Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][CH:2]1[C:11]2[C:6](=[C:7]([O:12][CH3:13])[CH:8]=[CH:9][CH:10]=2)[CH2:5][CH2:4][NH:3]1.C(N(CC)CC)C.[CH3:21][C:22]1[C:23](Cl)=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]>CN(C)C=O>[CH3:21][C:22]1[C:23]([N:3]2[CH2:4][CH2:5][C:6]3[C:11](=[CH:10][CH:9]=[CH:8][C:7]=3[O:12][CH3:13])[CH:2]2[CH3:1])=[N:24][C:25]([Cl:29])=[N:26][C:27]=1[CH3:28]
Reactant: Cc1nc(Cl)nc(Cl)c1C
Reactant: COc1cccc2c1CCNC2C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1cccc2c1CCN(c1nc(Cl)nc(C)c1C)C2C
Yield: 67.8 %

Procedure:
After 1-methyl-5-methoxy-1,2,3,4-tetrahydroisoquinoline(0.9 g, 5.1 mmol) and triethylamine(0.7 ml, 5.1 mmol) were added to a suspension of 5,6-dimethyl-2,4-dichloropyrimidine(0.8 g, 4.64 mmol) in dimethylformamide, 1.0 g of the titled compound was obtained in accordance with the same procedure as in Step 1 of Example 35. (Yield: 70.3%)
Reaction SMILES: [F:1][C:2]([F:16])([F:15])[C:3](=O)[CH2:4][C:5](=[O:13])[CH2:6][C:7]([C:9]([F:12])([F:11])[F:10])=O.[OH-].[NH4+:18]>>[F:1][C:2]([F:16])([F:15])[C:3]1[CH:4]=[C:5]([OH:13])[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[N:18]=1
Reactant: [NH4+]
Reactant: O=C(CC(=O)C(F)(F)F)CC(=O)C(F)(F)F
Agent: [OH-]
Product: Oc1cc(C(F)(F)F)nc(C(F)(F)F)c1
Temperature: 130 °C

Procedure:
A mixture of 30 g 1,5-di(trifluoromethyl)-1,3,5-trioxopentane and 125 ml 28% aqueous ammonium hydroxide was heated in an autoclave at 130° C. for 5 hours. The reaction mixture was concentrated in vacuo, dissolved in 350 ml ethanol and treated with 11 ml 6N hydrochloric acid. The resulting mixture was concentrated in vacuo, 100 ml water added to the residue and filtered to give 8.0 g 2,6-di(trifluoromethyl)-4-hydroxypyridine, m.p. 123°-130° C.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([O:8][CH2:9][C:10]([F:13])([F:12])[F:11])[C:5]([N+:14]([O-])=O)=[CH:4][C:3]=1[S:17]([NH:20][CH3:21])(=[O:19])=[O:18]>CO.[Pd]>[NH2:14][C:5]1[C:6]([O:8][CH2:9][C:10]([F:12])([F:13])[F:11])=[CH:7][C:2]([F:1])=[C:3]([S:17]([NH:20][CH3:21])(=[O:18])=[O:19])[CH:4]=1
Reactant: CNS(=O)(=O)c1cc([N+](=O)[O-])c(OCC(F)(F)F)cc1F
Agent: [Pd]
Solvent: CO
Product: CNS(=O)(=O)c1cc(N)c(OCC(F)(F)F)cc1F
Temperature: 45 °C
Reaction time: 10 h
Yield: 87.9 %

