Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1](NC1CCCCC1)([CH3:3])[CH3:2].C([Li])CCC.[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:37]2[CH:42]=[CH:41][CH:40]=[CH:39][CH:38]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)[C:21](=[O:53])[CH2:20]1)[CH:17]=[CH2:18].[O:54]1CCCC1>CCCCCC>[CH2:16]([CH:19]1[N:22]([C:23]([C:43]([O:45][CH2:46][C:47]2[CH:52]=[CH:51][CH:50]=[CH:49][CH:48]=2)=[O:44])=[P:24]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)[C:37]2[CH:38]=[CH:39][CH:40]=[CH:41][CH:42]=2)[C:21](=[O:53])[CH:20]1[C:1]([OH:54])([CH3:3])[CH3:2])[CH:17]=[CH2:18]
Reactant: C=CCC1CC(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: CC(C)NC1CCCCC1
Reactant: C1CCOC1
Agent: [Li]CCCC
Solvent: CCCCCC
Product: C=CCC1C(C(C)(C)O)C(=O)N1C(C(=O)OCc1ccccc1)=P(c1ccccc1)(c1ccccc1)c1ccccc1

Procedure:
A solution of N-isopropylcyclohexylamine (0.60 g) in dry tetrahydrofuran (10 cm3) was stirred under argon and cooled to -78°. This was treated with a 2.5 M solution of n-butyl lithium in n-hexane (1.70 cm3). After ten minutes, a solution of 4-allyl-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl) azetidin-2-one (1.00 g) in dry tetrahydrofuran (15 cm3) was added. Five minutes were allowed for the formation of the C(3) carbanion which was then quenched by the addition of dry acetone (0.71 cm3). The cooling bath was then removed and the mixture stirred for a further ten minutes before it was neutralised with acetic acid (0.56 g). The solvent was evaporated under reduced pressure and the residue chromatographed on silica gel 60 (<230 mesh), eluting with ethyl acetate/60°-80° petroleum ether mixtures grading from 1:1 to 7:3. this gave the two separate isomers of 4-allyl-3-(2-hydroxyprop-2-yl)-1-(1-benzyloxycarbonyl-1-triphenylphosphoranylidenemethyl)azetidin-2-one(0.30 g 27%) and (0.22 g, 20%); νmax (CHCl3) 3000, 1735 and 1620 cm-1.
Reaction SMILES: [CH2:1]([N:3]([CH2:30][CH3:31])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:20]=[C:19](C)[C:18](OC[C@@H]4CO4)=[C:17](CC)[CH:16]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:2].[CH3:32][CH2:33][N:34](C(C)C)C(C)C.[CH3:41][S:42](Cl)(=[O:44])=[O:43]>C(Cl)Cl.CCOC(C)=O>[CH2:30]([N:3]([CH2:1][CH3:2])[C:4]1[N:9]=[C:8]([C:10]2[O:14][N:13]=[C:12]([C:15]3[CH:16]=[CH:17][C:18]([CH2:32][CH2:33][NH:34][S:42]([CH3:41])(=[O:44])=[O:43])=[CH:19][CH:20]=3)[N:11]=2)[CH:7]=[C:6]([CH3:29])[N:5]=1)[CH3:31]
Reactant: CS(=O)(=O)Cl
Reactant: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC[C@@H]1CO1
Reactant: CCN(C(C)C)C(C)C
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: CCN(CC)c1nc(C)cc(-c2nc(-c3ccc(CCNS(C)(=O)=O)cc3)no2)n1
Temperature: 25 °C
Reaction time: 1 h
Yield: 58.9 %

