Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:3]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=2)=[N:4][CH:5]=[CH:6][CH:7]=1.[C:32]1([CH2:38][C:39](=O)[C:40](O)=[O:41])[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1>CO>[CH2:38]([C:39]1[C:40](=[O:41])[N:8]([C:9]2[CH:14]=[C:13]([NH:15][C:16]([C:18]3[CH:27]=[CH:26][C:25]4[C:20](=[CH:21][CH:22]=[CH:23][CH:24]=4)[CH:19]=3)=[O:17])[CH:12]=[C:11]([C:28]([O:30][CH3:31])=[O:29])[CH:10]=2)[C:3]2[N:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=1)[C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][CH:33]=1
Reactant: O=C(O)C(=O)Cc1ccccc1
Reactant: COC(=O)c1cc(NC(=O)c2ccc3ccccc3c2)cc(Nc2ncccc2N)c1
Solvent: CO
Product: COC(=O)c1cc(NC(=O)c2ccc3ccccc3c2)cc(-n2c(=O)c(Cc3ccccc3)nc3cccnc32)c1
Yield: 71.6 %

Procedure:
A mixture of 3-amino-2-[3-methoxycarbonyl-5-(2-naphthoylamino)phenylamino]pyridine (180 mg) and 3-phenylpyruvic acid (86 mg) in methanol (4 ml) was stirred under reflux for 4 hours. The precipitate was collected and washed with methanol to give 2-benzyl-4-[3-methoxycarbonyl-5-(2-naphthoylamino)phenyl]-3-oxo-3,4-dihydropyrido[2,3-b]pyrazine (169 mg).
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]2[C:8](=[CH:9][CH:10]=1)[NH:7][C:6]([C:11]([O:13][CH2:14][CH3:15])=[O:12])=[CH:5]2.[Cl:16]N1C(=O)CCC1=O>CN(C)C=O.C(OCC)(=O)C>[Cl:16][C:5]1[C:4]2[C:8](=[CH:9][CH:10]=[C:2]([F:1])[CH:3]=2)[NH:7][C:6]=1[C:11]([O:13][CH2:14][CH3:15])=[O:12]
Reactant: O=C1CCC(=O)N1Cl
Reactant: CCOC(=O)c1cc2cc(F)ccc2[nH]1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC(=O)c1[nH]c2ccc(F)cc2c1Cl
Temperature: 25 °C
Reaction time: 18 h
Yield: 81.5 %

Procedure:
Ethyl 5-fluoroindole-2-carboxylate (2.0 g) was dissolved in N,N-dimethylformamide (20 ml), and a solution of N-chlorosuccinimide (1.4 g) in N,N-dimethylformamide (10 ml) was added dropwise to the solution under ice cooling. The mixture was stirred at room temperature for 18 hours, and the reaction mixture was diluted with ethyl acetate and successively washed with a saturated aqueous solution of sodium hydrogencarbonate and saturated aqueous solution of sodium chloride. The resultant organic layer was then dried over anhydrous sodium sulfate, the solvent was distilled off under reduced pressure, and the residue was purified by column chromatography on silica gel (hexane:ethyl acetate=5:1) to obtain the title compound (1.9 g).
Reaction SMILES: C(O[CH:4](OCC)[CH2:5][NH:6][C:7]1[N:11]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)[N:10]=[N:9][N:8]=1)C.[ClH:21].[OH:22][C:23]1[CH:24]=[C:25]([CH:29]=[CH:30][C:31]=1[OH:32])[CH2:26][CH2:27][NH2:28].C(O)C.Cl>O>[ClH:21].[C:12]1([N:11]2[C:7]([NH:6][CH2:5][CH:4]3[C:29]4[C:25](=[CH:24][C:23]([OH:22])=[C:31]([OH:32])[CH:30]=4)[CH2:26][CH2:27][NH:28]3)=[N:8][N:9]=[N:10]2)[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1
Reactant: NCCc1ccc(O)c(O)c1
Reactant: CCOC(CNc1nnnn1-c1ccccc1)OCC
Agent: Cl
Solvent: CCO
Solvent: O
Product: Oc1cc2c(cc1O)C(CNc1nnnn1-c1ccccc1)NCC2
Yield: 59.7 %

