Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([N:4]([CH2:24][CH2:25][CH3:26])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH:12]C(OCC1C=CC=CC=1)=O)=[O:6])[CH2:2][CH3:3].C(OC(C)C)(=O)C.[C:34]([OH:40])([C:36]([F:39])([F:38])[F:37])=[O:35]>[Pd]>[F:37][C:36]([F:39])([F:38])[C:34]([OH:40])=[O:35].[CH2:24]([N:4]([CH2:1][CH2:2][CH3:3])[C:5]([CH2:7][O:8][C:9](=[O:23])[CH2:10][CH2:11][NH2:12])=[O:6])[CH2:25][CH3:26]
Reactant: CCCN(CCC)C(=O)COC(=O)CCNC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)OC(C)C
Product: CCCN(CCC)C(=O)COC(=O)CCN
Temperature: 20 °C
Reaction time: 3.5 h

Procedure:
A solution of 3-benzyloxycarbonylamino-propionic acid dipropylcarbamoylmethyl ester in isopropyl acetate (33.2 g, 91.0 mmol in 129.9 g total mass of solution) was treated with TFA (7.05 ml, 92.0 mmol) while the internal temperature was maintained at 20° C., followed by 10% Pd/C (3.3 g, 50% wet) and stirred under an atmosphere of H2 (3 atm) for 3.5 h to afford 3-amino-propionic acid dipropylcarbamoylmethyl ester trifluoroacetate. The solution was used directly in the next reaction without isolation.
Reaction SMILES: [C:1]([O:5][C:6](=[O:33])[NH:7][CH:8]([C:28]1[NH:29][CH:30]=[CH:31][N:32]=1)[CH2:9][C:10]1[CH:18]=[C:17]([CH3:19])[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:27])([CH3:26])[CH3:25])[N:15]=2)[CH:11]=1)([CH3:4])([CH3:3])[CH3:2].Cl[CH2:35][C:36]1[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=1.C(=O)([O-])[O-].[Cs+].[Cs+]>CN(C)C=O>[CH3:19][C:17]1[C:16]2[C:12](=[CH:13][N:14]([CH2:20][O:21][CH2:22][CH2:23][Si:24]([CH3:25])([CH3:27])[CH3:26])[N:15]=2)[CH:11]=[C:10]([CH2:9][CH:8]([NH:7][C:6](=[O:33])[O:5][C:1]([CH3:4])([CH3:2])[CH3:3])[C:28]2[N:29]([CH2:35][C:36]3[CH:37]=[N:38][CH:39]=[CH:40][CH:41]=3)[CH:30]=[CH:31][N:32]=2)[CH:18]=1
Reactant: ClCc1cccnc1
Reactant: Cc1cc(CC(NC(=O)OC(C)(C)C)c2ncc[nH]2)cc2cn(COCC[Si](C)(C)C)nc12
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: Cc1cc(CC(NC(=O)OC(C)(C)C)c2nccn2Cc2cccnc2)cc2cn(COCC[Si](C)(C)C)nc12
Temperature: 25 °C
Reaction time: 16 h

Procedure:
tert-Butyl-1-(1H-imidazol-2-yl)-2-(7-methyl-2-[{2-[trimethylsilyl]ethoxy}methyl]-2H-indazol-5-yl)ethylcarbamate (48 mg, 0.101 mmol), 3-(chloromethyl)pyridine (18.3 mg, 0.11 mmol, 1.05 equiv), and cesium carbonate (99.0 mg, 0.303 mmol) were combined in dimethylformamide (1.5 mL). After stirring at room temperature for 16 h, the solvents were removed and the residue purified by column chromatography to afford 51.0 mg (92%). Mass spec.: 563.3 (MH)+.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([SH:8])[CH:5]=[CH:4][C:3]=1[C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13].[C:18]([C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][CH2:27][CH2:28]Br)=[C:23]([CH2:32][CH2:33][CH3:34])[C:22]=1[OH:35])(=[O:20])[CH3:19].C(=O)([O-])[O-].[K+].[K+]>C(C(C)=O)C.C(OCC)(=O)C>[C:18]([C:21]1[CH:31]=[CH:30][C:24]([O:25][CH2:26][CH2:27][CH2:28][S:8][C:6]2[CH:5]=[CH:4][C:3]([C:9](=[O:17])[CH:10]([CH3:16])[CH2:11][C:12]([O:14][CH3:15])=[O:13])=[C:2]([Br:1])[CH:7]=2)=[C:23]([CH2:32][CH2:33][CH3:34])[C:22]=1[OH:35])(=[O:20])[CH3:19]
Reactant: COC(=O)CC(C)C(=O)c1ccc(S)cc1Br
Reactant: CCCc1c(OCCCBr)ccc(C(C)=O)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CCC(C)=O
Solvent: CCOC(C)=O
Product: CCCc1c(OCCCSc2ccc(C(=O)C(C)CC(=O)OC)c(Br)c2)ccc(C(C)=O)c1O
Temperature: 25 °C
Reaction time: 12 h

