Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [N+:1]([C:4]1[CH:17]=[CH:16][C:7]([CH2:8][P:9]2(=[O:15])[O:14][CH2:13][CH2:12][CH2:11][O:10]2)=[CH:6][CH:5]=1)([O-])=O>C1COCC1.[Pd]>[O:15]=[P:9]1([CH2:8][C:7]2[CH:16]=[CH:17][C:4]([NH2:1])=[CH:5][CH:6]=2)[O:10][CH2:11][CH2:12][CH2:13][O:14]1
Reactant: O=[N+]([O-])c1ccc(CP2(=O)OCCCO2)cc1
Agent: [Pd]
Solvent: C1CCOC1
Product: Nc1ccc(CP2(=O)OCCCO2)cc1
Temperature: 50 °C
Yield: 81.5 %

Procedure:
To a solution of 2-(4-nitrobenzyl)-1,3,2-dioxaphosphinane 2-oxide (Compound 230D, 70 mg, 0.27 mmol) in anhydrous THF was added 10% Pd/C (10 mg). The resulting mixture was heated at 50° C. under 50 psi H2 atmosphere for 6 h. Catalyst was filtered off and the filtrate was concentrated to give the desired product (50 mg, yield: 80%). 1H NMR (CD3OD, 400 MHz): δ=1.72-1.76 (m, 1H), 1.98-2.02 (m, 1H), 3.19 (d, J=20.4 Hz, 2H), 4.28-4.40 (m, 4H), 6.68 (d, J=8.0 Hz, 2H), 7.03 (d, J=8.4 Hz, 2H).
Reaction SMILES: [N:1]1([C:7]2[CH:8]=[CH:9][C:10]3[N:11]([C:13]([C:16]([F:19])([F:18])[F:17])=[N:14][N:15]=3)[N:12]=2)[CH2:6][CH2:5][NH:4][CH2:3][CH2:2]1.[CH:20]([C:22]1[CH:32]=[CH:31][C:25]([C:26]([N:28]([CH3:30])[CH3:29])=[O:27])=[CH:24][CH:23]=1)=O>>[CH3:30][N:28]([CH3:29])[C:26](=[O:27])[C:25]1[CH:31]=[CH:32][C:22]([CH2:20][N:4]2[CH2:3][CH2:2][N:1]([C:7]3[CH:8]=[CH:9][C:10]4[N:11]([C:13]([C:16]([F:17])([F:18])[F:19])=[N:14][N:15]=4)[N:12]=3)[CH2:6][CH2:5]2)=[CH:23][CH:24]=1
Reactant: FC(F)(F)c1nnc2ccc(N3CCNCC3)nn12
Reactant: CN(C)C(=O)c1ccc(C=O)cc1
Product: CN(C)C(=O)c1ccc(CN2CCN(c3ccc4nnc(C(F)(F)F)n4n3)CC2)cc1

Procedure:
Reductive amination of 6-(piperazin-1-yl)-3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazine with 4-formyl-N,N-dimethylbenzamide was carried out according to General Synthetic Method 7. The crude product was purified by hplc using a Waters XBridge Prep C18 OBD column, 5μ silica, 30 mm diameter, 100 mm length eluted with decreasingly polar mixtures of water (containing 0.1% aqueous ammonia) and acetonitrile as eluents to give N,N-dimethyl-4-[[4-[3-(trifluoromethyl)-[1,2,4]triazolo[4,3-b]pyridazin-6-yl]piperazin-1-yl]methyl]benzamide.
Reaction SMILES: [CH3:1][N:2]([CH3:28])[C:3]([C:5]1[O:6][C:7]2[C:13]([N:14]3[CH2:19][CH2:18][N:17]([CH2:20][CH2:21][C:22]4[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=4)[CH2:16][CH2:15]3)=[CH:12][CH:11]=[CH:10][C:8]=2[CH:9]=1)=[O:4].[Br:29]N1C(=O)CCC1=O>ClCCl>[Br:29][C:10]1[C:8]2[CH:9]=[C:5]([C:3]([N:2]([CH3:1])[CH3:28])=[O:4])[O:6][C:7]=2[C:13]([N:14]2[CH2:15][CH2:16][N:17]([CH2:20][CH2:21][C:22]3[CH:27]=[CH:26][CH:25]=[CH:24][N:23]=3)[CH2:18][CH2:19]2)=[CH:12][CH:11]=1
Reactant: CN(C)C(=O)c1cc2cccc(N3CCN(CCc4ccccn4)CC3)c2o1
Reactant: O=C1CCC(=O)N1Br
Solvent: ClCCl
Product: CN(C)C(=O)c1cc2c(Br)ccc(N3CCN(CCc4ccccn4)CC3)c2o1
Temperature: 25 °C
Reaction time: 1.5 h