Procedure:
To a solution of Intermediate 12 (100 mg, 0.28 mmol) and DIPEA (97 μL, 0.57 mmol) in DCM (2 mL) at 0° C. is added dropwise a solution of methanesulfonyl chloride (33 μL, 0.43 mmol) in DCM (2 mL). The reaction mixture is stirred at rt for 1 h and is then diluted with EtOAc, and washed with sat. aq. NaHCO3. The org. phase is dried over MgSO4, filtered, evaporated and purified by prep. TLC (eluting with Heptane/EtOAc 1:1) to give the title compound (71 mg) as a yellow solid; LC-MS: tR=1.07 min; [M+H]+=431.07.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:11](=O)[CH:12]=[N+:13]=[N-:14])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1.NN1[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[C:18]1=[O:31].C(N(CC)CC)C.CN(C=[O:43])C>CCOC(C)=O.C([O-])(=O)C1C=CC=CC=1.[Ag+]>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([CH2:11][C:12]([NH:13][N:14]3[N:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[C:24]4[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=4)[C:18]3=[O:31])=[O:43])[CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Nn1nc(C(F)(F)F)c2ccccc2c1=O
Reactant: CN(C)C=O
Reactant: [N-]=[N+]=CC(=O)C1(c2ccc(Cl)cc2)CC1
Agent: [Ag+]
Agent: O=C([O-])c1ccccc1
Solvent: CCOC(C)=O
Solvent: CCN(CC)CC
Product: O=C(CC1(c2ccc(Cl)cc2)CC1)Nn1nc(C(F)(F)F)c2ccccc2c1=O

Procedure:
A solution of the above crude 1-(1-(4-chlorophenyl)cyclopropyl)-2-diazoethanone (0.050 g, 0.23 mmol), the product from Example 11B (0.0505 g, 0.22 mmol), triethylamine (0.12 mL, 0.86 mmol), and silver benzoate (0.0504 g, 0.220 mmol) in DMF (1 mL) were stirred for 2 hours at 70° C., diluted with EtOAc, washed with saturated aqueous NaHCO3 and brine, dried (Na2SO4), and filtered. The residue was chromatographed on SiO2 (30% EtOAc/hexanes) to give the title compound (23.0 mg, 0.055 mmol) as a white solid: 1H NMR (300 MHz, DMSO-d6) δ ppm 11.56 (s, 1H), 8.41-8.44 (m, 1H), 7.95-8.20 (m, 3H), 7.22-7.42 (m, 4H), 2.72 (d, J=1.0 Hz, 2H), 1.04-1.10 (m, 2H), 0.84-0.90 (m, 2H); MS (ESI+) M/Z 422 (M+H)+, 439 (M+NH4)+.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[CH:2]1.[CH:6](OCC)([O:10][CH2:11][CH3:12])[O:7][CH2:8][CH3:9].C(=O)(O)[O-].[Na+]>C1(C)C=CC(S(O)(=O)=O)=CC=1.C(O)C>[CH2:8]([O:7][CH:6]([O:10][CH2:11][CH3:12])[N:1]1[CH:5]=[CH:4][N:3]=[CH:2]1)[CH3:9]
Reactant: CCOC(OCC)OCC
Reactant: c1c[nH]cn1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCO
Product: CCOC(OCC)n1ccnc1
Yield: 63 %

