDCl3) s (3H; 2.7 ppm), s (3H; 3.6 ppm), d (2H; 7.5 ppm), d (2H; 8.7 ppm).
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1.C(O[C@@H:17]1[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]1[O:19][C:20](=[O:22])[CH3:21])(=O)C.[Si](S(C(F)(F)F)(=O)=O)(C)(C)C>C(#N)C>[NH2:1][C:2]1[N:3]([C@@H:17]2[O:29][C@H:28]([CH2:30][O:31][C:32](=[O:34])[CH3:33])[C@@H:23]([O:24][C:25](=[O:27])[CH3:26])[C@H:18]2[O:19][C:20](=[O:22])[CH3:21])[C:4]2[CH:10]=[C:9]([Cl:11])[C:8]([Cl:12])=[CH:7][C:5]=2[N:6]=1
Reactant: Nc1nc2cc(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC[C@H]1O[C@@H](OC(C)=O)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Agent: C[Si](C)(C)S(=O)(=O)C(F)(F)F
Solvent: CC#N
Product: CC(=O)OC[C@H]1O[C@@H](n2c(N)nc3cc(Cl)c(Cl)cc32)[C@H](OC(C)=O)[C@@H]1OC(C)=O
Temperature: 60 °C
Yield: 15.5 %

Procedure:
2-Amino-5,6-dichlorobenzimidazole (4) (3 g, 16 mmole) was dissolved in dry acetonitrile (150 ml) and stirred in an inert atmosphere at 60° C. BSA (4.37 ml, 17 mmole) was added and the mixture was stirred for 10 minutes. 1,2,3,5-tetra-O-acetyl-β-D-ribofuranose (5.09 g, 16 mmole) and TMSTf (3.29 ml, 17 mmole) were added to the clear solution and the mixture was allowed to stir at 60° C. for 1 hr. The mixture was concentrated under reduced pressure and separated on a silica column to yield 1.14 g (15%) of 2-amino-5,6-dichloro-1-(2,3,5,tri-O-acetyl-β-D-ribofuranosyl) benzimidazole (43). 13C NMR (CDCl3): d 170.04 ppm, 169.56, 169.11, 154.57, 141.64, 132.53, 125.90, 1123.45, 117.72, 109.49, 85.78, 80.99, 70.95, 69.83, 62.91, 20.74, 20.54, 20.20. 1H NMR (CDCl3): d 0.96 ppm (s, 3H), 1.09 (s, 3H), 1.13 (s, 3H), 3.75 (m, 2H), 4.08 (dd, 1H), 5.00 (dd, 1H), 5.13 (t, 1H), 5.42 (s, 2H), 5.61 (d, 1H), 7.27 (s, 1H), 7.42 (s, 1H). MS (FAB): m/e 758, 718, 676, 460, 426, 259, 217, 139.