Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:16])[CH3:15])[N:6]=[CH:7]2.[CH3:21][Mg]Cl>C(OCC)C>[Br:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH2:4][C@H:5]([CH2:12][O:13][Si:14]([C:17]([CH3:20])([CH3:19])[CH3:18])([CH3:15])[CH3:16])[NH:6][C@H:7]2[CH3:21]
Reactant: CC(C)(C)[Si](C)(C)OC[C@H]1Cc2c(Br)cccc2C=N1
Reactant: C[Mg]Cl
Solvent: CCOCC
Product: C[C@@H]1N[C@@H](CO[Si](C)(C)C(C)(C)C)Cc2c(Br)cccc21
Temperature: -78 °C
Reaction time: 8 h
Yield: 106.4 %

Procedure:
Dissolve (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline (3.4 g, 9.59 mmol) in diethyl ether (160 mL). Cool to −78° C. on a dry ice-acetone bath. Add methylmagnesium chloride (26.9 mL, 80.6 mmol, 3M in THF) dropwise. Warm the reaction mixture slowly to room temperature and stir overnight. Quench with saturated ammonium chloride solution slowly. Extract with dichloromethane and dry over sodium sulfate, filter, and concentrate under reduced pressure. Combine with the crude product from a substantially same reaction run with 1.73 mmol of (3R)-5-bromo-3-({[tert-butyl(dimethyl)silyl]oxy}methyl)-3,4 dihydroisoquinoline. Purify the combined residues by silica gel chromatography eluting with ethyl acetate: hexanes (5-65% gradient) to give the title compound (3.78 g, 10.2 mmol). MS (m/z): 370 (M+1).
Reaction SMILES: [CH2:1]([N:4]([CH2:11][CH2:12][CH3:13])[CH:5]1[CH2:10][CH2:9][NH:8][CH2:7][CH2:6]1)[CH2:2][CH3:3].Br[CH2:15][C:16]#[N:17]>>[CH2:11]([N:4]([CH2:1][CH2:2][CH3:3])[CH:5]1[CH2:6][CH2:7][N:8]([CH2:15][C:16]#[N:17])[CH2:9][CH2:10]1)[CH2:12][CH3:13]
Reactant: N#CCBr
Reactant: CCCN(CCC)C1CCNCC1
Product: CCCN(CCC)C1CCN(CC#N)CC1

Procedure:
The title compound is synthesized by coupling of Dipropyl-piperidin-4-yl-amine (commercially available from CHESS GmbH) and bromoacetonitrile analogously to the preparation of Intermediate 149.2 as a colorless oil; ES-MS: M+=224.3: 1HNMR(DMSO-d6) 3.65 (s, 2H), 2.80-2.75 (m, 2H), 2.40-2.30 (m, 5H), 2.15-2.05 (m, 2H), 1.65-1.60 (m, 2H), 1.50-1.30 (m, 6H), 0.90 (t, 6H).
Reaction SMILES: [C:1]([O:4][C:5]1[C:6]2[N:7]([CH:11]=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2].[Br:15]N1C(=O)CCC1=O>C(O)C.C(OCC)(=O)C>[C:1]([O:4][C:5]1[C:6]2[N:7]([C:11]([Br:15])=[C:12]([CH3:14])[N:13]=2)[CH:8]=[CH:9][CH:10]=1)(=[O:3])[CH3:2]
Reactant: CC(=O)Oc1cccn2cc(C)nc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)Oc1cccn2c(Br)c(C)nc12
Reaction time: 0.5 h
Yield: 86.9 %

