Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([N+:15]([O-])=O)[CH:3]=1.[H][H]>[Pd].C(O)(C)C>[F:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=2)=[C:4]([NH2:15])[CH:3]=1
Reactant: [H][H]
Reactant: O=[N+]([O-])c1cc(F)ccc1Oc1ccccc1
Agent: [Pd]
Solvent: CC(C)O
Product: Nc1cc(F)ccc1Oc1ccccc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 94 %

Procedure:
The atmosphere over a stirred solution of 11,6 g (50 mmol) 4-fluoro-2-nitro-1-phenoxy-benzene and catalytic amount of palladium on carbon in 150 ml iso-propanol at 20° C. was saturated with hydrogen. The reaction mixture was stirred vigorously at 25° C. for 8 h. The reaction mixture was filtered over celite. The filtrate was evaporated. 200 ml water and 200 ml dichloromethane were added. The organic phase was separated. The aqueous phase was extracted three times with 100 ml dichloromethane each. The combined organic phases were washed with 50 ml water and 50 ml brine. The organic phase was dried with magnesium sulfate and evaporated. The crude product 1b was used without purification. The desired crude product 1b was obtained in 94% yield (9.54 g, 47 mmol) as yellow oil.
Reaction SMILES: [F:1][C:2]([F:26])([F:25])[C:3]1[N:8]2[N:9]=[CH:10][C:11]([C:12](O)=O)=[C:7]2[N:6]=[C:5]([C:15]2[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:23])[F:22])=[CH:17][CH:16]=2)[CH:4]=1.[OH:27][NH:28][C:29](=[NH:36])[C:30]1[CH:35]=[CH:34][CH:33]=[N:32][CH:31]=1>>[N:32]1[CH:33]=[CH:34][CH:35]=[C:30]([C:29]2[N:36]=[C:12]([C:11]3[CH:10]=[N:9][N:8]4[C:3]([C:2]([F:26])([F:25])[F:1])=[CH:4][C:5]([C:15]5[CH:20]=[CH:19][C:18]([C:21]([F:24])([F:22])[F:23])=[CH:17][CH:16]=5)=[N:6][C:7]=34)[O:27][N:28]=2)[CH:31]=1
Reactant: N=C(NO)c1cccnc1
Reactant: O=C(O)c1cnn2c(C(F)(F)F)cc(-c3ccc(C(F)(F)F)cc3)nc12
Product: FC(F)(F)c1ccc(-c2cc(C(F)(F)F)n3ncc(-c4nc(-c5cccnc5)no4)c3n2)cc1

Procedure:
The title compound was prepared from 7-trifluoromethyl-5-(4-trifluoromethyl-phenyl)-pyrazolo[1,5-a]pyrimidine-3-carboxylic acid (example C.2) (188 mg, 0.5 mmol) and commercially available N-hydroxy-nicotinamidine [CAS-No. 1594-58-7] (103 mg, 0.75 mmol) according to general procedure II. Obtained after purification by column chromatography (dichloromethane/MeOH/NH4OH) and crystallization (dichloromethane/MeOH/hexane) as a yellow solid (126 mg, 53%). MS (EI) 476.1 [(M+H)+]; mp 199° C.
Reaction SMILES: [CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]([NH2:11])=[S:10].Br[C:13]1([C:17](OCC)=[O:18])[CH2:16][CH2:15][CH2:14]1>>[CH:1]12[CH2:7][CH:4]([CH2:5][CH2:6]1)[CH2:3][CH:2]2[NH:8][C:9]1[S:10][C:13]2([C:17](=[O:18])[N:11]=1)[CH2:16][CH2:15][CH2:14]2
Reactant: NC(=S)NC1CC2CCC1C2
Reactant: CCOC(=O)C1(Br)CCC1
Product: O=C1N=C(NC2CC3CCC2C3)SC12CCC2

