Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[N:10]=[C:9]([F:11])[CH:8]=[CH:7][C:3]=1[C:4]([OH:6])=[O:5].S(=O)(=O)(O)O.O.[C:18](=O)([O-])[O-].[K+].[K+]>CO>[CH3:18][O:5][C:4](=[O:6])[C:3]1[CH:7]=[CH:8][C:9]([F:11])=[N:10][C:2]=1[F:1]
Reactant: O=C(O)c1ccc(F)nc1F
Reactant: O=C([O-])[O-]
Agent: O=S(=O)(O)O
Agent: [K+]
Solvent: CO
Solvent: O
Product: COC(=O)c1ccc(F)nc1F

Procedure:
To 2,6-difluoro-nicotinic acid (59, 5.60 g, 0.0352 mol) in methanol (60.0 mL) was added concentrated sulfuric acid (1.0 mL, 0.019 mol). The reaction was heated to reflux overnight, then poured into water, basified with 1M potassium carbonate to pH around 9, and extracted with ethyl acetate. The organic layer was dried over anhydrous sodium sulfate and concentrated to give a yellow oil (60, 3.5 g, 57.0%).
Reaction SMILES: Br[C:2]1[Se:3][CH:4]=[CH:5][CH:6]=1.[CH2:7]([CH:9]1[CH2:14][CH2:13][CH:12]([C:15]2[CH:20]=[CH:19][C:18](B(O)O)=[C:17]([F:24])[C:16]=2[F:25])[CH2:11][CH2:10]1)[CH3:8].C(=O)([O-])[O-].[Na+].[Na+]>C1(C)C=CC=CC=1.C(O)C.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>[CH2:7]([CH:9]1[CH2:10][CH2:11][CH:12]([C:15]2[CH:20]=[CH:19][C:18]([C:2]3[Se:3][CH:4]=[CH:5][CH:6]=3)=[C:17]([F:24])[C:16]=2[F:25])[CH2:13][CH2:14]1)[CH3:8]
Reactant: Brc1ccc[se]1
Reactant: CCC1CCC(c2ccc(B(O)O)c(F)c2F)CC1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: CCO
Solvent: Cc1ccccc1
Product: CCC1CCC(c2ccc(-c3ccc[se]3)c(F)c2F)CC1

Procedure:
A mixture of 8.9 g (42.4 mmol) of 2-bromoselenophene, 16.0 g (59.7 mmol) of 4-(4-ethylcyclohexyl)-2,3-difluorophenylboronic acid, 3.93 g (3.40 mmol) of tetrakis(triphenylphosphine)palladium(0) and 125 ml of 2 N sodium carbonate soln. in 600 ml of toluene/ethanol (1:1) is heated under reflux for 20 h. After cooling, the organic phase is separated off, and the aqueous phase is extracted with toluene. The combined organic phases are washed with sat. sodium chloride soln., and the solution is dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, toluene). The further purification is carried out by recrystallisation from n-heptane:EtOH=1:1 and IPA. 2-[4-(4-Ethylcyclohexyl)-2,3-difluorophenyl]selenophene is obtained as a pale-yellowish solid.
Reaction SMILES: [CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][C:18](=O)[CH3:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].CCOCC.O>O1CCCC1>[CH2:1]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([NH:17][CH2:18][CH3:19])[CH:14]=2)[CH2:9]1)[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)Nc1ccc2c(c1)CN(Cc1ccccc1)C2
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: CCOCC
Solvent: C1CCOC1
Solvent: O
Product: CCNc1ccc2c(c1)CN(Cc1ccccc1)C2

