Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][C:25](=[O:29])[CH:24]=4)=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12>C(OCC)C>[CH:1]1[CH:2]=[CH:3][N:4]2[CH2:10][C:9]3[CH:11]=[CH:12][CH:13]=[CH:14][C:8]=3[N:7]([C:15]([C:17]3[CH:22]=[CH:21][C:20]([C:23]4[CH2:28][CH2:27][CH2:26][CH:25]([OH:29])[CH:24]=4)=[C:19]([CH3:30])[CH:18]=3)=[O:16])[CH2:6][C:5]=12
Reactant: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CC(=O)CCC1
Solvent: CCOCC
Product: Cc1cc(C(=O)N2Cc3cccn3Cc3ccccc32)ccc1C1=CC(O)CCC1
Yield: 99.6 %

Procedure:
3-[4-(10,11-Dihydro-5H-pyrrolo[2,1-c][1,4]benzodiazepine-10-carbonyl)-2-methyl-phenyl]-cyclohex-2-enone of Example 39 (0.100 g, 0.252 mmol) was reacted in the manner of Example 25. The crude product was dissolved in boiling diethyl ether, filtered and the product precipitated from the filtrate by addition of pentane to provide the title compound (0.100 g) as a white solid.
Reaction SMILES: [CH2:1]([O:3][CH2:4][CH2:5][O:6][CH2:7][CH2:8]O)[CH3:2].[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([OH:17])=[O:16].CCCCCCCC(O[Sn](OC(CCCCCCC)=O)(CCCC)CCCC)=O>C1(C)C(C)=CC=CC=1>[O:10]1[CH:14]=[CH:13][CH:12]=[C:11]1[C:15]([O:17][CH2:2][CH2:1][O:3][CH2:4][CH2:5][O:6][CH2:7][CH3:8])=[O:16]
Reactant: CCOCCOCCO
Reactant: O=C(O)c1ccco1
Agent: CCCCCCCC(=O)O[Sn](CCCC)(CCCC)OC(=O)CCCCCCC
Solvent: Cc1ccccc1C
Product: CCOCCOCCOC(=O)c1ccco1

Procedure:
2-(2-Ethoxyethoxy) ethanol, carbitol solvent, 129 g (0.96 m), 90 g (0.8 m) furoic acid and 1 g dibutyltin dioctoate were heated with xylene to remove water by azeotropic distillation to acid number 1.4. Zylene removed by distillation at a pot temperature of 200° and product distilled. Carbitol furoate was collected in fraction 2, 121°-125°, 91% carbitol furoate by gc. Yield of carbitol furoate 144 g, 79%.
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([OH:19])=O)[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(OC(Cl)=O)C(C)C.C(N1CCOCC1)C.Cl.Cl.[NH2:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41]>CN(C)C=O.O1CCCC1>[CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:17]([NH:38][CH2:39][C:40]([NH:42][C:43]1[CH:48]=[CH:47][CH:46]=[CH:45][C:44]=1[C:49](=[O:57])[C:50]1[CH:55]=[C:54]([Br:56])[CH:53]=[CH:52][N:51]=1)=[O:41])=[O:19])[C@H:13]([CH2:15][CH3:16])[CH3:14])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Reactant: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: CC(C)COC(=O)Cl
Agent: CCN1CCOCC1
Agent: Cl
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: CC[C@H](C)[C@H](NC(=O)OCc1ccccc1)C(=O)NCC(=O)Nc1ccccc1C(=O)c1cc(Br)ccn1
Temperature: -10 °C
Reaction time: 0.33 h
Yield: 60 %

