Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Si]([O:8][CH2:9]/[C:10](=[CH:24]\[C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]2[CH:37]=[CH:36][N:35]=[C:34]([C:38]3[NH:39][CH2:40][CH2:41][N:42]=3)[CH:33]=2)[CH:26]=1)/[C:11]([NH:13][C:14]1[CH:19]=[CH:18][CH:17]=[C:16]([C:20]([CH3:23])([CH3:22])[CH3:21])[CH:15]=1)=[O:12])(C(C)(C)C)(C)C.N1C=CC=CC=1>C1COCC1.N1C=CC=CC=1.CCOC(C)=O>[C:20]([C:16]1[CH:15]=[C:14]([NH:13][C:11](=[O:12])/[C:10](/[CH2:9][OH:8])=[CH:24]/[C:25]2[CH:30]=[CH:29][CH:28]=[C:27]([O:31][C:32]3[CH:37]=[CH:36][N:35]=[C:34]([C:38]4[NH:39][CH2:40][CH2:41][N:42]=4)[CH:33]=3)[CH:26]=2)[CH:19]=[CH:18][CH:17]=1)([CH3:23])([CH3:21])[CH3:22]
Reactant: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)CO[Si](C)(C)C(C)(C)C)c1
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: c1ccncc1
Product: CC(C)(C)c1cccc(NC(=O)/C(=C/c2cccc(Oc3ccnc(C4=NCCN4)c3)c2)CO)c1
Temperature: 0 °C

Procedure:
(E)-2-((tert-butyldimethylsilyloxy)methyl)-N-(3-tert-butylphenyl)-3-(3-(2-(4,5-dihydro-1H-imidazol-2-yl)pyridin-4-yloxy)phenyl)acrylamide (107 mg, 0.18 mmol) was dissolved in a 1:1 mixture of THF/pyridine (3 mL). The reaction mixture was cooled to 0° C. and 20 drops of HF/pyridine were added. The reaction was sealed and allowed to warm to rt over 5 h. The mixture was diluted with EtOAc and washed with sat. NaHCO3, dried over Na2SO4, filtered, and concentrated. Purification by column chromatography (SiO2, 0-10% MeOH with 1% NH4OH in DCM) provided B-140 (32 mg). LCMS, FA: Rt=1.21 min, [MH+ 471.0]. 1H NMR (300 MHz, d4-MeOH): δ 8.48 (d, 1H), 7.68 (t, 1H), 7.56-7.51 (m, 3H), 7.48-7.44 (m, 1H), 7.41 (d, 1H), 7.31 (t, 1H), 7.25 (t, 1H), 7.19-7.15 (m, 2H), 7.08-7.05 (dd, 1H), 4.52 (s, 2H), 3.75 (s, 4H), and 1.32 (s, 9H).
Reaction SMILES: [Al].[Li].[H-].[CH2:4]([OH:8])[C:5]#[C:6][CH3:7].C(OCC)(=O)C.[CH2:15]([Sn:19](C[O-])([CH2:24][CH2:25][CH2:26][CH3:27])[CH2:20][CH2:21][CH2:22][CH3:23])[CH2:16][CH2:17][CH3:18]>C1COCC1.O.CO>[CH2:24]([Sn:19]([CH2:15][CH2:16][CH2:17][CH3:18])([CH2:20][CH2:21][CH2:22][CH3:23])/[C:6](/[CH3:7])=[CH:5]\[CH2:4][OH:8])[CH2:25][CH2:26][CH3:27]
Reactant: CC#CCO
Reactant: CCCC[Sn](C[O-])(CCCC)CCCC
Agent: [Al]
Agent: [H-]
Agent: [Li]
Solvent: CO
Solvent: CCOC(C)=O
Solvent: O
Product: CCCC[Sn](CCCC)(CCCC)/C(C)=C\CO
Temperature: 0 °C
Reaction time: 36 h

Procedure:
To 156.9 ml (156.9 mmol) of a 1 molar solution of lithium-aluminum-hydride in THF 0.77 g (14.3 mmol) sodium methylate have been added and the temperature has been lowered to 0° C. afterwards. Then a solution of 10.0 g (142.7 mmol) 2-butin-1-ol in 108 ml THF has been added dropwise with stirring at this temperature. Stirring was continued for 36 h at 4° C. Thereafter, at about 0° C., 28.6 ml (292.5 mmol) ethyl acetate was-added slowly while stirring. A strongly exothermic reaction was observed. Stirring was continued for 10 min without cooling. After cooling to about 0° C., 45.8 g (142.7 mmol) tri(n-butyl)stannyl-methanolate have been added dropwise while stirring. Stirring was continued for 2 d at 4° C. After addition of 112.9 g methanol stirring was continued for 1 h at ambient temperature. The reaction mixture was poured into 250 ml of water, extracted thrice with 150 ml diethyl ether each, the combined extracts were washed twice with 80 ml of water each, then once with 40 ml saturated aqueous sodium chloride solution, dried with sodium sulfate and concentrated in vacuo. Yield 48.6 g oil, which have been purified by chromatography on 300 g silica gel with hexane/MTBE (10:1). Final yield 34.6 g (67%) oil. δ=0.90 (m); 1.30 (m); 1.50 m); 1.97 (s); 4.02 (t); 6.27 (t).
