Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:48]=[CH:47][C:42]([C:43]([O:45]C)=[O:44])=[CH:41][C:40]=4[CH3:49])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1.[OH-].[Li+]>O1CCOCC1>[F:1][CH:2]1[CH2:5][N:4]([C:6]2[N:11]=[C:10]([CH2:12][N:13]3[C@@H:17]([CH3:18])[C@@H:16]([C:19]4[CH:24]=[CH:23][CH:22]=[C:21]([O:25][C:26]([F:29])([F:28])[F:27])[CH:20]=4)[O:15][C:14]3=[O:30])[C:9]([C:31]3[CH:32]=[C:33]([C:39]4[CH:48]=[CH:47][C:42]([C:43]([OH:45])=[O:44])=[CH:41][C:40]=4[CH3:49])[CH:34]=[N:35][C:36]=3[O:37][CH3:38])=[CH:8][N:7]=2)[CH2:3]1
Reactant: COC(=O)c1ccc(-c2cnc(OC)c(-c3cnc(N4CC(F)C4)nc3CN3C(=O)O[C@H](c4cccc(OC(F)(F)F)c4)[C@@H]3C)c2)c(C)c1
Agent: [Li+]
Agent: [OH-]
Solvent: C1COCCO1
Product: COc1ncc(-c2ccc(C(=O)O)cc2C)cc1-c1cnc(N2CC(F)C2)nc1CN1C(=O)O[C@H](c2cccc(OC(F)(F)F)c2)[C@@H]1C
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
Methyl 4-{5-[2-(3-fluoroazetidin-1-yl)-4-({(4S,5R)-4-methyl-2-oxo-5-[3-(trifluoromethoxy)phenyl]-1,3-oxazolidin-3-yl}methyl)pyrimidin-5-yl]-6-methoxypyridin-3-yl}-3-methylbenzoate (31.4 mg, 0.046 mmol) was dissolved in 1,4-dioxane (2 mL). Added 0.5N lithium hydroxide (0.50 mL, 0.25 mmol) and stirred at room temperature for 2.5 hours at which time LCMS shows complete hydrolysis. The reaction was quenched by adding 0.25 mL of 1N HCl, followed by water. The reaction was extracted with ethyl acetate. The ethyl acetate layer was dried over sodium sulfate, filtered and evaporated. The crude isolate was purified on a BIOTAGE SNAP C18 column, eluting with 40-100% CH3CN/water (0.05% TFA). The purified fractions were partitioned between pH 7 phosphate buffer and ethyl acetate. The aqueous was extracted a second time with ethyl acetate, then washed with pH 7.0 buffer and brine. The organic was dried over sodium sulfate, filtered and evaporated to give the title compound. LCMS (M+H)+: 668.2. 1H NMR (CDCl3, 500 MHz): δ 8.21 (br, 1H), 8.18 (s, 1H), 8.02 (s, 1H), 7.97 (br d, 1H), 7.47 (s, 1H), 7.41 (t, 1H), 7.33 (m, 1H), 7.21 (m, 2H), 7.13 (s, 1H), 5.55 (d, 1H), 5.51 (m, 0.5H), 5.40 (m, 0.5H), 4.71 (d, 1H), 4.48 (m, 2H), 4.30 (m, 3H), 4.00 (d, s, 4H), 2.37 (s, 3H), 0.73 (d, 3H). RTA IC50: 50 nM
Reaction SMILES: [Na].Cl.[OH:3][CH:4]1[O:12][C@H:11]([CH2:13][OH:14])[C@@H:9]([OH:10])[C@H:7]([OH:8])[C@H:5]1[NH2:6].[C:15]([CH:18]1[C:26](=[O:27])[C:25]2[C:20](=[CH:21][CH:22]=[CH:23][C:24]=2[N+:28]([O-:30])=[O:29])[C:19]1=[O:31])(=O)[CH3:16]>CO>[N+:28]([C:24]1[CH:23]=[CH:22][CH:21]=[C:20]2[C:25]=1[C:26](=[O:27])[C:18](=[C:15]([NH:6][C@@H:5]1[C@@H:7]([OH:8])[C@H:9]([OH:10])[C@@H:11]([CH2:13][OH:14])[O:12][CH:4]1[OH:3])[CH3:16])[C:19]2=[O:31])([O-:30])=[O:29]
Reactant: N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O
Reactant: CC(=O)C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Agent: Cl
Agent: [Na]
Solvent: CO
Product: CC(N[C@H]1C(O)O[C@H](CO)[C@@H](O)[C@@H]1O)=C1C(=O)c2cccc([N+](=O)[O-])c2C1=O
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 51 %

