Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: [NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4](Cl)[CH:3]=1.[NH:12]1[CH2:17][CH2:16][O:15][CH2:14][CH2:13]1.C(=O)([O-])[O-].[K+].[K+]>CS(C)=O.O>[NH2:1][C:2]1[C:9]([I:10])=[CH:8][C:5]([C:6]#[N:7])=[C:4]([N:12]2[CH2:17][CH2:16][O:15][CH2:14][CH2:13]2)[CH:3]=1
Reactant: C1COCCN1
Reactant: N#Cc1cc(I)c(N)cc1Cl
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CS(C)=O
Product: N#Cc1cc(I)c(N)cc1N1CCOCC1
Temperature: 100 °C
Reaction time: 40 h

Procedure:
To a flask containing 4-amino-2-chloro-5-iodobenzonitrile (1 g, 3.6 mmol) in DMSO (5.0 mL) was added morpholine (1.0 mL, 11.5 mmol) dropwise. Upon complete addition, the mixture was warmed to 100° C. After 40 h, the reaction mixture was cooled to rt, then an additional 2 mL of morpholine was added to the mixture. The reaction was re-heated to 100° C. and monitored with LC-MS. After 17 h, the reaction was cooled to rt, then 1 g of potassium carbonate was added in portions. The reaction was re-heated to 100° C. and monitored with LC-MS. After 13 days, the reaction was diluted with water then subsequently extracted five times with EtOAc. The organic extractions were then washed one time with brine and dried over anhydrous magnesium sulfate. After filtration and concentration, the residue was purified on silica gel (0-35% EtOAc in hexanes) to afford a pale brown solid as 4-amino-5-iodo-2-morpholinobenzonitrile. 1H NMR (500 MHz, CDCl3) δ ppm 7.80 (1H, m), 6.27 (1H, s), 4.57 (2H, br. s.), 3.92 (4H, m), 3.20 (4H, m). Mass Spectrum (pos.) m/e: 330.0 (M+H)+.
Reaction SMILES: [C:1]([OH:9])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1.O[N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17].C1(N=C=NC2CCCCC2)CCCCC1>O1CCOCC1>[C:1]([O:9][N:11]1[C:15](=[O:16])[CH2:14][CH2:13][C:12]1=[O:17])(=[O:8])[C:2]1[CH:7]=[CH:6][CH:5]=[N:4][CH:3]=1
Reactant: O=C1CCC(=O)N1O
Reactant: O=C(O)c1cccnc1
Agent: C(=NC1CCCCC1)=NC1CCCCC1
Solvent: C1COCCO1
Product: O=C(ON1C(=O)CCC1=O)c1cccnc1
Temperature: 25 °C
Reaction time: 3 h
Yield: 72 %

Procedure:
Nicotinic acid (4.025 g, 0.0327 mol) and N-hydroxysuccinimide (3.763 g, 0.0327 mol) were dissolved in 130 ml of dioxane. Dicyclohexylcarbodiimide (6.75 g, 0.032 mol in 20 ml of dioxane was added. The reaction mixture was then stirred at room temperature for 3 hours. The dicyclohexylurea which precipitated was removed by filtration and the solvent was removed by rotary evaporation. The crude product was recrystallized from ethyl acetate to give light yellow crystals which were then washed with anhydrous ether. The product, obtained in 72% yield (5.2 g) and melting at 129°-131° C., has the formula: ##STR1556##
Reaction SMILES: [F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH2:22])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2.[CH:23]([N:26]=[C:27]=[O:28])([CH3:25])[CH3:24]>>[F:1][C:2]1[CH:3]=[CH:4][CH:5]=[C:6]2[C:10]=1[CH:9]([NH:11][C:12]1[CH:21]=[CH:20][C:19]3[C:14](=[CH:15][CH:16]=[C:17]([NH:22][C:27]([NH:26][CH:23]([CH3:25])[CH3:24])=[O:28])[CH:18]=3)[N:13]=1)[CH2:8][CH2:7]2
Reactant: CC(C)N=C=O
Reactant: Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1
Product: CC(C)NC(=O)Nc1ccc2nc(NC3CCc4cccc(F)c43)ccc2c1