Procedure:
To a solution of 8-acetoxy-2-methylimidazo[1,2-a]pyridine (100 mg) in ethanol (1 ml) was added N-bromosuccinimide (103 mg) under ice-cooling, and the mixture was stirred for 30 minutes at the same temperature. The mixture was diluted with ethyl acetate and washed with saturated sodium bicarbonate solution, dried over magnesium sulfate and evaporated in vacuo. The residue was purified by preparative thin layer chromatography (ethyl acetate) to give 8-acetoxy-3-bromo-2-methylimidazo[1,2-a]pyridine (123 mg) as oil.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21]O)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2].[NH:28]1[CH2:33][CH2:32]O[CH2:30][CH2:29]1.C(S(C1C=C(C2C=C(CN(C)C)C=C3C=2C2C=C(C)C=NC=2N3)C=CC=1)(=O)=O)C>>[CH2:1]([S:3]([C:6]1[CH:7]=[C:8]([C:12]2[CH:20]=[C:19]([CH2:21][N:28]3[CH2:33][CH2:32][CH2:30][CH2:29]3)[CH:18]=[C:17]3[C:13]=2[C:14]2[CH:26]=[C:25]([CH3:27])[CH:24]=[N:23][C:15]=2[NH:16]3)[CH:9]=[CH:10][CH:11]=1)(=[O:5])=[O:4])[CH3:2]
Reactant: C1COCCN1
Reactant: CCS(=O)(=O)c1cccc(-c2cc(CO)cc3[nH]c4ncc(C)cc4c23)c1
Agent: CCS(=O)(=O)c1cccc(-c2cc(CN(C)C)cc3[nH]c4ncc(C)cc4c23)c1
Product: CCS(=O)(=O)c1cccc(-c2cc(CN3CCCC3)cc3[nH]c4ncc(C)cc4c23)c1

Procedure:
The title compound was prepared from Compound 133 and morpholine according to the procedure outline for the preparation of Compound 134. 1H NMR (400 MHz, CD3OD) δ 8.36 (br s, 1H), 8.23 (s, 1H), 8.13 (d, 1H, J=7.6 Hz), 8.04 (d, 1H, J=7.6 Hz), 7.96 (s, 1H), 7.91 (t, 1H, J=7.6 Hz), 7.87 (s, 1H), 7.47 (s, 1H), 4.62 (s, 2H), 3.51-3.60 (m, 2H), 3.20-3.36 (m, 4H), 2.39 (s, 3H), 2.15-2.23 (m, 2H), 1.99-2.07 (m, 2H), 1.29 (t, 3H, J=7.2 Hz). MS (ES) [m+H] calc'd for C25H27N3O2S, 434; found 434.
Reaction SMILES: [C:1]([CH2:3][C:4]([NH:6][CH2:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][N:9]=1)=O)#[N:2].P(Cl)(Cl)(Cl)=O.N>C(Cl)(Cl)Cl>[CH:7]1[N:6]=[C:4]([CH2:3][C:1]#[N:2])[N:9]2[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=12
Reactant: N#CCC(=O)NCc1ccccn1
Agent: N
Solvent: ClC(Cl)Cl
Solvent: O=P(Cl)(Cl)Cl
Product: N#CCc1ncc2ccccn12
Temperature: 0 °C
Yield: 35.9 %

