Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.[C:15](ON1C(=O)CCC1=O)([CH3:17])=[O:16].CN1CCOCC1>CN(C=O)C>[NH:1]([C:15]([CH3:17])=[O:16])[C@H:2]([C:12]([OH:14])=[O:13])[CH2:3][O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1
Reactant: N[C@@H](COCc1ccccc1)C(=O)O
Reactant: CC(=O)ON1C(=O)CCC1=O
Solvent: CN1CCOCC1
Solvent: CN(C)C=O
Product: CC(=O)N[C@@H](COCc1ccccc1)C(=O)O

Procedure:
The same compound was also prepared by a different route. Thus, H-Ser(Bzl)-OH (18.6 g, 95.4 mmol) was dissolved in 45 ml Triton B, evaporated to dryness, and the residue re-evaporated twice with DMF (100 ml each). The residue was then stirred with Ac-OSu (16.9 g, 95.4 mmol) in 150 ml DMF for 20 hours. N-Methylmorpholin was added from time to time in order to maintain the reaction slightly basic. Removal of the solvent and extraction of the product into EtOAc followed by washing with small volumes of 10% HOAc, H2O (the product is water soluble, use a small volume of H2O), dried over Na2SO4, evaporation to dryness again gave a clear oil (14.5 g, Ac-Ser(Bzl)-OH). The compound failed to crystallize. It was thus dissolved in a mixture of MeOH and H2O (300 ml:30 ml), titrated to pH 7.0 with 20% Cs2CO3 and evaporated to a solid mass. The salt was re-evaporated twice more with DMF and stirred with benzyl bromide (15.4 g, 91 mmol) in 250 ml DMF for 18 hours. On evaporation of the solvent, the residue was taken up in H2O (600 ml) and the oily product formed was extracted into EtOAc. It was washed with H2O, dried over Na2SO4 and evaporated to a syrup which on seeding crystallized immediately. It was recrystallized from EtOAc and petroleum ether to yield, 10.42 g (32.2% overall); mp 89°-91°.
Reaction SMILES: [NH:1]1[C:5]2=[CH:6][N:7]=[CH:8][CH:9]=[C:4]2[C:3]([CH:10]=[O:11])=[CH:2]1.[C:12]1([Mg]Cl)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>C1COCC1>[C:12]1([CH:10]([C:3]2[C:4]3[C:5](=[CH:6][N:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:11])[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=Cc1c[nH]c2cnccc12
Reactant: Cl[Mg]c1ccccc1
Solvent: C1CCOC1
Product: OC(c1ccccc1)c1c[nH]c2cnccc12
Temperature: -40 °C
Yield: 43 %

Procedure:
A mixture of 1H-pyrrolo[2,3-c]pyridine-3-carboxaldehyde (100 mg, 0.68 mmol) and THF (6.8 mL) was cooled to −40° C. and phenylmagnesium chloride (0.68 mL, 1.36 mmol) was added. The reaction mixture was warmed to room temperature and refluxed for 1 h. The reaction mixture was cooled to room temperature and quenched with saturated NH4Cl and then water was added. The aqueous layer was extracted with EtOAc (1×), dried (MgSO4) and filtered, and the solvent was removed. The crude material was purified by Biotage chromatography (90:10 to 85:15 methylene chloride/methanol) to give phenyl(1H-pyrrolo[2,3-c]pyridin-3-yl)methanol as a yellow solid (65.5 mg, 43%): Rf 0.11 (90:10 methylene chloride/methanol); 1H NMR (300 MHz, CD3OD) (6.09 (1H, s), 7.25-7.27 (1H, m), 7.32-7.35 (3H, m), 7.46-7.48 (3H, m), 7.96-7.97 (1H, d, J=5.6 Hz), 8.64 (1H, s); ESI MS m/z 225 [C14H12N2O+H]+; Estimated Purity: >90% by 1H NMR analysis.
Reaction SMILES: [N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([O:23]C(C)(C)C)=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.FC(F)(F)C(O)=O.FC(F)(F)C(O)=O.ClCCl>C(OCC)(=O)C.CCCCCC>[N:1]1([C:6]([N:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[N:11]3[CH:18]=[N:19][C:20]([C:21]([OH:23])=[O:22])=[C:10]3[CH2:9]2)=[O:7])[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: CC(C)(C)OC(=O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Solvent: O=C(O)C(F)(F)F
Solvent: CCCCCC
Solvent: ClCCl
Product: O=C(O)c1ncn2c1CN(C(=O)N1CCCC1)c1ccccc1-2
Reaction time: 0.5 h

