Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([CH2:14][OH:15])[CH2:12][CH2:11][N:10]([C:16](=[O:21])[C:17]([F:20])([F:19])[F:18])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C=CC=CC1=2)=O.S([O-])([O-])(=O)=S.[Na+].[Na+]>ClCCl>[F:1][C:2]1[CH:3]=[C:4]([C@H:8]2[C@H:13]([CH:14]=[O:15])[CH2:12][CH2:11][N:10]([C:16](=[O:21])[C:17]([F:18])([F:19])[F:20])[CH2:9]2)[CH:5]=[CH:6][CH:7]=1
Reactant: O=C(N1CC[C@@H](CO)[C@H](c2cccc(F)c2)C1)C(F)(F)F
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: O=S([O-])([O-])=S
Agent: [Na+]
Solvent: ClCCl
Product: O=C[C@@H]1CCN(C(=O)C(F)(F)F)C[C@H]1c1cccc(F)c1
Reaction time: 1.5 h
Yield: 122.8 %

Procedure:
To a solution of 1.50 g of rel-[(3R,4R)-3-(3-fluorophenyl)-1-(trifluoroacetyl)piperidin-4-yl]methanol in 15 mL of dichloromethane was added 2.29 of Dess-Martin Periodinane at room temperature, followed by stirring for 1.5 hours. To the reaction mixture were added a saturated aqueous sodium thiosulfate solution and a saturated aqueous sodium hydrogen carbonate solution, followed by extraction with chloroform. The organic layer was washed with water and saturated brine in this order, and dried over sodium sulfate. After filtration, the filtrate was concentrated under reduced pressure to obtain 1.83 g of crude rel-(3R,4R)-3-(3-fluorophenyl)-1-(trifluoroacetyl)piperidine-4-carbaldehyde as an orange oily compound.
Reaction SMILES: Cl[C:2]1[CH:16]=[CH:15][C:5]2[C:6](=[O:14])[NH:7][C:8]3[C:13]([C:4]=2[CH:3]=1)=[CH:12][CH:11]=[CH:10][N:9]=3.[NH2:17][C:18]1[CH:23]=[CH:22][CH:21]=[C:20]([CH3:24])[CH:19]=1>>[C:20]1([CH3:24])[CH:21]=[CH:22][CH:23]=[C:18]([NH:17][C:2]2[CH:16]=[CH:15][C:5]3[C:6](=[O:14])[NH:7][C:8]4[C:13]([C:4]=3[CH:3]=2)=[CH:12][CH:11]=[CH:10][N:9]=4)[CH:19]=1
Reactant: O=c1[nH]c2ncccc2c2cc(Cl)ccc12
Reactant: Cc1cccc(N)c1
Product: Cc1cccc(Nc2ccc3c(=O)[nH]c4ncccc4c3c2)c1
Yield: 22.4 %

Procedure:
The title compound was synthesized according to the procedure described for the preparation of Example 231 using 6 (100 mg, 0.43 mmol) and m-toluidine (0.07 mL, 0.65 mmol) to provide 241 (29 mg, 20% yield) as a black powder. LC-MS (M+H (parent)=302, obsd.=302).
Reaction SMILES: [Si:1]([O:18][CH:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([N:31]2[CH2:36][CH2:35][NH:34][C@H:33]([CH3:37])[CH2:32]2)=[CH:23][CH:22]=[C:21]3[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CS(O[CH2:43][CH2:44][C@H:45]1[C:50]2[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][C:49]=2[CH2:48][CH2:47][O:46]1)(=O)=O>>[Si:1]([O:18][CH:19]1[C:29]2=[C:30]3[C:25](=[CH:26][CH:27]=[CH:28]2)[C:24]([N:31]2[CH2:36][CH2:35][N:34]([CH2:43][CH2:44][C@H:45]4[C:50]5[CH:51]=[CH:52][C:53]([C:55]([NH2:57])=[O:56])=[CH:54][C:49]=5[CH2:48][CH2:47][O:46]4)[C@H:33]([CH3:37])[CH2:32]2)=[CH:23][CH:22]=[C:21]3[CH2:20]1)([C:14]([CH3:17])([CH3:16])[CH3:15])([C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1
Reactant: C[C@@H]1CN(c2ccc3c4c(cccc24)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)CCN1
Reactant: CS(=O)(=O)OCC[C@@H]1OCCc2cc(C(N)=O)ccc21
Product: C[C@@H]1CN(c2ccc3c4c(cccc24)C(O[Si](c2ccccc2)(c2ccccc2)C(C)(C)C)C3)CCN1CC[C@@H]1OCCc2cc(C(N)=O)ccc21

