Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[C:6]([OH:8])[C:5]([C:9]2[CH:14]=[CH:13][N:12]=[N:11][CH:10]=2)=[CH:4][C:3]=1[C:15]1[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=1.[Cl:22][C:23]1[C:24](F)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:31])=[O:30])[CH:28]=1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O>[Cl:22][C:23]1[C:24]([O:8][C:6]2[C:5]([C:9]3[CH:14]=[CH:13][N:12]=[N:11][CH:10]=3)=[CH:4][C:3]([C:15]3[CH:20]=[CH:19][C:18]([F:21])=[CH:17][CH:16]=3)=[C:2]([Cl:1])[CH:7]=2)=[CH:25][C:26]([F:49])=[C:27]([S:29]([N:32]([CH2:38][C:39]2[CH:44]=[CH:43][C:42]([O:45][CH3:46])=[CH:41][C:40]=2[O:47][CH3:48])[C:33]2[S:34][CH:35]=[N:36][N:37]=2)(=[O:30])=[O:31])[CH:28]=1
Reactant: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(F)cc2F)c(OC)c1
Reactant: Oc1cc(Cl)c(-c2ccc(F)cc2)cc1-c1ccnnc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CS(C)=O
Product: COc1ccc(CN(c2nncs2)S(=O)(=O)c2cc(Cl)c(Oc3cc(Cl)c(-c4ccc(F)cc4)cc3-c3ccnnc3)cc2F)c(OC)c1
Temperature: 20 °C
Reaction time: 18 h
Yield: 61.6 %

Procedure:
2-Chloro-4′-fluoro-5-(pyridazin-4-yl)biphenyl-4-ol (Preparation 71, 148 mg, 0.49 mmol) was dissolved in dimethylsulfoxide (3 mL) and 5-chloro-N-(2,4-dimethoxybenzyl)-2,4-difluoro-N-(1,3,4-thiadiazol-2-yl)benzenesulfonamide (Preparation 16, 273 mg, 0.59 mmol) and potassium carbonate (204 mg, 1.48 mmol) were added. The reaction was stirred at 20° C. for 18 hours and then partitioned between water and ethyl acetate. The aqueous phase was separated and extracted with ethyl acetate. The combined organic extracts were washed with brine, dried over MgSO4, filtered and concentrated in vacuo. The residue was purified by silica gel column chromatography (20% heptane in ethyl acetate) to give the title compound (224 mg, 62%) as an off-white solid.
Reaction SMILES: C([NH:5][C:6]([C:8]1[CH:9]=[C:10]2[C:15](=[CH:16][CH:17]=1)[N:14]=[C:13]([C:18]1[O:19][C:20]3[CH:26]=[CH:25][C:24]([F:27])=[CH:23][C:21]=3[CH:22]=1)[C:12]([N:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])=[N:11]2)=O)(C)(C)C.C(OC(C(F)(F)F)=O)(C(F)(F)F)=O>ClCCl>[F:27][C:24]1[CH:25]=[CH:26][C:20]2[O:19][C:18]([C:13]3[C:12]([N:28]([CH3:32])[CH:29]([CH3:31])[CH3:30])=[N:11][C:10]4[C:15](=[CH:16][CH:17]=[C:8]([C:6]#[N:5])[CH:9]=4)[N:14]=3)=[CH:22][C:21]=2[CH:23]=1
Reactant: CC(C)N(C)c1nc2cc(C(=O)NC(C)(C)C)ccc2nc1-c1cc2cc(F)ccc2o1
Solvent: O=C(OC(=O)C(F)(F)F)C(F)(F)F
Solvent: ClCCl
Product: CC(C)N(C)c1nc2cc(C#N)ccc2nc1-c1cc2cc(F)ccc2o1
Reaction time: 8 h
Yield: 80.4 %

