Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1([OH:8])[CH2:6][CH2:5][CH:4]([OH:7])[CH2:3][CH2:2]1.N1C=CC=CC=1.[C:15]1([CH3:25])[CH:20]=[CH:19][C:18]([S:21](Cl)(=[O:23])=[O:22])=[CH:17][CH:16]=1>C(Cl)(Cl)Cl>[OH:7][CH:4]1[CH2:5][CH2:6][CH:1]([O:8][S:21]([C:18]2[CH:19]=[CH:20][C:15]([CH3:25])=[CH:16][CH:17]=2)(=[O:23])=[O:22])[CH2:2][CH2:3]1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: OC1CCC(O)CC1
Solvent: ClC(Cl)Cl
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OC2CCC(O)CC2)cc1
Temperature: 25 °C
Reaction time: 17 h
Yield: 78.4 %

Procedure:
step 1—To a solution of 1,4-cyclohexanediol (20.0 g, 172 mmol) and pyridine (100 mL) cooled to 0° C. was added dropwise over 2 h a solution of 32.0 g (168 mmol)p-toluenesulfonyl chloride in CHCl3 (100 mL). After the addition was complete the reaction mixture was stirred at RT for 17 h. The solvent was evaporated in vacuo and the residue was taken up in refluxing toluene and petroleum ether was added until the solution became cloudy. The mixture was cooled and the supernatant was decanted. The remaining solid was dissolved in DCM and vacuum filtered through a pad of SiO2. The filter cake was washed with a mixture of DCM/MeOH (95:5). The dark golden oil was dried under vacuum to afford 35.6 g (78%) of toluene-4-sulfonic acid 4-hydroxy-cyclohexyl ester (76) contaminated with a small amount of bis-tosylate: 1H NMR (CDCl3, 300 MHz): δ 7.79 (dd, 2H), 7.73 (dd, 2H), 4.64-4.48 (m, 1H), 3.75-3.69 (m, 1H), 2.45 (s, 3H), 1.95-1.83 (m, 3H), 1.70-1.26 (m, 6H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]([CH2:7][O:8][C:9]([C@@H:11]2[C@@H:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[NH:12]2)=[O:10])=[CH:5][CH:4]=1.[N:21]1[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=1B(O)O.C(N(CC)CC)C>ClCCl.C([O-])(=O)C.[Cu+2].C([O-])(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([CH2:7][O:8][C:9]([CH:11]2[CH:14]([CH2:15][CH:16]=[CH2:17])[C:13](=[O:18])[N:12]2[C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][N:21]=2)=[O:10])=[CH:19][CH:20]=1
Reactant: C=CC[C@H]1C(=O)N[C@@H]1C(=O)OCc1ccc(OC)cc1
Reactant: OB(O)c1ccccn1
Agent: [Cu+2]
Agent: CC(=O)[O-]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: C=CCC1C(=O)N(c2ccccn2)C1C(=O)OCc1ccc(OC)cc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 24.8 %

Procedure:
A mixture of β-lactam 59 (60 mg, 0.22 mmol), Pyridin-2-boronic acid (81 mg, 0.66 mmol), copper acetate (120 mg, 0.66 mmol), triethylamine (0.153 mL, 1.1 mmol) and activated 4A molecular sieves (270 mg) in dichloromethane (5 mL) was stirred at room temperature for 2 days. The reaction mixture was filtered through celite and the filtrate was concentrated. Preparative TLC (20% EtOAc/Hexanes) of the residue gave the desired product 80 (19.2 mg, 24.8%) 1HNMR (300 MHz, CDCl3): 2.60 (m, 2H), 3.49 (m, 1H), 3.81 (s, 3H), 4.41 (d, J=2.61 Hz, 1H), 5.11-5.21 (m, 4H), 5.82 (m, 1H), 6.85 (d, J=8.7 Hz, 2H), 7.01 (m, 1H), 7.22 (d, J=8.1 Hz, 2H), 7.66-7.72 (m, 2H); 8.19 (d, J=4.7 Hz, 1H) Anal. C20H20N2O4, Mol. Wt.: 352.38. Found: ESI-MS: 352.9 (M+H)+.
Reaction SMILES: Cl[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1.C(N(CC)C(C)C)(C)C.[CH2:28]([NH:32][CH2:33][C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1)[CH2:29][CH2:30][CH3:31]>C(Cl)Cl>[CH2:28]([N:32]([CH2:33][C:34]1[CH:46]=[CH:45][C:37]([O:38][CH2:39][C:40]([O:42][CH2:43][CH3:44])=[O:41])=[C:36]([CH3:47])[CH:35]=1)[C:2]1[C:7]([CH3:8])=[C:6]([C:9]2[CH:14]=[CH:13][C:12]([C:15]([F:18])([F:17])[F:16])=[CH:11][CH:10]=2)[N:5]=[CH:4][N:3]=1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCNCc1ccc(OCC(=O)OCC)c(C)c1
Reactant: Cc1c(Cl)ncnc1-c1ccc(C(F)(F)F)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCCCN(Cc1ccc(OCC(=O)OCC)c(C)c1)c1ncnc(-c2ccc(C(F)(F)F)cc2)c1C
Temperature: 100 °C
Yield: 43.9 %

