Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([OH:10])[CH:7]=[CH:8][CH:9]=1)([O-:3])=[O:2].CN(C)C=O.C(=O)([O-])[O-].[K+].[K+].Cl[CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31]>O.C(OCC)(=O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:7]=[CH:8][CH:9]=1)[O:10][CH2:23][CH2:24][O:25][CH2:26][CH2:27][O:28][CH2:29][CH2:30][OH:31])([O-:3])=[O:2]
Reactant: OCCOCCOCCCl
Reactant: O=[N+]([O-])c1cccc(O)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: O=[N+]([O-])c1cccc(OCCOCCOCCO)c1

Procedure:
While stirring a mixture of 27.8 g of m-nitrophenol, 120 ml of N,N-dimethylformamide, and 25 g of potassium carbonate at 80° C., 37 g of 2-(2-(2-chloroethoxy)ethoxy)-ethanol was added dropwise to the mixture. After stirring the mixture for one hour at 80° C., 200 ml of ethyl acetate and 200 ml of water were added to the reaction mixture and the ethyl acetate layer was extracted. The ethyl acetate layer was washed with 200 ml of water and concentrated to remove ethyl acetate to provide 2-(2-(2-(3-nitrophenoxy)ethoxy)ethoxy)ethanol (1-A).
Reaction SMILES: CCN(CC)CC.Cl[C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12].[NH:17]1[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1.O>CCOC(C)=O>[N:17]1([C:9](=[O:16])[CH2:10][C:11]([O:13][CH2:14][CH3:15])=[O:12])[CH:26]2[CH:21]([CH2:22][CH2:23][CH2:24][CH2:25]2)[CH2:20][CH2:19][CH2:18]1
Reactant: C1CCC2NCCCC2C1
Reactant: CCOC(=O)CC(=O)Cl
Solvent: O
Solvent: CCN(CC)CC
Solvent: CCOC(C)=O
Product: CCOC(=O)CC(=O)N1CCCC2CCCCC21
Yield: 78.9 %

Procedure:
3.38 mL of Et3N and 1.44 mL (11 mmol) of ethyl 3-chloro-3-oxopropionate are added to a solution of 1.5 mL (10 mmol) of decahydroquinoline in 100 mL of AcOEt. The resulting solution is kept under stirring at reflux for 10 h. Then water is added and the organic phase is separated, the aqueous phase is extracted once again with AcOEt. The organic phases are pooled and they are first washed with 5% solution of NaHCO3 and subsequently with brine, they are dried over anhydrous Na2SO4, they are filtered and the solvent is evaporated under reduced pressure. 2.0 g of a yellow oil are obtained. It is identified as intermediate IIIa.1. Method A: tr: 6.76 min; m/z: 268.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([CH3:8])=[CH:4][C:3]=1[OH:9].[NH2:10][C:11]1[CH:12]=[C:13]([CH:17]=[CH:18][CH:19]=1)[C:14](O)=O>>[NH2:10][C:11]1[CH:12]=[C:13]([C:14]2[O:9][C:3]3[CH:4]=[C:5]([CH3:8])[CH:6]=[CH:7][C:2]=3[N:1]=2)[CH:17]=[CH:18][CH:19]=1
Reactant: Nc1cccc(C(=O)O)c1
Reactant: Cc1ccc(N)c(O)c1
Product: Cc1ccc2nc(-c3cccc(N)c3)oc2c1

