Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[C:5]([OH:7])[CH3:6])[CH2:4][CH2:3][CH2:2]1.[C:8]1(O)C=CC=C[CH:9]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].[OH-].[Na+]>C(OCC)(OCC)(OCC)C.CO>[CH:8]([C:1]1([CH:5]([OH:7])[CH3:6])[CH2:4][CH2:3][CH2:2]1)=[CH2:9]
Reactant: CC(O)=C1CCC1
Reactant: Oc1ccccc1
Agent: CCOC(C)(OCC)OCC
Agent: [Al+3]
Agent: [H-]
Solvent: CO
Product: C=CC1(C(C)O)CCC1
Reaction time: 24 h

Procedure:
Cyclobutylideneethanol (22.14 g, <60 mmol) was dissolved in triethyl orthoacetate (25 mL). To the solution, phenol (1.02 g, 11.6 mmol) was added, and the mixture was stirred for 1 day under heating to reflux. The mixture was allowed to cool, and saturated saline was then added thereto, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous sodium sulfate, and the solvent was distilled off under reduced pressure. To the residue, a 2 N potassium hydroxide-methanol solution (80 mL) was added, and the mixture was stirred overnight at room temperature. The solvent was distilled off under reduced pressure, and the residue was then dissolved in a 2 N aqueous sodium hydroxide solution and washed with diethyl ether. The aqueous layer was made acidic using concentrated hydrochloric acid under ice cooling, followed by extraction with ethyl acetate. The organic layer was washed with saturated saline and then dried over anhydrous magnesium sulfate, and the solvent was distilled off under reduced pressure. The residue was dissolved in tetrahydrofuran (70 mL). To the solution, lithium aluminum hydride (948.8 mg, 25 mmol) was then added under ice cooling. The mixture was brought to room temperature and then stirred for 7 hours under heating to reflux. Methanol (1.5 mL) and a 1 N aqueous sodium hydroxide solution (1.5 mL) were added thereto under ice cooling, and the mixture was further stirred at room temperature for 1 hour and then filtered through Celite. The residue was washed with dichloromethane and saturated saline. These filtrates were combined and separated into aqueous and organic layers. The organic layer was washed with a 1 N aqueous sodium hydroxide solution and saturated saline and then dried over anhydrous sodium sulfate. The solvent was distilled off under reduced pressure to obtain the compound of interest as a colorless oil substance (1.94 g, 25%).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][NH:7][CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2].[Cl:16][C:17]1[N:22]=[C:21](Cl)[C:20]([N+:24]([O-:26])=[O:25])=[CH:19][N:18]=1.C(=O)(O)[O-].[K+]>C(OCC)(=O)C.O>[CH2:1]([O:3][C:4](=[O:15])[CH:5]([CH3:14])[CH2:6][N:7]([C:19]1[C:20]([N+:24]([O-:26])=[O:25])=[CH:21][N:22]=[C:17]([Cl:16])[N:18]=1)[CH:8]1[CH2:13][CH2:12][O:11][CH2:10][CH2:9]1)[CH3:2]
Reactant: O=[N+]([O-])c1cnc(Cl)nc1Cl
Reactant: CCOC(=O)C(C)CNC1CCOCC1
Agent: O=C([O-])O
Agent: [K+]
Solvent: O
Solvent: CCOC(C)=O
Product: CCOC(=O)C(C)CN(c1nc(Cl)ncc1[N+](=O)[O-])C1CCOCC1
Reaction time: 3 h
Yield: 98.3 %

Procedure:
To a mixture of 2.05 g (0.0095 mole) of (rac)-2-methyl-3-(tetrahydro-pyran-4-ylamino)-propanoic acid ethyl ester, 1.85 g (0.0095 mole) of 2,4-dichloro-5-nitro-pyrimidine 50 mL of ethyl acetate and 25 mL of water was added 2.85 g (0.0286 mole) of potassium bicarbonate. The mixture was stirred for 3 hours and then diluted with 50 mL of ethyl acetate and 50 mL of water. The layers were separated, and the aqueous layer extracted with 100 mL of ethyl acetate. The organic layers were washed with 100 mL of brine, combined, dried over anhydrous magnesium sulfate, filtered and concentrated under reduced pressure. The residue was purified by silica gel chromatography, eluting with hexanes-ethyl acetate (75:25) to give 3.48 g of (rac)-3-[(2-chloro-5-nitro-pyrimidin-4-yl)-(tetrahydro-pyran-4-yl)-amino]-2-methyl-propanoic acid ethyl ester (IV-45) as pale yellow oil.
