Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[OH:41])([CH3:4])([CH3:3])[CH3:2].N1C=CC=CC=1.[C:49]1([CH2:55][C:56](Cl)=[O:57])[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1>>[C:1]([O:5][C:6](=[O:42])[C:7]1[CH:12]=[CH:11][C:10]([S:13]([O:16][C:17]2[C:22]([CH3:23])=[CH:21][C:20]([C:24]3[C:36]4[C:35]([CH3:37])=[C:34]([CH3:38])[S:33][C:32]=4[C:31]([Br:39])=[C:30]4[C:25]=3[CH:26]=[CH:27][CH:28]=[CH:29]4)=[CH:19][C:18]=2[CH3:40])(=[O:15])=[O:14])=[CH:9][C:8]=1[O:41][C:56](=[O:57])[CH2:55][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][CH:50]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: O=C(Cl)Cc1ccccc1
Reactant: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(O)c1
Solvent: c1ccncc1
Product: Cc1cc(-c2c3ccccc3c(Br)c3sc(C)c(C)c23)cc(C)c1OS(=O)(=O)c1ccc(C(=O)OC(C)(C)C)c(OC(=O)Cc2ccccc2)c1
Yield: 50.1 %

Procedure:
The title compound was prepared according to the procedure in Example 17, step 1, using 4-[4-(9-bromo-2,3-dimethyl-naphtho[2,3-b]thiophen-4-yl)-2, 6-dimethyl-phenoxysulfonyl]-2-hydroxy-benzoic acid tert-butyl ester (0.500 g, 0.691 mmol), pyridine (0.335 mL, 4.15 mmol) and phenylacetylchloride (0.183 mL, 1.38 mmol). Purification on Biotage KP-Sil eluting with 3% EtOAc/pet. ether gave 0.272 g (51%) of the title compound. 1H NMR (DMSO-d6) δ 1.51 (s, 9 H), 1.56 (s, 3 H), 2.14 (s, 6 H), 2.43 (s, 3 H), 4.04 (s, 2 H), 7.18 (s, 2H), 7.27-7.37 (m, 5 H), 7.46-7.49 (m, 2 H), 7.66 (ddd, 1 H), 8.01-8.07 (m, 2 H), 8.13-8.21 (m, 2 H).
Reaction SMILES: [C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32](OCC)=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:30])([F:29])[F:28])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2].[CH3:37][N:38]([CH3:42])[CH2:39][CH2:40][NH2:41]>>[C:1]([C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([C:14]3[CH:15]=[C:16]([C:32]([NH:41][CH2:40][CH2:39][N:38]([CH3:42])[CH3:37])=[O:33])[C:17](=[O:31])[N:18]([C:21]4[CH:26]=[CH:25][CH:24]=[C:23]([C:27]([F:28])([F:29])[F:30])[CH:22]=4)[C:19]=3[CH3:20])=[CH:12][CH:11]=[N:10]2)=[CH:5][CH:4]=1)#[N:2]
Reactant: CCOC(=O)c1cc(-c2ccnn2-c2ccc(C#N)cc2)c(C)n(-c2cccc(C(F)(F)F)c2)c1=O
Reactant: CN(C)CCN
Product: Cc1c(-c2ccnn2-c2ccc(C#N)cc2)cc(C(=O)NCCN(C)C)c(=O)n1-c1cccc(C(F)(F)F)c1
Yield: 67 %

