Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C1CCN2C(=NCCC2)CC1.[F:52][B-](F)(F)F>ClCCl>[CH2:1]([O:8][C@@H:9]1[C@@H:15]([O:16][CH2:17][C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)[C@H:14]([O:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)[C@@H:13]([CH2:32][O:33][CH2:34][C:35]2[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=2)[O:12][CH:10]1[F:52])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: OC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reactant: F[B-](F)(F)F
Solvent: C1CCC2=NCCCN2CC1
Solvent: ClCCl
Product: FC1O[C@H](COCc2ccccc2)[C@@H](OCc2ccccc2)[C@H](OCc2ccccc2)[C@H]1OCc1ccccc1
Reaction time: 1.5 h

Procedure:
To a solution of 2,3,4,6-tetra-O-benzyl-D-glucopyranose (100 mg, 0.18 mmol) and DBU (44 μL, 0.28 mmol) in dichloromethane (0.5 mL) is added diethylaminodifluorosulfinium tetrafluoroborate (68 mg, 0.28 mmol) at room temperature and under nitrogen. After 90 min of stirring, the reaction mixture is quenched at room temperature with a 5% aqueous sodium bicarbonate solution, stirred for 15 min, and the resulting mixture is extracted twice using dichloromethane. The organic phases are combined, dried over magnesium sulfate and filtered through a pad of silica gel. Solvents are evaporated to provide 2,3,4,6-tetra-O-benzyl-D-glucopyranosyl fluoride (96 mg, 96%, β:α anomers in a 1.1:1 ratio respectively) as a foam. 1H NMR (CDCl3, 300 MHz) δ 7.47-7.15 (m, 20H), 5.61 (dd, 2JH-F=53.2 Hz, 3JH-H=2.3 Hz, 0.48H, α-anomer), 5.31 (dd, 2JH-F=51.8 Hz, 3JH-H=6.4 Hz, 0.52H, β-anomer), 5.07-4.48 (m, 8H), 4.11-3.54 (m, 6H); 19F NMR (CDCl3, 282 MHz) δ −138.0 (dd, 1JF-H=53.4 Hz, 2JF-H=10.6 Hz, β-F), −149.44 (dd, 1JF-H=54.4 Hz, 2JF-H=25.8 Hz, α-F); 13C NMR (CDCl3, 75 MHz) δ 138.5, 138.3, 138.1, 137.9, 137.5, 128.6, 128.5, 128.2, 128.1, 128.0, 127.9, 127.8, 112.8 (d, 1JC-F=215.2 Hz, β-anomer), 108.6 (d, 1JC-F=228.7 Hz, α-anomer), 83.6, 83.4, 81.7, 81.5, 81.4, 79.5, 79.2, 77.5, 77.1, 77.0, 77.7, 75.9, 75.5, 75.2, 75.0, 74.9, 74.8, 74.5, 73.6, 73.5, 72.7, 68.4, 67.8.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][N:23]=[C:24]([O:25]C)[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6].B(Br)(Br)Br>C(Cl)(Cl)Cl.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[C:4]([CH:7]=[C:8]([Cl:27])[C:9]=1[NH:10][C:11]1[C:20]2[CH:21]=[CH:22][NH:23][C:24](=[O:25])[C:19]=2[C:18]2[C:13](=[CH:14][CH:15]=[N:16][CH:17]=2)[N:12]=1)[C:5]#[N:6]
Reactant: COc1nccc2c(Nc3c(Cl)cc(C#N)cc3Cl)nc3ccncc3c12
Agent: BrB(Br)Br
Solvent: ClC(Cl)Cl
Solvent: CCOC(C)=O
Product: N#Cc1cc(Cl)c(Nc2nc3ccncc3c3c(=O)[nH]ccc23)c(Cl)c1
Temperature: 85 °C

