Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: BrCCCCC(C)(C1C=CC(C)=CC=1)CO.[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1)[C:24](OCC)=[O:25].[Li+].[BH4-].CO>C(Cl)Cl>[Br:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][C:23]([CH3:35])([C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1)[CH2:24][OH:25]
Reactant: CCOC(=O)C(C)(CCCCCBr)c1ccccc1
Agent: Cc1ccc(C(C)(CO)CCCCBr)cc1
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(CO)(CCCCCBr)c1ccccc1
Yield: 97.7 %

Procedure:
According to the procedure given for the synthesis of 206e, 205h (60.0 g, 183 mmol) was reduced with LiBH4 (5.96 g, 274 mmol) and methanol (8.55 g, 269 mmol) in anhydrous CH2Cl2 (390 mL). After the typical workup, crude 206h (51.0 g, 98%) was obtained as a yellowish oil, which was used without further purification for the next step. 1H NMR (CDCl3): δ 7.25-7.08 (m, 5H), 3.64 (d, 1H, J=7.2), 3.50 (d, 1H, J=7.2), 3.35 (t, 2H, J=6 Hz), 1.92-0.95 (m, 9H), 1.28 (s, 3H). 13C NMR (CDCl3): δ 144.77, 128.51, 126.76, 126.21, 72.63, 43.45, 38.37, 34.06, 32.73, 28.96, 23.12, 21.59. HRMS (EI): Calcd for C14H21BrO (M+): 284.0776, found: 284.0787.
Reaction SMILES: [F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:19]=[C:18]([NH:20][C:21]3[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=3)[C:17]([OH:27])=[CH:16][N:15]=2)=[N:6]1.Br[CH2:33][CH:34](O)[CH2:35][OH:36].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]1[CH:31]=[CH:30][CH:29]=[CH:28][C:3]=1[CH2:4][N:5]1[C:13]2[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=2)[C:7]([C:14]2[N:15]=[CH:16][C:17]3[O:27][CH2:33][CH:34]([CH2:35][OH:36])[N:20]([C:21]4[CH:26]=[CH:25][N:24]=[CH:23][CH:22]=4)[C:18]=3[N:19]=2)=[N:6]1
Reactant: OCC(O)CBr
Reactant: Oc1cnc(-c2nn(Cc3ccccc3F)c3ccccc23)nc1Nc1ccncc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCC1COc2cnc(-c3nn(Cc4ccccc4F)c4ccccc34)nc2N1c1ccncc1
Temperature: 100 °C
Reaction time: 18 h

Procedure:
25 mg of 2-[1-(2-fluorobenzyl)-1H-indazol-3-yl]-4-(pyridin-4-ylamino)pyrimidin-5-ol (3-3, 0.061 mmol, 1. eq.), 28.2 mg of 3-bromopropane-1,2-diol (0.182 mmol, 3 eq.) and 41.9 mg of potassium carbonate (0.303 mmol, 5 eq.) were suspended in 470 μl of dry DMF under nitrogen atmosphere. The reaction mixture was stirred at 100° C. bath temperature for 18 hours. Then the mixture was partitioned between aqueous half saturated sodium chloride solution and ethyl acetate. The phases were separated and the aqueous layer was extracted once with ethyl acetate and once with dichloromethane/isopropanol 4:1. The combined organic layers were dried over magnesium sulfate and concentrated in vacuo. The residue was purified by preparative TLC in dichloromethane/methanol 9:1 to yield 6.26 mg (0.01 mmol, 19.8%) of the analytically pure target compound.
Reaction SMILES: [CH:1]([C@H:3]1[CH2:8][CH2:7][C@H:6]([CH2:9]O)[CH2:5][CH2:4]1)=[CH2:2].N1C=CN=C1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[I:35]I>C1(C)C=CC=CC=1>[I:35][CH2:9][C@H:6]1[CH2:7][CH2:8][C@H:3]([CH:1]=[CH2:2])[CH2:4][CH2:5]1
Reactant: II
Reactant: C=C[C@H]1CC[C@H](CO)CC1
Agent: c1c[nH]cn1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: Cc1ccccc1
Product: C=C[C@H]1CC[C@H](CI)CC1
Temperature: 5 °C