Procedure:
3.18 g. of N-benzyloxycarbonyl-L-isoleucine were dissolved in 25 ml. of dry tetrahydrofuran and cooled to -10° C. 1.57 ml. of isobutylchloroformate and 1.52 ml. of N-ethylmorpholine were added and the resulting solution was stirred at -10° C. for 20 minutes. 4.24 g. of 2-amino-N-(4-bromo-2-picolinoylphenyl)-acetamide dihydrochloride, prepared as described in part A)i) of Example 1, were added an the resulting suspension was cooled to -20° C. 3.13. ml. of N-ethylmorpholine in 25 ml. of dimethylformamide were added to the vigorously stirred suspension over a period of 0.5 hour. The resulting mixture was stirred at -20° C. for a further 40 minutes and left at room temperature overnight. The product was worked up in a manner analogous to that described in part A)ii) of Example 1. Recrystallisation from ethanol yielded 4.2 g (60%) of (N-benzyloxycarbonyl-L-isoleucyl)-N-(4-bromo-2-picolinoylphenyl)-glycinamide of melting point 714°-176° C.
Reaction SMILES: [O:1]=[C:2]1[N:11]2[C:6]([CH:7]=[CH:8][CH:9]=[CH:10]2)=[CH:5][CH:4]=[C:3]1[C:12]([O:14][CH2:15][CH3:16])=[O:13].O=P(Cl)(Cl)Cl.O.CN([CH:26]=[O:27])C>>[CH:26]([C:5]1[CH:4]=[C:3]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[C:2](=[O:1])[N:11]2[C:6]=1[CH:7]=[CH:8][CH:9]=[CH:10]2)=[O:27]
Reactant: CN(C)C=O
Reactant: CCOC(=O)c1ccc2ccccn2c1=O
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: CCOC(=O)c1cc(C=O)c2ccccn2c1=O
Reaction time: 1 h
Yield: 93 %

Procedure:
Ethyl 4-oxo-4H-quinolizine-3-carboxylate (1) (1 g, 4.0 mmol) was dissolved in 2 ml DMF followed by the addition of POCl3 (1.0 ml, 11 mmol). The reaction mixture was stirred for 1 h, poured into 100 ml water and extracted three times with 100 ml dichloromethane. Evaporation of the organic solvent gave a sticky yellow solid, which was further purified by flash chromatography (ethyl acetate), followed by overnight stirring with 10 ml ether to remove the last traces of DMF. Filtration of the suspension and drying in vacuo gave a bright yellow powder (920 mg, 93%). M.p. 179-181° C. 1H NMR (δ, CDCl3): 1.43 (t, J=7 Hz), 4.42 (q, J=7 Hz), 7.51 (dd, J=7 Hz, J=7 Hz, 1H), 8.06 (dd, J=7, J=7 Hz, 1H), 8.80 (s, 1H), 9.57 (d, J=7 Hz), 9.90 (s, 1H). MS: m/z 245.0683; required for C13H11NO4: 245.0688.
Reaction SMILES: Cl[C:2]1[CH:11]=[CH:10][C:9](O)=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[N:7]2.C1(NC2C=CC=CC=2)C=CC=CC=1.C(P(C(C)(C)C)C(C)(C)C)(C)(C)C.C[Si]([N-][Si](C)(C)C)(C)C.[Li+]>C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1CCOCC1.C1(C)C=CC=CC=1>[N:7]1[C:8]2[C:3](=[CH:2][CH:11]=[CH:10][CH:9]=2)[CH:4]=[CH:5][CH:6]=1
Reactant: Oc1ccc(Cl)c2cccnc12
Agent: [Pd]
Agent: CC(C)(C)P(C(C)(C)C)C(C)(C)C
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Solvent: Cc1ccccc1
Solvent: C1COCCO1
Product: c1ccc2ncccc2c1
Temperature: 25 °C

