Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: FC(F)(F)C(O)=O.[Cl:8][C:9]1[CH:14]=[C:13]2[NH:15][C:16](=[O:38])[C:17]3([CH:21]([C:22]4[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=4[F:29])[CH:20]([C:30](O)=[O:31])[NH:19][CH:18]3[CH2:33][C:34]([CH3:37])([CH3:36])[CH3:35])[C:12]2=[CH:11][CH:10]=1.C(N(C(C)C)CC)(C)C.C1(P(Cl)(C2C=CC=CC=2)=O)C=CC=CC=1.[NH2:63][C:64]1[CH:69]=[CH:68][C:67]([C:70](=[O:72])[CH3:71])=[CH:66][CH:65]=1>>[C:70]([C:67]1[CH:68]=[CH:69][C:64]([NH:63][C:30]([CH:20]2[NH:19][CH:18]([CH2:33][C:34]([CH3:36])([CH3:35])[CH3:37])[C:17]3([C:12]4[C:13](=[CH:14][C:9]([Cl:8])=[CH:10][CH:11]=4)[NH:15][C:16]3=[O:38])[CH:21]2[C:22]2[CH:27]=[CH:26][CH:25]=[C:24]([Cl:28])[C:23]=2[F:29])=[O:31])=[CH:65][CH:66]=1)(=[O:72])[CH3:71]
Reactant: CC(=O)c1ccc(N)cc1
Reactant: CC(C)(C)CC1NC(C(=O)O)C(c2cccc(Cl)c2F)C12C(=O)Nc1cc(Cl)ccc12
Agent: O=P(Cl)(c1ccccc1)c1ccccc1
Solvent: CCN(C(C)C)C(C)C
Solvent: O=C(O)C(F)(F)F
Product: CC(=O)c1ccc(NC(=O)C2NC(CC(C)(C)C)C3(C(=O)Nc4cc(Cl)ccc43)C2c2cccc(Cl)c2F)cc1
Yield: 37.2 %

Procedure:
In a manner similar to the method described in Example 5, rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid trifluoroacetic acid prepared in Example 4 (0.2 g, 0.36 mmol), was reacted with diisopropylethylamine (0.18 g, 1.4 mmol), diphenylphosphinic chloride (0.17 g, 0.71 mmol), then reacted with 1-(4-aminophenyl)ethanone (Aldrich) (0.058 g, 0.43 mmol) to give rac-(2′S,3′R,4′S,5′R)-6-chloro-4′-(3-chloro-2-fluoro-phenyl)-2′-(2,2-dimethyl-propyl)-2-oxo-1,2-dihydro-spiro[indole-3,3′-pyrrolidine]-5′-carboxylic acid (4-acetyl-phenyl)-amide as a yellow solid (Yield 0.078 g, 38%).
Reaction SMILES: CO[C:3](=O)[C@H:4]([NH:6][C:7](=[O:22])[C@@H:8]([NH:11][C:12](OCC1C=CC=CC=1)=[O:13])[CH2:9][OH:10])C.C1CCCCC=1>[Pd].CO>[OH:10][CH2:9][C@@H:8]1[NH:11][C:12](=[O:13])[C@@H:4]([CH3:3])[NH:6][C:7]1=[O:22]
Reactant: COC(=O)[C@@H](C)NC(=O)[C@H](CO)NC(=O)OCc1ccccc1
Agent: [Pd]
Solvent: C1=CCCCC1
Solvent: CO
Product: C[C@H]1NC(=O)[C@H](CO)NC1=O
Reaction time: 1 h
Yield: 81.5 %

