Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([C:7]2[N:8]=[C:9]([CH:31]=[O:32])[N:10](C(C3C=CC=CC=3)(C3C=CC=CC=3)C3C=CC=CC=3)[CH:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.FC(F)(F)C(O)=O>C(Cl)Cl>[C:1]1([C:7]2[N:8]=[C:9]([CH:31]=[O:32])[NH:10][CH:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=Cc1nc(-c2ccccc2)cn1C(c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=Cc1nc(-c2ccccc2)c[nH]1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 92.9 %

Procedure:
To a solution of 4-phenyl-1-trityl-1H-imidazole-2-carbaldehyde (414 mg, 1 mmol) in DCM (10 mL) was added 2,2,2-trifluoroacetic acid (1 mL). After stirring at room temperature for 30 minutes, the solvent was removed in vacuo. The resulting residue was diluted with DCM (50 mL) and saturated sodium bicarbonate (50 mL). The aqueous layer was extracted with DCM (2×50 mL). The combined organic layers were dried over sodium sulfate, filtered, concentrated and then purified by column chromatography to give 4-phenyl-1H-imidazole-2-carbaldehyde as a white solid (160 mg). MS (ESI): m/z 173 (M+H)+.
Reaction SMILES: [CH:1]([S:4][C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)([CH3:3])[CH3:2].OO.C([O-])([O-])=[O:19].[Na+].[Na+]>CC(O)=O>[CH:1]([S:4]([C:5]1[CH:15]=[CH:14][C:8]([C:9]([O:11][CH2:12][CH3:13])=[O:10])=[CH:7][CH:6]=1)=[O:19])([CH3:2])[CH3:3]
Reactant: O=C([O-])[O-]
Reactant: CCOC(=O)c1ccc(SC(C)C)cc1
Agent: OO
Agent: [Na+]
Solvent: CC(=O)O
Product: CCOC(=O)c1ccc(S(=O)C(C)C)cc1
Yield: 65 %

Procedure:
A solution of ethyl 4-isopropylsulfanylbenzoate (350 mg, 1.6 mmol) and H2O2 (180 μL of 30% w/v, 1.6 mmol) in AcOH (2 mL) was stirred at ambient temperature for 3 h. The mixture was poured into sat. aq. Na2CO3 and the pH was adjusted to 10 with solid Na2CO3. The mixture was extracted with EtOAc (3×). The organics were combined and washed with sat. aq. Na2CO3, water (2×), then brine. The organic layer was dried over magnesium sulfate and was evaporated to dryness. The residue was purified by column chromatography (20-50% EtOAc in hexanes) to give ethyl 4-isopropylsulfinylbenzoate (65%). ESI-MS m/z calc. 240.1, found 241.3 (M+1)+. Retention time: 1.16 minutes (3 min run).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][N:21](C(OC(C)(C)C)=O)[C@@H:20]([CH3:31])[CH2:19]3)=[N:10][N:9]=2)=[CH:4][CH:3]=1.Cl.CO>O1CCOCC1>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=3)[C:11]([N:18]3[CH2:23][CH2:22][NH:21][C@@H:20]([CH3:31])[CH2:19]3)=[N:10][N:9]=2)=[CH:6][CH:7]=1
Reactant: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1C(=O)OC(C)(C)C
Agent: Cl
Solvent: C1COCCO1
Solvent: CO
Product: C[C@H]1CN(c2nnc(-c3ccc(F)cc3)c3ccccc23)CCN1
Temperature: 25 °C
Reaction time: 2 h
Yield: 92.5 %

Procedure:
Treat a solution of (S)-tert-butyl 4-(4-(4-fluorophenyl)phthalazin-1-yl)-2-methylpiperazine-1-carboxylate (7.05 g, 16.2 mmol) in 1,4-dioxane (50 mL) with 4 M HCl in 1,4-dioxane (25 mL). Add MeOH to dissolve the resultant precipitate and stir for 2 h at ambient temperature. Concentrate the reaction mixture under reduced pressure. Dissolve residue in MeOH and pour onto a 50 g Varian® SCX column. Rinse with MeOH and CH2Cl2, then elute the product with 1:1 CH2Cl2: 2 M ammonia in MeOH. Concentrate the eluent under reduced pressure to provide the title compound as a pale yellow foam (4.83 g, 93%). ES/MS m/z 323.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]([NH2:10])=[NH:9])=[N:6][CH:7]=1.[CH3:11][CH:12]([C:18](=O)[CH3:19])[C:13](OCC)=[O:14].C(=O)([O-])[O-].[Na+].[Na+]>O.C(O)C>[NH2:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:10]=[C:13]([OH:14])[C:12]([CH3:11])=[C:18]([CH3:19])[N:9]=2)=[N:6][CH:7]=1
Reactant: CCOC(=O)C(C)C(C)=O
Reactant: N=C(N)c1ccc(N)cn1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: Cc1nc(-c2ccc(N)cn2)nc(O)c1C
Reaction time: 24 h