Procedure:
2-Cyano-N-(2-pyridylmethyl)acetamide (15.51 g) was dissolved in chloroform (80 ml). To the solution was added phosphorus oxychloride (40 ml), which was refluxed for 4 hours. The reaction mixture was added to ice-water in limited amounts, to which was added a 25% aqueous ammonia (140 ml) to neutralize, which was then shaken. The aqueous layer was subjected to extraction with ethyl acetate (150 ml) twice. The organic layers were combined and dried over anhydrous magnesium sulfate, followed by concentration. The concentrate was purified by means of a column chromatography (carrier: silica gel, 250 g, developing solvent: ethyl acetate) to afford the title compound (5.00 g).
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26](B5OC(C)(C)C(C)(C)O5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].Cl[C:40]1[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=1.C(=O)([O-])[O-].[K+].[K+].C(=O)([O-])O.[Na+]>C(COC)OC.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>[Si:1]([O:8][CH2:9][C:10]1([CH3:38])[S:16][CH2:15][CH2:14][N:13]2[C:17]([C:20]3([C:23]4[CH:28]=[CH:27][C:26]([C:40]5[N:41]=[N:42][C:43]([CH3:46])=[CH:44][CH:45]=5)=[CH:25][CH:24]=4)[CH2:22][CH2:21]3)=[N:18][N:19]=[C:12]2[CH2:11]1)([C:4]([CH3:7])([CH3:5])[CH3:6])([CH3:3])[CH3:2]
Reactant: Cc1ccc(Cl)nn1
Reactant: CC1(CO[Si](C)(C)C(C)(C)C)Cc2nnc(C3(c4ccc(B5OC(C)(C)C(C)(C)O5)cc4)CC3)n2CCS1
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: O=C([O-])[O-]
Solvent: COCCOC
Solvent: O
Product: Cc1ccc(-c2ccc(C3(c4nnc5n4CCSC(C)(CO[Si](C)(C)C(C)(C)C)C5)CC3)cc2)nn1
Temperature: 25 °C
Yield: 29.3 %

Procedure:
A solution of the compound (555 mg, 1.0 mmol) obtained in Example 16-5), 3-chloro-6-methylpyridazine (192 mg, 1.5 mmol), tetrakis(triphenylphosphine)palladium(0) (231 mg, 0.2 mmol), and potassium carbonate (276 mg, 2 mmol) in dimethoxyethane (4 mL) and water (1 mL) was stirred at 130° C. for 1.5 h under microwave irradiation. The reaction mixture was cooled to room temperature, saturated aqueous sodium hydrogencarbonate was added to the reaction mixture, the mixture was extracted with dichloromethane, and the organic layer was washed with saturated sodium chloride solution and dried with anhydrous sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (Isco Combiflash, 40 g, methanol:ethyl acetate=0:100 to 20:80, gradient) to obtain the title compound (153 mg, 29%) as a brown solid.
Reaction SMILES: [CH:1]1([C:4]2[C:8]([C:9]([OH:11])=O)=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1.C(N1C=CN=C1)([N:42]1C=CN=C1)=O.N.CCO>C1COCC1>[CH:1]1([C:4]2[C:8]([C:9]([NH2:42])=[O:11])=[C:7]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[CH:21][C:20]=4[S:25]([NH:28][C:29]([C:31]4[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=4)=[O:30])(=[O:27])=[O:26])=[CH:15][CH:14]=3)[N:6]([CH2:37][CH2:38][CH3:39])[N:5]=2)[CH2:3][CH2:2]1
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: CCCn1nc(C2CC2)c(C(=O)O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Agent: N
Solvent: CCO
Solvent: C1CCOC1
Product: CCCn1nc(C2CC2)c(C(N)=O)c1Cc1ccc(-c2ccccc2S(=O)(=O)NC(=O)c2ccccc2)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 40 %