Procedure:
To (R)-2-((S)-2-benzyloxycarbonylamino-3-hydroxy-propionylamino)-propionic acid methyl ester (172 g, 0.53 mol) was added 10% Pd/C (8.6 g), MeOH (530 mL) and cyclohexene (344 mL) under nitrogen. The mixture was heated to reflux for 17 h. MeOH (500 mL) was added and the reflux continued for 1 h. The hot reaction mixture was filtered through a pad of celite, cake washing with hot MeOH (2×500 mL). The combined filtrates were concentrated. The resulting solid was slurried in 2-butanone (400 mL) and petrol (400 mL) was added gradually over 10 min. After stirring for 30 min, the solids were filtered, cake washed with 2:1 petrol/2-butanone (300 mL). The filter cake was dried in vacuo at 40° C., to give the title compound (68.3 g) as an off white solid. 1H NMR (DMSO-d6): 8.08 (1H, s), 7.90 (1H, s), 5.11 (1H, t), 3.92 (1H, q), 3.80-3.71 (1H, m), 3.71-3.60 (1H, m), 3.58-3.47 (1H, m), 1.24 (3H, d).
Reaction SMILES: [NH2:1][C:2]1[N:3]=[N:4][C:5]([I:8])=[CH:6][CH:7]=1.Cl[CH2:10][C:11]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])=O.P([O-])([O-])(O)=O.[Na+].[Na+].O>CN(C)C(=O)C>[I:8][C:5]1[CH:6]=[CH:7][C:2]2[N:3]([CH:10]=[C:11]([NH:13][C:14](=[O:18])[O:15][CH2:16][CH3:17])[N:1]=2)[N:4]=1
Reactant: CCOC(=O)NC(=O)CCl
Reactant: Nc1ccc(I)nn1
Agent: O=P([O-])([O-])O
Agent: [Na+]
Solvent: CC(=O)N(C)C
Solvent: O
Product: CCOC(=O)Nc1cn2nc(I)ccc2n1
Temperature: 110 °C
Reaction time: 3 h
Yield: 81.4 %

Procedure:
To a solution of 3-amino-6-iodopyridazine (27.0 g, 122 mmol) in N,N-dimethylacetamide (270 mL) were added ethyl (chloroacetyl)carbamate (32.4 g, 195 mmol) and disodium hydrogenphosphate (43.4 g, 305 mmol), and the mixture was stirred at 110° C. for 3 hr. After cooling the mixture to room temperature, water (810 mL) was added, and the precipitated crystals were filtrated, and washed with acetonitrile and ether to give the title compound (33.0 g, 81%) as a dark brown powder.
Reaction SMILES: C([O:4][CH2:5][C:6]1[NH:15][C:14](=[O:16])[C:13]2[C:8](=[N:9][C:10]([OH:17])=[CH:11][N:12]=2)[N:7]=1)(=O)C.[OH-].[K+].O>C(O)C>[OH:17][C:10]1[N:9]=[C:8]2[C:13]([C:14](=[O:16])[NH:15][C:6]([CH2:5][OH:4])=[N:7]2)=[N:12][CH:11]=1
Reactant: CC(=O)OCc1nc2nc(O)cnc2c(=O)[nH]1
Agent: [K+]
Agent: [OH-]
Solvent: O
Solvent: CCO
Product: O=c1[nH]c(CO)nc2nc(O)cnc12

Procedure:
A mixture of 4.0 g (0.0169 mole) of 2-acetoxymethyl-7-hydroxy-4(3H)-pteridinone, 1.2 g (0.0214 mole) of potassium hydroxide and 5 ml of water in 80 ml of ethanol is refluxed for 4 hours. After cooling, the reaction mixture is filtered. The solid thereby isolated is washed with 30 ml of ethanol and taken up in 160 ml of water. The cloudy solution obtained is clarified by filtration and acidified with acetic acid to pH 3.6. The precipitate formed is isolated by filtration. It is purified by washing with ether and recrystallization from a mixture of ethanol and N,N-dimethylformamide. Yld: 2.0 g (61%), m.p. >300° C.
Reaction SMILES: [Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[CH:15]3)[CH:11]=1.FC(F)(F)C(O)=O.[CH3:34][N:35]1[CH2:40][CH2:39][C:38](=O)[CH2:37][CH2:36]1>C(O)(=O)C>[Cl:1][C:2]1[CH:25]=[CH:24][CH:23]=[C:22]([Cl:26])[C:3]=1[CH2:4][O:5][C:6]1[C:7]([NH2:21])=[N:8][CH:9]=[C:10]([C:12]2[CH:13]=[C:14]3[C:18](=[CH:19][CH:20]=2)[NH:17][CH:16]=[C:15]3[C:38]2[CH2:39][CH2:40][N:35]([CH3:34])[CH2:36][CH:37]=2)[CH:11]=1
Reactant: CN1CCC(=O)CC1
Reactant: Nc1ncc(-c2ccc3[nH]ccc3c2)cc1OCc1c(Cl)cccc1Cl
Solvent: O=C(O)C(F)(F)F
Solvent: CC(=O)O
Product: CN1CC=C(c2c[nH]c3ccc(-c4cnc(N)c(OCc5c(Cl)cccc5Cl)c4)cc23)CC1
Yield: 41 %

