Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([OH:15])=O)=[CH:4][CH:3]=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>>[CH3:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[O:12][N:11]=[CH:10][C:9]=2[C:13]([N:25]2[CH2:26][CH2:27][N:22]([C:17]3[CH:18]=[CH:19][CH:20]=[CH:21][N:16]=3)[CH2:23][CH2:24]2)=[O:15])=[CH:6][CH:7]=1
Reactant: c1ccc(N2CCNCC2)nc1
Reactant: Cc1ccc(-c2oncc2C(=O)O)cc1
Product: Cc1ccc(-c2oncc2C(=O)N2CCN(c3ccccn3)CC2)cc1

Procedure:
The title compound was prepared from 5-(4-methylphenyl)isoxazole-4-carboxylic acid (10.2 mg, 0.050 mmol) and 1-(2-pyridyl)piperazine (9.8 mg, 0.060 mmol) as described in synthetic method B and thereafter purified by preparative HPLC method B to give a solid (4.4 mg). Calcd for C20H20N4O2: 348.1586, found 348.1593.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([OH:29])=O)[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10].[NH2:33][C@H:34]1[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([CH:11]2[CH2:16][CH:15]([C:17]([F:20])([F:19])[F:18])[N:14]3[N:21]=[C:22]([C:24]4[CH:25]=[C:26]([CH:30]=[CH:31][CH:32]=4)[C:27]([NH:33][C@H:34]4[CH2:38][CH2:37][N:36]([C:39]([O:41][C:42]([CH3:45])([CH3:44])[CH3:43])=[O:40])[CH2:35]4)=[O:29])[CH:23]=[C:13]3[NH:12]2)[CH:6]=[CH:7][C:8]=1[O:9][CH3:10]
Reactant: CC(C)(C)OC(=O)N1CC[C@H](N)C1
Reactant: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)O)c4)cc3N2)cc1OC
Product: COc1ccc(C2CC(C(F)(F)F)n3nc(-c4cccc(C(=O)N[C@H]5CCN(C(=O)OC(C)(C)C)C5)c4)cc3N2)cc1OC
Yield: 20.4 %

Procedure:
Example ER-895811 was prepared in two steps from 3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzoic acid (24 mg, 0.054 mmol) and commercially available (S)-tert-butyl 3-aminopyrrolidine-1-carboxylate (40 mg, 0.215 mmol) in a manner similar to that of example D-6 to afford intermediate (3S)-tert-butyl 3-(3-(5-(3,4-dimethoxyphenyl)-7-(trifluoromethyl)-4,5,6,7-tetrahydropyrazolo[1,5-a]pyrimidin-2-yl)benzamido)pyrrolidine-1-carboxylate (7 mg, 0.011 mmol, 21% yield). Then, this intermediate (6 mg, 0.0097 mmol) was treated with HCl in a manner similar to that of example ER-897560 to afford the desired product ER-895811 (4.4 mg, 82% yield).
Reaction SMILES: [F:1][C:2]1[CH:14]=[CH:13][C:5]([C:6](=[O:12])[NH:7][CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.[CH3:15][O:16][C:17]1[CH:22]=[CH:21][C:20]([CH:23]([NH2:34])[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:33])([F:32])[F:31])[CH:25]=2)=[CH:19][CH:18]=1>>[F:1][C:2]1[CH:3]=[CH:4][C:5]([C:6]([NH:7][CH2:8][C:9](=[O:11])[NH:34][CH:23]([C:20]2[CH:19]=[CH:18][C:17]([O:16][CH3:15])=[CH:22][CH:21]=2)[C:24]2[CH:29]=[CH:28][CH:27]=[C:26]([C:30]([F:32])([F:33])[F:31])[CH:25]=2)=[O:12])=[CH:13][CH:14]=1
Reactant: COc1ccc(C(N)c2cccc(C(F)(F)F)c2)cc1
Reactant: O=C(O)CNC(=O)c1ccc(F)cc1
Product: COc1ccc(C(NC(=O)CNC(=O)c2ccc(F)cc2)c2cccc(C(F)(F)F)c2)cc1