Procedure:
To tert-butyl 4,5-dihydro-5-[(pyrrolidino)carbonyl]imidazo[1,5-a]quinoxaline-3-carboxylate (I, EXAMPLE 217, 2.97 g) are added 20 ml of a solution of trifluoroacetic acid and dichloromethane (1/1). After stirring for 3.5 hr an additional 2 ml of the trifluoroacetic acid/dichloromethane solution are added, followed an hour later by another 2 ml and 30 min later with a final 2 ml of the trifluoroacetic acid/dichloromethane solution. The reaction is stirred additional hours and then concentrated under reduced pressure. Dichloromethane is added to the residue and the mixture is again concentrated to give the title compound, which is crystallized from methanol/dichloromethane, mp 197°-200°; MS (m/z) at 312; NMR (DMSO-d6) 1.72, 3.15, 4.86, 7.18-7.22, 7.33, 7.90, 8.70 δ.
Reaction SMILES: [Br-:1].[Mg+2].[Br-].S(O[CH2:9][CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26])(=O)(=O)C.O>CCOCC>[CH2:9]([Br:1])[CH2:10][CH2:11][CH2:12][CH2:13]/[CH:14]=[CH:15]\[CH2:16]/[CH:17]=[CH:18]\[CH2:19]/[CH:20]=[CH:21]\[CH2:22][CH2:23][CH2:24][CH2:25][CH3:26]
Reactant: [Br-]
Reactant: CCCCC/C=C\C/C=C\C/C=C\CCCCCOS(C)(=O)=O
Agent: [Mg+2]
Solvent: O
Solvent: CCOCC
Product: CCCCC/C=C\C/C=C\C/C=C\CCCCCBr
Reaction time: 8 h

Procedure:
Magnesium bromide etherate (34 g, 110 mmol) and a stir bar were added to a 2000 mL round bottom flask. The flask was sealed and flushed with nitrogen. Anhydrous diethyl ether (400 mL) was added via canulla. A solution of γ-linolenyl mesylate (20 g, 58 mmol) in anhydrous ether (300 mL) was then added, and the suspension stirred overnight. The suspension was poured into 500 mL of chilled water and transferred to a 2000-mL separating funnel. After shaking, the organic phase was separated. The aqueous phase was then extracted with ether (2×250 mL) and all ether phases combined. The ether phase was washed with water (2×250 mL), brine (250 mL) and dried over anhydrous Mg2SO4. The solution was filtered, concentrated and purified by flash chromatography. Final yield 18.9 g, 99%.
Reaction SMILES: Cl.[OH:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>>[CH3:22][S:23]([O:2][CH2:3][CH2:4][CH2:5][C:6]1[N:11]2[CH:12]=[CH:13][N:14]=[C:10]2[CH:9]=[CH:8][CH:7]=1)(=[O:25])=[O:24]
Reactant: OCCCc1cccc2nccn12
Reactant: CS(=O)(=O)Cl
Agent: Cl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCCc1cccc2nccn12

Procedure:
Using 2.55 g (12 mmol) of 5-(3-hydroxypropyl)imidazo-[1,2-a]pyridine hydrochloride, 3.90 ml (28 mmol) of triethylamine and 1.08 ml (14 mmol) of methanesulfonyl chloride, the same procedure as in Reference Example 8 was followed, to yield 5-(3-methanesulfonyloxypropyl)imidazo-[1,2-a]pyridine.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[C:6]2=O.O.NN.O>C(OCC)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][CH:11]=1)[NH:8][C:7](=[O:12])[CH2:6]2
Reactant: COc1ccc2c(c1)C(=O)C(=O)N2
Agent: NN
Solvent: O
Solvent: CCOC(C)=O
Product: COc1ccc2c(c1)CC(=O)N2
Temperature: 25 °C
Yield: 15.2 %

