Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]1([SH:7])[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.Br[CH2:9][CH2:10][CH2:11][Cl:12]>>[Cl:12][CH2:11][CH2:10][CH2:9][S:7][C:1]1[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1
Reactant: ClCCCBr
Reactant: Sc1ccccc1
Product: ClCCCSc1ccccc1

Procedure:
Prepared by Procedure R and Scheme Z using benzenethiol and 1-bromo-3-chloropropane: 1H NMR (400 MHz, CDCl3) δ 7.37–7.34 (m, 2H), 7.32–7.26 (m, 2H), 7.19 (tt, 1H, J=1.4, 7.3 Hz), 3.67 (t, 2H, J=6.6 Hz), 3.08 (t, 2H, J=6.6 Hz), 2.06 (qt, 2H, J=6.6 Hz).
Reaction SMILES: C(OC(=O)[NH:7][C:8]1[CH:13]=[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])[C:11]([Cl:19])=[CH:10][C:9]=1[NH:20][C:21](=[O:38])[CH2:22][C:23]([C:25]1[CH:30]=[CH:29][CH:28]=[C:27]([C:31]2[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=2)[CH:26]=1)=O)(C)(C)C.C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:19][C:11]1[C:12]([NH:14][CH2:15][CH:16]([CH3:18])[CH3:17])=[CH:13][C:8]2[N:7]=[C:23]([C:25]3[CH:30]=[CH:29][CH:28]=[C:27]([C:31]4[CH:36]=[CH:35][N:34]=[C:33]([CH3:37])[CH:32]=4)[CH:26]=3)[CH2:22][C:21](=[O:38])[NH:20][C:9]=2[CH:10]=1
Reactant: Cc1cc(-c2cccc(C(=O)CC(=O)Nc3cc(Cl)c(NCC(C)C)cc3NC(=O)OC(C)(C)C)c2)ccn1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: Cc1cc(-c2cccc(C3=Nc4cc(NCC(C)C)c(Cl)cc4NC(=O)C3)c2)ccn1

Procedure:
The title compound was prepared from (4-chloro-5-isobutylamino-2-{3-[3-(2-methyl-pyridin-4-yl)-phenyl]-3-oxo-propionylamino}-phenyl)-carbamic acid tert-butyl ester (Example M72) (0.47 g, 0.85 mmol) by treatment with TFA in CH2Cl2 according to the general procedure N. Obtained as a light yellow solid (313 mg, 85%).
Reaction SMILES: [OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([OH:11])[CH:10]=1)[C:5]([OH:7])=[O:6].[Cl:16][C:17]([Cl:21])([Cl:20])[CH2:18]O.S(=O)(=O)(O)O>C1(C)C=CC=CC=1>[OH:1][C:2]1[C:3]([CH3:15])=[C:4]([C:8]([CH2:12][CH2:13][CH3:14])=[C:9]([OH:11])[CH:10]=1)[C:5]([O:7][CH2:18][C:17]([Cl:21])([Cl:20])[Cl:16])=[O:6]
Reactant: OCC(Cl)(Cl)Cl
Reactant: CCCc1c(O)cc(O)c(C)c1C(=O)O
Agent: O=S(=O)(O)O
Solvent: Cc1ccccc1
Product: CCCc1c(O)cc(O)c(C)c1C(=O)OCC(Cl)(Cl)Cl
Yield: 87.4 %

Procedure:
A mixture of 5.0 g of 3,5-dihydroxy-2-methyl-6-propyl benzoic acid, 4.48 g of 2,2,2-trichloroethanol, and 0, 1 ml of 98% sulfuric acid in 40 ml of toluene was heated at reflux for 3 hours, water being constantly removed by a Dean-Stark trap. The mixture was cooled, diluted with 80 ml of ethyl acetate and washed with brine. The organic layer was dried over sodium sulfate, and the solvent was evaporated in vacuo. Chromatography of the residue on silica gel using acetone/hexane (1:6, v/v) as eluent afforded 7.1 g of 2,2,2-trichloroethyl 3,5-dihydroxy-2-methyl-6-propylbenzoate as an oil.
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20]OS(C)(=O)=O)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.[Cl:26][C:27]1[CH:32]=[CH:31][CH:30]=[CH:29][C:28]=1[N:33]1[CH2:38][CH2:37][NH:36][CH2:35][CH2:34]1.C(=O)([O-])[O-].[Cs+].[Cs+]>>[Cl:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2([C:12]([N:14]3[CH2:19][CH2:18][CH2:17][CH:16]([CH2:20][N:36]4[CH2:35][CH2:34][N:33]([C:28]5[CH:29]=[CH:30][CH:31]=[CH:32][C:27]=5[Cl:26])[CH2:38][CH2:37]4)[CH2:15]3)=[O:13])[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: Clc1ccccc1N1CCNCC1
Reactant: CS(=O)(=O)OCC1CCCN(C(=O)C2(c3ccc(Cl)cc3)CCC2)C1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Product: O=C(N1CCCC(CN2CCN(c3ccccc3Cl)CC2)C1)C1(c2ccc(Cl)cc2)CCC1
Yield: 41.9 %

