Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9](Cl)(=[O:11])=[O:10])=[CH:5][CH:4]=1.N1C=CC=CC=1.[NH:19]([CH2:26][CH2:27][C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=1)[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=1.O>CC(OC)(C)C>[CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([S:9]([N:19]([C:20]2[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=2)[CH2:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][N:29]=2)(=[O:11])=[O:10])=[CH:5][CH:4]=1
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: c1ccc(NCCc2ccccn2)cc1
Solvent: COC(C)(C)C
Solvent: c1ccncc1
Solvent: O
Product: COc1ccc(S(=O)(=O)N(CCc2ccccn2)c2ccccc2)cc1
Temperature: 25 °C

Procedure:
To a 25 ml round bottom flask, 0.21 g 4-methoxybenzenesulfonyl chloride and 0.08 mL of pyridine were dissolved in 10 ml of MTBE. To this solution was added 0.2 g of 2-(2-anilinoethyl)pyridine. The reaction was heated at reflux for one hour and then let cool down to room temperature. To the reaction was added 10 mL of water. The organic layer was separated and washed with 10 mL of water. The organic layer was dried over MgSO4, filtered, and concentrated to yield a brown oil. The oil was purified on silica gel to recover 0.3 g of a tanned solid with the following spectroscopic properties:
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[CH:11]=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.P([O-])([O-])(O)=O.[NH4+].[NH4+].[N+:32]([O-])(OCCC)=O>C(O)(=O)C>[CH2:1]([O:8][C:9]1[CH:16]=[C:15]([O:17][CH2:18][C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[CH:14]=[CH:13][C:10]=1[C:11]#[N:32])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: O=Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Reactant: CCCO[N+](=O)[O-]
Agent: O=P([O-])([O-])O
Agent: [NH4+]
Solvent: CC(=O)O
Product: N#Cc1ccc(OCc2ccccc2)cc1OCc1ccccc1
Yield: 40 %

Procedure:
A mixture of 2,4-dibenzyloxybenzaldehyde (1.59 g), diammonium hydrogen phosphate (3.5 g) and n-propyl nitrate (15 mL) in glacial acetic acid (5 mL) is refluxed for 15 hours. The reaction mixture is evaporated to dryness in vacuo and the residue is stirred with water (100 mL). The insoluble material is filtered and dried at 50° C. to yield 2,4-dibenzyloxybenzonitrile as a tan coloured solid (0.6 g, 40%), m.p. 100° C. [Elemental analysis:- C,79.8; H,5.47; N,4.48%. Calculated:- C,80.0; H,5.43; N,4.44%].
Reaction SMILES: [F:1][C:2]1[CH:18]=[CH:17][C:5]([CH2:6][C:7]2[O:11][N:10]=[C:9]([C:12]([O:14]CC)=O)[N:8]=2)=[C:4]([C:19]([F:22])([F:21])[F:20])[CH:3]=1.Cl.[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH2:36].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(CC)C(C)C)(C)C>C1COCC1.[OH-].[Na+].O.CN(C=O)C>[Cl:24][C:25]1[CH:26]=[C:27]2[C:31](=[CH:32][CH:33]=1)[NH:30][CH:29]=[C:28]2[CH2:34][CH2:35][NH:36][C:12]([C:9]1[N:8]=[C:7]([CH2:6][C:5]2[CH:17]=[CH:18][C:2]([F:1])=[CH:3][C:4]=2[C:19]([F:20])([F:21])[F:22])[O:11][N:10]=1)=[O:14]
Reactant: NCCc1c[nH]c2ccc(Cl)cc12
Reactant: CCOC(=O)c1noc(Cc2ccc(F)cc2C(F)(F)F)n1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Solvent: C1CCOC1
Product: O=C(NCCc1c[nH]c2ccc(Cl)cc12)c1noc(Cc2ccc(F)cc2C(F)(F)F)n1