Reaction SMILES: Br[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1.[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1B(O)O)#[N:22].C1(B(O)O)C=CC=CC=1>>[C:21]([C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][C:24]=1[C:2]1[CH:20]=[CH:19][C:5]([O:6][C@@H:7]2[CH2:11][CH2:10][CH2:9][C@@H:8]2[NH:12][S:13]([CH:16]([CH3:18])[CH3:17])(=[O:15])=[O:14])=[CH:4][CH:3]=1)#[N:22]
Reactant: N#Cc1ccccc1B(O)O
Reactant: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(Br)cc1
Agent: OB(O)c1ccccc1
Product: CC(C)S(=O)(=O)N[C@H]1CCC[C@H]1Oc1ccc(-c2ccccc2C#N)cc1

Procedure:
The title compound of Step 7 was prepared according to the general procedure for the synthesis of Example 2, except that N-[(1S,2R)-2-(4-bromophenoxy)cyclopentyl]propane-2-sulfonamide was used instead of N-[(3S,4S)-4-(4-bromophenoxy)tetrahydrofuran-3-yl]propane-2-sulfonamide, and (2-cyanophenyl)boronic acid was added in place of phenylboronic acid. After the reaction mixture was concentrated in vacuo, it was directly purified by silica gel chromatography in this case (Eluant: 25% ethyl acetate in heptane), to afford the product as a sticky white foam. Trituration with hexanes gave product as a white powder. Yield: 53 mg, 0.14 mmol, 82%. MS (APCI) m/z 382.9 (M−1). 1H NMR (400 MHz, CDCl3) δ 1.36 (d, J=6.7 Hz, 3H), 1.40 (d, J=6.8 Hz, 3H), 1.66 (m, 1H), 1.82-2.03 (m, 4H), 2.15 (m, 1H), 3.15 (septet, J=6.8 Hz, 1H), 3.90 (m, 1H), 4.70 (m, 2H), 7.01 (d, J=8.8 Hz, 2H), 7.42 (ddd, J=7.6, 7.6, 1.2 Hz, 1H), 7.50 (m, 1H), 7.52 (d, J=8.8 Hz, 2H), 7.64 (ddd, J=7.7, 7.7, 1.4 Hz, 1H), 7.76 (m, 1H).