Procedure:
Compound 7 was prepared using the method of described in Example 3, starting with compound 2 (1.0 g, 2.60 mmol), 1-(2-chlorophenyl)piperazine (0.56 g, 2.86 mmol), and cesium carbonate (1.27 g, 3.90 mmol) to give 7 (0.53 g, 42%); C27H33Cl2N3O, LRMS (m/z)=487 (MH+).
Reaction SMILES: [CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[OH:13])[CH:8]=[O:9])[C:2]#[CH:3].C([O-])([O-])=O.[K+].[K+].CN(C=O)C.[Br:25][CH:26](Br)[CH3:27]>O>[CH2:1]([O:4][C:5]1[CH:6]=[C:7]([CH:10]=[CH:11][C:12]=1[O:13][CH2:27][CH2:26][Br:25])[CH:8]=[O:9])[C:2]#[CH:3]
Reactant: C#CCOc1cc(C=O)ccc1O
Reactant: CC(Br)Br
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: C#CCOc1cc(C=O)ccc1OCCBr
Temperature: 25 °C
Reaction time: 0.5 h
Yield: 76.5 %

Procedure:
To a dry two-neck flask, compound 8 (4.3 g, 24 mmol, 1 equiv) and K2CO3 (16 g, 120 mmol, 5 equiv) were added into anhydrous DMF (50 mL) under nitrogen. The mixture was stirred at rt for 30 min. Dibromoethane (21 mL, 240 mmol, 10 equiv) was then added in one portion and the resulting mixture was heated overnight at 55° C. under a nitrogen atmosphere. The mixture was poured into water (400 mL) and the product was extracted with ethyl acetate (3×200 mL). The combined organic extracts were concentrated to about 250 mL and were washed subsequently with 1 M NaOH (2×200 mL), water (250 mL) and brine (5×250 mL). The organic layer was dried over MgSO4, filtered and the solvent was removed under vacuum. The crude product as yellow oil was chromatographed on a silica gel column with the eluent of ethyl acetate/hexane (20/80) to give pure product as a white solid (5.2 g, yield: 77%). 1H NMR δ=9.88 (s, 1H, —CHO), 7.58 (d, J=1.8, 1H), 7.54 (dd, J1=1.8, J2=8, 1H), 7.02 (d, J=8, 1H), 4.83 (d, J=2.3, 2H, —OCH2), 4.43 (t, J=6.6, 2H, —OCH2CH2Br), 3.72 (t, J=6.6, 2H, —OCH2CH2Br), 2.54 (t, J=2.3, 1H, —C≡CH). 13C NMR δ=190.68 (—CHO), 153.70, 147.77, 130.79, 127.01, 113.95, 113.19, 78.01 (—C≡CH), 76.63 (—C≡CH), 68.98 (—OCH2CH2Br), 57.16 (—OCH2C≡CH), 28.45 (—OCH2CH2Br). HRMS calculated for C12H11BrO3 (M+), 281.9892; found, 281.9903.
Reaction SMILES: [Br:1][CH:2]([CH3:6])[C:3](Br)=[O:4].CN(C)C1C=CC=CC=1.S(=O)(=O)(O)O.[C:21]([OH:25])([CH3:24])([CH3:23])[CH3:22]>C(Cl)(Cl)Cl>[Br:1][CH:2]([CH3:6])[C:3]([O:25][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:4]
Reactant: CC(C)(C)O
Reactant: CC(Br)C(=O)Br
Agent: O=S(=O)(O)O
Solvent: ClC(Cl)Cl
Solvent: CN(C)c1ccccc1
Product: CC(Br)C(=O)OC(C)(C)C
Yield: 86.7 %

