Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH:10]([C:14]([F:17])([F:16])[F:15])[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.Cl[C:25]([O:27][CH2:28][CH3:29])=[O:26]>C(Cl)Cl>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:10]([C:14]([F:17])([F:15])[F:16])[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)Cl
Reactant: FC(F)(F)C1CN(Cc2ccccc2)CCN1
Solvent: c1ccncc1
Solvent: ClCCl
Product: CCOC(=O)N1CCN(Cc2ccccc2)CC1C(F)(F)F
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 1-benzyl-3-(trifluoromethyl)piperazine 34a (1.0 mmol) and pyridine (1.1 mmol) in DCM (5 mL), is added ethyl chloroformate (1.1 mmol). The resulting mixture is stirred at rt for 1 h. After the reaction is complete, the reaction mixture is diluted with DCM (15 mL) and washed with water. The organic layer is separated, dried over Na2SO4, filtered, and concentrated to afford ethyl 4-benzyl-2-(trifluoromethyl)piperazine-1-carboxylate 34b, which is used without purification. MS (m/z) (M+1)+: 317.1.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]2[CH2:18][C:17]([CH3:20])([CH3:19])[N:16]([O:21][CH:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)[C:15]([CH3:29])([CH3:28])[CH2:14]2)[N:5]=[C:4]([NH:30][CH2:31][CH2:32][CH2:33][CH2:34][CH:35]2[CH2:40][C:39]([CH3:42])([CH3:41])[N:38]([O:43][CH:44]3[CH2:49][CH2:48][CH2:47][CH2:46][CH2:45]3)[C:37]([CH3:51])([CH3:50])[CH2:36]2)[N:3]=1.[NH2:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56]>>[CH:44]1([O:43][N:38]2[C:39]([CH3:42])([CH3:41])[CH2:40][CH:35]([CH2:34][CH2:33][CH2:32][CH2:31][NH:30][C:4]3[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH2:11][CH2:12][CH:13]4[CH2:14][C:15]([CH3:29])([CH3:28])[N:16]([O:21][CH:22]5[CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[C:17]([CH3:20])([CH3:19])[CH2:18]4)[N:7]=[C:2]([NH:52][CH2:53][CH2:54][C:55]([OH:57])=[O:56])[N:3]=3)[CH2:36][C:37]2([CH3:51])[CH3:50])[CH2:45][CH2:46][CH2:47][CH2:48][CH2:49]1
Reactant: NCCC(=O)O
Reactant: CC1(C)CC(CCCCNc2nc(Cl)nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)n2)CC(C)(C)N1OC1CCCCC1
Product: CC1(C)CC(CCCCNc2nc(NCCCCC3CC(C)(C)N(OC4CCCCC4)C(C)(C)C3)nc(NCCC(=O)O)n2)CC(C)(C)N1OC1CCCCC1

Procedure:
The title compound is prepared from the reaction of 2-chloro-4,6-bis[N-(1-cyclohexyloxy-2,2,6,6-tetramethylpiperidin-4-yl)butylamino]-1,3,5-triazine and β-alanine according to the procedure of Example 15.
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4][CH2:5][O:6][C:7]1[CH:22]=[CH:21][C:10]2[C:11]([C:14]3[CH:19]=[CH:18][C:17]([Br:20])=[CH:16][CH:15]=3)=[N:12][S:13][C:9]=2[CH:8]=1.[CH3:23][O:24][CH2:25][CH2:26][NH:27][CH2:28][CH2:29][O:30][CH3:31]>>[Br:20][C:17]1[CH:18]=[CH:19][C:14]([C:11]2[C:10]3[CH:21]=[CH:22][C:7]([O:6][CH2:5][CH2:4][CH2:3][CH2:2][N:27]([CH2:28][CH2:29][O:30][CH3:31])[CH2:26][CH2:25][O:24][CH3:23])=[CH:8][C:9]=3[S:13][N:12]=2)=[CH:15][CH:16]=1
Reactant: COCCNCCOC
Reactant: BrCCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1
Product: COCCN(CCCCOc1ccc2c(-c3ccc(Br)cc3)nsc2c1)CCOC

