Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([CH:7]=[N:8][OH:9])=[CH:5][CH:4]=1.[N:12]1([CH2:17][C:18](=[CH2:23])[C:19]([O:21]C)=[O:20])[CH:16]=[N:15][CH:14]=[N:13]1>C(Cl)Cl>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:6]([C:7]2[CH2:23][C:18]([C:19]([OH:21])=[O:20])([CH2:17][N:12]3[CH:16]=[N:15][CH:14]=[N:13]3)[O:9][N:8]=2)=[CH:5][CH:4]=1
Reactant: COc1ccc(C=NO)cc1
Reactant: C=C(Cn1cncn1)C(=O)OC
Solvent: ClCCl
Product: COc1ccc(C2=NOC(Cn3cncn3)(C(=O)O)C2)cc1
Temperature: 25 °C
Reaction time: 12 h
Yield: 66 %

Procedure:
4-Methoxybenzaldehyde oxime (1.63, g, 10.8 mmol) and methyl 2-(1,2,4-triazol-1-ylmethyl)acrylate. (1.50 g, 8.97 mol) were added together with 100 mL of CH2Cl2. To the above mixture was added bleach (23 mL of 0.67M aqueous solution) dropwise at room temperature. The reaction mixture was then stirred at RT under N2 for 12 h. The mixture was diluted with CH2Cl2 and washed with water and brine, It was dried over MgSO4, concentrated, and chromatographed with 30-100% EtOAc in CH2Cl2 on silica gel to give 1.81 g of the desired product (66%).
Reaction SMILES: [CH2:1]([OH:17])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]CCCCCCCCCC.C1([CH2:24][CH2:25][CH2:26][C:27]([O-])=[O:28])C=CC=CC=1>>[C:1]1([O:17][C:27](=[O:28])[CH2:26][CH2:25][CH3:24])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: CCCCCCCCCCCCCCCCO
Reactant: O=C([O-])CCCc1ccccc1
Product: CCCC(=O)Oc1ccccc1
Temperature: 70 °C
Reaction time: 1 h

Procedure:
65 g of white petrolatum (Riedel-de Haen), 15 g of cetyl alcohol (Riedel-de Haen), 260 g of soft paraffin (Merck), 155 g of liquid paraffin (Merck), and 5 g of 4-phenylbutyrate (Merck) were mixed in a beaker and heated at 70° C. to form a paste. The paste was stirred at 400 rpm for 1 hour, and then cooled at room temperature.
Reaction SMILES: C([O:4][C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[F:11])C=C.F[C:13]1[CH:18]=CC=C[C:14]=1O.C(Br)C=C>CCOCC>[CH2:18]([C:10]1[C:5]([OH:4])=[C:6]([F:11])[CH:7]=[CH:8][CH:9]=1)[CH:13]=[CH2:14]
Reactant: C=CCOc1ccccc1F
Reactant: Oc1ccccc1F
Solvent: CCOCC
Solvent: C=CCBr
Product: C=CCc1cccc(F)c1O
Yield: 80 %

Procedure:
Other workers have prepared o-fluorophenyl allyl ether in a 90.5-93% yield from o-fluorophenol and allyl bromide. Thereafter using a thermal Claisen rearrangement of the ether gave 6-allyl-2-fluorophenol in an 80% yield. However, attempts to oxidize this last named compound to 3-fluorosalicylaldehyde using dichromate solutions gave no reproducible results, i.e., a 55% yield from the first experiment but less than 5% in subsequent runs.
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][CH2:11][CH2:12][C:13](=O)[CH3:14])=[CH:6][CH:5]=1)([O-:3])=[O:2].Cl.[CH2:17]([NH2:19])[CH3:18].C([BH3-])#N.[Na+].Cl>CO>[CH2:17]([NH:19][CH:13]([CH3:14])[CH2:12][CH2:11][CH2:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1)[CH3:18]
Reactant: CC(=O)CCCc1ccc([N+](=O)[O-])cc1
Reactant: CCN
Agent: Cl
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Product: CCNC(C)CCCc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 89.9 %

