Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][CH2:2]/[CH:3]=[C:4](/[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1)\[CH3:5].[N+](=[CH:17][C:18]([O:20][CH2:21][CH3:22])=[O:19])=[N-]>ClCCl.CC(O)=O.CC(O)=O.CC(O)=O.CC(O)=O.[Rh].[Rh]>[Cl:1][CH2:2][CH:3]1[CH:17]([C:18]([O:20][CH2:21][CH3:22])=[O:19])[C:4]1([CH3:5])[C:6]1[CH:11]=[CH:10][CH:9]=[C:8]([N+:12]([O-:14])=[O:13])[CH:7]=1
Reactant: C/C(=C\CCl)c1cccc([N+](=O)[O-])c1
Reactant: CCOC(=O)C=[N+]=[N-]
Agent: [Rh]
Solvent: CC(=O)O
Solvent: ClCCl
Product: CCOC(=O)C1C(CCl)C1(C)c1cccc([N+](=O)[O-])c1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of 1-[(E)-3-chloro-1-methyl-1-propenyl]-3-nitrobenzene (Preparation 3, 36 g, 0.17 mol) in dichloromethane (50 ml) was added rhodium (II) acetate dimer (1 g, 2.3 mmol). To the mixture was added dropwise at room temperature over 8 h a solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture was stirred at room temperature for 16 h. To the mixture was added dropwise at room temperature over 7 h a further solution of ethyl diazoacetate (50 ml, 54.25 g, 0.475 mol) in dichloromethane (50 ml), then the mixture was stirred at room temperature for a further 16 h. The mixture was concentrated in vacuo and the residue purified by silica column (1 kg) chromatography, eluting with 1:1 hexane/dichloromethane then dichloromethane. Product-containing fractions were combined and concentrated in vacuo, then concentrated under a stream of nitrogen for 16 h. The residue was purified further by silica column (2 kg) chromatography, eluting with 1:1 hexane/dichloromethane then dichloromethane. Product containing fractions were combined and concentrated in vacuo, to give the title compound as a very pale yellow oil (14.2 g, 29%).
Reaction SMILES: [CH3:1][N:2]1[C:6]([CH3:7])=[CH:5][N:4]=[C:3]1[N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][C:17]([N+:20]([O-])=O)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1>CO>[NH2:20][C:17]1[CH:18]=[CH:19][C:14]([CH:11]2[CH2:10][CH2:9][N:8]([C:3]3[N:2]([CH3:1])[C:6]([CH3:7])=[CH:5][N:4]=3)[CH2:13][CH2:12]2)=[CH:15][CH:16]=1
Reactant: Cc1cnc(N2CCC(c3ccc([N+](=O)[O-])cc3)CC2)n1C
Solvent: CO
Product: Cc1cnc(N2CCC(c3ccc(N)cc3)CC2)n1C

Procedure:
Hydrogenation of the product from part (i) above (0.60 g) in methanol (50 ml) according to the method of Example 1(ii) gave the title compound, (0.53 g), m.p. 219°-220° (with decomp).
Reaction SMILES: [NH:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:33]=[CH:32][C:29]([CH:30]=O)=[CH:28][CH:27]=2)[O:21][N:20]=1)(=[O:12])=[O:11].Cl.[CH3:35][NH2:36]>>[NH:3]1[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][C:5]=2[N:1]=[C:2]1[S:10]([N:13]1[CH2:18][CH2:17][CH2:16][CH2:15][CH:14]1[C:19]1[N:23]=[C:22]([CH2:24][O:25][C:26]2[CH:27]=[CH:28][C:29]([CH2:30][NH:36][CH3:35])=[CH:32][CH:33]=2)[O:21][N:20]=1)(=[O:12])=[O:11]
Reactant: CN
Reactant: O=Cc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1
Agent: Cl
Product: CNCc1ccc(OCc2nc(C3CCCCN3S(=O)(=O)c3nc4ccccc4[nH]3)no2)cc1

