Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1.[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])[CH:20]=O.CC([O-])(C)C.[K+]>C1COCC1.CC(O)(C)C>[CH3:15][O:16][C:17]1[CH:18]=[C:19]([CH:22]=[CH:23][C:24]=1[O:25][CH3:26])/[CH:20]=[CH:1]/[C:2]1[O:3][C:4]2[C:5](=[C:7]([C:11]([O:13][CH3:14])=[O:12])[CH:8]=[CH:9][CH:10]=2)[N:6]=1
Reactant: COC(=O)c1cccc2oc(C)nc12
Reactant: COc1ccc(C=O)cc1OC
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: C1CCOC1
Solvent: CC(C)(C)O
Product: COC(=O)c1cccc2oc(/C=C/c3ccc(OC)c(OC)c3)nc12
Temperature: 25 °C
Reaction time: 2 h
Yield: 21.5 %

Procedure:
A solution of methyl 2-methylbenzo[d]oxazole-4-carboxylate (0.63 g, 4.12 mmol) and 3,4-dimethoxybenzaldehyde (0.68 g, 4.12 mmol) in THF (25 mL) and t-BuOH (5 mL) was cooled to −50° C. under nitrogen and treated with a solution of t-BuOK in THF (1.0 mol/L, 4.94 mL, 4.94 mmol) at such a rate that the internal reaction temperature did not exceed −46° C. After 2 hours at −50° C., the cooling bath was removed and the mixture was stirred at room temperature for 12 h in the dark. Water was added and the mixture was made slightly acidic by addition of a 1N HCl solution then extracted with DCM. The organic layers were combined, washed with water and brine then dried over sodium sulfate and the solvent was removed under reduced pressure. The residue was purified by flash chromatography using petroleum ether: ethyl acetate 2:1 (v:v) as eluent to give (E)-methyl 2-(3,4-dimethoxystyryl)benzo[d]oxazole-4-carboxylate (0.30 g, 27%). LC-MS (ES-API); rt 9.25 min; m/z calculated for C19H17NO5 [M+H]+ 340.1, found 340.1.
Reaction SMILES: [OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26][CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:34])([F:33])[F:32])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1.C[OH:40].O>O1CCOCC1>[OH:1][C:2]1[CH:38]=[CH:37][C:5]2[CH:6]([CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][S:26]([CH2:27][CH2:28][CH2:29][C:30]([F:36])([F:35])[C:31]([F:32])([F:33])[F:34])=[O:40])[C:7]([C:11]3[CH:16]=[CH:15][C:14]([OH:17])=[CH:13][CH:12]=3)([CH3:10])[CH2:8][O:9][C:4]=2[CH:3]=1
Reactant: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCSCCCC(F)(F)C(F)(F)F
Reactant: CO
Solvent: C1COCCO1
Solvent: O
Product: CC1(c2ccc(O)cc2)COc2cc(O)ccc2C1CCCCCCCCS(=O)CCCC(F)(F)C(F)(F)F
Temperature: 25 °C
Reaction time: 8 h
Yield: 70 %

Procedure:
(3RS,4RS)-7-Hydroxy-3-(4-hydroxyphenyl)-3-methyl-4-[8-(4,4,5,5,5-pentafluoropentylthio)octyl]-2,3-dihydro-4H-benzopyran (53 mg, 0.095 mmol) was dissolved in 1,4-dioxane (1.2 ml), methanol (1.2 ml) and water (0.3 ml). NaIO4 (24 mg, 0.11 mmol) was added dropwise thereto, and the reaction mixture was stirred for 8 hours at room temperature and then filtered. The filtrate was concentrated and the residue was subjected to column chromatography (n-hexane:ethyl acetate=2:1) to obtain 38 mg (yield: 70%) of the title compound as a colorless oil.
Reaction SMILES: C([CH2:4][CH:5]1[CH2:10][CH2:9][C:8](=[O:11])[CH2:7][CH2:6]1)(O)=O.[CH2:12](O)[CH2:13][OH:14].S(=O)(=O)(O)[OH:17].C1C=CC=CC=1>O>[O:11]1[C:8]2([CH2:7][CH2:6][CH:5]([CH2:4][OH:17])[CH2:10][CH2:9]2)[O:14][CH2:13][CH2:12]1
Reactant: O=C(O)CC1CCC(=O)CC1
Reactant: OCCO
Reactant: O=S(=O)(O)O
Solvent: c1ccccc1
Solvent: O
Product: OCC1CCC2(CC1)OCCO2
Reaction time: 8 h

