Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH:20]=O)[CH:18]=3)[S:13][C:6]=12.CC(O)=O.[CH3:33][NH:34][CH2:35][CH2:36][OH:37].C(O[BH-](OC(=O)C)OC(=O)C)(=O)C.[Na+]>C(Cl)Cl.C([O-])(O)=O.[Na+]>[F:1][C:2]1[CH:25]=[C:24]([N+:26]([O-:28])=[O:27])[CH:23]=[CH:22][C:3]=1[O:4][C:5]1[CH:10]=[CH:9][N:8]=[C:7]2[CH:11]=[C:12]([C:14]3[CH:15]=[N:16][N:17]([CH2:19][CH2:20][N:34]([CH3:33])[CH2:35][CH2:36][OH:37])[CH:18]=3)[S:13][C:6]=12
Reactant: O=CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Reactant: CNCCO
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CC(=O)O
Product: CN(CCO)CCn1cc(-c2cc3nccc(Oc4ccc([N+](=O)[O-])cc4F)c3s2)cn1
Temperature: 25 °C
Yield: 100 %

Procedure:
To a solution of 146 (810 mg, 2.033 mmol) in DCM (40 mL) was added HOAc (0.233 mL, 4.07 mmol) and 2-(methylamino)ethanol (305 mg, 4.07 mmol), and the reaction mixture was stirred at RT for an hour. Sodium triacetoxyborohydride (1.293 g, 6.10 mmol) was added and the mixture was stirred at RT overnight. The mixture was then diluted with saturated NaHCO3 solution then solid NaHCO3 was added to neutralize the acid. The DCM layer was collected, dried over anhydrous Na2SO4, filtered and concentrated to afford title compound 147 (930 mg, 100% yield) that was used directly in the next step with no additional purification. MS (m/z)=458.50 (M+H).
Reaction SMILES: [F:1][C:2]([F:16])([S:6]([C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][CH:15]=1)[NH2:12])(=[O:8])=[O:7])[CH:3]([F:5])[Cl:4].[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([N:22]=[C:23]=[O:24])=[O:21]>C1(C)C=CC=CC=1>[F:17][C:18]1[CH:28]=[CH:27][CH:26]=[C:25]([F:29])[C:19]=1[C:20]([NH:22][C:23]([NH:12][C:11]1[CH:13]=[CH:14][CH:15]=[C:9]([S:6]([C:2]([F:1])([F:16])[CH:3]([F:5])[Cl:4])(=[O:7])=[O:8])[CH:10]=1)=[O:24])=[O:21]
Reactant: Nc1cccc(S(=O)(=O)C(F)(F)C(F)Cl)c1
Reactant: O=C=NC(=O)c1c(F)cccc1F
Solvent: Cc1ccccc1
Product: O=C(NC(=O)c1c(F)cccc1F)Nc1cccc(S(=O)(=O)C(F)(F)C(F)Cl)c1
Temperature: 25 °C
Reaction time: 2 h
Yield: 94.5 %

