Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH2:21])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:4])([CH3:3])[CH3:2].[C:29]([C:31]1[CH:32]=[C:33]([CH3:40])[C:34]([C:37](O)=[O:38])=[N:35][CH:36]=1)#[N:30].CCN=C=NCCCN(C)C.Cl.C1C=NC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C>[C:1]([O:5][C:6](=[O:28])[NH:7][C:8]1[C@:9]([CH3:27])([C:23]([F:26])([F:25])[F:24])[O:10][CH2:11][C@:12]([C:15]2[CH:20]=[C:19]([NH:21][C:37]([C:34]3[C:33]([CH3:40])=[CH:32][C:31]([C:29]#[N:30])=[CH:36][N:35]=3)=[O:38])[CH:18]=[CH:17][C:16]=2[F:22])([CH3:14])[N:13]=1)([CH3:2])([CH3:3])[CH3:4]
Reactant: Cc1cc(C#N)cnc1C(=O)O
Reactant: CC(C)(C)OC(=O)NC1=N[C@](C)(c2cc(N)ccc2F)CO[C@@]1(C)C(F)(F)F
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2cccnc21
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: Cc1cc(C#N)cnc1C(=O)Nc1ccc(F)c([C@]2(C)CO[C@@](C)(C(F)(F)F)C(NC(=O)OC(C)(C)C)=N2)c1
Reaction time: 16 h

Procedure:
To a solution of [(2R,5R)-5-(5-amino-2-fluoro-phenyl)-2,5-dimethyl-2-trifluoromethyl-5,6-di-hydro-2H-[1,4]oxazin-3-yl]-carbamic acid tert-butyl ester (82 mg, 0.20 mmol) in DMF (2 ml) was added 5-cyano-3-methyl-pyridine-2-carboxylic acid [Acid-3] (42 mg, 0.26 mmol), EDC.HCl (51 mg, 0.26 mmol), HOAt (31 mg, 0.22 mmol) and DIPEA (0.09 ml, 0.52 mmol) and the reaction mixture was kept at 25° C. for 16 h. The mixture was concentrated, the residue dissolved in EtOAc and washed with saturated NaHCO3 solution and brine, dried over MgSO4, filtered and purified by chromatography on silica gel (hexane-EtOAc 20:1 to 1:1) to provide the title compound as a light yellow foam: TLC (hexane-EtOAc 1:1): Rf=0.81; HPLC RtH5=1.437 min; ESIMS: 550 [(M+H)+]; 1H NMR (360 MHz, CDCl3): δ 10.96 (br s, 1H), 9.95 (br s, 1H), 8.63 (s, 2H), 7.88 (m, 1H), 7.71 (m, 1H), 7.54 (dd, 1H), 7.08 (dd, 1H), 4.34 (d, 1H), 4.02 (d, 1H), 2.77 (s, 3H), 1.63 (s, 3H), 1.47 (m, 12H).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([OH:8])[CH:5]=[CH:6][CH:7]=1.[Br:9][C:10]1[CH:11]=[C:12]([CH:15]=[CH:16][CH:17]=1)[CH2:13]Br.C([O-])([O-])=O.[K+].[K+]>>[Br:9][C:10]1[CH:11]=[C:12]([CH2:13][O:8][C:4]2[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][CH:5]=2)[CH:15]=[CH:16][CH:17]=1
Reactant: Oc1cccc(Br)c1
Reactant: BrCc1cccc(Br)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Product: Brc1cccc(COc2cccc(Br)c2)c1
Temperature: 25 °C

