Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([OH:14])=[O:13].[C:15]1(C)C=CC(S(O)(=O)=O)=C[CH:16]=1>C(O)C>[CH:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH:4]=[CH:3][C:2]=1[CH2:11][C:12]([O:14][CH2:15][CH3:16])=[O:13]
Reactant: O=C(O)Cc1ccc2ccccc2c1
Reactant: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CCO
Product: CCOC(=O)Cc1ccc2ccccc2c1
Yield: 906.6 %

Procedure:
To a solution of 2-naphtylacetic acid (5 g) in 50 ml of ethanol are added 0.5 g of paratoluensulfonic acid, then the reaction mixture is refluxed for about 4 hours. The solvent is evaporated off and the residue is dissolved in diethyl ether, washed twice with a saturated aqueous solution of sodium hydrogencarbonate and once with brine, then the pooled organic extracts are dried over sodium sulfate and concentrated to dryness. 5.64 g of the product as a yellow oil are obtained.
Reaction SMILES: BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CN(S(C3C=CC(C(C)(C)C)=CC=3)(=O)=O)C=2C=1.[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:51])[F:50])[CH:47]=[CH:48][C:42]=3[CH2:41][NH:40][C:39]=2[CH:53]=1.[F:54][C:55]([F:70])([F:69])[C:56]1([C:59]2[CH:64]=[CH:63][C:62]([S:65](Cl)(=[O:67])=[O:66])=[CH:61][CH:60]=2)[CH2:58][CH2:57]1.BrC1C=CC2NC3N=C(C(F)(F)F)C=CC=3CNC=2C=1.C(C1C=CC(S(Cl)(=O)=O)=CC=1)(C)(C)C>>[I:34][C:35]1[CH:36]=[CH:37][C:38]2[NH:44][C:43]3[N:45]=[C:46]([C:49]([F:52])([F:50])[F:51])[CH:47]=[CH:48][C:42]=3[CH2:41][N:40]([S:65]([C:62]3[CH:61]=[CH:60][C:59]([C:56]4([C:55]([F:54])([F:69])[F:70])[CH2:58][CH2:57]4)=[CH:64][CH:63]=3)(=[O:67])=[O:66])[C:39]=2[CH:53]=1
Reactant: FC(F)(F)c1ccc2c(n1)Nc1ccc(I)cc1NC2
Reactant: O=S(=O)(Cl)c1ccc(C2(C(F)(F)F)CC2)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)Cl)cc1
Agent: CC(C)(C)c1ccc(S(=O)(=O)N2Cc3ccc(C(F)(F)F)nc3Nc3ccc(Br)cc32)cc1
Agent: FC(F)(F)c1ccc2c(n1)Nc1ccc(Br)cc1NC2
Product: O=S(=O)(c1ccc(C2(C(F)(F)F)CC2)cc1)N1Cc2ccc(C(F)(F)F)nc2Nc2ccc(I)cc21

