Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:10])[C:4]=2[CH:3]=[N:2]1.[N+:11]([C:14]1[CH:39]=[CH:38][C:17](C(O[C@H]2CC[C@@H](N3C(=O)C4C(=CC=CC=4)C3=O)CC2)=O)=[CH:16][CH:15]=1)([O-])=O.O[C@@H]1CC[C@H](N2C(=O)C3C(=CC=CC=3)C2=O)CC1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.N(C(OCC1C=CC=CC=1)=O)=NC(OCC1C=CC=CC=1)=O.ClCCl>O1CCCC1>[NH:1]1[C:9]2[C:4](=[C:5]([O:10][C@H:17]3[CH2:38][CH2:39][C@H:14]([NH2:11])[CH2:15][CH2:16]3)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1
Reactant: O=C(O[C@H]1CC[C@@H](N2C(=O)c3ccccc3C2=O)CC1)c1ccc([N+](=O)[O-])cc1
Reactant: Oc1cccc2[nH]ncc12
Agent: O=C(N=NC(=O)OCc1ccccc1)OCc1ccccc1
Agent: O=C1c2ccccc2C(=O)N1[C@H]1CC[C@@H](O)CC1
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: C1CCOC1
Solvent: ClCCl
Product: N[C@H]1CC[C@H](Oc2cccc3[nH]ncc23)CC1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
To a solution of the 1H-indazol-4-ol (131 mg, 0.977 mmol) obtained in Example 320, (b) in tetrahydrofuran (10 ml) were added dropwise cis-2-(4-hydroxycyclohexyl)-1H-isoindole-1,3(2H)-dione (215 mg, 0.879 mmol), triphenylphosphine (283 mg, 1.07 mmol) and 40%-dibenzyl azodicarboxylate-dichloromethane solution (0.672 ml, 1.17 mmol) at 0° C. The resulting mixture was warmed up to room temperature 30 minutes after the addition. After stirring overnight, the reaction solution was concentrated under reduced pressure and the resulting residue was dissolved in chloroform (50 ml) and washed with a 1M-aqueous sodium hydroxide solution (20 ml). Extraction with chloroform (20 ml) was carried out again, and the organic layer was dried over anhydrous magnesium sulfate. The organic layer dried was concentrated under reduced pressure and the resulting residue was purified by a silica gel column chromatography (eluent: hexane/ethyl acetate). To the resulting mixture was added 30%-methylamine/ethanol (2 ml) at room temperature, and the resulting mixture was refluxed for 15 minutes. After 4 hours, the reaction solution was concentrated under reduced pressure at room temperature and the resulting residue was purified by a silica gel column chromatography (eluent: chloroform/methanol=10/1→chloroform/methanol/(1%-aqueous ammonia)=10/1) to obtain trans-4-(1H-indazol-4-yloxy)-cyclohexanamine (11 mg, 5.6%).
Reaction SMILES: [C:1]([C:5]1C=CC(C(NC2C=CC(C3C=C4C(CN([C@@H](C(C)C)C(O)=O)C4=O)=CC=3)=NC=2)=O)=[CH:7][CH:6]=1)(C)(C)[CH3:2].C([C:41]1[CH:74]=[CH:73][C:44]([C:45]([NH:47][C:48]2[CH:53]=[CH:52][C:51]([C:54]3[CH:62]=[C:61]4[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:71])[CH3:70])[C:65]([O:67]C)=[O:66])[C:60]4=[O:63])=[CH:56][CH:55]=3)=[CH:50][C:49]=2[F:72])=[O:46])=[CH:43][CH:42]=1)(C)(C)C>>[F:72][C:49]1[CH:50]=[C:51]([C:54]2[CH:62]=[C:61]3[C:57]([CH2:58][N:59]([C@@H:64]([CH:69]([CH3:70])[CH3:71])[C:65]([OH:67])=[O:66])[C:60]3=[O:63])=[CH:56][CH:55]=2)[CH:52]=[CH:53][C:48]=1[NH:47][C:45](=[O:46])[C:44]1[CH:73]=[CH:74][C:41]([CH2:2][CH2:1][CH2:5][CH2:6][CH3:7])=[CH:42][CH:43]=1
Reactant: COC(=O)[C@H](C(C)C)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)c(F)c3)cc2C1=O
Reactant: CC(C)[C@@H](C(=O)O)N1Cc2ccc(-c3ccc(NC(=O)c4ccc(C(C)(C)C)cc4)cn3)cc2C1=O
Product: CCCCCc1ccc(C(=O)Nc2ccc(-c3ccc4c(c3)C(=O)N([C@H](C(=O)O)C(C)C)C4)cc2F)cc1
Yield: 83 %