Procedure:
A mixture of 4-chloro-5-methyl-6-[4-(trifluoromethyl)phenyl]pyrimidine (0.229 g, 0.84 mmol), N,N-diisopropylethylamine (0.293 mL, 1.68 mmol) and ethyl {4-[(butylamino)methyl]-2-methylphenoxy}acetate (0.35 g, 1.26 mmol) was heated at 100° C. in a sealed reactivial for 18 h. The reaction mixture was then allowed to come to room temperature, and the residue dissolved in CH2Cl2 (50 mL), the organic extract was washed water (20 mL) and passed through a hydrophobic frit then concentrated in vacuo. Purification by Biotage™ chromatography (Silica, 90 g) eluting with 1:19–1:9 EtOAc:cyclohexane afforded the title compound as a colourless oil (0.19 g).
Reaction SMILES: [H-].[Na+].[NH2:3][C@@H:4]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C@H:7]([OH:14])[CH2:6][CH2:5]1.F[C:16]1[CH:17]=[CH:18][C:19]2[N:20]([C:22]([C:25]([CH3:32])([N:27]3[CH2:31][CH2:30][CH2:29][CH2:28]3)[CH3:26])=[N:23][N:24]=2)[CH:21]=1>CN(C=O)C>[CH3:32][C:25]([C:22]1[N:20]2[CH:21]=[C:16]([O:14][C@H:7]3[C:8]4[C:13](=[CH:12][CH:11]=[CH:10][CH:9]=4)[C@@H:4]([NH2:3])[CH2:5][CH2:6]3)[CH:17]=[CH:18][C:19]2=[N:24][N:23]=1)([N:27]1[CH2:28][CH2:29][CH2:30][CH2:31]1)[CH3:26]
Reactant: N[C@H]1CC[C@@H](O)c2ccccc21
Reactant: CC(C)(c1nnc2ccc(F)cn12)N1CCCC1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC(C)(c1nnc2ccc(O[C@@H]3CC[C@H](N)c4ccccc43)cn12)N1CCCC1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 54.7 %

Procedure:
To a suspension of NaH (60% in mineral oil, 135 mg, 3.37 mmol) in DMF (4.50 mL) was added Intermediate A (137 mg, 0.84 mmol) and the reaction stirred for 20 min. Intermediate 80b (209 mg, 0.84 mmol) was added in DMF (1.50 mL) and the reaction heated to 60° C. for 1 h. The reaction was cooled and quenched by dropwise addition of methanol, before being diluted with methanol and loaded onto an SCX-2 cartridge, which was washed with MeOH and product eluted with 2M NH3 in MeOH. The resulting residue was purified by FCC, using 0-10% [2M NH3 in MeOH] in DCM, to give the title compound (180 mg, 55%). LCMS (Method 4): Rt 0.31, m/z 392.2 [MH+].
Reaction SMILES: [C:1]([O:5][C:6](=[O:47])[N:7]([CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([C:33]([C:35]2[S:39][C:38]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:37]=3[C:36]=2[Cl:46])=[O:34])[CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31][CH3:32])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:11][CH2:10]1)[CH3:8])([CH3:4])([CH3:3])[CH3:2].C([O-])(O)=[O:49].[Na+].ClC1C=CC=C(C(OO)=O)C=1>C(Cl)Cl.[O-]S([O-])=O.[Na+].[Na+]>[C:1]([O:5][C:6](=[O:47])[N:7]([CH:9]1[CH2:10][CH2:11][CH:12]([N:15]([C:33]([C:35]2[S:39][C:38]3[C:40]([F:45])=[CH:41][CH:42]=[C:43]([F:44])[C:37]=3[C:36]=2[Cl:46])=[O:34])[CH2:16][C:17]2[CH:18]=[C:19]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[S:31]([CH3:32])=[O:49])[CH:20]=[CH:21][C:22]=2[O:23][CH3:24])[CH2:13][CH2:14]1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C([O-])O
Reactant: COc1ccc(-c2ccccc2SC)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Agent: O=C(OO)c1cccc(Cl)c1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: COc1ccc(-c2ccccc2S(C)=O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reaction time: 2 h

