Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][C:5](S(C)(=O)=O)=[N:6][CH:7]=1.ClC1C(C2C(C)=CC=CN=2)=NC(S(C)=O)=NC=1.[CH3:36][S:37]([CH2:40][CH:41]1[CH2:46][CH2:45][NH:44][CH2:43][CH2:42]1)(=[O:39])=[O:38].[F-].[Cs+]>CS(C)=O.O.CCOC(C)=O.CO.C(Cl)Cl>[Cl:1][C:2]1[C:3]([C:12]2[C:17]([CH3:18])=[CH:16][CH:15]=[CH:14][N:13]=2)=[N:4][C:5]([N:44]2[CH2:45][CH2:46][CH:41]([CH2:40][S:37]([CH3:36])(=[O:39])=[O:38])[CH2:42][CH2:43]2)=[N:6][CH:7]=1
Reactant: CS(=O)(=O)CC1CCNCC1
Reactant: Cc1cccnc1-c1nc(S(C)(=O)=O)ncc1Cl
Agent: Cc1cccnc1-c1nc(S(C)=O)ncc1Cl
Agent: [Cs+]
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: CO
Solvent: CS(C)=O
Product: Cc1cccnc1-c1nc(N2CCC(CS(C)(=O)=O)CC2)ncc1Cl
Temperature: 100 °C
Yield: 46 %

Procedure:
To a mixture of 5-chloro-4-(3-methylpyridin-2-yl)-2-(methylsulfonyl)pyrimidine and 5-chloro-4-(3-methylpyridin-2-yl)-2-(methylsulfinyl)pyrimidine (300 mg, 1.05 mmol) in DMSO (15 mL) was added 4-(methylsulfonylmethyl)piperidine (440 mg, 1.65 mmol) and CsF (640 mg, 4.2 mmol). The resulting mixture was heated at 100° C. at microwave for 30 min. TLC (CH2Cl2:MeOH=10:1) indicated that the reaction was complete. The mixture was then treated with EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was then extracted with EtOAc (30 mL×3). The combined organic layers were washed with brine (30 mL), dried over Na2SO4 and filtered. The filtrate was concentrated and the residue was purified via prep. HPLC to give title compound (183 mg, 46%) as a white solid. 1H NMR (400 MHz, CDCl3): δ 8.47-8.48 (d, 1H), 8.28 (s, 1H), 7.55-7.56 (dd, 1H), 7.20-7.24 (m, 1H), 4.66-4.69 (d, 1H), 2.88-2.92 (m, 7H), 2.30-2.34 (m, 1H), 2.18 (s, 3H), 1.94-1.97 (m, 2 H), 1.26-1.37 (m, 2H); m/z for C17H21ClN4O2S 381.4 (M+H)+.
Reaction SMILES: [S:1]([Cl:5])(Cl)(=[O:3])=[O:2].[Cl:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([CH:13]=[CH2:14])[CH:8]=1>CN(C=O)C>[Cl:6][C:7]1[CH:8]=[C:9](/[CH:13]=[CH:14]/[S:1]([Cl:5])(=[O:3])=[O:2])[CH:10]=[CH:11][CH:12]=1
Reactant: O=S(=O)(Cl)Cl
Reactant: C=Cc1cccc(Cl)c1
Solvent: CN(C)C=O
Product: O=S(=O)(Cl)/C=C/c1cccc(Cl)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 100 %

Procedure:
Sulfuryl chloride (3.2 mL, 38.5 mmol, 2 eq.) was added dropwise into a 2-neck mL round-bottomed flask containing 2.7 mL of DMF at 0° C. After stirring the mixture at room temperature for 30 min, 1-chloro-3-vinylbenzene (2.5 mL, 19.3 mmol, 1 eq.) was added and the reaction mixture was heated at 55° C. for 5 h. After the reaction mixture was cooled at room temperature, ice water was poured (20 mL) and the product was extracted three times from the aqueous phase with DCM. The resulting organic phase was washed once with water, brine and dried under Na2SO4. After the product was purified from the crude by flash column chromatography (5% EtOAc/hexanes), compound 1 (1.9785 g, 19.3 mmol) was obtained in a 44% yield. 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J=15.2 Hz, C═CH, 1H), 7.55 (s, ArH, 1H), 7.50 (dt, J=6.4, 2.2 Hz, ArH, 1H), 7.46-7.40 (m, ArH, 2H), 7.25 (d, J=15.1 Hz, C═CH, 1H). APT (100 MHz, CDCl3, δ): 143.47 (C═C8H), 135.59 (C5), 132.48 (C═C9H), 132.34 (C3), 131.19 (C1H), 130.71 (C2H), 128.77 (C4H), 127.40 (C6H). GC-MS m/z (% relative intensity, ion): 239.95 (2, M+4), 237.95 (13, M+2), 235.95 (19, M+), 201 (35, M+-Cl), 137 (100, M+-SO2Cl), 102(85), 75 (45), 51 (28). HPLC: 99.7% pure, retention time 4.98 min.
