Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14](=[O:28])[CH2:15][CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1C[C@H]2N(C[C@H]3[C@@H]4CCCCN4C[C@@H]2C3)CC1.[F:46][C:47]1[CH:52]=[CH:51][C:50]([C:53]2[CH:58]=[CH:57][C:56]([CH2:59][CH2:60][CH:61]=[O:62])=[CH:55][CH:54]=2)=[CH:49][CH:48]=1>ClCCl.[Ti](Cl)(Cl)(Cl)Cl>[CH2:1]([C@H:8]1[CH2:12][S:11][C:10](=[O:13])[N:9]1[C:14]([C@@H:15]([C@@H:61]([OH:62])[CH2:60][CH2:59][C:56]1[CH:57]=[CH:58][C:53]([C:50]2[CH:51]=[CH:52][C:47]([F:46])=[CH:48][CH:49]=2)=[CH:54][CH:55]=1)[CH2:16][N:17]1[C:22](=[O:23])[C:21]2[CH:24]=[CH:25][CH:26]=[CH:27][C:20]=2[N:19]=[N:18]1)=[O:28])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=CCCc1ccc(-c2ccc(F)cc2)cc1
Reactant: O=C(CCn1nnc2ccccc2c1=O)N1C(=O)SC[C@@H]1Cc1ccccc1
Agent: Cl[Ti](Cl)(Cl)Cl
Agent: C1CCN2C[C@@H]3C[C@@H](CN4CCCC[C@@H]34)[C@H]2C1
Solvent: ClCCl
Product: O=C1SC[C@H](Cc2ccccc2)N1C(=O)[C@H](Cn1nnc2ccccc2c1=O)[C@@H](O)CCc1ccc(-c2ccc(F)cc2)cc1
Temperature: 0 °C
Reaction time: 0.21 h

Procedure:
In a flame-dried flask, 3-{3-[(4S)-4-benzyl-2-oxo-1,3-thiazolidin-3-yl]-3-oxopropyl}-1,2,3-benzotriazin-4(3H)-one (0.25 g) was taken up in dichloromethane (10 mL) and cooled to 0° C. Titanium tetrachloride (0.76 mL, 1 M solution) was added drop-wise and the reaction mixture was stirred for 10 to 15 minutes. (−)-Sparteine (0.36 mL) was added slowly to the reaction mixture and stirred at 0° C. for 20 minutes. A solution of the compound obtained from step e above (0.17 g) in dichloromethane (10 mL) was added slowly, and stirring was continued at 0° C. After 3 hours, the reaction was quenched with the drop-wise addition of saturated ammonium chloride solution, and dichloromethane was added. The organic layer was separated and the aqueous layer was extracted with dichloromethane. The organic layer was washed with brine, dried over anhydrous sodium sulphate, and concentrated under reduced pressure. The crude product thus obtained was purified by silica gel flash column chromatography using 30% ethyl acetate in hexane as eluant to afford the title compound (0.2 g).
Reaction SMILES: [H-].[Na+].[CH2:3]([O:5][CH2:6][CH2:7][OH:8])[CH3:4].[CH:9]1([N:14]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16](F)[C:15]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10]1>C1COCC1>[CH:9]1([N:14]2[C:19]3[N:20]=[C:21]([S:24][CH3:25])[N:22]=[CH:23][C:18]=3[CH:17]=[C:16]([O:8][CH2:7][CH2:6][O:5][CH2:3][CH3:4])[C:15]2=[O:27])[CH2:13][CH2:12][CH2:11][CH2:10]1
Reactant: CCOCCO
Reactant: CSc1ncc2cc(F)c(=O)n(C3CCCC3)c2n1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CCOCCOc1cc2cnc(SC)nc2n(C2CCCC2)c1=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a suspension of sodium hydride (45 mg, 1.1 mmol, 60% oil dispersion) in THF (10 mL), under nitrogen, was added 2-ethoxyethanol (113 mg, 1.25 mmol). The reaction mixture was stirred at RT for 30 min. To this mixture, 8-cyclopentyl-6-fluoro-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one was added. The reaction mixture was then heated to reflux and stirred overnight. The cooled solution was quenched with water (25 mL) and extracted with ethyl acetate (50 mL). The organic layer was subsequently washed twice with aq. NH4Cl (20 mL each) and brine (20 mL). The organic layer was dried over magnesium sulfate. Removal of the drying agents and evaporation of the solvent gave a yellow oil, which was chromatographed on silica gel eluted with an ethyl acetate/hexane gradient to give 8-cyclopentyl-6-(2-ethoxy-ethoxy)-2-methylsulfanyl-8H-pyrido[2,3-d]pyrimidin-7-one as a clear oil (289 mg, 0.83 mmol). 1H NMR δ (400 MHz, CDCl3) 8.52 (s, 1H), 6.77 (s, 1H), 6.04–5.95 (m, 1H), 4.16 (t, J=4.0 Hz, 2H), 3.86 (t, J=4.0 Hz, 2H), 3.58 (q, J=8.0 Hz, 2H), 2.59 (s, 3H), 2.34–2.25 (m, 2H), 2.13–2.03 (m, 2H), 1.91–1.82 (m, 2H), 1.71–1.60 (m, 2H), 1.20 (t, J=8.0 Hz, 3H); MS (APCI+) 350 (M+1).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[O:3][C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1.Br[CH2:14][CH2:15][CH2:16][OH:17].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C>[F:1][C:2]([F:11])([F:12])[O:3][C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:14][CH2:15][CH2:16][OH:17]
Reactant: OCCCBr
Reactant: Oc1cccc(OC(F)(F)F)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: OCCCOc1cccc(OC(F)(F)F)c1
Temperature: 80 °C
Yield: 80.6 %