Procedure:
In 20 ml of toluene was dissolved 20 g of 3-(1,1,2-trifluoro-2-chloroethylsulfonyl)aniline, amd 1.4 g of 2,6-difluorobenzoyl isocyanate was added to the solution, followed by stirring at room temperature (20° to 25° C.) for 2 hours. The reaction mixture was concentrated under reduced pressure, and the crystals which separated out were recovered by filtration, and washed with cyclohexane to give 3.3 g of N-(2,6-difluorobenzoyl)-N'-(3-(1,1,2-trifluoro-2-chloroethylsulfonyl)phenyl]urea (Compound No. 38), m.p. of 192°-194° C.
Reaction SMILES: BrC1N(C(C)C)C2C(C3C=CC(Cl)=CC=3)N(C3C=CC([F:20])=C(Cl)C=3)C(=O)C=2C=1.[Cl:29][C:30]1[CH:31]=[CH:32][C:33](C)=[C:34]([N:36]2[C:43](=[O:44])[C:42]3[CH:41]=[C:40]([C:45]4[C:46]([O:53][CH3:54])=NC(OC)=N[CH:50]=4)[N:39]([CH:55]([CH3:57])[CH3:56])[C:38]=3[C@H:37]2[C:58]2[CH:63]=[CH:62][C:61]([Cl:64])=[CH:60][CH:59]=2)[CH:35]=1.Br[C:67]1N(C(C)C)C2[CH:75](C3C=CC(Cl)=CC=3)[N:76](C3C=C(Cl)C=CC=3C)[C:77](=[O:78])[C:69]=2[CH:68]=1.C(C1C=CC(OC)=C(B(O)O)C=1)#N>>[Cl:29][C:30]1[CH:35]=[C:34]([N:36]2[C:43](=[O:44])[C:42]3[CH:41]=[C:40]([C:45]4[CH:50]=[C:69]([CH:68]=[CH:67][C:46]=4[O:53][CH3:54])[C:77]([NH:76][CH3:75])=[O:78])[N:39]([CH:55]([CH3:57])[CH3:56])[C:38]=3[CH:37]2[C:58]2[CH:59]=[CH:60][C:61]([Cl:64])=[CH:62][CH:63]=2)[CH:33]=[CH:32][C:31]=1[F:20]
Reactant: COc1ncc(-c2cc3c(n2C(C)C)[C@@H](c2ccc(Cl)cc2)N(c2cc(Cl)ccc2C)C3=O)c(OC)n1
Reactant: CC(C)n1c(Br)cc2c1C(c1ccc(Cl)cc1)N(c1ccc(F)c(Cl)c1)C2=O
Reactant: Cc1ccc(Cl)cc1N1C(=O)c2cc(Br)n(C(C)C)c2C1c1ccc(Cl)cc1
Agent: COc1ccc(C#N)cc1B(O)O
Product: CNC(=O)c1ccc(OC)c(-c2cc3c(n2C(C)C)C(c2ccc(Cl)cc2)N(c2ccc(F)c(Cl)c2)C3=O)c1

Procedure:
The title compound was prepared in analogy to the procedure described for Example 17 but 2-bromo-5-(3-chloro-4-fluoro-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one (Intermediate D) and 2-methoxy-5-[(methylamino)carbonyl]phenylboronic acid (Intermediate R) were used instead of 2-bromo-5-(5-chloro-2-methyl-phenyl)-6-(4-chloro-phenyl)-1-isopropyl-5,6-dihydro-1H-pyrrolo[3,4-b]pyrrol-4-one and 5-cyano-2-methoxyphenylboronic acid respectively. The title compound was obtained as a white solid. tR: 7.27 min (HPLC 2); ESI-MS: tR=1.24 min, [M+H]+ 566/568/570 (LC-MS 1); TLC: Rf=0.07 (98:2 CH2Cl2/MeOH).
Reaction SMILES: Cl[C:2]1[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=[C:4]([NH:12][C:13]2[CH:18]=[CH:17][C:16]([P:19]([CH3:22])([CH3:21])=[O:20])=[CH:15][CH:14]=2)[N:3]=1.C(N(CC)CC)C.[NH2:30][N:31]1[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]1>C(O)C>[CH3:21][P:19]([C:16]1[CH:17]=[CH:18][C:13]([NH:12][C:4]2[N:3]=[C:2]([NH:30][N:31]3[CH2:36][CH2:35][N:34]([CH3:37])[CH2:33][CH2:32]3)[C:7]([C:8]([F:11])([F:10])[F:9])=[CH:6][N:5]=2)=[CH:14][CH:15]=1)([CH3:22])=[O:20]
Reactant: CN1CCN(N)CC1
Reactant: CP(C)(=O)c1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)cc1
Solvent: CCN(CC)CC
Solvent: CCO
Product: CN1CCN(Nc2nc(Nc3ccc(P(C)(C)=O)cc3)ncc2C(F)(F)F)CC1
Yield: 34 %