Procedure:
The title compound was prepared following procedure described for intermediate 53 substituting 8-iodo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine (intermediate 37) and 4-[1-(trifluoromethyl)-cyclopropyl]benzenesulfonyl chloride (intermediate 48) for 8-bromo-2-(trifluoromethyl)-6,11-dihydro-5H-pyrido[2,3-b][1,5]benzodiazepine, and [(4-tert-butylphenyl)-sulfonyl chloride. LC/MS: m/e 639.8 (M+H)+. 1H NMR (500 MHz, CDCl3): δ 7.93 (1H, d, J=2.1 Hz), 7.58 (1H, d, J=7.8 Hz), 7.55 (1H, dd, J=8.5, 2.1 Hz), 7.22 (2H, d, J=8.2 Hz), 7.10 (1H, d, J=7.6 Hz), 7.03 (2H, d, J=8.5 Hz), 6.75 (1H, s), 6.52 (1H, d, J=8.5 Hz), 4.70-4.90 (2H, br), 1.37-1.40 (4H, m), 0.95-1.05 (4H, m).
Reaction SMILES: O1CCOCC1.[F:7][C:8]([F:49])([F:48])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36](Cl)[CH:37]=4)=[CH:30][N:29]=[C:28]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:27]=3)[C@H:20]2[CH3:47])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1.[CH:50]1([B-](F)(F)F)[CH2:52][CH2:51]1.[K+].C([O-])([O-])=O.[K+].[K+]>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.O>[F:7][C:8]([F:49])([F:48])[C:9]1[CH:10]=[C:11]([C@H:19]2[O:23][C:22](=[O:24])[N:21]([CH2:25][C:26]3[C:31]([C:32]4[C:33]([O:39][CH3:40])=[N:34][CH:35]=[C:36]([CH:50]5[CH2:52][CH2:51]5)[CH:37]=4)=[CH:30][N:29]=[C:28]([N:41]4[CH2:46][CH2:45][O:44][CH2:43][CH2:42]4)[N:27]=3)[C@H:20]2[CH3:47])[CH:12]=[C:13]([C:15]([F:18])([F:17])[F:16])[CH:14]=1
Reactant: COc1ncc(Cl)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Reactant: F[B-](F)(F)C1CC1
Agent: Cl[Pd]Cl
Agent: CN(C)c1ccc(P(C(C)(C)C)C(C)(C)C)cc1
Agent: O=C([O-])[O-]
Solvent: O
Solvent: C1COCCO1
Product: COc1ncc(C2CC2)cc1-c1cnc(N2CCOCC2)nc1CN1C(=O)O[C@H](c2cc(C(F)(F)F)cc(C(F)(F)F)c2)[C@@H]1C
Temperature: 130 °C
Reaction time: 0.5 h

Procedure:
Bis(di-tert-butyl(4-dimethylaminophenyl)phosphine)dichloropalladium(II) (11.20 mg, 0.016 mmol) was added to a degassed dioxane (700 μl)/Water (100 μl) solution of (4S,5R)-5-[3,5-bis(trifluoromethyl)phenyl]-3-{[5-(5-chloro-2-methoxypyridin-3-yl)-2-(morpholin-4-yl)pyrimidin-4-yl]methyl}-4-methyl-1,3-oxazolidin-2-one (EXAMPLE 11, 100 mg, 0.158 mmol), potassium cyclopropyltrifluoroborate (46.8 mg, 0.316 mmol) and K2CO3 (65.6 mg, 0.475 mmol). After further degassing with N2 and vacuum for 3 cycles, the reaction was capped and stirred for 30 minutes at 130° C. in a Biotage microwave reactor. LCMS showed >80% conversion to product. The reaction was diluted with 5 mL acetonitrile and filtered through a 1 g RP C18 silica cartridge, eluting with 15 mL acetonitrile until the filtrate was colorless. The filtrate was concentrated and the crude purified under the following conditions: X-Bridge 21.2×150 mm RP column, sample loaded in 7:3:1 CH3CN/water/DMSO (5 mL) with the column eluted using a 10-100% acetonitrile/water (0.1% NH4OH) linear gradient at 15 mL/minute over 20 minutes to give the product as a white solid after lyophilization of the purified fractions. LCMS (M+H)+: 638.5. 1H NMR (500 MHz, CDCl3): δ 8.23 (br, 1H), 8.12 (br, 1H), 7.93 (br, 1H), 7.75 (br, 2H), 7.24 (br, 1H), 5.68 (m, 2H), 4.72 (d, J=17.6 Hz, 1H), 4.13 (d, J=17.6 Hz, 1H), 4.07 (m, 4H), 3.99 (s, 3H), 3.88 (m, 4H), 1.93 (m, 1H), 1.05 (m, 2H), 0.71 (m, 5H). SPA IC50: 530 nM
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[Br:10][CH2:11][CH2:12]Br>>[Br:10][CH2:11][CH2:12][N:1]1[C:9]2[C:4](=[CH:5][CH:6]=[CH:7][CH:8]=2)[CH:3]=[CH:2]1
Reactant: c1ccc2[nH]ccc2c1
Reactant: BrCCBr
Product: BrCCn1ccc2ccccc21