Reaction SMILES: [C:1](=[O:4])([O-])[O-].[K+].[K+].CI.[CH2:9]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[C:23](O)=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12].C(OCC)(=O)C>CC(C)=O>[CH2:9]([C:13]1[CH:26]=[CH:25][C:16]([CH2:17][C:18]2[C:23]([O:4][CH3:1])=[CH:22][CH:21]=[CH:20][N:19]=2)=[CH:15][CH:14]=1)[CH2:10][CH2:11][CH3:12]
Reactant: CCCCc1ccc(Cc2ncccc2O)cc1
Reactant: O=C([O-])[O-]
Agent: [K+]
Solvent: CI
Solvent: CC(C)=O
Solvent: CCOC(C)=O
Product: CCCCc1ccc(Cc2ncccc2OC)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 7.2 %

Procedure:
Potassium carbonate (33.0 mg, 0.239 mmol) and methyl iodide (14.9 μl, 0.239 mmol) were added to a solution of the compound of Example B230 (19.2 mg, 0.0796 mmol) in acetone (1 ml), and this reaction mixture was stirred at room temperature for 3 hours. After ethyl acetate was added, the reaction mixture was washed with saturated brine and concentrated under reduced pressure. The residue was purified by silica gel column chromatography to give the title compound (1.47 mg).
Reaction SMILES: F[P-](F)(F)(F)(F)F.N1(O[P+](N(C)C)(N(C)C)N(C)C)C2C=CC=CC=2N=N1.C(N(C(C)C)CC)(C)C.[CH3:37][N:38]1[CH2:43][CH2:42][CH:41]([N:44]2[CH2:49][CH2:48][NH:47][CH2:46][CH2:45]2)[CH2:40][CH2:39]1.[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][C:59]=1[F:60])[NH:56][C:55](=[O:61])[C:54]2([CH2:71][C:72](O)=[O:73])[C:62]1[C:63]([O:68][CH2:69][CH3:70])=[N:64][CH:65]=[CH:66][CH:67]=1.[OH-].[Na+]>ClCCl.C(OCC)(=O)C>[Cl:50][C:51]1[CH:52]=[C:53]2[C:57](=[CH:58][C:59]=1[F:60])[NH:56][C:55](=[O:61])[C:54]2([C:62]1[C:63]([O:68][CH2:69][CH3:70])=[N:64][CH:65]=[CH:66][CH:67]=1)[CH2:71][C:72]([N:47]1[CH2:48][CH2:49][N:44]([CH:41]2[CH2:40][CH2:39][N:38]([CH3:37])[CH2:43][CH2:42]2)[CH2:45][CH2:46]1)=[O:73]
Reactant: CN1CCC(N2CCNCC2)CC1
Reactant: CCOc1ncccc1C1(CC(=O)O)C(=O)Nc2cc(F)c(Cl)cc21
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCOc1ncccc1C1(CC(=O)N2CCN(C3CCN(C)CC3)CC2)C(=O)Nc2cc(F)c(Cl)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.3 %

Procedure:
200 mg (0.45 mmol) of BOP, 1.07 ml (6.17 mmol) of diisopropylethylamine and then 79 mg (0.43 mmol) of 1-(1-methylpiperidin-4-yl)piperazine were added to a solution of 150 mg (0.41 mmol) of [5-chloro-3-(2-ethoxypyridin-3-yl)-6-fluoro-2-oxo-2,3-dihydro-1H-indol-3-yl]acetic acid in 2 ml of dichloromethane. The reaction mixture was stirred at room temperature overnight. 6 ml of a 2-molar NaOH were added to the reaction solution, and it was stirred at room temperature for 15 minutes. The reaction mixture was diluted with ethyl acetate. The phases were separated and the aqueous phase was extracted with ethyl acetate (1×). The combined organic phase was again washed with water (1×) and saturated sodium chloride solution (1×), dried over magnesium sulfate and filtered, and the solvent was evaporated in vacuo. The residue was purified by chromatography on silica gel (Redisep cartridge, mobile phase gradient from 2 to 50% methanol in dichloromethane). 181 mg of the title compound were obtained as a white solid.