Procedure:
Intermediate A and N,N-dimethylethane-1,2-diamine were reacted together using an analogous method to that described in Step 1 of Example 1 to afford 5-[1-(4-cyanophenyl)-1H-pyrazol-5-yl]-N-[2-(dimethylamino)ethyl]-6-methyl-2-oxo-1-[3-(trifluoromethyl)phenyl]-1,2-dihydropyridine-3-carboxamide (154 mg, 67%); 1H NMR (500 MHz, DMSO) δ 1.72 (3H, s), 2.10 (6H, s), 2.32 (2H, t), 3.36-3.32 (2H, m), 6.72 (1H, d), 7.67-7.64 (2H, m), 7.71 (1H, d), 7.88-7.82 (2H, m), 7.96-7.90 (4H, m), 8.07 (1H, s), 9.37 (1H, t); APCI-MSm/z: 535[MH+H]
Reaction SMILES: [OH:1][C@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.[N:7]([C:10]1[CH:11]=[CH:12][C:13]([O:16][CH3:17])=[N:14][CH:15]=1)=[C:8]=[S:9]>>[OH:1][C@H:2]1[CH2:6][CH2:5][N:4]([C:8](=[S:9])[NH:7][C:10]2[CH:15]=[N:14][C:13]([O:16][CH3:17])=[CH:12][CH:11]=2)[CH2:3]1
Reactant: O[C@H]1CCNC1
Reactant: COc1ccc(N=C=S)cn1
Product: COc1ccc(NC(=S)N2CC[C@H](O)C2)cn1
Yield: 99 %

Procedure:
The title compound was prepared from (S)-3-hydroxypyrrolidine and 5-isothiocyanato-2-methoxypyridine (J. Org. Chem. (1980), 45, 4219), using the same method as that described for preparation 35, in 99% yield. 1H NMR (400 MHz, CD3OD) δ: 1.91-2.22 (m, 2H), 3.69-3.81 (m, 4H), 3.88 (s, 3H), 4.40-4.52 (m, 1H), 6.78 (d, 1H), 7.69 (dd, 1H), 8.00 (m, 1H); LCMS m/z 254 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:14])[NH:7][CH2:8][CH:9]([OH:13])[CH2:10][CH2:11][OH:12])([CH3:4])([CH3:3])[CH3:2].C(N(CC)CC)C.[CH3:22][S:23](Cl)(=[O:25])=[O:24]>ClCCl>[C:1]([O:5][C:6]([NH:7][CH2:8][CH:9]([O:13][S:23]([CH3:22])(=[O:25])=[O:24])[CH2:10][CH2:11][O:12][S:23]([CH3:22])(=[O:25])=[O:24])=[O:14])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)NCC(O)CCO
Reactant: CS(=O)(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CC(C)(C)OC(=O)NCC(CCOS(C)(=O)=O)OS(C)(=O)=O
Temperature: 0 °C
Reaction time: 2 h

Procedure:
To a solution of (2,4-Dihydroxy-butyl)-carbamic acid tert-butyl ester in dichloromethane (15 ml) was added triethylamine (1.96 ml). The reaction mixture was cooled to 0° C. and methanesulfonyl chloride (0.82 ml) was added drop wise. The mixture was stirred at 0° C. for 2 hours. The mixture was filtered and dichloromethane was added (200 ml). The mixture was washed with 0.2M hydrochloric acid (50 ml), water (30 ml) and 0.2M sodium carbonate (50 ml). The organic phase was dried over anhydrous sodium sulfate and concentrated to give crude methanesulfonic acid 1-(tert-butoxycarbonylamino-methyl)-3-methanesulfonyloxy-propyl ester (1.24 g) which was used in the next step without further purification.
Reaction SMILES: C([Li])CCC.C(NC(C)C)(C)C.C1(C)C=CC(S([CH:22]([C:25]([CH3:30])([CH3:29])[CH:26]([CH3:28])[CH3:27])[C:23]#[N:24])(=O)=O)=CC=1.P(O)(O)([O-])=O.[Na+]>O1CCCC1.C1CCCCC1>[CH3:28][C:26]1([CH3:27])[C:25]([CH3:29])([CH3:30])[CH:22]1[C:23]#[N:24]
Reactant: Cc1ccc(S(=O)(=O)C(C#N)C(C)(C)C(C)C)cc1
Agent: O=P([O-])(O)O
Agent: [Li]CCCC
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Solvent: C1CCCCC1
Product: CC1(C)C(C#N)C1(C)C
Reaction time: 0.17 h
Yield: 59.3 %