Procedure:
Sodium (126 mg, 5.47 mmol) was added to abs. methanol (50 ml) and the reaction mixture was stirred for 5 min. D-glucosamine hydrochloride (1.18 g, 5.47 mmol) was added to the resulting clear solution and the reaction mixture was stirred at room temperature for another 5 min. 2-acetyl-4-nitroindane-1,3-dion (1.91 g, 8.21 mmol) was added and the reaction mixture was stirred under reflux for 5 hours. The solution was cooled and the product was filtered off. The solid was washed with MeOH (10 ml), ether (50 ml) and dried, affording 2-Deoxy-2-[1-(4-nitro-1,3-dioxoindan-2-ylidene)ethylamino]-D-glucopyranose (22) 1.10 g, 55%).
Reaction SMILES: [NH2:1][NH2:2].[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11](=O)[CH2:12][C:13](=O)[C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:7][CH:6]=1>C(O)C>[CH3:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]([C:14]([O:16][CH2:17][CH3:18])=[O:15])[NH:1][N:2]=2)=[CH:7][CH:6]=1
Reactant: NN
Reactant: CCOC(=O)C(=O)CC(=O)c1ccc(OC)cc1
Solvent: CCO
Product: CCOC(=O)c1cc(-c2ccc(OC)cc2)n[nH]1
Temperature: 60 °C
Reaction time: 4 h
Yield: 96.5 %

Procedure:
1.52 ml (31.28 mmol) of hydrazine was added to an ethanol solution (50 ml) of 7.12 g (28.44 mmol) of the obtained ethyl 4-(4-methoxyphenyl)-2,4-dioxobutyrate, and then the reaction liquid was stirred at 60° C. for 4 hours. The reaction liquid was concentrated under reduced pressure, and the resulting solid was washed with diethyl ether to obtain 6.76 g (yield: 96%) of ethyl 5-(4-methoxyphenyl)-2H-pyrazole-3-carboxylate as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8](=[O:10])[NH2:9])=[CH:6][CH:5]=[CH:4][C:3]=1[NH:11][C:12]([C:14]1[S:15][C:16]([C:19](=[O:21])[CH3:20])=[CH:17][CH:18]=1)=O.C(O)(=O)C>CN(C)C=O>[C:19]([C:16]1[S:15][C:14]([C:12]2[NH:11][C:3]3[CH:4]=[CH:5][CH:6]=[C:7]([C:8]([NH2:9])=[O:10])[C:2]=3[N:1]=2)=[CH:18][CH:17]=1)(=[O:21])[CH3:20]
Reactant: CC(=O)c1ccc(C(=O)Nc2cccc(C(N)=O)c2N)s1
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: CC(=O)c1ccc(-c2nc3c(C(N)=O)cccc3[nH]2)s1
Temperature: 125 °C
Yield: 95.1 %

Procedure:
To a solution of EXAMPLE 6A (1.70 g) in hot N,N-dimethylformamide (60 mL) was added acetic acid (50 mL) and the solution heated at 125° C. for 3 hours. After cooling, the resulting yellow solid was collected by filtration, washed with methanol and dried to give the title compound (1.52 g, 95%). MS (APCI): 286 (M+1)+.
Reaction SMILES: [C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:8]2)(=[O:3])[CH3:2].[Cl:19]N1C(=O)CCC1=O.C(=O)([O-])[O-].[K+].[K+]>ClCCl>[C:1]([O:4][C:5]1[CH:6]=[C:7]2[C:11](=[CH:12][CH:13]=1)[NH:10][C:9]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[C:8]2[Cl:19])(=[O:3])[CH3:2]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cc(OC(C)=O)ccc2[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: ClCCl
Product: CCOC(=O)c1[nH]c2ccc(OC(C)=O)cc2c1Cl
Yield: 74.6 %