Procedure:
The title compound was prepared in accordance with the general method described in example 3 from rac-N2-(7-fluoro-indan-1-yl)-quinoline-2,6-diamine and isopropyl isocyanate; MS: m/e=379.4 (M+H+).
Reaction SMILES: [I:1]I.[CH3:3][CH:4]1[CH2:8][C:7]2[CH:9]=[C:10]([O:13][C:14]([F:17])([F:16])[F:15])[CH:11]=[CH:12][C:6]=2[O:5]1>C(Cl)(Cl)Cl.FC(F)(F)C([O-])=O.[Ag+]>[I:1][C:12]1[C:6]2[O:5][CH:4]([CH3:3])[CH2:8][C:7]=2[CH:9]=[C:10]([O:13][C:14]([F:15])([F:17])[F:16])[CH:11]=1
Reactant: II
Reactant: CC1Cc2cc(OC(F)(F)F)ccc2O1
Agent: [Ag+]
Agent: O=C([O-])C(F)(F)F
Solvent: ClC(Cl)Cl
Product: CC1Cc2cc(OC(F)(F)F)cc(I)c2O1
Temperature: 25 °C
Reaction time: 1 h
Yield: 99.3 %

Procedure:
Iodine (2.8 g, 11 mmol) was added in few portions to a stirred mixture of 2,3-dihydro-2-methyl-5-trifluoromethoxybenzofuran (Description 21; 2.8 g, 12.8 mmol), silver(I) trifluoroacetate (3.5 g, 15.8 mmol) in chloroform (60 ml). The mixture was stirred at room temperature for 1 hour, filtered through a pad of Celite™ and concentrated. The residue was treated with iso-hexane (150 ml), washed with aqueous sodium sulphite. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by chromatography on silica gel (iso-hexane:diethyl ether 0-4%) to give the title compound (3.76 g, 85%).
Reaction SMILES: Br[CH:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)[CH3:3].C([O-])(=[O:16])C.[Na+]>C(O)(=O)C>[C:2]([C:4]1[CH:13]=[CH:12][C:11]2[C:6](=[CH:7][CH:8]=[CH:9][CH:10]=2)[CH:5]=1)(=[O:16])[CH3:3]
Reactant: CC(=O)[O-]
Reactant: CC(Br)c1ccc2ccccc2c1
Agent: [Na+]
Solvent: CC(=O)O
Product: CC(=O)c1ccc2ccccc2c1

Procedure:
2-Acetylnaphthalene is prepared by treating 2-(1'-bromoethyl)naphthalene, prepared as described above, wtih sodium acetate in acetic acid to afford 2-(1'-acetonyethyl)naphthalene which upon base hydrolysis furnishes the 2-(1'-hydroxyethyl)naphthalene. The latter is oxidized with an equivalent of chromium trioxide in glacial acetic acid, or 8N sulfuric acid and acetone to furnish 2-acetylnaphthalene. 2-Carboxynaphthalene is prepared from 2-acetylnaphthalene by treating the latter with aqueous sodium hypochlorite. The 2-carboxynaphthalene is treated with diborane in an ether, such as diglyme (diethyleneglycol dimethyl ether), to yield 2-hydroxymethylnaphthalene.
Reaction SMILES: C(OC([NH:8][CH2:9][C:10]1[O:14][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:12][CH:11]=1)=O)(C)(C)C.FC(F)(F)C(O)=O>ClCCl>[NH2:8][CH2:9][C:10]1[O:14][C:13]([S:15]([NH2:18])(=[O:17])=[O:16])=[CH:12][CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1ccc(S(N)(=O)=O)o1
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: NCc1ccc(S(N)(=O)=O)o1
Temperature: 25 °C
Reaction time: 4 h
Yield: 98.6 %