Procedure:
To a solution of 4-chloro-N-[4-(dimethylphosphoryl)phenyl]-5-(trifluoromethyl)pyrimidin-2-amine (prepared as in Example 1: 40 mg, 0.12 mmol) in 2 mL of ethanol was added 50 L of triethylamine and 1-Amino-4-methyl-piperazine (13 mg, 0.12 mmol). The mixture was microwave at 120 degrees for 20 minutes. The reaction mixture was filtered through a syringe filter and purified by prep-HPLC (Waters Sunfire C18 column with ACN/water mobile phases) to yield a white solid as product (17 mg, 34% yield.) MS/ES+: m/z=429.
Reaction SMILES: [S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33]OC3C=CC(C4C(C#N)=CSC=4)=CC=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12].[OH:48][C:49]1[CH:54]=[CH:53][C:52]([C:55]2[N:62]=[CH:61][CH:60]=[CH:59][C:56]=2[C:57]#[N:58])=[CH:51][CH:50]=1>>[S:1]1[C:5]2[CH:6]=[CH:7][CH:8]=[CH:9][C:4]=2[N:3]=[C:2]1[NH:10][C:11]([C:13]1[CH:14]=[CH:15][CH:16]=[C:17]2[C:22]=1[CH2:21][N:20]([C:23]1[S:24][C:25]([CH2:31][CH2:32][CH2:33][O:48][C:49]3[CH:54]=[CH:53][C:52]([C:55]4[C:56]([C:57]#[N:58])=[CH:59][CH:60]=[CH:61][N:62]=4)=[CH:51][CH:50]=3)=[C:26]([C:28]([OH:30])=[O:29])[N:27]=1)[CH2:19][CH2:18]2)=[O:12]
Reactant: N#Cc1cccnc1-c1ccc(O)cc1
Reactant: N#Cc1cscc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1
Product: N#Cc1cccnc1-c1ccc(OCCCc2sc(N3CCc4cccc(C(=O)Nc5nc6ccccc6s5)c4C3)nc2C(=O)O)cc1

Procedure:
Title compound 56 was prepared in a similar manner to the synthesis of compound 51 by substituting compound 51A with compound 56A in step 2 of Example 51: 1H NMR (DMSO-d6): δ 8.86 (dd, J=4.76, 1.69 Hz, 1H), 8.34 (dd, J=7.82, 1.69 Hz, 1H), 8.01 (d, J=7.67 Hz, 1H), 7.82 (d, J=8.9 Hz, 2H), 7.77 (d, J=7.98 Hz, 1H), 7.66 (d, J=7.36 Hz, 1H), 7.32-7.53 (m, 5H), 7.07 (d, J=8.9 Hz, 2H), 4.83 (s, 2H), 4.07 (t, J=6.14 Hz, 2H), 3.70-3.73 (m, 2H), 3.18-3.22 (m, 2H), 3.01-3.03 (m, 2H), 2.00-2.08 (m, 2H). ESI (+)/MS: 673 (M+H)+.
Reaction SMILES: I[CH2:2][CH3:3].[Cl:4][C:5]1[C:6]([OH:13])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9].C([O-])([O-])=O.[K+].[K+]>CN(C=O)C>[Cl:4][C:5]1[C:6]([O:13][CH2:2][CH3:3])=[C:7]([CH:10]=[CH:11][CH:12]=1)[CH:8]=[O:9]
Reactant: CCI
Reactant: O=Cc1cccc(Cl)c1O
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOc1c(Cl)cccc1C=O
Temperature: 50 °C
Reaction time: 2.5 h
Yield: 91.4 %

Procedure:
Iodoethane (1.54 mL, 19.2 mmol) was added to a stirring solution of 3-chloro-2-hydroxy-benzaldehyde (2.01 g, 12.8 mmol) and K2CO3 (3.90 g, 28.2 mmol) in DMF (25 mL). The mixture was heated to 50° C. and stirred for 2.5 h. The heat was removed and reaction stirred at room temperature for 18 h. The reaction was quenched with H2O (70 mL). The mixture was extracted with EtOAc (3×50 mL). The combined organics were washed with brine (2×50 mL), dried over Na2SO4, filtered and concentrated to yield the title compound (2.16 g, 91%) as a yellow oil: 1H NMR (300 MHz, DMSO-d6) δ 10.27 (s, 1H), 7.85 (dd, J=7.8, 1.5 Hz, 1H), 7.72 (dd, J=7.8, 1.8 Hz, 1H), 7.33 (t, J=7.8 Hz, 1H), 4.14 (q, J=7.2 Hz, 2H), 1.39 (t, J=6.9 Hz, 3H).
Reaction SMILES: [CH3:1][N:2]1[CH2:7][CH2:6][CH:5]([C:8]2[N:12]3[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]3=[CH:10][N:9]=2)[CH2:4][C:3]1=[O:18].[Br:19]N1C(=O)CCC1=O>CN(C)C=O>[Br:19][C:10]1[N:9]=[C:8]([CH:5]2[CH2:6][CH2:7][N:2]([CH3:1])[C:3](=[O:18])[CH2:4]2)[N:12]2[CH:13]=[CH:14][N:15]=[C:16]([CH3:17])[C:11]=12
Reactant: Cc1nccn2c(C3CCN(C)C(=O)C3)ncc12
Reactant: O=C1CCC(=O)N1Br
Solvent: CN(C)C=O
Product: Cc1nccn2c(C3CCN(C)C(=O)C3)nc(Br)c12
Temperature: 25 °C
Reaction time: 0.25 h
Yield: 69.4 %

