Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[CH:8][CH:7]=[CH:6]2.OO.COC1C=C2C(=CC=1)[N+:23]([O-])=[CH:22]C=C2.C(Cl)(=O)C1C=CC=CC=1>[Ag]C#N.C(O)(=O)C>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:22]#[N:23])[CH:7]=[CH:6]2
Reactant: COc1ccc2ncccc2c1
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Agent: N#C[Ag]
Agent: OO
Solvent: CC(=O)O
Solvent: O=C(Cl)c1ccccc1
Product: COc1ccc2nc(C#N)ccc2c1

Procedure:
Compounds of formula II can be manufactured starting from commercially available 6-methoxy-quinoline (1) that can converted to the N-oxide 2 by reaction with hydrogen peroxide and a solvent like acetic acid under refluxing conditions. The 6-methoxy-quinoline-1-oxide is reacted with silver cyanide and benzoyl chloride to obtain the 6-methoxy-quinoline-2-carbonitrile 3 via a modification of the Reisset'sche reaction (Ber., 38, 1610 (1905). Hydrolysis of the cyano group can be affected by employing an acidic or basic medium. We find it convenient to use a base like sodium hydroxide and after acidic treatment of the mixture we obtained the corresponding 6-methoxy-quinoline-2-carboxylic acid 4. Removal of the methyl group with an acid like hydrobromic acid 48% in water gives 6-hydroxy-quinoline-2-carboxylic acid (5). The acid can be esterified with an alcohol like ethanol and an acid like sulfuric acid to yield the 6-hydroxy-quinoline-2-carboxylic acid ester II, for example 6-hydroxy-quinoline-2-carboxylic acid ethyl ester (IIa).
Reaction SMILES: Br[CH2:2][C:3]1[NH:8][C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)=[N:6][CH:5]([C:15]2[CH:20]=[CH:19][C:18]([F:21])=[CH:17][C:16]=2[Cl:22])[C:4]=1[C:23]([O:25][CH2:26][CH3:27])=[O:24].[NH:28]1[CH2:33][CH2:32][O:31][CH2:30][CH:29]1[C:34]([OH:36])=[O:35]>>[Cl:22][C:16]1[CH:17]=[C:18]([F:21])[CH:19]=[CH:20][C:15]=1[CH:5]1[N:6]=[C:7]([C:9]2[CH:14]=[CH:13][CH:12]=[CH:11][N:10]=2)[NH:8][C:3]([CH2:2][N:28]2[CH2:33][CH2:32][O:31][CH2:30][CH:29]2[C:34]([OH:36])=[O:35])=[C:4]1[C:23]([O:25][CH2:26][CH3:27])=[O:24]
Reactant: CCOC(=O)C1=C(CBr)NC(c2ccccn2)=NC1c1ccc(F)cc1Cl
Reactant: O=C(O)C1COCCN1
Product: CCOC(=O)C1=C(CN2CCOCC2C(=O)O)NC(c2ccccn2)=NC1c1ccc(F)cc1Cl
Yield: 54.6 %

Procedure:
Ethyl 6-(bromomethyl)-4-(2-chloro-4-fluorophenyl)-2-(pyridin-2-yl)-1,4-dihydropyrimidine-5-carboxylate (0.69 g, 1.53 mmol) (The compound was synthesized according to the procedure as described in WO2010069147) was reacted with morpholine-3-carboxylic acid (0.2 g, 1.53 mmol) according to the procedure as described in Example 28 to give the title compound as a yellow solid (0.42 g, 55%). The compound was characterized by the following spectroscopic data:
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([OH:12])=[O:11])[CH:8]=2)[CH:3]=[N:2]1.[C:13](=O)([O-])[O-].[Na+].[Na+].IC.C(=O)(O)[O-].[Na+]>CN(C)C=O>[NH:1]1[C:9]2[C:4](=[CH:5][CH:6]=[C:7]([C:10]([O:12][CH3:13])=[O:11])[CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O)c1ccc2cn[nH]c2c1
Reactant: O=C([O-])[O-]
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CI
Solvent: CN(C)C=O
Product: COC(=O)c1ccc2cn[nH]c2c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 90.5 %