Procedure:
A mixture of 4-carboxymethylcyclohexanone (21 g), ethylene glycol (19 g), conc. sulphuric acid (0.3 mL) and benzene (250 mL) was heated at reflux for 20 h with Dean Stark azeotropic removal of water. After cooling the solution was washed with sodium bicarbonate solution, dried over magnesium sulphate and concentrated. The crude ketal was then taken up in diethyl ether (250 mL) and lithium aluminium hydride (7 g) was added. The mixture was stirred overnight and then water (20 mL), 10% sodium hydroxide (30 mL) and water (30 mL) was added carefully. Sodium sulphate (30 g) was then added and the mixture stirred for 20 min, The insoluble material was removed by filtration and the organic phase concentrated in vacuo to give (1,4-dioxa-spiro[4.5]dec-8-yl)-methanol (21 g).
Reaction SMILES: [C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][OH:11])[CH3:8])([CH3:4])([CH3:3])[CH3:2].[Si:13](Cl)([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.N1C=CN=C1>CN(C=O)C.[Cl-].[Na+].O>[C:1]([O:5][C:6](=[O:12])[N:7]([CH2:9][CH2:10][O:11][Si:13]([C:26]([CH3:29])([CH3:28])[CH3:27])([C:20]1[CH:21]=[CH:22][CH:23]=[CH:24][CH:25]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)[CH3:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CN(CCO)C(=O)OC(C)(C)C
Reactant: CC(C)(C)[Si](Cl)(c1ccccc1)c1ccccc1
Agent: [Cl-]
Agent: [Na+]
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CN(CCO[Si](c1ccccc1)(c1ccccc1)C(C)(C)C)C(=O)OC(C)(C)C
Yield: 60.7 %

Procedure:
(2-Hydroxy-ethyl)-methyl-carbamic acid tert-butyl ester (400 mg, 2.28 mmol), TBDPS chloride (593 μL, 2.28 mmol) and imidazole (342 mg, 5.02 mmol) in DMF (2 mL) were stirred at RT for 12 h. The reaction mixture was diluted with brine and extracted with CH2Cl2. The combined organics were passed through a phase separation cartridge and concentrated in vacuo. The crude material was purified by silica gel column chromatography, eluting with isohexane and increasing the polarity to 50% EtOAc/isohexane to obtain [2-(tert-butyl-diphenyl-silanyloxy)-ethyl]-methyl-carbamic acid tert-butyl ester as a colourless oil (572 mg, 61%).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@H:12]([C:35]([O:37][CH3:38])=[O:36])[CH:13]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[S:14][CH2:15][CH2:16][NH:17]C(OC(C)(C)C)=O)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:39]>C(OCC)(=O)C>[ClH:39].[NH2:17][CH2:16][CH2:15][S:14][CH:13]([C:25]1[C:34]2[C:29](=[CH:30][CH:31]=[CH:32][CH:33]=2)[CH:28]=[CH:27][CH:26]=1)[C@@H:12]([C:35]([O:37][CH3:38])=[O:36])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)=[O:10]
Reactant: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCNC(=O)OC(C)(C)C)c1cccc2ccccc12
Agent: Cl
Solvent: CCOC(C)=O
Product: COC(=O)[C@@H](NC(=O)OCc1ccccc1)C(SCCN)c1cccc2ccccc12
Reaction time: 0.25 h

Procedure:
To a stirred solution of methyl N-[(benzyloxy)carbonyl]-S-{2-[(tert-butoxycarbonyl)amino]ethyl}-3-(1-naphthyl)cysteinate (25b) (3.3 g, 6.13 mmol) in ethyl acetate (80 mL) at −30° C., was bubbled over HCl gas for 10 min, stirred at −30° for 15 min and then allowed to RT for 3 h. Evaporation to near dryness and precipitation from ether afforded pure title compound (25) (2.6 g, 89%) as a white solid. MS APCI, m/z=439 (M+1), 2.34 min.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([N+:22]([O-])=[O:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1.[NH4+].[Cl-].CCCCCC.C(OCC)(=O)C>O.[Zn]>[Cl:1][C:2]1[N:7]=[C:6]([N:8]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][OH:23])[CH:17]=2)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[C:5]([F:25])=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N(c1cccc([N+](=O)[O-])c1)c1nc(Cl)ncc1F
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CCCCCC
Solvent: CCOC(C)=O
Solvent: O
Product: CC(C)(C)OC(=O)N(c1cccc(NO)c1)c1nc(Cl)ncc1F
Temperature: 60 °C
Reaction time: 0.75 h