Procedure:
To a flask, the 5-(tert-butoxycarbonylaminomethyl)furan-2-sulfonamide (5.2 g, 19 mmol) obtained above was added. 200 mL of a mixture of trifluoroacetic acid and dichloromethane (V/V=4:1) was then added to the flask. The reaction mixture was stirred at room temperature for 4 h. After the completion of the reaction, the reaction mixture was then concentrated to give 3.3 g (98.4% yield) of 5-(aminomethyl)furan-2-sulfonamide.
Reaction SMILES: CC[O-].[Na+].[C:5]([O:13]CC)(=O)[CH2:6][C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH2:16]([N:18]1[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21](=O)[O:20]C1=O)[CH3:17].Cl>CN(C)C=O>[CH2:10]([O:9][C:7]([C:6]1[C:5](=[O:13])[N:18]([CH2:16][CH3:17])[C:23]2[N:24]=[C:25]([C:28]3[CH:33]=[CH:32][CH:31]=[CH:30][CH:29]=3)[N:26]=[CH:27][C:22]=2[C:21]=1[OH:20])=[O:8])[CH3:11]
Reactant: CCn1c(=O)oc(=O)c2cnc(-c3ccccc3)nc21
Reactant: CCOC(=O)CC(=O)OCC
Agent: CC[O-]
Agent: Cl
Agent: [Na+]
Solvent: CN(C)C=O
Product: CCOC(=O)c1c(O)c2cnc(-c3ccccc3)nc2n(CC)c1=O

Procedure:
To a 40 ml. solution of NaOEt (1.0 g. Na-0.042 mole) was added 6.8 g. (0.042 mole) of diethyl malonate and this is stirred 10 minutes, then stripped to dryness. Dimethylformamide was added until a solution formed and to this was added 5.7 g. (0.021 mole) of 1-ethyl-7-phenyl-2H-pyrimido[4,5-d][1,3]oxazine-2,4(1H)-dione and the mixture heated at reflux for 2 hours. The reaction was then cooled and poured into dilute HCl and the resulting precipitate filtered off and rinsed well with water. Recrystallization with hexane-ethyl acetate gave 5.1 g. of the title product--m.p. 177°-180° C.
Reaction SMILES: [C:1]([C:3]1([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]1)#[CH:2].Br[C:12]1[CH:13]=[C:14]([CH2:18][CH2:19][CH2:20][NH:21][C:22](=[O:27])[C:23]([F:26])([F:25])[F:24])[CH:15]=[CH:16][CH:17]=1>>[F:24][C:23]([F:25])([F:26])[C:22]([NH:21][CH2:20][CH2:19][CH2:18][C:14]1[CH:15]=[CH:16][CH:17]=[C:12]([C:2]#[C:1][C:3]2([OH:10])[CH2:9][CH2:8][CH2:7][CH2:6][CH2:5][CH2:4]2)[CH:13]=1)=[O:27]
Reactant: C#CC1(O)CCCCCC1
Reactant: O=C(NCCCc1cccc(Br)c1)C(F)(F)F
Product: O=C(NCCCc1cccc(C#CC2(O)CCCCCC2)c1)C(F)(F)F

Procedure:
Coupling of 1-ethynylcycloheptanol with bromide 3, following the method used to prepare Example 17 gave 2,2,2-trifluoro-N-(3-(3-((1-hydroxycycloheptyl)ethynyl)phenyl)propyl)acetamide as a pale yellow oil. Yield (1.78 g, 60%): 1H NMR (400 MHz, DMSO-d6) δ 9.40 (s, 1H), 7.26 (t, J=7.6, 1H), 7.17-7.22 (m, 3H), 5.26 (s, 1H), 3.16 (q, J=6.0 Hz, 2H), 2.56 (t, J=7.2 Hz, 2H), 1.91-1.97 (m, 2H), 1.73-1.79 (m, 4H), 1.45-1.63 (m, 8H).
Reaction SMILES: [OH:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]4[CH:25]=[CH:24][C:23]([F:26])=[CH:22][CH:21]=4)[CH2:15][CH2:14]3)=[O:12])[O:7][C:6]=2[CH:34]=1.[C:35](Cl)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1>>[C:35]([O:1][C:2]1[CH:3]=[CH:4][C:5]2[O:10][CH:9]=[C:8]([C:11]([N:13]3[CH2:18][CH2:17][N:16]([CH:19]([C:27]4[CH:32]=[CH:31][C:30]([F:33])=[CH:29][CH:28]=4)[C:20]4[CH:21]=[CH:22][C:23]([F:26])=[CH:24][CH:25]=4)[CH2:15][CH2:14]3)=[O:12])[O:7][C:6]=2[CH:34]=1)(=[O:42])[C:36]1[CH:41]=[CH:40][CH:39]=[N:38][CH:37]=1
Reactant: O=C(Cl)c1cccnc1
Reactant: O=C(C1=COc2ccc(O)cc2O1)N1CCN(C(c2ccc(F)cc2)c2ccc(F)cc2)CC1
Product: O=C(Oc1ccc2c(c1)OC(C(=O)N1CCN(C(c3ccc(F)cc3)c3ccc(F)cc3)CC1)=CO2)c1cccnc1
Yield: 78 %