Procedure:
The compound of example 446 was prepared analogous to the compound of example 404 by hydrolysis of the compound of example 443.
Reaction SMILES: C([O:3][C:4](=[O:23])[C:5]([CH3:22])([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])[CH2:6][C:7]1[CH:12]=[CH:11][C:10]([OH:13])=[CH:9][CH:8]=1)C.[CH3:24][C:25]1[O:29][C:28]([C:30]2[S:31][CH:32]=[CH:33][CH:34]=2)=[N:27][C:26]=1[CH2:35][CH2:36]OS(C1C=CC(C)=CC=1)(=O)=O>>[CH3:22][C:5]([O:14][C:15]1[CH:20]=[CH:19][CH:18]=[CH:17][C:16]=1[CH3:21])([CH2:6][C:7]1[CH:8]=[CH:9][C:10]([O:13][CH2:36][CH2:35][C:26]2[N:27]=[C:28]([C:30]3[S:31][CH:32]=[CH:33][CH:34]=3)[O:29][C:25]=2[CH3:24])=[CH:11][CH:12]=1)[C:4]([OH:3])=[O:23]
Reactant: CCOC(=O)C(C)(Cc1ccc(O)cc1)Oc1ccccc1C
Reactant: Cc1ccc(S(=O)(=O)OCCc2nc(-c3cccs3)oc2C)cc1
Product: Cc1ccccc1OC(C)(Cc1ccc(OCCc2nc(-c3cccs3)oc2C)cc1)C(=O)O

Procedure:
The title compound was prepared using the representative Standard Procedure (E) from 3-(4-Hydroxyphenyl)-2-methyl-2-o-tolyloxy-propionic acid ethyl ester and toluene-4-sulfonic acid 2-(5-methyl-2-thiophen-2-yl-oxazol-4-yl)-ethyl ester. 1H NMR (400 MHz, CDCl3): • 7.59 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.36 (dd, 1H, J=3.91 Hz, 1.17 Hz), 7.14-7.11 (m, 3H), 7.08-7.04 (m, 2H), 6.91 (t, 1H, J=7.43 Hz), 6.82-6.77 (m, 3H), 4.15 (t, 2H, J=6.65 Hz), 3.25 (d, 1H, J=14.08 Hz), 3.19 (d, 1H, J=14.08 Hz), 2.94 (t, 2H, J=6.65 Hz), 2.33 (s, 3H), 2.17 (s, 3H, 1.48 (s, 3H). MS [ES+] m/z exact mass calcd for C27H28NO5S 478.1688, found 478.1676.
Reaction SMILES: COC1C=C(OC)C=CC=1C[N:6]1[C:9](=[O:10])[C@@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]2[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=2)[C@H:7]1[CH2:22][N:23]1C(C)=N[NH:25][NH:24]1.OP([O-])([O-])=O.[K+].[K+].[C:42](#[N:44])[CH3:43].O>>[CH3:43][C:42]1[N:25]=[N:24][N:23]([CH2:22][C@@H:7]2[C@H:8]([NH:11][C:12](=[O:21])[O:13][CH2:14][C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[C:9](=[O:10])[NH:6]2)[N:44]=1
Reactant: CC#N
Reactant: COc1ccc(CN2C(=O)[C@@H](NC(=O)OCc3ccccc3)[C@H]2CN2NNN=C2C)c(OC)c1
Agent: O=P([O-])([O-])O
Agent: [K+]
Solvent: O
Product: Cc1nnn(C[C@H]2NC(=O)[C@H]2NC(=O)OCc2ccccc2)n1
Temperature: 25 °C
Yield: 81 %