Procedure:
To a solution of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-nitrophenyl)carbamate (0.78 g) in mixture of ccetone (3 ml) and water (2 ml) was added NH4Cl (0.22 g) and the reaction mixture was heated to 60° C. Zn dust (289 mg) was added to the reaction mixture at 60° C. portion wise. The reaction mixture was stirred for 45 minute at 60° C. and monitored on TLC using hexane:ethyl acetate (3:7) as mobile phase. After completion of the reaction, the reaction mixture was poured in water. The product was extracted into ethyl acetate and the organic layer was washed with brine, dried over sodium sulfate and concentrated completely under reduce pressure to give crude product. Crude material was purified by using column chromatography. Desired product eluted with 5% ethyl acetate in hexane to give, after concentration, 0.409 g of tert-butyl (2-chloro-5-fluoropyrimidin-4-yl)(3-(hydroxyamino)phenyl)carbamate. M+1=354.8. 1H NMR: DMSO-d6 (400 MHz): 1.400 (s, 9H), 6.612 (d, 1H, J=7.6), 6.688 (s, 1H), 6.774 (d, 1H, J=8.4), 7.170-7.210 (t, 1H, J=8), 8.434 (d, 2H, J=6.4), 8.95 (s, 1H).
Reaction SMILES: C([N:8]1[CH2:19][CH2:18][C:11]2[N:12]=[C:13](Cl)[N:14]=[C:15](Cl)[C:10]=2[CH2:9]1)C1C=CC=CC=1.Cl.Cl.C[C@H]1CN[C@H](C)CN1.CCN(C(C)C)C(C)C.CC(O)C>C(OCC)C>[N:12]1[C:11]2[CH2:18][CH2:19][NH:8][CH2:9][C:10]=2[CH:15]=[N:14][CH:13]=1
Reactant: Clc1nc(Cl)c2c(n1)CCN(Cc1ccccc1)C2
Agent: C[C@@H]1CN[C@@H](C)CN1
Agent: Cl
Solvent: CC(C)O
Solvent: CCOCC
Solvent: CCN(C(C)C)C(C)C
Product: c1ncc2c(n1)CCNC2
Temperature: 80 °C

Procedure:
A mixture of 6-benzyl-2,4-dichloro-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine (2.0 g, 6.80 mmol), (trans)-2,5-dimethylpiperazine dihydrochloride (7.63 g, 40.8 mmol), DIEA (15.4 mL, 88 mmol) and iPrOH (180 mL) was heated at 80° C. for 3.5 days. At that time the reaction was diluted with diethyl ether and the solid was removed by filtration. The filtrate was then washed with brine and the organic layer was dried (Na2SO4), filtered and concentrated to provide crude racemic 6-benzyl-2-chloro-4-(trans)-2,5-dimethylpiperazin-1-yl)-5,6,7,8-tetrahydropyrido[4,3-d]pyrimidine, which was then carried to the next step without further purification. MS (ESI+) m/z 372.2 (M+H)+
Reaction SMILES: [Br:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=O)=[CH:4][N:3]=1.[CH3:11][C:12]1[CH:17]=[C:16]([CH3:18])[C:15]([CH3:19])=[CH:14][C:13]=1[N:20]1[CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>>[Br:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([N:23]2[CH2:24][CH2:25][N:20]([C:13]3[CH:14]=[C:15]([CH3:19])[C:16]([CH3:18])=[CH:17][C:12]=3[CH3:11])[CH2:21][CH2:22]2)=[O:8])=[CH:9][CH:10]=1
Reactant: O=C(O)c1ccc(Br)nc1
Reactant: Cc1cc(C)c(N2CCNCC2)cc1C
Product: Cc1cc(C)c(N2CCN(C(=O)c3ccc(Br)nc3)CC2)cc1C
Yield: 101 %

Procedure:
To a mixture of 1-Boc-piperazine (1.39 g), 1-bromo-2,4,5-trimethylbenzene (1 g), tris(dibenzylideneacetone)dipalladium (0) (257 mg), rac-2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (481 mg) and sodium tert-butoxide (669 mg) was added toluene (10 mL), and the mixture was refluxed for 3 hr. After cooling, water was added to the reaction mixture, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, and the solvent was evaporated. The residue was purified by column chromatography (ethyl acetate:hexane) to give 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g). 4-(2,4,5-trimethylphenyl)piperazine-1-carboxylic acid tert-butyl ester (1.53 g) was dissolved in dichloromethane (10 mL), 4N hydrogen chloride/dioxane (5 mL) was added, and the mixture was stirred at room temperature for 3 hr. Diethyl ether (100 mL) was added, and the precipitate was collected by filtration. To the obtained precipitate were added ethyl acetate and 1N aqueous sodium hydroxide solution, and the mixture was extracted with ethyl acetate and washed with saturated brine. The solvent was evaporated to give 1-(2,4,5-trimethylphenyl)piperazine (920 mg). By reaction and treatment in the same manner as in Preparation Example 27 and using 6-bromonicotinic acid (412 mg) and 1-(2,4,5-trimethylphenyl)piperazine (440 mg), the title compound (800 mg) was obtained.
Reaction SMILES: C(OC([N:8]1[CH2:14][CH2:13][C:12]2[C:15]([S:20]C(=O)N(C)C)=[C:16]([Cl:19])[CH:17]=[CH:18][C:11]=2[CH2:10][CH2:9]1)=O)(C)(C)C.Br[CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:28][CH3:29]>>[ClH:19].[Cl:19][C:16]1[CH:17]=[CH:18][C:11]2[CH2:10][CH2:9][NH:8][CH2:14][CH2:13][C:12]=2[C:15]=1[S:20][CH:27]([C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][N:31]=1)[CH2:28][CH3:29]
Reactant: CCC(Br)c1ccccn1
Reactant: CN(C)C(=O)Sc1c(Cl)ccc2c1CCN(C(=O)OC(C)(C)C)CC2
Product: CCC(Sc1c(Cl)ccc2c1CCNCC2)c1ccccn1
Product: Cl

Procedure:
Use method similar to the Preparation 177 to react 3-tert-butoxycarbonyl-7-chloro-6-dimethylcarbamoylthio-2,3,4,5-tetrahydro-1H-benzo[d]azepine with (±)-2-(1-bromopropyl)pyridine. Use a method similar to the General Procedure 1-5, basic workup, and a method similar to the General Procedure 2-2 to give the title compound as a white solid. MS (APCI+) m/z: 333 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:55]=[CH:54][C:21]([O:22][C:23]4[C:28]([C:29]5[CH:34]=[CH:33][N:32]=[C:31]([NH:35][P:36](=[O:53])([O:45]CC6C=CC=CC=6)[O:37]CC6C=CC=CC=6)[N:30]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[S:5][CH:6]=1.C(#N)C.C(Cl)Cl.[I:62][Si](C)(C)C>CO>[IH:62].[IH:62].[CH3:1][C:2]1[N:3]=[C:4]([C:7]2[C:16]3[C:11](=[CH:12][CH:13]=[CH:14][CH:15]=3)[C:10]([NH:17][C:18]3[CH:55]=[CH:54][C:21]([O:22][C:23]4[C:28]([C:29]5[CH:34]=[CH:33][N:32]=[C:31]([NH:35][P:36](=[O:37])([OH:45])[OH:53])[N:30]=5)=[CH:27][CH:26]=[CH:25][N:24]=4)=[CH:20][CH:19]=3)=[N:9][N:8]=2)[S:5][CH:6]=1
Reactant: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(NP(=O)(OCc5ccccc5)OCc5ccccc5)n4)cc3)c3ccccc23)n1
Reactant: C[Si](C)(C)I
Solvent: ClCCl
Solvent: CC#N
Solvent: CO
Product: Cc1csc(-c2nnc(Nc3ccc(Oc4ncccc4-c4ccnc(NP(=O)(O)O)n4)cc3)c3ccccc23)n1
Product: I
Reaction time: 0.08 h

Procedure:
To a yellow slurry of N-(4-(3-(2-aminopyrimidin-4-yl)pyridin-2-yloxy)phenyl)-4-(4-methylthiazol-2-yl)phthalazin-1-amine (0.335 g, 0.664 mmol) and tetrabenzyl pyrophosphate (0.501 g, 0.930 mmol) in 6.6 mL THF under nitrogen at 0° C. was added sodium bis(trimethylsilyl)amide 1 M in THF (2.32 ml, 2.32 mmol) dropwise over 3 min to give a deep red solution. The reaction was quenched with sat'd aq. NaHCO3, and diluted with EtOAc. The organic layer was washed 3× with saturated aq. NaHCO3, 1× brine, dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The material was purified by silica gel chromatography, ISCO, 40 g, 50 min run, 0-60% 90/10 DCM/MeOH in DCM to give dibenzyl 4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidate a yellow solid MS m/z=765 [M+H]+. Calc'd for C41H33N8O4PS: 764.8. Step 2. To a slightly cloudy mixture of dibenzyl 4-(2-(4-(4-(4-methylthiazol-2-yl)phthalazin-1-ylamino)phenoxy)pyridin-3-yl)pyrimidin-2-ylphosphoramidate (.086 g, 0.11 mmol) in 3 mL 5:1 ACN/DCM was added iodotrimethylsilane (0.16 ml, 1.1 mmol) dropwise via syringe at ambient temperature under nitrogen. After 5 min, 0.6 mL MeOH was added and the stir bar was removed. The reaction was concentrated in vacuo and suspended in DCM and filtered. The resulting orange solid was collected and dried in vacuo to provide
Reaction SMILES: [CH3:1][C:2]1([C:17]([O:19]CC)=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:13]=[CH:12][C:11]([N+:14]([O-:16])=[O:15])=[CH:10][CH:9]=2)[CH2:3]1.[Li+].[OH-].Cl>C1COCC1.CO>[CH3:1][C:2]1([C:17]([OH:19])=[O:18])[CH2:7][CH2:6][CH2:5][N:4]([C:8]2[CH:9]=[CH:10][C:11]([N+:14]([O-:16])=[O:15])=[CH:12][CH:13]=2)[CH2:3]1
Reactant: CCOC(=O)C1(C)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: CC1(C(=O)O)CCCN(c2ccc([N+](=O)[O-])cc2)C1
Temperature: 25 °C
Reaction time: 22 h
Yield: 95.4 %

Procedure:
To a solution of ethyl 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylate (2.920 g, 9.99 mmol) in THF (12.50 mL) and MeOH (12.5 mL) was added 2 M aqueous solution of LiOH (25 mL, 50 mmol). The resulting yellow solution was stirred at rt for 22 hrs. The reaction was adjusted with 3N aqueous HCl to pH=5. The solution was extracted with EtOAc (3×). The combined EtOAc extracts were washed with saturated aqueous NaCl (2×), dried over Na2SO4, filtered and concentrated. The obtained yellow solid was dried in high vacuum to give the desired product, 3-methyl-1-(4-nitrophenyl)piperidine-3-carboxylic acid (2.650 g, 9.53 mmol, 95% yield) as a yellow solid. Anal. Calcd. for C13H16N2O4 m/z 264.2, found: 265.1 (M+H)+; 1H NMR (400 MHz, CDCl3) δ ppm 8.08 (d, J=9.34 Hz, 2 H), 6.89 (d, J=9.34 Hz, 2 H), 4.13 (d, J=12.64 Hz, 1 H), 3.64 (ddd, J=12.50, 4.53, 4.40 Hz, 1 H), 3.10-2.99 (m, 1 H), 2.94 (d, J=13.19 Hz, 1 H), 2.33-2.18 (m, 1 H), 1.88-1.69 (m, 2 H), 1.53-1.37 (m, 1 H), 1.25 (s, 3 H).
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8].[NH:23]1[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]1.CCN(C(C)C)C(C)C>CC(O)C.CCOC(C)=O>[Br:1][C:2]1[C:3]([N:23]2[CH2:27][CH2:26][C@H:25]([OH:28])[CH2:24]2)=[N:4][CH:5]=[C:6]([CH:21]=1)[C:7]([NH:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=1)=[O:8]
Reactant: O[C@H]1CCNC1
Reactant: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(Cl)c(Br)c1
Solvent: CCOC(C)=O
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(Nc1ccc(OC(F)(F)F)cc1)c1cnc(N2CC[C@H](O)C2)c(Br)c1
Temperature: 140 °C

Procedure:
5-Bromo-6-chloro-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 12.2, 2.37 g, 6.0 mmol) and (S)-pyrrolidin-3-ol (0.627 g, 7.2 mmol) were dissolved in iPrOH (6 mL). DIPEA (2.1 mL, 12 mmol) was added and the RM mixture was heated at 140° C. for 1 h in a MW vial. After cooling to RT, the RM was dissolved in EtOAc, and washed with 0.5 M HCl and brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure until the crystallization began. The mixture was triturated with n-pentane, filtered and dried to afford the title compound as a beige crystalline solid. HPLC (Condition 4) tR=5.51 min, UPLC-MS (Condition 3) tR=1.09 min, m/z=448.1 [M+H]+; 1H-NMR (400 MHz, DMSO-d6) δ ppm 1.74-2.03 (m, 2H) 3.55 (d, J=11.34 Hz, 1H) 3.64-3.74 (m, 1H) 3.78-3.89 (m, 2H) 4.33 (br. s, br. s, 1H) 4.97 (d, J=3.13 Hz, 1H) 7.33 (d, J=8.99 Hz, 2H) 7.78-7.90 (m, 2H) 8.32 (d, J=1.56 Hz, 1H) 8.63-8.72 (m, 1H) 10.20 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=O.[CH2:12]([NH:19][C:20](=O)[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1>P(Cl)(Cl)(Cl)=O>[CH2:12]([N:19]1[C:4](=[O:6])[C:3]2[C:2](=[CH:10][C:9]([Cl:11])=[CH:8][CH:7]=2)[N:1]=[C:20]1[CH3:21])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CC(=O)NCc1ccccc1
Reactant: Nc1cc(Cl)ccc1C(=O)O
Solvent: O=P(Cl)(Cl)Cl
Product: Cc1nc2cc(Cl)ccc2c(=O)n1Cc1ccccc1
Reaction time: 0.17 h

Procedure:
2-Amino-4-chlorobenzoic acid (250 mg, 1 eq.) and N-benzylacetamide (261 mg, 1.2 eq.) were dissolved in phosphorus oxychloride (2 ml). The reaction was placed in the microwave for 10 minutes at 150° C. The reaction was quenched by pouring the mixture into ice. The crude product was extracted into ethyl acetate. The ethyl acetate layer was washed with water, 10% aqueous sodium hydroxide, dried with magnesium sulfate, filtered, and concentrated to yield 3-benzyl-7-chloro-2-methylquinazolin-4 (3H)-one as an orange solid.
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.[B-](F)(F)(F)F.[CH:23]1([C:28]([OH:30])=O)[CH2:27][CH2:26][CH2:25][CH2:24]1.[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40]2[N:41]=[N:42][N:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51][NH2:52])=[CH:47][CH:46]=3)[CH:44]=2)=[N:32]1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)Cl>[NH:31]1[C:39]2[C:34](=[CH:35][CH:36]=[CH:37][CH:38]=2)[C:33]([C:40]2[N:41]=[N:42][N:43]([C:45]3[CH:50]=[CH:49][C:48]([CH2:51][NH:52][C:28]([CH:23]4[CH2:24][CH2:25][CH2:26][CH2:27]4)=[O:30])=[CH:47][CH:46]=3)[CH:44]=2)=[N:32]1
Reactant: O=C(O)C1CCCC1
Reactant: NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[B-](F)(F)F
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCc1ccc(-n2cc(-c3n[nH]c4ccccc34)nn2)cc1)C1CCCC1
Temperature: 25 °C
Reaction time: 0.17 h