Procedure:
A solution of ethyl 5-acetoxyindole-2-carboxylate (500 mg) in dichloromethane (10 ml) was stirred at room temperature in the presence of N-chlorosuccinimide (297 mg) and potassium carbonate (279 mg) overnight. The resulting precipitate was collected by filtration, washed with cold dichloromethane followed by water and dried under vacuum overnight to give the desired product as a white powder (425 mg, 75%). NMR: δ 1.35 (t,3H), 2.25 (s,3H), 4.4 (q,2H), 7.1 (d,1H), 7.3 (s, 1H), 7.5 (d, 1H), 12.2 (s, 1H); m/z 281.9 (M+H+).
Reaction SMILES: [CH3:1][O:2][C:3]([C:5]1[CH:6]2[N:12]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([C:23]#[N:24])=[CH:15][CH:14]=3)[CH:9]([CH2:10][CH:11]=1)[CH2:8][CH2:7]2)=[O:4]>CO.[Pd]>[CH3:1][O:2][C:3]([CH:5]1[CH2:11][CH2:10][CH:9]2[N:12]([C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[C:16]([C:23]#[N:24])=[CH:15][CH:14]=3)[CH:6]1[CH2:7][CH2:8]2)=[O:4]
Reactant: COC(=O)C1=CCC2CCC1N2c1ccc(C#N)c2ccccc12
Agent: [Pd]
Solvent: CO
Product: COC(=O)C1CCC2CCC1N2c1ccc(C#N)c2ccccc12
Yield: 41.1 %

Procedure:
159JP95C (12 mg, 0.038 mmol) and palladium (10 mg, 10 wt. % on activated carbon) in methanol (10 mL) were stirred for 3 days at rt under hydrogen atmosphere (balloon). The suspension was filtered through a pad of Celite, concentrated in vacuo and purification by preparative TLC (ethyl acetate/n-heptane, 1:4, 2× eluted) afforded the title compound (5.0 mg, 42%) as a colorless oil.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:19]=[CH:20][CH:21]=1)[NH:7][C:8]1[CH:18]=[CH:17][CH:16]=[CH:15][C:9]=1[C:10]([NH:12][CH2:13][CH3:14])=[O:11])([O-:3])=[O:2].[O:22]1CCC[CH2:23]1.[H-].[Na+].C(Cl)(=O)OCC>O>[N+:1]([C:4]1[CH:5]=[C:6]([N:7]2[C:8]3[C:9](=[CH:15][CH:16]=[CH:17][CH:18]=3)[C:10](=[O:11])[N:12]([CH2:13][CH3:14])[C:23]2=[O:22])[CH:19]=[CH:20][CH:21]=1)([O-:3])=[O:2]
Reactant: CCNC(=O)c1ccccc1Nc1cccc([N+](=O)[O-])c1
Reactant: C1CCOC1
Agent: CCOC(=O)Cl
Agent: [H-]
Agent: [Na+]
Solvent: O
Product: CCn1c(=O)c2ccccc2n(-c2cccc([N+](=O)[O-])c2)c1=O
Reaction time: 0.5 h

Procedure:
To a solution of 2.9 g of 2-(m-nitroanilino)-N-ethylbenzamide and 25 ml of tetrahydrofuran was added 1.0 g of 50 % sodium hydride, and stirring was performed for 30 minutes at room temperature. To this was added dropwise under cooling 5.4 g of ethyl chlorocarbonate, and the mixture was allowed to stand for one hour at room temperature and then refluxed for 10 hours. After the reaction was complete, the solvent was evaporated from the reaction mixture under reduced pressure, and to the residue obtained was added water to prepicpitate a crude product. This product was recrystallized from methanol to give 2.5 g of 1-(m-nitrophenyl)-3-ethylquinazoline-2,4(1H, 3H)-dione as colorless prisms, melting at 193°-194° C.
Reaction SMILES: [F:1][C:2]([F:20])([F:19])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH2:13])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:7])([F:6])[F:5].[CH3:21][S:22](Cl)(=[O:24])=[O:23].O>N1C=CC=CC=1>[F:1][C:2]([F:19])([F:20])[C:3]([C:9]1[CH:15]=[C:14]([CH3:16])[C:12]([NH:13][S:22]([CH3:21])(=[O:24])=[O:23])=[C:11]([O:17][CH3:18])[CH:10]=1)([OH:8])[C:4]([F:6])([F:5])[F:7]
Reactant: CS(=O)(=O)Cl
Reactant: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1N
Solvent: c1ccncc1
Solvent: O
Product: COc1cc(C(O)(C(F)(F)F)C(F)(F)F)cc(C)c1NS(C)(=O)=O
Reaction time: 16 h

