Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][N:11]([C:14]2[CH:19]=[CH:18][C:17]([C:20]3[CH:21]=[C:22]4[C:28]([C:29]5[C:30]([CH3:43])=[N:31][N:32]([CH2:35][C:36]6[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=6)[C:33]=5[CH3:34])=[C:27]([CH:44]5[CH2:46][CH2:45]5)[N:26](C(OC(C)(C)C)=O)[C:23]4=[N:24][CH:25]=3)=[CH:16][CH:15]=2)[CH2:10][CH2:9]1)=O)(C)(C)C.CO.Cl.C(=O)(O)[O-].[Na+]>CO.C(Cl)(Cl)Cl>[CH:44]1([C:27]2[NH:26][C:23]3=[N:24][CH:25]=[C:20]([C:17]4[CH:18]=[CH:19][C:14]([N:11]5[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]5)=[CH:15][CH:16]=4)[CH:21]=[C:22]3[C:28]=2[C:29]2[C:30]([CH3:43])=[N:31][N:32]([CH2:35][C:36]3[CH:41]=[CH:40][CH:39]=[C:38]([F:42])[CH:37]=3)[C:33]=2[CH3:34])[CH2:46][CH2:45]1
Reactant: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c(C2CC2)n(C(=O)OC(C)(C)C)c2ncc(-c3ccc(N4CCN(C(=O)OC(C)(C)C)CC4)cc3)cc12
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Solvent: ClC(Cl)Cl
Product: Cc1nn(Cc2cccc(F)c2)c(C)c1-c1c(C2CC2)[nH]c2ncc(-c3ccc(N4CCNCC4)cc3)cc12
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 9.7 %

Procedure:
tert-butyl 5-(4-(4-(tert-butoxycarbonyl)piperazin-1-yl)phenyl)-2-cyclopropyl-3-(1-(3-fluorobenzyl)-3,5-dimethyl-1H-pyrazol-4-yl)-1H-pyrrolo[2,3-b]pyridine-1-carboxylate (100 mg) dissolved in 2 ml of methanol and added methanol/HCl (3 ml) at 0° C. and stirred at room temperature for 30 min. The reaction was monitored by TLC (10% methanol in chloroform). The reaction mixture was concentrated under reduced pressure to afford crude product. The residue was basified with saturated sodium bicarbonate solution and extracted with DCM (2×25 ml). The organic layer was dried over Na2SO4, and concentrated under reduced pressure to afford 7 mg (9.72% yield) of the pure required product. 1H NMR (DMSO-d6, 400 MHz): δ 11.30 (s, 1H), 8.34 (s, 1H), 7.64-7.39 (m, 5H), 7.15-7.11 (t, 1H), 7.01-6.95 (m, 4H), 5.34 (s, 2H), 4.20-4.00 (m, 4H), 3.10-3.00 (m, 4H), 2.09 (s, 3H), 2.08 (s, 3H), 1.82-1.79 (m, 1H), 0.96-0.95 (m, 4H). MS: m/z=521.4 (M+1), HPLC Purity: 80.32% Method: A.
Reaction SMILES: [CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([O:27]C)=[O:26].[OH-].[Na+]>CO>[CH3:1][C:2]1[N:7]=[C:6]2[S:8][C:9]3[CH2:14][CH2:13][CH2:12][CH2:11][C:10]=3[C:5]2=[C:4]([C:15]2[O:16][C:17]3[CH:23]=[CH:22][CH:21]=[CH:20][C:18]=3[CH:19]=2)[C:3]=1[CH:24]([CH2:29][CH2:30][CH3:31])[C:25]([OH:27])=[O:26]
Reactant: CCCC(C(=O)OC)c1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CCCC(C(=O)O)c1c(C)nc2sc3c(c2c1-c1cc2ccccc2o1)CCCC3
Temperature: 60 °C
Yield: 31.8 %

