Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:13]=[CH:12][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:10][CH:9]=1)[NH2:6].[Cl:26][C:27]1[CH:35]=[CH:34][CH:33]=[C:32]([Cl:36])[C:28]=1[C:29](Cl)=[O:30].C(N(C(C)C)CC)(C)C>ClCCl>[CH3:2][O:3][C:4](=[O:25])[C@H:5]([CH2:7][C:8]1[CH:9]=[CH:10][C:11]([C:14]2[C:15](=[O:24])[N:16]([CH3:23])[C:17](=[O:22])[N:18]([CH3:21])[C:19]=2[CH3:20])=[CH:12][CH:13]=1)[NH:6][C:29]([C:28]1[C:27]([Cl:26])=[CH:35][CH:34]=[CH:33][C:32]=1[Cl:36])=[O:30]
Reactant: COC(=O)[C@@H](N)Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COC(=O)[C@H](Cc1ccc(-c2c(C)n(C)c(=O)n(C)c2=O)cc1)NC(=O)c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 0.02 h
Yield: 92.8 %

Procedure:
To a suspension of 4-(1,3,6-trimethyl-2,4-dioxo-5-pyrirnidinyl)-L-phenylalanine methyl ester hydrochloride salt (3.12 mmol, 1.15 g) and 2,6-dichlorobenzoyl chloride (3.51 mmol, 0.735 g) in dichloromethane (40 mL) was added diisopropylethylamine (9.36 mmol, 1.63 mL) at room temperature. After 1 min, everything went into solution and the clear yellow solution was stirred for 20 h at room temperature. The resulting brown solution was diluted with dichloromethane (50 mL). The dichloromethane layer was washed successively with 1N hydrochloric acid (2×50 mL), saturated sodium bicarbonate solution (50 mL), and brine solution (50 mL) and was dried over anhydrous magnesium sulfate. Filtration of the drying agent and concentration of the solvent gave the crude product which was purified by silica gel chromatography using a Biotage (40m) column to afford 1.46 g (93% yield) of N-[(2,6-dichlorophenyl)carbonyl]-4-(1,3,6-trimethyl-2,4-dioxo-5-pyrimidinyl)-L-phenylalanine methyl ester as an amorphous white solid. FAB-HRMS m/e calcd for C24H23Cl2N3O5 (M+H) 504.1093, found 504.1083.
Reaction SMILES: [CH3:1][C@@H:2]([C@@H:8]1[C@@:12]2([CH3:27])[CH2:13][CH2:14][C@@H:15]3[C@@:20]4([CH3:26])[CH2:21][CH2:22][C@@H:23](O)[CH2:24][C@H:19]4[CH2:18][CH2:17][C@H:16]3[C@@H:11]2[CH2:10][CH2:9]1)[CH2:3][CH2:4][C:5]([OH:7])=[O:6]>C(OC(=O)C)(=O)C>[C:5]([OH:7])(=[O:6])[CH2:4][CH2:3][C@H:2]([C@@H:8]1[C@:12]2([CH3:27])[C@H:11]([C@H:16]3[C@H:15]([CH2:14][CH2:13]2)[C@:20]2([CH3:26])[CH:19]([CH2:24][CH2:23][CH2:22][CH2:21]2)[CH2:18][CH2:17]3)[CH2:10][CH2:9]1)[CH3:1]
Reactant: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CC[C@@H]4C[C@H](O)CC[C@]4(C)[C@H]3CC[C@]12C
Solvent: CC(=O)OC(C)=O
Product: C[C@H](CCC(=O)O)[C@H]1CC[C@H]2[C@@H]3CCC4CCCC[C@]4(C)[C@H]3CC[C@]12C
Yield: 50 %