Procedure:
A mixture of 2-fluoro-N-methyl-5-nitro-4-[(2,2,2-trifluoroethyl)oxy]benzene-sulfonamide (10 g, 30.1 mmol) in MeOH (150 mL) was treated with 10% Pd/C (1 g) and stirred under H2 (45 psi) at 45° C. for 10 hours before being filtered. The filtrate was concentrated to give 5-amino-2-fluoro-N-methyl-4-[(2,2,2-trifluoroethyl)oxy]benzene-sulfonamide (8 g, 88%) as a white solid. 1H NMR (400 MHz, DMSO-d6) δ ppm 7.40 (q, J=5.07 Hz, 1 H), 7.10 (d, J=11.69 Hz, 1 H), 7.05 (d, J=7.28 Hz, 1 H), 5.04 (s, 2 H), 4.83 (q, J=8.82 Hz, 2 H), 2.42 (d, J=4.41 Hz, 3 H). MS (m/z) 303.0 (M+H+).
Reaction SMILES: I[C:2]1[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)[N:3]=1.[CH3:15][CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22](B(O)O)=[CH:21][CH:20]=1)[CH3:17].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.O.C(OCC)(=O)C.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>[CH:16]([O:18][C:19]1[CH:24]=[CH:23][C:22]([C:2]2[C:6]([CH:7]=[O:8])=[CH:5][N:4]([CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[N:3]=2)=[CH:21][CH:20]=1)([CH3:17])[CH3:15]
Reactant: CC(C)Oc1ccc(B(O)O)cc1
Reactant: O=Cc1cn(C2CCCCO2)nc1I
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: O
Solvent: CCOC(C)=O
Solvent: Cc1ccccc1
Product: CC(C)Oc1ccc(-c2nn(C3CCCCO3)cc2C=O)cc1
Temperature: 98 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of 3-iodo-1-(oxan-2-yl)-1H-pyrazole-4-carbaldehyde (6 g, 19.60 mmol, 1.00 equiv), [4-(propan-2-yloxy)phenyl]boronic acid (7.0 g, 38.89 mmol, 1.98 equiv), Pd(PPh3)4 (2.2 g, 1.90 mmol, 0.10 equiv) and sodium carbonate (6.2 g, 58.50 mmol, 2.98 equiv) in toluene (60 mL) and water (5 mL) was stirred under nitrogen at 98° C. overnight. The reaction was cooled to room temperature then diluted with 600 mL of ethyl acetate. The resulting mixture was washed with 3×300 mL of brine, dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified on a silica gel column eluted with 3.0-6.5% ethyl acetate in petroleum ether to give 4.5 g (73%) of 3-(4-isopropoxyphenyl)-1-(tetrahydro-2H-pyran-2-yl)-1H-pyrazole-4-carbaldehyde as yellow oil. 1H NMR (300 MHz, CDCl3) δ: 9.98 (s, 1H), 8.23 (s, 1H), 7.70-7.65 (m, 2H), 7.26 (s, 1H), 6.98-6.93 (m, 2H), 5.45-5.41 (m, 1H), 4.65-4.57 (m, 1H), 4.13-4.09 (m, 1H), 3.78-3.73 (m, 1H), 2.21-2.03 (m, 3H), 1.71-1.63 (m, 3H), 1.36 (d, J=6.0 Hz, 6H) ppm. LCMS (method D, ESI): RT=1.57 min, m/z=315.0 [M+H]+.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].Br[C:15]1[CH:20]=[CH:19][C:18]([C:21]2[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]3[CH2:32][CH2:31][CH2:30][CH2:29]3)[N:25]=2)=[CH:17][CH:16]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]3[O:22][C:23]([CH3:33])=[C:24]([CH2:26][CH2:27][N:28]4[CH2:29][CH2:30][CH2:31][CH2:32]4)[N:25]=3)=[CH:17][CH:16]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: COc1ccc(B(O)O)cc1OC
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCCC1
Product: COc1ccc(-c2ccc(-c3nc(CCN4CCCC4)c(C)o3)cc2)cc1OC

Procedure:
The title compound is prepared in a manner substantially analogous to Example 35 starting from 3,4-Dimethoxybenzene boronic acid and 2-(4-Bromo-phenyl)-5-methyl-4-(2-pyrrolidin-1-yl-ethyl)-oxazole. MS (m/e): 393.2 (M+1)
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8](OS(C(F)(F)F)(=O)=O)=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:29][Si:30]([C:33]#[CH:34])([CH3:32])[CH3:31]>CN(C)C=O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([C:34]#[C:33][Si:30]([CH3:32])([CH3:31])[CH3:29])=[C:7]([N+:19]([O-:21])=[O:20])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)c1ccc(OS(=O)(=O)C(F)(F)F)c([N+](=O)[O-])c1
Reactant: C#C[Si](C)(C)C
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: CC(C)(C)c1ccc(C#C[Si](C)(C)C)c([N+](=O)[O-])c1
Temperature: 90 °C
Yield: 102.3 %