Procedure:
(1-phenyl-1H-tetrazol-5-yl)aminoacetaldehyde diethyl acetal (11 g.) and 3,4-dihydroxyphenethylamine hydrochloride (5.0 g.) were added to a mixture of ethanol (55 ml.) and water (20 ml.), and dissolved with heating and stirring. Conc. hydrochloric acid (6.0 g.) was added thereto and the mixture was refluxed for 8 hours. The reaction mixture was allowed to stand and the precipitated crystals were collected by filtration to give 1-(1-phenyl-1H-tetrazol-5-yl)aminomethyl-6,7-dihydroxy-1,2,3,4-tetrahydroisoquinoline hydrochloride (5.9 g.). The crystals were recrystallized from a mixture of isopropyl alcohol and water to give pure crystals (4.2 g.), mp 236° to 241° C (dec.).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]([C:11]2[CH:12]=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[C:14]([O:17][CH3:18])=[N:15][CH:16]=2)[CH:8]=[C:7]2[C:3]=1[CH:4]=[N:5][N:6]2[S:24]([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)(=[O:26])=[O:25].N1C=CC=CC=1.[Cl:39][CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46](Cl)=[O:47])[N:45]=1.C(=O)(O)[O-].[Na+]>C(Cl)Cl>[Cl:39][CH2:40][C:41]1[S:42][CH:43]=[C:44]([C:46]([NH:1][C:2]2[CH:10]=[C:9]([C:11]3[CH:16]=[N:15][C:14]([O:17][CH3:18])=[C:13]([NH:19][S:20]([CH3:23])(=[O:22])=[O:21])[CH:12]=3)[CH:8]=[C:7]3[C:3]=2[CH:4]=[N:5][N:6]3[S:24]([C:27]2[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=2)(=[O:26])=[O:25])=[O:47])[N:45]=1
Reactant: COc1ncc(-c2cc(N)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Reactant: O=C(Cl)c1csc(CCl)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: c1ccncc1
Product: COc1ncc(-c2cc(NC(=O)c3csc(CCl)n3)c3cnn(S(=O)(=O)c4ccccc4)c3c2)cc1NS(C)(=O)=O
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 74.5 %

Procedure:
N-[5-[4-Amino-1-(phenylsulfonyl)-1H-indazol-6-yl]-2-(methyloxy)-3-pyridinyl]methanesulfonamide (700 mg, 1.478 mmol) was dissolved in DCM (30 ml) and cooled to 0° C. before pyridine (0.179 ml, 2.217 mmol) was added. To this mixture was added 2-(chloromethyl)-1,3-thiazole-4-carbonyl chloride (290 mg, 1.478 mmol) as a solution in DCM (10 ml) dropwise over 15 mins. The mixture was stirred at 0° C. for 30 min. Saturated aqueous sodium bicarbonate solution (20 ml) was added to the mixture and it was stirred vigorously for 10 mins. The organic layer was separated using a hydrophobic frit, washed with water (20 ml) and concentrated in vacuo to give the title compound as an orange solid (697 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[C:14]([CH:15]=1)=[N+:13]([CH3:16])[C:12]1[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=1)[C:6]=2[C:17]([O:19][CH3:20])=[O:18].C(O)C.[BH4-].[K+]>O>[Cl:1][C:2]1[CH:3]=[CH:4][C:5]2[CH:6]([C:17]([O:19][CH3:20])=[O:18])[C:7]3[C:12]([N:13]([CH3:16])[C:14]=2[CH:15]=1)=[CH:11][CH:10]=[CH:9][CH:8]=3
Reactant: COC(=O)c1c2ccccc2[n+](C)c2cc(Cl)ccc12
Agent: [BH4-]
Agent: [K+]
Solvent: CCO
Solvent: O
Product: COC(=O)C1c2ccccc2N(C)c2cc(Cl)ccc21
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
5.3 gm of the methosulfate of 3-chloro-9-methoxycarbonyl-10-methyl-acridinium were added to a mixture of 50 cc of ethanol and 2.5 cc of water and after the addition of 5.3 gm potassium borohydride while maintaining a 25°C temperature, the mixture was stirred for 30 minutes and poured into water. After stirring for 30 minutes, the mixture was extracted with ether and the ether phase was washed with water, dried over magnesium sulfate and distilled to dryness in vacuo. The residue was dissolved in 30 cc of refluxing isopropyl ether, filtered and concentrated to 20 cc. The mixture was iced for 30 minutes and filtered. The precipitate was washed with iced isopropyl ether and dried in vacuo to obtain 3.18 gm of 3-chloro-9-methoxycarbonyl-10-methyl-acridane which was used as is for the next step.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[NH:13][CH:14]=2)[CH:5]=[CH:6][CH:7]=1.Cl.Cl[CH2:18][C:19]1[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=1>>[Cl:1][C:2]1[CH:3]=[C:4]([C:8]#[C:9][C:10]2[N:11]=[C:12]([CH3:15])[N:13]([CH2:18][C:19]3[CH:20]=[CH:21][C:22]([CH3:25])=[N:23][CH:24]=3)[CH:14]=2)[CH:5]=[CH:6][CH:7]=1
Reactant: Cc1nc(C#Cc2cccc(Cl)c2)c[nH]1
Reactant: Cc1ccc(CCl)cn1
Agent: Cl
Product: Cc1ccc(Cn2cc(C#Cc3cccc(Cl)c3)nc2C)cn1

