Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [CH2:1]([O:8][C:9]([N:11]1[CH2:16][CH2:15][CH:14]([CH2:17][CH2:18][CH2:19][CH2:20][CH2:21][OH:22])[CH2:13][CH2:12]1)=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.N1C=CC=CC=1.[S:29](Cl)([C:32]1[CH:38]=[CH:37][C:35]([CH3:36])=[CH:34][CH:33]=1)(=[O:31])=[O:30]>C(OCC)(=O)C>[C:35]1([CH3:36])[CH:37]=[CH:38][C:32]([S:29]([O:22][CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH:14]2[CH2:15][CH2:16][N:11]([C:9]([O:8][CH2:1][C:2]3[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=3)=[O:10])[CH2:12][CH2:13]2)(=[O:31])=[O:30])=[CH:33][CH:34]=1
Reactant: Cc1ccc(S(=O)(=O)Cl)cc1
Reactant: O=C(OCc1ccccc1)N1CCC(CCCCCO)CC1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Product: Cc1ccc(S(=O)(=O)OCCCCCC2CCN(C(=O)OCc3ccccc3)CC2)cc1
Temperature: 0 °C
Yield: 66.5 %

Procedure:
To a chilled mixture of 5-(1-benzyloxycarbonyl-4-piperidyl)pentanol (18 g) and pyridine (150 ml) is added portionwise tosyl chloride (14.6 g) for 30 minutes with stirring. After stirring for further 1 hour at ice-bath temperature, ice water (2 ml) is added dropwise and the resulting mixture is dissolved in ethyl acetate (500 ml). This solution is washed successively with 2N hydrochloric acid (500 ml), 1N hydrochloric acid (500 ml×2), sodium bicarbonate solution and water. The organic layer is dried over anhydrous magnesium sulfate and concentrated in vacuo. The oily residue is purified by silica gel column chromatography using hexane-ethyl acetate (3:1-2:1) to give 5-(1-benzyloxycarbonyl-4-piperidyl)pentyl p-toluenesulfonate (18 g) as an oil.
Reaction SMILES: [CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13](Cl)[C:12]=2[CH:11]=[CH:10]1>C(CN)O>[CH3:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[N:9]1[C:21]2[C:20]3[CH:19]=[CH:18][CH:17]=[C:16]([O:22][C:23]([F:26])([F:25])[F:24])[C:15]=3[N:14]=[C:13]([NH:14][CH2:15][CH2:16][OH:22])[C:12]=2[CH:11]=[CH:10]1
Reactant: Cc1cc(F)ccc1-n1ccc2c(Cl)nc3c(OC(F)(F)F)cccc3c21
Solvent: NCCO
Product: Cc1cc(F)ccc1-n1ccc2c(NCCO)nc3c(OC(F)(F)F)cccc3c21
Yield: 228 %

Procedure:
1-(2-Methyl-4-fluorophenyl)-4-chloro-6-trifluoromethoxypyrrolo[3,2-c]quinoline(394 mg, 1.0 mmol) was dissolved in ethanolamine(5 ml) in the pressure tube, and reacted at the same condition of Step 3 in the Example 20 to obtain 478 mg of desired compound as solid in 90% of yield.
Reaction SMILES: F[P-](F)(F)(F)(F)F.C[N+](C)=C(N(C)C)ON1C2N=CC=CC=2N=N1.[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([OH:45])=O)=[CH:31][CH:32]=2)[N:27]=1.CN(C)C=O.C(N(CC)C(C)C)(C)C.[NH2:60][C@@H:61]([CH2:64][C:65]1[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[CH:67][CH:66]=1)[C:62]#[N:63]>>[NH2:25][C:26]1[N:35]=[C:34]([N:36]2[CH2:41][CH2:40][N:39]([CH3:42])[CH2:38][CH2:37]2)[C:33]2[C:28](=[CH:29][C:30]([C:43]([NH:60][C@H:61]([C:62]#[N:63])[CH2:64][C:65]3[CH:70]=[CH:69][C:68]([O:71][CH:72]([CH3:74])[CH3:73])=[CH:67][CH:66]=3)=[O:45])=[CH:31][CH:32]=2)[N:27]=1
Reactant: CC(C)Oc1ccc(C[C@H](N)C#N)cc1
Reactant: CN1CCN(c2nc(N)nc3cc(C(=O)O)ccc23)CC1
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: CC(C)Oc1ccc(C[C@@H](C#N)NC(=O)c2ccc3c(N4CCN(C)CC4)nc(N)nc3c2)cc1
Reaction time: 0.17 h
Yield: 12.1 %