Procedure:
To Trifluoro-methanesulfonic acid 4-tert-butyl-2-nitro-phenyl ester (3.715 g, 11.35 mmol), dichlorobis(triphenylphoshpine)palladium(II) (336 mg, 0.478 mmol), cuprous iodide (168 mg, 0.882 mmol) was added dimethylformamide (45 mL), triethylamine (1.72 g, 17.0 mmol), and trimethylsilylacetylene (2.229 g, 22.70 mmol). The resulting mixture was heated at 90° C. under an atmosphere of nitrogen for 15 minutes. This was partitioned between ethylacetate and water. The ethylacetate layer was washed with brine, dried over anhydrous MgSO4, concentrated in vacuo, and purified by flash chromatography with elution with CH2Cl2 to yield (4-tert-Butyl-2-nitro-phenylethynyl)-trimethyl-silane (3.193 g, 11.61 mmol).
Reaction SMILES: [O:1]=[C:2]1[CH2:7][NH:6][CH2:5][CH2:4][N:3]1[C:8]1[CH:13]=[CH:12][C:11]([C:14]2([C:17]([N:19]3[CH2:23][CH2:22][C@@:21]4([C:27]5[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=5[C:25](=[O:32])[O:24]4)[CH2:20]3)=[O:18])[CH2:16][CH2:15]2)=[CH:10][CH:9]=1.C(#N)C.C(N(CC)CC)C.[CH3:43][S:44](Cl)(=[O:46])=[O:45]>>[CH3:43][S:44]([N:6]1[CH2:5][CH2:4][N:3]([C:8]2[CH:13]=[CH:12][C:11]([C:14]3([C:17]([N:19]4[CH2:23][CH2:22][C@@:21]5([C:27]6[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=6[C:25](=[O:32])[O:24]5)[CH2:20]4)=[O:18])[CH2:16][CH2:15]3)=[CH:10][CH:9]=2)[C:2](=[O:1])[CH2:7]1)(=[O:46])=[O:45]
Reactant: CS(=O)(=O)Cl
Reactant: O=C1O[C@]2(CCN(C(=O)C3(c4ccc(N5CCNCC5=O)cc4)CC3)C2)c2ccccc21
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CS(=O)(=O)N1CCN(c2ccc(C3(C(=O)N4CC[C@@]5(C4)OC(=O)c4ccccc45)CC3)cc2)C(=O)C1
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To a solution of (1R)-1′-({1-[4-(2-oxopiperazin-1-yl)phenyl]cyclopropyl}carbonyl)-3H-spiro[2-benzofuran-1,3′-pyrrolidin]-3-one (36 mg, 0.000083 mol) in acetonitrile (0.5 mL, 0.01 mol) were added triethylamine (29 μL, 0.00021 mol) and methanesulfonyl chloride. After stirring at rt for 3 hours, the crude product was isolated and purified by prep-HPLC. LC/MS: 510.2 (M+H+).
Reaction SMILES: [C:1]1([N:7]2[C:11]([CH2:12][CH2:13][CH:14]=O)=[CH:10][C:9]([CH:16]([CH3:18])[CH3:17])=[N:8]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]1.CCN(C(C)C)C(C)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>>[F:19][C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=1[N:26]1[CH2:31][CH2:30][N:29]([CH2:14][CH2:13][CH2:12][C:11]2[N:7]([C:1]3[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=3)[N:8]=[C:9]([CH:16]([CH3:18])[CH3:17])[CH:10]=2)[CH2:28][CH2:27]1
Reactant: CC(C)c1cc(CCC=O)n(-c2ccccc2)n1
Reactant: Fc1ccccc1N1CCNCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)c1cc(CCCN2CCN(c3ccccc3F)CC2)n(-c2ccccc2)n1

