Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[CH:4][C:5]([F:26])=[C:6]([C:8]2[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([C:18]4[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=4)[CH:16]=3)[C:11](=[O:24])[N:10]([CH3:25])[CH:9]=2)[CH:7]=1.[CH3:27][S:28](Cl)(=[O:30])=[O:29]>N1C=CC=CC=1.C(Cl)Cl>[F:26][C:5]1[CH:4]=[CH:3][C:2]([NH:1][S:28]([CH3:27])(=[O:30])=[O:29])=[CH:7][C:6]=1[C:8]1[C:17]2[C:12](=[CH:13][CH:14]=[C:15]([C:18]3[CH:19]=[N:20][N:21]([CH3:23])[CH:22]=3)[CH:16]=2)[C:11](=[O:24])[N:10]([CH3:25])[CH:9]=1
Reactant: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(N)ccc4F)c3c2)cn1
Reactant: CS(=O)(=O)Cl
Solvent: c1ccncc1
Solvent: ClCCl
Product: Cn1cc(-c2ccc3c(=O)n(C)cc(-c4cc(NS(C)(=O)=O)ccc4F)c3c2)cn1
Yield: 85.7 %

Procedure:
4-(5-Amino-2-fluorophenyl)-2-methyl-6-(1-methylpyrazol-4-yl)isoquinolin-1-one (25 mg, 0.07 mmol) in pyridine (0.1 mL) and anhydrous CH2Cl2 (0.3 mL) was treated with methanesulfonyl chloride (0.007 mL, 0.09 mmol) in a manner similar to Example 33. After a similar work up, silica gel chromatography, eluting with 50-100% EA in hexane over 4 min and continuing isocratic 100% EA, gave the title compound (24 mg, 0.06 mmol) as a white solid in 78% yield. 1H NMR (400 MHz, DMSO-d6) δ 3.06 (s, 3H), 3.56 (s, 3H), 3.85 (s, 3H), 7.22-7.45 (m, 4H), 7.59 (s, 1H), 7.76 (dd, J=8.34, 1.52 Hz, 1H), 7.85 (s, 1H), 8.16 (s, 1H), 8.29 (d, J=8.34 Hz, 1H), 9.82 (s, 1H). LCMS (M+H)+ 427.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][NH:5][CH2:4][CH2:3]1.[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28]Cl)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11].O>CN(C=O)C>[CH3:8][O:9][C:10]([C:12]1[CH:13]=[C:14]([CH3:34])[C:15]2[O:21][C:20]3[C:22]([Cl:30])=[CH:23][C:24]([NH:26][CH2:27][CH2:28][N:5]4[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]4)=[CH:25][C:19]=3[CH2:18][S:17](=[O:32])(=[O:31])[C:16]=2[CH:33]=1)=[O:11]
Reactant: CN1CCNCC1
Reactant: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCCl)cc(Cl)c1O2
Solvent: CN(C)C=O
Solvent: O
Product: COC(=O)c1cc(C)c2c(c1)S(=O)(=O)Cc1cc(NCCN3CCN(C)CC3)cc(Cl)c1O2
Temperature: 110 °C
Reaction time: 2 h