Procedure:
To 4.54 g (15 mmole) 4-(hexafluoro-2-hydroxy-2-propyl)-2-methoxy-6-methylaniline in 25 ml pyridine, add 1.94 g (17 mmole) methanesulfonyl chloride. After 16 hours, pour onto 200 ml H2O and filter the solid. Recrystallize from Et2O-hexane to obtain the product; m.p. 109°-110° C.
Reaction SMILES: CO[C:3]1[C:8]([O:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][C:11]=2[F:16])=[CH:7][CH:6]=[CH:5][C:4]=1[CH2:17][C:18]([OH:20])=[O:19].OC1C(OC2C=CC=CC=2F)=CC=CC=1CC(O)=O>C(OC(=O)C)(=O)C.I>[F:16][C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][C:10]=1[O:9][C:8]1[C:3]2[O:20][C:18](=[O:19])[CH2:17][C:4]=2[CH:5]=[CH:6][CH:7]=1
Reactant: COc1c(CC(=O)O)cccc1Oc1ccccc1F
Agent: I
Agent: O=C(O)Cc1cccc(Oc2ccccc2F)c1O
Solvent: CC(=O)OC(C)=O
Product: O=C1Cc2cccc(Oc3ccccc3F)c2O1
Yield: 62.8 %

Procedure:
A solution of 2-[2-methoxy-3-(2-fluorophenoxy)phenyl]acetic acid (5.4 g) in acetic anhydride (15 ml) and hydriodic acid (55-58%, 30 ml) were treated in a similar manner to that of Example 10-(7). The resultant oily residue, i.e. 2-[2-hydroxy-3-(2-fluorophenoxy)phenyl]acetic acid was treated with acetic anhydride (10 ml) in a similar manner to that of Example 10-(7). The resultant crystalline residue was recrystallized from ethanol to give 7-(2-fluorophenoxy)-2,3-dihydrobenzofuran-2-one (3 g). mp 82°-84° C.
Reaction SMILES: [N+](=C)=[N-].[CH3:4]N(N=O)S(C1C=CC(C)=CC=1)(=O)=O.[C:18]([O:21][C@H:22]1[CH2:43][CH2:42][C@@:41]2([CH3:44])[C:24](=[CH:25][CH2:26][C@@H:27]3[C@@H:40]2[CH2:39][CH2:38][C@@:37]2([CH3:45])[C@H:28]3[CH2:29][CH2:30][C@@H:31]2[C@@H:32]([C:34]([OH:36])=[O:35])[CH3:33])[CH2:23]1)(=[O:20])[CH3:19]>>[CH3:4][O:35][C:34]([C@H:32]([C@@H:31]1[C@:37]2([CH3:45])[C@H:28]([C@H:27]3[C@H:40]([CH2:39][CH2:38]2)[C@:41]2([CH3:44])[C:24]([CH2:23][C@@H:22]([O:21][C:18](=[O:20])[CH3:19])[CH2:43][CH2:42]2)=[CH:25][CH2:26]3)[CH2:29][CH2:30]1)[CH3:33])=[O:36]
Reactant: CC(=O)O[C@H]1CC[C@@]2(C)C(=CC[C@H]3[C@@H]4CC[C@H]([C@H](C)C(=O)O)[C@@]4(C)CC[C@@H]32)C1
Reactant: Cc1ccc(S(=O)(=O)N(C)N=O)cc1
Agent: C=[N+]=[N-]
Product: COC(=O)[C@@H](C)[C@H]1CC[C@H]2[C@@H]3CC=C4C[C@@H](OC(C)=O)CC[C@]4(C)[C@H]3CC[C@]12C
Yield: 99.4 %