Procedure:
9.15 ml of a cyclohexane solution of 1.75M of butyllithium were added with stirring under an inert atmosphere at -30° to -40° C. to a mixture of 2.49 ml of diisopropylamine and 5 ml of tetrahydrofuran and after 10 minutes of contact, the mixture was cooled to -60° to -70° C. A mixture of 4.068 g of 4-tolyl sulfonyl-4,3,3-trimethyl-pentanenitrile in 15 ml of tetrahydrofuran were added to the mixture over 5 minutes and the mixture was stirred at -60° to -70° C. for 10 minutes after which the temperature was allowed to rise to 20° to 25° C. The mixture was stirred for one hour and was then poured into an iced aqueous saturated monosodium phosphate solution. The mixture was extracted with n-pentane and the organic phase was dried and evaporated to dryness under reduced pressure. The residue was distilled under reduced pressure to obtain 1.064 g of pure 2,2,3,3-tetramethyl-cyclopropane-carbonitrile with a boiling point of 58°-60° C. at 12-14 mm Hg and a melting point of 17° C.
Reaction SMILES: C([O:8][C:9]1[CH:36]=[CH:35][C:12]2[NH:13][C:14]([C:19]3[C:20](=[O:34])[N:21]([NH:30][CH2:31][CH2:32][CH3:33])[C:22]4[C:27]([C:28]=3[OH:29])=[CH:26][CH:25]=[CH:24][CH:23]=4)=[N:15][S:16](=[O:18])(=[O:17])[C:11]=2[CH:10]=1)C1C=CC=CC=1.C([O-])=O.[NH4+]>O1CCCC1.[OH-].[Pd+2].[OH-].[Pd]>[OH:29][C:28]1[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[N:21]([NH:30][CH2:31][CH2:32][CH3:33])[C:20](=[O:34])[C:19]=1[C:14]1[NH:13][C:12]2[CH:35]=[CH:36][C:9]([OH:8])=[CH:10][C:11]=2[S:16](=[O:17])(=[O:18])[N:15]=1
Reactant: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(OCc4ccccc4)ccc3N2)c(O)c2ccccc21
Agent: [Pd+2]
Agent: [Pd]
Agent: O=C[O-]
Solvent: C1CCOC1
Product: CCCNn1c(=O)c(C2=NS(=O)(=O)c3cc(O)ccc3N2)c(O)c2ccccc21
Yield: 96.5 %

Procedure:
The product of Example 358B (0.020 g, 0.04 mmol) in tetrahydrofuran (5 mL) was treated with ammonium formate (13 mg, 0.19 mmole), palladium hydroxide (2 mg) and 10% Pd/C (1 mg) and the resulting mixture was refluxed for 1 hour. The catalyst was filtered off and the filtrate evaporated to give a white solid. The solid residue was partitioned between ethyl acetate (100 mL) and water (5 mL). The layers were separated and the organic solvent was removed under reduced pressure to give the title compound (0.016 g, 100%). MS (ESI−) m/z 413 (M−H)−.
Reaction SMILES: [BH4-].[Na+].OC(C(F)(F)F)=O.FC(F)(F)C(O)=O.CO[N:19]=[C:20]1[CH2:23][C@H:22]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[C@H:21]1[CH2:33][O:34][Si:35]([C:38]([CH3:41])([CH3:40])[CH3:39])([CH3:37])[CH3:36]>O1CCCC1>[CH3:41][C:38]([Si:35]([CH3:37])([CH3:36])[O:34][CH2:33][C@@H:21]1[C@@H:22]([CH2:24][O:25][Si:26]([C:29]([CH3:32])([CH3:31])[CH3:30])([CH3:28])[CH3:27])[CH2:23][C@H:20]1[NH2:19])([CH3:39])[CH3:40]
Reactant: CON=C1C[C@H](CO[Si](C)(C)C(C)(C)C)[C@H]1CO[Si](C)(C)C(C)(C)C
Agent: [BH4-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O=C(O)C(F)(F)F
Product: CC(C)(C)[Si](C)(C)OC[C@H]1C[C@@H](N)[C@@H]1CO[Si](C)(C)C(C)(C)C
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To 186.3 g (4.9 mol) of sodium borohydride in 4 of tetrahydrofuran (THF) was added (over a 30 minute period 376 mL (4.9 mol) of trifluoroacetic acid TFA), with ice water cooling to maintain temperature below 15° C. [2R,3S]-2,3-bis(((1,1-Dimethylethyl)di-methylsilyl)oxymethyl)cyclobutanone-O-methyl oxime (400 g, 1.03 mol), from Step 2E, in 3 L of THF was added with ice water cooling to maintain the temperature below 20° C. After stirring the reaction mixture at ambient temperature overnight, it was concentrated, diluted with methylene chloride 3 L) and washed portionwise (with cooling with 400 mL of brine. After filtration, the layers of the filtrate were separated and the aqueous layer was washed with methylene chloride. The combined methylene chloride solution was washed with brine, dried over anhydrous magnesium sulfate, filtered and concentrated to give crude title compound which was taken on to the next step without purification.
Reaction SMILES: [CH3:1][C:2]1[N:7]=C(C#N)[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1.[OH-].[Na+].[CH3:17][C:18]([OH:20])=[O:19]>CO>[CH3:1][C:2]1[N:7]=[C:17]([C:18]([OH:20])=[O:19])[C:5]([N:10]2[CH:14]=[CH:13][CH:12]=[N:11]2)=[CH:4][CH:3]=1
Reactant: CC(=O)O
Reactant: Cc1ccc(-n2cccn2)c(C#N)n1
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Product: Cc1ccc(-n2cccn2)c(C(=O)O)n1
Temperature: 25 °C
Yield: 94 %

