Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)CC)C.C(OC([NH:42][C@H:43]([C:50]([OH:52])=O)[CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)=O)C1C=CC=CC=1.[NH2:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57]>C(#N)C>[NH2:42][C@@H:43]([CH2:44][N:45]1[CH:49]=[CH:48][CH:47]=[N:46]1)[C:50]([NH:53][C@@H:54]([CH2:62][CH:63]1[CH2:68][CH2:67][CH2:66][CH2:65][CH2:64]1)[C@@H:55]([OH:61])[C@H:56]([CH:58]1[CH2:60][CH2:59]1)[OH:57])=[O:52]
Reactant: O=C(N[C@@H](Cn1cccn1)C(=O)O)OCc1ccccc1
Reactant: N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CC#N
Product: N[C@@H](Cn1cccn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 2 h

Procedure:
1.03 g (2.83 mmol) of HBTU and 0.39 ml (2.83 mmol) of triethylamine were added to a solution of 820 mg (2.83 mmol) of N-[(benzyloxy)carbonyl]-3-(pyrazol-1-yl)-L-alanine [J. Am. Chem. Soc. 107, 7105 (1985)]and 644 mg (2.83 mmol) of (1S,2R,3S)-3-amino-4-cyclohexyl-1-cyclopropyl-1,2-butanediol in 28 ml of acetonitrile and the mixture was stirred at room temperature overnight. The crystals obtained after filtration were dissolved in 30 ml of ethanol and hydrogenated at 400 for two hours. Filtration over diatomaceous earth and evaporation under reduced pressure yielded 670 mg of (S)-α-amino-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]-3-(pyrazol-1-yl)propionamide, MS: 365 (M+H)+, as a colourless foam.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[C:3](=[N:8][OH:9])[S:2]2.[CH3:10][N:11]=[C:12]=[O:13]>C(Cl)Cl>[CH3:10][NH:11][C:12]([O:9][N:8]=[C:3]1[CH:4]2[CH2:7][CH:1]([CH2:6][CH2:5]2)[S:2]1)=[O:13]
Reactant: ON=C1SC2CCC1C2
Reactant: CN=C=O
Solvent: ClCCl
Product: CNC(=O)ON=C1SC2CCC1C2
Yield: 98.6 %

Procedure:
A solution of 6.6 g (0.046 m) of 2-thiabicyclo[2.2.1]heptan-3-one oxime, 2.9 g (0.05 m) of methyl isocyanate, and 60 ml of methylene chloride was stirred at room temperature for 17 hours. Removal of solvent gave 9.1 g of yellow-tan solid which was purified by dry column chromatography on silica gel using ether-acetone as eluent. There was obtained 5.2 g of the title product as a cream colored solid, m. 121°-2° C.
Reaction SMILES: [OH:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1.[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24]O>>[Cl:15][C:16]1[CH:21]=[C:20]([CH2:22][CH3:23])[CH:19]=[CH:18][C:17]=1[CH2:24][O:1][C:2]1[N:6]([C:7]2[CH:12]=[C:11]([C:13]#[N:14])[CH:10]=[CH:9][N:8]=2)[N:5]=[CH:4][CH:3]=1
Reactant: N#Cc1ccnc(-n2nccc2O)c1
Reactant: CCc1ccc(CO)c(Cl)c1
Product: CCc1ccc(COc2ccnn2-c2cc(C#N)ccn2)c(Cl)c1

