Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([I:11])=[CH:7][C:3]=1[C:4](O)=[O:5].C(O)(=O)C.[CH:16](N)=[NH:17].O>C(O)C>[I:11][C:8]1[CH:7]=[C:3]2[C:2](=[CH:10][CH:9]=1)[N:1]=[CH:16][NH:17][C:4]2=[O:5]
Reactant: Nc1ccc(I)cc1C(=O)O
Reactant: N=CN
Solvent: O
Solvent: CC(=O)O
Solvent: CCO
Product: O=c1[nH]cnc2ccc(I)cc12

Procedure:
A mixture of 2-amino-5-iodobenzoic acid (2.0 g, 7.6 mmol) and formamidine acetate (0.99 g, 9.5 mmol) in absolute ethanol (80 mL) was heated at reflux for 2 h. The reaction was then cooled in an ice bath, and water (10 mL) was added with stirring. The resultant precipitate was collected by filtration to afford the desired product as pale crystals. LC/MS 272.7 (M+1).
Reaction SMILES: [CH2:1]([N:8]1[CH2:13][CH2:12][NH:11][CH2:10][CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1COCC1.C([Li])CCC.F[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[C:31]1[O:32][CH:33]=[CH:34][N:35]=1>O>[CH2:1]([N:8]1[CH2:13][CH2:12][N:11]([C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:31]2[O:32][CH:33]=[CH:34][N:35]=2)[CH2:10][CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: Fc1ccccc1-c1ncco1
Reactant: c1ccc(CN2CCNCC2)cc1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: O
Product: c1ccc(CN2CCN(c3ccccc3-c3ncco3)CC2)cc1
Temperature: 0 °C
Yield: 37.3 %

Procedure:
A mixture of N-benzylpiperazine (3.56 g, 20.2 mmol) and THF (25 mL) was cooled to 0° C. and n-butyllithium (2.5M in hexanes, 7.6 mL, 19 mmol) was added. The mixture was cooled 30 minutes with stirring at 0° C., stirred 1 hour at 25° C., then cooled to 0° C. and 2-fluoro-1-oxazol-2-ylbenzene (1.1 g, 6.75 mmol) was added slowly. The reaction mixture was allowed to warm to 25° C., then stirred 90 minutes and diluted with water. The aqueous layer was separated and extracted with ethyl acetate (3×30 mL). The combined extracts were washed with brine, dried (MgSO4) and concentrated. The residue was purified on silica gel by column chromatography eluting with hexanes/ethyl acetate (9:1) to give 4-benzyl-1-(2-oxazol-2-ylphenyl)piperazine (0.805 g, 2.52 mmol).
Reaction SMILES: [NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:30]=[CH:29][C:16]([C:17]([NH:19][C@H:20]([C:26]([OH:28])=[O:27])[CH2:21][CH2:22][C:23]([OH:25])=[O:24])=[O:18])=[CH:15][CH:14]=3)[C:5]=2[C:4](=[O:31])[N:3]=1.O.[OH-].[Na+:34].Cl>CC(C)=O>[Na+:34].[Na+:34].[NH2:1][C:2]1[NH:7][C:6]2[NH:8][CH:9]=[C:10]([CH2:11][CH2:12][C:13]3[CH:14]=[CH:15][C:16]([C:17]([NH:19][C@H:20]([C:26]([O-:28])=[O:27])[CH2:21][CH2:22][C:23]([O-:25])=[O:24])=[O:18])=[CH:29][CH:30]=3)[C:5]=2[C:4](=[O:31])[N:3]=1
Reactant: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)O)C(=O)O)cc3)c[nH]c2[nH]1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Nc1nc(=O)c2c(CCc3ccc(C(=O)N[C@@H](CCC(=O)[O-])C(=O)[O-])cc3)c[nH]c2[nH]1
Temperature: 2 °C
Reaction time: 10 h

