Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](Br)[C:6]([N+:11]([O-])=O)=[CH:7][C:8]=1[O:9][CH3:10].[CH3:15][O:16][C:17]1[CH:18]=[C:19](Br)[CH:20]=[CH:21][C:22]=1[O:23][CH3:24].[N+]([O-])(O)=O>C(O)(=O)C>[CH3:15][O:16][C:17]1[C:22]([O:23][CH3:24])=[CH:21][C:20]2[C:8]3[CH:7]=[N:11][C:6]4[CH:7]=[C:8]([O:9][CH3:10])[C:3]([O:2][CH3:1])=[CH:4][C:5]=4[C:3]=3[CH:4]=[CH:5][C:19]=2[CH:18]=1
Reactant: COc1cc(Br)c([N+](=O)[O-])cc1OC
Reactant: COc1ccc(Br)cc1OC
Solvent: O=[N+]([O-])O
Solvent: CC(=O)O
Product: COc1cc2ccc3c4cc(OC)c(OC)cc4ncc3c2cc1OC
Temperature: 10 °C
Reaction time: 1 h
Yield: 92 %

Procedure:
3,4-Dimethoxy-6-nitro-bromobenzene (16). 3,4-Dimethoxybromobenzene (5 g, 23 mmol) was slowly added to a stirred solution of 35 mL concentrated nitric acid and 105 mL glacial acetic acid maintained at 10° C. The reaction mixture was stirred at 15° C. for 1 h and then diluted with 200 mL ice cold water. The resulting mixture was extracted thrice with 200 mL portions of ether. The combined organic phase was dried and evaporated in vacuo. The crude product was recrystallized from ethanol to give bright yellow needle shaped crystals of compound 16 in 92% yield; mp=122-124° C.; IR (Nujol) 1510, 1312; 1H NMR δ 3.94 (3H, s), 3.97 (3H, s), 7.12 (1H, s), 7.57 (1H, s); 13C NMR δ 56.9, 57.2, 108.0, 109.5, 117.0, 148.7, 153.3; Anal. calcd for C8H8NO4Br: C, 36.72, H, 3.14, N, 5.30; Found: C, 36.70, H, 3.13, N, 5.29.
Reaction SMILES: [I:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.S(=O)(=O)(O)O.C(=O)(O)[O-].[Na+]>C(O)(C)(C)C.C(OCC)(=O)C.O>[C:6]([N:4]1[CH:5]=[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])[C:2]([I:1])=[N:3]1)([CH3:7])([CH3:2])[CH3:5]
Reactant: CCOC(=O)c1c[nH]nc1I
Agent: O=C([O-])O
Agent: O=S(=O)(O)O
Agent: [Na+]
Solvent: O
Solvent: CCOC(C)=O
Solvent: CC(C)(C)O
Product: CCOC(=O)c1cn(C(C)(C)C)nc1I
Temperature: 100 °C
Reaction time: 3 h

Procedure:
To a solution of ethyl 3-iodo-1H-pyrazole-4-carboxylate (1.10 g, 3.91 mmol) in tert-butanol (5 mL) was added sulfuric acid (0.40 mL, 4.18 mmol, 18 M). The reaction was heated to 100° C. and stirred for 3 hours. The reaction was cooled to room temperature and diluted with ethyl acetate (100 mL) and water (25 mL). The pH was adjusted to 8 with saturated aqueous sodium bicarbonate. The layers were separated and the organics were dried over sodium sulfate, filtered, and concentrated. Purification by flash column chromatography (7-60% ethyl acetate/heptanes) gave 2 regioisomeric products.
Reaction SMILES: [CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5]Cl)[CH3:2].[C:10]([O-:18])(=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[K+].CN(C=O)C.O>C(OCC)(=O)C>[CH2:1]([O:3][CH:4]([O:7][CH2:8][CH3:9])[CH2:5][O:18][C:10](=[O:17])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)[CH3:2]
Reactant: CCOC(CCl)OCC
Reactant: O=C([O-])c1ccccc1
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Solvent: O
Product: CCOC(COC(=O)c1ccccc1)OCC
Temperature: 25 °C
Yield: 23.3 %

