Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH3:1][N:2]=[C:3]=[O:4].Cl[C:6]1[CH:7]=[C:8]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:31][CH2:32][CH2:33][NH:34][CH3:35])[N:24]=[CH:23][N:22]=2)[CH:9]=C[C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1.[CH2:36]([Cl:38])Cl>>[Cl:38][C:36]1[CH:9]=[C:8]([NH:20][C:21]2[C:30]3[C:25](=[CH:26][CH:27]=[CH:28][C:29]=3[O:31][CH2:32][CH2:33][N:34]([CH3:35])[C:3]([NH:2][CH3:1])=[O:4])[N:24]=[CH:23][N:22]=2)[CH:7]=[CH:6][C:11]=1[O:12][CH2:13][C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][N:15]=1
Reactant: CN=C=O
Reactant: ClCCl
Reactant: CNCCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Product: CNC(=O)N(C)CCOc1cccc2ncnc(Nc3ccc(OCc4ccccn4)c(Cl)c3)c12
Reaction time: 2 h
Yield: 83 %

Procedure:
Methyl isocyanate (0.035 ml) was added slowly to a stirred solution of N-[3-chloro-4-(pyridin-2-ylmethoxy)phenyl]-5-[2-(methylamino)ethoxy]quinazolin-4-amine (obtained as described in Example 1, preparation of starting materials, 217 mg) in DCM (10 ml). The resulting solution was stirred for 2 hours and then evaporated. The residue was triturated with acetonitrile and the resulting solid washed with ether to give the title compound as a solid (205 mg, 83%); NMR spectrum (DMSO-d6 @ 373K) 2.85 (s, 3H), 2.95 (s, 3H), 3.75-3.85 (t, 2H), 4.35-4.45 (t, 2H), 5.25 (s, 2H), 5.90-6.00 (bs, 1H), 7.10-7.15 (d, 1H), 7.15-7.25 (d, 1H), 7.30-7.37 (t, 2H), 7.52-7.60 (m, 2H), 7.65-7.73 (t, 1H), 7.80-7.86 (m, 1H), 7.94-7.99 (d, 1H), 8.44 (s, 1,H), 8.55-8.60 (d, 1H), 9.80 (s, 1H); Mass spectrum MH+ 493.4.
Reaction SMILES: [O:1]1[C:10]2[C:5](=[N:6][CH:7]=[CH:8][CH:9]=2)[O:4][C@@H:3]([CH2:11][OH:12])[CH2:2]1.[Br:13]Br.[O-]S([O-])=O.[Na+].[Na+]>C(Cl)Cl.C([O-])([O-])=O.[Na+].[Na+]>[Br:13][C:8]1[CH:9]=[C:10]2[O:1][CH2:2][C@H:3]([CH2:11][OH:12])[O:4][C:5]2=[N:6][CH:7]=1.[Br:13][C:9]1[CH:8]=[CH:7][N:6]=[C:5]2[O:4][CH:3]([CH2:11][OH:12])[CH2:2][O:1][C:10]=12
Reactant: OC[C@H]1COc2cccnc2O1
Reactant: BrBr
Agent: O=C([O-])[O-]
Agent: O=S([O-])[O-]
Agent: [Na+]
Solvent: ClCCl
Product: OCC1COc2c(Br)ccnc2O1
Product: OC[C@H]1COc2cc(Br)cnc2O1
Temperature: 25 °C
Reaction time: 16 h

