Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:22]=[CH:21][C:6]([C:7]([C:9]2[C:18](=[O:19])[C:17]3[C:12](=[CH:13][CH:14]=[C:15]([CH3:20])[N:16]=3)[NH:11][CH:10]=2)=[O:8])=[CH:5][C:4]=1[CH3:23].[Br:24][C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([CH2:31]Br)[CH:26]=1>CN(C)C=O>[Br:24][C:25]1[CH:26]=[C:27]([CH:28]=[CH:29][CH:30]=1)[CH2:31][N:11]1[C:12]2[C:17](=[N:16][C:15]([CH3:20])=[CH:14][CH:13]=2)[C:18](=[O:19])[C:9]([C:7](=[O:8])[C:6]2[CH:21]=[CH:22][C:3]([O:2][CH3:1])=[C:4]([CH3:23])[CH:5]=2)=[CH:10]1
Reactant: COc1ccc(C(=O)c2c[nH]c3ccc(C)nc3c2=O)cc1C
Reactant: BrCc1cccc(Br)c1
Solvent: CN(C)C=O
Product: COc1ccc(C(=O)c2cn(Cc3cccc(Br)c3)c3ccc(C)nc3c2=O)cc1C
Yield: 19.7 %

Procedure:
Experimental conditions analogous to those described for Step 3 of Example 1 were used with 120 mg (0.390 mmol) of 3-(4-Methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one, 116.8 mg (0.467 mmol) of 1-bromo-3-bromomethyl-benzene, 19 mg (0.467 mmol, 60% dispersion in oil), and 1 mL of N,N dimethylformamide. The crude product was purified by flash column chromatography using a gradient of 20-100% ethyl acetate in hexane and further purified on the reverse phase HPLC with a C18 column, gradient of 20-70% acetonitrile—0.1% TFA to yield 36.6 mg of 1-(3-Bromo-benzyl)-3-(4-methoxy-3-methyl-benzoyl)-6-methyl-1H-[1,5]naphthyridin-4-one. LC-MSD, m/z for C25H21BrN2O3 [M+H]: 477.07 LC retention time on HPLC, C18 column gradient 20-95% acetonitrile with 0.1% TFA in 4 minutes: 2.4 min.
Reaction SMILES: [CH:1]1([N:4]2[C:13]3[C:8](=[C:9]([F:17])[C:10]([F:16])=[C:11](F)[C:12]=3[F:14])[C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5]2)[CH2:3][CH2:2]1.[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][NH:27][CH2:26]2.C1CCN2C(=NCCC2)CC1>CN(C=O)C>[F:22][C:23]1[CH:24]=[C:25]2[C:29](=[CH:30][CH:31]=1)[CH2:28][N:27]([C:11]1[C:12]([F:14])=[C:13]3[C:8]([C:7](=[O:18])[C:6]([C:19]([OH:21])=[O:20])=[CH:5][N:4]3[CH:1]3[CH2:3][CH2:2]3)=[C:9]([F:17])[C:10]=1[F:16])[CH2:26]2
Reactant: O=C(O)c1cn(C2CC2)c2c(F)c(F)c(F)c(F)c2c1=O
Reactant: Fc1ccc2c(c1)CNC2
Solvent: CN(C)C=O
Solvent: C1CCC2=NCCCN2CC1
Product: O=C(O)c1cn(C2CC2)c2c(F)c(N3Cc4ccc(F)cc4C3)c(F)c(F)c2c1=O
Yield: 37 %

Procedure:
210 mg of 1-cyclopropyl-5,6,7,8-tetrafluoro-1,4-dihydro-4-oxoquinoline-3-carboxylic acid, 106 mg of 5-fluoroisoindoline, 213 mg of DBU, and 1.5 ml of anhydrous DMF were processed in the same manner as in Example 20 to produce 108 mg of the target compound.
Reaction SMILES: C([O:3][C:4](=[O:15])[CH2:5][C@@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:7][CH:8]([CH3:10])[CH3:9])C.[OH-].[K+:17]>O>[K+:17].[K+:17].[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:5][C:4]([O-:15])=[O:3].[CH3:9][CH:8]([CH3:10])[CH2:7][C@H:6]([CH2:11][N+:12]([O-:14])=[O:13])[CH2:5][C:4]([O-:15])=[O:3]
Reactant: CCOC(=O)C[C@H](CC(C)C)C[N+](=O)[O-]
Agent: [K+]
Agent: [OH-]
Solvent: O
Product: CC(C)C[C@@H](CC(=O)[O-])C[N+](=O)[O-]
Reaction time: 5 h