Procedure:
2-benzyl-5-acetamidoisoindoline prepared above was dissolved in 30 ml of anhydrous tetrahydrofuran and to the solution was dropwise added 600 mg of lithium aluminum hydride dissolved in 10 ml of tetrahydrofuran over 10 minutes. After the mixture was refluxed for 2 hours, ether saturated with water was added to it. The resulting precipitatess were removed by filtration and the filtrate was concentrated. The residue was purified by column chromatography on silica gel (chloroform/methanol =25/1) to obtain 2.19 g of 2-benzyl-5-ethylaminoisoindoline as a dark brown oil.
Reaction SMILES: [C:1](Cl)(=[O:3])[CH3:2].[CH3:5][C:6]1([CH3:32])[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH2:16])=[CH:12][CH:13]=2)[N:8]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:30]=[CH:29][C:28]([F:31])=[CH:27][CH:26]=3)[CH2:19][CH2:18]2)[CH2:7]1.C(N(CC)CC)C.[OH-].[Na+]>O1CCCC1.O>[CH3:5][C:6]1([CH3:32])[C:14]2[C:9](=[CH:10][C:11]([CH2:15][NH:16][C:1](=[O:3])[CH3:2])=[CH:12][CH:13]=2)[N:8]([CH:17]2[CH2:22][CH2:21][N:20]([CH2:23][CH2:24][C:25]3[CH:26]=[CH:27][C:28]([F:31])=[CH:29][CH:30]=3)[CH2:19][CH2:18]2)[CH2:7]1
Reactant: CC1(C)CN(C2CCN(CCc3ccc(F)cc3)CC2)c2cc(CN)ccc21
Reactant: CC(=O)Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: CC(=O)NCc1ccc2c(c1)N(C1CCN(CCc3ccc(F)cc3)CC1)CC2(C)C
Yield: 73.7 %

Procedure:
Under ice cooling, acetyl chloride (0.05 ml) was added dropwise into a solution of 3,3-dimethyl-1-[1-(4-fluorophenethyl)piperidin-4-yl]-6-aminomethylindoline (0.22 g) obtained above and triethylamine (0.5 ml) in tetrahydrofuran (10 ml) and the resultant mixture was stirred at room temperature for 1 hr. Then a 1 N aqueous solution (5 ml) of sodium hydroxide and water (10 ml) were added to the reaction mixture, which was extracted with ethyl acetate, washed with brine and dried over magnesium sulfate. After evaporating the solvent, the residue was purified by silica gel column chromatography (chloroform/methanol system) and crystallized from ethyl acetate/hexane to give the title compound (0.18 g) as a yellowish white powder (yield: 73.7%).
Reaction SMILES: [Br:1][C:2]1[C:3]([C:8]([N:10]([CH2:15][CH2:16][CH2:17][CH3:18])[CH2:11][CH2:12][CH2:13][CH3:14])=[O:9])=[N:4][NH:5][C:6]=1[CH3:7].F[C:20]1[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=2)=[O:25])=[CH:22][C:21]=1[C:36]([N:38]1[CH2:47][CH2:46][C:45]2[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=2)[CH2:39]1)=[O:37]>>[Br:1][C:2]1[C:3]([C:8](=[O:9])[N:10]([CH2:11][CH2:12][CH2:13][CH3:14])[CH2:15][CH2:16][CH2:17][CH3:18])=[N:4][N:5]([C:20]2[CH:35]=[CH:34][C:23]([C:24]([O:26][CH2:27][C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)=[O:25])=[CH:22][C:21]=2[C:36]([N:38]2[CH2:47][CH2:46][C:45]3[C:40](=[CH:41][CH:42]=[CH:43][CH:44]=3)[CH2:39]2)=[O:37])[C:6]=1[CH3:7]
Reactant: O=C(OCc1ccccc1)c1ccc(F)c(C(=O)N2CCc3ccccc3C2)c1
Reactant: CCCCN(CCCC)C(=O)c1n[nH]c(C)c1Br
Product: CCCCN(CCCC)C(=O)c1nn(-c2ccc(C(=O)OCc3ccccc3)cc2C(=O)N2CCc3ccccc3C2)c(C)c1Br
Yield: 40.7 %

