Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl.[N:2]1[CH:7]=[CH:6][C:5]([CH2:8][C:9]([OH:11])=O)=[CH:4][CH:3]=1.Cl.[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH2:20].C(N[C@H](C(O)=O)C)(OC(C)(C)C)=O.Cl.COC(=O)[C@H](CC1C=CC=CC=1)N>CO.C(Cl)(Cl)Cl>[CH3:13][O:14][C:15](=[O:30])[C@H:16]([CH2:23][C:24]1[CH:29]=[CH:28][CH:27]=[CH:26][CH:25]=1)[NH:17][C:18](=[O:22])[C@H:19]([CH3:21])[NH:20][C:9](=[O:11])[CH2:8][C:5]1[CH:4]=[CH:3][N:2]=[CH:7][CH:6]=1
Reactant: O=C(O)Cc1ccncc1
Reactant: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)N
Agent: COC(=O)[C@@H](N)Cc1ccccc1
Agent: C[C@H](NC(=O)OC(C)(C)C)C(=O)O
Agent: Cl
Solvent: CO
Solvent: ClC(Cl)Cl
Product: COC(=O)[C@H](Cc1ccccc1)NC(=O)[C@H](C)NC(=O)Cc1ccncc1

Procedure:
Following General Procedure C and using 4-pyridylacetic acid hydrochloride (Aldrich) and N-(L-alaninyl)-L-phenylalanine methyl ester hydrochloride (prepared from N-BOC-L-alanine (Sigma) and L-phenylalanine methyl ester hydrochloride (Sigma) using General Procedure C, followed by removal of the BOC-group using General Procedure P), the title compound was prepared as a solid (mp=152-154° C.). The reaction was monitored by tlc (Rf=0.4 in 10% MeOH/CHCl3) and the product was purified by silica gel chromatography using 10% MeOH/CHCl3 as the eluent, followed by recrystallization from 1-chlorobutane/acetonitrile.
Reaction SMILES: B(F)(F)F.[CH3:5][CH2:6][O:7]CC.[CH3:10][C:11]1[C:16]2[S:17][CH:18]=[CH:19][C:15]=2[CH:14]=[CH:13][CH:12]=1.CC(OC(C)=O)=O>>[C:6]([C:19]1[C:15]2[CH:14]=[CH:13][CH:12]=[C:11]([CH3:10])[C:16]=2[S:17][CH:18]=1)(=[O:7])[CH3:5]
Reactant: Cc1cccc2ccsc12
Reactant: CCOCC
Agent: FB(F)F
Solvent: CC(=O)OC(C)=O
Product: CC(=O)c1csc2c(C)cccc12

Procedure:
420 mg of borontrifluoride-etherate are added to a mixture of 2 g of 7-methylbenzo[b]thiophene and 1.4 ml acetanhydride at 50° and the mixture warmed to 60° for 80 minutes. The resulting mixture is poured onto ice, extracted with ether and the organic phase washed, dried and concentrated on a rotary evaporator. The residue is chromatographed on silica gel (eluant: n-hexane) to obtain the title compound, contaminated with the 2-acetylisomer, as an oil for direct further reaction.
Reaction SMILES: [CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1OS(C)(=O)=O)([CH3:4])[CH3:3].[N-:29]=[N+:30]=[N-:31].[Li+]>CN(C=O)C>[CH3:1][C:2]([Si:5]([CH3:28])([CH3:27])[O:6][CH2:7][CH2:8][CH:9]1[CH:12]([CH2:13][O:14][Si:15]([C:18]([CH3:21])([CH3:20])[CH3:19])([CH3:17])[CH3:16])[CH2:11][CH:10]1[N:29]=[N+:30]=[N-:31])([CH3:4])[CH3:3]
Reactant: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1OS(C)(=O)=O
Reactant: [N-]=[N+]=[N-]
Agent: [Li+]
Solvent: CN(C)C=O
Product: CC(C)(C)[Si](C)(C)OCCC1C(CO[Si](C)(C)C(C)(C)C)CC1N=[N+]=[N-]
Temperature: 80 °C
Yield: 73.2 %

