Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: P(Cl)(Cl)(Cl)=O.[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[CH:12]=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:35])([CH3:34])[CH3:33])[CH2:24]1.O.CN(C)[CH:44]=[O:45]>>[Cl:6][C:7]1[CH:40]=[CH:39][CH:38]=[CH:37][C:8]=1[CH2:9][N:10]1[C:18]2[C:17](=[O:19])[N:16]([CH3:20])[C:15](=[O:21])[N:14]([CH3:22])[C:13]=2[C:12]([CH:44]=[O:45])=[C:11]1[N:23]1[CH2:28][CH2:27][CH2:26][C@@H:25]([NH:29][C:30](=[O:36])[O:31][C:32]([CH3:34])([CH3:35])[CH3:33])[CH2:24]1
Reactant: CN(C)C=O
Reactant: Cn1c(=O)c2c(cc(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Solvent: O=P(Cl)(Cl)Cl
Solvent: O
Product: Cn1c(=O)c2c(c(C=O)c(N3CCC[C@@H](NC(=O)OC(C)(C)C)C3)n2Cc2ccccc2Cl)n(C)c1=O
Reaction time: 0.08 h

Procedure:
Phosphorus oxychloride (551 μl) was added to dimethylformamide (10 ml) at room temperature and stirred for 5 minutes. A solution of tert-butyl {(3R)-1-[5-(2-chlorobenzyl)-1,3-dimethyl-2,4-dioxo-2,3,4,5-tetrahydro-1H-pyrrolo[3,2-d]pyrimidin-6-yl]piperidin-3-yl}carbamate (502 mg) in N,N-dimethylformamide (1 ml) was added to the reaction solution, and the resulting mixture was stirred at room temperature for 3 hours. Water was added to the reaction solution, followed by extraction with ethyl acetate (100 ml). The organic layer was washed with a 10% aqueous potassium hydrogensulfate solution and a saturated aqueous sodium chloride solution, dried over sodium sulfate and then filtered and the filtrate was concentrated under reduced pressure. The resulting residue was purified by a silica gel column chromatography (hexane/ethyl acetate=1/1) to obtain the title compound (290 mg).
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25]([CH:26]=O)=[CH:24][N:23]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:22]=2)=[CH:17][CH:16]=1.[CH2:36]([P:45](=[O:52])([O:49][CH2:50][CH3:51])[O:46][CH2:47][CH3:48])P(=O)(OCC)OCC.CN(C)C=O.[H-].[Na+]>O>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][CH:10]=[CH:11][CH:12]=2)=[N:4][C:3]=1[CH2:13][O:14][C:15]1[CH:35]=[CH:34][C:18]([CH2:19][O:20][C:21]2[C:25](/[CH:26]=[CH:36]/[P:45](=[O:52])([O:46][CH2:47][CH3:48])[O:49][CH2:50][CH3:51])=[CH:24][N:23]([C:28]3[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=3)[N:22]=2)=[CH:17][CH:16]=1
Reactant: CCOP(=O)(CP(=O)(OCC)OCC)OCC
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(COc2nn(-c3ccccc3)cc2C=O)cc1
Agent: [H-]
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: CCOP(=O)(/C=C/c1cn(-c2ccccc2)nc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1)OCC
Reaction time: 15 h
Yield: 66 %

Procedure:
To a mixture of 3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazole-4-carbaldehyde (0.60 g), tetraethyl methylenediphosphonate (0.40 g) and N,N-dimethylformamide (20 mL) was added sodium hydride (60% in oil, 0.05 g) at room temperature, and the mixture was stirred at the same temperature for 15 hrs. The reaction mixture was poured into water and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The residue was subjected to silica gel column chromatography to give diethyl (E)-2-[3-({4-[(5-methyl-2-phenyl-1,3-oxazol-4-yl)methoxy]benzyl}oxy)-1-phenyl-1H-pyrazol-4-yl]ethenylphosphonate as colorless crystals (0.51 g, yield 65%) from a fraction eluted with ethyl acetate-hexane (3:1, v/v). Recrystallization from ethyl acetate-hexane gave colorless prism crystals. melting point: 109-110° C.
Reaction SMILES: Cl[CH2:2][CH2:3][S:4](Cl)(=[O:6])=[O:5].[C:8]([NH2:16])([CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13])([CH3:10])[CH3:9].C(N(CC)CC)C>ClCCl>[CH3:9][C:8]([NH:16][S:4]([CH:3]=[CH2:2])(=[O:6])=[O:5])([CH3:10])[CH2:11][C:12]([CH3:15])([CH3:14])[CH3:13]
Reactant: CC(C)(C)CC(C)(C)N
Reactant: O=S(=O)(Cl)CCCl
Solvent: CCN(CC)CC
Solvent: ClCCl
Product: C=CS(=O)(=O)NC(C)(C)CC(C)(C)C
Temperature: 25 °C
Yield: 90 %