Procedure:
Prepared in an analogous manner to example 4, step 2 using benzyl ((2R,3S)-1-(2,4-dimethoxybenzyl)-2-((5-methyl-2H-tetrazol-1-yl)methyl)-4-oxoazetidin-3-yl)carbamate (202 mg, 0.433 mmol), K2S2O8 (164 mg, 0.606 mmol) and K2HPO4 (98 mg, 0.563 mmol) in ACN:water (2:1, 7.4 mL) at 90° C. for 1.5 h. More K2S2O8 (35 mg, 0.13 mmol) and K2HPO4 (20 mg, 0.11 mmol) were added and it was heated for an additional 30 min then cooled to rt then concentrated in vacuo. The mixture was diluted with EtOAc, washed with brine, dried over Na2SO4 and concentrated in vacuo. The crude residue was purified via silica gel chromatography (MeOH-DCM, 0-10%), to afford the title compound (111 mg, 81%). LCMS: Rt=0.58 min, m/z=317.2 (M+1) Method 2m_acidic; 1H NMR (400 MHz, CDCl3) δ 7.43-7.30 (m, 5H), 6.34 (br s, 1H), 6.01 (br s, 1H), 5.28-5.21 (m, 1H), 5.20-5.12 (m, 3H), 4.92 (dd, J=14.3, 3.9 Hz, 1H), 4.68 (dd, J=14.2, 7.9 Hz, 1H), 4.48-4.27 (m, 2H), 2.53 (s, 3H).
Reaction SMILES: [OH:1][C:2]1[CH:9]=[C:8]([OH:10])[CH:7]=[CH:6][C:3]=1[CH:4]=[O:5].[F-].[K+].[CH2:13](Cl)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C(#N)C>[CH2:13]([O:10][C:8]1[CH:7]=[CH:6][C:3]([CH:4]=[O:5])=[C:2]([OH:1])[CH:9]=1)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: ClCc1ccccc1
Reactant: O=Cc1ccc(O)cc1O
Agent: [F-]
Agent: [K+]
Solvent: CC#N
Product: O=Cc1ccc(OCc2ccccc2)cc1O
Yield: 76 %

Procedure:
To solution of 2,4-dihydroxybenzaldehyde (160 g, 1.16 moles) in acetonitrile (2 L) was added potassium fluoride (134 g, 2.30 moles) and benzyl chloride (257 g, 2.03 moles). The reaction was heated to reflux and the volume of solvent was reduced by distillation to approximately half of original over the period of 24 hours. When less than 8% of starting material remains as observed by HPLC the residual acetonitrile is evaporated at reduced pressure and the residue was suspended in water. The aqueous mixture was extracted with ethyl acetate several times and the combined extracts were washed with potassium carbonate, hydrochloric acid and brine. Evaporation of the organic solvent at reduced pressure afforded the crude product in 76% yield. If needed, the product may be recrystallized from t-butyl methyl ether and hexane.
Reaction SMILES: [NH2:1][C:2]1[CH:14]=[CH:13][C:5]([CH2:6][P:7](=[O:12])([O:10][CH3:11])[O:8][CH3:9])=[CH:4][CH:3]=1.[F:15][C:16]1[CH:21]=[CH:20][C:19]([C:22]2[N:26]([CH3:27])[N:25]=[CH:24][C:23]=2/[CH:28]=[CH:29]/[C:30](O)=[O:31])=[CH:18][CH:17]=1.O.ON1C2C=CC=CC=2N=N1.Cl.C(N=C=NCCCN(C)C)C.Cl>>[CH3:11][O:10][P:7]([CH2:6][C:5]1[CH:13]=[CH:14][C:2]([NH:1][C:30](=[O:31])/[CH:29]=[CH:28]/[C:23]2[CH:24]=[N:25][N:26]([CH3:27])[C:22]=2[C:19]2[CH:20]=[CH:21][C:16]([F:15])=[CH:17][CH:18]=2)=[CH:3][CH:4]=1)([O:8][CH3:9])=[O:12]
Reactant: COP(=O)(Cc1ccc(N)cc1)OC
Reactant: Cn1ncc(/C=C/C(=O)O)c1-c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: On1nnc2ccccc21
Solvent: O
Product: COP(=O)(Cc1ccc(NC(=O)/C=C/c2cnn(C)c2-c2ccc(F)cc2)cc1)OC
Temperature: 25 °C
Reaction time: 8 h
Yield: 64.5 %