Procedure:
1-Methyl-piperazine (0.191 g, 1.91 mol) was added to a solution of Example 56k (0.5 g, 1.16 mmol) in dry DMF (10 mL) and stirred at 110° C. for 2 h. The reaction mixture was treated with water and extracted with ethyl acetate. The organic layer was washed with water, brine, dried, concentrated and purified using flash chromatography (silica gel, methanol/chloroform) to obtain the title compound as a white solid. Yield: 0.350 g, (60.97%); 1H NMR (DMSO-d6): δ 2.2 (s, 3H, CH3), 2.5-2.60 (m, 10H, 5CH2), 2.70 (s, 3H, CH3), 3.10 (d, 2H, CH2), 3.90 (s, 3H, CH3), 5.10 (s, 2H, CH2), 6.7 (s, 2H, Ar), 8.01 (s, 1H, Ar), 8.20 (s, 1H, Ar); MS: m/e (ES+) 495 (M+1).
Reaction SMILES: [NH2:1][CH2:2][C:3]1[C:4]([NH:19][C@H:20]([C:22]2[CH:27]=[CH:26][C:25]([F:28])=[CH:24][CH:23]=2)[CH3:21])=[N:5][C:6]([NH:10][C:11]2[CH:15]=[C:14]([CH:16]3[CH2:18][CH2:17]3)[NH:13][N:12]=2)=[C:7]([F:9])[CH:8]=1.[F:29][C:30]([F:36])([F:35])[S:31](Cl)(=[O:33])=[O:32]>C1COCC1.CN(C1C=CN=CC=1)C>[CH:16]1([C:14]2[NH:13][N:12]=[C:11]([NH:10][C:6]3[N:5]=[C:4]([NH:19][C@H:20]([C:22]4[CH:23]=[CH:24][C:25]([F:28])=[CH:26][CH:27]=4)[CH3:21])[C:3]([CH2:2][NH:1][S:31]([C:30]([F:36])([F:35])[F:29])(=[O:33])=[O:32])=[CH:8][C:7]=3[F:9])[CH:15]=2)[CH2:18][CH2:17]1
Reactant: O=S(=O)(Cl)C(F)(F)F
Reactant: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CN)c1ccc(F)cc1
Agent: CN(C)c1ccncc1
Solvent: C1CCOC1
Product: C[C@H](Nc1nc(Nc2cc(C3CC3)[nH]n2)c(F)cc1CNS(=O)(=O)C(F)(F)F)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 15 h
Yield: 15 %

Procedure:
To a solution of (S)-3-(aminomethyl)-N6-(5-cyclopropyl-1H-pyrazol-3-yl)-5-fluoro-N2-(1-(4-fluorophenyl)ethyl)pyridine-2,6-diamine (Example 3, 0.10 g, 0.26 mmol) in THF (5 ml) at room temperature was added 1.1 equivalent of trifluoromethylsulfonyl chloride loaded TFP resin, and DMAP (0.031 g, 0.26 mmol). The reaction was then stirred at room temperature for 15 hours and filtered. The remaining resin was then washed with THF (2×10 ml for 20 min), and then combined organic fractions were concentrated. The resulting oil was purified by reverse-phase column chromatography (5-50% ACN) to give the title compound (0.02 g, 15%). 1H NMR (400 MHz, CD3OD) δ 7.40-7.37 (m, 2H), 7.17 (d, J=10.9 Hz, 1H), 7.02-6.97 (m, 2H), 5.90-5.60 (br s, 1H), 5.14-5.12 (m, 1H), 4.28-4.25 (m, 2H), 1.88-1.84 (m, 1H), 1.54 (d, J=7.0 Hz, 3H), 0.95-0.93 (m, 2H), 0.67-0.64 (m, 2H). MS: Calcd.: 516. Found: [M+H]+ 517.
Reaction SMILES: [C:1]([CH2:7][C:8]#[N:9])(=O)[C:2]([CH3:5])([CH3:4])[CH3:3].[C:10]1([NH:16][NH2:17])[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1.C(O)(=O)C>C(O)C>[NH2:9][C:8]1[N:16]([C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)[N:17]=[C:1]([C:2]([CH3:5])([CH3:4])[CH3:3])[CH:7]=1
Reactant: CC(C)(C)C(=O)CC#N
Reactant: NNc1ccccc1
Solvent: CC(=O)O
Solvent: CCO
Product: CC(C)(C)c1cc(N)n(-c2ccccc2)n1
Temperature: 0 °C