Procedure:
(a) A solution of 2-bromopropionyl bromide (25 g.) in dry chloroform (50 ml.) was dropwise added with stirring and ice-cooling to a solution of N,N-dimethylaniline (24 g.) in t-butanol (11 g.) and the mixture was refluxed for 2 hours. After cooling, the reaction mixture was poured into 6N sulfuric acid (150 ml.) and extracted with ether. The extract was in turn washed with 6N sulfuric acid, water, a 10% potassium carbonate aqueous solution and water and dried over magnesium sulfate. The solvent was distilled off to give oil of t-butyl 2-bromopropionate (21 g.).
Reaction SMILES: [F:1][C:2]([F:38])([F:37])[O:3][C:4]1[CH:9]=[CH:8][C:7]([N:10]2[CH:14]=[N:13][C:12]([C:15]3[CH:20]=[CH:19][C:18]([NH:21][C:22](=[O:36])[O:23][CH:24]([C:26]4[CH:27]=[N:28][C:29]([C:32]([F:35])([F:34])[F:33])=[CH:30][CH:31]=4)[CH3:25])=[CH:17][CH:16]=3)=[N:11]2)=[CH:6][CH:5]=1.[H-].[Na+].I[CH2:42][CH3:43]>CN(C=O)C>[CH2:42]([N:21]([C:18]1[CH:17]=[CH:16][C:15]([C:12]2[N:13]=[CH:14][N:10]([C:7]3[CH:8]=[CH:9][C:4]([O:3][C:2]([F:1])([F:37])[F:38])=[CH:5][CH:6]=3)[N:11]=2)=[CH:20][CH:19]=1)[C:22](=[O:36])[O:23][CH:24]([C:26]1[CH:27]=[N:28][C:29]([C:32]([F:34])([F:35])[F:33])=[CH:30][CH:31]=1)[CH3:25])[CH3:43]
Reactant: CC(OC(=O)Nc1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1)c1ccc(C(F)(F)F)nc1
Reactant: CCI
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCN(C(=O)OC(C)c1ccc(C(F)(F)F)nc1)c1ccc(-c2ncn(-c3ccc(OC(F)(F)F)cc3)n2)cc1
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 92.1 %

Procedure:
1-(6-(Trifluoromethyl)pyridin-3-yl)ethyl 4-(1-(4-(trifluoromethoxy)phenyl)-1H-1,2,4-triazol-3-yl)phenylcarbamate (54 mg, 0.10 mmol) was dissolved in anhydrous DMF (0.5 mL) under N2 and cooled to 0° C. NaH (60% suspension in mineral oil; 4.4 mg, 0.11 mmol) was added, and the mixture was stirred for 10 min at 0° C. Iodoethane (9 μL, 0.11 mmol) was added, and the mixture was warmed to ambient temperature and stirred for 1 h. Additional NaH (4 mg) and iodoethane (5 μL) were added at ambient temperature to promote complete consumption of the starting material. The mixture was quenched with aqueous NH4Cl and extracted with 80% EtOAc/hexanes (×3). The combined organic layers were washed with brine, dried over Na2SO4, and concentrated. The crude product was applied to a silica gel column, and elution with a 15% to 40% to 80% EtOAc/hexanes gradient provided the title compound (52.1 mg, 91%) as a light yellow oil: IR 3111, 2983, 2936, 1707, 1519, 1340, 1268, 1155 cm−1; 1H NMR (300 MHz, CDCl3) δ 8.62 (s, J=10.6 Hz, 1H), 8.58 (s, 1H), 8.21 (d, J=8.5 Hz, 2H), 7.81 (d, J=9.0 Hz, 2H), 7.73-7.58 (m, 2H), 7.40 (d, J=8.5 Hz, 2H), 7.30 (d, J=8.5 Hz, 2H), 5.95 (q, J=6.6 Hz, 1H), 3.84-3.70 (m, 2H), 1.53 (d, J=6.2 Hz, 3H), 1.19 (t, J=7.1 Hz, 3H); HRMS-FAB (m/z) [M+H]+ calcd for C26H21F6N5O3, 565.1549. found, 565.1568.
Reaction SMILES: Cl[C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1.[CH3:18][NH:19][CH2:20][CH2:21][NH:22][CH3:23]>>[CH3:18][N:19]([C:2]1[C:7]([O:8][CH2:9][CH2:10][O:11][C:12]2[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=2)=[N:6][CH:5]=[CH:4][N:3]=1)[CH2:20][CH2:21][NH:22][CH3:23]
Reactant: CNCCNC
Reactant: Clc1nccnc1OCCOc1ccccc1
Product: CNCCN(C)c1nccnc1OCCOc1ccccc1

