Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][CH2:18][C:19]([NH2:21])=[O:20])=[CH:16][C:3]1=2.C1C2CCC3C=CC=CC=3C(=O)C=2C=CC=1C1C(=O)N[C:40](=[O:44])[C:39]=1[OH:45]>>[O:1]=[C:2]1[C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][C:7]=2[CH2:6][O:5][C:4]2[CH:13]=[CH:14][C:15]([O:17][C:18]3[C:19](=[O:20])[NH:21][C:40](=[O:44])[C:39]=3[OH:45])=[CH:16][C:3]1=2
Reactant: O=C1NC(=O)C(c2ccc3c(c2)CCc2ccccc2C3=O)=C1O
Reactant: NC(=O)COc1ccc2c(c1)C(=O)c1ccccc1CO2
Product: O=C1NC(=O)C(Oc2ccc3c(c2)C(=O)c2ccccc2CO3)=C1O

Procedure:
When [(6,11-dihydro-11-oxodibenzo[b,e]-oxepin-2-yl)oxy]acetamide is employed as the starting amide there is obtained 4-[(6,11-dihydro-11-oxodibenzo[b,e]oxepin-2-yl)oxy]-3-hydroxy-3-pyrroline-2,5-dione.
Reaction SMILES: C[O:2][CH2:3][C@H:4]([CH3:35])[O:5][C:6]1[CH:7]=[C:8]([C:23]2[NH:27][C:26]([C:28]3[O:29][C@@H:30]([CH2:33][OH:34])[CH2:31][N:32]=3)=[CH:25][CH:24]=2)[CH:9]=[C:10]([O:12][C:13]2[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:21])=[O:20])=[CH:17][CH:18]=2)[CH:11]=1.B(Br)(Br)Br.[OH-].[Na+]>C(Cl)Cl>[OH:34][CH2:33][C@@H:30]1[O:29][C:28]([C:26]2[NH:27][C:23]([C:8]3[CH:7]=[C:6]([CH:11]=[C:10]([O:12][C:13]4[CH:14]=[N:15][C:16]([S:19]([CH3:22])(=[O:20])=[O:21])=[CH:17][CH:18]=4)[CH:9]=3)[O:5][C@@H:4]([CH3:35])[CH2:3][OH:2])=[CH:24][CH:25]=2)=[N:32][CH2:31]1
Reactant: COC[C@H](C)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Agent: BrB(Br)Br
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: C[C@@H](CO)Oc1cc(Oc2ccc(S(C)(=O)=O)nc2)cc(-c2ccc(C3=NC[C@H](CO)O3)[nH]2)c1
Temperature: 25 °C
Reaction time: 4 h
Yield: 29.2 %

Procedure:
{(5R)-2-[5-(3-[(1S)-2-Methoxy-1-methylethoxy]-5-{[6-(methylsulfonyl)pyridin-3-yl]oxy}phenyl)-1H-pyrrol-2-yl]-4,5-dihydro-1,3-oxazol-5-yl}methanol (520 mg, 1.04 mmol) synthesized in Example (82b) was dissolved in methylene chloride (10 mL), and boron tribromide (1.0 mol/L methylene chloride solution, 2.00 mL, 2.00 mmol) was added dropwise at −78° C., followed by stirring at room temperature for 4 hours under nitrogen atmosphere. To this reaction solution, a 1N aqueous sodium hydroxide solution (20 mL) was added, and extraction was carried out with methylene chloride (20 mL). The organic layer was washed with saturated brine, and subsequently dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and the resulting residue was purified using silica gel column chromatography (elution solvent: methanol/methylene chloride=3%-5%) to afford the desired compound (148 mg, yield 29%) as a white solid.
Reaction SMILES: [NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:24])([CH3:23])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([SH:27])[N:3]=1.Cl[CH2:29][C:30]1[N:31]=[C:32]([C:35]2[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=2)[O:33][CH:34]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C>[NH2:1][C:2]1[C:7]([C:8]#[N:9])=[C:6]([C:10]2[CH:15]=[CH:14][C:13]([O:16][CH2:17][C@@H:18]3[CH2:22][O:21][C:20]([CH3:23])([CH3:24])[O:19]3)=[CH:12][CH:11]=2)[C:5]([C:25]#[N:26])=[C:4]([S:27][CH2:29][C:30]2[N:31]=[C:32]([C:35]3[CH:40]=[CH:39][C:38]([Cl:41])=[CH:37][CH:36]=3)[O:33][CH:34]=2)[N:3]=1
Reactant: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(S)c3C#N)cc2)O1
Reactant: ClCc1coc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CN(C)C=O
Product: CC1(C)OC[C@@H](COc2ccc(-c3c(C#N)c(N)nc(SCc4coc(-c5ccc(Cl)cc5)n4)c3C#N)cc2)O1
Temperature: 25 °C
Reaction time: 20 h