Procedure:
Prepared in analogy to example 1.1 from 4-fluoro-hippuric acid (CA [366-79-0]) and rac-C-(4-methoxy-phenyl)-C-(3-trifluoromethyl-phenyl)-methylamine (example 4.7).
Reaction SMILES: [CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][O:20]CC2C=CC=CC=2)=[CH:9][CH:8]=1)[CH3:5]>CO.[Pd]>[CH3:1][O:2][C:3](=[O:29])[CH:4]([O:6][C:7]1[CH:12]=[CH:11][C:10]([NH:13][C:14](=[O:28])[CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][OH:20])=[CH:9][CH:8]=1)[CH3:5]
Reactant: COC(=O)C(C)Oc1ccc(NC(=O)CCCCCOCc2ccccc2)cc1
Agent: [Pd]
Solvent: CO
Product: COC(=O)C(C)Oc1ccc(NC(=O)CCCCCO)cc1
Reaction time: 16 h
Yield: 51.6 %

Procedure:
2-[4-(6-Benzyloxyhexanoylamino)phenoxy]propionic acid methyl ester 78 (15 g, 37.59 mmol) was dissolved in methanol (150 ml) in a pressure vessel, palladium on carbon (50% wet, 5%, 15 g) added and the mixture stirred under a hydrogen atmosph. (4 Kg) for 16 hrs. Catalyst was removed by filtration and methanol distilled off. The crude 79 was purified by column chromatography on silica gel using chloroform as eluant to get pure 79 (6 g, 51.6%) as a white powder. M.p: 62-64.5° C.
Reaction SMILES: [C:1]([C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][C:12]=1[OH:13])[N:9]=[CH:8][CH:7]=[C:6]2[O:14][C:15]1[CH:20]=[CH:19][C:18]([NH:21][C:22]([NH:24][CH:25]2[CH2:27][CH2:26]2)=[O:23])=[C:17]([Cl:28])[CH:16]=1)#[N:2].Br[CH2:30][CH:31]1[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:43])([CH3:42])[CH3:41])=[O:38])[CH2:33][CH2:32]1>>[Cl:28][C:17]1[CH:16]=[C:15]([CH:20]=[CH:19][C:18]=1[NH:21][C:22]([NH:24][CH:25]1[CH2:26][CH2:27]1)=[O:23])[O:14][C:6]1[C:5]2[C:10](=[CH:11][C:12]([O:13][CH2:30][CH:31]3[CH2:36][CH2:35][N:34]([C:37]([O:39][C:40]([CH3:41])([CH3:43])[CH3:42])=[O:38])[CH2:33][CH2:32]3)=[C:3]([C:1]#[N:2])[CH:4]=2)[N:9]=[CH:8][CH:7]=1
Reactant: CC(C)(C)OC(=O)N1CCC(CBr)CC1
Reactant: N#Cc1cc2c(Oc3ccc(NC(=O)NC4CC4)c(Cl)c3)ccnc2cc1O
Product: CC(C)(C)OC(=O)N1CCC(COc2cc3nccc(Oc4ccc(NC(=O)NC5CC5)c(Cl)c4)c3cc2C#N)CC1
Yield: 14.6 %

Procedure:
The title compound (275.8 mg, 0.466 mmol, 14.6%) was obtained as white crystals from an N-(4-(6-cyano-7-hydroxy-4-quinolyl)oxy-2-chlorophenyl)-N′-cyclopropylurea crude product (1.00 g, 3.20 mmol) and tert-butyl 4-(bromomethyl)-1-piperidinecarboxylate, by the same procedure as in Example 7.
Reaction SMILES: [OH:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:37])([CH3:36])[CH3:35])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38].C(N(CC)CC)C.[CH3:46][S:47](Cl)(=[O:49])=[O:48]>ClCCl>[CH3:46][S:47]([O:1][C:2]1[C:10]([CH3:11])=[CH:9][C:8]([C:12]2[N:13]([C:31]([O:33][C:34]([CH3:35])([CH3:37])[CH3:36])=[O:32])[C:14]3[C:19]([CH:20]=2)=[CH:18][C:17]([CH2:21][N:22]2[CH2:27][CH2:26][N:25]([CH2:28][CH2:29][OH:30])[CH2:24][CH2:23]2)=[CH:16][CH:15]=3)=[C:7]2[C:3]=1[CH2:4][NH:5][C:6]2=[O:38])(=[O:49])=[O:48]
Reactant: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1O)CNC2=O
Reactant: CS(=O)(=O)Cl
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: Cc1cc(-c2cc3cc(CN4CCN(CCO)CC4)ccc3n2C(=O)OC(C)(C)C)c2c(c1OS(C)(=O)=O)CNC2=O
Yield: 90.7 %