Procedure:
That compound is obtained in a yield of 78% starting from 7-hydroxy-2-{4-[bis-(4-fluorophenyl)methyl]piperazin-1-ylcarbonyl}-1,4-benzodioxin and nicotinoyl chloride by proceeding as for Example 53. ##STR76##
Reaction SMILES: [NH2:1][CH2:2][C:3]([NH:5][C@H:6]1[CH2:11][CH2:10][C@@H:9]([NH:12][C:13]([CH3:16])([CH3:15])[CH3:14])[CH2:8][C@H:7]1[CH2:17][CH2:18][CH2:19][CH3:20])=[O:4].Cl[C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1.C(N(CC)CC)C>C(O)C>[CH2:17]([C@@H:7]1[CH2:8][C@H:9]([NH:12][C:13]([CH3:14])([CH3:15])[CH3:16])[CH2:10][CH2:11][C@@H:6]1[NH:5][C:3](=[O:4])[CH2:2][NH:1][C:22]1[C:31]2[C:26](=[CH:27][CH:28]=[C:29]([Cl:32])[CH:30]=2)[N:25]=[CH:24][N:23]=1)[CH2:18][CH2:19][CH3:20]
Reactant: Clc1ccc2ncnc(Cl)c2c1
Reactant: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CN
Solvent: CCO
Solvent: CCN(CC)CC
Product: CCCC[C@@H]1C[C@H](NC(C)(C)C)CC[C@@H]1NC(=O)CNc1ncnc2ccc(Cl)cc12

Procedure:
Example 2ah, Step 1: A sample of 2-amino-N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)acetamide was combined with 4,6-dichloroquinazoline (1.2 equivalents) and triethylamine (1.2 equivalents) in ethanol. The resultant solution was heated at 100° C. in the microwvae for 1 hr. The reaction mixture was concentrated and the residue chromatographed on silica gel (eluting with 2-8% NH4OH/MeOH/CH2Cl2) to give N-((1S,2R,4R)-2-butyl-4-(tert-butylamino)cyclohexyl)-2-(6-chloroquinazolin-4-ylamino)acetamide. MS found: (M+H)+=446.44; 1H NMR (400 MHz, CDCl3) δ(TMS): 0.52-1.77 (m, 25H), 2.36-2.48 (m, 1H), 3.92-4.06 (m, 3H), 6.52-6.63 (M, 1H), 7.37-7.55 (m, 3H), 7.70-7.73 (m, 1H), 7.36-7.41 (m, 1H).
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.[CH2:14]([CH:17]1[CH2:22][CH2:21][CH:20]([CH:23]2[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]2)[CH2:19][CH2:18]1)[CH2:15][CH3:16].Cl>CCOCC.O>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:29])[CH2:25][CH2:24][CH:23]([CH:20]3[CH2:21][CH2:22][CH:17]([CH2:14][CH2:15][CH3:16])[CH2:18][CH2:19]3)[CH2:28][CH2:27]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCC1CCC(C2CCC(=O)CC2)CC1
Agent: Cl
Agent: [Li]CCCC
Solvent: CCOCC
Solvent: O
Product: CCCC1CCC(C2CCC(O)(c3ccc(Br)cc3)CC2)CC1
Temperature: 0 °C
Reaction time: 0.5 h