Procedure:
To a solution of N-tert-butyl-2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carboxamide (600 mg, crude) in dichloromethane (30 ml) was added TFAA (3 ml) with stifling overnight at room temperature. The reaction mixture was quenched with water (80 ml) and adjusted to pH 8 with sodium bicarbonate solution, extracted with dichloromethane (4×50 ml), and the organic layers combined and concentrated in vacuo to give the residue, which was purified by silica gel column chromatography (1% ethyl acetate in petroleum ether) to afford 2-(5-fluorobenzofuran-2-yl)-3-[methyl(propan-2-yl)amino]quinoxaline-6-carbonitrile as a yellow solid (400 mg, 80%).
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][C:5]([C:8](=[CH:14][C:15]2[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=[C:17]([O:23][CH3:24])[CH:16]=2)[C:9]([N:11]([CH3:13])[CH3:12])=[O:10])=[CH:4][CH:3]=1.[C:25](Cl)(=[O:32])[C:26]1[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=1>C1C=CC=CC=1>[CH3:24][O:23][C:17]1[CH:16]=[C:15]([CH:14]=[C:8]([C:5]2[CH:6]=[CH:7][C:2]([NH:1][C:25](=[O:32])[C:26]3[CH:31]=[CH:30][CH:29]=[CH:28][CH:27]=3)=[CH:3][CH:4]=2)[C:9](=[O:10])[N:11]([CH3:13])[CH3:12])[CH:20]=[C:19]([O:21][CH3:22])[CH:18]=1
Reactant: O=C(Cl)c1ccccc1
Reactant: COc1cc(C=C(C(=O)N(C)C)c2ccc(N)cc2)cc(OC)c1
Solvent: c1ccccc1
Product: COc1cc(C=C(C(=O)N(C)C)c2ccc(NC(=O)c3ccccc3)cc2)cc(OC)c1
Temperature: 90 °C

Procedure:
A mixture of 2-(4-aminophenyl)-3-(3,5-dimethoxyphenyl)-N,N-dimethylacrylamide, 43, (0.49 g, 1.2 mmol) and benzoyl chloride (0.26 g, 1.8 mmol) in anhydrous benzene (18.0 mL) was heated at 90° C. for 2 h. Solvent was evaporated and crude product was purified by silica gel chromatography.
Reaction SMILES: Cl.[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][NH:22][CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:7]=[CH:6][CH:5]=[CH:4][CH:3]=1.[C:25]1([C:31]2[CH:35]=[C:34]([CH:36]=O)[O:33][N:32]=2)[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=1>>[C:2]1([C:8]2[C:12]3=[C:13]([NH:17][CH2:18][CH:19]4[CH2:24][CH2:23][N:22]([CH2:36][C:34]5[O:33][N:32]=[C:31]([C:25]6[CH:26]=[CH:27][CH:28]=[CH:29][CH:30]=6)[CH:35]=5)[CH2:21][CH2:20]4)[N:14]=[N:15][CH:16]=[C:11]3[O:10][N:9]=2)[CH:3]=[CH:4][CH:5]=[CH:6][CH:7]=1
Reactant: c1ccc(-c2noc3cnnc(NCC4CCNCC4)c23)cc1
Reactant: O=Cc1cc(-c2ccccc2)no1
Agent: Cl
Product: c1ccc(-c2cc(CN3CCC(CNc4nncc5onc(-c6ccccc6)c45)CC3)on2)cc1

Procedure:
According to the same procedure described in Example 35, using the compound obtained in Example 84 instead of the compound obtained in Example 11 and the aldehyde obtained in Example 7 instead of 4-phenylthiophene-2-carbaldehyde, the title compound having the following physical data was obtained.
Reaction SMILES: C([O:9][CH2:10][C:11]#[C:12][C:13](=O)[C:14]1[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=1)(=O)C1C=CC=CC=1.[CH3:21][NH:22][NH2:23].[OH-].[Li+]>C(O)C.O>[CH3:21][N:22]1[C:11]([CH2:10][OH:9])=[CH:12][C:13]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)=[N:23]1
Reactant: O=C(C#CCOC(=O)c1ccccc1)c1ccccc1
Reactant: CNN
Agent: [Li+]
Agent: [OH-]
Solvent: CCO
Solvent: O
Product: Cn1nc(-c2ccccc2)cc1CO
Temperature: 25 °C
Reaction time: 2 h
Yield: 63.7 %