Procedure:
This compound was prepared according to method F with ethyl 5-(4-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxylate (0.099 g; 0.311 mmol) in THF (1 mL) and sodium hydroxide in water (2M, 1 mL); 2-(5-chloro-1H-indol-3-yl)ethanamine hydrochloride (0.080 g; 0.346 mmol), HATU (0.131 g; 0.346 mmol), N,N diisopropylethylamine (0.149 mL; 0.865 mmol), in DMF (3 mL). The crude mixture was purified by flash column chromatography on silica (eluent 20 to 100% ethyl acetate in heptane) and by preparative HPLC method 2 to yield 0.022 (14%) of N-(2-(5-chloro-1H-indol-3-yl)ethyl)-5-(4-fluoro-2-(trifluoromethyl)benzyl)-1,2,4-oxadiazole-3-carboxamide as a white solid.
Reaction SMILES: [C:1]([C:3]1[CH:20]=[CH:19][C:6]([CH2:7][N:8]2[C:13]([CH3:14])=[CH:12][C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[CH:9]2)=[CH:5][CH:4]=1)#[N:2].[Br:21]Br.O>C(O)(=O)C>[Br:21][C:12]1[C:11](=[O:15])[C:10]([C:16]([OH:18])=[O:17])=[CH:9][N:8]([CH2:7][C:6]2[CH:5]=[CH:4][C:3]([C:1]#[N:2])=[CH:20][CH:19]=2)[C:13]=1[CH3:14]
Reactant: BrBr
Reactant: Cc1cc(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Solvent: CC(=O)O
Solvent: O
Product: Cc1c(Br)c(=O)c(C(=O)O)cn1Cc1ccc(C#N)cc1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of 1-(4-cyano-benzyl)-6-methyl-4-oxo-1,4-dihydro-pyridine-3-carboxylic acid (preparation 1b, 12.9 g, 48.2 mmol) in glacial acetic acid (50 ml) is added at room temperature bromine (5.0 mL). The reaction mixture is stirred for 1 day at room temperature, then additional bromine (3.0 mL) is added. After stirring for an additional 4 days at room temperature, water is added to the reaction mixture and the formed precipitate is filtered off and dried. Yield: 14.0 g (84% of theory); ESI mass spectrum: [M+H]+=347 (bromine isotope pattern); Retention time HPLC: 1.07 min (Z002—005).
Reaction SMILES: CC(O[CH2:5][C:6]1[CH2:15][S:14][C@@H:9]2[C@H:10]([NH2:13])[C:11](=[O:12])[N:8]2[C:7]=1[C:16]([OH:18])=[O:17])=O.[OH-].[Na+].[CH3:21][C:22]1[S:23][C:24]([SH:27])=[N:25][N:26]=1.Cl>CC(C)=O.O>[CH3:21][C:22]1[S:23][C:24]([S:27][CH2:5][C:6]2[CH2:15][S:14][CH:9]3[N:8]([C:11](=[O:12])[CH:10]3[NH2:13])[C:7]=2[C:16]([OH:18])=[O:17])=[N:25][N:26]=1
Reactant: Cc1nnc(S)s1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CC(C)=O
Product: Cc1nnc(SCC2=C(C(=O)O)N3C(=O)C(N)C3SC2)s1

Procedure:
A mixture of 13.6 g. (0.05 M) of 7-aminocephalosporanic acid (7-ACA) in 100 ml. of water and 50 ml. of acetone are brought to pH 8 with sodium hydroxide while stirring. 7.5 g. (0.057 M) of 2-methyl-1,3,4-thiadiazole-5-thiol are added and the mixture is heated at 80° for four hours. After cooling to 5°, this is acidified to pH 3.5 with dilute hydrochloric acid and stirred for 15 minutes. The precipitated solid is filtered under suction and washed with acetone. This 3-[[(5-methyl-1,3,4-thiadiazol-2-yl)thio]methyl]-7-amino-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid is purified by dissolving in sodium bicarbonate solution and reprecipitating with 2N hydrochloric acid; yield 12.7 g., m.p. 206°.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([OH:34])[CH2:13][CH2:12][N:11]([CH2:14][CH2:15][CH:16]=[C:17]3[C:23]4[CH:24]=[CH:25][CH:26]=[N:27][C:22]=4[CH2:21][O:20][C:19]4[CH:28]=[CH:29][C:30]([OH:32])=[CH:31][C:18]3=4)[CH2:10][CH:9]2[CH3:33])=[CH:4][CH:3]=1.[H-].[Na+].Br[CH2:38][C:39]([O:41][CH3:42])=[O:40]>CN(C)C=O>[CH3:42][O:41][C:39](=[O:40])[CH2:38][O:32][C:30]1[CH:29]=[CH:28][C:19]2[O:20][CH:21]=[C:22]3[NH:27][CH:26]=[CH:25][CH:24]=[C:23]3[C:17](=[CH:16][CH2:15][CH2:14][N:11]3[CH2:12][CH2:13][C:8]([C:5]4[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=4)([OH:34])[CH:9]([CH3:33])[CH2:10]3)[C:18]=2[CH:31]=1
Reactant: COC(=O)CBr
Reactant: CC1CN(CCC=C2c3cc(O)ccc3OCc3ncccc32)CCC1(O)c1ccc(Cl)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COC(=O)COc1ccc2c(c1)C(=CCCN1CCC(O)(c3ccc(Cl)cc3)C(C)C1)C1=CC=CNC1=CO2
Temperature: 25 °C
Reaction time: 2 h
Yield: 45.5 %

