Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([NH2:19])[CH:5]=[N:6][C:7]=1[O:8][C:9]1[CH:10]=[N:11][C:12]2[C:17]([CH:18]=1)=[CH:16][CH:15]=[CH:14][CH:13]=2.[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28](Cl)(=[O:30])=[O:29]>>[Cl:20][C:21]1[CH:26]=[C:25]([Cl:27])[CH:24]=[CH:23][C:22]=1[S:28]([NH:19][C:4]1[CH:5]=[N:6][C:7]([O:8][C:9]2[CH:10]=[N:11][C:12]3[C:17]([CH:18]=2)=[CH:16][CH:15]=[CH:14][CH:13]=3)=[C:2]([Cl:1])[CH:3]=1)(=[O:30])=[O:29]
Reactant: O=S(=O)(Cl)c1ccc(Cl)cc1Cl
Reactant: Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1
Product: O=S(=O)(Nc1cnc(Oc2cnc3ccccc3c2)c(Cl)c1)c1ccc(Cl)cc1Cl

Procedure:
The title compound was prepared by reacting 5-chloro-6-(quinolin-3-yloxy)pyridin-3-amine (obtained as per procedure described in preparation 1) and 2,4-dichlorobenzene-1-sulfonyl chloride.
Reaction SMILES: [C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[C:17]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:24]=[CH:23][C:22]3[S:21][C:20]([CH:31](C)C(O)=O)=[CH:19][C:18]2=3)[CH2:13][CH2:12]1.C[C:37]([CH3:39])=[O:38]>>[C:1]1([S:7]([OH:10])(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[NH:11]1[CH2:16][CH2:15][C:14](=[C:17]2[C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][C:25]=3[CH:24]=[CH:23][C:22]3[S:21][C:20]([CH2:31][CH2:39][C:37]([OH:8])=[O:38])=[CH:19][C:18]2=3)[CH2:13][CH2:12]1
Reactant: CC(C)=O
Reactant: CC(C(=O)O)c1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Agent: O=S(=O)(O)c1ccccc1
Product: O=C(O)CCc1cc2c(s1)C=Cc1ccccc1C2=C1CCNCC1
Temperature: 25 °C
Yield: 30 %

Procedure:
3-(4-Piperidin-4-ylidene-4H-1-thiabenzo[f]azulen-2-yl-propionic acid benzenesulfonate of 99.6% purity (1.0 g) was dissolved in acetone (50 mL) by heating and allowed to cool down to room temperature and the crystals deposited therefrom were filtered to give 0.30 g (recovery rate: 30%) of 3-(4-piperidin-4-ylidene-4H-1-thiabenzo[f]azulen-2-yl) propionic acid benzenesulfonate of 100% purity.
Reaction SMILES: F[C:2]1[CH:10]=[N:9][CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].[F:11][C:12]([F:22])([F:21])[S:13][C:14]1[CH:20]=[CH:19][C:17]([NH2:18])=[CH:16][CH:15]=1.[Li+].C[Si]([N-][Si](C)(C)C)(C)C.Cl>C1COCC1>[F:11][C:12]([S:13][C:14]1[CH:20]=[CH:19][C:17]([NH:18][C:2]2[CH:10]=[N:9][CH:8]=[CH:7][C:3]=2[C:4]([OH:6])=[O:5])=[CH:16][CH:15]=1)([F:22])[F:21]
Reactant: O=C(O)c1ccncc1F
Reactant: Nc1ccc(SC(F)(F)F)cc1
Agent: C[Si](C)(C)[N-][Si](C)(C)C
Agent: Cl
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(O)c1ccncc1Nc1ccc(SC(F)(F)F)cc1
Temperature: -78 °C
Yield: 10 %