Procedure:
70 mg (0.18 mmol) of the compound from Example 38A and 46 mg (0.20 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-oxazole together with 46 mg (0.55 mmol) of sodium bicarbonate were suspended in 1.9 ml of dry DMF. The reaction mixture was stirred at RT for 20 h. The mixture was then freed from the solvent on a rotary evaporator, and the residue was purified by preparative HPLC (column: YMC GEL ODS-AQ S-5/15 μm; mobile phase gradient: acetonitrile/water 10:90→95:5).
Reaction SMILES: [C:1]([N:4]1[CH2:8][CH:7]([N:9]=[N+]=[N-])[CH2:6][CH:5]1[CH2:12][OH:13])(=[O:3])[CH3:2].[H][H]>[Pd].CO>[C:1]([N:4]1[CH2:8][C@@H:7]([NH2:9])[CH2:6][C@H:5]1[CH2:12][OH:13])(=[O:3])[CH3:2]
Reactant: [H][H]
Reactant: CC(=O)N1CC(N=[N+]=[N-])CC1CO
Agent: [Pd]
Solvent: CO
Product: CC(=O)N1C[C@@H](N)C[C@H]1CO
Yield: 89.6 %

Procedure:
92.4 g of 10% Pd—C was added to a solution of 534 g of N-acetyl-4-azido-2-hydroxymethylpyrrolidine and 2.6 L of methanol, and this was hydrogenated (30 hours) at a normal pressure until the raw material disappeared, while the atmosphere in the container was substituted for hydrogen gas every one hour. After filtration, the solution was concentrated under reduced pressure to obtain 411 g of (2S, 4S)-N-acetyl-4-amino-2-hydroxymethylpyrrolidine, more specifically, (2S,4S)-(−)-1-acetyl-4-amino-2-hydroxymethyl-pyrrolidine as an oil.
Reaction SMILES: [Cl:1][CH2:2][C@:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@H:4]([O:6]C1CCCCO1)[CH3:5].O.C1(C)C=CC(S(O)(=O)=O)=CC=1>CO>[Cl:1][CH2:2][C@:3]([C:14]1[CH:19]=[CH:18][C:17]([F:20])=[CH:16][C:15]=1[F:21])([OH:13])[C@H:4]([OH:6])[CH3:5]
Reactant: C[C@@H](OC1CCCCO1)[C@@](O)(CCl)c1ccc(F)cc1F
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: O
Solvent: CO
Product: C[C@@H](O)[C@@](O)(CCl)c1ccc(F)cc1F
Yield: 107.9 %