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[NH:7][CH:8]1[CH2:11][NH:10][CH2:9]1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.Cl[C:21]([O:23][CH2:24][CH2:25][CH2:26][CH3:27])=[O:22]>C(Cl)Cl>[CH2:24]([O:23][C:21]([N:10]1[CH2:11][CH:8]([NH:7][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:12])[CH2:9]1)=[O:22])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)(C)OC(=O)NC1CNC1
Reactant: CCCCOC(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CCCCOC(=O)N1CC(NC(=O)OC(C)(C)C)C1
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of 686 mg of Azetidin-3-yl-carbamic acid tert-butyl ester in 10 ml of DCM, 403 mg of triethylamine was added and the mixture was cooled to 0° C. Then, 598 mg of butyl chloroformate was slowly added. After the addition was completed the reaction mixture was allowed to warm to RT and to stir for 2 h. Then, 200 ml of DCM was added and the organic phase was washed two times with 0.1M aqueous hydrochloric acid and the with saturated aqueous sodium hydrogen carbonate solution. The organic phase was dried over MgSO4 and the solvents were removed under reduced pressure. The crude product was purified by chromatography on silica gel eluting with a gradient of n-heptane/ethyl acetate. The fractions containing the product were combined and the solvent evaporated under reduced pressure. Yield: 910 mg.
Reaction SMILES: [CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:17]=[CH:16][C:15](/[CH:18]=[CH:19]/[C:20]([O:22][CH3:23])=[O:21])=[CH:14][CH:13]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1>CO.[Pt](=O)=O>[CH3:1][N:2]([CH2:9][CH2:10][O:11][C:12]1[CH:13]=[CH:14][C:15]([CH2:18][CH2:19][C:20]([O:22][CH3:23])=[O:21])=[CH:16][CH:17]=1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][N:4]=1
Reactant: COC(=O)/C=C/c1ccc(OCCN(C)c2ccccn2)cc1
Agent: O=[Pt]=O
Solvent: CO
Product: COC(=O)CCc1ccc(OCCN(C)c2ccccn2)cc1

Procedure:
Methyl E-3-[4-[2-[N-methyl-N-(2-pyridyl)amino]ethoxy]phenyl]prop-2-enoate (7.00 g) was suspended in methanol (220 mL) and hydrogenated over platinum (IV) oxide catalyst (0.44 g total) for a total of 28 hrs. The mixture was filtered through filter aid and the solvent evaporated. The residue was chromatographed on silica gel with 1% methanol in dichloromethane as eluent to afford the title compound as a gum which was used without further purification.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[N:16]=[CH:15][C:14]([S:17]([C:20]2[CH:21]=[C:22]([CH:25]=[CH:26][CH:27]=2)[CH:23]=O)(=[O:19])=[O:18])=[CH:13][CH:12]=1.[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH2:29]1.C([BH3-])#N.[Na+].[OH-].[Na+]>CO.C(O)(=O)C>[F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1/[CH:9]=[CH:10]/[C:11]1[CH:12]=[CH:13][C:14]([S:17]([C:20]2[CH:27]=[CH:26][CH:25]=[C:22]([CH2:23][N:28]3[CH2:33][CH2:32][O:31][CH2:30][CH2:29]3)[CH:21]=2)(=[O:19])=[O:18])=[CH:15][N:16]=1
Reactant: O=Cc1cccc(S(=O)(=O)c2ccc(/C=C/c3ccc(F)cc3F)nc2)c1
Reactant: C1COCCN1
Agent: [BH3-]C#N