Procedure:
A 300 ml round bottom flask fitted with a calcium sulfate drying tube was charged with 6.681 g (0.0322 mol) of 5-(4-nitrophenyl)-2-pentanone in 100 ml of methanol. This mixture was charged with 13.2 g (0.161 mol) of ethylamine hydrochloride and 2.03 g (0.0322 mol) of sodium cyanoborohydride. The resulting suspension was stirred at room temperature over the weekend (about 72 hours) and acidified with concentrated hydrochloric acid. The volatiles were evaporated under reduced pressure and 300 ml of water was added to the residue. The mixture was extracted twice with diethyl ether and the organic phase was washed with water and a saturated sodium chloride solution. The organic phase was dried over anhydrous sodium sulfate and evaporated to dryness. This material was discarded. The aqueous phase was basified with 5N sodium hydroxide and extracted three times with diethyl ether. The organic extracts were combined, washed with saturated sodium chloride solution and dried over anhydrous sodium sulfate. Evaporation of the solvent afforded 6.838 g of N-ethyl-α-methyl-4-nitrobenzenebutanamine.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([CH:9]=[C:10]([O:12][CH3:13])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6].[H-].[Na+].Br[CH2:17][CH2:18][O:19][CH3:20]>CN(C=O)C>[CH3:13][O:12][C:10]1[CH:9]=[C:4]([CH:3]=[C:2]([O:1][CH2:17][CH2:18][O:19][CH3:20])[CH:11]=1)[C:5]([O:7][CH3:8])=[O:6]
Reactant: COCCBr
Reactant: COC(=O)c1cc(O)cc(OC)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1cc(OC)cc(C(=O)OC)c1
Temperature: 0 °C
Yield: 77.1 %

Procedure:
To a solution of methyl 3-hydroxy-5-methoxybenzoate (Example 1, step i, 0.5 g, 2.7 mmol) in DMF (10 ml) was added NaH (0.2 g, 5.4 mmol) at 0 under a nitrogen atmosphere. After stirring for minutes, 1-bromo-2-methoxy-ethane (0.75 g, 5.4 mmol) was added and the reaction mixture was stirred at 50 for 1 hour. The solution was poured into 100 ml ice water and extracted with ethyl acetate. The organic layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to give methyl 3-methoxy-5-(2-methoxyethoxy)benzoate (0.5 g). The crude product was used in the next step without further purification.
Reaction SMILES: C([O:8][C:9](=[O:32])[C@@H:10]1[CH2:14][CH2:13][CH2:12][N:11]1[C:15](=[O:31])[CH:16]([CH2:27][CH:28]([CH3:30])[CH3:29])[NH:17][S:18]([C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)(=[O:20])=[O:19])C1C=CC=CC=1.[H][H]>CO.[C].[Pd]>[C:21]1([S:18]([NH:17][CH:16]([C:15]([N:11]2[CH2:12][CH2:13][CH2:14][C@H:10]2[C:9]([OH:32])=[O:8])=[O:31])[CH2:27][CH:28]([CH3:30])[CH3:29])(=[O:20])=[O:19])[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1
Reactant: CC(C)CC(NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CO
Product: CC(C)CC(NS(=O)(=O)c1ccccc1)C(=O)N1CCC[C@H]1C(=O)O
Yield: 99.6 %

Procedure:
N-benzenesulfonyl-D,L-leucyl-L-proline benzyl ester (2 g) was dissolved in methanol (40 ml), and 10% palladium-carbon (200 mg) was added. The resulting mixture aerated with hydrogen was allowed to react at room temperature for 3 h, filtered and concentrated under reduced pressure to remove the solvent to give a white foam-like solid (1.6 g, 99%), which was directly used for the next reaction.
Reaction SMILES: [C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([O:19]C)=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:5]=1)(=[O:3])[NH2:2].CO.[OH-].[Na+].Cl>C1COCC1>[C:1]([C:4]1[C:9]2[NH:10][C:11]3[CH:12]=[C:13]([C:17]([OH:19])=[O:18])[CH:14]=[CH:15][C:16]=3[C:8]=2[N:7]=[C:6]([C:21]2[CH:26]=[CH:25][C:24]([O:27][CH3:28])=[C:23]([F:29])[CH:22]=2)[CH:5]=1)(=[O:3])[NH2:2]
Reactant: COC(=O)c1ccc2c(c1)[nH]c1c(C(N)=O)cc(-c3ccc(OC)c(F)c3)nc12
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccc(-c2cc(C(N)=O)c3[nH]c4cc(C(=O)O)ccc4c3n2)cc1F
Temperature: 25 °C
Reaction time: 24 h
Yield: 97.1 %

