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)[C:9](=[O:13])[CH2:8][CH2:7][CH2:6]2.C(NC(C)C)(C)C.[Li].C1(C)C=CC(S([Cl:31])(=O)=O)=CC=1>C1COCC1>[Cl:31][CH:8]1[CH2:7][CH2:6][C:5]2[C:10](=[CH:11][CH:12]=[C:3]([O:2][CH3:1])[CH:4]=2)[C:9]1=[O:13]
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: COc1ccc2c(c1)CCCC2=O
Agent: [Li]
Solvent: C1CCOC1
Solvent: CC(C)NC(C)C
Product: COc1ccc2c(c1)CCC(Cl)C2=O
Temperature: 25 °C
Reaction time: 0.5 h

Procedure:
A solution of 6-Methoxy-3,4-dihydro-2H-naphthalen-1-one (5.0 g, 28.37 mmol) in THF (25 ml) is slowly added under an atmosphere of argon at −78° C. to a solution of lithium diisopropyl amine in THF (25 ml; prepared from 4.0 ml of diisopropylamine (28.37 mmol) and 17.7 ml of 1.6 M n-BuLi in hexane (28.37 mmol)). After 30 minutes at −78° C., a solution of para-tolylsulfonyl chloride (5.41 g, 28.37 mmol) in THF (25 ml) is added during 20 minutes. The dry ice cooling bath is removed, and the reaction mixture is allowed to reach RT. After 1 h, TLC analysis indicates complete consumption of starting material. A sat. aqueous solution of NH4Cl (100 ml) is added, and the mixture is stirred at RT for 15 minutes. The organic layer is separated, washed with brine, dried over Na2SO4 and concentrated. Purification by FCC (hexane/EtOAc 920:80 to 880:120) yields the title compound. 1H NMR (CDCl3, 400 MHz): δ 2.54-2.63 (m, 1H), 2.68-2.75 (m, 1H), 3.04-3.12 (m, 1H), 3.38-3.46 (m, 1H), 4.02 (s, 3H); 4.72-4.76 (m, 1H), 6.87 (s, 1H), 7.00-7.04 (m, 1H), 8.22 (d, J=10 Hz, 1H). ES+-MS: 279.1, 280.9 [M+H]+.
Reaction SMILES: C([O:3][C:4]([CH:6]1[CH2:11][CH2:10][N:9]([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:8][CH2:7]1)=O)C.O.[NH2:19][NH2:20]>CO>[N:9]1([C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][N:13]=2)[CH2:10][CH2:11][CH:6]([C:4]([NH:19][NH2:20])=[O:3])[CH2:7][CH2:8]1
Reactant: NN
Reactant: CCOC(=O)C1CCN(c2ccccn2)CC1
Solvent: O
Solvent: CO
Product: NNC(=O)C1CCN(c2ccccn2)CC1
Temperature: 25 °C
Yield: 52.1 %

Procedure:
3,4,5,6-Tetrahydro-2H-[1,2′]bipyridinyl-4-carboxylic acid ethyl ester (1 g, 4.3 mmol)(see reference Farmaco, 1993, 48(10), 1439) was dissolved in methanol (20 ml) containing hydrazine hydrate (620 μl, 20 mmol) and was heated under reflux for 18 hours. The mixture was cooled to room temperature and evaporated under reduced pressure. The solid formed was triturated with propan-2-ol to give the title compound as a white solid (493 mg).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N+:9]([O-])=[CH:8][CH:7]=[CH:6]2.COC(Cl)=O.C([Mg]Br)[C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1>C1COCC1>[CH3:1][O:2][C:3]1[CH:4]=[C:5]2[C:10](=[CH:11][CH:12]=1)[N:9]=[C:8]([C:20]1[CH:25]=[CH:24][C:23]([O:26][CH3:27])=[CH:22][CH:21]=1)[CH:7]=[CH:6]2
Reactant: COc1ccc(C[Mg]Br)cc1
Reactant: COc1ccc2c(ccc[n+]2[O-])c1
Agent: COC(=O)Cl
Solvent: C1CCOC1
Product: COc1ccc(-c2ccc3cc(OC)ccc3n2)cc1
Temperature: -78 °C
Reaction time: 0.33 h
Yield: 52 %