Procedure:
The procedure is as for Example 39 using as substrate 1H-indole and 1,2-dibromoethane.
Reaction SMILES: [ClH:1].[NH2:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7](OC)[C:8]([N:15]3[CH2:19][CH:18]([CH:20]([NH2:22])[CH3:21])[C:17]([CH3:24])(C)[CH2:16]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH:27]2[CH2:29][CH2:28]2)[C:4]1=[O:30].[C:31]([O:35]C(=O)NC(C1C(C)(C)CN(C2C(OC)=C3C(C(=O)N(N)C(=O)N3C3CC3)=CC=2F)C1)C)(C)([CH3:33])[CH3:32]>>[ClH:1].[NH2:2][N:3]1[C:12](=[O:13])[C:11]2[C:6](=[C:7]([Cl:1])[C:8]([N:15]3[CH2:19][C@@H:18]([C:17]4[CH:24]=[CH:33][C:31]([OH:35])=[CH:32][CH:16]=4)[C@H:20]([NH2:22])[CH2:21]3)=[C:9]([F:14])[CH:10]=2)[N:5]([CH:27]2[CH2:28][CH2:29]2)[C:4]1=[O:30]
Reactant: COc1c(N2CC(C(C)N)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Reactant: COc1c(N2CC(C(C)NC(=O)OC(C)(C)C)C(C)(C)C2)c(F)cc2c(=O)n(N)c(=O)n(C3CC3)c12
Agent: Cl
Product: N[C@@H]1CN(c2c(F)cc3c(=O)n(N)c(=O)n(C4CC4)c3c2Cl)C[C@H]1c1ccc(O)cc1

Procedure:
(gggg) 3-Amino-7-[4-(1-aminoethyl)-3,3-dimethylpyrrolidin-1-yl]-1-cyclopropyl-6-fluoro-8-methoxy-1H-quinazoline-2,4-dione hydrochloride (Compound 86) (mp 230° C., MS ES: m/z 406 (MH+)) from {1-[1-(3-amino-1-cyclopropyl-6-fluoro-8-methoxy-2,4-dioxo-1,2,3,4-tetrahydroquinazolin-7-yl)-4,4-dimethylpyrrolidin-3-yl]ethyl}carbamic acid tert-butyl ester (Example 28w) using General Method A.
Reaction SMILES: Br[C:2]1[N:6]([CH3:7])[C:5]([C:8]([O:10][CH3:11])=[O:9])=[CH:4][CH:3]=1.[C:12]1(B(O)O)[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C([O-])([O-])=O.[Na+].[Na+].C(Cl)Cl>COCCOC.O.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>[CH3:7][N:6]1[C:2]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[CH:3][CH:4]=[C:5]1[C:8]([O:10][CH3:11])=[O:9]
Reactant: OB(O)c1ccccc1
Reactant: COC(=O)c1ccc(Br)n1C
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Solvent: O
Solvent: COCCOC
Product: COC(=O)c1ccc(-c2ccccc2)n1C
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 96 %

Procedure:
The product from step 152a is added to a solution of tetrakis(triphenylphosphine)palladium(0) (0.530 g, 0.459 mmol) in 90 mL of ethylene glycol dimethyl ether. The resulting solution is stirred under nitrogen for 5 min and then phenylboronic acid (1.34 g, 11.0 mmol) is added followed by a solution of Na2CO3 (19.5 g, 183 mmol) in 90 mL of H2O. The mixture is heated at reflux for 24 hours. The reaction mixture is allowed to cool to rt, 100 mL of CH2Cl2 is added, and the layers are separated. The aqueous layer is extracted with CH2Cl2 (3×50 mL) and combined organic layers are dried over MgSO4, filtered, and concentrated in vacuo. The crude product is purified by flash column chromatography (5% EtOAc in hexane) to give 1.89 g of methyl 1-methyl-5-phenyl-1H-pyrrole-2-carboxylate as a yellow oil (96% yield). MS for C13H13NO2 (ESI) (M+H)+ m/z 216.1.
Reaction SMILES: [O:1]=[C:2]1[CH2:10][CH2:9][CH2:8][C:7]2[NH:6][CH:5]=[C:4]([C:11]([OH:13])=[O:12])[C:3]1=2.[N+:14]([O-])([OH:16])=[O:15]>>[N+:14]([C:5]1[NH:6][C:7]2[CH2:8][CH2:9][CH2:10][C:2](=[O:1])[C:3]=2[C:4]=1[C:11]([OH:13])=[O:12])([O-:16])=[O:15]
Reactant: O=C(O)c1c[nH]c2c1C(=O)CCC2
Reactant: O=[N+]([O-])O
Product: O=C1CCCc2[nH]c([N+](=O)[O-])c(C(=O)O)c21
Temperature: 0 °C
Reaction time: 1.25 h