Procedure:
2-Chloro-1-ethane sulfonyl chloride (51.3 mL, 0.49 mol) in dichloromethane (400 mL) was added dropwise over 2 hours to a solution of tert-octylamine (236.3 mL, 1.47 mol) and triethylamine (68.3 mL, 0.49 mol) in dichloromethane (400 mL) at −18° C. The mixture temperature was maintained between −18° C. and −9° C. during the addition. The mixture was allowed to warm to ambient temperature over 1 hour then washed with 1N HCl (400 mL) and distilled water (2×200 mL). The organic layer was dried with MgSO4, filtered and concentrated in vacuo to give a pale yellow oil. The oil was dried under vacuum at 50° C. to give ethenesulfonic acid (1,1,3,3-tetramethyl-butyl)-amide, 96.0 g (90% yield) as a pale yellow oil.
Reaction SMILES: [CH2:1]([C:3]1([CH2:14][CH3:15])[O:8][C:7](=[O:9])[NH:6][C:5]2[CH:10]=[CH:11][CH:12]=[CH:13][C:4]1=2)[CH3:2].S(=O)(=O)(O)O.[N+:21]([O-])([OH:23])=[O:22]>C(O)(=O)C>[CH2:14]([C:3]1([CH2:1][CH3:2])[C:4]2[CH:13]=[C:12]([N+:21]([O-:23])=[O:22])[CH:11]=[CH:10][C:5]=2[NH:6][C:7](=[O:9])[O:8]1)[CH3:15]
Reactant: CCC1(CC)OC(=O)Nc2ccccc21
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Solvent: CC(=O)O
Product: CCC1(CC)OC(=O)Nc2ccc([N+](=O)[O-])cc21
Reaction time: 0.17 h

Procedure:
To a stirred suspension of 4,4-diethyl-1,4-dihydro-benzo[d][1,3]oxazin-2-one (6.00 g, 29.20 mmol) in a mixture of glacial acetic acid (25 mL) and concentrated sulfuric acid (25 mL) was slowly added concentrated nitric acid (5 mL). After stirring 10 minutes, the reaction mixture was quenched with a chilled brine solution (100 mL) and ice. A solid precipitated, which was collected on a filter and washed with water. After drying in vacuo, 4,4-diethyl-6-nitro-1,4-dihydro-2H-3,1-benzoxazin-2-one was obtained as a white solid (5.02 g, 69%). 1H NMR (DMSO-d6): δ 10.85 (s, 1H), 8.20 (dd, J=8.8, 2.5 Hz, 1H), 8.06 (d, J=2.4 Hz, 1H), 7.06 (d, J=8.8 Hz, 1H), 2.14 (m, 4H), 0.79 (t, J=7.3 Hz, 6H); MS (ESI) m/z 251 ([M+H]+); MS (ESI) m/z 249 ([M−H]−); Anal. calcd for C12H14N2O4: C, 57.59; H, 5.64; N, 11.19. Found: C, 57.44; H, 5.57; N, 11.16.
Reaction SMILES: [CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH2:21])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:22][S:23](NC1C=CC=CC=1N1CCN(C(OC(C)(C)C)=O)CC1)(=[O:25])=[O:24].CS(Cl)(=O)=O.N1C=CC=CC=1>>[CH2:1]([CH:8]1[CH2:13][CH:12]2[CH2:14][CH:9]1[CH2:10][CH:11]2[C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[NH:21][S:23]([CH3:22])(=[O:25])=[O:24])[C:2]1[CH:7]=[N:6][CH:5]=[CH:4][N:3]=1
Reactant: CC(C)(C)OC(=O)N1CCN(c2ccccc2NS(C)(=O)=O)CC1
Reactant: Nc1ccccc1C1CC2CC1CC2Cc1cnccn1
Agent: CS(=O)(=O)Cl
Solvent: c1ccncc1
Product: CS(=O)(=O)Nc1ccccc1C1CC2CC1CC2Cc1cnccn1