Procedure:
830 mg of (S)-5-methyl-3-nitromethyl-hexanoic acid ethyl ester (VIII, R1=ethyl) were suspended in 0.8 mL of H2O. 900 mg of 50% aqueous KOH were added. After 5 h at 25° C. conversion was complete (determination by HPLC). The solvent was removed under reduced pressure to give a solid consisting of the title compound and minor amounts of KOH.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]#[N:32])[CH2:27][CH:28]=3)=[CH:9]2)=[CH:4][CH:3]=1.[N-:33]=[N+:34]=[N-:35].[Na+].Cl.C(N(CC)CC)C>COCCOC>[F:1][C:2]1[CH:3]=[CH:4][C:5]([N:8]2[C:16]3[C:11](=[CH:12][C:13]([C:17]4[N:18]=[N:19][N:20]([CH3:22])[N:21]=4)=[CH:14][CH:15]=3)[C:10]([C:23]3[CH2:24][CH2:25][N:26]([CH2:29][CH2:30][C:31]4[NH:35][N:34]=[N:33][N:32]=4)[CH2:27][CH:28]=3)=[CH:9]2)=[CH:6][CH:7]=1
Reactant: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCC#N)CC2)cn3-c2ccc(F)cc2)n1
Reactant: [N-]=[N+]=[N-]
Agent: Cl
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: COCCOC
Product: Cn1nnc(-c2ccc3c(c2)c(C2=CCN(CCc4nnn[nH]4)CC2)cn3-c2ccc(F)cc2)n1
Reaction time: 0.5 h

Procedure:
A mixture of 3-[4-[5-(2-methyltetrazol-5-yl)-1-(4-fluorophenyl)-1H-indol-3-yl]-1,2,3,6-tetrahydropyridin-1-yl]propionitril 15a, (3.5 g), sodium azide (2.5 g), and triethylamine hydrochloride (4.5 g) in DME (25 mL) was boiled at reflux for 16 hours. The solvent was evaporated and water (25 mL) and ethyl acetate (1-2 mL) were added after stirring for 0.5 hours the precipitated title compound 16a, was filtered off and dried. Yield 3.2 g, mp 131-132° C.
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].[SH:7][C:8]1[CH:9]=[C:10]([CH2:14][OH:15])[CH:11]=[CH:12][CH:13]=1.Br[C:17]1[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=1)[C:22]#[N:23]>CC(N(C)C)=O.CCOC(C)=O>[OH:15][CH2:14][C:10]1[CH:9]=[C:8]([S:7][C:17]2[CH:18]=[N:19][CH:20]=[C:21]([CH:24]=2)[C:22]#[N:23])[CH:13]=[CH:12][CH:11]=1
Reactant: N#Cc1cncc(Br)c1
Reactant: OCc1cccc(S)c1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CC(=O)N(C)C
Solvent: CCOC(C)=O
Product: N#Cc1cncc(Sc2cccc(CO)c2)c1
Temperature: 110 °C
Yield: 99.1 %