Procedure:
The title compound was prepared by a similar method to Example 13 from 4-(3-[1-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzaldehyde [see Preparation 22] and methylamine hydrochloride to afford N-[4-(3-[1l-(1H-benzo[d]imidazol-2-ylsulfonyl)-2-piperidyl]-1,2,4-oxadiazol-5-ylmethoxy)benzyl]-N-methylamine as a white solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[C:8]2[N:9]=[C:10]([NH:12][C:13](=[O:23])[C:14]3[CH:19]=[CH:18][C:17]([CH2:20][NH:21][CH3:22])=[CH:16][CH:15]=3)[S:11][C:7]=2[C:6]([N:24]2[CH2:29][CH2:28][O:27][CH2:26][CH2:25]2)=[CH:5][CH:4]=1.[C:30](Cl)(=[O:32])[CH3:31]>>[C:30]([N:21]([CH2:20][C:17]1[CH:16]=[CH:15][C:14]([C:13]([NH:12][C:10]2[S:11][C:7]3[C:6]([N:24]4[CH2:25][CH2:26][O:27][CH2:28][CH2:29]4)=[CH:5][CH:4]=[C:3]([O:2][CH3:1])[C:8]=3[N:9]=2)=[O:23])=[CH:19][CH:18]=1)[CH3:22])(=[O:32])[CH3:31]
Reactant: CC(=O)Cl
Reactant: CNCc1ccc(C(=O)Nc2nc3c(OC)ccc(N4CCOCC4)c3s2)cc1
Product: COc1ccc(N2CCOCC2)c2sc(NC(=O)c3ccc(CN(C)C(C)=O)cc3)nc12

Procedure:
Using N-(4-methoxy-7-morpholin-4-yl-benzothiazol-2-yl)-4-methylaminomethyl-benzamide and acetyl chloride, the title compound was prepared as white crystals (77% yield). MS: m/e=455(M+H+).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH3:12])=[N:10][CH:11]=2)[CH2:3][CH2:2]1.ClC1C=C(C=CC=1)C(OO)=[O:18].C(=O)(O)[O-].[Na+].C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[CH:1]1([CH2:4][O:5][C:6]2[CH:7]=[CH:8][C:9]([CH2:12][OH:18])=[N:10][CH:11]=2)[CH2:2][CH2:3]1
Reactant: Cc1ccc(OCC2CC2)cn1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: OCc1ccc(OCC2CC2)cn1
Temperature: 25 °C
Reaction time: 1 h
Yield: 104.6 %

Procedure:
To a solution of 5-(cyclopropylmethoxy)-2-methylpyridine (3.9 g, 24 mmol) in dichloromethane (50 mL) was added 3-chlorobenzoperoxoic acid (7.6 g, 32 mmol) at room temperature. After being stirred at room temperature for 1 hour, the mixture was poured into saturated aqueous sodium bicarbonate solution. The organic phase was extracted with dichloromethane (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was dissolved in acetic anhydride (50 mL) and the mixture was stirred at 100° C. for 2 hours. Half of the solvent was removed under the reduced pressure. The residue was dissolved into methanol (50 mL). Potassium carbonate (20 g, 143 mmol) was added to the mixture carefully. The mixture was stirred at room temperature for 1 hour. The mixture was poured into H2O, and the aqueous phase was extracted with ethyl acetate (twice). The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by column chromatography on silica gel eluting with hexane/ethyl acetate (1:1 (v/v)) to give 4.5 g (quantitative yield) of the title compound as a brown oil:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:9]2[N:14]=[C:13]([CH3:15])[N:12]=[C:11]([NH2:16])[N:10]=2)[C:5](F)=[N:6][CH:7]=1.[NH2:17][C:18]1[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].C1COCC1>CN(C=O)C>[NH2:16][C:11]1[N:12]=[C:13]([CH3:15])[N:14]=[C:9]([C:4]2[C:5]([NH:17][C:18]3[CH:19]=[C:20]([NH:25][S:26]([CH3:29])(=[O:28])=[O:27])[C:21]([CH3:24])=[N:22][CH:23]=3)=[N:6][CH:7]=[C:2]([Cl:1])[CH:3]=2)[N:10]=1
Reactant: Cc1ncc(N)cc1NS(C)(=O)=O
Reactant: Cc1nc(N)nc(-c2cc(Cl)cnc2F)n1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: Cc1nc(N)nc(-c2cc(Cl)cnc2Nc2cnc(C)c(NS(C)(=O)=O)c2)n1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 113.7 %