Procedure:
The title compound, MS: m/e=322.5 (M+H+), was prepared in accordance with the general method of example 1 from 4-(3-chloro-phenylethynyl)-2-methyl-1H-imidazole and 5-chloromethyl-2-methyl-pyridine hydrochloride.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([CH:9]=[CH:10][C:11]2[CH:16]=[CH:15][C:14]([N+:17]([O-])=O)=[CH:13][CH:12]=2)=[CH:5][C:4]=1[O:20][CH3:21]>CN(C)C=O.[Pd]>[CH3:21][O:20][C:4]1[CH:5]=[C:6]([CH2:9][CH2:10][C:11]2[CH:12]=[CH:13][C:14]([NH2:17])=[CH:15][CH:16]=2)[CH:7]=[CH:8][C:3]=1[O:2][CH3:1]
Reactant: COc1ccc(C=Cc2ccc([N+](=O)[O-])cc2)cc1OC
Agent: [Pd]
Solvent: CN(C)C=O
Product: COc1ccc(CCc2ccc(N)cc2)cc1OC
Yield: 61.9 %

Procedure:
1,2-Dimethoxy-4-[2-(4-nitrophenyl)ethenyl]benzene (12.1 g, 0.042 mol) was reduced in the presence of 10% Pd—C (2.0 g) in dimethylformamide (DMF) (120 mL) at 25° C. under a hydrogen atmosphere. The reaction mixture was concentrated in vacuo to give a solid. The solid was recrystallized from MeOH (400 mL) to yield a white crystalline product, 6.8 g (0.026 mol, 63%) of the desired product. mp 115-116° C.
Reaction SMILES: [CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12](Cl)[CH3:13])=[CH:4][C:3]=2[O:2]1.[N:16]1[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=1[N:22]1[CH2:27][CH2:26][NH:25][CH2:24][CH2:23]1.C(N(CC)CC)C>C1(C)C=CC=CC=1>[CH2:1]1[O:9][C:8]2[CH:7]=[CH:6][C:5]([NH:10][C:11](=[O:15])[CH:12]([N:25]3[CH2:26][CH2:27][N:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=4)[CH2:23][CH2:24]3)[CH3:13])=[CH:4][C:3]=2[O:2]1
Reactant: CC(Cl)C(=O)Nc1ccc2c(c1)OCO2
Reactant: c1ccc(N2CCNCC2)nc1
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: CC(C(=O)Nc1ccc2c(c1)OCO2)N1CCN(c2ccccn2)CC1

Procedure:
The amide prepared in part (a) is condensed with 1-(2-pyridyl)-piperazine according to the method used in Example 1, using triethylamine as the base. The desired product is obtained with a melting point of 189°-191° C. (from toluene); Rf=0.44 (AcOEt); IR (nujol) νmax: 3280, 3250, 1680, 1660, 1595, 1540, 1520, 1490, 1450, 1440, 1250, 1165, 1035, 925, 775 cm-1.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][C:4]([N:7]2[CH2:11][CH2:10][NH:9][C:8]2=[O:12])=[CH:3][CH:2]=1.Br[CH2:14][C:15]#[CH:16]>>[CH2:16]([N:9]1[CH2:10][CH2:11][N:7]([C:4]2[CH:3]=[CH:2][N:1]=[CH:6][CH:5]=2)[C:8]1=[O:12])[C:15]#[CH:14]
Reactant: C#CCBr
Reactant: O=C1NCCN1c1ccncc1
Product: C#CCN1CCN(c2ccncc2)C1=O

