Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH2:9][C:10]([OH:12])=O)[CH:5]=[CH:6][C:7]=1[OH:8].[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30]/[C:31](=[N:34]/[H])/[NH:32]O)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]>CS(C)=O>[CH2:13]([N:17]1[C:25]2[N:24]=[C:23]([Cl:26])[NH:22][C:21]=2[C:20](=[O:27])[N:19]([CH2:28][CH2:29][CH2:30][C:31]2[N:32]=[C:10]([CH2:9][C:4]3[CH:5]=[CH:6][C:7]([OH:8])=[C:2]([Cl:1])[CH:3]=3)[O:12][N:34]=2)[C:18]1=[O:36])[CH2:14][CH2:15][CH3:16]
Reactant: O=C(O)Cc1ccc(O)c(Cl)c1
Reactant: [H]/N=C(/CCCn1c(=O)c2[nH]c(Cl)nc2n(CCCC)c1=O)NO
Solvent: CS(C)=O
Product: CCCCn1c(=O)n(CCCc2noc(Cc3ccc(O)c(Cl)c3)n2)c(=O)c2[nH]c(Cl)nc21
Temperature: 120 °C
Yield: 18.7 %

Procedure:
A solution of 3-chloro-4-hydroxyphenylacetic acid (24 mg, 0.13 mmol) in DMSO (1 ml) was treated with CDl (21 mg, 0.13 mmol) and left to react for 30 min. (1Z)-4-(3-Butyl-8-chloro-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-1-yl)-N-hydroxybutanimidamide (50 mg, 0.15 mmol) was added and the mixture heated in the microwave at 120° C. for 15 min. The solution was directly purified by MDAP to obtain the title compound as a white solid (12 mg, 17%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([OH:14])([CH2:12][CH3:13])[CH2:10][CH3:11].CCN(C(C)C)C(C)C.[CH2:24](Cl)[O:25][CH3:26].[NH4+].[Cl-]>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[C:6]([CH3:8])[CH:5]=[CH:4][C:3]=1[C:9]([O:14][CH2:24][O:25][CH3:26])([CH2:12][CH3:13])[CH2:10][CH3:11]
Reactant: COCCl
Reactant: CCC(O)(CC)c1ccc(C)cc1Br
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(CC)(OCOC)c1ccc(C)cc1Br
Temperature: 25 °C
Reaction time: 11 h
Yield: 57 %

Procedure:
To a stirring solution of 3-(2-bromo-4-methylphenyl)pentan-3-ol (6.0 g, 23.3 mmol) in DCM (20 mL) at rt were successively added DIPEA (8.1 mL, 47.4 mmol) and MOMCl (2.7 mL, 35.5 mmol) over a 10 min period. The solution was stirred 11 h at rt followed by addition of aqueous NH4Cl solution (100 mL). The aqueous phase was segregated, and the organic one was washed with water (100 mL), brine, dried with anhydrous Na2SO4, filtered, and concentrated to give pure 2-bromo-1-(3-(methoxymethoxy)pentan-3-yl)-4-methylbenzene (4.0 g, yield 57%).
Reaction SMILES: [F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11](O)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1.P(Br)(Br)(Br)=O.CCN(C(C)C)C(C)C.[CH3:41][C:42]1[NH:46][N:45]=[C:44]([NH2:47])[CH:43]=1>CN(C=O)C.C1(C)C=CC=CC=1>[F:1][C:2]([F:26])([C:19]1[CH:24]=[CH:23][C:22]([F:25])=[CH:21][N:20]=1)[C:3]1[N:12]=[C:11]([NH:47][C:44]2[CH:43]=[C:42]([CH3:41])[NH:46][N:45]=2)[C:10]2[C:5](=[C:6]([O:14][C:15]([F:18])([F:17])[F:16])[CH:7]=[CH:8][CH:9]=2)[N:4]=1
Reactant: Oc1nc(C(F)(F)c2ccc(F)cn2)nc2c(OC(F)(F)F)cccc12
Reactant: Cc1cc(N)n[nH]1
Agent: O=P(Br)(Br)Br
Solvent: CCN(C(C)C)C(C)C
Solvent: Cc1ccccc1
Solvent: CN(C)C=O
Product: Cc1cc(Nc2nc(C(F)(F)c3ccc(F)cn3)nc3c(OC(F)(F)F)cccc23)n[nH]1
Temperature: 105 °C
Reaction time: 2 h
Yield: 33.3 %