Procedure:
Prepared by the method of Example 1a), from 2-amino-5-methylphenol (448 mg, 3.6 mmol) and 3-aminobenzoic acid (500 mg, 3.6 mmol) the subtitle compound was obtained, 97 mg (12%). 1H NMR (CDCl3) δ 7.55(d, J=8.2 Hz, 2H), 7.49(t, J=1.9 Hz, 1H), 7.30(s, 1H), 7.22(t, J=7.5 Hz, 1H), 7.08(dd, J=1.1, 8.2 Hz, 1H), 6.76(dd, J=2.3, 7.9 Hz, 1H), 2.43(s, 3H). MS 225 m/z (M+H)+.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]#[N:18])=[CH:16][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.Cl.[NH2:20][OH:21].C(N(CC)CC)C>C(O)C>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[NH:12][C:11]3[CH:13]=[CH:14][C:15]([C:17]([NH:20][OH:21])=[NH:18])=[CH:16][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: NO
Reactant: N#Cc1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: CCO
Product: N=C(NO)c1ccc2[nH]c(-c3ccc(F)cc3)nc2c1
Reaction time: 6 h
Yield: 85 %

Procedure:
2-(4-Fluoro-phenyl)-1H-benzoimidazole-5-carbonitrile (1.898 g, 8 mmol; example 1), hydroxylamine hydrochloride (3.34 g, 48 mmol) and triethylamine (5.67 g, 56 mmol) were heated at reflux in 85 ml of ethanol for 6 hours. Heating was continued for further 6 hours after addition of 3 equivalents of hydroxylamine hydrochloride and triethylamine each and molecular sieve (3 Å). The molecular sieve was filtered, the solvent evaporated and the solid recrystallized from methanol. Yield: 85%. MS: m/e=271.05 (M+H+).
Reaction SMILES: [CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[NH:11][C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4].Cl[CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([N:5]1[C:13]2[C:12](=[O:14])[N:11]([CH2:18][CH2:19][CH2:20][CH2:21][C:22]([OH:25])([CH3:24])[CH3:23])[C:10](=[O:15])[N:9]([CH3:16])[C:8]=2[N:7]=[CH:6]1)[CH2:2][CH:3]=[CH2:4]
Reactant: C=CCCn1cnc2c1c(=O)[nH]c(=O)n2C
Reactant: CC(C)(O)CCCCCl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: C=CCCn1cnc2c1c(=O)n(CCCCC(C)(C)O)c(=O)n2C

Procedure:
22 g (0.1 mol) of the xanthine from stage (a) are reacted with 16.6 g (0.11 mol) of 1-chloro-5-hydroxy-5-methylhexane (Example 1a) and 15.2 g (0.11 mol) of potassium carbonate in 500 ml of dimethylformamide under the experimental conditions described in Example 2, and the mixture is worked up. The reaction product is obtained in pure form without prior column chromatography, by recrystallization once from ethyl acetate with the addition of petroleum ether, at the boil.
Reaction SMILES: [C:1]1([C:7]2[CH:8]=[CH:9][C:10]([CH2:19][OH:20])=[N:11][C:12]=2[C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.CI.[C:23]([O-])([O-])=O.[K+].[K+]>[OH-].[K+].CC(C)=O.O>[CH3:23][O:20][CH2:19][C:10]1[N:11]=[C:12]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)=[CH:8][CH:9]=1
Reactant: O=C([O-])[O-]
Reactant: OCc1ccc(-c2ccccc2)c(-c2ccccc2)n1
Agent: [K+]
Agent: [OH-]
Solvent: CI
Solvent: O
Solvent: CC(C)=O
Product: COCc1ccc(-c2ccccc2)c(-c2ccccc2)n1