Procedure:
Chloroacetaldehyde diethyl acetal (1.9 g), potassium benzoate (2.0 g) and DMF (20 mL) were placed in a three-neck flask, followed by refluxing. Twenty hours later, the reaction mixture was cooled to room temperature, and water (60 mL) and ethyl acetate (80 mL) were added thereto, followed by stirring. After filtration and separation, the organic layer was concentrated and thereby yielded the target compound (0.69 g) in a yield of 30%.
Reaction SMILES: [NH2:1][C:2]1[NH:3][C:4](=O)[C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][NH:8][C:6]=2[N:7]=1.C(OC(=O)C)(=O)C.C1(N(C)C)C=CC=CC=1.O=P(Cl)(Cl)[Cl:33].Cl>CC#N>[Cl:33][C:4]1[C:5]2[C:10]([CH:11]([CH3:13])[CH3:12])=[CH:9][NH:8][C:6]=2[N:7]=[C:2]([NH2:1])[N:3]=1
Reactant: O=P(Cl)(Cl)Cl
Reactant: CC(C)c1c[nH]c2nc(N)[nH]c(=O)c12
Agent: Cl
Solvent: CN(C)c1ccccc1
Solvent: CC(=O)OC(C)=O
Solvent: CC#N
Product: CC(C)c1c[nH]c2nc(N)nc(Cl)c12
Yield: 45 %

Procedure:
A mixture of 2-amino-5-isopropyl-3,7-dihydro-pyrrolo[2,3-d]pyrimidin-4-one and acetic anhydride (20 mL) was heated to reflux for 3 h and evaporated. The residue was treated with BnNEt3Cl (8.99 g, 40 mmol), PhNMe2 (4.9 mL) and POCl3 (17 mL, 120 mmol) in CH3CN (100 mL) at 100° C. for 40 min and concentrated. The residue was poured into ice water and neutralized with 2N NaOH, extracted with EtOAc (80 mL×3), and evaporated to give an oil which was digested with methanolic 4N HCl (50 mL) at 50° C. for 2 h. After cooling, and neutralization to pH 7 with 2N NaOH, the solid was collected by filtration and dried to give 4-chloro-5-isopropyl-7H-pyrrolo[2,3-d]pyrimidin-2-ylamine (1.88 g, 45%). HPLC Rt: 5.796 min. 1H-NMR (DMSO-d6): δ 11.170 (s, 1H), 6.82 (s, 1H), 6.42 (s, 2H), 3.24 (7, 1H), 1.25 (s, 3H), 1.23 (s, 3H).
Reaction SMILES: OCCC[N:5]1[C:9]2[CH:10]=[CH:11][C:12](C(F)(F)F)=[CH:13][C:8]=2[NH:7][C:6]1=[O:18].S(Cl)(Cl)=O>ClC(Cl)Cl>[N:5]1[C:6](=[O:18])[N:7]=[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=12
Reactant: O=c1[nH]c2cc(C(F)(F)F)ccc2n1CCCO
Solvent: O=S(Cl)Cl
Solvent: ClC(Cl)Cl
Product: O=C1N=c2ccccc2=N1
Reaction time: 1 h

Procedure:
To a stirred mixture of 23 parts of 1,3-dihydro-1-(3-hydroxypropyl)-5-(trifluoromethyl)-2H-benzimidazol-2-one in 150 parts of trichloromethane are added dropwise 32 parts of sulfinyl chloride. Upon completion, the whole is heated to reflux and stirring is continued for 1 hour at a reflux temperature. After cooling, the reaction mixture is evaporated and the residue is crystallized from 2,2'-oxybispropane, yielding 14 parts (56%) of 1-(3-chloropropyl)-1,3-dihydro-5-trifluoromethyl)-2H-benzimidazol-2-one.
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23](N(OC)C)=[O:24])[CH:17]=[CH:18][C:19]=1[F:20]>>[Br:13][C:14]1[CH:15]=[C:16]([CH:21]=[CH:22][C:23](=[O:24])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])[CH:17]=[CH:18][C:19]=1[F:20]
Reactant: CON(C)C(=O)C=Cc1ccc(F)c(Br)c1
Reactant: FC(F)(F)C(F)(F)I
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(F)c(Br)c1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 65.5 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (37.7 mL, 32.9 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (21.9 mL, 32.9 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(3-bromo-4-fluoro-phenyl)-N-methoxy-N-methylacrylamide (3.2 g, 11.0 mmol, in tetrahydrofuran 10.0 mL) prepared in Step 3 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with ethyl acetate. The extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/10) to give 2.5 g of the titled compound as a yellow liquid.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:10]=[C:11]2[C:16](=[CH:17][CH:18]=1)[N:15]=[CH:14][C:13]([NH2:19])=[C:12]2[NH:20][CH2:21][CH:22]([CH3:24])[CH3:23])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:25][O:26][CH2:27][C:28](Cl)=O>ClCCl>[CH2:1]([O:8][C:9]1[CH:18]=[CH:17][C:16]2[N:15]=[CH:14][C:13]3[N:19]=[C:28]([CH2:27][O:26][CH3:25])[N:20]([CH2:21][CH:22]([CH3:24])[CH3:23])[C:12]=3[C:11]=2[CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(C)CNc1c(N)cnc2ccc(OCc3ccccc3)cc12
Reactant: COCC(=O)Cl
Solvent: ClCCl
Product: COCc1nc2cnc3ccc(OCc4ccccc4)cc3c2n1CC(C)C
Reaction time: 1 h