Procedure:
Under a nitrogen atmosphere, (trans-4-vinyl cyclohexyl) methanol (7) (12.0 g), imidazole (7.6 g), and triphenylphosphine (Ph3P) (29.2 g) were put in toluene (200 ml) and stirred at 5° C. Iodine (27.2 g) was divided into 10 parts and added thereto in the temperature range of 5 to 10° C., and then stirred for another 3 hours . Completion of the reaction was confirmed by means of gas chromatographic analysis. The deposit was removed from the reaction mixture obtained by filtration, and the solvent was distilled off from the filtrate under reduced pressure. The residue obtained was purified with a fractional operation by means of column chromatography using heptane as the eluent and silica gel as the stationary phase powder, and dried, giving 15.2 g of 1-iodomethyl-trans-4-vinylcyclohexane (8). The yield based on the compound (7) was 71.0%.
Reaction SMILES: Br[CH2:2][C:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)=[O:4].C(N(CC)C(C)C)(C)C.[C:40]1([C@@H:46]([CH2:48][OH:49])[NH2:47])[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1>C1COCC1>[OH:4][C@H:3]([C:5]1[CH:6]=[CH:7][C:8]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:9]([N:11]([CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[S:12]([CH3:15])(=[O:14])=[O:13])[CH:10]=1)[CH2:2][NH:47][C@@H:46]([C:40]1[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=1)[CH2:48][OH:49]
Reactant: CS(=O)(=O)N(Cc1ccccc1)c1cc(C(=O)CBr)ccc1OCc1ccccc1
Reactant: N[C@H](CO)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CS(=O)(=O)N(Cc1ccccc1)c1cc([C@@H](O)CN[C@H](CO)c2ccccc2)ccc1OCc1ccccc1
Temperature: 25 °C
Reaction time: 5 h
Yield: 56.4 %

Procedure:
A solution of N-{5-(bromoacetyl)-2-[(phenylmethyl)oxy]phenyl}-N-(phenylmethyl) methanesulfonamide (570 mg) in THF (15 ml) was treated with N,N-diisopropylethylamine (0.41 ml) and (S)-(+)-2-phenylglycinol (191.8 mg). The mixture was stirred at room temperature for 5 h. The solvent was removed in vacuo and the resulting solid was suspended in dry MeOH (15 ml). The resulting suspension was cooled to 0°, treated with calcium carbonate (359 mg) and stirred for 0.5 h. The reaction mixture was treated with NaBH4 (88.8 mg), portionwise at 0° and was then allowed to warm to room temperature and stirred for 64 h. The mixture was concentrated in vacuo and the residue was partitioned between EtOAc and water. The organic phase was dried (MgSO4) and concentrated in vacuo. The mixture was purified by column chromatography (SPE, gradient 0 to 15% [MeOH-ammonia (10:1)] in DCM) to afford the title compound (360 mg).
Reaction SMILES: [OH:1][C@:2]1([C:16]2[S:17][CH:18]=[CH:19][N:20]=2)[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:4][CH2:3]1.C1C(=O)N([Br:28])C(=O)C1.[O-]S([O-])=O.[Na+].[Na+]>CN(C=O)C.O>[Br:28][C:18]1[S:17][C:16]([C@@:2]2([OH:1])[CH2:8][CH2:7][CH2:6][N:5]([C:9]([O:11][C:12]([CH3:13])([CH3:14])[CH3:15])=[O:10])[CH2:4][CH2:3]2)=[N:20][CH:19]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: CC(C)(C)OC(=O)N1CCC[C@](O)(c2nccs2)CC1
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CC(C)(C)OC(=O)N1CCC[C@](O)(c2ncc(Br)s2)CC1
Temperature: 40 °C
Yield: 94.7 %