Procedure:
A solution of 1 g of the lithocholic acid dimer prepared by the inventors, viz. bis(5(-cholan-24-oic-3(-yl) sebacate, in 6 ml of acetic anhydride was heated to 120° C. in an oil bath for 1 h. The solvent was partially removed and the mixed anhydride prepolymer was allowed to crystallize at -10° C. The product was filtered out, washed with a small amount of cold acetic anhydride and dried under vacuum at room temperature for two days. The requested bis (5(-cholan-24-oic acid 3(-yl) sebacate prepolymer (PreLCA) was obtained with a yield of 50%.
Reaction SMILES: [O:1]=[C:2]([CH2:9][CH3:10])[CH2:3][C:4]([O:6][CH2:7][CH3:8])=[O:5].[H-].[Na+].II.[OH2:15]>O1CCCC1>[C:2]([CH:3]([CH:3]([C:2](=[O:1])[CH2:9][CH3:10])[C:4]([O:6][CH2:7][CH3:8])=[O:15])[C:4]([O:6][CH2:7][CH3:8])=[O:5])(=[O:1])[CH2:9][CH3:10]
Reactant: CCOC(=O)CC(=O)CC
Reactant: O
Agent: II
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOC(=O)C(C(=O)CC)C(C(=O)CC)C(=O)OCC
Temperature: 25 °C
Reaction time: 1 h
Yield: 91 %

Procedure:
Ethyl 3-oxopentanoate (72 g, 0.5 mol) is added dropwise in a nitrogen atmosphere to a suspension of sodium hydride (0.52 mol) in 300 ml of 1:1 anhydrous ether-tetrahydrofuran. After one hour, a solution of iodine (63.5 g, 0.25 mol) in tetrahydrofuran (150 ml) is added and the resulting mixture stirred at ambient temperature for an additional one hour. Water (250 ml) is added and the phases separated. The ether solution is washed with two 50 ml portions of sodium sulfite and dried over sodium sulfate. Removal of the solvent affords 66 g (91%) of diethyl α,β-dipropionylsuccinate. Recrystallization from hexane gives 29 g of solid dimer, mp 80-83 C; IR (CHCl3) 1755, 1730 cm-1 ; NMR (CDCl3) 1.1 (t,6H), 1.3 (t,6H), 2.83 (d of q,4H), 4.18 (q,4H), 4.5 (s,2H).
Reaction SMILES: CN1CCC[C@@H]1C=O.[C:9]([N:16]1[CH2:18][CH:17]1[C:19](O)=[O:20])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]>>[C:9]([N:16]1[CH2:18][CH:17]1[CH:19]=[O:20])([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10]
Reactant: CC(C)(C)OC(=O)N1CC1C(=O)O
Agent: CN1CCC[C@@H]1C=O
Product: CC(C)(C)OC(=O)N1CC1C=O

Procedure:
The title compound was prepared following the procedure described in Intermediate 138 using 1-BOC-aziridine-2-carboxylic acid.
Reaction SMILES: CO/[N:3]=[C:4]1/[C:5](=O)[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[C:7]([CH3:10])([CH3:9])[CH2:8]/1.[H-].[H-].[H-].[H-].[Li+].[Al+3]>C1COCC1>[CH3:9][C:7]1([CH3:10])[N:6]([CH2:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[CH2:5][CH:4]([NH2:3])[CH2:8]1
Reactant: CO/N=C1\CC(C)(C)N(Cc2ccccc2)C1=O
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CC1(C)CC(N)CN1Cc1ccccc1
Temperature: 70 °C
Reaction time: 6.5 h
Yield: 90.8 %