Procedure:
Synthesis was performed from N-bicyclo[2.2.1]hept-2-ylthiourea and ethyl 1-bromocyclobutanecarboxylate according to Method D.
Reaction SMILES: [N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1Cl)[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2].[CH3:19][NH:20][CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28]>C(O)C>[N+:1]([C:4]1[CH:5]=[C:6]([CH:15]=[CH:16][C:17]=1[N:20]([CH3:19])[CH2:21][CH2:22][CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][CH3:28])[C:7]([C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][CH:10]=1)=[O:8])([O-:3])=[O:2]
Reactant: O=C(c1ccccc1)c1ccc(Cl)c([N+](=O)[O-])c1
Reactant: CCCCCCCCNC
Solvent: CCO
Product: CCCCCCCCN(C)c1ccc(C(=O)c2ccccc2)cc1[N+](=O)[O-]
Temperature: 0 °C

Procedure:
A mixture of 9.23 g. of 3-nitro-4-chloro-benzophenone, 10 ml. of ethanol and 10.3 g. of N-methyl-N-octylamine is stirred at 80° to 85° C. for 30 minutes, and then the mixture is poured onto 100 ml. of ice water. The aqueous phase is extracted with 2×75 ml. of benzene. The benzene phases are combined, washed with distilled water until chloride-free, dried over anhydrous magnesium sulphate, filtered, and evaporated in vacuo. 11.57 g. of 3-nitro-4-(N-methyl-N-octylamino)-benzophenone are obtained in the form of an oily residue. On the basis of thin layer chromatographical examination, a pure, uniform product is obtained.
Reaction SMILES: [ClH:1].F[C:3]1[CH:4]=[C:5]([C:9]([C:23]2[CH:28]=[CH:27][CH:26]=[C:25](F)[CH:24]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:6]=[CH:7][CH:8]=1.[OH-].[Na+].O.Cl>C(O)C>[ClH:1].[C:23]1([C:9]([C:5]2[CH:6]=[CH:7][CH:8]=[CH:3][CH:4]=2)=[CH:10][O:11][CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]=[C:16]([C:20]([OH:22])=[O:21])[CH2:15]2)[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1
Reactant: O=C(O)C1=CCCN(CCOC=C(c2cccc(F)c2)c2cccc(F)c2)C1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=C(O)C1=CCCN(CCOC=C(c2ccccc2)c2ccccc2)C1
Temperature: 25 °C
Reaction time: 2.5 h
Yield: 95.8 %

Procedure:
1-[2-[[2,2-Diphenylethenyl]oxy]ethyl]-1,2,5,6-tetrahydro3-pyridine carboxylic acid methyl ester (4.33 g, 0.01147 mol) (prepared as described in Method D) was dissolved in ethanol (50 ml) and 10N sodium hydroxide solution (11.5 ml) was introduced, followed by water (5 ml). The solution was stirred at room temperature for 2.5 h and stored at 4° C. for 18 h. 2N hydrochloric acid solution was added until the pH reached ca. 2, and the mixture was extracted with dichloromethane (3×60 ml). The combined extracts were dried (MgSO4) and evaporated to give a foam (4.24 g) which was crystallized from 2-propanol to provide the title compound (2.32 g, 52%) as a white solid, m.p. 173°-176°.
Reaction SMILES: [NH2:1][C:2]1[C:7]([CH3:8])=[CH:6][C:5]([OH:9])=[CH:4][C:3]=1[OH:10].C(=O)([O-])[O-].[K+].[K+].Br[CH2:18][C:19](Cl)=[O:20].Cl>C(#N)C.O>[OH:9][C:5]1[CH:6]=[C:7]([CH3:8])[C:2]2[NH:1][C:19](=[O:20])[CH2:18][O:10][C:3]=2[CH:4]=1
Reactant: Cc1cc(O)cc(O)c1N
Reactant: O=C(Cl)CBr
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CC#N
Product: Cc1cc(O)cc2c1NC(=O)CO2
Temperature: 70 °C
Reaction time: 1 h