Procedure:
(3R)-1-(1-{[tert-Butyl(diphenyl)silyl]oxy}-1,2-dihydro-5-acenaphthylenyl)-3-methylpiperazine was condensed with 2-[(1S)-6-(aminocarbonyl)-3,4-dihydro-1H-2-benzopyran-1-yl]ethyl methanesulfonate, as described for Example 1b).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][NH:17][CH2:16][CH2:15]1.[CH3:20][C:21]1[CH:22]=[C:23]([CH:26]=[CH:27][C:28]=1[CH3:29])[CH:24]=O>>[Cl:1][C:2]1[CH:3]=[C:4]2[C:9](=[CH:10][CH:11]=1)[O:8][C:7](=[O:12])[CH:6]=[C:5]2[NH:13][CH:14]1[CH2:19][CH2:18][N:17]([CH2:24][C:23]2[CH:26]=[CH:27][C:28]([CH3:29])=[C:21]([CH3:20])[CH:22]=2)[CH2:16][CH2:15]1
Reactant: Cc1ccc(C=O)cc1C
Reactant: O=c1cc(NC2CCNCC2)c2cc(Cl)ccc2o1
Product: Cc1ccc(CN2CCC(Nc3cc(=O)oc4ccc(Cl)cc34)CC2)cc1C

Procedure:
Prepared from 6-Chloro-4-(piperidin-4-ylamino)-chromen-2-one and 3,4-dimethyl benzaldehyde in a manner analogous to that described above. MS (ESI) m/e 397.1 (M+H)+. 1H NMR (500 MHz, MeOD-d4) δ ppm 8.12 (d, 1H), 7.60 (dd, 1H), 7.21-7.34 (m, 4H), 5.44 (s, 1H), 4.27 (s, 2H), 3.83-3.87 (m, 1H), 3.55-3.60 (m, 2H), 3.16-3.20 (m, 2H), 2.30-2.38 (m, 2H), 2.33 (s, 3H), 2.31 (s, 3H), 1.89-1.96 (m, 2H).
Reaction SMILES: C(OC([N:6]1[CH2:24][CH2:23][C@:13]23[C:14]4[C:15]5[O:22][C@H:12]2[C:11](=[O:25])[CH2:10][CH2:9][C@@:8]3([OH:26])[C@H:7]1[CH2:20][C:19]=4[CH:18]=[CH:17][C:16]=5[OH:21])=O)C.S(=O)(=O)(O)O>O>[O:22]1[C@@H:12]2[C@@:13]34[CH2:23][CH2:24][NH:6][C@@H:7]([C@:8]3([OH:26])[CH2:9][CH2:10][C:11]2=[O:25])[CH2:20][C:19]2=[C:14]4[C:15]1=[C:16]([OH:21])[CH:17]=[CH:18]2
Reactant: CCOC(=O)N1CC[C@]23c4c5ccc(O)c4O[C@H]2C(=O)CC[C@@]3(O)[C@H]1C5
Agent: O=S(=O)(O)O
Solvent: O
Product: O=C1CC[C@@]2(O)[C@H]3Cc4ccc(O)c5c4[C@@]2(CCN3)[C@H]1O5
Yield: 122.4 %

Procedure:
Product (5) (4,7 g) was dissolved in 28 ml of water and 5,6 ml of sulfuric acid and refluxed for approx. 24 h. The product was precipitated at pH=9 by dilution with water and 4,6 g of crude product (6) was obtained after filtration and drying. The product was purified by dissolution in ethanol, precipitation from this solvent at pH=2, dissolution in water, charcoal treatment and precipitation at pH=9. 1H NMR (400 M z, DMSO-d6) δ 1.17 (m, 1H), 1.41 (m, 1H), 1.72 (m, 1H), 2.07 (m, 1H), 2.29 (m, 1H), 2.36 (m, 1H), 2.62 (in 1H), 3.9 (m, 4H), 6.52 (d, 1H), 6.56 (d, 1H).
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.[CH3:18][CH:19]([CH3:22])[CH2:20][OH:21]>>[CH2:20]([O:21][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)[CH:19]([CH3:22])[CH3:18]
Reactant: CC(C)CO
Reactant: Clc1nc(Nc2cc[nH]n2)cc2ccccc12
Product: CC(C)COc1nc(Nc2cc[nH]n2)cc2ccccc12

