Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([C:14]([OH:16])=O)[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13].[NH2:17][C@@H:18]([CH2:31][C:32]1[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=1[C:38]([F:41])([F:40])[F:39])[CH2:19][N:20]1[C:28](=[O:29])[C:27]2[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=2)[C:21]1=[O:30].C(N(C(C)C)CC)(C)C.C1CN([P+](Br)(N2CCCC2)N2CCCC2)CC1.F[P-](F)(F)(F)(F)F>C(Cl)Cl>[Cl:1][C:2]1[CH:3]=[C:4]([C:14]([NH:17][C@@H:18]([CH2:31][C:32]2[CH:37]=[CH:36][CH:35]=[CH:34][C:33]=2[C:38]([F:41])([F:39])[F:40])[CH2:19][N:20]2[C:28](=[O:29])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]2=[O:30])=[O:16])[S:5][C:6]=1[C:7]1[N:11]([CH3:12])[N:10]=[CH:9][C:8]=1[Cl:13]
Reactant: Cn1ncc(Cl)c1-c1sc(C(=O)O)cc1Cl
Reactant: N[C@@H](Cc1ccccc1C(F)(F)F)CN1C(=O)c2ccccc2C1=O
Agent: Br[P+](N1CCCC1)(N1CCCC1)N1CCCC1
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: Cn1ncc(Cl)c1-c1sc(C(=O)N[C@@H](Cc2ccccc2C(F)(F)F)CN2C(=O)c3ccccc3C2=O)cc1Cl
Reaction time: 1 h
Yield: 81.3 %

Procedure:
To a solution of 4-chloro-5-(4-chloro-1-methyl-1H-pyrazol-5-yl)-2-thiophenecarboxylic acid (136.1 mg, 0.49 mmol), 2-{(2S)-2-amino-3-[2-(trifluoromethyl)phenyl]propyl}-1H-isoindole-1,3(2H)-dione (179 mg, 0.51 mmol) [prepared according to Preparation 6], diisopropylethyl amine (260 uL, 1.5 mmol) in DCM (5 mL) was added PyBrop (341 mg, 0.75 mmol) in one portion. After 1 h, the reaction contents were partitioned between H2O/DCM. The aqueous phase was washed several times with DCM and the combined organic fractions were dried over Na2SO4, concentrated and purified via column chromatography (silica, gradient 0-50% ethyl acetate/hexane) affording the title compound (242 mg, 82%) as a white solid: LCMS (ES) m/z=607 (M+H)+.
Reaction SMILES: Cl[C:2]([F:28])([F:27])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:16])[CH3:15])[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([CH:24]([CH3:26])[CH3:25])[N:4]=1.C(N(CC)CC)C>C(O)C.[Pd]>[F:28][CH:2]([F:27])[C:3]1[C:8]([C:9]([O:11][CH3:12])=[O:10])=[C:7]([CH2:13][CH:14]([CH3:15])[CH3:16])[C:6]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])=[C:5]([CH:24]([CH3:26])[CH3:25])[N:4]=1
Reactant: COC(=O)c1c(C(F)(F)Cl)nc(C(C)C)c(C(=O)OC(C)(C)C)c1CC(C)C
Agent: [Pd]
Solvent: CCO
Solvent: CCN(CC)CC
Product: COC(=O)c1c(C(F)F)nc(C(C)C)c(C(=O)OC(C)(C)C)c1CC(C)C
Yield: 90.8 %