Procedure:
1.0 g (7.2 mmol) 4-amino-5-methylbenzene-1,3-diol and 2.2 g (15.8 mmol) potassium carbonate in 20.0 mL acetonitrile were cooled in the ice bath. 0.65 mL (7.9 mmol) bromoacetyl chloride were added dropwise and the reaction mixture was stirred for 30 min at RT and for 1 h at 70° C. The mixture was combined with water, acidified with aqueous hydrochloric acid and extracted with dichloromethane. The organic phase was separated off, dried and evaporated down i.vac.
Reaction SMILES: [OH:1][C:2]1[CH:24]=[CH:23][C:5]2[N:6]=[C:7]([N:9]3[CH2:14][CH2:13][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:11][CH2:10]3)[O:8][C:4]=2[CH:3]=1.C(=O)([O-])[O-].[K+].[K+].Br[CH2:32][CH:33]1[CH2:35][CH2:34]1>CN(C=O)C.C(OCC)(=O)C>[CH:33]1([CH2:32][O:1][C:2]2[CH:24]=[CH:23][C:5]3[N:6]=[C:7]([N:9]4[CH2:10][CH2:11][CH:12]([CH2:15][CH2:16][CH:17]([NH:19][C:20](=[O:22])[CH3:21])[CH3:18])[CH2:13][CH2:14]4)[O:8][C:4]=3[CH:3]=2)[CH2:35][CH2:34]1
Reactant: BrCC1CC1
Reactant: CC(=O)NC(C)CCC1CCN(c2nc3ccc(O)cc3o2)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CC(=O)NC(C)CCC1CCN(c2nc3ccc(OCC4CC4)cc3o2)CC1
Temperature: 100 °C
Reaction time: 6 h
Yield: 54.9 %

Procedure:
To a solution of N-{3-[1-(6-hydroxy-1,3-benzoxazol-2-yl)piperidin-4-yl]-1-methylpropyl}acetamide (0.49 g) in DMF (15 mL) were added potassium carbonate (0.41 g) and (bromomethyl)cyclopropane (0.41 g), and the mixture was stirred at 100° C. for 6 hr. The reaction mixture was allowed to cool to room temperature, and diluted with ethyl acetate. The extract was washed with saturated brine and dried over anhydrous sodium sulfate. The solvent was evaporated under reduced pressure and the residue was purified by silica gel chromatography (ethyl acetate/methanol) and recrystallized from ethyl acetate/methanol to give the title compound (313 mg).
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]([NH:16][C:17]([C@@H:19]([NH:26][C:27]([C@H:29]([CH2:49][C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[CH2:30][S:31]([CH2:34][C:35]([NH:38]C(=O)OCC2C=CC=CC=2)([CH3:37])[CH3:36])(=[O:33])=[O:32])=[O:28])[CH2:20][C:21]2[N:22]=[CH:23][NH:24][CH:25]=2)=[O:18])[C@@H:9]([OH:15])[C@H:10]([CH:12]2[CH2:14][CH2:13]2)[OH:11])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.[OH2:56]>C(O)(=O)C.[Pd]>[C:10]([OH:11])(=[O:56])[CH3:9].[C:10]([OH:11])(=[O:56])[CH3:9].[NH2:38][C:35]([CH3:37])([CH3:36])[CH2:34][S:31]([CH2:30][C@@H:29]([CH2:49][C:50]1[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=1)[C:27]([NH:26][C@@H:19]([CH2:20][C:21]1[N:22]=[CH:23][NH:24][CH:25]=1)[C:17]([NH:16][C@@H:8]([CH2:7][CH:1]1[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1)[C@@H:9]([OH:15])[C@H:10]([CH:12]1[CH2:14][CH2:13]1)[OH:11])=[O:18])=[O:28])(=[O:32])=[O:33]
Reactant: O
Reactant: CC(C)(CS(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: CC(=O)O
Product: CC(C)(N)CS(=O)(=O)C[C@@H](Cc1ccccc1)C(=O)N[C@@H](Cc1c[nH]cn1)C(=O)N[C@@H](CC1CCCCC1)[C@@H](O)[C@@H](O)C1CC1
Reaction time: 3 h