Procedure:
An ethanolic ethereal solution of diazomethane (CH2N2), generated from N-methyl-N-nitroso-p-toluenesulfonamide (CH3C6H4SO2N(CH3)NO; Diazald), was added dropwise to a suspension of (20S)-3β-acetoxy-5-pregnene-20-carboxylic acid (10.0 g, 25.7 mmole; m.p. 228°-231° C.) in 1:9 ethanol-ether at room temperature until all the solids dissolved and pale yellow color due to an excess diazomethane persisted. Excess diazomethane was removed with a stream of N2 until the solution became colorless. Removal of solvent provided the desired methyl ester, (20S)-3β-acetoxy-5-pregnene-20-carboxylic acid methyl ester (10.3 g; Rf 0.63 on silica gel in 3:7 ethyl acetate-hexane; m.p. 140°-142° C.) in 99.4% yield. Mass spectrum, m/e (relative intensity) 402 (M+, 0), 342 (100), 327 (10), 283 (4), 255 (6), 239 (5), 234 (11 ), 221 (12), 213 (5); NMR (CDCl3) δ0.70 (s, 18--H3), 1.02 (s, 19--H3), 1.19 (d, J=6.8 Hz, 21--H3), 2.03 (s, 3--OCOCH3), 4.60 (m, 3--H), 5.37 (br d, J=4.8 Hz, 6--H).
Reaction SMILES: Cl.Cl.[NH:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:27][C:28]1[CH:33]=[C:32]([C:34]([F:37])([F:36])[F:35])[CH:31]=[CH:30][C:29]=1[C:38]([F:41])([F:40])[F:39].O>CN(C=O)C>[F:39][C:38]([F:40])([F:41])[C:29]1[CH:30]=[CH:31][C:32]([C:34]([F:37])([F:35])[F:36])=[CH:33][C:28]=1[CH2:27][N:3]1[CH2:8][CH2:7][CH:6](/[CH:9]=[C:10]2/[C:11]([NH:16][CH2:17][C:18]#[CH:19])=[N:12][C:13](=[O:15])[S:14]/2)[CH2:5][CH2:4]1
Reactant: FC(F)(F)c1ccc(C(F)(F)F)c(CBr)c1
Reactant: C#CCNC1=NC(=O)S/C1=C\C1CCNCC1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCNC1=NC(=O)S/C1=C\C1CCN(Cc2cc(C(F)(F)F)ccc2C(F)(F)F)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of (5Z)-5-(piperidin-4-ylmethylidene)-4-(prop-2-yn-1-ylamino)-1,3-thiazol-2(5H)-one dihydrochloride (200 mg) in DMF (3 mL) was added a solution of potassium carbonate (345 mg) and 2-(bromomethyl)-1,4-bis(trifluoromethyl)benzene (0.129 mL) in DMF (2 mL). The reaction mixture was stirred at room temperature overnight, water was added, and the mixture was extracted with ethyl acetate. The extract was washed with water and saturated brine, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate/hexane) and recrystallized from ethyl acetate/heptane to give the title compound (156 mg).
Reaction SMILES: Br[C:2]1[CH:15]=[CH:14][C:13]2[N:12]([S:16]([C:19]3[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=3)(=[O:18])=[O:17])[CH:11]([CH2:27][CH3:28])[C:10]3[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=3)[C:4]=2[CH:3]=1.[CH2:30]([Li])CCC.CCCCCC.IC.Cl.[Cl-].[Na+]>O1CCCC1>[CH2:27]([CH:11]1[C:10]2[C:5](=[CH:6][CH:7]=[C:8]([F:29])[CH:9]=2)[C:4]2[CH:3]=[C:2]([CH3:30])[CH:15]=[CH:14][C:13]=2[N:12]1[S:16]([C:19]1[CH:24]=[CH:23][C:22]([O:25][CH3:26])=[CH:21][CH:20]=1)(=[O:18])=[O:17])[CH3:28]
Reactant: CCC1c2cc(F)ccc2-c2cc(Br)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reactant: [Li]CCCC
Agent: Cl
Agent: [Cl-]
Agent: [Na+]
Solvent: CI
Solvent: C1CCOC1
Solvent: CCCCCC
Product: CCC1c2cc(F)ccc2-c2cc(C)ccc2N1S(=O)(=O)c1ccc(OC)cc1
Reaction time: 0.17 h