Procedure:
A solution of 5,6-diphenylpyridin-2-yl)methanol (Compound 90, 15 mg, 0.06 mmol), MeI (0.1 ml), K2CO3 (50 mg) and KOH (5N, 5 drops) in acetone was heated at 56° C. over night. The mixture was diluted with water and the product was extracted with ethyl acetate. The organic layer was washed with water, and brine, and dried over Na2SO4. The filtered solvent was concentrated in vacuo, and the residue was purified by silica gel chromatography (15% ethyl acetate in hexane) to give title compound as a solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[N:11]=[CH:10][C:9](=[O:12])[N:8]([CH2:13][C@@H:14]3[CH2:16][O:15]3)[C:7]=2[N:17]=1.[NH2:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1>C(O)C.O>[OH:15][C@H:14]([CH2:13][N:8]1[C:9](=[O:12])[CH:10]=[N:11][C:6]2[CH:5]=[CH:4][C:3]([O:2][CH3:1])=[N:17][C:7]1=2)[CH2:16][NH:18][CH2:19][C@@H:20]1[CH2:24][N:23]([C:25]2[CH:26]=[CH:27][C:28]3[O:29][CH2:30][C:31](=[O:35])[NH:32][C:33]=3[N:34]=2)[C:22](=[O:36])[CH2:21]1
Reactant: NC[C@H]1CC(=O)N(c2ccc3c(n2)NC(=O)CO3)C1
Reactant: COc1ccc2ncc(=O)n(C[C@@H]3CO3)c2n1
Solvent: CCO
Solvent: O
Product: COc1ccc2ncc(=O)n(C[C@@H](O)CNC[C@H]3CC(=O)N(c4ccc5c(n4)NC(=O)CO5)C3)c2n1
Temperature: 60 °C
Reaction time: 15 h
Yield: 27.7 %

Procedure:
In a mixed solvent (60 ml) of ethanol and water (9:1) were dissolved 6-methoxy-4-[(2R)-oxiran-2-ylmethyl]pyrido[2,3-b]pyrazin-3(4H)-one (2.94 g, 12.60 mmol) and 6-[(4R)-4-(aminomethyl)-2-oxopyrrolidin-1-yl]-2H-pyrido[3,2-b][1,4]oxazin-3(4H)-one (Reference Example 54; 3.30 g, 12.60 mmol), and the obtained mixture was then stirred in a sealed tube at 60° C. for 15 hours. Thereafter, the reaction solution was cooled in the air, and the solvent was then removed under reduced pressure. The residue was purified by silica gel column chromatography (chloroform/methanol) to yield 1.73 g (28%) of the above-captioned compound in the form of a light yellow solid.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][NH:8]1.Br[CH2:25][C:26](Br)=[O:27].[F:29][C:30]1[CH:37]=[CH:36][CH:35]=[CH:34][C:31]=1[CH2:32][NH2:33]>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:19]=[CH:20][C:21]=1[O:22][CH3:23])[CH2:6][CH:7]1[C:16]2[C:11](=[CH:12][C:13]([O:17][CH3:18])=[CH:14][CH:15]=2)[CH2:10][CH2:9][N:8]1[CH2:25][C:26]([NH:33][CH2:32][C:31]1[CH:34]=[CH:35][CH:36]=[CH:37][C:30]=1[F:29])=[O:27]
Reactant: COc1ccc2c(c1)CCNC2Cc1ccc(OC)c(OC)c1
Reactant: O=C(Br)CBr
Reactant: NCc1ccccc1F
Product: COc1ccc2c(c1)CCN(CC(=O)NCc1ccccc1F)C2Cc1ccc(OC)c(OC)c1

Procedure:
prepared by reaction of 1-(3,4-dimethoxy-benzyl)-6-methoxy-1,2,3,4-tetrahydroisoquinoline and 2-bromoacetyl bromide with 2-fluorobenzylamine
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][C:3]=1[C:9]([OH:12])([CH3:11])[CH3:10].CO[CH:15](O)[C:16]([F:19])([F:18])[F:17].S([O-])([O-])(=O)=O.[Mg+2]>C1(C)C=CC=CC=1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]2[NH:1][CH:15]([C:16]([F:19])([F:18])[F:17])[O:12][C:9]([CH3:10])([CH3:11])[C:3]=2[CH:4]=1
Reactant: COC(O)C(F)(F)F
Reactant: CC(C)(O)c1cc(Br)ccc1N
Agent: O=S(=O)([O-])[O-]
Agent: [Mg+2]
Solvent: Cc1ccccc1
Product: CC1(C)OC(C(F)(F)F)Nc2ccc(Br)cc21
Temperature: 80 °C

