Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1(=[O:5])[CH2:4][CH2:3][CH2:2]1.[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13]([O:15][Si](C)(C)C)=[CH2:14])=[CH:9][CH:8]=1>C(Cl)Cl.[Ti](Cl)(Cl)(Cl)Cl>[F:6][C:7]1[CH:12]=[CH:11][C:10]([C:13](=[O:15])[CH2:14][C:1]2([OH:5])[CH2:4][CH2:3][CH2:2]2)=[CH:9][CH:8]=1
Reactant: O=C1CCC1
Reactant: C=C(O[Si](C)(C)C)c1ccc(F)cc1
Agent: Cl[Ti](Cl)(Cl)Cl
Solvent: ClCCl
Product: O=C(CC1(O)CCC1)c1ccc(F)cc1
Temperature: 0 °C
Reaction time: 0.25 h
Yield: 98 %

Procedure:
Under nitrogen, 11.0 g (100 mmol) of titanium(IV) chloride in 140 mL of methylene chloride at 0° C. was slowly treated with a solution of 8.2 mL (110 mmol) of cyclobutanone in 30 mL of methylene chloride prior to the dropwise addition of a solution of 21.1 g (100 mmol) of 1-fluoro-4-[1[(trimethylsilyl)oxy]ethenyl]benzene (obtained from Step 2 ) in 15 mL of methylene chloride. The reaction was stirred for 15 minutes and then poured into 200 mL of ice/water; the phases were separated. The aqueous phase was extracted twice with 30 mL of methylene chloride and combined with the original methylene chloride phase. The combined extracts were washed 3 times with 120 mL of saturated sodium carbonate/water (1:1) and once with brine, dried (MgSO4), and concentrated in vacuo to give 20.4 g (98%) of crude 1-(4-fluorophenyl)-2-(1-hydroxycyclobutan-1-yl) ethan-1-one as an oil: NMR (CDCl3) δ1.53-1.70 (m, 1H), 1.80-1.94 (m, 1H), 1.99-2.10 (m, 2H), 2.17-2.31 (m, 2H), 3.31 (s, 2H), 7.10-7.19 (m, 2H), 7.95-8.03 (m, 2H).
Reaction SMILES: Cl.[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]6OCC[O:35]6)=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1.Cl>C1COCC1>[CH2:2]([N:9]1[C:17]2[C:12](=[CH:13][C:14]([NH:18][C:19]3[C:28]4[C:23](=[CH:24][C:25]([C:29]5[O:30][C:31]([CH:34]=[O:35])=[CH:32][CH:33]=5)=[CH:26][CH:27]=4)[N:22]=[CH:21][N:20]=3)=[CH:15][CH:16]=2)[CH:11]=[N:10]1)[C:3]1[CH:8]=[CH:7][CH:6]=[CH:5][CH:4]=1
Reactant: c1ccc(Cn2ncc3cc(Nc4ncnc5cc(-c6ccc(C7OCCO7)o6)ccc45)ccc32)cc1
Agent: Cl
Solvent: C1CCOC1
Product: O=Cc1ccc(-c2ccc3c(Nc4ccc5c(cnn5Cc5ccccc5)c4)ncnc3c2)o1

Procedure:
Prepared according to Procedure C from (1-benzyl-1H-indazol-5-yl)-[7-(5-(1,3-dioxolan-2-yl)furan-2-yl)quinazolin-4-yl]-amine hydrochloride (0.27 g) stirred in THF: 2N HCl (2:1, 15 ml) at 20° C. for 1 hour. Filtration gave 5-[4-(1-benzyl-1H-indazol-5-ylamino)-quinazolin-7-yl]-furan-2-carbaldehyde, which was not further characterised.
Reaction SMILES: [C:1]([C:5]1[N:14]=[C:8]2[CH:9]=[CH:10][C:11](I)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2].[C:15]1([C:21]#[CH:22])[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=1>>[C:1]([C:5]1[N:14]=[C:8]2[CH:9]=[CH:10][C:11]([C:22]#[C:21][C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)=[CH:12][N:7]2[N:6]=1)([CH3:4])([CH3:3])[CH3:2]
Reactant: C#Cc1ccccc1
Reactant: CC(C)(C)c1nc2ccc(I)cn2n1
Product: CC(C)(C)c1nc2ccc(C#Cc3ccccc3)cn2n1