Procedure:
Concentrated sulfuric acid (45 mL) containing 5 mL of water was warmed to 60° C. and 8.6 g of N-(2-hydroximinoacetyl)anisidine was added in one portion. The stirred mixture was heated to 93° C. for 10 minutes and then allowed to cool to room temperature. The mixture was poured into 500 g of ice and extracted 3 times with ethyl acetate. The combined extracts were dried over anhydrous sodium sulfate and concentrated to give 5.1 g (65% yield) of 5-methoxyisatin as a dark red solid. 5-Methoxyisatin (5.0 g) and 30 mL of hydrazine hydrate were heated to reflux for 15 minutes. The reaction mixture was cooled to room temperature and 50 mL of water was added. The mixture was extracted 3 times with 25 mL of ethyl acetate each time, the organic layers combined, dried over anhydrous sodium sulfate and concentrated to give a yellow solid. The solid was stirred in ethyl acetate and 1.1 g of insoluble material was removed by vacuum filtration and saved. This material proved to be 2-hydrazinocarbonylmethyl-4-anisidine. The filtrate was concentrated and chromatographed on silica gel eluting with ethyl acetate:hexane (1:1) to give 0.7 g of 5-methoxy-2-oxindole as a yellow solid. The 1.1 g of 2-hydrazino-carbonylmethyl-4-anisidine was refluxed for 1 hour in 20 mL of 1N sodium hydroxide. The mixture was cooled, acidified to pH 2 with concentrated hydrochloric acid and extracted 3 times with 25 mL of ethyl acetate each time. The organic extracts were combined, washed with brine, dried over anhydrous sodium sulfate and concentrated to give 0.8 g of 5-methoxy-2-oxindole as a yellow solid. The combined yield was 1.5 g or 33%.
Reaction SMILES: [CH3:1][O:2][P:3]([CH2:7][CH:8]=[CH2:9])(=[O:6])[O:4][CH3:5].[OH:10]O>CC(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.C/C(/O)=C/C(C)=O.[V]>[CH3:1][O:2][P:3]([CH2:7][CH:8]1[O:10][CH2:9]1)(=[O:6])[O:4][CH3:5]
Reactant: OO
Reactant: C=CCP(=O)(OC)OC
Agent: [V]
Agent: CC(=O)/C=C(/C)O
Solvent: CC(C)=O
Product: COP(=O)(CC1CO1)OC

Procedure:
In a flask having a capacity of 500 ml, equipped with a stirrer, thermostatic temperature control, reflux condenser, dropping funnel and internal thermometer, 0.5 g of vanadium (III) acetylacetonate is dissolved in 120 ml of acetone (previously purified with KMnO4). Then 75 g (0.5 mole) of allylphosphonic acid dimethyl ester is mixed in. With intense stirring, 65 ml of 30% hydrogen peroxide is added drop by drop over a period of about 20 minutes at 30° C. Then the mixture is refluxed for 2 hours, after which the acetone is largely removed by distillation, whereupon the product separates as the heavy phase. The aqueous phase is extracted with methylene chloride. 77 grams of glycidylphosphonic acid dimethyl ester are obtained by vacuum distillation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1.[BH4-].[Na+].CO.[NH4+].[Cl-]>C1COCC1.CCOC(C)=O>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]([OH:10])[CH3:9])=[C:4]([Cl:11])[CH:3]=1
Reactant: CC(=O)c1ccc(Br)cc1Cl
Agent: [BH4-]
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(O)c1ccc(Br)cc1Cl
Temperature: 30 °C
Reaction time: 8 h