Procedure:
A mixture of imidazole (15 g, 0.220 mol, 1 eq), triethyl orthoformate (130 g, 146.6 mL, 0.880 mol, 4, eq) and p-toluenesulfonic acid (1.17 g, 0.00616 mol, 0.028 eq) was heated at 145°-175° C. until no more ethanol was distillable from the reaction mixture. The excess orthoformate was removed in vacuo. Solid sodium bicarbonate (1.17 g, 0.011 mol) was added and the residue was vacuum distilled to give the title compound (23.6 g, 68%). b.p. 89°-91° C./0.3 mm Hg.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([C:19]1[C:20]([CH3:36])=[C:21]([NH:25][C:26](=[O:35])[O:27][CH2:28][C:29]2[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=2)[CH:22]=[CH:23][CH:24]=1)[C:4]1[C:12]2[C:7](=[CH:8][C:9]([N:13]3[CH2:18][CH2:17][O:16][CH2:15][CH2:14]3)=[CH:10][CH:11]=2)[NH:6][CH:5]=1.O=[CH:38][C:39]([O:41][CH2:42][CH3:43])=[O:40].C1(C)C=CC=CC=1.Cl.O1CCOCC1.C1(C)C=CC=CC=1>O1CCOCC1.CCOC(C)=O.[Pd]>[CH2:28]([O:27][C:26]([NH:25][C:21]1[C:20]([CH3:36])=[C:19]([C:3]2[C:4]3[C:12]4[C:7](=[CH:8][C:9]([N:13]5[CH2:14][CH2:15][O:16][CH2:17][CH2:18]5)=[CH:10][CH:11]=4)[NH:6][C:5]=3[C:38]([C:39]([O:41][CH2:42][CH3:43])=[O:40])=[N:1][CH:2]=2)[CH:24]=[CH:23][CH:22]=1)=[O:35])[C:29]1[CH:30]=[CH:31][CH:32]=[CH:33][CH:34]=1
Reactant: Cc1c(NC(=O)OCc2ccccc2)cccc1C(CN)c1c[nH]c2cc(N3CCOCC3)ccc12
Reactant: CCOC(=O)C=O
Agent: [Pd]
Agent: Cl
Solvent: C1COCCO1
Solvent: Cc1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)c1ncc(-c2cccc(NC(=O)OCc3ccccc3)c2C)c2c1[nH]c1cc(N3CCOCC3)ccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 20.4 %

Procedure:
To a homogeneous solution of benzyl 3-(2-amino-1-(6-morpholino-1H-indol-3-yl)ethyl)-2-methylphenylcarbamate (1.4934 g, 3.08 mmol) in dioxane (154 ml) were added 50% ethyl 2-oxoacetate/toluene (1.222 ml, 6.16 mmol) and 4N HCl/dioxane (1.541 ml, 6.16 mmol) under nitrogen. The reaction was stirred overnight. More 50% ethyl 2-oxoacetate/toluene (1.222 ml, 6.16 mmol) was added, and the reaction was stirred overnight. The reaction was concentrated in vacuo, dissolved in EtOAc (100 mL) and washed with water (25 mL) and brine (25 mL) successively, dried over MgSO4, and concentrated in vacuo to give a crude product, which was used in the subsequent step. To this crude were added 10% Pd/C (0.819 g, 0.770 mmol) and toluene (77 ml), and the mixture was refluxed overnight. The reaction was cooled to room temperature, diluted with EtOAc (200 mL), and filtered through a pad of CELITE®. The filtrate was washed with water (75 mL) and brine (75 mL), dried over MgSO4, and concentrated in vacuo. The residue was purified by flash chromatography using an ISCO 120 g column eluting with 15-70% EtOAc/CH2Cl2 to give the desired product (0.354 g, 0.627 mmol, 20.4% yield) as a tan solid.
Reaction SMILES: [CH3:1][S:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]2[CH2:14][C:13](=[O:15])[CH2:12][C:11](=[O:16])[CH2:10]2)=[CH:5][CH:4]=1.[Br:17]Br>CC(O)=O>[Br:17][CH:12]1[C:11](=[O:16])[CH2:10][CH:9]([C:6]2[CH:5]=[CH:4][C:3]([S:2][CH3:1])=[CH:8][CH:7]=2)[CH2:14][C:13]1=[O:15]
Reactant: BrBr
Reactant: CSc1ccc(C2CC(=O)CC(=O)C2)cc1
Solvent: CC(=O)O
Product: CSc1ccc(C2CC(=O)C(Br)C(=O)C2)cc1
Yield: 71.5 %

