Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: CCN=C=NCCCN(C)C.[NH:12]1[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1.[CH:21]1([NH:26][C:27]2[C:32]([C:33](O)=[O:34])=[CH:31][N:30]=[C:29]([S:36][CH3:37])[N:28]=2)[CH2:25][CH2:24][CH2:23][CH2:22]1>C(Cl)Cl>[N:12]1([C:33]([C:32]2[C:27]([NH:26][CH:21]3[CH2:25][CH2:24][CH2:23][CH2:22]3)=[N:28][C:29]([S:36][CH3:37])=[N:30][CH:31]=2)=[O:34])[C:16]2[CH:17]=[CH:18][CH:19]=[CH:20][C:15]=2[N:14]=[N:13]1
Reactant: CSc1ncc(C(=O)O)c(NC2CCCC2)n1
Reactant: c1ccc2[nH]nnc2c1
Agent: CCN=C=NCCCN(C)C
Solvent: ClCCl
Product: CSc1ncc(C(=O)n2nnc3ccccc32)c(NC2CCCC2)n1
Reaction time: 1 h
Yield: 53.9 %

Procedure:
EDCI (7.690 g, 40.26 mmol) and benzotriazole (4.796 g, 40.26 mmol) were added to a suspension of 4-cyclopentylamino-2-methylsulfanyl-pyrimidine-5-carboxylic acid (10.186 g, 40.26 mmol) in DCM (250 mL), at RT, and the reaction mixture was stirred for 1 h. The resulting mixture was washed 3 times with water; the combined aqueous extracts were extracted twice with DCM. The combined organic layers were dried over Na2SO4, filtered and evaporated under reduced pressure to give a crude oil. This material was triturated with hot tert-butyl methyl ether and the mixture was left to stand overnight. The white solid which formed was collected by filtration to give 7.698 g (54% yield) of benzotriazol-1-yl-(4-cyclopentylamino-2-methylsulfanyl-pyrimidin-5-yl)-methanone.
Reaction SMILES: Br[CH2:2][C:3]1[CH:10]=[CH:9][C:6]([CH:7]=[O:8])=[CH:5][C:4]=1[Cl:11].[C:12]1(=[O:22])[NH:16][C:15](=[O:17])[C:14]2=[CH:18][CH:19]=[CH:20][CH:21]=[C:13]12.[K]>CN(C=O)C.O>[Cl:11][C:4]1[CH:5]=[C:6]([CH:9]=[CH:10][C:3]=1[CH2:2][N:16]1[C:12](=[O:22])[C:13]2[C:14](=[CH:18][CH:19]=[CH:20][CH:21]=2)[C:15]1=[O:17])[CH:7]=[O:8]
Reactant: O=Cc1ccc(CBr)c(Cl)c1
Reactant: O=C1NC(=O)c2ccccc21
Agent: [K]
Solvent: CN(C)C=O
Solvent: O
Product: O=Cc1ccc(CN2C(=O)c3ccccc3C2=O)c(Cl)c1
Temperature: 60 °C
Yield: 66.7 %

Procedure:
To a stirred solution of 4-(bromomethyl)-3-chlorobenzaldehyde (3.8 g, 14 mmol) in DMF (40 mL) was added potassium pthalimide (3.54 g, 19.14 mmol), and the mixture was heated at 60° C. for 6 h. The reaction mixture was cooled to ambient temperature and diluted with H2O (100 mL). The solid obtained was separated by filtration and dried under vacuum to afford the title compound as a white solid (2.8 g, 60%): mp 123-126° C.; 1H NMR (400 MHz, CDCl3) δ 9.95 (s, 1H), 8.21 (s, 1H), 7.91 (m, 3H), 7.80 (m, 2H), 7.20 (m, 1H), 5.05 (s, 2H); ESIMS m/z 298.03 ([M−H]−).
Reaction SMILES: [Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:17])([F:16])[F:15])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[N+:18]([O-])=O.[Cl-].[Ca+2].[Cl-]>C(O)C.O.[Fe]>[Cl:1][C:2]1[N:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]([F:15])([F:16])[F:17])=[CH:12][CH:11]=[CH:10][N:9]=2)=[CH:4][C:3]=1[NH2:18]
Reactant: O=[N+]([O-])c1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Agent: [Fe]
Agent: [Ca+2]
Agent: [Cl-]
Solvent: CCO
Solvent: O
Product: Nc1cc(-c2ncccc2C(F)(F)F)cnc1Cl
Yield: 84.7 %