Procedure:
A solution of 5-{3-[4-(4-Chloro-phenyl)-4-hydroxy-3-methyl-piperidin-1-yl]-propylidene}-5,11-dihydro-10-oxa-1-aza-dibenzo[a,d]cyclohepten-7-ol (0.14 g, 0.28 mmol) in dimethylformamide (3 mL) was treated with sodium hydride (60% in mineral oil, 0.016 g, 0.4 mmol) and methyl bromoacetate (0.038 mL, 0.4 mmol). The mixture was allowed to stir at rt for 2 hr, then quenched with aqueous brine, and extracted with ethyl acetate (3×10 mL). The combined organics were washed several time with water, dried over sodium sulfate, and evaporated in vacuo. The residue was purified by silica gel chromatography (ethyl acetate→87:10:3 ethyl acetate/methanol/triethylamine) to yield 0.07 g (50%) of the title compound, ESI-MS m/z: 549 [M+1].
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[C:10]([CH3:13])[C:9]=2[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]2[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=2)=[CH:4][CH:3]=1.[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36](B3OC(C)(C)C(C)(C)O3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]>>[CH2:25]([O:27][C:28](=[O:48])[CH2:29][C:30]1([C:33]2[CH:38]=[CH:37][C:36]([C:2]3[CH:7]=[CH:6][C:5]([C:8]4[O:12][N:11]=[C:10]([CH3:13])[C:9]=4[CH:14]([OH:24])[CH2:15]/[CH:16]=[CH:17]/[C:18]4[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=4)=[CH:4][CH:3]=3)=[CH:35][CH:34]=2)[CH2:32][CH2:31]1)[CH3:26]
Reactant: Cc1noc(-c2ccc(Br)cc2)c1C(O)C/C=C/c1ccccc1
Reactant: CCOC(=O)CC1(c2ccc(B3OC(C)(C)C(C)(C)O3)cc2)CC1
Product: CCOC(=O)CC1(c2ccc(-c3ccc(-c4onc(C)c4C(O)C/C=C/c4ccccc4)cc3)cc2)CC1

Procedure:
Prepared according to the procedure described in Example 110, Step 3, using (E)-1-[5-(4-bromo-phenyl)-3-methyl-isoxazol-4-yl]-4-phenyl-but-3-en-1-ol and {1-[4-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-phenyl]-cyclopropyl}-acetic acid ethyl ester.
Reaction SMILES: [C:1]([O:5][C:6]([C:8]1[CH:13]=[CH:12][C:11]([N:14]2[C:18](=[O:19])[C:17]3([CH2:24][CH2:23][N:22](C(OCC4C=CC=CC=4)=O)[CH2:21][CH2:20]3)[N:16]([C:35]3[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=3)[CH2:15]2)=[CH:10][CH:9]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2]>[Pd].C(OCC)(=O)C.CO>[O:19]=[C:18]1[C:17]2([CH2:24][CH2:23][NH:22][CH2:21][CH2:20]2)[N:16]([C:35]2[CH:36]=[CH:37][CH:38]=[CH:39][CH:40]=2)[CH2:15][N:14]1[C:11]1[CH:10]=[CH:9][C:8]([C:6]([O:5][C:1]([CH3:2])([CH3:4])[CH3:3])=[O:7])=[CH:13][CH:12]=1
Reactant: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCN(C(=O)OCc4ccccc4)CC3)C2=O)cc1
Agent: [Pd]
Solvent: CO
Solvent: CCOC(C)=O
Product: CC(C)(C)OC(=O)c1ccc(N2CN(c3ccccc3)C3(CCNCC3)C2=O)cc1
Yield: 99 %