Procedure:
A reaction mixture of N,N-dimethyl-7-(4-(2-(pyridin-2-yl)ethyl)piperazin-1-yl)benzofuran-2-carboxamide (0.50 g, 1.32 mmol) (Example 11) and N-bromosuccinimide (0.12 mL, 1.45 mmol) in dichloromethane (10 mL) was stirred at rt for 1.5 h. The solvent was removed in vacuo. The product was purified by flash chromatography (SiO2; DCM/MeOH; gradient 0-3%) to give the title compound. Yield: 0.55 g (91%).
Reaction SMILES: [C:1]([OH:9])(=O)[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O=S(Cl)[Cl:12]>C1COCC1>[C:1]([Cl:12])(=[O:9])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C(O)c1cccnc1
Reactant: O=S(Cl)Cl
Solvent: C1CCOC1
Product: O=C(Cl)c1cccnc1
Temperature: 80 °C
Reaction time: 2 h

Procedure:
To a solution of nicotinic acid (2 g, 16.2 mmol) in anhydrous THF (30 mL) was added SOCl2 (2.4 mL, 32.5 mmol). After stirring at 80° C. for 2 hours, the mixture was concentrated in vacuo.
Reaction SMILES: FC(F)(F)S([O:6][S:7]([C:10]([F:13])([F:12])[F:11])(=[O:9])=[O:8])(=O)=O.[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:40])[F:39])[CH:32]=2)[CH:27]=[C:28](O)[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22].N1C=CC=CC=1.Cl>C(Cl)Cl>[CH3:16][O:17][C:18](=[O:42])[CH:19]([C:24]1[CH:25]=[C:26]([C:31]2[CH:36]=[CH:35][C:34]([Cl:37])=[C:33]([C:38]([F:41])([F:39])[F:40])[CH:32]=2)[CH:27]=[C:28]([O:6][S:7]([C:10]([F:11])([F:12])[F:13])(=[O:8])=[O:9])[CH:29]=1)[CH2:20][CH:21]([CH3:23])[CH3:22]
Reactant: O=S(=O)(OS(=O)(=O)C(F)(F)F)C(F)(F)F
Reactant: COC(=O)C(CC(C)C)c1cc(O)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Agent: Cl
Solvent: ClCCl
Solvent: c1ccncc1
Product: COC(=O)C(CC(C)C)c1cc(OS(=O)(=O)C(F)(F)F)cc(-c2ccc(Cl)c(C(F)(F)F)c2)c1
Temperature: 25 °C
Reaction time: 1 h
Yield: 101.2 %

Procedure:
Trifluoromethanesulphonic anhydride (93 μL, 0.57 mmol) was added dropwise to a stirred solution of 2-(4′-chloro-5-hydroxy-3′-trifluoromethyl-biphenyl-3-yl)-4-methyl-pentanoic acid methyl ester (prepared in Example A) (150 mg, 0.38 mmol) and pyridine (88 μL, 1.1 mmol) in DCM (3 mL) at 0° C. The reaction was warmed to room temperature and stirred for 1 h, then 1M hydrochloric acid was added. The organic layer was filtered through a polytetrafluoroethylene (PTFE) frit and concentrated in vacuo to give the title compound (205 mg, 100%) as an orange oil.
Reaction SMILES: [N:1]([CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH:5]1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1)=[N+]=[N-]>CO.[Pd]>[NH2:1][CH:4]1[CH2:8][CH2:7][CH:6]([C:9]2[N:13]([CH3:14])[CH:12]=[N:11][N:10]=2)[CH:5]1[C:15]1[CH:16]=[CH:17][C:18]([F:21])=[CH:19][CH:20]=1
Reactant: Cn1cnnc1C1CCC(N=[N+]=[N-])C1c1ccc(F)cc1
Agent: [Pd]
Solvent: CO
Product: Cn1cnnc1C1CCC(N)C1c1ccc(F)cc1
Yield: 24.4 %