Procedure:
3-Fluoro-isonicotinic acid (50 mg, 0.354 mmol) and 4-(trifluoromethylthio)aniline (68.5 mg, 0.354 mmol) was added to 2 ml dry THF and the mixture was cooled to −78° C. LiHMDS (1 M in THF, 1.24 ml) was added and the mixture was allowed to warm to room temperature over night. Hydrochloric acid (1 M in methanol, 5 ml) was added and the volatiles were removed in vacuo. The crude material was purified by preparative HPLC to give 11.4 mg (45 μmol; 10% yield) of pure desired product. LC-MS (method V): rt=3.09 min, m/z [M+H]+ 315.
Reaction SMILES: C[O:2][C:3]1[CH:8]=[C:7](OC)[CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([O:22]C(=O)C)[C:15]=2O.C[O:29]C1C=C(OC)C=CC=1C1C(C)=C2C(=CC(OC(=O)C)(O)C=C2)OC1=O>>[OH:2][C:3]1[C:8]([OH:29])=[CH:7][CH:6]=[CH:5][C:4]=1[C:11]1[C:12](=[O:27])[O:13][C:14]2[C:19]([C:20]=1[CH3:21])=[CH:18][CH:17]=[C:16]([OH:22])[CH:15]=2
Reactant: COc1ccc(-c2c(C)c3ccc(OC(C)=O)c(O)c3oc2=O)c(OC)c1
Reactant: COc1ccc(C2C(=O)OC3=CC(O)(OC(C)=O)C=CC3=C2C)c(OC)c1
Product: Cc1c(-c2cccc(O)c2O)c(=O)oc2cc(O)ccc12

Procedure:
The title compound was prepared according to the procedure described in Example 5 with substitution of acetic acid 3-(2,4-dimethoxyphenyl)-8-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl ester, prepared in Example 2, for acetic acid 3-(2,4-dimethoxyphenyl)-7-hydroxy-4-methyl-2-oxo-2H-chromen-7-yl ester.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=1.C(OO)(=[O:17])C>C(O)(=O)C>[F:1][C:2]1[CH:3]=[C:4]([CH:12]=[CH:13][CH:14]=1)[O:5][C:6]1[CH:7]=[N+:8]([O-:17])[CH:9]=[CH:10][CH:11]=1
Reactant: Fc1cccc(Oc2cccnc2)c1
Reactant: CC(=O)OO
Solvent: CC(=O)O
Product: [O-][n+]1cccc(Oc2cccc(F)c2)c1

Procedure:
A solution of 32 g of 3-(3-fluorophenoxy)pyridine [Fr. Pat. No. 1,472,619 (1967)] in 50 ml of glacial acetic acid is treated with 35 g of 40% peracetic acid in acetic acid and the mixture is refluxed 16 hours. The mixture is concentrated at reduced pressure and the oil is dissolved in 250 ml of dichloromethane. The dichloromethane solution is washed with excess 10% sodium hydroxide solution. The solution is dried and concentrated to dryness to yield 3-(3-fluorophenoxy)pyridine 1-oxide, m.p. 63°-66° C.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][S:5][CH2:6][C:7]1[CH:12]=[CH:11][N:10]=[CH:9][CH:8]=1.CC(C)([O-])C.[K+].CN(P(N(C)C)(N(C)C)=O)C.O>O1CCCC1.C(OCC)C>[N:10]1[CH:11]=[CH:12][C:7]([CH:6]2[CH2:2][CH2:3][CH2:4][S:5]2)=[CH:8][CH:9]=1
Reactant: ClCCCSCc1ccncc1
Agent: CC(C)(C)[O-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CN(C)P(=O)(N(C)C)N(C)C
Product: c1cc(C2CCCS2)ccn1
Temperature: 20 °C
Reaction time: 0.5 h
Yield: 70.4 %