Procedure:
To a 0° C. solution of (3E)-5,5-dimethyl-1-(phenylmethyl)-2,3-pyrrolidinedione 3-(O-methyloxime) (4.2872 g, 17.41 mmol) in THF (90 mL) was added LiAlH4 (2.64 g, 69.57 mmol) portionwise. The mixture was heated at 70° C. and stirred for 6.5 h. The mixture was then cooled to room temperature and quenched by addition of Na2SO4.10H2O (3 g), followed by 1 N aq. NaOH (100 mL). The mixture was extracted with Et2O (2×150 mL), and the combined organic phase was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo. The residue was diluted with DCM (200 mL), and the mixture was dried over anhydrous Na2SO4, filtered, and concentrated in vacuo to give crude racemic 5,5-dimethyl-1-(phenylmethyl)-3-pyrrolidinamine (3.2293 g, 86%) as a light yellow oil. LCMS: (M+H)+: 205.2.
Reaction SMILES: [OH:1][C:2]1[C:10]2[O:9][C:8]([CH2:11][C:12]3[CH:17]=[CH:16][C:15]([O:18][CH3:19])=[CH:14][CH:13]=3)=[C:7]([CH3:20])[C:6]=2[CH:5]=[C:4]([CH3:21])[C:3]=1[CH3:22].N(S([O-])(=O)=O)(S([O-])(=O)=[O:26])[O].[K+].[K+]>CC(C)=O.OP([O-])(O)=O.[K+]>[CH3:19][O:18][C:15]1[CH:16]=[CH:17][C:12]([CH2:11][C:8]2[O:9][C:10]3[C:2](=[O:1])[C:3]([CH3:22])=[C:4]([CH3:21])[C:5](=[O:26])[C:6]=3[C:7]=2[CH3:20])=[CH:13][CH:14]=1
Reactant: [O]N(S(=O)(=O)[O-])S(=O)(=O)[O-]
Reactant: COc1ccc(Cc2oc3c(O)c(C)c(C)cc3c2C)cc1
Agent: O=P([O-])(O)O
Agent: [K+]
Solvent: CC(C)=O
Product: COc1ccc(Cc2oc3c(c2C)C(=O)C(C)=C(C)C3=O)cc1
Temperature: 45 °C

Procedure:
A solution of 7-hydroxy-2-(4-methoxybenzyl)-3,5,6-trimethylbenzofuran from Step 4 (8.6g, 29 mmol) in acetone (1.5 L) was added rapidly to a solution of potassium nitrosodisulfonate (Fremy's salt) (25 g, 93 mmol) in 0.055M KH2PO4 buffer (1.5 L) at room temperature. The reaction was slowly heated to 45° C. over a period of 2 hr. The reaction was then cooled and the quinoline was extracted with EtOAc (2x, 500 mL). Evaporation of the organic solvent gave a solid residue which was crystallized and re-crystallized from EtOH, to give the title compound, mp 111°-113° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17](F)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8].[N:23]1[CH:28]=[CH:27][CH:26]=[C:25]([CH2:29][NH2:30])[CH:24]=1>>[Br:1][C:2]1[CH:3]=[C:4]([NH:9][C:10]2[C:19]3[C:14](=[CH:15][N:16]=[C:17]([NH:30][CH2:29][C:25]4[CH:24]=[N:23][CH:28]=[CH:27][CH:26]=4)[CH:18]=3)[N:13]=[CH:12][C:11]=2[C:21]#[N:22])[CH:5]=[CH:6][C:7]=1[CH3:8]
Reactant: NCc1cccnc1
Reactant: Cc1ccc(Nc2c(C#N)cnc3cnc(F)cc23)cc1Br
Product: Cc1ccc(Nc2c(C#N)cnc3cnc(NCc4cccnc4)cc23)cc1Br
Yield: 14 %