Procedure:
To a solution of 6′-chloro-5′-nitro-3-trifluoromethyl-[2,3′]bipyridinyl (25 g, 0.082 mol) and calcium chloride (11 g, 0.1 mol) in ethanol (300 mL) and water (50 mL), add iron powder (45 g, 0.82 mol). Heat the solution to reflux for 1.5 hours, cool and filter through Celite. Concentrate the mixture under reduced pressure, re-dissolve in ethyl acetate (300 mL) and wash with brine (200 mL). Concentrate the solution under reduced pressure and purify by flash chromatography on silica gel (50/ether/50% hexane) to give the title compound (19 g, 85%) as a pale yellow solid.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=[C:4]([NH2:14])[CH:3]=1.[Br:15][CH2:16][C:17](Br)=[O:18].C(N(CC)C(C)C)(C)C>C(Cl)Cl>[Br:15][CH2:16][C:17]([NH:14][C:4]1[CH:3]=[C:2]([Cl:1])[N:7]=[C:6]([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[N:5]=1)=[O:18]
Reactant: O=C(Br)CBr
Reactant: Nc1cc(Cl)nc(-c2ccccc2)n1
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: O=C(CBr)Nc1cc(Cl)nc(-c2ccccc2)n1
Reaction time: 1 h

Procedure:
6-chloro-2-phenylpyrimidin-4-amine (4) (830 mg) was dissolved in anhydrous DCM (50 ml). To this was added dropwise a solution of bromoacetylbromide (1.05 ml in 10 ml DCM), forming a precipitate after 10 min. To this was then added dropwise a solution of N,N-diisopropylethylamine (1.06 ml in 10 ml DCM) and the solution left for 1 hr. The solvent was removed in vacuo, then the crude solid purified by flash chromatography on silica gel eluting with a mixture of ethyl acetate and petroleum ether (1:9 then 1:1 v/v), furnishing the title compound as a solid (1.09 g).
Reaction SMILES: C([NH:20][CH:21]1[CH:28]2[CH2:29][CH:24]3[CH2:25][C:26]([O:31][CH2:32][C:33]4[CH:38]=[CH:37][C:36]([C:39]5[O:40][C:41]6[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=6[N:43]=5)=[CH:35][CH:34]=4)([CH2:30][CH:22]1[CH2:23]3)[CH2:27]2)(C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:48]>>[ClH:48].[O:40]1[C:41]2[CH:47]=[CH:46][CH:45]=[CH:44][C:42]=2[N:43]=[C:39]1[C:36]1[CH:35]=[CH:34][C:33]([CH2:32][O:31][C:26]23[CH2:30][CH:22]4[CH2:23][CH:24]([CH2:29][CH:28]([CH:21]4[NH2:20])[CH2:27]2)[CH2:25]3)=[CH:38][CH:37]=1
Reactant: c1ccc(C(NC2C3CC4CC2CC(OCc2ccc(-c5nc6ccccc6o5)cc2)(C4)C3)(c2ccccc2)c2ccccc2)cc1
Agent: Cl
Product: NC1C2CC3CC1CC(OCc1ccc(-c4nc5ccccc5o4)cc1)(C3)C2
Temperature: 25 °C