Procedure:
N,N,N′,N′-Tetramethyl-O-(7-azabenzotriazol-1-yl)uronium hexafluorophosphate (42 mg, 0.11 mmol) was added to a solution of 2-amino-4-(4-methylpiperazin-1-yl)quinazoline-7-carboxylic acid (20 mg, 0.07 mmol) in N,N-dimethylformamide (2 mL, 20 mmol) and N,N-diisopropylethylamine (24 uL, 0.14 mmol). The reaction was stirred for 10 min., and the (2S)-2-amino-3-(4-isopropoxyphenyl)propanenitrile (28 mg, 0.14 mmol) was added. The reaction was stirred for 1 h. at r.t., and was purified by RP-HPLC (pH=2) to afford the desired product (4 mg, 10%) as a white solid TFA salt. Analytical LCMS (M+H)+: m/z=474.1.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[SH:9].Br[CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[S:9][CH2:11][C:12]1[CH:21]=[CH:20][CH:19]=[CH:18][C:13]=1[C:14]([O:16][CH3:17])=[O:15]
Reactant: Nc1cc(F)ccc1S
Reactant: COC(=O)c1ccccc1CBr
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: COC(=O)c1ccccc1CSc1ccc(F)cc1N
Yield: 63.1 %

Procedure:
Following General Procedure A, the title compound (1.8 g, 60%) was prepared from 2-amino-4-fluorobenzenethiol (1.4 g, 9.79 mmol) and methyl 2-(bromomethyl)benzoate (2.2 g, 9.79 mmol), K2CO3 (4.0 g, 29.4 mmol) in DMF (50 ml).
Reaction SMILES: [F:1][C:2]1[CH:7]=[C:6]([CH2:8][C:9](=[O:11])[CH3:10])[CH:5]=[CH:4][C:3]=1[C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1.[Cl:18][C:19]1[CH:20]=[C:21]([CH:24]=[CH:25][C:26]=1[Cl:27])[CH2:22]Cl.[OH-].[Na+]>>[Cl:18][C:19]1[CH:20]=[C:21]([CH2:22][CH:8]([C:6]2[CH:5]=[CH:4][C:3]([C:12]3[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=3)=[C:2]([F:1])[CH:7]=2)[C:9](=[O:11])[CH3:10])[CH:24]=[CH:25][C:26]=1[Cl:27]
Reactant: ClCc1ccc(Cl)c(Cl)c1
Reactant: CC(=O)Cc1ccc(-c2ccccc2)c(F)c1
Agent: [Na+]
Agent: [OH-]
Product: CC(=O)C(Cc1ccc(Cl)c(Cl)c1)c1ccc(-c2ccccc2)c(F)c1
Temperature: 100 °C
Reaction time: 6 h
Yield: 84.9 %

Procedure:
45.1 g of the ketone compound thus obtained, 50.3 g of 3,4-dichlorobenzyl chloride and 15.8 g of sodium hydroxide were mixed, heated with stirring at 100° C. for 6 hours. The reaction solution was left to cool to room temperature and then extracted by an addition of ethyl acetate and water. The organic layer was post-treated by a conventional method. Then, the product was purified by silica gel column chromatography (hexane/ethyl acetate=50/1) to obtain 65.0 g (yield: 85%) of 4-(3,4-dichlorophenyl)-3-(2-fluoro-4-biphenylyl)-2-butanone.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1.[H-].[Na+].[CH2:20]([CH:22]([NH:25][C:26](=O)[O:27]C1C=CC=CC=1)[CH2:23][CH3:24])[CH3:21]>CN(C)C=O>[CH2:20]([CH:22]([NH:25][C:26]([N:1]1[C:9]2[C:4](=[CH:5][C:6]([O:10][C:11]3[CH:16]=[CH:15][N:14]=[C:13]([NH2:17])[CH:12]=3)=[CH:7][CH:8]=2)[CH:3]=[CH:2]1)=[O:27])[CH2:23][CH3:24])[CH3:21]
Reactant: CCC(CC)NC(=O)Oc1ccccc1
Reactant: Nc1cc(Oc2ccc3[nH]ccc3c2)ccn1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCC(CC)NC(=O)n1ccc2cc(Oc3ccnc(N)c3)ccc21
Temperature: 25 °C
Yield: 70.7 %