Procedure:
Following a procedure analogous to that for the synthesis of Intermediate 1E, 4-bromo-N,N-dibutyl-5-methyl-1H-pyrazole-3-carboxamide (Intermediate 163A, 268 mg, 0.85 mmol) and benzyl 4-fluoro-3-(1,2,3,4-tetrahydroisoquinoline-2-carbonyl)benzoate (Intermediate 122B, 300 mg, 0.77 mmol) were converted to the title compound (215 mg, 41%). 1H NMR (DMSO-d6, 2:1 mixture of amide rotamers) δ 8.21 (dd, J=8.3, 1.9 Hz, 1H), 8.11 (d, J=2.0 Hz, 0.5H), 8.08-8.03 (m, 0.5H), 7.85-7.78 (m, 1H), 7.55-7.33 (m, 5.5H), 7.25-7.06 (m, 3H), 7.05-6.96 (m, 0.5H), 5.47-5.32 (m, 2H), 4.82-4.42 (m, 2H), 3.92-3.71 (m, 0.5H), 3.58-3.34 (m, 3H), 3.23-2.91 (m, 2.5H), 2.82-2.74 (m, 2H), 2.27 (s, 2H), 2.22 (s, 1 H), 1.59-1.13 (m, 4H), 1.07-0.80 (m, 7H), 0.72-0.59 (m, 3H); MS(ESI+) m/z 687.5 (M+H)+.
Reaction SMILES: Cl.[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH:11][C:12]([C:14]2[CH:19]=[CH:18][N:17]=[CH:16][CH:15]=2)=[O:13])[CH:4]=1>O=[Pt]=O.C(O)C>[Cl:2][C:3]1[CH:8]=[CH:7][C:6]([O:9][CH3:10])=[C:5]([NH:11][C:12]([CH:14]2[CH2:15][CH2:16][NH:17][CH2:18][CH2:19]2)=[O:13])[CH:4]=1
Reactant: COc1ccc(Cl)cc1NC(=O)c1ccncc1
Agent: O=[Pt]=O
Agent: Cl
Solvent: CCO
Product: COc1ccc(Cl)cc1NC(=O)C1CCNCC1
Yield: 82.4 %

Procedure:
4-Chloro-2-(4-pyridinecarboxamido)anisole hydrochloride (from E14) (10 g) was hydrogenated over Adams' catalyst (0.25 g) at 300 psi in ethanol (250 ml) at 70° for 6 hours. The residue obtained after filtration and evaporation was taken up in a mixture of ethyl acetate and aqueous sodium carbonate, the organic layer was dried (Na2CO3) filtered and evaporated to give 4-chloro-2-(piperidine-4-carboxamido)anisole as a cream-coloured powder (7.4 g). (A portion was recrystallised from ethyl acetate to give white prisms, m.p. 124°-126°.)
Reaction SMILES: [NH2:1][C:2]1[CH:3]=[C:4]([CH:17]=[CH:18][CH:19]=1)[CH2:5][C:6]1[C:15]2[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=2)[C:9](=[O:16])[NH:8][N:7]=1.[CH3:20][C:21]1[C:22](=[O:27])[O:23][C:24](=O)[CH:25]=1.C(O)(=O)C>O>[CH3:20][C:21]1[C:22](=[O:27])[N:1]([C:2]2[CH:19]=[CH:18][CH:17]=[C:4]([CH2:5][C:6]3[C:15]4[C:10](=[CH:11][CH:12]=[CH:13][CH:14]=4)[C:9](=[O:16])[NH:8][N:7]=3)[CH:3]=2)[C:24](=[O:23])[CH:25]=1
Reactant: Nc1cccc(Cc2n[nH]c(=O)c3ccccc23)c1
Reactant: CC1=CC(=O)OC1=O
Solvent: O
Solvent: CC(=O)O
Product: CC1=CC(=O)N(c2cccc(Cc3n[nH]c(=O)c4ccccc34)c2)C1=O
Reaction time: 65 h