Procedure:
To a solution of the thiol from step C (2.9 g) and 3-(4-acetyl-3-hydroxy-2-propylphenoxy)propylbromide (3.74 g) in methyl ethyl ketone (25 c.c.) was added potassium carbonate (3.78 g, milled) and the suspension was refluxed for 21/2 hours, then stirred at R.T. for 12 hours. The mixture was diluted with ethyl acetate (25 c.c.) and the insolubles filtered off. The filtrate was concentrated to dryness in vacuo and the residue purified on silica gel to yield the title compound as an oil.
Reaction SMILES: [Cl:1][C:2]1[N:7]=[N:6][N:5]=[C:4]([Cl:8])[C:3]=1Cl.[NH3:10].[OH-].[Na+]>>[NH2:10][C:3]1[C:2]([Cl:1])=[N:7][N:6]=[N:5][C:4]=1[Cl:8]
Reactant: Clc1nnnc(Cl)c1Cl
Reactant: N
Agent: [Na+]
Agent: [OH-]
Product: Nc1c(Cl)nnnc1Cl

Procedure:
45 parts of a trichlorotriazine melt at 160° C. are sprayed through a pressure nozzle, below the surface, into a dispersion column which is supplied with 21 parts of a 30% aqueous ammonia solution. The reaction mixture is pumped continuously into a vessel where, at about 25° C. with maintenance of the pH value at 8.5 to 9.0 with sodium hydroxide solution, the substitution is completed. The amino-dichlorotriazine obtained in practically quantitative amounts can be used directly to produce a reactive dye.
Reaction SMILES: [CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20](Cl)(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:10])[C:4]1=[C:24]=[O:25])[CH3:2].[NH3:26]>>[CH2:1]([CH:3]1[CH:7]([CH3:8])[CH2:6][N:5]([C:9]([NH:11][CH2:12][CH2:13][C:14]2[CH:19]=[CH:18][C:17]([S:20]([NH2:26])(=[O:22])=[O:21])=[CH:16][CH:15]=2)=[O:10])[C:4]1=[C:24]=[O:25])[CH3:2]
Reactant: N
Reactant: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(=O)(=O)Cl)cc2)CC1C
Product: CCC1C(=C=O)N(C(=O)NCCc2ccc(S(N)(=O)=O)cc2)CC1C
Reaction time: 0.5 h

Procedure:
To a cooled (0–5° C.) solution of chlorosulfonic acid (22.4 ml), 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene (15 gm) was added in small portions over a period of 1 to 2 hrs. Further it was stirred for 30 minutes at this temperature and then temperature was gradually raised to 30 to 35° C. and stirred for 5 hrs. The reaction mixture was quenched into ice-water, and stirred for 1 hr and filtered to obtain the product 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (18.8 g). To a cooled (0–5° C.) solution of concentrated ammonia (100 ml), 4[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonyl chloride (10 gm) was added in small portions over 30 minutes. The reaction mixture was stirred at this temperature for 30 minutes and then the reaction mixture was allowed to come to room temperature and then stirred for 5 hrs and filtered and dried to obtain 4-[2-(3-Ethyl-4-methyl-2-carbonyl pyrrolidineamido)ethyl]benzene sulfonamide (7.9 gm) having HPLC purity of about 83 to 85%.
Reaction SMILES: [CH:1]1([CH2:7][C@H:8]2[C@H:12]([C@@H:13]([CH:15]3[CH2:17][CH2:16]3)[OH:14])[O:11][C:10]([CH3:19])([CH3:18])[N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:6][CH2:5][CH2:4][CH2:3][CH2:2]1.CC(OI1(OC(C)=O)(OC(C)=O)OC(=O)C2C1=CC=CC=2)=O.CCOCC.[OH-].[Na+]>C(Cl)Cl>[CH:1]1([CH2:7][C@H:8]2[C@H:12]([C:13]([CH:15]3[CH2:16][CH2:17]3)=[O:14])[O:11][C:10]([CH3:19])([CH3:18])[N:9]2[C:20]([O:22][C:23]([CH3:26])([CH3:25])[CH3:24])=[O:21])[CH2:2][CH2:3][CH2:4][CH2:5][CH2:6]1
Reactant: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H]([C@H](O)C2CC2)OC1(C)C
Agent: CC(=O)OI1(OC(C)=O)(OC(C)=O)OC(=O)c2ccccc21
Agent: [Na+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CCOCC
Product: CC(C)(C)OC(=O)N1[C@@H](CC2CCCCC2)[C@H](C(=O)C2CC2)OC1(C)C
Temperature: 25 °C
Reaction time: 3 h
Yield: 80.5 %