Procedure:
A mixture of 2-(2-amino-5-bromo-phenyl)-propan-2-ol (5 g, 21.7 mmol), trifluoroacetaldehyde methyl hemiacetal (5 mL), and magnesium sulfate (10 g) in toluene (75 mL) was heated at 80° C. under nitrogen. After disappearance of the starting material, the reaction was filtered through a pad of silica gel and the filtrate dried over sodium sulfate and concentrated to give 6-bromo-4,4-dimethyl-2-(trifluoromethyl)-1,4-dihydro-2H-3,1-benzoxazine as an amorphous solid: 1H-NMR (DMSO-d6) δ 7.31 (d, 1H, J=1.99 Hz), 7.19 (dd, 1H, J=8.73, 2.38 Hz), 6.88 (s 1H), 6.74 (d, 1H, J=8.33 Hz), 5.32 (m, 1H), 1.52 (s, 6H).
Reaction SMILES: O[CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1.C(Br)(Br)(Br)[Br:19].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Cl-].[Na+]>C(OCC)(=O)C.O.O1CCCC1>[Br:19][CH2:2][CH2:3][CH2:4][CH:5]1[CH2:10][CH2:9][N:8]([C:11]([O:13][C:14]([CH3:17])([CH3:16])[CH3:15])=[O:12])[CH2:7][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1CCC(CCCO)CC1
Reactant: BrC(Br)(Br)Br
Agent: [Cl-]
Agent: [Na+]
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: O
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)N1CCC(CCCBr)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 98 %

Procedure:
To a tetrahydrofuran (110 mL) solution of 10.7 g of tert-butyl 4-(3-hydroxypropyl)-1-piperidinecarboxylate was added 19.0 g of carbon tetrabromide under cooling with water, to which 15.0 g of triphenylphosphine was then added over a period of 13 minutes. This mixture was stirred at room temperature for 2 hours and 30 minutes and allowed to stand for 13 hours. To the reaction mixture were added water, ethyl acetate, and a saturated sodium chloride aqueous solution. The organic layer was separated, washed with a saturated sodium chloride aqueous solution, and dried with anhydrous magnesium sulfate, followed by distilling off the solvent under reduced pressure. The resultant residue was purified using silica gel column chromatography (eluent; hexane:ethyl acetate=3:1) to provide 13.2 g of tert-butyl 4-(3-bromopropyl)-1-piperidinecarboxylate as colorless oily form.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5](F)=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1.C(=O)([O-])[O-:13].[Cs+].[Cs+].I[CH:19]([CH3:21])[CH3:20]>O>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([O:13][CH:19]([CH3:21])[CH3:20])=[C:6]([N+:8]([O-:10])=[O:9])[CH:7]=1
Reactant: CC(C)I
Reactant: O=C([O-])[O-]
Reactant: O=[N+]([O-])c1cc(Br)ccc1F
Agent: [Cs+]
Solvent: O
Product: CC(C)Oc1ccc(Br)cc1[N+](=O)[O-]
Temperature: 95 °C
Reaction time: 1.5 h