Procedure:
Following the procedure described above in Example 1, 4-[(3-bromo-4-methylphenyl)amino]-6-fluoro-[1,7]naphthyridine-3-carbonitrile (300 mg, 1.1 mmol, 1 eq) was reacted with pyridine-3-ylmethylamine (2.8 mL, 20 eq). The crude product was purified via preparative HPLC to obtain 55 mg product (14% yield): HRMS (ESI+) calcd for C22H17BrN6 445.0771 (M+H), found (M+H) 445.0761.
Reaction SMILES: O.[CH3:2][O:3][C:4]1[CH:5]=[C:6]2[C:10](=[CH:11][C:12]=1[O:13][CH3:14])[C:9](=[O:15])[C:8](=O)[C:7]2=[O:17].Cl.[C:19]1([NH:25][C:26](=[O:29])[NH:27][NH2:28])[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1>>[OH2:3].[CH3:14][O:13][C:12]1[CH:11]=[C:10]2[C:6](=[CH:5][C:4]=1[O:3][CH3:2])[C:7](=[O:17])[C:8](=[N:28][NH:27][C:26]([NH:25][C:19]1[CH:20]=[CH:21][CH:22]=[CH:23][CH:24]=1)=[O:29])[C:9]2=[O:15]
Reactant: NNC(=O)Nc1ccccc1
Reactant: COc1cc2c(=O)c(=O)c(=O)c2cc1OC
Agent: Cl
Solvent: O
Product: COc1cc2c(=O)c(=NNC(=O)Nc3ccccc3)c(=O)c2cc1OC

Procedure:
5,6-dimethoxyindan-1,2,3-trione, monohydrate, 4-phenyl semicarbazide hydrochloride
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18])[CH:5]=[O:6].C(O)C.[BH4-].[Na+]>O1CCCC1>[Br:1][C:2]1[CH:3]=[C:4]([CH2:5][OH:6])[CH:7]=[CH:8][C:9]=1[O:10][C:11]1[CH:16]=[CH:15][C:14]([F:17])=[CH:13][C:12]=1[F:18]
Reactant: O=Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCO
Product: OCc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 98.4 %

Procedure:
To a solution of Example 287a (3.76 g, 12 mmol) in the mixture of ethanol (10 mL) and tetrahydrofuran (10 mL) was added sodium borohydride (0.136 g, 3.60 mmol). The reaction mixture was stirred at ambient temperature for 1 hour. The solvent was evaporated and the residue was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride, dried with anhydrous sodium sulfate, filtered, and concentrated to provide the title compound (3.72 g, 98%).
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:39]=[CH:38][CH:37]=[CH:36][CH:35]=2)[O:11][C:10]1=[O:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Br[C:42]1[CH:47]=[C:46]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)[C:45]([Cl:57])=[CH:44][C:43]=1[O:58][CH3:59].[Li]CCCC>C1COCC1>[CH2:1]([O:8][C@@H:9]1[C@@H:14]([O:15][CH2:16][C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)[C@H:13]([O:23][CH2:24][C:25]2[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=2)[C@@H:12]([CH2:31][O:32][CH2:33][C:34]2[CH:35]=[CH:36][CH:37]=[CH:38][CH:39]=2)[O:11][C@:10]1([C:42]1[CH:47]=[C:46]([CH2:48][C:49]2[CH:54]=[CH:53][C:52]([CH2:55][CH3:56])=[CH:51][CH:50]=2)[C:45]([Cl:57])=[CH:44][C:43]=1[O:58][CH3:59])[OH:40])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCc1ccc(Cc2cc(Br)c(OC)cc2Cl)cc1
Reactant: O=C1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: CCc1ccc(Cc2cc([C@]3(O)O[C@H](COCc4ccccc4)[C@@H](OCc4ccccc4)[C@H](OCc4ccccc4)[C@H]3OCc3ccccc3)c(OC)cc2Cl)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 64.3 %