Procedure:
{2-[2,5-Diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenyl}-(methylsulfonyl)amine was prepared from 2-[2,5-diaza-5-benzylbicyclo[2.2.1]hept-2-yl]phenylamine (Step 2) (690 mg, 2.5 mmol) according to the procedure for Preparation III using methanesulfonyl chloride (190 μl, 2.46 mmol) and pyridine (220 μl, 2.72 mmol). The crude mix was purified by flash chromatography (SiO2, 3% MeOH in CH2Cl2) to afford the desired sulfonamide (533 mg). MS (ESI, pos. ion) m/z: 358 (M+H), (ESI, neg. ion) m/z: 356 (M−H). Calc'd for Cl9H23N3O2S: 357.47.
Reaction SMILES: [C:1]1([C:7](=[C:14]2[CH2:19][CH2:18][N:17]([C:20](=[O:36])[C:21]([C:23]3[C:31]4[C:26](=[C:27]([O:34][CH3:35])[N:28]=[CH:29][C:30]=4[O:32][CH3:33])[NH:25][CH:24]=3)=[O:22])[CH2:16][CH2:15]2)[C:8]#[C:9][Si](C)(C)C)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.C([O-])([O-])=O.[K+].[K+]>CO>[C:1]1([C:7](=[C:14]2[CH2:15][CH2:16][N:17]([C:20](=[O:36])[C:21]([C:23]3[C:31]4[C:26](=[C:27]([O:34][CH3:35])[N:28]=[CH:29][C:30]=4[O:32][CH3:33])[NH:25][CH:24]=3)=[O:22])[CH2:18][CH2:19]2)[C:8]#[CH:9])[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=1
Reactant: COc1ncc(OC)c2c(C(=O)C(=O)N3CCC(=C(C#C[Si](C)(C)C)c4ccccc4)CC3)c[nH]c12
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CO
Product: C#CC(=C1CCN(C(=O)C(=O)c2c[nH]c3c(OC)ncc(OC)c23)CC1)c1ccccc1
Temperature: 25 °C
Reaction time: 6 h
Yield: 91 %

Procedure:
To a solution of 1-[4-(1-phenyl-1-(2-trimethylsilylethyn-1-yl)-methylene)-piperidin-1-yl]-2-(4,7-dimethoxy-6-azaindol-3-yl)-ethane-1,2-dione (0.035 g, 0.0699 mmol) in MeOH (1 mL) was added K2CO3 (0.010 g, 0.0724 mmol) and the mixture was allowed to stir at room temperature for 6 h. The mixture was then evaporated and the residue was purified by preparative HPLC to give the title compound as a colorless solid (0.027.g, 91%).
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:5]=[C:4]([Br:26])[C:3]=1[OH:27].O[C@@H:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([O:32]C)=[O:31].BrBr>C(Cl)(Cl)Cl>[Br:26][C:4]1[CH:5]=[C:6]([C:8]2[C:17]3[C:18]4[CH:24]=[CH:23][CH:22]=[CH:21][C:19]=4[S:20][C:16]=3[C:15]([I:25])=[C:14]3[C:9]=2[CH:10]=[CH:11][CH:12]=[CH:13]3)[CH:7]=[C:2]([Br:1])[C:3]=1[O:27][CH:29]([CH2:34][C:35]1[CH:40]=[CH:39][CH:38]=[CH:37][CH:36]=1)[C:30]([OH:32])=[O:31]
Reactant: COC(=O)[C@@H](O)Cc1ccccc1
Reactant: Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br
Agent: BrBr
Solvent: ClC(Cl)Cl
Product: O=C(O)C(Cc1ccccc1)Oc1c(Br)cc(-c2c3ccccc3c(I)c3sc4ccccc4c23)cc1Br