Procedure:
4-(1H-5-Indolyloxy)-2-pyridinamine (1.85 g, 8.2 mmol, CAS No. 417722-11-3) which was described in WO 02/32872 was dissolved in N,N-dimethylformamide (20 ml); and sodium hydride (394 mg, 9.84 mmol) was added thereto while stirring at room temperature. The reaction mixture was cooled with ice bath after 30 minutes; phenyl N-(1-ethylpropyl)carbamate (1.87 g, 9.03 mmol); and the reaction mixture was stirred at room temperature for 3 hours. The reaction mixture was partitioned between ethyl acetate and water; the organic layer was washed with water and brine, dried over anhydrous sodium sulfate, concentrated; and the residue was purified by silica gel column chromatography (Fuji Silysia NH, hexane:ethyl acetate=3:1) to yield the title compound as crystals (1.95 g, 5.8 mmol, 71%).
Reaction SMILES: Cl.[Cl:2][C:3]1[C:8]([C:9]2[C:10](=[O:16])[NH:11][C:12](=[O:15])[NH:13][CH:14]=2)=[CH:7][C:6]([F:17])=[CH:5][N:4]=1.C([O-])([O-])=O.[K+].[K+].Br[CH2:25][CH2:26][CH:27]([O:30][CH3:31])[O:28][CH3:29].O>CN(C=O)C>[CH3:29][O:28][CH:27]([O:30][CH3:31])[CH2:26][CH2:25][N:13]1[CH:14]=[C:9]([C:8]2[C:3]([Cl:2])=[N:4][CH:5]=[C:6]([F:17])[CH:7]=2)[C:10](=[O:16])[NH:11][C:12]1=[O:15]
Reactant: O=c1[nH]cc(-c2cc(F)cnc2Cl)c(=O)[nH]1
Reactant: COC(CCBr)OC
Agent: Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: COC(CCn1cc(-c2cc(F)cnc2Cl)c(=O)[nH]c1=O)OC
Yield: 48.5 %

Procedure:
5-(2-Chloro-5-fluoro-pyridin-3-yl)-1H-pyrimidine-2,4-dione hydrochloride (Prep71, 249 mg, 0.9 mmol), K2CO3 (124 mg, 0.9 mmol) and 3-bromo-1,1dimethoxy-propane (205 mg, 1.1 mmol) were suspended in DMF (3 ml). After stirring the reaction at room temperature for 18 hours, water was added. The aqueous layer washed with diethylether and then the product was extracted with ethyl acetate. The organic phase was dried (Na2SO4) and evaporated to give 150 mg of the final compound that was used without further purification in the next step (48% yield).
Reaction SMILES: [N+:1]([C:4]1[CH:9]=[CH:8][C:7]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)=[CH:6][CH:5]=1)([O-])=O.[H][H]>[Pd].CCO>[NH2:1][C:4]1[CH:5]=[CH:6][C:7]([CH2:10][C:11]2[NH:12][CH:13]=[C:14]([C:16]([O:18][CH3:19])=[O:17])[N:15]=2)=[CH:8][CH:9]=1
Reactant: [H][H]
Reactant: COC(=O)c1c[nH]c(Cc2ccc([N+](=O)[O-])cc2)n1
Agent: [Pd]
Solvent: CCO
Product: COC(=O)c1c[nH]c(Cc2ccc(N)cc2)n1
Yield: 91.1 %

