Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[S:9][C:10]1[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=1.C([C:19]1[C:20]([N:28]=[CH:29][N:30]([CH3:32])C)=[N:21][C:22]([CH:25]2[CH2:27][CH2:26]2)=[CH:23][CH:24]=1)#N.C(C1C(N=CN(C)C)=NC(C)=CC=1)#N>>[CH:25]1([C:22]2[CH:23]=[CH:24][C:19]3[C:32]([NH:1][C:2]4[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=4[S:9][C:10]4[CH:15]=[CH:14][C:13]([OH:16])=[CH:12][CH:11]=4)=[N:30][CH:29]=[N:28][C:20]=3[N:21]=2)[CH2:26][CH2:27]1
Reactant: Cc1ccc(Sc2ccc(O)cc2)c(N)c1
Reactant: CN(C)C=Nc1nc(C2CC2)ccc1C#N
Agent: Cc1ccc(C#N)c(N=CN(C)C)n1
Product: Cc1ccc(Sc2ccc(O)cc2)c(Nc2ncnc3nc(C4CC4)ccc23)c1

Procedure:
The product from Example 6c was reacted with the product from Example 119A using the procedure from Example 102 substituting the product from Example 119A for the product from Example 10B to provide the crude residue which was purified by trituration with methanol to provide the title compound. 1H NMR (300 MHz, DMSO-D6) δ ppm: 1.05-1.22 (m, J=1.84 Hz, 4H), 2.24-2.39 (m, 1H), 2.29 (s, 3H), 6.73 (d, J=8.82 Hz, 2H), 6.91 (d, J=8.09 Hz, 1H), 7.04 (dd, J=8.09, 1.47 Hz, 1H), 7.17 (d, J=8.82 Hz, 2H), 7.25 (s, 1H), 7.57 (d, J=8.82 Hz, 1H), 8.49 (s, 1H), 8.71 (d, J=8.46 Hz, 1H), 9.74 (s, 1H), 9.92 (s, 1H); MS (ESI)+ m/z 401 (M+H)+.
Reaction SMILES: [CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14](=O)[CH2:15][NH:16][C:17]2[N:18]=[C:19]3[CH:25]=[CH:24][N:23]([S:26]([C:29]4[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=4)(=[O:28])=[O:27])[C:20]3=[N:21][CH:22]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.COC1C=CC(P2(SP(C3C=CC(OC)=CC=3)(=S)S2)=S)=CC=1>>[CH2:1]([N:8]([CH2:38][C:39]1[CH:44]=[CH:43][CH:42]=[CH:41][CH:40]=1)[CH:9]1[CH2:13][CH:12]([C:14]2[N:18]3[C:19]4[CH:25]=[CH:24][N:23]([S:26]([C:29]5[CH:35]=[CH:34][C:32]([CH3:33])=[CH:31][CH:30]=5)(=[O:28])=[O:27])[C:20]=4[N:21]=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]([CH3:37])[CH2:10]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1ccc(S(=O)(=O)n2ccc3nc(NCC(=O)C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)cnc32)cc1
Agent: COc1ccc(P2(=S)SP(=S)(c3ccc(OC)cc3)S2)cc1
Product: Cc1ccc(S(=O)(=O)n2ccc3c2ncc2ncc(C4CC(N(Cc5ccccc5)Cc5ccccc5)CC4C)n23)cc1
Temperature: 60 °C
Reaction time: 1 h
Yield: 86.6 %