Procedure:
A solution of pyrid-4-yl-methyl 3-chloropropyl sulphide (81 g) in anhydrous tetrahydrofuran (100 cc) is added dropwise, in the course of 20 minutes and whilst keeping the temperature below 33° C., to a solution of potassium tert.-butoxide (69.5 g) in a mixture of anhydrous hexamethylphosphorotriamide (108 cc) and anhydrous tetrahydrofuran (560 cc). The reaction mixture is then stirred for 1 hour 30 minutes at a temperature of about 20° C.; it is then run into a mixture of distilled water (1000 cc) and diethyl ether (600 cc). After decantation, the aqueous phase is extracted twice with diethyl ether (400 cc in total). The ether extracts are combined, washed three times with distilled water (3000 cc in total), dried over anhydrous sodium sulphate and filtered and the filtrate is concentrated to dryness under reduced pressure (20 mm Hg; 2.7 kPa) at 40° C. 2-(Pyrid-4-yl)-tetrahydrothiophen (46.7 g) is thus obtained in the form of a brown oil.
Reaction SMILES: [O:1]1[C:5]2([CH2:10][CH2:9][CH:8]([OH:11])[CH2:7][CH2:6]2)[O:4][CH2:3][CH2:2]1.[CH3:12][S:13](Cl)(=[O:15])=[O:14]>C(Cl)Cl>[CH3:12][S:13]([O:11][CH:8]1[CH2:9][CH2:10][C:5]2([O:4][CH2:3][CH2:2][O:1]2)[CH2:6][CH2:7]1)(=[O:15])=[O:14]
Reactant: OC1CCC2(CC1)OCCO2
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Product: CS(=O)(=O)OC1CCC2(CC1)OCCO2

Procedure:
When n is the bridging group --C(Cl)=CH--, 1,4-cyclohexanedione mono-ethylene ketal is reduced with sodium borohydride in ethanol, yielding the corresponding 1,4-dioxaspiro[4.5]decan-8-ol. The so-prepared alcohol is then treated with methanesulfonyl chloride under basic conditions in methylene chloride, affording 8-methylsulfonyloxy-1,4-dioxaspiro[4.5]decane, which is in turn treated with sodium hydride in tetrahydrofuran, and then is reacted with trimethylsilylacetylene, yielding 8-(trimethylsilylethynyl)-1,4-dioxaspiro[4.5]decane. This compound is then treated with sodium carbonate in methanol to unprotect the ethynyl moiety, affording 8-ethynyl-1,4-dioxaspiro[4.5]decane. The so-prepared ethynyl compound is reacted with an appropriately substituted or unsubstituted phenyl iodide, for example, 3,5-di(trifluoromethyl)phenyl iodide, under basic conditions in the presence of bis(triphenylphosphine)palladium(II) chloride and copper(I) iodide in acetonitrile, and then is treated with 1N hydrochloric acid, yielding the corresponding 4-(phenylethynyl)cyclohexanone. The cyclohexanone is then reacted with cyanoguanidine, as previously described, affording the 2,4-diamino-6-phenylethynyl-5,6,7,8-tetrahydroquinazoline. Chlorination of the 6-phenylethynyl-5,6,7,8-tetrahydroquinazoline, using the methods of J. Cousseau (JCS Faraday II, 1973, 1821, and JCS Perkin I, 1977, 1797), affords the targeted 2,4-diamino-6-[1-chloro-2-phenylethenyl]-5,6,7,8-tetrahydroquinazoline. Example 8 provides a detailed description of how this reaction is conducted.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH:19]CC4C=CC(OC)=CC=4OC)=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.C1(OC)C=CC=CC=1.[C:39]([OH:45])([C:41]([F:44])([F:43])[F:42])=[O:40]>C(Cl)Cl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1.[F:42][C:41]([F:44])([F:43])[C:39]([OH:45])=[O:40].[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[N:6]([C:8]([CH:11]([C:13]3[N:18]=[N:17][C:16]([NH2:19])=[CH:15][CH:14]=3)[CH3:12])=[N:9][N:10]=2)[CH:7]=1
Reactant: COc1ccc(CNc2ccc(C(C)c3nnc4ccc(Br)cn34)nn2)c(OC)c1
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CC(c1ccc(N)nn1)c1nnc2ccc(Br)cn12
Temperature: 75 °C