Procedure:
To a solution of 3-(2,6-Dichloro-benzyloxy)-5-(1H-indol-5-yl)-pyridin-2-ylamine (example I-58, 200 mg, 0.52 mmol) in acetic acid (4 mL) and trifluoroacetic-acid (1 mL) was added 1-methyl-4-piperidone (0.32 mL, 2.6 mmol). The solution was refluxing for over night, and evaporated. The residue was dissolved in ethyl acetate, washed with saturated NaHCO3 and brine, dried over Na2SO4, and condensed. The crude product was purified on a silica gel column eluting with dichloromethane-methanol-triethyl amine (95:5:0.1) to provide 3-(2,6-dichloro-benzyloxy)-5-[3-(1-methyl-1,2,3,6-tetrahydro-pyridin-4-yl)-1H-indol-5-yl]-pyridin-2-ylamine (103.5 mg, 41% yield) as an orange crystalline solid.
Reaction SMILES: [C:1]([C:3]1[CH:18]=[CH:17][C:6]([C:7]([CH2:15][CH3:16])([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1)#N.[OH-].[NH4+].[NH2:21][CH2:22]C1C=CC(C(CC)(O)C2C=CC=CC=2)=CC=1>[Ni].C(O)C>[NH2:21][CH2:22][CH2:1][C:3]1[CH:18]=[CH:17][C:6]([C:7]([CH2:15][CH3:16])([OH:14])[C:8]2[CH:13]=[CH:12][CH:11]=[CH:10][CH:9]=2)=[CH:5][CH:4]=1
Reactant: CCC(O)(c1ccccc1)c1ccc(CN)cc1
Reactant: CCC(O)(c1ccccc1)c1ccc(C#N)cc1
Agent: [Ni]
Agent: [NH4+]
Agent: [OH-]
Solvent: CCO
Product: CCC(O)(c1ccccc1)c1ccc(CCN)cc1

Procedure:
24 g. of 4-cyano-α-ethyl-benzhydrol are dissolved in 192 ml. of ethanol, and 48 ml. of a 25% aqueous ammonium hydroxide solution and 9.6 g. of Raney-nickel are added. The reaction mixture is hydrogenated at 50° C. After the uptake of the theoretical amount of hydrogen the catalyst is filtered off, and the clear filtrate is evaporated to dryness under reduced pressure. The solid residue is recrystallized from a mixture of n-heptane and benzene to yield 17 g. of 4-aminomethyl-α-ethyl-benzhydrol melting at 97.5°-98.5° C.
Reaction SMILES: C([O:5][C:6](=[O:33])[C:7]([S:10][C:11]1[S:12][CH:13]=[C:14]([CH2:16][CH2:17][N:18]([C:26]2[N:31]=[CH:30][C:29](Br)=[CH:28][N:27]=2)[CH2:19][CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25])[N:15]=1)([CH3:9])[CH3:8])(C)(C)C.[NH:34]1[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]1.[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43]>ClCCl>[F:40][C:41]([F:46])([F:45])[C:42]([OH:44])=[O:43].[CH2:19]([N:18]([C:26]1[N:31]=[CH:30][C:29]([N:34]2[CH2:39][CH2:38][CH2:37][CH2:36][CH2:35]2)=[CH:28][N:27]=1)[CH2:17][CH2:16][C:14]1[N:15]=[C:11]([S:10][C:7]([CH3:8])([CH3:9])[C:6]([OH:5])=[O:33])[S:12][CH:13]=1)[CH2:20][CH2:21][CH2:22][CH2:23][CH2:24][CH3:25]
Reactant: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)OC(C)(C)C)n1)c1ncc(Br)cn1
Reactant: C1CCNCC1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCCCCCCN(CCc1csc(SC(C)(C)C(=O)O)n1)c1ncc(N2CCCCC2)cn1