Procedure:
A solution of 90 mg of the product from Step E in 5 mL of methanol was hydrogenated over 25 mg of 10% Pd/C at 40 psi for 2 h and then filtered and evaporated. The residue was purified by flash chromatography eluting with 1% NH4OH/10% methanol in methylene chloride to obtain 20 mg of title compound. T.l.c. (5% methanol in methylene chloride) Rf =0.1.
Reaction SMILES: [Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([C@H:16]2[CH2:21][CH2:20][C@H:19](C)[CH2:18][CH2:17]2)[CH:10]2[CH2:15][CH2:14][NH:13][CH2:12][CH2:11]2)=[N:4][CH:3]=1.[C:24](O)(=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30]>>[Cl:1][C:2]1[S:6][C:5]([NH:7][C:8](=[O:23])[N:9]([CH:10]2[CH2:15][CH2:14][N:13]([C:24](=[O:32])[CH2:25][CH2:26][CH2:27][CH2:28][C:29]([OH:31])=[O:30])[CH2:12][CH2:11]2)[CH:16]2[CH2:17][CH2:18][CH2:19][CH2:20][CH2:21]2)=[N:4][CH:3]=1
Reactant: C[C@H]1CC[C@H](N(C(=O)Nc2ncc(Cl)s2)C2CCNCC2)CC1
Reactant: O=C(O)CCCCC(=O)O
Product: O=C(O)CCCCC(=O)N1CCC(N(C(=O)Nc2ncc(Cl)s2)C2CCCCC2)CC1

Procedure:
Prepared as described in general procedure (G) using 3-(5-chloro-thiazol-2-yl)-1-(trans-4-methyl-cyclohexyl)-1-piperidin-4-yl-urea and adipic acid.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[CH:6][C:5]([C:8]2(O)[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1.C([SiH](CC)CC)C>C(Cl)Cl>[Br:1][C:2]1[CH:7]=[CH:6][C:5]([CH:8]2[CH2:11][CH2:10][CH2:9]2)=[CH:4][CH:3]=1
Reactant: OC1(c2ccc(Br)cc2)CCC1
Agent: CC[SiH](CC)CC
Solvent: ClCCl
Product: Brc1ccc(C2CCC2)cc1
Temperature: -78 °C
Reaction time: 8 h
Yield: 66.3 %

Procedure:
To a solution of 1.37 g of 1-(4-bromophenyl)-cyclobutanol (6 mmol) in 15 ml DCM were added 1.15 ml of triethylsilane (7.2 mmol) and the mixture was cooled to −78° C. Then 1.15 ml of boron trifluoride diethyl etherate complex were added and the reaction mixture was warmed to −40° C. and stirred for 8 h. The reaction was then quenched by addition of 10% aqueous KHCO3 and the mixture was extracted three times with DCM. The combined extracts were washed with brine, dried with magnesium sulfate and concentrated. The remaining residue was purified by column chromatography (silica gel; cyclohexane) to give 0.84 g (66%) of 1-bromo-4-cyclobutyl-benzene as a colorless liquid. 1H NMR (CDCl3, 300 MHz): δ 1.85 (m, 1H), 1.92-2.18 (m, 3H), 2.33 (m, 2H), 3.49 (quint, J=8.5 Hz, 1H), 7.08 (d, J=8.5 Hz, 2H), 7.40 (d, J=8.5 Hz, 2H).
Reaction SMILES: [CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14](C(=O)C)[CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2].[CH3:37][S:38](Cl)(=[O:40])=[O:39]>>[CH:1]([O:4][C:5]([N:7]1[CH2:13][CH2:12][CH2:11][CH:10]([N:14]([CH2:15][C:16]2[CH:21]=[C:20]([C:22]([F:25])([F:24])[F:23])[CH:19]=[C:18]([C:26]([F:29])([F:28])[F:27])[CH:17]=2)[S:38]([CH3:37])(=[O:40])=[O:39])[C:9]2[CH:33]=[CH:34][CH:35]=[CH:36][C:8]1=2)=[O:6])([CH3:3])[CH3:2]
Reactant: CS(=O)(=O)Cl
Reactant: CC(=O)N(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)C1CCCN(C(=O)OC(C)C)c2ccccc21
Product: CC(C)OC(=O)N1CCCC(N(Cc2cc(C(F)(F)F)cc(C(F)(F)F)c2)S(C)(=O)=O)c2ccccc21