Procedure:
Add K2CO3 (6.91 g, 50.0 mmol) to a solution of (3-mercaptophenyl)methanol (2.94 g, 21.0 mmol) and 5-bromonicotinonitrile (3.66 g, 20.0 mmol) in DMA (100 mL). Heat the mixture at 110° C. for 2 h. Cool to room temperature. Dilute with EtOAc. Filter. Wash the residue with EtOAc. Concentrate. Dissolve the residue in EtOAc and filter. Concentrate to afford the title compound (4.80 g, quant.): 1H NMR (CDCl3) δ 2.20 (t, J=5.5 Hz, 1H), 4.74 (d, J=5.5 Hz, 2H), 7.38-7.44 (m, 3H), 7.52-7.53 (m, 1H), 7.62 (dd, J=2.0, 2.3 Hz, 1H), 8.62 (dd, J=2.0, 2.3 Hz, 2H).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH2:22])[CH:17]=1)[C:10]([CH3:24])([CH3:23])[CH2:9]2)=[O:5])[CH3:2].[CH3:25][O:26][C:27](=[O:32])[C:28](Br)([CH3:30])[CH3:29].C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O>[CH2:1]([O:3][C:4]([C:6]1[CH:7]=[C:8]2[C:13](=[CH:14][CH:15]=1)[NH:12][CH:11]([C:16]1[CH:21]=[CH:20][CH:19]=[C:18]([NH:22][C:28]([C:27]([O:26][CH3:25])=[O:32])([CH3:30])[CH3:29])[CH:17]=1)[C:10]([CH3:23])([CH3:24])[CH2:9]2)=[O:5])[CH3:2]
Reactant: COC(=O)C(C)(C)Br
Reactant: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(N)c1)N2
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1ccc2c(c1)CC(C)(C)C(c1cccc(NC(C)(C)C(=O)OC)c1)N2
Temperature: 25 °C
Reaction time: 72 h
Yield: 99.8 %

Procedure:
A mixture of 2-(3-amino-phenyl)-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (0.52 g, 1.6 mmol), 2-bromo-2-methyl-propionic acid methyl ester (0.58 g, 3.2 mmol) and potassium carbonate (1.1 g, 8 mmol) in N,N-dimethylformamide (6 mL) was stirred at 25° C. for 72 h. Then the reaction mixture was extracted with ethyl acetate (2×100 mL), washed with water, dried over anhydrous sodium sulfate and concentrated in vacuo to afford 2-[3-(1-methoxycarbonyl-1-methyl-ethylamino)-phenyl]-3,3-dimethyl-1,2,3,4-tetrahydro-quinoline-6-carboxylic acid ethyl ester (678 mg, 100%) as a brown oil which was used for next step without further purification: LC/MS m/e calcd for C25H32N2O4 (M+H)+: 425.54, observed: 425.2.
Reaction SMILES: Cl[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5](=O)[O:6]C1C=CC=CC=1.[NH2:19][NH2:20].O>C(O)C>[NH2:19][N:20]1[CH2:2][CH2:3][N:4]([CH2:14][C:15]([F:18])([F:17])[F:16])[C:5]1=[O:6]
Reactant: NN
Reactant: O=C(Oc1ccccc1)N(CCCl)CC(F)(F)F
Solvent: CCO
Solvent: O
Product: NN1CCN(CC(F)(F)F)C1=O

Procedure:
Into a 250-mL round-bottom flask, was placed a solution of phenyl N-(2-chloroethyl)-N-(2,2,2-trifluoroethyl)carbamate (5.6 g, 19.88 mmol, 1.00 equiv) in ethanol (100 mL), NH2NH2.H2O (10 mL, 80%). The resulting solution was heated to reflux overnight in an oil bath. The resulting mixture was concentrated under vacuum. The residue was applied onto a silica gel column with ethyl acetate (1:1). This resulted in 0.8 g (22%) of 1-amino-3-(2,2,2-trifluoroethyl)imidazolidin-2-one as colorless oil. (ES, m/z): 184 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:3](F)=[CH:4][C:5]([Br:18])=[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)[CH:7]=1.CCO[C:23]([S-:25])=[S:24].[K+].Cl>CN(C)C=O>[Br:18][C:5]1[C:6]([N:8]2[C:12](=[O:13])[N:11]([CH:14]([F:16])[F:15])[C:10]([CH3:17])=[N:9]2)=[CH:7][C:2]2[N:1]=[C:23]([SH:25])[S:24][C:3]=2[CH:4]=1
Reactant: Cc1nn(-c2cc(N)c(F)cc2Br)c(=O)n1C(F)F
Reactant: CCOC(=S)[S-]
Agent: Cl
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1nn(-c2cc3nc(S)sc3cc2Br)c(=O)n1C(F)F
Temperature: 140 °C
Yield: 48 %