Procedure:
106 g (0.45 mol) of 1,4-dibromobenzene are initially introduced in 400 ml of Et2O at −45° C., and 275 ml (0.45 mol) of n-BuLi (15% soln. in hexane) are metered in. After 30 min at this temperature, a solution of 100 g (0.45 mol) of 4′-propylbicyclohexyl-4-one in 200 ml of Et2O is added dropwise, and the mixture is warmed to 0° C. After 1 h, water and dil. hydrochloric acid are added to the batch, and the organic phase is separated off. The aqueous phase is extracted with MTBE, and the combined organic phases are washed with water and subsequently dried using sodium sulfate. The solution is concentrated to completion, and the residue is used without further purification for the following reaction.
Reaction SMILES: C([N:14]1[CH2:17][C:16]([NH:21][CH2:22][CH3:23])([C:18]([NH2:20])=[O:19])[CH2:15]1)(C1C=CC=CC=1)C1C=CC=CC=1.[ClH:24]>CO.CC(OC)(C)C.[OH-].[OH-].[Pd+2]>[ClH:24].[CH2:22]([NH:21][C:16]1([C:18]([NH2:20])=[O:19])[CH2:17][NH:14][CH2:15]1)[CH3:23]
Reactant: CCNC1(C(N)=O)CN(C(c2ccccc2)c2ccccc2)C1
Agent: [Pd+2]
Agent: Cl
Agent: [OH-]
Solvent: CO
Solvent: COC(C)(C)C
Product: CCNC1(C(N)=O)CNC1

Procedure:
To a suspention of 1-benzhydryl-3-ethylaminoazetidine-3-carboxylic acid amide (I-2A-1f; 36.1 g, 117 mmol) in methanol (560 ml) at room temperature was added concentrated aqueous HCl (19.5 ml, 234 mmol), resulting in a clear solution. To 20% Pd(OH)2 on carbon (3.75 g) was added methanol (85 ml), followed by the methanolic solution of I-2A-1f. The mixture was placed on a Parr® shaker and then reduced (50 psi H2) at room temperature for 20 hours. The reaction was then filtered through Celite® and then concentrated to low volume under reduced pressure, at which point a precipitate formed. The suspension was diluted with MTBE (500 ml), stirred for an additional hour, and the precipitate collected by vacuum filtration. The solid was washed washed with MTBE and then dried, in vacuo, to afford I-2A-1g (24.8 g, 98%) as a colorless solid.
Reaction SMILES: [N:1]1([C:6]([C:8]2[S:12][C:11]([C:13]3(O)[CH2:22][CH2:21][C:16]4([O:20][CH2:19][CH2:18][O:17]4)[CH2:15][CH2:14]3)=[N:10][CH:9]=2)=[O:7])[CH2:5][CH2:4][CH2:3][CH2:2]1.S(Cl)([Cl:26])=O>N1C=CC=CC=1>[Cl:26][C:13]1([C:11]2[S:12][C:8]([C:6]([N:1]3[CH2:5][CH2:4][CH2:3][CH2:2]3)=[O:7])=[CH:9][N:10]=2)[CH2:22][CH2:21][C:16]2([O:20][CH2:19][CH2:18][O:17]2)[CH2:15][CH2:14]1
Reactant: O=C(c1cnc(C2(O)CCC3(CC2)OCCO3)s1)N1CCCC1
Reactant: O=S(Cl)Cl
Solvent: c1ccncc1
Product: O=C(c1cnc(C2(Cl)CCC3(CC2)OCCO3)s1)N1CCCC1
Temperature: 25 °C
Reaction time: 8 h
Yield: 8.4 %