Procedure:
A mixture of 1-(4-(dibenzylamino)-2-methylcyclopentyl)-2-(5-tosyl-5H-pyrrolo[2,3-b]pyrazin-2-ylamino)ethanone (5.32 g, 8.75 mmol) and Lawesson's reagent (1.88 g, 4.64 mmol) was heated at about 60° C. for about 2 h. Additional Lawesson's reagent (1.88 g, 4.64 mmol) was added. The reaction mixture was stirred at about 60° C. for about 1 h. The solvent was removed under reduced pressure and the residue was purified by silica gel chromatography eluting with a gradient of 0-8% MeOH in DCM to yield N,N-dibenzyl-3-methyl-4-(3-tosyl-3H-imidazo[1,2-a]pyrrolo[2,3-e]pyrazin-8-yl)cyclopentanamine (4.47 g, 87%) as a brown amorphous solid: LC/MS (Table 1, Method a) Rt=2.99 min; MS m/z 590 (M+H)+.
Reaction SMILES: CO[C:3]([C:5]1[N:6]([CH2:31][CH:32]=O)[CH:7]=[C:8]([C:20](=[O:30])[NH:21][CH2:22][C:23]2[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=2)[C:9](=[O:19])[C:10]=1[O:11]CC1C=CC=CC=1)=[O:4].Cl.Cl.[NH2:36][C@@H:37]([CH3:45])[CH2:38][CH2:39][NH:40][CH:41]1[CH2:44][CH2:43][CH2:42]1.O=C1N2CCCNC2CN2C=C(C(N)=O)C(=O)C(OCC3C=CC=CC=3)=C12>>[CH:41]1([N:40]2[CH2:39][CH2:38][C@H:37]([CH3:45])[N:36]3[C:3](=[O:4])[C:5]4[N:6]([CH:7]=[C:8]([C:20]([NH:21][CH2:22][C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)=[O:30])[C:9](=[O:19])[C:10]=4[OH:11])[CH2:31][C@@H:32]23)[CH2:44][CH2:43][CH2:42]1
Reactant: C[C@H](N)CCNC1CCC1
Reactant: COC(=O)c1c(OCc2ccccc2)c(=O)c(C(=O)NCc2ccc(F)cc2)cn1CC=O
Agent: Cl
Agent: NC(=O)c1cn2c(c(OCc3ccccc3)c1=O)C(=O)N1CCCNC1C2
Product: C[C@H]1CCN(C2CCC2)[C@@H]2Cn3cc(C(=O)NCc4ccc(F)cc4)c(=O)c(O)c3C(=O)N12

Procedure:
In a similar manner to that described in example Z-35a, from 16 (18 mg, 0.39 mmol) and [(3S)-3-Aminobutyl]cyclobutylamine bis-hydrochloride (23 mg, 0.107 mmol), (4S,12aS)-1-cyclobutyl-N-[(4-fluorophenyl)methyl)-4-methyl]-6,8-dioxo-7-[(phenylmethyl)oxy]-1,2,3,4,6,8,12,12a-octahydropyrido[1′,2′:4,5]pyrazino[1,2-a]pyrimidine-9-carboxamide was prepared as a white solid. This material was deprotected in a second step similar to that described in example Z-37 to give the title compound as a white solid after purification by HPLC (4.5 mg, 25% 2 steps). 1H NMR (CDCl3) δ 12.54 (s, 1H), 10.48 (s, 1H), 8.20 (s, 1H), 7.31 (m, 2H), 6.08 (m, 2H), 5.02 (m, 1H), 4.61-4.57 (m, 2H), 4.26-4.14 (m, 3H), 3.05 (m, 1H), 2.90 (m, 1H), 2.49 (m, 1H), 2.12 (m, 1H), 2.05-1.87 (m, 8H), 1.84-1.61 (m, 3H), 1.46 (m, 1H), 1.32 (m, 3H); ES+MS: 455 (M+1).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[NH:9][C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=1[CH2:16][C:17]([OH:19])=[O:18].[C:20]([NH:27][CH2:28][CH2:29]O)([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21].C1CCC(N=C=NC2CCCCC2)CC1>C(Cl)Cl.CN(C1C=CN=CC=1)C>[C:23]([O:22][C:20]([NH:27][CH2:28][CH2:29][O:18][C:17](=[O:19])[CH2:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[NH:9][C:3]1[C:2]([Cl:1])=[CH:7][CH:6]=[CH:5][C:4]=1[Cl:8])=[O:21])([CH3:26])([CH3:25])[CH3:24].[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:10]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[CH2:16][C:17]1=[O:19]
Reactant: O=C(O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Reactant: CC(C)(C)OC(=O)NCCO
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCCOC(=O)Cc1ccccc1Nc1c(Cl)cccc1Cl
Product: O=C1Cc2ccccc2N1c1c(Cl)cccc1Cl
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a stirred solution of [2-(2,6-Dichloro-phenylamino)-phenyl]-acetic acid] 2 (4.0 g, 0.01 mol, 1 eq) and N-BOC-Ethanolamine (2.39 g, 0.01 mol) in DCM (70 mL) was added DMAP (0.16 g, 0.001 mol) at rt. To this mixture was added DCC (5.5 g, 0.02 mol) in DCM (30 mL) drop-wise at 0-5° C. and resulting mixture was stirred at room temperature for 1 h. Reaction was monitored by TLC. After completion, reaction mixture was filtered and the solvent was removed under reduced pressure. Residue was dissolved in water (100 mL) and extracted with DCM (2×50 mL). Combined organic layer was dried over anhydrous Na2SO4 and evaporated under reduced pressure to obtained crude compound which was washed with hexane (2×20 mL), dried to get 6.0 g crude of Compound 4 and cyclized compound 1 as an off white solid. This mixture was used in the next step without any further purification: Mass: 439.3 (M++H).
Reaction SMILES: O.[OH-].[Li+].[CH2:4]([S:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[O:10][C:11]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][C:12]=1[C:13]([O:15]CC)=[O:14])[CH3:5]>O1CCCC1.O>[CH2:4]([S:6][C:7]1[CH:8]=[C:9]([CH:23]=[CH:24][CH:25]=1)[O:10][C:11]1[N:21]=[CH:20][C:19]([F:22])=[CH:18][C:12]=1[C:13]([OH:15])=[O:14])[CH3:5]
Reactant: CCOC(=O)c1cc(F)cnc1Oc1cccc(SCC)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CCSc1cccc(Oc2ncc(F)cc2C(=O)O)c1
Reaction time: 4 h
Yield: 90.5 %