Procedure:
Similar procedure as described in example 10 was used, starting from (1-chloro-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine and 2-methyl-propan-1-ol to give (1-isobutoxy-isoquinolin-3-yl)-(1H-pyrazol-3-yl)-amine. LC-MS m/e 283(MH+).
Reaction SMILES: [Br:1][C:2]1[C:6]([N+:7]([O-:9])=[O:8])=[C:5](Br)[N:4]([CH2:11][CH2:12][CH2:13][N:14]2[C:18](Br)=[C:17]([N+:20]([O-:22])=[O:21])[C:16]([Br:23])=[N:15]2)[N:3]=1.[CH2:24]([NH2:31])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1.O>C(O)CC>[CH2:24]([NH:31][C:18]1[N:14]([CH2:13][CH2:12][CH2:11][N:4]2[C:5]([NH:31][CH2:24][C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=3)=[C:6]([N+:7]([O-:9])=[O:8])[C:2]([Br:1])=[N:3]2)[N:15]=[C:16]([Br:23])[C:17]=1[N+:20]([O-:22])=[O:21])[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1
Reactant: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2Br)c1Br
Reactant: NCc1ccccc1
Solvent: CCCO
Solvent: O
Product: O=[N+]([O-])c1c(Br)nn(CCCn2nc(Br)c([N+](=O)[O-])c2NCc2ccccc2)c1NCc1ccccc1

Procedure:
11.6 g of 1,3-bis-(3,5-dibromo-4-nitropyrazol-1-yl)propane from step 5.1 are heated together with 6.5 g of benzylamine in 180 ml of n-propanol for 1 hour at 100° C. Subsequently the reaction mixture is cooled and poured into 1000 ml water. The precipitate is filtered with suction, washed with water and dried in vacuum at 60° C.
Reaction SMILES: [CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:18])[CH2:13][CH:14]([CH3:16])[CH3:15])[CH2:8][CH2:9]O)([CH3:4])[CH3:3].[Br:28][C:29]1[CH:30]=[C:31]2[C:35](=[CH:36][CH:37]=1)[C:34](=[O:38])[NH:33][C:32]2=[O:39].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC)=O)=NC(OCC)=O>CN(C=O)C>[CH3:1][C:2]([O:5][C:6](=[O:27])[C@H:7]([NH:11][C@H:12]([C:17]([NH:19][CH2:20][C:21]1[CH:22]=[CH:23][CH:24]=[CH:25][CH:26]=1)=[O:18])[CH2:13][CH:14]([CH3:15])[CH3:16])[CH2:8][CH2:9][N:33]1[C:32](=[O:39])[C:31]2[C:35](=[CH:36][CH:37]=[C:29]([Br:28])[CH:30]=2)[C:34]1=[O:38])([CH3:4])[CH3:3]
Reactant: O=C1NC(=O)c2cc(Br)ccc21
Reactant: CC(C)C[C@H](N[C@H](CCO)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Agent: CCOC(=O)N=NC(=O)OCC
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CN(C)C=O
Product: CC(C)C[C@H](N[C@H](CCN1C(=O)c2ccc(Br)cc2C1=O)C(=O)OC(C)(C)C)C(=O)NCc1ccccc1
Temperature: 0 °C
Reaction time: 16 h