Procedure:
Prepared from of 2,6-dibromo-4-(6-iodo-benzo[b]naphtho[2,3-d]thiophen-11 -yl)-phenol (Example 59) and (S)-2-hydroxy-3-phenylpropionic acid, methyl ester (Example 96). White solid: [a]25/D=+31.791° (9.940 mg/mL CHCl3); NMR (CDCl3); δ8.23 (ddd, J=8, 1, 1 Hz), 7.81 (ddd, J=8, 1, 1 Hz, 1 H), 7.64 (ddd, J=8,7, 1 Hz, 1 H), 7.58 (dd, J=9, 2Hz, 2 H), 7.52-7.39 (m, 7 H), 7.37-7.28 (m, 2 H), 6.68 (ddd, J=8,1, 1 Hz, 1 H), 5.48 (t, J=7 Hz, 1 H, -CH), 3.5 (d, J=7 Hz, 2 H); MS (+FAB): [M+], 2 bromine isotope pattern, 756 (65%), 758 (100%), 760 (90%); Anal. calc. for C31H19Br2IO3S: C, 49.10, H, 2.53, N, 0.00. Found: C, 50.75, H, 3.00, N, 0.09.
Reaction SMILES: [CH2:1]([C:8]1[N:12]=[C:11]([C:13]2[CH:18]=[CH:17][C:16]([NH:19][C:20](=[O:25])[C:21]([F:24])([F:23])[F:22])=[C:15]([Br:26])[CH:14]=2)[O:10][N:9]=1)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44]O)=[O:36])[C:28]1[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=1>>[CH2:27]([O:34][C:35]([N:37]1[CH2:41][CH2:40][CH2:39][C@@H:38]1[CH:42]=[CH:43][CH2:44][N:19]([C:16]1[CH:17]=[CH:18][C:13]([C:11]2[O:10][N:9]=[C:8]([CH2:1][C:2]3[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=3)[N:12]=2)=[CH:14][C:15]=1[Br:26])[C:20](=[O:25])[C:21]([F:22])([F:23])[F:24])=[O:36])[C:28]1[CH:29]=[CH:30][CH:31]=[CH:32][CH:33]=1
Reactant: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCO
Reactant: O=C(Nc1ccc(-c2nc(Cc3ccccc3)no2)cc1Br)C(F)(F)F
Product: O=C(OCc1ccccc1)N1CCC[C@@H]1C=CCN(C(=O)C(F)(F)F)c1ccc(-c2nc(Cc3ccccc3)no2)cc1Br
Yield: 88 %

Procedure:
4-(3-Benzyl-1,2,4-oxadiazol-5-yl)-2-bromo-1-trifluoroacetylaminobenzene and (R)-1-(N-benzyloxycarbonylpyrrolidin-2-yl)-3-hydroxypropene were used. Chromatography using elution with 5% either in methylene chloride afforded the title compound (88%) as a thick yellow oil: R1 =0.32 (CHCl3); LRMS (m/z, relative intensity) 669 (M+, 25).
Reaction SMILES: [CH2:1]([O:8][C:9]1[C:10]([C:37](O)=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:35])([CH3:34])[CH3:33])=[O:30])(=[O:22])=[O:21])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C.Cl.[NH2:74][CH2:75][C:76]1[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=1[C:78]([O:80][CH2:81][CH3:82])=[O:79]>ClCCl>[CH2:1]([O:8][C:9]1[C:10]([C:37]([NH:74][CH2:75][C:76]2[CH:86]=[CH:85][C:84]([F:87])=[CH:83][C:77]=2[C:78]([O:80][CH2:81][CH3:82])=[O:79])=[O:38])=[N:11][C:12]([N:19]([CH3:36])[S:20]([CH2:23][CH2:24][CH2:25][CH2:26][CH2:27][NH:28][C:29]([O:31][C:32]([CH3:33])([CH3:34])[CH3:35])=[O:30])(=[O:21])=[O:22])=[C:13]2[C:18]=1[N:17]=[CH:16][CH:15]=[CH:14]2)[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1
Reactant: CN(c1nc(C(=O)O)c(OCc2ccccc2)c2ncccc12)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C
Reactant: CCOC(=O)c1cc(F)ccc1CN
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CCOC(=O)c1cc(F)ccc1CNC(=O)c1nc(N(C)S(=O)(=O)CCCCCNC(=O)OC(C)(C)C)c2cccnc2c1OCc1ccccc1
Temperature: 25 °C
Reaction time: 0.08 h
Yield: 71 %