Procedure:
To a solution of 1-methyl-4-(8-methylimidazo[1,5-a]pyrazin-3-yl)piperidin-2-one (0.205 mmol, 50 mg) in N,N-dimethylformamide (0.6 ml) was added N-bromosuccinimide (0.225 mmol, 40.1 mg) and the reaction mixture was stirred at room temperature for 15 minutes. Extraction dichloromethane/aqueous sodium hydrogen carbonate, drying (sodium sulfate) and concentrating in vacuo yielded the crude product. Purification by column chromatography (silica gel; dichloromethane with 10% methanol) yielded 4-(1-bromo-8-methylimidazo[1,5-a]pyrazin-3-yl)-1-methylpiperidin-2-one (46 mg).
Reaction SMILES: C([O:3][P:4]([CH2:9][CH:10]([CH2:15][NH:16]C(OCC1C=CC=CC=1)=O)[CH2:11][CH:12]([CH3:14])[CH3:13])(=[O:8])[O:5]CC)C.Cl.O1CCOCC1.C(O)(=O)C>O>[NH2:16][CH2:15][CH:10]([CH2:11][CH:12]([CH3:14])[CH3:13])[CH2:9][P:4](=[O:3])([OH:8])[OH:5]
Reactant: CCOP(=O)(CC(CNC(=O)OCc1ccccc1)CC(C)C)OCC
Agent: Cl
Solvent: CC(=O)O
Solvent: C1COCCO1
Solvent: O
Product: CC(C)CC(CN)CP(=O)(O)O

Procedure:
Adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which methanol or tert-butanol was added to give (8) and then adding (8) to aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid or water to produce the amino acid (9); or adding the product of step f) above to a solvent selected from toluene, benzene, xylenes, or n-heptane to which benzyl alcohol was added to give (8) and then hydrogenating (8) over nickel or palladium or platinum to give lactam which was then hydrolyzed using aqueous hydrochloric acid at a concentration of from 0.01 M to 12 M in the presence or absence of a solvent such as 1,4-dioxane, acetic acid, or water to produce Example 42.
Reaction SMILES: [NH2:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]1[CH2:14][CH2:13][C:12]2[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=2)[CH2:6]1.[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19](F)[CH:18]=1.CCN(C(C)C)C(C)C>CC(O)C>[Br:16][C:17]1[CH:22]=[CH:21][N:20]=[C:19]([NH:1][CH2:2][CH:3]([OH:15])[CH2:4][N:5]2[CH2:14][CH2:13][C:12]3[C:7](=[CH:8][CH:9]=[CH:10][CH:11]=3)[CH2:6]2)[CH:18]=1
Reactant: Fc1cc(Br)ccn1
Reactant: NCC(O)CN1CCc2ccccc2C1
Solvent: CC(C)O
Solvent: CCN(C(C)C)C(C)C
Product: OC(CNc1cc(Br)ccn1)CN1CCc2ccccc2C1
Temperature: 100 °C
Reaction time: 26 h
Yield: 58.3 %

Procedure:
A mixture of 1-amino-3-(3,4-dihydroisoquinolin-2(1H)-yl)propan-2-ol (14.0 g, 67.9 mmol), 4-bromo-2-fluoropyridine (10.0 g, 56.8 mmol) and DIPEA (11.0 g, 85.3 mmol) in i-PrOH (35 mL) were combined in a sealed tube and stirred at 100° C. for 26 h. The reaction mixture was then concentrated and the residue purified by column chromatography to give the desired product (12.0 g, 58.5%). LCMS (m/z): 362.0/364.0 [M+H]+/[M+2+H]+
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([OH:18])=O)[CH:12]=2)[C:7]1=[O:19].[N:23]1([CH2:28][CH2:29][NH2:30])[CH2:27][CH2:26][CH2:25][CH2:24]1>>[Cl-:1].[Cl:1][C:2]1[CH:3]=[C:4]([CH:20]=[CH:21][CH:22]=1)[CH2:5][N:6]1[C:14](=[O:15])[C:13]2[C:8](=[CH:9][CH:10]=[C:11]([C:16]([NH:30][CH2:29][CH2:28][NH+:23]3[CH2:27][CH2:26][CH2:25][CH2:24]3)=[O:18])[CH:12]=2)[C:7]1=[O:19]
Reactant: NCCN1CCCC1
Reactant: O=C(O)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: O=C(NCC[NH+]1CCCC1)c1ccc2c(c1)C(=O)N(Cc1cccc(Cl)c1)C2=O
Product: [Cl-]