Procedure:
TBTU (185 mg; 0.58 mmol; 1.3 eq.) was added to a cooled (0° C.) solution of cyclopentane carboxylic acid (53 μl; 0.49 mmol; 1.1 eq.) in DMF (2.9 mL). After 10 min, a solution of 1-{4-[4-(1H-indazol-3-yl)-1H-1,2,3-triazol-1-yl]phenyl}methanamine (145 mg; 0.44 mmol; 1.0 eq.) and DIEA (174 μl; 1.02 mmol; 2.3 eq.) in DMF (2.9 mL) was added and the reaction mixture was stirred overnight at RT. DCM was added and the reaction mixture was washed with an aqueous saturated solution of NH4Cl and brine. The organic layer was dried over magnesium sulfate, filtered and concentrated. The crude was purified by preparative HPLC to afford the title compound as a white solid. 1H NMR (300 Mz, DMSO-d 6) δ: 13.36 (brs, 1H), 9.28 (s, 1H), 8.41 (t, J=6.0 Hz, 1H), 8.36 (dt, J=8.2 Hz, 1.0 Hz, 1H), 8.00 (d, J=8.6 Hz, 2H), 7.60 (dt, J=8.2 Hz, 1.0 Hz, 1H), 7.49-7.41 (m, 3H); 7.28-7.23 (m, 1H), 4.35 (d, J=6.0 Hz, 2H), 2.70-2.59 (m, 1H), 1.84-1.49 (m, 8H). HPLC (Condition A): Rt 3.59 min (purity 97.6%). MS (ESI+): 387.3, MS (ESI−): 385.4.
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH2:3][CH2:4][CH3:5].[C:9]([Cl:12])(=O)C>CO>[ClH:12].[NH2:1][C@H:2]([C:6]([O:8][CH3:9])=[O:7])[CH2:3][CH2:4][CH3:5]
Reactant: CC(=O)Cl
Reactant: CCC[C@H](N)C(=O)O
Solvent: CO
Product: CCC[C@H](N)C(=O)OC
Product: Cl
Reaction time: 18 h

Procedure:
L-Norvaline (0.82 g, 6.98 mmol) was added to a solution of acetyl chloride (0.60 mL, 8.44 mmol) in methanol (10 mL). The reaction mixture was allowed to stir for 18 h and then concentrated under reduced pressure. 1H NMR (400 MHz, CD3OD) δ 1.0 (t, 3H), 1.35-1.50 (m, 2H), 1.80-2.00 (m, 2H), 3.82 (s, 3H).
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([OH:8])=[CH:4][CH:3]=1.F[C:10]1[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=1.C(=O)([O-])[O-].[K+].[K+].O>CC(N(C)C)=O>[CH3:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:10]2[CH:17]=[CH:16][C:13]([CH:14]=[O:15])=[CH:12][CH:11]=2)=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(F)cc1
Reactant: Cc1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: Cc1ccc(Oc2ccc(C=O)cc2)cc1
Temperature: 25 °C

Procedure:
A solution of 4-methylphenol (4.52 g, 40.29 mmol), 4-fluorobenzaldehyde (5.00 g, 40.29 mmol) and potassium carbonate (6.70 g, 48.35 mmol) in dimethylacetamide (40 mL) was refluxed for 12 h and cooled to room temperature. Water was added and the reaction mixture was extracted with ethyl acetate. The organic extract was washed with brine, dried over sodium sulfate, filtered and concentrated to afford an oil which was chromatographed on silica gel (15% ethyl acetate/hexane) to afford 4-(4′-methylphenoxy)benzaldehyde.
Reaction SMILES: [OH:1][C:2]1[C:3]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=3)=[CH:12][S:11][C:4]=2[NH:5][C:6](=[O:10])[C:7]=1[C:8]#[N:9].[Br:26]NC(=O)CCC(N)=O>C(O)(=O)C>[Br:26][C:12]1[S:11][C:4]2[NH:5][C:6](=[O:10])[C:7]([C:8]#[N:9])=[C:2]([OH:1])[C:3]=2[C:13]=1[C:14]1[CH:19]=[CH:18][C:17]([C:20]#[C:21][CH2:22][CH2:23][CH2:24][OH:25])=[CH:16][CH:15]=1
Reactant: NC(=O)CCC(=O)NBr
Reactant: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)csc2[nH]c1=O
Solvent: CC(=O)O
Product: N#Cc1c(O)c2c(-c3ccc(C#CCCCO)cc3)c(Br)sc2[nH]c1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a stirred solution of 4-hydroxy-3-[4-(5-hydroxy-pent-1-ynyl)-phenyl]-6-oxo-6,7-dihydro-thieno[2,3-b]pyridine-5-carbonitrile (35 mg, 0.1 mmol) in acetic acid (1 mL) was added N-bromosuccinamide (18 mg, 0.1 mmol) in a single portion at room temperature, and stirred at rt overnight. The reaction mixture was concentrated and purified by reverse phase HPLC to afford the titled compound. MS (ESI) m/e 428 (M−H)+; 1H NMR (300 MHz, DMSO-d6): δ 1.68–1.75 (m, 2H), 3.51–3.57 (m, 2H), 4.54 (t, J=5.26 Hz, 2H), 7.19 (d, J=8.48 Hz, 2H), 7.31 (d, J=8.48 Hz, 2H).