Procedure:
A solution of 17 g (40 mmol) of crude 3-methyl 5-(1,1-dimethylethyl) 2-(chlorodifluoromethyl)-6-(1-methylethyl)-4-(2-methylpropyl)-3,5-pyridinedicarboxylate and 7 mL of triethylamine in 160 mL of ethanol was subjected to hydrogenolysis at ambient temperature and 2 atom pressure in the presence of 3 g of 5% palladium on charcoal for 18 hours. The suspension was filtered through celite and concentrated. Water and CH2Cl2 were added. The CH2Cl2 layer was separated, washed with H2O, dried and concentrated. Column chromatography on silica gel (2% ethyl acetate/cyclohexane) gave 14 g (91%) of 5-(1,1-dimethylethyl) 3-methyl 2-(difluoromethyl)-6-(1-methylethyl)-4-(2-methylpropyl)-3,5-Pyridinedicarboxylate as colorless oil, nD25 1.4713.
Reaction SMILES: Br[C:2]1[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]2[C:15]3[CH:22]=[N:21][N:20]([C:23]4[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=4)[C:16]=3[CH:17]=[N:18][CH:19]=2)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=1.[CH3:30][N:31]1[CH2:36][CH2:35][NH:34][CH2:33][CH2:32]1.CCN(C(C)C)C(C)C>C(O)CCC>[CH3:30][N:31]1[CH2:36][CH2:35][N:34]([C:2]2[CH:7]=[C:6]([C@@H:8]([NH:11][C:12]([C:14]3[C:15]4[CH:22]=[N:21][N:20]([C:23]5[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=5)[C:16]=4[CH:17]=[N:18][CH:19]=3)=[O:13])[CH2:9][CH3:10])[CH:5]=[CH:4][N:3]=2)[CH2:33][CH2:32]1
Reactant: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(Br)c1
Reactant: CN1CCNCC1
Solvent: CCN(C(C)C)C(C)C
Solvent: CCCCO
Product: CC[C@H](NC(=O)c1cncc2c1cnn2-c1ccc(F)cc1)c1ccnc(N2CCN(C)CC2)c1
Reaction time: 4 h

Procedure:
A microwave vessel charged with 1-(4-fluorophenyl)-1H-pyrazolo[3,4-c]pyridine-4-carboxylic acid [(S)-1-(2-bromopyridin-4-yl)-propyl]-amide (0.05 g, 0.11 mmol), 1-methylpiperazine (33.1 mg, 0.33 mmol) and DIPEA (115 μL, 0.66 mmol) in 1-butanol (1.5 mL) was irradiated at 200° C. After 4 hours, the reaction was cooled, evaporated to dryness and the residue was purified with reverse phase liquid chromatography to afford the title compound.
Reaction SMILES: [CH2:1]([OH:4])[C:2]#[CH:3].[N+:5](=[CH:7][C:8]([O:10][CH2:11][CH3:12])=[O:9])=[N-:6]>ClC(Cl)Cl>[CH2:11]([O:10][C:8]([C:7]1[NH:5][N:6]=[C:2]([CH2:1][OH:4])[CH:3]=1)=[O:9])[CH3:12]
Reactant: CCOC(=O)C=[N+]=[N-]
Reactant: C#CCO
Solvent: ClC(Cl)Cl
Product: CCOC(=O)c1cc(CO)n[nH]1

Procedure:
A solution of 2 g Prop-2-yn-1-ol and 3 g Ethyl diazoacetate in 16 ml trichloromethane was stirred at 70° C. for 24 h. Then the solvent was removed under reduced pressure and the residue was purified on silica gel eluting with a gradient n-heptane/ethyl acetate 1:1->1:2. The fractions containing the product were collected and evaporated under reduced pressure. Yield: 1.9 g.
Reaction SMILES: [OH:1][C:2]1[CH:3]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[CH:5]=[C:6]([CH:11]=1)[C:7]([O:9][CH3:10])=[O:8].Br[CH2:17][CH:18]([CH2:21][CH3:22])[CH2:19][CH3:20]>CC#N>[CH2:19]([CH:18]([CH2:21][CH3:22])[CH2:17][O:1][C:2]1[CH:11]=[C:6]([C:7]([O:9][CH3:10])=[O:8])[CH:5]=[C:4]([CH:3]=1)[C:12]([O:14][CH3:15])=[O:13])[CH3:20]
Reactant: CCC(CC)CBr
Reactant: COC(=O)c1cc(O)cc(C(=O)OC)c1
Solvent: CC#N
Product: CCC(CC)COc1cc(C(=O)OC)cc(C(=O)OC)c1
Reaction time: 0.38 h