Procedure:
To a solution of (3R,4S,5R,6R)-3,4,5-tris(benzyloxy)-6-(benzyloxymethyl)tetrahydro-2H-pyran-2-one 5 (1.10 g, 2.04 mmol) and 1-bromo-4-chloro-5-(4-ethylbenzyl)-2-methoxybenzene 22 (0.60 g, 1.77 mmol) in anhydrous THF (20 mL) at −78° C. was added a solution of n-BuLi (0.78 mL, 1.94 mmol, 2.5 M). The mixture was stirred for 1 h, warmed to ambient temperature, quenched with 10% sodium carbonate (100 mL), and extracted with ethyl acetate (2×50 mL). The organic phase was dried with anhydrous MgSO4, filtered, and evaporated to dryness. The residue was purified by silica gel column chromatography using 15-25% ethyl acetate in petroleum ether to give 23 (0.91 g, 64%). LC/MS m/z 822 (M+Na), 782 (M−OH).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](F)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1.[CH3:11][N:12]1[CH2:17][CH2:16][N:15]([C:18]2[CH:24]=[CH:23][C:21]([NH2:22])=[CH:20][CH:19]=2)[CH2:14][CH2:13]1.C(N(CC)CC)C>C(O)(C)C>[Br:1][C:2]1[CH:3]=[C:4]([NH:22][C:21]2[CH:20]=[CH:19][C:18]([N:15]3[CH2:14][CH2:13][N:12]([CH3:11])[CH2:17][CH2:16]3)=[CH:24][CH:23]=2)[C:5]([C:8]#[N:9])=[N:6][CH:7]=1
Reactant: N#Cc1ncc(Br)cc1F
Reactant: CN1CCN(c2ccc(N)cc2)CC1
Solvent: CCN(CC)CC
Solvent: CC(C)O
Product: CN1CCN(c2ccc(Nc3cc(Br)cnc3C#N)cc2)CC1

Procedure:
A solution of 5-bromo-3-fluoropicolinonitrile (1 g, 5 mmol), from EXAMPLE 49A, and 4-(4-methylpiperazin-1-yl)aniline (1.24 g, 6.5 mmol) in isopropanol (15 mL) was treated with triethylamine (0.76 mL, 7.5 mmol) was subjected to microwave irradiation (Biotage, Initiator) at 180° C. for 2 hours. The reaction mixture was concentrated and purified on silica gel with 2-25% methanol in dichloromethane to afford the title compound.
Reaction SMILES: [C:1]([NH:4][C:5]1[S:6][C:7]([C:11]2[S:15][C:14]([S:16](Cl)(=[O:18])=[O:17])=[CH:13][CH:12]=2)=[C:8]([CH3:10])[N:9]=1)(=[O:3])[CH3:2].[CH3:20][N:21]1[CH2:26][CH2:25][NH:24][CH2:23][CH2:22]1.CCN(C(C)C)C(C)C.O>C(Cl)Cl>[CH3:10][C:8]1[N:9]=[C:5]([NH:4][C:1](=[O:3])[CH3:2])[S:6][C:7]=1[C:11]1[S:15][C:14]([S:16]([N:24]2[CH2:25][CH2:26][N:21]([CH3:20])[CH2:22][CH2:23]2)(=[O:18])=[O:17])=[CH:13][CH:12]=1
Reactant: CN1CCNCC1
Reactant: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)Cl)s2)s1
Solvent: ClCCl
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)Nc1nc(C)c(-c2ccc(S(=O)(=O)N3CCN(C)CC3)s2)s1
Reaction time: 4 h

Procedure:
5-[2-(acetylamino)-4-methyl-1,3-thiazol-5-yl]thiophene-2-sulfonyl chloride, prepared as in Step II of Example 1 (280 mg; 0.84 mmol; 1 eq), is dissolved in DCM (10 ml). N-Methyl piperazine (8.4 ml; 8.4 mmol; 10 eq) and DIEA (0.17 ml; 0.98 mmol; 3 eq) are added. After four hours, water (1 ml) is added and the solvents are evaporated to dryness. The crude product is re-dissolved in DCM and washed with NH4Cl saturated solution, water and dried over MgSO4. After evaporation of the solvents, crude material is precipitated in a mixture of DCM and diethyl ether, affording after filtration, Compound (8) as a white solid (173 mg; 51%).
Reaction SMILES: [C:1]([C:5]1[CH:6]=[C:7]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([C@@H:50]5[CH2:54][CH2:53][CH2:52][N:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][O:19]C3CCCCO3)[CH:11]=2)[N:9]=1)([CH3:4])([CH3:3])[CH3:2].C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>CO.C([O-])(O)=O.[Na+]>[C:1]([C:5]1[CH:6]=[C:7]([NH:26][C:27]([NH:29][C@@H:30]2[C:39]3[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=3)[C@H:33]([O:40][C:41]3[CH:42]=[CH:43][C:44]4[N:45]([C:47]([C@@H:50]5[CH2:54][CH2:53][CH2:52][N:51]5[CH3:55])=[N:48][N:49]=4)[CH:46]=3)[CH2:32][CH2:31]2)=[O:28])[N:8]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([O:16][CH2:17][CH2:18][OH:19])[CH:11]=2)[N:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCOC5CCCCO5)c4)c4ccccc43)cn12
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CN1CCC[C@H]1c1nnc2ccc(O[C@@H]3CC[C@H](NC(=O)Nc4cc(C(C)(C)C)nn4-c4cccc(OCCO)c4)c4ccccc43)cn12
Temperature: 25 °C
Reaction time: 15 h