Procedure:
To a stirred suspension of thioanisole (286) (75 mg, 0.11 mmol) and NaHCO3 (46 mg, 0.55 mmol) in DCM (2 ml) at 0° C. was added dropwise a solution of m-chloroperbenzoic acid (34 mg, 0.2 mmol) in DCM (1 ml) over 2 min. After 2 h, LCMS showed a mixture of sulphoxide and sulphone. The reaction was diluted with aqueous Na2SO3 and extracted with DCM. The combined organic layers were dried (Na2SO4), filtered and reduced in vacuo before purification by chromatography with EtOAc/heptane to give the title compound.
Reaction SMILES: [OH:1][C:2]1[C:3]([C:18](=O)[CH3:19])=[N:4][N:5]([CH3:17])[C:6]=1[C:7]1[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=1.[CH2:21]([N:23]([CH2:35][CH3:36])[C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][NH2:34])=[O:32])=[CH:29][CH:30]=1)=[O:25])[CH3:22].C1(C)C=CC(S(O)(=O)=O)=CC=1>CC(O)C>[CH2:35]([N:23]([CH2:21][CH3:22])[C:24]([C:26]1[S:27][C:28]([C:31]([NH:33][N:34]=[C:18]([C:3]2[C:2]([OH:1])=[C:6]([C:7]3[CH:12]=[CH:11][C:10]([C:13]([F:16])([F:15])[F:14])=[CH:9][CH:8]=3)[N:5]([CH3:17])[N:4]=2)[CH3:19])=[O:32])=[CH:29][CH:30]=1)=[O:25])[CH3:36]
Reactant: CCN(CC)C(=O)c1ccc(C(=O)NN)s1
Reactant: CC(=O)c1nn(C)c(-c2ccc(C(F)(F)F)cc2)c1O
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: CCN(CC)C(=O)c1ccc(C(=O)NN=C(C)c2nn(C)c(-c3ccc(C(F)(F)F)cc3)c2O)s1
Yield: 53.2 %

Procedure:
1-[4-Hydroxy-1-methyl-5-(4-trifluoromethylphenyl)-1H-pyrazol-3-yl]ethanone (28 mg, 0.10 mmol, synthesized in accordance with WO2004/108683), 5-hydrazinocarbonylthiophene-2-carboxylic acid diethylamide (24 mg, 0.10 mmol) prepared in Reference Synthetic Example 1 and p-toluenesulfonic acid (6 mg) were heated with 2-propanol (4 mL) for 14 hours with reflux. After cooling, the solvent was evaporated, and the resulting solid was recrystallized from 2-propanol-diethyl ether-n-hexane to give 27 mg of the desired product (yield 53%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[C:5]([C:13]#[N:14])=[C:4](S(C)=O)[N:3]=1.[NH2:18][C:19]1[CH:26]=[CH:25][C:22]([CH2:23][NH2:24])=[CH:21][CH:20]=1>COCCOC>[NH2:1][C:2]1[N:3]=[C:4]([NH:24][CH2:23][C:22]2[CH:25]=[CH:26][C:19]([NH2:18])=[CH:20][CH:21]=2)[C:5]([C:13]#[N:14])=[C:6]([C:8]2[O:9][CH:10]=[CH:11][CH:12]=2)[N:7]=1
Reactant: CS(=O)c1nc(N)nc(-c2ccco2)c1C#N
Reactant: NCc1ccc(N)cc1
Solvent: COCCOC
Product: N#Cc1c(NCc2ccc(N)cc2)nc(N)nc1-c1ccco1