Procedure:
The starting raw material, 1-(2-propynyl)-3-(4-pyridyl)-2-imidazolidinone was synthesized similarly to Referential example 1, using 1-(4-pyridyl)-2-imidazolidinone as material and using 3-bromopropyne in place of 4-fluoronitrobenzene.
Reaction SMILES: [B].[NH2:2][C:3](=[N:25][OH:26])[C:4]1[CH:9]=[C:8]([Cl:10])[N:7]=[C:6]([N:11]2[CH2:16][CH2:15][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:13][CH2:12]2)[CH:5]=1.[CH2:27](OC(OCC)(OCC)C)C>>[Cl:10][C:8]1[N:7]=[C:6]([N:11]2[CH2:12][CH2:13][CH:14]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:21])([CH3:22])[CH3:23])[CH2:15][CH2:16]2)[CH:5]=[C:4]([C:3]2[N:2]=[CH:27][O:26][N:25]=2)[CH:9]=1
Reactant: CCOC(C)(OCC)OCC
Reactant: CC(C)(C)OC(=O)NC1CCN(c2cc(C(N)=NO)cc(Cl)n2)CC1
Agent: [B]
Product: CC(C)(C)OC(=O)NC1CCN(c2cc(-c3ncon3)cc(Cl)n2)CC1

Procedure:
Boron trifluoroetherate (0.1 ml) was added to a solution of tert-butyl 1-{4-[amino (hydroxyimino)methyl]-6-chloropyridin-2-yl}piperidin-4-ylcarbamate (Intermediate 54) (0.254 g, 0.69 mmol) in 1,1,1-triethoxyethane (1.5 ml) at room temperature. The mixture was refluxed for 10 minutes. The mixture was purified by flash chromatography on silica gel eluting with (n-hexanes:EtOAc; 70:30) to afford the title compound (50 mg).
Reaction SMILES: [Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([OH:13])[C:9]2=[O:12])=[CH:4][CH:3]=1.Cl.[CH3:16]O>>[Cl:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6](=[O:14])[CH:7]=[C:8]([O:13][CH3:16])[C:9]2=[O:12])=[CH:4][CH:3]=1
Reactant: CO
Reactant: O=C1C=C(O)C(=O)c2cc(Cl)ccc21
Agent: Cl
Product: COC1=CC(=O)c2ccc(Cl)cc2C1=O
Temperature: 25 °C

Procedure:
7-Chloro-2-hydroxy-1,4-naphthoquinone (0.73 g) was added to 4% (w/w) hydrogen chloride in methanol (14 mL). The solution was heated to reflux for 0.5 hour. Upon cooling to room temperature, a precipitate formed which was filtered, washed (methanol) and dried under vacuum (25° C., 15 Pa) to give an orange solid (0.72 g); 250 MHz NMR: 8.10 (d,1, J=2.2), 8.04 (d,1, J=8.3), 7.71 (dd,1, J=8.3, 2.2), 6.19 (s,1), 3.92 (s,3).
Reaction SMILES: [Li]CCCC.[CH2:6]([C:9]1[CH:10]=[N:11][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]3[CH:28]=[C:27]([F:29])[CH:26]=[C:25]([F:30])[CH:24]=3)=[CH:17][CH:16]=2)=[N:13][CH:14]=1)[CH2:7][CH3:8].[CH3:31][N:32](CCN(C)C)C.II>C1COCC1.C(OCC)C.O>[CH2:6]([C:9]1[CH:14]=[N:13][C:12]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][CH2:22][C:23]3[CH:24]=[C:25]([F:30])[C:26]([C:31]#[N:32])=[C:27]([F:29])[CH:28]=3)=[CH:17][CH:16]=2)=[N:11][CH:10]=1)[CH2:7][CH3:8]
Reactant: CCCc1cnc(-c2ccc(CCc3cc(F)cc(F)c3)cc2)nc1
Reactant: CN(C)CCN(C)C
Agent: II
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Solvent: C1CCOC1
Product: CCCc1cnc(-c2ccc(CCc3cc(F)c(C#N)c(F)c3)cc2)nc1
Temperature: 170 °C
Reaction time: 0.5 h