Procedure:
To a solution of 1H-indazole-6-carboxylic acid (3.00 g, 18.5 mmol) in N,N-dimethylformamide (46 mL) was added sodium carbonate (2.06 g, 19.4 mmol), followed by iodomethane (2.75 g, 1.21 mL, 19.4 mmol) dropwise. The mixture was stirred at room temperature overnight. The mixture was poured into half saturated sodium bicarbonate and extracted with ethyl acetate three times. The combined organic layers were washed with brine, dried over sodium sulfate, filtered and concentrated in vacuo to afford a brown oil. This residue was purified by flash column chromatography (12-100% ethyl acetate/heptanes) to afford methyl 1H-indazole-6-carboxylate as a yellow solid (2.95 g, 90%). 1H NMR (400 MHz, CDCl3, δ): 10.40 (br. s., 1H), 8.26 (s, 1H), 8.13 (s, 1H), 7.84 (d, J=8.4 Hz, 1H), 7.79 (d, J=8.4 Hz, 1H), 3.96 (s, 3H).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][C:9]1[CH:17]=[CH:16][CH:15]=[C:14]2[C:10]=1[CH:11]=[CH:12][N:13]2[C:18]([C:25]1[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=1)([CH2:23][CH3:24])[C:19](OC)=[O:20])=[O:7])([CH3:4])([CH3:3])[CH3:2].[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Cl:31][C:28]1[CH:27]=[CH:26][C:25]([C:18]([N:13]2[C:14]3[C:10](=[C:9]([NH:8][C:6](=[O:7])[O:5][C:1]([CH3:4])([CH3:3])[CH3:2])[CH:17]=[CH:16][CH:15]=3)[CH:11]=[CH:12]2)([CH2:23][CH3:24])[CH2:19][OH:20])=[CH:30][CH:29]=1
Reactant: CCC(C(=O)OC)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: C1CCOC1
Solvent: O
Product: CCC(CO)(c1ccc(Cl)cc1)n1ccc2c(NC(=O)OC(C)(C)C)cccc21
Temperature: 25 °C
Reaction time: 4 h

Procedure:
To a solution of methyl 2-(4-(tert-butoxycarbonylamino)-1H-indol-1-yl)-2-(4-chlorophenyl)butanoate (5 g, 11.3 mmol), as described in Example 3 Step A, in tetrahydrofuran (50 mL) was added lithium aluminium hydride (644 mg, 16.95 mmol) at 0° C. The mixture was gradually warmed to room temperature and stirred for 4 h. Water (10 mL) was carefully added to the reaction mixture, then extracted with ethyl acetate. The combined organic layers were washed with brine (30 mL), dried over anhydrous sodium sulfate, filtered and concentrated. The crude product was purified by silica gel chromatography eluting with PE/EA (30/1 to 10/1, v/v) to give the title compound as a colorless amorphous solid. LC/MS m/z=359.9 [M-tBu+H]+.
Reaction SMILES: C(O)=O.C([O:11][CH:12]1[CH2:15][CH:14]([C:16]2[C:21](=[O:22])[NH:20][N:19]3[C:23]([C:26]4[CH:31]=[CH:30][CH:29]=[CH:28][C:27]=4[F:32])=[N:24][N:25]=[C:18]3[CH:17]=2)[CH2:13]1)C1C=CC=CC=1.C([O-])=O.[NH4+]>CO>[F:32][C:27]1[CH:28]=[CH:29][CH:30]=[CH:31][C:26]=1[C:23]1[N:19]2[NH:20][C:21](=[O:22])[C:16]([CH:14]3[CH2:13][CH:12]([OH:11])[CH2:15]3)=[CH:17][C:18]2=[N:25][N:24]=1
Reactant: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(OCc2ccccc2)C1
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Solvent: O=CO
Product: O=c1[nH]n2c(-c3ccccc3F)nnc2cc1C1CC(O)C1
Temperature: 60 °C
Reaction time: 2 h