Procedure:
6-Benzyloxy-N4-(2-methylpropyl)quinoline-3,4-diamine was dissolved in 200 mL of dichloromethane and methoxyacetyl chloride (1.85 g, 17.1 mmol), diluted in 10 mL of dichloromethane, was added dropwise. After 1 hour, the solvent was removed and the resulting solid was dissolved in 250 mL of 3:1 methanol:water. Aqueous potassium carbonate (6M) was added and the reaction was heated at reflux temperature for 3 hours. The solvent was removed and the residue was partitioned between 200 mL of dichloromethane and 100 mL of water. The aqueous fraction was isolated and extracted three times with dichloromethane. The combined organic fractions were dried, filtered, and concentrated under reduced pressure. The resulting material was purified by flash column chromatography on silica gel eluting with a gradient of 0-4% methanol in dichloromethane. The clean fractions were combined and concentrated to give 4.2 g of 8-benzyloxy-1-(2-methylpropyl)-2-methoxymethyl-1H-imidazo[4,5-c]quinoline as a light brown solid.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7](O)=[O:8].[CH3:12][NH:13][CH3:14].C(N(C(C)C)CC)(C)C.C(OCC)(=O)C>CN(C)C=O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([I:11])=[C:6]([CH:10]=1)[C:7]([N:13]([CH3:14])[CH3:12])=[O:8]
Reactant: CNC
Reactant: O=C(O)c1cc(Br)ccc1I
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CN(C)C(=O)c1cc(Br)ccc1I
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-(7-Azabenzotriazol-1-yl)-N,N,N′,N-tetramethyluronium hexafluorophosphate (1.16 g, 3.06 mmol) was added to a solution of 5-bromo-2-iodo-benzoic acid (1.00 g, 3.06 mmol), dimethyl amine (2 M in THF, 3.06 ml, 3.06 mmol) and di-iso-propyl ethyl amine (1.59 ml, 9.18 mmol) in N,N-Dimethylformamide (12 ml). The reaction was stirred at room temperature overnight. Ethyl acetate was added and the mixture was washed with water, the organic layer was dried over magnesium sulfate and evaporated. The residue was purified by silica gel chromatography to yield 5-bromo-2-iodo-N,N-dimethyl-benzamide as a white solid. (0.96 g, 90%). MS: m/z 328.1 (M+H+).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:21][NH:22][C:23](Cl)=[O:24]>ClCCl>[CH3:21][NH:22][C:23]([N:11]1[CH2:12][CH2:13][N:8]([C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH2:9][CH2:10]1)=[O:24]
Reactant: CNC(=O)Cl
Reactant: CC(C)(C)OC(=O)N1CCNCC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CNC(=O)N1CCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a cold solution (ice bath) of piperazine-1-carboxylic acid tert-butyl ester (9.0 g, 48.32 mmol) and triethylamine (9.8 g, 96.64 mmol) in dichloromethane (100 mL) was slowly added a solution of methylaminoformyl chloride (5.0 g, 53.5 mmol) in dichloromethane at 0° C. The reaction mixture was allowed to warm to room temperature and stirred overnight, and then partitioned in dichloromethane (200 mL) and water (100 mL). Organic layer was separated, dried (MgSO4), and concentrated to yield tert-butyl 4-(methylcarbamoyl)piperazine-1-carboxylate as a solid which was dissolved in dichloromethane (100 mL) and TFA (20 mL). The solution was stirred for 12 h and the volatiles were evaporated under pressure, the oily residue was dissolved in methanol and 1N hydrogen chloride solution was added. The solid formed was filtered and washed with ether, dried to give N-methylpiperazine-1-carboxamide hydrochloride, 8.12 g (93%)
Reaction SMILES: ClC1C=C(C2C=C3C(=O)NCC(CNC(NCC4N5C=C(C6C=CC=C(Cl)C=6)C=C5C(=O)NC4)=O)N3C=2)C=CC=1.Cl.[NH2:42][CH2:43][CH2:44][C@@H:45]1[N:50]2[C:51]([C:65]3[CH:70]=[CH:69][CH:68]=[C:67]([CH3:71])[CH:66]=3)=[C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][C:61]([F:64])([F:63])[F:62])[CH:55]=3)[CH:53]=[C:49]2[C:48](=[O:72])[NH:47][CH2:46]1.[C:73]([N:77]=[C:78]=[O:79])([CH3:76])([CH3:75])[CH3:74].CCN(C(C)C)C(C)C.C([O-])(O)=O.[Na+]>C(Cl)Cl.C(OCC)(=O)C>[C:73]([NH:77][C:78]([NH:42][CH2:43][CH2:44][C@@H:45]1[N:50]2[C:51]([C:65]3[CH:70]=[CH:69][CH:68]=[C:67]([CH3:71])[CH:66]=3)=[C:52]([C:54]3[CH:59]=[CH:58][CH:57]=[C:56]([O:60][C:61]([F:64])([F:62])[F:63])[CH:55]=3)[CH:53]=[C:49]2[C:48](=[O:72])[NH:47][CH2:46]1)=[O:79])([CH3:76])([CH3:75])[CH3:74]
Reactant: Cc1cccc(-c2c(-c3cccc(OC(F)(F)F)c3)cc3n2[C@@H](CCN)CNC3=O)c1
Reactant: CC(C)(C)N=C=O
Agent: Cl
Agent: O=C(NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21)NCC1CNC(=O)c2cc(-c3cccc(Cl)c3)cn21
Agent: O=C([O-])O
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Product: Cc1cccc(-c2c(-c3cccc(OC(F)(F)F)c3)cc3n2[C@@H](CCNC(=O)NC(C)(C)C)CNC3=O)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 35 %