Procedure:
A solution of 4-oxo-4-phenylbut-2-yn-1-yl benzoate (1a) (750 mg, 2.84 mmol) and methylhydrazine (0.30 mL, 5.68 mmol) in ethanol (25 mL) was stirred overnight at room temperature. The reaction mixture was concentrated in vacuo and the residue was taken in a mixture of ethanol (3 mL) and tetrahydrofuran (9 mL). Lithium hydroxide (204 mg, 8.51 mmol), previously dissolved in water (3 mL) was added and the mixture was stirred at room temperature for 2 hours. Ethanol and tetrahydrofuran were removed under reduced pressure and the resulting aqueous layer was extracted with ethyl acetate (2×5 mL). The organic layer was successively washed with a saturated solution of sodium hydrogenocarbonate (5 mL) and brine (5 mL) before being dried over sodium sulfate and concentrated in vacuo. The residue was purified by flash chromatography on silica gel (cyclohexane/ethyl acetate 100/0 to 50/50) to provide (1-methyl-3-phenyl-1H-pyrazol-5-yl)methanol (1b) (341 mg, 1.81 mmol, 64%).
Reaction SMILES: [CH2:1]([O:3][C:4]1[CH:5]=[C:6]([C@H:12]([N:19]2[C:27](=[O:28])[C:26]3[C:21](=[CH:22][CH:23]=[CH:24][C:25]=3[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]2)[CH2:13][CH2:14][N:15]([CH:17]=[O:18])[OH:16])[CH:7]=[CH:8][C:9]=1[O:10][CH3:11])[CH3:2].[C:35](OC(=O)C)(=[O:37])[CH3:36]>C(#N)C>[C:35]([O:16][N:15]([CH2:14][CH2:13][C@@H:12]([N:19]1[C:27](=[O:28])[C:26]2[C:21](=[CH:22][CH:23]=[CH:24][C:25]=2[NH:29][C:30](=[O:34])[CH:31]([CH3:33])[CH3:32])[CH2:20]1)[C:6]1[CH:7]=[CH:8][C:9]([O:10][CH3:11])=[C:4]([O:3][CH2:1][CH3:2])[CH:5]=1)[CH:17]=[O:18])(=[O:37])[CH3:36]
Reactant: CCOc1cc([C@@H](CCN(O)C=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reactant: CC(=O)OC(C)=O
Solvent: CC#N
Product: CCOc1cc([C@@H](CCN(C=O)OC(C)=O)N2Cc3cccc(NC(=O)C(C)C)c3C2=O)ccc1OC
Reaction time: 4 h
Yield: 64.1 %

Procedure:
To a solution of (1R)-N-{2-[1-(3-ethoxy-4-methoxy-phenyl)-3-(N-formyl-N-hydroxy-amino)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide (300 mg, 0.64 mmol) in acetonitrile (6 mL) was added acetic anhydride (0.1 mL, 1 mmol) at room temperature. After 4 h, the solvent was removed in vacuo and the residue was purified by chromatography (Silica Gel) to give (1R)-N-{2-[3-(N-acetoxy-N-formyl-amino)-1-(3-ethoxy-4-methoxy-phenyl)-propyl]-3-oxo-2,3-dihydro-1H-isoindol-4-yl}-isobutyramide as a white solid (0.21 g, 64% yield): mp: 72-74° C. 1H NMR (DMSO-d6) δ 1.17 (d, J=7 Hz, 6H, 2CH3), 1.31 (t, J=7 Hz, 3H, CH3), 2.19 (s, 3H, CH3), 2.32-2.50 (m, 2H, CH2), 2.59-2.68 (m, 1H, CH), 3.60-3.67 (m, 2H, CH2), 3.73 (s, 3H, CH3), 3.99-4.09 (m, 3H, NCHH, CH2), 4.56 (d, J=17 Hz, 1H, NCHH), 5.30-5.38 (m, 1H, NCH), 6.88-6.93 (m, 3H, Ar), 7.18 (d, J=8 Hz, 1H, Ar), 7.50 (t, J=8 Hz, 1H, Ar), 8.11 (s, 1H, CH), 8.29 (d, J=8 Hz, 1H, Ar), 10.47 (s, 1H, NH); 13C NMR (DMSO-d6) δ 14.69, 18.01, 19.16, 28.87, 35.94, 45.87, 46.13, 51.18, 55.45, 63.80, 111.96, 112.32, 116.55, 117.55, 119.76, 131.30, 132.79, 137.14, 142.32, 147.99, 148.59, 157.50, 163.00, 167.31, 168.57, 174.94; Anal Calcd for C27H33N3O7+0.2 H2O: C, 62.95; H, 6.53; N, 8.16; H2O, 0.70. Found: C, 62.81; H, 6.63; N, 7.92; H2O, 0.59.
Reaction SMILES: C([O:3][C:4](=[O:34])[CH2:5][CH2:6][C:7]1[CH:12]=[CH:11][C:10]([O:13][C:14]2[CH:19]=[C:18]([CH3:20])[CH:17]=[C:16]([O:21][C:22]3[CH:27]=[CH:26][C:25]([C:28]([F:31])([F:30])[F:29])=[CH:24][C:23]=3Br)[CH:15]=2)=[CH:9][C:8]=1[CH3:33])C.[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1B(O)O>>[F:35][C:36]1[CH:41]=[CH:40][CH:39]=[CH:38][C:37]=1[C:23]1[CH:24]=[C:25]([C:28]([F:29])([F:31])[F:30])[CH:26]=[CH:27][C:22]=1[O:21][C:16]1[CH:15]=[C:14]([CH:19]=[C:18]([CH3:20])[CH:17]=1)[O:13][C:10]1[CH:11]=[CH:12][C:7]([CH2:6][CH2:5][C:4]([OH:3])=[O:34])=[C:8]([CH3:33])[CH:9]=1
Reactant: CCOC(=O)CCc1ccc(Oc2cc(C)cc(Oc3ccc(C(F)(F)F)cc3Br)c2)cc1C
Reactant: OB(O)c1ccccc1F
Product: Cc1cc(Oc2ccc(CCC(=O)O)c(C)c2)cc(Oc2ccc(C(F)(F)F)cc2-c2ccccc2F)c1