Procedure:
The title compound was prepared from 2-(5-hydroxy-1H-pyrazol-1-yl)pyridine-4-carbonitrile and (2-chloro-4-ethylphenyl)methanol according to the procedure for the preparation of Example 39, part C. 1H NMR (400 MHz, CDCl3): δ 1.24 (3H, t, J=7.6 Hz), 2.65 (2H, q, J=7.6 Hz), 5.30 (2H, s), 5.80 (1H, d, J=2.0 Hz), 7.12-7.14 (1H, m), 7.26 (1H, s), 7.39 (1H, dd, J=1.6 Hz, 4.8 Hz), 7.43 (1H, d, J=8.0 Hz), 7.58 (1H, d, J=2.0 Hz), 8.06 (1H, s), 8.71 (1H, d, J=4.4 Hz). [M+H] Calc'd for C18H15ClN4O, 339. Found, 339.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[N:8]=[CH:7][CH:6]=[C:5]2[O:12][C:13]1[CH:18]=[CH:17][C:16]([CH:19]([CH3:23])[C:20]([OH:22])=O)=[C:15]([O:24][CH3:25])[CH:14]=1.[NH2:26][C:27]1[C:31]([CH3:32])=[C:30]([CH3:33])[O:29][N:28]=1>>[CH3:32][C:31]1[C:27]([NH:26][C:20](=[O:22])[CH:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][C:5]3[C:4]4[C:9](=[CH:10][CH:11]=[C:2]([F:1])[CH:3]=4)[N:8]=[CH:7][CH:6]=3)=[CH:14][C:15]=2[O:24][CH3:25])[CH3:23])=[N:28][O:29][C:30]=1[CH3:33]
Reactant: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)O
Reactant: Cc1onc(N)c1C
Product: COc1cc(Oc2ccnc3ccc(F)cc23)ccc1C(C)C(=O)Nc1noc(C)c1C
Yield: 11 %

Procedure:
Using an analogous procedure to that described in Example 2, 2-[4-(6-fluoroquinolin-4-yloxy)-2-methoxyphenyl]propionic acid was reacted with 3-amino-4,5-dimethylisoxazole. The resultant mixture was evaporated and the residue was purified by preparative HPLC using a Waters ‘Xterra’ reversed-phase column (5 microns silica, 30 mm diameter, 150 mm length) using decreasingly polar mixtures of water (containing 0.2% ammonium carbonate) and acetonitrile as eluent. There was thus obtained the title compound as a solid in 11% yield; 1H NMR: (DMSOd6) 1.43 (s, 3H), 1.77 (s, 3H), 2.3 (s, 3H), 3.81 (s, 3H), 4.16 (q, 1H), 6.72 (d, 1H), 6.87 (m, 1H), 7.0 (d, 1H), 7.4 (d, 1H), 7.75 (m, 1H), 7.97 (m, 1H), 8.12 (m, 1H), 8.7 (d, 1H), 10.16 (s, 1H); Mass Spectrum: M+H+ 436.
Reaction SMILES: Cl[C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1.[Cl:18][C:19]1[CH:20]=[C:21]([OH:25])[CH:22]=[CH:23][CH:24]=1>>[Cl:18][C:19]1[CH:20]=[C:21]([CH:22]=[CH:23][CH:24]=1)[O:25][C:2]1[C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=[C:4]([NH:12][C:13]2[CH:17]=[CH:16][NH:15][N:14]=2)[N:3]=1
Reactant: Oc1cccc(Cl)c1
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: Clc1cccc(Oc2nc(Nc3cc[nH]n3)cc3ccccc23)c1

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 3-chloro-phenol to give [1-(3-chloro-phenoxy)-isoquinolin-3-yl]-(1H-pyrazol-3-yl)-amine. LC-MS m/e 337(MH+).
Reaction SMILES: [OH:1][CH:2]1[CH2:11][CH2:10][NH:9][C:8]2[N:7]=[CH:6][C:5]([C:12]3[CH:17]=[CH:16][C:15]([C:18]([N:20]4[CH2:25][CH2:24][N:23]([CH3:26])[CH2:22][CH2:21]4)=[O:19])=[CH:14][CH:13]=3)=[CH:4][C:3]1=2.O[C:28]1[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=1>CO.C(Cl)Cl>[CH3:26][N:23]1[CH2:22][CH2:21][N:20]([C:18]([C:15]2[CH:14]=[CH:13][C:12]([C:5]3[CH:6]=[N:7][C:8]4[NH:9][CH2:10][CH2:11][CH:2]([O:1][C:28]5[CH:29]=[N:30][CH:31]=[CH:32][CH:33]=5)[C:3]=4[CH:4]=3)=[CH:17][CH:16]=2)=[O:19])[CH2:25][CH2:24]1
Reactant: Oc1cccnc1
Reactant: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(O)CCN4)cc2)CC1
Solvent: ClCCl
Solvent: CO
Product: CN1CCN(C(=O)c2ccc(-c3cnc4c(c3)C(Oc3cccnc3)CCN4)cc2)CC1
Yield: 20 %