Procedure:
To a solution of intermediate (2-a) (0.03 mol) in DCM (50 ml) and Na2CO3 saturated (50 ml), bromine (0.09 mol) was added dropwise and the reaction mixture was stirred for 16 hours at room temperature. Then a Na2SO3-solution (10%) was added and the mixture was stirred for 5 minutes at room temperature and then neutralized with a saturated Na2CO3-solution. The aqueous layer was extracted with DCM and the separated combined organic layers were dried, filtered and the solvent was evaporated. The residue was purified by short open column chromatography over silica gel (eluent: CH2Cl2/(MeOH/NH3 saturated) 95/5). The desired fractions were collected and the solvent was evaporated. The residue was purified by high-performance liquid chromatography over silica gel (eluent: CH2Cl2/(MeOH/NH3 saturated) 97/3). The product fractions were collected and the solvent was evaporated, yielding 2.7 g of (S)-7-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol (intermediate 41) and 0.26 g of 8-bromo-2,3-dihydro-[1,4]dioxino[2,3-b]pyridine-3-methanol (intermediate 42)
Reaction SMILES: [N-:1]=[C:2]=[S:3].[Na+].N1C=CC=CC=1.CS(O[N:16]=[C:17](Cl)[C@H:18]1[CH2:22][O:21][C:20]2([CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]2)[O:19]1)(=O)=O.[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH2:50])=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[C:32]([CH3:51])[N:31]=1>C(#N)C>[CH3:29][C:30]1[C:35]([O:36][C:37]2[C:38]([NH:50][C:2]3[S:3][N:16]=[C:17]([C@H:18]4[CH2:22][O:21][C:20]5([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27]5)[O:19]4)[N:1]=3)=[N:39][CH:40]=[C:41]([S:43][C:44]3[CH:49]=[CH:48][CH:47]=[CH:46][N:45]=3)[CH:42]=2)=[CH:34][CH:33]=[C:32]([CH3:51])[N:31]=1
Reactant: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2N)c(C)n1
Reactant: CS(=O)(=O)ON=C(Cl)[C@H]1COC2(CCCCC2)O1
Reactant: [N-]=C=S
Agent: [Na+]
Solvent: CC#N
Solvent: c1ccncc1
Product: Cc1ccc(Oc2cc(Sc3ccccn3)cnc2Nc2nc([C@H]3COC4(CCCCC4)O3)ns2)c(C)n1
Temperature: 60 °C
Reaction time: 0.33 h
Yield: 41.4 %

Procedure:
To a solution of sodium isothiocyanate (0.24 g, 3.0 mmol) in acetonitrile (30 mL) was added pyridine (0.51 g, 6.5 mmol) followed by (R)—N-(methylsulfonyloxy)-1,4-dioxaspiro[4.5]decane-2-carbimidoyl chloride (0.77 g, 2.6 mmol) and the reaction was stirred at 60° C. for 20 minutes, followed by addition of 3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-amine (0.70 g, 2.2 mmol) and the reaction was stirred overnight at 60° C. The reaction was concentrated in vacuo and the residue partitioned between EtOAc and 2 M NaOH. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The material was purified over silica gel (30% EtOAc in CH2Cl2) to afford (S)—N-(3-(2,6-dimethylpyridin-3-yloxy)-5-(pyridin-2-ylthio)pyridin-2-yl)-3-(1,4-dioxaspiro[4.5]decan-2-yl)-1,2,4-thiadiazol-5-amine (0.50 g, 0.91 mmol, 42% yield).
Reaction SMILES: [CH3:1][O:2][CH2:3][CH2:4][N:5]1[CH2:10][CH2:9][CH:8]([CH2:11][OH:12])[CH2:7][CH2:6]1.CN1CCOCC1.Cl[C:21]([O:23][C:24]1[CH:29]=[CH:28][C:27]([N+:30]([O-:32])=[O:31])=[CH:26][CH:25]=1)=[O:22]>C(Cl)Cl>[C:21](=[O:22])([O:23][C:24]1[CH:25]=[CH:26][C:27]([N+:30]([O-:32])=[O:31])=[CH:28][CH:29]=1)[O:12][CH2:11][CH:8]1[CH2:9][CH2:10][N:5]([CH2:4][CH2:3][O:2][CH3:1])[CH2:6][CH2:7]1
Reactant: COCCN1CCC(CO)CC1
Reactant: O=C(Cl)Oc1ccc([N+](=O)[O-])cc1
Solvent: CN1CCOCC1
Solvent: ClCCl
Product: COCCN1CCC(COC(=O)Oc2ccc([N+](=O)[O-])cc2)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 51 %

Procedure:
To a solution of (1-(2-methoxyethyl)piperidin-4-yl)methanol (3.65 g, 21.1 mmol) and NMM (2.5 mL, 22.8 mmol) in DCM (100 mL) at 0° C. was added p-nitrophenyl chloroformate. The reaction mixture was stirred at room temperature overnight and then washed sequentially with sat aq NaHCO3 solution (5×100 mL), dried (MgSO4) and concentrated in vacuo. The resulting orange oil was recrystallised from EtOAc and heptane to give (1-(2-methoxyethyl)piperidin-4-yl)methyl 4-nitrophenyl carbonate (3.65 g, 51%) as an orange solid.
Reaction SMILES: C([O:3][C:4]([CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1)=O)C.Cl.[NH2:16][OH:17].[O-]CC.[Na+].Cl>C(O)C>[OH:17][NH:16][C:4]([CH2:6][C:7]1[N:8]2[CH:14]=[N:13][CH:12]=[C:9]2[S:10][CH:11]=1)=[O:3]
Reactant: CCOC(=O)Cc1csc2cncn12
Reactant: NO
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: O=C(Cc1csc2cncn12)NO
Temperature: 25 °C
Reaction time: 2 h
Yield: 73.1 %