Procedure:
A mixture of Intermediate 42a (230 mg, 0.300 mmol) and pyridinium p-toluenesulfonate (226 mg, 0.900 mmol) in MeOH (3 mL) was stirred at RT for 15 h. Pyridinium p-toluenesulfonate (113 mg, 0.450 mmol) was added and the mixture stirred at 50-55° C. for 8 h. The cooled mixture was diluted with sat. aq. NaHCO3 solution and extracted with DCM (3×15 mL). The combined organics were dried and concentrated in vacuo. The residue was purified by FCC, using 0-14% MeOH in DCM, to give the title compound as a white powder after freeze-drying (163 mg, 82%). LCMS (Method 5): Rt 3.33 min, m/z 665.3 [MH+]. 1H NMR (400 MHz, d6-DMSO): 1.28 (9H, s), 1.82-2.27 (11H, m), 2.31-2.39 (1H, m), 3.10-3.17 (1H, m), 3.71 (2H, q, J 5.1), 3.96-4.05 (3H, m), 4.79-4.89 (2H, m), 5.37-5.41 (1H, m), 6.34 (1H, s), 6.95-6.99 (1H, m), 7.05-7.15 (3H, m), 7.24-7.43 (6H, m), 7.75 (1H, d, J 9.9), 8.11 (1H, s), 8.25 (1H, br d).
Reaction SMILES: [F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[CH:4][C:3]=1[C:9]([CH3:24])([CH3:23])[C:10]([CH:12]([C:18]([O:20]CC)=O)[C:13]([O:15][CH2:16][CH3:17])=[O:14])=[O:11]>OS(O)(=O)=O>[F:1][C:2]1[C:7]([OH:8])=[CH:6][CH:5]=[C:4]2[C:3]=1[C:9]([CH3:24])([CH3:23])[C:10](=[O:11])[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[C:18]2[OH:20]
Reactant: CCOC(=O)C(C(=O)OCC)C(=O)C(C)(C)c1cccc(O)c1F
Agent: O=S(=O)(O)O
Product: CCOC(=O)C1=C(O)c2ccc(O)c(F)c2C(C)(C)C1=O
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.6 %