Procedure:
2-(3-chloro-benzyl)-1,3-dioxo-2,3-dihydro-1H-isoindol-5-carboxylic acid (100 mg, 0.316 mmol) and 2-pyrrolidin-1-yl-ethylamine (100 μL, 0.792 mmol) were reacted with each other. Target compound in the amount of 108 mg (76%) was obtained by following the procedure described in Example 1.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6](Cl)[N:5]2[N:9]=[C:10]([CH3:23])[C:11]([CH2:12][C:13]3[C:22]4[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=4)[CH:16]=[CH:15][CH:14]=3)=[C:4]2[N:3]=1.[OH-:24].[Na+].[NH:26]1[CH2:31][CH2:30][O:29][CH2:28][CH2:27]1>O1CCCC1.C(O)C>[CH3:23][C:10]1[C:11]([CH2:12][C:13]2[C:22]3[C:17](=[CH:18][CH:19]=[CH:20][CH:21]=3)[CH:16]=[CH:15][CH:14]=2)=[C:4]2[N:3]=[C:2]([N:26]3[CH2:31][CH2:30][O:29][CH2:28][CH2:27]3)[CH:7]=[C:6]([OH:24])[N:5]2[N:9]=1
Reactant: Cc1nn2c(Cl)cc(Cl)nc2c1Cc1cccc2ccccc12
Reactant: [OH-]
Reactant: C1COCCN1
Agent: [Na+]
Solvent: CCO
Solvent: C1CCOC1
Product: Cc1nn2c(O)cc(N3CCOCC3)nc2c1Cc1cccc2ccccc12
Temperature: 50 °C
Reaction time: 7 h
Yield: 30.5 %

Procedure:
To a solution of 5,7-dichloro-2-methyl-3-(1-naphthalenylmethyl)pyrazolo[1,5-a]pyrimidine (0.06 g, 0.175 mmol), prepared using a similar route as was used in Example 1 step c, in Tetrahydrofuran (THF) (5 mL), was added sodium hydroxide (0.877 mL, 1.753 mmol). The reaction was stirred at rt for 18 and 50° C. for 7 h. The reaction mixture was acidified and extracted with EtOAc (80 mL×2). The organic phases were combined, dried and concentrated. To the crude mixture in ethanol (1 mL) was added morpholine (0.076 mL, 0.877 mmol). The reaction mixture was subjected to MW irradiation at 150° C. for 3 h. The reaction mixture was concentrated. The residue was purified by reverse-phase HPLC (25˜55% CH3CN (0.1% TFA)/Water (0.1% TFA)) to give the product (0.02 g, 9%). 1H NMR (400 MHz, DMSO-d6) δ ppm 2.05 (br. s., 3H) 3.30 (m, 4H) 3.67 (m, 4H) 4.37 (br. s., 2H) 5.03 (br. s., 1H) 7.01 (br. s., 1H) 7.40 (t, J=7.71 Hz, 1H) 7.56 (m, 2H) 7.79 (d, J=8.34 Hz, 1H) 7.95 (d, J=7.33 Hz, 1H) 8.27 (m, 1H); LC/MS: MS (ES+) m/e 375.1 [M+H]+.
Reaction SMILES: [C:1]([OH:5])(=O)[CH2:2][SH:3].[CH2:6]=O.[Br:8][C:9]1[CH:10]=[C:11]([CH:13]=[CH:14][C:15]=1[Cl:16])[NH2:12]>C1(C)C=CC=CC=1>[Br:8][C:9]1[CH:10]=[C:11]([N:12]2[C:1](=[O:5])[CH2:2][S:3][CH2:6]2)[CH:13]=[CH:14][C:15]=1[Cl:16]
Reactant: Nc1ccc(Cl)c(Br)c1
Reactant: O=C(O)CS
Reactant: C=O
Solvent: Cc1ccccc1
Product: O=C1CSCN1c1ccc(Cl)c(Br)c1