Procedure:
The product of Step 2 (14.5 g, 48.6 mmol) was dissolved in DMF (58 mL) and then treated with NBS (11.24 g, 63.2 mmol) and warmed to 40° C. for 3 hours. The reaction was quenched with Na2SO3 (3.0 g, 24.30 mmol) in H2O (50 mL) and the solution was then extracted with EtOAc (100 mL), washed with brine (50 mL) and then chromatographed on silica gel to afford tert-butyl (4R)-4-(5-bromo-1,3-thiazol-2-yl)-4-hydroxyazepane-1-carboxylate (18.3 g, 46 mmol). MS ESI: [M+H-tBu]+ m/z 320.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH2:22])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1.[CH3:23][N:24]=[C:25]=[O:26]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([S:8]([C:11]2[CH:20]=[C:19]3[C:14]([CH2:15][CH2:16][C@H:17]([CH2:21][NH:22][C:25]([NH:24][CH3:23])=[O:26])[O:18]3)=[CH:13][CH:12]=2)(=[O:10])=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Solvent: ClCCl
Product: CNC(=O)NC[C@H]1CCc2ccc(S(=O)(=O)c3cccc(F)c3)cc2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.8 %

Procedure:
To a solution of C—[(R)-7-(3-Fluoro-benzenesulfonyl)-chroman-2-yl]-methylamine (0.130 g, 0.405 mmol) in methylene chloride (10 mL) at 0° C. was added methyl isocyanate (0.115 g, 2.03 mmol). The mixture was stirred at room temperature for one hour, and was then quenched by addition of MeOH. The mixture was partitioned between water and methylene chloride, and the organic phase was washed with water and brine, dried (Na2SO4), filtered and contrated under reduced pressure. Purification of the residue by flash chromatography (hexanes:EtOAc 1:9) gave 0.153 g of 1-[(R)-7-(3-fluoro-benzenesulfonyl)-chroman-2-ylmethyl]-3-methyl-urea as a foam. MS (M+H)=379.
Reaction SMILES: [CH:1]12[CH2:10][CH:5]3[CH2:6][CH:7]([CH2:9][CH:3]([CH2:4]3)[CH:2]1[C:11]([OH:13])=[O:12])[CH2:8]2.CO.[CH3:16][Si](C=[N+]=[N-])(C)C>C(OCC)(=O)C>[CH:3]12[CH2:9][CH:7]3[CH2:6][CH:5]([CH2:10][CH:1]([CH2:8]3)[CH:2]1[C:11]([O:13][CH3:16])=[O:12])[CH2:4]2
Reactant: O=C(O)C1C2CC3CC(C2)CC1C3
Reactant: C[Si](C)(C)C=[N+]=[N-]
Solvent: CCOC(C)=O
Solvent: CO
Product: COC(=O)C1C2CC3CC(C2)CC1C3
Temperature: 25 °C
Reaction time: 14 h

Procedure:
To a solution of adamantane-2-carboxylic acid 1 (0.486 g, 2.70 mmol) in ethyl acetate (10 mL)/methanol (5 mL) was dropwise added (trimethylsilyl)diazomethane (1.348 ml, 2.70 mmol) and the mixture was stirred at room temperature for 14 hours. The reaction mixture was concentrated and purified by flash chromotography (silica 40 g, 0%-30% ethyl acetate/hexanes).
Reaction SMILES: [C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([O-:18])=O)[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Na+].C(Cl)(=O)C([Cl:23])=O>C(Cl)Cl.CN(C)C=O>[C:1]([O:9][C:10]1[CH:14]=[C:13]([CH2:15][C:16]([Cl:23])=[O:18])[O:12][N:11]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])Cc1cc(OC(=O)c2ccccc2)no1
Reactant: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: O=C(Cl)Cc1cc(OC(=O)c2ccccc2)no1
Reaction time: 0.5 h