Procedure:
A mixture of dimethyl 4-aminobenzylphosphonate (0.86 g), (2E)-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylic acid (0.74 g), 1-hydroxy-1H-1,2,3-benzotriazole hydrate (0.61 g), 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide hydrochloride (0.77 g) and N,N-dimethylfomamide (8 ml) was stirred at room temperature overnight. The reaction mixture was poured into a 0.5N aqueous hydrochloric acid solution and extracted with ethyl acetate. The ethyl acetate layer was washed with saturated aqueous sodium hydrogen carbonate, and then with saturated brine, dried (MgSO4) and concentrated. The obtained solid was recrystallized from acetone-water to give (2E)-N-[4-(dimethylphosphonomethyl)phenyl]-3-[5-(4-fluorophenyl)-1-methyl-1H-pyrazol-4-yl]acrylamide (0.86 g, yield 65%) as colorless prism crystals. melting point: 209-210° C.
Reaction SMILES: CC(OC(/N=N/C(OC(C)C)=O)=O)C.[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][OH:34])=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1.[F:36][C:37]([F:46])([F:45])[C:38]1[CH:39]=[C:40](O)[CH:41]=[CH:42][CH:43]=1.C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1>ClCCl.C(OCC)(=O)C>[N:15]1([C:22]2[C:31]3[C:26](=[CH:27][C:28]([CH2:33][O:34][C:42]4[CH:41]=[CH:40][CH:39]=[C:38]([C:37]([F:46])([F:45])[F:36])[CH:43]=4)=[C:29]([CH3:32])[CH:30]=3)[N:25]=[C:24]([Cl:35])[CH:23]=2)[CH2:21][CH2:20][CH2:19][CH2:18][CH2:17][CH2:16]1
Reactant: Oc1cccc(C(F)(F)F)c1
Reactant: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1CO
Agent: CC(C)OC(=O)/N=N/C(=O)OC(C)C
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: ClCCl
Solvent: CCOC(C)=O
Product: Cc1cc2c(N3CCCCCC3)cc(Cl)nc2cc1COc1cccc(C(F)(F)F)c1
Yield: 79.7 %

Procedure:
Diisopropylazodicarboxylate (66 mg, 0.33 mmol) was added dropwise at r.t. to a solution of (4-Azepan-1-yl-2-chloro-6-methyl-quinolin-7-yl)-methanol (example 82, 100 mg, 0.33 mmol), 3-trifluoromethylphenol (53 mg, 0.33 mmol), and triphenylphosphine (86 mg, 0.33 mmol) in dichloromethane (2 mL), then after 2 h ethyl acetate was added and the solution was washed with 1 M aq. sodium hydroxide solution and brine, dried (MgSO4), and evaporated. Flash chromatography (SiO2, hexane/ethyl acetate gradient) yielded the title compound (118 mg, 80%). White solid, ISP-MS: m/e=449.4 ([M+H]+).
Reaction SMILES: [CH2:1]([C:3]1([CH2:18][CH2:19]O)[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17])[CH3:2].C1C=CC(P(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1.C(Cl)(Cl)(Cl)[Cl:41]>O>[Cl:41][CH2:19][CH2:18][C:3]1([CH2:1][CH3:2])[C:8]2[NH:9][C:10]3[C:15]([C:7]=2[CH2:6][CH2:5][O:4]1)=[CH:14][CH:13]=[CH:12][C:11]=3[CH2:16][CH3:17]
Reactant: ClC(Cl)(Cl)Cl
Reactant: CCc1cccc2c3c([nH]c12)C(CC)(CCO)OCC3
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: O
Product: CCc1cccc2c3c([nH]c12)C(CC)(CCCl)OCC3
Yield: 51 %