Procedure:
Lithium hydroxide hydrate (1.37 g, 33 mmol) was added to a solution of ethyl 2-[3-(ethylsulfanyl)phenoxy]-5-fluoronicotinate (4.21 g, 13 mmol) in tetrahydrofuran (50 ml) and water (30 ml). The mixture was stirred for 4 h, then the volatile solvent was removed under reduced pressure and the residue partitioned between diethyl ether and 2N hydrochloric acid. The organic phase was washed with water, dried over MgSO4 and the solvent removed under reduced pressure. The residue was purified by flash column chromatography using dichloromethane:methanol:acetic acid (95:5:0.5) as eluant to give 2-[3-(ethylsulfanyl)phenoxy]-5-fluoronicotinic acid (3.45 g) as a white solid.
Reaction SMILES: C(O)(=O)[C@@H]([C@H](C(O)=O)O)O.[CH2:11]([O:13][C:14](=[O:32])[C:15]([CH3:31])([O:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][NH:26][CH2:25]2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH3:16])[CH3:12].CN(C)CCCN=C=NCC.[CH3:44][C:45]1[N:46]=[C:47]([C:53]2[CH:58]=[CH:57][C:56]([C:59]([F:62])([F:61])[F:60])=[CH:55][CH:54]=2)[S:48][C:49]=1[C:50](O)=[O:51]>C(OCC)(=O)C.C(OCC)C>[CH2:11]([O:13][C:14](=[O:32])[C:15]([CH3:31])([O:17][C:18]1[CH:23]=[C:22]([CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([C:50]([C:49]3[S:48][C:47]([C:53]4[CH:54]=[CH:55][C:56]([C:59]([F:62])([F:60])[F:61])=[CH:57][CH:58]=4)=[N:46][C:45]=3[CH3:44])=[O:51])[CH2:25]2)[CH:21]=[CH:20][C:19]=1[CH3:30])[CH3:16])[CH3:12]
Reactant: Cc1nc(-c2ccc(C(F)(F)F)cc2)sc1C(=O)O
Reactant: CCOC(=O)C(C)(C)Oc1cc(C2CCCNC2)ccc1C
Agent: CCN=C=NCCCN(C)C
Agent: O=C(O)[C@H](O)[C@@H](O)C(=O)O
Solvent: CCOC(C)=O
Solvent: CCOCC
Product: CCOC(=O)C(C)(C)Oc1cc(C2CCCN(C(=O)c3sc(-c4ccc(C(F)(F)F)cc4)nc3C)C2)ccc1C
Temperature: 25 °C
Reaction time: 72 h
Yield: 91.6 %