Procedure:
A stirred mixture of 4-(3-aminobenzyl)-2H-phthalazin-1-one (0.1 g, 0.4 mmol; prepared in a manner similar to that described in Example 1), 3-methylfuran-2,5-dione (0.045 g, 0.4 mmol) and acetic acid (4 ml) was heated under reflux for 8.25 hours and allowed to stand at ambient temperature for 65 hours, then it was diluted with water (10 ml). The resulting solid was collected by filtration, washed with water (10 ml) and dried in vacuo to give 3-methyl-1-[3-(4oxo-3,4-dihydrophthalazin-1-ylmethyl)phenyl]pyrrole-2,5-dione (0.068 g) as an off-white solid, 250 MHz 1H-nmr (d6-DMSO) δ (ppm): 1.95 (s, 3H) (CH3), 4.3 (s, 2H) (ArCH2—), 6.7 (s, 1H) (—COCH═CMeCO—), 7.15 (d, 1H) (ArH), 7.2 (s, 1H) (ArH), 7.25–7.35 (m, 2H) (2×ArH), 7.7–7.9 (m, 3H) (3×ArH), 8.2 (d, 1H) (ArH), 12.55 (s, 1H) (CONH); m/z (M+H)+. 346, 100% purity.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][OH:13].[H-].[Na+].[CH3:16]I>C1COCC1>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][C:3]=1[CH2:11][CH2:12][O:13][CH3:16]
Reactant: CI
Reactant: O=[N+]([O-])c1ccc(Br)c(CCO)c1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Product: COCCc1cc([N+](=O)[O-])ccc1Br
Temperature: 0 °C
Yield: 79 %

Procedure:
A solution of 2-(2-bromo-5-nitrophenyl)ethanol (12 g, 48.7 mmol) in THF (100 mL) was cooled to 0° C., then NaH (2.53 g, 60%) was added slowly, followed by stirring at 0° C. for half an hour. Then MeI (33 mL, 487 mmol) was dropwise added, followed by stirring at room temperature overnight. The solvent was evaporated, water was added. The aqueous layer was extracted with ethyl acetate 3 times. The combined organic phase was washed with brine, dried over sodium sulfate and concentrated to give 1-bromo-2-(2-methoxyethyl)-4-nitrobenzene (10 g, yield 80%). 1H NMR: 400 MHz CDCl3 δ 8.15 (s, 1H), 7.95-7.92 (m, 1H), 7.72-7.70 (m, 1H), 3.68-3.65 (m, 2H), 3.37 (s, 3H), 3.12-3.09 (m, 2H).
Reaction SMILES: FC(F)(F)[C:3]1[CH:4]=[C:5]([N+:16]([O-])=O)[CH:6]=[CH:7][C:8]=1[S:9][C:10]1[CH:15]=[CH:14]N=CC=1.SC1C=C[N:25]=[CH:24][CH:23]=1.FC1C=CC([N+]([O-])=O)=CC=1C(F)(F)F.C(=O)([O-])[O-].[K+].[K+]>CN(C=O)C.CCOCC.O>[N:25]1[CH:24]=[CH:23][CH:14]=[CH:15][C:10]=1[S:9][C:8]1[CH:3]=[CH:4][C:5]([NH2:16])=[CH:6][CH:7]=1
Reactant: O=[N+]([O-])c1ccc(Sc2ccncc2)c(C(F)(F)F)c1
Reactant: Sc1ccncc1
Agent: O=C([O-])[O-]
Agent: O=[N+]([O-])c1ccc(F)c(C(F)(F)F)c1
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Solvent: CCOCC
Product: Nc1ccc(Sc2ccccn2)cc1
Yield: 54 %

Procedure:
3-(Trifluoromethyl)-4-(4-pyridinylthio)nitrobenzene: A solution of 4-mercaptopyridine (2.8 g, 24 mmoles), 2-fluoro-5-nitrobenzotrifluoride (5 g, 23.5 mmoles), and potassium carbonate (6.1 g, 44.3 mmoles) in anhydrous DMF (80 mL) was stirred at room temperature and under argon overnight. TLC showed complete reaction. The mixture was diluted with Et2O (100 mL) and water (100 mL) and the aqueous layer was back-extracted with Et2O (2×100 mL). The organic layers were washed with a saturated NaCl solution (100 mL), dried (MgSO4), and concentrated under reduced pressure. The solid residue was triturated with Et2O to afford the desired product as a tan solid (3.8 g, 54%): TLC (30% EtOAc/70% hexane) Rf 0.06; 1H-NMR (DMSO-d6) δ 7.33 (dd, J=1.2, 4.2 Hz, 2H), 7.78 (d, J=8.7 Hz, 1H), 8.46 (dd, J=2.4, 8.7 Hz, 1H), 8.54-8.56 (m, 3H).
Reaction SMILES: [C:1]([C:9]1[C:18]([OH:19])=[CH:17][C:12]2[C:13]([CH2:15][OH:16])=[CH:14][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.C(O)(=[O:22])C>[O-2].[O-2].[O-2].[Cr+6]>[C:1]([C:9]1[C:18]([OH:19])=[CH:17][C:12]2[C:13]([C:15]([OH:22])=[O:16])=[CH:14][C:11]=2[CH:10]=1)(=[O:8])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC(=O)O
Reactant: O=C(c1ccccc1)c1cc2c(cc1O)C(CO)=C2
Agent: [Cr+6]
Agent: [O-2]
Product: O=C(O)C1=Cc2cc(C(=O)c3ccccc3)c(O)cc21
Reaction time: 16 h