Procedure:
A mixture of 300 mg (0.38 mmol) of benzyl [2-[[(S)-2-[[(S)-1-[[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]carbamoyl]-2-imidazol-4-ylethyl]carbamoyl]-3-phenylpropyl]sulphonyl]-1,1-dimethylethyl]carbamate and 30 mg of palladium/carbon (10%) in 8 ml of acetic acid is hydrogenated at room temperature for 3 hours. Thereafter, the catalyst is filtered off, the reaction solution is evaporated and the residue obtained is lyophilized from water. There are obtained 240 mg of (S)-α-[(S)-α-[[(2-amino-2-methylpropyl)sulphonyl]methyl]hydrocinnamamido]-N-[(1S,2R,3S)-1-(cyclohexylmethyl)-3-cyclopropyl-2,3-dihydroxypropyl]imidazole-4-propionamide diacetate as a colourless, amorphous powder; MS: 646 (M+H)+.
Reaction SMILES: Cl[C:2]1[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=2)[N:3]=1.[CH3:16][O:17][C:18]1[CH:19]=[C:20]([CH:22]=[C:23]([O:27][CH3:28])[C:24]=1[O:25][CH3:26])[NH2:21]>CCOC(C)=O.C1CCCCC1>[CH3:28][O:27][C:23]1[CH:22]=[C:20]([NH:21][C:2]2[CH:7]=[N:6][CH:5]=[C:4]([O:8][C:9]3[CH:14]=[CH:13][CH:12]=[C:11]([F:15])[CH:10]=3)[N:3]=2)[CH:19]=[C:18]([O:17][CH3:16])[C:24]=1[O:25][CH3:26]
Reactant: COc1cc(N)cc(OC)c1OC
Reactant: Fc1cccc(Oc2cncc(Cl)n2)c1
Solvent: C1CCCCC1
Solvent: CCOC(C)=O
Product: COc1cc(Nc2cncc(Oc3cccc(F)c3)n2)cc(OC)c1OC
Yield: 61 %

Procedure:
Using Method EE with 2-chloro-6-(3-fluorophenyloxy)-pyrazine (200 mg, 0.89 mmol) and 3,4,5-trimethoxyaniline (196 mg, 1.07 mmol), and purification by column chromatography (AcOEt:cyclohexane, 1:1), the title compound was obtained (200 mg). Yield: 61%. 1H NMR (250 MHz, DMSO-d6) δ 3.44 (s, 6H, [CH3O]3+5), 3.55 (s, 3H, [CH3O]4), 6.77 (s, 2H, Harom 2′+6′), 7.02-7.09 (m, 2H, Harom 4+6), 7.16 (d, 1H, Harom 2, JF=8.8 Hz), 7.43 (q, 1H, Harom 5, J=8.5 Hz), 7.78 (s, 1H, HPz 5), 7.98 (s, 1H, HPz 3), 9.61 (s, 1H, NH). m/z: 372.1 [(M+H)+, calcd for C19H18FN3O4 371.1].
Reaction SMILES: C(OC(=O)[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:20](=[O:37])[CH2:21][C:22]([C:24]1[CH:29]=[CH:28][CH:27]=[C:26]([C:30]2[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=2)[CH:25]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[CH3:14][C:12]1[C:11]([C:15]([F:17])([F:16])[F:18])=[CH:10][C:9]2[NH:19][C:20](=[O:37])[CH2:21][C:22]([C:24]3[CH:29]=[CH:28][CH:27]=[C:26]([C:30]4[C:31]([CH3:36])=[N:32][CH:33]=[CH:34][CH:35]=4)[CH:25]=3)=[N:7][C:8]=2[CH:13]=1
Reactant: Cc1cc(NC(=O)OC(C)(C)C)c(NC(=O)CC(=O)c2cccc(-c3cccnc3C)c2)cc1C(F)(F)F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: Cc1cc2c(cc1C(F)(F)F)NC(=O)CC(c1cccc(-c3cccnc3C)c1)=N2

Procedure:
The title compound was prepared from (5-methyl-2-{3-[3-(2-methyl-pyridin-3-yl)-phenyl]-3-oxo-propionylamino}-4-trifluoromethyl-phenyl)-carbamic acid tert-butyl ester (Example M240) (416 mg, 0.79 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (246 mg, 76%).
Reaction SMILES: [CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17](S(C)(=O)=O)[N:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1)=[O:4].[CH:26]1[C:35]2[C:30](=[CH:31][CH:32]=[CH:33][CH:34]=2)[CH:29]=[CH:28][C:27]=1[NH:36]C1C=CC=CC=1>C(#N)C>[CH3:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([O:11][C:12]2[CH:13]=[C:14]3[C:19](=[CH:20][CH:21]=2)[N:18]=[C:17]([NH:36][C:27]2[CH:28]=[CH:29][C:30]4[C:35](=[CH:34][CH:33]=[CH:32][CH:31]=4)[CH:26]=2)[N:16]=[CH:15]3)[CH:8]=[CH:7][N:6]=1)=[O:4]
Reactant: CNC(=O)c1cc(Oc2ccc3nc(S(C)(=O)=O)ncc3c2)ccn1
Reactant: c1ccc(Nc2ccc3ccccc3c2)cc1
Solvent: CC#N
Product: CNC(=O)c1cc(Oc2ccc3nc(Nc4ccc5ccccc5c4)ncc3c2)ccn1
Temperature: 82.5 °C