Procedure:
The title compound, a yellow solid, MS: m/e=276.2 (M+H+), can be prepared in accordance with the general method of example 1 from 2-tert-butyl-6-iodo-[1,2,4]triazolo[1,5-a]pyridine (example 39, step 4) and phenylacetylene.
Reaction SMILES: [F:1][C:2]1([F:52])[CH2:7][CH2:6][CH:5]([C:8]2[C:17]3[C@@H:16]([OH:18])[CH2:15][C:14]([CH3:20])([CH3:19])[CH2:13][C:12]=3[N:11]=[C:10]([CH:21]3[CH2:26][CH2:25][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:38])[CH3:37])=[CH:29][N:28]=4)[CH2:23][CH2:22]3)[C:9]=2[C@@H:40]([F:51])[C:41]2[CH:46]=[CH:45][C:44]([C:47]([F:50])([F:49])[F:48])=[CH:43][CH:42]=2)[CH2:4][CH2:3]1.C(OC(C)C)(=O)C.[CH3:60][S:61](O)(=[O:63])=[O:62]>O>[CH3:60][S:61]([O:18][C@H:16]1[CH2:15][C:14]([CH3:19])([CH3:20])[CH2:13][C:12]2[N:11]=[C:10]([CH:21]3[CH2:22][CH2:23][N:24]([C:27]4[N:32]=[CH:31][C:30]([O:33][CH2:34][CH2:35][C:36]([OH:39])([CH3:37])[CH3:38])=[CH:29][N:28]=4)[CH2:25][CH2:26]3)[C:9]([C@@H:40]([F:51])[C:41]3[CH:46]=[CH:45][C:44]([C:47]([F:49])([F:48])[F:50])=[CH:43][CH:42]=3)=[C:8]([CH:5]3[CH2:4][CH2:3][C:2]([F:1])([F:52])[CH2:7][CH2:6]3)[C:17]1=2)(=[O:63])=[O:62]
Reactant: CS(=O)(=O)O
Reactant: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](O)CC(C)(C)C4)CC2)nc1
Solvent: CC(=O)OC(C)C
Solvent: O
Product: CC(C)(O)CCOc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3[C@@H](F)c3ccc(C(F)(F)F)cc3)[C@@H](OS(C)(=O)=O)CC(C)(C)C4)CC2)nc1
Temperature: 25 °C
Yield: 86.6 %

Procedure:
To 40.7 mg (0.055 mmol) of (5S)-4-(4,4-Difluorocyclohexyl)-3-{(S)-fluoro[4-(trifluoromethyl)phenyl]methyl}-2-{1-[5-(3-hydroxy-3-methylbutoxy)pyrimidin-2-yl]piperidin-4-yl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Reference Example 16, 0.28 ml of isopropyl acetate and 0.008 ml of ultrapure water were added, and the reaction mixture was stirred at room temperature to obtain a homogeneous solution. Then, 0.004 ml (0.062 mmol) of methanesulfonic acid was added thereto, and the reaction mixture was stirred at the same temperature for 90 minutes. The precipitated solid was obtained by filtration, washed with 0.04 ml of isopropyl acetate three times and then dried under reduced pressure at 40° C. to provide 38.7 mg of the title compound as a white powder (yield: 85%).
Reaction SMILES: F[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[N+:8]([O-:10])=[O:9].C(=O)([O-])[O-].[K+].[K+].[OH:17][CH2:18][CH2:19][N:20]1[CH2:26][CH2:25][CH2:24][NH:23][CH2:22][CH2:21]1>O>[N+:8]([C:3]1[CH:4]=[CH:5][C:6]([N:23]2[CH2:24][CH2:25][CH2:26][N:20]([CH2:19][CH2:18][OH:17])[CH2:21][CH2:22]2)=[CH:7][CH:2]=1)([O-:10])=[O:9]
Reactant: OCCN1CCCNCC1
Reactant: O=[N+]([O-])c1ccccc1F
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Product: O=[N+]([O-])c1ccc(N2CCCN(CCO)CC2)cc1
Temperature: 95 °C
Yield: 91.7 %