Procedure:
The titled compound was prepared following the procedures described in Example 1 for the synthesis of 5-[Acetyl-(3,5-bis-trifluoromethyl-benzyl)-amino]-2,3,4,5-tetrahydro-benzo[b]azepine-1-carboxylic acid isopropyl ester in step 8, by replacing acetic anhydride with methanesulfonyl chloride. MS (ES+): 553(M+).
Reaction SMILES: Br[C:2]1[CH:11]=[C:10]2[C:5]([CH:6]=[CH:7][C:8](=[O:39])[N:9]2[CH2:12][CH2:13][N:14]2[CH2:19][CH2:18][CH:17]([N:20]([CH2:28][C:29]3[N:34]=[CH:33][C:32]4[O:35][CH2:36][CH2:37][O:38][C:31]=4[CH:30]=3)[C:21](=[O:27])[O:22][C:23]([CH3:26])([CH3:25])[CH3:24])[CH2:16][CH2:15]2)=[N:4][CH:3]=1.C([Sn](CCCC)(CCCC)[C:45]1[O:46][CH:47]=[CH:48][N:49]=1)CCC>O1CCOCC1.CC(C)([P](C(C)(C)C)([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)C(C)(C)C)C>[O:38]1[C:31]2[CH:30]=[C:29]([CH2:28][N:20]([CH:17]3[CH2:18][CH2:19][N:14]([CH2:13][CH2:12][N:9]4[C:10]5[C:5](=[N:4][CH:3]=[C:2]([C:45]6[O:46][CH:47]=[CH:48][N:49]=6)[CH:11]=5)[CH:6]=[CH:7][C:8]4=[O:39])[CH2:15][CH2:16]3)[C:21](=[O:27])[O:22][C:23]([CH3:25])([CH3:24])[CH3:26])[N:34]=[CH:33][C:32]=2[O:35][CH2:36][CH2:37]1
Reactant: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(Br)cc32)CC1
Reactant: CCCC[Sn](CCCC)(CCCC)c1ncco1
Agent: CC(C)(C)[P]([Pd][P](C(C)(C)C)(C(C)(C)C)C(C)(C)C)(C(C)(C)C)C(C)(C)C
Solvent: C1COCCO1
Product: CC(C)(C)OC(=O)N(Cc1cc2c(cn1)OCCO2)C1CCN(CCn2c(=O)ccc3ncc(-c4ncco4)cc32)CC1
Reaction time: 0.5 h
Yield: 88.8 %

Procedure:
To a solution of 0.10 g of tert-butyl (1-(2-(7-bromo-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)(2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)carbamate in 2 mL of dioxane, 90 mg of 2-tributylstannyloxazole and 17 mg of bis(tri-tert-butylphosphine)palladium(0) were added under a nitrogen atmosphere, and the mixture was heated under reflux while stirring for 6 hours 30 minutes. The resultant residue was purified by flash silica gel column chromatography using gradient elution with chloroform:methanol=98:2 to 95:5 to obtain 87 mg of tert-butyl (2,3-dihydro(1,4)dioxino(2,3-c)pyridin-7-ylmethyl)(1-(2-(7-(1,3-oxazol-2-yl)-2-oxo-1,5-naphthyridin-1(2H)-yl)ethyl)piperidin-4-yl)carbamate as a yellow oily substance.
Reaction SMILES: [C:1]([NH:3][C:4]([NH:9][CH2:10][C:11]#[CH:12])=[N:5][CH2:6][CH2:7][SH:8])#[N:2].[O-]CC.[Na+].[CH3:17][C:18]1[N:19]=[CH:20][NH:21][C:22]=1[CH2:23]Cl>C(O)C.[Cl-].[Na+].O>[C:1]([NH:3][C:4]([NH:5][CH2:6][CH2:7][S:8][CH2:23][C:22]1[NH:21][CH:20]=[N:19][C:18]=1[CH3:17])=[N:9][CH2:10][C:11]#[CH:12])#[N:2]
Reactant: Cc1nc[nH]c1CCl
Reactant: C#CCNC(=NCCS)NC#N
Agent: CC[O-]
Agent: [Cl-]
Agent: [Na+]
Solvent: CCO
Solvent: O
Product: C#CCN=C(NC#N)NCCSCc1[nH]cnc1C
Temperature: 4 °C
Reaction time: 0.08 h
Yield: 50 %