Procedure:
A 500 mL round-bottom flask is charged with 6-methoxy quinoline-N-oxide (8 g, 0.04566 mol.) and placed under nitrogen. The solid is then dissolved in anhydrous THF (100 mL) and cooled to −78° C. with a dry ice/acetone bath, whereupon some of the dissolved solid begins to precipitate. From an addition funnel, methylchloroformate (4.4 ml, 0.05694 mol.) is added dropwise. The bath is removed 10 minutes after the addition, and replaced after 20 minutes. A dropwise addition of 0.5 M anisylmagnesium bromide (112 mL, 0.0560 mol.) is then made. The bath is removed after the addition and the reaction is allowed to warm to room temperature. The reaction is quenched with 5% sodium bicarbonate solution. The THF is removed in vacuo and the resulting mixture is diluted with water and extracted with methylene chloride. The extracts are collected and dried with anhydrous sodium sulfate and concentrated. The crude product is purified by flash chromatography (2-5% EtOAc/dichloromethane) to yield 6.30 g (52%) of the desired product. 1H NMR: ∂ 8.03-8.11 (m, 4H), 7.78 (d, J=8.8 Hz, 1H), 7.37 (dd, J=9 Hz, 3 Hz, 1H), 7.03-7.07 (m, 3H), 3.94 (s, 1H), 3.88 (s, 1H). LCMS: 2.188 min, 266 (M+).
Reaction SMILES: [OH:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7](=[O:13])[O:8][C:9]([CH3:12])([CH3:11])[CH3:10].N1C=CC=CC=1.[C:20](OC(=O)C)(=[O:22])[CH3:21]>C(OCC)(=O)C>[C:20]([O:1][CH2:2][CH2:3][CH2:4][CH2:5][NH:6][C:7]([O:8][C:9]([CH3:10])([CH3:12])[CH3:11])=[O:13])(=[O:22])[CH3:21]
Reactant: CC(=O)OC(C)=O
Reactant: CC(C)(C)OC(=O)NCCCCO
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: CC(=O)OCCCCNC(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 19 h
Yield: 97.2 %

Procedure:
To a mixture of tert-butyl 4-hydroxybutylcarbamate (3.83 g) obtained in Reference Synthetic Example 35 and ethyl acetate (20 mL) were added pyridine (1.80 mL) and acetic anhydride (2.27 g), and stirred at room temperature for 19 hrs. To the reaction solution was added ethyl acetate (100 mL), and washed with water (50 mL), aqueous solution of copper sulfate (30 mL), water (30 mL) and saturated brine (30 mL), followed by drying over anhydrous magnesium sulfate. The solution was concentrated under reduced pressure to give title compound as colorless oil (4.55 g).
Reaction SMILES: [CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:15]=[CH:14][C:13]([C:16]3[C:17]([C:22]([O:24]C(C)(C)C)=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:12][CH:11]=2)[C:7]2[CH:29]=[C:30]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3].FC(F)(F)C(O)=O>C(Cl)Cl>[CH2:1]([C:4]1[N:8]([CH2:9][C:10]2[CH:11]=[CH:12][C:13]([C:16]3[C:17]([C:22]([OH:24])=[O:23])=[CH:18][CH:19]=[CH:20][CH:21]=3)=[CH:14][CH:15]=2)[C:7]2[CH:29]=[C:30]([C:34]3[NH:35][C:36]4[CH:42]=[CH:41][CH:40]=[CH:39][C:37]=4[N:38]=3)[CH:31]=[C:32]([CH3:33])[C:6]=2[N:5]=1)[CH2:2][CH3:3]
Reactant: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)OC(C)(C)C)cc1
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: CCCc1nc2c(C)cc(-c3nc4ccccc4[nH]3)cc2n1Cc1ccc(-c2ccccc2C(=O)O)cc1