Procedure:
A flask was charged with crude N-[4-[2-(2-amino-4,7-dihydro-4-oxo-1H-pyrrolo[2,3-d]pyrimidin-5-yl)ethyl]benzoyl]-L-glutamic acid (4 g), water (28 ml) and NaOH (3 equivalents) at 25° C. Complete dissolution was obtained. The pH was corrected to 10.0 with HCl 1M and acetone (120 mL) was added drop wise over a period of 50 min. The obtained suspension was cooled to 2° C. in one hour, stirred at 2° C. for 10 hours and filtered. The solid was washed with acetone (30 mL) and dried at 40° C. under vacuum (18 mbar) for about 16 hours affording the title compound.
Reaction SMILES: O[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])[CH3:3]>C(C(O)=O)(F)(F)F>[C:2]([C:5]1[CH:6]=[CH:7][C:8]([S:11]([NH2:14])(=[O:13])=[O:12])=[N:9][CH:10]=1)([CH3:4])=[CH2:3]
Reactant: CC(C)(O)c1ccc(S(N)(=O)=O)nc1
Solvent: O=C(O)C(F)(F)F
Product: C=C(C)c1ccc(S(N)(=O)=O)nc1

Procedure:
A solution of 0.1 g of (5-(1-hydroxy-1-methyl-ethyl))-pyridine-2-sulfonic acid amide, product of example 14 b), in CF3CO2H (2 ml) was refluxed for 20 h. The solvent was then removed in vacuo to give 5-isopropenyl-pyridine-2-sulfonic acid amide as a white solid which was essentially pure. EI mass spectrum, m/e 198 (M calculated for C8H10N2O2S: 198).
Reaction SMILES: Br[CH2:2][C:3]1[S:11][C:10]2[C:9]([N:12]3[CH2:17][CH2:16][O:15][CH2:14][CH2:13]3)=[N:8][C:7]([Cl:18])=[N:6][C:5]=2[CH:4]=1.[C:19]([O:23][C:24]([N:26]1[CH2:33][CH:32]2[CH:28]([CH2:29][NH:30][CH2:31]2)[CH2:27]1)=[O:25])([CH3:22])([CH3:21])[CH3:20].C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.O.CCOC(C)=O>[C:19]([O:23][C:24]([N:26]1[CH2:27][CH:28]2[CH:32]([CH2:31][N:30]([CH2:2][C:3]3[S:11][C:10]4[C:9]([N:12]5[CH2:17][CH2:16][O:15][CH2:14][CH2:13]5)=[N:8][C:7]([Cl:18])=[N:6][C:5]=4[CH:4]=3)[CH2:29]2)[CH2:33]1)=[O:25])([CH3:22])([CH3:20])[CH3:21]
Reactant: Clc1nc(N2CCOCC2)c2sc(CBr)cc2n1
Reactant: CC(C)(C)OC(=O)N1CC2CNCC2C1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)N1CC2CN(Cc3cc4nc(Cl)nc(N5CCOCC5)c4s3)CC2C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 90.8 %

Procedure:
To a solution of 6-bromomethyl-2-chloro-4-morpholin-4-yl-thieno[3,2-d]pyrimidine (175 mg, 0.50 mmol) in DMF (5 mL) were added hexahydro-pyrrolo[3,4-c]pyrrole-2-carboxylic acid tert-butyl ester (160 mg, 0.754 mmol) and potassium carbonate (136 mg, 0.984 mmol). The resulting mixture was stirred at RT for 2 h, then diluted with water and EtOAc. The organic layer was isolated, then washed with brine, dried (MgSO4) and concentrated in vacuo. The resulting residue was purified by column chromatography to give the title compound as an off-white solid (218 mg, 90%).
Reaction SMILES: [CH3:1][CH:2]([N:4]1[C:8]2[N:9]=[C:10]([C:18]3[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=3)[CH:11]=[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])[C:7]=2[CH:6]=[N:5]1)[CH3:3].[Br:24]Br.C(=O)(O)[O-].[Na+]>C(O)(=O)C>[Br:24][C:6]1[C:7]2[C:12]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:11][C:10]([C:18]3[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=3)=[N:9][C:8]=2[N:4]([CH:2]([CH3:3])[CH3:1])[N:5]=1
Reactant: BrBr
Reactant: CCOC(=O)c1cc(-c2ccccc2)nc2c1cnn2C(C)C
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1cc(-c2ccccc2)nc2c1c(Br)nn2C(C)C
Temperature: 80 °C
Reaction time: 1 h