Reaction SMILES: [N:1]1([C:7]2[CH:12]=[CH:11][C:10]([NH:13][C:14]([C:16]3[O:17][C:18]4[C:23]([C:24](=[O:26])[CH:25]=3)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=4[N:29]3[CH2:34][CH2:33][N:32]([CH3:35])[CH2:31][CH2:30]3)=[O:15])=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:36]1([N:42]=[C:43]=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1>>[CH:36]1([NH:42][C:43]([N:4]2[CH2:5][CH2:6][N:1]([C:7]3[CH:8]=[CH:9][C:10]([NH:13][C:14]([C:16]4[O:17][C:18]5[C:23]([C:24](=[O:26])[CH:25]=4)=[CH:22][C:21]([O:27][CH3:28])=[CH:20][C:19]=5[N:29]4[CH2:30][CH2:31][N:32]([CH3:35])[CH2:33][CH2:34]4)=[O:15])=[CH:11][CH:12]=3)[CH2:2][CH2:3]2)=[O:44])[CH2:41][CH2:40][CH2:39][CH2:38][CH2:37]1
Reactant: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCNCC4)cc3)cc(=O)c2c1
Reactant: O=C=NC1CCCCC1
Product: COc1cc(N2CCN(C)CC2)c2oc(C(=O)Nc3ccc(N4CCN(C(=O)NC5CCCCC5)CC4)cc3)cc(=O)c2c1

Procedure:
This compound was prepared from 6-methoxy-8-(4-methyl-piperazin-1-yl)-4-oxo-4H-chromene-2-carboxylic acid (4-piperazin-1-yl-phenyl)-amide (Example 43) and commercially available cyclohexyl isocyanate (Aldrich) via the parallel synthesis described above. MS−base peak at m/z=603 by positive ion CI
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:11]([F:14])([F:13])[F:12])=[C:6]([CH:10]=1)[C:7](Cl)=[O:8].[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:35][CH2:34][NH:33][CH2:32][CH2:31]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1>>[CH:15]1([CH2:19][CH2:20][NH:21][C:22]([C:24]2[N:25]=[N:26][C:27]([N:30]3[CH2:31][CH2:32][N:33]([C:7](=[O:8])[C:6]4[CH:10]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=4[C:11]([F:14])([F:13])[F:12])[CH2:34][CH2:35]3)=[CH:28][CH:29]=2)=[O:23])[CH2:18][CH2:17][CH2:16]1
Reactant: O=C(Cl)c1cc(Cl)ccc1C(F)(F)F
Reactant: O=C(NCCC1CCC1)c1ccc(N2CCNCC2)nn1
Product: O=C(NCCC1CCC1)c1ccc(N2CCN(C(=O)c3cc(Cl)ccc3C(F)(F)F)CC2)nn1

Procedure:
Following the procedure of Example 3, making variations only as required to use 5-chloro-2-(trifluoromethyl)benzoyl chloride in place of isoxazole-5-carbonyl chloride to react with 6-piperazin-1-ylpyridazine-3-carboxylic acid (2-cyclobutyl-ethyl)amide, the title compound was obtained as a white powder (71% yield). 1H NMR (300 MHz, CDCl3) δ 8.07, 7.81, 7.66, 7.51, 7.34, 3.86-3.66, 3.40-3.34, 2.33, 2.03, 1.86-1.57. 13C NMR (75 MHz, CDCl3) δ 166.0, 162.8, 159.8, 145.5, 138.9, 135.9, 129.8, 128.5, 127.5, 127.3, 125.6, 125.2, 112.7, 46.4, 44.6, 44.5, 41.3, 37.6, 36.5, 33.7, 28.3, 18.6. MS (ES+) m/z 496.5 (M+1).