Procedure:
A mixture of 500 mg (1.36 mmol) of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-[(R)-cyclopropylhydroxymethyl)-2,2-dimethyl-3-oxazolidinecarboxylate and 750 mg (1.77 mmol) of 1,1-dihydro-1,1,1-triacetoxy-1,2-benziodoxol-3(1H)-one in 10 ml of methylene chloride is stirred at room temperature for 3 hours. Thereafter, 50 ml of ether and 20 ml of 2N sodium hydroxide solution are added and the mixture is stirred at room temperature for 1 hour. The organic phase is separated, washed with 20 ml of 2N sodium hydroxide solution, dried over sodium sulphate and evaporated. There are obtained 400 mg of tert-butyl (4S,5R)-4-(cyclohexylmethyl)-5-(cyclopropylcarbonyl)-2,2-dimethyl-3-oxazolidinecarboxylate as a yellow oil; MS: 366 (M+H)+.
Reaction SMILES: [NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]#[N:9])=[CH:6][N:7]=1.[NH2:14][OH:15]>C(O)C.O>[NH2:1][C:2]1[C:3]([C:10]([NH:12][CH3:13])=[O:11])=[N:4][C:5]([C:8]([NH:14][OH:15])=[NH:9])=[CH:6][N:7]=1
Reactant: NO
Reactant: CNC(=O)c1nc(C#N)cnc1N
Solvent: O
Solvent: CCO
Product: CNC(=O)c1nc(C(=N)NO)cnc1N
Temperature: 25 °C
Reaction time: 1 h
Yield: 67.2 %

Procedure:
3-Amino-6-cyano-N-methylpyrazine-2-carboxamide (839 mg, 4.7 mmol) was suspended in ethanol (25 mL) followed by addition of 50% aqueous hydroxylamine (2 mL, 31.3 mmol) and the mixture was stirred at room temperature for one hour. The suspension obtained was diluted with water (2 5mL) and the insoluble solid collected by filtration and washed with water. The solid was dried in vacuo to give 3-amino-6-[(hydroxyamino)(imino)methyl]-N-methylpyrazine-2-carboxamide (664 mg, 67% yield) as a white solid: MS (EI) for C7H10N6O2: 211 (MH+).
Reaction SMILES: [NH:1]1[C:5]2=[N:6][CH:7]=[CH:8][CH:9]=[C:4]2[CH:3]=[CH:2]1.[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]=[O:20])=[CH:13][CH:12]=1.CO.[OH-].[K+]>ClCCl>[Cl:10][C:11]1[N:16]=[C:15]([O:17][CH3:18])[C:14]([CH:19]([C:3]2[C:4]3[C:5](=[N:6][CH:7]=[CH:8][CH:9]=3)[NH:1][CH:2]=2)[OH:20])=[CH:13][CH:12]=1
Reactant: c1cnc2[nH]ccc2c1
Reactant: COc1nc(Cl)ccc1C=O
Agent: [K+]
Agent: [OH-]
Solvent: ClCCl
Solvent: CO
Product: COc1nc(Cl)ccc1C(O)c1c[nH]c2ncccc12
Temperature: 25 °C
Reaction time: 8 h
Yield: 55.1 %