Procedure:
To 2 ml of an ethanol solution containing 204.3 mg of 3-ethoxycarbonylmethylimidazo[5,1-b]thiazole, 108.2 mg of hydroxylamine hydrochloride and 210.2 mg of a sodium ethoxide powder were added, and the mixture was then stirred at room temperature for 2 hours. Under ice-cooling, 0.4 ml of 1N hydrochloric acid was added to the reaction solution to neutralize the solution. The solvent was evaporated under reduced pressure, and the resulting residue was purified by Diaion HP-20 Resin to obtain 140 mg of the title compound.
Reaction SMILES: [C:1]1([CH2:7][N:8]2[CH2:12][CH2:11][CH2:10][CH:9]2[C:13]2[CH:14]=[C:15]([OH:19])[CH:16]=[CH:17][CH:18]=2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.[CH3:20][N:21]=[C:22]=[O:23].C(=O)([O-])[O-].[K+].[K+]>O1CCCC1>[CH3:20][NH:21][C:22](=[O:23])[O:19][C:15]1[CH:16]=[CH:17][CH:18]=[C:13]([CH:9]2[CH2:10][CH2:11][CH2:12][N:8]2[CH2:7][C:1]2[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=2)[CH:14]=1
Reactant: Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reactant: CN=C=O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: C1CCOC1
Product: CNC(=O)Oc1cccc(C2CCCN2Cc2ccccc2)c1
Reaction time: 1 h
Yield: 70 %

Procedure:
To a solution of 3-[1-phenylmethyl-2-pyrrolidinyl]phenol (1.0 g) in dry tetrahydrofuran (50 ml) was added methyl isocyanate (0.24 ml) followed by milled potassium carbonate (0.7 g) at ambient temperature, under nitrogen. The reaction mixture was stirred for 1 hr, filtered through a pad of celite, and the filter cake was washed with ethyl acetate. The combined filtrates were concentrated. The residue was purified by flash column chromatography (silica gel, dichloromethane/0-10% ethyl acetate). The appropriate fractions were collected and concentrated to give 0.8 g (70%) of product.
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][CH:12]=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2].[Li][CH2:18]CCC.CI.[Cl-].[NH4+].N>C(OCC)C>[CH2:1]([O:3][C:4]1[CH:9]=[CH:8][C:7]([C:10]2[Se:11][C:12]([CH3:18])=[CH:13][CH:14]=2)=[C:6]([F:15])[C:5]=1[F:16])[CH3:2]
Reactant: [Li]CCCC
Reactant: CCOc1ccc(-c2ccc[se]2)c(F)c1F
Agent: N
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCOCC
Solvent: CI
Product: CCOc1ccc(-c2ccc(C)[se]2)c(F)c1F
Temperature: -70 °C
Reaction time: 22 h

Procedure:
6.25 g (20.7 mmol) of 2-(4-ethoxy-2,3-difluorophenyl)selenophene are initially introduced in 50 ml of diethyl ether, and 16.9 ml (26.9 mmol, 15% soln. in hexane) of n-BuLi are metered in rapidly. The mixture is heated under reflux for 25 min and subsequently cooled to −70° C. 7.0 ml (0.11 mol) of methyl iodide are added in one portion, and the mixture is warmed to RT and stirred for 22 h. Sat. ammonium chloride soln. and conc. ammonia soln. are added, and the batch is stirred vigorously for a few minutes. The organic phase is separated off, and the aqueous phase is extracted with MTBE. The combined organic phases are washed with 2 N hydrochloric acid and sat. sodium chloride soln. and dried using sodium sulfate. The solution is concentrated to dryness, and the residue is purified by column chromatography (SiO2, n-heptane:EtOAc=20:1→10:1→5:1). The further purification is carried out by recrystallisation from n-heptane; 2-(4-ethoxy-2,3-difluorophenyl)-5-methylselenophene is obtained as a colourless solid (m.p. 76° C.).
Reaction SMILES: [NH:1]1[CH2:5][CH2:4][CH2:3][CH2:2]1.Cl[C:7]1[CH:12]=[C:11]([C:13]2[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=2)[N:10]=[C:9]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=2)[CH:8]=1>CC(O)(CC)C.[Cl-].[Zn+2].[Cl-]>[N:1]1([C:7]2[CH:12]=[C:11]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][N:14]=3)[N:10]=[C:9]([C:19]3[CH:24]=[CH:23][CH:22]=[CH:21][N:20]=3)[CH:8]=2)[CH2:5][CH2:4][CH2:3][CH2:2]1
Reactant: C1CCNC1
Reactant: Clc1cc(-c2ccccn2)nc(-c2ccccn2)c1
Agent: [Cl-]
Agent: [Zn+2]
Solvent: CCC(C)(C)O
Product: c1ccc(-c2cc(N3CCCC3)cc(-c3ccccn3)n2)nc1