Procedure:
Ethyl 1-(1-methylethyl)-6-phenyl-1H-pyrazolo[3,4-b]pyridine-4-carboxylate (120 mg, 0.388 mmol), was suspended in acetic acid (2 mL) followed by addition of bromine (26 μl, 0.504 mmol). The reaction mixture was stirred with heating at 80° C. After 1 h, a second portion of bromine was added (26 μl, 0.504 mmol) and the reaction mixture heated at 80° C. for an additional 2 h. After cooling to room temperature, the solution was added to a saturated aqueous solution of sodium bicarbonate (6 mL) and extracted with dichloromethane (2×10 mL) The combined organic layers were concentrated in vacuo. The crude product was purified by silica gel chromatography (eluent: EtOAc/Hexanes, 0-50% gradient). The product was collected as a white powder (112 mg, 74%). LCMS E-S (M+H)=388.0/390.2. 1H NMR (400 MHz, CHLOROFORM-d) δ 8.18 (dd, J=1.52, 8.08 Hz, 2H), 8.00 (s, 1H), 7.48-7.58 (m, 3H), 5.47 (quin, J=6.76 Hz, 1H), 4.58 (q, J=7.16 Hz, 2H), 1.65 (d, J=6.82 Hz, 6H), 1.52 (t, J=7.20 Hz, 3H).
Reaction SMILES: N1C=CN=C1.[C:6]([Si:10](Cl)([CH3:12])[CH3:11])([CH3:9])([CH3:8])[CH3:7].[I:14][C:15]1[CH:20]=[CH:19][C:18]([OH:21])=[CH:17][CH:16]=1.O>CN(C)C=O>[I:14][C:15]1[CH:20]=[CH:19][C:18]([O:21][Si:10]([CH3:12])([CH3:11])[C:6]([CH3:9])([CH3:8])[CH3:7])=[CH:17][CH:16]=1
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: Oc1ccc(I)cc1
Agent: c1c[nH]cn1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)Oc1ccc(I)cc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 83.7 %

Procedure:
387 mg of imidazole and 411 mg of tertbutyldimethylsilyl chloride is added at ambient temperature and under an inert atmosphere to 500 mg of para-iodo-phenol in 4 ml of dimethylformamide and the mixture is maintained under agitation for 15 hours at ambient temperature then for 1 hour at 40° C. The reaction medium is poured into water, and the aqueous phase is extracted with dichloromethane. The organic phase is then dried and evaporated under reduced pressure. In this way 636 mg of expected product is obtained.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:18])OC2C=CC=CC=2)=[CH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1.[CH3:25][O:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][C:35]=1[C:36]([F:39])([F:38])[F:37])[NH:32][CH2:31][CH2:30]2>>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([N:32]2[C:33]3[C:29](=[CH:28][C:27]([O:26][CH3:25])=[C:35]([C:36]([F:38])([F:39])[F:37])[CH:34]=3)[CH2:30][CH2:31]2)=[O:18])=[CH:5][C:4]=1[C:19]1[CH:20]=[N:21][CH:22]=[CH:23][CH:24]=1
Reactant: COc1cc2c(cc1C(F)(F)F)NCC2
Reactant: COc1ccc(NC(=O)Oc2ccccc2)cc1-c1cccnc1
Product: COc1ccc(NC(=O)N2CCc3cc(OC)c(C(F)(F)F)cc32)cc1-c1cccnc1
Yield: 32 %