Procedure:
28 mg (0.065 mmol) of 1 (4S)-4-(2-aminoethyl)-6-(3-methylphenyl)-7-[3-(trifluoromethoxy)phenyl]-3,4-dihydropyrrolo[1,2-a]pyrazin-1(2H)-one hydrochloride were dissolved in 2 ml of DCM. To the obtained solution, 20 μl (0.20 mmol) of t-butyl isocyanate, 60 μl (0.33 mmol) of DIPEA, were added. The mixture was stirred at rt for 18 hours, the solution was portioned between ethyl acetate and saturated aqueous solution of NaHCO3, the organic layer was washed with brine, dried over Na2SO4 and evaporated under vacuum. The crude was purified by HPLC preparative method 1, to provide 1-tert-butyl-3-(2-{(4S)-6-(3-methylphenyl)-1-oxo-7-[3-(trifluoromethoxy)phenyl]-1,2,3,4-tetrahydropyrrolo[1,2-a]pyrazin-4-yl}ethyl)urea 12 mg (35%) as a white solid.
Reaction SMILES: Br[C:2]1[N:3]=[C:4]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[NH:8][C:7]3[N:15]=[CH:16][CH:17]=[CH:18][C:6]=3[N:5]2[C:19]=1[C:20]1[CH:25]=[CH:24][C:23]([C:26]2([NH:30][C:31](=[O:37])[O:32][C:33]([CH3:36])([CH3:35])[CH3:34])[CH2:29][CH2:28][CH2:27]2)=[CH:22][CH:21]=1.[CH3:38][O:39][C:40]1[CH:45]=[CH:44][C:43]([C:46]2[CH:51]=[CH:50][C:49](B3OC(C)(C)C(C)(C)O3)=[CH:48][N:47]=2)=[CH:42][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>CN(C=O)C.CCOC(C)=O.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.CC(P(C(C)(C)C)C1C=CC(N(C)C)=CC=1)(C)C.Cl[Pd]Cl>[C:33]([O:32][C:31](=[O:37])[NH:30][C:26]1([C:23]2[CH:24]=[CH:25][C:20]([C:19]3[N:5]4[C:6]5[CH:18]=[CH:17][CH:16]=[N:15][C:7]=5[NH:8][C:9]5[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=5[C:4]4=[N:3][C:2]=3[C:49]3[CH:48]=[N:47][C:46]([C:43]4[CH:42]=[CH:41][C:40]([O:39][CH3:38])=[CH:45][CH:44]=4)=[CH:51][CH:50]=3)=[CH:21][CH:22]=2)[CH2:27][CH2:28][CH2:29]1)([CH3:36])([CH3:35])[CH3:34]
Reactant: COc1ccc(-c2ccc(B3OC(C)(C)C(C)(C)O3)cn2)cc1
Reactant: CC(C)(C)OC(=O)NC1(c2ccc(-c3c(Br)nc4n3-c3cccnc3Nc3ccccc3-4)cc2)CCC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: COc1ccc(-c2ccc(-c3nc4n(c3-c3ccc(C5(NC(=O)OC(C)(C)C)CCC5)cc3)-c3cccnc3Nc3ccccc3-4)cn2)cc1
Yield: 102.3 %