Procedure:
To a solution of 3,5-dichloro-4-[(10-methoxypyrido[4,3-c]-1,6-naphthyridin-6-yl)amino]benzonitrile (140 mg, 0.35 mmol) in chloroform (3 mL) was added boron tribromide (2.5 mL, 2.5 mmol, 1M in dichloromethane) and the mixture was heated at 85° C. for 45 min in a sealed tube. After cooling to room temperature, the reaction was diluted with ethyl acetate and washed with saturated aqueous sodium bicarbonate, followed by brine. The organic layer was dried with sodium sulfate, filtered and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel eluting with MeOH in dichloromethane to afford the title compound.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([O:21]C)=[O:20])=[CH:17][CH:16]=2)[N:10]=1.[OH-].[Na+]>C1COCC1.O>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([F:8])[C:3]=1[C:9]1[NH:13][C:12](=[O:14])[N:11]([C:15]2[CH:24]=[CH:23][C:18]([C:19]([OH:21])=[O:20])=[CH:17][CH:16]=2)[N:10]=1
Reactant: COC(=O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: O=C(O)c1ccc(-n2nc(-c3c(F)cccc3Cl)[nH]c2=O)cc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 52 %

Procedure:
To a solution of methyl 4-[3-(2-chloro-6-fluorophenyl)-5-oxo-4,5-dihydro-1H-1,2,4-triazol-1-yl]benzoate (2.0 g, 5.76 mmol) in THF:water (5 mL:10 mL) was added sodium hydroxide (0.691 g, 17.27 mmol). The reaction mass was stirred at RT for 3 h. The reaction mass was diluted with water and washed the aqueous layer with diethyl ether and toluene. The aqueous layer was cooled to 15° C. and acidified with dilute HCl. The reaction mass was filtered off to afford 1.0 g of desired product. 1H NMR (300 MHz, DMSO d6): δ 7.50 (t, J=9.0 Hz, 1H), 7.58 (d, J=7.8 Hz, 1H), 7.67-7.74 (m, 1H), 8.06 (s, 4H), 12.77 (br s, 1H).
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=O)[CH:8]=2)[CH:3]=[N:2]1.[NH:13]1[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>>[N:13]1([C:10]([C:7]2[CH:8]=[C:9]3[C:4]([CH:3]=[N:2][NH:1]3)=[CH:5][CH:6]=2)=[O:12])[CH2:18][CH2:17][CH2:16][C@@H:15]2[C:19]3[CH:20]=[CH:21][CH:22]=[CH:23][C:24]=3[CH2:25][C@H:14]12
Reactant: c1ccc2c(c1)C[C@@H]1NCCC[C@H]21
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Product: O=C(c1ccc2cn[nH]c2c1)N1CCC[C@@H]2c3ccccc3C[C@@H]21
Yield: 5 %

Procedure:
The title compound is prepared from 1H-indazole-6-carboxylic acid and cis-2,3,4,4a,9,9a-hexahydro-1H-indeno[2,1-b]pyridine following a procedure analogous to that described in Example 1 [2-(7-aza-1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium hexafluorophosphate is used]. Yield: 5% of theory; LC (method 4): tR=1.92 min; Mass spectrum (ESI+): m/z=318 [M+H]+.
Reaction SMILES: C([O:5][C:6](=[O:34])[CH2:7][N:8]([C:16](=[O:33])[CH:17]([CH:27]1[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1)[CH2:18][C:19]1[CH:24]=[CH:23][C:22]([C:25]#[N:26])=[CH:21][CH:20]=1)[CH2:9][CH:10]1[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]1)(C)(C)C.Cl.[NH2:36][OH:37].C(N(CC)CC)C>C(O)(C)C>[CH:27]1([CH:17]([CH2:18][C:19]2[CH:20]=[CH:21][C:22]([C:25](=[NH:26])[NH:36][OH:37])=[CH:23][CH:24]=2)[C:16]([N:8]([CH2:7][C:6]([OH:34])=[O:5])[CH2:9][CH:10]2[CH2:15][CH2:14][CH2:13][CH2:12][CH2:11]2)=[O:33])[CH2:32][CH2:31][CH2:30][CH2:29][CH2:28]1
Reactant: CC(C)(C)OC(=O)CN(CC1CCCCC1)C(=O)C(Cc1ccc(C#N)cc1)C1CCCCC1
Reactant: NO
Agent: Cl
Solvent: CC(C)O
Solvent: CCN(CC)CC
Product: N=C(NO)c1ccc(CC(C(=O)N(CC(=O)O)CC2CCCCC2)C2CCCCC2)cc1