Agent: [Na+]
Agent: [OH-]
Solvent: CC(=O)O
Solvent: CO
Product: O=S(=O)(c1ccc(/C=C/c2ccc(F)cc2F)nc1)c1cccc(CN2CCOCC2)c1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
3-({6-[(E)-2-(2,4-Difluorophenyl)vinyl]pyridin-3-yl}sulfonyl)benzaldehyde (Step 1, 95 mg, 0.25 mmol) was suspended in methanol (1 mL) and acetic acid (70 μL). Morpholine (28 μL, 0.34 mmol) was added and the reaction stirred at room temperature under nitrogen for 30 minutes. Sodium cyanoborohydride (15 mg, 0.25 mmol) was added and stirring continued for 2 days. 5N sodium hydroxide was added and the products extracted into dichloromethane, washed with brine, dried over MgSO4 and concentrated in vacuo. Purification by flash column chromatography (90% ethyl acetate/isohexane) gave the title compound as a yellow foam which was treated with ethereal HCl to give the hydrochloride salt (8 mg, 7%). δH (500 MHz, d6 DMSO): 11.24 (1H, s), 9.11 (1H, d, J=2.1 Hz), 8.38 (1H, dd, J=2.1, 8.2 Hz), 8.33 (1H, s), 8.08 (1H, d, J=7.8 Hz), 7.93 (2H, q, J=8.0 Hz), 7.87 (1H, d, J=16.1 Hz), 7.76-7.70 (2H, m), 7.46 (1H, d, J=16.1 Hz), 7.37-7.31 (1H, m), 7.18 (1H, td, J=2.1, 8.4 Hz), 4.43 (2H, s), 3.91 (2H, d, J=11.8 Hz), 3.74 (2H, t, J=11.8 Hz), 3.20 (2H, d, J=11.6 Hz), 3.12-3.06 (2H, m); m/z (ES+) 457 [MH+].
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([NH:8][C:9]2[CH:10]=[C:11]3[C:15](=[CH:16][CH:17]=2)[NH:14][C:13](=[O:18])[CH2:12]3)[CH:5]=[CH:6][CH:7]=1.[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31](O)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1.C(N(CC)C(C)C)(C)C.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1>CN(C=O)C>[CH3:19][N:20]1[CH2:25][CH2:24][N:23]([CH2:26][C:27]2[CH:35]=[CH:34][C:30]([C:31]([NH:1][C:2]3[CH:7]=[CH:6][CH:5]=[C:4]([NH:8][C:9]4[CH:10]=[C:11]5[C:15](=[CH:16][CH:17]=4)[NH:14][C:13](=[O:18])[CH2:12]5)[CH:3]=3)=[O:32])=[CH:29][CH:28]=2)[CH2:22][CH2:21]1
Reactant: CN1CCN(Cc2ccc(C(=O)O)cc2)CC1
Reactant: Nc1cccc(Nc2ccc3c(c2)CC(=O)N3)c1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN1CCN(Cc2ccc(C(=O)Nc3cccc(Nc4ccc5c(c4)CC(=O)N5)c3)cc2)CC1
Reaction time: 12 h

Procedure:
To a solution of 5-(3-amino-phenylamino)-1,3-dihydro-indol-2-one (20 mg, 0.083 mmol) in DMF (2 ml) is added 4-(4-methyl-piperazin-1-ylmethyl)-benzoic acid (31 mg, 0.1 mmol), N,N-diisopropylethylamine (54 mg, 0.42 mmol), EDCI (32 mg, 0.17 mmol) and HOBt (11 mg, 0.083 mmol). The reaction is stirred for 12 hours and concentrated. The residue is purified by HPLC to afford the desired compound: LC-MS: 456.2 (MH+).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:10]=[CH:11][C:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])=[N:13][CH:14]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>C(O)C.C(O)(=O)C.[Pt]=O>[C:1]([O:5][C:6]([NH:8][C@H:9]1[CH2:14][NH:13][C@@H:12]([CH2:15][C:16]([O:18][CH2:19][CH3:20])=[O:17])[CH2:11][CH2:10]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CCOC(=O)Cc1ccc(NC(=O)OC(C)(C)C)cn1
Agent: O=[Pt]
Solvent: CC(=O)O