Reaction SMILES: O.[Cl-].COC1N=C(OC)N=C([N+]2(C)CCOCC2)N=1.[F:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:48][CH2:47][N:46]([CH3:49])[CH2:45][CH2:44]4)[CH2:39][CH2:38]3)=[O:36])[CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:50][C:51]([C:53]1([C:56](O)=[O:57])[CH2:55][CH2:54]1)=[O:52].[F:59][C:60]1[CH:66]=[CH:65][C:63]([NH2:64])=[CH:62][CH:61]=1.C(=O)([O-])O.[Na+]>CN(C)C=O.O1CCCC1>[F:20][C:21]1[CH:26]=[C:25]([O:27][C:28]2[CH:33]=[CH:32][N:31]=[C:30]([NH:34][C:35]([N:37]3[CH2:42][CH2:41][CH:40]([N:43]4[CH2:44][CH2:45][N:46]([CH3:49])[CH2:47][CH2:48]4)[CH2:39][CH2:38]3)=[O:36])[CH:29]=2)[CH:24]=[CH:23][C:22]=1[NH:50][C:51]([C:53]1([C:56]([NH:64][C:63]2[CH:65]=[CH:66][C:60]([F:59])=[CH:61][CH:62]=2)=[O:57])[CH2:54][CH2:55]1)=[O:52]
Reactant: Nc1ccc(F)cc1
Reactant: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)O)CC5)c(F)c4)ccn3)CC2)CC1
Agent: COc1nc(OC)nc([N+]2(C)CCOCC2)n1
Agent: O=C([O-])O
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: O
Solvent: CN(C)C=O
Product: CN1CCN(C2CCN(C(=O)Nc3cc(Oc4ccc(NC(=O)C5(C(=O)Nc6ccc(F)cc6)CC5)c(F)c4)ccn3)CC2)CC1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
4-(4,6-Dimethoxy[1,3,5]triazin-2-yl)-4-methylmorpholinium chloride hydrate (164 mg) was added to a suspension of 1-[2-fluoro-4-(2-{[4-(4-methylpiperazin-1-yl)piperidine-1-carbonyl]amino}pyridin-4-yloxy)phenylcarbamoyl]cyclopropanecarboxylic acid (100 mg) in mixture of tetrahydrofuran (1 ml), N,N-dimethylformamide (0.2 ml) and 4-fluoroaniline (0.0526 ml), followed by stirring at room temperature for 2.5 hours. A 5% aqueous solution of sodium hydrogencarbonate was added to the reaction mixture to quench the reaction, and ethyl acetate was added and the layers were separated. The organic layer was washed with water and concentrated. The residue was purified by silica gel column chromatography (Fuji Silysia NH, eluent; ethyl acetate, ethyl acetate:methanol=95:5). The eluate was concentrated. Ethyl acetate (2 ml) was added to the resultant residue, followed by stirring at room temperature for 30 minutes. Heptane (2 ml) was added, and the mixture was stirred for 30 minutes. The crystals were collected by filtration and dried to give the title compound (74 mg) as white crystals.