Procedure:
Pivaloyl acetonitrile (30.0 g; 0.24 mole) and ethanol (200 ml) were placed into a 500 ml round bottom flask. Phenylhydrazine (23.6 ml; 0.24 mole) was added with stirring followed by acetic acid (13.8 ml). The reaction was refluxed for 5 hours. Part of the ethanol was stripped off and the residue was poured into ice water. The product was filtered off and washed with water. The solid was dissolved in hot ethanol (100 ml), diluted with water, stirred, filtered, and washed with water. The yield of solid, m.p. 65°-7° C. was 46.3 g (90%).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]2[C:9](=[O:10])[N:8]([CH2:11][CH:12]([CH3:14])[CH3:13])[C:6](=[O:7])[C:5]2=[CH:15][CH:16]=1.Br[CH:18]([CH3:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:11]([N:8]1[C:9](=[O:10])[C:4]2=[CH:3][C:2]([O:1][CH:18]([CH3:20])[CH3:19])=[CH:16][CH:15]=[C:5]2[C:6]1=[O:7])[CH:12]([CH3:13])[CH3:14]
Reactant: CC(C)Br
Reactant: CC(C)CN1C(=O)c2ccc(O)cc2C1=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)CN1C(=O)c2ccc(OC(C)C)cc2C1=O
Temperature: 60 °C
Reaction time: 17 h

Procedure:
A mixture of 1 g of 4-hydroxy-N-isobutylphthalimide, 0.85 cm3 of 2-bromopropane and 1.38 g of potassium carbonate in 5 cm3 of dimethylformamide is stirred at a temperature in the region of 60° C. for 17 hours. The reaction mixture is then cooled to a temperature in the region of 20° C. and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. The residue is taken up in 70 cm3 of water and then extracted 3 times with 75 cm3 of ethyl acetate. The organic phases are combined, washed with saturated sodium chloride solution, dried over magnesium sulfate, filtered and then concentrated to dryness under reduced pressure (2 kPa) at a temperature in the region of 40° C. 1.16 g of N-isobutyl-4-isopropyloxyphthalimide are thus obtained in the form of a white solid. (Rf=0.50, thin layer chromatography on silica gel, eluent: cyclohexane/ethyl acetate (75/25 by volume)).
Reaction SMILES: [Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@@H:11]3[CH2:15][C@H:14]([CH2:16][OH:17])[C@@H:13]([OH:18])[C@H:12]3[OH:19])[C:4]=2[N:5]=[CH:6][N:7]=1.CO[C:22](OC)([CH3:24])[CH3:23].O.C1(C)C=CC(S(O)(=O)=O)=CC=1.C([O-])(O)=O.[Na+]>>[Cl:1][C:2]1[C:3]2[CH:10]=[CH:9][N:8]([C@H:11]3[C@@H:12]4[O:19][C:22]([CH3:24])([CH3:23])[O:18][C@@H:13]4[C@@H:14]([CH2:16][OH:17])[CH2:15]3)[C:4]=2[N:5]=[CH:6][N:7]=1
Reactant: OC[C@H]1C[C@@H](n2ccc3c(Cl)ncnc32)[C@H](O)[C@@H]1O
Reactant: COC(C)(C)OC
Agent: Cc1ccc(S(=O)(=O)O)cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Product: CC1(C)O[C@@H]2[C@@H](CO)C[C@@H](n3ccc4c(Cl)ncnc43)[C@@H]2O1
Reaction time: 1.25 h
Yield: 67.6 %

Procedure:
A mixture of crude (1R,2S,3R,5R)-3-(4-chloro-7H-pyrrolo[2,3-d]pyrimidin-7-yl)-5-(hydroxymethyl)cyclopentane-1,2-diol (10 g, ˜20 mmol, 54% pure by NMR) and 2,2-dimethoxypropane (100 mL, 800 mmol) was treated with p-toluenesulfonic acid monohydrate (7.28 g, 38.3 mmol) and the yellow-brown reaction mixture was stirred vigorously for 1.25 h, at which time the only solids were a fine tan precipitate; HPLC indicated nearly complete consumption of the starting material. The reaction mixture was diluted with water (30 mL) and neutralized with solid NaHCO3 (4.80 g, 57.1 mmol). The volatiles were carefully removed in vacuo and the resulting brown aqueous solution was extracted with EtOAc (3×100 mL). The combined organics were dried (Na2SO4) and concentrated in vacuo to afford a tan paste. Purification by column chromatography (4×22 cm silica; 0-66% EtOAc/Hex) afforded the title compound (4.38 g, 70%, one step) as a colorless foam/glass: MS (ESI+) for C15H18ClN3O3 m/z 324.2 (M+H)+; MS (ESI−) for C15H18ClN3O3 m/z 368.2 (M+HCO2)−; HPLC purity>95% (ret. time, 3.034 min).
Reaction SMILES: [CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][NH:4][N:3]=1.Cl[C:13]1[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=1.[H-].[Na+].CN(C)C=O>O>[CH3:1][C:2]1[C:6]([C:7]([O:9][CH2:10][CH3:11])=[O:8])=[CH:5][N:4]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:3]=1
Reactant: Clc1ccccn1
Reactant: CCOC(=O)c1c[nH]nc1C
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)c1cn(-c2ccccn2)nc1C
Temperature: 180 °C
Reaction time: 8 h
Yield: 73 %