Procedure:
To 1H-Pyrrolo[2,3-b]pyridine (1, 0.455 g, 3.85 mmol) and 6-chloro-2-methoxypyridine-3-carbaldehyde (26, 0.661 g, 3.85 mmol) was added methanol (10 mL) followed by potassium hydroxide (0.310 g, 5.52 mmol). The reaction was allowed to stir at room temperature overnight. The reaction was extracted with diethyl ether/ethyl acetate and water. The organic layer was separated, dried over anhydrous magnesium sulfate, filtered and volatiles were removed by rotary evaporation to provide a solid that was treated with dichloromethane and stored in a freezer overnight. The white solid was collected by vacuum filtration and dried in vacuo to give 613 mg of compound 27 (2.12 mmol, 55%). MS (ESI) [M+H+]+=290.1.
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][N:5]([CH2:8][C:9]2[CH:10]=[CH:11][C:12]([N+:38]([O-])=O)=[C:13]([NH:15][C:16]3[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:25][C@@H:26]([C:28]4[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=4[C:34]([F:37])([F:36])[F:35])[CH3:27])[CH:17]=3)[CH:14]=2)[CH2:4][CH2:3]1.Cl.COC(OC)OC>C1(C)C=CC=CC=1.[Pd]>[NH2:38][C:12]1[CH:11]=[CH:10][C:9]([CH2:8][N:5]2[CH2:6][CH2:7][N:2]([CH3:1])[CH2:3][CH2:4]2)=[CH:14][C:13]=1[NH:15][C:16]1[S:20][C:19]([C:21]([O:23][CH3:24])=[O:22])=[C:18]([O:25][C@@H:26]([C:28]2[CH:33]=[CH:32][CH:31]=[CH:30][C:29]=2[C:34]([F:35])([F:37])[F:36])[CH3:27])[CH:17]=1
Reactant: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2[N+](=O)[O-])cc1O[C@H](C)c1ccccc1C(F)(F)F
Agent: [Pd]
Agent: Cl
Solvent: Cc1ccccc1
Solvent: COC(OC)OC
Product: COC(=O)c1sc(Nc2cc(CN3CCN(C)CC3)ccc2N)cc1O[C@H](C)c1ccccc1C(F)(F)F

Procedure:
A mixture of methyl 5-({5-[(4-methyl-1-piperazinyl)methyl]-2-nitrophenyl}amino)-3-({(1R)-1-[2-(trifluoromethyl)phenyl]ethyl}oxy)-2-thiophenecarboxylate (0.24 g, 0.415 mmol), 5% Pd/C (0.144 g), HCl (1.25 M in MeOH, 0.034 mL, 0.043 mmol), trimethylorthoformate (1.66 mL, 15.2 mmol) in toluene (0.58 mL) was hydrogenated under a H2 atmosphere at 1.1 bar pressure overnight. The vessel was purged with N2 and the reaction mixture was analysed by HPLC to confirm presence of the title compound which was not purified, but used crude in the next step. LRMS found m/z [ES+] 549.
Reaction SMILES: [CH3:1][C:2]1[C:3]([CH:8]2[CH2:13][CH2:12][CH2:11][CH:10]([C:14]3[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=3)[NH:9]2)=[N:4][CH:5]=[CH:6][CH:7]=1.Br[CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[C:25]([C:29]#[N:30])[CH:24]=1.CCN(C(C)C)C(C)C>CN(C=O)C>[CH3:1][C:2]1[CH2:7][CH2:6][CH:5]=[N:4][C:3]=1[CH:8]1[CH2:13][CH2:12][CH2:11][CH:10]([C:14]2[C:19]([CH3:20])=[CH:18][CH:17]=[CH:16][N:15]=2)[N:9]1[CH2:22][C:23]1[CH:24]=[C:25]([CH:26]=[CH:27][CH:28]=1)[C:29]#[N:30]
Reactant: N#Cc1cccc(CBr)c1
Reactant: Cc1cccnc1C1CCCC(c2ncccc2C)N1
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC1=C(C2CCCC(c3ncccc3C)N2Cc2cccc(C#N)c2)N=CCC1
Yield: 75 %