Procedure:
In a similar manner to Step 1 of Example 289, 4-hydroxy-5-methyl-7-(1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl)isoindolinone (178 mg, 0.280 mmol) was dissolved in dichloromethane (6 mL), and the solution was treated with triethylamine (0.156 mL, 1.12 mmol) and methanesulfonyl chloride (0.043 mL, 0.56 mmol), followed by purification by slurry using hexane to obtain 4-methanesulfonyloxy-5-methyl-7-{1-(tert-butoxycarbonyl)-5-[4-(2-hydroxyethyl)pyperazin-1-ylmethyl]indol-2-yl}isoindolinone (152 mg, yield 76%).
Reaction SMILES: O.NN.C1(=O)[N:8]([CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:16][CH2:17][CH3:18])[O:13][CH2:14][CH3:15])C(=O)C2=CC=CC=C12>C(O)C>[NH2:8][CH2:9][CH2:10][CH2:11][P:12](=[O:19])([O:13][CH2:14][CH3:15])[O:16][CH2:17][CH3:18]
Reactant: CCOP(=O)(CCCN1C(=O)c2ccccc2C1=O)OCC
Agent: NN
Solvent: O
Solvent: CCO
Product: CCOP(=O)(CCCN)OCC
Reaction time: 12 h
Yield: 51.1 %

Procedure:
To this end, 23.08 g (46.1 mmol) of hydrazine monohydrate are added dropwise to 15 g (46.1 mmol) of diethyl phthalimidopropylphosphonate in about 500 ml of absolute ethanol. The reaction medium is stirred for 12 hours. The salts formed are filtered off and washed with ethanol. After evaporating off the ethanol, salts are again formed. These salts are washed with CH2Cl2 and filtered on a Millipore membrane (0.45 μm). The filtrate is recovered and the CH2Cl2 is evaporated off. A yellow oil is obtained. The crude product is purified by chromatography on a column of silica gel with a 90/10 CHCl3/MeOH mixture as eluent. 4.6 g of diethyl 3-aminopropylphosphonate (APPE) are obtained in a yield of 51.8%.
Reaction SMILES: [OH:1][C:2]1[C:7]([OH:8])=[C:6]([OH:9])[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11].C(=O)([O-])[O-].[K+].[K+].S(C1C=CC(C)=CC=1)([O:22][CH2:23][C@@H:24]1O[CH2:25]1)(=O)=O>CN(C=O)C>[OH:1][C:2]1[C:7]2[O:8][CH:24]([CH2:23][OH:22])[CH2:25][O:9][C:6]=2[CH:5]=[CH:4][C:3]=1[C:10](=[O:12])[CH3:11]
Reactant: CC(=O)c1ccc(O)c(O)c1O
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2CO2)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(=O)c1ccc2c(c1O)OC(CO)CO2
Temperature: 70 °C

