Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41](O)=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:22]=[CH:21][C:20]([Cl:23])=[CH:19][CH:18]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:4])([CH3:3])[CH3:2].[CH3:47][NH:48][CH:49]([CH3:51])[CH3:50]>>[C:1]([C:5]1[N:10]=[CH:9][C:8]([C:11]2[N:12]([C:32]([N:34]3[CH2:39][CH2:38][CH:37]([CH2:40][C:41]([N:48]([CH:49]([CH3:51])[CH3:50])[CH3:47])=[O:42])[CH2:36][CH2:35]3)=[O:33])[C@@:13]([C:25]3[CH:30]=[CH:29][C:28]([Cl:31])=[CH:27][CH:26]=3)([CH3:24])[C@@:14]([C:17]3[CH:18]=[CH:19][C:20]([Cl:23])=[CH:21][CH:22]=3)([CH3:16])[N:15]=2)=[C:7]([O:44][CH2:45][CH3:46])[CH:6]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)O)CC1
Reactant: CNC(C)C
Product: CCOc1cc(C(C)(C)C)ncc1C1=N[C@@](C)(c2ccc(Cl)cc2)[C@@](C)(c2ccc(Cl)cc2)N1C(=O)N1CCC(CC(=O)N(C)C(C)C)CC1

Procedure:
In a manner analogous to the method described in example 163, {1-[(4S,5R)-2-(6-tert-butyl-4-ethoxy-pyridin-3-yl)-4,5-bis-(4-chloro-phenyl)-4,5-dimethyl-4,5-dihydro-imidazole-1-carbonyl]-piperidin-4-yl}-acetic acid was reacted with n-methylisopropylamine (Aldrich) to give the title product. LC-MS (ES+) 720 [(M+H)+].
Reaction SMILES: [CH3:1][O-:2].[Na+].[C:4]([C:6]1[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:7]=1[O:8][CH:9](OCC1C=CC=CC=1)[C:10]([C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:11])#[N:5]>CO>[NH2:5][C:4]1[C:6]2[CH:29]=[C:28]([Cl:30])[CH:27]=[CH:26][C:7]=2[O:8][C:9]=1[C:10](=[O:11])[C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][C:17]=1[O:2][CH2:1][C:6]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:7]=1
Reactant: N#Cc1cc(Cl)ccc1OC(OCc1ccccc1)C(=O)c1ccccc1
Reactant: C[O-]
Agent: [Na+]
Solvent: CO
Product: Nc1c(C(=O)c2ccccc2OCc2ccccc2)oc2ccc(Cl)cc12

Procedure:
A solution of sodium methanolate (0.07 g, 1.3 mmol) in methanol is added to a solution of ω-(2-cyano-4-chlorophenoxy)-2-benzyloxy-acetophenone (0.5 g, 1.32 mmol) in methanol (30 ml) at 0° C. After 2 h at r.t. the reaction mixture is concentrated under reduced pressure. The residue is diluted with ethyl acetate and washed with water. Drying over sodium sulfate, filtering, evaporating the solvent and purification of the residue by silicagel column chromatography yields the title compound, having a m.p. of 158-160° C.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([CH:8]([OH:29])[CH2:9][NH:10][CH:11]([CH3:28])[CH2:12][C:13]2[CH:27]=[CH:26][C:16]3[O:17][C:18]([C:23]([OH:25])=[O:24])([C:20]([OH:22])=[O:21])[O:19][C:15]=3[CH:14]=2)[CH:5]=[CH:6][CH:7]=1.[O:30]1[CH2:34][CH2:33][CH:32]([CH2:35]O)[CH2:31]1.[K+].[Br-].Cl>>[O:30]1[CH2:34][CH2:33][CH:32]([CH2:35][O:24][C:23]([C:18]2([C:20]([O:22][CH2:35][CH:32]3[CH2:33][CH2:34][O:30][CH2:31]3)=[O:21])[O:17][C:16]3[CH:26]=[CH:27][C:13]([CH2:12][C@H:11]([NH:10][CH2:9][C@@H:8]([C:4]4[CH:5]=[CH:6][CH:7]=[C:2]([Cl:1])[CH:3]=4)[OH:29])[CH3:28])=[CH:14][C:15]=3[O:19]2)=[O:25])[CH2:31]1
Reactant: CC(Cc1ccc2c(c1)OC(C(=O)O)(C(=O)O)O2)NCC(O)c1cccc(Cl)c1
Reactant: OCC1CCOC1
Agent: Cl
Agent: [Br-]
Agent: [K+]
Product: C[C@H](Cc1ccc2c(c1)OC(C(=O)OCC1CCOC1)(C(=O)OCC1CCOC1)O2)NC[C@H](O)c1cccc(Cl)c1