Procedure:
From 2-amino-4-furan-2-yl-6-methanesulfinyl-pyrimidine-5-carbonitrile and 4-aminobenzylamine in DME. ES-MS m/e (%): 307 (M+H+, 100).
Reaction SMILES: [CH2:1]([NH2:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:9]([NH:12][NH:13][C:14](N)=[O:15])(N)=[O:10].Cl>CN1CCCC1=O>[CH2:1]([N:8]1[C:14](=[O:15])[NH:13][NH:12][C:9]1=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NCc1ccccc1
Reactant: NC(=O)NNC(N)=O
Agent: Cl
Solvent: CN1CCCC1=O
Product: O=c1[nH][nH]c(=O)n1Cc1ccccc1

Procedure:
53.5 g of benzylamine and 59 g of hydrazodicarbonamide are stirred in 100 ml of N-methyl pyrrolidone for 4 hours at 175° C. and for 5 hours at 200° C. The solvent is then distilled off in vacuo, the residue is triturated with 50 ml of a 10% sodium hydroxide solution and the residue is isolated by filtration under suction. The filtrate is neutralised with 10% hydrochloric acid. A deposit is formed which is filtered off under suction and washed with water, giving 67 g (70% of the theoretical yield) of 4-benzyl-1,2,4-triazolidine-3,5-dione in the form of colourless crystals melting at 185° to 188° C. (CH3CN).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([CH3:8])[CH:5]=[CH:4][CH:3]=1.[N+:9]([O-])([OH:11])=[O:10].C(=O)([O-])[O-].[Na+].[Na+]>OS(O)(=O)=O>[CH3:8][C:6]1[N:7]=[C:2]([NH2:1])[C:3]([N+:9]([O-:11])=[O:10])=[CH:4][CH:5]=1
Reactant: Cc1cccc(N)n1
Reactant: O=[N+]([O-])O
Agent: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [Na+]
Product: Cc1ccc([N+](=O)[O-])c(N)n1
Temperature: 0 °C
Reaction time: 3 h
Yield: 19 %

Procedure:
6-Amino picoline (5.0 g, 46 mmol) was cautiously suspended in H2SO4 (25 ml) and cooled in an ice bath. Fuming nitric acid (5 ml) was added slowly, and care was taken to keep the temperature of the reaction as low as possible. The reaction mixture was allowed to stir 3 h after the addition of the nitric acid was complete. The mixture was added to sodium carbonate (65 g), suspended in about ice water (500 ml). Once the neutralization was complete, the aqueous mixture was extracted four times with ethyl acetate. The combined ethyl acetate washings were washed with brine, dried using MgSO4, and concentrated under vacuum to yield the title product (1.3 g, 19%) as a red oil. 1H NMR (DMSO-d6): δ=8.27 (d, 1H, J=8.5 Hz), 7.88 (bs, 2H), 6.63 (1H, d, J=8.5), 2.39 (s, 3H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH:6]=[CH:5]2.[H][H]>C(O)C.CN(C)C=O.[Ni]>[F:1][C:2]1[CH:3]=[C:4]2[C:9](=[C:10]([F:13])[C:11]=1[F:12])[NH:8][C:7](=[O:14])[CH2:6][CH2:5]2
Reactant: [H][H]
Reactant: O=c1ccc2cc(F)c(F)c(F)c2[nH]1
Agent: [Ni]
Solvent: CN(C)C=O
Solvent: CCO
Product: O=C1CCc2cc(F)c(F)c(F)c2N1
Yield: 95.9 %