Procedure:
To a solution of the compound obtained in example 60 (0.15 g, 0.28 mmol) in THF (10 mL) was added 1,1'-carbonyldiimidazole (0.057 g, 0.35 mmol) and the mixture was stirred at room temperature under an argon atmosphere for 3 h. Next, ammonia (32% aqueous solution, 0.33 mL) and EtOH (0.7 mL) were added and the reaction mixture was stirred at room temperature overnight and then at reflux for 1 h. The solvent was removed, the residue was taken up in CH2Cl2 and H2O was added. The aqueous phase was acidified to pH=6 and extracted with EtOAc. The combined organic extracts were dried and concentrated to a crude product. This was chromatographed on silica gel (hexane-EtOAc mixtures of increasing polarity) to afford the title compound as a white solid (40%).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][N:5]=[C:4]([NH:8][CH2:9][CH:10]([OH:22])[CH2:11][N:12]2[CH2:21][CH2:20][C:19]3[C:14](=[CH:15][CH:16]=[CH:17][CH:18]=3)[CH2:13]2)[CH:3]=1.[CH3:23][N:24]1[C:28]2[CH:29]=[C:30](B3OC(C)(C)C(C)(C)O3)[CH:31]=[CH:32][C:27]=2[N:26]=[CH:25]1.C([O-])([O-])=O.[Na+].[Na+].O>O1CCOCC1.O.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[CH2:13]1[C:14]2[C:19](=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:20][CH2:21][N:12]1[CH2:11][CH:10]([OH:22])[CH2:9][NH:8][C:4]1[CH:3]=[C:2]([C:30]2[CH:31]=[CH:32][C:27]3[N:26]=[CH:25][N:24]([CH3:23])[C:28]=3[CH:29]=2)[CH:7]=[CH:6][N:5]=1
Reactant: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Reactant: Cn1cnc2ccc(B3OC(C)(C)C(C)(C)O3)cc21
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: Cn1cnc2ccc(-c3ccnc(NCC(O)CN4CCc5ccccc5C4)c3)cc21
Temperature: 100 °C
Reaction time: 2 h
Yield: 15.4 %

Procedure:
A mixture of 1-((4-bromopyridin-2-yl)amino)-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (170 mg, 0.47 mmol), 1-methyl-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-1H-benzo[d]imidazole (177 mg, 0.68 mmol), Pd(dppf)Cl2 (83 mg, 0.11 mmol) and Na2CO3 (151 mg, 1.43 mmol) in dioxane/H2O (5/2 mL) was stirred at 100° C. under N2 for 2 h. Upon completion, water was added to the mixture which was extracted with DCM. The organic layer was concentrated and purified by pre-HPLC to give the desired title compound (30 mg, yield 16%). 1H NMR (400 MHz, MeOD): δ 8.41 (s, 1H), 7.90 (d, J=6.8 Hz, 2H), 7.78 (d, J=8.0 Hz, 1H), 7.64 (d, J=8.0 Hz, 1H), 7.33-7.19 (m, 4H), 7.04 (d, J=5.6 Hz, 2H), 4.46 (s, 2H), 4.35 (br.s, 1H), 3.98 (s, 3H), 3.66-3.53 (m, 4H), 3.33-3.13 (m, 4H). LCMS (m/z): 414.2 (M+1).
Reaction SMILES: [CH:1]([C:4]1[CH:15]=[CH:14][CH:13]=[CH:12][C:5]=1[O:6][CH:7]([CH3:11])[C:8]([OH:10])=[O:9])([CH3:3])[CH3:2].[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32](O)[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:47])[CH3:46])[CH2:38]2)=[CH:25]1)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>>[Si:16]([O:23][C@H:24]1[CH2:33][C@H:32]([O:9][C:8](=[O:10])[CH:7]([O:6][C:5]2[CH:12]=[CH:13][CH:14]=[CH:15][C:4]=2[CH:1]([CH3:2])[CH3:3])[CH3:11])[C@H:31]2[C:26]([CH:27]=[CH:28][C@H:29]([CH3:52])[C@@H:30]2[CH2:35][CH2:36][C@H:37]2[O:42][C:41](=[O:43])[CH2:40][C@H:39]([O:44][Si:45]([C:48]([CH3:51])([CH3:50])[CH3:49])([CH3:46])[CH3:47])[CH2:38]2)=[CH:25]1)([C:19]([CH3:20])([CH3:21])[CH3:22])([CH3:18])[CH3:17]
Reactant: CC(Oc1ccccc1C(C)C)C(=O)O
Reactant: C[C@H]1C=CC2=C[C@@H](O[Si](C)(C)C(C)(C)C)C[C@H](O)[C@@H]2[C@H]1CC[C@@H]1C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O1
Product: CC(Oc1ccccc1C(C)C)C(=O)O[C@H]1C[C@H](O[Si](C)(C)C(C)(C)C)C=C2C=C[C@H](C)[C@H](CC[C@@H]3C[C@@H](O[Si](C)(C)C(C)(C)C)CC(=O)O3)[C@H]21
Yield: 97.4 %