Procedure:
0.59 g of sodium (3-benzoyloxyisoxazol-5-yl)acetate was suspended in 5 ml of methylene chloride, and 0.37 ml of oxalyl chloride were then added, with ice-cooling. After adding one drop of N,N-dimethylformamide, the mixture was stirred for 30 minutes. The solvent was then distilled off under reduced pressure to give (3-benzoyloxyisoxazol-5-yl)acetyl chloride, which was then dissolved in 5 ml of methylene chloride. This solution was added dropwise to a solution of 685 mg of benzhydryl 3-acetoxymethyl-7β-amino-7α-methoxy-3-cephem-4-carboxylate and 325 mg of N,N-diethylaniline in 5 ml of methylene chloride, maintaining the internal temperature at about -10° C. After stirring the mixture at a temperature between -10° C. and -5° C. for 45 minutes, the reaction mixture was evaporated to dryness under reduced pressure and the residue was adsorbed on a silica gel preparative thin layer chromatograph and developed by a 2:1 by volume mixture of benzene and ethyl acetate. The portion having an Rf value of 0.54 was extracted to give 660 mg (64.7%) of the benzhydryl ester of the desired Compound No. 4.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[C:3]([CH2:10][C:11]([OH:13])=O)=[CH:2]1.[CH3:14][NH:15][C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1.C1(N=C=N)CCCCC1>O1CCCC1>[CH3:14][N:15]([C@@H:16]1[CH2:21][CH2:20][CH2:19][CH2:18][C@H:17]1[N:22]1[CH2:26][CH2:25][CH2:24][CH2:23]1)[C:11](=[O:13])[CH2:10][C:3]1[C:4]2[C:9](=[CH:8][CH:7]=[CH:6][CH:5]=2)[NH:1][CH:2]=1
Reactant: CN[C@@H]1CCCC[C@H]1N1CCCC1
Reactant: O=C(O)Cc1c[nH]c2ccccc12
Agent: N=C=NC1CCCCC1
Solvent: C1CCOC1
Product: CN(C(=O)Cc1c[nH]c2ccccc12)[C@@H]1CCCC[C@H]1N1CCCC1

Procedure:
1H-Indole 3-acetic acid (1.05 g, Aldrich) and trans-N-methyl-2-(1-pyrrolidinyl)cyclohexanamine were dissolved in tetrahydrofuran (30 ml) and cyclohexyl carbodiimide (1.24 g) added. The resultant solution was stirred at room temperature overnight, during which time a white precipitate appeared. The solution was filtered and evaporated to an oil, which was chromatographed on silica. Elution with ether gave the product as a white solid (1.3 g), mp 175°-178° C.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2.[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH2:24]>>[F:21][C:22]1[CH:28]=[CH:27][CH:26]=[CH:25][C:23]=1[NH:24][C:2]1[CH:11]=[CH:10][N:9]=[C:8]2[C:3]=1[C:4]1[CH:16]=[C:15]([O:17][CH3:18])[C:14]([O:19][CH3:20])=[CH:13][C:5]=1[C:6](=[O:12])[NH:7]2
Reactant: COc1cc2c(=O)[nH]c3nccc(Cl)c3c2cc1OC
Reactant: Nc1ccccc1F
Product: COc1cc2c(=O)[nH]c3nccc(Nc4ccccc4F)c3c2cc1OC
Yield: 3.2 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 212 using Compound 211 (50 mg, 0.17 mmol) and 2-fluoroaniline (25 mg, 0.22 mmol) to provide 216 (2 mg, 3% yield) as a white solid. LC-MS (M+H=366, obsd.=366).
Reaction SMILES: [C:1]1([OH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:8](Cl)([Cl:10])=[O:9]>CN(C)C=O>[C:1]1([O:7][C:8]([Cl:10])=[O:9])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: Oc1ccccc1
Reactant: O=C(Cl)Cl
Solvent: CN(C)C=O
Product: O=C(Cl)Oc1ccccc1

Procedure:
In a device provided with a deep-freezing cooler as described in Example 1 a mixture of 94 g of phenol and 15 g of N,N-dimethyl-formamide was reacted at 80° C within 3 hours with 150 g of phosgene. After the reaction had been completed, the mixture was distilled. About 110g of chloroformic acid phenyl ester were obtained. In the distillation flask, a strongly hygroscopic residue remained wich served as catalyst for the following reaction.
Reaction SMILES: [H-].[Na+].[S:3]1[CH:7]=[CH:6][CH:5]=[C:4]1[CH:8]1[CH2:13][C:12](=[O:14])[CH2:11][C:10](=[O:15])[CH2:9]1.Cl[CH2:17][C:18](=O)[CH3:19]>CN(C)C=O>[CH3:19][C:18]1[C:11]2[C:10](=[O:15])[CH2:9][CH:8]([C:4]3[S:3][CH:7]=[CH:6][CH:5]=3)[CH2:13][C:12]=2[O:14][CH:17]=1
Reactant: CC(=O)CCl
Reactant: O=C1CC(=O)CC(c2cccs2)C1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: Cc1coc2c1C(=O)CC(c1cccs1)C2
Temperature: 25 °C
Reaction time: 1 h
Yield: 15 %