Procedure:
The compound obtained using 2-[(4-{2-[(5-bromopyrimidin-2-yl)(heptyl)amino]ethyl}-1,3-thiazol-2-yl)thio]-2-methylpropionic acid tert-butyl ester synthesized in Example 442-1 and piperidine as starting materials and by an operation similar to that of Example 442-2 was treated with dichloromethane and trifluoroacetic acid. The reaction solution was concentrated under reduced pressure, and the residue was purified by silica gel chromatography (elution solvent; chloroform:methanol=10:1) to give the title compound.
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[C:13]([F:14])=[CH:12][CH:11]=[C:10]([O:15][CH2:16][CH3:17])[C:9]=1[F:18])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:16]([O:15][C:10]1[C:9]([F:18])=[C:8]([NH2:7])[C:13]([F:14])=[CH:12][CH:11]=1)[CH3:17]
Reactant: CCOc1ccc(F)c(NC(=O)OC(C)(C)C)c1F
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOc1ccc(F)c(N)c1F
Temperature: 25 °C
Reaction time: 1 h
Yield: 71.5 %

Procedure:
A solution of (3-ethoxy-2,6-difluoro-phenyl)-carbamic acid tert-butyl ester (135 g, 0.525 mol) in a mixture of dichloromethane and 10 equivalents trifluoroacetic acid (598 g, 5.25 mol) was stirred at room temperature for 1 hour and concentrated in vacuo. The pH of the residue was adjusted to pH 8 with a saturated aqueous solution of sodium bicarbonate. The organic layer was separated and the aqueous layer is extracted with ethyl acetate (3×250 mL). The organic extracts were combined, washed with a saturated aqueous solution of sodium chloride (2×), dried and concentrated in vacuo. Chromatography of the yellow residual liquid down silica gel using 25:1 hexane:ethyl acetate gave 65 g (66%) of the title compound as oil.
Reaction SMILES: [C:1]([C:3]1[CH:8]=[C:7]([N+:9]([O-:11])=[O:10])[C:6](OS(C(F)(F)F)(=O)=O)=[C:5]([CH3:20])[CH:4]=1)#[N:2].[CH3:21][S:22]([C:25]1[CH:26]=[C:27]([C:34]([CH3:46])([CH3:45])[CH2:35][C:36]([C:41]([F:44])([F:43])[F:42])([OH:40])[CH2:37][C:38]#[CH:39])[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=1)(=[O:24])=[O:23]>C1(C)C=CC=CC=1.C(N(CC)CC)C.Cl[Pd](Cl)([P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1)[P](C1C=CC=CC=1)(C1C=CC=CC=1)C1C=CC=CC=1.[Cu]I>[OH:40][C:36]([C:41]([F:43])([F:44])[F:42])([CH2:35][C:34]([C:27]1[C:28]2[O:32][CH2:31][CH2:30][C:29]=2[CH:33]=[C:25]([S:22]([CH3:21])(=[O:24])=[O:23])[CH:26]=1)([CH3:45])[CH3:46])[CH2:37][C:38]#[C:39][C:6]1[C:7]([N+:9]([O-:11])=[O:10])=[CH:8][C:3]([C:1]#[N:2])=[CH:4][C:5]=1[CH3:20]
Reactant: Cc1cc(C#N)cc([N+](=O)[O-])c1OS(=O)(=O)C(F)(F)F
Reactant: C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Agent: Cl[Pd](Cl)([P](c1ccccc1)(c1ccccc1)c1ccccc1)[P](c1ccccc1)(c1ccccc1)c1ccccc1
Agent: [Cu]I
Solvent: Cc1ccccc1
Solvent: CCN(CC)CC
Product: Cc1cc(C#N)cc([N+](=O)[O-])c1C#CCC(O)(CC(C)(C)c1cc(S(C)(=O)=O)cc2c1OCC2)C(F)(F)F
Temperature: 60 °C
Yield: 42.8 %