Procedure:
The tile compound is prepared by reacting 3-{4-[3-(2-bromo-4-trifluoromethyl-phenoxy)-5-methyl-phenoxy]-2-methyl-phenyl}-propionic acid ethyl ester with 2-fluorobenzene boronic acid as in Example 38 to afford 0.216 g (88%). 1H NMR (400 MHz, CDCl3); HRMS (ES+) m/z exact mass calculated for C30H25O4F4 525.1689, found 525.1675.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[CH:10][C:5]2[C:6](=[O:9])[CH2:7][O:8][C:4]=2[C:3]=1[CH2:12][N:13]1[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]1.[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2[CH:36]=O.N1CCCCC1>CO>[Cl:26][C:27]1[CH:28]=[C:29]2[C:33](=[CH:34][CH:35]=1)[NH:32][CH:31]=[C:30]2/[CH:36]=[C:7]1\[O:8][C:4]2[C:3]([CH2:12][N:13]3[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]3)=[C:2]([OH:1])[CH:11]=[CH:10][C:5]=2[C:6]\1=[O:9]
Reactant: O=Cc1c[nH]c2ccc(Cl)cc12
Reactant: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2OCC3=O)CC1
Solvent: C1CCNCC1
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(Cc2c(O)ccc3c2O/C(=C\c2c[nH]c4ccc(Cl)cc24)C3=O)CC1
Temperature: 60 °C
Reaction time: 3 h
Yield: 49.9 %

Procedure:
A solution of tert-butyl 4-[(6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl)methyl]piperazine-1-carboxylate (0.100 g, 0.287 mmol) obtained in Example A16, Step 1 in methanol (1.2 mL) was added with 5-chloro-1H-indole-3-carboxaldehyde (0.0515 g, 0.287 mmol) and piperidine (0.00244 g, 0.0287 mmol), and the mixture was stirred at 60° C. for 3 hours. The reaction mixture was cooled to room temperature, and added with methanol (4 mL), and the solid was suspended in methanol and thereby washed to obtain tert-butyl (Z)-4-({2-[(5-chloro-1H-indol-3-yl)methylene]-6-hydroxy-3-oxo-2,3-dihydrobenzofuran-7-yl}methyl)piperazine-1-carboxylate (0.0730 g, 49%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:4]=[C:5](B(O)O)[CH:6]=[CH:7][CH:8]=1.Br[C:13]1[CH:18]=[CH:17][C:16]([C:19]2[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]3[CH2:30][CH2:29][CH2:28][C@H:27]3[CH3:31])[N:23]=2)=[CH:15][CH:14]=1>>[CH3:1][O:2][C:3]1[CH:4]=[C:5]([C:13]2[CH:18]=[CH:17][C:16]([C:19]3[O:20][C:21]([CH3:32])=[C:22]([CH2:24][CH2:25][N:26]4[CH2:30][CH2:29][CH2:28][C@H:27]4[CH3:31])[N:23]=3)=[CH:15][CH:14]=2)[CH:6]=[CH:7][CH:8]=1
Reactant: COc1cccc(B(O)O)c1
Reactant: Cc1oc(-c2ccc(Br)cc2)nc1CCN1CCC[C@H]1C
Product: COc1cccc(-c2ccc(-c3nc(CCN4CCC[C@H]4C)c(C)o3)cc2)c1

