Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:6]=[C:5]([CH3:7])[NH:4][C:3]=1/[CH:8]=[C:9]1\[C:10](=[O:25])[N:11]([C:18](N2C=CN=C2)=[O:19])[C:12]2[C:17]\1=[CH:16][CH:15]=[CH:14][CH:13]=2.[C:26]([OH:36])(=[O:35])[CH:27]=[CH:28][C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][CH:30]=1.C1C[O:40]CC1>C(N(CC)CC)C>[C:26](/[CH:27]=[CH:28]/[C:29]1[CH:30]=[CH:31][C:32]([O:40][C:18]([N:11]2[C:12]3[C:17](=[CH:16][CH:15]=[CH:14][CH:13]=3)/[C:9](=[CH:8]/[C:3]3[NH:4][C:5]([CH3:7])=[CH:6][C:2]=3[CH3:1])/[C:10]2=[O:25])=[O:19])=[CH:33][CH:34]=1)([OH:36])=[O:35]
Reactant: O=C(O)C=Cc1ccccc1
Reactant: C1CCOC1
Reactant: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)n3ccnc3)c3ccccc32)[nH]1
Solvent: CCN(CC)CC
Product: Cc1cc(C)c(/C=C2\C(=O)N(C(=O)Oc3ccc(/C=C/C(=O)O)cc3)c3ccccc32)[nH]1
Temperature: 60 °C
Reaction time: 8 h
Yield: 16 %

Procedure:
A reaction mixture of of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-1-(imidazol-1-ylcarbonyl)-1,3-dihydro-indol-2-one (165 mg, 0.5 mmol), cinnamic acid (85 mg, 0.5 mmol), and 2 drops of triethylamine in 3 mL of THF was stirred at 60° C. for 5 h and room temperature overnight and filtered. The solid was then washed with ethyl acetate and 1 N aqueous hydrogen chloride solution. The filtrate was concentrated and the residue was partitioned between ethyl acetate and water-acetic acid. The organic layer was washed with diluted sodium hydroxide solution, dried over magnesium sulfate, and concentrated. The resultant residue was suspended in warm ethyl acetate and filtered. The combined solid was then dried in a vacuum oven overnight to afford 35 mg (16%) of 3-[1-(3,5-dimethyl-1H-pyrrol-2-yl)-meth-(Z)-ylidene]-2-oxo-2,3-dihydro-indole-1-carboxylic acid 4-((E)-2-carboxy-vinyl)-phenyl ester. 1H NMR (400 MHz, DMSO-d6) δ 12.55 (s, 1H, NH-1′), 12.41 (s, br, 1H, COOH), 7.91–7.94 (m, 1H), 7.82–7.85 (m, 3H), 7.71 (s, 1H, H-vinyl), 7.65 (d, J=6.02 Hz, 1H), 7.44 (d, J=8.99 Hz, 1H), 7.24–7.26 (m, 2H), 6.57 (d, J=6.02 Hz, 1H), 6.15 (d, J=2.35 Hz, 1H, H-4′), 2.39 (s, 3H, CH3), and 2.37 (s, 3H, CH3).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([OH:26])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].Br[CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32].C([O-])([O-])=O.[Cs+].[Cs+]>CN(C=O)C.C(Cl)Cl>[C:1]([O:5][C:6]([N:8]1[CH2:14][CH2:13][CH2:12][N:11]([C:15]2[C:16]([O:26][CH2:28][CH2:29][CH2:30][C:31]([O:33][CH3:34])=[O:32])=[C:17]([CH3:25])[CH:18]=[C:19]3[C:24]=2[N:23]=[CH:22][CH:21]=[CH:20]3)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: Cc1cc2cccnc2c(N2CCCN(C(=O)OC(C)(C)C)CC2)c1O
Reactant: COC(=O)CCCBr
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Solvent: ClCCl
Product: COC(=O)CCCOc1c(C)cc2cccnc2c1N1CCCN(C(=O)OC(C)(C)C)CC1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
4-(7-Hydroxy-6-methyl-quinolin-8-yl)-[1,4]diazepane-1-carboxylic acid tert-butyl ester (1.3 g, 3.8 mmol) and methyl 4-bromobutyrate (680 mg, 3.8 mmol) were dissolved in DMF (7.5 mL). To this solution was added Cs2CO3 (3.7 g, 11.3 mmol) and reaction was stirred at room temperature for 18 h. The reaction was diluted with CH2Cl2 and washed with H2O (4×50 mL), then brine. The organic was then dried over MgSO4, filtered, and concentrated to give the crude product.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:5]=[C:4]([Cl:18])[N:3]=1.Cl.[CH3:20][O:21][CH:22]1[CH2:25][NH:24][CH2:23]1.CCN(C(C)C)C(C)C.O>CS(C)=O>[Cl:18][C:4]1[CH:5]=[C:6]([CH:8]2[CH2:13][CH2:12][N:11]([CH:14]3[CH2:17][O:16][CH2:15]3)[CH2:10][CH2:9]2)[CH:7]=[C:2]([N:24]2[CH2:25][CH:22]([O:21][CH3:20])[CH2:23]2)[N:3]=1
Reactant: COC1CNC1
Reactant: Clc1cc(C2CCN(C3COC3)CC2)cc(Cl)n1
Agent: Cl
Solvent: CS(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC1CN(c2cc(C3CCN(C4COC4)CC3)cc(Cl)n2)C1
Temperature: 100 °C
Reaction time: 16 h
Yield: 60.3 %