Procedure:
143 mg (99%) of target compound was obtained by using a method same as in Example 1 by using 3-(1-phenyl-3-isopropyl-1H-pyrazol-5-yl)propanal (86 mg, 0.357 mmol), 1-(2-fluorophenyl)piperazine (65 mg, 0.362 mmol), DIPEA (0.094 mL, 0.540 mmol) and NaBH(OAc)3 (237 mg, 1.118 mmol).
Reaction SMILES: Cl[C:2]1[N:7]=[N:6][C:5]([NH2:8])=[C:4]([C:9]2[C:10]3([CH2:15][CH2:16][CH2:17][CH:18]=2)[O:14][CH2:13][CH2:12][O:11]3)[CH:3]=1.C([O-])=O.[NH4+]>C(O)C.[C].[Pd]>[O:11]1[C:10]2([CH2:15][CH2:16][CH2:17][CH:18]=[C:9]2[C:4]2[CH:3]=[CH:2][N:7]=[N:6][C:5]=2[NH2:8])[O:14][CH2:13][CH2:12]1
Reactant: Nc1nnc(Cl)cc1C1=CCCCC12OCCO2
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CCO
Product: Nc1nnccc1C1=CCCCC12OCCO2

Procedure:
A solution of the 6-chloro-4-(1,4-dioxaspiro[4.5]dec-6-en-6-yl)pyridazin-3-amine (0.10 g, 0.37 mmol) prepared in Example 82b, ammonium formate (0.14 g, 2.24 mmol) and palladium carbon (10%; 0.10 g) in ethanol (3.7 mL) was stirred at 80° C. for 4 hours. After allowing to cool, the reaction solution was filtered through celite and concentrated to yield the title compound in a crude form.
Reaction SMILES: [CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[NH:13][C:12]=2[CH3:21])[CH:5]=1.Br[C:24]1[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=1>>[CH3:1][O:2][C:3](=[O:22])[C:4]1[CH:9]=[CH:8][N:7]=[C:6]([S:10][C:11]2[C:19]3[C:14](=[CH:15][C:16]([Cl:20])=[CH:17][CH:18]=3)[N:13]([C:24]3[CH:25]=[N:26][N:27]([CH3:29])[CH:28]=3)[C:12]=2[CH3:21])[CH:5]=1
Reactant: COC(=O)c1ccnc(Sc2c(C)[nH]c3cc(Cl)ccc23)c1
Reactant: Cn1cc(Br)cn1
Product: COC(=O)c1ccnc(Sc2c(C)n(-c3cnn(C)c3)c3cc(Cl)ccc23)c1

Procedure:
Prepared according to the procedure described in Example 3, Step 1, using the following starting materials: 2-(6-chloro-2-methyl-1H-indol-3-ylsulfanyl)-isonicotinic acid methyl ester and 4-bromo-1-methyl-1H-pyrazole.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16]C)=[CH:12][CH:11]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1.B(Br)(Br)Br.O>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([C:8]([C:10]2[CH:11]=[CH:12][C:13]([OH:16])=[CH:14][CH:15]=2)=[O:9])[CH:5]=[CH:6][CH:7]=1
Reactant: COc1ccc(C(=O)c2cccc(F)c2)cc1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: O
Product: O=C(c1ccc(O)cc1)c1cccc(F)c1
Temperature: 25 °C
Reaction time: 18 h
Yield: 73.5 %

Procedure:
(3-fluorophenyl)(4-methoxyphenyl)methanone (1.0 g, 4.34 mmol) in 50 mL DCM at −78° C. while stirring was treated with 1M boron tribromide (13.03 mL, 13.03 mmol) dropwise over 20 minutes. The mixture was allowed to warm to 25° C. and stir for 18 hours. The mixture was treated with water (1 mL) and stirred for 5 minutes, followed by additional water (2 mL) and stirred for 10 minutes, and finally treated with more water (50 mL) and stirred for 20 minutes. The mixture was then extracted with DCM (50 mL×2). The organic layers were combined, dried, filtered, and the filtrate evaporated under reduced pressure. The residue was purified by flash chromatography to provide the title compound (0.69 g, 74% yield). 1HNMR (300 MHz, CD3OD) δ 6.92 (d, 2H, J=8.9 Hz), 7.26 (m, 1H), 7.41-7.58 (m, 3H), 7.79 (d, 2H, J=8.9 Hz); MS (DCI) m/z 217 (M+H)+, 234 (M+NH4)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=2[O:14][CH3:15])[N:5]=[CH:4][N:3]=1.[NH2:16][NH2:17].C(=O)([O-])[O-].[K+].[K+]>O1CCOCC1>[CH3:15][O:14][C:9]1[CH:10]=[CH:11][CH:12]=[CH:13][C:8]=1[C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:16][NH2:17])[CH:7]=1
Reactant: COc1ccccc1-c1cc(Cl)ncn1
Reactant: NN
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1COCCO1
Product: COc1ccccc1-c1cc(NN)ncn1

Procedure:
[6-(2-Methoxy-phenyl)-pyrimidin-4-yl]-hydrazine was prepared from 4-Chloro-6-(2-methoxy-phenyl)pyrimidine (2.4 g, 11 mmol), hydrazine (1.3 mL, 43 mmol) and potassium carbonate (2.2 g, 16 mmol) in 25 mL of dioxane by a procedure similar to example 3, step 1 yielding 2.0 g (86%) of a white solid.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5](Cl)=[O:6].Cl.[NH2:9][CH:10]([C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)[CH:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[N:21]=[CH:20][CH:19]=[CH:18]2)[OH:12].C(N(CC)CC)C.[OH-].[Na+].[I-].[K+].P([O-])(O)(O)=O.[Na+]>CN(C=O)C>[F:29][C:26]1[CH:25]=[CH:24][C:23]([CH:10]([N:9]2[CH2:2][CH2:3][CH2:4][C:5]2=[O:6])[CH:11]([OH:12])[C:13]2[CH:14]=[CH:15][CH:16]=[C:17]3[C:22]=2[N:21]=[CH:20][CH:19]=[CH:18]3)=[CH:28][CH:27]=1
Reactant: O=C(Cl)CCCCl
Reactant: NC(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Agent: Cl
Agent: O=P([O-])(O)O
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: O=C1CCCN1C(c1ccc(F)cc1)C(O)c1cccc2cccnc12
Temperature: -8 °C
Reaction time: 1 h
Yield: 7.7 %

Procedure:
0.615 ml (5.18 mmol) of 4-chlorobutyryl chloride (95%) was slowly added dropwise to a solution of 1.5 g (4.7 mmol) of 2-amino-2-(4-fluorophenyl)-1-quinolin-8-ylethanol hydrochloride and 1.96 ml (14.1 mmol) of triethylamine in 15 ml of DMF cooled to −8° C. After stirring at −8 to −10° C. for 1 h, 2.25 g (56.3 mmol) of sodium hydroxide pellets and 156 mg (0.94 mmol) of potassium iodide were added, and the mixture was stirred at room temperature for 3 h. The mixture was poured into an aqueous sodium dihydrogen phosphate solution (80 g/l). Extraction twice with diisopropyl ether was followed by drying over magnesium sulfate. The residue after concentration in vacuo was purified by chromatography with petroleum benzene/ethyl acetate 50:50, then 30:70 to 0:100. 845 mg of 1-[1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]pyrrolidin-2-one (diastereoisomer A) (yield: 51%) and 127 mg of 1-[1-(4-fluorophenyl)-2-hydroxy-2-quinolin-8-ylethyl]pyrrolidin-2-one (diastereomer B) (yield: 8%) were obtained.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([N+:9]([O-])=O)=[CH:4][C:3]=1[I:12].[NH4+].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[C:6]([NH2:8])[C:5]([NH2:9])=[CH:4][C:3]=1[I:12]
Reactant: Nc1nc(Cl)c(I)cc1[N+](=O)[O-]
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: Nc1cc(I)c(Cl)nc1N
Yield: 97.1 %

Procedure:
To a solution of 6-chloro-3-nitropyridin-2-amine (630 mg, 3.63 mmol) in ethanol (11 mL) was add I2 (920 mg, 3.62 mmol) and Ag2SO4 (1132 mg, 3.63 mmol).). The resulting solution was stirred overnight at room temperature and dissolved in water (100 mL), then extracted with ethyl acetate (3×80 ml). The combined organic layers were washed with brine (50 ml), dried over anhydrous sodium sulfate and concentrated under vacuum to produce 6-chloro-5-iodo-3-nitropyridin-2-amine as a yellow solid (640 mg, 59%). Next, to a solution of 6-chloro-5-iodo-3-nitropyridin-2-amine (640 mg, 2.14 mmol) in ethanol (40 ml) and water (10 ml) was added Fe powder (1.93 g, 34.46 mmol) and NH4Cl (887 mg, 16.58 mmol). The resulting solution was heated to reflux for 4 h and then concentrated. The residue was dissolved in water (100 mL) and extracted with ethyl acetate (3×80 ml). The combined organic layers was washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 33% ethyl acetate in petroleum ether to produce 6-chloro-5-iodopyridine-2,3-diamine as a brown solid (560 mg, 97%). The mixture of 6-chloro-5-iodopyridine-2,3-diamine (100 mg, 0.37 mmol), (2,3-dichlorophenyl)boronic acid (147.3 mg, 0.77 mmol), Pd(Ph3P)4 (42.9 mg, 0.04 mmol) and sodium carbonate (118.2 mg, 1.12 mmol) in water (5 mL) and dioxane (15 mL) was heated to reflux overnight. Then the resulting solution was quenched with water (100 mL) and extracted with ethyl acetate (3×50 ml). The combined organic layers were washed with brine (50 mL), dried over anhydrous sodium sulfate and concentrated under vacuum. The residue was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine as a brown solid (80 mg, 75%). Finally, the solution of 6-chloro-5-(2,3-dichlorophenyl)pyridine-2,3-diamine (80 mg, 0.28 mmol) in trifluoroacetic acid (10 mL) and hydrochloric acid (conc., 2 mL) was heated to reflux overnight. Then the resulting mixture was quenched with water (100 mL), adjusted pH to 8 with sodium carbonate and extracted with ethyl acetate (3×80 mL). The combined organic layers was dried over anhydrous magnesium sulfate and concentrated to give a residue, which was purified by a silica gel column with 50% ethyl acetate in petroleum ether to produce 5-chloro-6-(2,3-dichlorophenyl)-2-(trifluoromethyl)-1H-imidazo[4,5-b]pyridine. Trifluoroacetic acid as a off-white solid (2 mg, 2%).
Reaction SMILES: C(Cl)CCl.[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:9]([OH:11])=[O:10].[C:16](O)([CH3:19])([CH3:18])[CH3:17]>CN(C1C=CN=CC=1)C.C(Cl)Cl.N1C=CC=CC=1>[Br:5][C:6]1[CH:7]=[C:8]([CH:12]=[C:13]([Br:15])[CH:14]=1)[C:9]([O:11][C:16]([CH3:19])([CH3:18])[CH3:17])=[O:10]
Reactant: O=C(O)c1cc(Br)cc(Br)c1
Reactant: CC(C)(C)O
Agent: CN(C)c1ccncc1
Solvent: c1ccncc1
Solvent: ClCCCl
Solvent: ClCCl
Product: CC(C)(C)OC(=O)c1cc(Br)cc(Br)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 63.7 %

Procedure:
EDC (14.0 g, 73.0 mmol) and DMAP (4.0 g) are added to a solution of 3,5-dibromobenzoic acid (10.0 g, 36.0 mmol) and tert-butanol (3.4 g, 46.8 mmol) in absolute CH2Cl2 (100 ml) and absolute pyridine (30 ml), and the mixture is stirred at RT for 1 h and then at 50° C. for 2 h. The reaction solution is diluted with CH2Cl2 (100 ml) and extracted with a semisaturated aqueous NH4Cl solution (200 ml) (2×), dried over MgSO4, filtered off and concentrated under reduced pressure. Further purification by chromatography [toluene/acetone (95:5)] on a silica gel column gives the title compound (7.7 g) as slightly yellow crystals. TLC, silica gel, glass plates, [toluene/acetone (7.5:2.5)], Rf=0.78.
Reaction SMILES: [OH:1][CH:2]([C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]([O-:5])=[O:4].C(=O)([O-])[O-].[K+].[K+].CO.Cl>O>[OH:1][CH:2]([C:6]#[C:7][C:8]([CH3:11])([CH3:10])[CH3:9])[C:3]([OH:5])=[O:4]
Reactant: CC(C)(C)C#CC(O)C(=O)[O-]
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Solvent: O
Product: CC(C)(C)C#CC(O)C(=O)O
Yield: 75 %

Procedure:
A magnetically stirred mixture comprising 2.10 g (0.01 mole) of twice distilled 2-hydroxy-5,5,-dimethyl-3-hexynoate, n-butyl ester, 1.40 g (0.01 mole) of potassium carbonate and 3 ml of methanol in 20 ml of water was heated, under a dry nitrogen atmosphere, at 75°-80° C. for 1.5 hours during which time the substrate dissolved to afford a faint yellow solution. After cooling, 20 ml of water was added and the solution was exhaustively extracted with ether. The aqueous phase was then treated with 1.5 g of Darco® activated carbon, filtered with suction through a Celite® pad and acidified in an ice bath with 2.0 ml (0.02 mole) of concentrated hydrochloric acid. The resulting oil was extracted with three 25 ml portions of ether and the combined extracts were washed with four 35 ml portions of water and dried over MgSO4. Filtration and concentration at the stripper afforded 1.20 g (75% yield) of 2-hydroxy-5,5-dimethyl- 3-hexynoic acid, a light yellow, viscous oil. Pumping down at 25° C./0.20 mm for one hour produced no observable reduction in product weight.
Reaction SMILES: [F:1][C:2]1[CH:21]=[CH:20][C:5]([CH2:6][N:7]2[C:15]3[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=3)[C:9]([CH2:16][C:17](O)=[O:18])=[CH:8]2)=[CH:4][CH:3]=1.C1(N=C=NC2CCCCC2)CCCCC1.[NH2:37][C:38]1[CH:43]=[CH:42][N:41]=[CH:40][CH:39]=1>O1CCCC1>[N:41]1[CH:42]=[CH:43][C:38]([NH:37][C:17](=[O:18])[CH2:16][C:9]2[C:10]3[C:15](=[CH:14][CH:13]=[CH:12][CH:11]=3)[N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([F:1])=[CH:21][CH:20]=3)[CH:8]=2)=[CH:39][CH:40]=1
Reactant: O=C(O)Cc1cn(Cc2ccc(F)cc2)c2ccccc12
Reactant: Nc1ccncc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1CCOC1
Product: O=C(Cc1cn(Cc2ccc(F)cc2)c2ccccc12)Nc1ccncc1
Temperature: 0 °C
Reaction time: 24 h

Procedure:
3.5 g (12.3 mMol) [1-(4-fluorobenzyl)indole-3-yl]acetic acid are dissolved in 100 ml anhydrous tetrahydrofuran. To this solution are added 2.54 g (12.3 mMol) dicyclohexylcarbodiimide and 1.16 g (12.3 mMol) 4-aminopyridine. After stirring for 24 hours at 0° C., the formed dicyclohexyl urea is separated off. After mixing in the solvent, the residue is purified by column chromatography on silica gel. Eluting agent:
Reaction SMILES: [CH2:1]([C:3]1[O:4][C:5]([NH2:13])=[C:6]([C:8]([O:10][CH2:11][CH3:12])=[O:9])[N:7]=1)[CH3:2].[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([N:19]=[C:20]=[O:21])=[O:18]>C(#N)C>[F:14][C:15]1[CH:25]=[CH:24][CH:23]=[C:22]([F:26])[C:16]=1[C:17]([NH:19][C:20]([NH:13][C:5]1[O:4][C:3]([CH2:1][CH3:2])=[N:7][C:6]=1[C:8]([O:10][CH2:11][CH3:12])=[O:9])=[O:21])=[O:18]
Reactant: CCOC(=O)c1nc(CC)oc1N
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: CC#N
Product: CCOC(=O)c1nc(CC)oc1NC(=O)NC(=O)c1c(F)cccc1F
Temperature: 25 °C
Reaction time: 3 h

Procedure:
To 0.5 g. 2-ethyl-4-carbethoxy-5-aminooxazole dissolved in 20 ml. acetonitrile was added 0.7 g. 2,6-difluorobenzoylisocyanate under nitrogen at about 25° C. The reaction mixture was stirred at about 25° C. for 3 hours and the solid was collected. Yield 0.36 g.