Procedure:
To a solution of compound of example 12 (0.2 g, 1.47 mmol) in water (5 mL) and ethanol (2.5 mL) was added ethyl 2-methyl-3-oxobutanoate (0.339 g, 2.35 mmol) and sodium carbonate (0.280 g, 2.64 mmol) at room temperature and the reaction mixture was stirred for 24 hours. Ethanol was removed under reduced pressure, and the reaction mixture was diluted with water and extracted with ethyl acetate (3×20 mL). The organic layer was dried over anhydrous sodium sulfate and concentrated to obtain the crude product, which was purified by column chromatography using silica gel and 1% methanol in chloroform as an eluent to obtain the title compound.
Reaction SMILES: [F:1][C:2]([F:19])([F:18])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10]([C:12]2[CH:13]=[N:14][O:15][C:16]=2[CH3:17])=[O:11])=[CH:5][CH:4]=1.[OH-].[Na+].Cl>CO.O>[F:1][C:2]([F:18])([F:19])[C:3]1[CH:8]=[CH:7][C:6]([NH:9][C:10](=[O:11])/[C:12](/[C:13]#[N:14])=[C:16](\[OH:15])/[CH3:17])=[CH:5][CH:4]=1
Reactant: Cc1oncc1C(=O)Nc1ccc(C(F)(F)F)cc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: C/C(O)=C(\C#N)C(=O)Nc1ccc(C(F)(F)F)cc1
Reaction time: 0.5 h

Procedure:
0.1 mol of N-(4-trifluoromethylphenyl)-5-methylisoxazole-4-carboxamide is dissolved in 100 ml of methanol and treated at +10° C. with a solution of 0.11 mol (4.4 g) of sodium hydroxide in 100 ml of water. The mixture is stirred for 30 minutes and, after diluting with water, is acidified with concentrated hydrochloric acid. The precipitated crop of crystals is filtered off with suction, washed with water and dried in air. The yield is 24.4 g of N-(4-trifluoromethylphenyl)-2-cyano-3-hydroxycrotonamide (compound 2). Melting point from methanol 205° to 206° C.
Reaction SMILES: [OH:1][C:2]1[C:7]([C:8](=[O:10])[CH3:9])=[C:6]([O:11][CH2:12][C:13]([O:15]C)=[O:14])[CH:5]=[CH:4][CH:3]=1.[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=O)=[CH:23][CH:22]=1)(=[O:19])[CH3:18].[OH-].[K+].Cl>C(O)C.O>[C:17]([NH:20][C:21]1[CH:28]=[CH:27][C:24]([CH:25]=[CH:9][C:8]([C:7]2[C:2]([OH:1])=[CH:3][CH:4]=[CH:5][C:6]=2[O:11][CH2:12][C:13]([OH:15])=[O:14])=[O:10])=[CH:23][CH:22]=1)(=[O:19])[CH3:18]
Reactant: COC(=O)COc1cccc(O)c1C(C)=O
Reactant: CC(=O)Nc1ccc(C=O)cc1
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: CC(=O)Nc1ccc(C=CC(=O)c2c(O)cccc2OCC(=O)O)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94.4 %