Reaction SMILES: CS(Cl)(=O)=O.[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][OH:17])[CH2:11][C@H:10]1[CH3:18])(=[O:8])[CH3:7].C(N(CC)CC)C.[F:26][C:27]([F:51])([F:50])[C:28]1[N:32]2[N:33]=[C:34]([N:37]3[CH2:42][CH2:41][CH:40]([C:43]4[CH:48]=[CH:47][C:46](O)=[CH:45][CH:44]=4)[CH2:39][CH2:38]3)[CH2:35][CH2:36][C:31]2=[N:30][N:29]=1.C(=O)([O-])[O-].[K+].[K+]>C(Cl)Cl.CN(C=O)C>[C:6]([N:9]1[CH2:14][CH2:13][N:12]([CH2:15][CH2:16][O:17][C:46]2[CH:47]=[CH:48][C:43]([CH:40]3[CH2:39][CH2:38][N:37]([C:34]4[CH2:35][CH2:36][C:31]5[N:32]([C:28]([C:27]([F:51])([F:50])[F:26])=[N:29][N:30]=5)[N:33]=4)[CH2:42][CH2:41]3)=[CH:44][CH:45]=2)[CH2:11][C@H:10]1[CH3:18])(=[O:8])[CH3:7]
Reactant: Oc1ccc(C2CCN(C3=Nn4c(nnc4C(F)(F)F)CC3)CC2)cc1
Reactant: CC(=O)N1CCN(CCO)C[C@H]1C
Agent: CS(=O)(=O)Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(=O)N1CCN(CCOc2ccc(C3CCN(C4=Nn5c(nnc5C(F)(F)F)CC4)CC3)cc2)C[C@H]1C
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 29.6 %

Procedure:
Methanesulfonyl chloride (0.165 mL, 2.12 mmol) was added dropwise to (R)-2-(4-acetyl-3-methylpiperazin-1-yl)ethanol (360 mg, 1.94 mmol) and triethylamine (0.404 mL, 2.90 mmol) in DCM (5 mL) at 0° C. under nitrogen. The resulting solution was stirred at 0° C. for 15 minutes, warmed to room temperature and stirred for 2 hours. The reaction mixture was diluted with DCM (50 mL) and washed with water (15 mL). The organic layer was passed through a phase separating cartridge and concentrated in vacuo. The residual orange gum was dissolved in DMF (5 mL) and added to 4-{1-[3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperidin-4-yl}phenol (obtained as described in Example 46, preparation of starting materials) (235 mg, 0.64 mmol) and potassium carbonate (445 mg, 3.22 mmol) in DMF (10 mL) at 20° C. under nitrogen. The resulting suspension was stirred at 100° C. for 3 hours and the solvent was removed in vacuo. The residue was partitioned between DCM (100 mL) and water (100 mL) and the organic phase was separated. The aqueous phase was re-extracted with DCM (100 mL), and the is combined organic phases were washed with brine (100 mL), passed through phase separating cartridge and concentrated under reduced pressure to give an orange gum. The crude product was purified by flash silica chromatography, elution gradient 0 to 10% MeOH in EtOAc. Pure fractions were evaporated to dryness to afford a pale yellow gum, which was triturated with ether to give 6-[4-(4-{2-[(3R)-4-acetyl-3-methylpiperazin-1-yl]ethoxy}phenyl)piperidin-1-yl]-3-(trifluoromethyl)-7,8-dihydro[1,2,4]triazolo[4,3-b]pyridazine (101 mg, 29.4%) as a white solid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH:9]2[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]2)[CH:5]=[CH:4][N:3]=1.[NH2:22][C:23]1[CH:24]=[C:25]([C:32]2[S:36][C:35]([C:37]3([OH:41])[CH2:40][CH2:39][CH2:38]3)=[N:34][CH:33]=2)[CH:26]=[C:27]([N+:29]([O-:31])=[O:30])[CH:28]=1.CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2.C(=O)([O-])[O-].[Cs+].[Cs+]>O1CCOCC1.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[OH:41][C:37]1([C:35]2[S:36][C:32]([C:25]3[CH:24]=[C:23]([NH:22][C:2]4[N:7]=[C:6]([O:8][CH:9]5[CH2:14][CH2:13][N:12]([C:15]([O:17][C:18]([CH3:21])([CH3:20])[CH3:19])=[O:16])[CH2:11][CH2:10]5)[CH:5]=[CH:4][N:3]=4)[CH:28]=[C:27]([N+:29]([O-:31])=[O:30])[CH:26]=3)=[CH:33][N:34]=2)[CH2:40][CH2:39][CH2:38]1
Reactant: Nc1cc(-c2cnc(C3(O)CCC3)s2)cc([N+](=O)[O-])c1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Cl)n2)CC1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccnc(Nc3cc(-c4cnc(C5(O)CCC5)s4)cc([N+](=O)[O-])c3)n2)CC1
Temperature: 100 °C
Yield: 70.4 %

Procedure:
To the product from Step 1 (900 mg, 2.87 mmol) and Intermediate 22 (836 mg, 2.87 mmol) in dioxane (28 mL) was added palladium acetate (129 mg, 0.574 mmol), XantPhos (498 mg, 0.860 mmol) and cesium carbonate (1.87 g, 5.74 mmol). The mixture was degassed with Ar for 10 min and then heated at 100° C. for 20 h. After cooling to ambient temperature, the reaction mixture was filtered through celite and washed with ethyl acetate and methanol. After solvent removal, the residue was purified by column chromatography on silica gel (0-90%, ethyl acetate: 10:1 methanol in hexanes) to afford tert-butyl 4-{[2-({3-[2-(1-hydroxycyclobutyl)-1,3-thiazol-5-yl]-5-nitrophenyl}amino)pyrimidin-4-yl]oxy}piperidine-1-carboxylate (1.15 g, 2.02 mmol, 70%). MS ESI: [M+H]+ m/z 569.2.