Procedure:
Fluoronitrobenzene (2.03 g, 14.4 mmol) is dissolved in water (10 ml), and then potassium carbonate (2.4 g, 17.3 mmol) and 1-(2-hydroxyethyl)-homopiperazine are added. The medium is heated at 95° C. for 4 hours and then cooled to room temperature and filtered. A dark orange-coloured powder is recovered which is placed in the oven (3.5 g, yield=91.7%).
Reaction SMILES: [C:1]1([CH2:7][N:8]([CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C:9]2[CH:16]=[CH:15][C:12]([CH:13]=O)=[CH:11][CH:10]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[C:24]([CH2:26][C:27]([O:29][CH3:30])=[O:28])#[N:25]>N1CCCCC1.CO>[C:18]1([CH2:17][N:8]([CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[C:9]2[CH:10]=[CH:11][C:12]([CH:13]=[C:26]([C:24]#[N:25])[C:27]([O:29][CH3:30])=[O:28])=[CH:15][CH:16]=2)[CH:19]=[CH:20][CH:21]=[CH:22][CH:23]=1
Reactant: O=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1
Reactant: COC(=O)CC#N
Solvent: CO
Solvent: C1CCNCC1
Product: COC(=O)C(C#N)=Cc1ccc(N(Cc2ccccc2)Cc2ccccc2)cc1

Procedure:
A mixture of 4-(bis(phenylmethyl)amino]benzaldehyde (60.2 g, 0.20 mol), methyl cyanoacetate (21.8 g, 0.22 mol), methanol (300 mL), and piperidine (10 drops) is heated at reflux for 1.5 hours. After cooling, the yellow product is collected by filtration, washed with methanol, and dried in air. The yellow colorant, methyl 3-[4-[bis(phenylmethyl)amino]phenyl]-2-cyano-propenoate, is obtained in a yield of 53.5 g (70.0% of theory).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([OH:24])=[O:23])[CH2:3]1.Cl.[CH:26](O)([CH3:28])[CH3:27]>>[OH:1][C@@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C@@H:4]([CH2:5][CH2:6][C@@H:7]3[C@@H:16]2[C:15](=[O:21])[CH2:14][C@@:12]2([CH3:13])[C@H:8]3[CH2:9][CH2:10][C@@H:11]2[C:22]([O:24][CH:26]([CH3:28])[CH3:27])=[O:23])[CH2:3]1
Reactant: C[C@]12CC[C@@H](O)C[C@@H]1CC[C@H]1[C@@H]3CC[C@H](C(=O)O)[C@@]3(C)CC(=O)[C@@H]12
Reactant: CC(C)O
Agent: Cl
Product: CC(C)OC(=O)[C@H]1CC[C@H]2[C@@H]3CC[C@H]4C[C@H](O)CC[C@]4(C)[C@H]3C(=O)C[C@]12C

Procedure:
A solution of 3α-hydroxy-11-oxo-5α-androstane-17β-carboxylic acid (550 mg.) in dry isopropanol containing 3.7%, by weight, of hydrogen chloride (100 ml.) was refluxed for 61/2 hours.
Reaction SMILES: C[O:2][C:3](=O)[CH2:4][NH:5][C:6](=[S:10])[CH2:7][CH2:8][CH3:9].[NH3:12]>CO>[C:6]([NH:5][CH2:4][C:3]([NH2:12])=[O:2])(=[S:10])[CH2:7][CH2:8][CH3:9]
Reactant: CCCC(=S)NCC(=O)OC
Reactant: N
Solvent: CO
Product: CCCC(=S)NCC(N)=O
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of the product of Example 5B (0.788 g, 4.496 mmol) in methanol (30 mL) was saturated with ammonia gas and the reaction was stirred in a stoppered flask at room temperature for 17 hours. The solvent was concentrated under vacuum giving the title compound and the solid purified by silica gel flash chromatography with 10% methanol/methylene chloride to give the title compound as a white solid (500 mg, 3.12 mmol, 69%).
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16](F)[CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24].[O:25]1[CH2:30][CH2:29][N:28]([CH2:31][CH2:32][NH2:33])[CH2:27][CH2:26]1.C([O-])([O-])=O.[K+].[K+]>C1COCC1>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][C:17]([N+:20]([O-:22])=[O:21])=[C:16]([NH:33][CH2:32][CH2:31][N:28]4[CH2:29][CH2:30][O:25][CH2:26][CH2:27]4)[CH:15]=3)=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[CH3:24]
Reactant: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(F)c2)ccc1F
Reactant: NCCN1CCOCC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: Cc1cc(-c2ncccc2-c2ccc([N+](=O)[O-])c(NCCN3CCOCC3)c2)ccc1F
Temperature: 60 °C