Procedure:
According to the method in example 5, 6-(4-Bromo-butoxy)-3-(4-bromo-phenyl)-benzo[d]isothiazole and bis(2-methoxyethyl)amine were converted to yield [4-[3-(4-Bromo-phenyl)-benzo[d]isothiazol-6-yloxy]-butyl]-bis-(2-methoxy-ethyl)-amine as light yellow oil, MS: 493 (MH+, 1Br).
Reaction SMILES: CS(O[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[C:17]([O:29][CH3:30])[C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[C:20]=2[O:23][CH3:24])[CH2:15]1)(=O)=O.[I-:31].[Na+].O>CC(C)=O>[I:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH:14]1[CH2:22][C:21]2[C:16](=[C:17]([O:29][CH3:30])[C:18]([O:27][CH3:28])=[C:19]([O:25][CH3:26])[C:20]=2[O:23][CH3:24])[CH2:15]1
Reactant: [I-]
Reactant: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCOS(C)(=O)=O)C2
Agent: [Na+]
Solvent: CC(C)=O
Solvent: O
Product: COc1c2c(c(OC)c(OC)c1OC)CC(CCCCCCCCI)C2
Yield: 96.5 %

Procedure:
The mixture of 8-(4,5,6,7-tetramethoxyindan-2-yl)octyl methanesulfonate (2.36 g), sodium iodide (2.38 g) in acetone (20 ml) was heated under reflux for 3 hr. Water was added to the reaction mixture, which was then extracted with ethyl acetate. The organic layer was washed with 5% aqueous sodium sulfite, water, and saturated aqueous sodium chloride, and dried. The solvent was removed in vacuo to yield the entitled compound (2.44 g) as an oil.
Reaction SMILES: [C@@H:1]1([N:9]2[C:19]3[N:18]=[C:16]([NH2:17])[NH:15][C:13](=O)[C:12]=3[N:11]=[CH:10]2)[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]1.FC(F)(F)C(OC(=O)C(F)(F)F)=O.[NH3:33]>N1C=CC=CC=1>[NH2:17][C:16]1[N:18]=[C:19]2[C:12]([N:11]=[CH:10][N:9]2[CH:1]2[O:8][C@H:5]([CH2:6][OH:7])[C@@H:3]([OH:4])[CH2:2]2)=[C:13]([NH2:33])[N:15]=1
Reactant: Nc1nc2c(ncn2[C@H]2C[C@H](O)[C@@H](CO)O2)c(=O)[nH]1
Reactant: N
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: c1ccncc1
Product: Nc1nc(N)c2ncn(C3C[C@H](O)[C@@H](CO)O3)c2n1
Yield: 34 %