Procedure:
Using General Procedure A: A solution of 3,3″-dimethyl-1′,2′,3′,4′,5′,6′-hexahydro-[2,2′;6′,2″]terpyridine (0.414 g, 1.55 mmol), α-bromo-m-tolunitrile (0.466 g, 2.38 mmol), KI (53 mg, 0.32 mmol), and DIPEA (0.55 mL, 3.16 mmol) in DMF (8 mL) was heated at 60° C. for 18 hours. Purification of the crude material by column chromatography on silica gel (40:1:1 CH2Cl2—CH3OH—NH4OH) provided 0.447 g (75%) of 3-(3,3″-dimethyl-3′,4′,5 ,6′-tetrahydro-2′H-[2,2′;6′,2″]terpyridin-1′-ylmethyl)-benzonitrile as a beige solid. 1H NMR (CDCl3) δ 1.56-1.72 (m, 3H), 2.05-2.10 (m, 1H), 2.18-2.34 (m, 2H), 2.41 (s, 6H), 3.53 (s, 2H), 4.10 (d, 2H, J=11.1 Hz), 6.71 (s, 1H), 6.83 (d, 1H, J=7.8 Hz), 6.93-7.00 (m, 3H), 7.13 (d, 1H, J=7.5 Hz), 7.25-7.27 (m, 2H), 8.39 (dd, 2H, J=4.8, 1.2 Hz); ES-MS m/z 383 (M+H).
Reaction SMILES: [H-].[Na+].[F:3][C:4]([F:18])([F:17])[C:5]1[CH:10]=[CH:9][CH:8]=[CH:7][C:6]=1[CH:11]([OH:16])[C:12]([F:15])([F:14])[F:13].[NH2:19][C:20]1[N:25]=[C:24](Cl)[CH:23]=[C:22]([Cl:27])[N:21]=1.O>C1COCC1.C(OCC)(=O)C>[Cl:27][C:22]1[CH:23]=[C:24]([O:16][CH:11]([C:6]2[CH:7]=[CH:8][CH:9]=[CH:10][C:5]=2[C:4]([F:17])([F:18])[F:3])[C:12]([F:13])([F:14])[F:15])[N:25]=[C:20]([NH2:19])[N:21]=1
Reactant: OC(c1ccccc1C(F)(F)F)C(F)(F)F
Reactant: Nc1nc(Cl)cc(Cl)n1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: Nc1nc(Cl)cc(OC(c2ccccc2C(F)(F)F)C(F)(F)F)n1
Temperature: 70 °C
Reaction time: 0.33 h
Yield: 71.8 %

Procedure:
NaH (80 mg, 60%, 3.0 mmol) was added to a solution of 1-(2-trifluoromethylphenyl)-2,2,2-trifluoro-ethanol (244 mg, 1 mmol) in 10 ml of anhydrous THF. The mixture was stirred for 20 minutes, 2-amino-4,6-dichloro-pyrimidine (164 mg, 1 mmol) was added and then the reaction mixture was heated at 70° C. for 1 hour. After cooling, 5 ml water was added and ethyl acetate (20 ml) was used to extract the product. The organic layer was dried over sodium sulfate. The solvent was removed by rotovap to give 267 mg of 4-chloro-6-[2,2,2-trifluoro-1-(2-trifluoromethylphenyl)-ethoxy]-pyrimidin-2-ylamine, yield 71%.
Reaction SMILES: C(OC(=O)[NH:10][CH2:11][C:12](=[O:28])[NH:13][CH:14]1[CH2:24][CH:17]2[CH2:18][N:19]([CH:21]([CH3:23])[CH3:22])[CH2:20][CH:16]2[CH:15]1[CH2:25][O:26][CH3:27])C1C=CC=CC=1>Br.C(O)(=O)C.CCOCC>[NH2:10][CH2:11][C:12]([NH:13][CH:14]1[CH2:24][CH:17]2[CH2:18][N:19]([CH:21]([CH3:22])[CH3:23])[CH2:20][CH:16]2[CH:15]1[CH2:25][O:26][CH3:27])=[O:28]
Reactant: COCC1C(NC(=O)CNC(=O)OCc2ccccc2)CC2CN(C(C)C)CC21
Agent: Br
Solvent: CC(=O)O
Solvent: CCOCC
Product: COCC1C(NC(=O)CN)CC2CN(C(C)C)CC21