Procedure:
To solution of 2-(4-fluoro-3-methylphenyl)-3-(3-fluoro-4-nitrophenyl)pyridine (100 mg) in 2 ml, THF was added 2-morpholinoethanamine (64 uL) and K2CO3 (76 mg). The reaction was heated at 60° C. for 15 hours in a sealed vial. The reaction mixture was cooled to room temperature, concentrated by rotary evaporation under vacuum and partitioned the concentrate between CH2Cl2/water. The organic layer was separated, dried with anhydrous Na2SO4, filtered and evaporated. The crude residue of 5-(2-(4-fluoro-3-methylphenyl)pyridin-3-yl)-N-(2-morpholinoethyl)-2-nitrobenzenamine was used in the next step with no further purification.
Reaction SMILES: C1(C)C=CC(S([O-])(=O)=O)=CC=1.C[S+](C)C1C=CC(O[C:21](=[O:35])[C@H:22]([CH3:34])[NH:23][C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=CC=1.[NH2:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH2:27]([O:26][C:24]([NH:23][C@H:22]([C:21]([NH:37][C@H:38]([C:42]([OH:44])=[O:43])[CH:39]([CH3:41])[CH3:40])=[O:35])[CH3:34])=[O:25])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: C[C@H](NC(=O)OCc1ccccc1)C(=O)Oc1ccc([S+](C)C)cc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: CC(C)[C@H](NC(=O)[C@H](C)NC(=O)OCc1ccccc1)C(=O)O
Temperature: 25 °C

Procedure:
In 50 ml of chloroform was dissolved 4.14 g of benzyloxycarbonylalanine p-dimethylsulfoniophenyl ester p-toluenesulfonate, and 20 ml of an aqueous solution of 0.91 g of valine and 1.1 ml of triethylamine was dropwise added thereto under stirring at room temperature. The reaction mixture was stirred for 8 hours at room temperature and then separated. The chloroform layer was washed with water, dried, and concentrated under reduced pressure, and ether was added to the residue to afford white crystals.
Reaction SMILES: C([N:4]1[C:12]2[C:7](=[CH:8][C:9]([C:13]3[NH:14][C:15]4[N:16]([N:20]=[C:21]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[N:22]=4)[C:17](=[O:19])[CH:18]=3)=[CH:10][CH:11]=2)[CH:6]=[N:5]1)(=O)C.C(=O)([O-])[O-].[K+].[K+]>CO>[F:29][C:26]1[CH:27]=[CH:28][C:23]([C:21]2[N:22]=[C:15]3[NH:14][C:13]([C:9]4[CH:8]=[C:7]5[C:12](=[CH:11][CH:10]=4)[NH:4][N:5]=[CH:6]5)=[CH:18][C:17](=[O:19])[N:16]3[N:20]=2)=[CH:24][CH:25]=1
Reactant: CC(=O)n1ncc2cc(-c3cc(=O)n4nc(-c5ccc(F)cc5)nc4[nH]3)ccc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: O=c1cc(-c2ccc3[nH]ncc3c2)[nH]c2nc(-c3ccc(F)cc3)nn12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of 5-(1-acetyl-1H-indazol-5-yl)-2-(4-fluorophenyl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one (100 mg, crude) in methanol (10 ml) was added a solution of potassium carbonate (50 mg, 0.36 mmol), and the resulting mixture was stirred overnight at room temperature. The solids were collected by filtration and washed with water (3 ml) and methanol (10 ml) to afford 2-(4-fluorophenyl)-5-(1H-indazol-5-yl)-[1,2,4]triazolo[1,5-α]pyrimidin-7(4H)-one as a light yellow solid (55 mg, 23% 2 steps).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[N:4]=[CH:3][C:2]=1[C:11]1[CH:12]=[C:13]([NH2:17])[CH:14]=[CH:15][CH:16]=1.[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([N:26]=[C:27]=[O:28])=[CH:22][CH:21]=1>C1(C)C=CC=CC=1>[CH3:18][O:19][C:20]1[CH:25]=[CH:24][C:23]([NH:26][C:27]([NH:17][C:13]2[CH:14]=[CH:15][CH:16]=[C:11]([C:2]3[CH:3]=[N:4][C:5]4[C:10](=[CH:9][CH:8]=[CH:7][CH:6]=4)[N:1]=3)[CH:12]=2)=[O:28])=[CH:22][CH:21]=1
Reactant: Nc1cccc(-c2cnc3ccccc3n2)c1
Reactant: COc1ccc(N=C=O)cc1
Solvent: Cc1ccccc1
Product: COc1ccc(NC(=O)Nc2cccc(-c3cnc4ccccc4n3)c2)cc1
Temperature: 25 °C
Yield: 62.1 %