Procedure:
0.1 m of n-BuLi (1,5 M in hexane) is added dropwise to a solution of 0.1 m of 1-[p-(5-n-propyl-2-pyrimidinyl)-phenyl]-2-(3,5-difluorophenyl)ethane (prepared in accordance with scheme 1) and 0.1 m of TMEDA in 300 ml of THF at approximately -90° . Stirring is carried out for a further 30 min at this temperature and then a solution of 0.1 m of I2 in 70 ml of THF is slowly added. After addition is complete, the solution is allowed to heat up to -20° and hydrolyzation is carried out with H2O. The product is completely dissolved by adding diethyl ether and excess I2 is removed by washing with sodium thiosulfate solution and H2O. After evaporating down, the product is left behind as a residue and without further purification, is heated with 0.12 m of (CuCN)x and 100 ml of NMP for 4 h at 170° C. in an oil bath. After this time, water and CH2CH2 are added to the cooled reaction mixture, and the organic phase is washed, dried and evaporated down. The pure product can be obtained by chromatography and crystallization. 1-[p-(5-n-propyl-2-pyrimidinyl)-phenyl]-2-(4-cyano-3,5difluorophenyl)ethane is obtained.
Reaction SMILES: N1C=CC=CC=1.[O:7]([C:14]1[S:15][C:16]([CH2:19][OH:20])=[CH:17][N:18]=1)[C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=1.[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:28])[Br:27])[C@H:23]1[C:29](Cl)=[O:30].Cl>C1C=CC=CC=1>[CH3:21][C:22]1([CH3:32])[C@@H:24]([CH:25]=[C:26]([Br:27])[Br:28])[C@H:23]1[C:29]([O:20][CH2:19][C:16]1[S:15][C:14]([O:7][C:8]2[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=2)=[N:18][CH:17]=1)=[O:30]
Reactant: CC1(C)[C@H](C(=O)Cl)[C@@H]1C=C(Br)Br
Reactant: OCc1cnc(Oc2ccccc2)s1
Agent: Cl
Solvent: c1ccncc1
Solvent: c1ccccc1
Product: CC1(C)[C@H](C(=O)OCc2cnc(Oc3ccccc3)s2)[C@@H]1C=C(Br)Br
Temperature: 20 °C
Reaction time: 8 h