Procedure:
6-Methyl-3-(1H-pyrazol-1-yl)picolinonitrile (0.60 g, 3.26 mmol) and NaOH (1.37 g, 34.2 mmol) were dissolved in methanol (3 mL) and stirred at reflux overnight. The reaction was cooled to rt, diluted with more methanol (5 mL), and acidified with AcOH to pH 4-5. The solvent was removed in vacuo to obtain the crude which was purified by silica gel chromatography (0˜100% DCM/EtOAc) to yield the title compound as a clear oil (0.62 g, 94%). MS (ESI) 204 (M+H).
Reaction SMILES: C([O:3][C:4](=[O:33])[CH:5]([S:22]([CH2:25][CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32])(=[O:24])=[O:23])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17]2)=[CH:9][CH:8]=1)C.[OH-].[Na+]>C(O)C>[CH2:25]([S:22]([CH:5]([CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][CH2:14][CH2:15][N:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[CH:9][CH:8]=1)[C:4]([OH:33])=[O:3])(=[O:24])=[O:23])[CH2:26][CH2:27][CH2:28][CH2:29][CH2:30][CH2:31][CH3:32]
Reactant: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)OCC
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: CCCCCCCCS(=O)(=O)C(Cc1ccc(OCCN2CCCCC2)cc1)C(=O)O

Procedure:
2-(Octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid was prepared according to the general method as outlined in example 9. Starting from 2-(octane-1-sulfonyl)-3-[4-(2-piperidin-yl-ethoxy)-phenyl]-propionic acid ethyl ester (8.9g, 18 mmol), ethanol (25 mL) and 10 N sodium hydroxide (25 mL). Yield 6.0g (72%).
Reaction SMILES: [CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([N+:15]([O-])=O)=[CH:11][CH:10]=2)[CH:3]=1.S(S([O-])=O)([O-])=O.[Na+].[Na+].C([O-])([O-])=O.[K+].[K+]>CO.C(Cl)Cl>[CH3:1][C:2]1[O:6][N:5]=[C:4]([CH2:7][O:8][C:9]2[CH:14]=[CH:13][C:12]([NH2:15])=[CH:11][CH:10]=2)[CH:3]=1
Reactant: Cc1cc(COc2ccc([N+](=O)[O-])cc2)no1
Agent: O=C([O-])[O-]
Agent: O=S([O-])S(=O)[O-]
Agent: [K+]
Solvent: CO
Solvent: ClCCl
Product: Cc1cc(COc2ccc(N)cc2)no1
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.6 %