Procedure:
To a 15 mL round-bottom flask was added 4-(5-chloro-2-fluoropyridin-3-yl)-6-methyl-1,3,5-triazin-2-amine (0.050 g, 0.209 mmol), N-(5-amino-2-methylpyridin-3-yl)methanesulfonamide (0.046 g, 0.230 mmol), and DMF (2.0 mL). The mixture was cooled to 0° C. under N2. Sodium bis(trimethylsilyl)amide, 1.0 m in THF (0.169 mL, 0.835 mmol) was then added to the solution in one portion. The now burgundy color mixture was stirred at 0° C. for 10 min then warmed up to rt and stirred for 1 h. The reaction mixture was quenched with sat. NH4Cl and partitioned between water and CHCl3. The aqueous layer was extracted with more CHCl3 (2×10 mL). The combined organic layers were dried over MgSO4 and concentrated. The crude product was purified by column chromatography (40 g, 3% MeOH in DCM) to afford the desired product as a yellow solid (100 mg). MS (ESI pos. ion) m/z: 421.0. 1H NMR (300 MHz, DMSO-d6) δ ppm 2.45 (s, 6H) 3.06 (s, 3H) 7.84 (br. s., 1H) 7.97 (br. s., 1H) 8.24 (d, J=2.05 Hz, 1H) 8.38 (d, J=2.63 Hz, 1H) 8.64 (d, J=2.19 Hz, 1H) 8.75 (d, J=2.63Hz, 1H) 9.32 (br. s., 1H) 11.98 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[NH:6][C@H:5]([C:7]([O:9]C)=O)[CH2:4][CH2:3]1.[H-].[Na+].[CH3:13]I.[BH4-].[Na+]>O1CCCC1.CO>[OH:9][CH2:7][C@H:5]1[N:6]([CH3:13])[C:2](=[O:1])[CH2:3][CH2:4]1
Reactant: CI
Reactant: COC(=O)[C@@H]1CCC(=O)N1
Agent: [BH4-]
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Product: CN1C(=O)CC[C@H]1CO
Temperature: 25 °C
Reaction time: 16 h
Yield: 50.3 %

Procedure:
To a solution of (S)-methyl 5-oxo-pyrrolidine-2-carboxylate (Aldrich, 2.86 g, 20 mmol) in tetrahydrofuran (50 mL) at 0° C. was added in portions 60% oil dispersion NaH (720 mg, 30 mmol). Methyl iodide (1.88 mL, 30 mmol) was added and the mixture was allowed to warm to ambient temperature and stirred for 16 h. The mixture was concentrated under reduced pressure and residue was partitioned between water and ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was redissolved in anhydrous tetrahydrofuran (50 mL), sodium borohydride (946 mg, 25 mmol) was added followed by dropwise addition (˜20 min) of methanol (20 mL) at 50° C. The reaction mixture was stirred for an additional 1 h at a range from 45° C. to 50° C., then cooled to room temperature and concentrated under reduced pressure. Citric acid (10%) was added and the mixture was extracted with ethyl acetate. The organic layer was washed with water, brine, dried with anhydrous MgSO4, filtered, and concentrated under reduced pressure. The residue was purified by chromatography (SiO2, ethyl acetate-ethanol 4:1) to afford 1.3 g of the title compound. 1H NMR (300 MHz, DMSO-d6) δ 1.77 (m 1H), 1.95 (m, 1H), 2.18 (m, 2H), 2.69 (s, 3H), 3.43 (m, 2H), 3.55 (m, 1H), 4.77 (t, J=6 Hz, 1H); MS (DCI/NH3) m/z 130 (M+H)+, 147 (M+NH4)+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([OH:19])=O)[CH:9]=2)=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.CCN(CC)CC.[NH:48]1[CH2:53][CH2:52][NH:51][CH2:50][CH:49]1[C:54]#[N:55]>ClCCl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:13]([Cl:14])=[CH:12][C:11]([O:15][CH3:16])=[C:10]([C:17]([N:51]3[CH2:52][CH2:53][NH:48][CH:49]([C:54]#[N:55])[CH2:50]3)=[O:19])[CH:9]=2)=[CH:6][CH:7]=1
Reactant: N#CC1CNCCN1
Reactant: COc1cc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COc1cc(Cl)c(-c2ccc(Cl)cc2)cc1C(=O)N1CCNC(C#N)C1
Temperature: 25 °C
Reaction time: 8 h
Yield: 61 %