Procedure:
To a stirred solution of 5-[4-(methylthio)phenyl]cyclohexane-1,3-dione (1.08 g, 4.6 mmol) in AcOH (10 mL) at r.t. was added bromine (0.74 g, 0.23 mL, 4.6 mmol) dropwise. The reaction was then carried out according to Method A to give the title compound (1.03 g, 70%) as a white solid. LCMS (ES+) 314.9 (M+H)+.
Reaction SMILES: [CH3:1][C:2]1C(=O)[N:6]([C:9]2[C:10](=[O:27])[O:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([N:19]2[C:23](=[O:24])[C:22]([CH3:25])=[CH:21][C:20]2=O)=[CH:14][CH:13]=3)[C:4](=[O:5])[CH:3]=1.[CH2:28]([SH:30])[CH3:29].C[S:32]([CH3:34])=O>>[CH2:2]([CH:3]1[C:4](=[O:5])[N:6]([C:9]2[C:10](=[O:27])[O:11][C:12]3[C:17]([CH:18]=2)=[CH:16][C:15]([N:19]2[C:23](=[O:24])[CH:22]([CH2:21][CH3:20])[CH2:25][C:34]2=[S:32])=[CH:14][CH:13]=3)[C:28](=[S:30])[CH2:29]1)[CH3:1]
Reactant: CS(C)=O
Reactant: CC1=CC(=O)N(c2ccc3oc(=O)c(N4C(=O)C=C(C)C4=O)cc3c2)C1=O
Reactant: CCS
Product: CCC1CC(=S)N(c2ccc3oc(=O)c(N4C(=O)C(CC)CC4=S)cc3c2)C1=O
Yield: 84 %

Procedure:
The reaction of 44 mg (0.12 mmol) of compound 6 in 3 mL dry DMSO with 27 μL ethanethiol (0.36 mmol) was carried out according to the same protocol used to obtain compound 7, giving compound 9 in 84% yield (49 mg, 0.1 mmol). FTIR (KBr) (cm−1): 1720, 1620, 600. 1H-NMR (CDCl3): δ (ppm) 8.21 (s, 1H), 7.57 (d, J=2.53 Hz, 1H), 7.39 (dd, J=8.47 Hz, J=2.67 Hz, 1H), 7.26 (d, J=8.35 Hz, 1H), 3.84 (s, 1H), 3.12 (s, 1H), 3.07 (s, 1H, 2.83 (m, 4H), 1.93 (d, J=7.08 Hz, 3H), 1.90 (d, J=7.25 Hz, 3H), 1.30 (t, J=7.28 Hz, 6H). 13C-NMR (DMSO-d6): δ (ppm) 175.04, 172.32, 167.92, 156.34, 150.73, 137.21, 129.87, 128.65, 124.34, 118.03, 117.04, 38.53, 34.29, 26.02, 20.68, 14.27, 11.67. HRMS expected for C23H24N2O6S2: 488.107580; found: 488.107213.
Reaction SMILES: [CH:1]1([C:6]2[C:7]3[S:19][C:18]([C:20]([O:22]C)=[O:21])=[CH:17][C:8]=3[NH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1.[OH-].[Na+]>C1COCC1.CO>[CH:1]1([C:6]2[C:7]3[S:19][C:18]([C:20]([OH:22])=[O:21])=[CH:17][C:8]=3[NH:9][C:10]=2[C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)[CH2:2][CH2:3][CH2:4][CH2:5]1
Reactant: COC(=O)c1cc2[nH]c(-c3ccccc3)c(C3CCCC3)c2s1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: O=C(O)c1cc2[nH]c(-c3ccccc3)c(C3CCCC3)c2s1
Reaction time: 0.15 h
Yield: 73 %