Procedure:
24.35 g of 6,7,8-trifluorocarbostyril in suspension in a mixture of 450 cm3 of ethanol and 150 cm3 of dimethylformamide are hydrogenated, with stirring, at about 50° C., in the presence of 5 g of Raney nickel under a pressure of 1 atmosphere until the absorption of hydrogen has ceased. The W-2 grade Raney nickel used is washed beforehand with 50 cm3 of an aqueous 2% acetic acid solution, twice 50 cm3 of water and 3 times 50 cm3 of ethanol. 250 cm3 of dimethylformamide are added to the reaction mixture and the mixture is filtered at about 50° C. through diatomaceous silica. The filtrate is concentrated under reduced pressure (20 kPa) at about 70° C. The dry extract is taken up in 150 cm3 of water, drained and washed with twice 50 cm3 of water. 23.6 g of 6,7,8-trifluoro-3,4-dihydrocarbostyril are obtained in the form of a light beige solid melting at 217° C., which is used for the subsequent steps without further purification.
Reaction SMILES: [CH2:1](OC1C=CC(CC(NC2C=C(OC)C=CC=2C2CCC3C(=CC=C(OC)C=3)C2)=O)=CC=1)[C:2]1C=CC=CC=1.[CH2:39]([O:46][C:47]1[CH:52]=[CH:51][C:50]([CH2:53][CH2:54][NH:55][C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:49][CH:48]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>>[CH2:39]([O:46][C:47]1[CH:48]=[CH:49][C:50]([CH2:53][CH2:54][N:55]([CH2:1][CH3:2])[C:56]2[CH:61]=[C:60]([O:62][CH3:63])[CH:59]=[CH:58][C:57]=2[CH:64]2[CH2:73][CH2:72][C:71]3[C:66](=[CH:67][CH:68]=[C:69]([O:74][CH3:75])[CH:70]=3)[CH2:65]2)=[CH:51][CH:52]=1)[C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NCCc1ccc(OCc3ccccc3)cc1)C2
Reactant: COc1ccc2c(c1)CCC(c1ccc(OC)cc1NC(=O)Cc1ccc(OCc3ccccc3)cc1)C2
Product: CCN(CCc1ccc(OCc2ccccc2)cc1)c1cc(OC)ccc1C1CCc2cc(OC)ccc2C1

Procedure:
Synthesized from 2-(4-benzyloxyphenyl)-N-[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]acetamide according to an analogous synthetic method to Example 337, [2-(4-benzyloxyphenyl)ethyl][5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (1.3 g) was used according to an analogous synthetic method to Example 36 to provide [2-(4-benzyloxyphenyl)ethyl]ethyl[5-methoxy-2-(6-methoxy-1,2,3,4-tetrahydronaphthalen-2-yl)phenyl]amine (1.2 g). The total amount of this compound was used according to an analogous synthetic method to Example 22 to provide the title compound (920 mg).
Reaction SMILES: [CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]#[N:16])=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18].[Na].[N-:20]=[N+:21]=[N-:22].[Cl-].[NH4+]>CN(C)C=O.N1C=CC=CC=1>[CH3:1][C:2]1[S:17][C:5]2[N:6]=[C:7]3[CH:14]=[CH:13][C:12]([C:15]4[NH:22][N:21]=[N:20][N:16]=4)=[CH:11][N:8]3[C:9](=[O:10])[C:4]=2[C:3]=1[CH3:18]
Reactant: [N-]=[N+]=[N-]
Reactant: Cc1sc2nc3ccc(C#N)cn3c(=O)c2c1C
Agent: [Cl-]
Agent: [NH4+]
Agent: [Na]
Solvent: c1ccncc1
Solvent: CN(C)C=O
Product: Cc1sc2nc3ccc(-c4nnn[nH]4)cn3c(=O)c2c1C