Procedure:
To 2 mmol of deoxyguanosine, dried by evaporation of pyridine and suspended in 20 mL of dry pyridine was added dropwise 2.3 mL (16 mmol) of trifluoroacetic anhydride, with cooling in an ice bath. After ten minutes 20 mL of cold, concentrated aqueous ammonia was added. After a further 11/2 hours the mixture was evaporated to dryness, the residue dissolved in water and the solution filtered through a 100 mL portion of Bio Rad AG 1-X2, hydroxide from resin to remove colored impurities. The resin was washed with 40% methanol in water to elute crude 2,6-diamino-9-(2-deoxy-Beta-D-erythro-pentofuranosyl)purine, which was further purified on the reversed-phase column described above using a gradient of 2-15% acetonitrile in water. Evaporation of appropriate fractions gave 192 mg (34%) of 2,6-diamino-9-(2-deoxy-D-erythro-pentofuranosyl)purine, a sample crystallized from water gave a mp of 148°. UVmax (MeOH) 282 nm, UVmin 256 nm; 1H NMR (DMSO-d6) delta (ppm) 7.91 (s, 1,H8), 6.73 (br s, 2, NH2), 6.17 ("t", 1, Japp =6 Hz, H1'), 5.73 (br s, 2, NH2), 5.25 (m, 2, 3'-OH & 5'-OH), 4.35 (m, 1, H3'), 3.84 (m, 1, H4'), 3.54 (m,2,H5',5"), 2.59 & 2.17 (m & m, 1 & 1, H2' & H2"). Anal. Calcd. for C10H14N6O3.H2O: C, 42.25; H, 5.67; N, 29,56. Found: C, 42.54; H, 5.33; N, 29.56.
Reaction SMILES: [Br:1][C:2]1[C:3]([OH:13])=[CH:4][CH:5]=[C:6]2[C:11]=1[N:10]=[C:9]([CH3:12])[CH:8]=[CH:7]2.C(N(CC)C(C)C)(C)C.[C:23]1([S:29](Cl)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1>C(Cl)Cl>[C:23]1([S:29]([O:13][C:3]2[C:2]([Br:1])=[C:11]3[C:6]([CH:7]=[CH:8][C:9]([CH3:12])=[N:10]3)=[CH:5][CH:4]=2)(=[O:31])=[O:30])[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1
Reactant: Cc1ccc2ccc(O)c(Br)c2n1
Reactant: O=S(=O)(Cl)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ccc2ccc(OS(=O)(=O)c3ccccc3)c(Br)c2n1
Temperature: 0 °C
Reaction time: 14 h
Yield: 97.2 %

Procedure:
A mixture of 8-bromo-2-methylquinolin-7-ol (1.10 g, 4.62 mmol) and N,N-diisopropylethylamine (1.19 g, 9.24 mmol) were dissolved in anhydrous DCM (10 mL), and the solution was cooled to 0° C. Benzenesulfonyl chloride (0.90 g, 5.10 mmol) in 5 mL DCM was added over 10 min, and the reaction mixture was stirred for 14 h at room temperature under argon. Solvent was removed in vacuo, and residue was dissolved in EtOAc and washed twice with saturated aq. NaHCO3 and then dried over anhydrous Na2SO4. Solvent was removed in vacuo, and the residue was purified by SiO2 column chromatography (Hexanes/EtOAc=1/1) to yield SO185 as a white solid (1.70 g, 4.49 mmol, 97% yield). 13CNMR (ppm, 500 MHz, CDCl3, 298 K) δ 161.588, 148.067, 145.802, 136.573, 135.924, 134.834, 129.444, 128.907, 128.029, 126.122, 123.236, 121.950, 118.038, 25.922. 1HNMR (ppm, 400 MHz, CDCl3, 298 K) δ: 8.049 (d, 1H, J=8.4 Hz), 7.976 (m, 1H), 7.958 (m, 1H), 7.758 (d, 1H, J=8.8 Hz), 7.701-7.657 (m, 1H), 7.599 (d, 1H, J=8.8 Hz), 7.554-7.507 (m, 2H), 7.346 (d, 1H, J=8.0 Hz), 2.785 (s, 3H). MS-ESI (m/z): [M+H]+ calculated for C16H13BrNO3S, 378.0 (79Br) and 380.0 (81Br); found 378.0 (79Br) and 379.9 (81Br).
Reaction SMILES: [CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH3:26])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14].[OH:29][CH2:30][CH:31](CO)[OH:32]>>[CH2:1]([NH:15][C:16]1[CH:17]=[C:18]([CH:22]([CH2:27][CH3:28])[C:23]([O:25][CH2:26][CH:31]([OH:32])[CH2:30][OH:29])=[O:24])[CH:19]=[CH:20][CH:21]=1)[CH2:2][CH2:3][CH:4]=[CH:5][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH3:14]
Reactant: OCC(O)CO
Reactant: CCCCCCCCCC=CCCCNc1cccc(C(CC)C(=O)OC)c1
Product: CCCCCCCCCC=CCCCNc1cccc(C(CC)C(=O)OCC(O)CO)c1
Temperature: 180 °C