Procedure:
A solution of methyl 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylate (75 mg, 0.19 mmol) in a mixture of THF (3 ml), MeOH (1 ml) and 1 N aqueous sodium hydroxide (3.0 ml, 3.0 mmol) was stirred at room temperature for 24 hr. This was neutralized with 1 N aqueous HCl and the organic solvents were removed on the rotary evaporator. The residue was dissolved in water and acidified to about pH 3 with 1 N aqueous HCl. The mixture was chilled in an ice bath and the precipitate was collected by filtration and dried to give 4-carbamoyl-2-(3-fluoro-4-methoxyphenyl)-5H-pyrido[3,2-b]indole-7-carboxylic acid (70 mg) as a yellow solid. MS (ESI) m/z 380.0 (M+H). 1H NMR (DMSO-d6) δ ppm 11.87 (1H, s), 8.64 (1H, br. s.), 8.50 (1H, s), 8.41 (1H, s), 8.36 (1H, d, J=7.93 Hz), 8.11-8.21 (2H, m), 7.96(1H, br. s.), 7.87 (1H, d, J=8.24 Hz), 7.36 (1H, t, J=8.85 Hz), 3.95 (3H, s).
Reaction SMILES: C([NH:4][C:5]1[CH:34]=[CH:33][C:8]([O:9][C:10]2[C:18]([S:19](=[O:25])(=[O:24])[NH:20]C(=O)C)=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:26][CH2:27][C:28]2[O:32][CH:31]=[CH:30][CH:29]=2)=[CH:7][CH:6]=1)(=O)C.[OH-].[Na+]>>[NH2:4][C:5]1[CH:6]=[CH:7][C:8]([O:9][C:10]2[C:18]([S:19](=[O:24])(=[O:25])[NH2:20])=[CH:17][C:13]([C:14]([OH:16])=[O:15])=[CH:12][C:11]=2[NH:26][CH2:27][C:28]2[O:32][CH:31]=[CH:30][CH:29]=2)=[CH:33][CH:34]=1
Reactant: CC(=O)Nc1ccc(Oc2c(NCc3ccco3)cc(C(=O)O)cc2S(=O)(=O)NC(C)=O)cc1
Agent: [Na+]
Agent: [OH-]
Product: Nc1ccc(Oc2c(NCc3ccco3)cc(C(=O)O)cc2S(N)(=O)=O)cc1
Temperature: 25 °C

Procedure:
The mixture of 1.1 g of 4-(4-acetamidophenoxy)-3-furfurylamino-5-acetylsulfamoylbenzoic acid and 11 ml of 2N aqueous sodium hydroxide is refluxed for two hours under nitrogen. After cooling to room temperature it is filtered, the filtrate acidified with glacial acetic acid to a pH of 4- 5 and the precipitate formed filtered off. It is recrystallized from 70% aqueous ethanol, to yield the 4-(4-aminophenoxy)-3-furfurylamino-5-sulfamoylbenzoic acid melting at 233°-235°.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1.[C:9]([Si:11]([CH3:14])([CH3:13])[CH3:12])#[CH:10]>Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[CH3:12][Si:11]([CH3:14])([CH3:13])[C:9]#[C:10][C:2]1[CH:3]=[C:4]([NH2:8])[CH:5]=[N:6][CH:7]=1
Reactant: C#C[Si](C)(C)C
Reactant: Nc1cncc(Br)c1
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Product: C[Si](C)(C)C#Cc1cncc(N)c1
Reaction time: 0.08 h
Yield: 27 %