Procedure:
A mixture of N-trityl-5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]decan-2-amine (200 mg) combined with ethanolic hydrogen chloride (5 ml) is stirred for an hour at room temperature. This is evaporated to dryness and the components separated via flash chromatography (eluting with 10% MeOH/CH2Cl2) to obtain 5-[4-(benzoxazol-2-yl)benzyloxy]tricyclo[3.3.1.13,7 ]-decan-2-amine hydrochloride (m.p. 278°-281° C.).
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]([N:9]([N:17]([CH2:24][CH2:25][CH3:26])C(=O)C(F)(F)F)[C:10]([O:12][C:13]([CH3:16])([CH3:15])[CH3:14])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2].O.[OH-].[Li+]>CO>[C:1]([C:3]1[CH:4]=[C:5]([N:9]([NH:17][CH2:24][CH2:25][CH3:26])[C:10]([O:12][C:13]([CH3:14])([CH3:15])[CH3:16])=[O:11])[CH:6]=[CH:7][CH:8]=1)#[N:2]
Reactant: CCCN(C(=O)C(F)(F)F)N(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Agent: [Li+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: CCCNN(C(=O)OC(C)(C)C)c1cccc(C#N)c1
Reaction time: 5 h
Yield: 63.8 %

Procedure:
5.64 g (15.187 mmol) of crude product 403 are dissolved in 100 ml of methanol and treated at RT with 10 ml of completely deionized water and 1.08 g (45.24 mmol) of lithium hydroxide. The reaction mixture is then stirred for 5 h. After customary work-up, 2.67 g (63.8%) of 404 are thus obtained as an oil; MS(FAB)=276.
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([C:9]([F:12])([F:11])[F:10])[C:5]([Br:8])=[CH:6][CH:7]=1.[OH-].[Na+].[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20](Cl)=[O:21])([O-:17])=[O:16]>CCOC(C)=O>[N+:15]([C:18]1[CH:26]=[CH:25][CH:24]=[CH:23][C:19]=1[C:20]([NH:1][C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[C:4]([C:9]([F:12])([F:10])[F:11])[CH:3]=1)=[O:21])([O-:17])=[O:16]
Reactant: O=C(Cl)c1ccccc1[N+](=O)[O-]
Reactant: Nc1ccc(Br)c(C(F)(F)F)c1
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Product: O=C(Nc1ccc(Br)c(C(F)(F)F)c1)c1ccccc1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 3-amino-6-bromobenzotrifluoride (Fluka, Buchs, Switzerland; 24.0 g, 100 mmol) in EtOAc (240 mL) is added to a stirred aqueous solution of sodium hydroxide (110 mL of 1 M) at room temperature. This stirred solution is then treated dropwise over 30 minutes with a solution of 2-nitrobenzoyl chloride (Fluka, Buchs, Switzerland; 14.5 mL, 110 mmol) in EtOAc (150 mL). The resulting mixture is then stirred for 30 min at ambient temperature. The mixture is extracted with EtOAc (3×100 mL) and the combined extracts are sequentially washed with hydrochloric acid (2×100 mL of 2M), water (2×100 mL), saturated aqueous sodium hydrogen carbonate solution (2×100 mL) and saturated aqueous sodium chloride (1×100 mL), dried (MgSO4), filtered and the solvent is evaporated under reduced pressure to yield the crude product which is purified by recrystallisation from EtOAc-hexane to give the title compound as a beige crystalline solid, m.p. 157–158° C.
Reaction SMILES: [CH2:1]([CH:3]([CH2:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[C:10]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:37][CH2:36][NH:35][CH2:34][CH2:33][NH:32][CH2:31][CH2:30][NH:29][CH2:28][CH2:27]2)[C:9]=1[I:40])[C:4]([OH:6])=[O:5])[CH3:2].Br[CH2:42][C:43]([OH:45])=[O:44]>CCO>[CH2:1]([CH:3]([CH2:7][C:8]1[C:13]([I:14])=[CH:12][C:11]([I:15])=[C:10]([NH:16][C:17](=[O:39])[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22][NH:23][C:24](=[O:38])[CH2:25][N:26]2[CH2:27][CH2:28][N:29]([CH2:42][C:43]([OH:45])=[O:44])[CH2:30][CH2:31][N:32]([CH2:42][C:43]([OH:45])=[O:44])[CH2:33][CH2:34][N:35]([CH2:3][C:4]([OH:6])=[O:5])[CH2:36][CH2:37]2)[C:9]=1[I:40])[C:4]([OH:6])=[O:5])[CH3:2]
Reactant: O=C(O)CBr
Reactant: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCNCCNCCNCC2)c1I)C(=O)O
Solvent: CCO
Product: CCC(Cc1c(I)cc(I)c(NC(=O)CCCCCNC(=O)CN2CCN(CC(=O)O)CCN(CC(=O)O)CCN(CC(=O)O)CC2)c1I)C(=O)O
Yield: 96.7 %