Procedure:
A mixture of ethyl 3-methyl-1H-pyrazole-4-carboxylate (7.95 g), 2-chloropyridine (5 ml), sodium hydride (0.60%, oil, 2.32 g) and N,N-dimethylformamide (150 ml) was stirred overnight at 180° C. The reaction mixture was poured into water and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give ethyl 3-methyl-1-(2-pyridyl)-1H-pyrazole-4-carboxylate (8.31 g, yield 73%) as colorless crystals from a fraction eluted with ethyl acetate-hexane (1:9, volume ratio). The crystals were recrystallized from ethyl acetate-hexane. melting point: 79-80° C.
Reaction SMILES: C(OC([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]1[C:31]2[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=2[C:25]2[C:20]1=[CH:21][CH:22]=[CH:23][CH:24]=2)=[O:16])=O)(C)(C)C.C(O)(C(F)(F)F)=O.C(Cl)Cl.FC(F)(F)C([O-])=O.[CH3:52][O:53][C:54]1[CH:59]=[CH:58][C:57]([S:60](Cl)(=[O:62])=[O:61])=[CH:56][CH:55]=1>>[O:53]([C:54]1[CH:59]=[CH:58][C:57]([S:60]([NH:8][C@H:9]([C:32]([OH:34])=[O:33])[CH2:10][CH2:11][CH2:12][CH2:13][NH:14][C:15]([O:17][CH2:18][CH:19]2[C:31]3[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=3[C:25]3[C:20]2=[CH:21][CH:22]=[CH:23][CH:24]=3)=[O:16])(=[O:62])=[O:61])=[CH:56][CH:55]=1)[CH3:52]
Reactant: COc1ccc(S(=O)(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCC1c2ccccc2-c2ccccc21)C(=O)O
Agent: O=C([O-])C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: COc1ccc(S(=O)(=O)N[C@@H](CCCCNC(=O)OCC2c3ccccc3-c3ccccc32)C(=O)O)cc1
Yield: 65 %

Procedure:
Nα-tert-butoxycarbonyl-Nε-(9-fluorenylmethoxycarbonyl)-L-lysine was deprotected at the α position by treatment with TFA/CH2Cl2 as described in the procedure outlined in example 24 and the resulting trifluoroacetate salt was alkylated with 4-methoxybenzenesulfonyl chloride as described in example 2, affording the title compound in 65% yield.
Reaction SMILES: [N:1]([CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1)=[N+]=[N-].O.[H][H]>C(O)C.[Pd]>[NH2:1][CH2:4][C:5]1[C:6](=[O:12])[NH:7][C:8](=[O:11])[NH:9][CH:10]=1
Reactant: [N-]=[N+]=NCc1c[nH]c(=O)[nH]c1=O
Reactant: [H][H]
Agent: [Pd]
Solvent: O
Solvent: CCO
Product: NCc1c[nH]c(=O)[nH]c1=O
Reaction time: 2 h
Yield: 86.4 %