Procedure:
A procedure similar to that described in Example 1, above, was followed, but using 749 mg of (2RS)-2-(2-isopropylphenoxy)propionic acid and 1.0 g of (4R,6R)-6-{(1S,2S,6S,8S,8aR)-2-[1,2,6,7,8,8a-hexahydro-6-t-butyldimethylsilyloxy-8-hydroxy-2-methyl-1-naphthyl]ethyl}tetrahydro-4-t-butyldimethylsilyloxy-2H-pyran-2-one [prepared as described in Example B, above], give 1.31 g of the title compound as a colorless foam.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([C:8]([NH2:10])=[O:9])[N:5]([CH3:7])[CH:6]=1.[C:11]([O:14][CH2:15][C:16]1[C:21](B2OC(C)(C)C(C)(C)O2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12].CC(C1C=C(C(C)C)C(C2C=CC=CC=2P(C2CCCCC2)C2CCCCC2)=C(C(C)C)C=1)C.[O-]P([O-])([O-])=O.[K+].[K+].[K+]>O.O1CCOCC1>[C:11]([O:14][CH2:15][C:16]1[C:21]([C:2]2[CH:3]=[C:4]([C:8](=[O:9])[NH2:10])[N:5]([CH3:7])[CH:6]=2)=[CH:20][CH:19]=[CH:18][C:17]=1[N:31]1[N:40]([CH3:41])[CH2:39][C:38]2[C:33](=[CH:34][CH:35]=[C:36]([C:42]([CH3:45])([CH3:44])[CH3:43])[CH:37]=2)[C:32]1=[O:46])(=[O:13])[CH3:12]
Reactant: Cn1cc(Br)cc1C(N)=O
Reactant: CC(=O)OCc1c(B2OC(C)(C)C(C)(C)O2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Agent: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: C1COCCO1
Product: CC(=O)OCc1c(-c2cc(C(N)=O)n(C)c2)cccc1N1C(=O)c2ccc(C(C)(C)C)cc2CN1C
Temperature: 125 °C
Yield: 15.6 %

Procedure:
In a 10 ml microwave vial, 4-bromo-1-methyl-1H-pyrrole-2-carboxamide (82.5 mg, 406 μmol, Eq: 1.00), [prepared in Example 12, Step 1], 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzyl acetate (200 mg, 406 μmol, Eq: 1.00), X-phos (19.4 mg, 40.6 μmol, Eq: 0.10), and potassium phosphate tribasic (259 mg, 1.22 mmol, Eq: 3.00) were combined with 1,4-dioxane (5 ml) and water (0.5 ml) to give a dark brown suspension. The reaction mixture was stirred while purging with argon for 10 min. The reaction mixture was heated at 125° C. in the microwave for 30 min. The reaction mixture was diluted with 50 mL of dichloromethane and dried (MgSO4). Concentrated in vacuo. The crude material was purified by flash chromatography (silica, 20%-100% ethyl acetate/hexanes gradient) to give 2-(6-tert-butyl-3-methyl-1-oxo-3,4-dihydrophthalazin-2(1H)-yl)-6-(5-carbamoyl-1-methyl-1H-pyrrol-3-yl)benzyl acetate (31 mg, 16%): 1H NMR (300 MHz, CHLOROFORM-d) δ ppm 1.37 (s, 9H) 1.98 (s, 3H) 2.68 (s, 3H) 3.99 (s, 2H) 5.28 (s, 2H) 6.72 (d, J=1.89 Hz, 1H) 6.84-6.94 (m, 1H) 7.23 (d, J=1.51 Hz, 1H) 7.27-7.52 (m, 5H) 7.61 (s, 1H) 8.04 (d, J=7.93 Hz, 1H).
Reaction SMILES: C([O:3][C:4](=[O:21])[C:5]([S:7][CH2:8][C:9]1[CH:18]=[C:17]([Br:19])[CH:16]=[C:15]2[C:10]=1[NH:11][C:12](=[O:20])[CH2:13][NH:14]2)=[O:6])C.O.[OH-].[Li+]>O1CCCC1.O>[Br:19][C:17]1[CH:16]=[C:15]2[C:10]([NH:11][C:12](=[O:20])[CH2:13][NH:14]2)=[C:9]([CH2:8][S:7][C:5](=[O:6])[C:4]([OH:21])=[O:3])[CH:18]=1
Reactant: CCOC(=O)C(=O)SCc1cc(Br)cc2c1NC(=O)CN2
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: O=C1CNc2cc(Br)cc(CSC(=O)C(=O)O)c2N1
Temperature: 20 °C
Reaction time: 48 h