Procedure:
5-Bromopyridin-3-amine (0.94 g, 5.43 mmol), PdCl2(PPh3)2 (0.076 g, 0.109 mmol) and ethynyltrimethylsilane (0.64 g, 6.52 mmol) were combined in TEA (12.0 mL). After stirring for 5 min, CuI (0.010 g, 0.054 mmol) was added. The reaction mixture was flushed with N2 and stirred at RT overnight, followed by at 55° C. overnight. The reaction was filtered and the solid was washed with EtOAc (30 mL). The combined organics were concentrated in vacuo and purified by chromatography to afford 5-(2-(trimethylsilyl)ethynyl)pyridin-3-amine (0.279 g, 27% yield) as a white solid. MS (ESI) m/z: 191.1 (M+H+).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([C:14]2[O:15][C:16](=[O:26])[C:17]3[N:23]=[C:22]([Cl:24])[CH:21]=[C:20]([CH3:25])[C:18]=3[N:19]=2)[N:5]([C:7]2[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=2)[N:6]=1.[CH3:27][O:28][C:29]([N:31]([CH3:33])[NH2:32])=[O:30]>CN(C=O)C>[CH3:27][O:28][C:29]([N:31]([CH3:33])[NH:32][C:16]([C:17]1[C:18]([NH:19][C:14]([C:4]2[N:5]([C:7]3[C:12]([Cl:13])=[CH:11][CH:10]=[CH:9][N:8]=3)[N:6]=[C:2]([Br:1])[CH:3]=2)=[O:15])=[C:20]([CH3:25])[CH:21]=[C:22]([Cl:24])[N:23]=1)=[O:26])=[O:30]
Reactant: COC(=O)N(C)N
Reactant: Cc1cc(Cl)nc2c(=O)oc(-c3cc(Br)nn3-c3ncccc3Cl)nc12
Solvent: CN(C)C=O
Product: COC(=O)N(C)NC(=O)c1nc(Cl)cc(C)c1NC(=O)c1cc(Br)nn1-c1ncccc1Cl
Temperature: 80 °C
Reaction time: 3 h
Yield: 65.1 %

Procedure:
2-[5-Bromo-2-(3-chloro-pyridin-2-yl)-2H-pyrazol-3-yl]-6-chloro-8-methyl-pyrido[3,2-d][1,3]oxazin-4-one (140 mg) (example 7, step 4) was dissolved in DMF (10 mL) and N-methyl-hydrazinecarboxylic acid methyl ester (161 mg) was added. The solution was stirred for 3 hours at 80° C., then 12 hours at room temperature and again for 3.5 hours at 80° C. The reaction mixture was quenched was diluted with MTB-ether and washed 4× with water, washed with brine, dried over MgSO4 and concentrated in vacuum. The residue was purified by column chromatography (hexane/ethyl acetate=2:1, then 1.5:1, Rf=0.15 in hexane/ethyl acetate=2:1) to afford 112 mg of compound 8 of the present invention of the formula
Reaction SMILES: Br[C:2]1[C:3]([C:8]2[O:9][CH2:10][C:11]([CH3:14])([CH3:13])[N:12]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[Na].[CH3:16][O:17][C:18]1[CH:25]=[CH:24][C:21]([CH2:22][SH:23])=[CH:20][CH:19]=1>>[CH3:13][C:11]1([CH3:14])[CH2:10][O:9][C:8]([C:3]2[C:2]([S:23][CH2:22][C:21]3[CH:24]=[CH:25][C:18]([O:17][CH3:16])=[CH:19][CH:20]=3)=[CH:7][CH:6]=[CH:5][N:4]=2)=[N:12]1
Reactant: CC1(C)COC(c2ncccc2Br)=N1
Reactant: COc1ccc(CS)cc1
Agent: [Na]
Product: COc1ccc(CSc2cccnc2C2=NC(C)(C)CO2)cc1