Procedure:
To a stirring solution of 1-(4-bromo-2-chlorophenyl)ethanone (700 mg, 2998 μmol) in THF (20 mL) was added sodium borohydride (340 mg, 8994 μmol) and methanol (5 mL). Reaction suspension stirred overnight at 30° C. Reaction then partioned between EtOAc (50 mL) and sat NH4Cl (25 mL). Aqueous further extracted with EtOAc (2×25 mL). Combined organics dried over MgSO4, concentrated, then purified on silica (40 g) eluting with 10>40% EtOAc/hexanes. Product isolated as a colorless oil.
Reaction SMILES: [C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([OH:10])=O)[CH3:4])#[N:2].C(Cl)(=O)C(Cl)=O.O1CCCC1.[NH2:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([CH:47]=1)[O:31][C:32]1[CH:33]=[CH:34][C:35]2[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]3[CH2:46][CH2:45]3)=[O:43])[N:40]=2)[N:37]=1>CN(C)C=O.CN1CCCC1=O>[C:1]([CH:3]([C:5]1[CH:6]=[C:7]([CH:11]=[CH:12][CH:13]=1)[C:8]([NH:25][C:26]1[CH:27]=[CH:28][C:29]([O:48][CH3:49])=[C:30]([O:31][C:32]2[CH:33]=[CH:34][C:35]3[N:36]([CH:38]=[C:39]([NH:41][C:42]([CH:44]4[CH2:46][CH2:45]4)=[O:43])[N:40]=3)[N:37]=2)[CH:47]=1)=[O:10])[CH3:4])#[N:2]
Reactant: COc1ccc(N)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Reactant: CC(C#N)c1cccc(C(=O)O)c1
Agent: O=C(Cl)C(=O)Cl
Solvent: CN1CCCC1=O
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: COc1ccc(NC(=O)c2cccc(C(C)C#N)c2)cc1Oc1ccc2nc(NC(=O)C3CC3)cn2n1
Yield: 56.4 %

Procedure:
Using 3-(1-cyanoethyl)benzoic acid (62 mg, 0.35 mmol), oxalyl chloride (38 μL, 0.44 mmol), N,N-dimethylformamide (1 drop), tetrahydrofuran (3.0 mL), N-[6-(5-amino-2-methoxyphenoxy)imidazo[1,2-b]pyridazin-2-yl]cyclopropanecarboxamide (100 mg, 0.30 mmol) and N-methylpyrrolidone (2.0 mL) as starting materials and in the same manner as in Example 335, the title compound (84 mg, 58%) was obtained as a white powder.
Reaction SMILES: N[C:2]1[N:6]([C:7]2[CH:12]=[CH:11][C:10]([F:13])=[CH:9][CH:8]=2)[C:5]([C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:4][C:3]=1[C:24]([O:26][CH3:27])=[O:25].N(OC(C)(C)C)=O>O1CCCC1>[F:13][C:10]1[CH:11]=[CH:12][C:7]([N:6]2[CH:2]=[C:3]([C:24]([O:26][CH3:27])=[O:25])[CH:4]=[C:5]2[C:14]2[CH:19]=[CH:18][C:17]([S:20]([CH3:23])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[CH:8][CH:9]=1
Reactant: COC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1N
Agent: CC(C)(C)ON=O
Solvent: C1CCOC1
Product: COC(=O)c1cc(-c2ccc(S(C)(=O)=O)cc2)n(-c2ccc(F)cc2)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 67 %

Procedure:
2.00 g (5.2 mmol) of 5-amino-1-(4-fluorophenyl)-4-methoxycarbonyl-2-(4-methylsulfonylphenyl)pyrrole [prepared as described in step (ii) above] were dissolved in 50 ml of anhydrous tetrahydrofuran, and 6.38 g (61.8 mmol) of t-butyl nitrite were added to the resulting solution at room temperature and under a nitrogen atmosphere. The mixture was then stirred at room temperature for 30 minutes, after which it was heated under reflux for 2 hours. The solvent was then removed by distillation under reduced pressure and the residue was applied to a silica gel chromatography column and eluted with a 2:3 by volume mixture of ethyl acetate and hexane, to give 1.30 g (yield 68%) of the title compound as a yellow powder, melting at 144-146° C.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([NH:11][C:12]2[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24](Cl)=[O:25].CCN(CC)CC.O>C(Cl)Cl>[Cl:21][C:22]1[CH:30]=[C:29]([Cl:31])[CH:28]=[CH:27][C:23]=1[C:24]([N:11]([C:5]1[CH:6]=[CH:7][C:8]([O:9][CH3:10])=[C:3]([O:2][CH3:1])[CH:4]=1)[C:12]1[S:13][C:14]([CH3:20])=[C:15]([C:17]([OH:19])=[O:18])[N:16]=1)=[O:25]
Reactant: COc1ccc(Nc2nc(C(=O)O)c(C)s2)cc1OC
Reactant: O=C(Cl)c1ccc(Cl)cc1Cl
Solvent: CCN(CC)CC
Solvent: O
Solvent: ClCCl
Product: COc1ccc(N(C(=O)c2ccc(Cl)cc2Cl)c2nc(C(=O)O)c(C)s2)cc1OC
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96.2 %