Procedure:
A solution (0.015 M) of methyl 6-cyclopentyl-5-phenyl-4H-thieno[3,2-b]pyrrole-2-carboxylate in THF/MeOH (1:1) was treated with aqueous NaOH (2 N solution, 20 eq.) then the mixture was heated to reflux for 45 min. After cooling down, the mixture was concentrated then the residue diluted with water and acidified to pH 2-3 with aqueous HCl (1 N) and extracted with AcOEt. The combined organic phase was dried and concentrated to give a residue that was purified by RP-HPLC (Conditions: Waters X-TERRA MS C18, 10 micron, 19×150 mm; flow: 20 mL/min; Gradient: A: H2O+0.05% TFA; B: MeCN+0.05% TFA; 90% A isocratic for 2 min then linear to 10% A in 9 min) to afford the title compound (73%) as a solid.
Reaction SMILES: [CH3:1][C:2]1[CH:11]=[C:10]([N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([OH:23])[CH:8]=2)[N:3]=1.Br[CH2:25][C:26]1[CH:31]=[CH:30][C:29]([S:32]([CH3:35])(=[O:34])=[O:33])=[CH:28][CH:27]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C=O)C.O>[CH3:35][S:32]([C:29]1[CH:30]=[CH:31][C:26]([CH2:25][O:23][C:7]2[CH:8]=[C:9]3[C:4](=[CH:5][CH:6]=2)[N:3]=[C:2]([CH3:1])[CH:11]=[C:10]3[N:12]2[CH2:16][CH2:15][CH:14]([C:17]3[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=3)[CH2:13]2)=[CH:27][CH:28]=1)(=[O:33])=[O:34]
Reactant: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(O)ccc2n1
Reactant: CS(=O)(=O)c1ccc(CBr)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: O
Solvent: CN(C)C=O
Product: Cc1cc(N2CCC(c3ccccc3)C2)c2cc(OCc3ccc(S(C)(=O)=O)cc3)ccc2n1

Procedure:
2-Methyl-4-(3-phenylpyrrolidin-1-yl)quinolin-6-ol (0.05 g; see Example 42 below), 1-bromomethyl-4-methanesulfonylbenzene (0.08 g), caesium carbonate (0.1 g) in DMF (2 mL) was heated in a microwave at 120° C. for 15 minutes. The reaction mixture was diluted with water and extracted with dichloromethane, washed with water, dried (MgSO4), filtered and evaporated to give an oil. The residue was purified by chromatography on silica, eluting with a mixture of dichloromethane, and methanol. Evaporation of the desired fractions gave the title compound as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:27])([F:26])[F:25])[CH:18]=3)[N:13]=[C:12]([NH:28][NH2:29])[N:11]=2)=[CH:4][CH:3]=1.[F:30][C:31]([F:42])([F:41])[O:32][C:33]1[CH:40]=[CH:39][C:36]([CH:37]=O)=[CH:35][CH:34]=1>C(O)C>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([CH2:8][NH:9][C:10]2[N:15]=[C:14]([NH:16][C:17]3[CH:22]=[CH:21][C:20]([F:23])=[C:19]([C:24]([F:25])([F:27])[F:26])[CH:18]=3)[N:13]=[C:12]([NH:28][N:29]=[CH:37][C:36]3[CH:39]=[CH:40][C:33]([O:32][C:31]([F:30])([F:41])[F:42])=[CH:34][CH:35]=3)[N:11]=2)=[CH:4][CH:3]=1
Reactant: NNc1nc(NCc2ccc(Cl)nc2)nc(Nc2ccc(F)c(C(F)(F)F)c2)n1
Reactant: O=Cc1ccc(OC(F)(F)F)cc1
Solvent: CCO
Product: Fc1ccc(Nc2nc(NCc3ccc(Cl)nc3)nc(NN=Cc3ccc(OC(F)(F)F)cc3)n2)cc1C(F)(F)F
Temperature: 25 °C
Reaction time: 24 h
Yield: 45.9 %