Procedure:
According to the procedure described in Example 2, 111 g of compound (A) α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[(1,4,7,10-tetraazacyclododec-1-yl-acetyl)amino]hexyl]amino]benzenepropanoic acid (0.12 mol) are reacted with 67.2 g of bromoacetic acid (0.48 mol) in 600 ml of 80% EtOH. 63 g of α-ethyl-2,4,6-triiodo-3-[[1-oxo-6-[[4,7,10-tris(carboxymethyl)-1,4,7,10-tetraazacyclododec-1-ylacetyl]amino]hexyl]amino]benzenepropanoic acid (0.058 mol) are obtained.
Reaction SMILES: [CH3:1][C:2]1[N:3]=[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][N:5]2[CH:10]=1.[CH2:11]([CH:13]([C:16]1[C:17]2[N:18]([C:23](I)=[C:24]([CH3:26])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:14][CH3:15])[CH3:12]>>[CH2:11]([CH:13]([C:16]1[C:17]2[N:18]([C:23]([C:10]3[N:5]4[CH:6]=[CH:7][CH:8]=[CH:9][C:4]4=[N:3][C:2]=3[CH3:1])=[C:24]([CH3:26])[N:25]=2)[N:19]=[C:20]([CH3:22])[CH:21]=1)[CH2:14][CH3:15])[CH3:12]
Reactant: CCC(CC)c1cc(C)nn2c(I)c(C)nc12
Reactant: Cc1cn2ccccc2n1
Product: CCC(CC)c1cc(C)nn2c(-c3c(C)nc4ccccn34)c(C)nc12
Yield: 20.5 %

Procedure:
Using a procedure analogous to Example 16B, 2-methyl-imidazo[1,2-a]pyridine (Chem. Ber. 1926; 59, 2054), (0.38 g, 2.92 mmol) and 8-(1-ethyl-propyl)-3-iodo-2,6-dimethyl-imidazo[1,2-b]pyridazine (1.00 g, 2.92 mmol) give the title compound (0.21 g, 0.60 mmol, 21%). 1H NMR (CDCl3): δ 0.91 (t, J=7.5 Hz, 3H), 0.92 (t, J=7.5 Hz, 3H), 1.80-1.95 (m, 4H), 2.42 (s, 3H), 2.43 (s, 3H), 2.45 (s, 3H), 3.34-3.42 (m, 1H), 6.73 (s, 1H), 6.74 (dt, J=6.6, 0.9 Hz, 1H), 7.21-7.25 (m, 1H), 7.52 (d, J=6.6 Hz, 1H), 7.64 (d, J=6.6 Hz, 1H) ppm. ES-MS (m/z): calcd for C21H25N5 (M+H)+: 348.5. found: 348.2.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[CH:4][N:3]=1.ClC1C=C(C=CC=1)C(OO)=[O:21].[OH-].[Na+]>ClCCl>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([S:8]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=2[F:15])=[O:21])=[CH:4][N:3]=1
Reactant: Fc1ccccc1Sc1ccc(Cl)nc1
Reactant: O=C(OO)c1cccc(Cl)c1
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Product: O=S(c1ccc(Cl)nc1)c1ccccc1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 61 %