Procedure:
A mixed solution of 0.15 g (0.47 mmol) of (2R,3R)-1-chloro-2-(2,4-difluorophenyl)-3-(3,4,5,6-tetrahydro-2H-pyran-2-yloxy)butan-2-ol, 5 mL of methanol, and 0.02 g of p-toluenesulfonic acid monohydrate was stirred at room temperature for 30 minutes. Concentration was performed under reduced pressure to obtain a crude product. The resulting product was purified by column on silica gel to obtain 0.12 g of the title compound (yield: 97%).
Reaction SMILES: [CH3:1][P:2]([C:5]1[N:10]=[C:9]([O:11][CH3:12])[C:8](N)=[CH:7][CH:6]=1)([CH3:4])=[O:3].Cl[C:15]1[N:20]=[C:19]([Cl:21])[C:18]([C:22]([F:25])([F:24])[F:23])=[CH:17][N:16]=1>CN(C)C(=O)C.C(N(C(C)C)CC)(C)C>[Cl:21][C:19]1[C:18]([C:22]([F:24])([F:23])[F:25])=[CH:17][N:16]=[C:15]([C:8]2[C:9]([O:11][CH3:12])=[N:10][C:5]([P:2]([CH3:4])([CH3:1])=[O:3])=[CH:6][CH:7]=2)[N:20]=1
Reactant: COc1nc(P(C)(C)=O)ccc1N
Reactant: FC(F)(F)c1cnc(Cl)nc1Cl
Solvent: CC(=O)N(C)C
Solvent: CCN(C(C)C)C(C)C
Product: COc1nc(P(C)(C)=O)ccc1-c1ncc(C(F)(F)F)c(Cl)n1
Temperature: 25 °C
Reaction time: 0.25 h

Procedure:
A suspension of 6-(dimethylphosphoryl)-2-methoxypyridin-3-ylamine (prepared in Example 32: 2.2 mmol) in 15 mL of N,N-Dimethylacetamide and 3.6 mL of Diisopropylethylamine, is allowed to stirred at room temperature for 15 minutes until a clear solution is obtained. 2,4-Dichloro-5-(trifluoromethyl)pyrimidine (5.7 g, 2.6 mmol) is added in four portions over 5 minutes. The reaction mixture is stirred at 60 degrees for 1 hour. The reaction mixture is cooled to room temperature and filtered to obtain a white solid. The white solid is washed with 50 mL of water three times and followed by 50 mL of Ethyl ether three times. The white solid is dried under vacuum to yield 4-chloro-2-[6-(dimethylphosphoryl)-2-methoxypyridin-3-yl]-5-(trifluoromethyl)pyrimidine.
Reaction SMILES: [CH3:1][O:2][CH2:3][C:4]#[C:5][C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[C:12](=[O:20])[CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C[Si]([N-][Si](C)(C)C)(C)C.[K+]>C1(C)C=CC=CC=1>[CH3:1][O:2][CH2:3][C:4]1[C:13]([C:14]2[CH:15]=[CH:16][CH:17]=[CH:18][CH:19]=2)=[C:12]([OH:20])[C:7]2[C:6]([CH:5]=1)=[CH:11][CH:10]=[CH:9][CH:8]=2
Reactant: COCC#Cc1ccccc1C(=O)Cc1ccccc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [K+]
Solvent: Cc1ccccc1
Product: COCc1cc2ccccc2c(O)c1-c1ccccc1
Yield: 22 %

Procedure:
A solution of 1-{2-[3-(methyloxy)-1-propyn-1-yl]phenyl}-2-phenylethanone (144) (0.21 g, 0.79 mmol) in toluene was treated with a KHMDS solution in toluene to give 46 mg (22%) of the title compound (145) as a light brown solid. 1H NMR (400 MHz, CDCl3): δ 3.28 (s, 3H), 4.26 (s, 2H), 5.29 (s, 1H), 7.36-7.42 (m, 2H), 7.44-7.58 (m, 6H), 7.80-7.85 (m, 1H), 8.18-8.24 (m, 1H). LCMS (ESI): m/z 265 (M+H)+, m/z 263 (M−H)−.
Reaction SMILES: [OH:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:4][CH:3]=1.Br[CH2:15][C:16]1[CH:17]=[C:18]([CH:21]=[CH:22][CH:23]=1)[C:19]#[N:20]>>[C:19]([C:18]1[CH:17]=[C:16]([CH:23]=[CH:22][CH:21]=1)[CH2:15][O:1][C:2]1[CH:3]=[CH:4][C:5]([CH:8]=[CH:9][C:10]([NH:12][CH3:13])=[O:11])=[CH:6][CH:7]=1)#[N:20]
Reactant: N#Cc1cccc(CBr)c1
Reactant: CNC(=O)C=Cc1ccc(O)cc1
Product: CNC(=O)C=Cc1ccc(OCc2cccc(C#N)c2)cc1
Yield: 75 %