Procedure:
{[3-(4-Cyano-phenyl)-2-(R,S)-cyclohexyl-propionyl]-cyclohexylmethyl-amino}-acetic acid tert-butyl ester (2.0 g, 4.29 mmol), hydroxylamine hydrochloride (0.89 g, 12.87 mmol) and triethylamine (1.3 g, 12.87 mmol) were stirred in isopropanol (80 ml) at room temperature for 24 hours. After evaporation, the residue was treated with potassium hydrogen sulfate solution and extracted with dichloromethane. The organic layer was dried and evaporated. Yield: 1.52 g (80%), MS m/z: 444.3 (M+H)+.
Reaction SMILES: [CH:1]1[CH:2]=[CH:3][C:4]([C@H:7]2[O:9][C@@H:8]2[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=2)=[CH:5][CH:6]=1.[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH2:26])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21].O>CC(C)=O>[CH2:16]([O:22][CH2:23][CH2:24][CH2:25][NH:26][CH:7]([C:4]1[CH:3]=[CH:2][CH:1]=[CH:6][CH:5]=1)[CH:8]([C:10]1[CH:11]=[CH:12][CH:13]=[CH:14][CH:15]=1)[OH:9])[CH2:17][CH2:18][CH2:19][CH2:20][CH3:21]
Reactant: CCCCCCOCCCN
Reactant: c1ccc([C@H]2O[C@@H]2c2ccccc2)cc1
Solvent: CC(C)=O
Solvent: O
Product: CCCCCCOCCCNC(c1ccccc1)C(O)c1ccccc1
Temperature: 140 °C
Reaction time: 44 h
Yield: 33.8 %

Procedure:
A mixture of trans-stilbene oxide (1.96 g, 0.010 mole) and 3-hexyloxypropylamine (1.75 g, 0.011 mole) was heated at 140° C. for 6 hours. After standing at ambient temperature for 44 hours, the reaction mixture was dissolved in acetone (10 ml) and the solution poured into water (150 ml). The light brown oil which separated from solution solidified on standing for 1 hour. The solid was collected and dried on absorbent paper for 18 hours. The solid was then triturated in isooctane (soluble) and the solution chilled to obtain a solid which was collected, washed with cold isooctane, and dried under ambient conditions to obtain 1.20 g (34%) of the product, m.p. 67°-69° C.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([OH:17])=O)=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH:23]1[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]1>>[CH2:1]([O:8][C:9]1[CH:19]=[CH:18][C:12]([CH:13]=[CH:14][C:15]([N:23]2[CH2:28][CH2:27][CH2:26][CH2:25][CH2:24]2)=[O:17])=[CH:11][C:10]=1[N+:20]([O-:22])=[O:21])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: C1CCNCC1
Reactant: O=C(O)C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1
Product: O=C(C=Cc1ccc(OCc2ccccc2)c([N+](=O)[O-])c1)N1CCCCC1
Yield: 65.3 %