Procedure:
A mixture of 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)-N-(2,4-dimethoxybenzyl)pyridazin-3-amine (750 mg, 1.598 mmol), anisole (0.349 mL, 3.20 mmol), and TFA (1.0 mL, 12.98 mmol) in DCM (5.0 mL) was heated in a microwave on high absorbance for 2 hrs at 75° C. The reaction was stripped to dryness via rotary evaporation, and the resulting oil was treated with Et2O to produce a solid. The solid was filtered and dried under vacuum to provide the title compound, 6-(1-(6-bromo-[1,2,4]triazolo[4,3-a]pyridin-3-yl)ethyl)pyridazin-3-amine 2,2,2-trifluoroacetate (400 mg, 0.923 mmol, 57.8% yield) as a yellow solid. 1H NMR 48F (400 MHz, DMSO-d6) δ ppm 1.77 (d, J=7.07 Hz, 3 H) 5.05 (d, J=7.07 Hz, 1 H) 7.44 (d, J=9.60 Hz, 1 H) 7.50 (dd, J=9.73, 1.64 Hz, 1 H) 7.73-7.84 (m, 1 H) 7.92 (d, J=9.60 Hz, 1 H) 8.56 (br. s., 2 H) 8.81 (s, 1 H). ESI-MS:m/z 319.1 (M+H)+.
Reaction SMILES: N#N.[OH:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1.N1C=CN=C1.[Si:19](Cl)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20].[NH4+].[Cl-]>C1COCC1.CC(=O)OCC>[Si:19]([O:3][CH2:4][C:5]1[O:6][CH:7]=[C:8]([C:10]([O:12][CH3:13])=[O:11])[N:9]=1)([C:22]([CH3:25])([CH3:24])[CH3:23])([CH3:21])[CH3:20]
Reactant: CC(C)(C)[Si](C)(C)Cl
Reactant: COC(=O)c1coc(CO)n1
Agent: N#N
Agent: [Cl-]
Agent: [NH4+]
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)c1coc(CO[Si](C)(C)C(C)(C)C)n1
Temperature: 25 °C
Reaction time: 2.5 h

Procedure:
In a flame dried round-bottomed flask equipped with a magnetic stir bar and under inert atmosphere (N2), a solution of methyl 2-(hydroxymethyl)oxazole-4-carboxylate (12.00 g, 76.37 mmol) in THF (360 mL) was treated with imidazole (10.40 g, 152.75 mmol) followed by tert-butyldimethylsilyl chloride (23.02 g, 152.75 mmol) and the resulting mixture was stirred at rt for 2.5 h. EA (360 mL) and sat. aq. NH4Cl (360 mL) were added. The layers were separated and the aq. layer was extracted with EA (360 mL). The combined org. layers were dried over MgSO4, filtered, and the solvents were removed under reduced pressure. Purification of the residue by FC (7:3 hept-EA) gave the title compound as a white solid: TLC: rf (7:3 hept-EA)=0.44. LC-MS-conditions 06: tR=0.98 min, [M+H]+=272.38.
Reaction SMILES: [CH2:1]([CH:5]1[C:10](=O)[CH:9]([CH3:12])[CH2:8][N:7]([CH2:13][C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[CH2:6]1)[C:2]([CH3:4])=O.[CH3:20][C:21]1[CH:28]=[CH:27][C:24]([CH2:25][NH2:26])=[CH:23][CH:22]=1>>[CH2:13]([N:7]1[CH2:8][CH:9]([CH3:12])[C:10]2[N:26]([CH2:25][C:24]3[CH:27]=[CH:28][C:21]([CH3:20])=[CH:22][CH:23]=3)[C:2]([CH3:4])=[CH:1][C:5]=2[CH2:6]1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: CC(=O)CC1CN(Cc2ccccc2)CC(C)C1=O
Reactant: Cc1ccc(CN)cc1
Product: Cc1ccc(Cn2c(C)cc3c2C(C)CN(Cc2ccccc2)C3)cc1