Procedure:
The title compound is prepared in a manner substantially analogous to example 133 starting from 3-methoxybenzene boronic acid (218 mg, 1.43 mmol) and 2-(4-Bromo-phenyl)-5-methyl-4-[2-((R)-2-methyl-pyrrolidin-1-yl)-ethyl]-oxazole (100 mg, 0.287 mmol) to give 21 mg (19%). MS (m/e) 377.2 (M+1)
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[C:9]2[C:5]([C:6]([CH3:14])([CH3:13])[C:7](=[O:12])[N:8]2[CH3:11])=[CH:4][C:3]=1[F:15].[C:16](O)(=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1>>[F:15][C:3]1[CH:4]=[C:5]2[C:9](=[CH:10][C:2]=1[NH:1][C:16](=[O:23])[C:17]1[CH:22]=[CH:21][N:20]=[CH:19][CH:18]=1)[N:8]([CH3:11])[C:7](=[O:12])[C:6]2([CH3:13])[CH3:14]
Reactant: O=C(O)c1ccncc1
Reactant: CN1C(=O)C(C)(C)c2cc(F)c(N)cc21
Product: CN1C(=O)C(C)(C)c2cc(F)c(NC(=O)c3ccncc3)cc21

Procedure:
Prepared in analogy to example 17 from 6-amino-5-fluoro-1,3,3-trimethylindolin-2-one and isonicotinic acid. The title compound was obtained as white powder.
Reaction SMILES: [F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH2:7])=[CH:4][CH:3]=1.C(N(CC)CC)C.[Cl:17][CH2:18][C:19](Cl)=[O:20]>O1CCCC1>[F:1][C:2]1[CH:9]=[CH:8][C:5]([CH2:6][NH:7][C:19](=[O:20])[CH2:18][Cl:17])=[CH:4][CH:3]=1
Reactant: O=C(Cl)CCl
Reactant: NCc1ccc(F)cc1
Solvent: C1CCOC1
Solvent: CCN(CC)CC
Product: O=C(CCl)NCc1ccc(F)cc1
Temperature: 25 °C
Reaction time: 0.17 h
Yield: 90.1 %

Procedure:
To a stirred mixture of 4-fluorobenzylamine (685 uL, 6.0 mmol) and dry tetrahydrofuran (20 mL) was added triethylamine (1.25 mL, 9.0 mmol) under nitrogen. The resulting mixture was stirred for 10 minutes at ambient temperature. Next, chloroacetyl chloride (477 uL, 6.0 mmol) was added and the resulting mixture was stirred for 1 h. at ambient temperature. The resulting mixture was partitioned between ethyl acetate and water. The organic layer was washed with water (2×20 mL) and brine (1×20 mL), dried over magnesium sulfate, and filtered. Evaporation of the filtrate in vacuo followed by chromatography on silica gel eluting with ethyl acetate-hexane gave 1.09 g (91%) of the pure title compound.
Reaction SMILES: Br[CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4].[CH3:13][O:14][CH2:15][CH2:16][NH:17][CH2:18][CH2:19][O:20][CH3:21]>ClCCl>[CH3:13][O:14][CH2:15][CH2:16][N:17]([CH2:2][C:3]([O:5][CH2:6][C:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1)=[O:4])[CH2:18][CH2:19][O:20][CH3:21]
Reactant: O=C(CBr)OCc1ccccc1
Reactant: COCCNCCOC
Solvent: ClCCl
Product: COCCN(CCOC)CC(=O)OCc1ccccc1
Reaction time: 0.5 h