Procedure:
The above prepared 3-bromo-2-(4,4-dimethyl-2-oxazolinyl)pyridine is reacted with the sodium salt of p-methoxybenzyl mercaptan by the procedure of Example 1 to give 2-(4,4-dimethyl-2-oxazolinyl)-3-(p-methoxybenzylthio)pyridine.
Reaction SMILES: O[C:2]1([C:22]2[CH:27]=[CH:26][C:25]3[O:28][CH2:29][O:30][C:24]=3[CH:23]=2)[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[C:4]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[C:3]1[C:17]([O:19]CC)=[O:18].C([SiH](CC)CC)C.B(F)(F)F.CCOCC.Cl>C(Cl)Cl>[CH2:29]1[O:28][C:25]2[CH:26]=[CH:27][C:22]([CH:2]3[C:10]4[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=4)[CH:4]([C:11]4[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=4)[CH:3]3[C:17]([OH:19])=[O:18])=[CH:23][C:24]=2[O:30]1
Reactant: CCOC(=O)C1=C(c2ccccc2)c2ccccc2C1(O)c1ccc2c(c1)OCO2
Agent: CC[SiH](CC)CC
Agent: Cl
Agent: FB(F)F
Solvent: CCOCC
Solvent: ClCCl
Product: O=C(O)C1C(c2ccccc2)c2ccccc2C1c1ccc2c(c1)OCO2
Reaction time: 0.25 h
Yield: 108.2 %

Procedure:
To a solution of ethyl (1RS)-1-hydroxy-1-(3,4-methylenedioxyphenyl)-3-phenylindene-2-carboxylate (1.03 g, 2.58 mmol) in CH2Cl2 (40 mL) was added triethylsilane (0.49 ml, 3.07 mmol), followed by boron trifluoride etherate (1.55 ml, 12.6 mmol). The reaction mixture was allowed to stir for 15 min, at which time was added slowly 3M HCl. The mixture was extracted with EtOAc. The organic extract was washed successively with H2O, 5% aqueous NaHCO3 and saturated aqueous NaCl. The solvent was removed in vacuo to provide the title compound (1.00 g, 100%) as a mixture of Δ1 and Δ2 double bond isomers.
Reaction SMILES: C(O[C:5](=[O:7])[CH3:6])(=O)C.[C:8]([C:10]1[CH:15]=[CH:14][C:13]([C:16]([F:19])([F:18])[F:17])=[CH:12][C:11]=1[N:20]=[N:21][NH:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]#[N:34])#[N:9].N1C=CC=CC=1>O>[C:5]([N:20]([C:11]1[CH:12]=[C:13]([C:16]([F:17])([F:18])[F:19])[CH:14]=[CH:15][C:10]=1[C:8]#[N:9])[N:21]=[N:22][C:23]1[CH:28]=[C:27]([C:29]([F:32])([F:31])[F:30])[CH:26]=[CH:25][C:24]=1[C:33]#[N:34])(=[O:7])[CH3:6]
Reactant: CC(=O)OC(C)=O
Reactant: N#Cc1ccc(C(F)(F)F)cc1N=NNc1cc(C(F)(F)F)ccc1C#N
Solvent: O
Solvent: c1ccncc1
Product: CC(=O)N(N=Nc1cc(C(F)(F)F)ccc1C#N)c1cc(C(F)(F)F)ccc1C#N