Procedure:
[4-(5-Hydroxy-5,6,7,8-tetrahydro-[1,8]naphthyridin-3-yl)phenyl]-(4-methylpiperazin-1-yl)methanone (20 mg) was reacted with 3-hydroxypyridine (16.2 mg) as in General Procedure 12. Silica gel chromatography using a gradient of 0-15% methanol/CH2Cl2 as the eluting solvent gave the title compound as a yellow foam (20% yield). LCMS: m/z=430.17 (M+H+), 1H-NMR (CDCl3, 400 MHz) δ 2.02-2.12 (m, 1H), 2.30-2.34 (m, 1H), 2.33 (s, 3H), 2.34-2.56 (m, 4H), 3.40-3.70 (m, 4H), 3.70-3.90 (m, 2H), 5.24 (bs, 1H), 5.44 (t, J=3.5 Hz, 1H), 7.26-7.29 (m, 1H), 7.31-7.37 (m, 1H), 7.41-7.50 (m, 4H), 7.58 (d, J=2.0 Hz, 1H), 8.28-8.33 (m, 2H), 8.43 (d, J=2.5 Hz, 1H).
Reaction SMILES: [CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([OH:20])=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28].C1C=CC2N(O)N=NC=2C=1.CCN=C=NCCCN(C)C>C(Cl)Cl.CN(C1C=CN=CC=1)C>[CH2:1]([O:8][N:9]1[C:15](=[O:16])[N:14]2[CH2:17][C@H:10]1[CH2:11][CH2:12][C@H:13]2[C:18]([NH:21][N:22]1[CH2:27][CH2:26][CH2:25][CH2:24][C:23]1=[O:28])=[O:20])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: NN1CCCCC1=O
Reactant: O=C(O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: On1nnc2ccccc21
Solvent: ClCCl
Product: O=C(NN1CCCCC1=O)[C@@H]1CC[C@@H]2CN1C(=O)N2OCc1ccccc1
Temperature: 25 °C
Reaction time: 48 h
Yield: 54.7 %

Procedure:
To a mixture of (2S,5R)-6-(benzyloxy)-7-oxo-1,6-diazabicyclo[3.2.1]octane-2-carboxylic acid 1 (0.250 g, 0.905 mmol) in DCM (15.0 mL) were added 1-aminopiperidin-2-one 256 (31 mg, 0.27 mmol),), HOBt (38 mg, 0.27 mmol), DMAP (32 mg, 0.27 mmol) and EDCI (53 mg, 0.27 mmol). The mixture was stirred at room temperature for 48 h and purified by column to afford 257 as foam (55 mg, 82%).
Reaction SMILES: [OH:1]/[N:2]=[C:3](/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)\[C:4]#[N:5].Cl[CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH:17]=[CH:16][CH:15]=1.[I-].[K+].C(=O)([O-])[O-].[Cs+].[Cs+]>C(#N)C.CN(C=O)C>[C:4](/[C:3](=[N:2]\[O:1][CH2:13][C:14]1[N:19]=[C:18]([NH:20][C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[CH:17]=[CH:16][CH:15]=1)/[C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][CH:7]=1)#[N:5]
Reactant: CC(C)(C)OC(=O)Nc1cccc(CCl)n1
Reactant: N#C/C(=N\O)c1ccccc1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Agent: [I-]
Solvent: CN(C)C=O
Solvent: CC#N
Product: CC(C)(C)OC(=O)Nc1cccc(CO/N=C(\C#N)c2ccccc2)n1
Temperature: 25 °C
Reaction time: 8 h
Yield: 80 %