Procedure:
8.98 g, 0.05 mol of 5-chloro-8-hydroxyquinoline (Aldrich), 10.15 g, 0.06 mol of diphenylamine, 350 mL of 1:1 dioxane/toluene, 0.917 g, 0.001 mol Pd2 DBA3, 0.4350 g, 0.0021 mol of tri-t-butylphosphine, and 18.42 g, 0.11 mol lithium bis(trimethylsilyl)amide were combined and refluxed together for a total of 180 hrs. The mixture was cooled to room temperature and filtered through celite with dichloromethane rinses. The mixture was partially evaporated and the organic layer was washed with 1N HCl then neutralized to pH 8 with saturated sodium bicarbonate. The organic layer was then dried with Na2SO4, filtered and concentrated by rotary evaporation. The product was purified by silica column chromatography using dichloromethane eluent. Yield 11.13 g of a bright yellow solid.
Reaction SMILES: [O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23]([C:26]#[C:27][CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:18][CH3:19])[CH2:16][CH3:17])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:8])([CH3:7])[CH3:6])([CH3:4])[CH3:3].[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[O:1]([C:9]1[CH:14]=[CH:13][C:12]([C:15]([C:20]2[CH:25]=[CH:24][C:23](/[CH:26]=[CH:27]/[CH:28]([OH:33])[C:29]([CH3:32])([CH3:31])[CH3:30])=[C:22]([CH3:34])[CH:21]=2)([CH2:16][CH3:17])[CH2:18][CH3:19])=[CH:11][C:10]=1[CH3:35])[Si:2]([C:5]([CH3:6])([CH3:7])[CH3:8])([CH3:3])[CH3:4]
Reactant: CCC(CC)(c1ccc(C#CC(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCC(CC)(c1ccc(/C=C/C(O)C(C)(C)C)c(C)c1)c1ccc(O[Si](C)(C)C(C)(C)C)c(C)c1
Temperature: 65 °C
Yield: 67.4 %

Procedure:
To a solution of 1-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl}-2-methylphenyl)-4,4-dimethylpent-1-yn-3-ol (0.22 g, 0.45 mmol) in anhyd THF (2 mL) was added LiAlH4 (19 mg, 0.49 mmol). The reaction mixture was heated at 65° C. for 6 h. After cooling to ambient temperature, the reaction mixture was quenched sequentially with H2O (0.21 mL), 15% NaOH (0.21 mL) and then H2O (0.63 mL). The resulting mixture was diluted with Et2O, filtered through Celite, washed with brine, dried (Na2SO4) and concentrated to yield (E)-1-(4-{1-[4-(tert-butyl-dimethylsiloxy)-3-methylphenyl]-1-ethylpropyl)-2-methylphenyl)-4,4-dimethylpent-1-en-3-ol (0.15 g, 68%), which was used without purification in the next step.
Reaction SMILES: [BH4-].[Na+].[CH3:3][C@@H:4]([O:11][C:12]([C:14]1[CH:19]=[CH:18][C:17]([C:20]2[CH:25]=[CH:24][C:23]([CH:26]3[CH2:31][CH2:30][C:29](=[O:32])[CH2:28][CH2:27]3)=[CH:22][CH:21]=2)=[CH:16][CH:15]=1)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10].Cl>COCCOC>[CH3:3][C@@H:4]([O:11][C:12]([C:14]1[CH:15]=[CH:16][C:17]([C:20]2[CH:25]=[CH:24][C:23]([C@H:26]3[CH2:27][CH2:28][C@H:29]([OH:32])[CH2:30][CH2:31]3)=[CH:22][CH:21]=2)=[CH:18][CH:19]=1)=[O:13])[CH2:5][CH2:6][CH2:7][CH2:8][CH2:9][CH3:10]
Reactant: CCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc(C3CCC(=O)CC3)cc2)cc1
Agent: Cl
Agent: [BH4-]
Agent: [Na+]
Solvent: COCCOC
Product: CCCCCC[C@@H](C)OC(=O)c1ccc(-c2ccc([C@H]3CC[C@H](O)CC3)cc2)cc1
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A suspension of 0.14 g of sodium borohydride in 10 ml of 1,2-dimethoxyethane was treated at 0° C. with a solution of 4-(4'-[(R)-2-octyl]oxycarbonyl-4biphenylyl)cyclohexanone in 10 ml of 1,2-dimethoxyethane. The reaction mixture was stirred at room temperature for a further 30 minutes and then treated with 25% hydrochloric acid. The reaction mixture was extracted three times with 50 ml of diethyl ether each time. The combined organic phases were washed with sodium hydrogen carbonate solution and several times with water and subsequently dried over magnesium sulfate, filtered and concentrated. The residue was recrystallized twice from hexane and gave 0.8 g of trans-4-(4'-[(R)-2-octyl]oxycarbonyl-4-biphenylyl)cyclohexanol.
Reaction SMILES: [Cl:1][C:2]1[C:19]([Cl:20])=[CH:18][C:5]2[NH:6][C:7]([C:9]([OH:17])([CH2:14][C:15]#[CH:16])[C:10]([F:13])([F:12])[F:11])=[N:8][C:4]=2[CH:3]=1.I[C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1.C(N(CC)CC)C>C1COCC1.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu](I)I>[Cl:20][C:19]1[C:2]([Cl:1])=[CH:3][C:4]2[NH:8][C:7]([C:9]([OH:17])([CH2:14][C:15]#[C:16][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[C:10]([F:13])([F:11])[F:12])=[N:6][C:5]=2[CH:18]=1
Reactant: Ic1ccccc1
Reactant: C#CCC(O)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: I[Cu]I
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: OC(CC#Cc1ccccc1)(c1nc2cc(Cl)c(Cl)cc2[nH]1)C(F)(F)F
Reaction time: 8 h