Procedure:
In dimethylformamide (10 ml) was suspended 60% sodium hydride (0.44 g, washed with hexane thrice), and to the suspension was added 5-(2-thienyl)cyclohexane-1,3-dione (1.9 g) and then was added chloroacetone (0.92 g). The mixture was stirred at room temperature for 1 hour and then at 150° C. for 13 hours. Under reduced pressure, the solvent was evaporated, and the residue was dissolved in ethyl acetate. The solution was washed with water and saturated brine, dried with magnesium sulfate and concentrated under reduced pressure, and the residue was purified with silica gel column chromatography (EtOAc/hexane). The resulting crystals were recrystallized from hexane to give colorless crystals of 3-methyl-6-(2-thienyl)-4,5,6,7-tetrahydrobenzofuran-4-one (0.34 g).
Reaction SMILES: OS(O)(=O)=O.[O:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[CH2:8][CH2:7]1.[CH3:17][O:18][C:19](=[O:28])[C:20]1[CH:25]=[CH:24][C:23]([CH:26]=O)=[CH:22][CH:21]=1>C(O)(=O)C>[O:16]=[C:9]1[C:10]2[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=2)[O:6][CH2:7][C:8]1=[CH:26][C:23]1[CH:24]=[CH:25][C:20]([C:19]([O:18][CH3:17])=[O:28])=[CH:21][CH:22]=1
Reactant: COC(=O)c1ccc(C=O)cc1
Reactant: O=C1CCOc2ccccc21
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: COC(=O)c1ccc(C=C2COc3ccccc3C2=O)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 82.2 %

Procedure:
Concentrated H2SO4 (2 ml) was slowly added to a solution of 4-chromanone (2.00 g, 13.50 mmol) and methyl-4-formylbenzoate (2.11 g, 12.86 mmol) in glacial acetic acid. The reaction mixture was stirred 16 h at room temperature. The solvent was concentrated to half volume the resulting precipitate was filtered and rinsed with ethyl acetate to afford the title compound 260 (3.11 g, 82%) as a purple solid. 1H NMR: (DMSO) δ (ppm): 8.05 (d, J=8.2 Hz, 2H), 7.90 (d, J=7.6 Hz, 1H), 7.79 (s, 1H), 7.64-7.59(m, 3H), 7.15 (dd, J=7.6, 7.6 Hz, 1H), 7.07 (d, J=8.2 Hz, 1H), 5.43 (s, 2H), 3.89 (s, 3H).
Reaction SMILES: FC(F)(F)S([O-])(=O)=O.C[N+]1[CH:14]=[CH:13][N:12]([S:15]([N:18]2[CH2:23][CH2:22][O:21][CH2:20][CH2:19]2)(=[O:17])=[O:16])C=1.[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=C(N)C=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1>C(#N)C>[C@H:24]1([NH:33][C:34]2[CH:43]=[CH:42][C:41]3[C:36](=[CH:37][CH:38]=[C:13]([NH:12][S:15]([N:18]4[CH2:19][CH2:20][O:21][CH2:22][CH2:23]4)(=[O:16])=[O:17])[CH:14]=3)[N:35]=2)[C:32]2[C:27](=[CH:28][CH:29]=[CH:30][CH:31]=2)[CH2:26][CH2:25]1
Reactant: Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1
Reactant: C[n+]1ccn(S(=O)(=O)N2CCOCC2)c1
Agent: O=S(=O)([O-])C(F)(F)F
Solvent: CC#N
Product: O=S(=O)(Nc1ccc2nc(N[C@@H]3CCc4ccccc43)ccc2c1)N1CCOCC1
Temperature: 80 °C
Reaction time: 16 h
Yield: 45.8 %