Procedure:
To a solution of 2′,3′,4′-trihydroxyacetophenone (10.6 g, 63.0 mmole) in DMF (75 mL) was added potassium carbonate (17.4 g, 126 mmole). After 5 minutes (R)-glycidyl tosylate (9.67 g, 42.3 mmole) was added, then the heterogeneous mixture was heated to 70° C. for 3 hours. After removal of the solvent in vacuum, the residue was taken into water (800 mL) and was then extracted with ethyl acetate (4×300 mL). The combined organic layers were dried over magnesium sulfate, filtered and evaporate to dryness in vacuum. The crude brown oil thus obtained was column chromatographed on silica gel with 40% hexane/ethyl acetate as eluant to give the (S)-enantiomer of the title compound as a yellow oil which solidifies upon standing (7.5 g, 78%). MS (ESI) m/z 223 (M−H)−.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH2:8][CH2:9][CH2:10][OH:11])=[CH:4][CH:3]=1.C(N(C(C)C)CC)(C)C.[CH3:21][S:22](Cl)(=[O:24])=[O:23]>ClCCl>[CH3:21][S:22]([O:11][CH2:10][CH2:9][CH2:8][C:5]1[CH:4]=[CH:3][C:2]([Br:1])=[CH:7][CH:6]=1)(=[O:24])=[O:23]
Reactant: OCCCc1ccc(Br)cc1
Reactant: CS(=O)(=O)Cl
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCl
Product: CS(=O)(=O)OCCCc1ccc(Br)cc1
Reaction time: 1 h
Yield: 98.9 %

Procedure:
To a stirred solution of 3-(4-Bromophenyl)propan-1-ol (500 g, 2.30 mol) and diisopropylethylamine (312 g, 2.40 mol) in anhydrous dichloromethane (4 L) at 0˜5° C. was added dropwise methanesulphonyl chloride (280 g, 2.40 mol) slowly. After addition, the reaction mixture was stirred for 1 hour at 0˜5° C. The reaction mixture was washed with brine (1 L) twice. The organic phase was concentrated in vacuo to afford the subtitle compound (i) (667 g). HPLC Retention Time=1.353 min.
Reaction SMILES: [Cl:1][C:2]1[C:3]([NH:16][C@@H:17]2[CH2:21][CH2:20][N:19](C(OC(C)(C)C)=O)[CH2:18]2)=[N:4][CH:5]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:7]=1.[ClH:29]>O1CCOCC1.CCO>[ClH:1].[ClH:29].[Cl:1][C:2]1[CH:7]=[C:6](/[CH:8]=[C:9](\[F:15])/[C:10]([O:12][CH2:13][CH3:14])=[O:11])[CH:5]=[N:4][C:3]=1[NH:16][C@@H:17]1[CH2:21][CH2:20][NH:19][CH2:18]1
Reactant: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCN(C(=O)OC(C)(C)C)C2)c(Cl)c1
Agent: Cl
Solvent: CCO
Solvent: C1COCCO1
Product: CCOC(=O)/C(F)=C/c1cnc(N[C@@H]2CCNC2)c(Cl)c1
Temperature: 25 °C
Reaction time: 4 h

Procedure:
A mixture of tert-butyl (3R)-3-({3-chloro-5-[(1Z)-3-ethoxy-2-fluoro-3-oxo-1-propen-1-yl]-2-pyridinyl}amino)-1-pyrrolidinecarboxylate (2.34 g) and 4N hydrogen chloride in dioxane solution (11 ml) in EtOH (10 ml) was stirred at ambient temperature for 4 hours. IPE (100 ml) was added to a reaction mixture and the precipitate was collected by filtration to give ethyl (2Z)-3-{5-chloro-6-[(3R)-3-pyrrolidinylamino]-3-pyridinyl}-2-fluoroacrylate dihydrochloride (1.95 g).
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([OH:6])=O.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)[C:39]2[N:40]=[CH:41][CH:42]=C[C:38]=2N=N1.C(N(C(C)C)CC)(C)C.C(NCC)C.C(=O)(O)[O-].[Na+]>CN(C=O)C.ClCCl>[NH2:1][C:2]1[CH:10]=[CH:9][C:8]([C:11]2[CH:12]=[C:13]3[C:19]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][C:21]=4[O:26][CH3:27])=[N:18][NH:17][C:14]3=[N:15][CH:16]=2)=[CH:7][C:3]=1[C:4]([N:40]([CH2:41][CH3:42])[CH2:39][CH3:38])=[O:6]
Reactant: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Reactant: COc1ccccc1-c1n[nH]c2ncc(-c3ccc(N)c(C(=O)O)c3)cc12
Agent: F[P-](F)(F)(F)(F)F
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CCNCC
Solvent: ClCCl
Solvent: CN(C)C=O
Product: CCN(CC)C(=O)c1cc(-c2cnc3[nH]nc(-c4ccccc4OC)c3c2)ccc1N
Yield: 7 %