Procedure:
A mixture of trifluoromethanesulfonic acid 4-cyano-2-methyl-6-nitrophenyl ester (217 mg, 0.7 mmol), dichlorobis(triphenylphosphine)palladium (II) (24.6 mg, 0.035 mmol), copper (I) iodide (13.3 mg, 0.7 mmol), and 6-(5-methanesulfonyl-2,3-dihydrobenzofuran-7-yl)-6-methyl-4-trifluoromethylhept-1-yn-4-ol (273 mg, 0.7 mmol) in a mixture of 0.8 mL of anhydrous toluene and 0.3 mL of anhydrous triethylamine was heated in a microwave at 60° C. for 10 minutes. The reaction mixture was applied to a column of SiO2 (50% ethyl acetate in hexanes) to give 165 mg of the title product as a light yellow oil (43% yield).
Reaction SMILES: C[O:2][C:3]([C:5]1[O:6][C:7]([C:10]2[CH:15]=[CH:14][CH:13]=[C:12]([F:16])[CH:11]=2)=[CH:8][CH:9]=1)=O.CS(O)(=O)=O.FC1C=CC=CC=1C1OC(C([NH:36][C:37]([NH2:39])=[NH:38])=O)=CC=1>CN(C=O)C.[Cl-].[Na+].O>[F:16][C:12]1[CH:11]=[C:10]([C:7]2[O:6][C:5]([C:3]([NH:38][C:37]([NH2:39])=[NH:36])=[O:2])=[CH:9][CH:8]=2)[CH:15]=[CH:14][CH:13]=1
Reactant: N=C(N)NC(=O)c1ccc(-c2ccccc2F)o1
Reactant: COC(=O)c1ccc(-c2cccc(F)c2)o1
Agent: CS(=O)(=O)O
Agent: [Cl-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N=C(N)NC(=O)c1ccc(-c2cccc(F)c2)o1
Temperature: 25 °C
Reaction time: 2 h
Yield: 89.4 %

Procedure:
5-(3-fluorophenyl)furan-2-carboxylic acid methyl ester (250 mg, 1.14 mmol) was dissolved in DMF (3 ml), to which 2 M guanidine solution (3.4 ml, 6.8 mmol) prepared in Example 1 was added, followed by stirring at room temperature for 2 hours. After completion of the reaction, the solution was added with saturated brine (20 ml) and extracted with ethyl acetate (30 ml×3). The organic layer was washed with 10% brine, dried over anhydrous magnesium sulfate (MgSO4), and concentrated in vacuo. The residue was purified by silica gel column chromatography (5% methanol/dichloromethane), to give 252 mg of a title compound (yield: 89%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[NH:8][C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2].Br[CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1)=[O:19]>CN(C=O)C.C(OCC)(=O)C>[CH2:1]([O:3][C:4]1[CH2:10][C:9](=[O:11])[N:8]([CH2:17][C:18]([N:20]([CH:27]([CH3:29])[CH3:28])[C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)=[O:19])[C:7]2[CH:12]=[CH:13][CH:14]=[CH:15][C:6]=2[N:5]=1)[CH3:2]
Reactant: CC(C)N(C(=O)CBr)c1ccccc1
Reactant: CCOC1=Nc2ccccc2NC(=O)C1
Solvent: CN(C)C=O
Solvent: CCOC(C)=O
Product: CCOC1=Nc2ccccc2N(CC(=O)N(c2ccccc2)C(C)C)C(=O)C1
Temperature: -17 °C
Reaction time: 0.33 h

Procedure:
To a solution of 4-ethoxy-1,3-dihydro-benzo[b][1,4]diazepin-2-one (Preparation 3(A) (5.0 g, 24.5 mmol) in DMF (100 mL) was added potassium bistrimethyl silyl amide (49 mL of 0.5 M solution in toluene, 24.5 mmol) at 0° C. The reaction mixture was stirred for 20 minutes and was cooled to −17° C. A solution of 2-bromo-N-isopropyl-N-phenyl-acetamide (Preparation 1 (A) (6.9 g, 27 mmol) in DMF (50 mL) was added dropwise so the internal temperature remained below −15° C. The reaction mixture was stirred at −16° C. for 1 hour, was warmed to room temperature and was diluted with ethyl acetate. The organic phase was washed with brine, dried over sodium sulfate and was concentrated. The resulting pale brown solid was triturated with ether to obtain 3.2 g of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide as a white powder. The filtrate was concentrated and the residue was triturated with ether/hexanes. The solid was collected by filtration to give a second crop of 2-(4-ethoxy-2-oxo-2,3-dihydro-benzo[b][1,4]diazepin-1-yl)-N-isopropyl-N-phenyl-acetamide (3.4 g). MS 380.2 (M+1).
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][CH2:20][CH2:21][P:22](=[O:29])([O:26]CC)[O:23]CC)=[CH:16][C:15]=3[CH3:32])=[CH:7][C:6]=2[C:5]2[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:4]=2[N:3]=1.C(O)(C(F)(F)F)=O>>[NH2:1][C:2]1[C:11]2[N:10]=[CH:9][C:8]([CH2:12][CH2:13][C:14]3[CH:31]=[CH:30][C:17]([O:18][CH2:19][CH2:20][CH2:21][P:22](=[O:23])([OH:26])[OH:29])=[CH:16][C:15]=3[CH3:32])=[CH:7][C:6]=2[C:5]2[CH:33]=[CH:34][C:35]([CH3:37])=[CH:36][C:4]=2[N:3]=1
Reactant: CCOP(=O)(CCCOc1ccc(CCc2cnc3c(N)nc4cc(C)ccc4c3c2)c(C)c1)OCC
Solvent: O=C(O)C(F)(F)F
Product: Cc1ccc2c(c1)nc(N)c1ncc(CCc3ccc(OCCCP(=O)(O)O)cc3C)cc12