Procedure:
To a solution of 3-(trifluoromethoxy)phenol (0.3 g, 1.68 mmol) in DMF (10 mL) was added 3-bromopropan-1-ol (0.47 g, 3.37 mmol) and potassium carbonate (0.47 g, 3.37 mmol). The reaction was heated at 80° C. overnight. The mixture was cooled and partitioned between ethyl acetate and water. The organic layer was dried over sodium sulfate, filtered and concentrated to give a crude product which was purified by column chromatography eluting with petroleum ether and ethyl acetate (10:1) to give 3-(3-(trifluoromethoxy)phenoxy)propan-1-ol (0.32 g, 80.6% yield) as yellow oil.
Reaction SMILES: [CH2:1]1[N:16]2[C:17]3[C:8]([O:9][C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:15]=42)=[CH:7][CH:6]=[CH:5][C:4]=3[C:3](=[O:18])[CH2:2]1.[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH:25]=O)[CH:20]=1>>[N:19]1[CH:24]=[CH:23][CH:22]=[C:21]([CH2:25][C:2]2[C:3](=[O:18])[C:4]3[CH:5]=[CH:6][CH:7]=[C:8]4[C:17]=3[N:16]([CH:1]=2)[C:15]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[O:9]4)[CH:20]=1
Reactant: O=C1CCN2c3ccccc3Oc3cccc1c32
Reactant: O=Cc1cccnc1
Product: O=c1c(Cc2cccnc2)cn2c3c(cccc13)Oc1ccccc1-2
Yield: 87.2 %