Procedure:
The 5-methyl-3-(4-nitrophenoxymethyl)isoxazole (3, X═H) (2.59 g, 11.07 mmol) was dissolved in MeOH:CH2Cl2 (1:1, 600 mL). An aqueous solution of (77 mL) sodium hydrosulfite (11.93 g, 68.5 mmol) and K2CO3 (9.55 g, 69 mmol) was added dropwise under nitrogen for 30 min. The reaction was allowed to stir at room temperature for 2 h, and the organic solvents were removed under reduced pressure, diluted with water (200 mL), extracted with CH2Cl2 (3×300 mL), dried over anhydrous Na2SO4 and solvent was removed under reduced pressure. The resulting product was finally dried under high vacuum to afford 1.03 g (46%) of the 5-methyl-3-(4-aminophenoxymethyl)isoxazole (4, X═H). 1H NMR (CDCl3): δ 6.78 (d, 2H, J=8.7 Hz), 6.61 (d, 2H, J=8.4 Hz), 6.07 (s, 1H), 5.01 (s, 2H), 3.44 (s, 2H), 2.40 (s, 3H); LCMS (m/z): 205 (MH+).
Reaction SMILES: [CH3:1][O:2][C:3]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:6](O)=[O:7])=[O:4].S(Cl)(Cl)=O.[C:35](=[O:39])([O:37][CH3:38])[NH2:36]>C1C=CC=CC=1>[CH3:38][O:37][C:35]([NH:36][C:6]([CH:5]([CH2:9][C:10]1[CH:15]=[CH:14][C:13]([O:16][CH2:17][CH2:18][C:19]2[N:20]=[C:21]([C:25]3[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=3)[O:22][C:23]=2[CH3:24])=[CH:12][CH:11]=1)[C:3]([O:2][CH3:1])=[O:4])=[O:7])=[O:39]
Reactant: COC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)O
Reactant: COC(N)=O
Solvent: O=S(Cl)Cl
Solvent: c1ccccc1
Product: COC(=O)NC(=O)C(Cc1ccc(OCCc2nc(-c3ccccc3)oc2C)cc1)C(=O)OC
Temperature: 85 °C
Reaction time: 0.5 h
Yield: 61.4 %

Procedure:
2-Methoxycarbonyl-3-[4-[2-(5-methyl-2-phenyl-4-oxazolyl)ethoxy]phenyl]propionic acid (2.00 g, 4.89 mmol) obtained in Example 1 was dissolved in benzene (15 ml), and thionyl chloride (392 μl, 5.38 mmol) was added at room temperature. The mixture was refluxed under heating for 1.5 hr and the solvent was evaporated. The residue was dissolved in toluene (6 ml), and methyl carbamate (440 mg, 5.87 mmol) was added. at room temperature. The mixture was stirred at 80-90° C. for 30 min. The solvent was evaporated and the resulting residue was purified by silica gel column chromatography (developing solvent; chloroform: methanol=30:1). The obtained white solid was recrystallized from methanol to give the title compound (1.40 g, yield 61%).
Reaction SMILES: [Br:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](Cl)=[C:7]([CH:13]=O)[C:8](=[O:12])[NH:9]2)=[CH:4][CH:3]=1.O.[NH2:17][NH2:18]>CN(C=O)C>[Br:1][C:2]1[CH:3]=[CH:4][C:5]2[C:6]3[NH:18][N:17]=[CH:13][C:7]=3[C:8](=[O:12])[NH:9][C:10]=2[CH:11]=1
Reactant: NN
Reactant: O=Cc1c(Cl)c2ccc(Br)cc2[nH]c1=O
Solvent: O
Solvent: CN(C)C=O
Product: O=c1[nH]c2cc(Br)ccc2c2[nH]ncc12
Temperature: 80 °C
Reaction time: 24 h
Yield: 71.9 %