Procedure:
Thioglycolic acid (8.65 g) and 37% aqueous formaldehyde (4.6 ml) was added to a stirred solution of 3-bromo-4-chloroaniline (9.73 g) in toluene (50 ml). The mixture was heated to reflux and the water collected in a Dean and Stark apparatus. After 3 hours the mixture was cooled, diluted with toluene then washed with aqueous sodium hydroxide and water. The organic layer was dried (MgSO4) and concentrated to give the subtitle compound as a solid.
Reaction SMILES: C(OC([N:11]1[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]1[C:21](=[O:26])[CH:22]([Br:25])[CH2:23]Br)=O)C1C=CC=CC=1.Br>C(O)(=O)C>[Br:25][CH:22]1[CH2:23][N:11]2[CH2:16][CH2:15][CH2:14][CH:13]([C:17]([O:19][CH3:20])=[O:18])[N:12]2[C:21]1=[O:26]
Reactant: COC(=O)C1CCCN(C(=O)OCc2ccccc2)N1C(=O)C(Br)CBr
Agent: Br
Solvent: CC(=O)O
Product: COC(=O)C1CCCN2CC(Br)C(=O)N12
Yield: 77.8 %

Procedure:
5.8 g of methyl 1-benzyloxycarbonyl-2-(2,3-dibromopropionyl)-hexahydro-3-pyridazinecarboxylate (2 racemates) were stirred for 1 hour at room temperature with 15 ml of 45% hydrogen bromide solution in glacial acetic acid and the mixture was then evaporated. The resulting oily solid was washed with diethyl ether and then partitioned between dichloromethane and saturated aqueous sodium bicarbonate solution. The organic phase was separated, dried over sodium sulphate and evaporated. The residue was chromatographed on silica gel. Elution with tert.butyl methyl ether gave firstly 0.4 g (12%) of methyl 2-bromo-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (racemate A) in the form of a white solid of melting point 115°-117° C. (from ethyl acetate/hexane) and secondly 2.54 g of (78%) of methyl 2-bromo-hexahydro-3-oxo-1H-pyrazolo[1,2-a]pyridazine-5-carboxylate (B) in the form of a white solid of melting point 109°-112° C. (from ethyl acetate/n-hexane).
Reaction SMILES: [N:1]([CH2:4][C@H:5]([CH:29]1[CH2:31][CH2:30]1)[C@H:6]([C@H:15]1[CH2:19][O:18]C(C)(C)[N:16]1[C:22]([O:24][C:25]([CH3:28])([CH3:27])[CH3:26])=[O:23])[O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])=[N+:2]=[N-:3].C(O)(C(F)(F)F)=O.CCN(C(C)C)C(C)C.C(OC(OC(C)(C)C)=O)(OC(C)(C)C)=O>CO>[N:1]([CH2:4][C@H:5]([CH:29]1[CH2:30][CH2:31]1)[C@@H:6]([OH:7])[C@H:15]([NH:16][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:27])[CH3:26])[CH2:19][OH:18])=[N+:2]=[N-:3].[N:1]([CH2:4][C@H:5]([CH:29]1[CH2:30][CH2:31]1)[C@@H:6]([O:7][Si:8]([C:11]([CH3:14])([CH3:13])[CH3:12])([CH3:10])[CH3:9])[C@H:15]([NH:16][C:22](=[O:23])[O:24][C:25]([CH3:28])([CH3:26])[CH3:27])[CH2:19][OH:18])=[N+:2]=[N-:3]
Reactant: CC(C)(C)OC(=O)N1[C@@H]([C@H](O[Si](C)(C)C(C)(C)C)[C@H](CN=[N+]=[N-])C2CC2)COC1(C)C
Agent: CC(C)(C)OC(=O)OC(=O)OC(C)(C)C
Solvent: O=C(O)C(F)(F)F
Solvent: CO
Solvent: CCN(C(C)C)C(C)C
Product: CC(C)(C)OC(=O)N[C@H](CO)[C@H](O)[C@H](CN=[N+]=[N-])C1CC1
Product: CC(C)(C)OC(=O)N[C@H](CO)[C@H](O[Si](C)(C)C(C)(C)C)[C@H](CN=[N+]=[N-])C1CC1
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 43 %
Yield: 50 %