Procedure:
A mixture of 2-chloro-3-(2-phenoxyethoxy)pyrazine (50 mg, 0.20 mmol; from Example 1, Step 1) and N,N′-dimethylethylenediamine (0.2 mL, 1.9 mmol) was heated in a MicroWell 10 microwave reactor for 6 min at 100W. The reaction mixture was partitioned between water and EtOAc and applied to a hydromatrix column. The column was eluted with EtOAc and the elute was concentrated. The product was purified by Amberchrom CG-161m LC using CH3CN/H2O (gradient: CH3CN 0% to 100%). Yield 2 mg (4%). MS m/z 303 (M+H)+.
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][CH2:5][N:6]1[C:10]2[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=2[N:8]=[N:7]1.[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:30][CH2:29][NH:28][CH2:27][CH2:26]1.C(N(C(C)C)CC)(C)C.[I-].[K+]>C(#N)C>[N:15]1[C:24]2[C:19](=[CH:20][CH:21]=[CH:22][CH:23]=2)[N:18]=[CH:17][C:16]=1[N:25]1[CH2:26][CH2:27][N:28]([CH2:2][CH2:3][CH2:4][CH2:5][N:6]2[C:10]3[CH:11]=[CH:12][CH:13]=[CH:14][C:9]=3[N:8]=[N:7]2)[CH2:29][CH2:30]1
Reactant: c1ccc2nc(N3CCNCC3)cnc2c1
Reactant: ClCCCCn1nnc2ccccc21
Agent: [I-]
Agent: [K+]
Solvent: CCN(C(C)C)C(C)C
Solvent: CC#N
Product: c1ccc2nc(N3CCN(CCCCn4nnc5ccccc54)CC3)cnc2c1
Temperature: 25 °C
Yield: 62.8 %

Procedure:
1-(4-chlorobutyl)-1H-benzotriazole (7.55 g, 0.036 mol) was dissolved into 100 ml of acetonitrile, 4-(2-quinoxalinyl)piperazine (6.4 g, 0.03 mol), diisopropylethylamine (15.5 g, 0.12 mol) and potassium iodide (5.0 g, 0.03 mol) were respectively added. The mixture was stirred and mixed, then heated and refluxed to react for 20 hours. The mixture was cooled down to ambient temperature and filtered. The filtrate was concentrated to produce oily products, and treated by chromatography with neutral Al2O3 and purified, eluted with dichloromethane to produce 7.3 g compound (I-48) with a yield of 62.7%. ESI-MS [M+H]+: m/z 387.2.
Reaction SMILES: [Cl:1][C:2]1[CH:29]=[CH:28][CH:27]=[C:26]([Cl:30])[C:3]=1[C:4]([NH:6][C@H:7]([C:23](O)=[O:24])[CH2:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:11][CH:10]=1)=[O:5].[C:31]([NH:35][OH:36])([CH3:34])([CH3:33])[CH3:32].CN([P+](ON1N=NC2C=CC=CC1=2)(N(C)C)N(C)C)C.F[P-](F)(F)(F)(F)F.CCN(C(C)C)C(C)C>C(Cl)Cl>[C:31]([N:35]([OH:36])[C:23](=[O:24])[C@H:7]([CH2:8][C:9]1[CH:10]=[CH:11][C:12]([C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=2[O:21][CH3:22])=[CH:13][CH:14]=1)[NH:6][C:4](=[O:5])[C:3]1[C:2]([Cl:1])=[CH:29][CH:28]=[CH:27][C:26]=1[Cl:30])([CH3:34])([CH3:33])[CH3:32]
Reactant: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)O)cc1
Reactant: CC(C)(C)NO
Agent: CN(C)[P+](On1nnc2ccccc21)(N(C)C)N(C)C
Agent: F[P-](F)(F)(F)(F)F
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: COc1ccccc1-c1ccc(C[C@H](NC(=O)c2c(Cl)cccc2Cl)C(=O)N(O)C(C)(C)C)cc1
Temperature: 25 °C
Reaction time: 8 h
Yield: 65.1 %