Procedure:
30 mL N,N-dimethylformamide was charged with 0.01 mol 1-(5-amino-2-bromo-4-fluorophenyl)-4-(difluoromethyl)-3-methyl-1H-1,2,4-triazol-5(4H)-one. The mixture was stirred until it became clear. Then, 0.02 mol potassium ethyl xanthogenate was added to the mixture in two portions. The mixture was refluxed at 140° C. for 7 h, cooled, and poured into 100 mL ice water slurry. Then, the mixture was acidified with 6 mol/L hydrochloric acid, and a large amount of solids crushed out. The title compound was obtained in a 48% yield as a white solid after filtration.
Reaction SMILES: [F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[NH:27][N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1.Br[CH2:31][CH2:32][OH:33]>>[F:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[C:13]([C:14]3[CH:15]=[CH:16][N:17]=[CH:18][CH:19]=3)=[C:12]([C:20]3[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=3)[N:11]=[C:10]3[N:27]([CH2:31][CH2:32][OH:33])[N:28]=[CH:29][C:9]=23)=[CH:4][CH:3]=1
Reactant: OCCBr
Reactant: Fc1ccc(-c2nc3[nH]ncc3c(-c3ccc(F)cc3)c2-c2ccncc2)cc1
Product: OCCn1ncc2c(-c3ccc(F)cc3)c(-c3ccncc3)c(-c3ccc(F)cc3)nc21

Procedure:
Following a similar procedure to that described in examples 22 and 23, but using 4,6-bis(4-fluorophenyl)-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine (obtained in example 1) instead of 4,6-diphenyl-5-(4-pyridyl)-1H-pyrazolo[3,4-b]pyridine and 2-bromoethanol instead of iodomethane, the title compound was obtained.
Reaction SMILES: [K].[CH2:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[OH:12])[CH2:3][CH2:4][CH3:5].Br[CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]Br>C(O)C>[CH2:2]([C:6]1[CH:11]=[CH:10][CH:9]=[CH:8][C:7]=1[O:12][CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][O:12][C:7]1[CH:8]=[CH:9][CH:10]=[CH:11][C:6]=1[CH2:2][CH2:3][CH2:4][CH3:5])[CH2:3][CH2:4][CH3:5]
Reactant: CCCCc1ccccc1O
Reactant: BrCCCCCCCCBr
Agent: [K]
Solvent: CCO
Product: CCCCc1ccccc1OCCCCCCCCOc1ccccc1CCCC

Procedure:
Two molar equivalents of the potassium salt of butylphenol and one molar equivalent of 1,8-dibromooctane are reacted in ethanol according to the procedure described in Example 1, to afford 1,8-bis (butylphenoxy) octane. Sulfonation with sulfur trioxide or chlorosulfonic acid, followed by neutralization of the disulfonic acid with methanolic potassium hydroxide, affords the potassium sulfonate.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([NH:11][N:12]2[C:21](=[O:22])[C:20]3[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=3)[C:14]([CH2:23][C:24](O)=[O:25])=[N:13]2)=[O:10])=[CH:4][CH:3]=1.[C:27]([NH2:31])([CH3:30])([CH3:29])[CH3:28]>>[C:27]([NH:31][C:24](=[O:25])[CH2:23][C:14]1[C:15]2[C:20](=[CH:19][CH:18]=[CH:17][CH:16]=2)[C:21](=[O:22])[N:12]([NH:11][C:9](=[O:10])[CH2:8][C:5]2[CH:6]=[CH:7][C:2]([Cl:1])=[CH:3][CH:4]=2)[N:13]=1)([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)N
Reactant: O=C(O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12
Product: CC(C)(C)NC(=O)Cc1nn(NC(=O)Cc2ccc(Cl)cc2)c(=O)c2ccccc12

Procedure:
The product of Example 114 and tert-butylamine were treated using a method similar to that described in Example 112 to give the title compound. 1H NMR (300 MHz, DMSO-d6) δ 11.60 (s, 1H), 8.30 (d, J=7.9, 1H), 8.02-7.85 (m, 4H), 7.45-7.37 (m, 4H), 3.78 (s, 2H), 3.67 (s, 2H), 1.25 (s, 9H); MS (ESI−) M/Z 425 (M−H)−.
Reaction SMILES: [O:1]=[C:2]1[N:6]([CH3:7])[C:5]([CH2:14][OH:15])([C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)[C:4](=[O:16])[N:3]1[C:17]1[CH:24]=[CH:23][C:20]([C:21]#[N:22])=[C:19]([C:25]([F:28])([F:27])[F:26])[CH:18]=1.[CH3:29][C:30]([CH3:43])([O:32][C:33]([NH:35][C@@H:36]([CH:40]([CH3:42])[CH3:41])[C:37](O)=[O:38])=[O:34])[CH3:31].Cl.CN(C)CCCN=C=NCC.O>CN(C)C1C=CN=CC=1.ClCCl>[C:21]([C:20]1[CH:23]=[CH:24][C:17]([N:3]2[C:4](=[O:16])[C:5]([CH2:14][O:15][C:37](=[O:38])[C@@H:36]([NH:35][C:33]([O:32][C:30]([CH3:29])([CH3:43])[CH3:31])=[O:34])[CH:40]([CH3:42])[CH3:41])([C:8]3[CH:9]=[CH:10][CH:11]=[CH:12][CH:13]=3)[N:6]([CH3:7])[C:2]2=[O:1])=[CH:18][C:19]=1[C:25]([F:28])([F:26])[F:27])#[N:22]
Reactant: CN1C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)C1(CO)c1ccccc1
Reactant: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccncc1
Agent: Cl
Solvent: ClCCl
Solvent: O
Product: CC(C)[C@H](NC(=O)OC(C)(C)C)C(=O)OCC1(c2ccccc2)C(=O)N(c2ccc(C#N)c(C(F)(F)F)c2)C(=O)N1C

Procedure:
A solution of 0.3 g of 4-[2,5-dioxo-4-(hydroxymethyl)-3-methyl-4-phenylimidazolidin-1-yl]-2-trifluoromethylbenzonitrile, 0.217 g of (2S)-2-[(1,1-dimethylethoxy)carbonylamino]-3-methylbutanoic acid, 0.122 g of 4-dimethylamino pyridine and 0.3 g of 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride in 50 mL of dichloromethane is stirred for 18 hours then poured into water and extracted with ethyl acetate. The organic layer is dried over magnesium sulfate, filtered and evaporated. The crude product is purified by chromatography over silica gel while eluting with 70/30 heptane/ethyl acetate mixture to provide the desired compound.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18](N)=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1.[OH-:24].[Na+].O.Cl>C(O)C>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]2[S:12][C:11]3[CH:13]=[CH:14][C:15]([CH:17]([CH3:21])[C:18]([OH:24])=[O:19])=[CH:16][C:10]=3[C:9](=[O:22])[CH2:8][C:7]=2[CH:23]=1
Reactant: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(N)=O)ccc1S2
Reactant: [OH-]
Agent: Cl
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: COc1ccc2c(c1)CC(=O)c1cc(C(C)C(=O)O)ccc1S2
Temperature: 0 °C
Yield: 34.9 %