Procedure:
Prepared analogously to Example 1 from tert.-butyl 4'-[[2-n-propyl-4-methyl-6-(benzimidazol-2-yl)-benzimidazol-1-yl]-methyl]-biphenyl-2-carboxylate and trifluoroacetic acid in methylene chloride.
Reaction SMILES: [C:1]1([CH:9]=[CH:8][CH:7]=[C:5]([OH:6])[C:3]=1[OH:4])[OH:2].[Cl-].[Al+3].[Cl-].[Cl-].C(Cl)(Cl)Cl.[C:18](=[O:21])([O-])[O-].[Na+].[Na+]>CN(C)C=O.ClCCl>[OH:2][C:1]1[CH:9]=[CH:8][C:7]2[C:18](=[O:21])[C:1]3[C:9]([O:6][C:5]=2[C:3]=1[OH:4])=[CH:8][CH:7]=[CH:5][CH:3]=3
Reactant: O=C([O-])[O-]
Reactant: Oc1cccc(O)c1O
Agent: [Al+3]
Agent: [Cl-]
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Solvent: ClC(Cl)Cl
Product: O=c1c2ccccc2oc2c(O)c(O)ccc12
Temperature: 25 °C
Reaction time: 17 h
Yield: 35.9 %

Procedure:
To a stirring solution of 2-fluorobenzoic acid (5.09 g, 36.3 mmol) and dichloromethane (110 mL) in an ice bath under argon was added dropwise a solution of oxalyl chloride (2.0 M in dichloromethane, 21 mL, 42 mmol), followed by dimethylformamide (6 drops). The ice bath was removed and the solution was stirred at room temperature for 1.5 h. The solution was then concentrated by rotary evaporation. The product was dissolved in hexane (3×50 mL) and the mixture was filtered. The filtrate was rotary evaporated to yield 5.42 g of colorless oil. The oil was added dropwise to a mixture of pyrogallol (6.48 g, 51.3 mmol), aluminum chloride (14.6 g, 110 mmol), chloroform (250 mL) and dichloromethane (700 mL), and the solution was stirred for 17 h at room temperature. The solution was then refluxed for 3 h and cooled to room temperature. The solution was washed with 1 N HCl (3×500 mL). The organic layer was filtered, dried over sodium sulfate, and evaporated to yield an oil. The oil was added to dimethylformamide (120 mL) with sodium carbonate (8.11 g, 76.5 mmol) and it was refluxed for 3.5 h. The solution was concentrated by rotary evaporation with heating, and the residue was purified by column chromatography (95:5 chloroform/methanol) to give a solid. The solid was washed with hexane (2×35 mL), filtered and dried to yield 2.10 g (25 %) of the title compound as an off-white solid. 1H NMR (DMSO-d6, 300 MHz): δ 8.16 (d, J=7.42 Hz, 1H), 7.84 (t, J=7.69 Hz, 1H), 7.64 (d, J=8.52 Hz, 1H), 7.57 (d, J=8.79 Hz, 1H), 7.44 (t, J=7.41 Hz, 1H), 6.94 (d, J=8.52 Hz, 1H).
Reaction SMILES: [CH:1]([C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[C:4]=1[CH3:19])=[O:2].C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C(=O)(O)[O-].[Na+]>ClCCCl.C(Cl)Cl>[OH:2][CH2:1][C:3]1[S:11][C:10]2[C:9](=[O:12])[C:8]([C:13]([O:15][CH2:16][CH3:17])=[O:14])=[CH:7][N:6]([CH3:18])[C:5]=2[C:4]=1[CH3:19]
Reactant: CCOC(=O)c1cn(C)c2c(C)c(C=O)sc2c1=O
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCCl
Solvent: ClCCl
Solvent: CC(=O)O
Product: CCOC(=O)c1cn(C)c2c(C)c(CO)sc2c1=O
Temperature: 0 °C
Reaction time: 0.08 h
Yield: 94.9 %

Procedure:
To a 0° C. mixture of ethyl 2-formyl-3,4-dimethyl-7-oxo-4,7-dihydrothieno[3,2-b]pyridine-6-carboxylate (695 mg, 2.49 mmol) and glacial acetic acid (0.71 mL, 12.5 mmol) in 1,2-dichloroethane (23 mL) was added sodium triacetoxyborohydride (1.06 g, 4.98 mmol). After stirring for 5 min at 0° C., the reaction was stirred at room temperature for 3.5 hours. The reaction was poured into sat. aqueous. sodium bicarbonate (50 mL) and methylene chloride (30 mL), stirred vigorously for 5 minutes, and filtered. The collected solid was washed with water and methylene chloride, then dried in vacuo, leaving an off-white solid (665 mg, 93%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][C:11](=O)[N:10](C)[CH:9]1[C:15]([CH3:18])(C)C)=[O:7])([CH3:4])([CH3:3])[CH3:2].C[C@H]1CNCCN1.C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH3:18][C@@H:15]1[NH:10][CH2:11][CH2:12][N:8]([C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH2:9]1
Reactant: CN1C(=O)CN(C(=O)OC(C)(C)C)C1C(C)(C)C
Agent: C[C@H]1CNCCN1
Solvent: CCN(CC)CC
Solvent: ClC(Cl)Cl
Product: C[C@H]1CN(C(=O)OC(C)(C)C)CCN1
Temperature: 25 °C
Reaction time: 15 h