Procedure:
To a solution of 8-(benzyloxy)-5-(5-(tert-butoxycarbonylamino)-N-methylpentylsulfonamido)-1,6-naphthyridine-7-carboxylic acid (Example 2.4; 3.82 mmol) in dichloro methane (38 ml) were added HBTU (4.58 mmol) and DIPEA (15.8 mmol). The mixture was stirred for 5 min at rt. Ethyl 2-(aminomethyl)-5-fluorobenzoate hydrochloride (Example 4; 4.58 mmol) was added portionwise at rt. The mixture was stirred overnight at rt. The product was extracted with CH2Cl2, dried over MgSO4 and concentrated. The crude product was purified by SiO2 column chromatography (AcOEt:Hex, 1:1) to afford the target compound in 71% yield.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([F:32])=[C:6]([NH:8][C:9]2[CH:14]=[C:13]([NH:15][CH:16]3[CH2:18][CH2:17]3)[N:12]3[N:19]=[CH:20][C:21](/[CH:22]=[C:23]4/[C:24](=[O:31])[N:25]([CH2:29][OH:30])[C:26](=[O:28])[NH:27]/4)=[C:11]3[N:10]=2)[CH:7]=1.[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42](O)=[O:43])[CH2:36][CH2:35]1.C1(N=C=NC2CCCCC2)CCCCC1>CN(C=O)C.CN(C1C=CN=CC=1)C.C(OCC)(=O)C>[CH3:33][N:34]1[CH2:39][CH2:38][N:37]([CH2:40][CH2:41][C:42]([O:30][CH2:29][N:25]2[C:24](=[O:31])/[C:23](=[CH:22]/[C:21]3[CH:20]=[N:19][N:12]4[C:13]([NH:15][CH:16]5[CH2:17][CH2:18]5)=[CH:14][C:9]([NH:8][C:6]5[CH:7]=[C:2]([Cl:1])[CH:3]=[CH:4][C:5]=5[F:32])=[N:10][C:11]=34)/[NH:27][C:26]2=[O:28])=[O:43])[CH2:36][CH2:35]1
Reactant: O=C1N/C(=C\c2cnn3c(NC4CC4)cc(Nc4cc(Cl)ccc4F)nc23)C(=O)N1CO
Reactant: CN1CCN(CCC(=O)O)CC1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Agent: CN(C)c1ccncc1
Solvent: CCOC(C)=O
Solvent: CN(C)C=O
Product: CN1CCN(CCC(=O)OCN2C(=O)N/C(=C\c3cnn4c(NC5CC5)cc(Nc5cc(Cl)ccc5F)nc34)C2=O)CC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 26.2 %

Procedure:
To (Z)-5-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-3-(hydroxymethyl)imidazolidine-2,4-dione (100 mg, 0.218 mmol) in DMF (3 mL) was added 3-(4-methylpiperazin-1-yl)propanoic acid (75 mg, 0.436 mmol), dicyclohexylcarbodiimide (90 mg, 0.436 mmol), and DMAP (4.0 mg, 0.33 mmol). The reaction mixture was stirred at room temperature overnight and then diluted with ethyl acetate and washed 1× water, 3× brine. The organic layer was dried with MgSO4, filtered and adsorbed onto silica gel. The crude material was purified by column chromatography eluting with 0-10% MeOH/CH2Cl2 gradient. Pure fractions were combined and the solvent was removed. This material was crystallized from ethyl acetate and hexane to provide 35 mg (26%) of (Z)-(4-((5-(5-chloro-2-fluorophenylamino)-7-(cyclopropylamino)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)-2,5-dioxoimidazolidin-1-yl)methyl 3-(4-methylpiperazin-1-yl)propanoate as a yellow solid. LCMS (ES): >95% pure, m/z 612 [M+1]+.
Reaction SMILES: [CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=O)=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1.N1CCCCC1.[NH:29]1[CH2:35][C:33](=[O:34])[NH:32][C:30]1=[O:31]>CCO>[CH:1]1([NH:4][C:5]2[N:10]3[N:11]=[CH:12][C:13]([CH:14]=[C:35]4[NH:29][C:30](=[O:31])[NH:32][C:33]4=[O:34])=[C:9]3[N:8]=[C:7]([C:16]3[CH:21]=[CH:20][CH:19]=[C:18]([OH:22])[CH:17]=3)[CH:6]=2)[CH2:3][CH2:2]1
Reactant: O=Cc1cnn2c(NC3CC3)cc(-c3cccc(O)c3)nc12
Reactant: O=C1CNC(=O)N1
Solvent: C1CCNCC1
Solvent: CCO
Product: O=C1NC(=O)C(=Cc2cnn3c(NC4CC4)cc(-c4cccc(O)c4)nc23)N1
Temperature: 50 °C
Reaction time: 8 h
Yield: 54.7 %