Procedure:
To a mixture of 4′,6-dichloro-4-methoxy-[1,1′-biphenyl]-3-carboxylic acid (309 mg, 1.04 mmol), EDCI (272 mg, 1.43 mmol), HOBt (195 mg, 1.43 mmol), Et3N (288 mg, 2.85 mmol) in dichloromethane (10 mL) at 0° C., piperazine-2-carbonitrile was added at 0° C. and the resulting mixture was stirred at RT for 8 h. The mixture was partitioned between dichloromethane and water. The organic layer was washed brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by flash column chromatography on silica gel (dichloromethane/methanol=50:1) to afford the desired product (225 mg, 61% yield). ESI-MS m/z: 444.3[M+H]+.
Reaction SMILES: [CH3:1][C:2]([CH3:11])([CH2:7][C:8](O)=[O:9])[CH2:3][C:4](O)=[O:5].B.C1COCC1.Cl>O1CCCC1>[CH3:1][C:2]([CH3:11])([CH2:7][CH2:8][OH:9])[CH2:3][CH2:4][OH:5]
Reactant: CC(C)(CC(=O)O)CC(=O)O
Agent: B
Agent: Cl
Solvent: C1CCOC1
Product: CC(C)(CCO)CCO
Temperature: 25 °C
Reaction time: 18 h
Yield: 35.5 %

Procedure:
To the solution of 3,3-dimethylglutaric acid (Aldrich) (5.1 g, 32 mmol) in anhydrous tetrahydrofuran (100 mL) at 0° C. was added a solution of BH3.THF (1 M, 100 mL, 100 mmol). The reaction mixture was stirred at room temperature for 18 h. Aqueous HCl solution was added, and the mixture was extracted with ethyl acetate. The organic layer was separated, washed with saturated aqueous NaHCO3 solution, brine, dried over MgSO4, and concentrated. The residue was purified by chromatography (EtOAc) to give 3,3-dimethyl-pentane-1,5-diol as a colorless oil (1.5 g, 34%).
Reaction SMILES: [O:1]=[CH:2][C@@H:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])[OH:4].[O-]S([O-])(=O)=O.[Mg+2].P([O-])([O-])([O-])=O>O>[OH:1][CH2:2][C:3]([C@H:5]([C@@H:7]([C@@H:9]([CH2:11][OH:12])[OH:10])[OH:8])[OH:6])=[O:4]
Reactant: O=C[C@H](O)[C@@H](O)[C@H](O)[C@H](O)CO
Agent: O=P([O-])([O-])[O-]
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: O
Product: O=C(CO)[C@@H](O)[C@H](O)[C@H](O)CO
Temperature: 70 °C

Procedure:
A mixture of 0.2 ml of 1 M aqueous D-glucose solution, 0.2 ml of 0.05 M aqueous MgSO4 ·7H2O solution, 0.2 ml of 0.5 M aqueous phosphate buffer (pH = 7.2) and a given amount of aqueous solution of extracted glucose isomerase is diluted with water to make it to 2 ml. The mixture is maintained at a temperature of 70° C for 60 minutes to effect the conversion which is terminated by the addition of 2 ml of 0.5 M perchloric acid. The amount of fructose produced is determined by the cystein carbazole method. The value obtained by dividing the amount of fructose produced by the amount of the extracted glucose isomerase solution is the activity, the unit of which is expressed by the abbreviation "U".
Reaction SMILES: [C:1](NCCCCC1C2C(=C3C(=CC=2)C=CC=N3)N=CC=1)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18].[N:39]1[C:52]2[C:51]3[C:46](=[CH:47][CH:48]=[CH:49][N:50]=3)[CH:45]=[C:44]([NH2:53])[C:43]=2[CH:42]=[CH:41][CH:40]=1>>[C:1]([NH:53][C:44]1[CH:45]=[C:46]2[C:51]([N:50]=[CH:49][CH:48]=[CH:47]2)=[C:52]2[C:43]=1[CH:42]=[CH:41][CH:40]=[N:39]2)(=[O:19])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH3:18]
Reactant: CCCCCCCCCCCCCCCCCC(=O)NCCCCc1ccnc2c1ccc1cccnc12
Reactant: Nc1cc2cccnc2c2ncccc12
Product: CCCCCCCCCCCCCCCCCC(=O)Nc1cc2cccnc2c2ncccc12