Procedure:
The title compound was prepared from 5-{2-[2-(3-chloro-phenyl)-2-hydroxy-ethylamino]-propyl}-benzo[1,3]dioxole-2,2-dicarboxylic acid and tetrahydrofuran-3-ylmethanol according to the procedure of Example 1 as an off-white solid; 1H NMR (DMSO-d6,400 MHz) δ 1.03 (d, J=6.37 Hz, 3H, CH3), 1.5 (m, 2H, CH2), 1.9 (m, 2H, CH2), 2.6 (m, 3H, CH), 3-3.3 (m, 3H, CH, CH2), 3.4 (brs, 1H, CH), 3.6-3.7 (m, 6H, CH2), 4.1-4.15 (m, 6H, CH2), 5.09 (m, 1H, CH), 6.36 (brs, 1H, OH), 6.86 (m, 1H, Ar--H), 7.07 (m, 2H, Ar--H), 7.38-7.42 (m, 3H, Ar--H), 7.47 (s, 1H, Ar--H), 8.84 (brs, 2H, NH, NH); IR (KBr, cm-1) 3300 (OH), 2900 (NH), 1760 (CO); MS m/e 590 (M+H)+ ; Analysis for: C30H36ClNO9 ×HCl: Calc'd: C, 57.51; H, 5.95; N, 2.24; Found: C, 57.80; H, 6.30; N, 2.21.
Reaction SMILES: C(=O)([O-])[O-].[Cs+].[Cs+].Br[C:8]1[CH:13]=[CH:12][C:11]([O:14][CH3:15])=[C:10]([F:16])[CH:9]=1.[NH2:17][C:18]1[N:33]=[CH:32][CH:31]=[CH:30][C:19]=1[C:20]([NH:22][C:23]1[CH:28]=[CH:27][C:26]([F:29])=[CH:25][CH:24]=1)=[O:21].O1CCOCC1>O.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.C1C=CC(/C=C/C(/C=C/C2C=CC=CC=2)=O)=CC=1.[Pd].[Pd]>[F:16][C:10]1[CH:9]=[C:8]([NH:17][C:18]2[N:33]=[CH:32][CH:31]=[CH:30][C:19]=2[C:20]([NH:22][C:23]2[CH:24]=[CH:25][C:26]([F:29])=[CH:27][CH:28]=2)=[O:21])[CH:13]=[CH:12][C:11]=1[O:14][CH3:15]
Reactant: Nc1ncccc1C(=O)Nc1ccc(F)cc1
Reactant: COc1ccc(Br)cc1F
Agent: [Pd]
Agent: O=C(/C=C/c1ccccc1)/C=C/c1ccccc1
Agent: O=C([O-])[O-]
Solvent: C1COCCO1
Solvent: O
Product: COc1ccc(Nc2ncccc2C(=O)Nc2ccc(F)cc2)cc1F
Temperature: 90 °C
Yield: 98 %

Procedure:
A 1 L round-bottomed flask was charged with cesium carbonate (11.1 g, 34.1 mmol), 4-bromo-2-fluoro-1-methoxybenzene (5.00 g, 24.4 mmol), 2-amino-N-(4-fluorophenyl)nicotinamide (7.61 g, 32.9 mmol), and dioxane (250 mL). The reaction mixture was degassed with nitrogen for 10 minutes, and Xanphos (0.564 g, 0.975 mmol) and Pd2dba3 (0.670 g, 0.732 mmol) were added. The reaction mixture was heated at 90° C. for 48 hours. The reaction mixture was cooled to ambient temperature and diluted with water. The reaction mixture was extracted with EtOAc, dried over sodium sulfate, filtered and concentrated. The crude material was purified by silica gel chromatography (biotage 65) eluting with DCM/MeOH (3%). Isolated 8.50 g (93%) of the product. LRMS M+1 (365.0) observed.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21](O)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8].ClC1C=C(N2C(C3C=NC=C(F)C=3)=CC([C:44]([N:46]3[CH2:50][C:49](=[O:51])[NH:48][CH2:47]3)=O)=N2)C=CC=1F.O=C1CNCCN1>>[Cl:1][C:2]1[CH:3]=[C:4]([N:9]2[C:13]([C:14]3[CH:15]=[N:16][CH:17]=[C:18]([Cl:20])[CH:19]=3)=[CH:12][C:11]([C:21]([N:46]3[CH2:44][CH2:47][NH:48][C:49](=[O:51])[CH2:50]3)=[O:22])=[N:10]2)[CH:5]=[CH:6][C:7]=1[F:8]
Reactant: O=C(O)c1cc(-c2cncc(Cl)c2)n(-c2ccc(F)c(Cl)c2)n1
Reactant: O=C1CN(C(=O)c2cc(-c3cncc(F)c3)n(-c3ccc(F)c(Cl)c3)n2)CN1
Agent: O=C1CNCCN1
Product: O=C1CN(C(=O)c2cc(-c3cncc(Cl)c3)n(-c3ccc(F)c(Cl)c3)n2)CCN1