Procedure:
To a solution of (3-quinoxalin-2-ylphenyl)amine (2.21 g, 10 mmol) in hot toluene, 4-methoxyphenyl isocyanate (1.42 g, 10 mmol) was added and the reaction mixture was heated at reflux for 2 hrs. The mixture was cooled to room temperature, the resulting precipitate was filtered, washed with hexane and dried to afford 1-(4-methoxyphenyl)-3-[3-(quinoxalin-2-yl)phenyl]urea (2.3 g, 62% yield). LCMS calculated for C22H18N4O2 (M+H): 370.41. found 371. 1H-NMR (DMSO-d6, 250 Mhz) δH: 9.52 (1H, s), 8.95 (1H, br. s), 8.55 (1H, br. s), 8.42 (1H, m), 8.20-8.10 (2H, m), 7.96-7.80 (3H, m), 7.75-7.65 (1H, m), 7.55-7.46 (1H, m), 7.45-7.35 (2H, m), 6.92-6.85 (2H, m), 3.72 (3H, s).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[O:14])[CH2:9][CH2:10][C:11](O)=[O:12])=[CH:4][C:3]=1[S:15](=[O:24])(=[O:23])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22].[CH2:25]([NH2:31])CCCCC>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:14])[N:31]([CH3:25])[C:11](=[O:12])[CH2:10][CH2:9]2)=[CH:4][C:3]=1[S:15](=[O:24])(=[O:23])[NH:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH3:22]
Reactant: CCCCCCN
Reactant: CCCCCCNS(=O)(=O)c1cc(C(=O)CCC(=O)O)ccc1Cl
Product: CCCCCCNS(=O)(=O)c1cc(C2(O)CCC(=O)N2C)ccc1Cl

Procedure:
The 4-(4-chloro-3-n-hexylsulfamoylphenyl)-4-oxobutanoic acid required is obtained analogously to the instructions indicated in Example 15(a) using 7.5 g of n-hexylamine.
Reaction SMILES: C([CH:3]1[CH2:12][CH2:11][C:10]2[C:5](=[CH:6][CH:7]=[C:8]([O:13][CH3:14])[CH:9]=2)[N:4]1[C:15]([O:17][CH2:18][CH3:19])=[O:16])=O.C[Mg]Br>C(OCC)C>[CH3:14][O:13][C:8]1[CH:9]=[C:10]2[C:5](=[CH:6][CH:7]=1)[N:4]1[C:15](=[O:16])[O:17][C@@H:18]([CH3:19])[C@@H:3]1[CH2:12][CH2:11]2
Reactant: CCOC(=O)N1c2ccc(OC)cc2CCC1C=O
Agent: C[Mg]Br
Solvent: CCOCC
Product: COc1ccc2c(c1)CC[C@H]1[C@H](C)OC(=O)N21
Temperature: 0 °C