Procedure:
500 mg (1.34 mmol) of 7-bromo-2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-ylmethylsulfanylacetic acid ethyl ester (Example 18) are suspended in 20 ml of tetrahydrofuran and 10 ml of water, and 225 mg (4 equiv.) of lithium hydroxide hydrate are added. The mixture is stirred at 20° C. for 48 hours. The tetrahydrofuran is concentrated by evaporation, 60 ml of water are added and the solution is acidified with 1 N hydrochloric acid. The solid is filtered off, washed with water and dried.
Reaction SMILES: [OH:1][CH2:2][CH2:3][NH2:4].[CH:5]1(Br)[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>>[CH:5]1([NH:4][CH2:3][CH2:2][OH:1])[CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1
Reactant: BrC1CCCCCC1
Reactant: NCCO
Product: OCCNC1CCCCCC1

Procedure:
2-Hydroxyethylamine was reacted with cycloheptyl bromide according to Method B2a to give N-cycloheptyl-N-(2-hydroxyethyl)amine. The alcohol was reacted with SOCl2 according to Method B7c to give N-cycloheptyl-N-(2-chloroethyl)ammonium chloride. The chloroethylamine was reacted with 2-methyl-4-nitrophenyl isothiocyanate to give 2-(2-methyl-4-nitrophenylimino)-3-cycloheptyl-1,3-thiazolidine.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH2:9][N+:8]([O-])=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1.[CH2:22]([CH:25]([CH2:38][CH2:39][CH3:40])[C:26]([O:28]C(=O)C(CCC)CCC)=[O:27])[CH2:23][CH3:24].C1CCCCC1.CC(C)=O.O>C(Cl)(Cl)Cl>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[NH:11][C:10](=[O:12])[CH:9]([O:28][C:26](=[O:27])[CH:25]([CH2:38][CH2:39][CH3:40])[CH2:22][CH2:23][CH3:24])[N:8]=[C:7]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[F:20])[C:6]=2[CH:21]=1
Reactant: O=C1C[N+]([O-])=C(c2ccccc2F)c2cc(Cl)ccc2N1
Reactant: CCCC(CCC)C(=O)OC(=O)C(CCC)CCC
Solvent: CC(C)=O
Solvent: O
Solvent: C1CCCCC1
Product: CCCC(CCC)C(=O)OC1N=C(c2ccccc2F)c2cc(Cl)ccc2NC1=O