Procedure:
Using a procedure to analogous to Example 3, 3-acetonyl-1-benzyl-5-methyl-4-piperidone may be reacted with p-methylbenzylamine to give the title compound.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([OH:15])=[CH:11][C:10]=1[CH3:16])([CH3:7])[CH3:6])[CH3:2].C([O-])([O-])=O.[Cs+].[Cs+].S(C1C=CC(C)=CC=1)(O[CH2:28][CH2:29][C:30]#[CH:31])(=O)=O>C(#N)C>[CH2:1]([O:3][C:4](=[O:17])[C:5]([O:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH2:31][CH2:30][C:29]#[CH:28])=[CH:11][C:10]=1[CH3:16])([CH3:6])[CH3:7])[CH3:2]
Reactant: C#CCCOS(=O)(=O)c1ccc(C)cc1
Reactant: CCOC(=O)C(C)(C)Oc1ccc(O)cc1C
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CC#N
Product: C#CCCOc1ccc(OC(C)(C)C(=O)OCC)c(C)c1
Temperature: 60 °C
Reaction time: 2.5 h

Procedure:
2.38 g (10.00 mmol) 2-(4-hydroxy-2-methyl-phenoxy)-2-methyl-propionic acid ethyl ester (described in WO 02/092590) and 1.63 g (5.00 mmol) Cs2CO3 were heated in 25 ml acetonitrile at reflux for 5 min. 2.34 (10.0 mmol) 3-Butynyl tosylate was added and heating was continued for 2.5 h. Then 1.63 g (5.00 mmol) Cs2CO3 and 2.34 (10.0 mmol) of 3-butynyl tosylate were added and the mixture was stirred at 60° C. (2.5 h). The temperature was raised to 95° C. and stirring continued for 12 h. Every 3 h 1.63 g (5.0 mmol) Cs2CO3 and 2.34 g (10.0 mmol) of 3-butynyl tosylate were added. The solvent was evaporated and the residue was redissolved in dichloromethane, dried (Na2SO4), filtered and evaporated. Purification by flash chromatography (SiO2, n-heptane/EtOAc 2.5%) yielded 0.67 g of the title compound as light yellow oil.
Reaction SMILES: C1CCC(N=C=NC2CCCCC2)CC1.S(O)(O)(=O)=O.[NH2:21][CH:22]([CH2:24][C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1)[CH3:23].CN1CCOCC1>CN(C=O)C.O1CCOCC1.O>[CH3:23][C@H:22]([NH2:21])[CH2:24][C:25]1[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=1
Reactant: CC(N)Cc1ccccc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: O=S(=O)(O)O
Solvent: CN1CCOCC1
Solvent: O
Solvent: CN(C)C=O
Product: C[C@H](N)Cc1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
O-Acetyl-l-carnitine·Cl (1.000 g, 4.17 mmol) was dissolved in 12.5 mL of a mixture of DMF/dioxane/water (2:2:1). NHS (0.528 g, 4.59 mmol) and DCC (0.947 g, 4.59 mmol) were added and the mixture was stirred overnight at ambient temperature. Solvents were evaporated and the remaining residue was dried overnight in high vacuum. The crude succinimidyl ester intermediate was dissolved in 20 mL of anhydrous DMF. Amphetamine sulfate (0.700 g, 1.90 mmol) and NMM (0.92 mL, 8.34 mmol) were added and the mixture stirred overnight. Solvent was evaporated to dryness and the remaining residue was leached with IPA. Solvent was evaporated to yield Carn-d-amphetamine.
Reaction SMILES: S([O-])([O-])(=O)=O.C([C:11]1[CH:16]=[CH:15][C:14]([I+:17][C:18]2[CH:23]=[CH:22][C:21](C(CC)(C)C)=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)(CC)(C)C.[C:29]([C:34]1C=CC([I+]C2C=CC(C(CC)(C)C)=CC=2)=C[CH:35]=1)([CH2:32][CH3:33])(C)C.[F:52][C:53]1[C:58]([S:59]([O-:62])(=[O:61])=[O:60])=[C:57]([F:63])[C:56]([F:64])=[C:55]([F:65])[C:54]=1[F:66].C[N+](C)(C)C>O>[F:52][C:53]1[C:58]([S:59]([O-:62])(=[O:61])=[O:60])=[C:57]([F:63])[C:56]([F:64])=[C:55]([F:65])[C:54]=1[F:66].[CH2:33]([C:11]1[CH:16]=[CH:15][C:14]([I+:17][C:18]2[CH:23]=[CH:22][C:21]([CH2:55][CH2:54][CH2:53][CH2:58][CH3:57])=[CH:20][CH:19]=2)=[CH:13][CH:12]=1)[CH2:32][CH2:29][CH2:34][CH3:35]
Reactant: CCC(C)(C)c1ccc([I+]c2ccc(C(C)(C)CC)cc2)cc1
Agent: C[N+](C)(C)C
Agent: O=S(=O)([O-])[O-]
Agent: O=S(=O)([O-])c1c(F)c(F)c(F)c(F)c1F
Solvent: O
Product: CCCCCc1ccc([I+]c2ccc(CCCCC)cc2)cc1