Procedure:
A mixture of 2.25 g. of methyl 3-(4-tetradecenylamino)phenylbutyrate, 280 mg. of glycerol, and 1.37 g. of p-touluenesulfonic acid is heated at 180° C. for 18 hours and then is partitioned between ether and 3% aqueous sodium carbonate solution. The ether layer is separated, dried, and evaporated to yield the product as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][NH:13][CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1.[CH2:20]=O>C(O)=O>[Br:1][C:2]1[C:7]2[O:8][CH2:9][C@@H:10]3[C@@H:15]([CH2:16][OH:17])[CH2:14][N:13]([CH3:20])[CH2:12][C@H:11]3[C:6]=2[CH:5]=[C:4]([O:18][CH3:19])[CH:3]=1
Reactant: C=O
Reactant: COc1cc(Br)c2c(c1)[C@@H]1CNC[C@H](CO)[C@H]1CO2
Solvent: O=CO
Product: COc1cc(Br)c2c(c1)[C@@H]1CN(C)C[C@H](CO)[C@H]1CO2

Procedure:
A solution of 1.65 g (±)-[4R*,4aS*,10bR*]-7-bromo-4-(hydroxymethyl)-1,3,4,4a,5,10b-hexahydro-9-methoxy-2H-[1]benzopyrano[4,3-c]pyridine in 0.5 ml 37% HCHO and 2.2 ml HCO2H is heated at 100° for 20 min. The reaction mixture is concentrated in vacuo and partitioned between 10 ml 2N NaOH and 50 ml CH2Cl2. The organic phase is dried over Na2SO4, filtered and concentrated under reduced pressure to yield the title compound; m.p. of HCl salt 262° dec.
Reaction SMILES: [NH:1]([C:29]([CH3:31])=[O:30])[C@@H:2]([C:10]([NH:12][C@H:13]([C:25]([O:27]C)=[O:26])[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[OH-].[Na+].O>O1CCOCC1.O>[NH:1]([C:29]([CH3:31])=[O:30])[C@@H:2]([C:10]([NH:12][C@H:13]([C:25]([OH:27])=[O:26])[CH2:14][C:15]1[CH:24]=[C:23]2[C:18]([CH:19]=[CH:20][CH:21]=[CH:22]2)=[CH:17][CH:16]=1)=[O:11])[CH2:3][C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1
Reactant: COC(=O)[C@H](Cc1ccc2ccccc2c1)NC(=O)[C@@H](Cc1ccccc1)NC(C)=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: O
Product: CC(=O)N[C@H](Cc1ccccc1)C(=O)N[C@@H](Cc1ccc2ccccc2c1)C(=O)O
Yield: 113.5 %

Procedure:
A solution of N-Ac-D-Phe-2-Nal-OMe (1.55 g) in 20 ml of dioxane/water=9/1 (v/v) was treated with sufficient 6N sodium hydroxide to keep the pH at 12 for 1 hours at room temperature. After acidification, the mixture was poured into water and was extracted with dichloromethane. The organic layer was washed with water and was dried on sodium sulfate. The filtrate was evaporated and yielded 1.7 g crude N-Ac-D-Phe-2-Nal-OH.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH2:8][OH:9])[CH:5]=[CH:4][N:3]=1.CCN(C(C)C)C(C)C.[CH3:19][S:20](Cl)(=[O:22])=[O:21]>ClCCl>[Br:1][C:2]1[CH:7]=[C:6]([CH2:8][O:9][S:20]([CH3:19])(=[O:22])=[O:21])[CH:5]=[CH:4][N:3]=1
Reactant: OCc1ccnc(Br)c1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)OCc1ccnc(Br)c1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a chilled (0° C.) solution of (2-bromopyridin-4-yl)-methanol (3.00 g, 16.0 mmol) and DIPEA (8.3 mL, 48 mmol) in dichloromethane (30 mL) is added methanesulfonyl chloride (1.30 mL, 16.8 mmol). The resulting mixture is warmed to room temperature. After 1 hour, the mixture is diluted with dichloromethane (20 mL) and washed with saturated aqueous ammonium chloride (3×10 mL), saturated aqueous sodium bicarbonate (10 mL) and brine (10 mL), dried over MgSO4, filtered and concentrated to afford crude methanesulfonic acid 2-bromopyridin-4-ylmethyl ester, which is used without purification.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:22])[CH2:5][CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[O:13])[CH2:8][CH2:7]1)[CH3:2].C[Si](C)(C)[N-][Si](C)(C)C.[Li+].[CH2:33](Br)[CH:34]=[CH2:35]>C1COCC1>[CH2:1]([O:3][C:4]([CH:5]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]([O:14][CH2:15][C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:35][CH:34]=[CH2:33])=[O:22])[CH3:2]
Reactant: C=CCBr
Reactant: CCOC(=O)CC1CCN(C(=O)OCc2ccccc2)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: C=CCC(C(=O)OCC)C1CCN(C(=O)OCc2ccccc2)CC1
Reaction time: 0.5 h
Yield: 72 %