Procedure:
To a solution of (2Z)-(hydroxyimino)(phenyl)acetonitrile (2.5 g, 17.10 mmol, 1 eq.) in 100 ml of acetonitrile and 10 ml DMF was added tert-butyl [6-(chloromethyl)pyridin-2-yl]carbamate (4.15 g, 17.10 mmol, 1 eq.) followed by potassium iodide (283 mg, 1.71 mmol, 0.1 eq.) and caesium carbonate (8.36 g, 25.65 mmol, 1.5 eq.). The reaction was stirred overnight at room temperature. The solvent was than evaporated and the residue dissolved in EtOAc (100 ml). The organic layer was washed with H2O and dried over MgSO4 then concentrated. tert-butyl {6-[({[(Z)-cyano(phenyl)methylene]amino}oxy)methyl]pyridin-2-yl}carbamate (5.39 g, 80% yield, only 1 oxime isomer) was obtained as a white solid.
Reaction SMILES: [C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[CH:14]=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C1C(=O)N([Cl:26])C(=O)C1>CC(O)=O.O.C(OCC)(=O)C>[C:1]1([O:7][C:8](=[O:18])[NH:9][C:10]2[C:14]([Cl:26])=[C:13]([CH:15]3[CH2:17][CH2:16]3)[O:12][N:11]=2)[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: O=C1CCC(=O)N1Cl
Reactant: O=C(Nc1cc(C2CC2)on1)Oc1ccccc1
Solvent: CCOC(C)=O
Solvent: CC(=O)O
Solvent: O
Product: O=C(Nc1noc(C2CC2)c1Cl)Oc1ccccc1
Temperature: 79 °C

Procedure:
(5-Cyclopropyl-isoxazol-3-yl)-carbamic acid phenyl ester (0.25 g, 1.024 mmol) is dissolved in AcOH (7.31 mL) and NCS (0.205 g, 1.53 mmol) is added and the reaction is heated to 79° C. for 2 hours. The reaction is cooled to room temperature and diluted with water and ethyl acetate. The organic layer is washed with 500 mL of water to remove the acid. The organic layer is dried (sodium sulfate) and concentrated to an oil (352 mg) to obtain the title compound that is used without further purification. MS (ESI) m/z 279.00 (M+1).
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:47]=[CH:46][C:25]([O:26][CH2:27][C:28](=[O:45])[CH:29]([O:31][C:32]2[CH:37]=[CH:36][C:35]([C:38]([O:40][C:41]([CH3:44])([CH3:43])[CH3:42])=[O:39])=[CH:34][CH:33]=2)[CH3:30])=[CH:24][CH:23]=1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.C(O)(=O)C.[F-].C([N+](CCCC)(CCCC)CCCC)CCC>O1CCCC1.C(OCC)(=O)C>[OH:18][CH2:19][CH2:20][CH2:21][C:22]1[CH:23]=[CH:24][C:25]([O:26][CH2:27][C:28](=[O:45])[CH:29]([O:31][C:32]2[CH:33]=[CH:34][C:35]([C:38]([O:40][C:41]([CH3:42])([CH3:43])[CH3:44])=[O:39])=[CH:36][CH:37]=2)[CH3:30])=[CH:46][CH:47]=1
Reactant: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)cc1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: [F-]
Solvent: CCOC(C)=O
Solvent: C1CCOC1
Solvent: CC(=O)O
Product: CC(Oc1ccc(C(=O)OC(C)(C)C)cc1)C(=O)COc1ccc(CCCO)cc1
Temperature: 70 °C
Yield: 91.6 %