Procedure:
5-(octadecanoylamino)-1,10-phenanthroline was prepared according to the procedure used in Example 5 to prepare 4-(4-(octadecanoylamino)butyl)-1,10-phenanthroline, with the exception that 1,10-phenanthrolin-5-amine was used in place of 4-(aminobutyl)-1,10-phenanthroline.
Reaction SMILES: [Cl:1][C:2]1[C:15]2[C:10](=[C:11]([OH:16])[CH:12]=[CH:13][CH:14]=2)[C:9]([OH:17])=[C:8]2[C:3]=1[C:4](=[O:19])[CH:5]=[CH:6][C:7]2=[O:18].O.[O:21]1CC[CH2:23][CH2:22]1>C(OC(=O)C)(=O)C.N1C=CC=CC=1>[C:22]([O:16][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:10]=1[C:9]([OH:17])=[C:8]1[C:3]([C:4](=[O:19])[CH:5]=[CH:6][C:7]1=[O:18])=[C:2]2[Cl:1])(=[O:21])[CH3:23]
Reactant: O=C1C=CC(=O)c2c1c(Cl)c1cccc(O)c1c2O
Reactant: C1CCOC1
Solvent: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: O
Product: CC(=O)Oc1cccc2c(Cl)c3c(c(O)c12)C(=O)C=CC3=O
Reaction time: 48 h

Procedure:
10-Chloro-8,9-dihydroxy-1,4-anthracenedione (compound 3) (180 mg) was dissolved with stirring in dry tetrahydrofuran (15 ml) at room temperature. Acetic anhydride (20 drops) and pyridine (15 drops) were added to the solution which was then stirred for 48 h. Acidified water was added and the suspension was extracted with dichloromethane. The combined organic layers were dried and evaporated, and the residue was column chromatographed on silica gel 60 (100 g) with chloroform/acetone mixture as the eluant. The major red band gave the product (compound 4) as a red solid (177 mg, 85%).
Reaction SMILES: CN(C)C=O.Br[CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28].[C:29]([O-:32])(=[O:31])[CH3:30].[K+]>O>[C:29]([O:32][CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[N:18]([CH3:19])[N:17]=[C:16]([C:20]3[C:25]([F:26])=[CH:24][CH:23]=[CH:22][C:21]=3[Cl:27])[N:15]=2)=[CH:10][C:9]=1[Cl:28])(=[O:31])[CH3:30]
Reactant: Cn1nc(-c2c(F)cccc2Cl)nc1-c1ccc(CBr)c(Cl)c1
Reactant: CC(=O)[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CC(=O)OCc1ccc(-c2nc(-c3c(F)cccc3Cl)nn2C)cc1Cl
Temperature: 130 °C
Reaction time: 3 h
Yield: 51.1 %

Procedure:
To N,N-dimethylformamide (200 ml) are added 5-(4-bromomethyl-3-chlorophenyl)-3-(2-chloro-6-fluorophenyl)-1-methyl-1H-1,2,4-triazole (24.3 g) and potassium acetate (29.0 g), which are stirred at 130° C. for 3 hours. The reaction mixture is cooled to room temperature, poured into water and extracted with ethyl acetate. The organic layer is washed with water, dried over anhydrous magnesium sulfate and concentrated under reduced pressure. The concentrate is purified by silica gel column chromatography using mixed solvent of hexane-ethyl acetate as eluent to give 11.8 g of desired compound.
Reaction SMILES: [C:1]1([CH2:7][CH2:8][O:9][CH2:10][CH2:11][CH2:12][CH2:13][C:14](=O)[CH3:15])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH2:17]([NH2:24])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1>C1(C)C=CC=CC=1.C(O)C.[Pt]=O>[CH3:15][CH:14]([NH:24][CH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[CH2:13][CH2:12][CH2:11][CH2:10][O:9][CH2:8][CH2:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: CC(=O)CCCCOCCc1ccccc1
Reactant: NCc1ccccc1
Agent: O=[Pt]
Solvent: Cc1ccccc1
Solvent: CCO
Product: CC(CCCCOCCc1ccccc1)NCc1ccccc1
Yield: 97.4 %