Procedure:
Following a procedure similar to that described in Example 1, but using 1 g of 4-benzyloxy-3-nitrocinnamic acid and 400 mg of piperidine, 0.8 g of the title compound were obtained, melting at 155°-156° C.
Reaction SMILES: [NH2:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:12]([NH:14][CH3:15])=[O:13])[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4].[C:40]([O:44][C:45]([NH:47][C:48]([CH3:53])([CH3:52])[C:49](O)=[O:50])=[O:46])([CH3:43])([CH3:42])[CH3:41].ON1C2C=CC=CC=2N=N1.CN1CCOCC1.CN(C)CCCN=C=NCC>CN(C=O)C>[C:40]([O:44][C:45](=[O:46])[NH:47][C:48]([C:49](=[O:50])[NH:1][CH:2]([CH2:32][C:33]1[CH:38]=[CH:37][C:36]([F:39])=[CH:35][CH:34]=1)[C:3]([N:5]1[CH2:10][CH2:9][N:8]([CH:11]([C:12](=[O:13])[NH:14][CH3:15])[CH2:16][C:17]2[CH:26]=[CH:25][C:24]3[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=3)[CH:18]=2)[C:7](=[O:27])[CH:6]1[CH2:28][CH:29]1[CH2:31][CH2:30]1)=[O:4])([CH3:53])[CH3:52])([CH3:43])([CH3:41])[CH3:42]
Reactant: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(N)Cc2ccc(F)cc2)C(CC2CC2)C1=O
Reactant: CC(C)(C)OC(=O)NC(C)(C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: On1nnc2ccccc21
Solvent: CN(C)C=O
Solvent: CN1CCOCC1
Product: CNC(=O)C(Cc1ccc2ccccc2c1)N1CCN(C(=O)C(Cc2ccc(F)cc2)NC(=O)C(C)(C)NC(=O)OC(C)(C)C)C(CC2CC2)C1=O
Reaction time: 3 h
Yield: 93 %

Procedure:
To a solution of 2-{4-[2-amino-3-(4-fluorophenyl)-propionyl]-3-cyclopropylmethyl-2-oxo-piperazin-1-yl}-N-methyl-3-naphthalen-2-yl-propionamide, 18, (44 mg, 0.068 mmol) in DMF (1 mL) are added 2-tert-butoxycarbonylamino-2-methyl-propionic acid (44 mg, 0.079 mmol), 1-hydroxybenzotriazole (20 mg, 0.148 mmol), N-methylmorpholine (41 mg, 0.41 mmol) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide (16 mg, 0.083 mmol) consecutively. The reaction mixture is stirred for 3 hours, quenched with aqueous NH4Cl and extracted several times with ethyl acetate. The combined extracts are dried over Na2SO4, filtered and concentrated in vacuo to a residue which is purified over silica gel (CH2Cl2/CH3OH, 13:1) to afford 45 mg (93% yield) of the desired product. MS (ESMS) m/z 716.3 (M+H)+.
Reaction SMILES: C(N(CC)CC)C.[CH:8]([C:11]1[CH:15]=[C:14]([CH:16]2[O:21][C:20](=[O:22])[CH2:19][C:18](=[O:23])[CH2:17]2)[O:13][N:12]=1)([CH3:10])[CH3:9].[C:24](Cl)(=[O:28])[CH2:25][CH2:26][CH3:27]>C1COCC1>[C:24]([CH:19]1[C:18](=[O:23])[CH2:17][CH:16]([C:14]2[O:13][N:12]=[C:11]([CH:8]([CH3:10])[CH3:9])[CH:15]=2)[O:21][C:20]1=[O:22])(=[O:28])[CH2:25][CH2:26][CH3:27]
Reactant: CC(C)c1cc(C2CC(=O)CC(=O)O2)on1
Reactant: CCCC(=O)Cl
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CCCC(=O)C1C(=O)CC(c2cc(C(C)C)no2)OC1=O
Temperature: 0 °C
Reaction time: 1 h
Yield: 35.5 %