Procedure:
Formic acid (8 ml) was added to a solution of 7-(3-benzyloxycyclobutyl)-3-(2-fluorophenyl)-1,2,4-triazolo[4,3-b]pyridazin-6-one (0.64 g, 1.64 mmol) and ammonium formate (1.034 g, 16.4 mmol) in methanol (40 ml). The solution was flushed with nitrogen and 10% palladium on carbon (0.3 g) was added. The resulting solution was stirred under an atmosphere of nitrogen for 2 hours at 60° C. The reaction was cooled, filtered, and concentrated under vacuum. The residue was purified by chromatography on silica using 0-10% methanol/dichloromethane as eluent to give the required product as a white solid. Data for the title compound: 1H NMR (360 MHz, DMSO), cis and traits isomers present in 5.5:1 ratio, δ1.89-1.98 (1.7H, m), 2.21-2.29 (0.3H, m), 2.40-2.48 (0.3H, m), 2.55-2.65 (1.7H, m), 2.88-3.00 (1H, m), 4.06-4.14 (0.85H, m), 4.20-4.30 (0.15H, m), 7.38-7.47 (2H, m), 7.60-7.65 (1H, m), 7.80-7.85 (1H, m), 7.97 (0.85H, s), 8.12 (0.15H, s); MS (ES+) m/e 301 [MH]+.
Reaction SMILES: [Br:1][C:2]1[C:3](Cl)=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8].[NH2:17][NH2:18]>CC(N(C)C)=O>[Br:1][C:2]1[C:3]([NH:17][NH2:18])=[N:4][C:5]([N:9]2[C:13]([CH3:14])=[CH:12][CH:11]=[C:10]2[CH3:15])=[N:6][C:7]=1[CH3:8]
Reactant: Cc1nc(-n2c(C)ccc2C)nc(Cl)c1Br
Reactant: NN
Solvent: CC(=O)N(C)C
Product: Cc1nc(-n2c(C)ccc2C)nc(NN)c1Br
Temperature: 100 °C

Procedure:
To a microwave vial was added 5-bromo-4-chloro-2-(2,5-dimethyl-1H-pyrrol-1-yl)-6-methylpyrimidine (4.95 g, 16.5 mmol) and hydrazine (0.57 ml, 18.1 mmol) hunig's base 95.74 ml, 32.9 mmol) and dimethyacetamide (24 ml) at R.T. After heating in the microwave for 30 mins at 100° C. The reaction mixture was concentrated under reduced pressure to dryness and the residue was trituarated with 1:1 ethyl acetate:methanol to obtain the desired product as a white solid weighted 2820 mg. The mother liquor was purified by column chromatography eluted with 30% EtOAc:hexane to give an additional batch of the desired product. Both lots were combined to give the titled compound as a white solid weighted 3620 mg 74%
Reaction SMILES: FC(F)(F)C1C=CC(CBr)=CC=1.Br[CH2:14][CH2:15][C:16]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[NH:18][CH:17]=1.[CH3:25][C:26]1[N:27]=[C:28]([N:36]2[CH2:40][CH2:39][NH:38][C:37]2=[O:41])[S:29][C:30]=1[C:31]([O:33][CH2:34][CH3:35])=[O:32]>>[NH:18]1[C:19]2[C:24](=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:16]([CH2:15][CH2:14][N:38]2[CH2:39][CH2:40][N:36]([C:28]3[S:29][C:30]([C:31]([O:33][CH2:34][CH3:35])=[O:32])=[C:26]([CH3:25])[N:27]=3)[C:37]2=[O:41])=[CH:17]1
Reactant: BrCCc1c[nH]c2ccccc12
Reactant: CCOC(=O)c1sc(N2CCNC2=O)nc1C
Agent: FC(F)(F)c1ccc(CBr)cc1
Product: CCOC(=O)c1sc(N2CCN(CCc3c[nH]c4ccccc34)C2=O)nc1C
Yield: 40 %