Procedure:
28 mg (<5 mol %) of zinc(II) chloride and 4.4 g (61.5 mmol) of pyrrolidine are added in succession to a mixture of 1.1 g (4.1 mmol) of 4′-chloro-[2,2′;6′,2″]terpyridine in 15 ml of 2-methyl-2-butanol. The mixture is heated at reflux for 20 hours, cooled and filtered. After recrystallisation from toluene, pure 4′-pyrrolidin-1-yl-[2,2′;6′,2″]terpyridine is obtained in the form of a white solid. MS (EI, 70 eV): m/z=303 (15); 302 (90, [M+]); 273 (100); 233 (25).
Reaction SMILES: [F:1][C:2]1[CH:11]=[C:10]([F:12])[CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][C:6](=[O:13])[NH:7]2.[H-].[Na+].[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34]Cl)[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:22]=[CH:21][CH:20]=[CH:19][CH:18]=1.C(OC(=O)NC1CCN(CCN2C3C(=CC=C(F)C=3F)C=CC2=O)CC1)(C)(C)C>>[CH2:16]([O:23][C:24]([NH:26][C@@H:27]1[CH2:32][CH2:31][N:30]([CH2:33][CH2:34][N:7]2[C:8]3[C:3](=[C:2]([F:1])[CH:11]=[C:10]([F:12])[CH:9]=3)[CH:4]=[CH:5][C:6]2=[O:13])[CH2:29][C@@H:28]1[C:36]([O:38][CH3:39])=[O:37])=[O:25])[C:17]1[CH:18]=[CH:19][CH:20]=[CH:21][CH:22]=1
Reactant: COC(=O)[C@H]1CN(CCCl)CC[C@H]1NC(=O)OCc1ccccc1
Reactant: O=c1ccc2c(F)cc(F)cc2[nH]1
Agent: CC(C)(C)OC(=O)NC1CCN(CCn2c(=O)ccc3ccc(F)c(F)c32)CC1
Agent: [H-]
Agent: [Na+]
Product: COC(=O)[C@H]1CN(CCn2c(=O)ccc3c(F)cc(F)cc32)CC[C@H]1NC(=O)OCc1ccccc1

Procedure:
5,7-Difluoroquinolin-2(1H)-one (Intermediate 25) (350 mg, 1.93 mmol) was deprotonated with sodium hydride (85 mg, 60% in oil, 2.13 mmol) and alkylated with methyl (3S,4R)-4-{[(benzyloxy)carbonyl]amino}-1-(2-chloroethyl)piperidine-3-carboxylate (Intermediate 36) (1.93 mmol) as described for Intermediate 20. Colorless hard foam, 604 mg (63%).
Reaction SMILES: [F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]3)=[CH:15][CH:14]=2)[N:9]=[CH:8][C:7]=1[CH2:25][C:26]([NH2:28])=[O:27].N1C=CC=CC=1.[CH3:40][S:41](Cl)(=[O:43])=[O:42].C(=O)(O)[O-].[Na+]>C(Cl)Cl.O>[F:1][C:2]1[C:32]([F:33])=[CH:31][CH:30]=[CH:29][C:3]=1[CH2:4][NH:5][C:6]1[CH:11]=[C:10]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([N:19]3[CH2:20][CH2:21][N:22]([S:41]([CH3:40])(=[O:43])=[O:42])[CH2:23][CH2:24]3)=[CH:15][CH:14]=2)[N:9]=[CH:8][C:7]=1[CH2:25][C:26]([NH2:28])=[O:27]
Reactant: NC(=O)Cc1cnc(Nc2ccc(N3CCNCC3)cc2)cc1NCc1cccc(F)c1F
Reactant: CS(=O)(=O)Cl
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: c1ccncc1
Solvent: ClCCl
Product: CS(=O)(=O)N1CCN(c2ccc(Nc3cc(NCc4cccc(F)c4F)c(CC(N)=O)cn3)cc2)CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 66.8 %