Procedure:
1.0 g of 4-benzoyl-5-hydroxybenzocyclobutene-1-methanol is dissolved in 50 ml of acetic acid and then 4.0 g of chromium trioxide are added in portions. The whole is stirred for 16 hours at 40°, concentrated to dryness by evaporation under reduced pressure, taken up in 20 ml of water and extracted by shaking with 80 ml of dichloromethane. The organic phase is dried over magnesium sulphate and concentrated by evaporation. After recrystallisation of the residue from ether/hexane, 4-benzoyl-5-hydroxybenzocyclobutene-1-carboxylic acid is obtained having a melting point of 167°-169°.
Reaction SMILES: Cl[C:2]1[N:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][N:11]=[C:10]([NH:14][C:15]3[CH:20]=[CH:19][C:18]([N:21]4[CH2:26][CH2:25][N:24]([CH3:27])[CH2:23][CH2:22]4)=[CH:17][CH:16]=3)[N:9]=2)=[CH:4][CH:3]=1>C(N)CN>[CH3:27][N:24]1[CH2:25][CH2:26][N:21]([C:18]2[CH:19]=[CH:20][C:15]([NH:14][C:10]3[N:9]=[C:8]([C:5]4[CH:4]=[CH:3][C:2]([NH:21][CH2:22][CH2:23][NH2:24])=[N:7][CH:6]=4)[CH:13]=[CH:12][N:11]=3)=[CH:16][CH:17]=2)[CH2:22][CH2:23]1
Reactant: CN1CCN(c2ccc(Nc3nccc(-c4ccc(Cl)nc4)n3)cc2)CC1
Solvent: NCCN
Product: CN1CCN(c2ccc(Nc3nccc(-c4ccc(NCCN)nc4)n3)cc2)CC1
Temperature: 120 °C
Yield: 71.8 %

Procedure:
0.15 g (0.39 mmol) of [4-(6-Chloro-pyridin-3-yl)-pyrimidin-2-yl]-[4-(4-methyl-piperazin-1-yl)-phenyl]-amine was dissolved in 2.5 mL ethylenediamine and heated in a sealed tube at 120° C. for 18 h. The reaction was cooled and evaporated to dryness and the crude product was purified by silica gel column chromatography using dichloromethane:methanol:triethylamine (9:1:0.05 to 1:1:0.05) to give the title compound as a pale yellow solid (58 mg, 0.14 mmol, 36%). The product was dissolved in dichloromethane (2 mL) then 0.51 M hydrochloric acid:diethyl ether (0.275 mL, 0.14 mmol) was added, it was stirred for 0.5 h. The mixture was evaporated and the residue was suspended in methanol and filtered to give N-(5-{2-[4-(4-Methyl-piperazin-1-yl)-phenylamino]-pyrimidin-4-yl}-pyridin-2-yl)-ethane-1,2-diamine hydrochloride (35.5 mg, 0.08 mmol, 21%). ESMS m/z 405 (M+H)+; 1H NMR (400 MHz, DMSO-d6) δ ppm 9.23 (s, 1H), 8.84 (d, J=2.0 Hz, 1H), 8.36 (d, J=5.3 Hz, 1H), 8.15 (dd, J=8.8, 2.3 Hz, 1H), 7.87 (br. S., 3H), 7.62 (d, J=9.3 Hz, 2H), 7.33 (t, J=6.3 Hz, 1H), 7.19 (d, J=5.3 Hz, 1H), 6.91 (d, J=9.3 Hz, 2H), 6.65 (d, J=8.5 Hz, 1H), 3.57 (q, J=6.3 Hz, 2H), 3.05-3.12 (m, 4H), 3.01 (t, J=6.3 Hz, 2H), 2.46-2.49 (m, 4H), 2.25 (s, 3H).
Reaction SMILES: C(OC(N1[CH2:12][CH2:11][CH:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])C1)=O)(C)(C)C.[C:31](N1CCC(N)C1)([O:33][C:34](C)([CH3:36])[CH3:35])=O>>[CH3:31][O:33][C:34]1[CH:35]=[C:10]([NH:13][C:14]([C:16]2[S:17][CH:18]=[CH:19][C:20]=2[NH:21][C:22]2[CH:27]=[CH:26][N:25]=[C:24]3[NH:28][CH:29]=[CH:30][C:23]=23)=[O:15])[CH:11]=[CH:12][CH:36]=1
Reactant: CC(C)(C)OC(=O)N1CCC(N)C1
Reactant: CC(C)(C)OC(=O)N1CCC(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)C1
Product: COc1cccc(NC(=O)c2sccc2Nc2ccnc3[nH]ccc23)c1