Procedure:
Benzyl 3-(4-(tert-butoxycarbonyl)phenyl)-4-oxo-1-phenyl-1,3,8-triazaspiro[4.5]decane-8-carboxylate (0.62 g, 1.14 mmol) and palladium on carbon (10 wt. %, wet, Degussa type E101 NE/W,) (0.12 g) in ethyl acetate (5 mL) and methanol (5 mL) was stirred at room temperature under hydrogen (balloon) for 3 hours. The catalyst was removed by filtration and the filtrate evaporated and dried under vacuum to give product as foam (0.46 g, quant.); MS for C24H29N3O3 m/z 408 (M+H)+.
Reaction SMILES: [NH:1]1[C:10]2[C:9]3[CH2:11][NH:12][CH2:13][CH2:14][C:8]=3[CH:7]=[CH:6][C:5]=2[NH:4][C:3](=[O:15])[C:2]1=[O:16].[N+:17]([O-])([OH:19])=[O:18]>FC(F)(F)C(O)=O>[N+:17]([C:7]1[C:8]2[CH2:14][CH2:13][NH:12][CH2:11][C:9]=2[C:10]2[NH:1][C:2](=[O:16])[C:3](=[O:15])[NH:4][C:5]=2[CH:6]=1)([O-:19])=[O:18]
Reactant: O=c1[nH]c2ccc3c(c2[nH]c1=O)CNCC3
Reactant: O=[N+]([O-])O
Solvent: O=C(O)C(F)(F)F
Product: O=c1[nH]c2cc([N+](=O)[O-])c3c(c2[nH]c1=O)CNCC3
Reaction time: 19 h
Yield: 58 %

Procedure:
A solution of the quinoxalinedione from Example 30 (50 mg, 0.23 mmol) in 2 mL of trifluoroacetic acid was treated with fuming nitric acid (0.1 mL, 2.3 mmol) and stirred under a nitrogen atmosphere for 19 h. After evaporating to dryness, the residue was triturated with acetone and the precipitant collected by filtration. The solid was suspended in water, heated on a hot plate and basified to pH 8 with an ammonium hydroxide solution. The solid was collected by filtration while hot, and dried in vacuo to give a yellow solid (35 mg, 65% yield). mp=245-240° C. CHN calc'd for C11H10N4O4 found within theoretical limit ±0.4.
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.CC1C=CC(S(O[CH2:24][CH2:25][C:26]2[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=2)(=O)=O)=CC=1.[CH3:32][C:33]1[CH:37]=[C:36]([N:38]2[CH2:42][CH2:41][NH:40][C:39]2=[O:43])[S:35][C:34]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]>>[CH3:32][C:33]1[CH:37]=[C:36]([N:38]2[CH2:42][CH2:41][N:40]([CH2:24][CH2:25][C:26]3[CH:27]=[CH:28][CH:29]=[CH:30][CH:31]=3)[C:39]2=[O:43])[S:35][C:34]=1[C:44]([O:46][CH2:47][CH3:48])=[O:45]
Reactant: CCOC(=O)c1sc(N2CCNC2=O)cc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2ccccc2)cc1
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CCc3ccccc3)C2=O)cc1C
Yield: 63 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with phenethyl 4-methylbenzenesulfonate to react with ethyl 3-methyl-5-(2-oxoimidazolidin-1-yl)thiophene-2-carboxylate, the title compound was obtained as a colorless solid in 63% yield: 1H NMR (300 MHz, CDCl3) δ 7.35-7.19 (m, 5H), 6.12 (s, 1H), 4.27 (q, J=7.1 Hz, 2H), 3.78-3.71 (m, 2H), 3.56 (t, J=7.4 Hz, 2H), 3.47-3.39 (m, 2H), 2.90 (t, J=7.4 Hz, 2H), 2.49 (s, 3H), 1.33 (t, J=7.1 Hz, 3H); MS (ES+) m/z 359.3 (M+1).
Reaction SMILES: [C@H:1]1([NH2:11])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1.[C:12](Cl)(=[O:22])[C:13]1[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:15](Cl)=[O:16]>C1COCC1.C(Cl)Cl>[C@H:1]1([N:11]2[C:15](=[O:16])[C:14]3[C:13](=[CH:21][CH:20]=[CH:19][CH:18]=3)[C:12]2=[O:22])[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][CH:9]=2)[CH2:4][CH2:3][CH2:2]1
Reactant: N[C@@H]1CCCc2ccccc21
Reactant: O=C(Cl)c1ccccc1C(=O)Cl
Solvent: C1CCOC1
Solvent: ClCCl
Product: O=C1c2ccccc2C(=O)N1[C@@H]1CCCc2ccccc21
Yield: 73.2 %