Procedure:
To a solution of methyl [2-methyl-4-(benzofuran-2-yl)-5,6,7,8-tetrahydro[1]benzothieno[2,3-b]pyridin-3-yl]pentanoate (0.302 g; 0.697 mmol) in methanol (7 mL) was added a solution of sodium hydroxide 5 N (1.4 mL) and the mixture was heated at 60° C. for 18 h. After cooling, the reaction mixture was concentrated under reduced pressure. The residue was dissolved in ethyl acetate and the mixture was acidified with HCl (1N) until pH 1. The organic layer was washed with brine, water, dried over magnesium sulphate and concentrated under reduced pressure. The crude residue was crystallized from a mixture ethyl acetate-heptane to furnish 0.093 g (32%) of the title compound as a light yellow solid.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:11]1[C:39]([CH3:40])=[CH:38][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][N:27](C(OC(C)(C)C)=O)[C@@H:26]([CH3:37])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:41]1[CH:46]=[CH:45][C:44]([Cl:47])=[CH:43][CH:42]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:4])([CH3:3])[CH3:2].Cl>O1CCOCC1>[C:1]([O:5][C@@H:6]([C:11]1[C:39]([CH3:40])=[CH:38][C:14]2[N:15]=[C:16]([C:18]3[CH:23]=[CH:22][N:21]=[C:20]([N:24]4[CH2:29][CH2:28][NH:27][C@@H:26]([CH3:37])[CH2:25]4)[N:19]=3)[S:17][C:13]=2[C:12]=1[C:41]1[CH:42]=[CH:43][C:44]([Cl:47])=[CH:45][CH:46]=1)[C:7]([O:9][CH3:10])=[O:8])([CH3:2])([CH3:3])[CH3:4]
Reactant: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN(C(=O)OC(C)(C)C)[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Agent: Cl
Solvent: C1COCCO1
Product: COC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4CCN[C@@H](C)C4)n3)sc2c1-c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
To crude (S)-tert-butyl 4-(4-(6-((S)-1-tert-butoxy-2-methoxy-2-oxoethyl)-7-(4-chlorophenyl)-5-methylbenzo[d]thiazol-2-yl)pyrimidin-2-yl)-2-methylpiperazine-1-carboxylate in 1,4-dioxane (1.25 mL) was added HCl (0.78 mL of a 4M solution in 1,4-dioxane). The reaction mixture was stirred at room temperature for 2.5 h then concentrated. The resulting solid was suspended in diethyl ether, concentrated and dried under high vacuum overnight. The resulting solid was taken up in water, basified with 2N NaOH, and extracted three times with DCM. The combined organic layers were dried over sodium sulfate, filtered, concentrated, and used without further purification. LCMS-ESI+ calc'd for C30H35ClN5O3S (M+H+): 580.2; Found: 580.2 (M+H+).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][C:9]1[N:10]=[C:11]([NH:14][C:15]2[C:20]([O:21][CH2:22][C:23]3[CH:24]=[C:25]([CH:31]=[CH:32][CH:33]=3)[O:26][CH2:27][C:28]([OH:30])=O)=[CH:19][CH:18]=[CH:17][N:16]=2)[S:12][CH:13]=1.C(N(CC)CC)C.[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH2:45].[ClH:47]>>[ClH:47].[ClH:47].[CH3:41][N:42]([CH3:46])[CH2:43][CH2:44][NH:45][C:28](=[O:30])[CH2:27][O:26][C:25]1[CH:31]=[CH:32][CH:33]=[C:23]([CH2:22][O:21][C:20]2[C:15]([NH:14][C:11]3[S:12][CH:13]=[C:9]([CH3:8])[N:10]=3)=[N:16][CH:17]=[CH:18][CH:19]=2)[CH:24]=1
Reactant: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)O)c2)n1
Reactant: CN(C)CCN
Agent: Cl
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: Cc1csc(Nc2ncccc2OCc2cccc(OCC(=O)NCCN(C)C)c2)n1
Yield: 56.1 %