Procedure:
N-methyl[4-(2-methylsulfonylquinazolin-6-yloxy)(2-pyridyl)]carboxamide 15 (1 eq) was treated with 2-naphthylaniline (2 eq) in acetonitrile (1 M) and heated at 80-85° C. The mixture was evaporated and purified on preparative chromatography to give the product.
Reaction SMILES: Cl.C([O:4][C:5](=[O:26])[CH2:6][CH2:7][N:8]1[C:17]2[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=2[C:11]2=[CH:18][C:19]([C:21]([O:23]CC)=[O:22])=[CH:20][N:10]2[CH2:9]1)C.[OH-].[K+]>CO.O>[C:21]([C:19]1[CH:18]=[C:11]2[C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=3[N:8]([CH2:7][CH2:6][C:5]([OH:26])=[O:4])[CH2:9][N:10]2[CH:20]=1)([OH:23])=[O:22]
Reactant: CCOC(=O)CCN1Cn2cc(C(=O)OCC)cc2-c2ccccc21
Agent: Cl
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CO
Product: O=C(O)CCN1Cn2cc(C(=O)O)cc2-c2ccccc21

Procedure:
A solution of the product of Example VI (2.75 g, 0.008 m) and KOH (4.0 g, 0.072 m) in MeOH (40 ml) and H2O (40 ml) was refluxed for 4 hr. The methanol was removed under vacuum and the resulting aqueous solution was acidified with HCl (10% aqueous). When the solution became acidic, a greenish solid formed. It was filtered and washed with H2O and dried, to yield 2.2 g of crude product. Crystallization from MeOH afforded the desired product; m.p. 234°-236°.
Reaction SMILES: C([O:3][C:4]([C:6]1[CH:7]=[C:8]2[N:14]=[C:13]([NH:15][C:16]3[S:17][C:18]4[CH:24]=[C:23]([O:25][C:26]([F:29])([F:28])[F:27])[CH:22]=[CH:21][C:19]=4[N:20]=3)[N:12]([CH3:30])[C:9]2=[N:10][CH:11]=1)=[O:5])C.[OH-].[Li+]>>[CH3:30][N:12]1[C:9]2=[N:10][CH:11]=[C:6]([C:4]([OH:5])=[O:3])[CH:7]=[C:8]2[N:14]=[C:13]1[NH:15][C:16]1[S:17][C:18]2[CH:24]=[C:23]([O:25][C:26]([F:29])([F:27])[F:28])[CH:22]=[CH:21][C:19]=2[N:20]=1
Reactant: CCOC(=O)c1cnc2c(c1)nc(Nc1nc3ccc(OC(F)(F)F)cc3s1)n2C
Agent: [Li+]
Agent: [OH-]
Product: Cn1c(Nc2nc3ccc(OC(F)(F)F)cc3s2)nc2cc(C(=O)O)cnc21
Yield: 62 %