Procedure:
A mixture of 2.74 g (9.3 mmol) 2-(3,4-Dimethoxy-phenylamino)-5-methyl-thiazole-4-carboxylic acid, 1.95 ml (14 mmol) 2,4-Dichlorobenzoyl chloride and 3.88 ml (27.9 mmol) NEt3 in 30 ml DCM was stirred at room temperature for 5 min and 50 ml water was added and the mixture was stirred at room temperature for 16 h. After removal of all volatiles the residue was extracted with DCM and evaporated under reduced pressure to yield 4.18 g of amorphous light brown solid which was used without further purification in the consecutive step. MS (m/e): 467.2 (MH+, 100%)
Reaction SMILES: [I:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:12]=[C:11]([OH:13])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:4][CH:3]=1.C(N(CC)CC)C.[CH:27]([Si:30](Cl)([CH:34]([CH3:36])[CH3:35])[CH:31]([CH3:33])[CH3:32])([CH3:29])[CH3:28]>C(Cl)Cl>[I:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:12]=[C:11]([O:13][Si:30]([CH:34]([CH3:36])[CH3:35])([CH:31]([CH3:33])[CH3:32])[CH:27]([CH3:29])[CH3:28])[N:10]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[N:9]=2)=[CH:6][CH:7]=1
Reactant: Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1
Reactant: CC(C)[Si](Cl)(C(C)C)C(C)C
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)[Si](Oc1cc(-c2ccc(I)cc2)nn1-c1ccccn1)(C(C)C)C(C)C
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 98 %

Procedure:
3-(4-iodophenyl)-1-(pyridin-2-yl)-1H-pyrazol-5-ol (0.5 mmol, 1 equivalent) was dissolved in CH2Cl2 (5 mL) to which 3 equivalents of triethylamine were then added. Under stream of nitrogen, 2 equivalents of triisopropylsilyl chloride (TIPSCl) were added thereto at 0° C., followed by stirring at room temperature. After 10 minutes, the solution was concentrated by distillation under reduced pressure and hexane was added thereto, followed by washing with a saturated NaHCO3 aqueous solution. After extraction with hexane twice, the organic layer was dried over anhydrous MgSO4, filtered, concentrated and then dried under vacuum to afford the title compound.
Reaction SMILES: C(Cl)(=O)C(Cl)=O.CS(C)=O.[CH2:11]([Sn:15]([CH2:24][CH2:25][CH2:26][CH3:27])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:16]=[CH:17]/[CH2:18][OH:19])[CH2:12][CH2:13][CH3:14].C(N(CC)CC)C>C(Cl)Cl.CCOCC>[CH2:24]([Sn:15]([CH2:11][CH2:12][CH2:13][CH3:14])([CH2:20][CH2:21][CH2:22][CH3:23])/[CH:16]=[CH:17]/[CH:18]=[O:19])[CH2:25][CH2:26][CH3:27]
Reactant: CCCC[Sn](/C=C/CO)(CCCC)CCCC
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: CS(C)=O
Product: CCCC[Sn](/C=C/C=O)(CCCC)CCCC
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A solution of oxalyl chloride (17.3 ml) in anhydrous methylene chloride (62 ml) is cooled to -78° C. and dimethylsulfoxide (3.7 ml) is added dropwise. The mixture is stirred for 15 minutes, E-3-tributylstannyl-2-propen-1-ol (10.7 g) in methylene chloride (26 ml) added dropwise, stirred for about 10 minutes, and triethylamine (19.4 ml) added. Stirring is stopped, the mixture allowed to warm to room temperature, then stirred for about 5 minutes, diluted with ether, and washed with water. The organic solution is dried over magnesium sulfate, filtered and concentrated in vacuo. The crude product is purified by flash chromatography to give the desired product.
Reaction SMILES: [O:1]([C:8]1[C:9]([NH:18][C:19]([NH2:21])=[S:20])=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:16])[F:15])[CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.Br.[C:32]([N:35]1[CH2:40][CH2:39][CH:38]([C:41](=O)[CH2:42]Br)[CH2:37][CH2:36]1)(=[O:34])[CH3:33]>C(O)C.C(OCC)(=O)C>[O:1]([C:8]1[C:9]([NH:18][C:19]2[S:20][CH:42]=[C:41]([CH:38]3[CH2:39][CH2:40][N:35]([C:32](=[O:34])[CH3:33])[CH2:36][CH2:37]3)[N:21]=2)=[N:10][CH:11]=[C:12]([C:14]([F:17])([F:15])[F:16])[CH:13]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)N1CCC(C(=O)CBr)CC1
Reactant: NC(=S)Nc1ncc(C(F)(F)F)cc1Oc1ccccc1
Agent: Br
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Solvent: CCOC(C)=O
Product: CC(=O)N1CCC(c2csc(Nc3ncc(C(F)(F)F)cc3Oc3ccccc3)n2)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 57.8 %