Procedure:
The title compound (0.21 g, 32%) was prepared from phenyl N-[4-methoxy-3-(pyrid-3-yl)phenyl]carbamate (D23) (0.48 g, 0.0015 mole) and 5-methoxy-6-trifluoromethylindoline (D11) using the method of Example 28.
Reaction SMILES: [CH3:1][C:2]1([CH3:20])[O:7][C:6](=[O:8])[C:5]2[C:9](S(C(F)(F)F)(=O)=O)=[CH:10][CH:11]=[CH:12][C:4]=2[O:3]1.[Li+].[Cl-].[CH2:23]([Sn](CCCC)(CCCC)CCCC)[CH:24]=[CH2:25].[F-].[K+]>CC1CNC(=O)C1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].O1C=CC=C1P(C1OC=CC=1)C1OC=CC=1>[CH2:25]([C:9]1[C:5]2[C:6](=[O:8])[O:7][C:2]([CH3:20])([CH3:1])[O:3][C:4]=2[CH:12]=[CH:11][CH:10]=1)[CH:24]=[CH2:23]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC1(C)OC(=O)c2c(cccc2S(=O)(=O)C(F)(F)F)O1
Agent: [Pd]
Agent: CC1CNC(=O)C1
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Product: C=CCc1cccc2c1C(=O)OC(C)(C)O2
Temperature: 25 °C
Reaction time: 48 h
Yield: 97.2 %

Procedure:
To a stirred suspension of 2,2-dimethyl-5-(trifluoromethanesulfonyl)benzo[1,3]dioxin-4-one (iii) (2.0 g, 6.13 mmol), anhydrous LiCl (0.8 g, 18.4 mmol), Pd2(dba)3 (112 mg, 0.12 mmol), and tri-(2-furyl)phosphine (115 mg, 0.49 mmol) in 4-methyl-2-pyrrolidinone (10 mL) was added allyltributyltin (2.35 mL, 7.36 mmol). After stirring for 48 h at rt, saturated aqueous KF (20 mL) was added and an extraction was performed with Et2O (3×). The combined organics were dried over MgSO4, concentrated in vacuo and the residue was purified by FC (4% EtOAc/hexanes) to give 1.3 g of 5-allyl-2,2-dimethyl-benzo[1,3]dioxin-4-one (iv) which was slightly impure.
Reaction SMILES: [OH:1][CH2:2][CH2:3][C:4]1[CH:5]=[CH:6][C:7]2[S:12][CH2:11][C:10](=[O:13])[NH:9][C:8]=2[CH:14]=1.C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[O:13]=[C:10]1[NH:9][C:8]2[CH:14]=[C:4]([CH2:3][CH2:2][O:1][S:23]([CH3:22])(=[O:25])=[O:24])[CH:5]=[CH:6][C:7]=2[S:12][CH2:11]1
Reactant: O=C1CSc2ccc(CCO)cc2N1
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CS(=O)(=O)OCCc1ccc2c(c1)NC(=O)CS2
Temperature: 25 °C
Reaction time: 15 h
Yield: 73.7 %

Procedure:
A solution of (h) (0.34 g, 1.7 mmol) and triethylamine (0.25 ml, 0.19 g, 1.8 mmol) in dichloromethane (5 ml) was cooled to −15° C. and treated dropwise with methanesulfonyl chloride (0.14 ml, 1.75 mmol). The ice bath was removed and the mixture stirred 15 hours at room temperature. The organic phase was separated, washed with water, dried over magnesium sulfate and evaporated. The crude product was chromatographed on silica gel eluting with ethyl acetate/heptane (2/1) to give a white solid (0.36 g, 75%).
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[C:13](=[O:14])[NH:12][C:11](=[O:15])[NH:10][C:9]2=[O:16])=[CH:4][CH:3]=1.[C:17]([Si:21](Cl)([CH3:23])[CH3:22])([CH3:20])([CH3:19])[CH3:18].N1C=CN=C1.Cl>>[C:17]([Si:21]([CH3:23])([CH3:22])[O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]2[C:9](=[O:16])[NH:10][C:11](=[O:15])[NH:12][C:13]2=[O:14])=[CH:6][CH:7]=1)([CH3:20])([CH3:19])[CH3:18]
Reactant: O=C1NC(=O)C(c2ccc(O)cc2)C(=O)N1
Reactant: CC(C)(C)[Si](C)(C)Cl
Agent: Cl
Agent: c1c[nH]cn1
Product: CC(C)(C)[Si](C)(C)Oc1ccc(C2C(=O)NC(=O)NC2=O)cc1
Temperature: 55 °C
Reaction time: 8 h
Yield: 75.7 %