Procedure:
To a −78 □C solution of benzyl 4-(2-ethoxy-2-oxoethyl)piperidine-1-carboxylate (5.02 g, 16.4 mmol) in THF (90 mL) was added lithium hexamethyldisilazide (1.0 M in THF, 18.1 mL, 18.1 mmol). After 1 h allyl bromide (2.19 g, 18.1 mmol) was added, the reaction stirred at this temperature for 0.5 h, then warmed to 25 □C. After 3 h the reaction was quenched by the addition of saturated aqueous ammonium chloride and extracted with ethyl acetate (2×). The combined organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. The crude product was purified by silica gel chromatography, eluting with a gradient of 0 to 60% EtOAc:hexanes to give the title compound (4.08 g). MS: m/z=346.1 (M+1).
Reaction SMILES: [Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[C:7](OCC)=[O:8].[Li+].[BH4-].CO>C(Cl)Cl>[Br:1][CH2:2][CH2:3][CH2:4][CH2:5][C:6]([CH3:13])([CH3:12])[CH2:7][OH:8]
Reactant: CCOC(=O)C(C)(C)CCCCBr
Agent: [BH4-]
Agent: [Li+]
Solvent: ClCCl
Solvent: CO
Product: CC(C)(CO)CCCCBr
Yield: 99.7 %

Procedure:
According to the procedure described for the synthesis of 206e (Ackerley, N. et al. J. Med. Chem. 1995, 38, 1608-1628; Manley, P. W. et al. J. Med. Chem. 1987, 30, 1812-1818), 205c (500.0 g, 2.0 mol) was reacted with LiBH4 (65.0 g, 3.0 mol) and methanol (95.0 g, 3.0 mol) in CH2Cl2 (6.0 L) to afford 206c (417.0 g, 99%) as an oil. 1H NMR (CDCl3): δ 3.38 (t, 2H, J=7.4), 3.50-3.40 (br. s, 1H, OH), 3.22 (d, 2H, J=5.6), 1.85 (qv, 2H, J=7.4), 1.50-1.35 (m, 2H), 1.30-1.20 (m, 2H), 0.85 (s, 6H). 13C NMR (CDCl3) δ 71.4, 37.5, 34.9, 33.9, 33.4, 23.7, 22.4.
Reaction SMILES: C[O:2][C:3](=[O:16])[C@H:4]([CH2:14][SH:15])[NH:5][C:6](=[O:13])[C@@H:7]1[CH2:11][CH2:10][C:9](=O)[NH:8]1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=[S:26])=CC=1.[OH-].[Na+]>>[S:26]=[C:9]1[NH:8][C@H:7]([C:6]([NH:5][C@H:4]([C:3]([OH:2])=[O:16])[CH2:14][SH:15])=[O:13])[CH2:11][CH2:10]1
Reactant: COC(=O)[C@H](CS)NC(=O)[C@@H]1CCC(=O)N1
Reactant: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Agent: [Na+]
Agent: [OH-]
Product: O=C(O)[C@H](CS)NC(=O)[C@@H]1CCC(=S)N1