Reaction SMILES: Cl[C:2]1[CH:3]=[CH:4][N:5]2[C:10]([C:11]=1[CH3:12])=[C:9]([CH:13]1[CH2:15][CH2:14]1)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]2=[O:20].CC1(C)C(C)(C)OB([C:29]2[CH:34]=[CH:33][C:32]([NH:35][S:36]([CH3:39])(=[O:38])=[O:37])=[CH:31][CH:30]=2)O1>>[CH3:39][S:36]([NH:35][C:32]1[CH:31]=[CH:30][C:29]([C:2]2[CH:3]=[CH:4][N:5]3[C:10]([C:11]=2[CH3:12])=[C:9]([CH:13]2[CH2:15][CH2:14]2)[CH:8]=[C:7]([C:16]([O:18][CH3:19])=[O:17])[C:6]3=[O:20])=[CH:34][CH:33]=1)(=[O:38])=[O:37]
Reactant: CC1(C)OB(c2ccc(NS(C)(=O)=O)cc2)OC1(C)C
Reactant: COC(=O)c1cc(C2CC2)c2c(C)c(Cl)ccn2c1=O
Product: COC(=O)c1cc(C2CC2)c2c(C)c(-c3ccc(NS(C)(=O)=O)cc3)ccn2c1=O

Procedure:
Methyl 8-(4-(methylsulfonamido)-phenyl)-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate was prepared according to General Procedure A from methyl 8-chloro-1-cyclopropyl-9-methyl-4-oxo-4H-quinolizine-3-carboxylate (74 mg, 0.25 mmol) and N-(4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-phenyl)-methane-sulfonamide (96 mg, 0.32 mmol). Compound precipitated from solution and was filtered off and dried in vacuum to afford the title compound 27 as a yellow solid (83 mg, 77%).
Reaction SMILES: [CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][CH:18]2[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][CH:31]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:52][Si]([N-][Si](C)(C)C)(C)C.[Na+].CI.CCOC(C)=O>CN(C=O)C>[CH2:1]([N:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[C:10]([CH2:17][C:18]2([CH3:52])[C:24](=[O:25])[N:23]([CH2:26][C:27]([N:29]([CH:38]([CH3:40])[CH3:39])[C:30]3[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][CH:35]=3)=[O:28])[C:22]3[CH:41]=[CH:42][CH:43]=[CH:44][C:21]=3[N:20]([C:45]3[CH:50]=[CH:49][CH:48]=[CH:47][CH:46]=3)[C:19]2=[O:51])=[N:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: C[Si](C)(C)[N-][Si](C)(C)C
Reactant: COc1ccc(N(C(=O)CN2C(=O)C(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COc1ccc(N(C(=O)CN2C(=O)C(C)(Cc3nn(Cc4ccccc4)c4ccccc34)C(=O)N(c3ccccc3)c3ccccc32)C(C)C)cc1
Temperature: 50 °C
Reaction time: 0.08 h

Procedure:
To a stirring solution of 200 mg (0.30 mmol) of 2-[3-(1-Benzyl-1H-indazol-3-ylmethyl)-2,4-dioxo-5-phenyl-2,3,4,5-tetrahydro-benzo[b][1,4]diazepin-1-yl]-N-isopropyl-N-(4-methoxy-phenyl) acetamide in 5 mL of DMF is added 0.45 mL (0.45 mmol, 1.5 equiv) of a 1.0M solution of NaN(TMS)2. The resulting solution is stirred 5 min, then 76 mg (0.54 mmol, 1.8 equiv) of methyl iodide is added. The resulting solution is stirred at RT for 1 h then heated to 50° C. for 16 h. The solution is cooled to RT, poured into 40 mL of EtOAc and extracted with H2O (1×40 mL), dried (MgSO4), and the solvent removed in vacuo. Purification of the resulting material by silica gel flash chromatography with hexane/ethyl acetate 3/2 as eluent gave 127 mg of the title compound as an off-white solid, contaminated with starting material, which is inseparable, in a ratio of approximately 1/1: 1H NMR (300 MHz, CDCl3) δ7.86 (d, 1H, J=8.1), 7.33-6.88 (m, 21H), 5.58 (s, 2H), 5.43 (s, 2H), 5.05 (m, 1H), 5.00 (m, 1H), 4.50 (d, 1H), 4.25 (m, 3H), 3.85 (s, 3H), 3.58 (dd, 1H, J=5.1, 16.0), 1. 