Procedure:
A mixture of 2,6-dichloro-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (450 mg, 1.57 mmol), 3-methoxyazetidine hydrochloride (963 mg, 7.83 mmol) and DIPEA (3 mL, 16.9 mmol) in DMSO (5 mL) was stirred at 100° C. for 16 h. The mixture was poured into water and extracted with EtOAc. The organic layer was washed with brine, dried over Na2SO4, evaporated and purified by flash column chromatography on silica gel (30% ethyl acetate in petroleum ether) to give 2-chloro-6-(3-methoxyazetidin-1-yl)-4-(1-(oxetan-3-yl)piperidin-4-yl)pyridine (320 mg, 60.3% yield). LCMS (ESI) [MH]+=337.8
Reaction SMILES: [CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10](S(C)(=O)=O)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[O:21]1[CH2:26][CH2:25][N:24]([C:27]2[CH:33]=[CH:32][C:30]([NH2:31])=[CH:29][CH:28]=2)[CH2:23][CH2:22]1.Cl.O1CCOCC1.C(=O)(O)[O-].[Na+]>O.CN1C(=O)CCC1>[CH:1]1([NH:7][C:8]2[C:13]([C:14]([NH2:16])=[O:15])=[CH:12][N:11]=[C:10]([NH:31][C:30]3[CH:29]=[CH:28][C:27]([N:24]4[CH2:25][CH2:26][O:21][CH2:22][CH2:23]4)=[CH:33][CH:32]=3)[N:9]=2)[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: CS(=O)(=O)c1ncc(C(N)=O)c(NC2CCCCC2)n1
Reactant: Nc1ccc(N2CCOCC2)cc1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN1CCCC1=O
Solvent: C1COCCO1
Product: NC(=O)c1cnc(Nc2ccc(N3CCOCC3)cc2)nc1NC1CCCCC1
Temperature: 90 °C
Reaction time: 1 h
Yield: 13.4 %

Procedure:
A 6 ml portion of NMP solution containing 303 mg of 4-cyclohexylamino-2-(methylsulfonyl)pyrimidine-5-carboxamide was mixed with 1.05 ml of 1 M n-tetrabutylammonium fluoride/THF solution, followed by stirring at 90° C. for 1 hour. Next, this was mixed with 200 mg of 4-morpholinoaniline and 2.77 ml of 4 M hydrogen chloride/1,4-dioxane solution, followed by stirring at 90° C. for 3 hours. The reaction mixture was cooled down to room temperature, diluted with water, mixed with saturated sodium bicarbonate aqueous solution and then extracted with ethyl acetate-THF mixed solution. The organic layer was washed with saturated brine, and then the solvent was evaporated and the resulting residue was purified by a silica gel column chromatography (chloroform:methanol) to obtain 54 mg of 4-cyclohexylamino-2-[(4-morpholinophenyl)amino]pyrimidine-5-carboxamide as a pale brown solid.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([NH:11][C@H:12]2[CH2:16][NH:15][C@H:14]([C:17]([O:19][CH3:20])=[O:18])[CH2:13]2)(=[O:10])=[O:9])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35](Cl)(=[O:37])=[O:36])=[CH:31][CH:30]=1>ClCCl>[Cl:28][C:29]1[CH:34]=[CH:33][C:32]([S:35]([N:15]2[CH2:16][C@H:12]([NH:11][S:8]([C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:7][CH:6]=3)(=[O:10])=[O:9])[CH2:13][C@H:14]2[C:17]([O:19][CH3:20])=[O:18])(=[O:37])=[O:36])=[CH:31][CH:30]=1
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1
Reactant: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COC(=O)[C@@H]1C[C@@H](NS(=O)(=O)c2ccc(Cl)cc2)CN1S(=O)(=O)c1ccc(Cl)cc1
Reaction time: 3 h
Yield: 74.3 %

Procedure:
To a solution of (2S,4R)-4-(4-chlorophenyl-sulfonylamino)-2-methoxycarbonylpyrrolidine (10.0 g) in dichloromethane (200 ml) were added triethylamine (4.8 ml) and 4-chlorobenzenesulfonyl chloride (6.62 g) in an ice bath and the mixture was stirred in an ice bath for 3 hours. The resulting solution was washed successively with diluted hydrochloric acid, saturated aqueous sodium bicarbonate and brine and dried over magnesium sulfate. The solvent was evaporated in vacuo to give (2S,4R)-1-(4-chlorophenylsulfonyl)-4-(4-chlorophenylsulfonylamino)-2-methoxycarbonylpyrrolidine (11.5 g).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22]([C:24]4[N:28]=[CH:27][N:26](C(C5C=CC=CC=5)(C5C=CC=CC=5)C5C=CC=CC=5)[N:25]=4)=[O:23])=[CH:17][CH:16]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4].[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].C([SiH](CC)CC)C>ClCCl>[F:58][C:59]([F:64])([F:63])[C:60]([OH:62])=[O:61].[CH2:1]([N:5]1[C:13]2[N:12]=[C:11]([CH2:14][C:15]3[CH:16]=[CH:17][C:18]([NH:21][C:22]([C:24]4[N:28]=[CH:27][NH:26][N:25]=4)=[O:23])=[CH:19][CH:20]=3)[NH:10][C:9]=2[C:8](=[O:48])[N:7]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][C:51]=2[F:56])[C:6]1=[O:57])[CH2:2][CH2:3][CH3:4]
Reactant: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4ncn(C(c5ccccc5)(c5ccccc5)c5ccccc5)n4)cc3)nc21
Agent: CC[SiH](CC)CC
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCCn1c(=O)n(Cc2ccccc2F)c(=O)c2[nH]c(Cc3ccc(NC(=O)c4nc[nH]n4)cc3)nc21
Temperature: 25 °C
Reaction time: 0.75 h
Yield: 40 %

Procedure:
A solution of 1-trityl-1H-[1,2,4]triazole-3-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide (15 mg, 0.02 mmol) in dichloromethane (1.0 mL) at 25° C. was treated with trifluoroacetic acid (1.0 mL). The resulting solution was stirred at 25° C. for 45 min. At this time, the reaction was treated with triethylsilane (0.003 mL, 0.02 mmol). This solution was stirred at 25° C. for 5 min and then was concentrated in vacuo. The resulting residue was purified by HPLC (20–90% acetonitrile/water (0.075% trifluoroacetic acid in both solvents) over 30 min). Fractions with the desired product were freeze dried to afford 1H-[1,2,4]triazole-3-carboxylic acid {4-[3-butyl-1-(2-fluoro-benzyl)-2,6-dioxo-2,3,6,7-tetrahydro-1H-purin-8-ylmethyl]-phenyl}-amide; compound with trifluoro-acetic acid (4.5 mg, 40%) as a white, fluffy solid: EI-HRMS m/e calcd for C26H25N8O3F (M+) 516.2033, found 516.2027.
Reaction SMILES: [C:1]([CH:4]1[CH2:10][CH:9]2[CH:7]([C:8]2([CH3:12])[CH3:11])[CH:6]([O:13]C)[O:5]1)(=[O:3])[CH3:2].O.S(=O)(=O)(O)O>CC(C)=O>[OH:5][CH:4]([C:1](=[O:3])[CH3:2])[CH2:10][C@@H:9]1[C:8]([CH3:12])([CH3:11])[C@@H:7]1[CH:6]=[O:13]
Reactant: COC1OC(C(C)=O)CC2C1C2(C)C
Agent: O=S(=O)(O)O
Solvent: CC(C)=O
Solvent: O
Product: CC(=O)C(O)C[C@H]1[C@@H](C=O)C1(C)C
Yield: 86 %

Procedure:
A 50-ml flask was charged with 4-acetyl-2-methoxy-7,7-dimethyl-3-oxabicyclo[4.1.0]heptane (10.1 mmol, 100% (1R,cis)), a 1:1 (v) mixture (20 ml) of water and acetone and concentrated sulphuric acid (1.5 mmol), sp. gr. 1.84. After stirring the contents of the flask for one hour at 20° C. the majority of acetone was distilled off at 1.3 kPa. The residue was extracted with two 10-ml portions of dichloromethane. The combined extract phases were washed with two 20-ml portions of a saturated aqueous solutions of sodium hydrogen carbonate and then with a 10%w aqueous solution (20 ml) of sodium chloride. The washed organic phase was dried over anhydrous magnesium sulphate and the solvent was evaporated from the dried organic phase at 1.3 kPa to leave a residue (1.6 g) containing 2-(2-hydroxy-3-oxobutyl)-3,3-dimethylcyclopropanecarbaldehyde (100% (1R,cis), yield 86%).
Reaction SMILES: [F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH:8]=[CH:9][CH:10]=1)[CH2:6]Cl.[C-:13]#[N:14].[Na+].CS(C)=O>O>[F:1][C:2]([F:12])([F:11])[C:3]1[CH:4]=[C:5]([CH2:6][C:13]#[N:14])[CH:8]=[CH:9][CH:10]=1
Reactant: [C-]#N
Reactant: FC(F)(F)c1cccc(CCl)c1
Agent: [Na+]
Solvent: O
Solvent: CS(C)=O
Product: N#CCc1cccc(C(F)(F)F)c1
Yield: 107.1 %

Procedure:
A mixture of 12.0 g (61.5 mmole) m-trifluoromethylbenzyl chloride, 9.56 g (195 mmole) sodium cyanide and 60 ml dimethylsulfoxide was heated at 50° to 80° C. for four hours and poured into water. The aqueous mixture was extracted with methylene chloride, the extracts dried over sodium sulfate and the solvent evaporated in vacuo to give 12.2 g of yellow oil which was used in the next step.
Reaction SMILES: [CH2:1]([Mg]Br)[CH3:2].[CH3:5][O:6][C:7]1[CH:8]=[C:9]([CH:12]=[CH:13][CH:14]=1)[C:10]#N.C1C[O:18]CC1.[Cl-].[NH4+]>C(OCC)C.O>[CH3:5][O:6][C:7]1[CH:8]=[C:9]([C:10](=[O:18])[CH2:1][CH3:2])[CH:12]=[CH:13][CH:14]=1
Reactant: CC[Mg]Br
Reactant: C1CCOC1
Reactant: COc1cccc(C#N)c1
Agent: [Cl-]
Agent: [NH4+]
Solvent: O
Solvent: CCOCC
Product: CCC(=O)c1cccc(OC)c1
Temperature: 40 °C
Reaction time: 8 h
Yield: 99 %

Procedure:
A solution of ethyl magnesium bromide in diethyl ether (58 ml, 3 M) was added dropwise at room temperature to a mixture of 3-methoxy benzonitrile (21.2 g, 0.159 mol) and dry THF (250 ml). When addition was complete the mixture was stirred for 1 h at room temperature, 3 h at 40° C. and finally stirred overnight at room temperature. Water (250 ml) was added followed by a saturated ammonium chloride solution (250 ml) and the mixture was stirred for 1 h at room temperature. The phases were separated and the aqueous phase was extracted with ethyl acetate (100 ml). The combined organic phases was dried over magnesium sulphate and the solvent evaporated in vacuo to give 25.9 g (99%) of 3'-methoxypropiophenone.
Reaction SMILES: [CH3:1][C:2]1[CH2:3][C@H:4]([OH:11])[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]=1[CH3:8].N1C=CC=CC=1.FC(F)(F)S(O[Si:24]([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25])(=O)=O.O>C(Cl)Cl>[Si:24]([O:11][C@@H:4]1[CH2:5][C:6]([CH3:10])([CH3:9])[C:7]([CH3:8])=[C:2]([CH3:1])[CH2:3]1)([C:27]([CH3:30])([CH3:29])[CH3:28])([CH3:26])[CH3:25]
Reactant: CC(C)(C)[Si](C)(C)OS(=O)(=O)C(F)(F)F
Reactant: CC1=C(C)C(C)(C)C[C@@H](O)C1
Solvent: O
Solvent: ClCCl
Solvent: c1ccncc1
Product: CC1=C(C)C(C)(C)C[C@@H](O[Si](C)(C)C(C)(C)C)C1
Temperature: 0 °C
Reaction time: 0.25 h

Procedure:
0.8 g (5.2 mmol) of the (1S)-3,4,5,5-tetramethyl-3-cyclohexen-1-ol obtained in Example 2B was dissolved in 5 ml of absolute methylene chloride, 0.5 ml of pyridine was added to the solution, and the mixture was cooled to 0° C. Subsequently 1.54 g (5.7 mmol) of tert-butyldimethylsilyl trifluorome-thanesulfonate were added and the mixture was stirred at 0° C. for 15 min and then poured into 10 ml of water. After extraction with 10 ml of methylene chloride, the organic phase was washed with 10 ml of 0.1 M H2SO4, 10 ml of saturated NaHCO3 solution and 10 ml of water, dried over MgSO4 and concentrated to result in 1.3 g (92% of theory) of the abovementioned product.
Reaction SMILES: [C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:33][C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26]4=[O:34])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:43]=[CH:42][C:41]([Cl:44])=[CH:40][CH:39]=1)[C:7]([O:9]CC)=[O:8])([CH3:4])([CH3:3])[CH3:2].C(I)C>N1C=CC=CC=1>[C:1]([O:5][C@@H:6]([C:12]1[C:36]([CH3:37])=[CH:35][C:15]2[N:16]=[C:17]([C:19]3[CH:24]=[CH:23][N:22]=[C:21]([N:25]4[CH2:33][C:32]5[CH:31]=[CH:30][N:29]=[CH:28][C:27]=5[C:26]4=[O:34])[CH:20]=3)[S:18][C:14]=2[C:13]=1[C:38]1[CH:39]=[CH:40][C:41]([Cl:44])=[CH:42][CH:43]=1)[C:7]([OH:9])=[O:8])([CH3:4])([CH3:2])[CH3:3]
Reactant: CCOC(=O)[C@@H](OC(C)(C)C)c1c(C)cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c1-c1ccc(Cl)cc1
Solvent: CCI
Solvent: c1ccncc1
Product: Cc1cc2nc(-c3ccnc(N4Cc5ccncc5C4=O)c3)sc2c(-c2ccc(Cl)cc2)c1[C@H](OC(C)(C)C)C(=O)O
Temperature: 170 °C

Procedure:
To a solution of (S)-ethyl 2-tert-butoxy-2-(7-(4-chlorophenyl)-5-methyl-2-(2-(3-oxo-1H-pyrrolo[3,4-c]pyridin-2(3H)-yl)pyridin-4-yl)benzo[d]thiazol-6-yl)acetate (28 mg, 0.044 mmol) in pyridine (2 mL) was added ethyl iodide (200 mg, excess). The reaction mixture was heated at 170° C. in microwave reactor for 90 minutes and the crude was concentrated and purified by reverse phase HPLC, eluting by 0-100% acetonitrile in H2O with 0.1% TFA to give the product. LCMS-ESI+: calc'd for C32H28ClN4O4S: 599.1 (M+H+); Found: 599.2 (M+H+). 1H NMR (400 MHz, CD3OD) δ: 8.80 (s, 1H), 8.58 (s, 2H), 8.18 (d, 1H), 7.57 (m, 2H), 7.50-7.43 (m, 4H), 7.33 (s, 1H), 5.14 (s, 1H), 4.68 (d, 2H), 2.33 (s, 3H), 0.90 (s, 9H).
Reaction SMILES: [Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1C(O)=O.C(Cl)(C(Cl)=O)=O.[N-:20]=[N+]=[N-].[Na+]>C(Cl)Cl.CN(C=O)C.O>[Cl:1][C:2]1[C:10]([O:11][CH3:12])=[CH:9][CH:8]=[C:7]([F:13])[C:3]=1[NH2:20]
Reactant: [N-]=[N+]=[N-]
Reactant: COc1ccc(F)c(C(=O)O)c1Cl
Agent: O=C(Cl)C(=O)Cl
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: O
Product: COc1ccc(F)c(N)c1Cl
Temperature: 25 °C
Reaction time: 1 h
Yield: 36.7 %

Procedure:
To a solution of 2-chloro-6-fluoro-3-methoxy-benzoic acid (2.7 g, 13.2 mmol, 1.0 eq) in a mixture of DCM (20 mL) and DMF (3 drops) at 0° C. was added (COCl)2 (5.0 g, 39.6 mmol, 3.0 eq) dropwise. The reaction mixture was stirred at room temperature for 1 h, and then concentrated to dryness; the residue was dissolved in acetone (20 mL) and added dropwise to a solution of NaN3 (2.6 g, 39.6 mmol, 3.0 eq) in water (15 mL) at 0° C. The reaction was stirred 1 h at 0° C., water (50 mL) was added, then the reaction heated at 70° C. overnight. The acetone was removed by distillation and the aqueous residue extracted with EtOAc. The combined organic extracts were washed with water and brine, dried (Na2SO4), filtered and evaporated in vacuo to give a residue, which was purified by column chromatography (EtOAc:petroleum ether, 0:1 to 1:30) to give the title compound as a yellow oil (0.85 g, 37%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)[C:3]=1[C:13]([NH:15][NH2:16])=[O:14].[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22](O)=O)[CH3:18]>>[CH2:17]([O:19][C:20]1[CH:28]=[CH:27][CH:26]=[CH:25][C:21]=1[C:22]1[O:14][C:13]([C:3]2[C:4]([C:7]3[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=3)=[N:5][O:6][C:2]=2[CH3:1])=[N:15][N:16]=1)[CH3:18]
Reactant: Cc1onc(-c2ccccc2)c1C(=O)NN
Reactant: CCOc1ccccc1C(=O)O
Product: CCOc1ccccc1-c1nnc(-c2c(-c3ccccc3)noc2C)o1
Yield: 42 %

Procedure:
As described for example 2, 5-methyl-3-phenyl-isoxazole-4-carboxylic acid hydrazide (200 mg, 0.92 mmol) was converted using 2-ethoxybenzoic acid instead of o-toluic acid to the title compound (SiO2, heptane:ethyl acetate=80:20 to 50:50, 135 mg, 42%) which was obtained as an off-white solid. MS: m/e=348.3 [M+H]+.
Reaction SMILES: C1N=CN(C(N2C=NC=C2)=O)C=1.[CH:13]1([C:18]([OH:20])=O)[CH2:17][CH2:16][CH2:15][CH2:14]1.Cl.[NH2:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25].C(N(CC)CC)C>CN(C=O)C>[CH:13]1([C:18]([NH:22][CH:23]([CH2:29][SH:30])[C:24]([O:26][CH2:27][CH3:28])=[O:25])=[O:20])[CH2:14][CH2:15][CH2:16][CH2:17]1
Reactant: O=C(O)C1CCCC1
Reactant: CCOC(=O)C(N)CS
Agent: Cl
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOC(=O)C(CS)NC(=O)C1CCCC1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
CDI (8.5 g) was added to a solution of cyclopentanecarboxylic acid (5.2 mL) in DMF (40 mL). The resulting mixture was stirred for 1 h and cooled in an ice bath. Ethyl 2-amino-3-mercaptopropanoate hydrochloride (8.88 g) was added, followed by triethylamine (10 mL). The resulting mixture was allowed to warm to RT and stirred overnight. The reaction was quenched with saturated sodium bicarbonate solution (50 mL) and the layers separated. The aqueous was extracted with DCM (2×100 mL). The combined organic solutions were washed with brine (100 mL), dried over sodium sulphate, filtered and evaporated. The resulting solid was purified by silica gel chromatography eluting with 4:1 to 1:1 isohexane:ethyl acetate gradient. The fractions containing product were combined and evaporated to give the subtitled compound as a white solid. Yield 7.7 g.
Reaction SMILES: [Cl:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([CH:11]=[O:12])[CH:9]=2)[O:4][CH:3]=1.Cl([O-])=[O:14].[Na+].OP([O-])(O)=O.[K+]>C1COCC1.CC(O)(C)C.O>[Cl:1][C:2]1[C:10]2[C:5](=[CH:6][N:7]=[C:8]([C:11]([OH:14])=[O:12])[CH:9]=2)[O:4][CH:3]=1
Reactant: [O-][Cl+][O-]
Reactant: O=Cc1cc2c(Cl)coc2cn1
Agent: O=P([O-])(O)O
Agent: [K+]
Agent: [Na+]
Solvent: O
Solvent: CC(C)(C)O
Solvent: C1CCOC1
Product: O=C(O)c1cc2c(Cl)coc2cn1
Temperature: 25 °C
Reaction time: 18 h
Yield: 105.9 %

Procedure:
3-Chlorofuro[2,3-c]pyridine-5-carbaldehyde (317 mg, 1.74 mmol) is dissolved in THF (10 mL)/t-BuOH (5 mL)/H2O (5 mL), treated with a single portion of sodium chlorite (592 mg, 5.24 mmol) and KH2PO4 (473 mg, 3.48 mmol) and stirred at rt for 18 h. The reaction mixture is concentrated in vacuo to dryness, suspended in water (10 μL), acidified to pH 3.5 with concentrated HCl and stirred at rt for 2 h. The resulting solid is filtered, washed with water and dried in a vacuum oven at 40° C. for 18 h to afford 364 mg of 3-chlorofuro[2,3-c]pyridine-5-carboxylic acid as a white solid. MS (EI) m/z: 197 (M+).
Reaction SMILES: Cl[CH2:2][C:3]([N:5]1[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]2[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=2)[CH2:7][C@H:6]1[CH3:20])=[O:4].[N+:21]([C:24]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:25]=1[OH:31])([O-:23])=[O:22].C(=O)([O-])[O-].[K+].[K+].[I-].[K+]>CC(=O)CC.O>[Cl:30][C:28]1[CH:27]=[CH:26][C:25]([O:31][CH2:2][C:3]([N:5]2[CH2:10][C@H:9]([CH3:11])[N:8]([CH2:12][C:13]3[CH:18]=[CH:17][C:16]([F:19])=[CH:15][CH:14]=3)[CH2:7][C@H:6]2[CH3:20])=[O:4])=[C:24]([N+:21]([O-:23])=[O:22])[CH:29]=1
Reactant: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)CCl
Reactant: O=[N+]([O-])c1cc(Cl)ccc1O
Agent: O=C([O-])[O-]
Agent: [I-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: O
Product: C[C@@H]1CN(Cc2ccc(F)cc2)[C@@H](C)CN1C(=O)COc1ccc(Cl)cc1[N+](=O)[O-]
Yield: 92.5 %

Procedure:
To a solution of 2-chloro-1-[4-(4-fluoro-benzyl)-(2R,5S)-2,5-dimethyl-piperazin-1-yl]-ethanone (1.0 g, 3.35 mmol) in butanone (35 mL) was added 2-nitro-4-chlorophenol (0.64 g, 3.69 mmol), potassium carbonate (0.93 g, 6.7mmol) and potassium iodide (0.56 g, 3.35 mmol). The reaction mixture was heated at reflux overnight. The reaction mixture was then cooled, diluted with water and extracted with ethyl acetate. The organic layer was dried over magnesium sulfate, filtered and concentrated to give an orange oil. Chromatography on silica gel gave the title compound (1.35 g).