Procedure:
12.6 g of triethylamine was added to 27.9 g of 6-(3-isopropylisoxazol-5-yl)-tetrahydropyran-2,4-dione in 200 ml of THF. At 0° C., 13.3 g of butyryl chloride was dripped in and the mixture was stirred for one hour at 0° C. The mixture was evaporated, followed by partitioning between methylene chloride and water. The organic phase was worked up, i.e., extracted with water, 10% strength sodium carbonate solution and again with water, dried with sodium sulfate and evaporated again. The residue was dissolved in anhydrous methylene chloride and stirred for 48 hours with 1.3 g of 4-(N,N-dimethylamino)-pyridine. Removal of the solvent was followed by chromatography over silica gel with methylene chloride and methanol (98.5:1.5). The isolated compound was recrystallized from a small amount of cyclohexane. There was obtained 13 g of product.
Reaction SMILES: [CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:25])([F:24])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26](OC4C=CC([N+]([O-])=O)=CC=4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:3][CH2:2]1.Cl.[F:39][C:40]1([F:46])[CH2:45][CH2:44][NH:43][CH2:42][CH2:41]1>>[CH:1]1([C:4]2[N:8]=[C:7]([CH:9]3[CH2:14][CH:13]([C:15]4[CH:20]=[CH:19][C:18]([O:21][C:22]([F:24])([F:25])[F:23])=[CH:17][CH:16]=4)[CH2:12][N:11]([C:26]([N:43]4[CH2:44][CH2:45][C:40]([F:46])([F:39])[CH2:41][CH2:42]4)=[O:27])[CH2:10]3)[O:6][N:5]=2)[CH2:2][CH2:3]1
Reactant: FC1(F)CCNCC1
Reactant: O=C(Oc1ccc([N+](=O)[O-])cc1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1
Agent: Cl
Product: O=C(N1CCC(F)(F)CC1)N1CC(c2ccc(OC(F)(F)F)cc2)CC(c2nc(C3CC3)no2)C1

Procedure:
100 mg (0.19 mmol) of the compound from Example 176A and 91 mg (0.58 mmol) of 4,4-difluoropiperidine hydrochloride were reacted according to the General Method 6. Yield: 48 mg (50% of theory)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[NH:10][CH2:11][CH3:12])[C:5]#[N:6].[F:13][C:14]1[CH:15]=[C:16]([N:20]2[C:24]([CH2:25][C:26](O)=O)=[CH:23][CH:22]=[N:21]2)[CH:17]=[CH:18][CH:19]=1.Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1>[CH2:11]([N:10]1[C:9]2[CH:8]=[CH:7][C:4]([C:5]#[N:6])=[CH:3][C:2]=2[N:1]=[C:26]1[CH2:25][C:24]1[N:20]([C:16]2[CH:17]=[CH:18][CH:19]=[C:14]([F:13])[CH:15]=2)[N:21]=[CH:22][CH:23]=1)[CH3:12]
Reactant: CCNc1ccc(C#N)cc1N
Reactant: O=C(O)Cc1ccnn1-c1cccc(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: c1ccncc1
Product: CCn1c(Cc2ccnn2-c2cccc(F)c2)nc2cc(C#N)ccc21
Temperature: 25 °C
Reaction time: 17.5 h

Procedure:
To a stirring solution of 3-amino-4-ethylaminobenzonitrile (887 mg, 5.5 mmol) and 1-(3-Fluorophenyl)-5-carboxymethylpyrazole (1.10 g, 5 mmol) in pyridine (5 mL) is added 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (1.15 g, 6 mmol). The mixture is stirred at room temperature for 17.5 h, then concentrated. The residue is cooled in an ice bath, aqueous HCl is added with stirring, the precipitate is collected by filtration, rinsed well with water and dried. The solid is added to acetic acid (75 mL) and heated at reflux for 5.5 h. The mixture is cooled, concentrated, and purified by silica gel chromatography to give 1-Ethyl-2-{[2-(3-fluorophenyl)-pyrazol-3-yl]methyl}-5-cyano-1H-benzimidazole. The product is converted to the mesylate salt in acetone. 1H NMR (CDCl3): δ 8.17 (s, 1H), 7.89 (d, J=8.52 Hz, 1H), 7.68-7.75 (m 1H), 7.44-7.54 (m, 2H), 7.37-7.40 (m, 1H), 7.21-7.28 (m, 1H), 6.35 (d, J=1.65 Hz, 1H) 4.65 (s, 2H), 4.29 (q, J=7.14 Hz, 2H), 2.34 (s, 3H), 1.19 (t, J=7.14 Hz, 3H). LCMS 346.0 (MH+), 344.4 (MH−).
Reaction SMILES: C(=O)([O-])[O-].[Na+].[Na+].[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=O.Cl.[NH2:20][OH:21]>CO>[CH3:7][C:8]([CH3:18])([CH3:17])[CH2:9][CH2:10][CH:11]1[CH2:15][CH2:14][CH2:13][C:12]1=[N:20][OH:21]
Reactant: CC(C)(C)CCC1CCCC1=O
Reactant: NO
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)CCC1CCCC1=NO
Temperature: 50 °C
Reaction time: 15 h