Procedure:
The solution of 5-(azidomethyl)-2,4(1H,3H)-pyrimidinedione (0.275 g, 1.64 mmol) in ethanol: water (25:5 ml) was degassed with nitrogen, palladium on carbon (5%) was added, reaction was charged with hydrogen (55 PSI) and shaken for 2 h. The reaction was filtered and concentrated to give the 5-(aminomethyl)-2,4(1H,3H)-pyrimidinedione (0.20 g, 85%) as a solid. MS found: (M+H)+=142.
Reaction SMILES: [C:1]([NH:8][C@H:9]([C:13]([OH:15])=O)[C@@H:10]([CH3:12])[OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Cl.Cl.[CH3:18][C:19]1[N:24]=[CH:23][C:22]([C:25]2[CH:26]=[N:27][C:28]([C@H:31]([NH2:33])[CH3:32])=[CH:29][CH:30]=2)=[CH:21][CH:20]=1.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)CC)(C)C>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@H:9]([C:13](=[O:15])[NH:33][C@@H:31]([C:28]1[N:27]=[CH:26][C:25]([C:22]2[CH:23]=[N:24][C:19]([CH3:18])=[CH:20][CH:21]=2)=[CH:30][CH:29]=1)[CH3:32])[C@H:10]([OH:11])[CH3:12])([CH3:5])([CH3:6])[CH3:7]
Reactant: Cc1ccc(-c2ccc([C@@H](C)N)nc2)cn1
Reactant: C[C@@H](O)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1ccc(-c2ccc([C@@H](C)NC(=O)[C@@H](NC(=O)OC(C)(C)C)[C@@H](C)O)nc2)cn1
Reaction time: 2 h
Yield: 107.7 %

Procedure:
To a mixture of N-Boc-(L)-threonine (0.13 g, 0.61 mmol), (R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylamine dihydrochloride (0.16 g, 0.56 mmol) and HATU (0.23 g, 0.61 mmol) was added THF (1 mL) followed by diisopropylethylamine (0.48 mL, 2.8 mmol). After 2 h, the volatiles were removed under a stream of N2 and the resulting oil was purified by flash chromatography on silica gel (0→5% MeOH/CH2Cl2) yielding 250 mg of {(1S,2R)-2-hydroxy-1-[(R)-1-(6′-methyl-[3,3′]bipyridinyl-6-yl)-ethylcarbamoyl]-propyl}-carbamic acid tert-butyl ester as a tan solid, m/z 415.8 [M+H]+.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:22][CH2:21][CH2:20][CH2:19][CH2:18]3)[C:14](O)=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:4][CH:3]=1.[NH2:29][C:30]1[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=1[F:38]>CCCCCCC.C(OCC)(=O)C>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[N:12]([CH:13]([CH:17]3[CH2:18][CH2:19][CH2:20][CH2:21][CH2:22]3)[C:14]([NH:29][C:30]3[CH:37]=[CH:36][C:33]([C:34]#[N:35])=[CH:32][C:31]=3[F:38])=[O:15])[C:11]3[CH:23]=[C:24]([F:28])[C:25]([F:27])=[CH:26][C:10]=3[N:9]=2)=[CH:6][CH:7]=1
Reactant: N#Cc1ccc(N)c(F)c1
Reactant: O=C(O)C(C1CCCCC1)n1c(-c2ccc(Cl)cc2)nc2cc(F)c(F)cc21
Solvent: CCOC(C)=O
Solvent: CCCCCCC
Product: N#Cc1ccc(NC(=O)C(C2CCCCC2)n2c(-c3ccc(Cl)cc3)nc3cc(F)c(F)cc32)c(F)c1