Procedure:
A solution of benzyl bromoacetate (28.9 g; 96.7 mmol) in dichloromethane (100 mL) at room temperature was treated with 2-methoxy-N-(2-methoxyethyl)ethanamine (40.6 g; 305 mmol), stirred for 30 minutes, diluted with dichloromethane, washed sequentially with saturated NH4Cl, water, and brine, dried (Na2SO4), filtered, and concentrated. The concentrate was purified by flash column chromatography on silica gel with 40% diethyl ether/dichloromethane to provide the desired product.
Reaction SMILES: C(NC1CCCCC1)(C)C.C([Li])CCC.[CH3:16][O:17][C:18](=[O:30])[CH2:19][C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=1.[Cl:31][C:32]1[N:37]=[C:36]([Cl:38])[C:35]([CH2:39]I)=[CH:34][N:33]=1>O1CCCC1.C(OCC)(=O)C>[CH3:16][O:17][C:18](=[O:30])[CH:19]([C:20]1[CH:25]=[C:24]([O:26][CH3:27])[CH:23]=[C:22]([O:28][CH3:29])[CH:21]=1)[CH2:39][C:35]1[C:36]([Cl:38])=[N:37][C:32]([Cl:31])=[N:33][CH:34]=1
Reactant: Clc1ncc(CI)c(Cl)n1
Reactant: COC(=O)Cc1cc(OC)cc(OC)c1
Agent: CC(C)NC1CCCCC1
Agent: [Li]CCCC
Solvent: C1CCOC1
Solvent: CCOC(C)=O
Product: COC(=O)C(Cc1cnc(Cl)nc1Cl)c1cc(OC)cc(OC)c1
Temperature: -78 °C
Reaction time: 0.5 h

Procedure:
To a solution of N-isopropylcyclohexylamine (1.44 g, 10.0 mmol) (Aldrich) in dry tetrahydrofuran (20 mL) was added n-butyllithium (2.5 M in hexanes, 4.0 mL, 10.0 mmol) (Aldrich) at −78° C. under argon. After 30 minutes, a solution of 3,5-dimethoxy-phenyl-acetic acid methyl ester (2.05 g, 9.76 mmol) (from Example 3a supra) in tetrahydrofuran (5 mL) was added by injection via a syringe and the reaction mixture was stirred at −78° C. for another 30 minutes. To this reaction mixture was added a solution of 2,4-dichloro-5-iodomethyl-pyrimidine (1.45 g, 5.0 mmol) (from Example 1c supra) in tetrahydrofuran (5 mL) at −78° C. and the reaction mixture was stirred at the same temperature for 1 hour then slowly allowed to warm up to −30° C. and stirred for 10 minutes. The reaction mixture was diluted with ethyl acetate (100 mL) and successively washed with saturated aqueous ammonium chloride solution (100 mL), water (50 mL) and brine (50 mL), dried over anhydrous sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by flash column chromatography to give 3-(2,4-dichloro-pyrimidin-5-yl)-2-(3,5-dimethoxy-phenyl)-propionic acid methyl ester as a colorless oil. (Yield 1.45 g, 78.0%).
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([OH:7])=O.Cl.[CH2:14]([O:16][CH2:17][CH2:18][N:19]1[C:23]2[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=2[N:21]=[C:20]1[N:28]1[CH2:34][CH2:33][CH2:32][N:31]([CH2:35][CH2:36][C:37]2([C:42]3[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=3)[CH2:41][CH2:40][NH:39][CH2:38]2)[CH2:30][CH2:29]1)[CH3:15]>>[CH3:1][O:2][C:3]1[CH:11]=[CH:10][C:9]([F:12])=[CH:8][C:4]=1[C:5]([N:39]1[CH2:40][CH2:41][C:37]([CH2:36][CH2:35][N:31]2[CH2:32][CH2:33][CH2:34][N:28]([C:20]3[N:19]([CH2:18][CH2:17][O:16][CH2:14][CH3:15])[C:23]4[CH:24]=[CH:25][CH:26]=[CH:27][C:22]=4[N:21]=3)[CH2:29][CH2:30]2)([C:42]2[CH:47]=[CH:46][CH:45]=[CH:44][CH:43]=2)[CH2:38]1)=[O:7]
Reactant: COc1ccc(F)cc1C(=O)O
Reactant: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCNC3)CC2)nc2ccccc21
Agent: Cl
Product: CCOCCn1c(N2CCCN(CCC3(c4ccccc4)CCN(C(=O)c4cc(F)ccc4OC)C3)CC2)nc2ccccc21