Procedure:
Under ice-cooling, 25 g of pentafluorobenzenesulfonyl and 66.8 g of concentrated sulfuric acid was gradually dropwise added to the mixture with ice-cooling. The mixture was stirred with ice-cooling for 2 hours and then at room temperature for 10 hours. With ice-cooling, 500 ml of water was added to the reaction solution, followed by extraction with dichloromethane. The organic phase was washed with sodium bicarbonate and water and then concentrated, thereby a di (4-t-amylphenyl) iodonium sulfate was obtained. The sulfate was added to a solution containing an excess amount of tetramethylammonium pentafluorobenzenesulfonate. Water (500 ml) was added to the solution, followed by extraction with dichloromethane. The organic phase was washed with a 5% aqueous solution of tetramethylammonium hydroxide and water, and then concentrated, thereby di (4-amylphenyl) iodonium pentafluorobenzenesulfonate was obtained.
Reaction SMILES: [CH:1]1([CH2:4][CH2:5][N:6]2[C:10](=[O:11])[N:9]([C:12]3[S:13][C:14]([C:18]([O:20]CC)=[O:19])=[C:15]([CH3:17])[N:16]=3)[CH:8]=[N:7]2)[CH2:3][CH2:2]1.O.[OH-].[Li+]>O1CCCC1.O>[CH:1]1([CH2:4][CH2:5][N:6]2[C:10](=[O:11])[N:9]([C:12]3[S:13][C:14]([C:18]([OH:20])=[O:19])=[C:15]([CH3:17])[N:16]=3)[CH:8]=[N:7]2)[CH2:3][CH2:2]1
Reactant: CCOC(=O)c1sc(-n2cnn(CCC3CC3)c2=O)nc1C
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: Cc1nc(-n2cnn(CCC3CC3)c2=O)sc1C(=O)O
Yield: 55 %