Solvent: CCO
Product: CCOC(=O)C[C@H]1CC[C@@H](NC(=O)OC(C)(C)C)CN1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.5 %

Procedure:
The mixture of ethyl {5-[(tert-butoxycarbonyl)amino]pyridin-2-yl}acetate (3.72 g, 15.6 mmol, step 4 of Example 1) and platinum oxide (300 mg) in ethanol (6 mL) and acetic acid (6 mL) was stirred under hydrogen (4 atom) at room temperature for 8 h. The mixture was filtered through a pad of Celite washing with ethanol and the filtrate was concentrated. The resulting residue was diluted with 2N aqueous sodium hydroxide solution (100 mL), and extracted with dichloromethane (100 mL×3). The combined organic layer was dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue was chromatographed on a column of silica gel eluting with dichloromethane/methanol (20:1) to give 2.48 g (65%) of the title compound as a colorless oil. (trans isomer 559 mg, 15% yield)
Reaction SMILES: [C:1]1(OB(O)O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C12(PC34CC5CC(CC(C5)C3)C4)CC3CC(CC(C3)C1)C2.[O-]P(OP(OP([O-])([O-])=O)([O-])=O)(=O)[O-].[K+].[K+].[K+].[K+].[K+].O.Cl[C:52]1[CH:57]=[CH:56][C:55]([O:58][CH3:59])=[CH:54][CH:53]=1>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH3:59][O:58][C:55]1[CH:56]=[CH:57][C:52]([C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)=[CH:53][CH:54]=1
Reactant: COc1ccc(Cl)cc1
Reactant: OB(O)Oc1ccccc1
Agent: [Pd+2]
Agent: C1C2CC3CC1CC(PC14CC5CC(CC(C5)C1)C4)(C2)C3
Agent: CC(=O)[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ccc(-c2ccccc2)cc1
Temperature: 100 °C
Reaction time: 0.08 h
Yield: 84 %

Procedure:
Phenylboric acid (366 mg, 3.0 mmols), palladium acetate (4.49 mg, 0.02 mmols), diadamantyl phosphine (12.1 mg, 0.04 mmols) and potassium triphosphate (1.273 g, 6 mmols) are placed in 6 ml of dioxane and water (0.18 ml, 10 mmols) under argon. The reaction mixture is heated in an oil bath of 100° C. and stirred for 5 minutes. Afterwards, 4-chloroanisole (0.27 ml, 2 mmols) is added. The reaction mixture is then stirred for 18 hours at 100° C. and subsequently cooled. The title compound is purified by flash chromatography over silica gel. The yield is 84%.
Reaction SMILES: OS(O)(=O)=O.[Br:6][C:7]1[CH:8]=[CH:9][C:10]([CH2:17][OH:18])=[C:11]([C:13](O)([CH3:15])[CH3:14])[CH:12]=1>O1CCOCC1.O>[Br:6][C:7]1[CH:12]=[C:11]2[C:10]([CH2:17][O:18][C:13]2([CH3:14])[CH3:15])=[CH:9][CH:8]=1
Reactant: CC(C)(O)c1cc(Br)ccc1CO
Agent: O=S(=O)(O)O
Solvent: C1COCCO1
Solvent: O
Product: CC1(C)OCc2ccc(Br)cc21
Temperature: 60 °C
Yield: 86.3 %

Procedure:
H2SO4 (0.4 mL conc, 1.6 mL H2O) was added to a solution of Intermediate 388.1 (0.25 g, 1.02 mmol) in dioxane (2 mL). The mixture was stirred at 60° C., diluted with H2O (10 mL), extracted with hexanes (2×25 mL). The organics were combined, washed with brine, dried (Na2SO4) and concentrated to yield 200 mg of Intermediate 388.2 as a clear oil. 1H NMR (400 MHz, CDCl3) δ ppm 1.47 (s, 6H) 5.01 (s, 2H) 6.98 (m, 1H) 7.32 (m, 1H) 7.37 (m, 1H).