Procedure:
To 20 mL concentrated H2SO4 stirred at room temperature, was added diethyl 2-(2-(2-fluoro-3-hydroxyphenyl)-2-methylpropanoyl)malonate (3.6 g, 11 mmol). The mixture was stirred at room temperature for 2 hours, M+1=295. The mixture was then poured into 100 g crushed ice and extracted with EtOAc (3×50 mL). The combined organic layers were washed with brine (20 mL), dried over anhydrous Na2SO4, concentrated in vacuo, and purified by column chromatography eluting with 10-30% EtOAc/hexane to give 2.9 g of the title compound as a pale yellow solid. MS (m/z)=295 (M+H)+.
Reaction SMILES: [O:1]=[C:2]1[CH2:7][CH:6]([CH2:8][NH:9][C:10]2[CH:11]=[CH:12][C:13]3[N:14]([C:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)=[CH:17][N:18]=3)[N:15]=2)[CH2:5][CH2:4][N:3]1C(OC(C)(C)C)=O.C(O)(C(F)(F)F)=O>C(Cl)Cl>[F:28][C:26]([F:27])([F:29])[O:25][C:21]1[CH:20]=[C:19]([C:16]2[N:14]3[N:15]=[C:10]([NH:9][CH2:8][CH:6]4[CH2:5][CH2:4][NH:3][C:2](=[O:1])[CH2:7]4)[CH:11]=[CH:12][C:13]3=[N:18][CH:17]=2)[CH:24]=[CH:23][CH:22]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CC1=O
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CC(CNc2ccc3ncc(-c4cccc(OC(F)(F)F)c4)n3n2)CCN1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 6.4 %

Procedure:
A solution of compound tert-butyl 2-oxo-4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidine-1-carboxylate (114 mg, 0.23 mmol) in CH2Cl2 (10 mL) was added TFA (2 mL). The mixture was stirred at room temperature for 30 min and condensed. The residue was purified by prep-HPLC to give 4-(((3-(3-(trifluoromethoxy)phenyl)imidazo[1,2-b]pyridazin-6-yl)amino)methyl)piperidin-2-one (6 mg, 6.6%) as white solid.
Reaction SMILES: [CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][NH:20][CH2:19][C:17]=3[N:18]=2)=[CH:9][CH:8]=1)=[O:5])[CH3:2].Cl[C:32]1[N:37]=[CH:36][CH:35]=[CH:34][N:33]=1>>[CH2:1]([NH:3][C:4]([NH:6][C:7]1[CH:8]=[CH:9][C:10]([C:13]2[N:14]=[C:15]([N:23]3[CH2:28][CH2:27][O:26][CH2:25][C@@H:24]3[CH2:29][CH3:30])[C:16]3[CH2:22][CH2:21][N:20]([C:32]4[N:37]=[CH:36][CH:35]=[CH:34][N:33]=4)[CH2:19][C:17]=3[N:18]=2)=[CH:11][CH:12]=1)=[O:5])[CH3:2]
Reactant: Clc1ncccn1
Reactant: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCNC3)cc1
Product: CCNC(=O)Nc1ccc(-c2nc3c(c(N4CCOC[C@@H]4CC)n2)CCN(c2ncccn2)C3)cc1