Procedure:
To a solution of ethyl 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylate (0.20 g, 2.78 mmol) in tetrahydrofuran (10 mL) and water (5 mL) was added lithium hydroxide monohydrate (0.15 g, 3.11 mmol) at ambient temperature. The resulting reaction mixture was heated to reflux for 20 hours. The solvent was removed in vacuo and the residue was neutralized to pH 4-5 with 10% hydrochloric acid. The resulting precipitate was collected by filtration and dried to afford 2-(1-(2-cyclopropylethyl)-5-oxo-1H-1,2,4-triazol-4(5H)-yl)-4-methylthiazole-5-carboxylic acid in 55% yield (0.10 g): MS (ES−) m/z 293.1 (M−1).
Reaction SMILES: [O:1]=[C:2]1[CH:7]=[C:6]([C:8]([OH:10])=[O:9])[O:5][C:4]2[C:11]([CH2:23][CH2:24][CH3:25])=[C:12]3[C:17](=[CH:18][C:3]1=2)[C:16](=[O:19])[CH:15]=[C:14]([C:20]([OH:22])=[O:21])[O:13]3.C(=O)([O-])[O-].[NH2:30][C:31]([NH2:33])=[NH2+:32].[NH2:34][C:35]([NH2:37])=[NH2+:36]>O>[NH2:32][C:31]([NH2:33])=[NH2+:30].[NH2:36][C:35]([NH2:37])=[NH2+:34].[O:19]=[C:16]1[CH:15]=[C:14]([C:20]([O-:22])=[O:21])[O:13][C:12]2[C:11]([CH2:23][CH2:24][CH3:25])=[C:4]3[C:3](=[CH:18][C:17]1=2)[C:2](=[O:1])[CH:7]=[C:6]([C:8]([O-:10])=[O:9])[O:5]3
Reactant: CCCc1c2oc(C(=O)O)cc(=O)c2cc2c(=O)cc(C(=O)O)oc12
Agent: NC(N)=[NH2+]
Agent: O=C([O-])[O-]
Solvent: O
Product: CCCc1c2oc(C(=O)[O-])cc(=O)c2cc2c(=O)cc(C(=O)[O-])oc12
Temperature: 25 °C
Yield: 62.2 %

Procedure:
4,6-Dioxo-10-propyl-4H,6H-benzo[1,2-b:5,4-b']dipyran-2,8-dicarboxylic acid (1.0 g) was added to a stirred solution of guanidinium carbonate (0.52 g) in water (20 ml) and the mixture was stirred at room temperature until effervescence had ceased. The precipitated solid was collected using a centrifuge, washed with water and acetone and dried in vacuo at 70° C. to give the title compound (0.83 g; 62%).
Reaction SMILES: [F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([OH:11])=O)[CH:6]=1.[Cl-].[CH2:23]([O:25][C:26](=[O:38])[CH:27]([OH:37])[CH:28]([NH3+:36])[CH2:29][C:30]1[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=1)[CH3:24]>>[F:1][C:2]1[C:3]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)=[N:4][N:5]([C:7]2[N:15]=[CH:14][CH:13]=[CH:12][C:8]=2[C:9]([NH:36][CH:28]([CH2:29][C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[CH:27]([OH:37])[C:26]([O:25][CH2:23][CH3:24])=[O:38])=[O:11])[CH:6]=1
Reactant: O=C(O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1
Reactant: CCOC(=O)C(O)C([NH3+])Cc1ccccc1
Agent: [Cl-]
Product: CCOC(=O)C(O)C(Cc1ccccc1)NC(=O)c1cccnc1-n1cc(F)c(-c2ccccc2)n1

Procedure:
The reaction was carried out in analogy to reaction step 1.1 by reacting 2-(4-fluoro-3-phenyl-1H-pyrazol-1-yl)nicotinic acid and 4-ethoxy-3-hydroxy-4-oxo-1-phenylbutan-2-aminium chloride. ESI-MS [M+H]+: 489.2
Reaction SMILES: CC1C=CC(S(OCC2CC3C=C(Cl)C=C(C(C)(C)C)C=3O2)(=O)=O)=CC=1.[N-]=[N+]=[N-].[Na+].[N:31]([CH2:34][CH:35]1[CH2:39][C:38]2[CH:40]=[C:41]([Cl:48])[CH:42]=[C:43]([C:44]([CH3:47])([CH3:46])[CH3:45])[C:37]=2[O:36]1)=[N+]=[N-].[N-]=[N+]=[N-].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>>[C:44]([C:43]1[C:37]2[O:36][CH:35]([CH2:34][NH2:31])[CH2:39][C:38]=2[CH:40]=[C:41]([Cl:48])[CH:42]=1)([CH3:47])([CH3:45])[CH3:46]
Reactant: CC(C)(C)c1cc(Cl)cc2c1OC(CN=[N+]=[N-])C2
Agent: Cc1ccc(S(=O)(=O)OCC2Cc3cc(Cl)cc(C(C)(C)C)c3O2)cc1
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Product: CC(C)(C)c1cc(Cl)cc2c1OC(CN)C2