Procedure:
A mixture of tert-butyl {1-[4-(2-bromo-9H-imidazo[1,2-d]pyrido[2,3-b][1,4]benzodiazepin-3-yl)phenyl]cyclobutyl}carbamate (50 mg, 0.090 mmol), 2-(4-methoxyphenyl)-5-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)pyridine (84 mg, 0.27 mmol), bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (6 mg, 0.09 mmol), and 2M Na2CO3 aq. (0.090 mL, 0.18 mmol) in DMF (2.5 mL) was treated with microwave (160° C. for 1 hour). The mixture was diluted with AcOEt, washed with water(×3), brine, dried over Na2SO4, then filtrated through Celite pad. The filtrate was concentrated and the residue was purified by preparative thin-layer chromatography (n-hexane/AcOEt=1:1) to afford the desired product (61 mg, quant) as a yellow solid. 1HNMR (CDCl3) 400 MHz δ: 8.79 (d, J=2.3 Hz, 1H), 8.17 (dd, J=7.4 Hz and 1.7 Hz, 1H), 8.06-8.00 (m, 2H), 7.95 (d, J=8.6 Hz, 2H), 7.63 (d, J=8.6 Hz, 1H), 7.39 (d, J=8.0 Hz, 2H), 7.32 (td, J=7.4 Hz and 1.7 Hz, 1H), 7.20 (d, J=8.0 Hz, 1H), 7.17 (td, J=8.0 Hz and 1.7 Hz, 1H), 7.00-6.95 (m, 3H), 6.83-6.78 (m, 1H), 6.61 (dd, J=8.0 Hz and 4.6 Hz, 1H), 6.26 (s, 1H), 5.12 (br s, 1H), 3.86 (s, 3H), 2.58-2.42 (m, 4H), 2.18-2.11 (m, 1H), 1.94-1.87 (m, 1H), 1.40 (br s, 9H). LCMS: 663 [M+H].
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[N:28](CC4C=CC(OC)=CC=4)[C:29]([CH3:32])=[CH:30][N:31]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:23])[F:22])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1.C([O-])=O.[NH4+]>[Pd].CCO>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([C:7]2[C:26]([C:27]3[NH:28][C:29]([CH3:32])=[CH:30][N:31]=3)=[CH:25][C:10]([C:11]([NH:13][C:14]3[CH:19]=[CH:18][C:17]([O:20][C:21]([F:24])([F:22])[F:23])=[CH:16][CH:15]=3)=[O:12])=[CH:9][N:8]=2)[CH2:3]1
Reactant: COc1ccc(Cn2c(C)cnc2-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)cc1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Cc1cnc(-c2cc(C(=O)Nc3ccc(OC(F)(F)F)cc3)cnc2N2CC[C@@H](O)C2)[nH]1