Procedure:
To a mixture of 6′-hydroxy-2′-(methoxycarbonylmethoxy)acetophenone (2.24 g) and 4-acetylaminobenzaldehyde (2.45 g) in ethanol (30 mL) were added water (10 mL) and potassium hydroxide (6.73 g), and the mixture was stirred at room temperature overnight. To the reaction mixture was added 2 mol/L hydrochloric acid (70 mL), and the precipitated crystals were collected by filtration. The crystals were washed with water and dried under reduced pressure to give 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.35 g). A mixture of the obtained 4-acetylamino-2′-(carboxymethoxy)-6′-hydroxychalcone (3.3 g) and 10% palladium-carbon powder (1 g) in methanol (50 mL) was stirred at room temperature under a hydrogen atmosphere overnight. The insoluble material was removed by filtration. The solvent of the filtrate was removed under reduced pressure, and the residue was dissolved in acetic acid (13.2 mL). To the solution were added sodium acetate (4.77 g) and acetic anhydride (4.8 mL), and the mixture was stirred at 115° C. for 20 hours. The reaction mixture was poured in to water, and the resulting mixture was extracted with ethyl acetate. The extract was washed with water and brine, and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was dissolved in methanol (10 mL). To the solution was added sodium methoxide (28% methanol solution, 5 mL), and the mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure. To the residue were added 1 mol/L hydrochloric acid (30 mL) and ethyl acetate, and the mixture was stirred for 1 hour. The reaction mixture was poured into a saturated aqueous sodium hydrogen carbonate solution, and the resulting mixture was extracted with ethyl acetate. The extract was washed with brine and dried over anhydrous sodium sulfate. The solvent was removed under reduced pressure, and the residue was treated with dichloromethane-methanol. The precipitated crystals were collected by filtration. The crystals were washed with dichloromethane and dried under reduced pressure to give the title compound (0.86 g).
Reaction SMILES: [CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15](O)=[O:16])[CH:11]=1)(=[O:5])=[O:4].C(Cl)(=O)C([Cl:22])=O>C(Cl)(Cl)Cl>[CH3:1][N:2]([CH3:18])[S:3]([C:6]1[CH:7]=[CH:8][C:9]2[N:10]([N:12]=[CH:13][C:14]=2[C:15]([Cl:22])=[O:16])[CH:11]=1)(=[O:5])=[O:4]
Reactant: CN(C)S(=O)(=O)c1ccc2c(C(=O)O)cnn2c1
Reactant: O=C(Cl)C(=O)Cl
Solvent: ClC(Cl)Cl
Product: CN(C)S(=O)(=O)c1ccc2c(C(=O)Cl)cnn2c1

Procedure:
6-Dimethylsulfamoyl-pyrazolo[1,5-a]pyridine-3-carboxylic acid (200 mg, 0.57 mmol) are dissolved in 4 ml chloroform and oxalylchloride (97 μl, 1.14 mmol; Fluka) are added. The reaction is refluxed for 3 hours and then volatiles are removed under reduced pressure. The crude product is directly used in the next step.
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][N:22](C(OC(C)(C)C)=O)[CH2:21][CH:20]2[O:32][CH2:33][CH2:34][O:35][C:36]2[CH:41]=[CH:40][C:39]([NH2:42])=[C:38]([NH2:43])[CH:37]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[ClH:44]>CO>[ClH:44].[CH2:1]([O:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]2[CH2:24][CH2:23][NH:22][CH2:21][CH:20]2[O:32][CH2:33][CH2:34][O:35][C:36]2[CH:37]=[C:38]([NH2:43])[C:39]([NH2:42])=[CH:40][CH:41]=2)=[CH:15][CH:14]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CC(C)(C)OC(=O)N1CCC(c2ccc(OCCCOCc3ccccc3)cc2)C(OCCOc2ccc(N)c(N)c2)C1
Agent: Cl
Solvent: CO
Product: Nc1ccc(OCCOC2CNCCC2c2ccc(OCCCOCc3ccccc3)cc2)cc1N

Procedure:
In an analogous manner to that described in Example 22 (l), from tert-butyl (3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-3-[2-(3,4-diamino-phenoxy)-ethoxy]-piperidine-1-carboxylate by cleavage of the BOC protecting group with hydrogen chloride in methanol there was obtained 4-[2-[(3RS,4RS)-4-[4-(3-benzyloxy-propoxy)-phenyl]-piperidin-3-yloxy]-ethoxy]-benzene-1,2-diamine hydrochloride (1:3) as pale violet crystals; MS: 492 (M+H)+.
Reaction SMILES: C(OC([N:8]1[CH2:12][CH2:11][CH:10]2[N:13]([CH:26]3[CH2:30][CH2:29][CH2:28][CH2:27]3)[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]12)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH:26]1([N:13]2[CH2:14][CH:15]([C:16]3[C:24]4[C:19](=[CH:20][C:21]([F:25])=[CH:22][CH:23]=4)[NH:18][CH:17]=3)[CH:9]3[NH:8][CH2:12][CH2:11][CH:10]23)[CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: CC(C)(C)OC(=O)N1CCC2C1C(c1c[nH]c3cc(F)ccc13)CN2C1CCCC1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Fc1ccc2c(C3CN(C4CCCC4)C4CCNC34)c[nH]c2c1
Temperature: 0 °C
Reaction time: 1 h
Yield: 93.1 %