Procedure:
A solution of 0.029 g (0.16 m mole) of the product of step A, in 1 ml ethanol containing 0.42 m mole sodium ethoxide, was placed under a nitrogen atmosphere and cooled to 4° C. with stirring. After 5 minutes, 0.035 g (0.21 m mole) of solid 4-methyl-5-chloromethylimidazole was added. The mixture was stirred for 40 minutes, poured into brine (30 ml) and then extracted with chloroform (3×15 ml). After drying (Na2SO4), the solvent was removed by evaporation. The residue was purified by thin layer chromatography on silica gel plates using a methanol-chloroform (1:4) solvent system to give 0.022 g (50%) of the title compound as a syrup which crystallized on standing at room temperature. Trituration with chloroform gave the crystalline product, m.p. 147°-149° C. I.R. (nujol): 3360 (NH), 3300 (C≡CH), 2160 (C≡N), 1600 and 1585 (C=N) cm-1 ; n.m.r. (acetone D6): δ 8.53 (1H, NH), 7.68 (s, 1H), 7.00 (1H, NH), 4.13 (q, 2H, J=2.5 Hz), 3.73 (s, 2H), 3.53 (m, 2H), 2.73 (m, 3H), 2.21 (s, 3H).
Reaction SMILES: [Cl:1][C:2]1[CH:10]=[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])[C:5]2[O:6][CH2:7][O:8][C:4]=2[C:3]=1[NH:17][C:18]1[C:27]2[C:22](=[CH:23][C:24]([O:30][CH2:31][CH2:32][CH2:33]Cl)=[C:25]([O:28][CH3:29])[CH:26]=2)[N:21]=[CH:20][N:19]=1.[CH3:35][O:36][CH2:37][CH2:38][NH:39][CH2:40][CH2:41][O:42][CH3:43]>COCCO>[CH3:35][O:36][CH2:37][CH2:38][N:39]([CH2:40][CH2:41][O:42][CH3:43])[CH2:33][CH2:32][CH2:31][O:30][C:24]1[CH:23]=[C:22]2[C:27]([C:18]([NH:17][C:3]3[C:4]4[O:8][CH2:7][O:6][C:5]=4[C:9]([C:11]#[C:12][CH2:13][CH2:14][O:15][CH3:16])=[CH:10][C:2]=3[Cl:1])=[N:19][CH:20]=[N:21]2)=[CH:26][C:25]=1[O:28][CH3:29]
Reactant: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCCl)c(OC)cc23)c2c1OCO2
Reactant: COCCNCCOC
Solvent: COCCO
Product: COCCC#Cc1cc(Cl)c(Nc2ncnc3cc(OCCCN(CCOC)CCOC)c(OC)cc23)c2c1OCO2
Yield: 61.1 %

Procedure:
This was prepared using the method described in example 13 using N-[5-chloro-7-(4-methoxybut-1-yn-1-yl)-1,3-benzodioxol-4-yl]-7-(3-chloropropoxy)-6-methoxyquinazolin-4-amine (200 mg, 0.40 mmol) and bis(2-methoxyethyl)amine (264 mg, 1.98 mmol) in 2-methoxyethanol (4 ml). The crude product was purified by column chromatography on silica using increasing concentrations of methanol in dichloromethane as eluent. There was thus obtained the title compound (147 mg, 66%) as a pale brown solid; NMR Spectrum:(DMSOd6) 1.91 (quintet, 2H), 2.65 (m, 6H), 2.72 (t, 2), 3.21 (s, 6H), 3.30 (s, 3H), 3.38 (t, 4H), 3.53 (t, 2H), 3.94 (s, 3H), 4.19 (t, 2H), 6.14 (s, 2H), 7.07 (s, 1H), 7.17 (s, 1H), 7.81 (s, 1H), 8.32 (s, 1H), 9.49 (s, 1H); Mass Spectrum: M+H+ 601/603.
Reaction SMILES: [CH:1]1[C:11]2[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]=3[C:6](=[C:16]3[CH2:21][CH2:20][N:19]([C:22](=[O:40])[C@@H:23]([NH:32]C(=O)OC(C)(C)C)[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28])[CH2:18][CH2:17]3)[C:5]=2[CH:4]=[CH:3][CH:2]=1.[ClH:41].C(OCC)(=O)C>C(OCC)(=O)C>[ClH:41].[NH2:32][C@H:23]([C:22]([N:19]1[CH2:18][CH2:17][C:16](=[C:6]2[C:5]3[CH:4]=[CH:3][CH:2]=[CH:1][C:11]=3[CH:10]=[CH:9][C:8]3[CH:12]=[CH:13][CH:14]=[CH:15][C:7]2=3)[CH2:21][CH2:20]1)=[O:40])[CH2:24][NH:25][C:26](=[O:31])[C:27]([CH3:30])([CH3:29])[CH3:28]
Reactant: CC(C)(C)OC(=O)N[C@@H](CNC(=O)C(C)(C)C)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Agent: Cl
Solvent: CCOC(C)=O
Product: CC(C)(C)C(=O)NC[C@H](N)C(=O)N1CCC(=C2c3ccccc3C=Cc3ccccc32)CC1
Reaction time: 3.5 h