Procedure:
100 mg (0.28 mmol) of the compound of Example 61A is reacted analogously to the synthesis of the compound of Example 98 with 31 mg (0.31 mmol) of 2-oxopiperazine. 71 mg (58% of theory) of the title compound is obtained.
Reaction SMILES: [I:1][C:2]1[CH:3]=[C:4]([N:8]2[C:12](=[O:13])[CH2:11][NH:10][C:9]2=[O:14])[CH:5]=[CH:6][CH:7]=1.[H-].[Na+].[CH2:17](Cl)[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1.Cl>CN(C=O)C>[CH2:17]([N:10]1[CH2:11][C:12](=[O:13])[N:8]([C:4]2[CH:5]=[CH:6][CH:7]=[C:2]([I:1])[CH:3]=2)[C:9]1=[O:14])[C:18]1[CH:23]=[CH:22][CH:21]=[CH:20][CH:19]=1
Reactant: ClCc1ccccc1
Reactant: O=C1CNC(=O)N1c1cccc(I)c1
Agent: Cl
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C1CN(Cc2ccccc2)C(=O)N1c1cccc(I)c1

Procedure:
A solution of 3-(3-iodophenyl)imidazolidine-2,4-dione (1.7 g) in DMF (20 ml) was treated with sodium hydride (60% oil dispersion, 280 mg) and benzylchloride (1.93 ml) at 20° C. After 2 h the reaction mixture was treated with aqueous 2M HCl, extracted with EtOAc and dried (MgSO4). The solvent was removed under reduced pressure and the residue was purified by chromatography on Biotage (40 g) eluting with petroleum ether-EtOAc (9:1 to 3:2) to give the title compound (1.38 g). LCMS RT=3.27 min.
Reaction SMILES: [OH:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1.[C:23](Cl)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1.O>N1C=CC=CC=1.C(Cl)Cl>[C:23]([O:1][C@H:2]1[CH2:19][CH2:18][C@@:17]2([CH3:20])[C:4](=[CH:5][CH2:6][C@@H:7]3[C@@H:16]2[CH2:15][CH2:14][C@@:12]2([CH3:13])[C@H:8]3[C@@H:9]3[CH2:22][C@@H:10]3[C:11]2=[O:21])[CH2:3]1)(=[O:30])[C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: C[C@]12CC[C@H](O)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Solvent: ClCCl
Solvent: O
Solvent: c1ccncc1
Product: C[C@]12CC[C@H](OC(=O)c3ccccc3)CC1=CC[C@H]1[C@@H]3[C@@H]4C[C@@H]4C(=O)[C@@]3(C)CC[C@@H]12
Temperature: 25 °C
Reaction time: 17 h

Procedure:
A solution of 5.0 g of 3β-hydroxy-15β,16β-methylene-5-androsten-17-one in 50 ml of pyridine was combined under ice cooling with 5 ml of benzoyl chloride and then stirred for 17 hours at room temperature. After the addition of 10 ml of water, the mixture was stirred for another hour; then the reaction solution was diluted with methylene chloride and washed with sodium carbonate solution and water. After drying and evaporation, the residue was triturated with diisopropyl ether and vacuum-filtered, thus obtaining 6.4 g of 3β-benzoyloxy-15β,16β-methylene-5-androsten-17-one, mp 250°-258° C.
Reaction SMILES: [CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:16]=[CH:15][C:10]([C:11]([O:13]C)=[O:12])=[CH:9][CH:8]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:20])=[O:19].[OH-].[Na+]>O1CCOCC1>[CH3:1][C:2]1[O:6][C:5]([C:7]2[CH:8]=[CH:9][C:10]([C:11]([OH:13])=[O:12])=[CH:15][CH:16]=2)=[N:4][C:3]=1[CH2:17][S:18]([C:21]1[CH:26]=[CH:25][C:24]([CH3:27])=[CH:23][C:22]=1[CH3:28])(=[O:20])=[O:19]
Reactant: COC(=O)c1ccc(-c2nc(CS(=O)(=O)c3ccc(C)cc3C)c(C)o2)cc1
Agent: [Na+]
Agent: [OH-]
Solvent: C1COCCO1
Product: Cc1ccc(S(=O)(=O)Cc2nc(-c3ccc(C(=O)O)cc3)oc2C)c(C)c1
Yield: 83.2 %