Procedure:
The title compound is prepared in analogy to example 11 b) from 3-(4-hydroxy-phenyl)-N-methyl-acrylamide and 3-bromomethyl-benzonitrile. Yield=75%. Colorless solid. MS: m/e=293.2 (M++H).
Reaction SMILES: [H-].[Na+].[Br:3][CH:4]([CH2:16][CH2:17]Br)[C:5]([NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=1)=[O:6]>C1COCC1>[Br:3][CH:4]1[CH2:16][CH2:17][N:7]([CH2:8][C:9]2[CH:14]=[CH:13][C:12]([F:15])=[CH:11][CH:10]=2)[C:5]1=[O:6]
Reactant: O=C(NCc1ccc(F)cc1)C(Br)CCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: O=C1C(Br)CCN1Cc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 76.6 %

Procedure:
A 60% dispersion of NaH in mineral oil (1.70 g, 42.5 mmol) was added to a stirred solution of 2,4-dibromo-N-(4-fluorobenzyl)butanamide (10.0 g, 28.3 mmol, intermediate Q) in THF (25 mL) at 0° C. The reaction mixture was allowed to warm to rt and stir for and additional 2 h. The reaction mixture was carefully quenched with ice and diluted with water. The resulting mixture was extracted with EtOAc. The combined organic layers were washed with water and then brine solution. The organic layer was over sodium sulfate, filtered, and concentrated in vacuo. The crude product was purified using silica gel column chromatography (10% EtOAc/hexanes) to afford the desired product (5.90 g, 64% yield): LCMS (ES-API), m/z 272.4, 274.3 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 2.12-2.27 (m, 1H) 2.56-2.68 (m, 1H) 3.27 (dd, J=7.78, 3.26 Hz, 2H) 4.29-4.38 (m, 1H) 4.40-4.57 (m, 1H) 4.73 (dd, J=7.03, 3.01 Hz, 1H) 7.04-7.35 (m, 4H).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21](I)[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1.[Cl-].[Li+].C([Mg]Cl)(C)C.[CH2:31]([Sn:35](Cl)([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:36][CH2:37][CH2:38][CH3:39])[CH2:32][CH2:33][CH3:34].[Cl-].[NH4+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[C:12]([C:14]([F:17])([F:16])[F:15])[N:11]=[C:10]([N:18]3[CH:22]=[C:21]([Sn:35]([CH2:36][CH2:37][CH2:38][CH3:39])([CH2:40][CH2:41][CH2:42][CH3:43])[CH2:31][CH2:32][CH2:33][CH3:34])[N:20]=[CH:19]3)[N:9]=2)=[CH:4][CH:3]=1
Reactant: CCCC[Sn](Cl)(CCCC)CCCC
Reactant: Fc1ccc(-c2cc(C(F)(F)F)nc(-n3cnc(I)c3)n2)cc1
Agent: CC(C)[Mg]Cl
Agent: [Cl-]
Agent: [Li+]
Solvent: C1CCOC1
Product: CCCC[Sn](CCCC)(CCCC)c1cn(-c2nc(-c3ccc(F)cc3)cc(C(F)(F)F)n2)cn1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 57.8 %