Procedure:
1.40 g (2.57 mmol) of the compound obtained in step 1 described above was dissolved in 12 ml of ethyl acetate. 10 ml of 4 N hydrochloric acid/ethyl acetate was added to the obtained solution under cooling with ice. The temperature was gradually elevated to room temperature. After stirring for 3.5 hours, the solvent was evaporated under reduced pressure to obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:3]=[N:4][C:5]([C:8]([N:10]([CH2:12][CH3:13])[CH3:11])=[O:9])=[N:6][CH:7]=1.[OH:14][C:15]1[C:20]2[CH:21]=[C:22]([CH3:24])[O:23][C:19]=2[CH:18]=[C:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=1.C([O-])([O-])=O.[Cs+].[Cs+].N1C2C(=CC=C3C=2N=CC=C3)C=CC=1>[Cu](I)I.CN(C)C=O>[CH2:12]([N:10]([CH3:11])[C:8]([C:5]1[N:4]=[CH:3][C:2]([O:14][C:15]2[C:20]3[CH:21]=[C:22]([CH3:24])[O:23][C:19]=3[CH:18]=[C:17]([C:25]([O:27][CH2:28][CH3:29])=[O:26])[CH:16]=2)=[CH:7][N:6]=1)=[O:9])[CH3:13]
Reactant: CCN(C)C(=O)c1ncc(Br)cn1
Reactant: CCOC(=O)c1cc(O)c2cc(C)oc2c1
Agent: I[Cu]I
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1cc(Oc2cnc(C(=O)N(C)CC)nc2)c2cc(C)oc2c1
Temperature: 90 °C
Yield: 27.6 %

Procedure:
The flask was charged with 5-bromo-N-ethyl-N-methylpyrimidine-2-carboxamide (SM-3: 615 mg, 2.5 mmol), ethyl 4-hydroxy-2-methylbenzofuran-6-carboxylate (I-1c: 378 mg, 1.7 mmol), Cs2CO3 (1.15 g, 3.5 mmol), 1,10-phenanthroline (30.3 mg, 0.17 mmol), copper iodide (16 mg, 0.08 mmol) and dimethylformamide (17 mL). The reaction mixture was degassed with N2 for 5 minutes and then heated to 90° C. for 16 hours under a N2 atmosphere. The reaction mixture was diluted with ethylacetate (250 mL), washed with water (3×100 mL), dried (MgSO4) and concentrated. The crude material was purified by a biotage 50 g silica gel column (20%-100% EtOAc in Hep) to afford the title compound ethyl 4-(2-(ethyl(methyl)carbamoyl)pyrimidin-5-yloxy)-2-methylbenzofuran-6-carboxylate (I-5a: 180 mg, 28%) as a yellow solid.
Reaction SMILES: [C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C:13]([N+:14]([O-])=O)=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([O:24][CH2:25][C:26]([F:29])([F:28])[F:27])[CH:9]=1)([CH3:4])([CH3:3])[CH3:2]>[Pd]>[C:1]([O:5][C:6](=[O:30])[NH:7][C:8]1[C:13]([NH2:14])=[CH:12][C:11]([C:17]2[CH:22]=[CH:21][CH:20]=[CH:19][C:18]=2[F:23])=[C:10]([O:24][CH2:25][C:26]([F:27])([F:28])[F:29])[CH:9]=1)([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1[N+](=O)[O-]
Agent: [Pd]
Product: CC(C)(C)OC(=O)Nc1cc(OCC(F)(F)F)c(-c2ccccc2F)cc1N