Procedure:
3 ml of pyridine were added dropwise at 5° C. to a solution of 2.1 gof the product of Step B in 50 ml of benzene and 3.5 g of (1R,3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylic acid chloride and the mixture was stirred at 20° C. for 8 hours and was poured into aqueous 2N hydrochloric acid. The decanted organic phase was dried and evaporated to dryness under reduced pressure. The residue was chromatographed over silica gel and eluted with a 95-5 benzene-ethyl acetate mixture to obtain 1.45 g of (2-phenoxy-5-thiazolyl)-methyl (1R3R) 2,2-dimethyl-3-[2,2-dibromoethenyl]-cyclopropane-1-carboxylate.
Reaction SMILES: [Si]([O:18][CH2:19][CH2:20][C:21]1([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][N:30](C(OC(C)(C)C)=O)[CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=[C:23]([C:42]2[CH:47]=[C:46]([F:48])[CH:45]=[CH:44][C:43]=2[F:49])[S:22]1)(C(C)(C)C)(C1C=CC=CC=1)C1C=CC=CC=1.Cl.O1CCOCC1.O>O1CCOCC1>[F:49][C:43]1[CH:44]=[CH:45][C:46]([F:48])=[CH:47][C:42]=1[C:23]1[S:22][C:21]([CH2:20][CH2:19][OH:18])([C:50]2[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=2)[N:25]([C:26]2[S:27][C:28]3[CH2:29][NH:30][CH2:31][CH2:32][C:33]=3[N:34]=2)[N:24]=1
Reactant: CC(C)(C)OC(=O)N1CCc2nc(N3N=C(c4cc(F)ccc4F)SC3(CCO[Si](c3ccccc3)(c3ccccc3)C(C)(C)C)c3ccccc3)sc2C1
Agent: Cl
Solvent: C1COCCO1
Solvent: O
Product: OCCC1(c2ccccc2)SC(c2cc(F)ccc2F)=NN1c1nc2c(s1)CNCC2
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of tert-butyl 2-(2-(2-(tert-butyldiphenylsilyloxy)ethyl)-5-(2,5-difluorophenyl)-2-phenyl-1,3,4-thiadiazol-3(2H)-yl)-6,7-dihydrothiazolo[5,4-c]pyridine-5(4H)-carboxylate (prepared according to Example 26, Steps A-D; 0.090 g, 0.113 mmol) in 1 mL of 1,4-dioxane was added 4M HCl/dioxane (1 mL). The mixture was stirred at room temperature for 16 hours then treated with 4M HCl/dioxane (2 mL) and stirred for a further 3 hours. Water (1 mL) was added and the mixture was stirred for 16 hours then concentrated and dried in vacuo. The residue was triturated with diethyl ether, filtered, washed with ether and dried in vacuo to afford the desired product as an orange/yellow solid, 0.023 g, 38%. MS ESI (+) m/z 459 (M+1) detected; 1H NMR (400 MHz, CDCl3) δ 7.59 (m, 1H), 7.46 (m, 2H), 7.33 (m, 3H), 7.07 (m, 2H), 4.12 (m, 1H), 3.95 (m, 1H), 3.87 (m, 2H), 3.65 (m, 2H), 3.05 (m, 2H), 2.84 (m, 1H), 2.43 (m, 2H) ppm.
Reaction SMILES: Cl.C(OC([N:9]1[CH2:14][CH2:13][CH:12]([O:15][C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][C:17]=2[C:22]([N:24]2[CH2:38][C:27]3=[C:28]4[N:33]([N:34]=[C:26]3[CH2:25]2)[C:32]([CH3:35])=[C:31]([Cl:36])[C:30]([CH3:37])=[N:29]4)=[O:23])[CH:11]([C:39]([F:42])([F:41])[F:40])[CH2:10]1)=O)(C)(C)C>O1CCOCC1>[ClH:36].[Cl:36][C:31]1[C:30]([CH3:37])=[N:29][C:28]2[N:33]([N:34]=[C:26]3[CH2:25][N:24]([C:22]([C:17]4[CH:18]=[CH:19][CH:20]=[CH:21][C:16]=4[O:15][CH:12]4[CH2:13][CH2:14][NH:9][CH2:10][CH:11]4[C:39]([F:41])([F:40])[F:42])=[O:23])[CH2:38][C:27]3=2)[C:32]=1[CH3:35]
Reactant: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCN(C(=O)OC(C)(C)C)CC1C(F)(F)F)C3
Agent: Cl
Solvent: C1COCCO1
Product: Cc1nc2c3c(nn2c(C)c1Cl)CN(C(=O)c1ccccc1OC1CCNCC1C(F)(F)F)C3
Temperature: 25 °C
Reaction time: 16 h
Yield: 122.6 %