Procedure:
Reaction of benzoate 43 (131 mg, 0.34 mmol) and 1 M NaOH (10 mL) in dioxane (10 mL) gave acid 44 (109 mg, 83%) as a white solid: mp (H2O) 235-238° C.; 1H NMR δ 13.15 (br s, 1H, CO2H), 8.06 (br d, J=8.5 Hz, 2H, H-2, H-6), 7.90 (br d, J=8.5 Hz, 2H, H-3, H-5), 7.57 (d, J=8.1 Hz, 1H, H-6′), 7.28 (br s, 1H, H-3′), 7.17 (br d, J=8.1 Hz, 1H, H-5′), 4.61 (s, 2H, CH2SO2), 2.56 (s, 3H, CH3), 2.33 (s, 3H, CH3), 2.16 (s, 3H, CH3); MS m/z 386.5 (MH+, 100%). Anal. calcd for C20H19NO5S.¾H2O: C, 62.69; H, 5.50; N, 3.32. Found: C, 62.52; H, 5.27; N, 3.48%.
Reaction SMILES: [Br:1][C:2]1[CH:7]=[C:6]([NH2:8])[CH:5]=[CH:4][N:3]=1.[H-].[Na+].[Cl:11][C:12]1[CH:20]=[CH:19][CH:18]=[C:17]([Cl:21])[C:13]=1[C:14](Cl)=[O:15]>CN(C=O)C>[Br:1][C:2]1[CH:7]=[C:6]([NH:8][C:14](=[O:15])[C:13]2[C:12]([Cl:11])=[CH:20][CH:19]=[CH:18][C:17]=2[Cl:21])[CH:5]=[CH:4][N:3]=1
Reactant: O=C(Cl)c1c(Cl)cccc1Cl
Reactant: Nc1ccnc(Br)c1
Agent: [H-]
Agent: [Na+]
Solvent: CN(C)C=O
Product: O=C(Nc1ccnc(Br)c1)c1c(Cl)cccc1Cl
Temperature: 0 °C
Reaction time: 0.33 h
Yield: 73.9 %

Procedure:
A solution of 2-bromopyridin-4-amine (0.74 g, 4.3 mmol) in DMF (5 mL) was added to a cooled (0° C.) mixture of NaH (0.31 g, 7.82 mmol, 60% in mineral oil) in DMF (15 mL). The resulting mixture was stirred for 20 minutes at 0° C. and then a solution of 2,6-dichlorobenzoyl chloride (0.82 g, 3.91 mmol) in DMF (5 mL) was added dropwise. The reaction was stirred at 0° C. for 4 hours and then poured onto ice-water (20 mL). The precipitate was collected and filtrate was extracted by EtOAc (2×50 mL). The combined organic extracts were dried over Na2SO4 and concentrated under reduced pressure. The resulting solid was combined with the precipitate to afford N-(2-bromopyridin-4-yl)-2,6-dichlorobenzamide (1.0 g, Yield: 74%). 1HNMR (DMSO-d6, 400 MHz): δ 11.41 (s, 1H), 8.33 (d, J=5.6 Hz, 1H), 7.99 (d, J=1.6 Hz, 1H), 7.64-7.54 (m, 4H). LCMS (ESI) m/z: 345.0 [M+H+].
Reaction SMILES: Br[CH2:2][CH2:3][CH2:4]Cl.[Cl:6][SiH:7]([Cl:9])[Cl:8]>[Cl-].C([P+](CCCC)(CCCC)CCCC)CCC>[Cl:6][Si:7]([Cl:9])([Cl:8])[CH2:2][CH2:3][CH2:4][Si:7]([Cl:9])([Cl:8])[Cl:6]
Reactant: Cl[SiH](Cl)Cl
Reactant: ClCCCBr
Agent: CCCC[P+](CCCC)(CCCC)CCCC
Agent: [Cl-]
Product: Cl[Si](Cl)(Cl)CCC[Si](Cl)(Cl)Cl
Yield: 51.9 %