Procedure:
To a stirred solution of 4-(4-fluoro-phenyl)-2-(4-iodo-imidazol-1-yl)-6-trifluoromethyl-pyrimidine (Example E.79) (0.87 g, 2.0 mmol) in THF (14 ml) was added at 0° C. iso-propylmagnesium chloride lithium chloride (1M in THF, 2.44 ml, 2.44 mmol). The reaction mixture was allowed to stir for 15 min at 0° C., tributyltin chloride (0.87 g, 2.67 mmol) was added, the reaction mixture was stirred at room temperature for 16 h, poured into saturated ammonium chloride solution (30 ml) and extracted with ethyl acetate (2×50 ml). The combined organic layers were washed with brine (30 ml), dried (MgSO4) and evaporated. The crude product was further purified by flash chromatography on silica gel (ethylacetate/heptane) to yield the title compound (0.69 g, 58%) as a light yellow oil. MS (ISP) 598.7 [(M+H)+].
Reaction SMILES: C(C1[C:9]([O:10][CH3:11])=[CH:8][CH:7]=[CH:6][C:4]=1[NH2:5])#N.[OH-].[K+].[C:14]([OH:17])(=[O:16])[CH3:15]>>[CH3:11][O:10][C:9]1[CH:8]=[CH:7][CH:6]=[C:4]([NH2:5])[C:15]=1[C:14]([OH:17])=[O:16]
Reactant: COc1cccc(N)c1C#N
Reactant: CC(=O)O
Agent: [K+]
Agent: [OH-]
Product: COc1cccc(N)c1C(=O)O

Procedure:
Fifty-four grams (0.364 mol) of the product prepared in (a) are refluxed with 800 ml of a 25% aqueous solution of potassium hydroxide for 16 hours. After cooling, the reaction solution is adjusted to a pH of 6 by the addition of acetic acid and then extracted several times, each time with one-half liter of ethyl acetate. The combined extracts are dried with sodium sulfate, and the ethyl acetate is distilled off. The residue is purified by column chromatography [silica gel; ethylene chloride/acetone (19:1)]. The uniform fractions are concentrated to dryness.
Reaction SMILES: [C:1]1([C:7]2[CH2:8][CH2:9][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH2:26][OH:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:11][CH:12]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CCOCC>C1COCC1.O=[Mn]=O>[C:1]1([C:7]2[CH2:12][CH2:11][N:10]([CH2:13][CH2:14][CH2:15][CH2:16][C:17]3[C:25]4[C:20](=[CH:21][CH:22]=[C:23]([CH:26]=[O:27])[CH:24]=4)[NH:19][CH:18]=3)[CH2:9][CH:8]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: OCc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Agent: O=[Mn]=O
Solvent: C1CCOC1
Solvent: CCOCC
Product: O=Cc1ccc2[nH]cc(CCCCN3CC=C(c4ccccc4)CC3)c2c1
Reaction time: 100 h

Procedure:
36 g of 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-hydroxymethylindole are dissolved in 1.6 liters of THF, and 300 ml of ether are added. 55 g of MnO2 are added with stirring. The mixture is stirred for 16 hours at 20°, a further 100 g of MnO2 are added in portions, and stirring is continued for a further 100 hours at 20°. Filtration and working up in the customary manner gives 3-[4-(4-phenyl-1,2,3,6-tetrahydropyridyl)-butyl]-5-formylindole, m.p. 131°.
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][C:5]2[N:11]3[CH2:12][CH2:13][NH:14][CH2:15][C@H:10]3[C:9]3[CH:16]=[CH:17][CH:18]=[CH:19][C:8]=3[CH2:7][C:6]=2[CH:20]=1.Br[CH2:22][CH2:23][N:24]1[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]2[C:25]1=[O:34]>>[C:25]1(=[O:34])[N:24]([CH2:23][CH2:22][N:14]2[CH2:13][CH2:12][N:11]3[C:5]4[CH:4]=[CH:3][C:2]([F:1])=[CH:20][C:6]=4[CH2:7][C:8]4[CH:19]=[CH:18][CH:17]=[CH:16][C:9]=4[C@@H:10]3[CH2:15]2)[C:28](=[O:29])[C:27]2=[CH:30][CH:31]=[CH:32][CH:33]=[C:26]12
Reactant: O=C1c2ccccc2C(=O)N1CCBr
Reactant: Fc1ccc2c(c1)Cc1ccccc1[C@@H]1CNCCN21
Product: O=C1c2ccccc2C(=O)N1CCN1CCN2c3ccc(F)cc3Cc3ccccc3[C@@H]2C1
Yield: 93 %