Procedure:
Dimethyl 5-hydroxyisophthalate (0.44 g, 2.10 mmol) cesium carbonate (1.37 g, 4.20 mmol) and CH3CN (20 mL) were added to a round-bottom flask and stirred for 15-30 min. 3-(Bromomethyl)pentane (0.42 g, 2.52 mmol) was added and the reaction was stirred for 16 h. The solvent was removed under reduced pressure and the reaction mixture was partitioned between EtOAc (50 mL) and H2O (50 mL). The layers were separated and the aqueous layer was extracted with EtOAc (50 mL). The combined organics were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford the desired product which was used without further purification.
Reaction SMILES: [CH3:1][C:2]1([CH3:10])[CH2:7][C:6](=[O:8])[CH2:5][C:4](=[O:9])[CH2:3]1.C(N(CC)CC)C.[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23](Cl)=[O:24])=[CH:21][CH:20]=1.C[Si](C#N)(C)C>C(#N)C>[Cl:18][C:19]1[CH:27]=[CH:26][C:22]([C:23]([CH:5]2[C:6](=[O:8])[CH2:7][C:2]([CH3:10])([CH3:1])[CH2:3][C:4]2=[O:9])=[O:24])=[CH:21][CH:20]=1
Reactant: CC1(C)CC(=O)CC(=O)C1
Reactant: O=C(Cl)c1ccc(Cl)cc1
Agent: C[Si](C)(C)C#N
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CC1(C)CC(=O)C(C(=O)c2ccc(Cl)cc2)C(=O)C1
Temperature: 25 °C

Procedure:
5,5-dimethylcyclohexane-1,3-dione (7.01 g, 0.05 mole), acetonitrile (80 ml), and triethylamine (21 ml, 0.15 mole) were combined in a flask, and placed under a nitrogen atmosphere. A solution of 4-chlorobenzoyl chloride (6.4 ml, 0.05 mole) in acetonitrile (20 ml) was added over 15 inutes while stirring and cooling with an ambient temperature water bath. Trimethylsilyl cyanide (0.33 ml, 2.55 mmole) was added, and the reaction was heated and stirred at 40° C. for 3 hours whereupon the reaction was complete.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([O:8][CH:9]2[CH2:14][CH2:13][CH2:12][CH2:11][O:10]2)=[C:4]([C:15]([CH3:18])([CH3:17])[CH3:16])[CH:3]=1.[C:19]12(C3C=CC(Br)=CC=3O)[CH2:28][CH:23]3CC(C[CH:21]([CH2:22]3)[CH2:20]1)C2.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1.O1C=CCCC1>ClCCl>[C:15]12([C:4]3[CH:3]=[C:2]([Br:1])[CH:7]=[CH:6][C:5]=3[O:8][CH:9]3[CH2:14][CH2:13][CH2:12][CH2:11][O:10]3)[CH2:18][CH:21]3[CH2:22][CH:23]([CH2:28][CH:19]([CH2:20]3)[CH2:16]1)[CH2:17]2
Reactant: CC(C)(C)c1cc(Br)ccc1OC1CCCCO1
Reactant: Oc1cc(Br)ccc1C12CC3CC(CC(C3)C1)C2
Agent: C1=COCCC1
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: c1cc[nH+]cc1
Solvent: ClCCl
Product: Brc1ccc(OC2CCCCO2)c(C23CC4CC(CC(C4)C2)C3)c1

Procedure:
Using the same general procedure as for the preparation of of 4-bromo-2-t-butyl-1-(2-tetrahydropyranoxy)benzene (Compound H), but instead using 9.17 g (29.9 mmol) of 2-(1-adamantyl)-4-bromophenol (Compound F), 0.75 g (3.0 mmol) of pyridinium p-toluenesulfonate, 3.77 g (4.1 ml, 44.8 mmql) of 3,4-dihydro-2H-pyran and 50 ml of dichloromethane produced a bright yellow solid. Purification by flash chromatography (preabsorbed onto silica with chloroform, eluted with 2% ethyl acetate in hexane) yielded the title compound as a nearly white solid. PMR (CDCl3): d 1.6-2.2 (21H, m), 3.6-3.7 (1H, m), 3.8-3.9 (1H, m), 5.43 (1H, t, J=2.4 Hz), 7.05 (1H, d, J=8.7 Hz), 7.23 (1H, dd, J=8.7, 2.5 Hz), 7.30 (1H, d, J=2.5 Hz).
Reaction SMILES: C(=O)([O-])[O-].[K+].[K+].[OH:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1.[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:26])([F:25])[F:24])[CH:18]=[C:19]([F:22])[C:20]=1F.Cl>CN(C=O)C>[Cl:14][C:15]1[CH:16]=[C:17]([C:23]([F:24])([F:25])[F:26])[CH:18]=[C:19]([F:22])[C:20]=1[O:7][C:8]1[CH:12]=[C:11]([CH3:13])[NH:10][N:9]=1
Reactant: Fc1cc(C(F)(F)F)cc(Cl)c1F
Reactant: Cc1cc(O)n[nH]1
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: Cc1cc(Oc2c(F)cc(C(F)(F)F)cc2Cl)n[nH]1
Temperature: 70 °C
Yield: 31.1 %