Procedure:
To a mixture of 8-[5-(pyrrolidin-1-ylcarbonyl)-1,3-thiazol-2-yl]-1,4-dioxaspiro[4.5]decan-8-ol (0.2 g, 3.32 mmol) in pyridine (3 mL) at 0° C. was added thionyl chloride (0.5 mL, 6.86 mmol) under N2. The mixture was warmed to room temperature and stirred overnight. After the reaction solution was concentrated, water and EtOAc were added. The aqueous layer was extracted with EtOAc (2×). The combined organic layers were washed with saturated NaCl, dried (MgSO4), concentrated and flash chromatographed (50% EtOAc/hexane to EtOAc) to give 0.10 g of the title compound in 53% yield. MS (EI) calcd: (M+1)+=356.1; found: 357.0.
Reaction SMILES: [NH2:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11].[CH3:25][O:26][CH2:27][C:28](Cl)=[O:29]>O1CCCC1>[CH3:25][O:26][CH2:27][C:28]([NH:1][C:2]1[CH:10]=[CH:9][CH:8]=[C:7]2[C:3]=1[C:4](=[O:24])[N:5]([CH:12]1[CH2:17][CH:16]([O:18][C:19](=[O:21])[CH3:20])[C:15](=[O:22])[NH:14][C:13]1=[O:23])[C:6]2=[O:11])=[O:29]
Reactant: COCC(=O)Cl
Reactant: CC(=O)OC1CC(N2C(=O)c3cccc(N)c3C2=O)C(=O)NC1=O
Solvent: C1CCOC1
Product: COCC(=O)Nc1cccc2c1C(=O)N(C1CC(OC(C)=O)C(=O)NC1=O)C2=O

Procedure:
A solution of 3-(4-amino-1,3-dioxoisoindolin-2-yl)-2,6-dioxo-5-acetoxypiperidine (1 g, 3.5 mmol) and methoxyacetyl chloride (0.38 g, 3.5 mmol) in tetrahydrofuran (20 mL) is heated at reflux for 1 hour. The solvent is removed in vacuo to give 3-[4- (2-methoxyacetylamino)-1,3-dioxoisoindolin-2-yl]-2,6-dioxo-5-acetoxypiperidine which is further purified by column chromatography.
Reaction SMILES: [O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[NH:5][CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15].O=C1N[C:27]2[CH:29]=[C:30](C)[CH:31]=[CH:32][C:26]=2NCC1NC(OC(C)(C)C)=O>>[O:1]=[C:2]1[NH:8][C:7]2[CH:9]=[CH:10][CH:11]=[CH:12][C:6]=2[N:5]([CH:32]2[CH2:31][CH2:30][CH2:29][CH:27]=[CH:26]2)[CH2:4][CH:3]1[NH:13][C:14]([O:16][C:17]([CH3:20])([CH3:19])[CH3:18])=[O:15]
Reactant: CC(C)(C)OC(=O)NC1CNc2ccccc2NC1=O
Reactant: Cc1ccc2c(c1)NC(=O)C(NC(=O)OC(C)(C)C)CN2
Product: CC(C)(C)OC(=O)NC1CN(C2C=CCCC2)c2ccccc2NC1=O

Procedure:
Step 1 of Referential Example 10 was repeated except that 2-oxo-3-tert-butoxycarbonylamino-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine obtained from Referential Example 1 was used instead of 2-oxo-3-tert-butoxycarbonylamino-8-methyl-1,3,4,5-tetrahydro-2H-1,5-benzodiazepine, to thereby obtain the title compound.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([O:8][CH3:9])=[CH:4][CH:3]=1.[Mg].[B:11](OC(C)C)([O:16]C(C)C)[O:12]C(C)C.Cl>C1COCC1>[CH3:9][O:8][C:5]1[CH:6]=[CH:7][C:2]([B:11]([OH:16])[OH:12])=[CH:3][CH:4]=1
Reactant: CC(C)OB(OC(C)C)OC(C)C
Reactant: COc1ccc(Br)cc1
Agent: Cl
Agent: [Mg]
Solvent: C1CCOC1
Product: COc1ccc(B(O)O)cc1
Temperature: 25 °C
Yield: 89.5 %