Procedure:
4-Oxo-4,5,6,7-tetrahydro-1H-indole-3-carboxylic acid (179 mg, 1 mmol) was added in portions over 30 minutes to fuming nitric acid (2 mL) at 0° C. The mixture was stirred an additonal 1.25 hours, then allowed to stir at ambient temperature for 1.25 hours. The mixture was poured into ice water and extracted 2X with ethyl acetate. The combined organic layers were dried over magnesium sulfate, filtered, and concentrated in vacuo to give the title compound(0.19 g).
Reaction SMILES: [CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19](Br)[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:23][N:24]([CH3:28])[CH2:25][CH2:26][NH2:27]>C(O)C>[CH2:1]([N:8]1[C:13](=[O:14])[C:12]2[N:15]=[C:16]([Br:18])[S:17][C:11]=2[N:10]=[C:9]1[CH:19]([NH:27][CH2:26][CH2:25][N:24]([CH3:28])[CH3:23])[CH2:20][CH3:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCC(Br)c1nc2sc(Br)nc2c(=O)n1Cc1ccccc1
Reactant: CN(C)CCN
Solvent: CCO
Product: CCC(NCCN(C)C)c1nc2sc(Br)nc2c(=O)n1Cc1ccccc1

Procedure:
A solution of 6-benzyl-2-bromo-5-(1-bromopropyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-2, 1 equiv) and N,N-dimethylethylenediamine (3 equiv) in ethanol is heated at reflux for 18 h. The reaction mixture is concentrated, and the residue is partitioned between EtOAc and brine. The organic layer is dried (MgSO4) and concentrated to provide 6-benzyl-2-bromo-5-(1-{[2-(dimethylamino)ethyl]-amino}propyl)[1,3]thiazolo[5,4-d]pyrimidin-7(6H)-one (1-3).
Reaction SMILES: C([CH:5]1[C@@:9]2([CH2:13][C:12](=[O:14])[N:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH2:10]2)[CH2:8][C@@H:7]([C:21]([OH:23])=[O:22])[N:6]1[C:24](=[O:39])[C@@H:25]([NH:30][C:31]([O:33][CH:34]1[CH2:38][CH2:37][CH2:36][CH2:35]1)=[O:32])[C:26]([CH3:29])([CH3:28])[CH3:27])(C)(C)C.N1CCC[C@H]1C(O)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[CH:34]1([O:33][C:31]([NH:30][C@@H:25]([C:26]([CH3:29])([CH3:28])[CH3:27])[C:24]([N:6]2[C@H:7]([C:21]([OH:23])=[O:22])[CH2:8][C@@:9]3([CH2:13][C:12](=[O:14])[N:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[CH2:10]3)[CH2:5]2)=[O:39])=[O:32])[CH2:35][CH2:36][CH2:37][CH2:38]1
Reactant: CC(C)(C)C1N(C(=O)[C@@H](NC(=O)OC2CCCC2)C(C)(C)C)[C@H](C(=O)O)C[C@]12CC(=O)N(c1ccccc1)C2
Agent: O=C(O)[C@@H]1CCCN1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(C)(C)[C@H](NC(=O)OC1CCCC1)C(=O)N1C[C@]2(CC(=O)N(c3ccccc3)C2)C[C@H]1C(=O)O
Yield: 100 %