Procedure:
To a solution of 7-bromo-4-chloro-2-oxo-1,2-dihydroquinoline-3-carbaldehyde (8.0 g, 27.9 mmol) in 150 mL of DMF at 80° C. is added hydrazine hydrate (2 mL, 33.5 mmol) at 80° C. The reaction medium is stirred for 24 hours at 80° C. and then cooled to room temperature and filtered. The solid obtained is washed with diisopropyl ether and dried to give 5.3 g of 7-bromo-1,5-dihydro-4H-pyrazolo[4,3-c]quinolin-4-one in the form of a pale yellow powder (yield: 72%).
Reaction SMILES: [C:1]1(=[O:7])[O:6][C:4](=[O:5])[CH:3]=[CH:2]1.[CH2:8]([NH2:14])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]>C1(C)C=CC=CC=1>[CH2:8]([NH:14][C:1](=[O:7])[CH:2]=[CH:3][C:4]([OH:6])=[O:5])[CH2:9][CH2:10][CH2:11][CH2:12][CH3:13]
Reactant: O=C1C=CC(=O)O1
Reactant: CCCCCCN
Solvent: Cc1ccccc1
Product: CCCCCCNC(=O)C=CC(=O)O
Reaction time: 2 h

Procedure:
Maleic anhydride (39.4 g, 0.40 mol) was partly dissolved in toluene (1 l) to form a milky suspension. N-hexylamine (53 ml, 0.40 mol) was diluted with toluene (500 ml) and added dropwise over a period of 1.5 h. After 2 h, the reaction mixture was filtered and the title compound was obtained as a Nvhite solid (76.4 g, 96%) after drying for 16 h in a vacuum oven at 40° C.
Reaction SMILES: S1C=CC(C=O)=C1.[OH-].[K+].[N+:10]([CH2:12][C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14])#[C-:11].[S:20]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:21]1>CO.C(OCC)(=O)C>[S:20]1[CH:24]=[CH:23][C:22]([C@@H:25]2[O:29][CH:28]=[N:27][C@H:26]2[C:30]([N:32]2[CH2:36][CH2:35][CH2:34][CH2:33]2)=[O:31])=[CH:21]1.[N:27]1[CH:24]=[CH:23][CH:22]=[CH:25][C:26]=1[C@@H:30]1[O:31][CH:11]=[N:10][C@H:12]1[C:13]([N:15]1[CH2:19][CH2:18][CH2:17][CH2:16]1)=[O:14]
Reactant: [C-]#[N+]CC(=O)N1CCCC1
Agent: O=C([C@@H]1N=CO[C@H]1c1ccsc1)N1CCCC1
Agent: O=Cc1ccsc1
Agent: [K+]
Solvent: CO
Solvent: CCOC(C)=O
Product: O=C([C@@H]1N=CO[C@H]1c1ccccn1)N1CCCC1
Yield: 40 %

Procedure:
BLE 04124A was prepared in accordance with method D using thiophen-3-carboxaldehyde (0.475 mL, 5.42 mmol), KOH (0.276 mg, 4.92 mmol) in methanol (5 mL) and 2-isocyano-1-(pyrrolidin-1-yl)ethanone BLE 04098 (0.75 g, 5.43 mmol). After work-up the residue obtained was recristallized from ethyl acetate to obtain after filtration trans-(4,5-dihydro-5-(thiophen-3-yl)oxazol-4-yl)(pyrrolidin-1-yl)methanone BLE 04110A as a yellow pale solid (0.498 g, 40% yield).
Reaction SMILES: [F:1][C:2]([F:24])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20](O)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:12])([F:11])[F:10])[CH:8]=1.Cl.[F:26][C:27]([F:34])([F:33])[C:28]1([OH:32])[CH2:31][NH:30][CH2:29]1.C(P1(=O)OP(CCC)(=O)OP(CCC)(=O)O1)CC.CCN(C(C)C)C(C)C>C(Cl)Cl>[F:24][C:2]([F:1])([F:23])[C:3]1[CH:4]=[C:5]([C:13]2[N:17]=[CH:16][N:15](/[CH:18]=[CH:19]\[C:20]([N:30]3[CH2:31][C:28]([OH:32])([C:27]([F:34])([F:33])[F:26])[CH2:29]3)=[O:21])[N:14]=2)[CH:6]=[C:7]([C:9]([F:10])([F:11])[F:12])[CH:8]=1
Reactant: O=C(O)/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1
Reactant: OC1(C(F)(F)F)CNC1
Agent: CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1
Agent: Cl
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: O=C(/C=C\n1cnc(-c2cc(C(F)(F)F)cc(C(F)(F)F)c2)n1)N1CC(O)(C(F)(F)F)C1
Temperature: -30 °C
Reaction time: 0.5 h
Yield: 14.8 %