Procedure:
From 0.43 g (0.0017 mol) of 2,3-dimethyl-4-oxo-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidine-7-carbonitrile (Example 32), 0.33 g (0.0051 mol) of sodium size azide and 0.3 g (0.0056 mol) of ammonium chloride in 80 ml of dimethylformamide, following the procedure of Example 34, there is obtained 0.14 g of 2,3-dimethyl-7-(1H-tetrazol-5-yl)-4H-pyrido[1,2-a]thieno[2,3-d]pyrimidin-4-one with pyridine (1:0.6); mp 292°-294° C. (dec) after recrystallization from pyridine.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[C:9]([F:11])[C:8]([C:12]2[O:13]CC(C)(C)N=2)=[C:7]([CH:19]2[O:24][CH2:23]CC[O:20]2)[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].CO.S(=O)(=O)(O)O>O>[C:1]([C:5]1[CH:6]=[C:7]2[C:8](=[C:9]([F:11])[CH:10]=1)[C:12](=[O:13])[O:20][CH:19]2[O:24][CH3:23])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC1(C)COC(c2c(F)cc(C(C)(C)C)cc2C2OCCCO2)=N1
Agent: O=S(=O)(O)O
Solvent: O
Solvent: CO
Product: COC1OC(=O)c2c(F)cc(C(C)(C)C)cc21
Yield: 87.9 %

Procedure:
A mixture of 101f (68.8 g, 205.4 mmol), methanol (1340 mL) and 50% aqueous sulfuric acid (881 mL) was stirred at reflux overnight. The reaction mixture was poured into 400 mL of water, extracted with DCM (3×1000 mL). The combined organic extracts were washed with 400 mL of brine, dried over Na2SO4, filtered and concentrated to dry to provide 101g (43 g) as a off-white solid which was used in the next step without further purification LCMS (ESI) m/z 225 (M+H)+.
Reaction SMILES: [N+](=[C:3]1[N:7]=[C:6]2[C:8]([CH3:17])=[CH:9][C:10]([N+:14]([O-:16])=[O:15])=[C:11]([CH2:12][CH3:13])[C:5]2=[N:4]1)=[N-].N([O-])=O.[Na+].[F:22][B-](F)(F)F.[H+]>>[CH2:12]([C:11]1[C:5]2[NH:4][C:3]([F:22])=[N:7][C:6]=2[C:8]([CH3:17])=[CH:9][C:10]=1[N+:14]([O-:16])=[O:15])[CH3:13]
Reactant: F[B-](F)(F)F
Reactant: CCc1c([N+](=O)[O-])cc(C)c2c1=NC(=[N+]=[N-])N=2
Agent: O=N[O-]
Agent: [H+]
Agent: [Na+]
Product: CCc1c([N+](=O)[O-])cc(C)c2nc(F)[nH]c12

Procedure:
2,4-Dinitro-3-ethyl-6-methylaniline (see Example 2) is treated with sodium sulfide to afford 1,2-diamino-3-ethyl-6-methyl-4-nitrobenzene. Treatment with cyanogen bromide affords to 2-amino-4-ethyl-7-methyl-5-nitrobenzimidazole. This is converted to 2-diazo-4-ethyl-7-methyl-5-nitrobenzimidazole tetrafuoroborate with sodium nitrite and tetrafluoroboric acid. Thermal decomposition of the diazonium salt gives 4-ethyl-2-fluoro-7-methyl-5-nitrobenzimidazole. Conversion to 4-ethyl-2-fluoro-5-(2-imidazolinylamino)benzimidazole is completed according to Scheme 5.
Reaction SMILES: [CH2:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3].C([O-])(=O)C.[Na+].[Br:27]Br.O>C(O)(=O)C>[Br:27][CH:1]([C:4]1[N:13]([CH2:14][C:15]2[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=2)[C:12](=[O:21])[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2ccccc2c(=O)n1Cc1ccccc1
Reactant: BrBr
Agent: CC(=O)[O-]
Agent: [Na+]
Solvent: O
Solvent: CC(=O)O
Product: CCC(Br)c1nc2ccccc2c(=O)n1Cc1ccccc1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
To a three-neck 250 mL round-bottom flask equipped with a thermometer, dropping funnel, and efficient magnetic stir bar was added compound 4 (27.8 g, 0.10 mole), anhydrous sodium acetate (10.0 g) and glacial acetic acid (130 mL). Bromine (16.0 g, 0.10 mole) dissolved in acetic acid (10 mL) was added dropwise to the above solution at 40° C. for 1-2 h. After addition was complete, the mixture was poured into water (1500 mL) and stirred for 1-2 h at room temperature. The precipitated product, 2-(1′-bromopropyl)-3-benzylquinazolin-4-one (5) was isolated by filtration, washed with warm water to remove traces of acetic acid, and rinsed with a small amount of isopropanol. Drying yielded compound 5 (33.0 g, 92%).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH:10]=[CH:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1>O1CCCC1.C(O)C.[Pt](=O)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[O:9][C:8]([CH2:10][CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[CH:7][C:6]=2[CH:20]=1
Reactant: COc1ccc(C=Cc2cc3cc(Br)ccc3o2)cc1
Agent: O=[Pt]=O
Solvent: C1CCOC1
Solvent: CCO
Product: COc1ccc(CCc2cc3cc(Br)ccc3o2)cc1
Reaction time: 4 h
Yield: 75.4 %