59 (s, 3H), 1.06 (2×d, 6H, J=6.6); Rf =0.15 in hexane/ethyl acetate 2/1.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:12]([CH:13]([CH3:15])[CH3:14])=[C:11]([NH2:16])[N:10]=[N:9]2)=[CH:4][CH:3]=1.[CH3:17][C:18]1[N:19]([CH:27]([CH3:31])[C:28](O)=[O:29])[CH:20]=[C:21]([C:23]([F:26])([F:25])[F:24])[N:22]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC>C(Cl)Cl.C(=O)(O)[O-].[Na+]>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:12]([CH:13]([CH3:14])[CH3:15])=[C:11]([NH:16][C:28](=[O:29])[CH:27]([N:19]3[CH:20]=[C:21]([C:23]([F:24])([F:26])[F:25])[N:22]=[C:18]3[CH3:17])[CH3:31])[N:10]=[N:9]2)=[CH:6][CH:7]=1
Reactant: CC(C)c1c(N)nnn1-c1ccc(Cl)cc1
Reactant: Cc1nc(C(F)(F)F)cn1C(C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C(F)(F)F)cn1C(C)C(=O)Nc1nnn(-c2ccc(Cl)cc2)c1C(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 10 %

Procedure:
A mixture of 1-(4-chlorophenyl)-5-isopropyltriazol-4-amine (from step f, 0.025 g, 0.11 mmol), 2-[2-methyl-4-(trifluoromethyl)imidazol-1-yl]propanoic acid (0.031 g, 0.13 mmol), HATU (0.057 g, 0.13 mmol), and 100 μL of Et3N in 1 mL of CH2Cl2 was stirred at room temperature. After 30 minutes, the reaction mixture was diluted with 10 mL of aqueous saturated sodium bicarbonate and extracted with EtOAc. The organic layer was washed with brine, dried (Na2SO4), filtered, and concentrated in vacuo. Purification by reverse phase HPLC (C18 column, acetonitrile-H2O with 0.1% TFA as eluent) provided the title compound as a colorless solid (0.0051 g, 0.011 mmol, 10%). 1H NMR (400 MHz, CDCl3) δ 9.14 (s, 1H), 7.65 (s, 1H), 7.54 (d, J=8.3 Hz, 2H), 7.34 (d, J=8.3 Hz, 2H), 5.26 (q, J=7.4 Hz, 1H), 3.0-2.98 (m, 1H), 2.62 (s, 3H), 1.86 (d, J=7.4 Hz, 3H), 1.14 (t, J=6.4 Hz, 6H). MS: (ES) m/z calculated for C19H20ClF3N6O [M+H]+ 441.1, found 441.2.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][CH:8]=1)[NH2:5].[Si:9]([O:16][CH:17]1[CH2:22][CH2:21][C:20](=O)[CH2:19][CH2:18]1)([C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:11])[CH3:10].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(O)(=O)C.C(=O)(O)[O-].[Na+]>ClCCCl.ClCCl>[C:12]([Si:9]([CH3:11])([CH3:10])[O:16][C@H:17]1[CH2:22][CH2:21][C@H:20]([NH:5][C:4]2[CH:6]=[CH:7][CH:8]=[C:2]([Cl:1])[CH:3]=2)[CH2:19][CH2:18]1)([CH3:15])([CH3:14])[CH3:13]
Reactant: Nc1cccc(Cl)c1
Reactant: CC(C)(C)[Si](C)(C)OC1CCC(=O)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Solvent: ClCCCl
Product: CC(C)(C)[Si](C)(C)O[C@H]1CC[C@H](Nc2cccc(Cl)c2)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 3-chloroaniline (1.27 g, 10 mmol) in 1,2-dichloroethane (20 ml) were added molecular sieves (4 g, size 0.4 nM) and 4-(tert-butyldimethylsilyloxy)-cyclohexanone (4.57 g, 20 mmol). After stirring the mixture for 30 min at room temperature sodium triacetoxyborohydride (8.48 g, 40 mmol) and acetic acid (1.2 g, 20 mmol) were added. The reaction mixture was stirred at room temperature overnight. For workup dichloromethane (100 ml) and 1 M sodium bicarbonate solution (40 ml) were added and the mixture was shaken. The organic layer was separated, dried over magnesium sulfate and evaporated. The residue was purified using flash chromatography (heptane/ethyl acetate=1:1) to yield a colourless liquid (0.80 mg, 23.5%); MS (EI): 339.2; 341.3 (M+.).