Procedure:
(Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)acrylic acid (0.10 g, 1.0 eq.) and 3-(trifluoromethyl)azetidin-3-ol hydrochloride (0.055 g, 1.1 eq.) were dissolved in DCM (3.0 mL) The reaction mixture was cooled to −30° C. where T3P (0.3 mL, 1.5 eq.) and DIPEA (0.12 mL, 2.5 eq.) were added. The reaction mixture was stirred at −30° C. for 30 min. and diluted by DCM, washed with water. The combined organic layers were dried over sodium sulfate and distilled under reduce pressure (250° C., 20 mmHg) to obtain crude product. The crude product was purified by preparative TLC (70% ethyl acetate-Hexane) to yield to 0.020 g of (Z)-3-(3-(3,5-bis(trifluoromethyl)phenyl)-1H-1,2,4-triazol-1-yl)-1-(3-hydroxy-3-(trifluoromethyl)azetidin-1-yl)prop-2-en-1-one. (Yield: 14.8%). 1H NMR (400 MHz, MeOD) δ 9.20 (s, 1H), 8.65 (s, 2H), 8.09 (s, 1H), 7.40-7.43 (d, J=10 Hz, 1H), 5.95-5.93 (d, J=10.6 Hz, 1H), 4.42-4.43 (m, 2H), 4.33-4.05 (m, 2H); LCMS calcd for C17H11F9N4O2 [M+H]+474.3. Found: 475.14 Retention time: 2.872 min,
Reaction SMILES: [NH2:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4].[OH-].[Na+].[C:11](Cl)(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1>O>[C:11]([NH:1][C@H:2]([C:6]([OH:8])=[O:7])[CH:3]([CH3:5])[CH3:4])(=[O:18])[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: CC(C)[C@H](N)C(=O)O
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: CC(C)[C@H](NC(=O)c1ccccc1)C(=O)O
Temperature: 30 °C

Procedure:
Dissolve 0.1 mol (11.7 g) of valine in 50 ml of water, add 0.25 mol of sodium hydroxide in aqueous solution, heat to 30° C. and then add dropwise 0.15 mol (17.5 ml) of benzoyl chloride. Wash the aqueous solution with ether, acidify and suction off the N-benzoylvaline crystals.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4](O)=[O:5].C(Cl)(=O)C(Cl)=O.[NH3:18].C1COCC1>C(Cl)Cl>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([I:11])[C:3]=1[C:4]([NH2:18])=[O:5]
Reactant: N
Reactant: O=C(O)c1c(Cl)cccc1I
Agent: O=C(Cl)C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: NC(=O)c1c(Cl)cccc1I

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-26 by using 2-chloro-6-iodobenzoic acid (2.7 g, 9.6 mmol), oxalyl chloride (1.4 g, 11.5 mmol), ammonia gas, THF (20 mL) and DCM (10 mL) to afford 2.3 g of the desired product. 1H NMR (300 MHz, DMSO d6): δ 7.11 (t, J=7.8 Hz, 1H), 7.49 (d, J=8.4 Hz, 1H), 7.73 (s, 1H), 7.80 (d, J=7.8 Hz, 1H), 8.00 (s, 1H); MS (m/z): 281.98 (M+H)+.
Reaction SMILES: [CH3:1][S:2](Cl)(=[O:4])=[O:3].[F:6][C:7]([F:22])([C:12]([F:21])([F:20])[C:13]([F:19])([F:18])[C:14]([F:17])([F:16])[F:15])[CH2:8][CH2:9][CH2:10][OH:11].C(N(CC)CC)C.O>ClCCl>[CH3:1][S:2]([O:11][CH2:10][CH2:9][CH2:8][C:7]([F:22])([F:6])[C:12]([F:20])([F:21])[C:13]([F:18])([F:19])[C:14]([F:15])([F:16])[F:17])(=[O:4])=[O:3]
Reactant: CS(=O)(=O)Cl
Reactant: OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Solvent: ClCCl
Solvent: CCN(CC)CC
Solvent: O
Product: CS(=O)(=O)OCCCC(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reaction time: 1 h
Yield: 87.5 %