Procedure:
Following the procedure as described in Example 13, making variations as required to replace 4-(trifluoromethyl)benzyl bromide with 3-(2-bromoethyl)-1H-indole to react with ethyl 4-methyl-2-(2-oxoimidazolidin-1-yl)thiazole-5-carboxylate, the title compound was obtained as a colorless solid in 40% yield: 1H NMR (300 MHz, CDC3) δ 8.09 (s, 1H), 7.63 (d, J=7.8 Hz, 1H), 7.39-7.36 (m, 1H), 7.24-7.09 (m, 3H), 4.29 (q, J=7.1 Hz, 2H), 4.04-3.99 (m, 2H), 3.69 (t, J=7.2 Hz, 2H), 3.52-3.46 (m, 2H), 3.08 (t, J=7.1 Hz, 2H), 2.62 (s, 3H), 1.34 (t, J=7.1 Hz, 3H); MS (ES+) m/z 399.3 (M+1).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH2:11])[S:10][C:6]=2[CH:5]=1)[CH3:2].[C:14]1([CH:20]([CH2:24][CH3:25])[C:21](O)=[O:22])[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1.C(N(CC)CC)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH2:1]([O:3][C:4]1[CH:13]=[CH:12][C:7]2[N:8]=[C:9]([NH:11][C:21](=[O:22])[CH:20]([C:14]3[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=3)[CH2:24][CH3:25])[S:10][C:6]=2[CH:5]=1)[CH3:2]
Reactant: CCOc1ccc2nc(N)sc2c1
Reactant: CCC(C(=O)O)c1ccccc1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(CC)CC
Solvent: CN(C)C=O
Product: CCOc1ccc2nc(NC(=O)C(CC)c3ccccc3)sc2c1
Reaction time: 16 h

Procedure:
6-Ethoxy-benzothiazol-2-ylamine (39 mg, 0.20 mmol) and 2-phenyl-butyric acid (33 mg, 0.20 mmol) were dissolved in N,N-dimethylformamide (1 mL) containing triethylamine (84.1 μL, 0.600 mmol). O-(7-Azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (84 mg, 0.22 mmol) was added and the solution was allowed to stir for 16 hours. The crude product was purified by reverse-phase preparative liquid chromatography (17 mg, 0.050 mmol, 25%), ESI-MS m/z calc. 340.1, found 340.9 (M+1)+ Retention time 3.55 minutes.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH2:8][C@H:9]([N:22]2[CH2:30][C:29]3[C:24](=[CH:25][CH:26]=[C:27]([C:31]4[N:35]([CH3:36])[N:34]=[CH:33][CH:32]=4)[CH:28]=3)[C:23]2=[O:37])[CH2:10][N:11]2[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]2=[O:21])[CH:5]=[CH:6][CH:7]=1.[B-](F)(F)(F)[F:39].[B-](F)(F)(F)F.C1[N+]2(CCl)CC[N+](F)(CC2)C1>O1CCCC1.O>[F:39][C:32]1[CH:33]=[N:34][N:35]([CH3:36])[C:31]=1[C:27]1[CH:28]=[C:29]2[C:24](=[CH:25][CH:26]=1)[C:23](=[O:37])[N:22]([C@@H:9]([CH2:8][C:4]1[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=1)[CH2:10][N:11]1[C:19](=[O:20])[C:18]3[C:13](=[CH:14][CH:15]=[CH:16][CH:17]=3)[C:12]1=[O:21])[CH2:30]2
Reactant: F[B-](F)(F)F
Reactant: Cn1nccc1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Agent: F[N+]12CC[N+](CCl)(CC1)CC2
Solvent: O
Solvent: C1CCOC1
Product: Cn1ncc(F)c1-c1ccc2c(c1)CN([C@@H](Cc1cccc(F)c1)CN1C(=O)c3ccccc3C1=O)C2=O
Temperature: 70 °C
Reaction time: 1 h
Yield: 30 %