Procedure:
A solution of compound 1 (136 mg, 0.5 mmol), PPh3 (262 mg, 1.0 mmol, 2.0 eq), and CCl4 (2.5 mL) was refluxed overnight. The resulting mixture was then diluted with water and extracted three times with CH2Cl2. The organic phases were combined, dried with Na2SO4, concentrated, and purified by column chromatography using 5:95:EtOAc:Hexane to give a white solid (74 mg, 51%): mp 106-107° C. (dec). 1HNMR (CDCl3, δ TMS): 0.93 (t, 3H), 1.37 (t, 3H), 1.91 (m, 2H), 2.34 (m, 2H), 2.76 (m, 2H), 2.87 (q, 2H), 3.46 (dm, 2H), 3.99 (m, 2H), 7.04-7.38 (m, 3H, Ar—H), 7.55 (br, 1H, NH). MS−: m/z 326 (MCl−), 290 ([M−H]−). Anal. (C17H22NOCl): C, H, N.
Reaction SMILES: C([Li])CCC.Br[C:7]1[CH:8]=[N:9][CH:10]=[N:11][CH:12]=1.[C:13](=[O:15])=[O:14].S(=O)(=O)(O)O>C1COCC1>[N:9]1[CH:8]=[C:7]([C:13]([OH:15])=[O:14])[CH:12]=[N:11][CH:10]=1
Reactant: O=C=O
Reactant: Brc1cncnc1
Agent: O=S(=O)(O)O
Agent: [Li]CCCC
Solvent: C1CCOC1
Product: O=C(O)c1cncnc1
Temperature: -100 °C
Reaction time: 0.25 h
Yield: 100 %

Procedure:
n-Butyllithium (1.6M in hexane, 6.9 ml, 11 mmol) was added to dry THF (10 ml) and the solution was cooled to -100° C. A solution of 5-bromopyrimidine (1.59 g, 10 mmol) in dry THF (50 ml) was added slowly. After 15 min at -80° to -100° C., the mixture was added dropwise onto solid carbon dioxide in dry THF. After warming to room temperature, the mixture was made slightly acidic with dilute sulphuric acid. The solid was filtered off and extracted with ethanol. The extract was filtered and evaporated and the residue was re-extracted with methanol. Evaporation of solvent gave the title compound (1.48 g, 100%).
Reaction SMILES: [O:1]1[CH2:3][C@H:2]1[CH2:4][O:5][C:6]1[CH:14]=[CH:13][CH:12]=[C:11]2[C:7]=1[CH2:8][C:9](=[O:15])[NH:10]2.NC[C:18]1([O:36][CH3:37])[CH:23]=[CH:22][C:21](N2CCCCC2)([S:24]([NH2:27])(=[O:26])=[O:25])[CH:20]=[C:19]1[O:34][CH3:35]>>[CH3:35][O:34][C:19]1[CH:20]=[C:21]([S:24]([N:27]2[CH2:9][CH2:8][CH:7]([CH2:11][NH:10][CH2:3][C@H:2]([OH:1])[CH2:4][O:5][C:6]3[CH:14]=[CH:13][CH:12]=[C:11]4[C:7]=3[CH2:8][C:9](=[O:15])[NH:10]4)[CH2:6][CH2:14]2)(=[O:25])=[O:26])[CH:22]=[CH:23][C:18]=1[O:36][CH3:37]
Reactant: O=C1Cc2c(cccc2OC[C@@H]2CO2)N1
Reactant: COC1=CC(N2CCCCC2)(S(N)(=O)=O)C=CC1(CN)OC
Product: COc1ccc(S(=O)(=O)N2CCC(CNC[C@H](O)COc3cccc4c3CC(=O)N4)CC2)cc1OC
Yield: 55.8 %

Procedure:
Prepared from 4-[(2S)-oxiranylmethoxy]-2-oxindole (0.205 g, 1.0 mmol) and 4-aminomethyl-1-piperidinyl-3,4-dimethoxybenzenesulfonamide (0.628 g, 2.0 mmol) according to procedure used for Example 2 to give 0.145 g of the title compound as a rose colored solid. Dissolved in CH2Cl2 and treated with 0.5 mL of 1N HCl in Et2O. Resulting solids filtered and dried to give 0.140 g of title compound as the HCl salt.
Reaction SMILES: C1(P(C2C=CC=CC=2)C2C=CC=CC=2)C=CC=CC=1.[Br:20]Br.[C:22]([O:26][C:27]([C@:29]1([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][C@H:33](O)[C@@H:32]2[C@H:30]1[C@H:31]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28])([CH3:25])([CH3:24])[CH3:23]>C1(C)C=CC=CC=1.N1C=CC=CC=1.C(OCC)(=O)C>[C:22]([O:26][C:27]([C@:29]1([NH:43][C:44]([O:46][C:47]([CH3:50])([CH3:49])[CH3:48])=[O:45])[CH2:34][C@@H:33]([Br:20])[C@@H:32]2[C@H:30]1[C@H:31]2[C:36]([O:38][C:39]([CH3:42])([CH3:41])[CH3:40])=[O:37])=[O:28])([CH3:25])([CH3:24])[CH3:23]
Reactant: BrBr
Reactant: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@H](O)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Agent: c1ccc(P(c2ccccc2)c2ccccc2)cc1
Solvent: CCOC(C)=O
Solvent: c1ccncc1
Solvent: Cc1ccccc1
Product: CC(C)(C)OC(=O)N[C@@]1(C(=O)OC(C)(C)C)C[C@@H](Br)[C@H]2[C@H](C(=O)OC(C)(C)C)[C@H]21
Temperature: 25 °C
Yield: 78.2 %