Procedure:
3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid (1) was prepared according to the procedure described in Example 1—Step 3, but using diethyl 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonate from the previous step. TFA was added to the 1H NMR sample to solubilize the compound for analysis. The 1H NMR (Dimethylsulfoxide-d6) obtained for 3-(4-(2-(5-amino-8-methylbenzo[f][1,7]naphthyridin-2-yl)ethyl)-3-methylphenoxy)propylphosphonic acid (1) was: δ 9.72 (br, 1H), 9.01 (s, 1H), 8.96 (br, 1H), 8.85 (s, 1H), 8.54 (d, 1H, J=8.4 Hz), 7.54 (s, 1H), 7.42 (d, 1H, J=8.2 Hz), 7.08 (d, 1H, J=8.4 Hz), 6.74 (s, 1H), 6.66 (d, 1H, J=8.3 Hz), 3.95 (t, 2H, J=6.4 Hz), 3.14 (t, 2H, J=8.6 Hz), 2.97 (t, 2H, J=8.6 Hz), 2.50 (s, 3H), 2.27 (s, 3H), 1.91-1.81 (m, 2H), 1.67-1.56 (m, 2H). LRMS [M+H]=466.2
Reaction SMILES: [CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH:18]=O)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2].[NH:22]1[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]1>>[CH2:1]([CH:3]([N:6]1[CH2:11][CH2:10][N:9]([C:12]([C:14]2[CH:21]=[CH:20][C:17]([CH2:18][N:22]3[CH2:27][CH2:26][CH2:25][CH2:24][CH2:23]3)=[CH:16][CH:15]=2)=[O:13])[CH2:8][CH2:7]1)[CH2:4][CH3:5])[CH3:2]
Reactant: C1CCNCC1
Reactant: CCC(CC)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Product: CCC(CC)N1CCN(C(=O)c2ccc(CN3CCCCC3)cc2)CC1

Procedure:
Prepared from the product of Example 12 and piperidine.
Reaction SMILES: [N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH2:15])=[N+:2]=[N-:3].[Cl:16][C:17]1[CH:18]=[C:19]2[C:24](=[C:25]([Cl:27])[CH:26]=1)[CH2:23][N:22]([CH2:28][CH3:29])[CH2:21][CH:20]2[C:30]1[CH:31]=[C:32]([S:36](Cl)(=[O:38])=[O:37])[CH:33]=[CH:34][CH:35]=1>C(Cl)Cl>[N:1]([CH2:4][CH2:5][O:6][CH2:7][CH2:8][O:9][CH2:10][CH2:11][O:12][CH2:13][CH2:14][NH:15][S:36]([C:32]1[CH:33]=[CH:34][CH:35]=[C:30]([CH:20]2[C:19]3[C:24](=[C:25]([Cl:27])[CH:26]=[C:17]([Cl:16])[CH:18]=3)[CH2:23][N:22]([CH2:28][CH3:29])[CH2:21]2)[CH:31]=1)(=[O:38])=[O:37])=[N+:2]=[N-:3]
Reactant: [N-]=[N+]=NCCOCCOCCOCCN
Reactant: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)Cl)c2)C1
Solvent: ClCCl
Product: CCN1Cc2c(Cl)cc(Cl)cc2C(c2cccc(S(=O)(=O)NCCOCCOCCOCCN=[N+]=[N-])c2)C1
Temperature: 25 °C
Reaction time: 1 h
Yield: 55.4 %