Procedure:
To a suspension of 60 mg of 4-[(2,3-difluorobenzyl)amino]-6-([4-(piperazin-1-yl)phenyl]amino)pyridine-3-carboxyamide (the compound of Example 220) in 2 mL of methylene chloride, under ice cooling, 20 mg of pyridine and 28 mg of methanesulfonyl chloride were added, and stirred at room temperature for 30 minutes. To the reaction mixture, saturated sodium bicarbonate in water was added, extracted with chloroform:methanol (5:1), washed with saturated saline, and dried on anhydrous sodium sulfate. The solvent was evaporated, the residue was purified by silica gel thin layer chromatography (chloroform:ammonia methanol=10:1) to obtain 47 mg (65%) of the title compound as a brown powder.
Reaction SMILES: C(OC([NH:8][CH:9]([C:13]1[CH:18]=[CH:17][C:16]([N:19]([CH3:23])[C:20]([NH2:22])=[O:21])=[CH:15][CH:14]=1)[C:10]([OH:12])=O)=O)(C)(C)C.CC(O[CH2:28][C:29]1[CH2:38][S:37][C@@H:32]2[C@H:33]([NH2:36])[C:34](=[O:35])[N:31]2[C:30]=1[C:39]([OH:41])=[O:40])=O.[SH:42][C:43]1[N:44]=[N:45][NH:46][CH:47]=1>>[NH:46]1[CH:47]=[C:43]([S:42][CH2:28][C:29]2[CH2:38][S:37][C@@H:32]3[CH:33]([NH:36][C:10](=[O:12])[CH:9]([C:13]4[CH:14]=[CH:15][C:16]([N:19]([CH3:23])[C:20]([NH2:22])=[O:21])=[CH:17][CH:18]=4)[NH2:8])[C:34](=[O:35])[N:31]3[C:30]=2[C:39]([OH:41])=[O:40])[N:44]=[N:45]1
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)[C@@H](N)[C@H]2SC1
Reactant: Sc1c[nH]nn1
Reactant: CN(C(N)=O)c1ccc(C(NC(=O)OC(C)(C)C)C(=O)O)cc1
Product: CN(C(N)=O)c1ccc(C(N)C(=O)NC2C(=O)N3C(C(=O)O)=C(CSc4c[nH]nn4)CS[C@H]23)cc1

Procedure:
When α-t-butoxycarbonylamino-p-(1-methylureido)phenylacetic acid is reacted with 7-ACA and 4-mercapto-1,2,3-triazole according to the procedure of Example 5, the title compound is obtained.
Reaction SMILES: [C:1]([N:9]1[CH2:13][CH:12]=[CH:11][CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH3:14][S:15](Cl)(=O)=O.[NH3:19].C(=O)([O-])[O-].[Na+].[Na+]>O1CCCC1.O.C(Cl)Cl>[C:1]([N:9]1[CH2:13][C@@H:12]([S:15][CH3:14])[C@H:11]([NH2:19])[CH2:10]1)(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CS(=O)(=O)Cl
Reactant: O=C(c1ccccc1)N1CC=CC1
Reactant: N
Agent: O=C([O-])[O-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: ClCCl
Solvent: O
Product: CS[C@@H]1CN(C(=O)c2ccccc2)C[C@H]1N
Temperature: 25 °C
Reaction time: 16 h