Procedure:
2-methyl-2-(2-methyl-5-piperidin-3-yl-phenoxy)-propionic acid ethyl ester L-tartaric acid salt (155 mg, 0.34 mmol) was dissolved in 50 mL ethyl acetate and washed with 50 mL saturated aqueous NaHCO3. The organic phase was dried over Na2SO4 and concentrated under reduced pressure. The resultant oil was taken up in 2 mL CH2Cl2 and 1-(3-dimethylaminopropyl)-3-ethyl carbodiimide (130 mg, 0.68 mmol) and 4-methyl-2-[4-(trifluoromethyl)phenyl]-1,3-thiazole-5-carboxylic acid (98 mg, 0.34 mmol) were added. The reaction was stirred at ambient temperature under nitrogen for 72 h. The reaction was diluted with 100 mL diethyl ether and washed with water (100 mL), 0.5 N HCl (2×100 mL), saturated aqueous NaHCO3 (2×100 mL), dried over Na2SO4 and concentrated under reduced pressure to yield 2-methyl-2-(2-methyl-5-{1-[4-methyl-2-(4-trifluoromethyl-phenyl)-thiazole-5-carbonyl]-piperidin-3-yl}-phenoxy)-propionic acid ethyl ester (179 mg, 91%) as a clear oil.
Reaction SMILES: Cl[C:2](Cl)([O:4]C(=O)OC(Cl)(Cl)Cl)Cl.[NH2:13][C:14]1[CH:19]=[C:18]([O:20][C:21]2[CH:30]=[C:29]3[C:24]([CH2:25][CH2:26][CH:27]([C:31]([NH:33][C:34]4[CH:39]=[CH:38][CH:37]=[C:36]([C:40]([CH3:43])([CH3:42])[CH3:41])[CH:35]=4)=[O:32])[CH2:28]3)=[CH:23][CH:22]=2)[CH:17]=[CH:16][N:15]=1>C1COCC1>[C:40]([C:36]1[CH:35]=[C:34]([NH:33][C:31]([CH:27]2[CH2:26][CH2:25][C:24]3[C:29](=[CH:30][C:21]([O:20][C:18]4[CH:17]=[CH:16][N:15]=[C:14]([N:13]=[C:2]=[O:4])[CH:19]=4)=[CH:22][CH:23]=3)[CH2:28]2)=[O:32])[CH:39]=[CH:38][CH:37]=1)([CH3:43])([CH3:42])[CH3:41]
Reactant: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N)c4)cc3C2)c1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Solvent: C1CCOC1
Product: CC(C)(C)c1cccc(NC(=O)C2CCc3ccc(Oc4ccnc(N=C=O)c4)cc3C2)c1
Temperature: 0 °C
Yield: 113.2 %

Procedure:
A solution of triphosgene (304 mg, 1.02 mmol) in THF (15 mL) was cooled to 0° C. To this solution was added TEA (0.74 mL, 5.32 mmol). A solution of 7-[(2-aminopyridin-4-yl)oxy]-N-(3-tert-butylphenyl)-1,2,3,4-tetrahydronaphthalene-2-carboxamide (850 mg, 2.04 mmol) in THF (6 mL) was added dropwise to the reaction mixture over the 20 min. The reaction mixture was allowed to stir at 0° C. and then to warm to rt and stir for 1 h. The reaction mixture was filtered and the filtrate was evaporated. The residue was purified by column chromatography to give N-(3-tert-butylphenyl)-7-[(2-isocyanatopyridin-4-yl)oxy]-1,2,3,4-tetrahydronaphthalene-2-carboxamide (510 mg, 56%) as yellow solid. LCMS: (FA) ES+442.5.
Reaction SMILES: [F:1][CH2:2][C:3]([CH2:7][F:8])([OH:6])[C:4]#[CH:5].[C:9]1([S:15](Cl)(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1.[H-].[Na+].CCCCCC.CCOCC>O1CCCC1>[C:9]1([S:15]([O:6][C:3]([CH2:7][F:8])([C:4]#[CH:5])[CH2:2][F:1])(=[O:17])=[O:16])[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1
Reactant: O=S(=O)(Cl)c1ccccc1
Reactant: C#CC(O)(CF)CF
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Solvent: CCCCCC
Product: C#CC(CF)(CF)OS(=O)(=O)c1ccccc1
Temperature: 25 °C
Reaction time: 4 h
Yield: 84.6 %