Procedure:
Thionation of N-(5-oxo-L-prolyl)-L-cysteine methyl ester with the Lawesson's reagent and the subsequent alkali hydrolysis with two sodium hydroxide equivalents in aqueous solution yields N-(5-thioxo-L-prolyl)-L-cysteine.
Reaction SMILES: [CH3:1][C@H:2]1[N:15]2[C:6]([CH2:7][O:8][C:9]3[C:14]2=[CH:13][C:12](B2OC(C)(C)C(C)(C)O2)=[CH:11][CH:10]=3)=[N:5][NH:4][C:3]1=[O:25].[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([CH3:47])([C:37](OS(C(F)(F)F)(=O)=O)=[CH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27].C([O-])([O-])=O.[Na+].[Na+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[C:26]([O:30][C:31]([N:33]1[CH2:36][C:35]([CH3:47])([C:37]([C:12]2[CH:13]=[C:14]3[C:9](=[CH:10][CH:11]=2)[O:8][CH2:7][C:6]2[N:15]3[C@H:2]([CH3:1])[C:3](=[O:25])[NH:4][N:5]=2)=[CH2:38])[CH2:34]1)=[O:32])([CH3:29])([CH3:28])[CH3:27]
Reactant: C=C(OS(=O)(=O)C(F)(F)F)C1(C)CN(C(=O)OC(C)(C)C)C1
Reactant: C[C@@H]1C(=O)NN=C2COc3ccc(B4OC(C)(C)C(C)(C)O4)cc3N21
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1COCCO1
Solvent: O
Product: C=C(c1ccc2c(c1)N1C(=NNC(=O)[C@H]1C)CO2)C1(C)CN(C(=O)OC(C)(C)C)C1
Temperature: 90 °C
Reaction time: 8 h
Yield: 25.4 %

Procedure:
A mixture of (R)-4-methyl-6-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (Preparation #11, Step E, 2 g, 5.83 mmol), 3-methyl-3-(1-trifluoromethanesulfonyloxy-vinyl)-azetidine-1-carboxylic acid tert-butyl ester (Preparation #20 3.02 g, 8.74 mmol), Na2CO3 (1.235 g, 11.66 mmol) and Pd(Ph3P)4 (3.37 g, 2.91 mmol) in dioxane (20 mL) and water (5 mL) was stirred at 90° C. overnight. The reaction mixture was cooled to ambient temperature. The solvent was removed in vacuo and the residue was purified by column chromatography on silica gel (eluting with 0-30% EtOAc in petroleum ether) to give 3-methyl-3-[1-((R)-4-methyl-3-oxo-2,3,4,10-tetrahydro-9-oxa-1,2,4a-triaza-phenanthren-6-yl)-vinyl]-azetidine-1-carboxylic acid tert-butyl ester (0.610 g, 25%) as a solid. LC/MS (Table 1, Method 25) Rt=0.867 min.; MS m/z: 413 [M+H]+ and 357 [M+H−56]+. 1H NMR (CDCl3, 400 MHz): δ 8.10 (br. s., 1H), 6.98 (d, J=8.4 Hz, 1H), 6.83 (d, J=8.4 Hz, 1H), 6.78 (s, 1H), 5.33 (s, 1H), 5.10 (s, 1H), 4.74 (m, 1H), 4.67-4.56 (d, J=15.2 Hz, 2H), 4.11 (m, 2H), 3.79 (m, 2H), 1.61 (d, J=15.2 Hz, 3H), 1.55 (m, 3H). 1.46 (s, 9H).
Reaction SMILES: [NH2:1][CH:2]1[N:8]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)[C:6]2[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=2[NH:4][C:3]1=[S:19].[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([N:27]=[C:28]=[O:29])=[CH:23][CH:22]=1>O1CCCC1>[Cl:20][C:21]1[CH:26]=[CH:25][C:24]([NH:27][C:28]([NH:1][CH:2]2[N:8]=[C:7]([C:9]3[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=3)[C:6]3[CH:15]=[CH:16][CH:17]=[CH:18][C:5]=3[NH:4][C:3]2=[S:19])=[O:29])=[CH:23][CH:22]=1
Reactant: O=C=Nc1ccc(Cl)cc1
Reactant: NC1N=C(c2ccccc2)c2ccccc2NC1=S
Solvent: C1CCOC1
Product: O=C(Nc1ccc(Cl)cc1)NC1N=C(c2ccccc2)c2ccccc2NC1=S
Temperature: 25 °C