Procedure:
41.5 g (0.24 mol) of 1-benzoyl-2,5-dihydropyrrole are initially introduced into 240 ml of methylene chloride, and 24.8 g (0.3 mol) of methanesulphonyl chloride are added dropwise at 0° C. The mixture is subsequently stirred at room temperature for 16 hours, the solvent is then stripped off under 8 mbar and the residue is taken up in 240 ml of tetrahydrofuran. After addition of 65 g of 25% strength ammonia solution, the mixture is heated at 80° C. in an autoclave for 10 hours. It is then poured into 5 times the amount of water, the pH is brought to 10-11 with sodium carbonate, the mixture is extracted with methylene chloride and the extract is dried over sodium sulphate and concentrated. The crude product (50 g) is chromatographed on silica gel (mobile phase initially ethanol:ethyl acetate 1:3, then ethanol; Rf value: 0.34 ethanol).
Reaction SMILES: [C:1]1([C:7]([C:50]2[CH:55]=[CH:54][CH:53]=[CH:52][CH:51]=2)([C:44]2[CH:49]=[CH:48][CH:47]=[CH:46][CH:45]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:24]=[CH:23][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[N+:41]([O-])=O)[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:21][CH:20]=3)=[N:11][N:10]=[N:9]2)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C(O)C.O.NN>[Pd].C(OCC)(=O)C>[C:50]1([C:7]([C:1]2[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=2)([C:44]2[CH:45]=[CH:46][CH:47]=[CH:48][CH:49]=2)[N:8]2[C:12]([C:13]3[CH:18]=[CH:17][CH:16]=[CH:15][C:14]=3[C:19]3[CH:20]=[CH:21][C:22]([CH2:25][O:26][C:27]4[CH:28]=[C:29]([CH:38]=[CH:39][C:40]=4[NH2:41])[C:30]([N:32]4[CH2:37][CH2:36][O:35][CH2:34][CH2:33]4)=[O:31])=[CH:23][CH:24]=3)=[N:11][N:10]=[N:9]2)[CH:51]=[CH:52][CH:53]=[CH:54][CH:55]=1
Reactant: O=C(c1ccc([N+](=O)[O-])c(OCc2ccc(-c3ccccc3-c3nnnn3C(c3ccccc3)(c3ccccc3)c3ccccc3)cc2)c1)N1CCOCC1
Agent: [Pd]
Agent: NN
Solvent: CCOC(C)=O
Solvent: O
Solvent: CCO
Product: Nc1ccc(C(=O)N2CCOCC2)cc1OCc1ccc(-c2ccccc2-c2nnnn2C(c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Temperature: 70 °C
Reaction time: 1 h
Yield: 116.5 %

Procedure:
A solution of the compound ([3]-(33)-587) (0.60 g) prepared in Example 37, ethanol (150 ml), and ethyl acetate (40 ml) was stirred at 70° C. for 15 minutes. After 10% Pd/C (0.10 g) and hydrazine monohydrate (1 ml) were added to the solution, the mixture was stirred at 70° C. for 1 hour. The insolubles were filtered through celite, and the filtrate was concentrated to obtain colorless foam (0.67 g). The product was purified by silica gel column chromatography (Kieselgel 60=80 g, chloroform/ethyl acetate=13/7) to obtain the compound ([3]-(34)-587) (0.09 g).
Reaction SMILES: [C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH2:7][C:6]=2[CH:5]=1)([OH:3])=[O:2].C[C:18](C)([O-:20])C.[K+].C(OCC)=O>CN(C)C=O>[C:1]([C:4]1[CH:16]=[CH:15][C:14]2[C:13]3[C:8](=[CH:9][CH:10]=[CH:11][CH:12]=3)[CH:7]([CH:18]=[O:20])[C:6]=2[CH:5]=1)([OH:3])=[O:2]
Reactant: O=C(O)c1ccc2c(c1)Cc1ccccc1-2
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: CCOC=O
Product: O=CC1c2ccccc2-c2ccc(C(=O)O)cc21
Temperature: 60 °C
Reaction time: 3 h

Procedure:
2-Carboxyfluorene (2.8 g, 0.014 mole) was dissolved in anhydrous dimethylformamide (DMF, 133 mL). Potassium t-butoxide (12.5 g, 0.11 mole) and ethyl formate (400 mL) were added to the reaction solution. The temperature of the solution was increased to 60° C. for 5-10 minutes. The reaction solution was cooled to room temperature. Total reaction time was three hours. Ethyl formate was distilled off and 1M hydrochloric acid (150 mL) was added to the reaction mixture. The solid was filtered and washed with distilled water. The precipitate was dried overnight under reduced pressure with phosphorous pentoxide present. NMR confirmed the structure by the appearance of one new proton at δ11.47 ppm (aldehyde hydrogen).
Reaction SMILES: C(=CN)C1C=CC=CC=1.[CH:10](=[N:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1>[Co]>[CH2:10]([NH:17][CH3:18])[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1.[CH2:10]([NH:17][C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1)[C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1
Reactant: C(=Nc1ccccc1)c1ccccc1
Agent: [Co]
Agent: NC=Cc1ccccc1
Product: CNCc1ccccc1
Product: c1ccc(CNc2ccccc2)cc1