Procedure:
An amount (1.2 g) of 1-fluoro-2-fluoromethyl-3-butyn-2-ol and benzenesulfonyl chloride (1.8 g) were dissolved in tetrahydrofuran (10 ml); to the solution under cooling with ice, 60% oily sodium hydride (0.48 g) was added in a nitrogen atmosphere. After the end of the addition, the mixture was stirred for 4 hours while its temperature was raised to room temperature. A hexane/ether mixed solvent (1/1) was added to the reaction mixture, which was then washed with water and a saturated aqueous solution of sodium chloride, dried with anhydrous sodium sulfate and concentrated under reduced pressure. The resulting residue was subjected to silica gel column chromatography (eluent; hexane/methylene chloride=1/1) to give the titled compound (2.2 g).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH2:28])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=3)[CH2:19][CH2:18]1)[N:11]=2.O.[C:30]([OH:34])(=[O:33])[CH:31]=O.Cl>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([CH2:26][CH2:27][NH:28][CH2:31][C:30]([OH:34])=[O:33])[CH:5]=[CH:6][C:7]=1[C:8]1[S:9][C:10]2[C:15]([N:16]=1)=[CH:14][CH:13]=[C:12]([C:17]1([C:20]3[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=3)[CH2:18][CH2:19]1)[N:11]=2
Reactant: NCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Reactant: O=CC(=O)O
Agent: Cl
Solvent: O
Solvent: ClCCl
Product: O=C(O)CNCCc1ccc(-c2nc3ccc(C4(c5ccccc5)CC4)nc3s2)c(F)c1
Temperature: 25 °C
Reaction time: 5 h

Procedure:
To 2-(3-fluoro-4-(5-(1-phenylcyclopropyl)thiazolo[5,4-b]pyridin-2-yl)phenyl)-ethanamine (83 mg, 0.213 mmol) was added glyoxylic acid monohydrate (39 mg, 0.426 mmol) and DCM (1 mL) before it was stirred for 5 h at ambient temperature. The reaction mixture was concentrated before adding concentrated hydrochloric acid (2.13 mL, 4.26 mmol) and heating to reflux for 16 h. The reaction mixture was diluted with 75 mL of DCM, added to a separatory funnel, partitioned with water, washed 1 time with 50 mL of water, separated, dried over sodium sulfate, and concentrated via rotovap to give the title compound after preparatory LC. MS (ESI) m/z: Calculated: 447.1; Observed: 448.1 (M++H).
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].Br[CH2:6][CH2:7][C:8]1[C:16]2[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=2)[NH:10][CH:9]=1.[CH3:17][O:18][C:19](=[O:22])[C:20]#[CH:21]>CN(C)C(=O)C>[NH:10]1[C:11]2[C:16](=[CH:15][CH:14]=[CH:13][CH:12]=2)[C:8]([CH2:7][CH2:6][N:1]2[CH:21]=[C:20]([C:19]([O:18][CH3:17])=[O:22])[N:3]=[N:2]2)=[CH:9]1
Reactant: [N-]=[N+]=[N-]
Reactant: C#CC(=O)OC
Reactant: BrCCc1c[nH]c2ccccc12
Agent: [Na+]
Solvent: CC(=O)N(C)C
Product: COC(=O)c1cn(CCc2c[nH]c3ccccc23)nn1
Temperature: 25 °C
Reaction time: 48 h