Procedure:
A solution of the Grignard reagent, prepared from 4-bromoanisole (80.0 g, 0.43 mol) and magnesium (11.96 g, 0.49 mol) in dry THF (300 ml) was added dropwise to a stirred, cooled (-78° C.) solution of tri-isopropyl borate (161.7 g, 0.86 mol) in dry THF (50 ml) under dry nitrogen. The stirred mixture was allowed to warm to room temperature overnight and was then stirred at room temperature for 1 h with 10% hydrochloric acid (300 ml). The product was extracted into ether (twice), the combined ethereal extracts were washed with water and dried (MgSO4). The solvent was removed in vacuo to yield a cream-coloured solid (58.5 g) which was recrystallised from water to give colourless crystals.
Reaction SMILES: [F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21](Cl)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10].[CH:25]([C:28]1[CH:33]=[CH:32][C:31]([OH:34])=[CH:30][CH:29]=1)([CH3:27])[CH3:26]>>[F:1][C:2]1[CH:3]=[C:4]([CH:14]([NH:16][C:17]([C:19]2[N:20]=[C:21]([O:34][C:31]3[CH:32]=[CH:33][C:28]([CH:25]([CH3:27])[CH3:26])=[CH:29][CH:30]=3)[O:22][CH:23]=2)=[O:18])[CH3:15])[CH:5]=[C:6]([F:13])[C:7]=1[NH:8][S:9]([CH3:12])(=[O:11])=[O:10]
Reactant: CC(C)c1ccc(O)cc1
Reactant: CC(NC(=O)c1coc(Cl)n1)c1cc(F)c(NS(C)(=O)=O)c(F)c1
Product: CC(C)c1ccc(Oc2nc(C(=O)NC(C)c3cc(F)c(NS(C)(=O)=O)c(F)c3)co2)cc1
Yield: 73.8 %

Procedure:
2-Chloro-oxazole-4-carboxylic acid [1-(3,5-difluoro-4-methanesulfonylamino-phenyl)-ethyl]-amide (50 mg, 0.13 mmol) was reacted with 4-isopropyl phenol (36 mg, 0.26 mmol) to give the title compound (46 mg, 73%) after purification by column chromatography (gradient 12% to 100% EtOAc in n-hexane).
Reaction SMILES: Br[CH2:2][CH2:3][O:4][N:5]=[C:6]([C:12]1([O:17][CH2:16][CH2:15][O:14]1)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8].[CH3:18]C(C)([O-])C.[K+]>CN(C)C=O>[CH:3]1([O:4][N:5]=[C:6]([C:12]2([O:17][CH2:16][CH2:15][O:14]2)[CH3:13])[C:7]([O:9][CH2:10][CH3:11])=[O:8])[CH2:18][CH2:2]1
Reactant: CC(C)(C)[O-]
Reactant: CCOC(=O)C(=NOCCBr)C1(C)OCCO1
Agent: [K+]
Solvent: CN(C)C=O
Product: CCOC(=O)C(=NOC1CC1)C1(C)OCCO1
Temperature: 0 °C
Yield: 38.2 %

Procedure:
To a solution of ethyl 2-(2-bromoethoxyimino)-3,3-ethylenedioxybutyrate (syn isomer)(50 g) in N,N-dimethylformamide (100 ml) was portionwise added potassium tert-butoxide (21 g) under -10° C. and the resulted mixture was allowed to be stirred under ice-cooling for 20 minutes. The mixture was poured into ice-water (400 ml) and extracted with methylene chloride (200 ml). The extract was washed with water (200 ml×3) and saturated aqueous solution of sodium chloride (400 ml) successively, dried over magnesium sulfate, and added methylene iodide (16.2 ml). To the solution was dropwise added a 35% (W/W) solution of diethylzinc in cyclohexane (55 ml) under reflux during 40 minutes under nitrogen. atmosphere. After refluxed for 18 hours, the mixture was poured into ice-water (400 ml) and adjusted to 40 with 1N hydrochloric acid. The organic layer was separated, washed with an aqueous solution of sodium bicarbonate and a saturated aqueous solution of sodium chloride successively, dried over magnesium sulfate, and concentrated in vacuo. The residue was subjected to column chromatography on silica gel (50 g) using diisopropyl ether as an eluent to give ethyl 2-cyclopropyloxyimino-3,3-ethylenedioxybutyrate (syn isomer)(15 g), the physical data of which were identical to those of the compound prepared in Preparation 10.
Reaction SMILES: Cl[C:2]1[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]2[CH:16]=[CH:15][C:14]([N:17]3[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]3)=[C:13]([O:24][CH3:25])[CH:12]=2)[N:3]=1.[Cl:26][C:27]1[C:32]([OH:33])=[CH:31][CH:30]=[CH:29][N:28]=1>>[Cl:26][C:27]1[C:32]([O:33][C:2]2[N:7]=[C:6]([O:8][CH3:9])[N:5]=[C:4]([NH:10][C:11]3[CH:16]=[CH:15][C:14]([N:17]4[CH:21]=[C:20]([CH2:22][OH:23])[N:19]=[CH:18]4)=[C:13]([O:24][CH3:25])[CH:12]=3)[N:3]=2)=[CH:31][CH:30]=[CH:29][N:28]=1
Reactant: Oc1cccnc1Cl
Reactant: COc1nc(Cl)nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)n1
Product: COc1nc(Nc2ccc(-n3cnc(CO)c3)c(OC)c2)nc(Oc2cccnc2Cl)n1
Yield: 43 %