Procedure:
128 g of 5-bromo-2-[2-(4-methoxyphenyl)vinyl]benzofuran as a mixture of two stereoisomers was dissolved in a solvent mixture of 1.3 l of tetrahydrofuran and 0.7 l of ethanol. The resulting solution was mixed with 3.0 g of platinum dioxide and subjected to 4 hours of catalytic hydrogenation undernormal pressure. Thereafter, the catalyst was removed by filtration, the resulting filtrate was concentrated, and crystals thus precipitated were collected by filtration and washed with ethanol. In this way, 97.08 g of 5-bromo-2-[2-(4-methoxyphenyl)ethyl]benzofuran was obtained.
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH:10]=[CH:11][C:12]([C:15]3[CH:16]=[N:17][C:18]([NH2:21])=[N:19][CH:20]=3)=[N:13][CH:14]=2)O1.Br[C:24]1[CH:29]=[CH:28][C:27]([C:30]([F:33])([F:32])[F:31])=[CH:26][C:25]=1[S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:36])=[O:35]>>[NH2:21][C:18]1[N:19]=[CH:20][C:15]([C:12]2[N:13]=[CH:14][C:9]([C:24]3[CH:29]=[CH:28][C:27]([C:30]([F:31])([F:32])[F:33])=[CH:26][C:25]=3[S:34]([NH:37][CH2:38][CH2:39][OH:40])(=[O:35])=[O:36])=[CH:10][CH:11]=2)=[CH:16][N:17]=1
Reactant: O=S(=O)(NCCO)c1cc(C(F)(F)F)ccc1Br
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)nc2)OC1(C)C
Product: Nc1ncc(-c2ccc(-c3ccc(C(F)(F)F)cc3S(=O)(=O)NCCO)cn2)cn1

Procedure:
The title compound was prepared in a manner similar to that described in Example 427 using 5-(5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridin-2-yl)pyrimidin-2-amine and 2-bromo-N-(2-hydroxyethyl)-5-(trifluoromethyl)benzenesulfonamide. MS (ESI): mass calcd. for C18H16F3N5O3S, 439.09; m/z found, 440.0 [M+H]+. 1H NMR (500 MHz, CD3OD) δ 8.96 (s, 2H), 8.64 (d, J=1.7, 1H), 8.39 (s, 1H), 8.01 (d, J=8.0, 1H), 7.95 (dd, J=8.2, 2.3, 1H), 7.87 (d, J=8.3, 1H), 7.64 (d, J=8.0, 1H), 3.46 (t, J=5.9, 2H), 2.91 (t, J=5.9, 2H).
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7](F)=[C:6]([N+:11]([O-:13])=[O:12])[CH:5]=1)=[O:3].[Br:14][C:15]1[CH:16]=[C:17]([CH:19]=[CH:20][CH:21]=1)[NH2:18].C(N(CC)CC)C>CN1C(=O)CCC1>[Br:14][C:15]1[CH:16]=[C:17]([NH:18][C:7]2[CH:8]=[CH:9][C:4]([C:2](=[O:3])[CH3:1])=[CH:5][C:6]=2[N+:11]([O-:13])=[O:12])[CH:19]=[CH:20][CH:21]=1
Reactant: Nc1cccc(Br)c1
Reactant: CC(=O)c1ccc(F)c([N+](=O)[O-])c1
Solvent: CN1CCCC1=O
Solvent: CCN(CC)CC
Product: CC(=O)c1ccc(Nc2cccc(Br)c2)c([N+](=O)[O-])c1
Temperature: 80 °C
Reaction time: 6 h
Yield: 87 %