Procedure:
According to Example 1<step 4>, 1,2-dihydro-3H-pyrido[3,2,1-kl]phenoxazin-3-one (1 g) prepared by the procedure described in literature (J. Org. Chem., 24, 1699 (1959)) was reacted with pyridine-3-aldehyde (0.7 g) to obtain the title compound (1.2 g; 88%). The chemical structure thereof is shown below.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][N:6]2[C:11]([C:12]([F:15])([F:14])[F:13])=[CH:10][C:9]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=3)=[N:8][C:7]=12)#[CH:2].Br[C:27]1[S:31][C:30]([S:32]([N:35]2[CH2:40][CH2:39][N:38]([CH3:41])[CH2:37][CH2:36]2)(=[O:34])=[O:33])=[CH:29][CH:28]=1>>[CH3:41][N:38]1[CH2:37][CH2:36][N:35]([S:32]([C:30]2[S:31][C:27]([C:2]#[C:1][C:3]3[CH:4]=[N:5][N:6]4[C:11]([C:12]([F:14])([F:13])[F:15])=[CH:10][C:9]([C:16]5[CH:21]=[CH:20][CH:19]=[C:18]([C:22]([F:25])([F:24])[F:23])[CH:17]=5)=[N:8][C:7]=34)=[CH:28][CH:29]=2)(=[O:34])=[O:33])[CH2:40][CH2:39]1
Reactant: C#Cc1cnn2c(C(F)(F)F)cc(-c3cccc(C(F)(F)F)c3)nc12
Reactant: CN1CCN(S(=O)(=O)c2ccc(Br)s2)CC1
Product: CN1CCN(S(=O)(=O)c2ccc(C#Cc3cnn4c(C(F)(F)F)cc(-c5cccc(C(F)(F)F)c5)nc34)s2)CC1

Procedure:
The title compound was prepared from 3-ethynyl-7-trifluoromethyl-5-(3-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine (example C.10) (178 mg, 0.5 mmol) and 1-(5-bromo-thiophene-2-sulfonyl)-4-methyl-piperazine (example B.50) (163 mg, 0.5 mmol) according to general procedure II. Obtained as an orange solid (210 mg, 70%). MS (EI) 599.1 [(M)+]; mp 191° C.
Reaction SMILES: [C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)([OH:3])=O.[CH:18]1[C:23]([C:24]([NH:26][NH2:27])=[O:25])=[CH:22][CH:21]=[N:20][CH:19]=1>>[C:24]([NH:26][NH:27][C:1]([C:4]1[C:5](=[O:17])[O:6][C:7]2[C:12]([CH:13]=1)=[C:11]([CH3:14])[CH:10]=[C:9]([O:15][CH3:16])[CH:8]=2)=[O:3])(=[O:25])[C:23]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1
Reactant: COc1cc(C)c2cc(C(=O)O)c(=O)oc2c1
Reactant: NNC(=O)c1ccncc1
Product: COc1cc(C)c2cc(C(=O)NNC(=O)c3ccncc3)c(=O)oc2c1

Procedure:
Compound 213 was prepared following the preparation of compound 26 except that 3-carboxy-5-methyl-7-methoxy-coumarin reacted with isoniazid to give the title compound 213.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[S:17][C:18]([CH:24]([CH3:26])[CH3:25])=[C:19]([CH:21]([CH3:23])[CH3:22])[CH:20]=2)=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([O:7]C)=[O:6]>[OH-].[Na+]>[CH3:1][O:2][C:3]1[CH:12]=[C:11]([NH:13][C:14]([C:16]2[S:17][C:18]([CH:24]([CH3:26])[CH3:25])=[C:19]([CH:21]([CH3:22])[CH3:23])[CH:20]=2)=[O:15])[CH:10]=[CH:9][C:4]=1[C:5]([OH:7])=[O:6]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)cc1OC
Agent: [Na+]
Agent: [OH-]
Product: COc1cc(NC(=O)c2cc(C(C)C)c(C(C)C)s2)ccc1C(=O)O
Yield: 86.5 %

Procedure:
The aforementioned ester (42 mg, 0.112 mmol) was hydrolyzed with sodium hydroxide in a conventional manner, and extraction and recrystallization were performed to obtain the title compound (42, 35 mg, 88%) as colorless needles.
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:15][CH2:14][CH2:13][CH:12]1[C:16]1[CH:24]=[CH:23][C:19]([C:20](O)=[O:21])=[C:18]([F:25])[CH:17]=1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.S(Cl)([Cl:28])=O>ClCCl>[Cl:28][C:20]([C:19]1[CH:23]=[CH:24][C:16]([CH:12]2[CH2:13][CH2:14][CH2:15][N:11]2[C:9]([O:8][CH2:1][C:2]2[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=2)=[O:10])=[CH:17][C:18]=1[F:25])=[O:21]
Reactant: O=C(O)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Reactant: O=S(Cl)Cl
Solvent: ClCCl
Product: O=C(Cl)c1ccc(C2CCCN2C(=O)OCc2ccccc2)cc1F
Temperature: 25 °C
Reaction time: 8 h
Yield: 100.1 %