Procedure:
The title compound was prepared in analogy to example 22, int. d) from [2-(4-chloro-phenyl)-5,6-difluoro-benzoimidazol-1-yl]-cyclohexyl-acetic acid and 4-amino-3-fluorobenzonitrile and using a gradient of heptane:ethyl acetate (1:1 to 4:1) as eluant. The title product was crystallized from tert-butyl methyl ether to give 0.79 g (61%) of a white solid (29%).
Reaction SMILES: [C:1]([N:3]1[CH2:8][CH2:7][CH:6]([N:9]([CH:23]2[CH2:25][CH2:24]2)[C:10](=[O:22])[C:11]2[CH:16]=[CH:15][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:13][CH:12]=2)[CH2:5][CH2:4]1)#[N:2].[OH:26][NH:27][C:28](=N)[CH2:29][CH:30]1[CH2:35][CH2:34][O:33][CH2:32][CH2:31]1>>[CH:23]1([N:9]([CH:6]2[CH2:5][CH2:4][N:3]([C:1]3[O:26][N:27]=[C:28]([CH2:29][CH:30]4[CH2:35][CH2:34][O:33][CH2:32][CH2:31]4)[N:2]=3)[CH2:8][CH2:7]2)[C:10](=[O:22])[C:11]2[CH:12]=[CH:13][C:14]([C:17]3[O:21][CH:20]=[N:19][CH:18]=3)=[CH:15][CH:16]=2)[CH2:25][CH2:24]1
Reactant: N=C(CC1CCOCC1)NO
Reactant: N#CN1CCC(N(C(=O)c2ccc(-c3cnco3)cc2)C2CC2)CC1
Product: O=C(c1ccc(-c2cnco2)cc1)N(C1CC1)C1CCN(c2nc(CC3CCOCC3)no2)CC1

Procedure:
The title compound is prepared from N-(1-cyano-piperidin-4-yl)-N-cyclopropyl-4-oxazol-5-yl-benzamide and N-hydroxy-2-(tetrahydro-pyran-4-yl)-acetamidine following a procedure analogous to that described in Example 1. LC (method 1): tR=1.13 min; Mass spectrum (ESI+): m/z=478 [M+H]+.
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][NH:5][CH2:6][CH2:7][O:8][CH3:9].[O-:10][N+:11]1[C:16]2[CH:17]=[C:18]3[C:22](=[CH:23][C:15]=2[N:14]=[C:13]([CH2:24][CH2:25][CH:26]=O)[N:12]=1)[CH2:21][CH2:20][CH2:19]3.[BH3-]C#N.[Na+].CC(O)=O>CO>[CH3:1][O:2][CH2:3][CH2:4][N:5]([CH2:6][CH2:7][O:8][CH3:9])[CH2:26][CH2:25][CH2:24][C:13]1[N:12]=[N+:11]([O-:10])[C:16]2[CH:17]=[C:18]3[C:22]([CH2:21][CH2:20][CH2:19]3)=[CH:23][C:15]=2[N:14]=1
Reactant: O=CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3
Reactant: COCCNCCOC
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CC(=O)O
Product: COCCN(CCCc1nc2cc3c(cc2[n+]([O-])n1)CCC3)CCOC
Reaction time: 0.5 h
Yield: 62.3 %