Procedure:
2-Chloro-5-[(2-fluorophenyl)thio]pyridine (Example 1 Step 1, 1.0 g, 4.17 mmol) was taken up in dichloromethane (20 mL) and 3-chloroperoxybenzoic acid (50%; 1.44 g, 4.17 mmol). The reaction was stirred at room temperature under nitrogen for 1 hour. 4N sodium hydroxide solution was added and the products extracted into dichloromethane (×2). The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo while loading onto silica. Dry flash column chromatography using toluene followed by 10% ethyl acetate/toluene gave 2-chloro-5-[(2-fluorophenyl)sulfinyl]pyridine (0.65 g, 61%). δH (500 MH, d6 DMSO) 8.71 (1H, s), 8.07 (1H, d, J 8.2), 7.83 (1H, t, J 6.7), 7.68 (1H, d, J 8.2), 7.63–7.59 (1H, m), 7.46 (1H, t, J 7.3), 7.33 (1H, t, J 9.1); m/z (ES+) 256, 258 [MH+].
Reaction SMILES: [CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([O:20]C)=[O:19])=[CH:14][CH:13]=1)=[O:10])[CH:2]([CH3:4])[CH3:3].[OH-].[Na+].O.Cl>C1COCC1>[CH2:1]([O:5][C:6]1[CH:7]=[C:8]([CH:22]=[C:23]([O:25][CH:26]([CH3:28])[CH3:27])[CH:24]=1)[C:9]([NH:11][C:12]1[N:17]=[CH:16][C:15]([C:18]([OH:20])=[O:19])=[CH:14][CH:13]=1)=[O:10])[CH:2]([CH3:4])[CH3:3]
Reactant: COC(=O)c1ccc(NC(=O)c2cc(OCC(C)C)cc(OC(C)C)c2)nc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)COc1cc(OC(C)C)cc(C(=O)Nc2ccc(C(=O)O)cn2)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 88 %

Procedure:
Methyl 6-[(3-isobutoxy-5-isopropoxybenzoyl)amino]-3-pyridinecarboxylate (230 mg, 0.62 mM) was dissolved in THF (8 ml) and a 2M NaOH solution (1.2 ml, 2.40 mM) was added. Water (7 ml) was added to the reaction mixture until it became monophasic. The reaction was stirred for 6 hours at ambient temperature and was then acidified to pH=1 with 1N aqueous HCl. The white solid which precipitated from the mixture was isolated by filtration and dried to give the title compound as a colourless solid (195 mg); H1 NMR δ (d6-DMSO) 0.99 (6H d) 1.12 (6H d) 2.00 (1H sept) 3.80 (2H d) 4.65 (1H sept) 6.62 (1H s) 7.19 (2H s) 8.30 (2H s) 8.86 (1H s) 11.09 (1H s br); [M+H]373; [M−H] 371.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12]O.[Br:14]P(Br)Br.C([O-])(O)=O.[Na+]>ClCCl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]([F:11])([F:10])[F:9])=[CH:4][C:3]=1[CH2:12][Br:14]
Reactant: OCc1cc(C(F)(F)F)ccc1Br
Reactant: BrP(Br)Br
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: FC(F)(F)c1ccc(Br)c(CBr)c1
Yield: 60.1 %

Procedure:
To a solution of (2-bromo-5-(trifluoromethyl)phenyl)methanol (1.6 g, 6.27 mmol) in dichloromethane (10 mL) at 0° C. was added tribromophosphine (1.698 g, 6.27 mmol) over 2 hours. To the reaction mixture was added saturated NaHCO3 and the organic layers was separated, dried with NaSO4, filtered, and concentrated. The residue was purified by column chromatography using an Analogix® Intelliflash280™ (SiO2, 0-100% EtOAc in hexane) to afford the title compound (1.2 g, 3.77 mmol, 60.2% yield). 1H NMR (300 MHz, CDCl3) δ ppm 4.60 (s, 2H) 7.53-7.61 (m, 2H) 7.84 (s, 1H).
Reaction SMILES: C([O:5][NH:6][C:7](=[O:26])[CH2:8][CH2:9][CH2:10][CH2:11][O:12][C:13]1[CH:18]=[CH:17][C:16]([C:19]2[CH:24]=[CH:23][C:22]([F:25])=[CH:21][CH:20]=2)=[CH:15][CH:14]=1)(C)(C)C>FC(F)(F)C(O)=O>[F:25][C:22]1[CH:21]=[CH:20][C:19]([C:16]2[CH:17]=[CH:18][C:13]([O:12][CH2:11][CH2:10][CH2:9][CH2:8][C:7]([NH:6][OH:5])=[O:26])=[CH:14][CH:15]=2)=[CH:24][CH:23]=1
Reactant: CC(C)(C)ONC(=O)CCCCOc1ccc(-c2ccc(F)cc2)cc1
Solvent: O=C(O)C(F)(F)F
Product: O=C(CCCCOc1ccc(-c2ccc(F)cc2)cc1)NO
Reaction time: 0.5 h
Yield: 38.4 %