Procedure:
To a stirred solution of 4-(1-(benzyloxycarbonyl)pyrrolidin-2-yl)-2-fluorobenzoic acid (8.4 g, 24.5 mmol) in anhydrous dichloromethane (300 mL) was added dropwise thionyl chloride (2.2 mL, 29.4 mmol) at 0° C. After the addition, the reaction mixture was stirred at room temperature overnight. The solvent was removed in vacuo to give benzyl 2-(4-(chlorocarbonyl)-3-fluorophenyl)pyrrolidine-1-carboxylate (8.87 g).
Reaction SMILES: [O-]CC.[Na+].Br[CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH:22]=[O:23].[CH2:24]([SH:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>C(O)C>[CH2:24]([S:31][CH2:6][CH2:7][CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[C:18]([CH:19]=[O:20])=[CH:17][C:16]([CH3:21])=[CH:15][C:14]=1[CH:22]=[O:23])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: Cc1cc(C=O)c(OCCCCCCBr)c(C=O)c1
Reactant: SCc1ccccc1
Agent: CC[O-]
Agent: [Na+]
Solvent: CCO
Product: Cc1cc(C=O)c(OCCCCCCSCc2ccccc2)c(C=O)c1

Procedure:
A solution of sodium ethoxide (69 mg sodium, 3 mmol in ethanol 1 ml) was added to a stirred suspension of 2-(6-bromohexyloxy)-5-methyl-1,3-benzenedicarboxaldehyde (0.98 g, 3 mmol) and benzyl mercaptan (0.35 g, 3 mmol) in ethanol (10 ml) at room temperature under nitrogen. After 1 hour evaporated, water (10 ml) and 2M sodium hydroxide (2 ml) added and extracted with diethyl ether (10 ml). The extracts were washed with water, dried, filtered and evaporated to an oil (1.12 g). Chromatography on silica eluting with dichloromethane gave 2-(6-benzylthiohexyloxy)-5-methyl-1,3-benzenedicarboxaldehyde as a colourless oil.
Reaction SMILES: Cl[C:2]1[CH:3]=[C:4](C#C)[C:5]2[O:9][C:8]([CH2:10][C:11]3[CH:16]=[C:15](C(C)(C)C)[C:14](O)=[C:13](C(C)(C)C)[CH:12]=3)=[N:7][C:6]=2[CH:26]=1.BrC1C=CC=C[N:31]=1>C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[N:31]1[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=1[C:11]#[C:10][C:8]1[O:9][C:5]2[CH:4]=[CH:3][CH:2]=[CH:26][C:6]=2[N:7]=1
Reactant: C#Cc1cc(Cl)cc2nc(Cc3cc(C(C)(C)C)c(O)c(C(C)(C)C)c3)oc12
Reactant: Brc1ccccn1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: CCN(CC)CC
Product: C(#Cc1nc2ccccc2o1)c1ccccn1
Temperature: 90 °C
Yield: 104.2 %