Procedure:
2-(2-(((1,1-Dimethylethyl)dimethylsilyl)oxy)ethyl)-3-(((1,1-dimethylethyl)dimethyl-silyl)oxymethyl)-1-O-methanesulfonylcyclobutanol (180 mg, 0.41 mmol) was mixed with 200 mg (4.1 mmol) of lithium azide in 4 mL of DMF. The reaction mixture was heated at 80° C. for 2 h then concentrated in vacuo. The residue was purified on a silica gel column eluted with 5% ethyl acetate in hexane to give 120 mg (73% yield) of the title compound; MS DCI-NH3M/Z: 400 (M+H)+, 417 (M+NH4)+.
Reaction SMILES: [Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1F)[CH:5]=[O:6].[F:11][C:12]1[CH:17]=[C:16]([F:18])[CH:15]=[CH:14][C:13]=1[OH:19].C(=O)([O-])[O-].[Cs+].[Cs+]>CS(C)=O>[Br:1][C:2]1[CH:3]=[C:4]([CH:7]=[CH:8][C:9]=1[O:19][C:13]1[CH:14]=[CH:15][C:16]([F:18])=[CH:17][C:12]=1[F:11])[CH:5]=[O:6]
Reactant: Oc1ccc(F)cc1F
Reactant: O=Cc1ccc(F)c(Br)c1
Agent: O=C([O-])[O-]
Agent: [Cs+]
Solvent: CS(C)=O
Product: O=Cc1ccc(Oc2ccc(F)cc2F)c(Br)c1
Temperature: 100 °C
Yield: 94.9 %

Procedure:
A mixture of 3-bromo-4-fluorobenzaldehyde (4.06 g, 20.0 mmol), 2,4-difluorophenol (2.60 g, 20.0 mmol) and cesium carbonate (7.17 g, 22.0 mmol) in dimethyl sulfoxide (20 mL) was heated at 100° C. for 1 hour. The reaction mixture was partitioned with ethyl acetate and water. The organic layer was washed with saturated aqueous sodium chloride twice, dried over anhydrous sodium sulfate, filtered, and concentrated. The residue was purified by flash chromatography (silica gel, 20% ethyl acetate in heptanes) to provide the title compound (5.94 g, 95%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH2:16][CH2:17][C:18]([OH:20])=O)[CH:13]=[CH:14][CH:15]=1)=[O:7])([CH3:4])([CH3:3])[CH3:2].CCN(C(C)C)C(C)C.CN(C(ON1N=NC2C=CC=CC1=2)=[N+](C)C)C.F[P-](F)(F)(F)(F)F.Cl.[CH3:55][O:56][C:57](=[O:66])[C@@H:58]1[CH2:62][C@H:61]([N:63]=[N+:64]=[N-:65])[CH2:60][NH:59]1>C(Cl)Cl.O.C(OCC)(=O)C>[CH3:55][O:56][C:57](=[O:66])[C@@H:58]1[CH2:62][CH:61]([N:63]=[N+:64]=[N-:65])[CH2:60][N:59]1[C:18](=[O:20])[CH2:17][CH2:16][C:12]1[CH:13]=[CH:14][CH:15]=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:2])([CH3:3])[CH3:4])=[O:7])[CH:11]=1
Reactant: CC(C)(C)OC(=O)NCc1cccc(CCC(=O)O)c1
Reactant: COC(=O)[C@@H]1C[C@H](N=[N+]=[N-])CN1
Agent: CN(C)C(On1nnc2ccccc21)=[N+](C)C
Agent: Cl
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCOC(C)=O
Solvent: CCN(C(C)C)C(C)C
Solvent: O
Product: COC(=O)[C@@H]1CC(N=[N+]=[N-])CN1C(=O)CCc1cccc(CNC(=O)OC(C)(C)C)c1
Reaction time: 0.08 h
Yield: 72.4 %