Procedure:
To a solution of 2-{(2S)-3-(3-fluorophenyl)-2-[5-(1-methyl-1H-pyrazol-5-yl)-1-oxo-1,3-dihydro-2H-isoindol-2-yl]propyl}-1H-isoindole-1,3(2H)-dione (200.0 mg, 0.4044 mmol) [prepared in Example 1] in tetrahydrofuran (7 mL) and water (0.5 mL) was added SELECTFLUOR® fluorinating reagent (1-chloromethyl-4-fluoro-1,4-diazoniabicyclo [2.2.2]-octane bis(tetrafluoroborate) (212.0 mg, 0.60 mmol). The reaction mixture was sealed and stirred at 70° C. for 1 h and then additional SELECTFLUOR® fluorinating reagent (212.0 mg, 0.60 mmol) was added. The reaction mixture was sealed again and stirred at 70° C. overnight. The reaction mixture was then filtered and the filtrate was concentrated under reduced pressure. The residue was purified by prep.—HPLC. The purification afforded 61 mg (30% yield) of the desired product as white solid. LC/MS found: 513.0 (M+1)+.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][OH:16])=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1.C(OC([N:25]1[C:33]2[N:28]([C:29](=[O:35])[N:30]=[C:31](Cl)[CH:32]=2)[CH2:27][C:26]1([CH3:37])[CH3:36])=O)(C)(C)C>>[Cl:1][C:2]1[CH:3]=[C:4]([O:8][C:9]2[CH:14]=[CH:13][C:12]([CH2:15][O:16][C:31]3[CH:32]=[C:33]4[NH:25][C:26]([CH3:37])([CH3:36])[CH2:27][N:28]4[C:29](=[O:35])[N:30]=3)=[CH:11][C:10]=2[F:17])[CH:5]=[N:6][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1c2cc(Cl)nc(=O)n2CC1(C)C
Reactant: OCc1ccc(Oc2cncc(Cl)c2)c(F)c1
Product: CC1(C)Cn2c(cc(OCc3ccc(Oc4cncc(Cl)c4)c(F)c3)nc2=O)N1

Procedure:
The title compound was prepared by a procedure similar to that described for E9 starting from (4-((5-chloropyridin-3-yl)oxy)-3-fluorophenyl)methanol and tert-butyl-7-chloro-2,2-dimethyl-5-oxo-2,3-dihydroimidazo[1,2-c]pyrimidine-1(5H)-carboxylate.
Reaction SMILES: C([O:8][C:9]1[CH:14]=[C:13]([O:15]CC2C=CC=CC=2)[C:12]([C:23]2[N:27]([CH2:28][CH2:29][CH2:30][CH3:31])[N:26]=[N:25][N:24]=2)=[CH:11][C:10]=1[C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([C:38](O)=[O:39])[CH:33]=1)C1C=CC=CC=1.[N:41]1([CH:46]2[CH2:51][CH2:50][NH:49][CH2:48][CH2:47]2)[CH2:45][CH2:44][CH2:43][CH2:42]1>>[CH2:28]([N:27]1[C:23]([C:12]2[C:13]([OH:15])=[CH:14][C:9]([OH:8])=[C:10]([C:32]3[CH:37]=[CH:36][CH:35]=[C:34]([C:38]([N:49]4[CH2:50][CH2:51][CH:46]([N:41]5[CH2:45][CH2:44][CH2:43][CH2:42]5)[CH2:47][CH2:48]4)=[O:39])[CH:33]=3)[CH:11]=2)=[N:24][N:25]=[N:26]1)[CH2:29][CH2:30][CH3:31]
Reactant: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)O)c2)c(OCc2ccccc2)cc1OCc1ccccc1
Reactant: C1CCN(C2CCNCC2)C1
Product: CCCCn1nnnc1-c1cc(-c2cccc(C(=O)N3CCC(N4CCCC4)CC3)c2)c(O)cc1O