Procedure:
To a solution of 5-(4-hydroxyphenyl)barbituric acid (1.9 g) and tertbutyl dimethylsilyl chloride (4.68 g) in 20 ml of anhydrous dimethylformlamde are added 4.4 g of imidazole and the mixture is heated to 55° C. for 5 hours. The temperature is then brought to room temperature and the reaction mixture is poured into 1 N hydrochloric acid and extracted twice with ethyl acetate. The pooled organic extracts are washed with water and dried over sodium sulfate. By concentration of the solution a white solid separates, which is kept at 0° C. overnight, then it is filtered to give 2.185 g of the product
Reaction SMILES: [C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](Br)=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1.[CH3:21][N:22]([CH3:26])[CH2:23][C:24]#[CH:25].ClC(OC)=O>C(OCC)(=O)C.ClCCl.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.C(N(CC)CC)C.CN(C=O)C>[C:1](=[O:20])([O:18][CH3:19])[O:2][C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6]([C:25]#[C:24][CH2:23][N:22]([CH3:26])[CH3:21])=[CH:5][C:4]=1[CH:13]1[CH2:17][CH2:16][CH2:15][CH2:14]1
Reactant: C#CCN(C)C
Reactant: COC(=O)Oc1cc([N+](=O)[O-])c(Br)cc1C1CCCC1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Agent: COC(=O)Cl
Solvent: CCOC(C)=O
Solvent: ClCCl
Solvent: CN(C)C=O
Product: COC(=O)Oc1cc([N+](=O)[O-])c(C#CCN(C)C)cc1C1CCCC1
Temperature: 100 °C
Reaction time: 0.17 h

Procedure:
4-Bromo-2-cyclopentyl-5-nitrophenyl methyl carbonate (1000 mg, 2.9 mmol), Pd(PPh3)2Cl2 (102 mg, 0.15 mmol), and CuI (17 mg, 0.087 mmol) were added to a large microwave tube which was flushed with N2 and capped. In a separate flask, DMF (10 mL), triethylamine (10 mL), and N,N-dimethylprop-2-yn-1-amine (725 mg, 929 μL, 8.72 mmol) were added and degassed by N2 bubbling (10 min). The degassed solution was then cannulated into the capped microwave tube under N2 atmosphere and heated under microwave irradiation for 10 min at 100° C. resulting in product formation with partial loss of the carbonate group. The reaction was diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to a red solid. The crude reaction mixture was dissolved in dichloromethane (35 mL) and triethylamine (1.17 g, 1.62 mL, 11.62 mmol) and treated dropwise with methyl chloroformate (549 mg, 449 μL, 5.81 mmol) at room temperature. The reaction was stirred for 10 min then diluted with ethyl acetate, washed with 50% saturated sodium bicarbonate solution (2×20 mL), water, and brine. The solution was dried over Na2SO4, filtered, and dried down to provide 2-cyclopentyl-4-(3-(dimethylamino)prop-1-ynyl)-5-nitrophenyl methyl carbonate as a brown/orange solid. 1H NMR (400.0 MHz, DMSO-d6) δ 8.14 (s, 1H), 7.68 (s, 1H), 3.89 (d, J=3.9 Hz, 3H), 3.54 (s, 2H), 3.23 (s, 1H), 3.14 (dd, J=9.3, 17.1 Hz, 1H), 2.25 (d, J=8.2 Hz, 6H), 1.99-1.92 (m, 2H), 1.79-1.73 (m, 2H), 1.69-1.51 (m, 3H).
Reaction SMILES: [CH:1]1(P(C2CCCCC2)C2C=CC=CC=2C2C(C(C)C)=CC(C(C)C)=CC=2C(C)C)CCCCC1.[NH2:35][C:36]1[C:37]([Cl:51])=[N:38][C:39]([Cl:50])=[CH:40][C:41]=1[NH:42][C:43](=[O:49])[O:44][C:45]([CH3:48])([CH3:47])[CH3:46].C([O-])([O-])=O.[Cs+].[Cs+].CI>C1(C)C=CC=CC=1.C(#N)C.C([O-])(=O)C.[Pd+2].C([O-])(=O)C>[Cl:51][C:37]1[C:36]([NH:35][CH3:1])=[C:41]([NH:42][C:43](=[O:49])[O:44][C:45]([CH3:46])([CH3:47])[CH3:48])[CH:40]=[C:39]([Cl:50])[N:38]=1
Reactant: CC(C)(C)OC(=O)Nc1cc(Cl)nc(Cl)c1N
Reactant: CC(C)c1cc(C(C)C)c(-c2ccccc2P(C2CCCCC2)C2CCCCC2)c(C(C)C)c1
Agent: [Pd+2]
Agent: CC(=O)[O-]
Agent: O=C([O-])[O-]
Solvent: CC#N
Solvent: Cc1ccccc1
Solvent: CI
Product: CNc1c(NC(=O)OC(C)(C)C)cc(Cl)nc1Cl
Temperature: 120 °C