Procedure:
Methanesulfonyl chloride (2.8 ml, 36.72 mmol) was added to a solution of 4,4,5,5,6,6,7,7,7-nonafluoroheptan-1-ol (6.0 g, 21.6 mmol) and triethylamine (6.0 ml, 43.2 mmol) in dichloromethane (60 ml) at 0° C., followed by stirring for 1 hour. After the reaction was completed, water was added to the reaction mixture, which was then extracted with dichloromethane. The organic layer was washed with water and saturated aqueous sodium chloride, and then dried over anhydrous magnesium sulfate. After distilling off the solvent, the residue was purified by silica gel column chromatography (eluent: ethyl acetate/hexane=1/3) to give 1-methanesulfonyloxy-4,4,5,5,6,6,7,7,7-nonafluoroheptane (6.73 g, Yield 92.2%) as a colorless oil.
Reaction SMILES: C([O:8][C:9]1[CH:10]=[C:11]([CH2:25][C:26]([OH:28])=[O:27])[CH:12]=[C:13]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:14]=1)C1C=CC=CC=1.[CH3:29][CH2:30]O>[Pd]>[CH2:29]([O:28][C:26](=[O:27])[CH2:25][C:11]1[CH:12]=[C:13]([C:15]2[CH:16]=[CH:17][C:18]([C:21]([F:23])([F:22])[F:24])=[CH:19][CH:20]=2)[CH:14]=[C:9]([OH:8])[CH:10]=1)[CH3:30]
Reactant: CCO
Reactant: O=C(O)Cc1cc(OCc2ccccc2)cc(-c2ccc(C(F)(F)F)cc2)c1
Agent: [Pd]
Product: CCOC(=O)Cc1cc(O)cc(-c2ccc(C(F)(F)F)cc2)c1
Reaction time: 5 h
Yield: 93 %

Procedure:
To a solution of (5-benzyloxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid (2.5 g, 5.5 mmol) in EtOH (50 mL) was added 10% Pd/C (5% wt) and the resultant black suspension stirred under an atmosphere of H2 for 5 hours. The resultant mixture was filtered through celite and evaporated to dryness. The residue was purified by flash column chromatography (EtOAc:petroleum ether) to give 2.3 g (93%) (5-hydroxy-4′-trifluoromethyl-biphenyl-3-yl)-acetic acid ethyl ester as a white solid.
Reaction SMILES: [Cl:1][C:2]1[N:6]2[N:7]=[C:8](Cl)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1.[NH2:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1>>[Cl:1][C:2]1[N:6]2[N:7]=[C:8]([NH:12][CH2:13][C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=3)[CH:9]=[CH:10][C:5]2=[N:4][CH:3]=1
Reactant: Clc1ccc2ncc(Cl)n2n1
Reactant: NCc1ccccn1
Product: Clc1cnc2ccc(NCc3ccccn3)nn12
Yield: 27 %

Procedure:
Prepared from 3,6-dichloroimidazo[1,2-b]pyridazine and 2-(aminomethyl)pyridine according to general procedure 3 providing the title compound (56 mg, 27%) as a white solid; 1H NMR (500 MHz, CD3OD) δ 8.50 (d, J=4.9 Hz, 1H), 7.79 (dt, J=1.7, 9.4, Hz, 1H), 7.61 (d, J=9.7 Hz, 1H), 7.54 (d, J=7.9 Hz, 1H), 7.34 (s, 1H), 7.30 (dd, J=5.3, 6.5 Hz, 1H), 6.81 (d, J=9.7 Hz, 1H), 4.68 (s, 1H); 13C NMR (75 MHz, CD3OD) δ 159.7, 155.5, 149.7, 138.7, 127.9, 126.1, 123.7, 123.6, 115.7, 114.6 (one carbon overlapping with solvent); HPLC tR=8.8 min (Synergi), 98.8 %; ES-MS: (M+H)=260 m/z.