Procedure:
Dissolve triphenylphosphine (41.97 g, 158.4 mmol) in fresh toluene (660 mL) and add bromine (8.14 mL, 158.4 mmol) until a yellow color persists. Add dropwise a solution of ditert-butyl(1S,2S,4S,5R,6R)-2-(tert-butoxycarbonylamino)-4-hydroxy-bicyclo[3.1.0]hexane-2,6-dicarboxylate (32.75 g, 79.2 mmol) in toluene (176 mL) and anhydrous pyridine (528 mL) during 45 min. Stir the reaction at 75° C. overnight. Cool to room temperature, dilute with ethyl acetate, filter and concentrate to dryness. Slurry the crude in methyl tert-butyl ether, filter to remove the solids and concentrate the filtrate to dryness. Purify the crude by silica gel chromatography (750 g) eluting with hexane:ethyl acetate (0:100 to 80:20) to obtain the title compound as a white solid (29.52 g, 78%). MS (m/z): 498, 500 (M+23).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[NH:13][C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1)=[CH:16][CH:15]=3.[N:30]#[C:31]Br.C(N(CC)CC)C.O>C(Cl)Cl.CN(C1C=CN=CC=1)C>[Cl:1][C:2]1[CH:7]=[C:6]([Cl:8])[CH:5]=[CH:4][C:3]=1[C:9]1[C:27](=[O:28])[N:26]([CH3:29])[C:12]2[N:13]([C:31]#[N:30])[C:14]3[C:19]([C:11]=2[CH:10]=1)=[CH:18][C:17]([C:20]1[CH:24]=[CH:23][N:22]([CH3:25])[N:21]=1)=[CH:16][CH:15]=3
Reactant: Cn1ccc(-c2ccc3[nH]c4c(cc(-c5ccc(Cl)cc5Cl)c(=O)n4C)c3c2)n1
Reactant: N#CBr
Agent: CN(C)c1ccncc1
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: Cn1ccc(-c2ccc3c(c2)c2cc(-c4ccc(Cl)cc4Cl)c(=O)n(C)c2n3C#N)n1
Temperature: 25 °C
Reaction time: 18 h