Procedure:
A stirred solution of 2-bromo-6-ethyl-8-fluoro-5-[(4-methoxyphenyl)sulfonyl]-5,6-dihydrophenanthridine (Example 44, Step c, 0.30 g, 0.63 mmol) in tetrahydrofuran (7 mL) was cooled to −78° C., and treated drop-wise under nitrogen with a solution of 1.4 M n-butyllithium in hexane (0.9 mL, 1.26 mmol). After stirring for 10 min, iodomethane (0.08 mL, 1.26 mmol) was added, and the reaction stirred until room temperature was reached. The reaction was quenched with a 0.1 N hydrochloric acid solution (15 mL, 1.5 mmol), and a saturated, aqueous, sodium chloride solution (150 mL). The separated aqueous phase was extracted with diethyl ether (3×20 mL). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to a crude product, which was used without further purification;
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]2[C:19]3=[C:20]([CH2:22][CH2:23][CH2:24][N:18]3[CH:17]=[C:16]([C:25]([O:27]CC)=[O:26])[C:15]2=[O:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[OH-].[Na+:32].C(=O)=O>O1CCCC1>[Na+:32].[C:1]([O:5][C:6]([NH:8][CH2:9][CH2:10][CH2:11][C:12]1[CH:13]=[C:14]2[C:19]3=[C:20]([CH2:22][CH2:23][CH2:24][N:18]3[CH:17]=[C:16]([C:25]([O-:27])=[O:26])[C:15]2=[O:30])[CH:21]=1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)c1cn2c3c(cc(CCCNC(=O)OC(C)(C)C)cc3c1=O)CCC2
Agent: O=C=O
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)NCCCc1cc2c3c(c1)c(=O)c(C(=O)[O-])cn3CCC2
Temperature: 50 °C

Procedure:
Ethyl 9-(3-tert-butoxycarbonylamino-propyl)-1-oxo-6,7-dihydro-1H,5H-pyrido[3,2,1-ij]quinoline-2-carboxylate (240 mg, 0.59 mmol) was dissolved in tetrahydrofuran (3 mL) and treated with 2N aqueous sodium hydroxide (0.32 mL). The solution was heated to 50° C. overnight then treated with excess solid carbon dioxide. Evaporation of the solvent gave the title compound as a beige solid. ESMS m/z 387 (MH+). NMR (DMSO-d6) δ 8.83 (s, 1H), 8.11 (bs, 1H), 7.99 (s, 1H), 7.57 (s, 1H), 6.89 (bt, 1H), 4.41 (bt, 2H), 3.04 (t, 2H), 2.94 (q, 2H), 2.71 (t,2H), 2.13 (m, 2H), 1.74 (m, 2H), 1.37 (s, 9H).
Reaction SMILES: [C:1]([O:5][C:6](=[O:23])[NH:7][C:8]1[S:9][CH2:10][CH2:11][C@:12]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[C:17](Br)[CH:16]=2)([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].C([Sn](CCCC)(CCCC)[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1)CCC>O1CCOCC1.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>[F:21][C:18]1[CH:19]=[CH:20][C:15]([C@:12]2([CH3:14])[CH2:11][CH2:10][S:9][C:8]([NH:7][C:6](=[O:23])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])=[N:13]2)=[CH:16][C:17]=1[C:29]1[CH:34]=[N:33][CH:32]=[CH:31][N:30]=1
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(Br)c2)CCS1
Reactant: CCCC[Sn](CCCC)(CCCC)c1cnccn1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)NC1=N[C@](C)(c2ccc(F)c(-c3cnccn3)c2)CCS1
Reaction time: 0.33 h
Yield: 14 %