Procedure:
This compound was prepared in analogy to example 3 from {1-[4-(4-chloro-6-methoxy-[1,3,5]triazin-2-ylamino)-2-methoxy-phenyl]-1H-imidazol-4-yl}-methanol and 2-chloro-3-hydroxypyridine. The title compound was isolated as a slightly brownish solid in 43% yield.
Reaction SMILES: [F:1][C:2]([F:54])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:52])([F:51])[F:50])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:30])([F:29])[F:28])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([O:43]CC)=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:19][CH2:18][O:17][CH2:16][CH2:15]2)=[CH:10][N:9]=1.[OH-].[Na+].Cl.C(OCC)(=O)C>C(O)C>[F:54][C:2]([F:1])([F:53])[C:3]1[CH:4]=[C:5]([CH:46]=[C:47]([C:49]([F:50])([F:52])[F:51])[CH:48]=1)[CH2:6][N:7]([CH2:20][C:21]1[CH:26]=[C:25]([C:27]([F:28])([F:29])[F:30])[CH:24]=[CH:23][C:22]=1[C:31]1[CH:36]=[CH:35][CH:34]=[CH:33][C:32]=1[O:37][CH2:38][CH2:39][CH2:40][C:41]([OH:43])=[O:42])[C:8]1[N:13]=[CH:12][C:11]([N:14]2[CH2:15][CH2:16][O:17][CH2:18][CH2:19]2)=[CH:10][N:9]=1
Reactant: CCOC(=O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Agent: Cl
Agent: [Na+]
Agent: [OH-]
Solvent: CCOC(C)=O
Solvent: CCO
Product: O=C(O)CCCOc1ccccc1-c1ccc(C(F)(F)F)cc1CN(Cc1cc(C(F)(F)F)cc(C(F)(F)F)c1)c1ncc(N2CCOCC2)cn1
Temperature: 25 °C
Reaction time: 2 h
Yield: 96.5 %

Procedure:
Ethyl 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyrate (157 mg) is dissolved in ethanol (4 ml), and thereto is added 1N-aqueous sodium hydroxide solution (1 ml), and the mixture is stirred at room temperature for 2 hours. To the reaction solution are added a 1N-hydrochloric acid and ethyl acetate and the mixture is separated, and the organic layer is washed with a saturated brine, dried over magnesium sulfate, and concentrated under reduced pressure. The resulting residue is purified by silica gel column chromatography (chloroform:methanol=1:0→9:1) to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid (146 mg). The resulting carboxylic acid is dissolved in ethanol (1 ml), and thereto is added 1N-aqueous sodium hydroxide solution (197 μl) and the reaction solution is concentrated under reduced pressure to give 4-(2′-{[(3,5-bis-trifluoromethyl-benzyl)-(5-morpholin-4-yl-pyrimidin-2-yl)-amino]-methyl}-4′-trifluoromethyl-biphenyl-2-yloxy)-butyric acid sodium salt (146 mg). MS (m/z): 741 [M−Na]−