Procedure:
460 mg (1.09 mmol) of compound from Example 37 above, 3-(2,4-dichlorophenyl)-1-methyl-6-(1-methyl-1H-pyrazol-3-yl)-1,9-dihydro-2H-pyrido[2,3-b]indol-2-one are dissolved in 50 ml of CH2Cl2. 576 mg (5.43 mmol) of CNBr, 44 mg (0.36 mmol) of DMAP and then 308 μl (2.17 mmol) of triethylamine are added. The mixture is stirred at ambient temperature for 18 h. H2O is added, the mixture is extracted with CH2Cl2, and the organic phase is dried over MgSO4, filtered and concentrated, and purification is carried out on a silica column, elution being carried out with EtOAc/50% cyclohexane.
Reaction SMILES: [Si:1]([O:8][CH2:9][CH2:10][N:11]([CH3:45])[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:27]=[CH:26][CH:25]=[CH:24][CH:23]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:34][CH2:33][CH2:32][CH2:31]2)[N:15]=1)=[O:13])([C:4]([CH3:7])([CH3:6])[CH3:5])([CH3:3])[CH3:2].[CH2:46](OC1C(C(O)=O)=NC(CC2(C3C4C(=CC=CC=4)C=CC=3)CCCC2)=NC=1O)[C:47]1C=CC=CC=1.[Si](OCCNC1CC1)(C(C)(C)C)(C)C>>[Si:1]([O:8][CH2:9][CH2:10][N:11]([CH:45]1[CH2:47][CH2:46]1)[C:12]([C:14]1[C:19]([O:20][CH2:21][C:22]2[CH:23]=[CH:24][CH:25]=[CH:26][CH:27]=2)=[C:18]([OH:28])[N:17]=[C:16]([CH2:29][C:30]2([C:35]3[C:44]4[C:39](=[CH:40][CH:41]=[CH:42][CH:43]=4)[CH:38]=[CH:37][CH:36]=3)[CH2:31][CH2:32][CH2:33][CH2:34]2)[N:15]=1)=[O:13])([C:4]([CH3:6])([CH3:7])[CH3:5])([CH3:2])[CH3:3]
Reactant: CN(CCO[Si](C)(C)C(C)(C)C)C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Reactant: O=C(O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1
Agent: CC(C)(C)[Si](C)(C)OCCNC1CC1
Product: CC(C)(C)[Si](C)(C)OCCN(C(=O)c1nc(CC2(c3cccc4ccccc34)CCCC2)nc(O)c1OCc1ccccc1)C1CC1

Procedure:
This compound was prepared following the same method as described for 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-methyl-amide (350) from 5-benzyloxy-6-hydroxy-2-(1-naphthalen-1-yl-cyclopentylmethyl)-pyrimidine-4-carboxylic acid (345) (250 mg, 0.55 mmol) and [2-(tert-butyl-dimethylsilanyloxy)-ethyl]-cyclopropyl-amine (8d) (177 mg, 0.83 mmol). The yield was 279 mg, 78% (white sticky mass).
Reaction SMILES: [Cl:1][CH:2]([CH3:13])[CH2:3][CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6].[N+:14]([O-])([OH:16])=[O:15]>S(=O)(=O)(O)O>[Cl:1][CH:2]([CH3:13])[CH:3]([N+:14]([O-:16])=[O:15])[CH2:4][C:5]([C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:6]
Reactant: CC(Cl)CCC(=O)c1ccccc1
Reactant: O=[N+]([O-])O
Agent: O=S(=O)(O)O
Product: CC(Cl)C(CC(=O)c1ccccc1)[N+](=O)[O-]

Procedure:
50 ml of concentrated sulphuric acid are treated, while stirring, with 9.9 g of 4-chloro-valerophenone, while cooling with an ice/sodium chloride mixture. The bulk of the product dissolves, a slightly exothermic reaction taking place, and a yellow suspension forms, which is treated, while stirring vigorously and at a temperature of -10° to -5°, with a mixture of 20 ml of concentrated sulphuric acid and 10.4 ml of concentrated nitric acid (d=1.52), in the course of 10 minutes. After a reaction time of five minutes, the mixture is poured onto ice and the aqueous mixture is extracted with chloroform. The organic extract is washed once with an aqueous solution of sodium carbonate and with water, dried over sodium sulphate and filtered through silica gel. 4-Chloro-3-nitro-valerophenone is obtained as an oily residue after evaporating the filtrate.
Reaction SMILES: Br[CH2:2][C:3]1[CH:12]=[C:11]([N+:13]([O-:15])=[O:14])[CH:10]=[C:9]2[C:4]=1[N:5]=[C:6]([O:18][CH3:19])[C:7]([O:16][CH3:17])=[N:8]2.[NH2:20][C:21]1[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=1)[C:24]([OH:26])=[O:25].C(N(CC)CC)C>C(#N)C>[CH3:17][O:16][C:7]1[C:6]([O:18][CH3:19])=[N:5][C:4]2[C:9](=[CH:10][C:11]([N+:13]([O-:15])=[O:14])=[CH:12][C:3]=2[CH2:2][NH:20][C:21]2[CH:22]=[C:23]([CH:27]=[CH:28][CH:29]=2)[C:24]([OH:26])=[O:25])[N:8]=1
Reactant: COc1nc2cc([N+](=O)[O-])cc(CBr)c2nc1OC
Reactant: Nc1cccc(C(=O)O)c1
Solvent: CCN(CC)CC
Solvent: CC#N
Product: COc1nc2cc([N+](=O)[O-])cc(CNc3cccc(C(=O)O)c3)c2nc1OC