Procedure:
A solution of (S)-[4-(3-bromo-4-fluoro-phenyl)-4-methyl-5,6-dihydro-4H-[1,3]thiazin-2-yl]-carbamic acid tert-butyl ester (100 mg, 250 μmoles, 1 equiv), tetrakis(triphenylphosphine)palladium (14 mg, 12.40 μmoles, 0.05 equiv) and 2-tributylstannylpyrazine (96 mg, 250 μmoles, 1 equiv) in dioxane (3 mL) is irradiated in a laboratory-grade microwave to a temperature of 130° C. and held for 20 minutes. The solvent is removed under reduced pressure and the residue is purified by silica gel chromatography eluting with a linear gradient of hexane to hexane:ethyl acetate (1:4) ramp 20 min to give the title compound (14% yield, 90% purity as determined by LCMS): MS (m/z): 403 (M+1).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[CH2:7]([NH:9][CH2:10][CH3:11])[CH3:8].[CH2:12]([O:19][C:20]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47]Br)=[CH:41][C:21]=1[C:22]([NH:24][C:25]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C(=O)(O)[O-].[Na+]>C(OCC)(=O)C.O.CC(C)=O>[CH2:12]([O:19][C:20]1[CH:44]=[CH:43][C:42]([O:45][CH2:46][CH2:47][N:9]([CH2:10][CH3:11])[CH2:7][CH3:8])=[CH:41][C:21]=1[C:22]([NH:24][C:25]1[CH:34]=[C:33]([C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[CH:32]=[CH:31][C:26]=1[C:27]([O:29][CH3:30])=[O:28])=[O:23])[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1
Reactant: CCNCC
Reactant: COC(=O)c1ccc(-c2ccccc2)cc1NC(=O)c1cc(OCCBr)ccc1OCc1ccccc1
Agent: O=C([O-])O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(C)=O
Solvent: O
Solvent: CCOC(C)=O
Product: CCN(CC)CCOc1ccc(OCc2ccccc2)c(C(=O)Nc2cc(-c3ccccc3)ccc2C(=O)OC)c1
Temperature: 25 °C

Procedure:
Potassium carbonate (0.15 g) and diethylamine (0.11 mL) were added to an acetone (2.0 mL) solution of methyl 2-(2-(benzyloxy)-5-(2-bromoethoxy)benzamido)-4-phenylbenzoate (0.20 g), followed by heating to reflux for 4 hour and 30 minutes. The reaction mixture was cooled to room temperature, and then potassium carbonate (0.049 g) and diethylamine (0.037 mL) were added thereto, followed by heating to reflux for 1 hour. The reaction mixture was cooled to room temperature, and then potassium carbonate (0.049 g) and diethylamine (0.037 mL) were added thereto, followed by heating to reflux for 1 hour and 15 minutes. The reaction mixture was cooled to room temperature, and then potassium carbonate (0.049 g) and diethylamine (0.037 mL) were added thereto, followed by heating to reflux for 5 hours and 30 minutes. The reaction mixture was cooled to room temperature, and water, a saturated aqueous solution of sodium bicarbonate, and ethyl acetate were added thereto. The organic layer was separated, washed with a saturated aqueous solution of sodium chloride, and dried over anhydrous magnesium sulfate, and the solvent was evaporated under reduced pressure. The obtained residue was purified by silica gel column chromatography [eluent: 100-97% chloroform/methanol] to obtain 0.15 g of methyl 2-(2-(benzyloxy)-5-(2-(diethylamino)ethoxy)benzamido)-4-phenylbenzoate.
Reaction SMILES: C(OC([O:8][C:9]1[CH:47]=[CH:46][C:45]([N:48]([CH2:53][CH:54]2[CH2:56][CH2:55]2)[S:49]([CH3:52])(=[O:51])=[O:50])=[CH:44][C:10]=1[C:11]([O:13][CH2:14][C:15]([O:17][C@H:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:38])[F:37])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[CH2:19][C:20]1[C:25]([Cl:26])=[CH:24][N+:23]([O-:27])=[CH:22][C:21]=1[Cl:28])=[O:16])=[O:12])=O)(C)(C)C.O1CCOCC1>C(Cl)Cl.Cl>[Cl:28][C:21]1[CH:22]=[N+:23]([O-:27])[CH:24]=[C:25]([Cl:26])[C:20]=1[CH2:19][C@@H:18]([C:29]1[CH:34]=[CH:33][C:32]([O:35][CH:36]([F:37])[F:38])=[C:31]([O:39][CH2:40][CH:41]2[CH2:43][CH2:42]2)[CH:30]=1)[O:17][C:15](=[O:16])[CH2:14][O:13][C:11](=[O:12])[C:10]1[CH:44]=[C:45]([N:48]([CH2:53][CH:54]2[CH2:55][CH2:56]2)[S:49]([CH3:52])(=[O:51])=[O:50])[CH:46]=[CH:47][C:9]=1[OH:8]
Reactant: CC(C)(C)OC(=O)Oc1ccc(N(CC2CC2)S(C)(=O)=O)cc1C(=O)OCC(=O)O[C@@H](Cc1c(Cl)c[n+]([O-])cc1Cl)c1ccc(OC(F)F)c(OCC2CC2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: CS(=O)(=O)N(CC1CC1)c1ccc(O)c(C(=O)OCC(=O)O[C@@H](Cc2c(Cl)c[n+]([O-])cc2Cl)c2ccc(OC(F)F)c(OCC3CC3)c2)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.7 %