Procedure:
Starting with a solution of ethyl 2-formyl-6-methoxy-1,2,3,4-tetrahydroquinoline-1-carboxylate in diethyl ether, cooled to 0° C., and methylmagnesium bromide, these reactants being treated under similar conditions to those of Step 1 of Example 1, the cis derivative,
Reaction SMILES: [NH:1]1[C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4][N:3]=[N:2]1.C(=O)([O-])[O-].[K+].[K+].[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24]Cl)=[CH:22][CH:21]=1>CN(C)C=O>[CH3:18][O:19][C:20]1[CH:27]=[CH:26][C:23]([CH2:24][N:3]2[N:2]=[N:1][C:5]([CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8])=[N:4]2)=[CH:22][CH:21]=1
Reactant: COc1ccc(CCl)cc1
Reactant: CCOC(=O)Cc1nnn[nH]1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)Cc1nnn(Cc2ccc(OC)cc2)n1
Temperature: 25 °C
Reaction time: 15 h
Yield: 42.8 %

Procedure:
Ethyl 2-(1H-1,2,3,4-tetrazol-5-yl)acetate (5.0 g, 32.0 mmol) was dissolved in dimethylformamide (20 ml), added with potassium carbonate (5.75 g, 41.6 mmol). The mixture was further added dropwise with 4-methoxybenzyl chloride (5.21 ml, 38.4 mmol) under ice cooling and stirred at the same temperature for 1 hour and 30 minutes and at room temperature for 15 hours. The solvent was evaporated, and the residue was diluted with toluene, washed with water and saturated brine, and dried over anhydrous sodium sulfate. Then, the solvent was evaporated and the residue was purified by silica gel column chromatography (hexane:ethyl acetate=2:1, v/v) to obtain the title compound (3.78 g, 42.7%) as colorless oil.
Reaction SMILES: C1(N=C=NC2CCCCC2)CCCCC1.[F:16][C:17]([F:25])=[CH:18][CH2:19][CH2:20][CH2:21][C:22]([OH:24])=O.[C:26]1([S:32][C:33]2[CH:39]=[CH:38][C:36]([NH2:37])=[CH:35][CH:34]=2)[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>ClCCl>[C:26]1([S:32][C:33]2[CH:39]=[CH:38][C:36]([NH:37][C:22](=[O:24])[CH2:21][CH2:20][CH2:19][CH:18]=[C:17]([F:16])[F:25])=[CH:35][CH:34]=2)[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=1
Reactant: O=C(O)CCCC=C(F)F
Reactant: Nc1ccc(Sc2ccccc2)cc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: ClCCl
Product: O=C(CCCC=C(F)F)Nc1ccc(Sc2ccccc2)cc1
Reaction time: 0.25 h