Procedure:
A solution containing 36 (2.0 g, 4.8 mmol) in DCM (20 mL) was cooled to 0° C. TFA (6 mL) was added and the pink reaction mixture was stirred at 0° C. After 1 h, the reaction mixture was warmed to ambient temperature then concentrated in vacuo. The residue was dissolved in EtOAc and the organic solution was washed successively with saturated aqueous NaHCO3 and brine, dried over anhydrous Na2SO4, filtered, and concentrated to afford 1.4 g of 37 which was used without further purification. 1H NMR (CDCl3, 300 MHz): δ8.50 (br s, 1H), 7.58 (dd, J=5.4, 8.4 Hz, 1H), 7.05-7.01 (m, 2H), 6.92-6.85 (m, 1H), 4.17-4.11 (m, 1H), 3.92 (app q, J=6.0 Hz, 1H), 3.74 (app q, J=6.6 Hz, 1H), 3.21-3.15 (m, 1H), 3.08-2.88 (m, 3H), 2.75-2.67 (m, 2H), 1.96-1.78 (m, 5H), 1.61 (m, 4H) ppm. Mass spectrum, m/z [314.2] (M+H)+.
Reaction SMILES: [F:1][C:2]1[N:7]=[C:6]([C:8]([OH:10])=O)[CH:5]=[CH:4][CH:3]=1.CCN=C=NCCCN(C)C.Cl.[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:42])[F:41])[N:28]2[CH2:35][C:36]([NH:38][NH2:39])=O.S(Cl)(C1C=CC(C)=CC=1)(=O)=O>CC#N>[Cl:23][C:24]1[C:32]([C:33]#[N:34])=[CH:31][CH:30]=[C:29]2[C:25]=1[CH:26]=[C:27]([CH:40]([F:41])[F:42])[N:28]2[CH2:35][C:36]1[O:10][C:8]([C:6]2[CH:5]=[CH:4][CH:3]=[C:2]([F:1])[N:7]=2)=[N:39][N:38]=1
Reactant: N#Cc1ccc2c(cc(C(F)F)n2CC(=O)NN)c1Cl
Reactant: O=C(O)c1cccc(F)n1
Agent: CCN=C=NCCCN(C)C
Agent: Cc1ccc(S(=O)(=O)Cl)cc1
Agent: Cl
Solvent: CC#N
Product: N#Cc1ccc2c(cc(C(F)F)n2Cc2nnc(-c3cccc(F)n3)o2)c1Cl
Temperature: 120 °C
Reaction time: 0.08 h
Yield: 31 %

Procedure:
To a solution of 6-fluoro-2-pyridinecarboxylic acid (0.006 g, 0.043 mmol) in MeCN (2 mL), under N2, was added EDCl (0.0085 g, 0.044 mmol). After 5 min, 2-[4-chloro-5-cyano-2-(difluoromethyl)-1H-indol-1-yl]acetohydrazide (0.012 g, 0.040 mmol) was added. After 1 h, additional 6-fluoro-2-pyridinecarboxylic acid (0.003 g, 0.02 mmol) and EDCl (0.0077 g, 0.040 mmol) were added. After another 15 min, additional 6-fluoro-2-pyridinecarboxylic acid (0.0014 g, 0.01 mmol) and EDCl (0.0046 g, 0.02 mmol) were added. After another 10 min, TsCl (0.009 g, 0.048 mmol) and P-BEMP (loading 2.2 mmol/g, 0.073 g, 0.16 mmol) were added and the mixture was heated at 120° C. for 20 min. Upon cooling, additional TsCl (0.0046 g, 0.024 mmol) and P-BEMP (0.037 g, 0.08 mmol) were added and the mixture was heated at 120° C. for another 20 min. Upon cooling, the resin was filtered off, washed with EtOAc and the filtrate was concentrated in vacuo. The residue was purified by flash chromatography (0-50% EtOAc-hexanes gradient) and the product was crystallized from CH2Cl2-hexanes to give the title compound as a white solid (0.005 g, 31% yield): MS (ES) m/z 404 (M+1).
Reaction SMILES: [CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](\[C:25]2[CH:30]=[CH:29][C:28](I)=[CH:27][CH:26]=2)/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7].[C:32]([C:34]1[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=1)#[CH:33]>O1CCCC1.C(N(CC)CC)C.[Pd].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cu]I>[CH3:1][C:2]1[CH:13]=[C:12]([O:14][CH2:15]/[CH:16]=[C:17](/[C:18]2[CH:23]=[CH:22][C:21]([CH3:24])=[CH:20][CH:19]=2)\[C:25]2[CH:26]=[CH:27][C:28]([C:33]#[C:32][C:34]3[CH:39]=[CH:38][CH:37]=[CH:36][N:35]=3)=[CH:29][CH:30]=2)[CH:11]=[CH:10][C:3]=1[O:4][CH2:5][C:6]([O:8][CH3:9])=[O:7]
Reactant: C#Cc1ccccn1
Reactant: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(I)cc2)cc1C
Agent: [Cu]I
Agent: [Pd]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)COc1ccc(OC/C=C(/c2ccc(C)cc2)c2ccc(C#Cc3ccccn3)cc2)cc1C
Temperature: 25 °C
Reaction time: 48 h