Procedure:
To 7-(cyclopropylamino)-5-(3hydroxyphenyl)pyrazolo[1,5-a]pyrimidine-3-carbaldehyde (100 mg, 0.34 mmol) in EtOH (2 mL) was added piperidine (67 μL, 0.68 mmol), and hydantoin (34 mg, 0.34 mmol). The reaction was stirred at 50° C. overnight. The solid formed was isolated by filtration to provide 70 mg of 5-((7-(cyclopropylamino)-5-(3-hydroxyphenyl)pyrazolo[1,5-a]pyrimidin-3-yl)methylene)imidazolidine-2,4-dione (55%). LCMS (M+1=377)
Reaction SMILES: [F:1][C:2]1[CH:11]=[CH:10][CH:9]=[C:8]2[C:3]=1[CH:4]=[CH:5][CH:6]=[C:7]2[NH:12]C(=O)C.[N+:16]([O-])([OH:18])=[O:17]>CC(O)=O>[NH2:12][C:7]1[C:8]2[C:3](=[C:2]([F:1])[CH:11]=[CH:10][CH:9]=2)[C:4]([N+:16]([O-:18])=[O:17])=[CH:5][CH:6]=1
Reactant: CC(=O)Nc1cccc2c(F)cccc12
Reactant: O=[N+]([O-])O
Solvent: CC(=O)O
Product: Nc1ccc([N+](=O)[O-])c2c(F)cccc12
Temperature: 10 °C
Reaction time: 0.25 h
Yield: 26.4 %

Procedure:
Compound 209A (133 mg, 0.645 mmol) was dissolved in 1 mL AcOH and the resulting solution was cooled to 10° C. At this temperature, 80.0 μL (2.00 mmol) of red fuming HNO3 was added and stirring was continued for 15 min before the reaction was quenched by the addition of crushed ice. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was dissolved in 3 mL EtOH, heated to reflux and treated with 0.5 mL of 40% aqueous NaOH solution. Stirring was continued for 15 min before the reaction was cooled and diluted with H2O. The aqueous layer was extracted with CH2Cl2 and the combined organic phases were dried over MgSO4 and concentrated in vacuo. The resulting residue was purified by flash chromatography on silica gel, eluting with 40 to 70% EtOAc in hexane to afford 36 mg (0.17 mmol, 27%) of compound 209B as a yellow solid.
Reaction SMILES: [NH2:1][CH2:2][CH2:3][C:4]1([C:9]([NH:11][C@@H:12]([CH2:16][C:17]2[CH:22]=[CH:21][C:20]([NH:23][C:24](=[O:33])[C:25]3[C:30]([Cl:31])=[CH:29][CH:28]=[CH:27][C:26]=3[Cl:32])=[CH:19][CH:18]=2)[C:13]([OH:15])=[O:14])=[O:10])[CH2:8][CH2:7][CH2:6][CH2:5]1.O=C1CCC(=O)N1[O:41][C:42](=O)[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]1[C:77](=[O:78])[CH:76]=[CH:75][C:74]1=[O:79].CCN(C(C)C)C(C)C>>[Cl:31][C:30]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:32])[C:25]=1[C:24]([NH:23][C:20]1[CH:19]=[CH:18][C:17]([CH2:16][C@H:12]([NH:11][C:9]([C:4]2([CH2:3][CH2:2][NH:1][C:42](=[O:41])[CH2:43][CH2:44][O:45][CH2:46][CH2:47][O:48][CH2:49][CH2:50][O:51][CH2:52][CH2:53][O:54][CH2:55][CH2:56][O:57][CH2:58][CH2:59][O:60][CH2:61][CH2:62][O:63][CH2:64][CH2:65][O:66][CH2:67][CH2:68][NH:69][C:70](=[O:80])[CH2:71][CH2:72][N:73]3[C:77](=[O:78])[CH:76]=[CH:75][C:74]3=[O:79])[CH2:8][CH2:7][CH2:6][CH2:5]2)=[O:10])[C:13]([OH:15])=[O:14])=[CH:22][CH:21]=1)=[O:33]
Reactant: NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1
Reactant: O=C(CCN1C(=O)C=CC1=O)NCCOCCOCCOCCOCCOCCOCCOCCOCCC(=O)ON1C(=O)CCC1=O
Solvent: CCN(C(C)C)C(C)C
Product: O=C(CCOCCOCCOCCOCCOCCOCCOCCOCCNC(=O)CCN1C(=O)C=CC1=O)NCCC1(C(=O)N[C@@H](Cc2ccc(NC(=O)c3c(Cl)cccc3Cl)cc2)C(=O)O)CCCC1