Procedure:
A 100-mL round bottomed flask was charged with methyl 2-[(4-nitrophenyl)methyl]-1H-imidazole-4-carboxylate (220 mg, 0.84 mmol), Pd/C (270 mg, 10 wt %, 0.255 mmol, 0.3 eq.) and EtOH (24 ml). The mixture was stirred under 1 atmosphere of hydrogen overnight. The insoluble material was removed by filtration and the organics was evaporated under reduced pressure to dryness to afford the title compound (177 mg, 91% yield). The product thus obtained was forwarded to the next step without any further purification.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([CH:6]=[CH:7][N:8]2[CH2:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])=[CH:4][CH:3]=1.[CH:19]([C:21]1[N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:23]([CH3:26])=[CH:24][CH:25]=1)=O.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>C(Cl)Cl>[C:15]([O:14][C:12](=[O:13])[CH2:11][N:8]1[C:9]2[C:5](=[CH:4][CH:3]=[C:2]([NH:1][CH2:26][C:23]3[N:22]([C:27]([O:29][C:30]([CH3:33])([CH3:32])[CH3:31])=[O:28])[C:21]([CH3:19])=[CH:25][CH:24]=3)[CH:10]=2)[CH:6]=[CH:7]1)([CH3:18])([CH3:17])[CH3:16]
Reactant: CC(C)(C)OC(=O)Cn1ccc2ccc(N)cc21
Reactant: Cc1ccc(C=O)n1C(=O)OC(C)(C)C
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: ClCCl
Product: Cc1ccc(CNc2ccc3ccn(CC(=O)OC(C)(C)C)c3c2)n1C(=O)OC(C)(C)C
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 58 %

Procedure:
A solution of tert-butyl 2-(6-amino-1H-indol-1-yl)acetate (intermediate A—for synthesis see above) (1.7368 mmol, 1.1 equiv.) in DCM (3 ml) was added at 0° C. to tert-butyl 2-formyl-5-methyl-1H-pyrrole-1-carboxylate (1.5789 mmol, 1.0 equiv.), dissolved in DCM (12 ml), and the mixture was stirred for 30 min at 25° C. At 0° C., Na(OAc)3BH (4.7368 mmol, 3.0 equiv.) was added in portions, and then the mixture was stirred for 12 h at 25° C. The reaction mixture was diluted with DCM (100 ml), washed with water and sat. NaCl solution (in each case 2×50 ml), dried over Na2SO4 and concentrated under reduced pressure. The crude product was purified by column chromatography (5% ethyl acetate in hexane). Yield: 58%
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10](C(O)=O)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C1(P([N:33]=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1.C(N(C(C)C)C(C)C)C.[OH-].[K+]>O1CCOCC1>[C:1]([O:5][C:6]([N:8]1[CH2:12][CH:11]([CH:13]2[CH2:15][CH2:14]2)[CH:10]([NH2:33])[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: CC(C)(C)OC(=O)N1CC(C(=O)O)C(C2CC2)C1
Reactant: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Agent: [K+]
Agent: [OH-]
Solvent: C1COCCO1
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N1CC(N)C(C2CC2)C1
Temperature: 80 °C
Reaction time: 4 h

Procedure:
101.5 To a stirred solution of 200 mg (3RS,4RS)-4-cyclopropyl-pyrrolidine-1,3-dicarboxylic acid 1-tert-butyl ester at 80° C. in 2 ml dioxane under an argon atmosphere were added 0.20 ml diphenylphosphoryl azide and 0.16 ml N-ethyldiisopropylamine. Stirring at 80° C. was continued for 4 hrs. Then, the hot mixture was poured onto 15 ml 1 N KOH and the product was extracted with EtOAc. The aqueous phase was back extracted with EtOAc. The combined organics were washed with H2O and brine, dried over MgSO4, filtered and concentrated. The crude product was purified by column chromatography (silica gel; gradient: CH2Cl2->CH2Cl2/MeOH 9:1) to give 34 mg (3RS,4SR)-3-amino-4-cyclopropyl-pyrrolidine-1-carboxylic acid tert-butyl ester as light brown gum. MS 227.3 ([M+H]+)
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([N+:18]([O-])=O)=[C:6]([CH:17]=1)[NH:7][CH2:8][C:9]1[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=1.[Cl-].[NH4+]>CCO.O.[Fe]>[Br:1][C:2]1[CH:17]=[C:6]([NH:7][CH2:8][C:9]2[CH:14]=[CH:13][C:12]([O:15][CH3:16])=[CH:11][CH:10]=2)[C:5]([NH2:18])=[CH:4][CH:3]=1
Reactant: COc1ccc(CNc2cc(Br)ccc2[N+](=O)[O-])cc1
Agent: [Fe]
Agent: [Cl-]
Agent: [NH4+]
Solvent: CCO
Solvent: O
Product: COc1ccc(CNc2cc(Br)ccc2N)cc1
Temperature: 60 °C
Reaction time: 4 h
Yield: 80.5 %