Procedure:
1-(3-phenoxy-5-(trifluoromethyl)pyridin-2-yl)thiourea (0.076 g, 0.243 mmol) was suspended in ethanol (3 mL) and diisopropylethylamine (0.127 mL, 0.728 mmol) was added, followed by 1-(1-acetylpiperidin-4-yl)-2-bromoethanone hydrobromide (0.120 g, 0.364 mmol). The mixture was heated to 60° C. and agitated for 3 hours, then diluted with ethyl acetate, washed with sodium bicarbonate, brine, dried and evaporated. The crude product was purified on silica gel (30% ethyl acetate/hexanes) to afford 1-(4-(2-(3-phenoxy-5-(trifluoromethyl)pyridin-2-ylamino)thiazol-4-yl)piperidin-1-yl)ethanone (0.065 g, 57.9% yield) as white solid. 1H NMR (d6-DMSO) δ 1.45-1.61 (m, 2H), 1.93-2.04 (m, 2H), 2.51-3.18 (m, 3H), 3.90 (d, 1H), 4.44 (d, 1H), 6.97 (s, 1H), 7.20-7.50 (m, 6H), 8.59 (s, 1H).
Reaction SMILES: [O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][N:18](C(OC(C)(C)C)=O)[CH2:17][CH2:16]1.[ClH:33].C(OCC)(=O)C>C(O)C>[ClH:33].[O:1]=[C:2]1[CH:11]=[CH:10][C:9]2[C:4](=[CH:5][N:6]=[CH:7][CH:8]=2)[N:3]1[CH2:12][CH2:13][CH2:14][C:15]1([C:28]([O:30][CH2:31][CH3:32])=[O:29])[CH2:20][CH2:19][NH:18][CH2:17][CH2:16]1
Reactant: CCOC(=O)C1(CCCn2c(=O)ccc3ccncc32)CCN(C(=O)OC(C)(C)C)CC1
Agent: Cl
Solvent: CCO
Solvent: CCOC(C)=O
Product: CCOC(=O)C1(CCCn2c(=O)ccc3ccncc32)CCNCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of 0.50 g of 1-tert-butyl 4-ethyl 4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-1,4-dicarboxylate in 3 mL of ethanol, 3.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution was added, and the mixture was stirred at room temperature for 1 hour. Thereto was added 2.0 mL of a 4.0 mol/L hydrogen chloride/ethyl acetate solution, and the mixture was stirred at room temperature for 1 hour. The solid was filtered off to obtain 0.29 g of ethyl 4-(3-(2-oxo-1,7-naphthyridin-1(2H)-yl)propyl)piperidine-4-carboxylate hydrochloride as a light yellow solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([C:8]([F:11])([F:10])[F:9])[CH:5]=[C:4]([Cl:12])[C:3]=1[N:13]1[C:21]2[C:16](=[CH:17][CH:18]=[C:19]([OH:22])[CH:20]=2)[CH:15]=[N:14]1.C(N(CC)CC)C.[CH3:30][O:31][C:32](Cl)=[O:33].O>ClCCl>[C:32](=[O:33])([O:22][C:19]1[CH:20]=[C:21]2[C:16]([CH:15]=[N:14][N:13]2[C:3]2[C:2]([Cl:1])=[CH:7][C:6]([C:8]([F:10])([F:9])[F:11])=[CH:5][C:4]=2[Cl:12])=[CH:17][CH:18]=1)[O:31][CH3:30]
Reactant: COC(=O)Cl
Reactant: Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: COC(=O)Oc1ccc2cnn(-c3c(Cl)cc(C(F)(F)F)cc3Cl)c2c1
Yield: 94.2 %