Procedure:
A solution in trifluoroacetic acid of O-tert-butyl 5-[4-(4-fluorophenyl)phenoxy]pentanohydroxamic acid (0.41 g, 1.1 mmol) was stirred overnight. The reaction mixture was concentrated in vacuo and the residue was suspended in acetonitrile and stirred for 30 minutes. The solid was filtered and dried in vacuo to give 5-[4-(4-fluorophenyl)phenoxy]pentanohydroxamic acid (128 mg) as a white solid. mp 160°-162° C. 1H NMR (DMSO-d6) δ 10.378 (s, 1H), 8.69 (s, 1H), 7.66-7.63 (m, 2H), 7.57-7.55 (d, 2H, J=8.8 Hz), 7.27-7.21 (t, 2H, J=8.8 Hz), 7.02-6.99 (d, 2H, J=8.8 Hz), 4.02-3.98 (t, 2H, J=5.9 Hz), 2.04-2.00 (t, 2H, J=7 Hz), 1.68-1.66 (m, 4H). 13C NMR (DMSO-d6) δ 21.76, 28.15, 31.87, 7.11, 114.85, 115.38, 115.66, 118.34, 127.66, 127.94, 128.03, 131.04, 136.20, 136.33, 158.18, 159.76, 162.98, 168.87. MS (DCI/NH3) 304 (M+H)+, 321 (M+NH4)+. Anal. Calcd for C17H18NO3F: C, 67.31; H, 5.98; N, 4.61. Found: C, 7.19; H, 6.03; N, 4.40.
Reaction SMILES: [C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH2:19])([CH3:4])([CH3:3])[CH3:2].C([O:25][C:26](=O)[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)(C)(C)C>>[C:1]([O:5][C:6](=[O:20])[NH:7][C:8]1[CH:13]=[C:12]([CH3:14])[C:11]([C:15]([F:18])([F:17])[F:16])=[CH:10][C:9]=1[NH:19][C:26](=[O:25])[CH2:27][C:28](=[O:48])[C:29]1[CH:34]=[CH:33][CH:32]=[C:31]([N:35]2[C:39]([CH2:40][O:41][CH:42]3[CH2:47][CH2:46][CH2:45][CH2:44][O:43]3)=[CH:38][N:37]=[N:36]2)[CH:30]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(N)cc1C(F)(F)F
Reactant: CC(C)(C)OC(=O)CC(=O)c1cccc(-n2nncc2COC2CCCCO2)c1
Product: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-n3nncc3COC3CCCCO3)c2)cc1C(F)(F)F

Procedure:
The title compound was prepared from (2-amino-5-methyl-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example J15) (1.0 g, 3.44 mmol) and (RS)-3-oxo-3-{3-[5-(tetrahydro-pyran-2-yloxymethyl)-[1,2,3]triazol-1-yl]-phenyl}-propionic acid tert-butyl ester (Example K5) (1.38 g, 3.44 mmol) according to the general procedure M. Obtained as an off-white foam (910 mg, 43%).
Reaction SMILES: [NH2:1][CH:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]23[CH2:23][CH:16]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:22]=42)[C:15]2[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=2)[CH2:4][CH2:3]1.Cl[C:25]1[N:30]=[CH:29][C:28]([C:31]2[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=2)=[CH:27][N:26]=1>>[CH:21]1[C:22]2[C:9]3([CH2:8][N:5]4[CH2:6][CH2:7][CH:2]([NH:1][C:25]5[N:26]=[CH:27][C:28]([C:31]6[CH:36]=[CH:35][CH:34]=[CH:33][CH:32]=6)=[CH:29][N:30]=5)[CH2:3][CH2:4]4)[CH2:23][CH:16]([C:15]4[C:10]3=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:17]=2[CH:18]=[CH:19][CH:20]=1
Reactant: NC1CCN(CC23CC(c4ccccc42)c2ccccc23)CC1
Reactant: Clc1ncc(-c2ccccc2)cn1
Product: c1ccc(-c2cnc(NC3CCN(CC45CC(c6ccccc64)c4ccccc45)CC3)nc2)cc1