Procedure:
Palladium on carbon 10% (5.63 mg) was added to a stirred mixture of (R)-6-(3-hydroxypyrrolidin-1-yl)-5-(1-(4-methoxybenzyl)-5-methyl-1H-imidazol-2-yl)-N-(4-(trifluoromethoxy)phenyl)nicotinamide (Stage 72.1, 300 mg, 0.053 mmol) and ammonium formate (33 mg, 0.529 mmol) in EtOH (5 mL) and the mixture was heated under reflux for 52 h. The RM was filtered through Hyflo® and the solvent was evaporated off under reduced pressure to give the crude product which was purified by SFC (Column DEAP, from 21% to 26% in 10 min) to afford the title compound as an amorphous solid. HPLC (Condition 4) tR=4.01 min, UPLC-MS (Condition 8) tR=0.76 min, m/z=448.2 [M+H]+; 1H-NMR (600 MHz, DMSO-d6) δ ppm 1.66-1.92 (m, 2H), 2.11-2.29 (m, 2H), 2.91 (br.s, 1H), 3.28 (br.s, 2H), 3.38-3.50 (m, 2H), 4.22 (br. s, 1H), 4.89 (br.s, 1H), 6.63-6.74 (m, 1H), 6.87-6.96 (m, 1H), 7.35 (d, J=8.59 Hz, 2H), 7.88 (d, J=8.92 Hz, 2H), 8.12 (s, 1H), 8.77 (s, 1H), 10.22 (s, 1H), 11.85-12.17 (m, 1H).
Reaction SMILES: N#N.C[Li].C[CH2:6][O:7]CC.[C:10]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[C:24](OC)[CH:25]=2)[C:20](=[O:29])[CH2:19][CH2:18]1)=[O:16])([CH3:13])([CH3:12])[CH3:11]>C1COCC1.CCOC(C)=O.CCCCCC.CCOC(C)=O>[C:10]([O:14][C:15]([N:17]1[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=2)[C:20]([OH:29])([O:7][CH3:6])[CH2:19][CH2:18]1)=[O:16])([CH3:11])([CH3:12])[CH3:13]
Reactant: CCOCC
Reactant: COc1ccc2c(c1)N(C(=O)OC(C)(C)C)CCC2=O
Agent: N#N
Agent: [Li]C
Solvent: CCOC(C)=O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: COC1(O)CCN(C(=O)OC(C)(C)C)c2ccccc21
Temperature: 140 °C
Reaction time: 1 h
Yield: 74 %

Procedure:
To a flame dried 250 mL 3-necked rb flask equivuipped with a magnetic stir bar was added Ce(III)Cl.7H2O (2.74 g, 7.35 mmol, 2 equiv). The flask was heated in a 140° C. oil bath under reduced pressure (~1 torr) for 2.5 h. The flask was cooled to rt and slowly filled with N2 g. The white powder was suspended in dry THF (30 mL), stirred at rt for 1 h and then cooled to -78° C. To the white suspension was added a 1.4M solution of methyl lithium (MeLi) in Et2O (5.25 mL, 7.35 mmol, 2 equiv) by syringe. The dark yellow/brown solution stirred at -78° C. for 1 h and then 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-7-methoxy4-quinolone dissolved in 3 mL THF was added. The solution stirred at -78° C. for 3 h and was warmed to 0° C. for 2 h. The reaction did not go to completion and staring material was observed by TLC (silica gel, hexane/EtOAc, 3:1). The reaction was quenched with H2O (1 mL) and allowed to warm to rt. The solution was neutralized with sat NH4Cl solution (5 mL), extracted with EtOAc (3×100 mL), washed with brine (1×100 mL), dried over Na2SO4 and concentrated in vacuo to give a mix of the desired alcohol and starting material. The mixture was taken up in EtOAc and concentrated on Celite™ to give a free flowing powder which was purified via flash column chromatography (silica gel, hexanes/EtOAc, 3:1) to give 796 mg (74%) of the desired product as a vicious clear colorless oil. Data for 1-t-butoxycarbonyl-1,2,3,4-tetrahydro-4-hydroxy-4-methyl-7-methoxy-quinoline: Rf =0.20 (hexanes/EtOAc, 3:1); 1H NMR (400 MHz, CDCl3) 7.42 (d, J=8.7, 1H), 7.33 (d, J=2.5, 1H), 6.66 (dd, J=2.5, 8.6, 1H), 3.98 (m, 1H), 3.79 (s, 3H, OCH3), 3.61 (m, 1H), 1.98 (m, 2H), 1.58 (s, 3H), 1.53 (s, 9H).
Reaction SMILES: [Te:1]([Cl:5])(Cl)(Cl)[Cl:2].[C:6]1([O:12][CH3:13])[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.Cl>>[CH3:13][O:12][C:6]1[CH:11]=[CH:10][C:9]([Te:1]([Cl:5])([Cl:2])[C:9]2[CH:10]=[CH:11][C:6]([O:12][CH3:13])=[CH:7][CH:8]=2)=[CH:8][CH:7]=1
Reactant: COc1ccccc1
Reactant: Cl[Te](Cl)(Cl)Cl
Agent: Cl
Product: COc1ccc([Te](Cl)(Cl)c2ccc(OC)cc2)cc1
Yield: 87 %