Procedure:
A mixture of 5.0 g of 5-bromo-2-fluoronitrobenzene, 14.8 g of caesium carbonate and 35.0 ml of 2-iodopropane is charged to two 20 ml microwave tubes, and irradiated at 60° C. with stirring for 1.5 h, and then stirred at ambient temperature overnight. The mixture is poured into 400 ml of water and then extracted three times with 300 ml of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure. The residue is reintroduced into a single-necked round-bottomed flask, into which 50 ml of 2-iodopropane and 10.0 g of caesium carbonate are added. The reaction mixture is heated at 95° C. for 10 min, and then at 60° C. for 3 h, and it is then stirred at ambient temperature overnight. The mixture is then poured into 400 ml of water and then extracted three times with 400 ml of ethyl acetate. The organic extracts are combined and then concentrated to dryness under reduced pressure, so as to obtain 5.6 g of 4-bromo-1-isopropoxy-2-nitrobenzene in the form of a brown oil.
Reaction SMILES: [C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([CH2:33][CH2:34]O)[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:27])([F:26])[F:25])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:4])([CH3:3])[CH3:2].C(N(C(C)C)CC)(C)C.[F:45]C(F)(S(F)(=O)=O)C(F)(F)C(F)(F)C(F)(F)F>CC#N.O>[C:1]([C:5]1[CH:10]=[CH:9][C:8]([CH2:11][C:12]([NH:14][C@@H:15]([C:28]2[N:29]=[N:30][N:31]([CH2:33][CH2:34][F:45])[CH:32]=2)[C:16]2[CH:21]=[CH:20][C:19]([O:22][CH2:23][C:24]([F:26])([F:25])[F:27])=[CH:18][N:17]=2)=[O:13])=[CH:7][CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: O=S(=O)(F)C(F)(F)C(F)(F)C(F)(F)C(F)(F)F
Reactant: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(CCO)nn2)cc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: CC#N
Product: CC(C)(C)c1ccc(CC(=O)N[C@H](c2ccc(OCC(F)(F)F)cn2)c2cn(CCF)nn2)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 53.3 %

Procedure:
To a solution of 2-(4-tert-Butylphenyl)-N-{(S)-[1-(2-hydroxyethyl)-1H-1,2,3-triazol-4-yl][5-(2,2,2-trifluoroethoxy)pyridin-2-yl]methyl}acetamide (32.00 mg, 0.0650 mmol) in 0.5 ml of anhydrous CH3CN at RT was added diisopropylethylamine (0.0450 ml, 0.260 mmol), diisopropylethylamine dihydrogen fluoride complex (0.0180 ml, 0.0980 mmol), and perfluorobutanesulfonyl fluoride (0.0230 ml, 0.130 mmol). The resulting solution was stirred at room temperature for 16 hours. The reaction mixture was diluted with water and extracted with CH2Cl2. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuum. Purification by preparative HPLC (20-90% CH3CN/H2O over 30 min, 0.05% added TFA, C18 column) to afford 0.0171 g (53%) of the title compound. 1H NMR (CDCl3, 400 MHz) δ 8.245 (d, J=2.93 Hz, 1H), 7.569 (s, 1H), 7.527 (d, J=7.14 Hz, 1H), 7.369 (m, 2H), 7.270 (m, 1H), 7.225 (m, 2H), 6.336 (d, J=7.14 Hz, 1H), 4.800 (AB q, J=4.53 Hz, 1H), 4.682 (AB q, J=4.21 Hz, 1H), 4.617 (AB q, J=4.53 Hz, 1H), 4.550 (AB q, J=4.67 Hz, 1H), 4.378 (q, J=7.88 Hz, 2H), 3.623 (s, 2H), 3.086 (br s, 1H), 1.314 (s, 9H). ES-MS [M+1]+: 494.2.
Reaction SMILES: [CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16]([CH2:18][N:19]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:37]=[CH:36][C:35]([C:38]([F:41])([F:40])[F:39])=[CH:34][CH:33]=2)=[CH:22][C:21]([C:42]([NH2:44])=O)=[N:20]1)=[O:17])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P(Cl)(Cl)(Cl)=O>N1C=CC=CC=1.C(OCC)(=O)C>[CH2:1]([O:8][CH:9]1[CH2:14][CH2:13][CH2:12][CH2:11][CH:10]1[NH:15][C:16](=[O:17])[CH2:18][N:19]1[C:23]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=2[C:32]2[CH:33]=[CH:34][C:35]([C:38]([F:40])([F:41])[F:39])=[CH:36][CH:37]=2)=[CH:22][C:21]([C:42]#[N:44])=[N:20]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NC(=O)c1cc(OCc2ccccc2-c2ccc(C(F)(F)F)cc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Solvent: O=P(Cl)(Cl)Cl
Solvent: c1ccncc1
Solvent: CCOC(C)=O
Product: N#Cc1cc(OCc2ccccc2-c2ccc(C(F)(F)F)cc2)n(CC(=O)NC2CCCCC2OCc2ccccc2)n1
Temperature: 0 °C
Reaction time: 2.5 h
Yield: 36.6 %