Procedure:
Prepare by the method of Example 56.1 using 2-methoxy-5-fluorobenzoic acid and 3-(2-(4-(1-(2-ethoxyethyl)-1H-benzimidazol-2-yl)[1,4]diazepan-1-yl)ethyl)-3-phenylpyrrolidine hydrochloric acid salt (prepared from (−)-3-phenyl-3-(2-hydroxyethyl)pyrrolidine (R,R)-di-p-anisoyltartaric acid salt) to give the title compound.
Reaction SMILES: [NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([OH:24])=O)=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:17]=[CH:16][CH:15]=[CH:14][CH:13]=1)=[O:9].Cl.[NH2:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35].CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.C(N(C(C)C)C(C)C)C>CN(C=O)C>[NH:1]([C:28]([CH3:30])=[O:29])[C@@H:2]([C:18]([N:20]1[CH2:27][CH2:26][CH2:25][C@@H:21]1[C:22]([NH:32][C@@H:33]([C:37]([NH2:39])=[O:38])[CH:34]([CH3:36])[CH3:35])=[O:24])=[O:19])[CH2:3][CH2:4][CH2:5][CH2:6][NH:7][C:8]([O:10][CH2:11][C:12]1[CH:13]=[CH:14][CH:15]=[CH:16][CH:17]=1)=[O:9]
Reactant: CC(C)[C@@H](N)C(N)=O
Reactant: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)O
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CN(C)C=O
Solvent: CCN(C(C)C)C(C)C
Product: CC(=O)N[C@H](CCCCNC(=O)OCc1ccccc1)C(=O)N1CCC[C@@H]1C(=O)N[C@@H](C(N)=O)C(C)C
Temperature: 5 °C
Reaction time: 1.65 h

Procedure:
In an inert thermostable reactor provided with a mechanical stirrer, 94.25 g of Ac-D-Lys(Z)-D-Pro-OH (XI) (224.7 mmol) are introduced followed by 470 ml of DMF. 32.58 g of HCl. H-D-Val-NH2 (V) (213.5 mmol, 0.95 eq) and 85.22 g of HBTU (1 eq) are then added. The medium is cooled down to 5° C., and 96.6 ml of ethyldiisopropylamine (2.5 eq) are added dropwise within 15 minutes. This is allowed to reach 0° C. again and after 1.30 to 2 hours, a strong crystallization could be observed. The reaction completion is CCM controlled. The reaction medium is then poured onto 2350 ml of AcOEt, stirred for 15 minutes, filtered and washed successively with 470 ml of AcOEt and 470 ml of diisopropyl ether. The derivate (XII) is vacuum dried at 25° C. This way, 107.2 g (92%) pf Ac-D-Lys(Z)-D-Pro-D-Val-NH2 are obtained.
Reaction SMILES: C(OP([CH2:9][C:10]#[N:11])(OCC)=O)C.[H-].[Na+].[F:14][C:15]1[CH:20]=[CH:19][C:18]([C:21]2[NH:22][CH:23]=[C:24]([CH:32]=O)[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:17][CH:16]=1.O>O1CCCC1>[F:14][C:15]1[CH:16]=[CH:17][C:18]([C:21]2[NH:22][CH:23]=[C:24]([CH:32]=[CH:9][C:10]#[N:11])[C:25]=2[C:26]2[CH:31]=[CH:30][N:29]=[CH:28][CH:27]=2)=[CH:19][CH:20]=1
Reactant: CCOP(=O)(CC#N)OCC
Reactant: O=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Agent: [H-]
Agent: [Na+]
Solvent: C1CCOC1
Solvent: O
Product: N#CC=Cc1c[nH]c(-c2ccc(F)cc2)c1-c1ccncc1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 67.7 %