Procedure:
1.61 g (5.7 mmol) of 3-(3-tert-butyloxycarbonylaminomethylphenyl)propionic acid (starting compound A11) are dissolved in 14 ml of CH2Cl2, and 2.1 ml of DIPEA are added. After stirring for 5 min., 2.2 g (5.7 mmol) of HBTU are added and, after a further 5 min., 1.0 g (4.8 mmol) of (2S,4S)-4-azidoproline methyl ester hydrochloride. After stirring at RT overnight, ethyl acetate and water are added and the phases are separated. The organic phase is washed once each with 1N sodium hydroxide solution,1N hydrochloric acid solution, saturated sodium bicarbonate solution and saturated brine. Drying over magnesium sulfate is followed by concentration and drying under high vacuum. Further purification takes place by chromatography [Tol/Ac (8:2)] on a silica gel column. The title compound (1.5 g) is obtained as a colorless oil. TLC, silica gel (glass plates), [toluene/acetone (8:2)], Rf=0.31. The mass spectrum shows the molecular peak MNH4+ at 449 Da.
Reaction SMILES: [NH2:1][C:2]1[CH:7]=[CH:6][CH:5]=[CH:4][C:3]=1[CH2:8][CH:9]([C:12]1[S:13][CH:14]=[CH:15][CH:16]=1)[NH:10][CH3:11].[C:17](OC)(OC)(OC)[CH:18]([CH3:20])[CH3:19]>C(O)(=O)C>[CH3:11][N:10]1[CH:9]([C:12]2[S:13][CH:14]=[CH:15][CH:16]=2)[CH2:8][C:3]2[CH:4]=[CH:5][CH:6]=[CH:7][C:2]=2[N:1]=[C:17]1[CH:18]([CH3:20])[CH3:19]
Reactant: CNC(Cc1ccccc1N)c1cccs1
Reactant: COC(OC)(OC)C(C)C
Solvent: CC(=O)O
Product: CC(C)C1=Nc2ccccc2CC(c2cccs2)N1C
Temperature: 25 °C
Reaction time: 8 h
Yield: 25.6 %

Procedure:
A stirred solution of 3.45 g of 2-amino-N-methyl-α-(2-thienyl)benzeneethaneamine and 13.34 g of trimethyl orthoisobutyrate was treated rapidly with 3.8 ml of glacial acetic acid. The reaction mixture was refluxed for 8 hours and cooled to room temperature overnight. The mixture was concentrated on a rotary evaporator at 70° C. After standing overnight under refrigeration, the residue was dissolved in 60 ml of 10% hydrochloric acid solution and extracted with diethyl ether (2×50 ml). The aqueous phase was basified with 10% sodium hydroxide solution and extracted with dichloromethane (2×75 ml). The combined organic phase was dried over anhydrous sodium sulfate, filtered, and concentrated to an oil. The oil was purified by HPLC (Water's Associates Prep LC/System 500; silica gel; sample applied in dichloromethane; methanol as eluent). Concentration of the appropriate fractions yielded 1.08 g of 4,5-dihydro-3-methyl-2-(1-methylethyl)-4-(2-thienyl)-3H-1,3-benzodiazepine as an oil.
Reaction SMILES: [Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[CH2:10][CH2:11][CH2:12][Cl:13])[CH:5]=[CH:4][C:3]=1[O:15][CH3:16].Cl.[CH3:18]NC.C=O.C(O)(=O)C>O.CN(C)C=O>[Cl:1][C:2]1[C:7]([Cl:8])=[C:6]([C:9](=[O:14])[C:10](=[CH2:18])[CH2:11][CH2:12][Cl:13])[CH:5]=[CH:4][C:3]=1[O:15][CH3:16]
Reactant: CNC
Reactant: COc1ccc(C(=O)CCCCl)c(Cl)c1Cl
Agent: C=O
Agent: Cl
Solvent: O
Solvent: CN(C)C=O
Solvent: CC(=O)O
Product: C=C(CCCl)C(=O)c1ccc(OC)c(Cl)c1Cl
Reaction time: 2 h
Yield: 48.4 %

Procedure:
2,3-Dichloro-4-(4-chlorobutyryl)anisole (28.1 gm, 0.1 mole), dimethylamine hydrochloride (36.7 mg, 0.45 mole), paraformaldehyde (7.65 gm, 0.255 mole) and acetic acid (2.6 ml) were united, stirred and heated on a steam bath for 2 hours. N,N-dimethylformamide (100 ml) was added and the stirring and heating was continued for another two hours. The mixture was then poured into ice diluted to 800 ml with water and extracted with ether. The combined extracts were washed with water, dried over MgSO4 and evaporated in vacuo to give 14.2 gm of product, m.p. 58°-60° C.
Reaction SMILES: [C:1]([O:5][C:6](=[O:21])[NH:7][CH2:8][C@H:9]1[CH2:14][CH2:13][C@H:12]([C:15](=[O:20])[N:16]([O:18][CH3:19])[CH3:17])[CH2:11][CH2:10]1)([CH3:4])([CH3:3])[CH3:2].[H-].[Na+].I[CH3:25].OS([O-])(=O)=O.[K+]>CC(N(C)C)=O.O.CCOCC>[C:1]([O:5][C:6](=[O:21])[N:7]([CH2:8][C@H:9]1[CH2:10][CH2:11][C@H:12]([C:15](=[O:20])[N:16]([O:18][CH3:19])[CH3:17])[CH2:13][CH2:14]1)[CH3:25])([CH3:4])([CH3:2])[CH3:3]
Reactant: CI
Reactant: CON(C)C(=O)[C@H]1CC[C@H](CNC(=O)OC(C)(C)C)CC1
Agent: O=S(=O)([O-])O
Agent: [H-]
Agent: [K+]
Solvent: CCOCC
Solvent: O
Solvent: CC(=O)N(C)C
Product: CON(C)C(=O)[C@H]1CC[C@H](CN(C)C(=O)OC(C)(C)C)CC1
Temperature: 0 °C
Reaction time: 1 h