Procedure:
To an ice cold solution of 310 mg (0.33 mmol max) of 1-[(2-benzyloxy-cyclohexylcarbamoyl)-methyl]-5-(4′-trifluoromethyl-biphenyl-2-ylmethoxy)-1H-pyrazole-3-carboxylic acid amide in 3 mL of pyridine was added 0.071 mL (0.76 mmol) of phosphorus oxychloride, and the resulting mixture was stirred at 0° C. for 2.5 h. The mixture was then diluted with ethyl acetate, washed with 1 N HCl solution, dried over sodium sulfate and concentrated. Since analysis by LC-MS indicated that some starting material was still present, the reaction was repeated under the same experimental conditions, and after complete consumption of starting material, it was worked up and purified via chromatography on silica gel (Biotage) with 3:1 hexane:ethyl acetate to give 71 mg (37% yield) of N-(2-benzyloxy-cyclohexyl)-2-[3-cyano-5-(4′-trifluoromethyl-biphenyl-2-ylmethoxy)-pyrazol-1-yl]-acetamide. LC-MS—calcd for C33H31F3N4O3 [M+H]+ 589.23, found 589.2.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7]([C:9]2[N:10]=[C:11]3[CH:16]=[CH:15][CH:14]=[N:13][N:12]3[CH:17]=2)[CH:8]=1)#[N:2].Cl.NO.C([N:28](CC)CC)C.[O:33](C(CCl)=O)[C:34]([CH2:36][Cl:37])=O>CCO>[Cl:37][CH2:36][C:34]1[O:33][N:28]=[C:1]([C:3]2[CH:4]=[C:5]([NH:18][S:19]([CH3:22])(=[O:21])=[O:20])[CH:6]=[C:7]([C:9]3[N:10]=[C:11]4[CH:16]=[CH:15][CH:14]=[N:13][N:12]4[CH:17]=3)[CH:8]=2)[N:2]=1
Reactant: CCN(CC)CC
Reactant: O=C(CCl)OC(=O)CCl
Reactant: CS(=O)(=O)Nc1cc(C#N)cc(-c2cn3ncccc3n2)c1
Agent: Cl
Agent: NO
Solvent: CCO
Product: CS(=O)(=O)Nc1cc(-c2cn3ncccc3n2)cc(-c2noc(CCl)n2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 90 %

Procedure:
A mixture of N-(3-cyano-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide (0.25 mmol), hydroxylamine hydrochloride (0.75 mmol) and triethylamine (1 mmol) in EtOH (12 mL) was refluxed for 4 hours. After removal of the solvent in vacuo, the residue was dissolved in THF (12 mL), added with (ClCH2CO)2O (0.75 mmol) and triethylamine (1 mmol), and stirred at room temperature for 1 hours. Then it was heated to reflux for another 8 hours. After removal of the solvent in vacuo and addition of water, the mixture was extracted with EtOAc. The combined organic layer was washed with water and brine sequentially, dried over anhydrous Na2SO4 and concentrated. The resulting residue was purified by column chromatography to give N-(3-(5-(chloromethyl)-1,2,4-oxadiazol-3-yl)-5-(imidazo[1,2-b]pyridazin-2-yl)phenyl)methanesulfonamide in 90% yield.
Reaction SMILES: [Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10](O)=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:22])[CH3:21])[C@H:15]1[CH3:23].Cl.CN(C)CCCN=C=NCC.C(N(CC)CC)C.[NH:43]1[CH2:48][CH2:47][O:46][CH2:45][CH2:44]1>CN(C)C=O.C(OCC)(=O)C>[Br:1][C:2]1[C:7](=[O:8])[N:6]([CH2:9][C:10]([N:43]2[CH2:48][CH2:47][O:46][CH2:45][CH2:44]2)=[O:11])[N:5]=[CH:4][C:3]=1[NH:13][C@@H:14]1[CH2:19][C@@H:18]2[CH2:20][C@@H:16]([C:17]2([CH3:21])[CH3:22])[C@H:15]1[CH3:23]
Reactant: C1COCCN1
Reactant: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)O)c(=O)c1Br)C2(C)C
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: C[C@@H]1[C@H]2C[C@@H](C[C@H]1Nc1cnn(CC(=O)N3CCOCC3)c(=O)c1Br)C2(C)C
Yield: 56.6 %