Procedure:
A suspension of 10 g of 7-chloro-5-(2'-fluoro-phenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one-4-oxide in 20 ml of absolute chloroform is mixed with 14.3 g of dipropyl acetic acid anhydride and is heated under reflux and with the exclusion of atmospheric moisture for such a length of time until a sample on the thin layer-chromatogram (silica gel 60 F 254 of the firm Merck, flow agent: cyclohexane/acetone=1:1) shows a complete conversion. Then, the cooled mixture is shaken out several times with water, the organic phase is dried with Na2SO4 and the filtrate is evaporated in the vacuum. Upon standing over night, the residue crystallizes, is washed with petroleum ether and recrystallized from aceontrile. One will obtain a colorless powder of 7-chloro-3-dipropylacetoxy-5-(2'-fluorophenyl)-1,3-dihydro-2H-1,4-benzodiazepine-2-one, which melts at 147°-149°.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([NH:19][C:20]2[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH2:18])[CH2:11][CH2:10]2)=[CH:4][CH:3]=1.[CH3:27][N:28]=[C:29]=[O:30]>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]([NH:19][C:20]2[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=2)[CH:9]2[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][CH2:17][NH:18][C:29]([NH:28][CH3:27])=[O:30])[CH2:11][CH2:10]2)=[CH:6][CH:7]=1
Reactant: CN=C=O
Reactant: NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: CNC(=O)NCCCN1CCC(C(Nc2ccc(F)cc2)c2ccc(F)cc2)CC1

Procedure:
The compound of Example 59 is reacted with methyl isocyanate in an aprotic solvent to obtain the title compound.
Reaction SMILES: [OH:1][C:2]1[CH:19]=[CH:18][C:5]([O:6][CH2:7][C:8]2[CH:17]=[CH:16][C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[N:9]=2)=[CH:4][CH:3]=1.Br[CH2:21][C:22]1[CH:37]=[CH:36][C:25]2[C:26](=[O:35])[CH:27]=[C:28]([C:30]([O:32][CH2:33][CH3:34])=[O:31])[O:29][C:24]=2[CH:23]=1.C(=O)([O-])[O-].[K+].[K+].O>CN(C)C=O>[C:30]([C:28]1[O:29][C:24]2[CH:23]=[C:22]([CH2:21][O:1][C:2]3[CH:3]=[CH:4][C:5]([O:6][CH2:7][C:8]4[CH:17]=[CH:16][C:15]5[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=5)[N:9]=4)=[CH:18][CH:19]=3)[CH:37]=[CH:36][C:25]=2[C:26](=[O:35])[CH:27]=1)([O:32][CH2:33][CH3:34])=[O:31]
Reactant: CCOC(=O)c1cc(=O)c2ccc(CBr)cc2o1
Reactant: Oc1ccc(OCc2ccc3ccccc3n2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cc(=O)c2ccc(COc3ccc(OCc4ccc5ccccc5n4)cc3)cc2o1
Temperature: 70 °C
Yield: 58.7 %

Procedure:
0.8 g of 2-(4-hydroxyphenoxy)methylquinoline, 0.99 g of 7-bromomethyl-2-carboethoxy-4-oxo-4H-1-benzopyran and 0.44 g of potassium carbonate are combined in 15 ml of dimethylformamide and heated at 70° C. for 18 hours. The mixture is poured into water and the aqueous mixture extracted with ethyl acetate. The organic solution is dried and evaporated and the resulting crude product is purified by column chromatography on silica gel to give 0.9 g of 2-carboethoxy-7-(4-(quinolin-2-ylmethoxy)phenoxymethyl)-4-oxo-4H-1-benzopyran.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12](O)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].S(=O)(=O)(O)O>O1CCCC1>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2([CH2:12][OH:13])[CH2:11][CH2:10][CH2:9]2)=[CH:6][CH:7]=1
Reactant: O=C(O)C1(c2ccc(Cl)cc2)CCC1
Agent: O=S(=O)(O)O
Agent: [Al+3]
Agent: [H-]
Solvent: C1CCOC1
Product: OCC1(c2ccc(Cl)cc2)CCC1
Temperature: 25 °C
Reaction time: 1 h
Yield: 79 %