Procedure:
In the same apparatus and procedure as Example 1 above, 0.44 g (1.50 mmol) of tetrabutylphosphonium chloride, 1.18 g (7.50 mmol) of 1-bromo-3-chloropropane, and 10.16 g (75.0 mmol) of trichlorosilane were reacted at 150° C. for 4 hrs. The resulting mixture was distilled to give 1.21 g of 1,3-bis(trichlorosily)propane (yield; 52%), 0.17 g of 3-(bromopropyl)trichlorosilane (yield; 9%), and 0.16 g of 3-(chloropropyl)trichlorosilane (yield; 10%).
Reaction SMILES: [C:1]([OH:7])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5].[CH3:8][S:9][CH2:10]Cl.C(N(CC)CC)C>>[C:1]([O:7][CH2:8][S:9][CH3:10])(=[O:6])[CH2:2][CH2:3][CH2:4][CH3:5]
Reactant: CSCCl
Reactant: CCCCC(=O)O
Solvent: CCN(CC)CC
Product: CCCCC(=O)OCSC

Procedure:
This product was prepared according to the procedure described in Example 1, by reacting valeric acid with chloromethyl methyl sulfide in the presence of one equivalent of triethylamine; b.p. 83°-85° C./12 mm Hg, nD20 1.4560.
Reaction SMILES: [NH:1]1[C:9]2[C:4](=[C:5](N)[CH:6]=[CH:7][CH:8]=2)[CH:3]=[N:2]1.S(=O)(=O)(O)[OH:12].[OH-].[Na+]>>[NH:1]1[C:9]2[CH:8]=[CH:7][CH:6]=[C:5]([OH:12])[C:4]=2[CH:3]=[N:2]1
Reactant: O=S(=O)(O)O
Reactant: Nc1cccc2[nH]ncc12
Agent: [Na+]
Agent: [OH-]
Product: Oc1cccc2[nH]ncc12

Procedure:
500 mg (375 mmol) of 1H-indazol-4-ylamine (prepared according to J. Chem. Soc. 1955, 2412, 2419) are stirred in 10% strength sulfuric acid at 180° C. in an autoclave at intrinsic pressure overnight. The reaction solution is cooled to room temperature and neutralized with 1N sodium hydroxide solution, and the salts are filtered off. The filtrate is concentrated to dryness.
Reaction SMILES: C[Si]([NH-])(C)C.C[Si]([NH-])(C)C.[Li+].[Li+].[C:13]([S:17][CH:18]1[N:21]([CH2:22][C:23]([O:25][CH2:26][C:27]2[CH:32]=[CH:31][C:30]([N+:33]([O-:35])=[O:34])=[CH:29][CH:28]=2)=[O:24])[C:20](=[O:36])[CH2:19]1)([CH3:16])([CH3:15])[CH3:14].[Cl:37][CH2:38][C:39]([CH3:44])([CH3:43])[C:40](Cl)=[O:41]>C1COCC1.C1(C)C=CC=CC=1.Cl.[Na+].[Cl-]>[C:13]([S:17][CH:18]1[N:21]([CH:22]([C:40](=[O:41])[C:39]([CH3:44])([CH3:43])[CH2:38][Cl:37])[C:23]([O:25][CH2:26][C:27]2[CH:28]=[CH:29][C:30]([N+:33]([O-:35])=[O:34])=[CH:31][CH:32]=2)=[O:24])[C:20](=[O:36])[CH2:19]1)([CH3:16])([CH3:14])[CH3:15]
Reactant: CC(C)(CCl)C(=O)Cl
Reactant: CC(C)(C)SC1CC(=O)N1CC(=O)OCc1ccc([N+](=O)[O-])cc1
Agent: C[Si](C)(C)[NH-]
Agent: Cl
Agent: [Cl-]
Solvent: C1CCOC1
Solvent: Cc1ccccc1
Product: CC(C)(C)SC1CC(=O)N1C(C(=O)OCc1ccc([N+](=O)[O-])cc1)C(=O)C(C)(C)CCl
Temperature: -70 °C
Reaction time: 0.5 h
Yield: 69.4 %