Procedure:
A solution of tert-butyl (4R)-4-((1R,2S)-3-azido-1-{[tert-butyl(dimethyl)silyl]oxy}-2-cyclopropylpropyl)-2,2-dimethyl-1,3-oxazolidine-3-carboxylate (1.16 g, 2.55 mmol) in MeOH (5 mL) was cooled on an ice bath, then TFA (4.9 mL, 64 mmol) was added. The reaction mixture was allowed to warm to ambient temperature and stirred for 30 min. The volatile organic solvents were removed under reduced pressure and the residue was azeotropically evaporated with toluene several times. The residue was then dissolved in anhydrous DCM (18 mL) and DIPEA (0.99 g, 7.6 mmol) and di-tert-butyl dicarbonate (0.84 g, 3.8 mmol) were added. The solution was stirred at ambient temperature for 4 h. The crude reaction mixture was concentrated under reduced pressure and the residue was purified by flash column chromatography (40 g silica gel, eluting with 0-100% EtOAc/DCM) to afford the desired product (0.33 g, 43%) and tert-butyl [(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate (0.50 g, 50%). LCMS (ESI) calc. for C13H25N4O4 [M+H]+ m/z=301.2. found: 301.2. For tert-butyl [(1R,2R,3S)-4-azido-2-{[tert-butyl(dimethyl)silyl]oxy}-3-cyclopropyl-1-(hydroxymethyl)butyl]carbamate: LCMS (ESI) calc. for C19H38N4O4SiNa [M+Na]+ m/z=437.3. found 437.0
Reaction SMILES: [H-].[Na+].[CH3:3][O:4][C:5](=[O:19])[CH:6]([NH:11][C:12]([O:14][C:15]([CH3:18])([CH3:17])[CH3:16])=[O:13])[C:7]([O:9][CH3:10])=[O:8].[CH2:20]([O:27][C:28]1[CH:29]=[C:30]([CH:33]=[CH:34][C:35]=1[N+:36]([O-:38])=[O:37])[CH2:31]I)[C:21]1[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=1>CCCCCC.CN(C=O)C.O>[CH3:3][O:4][C:5](=[O:19])[C:6]([CH2:31][C:30]1[CH:33]=[CH:34][C:35]([N+:36]([O-:38])=[O:37])=[C:28]([O:27][CH2:20][C:21]2[CH:26]=[CH:25][CH:24]=[CH:23][CH:22]=2)[CH:29]=1)([NH:11][C:12]([O:14][C:15]([CH3:16])([CH3:18])[CH3:17])=[O:13])[C:7]([O:9][CH3:10])=[O:8]
Reactant: COC(=O)C(NC(=O)OC(C)(C)C)C(=O)OC
Reactant: O=[N+]([O-])c1ccc(CI)cc1OCc1ccccc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CCCCCC
Solvent: CN(C)C=O
Product: COC(=O)C(Cc1ccc([N+](=O)[O-])c(OCc2ccccc2)c1)(NC(=O)OC(C)(C)C)C(=O)OC
Temperature: 25 °C
Reaction time: 0.67 h

Procedure:
Sodium hydride (60% in mineral oil, 729 mg, 18.22 mmol) is washed twice with dry hexane and suspended in DMF (15 mL). To the suspension is added dropwise a solution of t-butoxycarbonylamino-malonic acid dimethyl ester (4.92 g, 19.9 mmol) in DMF (15 mL) over a period of 10 min. The mixture is stirred at RT for 40 min and a solution of the title D compound, 3-benzyloxy-4-nitro-benzyl iodide (6.23 g, 16.9 mmol) in DMF (15 mL) is added dropwise over a period of 10 min and the mixture is stirred at RT overnight. The mixture is diluted with water (200 mL) and extracted 3 times with EtOAc. The organic extracts are washed with water and brine, dried over anhydrous MgSO4, filtered and evaporated. The residue is crystallized from ether-hexane to give 2-(3-benzyloxy-4-nitro-benzyl)-2-t-butoxycarbonylamino-malonic acid dimethyl ester: mp=114-116° C.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([OH:11])=O)[S:5][CH:6]=1.C(N(CC)CC)C.[N-:19]=[N+:20]=[N-:21].[Na+]>CC(C)=O.O>[Br:1][C:2]1[CH:3]=[C:4](/[CH:7]=[CH:8]/[C:9]([N:19]=[N+:20]=[N-:21])=[O:11])[S:5][CH:6]=1
Reactant: [N-]=[N+]=[N-]
Reactant: O=C(O)/C=C/c1cc(Br)cs1
Agent: [Na+]
Solvent: CCN(CC)CC
Solvent: CC(C)=O
Solvent: O
Product: [N-]=[N+]=NC(=O)/C=C/c1cc(Br)cs1
Temperature: 25 °C
Reaction time: 1 h
Yield: 87.5 %