Procedure:
The title compound was prepared from [2′-fluoro-5-nitro-2-(2,2,2-trifluoro-ethoxy)-biphenyl-4-yl]-carbamic acid tert.-butyl ester (Example D2) by hydrogenation with 10% Pd/C according to the general procedure J (method a). Obtained as a grey solid (1.17 g).
Reaction SMILES: [C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12][C@H:13]([N:20]1[CH2:29][CH2:28][CH2:27][CH2:26][CH:21]1[C:22]([O:24][CH3:25])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1>C1(C)C=CC=CC=1>[C:1]([OH:11])(=[O:10])[C@H:2]([C:4]1[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1)[OH:3].[CH3:12][C@H:13]([N:20]1[CH2:29][CH2:28][CH2:27][CH2:26][C@H:21]1[C:22]([O:24][CH3:25])=[O:23])[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1
Reactant: COC(=O)C1CCCCN1[C@@H](C)c1ccccc1
Agent: O=C(O)[C@@H](O)c1ccccc1
Solvent: Cc1ccccc1
Product: COC(=O)[C@@H]1CCCCN1[C@@H](C)c1ccccc1
Temperature: 70 °C
Reaction time: 0.5 h

Procedure:
L-(+)-mandelic acid (1.52 g) and toluene (8.67 g) were mixed and warmed to 70° C. To the solution was added a mixture of methyl N-[(S)-α-methylbenzyl]-(RS)-pipecolate (2.47 g) and toluene (8.67 g). The mixture was stirred for 0.5 hour, and the L-(+)-mandelic acid salt of methyl N-[(S)-α-methylbenzyl]-(S)-pipecolate, which was obtained in Example 6 (73% d.e.), as a seed crystal was added thereto. After this, the mixture was cooled to 0° C. over 3.5 hours with stirring. The crystals formed were separated by filtration and washed with cold toluene to yield an L-(+)-mandelic acid salt of methyl N-[(S)-α-methylbenzyl]-(S)-pipecolate (2.49 g) in 95.2% d.e. and a yield of 41.3%.
Reaction SMILES: [O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([NH:13][C:14](=[O:22])[CH2:15][C:16]1[CH:21]=[CH:20][CH:19]=[CH:18][CH:17]=1)[C:9]([O:11]C)=[O:10].[OH-].[Na+].Cl>O>[O:1]=[C:2]1[CH2:6][CH2:5][CH2:4][CH:3]1[CH2:7][CH:8]([NH:13][C:14](=[O:22])[CH2:15][C:16]1[CH:17]=[CH:18][CH:19]=[CH:20][CH:21]=1)[C:9]([OH:11])=[O:10]
Reactant: COC(=O)C(CC1CCCC1=O)NC(=O)Cc1ccccc1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: O
Product: O=C(Cc1ccccc1)NC(CC1CCCC1=O)C(=O)O
Temperature: 45 °C
Reaction time: 5 h

Procedure:
10.8 kg of compound (II) with R=═CH3, methyl 3-(2-oxocyclopentyl)-2-phenylacetylaminopropionate, 23.7 l of water and 5.5 kg of sodium hydroxide solution (33%) were introduced into a tank. The reaction mixture was heated to 45° C. and stirred at this temperature for 5 hours. It was cooled to 20° C., and the pH was adjusted at this temperature to pH 6.4 with hydrochloric acid (30%). The reaction mixture was diluted with 301 of water. The compound 3-(2-oxocyclopentyl)-2-phenylacetylamino-propionic acid (III) which was produced in the reaction and was in the form of a mixture of 2 diastereomeric racemates was processed further as aqueous solution in the following step without further purification.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[CH:4][C:5]([N:11]=[CH:12][CH2:13][N+:14]([O-:16])=[O:15])=[C:6]([CH:10]=1)[C:7](O)=[O:8].C([O-])(=O)C.[K+]>C(OC(=O)C)(=O)C>[Cl:1][C:2]1[CH:10]=[C:6]2[C:5](=[CH:4][CH:3]=1)[N:11]=[CH:12][C:13]([N+:14]([O-:16])=[O:15])=[C:7]2[OH:8]
Reactant: O=C(O)c1cc(Cl)ccc1N=CC[N+](=O)[O-]
Agent: CC(=O)[O-]
Agent: [K+]
Solvent: CC(=O)OC(C)=O
Product: O=[N+]([O-])c1cnc2ccc(Cl)cc2c1O
Reaction time: 0.67 h