Procedure:
This product was synthesized using 2′,4′-bis-benzyloxy-5′-(1-butyl-1H-tetrazol-5-yl)-biphenyl-3-carboxylic acid and 4-(1-pyrrolidinyl)piperidine as described in general procedure D. LCMS: 491 [M+H].
Reaction SMILES: Cl.[NH2:2][OH:3].C(=O)(O)[O-].[Na+].O.[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41]#[N:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1>C(O)C>[Cl:10][C:11]1[CH:12]=[C:13]([C:17]2[C:22]3[N:23]([CH2:33][C@H:34]4[CH2:39][CH2:38][C@H:37]([CH3:40])[CH2:36][CH2:35]4)[C:24]([N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH2:31][F:32])=[N:25][C:21]=3[CH:20]=[C:19]([C:41](=[N:2][OH:3])[NH2:42])[N:18]=2)[CH:14]=[N:15][CH:16]=1
Reactant: NO
Reactant: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C#N)nc(-c4cncc(Cl)c4)c32)CC1
Agent: Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CCO
Product: C[C@H]1CC[C@H](Cn2c(N3CCC[C@H]3CF)nc3cc(C(N)=NO)nc(-c4cncc(Cl)c4)c32)CC1
Temperature: 100 °C
Reaction time: 0.25 h

Procedure:
Hydroxylamine hydrochloride (108 mg, 1.56 mmol), sodium bicarbonate (196 mg, 2.34 mmol), and water (1.56 mL) were combined in a vial and stirred for 15 minutes. This solution was added to a vial containing 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carbonitrile (364 mg, 0.78 mmol) dissolved in ethanol (3.6 mL). The mixture was sealed and heated at 100° C. for 1 hour. The reaction was cooled to room temperature, quenched with water, and extracted with ethyl acetate (2×). The combined organic layers were dried over sodium sulfate, filtered, and concentrated to afford 4-(5-chloropyridin-3-yl)-2-[(2S)-2-(fluoromethyl)pyrrolidin-1-yl]-N′-hydroxy-3-[(trans-4-methylcyclohexyl)methyl]-3H-imidazo[4,5-c]pyridine-6-carboximidamide. MS ESI calc'd. for C25H31ClFN7O [M+H]+ 500. found 500.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([O:12][CH3:13])[C:5]([CH2:10]Br)=[C:6]([CH2:8]Br)[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[C:20]([NH2:39])([C:33]1[CH:38]=[CH:37][CH:36]=[CH:35][CH:34]=1)([C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][CH:28]=1)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1.O>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]2[C:5]([CH2:10][N:39]([C:20]([C:21]3[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=3)([C:33]3[CH:34]=[CH:35][CH:36]=[CH:37][CH:38]=3)[C:27]3[CH:28]=[CH:29][CH:30]=[CH:31][CH:32]=3)[CH2:8]2)=[C:4]([O:12][CH3:13])[CH:3]=1
Reactant: NC(c1ccccc1)(c1ccccc1)c1ccccc1
Reactant: COc1cc(Br)cc(CBr)c1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COc1cc(Br)cc2c1CN(C(c1ccccc1)(c1ccccc1)c1ccccc1)C2
Temperature: 90 °C
Reaction time: 8 h
Yield: 53.6 %

Procedure:
4.95 g of 5-bromo-1,2-bis(bromomethyl)-3-methoxybenzene (3-19) was dissolved in 150 ml of anhydrous DMF, to which 5.50 g of potassium carbonate and 4.30 g of tritylamine, and under an argon atmosphere, the resulting mixture was stirred at 90° C. for 8 hours. The reaction solution was poured into water, and extract with chloroform and the resulting organic layer was washed with saturated salt water, and thereafter, the resulting organic layer was dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure, and thereafter, the resulting residue was recrystallized with 2-propanol to obtain 3.35 g of 6-bromo-4-methoxy-2-tritylisoindoline (3-20).
Reaction SMILES: [C:1]([NH:4][C:5]1[CH:14]=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2].C(OC(=O)C)(=O)C.[N+:25]([O-])([OH:27])=[O:26]>C(O)(=O)C>[C:1]([NH:4][C:5]1[C:14]([N+:25]([O-:27])=[O:26])=[CH:13][C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([O:15][CH2:16][CH3:17])[CH:6]=1)(=[O:3])[CH3:2]
Reactant: O=[N+]([O-])O
Reactant: CCOc1cc(NC(C)=O)ccc1C(=O)OC
Solvent: CC(=O)O
Solvent: CC(=O)OC(C)=O
Product: CCOc1cc(NC(C)=O)c([N+](=O)[O-])cc1C(=O)OC
Temperature: 50 °C
Reaction time: 1 h
Yield: 47.9 %