Procedure:
To a solution of 5-bromo-N-(4-methoxybenzyl)-2-nitroaniline (750 mg, crude) in EtOH (8 mL) and H2O (8 mL) was added Fe powder (766 mg, 13.7 mmol) and ammonium chloride (733 mg, 13.7 mmol). The mixture was stirred at 60° C. for 4 h then filtered and the filtrate was concentrated to remove EtOH. The residue was then diluted with water and extracted with EtOAc. The organic layer was concentrated to give the desired product (550 mg, crude, 82% yield) with the crude product being used in next step without further purification. LCMS (m/z): 308.1 [M+H]+
Reaction SMILES: [NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([C:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH:16]=3)[N:6]2[N:5]=[CH:4][N:3]=1>C(O)(=O)C.[Pt](=O)=O>[NH2:1][C:2]1[C:7]2=[CH:8][CH:9]=[C:10]([CH:11]3[CH2:12][CH2:13][CH2:14][N:15]([C:17]([O:19][C:20]([CH3:23])([CH3:22])[CH3:21])=[O:18])[CH2:16]3)[N:6]2[N:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1C=C(c2ccc3c(N)ncnn23)CCC1
Agent: O=[Pt]=O
Solvent: CC(=O)O
Product: CC(C)(C)OC(=O)N1CCCC(c2ccc3c(N)ncnn23)C1
Reaction time: 64 h
Yield: 76 %

Procedure:
To a dry flask purged with N2 was added platinum (IV) oxide (150 mg, 0.66 mmol) followed by tert-butyl 5-(4-aminopyrrolo[2,1-f][1,2,4]triazin-7-yl)-3,4-dihydropyridine-1(2H)-carboxylate (2.09 mg, 6.63 mmol) as a solution in acetic acid (60 mL). The mixture was stirred under an H2 atmosphere for 64 h. The mixture was filtered through a pad of Celite® rinsing with acetic acid and EtOH. The solvent was evaporated under reduced pressure and the residue was dissolved in ethyl acetate (200 mL). The organic mixture was washed with saturated, aqueous NaHCO3 (200 mL) followed by brine, and was dried (Na2SO4) and concentrated to dryness to afford 1.60 g (76%) of the desired product. ES-MS m/z 318.22 [M+H]+, HPLC RT (min) 2.43.
Reaction SMILES: [O:1]=[C:2]1[C:9]2[C:5](=[C:6]([CH3:17])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH3:10])[CH2:4][CH2:3]1.[BH4-].[Na+]>C(O)C>[OH:1][CH:2]1[C:9]2[C:5](=[C:6]([CH3:17])[N:7]([C:11]3[CH:16]=[CH:15][CH:14]=[CH:13][CH:12]=3)[C:8]=2[CH3:10])[CH2:4][CH2:3]1
Reactant: Cc1c2c(c(C)n1-c1ccccc1)C(=O)CC2
Agent: [BH4-]
Agent: [Na+]
Solvent: CCO
Product: Cc1c2c(c(C)n1-c1ccccc1)C(O)CC2
Temperature: 0 °C
Reaction time: 8 h