Procedure:
3-Methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid (58 mg, 62%) was prepared by following General Procedure E starting from 3-methyl-2-(6-trifluoromethoxy-benzothiazol-2-ylamino)-3H-imidazo[4,5-b]pyridine-6-carboxylic acid ethyl ester (100 mg) and lithium hydroxide (38 mg). LC/MS: m/z 409.7. 1H NMR (DMSO-d6, 400 MHz): δ 13.00 (s, 1H), 8.16 (s, 1H), 7.95 (d, 1H), 7.86 (dd, 1H), 7.65 (d, 1H), 7.52 (d, 1H), 7.37 (d, 1H), 3.68 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]([C:18](=[O:34])[NH:19][C:20](=O)[C:21]1[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([O:31][CH3:32])[CH:22]=1)[NH:10]C(OC(C)(C)C)=O.FC(F)(F)C(O)=O>C(Cl)Cl>[Cl:1][C:2]1[CH:7]=[CH:6][CH:5]=[C:4]([Cl:8])[C:3]=1[N:9]1[C:18](=[O:34])[NH:19][C:20]([C:21]2[CH:26]=[CH:25][C:24]([C:27]([O:29][CH3:30])=[O:28])=[C:23]([O:31][CH3:32])[CH:22]=2)=[N:10]1
Reactant: COC(=O)c1ccc(C(=O)NC(=O)N(NC(=O)OC(C)(C)C)c2c(Cl)cccc2Cl)cc1OC
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: COC(=O)c1ccc(-c2nn(-c3c(Cl)cccc3Cl)c(=O)[nH]2)cc1OC
Yield: 52.5 %

Procedure:
The title compound was prepared according to the procedure described in step-2 of Intermediate-9 by using tert-butyl 2-(2,6-dichlorophenyl)-2-((3-methoxy-4-(methoxycarbonyl)benzoyl)carbamoyl)hydrazinecarboxylate (1.5 g, 2.9 mmol), DCM (20 mL) and trifluoro acetic acid (2.0 mL) to afford 0.600 g of desired product. 1H NMR (300 MHz, DMSO do): δ 3.80 (s, 3H), 3.80 (s, 3H), 7.49-7.71 (m, 3H), 7.74-7.79 (m, 3H), 12.85 (s, 1H); MS (m/z): 393.95 (M)+.
Reaction SMILES: [CH3:1][C:2]1([CH3:21])[CH2:7][CH:6]([C:8]2[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N:9]=2)[C:5]2[CH:15]=[C:16]([C:19]#[N:20])[CH:17]=[CH:18][C:4]=2[O:3]1.C([O:24]CC)C>>[C:19]([C:16]1[CH:17]=[CH:18][C:4]2[O:3][C:2]([CH3:21])([CH3:1])[CH2:7][CH:6]([C:8]3[CH:13]=[C:12]([CH3:14])[CH:11]=[CH:10][N+:9]=3[O-:24])[C:5]=2[CH:15]=1)#[N:20]
Reactant: CCOCC
Reactant: Cc1ccnc(C2CC(C)(C)Oc3ccc(C#N)cc32)c1
Product: Cc1cc[n+]([O-])c(C2CC(C)(C)Oc3ccc(C#N)cc32)c1

Procedure:
In an analogous manner to that described in the first paragraph of Example 7, from 3,4-dihydro-2,2-dimethyl-4-(4-methyl-2-pyridyl)-2H-1-benzopyran-6-carbonitrile there was obtained 2-(6-cyano-3,4-dihydro-2,2-dimethyl-2H-1-benzopyran-4-yl)-4-methylpyridine N-oxide of melting point 156°-159° C. (from diethyl ether).
Reaction SMILES: [C:1]([C:3]1[C:4]([C:20]([F:23])([F:22])[F:21])=[C:5]2[C:9](=[CH:10][CH:11]=1)[N:8]([CH:12]([CH3:18])/[C:13](=[N:16]/[H])/[NH:14][OH:15])[C:7]([CH3:19])=[CH:6]2)#[N:2].[F:24][C:25]([F:36])([F:35])[C:26]1[CH:27]=[C:28]([CH:32]=[CH:33][CH:34]=1)[C:29](Cl)=O>>[CH3:19][C:7]1[N:8]([CH:12]([C:13]2[N:16]=[C:29]([C:28]3[CH:32]=[CH:33][CH:34]=[C:26]([C:25]([F:24])([F:35])[F:36])[CH:27]=3)[O:15][N:14]=2)[CH3:18])[C:9]2[C:5]([CH:6]=1)=[C:4]([C:20]([F:23])([F:22])[F:21])[C:3]([C:1]#[N:2])=[CH:11][CH:10]=2
Reactant: O=C(Cl)c1cccc(C(F)(F)F)c1
Reactant: [H]/N=C(\NO)C(C)n1c(C)cc2c(C(F)(F)F)c(C#N)ccc21
Product: Cc1cc2c(C(F)(F)F)c(C#N)ccc2n1C(C)c1noc(-c2cccc(C(F)(F)F)c2)n1