Procedure:
A mixture of 118.6 parts of methyl 4-(acetylamino)-2-ethoxybenzoate, 200 parts of acetic acid and 156 parts of acetic acid anhydride was stirred and heated to 50° C. After cooling to 15° C. (ice-bath) there were added dropwise 47.1 parts of fuming nitric acid 100% using a bromine funnel: an exothermic reaction occured. The temperature was kept at about 20° C. by cooling in an ice-bath. Upon completion, the temperature was allowed to rise to 40° C. and stirring was continued at this temperature for one hour. If necessary the whole was cooled with ice-water to keep the temperature at about 40° C. When the exothermic reaction was ceased, the whole was allowed to cool for one hour and was further cooled to 0° C. The reaction mixture was poured onto ice-water while stirring. Upon stirring for one hour, the precipitated product was filtered off and dissolved in 1950 parts of dichloromethane. The solution was washed twice with 500 parts of water, dried, filtered and evaporated. The residue was crystallized overnight at room temperature from 2-propanol. The product was filtered off, washed with 2,2'-oxybispropane and dried, yielding 67.6 parts (47.9%) of methyl 4-(acetylamino)-2-ethoxy-5-nitrobenzoate; mp. 110° C. (intermediate 32).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22].[F-].[Cs+].[CH2:25]([O:29][C:30]1[CH:35]=[CH:34][C:33]([O:36][CH3:37])=[CH:32][C:31]=1B(O)O)[CH2:26][CH2:27][CH3:28]>C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.COCCOC>[CH2:25]([O:29][C:30]1[CH:31]=[CH:32][C:33]([O:36][CH3:37])=[CH:34][C:35]=1[C:2]1[CH:7]=[CH:6][C:5]([CH2:8][O:9][C:10]2[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([O:20][CH3:21])=[O:19])[CH:13]=[CH:14][CH:15]=2)=[CH:4][C:3]=1[CH3:22])[CH2:26][CH2:27][CH3:28]
Reactant: COC(=O)CCc1cccc(OCc2ccc(Br)c(C)c2)c1
Reactant: CCCCOc1ccc(OC)cc1B(O)O
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: [Cs+]
Agent: [F-]
Solvent: COCCOC
Product: CCCCOc1ccc(OC)cc1-c1ccc(COc2cccc(CCC(=O)OC)c2)cc1C
Temperature: 85 °C
Yield: 94.6 %

Procedure:
To a 2 dram vial charged with 1.3 (0.0200 g, 0.0551 mmol), tetrakis(triphenylphosphine)palladium (0) (0.0127 g, 0.0110 mmol), cesium fluoride (0.0102 mL, 0.275 mmol), and 2-butoxy-5-methoxyphenylboronic acid 4.2 (0.0247 g, 0.110 mmol), was added DME (1 mL). The resulting mixture was then heated at 85° C. overnight. The reaction was allowed to cool and then filtered and concentrated. The crude was purified by combiflash (0 to 20% EtOAc/hexanes) yielding 4.3 (0.0241 g, 95% yield).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:14][C:13]2[CH:15]=[CH:16][C:17]([F:19])=[CH:18][C:12]=2[NH:11][C:10](=S)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:21]([NH:23][NH2:24])=O.CS(C)=O>C1C=CC=CC=1>[C:1]([O:5][C:6]([N:8]1[CH2:9][C:10]2[N:11]([CH:21]=[N:23][N:24]=2)[C:12]2[CH:18]=[C:17]([F:19])[CH:16]=[CH:15][C:13]=2[CH2:14]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(=S)Nc2cc(F)ccc2C1
Reactant: NNC=O
Solvent: CS(C)=O
Solvent: c1ccccc1
Product: CC(C)(C)OC(=O)N1Cc2ccc(F)cc2-n2cnnc2C1
Temperature: 80 °C
Yield: 60 %