Procedure:
To a solution of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine (0.098 g) and tert-butylhydroxylamine (0.047 g) in CH2Cl2 (5 mL) was added BOP reagent (0.17 g) followed by DIEA (0.1 mL) and the mixture was stirred overnight at room temperature. The mixture was evaporated and the residue was dissolved in EtOAc (30 mL). The EtOAc solution was successively washed with 1 N HCl, satd. NaHCO3, satd. LiCl, dried (MgSO4), and concentrated. The residue was purified by preparative TLC (silica gel; eluent: hexane/EtOAc/CH2Cl2 6/1/1) and recrystallization from CH2Cl2/hexane to give 74 mg of N-(2,6-dichlorobenzoyl)-4-(2-methoxyphenyl)-L-phenylalanine N-(tert-butyl)-N-hydroxyamide. ESMS: m/z 515 (MH+).
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12].[F-].[Cs+].[CH2:24]([Sn](CCCC)(CCCC)CCCC)[CH:25]=[CH2:26]>C1COCC1>[CH2:26]([C:2]1[CH:3]=[C:4]([Cl:21])[C:5]([Cl:20])=[C:6]([CH:19]=1)[CH2:7][N:8]([CH:16]1[CH2:18][CH2:17]1)[C:9](=[O:15])[O:10][C:11]([CH3:14])([CH3:13])[CH3:12])[CH:25]=[CH2:24]
Reactant: C=CC[Sn](CCCC)(CCCC)CCCC
Reactant: CC(C)(C)OC(=O)N(Cc1cc(Br)cc(Cl)c1Cl)C1CC1
Agent: [Cs+]
Agent: [F-]
Solvent: C1CCOC1
Product: C=CCc1cc(Cl)c(Cl)c(CN(C(=O)OC(C)(C)C)C2CC2)c1

Procedure:
A THF solution (0.12 M) of tert-butyl (5-bromo-2,3-dichlorobenzyl)cyclopropylcarbamate from the previous step (1 eq.), Pd(PCy3)2 (0.05 eq.) and cesium fluoride (2.0 eq.) was added allyl tributylstannane (1.2 eq.). The resulting brown solution was heated at reflux for 8 h and then filtered through a pad of SiO2. The insolubles were rinsed further with ether and the filtrate was concentrated in vacuo to afford a brown semisolid. Purification of the crude product thus obtained by way of column chromatography (SiO2, Hex→90:10 (v/v) Hex:Et2O) afforded the title compound as a pale yellow oil.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH2:9])=[O:8].C([N-]C(C)C)(C)C.[Li+].Cl[C:19]([O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:20]>C1COCC1>[N:1]1[CH:6]=[CH:5][CH:4]=[CH:3][C:2]=1[C:7]([NH:9][C:19](=[O:20])[O:21][C:22]1[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=1)=[O:8]
Reactant: O=C(Cl)Oc1ccccc1
Reactant: NC(=O)c1ccccn1
Agent: CC(C)[N-]C(C)C
Agent: [Li+]
Solvent: C1CCOC1
Product: O=C(NC(=O)c1ccccn1)Oc1ccccc1
Temperature: -10 °C
Reaction time: 0.25 h
Yield: 16.9 %