Procedure:
2-(3-((2-(4-Methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetic acid trifluoroacetate (prepared according to Example 26; 70 mg, 0.14 mmol), triethylamine (0.10 mL, 0.72 mmol) ethyl chloroformate (0.035 mL, 0.36 mmol) and N1,N1-dimethylethane-1,2-diamine (0.079 mL, 0.72 mmol) were reacted according to the method of Example 30 to provide N-(2-(dimethylamino)ethyl)-2-(3-((2-(4-methylthiazol-2-ylamino)pyridin-3-yloxy)methyl)phenoxy)acetamide dihydrochloride (43.8 mg, 56.1% yield) as a white solid after HCl salt formation. 1H NMR (d6-DMSO) δ 11.54 (bs, 1H), 10.76 (bs, 1H), 8.54 (t, 1H), 8.00 (d, 1H), 7.66 (d, 1H), 7.32 (m, 2H), 7.18 (m, 2H), 6.97 (dd, 1H), 6.93 (s, 1H), 5.34 (s, 2H), 4.60 (s, 2H), 3.53 (q, 2H), 3.19 (q, 2H), 2.76 (s, 6H), 2.35 (s, 3H). Mass spectrum (apci) m/z 442.1 (M+H-2HCl).
Reaction SMILES: C1CC(N)(C(O)=[O:6])C1.[OH-].[K+].C1NC1.[CH2:14]([C:16]([CH2:21][OH:22])([CH2:19][OH:20])[CH2:17]C)[OH:15]>>[CH2:14]([C:16]([CH2:21][OH:22])([CH3:17])[C:19]([OH:6])=[O:20])[OH:15]
Reactant: CCC(CO)(CO)CO
Reactant: NC1(C(=O)O)CCC1
Agent: C1CN1
Agent: [K+]
Agent: [OH-]
Product: CC(CO)(CO)C(=O)O

Procedure:
Examples of polyester polyols selected for the ACBC layer, and, in embodiments, for reaction with the polyisocyanate are known, and can be obtained from Perstorp Specialty Chemicals (Perstorp, Sweden) as BOLTORN® P500 (OH value of 560 to 630 milligram KOH/gram, Mw (GPC)=1,800), P1000 (OH value of 430 to 490 mg KOH/grams, Mw (GPC)=1,500), H20 (OH value of 490 to 520 mg KOH/grams, Mw (GPC)=2,100, Tg=25° C.), H2003 (OH value of 280 to 310 mg KOH/grams, Mw (GPC)=2,500, Tg=−5° C.), H2004 (OH value of 110 to 130 mg KOH/grams, Mw (GPC)=3,200, Tg=−35° C.), H30 (OH value of 490 to 510 mg KOH/grams, Mw (GPC)=3,500, Tg=35° C.), H40 (OH value of 470 to 500 mg KOH/grams, Mw (GPC)=5,100, Tg=40° C.), U3000 (OH value of 77 mg KOH/grams, Mw (GPC)=6,500), and W3000 (OH value of 45 mg KOH/grams, Mw (GPC)=10,000). In embodiments, a dendritic polyester polyol selected for the ACBC layer formation can be formed by, for example, the polymerization of a core such as trimethylolpropane and branches extending therefrom of 2,2-dimethylol propionic acid (Bis-MPA), and which resulting products can be referred to as hydroxyl-functional dendritic polyesters.
Reaction SMILES: [Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:11])[NH:7][C:6]=2[CH:5]=[C:4]([Cl:12])[C:3]=1[Cl:13].C/C(/O[Si](C)(C)C)=N\[Si](C)(C)C.C(O[CH:30]1[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]1[O:32][C:33](=[O:35])[CH3:34])(=O)C.C[Si](OS(C(F)(F)F)(=O)=O)(C)C>C(#N)C.C(OCC)(=O)C>[Br:1][C:2]1[C:10]2[N:9]=[C:8]([Cl:11])[N:7]([C@@H:30]3[O:42][C@H:41]([CH3:43])[C@@H:36]([O:37][C:38](=[O:40])[CH3:39])[C@H:31]3[O:32][C:33](=[O:35])[CH3:34])[C:6]=2[CH:5]=[C:4]([Cl:12])[C:3]=1[Cl:13]
Reactant: Clc1nc2c(Br)c(Cl)c(Cl)cc2[nH]1
Reactant: CC(=O)OC1O[C@H](C)[C@@H](OC(C)=O)[C@H]1OC(C)=O
Agent: C/C(=N\[Si](C)(C)C)O[Si](C)(C)C
Agent: C[Si](C)(C)OS(=O)(=O)C(F)(F)F
Solvent: CC#N
Solvent: CCOC(C)=O
Product: CC(=O)O[C@@H]1[C@H](OC(C)=O)[C@@H](C)O[C@H]1n1c(Cl)nc2c(Br)c(Cl)c(Cl)cc21
Temperature: 65 °C
Reaction time: 0.25 h
Yield: 55.9 %