Procedure:
2.92 ml (18.02 mmol) of diethylphosphonoacetonitrile were added to 16 ml of tetrahydrofuran and the resulting solution was added to a suspension of 786 mg (18.02 mmol) of 55% sodium hydride in 60 ml of tetrahydrofuran with ice-cooling, and the resulting mixture was then stirred at room temperature for 1.5 hours. At the end of this time, a suspension of 4.00 g (15.02 mmol) of 2-(4-fluorophenyl)-4-formyl-3-(pyridin-4-yl)-1H-pyrrole [prepared as described in step (iii) above] in 30 ml of tetrahydrofuran was added to this mixture and the resulting mixture was stirred at room temperature for 1 hour. At the end of this time, water was added to the reaction mixture and the resulting mixture was extracted with ethyl acetate. The organic extract was washed with water, dried over anhydrous magnesium sulfate and then concentrated by evaporation under reduced pressure to afford a solid which was washed with diethyl ether to give 2.94 g (yield 68%) of the title compound as a pale brown powder.
Reaction SMILES: C(Cl)Cl.[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10](Cl)=[O:11])=[CH:8][CH:7]=1.[NH2:15][C:16]1[CH:28]=[C:27]([O:29][C:30]2[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=2)[CH:26]=[CH:25][C:17]=1[C:18]([O:20][C:21]([CH3:24])([CH3:23])[CH3:22])=[O:19].C(=O)([O-])O.[Na+]>C(N(CC)CC)C>[CH3:4][O:5][C:6]1[CH:14]=[CH:13][C:9]([C:10]([NH:15][C:16]2[CH:28]=[C:27]([O:29][C:30]3[CH:35]=[CH:34][CH:33]=[CH:32][CH:31]=3)[CH:26]=[CH:25][C:17]=2[C:18]([O:20][C:21]([CH3:22])([CH3:23])[CH3:24])=[O:19])=[O:11])=[CH:8][CH:7]=1
Reactant: COc1ccc(C(=O)Cl)cc1
Reactant: CC(C)(C)OC(=O)c1ccc(Oc2ccccc2)cc1N
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: COc1ccc(C(=O)Nc2cc(Oc3ccccc3)ccc2C(=O)OC(C)(C)C)cc1
Reaction time: 1 h

Procedure:
5.0 mL of methylene chloride, 0.056 mL of triethylamine and 51 mg of 4-methoxybenzoyl chloride were added sequentially to 57 mg of tert-butyl 2-amino-4-phenoxybenzoate at room temperature, and stirred at the same temperature for 1 hour. A saturated sodium hydrogen carbonate aqueous solution was added to the reaction mixture, and the organic layer was separated, and the solvent was evaporated under reduced pressure. The obtained residue was purified with silica gel column chromatography [Flash Tube 2008 manufacture by Trikonex Company, eluent; hexane:ethyl acetate=4:1]to obtain tert-butyl 2-(4-methoxybenzamido)-4-phenoxybenzoate.
Reaction SMILES: [C-:1]#[N:2].[Na+].[C:4]1([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[N:11]2[CH2:16][CH2:15][CH:14]([CH2:17]Cl)[CH2:13][CH2:12]2)[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=1.C([O-])(O)=O.[Na+]>CS(C)=O>[C:1]([CH2:17][CH:14]1[CH2:15][CH2:16][N:11]([CH:10]([C:19]2[CH:24]=[CH:23][CH:22]=[CH:21][CH:20]=2)[C:4]2[CH:9]=[CH:8][CH:7]=[CH:6][CH:5]=2)[CH2:12][CH2:13]1)#[N:2]
Reactant: [C-]#N
Reactant: ClCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CS(C)=O
Product: N#CCC1CCN(C(c2ccccc2)c2ccccc2)CC1
Temperature: 60 °C
Yield: 61.4 %

Procedure:
Step 3): NaCN (2.5 g, 51 mmol) was added to a solution of 1-diphenylmethyl-4-chloromethyl-piperidine (8.9 g, 29.7 mmol) in dimethyl sulfoxide (DMSO) (100 ml). The mixture was heated at 60° C. for 20 hours and then poured into 3% NaHCO3 solution and extracted with ethyl acetate. The organic layer was dried (MgSO4) and concentrated. The residue was purified by column chromatography on silica gel (10% ethyl acetate in hexane) to give 4-cyanomethyl-1-diphenylmethylpiperidine (61.4%): mp 103°-104° C. and 3-(2-cyanoethyl)-1-diphenylmethyl pyrrolidine (20.9%):oil.