Procedure:
To a solution of (R)-1,2,3,4-tetrahydro-1-naphthylamine (6.0 g) in THF (150 mL) at 0° C. was added TEA (18.5 mL) and phthaloyl chloride (8.2 g), and the resultant mixture was stirred at room temperature overnight and 70° C. for 3 h. The mixture was diluted with CH2Cl2, washed with saturated NaHCO3, dried over MgSO4, and concentrated in vacuo. The resulting crude was chromatographed on silica gel (EtOAc/hexane, 5/95 to 30/70) to afford 8.2 g of the title compound.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]([C:20]([O:22]C)=[O:21])=[N:3]1.[OH-].[Li+]>CO.C1COCC1.O>[CH3:1][N:2]1[C:7](=[O:8])[C:6]([C:9]2[CH2:13][CH:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[O:11][N:10]=2)=[CH:5][C:4]([C:20]([OH:22])=[O:21])=[N:3]1
Reactant: COC(=O)c1cc(C2=NOC(c3ccccc3)C2)c(=O)n(C)n1
Agent: [Li+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Solvent: O
Product: Cn1nc(C(=O)O)cc(C2=NOC(c3ccccc3)C2)c1=O
Temperature: 25 °C
Reaction time: 3 h
Yield: 78.6 %

Procedure:
To a solution of methyl 1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxylate (200 mg, 0.638 mmol, Preparation #33) in a mixture of methanol (2 mL) and THF (4 mL) was added lithium hydroxide (30.6 mg, 1.277 mmol, Spectrochem) dissolved in water (2 mL). The reaction mixture was stirred at RT for about 3 h. The reaction mixture was concentrated under vacuum and dissolved in water (10 mL). Further it was acidified to pH 2 with 2N HCl and the solids obtained were collected by filtration to afford 1-methyl-6-oxo-5-(5-phenyl-4,5-dihydroisoxazol-3-yl)-1,6-dihydropyridazine-3-carboxylic acid 0.150 g (79%) as light brown solids. 1H NMR (400 MHz, DMSO) δ 13.8 (br s, 1H), 8.122 (s, 1H), 7.405-7.331 (m, 5H), 5.806-5.757 (m, 1H), 3.958-3.886 (m, 1H) 3.762 (s, 3H), 3.506-3.441 (m, 1H). MS m/z: 298.0 (M−H)−
Reaction SMILES: C[O:2][C:3]1[C:8]([CH2:9][C:10]([F:13])([F:12])[F:11])=[CH:7][CH:6]=[CH:5][C:4]=1[CH3:14].B(Br)(Br)Br>ClCCl>[CH3:14][C:4]1[CH:5]=[CH:6][CH:7]=[C:8]([CH2:9][C:10]([F:11])([F:12])[F:13])[C:3]=1[OH:2]
Reactant: COc1c(C)cccc1CC(F)(F)F
Agent: BrB(Br)Br
Solvent: ClCCl
Product: Cc1cccc(CC(F)(F)F)c1O
Temperature: 25 °C
Reaction time: 12 h
Yield: 79.3 %