Reaction SMILES: C([Li])CCC.[CH2:6]([O:13][C:14]1[CH:19]=[C:18]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:17](Br)=[CH:16][C:15]=1[C:29]1[O:33][N:32]=[C:31]([CH3:34])[C:30]=1[C:35]1[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=1)[C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1.Cl[C:44]([O:46][CH3:47])=[O:45]>O1CCCC1>[CH3:47][O:46][C:44](=[O:45])[C:17]1[CH:16]=[C:15]([C:29]2[O:33][N:32]=[C:31]([CH3:34])[C:30]=2[C:35]2[CH:40]=[CH:39][C:38]([O:41][CH3:42])=[CH:37][CH:36]=2)[C:14]([O:13][CH2:6][C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[CH:19][C:18]=1[O:20][CH2:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1
Reactant: COC(=O)Cl
Reactant: COc1ccc(-c2c(C)noc2-c2cc(Br)c(OCc3ccccc3)cc2OCc2ccccc2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2onc(C)c2-c2ccc(OC)cc2)c(OCc2ccccc2)cc1OCc1ccccc1
Temperature: -70 °C
Reaction time: 0.5 h

Procedure:
n-Butyl lithium (100 μl) was added to a solution of 5-(2,4-bis-benzyloxy-5-bromo-phenyl)-4-(4-methoxy-phenyl)-3-methyl-isoxazole (154 mg, 0.28 mmol) in tetrahydrofuran (2.5 ml) under a nitrogen atmosphere at −78° C. Solution stirred at −70° C. for 30 minutes to give an orange solution. The ion was quenched with methyl chloroformate (100 μl, 3 eq) and allowed to warm to room temperature for 30 minutes. The solution was quenched with saturated aqueous ammonium chloride (5 ml). The mixture was extracted with ethyl acetate (3×5 ml). The combined extracts were washed with water (2×5 ml) and saturated aqueous sodium chloride solution (5 ml). The solution was dried over anhydrous magnesium sulphate and concentrated. The crude products were purified by column chromatography, silica, eluting with ethyl acetate in hexane (gradient 20% to 60% ethyl acetate) to give 2,4-Bis-benzyloxy-5-[4-(4-methoxy-phenyl)-3-methyl-isoxazol-5-yl]-benzoic acid methyl ester (72 mg).