Procedure:
At 0° C., aq. sodium carbonate solution is added to a solution consisting of 20.0 g of (119 mmol) of 2-(3,3-dimethylbutyl)cyclopentanone and 16.5 g (238 mmol) of hydroxylamine hydrochloride in 200 ml of methanol until the pH is 8. The mixture is then stirred at 50° C. for 15 hours. After the reaction has ended, the mixture is cooled to room temperature and filtered off and the product is concentrated under reduced pressure. The residue is extracted with water/diethyl ether. The org. phase is dried with sodium sulphate and concentrated under reduced pressure. This gives 20.0 g (92% of theory) of an 2-(3,3-dimethylbutyl)-N-hydroxycyclopentanimine.
Reaction SMILES: [N:1]1([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.C(N(C(C)C)CC)(C)C.[Cl:38][CH2:39][C:40](Cl)=[O:41]>C(Cl)Cl>[Cl:38][CH2:39][C:40]([N:4]1[CH2:5][CH2:6][N:1]([C:7]2[CH:28]=[CH:27][C:10]([NH:11][C:12]3[N:17]=[C:16]([C:18]4[N:22]([CH:23]([CH3:25])[CH3:24])[C:21]([CH3:26])=[N:20][CH:19]=4)[CH:15]=[CH:14][N:13]=3)=[CH:9][CH:8]=2)[CH2:2][CH2:3]1)=[O:41]
Reactant: Cc1ncc(-c2ccnc(Nc3ccc(N4CCNCC4)cc3)n2)n1C(C)C
Reactant: O=C(Cl)CCl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cc1ncc(-c2ccnc(Nc3ccc(N4CCN(C(=O)CCl)CC4)cc3)n2)n1C(C)C
Reaction time: 2 h
Yield: 86.3 %

Procedure:
2-[4-(Piperazin-1-yl)anilino]-4-(1-isopropyl-2-methyl-1H-imidazol-5-yl)pyrimidine (Example 20; 1.89 g, 5 mmol), di-isopropylethylamine (0.956 ml, 5.5 mmol) in DCM (25 ml) was treated at 0° C. with chloroacetyl chloride (0.438 ml, 5.5 mmol). The mixture was stirred at ambient for 2 hours, diluted with DCM (25 ml), washed with aqueous saturated sodium bicarbonate solution (20 ml) and aqueous saturated sodium chloride solution (20 ml). The solution was dried and evaporated at reduced pressure to give the title compound, (1.96 g, 87%). NMR (CDCl3) 8.30 (d, 1H), 7.44 (d, 2H), 7.35 (s, 1H), 6.96 (s, 1H), 6.92 (d, 1H), 6.85 (d, 1H), 5.68-5.56 (m, 1H), 4.12 (s, 2H), 3.83-3.76 (m, 2H), 3.72-3.67 (m, 2H), 3.22-3.11 (m, 4H), 2.59 (s, 3H), 1.48 (d, 6H); m/z 454.
Reaction SMILES: S(Cl)(Cl)=O.[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([OH:10])=O.[Br:16][C:17]1[C:18]([CH3:24])=[C:19]([CH:21]=[CH:22][CH:23]=1)[NH2:20].C([O-])([O-])=O.[K+].[K+]>C1COCC1>[NH2:5][C:6]1[C:14]([CH3:15])=[CH:13][CH:12]=[CH:11][C:7]=1[C:8]([NH:20][C:19]1[CH:21]=[CH:22][CH:23]=[C:17]([Br:16])[C:18]=1[CH3:24])=[O:10]
Reactant: Cc1cccc(C(=O)O)c1N
Reactant: Cc1c(N)cccc1Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O=S(Cl)Cl
Solvent: C1CCOC1
Product: Cc1cccc(C(=O)Nc2cccc(Br)c2C)c1N
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 40.5 %