Procedure:
A solution of 1.5 g. (0.067 mole) of 4-oxo-1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole, described above in Example 10, and 254 mg. (0.0067 mole) of sodium borohydride in 15 ml. of ethanol was stirred for sixteen hours at 0°-5° C., then for an additional eight hours at ambient temperature and poured into ice/water. The mixture was extracted with ether, and the ether extracts were dried and evaporated to dryness to give 4-hydroxy-1,3-dimethyl-2-phenyl-2,4,5,6-tetrahydrocyclopenta[c]pyrrole as an oil.
Reaction SMILES: [N-:1]=[N+:2]=[N-:3].[Na+].[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15](Cl)(=[O:17])=[O:16]>O.CC(C)=O>[CH:5]1[C:14]2[C:9](=[CH:10][CH:11]=[CH:12][CH:13]=2)[CH:8]=[CH:7][C:6]=1[S:15]([N:1]=[N+:2]=[N-:3])(=[O:16])=[O:17]
Reactant: [N-]=[N+]=[N-]
Reactant: O=S(=O)(Cl)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: O
Solvent: CC(C)=O
Product: [N-]=[N+]=NS(=O)(=O)c1ccc2ccccc2c1
Reaction time: 2 h
Yield: 74.8 %

Procedure:
A solution of sodium azide (3.1 g, 44 mmol) in water (10 ml) was added dropwise at RT to a stirred solution of 2-naphthalenesulfonyl chloride (10 g, 44 mmol) in acetone (60 ml) and stirring was continued for 2 hours. Water (50 ml) was added and the resulting mixture was decanted. The surnatant was discarded, while the brown oily residue was recrystallized from light petroleum producing after drying pure title compound (7.67 g, 32.9 mmol, yield 74.7%) as white needles, m.p.=45°.
Reaction SMILES: [N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([O:12]C)=[O:11])[CH2:2]2>Cl>[N:1]12[CH2:8][CH2:7][CH:4]([CH2:5][CH2:6]1)[CH:3]([CH2:9][C:10]([OH:12])=[O:11])[CH2:2]2
Reactant: COC(=O)CC1CN2CCC1CC2
Agent: Cl
Product: O=C(O)CC1CN2CCC1CC2
Temperature: 70 °C
Reaction time: 18 h

Procedure:
A mixture of methyl 2-(quinuclidin-3-yl)acetate (1.1 g, 6.0 mmol) and 50 mL of conc. HCl [12M] was stirred at 70° C. for 18 h. The reaction mixture was concentrated under reduced pressure to afford crude 2-(quinuclidin-3-yl)acetic acid, which was used without purification in the next step (900 mg, 86%).
Reaction SMILES: CS(C)=O.F[C:6]1[CH:11]=[CH:10][C:9]([N+:12]([O-:14])=[O:13])=[C:8]([CH3:15])[CH:7]=1.C(=O)([O-])[O-].[K+].[K+].[NH:22]1[CH2:27][CH2:26][O:25][CH2:24][CH2:23]1>O>[CH3:15][C:8]1[CH:7]=[C:6]([N:22]2[CH2:27][CH2:26][O:25][CH2:24][CH2:23]2)[CH:11]=[CH:10][C:9]=1[N+:12]([O-:14])=[O:13]
Reactant: Cc1cc(F)ccc1[N+](=O)[O-]
Reactant: C1COCCN1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Solvent: O
Product: Cc1cc(N2CCOCC2)ccc1[N+](=O)[O-]
Temperature: 80 °C
Reaction time: 18 h
Yield: 95 %

Procedure:
To a DMSO solution (8 ml) of 4-fluoro-2-methyl-1-nitro-benzene (500 mg), potassium carbonate (668 mg) and morpholine (0.42 ml) were added, followed by stirring at 80° C. for 18 hours. This was cooled to room temperature, and water (30 ml) was added, followed by extraction with ethyl acetate (50 ml×2). The organic layer was washed with saturated aqueous sodium chloride solution, followed by drying over magnesium sulfate. After the magnesium sulfate was filtered off, the solvent was distilled off under reduced pressure, to obtain the desired compound as a yellow solid (680 mg, 95%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:8]=[CH:7][C:6]([C:9]2[C:10]([C:17]3[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=3)=[C:11]([NH:15][NH2:16])[N:12]=[N:13][CH:14]=2)=[CH:5][CH:4]=1.[C:23](N1C=CN=C1)(N1C=CN=C1)=[O:24]>>[CH3:1][O:2][C:3]1[CH:4]=[CH:5][C:6]([C:9]2[CH:14]=[N:13][N:12]3[C:23](=[O:24])[NH:16][N:15]=[C:11]3[C:10]=2[C:17]2[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=2)=[CH:7][CH:8]=1
Reactant: COc1ccc(-c2cnnc(NN)c2-c2ccncc2)cc1
Reactant: O=C(n1ccnc1)n1ccnc1
Product: COc1ccc(-c2cnn3c(=O)[nH]nc3c2-c2ccncc2)cc1