Procedure:
A mixture of 3-bromophenol (13.8 g, 80 mmol), 3-bromobenzyl bromide (10 g, 40 mmol), K2CO3 (16.6 g. 120 mmol) and 12 hours. The reaction mixture was cooled to rt, concentrated in vacuo and partitioned between Et2O (300 mL) and water (300 mL). The organic phase was washed with aqueous NaOH (1 M, 300 mL), dried (Na2SO4), filtered and concentrated in vacuo to give 3-[(m-bromophenyl)methoxy]bromobenzene as a clear oil. MS (APCI) m/z 339 (M+−3, 50%), 341 (M+−1, 100%), 343 (M++3, 50%), 13C NMR (50 MHz, CDCl3); δ 68.9, 113.4, 117.9, 122.5, 122.6, 124.1, 125.6, 129.9, 130.0, 130.4, 130.9, 138.4, 158.9.
Reaction SMILES: CS(C)=O.C(Cl)(=O)C(Cl)=O.[OH:11][CH2:12][C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16][O:15][CH2:14]1.C(N(CC)CC)C>ClCCl.O>[CH:12]([C:13]1([CH2:17][CH2:18][CH3:19])[CH2:16][O:15][CH2:14]1)=[O:11]
Reactant: CCCC1(CO)COC1
Agent: O=C(Cl)C(=O)Cl
Solvent: ClCCl
Solvent: O
Solvent: CCN(CC)CC
Product: CCCC1(C=O)COC1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 106.7 %

Procedure:
A solution of dimethyl sulphoxide (12 ml) in dry dichloromethane (4.0 ml) was added to a solution of oxalyl chloride (7.4 ml) in dichloromethane (25 ml) stirred at -70° under nitrogen. After the addition was complete the resulting mixture was stirred for a further 5 minutes at -70° before a solution of 3-hydroxymethyl-3-n-propyl oxetane (10.0 g) in dichloromethane (25 ml) was added, dropwise, over 10 minutes. The resulting mixture was allowed to stir for a further 30 minutes when neat triethylamine (54 ml) was added over approximately 30 minutes. The reaction mixture was allowed to warm to room temperature over 3 hours when it was poured into water. The organic phase was separated and the aqueous layer was further extracted with dichloromethane. The combined organic extracts were washed with dilute hydrochloric acid, saturated sodium bicarbonate and brine. The resulting organic phase was dried over anhydrous magnesium sulphate and evaporated in vacuo to give 3-formyl-3-n-propyloxetane (10.5 g) (European Patent Application No. 216624) as a yellow oil.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]=[CH:7]1.[CH3:21][S:22]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=2)[CH:27]=1)(=[O:24])=[O:23].C1CCC(N=C=NC2CCCCC2)CC1>CN(C1C=CN=CC=1)C.N1C=CC=CC=1>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[N:6]1([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=4)[CH:27]=3)=[O:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9][N:8]=[CH:7]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To 1.03 g of 4-(2-imidazolinyl)amino-benzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 mg of DMAP and 1.06 g of DCC was added 5 ml of anhydrous pyridine. The resulting mixture was stirred overnight at room temperature. To the mixture was added 50 ml of aceone and the precipitate which was formed was collected by filtration. To the precipitate was added 40 ml of DMF. After stirring the precipitate which was formed was collected by filtration and 20 ml of water was added to the precipitate. The insolubles were removed by filtration. The filtrate was distilled under reduced pressure. To the residue was added 200 ml of acetone. The precipitate which was formed was collected by filtration to obtain 0.8 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dimethanesulfonate.
Reaction SMILES: [CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[N:6]1([NH:11][C:12]2[CH:20]=[CH:19][C:15]([C:16]([OH:18])=[O:17])=[CH:14][CH:13]=2)[CH2:10][CH2:9][N:8]=[CH:7]1.[CH3:21][S:22]([O:25][C:26]1[CH:35]=[CH:34][C:33]2[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:38])[NH2:37])[CH:32]=2)[CH:27]=1)(=[O:24])=[O:23].C1CCC(N=C=NC2CCCCC2)CC1.N1C=CC=CC=1>CN(C1C=CN=CC=1)C.CC(C)=O>[CH3:1][S:2]([OH:5])(=[O:4])=[O:3].[CH3:21][S:22]([OH:25])(=[O:24])=[O:23].[N:6]1([NH:11][C:12]2[CH:13]=[CH:14][C:15]([C:16]([O:18][C:26]3[CH:35]=[CH:34][C:33]4[C:28](=[CH:29][CH:30]=[C:31]([C:36](=[NH:37])[NH2:38])[CH:32]=4)[CH:27]=3)=[O:17])=[CH:19][CH:20]=2)[CH2:10][CH2:9][N:8]=[CH:7]1
Reactant: CS(=O)(=O)Oc1ccc2cc(C(=N)N)ccc2c1
Reactant: O=C(O)c1ccc(NN2C=NCC2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Agent: CS(=O)(=O)O
Solvent: CC(C)=O
Solvent: c1ccncc1
Product: N=C(N)c1ccc2cc(OC(=O)c3ccc(NN4C=NCC4)cc3)ccc2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 41.4 %