Procedure:
A solution of [(2-isopropyl-4-methoxymethyloctahydrocyclopenta[c]pyrrol-5-ylcarbamoyl)methyl]carbamic acid benzyl ester in 30% hydrogen bromide in acetic acid is stirred at room temperature until the reaction is complete. The mixture is diluted with ether and the precipitated material is purified by trituration with additional ether, followed if necessary by reverse phase HPLC and lyophilization, providing the title product.
Reaction SMILES: C[O:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]2.B(Br)(Br)Br.CO>ClCCl>[OH:2][C:3]1[C:4]([CH3:17])=[C:5]2[C:9](=[CH:10][CH:11]=1)[CH2:8][CH:7]([C:12]([O:14][CH2:15][CH3:16])=[O:13])[CH2:6]2
Reactant: CCOC(=O)C1Cc2ccc(OC)c(C)c2C1
Agent: BrB(Br)Br
Solvent: ClCCl
Solvent: CO
Product: CCOC(=O)C1Cc2ccc(O)c(C)c2C1
Temperature: 0 °C
Reaction time: 0.5 h
Yield: 66.6 %

Procedure:
To a solution of ethyl 5-methoxy-4-methylindane-2-carboxylate (896 mg, 3.82 mmol, from Step B) in dichloromethane (10 mL) cooled to 0° C., BBr3 (1.0 M in CH2Cl2, 19.1 mL, 19.1 mmol) was added dropwise. The reaction mixture was stirred for 30 min at 0° C. and warmed to ambient temperature. After 2 hr, the reaction mixture was slowly transferred to an ice-old solution of methanol (10 mL). The resulting solution was warmed to ambient temperature, concentrated in vacuo, and azeotroped with methanol (2×5 mL). The residue was partitioned between EtOAc (15 mL) and sat. NaH2PO4 (5 mL). The layers were separated, and the EtOAc layer was washed with H2O (1×5 mL), brine (1×5 mL) and dried (MgSO4). The mixture was filtered, concentrated in vacuo and purified by flash chromatography (10, 20% EtOAc/hexanes) on SiO2 to afford 560 mg of the title compound: 1H NMR (500 MHz, CDCl3) δ 2.15 (s, 3H), 3.13-3.22 (m, 4H), 3.35 (quintet, 1H, J=8.6 Hz), 3.73, (s, 3H), 4.66 (s, 1H), 6.61 (d, 1H, J=8.1 Hz), 6.89 (d, 1H, J=8.1 Hz).
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C:14](=[N:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][CH:12]1[CH3:28])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.O>C(O)(=O)C.C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+].C1CCCCC1>[CH2:1]([O:8][C:9]([N:11]1[C:20]2[C:15](=[CH:16][CH:17]=[CH:18][CH:19]=2)[C@H:14]([NH:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)[CH2:13][C@@H:12]1[CH3:28])=[O:10])[C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: CC1CC(=Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: C1CCCCC1
Solvent: O
Solvent: CC(=O)O
Product: C[C@H]1C[C@@H](Nc2ccccc2)c2ccccc2N1C(=O)OCc1ccccc1
Temperature: 25 °C
Yield: 32.9 %

Procedure:
To a solution of 2-methyl-4-phenylimino-3,4-dihydro-2H-quinoline-1-carboxylic acid benzyl ester (16 g) in acetic acid (450 ml), sodium triacetoxyborohydride was added in small amounts (32.32 g), under stirring, at room temperature. The reaction mixture was then stirred at room temperature for one hour and poured on 1 liter of cold water under stirring. After precipitation, the mixture was filtered, dissolved in ethyl acetate and then, washed with water. The organic layer was separated and dried over sodium sulfate. The solvent was removed to give the crude compound (9g), recristallised in hot cyclohexane (40 ml), and then filtered at room temperature to give the desired compound (5.3 g, 46.6% yield).
Reaction SMILES: [CH2:1]1[C:5]2[CH:6]=[C:7]3[C:13](=[C:14]([OH:15])[C:4]=2[O:3][CH2:2]1)[O:12][C:10](=[O:11])[CH:9]=[CH:8]3.S(OC)(O[CH3:20])(=O)=O>>[CH3:20][O:15][C:14]1[C:4]2[O:3][CH2:2][CH2:1][C:5]=2[CH:6]=[C:7]2[CH:8]=[CH:9][C:10]([O:12][C:13]=12)=[O:11]
Reactant: COS(=O)(=O)OC
Reactant: O=c1ccc2cc3c(c(O)c2o1)OCC3
Product: COc1c2c(cc3ccc(=O)oc13)CCO2