Procedure:
To a suspension of 4-bromo-2,5,6-trichloro-1H-benzimidazole (0.30 g, 1 mmol), in acetonitrile (5 mL) was added N,O-bis(trimethylsilyl)acetamide (0.25 mL, 1 mmol). The resulting mixture was allowed to stir at 65° C. for 15 min., followed by the addition of 1,2,3-tri-O-acetyl-5-deoxyribofuranose (0.31 g, 1.2 mmol) in acetonitrile (5 mL) and trimethylsilyltrifluoromethane sulfonate (0.25 mL, 1.3 mmol). The mixture was allowed to stir at 65° C. for 20 min and was then allowed to cool to RT. The mixture was diluted with ethyl acetate and was washed with a saturated NaHCO3/NaCl solution, dried over MgSO4 and the solvents were removed by rotary evaporation. The product was purified by flash chromatography using chloroform as eluent followed by recrystallization from methanol to provide 0.28 g (55%) of the title compound as white crystals; m.p. 138-141° C.; 1H NMR (DMSO-d6) δ: 8.18 (s, 1H), 6.19 (d, 1H), 5.61 (dd, 1H), 5.25 (dd, 1H), 4.24 (m, 1H), 2.14 (s, 3H), 2.02 (s, 3H), 1.50 (d, 3H).
Reaction SMILES: O=O.[CH2:3]([N:10]1[CH2:14][C:13]([C:15]2[CH:20]=[CH:19][C:18]([Cl:21])=[CH:17][CH:16]=2)=[C:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.[H][H]>CO>[CH2:3]([N:10]1[CH2:14][C@H:13]([C:15]2[CH:16]=[CH:17][C:18]([Cl:21])=[CH:19][CH:20]=2)[C@H:12]([C:22]([OH:24])=[O:23])[CH2:11]1)[C:4]1[CH:5]=[CH:6][CH:7]=[CH:8][CH:9]=1
Reactant: O=C(O)C1=C(c2ccc(Cl)cc2)CN(Cc2ccccc2)C1
Reactant: [H][H]
Agent: O=O
Solvent: CO
Product: O=C(O)[C@@H]1CN(Cc2ccccc2)C[C@@H]1c1ccc(Cl)cc1
Temperature: 2.5 °C
Reaction time: 2 h
Yield: 99.6 %

Procedure:
A 185-ml stainless steel autoclave was charged under argon in a glove box (O2 content<2 ppm) with 1-benzyl-4-(4-chloro-phenyl)-2,5-dihydro-1H-pyrrole-3-carboxylic acid (5.00 g, 15.1 mmol), [Ru(OAc)2((R)-2-Furyl-MeOBIPHEP] (3.8 mg, 5.0 μmol) (S/C 5′000) and methanol (150 mL). The asymmetric hydrogenation was run under 40 bar of hydrogen for 20 h at 30° C. and additional 2 h at 60° C. to complete the conversion (>99.6% conversion and 99.9% ee). After the pressure was released, the white suspension was stirred at 0-5° C. for 2 h, filtered off and the filter cake was washed with cold (0-5° C.) methanol (20 mL) and dried under vacuum at room temperature to yield the title product (4.75 g, 99%) with 99% purity and 99.9% ee. ES-MS m/e: 316.1 (M+H+).
Reaction SMILES: [OH:1]O.[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]#[N:13])=[C:10]([C:16]([F:19])([F:18])[F:17])[CH:9]=1)(=[O:7])=[O:6].[OH-].[Na+].[Cl-].[Na+]>C(O)C.O>[CH3:3][N:4]([CH3:20])[S:5]([C:8]1[CH:15]=[CH:14][C:11]([C:12]([NH2:13])=[O:1])=[C:10]([C:16]([F:17])([F:19])[F:18])[CH:9]=1)(=[O:6])=[O:7]
Reactant: CN(C)S(=O)(=O)c1ccc(C#N)c(C(F)(F)F)c1
Reactant: OO
Agent: [Cl-]
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: CN(C)S(=O)(=O)c1ccc(C(N)=O)c(C(F)(F)F)c1