Reaction SMILES: [CH3:1][NH:2][CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1.[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([N:16]=[C:17]=[O:18])([CH3:15])[CH3:14].[C-]#N>CCCCCC.C1C=CC=CC=1>[Cl:9][C:10]1[CH:11]=[C:12]([CH:19]=[CH:20][CH:21]=1)[C:13]([NH:16][C:17](=[O:18])[N:2]([CH:3]1[CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)[CH3:1])([CH3:15])[CH3:14]
Reactant: CNC1CCCCC1
Reactant: CC(C)(N=C=O)c1cccc(Cl)c1
Agent: [C-]#N
Solvent: CCCCCC
Solvent: c1ccccc1
Product: CN(C(=O)NC(C)(C)c1cccc(Cl)c1)C1CCCCC1
Reaction time: 6 h
Yield: 90.7 %

Procedure:
A solution of 1.2 g of N-methyl-N-cyclohexylamine in 5 ml of n-hexane was added to a solution of 0.01 mole of m-chloro-α,α-dimethylbenzyl isocyanate (prepared from the corresponding cyanide in the same way as shown in Synthesis Example 1) in 10 ml of benzene. The mixture was kept at room temperature for 6 hours and concentrated under reduced pressure to obtain crystals, which were recrystallized from n-hexane to give 2.8 g of the title compound as white crystals.
Reaction SMILES: C[Si]([C:5]#[C:6][C:7]1([OH:14])[CH2:12][CH:11]2[CH2:13][CH:8]1[CH2:9][CH2:10]2)(C)C.CCCC[N+](CCCC)(CCCC)CCCC.[F-]>C1COCC1>[C:6]([C:7]1([OH:14])[CH2:12][CH:11]2[CH2:13][CH:8]1[CH2:9][CH2:10]2)#[CH:5]
Reactant: C[Si](C)(C)C#CC1(O)CC2CCC1C2
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: C1CCOC1
Product: C#CC1(O)CC2CCC1C2

Procedure:
2-((trimethylsilyl)ethynyl)bicyclo[2.2.1]heptan-2-ol (700 mg, 5.1 mmol) was dissolved in THF (25 mL) and treated with TBAF (2.7 g, 10.2 mmol) at 0° C. for 30 min. Purification by gel chromatography afforded the title compound; 1H NMR (400 MHz, DMSO) delta 1.15-1.44 (m, 4H), 1.64-1.67 (m, 1H), 1.88-1.93 (m, 2H), 2.07-2.22 (m, 3H), 3.25 (s, 1H)
Reaction SMILES: CS([C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)(=O)=O.[CH2:29]([NH2:36])[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1>>[CH2:29]([NH:36][C:5]1[N:10]=[C:9]([C:11]2[N:15]3[CH:16]=[CH:17][N:18]=[C:19]([NH:20][CH2:21][CH2:22][N:23]4[CH2:28][CH2:27][O:26][CH2:25][CH2:24]4)[C:14]3=[N:13][CH:12]=2)[CH:8]=[CH:7][N:6]=1)[C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1
Reactant: CS(=O)(=O)c1nccc(-c2cnc3c(NCCN4CCOCC4)nccn23)n1
Reactant: NCc1ccccc1
Product: c1ccc(CNc2nccc(-c3cnc4c(NCCN5CCOCC5)nccn34)n2)cc1
Temperature: 140 °C
Reaction time: 2 h

Procedure:
The mixture of [3-(2-methanesulfonyl-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine (from Example 50 supra) (120 mg, 0.30 mmol) and benzylamine (128 mg, 1.19 mmol) was heated at 140° C. with stirring for 2 hours. The oil was purified by chromatography (silica gel, 10 g, 200-300 mesh, eluting with dichloromethane:methanol, 30:1 to 10:1) to afford the crude product (100 mg). The crude product was purified by prep-HPLC. Several drops of concentrated HCl were added to the fractions with product. After sonicating for several minutes, solution was concentrated under reduced pressure to afford [3-(2-benzylamino-pyrimidin-4-yl)-imidazo[1,2-a]pyrazin-8-yl]-(2-morpholin-4-yl-ethyl)-amine; hydrochloride. (Yield 25 mg, 19.5%). 1H NMR (300 MHz, CD3OD): δ 8.77 (s, 1H), 8.57-8.38 (m, 2H), 7.62 (d, 1H, J=6.6 Hz), 7.48-7.34 (m, 6H), 4.82 (brs, 2H), 4.21 (brs, 2H), 3.99 (brs, 4H), 3.63-3.47 (m, 6H). LC-MS: [M+H]+ 431.