Procedure:
To a solution of 4-fluoro-3-nitroacetophenone (165 g, 0.9 mol) in NMP (350 ml) was added 3-bromoaniline (98 ml, 0.9 mol) and triethyl amine (125.4 ml, 0.9 mol) and the reaction mixture was stirred at 80° C. for 6 hours and then left with stirring at room temperature over night. The resultant suspension was poured into ice-water and the precipitate was filtered off and washed with water and diethyl ether, successively. Drying in the air afforded the desired product (262g, 87%).
Reaction SMILES: [N:1]1([CH2:10][C:11]2[CH:27]=[CH:26][C:14]([C:15]([NH:17][C@H:18]([C:22]([O:24][CH3:25])=[O:23])[C@@H:19]([CH3:21])O)=[O:16])=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1.CC[N+](S(N=C(OC)[O-])(=O)=O)(CC)CC>C1COCC1>[N:1]1([CH2:10][C:11]2[CH:27]=[CH:26][C:14]([C:15]3[O:16][C:19]([CH3:21])=[C:18]([C:22]([O:24][CH3:25])=[O:23])[N:17]=3)=[CH:13][CH:12]=2)[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[CH:2]1
Reactant: COC(=O)[C@@H](NC(=O)c1ccc(Cn2cnc3ccccc32)cc1)[C@@H](C)O
Agent: CC[N+](CC)(CC)S(=O)(=O)N=C([O-])OC
Solvent: C1CCOC1
Product: COC(=O)c1nc(-c2ccc(Cn3cnc4ccccc43)cc2)oc1C
Temperature: 60 °C
Reaction time: 2 h
Yield: 47 %

Procedure:
A stirred solution of methyl N-[4-(1H-benzimidazol-1-ylmethyl)benzoyl]thre-oninate (0.34 g, 0.94 mmol) in THF was treated with Burgess reagent (0.27 g, 1.12 mmol), heated to 60° C., stirred for 2 h at 60° C., cooled to room temperature and concentrated under reduced pressure. The resultant residue was purified by column chromatography (silica, CH2Cl2:CH3OH 95:5) to afford the title product in 47% yield, identified by NMR and mass spectral analyses. LCMS (ESI+) 350 (MH+).
Reaction SMILES: [CH2:1]([NH:5][C:6](=[O:10])[C@H:7]([CH3:9])[NH2:8])[CH:2]([CH3:4])[CH3:3].[F:11][C:12]1[CH:13]=[C:14]([CH2:19][C@H:20]([NH:24][C:25](=[O:31])[O:26][C:27]([CH3:30])([CH3:29])[CH3:28])[C@H:21]2[CH2:23][O:22]2)[CH:15]=[C:16]([F:18])[CH:17]=1>C(O)(C)C>[C:27]([O:26][C:25](=[O:31])[NH:24][CH:20]([CH2:19][C:14]1[CH:13]=[C:12]([F:11])[CH:17]=[C:16]([F:18])[CH:15]=1)[CH:21]([OH:22])[CH2:23][NH:8][CH:7]([C:6](=[O:10])[NH:5][CH2:1][CH:2]([CH3:4])[CH3:3])[CH3:9])([CH3:28])([CH3:29])[CH3:30]
Reactant: CC(C)CNC(=O)[C@H](C)N
Reactant: CC(C)(C)OC(=O)N[C@@H](Cc1cc(F)cc(F)c1)[C@H]1CO1
Solvent: CC(C)O
Product: CC(C)CNC(=O)C(C)NCC(O)C(Cc1cc(F)cc(F)c1)NC(=O)OC(C)(C)C

Procedure:
N1-Isobutyl-L-alaninamide (3.8 g, 26 mmol) and tert-butyl (1S)-2-(3,5-difluorophenyl)-1-[(2S)-oxiran-2-yl]ethylcarbamate prepared by the method in EXAMPLE S-3 (3.1 g, 10.4 mmol) in isopropanol (50 mL) are refluxed 4 h. The reaction is cooled and concentrated under reduced pressure. Purification by flash column chromatography (silica, 8% methanol/chloroform) gives the title compound. ESI MS m/z 444.1 [M+H]+.