Procedure:
To a solution of 1-(tert-butoxycarbonyl)-2-tert-butyl-3-methyl-4-imidazolidinone (2 g, 8,3 mmol) (BOC-ON) in chloroform (15 ml) was added (2S)-2-methylpiperazine (5 g, 50 mmol), a compound of formula (6), and triethylamine (1.25 g, 12.5 mmol) in chloroform. The mixture was stirred for about 15 hours at room temperature, and then washed with water, the solvent removed from the organic layer under reduced pressure, and the residue purified using column chromatography, to give tert-butyl (3S)-3-methylpiperazinecarboxylate, a compound of formula (7).
Reaction SMILES: [CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[NH:7][C:6]=2[CH:5]=[CH:4][CH:3]=1.F[C:20]1[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=1.N1C=CC=CC=1N1C2C=CC=CC=2N=C1/C=C/C1C=CC=CC=1.[ClH:49]>CO>[ClH:49].[CH3:1][C:2]1[C:10]2[N:9]=[C:8](/[CH:11]=[CH:12]/[C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][CH:14]=3)[N:7]([C:20]3[CH:25]=[CH:24][CH:23]=[CH:22][N:21]=3)[C:6]=2[CH:5]=[CH:4][CH:3]=1
Reactant: Fc1ccccn1
Reactant: Cc1cccc2[nH]c(/C=C/c3ccccc3)nc12
Agent: C(=C/c1nc2ccccc2n1-c1ccccn1)\c1ccccc1
Agent: Cl
Solvent: CO
Product: Cc1cccc2c1nc(/C=C/c1ccccc1)n2-c1ccccn1

Procedure:
Free base of the titled compound was prepared from (E)-4-methyl-2-styryl-1H-benzimidazole and 2-fluoropyridine according to the preparation of (E)-1-(2-pyridyl)-2-styryl-1H-benzimidazole (Example 1, method B). The free base was treated with a 10% methanol solution of hydrogen chloride and concentrated to dryness. The residue was recrystallized from 2-propanol/isopropyl ether to give the titled compound.
Reaction SMILES: CC(C)(C)C(NC1C=CC=CC=1[C:12]1[C:25]2[C:24](=O)[C:23]3[C:18](=[CH:19][CH:20]=[CH:21][CH:22]=3)[N:17]([CH3:27])[C:16]=2[CH:15]=[CH:14][CH:13]=1)=O.C([O-])([O-])=O.[Na+].[Na+]>C1COCC1>[CH3:27][N:17]1[C:16]2[C:25]3[C:12](=[C:15]4[C:16](=[N:17][C:24]=3[C:23]3[CH:22]=[CH:21][CH:20]=[CH:19][C:18]1=3)[CH:25]=[CH:12][CH:13]=[CH:14]4)[CH:13]=[CH:14][CH:15]=2
Reactant: Cn1c2ccccc2c(=O)c2c(-c3ccccc3NC(=O)C(C)(C)C)cccc21
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Product: CN1c2ccccc2-c2nc3ccccc3c3cccc1c23
Yield: 95 %