Procedure:
The resin (4-(bromomethyl)-phenoxyethyl-polystyrene HL) (5.00 g, 5.5 mmol) was suspended in N,N-dimethylacetamide (DMA) (30 ml), sodium azide (178 g, 27.5 mmol, 5 eq.) was added and the mixture was stirred at RT for 48 h. The resin was filtered off, washed with methanol and dried. The resin was suspended in DMA (100 ml) again, 3-(2-bromoethyl)indole (0.60 g, 2.67 mmol) was added and the mixture was stirred at RT for 5 d. Propiolic acid methyl ester (0.24 ml, 2.67 mmol) was then added, the mixture was stirred at 80° C. for 20 h and the solvent was removed i. vac. The residue was separated by flash chromatography with CHCl3/MeOH (9:1). In addition to the desired product, 3-(2-bromoethyl)indole (103 mg, 17%) was recovered. Yield: 342 mg (Ind-63, 47%)
Reaction SMILES: [Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH2:11])[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1.Br[C:15]1[N:23]=[CH:22][N:21]=[C:20]2[C:16]=1[N:17]=[CH:18][N:19]2[CH:24]1[CH2:29][CH2:28][CH2:27][CH2:26][O:25]1.C(N(CC)C(C)C)(C)C.C(=O)(O)[O-].[Na+]>C(O)C>[Br:1][C:2]1[C:3]([O:12][CH3:13])=[C:4]([CH:9]([NH:11][C:15]2[N:23]=[CH:22][N:21]=[C:20]3[C:16]=2[N:17]=[CH:18][N:19]3[CH:24]2[CH2:29][CH2:28][CH2:27][CH2:26][O:25]2)[CH3:10])[CH:5]=[C:6]([Cl:8])[CH:7]=1
Reactant: COc1c(Br)cc(Cl)cc1C(C)N
Reactant: Brc1ncnc2c1ncn2C1CCCCO1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CCO
Product: COc1c(Br)cc(Cl)cc1C(C)Nc1ncnc2c1ncn2C1CCCCO1
Yield: 98.3 %

Procedure:
A solution of 1-(3-bromo-5-chloro-2-methoxyphenyl)ethanamine (2.2 g, 8.5 mmol) in ethanol (69 mL), was treated with 6-bromo-9-(tetrahydro-2H-pyran-2-yl)-9H-purine (3.6 g, 13 mmol, from Example 108, Step 1) and N,N-diisopropylethylamine (4.4 mL, 25 mmol) and heated at reflux overnight. The reaction mixture was cooled, poured into sodium bicarbonate (150 mL) and extracted with ethyl acetate (2×150 mL). The combined organic layers were washed with water and brine, dried with sodium sulfate, filtered, and concentrated to a crude residue. Purification by flash column chromatography using acetonitrile in dichloromethane (5%-10%) and then ethyl acetate in hexanes (60%-100%) gave the desired product (3.9 g, 98%). LCMS for C19H22BrClN5O2 (M+H)+: m/z=466.1, 468.1. Found: 466.0, 468.0.
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([OH:9])=O)=[CH:5][O:4][N:3]=1.C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[NH2:31][C@H:32]1[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1>C(Cl)Cl.CN(C=O)C>[CH:32]1([NH:31][C:7]([C:6]2[C:2]([CH3:1])=[N:3][O:4][CH:5]=2)=[O:9])[C:41]2[C:36](=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:35][CH2:34][CH2:33]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: Cc1nocc1C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1nocc1C(=O)NC1CCCc2ccccc21
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 62.5 %