Procedure:
A mixture of thionyl chloride (3.15 g, 26.5 mmol) and 2-amino-3-methylbenzoic acid (2.00 g, 13.23 mmol) in THF (50 mL) was heated at reflux for 2 h. The cooled mixture was concentrated and the residue was combined with 3-bromo-2-methylaniline (4.92 g, 26.5 mmol) in THF (50 mL) and heated at reflux for 5 h. The mixture was cooled to room temperature, treated with 10% aqueous K2CO3 and stirred at room temperature for 30 min. The resulting mixture was extracted 3 times with DCM, and the combined organic phases were washed with water, dried and concentrated. The residue was purified by column chromatography on silica gel (330 g), eluting with EtOAc-hexanes (gradient from 0-20%), to give 2-amino-N-(3-bromo-2-methylphenyl)-3-methylbenzamide as a yellow solid (1.71 g, 40% yield). Mass spectrum m/z 319, 321 (M+H)+. 1H NMR (400 MHz, chloroform-d) δ 7.70 (d, J=7.9 Hz, 1H), 7.64 (br. s., 1H), 7.50-7.40 (m, 2H), 7.24 (d, J=7.3 Hz, 1H), 7.14 (t, J=8.0 Hz, 1H), 6.70 (t, J=7.6 Hz, 1H), 5.67 (br. s., 2H), 2.44 (s, 3H), 2.23 (s, 3H).
Reaction SMILES: Cl.[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][NH:17][CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1.C(N(CC)C(C)C)(C)C.[C:30](Cl)(=[O:33])[CH2:31][CH3:32]>ClCCl>[Br:2][C:3]1[CH:8]=[CH:7][C:6]([N:9]2[C:13]([CH2:14][C@@H:15]3[CH2:19][CH2:18][N:17]([C:30](=[O:33])[CH2:31][CH3:32])[CH2:16]3)=[N:12][NH:11][C:10]2=[O:20])=[CH:5][CH:4]=1
Reactant: CCC(=O)Cl
Reactant: O=c1[nH]nc(C[C@@H]2CCNC2)n1-c1ccc(Br)cc1
Agent: Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CCC(=O)N1CC[C@@H](Cc2n[nH]c(=O)n2-c2ccc(Br)cc2)C1
Temperature: 25 °C
Reaction time: 2 h
Yield: 61.7 %

Procedure:
In a 4 mL screwcap vial was placed 4-(4-bromophenyl)-5-[(3S)-3-pyrrolidinylmethyl]-2,4-dihydro-3H-1,2,4-triazol-3-one hydrochloride (0.278 mmol). Added to the vial were dichloromethane (2 mL) and N,N-diisopropylethylamine (0.859 mmol). The vial contents were stirred for 1 min, at which point propanoyl chloride (0.319 mmol) was added. The vial was capped and the contents were stirred at room temperature for 2 h. The reaction was quenched with saturated aq NH4Cl (1 mL) and the solution was stirred vigorously for 1 min. The separation of the two layers occurred upon settling of the solution. The organic layer was removed, dried over sodium sulfate, filtered, and concentrated in vacuo. Silica gel chromatography (0-10% methanol:ethyl acetate) was utilized to purify the title compound (65 mg, 61% yield). MS(ES)+ m/e 379.1, 380.8 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([N+:21]([O-])=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[C:24]1([C:30]2[O:31][C:32]([C:38]([F:41])([F:40])[F:39])=[C:33]([C:35](O)=[O:36])[N:34]=2)[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1>>[C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][CH:11]([O:14][C:15]2[CH:20]=[CH:19][C:18]([NH:21][C:35]([C:33]3[N:34]=[C:30]([C:24]4[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=4)[O:31][C:32]=3[C:38]([F:40])([F:41])[F:39])=[O:36])=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: O=C(O)c1nc(-c2ccccc2)oc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc([N+](=O)[O-])cc2)CC1
Product: CC(C)(C)OC(=O)N1CCC(Oc2ccc(NC(=O)c3nc(-c4ccccc4)oc3C(F)(F)F)cc2)CC1