Procedure:
To 2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethanamine (300 mg, 1.51 mmol, 1.00 equiv) in DCM (10 mL) was added TEA (375 mg, 3.00 equiv) followed by the portionwise addition of 3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzene-1-sulfonyl chloride (500 mg, 1.23 mmol, 1.00 equiv). The resulting solution was stirred for 1 h at room temperature and then concentrated under vacuum. The residue was applied onto a silica gel column and eluted with ethyl acetate/petroleum ether (1:2) to afford 0.4 g (41%) of N-(2-(2-(2-(2-azidoethoxy)ethoxy)ethoxy)ethyl)-3-(6,8-dichloro-2-ethyl-1,2,3,4-tetrahydroisoquinolin-4-yl)benzenesulfonamide as yellow oil.
Reaction SMILES: C([O:5][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([O:30]C(C)(C)C)=[O:29])[C:19]([O:21]C(C)(C)C)=[O:20])([CH2:8][NH:9][CH2:10][C:11]1[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=1)=[O:7])(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[CH2:10]([NH:9][CH2:8][P:6]([CH2:17][CH:18]([CH2:26][CH2:27][C:28]([OH:30])=[O:29])[C:19]([OH:21])=[O:20])([OH:7])=[O:5])[C:11]1[CH:12]=[CH:13][CH:14]=[CH:15][CH:16]=1
Reactant: CC(C)(C)OC(=O)CCC(CP(=O)(CNCc1ccccc1)OC(C)(C)C)C(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: O=C(O)CCC(CP(=O)(O)CNCc1ccccc1)C(=O)O
Temperature: 25 °C
Yield: 52.8 %

Procedure:
To a solution of di-tert-butyl 2-[((tert-butoxy)-{[benzylamino]methyl}phosphoryl)methyl]pentane-1,5-dioate (0.498 g, 1.0 mmol) in dichloromethane (10 mL) was added trifluoroacetic acid (5 mL) at 0° C., and the mixture was stirred at room temperature for eighteen hours. The solvent was removed under reduced pressure. The residual oil was taken up with dichloromethane (10 mL) and concentrated. This process was repeated three times to remove trifluoroacetic acid completely. The resulting oil was crystallized from methanol to give 0.174 g of white solid (53% yield): 1H NMR (D2O) δ 1.40-1.48 (m, 27H), 1.7-2.1 (m, 4H), 2.2-2.4 (m, 3H), 2.6-3.0 (m, 3H), 3.8-4.0 (m, 2H), 7.2-7.4 (m, 5H).
Reaction SMILES: [OH:1][CH2:2][C:3]1[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=1[CH:5]([C:8]1[S:12][CH2:11][N:10]([CH3:13])[CH:9]=1)[O:6][CH3:7].O1CCCC1.Cl[C:24]1[C:29]([Cl:30])=[CH:28][C:27]([C:31]([F:34])([F:33])[F:32])=[CH:26][N:25]=1.[H-].[Na+]>CCOCC>[Cl:30][C:29]1[C:24]([O:1][CH2:2][C:3]2[CH:17]=[CH:16][CH:15]=[CH:14][C:4]=2[CH:5]([C:8]2[S:12][CH2:11][N:10]([CH3:13])[CH:9]=2)[O:6][CH3:7])=[N:25][CH:26]=[C:27]([C:31]([F:33])([F:32])[F:34])[CH:28]=1
Reactant: FC(F)(F)c1cnc(Cl)c(Cl)c1
Reactant: COC(C1=CN(C)CS1)c1ccccc1CO
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: CCOCC
Product: COC(C1=CN(C)CS1)c1ccccc1COc1ncc(C(F)(F)F)cc1Cl
Temperature: 25 °C
Reaction time: 2 h
Yield: 82.5 %