Procedure:
40 mg (0.11 mmol) of 2-amino-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzoic acid and 63 mg (0.16 mmol) of O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate were dissolved in 2 mL of DMF. 40 μL (30 mg, 0.23 mmol) of di-iso-propyl ethyl amine and 100 μL (70 mg, 0.96 mmol) of diethylamine were added and the resulting mixture irradiated in a Personal Chemistry® Optimizer to 130° C. for 30 min. The resulting mixture was distributed between a saturated aqueous solution of sodium bicarbonate and dichloromethane and the organic phase was dried over sodium sulfate and evaporated. The resulting crude was purified by mass-triggered reverse-phase HPLC to afford 3.2 mg (7.7 μmol, 7%) of 2-amino-N,N-diethyl-5-[3-(2-methoxy-phenyl)-1H-pyrazolo[3,4-b]pyridin-5-yl]-benzamide as an off-white solid. 1H NMR (500 MHz, DMSO-d6) δ 13.72 (s, br., 1H), 8.75 (d, 1H), 8.17 (d, 1H), 7.64 (dd, 1H), 7.49 (dd, 1H), 7.46 (ddd, 1H), 7.32 (d, 1H), 7.21 (d(d), 1H), 7.09 (ddd, 1H), 6.85 (d, 1H), 3.84 (s, 3H), 3.4-3.3 (m, 4H), 1.15-1.05 (m, br., 6H), MS: m/z 416.1 (M+H+).
Reaction SMILES: Br[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)[CH:5]=[CH:4][C:3]=1[Cl:16].[Cl:17][C:18]1[C:19](B(O)O)=[CH:20][C:21]([F:24])=[N:22][CH:23]=1.C(Cl)Cl>COCCOC.CCOC(C)=O.C(=O)([O-])[O-].[Na+].[Na+].C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.C1C=CC(P(C2C=CC=CC=2)[C-]2C=CC=C2)=CC=1.Cl[Pd]Cl.[Fe+2]>[Cl:16][C:3]1[C:2]([C:19]2[C:18]([Cl:17])=[CH:23][N:22]=[C:21]([F:24])[CH:20]=2)=[N:7][C:6]([NH:8][CH2:9][CH:10]2[CH2:15][CH2:14][O:13][CH2:12][CH2:11]2)=[CH:5][CH:4]=1
Reactant: OB(O)c1cc(F)ncc1Cl
Reactant: Clc1ccc(NCC2CCOCC2)nc1Br
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CCOC(C)=O
Solvent: COCCOC
Solvent: ClCCl
Product: Fc1cc(-c2nc(NCC3CCOCC3)ccc2Cl)c(Cl)cn1
Temperature: 25 °C
Yield: 40 %

Procedure:
A mixture of 6-bromo-5-chloro-N-((tetrahydro-2H-pyran-4-yl)methyl)pyridin-2-amine (E, 300 mg, 0.982 mmol), 5-chloro-2-fluoropyridin-4-ylboronic acid (344 mg, 1.963 mmol), PdCl2(dppf).CH2Cl2 adduct (80 mg, 0.098 mmol) in DME (4.5 mL) and 2M aqueous sodium carbonate (4.5 mL, 4.50 mmol) was heated in a sealed tube at about 103° C. for about 16 hr. The reaction mixture was cooled to ambient temperature, diluted with EtOAc (˜100 mL) and saturated aqueous sodium carbonate solution. The organic layer was separated, washed with saturated aqueous sodium carbonate solution (2×), dried over sodium sulfate, filtered off and concentrated in vacuo. The resulting resulting residue was purified by column chromatography [ISCO, SiO2, 25 g, EtOAc/heptane=0/100 to 25/75]. Fractions were combined and concentrated in vacuo providing 3,5′-dichloro-2′-fluoro-N-((tetrahydro-2H-pyran-4-yl)methyl)-2,4′-bipyridin-6-amine (140 mg) as a light brown liquid. LCMS (m/z): 356.1 [M+H]+; Retention time=0.96 min.
Reaction SMILES: [CH:1]([C:3]1[CH:16]=[CH:15][C:6]([CH:7]=[C:8]2[S:12][C:11](=[O:13])[NH:10][C:9]2=[O:14])=[CH:5][CH:4]=1)=O.[NH2:17][C:18]1[C:23]([NH2:24])=[CH:22][CH:21]=[CH:20][C:19]=1[OH:25]>>[O:13]=[C:11]1[NH:10][C:9](=[O:14])[C:8](=[CH:7][C:6]2[CH:15]=[CH:16][C:3]([C:1]3[NH:17][C:18]4[C:19]([OH:25])=[CH:20][CH:21]=[CH:22][C:23]=4[N:24]=3)=[CH:4][CH:5]=2)[S:12]1
Reactant: Nc1cccc(O)c1N
Reactant: O=Cc1ccc(C=C2SC(=O)NC2=O)cc1
Product: O=C1NC(=O)C(=Cc2ccc(-c3nc4cccc(O)c4[nH]3)cc2)S1