Procedure:
The title compound was prepared using a similar procedure as described in Example 1, Step 11, starting from (S)-2-[[1-(2-aminoethyl)cyclopentanecarbonyl]amino]-3-[4-(2,6-dichlorobenzoylamino)phenyl]propionic acid (607 mg, 1.0 mmol), 3-[2-[2-[2-[2-[2-[2-[2-[2-[3-(2,5-dioxo-2,5-dihydro-pyrrol-1-yl)propionylamino]- ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]ethoxy]propionic acid-2,5-dioxo-pyrrolidin-1-yl ester (689 mg, 1.0 mmol), and DIPEA (388 mg, 522 uL, 3.0 mmol), and after HPLC purification, resulted in a light yellow solid (788 mg, 74%). ES(+)-HRMS m/e calcd. for C50H69Cl2N5O16 (M+H)+ 1066.4189, obsd. 1066.4182.
Reaction SMILES: [C:1]([CH2:5][CH2:6][C:7]#[C:8][CH2:9][CH2:10][C:11]([O:13][CH3:14])=[O:12])([O:3][CH3:4])=[O:2].N1C2C(=CC=CC=2)C=CC=1>[Pd].CC([O-])=O.CC([O-])=O.[Pb+2].CO>[C:11]([CH2:10][CH2:9]/[CH:8]=[CH:7]\[CH2:6][CH2:5][C:1]([O:3][CH3:4])=[O:2])([O:13][CH3:14])=[O:12]
Reactant: COC(=O)CCC#CCCC(=O)OC
Agent: [Pd]
Agent: CC(=O)[O-]
Agent: [Pb+2]
Solvent: c1ccc2ncccc2c1
Solvent: CO
Product: COC(=O)CC/C=C\CCC(=O)OC
Yield: 93.1 %

Procedure:
A mixture of 1,6-dicarbomethoxy-3-hexyne [II-1] (5 g), a Lindlar catalyst (5% Pd-CaCO3 -PbO) (50 mg), quinoline (25 mg) and methanol (15 ml) is charged in an atmospheric hydrogenation apparatus and subjected to reduction at room temperature under atmospheric pressure. After completion of the reaction, the catalyst is removed by filtration and the filtrate is concentrated to give 1,6-dicarbomethoxy-cis-3-hexene [II-2] (4.70 g, yield; 93.0%), b.p. 92°-95° C./0.3 mmHg.
Reaction SMILES: [CH2:1]([O:3][C:4](=[O:29])[CH2:5][C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2].[Br:30]N1C(=O)CCC1=O>C(#N)C.C(Cl)Cl>[CH2:1]([O:3][C:4](=[O:29])[CH:5]([Br:30])[C:6]1[N:7]=[C:8]([NH:11][C:12]([NH:14][C:15]2[CH:20]=[CH:19][C:18]([CH3:21])=[CH:17][C:16]=2[C:22]([CH:24]2[CH2:28][CH2:27][CH2:26][CH2:25]2)=[O:23])=[O:13])[S:9][CH:10]=1)[CH3:2]
Reactant: O=C1CCC(=O)N1Br
Reactant: CCOC(=O)Cc1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Solvent: CC#N
Solvent: ClCCl
Product: CCOC(=O)C(Br)c1csc(NC(=O)Nc2ccc(C)cc2C(=O)C2CCCC2)n1
Reaction time: 8 h
Yield: 16.9 %