Reaction SMILES: BrC1C(N2CCN(C(NC3C=CC=CC=3)=O)CC2)=C2N=C(C3C=CC(N(C)C)=CC=3)NC2=NC=1.[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]4[C:56]([Br:57])=[CH:55][N:54]=[C:53]([NH2:58])[C:52]=4[N+:59]([O-])=O)[CH2:47][CH2:46]3)[C:38]=2[O:37][CH2:36]1.[O-]S(S([O-])=O)=O.[Na+].[Na+].[CH3:70][O:71][C:72]1[CH:77]=[CH:76][C:75]([CH:78]=O)=[CH:74][CH:73]=1>C(O)C.CN(C=O)C>[O:35]1[C:39]2[CH:40]=[CH:41][CH:42]=[C:43]([CH2:44][N:45]3[CH2:50][CH2:49][N:48]([C:51]4[C:56]([Br:57])=[CH:55][N:54]=[C:53]5[NH:58][C:78]([C:75]6[CH:76]=[CH:77][C:72]([O:71][CH3:70])=[CH:73][CH:74]=6)=[N:59][C:52]=45)[CH2:47][CH2:46]3)[C:38]=2[O:37][CH2:36]1
Reactant: Nc1ncc(Br)c(N2CCN(Cc3cccc4c3OCO4)CC2)c1[N+](=O)[O-]
Reactant: COc1ccc(C=O)cc1
Agent: CN(C)c1ccc(-c2nc3c(N4CCN(C(=O)Nc5ccccc5)CC4)c(Br)cnc3[nH]2)cc1
Agent: O=S([O-])S(=O)[O-]
Agent: [Na+]
Solvent: CCO
Solvent: CN(C)C=O
Product: COc1ccc(-c2nc3c(N4CCN(Cc5cccc6c5OCO6)CC4)c(Br)cnc3[nH]2)cc1
Reaction time: 6 h
Yield: 61.9 %

Procedure:
This was prepared using the same procedure as for 4-(6-bromo-2-(4-(dimethylamino)phenyl)-3H-imidazo[4,5-b]pyridin-7-yl)-N-phenylpiperazine-1-carboxamide, but here using 4-(4-(benzo[d][1,3]dioxol-4-ylmethyl)piperazin-1-yl)-5-bromo-3-nitropyridin-2-amine (30 mg, 0.068 mmol), DMF (0.15 mL), ethanol (0.85 mL), 1M Na2S2O4 (3 eq, 0.21 mmol, 0.21 mL) and 4-methoxybenzene carboxaldehyde (1.1 eq, 0.075 mmol, 10 mg). After 6 h, concentration in vacuo and purification by preparative tlc (CH2Cl2-MeOH, 95:5) gave the product (22 mg, 63%) as a colourless solid; δH (500 MHz, DMSO-d6) 2.63 (s, br, 4H, piperazine N(CH2)2), 3.55 (s, 2H, NCH2), 3.65 (t, J=4.3 Hz, 4H, piperazine N(CH2)2), 3.84 (s, 3H, OCH3), 6.02 (s, 2H, OCH2), 6.83 (d, J=4.2 Hz, 2H, benzo[d][1,3]dioxyl H-4 & H-6), 6.90 (app. q, J=4.4 Hz, 1H, benzo[d][1,3]dioxyl H-5), 7.09 (d, J=8.9 Hz, 2H, methoxyphenyl H-2 & H-6), 8.14 (d, J=8.9 Hz, 2H, methoxyphenyl H-3 & H-5), 8.20 (s, 1H, imidazo[4,5-b]pyridine H-5), 13.34 (s, br, 1H, imidazo[4,5-b]pyridine NH);
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:12](=[CH:23][C:24]#N)[CH:11]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].C([Al+]CC(C)C)C(C)C.C(C(C(C([O-])=O)O)O)([O-])=[O:45].[Na+].[K+]>C1(C)C=CC=CC=1>[CH2:1]([O:8][CH:9]1[CH2:14][CH:13]([O:15][Si:16]([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17])[C:12](=[CH:23][CH:24]=[O:45])[CH:11]([O:26][Si:27]([C:30]([CH3:33])([CH3:32])[CH3:31])([CH3:29])[CH3:28])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=C([O-])C(O)C(O)C(=O)[O-]