Procedure:
2-[4-[(2,4-Dioxothiazolidin-5-ylidene)methyl]phenyl]-4-hydroxybenzimidazole was prepared from 5-(4-formylbenzylidene)-2,4-thiazolidinedione and 2,3-diaminophenol by following General Procedure 2.
Reaction SMILES: [CH3:1][C:2]([C:4]1[CH:9]=[CH:8][C:7]([Br:10])=[CH:6][CH:5]=1)=O.[C:11]1([Li])[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>C(OCC)C>[Br:10][C:7]1[CH:8]=[CH:9][C:4]([C:2]([C:11]2[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=2)=[CH2:1])=[CH:5][CH:6]=1
Reactant: CC(=O)c1ccc(Br)cc1
Reactant: [Li]c1ccccc1
Solvent: CCOCC
Product: C=C(c1ccccc1)c1ccc(Br)cc1
Temperature: 120 °C
Yield: 84.6 %

Procedure:
A solution of 4-bromoacetophenone (10.0 g, 50.2 mmol) in 130 mL of dry diethyl ether was added over 1.5 hours to a solution of phenyllithium (30.7 mL of 1.8 M a solution in dibutyl ether, 55.2 mmol) in 70 mL of dry diethyl ether at room temperature under an inert atmosphere. The reaction mixture was stirred while heating to reflux for 3 hours and then was examined by [C-MS which showed complete consumption of starting material. The reaction was quenched with water (500 mL), until gas evolution ceased, and 1 N HCL (31 mL). The organic layer was separated, dried over sodium sulfate and concentrated under reduced pressure. The crude product was used without any further purification. A solution of the crude (1-(4-bromo-phenyl)-1-phenyl-ethanol) and a catalytic amount of p-toluenesulfonic acid in toluene (100 mL) was heated at 120° C. for 16 h in a flask equipped with a Dean-Stark apparatus. The reaction mixture was examined by LC-MS which showed complete consumption of starting material. Solvent was evaporated under reduced pressure and the crude was purified by flash chromatography eluting with cyclohexane/ethyl acetate (100:0 to 98:2) giving 11 g of the title compound as a colorless oil (Yield: 84%)
Reaction SMILES: CN(C=[N:5][S:6]([C:9]1[C:10]([C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:22]3[C:26](C=O)=[C:25]([Cl:29])[N:24]=[C:23]3[C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)=[CH:17][CH:16]=2)=[CH:11][CH:12]=[CH:13][CH:14]=1)(=[O:8])=[O:7])C.Cl.C(O)C>O>[Cl:29][C:25]1[N:24]=[C:23]([C:30]2[CH:31]=[CH:32][CH:33]=[CH:34][CH:35]=2)[N:22]([CH2:21][C:18]2[CH:17]=[CH:16][C:15]([C:10]3[C:9]([S:6]([NH2:5])(=[O:7])=[O:8])=[CH:14][CH:13]=[CH:12][CH:11]=3)=[CH:20][CH:19]=2)[CH:26]=1
Reactant: CN(C)C=NS(=O)(=O)c1ccccc1-c1ccc(Cn2c(-c3ccccc3)nc(Cl)c2C=O)cc1
Agent: Cl
Solvent: O
Solvent: CCO
Product: NS(=O)(=O)c1ccccc1-c1ccc(Cn2cc(Cl)nc2-c2ccccc2)cc1
Yield: 0.5 %