Procedure:
(Method H-2) (Cyclisation) 2,2-Dimethyl-N-[2-(10-methyl-9-oxo-9,10-dihydro-acridin-1-yl)-phenyl]-propionamide, 25 (50 mg, 0.13 mmol) was dissolved in 1:1 THF/6N HCl (20 mL) and the mixture heated to reflux for 5 days giving a bright orange solution. The mixture was basified (aq. Na2CO3) and extracted with ethyl acetate (50 mL) and the organic layer dried (Na2SO4), and evaporated under reduced pressure. The crude product was purified by column chromatography (1:4 EtOAc: hexane) to give the title compound as a yellow solid (35 mg, 0.12 mmol, 95%).
Reaction SMILES: [OH:1][NH:2][C:3]([C:5]1[CH:10]=[C:9]([SH:11])[N:8]2[N:12]=[C:13]([CH3:15])[N:14]=[C:7]2[N:6]=1)=[O:4].CC(O[CH2:20][C:21]1[CH2:30][S:29][C@@H:24]2[C@H:25]([NH2:28])[C:26](=[O:27])[N:23]2[C:22]=1[C:31]([OH:33])=[O:32])=O.B(F)(F)F.CCOCC.ClCCl>S1(CCCC1)(=O)=O.ClCCl>[NH2:28][C@@H:25]1[C:26](=[O:27])[N:23]2[C@@H:24]1[S:29][CH2:30][C:21]([CH2:20][S:11][C:9]1[N:8]3[N:12]=[C:13]([CH3:15])[N:14]=[C:7]3[N:6]=[C:5]([C:3](=[O:4])[NH:2][OH:1])[CH:10]=1)=[C:22]2[C:31]([OH:33])=[O:32]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Cc1nc2nc(C(=O)NO)cc(S)n2n1
Agent: FB(F)F
Solvent: ClCCl
Solvent: O=S1(=O)CCCC1
Solvent: CCOCC
Product: Cc1nc2nc(C(=O)NO)cc(SCC3=C(C(=O)O)N4C(=O)[C@@H](N)[C@H]4SC3)n2n1
Temperature: 25 °C
Reaction time: 3 h
Yield: 67.4 %

Procedure:
N-Hydroxy-7-mercapto-2-methyl-s-triazolo[1,5-a]pyrimidine-5-carboxamide (250 mg) (1.1 mmol) and 275 mg (1.0 mmol) of 7-amino-cephalosporanic acid are suspended in 15 ml of sulpholane/dichloromethane (1:1 v/v) and treated at 0° C. with 3.5 ml of boron trifluoride diethyl etherate. The mixture is stirred at 0°-5° C. for 2 hours and at room temperature for 3 hours. Subsequently, 60 ml of dichloromethane are added. Insoluble material is filtered off under suction, dissolved in water and treated with saturated sodium bicarbonate solution until pH value 3 has been reached. The precipitated product is filtered off under suction and washed in succession with water and diethyl ether. There are obtained 295 mg of (6R,7R)-7-amino-3-[[[5-(hydroxycarbamoyl)-2-methyl-s-triazolo[1,5-a]pyrimidin-7-yl]thio]methyl]-8-oxo-5-thia-1-azabicyclo[4.2.0]oct-2-ene-2-carboxylic acid as a beige powder.
Reaction SMILES: Cl.Cl.[Cl:3][C:4]1C=C(C2(O)CCCCC2CCN2CCN(C)CC2)C=CC=1OCC1C=CC=CC=1C(F)(F)F.Cl.Cl.[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:66][CH2:65][NH:64][CH2:63][CH2:62]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]([F:58])([F:57])[F:56]>>[ClH:3].[ClH:40].[Cl:40][C:41]1[CH:42]=[C:43]([CH:59]([C:67]2([OH:73])[CH2:72][CH2:71][CH2:70][CH2:69][CH2:68]2)[CH2:60][N:61]2[CH2:62][CH2:63][N:64]([CH3:4])[CH2:65][CH2:66]2)[CH:44]=[CH:45][C:46]=1[O:47][CH2:48][C:49]1[CH:54]=[CH:53][CH:52]=[CH:51][C:50]=1[C:55]([F:57])([F:58])[F:56]
Reactant: CN1CCN(CCC2CCCCC2(O)c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)CC1
Reactant: OC1(C(CN2CCNCC2)c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)CCCCC1
Agent: Cl
Product: CN1CCN(CC(c2ccc(OCc3ccccc3C(F)(F)F)c(Cl)c2)C2(O)CCCCC2)CC1