Procedure:
2-Methoxy-1-methyl-3-(2,2,2-trifluoro-ethyl)-benzene (6.0 g) was dissolved in dichloromethane (100 ml) and BBr3 (100 ml) added. The reaction was allowed to stir at room temperature for 12 hrs, after which time it was quenched slowly with cHCl. The mixture was then made basic with 2N NaOH solution and the organics discarded. The aqueous was acidified with 1N HCl and the product extracted with ethyl acetate to afford the title compound as a brown oil (4.43 g). LCMS: APCI−VE=189
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[CH:9][C:5]([C:6](Cl)=[O:7])=[CH:4][N:3]=1.[N+:11]([C:14]1[CH:20]=[C:19]([CH3:21])[CH:18]=[C:17]([CH3:22])[C:15]=1[NH2:16])([O-:13])=[O:12]>>[Cl:1][C:2]1[N:3]=[CH:4][C:5]([C:6]([NH:16][C:15]2[C:17]([CH3:22])=[CH:18][C:19]([CH3:21])=[CH:20][C:14]=2[N+:11]([O-:13])=[O:12])=[O:7])=[CH:9][CH:10]=1
Reactant: O=C(Cl)c1ccc(Cl)nc1
Reactant: Cc1cc(C)c(N)c([N+](=O)[O-])c1
Product: Cc1cc(C)c(NC(=O)c2ccc(Cl)nc2)c([N+](=O)[O-])c1

Procedure:
The title compound was prepared from 6-chloronicotinoyl chloride and 2-nitro-4,6-dimethylaniline as a light yellow solid as described in Example 1. 1H NMR (CDCl3): 9.09 (s, 1H), 8.97 (d, J=2.4, 1H), 8.22-8.18 (m, 1H), 7.60 (d, J=1.2, 1H), 7.50 (d, J=8.1, 1H), 7.42 (s, 1H), 2.43 (s, 3H), 2.35 (s, 3H).
Reaction SMILES: [C:1]([C:4]1[CH:5]=[C:6]2[C:11](=[CH:12][CH:13]=1)[CH2:10][CH2:9][CH2:8][CH2:7]2)(=O)[CH3:2].Cl.[NH2:15][OH:16].C([O-])(=O)C.[Na+]>CO>[CH:5]1[C:6]2[CH2:7][CH2:8][CH2:9][CH2:10][C:11]=2[CH:12]=[CH:13][C:4]=1[C:1](=[N:15][OH:16])[CH3:2]
Reactant: CC(=O)c1ccc2c(c1)CCCC2
Reactant: NO
Agent: CC(=O)[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: CC(=NO)c1ccc2c(c1)CCCC2
Reaction time: 8 h
Yield: 70.1 %