Procedure:
To a solution of 3-Methyl-isoxazole-4-carboxylic acid (0.52 g, 4.06 mmol) in DCM (15 mL) and DMF (2 mL), was added HOBt (1.1 g, 8.14 mmol) and EDCI (0.896 g 4.67 mmol). The clear yellow solution was cooled to 0 C and allowed to stir under Ar for 15 minutes. To the solution was added (R)-1-Amino-1,2,3,4-tetrahydronaphthalene (0.73 mL, 5.04 mmol and the reaction mixture was allowed to slowly warm to ambient temperature and was stirred for overnight. Dilution with DCM (50 mL) was followed by aqueous extraction (NaHCO3 water, brine (50 mL), drying over MgSO4, filtration and removal of solvent in vacuo. Silica gel chromatography (0-25% Hexane:EtOAc) afforded the title compound (650 mg; 62.5%) as a sticky solid. 1H NMR (CDCl3) δ 1.88 (m, 3H), 2.12 (m, 1H), 2.51 (s, 3H), 2.81 (m, 2H), 5.32 (m, 1H), 5.99 (bd, 1H), 7.13 (m, 1H), 7.20 (m, 2H) 7.20 (m, 2H); 13C NMR (CDCl3) δ 11.22, 20.15, 29.41, 30.35, 47.93, 116.73, 126.72, 127.88, 128.88, 129.65, 136.25, 138.00, 158.45, 160.28. ESIMS: 257 (M+H) EA calc'd for C15H16N2O2: C, 70.29; H, 6.29; N, 10.93. found C, 70.61; H, 6.11; N, 11.09.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH2:28][OH:29])[CH2:23][CH2:22]1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(N(C(C)C)CC)(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl>[CH2:11]([O:18][C@@H:19]1[CH2:41][C@@H:40]2[C@:35]([CH3:49])([CH2:36][CH2:37][C@H:38]([O:42][CH:43]3[CH2:48][CH2:47][CH2:46][CH2:45][O:44]3)[CH2:39]2)[C@@H:34]2[C@@H:20]1[C@H:21]1[C@:31]([CH3:50])([CH2:32][CH2:33]2)[C@@H:24]([C@H:25]([CH3:30])[CH2:26][CH2:27][CH:28]=[O:29])[CH2:23][CH2:22]1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: C[C@H](CCCO)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Agent: O=C(Cl)C(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: C[C@H](CCC=O)[C@H]1CC[C@H]2[C@@H]3[C@H](OCc4ccccc4)C[C@H]4C[C@@H](OC5CCCCO5)CC[C@]4(C)[C@H]3CC[C@]12C
Temperature: -78 °C
Reaction time: 0.25 h
Yield: 97 %

Procedure:
DMSO (0.01 ml, 0.14 mmol) in CH2Cl2 (0.1 ml) was added dropwise to a stirred solution of oxalyl chloride (0.008 ml, 0.0917 mmol) in anhydrous CH2Cl2 (2 ml) at -78° C. under anhydrous conditions (drying tube). This solution was stirred at -78° C. for 15 minutes. Steroid 2008 (0.0234 g, 0.0423 mmol) in dry CH2Cl2 (0.5 ml) was then added dropwise and the solution stirred for 40 minutes at -780° C. Diisopropylethylamine (DIPEA) (0.08 ml, 0.458 mmol) was added and the solution allowed to warm to 0° C. with stirring over a 30-minute period. Aqueous saturated NaHCO3 solution (5 ml) was added and the solution extracted 3x with 5 ml CH2Cl2. The combined organic extracts were washed 2x with 5 ml of aqueous saturated NaCl solution, dried over anhydrous MgSO4, filtered, and the solvent removed in vacuo. Flash chromatography (SiO2, 10:1 hexanes:EtOAc) gave compound 2009 (0.0226 g, 97%) as a white solid foam. 1H NMR (500 MHz, CDCl3) δ: 9.76 (s, 1H, C-24 H), 7.35-7.34 (m, 5H, benzyl Ar-H), 4.71-4.69 (m, 1H, THP ether methine H), 4.59 (d, J=11.8 Hz, 1/2H, benzyl-CH2), 4.585 (d, J =11.8 Hz, 1/2H, benzyl-CH2), 4.30 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 4.29 (d, J=12.0 Hz, 1/2H, benzyl-CH2), 3.95-3.89 (m, 1H, THP OCH2), 3.63-3.58 (m, 3H, C-24 H & THP OCH2) , 3.50-3.47 (m, 1H, C-3 H), 3.45 (s, 1H, 7-H), 2.49-2.42 (m, 1H, C-23H), 2.37-2.31 (m, 1H, C-23 H), 0.958 (d, J=6.5 Hz, 3H, C-21 H), 0.81 (s, 3H, C-19 H), 0.63 (s, 3H, C-18 H) (Note: product is a mixture of diastereomers); IR (CHCl3) 2900, 1700 cm-1 ; MS (CI/isobutane) m/z 552 (M+1, 0.4%), 465 (M+1-THP, 3%), 449 (M+1-THPO, 14%), 375 (M+1-THP-Bn, 7%), 359 (M+1-THP-HOBn, 68%), 341 (M+1-THP-HOBn-H2O, 100%); m.p. 50°-54° C.; Anal. calcd. for C36H54O4 : C=78.50, H=9.88; Found: C=78.11, H=10.04.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=[O:14])[CH2:12][Br:13])=[CH:7][C:6]=1[CH2:15][O:16]C(=O)C)(=O)C.Br.O>CO>[Br:13][CH2:12][C:11]([C:8]1[CH:9]=[CH:10][C:5]([OH:4])=[C:6]([CH2:15][OH:16])[CH:7]=1)=[O:14]
Reactant: CC(=O)OCc1cc(C(=O)CBr)ccc1OC(C)=O
Agent: Br
Solvent: CO
Solvent: O
Product: O=C(CBr)c1ccc(O)c(CO)c1
Yield: 68.9 %