Procedure:
To a solution of {2-[3-(2-cyclopentanecarbonyl-4-methyl-phenyl)-ureido]-thiazol-4-yl}-acetic acid ethyl ester (0.05 g, 0.12 mmol) in 2 ml of acetonitrile was added N-bromosuccinimide (0.024 g, 0.13 mmol). The reaction mixture was stirred under nitrogen in a pressure bottle excluded from light overnight at 25° C. The mixture was diluted with 15 ml of DCM, washed (1N HCl, saturated NaHCO3, water), dried (MgSO4) and concentrated under reduced pressure. The crude product was purified by preparative HPLC to afford the title compound (0.010 g, 17%).
Reaction SMILES: [CH2:1]([C:3]1[CH:18]=[C:17]([C:19]2[N:23]=[C:22]([C:24]3[CH:29]=[C:28]([CH3:30])[N:27]=[C:26]([NH:31][CH2:32][CH3:33])[N:25]=3)[O:21][N:20]=2)[CH:16]=[C:15]([CH3:34])[C:4]=1[O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])[CH3:2].[CH2:35](N(CC)C1N=C(C(O)=O)C=C(C)N=1)[CH3:36]>>[CH2:32]([N:31]([CH2:35][CH3:36])[C:26]1[N:25]=[C:24]([C:22]2[O:21][N:20]=[C:19]([C:17]3[CH:16]=[C:15]([CH3:34])[C:4]([O:5][CH2:6][C@@H:7]([OH:14])[CH2:8][NH:9][C:10](=[O:13])[CH2:11][OH:12])=[C:3]([CH2:1][CH3:2])[CH:18]=3)[N:23]=2)[CH:29]=[C:28]([CH3:30])[N:27]=1)[CH3:33]
Reactant: CCNc1nc(C)cc(-c2nc(-c3cc(C)c(OC[C@@H](O)CNC(=O)CO)c(CC)c3)no2)n1
Reactant: CCN(CC)c1nc(C)cc(C(=O)O)n1
Product: CCc1cc(-c2noc(-c3cc(C)nc(N(CC)CC)n3)n2)cc(C)c1OC[C@@H](O)CNC(=O)CO

Procedure:
N((S)-3-{4-[5-(2-Diethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-2-ethyl-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide is prepared in analogy to N—((S)-3-{2-ethyl-4-[5-(2-ethylamino-6-methyl-pyrimidin-4-yl)-[1,2,4]oxadiazol-3-yl]-6-methyl-phenoxy}-2-hydroxy-propyl)-2-hydroxy-acetamide using 2-diethylamino-6-methyl-pyrimidine-4-carboxylic acid; LC-MS: tR=1.03 min; [M+H]+=499.23. 1H NMR (D6-DMSO): δ 1.18 (t, J=7.0 Hz, 6H), 1.22 (t, J=7.3 Hz, 3H), 2.35 (s, 3H), 2.44 (s, 3H), 2.73 (q, J=7.3 Hz, 2 H), 3.25 (m, 1H), 3.44 (m, 1H), 3.67 (q, J=7.0 Hz, 4H), 3.76 (m, 2H), 3.84 (d, J=5.8 Hz, 2H), 3.96 (m, 1H), 5.31 (d, J=5.0 Hz, 1H), 5.55 (t, J=5.5 Hz, 1H), 7.30 (s, 1H), 7.69 (t, J=5.5 Hz, 1H), 7.78 (s, 2H).