Procedure:
The process of claim 1, in which the 2,3-dihydroxanthotoxol of step 4 is methylated with dimethyl sulfate to form 2,3-dihydroxanthotoxin.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH2:14][N:15]2C(=O)C3C(=CC=CC=3)C2=O)[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:13])([F:12])[F:11].[ClH:26]>O1CCOCC1>[ClH:26].[Br:1][C:2]1[CH:3]=[C:4]([CH2:14][NH2:15])[CH:5]=[N:6][C:7]=1[O:8][CH2:9][C:10]([F:11])([F:12])[F:13]
Reactant: O=C1c2ccccc2C(=O)N1Cc1cnc(OCC(F)(F)F)c(Br)c1
Agent: Cl
Solvent: C1COCCO1
Product: NCc1cnc(OCC(F)(F)F)c(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 94 %

Procedure:
Free base of the title compound is prepared in 97% yield (510 mg, clear colorless oil) from 2-((5-bromo-6-(2,2,2-trifluoroethoxy)pyridin-3-yl)methyl)isoindoline-1,3-dione (770 mg, 1.8 mmol, Step-2) by the similar manner in Step-4 of Amine-24. The obtained amine is suspended in 4M hydrochloric acid in dioxane (3 mL), and the mixture is stirred for 30 minutes at room temperature to give a white precipitate. The precipitate is collected by filtration, washed with dichloromethane, dried in vacuo to give 540 mg (94% yield) of the title compound as a white solid.
Reaction SMILES: Cl[C:2]([N:4]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[C:8](=[O:15])[NH:7][C:6]2[CH:16]=[CH:17][CH:18]=[N:19][C:5]1=2)=[O:3].[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH2:37])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1.N>ClCCl.CO>[N:20]1([CH2:26][CH2:27][CH2:28][CH:29]2[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][NH:37][C:2]([N:4]3[C:10]4[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=4[C:8](=[O:15])[NH:7][C:6]4[CH:16]=[CH:17][CH:18]=[N:19][C:5]3=4)=[O:3])[CH2:30]2)[CH2:25][CH2:24][CH2:23][CH2:22][CH2:21]1
Reactant: NCCN1CCCC(CCCN2CCCCC2)C1
Reactant: O=C1Nc2cccnc2N(C(=O)Cl)c2ccccc21
Agent: N
Solvent: ClCCl
Solvent: CO
Product: O=C1Nc2cccnc2N(C(=O)NCCN2CCCC(CCCN3CCCCC3)C2)c2ccccc21
Yield: 14 %

Procedure:
Prepared analogously to Example 46 from 11-(chlorocarbonyl)-5,11-dihydro-6H-pyrido[2,3-b][1,4]benzodiazepin-6-one and 2[3-[3-(piperidin-1-yl)propyl]-piperidin-1-yl]ethanamine in a yield of 14% of theory. Colourless amorphous substance, RF 0.13 (Macherey-Nagel, Polygram® SIL G/UV254, pre-coated plastic sheets for TLC, eluant: dichloromethane/methanol/conc. ammonia 90/10/1 v/v).
Reaction SMILES: Cl.Cl.[NH2:3][CH:4]([C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:5]([O:7][C@@H:8]1[CH:13]2[CH2:14][CH2:15][N:10]([CH2:11][CH2:12]2)[CH2:9]1)=[O:6].C(N(CC)CC)C.[CH3:29][C:30]1[S:31][C:32]([S:36](Cl)(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1>C(Cl)Cl>[CH3:29][C:30]1[S:31][C:32]([S:36]([NH:3][CH:4]([C:16]2[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=2)[C:5]([O:7][C@@H:8]2[CH:13]3[CH2:12][CH2:11][N:10]([CH2:15][CH2:14]3)[CH2:9]2)=[O:6])(=[O:38])=[O:37])=[C:33]([CH3:35])[N:34]=1
Reactant: NC(C(=O)O[C@H]1CN2CCC1CC2)c1ccccc1
Reactant: Cc1nc(C)c(S(=O)(=O)Cl)s1
Agent: Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: Cc1nc(C)c(S(=O)(=O)NC(C(=O)O[C@H]2CN3CCC2CC3)c2ccccc2)s1
Temperature: 25 °C
Reaction time: 3 h
Yield: 43.9 %