Procedure:
A solution of 95 g (corresponds to 301.26 mmol) of crude trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-carbamic acid tert-butyl ester in 300 ml of DMA was treated at 0° C. with 19.72 g (451.9 mmol) of NaH (55% in oil) in small portions. The reaction was stirred for 1 h at 0° C., then treated slowly (1.5 h) with 150 ml (2.41 mol) of iodomethane. After the addition of 60 ml of iodomethane (1 h), the reaction started, the addition was stopped and continued after reaction was cooled down again. After warming up to RT over night, the reaction was cooled, neutralized with aqueous 10% KHSO4 and poured into water/Et2O (3×). The organic phase was washed with aqueous 10% NaCl, dried over Na2SO4 evaporated and purified by flash silica gel column (CH2Cl2/EtOAc 9:1 to 1:1) to yield 99 g (quantitative) of trans-[4-(Methoxy-methyl-carbamoyl)-cyclohexylmethyl]-methyl-carbamic acid tert-butyl ester, MS: 315 (MH+).
Reaction SMILES: [Cl:1][C:2]1[CH:7]=[CH:6][C:5]([NH:8][C:9]([C@@:11]23[C:17]([CH3:19])([CH3:18])[C@@:14]([CH3:20])([CH2:15][CH2:16]2)[C:13](=[O:21])[O:12]3)=[O:10])=[C:4]([C@@:22]([OH:32])([C:27]#[C:28][CH:29]2[CH2:31][CH2:30]2)[C:23]([F:26])([F:25])[F:24])[CH:3]=1.ClCCl.C(N(CC)CC)C.Cl[C:44]([O:46][CH:47]([Cl:49])[CH3:48])=[O:45]>O>[C:44](=[O:45])([O:46][CH:47]([Cl:49])[CH3:48])[O:32][C@:22]([C:4]1[CH:3]=[C:2]([Cl:1])[CH:7]=[CH:6][C:5]=1[NH:8][C:9]([C@@:11]12[C:17]([CH3:18])([CH3:19])[C@@:14]([CH3:20])([CH2:15][CH2:16]1)[C:13](=[O:21])[O:12]2)=[O:10])([C:27]#[C:28][CH:29]1[CH2:31][CH2:30]1)[C:23]([F:24])([F:25])[F:26]
Reactant: CC1(C)[C@@]2(C)CC[C@]1(C(=O)Nc1ccc(Cl)cc1[C@@](O)(C#CC1CC1)C(F)(F)F)OC2=O
Reactant: CC(Cl)OC(=O)Cl
Solvent: CCN(CC)CC
Solvent: ClCCl
Solvent: O
Product: CC(Cl)OC(=O)O[C@@](C#CC1CC1)(c1cc(Cl)ccc1NC(=O)[C@@]12CC[C@@](C)(C(=O)O1)C2(C)C)C(F)(F)F
Temperature: 7.5 °C
Reaction time: 1 h

Procedure:
A solution of (1S,4R)-N-(4-chloro-2-((S)-4-cyclopropyl-1,1,1-trifluoro-2-hydroxybut-3-yn-2-yl) phenyl)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamide (10, 20 g, 42.6 mmol), dichloromethane (100 mL) and triethylamine (5.17 g, 51.1 mmol) was stirred at 0-5° C. for 20 minutes, then 1-chloroethyl chloroformate (7.3 g, 51.1 mmol) was added dropwise. The mixture was stirred at 5-10° C. for 1 hour. Water (60 ml) was added with stirring and then the layers were separated. The organic solution was concentrated and MTBE (180 ml) was added. After washing with water twice, the system was concentrated to 30 ml and then MTBE (10 ml) and hexane (60 ml) were added. The suspension was stirred at 70° C. for 30 min and filtered to give (S)-2-(5-chloro-2-((1S,4R)-4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptane-1-carboxamido)phenyl)-4-cyclopropyl-1,1,1-trifluorobut-3-yn-2-yl 1-chloroethyl carbonate (7, R1 is 4,7,7-trimethyl-3-oxo-2-oxabicyclo[2.2.1]heptyl, R3 is 1-chloroethyl) as a white solid. 1H NMR (CDCl3) δ9.43, 9.30 (s, 1H), 8.17, 8.06 (d, J=8.7 Hz, 1H), 7.62, 7.54 (s, 1H), 7.42 (d, J=8.7 Hz, 1H), 6.36 (q, J=5.7 Hz, 1H), 2.60-2.50 (m, 1H), 2.09-1.93 (m, 2H), 1.89-1.86 (at, J=4.5 Hz, 3H), 1.77-1.61 (m, 2H), 1.16 (d, J=10.5 Hz, 6H), 1.01 (d, J=7.5 Hz, 3H), 0.97-0.92 (m, 2H), 0.88-0.84 (m, 2H).
Reaction SMILES: CON(C)[C:4]([C:6]1[C:7]([NH2:15])=[N:8][C:9]([S:12][CH2:13][CH3:14])=[N:10][CH:11]=1)=[O:5].Br[C:18]1[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=1[O:25][CH3:26]>>[NH2:15][C:7]1[C:6]([C:4]([C:18]2[CH:23]=[C:22]([Cl:24])[CH:21]=[CH:20][C:19]=2[O:25][CH3:26])=[O:5])=[CH:11][N:10]=[C:9]([S:12][CH2:13][CH3:14])[N:8]=1
Reactant: COc1ccc(Cl)cc1Br
Reactant: CCSc1ncc(C(=O)N(C)OC)c(N)n1
Product: CCSc1ncc(C(=O)c2cc(Cl)ccc2OC)c(N)n1

Procedure:
The same procedure as described in Example 47 was used, starting from 4-amino-2-ethylsulfanyl-pyrimidine-5-carboxylic acid methoxy-methyl-amide, Example 1, and 2-bromo-4-chloroanisole (Aldrich), to give (4-amino-2-ethylsulfanyl-pyrimidin-5-yl)-(5-chloro-2-methoxy-phenyl)-methanone as a white solid. MS (M+H)+, 324.
Reaction SMILES: Cl.[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([OH:26])=[O:25])=[C:16]([CH2:19]OC(=O)C)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[CH3:31][C:32]1[N:36]=[C:35]([SH:37])[S:34][N:33]=1.C(=O)([O-])O.[Na+:42].O>P([O-])([O-])([O-])=O.C(O)C>[NH:2]=[C:3]1[NH:7][C:6]([C:8](=[N:29][OH:30])[C:9]([NH:11][CH:12]2[C:27](=[O:28])[N:14]3[C:15]([C:24]([O-:26])=[O:25])=[C:16]([CH2:19][S:37][C:35]4[S:34][N:33]=[C:32]([CH3:31])[N:36]=4)[CH2:17][S:18][C@H:13]23)=[O:10])=[CH:5][S:4]1.[Na+:42]
Reactant: CC(=O)OCC1=C(C(=O)O)N2C(=O)C(NC(=O)C(=NO)c3csc(=N)[nH]3)[C@H]2SC1
Reactant: Cc1nsc(S)n1
Agent: Cl
Agent: O=C([O-])O
Agent: O=P([O-])([O-])[O-]
Solvent: O
Solvent: CCO
Product: Cc1nsc(SCC2=C(C(=O)[O-])N3C(=O)C(NC(=O)C(=NO)c4csc(=N)[nH]4)[C@H]3SC2)n1
Temperature: 70 °C
Reaction time: 3.5 h

Procedure:
In 20 ml of phosphate buffer (0.2M, pH 6.4) there was dissolved 0.663 g of 7-[2-(2-imino-4-thiazolin-4-yl)-2-hydroxyimino-acetamido]-3-acetoxymethyl-3-cephem-4-carboxylic acid hydrochloride (syn-isomer) together with 0.198 g of 3-methyl-1,2,4-thiadiazole-5-thiol and 0.252 g of sodium hydrogen carbonate and the mixture was stirred at a temperature of 70° C. for 3.5 hours. The reaction mixture was subjected to column chromatography on polystyrene resin (Amberlite XAD-2, Rohm and Haas Co.), development being carried out with water and 20% ethanol in the order mentioned. The fractions containing the desired product were pooled and lyophilized. By the above procedure there was obtained 0.142 g of the captioned compound.
Reaction SMILES: [OH:1][C:2]1[CH:11]=[C:10]2[C:5]([C:6]([CH:14]([CH3:16])[CH3:15])=[CH:7][C:8]([CH3:13])([CH3:12])[O:9]2)=[CH:4][C:3]=1[C:17](=[O:19])[CH3:18].I[CH2:21][CH2:22][CH3:23]>>[CH:14]([C:6]1[C:5]2[C:10](=[CH:11][C:2]([O:1][CH2:21][CH2:22][CH3:23])=[C:3]([C:17](=[O:19])[CH3:18])[CH:4]=2)[O:9][C:8]([CH3:13])([CH3:12])[CH:7]=1)([CH3:15])[CH3:16]
Reactant: CCCI
Reactant: CC(=O)c1cc2c(cc1O)OC(C)(C)C=C2C(C)C
Product: CCCOc1cc2c(cc1C(C)=O)C(C(C)C)=CC(C)(C)O2

Procedure:
Following General Procedure A, 1-(7-hydroxy-4-isopropyl-2,2-dimethyl-2H-chromen-6-yl)ethanone (Compound 62, 400 mg, 1.38 mmol) and 1-iodopropane (0.70 mL, 6.90 mmol) were reacted to produce the title compound as a colorless oil.
Reaction SMILES: [Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][OH:5].[O:10]1[CH:15]=[CH:14][CH2:13][CH2:12][CH2:11]1.C(=O)(O)[O-].[Na+]>ClCCl.C1(C)C=CC(S([O-])(=O)=O)=CC=1.[NH+]1C=CC=CC=1>[Br:1][C:2]1[CH:9]=[CH:8][CH:7]=[CH:6][C:3]=1[CH2:4][O:5][CH:11]1[CH2:12][CH2:13][CH2:14][CH2:15][O:10]1
Reactant: C1=COCCC1
Reactant: OCc1ccccc1Br
Agent: Cc1ccc(S(=O)(=O)[O-])cc1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: ClCCl
Product: Brc1ccccc1COC1CCCCO1
Temperature: 25 °C
Reaction time: 2 h
Yield: 99.1 %

Procedure:
Pyridinium p-toluenesulfonate (0.30 g, 0.0012 mol) was added to a solution of 2-bromobenzylalcohol (25 g, 0.134 mol) in dichloromethane (100 ml), and the mixture was stirred at room temperature-3,4-Dihydro-2H-pyran (16.86 g, 0.20 mol) was added thereto. The mixture was stirred at room temperature for 2 hours. Then, saturated aqueous sodium bicarbonate solution (200 ml) was added, and the mixture was extracted with dichloromethane (200 ml). After drying over anhydrous magnesium sulfate, the solvent was evaporated to give the desired 1-bromo-2-(2-tetrahydropyranyloxymethyl)-benzene (36.00 g, yield: 99.3%) as an oil.
Reaction SMILES: [C:1]1([C@@H:7]2[CH2:9][C@H:8]2[C:10]([OH:12])=O)[CH:6]=[CH:5][CH:4]=[CH:3][CH:2]=1.O=C1N(P(Cl)(N2CCOC2=O)=O)CCO1.C(N(CC)CC)C.[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH2:45])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1.C([O-])([O-])=O.[Na+].[Na+]>C(Cl)Cl>[Br:35][C:36]1[C:37]([F:46])=[C:38]2[C:44]([NH:45][C:10]([C@@H:8]3[CH2:9][C@H:7]3[C:1]3[CH:2]=[CH:3][CH:4]=[CH:5][CH:6]=3)=[O:12])=[CH:43][NH:42][C:39]2=[N:40][CH:41]=1
Reactant: Nc1c[nH]c2ncc(Br)c(F)c12
Reactant: O=C(O)[C@@H]1C[C@H]1c1ccccc1
Agent: O=C([O-])[O-]
Agent: O=C1OCCN1P(=O)(Cl)N1CCOC1=O
Agent: [Na+]
Solvent: ClCCl
Solvent: CCN(CC)CC
Product: O=C(Nc1c[nH]c2ncc(Br)c(F)c12)[C@@H]1C[C@H]1c1ccccc1
Temperature: 25 °C
Reaction time: 1 h
Yield: 61.9 %

Procedure:
trans-2-Phenylcyclopropanecarboxylic acid (705 mg, 4.35 mmol), bis(2-oxooxazolidin-3-yl)phosphinic chloride (1107 mg, 4.35 mmol) and triethylamine (1100 mg, 10.9 mmol) were added to 5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-amine (500 mg, 2.17 mmol) in DCM (100 mL). The reaction was stirred at room temperature for 1 hour, and then 2N aqueous Na2CO3 was added (50 mL). The resulting suspension was filtered and the solid rinsed with DCM and water. After drying, trans-N-(5-bromo-4-fluoro-1H-pyrrolo[2,3-b]pyridin-3-yl)-2-phenylcyclopropanecarboxamide (503 mg, 61.8% yield) was obtained as a solid.
Reaction SMILES: Cl[C:2]1[CH:7]=[C:6]([Cl:8])[N:5]=[CH:4][N:3]=1.[NH2:9][C:10]1[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:22])([CH3:21])[CH3:20])[CH:13]=[CH:14][CH:15]=1.C(N(CC)CC)C>C(O)C>[Cl:8][C:6]1[N:5]=[CH:4][N:3]=[C:2]([NH:9][C:10]2[CH:11]=[C:12]([NH:16][C:17](=[O:23])[O:18][C:19]([CH3:21])([CH3:20])[CH3:22])[CH:13]=[CH:14][CH:15]=2)[CH:7]=1
Reactant: Clc1cc(Cl)ncn1
Reactant: CC(C)(C)OC(=O)Nc1cccc(N)c1
Solvent: CCO
Solvent: CCN(CC)CC
Product: CC(C)(C)OC(=O)Nc1cccc(Nc2cc(Cl)ncn2)c1
Temperature: 80 °C

Procedure:
4,6-Dichloropyrimidine (1.5 g, 10 mmol), tert-butyl 3-aminophenylcarbamate (2.1 g, 10 mmol) and triethylamine (2.2 g, 20 mmol) were mixed in ethanol (20 mL), heated at 80° C. for 16 hr. The reaction mixture was cooled to RT and solvent was removed in vacuo. The gummy crude product was mixed with 20 mL of DCM and was stirred at RT to give an off-white solid, which was filtered and dried under vacuum (1.6 g, 5 mmol). MS (m/z): MH+=321, 323.
Reaction SMILES: [C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([C:17]3[CH2:18][CH2:19][O:20][CH2:21][CH:22]=3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:3])[CH3:2].C([O-])=O.[NH4+]>CO.[Pd]>[C:1]([O:5][C:6]([N:8]1[CH2:16][C:15]2[C:10](=[CH:11][CH:12]=[C:13]([CH:17]3[CH2:18][CH2:19][O:20][CH2:21][CH2:22]3)[CH:14]=2)[CH2:9]1)=[O:7])([CH3:4])([CH3:2])[CH3:3]
Reactant: CC(C)(C)OC(=O)N1Cc2ccc(C3=CCOCC3)cc2C1
Agent: [Pd]
Agent: O=C[O-]
Agent: [NH4+]
Solvent: CO
Product: CC(C)(C)OC(=O)N1Cc2ccc(C3CCOCC3)cc2C1
Temperature: 25 °C
Yield: 92 %

Procedure:
To a stirred solution 7.27 mmol 5-(3,6-dihydro-2H-pyran-4-yl)-1,3-dihydro-isoindole-2-carboxylic acid tert-butyl ester in 60 ml methanol were added 1.60 g 10% palladium on charcoal and 72.7 mmol ammonium formate and the mixture was heated at reflux for 30 min. The reaction mixture was then cooled to room temperature, filtered, and the filtrate concentrated in vacuo. The residue was taken up in THF and washed with brine. The organic phase was then dried over sodium sulfate and concentrated in vacuo. The residue was purified by chromatography (SiO2, heptane/ethyl acetate) to yield the title compound as a white solid (92% yield). MS (m/e): 248.3 ([M+H−Me2C═CH2]+, 100%).
Reaction SMILES: Cl[C:2]1[CH:7]=[CH:6][C:5]([N+:8]([O-:10])=[O:9])=[CH:4][CH:3]=1.[NH:11]1[CH2:16][CH2:15][S:14][CH2:13][CH2:12]1>C(O)CCC>[N+:8]([C:5]1[CH:6]=[CH:7][C:2]([N:11]2[CH2:16][CH2:15][S:14][CH2:13][CH2:12]2)=[CH:3][CH:4]=1)([O-:10])=[O:9]
Reactant: C1CSCCN1
Reactant: O=[N+]([O-])c1ccc(Cl)cc1
Solvent: CCCCO
Product: O=[N+]([O-])c1ccc(N2CCSCC2)cc1
Yield: 75.1 %

Procedure:
A solution of 1-chloro-4-nitrobenzene (1.5 g, 9.5 mmol) and thiomorpholine (1.0 g, 9.7 mmol) in n-butanol was heated at reflux for 24 h. The solvent was evaporated under reduced pressure to give a residue, which on trituration with water gave a solid. This was filtered off and washed thoroughly with water then with a small amount of petroleum ether. This gave a solid which was recrystallised from ethanol to yield 4-(4-nitro-phenyl)-thiomorpholine (1.6 g, 76%).
Reaction SMILES: [C:1]([O:5][C:6]([NH:8][CH2:9][C:10]1[CH:11]=[C:12]([CH:16]=[C:17]([Cl:20])[C:18]=1[F:19])[C:13]([OH:15])=[O:14])=[O:7])([CH3:4])([CH3:3])[CH3:2].CO.[CH3:23][Si](C=[N+]=[N-])(C)C>C(Cl)Cl>[CH3:23][O:14][C:13](=[O:15])[C:12]1[CH:16]=[C:17]([Cl:20])[C:18]([F:19])=[C:10]([CH2:9][NH:8][C:6]([O:5][C:1]([CH3:4])([CH3:2])[CH3:3])=[O:7])[CH:11]=1
Reactant: C[Si](C)(C)C=[N+]=[N-]
Reactant: CC(C)(C)OC(=O)NCc1cc(C(=O)O)cc(Cl)c1F
Solvent: CO
Solvent: ClCCl
Product: COC(=O)c1cc(Cl)c(F)c(CNC(=O)OC(C)(C)C)c1
Reaction time: 4.5 h

Procedure:
To a solution of 3-(tert-butoxycarbonylamino-methyl)-5-chloro-4-fluoro-benzoic acid (4.00 g, 13.2 mmol) in CH2Cl2 (100 mL) were added MeOH (6.94 mL, 171 mmol) and subsequently trimethylsilyldiazomethane (8.56 mL, 17.1 mmol) in a dropwise manner over 15 min. Stirring was continued at RT for 4.5 h. Volatiles were then evaporated under reduced pressure to afford the title compound as a colorless oil, which was used directly in the next step without further purification. TLC Rf (c-hexane/EtOAc 6:1)=0.40; tR (HPLC conditions c): 5.56 min.
Reaction SMILES: [Cl:1][C:2]1[N:3]=[CH:4][N:5](COCC[Si](C)(C)C)[C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8].C(O)(C(F)(F)F)=O>C(Cl)Cl>[Cl:1][C:2]1[N:3]=[CH:4][NH:5][C:6]=1[C:7]([NH:9][CH2:10][C:11]1[CH:16]=[CH:15][C:14]([Cl:17])=[C:13]([O:18][C:19]2[CH:24]=[C:23](/[CH:25]=[CH:26]/[C:27]#[N:28])[CH:22]=[C:21]([Cl:29])[CH:20]=2)[C:12]=1[F:30])=[O:8]
Reactant: C[Si](C)(C)CCOCn1cnc(Cl)c1C(=O)NCc1ccc(Cl)c(Oc2cc(Cl)cc(/C=C/C#N)c2)c1F
Solvent: O=C(O)C(F)(F)F
Solvent: ClCCl
Product: N#C/C=C/c1cc(Cl)cc(Oc2c(Cl)ccc(CNC(=O)c3[nH]cnc3Cl)c2F)c1
Temperature: 25 °C
Reaction time: 6 h
Yield: 87.1 %

Procedure:
To a solution of 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1-({[2-(trimethylsilyl)ethyl]oxy}methyl)-1H-imidazole-5-carboxamide (106 mg, 0.178 mmol) in DCM (5 ml) was added TFA (2.0 mL) and the reaction mixture was stirred at room temperature for 6 hours. The solvent was removed and the crude material was purified via reverse phase HPLC to give 4-chloro-N-{[4-chloro-3-({3-chloro-5-[(E)-2-cyanoethenyl]phenyl}oxy)-2-fluorophenyl]methyl}-1H-imidazole-5-carboxamide (72 mg, 0.155 mmol, 87% yield). 1H NMR (400 MHz, DMSO-d6) δ ppm 12.81-13.40 (m, 1H), 8.08-8.51 (m, 1H), 7.72 (s, 1H), 7.51-7.62 (m, 2H), 7.45 (d, 1H), 7.31 (t, 1H), 7.23 (s, 1H), 7.00 (s, 1H), 6.58 (d, 1H), 4.48 (d, 2H). LC-MS (ES+) m/z 464.94, [M+H].