Procedure:
To a solution of (E)-3-(4-bromothiophen-2-yl)acrylic acid (9.30 g, 39.9 mmol) in acetone (100 mL), triethylamine (4.24 g, 41.9 mmol) was added under nitrogen atmosphere. At 0° C., isobutyl chloroformiate (5.72 g, 41.9 mmol) was slowly added and then, the mixture was stirred for 1 h. 4.67 g (71.8 mmol) of sodium azide dissolved in 10 mL of water was slowly added at 0° C., the mixture was stirred at 0° C. for a further hour and then warmed up to room temperature overnight. The reaction mixture was extracted with EA/water. The organic phase was washed aq. NaHCO3 solution and then with brine. The organic phase was dried over MgSO4, concentrated to dryness and the residue was purified by trituration with diisopropyl ether to afford a bright beige solid (9.00 g, 34.9 mmol). Yield: 87%.
Reaction SMILES: [CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][NH:19][CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1.[C:22]1([CH2:28][CH2:29][C:30](O)=[O:31])[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1>>[CH3:1][C:2]1([CH2:15][N:16]2[CH2:21][CH2:20][N:19]([C:30](=[O:31])[CH2:29][CH2:28][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=3)[CH2:18][CH2:17]2)[CH2:6][C:5]2[C:7]([CH3:14])=[C:8]([NH2:13])[C:9]([CH3:12])=[C:10]([CH3:11])[C:4]=2[O:3]1
Reactant: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCNCC1)O2
Reactant: O=C(O)CCc1ccccc1
Product: Cc1c(C)c2c(c(C)c1N)CC(C)(CN1CCN(C(=O)CCc3ccccc3)CC1)O2
Yield: 73 %

Procedure:
Using 2,3-dihydro-2,4,6,7-tetramethyl-2-[(1-piperazinyl)methyl]-5-benzofuranamine and 3-phenylpropionic acid, the procedure of Example 10 was otherwise repeated to provide the title compound. Yield 73%.
Reaction SMILES: [Br:1][C:2]1[CH:14]=[CH:13][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)C[C:4]=2[CH:3]=1.[OH-].[K+].[CH3:18]I.C(O[CH2:24][CH3:25])(=O)C>CS(C)=O>[Br:1][C:2]1[CH:3]=[CH:4][C:12]2[C:11]3[C:6](=[CH:7][C:8]([Br:15])=[CH:9][CH:10]=3)[C:24]([CH3:25])([CH3:18])[C:13]=2[CH:14]=1
Reactant: Brc1ccc2c(c1)Cc1cc(Br)ccc1-2
Reactant: CCOC(C)=O
Reactant: CI
Agent: [K+]
Agent: [OH-]
Solvent: CS(C)=O
Product: CC1(C)c2cc(Br)ccc2-c2ccc(Br)cc21
Temperature: 25 °C
Reaction time: 16 h
Yield: 100 %

Procedure:
To a stirred solution of 2,7-dibromo-9H-fluorene (1.0 g, 3.1 mmol), KI (50 mg, 0.3 mmol) and KOH (750 mg, 13.3 mmol) in DMSO was added methyl iodide (0.42 mL, 6.8 mmol). The mixture was stirred at room temperature for 16 hours, then diluted with ethyl acetate (100 mL). The organic layer was washed with water and brine, dried over Na2SO4, filtered and concentrated in vacuo. The obtained residue was purified by flash chromatography to provide the desired product 2,7-Dibromo-9,9-dimethyl-9H-fluorene as a white solid (1.1 g, 100%).