Procedure:
A mixture of 0.1 g of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionamide, 1.0 g of sodium hydroxide, 10 ml of water and 20 ml of ethanol was refluxed for 3 hours. After the completion of the reaction, the solvent was removed by distillation to obtain a residue, to which was added ice water, and the mixture was acidified with hydrochloric acid and extracted with chloroform. The extract was washed with water and dried over anhydrous sodium sulfate. The solvent was distilled off to obtain a residue, which was chromatographed over silica gel and eluted with chloroform/benzene (4/1), thereby obtaining a solid substance. This substance was recrystallized from benzene-n-hexane to give 35 mg (yield: 35%) of 2-(10,11-dihydro-8-methoxy-11-oxodibenzo[b,f]thiepin-2-yl)-propionic acid as a powder having a melting point of 152°-153° C.
Reaction SMILES: [Si:1]([O:8][C@@H:9]([CH2:25][O:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH:35]=[CH2:36])[CH3:28])[CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[CH:18]=1)([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].C12BC(CCC1)CCC2.[O:46]1CCCC1>O>[Si:1]([O:8][C@H:9]([CH2:10][N:11]1[CH2:15][CH2:14][CH2:13][C@H:12]1[CH2:16][C:17]1[CH:22]=[CH:21][C:20]([CH3:23])=[C:19]([F:24])[CH:18]=1)[CH2:25][O:26][C@@H:27]([C:29]1[CH:34]=[CH:33][CH:32]=[CH:31][C:30]=1[CH2:35][CH2:36][OH:46])[CH3:28])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: C=Cc1ccccc1[C@@H](C)OC[C@@H](CN1CCC[C@H]1Cc1ccc(C)c(F)c1)O[Si](C)(C)C(C)(C)C
Reactant: C1CCOC1
Agent: B1C2CCCC1CCC2
Solvent: O
Product: Cc1ccc(C[C@@H]2CCCN2C[C@H](CO[C@H](C)c2ccccc2CCO)O[Si](C)(C)C(C)(C)C)cc1F
Temperature: 25 °C
Reaction time: 16 h
Yield: 84 %

Procedure:
(2S)-1-{(2R)-2-{[Tert-butyl(dimethyl)silyl]oxy}-3-[(1R)-1-(2-ethenylphenyl)ethoxy]propyl}-2-(3-fluoro-4-methylbenzyl)pyrrolidine (1.20 g, 2.35 mmol), which had been obtained in Example 180 (180c), was dissolved in tetrahydrofuran (20 mL) and added with a 0.5 M solution of 9-borabicyclo[3,3,1]nonane in tetrahydrofuran (5.6 mL, 2.82 mmol). After raising the temperature to room temperature, the mixture was stirred for 16 hours. Separately, the reaction solution was added dropwise in small portions to a solution in which sodium perborate hydrate (1.40 g, 14 mmol) was dissolved in water (20 mL), and the resulting mixture was stirred at room temperature for 2 hours. The reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated brine and dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure. The residue was purified by basic silica gel chromatography (n-hexane/ethyl acetate=3/1) to give the title compound as a colorless oily substance (1.05 g, yield 84%).
Reaction SMILES: [CH3:1][C:2]1[CH:3]=[C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH3:17])[CH:5]=[CH:6][C:7]=1[N+:8]([O-])=O.C.[H][H]>C(O)C>[NH2:8][C:7]1[CH:6]=[CH:5][C:4]([N:11]2[CH:15]=[C:14]([CH3:16])[N:13]=[C:12]2[CH3:17])=[CH:3][C:2]=1[CH3:1]
Reactant: Cc1cn(-c2ccc([N+](=O)[O-])c(C)c2)c(C)n1
Reactant: [H][H]
Solvent: CCO
Product: Cc1cn(-c2ccc(N)c(C)c2)c(C)n1