Procedure:
The protected proline (3S,5R)-tert-butyl-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylate (H6a) (9.2 mg, 17 μmol) was dissolved in CH2Cl2 (1.0 ml) and treated with trifluoroacetic acid (0.3 ml) for 4 hrs at room temperature. The reaction was concentrated to dryness under high vacuum to give (3S,5R)-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (I6a) (17 μmol). The minor diastereomer (3S,5S)-2-((S)-2-(cyclopentyloxycarbonylamino)-3,3-dimethylbutanoyl)-8-oxo-7-phenyl-2,7-diazaspiro[4.4]nonane-3-carboxylic acid (I6b) (5 μmol) was obtained in similar fashion.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:12])[CH2:9][CH2:10][CH3:11])=[CH:4][CH:3]=1.Br[CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16]>>[C:8]([C:5]1[CH:4]=[CH:3][C:2]([O:1][CH:14]([CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH3:27])[C:15]([O:17][CH2:18][CH3:19])=[O:16])=[CH:7][CH:6]=1)(=[O:12])[CH2:9][CH2:10][CH3:11]
Reactant: CCCC(=O)c1ccc(O)cc1
Reactant: CCCCCCCCC(Br)C(=O)OCC
Product: CCCCCCCCC(Oc1ccc(C(=O)CCC)cc1)C(=O)OCC
Yield: 85 %

Procedure:
1-[4-Hydroxyphenyl]-1-butanone (328 mg, 2.0 mmol) and ethyl (RS)-2-bromodecanoate (614 mg, 2.2 mmol) were reacted according to the procedure used for the preparation of I to give Ethyl (RS)-2-[4-Butyrylphenoxy]decanoate (616 mg, 85%) as a clear, colourless oil. 1H NMR (400 MHz, CDCl3): δ 7.88 (d, J=9.0 Hz, 2H), 6.86 (d, J=9.0 Hz, 2H), 4.64 (dd, J=5.7, 6.8 Hz, 1H), 4.17 (q, J=7.2 Hz, 2H), 2.83 (t, J=7.3 Hz, 2H), 1.85-1.99 (m, 2H), 1.65-1.75 (m, 2H), 1.39-1.44 (m, 2H), 1.22-1.34 (m, 10H), 1.20 (t, J=7.2 Hz, 3H), 0.94 (t, J=7.4 Hz, 3H), 0.83 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.04, 171.39, 161.80, 130.98, 130.48 (2C), 114.74 (2C), 76.68, 61.55, 40.37, 32.85, 32.01, 29.53, 29.37 (2C), 25.33, 22.84, 18.11, 14.34, 14.29, 14.10. The resulting ester (616 mg, 1.70 mmol) was saponified with lithium hydroxide (203 mg, 8.5 mmol) according to the procedure used for the preparation of I to give (RS)-2-[4-Butyrylphenoxy]decanoic Acid (166 mg, 29%). 1H NMR (400 MHz, CDCl3): δ 10.06 (br s, 1H), 7.91 (d, J=9.0 Hz, 2H), 6.90 (d, J=9.0 Hz, 2H), 4.70 (dd, J=5.9, 6.4 Hz, 1H), 2.87 (t, J=7.3 Hz, 2H), 1.96-2.02 (m, 2H), 1.68-1.77 (m, 2H), 1.44-1.59 (m, 2H), 1.24-1.37 (m, 10H), 0.97 (t, J=7.4 Hz, 3H), 0.86 (t, J=7.0 Hz, 3H); 13C NMR (101 MHz, CDCl3): δ 199.95, 176.56, 161.74, 131.03, 130.73 (2C), 114.82 (2C), 76.16, 40.47, 32.79, 32.03, 29.53, 29.39, 29.37, 25.38, 22.86, 18.26, 14.31, 14.12. The acid (166 mg, 0.5 mmol) was then converted to the sodium salt according to the procedure used for the preparation of I to give Sodium (RS)-2-[4-Butyrylphenoxy]decanoate (149 mg, 85%) as a white solid. mp 262-278° C.; 1H NMR (400 MHz, CD3OD): δ 7.91 (d, J=9.0 Hz, 2H), 6.96 (d, J=9.0 Hz, 2H), 4.70 (dd, J=6.1, 6.5 Hz, 1H), 2.90 (t, J=7.3 Hz, 2H), 1.88-1.93 (m, 2H), 1.67 (tq, J=7.4, 7.4 Hz, 2H), 1.41-1.57 (m, 2H), 1.20-1.35 (m, 10H), 0.95 (t, J=7.4 Hz, 3H), 0.83 (t, J=6.9 Hz, 3H); 13C NMR (101 MHz, CD3OD): δ201.82, 178.07, 163.36, 130.53 (2C), 129.54, 114.83 (2C), 79.46, 39.99, 33.11, 31.80, 29.40, 29.27, 29.15, 25.72, 22.54, 18.30, 14.46, 14.15; LRMS (ESI): m/z 713 (M2H+), 669 (2M-2Na++3H+), 335 (M-Na++2H+); HPLC: 3 min.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.S(OS(C(F)(F)F)(=O)=O)(C(F)(F)F)(=O)=O.[F:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1[C:45]([CH3:51])([CH2:48][CH2:49][OH:50])[CH2:46]O.C(=O)([O-])[O-].[K+].[K+]>ClCCl.O>[F:35][C:36]1[CH:41]=[CH:40][C:39]([N+:42]([O-:44])=[O:43])=[CH:38][C:37]=1[C:45]1([CH3:51])[CH2:48][CH2:49][O:50][CH2:46]1
Reactant: CC(CO)(CCO)c1cc([N+](=O)[O-])ccc1F
Agent: O=C([O-])[O-]
Agent: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Agent: [K+]
Solvent: O
Solvent: ClCCl
Product: CC1(c2cc([N+](=O)[O-])ccc2F)CCOC1
Temperature: 25 °C

Procedure:
To a solution of triphenylphosphine(2 eq) in dichloromethane at 0° C. under nitrogen was added dropwise triflic anhydride(1 eq). After 15 minutes 2-(2-fluoro-5-nitrophenyl)-2-methylbutane-1,4-diol(1 eq)was added in dichloromethane followed by potassium carbonate(1 eq). The resulting mixture was allowed to warm to room temperature for 5 h. To the mixture was added water and extracted with dichloromethane. The organic layer was washed with brine and dried with sodium sulfate and concentrated. Crude product was purified using flash chromatography (85% Hex:15% EtoAc) on silica to afford 3-(2-fluoro-5-nitrophenyl)-tetrahydro-3-methylfuran.
Reaction SMILES: Br[C:2]1[CH:3]=[CH:4][C:5]([F:8])=[N:6][CH:7]=1.[B:9](OC(C)C)([O:14]C(C)C)[O:10]C(C)C.C([Li])CCC.Cl>O1CCCC1.C1(C)C=CC=CC=1>[F:8][C:5]1[N:6]=[CH:7][C:2]([B:9]([OH:14])[OH:10])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: Fc1ccc(Br)cn1
Agent: Cl
Agent: [Li]CCCC
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: OB(O)c1ccc(F)nc1
Temperature: -42.5 °C
Reaction time: 5 h
Yield: 1624.3 %

Procedure:
A 72 L reactor equipped with reflux condenser, and temperature probe. To the reactor 5-bromo-2-fluoropyridine (1.17 L, 0.568 mol), toluene (18.2 L), and triisopropyl borate (3.13 L, 0.68 mol, 1.2 equiv.) were charged and stirred. Tetrahydrofuran (4.4 L) was added to the reactor and the reaction mixture was cooled to between −35 to −50° C. While maintaining a temperature between −35 to −45° C., n-butyl lithium (2.5 M solution of hexanes, 5.44 L, 0.68 mol, 1.2 equiv.) was cautiously added to the reactor. After 5 h, the reaction was deemed complete and the reaction mixture was warmed to between −15 to −20° C. To the reaction was added 2M HCl (11.80 L) to the reactor while maintaining a temperature between −15° C. and 0° C. The reaction mixture was stirred at 18 to 23° C. for (16 h) and the phases were separated. The organics were then extracted with 6 M sodium hydroxide (6.0 L). The acidic anbasic aqueous phases were mixed in the reactor and 6 M HCl (2.5 L) was added until pH 7.5 was achieved. Sodium chloride (6.0 kg) was then added to the aqueous phase. The aqueous phase was then extracted with THF (3×20 L). The combined organics were dried with magnesium sulfate and concentrated to give 1300 g of a tan solid (81% crude yield).
Reaction SMILES: [S:1]1[CH2:5][C:4](=[O:6])[NH:3][C:2]1=[O:7].[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=1.N1CCCCC1>C(O)C>[Cl:8][C:9]1[CH:16]=[CH:15][C:12]([CH:13]=[C:5]2[S:1][C:2](=[O:7])[NH:3][C:4]2=[O:6])=[CH:11][CH:10]=1
Reactant: O=Cc1ccc(Cl)cc1
Reactant: O=C1CSC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2ccc(Cl)cc2)S1
Yield: 43.3 %