Procedure:
2-(5,6-Dichloro-1H-benzoimidazol-2-yl)-1,1,1-trifluoro-pent-4-yn-2-ol (0.27 g; 0.83 mmol), iodobenzene (0.14 mL; 1.3 mmol), dichlorobis(triphenylphosphine)palladium (31.7 mg; 0.045 mmol), copper iodide (17.8 mg; 0.093 mmol) and triethylamine (0.25 mL; 1.8 mmol) were suspended in THF (5 mL) and the resulting mixture stirred vigorously overnight. The reaction mixture was then concentrated in vacuo and the resulting crude brown oil was purified by column chromatography (SiO2; 50% ether/CH2Cl2) to yield the title compound as an orange-yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:45])[CH2:7][C:8]1[CH:9]=[C:10]2[C:14](=[CH:15][CH:16]=1)[N:13](C1CCCCO1)[N:12]=[C:11]2[C:23]1[N:28]=[C:27]([O:29][C@H:30]2[CH2:37][N:36](C(OC(C)(C)C)=O)[CH2:35][CH2:34][C:31]32[CH2:33][CH2:32]3)[CH:26]=[N:25][CH:24]=1)(C)([CH3:3])[CH3:2].CC(O)C>Cl>[CH2:32]1[C:31]2([CH2:34][CH2:35][NH:36][CH2:37][C@@H:30]2[O:29][C:27]2[N:28]=[C:23]([C:11]3[C:10]4[C:14](=[CH:15][CH:16]=[C:8]([CH2:7][C:6]([O:5][CH:1]([CH3:3])[CH3:2])=[O:45])[CH:9]=4)[NH:13][N:12]=3)[CH:24]=[N:25][CH:26]=2)[CH2:33]1
Reactant: CC(C)(C)OC(=O)Cc1ccc2c(c1)c(-c1cncc(O[C@H]3CN(C(=O)OC(C)(C)C)CCC34CC4)n1)nn2C1CCCCO1
Agent: Cl
Solvent: CC(C)O
Product: CC(C)OC(=O)Cc1ccc2[nH]nc(-c3cncc(O[C@H]4CNCCC45CC5)n3)c2c1
Yield: 94.5 %