Procedure:
The product of step (i) (4.16 g) and benzylamine (2.03 g) in toluene (50 ml) was refluxed using a Dean-Stark apparatus for 1 h. The toluene solution in ethanol (100 ml) was hydrogenated over pre-reduced 5% platinum oxide on charcoal (0.40 g). The reaction mixture was filtered (hyflo) and evaporated to give an oil (5.73 g) which was purified by FCC eluting with EA-CX (1:4)+1% TE to give the title compound as a yellow oil (4.51 g). T.l.c. (EA-CX 1:4+few drops TE) Rf 0.11.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][C:9]([C:12]3[CH:13]=[C:14](N)[CH:15]=[CH:16][CH:17]=3)=[N:10][CH:11]=2)[CH:3]=[N:2]1.[I:19]CI.N(OCCC(C)C)=O>O1CCOCC1.[Cu]I>[I:19][C:14]1[CH:13]=[C:12]([C:9]2[N:8]=[CH:7][C:6]([C:4]3[CH:3]=[N:2][NH:1][CH:5]=3)=[CH:11][N:10]=2)[CH:17]=[CH:16][CH:15]=1
Reactant: ICI
Reactant: Nc1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Agent: [Cu]I
Agent: CC(C)CCON=O
Solvent: C1COCCO1
Product: Ic1cccc(-c2ncc(-c3cn[nH]c3)cn2)c1
Temperature: 100 °C
Reaction time: 2 h
Yield: 37.8 %

Procedure:
To a suspension of 3-[5-(1H-Pyrazol-4-yl)-pyrimidin-2-yl]-phenylamine (12.6 g; 53.2 mmol; 1.0 eq.) in Dioxane (500 mL) were added diiodomethane (21.6 mL; 266 mmol; 5.0 eq.), Copper(I) iodide (10.1 g; 53.2 mmol; 1.0 eq.) and isopentyl nitrite (21.5 mL; 159 mmol; 3.0 eq.). The reaction mixture was stirred at 100° C. for 2 hours and filtered. The filtrate was kept in a flask. The resulting green solid was suspended in dioxane (100 mL) and stirred at 100° C. for 30 minutes. The solid was then filtered off and the two filtrates were combined and concentrated under reduced pressure. The dark brown residue was sonicated in EtOAc (20 mL) and pentane (80 mL). The resulting brown solid was filtered, further washed with pentane and dried few hours under high vacuum to give the title compound as a brown solid (7.0 g; 38%). 1H NMR (300 MHz, DMSO-d6) δ 13.27 (brs, 1H), 9.20 (s, 2H), 8.71 (t, J=1.5 Hz, 1H), 8.52 (m, 1H), 8.39 (dt, J=8.0 Hz, 1.5 Hz, 1H), 8.21 (m, 1H), 7.89-7.86 (m, 1H), 7.35 (t, J=8.0 Hz, 1H). HPLC (Condition A): Rt 3.86 min (purity 67.6%). MS (ESI+): 349.3
Reaction SMILES: [N+:1]([C:4]1[CH:30]=[CH:29][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([O:26]CC)=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl>C(O)C.O1CCCC1.[OH-].[Na+]>[N+:1]([C:4]1[CH:5]=[CH:6][C:7]([C:8]([N:10]2[C:16]3[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=3[C:14]3[S:21][C:22]([C:24]([OH:26])=[O:25])=[CH:23][C:13]=3[CH2:12][CH2:11]2)=[O:9])=[CH:29][CH:30]=1)([O-:3])=[O:2]
Reactant: CCOC(=O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(s1)-c1ccccc1N(C(=O)c1ccc([N+](=O)[O-])cc1)CC2
Temperature: 25 °C
Reaction time: 22 h
Yield: 96.4 %

Procedure:
A mixture of 0.80 g of ethyl 4,5-dihydro-6-(4-nitrobenzoyl)-6H-thieno[3,2-d][1]-benzazepine-2-carboxylate in 25 ml of ethanol, 6 ml of tetrahydrofuran and 3.13 ml of 1M sodium hydroxide is stirred at room temperature for 22 hours. The mixture is acidified with 2 ml of 2M HCl and the solvents removed. The residue is dried under vacuum and extracted several times with CHCl3 --CH3 OH (1:1). The extracts are combined and the solvent removed to give 0.72 g of 4,5-dihydro-6-(4-nitro-benzoyl)-6H-thieno[3,2-d][1]benzazepine-2-carboxylic acid as a yellow solid; mass spectrum (CI) 395 (MH+).
Reaction SMILES: [O:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.C([Li])CCC.[O:11]1[CH:15]=[C:14]([CH:16]=[O:17])[N:13]=[CH:12]1>C1COCC1>[O:1]1[CH:5]=[C:4]([CH:16]([C:14]2[N:13]=[CH:12][O:11][CH:15]=2)[OH:17])[N:3]=[CH:2]1
Reactant: O=Cc1cocn1
Reactant: c1cocn1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: OC(c1cocn1)c1cocn1
Temperature: -78 °C
Reaction time: 0.67 h
Yield: 29.6 %