Procedure:
2-{5-Bromo-6-oxo-4-[(1R,2R,3R,5S)-2,6,6-trimethylbicyclo[3.1.1]hept-3-ylamino]pyridazin-1(6H)-yl}acetic acid (30 mg, 0.078 mmol), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (22 mg, 0.117 mmol), 1-hydroxybenzotriazole anhydride (16 mg, 0.117 mmol) and triethylamine (16 μL, 0.117 mmol) in N,N-dimethylformamide (0.3 mL) was stirred with morpholine (10 μL, 0.117 mmol) at room temperature for 5 hours. After completion of the reaction, ethyl acetate was added, and the organic layer was washed with saturated aqueous ammonium sulfate and saturated aqueous sodium hydrogen carbonate and saturated aqueous sodium chloride, dried over anhydrous magnesium sulfate and evaporated under reduced pressure. The resulting residue was purified by silica gel chromatography (chloroform/ethyl acetate=1/1) to give the desired product (20 mg, 57% yield).
Reaction SMILES: [N:1]1([C:6]2[CH:7]=[C:8]([C:15]([O:17][CH3:18])=[O:16])[CH:9]=[C:10]([CH:14]=2)[C:11](O)=[O:12])[CH:5]=[CH:4][CH:3]=[CH:2]1.C(N(CC)CC)C.ClC(OCC(C)C)=O>O1CCCC1>[OH:12][CH2:11][C:10]1[CH:9]=[C:8]([CH:7]=[C:6]([N:1]2[CH:5]=[CH:4][CH:3]=[CH:2]2)[CH:14]=1)[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)c1cc(C(=O)O)cc(-n2cccc2)c1
Agent: CC(C)COC(=O)Cl
Solvent: CCN(CC)CC
Solvent: C1CCOC1
Product: COC(=O)c1cc(CO)cc(-n2cccc2)c1
Reaction time: 0.75 h
Yield: 83 %