Procedure:
A suspension of 5-chloro-2-(3,5-di-t-butyl-4-hydroxy-benzyl)-7-ethynyl-benzoxazole (2.38 g, 6.0 mM), 2-bromo-pyridine (0.66 ml, 98%, 6.6 mM), bis(triphenylphosphine)palladium(II) dichloride (21.1 mg, 30 uM) and copper (I) iodide (1.2 mg, 6 uM) in triethylamine (12 ml) was heated at 90° C., under argon, for 1.5 hours. The triethylamine was removed in-vacuo and the residue dissolved in ether (100 ml). The organics were washed with water (50 ml), 1N HCl (100 ml) and saturated aqueous sodium hydrogen carbonate (100 ml), dried (Na2SO4) and evaporated in-vacuo to give 2.96 g (104.2%) of crude pyridylethynylbenzoxazole. The crude benzoxazole was purified by column chromatography (SiO2 ; dichloromethane), and the product crystallized from methanol and suspended in hot water. The resulting crystals were collected, washed, and dried to give 1.49 g (52.5%) of the title compound (top 138°-9° C.).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]2[C:10]3[C:17]([CH3:18])=[C:16]([C:19](O)=[O:20])[S:15][C:11]=3[N:12]=[CH:13][N:14]=2)=[C:4]([O:22][C@H:23]2[CH2:28][CH2:27][C@H:26]([N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]2)[CH:3]=1.[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH2:39]>>[CH3:34][N:35]([CH3:40])[CH2:36][CH2:37][CH2:38][NH:39][C:19]([C:16]1[S:15][C:11]2[N:12]=[CH:13][N:14]=[C:9]([NH:8][C:5]3[CH:6]=[CH:7][C:2]([F:1])=[CH:3][C:4]=3[O:22][C@H:23]3[CH2:28][CH2:27][C@H:26]([N:29]([CH3:33])[C:30](=[O:32])[CH3:31])[CH2:25][CH2:24]3)[C:10]=2[C:17]=1[CH3:18])=[O:20]
Reactant: CC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)O)c(C)c23)CC1
Reactant: CN(C)CCCN
Product: CC(=O)N(C)[C@H]1CC[C@H](Oc2cc(F)ccc2Nc2ncnc3sc(C(=O)NCCCN(C)C)c(C)c23)CC1

Procedure:
Prepared analogously to 1.4 from 0.094 g 4-(4-Fluoro-2-(trans-4-(N-methylacetamido)cyclohexyloxy)phenylamino)-5-methylthieno[2,3-d]pyrimidine-6-carboxylic acid (cpd.7.2) and 3-(dimethylamino)propylamine (126 μl).
Reaction SMILES: [NH2:1][C:2]1[CH:18]=[C:17]([O:19][CH3:20])[CH:16]=[CH:15][C:3]=1[C:4]([NH:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([Br:13])[C:8]=1[CH3:14])=[O:5].Cl[C:22](Cl)([O:24]C(=O)OC(Cl)(Cl)Cl)Cl.C([O-])(O)=O.[Na+]>C1COCC1>[Br:13][C:9]1[C:8]([CH3:14])=[C:7]([N:6]2[C:4](=[O:5])[C:3]3[C:2](=[CH:18][C:17]([O:19][CH3:20])=[CH:16][CH:15]=3)[NH:1][C:22]2=[O:24])[CH:12]=[CH:11][CH:10]=1
Reactant: O=C(OC(Cl)(Cl)Cl)OC(Cl)(Cl)Cl
Reactant: COc1ccc(C(=O)Nc2cccc(Br)c2C)c(N)c1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: C1CCOC1
Product: COc1ccc2c(=O)n(-c3cccc(Br)c3C)c(=O)[nH]c2c1
Yield: 68.4 %

Procedure:
A solution of 2-amino-N-(3-bromo-2-methylphenyl)-4-methoxybenzamide (596 mg, 1.78 mmol) and triphosgene (633 mg, 2.13 mmol) in THF (30 mL) was stirred at room temperature for 2 h. The mixture was treated with saturated aqueous NaHCO3 and stirred until gas evolution ceased. The resulting mixture was extracted twice with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (40 g), eluting with EtOAc -hexanes (gradient from 0-100%), to give 3-(3-bromo-2-methylphenyl)-7-methoxyquinazoline-2,4(1H,3H)-dione as a white solid (440 mg, 68% yield). Mass spectrum m/z 361, 363 (M+H)+.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)[CH2:10][OH:11])=[O:7])([CH3:4])([CH3:3])[CH3:2].C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.CO>CCOCC.CCCCCC.C(Cl)Cl.CCN(CC)CC>[C:1]([O:5][C:6]([NH:8][C@@H:9]([C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)[C:10]([Br:19])=[O:11])=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: BrC(Br)(Br)Br
Reactant: CC(C)(C)OC(=O)N[C@H](CO)c1ccccc1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)N[C@H](C(=O)Br)c1ccccc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 76.4 %