Procedure:
A 20 mL flask was charged with N-(6-chloropyridin-3-yl-methyl)-N′-(4-fluoro-3-trifluoromethylphenyl)-6-hydrazino-1,3,5-triazine-2,4-diamine (XIX) (285 mg, 0.66 mmol), 4-(trifluoromethoxy)benzaldehyde (251 mg, 1.32 mmol), and ethanol (10 mL), and the resulting mixture stirred at ambient temperature for 24 h. The mixture was concentrated under vacuum, the residue washed with hexanes and recrystallized from hexanes-ethyl ether to afford the titled compound (2) as a white solid (182 mg, 45% yield): m.p. 117-125° C.; 1H NMR (CDCl3): δ 8.65 (bs, 1H); 8.54 (d, J=4.5 Hz, 1H); 8.35 (bs, 1H); 7.84 (s, 1H); 7.73 (d, J=7.2 Hz, 2H); 7.49-7.7 (m, 4H); 7.26 (m, 3H); 7.2 (t, J=6.0 Hz, 1H); 4.66 (d, J=6.0 Hz, 2H); Anal. Calcd for C24H17F7N8O: C, 50.89, H, 3.03, N, 19.78. Found C, 50.49; H, 3.17; N, 19.31
Reaction SMILES: [CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8](SC)=[CH:7][CH:6]=2.Cl[C:29]1C=C(C=CC=1)C(OO)=O.C(=O)(O)[O-].[Na+].[S:44]([O-:48])([O-])(=O)=[O:45].[Na+].[Na+]>ClCCl>[CH3:1][C:2]1[C:3]([C:18]2[CH:23]=[CH:22][CH:21]=[C:20]([C:24]([F:27])([F:26])[F:25])[CH:19]=2)=[N:4][C:5]2[C:10]([C:11]=1[C:12]([O:14][CH3:15])=[O:13])=[CH:9][C:8]([S:44]([CH3:29])(=[O:48])=[O:45])=[CH:7][CH:6]=2
Reactant: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(SC)cc12
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: O=S(=O)([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: COC(=O)c1c(C)c(-c2cccc(C(F)(F)F)c2)nc2ccc(S(C)(=O)=O)cc12
Reaction time: 0.5 h
Yield: 75 %

Procedure:
A solution of methyl 3-methyl-6-(methylthio)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.5 g, 3.83 mmol) and 3-chloroperoxybenzoic acid (1.46 g, 8.43 mmol) in dichloromethane (50 mL) was stirred overnight. Saturated aqueous sodium bicarbonate and sodium sulfate were added and the mixture was stirred for 30 min. The aqueous mixture was extracted with methylene chloride (3 times). The combined organic extracts were washed with brine, dried over Na2SO4, filtered, and concentrated in vacuo. The residue was purified via column chromatography (ISCO, 10-40% ethyl acetate/hexanes) to afford methyl 3-methyl-6-(methylsulfonyl)-2-[3-(trifluoromethyl)phenyl]-4-quinolinecarboxylate (1.22 g, 75% yield). 1H NMR (400 MHz, DMSO-d6) δ 8.31-8.39 (m, 2H), 8.26-8.31 (m, 1H), 8.00-8.08 (m, 2H), 7.93 (d, J=7.78 Hz, 1H), 7.80 (t, J=7.65 Hz, 1H), 4.12 (s, 3H), 3.40 (s, 3H), 2.42 (s, 3H); MS (m/z) 424.0 (M+H+).
Reaction SMILES: [O:1]([C:8]1[CH:13]=[CH:12][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]([O:31]C)=[O:30])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-].Cl>C1COCC1.O.CCOC(C)=O>[O:1]([C:8]1[CH:9]=[CH:10][C:11]([CH2:14][CH2:15][C:16]([C:18]2[O:19][C:20]([C:23]3[N:28]=[CH:27][C:26]([C:29]([OH:31])=[O:30])=[CH:25][CH:24]=3)=[CH:21][N:22]=2)=[O:17])=[CH:12][CH:13]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: COC(=O)c1ccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Agent: Cl
Agent: [Li+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: O
Product: O=C(O)c1ccc(-c2cnc(C(=O)CCc3ccc(Oc4ccccc4)cc3)o2)nc1
Yield: 57.5 %