Procedure:
325 mg of 2-(R)-[1-(S)-(benzylamino)carbonyl-3-methyl-butylamino]-4-hydroxy-butanoic acid-1,1-dimethylethyl ester, prepared as described for Example N, was added to 10 mL DMF, followed by 226 mg 5-bromo-1,3-dihydro-1,3-dioxo-2H-isoindole. 231 mg of triphenylphosphine was added and the mixture was cooled to 0° C. 0.14 mL diethyl azodicarboxylate was added and the mixture was warmed to RT with stirring for 16 h. The solvents were removed by evaporation and the resulting residue was purified by reverse phase H.P.L.C. to give the title compound; 53 mg.
Reaction SMILES: [NH2:1][CH:2]([C:11]1[C:16]([O:17][CH3:18])=[CH:15][CH:14]=[CH:13][C:12]=1[O:19][CH3:20])[CH2:3][CH:4]([CH3:10])[C:5]([O:7]CC)=O.[F:21][C:22]([F:33])([F:32])[S:23][C:24]1[CH:31]=[CH:30][C:27]([CH:28]=O)=[CH:26][CH:25]=1>>[CH3:18][O:17][C:16]1[CH:15]=[CH:14][CH:13]=[C:12]([O:19][CH3:20])[C:11]=1[CH:2]1[N:1]([CH2:28][C:27]2[CH:30]=[CH:31][C:24]([S:23][C:22]([F:33])([F:21])[F:32])=[CH:25][CH:26]=2)[C:5](=[O:7])[CH:4]([CH3:10])[CH2:3]1
Reactant: O=Cc1ccc(SC(F)(F)F)cc1
Reactant: CCOC(=O)C(C)CC(N)c1c(OC)cccc1OC
Product: COc1cccc(OC)c1C1CC(C)C(=O)N1Cc1ccc(SC(F)(F)F)cc1

Procedure:
Prepared according to the described general procedure 2 (GP2) by reaction of ethyl 4-amino-4-(2,6-dimethoxyphenyl)-2-methylbutanoate with commercially available 4-((trifluoromethyl)thio)benzaldehyde. Subsequent purification by preparative HPLC afforded the target compound. LC-MS (conditions A): tR=0.97 min.; [M+H]+: 425.95 g/mol.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([S:8][CH2:9][C:10]2[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=2)=[CH:4][C:3]=1/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19].[Cl:23][C:24]1[C:29]([Cl:30])=[CH:28][C:27](I)=[C:26]([O:32][CH3:33])[N:25]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CCOC(C)=O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>[CH2:9]([S:8][C:5]1[CH:6]=[CH:7][C:2]([NH:1][C:27]2[C:26]([O:32][CH3:33])=[N:25][C:24]([Cl:23])=[C:29]([Cl:30])[CH:28]=2)=[C:3](/[CH:16]=[CH:17]/[C:18]([O:20][CH2:21][CH3:22])=[O:19])[CH:4]=1)[C:10]1[CH:15]=[CH:14][CH:13]=[CH:12][CH:11]=1
Reactant: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1N
Reactant: COc1nc(Cl)c(Cl)cc1I
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: CCOC(C)=O
Product: CCOC(=O)/C=C/c1cc(SCc2ccccc2)ccc1Nc1cc(Cl)c(Cl)nc1OC
Temperature: 90 °C
Yield: 81.3 %

Procedure:
A RBF was charged with (E)-ethyl 3-(2-amino-5-(benzylthio)phenyl)acrylate (2.0 g, 6.38 mmol)), 2,3-dichloro-5-iodo-6-methoxypyridine (2.327 g, 7.66 mmol)), xantphos (0.185 g, 0.319 mmol)), Pd2(dba)3 (0.146 g, 0.160 mmol)), and cesium carbonate (2.91 g, 8.93 mmol)) were added. A reflux condenser was attached and the flask was heated at 90° C. overnight. The mixture was cooled to RT, diluted with EtOAc, and filtered through celite, with the aid of EtOAc. The filtrate was concentrated and i-PrOH was added. The mixture was heated to 110° C. until all the material dissolved, then the solution was allowed to cool to RT overnight causing a yellow solid to crash out of solution. The solids were filtered and washed with i-PrOH, then dried under a nitrogen blanket to afford (E)-ethyl 3-(5-(benzylthio)-2-((5,6-dichloro-2-methoxypyridin-3-yl)amino)phenyl)acrylate (2.54 g, 5.19 mmol, 81% yield) as a yellow solid. m/z (ESI) 491.1 (M+H)+.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4](/[C:8](/[CH2:38][CH3:39])=[C:9](\[C:25]2[CH:30]=[CH:29][C:28](/[CH:31]=[CH:32]/[C:33]([O:35]CC)=[O:34])=[CH:27][CH:26]=2)/[C:10]2[CH:11]=[C:12]3[C:16](=[CH:17][CH:18]=2)[N:15](C2CCCCO2)[N:14]=[CH:13]3)[CH:5]=[CH:6][CH:7]=1.[CH3:40][C:41]1[N:46]=[CH:45][C:44](B(O)O)=[CH:43][CH:42]=1.BrC1C=CC(OC2C=CC=CC=2)=CC=1Cl>>[NH:15]1[C:16]2[C:12](=[CH:11][C:10](/[C:9](/[C:25]3[CH:26]=[CH:27][C:28](/[CH:31]=[CH:32]/[C:33]([OH:35])=[O:34])=[CH:29][CH:30]=3)=[C:8](/[C:4]3[CH:5]=[CH:6][CH:7]=[C:2]([O:1][C:44]4[CH:45]=[N:46][C:41]([CH3:40])=[CH:42][CH:43]=4)[CH:3]=3)\[CH2:38][CH3:39])=[CH:18][CH:17]=2)[CH:13]=[N:14]1
Reactant: CCOC(=O)/C=C/c1ccc(/C(=C(/CC)c2cccc(O)c2)c2ccc3c(cnn3C3CCCCO3)c2)cc1
Reactant: Cc1ccc(B(O)O)cn1
Agent: Clc1cc(Oc2ccccc2)ccc1Br
Product: CC/C(=C(/c1ccc(/C=C/C(=O)O)cc1)c1ccc2[nH]ncc2c1)c1cccc(Oc2ccc(C)nc2)c1