Procedure:
350 mg (1.06 mmol) of 5-bromomethyl-2,3-dimethoxy-7-nitro-quinoxaline, 153 mg (1.05 equiv.) of 3-aminobenzoic acid and 0.165 ml (1.1 equiv.) of triethylamine are combined in 10 ml of acetonitrile, and heated at boiling at reflux for 24 hours. The reacton mixture is concentrated by evaporation, extracted with ethyl acetate and 1 N HCl and washed once with brine. The organic phases are combined, dried over magnesium sulfate and concentrated by evaporation.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[C:15](OCC)=[O:16])=[CH:10][CH:9]=2)=[CH:4][CH:3]=1.[H-].[Al+3].[Li+].[H-].[H-].[H-].O>O1CCCC1>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([C:8]2[CH:13]=[CH:12][C:11]([C:14]([CH3:21])([CH3:20])[CH2:15][OH:16])=[CH:10][CH:9]=2)=[CH:6][CH:7]=1
Reactant: CCOC(=O)C(C)(C)c1ccc(-c2ccc(Br)cc2)cc1
Agent: [Al+3]
Agent: [H-]
Agent: [Li+]
Solvent: O
Solvent: C1CCOC1
Product: CC(C)(CO)c1ccc(-c2ccc(Br)cc2)cc1
Reaction time: 1.5 h
Yield: 88.9 %

Procedure:
Ethyl 2-(4′-bromobiphenyl-4-yl)-2-methylpropionate (6.2 g, 18 mmol) was dissolved in tetrahydrofuran (150 mL), and lithium aluminum hydride (0.68 g, 18 mmol) was added at 0° C., followed by stirring at the same temperature for 1.5 hours. Water was added to the reaction solution, and the insolubles were filtered with celite, followed by extraction with ethyl acetate. After the solvent was distilled off under reduced pressure, the resulting residue was purified by chromatography on a silica gel column (Moritex Corporation, elution solvent: hexane/ethyl acetate), and a fraction corresponding to the Rf value=0.40 (hexane/ethyl acetate=1/1) by thin layer chromatography was concentrated under reduced pressure to afford the title compound (5.0 g, 16 mmol) as a white solid (yield 92%).
Reaction SMILES: [NH2:1][C:2]1[N:7]=[N:6][C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)=[CH:4][C:3]=1[Br:18].Cl[CH2:20][CH:21](OCC)OCC.CC1C=CC(S(O)(=O)=O)=CC=1>C(O)(C)C>[Br:18][C:3]1[C:2]2[N:7]([CH:20]=[CH:21][N:1]=2)[N:6]=[C:5]([C:8]2[CH:17]=[CH:16][C:11]([C:12]([O:14][CH3:15])=[O:13])=[CH:10][CH:9]=2)[CH:4]=1
Reactant: CCOC(CCl)OCC
Reactant: COC(=O)c1ccc(-c2cc(Br)c(N)nn2)cc1
Agent: Cc1ccc(S(=O)(=O)O)cc1
Solvent: CC(C)O
Product: COC(=O)c1ccc(-c2cc(Br)c3nccn3n2)cc1
Temperature: 25 °C
Yield: 36.2 %

Procedure:
A solution of methyl 4-(6-amino-5-bromopyridazin-3-yl)benzoate (1.64 g, 5.32 mmol), 2-chloro-1,1-diethoxyethane (0.984 g, 6.39 mmol) and PTSA (1.215 g, 6.39 mmol) in isopropanol (50 mL) was heated to 80° C. for 40 h. After cooling to room temperature, the solution was concentrated in vacuo. The resulting mixture was treated with a saturated NaHCO3 solution (50 mL), extracted with dichloromethane (50 mL×3), dried over Na2SO4, filtered and concentrated. The residue was purified by chromatography (silica gel, 200-300 mesh, petroleum ether:ethyl acetate=3:1) to give methyl 4-(8-bromoimidazo[1,2-b]pyridazin-6-yl)benzoate (640 mg, 36%) as a white solid. LC-MS: [M+H]+, 333.9, tR=1.637 min.