Procedure:
Palladium (II) acetate (0.21 g, 0.31 mmol) and 2-Dicyclohexylphosphino-2′,4′,6′-triisopropylbiphenyl (X-phos) (0.36 g, 0.75 mmol) were combined in toluene and heated at 120° C. for 3 min in microwave reactor. To this mixture tert-butyl 3-amino-2,6-dichloropyridin-4-ylcarbamate 2.43 (0.87 g, 3.12 mmol), Cs2CO3 (3.06 g, 9.38 mmol) and methyl iodide (0.196 mL, 3.12 mmol) were added and heated at 90° C. for 2 hr in a microwave reactor. After completion of the reaction, solvent was removed under reduced pressure. Solids were dissolved and extracted with ethyl acetate and water. Organic layer was washed with brine, dried over MgSO4, filtered, and concentrated under reduced pressure. The residue obtained was heated in acetonitrile and solids were filtered out to obtain tert-butyl 2,6-dichloro-3-(methylamino)pyridin-4-ylcarbamate 2.44 that was used for next step without further purification.
Reaction SMILES: [OH-].[Na+].C([O:5][C:6]([C:8]1[CH:12]=[C:11]([CH2:13][CH:14]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[CH3:15])[NH:10][N:9]=1)=[O:7])C>CO>[C:16]1([CH:14]([CH3:15])[CH2:13][C:11]2[NH:10][N:9]=[C:8]([C:6]([OH:7])=[O:5])[CH:12]=2)[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1
Reactant: CCOC(=O)c1cc(CC(C)c2ccccc2)[nH]n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: CC(Cc1cc(C(=O)O)n[nH]1)c1ccccc1
Yield: 68.4 %