Procedure:
Synthesized as described in Example 32B from (1Z)-2-[5-cyano-2-methyl-4-(trifluoromethyl)-1H-indol-1-yl]-N-hydroxypropanimidamide and 3-(trifluoromethyl)benzoyl chloride: MS (ES) m/z 465 (M+1).
Reaction SMILES: [Br:1][C:2]1[N:3]([CH2:24][C:25](O)=[O:26])[C:4]2[C:9]([C:10]=1[CH:11]1[CH2:16][CH2:15][CH2:14][CH2:13][CH2:12]1)=[CH:8][CH:7]=[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:5]=2.[Br:28][C:29]1[CH:41]=[CH:40][C:39]([Cl:42])=[CH:38][C:30]=1[CH2:31][NH:32][CH2:33][CH2:34][N:35]([CH3:37])[CH3:36].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[C:20]([O:19][C:17]([C:6]1[CH:5]=[C:4]2[C:9]([C:10]([CH:11]3[CH2:12][CH2:13][CH2:14][CH2:15][CH2:16]3)=[C:2]([Br:1])[N:3]2[CH2:24][C:25]([N:32]([CH2:31][C:30]2[CH:38]=[C:39]([Cl:42])[CH:40]=[CH:41][C:29]=2[Br:28])[CH2:33][CH2:34][N:35]([CH3:37])[CH3:36])=[O:26])=[CH:8][CH:7]=1)=[O:18])([CH3:21])([CH3:23])[CH3:22]
Reactant: CN(C)CCNCc1cc(Cl)ccc1Br
Reactant: CC(C)(C)OC(=O)c1ccc2c(C3CCCCC3)c(Br)n(CC(=O)O)c2c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CN(C)CCN(Cc1cc(Cl)ccc1Br)C(=O)Cn1c(Br)c(C2CCCCC2)c2ccc(C(=O)OC(C)(C)C)cc21
Temperature: 25 °C
Reaction time: 8 h
Yield: 56 %

Procedure:
To a solution of [2-bromo-6-(tert-butoxycarbonyl)-3-cyclohexyl-1H-indol-1-yl]acetic acid (from Step 7, 1 eq) in DCM (0.07 M), N′-(2-bromo-5-chlorobenzyl)-N,N-dimethylethane-1,2-diamine (from Step 3, 2.1 eq), DIPEA (3 eq) and HATU (2 eq) were added and the mixture stirred at RT overnight. The solution was diluted with DCM and washed with HCl (1 N), a saturated aqueous solution of NaHCO3 and brine, dried (Na2SO4), filtered and concentrated in vacuo to afford the title compound (56%) that was used in the next step without further purification; MS (ES+) m/z 710 (M+H)+.
Reaction SMILES: [CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH:13]=[CH:14][N:15]=[CH:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1>CO.[Pt]=O>[CH2:1]([O:8][C:9]1[CH:18]=[C:17]2[C:12]([CH2:13][CH2:14][NH:15][CH2:16]2)=[CH:11][CH:10]=1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(COc2ccc3ccncc3c2)cc1
Agent: O=[Pt]
Solvent: CO
Product: c1ccc(COc2ccc3c(c2)CNCC3)cc1
Yield: 63 %

Procedure:
7-Benzyloxyisoquinoline (1.5 g, 6.37 mmol) in methanol (100 ml) was hydrogenated at 50 psi on a Parr apparatus using platinum oxide (100 mg) as catalyst. The catalyst was collected by filtration, the filtrate evaporated under reduced pressure to give an oil which crystallised on treatment with hexane/diethyl ether to give the title compound (0.96 g, 64%); δH (CDCl3) 2.72 (2H, t, J 6 Hz, CH2), 3.11 (2H, t, J 6 Hz, CH2), 3.90 (2H, s, CH2), 6.62 (1H, d, J 2.25 Hz, tetrahydroisoquinolinyl H), 6.78 (1H, dd, J 5.75, 2.75 Hz, tetrahydroisoquinolinyl H), 6.99 (1H, d, J 9.25 Hz, tetrahydroisoquinolinyl H), and 7.25-7.43 (5H, m, ArH).
Reaction SMILES: C(OC([NH:11][CH2:12][CH2:13][CH2:14][CH2:15][C@@H:16]([C:25]([OH:27])=O)[NH:17][C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19])=O)C1C=CC=CC=1.[NH:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1>>[C:21]([O:20][C:18]([NH:17][C@H:16]([C:25](=[O:27])[N:28]1[CH2:32][CH2:31][CH2:30][CH2:29]1)[CH2:15][CH2:14][CH2:13][CH2:12][NH2:11])=[O:19])([CH3:22])([CH3:23])[CH3:24]
Reactant: CC(C)(C)OC(=O)N[C@@H](CCCCNC(=O)OCc1ccccc1)C(=O)O
Reactant: C1CCNC1
Product: CC(C)(C)OC(=O)N[C@@H](CCCCN)C(=O)N1CCCC1