Procedure:
A solution of methyl (Z)-[2-methyl-4-[3-(4-iodophenyl)-3-(4-methylphenyl)allyloxy]-phenoxy]acetate (310 mg, 0.587 mmol; example 3) in a mixture of tetrahydrofuran (9 mL) and triethylamine (9 mL) was degassed and 2-ethynylpyridine (121 mg, 1.17 mmol) was added in argon atmosphere. The solution was cooled down; tetrakis(triphenylphosphine)-palladium (55 mg, 0.047 mmol) and copper(I) iodide (17.8 mg, 0.094 mmol) were added. The reaction mixture was stirred at ambient temperature for 48 h, then evaporated in vacuo and the residue was dissolved in ethyl acetate (20 mL). The solution was washed with water (3×15 mL), dried with anhydrous magnesium sulphate and evaporated in vacuo. The residue was purified by flash column chromatography (silica gel Fluka 60, hexanes/ethyl acetate 7:3) yielding methyl (Z)-[2-methyl-4-[3-(4-methylphenyl)-3-[4-(pyridin-2-ylethynyl)phenyl]allyloxy]-phenoxy]acetate.
Reaction SMILES: [NH2:1][C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([CH3:10])[N:3]=1.[S:11]1[CH:15]=[CH:14][CH:13]=[C:12]1[S:16]([N:19]=[C:20]=[O:21])(=[O:18])=[O:17]>C(#N)C>[CH3:9][O:8][C:6]1[N:5]=[C:4]([CH3:10])[N:3]=[C:2]([NH:1][C:20]([NH:19][S:16]([C:12]2[S:11][CH:15]=[CH:14][CH:13]=2)(=[O:17])=[O:18])=[O:21])[N:7]=1
Reactant: COc1nc(C)nc(N)n1
Reactant: O=C=NS(=O)(=O)c1cccs1
Solvent: CC#N
Product: COc1nc(C)nc(NC(=O)NS(=O)(=O)c2cccs2)n1
Reaction time: 6 h