Procedure:
A 4M solution of HCl in 1,4-dioxane (4 mL; 16 mmol; 82 eq.) was added to a solution of 4-[2-(6-chloro-5,7-dimethyl-1H,3H-2,4,7a,8-tetraaza-cyclopenta[a]indene-2-carbonyl)-phenoxy]-3-trifluoromethyl-piperidine-1-carboxylic acid tert-butyl ester (116 mg; 0.20 mmol; 1 eq.) in 1,4-dioxane (2 mL) and the reaction mixture was stirred at room temperature for 16 hours then concentrated in vacuo. Crystallization from cold iPrOH afforded the title compound (65 mg, 62%) as a white solid. 1H NMR (DMSO-d6) δ 9.14 (s, 2H), 7.48 (d, J=7.6 Hz, 1H), 7.44-7.34 (m, 1H), 7.30 (d, J=8.5 Hz, 1H), 7.15 (t, J=7.4 Hz, 1H), 5.23 (br s, 1H), 4.87 (d, J=6.3 Hz, 2H), 4.63-4.34 (m, 2H), 3.52-3.38 (m, 1H), 3.31-3.23 (m, 1H), 3.20-2.88 (m, 3H), 2.85 (s, 1.5H), 2.81 (s, 1.5H), 2.62 (s, 1.5H), 2.56 (s, 1.5H), 2.16-2.03 (m, 1H), 2.00-1.86 (m, 1H). HPLC (max plot) 96.5%, Rt 3.12 min. UPLC/MS: (MS+) 494.3 ([M+H]+).
Reaction SMILES: [CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([N+:14]([O-])=O)[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:17][C:18]2[CH:23]=[CH:22][C:21]([O:24][CH2:25][CH3:26])=[CH:20][CH:19]=2)[CH2:3][CH2:2]1>CCOC(C)=O.C(O)(=O)C.[Pd]>[CH:1]1([CH2:4][N:5]2[C:9]3=[N:10][CH:11]=[C:12]([NH2:14])[CH:13]=[C:8]3[N:7]=[C:6]2[CH2:17][C:18]2[CH:19]=[CH:20][C:21]([O:24][CH2:25][CH3:26])=[CH:22][CH:23]=2)[CH2:3][CH2:2]1
Reactant: CCOc1ccc(Cc2nc3cc([N+](=O)[O-])cnc3n2CC2CC2)cc1
Agent: [Pd]
Solvent: CC(=O)O
Solvent: CCOC(C)=O
Product: CCOc1ccc(Cc2nc3cc(N)cnc3n2CC2CC2)cc1
Reaction time: 72 h
Yield: 95 %

Procedure:
To a solution of 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine (1.35 g, 3.84 mmol) in EtOAc (20 mL) and acetic acid (1 mL) at room temperature was added Pd/C (308 mg, 10% grade). The mixture was placed in a Parr apparatus under 35 psi H2. The mixture was shaken for 72 hours. The reaction was filtered over Celite. The filtrate was taken up into 1 M NaOH aqueous solution (25 mL) and EtOAc (50 mL) and the phases separated. The aqueous phase was back-extracted with additional EtOAc (2×50 mL). The organic phases were combined, dried with MgSO4, filtered and concentrated in vacuo. The process gave 1.18 g of the title compound 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-3H-imidazo[4,5-b]pyridin-6-amine (95% yield from 3-(cyclopropylmethyl)-2-[(4-ethoxyphenyl)methyl]-6-nitro-3H-imidazo[4,5-b]pyridine), with purity>95% by HPLC analysis. The residue was used without further purification. 1H-NMR (400 MHz, CDCl3): δ 0.35 (m, 2H), 0.46 (m, 2H), 1.11 (m, 1H), 1.39 (t, J=6.8 Hz, 3H), 3.26 (br s, 2H), 3.98 (m, 4H), 4.25 (s, 2H), 6.83 (d, J=8.8 Hz, 2H), 7.16 (d, J=8.8 Hz, 2H), 7.34 (d, J=2.3 Hz, 1H), 7.87 (d, J=2.3 Hz, 1H). MS (ESI) (M+H)+: 323.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:9](N)=[C:8]2[C:3]=1[CH:4]=[CH:5][N:6]=[CH:7]2.[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=[O:14].[K+].[K+].[Cr](O[Cr]([O-])(=O)=O)([O-])(=O)=O.C(Cl)Cl>O.S(=O)(=O)(O)O>[CH:7]1[C:8]2[C:9](=[O:14])[CH:10]=[CH:11][C:2](=[O:1])[C:3]=2[CH:4]=[CH:5][N:6]=1
Reactant: Nc1ccc(O)c2ccncc12
Reactant: O=[Cr](=O)([O-])O[Cr](=O)(=O)[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: ClCCl
Solvent: O
Product: O=C1C=CC(=O)c2cnccc21