Procedure:
This compound was prepared in an analogous manner as 3-{[3-(1H-Pyrrolo[2,3-b]pyridin-4-ylamino)-thiophene-2-carbonyl]-amino}-pyrrolidine-1-carboxylic acid tert-butyl ester using 3-methoxaniline instead of 1-BOC-3-aminopyrrolidine. LCMS (ESI) 365 (M+H) 1H NMR (400 MHz, DMSO-d6) δ ppm 11.55 (1H, br. s.) 10.06 (1H, s) 9.83 (1H, s) 8.03 (1H, d, J=5.42 Hz) 7.90 (1H, d, J=5.42 Hz) 7.49 (1H, d, J=5.42 Hz) 7.32 (1H, dd, J=3.51, 2.44 Hz) 7.20-7.30 (3H, m) 6.81 (1H, d, J=5.42 Hz) 6.68 (1H, dt, J=7.42, 2.12 Hz) 6.47 (1H, dd, J=3.56, 1.90 Hz) 3.74 (3H, s)
Reaction SMILES: C([O-])([O-])=O.[K+].[K+].F[C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1.[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[OH:26])[C:20]([NH2:22])=[O:21]>CN(C=O)C>[Br:16][C:17]1[CH:18]=[C:19]([CH:23]=[CH:24][C:25]=1[O:26][C:8]1[CH:15]=[CH:14][C:11]([CH:12]=[O:13])=[CH:10][CH:9]=1)[C:20]([NH2:22])=[O:21]
Reactant: NC(=O)c1ccc(O)c(Br)c1
Reactant: O=Cc1ccc(F)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: NC(=O)c1ccc(Oc2ccc(C=O)cc2)c(Br)c1
Temperature: 25 °C
Yield: 57.8 %

Procedure:
Add K2CO3 (1.49 g, 10.8 mmol) to a solution of 4-fluorobenzaldehyde (1.16 mL, 10.8 mmol) and 3-bromo-4-hydroxy-benzamide (1.16 g, 5.4 mmol) in DMF (20 mL). Heat the mixture under N2 overnight. Cool the mixture at room temperature and pour it into ice-water. Extract the aqueous layer with EtOAc. Dry the organic layer over Na2SO4. Eliminate the solvent. Purify by flash chromatography (eluent: EtOAc/hexane 2/1 and 4/1) to get the title compound (1.0 g, 58%). 1H-NMR (metanol-d4, 300 MHz): 9.84 (s, 1H), 8.18 (d, 1H, J=2.0 Hz), 7.88-7.83 (m, 3H), 7.13 (d, 1H, J=8.5 Hz), 7.04-7.01 (m, 2H).
Reaction SMILES: [Cl:1][C:2]1[C:3]([C:10]([OH:12])=[O:11])=[N:4][NH:5][C:6]=1[N+:7]([O-])=O>O.[Mn].[Ni]>[NH2:7][C:6]1[NH:5][N:4]=[C:3]([C:10]([OH:12])=[O:11])[C:2]=1[Cl:1]
Reactant: O=C(O)c1n[nH]c([N+](=O)[O-])c1Cl
Agent: [Mn]
Agent: [Ni]
Solvent: O
Product: Nc1[nH]nc(C(=O)O)c1Cl