Procedure:
2-Acetoxymethyl-4-bromoacetylphenyl acetate (18.6 g) was dissolved in 90 ml of methanol, 100 ml of 47% hydrobromic acid was added with stirring under ice-cooling, and the mixture was subjected to 16 hours of reaction at room temperature. Water was added to the reaction solution with stirring under ice-cooling, and the resulting precipitates were collected by filtration and washed with water and hexane to give 9.54 g of 2-bromo-4'-hydroxy-3'-hydroxymethylacetophenone having a melting point of 117 to 119° C.
Reaction SMILES: [Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([OH:7])=O.[CH2:13]([NH2:15])[CH3:14]>>[Cl:1][C:2]1[C:3]([OH:12])=[C:4]([CH:8]=[C:9]([Cl:11])[CH:10]=1)[C:5]([NH:15][CH2:13][CH3:14])=[O:7]
Reactant: CCN
Reactant: O=C(O)c1cc(Cl)cc(Cl)c1O
Product: CCNC(=O)c1cc(Cl)cc(Cl)c1O

Procedure:
The title compound was prepared from 3,5-dichloro-2-hydroxybenzoic acid and ethylamine, using a similar method to that of preparation 52, to afford the title compound as a pale yellow solid. 1HNMR (400 MHz, CDCl3) δ: 1.28 (3H, t), 3.47–3.54 (2H, m), 6.29–6.36 (1H, bs), 7.27 (1H, d), 7.48 (1H, d); LRMS ESI m/z 232 [M−H]−
Reaction SMILES: [Br:1][CH:2]([CH2:18][CH3:19])[C:3]([C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)=O.[NH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][N:22]=1>C(#N)C>[BrH:1].[CH2:18]([C:2]1[N:22]2[CH:23]=[CH:24][CH:25]=[CH:26][C:21]2=[N:20][C:3]=1[C:5]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[C:11]2[C:6]=1[CH2:7][CH2:8][C:9](=[O:17])[NH:10]2)[CH3:19]
Reactant: CCC(Br)C(=O)c1ccc(OC)c2c1CCC(=O)N2
Reactant: Nc1ccccn1
Solvent: CC#N
Product: Br
Product: CCc1c(-c2ccc(OC)c3c2CCC(=O)N3)nc2ccccn12
Yield: 60.5 %

Procedure:
5-(α-bromobutyryl)-8-methoxy-3,4-dihydrocarbostyril (5 g), 2-aminopyridine (4.33 g) and acetonitrile (20 ml) were reacted by refluxing for 6 hours. The reaction mixture was concentrated to dryness and the residue was crystallized by the addition of water. The crystals were collected by filtration and washed with water. The crystals were dissolved in acetone and the solution was adjusted to pH of about 1 to 2 by the addition of 48% hydrobromic acid. Crystals which formed were collected by filtration. The crude crystals thus obtained were recrystallized from methanol-ether to give 3.73 g of 5-(3-ethylimidazo[1,2-a]pyridine-2-yl)-8-methoxy-3,4-dihydrocarbostyril monohydrobromide.