Procedure:
A round bottom flask was charged with oxazole (476 μL, 7.2 mmol) and THF (100 mL). The solution was cooled to −78° C. A solution of n-butyllithium (2.3M in hexanes, 3.5 mL, 8.05 mmol) was added dropwise. After stirring at −78° C. for 40 min, a solution of oxazole-4-carbaldehyde (773 mg, 7.96 mmol, in 8 mL THF) was added dropwise. The reaction was allowed to warm to room temperature. After 30 min, the reaction was quenched with sat NH4Cl and extracted with CH2Cl2 (3×). The organics were dried (Na2SO4), filtered, and concentrated under reduced pressure. The residue was chromatographed on a silica gel column (100% CH2Cl2 to 10% MeOH in CH2Cl2) and yielded bis(oxazol-4-yl)methanol (354 mg, 29%) as a light brown solid. 1H NMR 400 MHz (CDCl3) δ 7.93 (s, 2H), 7.73 (s, 2H), 5.87 (s, 1H), 3.52 (s, 1H). LCMS (ESI, m/z): 167 [M+H]+.
Reaction SMILES: [Br:1][C:2]1[C:7]([OH:8])=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:14])[F:13])=[CH:4][CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:22][C:23]1([CH2:27][OH:28])[CH2:26][O:25][CH2:24]1>C(#N)C>[Br:1][C:2]1[C:7]([O:8][CH2:22][C:23]2([CH2:27][OH:28])[CH2:26][O:25][CH2:24]2)=[C:6]([O:9][CH3:10])[C:5]([O:11][CH:12]([F:13])[F:14])=[CH:4][CH:3]=1
Reactant: OCC1(CBr)COC1
Reactant: COc1c(OC(F)F)ccc(Br)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Product: COc1c(OC(F)F)ccc(Br)c1OCC1(CO)COC1
Temperature: 80 °C
Yield: 10.9 %

Procedure:
To a stirring solution of 6-bromo-3-(difluoromethoxy)-2-methoxyphenol (200 mg, 0.743 mmol) in acetonitrile (10 mL) was added potassium carbonate (307 mg, 2.23 mmol) and (3-(bromomethyl)oxetan-3-yl)methanol (267 mg, 1.48 mmol) and the resultant reaction mixture was heated to 80° C. for 16 h. The reaction mixture was cooled to RT, filtered through celite and the filtrate was concentrated under reduced pressure to afford 30 mg of (3-((6-Bromo-3-(difluoromethoxy)-2-methoxyphenoxy)methyl)oxetan-3-yl)methanol as a solid.
Reaction SMILES: [CH:1]([C:9]1[NH:13][C:12]2[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=2[N:10]=1)=[CH:2][C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[Cl:18][C:19]1[C:24]([C:25]#[N:26])=[CH:23][CH:22]=[CH:21][N:20]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.Cl>CO>[ClH:18].[C:25]([C:24]1[C:19]([N:13]2[C:12]3[CH:14]=[CH:15][CH:16]=[CH:17][C:11]=3[N:10]=[C:9]2[CH:1]=[CH:2][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=2)=[N:20][CH:21]=[CH:22][CH:23]=1)#[N:26]
Reactant: N#Cc1cccnc1Cl
Reactant: C(=Cc1nc2ccccc2[nH]1)c1ccccc1
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: N#Cc1cccnc1-n1c(C=Cc2ccccc2)nc2ccccc21

Procedure:
Free base of the titled compound was prepared from 2-styryl-1H-benzimidazole and 2-Chloro-3-Cyanopyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from ethyl acetate to give the titled compound. MW: 334.38; mp: 171.5-172.5° C.; 1H-NMR (CDCl3) δ: 8.98 (1H, dd, J=4.8, 1.8 Hz) 8.32 (1H, dd, J=7.7, 1.8 Hz), 7.98 (1H, d, J=16.1 Hz), 7.89-7.85 (1H, m), 7.67 (1H, dd, J=7.7, 4.8 Hz), 7.52-7.47 (2H, m), 7.42-7.26 (5H, m), 7.23-7.19 (1H, m), 6.83 (1H, d, J=16.1 Hz).