Procedure:
In an analogous manner to Example 24, 1-[1-(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)-2-(4-methylpiperazin-1-yl)ethylcyclohexanol dihydrochloride was prepared from 1-[1-(3-chloro-4-{[2-(trifluoromethyl)benzyl]oxy}phenyl)-2-piperazin-1-ylethyl]cyclohexanol dihydrochloride (See Example 421). MS (ESI) m/z 511; HRMS: calcd for C27H34ClF3N2O2+H+, 511.23336; found (ESI, [M+H]+), 511.2314.
Reaction SMILES: Br[C:2]1[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=[C:6]([Br:8])[CH:7]=1.[NH:11]1[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:23])([CH3:22])[CH3:21])[CH2:12]1.C(=O)([O-])[O-].[Cs+].[Cs+].CC1(C)C2C(=C(P(C3C=CC=CC=3)C3C=CC=CC=3)C=CC=2)OC2C(P(C3C=CC=CC=3)C3C=CC=CC=3)=CC=CC1=2>O1CCOCC1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[Br:8][C:6]1[CH:7]=[C:2]([N:11]2[CH2:16][CH2:15][CH2:14][C@H:13]([NH:17][C:18](=[O:24])[O:19][C:20]([CH3:22])([CH3:21])[CH3:23])[CH2:12]2)[C:3](=[O:10])[N:4]([CH3:9])[CH:5]=1
Reactant: Cn1cc(Br)cc(Br)c1=O
Reactant: CC(C)(C)OC(=O)N[C@H]1CCCNC1
Agent: [Pd]
Agent: CC1(C)c2cccc(P(c3ccccc3)c3ccccc3)c2Oc2c(P(c3ccccc3)c3ccccc3)cccc21
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Solvent: C1COCCO1
Product: Cn1cc(Br)cc(N2CCC[C@H](NC(=O)OC(C)(C)C)C2)c1=O
Temperature: 110 °C
Reaction time: 8 h
Yield: 59.4 %

Procedure:
A mixture of 3,5-dibromo-1-methyl-pyridin-2-one (2.000 mmol; 533.8 mg), tert-butyl N-[(3S)-3-piperidyl]carbamate (2.00 mmol; 401 mg), cesium carbonate (4.0 mmol; 1303 mg), Xantphos (0.3400 mmol; 202.8 mg), and tris(dibenzylideneacetone)dipalladium(0) (0.2000 mmol; 185.0 mg) in 1,4-Dioxane (10 mL) was purged with Argon, then sealed and stirred at 110° C. overnight. The mixture was cooled to room temperature and filtered through Celite. The filtrate was concentrated and the residue was purified on silica eluted with 0 to 100% EtOAc in Heptane to afford tert-butyl N-[(3S)-1-(5-bromo-1-methyl-2-oxo-3-pyridyl)-3-piperidyl]carbamate as a yellow solid (458.6 mg, 59%).
Reaction SMILES: [Br:1][C:2]1[C:9]([OH:10])=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[OH-].[K+].F[C:16]1[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=1>CS(C)=O.O>[Br:1][C:2]1[C:9]([O:10][C:16]2[CH:21]=[CH:20][C:19]([N+:22]([O-:24])=[O:23])=[CH:18][CH:17]=2)=[C:8]([O:11][CH3:12])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5]
Reactant: COc1ccc(C=O)c(Br)c1O
Reactant: O=[N+]([O-])c1ccc(F)cc1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Solvent: O
Product: COc1ccc(C=O)c(Br)c1Oc1ccc([N+](=O)[O-])cc1
Temperature: 130 °C
Reaction time: 3 h