Procedure:
6 ml of a 1M solution of lithium bis(trimethylsilylamide) in THF is slowly added dropwise to a stirred mixture, at 70° C., of 1.06 g (3 mmol) of p-nitrobenzyl 2-(4-tertbutylthio-2-oxo-1-azetidinyl)acetate and 410 μl (3.17 mmol) of chloropivaloyl chloride in 38 ml of absolute tetrahydrofuran, and the mixture is stirred for a further 30 minutes at -70° C. The reaction mixture is diluted with 250 ml of toluene, and 10 ml of 2N aqueous HCl and 100 ml of saturated NaCl solution are added. After separation, the organic phase is again washed with 100 ml of saturated NaCl solution then dried over MgSO4, and filtered, and the solvent is removed in vacuo on a rotary evaporator. The non-crystalline residue is chromatographed over 46 g of silica gel using toluene:ethyl acetate (19:1), to give 980 mg of non-crystalline title compound. IR in CH2Cl2 : 2930, 1770, 1760, 1725, 1615, 1530, 1465, 1370, 1250, 1215, 1190, 1110, 1040, 1000, 847 cm-1.
Reaction SMILES: [CH3:1][C:2]1[CH:8]=[C:7]([Br:9])[CH:6]=[CH:5][C:3]=1[NH2:4].[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH2:21][CH:22]=O)[CH2:19][CH2:18][O:17][CH2:16][CH2:15]1)=[O:13].C(O)(=O)C.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+].NC1C=CC=CC=1>ClCCCl.C(Cl)Cl.CO>[CH3:10][O:11][C:12]([C:14]1([CH2:20][CH2:21][CH2:22][NH:4][C:3]2[CH:5]=[CH:6][C:7]([Br:9])=[CH:8][C:2]=2[CH3:1])[CH2:15][CH2:16][O:17][CH2:18][CH2:19]1)=[O:13]
Reactant: Cc1cc(Br)ccc1N
Reactant: COC(=O)C1(CCC=O)CCOCC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: [Na+]
Solvent: CC(=O)O
Solvent: Nc1ccccc1
Solvent: ClCCl
Product: COC(=O)C1(CCCNc2ccc(Br)cc2C)CCOCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 45.9 %

Procedure:
2-Methyl-4-bromo-aniline (930 mg, 5 mmol) was dissolved in DCE (50 mL); to this solution was transferred a solution of 4-(3-oxo-propyl)-tetrahydro-pyran-4-carboxylic acid methyl ester (1.0 g, 5 mmol) in DCE (50 mL). The flask was submerged in a water bath at rt. To this clear solution was then added acetic acid (930 mg, 15.5 mmol, 3.1 equiv), followed by addition of powder NaBH(OAc)3 (3.18 g, 15 mmol, 3 equiv.) in 1 portion under N2 at r.t. The yellowish milky suspension was stirred at r.t. overnight. LC/MS showed m/z 372/370 at t=3.872 min. along with small amount of aniline starting material (MS: 186/188). TLC (5% of MeOH in DCM) showed no SM. of aldehyde, but aniline. The reaction was diluted with DCM (100 mL), cooled to ice-water bath, and quenched with 5 mL of conc. NH4OH (7.45M) in 150 mL of water. (2 M of NH4OH). The two layers were separated, and the aqueous layer was extracted with DCM (20 mL×2). The combined DCM extracts were washed with sodium bicarbonate (10 mL), and brine (10 mL), dried (anhydrous potassium carbonate), filtered, and concentrated. The product was purified on a 25-g-silica gel column eluted with DCM to elute aniline; 2.5% MeOH in DCM for the product to get 0.85 g (46%) of the title compound as an oil.
Reaction SMILES: [CH3:1][N:2]1[C:7](=[O:8])[CH:6]=[C:5]([N:9]2[CH2:14][CH2:13][O:12][CH2:11][CH2:10]2)[N:4]=[C:3]1[CH2:15][C:16]([O-:18])=O.[Na+].[F:20][C:21]1[CH:22]=[C:23]([CH:25]=[CH:26][C:27]=1[F:28])[NH2:24].Cl.CN(C)CCCN=C=NCC>N1C=CC=CC=1.CN(C)C=O>[F:20][C:21]1[CH:22]=[C:23]([NH:24][C:16](=[O:18])[CH2:15][C:3]2[N:2]([CH3:1])[C:7](=[O:8])[CH:6]=[C:5]([N:9]3[CH2:10][CH2:11][O:12][CH2:13][CH2:14]3)[N:4]=2)[CH:25]=[CH:26][C:27]=1[F:28]
Reactant: Cn1c(CC(=O)[O-])nc(N2CCOCC2)cc1=O
Reactant: Nc1ccc(F)c(F)c1
Agent: CCN=C=NCCCN(C)C
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Solvent: c1ccncc1
Product: Cn1c(CC(=O)Nc2ccc(F)c(F)c2)nc(N2CCOCC2)cc1=O
Yield: 54.4 %