Procedure:
To a stirred solution of N-(tert-butoxycarbonyl)-2(S)-phenylglycinol (1.67 g, 7.0 mmol) and carbon tetrabromide (5.0 g, 15 mmol) in 35 mL of anhydrous ether was added a solution of triphenylphosphine (4.09 g, 15.4 mmol) in 25 mL of anhydrous ether at 0° C. The reaction mixture was stirred at room temperature for 12 h. The ether suspension was filtered with a sintered glass funnel containing a bed of celite. The ether filtrate was concentrated under reduced pressure to give a crude product. Flash chromatography (silica gel, 0.2% MeOH, 0.004% Et3N, 40% methylene chloride in hexane) afforded 1.68 g of product (80% yield) as a white solid, mp 108-109° C. 1H NMR (CDCl3) δ 1.431 (s, 9H, tert-Bu) 3.664 (s, 2H, BrCH2), 5.001 (s, 1H, NH), 5.272 (d, 1H, J=7.8 Hz, benzyl), 7.25-7.38 (m, 5H, aryl); 13C NMR (CDCl3) δ 28.24 (CH3) 37.00 (BrCH2), 54.80 (CMe3), 79.98 (NCH), 126.35 (aromatic), 127.88, 128.59, 139.40, 154.91.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([N+:18]([O-])=O)=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2.CO.[Cl-].[NH4+]>C1COCC1.[Zn]>[Cl:1][C:2]1[CH:3]=[CH:4][N:5]2[C:10]=1[C:9]([O:11][C:12]1[CH:17]=[CH:16][C:15]([NH2:18])=[CH:14][C:13]=1[F:21])=[N:8][CH:7]=[N:6]2
Reactant: O=[N+]([O-])c1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Agent: [Cl-]
Agent: [NH4+]
Agent: [Zn]
Solvent: CO
Solvent: C1CCOC1
Product: Nc1ccc(Oc2ncnn3ccc(Cl)c23)c(F)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 83.6 %

Procedure:
To a solution of 5-chloro-4-(2-fluoro-4-nitrophenoxy)pyrrolo[2,1-f][1,2,4]triazine (2.00 g, 6.48 mmol) in THF (50 mL)/MeOH (80 mL) was added zinc dust (2.12 g, 32.4 mmol) followed by ammonium chloride (1.73 g, 32.4 mmol). After stirring at rt for 8 h, the reaction mixture was filtered through Celite® with MeOH and then concentrated in vacuo. The residue was taken up in ethyl acetate (200 mL) and washed with water (2×100 mL) then brine (1×100 mL). The organic phase was dried over anhydrous Na2SO4 and concentrated in vacuo. The crude product was purified by flash chromatography on silica gel (50% EtOAc/hexanes) to give the title compound (1.51 g, 84%) as a pale yellow solid. 1H NMR (CDCl3) δ 7.95 (s, 1H), 7.69 (d, 1H, J=2.8 Hz), 7.09 (t, 1H, J=8.4 Hz), 6.79 (d, 1H, J=2.8 Hz), 6.58 (dd, 1H, J=11.6, 2.6 Hz), 6.51 (d, 1H, J=8.7 Hz), 3.92 (br s, 2H); MS(ESI+) m/z 279.2 (M+H)+.
Reaction SMILES: CCN(C(C)C)C(C)C.Cl.[NH2:11][CH2:12][C:13]([N:15]1[CH2:20][CH2:19][N:18]([C:21](=[O:32])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=2[C:28]([F:31])([F:30])[F:29])[CH2:17][CH2:16]1)=[O:14].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C.[N:54]1([C:59]2[CH:67]=[CH:66][C:62]([C:63](O)=[O:64])=[CH:61][CH:60]=2)[CH:58]=[CH:57][N:56]=[CH:55]1>CN(C=O)C.O>[N:54]1([C:59]2[CH:60]=[CH:61][C:62]([C:63]([NH:11][CH2:12][C:13](=[O:14])[N:15]3[CH2:16][CH2:17][N:18]([C:21](=[O:32])[C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][C:23]=4[C:28]([F:31])([F:29])[F:30])[CH2:19][CH2:20]3)=[O:64])=[CH:66][CH:67]=2)[CH:58]=[CH:57][N:56]=[CH:55]1
Reactant: NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1
Reactant: O=C(O)c1ccc(-n2ccnc2)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(NCC(=O)N1CCN(C(=O)c2ccccc2C(F)(F)F)CC1)c1ccc(-n2ccnc2)cc1
Temperature: 25 °C
Reaction time: 0.03 h
Yield: 33.8 %