Procedure:
Hydrogen peroxide (30%, 100 ml) was added to a stirred mixture of 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzonitrile (20.37 g) and sodium hydroxide (1.0 g) in ethanol under an inept atmosphere maintaining the temperature at 40°-45° C. The mixture was stirred and heated at that temperature for 3.5 hours. It was cooled, poured into water, sodium chloride was added and it was extracted with ethyl acetate, washed with water, dried (MgSO4) and filtered. The filtrate was evaporated to dryness and the residue was re-crystallized from a mixture of ethyl acetate and toluene to give 4-(N,N-dimethylaminosulphonyl)-2-trifluoromethylbenzamide (16.44 g) as white crystals, m.p. 149°-156° C.
Reaction SMILES: [CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([OH:18])=[CH:14][CH:13]=2)[N:4]=1)[CH3:2].[H-].[Na+].CN(C=O)C.[CH3:26][N:27]1[C:31]2=[N:32][CH:33]=[CH:34][CH:35]=[C:30]2[N:29]=[C:28]1S(C)(=O)=O>CO>[CH2:1]([C:3]1[C:11]2[C:6](=[N:7][CH:8]=[CH:9][CH:10]=2)[N:5]([C:12]2[CH:17]=[CH:16][C:15]([O:18][C:28]3[N:27]([CH3:26])[C:31]4=[N:32][CH:33]=[CH:34][CH:35]=[C:30]4[N:29]=3)=[CH:14][CH:13]=2)[N:4]=1)[CH3:2]
Reactant: Cn1c(S(C)(=O)=O)nc2cccnc21
Reactant: CCc1nn(-c2ccc(O)cc2)c2ncccc12
Agent: [H-]
Agent: [Na+]
Solvent: CO
Solvent: CN(C)C=O
Product: CCc1nn(-c2ccc(Oc3nc4cccnc4n3C)cc2)c2ncccc12
Temperature: 180 °C
Reaction time: 1 h
Yield: 64.6 %

Procedure:
To a mixture of 4-(3-ethyl-1H-pyrazolo[3,4-b]pyridin-1-yl)phenol (120 mg) obtained in Example 8, step D), sodium hydride (60% in oil, 20.1 mg) and DMF (5.0 ml) was added 3-methyl-2-(methylsulfonyl)-3H-imidazo[4,5-b]pyridine (106 mg), and the mixture was stirred under microwave irradiation at 180° C. for 1 hr. The reaction mixture diluted with methanol, and the mixture was concentrated under reduced pressure. The residue was purified by silica gel column chromatography (hexane/ethyl acetate) to give the title compound (120 mg).
Reaction SMILES: [ClH:1].Br[C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2.[CH:15]([NH:18][C:19](NC(C)C)=O)([CH3:17])[CH3:16]>O>[ClH:1].[CH3:19][N:18]([C:3]12[CH2:12][C:7]3([CH3:13])[CH2:8][CH:9]([CH2:11][C:5]([CH3:14])([CH2:6]3)[CH2:4]1)[CH2:10]2)[CH:15]([CH3:17])[CH3:16]
Reactant: CC(C)NC(=O)NC(C)C
Reactant: CC12CC3CC(C)(C1)CC(Br)(C3)C2
Agent: Cl
Solvent: O
Product: CC(C)N(C)C12CC3CC(C)(CC(C)(C3)C1)C2
Reaction time: 0.17 h
Yield: 44 %

Procedure:
2.43 grams of 1-bromo-3,5-dimethyl-adamantane hydrochloride were heated in a closed vessel for 40 minutes at 180° C., with 2.8 grams of N,N'-di-isopropylurea. After cooling, the reaction product was suspended in 50 ml. of water, acidified, and extracted with two 10-ml. portions of ether. Next, the water phase was brought to a pH of between 12 and 13 with sodium hydroxide, stirred for 10 minutes, and extracted with four 10-ml. portions of benzene. The benzene extracts were combined, the benzene stripped off, and the residue refluxed for 10 hours with 4 ml. of a 32% formaldehyde solution and 4 ml. of concentrated formic acid. After cooling, the solution was worked up as in Example 6. It yielded 1.04 grams of 1-(N-methyl,N-isopropylamino)-3,5-dimethyl-adamantane hydrochloride. Yield: 38% of theoretical yield.
Reaction SMILES: Cl.[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][NH:30][CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.[CH3:34][S:35](Cl)(=[O:37])=[O:36].C(N(CC)C(C)C)(C)C>CN(C=O)C>[CH2:2]([N:9]1[CH:17]=[C:16]2[C:11]([CH:12]=[C:13]([C:18]3[CH:19]=[C:20]([CH:28]4[CH2:33][CH2:32][CH2:31][N:30]([S:35]([CH3:34])(=[O:37])=[O:36])[CH2:29]4)[N:21]4[C:26]=3[C:25]([NH2:27])=[N:24][CH:23]=[N:22]4)[CH:14]=[CH:15]2)=[N:10]1)[C:3]1[CH:4]=[CH:5][CH:6]=[CH:7][CH:8]=1
Reactant: Nc1ncnn2c(C3CCCNC3)cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CS(=O)(=O)N1CCCC(c2cc(-c3ccc4cn(Cc5ccccc5)nc4c3)c3c(N)ncnn23)C1
Temperature: 25 °C
Reaction time: 17 h
Yield: 22.7 %

Procedure:
To a solution of 5-(2-benzyl-2H-indazol-6-yl)-7-piperidin-3-ylpyrrolo[2,1-f][1,2,4]triazin-4-amine hydrochloride (100 mg, 0.22 mmol) in DMF (1.5 mL) was added methanesulfonyl chloride (19 μL, 0.24 mmol) and N,N-diisopropylethylamine (114 μL, 0.65 mmol). The reaction was stirred at rt for 17 h. The crude mixture was purified by preparative HPLC using a gradient elution from 20% to 50% acetonitrile in water followed by filtration through an acidic resin, washing with MeOH. The product was eluted with 2M NH3 in MeOH and the filtrate was concentrated to provide 25 mg (23%) of the desired product. 1H NMR (400 MHz, DMSO-d6) δ 8.54 (s, 1 H), 7.93 (s, 1 H), 7.80 (d, 1 H), 7.58 (s, 1 H), 7.27-7.37 (m, 5 H), 7.13 (dd, 1 H), 6.70 (s, 1 H), 5.64 (s, 2 H), 3.82-3.88 (m, 1 H), 3.55 (d, 1 H), 3.34-3.46 (m, 1 H), 2.86 (s, 3 H), 2.74-2.85 (m, 2 H), 2.03-2.13 (m, 1 H), 1.78-1.89 (m, 1 H), 1.57-1.77 (m, 2 H); ES-MS m/z 502.47 [M+H]+, HPLC RT (min) 3.04.
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].C([O:10][C:11]1[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH2:19][O:20][P:21]([O:31][CH2:32][C:33]2[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=2)([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[O:22])=[CH:13][C:12]=1[O:39][CH3:40])(=O)C>CO>[P:21]([O:20][CH2:19][CH2:18][O:17][C:14]1[CH:15]=[CH:16][C:11]([OH:10])=[C:12]([O:39][CH3:40])[CH:13]=1)([O:31][CH2:32][C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([O:23][CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1)=[O:22]
Reactant: COc1cc(OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1OC(C)=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: COc1cc(OCCOP(=O)(OCc2ccccc2)OCc2ccccc2)ccc1O
Temperature: 25 °C
Reaction time: 1 h

Procedure:
Potassium carbonate (0.072 g, 0.524 mmol) was added to a stirred solution of 4-(2-{[bis(benzyloxy)phosphoryl]oxy}ethoxy)-2-methoxyphenyl acetate (0.1274 g, 0.262 mmol) in MeOH (17.5 mL) at 25° C. The reaction was stirred at 25° C. for 1 h. The reaction mixture was concentrated in vacuo and the resulting residue was partitioned between water (20 mL) and EtOAc (20 mL). The aqueous layer was separated and extracted with EtOAc (2×20 mL). The combined organic extracts were dried (MgSO4) and concentrated in vacuo to afford dibenzyl 2-(4-hydroxy-3-methoxyphenoxy)ethyl phosphate, as an oil. LCMS calc.=445.1; found=444.9 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[N:9]=[CH:8][C:7](Br)=[CH:6][C:3]=1[CH:4]=[O:5].[CH3:11][O:12][C:13]1[CH:18]=[CH:17][C:16](B(O)O)=[CH:15][CH:14]=1.C(=O)([O-])[O-].[K+].[K+]>CC#N.O>[NH2:1][C:2]1[N:9]=[CH:8][C:7]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH3:11])=[CH:14][CH:15]=2)=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: Nc1ncc(Br)cc1C=O
Reactant: COc1ccc(B(O)O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC#N
Solvent: O
Product: COc1ccc(-c2cnc(N)c(C=O)c2)cc1
Yield: 46.6 %

Procedure:
2-amino-5-bromonicotinaldehyde (1.61 g, 8 mmol), 4-methoxyphenylboronic acid (2.43 g, 16 mmol) and anhydrous potassium carbonate (2.21 g, 16 mmol) were dissolved in 50 ml of CH3CN/H2O (8:2), and 1 mol % of dichlorobis(triphenylphopsine)palladium(II) (56 mg, 0.08 mmol) was added while stirring. The reaction mixture was heated to reflux and stirred for 2 h. The reaction mixture was allowed to cool, and then partitioned between diethyl ether and water. The aqueous layer was extracted with another portion of diethyl ether. The combined organics were washed with brine, dried over anhydrous Na2SO4, filtered and concentrated in vacuo. The compound was purified by chromatography on silica gel eluting with with 30% EtOAc/hexanes to yield 2-amino-5-(4-methoxyphenyl)nicotinaldehyde (0.85 g, 47%).
Reaction SMILES: [CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12](O)=[O:13].[NH:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1.CCN=C=NCCCN(C)C.Cl>CN(C)C1C=CN=CC=1.C(Cl)Cl>[CH3:1][O:2][C:3]1[C:4]([CH3:31])=[C:5]([C:22]([O:29][CH3:30])=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[CH2:6][C:7]1[CH:8]=[CH:9][C:10]([C:16]2[CH:17]=[N:18][CH:19]=[CH:20][CH:21]=2)=[C:11]([CH:15]=1)[C:12]([N:32]1[CH2:37][CH2:36][O:35][CH2:34][CH2:33]1)=[O:13]
Reactant: C1COCCN1
Reactant: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)O)c2)c(OC)c(OC)c1OC
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Product: COc1c(C)c(Cc2ccc(-c3cccnc3)c(C(=O)N3CCOCC3)c2)c(OC)c(OC)c1OC
Temperature: 25 °C
Reaction time: 16 h
Yield: 54.9 %

Procedure:
5-(3,4,5,6-Tetramethoxy-2-methylbenzyl)-2-(3-pyridyl)benzoic acid (80 mg, 0.1886 mmol), 4-dimethylaminopyridine (12 mg, 0.0983 mmol) and morpholine (33 mg, 0.3793 mmol) were dissolved in methylene chloride (10 ml), WSC-HCl (109 mg, 0.5685 mmol) was added thereto and the mixture was stirred at room temperature for 16 hours. The reaction solution was washed with water and dried and the solvent was evaporated therefrom. The residue was purified by preparative thin layer chromatography (methylene chloride:methanol=95:5) to give the title compound (51 mg, 0.1036 mmol, 55%).
Reaction SMILES: [CH2:1]([NH:8]CCC1C2C(=CC=C(F)C=2OC)N(C)C=1)C1C=CC=CC=1.[F:24][C:25]1[CH:26]=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36]O>>[F:24][C:25]1[CH:26]=[C:27]([C:40]2[CH:45]=[CH:44][CH:43]=[CH:42][CH:41]=2)[C:28]([O:38][CH3:39])=[C:29]2[C:33]=1[N:32]([CH3:34])[CH:31]=[C:30]2[CH2:35][CH2:36][NH:8][CH3:1]
Reactant: COc1c(F)ccc2c1c(CCNCc1ccccc1)cn2C
Reactant: COc1c(-c2ccccc2)cc(F)c2c1c(CCO)cn2C
Product: CNCCc1cn(C)c2c(F)cc(-c3ccccc3)c(OC)c12
Yield: 47 %

Procedure:
Following the procedure (step 6, scheme 17) used to prepare compound 17-7, compound 22-4 was used as starting material, giving compound 22-5 in 47% yield as a colorless oil, which was converted to the hydrochloride salt. 1H NMR (DMSO-d6, 300 MHz) δ (ppm) (HCl salt): 8.63 (br, 2H), 7.57-7.60 (m, 2H), 7.45 (t, J=7.4 Hz, 2H), 7.30-7.36 (m, 1H), 7.23 (s, 1H), 6.93 (d, J=12.9 Hz, 1H), 3.90 (d, J=1.9 Hz, 3H), 3.36 (s, 3H), 3.16-3.21 (m, 2H), 3.06-3.11 (m, 2H), 2.59 (s, 3H). LRMS: calc 312.2 found 313.1 [MH]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[C:7](F)[C:6]([CH3:10])=[CH:5][C:4]=1[N+:11]([O-:13])=[O:12].C([O-])([O-])=O.[K+].[K+].FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.[NH:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:45][CH2:44][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:42][CH2:41]2)[CH2:36][CH2:35]1.O>CS(C)=O>[CH3:10][C:6]1[CH:5]=[C:4]([N+:11]([O-:13])=[O:12])[C:3]([O:2][CH3:1])=[CH:8][C:7]=1[N:34]1[CH2:39][CH2:38][CH:37]([N:40]2[CH2:41][CH2:42][N:43]([C:46]([O:48][CH2:49][C:50]3[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=3)=[O:47])[CH2:44][CH2:45]2)[CH2:36][CH2:35]1
Reactant: O=C(OCc1ccccc1)N1CCN(C2CCNCC2)CC1
Reactant: COc1cc(F)c(C)cc1[N+](=O)[O-]
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Solvent: O=C(O)C(F)(F)F
Product: COc1cc(N2CCC(N3CCN(C(=O)OCc4ccccc4)CC3)CC2)c(C)cc1[N+](=O)[O-]
Reaction time: 8 h
Yield: 65.9 %

Procedure:
5-Fluoro-4-methyl-2-nitrophenyl methyl ether (2.76 g, 14.9 mmol) was dissolved in DMSO (50 mL), and K2CO3 (10.3 g, 74.5 mmol) and phenylmethyl 4-(4-piperidinyl)-1-piperazinecarboxylate bis(trifluoroacetate) salt (Example 112, step B) (8.0 g, 15 mmol) were added. Reaction was stirred overnight. Poured into H2O and extracted (2×) with EtOAc. Combined organic layers were back-extracted (5×) with H2O and then dried over MgSO4, filtered, concentrated on to silica gel and flash chromatographed to give the title compound of step C (4.6 g, 66%). 1H NMR (400 MHz, DMSO-d6) δ ppm 7.72 (s, 1H), 7.03-7.46 (m, 5H), 6.64 (s, 1H), 5.03 (s, 2H), 3.85 (s, 3H), 3.06-3.59 (m, 6H), 2.67 (t, J=11.5 Hz, 2H), 2.26-2.57 (m, 5H), 2.15 (s, 3H), 1.81 (d, J=11.5 Hz, 2H), 1.36-1.68 (m, 2H).