Procedure:
Starting from (S)-N6-(benzyloxycarbonyl)-N2-(tert-butyloxycarbonyl)-lysine and pyrrolidine, the expected product is obtained according to the procedure described in Steps A and B of Example 3.
Reaction SMILES: [Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]([OH:25])[C:17]2[N:18]=[CH:19][N:20]3[CH:24]=[CH:23][S:22][C:21]=23)[CH:13]=[N:14][CH:15]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2]>ClCCl.[O-2].[O-2].[Mn+4]>[Si:1]([O:8][CH2:9][C:10]1[CH:11]=[C:12]([C:16]([C:17]2[N:18]=[CH:19][N:20]3[CH:24]=[CH:23][S:22][C:21]=23)=[O:25])[CH:13]=[N:14][CH:15]=1)([C:4]([CH3:5])([CH3:6])[CH3:7])([CH3:3])[CH3:2]
Reactant: CC(C)(C)[Si](C)(C)OCc1cncc(C(O)c2ncn3ccsc23)c1
Agent: [Mn+4]
Agent: [O-2]
Solvent: ClCCl
Product: CC(C)(C)[Si](C)(C)OCc1cncc(C(=O)c2ncn3ccsc23)c1
Temperature: 25 °C
Reaction time: 16 h
Yield: 89.1 %

Procedure:
Manganese dioxide (1.43 g) was added to a solution of 803 mg of 7-[[5-(t-butyldimethylsilyloxymethyl)-pyridin-3-yl]hydroxymethyl]imidazo[5,1-b]thiazole in 10 ml of dichloromethane, and the mixture was stirred at room temperature for 16 hr. The reaction solution was filtered through Celite, followed by washing with dichloromethane. The filtrate was concentrated under the reduced pressure to give 712 mg of 7-[5-(t-butyldimethylsilyloxymethyl)pyridin-3-yl]carbonyl imidazo[5,1-b]thiazole.
Reaction SMILES: [NH:1]1[CH:5]=[CH:4][N:3]=[N:2]1.[H-].[Na+].F[C:9]1[CH:16]=[C:15]([F:17])[CH:14]=[CH:13][C:10]=1[C:11]#[N:12]>C1COCC1.CN(C=O)C>[F:17][C:15]1[CH:16]=[CH:9][C:10]([C:11]#[N:12])=[C:13]([N:2]2[N:3]=[CH:4][CH:5]=[N:1]2)[CH:14]=1
Reactant: c1c[nH]nn1
Reactant: N#Cc1ccc(F)cc1F
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CN(C)C=O
Product: N#Cc1ccc(F)cc1-n1nccn1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 3.6 %

Procedure:
To a solution of 1H-1,2,3-triazole (3.5 g, 50.7 mmol) in THF (10 mL) and DMF (20 mL) was added portionwise, NaH (1.3 g, 51 mmol, 95%). The mixture was stirred at room temp for 30 min. Added to this was 2,4-difluorobenzonitrile (7.6 g, 55 mmol) and the mixture was stirred at 85° C. for 3 h. The white mixture was concentrated and purified by flash chromatography eluting with 0%-5%-10% EtOAc/hexane to give the title compound as white needles (0.34 g, 3% yield). 1H-NMR (300 MHz, CDCl3) δ: 7.92 (2H, s), 7.88-7.79 (2H, m), 7.19-7.12 (1H, m). LCMS [M+H]+calcd for C9H6N4F: 189.05; found: 189.12.