Procedure:
Potassium carbonate (1.66 g, 12 mmol) was added to a solution of 3-hydroxy-5-methylpyrazole (2.45 g, 25.0 mmol) and 3-chloro-4,5-difluorobenzotrifluoride (2.5 g, 25.0 mmol) in DMF (40 ml), and the mixture was stirred under heating at 70° C. for 4 hours. After completion of the reaction, the reaction mixture was poured into 2N hydrochloric acid (100 ml) and extracted with ethyl acetate (50 ml×3). An organic layer was washed with water, dried over anhydrous magnesium sulfate and filtered to remove a desiccant, and the solvent was distilled off from the filtrate under reduced pressure. The resultant crude product was purified with a silica gel column (ethyl acetate/hexane=1/5), to give a white solid of 3-(2-chloro-6-fluoro-4-trifluoromethylphenyloxy)-5-methylpyrazole (2.29 g, yield: 33.8%). mp: 171-174° C.; 1H-NMR (CDCl3, TMS, ppm): δ 2.27 (s, 3H), 5.71 (s, 1H), 7.37 (dd, JHF=1.8 and 9.4 Hz, 1H), 7.54 (s, 1H), 8.85-9.55 (br s, 1H).
Reaction SMILES: [C:1]([C:9]1[CH:13]=[CH:12][O:11][C:10]=1[C:14]([OH:16])=O)(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[NH2:17][NH2:18]>[NH4+].[Cl-].CCOC(C)=O>[C:2]1([C:1]2[C:9]3[CH:13]=[CH:12][O:11][C:10]=3[C:14]([OH:16])=[N:18][N:17]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: NN
Reactant: O=C(c1ccccc1)c1ccoc1C(=O)O
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOC(C)=O
Product: Oc1nnc(-c2ccccc2)c2ccoc12

Procedure:
A brown solution of 3-benzoylfuran-2-carboxylic acid (0.770 g, 3.56 mmol) and anhydrous hydrazine (0.568 ml, 17.8 mmol) was heated to 100° C. in a sealed tube for approx. 72 h. The reaction was cooled, and diluted with sat'd aq. NH4Cl and EtOAc. The organic layer was washed with sat'd aq. NH4Cl and brine, and dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo to give 4-phenylfuro[3,2-d]pyridazin-7-ol which was carried on without further purification. MS m/z=213 [M+H]+. Calc'd for C12H8N2O2: 212.2.
Reaction SMILES: [CH3:1][C:2]1[C:29]([CH3:30])=[CH:28][C:5]2[NH:6][C:7](=S)[CH2:8][C:9]([C:11]3[CH:16]=[CH:15][C:14]([N:17]4[C:25]5[CH:24]=[CH:23][N:22]=[CH:21][C:20]=5[N:19]=[C:18]4[CH3:26])=[CH:13][CH:12]=3)=[N:10][C:4]=2[CH:3]=1.[NH3:31]>C(O)CCC.CO>[NH2:31][C:7]1[CH2:8][C:9]([C:11]2[CH:16]=[CH:15][C:14]([N:17]3[C:25]4[CH:24]=[CH:23][N:22]=[CH:21][C:20]=4[N:19]=[C:18]3[CH3:26])=[CH:13][CH:12]=2)=[N:10][C:4]2[CH:3]=[C:2]([CH3:1])[C:29]([CH3:30])=[CH:28][C:5]=2[N:6]=1
Reactant: Cc1cc2c(cc1C)NC(=S)CC(c1ccc(-n3c(C)nc4cnccc43)cc1)=N2
Reactant: N
Solvent: CCCCO
Solvent: CO
Product: Cc1cc2c(cc1C)N=C(c1ccc(-n3c(C)nc4cnccc43)cc1)CC(N)=N2
Temperature: 120 °C
Reaction time: 3 h
Yield: 38 %

Procedure:
A mixture of the thioamide (from Example 19) (2.98 g, 7.24 mmol) and red mercuric oxide (1.57 g, 7.24 mmol) in n-butanol (40 ml) was saturated with ammonia gas at room temperature, and then stirred at 120° C. for 3 hours. After being cooled, the mixture was diluted with methanol (150 ml) and filtered through Arbocel filter aid. The filtrate was concentrated under reduced pressure, and the residue was purified by flash chromatography (eluting with ethyl acetate:methanol:diethylamine=100:10:5). Fractions containing the product were evaporated to give the title compound as a bright yellow solid (1.085 g, 38%), m.p. 299°-302° C.
Reaction SMILES: Cl[CH2:2][C:3]([C:5]1[C:6]([CH3:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[C:8]#[N:9])=[O:4].[C:14]([N:21]1[CH2:26][CH2:25][NH:24][C@@H:23]([CH2:27][OH:28])[CH2:22]1)([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].CCN(C(C)C)C(C)C>C1COCC1>[C:8]([C:7]1[C:6]([CH3:13])=[C:5]([C:3](=[O:4])[CH2:2][N:24]2[CH2:25][CH2:26][N:21]([C:14]([O:16][C:17]([CH3:18])([CH3:19])[CH3:20])=[O:15])[CH2:22][C@@H:23]2[CH2:27][OH:28])[CH:12]=[CH:11][CH:10]=1)#[N:9]
Reactant: Cc1c(C#N)cccc1C(=O)CCl
Reactant: CC(C)(C)OC(=O)N1CCN[C@@H](CO)C1
Solvent: C1CCOC1
Solvent: CCN(C(C)C)C(C)C
Product: Cc1c(C#N)cccc1C(=O)CN1CCN(C(=O)OC(C)(C)C)C[C@@H]1CO
Temperature: 25 °C

Procedure:
To a solution of 3-(chloroacetyl)-2-methylbenzonitrile (1.7 g, 8.8 mmol) in THF (17.6 mL) was added (R)-4-N-boc-2-hydroxymethyl-piperazine (2.279 g, 10.54 mmol) and DIPEA (3.07 mL, 17.56 mmol) at rt. The reaction mixture was stirred at rt over the weekend. After concentration, the residue was partitioned between EtOAc and aqueous NaHCO3 (saturated). The aqueous layer was extracted with EtOAc (2×). The combined organic phase was washed with brine, dried over anhydrous MgSO4, and filtered. Concentration was followed by purification by prep TLC (silica gel; 10% MeOH/DCM) to give the title compound: LC/MS (M+1)+=374.14
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4].[F:8][C:9]1([F:53])[CH2:14][CH2:13][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:27])([CH3:26])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:33][CH2:32][N:31]([C:34]4[N:39]=[CH:38][C:37]([OH:40])=[CH:36][N:35]=4)[CH2:30][CH2:29]3)[C:16]=2[CH:41]([F:52])[C:42]2[CH:47]=[CH:46][C:45]([C:48]([F:51])([F:50])[F:49])=[CH:44][CH:43]=2)[CH2:11][CH2:10]1>>[F:53][C:9]1([F:8])[CH2:10][CH2:11][CH:12]([C:15]2[C:24]3[CH:23]([OH:25])[CH2:22][C:21]([CH3:26])([CH3:27])[CH2:20][C:19]=3[N:18]=[C:17]([CH:28]3[CH2:29][CH2:30][N:31]([C:34]4[N:39]=[CH:38][C:37]([O:40][CH2:2][C:3]([O:5][CH2:6][CH3:7])=[O:4])=[CH:36][N:35]=4)[CH2:32][CH2:33]3)[C:16]=2[CH:41]([F:52])[C:42]2[CH:43]=[CH:44][C:45]([C:48]([F:49])([F:51])[F:50])=[CH:46][CH:47]=2)[CH2:13][CH2:14]1
Reactant: CC1(C)Cc2nc(C3CCN(c4ncc(O)cn4)CC3)c(C(F)c3ccc(C(F)(F)F)cc3)c(C3CCC(F)(F)CC3)c2C(O)C1
Reactant: CCOC(=O)CBr
Product: CCOC(=O)COc1cnc(N2CCC(c3nc4c(c(C5CCC(F)(F)CC5)c3C(F)c3ccc(C(F)(F)F)cc3)C(O)CC(C)(C)C4)CC2)nc1