Procedure:
Following a procedure similar to that described in Preparation 14(a), but using (14bR)-8-fluoro-1,2,3,4,10,14b-hexahydrodibenzo[c,f]pyrazino[1,2-a]azepine and N-(2-bromoethyl)phthalimide, the title compound was obtained in a yield of 93%.
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12][C:13]2([CH2:20][C:21]([OH:23])=[O:22])O>ClCCl>[Cl:8][C:9]1[CH:17]=[C:16]([F:18])[CH:15]=[C:14]2[C:10]=1[CH2:11][CH2:12]/[C:13]/2=[CH:20]\[C:21]([OH:23])=[O:22]
Reactant: O=C(O)CC1(O)CCc2c(Cl)cc(F)cc21
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C(O)/C=C1\CCc2c(Cl)cc(F)cc21
Reaction time: 1.5 h
Yield: 93.5 %

Procedure:
Trifluoroacetic acid (27.4 ml) was added to a stirred, chilled (ice-methanol bath) solution of 2-(4-chloro-6-fluoro-1-hydroxy-1-indanyl)acetic acid (12.5 g, 0.05 mol) in dichloromethane (200 ml). After 1.5 h, the mixture was concentrated in vacuo. Dichloromethane was added to the residue and the mixture was concentrated in vacuo to give 10.6 g of crude (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetic acid. Chromatography of a 1.0 g sample on silica gel with ethyl acetate:hexanes (1:1) as eluent gave 0.32 g of (E)-2-(4-chloro-6-fluoro-1-indanylidene)acetic acid as a white solid: mp 229°-230° C.
Reaction SMILES: [OH:1][C:2]1[CH:18]=[CH:17][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])=[O:7])=[CH:4][CH:3]=1.Br[C:20]1[CH:21]=[CH:22][C:23]([N+:26]([O-:28])=[O:27])=[N:24][CH:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[N+:26]([C:23]1[N:24]=[CH:25][C:20]([O:1][C:2]2[CH:3]=[CH:4][C:5]([C:6]([NH:8][NH:9][C:10]([O:12][C:13]([CH3:15])([CH3:14])[CH3:16])=[O:11])=[O:7])=[CH:17][CH:18]=2)=[CH:21][CH:22]=1)([O-:28])=[O:27]
Reactant: O=[N+]([O-])c1ccc(Br)cn1
Reactant: CC(C)(C)OC(=O)NNC(=O)c1ccc(O)cc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CC(C)(C)OC(=O)NNC(=O)c1ccc(Oc2ccc([N+](=O)[O-])nc2)cc1
Temperature: 80 °C
Reaction time: 8 h
Yield: 72 %