Procedure:
1-Methyl-3-(morpholine-4-sulfonyl)-3H-imidazol-1-ium trifluoromethanesulfonate (0.139 g, 0.36 mmol) and (R)—N2-indan-1-yl-quinoline-2,6-diamine (0.10 g, 0.36 mmol) were dissolved in acetonitrile (2 mL) and stirred for 16 h at 80° C. The solvent was removed and the residue subjected to column chromatography (silica gel, heptane, ethyl acetate 4:1/1:1) to yield morpholine-4-sulfonic acid [2-((R)-indan-1-ylamino)-quinolin-6-yl]-amide (0.07 g, 45%) as a yellow solid; MS: m/e=425.7 (M+H+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][N:4]1[CH2:9][CH2:8][NH:7][CH2:6][CH2:5]1.[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23]OS(C3C=CC(C)=CC=3)(=O)=O)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36].C1(C)C=CC=CC=1>O>[CH3:10][O:11][C:12]1[C:13]([CH3:38])=[C:14]([CH3:37])[C:15]2[O:20][C:19]([CH2:22][CH2:23][N:7]3[CH2:8][CH2:9][N:4]([CH2:3][CH2:2][OH:1])[CH2:5][CH2:6]3)([CH3:21])[CH2:18][CH2:17][C:16]=2[C:35]=1[CH3:36]
Reactant: OCCN1CCNCC1
Reactant: COc1c(C)c(C)c2c(c1C)CCC(C)(CCOS(=O)(=O)c1ccc(C)cc1)O2
Solvent: O
Solvent: Cc1ccccc1
Product: COc1c(C)c(C)c2c(c1C)CCC(C)(CCN1CCN(CCO)CC1)O2
Temperature: 25 °C
Yield: 81.4 %

Procedure:
A solution composed of 20 g of N-(2-hydroxyethyl)piperazine, 5 g of 3,4-dihydro-6-methoxy-2-[2-(p-toluenesulfonyloxy)ethyl]-2,5,7,8-tetramethyl-2H-benzopyran and 100 ml of toluene was refluxed for 8 hours in a nitrogen atmosphere. After cooling to room temperature, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water and dried over anhydrous sodium sulfate. Low-boiling substances were distilled off under reduced pressure and the residue was purified by silica gel column chromatography to give 3.66 g of 1-[2-(3,4-dihydro-6-methoxy-2,5,7,8-tetramethyl-2H-benzopyran-2-yl)ethyl]-4-(2-hydroxyethyl)piperazine [Compound (35)] having the following physical characteristics.
Reaction SMILES: [CH3:1][N:2]1[C:10]2[CH:9]=[C:8]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][NH:21][CH3:22])=[C:13]([C:23]([F:26])([F:25])[F:24])[CH:12]=3)[N:7]=[C:6]([C:27]#[N:28])[C:5]=2[N:4]=[CH:3]1.C(N(CC)CC)C.Cl.[CH3:37][N:38]1[CH2:43][CH2:42][CH2:41][CH2:40][CH:39]1[C:44]([OH:46])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2C=CC=CC=2N=N1>C(Cl)Cl>[C:27]([C:6]1[C:5]2[N:4]=[CH:3][N:2]([CH3:1])[C:10]=2[CH:9]=[C:8]([C:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][CH2:20][N:21]([CH3:22])[C:44]([CH:39]3[CH2:40][CH2:41][CH2:42][CH2:43][N:38]3[CH3:37])=[O:46])=[C:13]([C:23]([F:26])([F:24])[F:25])[CH:12]=2)[N:7]=1)#[N:28]
Reactant: CN1CCCCC1C(=O)O
Reactant: CNCCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(CCCOc1ccc(-c2cc3c(ncn3C)c(C#N)n2)cc1C(F)(F)F)C(=O)C1CCCCN1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 22.6 %