Procedure:
Crude 16 (10.0 g, 52.2 mmol) was heated in water (100 mL) to 60° C. int. temperature. The product intermediate 16 contained manganese salts as an impurity, but could be used unpurified in the Raney-Ni reduction to obtain intermediate 17. To this solution was added Raney-Ni (7 g, 50% slurry in water) and dropwise over 4 hours a solution of hydrazine monohydrate (20 mL) in water (200 mL). Hydrazine was more effective as a hydrogen source in this reduction than hydrogen provided at 1 bar. After 1 hour at 60° C. int. temperature the mixture was allowed to cool to ambient temperature, filtered through celite, the filter cake washed with water (200 mL) and the combined filtrates evaporated and dried in vacuo to afford crude 17 (15 g, max. 52.2 mmol), which contained some Ni salts and was used unpurified in the next step.
Reaction SMILES: C([N:8]1[CH2:13][CH2:12][CH:11]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=2)[CH2:10][CH2:9]1)C1C=CC=CC=1>CO.[OH-].[Pd+2].[OH-]>[N:15]1[CH:16]=[CH:17][CH:18]=[CH:19][C:14]=1[CH:11]1[CH2:12][CH2:13][NH:8][CH2:9][CH2:10]1
Reactant: c1ccc(CN2CCC(c3ccccn3)CC2)cc1
Agent: [Pd+2]
Agent: [OH-]
Solvent: CO
Product: c1ccc(C2CCNCC2)nc1
Reaction time: 24 h
Yield: 100.3 %

Procedure:
To 1-benzyl-4-(2-pyridyl)-piperidine (3.26 g, 12.9 mmol) in dry methanol (25 mL), 10% palladium hydroxide (1.9 g) was added and the solution was hydrogenated at 200 psi for 24 hours. The solution was filtered over celite, concentrated to give 2.1 g (99%) of 4-(2-pyridyl)-piperidine which was used as such for the subsequent step. A mixture of 3-bromopropylamine hydrobromide (20 g, 91.3 mmol), potassium carbonate (37.85 g, 273.9 mmol) and di-tert-butyldicarbonate (21.90 g, 100 mmol) in methanol was stirred at room temperature for 24 hours. The reaction mixture was concentrated and partitioned between 250 mL EtOAc and 50 mL water, dried over sodium sulfate, filtered and concentrated. Purification of the crude product by column chromatography (hexane: EtOAc, 4.5:0.5) gave 17.5 g (80%) of the product as a pale yellow oil. To a stirred solution of the 4-(2-pyridyl)-piperidine (1.86 g, 11.4 mmol) in dioxane (20 mL), N-(tert-butoxycarbonyl)-3-bromopropylamine (2.82 g, 11.4 mmol) and potassium carbonate (3.16 g, 22.9 mmol) were added and the solution was refluxed for 24 hours. The reaction mixture was cooled to room temperature, concentrated and partitioned between 40 mL chloroform and 5 mL water. The organic layer was dried over sodium sulfate, filtered and concentrated. The crude product was purified by column chromatography (ethyl acetate: methanol, 4:1) to yield 1.86 g (49%) of the required product as a colorless oil; 1H-NMR (CDCl3): δ1.45 (s, 9 H), 1.54-1.69 (m, 8 H), 2.21-2.68 (m, 2 H), 2.74-2.80 (m, 1 H), 3.02-3.22 (m, 4 H), 5.41 ( s, 1 H), 7.13-7.17 (m, 1 H), 7.33 (d, J=7.93 Hz, 1 H), 7.63 (t, J=7.6 Hz, 1 H), 8.54 (d, J=4.6 Hz, 1 H). To N-(tert-butoxycarbonyl)-3-[4-(2-pyridyl)-piperidin-1-yl]propylamine (0.15 g, 0.45 mmol) in 5 mL of dichloromethane, 1 mL of trifluoroacetic acid was added and the solution was stirred at room temperature for 1 hour. The solution was concentrated, neutralized with 10% KOH solution and extracted into 25 mL of dichloromethane. The organic layer was dried over sodium sulfate, filtered, and concentrated to give 0.098 g (100%) of 3-[4-2-pyridyl)-piperidin-1-yl]propylamine which was used as such for the subsequent step.
Reaction SMILES: Br[CH2:2][CH2:3][O:4][C:5]1[CH:10]=[CH:9][C:8]([N:11]2[CH:16]=[CH:15][C:14]([O:17][CH2:18][C:19]3[CH:24]=[CH:23][C:22]([Cl:25])=[CH:21][N:20]=3)=[CH:13][C:12]2=[O:26])=[CH:7][CH:6]=1.[CH:27]([NH:30][CH3:31])([CH3:29])[CH3:28].CN(C=O)C>O>[Cl:25][C:22]1[CH:23]=[CH:24][C:19]([CH2:18][O:17][C:14]2[CH:15]=[CH:16][N:11]([C:8]3[CH:9]=[CH:10][C:5]([O:4][CH2:3][CH2:2][N:30]([CH:27]([CH3:29])[CH3:28])[CH3:31])=[CH:6][CH:7]=3)[C:12](=[O:26])[CH:13]=2)=[N:20][CH:21]=1
Reactant: CNC(C)C
Reactant: O=c1cc(OCc2ccc(Cl)cn2)ccn1-c1ccc(OCCBr)cc1
Solvent: O
Solvent: CN(C)C=O
Product: CC(C)N(C)CCOc1ccc(-n2ccc(OCc3ccc(Cl)cn3)cc2=O)cc1
Temperature: 60 °C
Reaction time: 48 h
Yield: 98.9 %