Procedure:
To a mixture of tert-butyl 2-(4-hydroxybenzoyl)hydrazinecarboxylate (0.688 g, 2.73 mmol) and 5-bromo-2-nitropyridine (0.554 mg, 2.73 mmol) and caesium carbonate (1.33 g, 4.08 mmol) in N,N-dimethylformamide (7 mL) was stirred overnight at 80° C. The solution was concentrated and the residue was taken with dichloromethane and water. The organic phase was dried on MgSO4 and concentrated. The crude product was purified by column chromatography (silica gel, 5% MeOH in CH2Cl2), to give 736 mg of the mixture nitropyridine and bromopyridine.
Reaction SMILES: BrN1C(=O)CCC1=O.[Cl:9][C:10]1[N:15]=[C:14]([CH2:16][C:17]([C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)=O)[CH:13]=[CH:12][N:11]=1.[NH2:33][C:34](=[S:46])[C:35]([NH:38][C:39](=[O:45])[O:40][C:41]([CH3:44])([CH3:43])[CH3:42])([CH3:37])[CH3:36]>ClCCl.CCOC(C)=O>[Cl:9][C:10]1[N:15]=[C:14]([C:16]2[S:46][C:34]([C:35]([NH:38][C:39]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:45])([CH3:37])[CH3:36])=[N:33][C:17]=2[C:19]2[C:20]([F:32])=[C:21]([NH:25][C:26](=[O:31])[O:27][CH2:28][CH:29]=[CH2:30])[CH:22]=[CH:23][CH:24]=2)[CH:13]=[CH:12][N:11]=1
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(N)=S
Reactant: C=CCOC(=O)Nc1cccc(C(=O)Cc2ccnc(Cl)n2)c1F
Agent: O=C1CCC(=O)N1Br
Solvent: CCOC(C)=O
Solvent: ClCCl
Product: C=CCOC(=O)Nc1cccc(-c2nc(C(C)(C)NC(=O)OC(C)(C)C)sc2-c2ccnc(Cl)n2)c1F
Temperature: 80 °C
Reaction time: 1 h
Yield: 54.4 %

Procedure:
N-Bromosuccinimide (0.763 g, 4.29 mmol) was added to a solution of 2-propen-1-yl {3-[(2-chloro-4-pyrimidinyl)acetyl]-2-fluorophenyl}carbamate (1.5 g, 4.29 mmol) in dichloromethane (DCM) (50 mL). After 1 h of stirring, 1,1-dimethylethyl (2-amino-1,1-dimethyl-2-thioxoethyl)carbamate (0.936 g, 4.29 mmol) was added to the reaction mixture and heated to 80° C. for 2 h. The reaction mixture was diluted with 150 cc of EtOAc and washed with water (5×100 cc). The EtOAc layer was dried over MgSO4 and filtered and concentrated in vacuo. The residue was purified via chromatography on silica gel using Hex to 25% EtOAc in Hex to obtain the title compound (1.28 g, 54% yield). MS (ESI): 548.3 [M+H]+
Reaction SMILES: [Br:1][C:2]1C=[CH:6][CH:5]=[CH:4][C:3]=1C.[C:9]([OH:12])(=[O:11])[CH3:10]>O.O.O.O.C([O-])(=O)C.[Co+2].C([O-])(=O)C.[Br-].[Na+].C([O-])(=O)C.[Na+].O>[Br:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][C:10]=1[C:9]([OH:12])=[O:11]
Reactant: Cc1ccccc1Br
Reactant: CC(=O)O
Agent: [Co+2]
Agent: CC(=O)[O-]
Agent: [Br-]
Solvent: O
Product: O=C(O)c1ccccc1Br
Yield: 61.5 %

Procedure:
The test described in Example 1 was repeated using 300 g of o-bromotoluene, 660 g of acetic acid, 60 g of water, 6 g of cobalt acetate tetrahydrate, 5 g of sodium bromide and 5 g of sodium acetate. After a reaction time of 155 minutes, 217 g of o-bromobenzoic acid was obtained (61.6% of the theory).
Reaction SMILES: N([O-])=O.[Na+].[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9](N)=[CH:8][CH:7]=1.[I-:15].[K+]>O.Cl>[Br:5][C:6]1[N:11]=[C:10]([O:12][CH3:13])[C:9]([I:15])=[CH:8][CH:7]=1
Reactant: [I-]
Reactant: COc1nc(Br)ccc1N
Agent: Cl
Agent: O=N[O-]
Agent: [K+]
Solvent: O
Product: COc1nc(Br)ccc1I
Reaction time: 0.33 h
Yield: 85.3 %