Procedure:
Imines were hydrogenated using in situ-generated complex 2. Hydrogenation of N-benzylidene benzylamine proceeded under 4 atm H2 at 60° C. to afford dibenzylamine in 84% isolated yield using 2 mol % of complex 2 (Table 2, entry 13). N-Benzylidenemethylamine and N-benzylideneaniline were also hydrogenated by the cobalt catalyst, affording N-benzyl methyl amine and N-benzylaniline in good yields (Table 2, entries 14 and 15). Previous examples of cobalt-catalyzed imine hydrogenation are scarce.
Reaction SMILES: [S:1](Cl)([C:4]1[C:16]2[CH:15]=[CH:14][CH:13]=[C:9]([N:10]([CH3:12])[CH3:11])[C:8]=2[CH:7]=[CH:6][CH:5]=1)(=[O:3])=[O:2].[CH2:18]([CH2:20][NH2:21])[OH:19].C(N(CC)CC)C>C(Cl)Cl>[CH3:11][N:10]([CH3:12])[C:9]1[CH:13]=[CH:14][CH:15]=[C:16]2[C:8]=1[CH:7]=[CH:6][CH:5]=[C:4]2[S:1]([NH:21][CH2:20][CH2:18][OH:19])(=[O:3])=[O:2]
Reactant: NCCO
Reactant: CN(C)c1cccc2c(S(=O)(=O)Cl)cccc12
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: CN(C)c1cccc2c(S(=O)(=O)NCCO)cccc12
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
Under nitrogen, dansyl chloride (5.05 g, 18.72 mmol) was placed in a dry 250 mL round bottom flask equipped with a stir bar. Dry methylene chloride (50 mL) was added via syringe, the flask attached to an addition funnel and the system cooled to 0° C. Ethanolamine (1.25 g, 1.24 mL, 20.59 mmol), triethylamine (2.27 g, 3.13 mL, 22.46 mmol), and 75 mL of dry methylene chloride were loaded into the addition funnel, and the solution was added dropwise with stirring over 30 min. The solution was stirred for an additional 30 min before the ice bath was removed, the solution allowed to reach ambient temperature and left to stir for an additional 14 hours.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1)[NH2:5].C[Al](C)C.C[O:23][C:24](=O)/[CH:25]=[C:26](\[NH:28][C:29](=O)[CH2:30][O:31][C:32]1[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=1)/[CH3:27]>C(Cl)Cl>[F:1][C:2]1[CH:3]=[C:4]([N:5]2[C:24](=[O:23])[CH:25]=[C:26]([CH3:27])[N:28]=[C:29]2[CH2:30][O:31][C:32]2[CH:37]=[CH:36][CH:35]=[C:34]([F:38])[CH:33]=2)[CH:6]=[CH:7][C:8]=1[O:9][CH2:10][CH2:11][N:12]1[CH2:13][CH2:14][O:15][CH2:16][CH2:17]1
Reactant: COC(=O)/C=C(/C)NC(=O)COc1cccc(F)c1
Reactant: Nc1ccc(OCCN2CCOCC2)c(F)c1
Agent: C[Al](C)C
Solvent: ClCCl
Product: Cc1cc(=O)n(-c2ccc(OCCN3CCOCC3)c(F)c2)c(COc2cccc(F)c2)n1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 30.3 %

Procedure:
To a solution of 3-fluoro-4-(2-morpholinoethoxy)aniline (0.33 g, 1.37 mmol) in DCM (20 mL) was added trimethylaluminium (2.7 mL, 5.40 mmol, 2 M in toluene) and the mixture was stirred at rt for 0.5 h. A solution of (Z)-methyl-3-(2-(3-fluorophenoxy)acetamido)but-2-enoate (0.37 g, 1.38 mmol) in DCM (5 mL) was added slowly and the resulting mixture was stirred at rt for 24 h. The mixture was quenched with saturated NH4Cl aqueous solution and extracted with CH2Cl2 (50 mL×2). The combined organic phases were washed with brine (100 mL), dried over anhydrous Na2SO4 and concentrated in vacuo. The residue was purified by a silica gel column chromatography (PE/EtOAc (V/V)=30:1) to give the title compound as a pale yellow solid (0.19 g, 30%). The compound was characterized by the following spectroscopic data: