Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Br[C:2]1[S:3][C:4]([C:7]2[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=2)=[N:5][N:6]=1.[CH2:21]([C:23]1[C:30](B2OC(C)(C)C(C)(C)O2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22].P([O-])([O-])([O-])=O.[K+].[K+].[K+]>CN(C)C=O.O.C1C=CC([P]([Pd]([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)([P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)[P](C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)(C2C=CC=CC=2)C2C=CC=CC=2)=CC=1>[CH2:21]([C:23]1[C:30]([C:2]2[S:3][C:4]([C:7]3[CH:12]=[CH:11][C:10]([O:13][CH:14]([CH3:16])[CH3:15])=[C:9]([C:17]([F:20])([F:19])[F:18])[CH:8]=3)=[N:5][N:6]=2)=[CH:29][CH:28]=[CH:27][C:24]=1[CH:25]=[O:26])[CH3:22]
Reactant: CC(C)Oc1ccc(-c2nnc(Br)s2)cc1C(F)(F)F
Reactant: CCc1c(C=O)cccc1B1OC(C)(C)C(C)(C)O1
Agent: c1ccc([P](c2ccccc2)(c2ccccc2)[Pd]([P](c2ccccc2)(c2ccccc2)c2ccccc2)([P](c2ccccc2)(c2ccccc2)c2ccccc2)[P](c2ccccc2)(c2ccccc2)c2ccccc2)cc1
Agent: O=P([O-])([O-])[O-]
Agent: [K+]
Solvent: O
Solvent: CN(C)C=O
Product: CCc1c(C=O)cccc1-c1nnc(-c2ccc(OC(C)C)c(C(F)(F)F)c2)s1
Temperature: 130 °C
Yield: 52.7 %

Procedure:
To a solution of 2-bromo-5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazole (D4) (100 mg), 2-ethyl-3-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzaldehyde (D5) (85 mg) and tripotassium phosphate (145 mg) in N,N-dimethylformamide (DMF) (6 mL) and water (1.5 mL) stirred under nitrogen at room temperature was added Pd(Ph3P)4 (31.5 mg). The reaction vessel was sealed and heated under microwave at 130° C. for 8 min. After cooling the reaction, water was added to quench the reaction. After filtered through the celite, the filtrate was partitioned between the organic and aqueous layers. The aqueous layer was extracted with EA for 3 times. The combined organic layers were washed with brine, dried over anhydrous sodium sulfate. The dried solution was concentrated, and purified by column chromatography to afford 2-ethyl-3-{5-[4-[(1-methylethyl)oxy]-3-(trifluoromethyl)phenyl]-1,3,4-thiadiazol-2-yl}benzaldehyde (D6) (60.4 mg). MS (ES): C21H19F3N2O2S requires 420. found 421.1 (M+H+).
Reaction SMILES: [C:1]([NH:8][C@:9]([CH2:33]C)([CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([O:31][CH3:32])[CH:15]=1)[CH2:10][OH:11])([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].C(N(CC)[P:38]1[O:44][CH2:43][C:42]2[CH:45]=[CH:46][CH:47]=[CH:48][C:41]=2[CH2:40][O:39]1)C.N1C=NN=N1.[OH:56]O>C1COCC1>[C:4]([O:3][C:1](=[O:2])[NH:8][C@@:9]([CH3:33])([CH2:10][O:11][P:38]1(=[O:56])[O:39][CH2:40][C:41]2[CH:48]=[CH:47][CH:46]=[CH:45][C:42]=2[CH2:43][O:44]1)[CH2:12][CH2:13][C:14]1[CH:19]=[CH:18][C:17]([O:20][CH2:21][CH2:22][CH2:23][CH2:24][C:25]2[CH:30]=[CH:29][CH:28]=[CH:27][CH:26]=2)=[C:16]([O:31][CH3:32])[CH:15]=1)([CH3:7])([CH3:6])[CH3:5]
Reactant: OO
Reactant: CC[C@](CO)(CCc1ccc(OCCCCc2ccccc2)c(OC)c1)NC(=O)OC(C)(C)C
Reactant: CCN(CC)P1OCc2ccccc2CO1
Agent: c1nnn[nH]1
Solvent: C1CCOC1
Product: COc1cc(CC[C@](C)(COP2(=O)OCc3ccccc3CO2)NC(=O)OC(C)(C)C)ccc1OCCCCc1ccccc1
Reaction time: 2 h

Procedure:
To a solution of N-Boc-(R)-2-Amino-2-ethyl-4-[3-methoxy-4-(4-phenyl-butoxy)-phenyl]-butan-1-ol (0.23 g; 0.5 mmol) in THF (5 ml) is added N,N-diethyl-1,5-dihydro-2,4,3-benzodioxaphosphepin-3-amine (0.24 g; 1 mmol) and tetrazole (0.11 g; 1.5 mmol). After 2 hours at RT H2O2 (30% in water; 0.58 ml) is added and the mixture is kept at RT for further two hours. The reaction mixture is quenched with Na2S2O3 and extracted with ethyl acetate and then washed with aqueous citric acid and aqueous saturated NaHCO3 solution. The organic layer is dried and concentrated and then purified on a silica gel using dichloromethane/ethanol (95/5) as mobile phase.
Reaction SMILES: [NH2:1][C:2]1[CH:9]=[C:8](F)[C:5]([C:6]#[N:7])=[CH:4][N:3]=1.[CH3:11][N:12]1[CH2:16][CH2:15][CH2:14][C@H:13]1[CH2:17][OH:18]>>[NH2:1][C:2]1[CH:9]=[C:8]([O:18][CH2:17][C@@H:13]2[CH2:14][CH2:15][CH2:16][N:12]2[CH3:11])[C:5]([C:6]#[N:7])=[CH:4][N:3]=1
Reactant: N#Cc1cnc(N)cc1F
Reactant: CN1CCC[C@H]1CO
Product: CN1CCC[C@H]1COc1cc(N)ncc1C#N

Procedure:
From intermediate 21 and (S)-(1-methylpyrrolidin-2-yl)methanol, reacted in an analogous manner to the preparation of intermediate 47. (UPLC-MS 3) tR 0.30 min; ESI-MS 233.2 [M+H]+.
Reaction SMILES: C[C:2]1[N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[CH:10]=2)[C:5]([CH2:21][C:22]([O:24][CH3:25])=[O:23])=[CH:4][N:3]=1.[H-].[Na+].[CH3:28]I.[CH:30]([O:32][CH3:33])=O>COCCOC.CCOCC>[CH3:28][C:4]1[N:3]=[CH:2][N:7]=[C:6]([O:8][C:9]2[CH:14]=[CH:13][CH:12]=[C:11]([C:15]3[CH:16]=[CH:17][CH:18]=[CH:19][CH:20]=3)[CH:10]=2)[C:5]=1[C:21](=[CH:30][O:32][CH3:33])[C:22]([O:24][CH3:25])=[O:23]
Reactant: COC=O
Reactant: CI
Reactant: COC(=O)Cc1cnc(C)nc1Oc1cccc(-c2ccccc2)c1
Agent: [H-]
Agent: [Na+]
Solvent: COCCOC
Solvent: CCOCC
Product: COC=C(C(=O)OC)c1c(C)ncnc1Oc1cccc(-c2ccccc2)c1

Procedure:
Methyl α-[2-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-acetate (8 mmol) are dissolved in methyl formate (10 ml) and added to a suspension of NaH (0.6 g, 80% in oil, 20 mmol) in 1,2-dimethoxyethane at room temperature. After 16 hours methyl iodide (2.5 ml, 40 mmol) is added with cooling. After further 2 hurs the reaction mixture is diluted with ether and washed with brine. Drying and chromatography on silicagel (eluent: hexane/ethlyacetate 1:1) gives the pure methyl α-[6-methyl-4-(3-phenylphenoxy)-5-pyrimidinyl]-β-methoxyacrylate as an oil.
Reaction SMILES: [CH3:1][S:2]([O:5]C)(=[O:4])=[O:3].[N:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1>O1CCOCC1>[CH3:1][S:2]([O-:5])(=[O:4])=[O:3].[CH3:1][N+:7]1[CH:12]=[CH:11][CH:10]=[CH:9][CH:8]=1
Reactant: COS(C)(=O)=O
Reactant: c1ccncc1
Solvent: C1COCCO1
Product: CS(=O)(=O)[O-]
Product: C[n+]1ccccc1

Procedure:
A 220.3 mg (2 millimole) quantity of methyl methanesulfonate and 158.2 mg (2millimole) of dry pyridine were dissolved in 80 ml of dry dioxane, and were heated under reflux for one hour to produce N-methylpyridinium methanesulfonate. To the salt was added 914 mg (2 millimole) or the p-methoxybenzyl ester of benzylpenicillin sulfoxide and the mixture was heated under reflux for 11 hours. At this time, a condensed solvent was passed through calcium oxide before the condensed solvent was returned to the reaction container or vessel. After the completion of the reaction, the insoluble materials were removed therefrom, and the solvent was evaporated under reduced pressure. The residue was dissolved in 50 ml of ethyl acetate, and after the solution was washed with water and dried, ethyl acetate was distilled. When the product thus obtained was washed with diethyl ether, 604.7 mg (66.9%) of the p-methoxybenzyl ester of 7-phenylacetamidodesacetoxy cephalosporanic acid having a melting point of 162.5° to 168°C were obtained. The acid was very pure. However, recrystallization of the acid gave a completely pure product having a melting point of 179.5° to 181°C.
Reaction SMILES: [NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][O:36][CH2:37][CH3:38])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:34])[CH2:21][CH2:22][C:23]([NH:25][NH:26]C(OC(C)(C)C)=O)=[O:24])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1.FC(F)(F)C(O)=O>ClCCl>[NH2:1][C:2]1[C:11]2[N:12]=[C:13]([CH2:35][O:36][CH2:37][CH3:38])[N:14]([CH2:15][C:16]([NH:19][C:20](=[O:34])[CH2:21][CH2:22][C:23]([NH:25][NH2:26])=[O:24])([CH3:18])[CH3:17])[C:10]=2[C:9]2[CH:8]=[CH:7][CH:6]=[CH:5][C:4]=2[N:3]=1
Reactant: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NNC(=O)OC(C)(C)C
Solvent: ClCCl
Solvent: O=C(O)C(F)(F)F
Product: CCOCc1nc2c(N)nc3ccccc3c2n1CC(C)(C)NC(=O)CCC(=O)NN
Reaction time: 2 h
Yield: 53 %

Procedure:
A solution of tert-butyl 2-[4-({2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}amino)-4-oxobutanoyl]hydrazinecarboxylate (792 mg, 1.50 mmol) in dichloromethane (30 mL) was treated with trifluoroacetic acid (3 mL). After stirring for 2 hours, additional trifluoroacetic acid (3 mL) was added to the reaction mixture and stirring was continued for 1 hour. The reaction mixture was concentrated under reduced pressure and the resulting syrup was dissolved in water. The solution was made basic by the addition of concentrated ammonium hydroxide and then was extracted repeatedly with 10% methanol/chloroform. The combined organic portions were dried over sodium sulfate, filtered, and concentrated under reduced pressure. The crude white solid was purified by chromatography on silica gel (gradient elution, 25%-75% CMA in chloroform) gave 340 mg of N-{2-[4-amino-2-(ethoxymethyl)-1H-imidazo[4,5-c]quinolin-1-yl]-1,1-dimethylethyl}-4-hydrazino-4-oxobutanamide.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:13][CH2:12][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH:21]=O)=[CH:17][CH:16]=2)[CH2:10][CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].[NH:24]1[CH2:29][CH2:28][O:27][CH2:26][CH2:25]1.[BH-](OC(C)=O)(OC(C)=O)OC(C)=O.[Na+]>CO.C([O-])(O)=O.[Na+]>[C:1]([O:5][C:6]([N:8]1[CH2:9][CH2:10][N:11]([C:14](=[O:23])[C:15]2[CH:20]=[CH:19][C:18]([CH2:21][N:24]3[CH2:29][CH2:28][O:27][CH2:26][CH2:25]3)=[CH:17][CH:16]=2)[CH2:12][CH2:13]1)=[O:7])([CH3:4])([CH3:3])[CH3:2]
Reactant: C1COCCN1
Reactant: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(C=O)cc2)CC1
Agent: CC(=O)O[BH-](OC(C)=O)OC(C)=O
Agent: O=C([O-])O
Agent: [Na+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1CCN(C(=O)c2ccc(CN3CCOCC3)cc2)CC1
Reaction time: 3 h

Procedure:
A solution of 4-(4-formyl-benzoyl)-piperazine-1-carboxylic acid tert-butyl ester (2.06 g) in methanol (100 mL) was treated with morpholine (4 mL) and NaBH(OAc)3 (6.98 g, in portions over 1 h). After 3 h, the mixture was diluted with saturated aquoues NaHCO3 and extracted with CH2Cl2. The organic layer was dried (Na2SO4) and concentrated. The residue was purified by column chromatography (SiO2) to yield the title compound.
Reaction SMILES: [CH3:1][C:2]1[C:6]2[C:7]([CH:26]3[CH2:31][CH2:30][NH:29][CH2:28][CH2:27]3)=[N:8][C:9]3[N:10]([N:11]=[CH:12][C:13]=3[C:14]3[CH:15]=[N:16][C:17]([C:20]4[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=4)=[CH:18][CH:19]=3)[C:5]=2[NH:4][N:3]=1.[C:32](O)(=[O:36])[C@@H:33]([CH3:35])[OH:34].C1C=CC2N(O)N=NC=2C=1.CCN(C(C)C)C(C)C>CN(C=O)C.C(Cl)CCl>[OH:34][C@H:33]([CH3:35])[C:32]([N:29]1[CH2:30][CH2:31][CH:26]([C:7]2[C:6]3[C:2]([CH3:1])=[N:3][NH:4][C:5]=3[N:10]3[N:11]=[CH:12][C:13]([C:14]4[CH:15]=[N:16][C:17]([C:20]5[CH:25]=[CH:24][CH:23]=[CH:22][CH:21]=5)=[CH:18][CH:19]=4)=[C:9]3[N:8]=2)[CH2:27][CH2:28]1)=[O:36]
Reactant: C[C@@H](O)C(=O)O
Reactant: Cc1n[nH]c2c1c(C1CCNCC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Agent: On1nnc2ccccc21
Solvent: CCN(C(C)C)C(C)C
Solvent: ClCCCl
Solvent: CN(C)C=O
Product: Cc1n[nH]c2c1c(C1CCN(C(=O)[C@@H](C)O)CC1)nc1c(-c3ccc(-c4ccccc4)nc3)cnn12
Temperature: 25 °C
Reaction time: 2 h

Procedure:
A mixture of 3-methyl-6-(6-phenylpyridin-3-yl)-4-(piperidin-4-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidine (Int-9l, 42 mg, (\10 mmoL), D-(−)-lactic acid (9.3 mg, 0.10 mmoL), EDC (39.4 mg, 0.20 mmoL), HOBt (13.9 mg, 0.10 mmoL) and DIEA (89 μL, 0.51 mmoL) in DMF (4 mL) was stirred at room temperature for 2 hr. Purification with prep-LC provided (R)-2-hydroxy-1-(4-(3-methyl-6-(6-phenylpyridin-3-yl)-1H-dipyrazolo[1,5-a:4′,3′-e]pyrimidin-4-yl)piperidin-1-yl)propan-1-one (30): LCMS tR=3.07 min (10 min run, UV254nm) Mass calculated for, M+481.2, observed LC/MS m/z 482.6 (M+H).
Reaction SMILES: CC1(C)C(C)(C)OB([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:30])([F:29])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)O1.C([O:36][C:37]1[CH:42]=[C:41](Br)[CH:40]=[CH:39][C:38]=1[F:44])(=O)C>>[F:44][C:38]1[CH:39]=[CH:40][C:41]([C:9]2[CH2:14][CH2:13][N:12]([C:15]3[N:20]=[CH:19][N:18]([CH2:21][C:22]4[S:23][C:24]([C:27]([F:29])([F:30])[F:28])=[CH:25][CH:26]=4)[C:17](=[O:31])[N:16]=3)[CH2:11][CH:10]=2)=[CH:42][C:37]=1[OH:36]
Reactant: CC1(C)OB(C2=CCN(c3ncn(Cc4ccc(C(F)(F)F)s4)c(=O)n3)CC2)OC1(C)C
Reactant: CC(=O)Oc1cc(Br)ccc1F
Product: O=c1nc(N2CC=C(c3ccc(F)c(O)c3)CC2)ncn1Cc1ccc(C(F)(F)F)s1
Yield: 35 %

Procedure:
The synthesis was performed using a crude product obtained by synthesis using 4-[4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-5,6-dihydropyridin-1(2H)-yl]-1-{[5-(t rifluoromethyl)thiophen-2-yl]methyl}-1,3,5-triazin-2(1H)-one synthesized in Reference Synthesis Example 346 and 5-bromo-2-fluorophenyl acetate in a similar manner to Reference Synthesis Example 139, in a similar manner to Reference Synthesis Example 2 (two step yield 35%).
Reaction SMILES: [CH3:1]C(C)([O-])C.[K+].[F:7][C:8]([F:20])([F:19])[C:9]1[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11][NH:12][CH:13]=1.CI.O>O1CCCC1>[CH3:1][N:12]1[CH:13]=[C:9]([C:8]([F:7])([F:19])[F:20])[C:10]([C:14]([O:16][CH2:17][CH3:18])=[O:15])=[CH:11]1
Reactant: CCOC(=O)c1c[nH]cc1C(F)(F)F
Reactant: CC(C)(C)[O-]
Agent: [K+]
Solvent: CI
Solvent: O
Solvent: C1CCOC1
Product: CCOC(=O)c1cn(C)cc1C(F)(F)F
Reaction time: 0.5 h

Procedure:
A solution of potassium t-butoxide (4.5 g, 0.04 mol) in tetrahydrofuran is treated dropwise with a solution of ethyl 4-(trifluoromethyl)pyrrole-3-carboxylate (8.3 g, 0.04 mol) in tetrahydrofuran over a 20 minute period at 20°-25° C., stirred for 30 minutes, treated dropwise with methyl iodide (5.7 g, 0.04 mol), stirred at room temperature for 24 hours and poured into water. The resultant mixture is extracted with ether and the combined extracts are washed with brine, dried (MgSO4) and concentrated in vacuo to afford a brown oil residue. The residue is distilled using a Kugelrohr distillation apparatus to give a gummy solid at 80°-85° C./0.2 mm Hg. The solid is purified using ether and basic alumina to yield the title compound as a clear oil, 6.37 g (72%), identified by NMR and elemental analyses.
Reaction SMILES: [F:1][C:2]([S:5][C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)([F:4])[F:3].[OH:15]OS([O-])=O.[K+]>CO.C1COCC1.O>[F:1][C:2]([F:4])([F:3])[S:5]([C:6]1[CH:7]=[C:8]([C:12](=[O:14])[CH3:13])[CH:9]=[CH:10][CH:11]=1)=[O:15]
Reactant: CC(=O)c1cccc(SC(F)(F)F)c1
Reactant: O=S([O-])OO
Agent: [K+]
Solvent: C1CCOC1
Solvent: O
Solvent: CO
Product: CC(=O)c1cccc(S(=O)C(F)(F)F)c1
Temperature: 60 °C
Reaction time: 72 h
Yield: 44 %

Procedure:
To a solution of 1-(3-trifluoromethylsulfanyl-phenyl)ethanone (1.4 g, 6.36 mmol) in methanol (30 ml) and THF (30 ml) a solution of oxone, monopersulfate compound (10.94 g, 17.8 mmol) in water (50 ml) was added dropwise over a period of 10 min. The reaction mixture was stirred at 60° C. for 3 days. The organic solvent was removed in vacuo and the aqueous phase was extracted with dichloromethane. Evaporation of the combined organic layers and purification of the crude product by silica gel chromatography using ethyl acetate/n-heptane gave the desired product (0.66 g, 44%). 1-(3-Trifluoromethanesulfonyl-phenyl)ethanone (190 mg, 12%) was obtained as a side product which was used for the synthesis of example 77.
Reaction SMILES: [NH2:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1.O=[C:15]([CH2:21][CH2:22][C:23]1[CH:28]=[CH:27][CH:26]=[CH:25][CH:24]=1)[C:16]([O:18][CH2:19][CH3:20])=[O:17].C([BH3-])#N.[Na+]>CO.C(O)(=O)C>[C:16]([CH:15]([NH:1][CH:2]1[C:8](=[O:9])[NH:7][C:6]2[CH:10]=[CH:11][CH:12]=[CH:13][C:5]=2[O:4][CH2:3]1)[CH2:21][CH2:22][C:23]1[CH:24]=[CH:25][CH:26]=[CH:27][CH:28]=1)([O:18][CH2:19][CH3:20])=[O:17]
Reactant: NC1COc2ccccc2NC1=O
Reactant: CCOC(=O)C(=O)CCc1ccccc1
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CC(=O)O
Solvent: CO
Product: CCOC(=O)C(CCc1ccccc1)NC1COc2ccccc2NC1=O
Reaction time: 8 h

Procedure:
The 3-amino-2,3-dihydro-1,5-benzoxazepin-4(5H)-one (0.250 g) is dissolved in 5 ml of methanol and 2.88 g of ethyl 2-oxo-4-phenylbutyrate is added. This is followed by the addition of a solution of 88 mg of sodium cyanoborohydride in 3 ml of methanol and 0.8 ml of glacial acetic acid. The reaction is stirred overnight under nitrogen and concentrated. The residue is dissolved in 20 ml of methylene chloride and washed with 10 ml of cold saturated sodium carbonate. After drying over magnesium sulfate the solution is concentrated to an oil which is purified by flash chromatography on silica gel [solvent, acetone, hexane (1:4)] to afford 3-[N-(1-carboethoxy-3-phenylpropyl)amino]-2,3-dihydro-1,5-benzoxazepin-4(5H)-one; NMR (CDCl3) δ 9.35 (s (broad, 1], 6.50-7.30 (m, 10, 4.10 (q, 2), 2.67 (t (broad), 2], 1.21 (t, 3); IR (neat) 3220 (NH), 1730 (C=O, ester), 1685 (C=O, lactam) cm-1.
Reaction SMILES: Br[C:2]1[CH:7]=[CH:6][C:5]([Br:8])=[CH:4][CH:3]=1.[Li]CCCC.CCCCCC.[CH2:20]([CH:23]1[CH2:28][CH2:27][C:26](=[O:29])[CH2:25][CH2:24]1)[CH2:21][CH3:22].O>C1COCC1>[Br:8][C:5]1[CH:6]=[CH:7][C:2]([C:26]2([OH:29])[CH2:27][CH2:28][CH:23]([CH2:20][CH2:21][CH3:22])[CH2:24][CH2:25]2)=[CH:3][CH:4]=1
Reactant: Brc1ccc(Br)cc1
Reactant: CCCC1CCC(=O)CC1
Agent: [Li]CCCC
Solvent: O
Solvent: CCCCCC
Solvent: C1CCOC1
Product: CCCC1CCC(O)(c2ccc(Br)cc2)CC1
Temperature: -69 °C
Reaction time: 1 h
Yield: 105.5 %

Procedure:
37.7 g of 1,4-dibromobenzene (13) and 300 mL of THF were placed in a reactor under nitrogen atmosphere and stirred at −69° C. 100 mL of a 1.6M n-BuLi hexane solution was added dropwise thereto at a temperature range of from −69 to −62° C. over 1 hour, and then further stirred at −70° C. for 1 hour. 22.4 g of 4-propylcyclohexanone (14) dissolved in 20 mL of THF was slowly added dropwise to the reaction solution at a temperature range of from −70 to −60° C. After gradually warming the reaction solution to 0° C., the reaction solution was slowly poured into 1,000 mL of water and extracted with 500 mL of toluene. The resulting organic layer was washed with 1N hydrochloric acid, a saturated sodium bicarbonate aqueous solution and water, followed by drying over anhydrous magnesium sulfate. Thereafter, the solvent was removed by distillation under reduced pressure to obtain 50.1 g of 1-(4-bromophenyl)-4-propylcyclohexanol (15). The resulting compound (15) was a yellow oily matter.
Reaction SMILES: OCCCN1C=C(C2C=CC(NC3C(C(F)(F)F)=CN=C(NC4C=CC(CP(=O)(OCC)OCC)=CC=4OC)N=3)=C3C=2CN(C)C3=O)C=N1.[NH2:50][C:51]1[C:52]([C:66]([NH:68][CH3:69])=[O:67])=[N:53][C:54]([C:57]2[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=2)=[CH:55][CH:56]=1.ClC1C(C(F)(F)F)=CN=C(NC2C=CC(CP(=O)(OCC)OCC)=CC=2OC)N=1.[Cl:99][C:100]1[CH:101]=[C:102]([CH:112]=[CH:113][C:114]=1[NH:115][C:116]1[N:121]=[C:120](Cl)[C:119]([C:123]([F:126])([F:125])[F:124])=[CH:118][N:117]=1)[CH2:103][P:104](=[O:111])([O:108][CH2:109][CH3:110])[O:105][CH2:106][CH3:107]>>[Cl:99][C:100]1[CH:101]=[C:102]([CH:112]=[CH:113][C:114]=1[NH:115][C:116]1[N:117]=[C:118]([NH:50][C:51]2[C:52]([C:66](=[O:67])[NH:68][CH3:69])=[N:53][C:54]([C:57]3[CH:58]=[N:59][N:60]([CH2:62][CH2:63][CH2:64][OH:65])[CH:61]=3)=[CH:55][CH:56]=2)[C:119]([C:123]([F:126])([F:124])[F:125])=[CH:120][N:121]=1)[CH2:103][P:104](=[O:111])([O:108][CH2:109][CH3:110])[O:105][CH2:106][CH3:107]
Reactant: CNC(=O)c1nc(-c2cnn(CCCO)c2)ccc1N
Reactant: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(Cl)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Cl)n2)c(OC)c1)OCC
Agent: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)c4c3C(=O)N(C)C4)n2)c(OC)c1)OCC
Product: CCOP(=O)(Cc1ccc(Nc2ncc(C(F)(F)F)c(Nc3ccc(-c4cnn(CCCO)c4)nc3C(=O)NC)n2)c(Cl)c1)OCC
Yield: 25 %

Procedure:
Prepared analogously to Compound 1B replacing Compound 1C with 3-amino-6-[1-(3-hydroxypropyl)-1H-pyrazol-4-yl]-n-methylpyridine-2-carboxamide (Compound 6C, 278 mg, 1.01 mmol) and Compound 1E with diethyl (3-chloro-4-{[4-chloro-5-(trifluoromethyl)pyrimidin-2-yl]amino}benzyl)phosphonate (Compound 24C, 463 mg, 1.01 mmol) to afford 176 mg of the title compound (25%). 1H NMR (400 MHz, CD3OD) δ=8.64-8.79 (m, 1H), 8.55 (s, 1H), 8.44 (s, 1H), 8.35 (s, 1H), 7.73 (d, J=9.1 Hz, 1H), 7.65 (t, J=2.3 Hz, 1H), 7.60 (d, J=8.3 Hz, 1H), 7.44-7.49 (m, 1H), 4.28-4.35 (m, 2H), 4.08-4.18 (m, 4H), 3.56 (t, J=6.2 Hz, 2H), 3.42 (d, J=21.0 Hz, 2H), 3.00 (s, 3H), 2.11 (quin, J=6.5 Hz, 2H), 1.26 (t, J=7.1 Hz, 6H). MS (ESI): m/z=697.72 [M+H]+. UPLC: tR=1.28 min (UPLC-SQD: analytical—2 min).
Reaction SMILES: Br[C:2]1[CH:11]=[CH:10][C:9]([O:12][CH:13]2[CH2:18][CH2:17][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:15][CH2:14]2)=[C:8]2[C:3]=1[CH:4]=[N:5][C:6]([NH:26][C:27]1[CH:32]=[CH:31][C:30]([N:33]3[CH2:38][CH2:37][O:36][CH2:35][CH2:34]3)=[C:29]([Cl:39])[CH:28]=1)=[N:7]2.[C:40](=O)([O-])[O-].[Na+].[Na+].CB1OB(C)OB(C)O1.C(Cl)Cl>CN(C=O)C>[Cl:39][C:29]1[CH:28]=[C:27]([NH:26][C:6]2[N:5]=[CH:4][C:3]3[C:8](=[C:9]([O:12][CH:13]4[CH2:14][CH2:15][N:16]([C:19]([O:21][C:22]([CH3:25])([CH3:24])[CH3:23])=[O:20])[CH2:17][CH2:18]4)[CH:10]=[CH:11][C:2]=3[CH3:40])[N:7]=2)[CH:32]=[CH:31][C:30]=1[N:33]1[CH2:38][CH2:37][O:36][CH2:35][CH2:34]1
Reactant: CC(C)(C)OC(=O)N1CCC(Oc2ccc(Br)c3cnc(Nc4ccc(N5CCOCC5)c(Cl)c4)nc23)CC1
Reactant: O=C([O-])[O-]
Agent: CB1OB(C)OB(C)O1
Agent: [Na+]
Solvent: ClCCl
Solvent: CN(C)C=O
Product: Cc1ccc(OC2CCN(C(=O)OC(C)(C)C)CC2)c2nc(Nc3ccc(N4CCOCC4)c(Cl)c3)ncc12
Reaction time: 0.17 h

Procedure:
To a solution of tert-butyl 4-(5-bromo-2-(3-chloro-4-morpholinophenylamino) quinazolin-8-yloxy)piperidine-1-carboxylate (See example 45 for synthesis) (1 eq) in DMF was added 2M sodium carbonate solution, trimethylboroxine (3 eq) and Pd (dppf)2Cl2.CH2Cl2 (0.05 eq). The reaction mixture was micro waved for 10 min at 120° C. The reaction mixture was then partitioned between ethyl acetate and water. The organic layer was washed with brine, dried, concentrated and purified by semi-preparative HPLC to provide pure product. ES/MS m/z 554.1 (MH+).
Reaction SMILES: Cl[CH2:2][C:3]1[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]2[N:10]=[C:11]([C:15]3[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=3)[O:12][C:13]=2[CH3:14])=[CH:5][CH:4]=1.[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([OH:39])=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24].C(=O)([O-])[O-].[K+].[K+].CN(C)C=O>O>[CH2:23]([O:25][C:26]1[CH:27]=[CH:28][C:29]([O:39][CH2:2][C:3]2[CH:22]=[CH:21][C:6]([O:7][CH2:8][C:9]3[N:10]=[C:11]([C:15]4[CH:20]=[CH:19][CH:18]=[CH:17][CH:16]=4)[O:12][C:13]=3[CH3:14])=[CH:5][CH:4]=2)=[C:30]([CH2:32][CH2:33][C:34]([O:36][CH2:37][CH3:38])=[O:35])[CH:31]=1)[CH3:24]
Reactant: CCOC(=O)CCc1cc(OCC)ccc1O
Reactant: Cc1oc(-c2ccccc2)nc1COc1ccc(CCl)cc1
Agent: O=C([O-])[O-]
Agent: [K+]
Solvent: CN(C)C=O
Solvent: O
Product: CCOC(=O)CCc1cc(OCC)ccc1OCc1ccc(OCc2nc(-c3ccccc3)oc2C)cc1
Temperature: 90 °C
Reaction time: 2 h
Yield: 72.6 %

Procedure:
A mixture of 4-(4-chloromethylphenoxymethyl)-5-methyl-2-phenyloxazole (1.44 g), ethyl 3-(5-ethoxy-2-hydroxyphenyl)propionate (1.0 g), anhydrous potassium carbonate (0.58 g) and N,N-dimethylformamide (50 mL) was stirred at 90° C. for 2 hrs. The reaction mixture was poured into water and extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate and concentrated. The obtained residue was subjected to silica gel column chromatography to give ethyl 3-[5-ethoxy-2-[4-[(5-methyl-2-phenyl-4-oxazolyl)methoxy]benzyloxy]phenyl]propionate as an oil (1.57 g, 72%) from a fraction eluted with ethyl acetate-hexane (1:6, v/v).