Procedure:
The product is prepared according to the procedure described in example 5, using 250 mg of sodium [1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetate prepared in stage 1 of example 68, 169 mg of 3,4-difluoroaniline, and 285 mg of N-[3-(dimethylamino)propyl]-N′ethylcarbodiimide hydrochloride in a mixture of 2 ml of pyridine and 2 ml of N,N-dimethylformamide. 180 mg of N-(3,4-difluorophenyl)-2-[1-methyl-4-(morpholin-4-yl)-6-oxo-1,6-dihydropyrimidin-2-yl]acetamide are obtained in the form of a white solid, the characteristics of which are the following:
Reaction SMILES: COCCO[AlH2-]OCCOC.[Na+].C([O:15][C:16]([C:18]1[N:19]=[C:20]([C:27]2[CH:32]=[C:31]([O:33][C:34]3[CH:55]=[CH:54][C:37]4[N:38]([CH3:53])[C:39]([NH:41][C:42]5[CH:47]=[C:46]([C:48]([F:51])([F:50])[F:49])[CH:45]=[CH:44][C:43]=5[F:52])=[N:40][C:36]=4[CH:35]=3)[CH:30]=[CH:29][N:28]=2)[NH:21][C:22]=1[C:23]([F:26])([F:25])[F:24])=O)C>C1(C)C=CC=CC=1>[F:52][C:43]1[CH:44]=[CH:45][C:46]([C:48]([F:51])([F:50])[F:49])=[CH:47][C:42]=1[NH:41][C:39]1[N:38]([CH3:53])[C:37]2[CH:54]=[CH:55][C:34]([O:33][C:31]3[CH:30]=[CH:29][N:28]=[C:27]([C:20]4[NH:21][C:22]([C:23]([F:26])([F:24])[F:25])=[C:18]([CH2:16][OH:15])[N:19]=4)[CH:32]=3)=[CH:35][C:36]=2[N:40]=1
Reactant: CCOC(=O)c1nc(-c2cc(Oc3ccc4c(c3)nc(Nc3cc(C(F)(F)F)ccc3F)n4C)ccn2)[nH]c1C(F)(F)F
Agent: COCCO[AlH2-]OCCOC
Agent: [Na+]
Solvent: Cc1ccccc1
Product: Cn1c(Nc2cc(C(F)(F)F)ccc2F)nc2cc(Oc3ccnc(-c4nc(CO)c(C(F)(F)F)[nH]4)c3)ccc21
Reaction time: 0.33 h
Yield: 61.3 %

Procedure:
Red-Al (sodium bis(2-methoxyethoxy)aluminium hydride, 65% wt in toluene, 0.1 mL) was added dropwise to a solution of 2-{4-[2-(2-fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazole-4-carboxylic acid ethyl ester (0.0104 g, 0.017 mmol) in toluene. Effervescence was observed and after 20 min, the reaction was quenched with H2O, NaOH and extracted with EtOAc. The organic layer was washed with H2O, dried over Na2SO4, filtered and concentrated to give 5.9 mg of crude (2-{4-[2-(2-fluoro-5-trifluoromethyl-phenylamino)-1-methyl-1H-benzoimidazol-5-yloxy]-pyridin-2-yl}-5-trifluoromethyl-1H-imidazol-4-yl)-methanol which was further purified by RP HPLC (reverse phase HPLC) to give 1.1 mg of the pure compound (98% purity). LCMS m/z 567.1 (MH+), Rt 2.40 min.
Reaction SMILES: O1CCCCC1[O:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][F:22])[C:15]([O:17][CH3:18])=[O:16]>CO>[OH:7][C:8]1[CH:13]=[CH:12][CH:11]=[CH:10][C:9]=1[C:14](=[CH:19][O:20][CH2:21][F:22])[C:15]([O:17][CH3:18])=[O:16]
Reactant: COC(=O)C(=COCF)c1ccccc1OC1CCCCO1
Solvent: CO
Product: COC(=O)C(=COCF)c1ccccc1O
Yield: 72.9 %