Procedure:
At from 0° to 10°, 20.6 g of N,N'-dicyclohexylcarbodiimide are added, while stirring, in portions to 15 g of 6,6-difluorohex-5-enoic acid in 150 ml of dichloromethane. The mixture is stirred for a further 15 minutes under cooling and then 20.1 g of 4-phenylthioaniline are added in portions. The reaction mixture is stirred for 3 hours at room temperature and then filtered. The organic phase is washed with saturated sodium hydrogen carbonate solution and then dried over sodium sulfate. After concentration by evaporation, the residue is recrystallised from toluene/hexane, yielding the title compound having a melting point of from 80° to 81° (compound no. 2-1).
Reaction SMILES: [CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[N:11]([CH2:12][CH2:13][O:14][C:15]4[CH:22]=[CH:21][C:20]([S:23][CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:25]5)=[CH:19][C:16]=43)[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2].C(O)(C(F)(F)F)=[O:37].C1C=C(Cl)C=C(C(OO)=O)C=1>C(Cl)Cl>[CH:1]([N:4]1[C:8]([C:9]2[N:18]=[C:17]3[C:16]4[CH:19]=[C:20]([S:23]([CH:24]5[CH2:29][CH2:28][N:27]([C:30]([CH3:35])([CH3:34])[C:31]([NH2:33])=[O:32])[CH2:26][CH2:25]5)=[O:37])[CH:21]=[CH:22][C:15]=4[O:14][CH2:13][CH2:12][N:11]3[CH:10]=2)=[N:7][CH:6]=[N:5]1)([CH3:3])[CH3:2]
Reactant: O=C(O)C(F)(F)F
Reactant: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(SC3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Agent: O=C(OO)c1cccc(Cl)c1
Solvent: ClCCl
Product: CC(C)n1ncnc1-c1cn2c(n1)-c1cc(S(=O)C3CCN(C(C)(C)C(N)=O)CC3)ccc1OCC2
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
To an ice-cooled solution of 2-{4-[2-(2-isopropyl-2H-[1,2,4]triazol-3-yl)-4,5-dihydro-6-oxa-1,3a-diazabenzo[e]azulen-9-ylsulfanyl]piperidin-1-yl}isobutyramide from Example 192 (233 mg, 0.470 mmol) in DCM (20 mL) was added TFA (109 μL, 1.41 mmol) followed by a solution of m-CPBA (89 mg, 0.512 mmol) in DCM (2 mL). The resulting mixture was stirred for 30 min at 0° C. then volatiles were removed under reduced pressure. The crude material was purified by column chromatography (C18, gradient 10-40% MeOH in 0.5% TFA/H2O) and then loaded onto an Isolute® SCX-2 cartridge. The cartridge was washed with MeOH and the product was eluted with 0.5M NH3 in MeOH affording 193 as a colorless foam (116 mg, 48%). LCMS: RT 2.42 min [M+H]+ 512.1. 1H NMR (DMSO, 400 MHz): δ 8.61 (1H, d, J=2.26 Hz), 7.98 (1H, s), 7.93 (1H, s), 7.55 (1H, dd, J=8.53, 2.28 Hz), 7.26 (1H, d, J=8.53 Hz), 7.09 (1H, d, J=3.29 Hz), 6.87 (1H, d, J=3.29 Hz), 5.78-5.67 (1H, m), 4.61-4.54 (4H, m), 2.80 (2H, bd, J=10.79 Hz), 2.74-2.64 (1H, m), 2.13-2.00 (2H, m), 1.78 (1H, bd, J=12.05 Hz), 1.69-1.55 (3H, m), 1.49 (3H, d, J=6.6 Hz), 1.47 (3H, d, J=6.6 Hz), 1.02 (6H, s)
Reaction SMILES: [N+:1]([C:4]1[CH:37]=[CH:36][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([N+:23]([O-])=O)=[C:19]([O:26]CC4C=CC=CC=4)[CH:18]=3)[C:12]([F:34])=[C:11]([F:35])[N:10]=2)=[CH:6][C:5]=1[O:38]CC1C=CC=CC=1)([O-])=O.[H][H]>O1CCCC1.C(OCC)(=O)C.[Pd]>[NH2:1][C:4]1[CH:37]=[CH:36][C:7]([O:8][C:9]2[C:14]([F:15])=[C:13]([O:16][C:17]3[CH:22]=[CH:21][C:20]([NH2:23])=[C:19]([OH:26])[CH:18]=3)[C:12]([F:34])=[C:11]([F:35])[N:10]=2)=[CH:6][C:5]=1[OH:38]
Reactant: O=[N+]([O-])c1ccc(Oc2nc(F)c(F)c(Oc3ccc([N+](=O)[O-])c(OCc4ccccc4)c3)c2F)cc1OCc1ccccc1
Reactant: [H][H]
Agent: [Pd]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Product: Nc1ccc(Oc2nc(F)c(F)c(Oc3ccc(N)c(O)c3)c2F)cc1O
Reaction time: 72 h
Yield: 93 %