Procedure:
The title compound was prepared by reacting 1-(5-(4-methoxyphenyl)-4-(pyridin-4-yl)pyridazin-3-yl)hydrazine with carbonyldiimidazole (CDI) by procedures analogous to those described in Example 279F to give 7-(4-methoxyphenyl)-8-(pyridine-4-yl)-[1,2,4]triazolo[4,3-b]pyridazin-3(2H)-one. LC/MS (method A): RT=1.37 min, (M+H)+=320.
Reaction SMILES: [CH2:1]([P:8]([CH2:11][CH:12]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:23][CH:24]=1)[C:13]([O:15]CC)=[O:14])(=[O:10])[OH:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[Li+].[OH-]>C1COCC1.O>[CH2:1]([P:8]([CH2:11][CH:12]([CH2:18][C:19]1[CH:20]=[N:21][C:22]([NH:25][C:26]([O:28][C:29]([CH3:32])([CH3:31])[CH3:30])=[O:27])=[CH:23][CH:24]=1)[C:13]([OH:15])=[O:14])([OH:10])=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CCOC(=O)C(Cc1ccc(NC(=O)OC(C)(C)C)nc1)CP(=O)(O)Cc1ccccc1
Agent: [Li+]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: O
Product: CC(C)(C)OC(=O)Nc1ccc(CC(CP(=O)(O)Cc2ccccc2)C(=O)O)cn1
Temperature: 25 °C
Reaction time: 8 h
Yield: 81.5 %

Procedure:
Benzyl[2-({6-[(tert-butoxycarbonyl)amino]pyridin-3-yl}methyl)-3-ethoxy-3-oxopropyl]phosphinic acid (62 mg; 0.13 mmol) was dissolved in THF (1 mL) and water (1 mL). LiOH (12 mg; 0.5 mmol) was added, and the reaction was stirred at room temperature overnight. The reaction mixture was concentrated, water (1 mL) was added and the aqueous solution was extracted with CHCl3 (1×1 mL). 0.5 M aqueous HCl (1 mL) was added to the aqueous solution, and the resulting acidic aqueous solution was extracted with CHCl3 (3×2 mL). The combined organic phases were dried and concentrated to afford 46 mg (81%) of 3-[benzyl(hydroxy)phosphoryl]-2-({6-[(tert-butoxycarbonyl)amino]-pyridin-3-yl}methyl)propanoic acid.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:5]=[C:4]([NH:12][CH2:13][CH2:14][CH3:15])[N:3]=1.Cl.Cl.[CH3:18][NH:19][NH:20][CH3:21].[OH-].[Na+]>O1CCOCC1.O>[CH2:13]([NH:12][C:4]1[N:5]=[C:6]([NH:8][CH2:9][CH2:10][CH3:11])[N:7]=[C:2]([N:19]([CH3:18])[NH:20][CH3:21])[N:3]=1)[CH2:14][CH3:15]
Reactant: CCCNc1nc(Cl)nc(NCCC)n1
Reactant: CNNC
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Solvent: C1COCCO1
Product: CCCNc1nc(NCCC)nc(N(C)NC)n1
Temperature: 60 °C
Yield: 42.4 %