Procedure:
Reactions similar to those of Example 13 were performed except for using ethyl bromoacetate instead of ethyl iodide, and from 82 mg (0.13 mmol) of (−)-4-(4,4-Difluorocyclohexyl)-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-2-[1-(5-hydroxypyrimidin-2-yl)piperidin-4-yl]-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol, which was prepared by a method similar to that of Example 4, 61 mg of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(2-ethoxy-2-oxoethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol was obtained. To a solution of 61 mg (0.083 mmol) of 4-(4,4-Difluorocyclohexyl)-2-{1-[5-(2-ethoxy-2-oxoethoxy)pyrimidin-2-yl]piperidin-4-yl}-3-{fluoro[4-(trifluoromethyl)phenyl]methyl}-7,7-dimethyl-5,6,7,8-tetrahydroquinolin-5-ol obtained above in 5 ml of diethyl ether, 0.30 ml (0.33 mmol) of 1.1 N methyl magnesium bromide-diethyl ether solution was added at 0° C. The temperature of the reaction solution was raised to room temperature and the reaction solution was stirred for 1 hour. After completion of the reaction, an ammonium chloride aqueous solution was poured into the reaction solution and the reaction solution was extracted with ethyl acetate. The organic layer was washed with saturated sodium chloride aqueous solution and dried with anhydrous sodium sulfate, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by thin layer silica gel chromatography [n-hexane/ethyl acetate=5/6 (V/V)] to provide 18 mg of the title compound as a white solid (yield: 30%).
Reaction SMILES: [CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([OH:21])=O)=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(CC)CC.[N:54]1([CH:59]2[CH2:64][CH2:63][NH:62][CH2:61][CH2:60]2)[CH2:58][CH2:57][CH2:56][CH2:55]1>CN(C=O)C>[CH2:1]([C:7]1[CH:8]=[C:9]([C:13]2[N:17]([CH3:18])[C:16]([C:19]([N:62]3[CH2:63][CH2:64][CH:59]([N:54]4[CH2:58][CH2:57][CH2:56][CH2:55]4)[CH2:60][CH2:61]3)=[O:21])=[C:15]([I:22])[N:14]=2)[CH:10]=[CH:11][CH:12]=1)[CH2:2][CH2:3][CH2:4][CH2:5][CH3:6]
Reactant: C1CCN(C2CCNCC2)C1
Reactant: CCCCCCc1cccc(-c2nc(I)c(C(=O)O)n2C)c1
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: CCCCCCc1cccc(-c2nc(I)c(C(=O)N3CCC(N4CCCC4)CC3)n2C)c1
Reaction time: 16 h
Yield: 90.1 %

Procedure:
7.20 g (17.5 mmol) of 2-(3-hexyl-phenyl)-5-iodo-3-methyl-3H-imidazole-4-carboxylic acid (intermediate 1) were dissolved in 290 ml of DMF and treated with 6.846 g (17.5 mmol) of HATU. 7.30 ml=5.30 g (52.4 mmol) of Et3N were added and after 30 min, a solution of 2.72 g (17.5 mmol) of 4-pyrrolidin-1-yl-piperidine in 70 ml of DMF was added. After 16 hours, the reaction mixture was poured into crashed ice and extracted three times with Et2O; the organic phases were washed with water, dried over magnesium sulfate, filtered and evaporated. The residue was purified by flash column chromatography (CH2Cl2/MeOH 1:0 to 9:1) to give 8.65 g (90%) of the title compound as light brown foam. MS: 549.3 (MH+).
Reaction SMILES: [OH:1][C@@H:2]1[CH2:6][CH2:5][NH:4][CH2:3]1.CCN(CC)CC.[CH2:14](Br)[C:15]#[CH:16]>C(Cl)Cl>[OH:1][C@@H:2]1[CH2:6][CH2:5][N:4]([CH2:16][C:15]#[CH:14])[CH2:3]1
Reactant: C#CCBr
Reactant: O[C@@H]1CCNC1
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C#CCN1CC[C@@H](O)C1