Procedure:
The title compound was prepared from (E)-ethyl 3-(4-((E)-2-(3-hydroxyphenyl)-1-(1-(tetrahydro-2H-pyran-2-yl)-1H-indazol-5-yl)but-1-en-1-yl)phenyl)acrylate (Compound 346, Step 1) and (6-methylpyridin-3-yl)boronic acid following the procedure outlined for Intermediate 65 and then General Procedures F and G. LCMS: 502 (M+H)+.
Reaction SMILES: C[O:2][C:3]([C:5]1[C:10]2[NH:11][C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])=[N:13][C:9]=2[CH:8]=[CH:7][C:6]=1[CH:22](C(OCC)=O)[C:23]([O:25]CC)=[O:24])=[O:4].[OH-].[Na+]>C1COCC1.CO>[C:23]([CH2:22][C:6]1[CH:7]=[CH:8][C:9]2[N:13]=[C:12]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][C:15]=3[O:20][CH3:21])[NH:11][C:10]=2[C:5]=1[C:3]([OH:4])=[O:2])([OH:25])=[O:24]
Reactant: CCOC(=O)C(C(=O)OCC)c1ccc2nc(-c3ccccc3OC)[nH]c2c1C(=O)OC
Agent: [Na+]
Agent: [OH-]
Solvent: CO
Solvent: C1CCOC1
Product: COc1ccccc1-c1nc2ccc(CC(=O)O)c(C(=O)O)c2[nH]1
Temperature: 0 °C
Yield: 100.9 %

Procedure:
A solution of diethyl [7-(methoxycarbonyl)-2-(2-methoxyphenyl)-1H-benzimidazol-6-yl]malonate (4.96 g, 11.3 mmol) and aqueous 2 N NaOH solution (50.0 mL, 100 mmol) in THF (112 mL) and MeOH (45 mL) was stirred at room temperature for 17 h. The mixture was concentrated under reduced pressure. The residual aqueous solution was cooled to 0° C. and aqueous 2 N HCl solution (50 mL) was slowly added (pH 4 obtained). The resulting suspension was heated at 70° C. for 15 h. The cooled suspension was filtered to give the title compound (3.72 g, 100% yield) as a white solid.
Reaction SMILES: [NH:1]1[CH2:6][CH2:5][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[CH:26][CH:25]=[C:24](C(F)(F)F)[C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:3][CH2:2]1.ClC1SC2C=C([O:42][C:43]([F:46])([F:45])[F:44])C=CC=2N=1>>[NH:1]1[CH2:2][CH2:3][CH:4]([N:7]2[CH:11]=[C:10]([C:12]3[CH:13]=[C:14]([C:19]4[S:20][C:21]5[CH:27]=[C:26]([O:42][C:43]([F:46])([F:45])[F:44])[CH:25]=[CH:24][C:22]=5[N:23]=4)[C:15]([NH2:18])=[N:16][CH:17]=3)[CH:9]=[N:8]2)[CH2:5][CH2:6]1
Reactant: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2c(C(F)(F)F)cccc2s1
Reactant: FC(F)(F)Oc1ccc2nc(Cl)sc2c1
Product: Nc1ncc(-c2cnn(C3CCNCC3)c2)cc1-c1nc2ccc(OC(F)(F)F)cc2s1