Procedure:
2-Bromo-3-hydroxy-4-methoxy-benzaldehyde (15.0 g, 64.9 mmoles) is dissolved in DMSO (100 mL). Potassium hydroxide (4.01 g, 71.4 mmoles) and 1-Fluoro-4-nitro-benzene (13.74 g, 97.4 mmoles) are added to the solution. The reaction mixture is stirred at 130° C. for 3 hours. As the crude is poured in water (500 mL), precipitation occurs. The solid is filtered, washed with water and dried under vacuum overnight. The pale-brown solid obtained (23.4 g) is used in the next step without further purification.
Reaction SMILES: C12(CS(O)(=O)=O)C(C)(C)C(CC1)CC2=O.[NH2:16][C:17]1[CH:18]=[CH:19][C:20]2[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[NH:22][C:21]=2[CH:28]=1.[CH:29]1([CH2:32][NH:33][C:34](=[O:51])[C:35]2[CH:40]=[CH:39][CH:38]=[C:37]([F:41])[C:36]=2[NH:42][C:43]2[C:48]([Cl:49])=[CH:47][N:46]=[C:45](Cl)[N:44]=2)[CH2:31][CH2:30]1.C(O)(C)C>C(#N)C.O>[Cl:49][C:48]1[C:43]([NH:42][C:36]2[C:37]([F:41])=[CH:38][CH:39]=[CH:40][C:35]=2[C:34]([NH:33][CH2:32][CH:29]2[CH2:31][CH2:30]2)=[O:51])=[N:44][C:45]([NH:16][C:17]2[CH:18]=[CH:19][C:20]3[CH2:26][CH2:25][CH2:24][C:23](=[O:27])[NH:22][C:21]=3[CH:28]=2)=[N:46][CH:47]=1
Reactant: Nc1ccc2c(c1)NC(=O)CCC2
Reactant: O=C(NCC1CC1)c1cccc(F)c1Nc1nc(Cl)ncc1Cl
Agent: CC1(C)C2CCC1(CS(=O)(=O)O)C(=O)C2
Solvent: CC#N
Solvent: CC(C)O
Solvent: O
Product: O=C1CCCc2ccc(Nc3ncc(Cl)c(Nc4c(F)cccc4C(=O)NCC4CC4)n3)cc2N1

Procedure:
10-Camphorsulfonic acid (21 mg, 0.090 mmol), 8-Amino-1,3,4,5-tetrahydro-benzo[b]azepin-2-one (53 mg, 0.30 mmol) and N-Cyclopropylmethyl-2-(2,5-dichloro-pyrimidin-4-ylamino)-3-fluoro-benzamide (110 mg, 0.30 mmol) in Acetonitrile (3 mL) was irradiated in a CEM microwave (120° C., 40 min) Only partial conversion, due to poor solvation. Add Isopropyl alcohol (2 mL) and irradiate an additional 3 h, 120° C. Work up by pouring into 20 mL 1:1 water:satd. aq. sodium bicarbonate and extract with DCM (2×15 mL), wash with brine, dry over sodium sulfate and conc. onto 1 g silica gel. Chromatography (ISCO, 2×12 g silica, 0-5% MeOH:DCM) to afford 2-[5-Chloro-2-(2-oxo-2,3,4,5-tetrahydro-1H-benzo[b]azepin-8-ylamino)-pyrimidin-4-ylamino]-N-cyclopropylmethyl-3-fluoro-benzamide as an off white film (60 mg, 40%). LCMS: 495 (M+H); 1H-NMR (DMSO): 9.32 (s, 1H), 9.25 (s, 1H), 9.13 (s, 1H), 8.49 (m, 1H), 8.16 (s, 1H), 7.45 (m, 2H), 7.38 (m, 1H), 7.19 (d, 1H, J=8.4 Hz), 7.09 (s, 1H), 6.92 (d, 1H, J=8.2 Hz), 3.31 (s, 2H), 3.07 (t, 2H, J=6.0 Hz), 2.55 (m, 2H), 2.03 (m, 4H), 0.89 (m, 1H), 0.35 (m, 2H), 0.14 (m, 2H); 19F-NMR (DMSO): −115.
Reaction SMILES: O1[C:5]2([CH2:10][CH2:9][C:8]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][C:12]=3[CH2:17][OH:18])=[CH:7][CH2:6]2)[O:4]CC1.C(O)(C(F)(F)F)=O>C(Cl)Cl>[C:8]12([CH2:9][CH2:10][C:5](=[O:4])[CH2:6][CH2:7]1)[C:11]1[C:12](=[CH:13][CH:14]=[CH:15][CH:16]=1)[CH2:17][O:18]2
Reactant: OCc1ccccc1C1=CCC2(CC1)OCCO2
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: O=C1CCC2(CC1)OCc1ccccc12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a solution of [2-(1,4-dioxa-spiro[4.5]dec-7-en-8-yl)-phenyl]-methanol (1 g, 4.06 mmol, as prepared in the previous step) in DCM (2 mL) was added TFA (8 mL) and stirred at RT, 2 hours followed by removal of solvent in vacuo to afford the title compound.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([C:8]2[CH:9]=[CH:10][C:11]([C:14]([OH:16])=O)=[N:12][CH:13]=2)[CH:5]=[CH:6][CH:7]=1.[F:17][C:18]1[CH:23]=[C:22]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH2:31][NH2:32])=[CH:26][N:25]=2)[CH:21]=[CH:20][N:19]=1.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1.CCN(C(C)C)C(C)C>CN(C=O)C.CS(C)=O>[F:17][C:18]1[CH:23]=[C:22]([C:24]2[C:29]([CH3:30])=[CH:28][C:27]([CH2:31][NH:32][C:14](=[O:16])[C:11]3[CH:10]=[CH:9][C:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([F:1])[CH:3]=4)=[CH:13][N:12]=3)=[CH:26][N:25]=2)[CH:21]=[CH:20][N:19]=1
Reactant: O=C(O)c1ccc(-c2cccc(F)c2)cn1
Reactant: Cc1cc(CN)cnc1-c1ccnc(F)c1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CS(C)=O
Solvent: CN(C)C=O
Product: Cc1cc(CNC(=O)c2ccc(-c3cccc(F)c3)cn2)cnc1-c1ccnc(F)c1
Temperature: 25 °C
Reaction time: 2 h