Procedure:
A solution of (3R and 3S)-1-[4-[3-(tert-butyldiphenylsilyloxy)propyl]phenoxy]-3-[4-(tert-butoxycarbonyl)phenoxy]-2-butanone (2.82 g, 4.32 mmol) in tetrahydrofuran (70 ml) was treated with acetic acid (1.5 ml) followed by 1M tetrabutylammonium fluoride in tetrahydrofuran (10 ml, 10.0 mmol). The mixture was then heated at 70° C. for 3.5 hours. The cooled mixture was then diluted with ethyl acetate, washed with saturated sodium bicarbonate, brine and dried (magnesium sulfate). Evaporation of the solvent and chromatography of the residue on silica gel (elution toluene-ethyl acetate 8:2) gave 1.64 g (91%) of the title material as an oil.
Reaction SMILES: [S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:24])[CH2:11][O:12][CH2:13][CH:14]3[CH2:19][N:18](C=O)[CH2:17][CH2:16][N:15]3C=O)[CH:8]=[CH:9][C:2]1=2.[ClH:25].C(O)C>CO>[ClH:25].[ClH:25].[S:1]1[CH:5]=[CH:4][C:3]2[CH:6]=[C:7]([CH:10]([OH:24])[CH2:11][O:12][CH2:13][CH:14]3[CH2:19][NH:18][CH2:17][CH2:16][NH:15]3)[CH:8]=[CH:9][C:2]1=2
Reactant: O=CN1CCN(C=O)C(COCC(O)c2ccc3sccc3c2)C1
Agent: Cl
Solvent: CCO
Solvent: CO
Product: OC(COCC1CNCCN1)c1ccc2sccc2c1
Reaction time: 8 h

Procedure:
In 1.5 ml of methanol was dissolved 270 mg of 1-(benzo[b]thiophen-5-yl)-2-[(1,4-diformylpiperazin-2-yl)methoxy]ethanol. To the solution was added 1.5 ml of a 5N dry hydrogen chloride-ethanol solution. The resulting mixture was allowed to stand at room temperature overnight. The resulting crystals were collected by filtration, washed with ethanol, and dried to obtain 150 mg of 1-(benzo[b]thiophen-5-yl)-2[-(piperazin-2-yl)methoxy]ethanol dihydrochloride (compound No. 355).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH2:11][OH:12])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>[O-2].[O-2].[Mn+4]>[CH2:1]([O:8][C:9]1[C:16]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=2)=[CH:15][CH:14]=[CH:13][C:10]=1[CH:11]=[O:12])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: OCc1cccc(-c2ccccc2)c1OCc1ccccc1
Agent: [Mn+4]
Agent: [O-2]
Product: O=Cc1cccc(-c2ccccc2)c1OCc1ccccc1

Procedure:
2-Benzyloxy-3-phenylbenzyl alcohol was oxidised with manganese dioxide using a similar method to that described in Reference Example 29 to give 2-benzyloxy-3-phenylbenzaldehyde.
Reaction SMILES: [C:1]([C:4]1[N:5]([N:9]2C(=O)C3C(=CC=CC=3)C2=O)[CH:6]=[CH:7][CH:8]=1)(=[O:3])[CH3:2].CN.O>CN(C)C=O>[NH2:9][N:5]1[CH:6]=[CH:7][CH:8]=[C:4]1[C:1](=[O:3])[CH3:2]
Reactant: CC(=O)c1cccn1N1C(=O)c2ccccc2C1=O
Agent: CN
Solvent: CN(C)C=O
Solvent: O
Product: CC(=O)c1cccn1N
Reaction time: 2.5 h
Yield: 93.2 %