Procedure:
A mixture of 2-chloro-N-(4,6-bis-(n-propylamino)-[1,3,5]triazine (XXXIV) (2.50 g, 10.88 mmol), N,N′-dimethyl-hydrazine dihydrochloride (2.89 g, 21.76 mmol) and NaOH (2.18 g, 54.40 mmol) in 1,4-dioxane (40 mL) and water (20 mL) was heated at 60° C. for 18 h. The volatiles were removed under reduced pressure. Saturated NaHCO3 solution (100 mL) was added to the residue, the mixture was extracted with EtOAc (3×50 mL). The combined organic extracts were washed with water (75 mL), brine (75 mL) and dried over Na2SO4. The solvent was removed under reduced pressure and the crude product was purified by flash column chromatography using gradient elution (CH2Cl2/EtOH (99:1) to CH2Cl2/EtOH (95:5)) to yield N-(4,6-Bis-propylamino-[1,3,5]triazin-2-yl)-N,N′-dimethyl-hydrazine (1.17 g, 42%). 200 MHz 1H NMR (DMSO-d6, ppm): 6.81-6.44 (2H, m), 5.31 (1H, br s), 3.24-3.08 (4H, m), 3.05 (3H, s), 2.47-2.40 (3H, m), 1.57-1.37 (4H, m), 0.84 (6H, t, J=7.4 Hz). ESI-MS (m/z): 254 [M+H]+.
Reaction SMILES: [C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14](I)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2].[NH2:27][C:28]([C:30]1[CH:31]=[C:32](B(O)O)[CH:33]=[CH:34][CH:35]=1)=[O:29]>>[C:1]([O:5][C:6](=[O:26])[NH:7][CH:8]([C:18]1[CH:23]=[CH:22][C:21]([Cl:24])=[C:20]([Cl:25])[CH:19]=1)[C:9]([C:11]1[CH:16]=[CH:15][C:14]([C:34]2[CH:33]=[CH:32][CH:31]=[C:30]([C:28](=[O:29])[NH2:27])[CH:35]=2)=[CH:13][CH:12]=1)=[O:10])([CH3:4])([CH3:3])[CH3:2]
Reactant: NC(=O)c1cccc(B(O)O)c1
Reactant: CC(C)(C)OC(=O)NC(C(=O)c1ccc(I)cc1)c1ccc(Cl)c(Cl)c1
Product: CC(C)(C)OC(=O)NC(C(=O)c1ccc(-c2cccc(C(N)=O)c2)cc1)c1ccc(Cl)c(Cl)c1

Procedure:
The title compound was prepared from rac-[1-(3,4-dichloro-phenyl)-2-(4-iodo-phenyl)-2-oxo-ethyl]-carbamic acid tert-butyl ester and 3-aminocarbonylphenyl-boronic acid in analogy to Example 2b): MS (ISN): 497.2 and 499.2 (M−H)−.
Reaction SMILES: C([NH:4][C:5](=[CH:9][CH2:10][PH:11]([CH2:13]O)=[O:12])[C:6]([OH:8])=[O:7])(=O)C.[ClH:15].C[OH:17]>>[ClH:15].[ClH:15].[NH2:4][C@H:5]([C:6]([OH:8])=[O:7])[CH2:9][CH2:10][P:11]([CH3:13])(=[O:17])[OH:12]
Reactant: CC(=O)NC(=CC[PH](=O)CO)C(=O)O
Reactant: CO
Agent: Cl
Product: CP(=O)(O)CC[C@H](N)C(=O)O
Yield: 91.9 %

Procedure:
0.0087 g (0.019 mmol) of chloronorbornadienerhodium(I) dimer and 0.022 g (0.053 mmol) of the compound Va are dissolved in 5 ml of methanol under an atmosphere of argon. The catalyst solution obtained is added under argon to a solution of 2.21 g (0.01 mol) of 2-acetamido-4-(hydroxymethylphosphinyl)-2-butenoic acid in 45 ml of methanol. The reaction vessel is evacuated, then hydrogenation is performed at a pressure of 3.0 bar. After a reaction time of 44 hours, the reaction vessel is depressurized, the reaction mixture evaporated down, the residue taken up in water and the precipitated catalyst separated off. As a result of adding an equivalent quantity of concentrated hydrochloric acid to the filtrate, a 6N hydrochloric acid solution is prepared which is boiled under reflux for 12 hours. After evaporating this solution down, 2.0 g (91.9% of theory) of L-homoalanin-4-yl(methyl)phosphinic acid hydrochloride is obtained as a white solid which is purified by recrystallization from an ethanol/water mixture.