Procedure:
To a suspension of 14.0 g of 2-amino-4-methoxy-6-methyl-1,3,5-triazine in 300 ml. of acetonitrile was added, dropwise, 19 g of thiophene-2-sulfonyl isocyanate. After stirring for six hours, the mixture was filtered to yield the desired solid product melting at 182°-184° C.
Reaction SMILES: C1N=C[N:3](C(N2C=NC=C2)=O)C=1.[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:24]([OH:26])=O)[C:22]=1[F:23])[NH:19][CH:18]=[CH:17]2>C(Cl)Cl>[Br:13][C:14]1[CH:15]=[C:16]2[C:20](=[C:21]([C:24]([NH2:3])=[O:26])[C:22]=1[F:23])[NH:19][CH:18]=[CH:17]2
Reactant: O=C(n1ccnc1)n1ccnc1
Reactant: O=C(O)c1c(F)c(Br)cc2cc[nH]c12
Solvent: ClCCl
Product: NC(=O)c1c(F)c(Br)cc2cc[nH]c12
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (0.7 g, 4.3 mmol) was added in portions to a stirred solution/suspension of 5-bromo-6-fluoro-1H-indole-7-carboxylic acid (1.0 g, 3.9 mmol) in DCM (20 mL). The mixture was stirred at room temperature for 1 hour and then heated at reflux for 30 min. The mixture was cooled in ice, and NH3 gas was bubbled through the solution for 30 min. The reaction mixture stirred at room temperature overnight. The resulting solid was filtered off and triturated sequentially with water, ether and IPA giving 260 mg (26%) of the title compound as a brown solid.
Reaction SMILES: F[C:2]1[CH:11]=[C:10]2[C:5]([NH:6][C:7](=[O:13])[C:8](=[O:12])[NH:9]2)=[CH:4][C:3]=1[N+:14]([O-:16])=[O:15].[Cl:17][C:18]1[CH:19]=[N:20][CH:21]=[CH:22][C:23]=1[OH:24].[OH-].[K+].Cl>CS(C)=O>[N+:14]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:2]=1[N:20]1[CH:21]=[CH:22][C:23](=[O:24])[C:18]([Cl:17])=[CH:19]1)[NH:9][C:8](=[O:12])[C:7](=[O:13])[NH:6]2)([O-:16])=[O:15]
Reactant: O=c1[nH]c2cc(F)c([N+](=O)[O-])cc2[nH]c1=O
Reactant: Oc1ccncc1Cl
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: O=c1ccn(-c2cc3[nH]c(=O)c(=O)[nH]c3cc2[N+](=O)[O-])cc1Cl
Temperature: 0 °C
Yield: 94.7 %

Procedure:
First, 267 mg of 7-fluoro-6-nitro-1,4-dihydroquinoxaline-2,3-dione, 171 mg of 3-chloro-4-hydroxypyridine, and 92 mg of powdered potassium hydroxide were added to 3 ml of dry dimethylsulfoxide. The mixture was allowed to react at 130° C. for 80 minutes in a nitrogen atmosphere. Ice water and 4N hydrochloric acid were then added to the reaction mixture so as to adjust its pH to about 2. The resultant yellow precipitate was filtered and washed with water. The precipitate was recrystallized with a mixture of dimethylformaldehyde and water to give 376 mg of yellowish white 6-nitro-7-(3-chloro-4-oxo-4H-pyridin-1-yl)-1,4-dihydroquinoxaline-2,3-dione.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([S:10](Cl)(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].C(OC(C)C)(=O)C.[F:21][CH:22]([F:25])[CH2:23][OH:24].C(N(CC)CC)C>>[N+:1]([C:4]1[CH:5]=[C:6]([S:10]([O:24][CH2:23][CH:22]([F:25])[F:21])(=[O:12])=[O:11])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2]
Reactant: OCC(F)F
Reactant: O=[N+]([O-])c1cccc(S(=O)(=O)Cl)c1
Solvent: CCN(CC)CC
Solvent: CC(=O)OC(C)C
Product: O=[N+]([O-])c1cccc(S(=O)(=O)OCC(F)F)c1
Temperature: 2.5 °C
Yield: 97.4 %

Procedure:
194 g 3-nitro-benzenesulfonyl chloride (1.13 equiv.) were charged in the reaction vessel followed by 1.3 l isopropyl acetate and the solution was cooled to 0-5° C. A solution of 65 g 2,2-difluoroethanol (753 mmol, 1 equiv.), 163 ml triethylamine (1.55 equiv.) and 325 ml isopropyl acetate was added dropwise over 30 min, keeping the temperature between 0-5° C. After 4 h reaction (HPLC in process control), the reaction mixture was washed with 650 ml water. The water phase was re-extracted with 650 ml isopropyl acetate. The organic phases were washed with 650 ml 1M HClaq and 650 ml 10% NaClaq solution. The organic phases were combined, dried over MgSO4, filtered and concentrated to dryness under reduced pressure to give 196 g 2,2-difluoroethyl 3-nitrobenzenesulfonate (97% yield) as a viscous oil which crystallized on standing. The product can also be crystallized from isopropanol (seeding at 30° C., concentration: ca 13 L/kg product).
Reaction SMILES: [C:1](Cl)(Cl)=[O:2].[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[C:15]([NH2:27])[CH:14]=1)=[O:12]>C1(C)C=CC=CC=1>[N:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[C:11]([C:13]1[CH:18]=[CH:17][C:16]([O:19][CH2:20][C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=2)=[C:15]([N:27]=[C:1]=[O:2])[CH:14]=1)=[O:12]
Reactant: O=C(Cl)Cl
Reactant: Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1
Solvent: Cc1ccccc1
Product: O=C=Nc1cc(C(=O)c2ccccn2)ccc1OCc1ccccc1