Procedure:
To a solution of (R)-3-hydroxy-pyrrolidine (2.00 g, 22.95 mmol) (Aldrich) and Et3N (9.00 g, 88.93 mmol) in 45 mL of CH2Cl2 at 0° C. it was added propargyl bromide (3.00 g, 25.21 mmol) in a dropwise manner. Upon completion of the addition, the reaction mixture was filtered and the filtrate was washed with brine, dried over Na2SO4 and concentrated. (R)-3-Hydroxy-1-prop-2-ynyl-pyrrolidine was obtained after Krugerhor distitation (Yield 700 mg, 24%).
Reaction SMILES: [CH3:1][CH:2]([CH3:14])[CH2:3][N:4]1[CH:9]=[CH:8][C:7]([C:10]([OH:12])=O)=[CH:6][C:5]1=[O:13].CN(C(ON1N=NC2C=CC=NC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.O[NH:49][C:50]([C:52]1[C:53]2[CH:54]=[CH:55][N:56]=[CH:57][C:58]=2[CH:59]=[CH:60][CH:61]=1)=[NH:51]>CN(C=O)C>[CH:57]1[C:58]2[C:53](=[C:52]([C:50]3[N:49]=[C:10]([C:7]4[CH:8]=[CH:9][N:4]([CH2:3][CH:2]([CH3:1])[CH3:14])[C:5](=[O:13])[CH:6]=4)[O:12][N:51]=3)[CH:61]=[CH:60][CH:59]=2)[CH:54]=[CH:55][N:56]=1
Reactant: CC(C)Cn1ccc(C(=O)O)cc1=O
Reactant: N=C(NO)c1cccc2cnccc12
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)Cn1ccc(-c2nc(-c3cccc4cnccc34)no2)cc1=O
Temperature: 120 °C
Yield: 5.4 %

Procedure:
1-(2-Methylpropyl)-2-oxo-1,2-dihydro-4-pyridinecarboxylic acid (D28; 57 mg, 0.294 mmol) was stirred in DMF (0.5 ml) with HATU (122 mg, 0.321 mmol) and DIPEA (0.14 ml, 0.802 mmol) at room temperature for 30 mins before adding a solution of N-hydroxy-5-isoquinolinecarboximidamide (D1, 50 mg, 0.267 mmol) in DMF (0.5 ml). The resulting mixture was heated to 120° C. for 40 mins in a Biotage Initiator microwave. The solvent was removed under vacuum, and the residue was purified by column chromatography on silica, eluting with 0-4% methanol in dichloromethane. The relevant fractions were combined and concentrated under vacuum to give the title compound as a pale yellow oil (5 mg).
Reaction SMILES: [NH2:1][C:2]1[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=1[C:4]([NH:6][CH3:7])=[O:5].CN1C(=O)CCC1.CCN(C(C)C)C(C)C.[Cl:30][C:31]1[N:36]=[C:35](Cl)[C:34]([Cl:38])=[CH:33][N:32]=1>>[Cl:30][C:31]1[N:36]=[C:35]([NH:1][C:2]2[C:11]([F:12])=[CH:10][C:9]([F:13])=[CH:8][C:3]=2[C:4]([NH:6][CH3:7])=[O:5])[C:34]([Cl:38])=[CH:33][N:32]=1
Reactant: Clc1ncc(Cl)c(Cl)n1
Reactant: CNC(=O)c1cc(F)cc(F)c1N
Solvent: CN1CCCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)c1cc(F)cc(F)c1Nc1nc(Cl)ncc1Cl
Temperature: 100 °C