Reaction SMILES: [H-].[Na+].[C:3]1([C:9]2[N:14]=[C:13]3[N:15]=[C:16]([NH2:19])[CH:17]=[CH:18][C:12]3=[N:11][CH:10]=2)[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH2:20]([N:23]=[C:24]=[S:25])[CH:21]=[CH2:22]>CN(C)C=O>[CH2:20]([NH:23][C:24]([NH:19][C:16]1[CH:17]=[CH:18][C:12]2[C:13]([N:15]=1)=[N:14][C:9]([C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1)=[CH:10][N:11]=2)=[S:25])[CH:21]=[CH2:22]
Reactant: Nc1ccc2ncc(-c3ccccc3)nc2n1
Reactant: C=CCN=C=S
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: C=CCNC(=S)Nc1ccc2ncc(-c3ccccc3)nc2n1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
0.246 g of sodium hydride (6.14 mmol) is introduced into 5 ml of anhydrous dimethylformamide under nitrogen as protective gas. The mixture is cooled to 0° C. in an ice bath. 1.05 g of 3-phenylpyrido[2,3-b]pyrazin-6-ylamine (4.72 mmol) are dissolved in 5 ml of anhydrous dimethylformamide and added dropwise. The cooling bath is removed, and the mixture is left to stir at RT for 30 minutes. The mixture is then cooled to 0° C. again in the ice bath, and 0.469 g of allyl isothiocyanate (4.72 mmol), dissolved in 4 ml of anhydrous dimethylformamide, is added dropwise. After the addition is complete, the cooling bath is removed, and the mixture is then left to stir at room temperature for 1.5 hours. For working up, the mixture is poured into about 250 ml of distilled water, and the precipitated orange solid is filtered off with suction. Purification by column chromatography several times (mobile phases dichloromethane/methanol mixtures) and subsequent purification by preparative HPLC afford a yellow solid.