Procedure:
Methyl 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylate (57 mg, 0.13 mmol) was dissolved in THF/H2O (3:2, 7.5 mL) and LiOH (10 mg, 0.40 mmol) was added. The reaction solution was stirred at room temperature under an atmosphere of Ar for 2 h before the addition of 1 N HCl to adjust the solution to an acidic pH to quench the reaction. The reaction solution was diluted with EtOAc and the organic and aqueous layers were separated. The aqueous layer was extracted with EtOAc (3×). The organic phases were combined and washed with saturated aqueous NaCl, dried over Na2SO4, and concentrated in vacuo. The crude product was purified by flash chromatography (SiO2, 1% AcOH/EtOAc) to provide 6-(2-(3-(4-phenoxyphenyl)propanoyl)oxazol-5-yl)pyridine-3-carboxylic acid as a light tan solid (31 mg, 56%): 1H NMR (THF-d8, 600 MHz) δ 9.18 (s, 1H), 8.41 (dd, 1H, J=8.4, 1.8 Hz), 7.98 (s, 1H), 7.97 (d, 1H, J=8.4 Hz), 7.30-7.25 (m, 4H), 7.03 (t, 1H, J=7.8 Hz), 6.94 (d, 2H, J=7.8 Hz), 6.91 (d, 2H, J=8.4 Hz), 3.42 (t, 2H, J=7.8 Hz), 3.04 (t, 2H, J=7.8 Hz); 13C NMR (CDCl3, 150 MHz) δ 187.3, 166.2, 159.7, 158.9, 156.7, 153.7, 152.4, 150.5, 139.4, 137.1, 130.7, 130.6, 129.3, 127.6, 123.8, 120.3, 120.0, 119.4, 41.7, 29.8; HR ESI-TOF m/z 415.1284 (M+H+, C24H18N2O5, requires 415.1288).
Reaction SMILES: [CH3:1][CH:2](O)[CH2:3][CH:4]=[CH2:5].[C:7]1(=[O:17])[NH:11][C:10](=[O:12])[C:9]2=[CH:13][CH:14]=[CH:15][CH:16]=[C:8]12.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>C1COCC1.O>[CH2:1]=[CH:2][CH2:3][CH:4]([N:11]1[C:7](=[O:17])[C:8]2=[CH:16][CH:15]=[CH:14][CH:13]=[C:9]2[C:10]1=[O:12])[CH3:5]
Reactant: C=CCC(C)O
Reactant: O=C1NC(=O)c2ccccc21
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Solvent: C1CCOC1
Product: C=CCC(C)N1C(=O)c2ccccc2C1=O
Temperature: 0 °C
Reaction time: 12 h
Yield: 70.1 %

Procedure:
To a stirred solution of 4-penten-2-ol (5.00 g, 58.1 mmol), phthalimide (8.55 g, 58.1 mmol), and triphenylphosphine (15.2 g, 58.1 mmol) in THF (40 mL), at 0° C. under nitrogen, was added a solution of diethyl azodicarboxylate (10.1 g, 58.1 mmol) in THF (20 mL) dropwise. The mixture was stirred at 0° C. (12 h) and then at 25° C. (12 h). The mixture was diluted with water and extracted three times with chloroform. The chloroform extracts were dried (Na2SO4), evaporated and column chromatographed on Merck silica gel 60 (70-230 mesh) with chloroform to give 8.77 g (70.2% yield) of colorless oil.
Reaction SMILES: [OH:1][NH:2][C:3](=[O:12])[O:4][CH2:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1.C(N(CC)CC)C.[P:20](Cl)([Cl:29])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]>C(OCC)C>[P:20]([Cl:29])([O:1][NH:2][C:3]([O:4][CH2:5][C:6]1[CH:7]=[CH:8][CH:9]=[CH:10][CH:11]=1)=[O:12])([O:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)=[O:21]
Reactant: O=P(Cl)(Cl)Oc1ccccc1
Reactant: O=C(NO)OCc1ccccc1
Solvent: CCOCC
Solvent: CCN(CC)CC
Product: O=C(NOP(=O)(Cl)Oc1ccccc1)OCc1ccccc1
Temperature: 0 °C
Yield: 102.4 %