Procedure:
A solution of (4R)-tert-butyl 4-((6-(5-(2-(tert-butoxy)-2-oxoethyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-3-yl)pyrazin-2-yl)oxy)-6-azaspiro[2.5]octane-6-carboxylate (280 mg, 0.452 mmol) in hydrogen chloride in IPA (9036 μl, 45.2 mmol) was stirred at 80° C. for 2 h. The mixture was concentrated and was diluted with EtOAc (150 ml), added to a separatory funnel, and washed with 1 N NaOH (2×75 ml) before the organic layer was separated, dried over Na2SO4, and concentrated to give (R)-isopropyl 2-(3-(6-(6-azaspiro[2.5]octan-4-yloxy)pyrazin-2-yl)-1H-indazol-5-yl)acetate (180 mg, 0.427 mmol, 95% yield) and was used as is. MS (ESI, pos. ion) m/z: 422.1 (M+1).
Reaction SMILES: C([O:4][CH2:5][CH2:6][C:7]1[C:12]([N+:13]([O-])=O)=[CH:11][CH:10]=[CH:9][N:8]=1)(=O)C.O.O.[Sn](Cl)Cl>C(OCC)(=O)C>[NH:13]1[C:12]2[C:7](=[N:8][CH:9]=[CH:10][CH:11]=2)[CH2:6][C:5]1=[O:4]
Reactant: CC(=O)OCCc1ncccc1[N+](=O)[O-]
Agent: Cl[Sn]Cl
Solvent: CCOC(C)=O
Solvent: O
Product: O=C1Cc2ncccc2N1
Yield: 32.6 %

Procedure:
A mixture of 2-(3-nitro-2-pyridyl)ethyl acetate (10.1, 48 mmol), tin(II)chloride dihydrate (54.3 g, 240 mmol) and ethyl acetate was stirred and heated at reflux for 5 hours. The reaction mixture was allowed to cool overnight, filtered through diatomaceous earth and the solvent was removed by evaporation. The resulting oil was purified by flash chromatography using increasingly polar solvent mixtures starting with methylene chloride and ending with methylene chloride/methanol (10/1). Removal of the solvent by evaporation gave 4-azaoxindole (2.1 g, 33%).
Reaction SMILES: [CH3:1][Mg]Br.[C:4]([O:8][C:9](=[O:42])[NH:10][C:11]1[C:15]([C:16]2[CH:21]=[CH:20][C:19]([CH2:22][C:23]([C:25]3[N:26]([S:35]([N:38]([CH3:40])[CH3:39])(=[O:37])=[O:36])[CH:27]=[C:28]([CH2:30][C:31]([CH3:34])([CH3:33])[CH3:32])[N:29]=3)=[O:24])=[CH:18][CH:17]=2)=[CH:14][N:13]([CH3:41])[N:12]=1)([CH3:7])([CH3:6])[CH3:5]>O1CCCC1>[CH3:40][N:38]([CH3:39])[S:35]([N:26]1[CH:27]=[C:28]([CH2:30][C:31]([CH3:34])([CH3:32])[CH3:33])[N:29]=[C:25]1[C:23]([OH:24])([CH3:1])[CH2:22][C:19]1[CH:20]=[CH:21][C:16]([C:15]2[C:11]([NH:10][C:9](=[O:42])[O:8][C:4]([CH3:7])([CH3:5])[CH3:6])=[N:12][N:13]([CH3:41])[CH:14]=2)=[CH:17][CH:18]=1)(=[O:37])=[O:36]
Reactant: C[Mg]Br
Reactant: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(=O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Solvent: C1CCOC1
Product: CN(C)S(=O)(=O)n1cc(CC(C)(C)C)nc1C(C)(O)Cc1ccc(-c2cn(C)nc2NC(=O)OC(C)(C)C)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Methylmagnesium bromide (3 M in diethyl ether) (0.04 mL, 0.11 mmol) was added to a 0° C. solution of tert-butyl[4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazol-2-yl]-2-oxoethyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate (32 mg, 0.06 mmol) in tetrahydrofuran (3 mL). After stirring at 0° C. for 30 min, the reaction mixture was quenched with saturated aqueous ammonium chloride and extracted with methylene chloride and ethyl acetate. The combined organic extracts were dried (magnesium sulfate) and concentrated in vacuo to afford tert-butyl [4-(4-{2-[1-[(dimethylamino)sulfonyl]-4-(2,2-dimethylpropyl)-1H-imidazo 1-2-yl]-2-hydroxypropyl}phenyl)-1-methyl-1H-pyrazol-3-yl]carbamate which was used in the subsequent step without further purification.
Reaction SMILES: CS([O:5][CH2:6][CH2:7][N:8]1[C:13](=[O:14])[CH:12]=[CH:11][C:10]([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:9]1)(=O)=O.O[C:29]1[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=1)[O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37].C([O-])([O-])=O.[K+].[K+].[I-].[Na+]>CCOC(C)=O.CN(C=O)C>[C:16]1([CH:15]([C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[C:10]2[CH:11]=[CH:12][C:13](=[O:14])[N:8]([CH2:7][CH2:6][O:5][C:29]3[CH:30]=[C:31]([CH:41]=[CH:42][CH:43]=3)[O:32][CH2:33][CH2:34][CH2:35][C:36]([O:38][CH2:39][CH3:40])=[O:37])[N:9]=2)[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1
Reactant: CS(=O)(=O)OCCn1nc(C(c2ccccc2)c2ccccc2)ccc1=O
Reactant: CCOC(=O)CCCOc1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CCOC(=O)CCCOc1cccc(OCCn2nc(C(c3ccccc3)c3ccccc3)ccc2=O)c1
Temperature: 80 °C
Reaction time: 2 h
Yield: 32.6 %