Procedure:
Following the procedure for 5-(1-piperidin-4-yl-1H-pyrazol-4-yl)-3-(4-trifluoromethylbenzothiazol-2-yl)-pyridin-2-ylamine, but using 2-chloro-6-trifluoromethoxy-1,3-benzothiazole, the title compound was obtained as yellow solid. MS (ES+): m/z=461.08 [MH+].
Reaction SMILES: [C:1]([NH:9][CH:10]([CH3:22])[C:11]([N:13]([CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)C)=[O:12])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.F[C:24](F)(F)C(OC(=O)C(F)(F)F)=O.C(=O)([O-])[O-].[Na+].[Na+]>C(Cl)(Cl)Cl>[CH2:16]([CH2:15][NH:13][C:11]1[O:12][C:1]([C:2]2[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=2)=[N:9][C:10]=1[CH3:22])[C:21]1[CH:20]=[CH:19][CH:18]=[CH:17][CH:24]=1
Reactant: CC(NC(=O)c1ccccc1)C(=O)N(C)Cc1ccccc1
Reactant: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: ClC(Cl)Cl
Product: Cc1nc(-c2ccccc2)oc1NCCc1ccccc1
Yield: 82.8 %

Procedure:
2-Benzamido-N-benzyl-N-methylpropanamide (8.0 g., 0.0269 mol.), was dissolved in dry chloroform (40 ml.) and trifluoroacetic anhydride (17.0 g., 0.0809 mol.) was added dropwise with stirring under nitrogen. The mixture was stirred for 4 hours, then sufficient anhydrous sodium carbonate was added portionwise to neutralise the acid formed. The solid was filtered off and washed with dry chloroform (2× 10 ml.). The combined filtrates were evaporated under reduced pressure to give a brown oil, which was extracted with warm pentane. The pentane solution was evaporated to give a yellow oil 6.20 g. (82.5% IR and NMR confirm the structure.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[CH:7][CH:6]=[C:5]([CH3:9])[C:3]=1[NH2:4].C([Li])CCC.[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]#[N:21])=[CH:18][CH:17]=1>O>[CH3:15][C:16]1[CH:23]=[CH:22][C:19]([C:20]([NH:4][C:3]2[C:5]([CH3:9])=[CH:6][CH:7]=[CH:8][C:2]=2[CH3:1])=[NH:21])=[CH:18][CH:17]=1
Reactant: Cc1cccc(C)c1N
Reactant: Cc1ccc(C#N)cc1
Agent: [Li]CCCC
Solvent: O
Product: Cc1ccc(C(=N)Nc2c(C)cccc2C)cc1
Reaction time: 1 h
Yield: 93.9 %