Procedure:
26.5 g (0.109 mol) of 5-chloro-2-[2-nitro-ethylideneamino]-benzoic acid (Example 23a) in 116 ml acetic anhydride are heated and kept at 110° C. 12.92 g (0.131 mol) potassium acetate are added in 2 min and heating is continued for 40 min at 130-135° C. After 10 min, the title compound starts to crystallize. The reaction vessel is cooled to rt and the solid filtered off and washed with acetic acid and water. Drying follows at 95° C. for 16 h (high vacuum). mp: 341-342° C. (dec.). MS: 225 (M++1); HPLC: tret=7.33 min (Grad 1).
Reaction SMILES: [Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH:8]([C:10]2[CH:15]=[CH:14][C:13]([O:16][C:17]([F:20])([F:19])[F:18])=[CH:12][CH:11]=2)O)[CH:7]=1>ClCCl>[Br:1][C:2]1[CH:3]=[CH:4][C:5]([Cl:21])=[C:6]([CH2:8][C:10]2[CH:11]=[CH:12][C:13]([O:16][C:17]([F:20])([F:18])[F:19])=[CH:14][CH:15]=2)[CH:7]=1
Reactant: OC(c1ccc(OC(F)(F)F)cc1)c1cc(Br)ccc1Cl
Solvent: ClCCl
Product: FC(F)(F)Oc1ccc(Cc2cc(Br)ccc2Cl)cc1
Temperature: 25 °C
Reaction time: 16 h
Yield: 77.6 %

Procedure:
To a solution of (5-bromo-2-chloro-phenyl)-[4-(trifluoromethoxy)phenyl]methanol 15f (5.0 g, 13.0 mmol) in dichloromethane (50 mL) was added triethyl silicane (4.57 g, 39.0 mmol) at 0° C., and then boron fluoride ethyl ether (3.72 g, 26.0 mmol) was added slowly. The resulting mixture was allowed to warm up to room temperature and further stirred for 16 hours. The reaction mixture was quenched with saturated aqueous sodium bicarbonate (10 mL), and then separated. The aqueous layer was extracted with dichloromethane (20 mL×2). The combined organic layers were washed with saturated brine (30 mL×2), dried over anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and the residue was purified by silica gel chromatography eluted with PE to give the title compound 15g as colourless oil (3.69 g, 77.0%). The compound was characterized by the following spectroscopic data: 1H NMR (400 MHz, CDCl3) δ (ppm): 7.34 (dd, 1H), 7.31 (d, 1H), 7.28 (s, 1H), 7.22 (d, 2H), 7.17 (d, 2H), 4.08 (s, 2H).
Reaction SMILES: [C:1]([O:6][CH2:7][CH3:8])(=[O:5])[C:2]([CH3:4])=[O:3].C(O[CH:12](OCC)[N:13]([CH3:15])[CH3:14])C.C(O)C.C>C(OCC)C>[CH3:12][N:13]([CH3:15])[CH:14]=[CH:4][C:2](=[O:3])[C:1]([O:6][CH2:7][CH3:8])=[O:5]
Reactant: CCOC(=O)C(C)=O
Reactant: CCOC(OCC)N(C)C
Solvent: CCOCC
Solvent: CCO
Product: CCOC(=O)C(=O)C=CN(C)C
Temperature: 5 °C
Reaction time: 3 h
Yield: 31.4 %

Procedure:
Ethyl pyruvate (1,500 g) is added in the course of 2 hours, while the temperature is maintained at approximately 5° C., to N,N-dimethylformamide diethyl acetal (2,100 g) cooled to a temperature in the region of 5° C. The mixture is then stirred for 3 hours at a temperature in the region of 20° C. The reaction ethanol is evaporated off to dryness and the residue obtained is pounded with diethyl ether (12 liters) and charcoal 3S (30 g) and then filtered on supercel. The filtrate is taken up with water (500 cc), and the organic phase is decanted and the aqueous phase is extracted with dichloromethane (3×2000 cc). The organic phases are mixed, dried over sodium sulphate, filtered and concentrated to dryness at 40° C. under reduced pressure (20 mm Hg; 2.7 kPa). The oil obtained is purified by distillation (b.p.0.1 mm Hg 146°-149° C.). Ethyl 4-dimethylamino-2-oxo-3-butenoate (695 g) is thereby obtained, and is used in the crude state in the subsequent syntheses.