Procedure:
A mixture of 2-[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]ethyl methanesulfonate (200 mg), ethyl 4-(3-hydroxyphenoxy)butanoate (140 mg), K2CO3 (93 mg), sodium iodide (94 mg), and DMF (2 mL) was stirred at 80° C. for 2 hours. After cooling, the reaction mixture was diluted with EtOAc (50 mL) and washed with water (30 mL) and brine (30 mL) two times. The organic layer was dried over anhydrous MgSO4, filtered and evaporated in vacuo to give crude oil. The crude oil was purified by silica gel column chromatography (n-hexane:EtOAc=1:1) to give ethyl 4-(3-{2-[3-(diphenylmethyl)-6-oxopyridazin-1(6H)-yl]ethoxy}phenoxy)butanoate (87 mg) as a pale yellow oil.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH2:6](Br)[CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]>>[CH2:21]([N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][CH2:9][CH2:8][CH2:7][CH3:6]
Reactant: CCCCCCCCCCCCCCCCBr
Reactant: c1c[nH]cn1
Product: CCCCCCCCCCCCCCCCn1ccnc1

Procedure:
N-hexadecylimidazole was synthesized from imidazole and hexadecyl bromide with reference to the document (T. G. Traylor et al., J. Am. Chem. Soc., 115, 4808-4813 (1993)).
Reaction SMILES: [O-]P([O-])([O-])=O.[K+].[K+].[K+].[Br:9][C:10]1[N:14]2[CH:15]=[C:16](I)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1.C(O)CO.[NH2:24][C@H:25]1[CH2:30][CH2:29][C@H:28]([OH:31])[CH2:27][CH2:26]1>C(O)(C)C.[Cu]I>[Br:9][C:10]1[N:14]2[CH:15]=[C:16]([NH:24][CH:25]3[CH2:30][CH2:29][CH:28]([OH:31])[CH2:27][CH2:26]3)[CH:17]=[CH:18][C:13]2=[N:12][CH:11]=1
Reactant: Brc1cnc2ccc(I)cn12
Reactant: N[C@H]1CC[C@H](O)CC1
Agent: [Cu]I
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: OCCO
Solvent: CC(C)O
Product: OC1CCC(Nc2ccc3ncc(Br)n3c2)CC1
Temperature: 80 °C