Procedure:
A stirred solution of 40 g (0.41 mol) of phosgene in 150 ml of toluene is held at 25° C while a mixture of (52.5 mmol) of 3-amino-4-benzyloxyphenyl 2-pyridyl ketone and 300 ml of toluene is added slowly. The mixture is refluxed for 30 minutes and then is concentrated to give 4-benzyloxy-3-isocyanatophenyl 2-pyridyl ketone.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=1[NH2:8].[CH3:12][N:13]1[CH2:18][CH2:17][NH:16][CH2:15][CH2:14]1>CCOC(C)=O.O>[CH3:12][N:13]1[CH2:18][CH2:17][N:16]([C:2]2[CH:3]=[N:4][CH:5]=[C:6]([N+:9]([O-:11])=[O:10])[C:7]=2[NH2:8])[CH2:15][CH2:14]1
Reactant: CN1CCNCC1
Reactant: Nc1c(Br)cncc1[N+](=O)[O-]
Solvent: O
Solvent: CCOC(C)=O
Product: CN1CCN(c2cncc([N+](=O)[O-])c2N)CC1
Yield: 56.9 %

Procedure:
A solution of 3-bromo-5-nitropyridin-4-amine (LXIX) (618 mg, 2.83 mmol) in 1-methylpiperazine (1 mL, 8.51 mmol) was heated at 140° C. overnight. The reaction was poured into an EtOAc/H2O mixture; the organic layer was separated, dried over MgSO4 and concentrated under vacuum. The crude product was purified on a silica gel column (100% CHCl3→3:97 MeOH(7N NH3):CHCl3) to give 3-(4-methylpiperazin-1-yl)-5-nitropyridin-4-amine (CXVII) as a yellow solid (382 mg, 1.61 mmol, 56.7% yield). 1H NMR (CDCl3, 500 MHz) δ ppm 2.20 (s, 3H), 2.35-2.37 (m, 4H), 4.52-3.54 (m, 4H), 5.96 (s, 1H), 7.42 (s, 2H), 8.78 (s, 1H); ESIMS found C10H15N5O2 m/z 238 (M+H).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]1[N:12]=[CH:11][C:10]([C:13]([OH:15])=O)=[CH:9][N:8]=1.O[N:17]1[C:21]2[CH:22]=[CH:23][CH:24]=[CH:25][C:20]=2N=N1.C1CCC(N=C=NC2CCCCC2)CC1.NC1C=CC=CC=1.C(O)C(N)(CO)CO>CN(C=O)C>[C:21]1([NH:17][C:13]([C:10]2[CH:11]=[N:12][C:7]([C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][N:1]=3)=[N:8][CH:9]=2)=[O:15])[CH:22]=[CH:23][CH:24]=[CH:25][CH:20]=1
Reactant: O=C(O)c1cnc(-c2ccccn2)nc1
Reactant: On1nnc2ccccc21
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: NC(CO)(CO)CO
Solvent: CN(C)C=O
Solvent: Nc1ccccc1
Product: O=C(Nc1ccccc1)c1cnc(-c2ccccn2)nc1
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 23 %

Procedure:
A mixture of 2-pyridin-2-yl-pyrimidine-5-carboxylic acid (100 mg, 0.5 mmol, prepared according to the general procedure described in Example 2, steps 1 and 2), 1-hydroxybenzotriazole (76.1 mg, 0.56 mmol) and PS-DCC (518 mg, 1.28 mmol/g, 0.66 mmol) in 8 mL of DMF is shaken at room temperature for 15 minutes, and aniline (31 mg, 0.33 mmol) is added. After shaking at room temperature for 18 hours, PS-trisamine (400 mg, 3.75 mmol/g, 1.5 mmol) is added and the mixture is continually shaken at room temperature for 18 hours. The solid is filtered and washed with DCM. The filtrate is concentrated to yield 2-pyridin-2-yl-pyrimidine-5-carboxylic acid phenylamide (21 mg, 23%) as a solid. MS: 277 (M+H).