Procedure:
To a mixture of 5-(3-fluorophenyl)picolinic acid 6-7 (32 mg, 0.15 mmol), (2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methanamine 30-5 (28 mg, 0.13 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluroniumhexafluorophosphate (HATU) (60 mg, 0.16 mmol) in DMF (1.0 mL) was added DIEA (0.068 mL, 0.39 mmol) at room temperature. The mixture was stirred at room temperature for 2 hours. The reaction mixture was diluted into DMSO and purified by HPLC to give N-((2′-fluoro-3-methyl-2,4′-bipyridin-5-yl)methyl)-5-(3-fluorophenyl)picolinamide 30 as a white solid. MS m/z 417.2 (M+1). 1H NMR 400 MHz (DMSO-d6) δ 9.54 (t, 1H), 8.95 (dd, 1H), 8.47 (d, 1H), 8.29 (m, 2H), 8.07 (dd, 1H), 7.69 (m, 2H), 7.63 (m, 1H), 7.55 (m, 1H), 7.48 (m, 1H), 7.29 (m, 2H), 4.52 (d, 2H), 2.28 (s, 3H).
Reaction SMILES: [H-].[Na+].[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([SH:12])=[CH:8][CH:7]=1)([O-:5])=[O:4].Cl.Cl[CH2:15][CH2:16][C:17]1[N:18]=[CH:19][NH:20][CH:21]=1>CN(C)C=O.[I-].C([N+](CCCC)(CCCC)CCCC)CCC>[N+:3]([C:6]1[CH:11]=[CH:10][C:9]([S:12][CH2:15][CH2:16][C:17]2[N:18]=[CH:19][NH:20][CH:21]=2)=[CH:8][CH:7]=1)([O-:5])=[O:4]
Reactant: O=[N+]([O-])c1ccc(S)cc1
Reactant: ClCCc1c[nH]cn1
Agent: CCCC[N+](CCCC)(CCCC)CCCC
Agent: Cl
Agent: [H-]
Solvent: CN(C)C=O
Product: O=[N+]([O-])c1ccc(SCCc2c[nH]cn2)cc1
Temperature: 25 °C
Reaction time: 1 h

Procedure:
200 mg (60% in oil, 5 mmol) of sodium hydride are added to a solution of 1.86 g (12 mmol) of 4-nitrothiophenol in 10 ml of dimethylformamide. The mixture is stirred at room temperature for 1 hour under nitrogen. 200 g (1.2 mmol) of 4-(2-chloroethyl)-1H-imidazole hydrochloride and tetrabutylammonium iodide (catalytic amount) are then added. The mixture is heated for 1 day at 80° C. and then the solvent is evaporated under reduced pressure. The residue is stirred in diethyl ether and filtered. Dilute hydrochloric acid is added to the filtrate and the excess 4-nitrothiophenol is removed by extracting with diethyl ether. The aqueous solution is basified with potassium carbonate and then the title compound is extracted with chloroform and crystallized from ethanol, M.p.: 167°-168° C.