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:22]=[CH:21][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH:31]CC=C)=[CH:25][C:24]=2[O:35][CH3:36])=[CH:19][CH:18]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]>CC#N.O.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.[Cl-].[Rh]>[CH3:1][O:2][C:3](=[O:37])[C@H:4]([CH2:16][C:17]1[CH:18]=[CH:19][C:20]([C:23]2[C:28]([O:29][CH3:30])=[CH:27][C:26]([NH2:31])=[CH:25][C:24]=2[O:35][CH3:36])=[CH:21][CH:22]=1)[NH:5][C:6](=[O:15])[C:7]1[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][C:8]=1[Cl:14]
Reactant: C=CCNc1cc(OC)c(-c2ccc(C[C@H](NC(=O)c3c(Cl)cccc3Cl)C(=O)OC)cc2)c(OC)c1
Agent: [Rh]
Agent: [Cl-]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: CC#N
Product: COC(=O)[C@H](Cc1ccc(-c2c(OC)cc(N)cc2OC)cc1)NC(=O)c1c(Cl)cccc1Cl
Reaction time: 2 h
Yield: 82.2 %

Procedure:
N-(2,6-Dichlorobenzoyl)-4-(4-allylamino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (0.93 g) was dissolved in MeCN/water (40 mL of 84:16) under N2. Wilkinson's catalyst (79 mg) was added and the mixture was brought to boiling. After 2 h, more catalyst (170 mg) was added and the reaction continued for another 6 h. The solvent was evaporated and the residual water coevaporated with MeCN. The residue was purified by preparative TLC (silica gel; eluent: hexane/AcOEt 2:1 to 1:2) to give N-(2,6-dichlorobenzoyl)-4-(4-amino-2,6-dimethoxyphenyl)-L-phenylalanine methyl ester (708 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21](O)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10].[NH2:30][C:31]1[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=1.CN1C=CN=C1.CCN=C=NCCCN(C)C>CN(C=O)C.O.C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([NH:11][C:12]2[C:13]3[N:14]([CH:27]=[CH:28][N:29]=3)[N:15]=[C:16]([C:18]3[CH:19]=[C:20]([CH:24]=[CH:25][CH:26]=3)[C:21]([NH:30][C:31]3[CH:40]=[CH:39][C:34]([C:35]([O:37][CH3:38])=[O:36])=[C:33]([O:41][CH3:42])[CH:32]=3)=[O:22])[CH:17]=2)=[N:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(Nc2cc(-c3cccc(C(=O)O)c3)nn3ccnc23)nc1OC
Reactant: COC(=O)c1ccc(N)cc1OC
Agent: CCN=C=NCCCN(C)C
Agent: Cn1ccnc1
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: COC(=O)c1ccc(NC(=O)c2cccc(-c3cc(Nc4ccc(OC)c(OC)n4)c4nccn4n3)c2)cc1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 47.5 %

Procedure:
A mixture of 3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzoic acid (150 mg, 0.38 mmol), methyl 4-amino-2-methoxybenzoate (70 mg, 0.38 mmol), 1-methyl-1H-imidazole (126 mg, 1.53 mmol) and EDCI (293 mg, 1.53 mmol) in DMF (3 mL) was stirred for 16 h at room temperature. Ethyl acetate (5 mL) and water (5 mL) were added. The organic layer was separated and the aqueous phase was extracted with ethyl acetate (20 mL). The combined organic phases were washed with brine (10 mL) and dried over Na2SO4. The residue was concentrated and purified by chromatography (silica gel, 200-300 mesh, dichloromethane:MeOH=50:1) to give methyl 4-(3-(8-(5,6-dimethoxypyridin-2-ylamino)imidazo[1,2-b]pyridazin-6-yl)benzamido)-2-methoxybenzoate (100 mg, 47%) as brown liquid. LC-MS: [M+H]+, 555.1, tR=1.701 min
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]([C:17]([OH:19])=O)=[CH:11][N:12]([CH3:16])[C:13](=[O:15])[CH:14]=2)=[C:4]([F:20])[CH:3]=1.CCN=C=NCCCN(C)C.C1C=CC2N(O)N=NC=2C=1.[CH:42]1([CH2:45][O:46][NH2:47])[CH2:44][CH2:43]1.CCN(CC)CC>CN(C=O)C.CCOC(C)=O>[CH:42]1([CH2:45][O:46][NH:47][C:17]([C:10]2[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([Br:1])=[CH:3][C:4]=3[F:20])=[CH:14][C:13](=[O:15])[N:12]([CH3:16])[CH:11]=2)=[O:19])[CH2:44][CH2:43]1
Reactant: Cn1cc(C(=O)O)c(Nc2ccc(Br)cc2F)cc1=O
Reactant: NOCC1CC1
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: Cn1cc(C(=O)NOCC2CC2)c(Nc2ccc(Br)cc2F)cc1=O
Reaction time: 0.5 h
Yield: 88.4 %

Procedure:
A mixture of 4-(4-bromo-2-fluorophenylamino)-1-methyl-6-oxo-1,6-dihydropyridine-3-carboxylic acid (0.078 g, 0.229 mmol), EDCI (0.13 g, 0.69 mmol), and HOBt (0.093 g, 0.69 mmol) in DMF (5 mL) was stirred for 30 minutes. O-Cyclopropylmethyl-hydroxylamine (0.060 g, 0.69 mmol) was added followed by Et3N (0.096 mL, 0.69 mmol). After 1 hour, the reaction mixture was diluted with EtOAc and washed with saturated NH4Cl solution, saturated NaHCO3 solution and brine. The organic layer was dried (MgSO4) and concentrated to yield 83 mg (89%) clean desired product. MS APCI (+) m/z 410, 412 (M+, Br pattern) detected; 1H NMR (400 MHz, DMSO-d6) δ 11.57 (s, 1H), 9.42 (s, 1H), 8.10 (s, 1H), 7.67 (d, 1H), 7.43 (m, 2H), 3.70 (d, 2H), 3.35 (s, 3H), 1.11 (m, 1H), 0.54 (m, 2H), 0.27 (m, 2H).
Reaction SMILES: [NH2:1][C@@H:2]([C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1)[CH2:3][OH:4].C(#N)C.[C:14](ON1C(=O)CCC1=O)(=[O:25])[C:15]1[C:16](=[CH:21][CH:22]=[CH:23][CH:24]=1)[C:17](OC)=[O:18]>O>[OH:4][CH2:3][C@@H:2]([N:1]1[C:17](=[O:18])[C:16]2[C:15](=[CH:24][CH:23]=[CH:22][CH:21]=2)[C:14]1=[O:25])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][CH:6]=1
Reactant: N[C@H](CO)c1ccccc1
Reactant: COC(=O)c1ccccc1C(=O)ON1C(=O)CCC1=O
Solvent: CC#N
Solvent: O
Product: O=C1c2ccccc2C(=O)N1[C@H](CO)c1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 39.6 %

Procedure:
To a solution of (S)-2-amino-2-phenylethanol (3 g, 21.87 mmol) in water (26.5 mL), and acetonitrile (46.4 mL) was added 2,5-dioxopyrrolidin-1-yl methyl phthalate (5.76 g, 20.78 mmol) at room temperature. The reaction mixture was stirred at room temperature for overnight. After acetonitrile was removed in vacuo, the reaction mixture was then extracted with EtOAc. The organic was washed by water and brine, dried over anhydrous sodium sulfate, filtered off, and concentrated in vacuo yielding (S)-2-(2-hydroxy-1-phenylethyl)isoindoline-1,3-dione (2.2 g, 40%). LCMS (m/z): 268 (MH+), 0.79 min.