Procedure:
9.2 g of 4′-(4-chloro-5-formyl-2-phenylimidazol-1-ylmethyl)biphenyl-2-sulfonic acid dimethylaminomethylenamide (Example 11a), 95 ml of a saturated aqueous HCl solution and 95 ml of ethanol are refluxed for 2 h. After cooling, the mixture is diluted with 500 ml of water and extracted twice using 500 ml of EA each time and the organic phase is washed twice using 100 ml of a saturated aqueous NaCl solution each time. The extract is dried over Na2SO4 and the solvent is removed in vacuo. The product mixture is recrystallized from 200 ml of EA and 6.2 g of 4′-(4-chloro-5-formyl-2-phenyl-imidazol-1-ylmethyl)biphenyl-2-sulfonamide (compare Example 11b) are obtained. The solvent of the mother liquor is removed in vacuo and the residue is chromatographed on silica gel using MTB/DIP 1:1. 40 mg of a colorless oil are obtained.
Reaction SMILES: [H-].[Na+].[O:3]=[C:4]1[C:9]([C:10]([O:12]C)=[O:11])=[CH:8][CH:7]=[CH:6][N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>CS(C)=O>[O:3]=[C:4]1[C:9]([C:10]([OH:12])=[O:11])=[CH:8][CH:7]=[CH:6][N:5]1[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)c1cccn(-c2ccccc2)c1=O
Agent: [H-]
Agent: [Na+]
Solvent: CS(C)=O
Product: O=C(O)c1cccn(-c2ccccc2)c1=O

Procedure:
The heterocyclic amide derivatives 100 and 105 can be prepared according to the synthetic routes described in Schemes 18 and 19. To this end, methyl 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylate (97) can be obtained in a two step process beginning with commercially available (E)-dimethyl 2-(3-methoxyallylidene)malonate (95) (Scheme 18). Thus, treatment of compound 95 with aniline at room temperature can provide intermediate 96, which can then cyclized in the presence of a base, such as sodium hydride in dimethylsulfoxide to generate 97. Hydrolysis of intermediate 97 under basic conditions can provide 2-oxo-1-phenyl-1,2-dihydropyridine-3-carboxylic acid (98). The carboxylic acid 98 can then be coupled with the aniline derivative 99 in the presence of a coupling reagent, such as 1-(dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDCI) and hydroxybenzotriazole (HOBt) in DMF to furnish the desired compound 100.
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6](B2OC(C)(C)C(C)(C)O2)[CH:5]=[CH:4][C:3]=1[C:17]1[CH:18]=[N:19][C:20]([NH2:23])=[N:21][CH:22]=1.Br[C:25]1[CH:30]=[CH:29][CH:28]=[CH:27][C:26]=1[S:31]([C:34]1([CH2:39][NH2:40])[CH2:38][CH2:37][CH2:36][CH2:35]1)(=[O:33])=[O:32]>>[NH2:40][CH2:39][C:34]1([S:31]([C:26]2[CH:25]=[CH:30][CH:29]=[CH:28][C:27]=2[C:6]2[CH:5]=[CH:4][C:3]([C:17]3[CH:22]=[N:21][C:20]([NH2:23])=[N:19][CH:18]=3)=[C:2]([F:1])[CH:7]=2)(=[O:33])=[O:32])[CH2:38][CH2:37][CH2:36][CH2:35]1
Reactant: CC1(C)OB(c2ccc(-c3cnc(N)nc3)c(F)c2)OC1(C)C
Reactant: NCC1(S(=O)(=O)c2ccccc2Br)CCCC1
Product: NCC1(S(=O)(=O)c2ccccc2-c2ccc(-c3cnc(N)nc3)c(F)c2)CCCC1