Procedure:
Bis-(2-methoxyethyl)amine (3.0 g, 22.5 mmol) was added to a stirred solution of propanal 75 (1.2 g, 4.9 mmol) in MeOH (100 ml) at 0° C. and the solution stirred for 30 min. NaCNBH3 (1.5 g, 24 mmol) was added and the solution stirred at 0° C. for 30 min and then HOAc (2 mL) was added and the mixture was stirred at 20° C. for 16 h. The solvent was evaporated and the residue was partitioned between DCM (200 mL) and water (200 mL). The aqueous phase was extracted with DCM (2×200 ml), the combined organic phase was dried and the solvent evaporated. The residue was purified by chromatography, eluting with 10% MeOH/EtOAc, to give 1-oxide 80 (1.1 g, 50%) as a yellow oil: 1H NMR [(CD3)2SO] δ 8.19 (s, 1H, H-9), 7.83 (s, 1H, H-5), 3.61-3.68 (m, 4H, 2×CH2O), 3.31-3.38 (m, 4H, 2×CH2N), 3.26 (s, 6H, 2×OCH3), 3.20-3.14 (m, 4H, 2×CH2), 3.07-3.12 (m, 4H, H-6, H-8), 2.15-2.10 (m, 4H, H-7, CH2); 13C NMR δ 163.9, 154.7, 149.0, 146.7, 131.8, 122.2, 113.6, 58.0 (2), 57.4 (2), 52.4, 52.3, 32.5, 32.2, 25.3, 23.0 (2), 19.1; HRMS (FAB+) calcd for C19H29N4O3 (MH+) m/z 361.2240, found 361.2243.
Reaction SMILES: [Cl:1][CH2:2][C:3]1[CH:11]=[CH:10][C:6]([C:7](Cl)=[O:8])=[CH:5][CH:4]=1.C(N(CC)CC)C.[Cl:19][C:20]1[CH:25]=[CH:24][C:23]([CH:26]2[CH:30]([C:31]3[CH:36]=[CH:35][C:34]([Cl:37])=[CH:33][CH:32]=3)[NH:29][C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:47])([F:46])[F:45])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:22][CH:21]=1>C(Cl)Cl>[Cl:19][C:20]1[CH:21]=[CH:22][C:23]([CH:26]2[CH:30]([C:31]3[CH:32]=[CH:33][C:34]([Cl:37])=[CH:35][CH:36]=3)[N:29]([C:7]([C:6]3[CH:10]=[CH:11][C:3]([CH2:2][Cl:1])=[CH:4][CH:5]=3)=[O:8])[C:28]([C:38]3[CH:43]=[C:42]([C:44]([F:45])([F:46])[F:47])[CH:41]=[CH:40][C:39]=3[O:48][CH2:49][CH3:50])=[N:27]2)=[CH:24][CH:25]=1
Reactant: O=C(Cl)c1ccc(CCl)cc1
Reactant: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: CCOc1ccc(C(F)(F)F)cc1C1=NC(c2ccc(Cl)cc2)C(c2ccc(Cl)cc2)N1C(=O)c1ccc(CCl)cc1
Temperature: 25 °C
Reaction time: 2 h
Yield: 85.6 %

Procedure:
4-Chloromethylbenzoyl chloride (140 mg, 0.74 mmol) was added to a cooled solution of triethylamine (0.20 mL, 1.44 mmol) and 4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-1H-imidazole (300 mg, 0.61 mmol). The reaction mixture was stirred at room temperature for 2 h. The reaction was diluted with methylene chloride and washed with water and brine, and dried over anhydrous sodium sulfate. The solvents were removed under reduced pressure and flash chromatography of the residue over silica gel using 10-25% ethyl acetate in hexanes gave [4,5-bis-(4-chloro-phenyl)-2-(2-ethoxy-5-trifluoromethyl-phenyl)-4,5-dihydro-imidazol-1-yl]-(4-chloromethyl-phenyl)-methanone (330 mg, 84%).
Reaction SMILES: F[C:2]1[C:7]([CH:8]=O)=[C:6]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([I:17])=[CH:13][C:12]=2[F:18])[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=1.O.[NH2:25][NH2:26]>COCCOC>[F:18][C:12]1[CH:13]=[C:14]([I:17])[CH:15]=[CH:16][C:11]=1[NH:10][C:6]1[C:5]([N+:19]([O-:21])=[O:20])=[C:4]([O:22][CH3:23])[CH:3]=[C:2]2[C:7]=1[CH:8]=[N:25][NH:26]2
Reactant: COc1cc(F)c(C=O)c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Reactant: NN
Solvent: O
Solvent: COCCOC
Product: COc1cc2[nH]ncc2c(Nc2ccc(I)cc2F)c1[N+](=O)[O-]
Temperature: 25 °C
Reaction time: 4 h
Yield: 64 %

Procedure:
A biphasic mixture of 6-fluoro-2-(2-fluoro-4-iodo-phenylamino)-4-methoxy-3-nitro-benzaldehyde (1.5 g, 3.46 mmol) in hydrazine hydrate (10 mL) and DME (10 mL) was stirred at room temperature for 4 hours, then heated at 50° C. for 3 hours. The reaction mixture was concentrated in vacuo, the residue treated with water and the resultant solid precipitate collected by filtration to give a red/orange solid. The solid was recrystallised from IMS to give the title compound as a yellow solid (956 mg, 64%). LCMS (Method B) RT=3.62 min, [M+H]+=429 [M−H]−=427.
Reaction SMILES: [OH:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1.[OH-].[Na+].[C:13](Cl)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]>O>[C:13]([O:1][C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][CH:3]=1)([O:15][CH2:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1)=[O:14]
Reactant: O=C(Cl)OCc1ccccc1
Reactant: O=C(O)c1ccc(O)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(OCc1ccccc1)Oc1ccc(C(=O)O)cc1
Reaction time: 24 h
Yield: 100.2 %