Procedure:
The following compound was prepared similarly to Preparation 56, using 1-(3-methyl-4-nitrophenyl)-2,4-dimethylimidazole and 5% palladised charcoal/H2 as the starting materials and ethanol as the solvent. The crude solid melted at 78°-82°. Recrystallisation from toluene gave 1-(4-amino-3-methylphenyl)-2,4-dimethylimidazole, m.p. 118°-120° C.
Reaction SMILES: Cl[CH2:2][C:3]1[NH:4][C:5]2[CH:10]=[C:9]([C:11]3[CH:16]=[CH:15][C:14]([O:17][CH2:18][CH3:19])=[C:13]([C:20]([F:23])([F:22])[F:21])[CH:12]=3)[N:8]=[C:7]([C:24]#[N:25])[C:6]=2[N:26]=1.[CH3:27][N:28]1[CH2:33][CH2:32][NH:31][CH2:30][CH2:29]1>CN(C=O)C.CO>[CH2:18]([O:17][C:14]1[CH:15]=[CH:16][C:11]([C:9]2[N:8]=[C:7]([C:24]#[N:25])[C:6]3[N:26]=[C:3]([CH2:2][N:31]4[CH2:32][CH2:33][N:28]([CH3:27])[CH2:29][CH2:30]4)[NH:4][C:5]=3[CH:10]=2)=[CH:12][C:13]=1[C:20]([F:23])([F:22])[F:21])[CH3:19]
Reactant: CCOc1ccc(-c2cc3[nH]c(CCl)nc3c(C#N)n2)cc1C(F)(F)F
Reactant: CN1CCNCC1
Solvent: CN(C)C=O
Solvent: CO
Product: CCOc1ccc(-c2cc3[nH]c(CN4CCN(C)CC4)nc3c(C#N)n2)cc1C(F)(F)F
Temperature: 120 °C
Yield: 34 %

Procedure:
2-Chloromethyl-6-(4-ethoxy-3-trifluoromethyl-phenyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile (20 mg, 0.053 mmol) was dissolved in DMF and N-methyl piperazine (26 mg, 0.26 mmol) was added. The mixture was heated to 120° C. for five minutes in a Smith Creator microwave. Mixture was diluted with methanol (4 ml) and loaded onto an SCX cartridge. Cartridge was washed three times with methanol (5 ml) then eluted with 2M methanolic ammonia. Methanolic ammonia was removed by evaporation under reduced pressure then mixture was prep HPLC purified to afford 8 mg of 6-(4-ethoxy-3-trifluoromethyl-phenyl)-2-(4-methyl-piperazin-1-ylmethyl)-1H-imidazo[4,5-c]pyridine-4-carbonitrile as a white solid. 1H NMR (MeOH) δ 8.28-8.20 (m, 2H), 8.13 (s, 1H), 7.26 (d, 1H), 4.22 (q, 2H), 3.92 (s, 2H), 2,67 (m, 8H), 2.38 (s, 3H), 1.45 (t, 3H). MS m/z 445.5 (M+1).
Reaction SMILES: [CH3:1][C:2]1[O:3][C:4]([C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[C:5]([C:7]2[CH:13]=[CH:12][C:10]([NH2:11])=[CH:9][CH:8]=2)[N:6]=1.[CH2:33]([N:35]=[C:36]=[O:37])[CH3:34]>>[CH2:33]([NH:35][C:36]([NH:11][C:10]1[CH:9]=[CH:8][C:7]([C:5]2[N:6]=[C:2]([CH3:1])[O:3][C:4]=2[C:14]2[CH:19]=[CH:18][N:17]=[C:16]3[N:20]([S:23]([C:26]4[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=4)(=[O:25])=[O:24])[CH:21]=[CH:22][C:15]=23)=[CH:13][CH:12]=1)=[O:37])[CH3:34]
Reactant: Cc1ccc(S(=O)(=O)n2ccc3c(-c4oc(C)nc4-c4ccc(N)cc4)ccnc32)cc1
Reactant: CCN=C=O
Product: CCNC(=O)Nc1ccc(-c2nc(C)oc2-c2ccnc3c2ccn3S(=O)(=O)c2ccc(C)cc2)cc1

Procedure:
Following the procedure described for Intermediate 31 with 4-(2-methyl-5-{1-[(4-methylphenyl)sulfonyl]-1H-pyrrolo[2,3-b]pyridin-4-yl}-1,3-oxazol-4-yl)aniline and ethyl isocyanate provided the title compound. ESMS [M+H]+: 516.2
Reaction SMILES: [C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19]O)[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(Br)(Br)(Br)[Br:22].C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.C(OCC)C>C(Cl)Cl>[C:1]1([S:7]([N:10]2[C:18]3[C:13](=[C:14]([CH2:19][Br:22])[CH:15]=[CH:16][CH:17]=3)[CH:12]=[CH:11]2)(=[O:9])=[O:8])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: BrC(Br)(Br)Br
Reactant: O=S(=O)(c1ccccc1)n1ccc2c(CO)cccc21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOCC
Solvent: ClCCl
Product: O=S(=O)(c1ccccc1)n1ccc2c(CBr)cccc21
Reaction time: 1 h
Yield: 86.4 %