Procedure:
Tellurium tetrachloride (7.50 g, 28 mmol) and anisole (15 g, 139 mmol) were stirred at 180° for 18 h under a slow stream of nitrogen. After this time 48 mmol of hydrogen chloride had been evolved and the excess anisole was removed under high vacuum. The remaining brown solid was recrystallised from benzene to afford bis-(p-methoxyphenyl)tellurium dichloride (10.05 g, 88%), m.p. 181°-182° (lit., 181°-182°), δ(CDCl3) 8.01 (4H,d,J 9 Hz), 7.03 (4H,d,J 9 Hz) and 3.89 (6H,s).
Reaction SMILES: [NH2:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1.[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20](Cl)(=[O:22])=[O:21]>>[CH3:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=1[S:20]([NH:1][C:2]1[S:3][CH:4]=[C:5]([CH2:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:6]=1)(=[O:22])=[O:21]
Reactant: Cc1ccccc1S(=O)(=O)Cl
Reactant: CCOC(=O)Cc1csc(N)n1
Product: CCOC(=O)Cc1csc(NS(=O)(=O)c2ccccc2C)n1

Procedure:
The title compound was prepared from ethyl 2-amino-4-thiazolylacetate and 2-methylbenzenesulfonyl chloride according to METHOD A, giving 0.22 g (32%) of a pink powder: 1H NMR (CDCl3) δ: 1.3 (3H, t), 2.5 (3H, s), 3.9 (2H, s), 4.2 (2H, q), 6.4 (1H, s), 7.8-7.2 (3H, m), 8.1 (1H, t).
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([OH:14])=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:15][O:16][C:17]([C:19]1[S:20][C:21]([CH:24]=O)=[CH:22][CH:23]=1)=[O:18].C(OC(=O)C)(=O)C.C(N(CC)CC)C>O.C(O)(=O)C>[CH3:15][O:16][C:17]([C:19]1[S:20][C:21](/[CH:24]=[C:11](\[C:8]2[CH:9]=[CH:10][C:5]([C:1]([CH3:4])([CH3:2])[CH3:3])=[CH:6][CH:7]=2)/[C:12]([OH:14])=[O:13])=[CH:22][CH:23]=1)=[O:18]
Reactant: COC(=O)c1ccc(C=O)s1
Reactant: CC(C)(C)c1ccc(CC(=O)O)cc1
Solvent: CC(=O)OC(C)=O
Solvent: CC(=O)O
Solvent: CCN(CC)CC
Product: COC(=O)c1ccc(/C=C(/C(=O)O)c2ccc(C(C)(C)C)cc2)s1
Temperature: 120 °C
Reaction time: 16 h
Yield: 67.2 %

Procedure:
To (4-tert-butyl-phenyl)-acetic acid (1.15 g, 6.0 mmol) was added 5-formyl-thiophene-2-carboxylic acid methyl ester (1 g, 5.7 mmol), acetic anhydride (3.08 g, 30.2 mmol), and triethyl amine (574 mg, 5.7 mmol). The resulting mixture was stirred at 120° C. for 16 hours and cooled down. Water (1.9 ml) was added. The reaction mixture was heated up to 100° C. for 5 minutes in microwave and cooled down to 23° C. A mixture of acetic acid and water (2.5 ml:2.5 ml) was added. The resulting reaction mixture was stirred at 23° C. for 1 hour. The precipitate was filtered off, washed with 25% aqueous acetic acid, then water. The solid was dried under high vacuum to afford 5-[(E)-2-(4-tert-Butyl-phenyl)-2-carboxy-vinyl]-thiophene-2-carboxylic acid methyl ester as a brownish solid (1.32 g, 67%).