Procedure:
6.2 g (0.02 mol) of methyl 2-[2-(tetrahydropyran-2-yloxy)-phenyl]-3-fluoromethoxy-acrylate are stirred in 30 ml of methanol at 20° C. for 18 hours with 0.5 g of acidic ion exchanger. The ion exchanger is filtered off and the filtrate is concentrated. The residue is chromatographed on silica gel using hexane/acetone (7:3). 3.3 g (73% of theory) of methyl 2-(2-hydroxyphenyl)-3-fluoromethoxy-acrylate are obtained as a pale yellow, viscous oil.
Reaction SMILES: Cl.[NH2:2][C:3](=[NH:10])[CH2:4][C:5]([O:7][CH2:8][CH3:9])=[O:6].[O-]CC.[Na+].Br[CH2:16][C:17]([C:19]1[CH:28]=[CH:27][CH:26]=[C:25]2[C:20]=1[N:21]=[C:22]([F:30])[C:23]([CH3:29])=[N:24]2)=O>CCO>[NH2:10][C:3]1[NH:2][C:17]([C:19]2[CH:28]=[CH:27][CH:26]=[C:25]3[C:20]=2[N:21]=[C:22]([F:30])[C:23]([CH3:29])=[N:24]3)=[CH:16][C:4]=1[C:5]([O:7][CH2:8][CH3:9])=[O:6]
Reactant: Cc1nc2cccc(C(=O)CBr)c2nc1F
Reactant: CCOC(=O)CC(=N)N
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CCO
Product: CCOC(=O)c1cc(-c2cccc3nc(C)c(F)nc23)[nH]c1N
Temperature: 0 °C
Reaction time: 0.17 h
Yield: 52.3 %

Procedure:
A glass microwave reaction vessel was charged with ethyl 3-amino-3-iminopropanoate hydrochloride (1.248 g, 7.49 mmol, Tyger Scientific, Inc., Ewing, N.J.) in EtOH (5 mL) and the solution was cooled to 0° C. Sodium ethoxide (21% w/w solution in EtOH; 2.80 mL, 7.49 mmol) was added dropwise and a precipitate was formed. After 10 min, 2-bromo-1-(3-fluoro-2-methylquinoxalin-5-yl)ethanone (Example 126h; 1.06 g, 3.74 mmol) was added, and the reaction was stirred at RT for 3 h. The reaction was quenched with water and extracted with DCM. The combined organic layers were dried (MgSO4), filtered and concentrated. The residue was purified with silica gel chromatography (10-25% EtOAc in Hexanes) to give ethyl 2-amino-5-(3-fluoro-2-methylquinoxalin-5-yl)-1H-pyrrole-3-carboxylate (615 mg, 1.957 mmol, 52% yield) as an orange solid. MS (ESI, pos. ion) m/z: 315.0 (M+1).
Reaction SMILES: [CH2:1]([O:8][C:9]([NH:11][C@@H:12]([C:17]([OH:19])=O)[CH2:13][C:14](=[O:16])[NH2:15])=[O:10])[C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.Cl.[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH2:25].C1(P(N=[N+]=[N-])(C2C=CC=CC=2)=O)C=CC=CC=1>CN(C)C=O.C(N(CC)CC)C>[CH3:21][O:22][C:23](=[O:30])[C@H:24]([CH2:26][CH:27]([CH3:29])[CH3:28])[NH:25][C:17](=[O:19])[C@@H:12]([CH2:13][C:14](=[O:16])[NH2:15])[NH:11][C:9]([O:8][CH2:1][C:2]1[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1)=[O:10]
Reactant: COC(=O)[C@@H](N)CC(C)C
Reactant: NC(=O)C[C@@H](NC(=O)OCc1ccccc1)C(=O)O
Agent: Cl
Agent: [N-]=[N+]=NP(=O)(c1ccccc1)c1ccccc1
Solvent: CN(C)C=O
Solvent: CCN(CC)CC
Product: COC(=O)[C@H](CC(C)C)NC(=O)[C@@H](CC(N)=O)NC(=O)OCc1ccccc1
Temperature: 5 °C
Reaction time: 72 h

Procedure:
Nα -Benzyloxycarbonyl-D-asparagine, 5.325 g., and 3.814 g. of leucine methyl ester hydrochloride are dissolved in 50 ml. of dimethylformamide. The solution is cooled to 5° C. and treated slowly with 3.0 ml. of diphenylphosphorylazide in 10 ml. of dimethylformamide and 5.9 ml. of triethylamine in 10 ml. of dimethylformamide. The reaction is stirred with ice cooling for two and a half hours and at room temperature for three days. The mixture is filtered and the filtrate evaporated to dryness under reduced pressure. The residue is crystallized from ethyl acetate; 2.5 g.; m.p. 191°-193° C.; [α]D25 -14.4° (c 1.015, DMF). A further quantity of material, 1.25 g., is obtainable from the mother liquor of the crystallization.