Procedure:
To a stirred solution of 0.78 g (2.71 mmol) of alcohol (30) and 1.13 g (3.41 mmol) of carbontetrabromide in 10 ml of CH2Cl2 at 0° C. was added 1.07 g (4.08 mmol) of triphenylphosphine. After one hour at 0° C., the solvent was removed under reduced pressure. The residue was flash chromatographed on silica, eluting CH2Cl2. After trituration with diethyl ether there was obtained 0.82 g (80% yield) of 1-benzenesulfonyl-4-bromomethyl-1H-indole (31) as a white solid, m.p. 127°-128° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([O:13]C)[CH:7]=2)#[N:2].[Cl-].[Cl-].[Cl-].[Al+3]>C1C=CC=CC=1>[C:1]([C:3]1[CH:4]=[N:5][C:6]2[C:11]([CH:12]=1)=[CH:10][CH:9]=[C:8]([OH:13])[CH:7]=2)#[N:2]
Reactant: COc1ccc2cc(C#N)cnc2c1
Agent: [Al+3]
Agent: [Cl-]
Solvent: c1ccccc1
Product: N#Cc1cnc2cc(O)ccc2c1
Reaction time: 1 h
Yield: 66.6 %

Procedure:
3-Cyano-7-methoxyquinoline (380 mg, 2.1 mmol) was suspended in benzene (10 ml), aluminium trichloride (826 mg, 6.2 mmol) was added and the mixture heated at reflux for 30 minutes. More aluminium trichloride (275 mg, 2.1 mmol) was added and the mixture refluxed for a further 2 hours. The solvent was evaporated, the dark green solid was added to ice and extracted with ethyl acetate. The organic phase was washed with brine, dried (MgSO4) and evaporated. The solid was found to contain some aluminium salts which were removed as follows. The solid was dissolved in dichloromethane (200 ml) was stirred vigorously with a saturated sodium hydrogen carbonate solution for 1 hour. The product was collected by filtration of the aqueous phase and dried over phosphorus pentoxide under vacuum to give 3-cyano-7-hydroxyquinoline (238 mg, 68%).
Reaction SMILES: [CH3:1][NH:2][CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6].[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23](=[O:37])[C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32](Cl)[N:31]=4)=[CH:26][CH:25]=3)[CH:18]=2)[NH:13][CH:12]=1)#[N:10]>>[C:9]([C:11]1[C:19]2[C:14](=[CH:15][CH:16]=[C:17]([CH2:20][CH2:21][NH:22][C:23]([C:24]3[CH:29]=[CH:28][C:27]([C:30]4[CH:35]=[CH:34][N:33]=[C:32]([N:2]([CH3:1])[CH2:3][CH2:4][S:5]([OH:8])(=[O:7])=[O:6])[N:31]=4)=[CH:26][CH:25]=3)=[O:37])[CH:18]=2)[NH:13][CH:12]=1)#[N:10]
Reactant: CNCCS(=O)(=O)O
Reactant: N#Cc1c[nH]c2ccc(CCNC(=O)c3ccc(-c4ccnc(Cl)n4)cc3)cc12
Product: CN(CCS(=O)(=O)O)c1nccc(-c2ccc(C(=O)NCCc3ccc4[nH]cc(C#N)c4c3)cc2)n1

Procedure:
Using 2-methylamino-ethyl sulphonic acid and N-[2-(3-Cyano-1H-indol-5-yl)-ethyl]-4-[2-chloro-pyrimidin-4-yl]-benzamide (reference example 1az) as substrates.