Procedure:
A solution of sodium nitrite (5.44 g) in water (15 mL) was added dropwise to a suspension of 6-bromo-2-methoxypyridin-3-amine (16.0 g) in concentrated hydrochloric acid (130 mL) and water (175 mL) at an internal temperature of 5° C. or less, and the mixture was stirred as such for 20 minutes. This suspension was added dropwise to a solution of potassium iodide (39.2 g) in water (760 mL) at an internal temperature of 5° C. or less. The mixture was brought to room temperature and then stirred at 60° C. for two hours. The reaction solution was brought to room temperature and then extracted with ethyl acetate. The organic layer was washed with a saturated sodium thiosulfate solution and brine, dried over anhydrous magnesium sulfate and filtered, after which the filtrate was concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography (hexane:ethyl acetate=95:5→85:15) to give 6-bromo-3-iodo-2-methoxypyridine as a pale orange powder (21.1 g).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][C:11]([C:26](=[O:35])[C:27]2[CH:32]=[C:31]([CH3:33])[CH:30]=[C:29]([CH3:34])[CH:28]=2)([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[CH3:24])[CH2:10][CH2:9]1)=O)(C)(C)C>C(Cl)Cl.FC(F)(F)C(O)=O>[CH3:33][C:31]1[CH:32]=[C:27]([CH:28]=[C:29]([CH3:34])[CH:30]=1)[C:26]([C:11]1([NH:14][C:15](=[O:25])[C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([O:22][CH3:23])[C:17]=2[CH3:24])[CH2:10][CH2:9][NH:8][CH2:13][CH2:12]1)=[O:35]
Reactant: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCN(C(=O)OC(C)(C)C)CC2)c1C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1cccc(C(=O)NC2(C(=O)c3cc(C)cc(C)c3)CCNCC2)c1C

Procedure:
A solution of 4-(3,5-dimethyl-benzoyl)-4-(3-methoxy-2-methyl-benzoylamino)-piperidine-1-carboxylic acid tert-butyl ester in CH2Cl2 and trifluoroacetic acid (20 mL) was stirred at room temperature for 2 hours. The solvent was removed on a rotary evaporator, and the residue was partitioned between ether (150 mL) and saturated aqueous NaHCO3 (50 mL). Significant amounts of undissolved solid were present. The ether layer was dried over MgSO4 and evaporated to leave N-[4-(3,5-dimethyl-benzoyl)-piperidin-4-yl]-3-methoxy-2-methyl-benzamide (0.50 g) as a solid. Additional product (0.11 g) was obtained by extraction and concentration of the aqueous layer with CH2Cl2 (2×50 mL). 1H NMR (500 MHz, CDCl3) δ(ppm): 7.55 (s, 2H), 7.12 (m, 2H), 6.87 (d, 1H), 6.77 (d, 1H), 6.65 (br, 1H), 3.8 (s, 3H), 3.1 (br, 2H), 2.95 (br, 2H), 2.3 (s, 6H), 2.25 (br s, 4H), 1.94 (s, 3H).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10](O)=[O:11])=[CH:5][CH:4]=1.C(Cl)(=O)C([Cl:22])=O.CN(C)C=O>ClCCl>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]([CH3:18])([CH2:13][CH2:14][CH:15]([CH3:17])[CH3:16])[C:10]([Cl:22])=[O:11])=[CH:5][CH:4]=1
Reactant: O=C(Cl)C(=O)Cl
Reactant: COc1ccc(C(C)(CCC(C)C)C(=O)O)cc1
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COc1ccc(C(C)(CCC(C)C)C(=O)Cl)cc1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To a cooled solution of Example 155C (8.52 g, 0.034 mol) in 200 mL anhydrous dichloromethane was added 2 N oxalyl chloride in dichloromethane (26 mL, 0.052 mol) and drops of dimethylforamide. The solution was stirred for 30 minutes at 0° C. and then room temperature for 2 hours. The solvent was removed under vacuum and the crude product used directly.