Procedure:
To a solution of 1-(2,6-dichloro-4-trifluoromethylphenyl)-6-hydroxyindazole [Compound No. 80] (10 g) in dichloromethane (30 ml), triethylamine (5 g) and methoxycarbonyl chloride (7 g) were added, and the resultant mixture was refluxed for 3 hours. After completion of the reaction, the reaction mixture was poured into water and extracted with diethyl ether. The extract was washed with water, dried over magnesium sulfate and concentrated under reduced pressure. The residue was purified by silica gel column chromatography with hexane-ethyl acetate (4:1) to give methyl 1-(2,6-dichloro-4-trifluoromethylphenyl)indazol-6-yl carbonate (11 g).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[CH:6]2.Cl.Cl[CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2.[Li+].[OH-]>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9]([CH2:15][CH2:16][CH3:17])=[N:8][C:7]([OH:18])=[C:6]2[CH2:21][C:22]1[C:23]([NH:34][CH2:35][CH2:36][O:37][CH3:38])=[N:24][C:25]2[C:30]([CH:31]=1)=[CH:29][C:28]([O:32][CH3:33])=[CH:27][CH:26]=2
Reactant: CCCc1nc(O)cc2cc(OC)c(OC)cc12
Reactant: COCCNc1nc2ccc(OC)cc2cc1CCl
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CCCc1nc(O)c(Cc2cc3cc(OC)ccc3nc2NCCOC)c2cc(OC)c(OC)cc12
Temperature: 25 °C

Procedure:
To a solution of 6,7-dimethoxy-1-propylisoquinolin-3-ol RBO 35134 (312 mg, 1.3 mmol) in THF (13 mL) in a 20 mL microwave vial equipped with a magnetic stirrer were added 3-(chloromethyl)-6-methoxy-N-(2-methoxyethyl)quinolin-2-amine hydrochloride SLA 47064B (400 mg, 1.3 mmol) and a 2 N aq. LiOH solution (1.26 mL, 2.52 mmol) and the mixture was stirred at 160° C. for 1.5 h under microwave irradiation. After cooling to room temperature, THF was removed at 40° C. under vacuum and the residue was then taken up in CH2Cl2 (50 mL), washed with brine (10 mL), dried over Na2SO4, filtered, and concentrated under vacuum. Purification by column chromatography (SiO2, eluent CH3CN:H2O:TFA=100:0:0.05 to 50:50:0.05) gave 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol. This free base was dissolved in MeOH (2 mL) in a 10 mL round-bottomed flask equipped with a magnetic stirrer before addition of a 0.149 M HCl solution in MeOH (2.0 mL). The reaction mixture was stirred for 5 min at room temperature and concentrated at 40° C. under vacuum to afford 6,7-dimethoxy-4-((6-methoxy-2-(2-methoxyethylamino)quinolin-3-yl)methyl)-1-propylisoquinolin-3-ol dihydrochloride 76 as a brown solid (39.5 mg, 5% yield).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[CH:17][C:14]3=[N:15][CH:16]=2)[CH:6]=[C:7]([O:9][CH3:10])[CH:8]=1.[I:20]N1C(=O)CCC1=O>C(Cl)Cl>[CH3:10][O:9][C:7]1[CH:6]=[C:5]([C:11]2[CH:12]=[C:13]3[NH:19][N:18]=[C:17]([I:20])[C:14]3=[N:15][CH:16]=2)[CH:4]=[C:3]([O:2][CH3:1])[CH:8]=1
Reactant: O=C1CCC(=O)N1I
Reactant: COc1cc(OC)cc(-c2cnc3cn[nH]c3c2)c1
Solvent: ClCCl
Product: COc1cc(OC)cc(-c2cnc3c(I)n[nH]c3c2)c1
Yield: 94.4 %

Procedure:
At r.t. to a solution of 6-(3,5-dimethoxyphenyl)-1H-pyrazolo[4,3-b]pyridine (0.38 g, 1.5 mmol) in methylene chloride (5 mL) was added N-iodosuccinimide (0.352 g, 1.56 mmol) with stirring. The mixture was stirred at r.t. overnight. Then the solvent was removed, the residue was treated with methanol. The solid was collected by filtration to afford the desired product (0.54 g) which was directly used in next step reaction without further purification. LCMS (M+H)+=382.1.