Procedure:
To a solution of 5-(pyrrol-1-yl)-3-methoxycarbonylbenzoic acid (9.37 g) in tetrahydrofuran (100 ml) was added triethylamine (6.4 ml) followed by slow addition of isobutyl chloroformate (5.9 ml) under nitrogen at -40° C. to -30° C. The reaction mixture was stirred below -20° C. for 45 minutes. Then, triethylamine hydrochloride was filtered off and washed with cold tetrahydrofuran, and the filtrate was added as quickly as possible to a suspension of sodium borohydride (4.35 g) in tetrahydrofuran-water (8:1, 80 ml) at 0° C. with vigorous stirring. The stirring was continued at ambient temperature for 5 hours, followed by acidification of the solution to pH 5. The tetrahydrofuran was removed under reduced pressure, and the product was extracted with ethyl acetate. The ethyl acetate extracts were washed with water and brine, dried over magnesium sulfate and evaporated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with a mixture of chloroform and methanol (30:1). The eluted fractions containing the desired product were collected and evaporated in vacuo to give methyl 3-hydroxymethyl-5-(pyrrol-1-yl)benzoate (7.33 g).
Reaction SMILES: FC(F)(F)C(O)=O.[CH3:8][S:9][CH2:10][C:11]1[CH:12]=[CH:13][CH:14]=[C:15]2[C:19]=1[NH:18][CH:17]=[CH:16]2.[CH:20]1([C:23]([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)(O)[CH3:24])[CH2:22][CH2:21]1>ClCCl>[CH:20]1([C:23]([C:16]2[C:15]3[C:19](=[C:11]([CH2:10][S:9][CH3:8])[CH:12]=[CH:13][CH:14]=3)[NH:18][CH:17]=2)([C:26]2[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=2)[CH3:24])[CH2:22][CH2:21]1
Reactant: Cc1ccc(C(C)(O)C2CC2)cc1
Reactant: CSCc1cccc2cc[nH]c12
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CSCc1cccc2c(C(C)(c3ccc(C)cc3)C3CC3)c[nH]c12
Temperature: 25 °C
Reaction time: 8 h

Procedure:
0.23 ml (3.00 mmol) of trifluoroacetic acid was added to 885 mg (4.99 mmol) of the compound from Example 8A and 440 mg (2.50 mmol) of the compound from Example 137A in 44 ml of dichloromethane, and the mixture was stirred at RT overnight. The reaction mixture was concentrated in a rotary evaporator. The residue was purified by preparative HPLC (RP18 column; mobile phase: acetonitrile/water gradient with addition of 0.1% formic acid) to result in 87.4 mg (10% of theory) of the title compound as mixture of diastereomers.
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([O:31]C)=[O:30])([CH2:26][CH:27]=[CH2:28])[CH2:10][CH:11]1[CH2:16][CH2:15][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:25])([CH3:24])[CH3:23])=[O:18])[CH2:13][CH2:12]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C(OC(NC(C(OC)=O)(CC=C)C[C@@H]1CCCCN1C(OCC[Si](C)(C)C)=O)=O)(C)(C)C.C[Si](C=[N+]=[N-])(C)C.C(O)(=O)C>CO.CCCCCC>[C:1]([O:5][C:6]([NH:8][C@@:9]([C:29]([OH:31])=[O:30])([CH2:26][CH:27]=[CH2:28])[CH2:10][CH:11]1[CH2:12][CH2:13][N:14]([C:17]([O:19][CH2:20][CH2:21][Si:22]([CH3:23])([CH3:25])[CH3:24])=[O:18])[CH2:15][CH2:16]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: C=CCC(C[C@@H]1CCCCN1C(=O)OCC[Si](C)(C)C)(NC(=O)OC(C)(C)C)C(=O)OC
Agent: C[Si](C)(C)C=[N+]=[N-]
Solvent: CO
Solvent: CC(=O)O
Solvent: CCCCCC
Product: C=CC[C@@](CC1CCN(C(=O)OCC[Si](C)(C)C)CC1)(NC(=O)OC(C)(C)C)C(=O)O
Temperature: 0 °C
Reaction time: 1 h

Procedure:
2-Trimethylsilanylethyl (S)-4-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate 1.1 g of 2-trimethylsilanylethyl (S)-(2-tert-butoxycarbonylamino-2-methoxycarbonylpent-4-enyl)piperidine-1-carboxylate were dissolved in 33 ml of methanol and cooled to 0° C. 2.3 ml of a 2 N solution of trimethylsilyldiazomethane in hexane were added dropwise. The mixture was allowed to reach room temperature in the course of 3 h, and then a further 2.3 ml of the trimethylsilyldiazomethane solution were added dropwise. The mixture was stirred for 1 h and then the reaction was stopped by adding 1 ml of acetic acid. After stirring for 30 min, the solvents are removed in vacuo and the residue was chromatographed on silica gel.