Procedure:
1,3-Dihydro-3-amino-5-phenyl-2H-1,4-benzodiazepin-2-thione (1.5 mmole) and 4-chlorophenylisocyanate (1.5 mmole) were combined in 40 mL of dry tetrahydrofuran at 0° C. The reaction mixture was warmed to room temperature over a 1 hour period and diluted with 20 mL of tetrahydrofuran. The reaction mixture was filtered and concentrated under reduced pressure. The residual material was chromatographed on silica gel (96:4:0.4 chloroform-methanol-concentrated ammonium hydroxide) to give the title compound analytically pure after trituration with ether/petroleum ether: the 1HNMR spectrum is consistent with the structure of the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:6]=[CH:5][S:4][C:3]=1[CH2:7][CH:8]([NH2:10])[CH3:9].[Br:11]Br.C(OC)(C)(C)C.[OH-].[Na+]>C(O)(=O)C>[Br:11][C:5]1[S:4][C:3]([CH2:7][CH:8]([NH2:10])[CH3:9])=[C:2]([Cl:1])[CH:6]=1
Reactant: CC(N)Cc1sccc1Cl
Reactant: BrBr
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: COC(C)(C)C
Product: CC(N)Cc1sc(Br)cc1Cl
Temperature: 15 °C

Procedure:
In a sulfonation flask 5 g (0.028 mol) 2-(3-chlorothiphen-2-yl)-1-methylethylamine is dissolved in 70 ml of acetic acid. The mixture is then cooled to 15° C. and 4.8 g (0.30 m) of bromine is added under stirring (internal temperature 15-17° C.). After warming up to rt, the mixture is stirred for 16 hours. Then the mixture is poured to a mixture of tert. butylmethylether (ca. 250 ml) and 2N sodiumhydroxide. The final pH is 11. After washing with brine, drying with sodium sulphate and evaporation of the solvent the crude material is obtained. Purification is achieved by column chromatography over silicagel (eluent: tert. butylmethylether/EtOH 10:1). Yield: 5.4 g (75% of theory) of a colourless oil (1H-NMR: 1.18/d/3H, 2.68-2.87/m (diasterotopic protons)/2H, 3.2/m/1H, 6.87/s/1H).
Reaction SMILES: [CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[NH:31][C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:33]([C:35]1[CH:42]=[CH:41][CH:40]=[CH:39][C:36]=1[CH2:37]Br)#[N:34]>>[CH2:1]([O:8][C:9](=[O:32])[NH:10][CH:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]2[N:31]([CH2:37][C:36]3[CH:39]=[CH:40][CH:41]=[CH:42][C:35]=3[C:33]#[N:34])[C:20]3[C:21](=[O:30])[N:22]([CH3:29])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:28]=4[C:19]=3[N:18]=2)[CH2:12]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccccc1CBr
Reactant: Cn1c(=O)c2[nH]c(C3CCCC(NC(=O)OCc4ccccc4)C3)nc2c2ccccc21
Product: Cn1c(=O)c2c(nc(C3CCCC(NC(=O)OCc4ccccc4)C3)n2Cc2ccccc2C#N)c2ccccc21
Yield: 82 %