Procedure:
To a solution of 20 g (171 mmol) of 2,4-thiazolidinedione and 17.4 ml (171 mmol) of 4-chlorobenzaldehyde in 350 ml of ethanol, 1.68 ml (17.1 mmol) of piperidine was added, and the mixture was heated under reflux for 5 hours. After cooling, the precipitated crystals were filtered and washed with cooled ethanol to give 17.75 g of the desired compound (43.4% yield, pale yellow crystals).
Reaction SMILES: [H-].[Na+].[CH2:3](O)[CH:4]=C.[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2/[CH:24]=[CH:25]/[C:26]([O:28][CH3:29])=[O:27])[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1>C1(C)C=CC=CC=1>[CH2:7]([O:14][C:15]1[CH:16]=[C:17]2[C:21](=[CH:22][CH:23]=1)[NH:20][CH:19]=[C:18]2/[CH:24]=[CH:25]/[C:26]([O:28][CH2:29][CH:3]=[CH2:4])=[O:27])[C:8]1[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=1
Reactant: COC(=O)/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12
Reactant: C=CCO
Agent: [H-]
Agent: [Na+]
Solvent: Cc1ccccc1
Product: C=CCOC(=O)/C=C/c1c[nH]c2ccc(OCc3ccccc3)cc12

Procedure:
17.45 g of a 55% w/w suspension of sodium hydride in mineral oil were suspended in 400 ml of toluene; to the resulting suspension were added 400 ml of allyl alcohol, whilst ice-cooling and under a nitrogen atmosphere. 122.93 g of methyl (E)-3-(5-benzyloxy-1H-indol-3-yl)acrylate were added thereto, and the mixture was heated under reflux for 10 minutes. The reaction mixture was then washed, in turn, with a saturated aqueous solution of citric acid, with a saturated aqueous solution of sodium hydrogen carbonate, with water and with a saturated aqueous solution of sodium chloride, and then dried over anhydrous magnesium sulfate. It was then condensed by evaporation under reduced pressure. The residue was purified by silica gel column chromatography using 20% v/v ethyl acetate in hexane as eluent, to give 100.12 g of the title compound as crystals melting at 73°-77° C.
Reaction SMILES: [C:1]1([CH2:7][O:8][CH2:9][C@@H:10]2[C@@H:15]([CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:14][CH:12](O)[C@@H:11]2[OH:25])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CC(CC(O)=O)=O.C[Si](Br)(C)C.[H-].C([Al+]CC(C)C)C(C)C>ClCCl.C1(C)C=CC=CC=1>[C:1]1([CH2:7][O:8][CH2:9][C@@H:10]2[C@@H:15]([CH2:16][O:17][CH2:18][C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=3)[O:14][CH2:12][C@@H:11]2[OH:25])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](COCc2ccccc2)[C@H]1O
Agent: CC(=O)CC(=O)O
Agent: CC(C)C[Al+]CC(C)C
Agent: C[Si](C)(C)Br
Solvent: ClCCl
Solvent: Cc1ccccc1
Product: O[C@H]1CO[C@H](COCc2ccccc2)[C@H]1COCc1ccccc1
Temperature: 0 °C
Reaction time: 6.5 h