Procedure:
Picolinamide (0.500 g, 16 mmol) was dissolved in THF (25 mL) and cooled to −10° C. To the solution, lithium diisopropyl amide (5.1 mL, 2.0 M in heptane/THF/ethyl benzene, 10 mmol) was added dropwise. The resulting mixture was stirred at −10° C. for 15 minutes then treated with phenyl chloroformate (1.69 mL, 12.3 mmol) in THF (5 mL). After 20 minutes the reaction was warmed to room temperature and stirred for 3 hours at which time the reaction was quenched with saturated aqueous ammonium chloride. The mixture was extracted with EtOAc and the combined organic layer was dried over anhydrous sodium sulfate, filtered and concentrated. The residue was purified by silica gel chromatography (20-50% EtOAc in heptane) to provide the desired product (0.504 g). 1H NMR (400 MHz, CDCl3) δ ppm 7.18-7.26 (m, 3H) 7.34-7.41 (m, 2H) 7.54 (ddd, J=7.63, 4.78, 1.23 Hz, 1H) 7.92 (td, J=7.74, 1.70 Hz, 1H) 8.28 (dt, J=7.82, 1.09 Hz, 1H) 8.62 (ddd, J=4.77, 1.67, 0.93 Hz, 1H) 10.47 (s, 1H).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[C:6]([F:8])[CH:5]=[CH:4][C:3]=1[NH:9][C:10]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:11].Cl.C(N=C=NCCCN(C)C)C.[C:33]([C:37]1[CH:38]=[C:39]([CH:43]=[C:44]([C:47]([CH3:50])([CH3:49])[CH3:48])[C:45]=1[OH:46])[C:40](O)=[O:41])([CH3:36])([CH3:35])[CH3:34]>ClCCl>[F:8][C:6]1[CH:5]=[CH:4][C:3]([NH:9][C:10]([N:12]([CH2:14][CH2:15][CH2:16][CH2:17][CH2:18][CH2:19][CH3:20])[CH3:13])=[O:11])=[C:2]([NH:1][C:40](=[O:41])[C:39]2[CH:43]=[C:44]([C:47]([CH3:48])([CH3:49])[CH3:50])[C:45]([OH:46])=[C:37]([C:33]([CH3:36])([CH3:35])[CH3:34])[CH:38]=2)[CH:7]=1
Reactant: CC(C)(C)c1cc(C(=O)O)cc(C(C)(C)C)c1O
Reactant: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1N
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Solvent: ClCCl
Product: CCCCCCCN(C)C(=O)Nc1ccc(F)cc1NC(=O)c1cc(C(C)(C)C)c(O)c(C(C)(C)C)c1
Temperature: 25 °C
Reaction time: 8 h
Yield: 56.1 %

Procedure:
A solution of 1-(2-amino-4-fluorophenyl)-3-heptyl-3-methylurea (0.82 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide monohydrochloride (0.67 g) and 3,5-di-t-butyl-4-hydroxybenzoic acid (0.88 g) dissolved in dichloromethane (10 ml) was stirred at room temperature overnight. The reaction solution was washed with water, saturated saline, dried over anhydrous MgSO4, and the solvent was distilled off. Purification of the residue by a silica gel column chromatography gave N-[5-fluoro-2-(3-heptyl-3-methylureido)phenyl]-3,5-di-t-butyl-4-hydroxybenzamide (0.84 g, 56%).
Reaction SMILES: [OH:1][CH:2]([C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=2)[N:25]=[CH:24][CH:23]=1)[CH2:3][N:4]1[CH2:9][CH2:8][CH2:7][CH:6]([CH2:10][NH:11]C(=O)OCC2C=CC=CC=2)[CH2:5]1>C1COCC1.CO.[OH-].[OH-].[Pd+2]>[NH2:11][CH2:10][C@@H:6]1[CH2:7][CH2:8][CH2:9][N:4]([CH2:3][CH:2]([C:22]2[C:31]3[C:26](=[CH:27][CH:28]=[C:29]([O:32][CH3:33])[CH:30]=3)[N:25]=[CH:24][CH:23]=2)[OH:1])[CH2:5]1
Reactant: COc1ccc2nccc(C(O)CN3CCCC(CNC(=O)OCc4ccccc4)C3)c2c1
Agent: [Pd+2]
Agent: [OH-]
Solvent: C1CCOC1
Solvent: CO
Product: COc1ccc2nccc(C(O)CN3CCC[C@@H](CN)C3)c2c1