Procedure:
According to the procedure described in example 3, step E; [3-(5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl)-cyclohexyl]-carbamic acid benzyl ester (90 mg, 0.21 mmol) was alkylated with 2-cyanobenzyl bromide (61 mg, 0.31 mmol) to give, after work-up and chromatography, {3-[3-(2-cyano-benzyl)-5-methyl-4-oxo-4,5-dihydro-3H-imidazo[4,5-c]quinolin-2-yl]-cyclohexyl}-carbamic acid benzyl ester (94 mg, 82% yield). 1H-NMR (CDCl3): δ 8.38 (m, 1H), 7.74 (m, 1H), 7.25–7.57 (m, 10H), 6.82 (m, 1H), 6.21 (m, 1H), 5.97 (m, 1H), 5.08 (s, 2H), 3.78 (s, 3H), 3.67 (m, 1H), 2.87 (m, 1H), 2.08 (m, 1H), 2.0 (m, 1H), 1.87 (m, 2H), 1.72 (m, 2H), 1.61 (m, 1H), 1.49 (m, 1H), 1.32 (m, 1H). MS: calculated for C33H31N5O3+H 546.3; found: 546.2.
Reaction SMILES: [Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([CH2:16][CH3:17])=[CH:12][CH:11]=2)[CH:5]=[C:4]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:56]=[CH:55][CH:54]=[CH:53][CH:52]=3)[O:19]2)[C:3]=1[OH:57].C([O-])([O-])=O.[K+].[K+].Br[CH2:65][CH2:66][OH:67]>CC(C)=O>[Br:1][C:2]1[C:7]([Cl:8])=[C:6]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([CH2:16][CH3:17])=[CH:14][CH:15]=2)[CH:5]=[C:4]([CH:18]2[C@H:23]([O:24][CH2:25][C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)[C@@H:22]([O:32][CH2:33][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=3)[C@H:21]([O:40][CH2:41][C:42]3[CH:43]=[CH:44][CH:45]=[CH:46][CH:47]=3)[C@@H:20]([CH2:48][O:49][CH2:50][C:51]3[CH:52]=[CH:53][CH:54]=[CH:55][CH:56]=3)[O:19]2)[C:3]=1[O:57][CH2:65][CH2:66][OH:67]
Reactant: OCCBr
Reactant: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(O)c(Br)c2Cl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Product: CCc1ccc(Cc2cc(C3O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OCCO)c(Br)c2Cl)cc1
Temperature: 50 °C
Reaction time: 15 h

Procedure:
To a mixture of the intermediate 32 (2.99 g, 3.53 mmol) and K2CO3 (0.73 g, 5.29 mmol) in acetone (35 mL) was added 2-bromoethanol (0.38 mL, 5.29 mmol) at rt. After stirring for 15 h at 50° C., the reaction mixture was cooled to rt. The precipitate was removed by filtration and the filtrate was concentrated in vacuo. The residue was dissolved in EtOAc (100 mL), washed with brine, dried over anhydrous MgSO4, filtered and concentrated in vacuo to provide the crude intermediate 33, which was used without further purification (3.04 g, 3.41 mmol, 97%).
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[CH2:12][CH2:11][NH:10]2)=[CH:5][CH:4]=1.CCN(C(C)C)C(C)C.[CH2:30]([N:37]=[C:38]=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1>C(Cl)Cl>[CH2:30]([NH:37][C:38]([N:10]1[CH2:11][CH2:12][C:13]2[C:18](=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:9]1[C:6]1[CH:5]=[CH:4][C:3]([C:2]([F:1])([F:19])[F:20])=[CH:8][CH:7]=1)=[O:39])[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=1
Reactant: O=C=NCc1ccccc1
Reactant: FC(F)(F)c1ccc(C2NCCc3ccccc32)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccccc1)N1CCc2ccccc2C1c1ccc(C(F)(F)F)cc1

Procedure:
To a solution of 1-(4-(trifluoromethyl)phenyl)-1,2,3,4-tetrahydroisoquinoline (100 mg, 0.36 mmol, example 9 (step 3) and DIEA (62.8 μL, 0.36 mmol) in DCM (2 mL) was added benzyl isocyanate (44.2 μL, 0.36 mmol). The resulting mixture was reacted under the same conditions as described for example 10 to give the title compound as a white solid. MS (ESI, positive ion) m/z: 411 (M+H).