Reaction SMILES: [CH:1]1([C:7]2[C:8]3[CH:9]=[CH:10][C:11]([C:47]([O:49][CH3:50])=[O:48])=[CH:12][C:13]=3[N:14]3[C:20]=2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]([CH3:25])[CH:16]([CH2:26][N:27]([CH3:46])[CH2:28][CH2:29][N:30]([CH3:45])[CH2:31][CH2:32][CH2:33][S:34](=[O:44])(=[O:43])[NH:35]C(=O)OC(C)(C)C)[CH2:15]3)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[NH2:35][S:34]([CH2:33][CH2:32][CH2:31][N:30]([CH3:45])[CH2:29][CH2:28][N:27]([CH2:26][CH:16]1[CH2:15][N:14]2[C:13]3[CH:12]=[C:11]([C:47]([O:49][CH3:50])=[O:48])[CH:10]=[CH:9][C:8]=3[C:7]([CH:1]3[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]3)=[C:20]2[C:19]2[CH:21]=[CH:22][CH:23]=[CH:24][C:18]=2[N:17]1[CH3:25])[CH3:46])(=[O:43])=[O:44]
Reactant: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(=O)(=O)NC(=O)OC(C)(C)C)N(C)c1ccccc1-3
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COC(=O)c1ccc2c(C3CCCCC3)c3n(c2c1)CC(CN(C)CCN(C)CCCS(N)(=O)=O)N(C)c1ccccc1-3

Procedure:
Methyl 13-cyclohexyl-5-methyl-6-(2,5,13,13-tetramethyl-9,9-dioxido-11-oxo-12-oxa-9-thia-2,5,10-triazatetradec-1-yl)-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was dissolved in DCM (0.05M) and TFA was added. The mixture was left standing at RT. After 1 h all volatiles were evaporated in vacuo. The residual material was coevaporated with toluene. Methyl 6-{[{2-[[3-(aminosulfonyl)propyl]-(methyl)amino]ethyl}(methyl)amino]methyl}-13-cyclohexyl-5-methyl-6,7-dihydro-5H-indolo[1,2-d][1,4]benzodiazepine-10-carboxylate was obtained as a reddish sticky solid. The material was dissolved in MeOH/THF (0.05 M) and 1M aqueous KOH solution (4 eq.) was added. The mixture was stirred at RT overnight and then warmed for 5 h to 70° C. After cooling to RT the solution was diluted with water and adjusted with 1M aqueous HCl to pH 6. The resulting suspension was extracted with EtOAc. The combined organic phases were washed with brine and dried over Na2SO4. All volatiles were evaporated in vacuo. The residual material was used without further purification in the next reaction (95%). (ES+) m/z 611 (M+H)+.
Reaction SMILES: [C:1]([C:7]([O:9][CH3:10])=[O:8])#[C:2][C:3]([O:5]C)=O.[CH3:11][O:12][C:13]1[CH:19]=[CH:18][CH:17]=[CH:16][C:14]=1[NH2:15].O(C1C=CC=CC=1)C1C=CC=CC=1>CO.C1(C)C=CC=CC=1.CCCCCC>[CH3:10][O:9][C:7]([C:1]1[CH:2]=[C:3]([OH:5])[C:16]2[C:14](=[C:13]([O:12][CH3:11])[CH:19]=[CH:18][CH:17]=2)[N:15]=1)=[O:8]
Reactant: COC(=O)C#CC(=O)OC
Reactant: COc1ccccc1N
Solvent: CCCCCC
Solvent: Cc1ccccc1
Solvent: CO
Product: COC(=O)c1cc(O)c2cccc(OC)c2n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 57.5 %

Procedure:
145.6 g of dimethyl acetylenedicarboxylate was dropwise added to a solution of 123.15 g of 2-methoxyaniline in MeOH (600 mL) at 0° C. over 30 minutes. The mixture was stirred at room temperature overnight, and the resulting solution was added to 700 mL of Ph2O heated at 235° C. (inner temperature) over 30 minutes. This was then heated for an additional 30 minutes. After cooled to room temperature, the reaction mixture was diluted with 700 mL of toluene and 700 mL of n-hexane, and stirred at 0° C. for 3 hours. The resulting precipitate was taken out through filtration, washed with MeOH, and 134 g of 4-hydroxy-8-methoxyquinoline-2-carboxylic acid methyl ester was obtained as an off-white solid.