Reactant: CC(C)(C)[Si](C)(C)OC1CC(OCc2ccccc2)CC(O[Si](C)(C)C(C)(C)C)C1=CC#N
Agent: CC(C)C[Al+]CC(C)C
Agent: [H-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: CC(C)(C)[Si](C)(C)OC1CC(OCc2ccccc2)CC(O[Si](C)(C)C(C)(C)C)C1=CC=O
Temperature: 0 °C
Reaction time: 1.5 h
Yield: 93 %

Procedure:
To a solution of Compound 30 (310 mg, 0.635 mmol, 30a:30b=ca. 1:2) in dry toluene (3 mL) cooled to −78° C. was slowly added diisobutylaluminum hydride (763 μL, 0.763 mmol, 1.0 M solution in toluene), and the mixture was stirred for 1.5 h. Excess reagent was decomposed by adding an aqueous solution of saturated potassium sodium tartrate, thereby quenching reaction, and into the mixture was poured ice water, and then extracted with AcOEt. The organic layer was washed with saturated brine, dried over anhydrous MgSO4, and evaporated in vacuo. The residue was purified by silica gel column chromatography (13 g; 5% AcOEt/hexane) to afford Compound 31 (288.5 mg, 93%) as a mixture of two stereoisomers. The ratio of the stereoisomers constituting the mixture was ca. 1:2. It was impossible to know whether the major product was aS*,2R,6R isomer or aR*,2R,6R isomer.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([CH2:22][C:23]2[CH:31]=[CH:30][C:26]([C:27](O)=[O:28])=[CH:25][C:24]=2[F:32])[C@@H:12]2[CH2:18][C:17]([CH3:20])([CH3:19])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])(=[O:10])=[O:9])=[CH:4][CH:3]=1.[H-].[H-].[H-].[H-].[Li+].[Al+3].O.[OH-].[Na+]>C1COCC1>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([N:11]([C@@H:12]2[CH2:18][C:17]([CH3:19])([CH3:20])[CH2:16][CH2:15][NH:14][C:13]2=[O:21])[CH2:22][C:23]2[CH:31]=[CH:30][C:26]([CH2:27][OH:28])=[CH:25][C:24]=2[F:32])(=[O:9])=[O:10])=[CH:4][CH:3]=1
Reactant: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(C(=O)O)cc2F)S(=O)(=O)c2ccc(Cl)cc2)C1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC1(C)CCNC(=O)[C@H](N(Cc2ccc(CO)cc2F)S(=O)(=O)c2ccc(Cl)cc2)C1
Reaction time: 0.25 h

Procedure:
4-{[(4-Chloro-benzenesulfonyl)-((R)-5,5-dimethyl-2-oxo-azepan-3-yl)-amino]-methyl}-3-fluoro-benzoic acid (0.05 g, 0.10 mmol) was dissolved in THF (2 ml) and added dropwise to a suspension of LiAlH4 (0.04 g, 1 mmol) in THF (2 ml). After 6 h to the reaction mixture was added water (0.5 ml), 1 N NaOH (0.2 ml) and after 15 min of vigorous stirring it was filtered. The filtrate was concentrated under reduced pressure and purified using preparative RP(C18) chromatography: lyophilisate 5 mg; MS: m/e=469.1 (MH+).