Procedure:
20% Pd(OH)2 on carbon (0.7 g) was added to a solution of benzyl {1-[2-hydroxy-2-(6-methoxy-quinolin-4-yl)-ethyl]-piperidin-3-ylmethyl}carbamate (2.51 g, 5.58 mmol) in THF (35 ml), MeOH (7 ml) was added and hydrogenation was carried out under a hydrogen atmosphere (1 bar). The reaction mixture was filtered and the filtrate was concentrated.
Reaction SMILES: [N:1]1[CH:6]=[CH:5][CH:4]=[N:3][C:2]=1[N:7]1[CH2:18][CH2:17][C:10]2([NH:14][C:13](=[O:15])[NH:12][C:11]2=[O:16])[CH2:9][CH2:8]1.C([O-])([O-])=O.[K+].[K+].Br[CH2:26][C:27]1[N:37]([CH2:38][C:39]([CH3:42])([CH3:41])[CH3:40])[C:30]2[N:31]=[C:32]([C:35]#[N:36])[N:33]=[CH:34][C:29]=2[CH:28]=1>CN(C=O)C>[CH3:40][C:39]([CH3:42])([CH3:41])[CH2:38][N:37]1[C:30]2[N:31]=[C:32]([C:35]#[N:36])[N:33]=[CH:34][C:29]=2[CH:28]=[C:27]1[CH2:26][N:12]1[C:11](=[O:16])[C:10]2([CH2:9][CH2:8][N:7]([C:2]3[N:3]=[CH:4][CH:5]=[CH:6][N:1]=3)[CH2:18][CH2:17]2)[NH:14][C:13]1=[O:15]
Reactant: O=C1NC(=O)C2(CCN(c3ncccn3)CC2)N1
Reactant: CC(C)(C)Cn1c(CBr)cc2cnc(C#N)nc21
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Product: CC(C)(C)Cn1c(CN2C(=O)NC3(CCN(c4ncccn4)CC3)C2=O)cc2cnc(C#N)nc21
Temperature: 25 °C
Reaction time: 5 h
Yield: 57.9 %

Procedure:
To a solution of 180.0 mg (0.728 mmoles) of 8-pyrimidin-2-yl-1,3,8-triaza-spiro[4.5]decane-2,4-dione in 2.0 ml of DMF, 99.4 mg (0.719 mmoles) of K2CO3 and 170.0 mg (0.553 mmoles) of 6-bromomethyl-7-(2,2-dimethyl-propyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile are added at ambient temperature. The mixture is stirred for 5 hours at ambient temperature and filtered. The mixture is diluted with AcOEt and H2O, and then extracted with AcOEt. The combined extracts are washed with water and brine, dried over MgSO4 and concentrated under reduced pressure. The residue is purified by silica gel column chromatography to give 151.5 mg of desired 7-(2,2-dimethyl-propyl)-6-(2,4-dioxo-8-pyrimidin-2-yl-1,3,8-triaza-spiro[4.5]dec-3-ylmethyl)-7H-pyrrolo[2,3-d]pyrimidine-2-carbonitrile in 58% yield.
Reaction SMILES: [CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][NH:13][N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2].[N:34]1[C:41]([F:42])=[N:40][C:38](F)=[N:37][C:35]=1[F:36].C(N(CC)CC)C>C(Cl)(Cl)Cl>[CH:1]([NH:4][C:5]([C:7]1[C:15]2[C:11](=[CH:12][N:13]([C:38]3[N:40]=[C:41]([F:42])[N:34]=[C:35]([F:36])[N:37]=3)[N:14]=2)[CH:10]=[C:9]([CH3:16])[C:8]=1[NH:17][C:18]([C:20]1[N:21]([C:27]2[C:32]([Cl:33])=[CH:31][CH:30]=[CH:29][N:28]=2)[N:22]=[C:23]([O:25][CH3:26])[CH:24]=1)=[O:19])=[O:6])([CH3:3])[CH3:2]
Reactant: COc1cc(C(=O)Nc2c(C)cc3c[nH]nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Reactant: Fc1nc(F)nc(F)n1
Solvent: ClC(Cl)Cl
Solvent: CCN(CC)CC
Product: COc1cc(C(=O)Nc2c(C)cc3cn(-c4nc(F)nc(F)n4)nc3c2C(=O)NC(C)C)n(-c2ncccc2Cl)n1
Temperature: 20 °C
Reaction time: 3 h