Procedure:
Freshly prepared aq. NaOH (10 M in H2O, 0.947 mmol) was added to a stirring, room temperature solution of 57 (0.0489 g, 0.1893 mmol) in MeOH (0.47 mL, 0.4 M) under N2. The reaction was then heated to reflux until the reaction was judged complete by HPLC (8 min): The reaction was concentrated, redissolved in H2O, and extracted with EtOAc (1 mL): 10% aq. HCl was added dropwise to the aqueous layer until the pH=2. The white solid that precipitated from the reaction was filtered off and washed with cold H2O. The solid was dried under vacuum overnight to obtain 0.0298 g (68.3%) of 58. 1H (CD3OD, 400 MHz): δ 7.24 (2H, t, J=7.3 Hz), 7.18 (2H, d, J=7.3 Hz), 7.14 (1H, t, J=7.3 Hz), 6.42 (1H, s), 3.11-3.01 (1H, m), 2.95 (1H, dd, J=14.1, 7.3 Hz), 2.89 (1H, dd, J=14.1, 7.8 Hz), 1.26 (3H, d, J=6.8 Hz) ppm. 13C (CD3OD, 100 MHz): δ 164.83, 147.35, 147.13, 143.02, 129.45, 127.92, 127.35, 108.07, 41.46, 35.58, 22.05 ppm. DEPT (CD3OD, 100 MHz): CH3 carbons: 22.05; CH2 carbons: 35.58; CH carbons: 129.45, 127.92, 127.35, 108.07, 41.46 ppm. HPLC: 8.764 min.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6](B(O)O)[CH:7]=1.[OH:12]O.[OH-].[Na+]>O1CCCC1.O.[O-2].[O-2].[Mn+4]>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([F:11])=[C:6]([OH:12])[CH:7]=1
Reactant: OO
Reactant: OB(O)c1cc(Br)ccc1F
Agent: [Mn+4]
Agent: [Na+]
Agent: [O-2]
Solvent: O
Solvent: C1CCOC1
Product: Oc1cc(Br)ccc1F
Temperature: 25 °C
Reaction time: 14 h
Yield: 90 %

Procedure:
A solution of 5-bromo-2-fluorobenzeneboronic acid (25 g, 114 mmol) in tetrahydrofuran was treated with hydrogen peroxide (7.8 ml of a 35 wt % solution in water) then with sodium hydroxide (1.4 ml of a 4N solution in water). A mild exotherm caused the internal temperature to reach 40° C. This mixture was left to stir at ambient temperature for 14 h then treated with manganese dioxide (200 mg) and stirring was continued for 90 min before filtering the reaction (GF/A filter paper). The filtrate was concentrated on a rotary evaporator and the residue partitioned between ether (400 ml) and water. The organics were washed with more water and brine, and dried over anhydrous magnesium sulphate. Filtration and evaporation to dryness afforded 5-bromo-2-fluorophenol (19.7 g, 90%) as a colourless liquid: δH (400 MHz, d6-DMSO) 6.93-6.97 (1H, m), 7.09-7.14 (2H, m), 10.36 (1H, br).
Reaction SMILES: [CH3:1][C@@H:2]1[C@H:6]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[O:5][C:4](=[O:13])[N:3]1[C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Li+].[CH:33]1([CH2:38]OS(C(F)(F)F)(=O)=O)[CH2:37][CH2:36][CH2:35][CH2:34]1>C1COCC1.C(OCC)(=O)C>[CH:33]1([CH2:38][C@H:15]([C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:14]([N:3]2[C@H:2]([CH3:1])[C@H:6]([C:7]3[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=3)[O:5][C:4]2=[O:13])=[O:22])[CH2:37][CH2:36][CH2:35][CH2:34]1
Reactant: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)Cc1ccccc1
Reactant: O=S(=O)(OCC1CCCC1)C(F)(F)F
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Li+]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: C[C@@H]1[C@H](c2ccccc2)OC(=O)N1C(=O)[C@H](CC1CCCC1)c1ccccc1
Temperature: -78 °C
Reaction time: 0.17 h