Procedure:
To a solution of 3-deoxy-3-[(phenylmethoxy)methyl]-5-O-(phenylmethyl)-D-ribofuranose, diacetate (4.81 g, 11.23 mmol) in dichloromethane (100 ml) at 0° C. was added trimethylsilyl bromide (2.59 ml, 19.65 mmol). The reaction was stirred at 0° C. for 30 minutes and at room temperature for 6.5 hours. At this time, the reaction was cooled to 0° C. and transferred via canula to a toluene solution of diisobutylaluminum hydride (100 ml, 1M), also at 0° C. The reaction mixture was kept at 0° C. for 40 minutes and then quenched cautiously with methanol (14.2 ml) and then water (20 ml). After stirring at room temperature for 1 hour, the mixture was filtered through Celite, washing well with ether and ethyl acetate. The volatiles were evaporated in vacuo and the resulting oil (4.04 g) was combined with the crude product (7.6 g) from an identical reaction starting with 23.16 mmol of 3-deoxy-3[(phenylmethoxy)methyl]-5-O-(phenylmethyl)-D-ribofuranose, diacetate. The combined products were purified by flash chromatography (Merck silica gel-60, 230-400 mesh) eluting with a step-wise gradient of dichloromethane and dichloromethane/dioxane (20:1 and then 7:3). The resulting material was further purified by flash chromatography (Merck silica gel-60, 230-400 mesh) eluting with dichloromethane/dioxane (15:1) to give the title compound as a colorless oil (3.4 g). The mixed fractions were purified by flash chromatography (Merck silica gel-60, 230-400 mesh) eluting with dichloromethane/dioxane (20:1) to give additional title compound as a colorless oil (1.5 g pure and 1.66 g ~90% pure by 1H NMR).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:10]2[N:18]([CH3:19])[C:17](=[O:20])[C:16](C(O)=O)=[CH:15][C:11]=2[CH:12]=[N:13][N:14]=1.C1COCC1.O.O.C([O-])(=O)C.[Li+].C1C(=O)N([Br:43])C(=O)C1>O>[Br:43][C:16]1[C:17](=[O:20])[N:18]([CH3:19])[C:10]2[C:9]([C:3]3[CH:4]=[CH:5][C:6]([F:8])=[CH:7][C:2]=3[F:1])=[N:14][N:13]=[CH:12][C:11]=2[CH:15]=1
Reactant: O=C1CCC(=O)N1Br
Reactant: Cn1c(=O)c(C(=O)O)cc2cnnc(-c3ccc(F)cc3F)c21
Agent: CC(=O)[O-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: Cn1c(=O)c(Br)cc2cnnc(-c3ccc(F)cc3F)c21
Temperature: 55 °C

Procedure:
To a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (1.00 g, 3.15 mmol) in 10:1 THF:H2O (11 mL), stirred at 55° C., was added lithium acetate dihydrate (67 mg, 0.66 mmol). The mixture was stirred at 55° C. and treated with NBS (1.51 g, 8.48 mmol) in three equal portions at 30 min intervals. After addition of NBS was complete, the reaction mixture was stirred an additional 1 h at 55° C. In a separate flask, a suspension of 8-(2,4-difluorophenyl)-1-methyl-2-oxo-1,2-dihydropyrido[3,2-d]pyridazine-3-carboxylic acid (7) (0.92 g, 2.89 mmol) in 10:1 THF:H2O (10 mL) stirred at 55° C. was treated with lithium acetate dihydrate (62 mg, 0.61 mmol) followed by NBS (1.39 g, 7.80 mmol) under the same conditions. Upon complete reaction, the two reaction mixtures were combined, diluted with water, and extracted with CH2Cl2. The combined organic layers were washed with 20% THF in water, dried over MgSO4, filtered, and concentrated in vacuo. The resulting residue was purified by silica gel chromatography [eluting with a gradient of 10-40% B in A where the eluents were: A=CH2Cl2; B=1:49.5:49.5 MeOH:EtOAc:CH2Cl2] to give 3-bromo-8-(2,4-difluorophenyl)-1-methylpyrido[3,2-d]pyridazin-2(1H)-one as a yellow solid. MS (ESI, pos. ion) m/z: 350, 352 (M+1, M+3).