Procedure:
To 1.03 g of 4-(2-imidazolinyl)amino-benzoic acid methanesulfonate, 0.96 g of 6-amidino-2-naphthol methanesulfonate, 42 mg of DMAP and 1.06 g of DCC was added 5 ml of anhydrous pyridine. The resulting mixture was stirred overnight at room temperature. To the mixture was added 50 ml of acetone and the precipitate which was formed was collected by filtration. To the precipitate was added 40 ml of DMF. After stirring the precipitate which was formed was collected by filtration and 20 ml of water was added to the precipitate. The insolubles were removed by filtration. The filtrate was distilled under reduced pressure. To the residue was added 200 ml of acetone. The precipitate which was formed was collected by filtration to obtain 0.8 g of 6-amidino-2-naphthyl 4-(2-imidazolinyl)amino-benzoate dimethanesulfonate.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[Ca+2].C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: [Ca+2]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 220 °C
Yield: 85 %

Procedure:
p-Acetaminophenol 15 g, calcium carbonate 60 g, and solid catalyst Y-type molecular sieve 7.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 2.0 MPa and heated to 220° C., maintained for 1 hour, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve calcium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 96% and the yield is 85%.
Reaction SMILES: [NH:1]([C:5]1[CH:10]=[CH:9][C:8]([OH:11])=[CH:7][CH:6]=1)C(C)=O.[C:12](=O)([O-:14])[O-:13].[K+].[K+].[Si](=O)=O.C(=O)=O>>[NH2:1][C:5]1[CH:6]=[C:7]([C:12]([OH:14])=[O:13])[C:8]([OH:11])=[CH:9][CH:10]=1
Reactant: CC(=O)Nc1ccc(O)cc1
Reactant: O=C([O-])[O-]
Agent: O=C=O
Agent: O=[Si]=O
Agent: [K+]
Product: Nc1ccc(O)c(C(=O)O)c1
Temperature: 170 °C
Yield: 88 %

Procedure:
p-Acetaminophenol 15 g, potassium carbonate 22.5 g, and silicon dioxide 7.5 g were added into a 500 ml autoclave, and CO2 was introduced to perform a carboxylation reaction under a reaction pressure of 1.5 MPa and heated to 170° C., maintained for 4 hours, then the reaction was terminated, cooled to 80° C., and 1500 ml distilled water was added to dissolve potassium 5-aminosalicylate. After decolorization, the aqueous phase was acidified with 20˜30% hydrochloric acid until pH=4, cooled and then filtered to obtain the product of 5-aminosalicylic acid, the content is 99.8% and the yield is 88%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH2:11][OH:12])[CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9]>C(Cl)Cl.[O-2].[Mn+4].[O-2]>[CH3:1][C:2]1[CH:3]=[C:4]([CH:5]=[CH:6][C:7]=1[N+:8]([O-:10])=[O:9])[CH:11]=[O:12]
Reactant: Cc1cc(CO)ccc1[N+](=O)[O-]
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: Cc1cc(C=O)ccc1[N+](=O)[O-]
Temperature: 40 °C
Yield: 87.8 %

Procedure:
A flask was charged with (3-methyl-4-nitro-phenyl)-methanol (66.9 g, 0.400 mol), manganese(IV) oxide (85%, 5 μm powder, 409.1 g, 4.00 mol), and CH2Cl2 (1337 mL). The mixture was stirred at 40° C. for at least 2 h or until HPLC analysis showed that the reaction had proceeded to greater the 97% completion. The cooled batch was diluted with CH2Cl2 (1 L) and filtered through a Celite® pad (34 g), and the filter cake was rinsed with more CH2Cl2 (1 L). The filtrate and washes were concentrated under in vacuo to dryness to give the title compound as a yellow solid (58 g, 87% yield).
Reaction SMILES: Cl[CH2:2][CH2:3][C:4]1[C:9](=[O:10])[N:8]2[CH2:11][CH2:12][CH2:13][CH2:14][C:7]2=[N:6][C:5]=1[CH3:15].[F:16][C:17]1[CH:31]=[CH:30][C:20]2[C:21]([CH:24]3[CH2:29][CH2:28][NH:27][CH2:26][CH2:25]3)=[N:22][O:23][C:19]=2[CH:18]=1.C(=O)([O-])[O-].[Na+].[Na+]>[I-].[K+].C(O)(C)C>[CH3:15][C:5]1[N:6]=[C:7]2[N:8]([CH2:11][CH2:12][CH2:13][CH2:14]2)[C:9](=[O:10])[C:4]=1[CH2:3][CH2:2][N:27]1[CH2:26][CH2:25][CH:24]([C:21]2[C:20]3[CH:30]=[CH:31][C:17]([F:16])=[CH:18][C:19]=3[O:23][N:22]=2)[CH2:29][CH2:28]1
Reactant: Cc1nc2n(c(=O)c1CCCl)CCCC2
Reactant: Fc1ccc2c(C3CCNCC3)noc2c1
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CC(C)O
Product: Cc1nc2n(c(=O)c1CCN1CCC(c3noc4cc(F)ccc34)CC1)CCCC2
Yield: 73.1 %

Procedure:
Isopropanol (20 mL), 3-(2-chloroethyl)-6,7,8,9-tetrahydro-2-methyl-4H-pyrido[1,2-a]pyrimidin-4-one (Compound II)(“the chlorine derivative”)(2.63 g, 10 mmoles, 1 eq.), 6-fluoro-3-(4-piperidinyl)-1,2-benzisoxazole (Compound I)(“the piperidine derivative”) (2.17 g, 10 mmoles, 1 eq.), sodium carbonate (3.18 g, 30 mmoles, 3 eq.), and potassium iodide (66 mg) were added to a 100 mL round bottom flask and stirred with a magnetic stir bar. The flask was placed in an oil bath at 80° C. and allowed to reflux for 9 hours. The flask was then cooled in an ice bath and the contents was filtered. The filter cake was washed in the filter with a small amount of isopropanol. The filter cake was then slurried 3 times in 20 mL of water and filtered. The resulting slurry was dried to give 3 g of material in 73% yield. The slurry was recrystallized by dissolving in 37 mL of boiling isopropanol, filtered hot and allowed to cool and filtered to give material which had a purity of 99.7% and an overall yield of 60%.
Reaction SMILES: [CH:1]1[C:13]2[NH:12][C:11]3[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[Br:14][CH2:15][CH2:16][CH2:17]Br.[H-].[Na+]>C1COCC1.O.C(O)C>[Br:14][CH2:15][CH2:16][CH2:17][N:12]1[C:11]2[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=2[C:5]2[C:13]1=[CH:1][CH:2]=[CH:3][CH:4]=2
Reactant: c1ccc2c(c1)[nH]c1ccccc12
Reactant: BrCCCBr
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Solvent: CCO
Product: BrCCCn1c2ccccc2c2ccccc21
Temperature: 78 °C
Reaction time: 40 h
Yield: 29.8 %

Procedure:
Carbazole (15.00 g, 89.71 mmol) and 1,3-dibromopropane (45.5 mL, 450 mmol) were dissolved in ˜200 mL dry THF and stirred under argon in a 500 mL rbf. Sodium hydride (3.23 g, 134.56 mmol) was added and the mixture was brought to reflux (˜78° C.) and allowed to do so for 40 hours. After cooling the mixture was diluted in ˜800 mL water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate and concentrated by rotary evaporation to leave an orange oil and light brown solid. This was distilled under high vacuum (0.05 Torr) at 100° C. for 2 hours to remove excess dibromo compound. A tlc in 30:1 hexanes:ethyl acetate showed 6 spots. A column was run in 30:1 hexanes:ethyl acetate and the third spot was isolated as a thick yellow oil. This oil was dissolved in hot ethanol and put in the −20° C. freezer overnight to yield a white solid (7.70 g, 30% yield). This compound is reported in the literature and the 1H NMR is consistent with the structure.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8](Cl)(=[O:10])=[O:9])=[CH:4][CH:3]=1.[CH2:12]([CH2:14][NH2:15])[OH:13]>>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:15][CH2:14][CH2:12][OH:13])(=[O:10])=[O:9])=[CH:4][CH:3]=1
Reactant: NCCO
Reactant: O=S(=O)(Cl)c1ccc(Br)cc1
Product: O=S(=O)(NCCO)c1ccc(Br)cc1
Yield: 96.4 %

Procedure:
Prepared by general procedure III from 4-bromobenzenesulfonyl chloride (5.0 g, 20 mmol) and ethanolamine (1.32 g, 22 mmol) to give the title compound (5.4 g, 98%) as an off-white solid. MS (ISP) 280.0[(M+H)+].
Reaction SMILES: [C:1]([CH:3]1[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2].F[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=1.C[Si]([N-][Si](C)(C)C)(C)C.[Na+].[Cl-].[NH4+]>O1CCCC1>[C:1]([C:3]1([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][N:18]=2)[CH2:8][CH2:7][N:6]([C:9]([O:11][C:12]([CH3:15])([CH3:14])[CH3:13])=[O:10])[CH2:5][CH2:4]1)#[N:2]
Reactant: Fc1ccccn1
Reactant: CC(C)(C)OC(=O)N1CCC(C#N)CC1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(C#N)(c2ccccn2)CC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
To a solution of tert-butyl 4-cyanopiperidine-1-carboxylate (0.220 g, 1.05 mmol) and 2-fluoropyridine (0.107 g, 1.10 mmol) in 5 mL of tetrahydrofuran at −78° C. was added sodium bis(trimethylsilyl)amide (1 M solution in diethyl ether, 1.47 mL, 1.47 mmol) dropwise. After 1 hr, the mixture was slowly warmed to ambient temperature, treated with saturated aqueous ammonium chloride, and extracted 3× with dichloromethane. The combined organic extracts were dried with sodium sulfate, filtered, and concentrated in vacuo. The residue was purified via silica gel chromatography, eluting with 0-20% ethyl acetate in hexanes, to provide tert-butyl 4-cyano-4-pyridin-2-ylpiperidine-1-carboxylate.
Reaction SMILES: O1CCOCC1.[NH2:7][C:8]1[CH:9]=[CH:10][C:11]([CH3:15])=[CH:12][C:13]=1[OH:14].C(=O)([O-])[O-].[Ca+2].[Cl:21][CH2:22][C:23](Cl)=[O:24]>O>[OH:14][C:13]1[CH:12]=[C:11]([CH3:15])[CH:10]=[CH:9][C:8]=1[NH:7][C:23](=[O:24])[CH2:22][Cl:21]
Reactant: Cc1ccc(N)c(O)c1
Reactant: O=C(Cl)CCl
Agent: O=C([O-])[O-]
Agent: [Ca+2]
Solvent: O
Solvent: C1COCCO1
Product: Cc1ccc(NC(=O)CCl)c(O)c1
Temperature: 60 °C
Reaction time: 2 h
Yield: 72.4 %

Procedure:
To 130 ml of dioxane, were added 20.0 g (163 mmol) of 6-amino-m-cresol and 9.2 g (92 mmol) of calcium carbonate, followed by heating to 60° C. To the obtained solution, there was added 22.1 g (196 mmol) of chloroacetyl chloride over 40 minutes and the mixture was further stirred at 60° C. for 2 hours. After cooling, the mixture was poured into 500 ml of water, extracted with 700 ml of ethyl acetate and dried over anhydrous Glauber's salt. After distilling off the solvent under reduced pressure, the obtained greenish brown solid was recrystallized from acetonitrile. Thus 23.5 g (118 mmol) of N-(2-hydroxy-4-methylphenyl)chloroacetamide was obtained as pale green crystals. The yield was 72%.
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([CH:8]=[C:9]([CH3:12])[C:10]=1[OH:11])[C:5]([OH:7])=[O:6].[C:13](OC(=O)C)(=[O:15])[CH3:14]>N1C=CC=CC=1>[C:13]([O:11][C:10]1[C:9]([CH3:12])=[CH:8][C:4]([C:5]([OH:7])=[O:6])=[CH:3][C:2]=1[CH3:1])(=[O:15])[CH3:14]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Temperature: 25 °C
Reaction time: 4 h

Procedure:
The compound 3,5-dimethyl-4-hydroxybenzoic acid (5.04 g, 30.33 mmol) was mixed with pyridine (20 mL). Acetic anhydride (3.72 g, 36.4 mmol) was added and the mixture was stirred at room temperature for 4 h. The solvent was evaporated in vacuo to obtain 4-acetoxy-3,5-dimethyl-benzoic acid in quantitative yield (6.33 g). The compound 4-acetoxy-3,5-dimethyl-benzoic acid (0.36 g, 1.73 mmol)) was dissolved in dichloromethane (5 mL) and oxalyl chloride (0.3 mL, 3.46 mmol) was added dropwise, followed by 1 drop of DMF. The reaction mixture was stirred at room temperature under nitrogen for 2 h. The solvent was evaporated in vacuo to obtain acetic acid 4-chlorocarbonyl-2,6-dimethyl-phenyl ester in quantitative yield (0.392 g).
Reaction SMILES: C1C=CC=CC=1.[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[OH:17])[C:11]([OH:13])=[O:12].[C:19](OC(=O)C)(=[O:21])[CH3:20]>N1C=CC=CC=1>[CH3:7][C:8]1[CH:9]=[C:10]([CH:14]=[C:15]([CH3:18])[C:16]=1[O:17][C:19](=[O:21])[CH3:20])[C:11]([OH:13])=[O:12]
Reactant: Cc1cc(C(=O)O)cc(C)c1O
Reactant: CC(=O)OC(C)=O
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC(=O)Oc1c(C)cc(C(=O)O)cc1C
Reaction time: 12 h
Yield: 56.8 %

Procedure:
To 60 ml of benzene was suspended 10 g/60 mmol of 3,5-dimethyl-4-hydroxybenzoic acid, and 7.5 g/74 mmol of acetic anhydride and 150 μl of pyridine were added to the suspension. The reaction mixture was refluxed under heat for 12 hours, and allowed to stand at room temperature for 12 hours. The precipitated crystals were separated by filtration and washed with a small amount of benzene and air dried to obtain 7.1 g of the desired 3,5-dimethyl-4-acetoxybenzoic acid. 1H-NMR (CDCl3): δ2.22 (6H, s), 2.37 (3H, s), 7.85 (2H, s), 11.53 (1H, s).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][N:5]=[C:4]2[NH:8][CH:9]=[CH:10][C:3]=12.[CH2:11]([O:18][C:19]1[CH:24]=[CH:23][C:22]([OH:25])=[CH:21][CH:20]=1)[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.C(O)(C(F)(F)F)=O>CCN(CC)CC>[CH2:11]([O:18][C:19]1[CH:20]=[CH:21][C:22]([O:25][C:2]2[CH:7]=[CH:6][N:5]=[C:4]3[NH:8][CH:9]=[CH:10][C:3]=23)=[CH:23][CH:24]=1)[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: Oc1ccc(OCc2ccccc2)cc1
Reactant: Clc1ccnc2[nH]ccc12
Solvent: CCN(CC)CC
Solvent: O=C(O)C(F)(F)F
Product: c1ccc(COc2ccc(Oc3ccnc4[nH]ccc34)cc2)cc1

Procedure:
A mixture of 4-chloro-1H-pyrrolo[2,3-b]pyridine (1 g, 6.5 mmol), 4-benzyloxyphenol (1.5 g, 7.5 mmol) and Et3N:TFA (1.2 mL) was heated to 150° C. for 96 h. Formation of the compound was monitored by HPLC-mass spec. The crude was directly purified on silica gel without work-up using a Hexanes/EtOAc gradient (100/0 to 0/100) to afford 4-(4-benzyloxy-phenoxy)-1H-pyrrolo[2,3-b]pyridine.
Reaction SMILES: [C:1]([OH:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].C[Li].C.[Cl-].[Cl-].[Zn+2:13].C1COCC1>>[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3].[Zn+2:13].[C:1]([O-:7])(=[O:6])[C:2]([CH3:5])([CH3:4])[CH3:3]
Reactant: CC(C)(C)C(=O)O
Agent: C
Agent: [Cl-]
Agent: [Li]C
Solvent: C1CCOC1
Product: CC(C)(C)C(=O)[O-]
Temperature: 0 °C
Reaction time: 2 h

Procedure:
Pivalic acid (20.4 g, 22.6 mL, 200 mmol) is placed in a dry and argon-flushed 500 mL Schlenk-flask equipped with a magnetic stirring bar and a septum, and the pivalic acid is dissolved in dry THF (100 mL). The solution is cooled to 0° C. and methyllithium (135 mL, 1.63 M in diethyl ether, 220 mmol) is added dropwise. After the evolution of methane gas has stopped, ZnCl2 in THF (100 mL, 1.0 M, 100 mmol) is added and the mixture is stirred for 2 h at 25° C. The solvent is removed in vacuo and zinc pivalate.2LiCl (2a) is obtained as a colourless solid in quantitative yield.
Reaction SMILES: [Cl:1][C:2]1[C:3](O)=[N:4][CH:5]=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(#N)C.P(Cl)(Cl)([Cl:17])=O>O>[Cl:17][C:3]1[C:2]([Cl:1])=[CH:7][C:6]([N+:8]([O-:10])=[O:9])=[CH:5][N:4]=1
Reactant: O=[N+]([O-])c1cnc(O)c(Cl)c1
Reactant: O=P(Cl)(Cl)Cl
Solvent: O
Solvent: CC#N
Product: O=[N+]([O-])c1cnc(Cl)c(Cl)c1
Temperature: 80 °C
Reaction time: 15 h

Procedure:
A mixture of 3-chloro-2-hydroxy-5-nitropyridine (36.0 g), acetonitrile (72 mL), and phosphorus oxychloride (37.5 g) was heated to 80° C. The reaction was then stirred at this temperature for about 15 hours. After cooling the reaction to 40° C., water (27 g) was added, while maintaining the temperature below 70° C. The temperature was adjusted to 45° C., and then more water (189 g) was added slowly. The reaction was then cooled to 23° C., stirred for at least 12 hours, and then filtered. After washing the wet cake with water, the product was dried in a vacuum oven. 1H NMR (400 MHz/CDCl3) δ 9.10 (d, J=2.5 Hz, 1H), 8.56 (d, J=2.4 Hz, 1H)
Reaction SMILES: C[O:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([O:14]C)[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6].B(Br)(Br)Br>ClCCl.C(OCC)(=O)C>[OH:2][C:3]1[CH:13]=[CH:12][CH:11]=[C:10]([OH:14])[C:4]=1[C:5]([N:7]([CH3:9])[CH3:8])=[O:6]
Reactant: COc1cccc(OC)c1C(=O)N(C)C
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: CN(C)C(=O)c1c(O)cccc1O
Reaction time: 16 h
Yield: 36.8 %

Procedure:
To a mixture of 2,6-dimethoxy-N,N-dimethylbenzamide (64 mg, 0.3 mmol) dissolved in dichloromethane (2 mL) was added 1M BBr3 in dichloromethane (1 mL, 1.0 mmol)) under nitrogen atmosphere and stirred for 16 hours. The mixture was diluted with ethyl acetate and the mixture was washed with water (2×30 mL) and brine (2×30 mL). The organic phase was dried (MgSO4), filtered and concentrated under reduced pressure to provide titled compound (20 mg). MS ESI(−)) m/e 180 (M−H)+; 1H NMR (300 MHz, DMSO-d6) 9.36 (s, 2H), 6.92 (t, 1H), 6.30 (d, 2H), 2.97-2.73 (m, 6H).