Procedure:
To an aqueous solution of 55 mmol (7.6 g) of p-hydroxybenzoic acid and 65 mmol (2.6 g) of sodium hydroxide in 200 ml of water was added 65 mmol (10.6 g) of carbobenzoxy chloride dropwise during cooling with ice. After 24 hours, the generated precipitate was washed with water, filtered, dried, and purified by column chromatography, to obtain 15.0 g of 4-carbobenzoxyoxybenzoic acid (m.p.: 181.9°-183.1° C.). (Yield: 99%).
Reaction SMILES: Cl[C:2]1[N:10]=[C:9]([Cl:11])[CH:8]=[CH:7][C:3]=1[C:4]([NH2:6])=O.[CH3:12][O-:13].[Na+].Cl>CO>[Cl:11][C:9]1[CH:8]=[C:7]([O:13][CH3:12])[C:3]([C:4]#[N:6])=[CH:2][N:10]=1
Reactant: NC(=O)c1ccc(Cl)nc1Cl
Reactant: C[O-]
Agent: Cl
Agent: [Na+]
Solvent: CO
Product: COc1cc(Cl)ncc1C#N
Temperature: 60 °C
Yield: 83.9 %

Procedure:
To a solution of 4,6-dichloro-nicotinonitrile (1) (200 mg, 1.06 mmol) in methanol (anhydrous, 10 mL) was added sodium methoxide solution (0.5 M/MeOH, 2.12 mL, 1.06 mmol). The reaction was heated at 60° C. overnight. After cooling the reaction solution to room temperature, HCl (1M, 8 mL) was added. The volatile components were evaporated in vacuo. Purification was accomplished by Biotage (10%-50% EtOAc/hexanes gradient mobile phase) to afford 150 mg (77% yield) of the title compound. 1H NMR (400 MHz, CHLOROFORM-d) δ ppm 8.48 (s, 1H), 6.98 (s, 1H), 4.03 (s, 3H)
Reaction SMILES: [CH2:1]([Sn:5]([CH2:14][CH2:15][CH2:16][CH3:17])([O:10]C(=O)C)[O:6][C:7](=[O:9])[CH3:8])[CH2:2][CH2:3][CH3:4].[CH2:18]([Sn:22](CCCC)([CH2:27][CH2:28][CH2:29][CH3:30])[O:23][C:24](=[O:26])[CH3:25])[CH2:19][CH2:20][CH3:21]>>[CH2:14]([Sn:5]([CH2:1][CH2:2][CH2:3][CH3:4])([O:6][C:7](=[O:9])[CH3:8])[O:10][Sn:22]([CH2:18][CH2:19][CH2:20][CH3:21])([CH2:27][CH2:28][CH2:29][CH3:30])[O:23][C:24](=[O:26])[CH3:25])[CH2:15][CH2:16][CH3:17]
Reactant: CCCC[Sn](CCCC)(CCCC)OC(C)=O
Reactant: CCCC[Sn](CCCC)(OC(C)=O)OC(C)=O
Product: CCCC[Sn](CCCC)(OC(C)=O)O[Sn](CCCC)(CCCC)OC(C)=O

Procedure:
199.3 g of a mixture containing di-n-butyl diacetoxy tin, tri-n-butyl acetoxy tin and 1,1,3,3-tetra-n-butyl-1,3-diacetoxy distannoxane was obtained by carrying out the same method as step (2-2) of Example 2 with the exception of using 200.1 g of the mixture obtained in step (5-1) instead of the mixture obtained in step (2-1). The content of di-n-butyl diacetoxy tin in this mixture was 63.7 wt %, the content of tri-n-butyl acetoxy tin was about 1 wt %, and the content of 1,1,3,3-tetra-n-butyl-1,3-diacetoxy distannoxane was 32.3 wt %.