Procedure:
A mixture of 1-methyl-6-(4-(3-(methylamino)propoxy)-3-(trifluoromethyl)phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (50 mg), triethylamine (71 μL), 1-methylpiperidine-2-carboxylic acid hydrochloride (17 mg), and O-benzotriazol-1-yl-N,N,N′,N′-tetramethyluronium hexafluorophosphate (58 mg) in DCM (1.5 ml) was stirred overnight at room temperature. The mixture was washed with sodium bicarbonate and then purified by prep HPLC (acidic) to give the expected product (11 mg). NMR (CD3OD) δ: 8.29-8.52 (m, 4H), 7.27-7.40 (m, 1H), 4.16-4.36 (m, 2H), 4.06 (s, 3H), 3.58-3.92 (m, 2H), 2.86-3.27 (m, 5H), 2.14-2.37 (m, 6H), 1.26-1.90 (m, 6H). MS m/z 515 (M+H).
Reaction SMILES: C([N:20]1[C:24]2[CH:25]=[CH:26][C:27]([NH:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:28][C:23]=2[N:22]=[CH:21]1)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH2:46](Br)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1>C1COCC1.O>[CH2:46]([N:29]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[C:27]1[CH:26]=[CH:25][C:24]2[NH:20][CH:21]=[N:22][C:23]=2[CH:28]=1)[C:47]1[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=1
Reactant: c1ccc(Nc2ccc3c(c2)ncn3C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Reactant: BrCc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN(c2ccccc2)c2ccc3[nH]cnc3c2)cc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
N1-Trityl-N-phenyl-benzimidazol-5-amine (1.13 g; 2.5 mmol; 1 eq.) was dissolved in THF (5 ml), cooled to 0° C. and treated with lithiumbis(trimethylsilyl)amide 1M in THF (3 ml; 3 mmol; 1.2 eq.). Benzylbromide (3 mmol; 1.2 eq.) was added and stirred at room temperature for 24 h. The mixture was diluted with water and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was dissolved in MeOH (5 ml) and treated with TFA (1 ml). After heating to reflux overnight the mixture was poured into saturated NaHCO3-solution and extracted with ethyl acetate (3×25 ml). The combined organic layers were dried over Na2SO4 and evaporated. The residue was purified by flash chromatography on silica using a CHCl3/MeOH gradient. Yield: 0.046 g (6.2%); MS m/z: 300.1 [M+H]+; 1H-NMR, 500 MHz, 1H-NMR (500 MHz, DMSO d6): δ 5.00 (s, 2H); 6.70-6.73 (m, 1H); 6.78-6.79 (m, 2H); 7.06-7.08 (m, 1H); 7.10-7.13 (m, 2H); 7.18-7.21 (m, 1H); 7.29-7.31 (m, 2H); 7.36-7.37 (m, 3H); 7.54 (d, 1H, 3J=8.5 Hz); 8.30 (s, 1H); 12.32 (br s, 1H); HPLC (METHOD [A]): rt 15.47 min (95.1%)
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8](=S)[NH:9][N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1.[NH2:21][CH2:22][C:23]1([CH3:28])OCCO1.O>COCCO>[CH3:1][O:2][C:3]1[CH:20]=[CH:19][C:6]2[CH2:7][C:8]3[N:9]([C:23]([CH3:28])=[CH:22][N:21]=3)[N:10]=[C:11]([C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[C:5]=2[CH:4]=1
Reactant: COc1ccc2c(c1)C(c1ccccc1)=NNC(=S)C2
Reactant: CC1(CN)OCCO1
Solvent: O
Solvent: COCCO
Product: COc1ccc2c(c1)C(c1ccccc1)=Nn1c(C)cnc1C2

Procedure:
500 mg of 8-methoxy-1-(phenyl)-4,5-dihydro-3H-2,3-benzodiazepine-4-thione is stirred in 1.5 ml of ethylene glycol monomethyl ether (Cellosolve®) and 548 mg of 2-aminomethyl-2-methyl-1,3-dioxolane while argon is passing through it for 10 hours at 60° C. After filtration and washing with cold ethanol and diisopropyl ether, 550 mg of imino compound, which is dissolved in 10 ml of ethanol, mixed with 10 ml of concentrated hydrochloric acid and refluxed for 3 hours, is obtained. It is added to water, set at pH 11 and extracted with ethyl acetate. The ethyl acetate phase is washed with water, dried, filtered and concentrated by evaporation. After recrystallization from ethyl acetate/diisopropyl ether, 240 mg of 8-methoxy-3-methyl-6-phenyl-11H-imidazo[1,2-c][2,3]benzodiazepine with a melting point of 140° C. is obtained.