Procedure:
Using a procedure similar to that described in Example 86 except starting with 4-amino-1-(9,10-dihydro-9,10-methanoanthracene-9-ylmethyl)piperidine (prepared as described in Example 8b) and 2-chloro-5-phenylpyrimidine the hydrochloride salt of the title compound was obtained as a white solid (60%), mp 292°-294° C.; MS(CI): 459 (M+H); NMR (300MHz, DMSO-d6): 9.95(br s, 1H), 8.70-8.66(m, 2H), 7.66-7.62(m, 3H), 7.47-7.33(m, 7H), 7.04-6.96(m, 4H), 4.46(s, 1H), 4.35-4.33(m, 2H), 4.25-4.00(br m, 1H), 3.0-3.35(m, 4H), 2.74(s, 2H), 2.15-1.91(m, 4H).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([OH:10])=[CH:6][CH:5]=1)([O-:3])=[O:2].[H-].[Na+].[CH3:13][O:14][CH2:15][CH2:16]Br>CN(C=O)C>[CH3:13][O:14][CH2:15][CH2:16][O:10][C:7]1[CH:8]=[CH:9][C:4]([N+:1]([O-:3])=[O:2])=[CH:5][CH:6]=1
Reactant: COCCBr
Reactant: O=[N+]([O-])c1ccc(O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: COCCOc1ccc([N+](=O)[O-])cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 104.1 %

Procedure:
A stirred solution of 4-nitrophenol (Fluka) (0.511 g, 3.67 mmol) in DMF (10 mL) was treated with 60% sodium hydride (Aldrich) (0.170 g, 4.25 mmol) added in portions at 0° C. The yellow mixture was stirred at that temperature for 10 min, then 2-bromoethyl methyl ether (Aldrich) (0.380 mL, 4.04 mmol) was added dropwise at 0° C. The mixture was stirred at that temperature for 5 min, warmed up to rt and stirred for 3.5 h then at 70° C. overnight. The reaction mixture was poured into ice-water (100 mL). The aqueous phase was extracted with EtOAc (2×70 mL). The combined organic phases were dried over sodium sulfate, filtered and concentrated in vacuo to give 1-(2-methoxyethoxy)-4-nitrobenzene (0.753 g, 105% yield) as an off-white solid. 1H NMR (400 MHz, CDCl3) δ 8.16-8.25 (m, 2H); 6.95-7.03 (m, 2H); 4.17-4.26 (m, 2H); 3.73-3.84 (m, 2H); 3.46 (s, 3H). m/z (ESI, +ve ion) 198.1 (M+H)+.
Reaction SMILES: ClC1C=CC=C(C(OO)=[O:9])C=1.[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:26])[F:25])=[CH:22][N:21]=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]>C(Cl)(Cl)Cl>[CH3:12][O:13][C:14]1[C:33]([O:34][CH3:35])=[C:32]([O:36][CH3:37])[CH:31]=[C:30]([CH3:38])[C:15]=1[C:16]([C:18]1[C:23]([C:24]([F:27])([F:25])[F:26])=[CH:22][N+:21]([O-:9])=[CH:20][C:19]=1[O:28][CH3:29])=[O:17]
Reactant: O=C(OO)c1cccc(Cl)c1
Reactant: COc1cc(C)c(C(=O)c2c(OC)cncc2C(F)(F)F)c(OC)c1OC
Solvent: ClC(Cl)Cl
Product: COc1cc(C)c(C(=O)c2c(OC)c[n+]([O-])cc2C(F)(F)F)c(OC)c1OC
Temperature: 25 °C
Reaction time: 18 h
Yield: 96.3 %