Procedure:
Procedure as described for Amidine I using the following amounts: 6.15 mL of 2,6-dimethylaniline (50.0 mmol); 25.0 mL of 2.0 M butyllithium (50.0 mmol), 5.86 g of 4-methylbenzonitrile (50.0 mmol). After refluxing overnight, the solution was deep red. Addition of water yielded a yellow solution with suspended solid. Solution was filtered, taken to dryness, resuspended in 100 mL of pentane and stirred vigorously for 1 hour. The resulting white solid was filtered, washed with 10 mL of pentane and dried in vacuo yielding 11.19 g (90%) of white powder. 1H NMR (400 MHz, CDCl3): 7.83 (d, 2H), 7.26 (d, 2H), 7.05 (d, 2H), 6.89 (t, 1H), 4.54 (s, 2H), 2.42 (s, 3H), 2.15 (s, 6H).
Reaction SMILES: FC(F)(F)C(C1SC(C(O)=O)=CC=1)=O.C1N=CN(C(N2C=NC=C2)=O)C=1.FC1C=CC(CS(CC(=N)NO)(=O)=O)=CC=1.[F:43][C:44]1[CH:71]=[CH:70][C:47]([CH2:48][S:49]([CH2:52]/[C:53](=[N:55]/[O:56][C:57]([C:59]2[S:60][C:61]([C:64](=[O:69])[C:65]([F:68])([F:67])[F:66])=[CH:62][CH:63]=2)=O)/[NH2:54])(=[O:51])=[O:50])=[CH:46][CH:45]=1>CN(C=O)C.O.CC#N>[F:66][C:65]([F:68])([F:67])[C:64]([C:61]1[S:60][C:59]([C:57]2[O:56][N:55]=[C:53]([CH2:52][S:49]([CH2:48][C:47]3[CH:70]=[CH:71][C:44]([F:43])=[CH:45][CH:46]=3)(=[O:51])=[O:50])[N:54]=2)=[CH:63][CH:62]=1)=[O:69]
Reactant: N/C(CS(=O)(=O)Cc1ccc(F)cc1)=N\OC(=O)c1ccc(C(=O)C(F)(F)F)s1
Agent: N=C(CS(=O)(=O)Cc1ccc(F)cc1)NO
Agent: O=C(O)c1ccc(C(=O)C(F)(F)F)s1
Agent: O=C(n1ccnc1)n1ccnc1
Solvent: O
Solvent: CC#N
Solvent: CN(C)C=O
Product: O=C(c1ccc(-c2nc(CS(=O)(=O)Cc3ccc(F)cc3)no2)s1)C(F)(F)F
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
The above acid (A1) was dissolved in DMF and a solution of CDI (1.1 eq) in DMF was added. The mixture was stirred at RT for 30 min, then 2-[(4-fluorobenzyl)sulfonyl]-N-hydroxyethanimidamide (1.1 eq.) in DMF was added and the mixture stirred at RT overnight. The resulting intermediate (1Z)-2-[(4-fluorobenzyl)sulfonyl]-N′-({[5-(trifluoroacetyl)-2-thienyl]carbonyl}oxy)ethanimidamide (MS (ES) C16H12F4N2O5S2 requires: 452, found: 471 (M+H2O+H)+) was not isolated, instead CDI (1.1 eq) in DMF was added and the mixture was heated in a microwave oven (sealed tube, 140° C., 2 min). The product was isolated by preparative RP-HPLC, using H2O (0.1% TFA) and MeCN (0.1% TFA) as eluents (column: C18). The pooled product fractions were evaporated to afford the title compound. 1H NMR (300 MHz, CD3CN): 8.1-8.07 (2H, m), 7.91 (0.1H, d, J=4 Hz, hydrate form), 7.58-7.49 (2H, m), 7.41 (0.1H, d, J=4 Hz, hydrate form), 7.25-7.12 (2H, m), 4.57 (2H, s), 4.54 (2H, s), 4.48 (0.2H, s, hydrate form). 19F NMR decoupled (282 MHz, CD3CN): −73.78 (keto form), −85.45 (hydrate form), −114.51. MS (ES) C16H10F4N2O4S2 requires: 434, found: 453 (M+H2O+H)+, MS (ES−) 433 (M−H+e)−.
Reaction SMILES: [Al+3].[Cl-].[Cl-].[Cl-].[Br:5][C:6]1[C:11]([C:12]2(O)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][N:7]=1.[OH-].[Na+].[F:20][C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>>[Br:5][C:6]1[C:11]([C:12]2([C:24]3[CH:25]=[CH:26][C:21]([F:20])=[CH:22][CH:23]=3)[CH2:16][CH2:15][CH2:14][CH2:13]2)=[CH:10][CH:9]=[CH:8][N:7]=1
Reactant: Fc1ccccc1
Reactant: OC1(c2cccnc2Br)CCCC1
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Product: Fc1ccc(C2(c3cccnc3Br)CCCC2)cc1
Temperature: 0 °C
Reaction time: 8 h
Yield: 69 %