Procedure:
To a solution of 6-{[2-(3-chloro-pyridin-2-yl)-5-methoxy-2H-pyrazole-3-carbonyl]-amino}-5-methyl-2H-indazole-7-carboxylic acid isopropyl amide (0.300 g, 0.641 mmol) in chloroform (2.0 ml) was added cyanuryl fluoride (2,4,6-trifluoro-1,3,5-triazine) (0.220 g, 1.669 mmol) followed by triethylamine (0.090 ml, 0.046 mmol). The reaction mixture was stirred at 20° C. for three hours, then evaporated to dryness and submitted to high vacuum. The residue was taken up in a small amount of chloroform and separated from some less soluble material, then evaporated to give the compound showing the physical data described in the table under P.43.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([OH:13])=O)[CH:10]=2)[CH:7]=1.[CH3:14][CH:15]1[C:24]2[C:19](=[CH:20][C:21]([C:25]3[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=3)=[CH:22][CH:23]=2)[CH2:18][CH2:17][NH:16]1>>[Br:1][C:2]1[CH:3]=[N:4][C:5]2[N:6]([N:8]=[C:9]([C:11]([N:16]3[CH2:17][CH2:18][C:19]4[C:24](=[CH:23][CH:22]=[C:21]([C:25]5[CH:30]=[CH:29][CH:28]=[CH:27][N:26]=5)[CH:20]=4)[CH:15]3[CH3:14])=[O:13])[CH:10]=2)[CH:7]=1
Reactant: CC1NCCc2cc(-c3ccccn3)ccc21
Reactant: O=C(O)c1cc2ncc(Br)cn2n1
Product: CC1c2ccc(-c3ccccn3)cc2CCN1C(=O)c1cc2ncc(Br)cn2n1

Procedure:
In close analogy to the procedure described in Example 1, 6-bromo-pyrazolo[1,5-a]pyrimidine-2-carboxylic acid is reacted with 1-Methyl-6-pyridin-2-yl-1,2,3,4-tetrahydro-isoquinoline to provide the title compound in moderate yield.
Reaction SMILES: C([O:3][C:4](=[O:40])[CH2:5][CH2:6][CH2:7][O:8][C:9]1[CH:14]=[CH:13][C:12]([C:15]([N:17]2[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][CH:25]=3)[C@H:20]([N:27]([C:32]3[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=3)[C:28](=[O:31])[CH2:29][CH3:30])[CH2:19][C@@H:18]2[CH3:39])=[O:16])=[CH:11][CH:10]=1)C.C(=O)([O-])[O-].[K+].[K+]>O.CO>[Cl:38][C:35]1[CH:34]=[CH:33][C:32]([N:27]([C:28](=[O:31])[CH2:29][CH3:30])[C@H:20]2[C:21]3[C:26](=[CH:25][CH:24]=[CH:23][CH:22]=3)[N:17]([C:15]([C:12]3[CH:11]=[CH:10][C:9]([O:8][CH2:7][CH2:6][CH2:5][C:4]([OH:40])=[O:3])=[CH:14][CH:13]=3)=[O:16])[C@@H:18]([CH3:39])[CH2:19]2)=[CH:37][CH:36]=1
Reactant: CCOC(=O)CCCOc1ccc(C(=O)N2c3ccccc3[C@H](N(C(=O)CC)c3ccc(Cl)cc3)C[C@@H]2C)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CO
Product: CCC(=O)N(c1ccc(Cl)cc1)[C@@H]1C[C@H](C)N(C(=O)c2ccc(OCCCC(=O)O)cc2)c2ccccc21
Temperature: 25 °C
Yield: 31 %

Procedure:
(±)-Cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid was prepared from (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-1-carbonyl}-phenoxy)-butyric acid ethyl ester. Potassium carbonate (300 mg) was dissolved in water (5 mL) and (±)-cis-4-(4-{4-[(4-chloro-phenyl)-propionyl-amino]-2-methyl-3,4-dihydro-2H-quinoline-carbonyl}-phenoxy)-butyric acid ethyl ester (171 mg, 0.303 mmol) was dissolved in methanol (5 mL) was added. The reaction was allowed to stir over night at room temperature. The methanol was removed in vacuo and hydrochloric acid (1 N) was added until acidic. Dichloromethane was added, extracted 2×; the combined organics were dried over magnesium sulfate, filtered and concentrated to afford the carboxylic acid (50 mg, 31%).