Reaction SMILES: [H-].[Na+].ClCCl.CN(C)C=O.[F:11][C:12]([F:32])([F:31])[C:13]1[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:30])[CH2:21][C@@H:22](OS(C)(=O)=O)[CH2:23][CH3:24])=[CH:15][CH:14]=1>O>[CH2:23]([C@H:22]1[N:19]([C:16]2[CH:17]=[CH:18][C:13]([C:12]([F:32])([F:31])[F:11])=[CH:14][CH:15]=2)[C:20](=[O:30])[CH2:21]1)[CH3:24]
Reactant: CC[C@@H](CC(=O)Nc1ccc(C(F)(F)F)cc1)OS(C)(=O)=O
Agent: [H-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: CC[C@@H]1CC(=O)N1c1ccc(C(F)(F)F)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
158.7 mg of sodium hydride (60 wt %; 3.97 mmol) was suspended in a mixed solution of dichloromethane (2.7 mL) and dimethylformamide (10.8 mL) and to the solution, a mixed solution of 1,346.2 mg (3.97 mmol) of (S)-N-[4-(trifluoromethyl)phenyl]-3-methanesulfonyloxypentanoic acid amide produced in Example 3, dichloromethane (2.7 mL) and dimethylformamide (10.8 mL) was added dropwise at room temperature for 15 minutes. After stirring at room temperature for further 1 hour, water (25 mL) was added and extraction was carried out with ethyl acetate. The organic layer was washed with saturated brine and the product was dried with anhydrous sodium sulfate. The solvent was removed by distillation under reduced pressure to obtain (R)-4-ethyl-1-[4-(trifluoromethyl)phenyl]-2-azetidinone as a brown solid (996.3 mg, crude yield: 87%). The optical purity of the product was determined by HPLC analysis (column; Daicel Chiral Pack AD-H 4.6×250 mm: eluent; hexane/isopropanol=95/5: flow rate; 1.0 mL/min: column temperature; 30° C.: detector; UV 210 nm: retention time; (S) antipode=7.6 minutes, (R) antipode=8.8 minutes) to be 83.0% ee. 1H-NMR (CDCl3, 400 MHz/ppm): δ 0.99 (3H, t), 1.63-1.73 (1H, m), 2.11-2.21 (1H, m), 2.79 (1H, dd), 3.23 (1H, dd), 4.07-4.13 (1H, m), 7.47 (2H, d), 7.58 (2H, d)
Reaction SMILES: [CH2:1]([O:3][C:4]([CH:6]1[CH2:11][NH:10][CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)(=[O:14])=[O:13])=[O:5])[CH3:2].[C:22](=O)([O-])[O-].[K+].[K+].IC>CN(C=O)C.CCOCC>[CH2:1]([O:3][C:4]([CH:6]1[CH2:11][N:10]([CH3:22])[CH2:9][CH2:8][N:7]1[S:12]([C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1)(=[O:13])=[O:14])=[O:5])[CH3:2]
Reactant: CCOC(=O)C1CNCCN1S(=O)(=O)c1ccc(F)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CCOCC
Solvent: CN(C)C=O
Product: CCOC(=O)C1CN(C)CCN1S(=O)(=O)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 91 %

Procedure:
To a solution of 0.469 g (1.484 mmol) of the product of Example 52 dissolved in 10 mL of DMF was added 0.614 g (4.452 mmol) of potassium carbonate followed by 0.092 mL (1.484 mmol) of iodomethane and the resulting mixture was stirred at room temperature for 3 h. The reaction mixture was then diluted with ether and washed with water. The organics were dried over Na2SO4, filtered and concentrated in vacuo to provide 0.446 g (91%) of the N-methyl amine as a colorless oil. Electrospray Mass Spec: 330.9 (M+H)+
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:25])/[C:5](/[O:22][CH2:23][CH3:24])=[CH:6]/[C:7]1[CH:12]=[CH:11][C:10]([O:13]CC2C=CC=CC=2)=[CH:9][C:8]=1[CH3:21])[CH3:2]>C(O)C.[Pd]>[CH2:1]([O:3][C:4](=[O:25])[CH:5]([O:22][CH2:23][CH3:24])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][C:8]=1[CH3:21])[CH3:2]
Reactant: CCOC(=O)/C(=C/c1ccc(OCc2ccccc2)cc1C)OCC
Agent: [Pd]
Solvent: CCO
Product: CCOC(=O)C(Cc1ccc(O)cc1C)OCC
Yield: 82.8 %

Procedure:
A solution of 3-(4-benzyloxy-2-methyl-phenyl)-2Z-ethoxy-acrylic acid ethyl ester (1 g, 2.9 mmol) in ethanol (50 ml) was hydrogenated over 10% palladium on charcoal (250 mg) at ambient temperature for 2 h. The catalyst was filtered off and the solvent evaporated under reduced pressure to give 600 mg (2.4 mmol, 81%) of the title compound as yellow liquid which was used in the next stage without further purification.