Procedure:
To a solution of 8-fluoro-2-thioxo-1,2,3,5-tetrahydro-benzo[e][1,4]diazepine-4-carboxylic acid tert-butyl ester (2.36 g, 7.97 mmol) in dry benzene (25 mL), was added formic acid hydrazide dissolved in 5 mL of dry DMSO (1.43 g, 23.91 mmol) at room temperature. The reaction mixture was heated at 80° C., using Dean-Stark apparatus for 18 h. After the completion of the reaction, as confirmed by TLC, distilled water (40 mL) was added and the crude compound was extracted with diethyl ether (3×40 mL). The combined organic layers were dried over Na2SO4 and concentrated in vacuo to afford the crude compound which, was purified by column chromatography [silica gel, 1.5:8.5 Acetone:Pet. ether] to afford 9-fluoro-4H,6H-2,3,5,10b-tetraaza-benzo[e]azulene-5-carboxylic acid tert-butyl ester, (1.455 g, 60%) as a white solid.
Reaction SMILES: [Br:1][C:2]1[C:10]2[C:9](Cl)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1.[CH3:12][N:13]([CH3:21])[CH:14]1[CH2:19][CH2:18][CH:17]([NH2:20])[CH2:16][CH2:15]1.C(=O)([O-])[O-].[K+].[K+]>CN(C)C=O.O>[Br:1][C:2]1[C:10]2[C:9]([NH:20][CH:17]3[CH2:18][CH2:19][CH:14]([N:13]([CH3:21])[CH3:12])[CH2:15][CH2:16]3)=[N:8][CH:7]=[N:6][C:5]=2[S:4][CH:3]=1
Reactant: Clc1ncnc2scc(Br)c12
Reactant: CN(C)C1CCC(N)CC1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CN(C)C1CCC(Nc2ncnc3scc(Br)c23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
A 50-mL round-bottom flask was charged with commercially available 5-bromo-4-chlorothieno[2,3-d]pyrimidine (300 mg, 1.20 mmol, 1.00 equiv), 1-N,1-N-dimethylcyclohexane-1,4-diamine (205 mg, 1.44 mmol, 1.20 equiv), potassium carbonate (497 mg, 3.60 mmol, 3.00 equiv) in N,N-dimethylformamide (10 mL). The resulting solution was stirred overnight at room temperature. The resulting solution was diluted with 100 mL of water. The resulting solution was extracted with 3×100 mL of ethyl acetate and the organic layers combined. The resulting mixture was washed with 3×200 mL of brine. The mixture was dried over anhydrous sodium sulfate and concentrated under vacuum. This resulted in 250 mg (59%) of 4-N-[5-bromothieno[2,3-d]pyrimidin-4-yl]-1-N,1-N-dimethylcyclohexane-1,4-diamine as a yellow oil.
Reaction SMILES: [F:1][C:2]([F:14])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH2:12])[CH:9]=[N:8]1.[CH3:15][C:16]1[O:17][C:18]([C:24]2[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=2)=[C:19]([C:21](O)=[O:22])[N:20]=1>>[F:14][C:2]([F:1])([CH3:13])[CH2:3][CH2:4][CH2:5][CH2:6][N:7]1[CH:11]=[C:10]([NH:12][C:21]([C:19]2[N:20]=[C:16]([CH3:15])[O:17][C:18]=2[C:24]2[CH:25]=[CH:26][CH:27]=[CH:28][CH:29]=2)=[O:22])[CH:9]=[N:8]1
Reactant: Cc1nc(C(=O)O)c(-c2ccccc2)o1
Reactant: CC(F)(F)CCCCn1cc(N)cn1
Product: Cc1nc(C(=O)Nc2cnn(CCCCC(C)(F)F)c2)c(-c2ccccc2)o1

Procedure:
Following general procedure B, starting from 1-(5,5-difluoro-hexyl)-1H-pyrazol-4-ylamine and 2-methyl-5-phenyl-oxazole-4-carboxylic acid. LC-MS-conditions 05b: tR=1.14 min; [M+H]+=389.28.