Procedure:
A mixture of benzyl N-hydroxycarbamate (0.35 g, 2.1 mmol) and triethylamine (0.21 g, 2.1 mmol) in diethyl ether is cooled at 0° C. with stirring. To this is added a solution of phenyl dichlorophosphate (0.43 g, 2 mmol) in diethyl ether (1 ml). The resulting suspension is stirred at room temperature for 3 hours. It is then filtered and the solvents evaporated under reduced pressure to give 0.70 g of a colorless oil.
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:11]=[CH:10][C:9]([S:12]([NH:15][CH2:16][CH2:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])(=[O:14])=[O:13])=[CH:8][CH:7]=1)[C:2]#[C:3][CH3:4].[H-].[Na+].I[CH3:28]>CN(C)C=O.C(OCC)(=O)C>[C:21]([O:20][C:18](=[O:19])[CH2:17][CH2:16][N:15]([S:12]([C:9]1[CH:8]=[CH:7][C:6]([O:5][CH2:1][C:2]#[C:3][CH3:4])=[CH:11][CH:10]=1)(=[O:14])=[O:13])[CH3:28])([CH3:24])([CH3:23])[CH3:22]
Reactant: CI
Reactant: CC#CCOc1ccc(S(=O)(=O)NCCC(=O)OC(C)(C)C)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC#CCOc1ccc(S(=O)(=O)N(C)CCC(=O)OC(C)(C)C)cc1
Yield: 96.2 %

Procedure:
To a solution of tert-butyl 3-({[4-(2-butynyloxy)phenyl]-sulfonyl}amino)propanoate (1.0 g, 2.83 mmol) in dimethylformamide (5 mL) at 0° C. was added sodium hydride (3.39 mmol) followed by iodomethane (211 uL, 3.39 mmol). After 72 hours the reaction mixture was diluted with ethyl acetate and washed with water and brine and dried over anhydrous sodium sulfate. Filtration and concentration in vacuo gave tert-butyl-3-[{[4-(2-butynyloxy)phenyl]-sulfonyl}(methyl)amino]propanoate (1.0 g) as a colorless oil. Electrospray Mass Spec 368.2 (M+H)+.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2.[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18](C1C=CC(OC)=C2C=1C=CN2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]>>[CH2:13]([O:15][C:16](=[O:36])[CH:17]=[C:18]([C:2]1[CH:3]=[C:4]2[C:8](=[C:9]([O:11][CH3:12])[CH:10]=1)[NH:7][CH:6]=[CH:5]2)[C:19]1[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=1)[CH3:14]
Reactant: CCOC(=O)C=C(c1ccccc1)c1ccc(OC)c2[nH]ccc12
Reactant: COc1cc(Br)cc2cc[nH]c12
Product: CCOC(=O)C=C(c1ccccc1)c1cc(OC)c2[nH]ccc2c1
Yield: 50 %

Procedure:
3-(7-Methoxy-1H-indol-5-yl)-3-phenyl-acrylic acid ethyl ester CVI (120 mg, 50% yield) was prepared from 5-bromo-7-methoxyindole using the procedure described above for preparation of 3-(7-Methoxy-1H-Indol-4-yl)-3-phenyl-acrylic acid ethyl ester LIII (Example 13).
Reaction SMILES: O=[C:2]1[CH2:20][C:4]2([CH2:7][CH:6]([CH2:8][NH:9]C(=O)OCC3C=CC=CC=3)[CH2:5]2)[CH2:3]1.O.NN.[OH-].[Na+]>C(O)COCCOCCO>[CH2:5]1[C:4]2([CH2:20][CH2:2][CH2:3]2)[CH2:7][CH:6]1[CH2:8][NH2:9]
Reactant: O=C1CC2(C1)CC(CNC(=O)OCc1ccccc1)C2
Agent: NN
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: OCCOCCOCCO
Product: NCC1CC2(CCC2)C1
Temperature: 200 °C
Yield: 73.1 %

Procedure:
Compound 4-5 (2 g, 7.32 mmol) and hydrazine monohydrate (0.828 g, 16.5 mmol) and NaOH (0.585 g, 14.63 mmol) were added to triethylene glycol (20 mL) and heated under reflux for 1 hour. Then remove the condenser, heated to 200° C. in an oil bath and maintained for 3 hours, and after cooling purified by column chromatography to give Compound 4-6 (0.67 g, 73% yield).