Procedure:
To a solution of 6-acetyltetralin (5.0 g, 29 mmol) in methanol (30 mL) under a nitrogen atmosphere was added hydroxylamine hydrochloride (2.18 g, 32 mmol) and sodium acetate (2.59 g, 32 mmol) and the resulting mixture was stirred overnight. The reaction mixture was concentrated under reduced pressure and the residue was taken up in diethyl ether and washed with water and then with saturated sodium chloride solution. The organic phase was dried (MgSO4) and concentrated under reduced pressure to afford an oil which solidified. The solid was pulverized and rinsed with hexanes to afford the title compound of Step C (3.85 g) as an off-white solid. 1H NMR (CDCl3): δ 9.1 (br s,1H), 7.33 (m,2H), 7.07 (d,1H), 2.78 (m,4H), 2.27 (s,3H), 1.79 (m,4H).
Reaction SMILES: I.CS[C:4]1[NH:8][C@@H:7]2[CH2:9][CH2:10][CH2:11][CH2:12][C@H:6]2[N:5]=1.[C:13]1([CH:19]([C:23]2[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=2)[CH2:20][CH2:21][NH2:22])[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=1.C.[ClH:30]>CO.[OH-].[Na+].C(Cl)Cl>[ClH:30].[C:23]1([CH:19]([C:13]2[CH:14]=[CH:15][CH:16]=[CH:17][CH:18]=2)[CH2:20][CH2:21][NH:22][C:4]2[NH:8][C@@H:7]3[CH2:9][CH2:10][CH2:11][CH2:12][C@H:6]3[N:5]=2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: CSC1=N[C@@H]2CCCC[C@H]2N1
Reactant: NCCC(c1ccccc1)c1ccccc1
Agent: Cl
Agent: I
Agent: [Na+]
Solvent: ClCCl
Solvent: CO
Product: c1ccc(C(CCNC2=N[C@@H]3CCCC[C@H]3N2)c2ccccc2)cc1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A flask containing 2-methylthio-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole hydroiodide (3.00 g, 1.01×10-2 mole) and 3,3-diphenylpropylamine (2.13 g, 1.01×10-2 mole) was immersed in an oil bath which had been preheated to ca. 155° C. The reaction was stirred at between 150°-160° C. for 1 hour. The resulting yellow glass was dissolved in methanol. The solution was treated with charcoal which was subsequently removed by filtration through a pad of celite. The filtrate was evaporated at reduced pressure affording a foam which was dissolved in a stirred, two phase mixture of 5 molar aqueous NaOH (70 ml) and CH2Cl2 (65 ml). After stirring over the weekend, the CH2Cl2 layer was separated. The aqueous alkaline layer was extracted with CH2Cl2 (2×). The CH2Cl2 layers were combined, washed with H2O (2×), washed with saturated aqueous NaCl, and dried over anhydrous Na2SO4. The drying agent was removed by filtration and the filtrate was evaporated at reduced pressure leaving an oil which was dissolved in methanol (43 ml). This solution was cooled to 0° C. before being treated with a methanolic solution of HCl. This solution was treated with charcoal which was subsequently removed by filtration through a pad of celite. The filtrate was evaporated on the steam bath and 2-butanone was added periodically until the temperature approached 80° C. The solution was then placed in the freezer. After ca. 3 days, a solid was collected by filtration. This material was recrystallized two times from methanol/2-butanone affording 2-(3,3-diphenylpropylamino)-trans-3a,4,5,6,7,7a-hexahydro-1H-benzimidazole hydrochloride as a colorless solid: 1.18 g (32%), m.p. 155°-157° C.
Reaction SMILES: C(O[C:6]([N:8]([C@H:10]1[CH2:14][CH2:13][N:12]([S:15]([C:18]2[C:19]3[C:20]([Br:28])=[CH:21][N:22]=[CH:23][C:24]=3[CH:25]=[CH:26][CH:27]=2)(=[O:17])=[O:16])[CH2:11]1)C)=O)(C)(C)C.[ClH:29].CO>>[Br:28][C:20]1[C:19]2[C:18]([S:15]([N:12]3[CH2:13][CH2:14][C@H:10]([NH:8][CH3:6])[CH2:11]3)(=[O:16])=[O:17])=[CH:27][CH:26]=[CH:25][C:24]=2[CH:23]=[N:22][CH:21]=1.[ClH:29]
Reactant: CN(C(=O)OC(C)(C)C)[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Agent: Cl
Solvent: CO
Product: CN[C@H]1CCN(S(=O)(=O)c2cccc3cncc(Br)c23)C1
Temperature: 25 °C
Reaction time: 12 h

Procedure:
Intermediate 20a (0.157 g) prepared in Step A mentioned above was added with 10% hydrogen chloride/methanol (2 ml), and the mixture was stirred at room temperature for 12 hours. The solvent was evaporated under reduced pressure to obtain the title compound as hydrochloride (125 mg).
Reaction SMILES: [C:1]([C:4]1[CH:9]=[CH:8][CH:7]=[C:6]([C:10](=O)[CH3:11])[N:5]=1)(=[O:3])[CH3:2].[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[NH2:16]>C1(C)C=CC=CC=1.C1COCC1>[F:13][C:14]1[CH:20]=[CH:19][CH:18]=[C:17]([F:21])[C:15]=1[N:16]=[C:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([C:1](=[O:3])[CH3:2])[N:5]=1)[CH3:11]
Reactant: CC(=O)c1cccc(C(C)=O)n1
Reactant: Nc1c(F)cccc1F
Solvent: Cc1ccccc1
Solvent: C1CCOC1
Product: CC(=O)c1cccc(C(C)=Nc2c(F)cccc2F)n1
Temperature: 25 °C
Reaction time: 120 h
Yield: 19.9 %