Reaction SMILES: [CH3:1]N(C)C=O.[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:29]=[CH:28][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[NH:32][C:31]2=[O:46])=[CH:26][CH:25]=1)[NH:12][C:13](=[O:22])[C:14]1[C:19]([Cl:20])=[CH:18][CH:17]=[CH:16][C:15]=1[Cl:21])([CH3:8])[CH3:7].C(=O)([O-])[O-].[K+].[K+].C1(C)C=CC(S(OC)(=O)=O)=CC=1>O.C(O)(=O)C>[CH:6]([O:9][C:10](=[O:47])[C@H:11]([CH2:23][C:24]1[CH:25]=[CH:26][C:27]([N:30]2[C:39](=[O:40])[C:38]3[C:33](=[CH:34][CH:35]=[C:36]([CH2:41][N:42]([CH:44]=[O:45])[CH3:43])[CH:37]=3)[N:32]([CH3:1])[C:31]2=[O:46])=[CH:28][CH:29]=1)[NH:12][C:13](=[O:22])[C:14]1[C:15]([Cl:21])=[CH:16][CH:17]=[CH:18][C:19]=1[Cl:20])([CH3:8])[CH3:7]
Reactant: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)[nH]c3ccc(CN(C)C=O)cc3c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Reactant: CN(C)C=O
Agent: COS(=O)(=O)c1ccc(C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC(=O)O
Product: CC(C)OC(=O)[C@H](Cc1ccc(-n2c(=O)c3cc(CN(C)C=O)ccc3n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 23 °C
Yield: 94 %

Procedure:
There was added, to 21.26 L of N,N-dimethylformamide (DMF), 5.445 kg of Nα-(2,6-dichlorobenzoyl)-4-{6-(N-formyl-N-methylamino-methyl)-quinazoline-2,4[1H,3H]-dion-3-yl}-L-phenylalanine isopropyl ester, the resulting mixture was stirred at 23° C. and in a nitrogen gas stream to dissolve the isopropyl ester compound. Then 2.46 kg of potassium carbonate and 2.491 kg of methyl p-toluene-sulfonate were added to the resulting solution and the mixture was stirred with heating at 55 to 65° C. After the confirmation of the progress of the N-methylation reaction by HPLC, 2.14 kg of acetic acid was added to the mixture and subsequently the mixture was stirred with heating at 50° C. for one hour. To the reaction solution, there was dropwise added 10.9 L of water, followed by the addition of 6 g of seed crystals and stirring of the mixture at 50° C. for 2 hours. To the resulting slurry, there was further added 10.9 L of water, the mixture was cooled to 25° C. and stirred overnight. The precipitates thus obtained were recovered by the filtration using a centrifuge and the resulting cake was washed with 21.8 kg of water. The resulting wet crystals were dried under reduced pressure at 60° C. to thus give 5.235 kg of the title compound as a white crystalline solid (yield: 94%).
Reaction SMILES: [O:1]=[C:2]1[N:7]([CH2:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[N:20]=[CH:19][C:18]([O:21][CH2:22][CH:23]4[CH2:28][CH2:27][NH:26][CH2:25][CH2:24]4)=[CH:17][N:16]=3)[CH:10]=2)[N:6]=[C:5]([C:29]2[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=2)[C:32]#[N:33])[CH:4]=[CH:3]1.C(=O)([O-])[O-].[Cs+].[Cs+].Br[CH2:44][CH3:45].O>CN(C=O)C>[CH2:44]([N:26]1[CH2:25][CH2:24][CH:23]([CH2:22][O:21][C:18]2[CH:17]=[N:16][C:15]([C:11]3[CH:10]=[C:9]([CH:14]=[CH:13][CH:12]=3)[CH2:8][N:7]3[C:2](=[O:1])[CH:3]=[CH:4][C:5]([C:29]4[CH:30]=[C:31]([CH:34]=[CH:35][CH:36]=4)[C:32]#[N:33])=[N:6]3)=[N:20][CH:19]=2)[CH2:28][CH2:27]1)[CH3:45]
Reactant: CCBr
Reactant: N#Cc1cccc(-c2ccc(=O)n(Cc3cccc(-c4ncc(OCC5CCNCC5)cn4)c3)n2)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: O
Product: CCN1CCC(COc2cnc(-c3cccc(Cn4nc(-c5cccc(C#N)c5)ccc4=O)c3)nc2)CC1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
100 mg (0.21 mmol) of 3-(6-oxo-1-{3-[5-(piperidin-4-ylmethoxy)pyrimidin-2-yl]benzyl}-1,6-dihydropyridazin-3-yl)benzonitrile are dissolved in 3 ml of DMF, 204 mg (0.63 mmol) of caesium carbonate and 16 μl (0.21 mmol) of bromoethane are added. The reaction mixture is stirred at room temperature for 15 h, a further 16 μl (0.21 mmol) of bromoethane are added, and the mixture is stirred at room temperature for a further 24 h. Water is added to the reaction mixture, which is then extracted with dichloromethane, dried and evaporated. The crude mixture is purified by means of preparative HPLC.