Procedure:
To a solution of 4-fluoronitrobenzene (1.41 g, 10 mmol) in THF (50 mL) was added N-Boc-4-hydroxypiperidine (2.01 g, 10 mmol) and sodium hydride (60% in mineral oil, 583 mg, 14.5 mmol). The mixture was stirred at room temperature for 14 hrs. After purification through flash column chromatography, 4-(4-nitro-phenoxy)-piperidine-1-carboxylic acid tert-butyl ester (2.51 g, 78% yield) was obtained as a solid. This nitro compound was hydrogenated to the corresponding amine and coupled with 2-phenyl-5-trifluoromethyloxazole-4-carboxylic acid to give 4-{4-[(2-phenyl-5-trifluoromethyloxazole-4-carbonyl)-amino]-phenoxy}-piperidine-1-carboxylic acid tert-butyl ester. LC-MS showed a single peak with a retention time of 4.08 min. LRMS calcd for C27H28F3N3O5 (M+1) 532.20, obsd 532.1
Reaction SMILES: [F:1][C:2]([F:8])([F:7])[C:3]([F:6])([F:5])I.C[Li].[Br-].[Li+].[Br:13][C:14]1[CH:19]=[CH:18][C:17]([CH:20]=[CH:21][C:22](N(OC)C)=[O:23])=[CH:16][CH:15]=1>>[Br:13][C:14]1[CH:15]=[CH:16][C:17]([CH:20]=[CH:21][C:22](=[O:23])[C:3]([F:6])([F:5])[C:2]([F:8])([F:7])[F:1])=[CH:18][CH:19]=1
Reactant: FC(F)(F)C(F)(F)I
Reactant: CON(C)C(=O)C=Cc1ccc(Br)cc1
Agent: [Br-]
Agent: [Li+]
Agent: [Li]C
Product: O=C(C=Cc1ccc(Br)cc1)C(F)(F)C(F)(F)F
Reaction time: 0.33 h
Yield: 49.3 %

Procedure:
To a saturated solution of pentafluoroiodoethane (0.84 M, in diethyl ether) (198.3 mL, 166.6 mmol), was slowly added a solution of methyllithium/lithium bromide (1.5 M, in diethyl ether) (111.1 mL, 166.6 mmol) under nitrogen atmosphere at −78° C. The reaction mixture was stirred for 20 minutes and then a solution of 3-(4-bromo-phenyl)-N-methoxy-N-methyl-acrylamide (15.0 g, 55.5 mmol, in diethyl ether 20.0 mL) prepared in Step 1 was slowly added thereto at −78° C. The reaction mixture was stirred at room temperature, quenched with distilled water, acidified by a 10% potassium hydrogen sulfate solution (pH=5), and then extracted with diethyl ether three times. The combined extract was washed with a saturated solution of sodium hydrogen carbonate, dried on anhydrous magnesium sulfate, and then concentrated under reduced pressure to give a yellow liquid residue. The resulting residue was purified by silica gel column chromatography (eluent: ethyl acetate/n-hexane=1/60) to give 9.0 g of the titled compound as a yellow solid.