Procedure:
Compound gs was synthesized using the general procedure described in Example 2 by reacting (S)-1-ethyl-3-(4-(4-(3-ethylmorpholino)-5,6,7,8-tetrahydropyrido[3,4-d]pyrimidin-2-yl)phenyl)urea with 2-chloropyrimidine: LC-MS: m/z=+489 (M+H)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[N:4][CH:5]=[C:6]([OH:8])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH:16]([CH2:26][O:27][CH3:28])[C:17]([NH:19][C:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23])=[O:18].O>CN(C)C=O.C(OCC)C>[Cl:1][C:2]1[CH:7]=[C:6]([O:8][CH:16]([CH2:26][O:27][CH3:28])[C:17]([NH:19][C:20]([CH3:25])([CH3:24])[C:21]#[C:22][CH3:23])=[O:18])[CH:5]=[N:4][CH:3]=1
Reactant: Oc1cncc(Cl)c1
Reactant: CC#CC(C)(C)NC(=O)C(Br)COC
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: CN(C)C=O
Solvent: O
Product: CC#CC(C)(C)NC(=O)C(COC)Oc1cncc(Cl)c1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
3-Chloro-5-hydroxypyridine (0.074 g), anhydrous potassium carbonate (0.087 g) and 2-bromo-N-(4-methylpent-2-yn-4-yl)-3-methoxypropionamide (0.150 g) in dry N,N-dimethylformamide (3 ml) were stirred at 80° C. for 5 hours. The mixture was allowed to cool to ambient temperature and stored for 2 days. The mixture was poured into water, extracted with ethyl acetate and the organic phases were combined, washed with water, dried over magnesium sulphate and evaporated under reduced pressure to a gum. The gum was fractionated by chromatography (silica; ethyl acetate:hexane, 2:3 by volume) to give a colourless gum that was dissolved in diethyl ether and extracted with aqueous hydrochloric acid (3M). The aqueous acidic fraction was collected and treated with potassium carbonate until basic then extracted with diethyl ether. The ether extracts were combined, dried over magnesium sulphate and evaporated under reduced pressure to give the required product, 0.094 g, as a colourless gum.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[NH:12][C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2].[Br:21][C:22]1[CH:23]=[C:24]2[C:28](=[C:29]([CH2:31][N+](C)(C)C)[CH:30]=1)[N:27]([CH3:36])[CH:26]=[CH:25]2.[I-].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C.O>[CH2:1]([O:3][C:4](=[O:20])[CH2:5][CH:6]([N:10]1[C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][C:13]=2[N:12]([CH2:31][C:29]2[CH:30]=[C:22]([Br:21])[CH:23]=[C:24]3[C:28]=2[N:27]([CH3:36])[CH:26]=[CH:25]3)[C:11]1=[O:19])[CH2:7][CH2:8][CH3:9])[CH3:2]
Reactant: CCCC(CC(=O)OCC)n1c(=O)[nH]c2ccccc21
Reactant: Cn1ccc2cc(Br)cc(C[N+](C)(C)C)c21
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCCC(CC(=O)OCC)n1c(=O)n(Cc2cc(Br)cc3ccn(C)c23)c2ccccc21
Yield: 55 %

Procedure:
To a solution of 3-(2-Oxo-2,3-dihydro-benzimidazol-1-yl)-hexanoic acid ethyl ester (50 mg, 0.18 mmol) in DMF (10 mL) were added (5-Bromo-1-methyl-1H-indol-7-ylmethyl)-trimethyl-ammonium; iodide (111 mg, 0.27 mmol) and K2CO3 (75 mg, 0.54 mmol) at room temperature under nitrogen atmosphere. The solution was heated to 100 C for 2 hours. The solution was cooled down and water was added. The solution was extracted with EtOAc and the combined organic layer was dried with MgSO4. The solution was filtered and the filtrate was concentrated. The residue was purified by CombiFlash with 20% EtOAc in Hexane as the eluent to afford the desirable product 3-[3-(5-Bromo-1-methyl-1H-indol-7-ylmethyl)-2-oxo-2,3-dihydro-benzimidazol-1-yl]-hexanoic acid ethyl ester (50 mg, 55%) as a colorless foam.
Reaction SMILES: [F:1][C:2]([F:23])([F:22])[C:3]1[CH:21]=[CH:20][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([OH:16])=[O:15])=[CH:10][CH:9]=2)=[CH:5][CH:4]=1.[OH-].[Na+:25]>C(O)C.O>[F:1][C:2]([F:22])([F:23])[C:3]1[CH:4]=[CH:5][C:6]([O:7][C:8]2[CH:19]=[CH:18][C:11]([O:12][CH:13]([CH3:17])[C:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)=[CH:20][CH:21]=1.[Na+:25]
Reactant: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(Oc1ccc(Oc2ccc(C(F)(F)F)cc2)cc1)C(=O)[O-]
Temperature: 90 °C
Yield: 98 %

Procedure:
32.6 g of α-[4-(4-trifluoromethylphenoxy)phenoxy]propionic acid was dissolved in 30 ml of ethanol, and an aqueous solution of 4.0 g of sodium hydroxide in 40 ml of water was added. The mixture was maintained at 70° to 75° C. for 1 hour. Then, ethanol and water were removed from the reaction product at reduced pressure. The residue was heated at 90° C. for 4 hours to afford 34.1 g (yield: 98%) of the final product as a white solid.