Procedure:
To a solution of 2-Amino-3,5-difluoro-N-methyl-benzamide (1.099 g, 0.006 mol) and NMP (6 mL, 0.06 mol) was added DIEA (1.23 mL, 7.8 mmol) followed by 2,4,5-Trichloro-pyrimidine (0.812 mL, 7.1 mmol) and the reaction mixture was heated at 100° C. for 16 h. Title compound isolated as an off-white solid (1.10 g, 56%), MP=220-221, HPLC purity=95%, LCMS=333.38 (M+H), 1H-NMR (CDCl3, 400 MHz) δ 8.94 (s, 1H), 8.22 (s, 1H), 7.12-7.06 (m, 2H), 6.17 (s, 1H), 2.99 (s, 3H).
Reaction SMILES: [NH2:1][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)=[CH:4][C:3]=1[S:15]([NH2:18])(=[O:17])=[O:16].[Br:19][C:20]1[CH:21]=[C:22]([S:26](Cl)(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1>N1C=CC=CC=1>[Br:19][C:20]1[CH:21]=[C:22]([S:26]([NH:1][C:2]2[CH:7]=[CH:6][C:5]([O:8][C:9]3[CH:10]=[CH:11][CH:12]=[CH:13][CH:14]=3)=[CH:4][C:3]=2[S:15]([NH2:18])(=[O:16])=[O:17])(=[O:28])=[O:27])[CH:23]=[CH:24][CH:25]=1
Reactant: O=S(=O)(Cl)c1cccc(Br)c1
Reactant: Nc1ccc(Oc2ccccc2)cc1S(N)(=O)=O
Solvent: c1ccncc1
Product: NS(=O)(=O)c1cc(Oc2ccccc2)ccc1NS(=O)(=O)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 72.4 %

Procedure:
To a solution of 2-amino-5-phenoxybenzenesulfonamide (528 mg, 2 mmol) in pyridine (15 mL), 3-bromobenzenesulphonyl chloride (669.3 mg, 2.3 mmol) was added portionwise at 0° C. The reaction was stirred at RT overnight. The pyridine was removed in vacuo and the residue was dissolved in ethyl acetate. The organic phase was washed with aqueous 1N HCl, water and brine, dried over sodium sulfate, and concentrated under reduced pressure. The crude product was purified by flash column chromatography using ethyl acetate/hexane (1:3) as eluent to give the title compound (700 mg, 72%).
Reaction SMILES: [NH2:1][C:2]1[C:11]([NH2:12])=[C:10]([O:13][CH3:14])[CH:9]=[CH:8][C:3]=1[C:4]([O:6][CH3:7])=[O:5].C(N(CC)CC)C.[CH2:22](Cl)[C:23]1[CH:28]=[CH:27][CH:26]=[N:25][CH:24]=1>ClCCl>[CH3:14][O:13][C:10]1[C:11]2[N:12]=[C:22]([C:23]3[CH:24]=[N:25][CH:26]=[CH:27][CH:28]=3)[NH:1][C:2]=2[C:3]([C:4]([O:6][CH3:7])=[O:5])=[CH:8][CH:9]=1
Reactant: ClCc1cccnc1
Reactant: COC(=O)c1ccc(OC)c(N)c1N
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: COC(=O)c1ccc(OC)c2nc(-c3cccnc3)[nH]c12
Temperature: 25 °C
Reaction time: 2 h
Yield: 43.6 %

Procedure:
A solution of methyl 2,3-diamino-4-methoxybenzoate [0.73 g, Reference Example 8(a)] and triethylamine (0.94 g) in dry dichloromethane (20 ml), at 0° C., was treated with nicotinyl chloride (0.53 g). The reaction mixture was stirred at ambient temperature for 2 hours and then evaporated. The residue was dissolved in acetic acid (8 ml) and the solution heated at 80° C. for 2 hours. After cooling to room temperature the reaction mixture was treated with water. The insoluble material was subjected to flash chromatography on silica to give the title compound (0.46 g). NMR (CDCl3): δ 4.00(s, 3H), 4.15(s, 3H), 6.70(d, 1H), 7.40(m, 1H), 7.90(d, 1H), 8.45(m, 1H), 8.75(d, 1H), 9.30(d, 1H), 10.80(s, 1H)].