Procedure:
15.6 g of 1-(4-chlorophenyl)-cyclobutane-1-carboxylic acid, dissolved in 80 ml of absolute tetrahydrofuran, were added dropwise to 7.68 g of lithium aluminum hydride in 250 ml of absolute tetrahydrofuran at room temperature, under nitrogen. The mixture was stirred for 1 hour under reflux and for 12 hours at room temperature, after which it was hydrolyzed with ice water, acidified with 10% strength sulfuric acid and extracted with methylene chloride. The extract was dried and the solvent was evaporated to give 11.5 g of 1-(4-chlorophenyl)-1-hydroxymethylcyclobutane of melting point 53°-54° C. This was dissolved in 105 ml of pyridine in the absence of moisture, and 7.8 g of methanesulfonyl chloride were added dropwise at 0°-5° C. Stirring was continued for 2 hours at this temperature, after which the suspension was poured into ice water and extracted with methylene chloride, the combined organic phases were washed with water and dried, the solvent was removed and the product was recrystallized from cyclohexane. 5.1 g of [1-(4-chlorophenyl)-cyclobut-1-yl]-methyl methanesulfonate of melting point 66°-70° C. were obtained.
Reaction SMILES: [C:1]([O:5][C:6]([C@H:8]([C@@H:18]([CH2:29][CH:30]([CH3:32])[CH3:31])[C:19]([NH:21][NH:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:20])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH2:33]([S:40](Cl)(=[O:42])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1>>[CH2:33]([S:40]([N:22]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[NH:21][C:19](=[O:20])[C@@H:18]([C@@H:8]([C:6]([O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[O:7])[CH2:9]/[CH:10]=[CH:11]/[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[CH2:29][CH:30]([CH3:32])[CH3:31])(=[O:42])=[O:41])[C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=1
Reactant: CC(C)C[C@@H](C(=O)NNc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Reactant: O=S(=O)(Cl)Cc1ccccc1
Product: CC(C)C[C@@H](C(=O)NN(c1ccccc1)S(=O)(=O)Cc1ccccc1)[C@H](C/C=C/c1ccccc1)C(=O)OC(C)(C)C
Yield: 77.8 %

Procedure:
In an analogous manner to that described in Example 1, part (ii), starting from 0.3 g of (E)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide and 0.543 g of benzylsulphonyl chloride there was obtained 0.316 g of (E)-2′-(benzylsulphonyl)-2(R)-[1(S)-(tert-butoxycarbonyl)-4-phenyl-3-butenyl]-4-methyl-2′-phenylvalerohydrazide in the form of a white solid.
Reaction SMILES: [CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH2:26][OH:27])[CH:23]=[CH:24][CH:25]=3)[CH:19]=2)[CH:10]=[CH:9][CH:8]=1>ClCCl.O=[Mn]=O>[CH3:1][CH:2]1[CH2:6][CH2:5][CH2:4][N:3]1[C:7]1[N:12]=[C:11]([NH:13][C:14]2[C:15]3[N:16]([CH:28]=[CH:29][N:30]=3)[N:17]=[C:18]([C:20]3[CH:21]=[C:22]([CH:23]=[CH:24][CH:25]=3)[CH:26]=[O:27])[CH:19]=2)[CH:10]=[CH:9][CH:8]=1
Reactant: CC1CCCN1c1cccc(Nc2cc(-c3cccc(CO)c3)nn3ccnc23)n1
Agent: O=[Mn]=O
Solvent: ClCCl
Product: CC1CCCN1c1cccc(Nc2cc(-c3cccc(C=O)c3)nn3ccnc23)n1
Temperature: 40 °C
Reaction time: 24 h
Yield: 45.2 %

Procedure:
(3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)phenyl)methanol (20 mg, 0.05 mmol) and MnO2 (86 mg, 1.0 mmol) were dissolved in dichloromethane (10 mL), the reaction mixture was heated up to 40° C. with stirring for 24 h, filtered, washed with dichloromethane (30 mL) and then the filtrate was concentrated in vacuo to give a solid which was purified by chromatography on a aluminum oxide eluted with dichloromethane to give 3-(8-(6-(2-methylpyrrolidin-1-yl)pyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzaldehyde (9 mg, 45%) as an orange solid. LC-MS: 399 [M+H]+, tR=1.88 min.