Procedure:
(R)-quinuclidin-3-yl 2-amino-2-phenylacetate dihydrochloride (I25) (116 mg, 0.35 mmol) was suspended in DCM (6 ml), and triethylamine (102 μl, 1.39 mmol) was added obtaining a clear solution. 2,4-Dimethylthiazole-5-sulfonyl chloride (88.0 mg, 0.42 mmol) was added, and the reaction was stirred at RT for 3 hours. The reaction was diluted with DCM and washed with water and brine. The organic phase was dried with Na2SO4, filtered and evaporated to dryness. The crude was purified by flash chromatography (DCM/MeOH=85/15) to obtain (R)-quinuclidin-3-yl 2-(2,4-dimethylthiazole-5-sulfonamido)-2-phenylacetate (67 mg; 44.2% yield).
Reaction SMILES: ClC1C=CC=C(Cl)C=1C([N:6]1[C:10]2=[N:11][CH:12]=[C:13](B3OC(C)(C)C(C)(C)O3)[CH:14]=[C:9]2[C:8]([C:24]([C:26]2[C:27]([F:40])=[C:28]([NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35])[CH:29]=[CH:30][C:31]=2[F:32])=[O:25])=[CH:7]1)=O.Br[C:47]1[CH:48]=[N:49][N:50]([C:52]2[N:57]=[CH:56][CH:55]=[CH:54][N:53]=2)[CH:51]=1.C(=O)([O-])[O-].[K+].[K+].C(O)(=O)C>C(#N)C.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]>[F:40][C:27]1[C:26]([C:24]([C:8]2[C:9]3[C:10](=[N:11][CH:12]=[C:13]([C:47]4[CH:48]=[N:49][N:50]([C:52]5[N:57]=[CH:56][CH:55]=[CH:54][N:53]=5)[CH:51]=4)[CH:14]=3)[NH:6][CH:7]=2)=[O:25])=[C:31]([F:32])[CH:30]=[CH:29][C:28]=1[NH:33][S:34]([CH2:37][CH2:38][CH3:39])(=[O:36])=[O:35]
Reactant: Brc1cnn(-c2ncccn2)c1
Reactant: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2cn(C(=O)c3c(Cl)cccc3Cl)c3ncc(B4OC(C)(C)C(C)(C)O4)cc23)c1F
Agent: Cl[Pd]Cl
Agent: [Fe+2]
Agent: O=C([O-])[O-]
Solvent: CC(=O)O
Solvent: CC#N
Product: CCCS(=O)(=O)Nc1ccc(F)c(C(=O)c2c[nH]c3ncc(-c4cnn(-c5ncccn5)c4)cc23)c1F

Procedure:
To a solution of propane-1-sulfonic acid {3-[1-(2,6-dichloro-benzoyl)-5-(4,4,5,5-tetramethyl-[1,3,2]dioxaborolan-2-yl)-1H-pyrrolo[2,3-b]pyridine-3-carbonyl]-2,4-difluoro-phenyl}-amide (32, 18 mg, 0.026 mmol) and 2-(4-bromo-pyrazol-1-yl)-pyrimidine (33, 4.95 mg, 0.022 mmol) in 800 μL of acetonitrile is added 400 μL of 1M aqueous potassium carbonate and approximately 1-2 mg of [1,1′-bis(diphenylphosphino)ferrocene]dichloro-palladium (II) (PdCl2 dppf). The reaction mixture is microwave irradiated at 145° C. for 15 minutes, then neutralized with acetic acid, and extracted with 2×1 mL of ethyl acetate. The combined organic layer is concentrated under vacuum, the residue dissolved in 500 μL of dimethylsulfoxide and purified by HPLC using a C18 column, eluting with water/acetonitrile and 0.1% trifluoroacetic acid, 20-100% acetonitrile at 6 mL per minute. Appropriate fractions are combined and concentrated under vacuum to provide the desired compound. MS (ESI) [M+H+]+=524.5.