Procedure:
To 2-(difluoro(5-fluoropyridin-2-yl)methyl)-8-(trifluoromethoxy)quinazolin-4-ol (250 mg, 0.66 mmol) was added phosphoryl tribromide (2.3 g) and toluene (2 mL) followed by DIEA (0.232 mL, 1.33 mmol). The mixture was heated at 105° C. for 0.5 h, then allowed to cool to rt. The mixture partitioned between EtOAc and saturated aq sodium bicarbonate and the organic layer was dried over sodium sulfate and concentrated under reduced pressure. To the residue was added a solution of 5-methyl-1H-pyrazol-3-amine (280 mg, 2.8 mmol) in DMF (5 mL) and the mixture was stirred at rt for 2 h. The crude mixture was purified by preparative HPLC (Varian diphenyl reverse phase column, eluting with a gradient of solvent B=0.05% HOAc/ACN and solvent A=0.05% HOAc/H2O) to afford 2-(difluoro(5-fluoropyridin-2-yl)methyl)-N-(5-methyl-1H-pyrazol-3-yl)-8-(trifluoromethoxy)quinazolin-4-amine (100 mg, 33%). 1H NMR (300 MHz, DMSO-d6) δ ppm 2.19 (s, 3H) 6.02 (s, 1H) 7.71 (t, J=8.10 Hz, 1H) 7.86-8.10 (m, 3H) 8.60-8.79 (m, 2H) 10.95 (s, 1H) 12.25 (br s, 1H); LC-MS (ESI) m/z 455 (M+H)+.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([NH:10][C:11](=[O:18])[C:12]3[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=3)[CH:8]=2)[CH:3]=[CH:2]1.[CH3:19][N:20]1[C:24](=[O:25])[CH:23]=[CH:22][C:21]1=[O:26]>C(O)(=O)C>[CH3:19][N:20]1[C:24](=[O:25])[CH2:23][CH:22]([C:3]2[C:4]3[C:9](=[CH:8][C:7]([NH:10][C:11](=[O:18])[C:12]4[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=4)=[CH:6][CH:5]=3)[NH:1][CH:2]=2)[C:21]1=[O:26]
Reactant: CN1C(=O)C=CC1=O
Reactant: O=C(Nc1ccc2cc[nH]c2c1)c1ccccc1
Solvent: CC(=O)O
Product: CN1C(=O)CC(c2c[nH]c3cc(NC(=O)c4ccccc4)ccc23)C1=O
Yield: 45.1 %

Procedure:
Compound 114 (3.5 g, 14.813 mmol) and N-methylmaleimide (4.07 g, 37.033 mmol) in glacial acetic acid (100 mL) was refluxed for 56 h. The reaction was brought to room temperature and acetic acid was evaporated. The crude solid was taken into ethyl acetate (100 mL), washed with sat. NaHCO3 solution (3×20 mL), brine (20 mL) and dried (Na2SO4). Solvent was evaporated and crude was purified by column chromatography (EtOAc: Hexanes, 1:3 to 1:1) to obtain compound 115 (2.32 g, 45%) as a foam. 1H NMR (DMSO-d6) δ 2.80 (dd, 1H, J=5.1, 18.0 Hz), 2.92 (s, 3H), 3.23 (dd, 1H, J=9.3, 18.0 Hz), 4.34 (dd, 1H, J=5.1, 9.3 Hz), 7.26-7.36 (m, 2H), 7.45-7.60 (m, 4H), 7.95-7.98 (m, 2H), 8.07 (s, 1H), 10.17 (s, 1H), 11.02 (s, 1H); ESI-MS (m/z, %) 370 (M+Na, 100), 348 (MH+, 58).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=O.Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>C(O)C.O>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[O:9][CH2:8][CH2:7][C:6]2=[N:15][OH:16]
Reactant: COc1ccc2c(c1)C(=O)CCO2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: COc1ccc2c(c1)C(=NO)CCO2
Temperature: 65 °C
Reaction time: 1.5 h