Procedure:
To a solution of (S)-4-(2-(2-(2-(tert-butoxycarbonyloxy)-5-(N-(cyclopropyl-methyl)methylsulfonamido)benzoyloxy)acetoxy)-2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)ethyl)-3,5-dichloropyridine 1-oxide (0.326 g, 0.385 mmol) in DCM (15 ml), HCl 4M in dioxane (1 ml, 4.00 mmol) was added, and the mixture was stirred at RT overnight. Additional HCl 4M in dioxane (1 ml, 4.00 mmol) was added, and the mixture was stirred at the same temperature for 3 days. The solvent was removed and the crude was triturated with MeOH. The solid was collected by filtration and washed with ethyl ether. A further trituration with EtOAc was required to afford (S)-3,5-dichloro-4-(2-(3-(cyclopropylmethoxy)-4-(difluoromethoxy)phenyl)-2-(2-(5-(N-(cyclopropylmethyl)-methylsulfonamido)-2-hydroxybenzoyloxy)acetoxy)ethyl)pyridine 1-oxide as a white solid (0.160 g, 0.215 mmol, 55.7% yield, MS/ESI+ 745.19 [MH]+, [αD]=−36.29, c=0.49, DCM).
Reaction SMILES: CS([O:5][CH2:6][C:7]1[CH:12]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[N:10]=[C:9]([Cl:18])[N:8]=1)(=O)=O.[F:19][C:20]([F:25])([F:24])[CH2:21][CH2:22]O.[OH-].[Na+]>C1C=CC=CC=1.S([O-])(O)(=O)=O.C([N+](CCCC)(CCCC)CCCC)CCC>[Cl:18][C:9]1[N:10]=[C:11]([C:13]([O:15][CH2:16][CH3:17])=[CH2:14])[CH:12]=[C:7]([CH2:6][O:5][CH2:22][CH2:21][C:20]([F:25])([F:24])[F:19])[N:8]=1
Reactant: C=C(OCC)c1cc(COS(C)(=O)=O)nc(Cl)n1
Reactant: OCCC(F)(F)F
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: O=S(=O)([O-])O
Agent: [Na+]
Solvent: c1ccccc1
Product: C=C(OCC)c1cc(COCCC(F)(F)F)nc(Cl)n1
Temperature: 25 °C
Yield: 11.5 %

Procedure:
To a solution of (2-chloro-6-(1-ethoxyvinyl)pyrimidin-4-yl)methyl methanesulfonate (0.452 g, 1.54 mmol) in benzene (7 mL) were added 3,3,3-trifluoropropan-1-ol (0.264 g, 2.32 mmol), sodium hydroxide (5 M, 0.463 mL, 2.32 mmol) and tetrabutylammonium hydrogen sulfate (0.052 g, 0.15 mmol). The mixture was stirred vigourously over night at room temperature. The mixture was filtered through a short silica plug with magnesium sulfate on top. The filter was washed with EtOAc. The mixture was purified by preparative HPLC to give 2-chloro-4-(1-ethoxyvinyl)-6-((3,3,3-trifluoropropoxy)methyl)pyrimidine 0.055 g 11%).