Procedure:
DIPEA (247.2 mg, 0.33 mL, 1.9 mmol) was added to a stirred solution of 2-amino-1-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethanone hydrochloride salt (164.3 mg, 0.46 mmol) in DMF (2 mL). HOBT (63.1 mg, 0.46 mmol) and EDCI (179.2 mg, 0.93 mmol) were then added at room temperature. After 2 minutes, 4-imidazol-1-yl-benzoic acid (80 mg, 0.42 mmol) was added and the resulting mixture was stirred at room temperature overnight. Cold water was then added and the product was extracted with EtOAc and the organic layer was washed with brine. The organic phase was dried over Na2SO4 and concentrated under reduced pressure to get the residue. The obtained residue was purified by column chromatography (using silica gel of 60-120 mesh and 50% EtOAc in Hexane as eluent) to afford 69 mg (33.4% yield) 4-imidazol-1-yl-N-{2-oxo-2-[4-(2-trifluoromethyl-benzoyl)-piperazin-1-yl]-ethyl}-benzamide. LCMS Purity: 94.26%. 1H NMR (DMSO-d6): δ 8.8-8.7 (s, 1H), 8.4 (s, 1H), 8.1-8.0 (d, 2H), 7.9-7.7 (m, 5H), 7.7-7.62 (m, 1H), 7.62-7.5 (t, 1H), 7.2-7.1 (s, 1H), 4.3-4.1 (d, 2H), 3.8-3.5 (m, 4H), 3.5-3.4 (m, 2H), 3.24-3.0 (m, 2H).
Reaction SMILES: C[O:2][C:3]1[CH:12]=[C:11]([CH3:13])[C:10]2[N:9](COCC[Si](C)(C)C)[C:8](=[O:22])[C:7]3[S:23][C:24]([CH3:26])=[CH:25][C:6]=3[C:5]=2[C:4]=1[C:27]1[CH:32]=[CH:31][C:30]([C@@H:33]([CH3:43])[CH2:34][NH:35]C(=O)OC(C)(C)C)=[CH:29][CH:28]=1.B(Br)(Br)Br>>[NH2:35][CH2:34][C@@H:33]([C:30]1[CH:29]=[CH:28][C:27]([C:4]2[C:5]3[C:6]4[CH:25]=[C:24]([CH3:26])[S:23][C:7]=4[C:8](=[O:22])[NH:9][C:10]=3[C:11]([CH3:13])=[CH:12][C:3]=2[OH:2])=[CH:32][CH:31]=1)[CH3:43]
Reactant: COc1cc(C)c2c(c1-c1ccc([C@@H](C)CNC(=O)OC(C)(C)C)cc1)c1cc(C)sc1c(=O)n2COCC[Si](C)(C)C
Agent: BrB(Br)Br
Product: Cc1cc2c(s1)c(=O)[nH]c1c(C)cc(O)c(-c3ccc([C@@H](C)CN)cc3)c12
Reaction time: 1 h