Procedure:
6.1 g (28 mmol) of m-chloroperbenzoic acid (m-CPBA) was added at 0° C. to a chloroform 100 ml solution of 5.6 g (15 mmol) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine (Compound No. 122), followed by stirring at room temperature for 18 hours. The reaction solution was washed with a sodium hydroxide aqueous solution, and the solvent was distilled off under reduced pressure to obtain 5.8 g (yield: 99%) of 4-(2,3,4-trimethoxy-6-methylbenzoyl)-3-methoxy-5-trifluoromethylpyridine-N-oxide (melting point 128 to 134° C.).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:12]=[C:11]2[C:6]([CH:7]=[CH:8][C:9](=O)[O:10]2)=[CH:5][CH:4]=1.CO[CH2:16][N:17](CC1C=CC=CC=1)[CH2:18][Si](C)(C)C>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[C@@H:7]3[CH2:18][NH:17][CH2:16][C@@H:8]3[CH2:9][O:10][C:11]=2[CH:12]=1
Reactant: COc1ccc2ccc(=O)oc2c1
Reactant: COCN(Cc1ccccc1)C[Si](C)(C)C
Product: COc1ccc2c(c1)OC[C@H]1CNC[C@@H]21

Procedure:
From 7-methoxy-coumarin and N-methoxymethyl-N-trimethylsilylmethyl-benzylamine in an analogous manner as described in Examples 1A-C: 1H NMR (300 MHz, CDCl3) δ 1.92 (br s, 1H), 2.60 (m, 1H), 2.81 (m, 2H), 3.17 (q, 1H), 3.29 (dd, 1H), 3.40 (dd, 1H), (s, 3H), 3.78 (t, 1H), 4.10 (dd, 1H), 6.43 (d, 1H), 6.52 (dd, 1H), 7.03 (d, 1H).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([NH:12][C:13]([CH3:18])([CH3:17])[C:14]([OH:16])=O)[CH:5]=[CH:6][C:7]=1[C:8](=[O:11])[NH:9][CH3:10].[NH2:19][C:20]1[CH:27]=[CH:26][C:23]([C:24]#[N:25])=[C:22]([C:28]([F:31])([F:30])[F:29])[CH:21]=1.O>C(Cl)Cl>[C:24]([C:23]1[CH:26]=[CH:27][C:20]([NH:19][C:14]([C:13]([NH:12][C:4]2[CH:5]=[CH:6][C:7]([C:8]([NH:9][CH3:10])=[O:11])=[C:2]([F:1])[CH:3]=2)([CH3:18])[CH3:17])=[O:16])=[CH:21][C:22]=1[C:28]([F:29])([F:30])[F:31])#[N:25]
Reactant: N#Cc1ccc(N)cc1C(F)(F)F
Reactant: CNC(=O)c1ccc(NC(C)(C)C(=O)O)cc1F
Solvent: O
Solvent: ClCCl
Product: CNC(=O)c1ccc(NC(C)(C)C(=O)Nc2ccc(C#N)c(C(F)(F)F)c2)cc1F
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 30.8 %

Procedure:
The title compound was made in accordance with General Method 1. 2-(3-Fluoro-4-methylcarbamoyl-phenylamino)-2-methyl-propionic acid (1.27 g) was dissolved in DCM. EDC1-HCl (1.91 g) was added to it and the reaction mixture was stirred for 5 min at RT. 4-Amino-2-(trifluoromethyl)benzonitrile (1.00 g) was added portionwise and stirring was continued for 5 h at RT. Water was added to the reaction mixture, and the product was extracted with DCM. The combined organic layer was washed with water, dried over sodium sulfate and evaporated under reduced pressure. The residue was purified by silica gel chromatography (100-200 mesh silica gel) eluting with 5% MeOH-DCM to obtain 650 mg of 4-[1-(4-Cyano-3-trifluoromethyl-phenylcarbamoyl)-1-methyl-ethylamino]-2-fluoro-N-methyl-benzamide, HPLC, Column: YMC ODS AQ, 4.6×250 mm, 5 μm, Mobile Phase A: 0.05% TFA, Mobile Phase B: ACN, Gradient: 10% to 90% B in 10 min, hold for 10 min, 90% to 10% B in 1 min, Flow Rate: 1 mL/min, Retention time: 11.174 min, M+1: 423.