Procedure:
To a suspension of 2-(2-acetyl-1H-pyrrol-1-yl)-1H-isoindole-1,3(2H)dione (8.53 g) in dimethylformamide (25 ml) was added 33 ml of 40% methylamine solution. After 2.5 hours, the reaction mixture was poured into water (300 ml) and was extracted 4 times with EtOAc. The combined organics were washed once with water and brine, dried (MgSO4), filtered and concentrated to give the crude product. Purification via flash column chromatography (silica gel, 30% EtOAc/hexane) afforded 3.88 g of the product as an oil.
Reaction SMILES: C([O:4][CH2:5][C:6]1[N:10]([C:11]2[CH:16]=[C:15]([C:17]([F:20])([F:19])[F:18])[C:14]([C:21]#[N:22])=[CH:13][C:12]=2[CH3:23])[N:9]=[N:8][N:7]=1)(=O)C.O.[OH-].[Li+]>O.O1CCCC1>[OH:4][CH2:5][C:6]1[N:10]([C:11]2[C:12]([CH3:23])=[CH:13][C:14]([C:21]#[N:22])=[C:15]([C:17]([F:20])([F:19])[F:18])[CH:16]=2)[N:9]=[N:8][N:7]=1
Reactant: CC(=O)OCc1nnnn1-c1cc(C(F)(F)F)c(C#N)cc1C
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: Cc1cc(C#N)c(C(F)(F)F)cc1-n1nnnc1CO
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
To a solution of {1-[4-cyano-2-methyl-5-(trifluoromethyl)phenyl]-1H-tetrazol-5-yl}methyl acetate (Intermediate 62, 433 mg, 1.33 mmol) in water (2 mL) and tetrahydrofuran (4 mL), cooled in an ice bath, was added lithium hydroxide monohydrate (56 mg, 1.33 mmol). The reaction was stirred at room temperature for 1 hour and 30 min.
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH2:12][C:13](=[NH:16])[NH:14][OH:15])[C:7]([CH2:17][CH2:18][CH3:19])=[CH:6]2)#[N:2].[Cl:24][C:25]1[C:30]([C:31](Cl)=O)=[CH:29][CH:28]=[CH:27][N:26]=1.C(N(CC)CC)C>C(#N)C>[Cl:24][C:25]1[C:30]([C:31]2[O:15][N:14]=[C:13]([CH2:12][N:8]3[C:9]4[C:5](=[C:4]([C:20]([F:22])([F:23])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=4)[CH:6]=[C:7]3[CH2:17][CH2:18][CH3:19])[N:16]=2)=[CH:29][CH:28]=[CH:27][N:26]=1
Reactant: O=C(Cl)c1cccnc1Cl
Reactant: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1CC(=N)NO
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CCCc1cc2c(C(F)(F)F)c(C#N)ccc2n1Cc1noc(-c2cccnc2Cl)n1
Temperature: 150 °C
Yield: 34.2 %

Procedure:
To a solution of 2-[5-cyano-2-propyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxyethanimidamide (Example 275A) (0.100 g, 0.308 mmol) in anhydrous acetonitrile (10.0 mL) under N2, was added 2-chloro-3-pyridinecarbonyl chloride (0.186 g, 1.10 mmol) and triethylamine (1.0 mL, 13.6 mmol). The mixture was then heated in a microwave at 150° C. for 30 min. Upon cooling, the mixture was poured onto a biotage prepak column and the mixture was purified by flash chromatography (0-25% EtOAc-hexanes gradient) to give 0.047 g (40% yield) of pure product: MS (ES) m/z 445 (M+).
Reaction SMILES: C(OC([N:8]1[CH2:13][CH2:12][CH2:11][CH2:10][CH:9]1[CH2:14][CH2:15][O:16][C:17]1[C:26]2[C:21](=[CH:22][C:23]([Cl:30])=[C:24]([N+:27]([O-:29])=[O:28])[CH:25]=2)[NH:20][C:19](=[O:31])[C:18]=1[C:32]1[S:33][CH:34]=[CH:35][CH:36]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>C1(OC)C=CC=CC=1>[Cl:30][C:23]1[CH:22]=[C:21]2[C:26]([C:17]([O:16][CH2:15][CH2:14][CH:9]3[CH2:10][CH2:11][CH2:12][CH2:13][NH:8]3)=[C:18]([C:32]3[S:33][CH:34]=[CH:35][CH:36]=3)[C:19](=[O:31])[NH:20]2)=[CH:25][C:24]=1[N+:27]([O-:29])=[O:28]
Reactant: CC(C)(C)OC(=O)N1CCCCC1CCOc1c(-c2cccs2)c(=O)[nH]c2cc(Cl)c([N+](=O)[O-])cc12
Solvent: COc1ccccc1
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc(Cl)c([N+](=O)[O-])cc2c(OCCC2CCCCN2)c1-c1cccs1
Temperature: 25 °C
Yield: 68.4 %