Procedure:
The title A compound, (4R,5S)-4-methyl-5-phenyl-3-phenylacetyl-oxazolidin-2-one (5.00 g, 16.93 mmol) is dissolved in anhydrous THF (50 mL) and cooled to −78° C. Lithium bis(trimethylsilyl)amide (1 M in THF, 16.93 mL, 16.93 mmol) is added dropwise over 10 min. To this is added a solution of the title B compound, trifluoromethanesulfonic acid cyclopentylmethyl ester (3.93 g, 16.93 mmol) in anhydrous THF (15 mL). The reaction is stirred at −78° C. for 10 min, then the cold bath is removed. The reaction is allowed to stir and warm to RT. After one hour, the reaction is concentrated to remove the solvent, resulting in a yellow oil. This is dissolved in ethyl acetate (300 mL) and washed with water (2×200 mL). The organic solution is dried over anhydrous sodium sulfate, filtered, and concentrated to a yellow oil. This is recrystallized from hexanes to afford (4R,5S)-3-((R)-3-cyclopentyl-2-phenyl-propionyl)-4-methyl-5-phenyl-oxazolidin-2-one as a white solid: 1H NMR (400 MHz, DMSO-D6) 0.8 (d, J=6.6 Hz, 3 H) 1.1 (d, J=16.2 Hz, 2 H) 1.4 (m, 2 H) 1.5 (d, J=5.8 Hz, 2 H) 1.6 (s, 2 H) 1.8 (d, J=7.1 Hz, 2 H) 2.0 (d, J=13.4 Hz, 1 H) 4.8 (s, 1 H) 5.1 (s, 1 H) 5.7 (d, J=7.1 Hz, 1 H) 7.3 (s, 1 H) 7.4 (m, 9 H); LC/MS 378.2 (M+1).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5](F)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1.C(N(C(C)C)CC)(C)C.[NH:21]1[CH:25]=[CH:24][N:23]=[CH:22]1>C(#N)C>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N:21]2[CH:25]=[CH:24][N:23]=[CH:22]2)=[C:4]([N+:9]([O-:11])=[O:10])[CH:3]=1
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Reactant: c1c[nH]cn1
Solvent: CC#N
Solvent: CCN(C(C)C)C(C)C
Product: O=[N+]([O-])c1cc(Br)ccc1-n1ccnc1
Yield: 73.7 %

Procedure:
To a solution of 4-bromo-1-fluoro-2-nitrobenzene (1.12 mL; 9.09 mmol; 1 eq) and diisopropylethylamine (1.58 mL; 9.09 mmol; 1 eq;) in anhydrous acetonitrile (80 mL) is added imidazole (620 mg; 9.09 mmol; 1 eq) under argon. The reaction mixture is allowed to stir under reflux for 65 hours until complete consumption of starting material. The crude mixture is concentrated under vacuum and the resulting powder dissolved in ethyl acetate (60 mL). The organic phase is then washed with water (50 mL), brine (50 mL) and dried over sodium sulfate to provide an orange powder after concentration under vacuum. Further purification by flash chromatography on silica gel (ethyl acetate/cyclohexane 9:1) afforded the title compound (1.81 g; 6.7 mmol; 74%) as an orange powder.
Reaction SMILES: [Br:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([OH:10])=[O:9].S(=O)(=O)(O)O.[CH3:21]O>>[Br:1][C:2]1[C:3]2[CH:15]=[CH:14][CH:13]=[CH:12][C:4]=2[S:5][C:6]=1[CH:7]([OH:11])[C:8]([O:10][CH3:21])=[O:9]
Reactant: CO
Reactant: O=C(O)C(O)c1sc2ccccc2c1Br
Agent: O=S(=O)(O)O
Product: COC(=O)C(O)c1sc2ccccc2c1Br
Yield: 91 %

Procedure:
A solution of (3-bromo-benzo[b]thiophen-2-yl)-hydroxy-acetic acid (21b) (590 mg, 2.05 mmol) and sulfuric acid (500 μL) in methanol (10 mL) was refluxed for 1 hour. The reaction mixture was then concentrated in vacuo and the residue was diluted with ethyl acetate (20 mL). The organic layer was washed with water (2×20 mL), a saturated solution of sodium bicarbonate (20 mL), brine (20 mL), dried over sodium sulfate, filtered and evaporated under reduced pressure to afford the desired ester (21c) as a orange solid (560 mg, 1.86 mmol, 91%) without further purification.