Procedure:
99 g of 2,4-bis(4-nitro-3-benzyloxyphenoxy)-3,5,6-trifluoropyridine prepared as described in Example 5 (0.16 mol) are dissolved in 600 ml of a mixture of tetrahydrofuran and ethyl acetate (volume ratio 1:1), and 10 g of Pd/C (palladium/carbon) are added to the solution. The mixture is then hydrogenated at room temperature in an autoclave with vigorous stirring using hydrogen at a pressure of 1 bar; after 3 days, the reaction is terminated. The yellow-beige solution is evaporated to half in a rotary evaporator and left to stand overnight at room temperature, during which the reaction product precipitates in crystalline form. The reaction product is then collected and dried for 48 hours under nitrogen at 40° C./10 mbar in a vacuum drying cabinet (yield: 93%).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:9][C:10](=[O:16])[O:11][C:12]([CH3:15])([CH3:14])[CH3:13])[CH:6]=[CH:7][CH:8]=1)#[CH:2].I[C:18]1[CH:23]=[C:22]([N+:24]([O-:26])=[O:25])[CH:21]=[CH:20][C:19]=1[O:27][CH3:28].C(N(CC)CC)C>CN(C)C=O.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>[C:12]([O:11][C:10](=[O:16])[NH:9][C:5]1[CH:6]=[CH:7][CH:8]=[C:3]([C:1]#[C:2][C:20]2[CH:21]=[C:22]([N+:24]([O-:26])=[O:25])[CH:23]=[CH:18][C:19]=2[O:27][CH3:28])[CH:4]=1)([CH3:13])([CH3:15])[CH3:14]
Reactant: C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Reactant: COc1ccc([N+](=O)[O-])cc1I
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COc1ccc([N+](=O)[O-])cc1C#Cc1cccc(NC(=O)OC(C)(C)C)c1
Temperature: 80 °C
Yield: 40 %

Procedure:
tert-Butyl (3-ethynylphenyl)carbamate was stirred with 2-iodo-1-methoxy-4-nitrobenzene (2.60 g, 9.31 mmol) and bis(triphenylphosphine)palladium(II) chloride (163 mg, 0.23 mmol) in N,N-dimethylformamide (15 mL), and triethylamine (2.59 mL, 18.6 mmol) was added. The reaction mixture was heated at 80° C. for 15 minutes. Purification by preparative LCMS (pH 10) gave the desired compound (1.38 g, 40%). 1H NMR (300 MHz, DMSO-d6): δ 9.53 (s, 1H), 8.25 (m, 2H), 7.71 (s, 1H), 7.42 (d, 1H), 7.25 (m, 2H), 7.18 (d, 1H), 4.00 (s, 3H), 1.42 (s, 9H). LCMS for C20H21N2O5 (M+H)+: m/z=369.1.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH3:15])[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=1)[C:7]#[N:8].C(=O)([O-])[O-].[K+].[K+].[C:22]1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=C[CH:23]=1>C1(C)C=CC=CC=1>[CH3:15][C:4]1[C:5]([N:10]2[CH:14]=[N:13][CH:12]=[N:11]2)=[C:6]([CH:9]=[C:2]([CH:22]=[CH2:23])[CH:3]=1)[C:7]#[N:8]
Reactant: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Reactant: Cc1cc(Br)cc(C#N)c1-n1cncn1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: Cc1ccccc1
Product: C=Cc1cc(C)c(-n2cncn2)c(C#N)c1
Temperature: 25 °C
Yield: 1043.1 %

Procedure:
A mixture of 5-bromo-3-methyl-2-(1H-1,2,4-triazol-1-yl)benzonitrile (0.6 g, 2.3 mmol), potassium carbonate (0.95 g, 6.87 mmol), vinyl boronic anhydride (0.82 g, 3.43 mmol) and triphenylphosphine (0.13 g, 0.114 mmol) in toluene (20.0 mL) were stirred and degassed with argon for 30 min. The reaction mixture was heated to reflux for 18 h. The reaction mixture was cooled to ambient temperature, diluted with water and extracted with ethyl acetate (2×100 mL). The combined ethyl acetate layer was washed with brine, dried over Na2SO4 and concentrated under reduced pressure to afford the crude compound that was purified by flash column chromatography (SiO2, 100-200 mesh; eluting with 30% ethyl acetate/pet ether) to afford the title compound as a pink solid (0.25 g, 52%): 1H NMR (400 MHz, CDCl3) δ 8.33 (s, 1H), 8.22 (s, 1H), 7.67 (s, 1H), 7.60 (s, 1H), 6.75 (dd, J=17.6, 10.8 Hz, 1H), 5.92 (d, J=17.6, 1H), 5.52 (d, J=10.8 Hz, 1H), 2.21 (s, 3H), ESIMS m/z 211.35 ([M+H]+); IR (thin film) 2236, 1511 cm−1.