Procedure:
To a solution of 2-[2-(7-chloro-6-nitro-2-oxo-3-thiophen-2-yl-1,2-dihydro-quinolin-4-yloxy)-ethyl]-piperidine-1-carboxylic acid tert-butyl ester (45 mg in 2.0 mL methylene chloride) was added 2 drops of anisole followed by 1.0 mL of trifluoroacetic acid and the mixture stirred at room temperature. After 45 minutes the solvents were removed in vacuo and the resulting residue purified by flash chromatography on silica gel (methylene chloride:methanol, 95:5) to give the title compound (25 mg).
Reaction SMILES: [S:1]([O-:4])([O-:3])=[O:2].[Na+].[Na+].C[O:8][C:9](=[O:26])[CH2:10][CH2:11][CH2:12][CH2:13][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24]Br.[OH-].[Na+].S(=O)(=O)(O)O.S(=O)=O>O.C(O)CC.O1CCCC1.CO>[S:1]([CH2:24][CH2:23][CH2:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16][CH2:15][CH2:14][CH2:13][CH2:12][CH2:11][CH2:10][C:9]([OH:26])=[O:8])([OH:4])(=[O:3])=[O:2]
Reactant: O=S([O-])[O-]
Reactant: COC(=O)CCCCCCCCCCCCCCCBr
Agent: O=S(=O)(O)O
Agent: O=S=O
Agent: [Na+]
Solvent: CO
Solvent: C1CCOC1
Solvent: CCCO
Product: O=C(O)CCCCCCCCCCCCCCCS(=O)(=O)O
Temperature: 27 °C
Reaction time: 5 h

Procedure:
Solutions of sodium sulfite (327 g, 2.60 mol) in water (1.26 L) and 16-bromo-hexadecanoic acid methyl ester (728 g, 2.00 mol, 96% purity) in 1-propanol (945 mL) and methanol (420 mL) were heated to reflux in 6 L reactor equipped with mechanical stirrer for 48 hours. The reaction mixture was cooled to 27° C. and diluted with tetrahydrofuran (2 L). Reaction mixture was filtered and solid material was washed with tetrahydrofuran (3×700 mL). Filtrate was cooled to 0° C. and another portion of material was precipitated. This precipitate was filtered and washed with tetrahydrofuran (2×200 mL). Solids were combined and mixed with water (8.4 L) in 20 L pot. Solution of sodium hydroxide (120 g, 3.00 mol) was added. The mixture was heated to boiling for about 5 hours. Solution of sulfuric acid (430 mL, 8.00 mol) in water (500 mL) was slowly added into the reaction mixture (sulfur dioxide is formed). Reaction mixture was heated to boiling for 10 minutes and then let to cool to 15° C. (ice bath). The mixture was filtered on Büchner funnel through filter paper Seitz (several layers filter) applying vacuo. This procedure was very slow and took two days. Solid material was several times washed with distilled water until pH of filtrate was between 2 and 3. This procedure took about three days. Muddy white material was dried in oven at 80° C. giving desired product.
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4](Cl)=[O:5].[Cl-].[Al+3].[Cl-].[Cl-]>C1(C)C=CC=CC=1>[Cl:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]([Cl:11])[C:3]=1[C:4]([C:9]1[CH:8]=[CH:7][C:3]([CH3:4])=[CH:2][CH:10]=1)=[O:5]
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Agent: [Al+3]
Agent: [Cl-]
Solvent: Cc1ccccc1
Product: Cc1ccc(C(=O)c2c(Cl)cccc2Cl)cc1
Reaction time: 12 h
Yield: 115.1 %