Procedure:
To a solution of (R)-tert-butyl 2-(4-(8-methoxy-2,6-dimethyl-4-oxo-5-((2-(trimethylsilyl)ethoxy)methyl)-4,5-dihydrothieno[2,3-c]quinolin-9-yl)phenyl)propylcarbamate (40 mg, 0.064 mmol) in CH2C2 (1 mL) at 0° C. was added BBr3 (1.0 M in methylene chloride, 1.0 mL, 1.0 mmol) and the reaction was stirred at that temperature for 1 h and quenched by pouring onto water or ice-water. The resulting mixture was concentrated and the residue was dissolved methanol (2 mL) and treated with NH4OH (2 mL). The resulting mixture was stirred at rt for 2 h and purified by preparatory HPLC (C18 silica, acetonitrile/water (with 0.05% TFA) gradient). The desired fractions were combined, concentrated and the residue was dissolved in aqueous HCl, concentrated and dried under high vacuum to afford the desired product as a hydrochloride salt: 1H NMR (500 MHz, CD3OD) δ 7.55 (dd, J=7.9, 1.9 Hz, 1H), 7.45 (dd, J=7.7, 1.9 Hz, 1H), 7.34 (dd, J=7.9, 1.8 Hz, 1H), 7.28 (dd, J=7.7, 1.7 Hz, 1H), 7.06 (d, J=0.7 Hz, 1H), 5.70 (d, J=1.1 Hz, 1H), 3.29-3.13 (m, 3H), 2.55 (s, 3H), 2.30 (d, J=1.0 Hz, 3H), 1.50 (d, J=6.5 Hz, 3H); ESI MS m/z 378 [C22H22N2O2S+H]+.
Reaction SMILES: O=P(Cl)(Cl)Cl.[CH3:6][O:7][C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[CH:10][C:9]=1[OH:16].CN([CH:20]=[O:21])C.[OH-].[Na+].OS([O-])(=O)=O.[Na+]>O.CCOCC>[OH:16][C:9]1[C:8]([O:7][CH3:6])=[CH:13][C:12]([CH:20]=[O:21])=[C:11]([O:14][CH3:15])[CH:10]=1
Reactant: CN(C)C=O
Reactant: COc1ccc(OC)c(O)c1
Agent: O=S(=O)([O-])O
Agent: [Na+]
Agent: [OH-]
Solvent: CCOCC
Solvent: O
Solvent: O=P(Cl)(Cl)Cl
Product: COc1cc(C=O)c(OC)cc1O
Reaction time: 48 h
Yield: 9.4 %

Procedure:
POCl3 was added dropwise (T<20° C.) to a solution of intermediate 57, 2,5-Dimethoxyphenol (10.8 g, 0.07 mol) in DMF (22 mL, 0.28 mol) under vigorous stirring and cooling with an ice bath. The reaction mixture was stirred at room temperature for 72 h, then at 50° C. for 48 h, cooled, and diluted with H2O and ether (50 mL each). The solution was alkalized to pH 6 with a 10 N solution of NaOH. The aqueous layer was separated and subjected to extraction with ether. The combined extracts were dried and evaporated. The residue was recrystallized from ether. The obtained crystals were dissolved under argon in MeOH (20 mL). NaOH (0.5 g, 12 mmol) was added, and the mixture was stirred for 12 h. Then pH was brought to 6 with a 5 M solution of NaHSO4 (2.4 mL), and the mixture was evaporated. The residue was dissolved in CHCl3. The solution was washed with H2O, dried, and evaporated to give the title compound (1.2 g, 10%) as yellow crystals. 1H NMR data (DMSO-d6): 10.37 (s, 1H, —COH), 10.14 (s, 1H, Ar—OH), 7.17 (s, 1H, Ar—H), 6.60 (s, 1H, Ar—H), 3.81 (s, 3H, —OCH3), 3.76 (s, 3H, —OCH3).