Procedure:
A mixture of 1-[4-(2-bromoethoxy)phenyl]-4-[(5-chloro-2-pyridinyl)methoxy]-1H-pyridin-2-one (1.1 g, 2.6 mmols, Step (1) of Example 109), isopropyl(methyl)amine (0.811 mL, 7.8 mmols) and DMF (2.6 mL) was stirred at 60° C. for 2 days. Water was added to the reaction liquid and filtered. So obtained crude title compound was purified on silica gel column chromatography (KP-Sil FLASH 25+M, chloroform:methanol=1:0→5:1) to provide the title compound (1.1 g, 99%).
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][C:11]([CH2:15][NH2:16])([F:14])[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[CH:17]1[C:29]2[CH:28]([CH2:30][O:31][C:32]([N:34]=[C:35]=[S:36])=[O:33])[C:27]3[C:22](=[CH:23][CH:24]=[CH:25][CH:26]=3)[C:21]=2[CH:20]=[CH:19][CH:18]=1>O1CCCC1>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][C:11]([CH2:15][NH:16][C:35]([NH:34][C:32]([O:31][CH2:30][CH:28]2[C:27]3[CH:26]=[CH:25][CH:24]=[CH:23][C:22]=3[C:21]3[C:29]2=[CH:17][CH:18]=[CH:19][CH:20]=3)=[O:33])=[S:36])([F:14])[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CCC(F)(CN)CC1
Reactant: O=C(N=C=S)OCC1c2ccccc2-c2ccccc21
Solvent: C1CCOC1
Product: CC(C)(C)OC(=O)N1CCC(F)(CNC(=S)NC(=O)OCC2c3ccccc3-c3ccccc32)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
After dissolving 4-(aminomethyl)-4-fluoropiperidinecarboxylic acid tert-butyl ester (1071 mg, 4.61 mmol) in tetrahydrofuran (10 ml), FmocNCS (9-fluorenylmethoxycarbonyl isothiocyanate) (1425 mg, 5.07 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the mixture was concentrated and purified by silica gel column chromatography (hexane/ethyl acetate=10/1-5/1) to obtain 4-[({[(fluoren-9-ylmethoxy)carbonylamino] thioxomethyl}amino)methyl]-4-fluoropiperidinecarboxylic acid tert-butyl ester. The compound was identified by LC-MS.