Reaction SMILES: C(O[C:6](=O)[N:7]([CH:9]([CH3:39])[C:10]([NH:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[C:24]([CH3:25])=[CH:23][N:22]=[CH:21][C:20]=2[CH3:26])=[C:15]([C:27]#[C:28][C:29]2[CH:30]=[C:31]3[C:36](=[CH:37][CH:38]=2)[N:35]=[CH:34][CH:33]=[CH:32]3)[N:14]=1)=[O:11])C)(C)(C)C.C(Cl)Cl.C(O)(C(F)(F)F)=O>C1(C)C=CC=CC=1>[CH3:26][C:20]1[CH:21]=[N:22][CH:23]=[C:24]([CH3:25])[C:19]=1[C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:10](=[O:11])[CH:9]([NH:7][CH3:6])[CH3:39])=[N:14][C:15]=1[C:27]#[C:28][C:29]1[CH:30]=[C:31]2[C:36](=[CH:37][CH:38]=1)[N:35]=[CH:34][CH:33]=[CH:32]2
Reactant: Cc1cncc(C)c1-c1ccc(NC(=O)C(C)N(C)C(=O)OC(C)(C)C)nc1C#Cc1ccc2ncccc2c1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Solvent: Cc1ccccc1
Product: CNC(C)C(=O)Nc1ccc(-c2c(C)cncc2C)c(C#Cc2ccc3ncccc3c2)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A mixture of tert-butyl-N-[1-[[5-(3,5-dimethylpyridin-4-yl)-6-(2-quinolin-6-ylethynyl)pyridin-2-yl]amino]-1-oxopropan-2-yl]-N-methylcarbamate G1a (28 mg, 0.05 mmol) and DCM:TFA (8:2, 10 ml) is stirred at RT for 15 minutes. The mixture is diluted with toluene (10 ml) and concentrated in vacuo. The product is purified by RP HPLC. Yield: 16 mg (70%). HPLC-MS: M+H=436; tR=1.09 min (*Method—1).
Reaction SMILES: [CH3:1][C:2]([OH:10])([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5].[CH2:11]([Si:13](Cl)([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12].CN(C)C=O.C(N(CC)CC)C>O.C1C=CC=CC=1>[CH2:11]([Si:13]([O:10][C:2]([CH3:1])([C:6]#[C:7][CH2:8][CH3:9])[CH2:3][C:4]#[CH:5])([CH2:16][CH3:17])[CH2:14][CH3:15])[CH3:12]
Reactant: C#CCC(C)(O)C#CCC
Reactant: CC[Si](Cl)(CC)CC
Solvent: c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C#CCC(C)(C#CCC)O[Si](CC)(CC)CC
Temperature: 25 °C
Reaction time: 24 h

Procedure:
A mixture consisting of 1.25 parts of 4-methyl-1,5-octadiyn-4(RS)-ol, 1.5 parts of triethylsilyl chloride, 2.5 parts by volume of dimethylformamide and 1 part by volume of triethylamine was stirred in an atmosphere of nitrogen at room temperature for about 24 hours. The mixture was then poured into benzene and diluted with water. The layers were separated and the organic layer was washed successively with dilute hydrochloric acid, water and saturated aqueous potassium bicarbonate, dried over anhydrous sodium sulfate and the solvent was removed under reduced pressure. Adsorption of the residue on a silica gel chromatographic column followed by elution with hexane afforded 4-methyl-1,5-octadiyn-4(RS)-ol triethylsilyl ether.