Procedure:
Copper (I) iodide (0.1 eq, 1.45 g, 7.68 mmol) and potassium phosphate tribasic (2 eq, 0.153 mol, 32.5 g) are stirred at RT under an atmosphere of argon during the addition of 3-bromo-6-iodo-imidazo[1,2-a]pyridine (Intermediate F) (25 g, 77 mmol, 1 eq) in isopropyl alcohol (200 ml), ethylene glycol (2 eq, 0.153 mol, 8.5 ml) and finally trans-4-aminocyclohexanol (2 eq, 17.5 g, 153 mmol) The reaction is heated at 80° C. for 40 hours. The majority of the solvent is removed in vacuo and the residue is diluted with water (500 ml) and extracted with EtOAc (3×500 ml). The combined organic portions are dried (MgSO4) and concentrated in vacuo. Purification by flash chromatography on silica eluting with 0-15% MeOH in EtOAc gives 4-(3-bromo-imidazo[1,2-a]pyridin-6-ylamino)-cyclohexanol; [M+H]+=310 (312)
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=1.F[C:15]1[CH:20]=[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])[C:18]([F:34])=[CH:17][C:16]=1[N+:35]([O-:37])=[O:36].C(=O)([O-])[O-].[K+].[K+].Cl>O.CN(C)C=O>[F:34][C:18]1[C:19]([N:21]2[C:26](=[O:27])[CH:25]=[C:24]([C:28]([F:31])([F:30])[F:29])[N:23]([CH3:32])[C:22]2=[O:33])=[CH:20][C:15]([O:1][C:2]2[CH:3]=[CH:4][C:5]([O:8][CH2:9][C:10]([O:12][CH3:13])=[O:11])=[N:6][CH:7]=2)=[C:16]([N+:35]([O-:37])=[O:36])[CH:17]=1
Reactant: COC(=O)COc1ccc(O)cn1
Reactant: Cn1c(C(F)(F)F)cc(=O)n(-c2cc(F)c([N+](=O)[O-])cc2F)c1=O
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc(Oc2cc(-n3c(=O)cc(C(F)(F)F)n(C)c3=O)c(F)cc2[N+](=O)[O-])cn1
Temperature: 50 °C
Reaction time: 1.5 h
Yield: 79.4 %

Procedure:
To a mixture of 0.5 g of 5-hydroxy-2-(methoxycarbonyl)methoxypyridine, 0.80 g of 2,5-difluoro-4-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-y]nitrobenzene and 5 ml of N,N-dimethylformamide was added 0.35 g of potassium carbonate, and the mixture was stirred for 1.5 hours at 50° C. The solution was cooled to room temperature, poured into a mixture of water, hydrochloric acid and saline, and extracted with ethyl acetate. The organic layer was washed with saturated saline, dried over anhydrous magnesium sulfate, and concentrated. The residue was subjected to silica gel column chromatography to obtain 0.93 g of 5-{4-fluoro-5-[3-methyl-2,6-dioxo-4-(trifluoromethyl)-1,2,3,6-tetrahydropyrimidin-1-yl]-2-nitrophenoxy}-2-(methoxycarbonyl)methoxypyridine.
Reaction SMILES: [CH2:1]([S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][N:12]2C(=O)C)=[CH:8][C:7]=1[F:20])(=[O:5])=[O:4])[CH3:2].Cl>>[CH2:1]([S:3]([C:6]1[CH:14]=[C:13]2[C:9]([C:10]([CH3:19])([CH3:18])[CH2:11][NH:12]2)=[CH:8][C:7]=1[F:20])(=[O:5])=[O:4])[CH3:2]
Reactant: CCS(=O)(=O)c1cc2c(cc1F)C(C)(C)CN2C(C)=O
Agent: Cl
Product: CCS(=O)(=O)c1cc2c(cc1F)C(C)(C)CN2
Yield: 58.7 %