Procedure:
2,6-Diacetylpyridine (4.04 g, 24.7 mmol) and 2,6-difluoroaniline (3.2 g, 24.7 mmol) were dissolved in 50 ml of toluene. To this solution, molecular sieves (4 Å) were added. After standing for 5 days at room temperature, the mixture was filtered. The solvent was removed in vacuo. From the resulting mixture of 2,6-diacetylpyridine, monoimine, and diimine. Most of the 2,6-diacetylpyridine was removed by sublimation in vacuo at 80-90° C. The residue contained based on 1H-NMR data 0.35 mmol 2,6-diacetylpyridine , 1.28 mmol diimine and 5.46 mmol monoimine. This mixture was reacted with 162 mg (1.28 mmol) FeCl2 in 10 ml THF to remove the diimine. After stirring for 16 h at room temperature, the solvent was removed in vacuo. Toluene (50 ml) was added to the resulting mixture. The precipitated complex was filtered off over a small layer of silica, yielding a yellow solution. The solvent was removed in vacuo. Crystallisation from ethanol yielded 1.35 g of 2-[1-(2,6-difluorophenylimino)ethyl]-6-acetylpyridine (18) (19.8%).
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:11]=[CH:10][C:9]([C:12]2[CH:17]=[C:16]([NH:18][C:19]([CH:21]3[CH2:23][CH2:22]3)=[O:20])[CH:15]=[CH:14][C:13]=2[O:24][CH3:25])=[CH:8][CH:7]=1)=[O:5])C>C(O)C.[OH-].[Na+]>[CH:21]1([C:19]([NH:18][C:16]2[CH:15]=[CH:14][C:13]([O:24][CH3:25])=[C:12]([C:9]3[CH:10]=[CH:11][C:6]([C:4]([OH:5])=[O:3])=[CH:7][CH:8]=3)[CH:17]=2)=[O:20])[CH2:23][CH2:22]1
Reactant: CCOC(=O)c1ccc(-c2cc(NC(=O)C3CC3)ccc2OC)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: CCO
Product: COc1ccc(NC(=O)C2CC2)cc1-c1ccc(C(=O)O)cc1
Reaction time: 18 h

Procedure:
A mixture of 5′-(cyclopropanecarbonyl-amino)-2′-methoxy-biphenyl-4-carboxylic acid ethyl ester (88 mg) in ethanol (7 ml) and 2M sodium hydroxide (4 ml) was stirred at 20 C for 18 h. The ethanol was then evaporated and the residue acidified. The solid thus formed was collected by filtration and dried (55 mg)
Reaction SMILES: [F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1/[CH:11]=[C:12](/[C:15](=O)[CH3:16])\[C:13]#[N:14].[CH3:18][C:19]1[CH:23]=[C:22]([NH2:24])[O:21][N:20]=1>>[F:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[N:7][NH:8]2)=[CH:4][C:3]=1[CH:11]1[C:12]([C:13]#[N:14])=[C:15]([CH3:16])[NH:24][C:22]2[O:21][N:20]=[C:19]([CH3:18])[C:23]1=2
Reactant: CC(=O)/C(C#N)=C/c1cc2cn[nH]c2cc1F
Reactant: Cc1cc(N)on1
Product: CC1=C(C#N)C(c2cc3cn[nH]c3cc2F)c2c(C)noc2N1

Procedure:
100 mg (0.44 mmol) (2E)-2-[(6-fluoro-1H-indazol-5-yl)methylidene]-3-oxobutanenitrile (Example 13A) were treated with 3-methyl-1,2-oxazol-5-amine following the procedure described in Example 2. The crude material was purified by preparative RP-HPLC (methanol/water+0.1% TFA gradient) to yield 55 mg (41% of th.) of the racemic title compound.