Procedure:
The title compound was prepared using conditions analogous to those used to make Example 6 5-(2-fluoro-4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)phenyl)pyrimidin-2-amine and (1-((2-bromophenyl)sulfonyl)cyclopentyl)methanamine. MS (ESI): mass calcd. for C22H23FN5O2S, 426.15; m/z found, 427.1 [M+H]+. 1H NMR (400 MHz, CD3OD) δ 8.54 (d, J=1.3, 2H), 8.20 (dd, J=7.9, 1.2, 1H), 7.83 (m, 1H), 7.73 (m, 1H), 7.57-7.46 (m, 2H), 7.35-7.32 (m, 2H), 2.92 (s, 2H), 2.13-1.99 (m, 2H), 1.65-1.42 (m, 6H).
Reaction SMILES: [F:1][C:2]1[C:10]2[C:6](=[N:7][O+:8]([O-])[N:9]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23].[N-]=[N+]=[N-].[Na+]>C(O)CO>[F:1][C:2]1[C:10]2[C:6](=[N:7][O:8][N:9]=2)[CH:5]=[C:4]([C:12]([O:14][CH3:15])=[O:13])[C:3]=1[NH:16][C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=1[CH3:23]
Reactant: COC(=O)c1cc2n[o+]([O-])nc2c(F)c1Nc1ccccc1C
Agent: [N-]=[N+]=[N-]
Agent: [Na+]
Solvent: OCCO
Product: COC(=O)c1cc2nonc2c(F)c1Nc1ccccc1C

Procedure:
A solution comprised of methyl 7-fluoro-6-(2-methyl-phenylamino)-benzo[1,2,5]oxadiazole-5-carboxylate 2-oxide and sodium azide (1.38 equiv.) in ethylene glycol is heated to 140–150° C. for 30 minutes to obtain, after column chromatography, the desired product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16](Cl)=[CH:17][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2].O.[NH2:24][NH2:25]>>[CH2:1]([O:3][C:4]1[CH:22]=[CH:21][C:7]([C:8]([N:10]2[CH2:20][CH2:19][C:13]3[N:14]=[N:15][C:16]([NH:24][NH2:25])=[CH:17][C:12]=3[CH2:11]2)=[O:9])=[CH:6][CH:5]=1)[CH3:2]
Reactant: NN
Reactant: CCOc1ccc(C(=O)N2CCc3nnc(Cl)cc3C2)cc1
Solvent: O
Product: CCOc1ccc(C(=O)N2CCc3nnc(NN)cc3C2)cc1

Procedure:
11.1 g of 6-(p-ethoxybenzoyl)-3-chloro-5,6,7,8-tetrahydropyrido[4,3-c]pyridazine and 60 cc of hydrazine hydrate are stirred at a bath temperature of 100° for 1 hour and 40 minutes. The title compound has a M.P. of 171°-173° (decomp., from absolute ethanol).
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH:10]2[CH2:15][CH2:14][N:13](C([O-])=O)[CH2:12][CH2:11]2)=[O:8])[CH:2]=1>Cl>[N:1]1[CH:6]=[CH:5][CH:4]=[C:3]([C:7]([NH:9][CH:10]2[CH2:11][CH2:12][NH:13][CH2:14][CH2:15]2)=[O:8])[CH:2]=1
Reactant: O=C(NC1CCN(C(=O)[O-])CC1)c1cccnc1
Agent: Cl
Product: O=C(NC1CCNCC1)c1cccnc1

Procedure:
A mixture of 1.2 g of the ethylene ketal of 4-(3-pyridinecarbonylamino)-1-piperidinecarboxylate and 20 mL of 6N HCl was heated under reflux for 6 h. The mixture was cooled, extracted with 20 mL of dichloromethane, then basified with 6N NaOH and extracted with 3×50 mL of chloroform. The combined chloroform extracts were dried over MgSO4 and concentrated under reduced pressure. Drying under vacuum gave 0.6 g of 4-(3-pyridinecarbonylamino)piperidine as an oil: 1H NMR (400 MHz, CDCl3) 8.96 (d, J=2 Hz, 1H), 8.72 (m, 1H), 8.10 (m, 1H), 7.40 (m, 2H).