Procedure:
Nineteen grams of 5-hydroxy-8-amino-isoquinoline were dissolved in 450 ml of water and 10 ml of concentrated sulfuric acid. The solution was cooled in an ice bath and then 50 ml of a potassium dichromate solution were added. (The dichromate solution was made by dissolving 50 g of potassium dichromate in 500 ml of water.) Forty ml of concentrated sulfuric acid were added, followed by 190 ml of the potassium dichromate solution, then 20 ml of concentrated sulfuric acid, and finally 400 ml of methylene chloride.
Reaction SMILES: [OH-].[Na+].[F:3][C:4]1[C:19]([N:20]([CH3:29])[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][CH:12]=[CH:11][C:10]=1[Br:15])=[O:7].[F:30][C:31]([F:40])([F:39])[C:32](I)([F:37])[C:33]([F:36])([F:35])[F:34]>CN(C)C=O.O.O.O.O.O.O.O.S([O-])([O-])(=O)=O.[Fe+2]>[F:3][C:4]1[C:19]([N:20]([CH3:29])[C:21](=[O:28])[C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[CH:18][CH:17]=[CH:16][C:5]=1[C:6]([NH:8][C:9]1[CH:14]=[CH:13][C:12]([C:32]([F:37])([C:33]([F:36])([F:35])[F:34])[C:31]([F:40])([F:39])[F:30])=[CH:11][C:10]=1[Br:15])=[O:7]
Reactant: FC(F)(F)C(F)(I)C(F)(F)F
Reactant: CN(C(=O)c1ccccc1)c1cccc(C(=O)Nc2ccccc2Br)c1F
Agent: [Fe+2]
Agent: O=S(=O)([O-])[O-]
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: O
Product: CN(C(=O)c1ccccc1)c1cccc(C(=O)Nc2ccc(C(F)(C(F)(F)F)C(F)(F)F)cc2Br)c1F
Temperature: 25 °C
Reaction time: 3 h
Yield: 11 %

Procedure:
0.47 g (12 mmol) of powdery sodium hydroxide and 0.54 g (1.9 mmol) of iron(II) sulfate heptahydrate were stirred in an ice bath, until the color of the mixture changed to black. Immediately after the discoloration, 3 g of N,N-dimethylformamide were added thereto, and then, a solution obtained by dissolving 0.60 g (1.4 mmol) of 2-fluoro-3-(N-methylbenzamido)-N-(2-bromo-phenyl)benzamide and 0.57 g (1.9 mmol) of heptafluoroisopropyl iodide in 3 g of N,N-dimethylformamide was added thereto, followed by stirring at room temperature for 3 hours. The obtained reaction liquid was filtered through cerite and the residue was washed with 50 mL of ethyl acetate. Then, 40 g of water were added to the resulting reaction liquid, and after performing extraction, the organic layer was dried over magnesium sulfate. Then, magnesium sulfate was filtered off, and the solvent was distilled off under reduced pressure. Thereafter, the condensed residue was purified by silica gel chromatography, to obtain 0.092 g (yield 11%) of the title compound as a white solid.
Reaction SMILES: I[C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=1)[C:5]#[N:6].C([Mg]Cl)(C)C.[Cl:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2(/[CH:26]=[CH:27]/[N+:28]([O-:30])=[O:29])[CH2:25][CH2:24][CH2:23]2)=[CH:18][CH:17]=1>O1CCCC1>[Cl:15][C:16]1[CH:17]=[CH:18][C:19]([C:22]2([CH:26]([C:2]3[CH:3]=[C:4]([CH:7]=[CH:8][CH:9]=3)[C:5]#[N:6])[CH2:27][N+:28]([O-:30])=[O:29])[CH2:23][CH2:24][CH2:25]2)=[CH:20][CH:21]=1
Reactant: O=[N+]([O-])/C=C/C1(c2ccc(Cl)cc2)CCC1
Reactant: N#Cc1cccc(I)c1
Agent: CC(C)[Mg]Cl
Solvent: C1CCOC1
Product: N#Cc1cccc(C(C[N+](=O)[O-])C2(c3ccc(Cl)cc3)CCC2)c1
Temperature: -30 °C

Procedure:
3-Iodobenzonitrile (3.76 g, 16.41 mmol) dissolved in tetrahydrofuran (1.5 ml) was cooled to −30° C. A solution of isopropylmagnesium chloride in tetrahydrofuran (2 M, 8.84 ml, 17.67 mmol) was added dropwise at −30° C. over 25 min. The reaction mixture was cooled to −78° C. A solution of (E)-1-chloro-4(1-(2-nitrovinyl)cyclobutyl)benzene (3.0 g, 12.62 mmol) in tetrahydrofuran (0.5 ml) was added dropwise. Aqueous work-up yielded the desired product which was used without further purification for the next step. Yield: 3.3 g (8.71 mmol, 69%, purity: 90% by HPLC)