Procedure:
To a mixture of 0.21 g (0.9 mmol) of 5-(2-hydroxymethyl-α-methoxybenzyl)-3-methylthiazole, 3 ml of tetrahydrofuran and 0.29 g (1.35 mmol) of 2,3-dichloro-5-trifluoromethylpyridine was added 0.05 g (1.3 mmol) of 60% sodium hydride under ice-cooling and stirred at room temperature for 2 hours. After completion of the reaction, 100 ml of ether was added and washed with 80 ml of brine. The ether layer was dried over anhydrous magnesium and concentrated under reduced pressure. The residue was purified by column chromatography on silica gel (ethyl acetate/n-hexane) to give 5-[2-(3-chloro-5-trifluoromethyl-2-pyridyloxymethyl)-α-methoxybenzyl]-3-methylthiazole (0.32 g, 86.1%) as colorless oil.
Reaction SMILES: [N+:1]([CH2:4][CH2:5][CH3:6])([O-:3])=[O:2].CO[CH:9]([O:15]C)[CH2:10][CH2:11][CH2:12][CH:13]=O>CCOC(C)=O.CCCCCC>[N+:1](/[C:4](/[CH2:5][CH3:6])=[CH:13]/[CH2:12][CH2:11][CH2:10][CH:9]=[O:15])([O-:3])=[O:2]
Reactant: COC(CCCC=O)OC
Reactant: CCC[N+](=O)[O-]
Solvent: CCOC(C)=O
Solvent: CCCCCC
Product: CC/C(=C\CCCC=O)[N+](=O)[O-]
Yield: 55.1 %

Procedure:
Prepared according to the general procedure A from 1-nitropropane 112c (80 mmol) and 5,5-dimethoxypentanal 131 (16 mmol) to provide the title compound as yellow oil (1.51 g, 55% yield) after silica gel chromatography (EtOAc/Hexane).
Reaction SMILES: [NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH2:16])=[O:8])[N:6]=1.[O:24]1[C:28]2=[CH:29][CH:30]=[CH:31][C:32]([C:33](O)=[O:34])=[C:27]2[CH2:26][CH2:25]1>>[NH2:1][C:2]1[S:3][C:4]([C:17]2[CH:22]=[CH:21][CH:20]=[C:19]([F:23])[CH:18]=2)=[C:5]([C:7]([N:9]2[CH2:14][C@H:13]3[C@H:11]([CH2:12]3)[C@H:10]2[CH2:15][NH:16][C:33]([C:32]2[CH:31]=[CH:30][CH:29]=[C:28]3[O:24][CH2:25][CH2:26][C:27]=23)=[O:34])=[O:8])[N:6]=1
Reactant: NC[C@@H]1[C@H]2C[C@H]2CN1C(=O)c1nc(N)sc1-c1cccc(F)c1
Reactant: O=C(O)c1cccc2c1CCO2
Product: Nc1nc(C(=O)N2C[C@@H]3C[C@@H]3[C@H]2CNC(=O)c2cccc3c2CCO3)c(-c2cccc(F)c2)s1

Procedure:
prepared by reaction of [2-Amino-5-(3-fluoro-phenyl)-thiazol-4-yl]-((1S,2 S,5R)-2-aminomethyl-3-aza-bicyclo[3.1.0]hex-3-yl)-methanone with 2,3-Dihydro-benzofuran-4-carboxylic acid. LC-MS (basic): tR=0.79 min; [M+H]+=479.4.
Reaction SMILES: [OH-].[K+].[Br:3][C:4]1[CH:5]=[C:6]([NH:10][C:11](=[O:16])[CH:12]=[C:13]([CH3:15])[CH3:14])[CH:7]=[CH:8][CH:9]=1.[CH3:17]I>CS(C)=O>[CH3:17][N:10]([C:6]1[CH:7]=[CH:8][CH:9]=[C:4]([Br:3])[CH:5]=1)[C:11](=[O:16])[CH:12]=[C:13]([CH3:14])[CH3:15]
Reactant: CI
Reactant: CC(C)=CC(=O)Nc1cccc(Br)c1
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC(C)=CC(=O)N(C)c1cccc(Br)c1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 85.2 %

Procedure:
28.7 g of powdered potassium hydroxide were suspended in 300 ml of dimethyl sulfoxide and a solution of 32.6 g of N-(3-bromophenyl)-3,3-dimethyl-acrylamide in 200 ml of dimethylsulfoxide (DMSO) was added dropwise thereto. The mixture was stirred at room temperature for 30 minutes and subsequently a solution of 27.5 g of methyl iodide in 150 ml of DMSO was added dropwise thereto. After 2.5 hours the mixture was poured on to 1 l of ice/water and extracted with ethyl acetate. The organic phase was washed repeatedly with water, dried and evaporated. The oily residue was distilled in a high vacuum. There were obtained 29.3 g of N-methyl-N-(3-bromophenyl)-3,3-dimethyl-acrylamide as a slightly yellow oil, boiling point 112°-114° C./67 Pa.