Procedure:
Treatment of (±)-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methyl 4-methylbenzenesulfonate (13.74 g, 34.8 mmol) with sodium azide (9.05 g, 0.139 mol) generally according to the procedure described for Intermediate 98 afforded (±)-2-(azidomethyl)-7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran. Treatment of the azide with triphenylphoshine (9.13 g, 34.8 mmol) generally according to the procedure described for Example 21 afforded 4.43 (46 of (±)-1-(7-tert-butyl-5-chloro-2,3-dihydro-1-benzofuran-2-yl)methanamine as a white solid, hydrochloride salt. mp 229-231° C.; Anal. calcd. for C13H18ClNOHCl: C, 56.53; H, 6.93; N, 5.07. Found: C, 56.49; H, 6.71; N, 4.86.
Reaction SMILES: N1CCCCC1.FC(F)OC1C=C(C=CC=1OC(F)F)C=O.C(CC(N[C:30]1[CH:38]=[CH:37][CH:36]=[CH:35][C:31]=1[C:32]([OH:34])=[O:33])=O)(O)=O>C1(C)C=CC=CC=1>[C:32]([OH:34])(=[O:33])[C:31]1[CH:35]=[CH:36][CH:37]=[CH:38][CH:30]=1
Reactant: O=C(O)CC(=O)Nc1ccccc1C(=O)O
Agent: O=Cc1ccc(OC(F)F)c(OC(F)F)c1
Solvent: C1CCNCC1
Solvent: Cc1ccccc1
Product: O=C(O)c1ccccc1
Temperature: 25 °C
Yield: 230.5 %

Procedure:
Piperidine (100 μL, 1.01 mmol) was added to a suspension of 3,4-bis(difluoromethoxy)benzaldehyde (240 mg, 1.01 mmol) and 2-[(carboxyacetyl)amino]benzoic acid (204 mg, 0.92 mmol) in toluene (5.0 mL). The reaction flask was fitted with a Dean-Stark apparatus and heated to reflux for 30 min. The reaction was then cooled to rt and the resulting suspension was filtered and washed with toluene. The piperidinium salt was dissolved in MeOH (5 mL) and water (2 mL) and the solution was acidified with 50% aqueous AcOH. The crude product was collected by filtration and recrystallised from EtOH/water, filtered and washed with water to afford (E)-2-[[3,4-bis(difluoromethoxy)phenyl)-1-oxo-2-propenyl]amino]benzoic acid (259 mg, 71%) as a colourless crystalline solid; mp 190-193° C.; δH (400 MHz, DMSO-d6) 6.96 (d, J=15.6 Hz, 1H, CH═CHCO), 7.18 (t, J3,4=J4,5=8.0 Hz, 1H, H4), 7.27 (t, J=73 Hz, 1H, OCHF2), 7.38 (d, J5′,6′=8.0 Hz, 1H, H5′), 7.61 (d, J=15.6 Hz, 1H, CH═CHCO), 7.62 (t, J4,5=J5,6=8.0 Hz, 1H, H5), 7.78 (d, J2′,6′=1.6 Hz, 1H, H2′), 7.68 (dd, J5′,6′=8.0, J2′,6′=1.6 Hz, 1H, H6′), 8.00 (d, J3,4=8.0 Hz, 1H, H3), 8.69 (d, J5,6=8.0 Hz, 1H, H6), 11.35 (s, 1H, NH), 13.56 (br s, 1H, CO2H); δC (100 MHz, DMSO-d6) 116.3 (t, J=258 Hz), 116.5 (t, J=258 Hz), 117.0, 120.1, 120.5, 120.8, 123.0, 123.8, 126.7, 131.1, 132.8, 133.9, 139.3, 140.7, 141.9, 142.7, 163.5, 169.4; HRMS (ESI−) calculated for C18H13F4NO5 [M-H ]− 398.0646, found 398.0652; νmax 1034, 1217, 1513, 1604, 1683, 2892, 3466 cm−1.