Procedure:
5.2 g (29.2 mmol) of 6-methoxychroman-4-one were dissolved in ethanol and 2.53 g (36.5 mmol) hydroxylamine hydrochloride and 2.99 g (36.5 mmol) sodium acetate dissolved in 10 ml of water were added. The mixture was stirred at 65° C. for 1.5 hours. The mixture was allowed to cool to room temperature and concentrated. The residue was dissolved in methyl-tert-butylether. The organic phase was washed with water, dried over MgSO4 and concentrated to give 5.6 g (29.4 mmol, quant.) of crude product, which was directly used in the next step.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1.[CH2:34]=O.[BH4-].[Na+]>CO>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:9]=[C:10]([CH:28]3[CH2:33][CH2:32][N:31]([CH3:34])[CH2:30][CH2:29]3)[S:11][C:12]=2[C:13]2[CH:18]=[CH:17][N:16]=[C:15]([NH:19][C@H:20]([C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH3:21])[CH:14]=2)=[CH:4][CH:3]=1
Reactant: C[C@H](Nc1cc(-c2sc(C3CCNCC3)nc2-c2ccc(F)cc2)ccn1)c1ccccc1
Reactant: C=O
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: C[C@H](Nc1cc(-c2sc(C3CCN(C)CC3)nc2-c2ccc(F)cc2)ccn1)c1ccccc1
Yield: 106.8 %

Procedure:
4-(4-Fluorophenyl)-2-(4-piperidinyl)-5-(2-(1-(S)-phenylethyl)amino-4-pyridinyl)thiazole (500 mg 1.09 mmol) is dissolved in MeOH (11 ml) and treated with an aqueous 36%-solution of formaldehyde (0.17 ml 2.18 mmol) and NaBH4 (83 mg 2.18 mmol), which is added as a solid in 3 portions. After 30 min at room temperature the reaction mixture is poured on water and extracted three times with ethyl acetate. The combined organic phases are dried over Na2SO4, filtered, evaporated to dryness and purified by SiO2 chromatography (tert.butyl methyl ether/MeOH/NH3conc. 95/4.5/0.5) to yield the title compound (550 mg 86%) as pale yellow foam.
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH:22]=[CH:23][N:24]=[CH:25][C:20]3=[CH:19][N:18]=2)[N:2]=1.[H][H]>[Pd].CO>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[C:3]([NH:11][C:12](=[O:40])[O:13][CH2:14][C@@H:15]([N:26]([CH3:39])[C:27]([NH:29][CH2:30][C:31]2[CH:36]=[CH:35][CH:34]=[C:33]([F:37])[C:32]=2[Cl:38])=[O:28])[CH2:16][C:17]2[N:21]3[CH2:22][CH2:23][NH:24][CH2:25][C:20]3=[CH:19][N:18]=2)[N:2]=1
Reactant: [H][H]
Reactant: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2cnccn12
Agent: [Pd]
Solvent: CO
Product: CN(C(=O)NCc1cccc(F)c1Cl)[C@H](COC(=O)Nc1cc2ccccc2cn1)Cc1ncc2n1CCNC2
Yield: 34.7 %

Procedure:
To a solution of (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(imidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (100 mg, 0.178 mmol) and MeOH (5 mL) were added 10% Pd—C (100 mg). The resulting mixture was stirred under 12 psi of hydrogen for h. The mixture was filtered and concentrated. The resulting residue was purified on prep-HPLC (ACN/H2O with 0.1% HCOOH) to give (S)-2-(3-(2-chloro-3-fluorobenzyl)-1-methylureido)-3-(5,6,7,8-tetrahydroimidazo[1,5-a]pyrazin-3-yl)propyl isoquinolin-3-ylcarbamate (35 mg, 35%). LRMS (M+H+) m/z 566.1.
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[N:20]=[CH:19][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31]([OH:33])=O)[CH2:25]2)=[O:22])=[CH:17][CH:16]=1.[F:34][C:35]([F:39])([F:38])[CH2:36][NH2:37]>>[CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[CH2:13][O:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]([NH:23][CH:24]2[CH2:29][CH2:28][CH2:27][N:26]([CH2:30][C:31](=[O:33])[NH:37][CH2:36][C:35]([F:39])([F:38])[F:34])[CH2:25]2)=[O:22])=[CH:19][N:20]=1
Reactant: NCC(F)(F)F
Reactant: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)O)C2)cn1
Product: Cc1onc(-c2ccccc2)c1COc1ccc(C(=O)NC2CCCN(CC(=O)NCC(F)(F)F)C2)cn1
Yield: 62 %

Procedure:
As described for example 42, (3-{[6-(5-methyl-3-phenyl-isoxazol-4-ylmethoxy)-pyridine-3-carbonyl]-amino}-piperidin-1-yl)-acetic acid (70 mg, 0.16 mmol) was converted, using 2,2,2-trifluoroethylamine instead of methylamine, to the title compound (51 mg, 62%) which was obtained as an off white solid. MS: m/e=532.0 [M+H]+.
Reaction SMILES: [CH2:1]([C:4]1([CH2:17][CH3:18])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH:2]=[CH2:3].C1(=O)C=CC(=[O:25])C=C1.O.Cl(O)(=O)(=O)=O>C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[CH2:17]([C:4]1([CH2:1][C:2](=[O:25])[CH3:3])[CH2:13][CH2:12][C:11]2[C:6](=[CH:7][CH:8]=[C:9]([O:14][CH3:15])[CH:10]=2)[C:5]1=[O:16])[CH3:18]
Reactant: O=C1C=CC(=O)C=C1
Reactant: C=CCC1(CC)CCc2cc(OC)ccc2C1=O
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: [O-][Cl+3]([O-])([O-])O
Solvent: CC#N
Solvent: O
Product: CCC1(CC(C)=O)CCc2cc(OC)ccc2C1=O
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A solution of 2-allyl-2-ethyl-6-methoxy-3,4-dihydro-1(2H)-naphthalenone (931 mg, 3.82 mmol) in acetonitrile (11 mL) was treated with benzoquinone (619 mg, 5.73 mmol), palladium(II) acetate (172 mg, 0.76 mmol), water (0.56 mL, 31 mmol), and perchloric acid (70%, 0.15 mL, 1.74 mmol). The resulting mixture was stirred overnight at room temperature, then filtered through a small plug of silica gel. The filtrate was diluted with CH2Cl2, washed with water, and the aqueous phase was back-extracted with CH2Cl2. The combined organics were washed with brine, dried over MgSO4, filtered, and concentrated under vacuum to afford crude 2-ethyl-6-methoxy-2-(2-oxopropyl)-3,4-dihydro-1(2H)-naphthalenone as an orange oil.
Reaction SMILES: CC(OC1C=CC=C(OC(C)C)C=1C1C(P(C2CCCCC2)C2CCCCC2)=CC=CC=1)C.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56].CCCCCC.CCOC(C)=O.[CH3:80][NH:81][CH3:82]>C1COCC1>[CH3:80][N:81]([CH3:82])[C:45]1[CH:54]=[CH:53][CH:52]=[C:51]2[C:46]=1[CH:47]=[C:48]1[CH2:67][C:59]3([CH2:64][O:63][C:62]([CH3:66])([CH3:65])[O:61][CH2:60]3)[CH2:58][C:49]1=[C:50]2[C:55](=[O:57])[CH3:56]
Reactant: CNC
Reactant: CC(=O)c1c2c(cc3c(Cl)cccc13)CC1(COC(C)(C)OC1)C2
Agent: CC(C)Oc1cccc(OC(C)C)c1-c1ccccc1P(C1CCCCC1)C1CCCCC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CC(=O)c1c2c(cc3c(N(C)C)cccc13)CC1(COC(C)(C)OC1)C2
Yield: 62 %

Procedure:
Follows general procedure (pag. 13): [RuPhos Palladacyle] (0.0015 g, 0.0021 mmol), LHMDS (0.17 mL of a 1.0 M solution in THF, 0.17 mmol), 5a (0.030 g, 0.087 mmol) in THF (0.3 mL), dimethylamine (0.065 mL of a 2.0 M solution in THF, 0.13 mmol). The title compound was isolated (n-hexane/AcOEt 8:2, 0.019 g, 62% yield) as a yellow solid.
Reaction SMILES: CS(O[CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]#[C:16][C:17]2[CH:22]=[CH:21][C:20]([C:23]3[CH:28]=[CH:27][C:26]([Cl:29])=[CH:25][CH:24]=3)=[CH:19][N:18]=2)=[CH:11][C:10]=1[CH3:30])(=O)=O.[NH:31]1[CH2:35][CH:34]=[CH:33][CH2:32]1>>[Cl:29][C:26]1[CH:27]=[CH:28][C:23]([C:20]2[CH:21]=[CH:22][C:17]([C:16]#[C:15][C:12]3[CH:13]=[CH:14][C:9]([O:8][CH2:7][CH2:6][N:31]4[CH2:35][CH:34]=[CH:33][CH2:32]4)=[C:10]([CH3:30])[CH:11]=3)=[N:18][CH:19]=2)=[CH:24][CH:25]=1
Reactant: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCOS(C)(=O)=O
Reactant: C1=CCNC1
Product: Cc1cc(C#Cc2ccc(-c3ccc(Cl)cc3)cn2)ccc1OCCN1CC=CC1

Procedure:
Prepared analogously to Example 5d from 110 mg (0.25 mmol) 2-{4-[5-(4-chloro-phenyl)-pyridin-2-ylethynyl]-2-methyl-phenoxy}-ethyl methanesulphonate and 1.92 mL (25 mmol) 2,5-dihydro-1H-pyrrole.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH:11]([C:13]3[N:14]([CH2:27][CH3:28])[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH:17]=3)O)=[CH:9][N:8]([Si](C(C)C)(C(C)C)C(C)C)[C:5]2=[N:6][CH:7]=1.C([SiH](CC)CC)C.FC(F)(F)C(O)=O>C(#N)C>[Cl:1][C:2]1[CH:3]=[C:4]2[C:10]([CH2:11][C:13]3[N:14]([CH2:27][CH3:28])[N:15]=[C:16]([NH:18][CH2:19][C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH:17]=3)=[CH:9][NH:8][C:5]2=[N:6][CH:7]=1
Reactant: CCn1nc(NCc2ccc(F)cc2)cc1C(O)c1cn([Si](C(C)C)(C(C)C)C(C)C)c2ncc(Cl)cc12
Agent: CC[SiH](CC)CC
Solvent: CC#N
Solvent: O=C(O)C(F)(F)F
Product: CCn1nc(NCc2ccc(F)cc2)cc1Cc1c[nH]c2ncc(Cl)cc12
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 21.9 %

Procedure:
(5-Chloro-1-triisopropylsilanyl-1H-pyrrolo[2,3-b]pyridin-3-yl)-[2-ethyl-5-(4-fluoro-benzylamino)-2H-pyrazol-3-yl]-methanol (630, 0.045 g, 0.081 mmol) was dissolved in acetonitrile (5 mL) and triethylsilane (0.4 mL, 2.0 mmol) was added, followed by trifluoroacetic acid (0.2 mL, 2.0 mmol). The reaction was stirred at room temperature for 45 minutes, then stirred at 60° C. for 45 minutes. The solvent was removed under reduced pressure, ethyl acetate was added and the organic was washed with sodium bicarbonate saturated solution and brine. After drying over anhydrous sodium sulfate, the solvent was evaporated to dryness. Purification with silica gel column chromatography eluting with a gradient of ethyl acetate (40-100%) in hexanes gave the isolation of the desired compound (P-0185, 0.0068 g, 22%). MS (ESI) [M+H+]+=384.1.
Reaction SMILES: C(OO)(C)(C)C.C([O:15][CH:16]1[CH2:21][C:20]([CH3:23])([CH3:22])[N:19]([OH:24])[C:18]([CH3:26])([CH3:25])[CH2:17]1)(=O)C1C=CC=CC=1.[CH3:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34]>[Mo](=O)(=O)=O.O>[OH:15][CH:16]1[CH2:17][C:18]([CH3:25])([CH3:26])[N:19]([O:24][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH2:32][CH2:33][CH3:34])[C:20]([CH3:22])([CH3:23])[CH2:21]1
Reactant: CCCCCCCC
Reactant: CC1(C)CC(OC(=O)c2ccccc2)CC(C)(C)N1O
Agent: O=[Mo](=O)=O
Agent: CC(C)(C)OO
Solvent: O
Product: CCCCCCCCON1C(C)(C)CC(O)CC1(C)C

Procedure:
A solution of 121.8 grams (946 mmol) of 70% aqueous tert-butyl hydroperoxide is added over a 3-hour period to a mixture of 101.5 grams (367 mmol)of 4-benzoyloxy-1-oxyl-2,2,6,6-tetramethylpiperidine, 1.3 gram of molybdenum trioxide, and 650 ml of n-octane that is preheated to 120° C. The reaction mixture is maintained at reflux temperature throughout the addition, and water is collected in a Dean-Stark trap. The reaction mixture is heated at reflux for 8.5 hours after the addition is complete in order to discharge the red color of the nitroxyl starting material. The crude reaction mixture is purified by flash chromatography (50:1 heptane: ethyl acetate) and then hydrolyzed using potassium hydroxide in ethanol to obtain the title compound as a colorless oil.
Reaction SMILES: [F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[C:10]1(=O)[O:14][CH2:13][CH2:12][CH2:11]1.C1(C)C=CC(S(O)(=O)=O)=CC=1>O>[F:1][C:2]1[CH:8]=[C:7]([F:9])[CH:6]=[CH:5][C:3]=1[N:4]1[CH2:10][CH2:11][CH2:12][C:13]1=[O:14]
Reactant: Nc1ccc(F)cc1F
Reactant: O=C1CCCO1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Product: O=C1CCCN1c1ccc(F)cc1F
Temperature: 100 °C

Procedure:
A mixture of 64.6 g of 2,4-difluoroaniline, 51.7 g of butyrolactone, 2 g of p-toluenesulphonic acid and a few drops of water is warmed to reflux (100 ° C.) with stirring. The water which forms is removed by distillation via a vigorous stream of nitrogen. During this operation, the internal temperature increases to 162° over the course of 15 hours. After cooling to room temperature, the mixture is diluted with 100 ml of diethyl ether. The ether solution is washed first with 5% strength HCl and then with 10% strength NaOH, dried and evaporated. The crystalline residue is recrystallized from ethanol. The 1-(2,4-difluorophenyl)pyrrolid-2-one obtained melts at 95°-97°.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2.N1C=CN=C1.[Si:16](Cl)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]>C(Cl)Cl>[Si:16]([O:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][CH:6]=[CH:5]2)([C:19]([CH3:22])([CH3:21])[CH3:20])([CH3:18])[CH3:17]
Reactant: Oc1ccc2[nH]ccc2c1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: c1c[nH]cn1
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)Oc1ccc2[nH]ccc2c1
Temperature: 0 °C
Reaction time: 12 h

Procedure:
To a stirred solution of 5-hydroxyindole in DCM (0.3 M) was added imidazole (2.0 eq). The mixture was cooled to 0° C. and treated with tert-butyldimethylsilyl chloride (1.0 eq). The resulting mixture was stirred at room temperature for 12 h, diluted with DCM, washed sequentially with H2O, 1N HCl (aq) and finally with brine. The combined organic fractions were dried over Na2SO4. The crude was purified by column chromatography on silica gel (Petroleum ether:Diethyl ether 90/10) to afford the title compound as a white solid.
Reaction SMILES: [CH:1]1([CH2:7][NH:8][C:9]2[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:24])([CH3:23])[CH3:22])[CH:12]=[CH:13][CH:14]=2)CCCCC1.[S:26]1[CH:30]=[CH:29][N:28]=C1C=O.[BH4-].[Na+]>CO>[S:26]1[CH:30]=[CH:29][N:28]=[C:1]1[CH2:7][NH:8][C:9]1[CH:10]=[C:11]([CH2:15][CH2:16][CH2:17][NH:18][C:19](=[O:25])[O:20][C:21]([CH3:22])([CH3:23])[CH3:24])[CH:12]=[CH:13][CH:14]=1
Reactant: CC(C)(C)OC(=O)NCCCc1cccc(NCC2CCCCC2)c1
Reactant: O=Cc1nccs1
Agent: [BH4-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)NCCCc1cccc(NCc2nccs2)c1
Reaction time: 18 h

Procedure:
A-3 Molecular seives were added to a solution of aniline 17 (0.4 g, 1.6 mmol) and thiazole-2-carbaldehyde (0.18 g, 1.6 mmol) in MeOH. The reaction mixture was stirred for 18 h and then NaBH4 (0.121 g, 3.2 mmol) was added and the reaction mixture was stirred for overnight. The reaction mixture was filtered through Celite, concentrated under reduced pressure Purification by column chromatography (100-200 silica mesh, 20% EtOAc in hexane) gave tert-butyl 3-(3-(thiazol-2-ylmethylamino)phenyl)propylcarbamate as a brown oil. Yield (0.17 g, 31%); 1H NMR (400 MHz, DMSO-d6) δ 7.73 (d, J=3.2 Hz, 1H), 7.56 (d, J=3.2 Hz, 1H), 6.96 (t, J=7.6 Hz, 1H), 6.80 (bs, 1H), 6.45-6.38 (m, 4H), 4.55 (d, J=6.0 Hz, 2H), 2.91 (q, J=6.4 Hz, 2H), 2.39 (t, J=7.2 Hz, 2H), 1.59 (quintet, J=7.2 Hz, 2H), 1.37 (s, 9H).
Reaction SMILES: [CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](N5CCOCC5)=[O:22])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1.[CH3:31][Mg]Br>C1COCC1.C1(C)C=CC=CC=1.C1COCC1>[CH:1]1([CH2:4][O:5][C:6]2[CH:30]=[CH:29][C:9]3[N:10]=[C:11]([C@H:13]4[CH2:18][CH2:17][C@H:16]([O:19][CH2:20][C:21](=[O:22])[CH3:31])[CH2:15][CH2:14]4)[O:12][C:8]=3[CH:7]=2)[CH2:3][CH2:2]1
Reactant: C[Mg]Br
Reactant: O=C(CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1)N1CCOCC1
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)CO[C@H]1CC[C@H](c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
To a solution of 6-(cyclopropylmethoxy)-2-[trans-4-(2-(morpholin-4-yl)-2-oxoethoxy)cyclohexyl]-1,3-benzoxazole (427 mg) in THF (5 mL) was added a solution (1.5 M, 1.37 mL) of methylmagnesium bromide in toluene/THF under ice-cooling. The reaction mixture was stirred at 0° C. for 1 hr, and extracted with ethyl acetate and 1M hydrochloric acid. The obtained organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The obtained residue was purified by silica gel chromatography (hexane/ethyl acetate) to give the title compound (260 mg).
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3](B(O)O)=[CH:2]1.Br[C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH:13]=[O:14].C(=O)([O-])[O-].[Na+].[Na+].O>COCCOC.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[S:1]1[CH:5]=[CH:4][C:3]([C:10]2[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=2)[CH:13]=[O:14])=[CH:2]1
Reactant: O=Cc1cccc(Br)c1
Reactant: OB(O)c1ccsc1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: COCCOC
Solvent: O
Product: O=Cc1cccc(-c2ccsc2)c1
Temperature: 80 °C
Yield: 86 %

Procedure:
3.11 g of 3-thiopheneboronic acid (0.024 mol) are added to a solution of 3-bromobenzaldehyde (3 g, 0.016 mol) in 1,2-dimethoxyethane (80 ml), followed by addition of aqueous 2N sodium carbonate solution (5.15 g, 0.048 mol) and a catalytic amount of tetrakis(triphenylphosphine)palladium (0.56 g, 4.9 10−4 mol). The reaction mixture is heated at 80° C. for 16 hours and is then cooled to room temperature and poured into water. The resulting mixture is extracted with ethyl acetate and the organic phase is washed with saturated aqueous sodium chloride solution. The organic phase is dried over magnesium sulfate and filtered, and the solvent is evaporated off under reduced pressure. The title product is isolated by chromatography on a column of silica (eluent: 90/10 cyclohexane/ethyl acetate). 2.61 g of a pale yellow solid are recovered.
Reaction SMILES: [H-].[Na+].[F:3][C:4]1[CH:22]=[C:21]([CH2:23][OH:24])[CH:20]=[CH:19][C:5]=1[O:6][C:7]1[CH:14]=[CH:13][C:10]([C:11]#[N:12])=[C:9]([C:15]([F:18])([F:17])[F:16])[CH:8]=1.Cl[C:26]1[CH:27]=[C:28]2[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]2[C:30](=[O:32])[N:31]=1>>[C:11]([C:10]1[CH:13]=[CH:14][C:7]([O:6][C:5]2[CH:19]=[CH:20][C:21]([CH2:23][O:24][C:26]3[CH:27]=[C:28]4[N:35]([C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])[CH2:34][CH2:33][N:29]4[C:30](=[O:32])[N:31]=3)=[CH:22][C:4]=2[F:3])=[CH:8][C:9]=1[C:15]([F:18])([F:16])[F:17])#[N:12]
Reactant: N#Cc1ccc(Oc2ccc(CO)cc2F)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCn2c1cc(Cl)nc2=O
Agent: [H-]
Agent: [Na+]
Product: CC(C)(C)OC(=O)N1CCn2c1cc(OCc1ccc(Oc3ccc(C#N)c(C(F)(F)F)c3)c(F)c1)nc2=O

Procedure:
The title compound was prepared by a procedure similar to that described for E1 starting from NaH, 4-(2-fluoro-4-(hydroxymethyl)phenoxy)-2-(trifluoromethyl)benzonitrile and tert-butyl 7-chloro-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.