Procedure:
An 80° C., stirred solution of 2,6-dichlorobenzoyl chloride (17.3 g, 82.6 mmol) in toluene (30 ml) was treated in portions with aluminum chloride (11.0 g, 82.3 mmol). After 12 hours at 80° C., the mixture was cooled, quenched with ice water and concentrated hydrochloric acid (10 ml), and separated. The aqueous phase was extracted with diethyl ether (2×150 ml) and the combined organic phases were washed twice with water, dried over anhydrous magnesium sulfate, and evaporated to dryness under vacuum. The residue was crystallized from hexane to provide 12.6 g (58%) 4-(2,6-dichlorobenzoyl)toluene, m.p. 109°-111.5° C.
Reaction SMILES: [NH:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1.C(=O)([O-])[O-].[K+].[K+].Br[C:19]([CH3:26])([CH3:25])[C:20]([O:22][CH2:23][CH3:24])=[O:21]>CN(C=O)C>[CH2:23]([O:22][C:20](=[O:21])[C:19]([CH3:26])([N:1]1[CH:5]=[C:4]([C:6]2[CH:7]=[N:8][CH:9]=[CH:10][CH:11]=2)[N:3]=[CH:2]1)[CH3:25])[CH3:24]
Reactant: CCOC(=O)C(C)(C)Br
Reactant: c1cncc(-c2c[nH]cn2)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(C)(C)n1cnc(-c2cccnc2)c1
Reaction time: 1 h
Yield: 33 %

Procedure:
To a solution of 3-(1H-Imidazol-4-yl)-pyridine (1 eq) in DMF was added potassium carbonate (2 eq) under dry condition. After stirring for 1 hour, ethyl 2-bromoisobutyrate (5 eq) was added to the mixture. The solution was left stirring over 36 hours at room temperature. The reaction solvent was removed in vacuo and the solid was diluted with ethyl acetate washed with H2O, NaCl(sat), dried over sodium sulfate, filtered and concentrated. The crude product was purified by flash chromatography using a solvent gradient of 97% DCM, 3% MeOH and 0.1% TEA to yield 2-Methyl-2-(4-pyridin-3-yl-imidazol-1-yl)-propionic acid ethyl ester (33%). MH+(260).
Reaction SMILES: [F:1][C:2](Br)([F:4])[F:3].[CH3:6][C:7]1[CH:8]=[C:9]([CH:13]=[CH:14][C:15]=1[CH3:16])[C:10](Cl)=[O:11].CCCCCC>C(Cl)Cl>[CH3:6][C:7]1[CH:8]=[C:9]([C:10](=[O:11])[C:2]([F:4])([F:3])[F:1])[CH:13]=[CH:14][C:15]=1[CH3:16]
Reactant: Cc1ccc(C(=O)Cl)cc1C
Reactant: FC(F)(F)Br
Solvent: CCCCCC
Solvent: ClCCl
Product: Cc1ccc(C(=O)C(F)(F)F)cc1C
Temperature: 25 °C
Reaction time: 1 h
Yield: 41.2 %

Procedure:
Under protective gas, 41 g (0.27 mol) of trifluoromethyl bromide are condensed into a solution of 42 g (0.25 mol) of 3,4-dimethylbenzoyl chloride in 150 ml of CH2Cl2 in a round-bottomed flask at about -70° C. A solution of 66.7 g (0.27 mol) of phosphorous acid trisdiethylamide in 50 ml of CH2Cl2 are then metered in at about -70° C., the first 90% of the solution being added rapidly and the last 10% of the solution being metered in slowly (during the course of about 2 hours). The mixture is subsequently stirred for one hour more at this temperature and then warmed to room temperature. After addition of the same volume of hexane, 2 phases are formed. After phase separation, the lower phase is carefully extracted using hexane; the combined hexane phases are concentrated and distilled under reduced pressure. 20.8 g (41% yield) of 1-(3,4-dimethylphenyl)- 2,2,2-trifluoroethan-1-one of b.p. 98°-99° C./22 mbar are obtained.