Procedure:
To a suspension of AlCl3 (4.05 g, 30.36 mmol) in fluorobenzene (10 mL) was added a solution of the 1-(2-bromo-pyridin-3-yl)-cyclopentanol (1.05 g, 4.33 mmol) in fluorobenzene (15 mL) and the resulting mixture was stirred overnight. The mixture was poured into ice (100 ml), basified with NaOH (10 N) to pH14, and extracted with EtOAc (4×40 mL). The combined organic extracts were washed with brine (2×50 mL), dried (MgSO4), filtered, and concentrated to afford a brown oil. Purification by flash column chromatography on silica gel using hexanes/EtOAc (2:1) afforded 2-bromo-3-[1-(4-fluoro-phenyl)-cyclopentyl]-pyridine as a yellow oil (956 mg, 69%).
Reaction SMILES: [CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15](OC3C=CC=CC=3)[C:14]=2[N:13]=[C:12]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C([O-])(=O)C.[NH4+:34].[OH-].[K+]>>[CH2:1]([O:8][CH2:9][CH2:10][N:11]1[C:19]2[C:18]([CH3:20])=[C:17]([CH3:21])[N:16]=[C:15]([NH2:34])[C:14]=2[N:13]=[C:12]1[CH3:29])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: Cc1nc(Oc2ccccc2)c2nc(C)n(CCOCc3ccccc3)c2c1C
Reactant: [NH4+]
Agent: CC(=O)[O-]
Agent: [K+]
Agent: [OH-]
Product: Cc1nc(N)c2nc(C)n(CCOCc3ccccc3)c2c1C
Temperature: 150 °C
Yield: 55 %

Procedure:
1-[2-(Benzyloxy)ethyl]-2,6,7-trimethyl-4-phenoxy-1H-imidazo[4,5-c]pyridine (5.113 g, 13.195 mmol) from Part A and ammonium acetate (51 g) were combined in a dried glass pressure flask under nitrogen. The flask was sealed and heated to 150° C. for 46 hours. The reaction was complete, and the resulting solution was cooled and basified to a pH of about 12 with 1 N potassium hydroxide. The basic solution was extracted with dichloromethane (3×), and the organic layers were combined, washed with water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was triturated with diethyl ether, and the resulting solids were filtered off. NMR analysis of the solids indicated residual phenol. The solids were dissolved in ethyl acetate. The ethyl acetate solution was washed with 1 N potassium hydroxide (4×), water (3×) and brine (3×), dried with magnesium sulfate, filtered, and concentrated under reduced pressure. The resulting oil was diluted with diethyl ether, and after several hours the resulting crystals were filtered off and rinsed with diethyl ether. The resulting solids, which by NMR analysis were free of the phenol, were dried at 60° C. for 17 hours under high vacuum to provide 2.2515 g of 1-[2-(benzyloxy)ethyl]-2,6,7-trimethyl-1H-imidazo[4,5-c]pyridin-4-amine, m.p. 136.8-137.5° C.
Reaction SMILES: [CH2:1]([C:4]1[CH:9]=[CH:8][N+:7]([O-])=[CH:6][C:5]=1C1C=CC=CC=1)[CH2:2][CH3:3].ClCCl.CN(C)C(Cl)=O.[C:26](=O)([O-:28])[O-:27].[K+].[K+]>Cl>[CH2:1]([C:4]1[CH:5]=[CH:6][N:7]=[C:8]([C:26]([OH:28])=[O:27])[CH:9]=1)[CH2:2][CH3:3]
Reactant: CCCc1cc[n+]([O-])cc1-c1ccccc1
Reactant: O=C([O-])[O-]
Agent: CN(C)C(=O)Cl
Agent: Cl
Agent: [K+]
Solvent: ClCCl
Product: CCCc1ccnc(C(=O)O)c1
Temperature: 25 °C
Reaction time: 24 h
Yield: 86 %

Procedure:
To 4-propyl-(3-phenyl)pyridine-N-Oxide (1 g, 4.69 mmol) in dichloromethane (10 mL) trimethylsilyl cyanide (1.3 mL, 10 mmol) and dimethylcarbamyl chloride (1 mL, 10 mmol) was added and stirred at room temperature for 24 hours. Aqueous potassium carbonate (10%, 10 mL) was added and extracted with dichloromethane (100 mL). The crude product obtained on removal of solvent was taken in hydrochloric acid (6N, 30 mL) and refluxed for 24 hours. Removal of acid followed by crystallization of the crude product from acetonitrile resulted in acid 10b (1 g, 86%): MS (ESPOS): 240 [M−1]; 1H NMR (300 MHz, CD3OD) δ 2.03-2.17 (m, 2), 2.74 (t, J=7.2, 2), 3.04 (t, J=7.8, 2), 7.16-7.38 (m, 5), 8.07 (d, J=4.2, 1), 8.40 (s, 1), 8.71 (d, J=5.7, 1).