Procedure:
Alternatively, 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene is prepared by addition of 25 ml. of acetic anhydride to a solution of 5.0 g. (0.013 mol.) of 1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene in 65 ml. of pyridine. The reaction mixture is stirred at 25° for twelve hours, then it is poured into water. The aqueous mixture is extracted with ether, the layers are separated and the ether phase is washed with water, 5% aqueous sodium bicarbonate and water, dried (MgSO4) and concentrated to give 3-acetyl-1,3-bis(2-cyano-5-trifluoromethylphenyl)triazene.
Reaction SMILES: [CH2:1]([OH:7])[C:2]1[O:6][CH:5]=[CH:4][CH:3]=1.[CH3:8][C:9]1[CH:14]=[C:13]([CH3:15])[CH:12]=[C:11]([CH3:16])[C:10]=1[CH:17]1[C:21](=[O:22])[CH:20]=[CH:19][C:18]1=[O:23].[Mg+2].[I-].[I-]>>[OH:7][CH2:1][C:2]12[O:6][CH:5]([CH:4]=[CH:3]1)[CH:19]1[CH:20]2[C:21](=[O:22])[CH:17]([C:10]2[C:11]([CH3:16])=[CH:12][C:13]([CH3:15])=[CH:14][C:9]=2[CH3:8])[C:18]1=[O:23]
Reactant: OCc1ccco1
Reactant: Cc1cc(C)c(C2C(=O)C=CC2=O)c(C)c1
Agent: [I-]
Agent: [Mg+2]
Product: Cc1cc(C)c(C2C(=O)C3C4C=CC(CO)(O4)C3C2=O)c(C)c1
Reaction time: 17 h

Procedure:
Furfuryl alcohol (4 ml, 46.7 mmol) is added to 2-(2,4,6-trimethylphenyl)cyclopent-4-ene-1,3-dione (2.0 g, 9.3 mmol) and MgI2 (520 mg, 1.86 mmol) and the reaction is stirred for 17 hours. The reaction mixture is adsorbed onto silica gel and purified by column chromatography on silica gel to give (1RS,2SR,6RS,7SR)-1-hydroxymethyl-4-(2,4,6-trimethylphenyl)-10-oxatricyclo-[5.2.1.02,6]dec-8-ene-3,5-dione.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:14]([C:15]3[CH2:19][CH2:18][CH2:17][CH:16]=3)[CH:13]3[CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:28]([O:30]C)=[O:29])[CH:25]=[CH:26][C:27]=4[C:12]3=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9].[OH-].[Na+]>CO.O1CCCC1>[Cl:1][C:2]1[CH:3]=[C:4]([N:10]2[CH:14]([C:15]3[CH2:19][CH2:18][CH2:17][CH:16]=3)[CH:13]3[CH2:20][O:21][C:22]4[CH:23]=[C:24]([C:28]([OH:30])=[O:29])[CH:25]=[CH:26][C:27]=4[C:12]3=[N:11]2)[CH:5]=[CH:6][C:7]=1[C:8]#[N:9]
Reactant: COC(=O)c1ccc2c(c1)OCC1C2=NN(c2ccc(C#N)c(Cl)c2)C1C1=CCCC1
Agent: [Na+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: N#Cc1ccc(N2N=C3c4ccc(C(=O)O)cc4OCC3C2C2=CCCC2)cc1Cl
Temperature: 25 °C
Reaction time: 20 h
Yield: 21.7 %

Procedure:
To a solution of methyl 2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylate (190 mg, 0.44 mmol) in methanol (2 mL) and tetrahydrofuran (2 mL) was added 1M aqueous sodium hydroxide (2 mL). The solution was stirred for 20 hours at ambient temperature. The resulting slurry was concentrated to half volume and acidified to pH=2 with 1M hydrochloric acid. The resulting solid was collected by vacuum filtration. The solid was treated with hot N,N-dimethylformamide and methanol to provide 2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid (yellow solid, 40 mg, 22% yield). The title compound was largely present as 3RS,3aRS)-2-(3-chloro-4-cyanophenyl)-3-cyclopentenyl-2,3,3a,4-tetrahydrochromeno[4,3-c]pyrazole-7-carboxylic acid. Reversed-phase HPLC on 4.6×50 mm C-18 column, tR=3.05 minutes (10 to 90% acetonitrile/water over 4 minutes at 4 mL/minute with detection 254 nm, at 20° C.); HRMS Calculated for C23H18ClN3O3: 420.1109 (M+H)+. Found: 420.1127; 1H NMR (400 MHz, DMSO-d6) δ ppm 1.59-1.89 (m, 2H), 2.03-2.14 (m, 2H), 2.14-2.23 (m, 2H), 3.89 (dd, J=13.02, 10.34 Hz, 1H), 4.05 (ddd, J=12.89, 10.74, 5.91 Hz, 1H), 4.67 (dd, J=10.34, 5.77 Hz, 1H), 5.51 (d, J=11.01 Hz, 1H), 5.63 (br. s., 1H), 7.00 (br. s., 1H) 7.29 (br. s., 1H), 7.43 (d, J=1.61 Hz, 1H), 7.56 (dd, J=8.19, 1.48 Hz, 1H), 7.71 (d, J=8.59 Hz, 1H), 7.94 (d, J=8.06 Hz, 1H), 13.16 (br. s., 1H).
Reaction SMILES: C(O[C:4](=[O:21])[C@H:5]([N:7]1[C:12]2[CH:13]=[C:14]([N+:17]([O-:19])=[O:18])[CH:15]=[CH:16][C:11]=2[O:10][CH2:9][C:8]1=S)[CH3:6])C.O.[NH2:23][NH2:24]>C(O)C>[CH3:6][C@@H:5]1[C:4](=[O:21])[NH:24][N:23]=[C:8]2[CH2:9][O:10][C:11]3[CH:16]=[CH:15][C:14]([N+:17]([O-:19])=[O:18])=[CH:13][C:12]=3[N:7]12
Reactant: NN
Reactant: CCOC(=O)[C@@H](C)N1C(=S)COc2ccc([N+](=O)[O-])cc21
Solvent: CCO
Solvent: O
Product: C[C@@H]1C(=O)NN=C2COc3ccc([N+](=O)[O-])cc3N21
Temperature: 25 °C
Reaction time: 16 h
Yield: 79 %

Procedure:
To a solution of (R)-2-(6-nitro-3-thioxo-2,3-dihydro-benzo[1,4]oxazin-4-yl)-propionic acid ethyl ester (150.0 g, 483.0 mmol) in ethanol (1.5 L) was added hydrazine hydrate (98%, 48.4 g, 967.0 mmol) and the reaction mixture was stirred at 25° C. for 16 h. The reaction mixture was filtered and the filter cake was washed with EtOH (3×100 mL) to give (R)-1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (100.0 g, 79%). SFC (Table 2, Method 4) Rt=3.19 min. 1H NMR (DMSO-d6, 400 MHz): δ 10.92 (s, 1H), 7.98 (d, J=2.4 Hz, 1H), 7.87 (dd, J=2.4, 8.8 Hz, 1H), 7.22 (d, J=8.8 Hz, 1H), 4.98 (q, J=6.8 Hz, 1H), 4.83-4.74 (d, J=12.8 Hz, 2H), 1.36 (d, J=6.8 Hz, 3H). The crude (R)-1-methyl-9-nitro-3,5-dihydrobenzo[5,6][1,4]oxazino[3,4-c][1,2,4]triazin-2(1H)-one (33 g, 142 mmol, e.e. =77%) was dissolved in refluxing MeOH (2.1 L) and then cooled slowly to ambient temperature. The crystals were removed by filtration and the filtrate was concentrated in vacuo to give (R)-4-methyl-6-nitro-2,10-dihydro-9-oxa-1,2,4a-triaza-phenanthren-3-one (26 g, 79%) as a yellow solid. SFC (Table 2, Method 4) Rt=3.06 min, e.e. =98%.
Reaction SMILES: CC1(C)[O:6][C@H:5]([CH2:7][OH:8])[CH2:4][O:3]1.C(N(CC)CC)C.[S:17](Cl)([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]>C(Cl)(Cl)Cl>[S:17]([O:3][CH2:4][C@@H:5]([OH:6])[CH2:7][OH:8])([C:20]1[CH:26]=[CH:25][C:23]([CH3:24])=[CH:22][CH:21]=1)(=[O:19])=[O:18]
Reactant: CC1(C)OC[C@@H](CO)O1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: Cc1ccc(S(=O)(=O)OC[C@@H](O)CO)cc1
Yield: 67.8 %

Procedure:
8.6 g of (R)-glycerol acetonide [bp.: 88°-106° C. (18 mmHg); specific rotation: [α]D25 -12.10° (c 5.64, methanol)] was dissolved in 70 ml of chloroform, and 10.0 g of triethylamine was added. With stirring and ice cooling, a solution of 13.8 g of tosyl chloride in 30 ml of chloroform was added dropwise, and the mixture was stirred overnight. The reaction mixture was washed with an aqueous solution of potassium hydrogen carbonate and water, and the solvent was evaporated. The residue (18.7 g) was dissolved in 75 ml of acetone, and 225 ml of 1N hydrochloric acid was added. The mixture was stirred at 80° C. for 30 minutes. The reaction mixture was concentrated and extracted with 450 ml of ethyl acetate. The extract was washed with water, and the solvent was evaporated. The residue was purified by silica gel column chromatography [solvent: chloroform-methanol (40:1)] to give 10.86 g (yield 67.8%) of (S)-3-tosyloxy-1,2-propanediol as colorless needles having a melting point of 57° to 60° C.
Reaction SMILES: [I:1]N1C(=O)CCC1=O.[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([CH:19]=[CH:20][N:21]=2)[CH:18]=1)=[O:12]>C(#N)C.C(OCC)(=O)C>[CH3:9][O:10][C:11]([C:13]1[C:14]([NH:23][C:24]2[CH:29]=[CH:28][C:27]([CH3:30])=[CH:26][C:25]=2[F:31])=[C:15]([F:22])[C:16]2[N:17]([C:19]([I:1])=[CH:20][N:21]=2)[CH:18]=1)=[O:12]
Reactant: COC(=O)c1cn2ccnc2c(F)c1Nc1ccc(C)cc1F
Reactant: O=C1CCC(=O)N1I
Solvent: CC#N
Solvent: CCOC(C)=O
Product: COC(=O)c1cn2c(I)cnc2c(F)c1Nc1ccc(C)cc1F
Yield: 100.7 %

Procedure:
N-iodosuccinimide (134 mg, 0.60 mmol) was added in a single portion to a solution of 8-fluoro-7-(2-fluoro-4-methylphenylamino)-imidazo[1,2-a]pyridine-6-carboxylic acid methyl ester (172 mg, 0.54 mmol) in acetonitrile (10 mL) resulting in a thick precipitate after ten minutes of stirring. The suspension was diluted with ethyl acetate, washed with NaHSO3, saturated NaHCO3, water, brine, and dried over Na2SO4. Concentration provided the desired product as a yellow solid (241 mg, 100%). MS APCI (+) m/z 444 (M+1) detected. 1H NMR (400 MHz, CD3OD) δ 8.78 (s, 1H), 7.62 (s, 1H), 6.95 (m, 3H), 4.00 (s, 3H), 2.33 (s, 3H). 19F NMR (376 MHz, CD3OD)−131.11 (s, 1F), −146.71 (s, 1F).
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18](Br)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2].[F:24][C:25]1[CH:26]=[C:27](B(O)O)[CH:28]=[CH:29][CH:30]=1>>[CH2:1]([O:3][C:4](=[O:23])[CH2:5][O:6][C:7]1[CH:12]=[CH:11][CH:10]=[C:9]([NH:13][C:14]([C:16]2[CH:21]=[CH:20][CH:19]=[C:18]([C:29]3[CH:28]=[CH:27][CH:26]=[C:25]([F:24])[CH:30]=3)[N:17]=2)=[O:15])[CH:8]=1)[CH3:2]
Reactant: OB(O)c1cccc(F)c1
Reactant: CCOC(=O)COc1cccc(NC(=O)c2cccc(Br)n2)c1
Product: CCOC(=O)COc1cccc(NC(=O)c2cccc(-c3cccc(F)c3)n2)c1

Procedure:
The pyridyl bromide (166) (100 mg, 0.26 mmol) was coupled to 3-fluoro-phenylboronic acid (34 mg, 0.24 mmol) using Method E. During this reaction, partial hydrolysis occurred. The residue was extracted using Work-up E1 to give a mixture of acid and ester, which was used without further purification.