Procedure:
1-(6-Ethanesulfonyl-5-fluoro-3,3-dimethyl-2,3-dihydro-indol-1-yl)-ethanone (160 mg, 0.53 mmol) was treated with hydrochloric acid (5 M, 1.1 mL) following similar methods to those described in Preparation 66 to give the title compound (80 mg). MS: [M+H]+ 258.
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([CH2:15][OH:16])[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[N:17]([C:20]1[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=1)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[C:18]=[O:19]>C1COCC1>[CH2:1]([N:8]1[CH2:13][CH:12]2[CH:14]([CH2:15][O:16][C:18]([NH:17][C:20]3[CH:21]=[C:22]([CH:28]=[CH:29][CH:30]=3)[C:23]([O:25][CH2:26][CH3:27])=[O:24])=[O:19])[CH:9]1[CH2:10][CH2:11]2)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CCOC(=O)c1cccc(N=C=O)c1
Reactant: OCC1C2CCC1N(Cc1ccccc1)C2
Solvent: C1CCOC1
Product: CCOC(=O)c1cccc(NC(=O)OCC2C3CCC2N(Cc2ccccc2)C3)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 58.6 %

Procedure:
200.00 mg (0.920 mmol) of (2-benzyl-2-aza-bicyclo[2.2.1]hept-7yl)methanol were dissolved in 3 ml of dry THF and then 176.00 mg (0.920 mmol) of ethyl 3-isocyanatobenzoate in 1 ml of dry THF were added at room temperature. After stirring for 6 hours at room temperature, 125 mg (0.30 mmol) of tris-(2-aminoethyl)amine-polystyrene and 250 mg (0.30 mmol) of methyl isocyanate-polystyrene (each from NovaBiochem) were added and stirred at 50° C. overnight. After the resins had been filtered off, the solvent was removed and the required product was purified by chromatography with ethyl acetate as mobile phase. In this way, 220.00 mg (0.539 mmol) of ethyl 3-(2-benzyl-2-azabicyclo[2.2.1]hept-7-ylmethoxycarbonylamino)benzoate were obtained in the form of a colorless solid.
Reaction SMILES: [CH:1]1([NH:8][C:9]([NH:11][C:12]2[CH:17]=[C:16](B3OC(C)(C)C(C)(C)O3)[CH:15]=[CH:14][C:13]=2[F:27])=[O:10])[CH2:7][CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)S(O[C:34]1[C:35]([CH3:45])=[N:36][C:37]2[C:42]([CH:43]=1)=[CH:41][N:40]=[C:39]([Cl:44])[CH:38]=2)(=O)=O.C([O-])([O-])=O.[K+].[K+]>O1CCOCC1.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[Cl:44][C:39]1[CH:38]=[C:37]2[C:42]([CH:43]=[C:34]([C:16]3[CH:15]=[CH:14][C:13]([F:27])=[C:12]([NH:11][C:9]([NH:8][CH:1]4[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6][CH2:7]4)=[O:10])[CH:17]=3)[C:35]([CH3:45])=[N:36]2)=[CH:41][N:40]=1
Reactant: Cc1nc2cc(Cl)ncc2cc1OS(=O)(=O)C(F)(F)F
Reactant: CC1(C)OB(c2ccc(F)c(NC(=O)NC3CCCCCC3)c2)OC1(C)C
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: [K+]
Solvent: O
Solvent: C1COCCO1
Product: Cc1nc2cc(Cl)ncc2cc1-c1ccc(F)c(NC(=O)NC2CCCCCC2)c1
Temperature: 60 °C
Yield: 142.5 %

Procedure:
Sparge a suspension of 1-cycloheptyl-3-(2-fluoro-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)urea (0.420 g, 1.116 mmol), 7-chloro-2-methyl-1,6-naphthyridin-3-yl trifluoromethanesulfonate (0.438 g, 1.339 mmol) and K2CO3 (0.463 g, 3.35 mmol) in dioxane (4 mL) and H2O (1 mL) with Ar, add Pd(PPh3)4 (0.064 g, 0.056 mmol) and heat at 60° C. for 3 h. Concentrate the mixture to dryness and purify via silica gel chromatography (EtOAc/Hex) to afford the title compound (679 mg, 61%) as a white solid. MS(ESI) m/z: 427.1 (M+H+).